CA2540343A1 - Indole derivatives - Google Patents
Indole derivatives Download PDFInfo
- Publication number
- CA2540343A1 CA2540343A1 CA002540343A CA2540343A CA2540343A1 CA 2540343 A1 CA2540343 A1 CA 2540343A1 CA 002540343 A CA002540343 A CA 002540343A CA 2540343 A CA2540343 A CA 2540343A CA 2540343 A1 CA2540343 A1 CA 2540343A1
- Authority
- CA
- Canada
- Prior art keywords
- unsubstituted
- alkyl
- substituted
- compound
- hydrogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 229940054051 antipsychotic indole derivative Drugs 0.000 title abstract description 4
- 150000002475 indoles Chemical class 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 360
- 238000000034 method Methods 0.000 claims abstract description 189
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 36
- 125000000217 alkyl group Chemical group 0.000 claims description 177
- 125000003118 aryl group Chemical group 0.000 claims description 122
- 125000003342 alkenyl group Chemical group 0.000 claims description 121
- 125000000304 alkynyl group Chemical group 0.000 claims description 120
- 229910052739 hydrogen Inorganic materials 0.000 claims description 118
- 239000001257 hydrogen Substances 0.000 claims description 116
- 125000001072 heteroaryl group Chemical group 0.000 claims description 108
- -1 -C(O)H Chemical group 0.000 claims description 107
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 100
- 229910052736 halogen Inorganic materials 0.000 claims description 99
- 206010028980 Neoplasm Diseases 0.000 claims description 88
- 150000002367 halogens Chemical group 0.000 claims description 87
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 86
- 150000003839 salts Chemical class 0.000 claims description 85
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 81
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 74
- 239000000203 mixture Substances 0.000 claims description 63
- 125000001188 haloalkyl group Chemical group 0.000 claims description 62
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 48
- 125000003545 alkoxy group Chemical group 0.000 claims description 45
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 43
- 125000001424 substituent group Chemical group 0.000 claims description 43
- 201000010099 disease Diseases 0.000 claims description 40
- 238000011282 treatment Methods 0.000 claims description 40
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 36
- 201000011510 cancer Diseases 0.000 claims description 35
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 35
- 239000003795 chemical substances by application Substances 0.000 claims description 34
- 241000124008 Mammalia Species 0.000 claims description 26
- 229910052799 carbon Inorganic materials 0.000 claims description 26
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 claims description 23
- 239000002246 antineoplastic agent Substances 0.000 claims description 23
- 229940034982 antineoplastic agent Drugs 0.000 claims description 22
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 claims description 20
- 230000033115 angiogenesis Effects 0.000 claims description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 19
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 18
- 239000002207 metabolite Substances 0.000 claims description 18
- 229910052760 oxygen Inorganic materials 0.000 claims description 18
- 239000000651 prodrug Substances 0.000 claims description 18
- 229940002612 prodrug Drugs 0.000 claims description 18
- 229910052717 sulfur Inorganic materials 0.000 claims description 18
- 210000001519 tissue Anatomy 0.000 claims description 18
- 150000001412 amines Chemical class 0.000 claims description 17
- 230000009826 neoplastic cell growth Effects 0.000 claims description 17
- 102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 claims description 16
- 108050003243 Prostaglandin G/H synthase 1 Proteins 0.000 claims description 16
- 230000002401 inhibitory effect Effects 0.000 claims description 16
- 230000001404 mediated effect Effects 0.000 claims description 16
- 230000002159 abnormal effect Effects 0.000 claims description 15
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 14
- 125000005843 halogen group Chemical group 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 125000005336 allyloxy group Chemical group 0.000 claims description 12
- 230000005764 inhibitory process Effects 0.000 claims description 12
- 208000024827 Alzheimer disease Diseases 0.000 claims description 11
- 206010009944 Colon cancer Diseases 0.000 claims description 9
- 206010027476 Metastases Diseases 0.000 claims description 9
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 claims description 9
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 claims description 9
- 125000005189 alkyl hydroxy group Chemical group 0.000 claims description 9
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 9
- 208000011231 Crohn disease Diseases 0.000 claims description 8
- 206010060862 Prostate cancer Diseases 0.000 claims description 8
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 8
- 230000009401 metastasis Effects 0.000 claims description 8
- 208000026310 Breast neoplasm Diseases 0.000 claims description 7
- 208000002193 Pain Diseases 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 208000029742 colonic neoplasm Diseases 0.000 claims description 7
- 230000036407 pain Effects 0.000 claims description 7
- 206010005003 Bladder cancer Diseases 0.000 claims description 6
- 206010006187 Breast cancer Diseases 0.000 claims description 6
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 6
- 206010013935 Dysmenorrhoea Diseases 0.000 claims description 6
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 claims description 6
- 206010020751 Hypersensitivity Diseases 0.000 claims description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 6
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 6
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 6
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 6
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 6
- 229940100198 alkylating agent Drugs 0.000 claims description 6
- 239000002168 alkylating agent Substances 0.000 claims description 6
- 206010003246 arthritis Diseases 0.000 claims description 6
- 201000010881 cervical cancer Diseases 0.000 claims description 6
- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 claims description 6
- 239000003862 glucocorticoid Substances 0.000 claims description 6
- 208000032839 leukemia Diseases 0.000 claims description 6
- 201000007270 liver cancer Diseases 0.000 claims description 6
- 208000014018 liver neoplasm Diseases 0.000 claims description 6
- 201000005202 lung cancer Diseases 0.000 claims description 6
- 208000020816 lung neoplasm Diseases 0.000 claims description 6
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 6
- 201000000849 skin cancer Diseases 0.000 claims description 6
- 230000001988 toxicity Effects 0.000 claims description 6
- 231100000419 toxicity Toxicity 0.000 claims description 6
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 6
- 206010002556 Ankylosing Spondylitis Diseases 0.000 claims description 5
- 201000001320 Atherosclerosis Diseases 0.000 claims description 5
- 208000023275 Autoimmune disease Diseases 0.000 claims description 5
- 208000018084 Bone neoplasm Diseases 0.000 claims description 5
- 206010006811 Bursitis Diseases 0.000 claims description 5
- 208000007882 Gastritis Diseases 0.000 claims description 5
- 201000005569 Gout Diseases 0.000 claims description 5
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 5
- 206010029113 Neovascularisation Diseases 0.000 claims description 5
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 5
- 208000018737 Parkinson disease Diseases 0.000 claims description 5
- 206010037660 Pyrexia Diseases 0.000 claims description 5
- 208000009956 adenocarcinoma Diseases 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- 238000011161 development Methods 0.000 claims description 5
- 206010020718 hyperplasia Diseases 0.000 claims description 5
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 5
- NGHTXZCKLWZPGK-UHFFFAOYSA-N nefiracetam Chemical compound CC1=CC=CC(C)=C1NC(=O)CN1C(=O)CCC1 NGHTXZCKLWZPGK-UHFFFAOYSA-N 0.000 claims description 5
- 210000000056 organ Anatomy 0.000 claims description 5
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 5
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 5
- 208000003120 Angiofibroma Diseases 0.000 claims description 4
- 208000030016 Avascular necrosis Diseases 0.000 claims description 4
- 206010004146 Basal cell carcinoma Diseases 0.000 claims description 4
- 208000027496 Behcet disease Diseases 0.000 claims description 4
- 208000009137 Behcet syndrome Diseases 0.000 claims description 4
- 206010005949 Bone cancer Diseases 0.000 claims description 4
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 4
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 4
- 206010010741 Conjunctivitis Diseases 0.000 claims description 4
- 206010011017 Corneal graft rejection Diseases 0.000 claims description 4
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 4
- 201000009273 Endometriosis Diseases 0.000 claims description 4
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 4
- 201000003741 Gastrointestinal carcinoma Diseases 0.000 claims description 4
- 208000010412 Glaucoma Diseases 0.000 claims description 4
- 206010061523 Lip and/or oral cavity cancer Diseases 0.000 claims description 4
- 206010062038 Lip neoplasm Diseases 0.000 claims description 4
- 206010025323 Lymphomas Diseases 0.000 claims description 4
- 208000003445 Mouth Neoplasms Diseases 0.000 claims description 4
- 201000002481 Myositis Diseases 0.000 claims description 4
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 4
- 206010031264 Osteonecrosis Diseases 0.000 claims description 4
- 206010033128 Ovarian cancer Diseases 0.000 claims description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 4
- 208000006265 Renal cell carcinoma Diseases 0.000 claims description 4
- 208000007135 Retinal Neovascularization Diseases 0.000 claims description 4
- 206010038933 Retinopathy of prematurity Diseases 0.000 claims description 4
- 206010040070 Septic Shock Diseases 0.000 claims description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 4
- 208000007107 Stomach Ulcer Diseases 0.000 claims description 4
- 208000006011 Stroke Diseases 0.000 claims description 4
- 208000000491 Tendinopathy Diseases 0.000 claims description 4
- 206010043255 Tendonitis Diseases 0.000 claims description 4
- 208000025865 Ulcer Diseases 0.000 claims description 4
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 4
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 4
- 208000007502 anemia Diseases 0.000 claims description 4
- 208000006673 asthma Diseases 0.000 claims description 4
- 208000010668 atopic eczema Diseases 0.000 claims description 4
- YTKUWDBFDASYHO-UHFFFAOYSA-N bendamustine Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 YTKUWDBFDASYHO-UHFFFAOYSA-N 0.000 claims description 4
- 229960002707 bendamustine Drugs 0.000 claims description 4
- 206010006451 bronchitis Diseases 0.000 claims description 4
- 208000010247 contact dermatitis Diseases 0.000 claims description 4
- 208000035475 disorder Diseases 0.000 claims description 4
- 201000004101 esophageal cancer Diseases 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 206010017758 gastric cancer Diseases 0.000 claims description 4
- 201000005917 gastric ulcer Diseases 0.000 claims description 4
- 208000007565 gingivitis Diseases 0.000 claims description 4
- 208000015181 infectious disease Diseases 0.000 claims description 4
- 201000002313 intestinal cancer Diseases 0.000 claims description 4
- 208000017169 kidney disease Diseases 0.000 claims description 4
- 201000006721 lip cancer Diseases 0.000 claims description 4
- 201000006417 multiple sclerosis Diseases 0.000 claims description 4
- 206010028417 myasthenia gravis Diseases 0.000 claims description 4
- 201000000050 myeloid neoplasm Diseases 0.000 claims description 4
- 208000010125 myocardial infarction Diseases 0.000 claims description 4
- 201000009240 nasopharyngitis Diseases 0.000 claims description 4
- 210000001989 nasopharynx Anatomy 0.000 claims description 4
- 201000003142 neovascular glaucoma Diseases 0.000 claims description 4
- 208000004296 neuralgia Diseases 0.000 claims description 4
- 208000005987 polymyositis Diseases 0.000 claims description 4
- 208000037803 restenosis Diseases 0.000 claims description 4
- 201000000306 sarcoidosis Diseases 0.000 claims description 4
- 201000000980 schizophrenia Diseases 0.000 claims description 4
- 201000011549 stomach cancer Diseases 0.000 claims description 4
- 201000004595 synovitis Diseases 0.000 claims description 4
- 201000004415 tendinitis Diseases 0.000 claims description 4
- 206010043778 thyroiditis Diseases 0.000 claims description 4
- 230000029663 wound healing Effects 0.000 claims description 4
- SUHQNCLNRUAGOO-KQCZLNONSA-N (4s,5r,6r,7s,8r)-4,6,7,8,9-pentahydroxy-5-[(2-hydroxyacetyl)amino]-2-oxononanoic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](NC(=O)CO)[C@@H](O)CC(=O)C(O)=O SUHQNCLNRUAGOO-KQCZLNONSA-N 0.000 claims description 3
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 3
- 201000006474 Brain Ischemia Diseases 0.000 claims description 3
- 206010006895 Cachexia Diseases 0.000 claims description 3
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 3
- 208000005145 Cerebral amyloid angiopathy Diseases 0.000 claims description 3
- 206010008120 Cerebral ischaemia Diseases 0.000 claims description 3
- 229940122041 Cholinesterase inhibitor Drugs 0.000 claims description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 3
- 208000033131 Congenital factor II deficiency Diseases 0.000 claims description 3
- 208000028006 Corneal injury Diseases 0.000 claims description 3
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 3
- 208000005171 Dysmenorrhea Diseases 0.000 claims description 3
- 206010014561 Emphysema Diseases 0.000 claims description 3
- 206010014989 Epidermolysis bullosa Diseases 0.000 claims description 3
- 208000012671 Gastrointestinal haemorrhages Diseases 0.000 claims description 3
- 206010019196 Head injury Diseases 0.000 claims description 3
- 206010019280 Heart failures Diseases 0.000 claims description 3
- 208000031220 Hemophilia Diseases 0.000 claims description 3
- 208000009292 Hemophilia A Diseases 0.000 claims description 3
- 208000023105 Huntington disease Diseases 0.000 claims description 3
- 208000007646 Hypoprothrombinemias Diseases 0.000 claims description 3
- 208000029462 Immunodeficiency disease Diseases 0.000 claims description 3
- 206010024453 Ligament sprain Diseases 0.000 claims description 3
- 208000019695 Migraine disease Diseases 0.000 claims description 3
- 206010050031 Muscle strain Diseases 0.000 claims description 3
- 208000008589 Obesity Diseases 0.000 claims description 3
- 208000001132 Osteoporosis Diseases 0.000 claims description 3
- 208000008469 Peptic Ulcer Diseases 0.000 claims description 3
- 208000006399 Premature Obstetric Labor Diseases 0.000 claims description 3
- 206010036600 Premature labour Diseases 0.000 claims description 3
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 3
- 241000606651 Rickettsiales Species 0.000 claims description 3
- 206010039705 Scleritis Diseases 0.000 claims description 3
- 206010040047 Sepsis Diseases 0.000 claims description 3
- 206010064390 Tumour invasion Diseases 0.000 claims description 3
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 3
- 125000005036 alkoxyphenyl group Chemical group 0.000 claims description 3
- 208000026935 allergic disease Diseases 0.000 claims description 3
- 230000000172 allergic effect Effects 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- 208000007474 aortic aneurysm Diseases 0.000 claims description 3
- 230000009400 cancer invasion Effects 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 206010008118 cerebral infarction Diseases 0.000 claims description 3
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 claims description 3
- 229960004630 chlorambucil Drugs 0.000 claims description 3
- 239000000544 cholinesterase inhibitor Substances 0.000 claims description 3
- 230000015271 coagulation Effects 0.000 claims description 3
- 238000005345 coagulation Methods 0.000 claims description 3
- 230000019771 cognition Effects 0.000 claims description 3
- 229960004397 cyclophosphamide Drugs 0.000 claims description 3
- 206010012601 diabetes mellitus Diseases 0.000 claims description 3
- 208000007784 diverticulitis Diseases 0.000 claims description 3
- XWAIAVWHZJNZQQ-UHFFFAOYSA-N donepezil hydrochloride Chemical compound [H+].[Cl-].O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 XWAIAVWHZJNZQQ-UHFFFAOYSA-N 0.000 claims description 3
- 229960003135 donepezil hydrochloride Drugs 0.000 claims description 3
- 229940011871 estrogen Drugs 0.000 claims description 3
- 239000000262 estrogen Substances 0.000 claims description 3
- 229960003980 galantamine Drugs 0.000 claims description 3
- ASUTZQLVASHGKV-UHFFFAOYSA-N galanthamine hydrochloride Natural products O1C(=C23)C(OC)=CC=C2CN(C)CCC23C1CC(O)C=C2 ASUTZQLVASHGKV-UHFFFAOYSA-N 0.000 claims description 3
- 208000030304 gastrointestinal bleeding Diseases 0.000 claims description 3
- 231100001014 gastrointestinal tract lesion Toxicity 0.000 claims description 3
- 230000002489 hematologic effect Effects 0.000 claims description 3
- 230000002390 hyperplastic effect Effects 0.000 claims description 3
- 230000009610 hypersensitivity Effects 0.000 claims description 3
- 239000007943 implant Substances 0.000 claims description 3
- 208000002780 macular degeneration Diseases 0.000 claims description 3
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 claims description 3
- 229960001924 melphalan Drugs 0.000 claims description 3
- 229960001952 metrifonate Drugs 0.000 claims description 3
- 206010027599 migraine Diseases 0.000 claims description 3
- 210000003205 muscle Anatomy 0.000 claims description 3
- 230000001777 nootropic effect Effects 0.000 claims description 3
- 235000020824 obesity Nutrition 0.000 claims description 3
- 208000028169 periodontal disease Diseases 0.000 claims description 3
- 208000033808 peripheral neuropathy Diseases 0.000 claims description 3
- 201000006292 polyarteritis nodosa Diseases 0.000 claims description 3
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 claims description 3
- 229960004618 prednisone Drugs 0.000 claims description 3
- 208000026440 premature labor Diseases 0.000 claims description 3
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 201000007183 prothrombin deficiency Diseases 0.000 claims description 3
- 230000000306 recurrent effect Effects 0.000 claims description 3
- 230000001850 reproductive effect Effects 0.000 claims description 3
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 claims description 3
- 229960001534 risperidone Drugs 0.000 claims description 3
- 229960004323 rivastigmine tartrate Drugs 0.000 claims description 3
- 230000036303 septic shock Effects 0.000 claims description 3
- 208000017520 skin disease Diseases 0.000 claims description 3
- 208000020431 spinal cord injury Diseases 0.000 claims description 3
- YONPGGFAJWQGJC-UHFFFAOYSA-K titanium(iii) chloride Chemical compound Cl[Ti](Cl)Cl YONPGGFAJWQGJC-UHFFFAOYSA-K 0.000 claims description 3
- NFACJZMKEDPNKN-UHFFFAOYSA-N trichlorfon Chemical compound COP(=O)(OC)C(O)C(Cl)(Cl)Cl NFACJZMKEDPNKN-UHFFFAOYSA-N 0.000 claims description 3
- 230000004614 tumor growth Effects 0.000 claims description 3
- 230000036269 ulceration Effects 0.000 claims description 3
- 208000004804 Adenomatous Polyps Diseases 0.000 claims description 2
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 2
- 230000037390 scarring Effects 0.000 claims description 2
- 208000011580 syndromic disease Diseases 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 7
- 229910006074 SO2NH2 Inorganic materials 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 description 128
- 230000015572 biosynthetic process Effects 0.000 description 124
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 113
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 106
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 99
- 239000007787 solid Substances 0.000 description 81
- 239000000243 solution Substances 0.000 description 76
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 64
- 238000005160 1H NMR spectroscopy Methods 0.000 description 57
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 54
- 210000004027 cell Anatomy 0.000 description 50
- 101150041968 CDC13 gene Proteins 0.000 description 49
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 42
- 235000019439 ethyl acetate Nutrition 0.000 description 40
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 39
- 235000019441 ethanol Nutrition 0.000 description 38
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 35
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 35
- 150000002148 esters Chemical class 0.000 description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 33
- 239000003921 oil Substances 0.000 description 32
- 235000019198 oils Nutrition 0.000 description 32
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 30
- 239000012448 Lithium borohydride Substances 0.000 description 27
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 27
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 27
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 27
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 25
- 229960000583 acetic acid Drugs 0.000 description 24
- 239000000741 silica gel Substances 0.000 description 24
- 229910002027 silica gel Inorganic materials 0.000 description 24
- 239000000284 extract Substances 0.000 description 21
- 235000019341 magnesium sulphate Nutrition 0.000 description 21
- 108090000623 proteins and genes Proteins 0.000 description 21
- MBBOMCVGYCRMEA-UHFFFAOYSA-N tryptophol Chemical compound C1=CC=C2C(CCO)=CNC2=C1 MBBOMCVGYCRMEA-UHFFFAOYSA-N 0.000 description 21
- 230000002829 reductive effect Effects 0.000 description 20
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 19
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 19
- 238000005481 NMR spectroscopy Methods 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
- 230000000694 effects Effects 0.000 description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 239000012043 crude product Substances 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- 239000002253 acid Substances 0.000 description 15
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 description 15
- 108010058546 Cyclin D1 Proteins 0.000 description 14
- 102100024165 G1/S-specific cyclin-D1 Human genes 0.000 description 14
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 14
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 14
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 235000018102 proteins Nutrition 0.000 description 14
- 102000004169 proteins and genes Human genes 0.000 description 14
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 13
- NNYBQONXHNTVIJ-UHFFFAOYSA-N etodolac Chemical compound C1COC(CC)(CC(O)=O)C2=C1C(C=CC=C1CC)=C1N2 NNYBQONXHNTVIJ-UHFFFAOYSA-N 0.000 description 13
- 239000000725 suspension Substances 0.000 description 13
- 241000282414 Homo sapiens Species 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 12
- 239000003153 chemical reaction reagent Substances 0.000 description 12
- 238000003818 flash chromatography Methods 0.000 description 12
- 238000003018 immunoassay Methods 0.000 description 12
- 230000035772 mutation Effects 0.000 description 12
- 239000012038 nucleophile Substances 0.000 description 12
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 12
- 229960005293 etodolac Drugs 0.000 description 11
- 230000014509 gene expression Effects 0.000 description 11
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 11
- 125000006239 protecting group Chemical group 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 10
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 10
- 238000003556 assay Methods 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- 239000006184 cosolvent Substances 0.000 description 10
- DONAHNRHLJDHKU-UHFFFAOYSA-N 2-(8-bromo-1-ethyl-6-propan-2-yl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)ethanol Chemical compound N1C2=C(Br)C=C(C(C)C)C=C2C2=C1C(CC)(CCO)OCC2 DONAHNRHLJDHKU-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 230000035508 accumulation Effects 0.000 description 9
- 238000009825 accumulation Methods 0.000 description 9
- 229920001223 polyethylene glycol Polymers 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 206010061218 Inflammation Diseases 0.000 description 8
- 150000001298 alcohols Chemical class 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- 238000009472 formulation Methods 0.000 description 8
- 238000003364 immunohistochemistry Methods 0.000 description 8
- 230000004054 inflammatory process Effects 0.000 description 8
- 239000012299 nitrogen atmosphere Substances 0.000 description 8
- 210000004940 nucleus Anatomy 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 7
- 102000013814 Wnt Human genes 0.000 description 7
- 108050003627 Wnt Proteins 0.000 description 7
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 210000000805 cytoplasm Anatomy 0.000 description 7
- 239000012039 electrophile Substances 0.000 description 7
- 229940088598 enzyme Drugs 0.000 description 7
- 150000002576 ketones Chemical class 0.000 description 7
- 239000002243 precursor Substances 0.000 description 7
- 230000002265 prevention Effects 0.000 description 7
- 239000000523 sample Substances 0.000 description 7
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 6
- 108010010803 Gelatin Proteins 0.000 description 6
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 125000003282 alkyl amino group Chemical group 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 6
- 229960002327 chloral hydrate Drugs 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 238000000684 flow cytometry Methods 0.000 description 6
- 125000000524 functional group Chemical group 0.000 description 6
- 229920000159 gelatin Polymers 0.000 description 6
- 239000008273 gelatin Substances 0.000 description 6
- 235000019322 gelatine Nutrition 0.000 description 6
- 235000011852 gelatine desserts Nutrition 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 230000001105 regulatory effect Effects 0.000 description 6
- 125000006413 ring segment Chemical group 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- UVSDNCAZVSQJQA-UHFFFAOYSA-N 2-(7-ethyl-1h-indol-3-yl)ethanol Chemical compound CCC1=CC=CC2=C1NC=C2CCO UVSDNCAZVSQJQA-UHFFFAOYSA-N 0.000 description 5
- 101150030271 AXIN1 gene Proteins 0.000 description 5
- 102000051172 Axin Human genes 0.000 description 5
- 108700012045 Axin Proteins 0.000 description 5
- 201000009030 Carcinoma Diseases 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 102100038824 Peroxisome proliferator-activated receptor delta Human genes 0.000 description 5
- 239000002202 Polyethylene glycol Substances 0.000 description 5
- 229920002472 Starch Polymers 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 239000013543 active substance Substances 0.000 description 5
- 150000001299 aldehydes Chemical class 0.000 description 5
- 150000001350 alkyl halides Chemical class 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 229910002092 carbon dioxide Inorganic materials 0.000 description 5
- 230000015556 catabolic process Effects 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 238000006731 degradation reaction Methods 0.000 description 5
- 230000018109 developmental process Effects 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 210000002919 epithelial cell Anatomy 0.000 description 5
- 230000012010 growth Effects 0.000 description 5
- 230000002209 hydrophobic effect Effects 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- 230000037361 pathway Effects 0.000 description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 5
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 5
- 101150075122 ppard gene Proteins 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- SGGRZOUTFZRJBZ-UHFFFAOYSA-N 2-hydroxyimino-n-(2-propan-2-ylphenyl)acetamide Chemical compound CC(C)C1=CC=CC=C1NC(=O)C=NO SGGRZOUTFZRJBZ-UHFFFAOYSA-N 0.000 description 4
- PRRBQHNMYJRHFW-UHFFFAOYSA-M 3-oxoheptanoate Chemical compound CCCCC(=O)CC([O-])=O PRRBQHNMYJRHFW-UHFFFAOYSA-M 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- 101150071146 COX2 gene Proteins 0.000 description 4
- 101100114534 Caenorhabditis elegans ctc-2 gene Proteins 0.000 description 4
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 4
- 102000016736 Cyclin Human genes 0.000 description 4
- 108050006400 Cyclin Proteins 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- 101150000187 PTGS2 gene Proteins 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical class OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 4
- 230000033228 biological regulation Effects 0.000 description 4
- 238000001574 biopsy Methods 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 230000036952 cancer formation Effects 0.000 description 4
- 230000001767 chemoprotection Effects 0.000 description 4
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 230000002074 deregulated effect Effects 0.000 description 4
- 239000008298 dragée Substances 0.000 description 4
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 239000012091 fetal bovine serum Substances 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 150000007522 mineralic acids Chemical class 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- MSFHDQUXFZCDCZ-UHFFFAOYSA-N n-(4-bromo-2-ethylphenyl)-2-hydroxyiminoacetamide Chemical compound CCC1=CC(Br)=CC=C1NC(=O)C=NO MSFHDQUXFZCDCZ-UHFFFAOYSA-N 0.000 description 4
- 230000004942 nuclear accumulation Effects 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 201000008482 osteoarthritis Diseases 0.000 description 4
- 239000012188 paraffin wax Substances 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 239000013612 plasmid Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 150000003180 prostaglandins Chemical class 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 230000019491 signal transduction Effects 0.000 description 4
- 239000003381 stabilizer Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 235000000346 sugar Nutrition 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 238000013518 transcription Methods 0.000 description 4
- 230000035897 transcription Effects 0.000 description 4
- 238000001890 transfection Methods 0.000 description 4
- NNYBQONXHNTVIJ-QGZVFWFLSA-N (R)-etodolac Chemical compound C1CO[C@](CC)(CC(O)=O)C2=C1C(C=CC=C1CC)=C1N2 NNYBQONXHNTVIJ-QGZVFWFLSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 208000032467 Aplastic anaemia Diseases 0.000 description 3
- 229910015900 BF3 Inorganic materials 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- 208000005623 Carcinogenesis Diseases 0.000 description 3
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 3
- 108010068192 Cyclin A Proteins 0.000 description 3
- 102000003910 Cyclin D Human genes 0.000 description 3
- 108090000259 Cyclin D Proteins 0.000 description 3
- 102100025191 Cyclin-A2 Human genes 0.000 description 3
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 3
- 206010063045 Effusion Diseases 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 102000002254 Glycogen Synthase Kinase 3 Human genes 0.000 description 3
- 108010014905 Glycogen Synthase Kinase 3 Proteins 0.000 description 3
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical class OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 3
- 238000007341 Heck reaction Methods 0.000 description 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 3
- 231100000002 MTT assay Toxicity 0.000 description 3
- 238000000134 MTT assay Methods 0.000 description 3
- 102100038895 Myc proto-oncogene protein Human genes 0.000 description 3
- 101710135898 Myc proto-oncogene protein Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 229930012538 Paclitaxel Natural products 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 201000004681 Psoriasis Diseases 0.000 description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 3
- 102000019197 Superoxide Dismutase Human genes 0.000 description 3
- 108010012715 Superoxide dismutase Proteins 0.000 description 3
- 238000006069 Suzuki reaction reaction Methods 0.000 description 3
- 101710150448 Transcriptional regulator Myc Proteins 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 230000000118 anti-neoplastic effect Effects 0.000 description 3
- 230000006907 apoptotic process Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 229940114079 arachidonic acid Drugs 0.000 description 3
- 235000021342 arachidonic acid Nutrition 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 235000011089 carbon dioxide Nutrition 0.000 description 3
- 231100000504 carcinogenesis Toxicity 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 210000000170 cell membrane Anatomy 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 210000001072 colon Anatomy 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 229960000684 cytarabine Drugs 0.000 description 3
- 230000001086 cytosolic effect Effects 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 229960004679 doxorubicin Drugs 0.000 description 3
- LFSUQWWHAVAWBX-UHFFFAOYSA-N ethyl 3-[1-ethyl-1-(2-hydroxyethyl)-8-propan-2-yl-4,9-dihydro-3h-pyrano[3,4-b]indol-6-yl]propanoate Chemical compound C12=CC(CCC(=O)OCC)=CC(C(C)C)=C2NC2=C1CCOC2(CC)CCO LFSUQWWHAVAWBX-UHFFFAOYSA-N 0.000 description 3
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 3
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 208000014674 injury Diseases 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 3
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 238000013188 needle biopsy Methods 0.000 description 3
- 230000002611 ovarian Effects 0.000 description 3
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 3
- 229960001592 paclitaxel Drugs 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 230000036470 plasma concentration Effects 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 3
- 229940068968 polysorbate 80 Drugs 0.000 description 3
- 229920000053 polysorbate 80 Polymers 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 210000002307 prostate Anatomy 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical class OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 125000003003 spiro group Chemical group 0.000 description 3
- 150000008163 sugars Chemical class 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 238000013268 sustained release Methods 0.000 description 3
- 239000012730 sustained-release form Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 150000003568 thioethers Chemical class 0.000 description 3
- 239000001993 wax Substances 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- ZGNLFUXWZJGETL-YUSKDDKASA-N (Z)-[(2S)-2-amino-2-carboxyethyl]-hydroxyimino-oxidoazanium Chemical compound N[C@@H](C\[N+]([O-])=N\O)C(O)=O ZGNLFUXWZJGETL-YUSKDDKASA-N 0.000 description 2
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 2
- GTADQMQBQBOJIO-UHFFFAOYSA-N 1,12-Dihydroxy-1,6,12,17-tetraazacyclodocosane-2,5,13,16-tetrone Chemical compound ON1CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC1=O GTADQMQBQBOJIO-UHFFFAOYSA-N 0.000 description 2
- MAUYWACILHVRLR-UHFFFAOYSA-N 1-(morpholin-4-ylmethyl)-4-[2-[4-(morpholin-4-ylmethyl)-3,5-dioxopiperazin-1-yl]propyl]piperazine-2,6-dione Chemical compound C1C(=O)N(CN2CCOCC2)C(=O)CN1C(C)CN(CC1=O)CC(=O)N1CN1CCOCC1 MAUYWACILHVRLR-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- VHJWDTPKSIFZBV-UHFFFAOYSA-N 2,5,7-trihydroxy-4-(4-hydroxy-3,5-dimethoxy-6-methyloxan-2-yl)oxy-3,9-dimethoxy-2-methyl-3,4-dihydrotetracene-1,6,11-trione Chemical compound COC1C(O)C(OC)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=C(OC)C=C3C3=O)=C3C=C2C(=O)C(C)(O)C1OC VHJWDTPKSIFZBV-UHFFFAOYSA-N 0.000 description 2
- QFEGDUATXAMDLT-UHFFFAOYSA-N 2-(5-methyl-1h-indol-3-yl)ethanol Chemical compound CC1=CC=C2NC=C(CCO)C2=C1 QFEGDUATXAMDLT-UHFFFAOYSA-N 0.000 description 2
- GZVAZIQGRGFXGN-UHFFFAOYSA-N 2-(6-bromo-1-ethyl-8-propan-2-yl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)ethanol Chemical compound N1C2=C(C(C)C)C=C(Br)C=C2C2=C1C(CC)(CCO)OCC2 GZVAZIQGRGFXGN-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- YKOLZVXSPGIIBJ-UHFFFAOYSA-N 2-Isopropylaniline Chemical compound CC(C)C1=CC=CC=C1N YKOLZVXSPGIIBJ-UHFFFAOYSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- SSAHMDMEYZOZLN-UHFFFAOYSA-N 2-hydroxyimino-n-[2-(trifluoromethyl)phenyl]acetamide Chemical compound ON=CC(=O)NC1=CC=CC=C1C(F)(F)F SSAHMDMEYZOZLN-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- LGOZNQPHTIGMQJ-UHFFFAOYSA-N 4-bromo-2-ethylaniline Chemical compound CCC1=CC(Br)=CC=C1N LGOZNQPHTIGMQJ-UHFFFAOYSA-N 0.000 description 2
- DVHNMQQXLMOZKB-UHFFFAOYSA-N 5,7-dimethyl-1h-indole Chemical compound CC1=CC(C)=C2NC=CC2=C1 DVHNMQQXLMOZKB-UHFFFAOYSA-N 0.000 description 2
- SJJDMAUWJKZIJL-UHFFFAOYSA-N 5-bromo-7-ethyl-1h-indole Chemical compound CCC1=CC(Br)=CC2=C1NC=C2 SJJDMAUWJKZIJL-UHFFFAOYSA-N 0.000 description 2
- CTGQHGOEVARVKX-UHFFFAOYSA-N 5-bromo-7-ethyl-1h-indole-2,3-dione Chemical compound CCC1=CC(Br)=CC2=C1NC(=O)C2=O CTGQHGOEVARVKX-UHFFFAOYSA-N 0.000 description 2
- PAVLMIFDZYPNCQ-UHFFFAOYSA-N 5-bromo-7-propan-2-yl-1h-indole Chemical compound CC(C)C1=CC(Br)=CC2=C1NC=C2 PAVLMIFDZYPNCQ-UHFFFAOYSA-N 0.000 description 2
- PRBCLRPANHSTBW-UHFFFAOYSA-N 7-propan-2-yl-1h-indole Chemical compound CC(C)C1=CC=CC2=C1NC=C2 PRBCLRPANHSTBW-UHFFFAOYSA-N 0.000 description 2
- XWJSENVAAAAHBN-UHFFFAOYSA-N 7-propan-2-yl-1h-indole-2,3-dione Chemical compound CC(C)C1=CC=CC2=C1NC(=O)C2=O XWJSENVAAAAHBN-UHFFFAOYSA-N 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- 208000005748 Aggressive Fibromatosis Diseases 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- 208000005440 Basal Cell Neoplasms Diseases 0.000 description 2
- 229940124638 COX inhibitor Drugs 0.000 description 2
- 101100297347 Caenorhabditis elegans pgl-3 gene Proteins 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical class [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 2
- 108010092160 Dactinomycin Proteins 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 238000011891 EIA kit Methods 0.000 description 2
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 description 2
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 2
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 2
- 206010018364 Glomerulonephritis Diseases 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 102100023915 Insulin Human genes 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- MLFKVJCWGUZWNV-UHFFFAOYSA-N L-alanosine Natural products OC(=O)C(N)CN(O)N=O MLFKVJCWGUZWNV-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 208000034578 Multiple myelomas Diseases 0.000 description 2
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 2
- 239000000020 Nitrocellulose Substances 0.000 description 2
- 102000007399 Nuclear hormone receptor Human genes 0.000 description 2
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- RKJCLPSFLUKWQY-UHFFFAOYSA-N Tricrozarin A Chemical compound OC1=C2C(=O)C(OC)=C(OC)C(=O)C2=C(O)C2=C1OCO2 RKJCLPSFLUKWQY-UHFFFAOYSA-N 0.000 description 2
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 2
- 208000036142 Viral infection Diseases 0.000 description 2
- 239000005862 Whey Substances 0.000 description 2
- 102000007544 Whey Proteins Human genes 0.000 description 2
- 108010046377 Whey Proteins Proteins 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 239000003377 acid catalyst Substances 0.000 description 2
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 150000001266 acyl halides Chemical class 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 229950005033 alanosine Drugs 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 150000001345 alkine derivatives Chemical class 0.000 description 2
- ANVAOWXLWRTKGA-XHGAXZNDSA-N all-trans-alpha-carotene Chemical compound CC=1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1C(C)=CCCC1(C)C ANVAOWXLWRTKGA-XHGAXZNDSA-N 0.000 description 2
- JKOQGQFVAUAYPM-UHFFFAOYSA-N amifostine Chemical class NCCCNCCSP(O)(O)=O JKOQGQFVAUAYPM-UHFFFAOYSA-N 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 239000002256 antimetabolite Substances 0.000 description 2
- 239000008135 aqueous vehicle Substances 0.000 description 2
- 150000001502 aryl halides Chemical class 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 210000001124 body fluid Anatomy 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 150000003857 carboxamides Chemical class 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 230000005754 cellular signaling Effects 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940127271 compound 49 Drugs 0.000 description 2
- 229940111134 coxibs Drugs 0.000 description 2
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 2
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 2
- 229960000640 dactinomycin Drugs 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 230000003831 deregulation Effects 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000001962 electrophoresis Methods 0.000 description 2
- 208000037828 epithelial carcinoma Diseases 0.000 description 2
- SEBNXWUYDLIVNR-UHFFFAOYSA-N ethyl 2-(5-bromo-7-ethyl-1h-indol-3-yl)-2-oxoacetate Chemical compound C1=C(Br)C=C2C(C(=O)C(=O)OCC)=CNC2=C1CC SEBNXWUYDLIVNR-UHFFFAOYSA-N 0.000 description 2
- XBUBXNYAXTZIHJ-UHFFFAOYSA-N ethyl 2-(6-bromo-1,8-diethyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetate Chemical compound N1C2=C(CC)C=C(Br)C=C2C2=C1C(CC(=O)OCC)(CC)OCC2 XBUBXNYAXTZIHJ-UHFFFAOYSA-N 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 2
- 229960005420 etoposide Drugs 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000010685 fatty oil Substances 0.000 description 2
- 229940012952 fibrinogen Drugs 0.000 description 2
- 229940126864 fibroblast growth factor Drugs 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229960002949 fluorouracil Drugs 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- CHPZKNULDCNCBW-UHFFFAOYSA-N gallium nitrate Chemical compound [Ga+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O CHPZKNULDCNCBW-UHFFFAOYSA-N 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 230000000762 glandular Effects 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 238000007327 hydrogenolysis reaction Methods 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 238000010324 immunological assay Methods 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- 150000002513 isocyanates Chemical class 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 230000037356 lipid metabolism Effects 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- 239000012139 lysis buffer Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 2
- UPBAOYRENQEPJO-UHFFFAOYSA-N n-[5-[[5-[(3-amino-3-iminopropyl)carbamoyl]-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]-4-formamido-1-methylpyrrole-2-carboxamide Chemical class CN1C=C(NC=O)C=C1C(=O)NC1=CN(C)C(C(=O)NC2=CN(C)C(C(=O)NCCC(N)=N)=C2)=C1 UPBAOYRENQEPJO-UHFFFAOYSA-N 0.000 description 2
- 230000001613 neoplastic effect Effects 0.000 description 2
- 150000002826 nitrites Chemical class 0.000 description 2
- 229920001220 nitrocellulos Polymers 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229960003552 other antineoplastic agent in atc Drugs 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 239000001301 oxygen Chemical group 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- 229940068886 polyethylene glycol 300 Drugs 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000003753 real-time PCR Methods 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 201000003068 rheumatic fever Diseases 0.000 description 2
- 150000003335 secondary amines Chemical class 0.000 description 2
- 239000004017 serum-free culture medium Substances 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 208000017572 squamous cell neoplasm Diseases 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 2
- 229960000894 sulindac Drugs 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 229940037128 systemic glucocorticoids Drugs 0.000 description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical group CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 description 2
- 150000003573 thiols Chemical class 0.000 description 2
- 210000001685 thyroid gland Anatomy 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 2
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 230000009385 viral infection Effects 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- 235000020138 yakult Nutrition 0.000 description 2
- BMKDZUISNHGIBY-ZETCQYMHSA-N (+)-dexrazoxane Chemical compound C([C@H](C)N1CC(=O)NC(=O)C1)N1CC(=O)NC(=O)C1 BMKDZUISNHGIBY-ZETCQYMHSA-N 0.000 description 1
- XEEQGYMUWCZPDN-DOMZBBRYSA-N (-)-(11S,2'R)-erythro-mefloquine Chemical compound C([C@@H]1[C@@H](O)C=2C3=CC=CC(=C3N=C(C=2)C(F)(F)F)C(F)(F)F)CCCN1 XEEQGYMUWCZPDN-DOMZBBRYSA-N 0.000 description 1
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 1
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- LLWMPGSQZXZZAE-JZFVXYNCSA-N (1s,2s,4ar,4bs,7s,8ar,10ar)-7-hydroxy-2,4b,7',8,8,10a-hexamethylspiro[2,3,4,4a,5,6,7,8a,9,10-decahydrophenanthrene-1,2'-3h-1-benzofuran]-4',5'-dione Chemical compound C1C(C(C(=O)C=C2C)=O)=C2O[C@]21[C@]1(C)CC[C@H]3C(C)(C)[C@@H](O)CC[C@]3(C)[C@H]1CC[C@@H]2C LLWMPGSQZXZZAE-JZFVXYNCSA-N 0.000 description 1
- JLSPXOVSIVYMCY-UHFFFAOYSA-N (2,4-dichlorophenyl)methyl thiocyanate Chemical compound ClC1=CC=C(CSC#N)C(Cl)=C1 JLSPXOVSIVYMCY-UHFFFAOYSA-N 0.000 description 1
- QQLRSCZSKQTFGY-UHFFFAOYSA-N (2,4-difluorophenyl)boronic acid Chemical compound OB(O)C1=CC=C(F)C=C1F QQLRSCZSKQTFGY-UHFFFAOYSA-N 0.000 description 1
- INLNROXDMBMFKA-UHFFFAOYSA-N (2-bromo-3-methoxyphenyl)boronic acid Chemical compound COC1=CC=CC(B(O)O)=C1Br INLNROXDMBMFKA-UHFFFAOYSA-N 0.000 description 1
- PHCYUJRYSFMJMG-UHFFFAOYSA-N (2-bromophenyl)hydrazine;hydron;chloride Chemical compound Cl.NNC1=CC=CC=C1Br PHCYUJRYSFMJMG-UHFFFAOYSA-N 0.000 description 1
- HBHPTOKYVGZBAJ-UHFFFAOYSA-N (2-ethylanilino)azanium;chloride Chemical compound Cl.CCC1=CC=CC=C1NN HBHPTOKYVGZBAJ-UHFFFAOYSA-N 0.000 description 1
- VFZYLSYYMHFPSY-UHFFFAOYSA-N (2-fluoroanilino)azanium;chloride Chemical compound Cl.NNC1=CC=CC=C1F VFZYLSYYMHFPSY-UHFFFAOYSA-N 0.000 description 1
- KJGFNDCSTWGUDT-UHFFFAOYSA-N (2-methylanilino)azanium;chloride Chemical compound Cl.CC1=CC=CC=C1NN KJGFNDCSTWGUDT-UHFFFAOYSA-N 0.000 description 1
- PQZVBIJEPVKNOZ-PCLZMVHQSA-N (2R)-2-[(1S)-1-hydroxy-1-[(5R,6R,8R,9S,10R,13S,14R,17S)-5,6,14,17-tetrahydroxy-10,13-dimethyl-1-oxo-6,7,8,9,11,12,15,16-octahydro-4H-cyclopenta[a]phenanthren-17-yl]ethyl]-4,5-dimethyl-2,3-dihydropyran-6-one Chemical class C1C(C)=C(C)C(=O)O[C@H]1[C@](C)(O)[C@@]1(O)[C@@]2(C)CC[C@@H]3[C@@]4(C)C(=O)C=CC[C@]4(O)[C@H](O)C[C@H]3[C@]2(O)CC1 PQZVBIJEPVKNOZ-PCLZMVHQSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- KZMHNEBMQDBQND-LBNZKSCFSA-N (2e,5s,6r,7s,9s,10e,12e,15r,16z,18e)-17-ethyl-6-hydroxy-9-(hydroxymethyl)-3,5,7,11,15-pentamethyl-19-[(2s,3s)-3-methyl-6-oxo-2,3-dihydropyran-2-yl]-8-oxononadeca-2,10,12,16,18-pentaenoic acid Chemical compound OC(=O)/C=C(C)/C[C@H](C)[C@@H](O)[C@H](C)C(=O)[C@H](CO)/C=C(\C)/C=C/C[C@@H](C)/C=C(/CC)\C=C\[C@@H]1OC(=O)C=C[C@@H]1C KZMHNEBMQDBQND-LBNZKSCFSA-N 0.000 description 1
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 1
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- OKNKQPUDKRCBIK-MAVIPZKQSA-N (2r,3r,4s,5s)-2-(9-hydroxy-5,11-dimethyl-6h-pyrido[4,3-b]carbazol-2-ium-2-yl)oxane-3,4,5-triol;bromide Chemical compound [Br-].C=1C=C2C(C)=C3NC4=CC=C(O)C=C4C3=C(C)C2=C[N+]=1[C@@H]1OC[C@H](O)[C@H](O)[C@H]1O OKNKQPUDKRCBIK-MAVIPZKQSA-N 0.000 description 1
- ZZKNRXZVGOYGJT-VKHMYHEASA-N (2s)-2-[(2-phosphonoacetyl)amino]butanedioic acid Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)CP(O)(O)=O ZZKNRXZVGOYGJT-VKHMYHEASA-N 0.000 description 1
- JAUGQKWRVWARPG-GFOUHAFJSA-N (2s)-2-[(3s)-1-[(2s,3s,4s,6r)-6-[[(1s,3s)-3-acetyl-3,5,10,12-tetrahydroxy-6,11-dioxo-2,4-dihydro-1h-tetracen-1-yl]oxy]-4-amino-2-methyloxan-3-yl]oxy-3-hydroxybutoxy]propanal Chemical compound O1[C@@H](C)[C@@H](OC(O[C@@H](C)C=O)C[C@@H](O)C)[C@@H](N)C[C@@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 JAUGQKWRVWARPG-GFOUHAFJSA-N 0.000 description 1
- QJERBBQXOMUURJ-INIZCTEOSA-N (2s)-2-[(4-chlorobenzoyl)amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C1=CC=C(Cl)C=C1 QJERBBQXOMUURJ-INIZCTEOSA-N 0.000 description 1
- VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- ZUQBAQVRAURMCL-CVRLYYSRSA-N (2s)-2-[[4-[2-(2-amino-4-oxo-5,6,7,8-tetrahydro-1h-pyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoyl]amino]pentanedioic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2CC1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 ZUQBAQVRAURMCL-CVRLYYSRSA-N 0.000 description 1
- ZUQBAQVRAURMCL-DOMZBBRYSA-N (2s)-2-[[4-[2-[(6r)-2-amino-4-oxo-5,6,7,8-tetrahydro-1h-pyrido[2,3-d]pyrimidin-6-yl]ethyl]benzoyl]amino]pentanedioic acid Chemical compound C([C@@H]1CC=2C(=O)N=C(NC=2NC1)N)CC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 ZUQBAQVRAURMCL-DOMZBBRYSA-N 0.000 description 1
- QXOPTIPQEVJERB-JQWIXIFHSA-N (2s)-2-[[5-[2-[(6s)-2-amino-4-oxo-5,6,7,8-tetrahydro-1h-pyrido[2,3-d]pyrimidin-6-yl]ethyl]-4-methylthiophene-2-carbonyl]amino]pentanedioic acid Chemical compound C1=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)SC(CC[C@H]2CC=3C(=O)N=C(N)NC=3NC2)=C1C QXOPTIPQEVJERB-JQWIXIFHSA-N 0.000 description 1
- YEORLXJBCPPSOC-SSDOTTSWSA-N (2s)-2-amino-5-(diaminomethylideneamino)-2-(difluoromethyl)pentanoic acid Chemical compound NC(=N)NCCC[C@@](N)(C(F)F)C(O)=O YEORLXJBCPPSOC-SSDOTTSWSA-N 0.000 description 1
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 1
- KJTPWUVVLPCPJD-AUWJEWJLSA-N (2z)-7-amino-2-[(4-hydroxy-3,5-dimethylphenyl)methylidene]-5,6-dimethoxy-3h-inden-1-one Chemical compound O=C1C=2C(N)=C(OC)C(OC)=CC=2C\C1=C\C1=CC(C)=C(O)C(C)=C1 KJTPWUVVLPCPJD-AUWJEWJLSA-N 0.000 description 1
- RMGYQBHKEWWTOY-UHFFFAOYSA-N (3,4-difluorophenyl)boronic acid Chemical compound OB(O)C1=CC=C(F)C(F)=C1 RMGYQBHKEWWTOY-UHFFFAOYSA-N 0.000 description 1
- DJGHSJBYKIQHIK-UHFFFAOYSA-N (3,5-dimethylphenyl)boronic acid Chemical compound CC1=CC(C)=CC(B(O)O)=C1 DJGHSJBYKIQHIK-UHFFFAOYSA-N 0.000 description 1
- SSCSSDNTQJGTJT-UHFFFAOYSA-N (3,6-dihydroxy-1-methyl-2,3-dihydroindol-5-yl)iminourea Chemical compound CN1CC(O)C2=CC(N=NC(N)=O)=C(O)C=C12 SSCSSDNTQJGTJT-UHFFFAOYSA-N 0.000 description 1
- XDBHWPLGGBLUHH-UHFFFAOYSA-N (3-cyanophenyl)boronic acid Chemical compound OB(O)C1=CC=CC(C#N)=C1 XDBHWPLGGBLUHH-UHFFFAOYSA-N 0.000 description 1
- BWYWXDFYJSIUBE-UHFFFAOYSA-N (3-fluoro-4-phenylphenyl)boronic acid Chemical compound FC1=CC(B(O)O)=CC=C1C1=CC=CC=C1 BWYWXDFYJSIUBE-UHFFFAOYSA-N 0.000 description 1
- HJBGZJMKTOMQRR-UHFFFAOYSA-N (3-formylphenyl)boronic acid Chemical compound OB(O)C1=CC=CC(C=O)=C1 HJBGZJMKTOMQRR-UHFFFAOYSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 1
- JEMVIRAQUIJOCL-XURVNGJNSA-N (3r,4ar,12bs)-4a,8,12b-trihydroxy-9-[(2r,4r,5s,6r)-4-hydroxy-6-methyl-5-[(2s,5s,6s)-6-methyl-5-[(2r,6s)-6-methyl-5-oxooxan-2-yl]oxyoxan-2-yl]oxyoxan-2-yl]-3-methyl-3-[(2s,5s,6s)-6-methyl-5-[(2r,6s)-6-methyl-5-oxooxan-2-yl]oxyoxan-2-yl]oxy-2,4-dihydrobenzo Chemical compound O([C@H]1CC[C@@H](O[C@H]1C)O[C@H]1[C@@H](C[C@@H](O[C@@H]1C)C=1C(=C2C(=O)C3=C([C@]4(C(=O)C[C@@](C)(C[C@@]4(O)C=C3)O[C@@H]3O[C@@H](C)[C@@H](O[C@@H]4O[C@@H](C)C(=O)CC4)CC3)O)C(=O)C2=CC=1)O)O)[C@H]1CCC(=O)[C@H](C)O1 JEMVIRAQUIJOCL-XURVNGJNSA-N 0.000 description 1
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 1
- IEFNEZUQHDYNRM-UHFFFAOYSA-L (4-azanidyl-2-methylbutyl)azanide;cyclobutane-1,1-dicarboxylate;platinum(4+) Chemical compound [Pt+4].[NH-]CC(C)CC[NH-].[O-]C(=O)C1(C([O-])=O)CCC1 IEFNEZUQHDYNRM-UHFFFAOYSA-L 0.000 description 1
- VOAAEKKFGLPLLU-UHFFFAOYSA-N (4-methoxyphenyl)boronic acid Chemical compound COC1=CC=C(B(O)O)C=C1 VOAAEKKFGLPLLU-UHFFFAOYSA-N 0.000 description 1
- HMHWNJGOHUYVMD-UHFFFAOYSA-N (4-methylanilino)azanium;chloride Chemical compound Cl.CC1=CC=C(NN)C=C1 HMHWNJGOHUYVMD-UHFFFAOYSA-N 0.000 description 1
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 1
- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 description 1
- JFCLNCVCDFUJPO-UHFFFAOYSA-N (5-chlorothiophen-2-yl)boronic acid Chemical compound OB(O)C1=CC=C(Cl)S1 JFCLNCVCDFUJPO-UHFFFAOYSA-N 0.000 description 1
- ICYICMXERRTCPY-UHFFFAOYSA-N (6-carbamimidoylnaphthalen-2-yl) 4-(4,5-dihydro-1h-imidazol-2-ylamino)benzoate;methanesulfonic acid Chemical compound CS(O)(=O)=O.CS(O)(=O)=O.C1=CC2=CC(C(=N)N)=CC=C2C=C1OC(=O)C(C=C1)=CC=C1NC1=NCCN1 ICYICMXERRTCPY-UHFFFAOYSA-N 0.000 description 1
- LKBBOPGQDRPCDS-YAOXHJNESA-N (7s,9r,10r)-7-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-9-ethyl-4,6,9,10,11-pentahydroxy-8,10-dihydro-7h-tetracene-5,12-dione Chemical compound O([C@H]1C[C@]([C@@H](C2=C(O)C=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)O)(O)CC)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 LKBBOPGQDRPCDS-YAOXHJNESA-N 0.000 description 1
- JXVAMODRWBNUSF-KZQKBALLSA-N (7s,9r,10r)-7-[(2r,4s,5s,6s)-5-[[(2s,4as,5as,7s,9s,9ar,10ar)-2,9-dimethyl-3-oxo-4,4a,5a,6,7,9,9a,10a-octahydrodipyrano[4,2-a:4',3'-e][1,4]dioxin-7-yl]oxy]-4-(dimethylamino)-6-methyloxan-2-yl]oxy-10-[(2s,4s,5s,6s)-4-(dimethylamino)-5-hydroxy-6-methyloxan-2 Chemical compound O([C@@H]1C2=C(O)C=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C2[C@@H](O[C@@H]2O[C@@H](C)[C@@H](O[C@@H]3O[C@@H](C)[C@H]4O[C@@H]5O[C@@H](C)C(=O)C[C@@H]5O[C@H]4C3)[C@H](C2)N(C)C)C[C@]1(O)CC)[C@H]1C[C@H](N(C)C)[C@H](O)[C@H](C)O1 JXVAMODRWBNUSF-KZQKBALLSA-N 0.000 description 1
- BHMLHEQFWVQAJS-IITOGVPQSA-N (7s,9s)-9-acetyl-9-amino-7-[(2s,4s,5r)-4,5-dihydroxyoxan-2-yl]oxy-6,11-dihydroxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical compound Cl.O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC=C4C(=O)C=3C(O)=C21)(N)C(=O)C)[C@H]1C[C@H](O)[C@H](O)CO1 BHMLHEQFWVQAJS-IITOGVPQSA-N 0.000 description 1
- XZBDBOWXMULUPE-UHFFFAOYSA-N (8-ethylspiro[4,9-dihydro-3h-pyrano[3,4-b]indole-1,4'-cyclohexane]-1'-yl)methanol Chemical compound C1=2NC=3C(CC)=CC=CC=3C=2CCOC21CCC(CO)CC2 XZBDBOWXMULUPE-UHFFFAOYSA-N 0.000 description 1
- DIPVWSTVQDONTF-NUAZBEIESA-N (8E)-2-[(2S,3R,4R,5R,6S)-3,4-dihydroxy-6-methyl-5-(methylamino)oxan-2-yl]oxy-6-methoxy-8-propylidene-6,6a,7,9-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound CC\C=C1/CC2C(Nc3ccc(O[C@@H]4O[C@@H](C)[C@H](NC)[C@@H](O)[C@H]4O)cc3C(=O)N2C1)OC DIPVWSTVQDONTF-NUAZBEIESA-N 0.000 description 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- JEZZKSQFJNWDCY-NSIKDUERSA-N (8z)-2-[3,4-dihydroxy-4,6-dimethyl-5-(methylamino)oxan-2-yl]oxy-8-propylidene-7,9-dihydro-6ah-pyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound C1=C2C(=O)N3CC(=C/CC)\CC3C=NC2=CC=C1OC1OC(C)C(NC)C(C)(O)C1O JEZZKSQFJNWDCY-NSIKDUERSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- SYTBZMRGLBWNTM-SNVBAGLBSA-N (R)-flurbiprofen Chemical compound FC1=CC([C@H](C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-SNVBAGLBSA-N 0.000 description 1
- AJMWJDGKNKNYEW-WYMLVPIESA-N (e)-1-(2,5-dimethoxyphenyl)-3-[4-(dimethylamino)phenyl]-2-methylprop-2-en-1-one Chemical compound COC1=CC=C(OC)C(C(=O)C(\C)=C\C=2C=CC(=CC=2)N(C)C)=C1 AJMWJDGKNKNYEW-WYMLVPIESA-N 0.000 description 1
- OQMYRVPMCIOFHL-GCOHUWJYSA-N (e)-3-[(6r)-6-hydroxy-4-methoxy-11-oxo-5,6,6a,7-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-8-yl]-n,n-dimethylprop-2-enamide Chemical compound N1[C@H](O)C2CC(\C=C\C(=O)N(C)C)=CN2C(=O)C2=C1C(OC)=CC=C2 OQMYRVPMCIOFHL-GCOHUWJYSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- ZTXDHEQQZVFGPK-UHFFFAOYSA-N 1,2,4-tris(oxiran-2-ylmethyl)-1,2,4-triazolidine-3,5-dione Chemical compound C1OC1CN1C(=O)N(CC2OC2)C(=O)N1CC1CO1 ZTXDHEQQZVFGPK-UHFFFAOYSA-N 0.000 description 1
- DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 1
- QUKGLNCXGVWCJX-UHFFFAOYSA-N 1,3,4-thiadiazol-2-amine Chemical compound NC1=NN=CS1 QUKGLNCXGVWCJX-UHFFFAOYSA-N 0.000 description 1
- HJTAZXHBEBIQQX-UHFFFAOYSA-N 1,5-bis(chloromethyl)naphthalene Chemical compound C1=CC=C2C(CCl)=CC=CC2=C1CCl HJTAZXHBEBIQQX-UHFFFAOYSA-N 0.000 description 1
- OUPZKGBUJRBPGC-HLTSFMKQSA-N 1,5-bis[[(2r)-oxiran-2-yl]methyl]-3-[[(2s)-oxiran-2-yl]methyl]-1,3,5-triazinane-2,4,6-trione Chemical compound O=C1N(C[C@H]2OC2)C(=O)N(C[C@H]2OC2)C(=O)N1C[C@H]1CO1 OUPZKGBUJRBPGC-HLTSFMKQSA-N 0.000 description 1
- PGTYFDUOJOEBNJ-UHFFFAOYSA-N 1-(1-ethyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)ethanol Chemical compound N1C2=CC=CC=C2C2=C1C(CC)(C(C)O)OCC2 PGTYFDUOJOEBNJ-UHFFFAOYSA-N 0.000 description 1
- KHWIRCOLWPNBJP-UHFFFAOYSA-N 1-(2-chloroethyl)-3-(2,6-dioxopiperidin-3-yl)-1-nitrosourea Chemical compound ClCCN(N=O)C(=O)NC1CCC(=O)NC1=O KHWIRCOLWPNBJP-UHFFFAOYSA-N 0.000 description 1
- YJZJEQBSODVMTH-UHFFFAOYSA-N 1-(2-chloroethyl)-3-(2-hydroxyethyl)-1-nitrosourea Chemical compound OCCNC(=O)N(N=O)CCCl YJZJEQBSODVMTH-UHFFFAOYSA-N 0.000 description 1
- BQIFCAGMUAMYDV-DHBOJHSNSA-N 1-(2-chloroethyl)-3-[(2r,6s)-2,6-dihydroxycyclohexyl]-1-nitrosourea Chemical compound O[C@H]1CCC[C@@H](O)C1NC(=O)N(CCCl)N=O BQIFCAGMUAMYDV-DHBOJHSNSA-N 0.000 description 1
- RCLLNBVPCJDIPX-UHFFFAOYSA-N 1-(2-chloroethyl)-3-[2-(dimethylsulfamoyl)ethyl]-1-nitrosourea Chemical compound CN(C)S(=O)(=O)CCNC(=O)N(N=O)CCCl RCLLNBVPCJDIPX-UHFFFAOYSA-N 0.000 description 1
- JQJSFAJISYZPER-UHFFFAOYSA-N 1-(4-chlorophenyl)-3-(2,3-dihydro-1h-inden-5-ylsulfonyl)urea Chemical compound C1=CC(Cl)=CC=C1NC(=O)NS(=O)(=O)C1=CC=C(CCC2)C2=C1 JQJSFAJISYZPER-UHFFFAOYSA-N 0.000 description 1
- ICAYNKLSQSKOJZ-UHFFFAOYSA-N 1-(4-fluorophenyl)-4-[4-[(4-fluorophenyl)-hydroxymethyl]piperidin-1-yl]butan-1-one Chemical compound C=1C=C(F)C=CC=1C(O)C(CC1)CCN1CCCC(=O)C1=CC=C(F)C=C1 ICAYNKLSQSKOJZ-UHFFFAOYSA-N 0.000 description 1
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 description 1
- VSWUWZJXMRATTF-UHFFFAOYSA-N 1-propan-2-yl-1h-pyrrolizine Chemical compound C1=CC=C2C(C(C)C)C=CN21 VSWUWZJXMRATTF-UHFFFAOYSA-N 0.000 description 1
- AQBUFJBHZGRZRV-NCIKYIMWSA-N 10-[(2R,4S,5S,6S)-4-(dimethylamino)-5-hydroxy-4,6-dimethyloxan-2-yl]-11-hydroxy-5-methyl-2-[(2R,3S)-2-methyl-3-[(2R,3S)-3-methyloxiran-2-yl]oxiran-2-yl]naphtho[2,3-h]chromene-4,7,12-trione Chemical compound C[C@@H]1O[C@H]1[C@H]1[C@@](C=2OC3=C4C(=O)C5=C(O)C([C@@H]6O[C@@H](C)[C@@H](O)[C@](C)(C6)N(C)C)=CC=C5C(=O)C4=CC(C)=C3C(=O)C=2)(C)O1 AQBUFJBHZGRZRV-NCIKYIMWSA-N 0.000 description 1
- SCWWNJYIUMBQKK-UHFFFAOYSA-N 10-[4-(dimethylamino)-5,6-dihydroxy-4,6-dimethyloxan-2-yl]-8-[4-(dimethylamino)-5-hydroxy-6-methyloxan-2-yl]-2-[3-(3,3-dimethyloxiran-2-yl)-2-methyloxiran-2-yl]-11-hydroxy-5-methylnaphtho[2,3-h]chromene-4,7,12-trione Chemical compound C1C(N(C)C)C(O)C(C)OC1C1=CC(C2OC(C)(O)C(O)C(C)(C2)N(C)C)=C(O)C2=C1C(=O)C(C=C(C)C=1C(C=C(OC3=1)C1(C)C(O1)C1C(O1)(C)C)=O)=C3C2=O SCWWNJYIUMBQKK-UHFFFAOYSA-N 0.000 description 1
- USPFJPDEADLGIG-UHFFFAOYSA-N 1ld8 Chemical compound C1CN(C=2C3=CC(O4)=CC=C3C=CC=2)C(=O)C1NCC1=CN=CN1CC1=CC=C(C#N)C4=C1 USPFJPDEADLGIG-UHFFFAOYSA-N 0.000 description 1
- OOMDVERDMZLRFX-UHFFFAOYSA-N 2,2-bis(aminomethyl)propane-1,3-diol;cyclobutane-1,1-dicarboxylic acid;platinum Chemical compound [Pt].NCC(CN)(CO)CO.OC(=O)C1(C(O)=O)CCC1 OOMDVERDMZLRFX-UHFFFAOYSA-N 0.000 description 1
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 description 1
- HCSBTDBGTNZOAB-UHFFFAOYSA-N 2,3-dinitrobenzoic acid Chemical class OC(=O)C1=CC=CC([N+]([O-])=O)=C1[N+]([O-])=O HCSBTDBGTNZOAB-UHFFFAOYSA-N 0.000 description 1
- BOMZMNZEXMAQQW-UHFFFAOYSA-N 2,5,11-trimethyl-6h-pyrido[4,3-b]carbazol-2-ium-9-ol;acetate Chemical compound CC([O-])=O.C[N+]1=CC=C2C(C)=C(NC=3C4=CC(O)=CC=3)C4=C(C)C2=C1 BOMZMNZEXMAQQW-UHFFFAOYSA-N 0.000 description 1
- 150000003923 2,5-pyrrolediones Chemical class 0.000 description 1
- PNLPAMZWYGYHRH-UHFFFAOYSA-N 2-(1,8-diethyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)-n,n-dimethylacetamide Chemical compound C1COC(CC)(CC(=O)N(C)C)C2=C1C(C=CC=C1CC)=C1N2 PNLPAMZWYGYHRH-UHFFFAOYSA-N 0.000 description 1
- FVGKDAYQHVFRGK-UHFFFAOYSA-N 2-(1,8-diethyl-9-methyl-3,4-dihydropyrano[3,4-b]indol-1-yl)acetic acid Chemical compound C1COC(CC)(CC(O)=O)C2=C1C(C=CC=C1CC)=C1N2C FVGKDAYQHVFRGK-UHFFFAOYSA-N 0.000 description 1
- BRXMOWUEDPMTLL-UHFFFAOYSA-N 2-(1,8-diethyl-9-methyl-3,4-dihydropyrano[3,4-b]indol-1-yl)ethanol Chemical compound C1COC(CC)(CCO)C2=C1C(C=CC=C1CC)=C1N2C BRXMOWUEDPMTLL-UHFFFAOYSA-N 0.000 description 1
- FQMZXMVHHKXGTM-UHFFFAOYSA-N 2-(1-adamantyl)-n-[2-[2-(2-hydroxyethylamino)ethylamino]quinolin-5-yl]acetamide Chemical compound C1C(C2)CC(C3)CC2CC13CC(=O)NC1=CC=CC2=NC(NCCNCCO)=CC=C21 FQMZXMVHHKXGTM-UHFFFAOYSA-N 0.000 description 1
- OVKMSIKSGLLUIS-UHFFFAOYSA-N 2-(1-ethyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetic acid Chemical compound N1C2=CC=CC=C2C2=C1C(CC)(CC(O)=O)OCC2 OVKMSIKSGLLUIS-UHFFFAOYSA-N 0.000 description 1
- WXJRVSRAOZFFLP-UHFFFAOYSA-N 2-(1-ethyl-6,8-dimethyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetic acid Chemical compound N1C2=C(C)C=C(C)C=C2C2=C1C(CC)(CC(O)=O)OCC2 WXJRVSRAOZFFLP-UHFFFAOYSA-N 0.000 description 1
- WOPNRXULESXCCX-UHFFFAOYSA-N 2-(1-ethyl-6-fluoro-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)ethanol Chemical compound N1C2=CC=C(F)C=C2C2=C1C(CC)(CCO)OCC2 WOPNRXULESXCCX-UHFFFAOYSA-N 0.000 description 1
- UKVKUJDVXLUUHS-UHFFFAOYSA-N 2-(1-ethyl-6-methoxy-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetic acid Chemical compound N1C2=CC=C(OC)C=C2C2=C1C(CC)(CC(O)=O)OCC2 UKVKUJDVXLUUHS-UHFFFAOYSA-N 0.000 description 1
- LGTYIZPHGAPCGR-UHFFFAOYSA-N 2-(1-ethyl-6-methoxy-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)ethanol Chemical compound N1C2=CC=C(OC)C=C2C2=C1C(CC)(CCO)OCC2 LGTYIZPHGAPCGR-UHFFFAOYSA-N 0.000 description 1
- VIHUARUHJVCGEC-UHFFFAOYSA-N 2-(1-ethyl-6-methyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetic acid Chemical compound N1C2=CC=C(C)C=C2C2=C1C(CC)(CC(O)=O)OCC2 VIHUARUHJVCGEC-UHFFFAOYSA-N 0.000 description 1
- XCVVHOFGERLRDI-UHFFFAOYSA-N 2-(1-ethyl-7-fluoro-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetic acid Chemical compound N1C2=CC(F)=CC=C2C2=C1C(CC)(CC(O)=O)OCC2 XCVVHOFGERLRDI-UHFFFAOYSA-N 0.000 description 1
- XQOITAYLHDJYQM-UHFFFAOYSA-N 2-(1-ethyl-7-fluoro-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)ethanol Chemical compound N1C2=CC(F)=CC=C2C2=C1C(CC)(CCO)OCC2 XQOITAYLHDJYQM-UHFFFAOYSA-N 0.000 description 1
- BLHWGPKNBTYAHI-UHFFFAOYSA-N 2-(1-ethyl-8-fluoro-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)ethanol Chemical compound N1C2=C(F)C=CC=C2C2=C1C(CC)(CCO)OCC2 BLHWGPKNBTYAHI-UHFFFAOYSA-N 0.000 description 1
- JHGYMRJCQPQYJB-UHFFFAOYSA-N 2-(1-ethyl-8-propan-2-yl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetic acid Chemical compound N1C2=C(C(C)C)C=CC=C2C2=C1C(CC)(CC(O)=O)OCC2 JHGYMRJCQPQYJB-UHFFFAOYSA-N 0.000 description 1
- FBFNMTGUOBUGFQ-UHFFFAOYSA-M 2-(2,5-diphenyltetrazol-1-ium-1-yl)-4,5-dimethyl-1,3-thiazole;bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=C(C=2C=CC=CC=2)N=NN1C1=CC=CC=C1 FBFNMTGUOBUGFQ-UHFFFAOYSA-M 0.000 description 1
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 1
- LAINPTZBIXYTIZ-UHFFFAOYSA-N 2-(3-hydroxy-2,4,5,7-tetraiodo-6-oxo-9-xanthenyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C1=C2C=C(I)C(=O)C(I)=C2OC2=C(I)C(O)=C(I)C=C21 LAINPTZBIXYTIZ-UHFFFAOYSA-N 0.000 description 1
- UAAJRDHCJCQAGD-UHFFFAOYSA-N 2-(5-chloro-1-ethyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetic acid Chemical compound N1C2=CC=CC(Cl)=C2C2=C1C(CC)(CC(O)=O)OCC2 UAAJRDHCJCQAGD-UHFFFAOYSA-N 0.000 description 1
- MFMOMSTUYIODMD-UHFFFAOYSA-N 2-(6,8-dichloro-1-ethyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetic acid Chemical compound N1C2=C(Cl)C=C(Cl)C=C2C2=C1C(CC)(CC(O)=O)OCC2 MFMOMSTUYIODMD-UHFFFAOYSA-N 0.000 description 1
- GBPZNAIFXGXJDI-UHFFFAOYSA-N 2-(6,8-dichloro-1-ethyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)ethanol Chemical compound N1C2=C(Cl)C=C(Cl)C=C2C2=C1C(CC)(CCO)OCC2 GBPZNAIFXGXJDI-UHFFFAOYSA-N 0.000 description 1
- FEDANGZXMSYBKD-UHFFFAOYSA-N 2-(6-bromo-1,8-diethyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)ethanol Chemical compound C1COC(CC)(CCO)C2=C1C(C=C(Br)C=C1CC)=C1N2 FEDANGZXMSYBKD-UHFFFAOYSA-N 0.000 description 1
- HHXOKNXIEAREDS-UHFFFAOYSA-N 2-(6-chloro-1-ethyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetic acid Chemical compound N1C2=CC=C(Cl)C=C2C2=C1C(CC)(CC(O)=O)OCC2 HHXOKNXIEAREDS-UHFFFAOYSA-N 0.000 description 1
- KYBGGFYUIBNNFP-UHFFFAOYSA-N 2-(6-chloro-1-ethyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)ethanol Chemical compound N1C2=CC=C(Cl)C=C2C2=C1C(CC)(CCO)OCC2 KYBGGFYUIBNNFP-UHFFFAOYSA-N 0.000 description 1
- VSYNDXRESPIELJ-UHFFFAOYSA-N 2-(7-bromo-1,8-diethyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetic acid Chemical compound C1COC(CC)(CC(O)=O)C2=C1C(C=CC(Br)=C1CC)=C1N2 VSYNDXRESPIELJ-UHFFFAOYSA-N 0.000 description 1
- JQENGPMDJPMKNO-UHFFFAOYSA-N 2-(7-bromo-1,8-diethyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)ethanol Chemical compound C1COC(CC)(CCO)C2=C1C(C=CC(Br)=C1CC)=C1N2 JQENGPMDJPMKNO-UHFFFAOYSA-N 0.000 description 1
- DRKJEMJEVFDISC-UHFFFAOYSA-N 2-(7-bromo-1h-indol-3-yl)ethanol Chemical compound C1=CC=C2C(CCO)=CNC2=C1Br DRKJEMJEVFDISC-UHFFFAOYSA-N 0.000 description 1
- UNRUGUODWCQQNT-UHFFFAOYSA-N 2-(7-chloro-1-ethyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetic acid Chemical compound N1C2=CC(Cl)=CC=C2C2=C1C(CC)(CC(O)=O)OCC2 UNRUGUODWCQQNT-UHFFFAOYSA-N 0.000 description 1
- RQMRAOMVQNWHIJ-UHFFFAOYSA-N 2-(7-chloro-1-ethyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)ethanol Chemical compound N1C2=CC(Cl)=CC=C2C2=C1C(CC)(CCO)OCC2 RQMRAOMVQNWHIJ-UHFFFAOYSA-N 0.000 description 1
- UYXLBSLCMNIDTL-UHFFFAOYSA-N 2-(7-chloro-1h-indol-3-yl)ethanol Chemical compound C1=CC=C2C(CCO)=CNC2=C1Cl UYXLBSLCMNIDTL-UHFFFAOYSA-N 0.000 description 1
- KTAGFSNEQJNKGY-UHFFFAOYSA-N 2-(7-fluoro-1h-indol-3-yl)ethanol Chemical compound C1=CC=C2C(CCO)=CNC2=C1F KTAGFSNEQJNKGY-UHFFFAOYSA-N 0.000 description 1
- KGZBKPDQVCRMSP-UHFFFAOYSA-N 2-(7-methyl-1h-indol-3-yl)ethanol Chemical compound CC1=CC=CC2=C1NC=C2CCO KGZBKPDQVCRMSP-UHFFFAOYSA-N 0.000 description 1
- HCHUBIHXFFFRRA-UHFFFAOYSA-N 2-(7-propan-2-yl-1h-indol-3-yl)ethanol Chemical compound CC(C)C1=CC=CC2=C1NC=C2CCO HCHUBIHXFFFRRA-UHFFFAOYSA-N 0.000 description 1
- ZBPIBFCWQBOJLY-UHFFFAOYSA-N 2-(8-chloro-1-ethyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetic acid Chemical compound N1C2=C(Cl)C=CC=C2C2=C1C(CC)(CC(O)=O)OCC2 ZBPIBFCWQBOJLY-UHFFFAOYSA-N 0.000 description 1
- PRTVRVSEOMOFDT-UHFFFAOYSA-N 2-(8-dibenzofuran-3-yl-1-ethyl-6-propan-2-yl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)ethanol Chemical compound C1=C2OC3=CC=CC=C3C2=CC=C1C(C=C(C=C12)C(C)C)=C2NC2=C1CCOC2(CCO)CC PRTVRVSEOMOFDT-UHFFFAOYSA-N 0.000 description 1
- FCSFORLYLNCXPD-UHFFFAOYSA-N 2-(8-ethyl-1-methyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetic acid Chemical compound C1COC(C)(CC(O)=O)C2=C1C(C=CC=C1CC)=C1N2 FCSFORLYLNCXPD-UHFFFAOYSA-N 0.000 description 1
- VXULPWPILJAOHL-UHFFFAOYSA-N 2-(8-ethyl-1-methyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)ethanol Chemical compound C1COC(C)(CCO)C2=C1C(C=CC=C1CC)=C1N2 VXULPWPILJAOHL-UHFFFAOYSA-N 0.000 description 1
- WUMHHBCNIROCAW-UHFFFAOYSA-N 2-(8-ethyl-1-phenyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetic acid Chemical compound C1=2NC=3C(CC)=CC=CC=3C=2CCOC1(CC(O)=O)C1=CC=CC=C1 WUMHHBCNIROCAW-UHFFFAOYSA-N 0.000 description 1
- UHJDEENUGFNBHZ-UHFFFAOYSA-N 2-(8-ethyl-1-phenyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)ethanol Chemical compound C1=2NC=3C(CC)=CC=CC=3C=2CCOC1(CCO)C1=CC=CC=C1 UHJDEENUGFNBHZ-UHFFFAOYSA-N 0.000 description 1
- ZYYZBAXQYNUZCT-UHFFFAOYSA-N 2-(8-ethyl-1-propan-2-yl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetic acid Chemical compound C1COC(CC(O)=O)(C(C)C)C2=C1C(C=CC=C1CC)=C1N2 ZYYZBAXQYNUZCT-UHFFFAOYSA-N 0.000 description 1
- ABKJMNGZTJSZCN-UHFFFAOYSA-N 2-(8-ethyl-1-propan-2-yl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)ethanol Chemical compound C1COC(CCO)(C(C)C)C2=C1C(C=CC=C1CC)=C1N2 ABKJMNGZTJSZCN-UHFFFAOYSA-N 0.000 description 1
- YJAXAFPOOSEKDP-UHFFFAOYSA-N 2-(8-ethyl-1-propyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetic acid Chemical compound N1C2=C(CC)C=CC=C2C2=C1C(CCC)(CC(O)=O)OCC2 YJAXAFPOOSEKDP-UHFFFAOYSA-N 0.000 description 1
- OBPTVCHHEGBBBI-UHFFFAOYSA-N 2-(8-ethyl-1-propyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)ethanol Chemical compound N1C2=C(CC)C=CC=C2C2=C1C(CCC)(CCO)OCC2 OBPTVCHHEGBBBI-UHFFFAOYSA-N 0.000 description 1
- UIJCMVLBZUPLFX-UHFFFAOYSA-N 2-(9-benzyl-1,8-diethyl-3,4-dihydropyrano[3,4-b]indol-1-yl)acetic acid Chemical compound C1=2C(CC)=CC=CC=2C=2CCOC(CC)(CC(O)=O)C=2N1CC1=CC=CC=C1 UIJCMVLBZUPLFX-UHFFFAOYSA-N 0.000 description 1
- KZLMMBGYUCZNSZ-UHFFFAOYSA-N 2-(9-benzyl-1,8-diethyl-3,4-dihydropyrano[3,4-b]indol-1-yl)ethanol Chemical compound C1=2C(CC)=CC=CC=2C=2CCOC(CC)(CCO)C=2N1CC1=CC=CC=C1 KZLMMBGYUCZNSZ-UHFFFAOYSA-N 0.000 description 1
- VBLXCTYLWZJBKA-UHFFFAOYSA-N 2-(trifluoromethyl)aniline Chemical compound NC1=CC=CC=C1C(F)(F)F VBLXCTYLWZJBKA-UHFFFAOYSA-N 0.000 description 1
- ADODRSVGNHNKAT-UHFFFAOYSA-N 2-Chlorophenylhydrazine hydrochloride Chemical compound Cl.NNC1=CC=CC=C1Cl ADODRSVGNHNKAT-UHFFFAOYSA-N 0.000 description 1
- RESLLYWPDIZOAF-UHFFFAOYSA-N 2-[1-ethyl-8-(2-phenylethenyl)-6-propan-2-yl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl]ethanol Chemical compound OCCC1(CC)OCCC(C2=CC(=C3)C(C)C)=C1NC2=C3C=CC1=CC=CC=C1 RESLLYWPDIZOAF-UHFFFAOYSA-N 0.000 description 1
- UJOINXLZTVQLEQ-UHFFFAOYSA-N 2-[1-ethyl-8-(2-phenylethynyl)-6-propan-2-yl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl]ethanol Chemical compound OCCC1(CC)OCCC(C2=CC(=C3)C(C)C)=C1NC2=C3C#CC1=CC=CC=C1 UJOINXLZTVQLEQ-UHFFFAOYSA-N 0.000 description 1
- ZYZKJBWNDXDHNX-UHFFFAOYSA-N 2-[1-ethyl-8-(3-fluoro-4-phenylphenyl)-6-propan-2-yl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl]ethanol Chemical compound OCCC1(CC)OCCC(C2=CC(=C3)C(C)C)=C1NC2=C3C(C=C1F)=CC=C1C1=CC=CC=C1 ZYZKJBWNDXDHNX-UHFFFAOYSA-N 0.000 description 1
- XIBRNZOPAUUFBK-UHFFFAOYSA-N 2-[1-ethyl-8-(trifluoromethyl)-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl]ethanol Chemical compound N1C2=C(C(F)(F)F)C=CC=C2C2=C1C(CC)(CCO)OCC2 XIBRNZOPAUUFBK-UHFFFAOYSA-N 0.000 description 1
- XXVLKDRPHSFIIB-UHFFFAOYSA-N 2-[2-(dimethylamino)ethyl]-5-nitrobenzo[de]isoquinoline-1,3-dione Chemical compound [O-][N+](=O)C1=CC(C(N(CCN(C)C)C2=O)=O)=C3C2=CC=CC3=C1 XXVLKDRPHSFIIB-UHFFFAOYSA-N 0.000 description 1
- HGLRIYIVJRXBQM-UHFFFAOYSA-N 2-[2-[amino-[bis(2-chloroethyl)amino]phosphoryl]oxyethyl]-1,3-thiazinane-4-carboxylic acid Chemical compound ClCCN(CCCl)P(=O)(N)OCCC1NC(C(O)=O)CCS1 HGLRIYIVJRXBQM-UHFFFAOYSA-N 0.000 description 1
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 1
- JSPUCPNQXKTYRO-LWILDLIXSA-N 2-[[(1r,2s,4as,8as)-1,2,4a,5-tetramethyl-2,3,4,7,8,8a-hexahydronaphthalen-1-yl]methyl]benzene-1,4-diol Chemical compound C([C@@]1(C)[C@H]2[C@](C(=CCC2)C)(C)CC[C@@H]1C)C1=CC(O)=CC=C1O JSPUCPNQXKTYRO-LWILDLIXSA-N 0.000 description 1
- PBUUPFTVAPUWDE-UGZDLDLSSA-N 2-[[(2S,4S)-2-[bis(2-chloroethyl)amino]-2-oxo-1,3,2lambda5-oxazaphosphinan-4-yl]sulfanyl]ethanesulfonic acid Chemical compound OS(=O)(=O)CCS[C@H]1CCO[P@](=O)(N(CCCl)CCCl)N1 PBUUPFTVAPUWDE-UGZDLDLSSA-N 0.000 description 1
- RTQWWZBSTRGEAV-PKHIMPSTSA-N 2-[[(2s)-2-[bis(carboxymethyl)amino]-3-[4-(methylcarbamoylamino)phenyl]propyl]-[2-[bis(carboxymethyl)amino]propyl]amino]acetic acid Chemical compound CNC(=O)NC1=CC=C(C[C@@H](CN(CC(C)N(CC(O)=O)CC(O)=O)CC(O)=O)N(CC(O)=O)CC(O)=O)C=C1 RTQWWZBSTRGEAV-PKHIMPSTSA-N 0.000 description 1
- FMKGJQHNYMWDFJ-CVEARBPZSA-N 2-[[4-(2,2-difluoropropoxy)pyrimidin-5-yl]methylamino]-4-[[(1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl]amino]pyrimidine-5-carbonitrile Chemical compound FC(COC1=NC=NC=C1CNC1=NC=C(C(=N1)N[C@H]1CC([C@H](CC1)O)(C)C)C#N)(C)F FMKGJQHNYMWDFJ-CVEARBPZSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- AKSIYNOQZYMJED-UHFFFAOYSA-N 2-amino-4-(aminomethoxy)butanoic acid Chemical compound NCOCCC(N)C(O)=O AKSIYNOQZYMJED-UHFFFAOYSA-N 0.000 description 1
- LHNIUFUSFGYJEO-UHFFFAOYSA-N 2-amino-5-phenylsulfanyl-1h-indole-3-carbonitrile Chemical compound C1=C2C(C#N)=C(N)NC2=CC=C1SC1=CC=CC=C1 LHNIUFUSFGYJEO-UHFFFAOYSA-N 0.000 description 1
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- OCLZPNCLRLDXJC-NTSWFWBYSA-N 2-amino-9-[(2r,5s)-5-(hydroxymethyl)oxolan-2-yl]-3h-purin-6-one Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@H]1CC[C@@H](CO)O1 OCLZPNCLRLDXJC-NTSWFWBYSA-N 0.000 description 1
- NGULVTOQNLILMZ-UHFFFAOYSA-N 2-bromobenzene-1,4-diamine Chemical compound NC1=CC=C(N)C(Br)=C1 NGULVTOQNLILMZ-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- IKCLCGXPQILATA-UHFFFAOYSA-N 2-chlorobenzoic acid Chemical class OC(=O)C1=CC=CC=C1Cl IKCLCGXPQILATA-UHFFFAOYSA-N 0.000 description 1
- NADDOZUGAJXMGT-UHFFFAOYSA-Q 2-diphenylphosphaniumylethyl(diphenyl)phosphanium gold(1+) chloride Chemical compound Cl[Au].C(C[PH+](c1ccccc1)c1ccccc1)[PH+](c1ccccc1)c1ccccc1.C(C[PH+](c1ccccc1)c1ccccc1)[PH+](c1ccccc1)c1ccccc1 NADDOZUGAJXMGT-UHFFFAOYSA-Q 0.000 description 1
- HZLCGUXUOFWCCN-UHFFFAOYSA-N 2-hydroxynonadecane-1,2,3-tricarboxylic acid Chemical compound CCCCCCCCCCCCCCCCC(C(O)=O)C(O)(C(O)=O)CC(O)=O HZLCGUXUOFWCCN-UHFFFAOYSA-N 0.000 description 1
- LFOIDLOIBZFWDO-UHFFFAOYSA-N 2-methoxy-6-[6-methoxy-4-[(3-phenylmethoxyphenyl)methoxy]-1-benzofuran-2-yl]imidazo[2,1-b][1,3,4]thiadiazole Chemical compound N1=C2SC(OC)=NN2C=C1C(OC1=CC(OC)=C2)=CC1=C2OCC(C=1)=CC=CC=1OCC1=CC=CC=C1 LFOIDLOIBZFWDO-UHFFFAOYSA-N 0.000 description 1
- GJJVAFUKOBZPCB-UHFFFAOYSA-N 2-methyl-2-(4,8,12-trimethyltrideca-3,7,11-trienyl)-3,4-dihydrochromen-6-ol Chemical compound OC1=CC=C2OC(CCC=C(C)CCC=C(C)CCC=C(C)C)(C)CCC2=C1 GJJVAFUKOBZPCB-UHFFFAOYSA-N 0.000 description 1
- RBFPKTBMLPIPMA-UHFFFAOYSA-N 2-methyl-n-phenylacridin-1-amine Chemical compound CC1=CC=C2N=C3C=CC=CC3=CC2=C1NC1=CC=CC=C1 RBFPKTBMLPIPMA-UHFFFAOYSA-N 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- AWGBKZRMLNVLAF-UHFFFAOYSA-N 3,5-dibromo-n,2-dihydroxybenzamide Chemical compound ONC(=O)C1=CC(Br)=CC(Br)=C1O AWGBKZRMLNVLAF-UHFFFAOYSA-N 0.000 description 1
- UKVFKRGLLNSVNJ-UHFFFAOYSA-L 3,5-dichloro-4-[1,2-diamino-2-(2,6-dichloro-4-hydroxyphenyl)ethyl]phenol;platinum(2+);sulfate;dihydrate Chemical compound O.O.[Pt+2].[O-]S([O-])(=O)=O.ClC=1C=C(O)C=C(Cl)C=1C(N)C(N)C1=C(Cl)C=C(O)C=C1Cl UKVFKRGLLNSVNJ-UHFFFAOYSA-L 0.000 description 1
- HQLHJCFATKAUSO-UHFFFAOYSA-N 3,7-dihydroxytropolone Chemical compound OC1=CC=CC(=O)C(O)=C1O HQLHJCFATKAUSO-UHFFFAOYSA-N 0.000 description 1
- IOSAAWHGJUZBOG-UHFFFAOYSA-N 3-(6-amino-9h-purin-9-yl)nonan-2-ol Chemical compound N1=CN=C2N(C(C(C)O)CCCCCC)C=NC2=C1N IOSAAWHGJUZBOG-UHFFFAOYSA-N 0.000 description 1
- PWMYMKOUNYTVQN-UHFFFAOYSA-N 3-(8,8-diethyl-2-aza-8-germaspiro[4.5]decan-2-yl)-n,n-dimethylpropan-1-amine Chemical compound C1C[Ge](CC)(CC)CCC11CN(CCCN(C)C)CC1 PWMYMKOUNYTVQN-UHFFFAOYSA-N 0.000 description 1
- OHOZDJHIIQDBNB-UHFFFAOYSA-N 3-[1-ethyl-1-(2-hydroxyethyl)-6-propan-2-yl-4,9-dihydro-3h-pyrano[3,4-b]indol-8-yl]benzaldehyde Chemical compound OCCC1(CC)OCCC(C2=CC(=C3)C(C)C)=C1NC2=C3C1=CC=CC(C=O)=C1 OHOZDJHIIQDBNB-UHFFFAOYSA-N 0.000 description 1
- WPZPGAUFAMUFPI-UHFFFAOYSA-N 3-[1-ethyl-1-(2-hydroxyethyl)-6-propan-2-yl-4,9-dihydro-3h-pyrano[3,4-b]indol-8-yl]benzonitrile Chemical compound OCCC1(CC)OCCC(C2=CC(=C3)C(C)C)=C1NC2=C3C1=CC=CC(C#N)=C1 WPZPGAUFAMUFPI-UHFFFAOYSA-N 0.000 description 1
- IKECFJZOZSWJJB-UHFFFAOYSA-N 3-[1-ethyl-1-(2-hydroxyethyl)-8-propan-2-yl-4,9-dihydro-3h-pyrano[3,4-b]indol-6-yl]propan-1-ol Chemical compound N1C2=C(C(C)C)C=C(CCCO)C=C2C2=C1C(CC)(CCO)OCC2 IKECFJZOZSWJJB-UHFFFAOYSA-N 0.000 description 1
- BMUDPLZKKRQECS-UHFFFAOYSA-K 3-[18-(2-carboxyethyl)-8,13-bis(ethenyl)-3,7,12,17-tetramethylporphyrin-21,24-diid-2-yl]propanoic acid iron(3+) hydroxide Chemical compound [OH-].[Fe+3].[N-]1C2=C(C)C(CCC(O)=O)=C1C=C([N-]1)C(CCC(O)=O)=C(C)C1=CC(C(C)=C1C=C)=NC1=CC(C(C)=C1C=C)=NC1=C2 BMUDPLZKKRQECS-UHFFFAOYSA-K 0.000 description 1
- QNKJFXARIMSDBR-UHFFFAOYSA-N 3-[2-[bis(2-chloroethyl)amino]ethyl]-1,3-diazaspiro[4.5]decane-2,4-dione Chemical compound O=C1N(CCN(CCCl)CCCl)C(=O)NC11CCCCC1 QNKJFXARIMSDBR-UHFFFAOYSA-N 0.000 description 1
- RJCFTKZFLQWQQX-UHFFFAOYSA-N 3-[3-(methylamino)propylamino]propylsulfanylphosphonic acid Chemical compound CNCCCNCCCSP(O)(O)=O RJCFTKZFLQWQQX-UHFFFAOYSA-N 0.000 description 1
- WUIABRMSWOKTOF-OYALTWQYSA-N 3-[[2-[2-[2-[[(2s,3r)-2-[[(2s,3s,4r)-4-[[(2s,3r)-2-[[6-amino-2-[(1s)-3-amino-1-[[(2s)-2,3-diamino-3-oxopropyl]amino]-3-oxopropyl]-5-methylpyrimidine-4-carbonyl]amino]-3-[(2r,3s,4s,5s,6s)-3-[(2r,3s,4s,5r,6r)-4-carbamoyloxy-3,5-dihydroxy-6-(hydroxymethyl)ox Chemical compound OS([O-])(=O)=O.N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C WUIABRMSWOKTOF-OYALTWQYSA-N 0.000 description 1
- MIEMDQVNFRNROW-UHFFFAOYSA-N 3-[[5-[10-[4-(dimethylamino)-5-hydroxy-4,6-dimethyloxan-2-yl]-8-[4-(dimethylamino)-5-hydroxy-6-methyloxan-2-yl]-11-hydroxy-5-methyl-2-[2-methyl-3-(3-methyloxiran-2-yl)oxiran-2-yl]-4,7-dioxo-12h-naphtho[3,2-h]chromen-12-yl]-1-hydroxypyrrole-2-carbonyl]amin Chemical compound CC1OC1C1C(C=2OC3=C4C(C=5N(C(C(=O)NCCC(O)=O)=CC=5)O)C5=C(O)C(C6OC(C)C(O)C(C)(C6)N(C)C)=CC(=C5C(=O)C4=CC(C)=C3C(=O)C=2)C2OC(C)C(O)C(C2)N(C)C)(C)O1 MIEMDQVNFRNROW-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- PDQGEKGUTOTUNV-TZSSRYMLSA-N 4'-deoxy-4'-iododoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](I)[C@H](C)O1 PDQGEKGUTOTUNV-TZSSRYMLSA-N 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 1
- JARCFMKMOFFIGZ-UHFFFAOYSA-N 4,6-dioxo-n-phenyl-2-sulfanylidene-1,3-diazinane-5-carboxamide Chemical compound O=C1NC(=S)NC(=O)C1C(=O)NC1=CC=CC=C1 JARCFMKMOFFIGZ-UHFFFAOYSA-N 0.000 description 1
- AKJHMTWEGVYYSE-AIRMAKDCSA-N 4-HPR Chemical compound C=1C=C(O)C=CC=1NC(=O)/C=C(\C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C AKJHMTWEGVYYSE-AIRMAKDCSA-N 0.000 description 1
- WFWMIUSHSIJAKH-DBRKOABJSA-N 4-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1-oxido-1,2,4-triazin-1-ium-3-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N=[N+]([O-])C=C1 WFWMIUSHSIJAKH-DBRKOABJSA-N 0.000 description 1
- YIMDLWDNDGKDTJ-ABYLTEMBSA-N 4-[(2s,3s,4s)-3-hydroxy-2-methyl-6-[[(1s,3s)-3,5,12-trihydroxy-3-(2-hydroxyacetyl)-10-methoxy-6,11-dioxo-2,4-dihydro-1h-tetracen-1-yl]oxy]oxan-4-yl]morpholine-3-carbonitrile Chemical compound N1([C@H]2CC(O[C@@H](C)[C@H]2O)O[C@H]2C[C@@](O)(CC=3C(O)=C4C(=O)C=5C=CC=C(C=5C(=O)C4=C(O)C=32)OC)C(=O)CO)CCOCC1C#N YIMDLWDNDGKDTJ-ABYLTEMBSA-N 0.000 description 1
- PZEUAMSVHLMPBZ-UHFFFAOYSA-N 4-[[5-(carboxymethyl)-4-methyl-1,3-thiazol-2-yl]sulfanyl]butanoic acid Chemical compound CC=1N=C(SCCCC(O)=O)SC=1CC(O)=O PZEUAMSVHLMPBZ-UHFFFAOYSA-N 0.000 description 1
- QGMGHALXLXKCBD-UHFFFAOYSA-N 4-amino-n-(2-aminophenyl)benzamide Chemical compound C1=CC(N)=CC=C1C(=O)NC1=CC=CC=C1N QGMGHALXLXKCBD-UHFFFAOYSA-N 0.000 description 1
- SIAVMDKGVRXFAX-UHFFFAOYSA-N 4-carboxyphenylboronic acid Chemical compound OB(O)C1=CC=C(C(O)=O)C=C1 SIAVMDKGVRXFAX-UHFFFAOYSA-N 0.000 description 1
- SVLZRCRXNHITBY-UHFFFAOYSA-N 4-chloro-1h-indole Chemical compound ClC1=CC=CC2=C1C=CN2 SVLZRCRXNHITBY-UHFFFAOYSA-N 0.000 description 1
- ZWKIJOPJWWZLDI-UHFFFAOYSA-N 4-fluoro-1h-indole Chemical compound FC1=CC=CC2=C1C=CN2 ZWKIJOPJWWZLDI-UHFFFAOYSA-N 0.000 description 1
- RKGKZFMRYKCMEJ-UHFFFAOYSA-N 5,7-dichloro-1h-indole Chemical compound ClC1=CC(Cl)=C2NC=CC2=C1 RKGKZFMRYKCMEJ-UHFFFAOYSA-N 0.000 description 1
- AYGGQJHJRFZDFH-UHFFFAOYSA-N 5,7-dichloro-1h-indole-2,3-dione Chemical compound ClC1=CC(Cl)=CC2=C1NC(=O)C2=O AYGGQJHJRFZDFH-UHFFFAOYSA-N 0.000 description 1
- HFZSCCJTJGWTDZ-UHFFFAOYSA-N 5,7-dimethyl-1h-indole-2,3-dione Chemical compound CC1=CC(C)=CC2=C1NC(=O)C2=O HFZSCCJTJGWTDZ-UHFFFAOYSA-N 0.000 description 1
- NUFNKYNBZYIQDG-UHFFFAOYSA-N 5-[4-[benzyl(methyl)amino]-3-nitrophenyl]-6-ethylpyrimidine-2,4-diamine Chemical compound CCC1=NC(N)=NC(N)=C1C(C=C1[N+]([O-])=O)=CC=C1N(C)CC1=CC=CC=C1 NUFNKYNBZYIQDG-UHFFFAOYSA-N 0.000 description 1
- UPALIKSFLSVKIS-UHFFFAOYSA-N 5-amino-2-[2-(dimethylamino)ethyl]benzo[de]isoquinoline-1,3-dione Chemical compound NC1=CC(C(N(CCN(C)C)C2=O)=O)=C3C2=CC=CC3=C1 UPALIKSFLSVKIS-UHFFFAOYSA-N 0.000 description 1
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 description 1
- VXWVFZFZYXOBTA-UHFFFAOYSA-N 5-bromo-1h-indole Chemical compound BrC1=CC=C2NC=CC2=C1 VXWVFZFZYXOBTA-UHFFFAOYSA-N 0.000 description 1
- WFUBYVFLEJSKTL-UHFFFAOYSA-N 5-bromo-7-propan-2-yl-1h-indole-2,3-dione Chemical compound CC(C)C1=CC(Br)=CC2=C1NC(=O)C2=O WFUBYVFLEJSKTL-UHFFFAOYSA-N 0.000 description 1
- WCRCXCYDFCQTKU-UHFFFAOYSA-N 5-bromo-7-propan-2-yl-1h-indole-2,3-dione;7-propan-2-yl-1h-indole-2,3-dione Chemical compound CC(C)C1=CC=CC2=C1NC(=O)C2=O.CC(C)C1=CC(Br)=CC2=C1NC(=O)C2=O WCRCXCYDFCQTKU-UHFFFAOYSA-N 0.000 description 1
- ODFFPRGJZRXNHZ-UHFFFAOYSA-N 5-fluoroindole Chemical compound FC1=CC=C2NC=CC2=C1 ODFFPRGJZRXNHZ-UHFFFAOYSA-N 0.000 description 1
- ISBUYSPRIJRBKX-UHFFFAOYSA-N 5-methyl-2-(2-naphthalen-2-yloxyethyl)-4h-pyrazol-3-one Chemical compound O=C1CC(C)=NN1CCOC1=CC=C(C=CC=C2)C2=C1 ISBUYSPRIJRBKX-UHFFFAOYSA-N 0.000 description 1
- SCUPIRGJNHINID-UHFFFAOYSA-N 5-o-[2-[benzyl(methyl)amino]ethyl] 3-o-methyl 2,6-dimethyl-4-(2-propan-2-ylpyrazolo[1,5-a]pyridin-3-yl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CC(C)C1=NN2C=CC=CC2=C1C1C(C(=O)OC)=C(C)NC(C)=C1C(=O)OCCN(C)CC1=CC=CC=C1 SCUPIRGJNHINID-UHFFFAOYSA-N 0.000 description 1
- MMRCWWRFYLZGAE-ZBZRSYSASA-N 533u947v6q Chemical compound O([C@]12[C@H](OC(C)=O)[C@]3(CC)C=CCN4CC[C@@]5([C@H]34)[C@H]1N(C)C1=C5C=C(C(=C1)OC)[C@]1(C(=O)OC)C3=C(C4=CC=CC=C4N3)CCN3C[C@H](C1)C[C@@](C3)(O)CC)C(=O)N(CCCl)C2=O MMRCWWRFYLZGAE-ZBZRSYSASA-N 0.000 description 1
- VJXSSYDSOJBUAV-UHFFFAOYSA-N 6-(2,5-dimethoxy-benzyl)-5-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine Chemical compound COC1=CC=C(OC)C(CC=2C(=C3C(N)=NC(N)=NC3=NC=2)C)=C1 VJXSSYDSOJBUAV-UHFFFAOYSA-N 0.000 description 1
- YTYIMDRWPTUAHP-UHFFFAOYSA-N 6-Chloroindole Chemical compound ClC1=CC=C2C=CNC2=C1 YTYIMDRWPTUAHP-UHFFFAOYSA-N 0.000 description 1
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 1
- KXBCLNRMQPRVTP-UHFFFAOYSA-N 6-amino-1,5-dihydroimidazo[4,5-c]pyridin-4-one Chemical compound O=C1NC(N)=CC2=C1N=CN2 KXBCLNRMQPRVTP-UHFFFAOYSA-N 0.000 description 1
- MRFRLYAOBSTHHU-MVNLRXSJSA-N 6-amino-3-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,4-dihydro-1,3,5-triazin-2-one;hydrochloride Chemical compound Cl.C1NC(N)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 MRFRLYAOBSTHHU-MVNLRXSJSA-N 0.000 description 1
- YYFFEPUCAKVRJX-UHFFFAOYSA-N 6-fluoro-1h-indole Chemical compound FC1=CC=C2C=CNC2=C1 YYFFEPUCAKVRJX-UHFFFAOYSA-N 0.000 description 1
- MXLDJTXXAYVWDF-UHFFFAOYSA-N 7-(trifluoromethyl)-1h-indole-2,3-dione Chemical compound FC(F)(F)C1=CC=CC2=C1NC(=O)C2=O MXLDJTXXAYVWDF-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- PQMIPLRIRFVQJZ-QBYYVRQOSA-N 7-[2-[(2s,4s)-4-[(2r,3r,4r,5s,6s)-3-fluoro-4,5-dihydroxy-6-methyloxan-2-yl]oxy-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-3,4-dihydro-1h-tetracen-2-yl]-2-oxoethoxy]-7-oxoheptanoic acid Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)COC(=O)CCCCCC(O)=O)[C@@H]1O[C@@H](C)[C@@H](O)[C@@H](O)[C@H]1F PQMIPLRIRFVQJZ-QBYYVRQOSA-N 0.000 description 1
- XDWTWQBKYQZMSW-UHFFFAOYSA-N 7-bromo-5-propan-2-yl-1h-indole-2,3-dione Chemical compound BrC1=CC(C(C)C)=CC2=C1NC(=O)C2=O XDWTWQBKYQZMSW-UHFFFAOYSA-N 0.000 description 1
- CRIIVEDXIRIPQT-UHFFFAOYSA-N 7-piperidin-1-yl-5,10-dihydro-3h-imidazo[2,1-b]quinazolin-2-one;dihydrochloride Chemical compound Cl.Cl.C=1C=C2NC3=NC(=O)CN3CC2=CC=1N1CCCCC1 CRIIVEDXIRIPQT-UHFFFAOYSA-N 0.000 description 1
- GOJJWDOZNKBUSR-UHFFFAOYSA-N 7-sulfamoyloxyheptyl sulfamate Chemical compound NS(=O)(=O)OCCCCCCCOS(N)(=O)=O GOJJWDOZNKBUSR-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- SRIOCKJKFXAKHK-UHFFFAOYSA-N 8-amino-10h-isoindolo[1,2-b]quinazolin-12-one Chemical compound C1=CC=C2C3=NC4=CC=C(N)C=C4CN3C(=O)C2=C1 SRIOCKJKFXAKHK-UHFFFAOYSA-N 0.000 description 1
- XPQVKOAQOVKONY-UHFFFAOYSA-N 8-ethylspiro[4,9-dihydro-3h-pyrano[3,4-b]indole-1,4'-cyclohexane]-1'-carboxylic acid Chemical compound C1=2NC=3C(CC)=CC=CC=3C=2CCOC21CCC(C(O)=O)CC2 XPQVKOAQOVKONY-UHFFFAOYSA-N 0.000 description 1
- OWWBUEMWTMDEBK-UHFFFAOYSA-N 9-acetyl-7-[4-amino-5-[3-hydroxy-1-(3-hydroxy-5-oxohexan-2-yl)oxybutoxy]-6-methyloxan-2-yl]oxy-4,6,9,11-tetrahydroxy-8,10-dihydro-7h-tetracene-5,12-dione Chemical compound O1C(C)C(OC(OC(C)C(O)CC(C)=O)CC(O)C)C(N)CC1OC1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 OWWBUEMWTMDEBK-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 206010065040 AIDS dementia complex Diseases 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- PBZVIYIWLYRXNM-ZGRMKTROSA-N Acanthifolicin Chemical compound O([C@@]12[C@@H]3S[C@]3(C)C[C@H](O2)[C@H](C)/C=C/[C@H]2CC[C@@]3(CC[C@H]4O[C@@H](C([C@@H](O)[C@@H]4O3)=C)C(O)C[C@H](C)[C@@H]3[C@@H](CC[C@@]4(OCCCC4)O3)C)O2)[C@H](C[C@@](C)(O)C(O)=O)CC[C@H]1O PBZVIYIWLYRXNM-ZGRMKTROSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 239000004925 Acrylic resin Substances 0.000 description 1
- 229920000178 Acrylic resin Polymers 0.000 description 1
- 229930191984 Actinoplanone Natural products 0.000 description 1
- BGYNLOSBKBOJJD-IUCAKERBSA-N Aeroplysinin 1 Chemical class COC1=C(Br)[C@H](O)[C@](O)(CC#N)C=C1Br BGYNLOSBKBOJJD-IUCAKERBSA-N 0.000 description 1
- QMGUSPDJTPDFSF-UHFFFAOYSA-N Aldophosphamide Chemical class ClCCN(CCCl)P(=O)(N)OCCC=O QMGUSPDJTPDFSF-UHFFFAOYSA-N 0.000 description 1
- 208000035939 Alveolitis allergic Diseases 0.000 description 1
- 102100032187 Androgen receptor Human genes 0.000 description 1
- 108010029748 Angiostat Proteins 0.000 description 1
- AQBUFJBHZGRZRV-UHFFFAOYSA-N Ankinomycin Natural products CC1OC1C1C(C=2OC3=C4C(=O)C5=C(O)C(C6OC(C)C(O)C(C)(C6)N(C)C)=CC=C5C(=O)C4=CC(C)=C3C(=O)C=2)(C)O1 AQBUFJBHZGRZRV-UHFFFAOYSA-N 0.000 description 1
- TYGJUQYJMIOZLZ-VTYVZKAMSA-N Antibiotic BU 2867TA Natural products O=C(N[C@H]1C(=O)N[C@@H](C)/C=C\C(=O)NCC[C@@H](O)C1)[C@@H](NC(=O)/C=C/C=C\CCCCCCC)[C@@H](O)C TYGJUQYJMIOZLZ-VTYVZKAMSA-N 0.000 description 1
- OSEDIRANPWGFRX-BONVTDFDSA-N Antibiotic DOB 41 Natural products O([C@@H](C)c1c2nc3c(c(C(=O)O)ccc3)nc2ccc1)C(=O)[C@@H](OC)CO OSEDIRANPWGFRX-BONVTDFDSA-N 0.000 description 1
- 101100397240 Arabidopsis thaliana ISPD gene Proteins 0.000 description 1
- 241001553178 Arachis glabrata Species 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 102000015790 Asparaginase Human genes 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- 206010003645 Atopy Diseases 0.000 description 1
- 108090001008 Avidin Proteins 0.000 description 1
- DGAKHGXRMXWHBX-ONEGZZNKSA-N Azoxymethane Chemical compound C\N=[N+](/C)[O-] DGAKHGXRMXWHBX-ONEGZZNKSA-N 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 description 1
- GTHQOPUWLHFKFZ-NNUXYFOWSA-N Baccharin Natural products CC(O)C1OCC(O)C2(C)OC2C(=O)OCC34CCC5(C)OC5C3OC6CC(OC(=O)C=C/C=C/1)C4C6=O GTHQOPUWLHFKFZ-NNUXYFOWSA-N 0.000 description 1
- 208000008035 Back Pain Diseases 0.000 description 1
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 206010065687 Bone loss Diseases 0.000 description 1
- ZOXJGFHDIHLPTG-BJUDXGSMSA-N Boron-10 Chemical compound [10B] ZOXJGFHDIHLPTG-BJUDXGSMSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- DGGZCXUXASNDAC-QQNGCVSVSA-N C-1027 chromophore Chemical compound COc1cc2OC(=C)C(=O)Nc2c(c1)C(=O)O[C@H]3COC(=O)C[C@H](N)c4cc(O)c(O[C@@H]5C#C\C=C\3/C#CC6=CC=C[C@]56O[C@@H]7OC(C)(C)[C@H]([C@@H](O)[C@H]7O)N(C)C)c(Cl)c4 DGGZCXUXASNDAC-QQNGCVSVSA-N 0.000 description 1
- KCBAMQOKOLXLOX-BSZYMOERSA-N CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O Chemical compound CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O KCBAMQOKOLXLOX-BSZYMOERSA-N 0.000 description 1
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 1
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
- FVLVBPDQNARYJU-XAHDHGMMSA-N C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O Chemical compound C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O FVLVBPDQNARYJU-XAHDHGMMSA-N 0.000 description 1
- 102000000905 Cadherin Human genes 0.000 description 1
- 108050007957 Cadherin Proteins 0.000 description 1
- 101100496968 Caenorhabditis elegans ctc-1 gene Proteins 0.000 description 1
- 101100275473 Caenorhabditis elegans ctc-3 gene Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010058019 Cancer Pain Diseases 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- AOCCBINRVIKJHY-UHFFFAOYSA-N Carmofur Chemical compound CCCCCCNC(=O)N1C=C(F)C(=O)NC1=O AOCCBINRVIKJHY-UHFFFAOYSA-N 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- 102100028003 Catenin alpha-1 Human genes 0.000 description 1
- 101710106619 Catenin alpha-3 Proteins 0.000 description 1
- 102000016362 Catenins Human genes 0.000 description 1
- 108010067316 Catenins Proteins 0.000 description 1
- 241001227713 Chiron Species 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- RNZAEKUSZHXFMR-UHFFFAOYSA-N Cl.Cl.Cl.S1C2=CC(O)=CC=C2C2=NN(CCN(CC)CC)C3=C2C1=C(NCCN)C=C3 Chemical compound Cl.Cl.Cl.S1C2=CC(O)=CC=C2C2=NN(CCN(CC)CC)C3=C2C1=C(NCCN)C=C3 RNZAEKUSZHXFMR-UHFFFAOYSA-N 0.000 description 1
- ZDJRSUWWMAYYID-ZXHXBDCOSA-N Cl.N1([C@H]2C[C@@H](O[C@@H](C)[C@H]2O)O[C@H]2C[C@]([C@@H](C3=C(O)C=4C(=O)C5=CC=CC(O)=C5C(=O)C=4C(O)=C32)O)(O)CC)CCOCC1 Chemical compound Cl.N1([C@H]2C[C@@H](O[C@@H](C)[C@H]2O)O[C@H]2C[C@]([C@@H](C3=C(O)C=4C(=O)C5=CC=CC(O)=C5C(=O)C=4C(O)=C32)O)(O)CC)CCOCC1 ZDJRSUWWMAYYID-ZXHXBDCOSA-N 0.000 description 1
- 208000015943 Coeliac disease Diseases 0.000 description 1
- 208000027932 Collagen disease Diseases 0.000 description 1
- 241000272201 Columbiformes Species 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 229940127007 Compound 39 Drugs 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 206010055665 Corneal neovascularisation Diseases 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- YVGGHNCTFXOJCH-UHFFFAOYSA-N DDT Chemical compound C1=CC(Cl)=CC=C1C(C(Cl)(Cl)Cl)C1=CC=C(Cl)C=C1 YVGGHNCTFXOJCH-UHFFFAOYSA-N 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- 206010059352 Desmoid tumour Diseases 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
- GZDFHIJNHHMENY-UHFFFAOYSA-N Dimethyl dicarbonate Chemical compound COC(=O)OC(=O)OC GZDFHIJNHHMENY-UHFFFAOYSA-N 0.000 description 1
- MUVMZSPKUBTGDH-UHFFFAOYSA-N Ditrisarubicin B Natural products O1C2CC(=O)C(C)OC2OC(C(C)O2)C1CC2OC(C(C)O1)C(N(C)C)CC1OC1C2=C(O)C(C(=O)C3=CC=CC(O)=C3C3=O)=C3C(O)=C2C(OC2OC(C)C(OC3OC(C)C4OC5OC(C)C(=O)CC5OC4C3)C(C2)N(C)C)CC1(O)CC MUVMZSPKUBTGDH-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- MGQRRMONVLMKJL-UHFFFAOYSA-N Elsamicin A Natural products O1C(C)C(O)C(OC)C(N)C1OC1C(O)(C)C(O)C(C)OC1OC1=CC=CC2=C(O)C(C(O3)=O)=C4C5=C3C=CC(C)=C5C(=O)OC4=C12 MGQRRMONVLMKJL-UHFFFAOYSA-N 0.000 description 1
- 206010014824 Endotoxic shock Diseases 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- GKKZMYDNDDMXSE-UHFFFAOYSA-N Ethyl 3-oxo-3-phenylpropanoate Chemical compound CCOC(=O)CC(=O)C1=CC=CC=C1 GKKZMYDNDDMXSE-UHFFFAOYSA-N 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 102100027286 Fanconi anemia group C protein Human genes 0.000 description 1
- 208000027445 Farmer Lung Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 102000003974 Fibroblast growth factor 2 Human genes 0.000 description 1
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 208000012895 Gastric disease Diseases 0.000 description 1
- 208000034826 Genetic Predisposition to Disease Diseases 0.000 description 1
- 102100033299 Glia-derived nexin Human genes 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 206010018634 Gouty Arthritis Diseases 0.000 description 1
- JEMVIRAQUIJOCL-UHFFFAOYSA-N Grincamycin Natural products CC1OC(OC2C(CC(OC2C)C=2C(=C3C(=O)C4=C(C5(C(=O)CC(C)(CC5(O)C=C4)OC4OC(C)C(OC5OC(C)C(=O)CC5)CC4)O)C(=O)C3=CC=2)O)O)CCC1OC1CCC(=O)C(C)O1 JEMVIRAQUIJOCL-UHFFFAOYSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 description 1
- 101000725401 Homo sapiens Cytochrome c oxidase subunit 2 Proteins 0.000 description 1
- 101000605127 Homo sapiens Prostaglandin G/H synthase 2 Proteins 0.000 description 1
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 1
- 241000701806 Human papillomavirus Species 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 208000005016 Intestinal Neoplasms Diseases 0.000 description 1
- 208000004882 Intestinal Polyposis Diseases 0.000 description 1
- SHGAZHPCJJPHSC-NUEINMDLSA-N Isotretinoin Chemical compound OC(=O)C=C(C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-NUEINMDLSA-N 0.000 description 1
- 208000003456 Juvenile Arthritis Diseases 0.000 description 1
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 description 1
- 208000011200 Kawasaki disease Diseases 0.000 description 1
- 229930185217 Kesarirhodin Natural products 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- AEFLONBTGZFSGQ-VKHMYHEASA-N L-isoglutamine Chemical compound NC(=O)[C@@H](N)CCC(O)=O AEFLONBTGZFSGQ-VKHMYHEASA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 229910010084 LiAlH4 Inorganic materials 0.000 description 1
- 102000003820 Lipoxygenases Human genes 0.000 description 1
- 108090000128 Lipoxygenases Proteins 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- 208000008930 Low Back Pain Diseases 0.000 description 1
- 108060001084 Luciferase Proteins 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 235000019759 Maize starch Nutrition 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- DTXXSJZBSTYZKE-ZDQKKZTESA-N Maxacalcitol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](OCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C DTXXSJZBSTYZKE-ZDQKKZTESA-N 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 1
- BNQSTAOJRULKNX-UHFFFAOYSA-N N-(6-acetamidohexyl)acetamide Chemical compound CC(=O)NCCCCCCNC(C)=O BNQSTAOJRULKNX-UHFFFAOYSA-N 0.000 description 1
- QJMCKEPOKRERLN-UHFFFAOYSA-N N-3,4-tridhydroxybenzamide Chemical compound ONC(=O)C1=CC=C(O)C(O)=C1 QJMCKEPOKRERLN-UHFFFAOYSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- BLXXJMDCKKHMKV-UHFFFAOYSA-N Nabumetone Chemical compound C1=C(CCC(C)=O)C=CC2=CC(OC)=CC=C21 BLXXJMDCKKHMKV-UHFFFAOYSA-N 0.000 description 1
- WPMGFKKSCCXUAK-YFZUDYRPSA-N Nbeta-acetylstreptothricin D Chemical compound NCCC[C@H](N)CC(=O)NCCC[C@H](N)CC(=O)NCCC[C@H](NC(=O)C)CC(=O)N[C@@H]1[C@H](O)[C@@H](OC(N)=O)[C@@H](CO)O[C@H]1NC1=N[C@@H]2C(=O)NC[C@@H](O)[C@H]2N1 WPMGFKKSCCXUAK-YFZUDYRPSA-N 0.000 description 1
- 206010028836 Neck pain Diseases 0.000 description 1
- 229930190254 Neoenactin Natural products 0.000 description 1
- 208000008636 Neoplastic Processes Diseases 0.000 description 1
- 206010029164 Nephrotic syndrome Diseases 0.000 description 1
- 208000009905 Neurofibromatoses Diseases 0.000 description 1
- 102100026379 Neurofibromin Human genes 0.000 description 1
- 101100221647 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) cox-1 gene Proteins 0.000 description 1
- 101100168274 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) cox-3 gene Proteins 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- KYRVNWMVYQXFEU-UHFFFAOYSA-N Nocodazole Chemical class C1=C2NC(NC(=O)OC)=NC2=CC=C1C(=O)C1=CC=CS1 KYRVNWMVYQXFEU-UHFFFAOYSA-N 0.000 description 1
- ILUJQPXNXACGAN-UHFFFAOYSA-N O-methylsalicylic acid Chemical class COC1=CC=CC=C1C(O)=O ILUJQPXNXACGAN-UHFFFAOYSA-N 0.000 description 1
- 108010016076 Octreotide Proteins 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- LKBBOPGQDRPCDS-UHFFFAOYSA-N Oxaunomycin Natural products C12=C(O)C=3C(=O)C4=C(O)C=CC=C4C(=O)C=3C(O)=C2C(O)C(CC)(O)CC1OC1CC(N)C(O)C(C)O1 LKBBOPGQDRPCDS-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 101150014691 PPARA gene Proteins 0.000 description 1
- 101150062589 PTGS1 gene Proteins 0.000 description 1
- VREZDOWOLGNDPW-ALTGWBOUSA-N Pancratistatin Chemical compound C1=C2[C@H]3[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)[C@@H]3NC(=O)C2=C(O)C2=C1OCO2 VREZDOWOLGNDPW-ALTGWBOUSA-N 0.000 description 1
- VREZDOWOLGNDPW-MYVCAWNPSA-N Pancratistatin Natural products O=C1N[C@H]2[C@H](O)[C@H](O)[C@H](O)[C@H](O)[C@@H]2c2c1c(O)c1OCOc1c2 VREZDOWOLGNDPW-MYVCAWNPSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 108010057150 Peplomycin Proteins 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- IGVPBCZDHMIOJH-UHFFFAOYSA-N Phenyl butyrate Chemical class CCCC(=O)OC1=CC=CC=C1 IGVPBCZDHMIOJH-UHFFFAOYSA-N 0.000 description 1
- 229940124154 Phospholipase inhibitor Drugs 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)O[C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 description 1
- 229920002642 Polysorbate 65 Polymers 0.000 description 1
- 229930187104 Porothramycin Natural products 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- HFVNWDWLWUCIHC-GUPDPFMOSA-N Prednimustine Chemical compound O=C([C@@]1(O)CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)[C@@H](O)C[C@@]21C)COC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 HFVNWDWLWUCIHC-GUPDPFMOSA-N 0.000 description 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 1
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 102000052575 Proto-Oncogene Human genes 0.000 description 1
- 108700020978 Proto-Oncogene Proteins 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 108010010225 RA VII Proteins 0.000 description 1
- AHHFEZNOXOZZQA-ZEBDFXRSSA-N Ranimustine Chemical compound CO[C@H]1O[C@H](CNC(=O)N(CCCl)N=O)[C@@H](O)[C@H](O)[C@H]1O AHHFEZNOXOZZQA-ZEBDFXRSSA-N 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 208000007014 Retinitis pigmentosa Diseases 0.000 description 1
- 102000034527 Retinoid X Receptors Human genes 0.000 description 1
- 108010038912 Retinoid X Receptors Proteins 0.000 description 1
- OWPCHSCAPHNHAV-UHFFFAOYSA-N Rhizoxin Natural products C1C(O)C2(C)OC2C=CC(C)C(OC(=O)C2)CC2CC2OC2C(=O)OC1C(C)C(OC)C(C)=CC=CC(C)=CC1=COC(C)=N1 OWPCHSCAPHNHAV-UHFFFAOYSA-N 0.000 description 1
- JZVJCTVXALSTOA-UHFFFAOYSA-N Rubia akane RA-I Natural products C1=CC(OC)=CC=C1CC(N(C)C(=O)C(CO)NC(=O)C(C)NC(=O)C(N(C1=O)C)C2)C(=O)NC(C)C(=O)N(C)C1CC(C=C1)=CC=C1OC1=CC2=CC=C1O JZVJCTVXALSTOA-UHFFFAOYSA-N 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 108010005113 Serpin E2 Proteins 0.000 description 1
- JEZZKSQFJNWDCY-UHFFFAOYSA-N Sibanomicin Natural products C1=C2C(=O)N3CC(=CCC)CC3C=NC2=CC=C1OC1OC(C)C(NC)C(C)(O)C1O JEZZKSQFJNWDCY-UHFFFAOYSA-N 0.000 description 1
- 241000580858 Simian-Human immunodeficiency virus Species 0.000 description 1
- 241000710960 Sindbis virus Species 0.000 description 1
- 208000021386 Sjogren Syndrome Diseases 0.000 description 1
- OCOKWVBYZHBHLU-UHFFFAOYSA-N Sobuzoxane Chemical compound C1C(=O)N(COC(=O)OCC(C)C)C(=O)CN1CCN1CC(=O)N(COC(=O)OCC(C)C)C(=O)C1 OCOKWVBYZHBHLU-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 206010068771 Soft tissue neoplasm Diseases 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- OTABDKFPJQZJRD-UHFFFAOYSA-N Sorangicin A2 Natural products O1C2C=CC=CC=CC(=O)OC(C=C3)C(C(C)=CC(CCCCC(O)=O)C)OC3CC=CCCC=CC(O)C(O)C(O3)CC(O)C(C)C3CC=CC3C(C)C1CC2O3 OTABDKFPJQZJRD-UHFFFAOYSA-N 0.000 description 1
- 208000010040 Sprains and Strains Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical class OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 206010042496 Sunburn Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 108010048992 Transcription Factor 4 Proteins 0.000 description 1
- 102100023489 Transcription factor 4 Human genes 0.000 description 1
- GBOGMAARMMDZGR-UHFFFAOYSA-N UNPD149280 Natural products N1C(=O)C23OC(=O)C=CC(O)CCCC(C)CC=CC3C(O)C(=C)C(C)C2C1CC1=CC=CC=C1 GBOGMAARMMDZGR-UHFFFAOYSA-N 0.000 description 1
- 229910052770 Uranium Inorganic materials 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- JAVFSUSPBIUPLW-QEWGJZFKSA-N Withanolide Natural products O=C1[C@@H](C)[C@H](C)C[C@H]([C@@H](C)[C@@H]2[C@@]3(C)[C@H]([C@@H]4[C@@H]([C@]5(C)[C@@H](CC4)CCCC5)CC3)CC2)O1 JAVFSUSPBIUPLW-QEWGJZFKSA-N 0.000 description 1
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- ZMQRJWIYMXZORG-GZIFKOAOSA-N [(1e,3r,4r,6r,7z,9z,11e)-3,6,13-trihydroxy-3-methyl-1-[(2s)-6-oxo-2,3-dihydropyran-2-yl]trideca-1,7,9,11-tetraen-4-yl] dihydrogen phosphate Chemical compound OC/C=C/C=C\C=C/[C@H](O)C[C@@H](OP(O)(O)=O)[C@@](O)(C)\C=C\[C@@H]1CC=CC(=O)O1 ZMQRJWIYMXZORG-GZIFKOAOSA-N 0.000 description 1
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 1
- SPXSEZMVRJLHQG-XMMPIXPASA-N [(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound C(C1=CC=CC=C1)OC=1C=C(OCC2=CC=C(CN3[C@H](CCC3)CO)C=C2)C=CC=1 SPXSEZMVRJLHQG-XMMPIXPASA-N 0.000 description 1
- VUPBDWQPEOWRQP-RTUCOMKBSA-N [(2R,3S,4S,5R,6R)-2-[(2R,3S,4S,5S,6S)-2-[(1S,2S)-3-[[(2R,3S)-5-[[(2S,3R)-1-[[2-[4-[4-[[4-amino-6-[3-(4-aminobutylamino)propylamino]-6-oxohexyl]carbamoyl]-1,3-thiazol-2-yl]-1,3-thiazol-2-yl]-1-[(2S,3R,4R,5S,6S)-5-amino-3,4-dihydroxy-6-methyloxan-2-yl]oxy-2-hydroxyethyl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-3-hydroxy-5-oxopentan-2-yl]amino]-2-[[6-amino-2-[(1S)-3-amino-1-[[(2S)-2,3-diamino-3-oxopropyl]amino]-3-oxopropyl]-5-methylpyrimidine-4-carbonyl]amino]-1-(1H-imidazol-5-yl)-3-oxopropoxy]-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]oxy-3,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl] carbamate Chemical compound C[C@@H](O)[C@H](NC(=O)C[C@H](O)[C@@H](C)NC(=O)[C@@H](NC(=O)c1nc(nc(N)c1C)[C@H](CC(N)=O)NC[C@H](N)C(N)=O)[C@H](O[C@@H]1O[C@@H](CO)[C@@H](O)[C@H](O)[C@@H]1O[C@H]1O[C@H](CO)[C@@H](O)[C@H](OC(N)=O)[C@@H]1O)c1cnc[nH]1)C(=O)NC(O[C@@H]1O[C@@H](C)[C@@H](N)[C@@H](O)[C@H]1O)C(O)c1nc(cs1)-c1nc(cs1)C(=O)NCCCC(N)CC(=O)NCCCNCCCCN VUPBDWQPEOWRQP-RTUCOMKBSA-N 0.000 description 1
- LJBKHHZPVCABCX-ZYUZMQFOSA-N [(2r,3r,4r,5r)-2,5-dihydroxy-3,4-dimethoxy-6-methylsulfonyloxyhexyl] methanesulfonate Chemical compound CS(=O)(=O)OC[C@@H](O)[C@@H](OC)[C@H](OC)[C@H](O)COS(C)(=O)=O LJBKHHZPVCABCX-ZYUZMQFOSA-N 0.000 description 1
- DJUWKQJNJVMFIU-IHAUNJBESA-N [(2r,3r,4s,5r)-3,4,5-triacetyloxy-6-[bis(2-chloroethyl)amino]oxan-2-yl]methyl acetate Chemical compound CC(=O)OC[C@H]1OC(N(CCCl)CCCl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O DJUWKQJNJVMFIU-IHAUNJBESA-N 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- PSLUFJFHTBIXMW-WYEYVKMPSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-6-(2-pyridin-2-ylethylcarbamoyloxy)-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-5-yl] acetate Chemical compound O([C@@H]1[C@@H]([C@]2(O[C@](C)(CC(=O)[C@]2(O)[C@@]2(C)[C@@H](O)CCC(C)(C)[C@@H]21)C=C)C)OC(=O)C)C(=O)NCCC1=CC=CC=N1 PSLUFJFHTBIXMW-WYEYVKMPSA-N 0.000 description 1
- YJHYHDSHHWKEIS-CJUKMMNNSA-N [(4S,6S,7R,8S)-11-(2-hydroxyethoxy)-7-methoxy-12-methyl-10,13-dioxo-2,5-diazatetracyclo[7.4.0.02,7.04,6]trideca-1(9),11-dien-8-yl]methyl carbamate Chemical compound CO[C@]12[C@H]3N[C@H]3CN1C1=C([C@H]2COC(N)=O)C(=O)C(OCCO)=C(C)C1=O YJHYHDSHHWKEIS-CJUKMMNNSA-N 0.000 description 1
- VORIUEAZEKLUSJ-UHFFFAOYSA-M [(6-chlorobenzotriazol-1-yl)oxy-(dimethylamino)methylidene]-dimethylazanium;trifluoroborane;fluoride Chemical compound [F-].FB(F)F.C1=C(Cl)C=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 VORIUEAZEKLUSJ-UHFFFAOYSA-M 0.000 description 1
- IFJUINDAXYAPTO-UUBSBJJBSA-N [(8r,9s,13s,14s,17s)-17-[2-[4-[4-[bis(2-chloroethyl)amino]phenyl]butanoyloxy]acetyl]oxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-3-yl] benzoate Chemical compound C([C@@H]1[C@@H](C2=CC=3)CC[C@]4([C@H]1CC[C@@H]4OC(=O)COC(=O)CCCC=1C=CC(=CC=1)N(CCCl)CCCl)C)CC2=CC=3OC(=O)C1=CC=CC=C1 IFJUINDAXYAPTO-UUBSBJJBSA-N 0.000 description 1
- ZUIGQZNTMIGKHP-UHFFFAOYSA-N [1-methyl-5-(methylcarbamoyloxymethyl)-2-methylsulfanylimidazol-4-yl]methyl n-methylcarbamate;hydrochloride Chemical compound Cl.CNC(=O)OCC=1N=C(SC)N(C)C=1COC(=O)NC ZUIGQZNTMIGKHP-UHFFFAOYSA-N 0.000 description 1
- ODEDPKNSRBCSDO-UHFFFAOYSA-N [2-(hexadecylsulfanylmethyl)-3-methoxypropyl] 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCCSCC(COC)COP([O-])(=O)OCC[N+](C)(C)C ODEDPKNSRBCSDO-UHFFFAOYSA-N 0.000 description 1
- JNSBEPKGFVENFS-UHFFFAOYSA-N [2-(trifluoromethyl)phenyl]boronic acid Chemical compound OB(O)C1=CC=CC=C1C(F)(F)F JNSBEPKGFVENFS-UHFFFAOYSA-N 0.000 description 1
- UWDFWVLAHRQSKK-UHFFFAOYSA-N [3-(trifluoromethoxy)phenyl]boronic acid Chemical compound OB(O)C1=CC=CC(OC(F)(F)F)=C1 UWDFWVLAHRQSKK-UHFFFAOYSA-N 0.000 description 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- MHVFYGIQJNFWGQ-UHFFFAOYSA-N [[4,6-bis[hydroxymethyl(methyl)amino]-1,3,5-triazin-2-yl]-methylamino]methanol Chemical compound OCN(C)C1=NC(N(C)CO)=NC(N(C)CO)=N1 MHVFYGIQJNFWGQ-UHFFFAOYSA-N 0.000 description 1
- JURAJLFHWXNPHG-UHFFFAOYSA-N [acetyl(methylcarbamoyl)amino] n-methylcarbamate Chemical compound CNC(=O)ON(C(C)=O)C(=O)NC JURAJLFHWXNPHG-UHFFFAOYSA-N 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 210000003815 abdominal wall Anatomy 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Chemical group CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical group 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229960005339 acitretin Drugs 0.000 description 1
- USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 description 1
- 229960004176 aclarubicin Drugs 0.000 description 1
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 238000011374 additional therapy Methods 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- BYRVKDUQDLJUBX-JJCDCTGGSA-N adozelesin Chemical compound C1=CC=C2OC(C(=O)NC=3C=C4C=C(NC4=CC=3)C(=O)N3C[C@H]4C[C@]44C5=C(C(C=C43)=O)NC=C5C)=CC2=C1 BYRVKDUQDLJUBX-JJCDCTGGSA-N 0.000 description 1
- 229940040563 agaric acid Drugs 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- IAJILQKETJEXLJ-RSJOWCBRSA-N aldehydo-D-galacturonic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-RSJOWCBRSA-N 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 125000003302 alkenyloxy group Chemical group 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 125000004422 alkyl sulphonamide group Chemical group 0.000 description 1
- IHUNBGSDBOWDMA-AQFIFDHZSA-N all-trans-acitretin Chemical compound COC1=CC(C)=C(\C=C\C(\C)=C\C=C\C(\C)=C\C(O)=O)C(C)=C1C IHUNBGSDBOWDMA-AQFIFDHZSA-N 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- 229940061720 alpha hydroxy acid Drugs 0.000 description 1
- 150000001280 alpha hydroxy acids Chemical class 0.000 description 1
- 239000011795 alpha-carotene Substances 0.000 description 1
- ANVAOWXLWRTKGA-HLLMEWEMSA-N alpha-carotene Natural products C(=C\C=C\C=C(/C=C/C=C(\C=C\C=1C(C)(C)CCCC=1C)/C)\C)(\C=C\C=C(/C=C/[C@H]1C(C)=CCCC1(C)C)\C)/C ANVAOWXLWRTKGA-HLLMEWEMSA-N 0.000 description 1
- 235000003903 alpha-carotene Nutrition 0.000 description 1
- QVBOOBQEGOUUGN-RCBQFDQVSA-N alstonine Chemical compound C1=C[CH]C2=NC3=C(C[C@@H]4C(C(=O)OC)=CO[C@@H](C)[C@@H]4C4)[N+]4=CC=C3C2=C1 QVBOOBQEGOUUGN-RCBQFDQVSA-N 0.000 description 1
- WYTGDNHDOZPMIW-RCBQFDQVSA-N alstonine Natural products C1=CC2=C3C=CC=CC3=NC2=C2N1C[C@H]1[C@H](C)OC=C(C(=O)OC)[C@H]1C2 WYTGDNHDOZPMIW-RCBQFDQVSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229960000473 altretamine Drugs 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229960001097 amifostine Drugs 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229960004701 amonafide Drugs 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 229960001220 amsacrine Drugs 0.000 description 1
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 229950001003 anaxirone Drugs 0.000 description 1
- 108010080146 androgen receptors Proteins 0.000 description 1
- 230000002491 angiogenic effect Effects 0.000 description 1
- 238000002399 angioplasty Methods 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 230000001760 anti-analgesic effect Effects 0.000 description 1
- 230000001772 anti-angiogenic effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- XVPSPMLUMQEEIU-PWLJWKHCSA-N antibiotic fr 900482 Chemical compound C1[C@H]2N[C@H]2[C@@]2(O)[C@@H](COC(=O)N)C3=C(O)C=C(C=O)C=C3N1O2 XVPSPMLUMQEEIU-PWLJWKHCSA-N 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 108010005272 antineoplaston A2 Proteins 0.000 description 1
- 108010005286 antineoplaston A3 Proteins 0.000 description 1
- 108010005569 antineoplaston A5 Proteins 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- SGPJMFVJKNVPLI-CJXLBUIWSA-N aphig Chemical compound Cl.C1[C@@]23[C@@]4(C)CC[C@@H](O)[C@@](C)(CO)[C@@H]4CC[C@H]3C[C@H]1[C@](COC(=O)CN)(O)CC2 SGPJMFVJKNVPLI-CJXLBUIWSA-N 0.000 description 1
- 208000002399 aphthous stomatitis Diseases 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- GOLCXWYRSKYTSP-UHFFFAOYSA-N arsenic trioxide Inorganic materials O1[As]2O[As]1O2 GOLCXWYRSKYTSP-UHFFFAOYSA-N 0.000 description 1
- 229960002594 arsenic trioxide Drugs 0.000 description 1
- 125000001769 aryl amino group Chemical group 0.000 description 1
- 229960003272 asparaginase Drugs 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-M asparaginate Chemical compound [O-]C(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-M 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- TWHSQQYCDVSBRK-UHFFFAOYSA-N asulacrine Chemical compound C12=CC=CC(C)=C2N=C2C(C(=O)NC)=CC=CC2=C1NC1=CC=C(NS(C)(=O)=O)C=C1OC TWHSQQYCDVSBRK-UHFFFAOYSA-N 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- FQCKMBLVYCEXJB-MNSAWQCASA-L atorvastatin calcium Chemical compound [Ca+2].C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1.C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 FQCKMBLVYCEXJB-MNSAWQCASA-L 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- TXJPJZWNYUQWCP-UHFFFAOYSA-N avarol Natural products CC1CCC2(C)C(=CCCC2(C)C1(C)Cc3cc(O)ccc3O)C TXJPJZWNYUQWCP-UHFFFAOYSA-N 0.000 description 1
- 229940120638 avastin Drugs 0.000 description 1
- KLNFSAOEKUDMFA-UHFFFAOYSA-N azanide;2-hydroxyacetic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OCC(O)=O KLNFSAOEKUDMFA-UHFFFAOYSA-N 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- DGBITFNXKQHKLI-WXCPUVJDSA-N baccharin Chemical compound C([C@@]12[C@]3(C)[C@H]4C[C@H]1O[C@@H]1[C@@H]5O[C@]5(C)CC[C@@]13COC(=O)[C@H]1O[C@@]1(C)[C@@H](O)CO[C@H](\C=C\C=C/C(=O)O4)[C@H](O)C)O2 DGBITFNXKQHKLI-WXCPUVJDSA-N 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 229950006062 benzotript Drugs 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229920000249 biocompatible polymer Polymers 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 229950008548 bisantrene Drugs 0.000 description 1
- 108010014245 bisucaberin Proteins 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M bisulphate group Chemical group S([O-])(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 229960004395 bleomycin sulfate Drugs 0.000 description 1
- ZNDJOCJUBZZAMN-USYHLRJESA-N bmy-25067 Chemical compound C([C@@H]1N[C@@H]1[C@@]1([C@@H]2COC(N)=O)OC)N1C(C(C=1C)=O)=C2C(=O)C=1NCCSSC1=CC=C([N+]([O-])=O)C=C1 ZNDJOCJUBZZAMN-USYHLRJESA-N 0.000 description 1
- JSKFWUPVIZYJMR-UDOAKELVSA-N bmy-27557 Chemical compound O=C1N(CCN(CC)CC)C(=O)C(C2=C3[CH]C=CC(Cl)=C3NC2=C23)=C1C2=C1C=CC=C(Cl)[C]1N3[C@@H]1O[C@H](CO)[C@@H](OC)[C@H](O)[C@H]1O JSKFWUPVIZYJMR-UDOAKELVSA-N 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 125000005621 boronate group Chemical class 0.000 description 1
- PZOHOALJQOFNTB-UHFFFAOYSA-M brequinar sodium Chemical compound [Na+].N1=C2C=CC(F)=CC2=C(C([O-])=O)C(C)=C1C(C=C1)=CC=C1C1=CC=CC=C1F PZOHOALJQOFNTB-UHFFFAOYSA-M 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- MJQUEDHRCUIRLF-TVIXENOKSA-N bryostatin 1 Chemical compound C([C@@H]1CC(/[C@@H]([C@@](C(C)(C)/C=C/2)(O)O1)OC(=O)/C=C/C=C/CCC)=C\C(=O)OC)[C@H]([C@@H](C)O)OC(=O)C[C@H](O)C[C@@H](O1)C[C@H](OC(C)=O)C(C)(C)[C@]1(O)C[C@@H]1C\C(=C\C(=O)OC)C[C@H]\2O1 MJQUEDHRCUIRLF-TVIXENOKSA-N 0.000 description 1
- 229960005539 bryostatin 1 Drugs 0.000 description 1
- 229950002361 budotitane Drugs 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Chemical class 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 208000020670 canker sore Diseases 0.000 description 1
- 229950009338 caracemide Drugs 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229960004424 carbon dioxide Drugs 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000005800 cardiovascular problem Effects 0.000 description 1
- 229960003261 carmofur Drugs 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 208000025434 cerebellar degeneration Diseases 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- ORJRBJIJTSDUCG-UHFFFAOYSA-N cervinomycin a2 Chemical compound C1C2(C)OCCN2C(=O)C2=C(O)C3=C(C(=O)C4=C(OC=5C=C(C(=CC=5C4=O)OC)OC)C4=O)C4=CC=C3C=C21 ORJRBJIJTSDUCG-UHFFFAOYSA-N 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- JZVJCTVXALSTOA-XMPIZRASSA-N chembl1288988 Chemical compound C1=CC(OC)=CC=C1C[C@H](N(C)C(=O)[C@H](CO)NC(=O)[C@@H](C)NC(=O)[C@@H](N(C1=O)C)C2)C(=O)N[C@@H](C)C(=O)N(C)[C@H]1CC(C=C1)=CC=C1OC1=CC2=CC=C1O JZVJCTVXALSTOA-XMPIZRASSA-N 0.000 description 1
- QEWPVAOWLNMLRI-UHFFFAOYSA-N chembl203666 Chemical compound OCCNCCN1N=C2C3=C(O)C=CC(O)=C3C(=O)C3=C2C1=CC=C3NCCCN QEWPVAOWLNMLRI-UHFFFAOYSA-N 0.000 description 1
- XASBSYHEEHVCSJ-UHFFFAOYSA-N chembl24329 Chemical compound OCCNCCN1N=C2C3=C(O)C=CC(O)=C3C(=O)C3=C2C1=CC=C3NCCNC XASBSYHEEHVCSJ-UHFFFAOYSA-N 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 208000037893 chronic inflammatory disorder Diseases 0.000 description 1
- 201000010354 chronic purulent otitis media Diseases 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 229950005158 clanfenur Drugs 0.000 description 1
- 208000029664 classic familial adenomatous polyposis Diseases 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 238000009096 combination chemotherapy Methods 0.000 description 1
- 229940000425 combination drug Drugs 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940127204 compound 29 Drugs 0.000 description 1
- 229940125877 compound 31 Drugs 0.000 description 1
- 229940125878 compound 36 Drugs 0.000 description 1
- 229940125807 compound 37 Drugs 0.000 description 1
- 229940127573 compound 38 Drugs 0.000 description 1
- 229940126540 compound 41 Drugs 0.000 description 1
- 229940125936 compound 42 Drugs 0.000 description 1
- 229940125844 compound 46 Drugs 0.000 description 1
- 229940127113 compound 57 Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000004624 confocal microscopy Methods 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 201000000159 corneal neovascularization Diseases 0.000 description 1
- 210000003683 corneal stroma Anatomy 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- SBRXTSOCZITGQG-UHFFFAOYSA-N crisnatol Chemical compound C1=CC=C2C(CNC(CO)(CO)C)=CC3=C(C=CC=C4)C4=CC=C3C2=C1 SBRXTSOCZITGQG-UHFFFAOYSA-N 0.000 description 1
- 229950007258 crisnatol Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- BVQPGVHVDXIPJF-UHFFFAOYSA-L cyclohexane-1,2-diamine;hydron;2-[(2-phosphonatoacetyl)amino]butanedioate;platinum(2+) Chemical compound [H+].[H+].[Pt+2].NC1CCCCC1N.[O-]C(=O)CC(C([O-])=O)NC(=O)CP([O-])([O-])=O BVQPGVHVDXIPJF-UHFFFAOYSA-L 0.000 description 1
- 239000003260 cyclooxygenase 1 inhibitor Substances 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- GBOGMAARMMDZGR-TYHYBEHESA-N cytochalasin B Chemical compound C([C@H]1[C@@H]2[C@@H](C([C@@H](O)[C@@H]3/C=C/C[C@H](C)CCC[C@@H](O)/C=C/C(=O)O[C@@]23C(=O)N1)=C)C)C1=CC=CC=C1 GBOGMAARMMDZGR-TYHYBEHESA-N 0.000 description 1
- GBOGMAARMMDZGR-JREHFAHYSA-N cytochalasin B Natural products C[C@H]1CCC[C@@H](O)C=CC(=O)O[C@@]23[C@H](C=CC1)[C@H](O)C(=C)[C@@H](C)[C@@H]2[C@H](Cc4ccccc4)NC3=O GBOGMAARMMDZGR-JREHFAHYSA-N 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000006743 cytoplasmic accumulation Effects 0.000 description 1
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Natural products NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 125000005534 decanoate group Chemical class 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 201000006827 desmoid tumor Diseases 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- 229950010621 dezaguanine Drugs 0.000 description 1
- ZXHUJRZYLRVVNP-UHFFFAOYSA-N dibenzofuran-4-ylboronic acid Chemical compound C12=CC=CC=C2OC2=C1C=CC=C2B(O)O ZXHUJRZYLRVVNP-UHFFFAOYSA-N 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- 229940042935 dichlorodifluoromethane Drugs 0.000 description 1
- 229940087091 dichlorotetrafluoroethane Drugs 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 229950009278 dimesna Drugs 0.000 description 1
- 235000010300 dimethyl dicarbonate Nutrition 0.000 description 1
- FEDBYSNFQHOGCJ-UHFFFAOYSA-N dimethyl-[2-(7-oxobenzo[c]fluoren-5-yl)oxyethyl]azanium;chloride Chemical compound [Cl-].C12=CC=CC=C2C(OCC[NH+](C)C)=CC2=C1C1=CC=CC=C1C2=O FEDBYSNFQHOGCJ-UHFFFAOYSA-N 0.000 description 1
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 1
- 229960002986 dinoprostone Drugs 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- PFWDHRASWSUTIA-KAFJHEIMSA-L disodium;(2s)-5-amino-5-oxo-2-[(2-phenylacetyl)amino]pentanoate;2-phenylacetate Chemical compound [Na+].[Na+].[O-]C(=O)CC1=CC=CC=C1.NC(=O)CC[C@@H](C([O-])=O)NC(=O)CC1=CC=CC=C1 PFWDHRASWSUTIA-KAFJHEIMSA-L 0.000 description 1
- KQYGMURBTJPBPQ-UHFFFAOYSA-L disodium;2-(2-sulfonatoethyldisulfanyl)ethanesulfonate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)CCSSCCS([O-])(=O)=O KQYGMURBTJPBPQ-UHFFFAOYSA-L 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- OSEDIRANPWGFRX-UHFFFAOYSA-N dob-41 Chemical compound C1=CC=C2N=C3C(C(C)OC(=O)C(CO)OC)=CC=CC3=NC2=C1C(O)=O OSEDIRANPWGFRX-UHFFFAOYSA-N 0.000 description 1
- ZWAOHEXOSAUJHY-ZIYNGMLESA-N doxifluridine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZWAOHEXOSAUJHY-ZIYNGMLESA-N 0.000 description 1
- 229950005454 doxifluridine Drugs 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- FSIRXIHZBIXHKT-MHTVFEQDSA-N edatrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CC(CC)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FSIRXIHZBIXHKT-MHTVFEQDSA-N 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 229950000549 elliptinium acetate Drugs 0.000 description 1
- 229950003860 elmustine Drugs 0.000 description 1
- MGQRRMONVLMKJL-KWJIQSIXSA-N elsamitrucin Chemical compound O1[C@H](C)[C@H](O)[C@H](OC)[C@@H](N)[C@H]1O[C@@H]1[C@](O)(C)[C@@H](O)[C@@H](C)O[C@H]1OC1=CC=CC2=C(O)C(C(O3)=O)=C4C5=C3C=CC(C)=C5C(=O)OC4=C12 MGQRRMONVLMKJL-KWJIQSIXSA-N 0.000 description 1
- 230000013020 embryo development Effects 0.000 description 1
- 230000032692 embryo implantation Effects 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 230000002357 endometrial effect Effects 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940079360 enema for constipation Drugs 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 239000003822 epoxy resin Substances 0.000 description 1
- 229940082789 erbitux Drugs 0.000 description 1
- SIHZWGODIRRSRA-ONEGZZNKSA-N erbstatin Chemical compound OC1=CC=C(O)C(\C=C\NC=O)=C1 SIHZWGODIRRSRA-ONEGZZNKSA-N 0.000 description 1
- OFKDAAIKGIBASY-VFGNJEKYSA-N ergotamine Chemical compound C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@@](C(N21)=O)(C)NC(=O)[C@H]1CN([C@H]2C(C3=CC=CC4=NC=C([C]34)C2)=C1)C)C1=CC=CC=C1 OFKDAAIKGIBASY-VFGNJEKYSA-N 0.000 description 1
- 229960004943 ergotamine Drugs 0.000 description 1
- XCGSFFUVFURLIX-UHFFFAOYSA-N ergotaminine Natural products C1=C(C=2C=CC=C3NC=C(C=23)C2)C2N(C)CC1C(=O)NC(C(N12)=O)(C)OC1(O)C1CCCN1C(=O)C2CC1=CC=CC=C1 XCGSFFUVFURLIX-UHFFFAOYSA-N 0.000 description 1
- ITSGNOIFAJAQHJ-BMFNZSJVSA-N esorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)C[C@H](C)O1 ITSGNOIFAJAQHJ-BMFNZSJVSA-N 0.000 description 1
- 229950002017 esorubicin Drugs 0.000 description 1
- 229960001766 estramustine phosphate sodium Drugs 0.000 description 1
- IIUMCNJTGSMNRO-VVSKJQCTSA-L estramustine sodium phosphate Chemical compound [Na+].[Na+].ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)OP([O-])([O-])=O)[C@@H]4[C@@H]3CCC2=C1 IIUMCNJTGSMNRO-VVSKJQCTSA-L 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- HYSIJEPDMLSIQJ-UHFFFAOYSA-N ethanolate;1-phenylbutane-1,3-dione;titanium(4+) Chemical compound [Ti+4].CC[O-].CC[O-].CC(=O)[CH-]C(=O)C1=CC=CC=C1.CC(=O)[CH-]C(=O)C1=CC=CC=C1 HYSIJEPDMLSIQJ-UHFFFAOYSA-N 0.000 description 1
- GLFJQXMGTAJTGY-AVBZIYQWSA-N ethyl (2s,5s)-5-[[(2s)-2-amino-3-(4-fluorophenyl)propanoyl]amino]-6-[3-[bis(2-chloroethyl)amino]phenyl]-2-(2-methylsulfanylethyl)-4-oxohexanoate;hydrochloride Chemical compound Cl.C([C@@H](C(=O)C[C@@H](CCSC)C(=O)OCC)NC(=O)[C@@H](N)CC=1C=CC(F)=CC=1)C1=CC=CC(N(CCCl)CCCl)=C1 GLFJQXMGTAJTGY-AVBZIYQWSA-N 0.000 description 1
- SQUIXJAIFQQSHB-UHFFFAOYSA-N ethyl 2-(1-ethyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetate Chemical compound N1C2=CC=CC=C2C2=C1C(CC(=O)OCC)(CC)OCC2 SQUIXJAIFQQSHB-UHFFFAOYSA-N 0.000 description 1
- AIGMRLNXPMNHSZ-UHFFFAOYSA-N ethyl 2-(1-ethyl-5-fluoro-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetate Chemical compound N1C2=CC=CC(F)=C2C2=C1C(CC(=O)OCC)(CC)OCC2 AIGMRLNXPMNHSZ-UHFFFAOYSA-N 0.000 description 1
- UHWAONUPDRTLSV-UHFFFAOYSA-N ethyl 2-(1-ethyl-6,8-dimethyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetate Chemical compound N1C2=C(C)C=C(C)C=C2C2=C1C(CC(=O)OCC)(CC)OCC2 UHWAONUPDRTLSV-UHFFFAOYSA-N 0.000 description 1
- NVIXDFVLYYAYRN-UHFFFAOYSA-N ethyl 2-(1-ethyl-6-fluoro-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetate Chemical compound N1C2=CC=C(F)C=C2C2=C1C(CC(=O)OCC)(CC)OCC2 NVIXDFVLYYAYRN-UHFFFAOYSA-N 0.000 description 1
- KNXOLALNMXLRFV-UHFFFAOYSA-N ethyl 2-(1-ethyl-6-methoxy-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetate Chemical compound N1C2=CC=C(OC)C=C2C2=C1C(CC(=O)OCC)(CC)OCC2 KNXOLALNMXLRFV-UHFFFAOYSA-N 0.000 description 1
- VROCUWRLNKMADI-UHFFFAOYSA-N ethyl 2-(1-ethyl-6-methyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetate Chemical compound N1C2=CC=C(C)C=C2C2=C1C(CC(=O)OCC)(CC)OCC2 VROCUWRLNKMADI-UHFFFAOYSA-N 0.000 description 1
- RHBIUKUOIIMLSL-UHFFFAOYSA-N ethyl 2-(1-ethyl-7-fluoro-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetate Chemical compound N1C2=CC(F)=CC=C2C2=C1C(CC(=O)OCC)(CC)OCC2 RHBIUKUOIIMLSL-UHFFFAOYSA-N 0.000 description 1
- JIPGVDFYZDNDHJ-UHFFFAOYSA-N ethyl 2-(1-ethyl-8-fluoro-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetate Chemical compound N1C2=C(F)C=CC=C2C2=C1C(CC(=O)OCC)(CC)OCC2 JIPGVDFYZDNDHJ-UHFFFAOYSA-N 0.000 description 1
- JRXUULLTCHOGSP-UHFFFAOYSA-N ethyl 2-(1-ethyl-8-methyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetate Chemical compound N1C2=C(C)C=CC=C2C2=C1C(CC(=O)OCC)(CC)OCC2 JRXUULLTCHOGSP-UHFFFAOYSA-N 0.000 description 1
- RHPNPGRWVDOHFF-UHFFFAOYSA-N ethyl 2-(1-ethyl-8-propan-2-yl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetate Chemical compound N1C2=C(C(C)C)C=CC=C2C2=C1C(CC(=O)OCC)(CC)OCC2 RHPNPGRWVDOHFF-UHFFFAOYSA-N 0.000 description 1
- IEMGWBMVQLVHEY-UHFFFAOYSA-N ethyl 2-(3-amino-6,7-dihydro-5h-cyclopenta[b]pyridin-7-yl)acetate Chemical compound NC1=CN=C2C(CC(=O)OCC)CCC2=C1 IEMGWBMVQLVHEY-UHFFFAOYSA-N 0.000 description 1
- OATQPIQQPUDTJF-UHFFFAOYSA-N ethyl 2-(4-chloro-1h-indol-3-yl)-2-oxoacetate Chemical compound C1=CC(Cl)=C2C(C(=O)C(=O)OCC)=CNC2=C1 OATQPIQQPUDTJF-UHFFFAOYSA-N 0.000 description 1
- BYSGINJAXNGBJE-UHFFFAOYSA-N ethyl 2-(4-fluoro-1h-indol-3-yl)-2-oxoacetate Chemical compound C1=CC(F)=C2C(C(=O)C(=O)OCC)=CNC2=C1 BYSGINJAXNGBJE-UHFFFAOYSA-N 0.000 description 1
- WJBYYUCEOVCMSE-UHFFFAOYSA-N ethyl 2-(5,7-dichloro-1h-indol-3-yl)-2-oxoacetate Chemical compound C1=C(Cl)C=C2C(C(=O)C(=O)OCC)=CNC2=C1Cl WJBYYUCEOVCMSE-UHFFFAOYSA-N 0.000 description 1
- RWRJTBKTEPHCJU-UHFFFAOYSA-N ethyl 2-(5,7-dimethyl-1h-indol-3-yl)-2-oxoacetate Chemical compound C1=C(C)C=C2C(C(=O)C(=O)OCC)=CNC2=C1C RWRJTBKTEPHCJU-UHFFFAOYSA-N 0.000 description 1
- BUQBKBPIDKCCOZ-UHFFFAOYSA-N ethyl 2-(5-bromo-1h-indol-3-yl)-2-oxoacetate Chemical compound C1=C(Br)C=C2C(C(=O)C(=O)OCC)=CNC2=C1 BUQBKBPIDKCCOZ-UHFFFAOYSA-N 0.000 description 1
- DSYYRDSGCRUZPI-UHFFFAOYSA-N ethyl 2-(5-bromo-7-propan-2-yl-1h-indol-3-yl)-2-oxoacetate Chemical compound C1=C(Br)C=C2C(C(=O)C(=O)OCC)=CNC2=C1C(C)C DSYYRDSGCRUZPI-UHFFFAOYSA-N 0.000 description 1
- HRLNWTUFMQGNIS-UHFFFAOYSA-N ethyl 2-(5-chloro-1-ethyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetate Chemical compound N1C2=CC=CC(Cl)=C2C2=C1C(CC(=O)OCC)(CC)OCC2 HRLNWTUFMQGNIS-UHFFFAOYSA-N 0.000 description 1
- WXWCGWHURZEBEH-UHFFFAOYSA-N ethyl 2-(5-chloro-1h-indol-3-yl)-2-oxoacetate Chemical compound C1=C(Cl)C=C2C(C(=O)C(=O)OCC)=CNC2=C1 WXWCGWHURZEBEH-UHFFFAOYSA-N 0.000 description 1
- JLGFKONPMDVGBH-UHFFFAOYSA-N ethyl 2-(5-fluoro-1h-indol-3-yl)-2-oxoacetate Chemical compound C1=C(F)C=C2C(C(=O)C(=O)OCC)=CNC2=C1 JLGFKONPMDVGBH-UHFFFAOYSA-N 0.000 description 1
- WLUMFWLJYKUVEG-UHFFFAOYSA-N ethyl 2-(6,8-dichloro-1-ethyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetate Chemical compound N1C2=C(Cl)C=C(Cl)C=C2C2=C1C(CC(=O)OCC)(CC)OCC2 WLUMFWLJYKUVEG-UHFFFAOYSA-N 0.000 description 1
- ITOMJZLZTIVHQP-UHFFFAOYSA-N ethyl 2-(6-bromo-1-ethyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetate Chemical compound N1C2=CC=C(Br)C=C2C2=C1C(CC(=O)OCC)(CC)OCC2 ITOMJZLZTIVHQP-UHFFFAOYSA-N 0.000 description 1
- LMRSXZMPMYMAPX-UHFFFAOYSA-N ethyl 2-(6-bromo-1-ethyl-8-propan-2-yl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetate Chemical compound N1C2=C(C(C)C)C=C(Br)C=C2C2=C1C(CC(=O)OCC)(CC)OCC2 LMRSXZMPMYMAPX-UHFFFAOYSA-N 0.000 description 1
- LRDVIHFOCWVOHL-UHFFFAOYSA-N ethyl 2-(6-chloro-1-ethyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetate Chemical compound N1C2=CC=C(Cl)C=C2C2=C1C(CC(=O)OCC)(CC)OCC2 LRDVIHFOCWVOHL-UHFFFAOYSA-N 0.000 description 1
- HEGORNPQWKDURQ-UHFFFAOYSA-N ethyl 2-(6-chloro-1h-indol-3-yl)-2-oxoacetate Chemical compound ClC1=CC=C2C(C(=O)C(=O)OCC)=CNC2=C1 HEGORNPQWKDURQ-UHFFFAOYSA-N 0.000 description 1
- BVGFMLFFJGZOBL-UHFFFAOYSA-N ethyl 2-(6-fluoro-1h-indol-3-yl)-2-oxoacetate Chemical compound FC1=CC=C2C(C(=O)C(=O)OCC)=CNC2=C1 BVGFMLFFJGZOBL-UHFFFAOYSA-N 0.000 description 1
- MRCPJVWNIGSOOH-UHFFFAOYSA-N ethyl 2-(7-bromo-1,8-diethyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetate Chemical compound N1C2=C(CC)C(Br)=CC=C2C2=C1C(CC(=O)OCC)(CC)OCC2 MRCPJVWNIGSOOH-UHFFFAOYSA-N 0.000 description 1
- WRJJAKMQXKPBMJ-UHFFFAOYSA-N ethyl 2-(7-bromo-5-propan-2-yl-1h-indol-3-yl)-2-oxoacetate Chemical compound C1=C(C(C)C)C=C2C(C(=O)C(=O)OCC)=CNC2=C1Br WRJJAKMQXKPBMJ-UHFFFAOYSA-N 0.000 description 1
- RMODZSMYHSPWKE-UHFFFAOYSA-N ethyl 2-(7-chloro-1-ethyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetate Chemical compound N1C2=CC(Cl)=CC=C2C2=C1C(CC(=O)OCC)(CC)OCC2 RMODZSMYHSPWKE-UHFFFAOYSA-N 0.000 description 1
- WODLLVMVMYBIFC-UHFFFAOYSA-N ethyl 2-(8-bromo-1-ethyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetate Chemical compound N1C2=C(Br)C=CC=C2C2=C1C(CC(=O)OCC)(CC)OCC2 WODLLVMVMYBIFC-UHFFFAOYSA-N 0.000 description 1
- CSDTYFLKAPFTLV-UHFFFAOYSA-N ethyl 2-(8-bromo-1-ethyl-6-propan-2-yl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetate Chemical compound N1C2=C(Br)C=C(C(C)C)C=C2C2=C1C(CC(=O)OCC)(CC)OCC2 CSDTYFLKAPFTLV-UHFFFAOYSA-N 0.000 description 1
- DNXAFKDWSKEXPP-UHFFFAOYSA-N ethyl 2-(8-chloro-1-ethyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetate Chemical compound N1C2=C(Cl)C=CC=C2C2=C1C(CC(=O)OCC)(CC)OCC2 DNXAFKDWSKEXPP-UHFFFAOYSA-N 0.000 description 1
- WGWGEDYHXBSDDH-UHFFFAOYSA-N ethyl 2-(8-ethyl-1-methyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetate Chemical compound N1C2=C(CC)C=CC=C2C2=C1C(CC(=O)OCC)(C)OCC2 WGWGEDYHXBSDDH-UHFFFAOYSA-N 0.000 description 1
- REGGSHHYQYKNCI-UHFFFAOYSA-N ethyl 2-(8-ethyl-1-phenyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetate Chemical compound O1CCC(C2=CC=CC(CC)=C2N2)=C2C1(CC(=O)OCC)C1=CC=CC=C1 REGGSHHYQYKNCI-UHFFFAOYSA-N 0.000 description 1
- LXBZOHQMBNUAQF-UHFFFAOYSA-N ethyl 2-(8-ethyl-1-propan-2-yl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetate Chemical compound N1C2=C(CC)C=CC=C2C2=C1C(CC(=O)OCC)(C(C)C)OCC2 LXBZOHQMBNUAQF-UHFFFAOYSA-N 0.000 description 1
- VQFYKHFMNFSWNP-UHFFFAOYSA-N ethyl 2-(8-ethyl-1-propyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetate Chemical compound N1C2=C(CC)C=CC=C2C2=C1C(CCC)(CC(=O)OCC)OCC2 VQFYKHFMNFSWNP-UHFFFAOYSA-N 0.000 description 1
- XZRQSUFBRCXRIA-UHFFFAOYSA-N ethyl 2-[1-ethyl-8-(trifluoromethyl)-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl]acetate Chemical compound N1C2=C(C(F)(F)F)C=CC=C2C2=C1C(CC(=O)OCC)(CC)OCC2 XZRQSUFBRCXRIA-UHFFFAOYSA-N 0.000 description 1
- WHVWZFDDKZVNBJ-UHFFFAOYSA-N ethyl 2-oxo-2-(7-propan-2-yl-1h-indol-3-yl)acetate Chemical compound C1=CC=C2C(C(=O)C(=O)OCC)=CNC2=C1C(C)C WHVWZFDDKZVNBJ-UHFFFAOYSA-N 0.000 description 1
- KQWWVLVLVYYYDT-UHFFFAOYSA-N ethyl 3-oxohexanoate Chemical compound CCCC(=O)CC(=O)OCC KQWWVLVLVYYYDT-UHFFFAOYSA-N 0.000 description 1
- XCLDSQRVMMXWMS-UHFFFAOYSA-N ethyl 4-methyl-3-oxopentanoate Chemical compound CCOC(=O)CC(=O)C(C)C XCLDSQRVMMXWMS-UHFFFAOYSA-N 0.000 description 1
- ZXYAWONOWHSQRU-UHFFFAOYSA-N ethyl 4-oxocyclohexanecarboxylate Chemical compound CCOC(=O)C1CCC(=O)CC1 ZXYAWONOWHSQRU-UHFFFAOYSA-N 0.000 description 1
- WDSKTNIJSXJLTJ-UHFFFAOYSA-N ethyl 8-ethylspiro[4,9-dihydro-3h-pyrano[3,4-b]indole-1,4'-cyclohexane]-1'-carboxylate Chemical compound C1CC(C(=O)OCC)CCC21C(NC=1C3=CC=CC=1CC)=C3CCO2 WDSKTNIJSXJLTJ-UHFFFAOYSA-N 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- LIQODXNTTZAGID-OCBXBXKTSA-N etoposide phosphate Chemical compound COC1=C(OP(O)(O)=O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 LIQODXNTTZAGID-OCBXBXKTSA-N 0.000 description 1
- HQMNCQVAMBCHCO-DJRRULDNSA-N etretinate Chemical compound CCOC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)C=C(OC)C(C)=C1C HQMNCQVAMBCHCO-DJRRULDNSA-N 0.000 description 1
- 229960002199 etretinate Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 229950000484 exisulind Drugs 0.000 description 1
- 201000005577 familial hyperlipidemia Diseases 0.000 description 1
- 208000022195 farmer lung disease Diseases 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- NMUSYJAQQFHJEW-ARQDHWQXSA-N fazarabine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-ARQDHWQXSA-N 0.000 description 1
- 229950005096 fazarabine Drugs 0.000 description 1
- 210000004996 female reproductive system Anatomy 0.000 description 1
- 229950003662 fenretinide Drugs 0.000 description 1
- 230000027950 fever generation Effects 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- FBXPCVIKIBWXAE-ZJZHAWLTSA-N fk973 Chemical compound O1N2C[C@@H]3N(C(C)=O)[C@@H]3[C@]1(OC(C)=O)[C@@H](COC(N)=O)C1=C2C=C(C=O)C=C1OC(=O)C FBXPCVIKIBWXAE-ZJZHAWLTSA-N 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- 229960000961 floxuridine Drugs 0.000 description 1
- 229960005304 fludarabine phosphate Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 1
- 229960002390 flurbiprofen Drugs 0.000 description 1
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 229950010404 fostriecin Drugs 0.000 description 1
- 229960004783 fotemustine Drugs 0.000 description 1
- YAKWPXVTIGTRJH-UHFFFAOYSA-N fotemustine Chemical compound CCOP(=O)(OCC)C(C)NC(=O)N(CCCl)N=O YAKWPXVTIGTRJH-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229940044658 gallium nitrate Drugs 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- OKKDEIYWILRZIA-OSZBKLCCSA-N gemcitabine hydrochloride Chemical compound [H+].[Cl-].O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 OKKDEIYWILRZIA-OSZBKLCCSA-N 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- QKMXESBAFIKRAD-LPHDITAFSA-N genkwadaphnin Chemical compound O([C@@H]1[C@H]([C@@]23[C@H]4[C@](C(C(C)=C4)=O)(O)[C@H](O)[C@@]4(CO)O[C@H]4[C@H]3[C@H]3O[C@](O2)(O[C@]31C(C)=C)C=1C=CC=CC=1)C)C(=O)C1=CC=CC=C1 QKMXESBAFIKRAD-LPHDITAFSA-N 0.000 description 1
- QKMXESBAFIKRAD-UHFFFAOYSA-N genkwadaphnin Natural products CC(=C)C12OC(O3)(C=4C=CC=CC=4)OC1C1C4OC4(CO)C(O)C(C(C(C)=C4)=O)(O)C4C31C(C)C2OC(=O)C1=CC=CC=C1 QKMXESBAFIKRAD-UHFFFAOYSA-N 0.000 description 1
- 229930189446 glidobactin Natural products 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 229960004275 glycolic acid Drugs 0.000 description 1
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 229920000591 gum Polymers 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 201000011066 hemangioma Diseases 0.000 description 1
- 229940109738 hematin Drugs 0.000 description 1
- 208000014951 hematologic disease Diseases 0.000 description 1
- 208000006359 hepatoblastoma Diseases 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical class CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- MCAHMSDENAOJFZ-BVXDHVRPSA-N herbimycin Chemical compound N1C(=O)\C(C)=C\C=C/[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@@H](OC)[C@@H](OC)C[C@H](C)[C@@H](OC)C2=CC(=O)C=C1C2=O MCAHMSDENAOJFZ-BVXDHVRPSA-N 0.000 description 1
- 229930193320 herbimycin Natural products 0.000 description 1
- KKLGDUSGQMHBPB-UHFFFAOYSA-N hex-2-ynedioic acid Chemical class OC(=O)CCC#CC(O)=O KKLGDUSGQMHBPB-UHFFFAOYSA-N 0.000 description 1
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- HYFHYPWGAURHIV-UHFFFAOYSA-N homoharringtonine Natural products C1=C2CCN3CCCC43C=C(OC)C(OC(=O)C(O)(CCCC(C)(C)O)CC(=O)OC)C4C2=CC2=C1OCO2 HYFHYPWGAURHIV-UHFFFAOYSA-N 0.000 description 1
- 229940125697 hormonal agent Drugs 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 229920001600 hydrophobic polymer Polymers 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 230000001969 hypertrophic effect Effects 0.000 description 1
- 229960001001 ibritumomab tiuxetan Drugs 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 229930190064 illudin Natural products 0.000 description 1
- 229950006905 ilmofosine Drugs 0.000 description 1
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 description 1
- 150000002463 imidates Chemical class 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 238000003119 immunoblot Methods 0.000 description 1
- 238000002991 immunohistochemical analysis Methods 0.000 description 1
- 238000012151 immunohistochemical method Methods 0.000 description 1
- 239000000677 immunologic agent Substances 0.000 description 1
- 229940124541 immunological agent Drugs 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000000593 indol-1-yl group Chemical group [H]C1=C([H])C([H])=C2N([*])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 201000009019 intestinal benign neoplasm Diseases 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- 239000011630 iodine Chemical group 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229950010897 iproplatin Drugs 0.000 description 1
- KLEAIHJJLUAXIQ-JDRGBKBRSA-N irinotecan hydrochloride hydrate Chemical compound O.O.O.Cl.C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 KLEAIHJJLUAXIQ-JDRGBKBRSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 208000037906 ischaemic injury Diseases 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical class CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002540 isothiocyanates Chemical class 0.000 description 1
- 229960005280 isotretinoin Drugs 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- BIOSTZMAOGCGSC-CYUGEGSCSA-N kt6149 Chemical compound C1N2C(C(C(C)=C(NCCSSCCNC(=O)CC[C@H](N)C(O)=O)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 BIOSTZMAOGCGSC-CYUGEGSCSA-N 0.000 description 1
- 238000011005 laboratory method Methods 0.000 description 1
- 239000004922 lacquer Substances 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 108010002060 leukoregulin Proteins 0.000 description 1
- HEFNNWSXXWATRW-SNVBAGLBSA-N levibuprofen Chemical compound CC(C)CC1=CC=C([C@@H](C)C(O)=O)C=C1 HEFNNWSXXWATRW-SNVBAGLBSA-N 0.000 description 1
- 108700020781 liblomycin Proteins 0.000 description 1
- 229960005535 lidamycin Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 229940002661 lipitor Drugs 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- RENRQMCACQEWFC-UGKGYDQZSA-N lnp023 Chemical compound C1([C@H]2N(CC=3C=4C=CNC=4C(C)=CC=3OC)CC[C@@H](C2)OCC)=CC=C(C(O)=O)C=C1 RENRQMCACQEWFC-UGKGYDQZSA-N 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 229960003538 lonidamine Drugs 0.000 description 1
- WDRYRZXSPDWGEB-UHFFFAOYSA-N lonidamine Chemical compound C12=CC=CC=C2C(C(=O)O)=NN1CC1=CC=C(Cl)C=C1Cl WDRYRZXSPDWGEB-UHFFFAOYSA-N 0.000 description 1
- XDMHALQMTPSGEA-UHFFFAOYSA-N losoxantrone hydrochloride Chemical compound Cl.Cl.OCCNCCN1N=C2C3=CC=CC(O)=C3C(=O)C3=C2C1=CC=C3NCCNCCO XDMHALQMTPSGEA-UHFFFAOYSA-N 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- JMZFEHDNIAQMNB-UHFFFAOYSA-N m-aminophenylboronic acid Chemical compound NC1=CC=CC(B(O)O)=C1 JMZFEHDNIAQMNB-UHFFFAOYSA-N 0.000 description 1
- 229950000547 mafosfamide Drugs 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 150000002690 malonic acid derivatives Chemical class 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- HCZKYJDFEPMADG-TXEJJXNPSA-N masoprocol Chemical compound C([C@H](C)[C@H](C)CC=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 HCZKYJDFEPMADG-TXEJJXNPSA-N 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229960001962 mefloquine Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- LWYJUZBXGAFFLP-OCNCTQISSA-N menogaril Chemical compound O1[C@@]2(C)[C@H](O)[C@@H](N(C)C)[C@H](O)[C@@H]1OC1=C3C(=O)C(C=C4C[C@@](C)(O)C[C@H](C4=C4O)OC)=C4C(=O)C3=C(O)C=C12 LWYJUZBXGAFFLP-OCNCTQISSA-N 0.000 description 1
- 229950002676 menogaril Drugs 0.000 description 1
- DZVCFNFOPIZQKX-LTHRDKTGSA-M merocyanine Chemical class [Na+].O=C1N(CCCC)C(=O)N(CCCC)C(=O)C1=C\C=C\C=C/1N(CCCS([O-])(=O)=O)C2=CC=CC=C2O\1 DZVCFNFOPIZQKX-LTHRDKTGSA-M 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000005341 metaphosphate group Chemical group 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- AZVARJHZBXHUSO-DZQVEHCYSA-N methyl (1R,4R,12S)-4-methyl-3,7-dioxo-10-(5,6,7-trimethoxy-1H-indole-2-carbonyl)-5,10-diazatetracyclo[7.4.0.01,12.02,6]trideca-2(6),8-diene-4-carboxylate Chemical compound COC1=C(OC)C(OC)=C2NC(C(=O)N3C[C@H]4C[C@]44C5=C(C(C=C43)=O)N[C@@](C5=O)(C)C(=O)OC)=CC2=C1 AZVARJHZBXHUSO-DZQVEHCYSA-N 0.000 description 1
- JSEPROTUIPPOJT-CDHBAGNOSA-N methyl (2r,4s,5r,6r)-2-[[(3ar,4r,6r,6ar)-4-(5-fluoro-2,4-dioxopyrimidin-1-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methoxy]-5-acetamido-4-acetyloxy-6-[(1s,2r)-1,2,3-triacetyloxypropyl]oxane-2-carboxylate Chemical compound C([C@@H]1[C@H]2OC(C)(C)O[C@H]2[C@@H](O1)N1C(NC(=O)C(F)=C1)=O)O[C@]1(C(=O)OC)C[C@H](OC(C)=O)[C@@H](NC(C)=O)[C@H]([C@H](OC(C)=O)[C@@H](COC(C)=O)OC(C)=O)O1 JSEPROTUIPPOJT-CDHBAGNOSA-N 0.000 description 1
- BOGFADYROAVVTF-MZHQLVBMSA-N methyl (2r,8s)-8-(chloromethyl)-4-hydroxy-2-methyl-1-oxo-6-(5,6,7-trimethoxy-1h-indole-2-carbonyl)-7,8-dihydro-3h-pyrrolo[3,2-e]indole-2-carboxylate Chemical compound COC1=C(OC)C(OC)=C2NC(C(=O)N3C[C@@H](CCl)C=4C5=C(C(=CC=43)O)N[C@@](C5=O)(C)C(=O)OC)=CC2=C1 BOGFADYROAVVTF-MZHQLVBMSA-N 0.000 description 1
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 1
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical class COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- PQLXHQMOHUQAKB-UHFFFAOYSA-N miltefosine Chemical compound CCCCCCCCCCCCCCCCOP([O-])(=O)OCC[N+](C)(C)C PQLXHQMOHUQAKB-UHFFFAOYSA-N 0.000 description 1
- 229960003775 miltefosine Drugs 0.000 description 1
- 108010087673 minactivin Proteins 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- 239000003226 mitogen Substances 0.000 description 1
- 229950010913 mitolactol Drugs 0.000 description 1
- VFKZTMPDYBFSTM-GUCUJZIJSA-N mitolactol Chemical compound BrC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-GUCUJZIJSA-N 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 229950001745 mitonafide Drugs 0.000 description 1
- BFRVNBMAWXNICS-UHFFFAOYSA-N mitoquidone Chemical compound C1=CC=C2C(=O)C3=CN(CC=4C(=CC=CC=4)C4)C4=C3C(=O)C2=C1 BFRVNBMAWXNICS-UHFFFAOYSA-N 0.000 description 1
- 229950007466 mitoquidone Drugs 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- FOYWNSCCNCUEPU-UHFFFAOYSA-N mopidamol Chemical compound C12=NC(N(CCO)CCO)=NC=C2N=C(N(CCO)CCO)N=C1N1CCCCC1 FOYWNSCCNCUEPU-UHFFFAOYSA-N 0.000 description 1
- 229950010718 mopidamol Drugs 0.000 description 1
- IYIYMCASGKQOCZ-DJRRULDNSA-N motretinide Chemical compound CCNC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)C=C(OC)C(C)=C1C IYIYMCASGKQOCZ-DJRRULDNSA-N 0.000 description 1
- 229960005406 motretinide Drugs 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 208000001725 mucocutaneous lymph node syndrome Diseases 0.000 description 1
- 208000013465 muscle pain Diseases 0.000 description 1
- 210000002346 musculoskeletal system Anatomy 0.000 description 1
- PAVKBQLPQCDVNI-UHFFFAOYSA-N n',n'-diethyl-n-(9-methoxy-5,11-dimethyl-6h-pyrido[4,3-b]carbazol-1-yl)propane-1,3-diamine Chemical compound N1C2=CC=C(OC)C=C2C2=C1C(C)=C1C=CN=C(NCCCN(CC)CC)C1=C2C PAVKBQLPQCDVNI-UHFFFAOYSA-N 0.000 description 1
- HRKICRHARITSQS-UHFFFAOYSA-N n'-(3-aminopropyl)propane-1,3-diamine;trihydrochloride Chemical compound Cl.Cl.Cl.NCCCNCCCN HRKICRHARITSQS-UHFFFAOYSA-N 0.000 description 1
- HOTMAJBEISISGZ-UHFFFAOYSA-N n-(2-bromo-4-propan-2-ylphenyl)-2-hydroxyiminoacetamide Chemical compound CC(C)C1=CC=C(NC(=O)C=NO)C(Br)=C1 HOTMAJBEISISGZ-UHFFFAOYSA-N 0.000 description 1
- ZJVAVRRLTFVZIP-UHFFFAOYSA-N n-(2-bromoethyl)-3-(2-chloroethyl)-2-oxo-1,3,2$l^{5}-oxazaphosphinan-2-amine Chemical compound ClCCN1CCCOP1(=O)NCCBr ZJVAVRRLTFVZIP-UHFFFAOYSA-N 0.000 description 1
- QEIMBUYAZCMEGX-UHFFFAOYSA-N n-(2-chloroethyldiazenyl)-n-methylacetamide Chemical compound CC(=O)N(C)N=NCCCl QEIMBUYAZCMEGX-UHFFFAOYSA-N 0.000 description 1
- OQGRFQCUGLKSAV-JTQLQIEISA-N n-[(3s)-2,6-dioxopiperidin-3-yl]-2-phenylacetamide Chemical compound N([C@@H]1C(NC(=O)CC1)=O)C(=O)CC1=CC=CC=C1 OQGRFQCUGLKSAV-JTQLQIEISA-N 0.000 description 1
- SRLPZQAEBMZCIJ-UHFFFAOYSA-N n-[(4-chlorophenyl)carbamoyl]-2-(dimethylamino)-6-fluorobenzamide Chemical compound CN(C)C1=CC=CC(F)=C1C(=O)NC(=O)NC1=CC=C(Cl)C=C1 SRLPZQAEBMZCIJ-UHFFFAOYSA-N 0.000 description 1
- NJSMWLQOCQIOPE-OCHFTUDZSA-N n-[(e)-[10-[(e)-(4,5-dihydro-1h-imidazol-2-ylhydrazinylidene)methyl]anthracen-9-yl]methylideneamino]-4,5-dihydro-1h-imidazol-2-amine Chemical compound N1CCN=C1N\N=C\C(C1=CC=CC=C11)=C(C=CC=C2)C2=C1\C=N\NC1=NCCN1 NJSMWLQOCQIOPE-OCHFTUDZSA-N 0.000 description 1
- XEFNBUBDJCJOGM-OUJCMCIWSA-N n-[1-[(2r,3s,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-2-oxopyrimidin-4-yl]hexadecanamide Chemical compound O=C1N=C(NC(=O)CCCCCCCCCCCCCCC)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 XEFNBUBDJCJOGM-OUJCMCIWSA-N 0.000 description 1
- BLSOATWWAGIRGE-UHFFFAOYSA-N n-[5-[[5-[(3-amino-3-iminopropyl)carbamoyl]-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]-4-[[4-[bis(2-chloroethyl)amino]benzoyl]amino]-1-methylpyrrole-2-carboxamide;hydrochloride Chemical compound Cl.C1=C(C(=O)NCCC(N)=N)N(C)C=C1NC(=O)C1=CC(NC(=O)C=2N(C=C(NC(=O)C=3C=CC(=CC=3)N(CCCl)CCCl)C=2)C)=CN1C BLSOATWWAGIRGE-UHFFFAOYSA-N 0.000 description 1
- WKXWMGOTZJGIIK-UHFFFAOYSA-N n-[[4-(5-bromopyrimidin-2-yl)oxy-3-chlorophenyl]carbamoyl]-2-nitrobenzamide Chemical compound [O-][N+](=O)C1=CC=CC=C1C(=O)NC(=O)NC(C=C1Cl)=CC=C1OC1=NC=C(Br)C=N1 WKXWMGOTZJGIIK-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- AUWFXUHWMBMPTI-UHFFFAOYSA-N n-pyrazin-2-ylnitrous amide Chemical compound O=NNC1=CN=CC=N1 AUWFXUHWMBMPTI-UHFFFAOYSA-N 0.000 description 1
- 229960004270 nabumetone Drugs 0.000 description 1
- 229950011492 nafazatrom Drugs 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical class C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical class C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 201000004931 neurofibromatosis Diseases 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 210000000633 nuclear envelope Anatomy 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- YVPOTNAPPSUMJX-UHFFFAOYSA-N octadecanoic acid;phosphoric acid Chemical compound OP(O)(O)=O.CCCCCCCCCCCCCCCCCC(O)=O YVPOTNAPPSUMJX-UHFFFAOYSA-N 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical class CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 229960002700 octreotide Drugs 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 229960002230 omacetaxine mepesuccinate Drugs 0.000 description 1
- HYFHYPWGAURHIV-JFIAXGOJSA-N omacetaxine mepesuccinate Chemical compound C1=C2CCN3CCC[C@]43C=C(OC)[C@@H](OC(=O)[C@@](O)(CCCC(C)(C)O)CC(=O)OC)[C@H]4C2=CC2=C1OCO2 HYFHYPWGAURHIV-JFIAXGOJSA-N 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229920000620 organic polymer Polymers 0.000 description 1
- 239000003791 organic solvent mixture Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 125000001979 organolithium group Chemical group 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 229940116315 oxalic acid Drugs 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 150000002924 oxiranes Chemical class 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- VREZDOWOLGNDPW-UHFFFAOYSA-N pancratistatine Natural products C1=C2C3C(O)C(O)C(O)C(O)C3NC(=O)C2=C(O)C2=C1OCO2 VREZDOWOLGNDPW-UHFFFAOYSA-N 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- LPHSYQSMAGVYNT-UHFFFAOYSA-N pazelliptine Chemical compound N1C2=CC=NC=C2C2=C1C(C)=C1C=CN=C(NCCCN(CC)CC)C1=C2 LPHSYQSMAGVYNT-UHFFFAOYSA-N 0.000 description 1
- 229950006361 pazelliptine Drugs 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 229960002340 pentostatin Drugs 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- QIMGFXOHTOXMQP-GFAGFCTOSA-N peplomycin Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCCN[C@@H](C)C=1C=CC=CC=1)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C QIMGFXOHTOXMQP-GFAGFCTOSA-N 0.000 description 1
- 229950003180 peplomycin Drugs 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 239000003614 peroxisome proliferator Substances 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 1
- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical class CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical class OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 239000003428 phospholipase inhibitor Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 125000005498 phthalate group Chemical class 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- FGNPPWFDUWSHQL-UPEPMZDMSA-N pilatin Chemical compound O=CC1=C[C@]2(O)[C@H](OC(=O)/C=C/CCC)C(C)(C)C[C@@H]2[C@]23C(=O)O[C@H](O)[C@@]21C3 FGNPPWFDUWSHQL-UPEPMZDMSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229960001221 pirarubicin Drugs 0.000 description 1
- 229950001030 piritrexim Drugs 0.000 description 1
- 229950001746 piroxantrone Drugs 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 210000003281 pleural cavity Anatomy 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 229920000647 polyepoxide Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 235000010988 polyoxyethylene sorbitan tristearate Nutrition 0.000 description 1
- 239000001816 polyoxyethylene sorbitan tristearate Substances 0.000 description 1
- 208000015768 polyposis Diseases 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 229940099511 polysorbate 65 Drugs 0.000 description 1
- 150000004032 porphyrins Chemical class 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 210000000229 preadipocyte Anatomy 0.000 description 1
- 238000012910 preclinical development Methods 0.000 description 1
- 229960004694 prednimustine Drugs 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 229960003857 proglumide Drugs 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical class CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-N propynoic acid Chemical class OC(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-N 0.000 description 1
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 1
- 210000005267 prostate cell Anatomy 0.000 description 1
- 230000002633 protecting effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000029983 protein stabilization Effects 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- ONQBBCUWASUJGE-UHFFFAOYSA-N putrebactin Natural products ON1CCCCNC(=O)CCC(=O)N(O)CCCCNC(=O)CCC1=O ONQBBCUWASUJGE-UHFFFAOYSA-N 0.000 description 1
- QLULGIRFKAWHOJ-UHFFFAOYSA-N pyridin-4-ylboronic acid Chemical compound OB(O)C1=CC=NC=C1 QLULGIRFKAWHOJ-UHFFFAOYSA-N 0.000 description 1
- BOGFADYROAVVTF-UHFFFAOYSA-N pyrindamycin A Natural products COC1=C(OC)C(OC)=C2NC(C(=O)N3CC(CCl)C=4C5=C(C(=CC=43)O)NC(C5=O)(C)C(=O)OC)=CC2=C1 BOGFADYROAVVTF-UHFFFAOYSA-N 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 239000000718 radiation-protective agent Substances 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 229960002185 ranimustine Drugs 0.000 description 1
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
- BMKDZUISNHGIBY-UHFFFAOYSA-N razoxane Chemical compound C1C(=O)NC(=O)CN1C(C)CN1CC(=O)NC(=O)C1 BMKDZUISNHGIBY-UHFFFAOYSA-N 0.000 description 1
- 229960000460 razoxane Drugs 0.000 description 1
- 230000008327 renal blood flow Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 108010026350 restrictin-P Proteins 0.000 description 1
- 229950002225 retelliptine Drugs 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- OWPCHSCAPHNHAV-LMONGJCWSA-N rhizoxin Chemical compound C/C([C@H](OC)[C@@H](C)[C@@H]1C[C@H](O)[C@]2(C)O[C@@H]2/C=C/[C@@H](C)[C@]2([H])OC(=O)C[C@@](C2)(C[C@@H]2O[C@H]2C(=O)O1)[H])=C\C=C\C(\C)=C\C1=COC(C)=N1 OWPCHSCAPHNHAV-LMONGJCWSA-N 0.000 description 1
- 229940100486 rice starch Drugs 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- 229950004892 rodorubicin Drugs 0.000 description 1
- 229910052701 rubidium Inorganic materials 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000036573 scar formation Effects 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical class OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003349 semicarbazides Chemical class 0.000 description 1
- 229960003440 semustine Drugs 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- DRNXZGJGRSUXHW-UHFFFAOYSA-N silyl carbamate Chemical class NC(=O)O[SiH3] DRNXZGJGRSUXHW-UHFFFAOYSA-N 0.000 description 1
- 201000009890 sinusitis Diseases 0.000 description 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- RQHZAASWYUEYCJ-JVWHUAOPSA-N siwenmycin Chemical compound O=C1C2=C(O)C=CC=C2C(=O)C2=C1C(O)=C1[C@@H](O[C@@H]3O[C@@H](C)[C@@H](O[C@@H]4O[C@@H](C)[C@H]5O[C@@H]6O[C@H](C)C(=O)C[C@@H]6O[C@H]5C4)[C@H](C3)N(C)C)C[C@@](CC)(O)[C@H](C(=O)OC)C1=C2 RQHZAASWYUEYCJ-JVWHUAOPSA-N 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 229950010372 sobuzoxane Drugs 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- DVQHRBFGRZHMSR-UHFFFAOYSA-N sodium methyl 2,2-dimethyl-4,6-dioxo-5-(N-prop-2-enoxy-C-propylcarbonimidoyl)cyclohexane-1-carboxylate Chemical compound [Na+].C=CCON=C(CCC)[C-]1C(=O)CC(C)(C)C(C(=O)OC)C1=O DVQHRBFGRZHMSR-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- OTABDKFPJQZJRD-QLGZCQHWSA-N sorangicin a Chemical compound C([C@@H]1O[C@H]([C@@H](OC(=O)/C=C\C=C/C=C/[C@H]2O3)C=C1)C(/C)=C/[C@@H](CCCCC(O)=O)C)\C=C\CC\C=C\[C@H](O)[C@H](O)[C@H](O1)C[C@H](O)[C@@H](C)[C@H]1C\C=C\[C@H]1[C@H](C)[C@H]3C[C@H]2O1 OTABDKFPJQZJRD-QLGZCQHWSA-N 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- XKLZIVIOZDNKEQ-CLQLPEFOSA-N sparsomycin Chemical compound CSC[S@](=O)C[C@H](CO)NC(=O)\C=C\C1=C(C)NC(=O)NC1=O XKLZIVIOZDNKEQ-CLQLPEFOSA-N 0.000 description 1
- 229950009641 sparsomycin Drugs 0.000 description 1
- XKLZIVIOZDNKEQ-UHFFFAOYSA-N sparsomycin Natural products CSCS(=O)CC(CO)NC(=O)C=CC1=C(C)NC(=O)NC1=O XKLZIVIOZDNKEQ-UHFFFAOYSA-N 0.000 description 1
- MFIWRSIQAIKKEY-DSQGJUKISA-N spatol Chemical compound O([C@H]1[C@H]2O[C@@H]2C(=C)[C@H]2[C@H]3[C@H]4[C@@H]([C@]3([C@H](O)C2)C)CC[C@H]4C)C1(C)C MFIWRSIQAIKKEY-DSQGJUKISA-N 0.000 description 1
- MFIWRSIQAIKKEY-UHFFFAOYSA-N spatol Natural products CC1CCC(C2(C(O)C3)C)C1C2C3C(=C)C1OC1C1OC1(C)C MFIWRSIQAIKKEY-UHFFFAOYSA-N 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 208000002320 spinal muscular atrophy Diseases 0.000 description 1
- 229950006315 spirogermanium Drugs 0.000 description 1
- 229950006050 spiromustine Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000007447 staining method Methods 0.000 description 1
- 108010042747 stallimycin Proteins 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 208000018556 stomach disease Diseases 0.000 description 1
- LLWMPGSQZXZZAE-UHFFFAOYSA-N stypoldione Natural products C1C(C(C(=O)C=C2C)=O)=C2OC21C1(C)CCC3C(C)(C)C(O)CCC3(C)C1CCC2C LLWMPGSQZXZZAE-UHFFFAOYSA-N 0.000 description 1
- 230000004960 subcellular localization Effects 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-N suberic acid Chemical class OC(=O)CCCCCCC(O)=O TYFQFVWCELRYAO-UHFFFAOYSA-N 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical class [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- MVGSNCBCUWPVDA-MFOYZWKCSA-N sulindac sulfone Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)(=O)=O)C=C1 MVGSNCBCUWPVDA-MFOYZWKCSA-N 0.000 description 1
- SRXBXVZOQNUGMC-UBOCCBBCSA-N sun-0237 Chemical compound O[C@@H]([C@]1(C)[C@@H]23)C(=O)C=C(C)[C@@H]1C[C@@H]1[C@@]43CO[C@@]2(O)[C@H](O)C(=C)[C@@H]4[C@@H](OC(=O)/C=C/CCCCCCCC)C(=O)O1 SRXBXVZOQNUGMC-UBOCCBBCSA-N 0.000 description 1
- XOCICDFNNMOAKJ-OLGFVZGESA-N sun-2071 Chemical compound O[C@@H]([C@]1(C)[C@@H]23)C(=O)C=C(C)[C@@H]1C[C@@H]1[C@@]43CO[C@@]2(O)[C@H](O)C(=C)[C@@H]4[C@@H](OC(=O)/C=C(C)/CCCCC)C(=O)O1 XOCICDFNNMOAKJ-OLGFVZGESA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 108700003774 talisomycin Proteins 0.000 description 1
- 229950002687 talisomycin Drugs 0.000 description 1
- 108010021891 tallimustine Proteins 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 229950010168 tauromustine Drugs 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 229950008703 teroxirone Drugs 0.000 description 1
- ISTOHHFNKVUOKP-BRUMOIPRSA-N terpentecin Chemical compound O=CC(=O)[C@@]1([C@H](O)C[C@@]2(C)[C@H]3[C@](C(=CCC3)C)(C)C(=O)[C@H](O)[C@H]2C)CO1 ISTOHHFNKVUOKP-BRUMOIPRSA-N 0.000 description 1
- ISTOHHFNKVUOKP-UHFFFAOYSA-N terpentecin Natural products CC1C(O)C(=O)C(C(=CCC2)C)(C)C2C1(C)CC(O)C1(C(=O)C=O)CO1 ISTOHHFNKVUOKP-UHFFFAOYSA-N 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- ZCTJIMXXSXQXRI-UHFFFAOYSA-N thaliblastine Natural products CN1CCC2=CC(OC)=C(OC)C3=C2C1CC1=C3C=C(OC)C(OC2=C(CC3C4=CC(OC)=C(OC)C=C4CCN3C)C=C(C(=C2)OC)OC)=C1 ZCTJIMXXSXQXRI-UHFFFAOYSA-N 0.000 description 1
- ZCTJIMXXSXQXRI-KYJUHHDHSA-N thalicarpine Chemical compound CN1CCC2=CC(OC)=C(OC)C3=C2[C@@H]1CC1=C3C=C(OC)C(OC2=C(C[C@H]3C4=CC(OC)=C(OC)C=C4CCN3C)C=C(C(=C2)OC)OC)=C1 ZCTJIMXXSXQXRI-KYJUHHDHSA-N 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 150000007944 thiolates Chemical class 0.000 description 1
- 150000003585 thioureas Chemical class 0.000 description 1
- 210000000779 thoracic wall Anatomy 0.000 description 1
- 229960003723 tiazofurine Drugs 0.000 description 1
- FVRDYQYEVDDKCR-DBRKOABJSA-N tiazofurine Chemical compound NC(=O)C1=CSC([C@H]2[C@@H]([C@H](O)[C@@H](CO)O2)O)=N1 FVRDYQYEVDDKCR-DBRKOABJSA-N 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 description 1
- 229950004047 tiprotimod Drugs 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 229930003802 tocotrienol Natural products 0.000 description 1
- 239000011731 tocotrienol Substances 0.000 description 1
- 235000019148 tocotrienols Nutrition 0.000 description 1
- 208000004371 toothache Diseases 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960005267 tositumomab Drugs 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 239000012096 transfection reagent Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical class [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 1
- 229960001099 trimetrexate Drugs 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 239000000717 tumor promoter Substances 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000007631 vascular surgery Methods 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- KDQAABAKXDWYSZ-PNYVAJAMSA-N vinblastine sulfate Chemical compound OS(O)(=O)=O.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 KDQAABAKXDWYSZ-PNYVAJAMSA-N 0.000 description 1
- 229960004982 vinblastine sulfate Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- IQDSXWRQCKDBMW-NSFJATOBSA-N vintriptol Chemical compound C([C@@H](C[C@@](O)(CC)C1)C[C@@]2(C3=C(OC)C=C4N(C)[C@H]5[C@@]([C@@H]([C@]6(CC)C=CCN7CC[C@]5([C@H]67)C4=C3)O)(O)C(=O)N[C@@H](CC=3C4=CC=CC=C4NC=3)C(=O)OCC)C(=O)OC)N1CCC1=C2NC2=CC=CC=C12 IQDSXWRQCKDBMW-NSFJATOBSA-N 0.000 description 1
- 229950003415 vintriptol Drugs 0.000 description 1
- 229950005839 vinzolidine Drugs 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- GDJZZWYLFXAGFH-UHFFFAOYSA-M xylenesulfonate group Chemical group C1(C(C=CC=C1)C)(C)S(=O)(=O)[O-] GDJZZWYLFXAGFH-UHFFFAOYSA-M 0.000 description 1
- 229960000523 zalcitabine Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 description 1
- 229940002005 zometa Drugs 0.000 description 1
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
- 229960000641 zorubicin Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/06—Antiabortive agents; Labour repressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
Abstract
Provided herein are indole derivatives, pharmaceutical compositions containing them, methods for their use, and methods for preparing these compounds.
Description
INDOLE DERIVATIVES
This application claims priority to U.S. Provisional Application No.
60/508,592, filed October 2, 2003, and U.S. Provisional Application No. 60/556,599, filed March 26, 2004, which are incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
This invention relates to antineoplastic, anti-inflammatory and analgesic indole derivatives, pharmaceutical compositions containing them, methods for their use, and methods for preparing these compounds.
BACKGROUND OF THE INVENTION
Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for the treatment of inflammation, pain, and acute and chronic inflammatory disorders such as osteoarthritis and rheumatoid arthritis. These compounds are thought to work by inhibiting the enzyme cyclooxygenase (COX), which is also known as prostaglandin G/H
synthase. COX catalyzes the conversion of arachidonic acid to prostaglandins.
Various forms of COX enzymes have been reported. They include a constitutive form known as COX-1, an inducible form known as COX-2 and the recently discovered COX-3, a variant of COX-1 that is inhibited by acetaminophen. COX-2 is inducible by mitogens, endotoxin, hormones, tumor promoters and growth factors. COX-1 is responsible for endogenous release of prostaglandins important for maintenance of gastrointestinal integrity and renal blood flow. Many of the side effects associated with NSAIDs are believed to be due to the inhibition of COX-1. Because of this, compounds that are selective for COX-2 have been developed and marketed. However, COX-2 inhibitors have been reported to cause dyspepsia, gastropathy and cardiovascular problems.
NSAIDs have also been used for cancer prevention and cancer treatment. The mechanism by which NSAIDs work in cancer treatment and cancer prevention may be related to COX overexpression. For example, some studies appear to indicate a link between COX expression and carcinogenesis. For example, cell lines that overexpress COX-2 are reported to be resistant to apoptosis, have increased invasiveness, and increased angiogenesis potential. Further, studies indicate that increased amounts of prostaglandins and COX-2 are commonly found in premalignant tissues and malignant tumors. Researchers have reported that COX-2 is up-regulated in several types of human cancers, including colon, pancreatic and breast.
Other studies report that the chemoprotective and antineoplastic properties of NSA>Ds may occur in a COX-independent mechanism. For example, R-flurbiprofen is chemoprotective in the mouse model of intestinal polyposis and prostate cancer even though it does not have COX inhibitory activity. Similarly, sulindac sulfone, a metabolite of the NSA>D sulindac, inhibits azoxy-methane-induced colon tumors in rats even though it does not have COX inhibitory activity. Further, NSA>Ds can induce apoptosis in cancer cells that do not express COX-2 (Baek et al. 2001 Mol. Pharmacol. 59:901-908).
The authors of these studies report that the chemoprotective and antineoplastic effects of NSA>Ds occur via COX-dependent and COX-independent mechanisms.
(3-catenin (also known as cadherin-associated protein) is a protooncogene in the downstream pathway of the wingless/frizzled (wntlfzd) signaling pathway.
Alterations in the pathways involved in regulating (3-catenin are associated in the pathogenesis of many human cancers, including colorectal, desmoid (aggressive fibromatosis), endometrial, hepatocellular, leukemias, kidney, medulloblastoma, melanoma, ovarian, pancreatic, prostate, thyroid and uterine (Polakis, 2000 Genes Dev. 14:1837-1851; Chung et al. 2002 Blood 100:982-990).
~3-catenin is reported to exist in at least three forms: membrane-bound (adherens complex), cytosolic, and nuclear. The nuclear accumulation of (3-catenin, in concert with TCF/LEF proteins, induces downstream genes, including many genes implicated in tumorigenesis, for example, cyclin D1, and c-myc. The literature also reports that ~i-catenin is involved in the gene regulation of the androgen receptor, providing evidence for a role for the Wnt/(3-catenin-TCF pathway for normal and neoplastic prostate growth (Amir et al., 2003, J. Biol. Chem. 278:30828-30834). The literature also reports that (3-catenin may up-regulate COX-2 (Okamura et al., 2003, Cancer Res. 63:728-34).
(3-catenin levels are reported to be regulated posttranslationally by the Wnt/fzd signaling pathway. In the absence of a Wnt signal, any (3-catenin not bound to adherins is marked for degradation by a complex of proteins bound to (3-catenin that includes glycogen synthase kinase-3(3 (GSK-3(3), adenomatous polyposis coli (APC) protein, and axin. This complex facilitates the phosphorylation of ~3-catenin by GSK-3[3 and subsequent rapid degradation of (3-catenin through proteasome degradation.
Binding of Wnts to their receptors results in disruption of the (3-catenin complex and inhibition of (3-catenin degradation. This results in the accumulation of (3-catenin in the cytoplasm and nucleus where it interacts with TCF/LEF proteins to regulate gene expression.
Mutations in APC, (3-catenin, or axin have been reported to increase the nuclear accumulation of (3-catenin in cancers of epithelial origin.
The accumulation of (3-catenin in the cytoplasm and nucleus has been reported in tumors with or without (3-catenin mutations. In colorectal cancers, APC is mutated in 80%
of all cases. In cases without APC mutations, (3-catenin mutations are found in 50% of the cases. Accumulation of (3-catenin is reported to occur in a very high percentage of cases in hepatoblastomas even though ~i-catenin is mutated in only 34% of the samples (Blaker et al., 1999 Genes Chromosomes Cancer 25:399-402). In hepatocellular carcinomas, ~i-catenin accumulation results from (3-catenin mutations or axin mutation, but rarely APC
mutations. Forty-two percent of samples in anaplastic thyroid demonstrate nuclear accumulation of ~3-catenin. Further, this high accumulation has been reported to correlate with a decrease in survival rate (Garcia-Rostan et al. 1999 Cancer Res.
59:1811-5).
Rubinfeld et al. reported abnormal ~i-catenin regulation in 30% of melanoma cell lines (1997 Science 275:1790-2). Uterine endometriuim is reported to be associated with (3-catenin accumulation in both samples that contain ~i-catenin mutations and samples without (3-catenin mutations (Fukuchi et al. 1998 Cancer Res. 58:3526-3528.) Iwao et al.
report that 63% of bone and soft-tissue tumors lacking a specific /3-catenin mutation still demonstrate (3 -catenin accumulation (1999 Jpn. J. Cancer Res. 90:205-209).
Lin et al. reported that immunohistochemical analysis of cyclin D1 and,-catenin in breast tumors indicated that of 53 samples positive for cyclin D1, 49 of those were also ~3-catenin positive with (3-catenin observed in both the nucleus and cytoplasm (2000 Proc.
Natl. Acad. Sci. USA 97:4262-4266). A relationship between (3-catenin and cyclin D1 has been reported for colon cancer and hepatocellular carcinoma (Tetsue et al.
1999 Nature 398:422-426; Ueta et al. 2002 Oncology Reports 9:1197-1203). Cyclin D1 is reported to be involved in the pathogenesis of squamous cell carcinoma (Xu et al. 1994 Int J. Cancer 59:383-387).
NSAIDs have been reported to affect (3-catenin activity. For example, both aspirin and indomethacin have been reported to inhibit transcription of the (3-catenin /TCF target cyclin Dl (Dihlmann et al. 2001 Oncogene 20:645-53). Sulindac was reported to decrease ~3-catenin in intestinal tumors from Min/+ mice (McEntee et al. 1999 Carcinogenesis 20:635-640). Noda et al., report that etodolac increases the expression and cytoplasmic accumulation of cytoplasmic E-cadherin in Caco2 cells, but had no quantitative change in (3-catenin expression (2002 J. Gastorenterol. 37(11):896-904).
Peroxisome proliferators-activated receptors (PPARs) are nuclear hormone receptors that have been reported to be involved in many cellular processes, including lipid metabolism and disease-related processes. PPARs form dimers with retinoid-X
receptor and mediate their effects after ligand binding through gene transcription.
Three isoforms of PPAR are known to date- a, y, and 8. PPARa is highly expressed in liver and has been reported to stimulate lipid metabolism. PPARy is highly expressed in adipose tissue and is reported to be involved in activating adipogeneisis.
PPARy is reported to be involved in insulin resistance and a number of neoplastic processes including colorectal cancer. Shimada et al. hypothesize that activation of PPARy signaling may compensate for deregulated c-myc expression in cells with mutated APC (2002 Gut 50:658-664). Ohta et al. report that a PPARy ligand can cause a shift in ~3-catenin from the nucleus to the cytoplasm and induction of differentiation in pancreatic cancer cells (2002 Int J. Oncol. 21:37-42). PPARB is expressed in many tissues and organs with the highest expression are brain, colon, and skin. Investigators have implicated PPARB in cholesterol efflux, colon cancer, embryo implantation, preadipocyte proliferation and epidermal maturation. Investigators report that PPARB is a downstream target of (3-catenin/TCF-4 transcription complex (He et al., 1999 Cell 99:335-345). Also, PPARB mRNA is reported to be overexpressed in many colorectal cancers.
NSA>Ds have been reported to activate PPAR receptors (Lehmann et al. 1997 J
Biol. Chem. 272:3406-3410). Researchers also report that NSAIDs may inhibit PPARB, which might contribute to the chemoprotective effects of NSAIDs in preventing colorectal cancers (He et al. 1999).
Epidemiological studies indicate that NSAIDs may reduce or prevent the occurrence of Alzheimer's disease. A connection between the COX pathway and S Alzheimer's disease has been reported and is mainly based on epidemiological studies.
Studies indicate that Cox-2 is up-regulated in areas of the brain related to memory (Hint et al. 2002 J. Pharm. Exp. Ther. 300:367-375). Weggen et al. report that some NSAIDs may reduce the pathogenic amyloid (3 peptide, A(342, by as much as 80% (2001 Nature 414:212-216). This reduction has been reported to occur in a COX-independent mechanism (Eriksen et al. 2002 J. Clinical Invest. 112:440-449). Eriksen also report that flurbiprofen and its enantiomers lower A~342 by targeting the y-secretase complex that produces A(3 from amyloid ~3 protein precursor. US Patent No. 6,255,347 discloses the use of R-ibuprofen for the treatment or prevention of Alzheimer's disease.
Analogs of etodolac are known in the art see, for example, US Patent Nos. US
This application claims priority to U.S. Provisional Application No.
60/508,592, filed October 2, 2003, and U.S. Provisional Application No. 60/556,599, filed March 26, 2004, which are incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
This invention relates to antineoplastic, anti-inflammatory and analgesic indole derivatives, pharmaceutical compositions containing them, methods for their use, and methods for preparing these compounds.
BACKGROUND OF THE INVENTION
Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for the treatment of inflammation, pain, and acute and chronic inflammatory disorders such as osteoarthritis and rheumatoid arthritis. These compounds are thought to work by inhibiting the enzyme cyclooxygenase (COX), which is also known as prostaglandin G/H
synthase. COX catalyzes the conversion of arachidonic acid to prostaglandins.
Various forms of COX enzymes have been reported. They include a constitutive form known as COX-1, an inducible form known as COX-2 and the recently discovered COX-3, a variant of COX-1 that is inhibited by acetaminophen. COX-2 is inducible by mitogens, endotoxin, hormones, tumor promoters and growth factors. COX-1 is responsible for endogenous release of prostaglandins important for maintenance of gastrointestinal integrity and renal blood flow. Many of the side effects associated with NSAIDs are believed to be due to the inhibition of COX-1. Because of this, compounds that are selective for COX-2 have been developed and marketed. However, COX-2 inhibitors have been reported to cause dyspepsia, gastropathy and cardiovascular problems.
NSAIDs have also been used for cancer prevention and cancer treatment. The mechanism by which NSAIDs work in cancer treatment and cancer prevention may be related to COX overexpression. For example, some studies appear to indicate a link between COX expression and carcinogenesis. For example, cell lines that overexpress COX-2 are reported to be resistant to apoptosis, have increased invasiveness, and increased angiogenesis potential. Further, studies indicate that increased amounts of prostaglandins and COX-2 are commonly found in premalignant tissues and malignant tumors. Researchers have reported that COX-2 is up-regulated in several types of human cancers, including colon, pancreatic and breast.
Other studies report that the chemoprotective and antineoplastic properties of NSA>Ds may occur in a COX-independent mechanism. For example, R-flurbiprofen is chemoprotective in the mouse model of intestinal polyposis and prostate cancer even though it does not have COX inhibitory activity. Similarly, sulindac sulfone, a metabolite of the NSA>D sulindac, inhibits azoxy-methane-induced colon tumors in rats even though it does not have COX inhibitory activity. Further, NSA>Ds can induce apoptosis in cancer cells that do not express COX-2 (Baek et al. 2001 Mol. Pharmacol. 59:901-908).
The authors of these studies report that the chemoprotective and antineoplastic effects of NSA>Ds occur via COX-dependent and COX-independent mechanisms.
(3-catenin (also known as cadherin-associated protein) is a protooncogene in the downstream pathway of the wingless/frizzled (wntlfzd) signaling pathway.
Alterations in the pathways involved in regulating (3-catenin are associated in the pathogenesis of many human cancers, including colorectal, desmoid (aggressive fibromatosis), endometrial, hepatocellular, leukemias, kidney, medulloblastoma, melanoma, ovarian, pancreatic, prostate, thyroid and uterine (Polakis, 2000 Genes Dev. 14:1837-1851; Chung et al. 2002 Blood 100:982-990).
~3-catenin is reported to exist in at least three forms: membrane-bound (adherens complex), cytosolic, and nuclear. The nuclear accumulation of (3-catenin, in concert with TCF/LEF proteins, induces downstream genes, including many genes implicated in tumorigenesis, for example, cyclin D1, and c-myc. The literature also reports that ~i-catenin is involved in the gene regulation of the androgen receptor, providing evidence for a role for the Wnt/(3-catenin-TCF pathway for normal and neoplastic prostate growth (Amir et al., 2003, J. Biol. Chem. 278:30828-30834). The literature also reports that (3-catenin may up-regulate COX-2 (Okamura et al., 2003, Cancer Res. 63:728-34).
(3-catenin levels are reported to be regulated posttranslationally by the Wnt/fzd signaling pathway. In the absence of a Wnt signal, any (3-catenin not bound to adherins is marked for degradation by a complex of proteins bound to (3-catenin that includes glycogen synthase kinase-3(3 (GSK-3(3), adenomatous polyposis coli (APC) protein, and axin. This complex facilitates the phosphorylation of ~3-catenin by GSK-3[3 and subsequent rapid degradation of (3-catenin through proteasome degradation.
Binding of Wnts to their receptors results in disruption of the (3-catenin complex and inhibition of (3-catenin degradation. This results in the accumulation of (3-catenin in the cytoplasm and nucleus where it interacts with TCF/LEF proteins to regulate gene expression.
Mutations in APC, (3-catenin, or axin have been reported to increase the nuclear accumulation of (3-catenin in cancers of epithelial origin.
The accumulation of (3-catenin in the cytoplasm and nucleus has been reported in tumors with or without (3-catenin mutations. In colorectal cancers, APC is mutated in 80%
of all cases. In cases without APC mutations, (3-catenin mutations are found in 50% of the cases. Accumulation of (3-catenin is reported to occur in a very high percentage of cases in hepatoblastomas even though ~i-catenin is mutated in only 34% of the samples (Blaker et al., 1999 Genes Chromosomes Cancer 25:399-402). In hepatocellular carcinomas, ~i-catenin accumulation results from (3-catenin mutations or axin mutation, but rarely APC
mutations. Forty-two percent of samples in anaplastic thyroid demonstrate nuclear accumulation of ~3-catenin. Further, this high accumulation has been reported to correlate with a decrease in survival rate (Garcia-Rostan et al. 1999 Cancer Res.
59:1811-5).
Rubinfeld et al. reported abnormal ~i-catenin regulation in 30% of melanoma cell lines (1997 Science 275:1790-2). Uterine endometriuim is reported to be associated with (3-catenin accumulation in both samples that contain ~i-catenin mutations and samples without (3-catenin mutations (Fukuchi et al. 1998 Cancer Res. 58:3526-3528.) Iwao et al.
report that 63% of bone and soft-tissue tumors lacking a specific /3-catenin mutation still demonstrate (3 -catenin accumulation (1999 Jpn. J. Cancer Res. 90:205-209).
Lin et al. reported that immunohistochemical analysis of cyclin D1 and,-catenin in breast tumors indicated that of 53 samples positive for cyclin D1, 49 of those were also ~3-catenin positive with (3-catenin observed in both the nucleus and cytoplasm (2000 Proc.
Natl. Acad. Sci. USA 97:4262-4266). A relationship between (3-catenin and cyclin D1 has been reported for colon cancer and hepatocellular carcinoma (Tetsue et al.
1999 Nature 398:422-426; Ueta et al. 2002 Oncology Reports 9:1197-1203). Cyclin D1 is reported to be involved in the pathogenesis of squamous cell carcinoma (Xu et al. 1994 Int J. Cancer 59:383-387).
NSAIDs have been reported to affect (3-catenin activity. For example, both aspirin and indomethacin have been reported to inhibit transcription of the (3-catenin /TCF target cyclin Dl (Dihlmann et al. 2001 Oncogene 20:645-53). Sulindac was reported to decrease ~3-catenin in intestinal tumors from Min/+ mice (McEntee et al. 1999 Carcinogenesis 20:635-640). Noda et al., report that etodolac increases the expression and cytoplasmic accumulation of cytoplasmic E-cadherin in Caco2 cells, but had no quantitative change in (3-catenin expression (2002 J. Gastorenterol. 37(11):896-904).
Peroxisome proliferators-activated receptors (PPARs) are nuclear hormone receptors that have been reported to be involved in many cellular processes, including lipid metabolism and disease-related processes. PPARs form dimers with retinoid-X
receptor and mediate their effects after ligand binding through gene transcription.
Three isoforms of PPAR are known to date- a, y, and 8. PPARa is highly expressed in liver and has been reported to stimulate lipid metabolism. PPARy is highly expressed in adipose tissue and is reported to be involved in activating adipogeneisis.
PPARy is reported to be involved in insulin resistance and a number of neoplastic processes including colorectal cancer. Shimada et al. hypothesize that activation of PPARy signaling may compensate for deregulated c-myc expression in cells with mutated APC (2002 Gut 50:658-664). Ohta et al. report that a PPARy ligand can cause a shift in ~3-catenin from the nucleus to the cytoplasm and induction of differentiation in pancreatic cancer cells (2002 Int J. Oncol. 21:37-42). PPARB is expressed in many tissues and organs with the highest expression are brain, colon, and skin. Investigators have implicated PPARB in cholesterol efflux, colon cancer, embryo implantation, preadipocyte proliferation and epidermal maturation. Investigators report that PPARB is a downstream target of (3-catenin/TCF-4 transcription complex (He et al., 1999 Cell 99:335-345). Also, PPARB mRNA is reported to be overexpressed in many colorectal cancers.
NSA>Ds have been reported to activate PPAR receptors (Lehmann et al. 1997 J
Biol. Chem. 272:3406-3410). Researchers also report that NSAIDs may inhibit PPARB, which might contribute to the chemoprotective effects of NSAIDs in preventing colorectal cancers (He et al. 1999).
Epidemiological studies indicate that NSAIDs may reduce or prevent the occurrence of Alzheimer's disease. A connection between the COX pathway and S Alzheimer's disease has been reported and is mainly based on epidemiological studies.
Studies indicate that Cox-2 is up-regulated in areas of the brain related to memory (Hint et al. 2002 J. Pharm. Exp. Ther. 300:367-375). Weggen et al. report that some NSAIDs may reduce the pathogenic amyloid (3 peptide, A(342, by as much as 80% (2001 Nature 414:212-216). This reduction has been reported to occur in a COX-independent mechanism (Eriksen et al. 2002 J. Clinical Invest. 112:440-449). Eriksen also report that flurbiprofen and its enantiomers lower A~342 by targeting the y-secretase complex that produces A(3 from amyloid ~3 protein precursor. US Patent No. 6,255,347 discloses the use of R-ibuprofen for the treatment or prevention of Alzheimer's disease.
Analogs of etodolac are known in the art see, for example, US Patent Nos. US
5,830,911; 5,824,699; 5,776,967; 5,420,289; 4,748,252; 4,686,213; 4,070,371;
3,939,178;
and 3,843,681.
The use of etodolac and enantiomers of etodolac to treat cancer is described in US
Patents Nos. 6,573,292; 6,545,034; and 5,955,504.
The use of NSAIDs to treat inflammation, cancer, and angiogenesis have been reported in the art see, for example, US Patent Nos. 5,972,986; 6,025,353;
5,955,504; and 5,561,151.
SUMMARY OF THE INVENTION
Compounds of Formula I, pharmaceutical compositions comprising them, and methods of using them are provided herein:
Formula I
wherein:
(a) X is C, S or O;
(b) R~ is hydrogen; halogen; -CN; -OH; -SH; -NO2; or an unsubstituted or substituted moiety selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl, wherein the substituted groups are substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, -CN, -NOZ, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted heteroalkyl, unsubstituted haloalkyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted heteroaryl, and -(CH2)ZCN where z is an integer from 0 to 6;
(c) R2, R3, R4 and RS are each independently hydrogen; halogen; -CN; -OH;
-SH; -NO2; or an unsubstituted or substituted moiety selected from lower alkyl, lower alkynyl, lower alkenyl, alkoxy, haloalkyl, aryl, and heteroaryl;
(d) R4, R7, R8 and R9 are each independently hydrogen; halogen; -CN; -OH;
-SH; -N02; or an unsubstituted or substituted moiety selected from alkyl, alkenyl, alkynyl, alkoxy, allyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein at least one of R6, R7, R8 and R9 is an unsubstituted or substituted moiety selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkenyl, and alkynyl;
(e) Rlo is hydrogen; or an unsubstituted or substituted moiety selected from lower alkyl, lower alkenyl, lower alkynyl, aryl; heteroaryl, heterocycloalkyl, and cycloalkyl;
Y is an unsubstituted or substituted moiety selected from alkyl, alkenyl, and alkynyl; and (g) Z is a moiety selected from -OH, -NH2, -SH, -SOZOH, -S(O)H, -OC(O)NHZ, -S(O)ZNH2, -NHC(O)H, C(O)NH2, unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of alkyl, haloalkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;
wherein Rl and Y may cyclize to form an unsubstituted or substituted cycloalkyl group or an unsubstituted or substituted heterocycloalkyl group;
or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt thereof.
3,939,178;
and 3,843,681.
The use of etodolac and enantiomers of etodolac to treat cancer is described in US
Patents Nos. 6,573,292; 6,545,034; and 5,955,504.
The use of NSAIDs to treat inflammation, cancer, and angiogenesis have been reported in the art see, for example, US Patent Nos. 5,972,986; 6,025,353;
5,955,504; and 5,561,151.
SUMMARY OF THE INVENTION
Compounds of Formula I, pharmaceutical compositions comprising them, and methods of using them are provided herein:
Formula I
wherein:
(a) X is C, S or O;
(b) R~ is hydrogen; halogen; -CN; -OH; -SH; -NO2; or an unsubstituted or substituted moiety selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl, wherein the substituted groups are substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, -CN, -NOZ, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted heteroalkyl, unsubstituted haloalkyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted heteroaryl, and -(CH2)ZCN where z is an integer from 0 to 6;
(c) R2, R3, R4 and RS are each independently hydrogen; halogen; -CN; -OH;
-SH; -NO2; or an unsubstituted or substituted moiety selected from lower alkyl, lower alkynyl, lower alkenyl, alkoxy, haloalkyl, aryl, and heteroaryl;
(d) R4, R7, R8 and R9 are each independently hydrogen; halogen; -CN; -OH;
-SH; -N02; or an unsubstituted or substituted moiety selected from alkyl, alkenyl, alkynyl, alkoxy, allyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein at least one of R6, R7, R8 and R9 is an unsubstituted or substituted moiety selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkenyl, and alkynyl;
(e) Rlo is hydrogen; or an unsubstituted or substituted moiety selected from lower alkyl, lower alkenyl, lower alkynyl, aryl; heteroaryl, heterocycloalkyl, and cycloalkyl;
Y is an unsubstituted or substituted moiety selected from alkyl, alkenyl, and alkynyl; and (g) Z is a moiety selected from -OH, -NH2, -SH, -SOZOH, -S(O)H, -OC(O)NHZ, -S(O)ZNH2, -NHC(O)H, C(O)NH2, unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of alkyl, haloalkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;
wherein Rl and Y may cyclize to form an unsubstituted or substituted cycloalkyl group or an unsubstituted or substituted heterocycloalkyl group;
or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt thereof.
In some embodiments, the substituted groups in Rz, R3, R4, R5, R6, R7, Rg, R9 and R1o of Formula I are substituted with one, two or three suitable substituents each independently selected from the group consisting of: halogens, =O, =S, -CN, -NOz, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CHz)ZCN where z is an integer from 0 to 6, =NH, -NHOH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -OC(O)OC(O)H, -OOH, -C(NH)NHz, -NHC(NH)NHz, -C(S)NHz, -NHC(S)NHz, -NHC(O)NHz, -S(Oz)H, -S(O)H, -NHz, -C(O)NHz, -OC(O)NHz, -NHC(O)H, -NHC(O)OH, -C(O)NHC(O)H, -OS(Oz)H, -OS(O)H, -OSH, -SC(O)H, -S(O)C(O)OH, -S02C(O)OH, -NHSH, -NHS(O)H, -NHSOzH, -C(O)SH, -C(O)S(O)H, -C(O)S(Oz)H, -C(S)H, -C(S)OH, -C(SO)OH, -C(SOz)OH, -NHC(S)H, -OC(S)H, -OC(S)OH, -OC(SOz)H, -S(Oz)NHz, -S(O)NHz, -SNHz,-NHCS(Oz)H, -NHC(SO)H, -NHC(S)H, and -SH groups unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, =O, -N02, -CN, -OH, -SH, -(CH2)z-CN where z is an integer from 0 to 6, -OR~, -NR~OR~, -NR~R~, -C(O)NR~, -C(O)OR~, -C(O)R~, -NR~C(O)NR~R~, -NR~C(O)R~, -OC(O)OR~, -OC(O)NR~R~, -SRc, unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls, where R~ is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted heteroaryl, or two or more R~ groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group.
In other embodiments, the substituted groups in Rz, R3, R4, R5, R6, R7, Rg, R9, and Rlo of Formula I are substituted with one, two or three suitable substituents each independently selected from the group consisting o~ halogens, =O, =S, -CN, -NOz, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CHz)ZCN where z is an integer from 0 to 6, =NH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -C(NH)NHz, -NHC(O)NHz, -S(O)H, -NHz, -C(O)NHz, -OC(O)NHz, -NHC(O)H, -NHC(O)OH, -C(S)H, and -SH groups unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, =O, -N02, -CN, -OH, -SH, -(CH2)z-CN where z is an integer from 0 to 6, unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls.
Compounds of Formula I, pharmaceutical compositions comprising them, and methods of using them are provided herein wherein X is S or O; Rl is hydrogen;
or an S unsubstituted moiety selected from lower alkyl, lower alkenyl, lower alkynyl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl; R2, R3, R4, and RS are each independently hydrogen; or an unsubstituted moiety selected from lower alkyl, lower alkynyl, lower alkenyl, alkoxy, haloalkyl, aryl, and heteroaryl; R6, R7, R8, and R9 are each independently hydrogen; or an unsubstituted or substituted moiety selected from alkyl, alkenyl, alkynyl, alkoxy, allyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein at least one, but not more than two, of R~, R7, Rg, and R9 is an unsubstituted or substituted moiety selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkenyl, and alkynyl; and Rio is hydrogen; or an unsubstituted moiety selected from lower alkyl, lower alkenyl, lower alkynyl, aryl, benzyl, heteroaryl, heterocycloalkyl, and cycloalkyl.
Compounds of Formula I, pharmaceutical compositions comprising them, and methods of using them are provided herein, wherein X is O; Rl is an unsubstituted alkyl group or unsubstituted aryl group; R2, R3, R4, and RS are each hydrogen; R7 is an unsubstituted or substituted moiety selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl; and Rlo is hydrogen. In some embodiments, R9 is an unsubstituted alkyl group. In other embodiments, Y is an unsubstitued alkyl group. In still other embodiments Z is hydroxyl. In still other embodiments, R7 is an aryl or heteroaryl group unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, =O, =S, -CN, -NO2, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2)ZCN
where z is an integer from 0 to 6, =NH, -OH, -C(O)H,-OC(O)H, -C(O)OH, -OC(O)OH, -C(NH)NH2, -NHC(O)NH2, -S(O)H, -NHZ, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(S)H, and -SH groups unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, =O, -NOZ, -CN, -OH, -SH, -(CH2)z-CN where z is an integer from 0 to 6, unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls.
In other embodiments, the substituted groups in Rz, R3, R4, R5, R6, R7, Rg, R9, and Rlo of Formula I are substituted with one, two or three suitable substituents each independently selected from the group consisting o~ halogens, =O, =S, -CN, -NOz, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CHz)ZCN where z is an integer from 0 to 6, =NH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -C(NH)NHz, -NHC(O)NHz, -S(O)H, -NHz, -C(O)NHz, -OC(O)NHz, -NHC(O)H, -NHC(O)OH, -C(S)H, and -SH groups unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, =O, -N02, -CN, -OH, -SH, -(CH2)z-CN where z is an integer from 0 to 6, unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls.
Compounds of Formula I, pharmaceutical compositions comprising them, and methods of using them are provided herein wherein X is S or O; Rl is hydrogen;
or an S unsubstituted moiety selected from lower alkyl, lower alkenyl, lower alkynyl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl; R2, R3, R4, and RS are each independently hydrogen; or an unsubstituted moiety selected from lower alkyl, lower alkynyl, lower alkenyl, alkoxy, haloalkyl, aryl, and heteroaryl; R6, R7, R8, and R9 are each independently hydrogen; or an unsubstituted or substituted moiety selected from alkyl, alkenyl, alkynyl, alkoxy, allyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein at least one, but not more than two, of R~, R7, Rg, and R9 is an unsubstituted or substituted moiety selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkenyl, and alkynyl; and Rio is hydrogen; or an unsubstituted moiety selected from lower alkyl, lower alkenyl, lower alkynyl, aryl, benzyl, heteroaryl, heterocycloalkyl, and cycloalkyl.
Compounds of Formula I, pharmaceutical compositions comprising them, and methods of using them are provided herein, wherein X is O; Rl is an unsubstituted alkyl group or unsubstituted aryl group; R2, R3, R4, and RS are each hydrogen; R7 is an unsubstituted or substituted moiety selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl; and Rlo is hydrogen. In some embodiments, R9 is an unsubstituted alkyl group. In other embodiments, Y is an unsubstitued alkyl group. In still other embodiments Z is hydroxyl. In still other embodiments, R7 is an aryl or heteroaryl group unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, =O, =S, -CN, -NO2, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2)ZCN
where z is an integer from 0 to 6, =NH, -OH, -C(O)H,-OC(O)H, -C(O)OH, -OC(O)OH, -C(NH)NH2, -NHC(O)NH2, -S(O)H, -NHZ, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(S)H, and -SH groups unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, =O, -NOZ, -CN, -OH, -SH, -(CH2)z-CN where z is an integer from 0 to 6, unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls.
Compounds of Formula I, pharmaceutical compositions comprising them, and methods of using them are provided herein where X is O; Rl is an unsubstituted lower alkyl group or unsubstituted aryl group; R2, R3, R4, and RS are each hydrogen;
R9 is an unsubstituted or substituted moiety selected from alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; and Rlo is hydrogen. In some embodiments, R7 is an unsubstituted lower alkyl group. In other embodiments, Y is an unsubstituted lower alkyl group. In further embodiments, Z is hydroxyl. In still other embodiments, R7 is an aryl or heteroaryl group unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of: halogens, =O, =S, -CN, -NOZ, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2)ZCN where z is an integer from 0 to 6, =NH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -C(NH)NHz, -NHC(O)NH2, -S(O)H, -NHZ, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(S)H, and -SH groups unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, =O, -N02, -CN, -OH, -SH, -(CH2)z-CN where z is an integer from 0 to 6, unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls.
Compounds of Formula I, pharmaceutical compositions comprising them, and methods of using them are provided herein where X is O; R1 is an unsubstituted moiety selected from aryl, alkyl, and lower-alkoxy; R2, R3, R4, and RS are each hydrogen; R6 and Rg are each hydrogen or halogen; R7 is an unsubstituted or substituted moiety selected from aryl and heteroaryl; R9 is selected from halogen; unsubstituted alkyl;
and an unsubstituted or substituted moiety selected from aryl, heteroaryl, cycloalkyl, alkenyl, and alkynyl; and Rlo is hydrogen; wherein the substituted groups in R7 and R9 are substituted with one, two or three suitable substituents independently selected from the group consisting of: halogens, =O, =S, -CN,-NOZ, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2)ZCN where z is an integer from 0 to 6, =NH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -C(NH)NH2, -NHC(O)NH2, -S(O)H, -NH2, -C(O)NH2, -OC(O)NHz, -NHC(O)H,-NHC(O)OH, -C(S)H, and -SH
groups unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, =O, -N02, -CN, -OH, -SH, -(CH2)z-CN where z is an integer from 0 to 6, unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls. In some embodiments, Y is an unsubstituted lower alkyl group.
In other embodiments, Z is hydroxyl.
Also provided herein are compounds of Formula I, pharmaceutical compositions comprising one or more compounds of Formula I, and methods of using them wherein:
o Ra Formula I
(a) X is C, S or O;
(b) RI is hydrogen; halogen; -CN; -OH; -SH; -N02; or an unsubstituted or substituted moiety selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl, wherein the substituted groups are substituted with one, two or three suitable substituents each independently selected from the group consisting of:
halogens, -CN, -OH, -SH, -NOZ, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted heteroalkyl, unsubstituted haloalkyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted heteroaryl, and -(CH2)ZCN where z is an integer from 0 to 6;
(c) R2, R3, R4 and RS are each independently hydrogen; halogen; -CN; -OH; -SH;
-NOZ; or an unsubstituted or substituted moiety selected from lower alkyl, lower alkynyl, lower alkenyl, alkoxy, haloalkyl, aryl, and heteroaryl;
(d) R6, R8 and R9 are each independently hydrogen; halogen; -CN; -OH; -SH; -NOz; or an unsubstituted or substituted moiety selected from alkyl, alkenyl, alkynyl, alkoxy, allyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;
(e) R7 is hydrogen; halogen; -CN; -OH; -SH; -NOz; or an unsubstituted or substituted moiety selected from alkyl, alkenyl, and alkynyl.
(f) Rlo is hydrogen; or an unsubstituted or substituted moiety selected from lower alkyl, lower alkenyl, lower alkynyl, aryl; heteroaryl, heterocycloalkyl, and cycloalkyl;
(g) Y is an unsubstituted or substituted moiety selected from alkyl, alkenyl, and alkynyl; wherein the substituted moiety is substituted with one, two or three substitutents each independently selected from halogen; -CN; -OH; -SH; -NOz; unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls; and (h) Z is a moiety selected from -OH, -NHz, -SH, -OC(O)NHz, -S(O)zNHz, -S020H, -S(O)H,-NHC(O)H, C(O)NHz, unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of alkyl, haloalkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;
wherein R~ and Y may cyclize to form an unsubstituted or substituted cycloalkyl group or an unsubstituted or substituted heterocycloalkyl group; and at least one of R6, R7, Rg and R9 is not hydrogen; or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt thereof.
In some embodiments, the IC50 of the compound is greater than about 50 ~M for at least one of COX-1 or COX-2. In other embodiments, the IC50 of the compound is greater than about 100 p.M for at least one of COX-1 or COX-2. In yet other embodiments, the IC50 of the compound is greater than about 200 pM for at least one of COX-1 or COX-2.
In other embodiments, the ICSO of the compound is greater than about 50 p,M
for both COX-1 and COX-2. In other embodiments, the IC50 of the compound is greater than about 100 pM for both COX-1 and COX-2. In yet other embodiments, the IC50 of the compound is greater than about 200 p,M for both COX-1 and COX-2.
Compounds of Formula I are described herein wherein: (i) at least one of R6, R7, R8 and R9 is not hydrogen; (ii) when Rl is propyl, Y-Z is ethoxy and R9 is fluorine, R6 is not substituted with a -C(O)-heterocycloalkyl group; (iii) when Y-Z is propoxy and R9 is ethyl, Rl is not CN; (iv) when Rl is ethyl and R9 is ethyl, Y-Z is not unsubstituted or substituted methoxy or unsubstituted or substituted ethoxy; (v) when R~ is methyl and R9 is methyl, Y-Z is not methoxy or ethoxy; (vi) when Y-Z is ethoxy and R9 is ethyl, R~ is not ethoxy; and (vii) when Z is a substituted amide or a substituted amine; R6 is not methyl or chloro; and R7 is not hydroxy, alkoxy-phenyl or methoxy. In some embodiments, Z is unsubstituted hydroxyl.
Compounds of Formula I, pharmaceutical compositions comprising them, and methods of using them are provided herein wherein R~ is hydrogen; or an unsubstituted moiety selected from lower alkyl, lower alkyl-hydroxy, lower alkenyl, lower alkenyl-hydroxy, lower alkynyl, lower alkynyl-hydroxy, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl. In some embodiments, Rl cyclizes with Y to from a substituted or unsubstitued cycloalkyl or heterocycloalkyl group.
Compounds of Formula I, pharmaceutical compositions comprising them, and methods of using them are provided herein wherein R2, R3, Ra and RS are each independently hydrogen; or an unsubstituted moiety selected from lower alkyl, lower alkynyl, lower alkenyl, alkoxy, haloalkyl, aryl, and heteroaryl. In some embodiments, RZ, R3, R4 and RS are each independently hydrogen.
Compounds of Formula I, pharmaceutical compositions comprising them, and methods of using them are provided herein wherein R6, Rg and R9 are each independently hydrogen; or an unsubstituted or substituted moiety selected from alkyl, alkenyl, alkynyl, alkoxy, allyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein at least one of R6, Rg and R9 is not hydrogen. In some embodiments, the substituted moieties are each independently selected from the group consisting of halogen, -CN, alkyl, alkoxy, -NHZ, -O-haloalkyl, -CH(O), haloalkyl, aryl, heteroaryl, heterocycloalkyl, alkenyl, alkynyl, -OH, -C(O)2-alkyl, and -C(O)ZH.
Compounds of Formula I, pharmaceutical compositions comprising them, and methods of using them are provided herein wherein R7 is hydrogen; halogen; or an unsubstituted or substituted moiety selected from alkyl and alkoxy, wherein the substituted moiety is substituted with one, two or three substituents independently selected from the group consisting of -OH, -SH, -C(O)2-alkyl, -C(O)ZH, alkoxy, -O-haloalkyl, halogen, alkyl, haloalkyl, and NHZ. In some embodiments, R7 is hydrogen; halogen; -CN; -OH; -SH; -NOZ; unsubstituted lower alkyl, unsubstituted lower alkenyl, unsubstituted lower alkynyl, lower alkyl-C(O)ZH, lower alkyl-C(O)2-lower alkyl, or alkoxy.
Compounds of Formula I, pharmaceutical compositions comprising them, and methods of using them are provided herein wherein R6 is hydrogen or halogen.
Compounds of Formula I and methods of using them are provided herein wherein Rg is hydrogen or halogen.
S Compounds of Formula I, pharmaceutical compositions comprising them, and methods of using them are provided herein wherein R9 is hydrogen; halogen; or an unsubstituted or substituted moiety selected from alkyl, aryl, heteroaryl, heterocycloalkyl, haloalkyl, alkynyl, alkenyl, haloalkyl, wherein the substituted moiety is substituted with one, two or three substitutents independently selected from the group consisting of alkyl, -C(O)H, -CN, halogen, alkoxy, aryl, and -C(O)ZH.
Compounds of Formula I, pharmaceutical compositions comprising them, and methods of using them are provided herein wherein Rlo is hydrogen, alkyl, or alkyl-aryl.
In some embodiments, X is O. In other embodiments, Y is lower alkyl.
Compounds of Formula I, pharmaceutical compositions comprising them, and methods of using them are provided herein wherein Z is hydroxy. In some embodiments, Z is (C)(O)NHZ unsubstituted or substituted with one or two alkyl groups. In other embodiments, Z is hydroxyl, unsubstituted or substituted lower alkoxy, amino, lower alkylamino, di(lower)alkylamino, arylamino, (aryl)lower alkylamino, di(aryl)lower alkylamino, di(aryl)amino, (heterocycle)amino, (heterocycle)lower alkylamino, di(heterocycle)lower alkylamino, and di(heterocycles)amino.
Compounds of Formula I, pharmaceutical compositions comprising them, and methods of using them are provided herein wherein:
(a) X is S or O;
(b) Rl is hydrogen; or an unsubstituted moiety selected from lower alkyl, lower alkyl-hydroxy, lower alkenyl, lower alkenyl-hydroxy, lower alkynyl, lower alkynyl-hydroxy, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl;
(c) R2, R3, R4 and RS are each independently hydrogen; or an unsubstituted moiety selected from lower alkyl, lower alkynyl, lower alkenyl, alkoxy, haloalkyl, aryl, and heteroaryl;
(d) R6, R8 and R9 are each independently hydrogen; or an unsubstituted or substituted moiety selected from alkyl, alkenyl, alkynyl, alkoxy, allyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein the substituted moieties are each independently selected from the group consisting of halogen, CN, alkyl, alkoxy, NHz, O-haloalkyl, CH(O), haloalkyl, aryl, heteroaryl, heterocycloalkyl, alkenyl, alkynyl, OH, C(O)z-alkyl, and C(O)zH;
S (e) R7 is hydrogen; halogen; -CN; -OH; -SH; -NOz; unsubstituted lower alkyl, unsubstituted lower alkenyl, unsubstituted lower alkynyl, lower alkyl-C(O)zH, lower alkyl-C(O)z-lower alkyl, or lower alkoxy; and (f) Rlo is hydrogen; or an unsubstituted moiety selected from lower alkyl, lower alkenyl, lower alkynyl, aryl, benzyl, heteroaryl, heterocycloalkyl, and cycloalkyl.
Compounds of Formula I, pharmaceutical compositions comprising them, and methods of using them are provided herein wherein:
(a) X is O;
(b) R1 is an unsubstituted alkyl group or unsubstituted aryl group;
(c) Rz, R3, R4 and RS are each hydrogen;
(d) R7 is hydrogen, halogen, unsubstituted lower alkyl, lower alkyl-C(O)zH, lower alkyl-C(O)z-lower alkyl, or alkoxy;
(e) R9 is hydrogen, halogen or an unsubstituted alkyl group;
(f) Y is an unsubstitued alkyl group;
(g) Rlo is hydrogen; and (h) Z is hydroxyl.
Compounds of Formula I, pharmaceutical compositions comprising them, and methods of using them are provided herein wherein at least one of R6, R$ and R9 is an aryl group unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, =O, =S, -CN, -NOz, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CHz)ZCN where z is an integer from 0 to 6, =NH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -C(NH)NHz, -NHC(O)NHz,-S(O)H, -NHz, -C(O)NHz, -OC(O)NHz, -NHC(O)H, -NHC(O)OH, -C(S)H, and -SH groups unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, =O, -NOz, -CN, -OH, -SH, -(CH2)z-CN where z is an integer from 0 to 6, unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls. In some embodiments, at least one of R6, Rg and R9 is a heteroaryl group unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of:
halogens, =O, =S, -CN, -NOz, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CHz)ZCN where z is an integer from 0 to 6, =NH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -C(NH)NHz, -NHC(O)NHz, -S(O)H, -NHz, -C(O)NHz, -OC(O)NHz, -NHC(O)H, -NHC(O)OH, -C(S)H, and -SH
groups unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, =O, -NOz, -CN, -OH, -SH, -(CHz)z-CN where z is an integer from 0 to 6, unsubstituted alkyls, unsubstituted allcenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls. In other embodiments, at least one of Rb, Rg and R9 is a heterocycloalkyl group unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of: halogens, =O, =S, -CN, -NOz, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CHz)ZCN where z is an integer from 0 to 6, =NH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -C(NH)NHz, -NHC(O)NHz,-S(O)H, -NHz, -C(O)NHz, -OC(O)NHz, -NHC(O)H, -NHC(O)OH, -C(S)H, and -SH groups unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, =O, -NOz, -CN, -OH, -SH, -(CHz)z-CN where z is an integer from 0 to 6, unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls.
Compounds of Formula I, pharmaceutical compositions comprising them, and methods of using them are provided herein wherein:
(a) X is O or S;
(b) Rl is an unsubstituted lower alkyl group or unsubstituted aryl group;
(c) Rz, R3, R4 and RS are each hydrogen;
(d) R6 is hydrogen or halogen;
(e) R7 is hydrogen, halogen, unsubstituted lower alkyl, lower alkyl-C(O)zH, lower alkyl-C(O)z-lower alkyl, or alkoxy;
(f) Rg is hydrogen or halogen;
(g) R9 is hydrogen; or an unsubstituted or substituted moiety selected from alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; and (h) R~o is hydrogen. In some embodiments, Y is an unsubstituted lower alkyl group and Z is hydroxyl.
In some embodiments, R9 is a branched alkyl group. In other embodiments, R7 is not hydrogen. In still other embodiments, R7 is a small chemical group, wherein small is defined as taking up less space than a phenyl group. In still other embodiments, Y-Z is an unsubstituted ethoxy group. In yet other embodiments, Rl is an unsubstituted ethyl group.
In yet other embodiments, Z is a moiety selected from -OH, - -SH and -OC(O)NH2.
Pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable carrier are provided herein.
Exemplary compounds within Formulas I are shown below:
_. ~- ..~ _~. mA _~.:. ~..~ :~ ~ , _u.. ,.. ~ w .- , ..._. ;,.~ ..~ .~_~ ., ~ ~ ;~ __.~ .~ W.. ~ .:_. . ~ :: .. ~ . :.~......
-- .~: .~,.~-__.~, ~n a~-. .~"..
~:..f ~~.
STRITC'TU-RE .,... ~..~. NU.A TRUCTURE'~' rtNO :. ~~~ ... ~ ~~5 .r . . W. __ _ _ __.
,: -.~_. ~ ...~.. ._ ~ ~-. ._. ~.._ _. .. W _.. ~T . .~~ _, , . _ .", ~...,-~ F t "a', ~~,:.,-:.f .~m._,..::', __",:.. -:.'. _~:~-.-""w' ~:.;~:d. .,.,~ ".:.:.,.,..,..., ,,;;~;
".... -. _.._-,". , ,:;u ..,"....",~"_... "...:~._ ..,......,_ gm"," ~.....,... , " w .. ,. ~ .,m-- ,....,>."-~" --, a~,~.r .,...".. : ,.,...... , .....ate ~y...,.. ., .,..,.. " ,; ", ,., :" ..."..,Mw"
....
.. ..~... ... ". ," ......,.. . , --.. .,... . . .....,....e..
,~ > ,..w ,. w, , , ...,. , , .-., , .,. ,."..., .. ....... . .. -, : ~ , ""."..... , ",.,.,..,...., ~-. , .....", ...,.. ,...., '~_..._...- -....:as'~~.,.. , -~.~,:,,.,~, ....... ~ ",.,.,... .. ",~~,..y~ , ,....,.. ...,., " '.a...z.....", " ... - m ........,-, -..., ....--;,:.:.:.
""".. "~ ... ,.,..,._..,."., " , ..,....
O
J
1 \ ~ / \ /
~/v ~' / \ \ o H~ \ OH ~ i H ~~OH
OCF3 _ / \
3 / \ ' 4 ~ \ \ O
\ o H OH
H ~~OH
F ~ F
\ / ~; N
\ /
5 / ~ ° 6 / \ \ o \ o H OH
H/~~OH
F NHz \/ ~/
/ ~ \ o / ~ \ o H/~OH H/~OH
.;~~ - ~z ~ '~; . :~~ r,NO a ~ ,_. -,~ STRUCTURE:' NU M.~ :. ~ , x ~'T.RU~TURE ::
. ~
oho F F
\ /
R9 is an unsubstituted or substituted moiety selected from alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; and Rlo is hydrogen. In some embodiments, R7 is an unsubstituted lower alkyl group. In other embodiments, Y is an unsubstituted lower alkyl group. In further embodiments, Z is hydroxyl. In still other embodiments, R7 is an aryl or heteroaryl group unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of: halogens, =O, =S, -CN, -NOZ, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2)ZCN where z is an integer from 0 to 6, =NH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -C(NH)NHz, -NHC(O)NH2, -S(O)H, -NHZ, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(S)H, and -SH groups unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, =O, -N02, -CN, -OH, -SH, -(CH2)z-CN where z is an integer from 0 to 6, unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls.
Compounds of Formula I, pharmaceutical compositions comprising them, and methods of using them are provided herein where X is O; R1 is an unsubstituted moiety selected from aryl, alkyl, and lower-alkoxy; R2, R3, R4, and RS are each hydrogen; R6 and Rg are each hydrogen or halogen; R7 is an unsubstituted or substituted moiety selected from aryl and heteroaryl; R9 is selected from halogen; unsubstituted alkyl;
and an unsubstituted or substituted moiety selected from aryl, heteroaryl, cycloalkyl, alkenyl, and alkynyl; and Rlo is hydrogen; wherein the substituted groups in R7 and R9 are substituted with one, two or three suitable substituents independently selected from the group consisting of: halogens, =O, =S, -CN,-NOZ, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2)ZCN where z is an integer from 0 to 6, =NH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -C(NH)NH2, -NHC(O)NH2, -S(O)H, -NH2, -C(O)NH2, -OC(O)NHz, -NHC(O)H,-NHC(O)OH, -C(S)H, and -SH
groups unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, =O, -N02, -CN, -OH, -SH, -(CH2)z-CN where z is an integer from 0 to 6, unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls. In some embodiments, Y is an unsubstituted lower alkyl group.
In other embodiments, Z is hydroxyl.
Also provided herein are compounds of Formula I, pharmaceutical compositions comprising one or more compounds of Formula I, and methods of using them wherein:
o Ra Formula I
(a) X is C, S or O;
(b) RI is hydrogen; halogen; -CN; -OH; -SH; -N02; or an unsubstituted or substituted moiety selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl, wherein the substituted groups are substituted with one, two or three suitable substituents each independently selected from the group consisting of:
halogens, -CN, -OH, -SH, -NOZ, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted heteroalkyl, unsubstituted haloalkyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted heteroaryl, and -(CH2)ZCN where z is an integer from 0 to 6;
(c) R2, R3, R4 and RS are each independently hydrogen; halogen; -CN; -OH; -SH;
-NOZ; or an unsubstituted or substituted moiety selected from lower alkyl, lower alkynyl, lower alkenyl, alkoxy, haloalkyl, aryl, and heteroaryl;
(d) R6, R8 and R9 are each independently hydrogen; halogen; -CN; -OH; -SH; -NOz; or an unsubstituted or substituted moiety selected from alkyl, alkenyl, alkynyl, alkoxy, allyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;
(e) R7 is hydrogen; halogen; -CN; -OH; -SH; -NOz; or an unsubstituted or substituted moiety selected from alkyl, alkenyl, and alkynyl.
(f) Rlo is hydrogen; or an unsubstituted or substituted moiety selected from lower alkyl, lower alkenyl, lower alkynyl, aryl; heteroaryl, heterocycloalkyl, and cycloalkyl;
(g) Y is an unsubstituted or substituted moiety selected from alkyl, alkenyl, and alkynyl; wherein the substituted moiety is substituted with one, two or three substitutents each independently selected from halogen; -CN; -OH; -SH; -NOz; unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls; and (h) Z is a moiety selected from -OH, -NHz, -SH, -OC(O)NHz, -S(O)zNHz, -S020H, -S(O)H,-NHC(O)H, C(O)NHz, unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of alkyl, haloalkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;
wherein R~ and Y may cyclize to form an unsubstituted or substituted cycloalkyl group or an unsubstituted or substituted heterocycloalkyl group; and at least one of R6, R7, Rg and R9 is not hydrogen; or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt thereof.
In some embodiments, the IC50 of the compound is greater than about 50 ~M for at least one of COX-1 or COX-2. In other embodiments, the IC50 of the compound is greater than about 100 p.M for at least one of COX-1 or COX-2. In yet other embodiments, the IC50 of the compound is greater than about 200 pM for at least one of COX-1 or COX-2.
In other embodiments, the ICSO of the compound is greater than about 50 p,M
for both COX-1 and COX-2. In other embodiments, the IC50 of the compound is greater than about 100 pM for both COX-1 and COX-2. In yet other embodiments, the IC50 of the compound is greater than about 200 p,M for both COX-1 and COX-2.
Compounds of Formula I are described herein wherein: (i) at least one of R6, R7, R8 and R9 is not hydrogen; (ii) when Rl is propyl, Y-Z is ethoxy and R9 is fluorine, R6 is not substituted with a -C(O)-heterocycloalkyl group; (iii) when Y-Z is propoxy and R9 is ethyl, Rl is not CN; (iv) when Rl is ethyl and R9 is ethyl, Y-Z is not unsubstituted or substituted methoxy or unsubstituted or substituted ethoxy; (v) when R~ is methyl and R9 is methyl, Y-Z is not methoxy or ethoxy; (vi) when Y-Z is ethoxy and R9 is ethyl, R~ is not ethoxy; and (vii) when Z is a substituted amide or a substituted amine; R6 is not methyl or chloro; and R7 is not hydroxy, alkoxy-phenyl or methoxy. In some embodiments, Z is unsubstituted hydroxyl.
Compounds of Formula I, pharmaceutical compositions comprising them, and methods of using them are provided herein wherein R~ is hydrogen; or an unsubstituted moiety selected from lower alkyl, lower alkyl-hydroxy, lower alkenyl, lower alkenyl-hydroxy, lower alkynyl, lower alkynyl-hydroxy, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl. In some embodiments, Rl cyclizes with Y to from a substituted or unsubstitued cycloalkyl or heterocycloalkyl group.
Compounds of Formula I, pharmaceutical compositions comprising them, and methods of using them are provided herein wherein R2, R3, Ra and RS are each independently hydrogen; or an unsubstituted moiety selected from lower alkyl, lower alkynyl, lower alkenyl, alkoxy, haloalkyl, aryl, and heteroaryl. In some embodiments, RZ, R3, R4 and RS are each independently hydrogen.
Compounds of Formula I, pharmaceutical compositions comprising them, and methods of using them are provided herein wherein R6, Rg and R9 are each independently hydrogen; or an unsubstituted or substituted moiety selected from alkyl, alkenyl, alkynyl, alkoxy, allyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein at least one of R6, Rg and R9 is not hydrogen. In some embodiments, the substituted moieties are each independently selected from the group consisting of halogen, -CN, alkyl, alkoxy, -NHZ, -O-haloalkyl, -CH(O), haloalkyl, aryl, heteroaryl, heterocycloalkyl, alkenyl, alkynyl, -OH, -C(O)2-alkyl, and -C(O)ZH.
Compounds of Formula I, pharmaceutical compositions comprising them, and methods of using them are provided herein wherein R7 is hydrogen; halogen; or an unsubstituted or substituted moiety selected from alkyl and alkoxy, wherein the substituted moiety is substituted with one, two or three substituents independently selected from the group consisting of -OH, -SH, -C(O)2-alkyl, -C(O)ZH, alkoxy, -O-haloalkyl, halogen, alkyl, haloalkyl, and NHZ. In some embodiments, R7 is hydrogen; halogen; -CN; -OH; -SH; -NOZ; unsubstituted lower alkyl, unsubstituted lower alkenyl, unsubstituted lower alkynyl, lower alkyl-C(O)ZH, lower alkyl-C(O)2-lower alkyl, or alkoxy.
Compounds of Formula I, pharmaceutical compositions comprising them, and methods of using them are provided herein wherein R6 is hydrogen or halogen.
Compounds of Formula I and methods of using them are provided herein wherein Rg is hydrogen or halogen.
S Compounds of Formula I, pharmaceutical compositions comprising them, and methods of using them are provided herein wherein R9 is hydrogen; halogen; or an unsubstituted or substituted moiety selected from alkyl, aryl, heteroaryl, heterocycloalkyl, haloalkyl, alkynyl, alkenyl, haloalkyl, wherein the substituted moiety is substituted with one, two or three substitutents independently selected from the group consisting of alkyl, -C(O)H, -CN, halogen, alkoxy, aryl, and -C(O)ZH.
Compounds of Formula I, pharmaceutical compositions comprising them, and methods of using them are provided herein wherein Rlo is hydrogen, alkyl, or alkyl-aryl.
In some embodiments, X is O. In other embodiments, Y is lower alkyl.
Compounds of Formula I, pharmaceutical compositions comprising them, and methods of using them are provided herein wherein Z is hydroxy. In some embodiments, Z is (C)(O)NHZ unsubstituted or substituted with one or two alkyl groups. In other embodiments, Z is hydroxyl, unsubstituted or substituted lower alkoxy, amino, lower alkylamino, di(lower)alkylamino, arylamino, (aryl)lower alkylamino, di(aryl)lower alkylamino, di(aryl)amino, (heterocycle)amino, (heterocycle)lower alkylamino, di(heterocycle)lower alkylamino, and di(heterocycles)amino.
Compounds of Formula I, pharmaceutical compositions comprising them, and methods of using them are provided herein wherein:
(a) X is S or O;
(b) Rl is hydrogen; or an unsubstituted moiety selected from lower alkyl, lower alkyl-hydroxy, lower alkenyl, lower alkenyl-hydroxy, lower alkynyl, lower alkynyl-hydroxy, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl;
(c) R2, R3, R4 and RS are each independently hydrogen; or an unsubstituted moiety selected from lower alkyl, lower alkynyl, lower alkenyl, alkoxy, haloalkyl, aryl, and heteroaryl;
(d) R6, R8 and R9 are each independently hydrogen; or an unsubstituted or substituted moiety selected from alkyl, alkenyl, alkynyl, alkoxy, allyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein the substituted moieties are each independently selected from the group consisting of halogen, CN, alkyl, alkoxy, NHz, O-haloalkyl, CH(O), haloalkyl, aryl, heteroaryl, heterocycloalkyl, alkenyl, alkynyl, OH, C(O)z-alkyl, and C(O)zH;
S (e) R7 is hydrogen; halogen; -CN; -OH; -SH; -NOz; unsubstituted lower alkyl, unsubstituted lower alkenyl, unsubstituted lower alkynyl, lower alkyl-C(O)zH, lower alkyl-C(O)z-lower alkyl, or lower alkoxy; and (f) Rlo is hydrogen; or an unsubstituted moiety selected from lower alkyl, lower alkenyl, lower alkynyl, aryl, benzyl, heteroaryl, heterocycloalkyl, and cycloalkyl.
Compounds of Formula I, pharmaceutical compositions comprising them, and methods of using them are provided herein wherein:
(a) X is O;
(b) R1 is an unsubstituted alkyl group or unsubstituted aryl group;
(c) Rz, R3, R4 and RS are each hydrogen;
(d) R7 is hydrogen, halogen, unsubstituted lower alkyl, lower alkyl-C(O)zH, lower alkyl-C(O)z-lower alkyl, or alkoxy;
(e) R9 is hydrogen, halogen or an unsubstituted alkyl group;
(f) Y is an unsubstitued alkyl group;
(g) Rlo is hydrogen; and (h) Z is hydroxyl.
Compounds of Formula I, pharmaceutical compositions comprising them, and methods of using them are provided herein wherein at least one of R6, R$ and R9 is an aryl group unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, =O, =S, -CN, -NOz, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CHz)ZCN where z is an integer from 0 to 6, =NH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -C(NH)NHz, -NHC(O)NHz,-S(O)H, -NHz, -C(O)NHz, -OC(O)NHz, -NHC(O)H, -NHC(O)OH, -C(S)H, and -SH groups unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, =O, -NOz, -CN, -OH, -SH, -(CH2)z-CN where z is an integer from 0 to 6, unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls. In some embodiments, at least one of R6, Rg and R9 is a heteroaryl group unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of:
halogens, =O, =S, -CN, -NOz, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CHz)ZCN where z is an integer from 0 to 6, =NH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -C(NH)NHz, -NHC(O)NHz, -S(O)H, -NHz, -C(O)NHz, -OC(O)NHz, -NHC(O)H, -NHC(O)OH, -C(S)H, and -SH
groups unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, =O, -NOz, -CN, -OH, -SH, -(CHz)z-CN where z is an integer from 0 to 6, unsubstituted alkyls, unsubstituted allcenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls. In other embodiments, at least one of Rb, Rg and R9 is a heterocycloalkyl group unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of: halogens, =O, =S, -CN, -NOz, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CHz)ZCN where z is an integer from 0 to 6, =NH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -C(NH)NHz, -NHC(O)NHz,-S(O)H, -NHz, -C(O)NHz, -OC(O)NHz, -NHC(O)H, -NHC(O)OH, -C(S)H, and -SH groups unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, =O, -NOz, -CN, -OH, -SH, -(CHz)z-CN where z is an integer from 0 to 6, unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls.
Compounds of Formula I, pharmaceutical compositions comprising them, and methods of using them are provided herein wherein:
(a) X is O or S;
(b) Rl is an unsubstituted lower alkyl group or unsubstituted aryl group;
(c) Rz, R3, R4 and RS are each hydrogen;
(d) R6 is hydrogen or halogen;
(e) R7 is hydrogen, halogen, unsubstituted lower alkyl, lower alkyl-C(O)zH, lower alkyl-C(O)z-lower alkyl, or alkoxy;
(f) Rg is hydrogen or halogen;
(g) R9 is hydrogen; or an unsubstituted or substituted moiety selected from alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; and (h) R~o is hydrogen. In some embodiments, Y is an unsubstituted lower alkyl group and Z is hydroxyl.
In some embodiments, R9 is a branched alkyl group. In other embodiments, R7 is not hydrogen. In still other embodiments, R7 is a small chemical group, wherein small is defined as taking up less space than a phenyl group. In still other embodiments, Y-Z is an unsubstituted ethoxy group. In yet other embodiments, Rl is an unsubstituted ethyl group.
In yet other embodiments, Z is a moiety selected from -OH, - -SH and -OC(O)NH2.
Pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable carrier are provided herein.
Exemplary compounds within Formulas I are shown below:
_. ~- ..~ _~. mA _~.:. ~..~ :~ ~ , _u.. ,.. ~ w .- , ..._. ;,.~ ..~ .~_~ ., ~ ~ ;~ __.~ .~ W.. ~ .:_. . ~ :: .. ~ . :.~......
-- .~: .~,.~-__.~, ~n a~-. .~"..
~:..f ~~.
STRITC'TU-RE .,... ~..~. NU.A TRUCTURE'~' rtNO :. ~~~ ... ~ ~~5 .r . . W. __ _ _ __.
,: -.~_. ~ ...~.. ._ ~ ~-. ._. ~.._ _. .. W _.. ~T . .~~ _, , . _ .", ~...,-~ F t "a', ~~,:.,-:.f .~m._,..::', __",:.. -:.'. _~:~-.-""w' ~:.;~:d. .,.,~ ".:.:.,.,..,..., ,,;;~;
".... -. _.._-,". , ,:;u ..,"....",~"_... "...:~._ ..,......,_ gm"," ~.....,... , " w .. ,. ~ .,m-- ,....,>."-~" --, a~,~.r .,...".. : ,.,...... , .....ate ~y...,.. ., .,..,.. " ,; ", ,., :" ..."..,Mw"
....
.. ..~... ... ". ," ......,.. . , --.. .,... . . .....,....e..
,~ > ,..w ,. w, , , ...,. , , .-., , .,. ,."..., .. ....... . .. -, : ~ , ""."..... , ",.,.,..,...., ~-. , .....", ...,.. ,...., '~_..._...- -....:as'~~.,.. , -~.~,:,,.,~, ....... ~ ",.,.,... .. ",~~,..y~ , ,....,.. ...,., " '.a...z.....", " ... - m ........,-, -..., ....--;,:.:.:.
""".. "~ ... ,.,..,._..,."., " , ..,....
O
J
1 \ ~ / \ /
~/v ~' / \ \ o H~ \ OH ~ i H ~~OH
OCF3 _ / \
3 / \ ' 4 ~ \ \ O
\ o H OH
H ~~OH
F ~ F
\ / ~; N
\ /
5 / ~ ° 6 / \ \ o \ o H OH
H/~~OH
F NHz \/ ~/
/ ~ \ o / ~ \ o H/~OH H/~OH
.;~~ - ~z ~ '~; . :~~ r,NO a ~ ,_. -,~ STRUCTURE:' NU M.~ :. ~ , x ~'T.RU~TURE ::
. ~
oho F F
\ /
\ / \
\ O
" __(~o" H ~OH
CI S
\ O
\ O
" __(~o" H ~OH
CI S
\ O
11 \ '12 /~ \
\ O
' ~ H ~~OH
'' -H~>
13 / \ \ ~ H~3.14 / \ \ O
N p N
H ~ OOH v ~ H ~ OOH
\ ~ \ /
CN ~ Br / \ O
/~~
15 OH 1 ( N _ ~ H ~ H ~ ~OH
\ / \ /
F
\ / H02C
/ \ \
17 ~ N\ ~ ~~~18 H ~V OOH J H ~~OH
\ / \ /
CHO
/ \
O
H /~_ ~
19 ~ 20 N
~ \ H
OH ~~OH
\ /
O
\ /
'- ~ ~ ..rv ~~-~"
~~'',f ~ .
TRUCII'U:RE~
1'10 ~ ~~~TRI~TCTU=RE r~' ~~10 ~~ $~
_.. ~ ..a ~ ~, ~ ~:
22 \ ~ ~ °
21 H/~~OH \ ~
H / v \OH
J
23 ~° ~ I ~ ° °H 24 -~'v ~ OH
N~~~~ ~ N
H \ H
i 25 \ ~ ~ ~ 26 \
H OH ~"' F H OH
27 \ ~ ~ ~ 28 \ ~ ~ °
H OH ~~ H~~J'~_~~OH
a e~
29 ~ ~ 30 N v ° H OH
H OH
i 31 ~\ \ 4~ 32 \H H OH
HO
i v 33 \ ~ ~ ~ \NH 3 A \
~+ ~N
H
H O
~ '" off i 35 \ ~ ~ \ ~M 36 \
H ~//~~~~~OH ~ ,, H C v \OH
CI
37 \ ~ ~ \ 38 ~ ~ °
F \H/ --~OH
F H v \OH
F
M ,~ ~ ~-~~ ~ ~
N~. ~,~ ~~~~~~~~, ;
~-~~ STRLICT~U~R,E~N.r O ;,, ~ , "~ r STRI~TUC URE
ON
O
O-O p 55 '56 w \ p \N ~7~\~
H ~~OH
OH ~,, .:~, iii' OH
s z r.
~z;
57 a OH ~:~'7~:
or pharmaceutically acceptable salts thereof.
Pharmaceutical compositions comprising a therapeutically effective amount of a prodrug, active metabolite, or pharmaceutically acceptable salt of a compound of Formula I, as well as pharmaceutically acceptable salts of such active metabolites, are also provided herein.
Methods of treating a neoplasia comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising a compound of Formula I are provided herein. In some embodiments, the neoplasia is a hematological cancer. In other embodiments, the neoplasia is selected from leukemias such as chronic lymphocytic leukemia, myelomas such as multiple myeloma, and lymphomas. In still other embodiments, the cancer is selected from brain cancer, bone cancer, basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, mouth cancer, esophageal cancer, small bowel cancer, stomach cancer, colon cancer, liver cancer, bladder cancer, 1 S pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer, skin cancer, prostate cancer, and renal cell carcinoma.
Methods for treating cancer by administering a composition comprising a therapeutically effective amount of a composition of Formula I given in combination with another antineoplastic agent are provided herein. In some embodiments, the antineoplastic agent is an alkylating agent. In other embodiments, the alkylating agent is selected from the group consisting of bendamustine, chlorambucil, cyclophosphamide and melphalan.
In still other embodiments, the antineoplastic agent is a glucocorticoid. In yet other embodiments, the glucocoritcoid is prednisone. In some embodiments, the glucocorticoid is given in combination with additional antineoplastic agents.
Methods for treating a disease mediated by ~i-catenin in a subject in need of such therapy wherein a therapeutically effective amount of a compound of Formula I
is administered to the subj ect, are provided herein.
Methods for treating a disease mediated by Cyclin D1 in a subject in need of such therapy wherein a therapeutically effective amount of a compound of Formula I
is administered to the subject, are also provided herein.
Methods for reducing or preventing the development of Alzheimer's disease comprising administering to a subject in thereof a therapeutically effective amount of a composition comprising a compound of Formula I are provided herein. In some embodiments, the method comprises administering to a mammal in need of such treatment a therapeutically effective amount of: (a) at least one compound, pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite of Formula I; and (b) at least one agent selected from the group consisting of estrogen, risperidone, a thiobenzodiazepine, ampakine, [N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide, DM9384, a cholinesterase inhibitor, donepezil hydrochloride, rivastigmine tartrate, galantamine, NGF, and metrifonate.
Methods for treating a disease in a mammal treatable by administration of a COX-1 and/or COX-2 inhibitor comprising administering to the mammal a therapeutically effective amount of a compound of Formula I which inhibits one or both of COX-1 or COX-2 are provided herein. In some embodiments, the disease is an inflammatory disease.
Methods for treating a hyperplastic disease in a mammal comprising administration to the mammal a therapeutically effective amount of a compound of Formula I are provided herein.
Methods for inhibiting or delaying the onset of a neoplasia in a mammal in need of such treatment comprising administration to the mammal a therapeutically effective amount of a compound of Formula I are provided herein. In some embodiments, the neoplasia is selected from the group consisting of adenomatous polyps, gastrointestinal cancer, liver cancer, bladder cancer, cervical cancer, prostate cancer, lung cancer, breast cancer, and skin cancer.
Methods for treating, inhibiting or delaying the onset of uncontrolled or abnormal angiogenesis in a subject in need of such treatment, inhibition or delay, wherein the uncontrolled or abnormal angiogenesis is selected from the group consisting of metastasis, corneal graft rejection, ocular neovascularization, retinal neovascularization, diabetic retinopathy, retrolental fibroplasia, neovascular glaucoma, gastric ulcer, infantile hemaginomas, angiofibroma of the nasopharynx, avascular necrosis of bone, and endometriosis, and the method comprises treating the subject with a therapeutically effective amount of a compound of Formula I are provided herein.
Pharmaceutical compositions for the treatment of one or more conditions selected from the group consisting of arthritis, fever, common cold, dysmenorrhea, menstrual cramps, inflammatory bowel disease, Crohn's disease, emphysema, acute respiratory distress syndrome, asthma, bronchitis, chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer, tissue ulceration, peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis, recurrent gastrointestinal lesion, gastrointestinal bleeding, coagulation, anemia, synovitis, gout, ankylosing spondylitis, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, loosening of artificial joint implants, atherosclerosis, aortic aneurysm, periarteritis nodosa, congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neuralgia, neuro-degenerative disorders, autoimmune disorders, Huntington's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain, gingivitis, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, conjunctivitis, abnormal wound healing, muscle or joint sprains or strains, tendonitis, skin disorders, myasthenia gravis, polymyositis, myositis, bursitis, bums, diabetes, tumor invasion, tumor growth, tumor metastasis, corneal scarnng, scleritis, immunodeficiency diseases, sepsis, premature labor, hypoprothrombinemia, hemophilia, thyroiditis, sarcoidosis, Behcet's syndrome, hypersensitivity, schizophrenia, kidney disease, Rickettsial infections, Protozoan diseases, reproductive disorders, obesity, and septic shock in a mammal, comprising an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof effective in such treatments and a pharmaceutically acceptable carrier are provided herein.
Methods of treating a neoplasia in a subject in need of treatment where the subject is treated with a composition comprising a compound of Formula I. Neoplasms that can be treated include, but are not limited to, hematological cancers, such as leukemias, myelomas and lymphomas, brain cancer, bone cancer, epithelial cell derived neoplasia (epithelial carcinoma) such as basal cell carcinoma, adenocarcinoma, gastrointestinal cancer such as lip cancer, mouth cancer, esophageal cancer, small bowel cancer, stomach cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer, skin cancer such as squamous cell and basal cell cancers, prostate cancer, renal cell carcinoma, and other known cancers that effect epithelial cells throughout the body and cancers of the bone marrow.
Methods for treating one or more conditions selected from the group consisting of arthritis, fever, common cold, dysmenorrhea, menstrual cramps, inflammatory bowel disease, Crohn's disease, emphysema, acute respiratory distress syndrome, obesity, asthma, bronchitis, chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer, tissue ulceration, peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis, recurrent gastrointestinal lesion, gastrointestinal bleeding, coagulation, anemia, synovitis, gout, ankylosing spondylitis, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, loosening of artificial joint implants, atherosclerosis, aortic aneurysm, periarteritis nodosa, congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neuralgia, neuro-degenerative disorders, autoimmune disorders, Huntington's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain, gingivitis, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, conjunctivitis, abnormal wound healing, muscle or joint sprains or strains, tendonitis, skin disorders, myasthenia gravis, polymyositis, myositis, bursitis, burns, diabetes, tumor invasion, tumor growth, tumor metastasis, corneal scarring, scleritis, immunodeficiency diseases, sepsis, premature labor, hypoprothrombinemia, hemophilia, thyroiditis, sarcoidosis, Behcet's syndrome, hypersensitivity, schizophrenia, kidney disease, Rickettsial infections, Protozoan diseases, reproductive disorders, and septic shock in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof effective in treating such a condition, are provided herein.
In some embodiments, methods for treating a hyperplastic disease in a mammal by administering to the mammal a therapeutically effective amount of a compound of Formula I.
In other embodiments, methods for treating, inhibiting, or delaying the onset of uncontrolled or abnormal angiogenesis in a subject in need of such treatment, inhibition, or delay by administering a therapeutically effective amount of a compound of Formula I, are provided. In one embodiment of this method, the uncontrolled or abnormal angiogenesis to be treated is selected from the group including, but not limited to, metastasis, corneal graft rejection, ocular neovascularization, retinal neovascularization, diabetic retinopathy, retrolental fibroplasia, neovascular glaucoma, gastric ulcer, infantile hemaginomas, angiofibroma of the nasopharynx, avascular necrosis of bone, and endometriosis.
In still other embodiments, methods for selecting a subject for treatment of a disease or condition mediated by (3-catenin where the method involves obtaining a sample of the subject's tumor, determining if (3-catenin is activated in the tumor, and treating the subject with an agent that modulates (3-catenin activity. In one related method, (3-catenin activation is determined with immunohistochemical methods.
In still other embodiments, methods for selecting a subject for treatment of a disease or condition mediated by Cyclin Dl where the method involves obtaining a sample of the subject's tumor, determining if Cyclin D1 is overexpressed in the tumor, and treating the subject with an agent that modulates Cyclin D1 activity.
Preferred compounds for use in the method are compounds of Formula I. In one related method, Cyclin D1 overexpression is determined using quantitative PCR.
BRIEF DESCRIPTION OF THE DRAWINGS
FIGURE 1 shows inhibition of (3-catenin:TOP flash by R-etodolac and compounds of the invention.
FIGURE 2 shows inhibition of Cyclin D1 mRNA expression by R-etodolac and compounds of the invention.
DETAILED DESCRIPTION OF THE INVENTION
To more readily facilitate an understanding of the invention and its preferred embodiments, the meanings of terms used herein will become apparent from the context of this specification in view of common usage of various terms and the explicit definitions of other terms provided in the glossary below or in the ensuing description.
Glossary of Terms As used herein, the terms "comprising," "including," and "such as" are used in their open, non-limiting sense.
As used herein and in the appended claims, the singular forms "a", "an", and "the"
include plural reference unless the context clearly dictates otherwise.
../
In accordance with a convention used in the art, %~w is used in structural formulae herein to depict the bond that is the point of attachment of the moiety or substituent to the core or backbone structure.
In accordance with a convention used in the art, the symbol ~ represents a methyl group, ~ represents an ethyl group, ~ represents a cyclopentyl group, etc.
The term "alkyl" as used herein refers to a straight- or branched-chain alkyl group having one to twelve carbon atoms. Exemplary alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and the like. The term "lower alkyl" designates an alkyl having from 1 to 6 carbon atoms (a C1_6-alkyl).
The term "heteroalkyl" as used herein refers to straight- and branched-chain alkyl groups having from one to twelve atoms containing one or more heteroatoms selected from S, O, and N. The term "lower heteroalkyl" designates a heteroalkyl having from 1 to 6 carbon atoms (a Cl_6-heteroalkyl).
The term "alkenyl" means an alkyl radical having one or more double bonds and two to twelve carbon atoms. Alkenyl groups containing three or more carbon atoms may be straight or branched. Alkenyl groups as used herein include either the cis or trans configurations. Illustrative alkenyl groups include prop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, hex-2-enyl, and the like. The term "lower alkenyl"
designates an alkyl having from 1 to 6 carbon atoms (a C1_6-alkenyl).
The term "allyloxy" refers to an alkenyloxy group which is CHZ=CHCHZ-O-.
The term "alkynyl" means an alkyl radical having one or more triple bonds and two to twelve carbon atoms. Alkynyl groups containing three or more carbon atoms may be straight or branched. Alkynyl groups as used herein include either the cis or traps configurations. Illustrative alkynyl groups include prop-2-ynyl, but-2-ynyl, but-3-ynyl, 2-methylbut-2-ynyl, hex-2-ynyl, and the like. The term "lower alkynyl"
designates an alkyl having from 1 to 6 carbon atoms (a CI_6-alkynyl).
The term "aryl" (Ar) refers to a monocyclic, or fused or spiro polycyclic, aromatic carbocycle (ring structure having ring atoms that are all carbon) having from three to twelve ring atoms per ring. Illustrative examples of aryl groups include the following moieties:
\ \ I \ \ \ I ~\ I \ \
~ ~ ~ , ~ ~ , ~ ~ , and the like.
The term "heteroaryl" (heteroAr) refers to a monocyclic, or fused or spiro polycyclic, aromatic heterocycle (ring structure having ring atoms selected from carbon atoms as well as nitrogen, oxygen, and sulfur heteroatoms) having from three to twelve ring atoms per ring. Illustrative examples of heteroaryl groups include the following moieties:
N~N N~N I ~ ~ I ~ O I ~ N\
~N ~ NON , / , / ~ , / N// , N S O ,O N S ,S
W , W , ~~ ~ N~ ~ , ~ ~ ~ ~~ N~ ~ , N N N
N~N O INS N ~ INS INN
,, " , ~ . c~ . .
~N ~ N > > S
s o \ /
I N \ \ ~N ~ O
S~ ~ I / N~ ~ I / ~, I / , and the like.
The term "cycloalkyl" refers to a saturated or partially saturated, monocyclic or fused or spiro polycyclic, carbocycle having from three to twelve ring atoms per ring.
Illustrative examples of cycloalkyl groups include the following moieties:
> > , , ~~ a > > > >
~ ~ ~, ~
to > > > > >
and the like.
A "heterocycloalkyl" refers to a monocyclic, or fused or spiro polycyclic, ring structure that is saturated or partially saturated and has from three to twelve ring atoms per ring selected from C atoms and N, O, and S heteroatoms. Illustrative examples of 1 S heterocycloalkyl groups include:
O O O O O O
~S~ N
S N~N N O O O
U
, ,~ ~ , N N~ O O C N
O
U ~ ~ , U , ~N , , U , N-N , N
O
O S II
I I N N ~O O
n c~ c~
, n N , N ~ ~ c ~ , N N N ~ , O
N_S O N N I \ O S
N , , ~ ~ ~ U, , O and the hke.
The term "alkoxy" refers to O-alkyl. Illustrative examples include methoxy, ethoxy, propoxy, and the like.
The term "halogen" represents chlorine, fluorine, bromine or iodine. The term "halo" represents chloro, fluoro, bromo or iodo.
Unless otherwise defined, the term "substituted" as used herein means at least one hydrogen atom is replaced with a suitable substituent.
The term "unsubstituted" means that the specified group bears no substituents.
The term "lower" when refernng to a group such as an alkyl, alkenyl, alkynyl, alkoxy or other group refers to such a group having up to 6 carbon atoms.
As used herein "tumors" or "neoplasms" include growths of tissue cells wherein multiplication of cells is uncontrolled and progressive. Some such growths are benign, but others are termed malignant and can lead to death of the organism. Malignant neoplasms, or cancers are distinguished from benign growths in that in addition to exhibiting aggressive cellular proliferation can invade surrounding tissues and metastasize.
Malignant neoplasms may be characterized by showing a greater loss of differentiation and organization relative to one another and surrounding tissues.
"Hyperplasia" refers to the abnormal multiplication or increase in the number of normal cells in normal arrangement in a tissue.
The term "subject" for purposes of treatment includes any human or animal subject who has any one of the known diseases or conditions described herein, e.g., cancer, hyperplasia, inflammation, Alzheimer's, and abnormal angiogenesis. For methods of prevention, the subject is any human or animal subject, and preferably is a human subject who is at risk for the disease or conditions described herein, e.g., cancer.
The subject may be at risk due to a genetic predisposition, and/or exposure to various agents, including chemicals and viral agents. Besides being useful for human treatment, the compounds described herein are also useful for veterinary treatment of mammals, including companion animals and farm animals, such as horses, dogs, cats, cows, sheep and pigs.
Preferably, subject means a human.
As used herein "a disease mediated by a-catenin" means a disease that is associated with changes in (3-catenin regulation such that the its levels, distribution and/or association with other proteins in the cytoplasm and nucleus differ from that found in normal cells. Changes in ~3-catenin levels, associations, and/or distribution, e.g., nuclear accumulation may result from mutations in ~3 -catenin, APC, axin or other proteins involved in the trafficking of ~i-catenin. ,Q -catenin accumulation, levels and/or distribution may also be affected by changes in the wnt/fzd signaling pathway. ~i-catenin accumulation in the nucleus may lead to the transcription of genes involved in tumorgenesis, such as cyclin Dl and c-myc.
As used herein "activated ~i-catenin" represents ~3-catenin that is not marked for degradation.
As used herein "a disease mediated by Cyclin D1" means a disease that is associated with changes in Cyclin D1 expression such that the its levels, distribution and/or association with other proteins in the cell differ from that found in normal cells.
As used herein "angiogenesis" is the development of new blood vessels into a tissue or organ. Under normal conditions, angiogenesis is observed in wound healing and embryonal development. Uncontrolled or abnormal angiogenesis is associated with neoplastic disease, tumor metastasis and other angiogenesis-related diseases.
"A pharmaceutically acceptable salt" is intended to mean a salt that retains the biological effectiveness of the free acids and bases of the specified compound and that is not biologically or otherwise undesirable.
As used herein a "pharmaceutically acceptable prodrug" is a compound that may be converted under physiological conditions or by solvolysis to the specified compound or to a pharmaceutically acceptable salt of such compound.
The term "a pharmaceutically active metabolite" is intended to mean a pharmacologically active product produced through metabolism in the body of a specified compound or salt thereof.
An "effective amount" is intended to mean that amount of an agent that, when administered to a subject in need of such treatment, is sufficient to effect treatment for a disease and/or condition associated with (3-catenin, COX, PPAR, Cyclin D
and/or A(342.
Thus, e.g., a therapeutically effective amount of a compound of the Formula I, salt, active metabolite or prodrug thereof is a quantity sufficient to modulate, regulate, or inhibit the activity of (3-catenin, COX, PPAR, Cyclin D and/or A(342 such that a disease and/or condition which is mediated by that activity is reduced or alleviated.
The terms "treating", "treat" and "treatment" refer to any treatment of a COX, ~i-catenin, PPAR, or amyloid-[3 mediated disease and/or condition in a mammal, particularly a human, and include: (i) preventing the disease or condition from occurring in a subject which may be predisposed to the condition, for example subjects with accumulated A~3 peptides, such that the treatment constitutes prophylactic treatment for the pathologic condition; (ii) modulating or inhibiting the disease or condition, i.e., arresting its development; (iii) relieving the disease or condition, i.e., causing regression of the disease or condition; or (iv) relieving and/or alleviating disease or condition or the symptoms resulting from the disease or condition, e.g., relieving an inflammatory response without addressing the underlining disease or condition.
By "efficacious levels" is meant levels in which the effects of (3-catenin, COX, PPAR, Cyclin D and/or A(342 activity or amounts are, at a minimum, regulated.
The phrase "conjunctive therapy" (or "combination therapy"), in defining use of a compound of the invention and another pharmaceutical agent, is intended to embrace administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended as well to embrace co-administration of these agents in a substantially simultaneous manner, such as in a single formulation having a fixed ratio of these active agents, or in multiple, separate formulations for each agent.
COMPOUNDS
Applicants have discovered compounds, as represented by Formulas I, which possess COX inhibitory activity, ~3-catenin inhibitory activity, cyclin D1 activity, and/or are cytotoxic to cancer cell lines.
Provided herein are compounds represented by Formulas I:
o Rz or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt thereof, wherein Rl-Rlo, X, Y, Z and n are as defined herein.
The compounds of Formula I may exhibit the phenomenon of tautomerism. While Formulas I cannot expressly depict all possible tautomeric forms, it is to be understood that Formula I are intended to represent any tautomeric form of the depicted compound and are not to be limited merely to a specific compound form depicted by the formula drawings.
The compounds of Formula I may have one or more asymmetric centers depending upon the nature of the various substituents on the molecule. As a consequence of these asymmetric centers, the compounds of Formulas I may exist as single stereoisomers (i.e., essentially free of other stereoisomers), racemates, and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present invention. Preferably, the inventive compounds that are optically active are used in optically pure form.
As generally understood by those skilled in the art, an optically pure compound having one chiral center (i.e., one asymmetric carbon atom) is one that consists essentially of one of the two possible enantiomers (i.e., is enantiomerically pure), and an optically pure compound having more than one chiral center is one that is both diastereomerically pure and enantiomerically pure. The compounds of the present invention can be used in a R9 rormwa i form that is at least 90% optically pure, that is, a form that contains at least 90% of a single isomer (80% enantiomeric excess ("e.e.") or diastereomeric excess ("d.e.")). In some cases, e.g., to reduce toxicity, the compounds can be used in a form that contains at least 95% (90% e.e. or d.e.), even more preferably at least 97.5% (95% e.e. or d.e.), and S most preferably at least 99% (98% e.e. or d.e.) of a single isomer e.e. or d.e.
Additionally, Formula I are intended to cover solvated as well as unsolvated forms of the identified structures. For example, Formula I include compounds of the indicated structure in both hydrated and non-hydrated forms. Other examples of solvates include the structures in combination with isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.
In addition to compounds of Formula I, the invention includes pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts of such compounds and metabolites.
Prodrugs and active metabolites of a compound may be identified using routine techniques known in the art. See, e.g., Bertolini et al., J. Med. Chem., 40, (1997); Shan, et al., J. Pharm. Sci., 86 (7), 765-767; Bagshawe, Drug Dev.
Res., 34, 220-230 (1995); Bodor, Advances in Drug Res., 13, 224-331 (1984); Bundgaard, Design of Prodrugs (Elsevier Press 1985); Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991); Dear et al., J. Chromatogr. B, 748, 281-293 (2000); Spraul et al., J.
Pharmaceutical & Biomedical Analysis, 10, 601-605 (1992); and Prox et al., Xenobiol., 3, 103-112 (1992).
A compound of the invention may possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. Exemplary pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an inorganic base, such as salts including sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, g-hydroxybutyrates, glycolates, tartrates, methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.
If the inventive compound is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, malefic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
If the inventive compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
In the case of agents that are solids, it is understood by those skilled in the art that the inventive compounds and salts may exist in different crystal or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulas.
Therapeutically effective amounts of the agents of the invention may be used to treat or prevent diseases and/or conditions mediated by modulation or regulation of ~3-catenin, COX, A(342, and PPAR.
The amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the subject in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
The active agents of the invention may be formulated into pharmaceutical compositions as described below. Pharmaceutical compositions of this invention comprise S an effective modulating, regulating, or inhibiting amount of a compound of Formula I and an inert, pharmaceutically acceptable carrier or diluent. In one embodiment of the pharmaceutical compositions, efficacious levels of the inventive agents are provided so as to provide therapeutic benefits involving modulation of (3-catenin, COX, PPAR, and/or A(342. These compositions are prepared in unit-dosage form appropriate for the mode of administration, e.g., parenteral or oral administration.
An inventive agent can be administered in conventional dosage form prepared by combining a therapeutically effective amount of an agent (e.g., a compound of Formula I) as an active ingredient with appropriate pharmaceutical carriers or diluents according to conventional procedures. These procedures may involve mixing, granulating and 1 S compressing or dissolving the ingredients as appropriate to the desired preparation.
The pharmaceutical carrier employed may be either a solid or liquid. Exemplary of solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may include time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate and the like.
A variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge. The amount of solid carrier may vary, but generally will be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation will be in the form of syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial or non-aqueous liquid suspension.
To obtain a stable water-soluble dose form, a pharmaceutically acceptable salt of an inventive agent is dissolved in an aqueous solution of an organic or inorganic acid, such as 0.3M solution of succinic acid or citric acid. If a soluble salt form is not available, the agent may be dissolved in a suitable cosolvent or combinations of cosolvents.
Examples of suitable cosolvents include, but are not limited to, alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, gylcerin and the like in concentrations ranging from 0-60% of the total volume. In an exemplary embodiment, a compound of Formula I
is dissolved in DMSO and diluted with water. The composition may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle such as water or isotonic saline or dextrose solution.
It will be appreciated that the actual dosages of the agents used in the compositions of this invention will vary according to the particular complex being used, the particular composition formulated, the mode of administration and the particular site, host and disease and/or condition being treated. Optimal dosages for a given set of conditions can be ascertained by those skilled in the art using conventional dosage-determination tests in view of the experimental data for an agent. For oral administration, an exemplary daily dose generally employed is from about 0.001 to about 3000 mg/kg of body weight, with courses of treatment repeated at appropriate intervals. In some embodiments, the daily dose is from about 1 to 3000 mg/kg of body weight.
Typical daily doses in a pateint may be anywhere between about 500 mg to about 3000 mgs, given once or twice daily, e.g., 3000 mg can be given twice daily for a total dose of 6000 mg.. In one embodiment, the dose is between about 1000 to about 3000 mgs.
In another embodiment, the dose is between about 1500 to about 2800 mgs. In other embodiments, the dose is between about 2000 to about 3000 mgs.
Plasma concentrations in the subjects may be between about 100 p,M to about ~M. In some embodiments, the plasma concentration may be between about 200 ~,M
to about 800 pM. In other embodiments, the concentration is about 300 ~M to about ~M. In still other embodiments the plasma concentration may be between about 400 to about 800 ~M. Administration of prodrugs is typically dosed at weight levels, which are chemically equivalent to the weight levels of the fully active form.
The compositions of the invention may be manufactured using techniques generally known for preparing pharmaceutical compositions, e.g., by conventional techniques such as mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing. Pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers, which may be selected from excipients and auxiliaries that facilitate processing of the active compounds into preparations, which can be used pharmaceutically.
Proper formulation is dependent upon the route of administration chosen. For injection, the agents of the invention may be formulated into aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers known in the art. Such Garners enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurnes, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained using a solid excipient in admixture with the active ingredient (agent), optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include:
fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as crosslinked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active agents.
Pharmaceutical preparations, which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the active agents may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.
For administration intranasally or by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of 1 S gelatin for use in an inhaler or insufflator and the like may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit-dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active agents may be prepared as appropriate oily injection suspensions.
Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents, which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
In addition to the formulations described above, the compounds may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion-exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
An exemplary pharmaceutical carrier for hydrophobic compounds is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. The cosolvent system may be a VPD co-solvent system.
VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol. The VPD co-solvent system (VPD:SW) contains VPD diluted 1:1 with a 5%
dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration.
Naturally, the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied;
other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may be substituted for dextrose.
Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are known examples of delivery vehicles or Garners for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity.
Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
Various sustained-release materials have been established and are known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.
The pharmaceutical compositions also may comprise suitable solid- or gel-phase Garners or excipients. Examples of such Garners or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
Some of the compounds of the invention may be provided as salts with pharmaceutically compatible counter ions. Pharmaceutically compatible salts may be formed with many acids, including hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free-base forms.
The administration of the present invention may be for either prevention or treatment purposes. When used for the treatment and/or prevention of neoplasia, or Alzheimer's, or for the treatment of diseases treatable by inhibiting COX, the methods and compositions described herein may be used alone or in conjunction with additional therapies known to those skilled in the art. Alternatively, the methods and compositions described herein may be used as conjunctive therapy. By way of example, the compounds described herein may be administered alone or in conjunction with other antineoplastic agents, glucocorticoids or other growth inhibiting agents or other drugs or nutrients.
There are large numbers of antineoplastic agents available in commercial use, in clinical evaluation and in pre-clinical development, which could be selected for treatment of neoplasia by combination drug chemotherapy. Such antineoplastic agents fall into several major categories, namely, antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, including glucocorticoids such as prednisone and dexamethasone, immunological agents, interferon-type agents and a category of miscellaneous agents. Alternatively, other anti-neoplastic agents, such as metallomatrix proteases (MMP), SOD mimics or alpha" beta3 inhibitors may be used.
One family of antineoplastic agents which may be used in combination with the compounds of the inventions consists of antimetabolite-type antineoplastic agents.
Suitable antimetabolite antineoplastic agents may be selected from the group consisting of alanosine, AG2037 (Pfizer), S-FU-fibrinogen, acanthifolic acid, aminothiadiazole, brequinar sodium, carmofur, Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabine phosphate stearate, cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC, dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC, doxifluridine, Wellcome EHNA, Merck & Co. EX-015, fazarabine, floxuridine, fludarabine phosphate, 5-fluorouracil, N-(2'-furanidyl)-5-fluorouracil, Daiichi Seiyaku FO-152, isopropyl pyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim, methotrexate, Wellcome MZPES, norspermidine, NCI NSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA, pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, Takeda TAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, tyrosine kinase inhibitors, tyrosine protein kinase inhibitors, Taiho UFT
and uricytin.
A second family of antineoplastic agents which may be used in combination with the compounds of the invention consists of alkylating-type antineoplastic agents. Suitable alkylating-type antineoplastic agents may be selected from the group consisting of Shionogi 254-S, aldo-phosphamide analogues, altretamine, anaxirone, Boehringer Mannheim BBR-2207, bendamustine, bestrabucil, budotitane, Wakunaga CA-102, carboplatin, carmustine, Chinoin-139, Chinoin-153, chlorambucil, cisplatin, cyclophosphamide, American Cyanamid CL-286558, Sanofi CY-233, cyplatate, Degussa D-19-384, Sumimoto DACHP(Myr)2, diphenylspiromustine, diplatinum cytostatic, Erba distamycin derivatives, Chugai DWA-21148, ITI E09, elmustine, Erbamont FCE-24517, estramustine phosphate sodium, fotemustine, Unimed G-6-M, Chinoin GYKI-17230, hepsul-fam, ifosfamide, iproplatin, lomustine, mafosfamide, melphalan, mitolactol, Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC-342215, oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-119, ranimustine, semustine, SmithKline SK&F-101772, Yakult Honsha SN-22, spiromustine, Tanabe Seiyaku TA-077, tauromustine, temozolomide, teroxirone, tetraplatin and trimelamol.
Another family of antineoplastic agents which may be used in combination with the compounds of the invention consists of antibiotic-type antineoplastic agents. Suitable antibiotic-type antineoplastic agents may be selected from the group consisting of Taiho 4181-A, aclarubicin, actinomycin D, actinoplanone, alanosine, Erbamont ADR-456, aeroplysinin derivative, Ajinomoto AN-201-II, Ajinomoto AN-3, Nippon Soda anisomycins, anthracycline, azino-mycin-A, bisucaberin, Bristol-Myers BL-6859, Bristol-Myers BMY-25067, Bristol-Myers BMY-25551, Bristol-Myers BMY-26605, Bristol-Myers BMY-27557, Bristol-Myers BMY-28438, bleomycin sulfate, bryostatin-1, Taiho C-1027, calichemycin, chromoximycin, dactinomycin, daunorubicin, Kyowa Hakko DC-102, Kyowa Hakko DC-79, Kyowa Hakko DC-88A, Kyowa Hakko DC89-Al, Kyowa Hakko DC92-B, ditrisarubicin B, Shionogi DOB-41, doxorubicin, doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin, esorubicin, esperamicin-Al, esperamicin-Alb, Erbamont FCE-21954, Fujisawa FK-973, fostriecin, Fujisawa FR-900482, glidobactin, gregatin-A, grincamycin, herbimycin, idarubicin, illudins, kazusamycin, kesarirhodins, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, American Cyanamid LL-D49194, Meiji Seika ME 2303, menogaril, mitomycin, mitoxantrone, SmithKline M-TAG, neoenactin, Nippon Kayaku NK-313, Nippon Kayaku NKT-O1, SRI International NSC-357704, oxalysine, oxaunomycin, peplomycin, pilatin, pirarubicin, porothramycin, pyrindamycin A, Tobishi RA-I, rapamycin, rhizoxin, rodorubicin, sibanomicin, siwenmycin, Sumitomo SM-5887, Snow Brand SN-706, Snow Brand SN-07, sorangicin-A, sparsomycin, SS
Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS Pharmaceutical SS-9816B, steffimycin B, Taiho 4181-2, talisomycin, Takeda TAN-868A, terpentecin, thrazine, tricrozarin A, Upjohn U-73975, Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024 and zorubicin.
A fourth family of antineoplastic agents which may be used in combination with the compounds of the invention include a miscellaneous family of antineoplastic agents selected from the group consisting of alpha-carotene, alpha-difluoromethyl-arginine, acitretin, arsenic trioxide, Avastin ~ (bevacizumab), Biotec AD-5, Kyorin AHC-52, alstonine, amonafide, amphethinile, amsacrine, Angiostat, ankinomycin, anti-neoplaston A10, antineoplaston A2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, Henkel APD, aphidicolin glycinate, asparaginase, Avarol, baccharin, batracylin, benfluron, benzotript, Ipsen-Beaufour BIM-23015, bisantrene, Bristo-Myers BMY-40481, Vestar boron-10, bromofosfamide, Wellcome BW-502, Wellcome BW-773, caracemide, carmethizole hydrochloride, Ajinomoto CDAF, chlorsulfaquinoxalone, Chemes CHX-2053, Chemex CHX-100, Warner-Lambent CI-921, Warner-Lambent CI-937, Warner-Lambert CI-941, Warner-Lambert CI-958, clanfenur, claviridenone, ICN compound 1259, ICN compound 4711, Contracan, Yakult Honsha CPT-11, crisnatol, curaderm, cytochalasin B, cytarabine, cytocytin, Merz D-609, DABIS maleate, dacarbazine, datelliptinium, didemnin- B, dihaematoporphyrin ether, dihydrolenperone, dinaline, distamycin, Toyo Pharmar DM-341, Toyo Pharmar DM-75, Daiichi Seiyaku DN-9693, elliprabin, elliptinium acetate, epothionesTsumura EPMTC, erbitux, ergotamine, erlotnib, etoposide, etretinate, fenretinide, Fujisawa FR-57704, gallium nitrate, genkwadaphnin, Glivec (imatnib), Chugai GLA-43, Glaxo GR-63178, gefitinib, grifolan NMF-SN, hexadecylphosphocholine, Green Cross HO-221, homoharringtonine, hydroxyurea, BTG
ICRF-187, indanocine, ilmofosine, isoglutamine, isotretinoin, Otsuka JI-36, Ramot K-477, Otsuak K-76COONa, Kureha Chemical K-AM, MECT Corp KI-8110, American Cyanamid L-623, leukoregulin, lonidamine, Lundbeck LU-23-112, Lilly LY-186641, NCI
(US) MAP, marycin, mefloquine, Merrel Dow MDL-27048, Medco MEDR-340, merbarone, merocyanine derivatives, methylanilinoacridine, Molecular Genetics MGI-136, minactivin, mitonafide, mitoquidone, mopidamol, motretinide, Zenyaku Kogyo MST-16, N-(retinoyl)amino acids, Nisshin Flour Milling N-021, N- acylated-dehydroalanines, nafazatrom, Taisho NCU-190, nocodazole derivative, Normosang, NCI
NSC-145813, NCI NSC-361456, NCI NSC-604782, NCI NSC-95580, octreotide, Ono ONO-112, oquizanocine, Akzo Org-10172, paclitaxel, pancratistatin, pazelliptine, Warner-Lambert PD-111707, Warner-Lambert PD-115934, Warner-Lambert PD-131141, Pierre Fabre PE-1001, ICRT peptide D, piroxantrone, polyhaematoporphyrin, polypreic acid, Efamol porphyrin, probimane, procarbazine, proglumide, Invitron protease nexin I, Tobishi RA-700, razoxane, Sapporo Breweries RBS, restrictin-P, retelliptine, retinoic acid, Rhone-Poulenc RP-49532, Rhone-Poulenc RP-56976, Rituxan~ (and other anti CD20 antibodies, e.g. Bexxar~, Zevalin~), SmithKline SK&F-104864, statins (Lipitor~
etc.), Sumitomo SM-108, Kuraray SMANCS, SeaPharm SP-10094, spatol, spirocyclopropane derivatives, spirogermanium, Unimed, SS Pharmaceutical SS-554, strypoldinone, Stypoldione, Suntory SUN 0237, Suntory SUN 2071, superoxide dismutase, Thalidomide, Toyama T-506, Toyama T-680, taxol, Teijin TEI-0303, teniposide, thaliblastine, Eastman Kodak TJB-29, tocotrienol, Topostin, Teijin TT-82, Kyowa Hakko UCN-Ol, Kyowa Hakko UCN-1028, ukrain, Eastman Kodak USB-006, vinblastine sulfate, vincristine, vindesine, vinestramide, vinorelbine, vintriptol, vinzolidine, withanolides and Yamanouchi YM-534, zometa.
Examples of radioprotective agents which may be used in the combination chemotherapy of this invention are AD-S, adchnon, amifostine analogues, detox, dimesna, 1-102, MM-159, N-acylated-dehydroalanines, TGF-Genentech, tiprotimod, amifostine, WR-151327, FUT-187, ketoprofen transdermal, nabumetone, superoxide dismutase (Chiron) and superoxide dismutase Enzon.
Methods for preparation of the antineoplastic agents described above may be found in the literature. Methods for preparation of doxorubicin, for example, are described in U.S. Pat. Nos. 3,590,028 and 4,012,448. Methods for preparing metallomatrix protease inhibitors are described in EP 780386. Methods for preparing SOD mimics are described in EP 524,101. Methods for preparing .alpha,, .beta3 inhibitors are described in W097/08174.
Additionally, the compounds of Formula I may be administered either alone or in combination with other compounds effective for treating Alzheimer's or dementia. For example, the compounds of the invention may be administered in combination with other 1 S agents used to treat amyloid-(3-mediated diseases or conditions, such as estrogen, risperidone, a thiobenzodiazepine, ampakine, [N-(2,6-dimethylphenyl)-2-(2-oxo-pyrrolidinyl)acetamide, DM9384, a cholinesterase inhibitor, donepezil hydrochloride, rivastigmine tartrate, galantamine, NGF, and metrifonate.
COX INHIBITORS
The compounds of Formula I described herein or pharmaceutically acceptable salts may possess COX-inhibiting activity and possess anti-inflammatory, antipyretic, analgesic, antithrombotic, and anti-cancer activities. The compounds of Formula I and pharmaceutically acceptable salt thereof, therefore, are useful for treating and/or preventing COX-mediated diseases, inflammatory conditions, pain, fever, rheumatic fever, collagen diseases, autoimmune diseases, various immunological diseases, thrombosis, cancer and neurodegenerative diseases in human beings or animals by using administered systemically or topically. More particularly, the compounds and pharmaceutically acceptable salts thereof are useful for treating and/or preventing inflammation and acute or chronic joint and muscle pain [e.g. rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, juvenile arthritis, etc.], inflammatory skin condition [e.g.
sunburn, burns, eczema, dermatitis, etc.], inflammatory eye condition (e.g.
conjunctivitis, etc.], lung disorder in which inflammation is involved [e.g. asthma, bronchitis, pigeon fancier's disease, farmer's lung, etc.], conditions of the gastrointestinal tract associated with inflammation [e.g. aphthous ulcer, Crohn's disease, atopic gastritis, gastritis varialoforme, ulcerative colitis, coeliac disease, regional ileitis, irntable bowel syndrome, etc.], gingivitis, inflammation, pain and tumescence after operation or injury, pyrexia, pain and other conditions associated with inflammation, particularly those in which lipoxygenase and cyclooxygenase products are a factor, systemic lupus erythematosus, scleroderma, polymyositis, tendonitis, bursitis, periarteritisnodose, rheumatic fever, Sjogren's syndrome, Behcet disease, thyroiditis, type I diabetes, nephrotic syndrome, aplastic anemia, myasthenia gravis, uveitis contact dermatitis, psoriasis, Kawasaki disease, sarcoidosis, Hodgkin's disease, Alzheimer's disease, Parkinson's disease, symptoms associated with influenza and other viral infections, common cold, low back and neck pain, dysmenorrheal, headache, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis including rheumatoid arthritis, degenerative joint disease or osteoarthritis, gout, ankylosing spondylitis, bursitis, injuries following surgical and dental procedures, bone loss, or the like. Additionally, the compounds disclosed herein or a salt thereof is expected to be useful as therapeutical and/or preventive agents for cardiovascular or cerebrovascular diseases, the diseases caused by hyperglycemia and hyperlipemia.
The anti-inflammatory activity of the compounds of this invention may be assayed by measuring the ability of the compound to inhibit COX-l and COX-2.
Techniques for measuring COX inhibition is described herein and in the literature, for example, see US
Patent Application No. 2002/0107280; Winter et al. 1962 Proc. Soc. Exp. Biol.
Med.
111:544 both incorporated herein by reference.
In still other embodiments preferred compounds of Formula 1 are those compound with no or little COX activity.
CANCER
Neoplasms treatable by the present invention include solid tumors, i.e., carcinomas and sarcomas. Carcinomas include malignant neoplasms derived from epithelial cells which infiltrate surrounding tissues and give rise to metastases.
Adenocarcinomas are carcinomas derived from glandular tissue, or from tissues that form recognizable glandular structures. Another broad category of cancers includes sarcomas, which are tumors whose cells are embedded in a fibrillar or homogeneous substance, like embryonic connective tissue. The invention also enables treatments of cancer of the myeloid or lymphoid systems, including leukemias, such as CLL, myelomas, such as multiple myeloma, lymphomas, and other cancers that typically are not present as a tumor mass, but are distributed in the vascular or lymphoreticular systems.
Cancers that may be treated using the compounds described herein include, without limitation, brain cancer, bone cancer, epithelial cell derived neoplasia (epithelial carcinoma) such as basal cell carcinoma, adenocarcinoma, gastrointestinal cancer such as lip cancer, mouth cancer, esophageal cancer, small bowel cancer, stomach cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer, skin cancer such as squamous cell and basal cell cancers, prostate cancer, renal cell carcinoma, and other known cancers that effect epithelial cells throughout the body.
The activity of compounds of Formula I against various cancers can be tested using assays known in the art, e.g., MTT assay to cancer cell lines in vitro and animal tumor models-see, for example, Romijn et al., 1988 Prostate 12:99-110.
Cancers amenable to treatment with the compounds of the invention include those mentioned above and those mediated by (3-catenin. Exemplary cancers would include those having mutations in APC, the wnt/fzd signaling pathway, axin and/or ~i-catenin resulting in [3-catenin deregulation and a subsequent increase in free (3-catenin in the cytoplasm and nucleus.
The identification of cancers mediated by (3-catenin can be determined using a variety of techniques known in the art. For example, the expression of wnt and/or fzd RNA can be measured in cancer cells and compared to normal cells as described in International Publications Nos. WO 02/092635 and WO 02/088081 (both incorporated herein by reference in their entireties). Cancers that overexpress wnt and/or fzd would be expected to have deregulated ~3-catenin.
Deregulation of (3-catenin can also be shown by analyzing the subcellular localization of ~3-catenin, e.g., cytoplasmic, nuclear and/or plasma membrane in cancer cells as compared to normal cells of the same type. Such characterization can be done using techniques know in the art including immunohistochemistry, confocal microscopy, and immunoblot analysis.
Samples for (3-catenin analysis can be obtained using standard procedures know to those of skill in the art and include generally known biopsy methods including fine-needle aspiration, surgical biopsy, and core-needle biopsy. Samples for analysis can also be fixed and embedded in such materials as paraffin.
For a review of immunological and immunoassay procedures in general, see Stites et al. (eds.) (1991) Basic and Clinicallmmunology (7th ed.). Immunoassays to detect (3-catenin can be performed in any of several configurations, which are reviewed extensively in Maggio (ed.) (1980) Enzyme Immunoassay CRC Press, Boca Raton, Fla.; Tijan (1985) "Practice and Theory of Enzyme Immunoassays," Laboratory Techniques in Biochemistry and Molecular Biology, Elsevier Science Publishers B. V., Amsterdam; and Harlow and Lane Antibodies, A Laboratory Manual, supra, each of which is incorporated herein by reference. See also Chan (ed.) (1987) Immunoassay: A Practical C'ruide Academic Press, Orlando, Fla.; Price et al. (eds.) (1997) Principles and Practice oflmmunoassay (2°a ed), Groves Dictionaries, Inc.; Boenisch (ed.) (2001) Handbooklmmunochemical Staining Methods DAKO Corp. Carpinteria, CA, USA; and Ngo (ed.). (1988) Non-isotopic Immunoassays Plenum Press, NY; all incorporated herein by reference.
In general, immunoassay design considerations include preparation of antibodies (e.g., monoclonal or polyclonal) having sufficiently high-binding specificity for their antigen so the specifically bound antibody-antigen complex can be distinguished reliably from nonspecific interactions. Polyclonal and monoclonal antibodies that detect (3-catenin are known in the art and are commercially available, e.g., Upstate Cell Signaling Solutions, Charlottesville, VA-catalogue nos. 06-734; 05-601; and 05-482.
Western blot analysis can be used to quantitate the amount of ~3-catenin protein in a sample. Electrophoresis is carried out, e.g., on a tissue sample suspected of containing the protein. Following electrophoresis to separate the proteins, and transfer of the proteins to a suitable solid support such as a nitrocellulose filter, the solid support is incubated with an antibody reactive with the denatured protein. This antibody may be labeled, or alternatively may be it may be detected by subsequent incubation with a second labeled antibody that binds the primary antibody.
A preferred method for identifying cancers that have deregulated (3-catenin is immunohistochemistry (IHC). Immunohistochemistry allows for the evaluation of micro-anatomical detail and heterogeneity in tissues and tumors.
Immunohistochemistry is advantageous over other methods of analyses because it is the only method that can S directly localize proteins to individual cell types and specific cell locations, e.g., plasma membrane, cytoplasm, and/or nucleus. Differences among gene expression of normal and tumor tissue can be detected while simultaneously noting the changes in cell number and composition. In contrast, techniques, such as Western blotting require the use of cell extracts; therefore, a possibility exists of contamination of different cell types. For IHC, a primary (3-catenin antibody that recognizes (3-catenin protein is introduced to a biological specimen. ABer incubation with the primary antibody, a wash can be performed to remove unbound antibody. Then, a secondary antibody, directed against the primary antibody and labeled with an enzyme, can be incubated with the biological specimen.
During incubation, the secondary antibody will bind to the primary antibody.
Alternatively, the second antibody may lack a label, but it may, in turn, be bound by a labeled third antibody specific to antibodies of the species from which the second antibody is derived.
The primary antibody can be labeled with an enzyme thus eliminating the need for a second antibody. Alternatively, the labeled (3-catenin antibody can be labeled with biotin rather than an enzyme. Then, in an additional step, enzyme-labeled avidin or streptavidin is introduced to the sample and allowed to bind to the biotinylated antibody.
For immunohistochemistry, the tissue sample may be fresh or frozen or may be embedded, for example, in paraffin or other waxes, nitrocellulose, carbowax (also known as water soluble polyethylene glycol (see, Gao ed. (1993) "Polyethylene Glycol as an Embedment for Microscopy and Histochemistry," CRC Press, Inc. Boca Raton, Fl.), plastic, including resins such as acrylic and epoxy resins, or OCT embedded frozen blocks. Preferably, the samples are embedded in paraffin or other waxes, nictrocellulose, carbowax, or plastic. The samples can be fixed with a preservative, such as formalin, for example.
Samples for immunohistochemistry can be obtained from surgical biopsies, fine-needle biopsies, fine-needle aspiration biopsies, core-needle biopsies, effusions from body cavities, such as the abdominal cavity, the pleural cavities and the pericardial cavity, and cells collected from other bodily fluids, such as blood and urine and the like. Methods of obtaining such samples are known in the art. For example, an effusion sample can be collected by puncturing the chest wall or abdominal wall with a needle and evacuating the fluid. Samples from fine-needle aspirations, effusions or other bodily fluids can be spun onto slides using conventional centrifugation or Cytospin~ (Shandon, Runcorn, U.K.) or smeared onto an appropriate slide for staining and/or fixation. Cell blocks can also be prepared from such samples by concentrating the cells contained therein. For example, cells can be concentrated, e.g., by centrifugation. After concentration, the cells can be fixed in a suitable fixing agent, such as formalin or alcohol and then embedded into paraffin or other suitable material as done for tissue in surgical pathology.
Concentrated cells can also be processed for ThinPrep~ preparation using, for example, a Cytyc Thin Prep processor (Cytyc Corp Boxborough, MA).
Yet another technique for detecting (3-catenin is Flow Cytometry (FACS). The theory of Flow Cytometry is discussed in Ormerod (ed) Flow Cytometry: A
Practical Approach (IRL Press, Oxford. 1994); Shapiro, Practical Flow Cytometry. 3rd Edition;
(Alan R Liss, Inc.). Givan, Flow Cytometry. First Principles (Whey-Liss, New York, 1992.); Robinson (ed.) Handbook o. f Flow Cytometry Methods. (Wiley-Liss, New York, 1993) FACs provides the means of scanning individual cells for the presence of deregulated /3-catenin.
Antibodies reactive with a particular protein can also be measured by a variety of immunoassay methods, as discussed herein. For reviews of immunological and immunoassay procedures applicable to the measurement of antibodies by immunoassay techniques, see, e.g., Stites and Terr (eds.) Basic and Clinical Immunology (7th ed.) supra;
Maggio (ed.) Enzyme Immunoassay, supra; and Harlow and Lane Antibodies, A
Laboratory Manual, supra.
Techniques for determining (3-catenin localization in cells using immunoassays are known in the art, for example, see Wakita et al. 2001 Cancer Res. 61:854-858;
Carayol et al. 2002 Am J. Respir Cell Mol Biol. 26:341-347; Lim et al 2002 Oncology Reports 9:915-928; and Sakai et al. 2002 Int. J. Oncology 21:547-552; all incorporated herein by reference.
OTHER CONDITIONS AND DISEASES
Other conditions and disease processes amenable to treatment with the compounds described herein include, e.g., benign prostatic hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, fibrosis which occurs S with radiation therapy, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, hypertrophic scar formation, inflammatory bowel disease, transplantation rejection, endotoxic shock, and fungal infections; and defective apoptosis-associated conditions, such as cancers (including, but not limited to, those types mentioned herein above), viral infections (including, but not limited to, HIV, human papilloma virus, herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), prevention of AIDS development in HIV-infected individuals, autoimmune diseases (including, but not limited to, systemic lupus erythematosus, rheumatoid arthritis, psoriasis, autoimmune mediated glomerulonephritis, inflammatory bowel disease and autoimmune diabetes mellitus), neurodegenerative disorders (including, but not limited to, Alzheimer's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, Parkinson's disease, AIDS-related dementia, spinal muscular atrophy and cerebellar degeneration), myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol related liver diseases, hematological diseases (including, but not limited to, chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including, but not limited to, osteroporosis and arthritis), aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, schizophrenia, kidney diseases, abnormal angiogenesis, and cancer pain.
Compounds that inhibit uncontrolled or abnormal angiogenesis are useful for treatment of neoplasia, including metastasis; ophthalmological conditions such as corneal graft rejection, ocular neovascularization, retinal neovascularization including neovascularization following injury or infection, diabetic retinopathy, retrolental fibroplasia and neovascular glaucoma; ulcerative diseases such as gastric ulcer;
pathological, but non-malignant, conditions such as hemangiomas, including infantile hemaginomas, angiofibroma of the nasopharynx and avascular necrosis of bone;
and disorders of the female reproductive system such as endometriosis.
PREPARATION OF COMPOUNDS OF THE INVENTION
Compounds of the present invention may be synthesized using standard synthetic techniques known to those of skill in the art or using methods known in the art in combination with methods described herein. See, e.g., March, ADVANCED ORGANIC
CHEMISTRY 4th Ed., (Whey 1992); Caret' and Sundberg, ADVANCED ORGANIC
CHEMISTRY
S 3ra Ed., Vols. A and B (Plenum 1992), and Green and Wuts, PROTECTIVE GROUPS
IN
ORGANIC SYNTHESIS 2°a Ed. (Whey 1991). General methods for the preparation of compound as disclosed herein may be derived from known reactions in the field, and the reactions may be modified by the use of appropriate reagents and conditions, as would be recognized by the skilled person, for the introduction of the various moieties found in the formulae as provided herein.
Selected examples of covalent linkages and precursor functional groups which yield them are given in the Table entitled "Examples of Covalent Linkages and Precursors Thereof." Precursor functional groups are shown as electrophilic groups and nucleophilic groups. The functional group on the organic substance may be attached directly, or 1 S attached via any useful spacer or linker as defined below.
Examples of Covalent Linkages and Precursors Thereof .~ ,,z ,._ .r: ~~_._. Nucleo hale., ..Covalent~Ltnka a Procluct~ .~ ; :Electi=o __ h~le ~ ~
Carboxamides Activated esters amines/anilines Carboxamides acyl azides amines/anilines Carboxamides acyl halides amines/anilines Esters acyl halides alcohols/phenols Esters acyt nitrites alcohols/ henols Carboxamides ac 1 nitrites amines/anilines Imines Aldehydes amines/anilines Hydrazones aldehydes or ketonesHydrazines Oximes aldehydes or ketonesHydroxylamines Alkyl amines alkyl halides amines/anitines Esters alkyl halides carboxylic acids Thioethers alkyl halides Thiols Ethers alkyl halides alcohots/ henols Thioethers alkyl sulfonates Thiols Esters alkyl sulfonates carboxylic acids Ethers alkyl sulfonates alcohots/phenots Esters Anhydrides alcohots/phenols Carboxamides Anhydrides amines/anitines Thiophenols aryl halides Thiols Aryl amines aryl halides Amines m ,w ~ ;,, -_ , .T.. Nucleo bile ' ,: .. ..... =~.~~Electro hyhe~
~,~ Covalenf~Lwka a Product Thioethers Azindines Thiols Boronate esters Boronates Glycols Carboxamides carboxylic acids amines/anilines Esters carboxylic acids Alcohols Hydrazines Hydrazides carboxylic acids N-acylureas or Anhydrides carbodiimides carbox lic acids Esters diazoalkanes carboxylic acids Thioethers Epoxides Thiols Thioethers haloacetamides Thiols Ammotriazines halotriazines amines/anilines Triazinyl ethers halotriazines alcohols/phenols Amidines imido esters amines/anilines Ureas Isocyanates amines/anilines Urethanes Isocyanates alcohols/ henols Thioureas isothiocyanates amines/anilines Thioethers Maleimides Thiols Phosphite esters phos horamidites Alcohols Silyl ethers silyl halides Alcohols Alkyl amines sulfonate esters amines/anilines Thioethers sulfonate esters Thiols Esters sulfonate esters carboxylic acids Ethers sulfonate esters Alcohols Sulfonamides sulfonyl halides amines/anilines Sulfonate esters sulfonyl halides phenols/alcohols In general, carbon electrophiles are susceptible to attack by complementary nucleophiles, including carbon nucleophiles, wherein an attacking nucleophile brings an electron pair to the carbon electrophile in order to form a new bond between the nucleophile and the carbon electrophile.
Suitable carbon nucleophiles include, but are not limited to alkyl, alkenyl, aryl and alkynyl Grignard, organolithium, organozinc, alkyl-, alkenyl , aryl- and alkynyl-tin reagents (organostannanes), alkyl-, alkenyl-, aryl- and alkynyl-borane reagents (organoboranes and organoboronates); these carbon nucleophiles have the advantage of being kinetically stable in water or polar organic solvents. Other carbon nucleophiles include phosphorus ylids, enol and enolate reagents; these carbon nucleophiles have the advantage of being relatively easy to generate from precursors well known to those skilled in the art of synthetic organic chemistry. Carbon nucleophiles, when used in conjunction with carbon electrophiles, engender new carbon-carbon bonds between the carbon nucleophile and carbon electrophile.
Non-carbon nucleophiles suitable for coupling to carbon electrophiles include but are not limited to primary and secondary amines, thiols, thiolates, and thioethers, alcohols, alkoxides, azides, semicarbazides, and the like. These non-carbon nucleophiles, when used in conjunction with carbon electrophiles, typically generate heteroatom linkages (C-X-C), wherein X is a hetereoatom, e. g, oxygen or nitrogen.
The term "protecting group" refers to chemical moieties that block some or all reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. It is preferred that each protective group be removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal. Protective groups can be removed by acid, base, and hydrogenolysis. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and may be used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile.
Carboxylic acid and hydroxy reactive moieties may be blocked with base labile groups such as, without limitation, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as t-butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable.
Carboxylic acid and hydroxy reactive moieties may also be blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids may be blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties may be protected by conversion to simple ester derivatives as exemplified herein, or they may be blocked with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while co-existing amino groups may be blocked with fluoride labile silyl carbamates.
Allyl blocking groups are useful in then presence of acid- and base-protecting groups since the former are stable and can be subsequently removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid can be deprotected with a Pdo-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate may be attached. As long as the residue is attached to the resin, that functional group is blocked and cannot react. Once released from the resin, the functional group is available to react.
Typically blocking/protecting groups may be selected from:
HZ H O
i C~ , C~ H ,O
H C C~C~C\ ~ I ~ ~ O~ H2C~C'H ~ H3Ci allyl Bn Cbz alloc Me H3C~ CH3 H O
z f-/3C~C~ ~H3C)3C~ (H3C~3C,SI~ ~Cl..ls)3C~SI~O
Et t-butyl TBDMS Teoc O
O
O / C~ O HzC
UH3~3C ~ ~ ~C6H5~3C~ H
Boc pMBn trityl acetyl Fmoc Other protecting groups are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, which is incorporated herein by reference in its entirety.
In various embodiments, the compounds of the present invention can be prepared according to the following reaction schemes and examples, or modifications thereof.
Starting materials can be purchased or made from procedures known in the art or as illustrated. In these reactions, one skilled in the art can make use of variations that are not described in greater detail. Other methods for preparing compounds of the invention will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. For example, the synthesis of non-exemplified compounds according to the invention may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or generally known in the art will be recognized as having applicability for preparing other compounds of the invention. Unless otherwise indicated, the variables are as defined above.
The abbreviations employed throughout the application have the following meaning unless otherwise indicated: EtOH: ethyl alcohol; NHZOH.HCI:
hydroxylamine;
CC13CH(OH)2: chloral hydrate; H2S04: sulfuric acid; LiBH4: lithium borohydride;
C1COCOCI: oxalyl chloride; HCI: Hydrochloric acid; NaOH: sodium hydroxide;
S BF3.Etz0: boron trifluoride etherate; CHZCIz: dichloromethane; [R]: partial reduction.
General Scheme lA shows the preparation of pyranoindol-1-yl alcohols from starting material 1.
General Scheme 1 1A.
X X X O X
CCI3CH(OH)z I ~ ~ H2S04 / \ LiBH4 r ~NOH / \ \ 1)CICOCOCI
~
NHz NHZOH HCI R H R N O Rte' 2) EtOH
N
I II III H IV H
X O
O LiBH4 X / \ OH + Oj~ Ou BF3 X / \ O
j \ ~ OEt ~ Et O ~ r ~ R~~(CHz)~OEt \ O ~
R R CHzCIz R
N N
OEt CH
V H H z)n VI H R~ ( VII
X Ar LiBH4 R~ \ \ O ArB(OH)z ~ \ \ O
Pd(L)n R
VIII H R~ (CHz)o OH IX H R' (CHz)/_OH
Rz-(CHz)n Rz (CHz)n Pd(L)m / O
R H R~ (CHz)/~OH
X
[R) Rz-(CHz)n Rz (CH2)n~
/ \
Pd(L)m R ~ ~ O
H R~ (CHz)~OH
XI
In General Scheme 1, 1,3,4,9-tetrahydro-pyrano[3,4-bJindole of this invention may be prepared by techniques well known to those skilled in the art of organic synthesis. The substituted tryptophols (VI) may be prepared by the appropriate segment of the pathway illustrated in General Scheme lA, starting with an aniline (I), an isatin (III), or an indole (IV). The suitable starting materials are commercially available anilines with the desired R or may be readily prepared. The aniline may be converted into a corresponding isatin 1 S (III) by treatment of aniline with chloral hydrate and hydroxylamine, followed by heating with sulfuric acid. The indole (IV) may be obtained by reduction of isatin with lithium borohydride or other reducing agents. The tryptophol (VI) may be prepared by acylation at 3-position of indole (IV) with a suitable reagent, e.g., oxalyl chloride, followed by reduction of glyoxylate (V) with lithium borohydride. The substituted tryptopholes (VI) may be condensed with an appropriate ketone or aldehyde, in the presence of an acid catalyst, to provide 1,3,4,9-tetradydro-pyrano[3,4-b]indole (VII). After the ester (VII) is reduced by an appropriate reducing reagent, e.g., lithium borohydride, the title compounds (IX) may be prepared from (VIII) by displacement of the halogen with an appropriately activated Ar moiety. For example, in the presence of an appropriate Pd(L)m catalyst, Ar-boronic acids may be coupled via a Suzuki reaction to give the title compounds (IX).
Compounds (X) and (XI) may be prepared, via Heck reaction, from suitable alkyne and alkene precursors in the presence of an appropriate Pd(L)m catalyst. The cis isomer of (XI) may also be prepared by partial reduction of (X) by hydrogenation over palladium on activated carbon that has been treated with quinoline.
General Scheme 1B shows the preparation of pyranoindol-1-yl alkylsulfonamides from starting material 6.
Scheme 1B.
X X
/ \ OH ~O BF3 EtzO / \ Ar R/ ~ N~ + R~~(CHp)n SOzY CHzCIz R/ ~ N\ O ~SOZY A~(OH~ / \
O
H H R~ (CHz)" Pd(L)m R\~ ~SOzY
VI XII H R~ (CHz)n XIII
R-(CHz)"
R (CHz)n = \\
Y=H, OH, NHz, NHR, NRR, R /
X= Br,l Pd(L)m / ~ O
R=unsubstituted or substituted alkyl, aryl, alkenyl, or alkynyl R N ,SOzY
Ar= unsubstituted or substituted aryl H R~ (CHz)"
R~= hydrogen, lower alkyl, lower alkenyl, lower alkynyl, XIV
lower alkoxy, lower cycloalkyl, phenyl, benzyl and 2-thienyl n=0 to 6 [R]
R-(CHz)"
R-(CHz)n~ \
/ ~ O
Pd(L)m R/ ~ SOzY
H R~ (CHz)n XV
Scheme 1B illustrates syntheses of the title compounds (XIII), (XIV), or (XV) wherein -(CHZ)nSOZY is substituted at 1-position of 1,3,4,9-tetradydro-pyrano[3,4-b]indole. The compounds (XIII) may be prepared by condensation of tryptophols (VI) with an appropriate ketone or aldehyde bearing -SOZY in the presence of a suitable acid, followed by coupling reactions, which may be via Suzuki reaction with a suitable activated Ar moiety in the presence of an appropriate Pd(L)m catalyst.
Analogously, compounds (XIV) and (XV) may be prepared, via Heck reaction, from suitable alkyne and alkene in the presence of an appropriate Pd(L)m catalyst.
General Scheme 2 illustrates the additional embodiment wherein R]o is lower alkyl, lower alkenyl, lower alkynyl, or aryl. The nitrogen of compound (VII) may be alkylated with an appropriate alkyl halide in the presence of a suitable base. After the ester is reduced to the alcohol (XVII) by a suitable reducing reagent, e.g., lithium borohydride, the title compounds (XVIII), (XIX), or (XX) may be prepared by coupling reactions, e.g., Suzuki reaction or Heck reaction.
General Scheme 2 X
X
~~~0 O td~~base X
R N ~ R j \ \ O ~ LiBH4 / ~ Ar8(OH)z Ar H Rt (CHz)n OEt R Rto Rt (CHz)n OEt R/ ~ N\ 0 OOH ~ / ~ \ 0 VII R Rt (CHz)n Pd(L)m R~ /'~OI
XVI Rto Rt (CHz) XVII XVIII
R-(CHz)~
R-(CHz)n = \\
/' \ \ l0 Pd(L)m R N Rt (CHz)~OH
Rto Rto= lower alkyl, lower alkenyl, lower alkynyl, benzyl, or aryl X= Br, I XIX
[R]
R-(CHz)n R-(CHz)n~ /
Pd(L)m O
R
N Rt (CHz)~OH
Rto XX
General Scheme 3 illustrates the synthesis of compounds where R7 is substituted, R9 is an isopropyl group, Rl is ethyl, and Y-Z is ethylalcohol.
Scheme 3 y HCI / \ HyS04 / \ O
+ CI3CCH(OH)2 + NHZOH HCI
NHZ HZO NHCOCH=NOH H20 N O AcOH,heat Na2S04 H
Br Br Br O Br \ O LiBH4 / \ CIEt200C1 / \ CpZEt LiBH4 / \ BF3~Et20 ~O THF \ EtOH ~ THF \ OH
N N N CHZCIZ
H H H
Br Br EtO2C
\ LiBH4 / \ ~CO2Et \ Hp _ ~ O /
H\ 0 COZEt THF H\ OH Pd(L)n I H\ O OH
EtO2C HOZC HO
/ \ LiOH \ LAH \
\ p ~ ~ \ \O / \ \O
H OH H~pH ! H~OH
TBDMSiCI
EtO2C 1 HO
LAH
/ \ \ O ~ / \ \ O ~ / \ \ O
H~OSiTBDM H~OSiTBDM H~OH
General Scheme 4 illustrates the synthesis of of pyranoindol-1-yl alcohols.
Scheme 4 NHNHp R s \ OH Rte \
Rt i / + ~~ t ~ ~ + RZCO(CHZ)nC02R ~ ~ ~ O
H H Rp (CHZ)nCOpR
Ros \ ~ O Ry \ ~ O
H RZ (CHz)nCO2H H Rz (CHz)nCH20H
EXAMPLES
EXAMPLE 1: SYNTHESIS OF COMPOUNDS
COMPOiJND l: 2-(1,H-DIETHYL-E-PHENYL-1,3,4,9-TETRAHYDRO-PYRAN0~3,4-B~INDOL-1-YL~-ETHANOL
l.A. Synthesis of N (4-Bromo-2-ethyl phenyl)-2-hydroximino-acetoamide To a suspension of 4-bromo-2-ethylaniline (50.0 g, 250 mmol) in water (1000 mL) was added concentrated hydrochloric acid (25 mL), sodium sulfate (220 g), and S hydroxylamine hydrochloride (56.25 g), followed by addition of chloral hydrate (44.0 g).
The reaction mixture was heated to 90°C using an oil bath for 1 hour.
After cooling down to room temperature, it was extracted with ethyl acetate. Extract was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (31.1 g, 46% yield). 1H NMR (DMSO-db) 8 12.24 (s, 1H), 9.56 (s, 1H), 7.68 (s, 1H), 7.41 (m, 3H), 2.58 (q, 2H), 1.11 (t, 3H).
LB. Synthesis of S-Bromo-7-ethyl-IH indole-2,3-dione To a solution of sulfuric acid (100 mL) and water (10 mL) at 80°C (oil bath) was added N-(4-bromo-2-ethyl-phenyl)-2-hydroximino-acetoamide (61.0 g, 225 mmol) in small portions over 20 minutes. The reaction mixture was heated at 80°C
(oil bath) for 15 minutes. After cooling to room temperature, ice-water (500 mL) was added and the mixture was extracted with ethyl acetate. Extracts were washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (42.3 g, 74% yield). 1H NMR (DMSO-d6) 8 8.87 (s, 1H), 7.75 (d, 1H), 7.71 (d, 1H), 2.75 (q, 2H), 1.44 (t, 3H).
LC. Synthesis of (S-Bromo-7-ethyl-IH indol-3 yl)-oxo-acetic acid ethyl ester To a solution of 5-bromo-7-ethyl-1H-indole-2,3-dione (36.g, 144 mmol) in tetrahydrofuran (120 mL) at room temperature was dropped a 2.0 M solution of lithium borohydride in tetrahydrofuran. The reaction mixture was stirred at 90°C (oil bath) for S
hours. After cooling down to room temperature, it was quenched with 5%
hydrochloric acid solution until the excess lithium borohydride was destroyed. To the mixture was added saturated sodium bicarbonate solution (300 mL) and extracted with ethyl acetate.
Extracts were dried over magnesium sulfate and concentrated under reduced pressure to give the crude product of 5-bromo-7-ethyl-1H-indole, which went to next reaction without further purification.
To a solution of 5-bromo-7-ethyl-1H-indole in ethyl ether (400 mL) at room temperature under nitrogen was added a 2.0 M solution of oxalyl chloride in dichloromethane. After the reaction mixture was stirred at room temperature for 6 hours, the solvents were removed under reduce pressure. To the residue was added ethyl alcohol (400 mL) and stirred at room temperature overnight. After ethyl alcohol was removed under reduce pressure, to the residue was added saturated sodium bicarbonate solution (300 mL) and extracted with ethyl acetate. Extract was dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 30-50% ethyl acetatelhexane) to give the title compound (14.5 g, 31% yield). ES-MS (m/z) 324 [M+1]+, 322 [M-1]-.
LD. Synthesis of (6-Bromo-1,8-diethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1-yl)-acetic acid ethyl ester To a solution of (5-bromo-7-ethyl-1H-indol-3-yl)-oxo-acetic acid ethyl ester (1.55 g, 4.8 mmol) in tetrahydrofuran at room temperature under nitrogen was dropped a 2.0 M
solution of lithium borohydride in tetrahydrofuran. The reaction mixture was heated at 90°C oil bath for 5 hours. After cooling to room temperature, it was quenched with 5%
hydrochloric acid solution until the excess lithium borohydride was destroyed.
To the mixture was added saturated sodium bicarbonate solution and extracted with ethyl acetate.
Extracts were dried over magnesium sulfate and concentrated under reduced pressure to give the crude product of 2-(S-bromo-7-ethyl-1H-indol-3-yl)-ethanol, which went to the next reaction without further purification.
To a solution of 2-(S-bromo-7-ethyl-1H-indol-3-yl)-ethanol in dichloromethane at room temperature under nitrogen was added boron trifluoride diethyl etherate (0.809 g, 5.7 mmol), followed by ethyl propionylacetate (1.038 g, 7.2 mmol). The reaction mixture was stirred at room temperature for 5 hours. It was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 15-20% ethyl acetate/hexane) to give the title compound (0.994 g, 53% yield). ES-MS (m/z) 394 [M+1]+, 392 [M-1]-.
LE. Synthesis of 2-(6-Bromo-1,8-diethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-ethanol To a solution of (6-bromo-1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester (5.2 g, 13.2 mmol) in tetrhydrofuran at room temperature under nitrogen was dropped a 2.0 M solution of lithium borohydride in tetrahydrofuran. The reaction mixture was heated at 90°C (oil bath) for 5 hours. After cooling to room temperature, it was quenched with 5% hydrochloric acid solution until the excess lithium borohydride was destroyed. Water was added and the mixture extracted with ethyl acetate. Extracts were dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 50%
ethyl acetate/hexane) to give the title compound (3.80 g, 82% yield). 1H NMR
(CDC13) 8 8.07 (s, 1H), 7.64 (d, 1H), 7.26 (d, 1H), 4.17 (m, 2H), 3.86 (m, 2H), 2.94 (m, 3H), 2.87 (dt, 1H), 2.76 (t, br, 1H), 2.36 (m, 1H), 2.24 (m, 1H), 2.13 (m, 2H), 1.49 (t, 3H), 1.08 (t, 3H).
ES-MS (m/z) 352 [M+1]+, 350 [M-1]-.
LF. Synthesis of 2-(1,8-Diethyl-6 phenyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-ethanol To a solution of 2-(6-bromo-1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-yl)-ethanol (3.8 g, 10.8 mmol) in ethylene glycol dimethyl ether (50 mL) was added potassium phosphate (6.37 g, 30 mmol), phenylboronic acid (1.83 g, 15 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane.
The reaction mixture was heated at 90°C (oil bath) overnight. It was quenched with water and extracted with ethyl acetate. Extracts were dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 50% ethyl acetate/hexane, followed by Sephadex LH-20, 50%
chloroform/hexane) to give the title compound (0.75 g, 20% yield).'H NMR
(CDC13) 8 7.77 (s, 1H), 7.66 (d, 1H), 7.63 (m, 1H), 7.56 (d, 1H), 7.44 (m, 3H), 7.32 (m, 1H), 4.06 (m, 2H), 3.72 (m, 3H), 2.91 (m, 3H), 2.81 (dt, 1H), 2.65 (dd, 1H), 2.20 (m, 1H), 2.07 (m, 2H), 1.40 (t, 3H), 0.95 (t, 3H). ES-MS (m/z) 348 [M-1]-.
COMPOUND 2: 2-[1,8-DIETI-IYL-6-(4-METHOXY-PHENYL)-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL]- ETHANOL
The title compound is prepared in a manner analogous to Example 1, except using 4-methoxyphenylboronic acid in step 1.F.
COMPOUND 3: 2-~l,S-DIETHYL-C7-~3-TRIFLUOROMETHOXY-PHENYL-1,3,4,9-TETRAHYDRO-PYRANO ~3,4-B~ INDOL-1-YL~-ETHANOL
The title compound is prepared in a manner analogous to Example 1, except using 3-trifluoromethoxyphenylboronic acid in step 1.F.
COMPOUND 4: 2-~l,g-DIETHYL-6-(2-TRIFLUOROMETHYL-PHENYL-1,3,4,9-TETRAHYDRO-1 O PYRAN0~3,4-B~INDOL-1-YL~-ETHANOL
~ O
H/~OH
The title compound is prepared as described in Example 1, except using 2-trifluoromethylphenylboronic acid in step 1.F.
COMPOUND S: Z-~6-~2,4-DIFLUORO-PHENYL-1,g-DIETHYL-1,3,4,9-TETRAHYDRO-1 S PYRAN0~3,4-B~INDOL-1-YL~- ETHANOL
The title compound is prepared in a manner analogous to Example 1, except using 2,4-difluorophenylboronic acid in step l .F.
COMPOUND 6: 2-(1,H-DIETHYL-6-PYRIDIN-4-YL-1,3,4,9-TETRAHYDRO-PYRAN0~3,4-B~INDOL- I -YL~-ETHANOL
The title compound is prepared in a manner analogous to Example 1, except using pyridine-4-boronic acid in step 1.F.
COMPOUND H: 2-~6-~3-AMINO-PHENYL-1,8-DIETHYL-1,3,4,9-TETRAHYDRO-PYRAN0~3,4-B~INDOL-I-YL~-ETHANOL
NHS
1~
The title compound is prepared in a manner analogous to Example l, except using 3-aminophenylboronic acid in step 1.F.
COMPOUND 10: 2-[6-(3,4-DIFLUORO-PHENYL)-1,8-DIETHYL-1,3,4,9-TETRAHYDRO-PYRAN0~3,4-B~INDOL-1-YL~-ETHANOL
F
I$
The title compound is prepared in a manner analogous to Example 1, except using 3,4-difluorophenylboronic acid in step l.F.
COMPOUND 11: 2-[6-(5-CHLORO-THIOPHEN-2-YL)-1,8-DIETHYL-1,3,4,9-TETRAHYDRO-PYRAN0~3,4-B~INDOL-1-YL~-ETHANOL
CI / ' S
\ O
H/~~OH
The title compound is prepared in a manner analogous to Example 1, except using 5-chloro-2-thiopheneboronic acid in step 1.F.
COMPOUND 12: 2-(1-ETHYL-6-ISOPROPYL-8-PHENYL-1,3,4,9-TETRAHYDRO-PYRAN0~3,4-B~INDOL-1-YL)-ETHANOL
\ O
' ~ H ~~OH
'' -H~>
13 / \ \ ~ H~3.14 / \ \ O
N p N
H ~ OOH v ~ H ~ OOH
\ ~ \ /
CN ~ Br / \ O
/~~
15 OH 1 ( N _ ~ H ~ H ~ ~OH
\ / \ /
F
\ / H02C
/ \ \
17 ~ N\ ~ ~~~18 H ~V OOH J H ~~OH
\ / \ /
CHO
/ \
O
H /~_ ~
19 ~ 20 N
~ \ H
OH ~~OH
\ /
O
\ /
'- ~ ~ ..rv ~~-~"
~~'',f ~ .
TRUCII'U:RE~
1'10 ~ ~~~TRI~TCTU=RE r~' ~~10 ~~ $~
_.. ~ ..a ~ ~, ~ ~:
22 \ ~ ~ °
21 H/~~OH \ ~
H / v \OH
J
23 ~° ~ I ~ ° °H 24 -~'v ~ OH
N~~~~ ~ N
H \ H
i 25 \ ~ ~ ~ 26 \
H OH ~"' F H OH
27 \ ~ ~ ~ 28 \ ~ ~ °
H OH ~~ H~~J'~_~~OH
a e~
29 ~ ~ 30 N v ° H OH
H OH
i 31 ~\ \ 4~ 32 \H H OH
HO
i v 33 \ ~ ~ ~ \NH 3 A \
~+ ~N
H
H O
~ '" off i 35 \ ~ ~ \ ~M 36 \
H ~//~~~~~OH ~ ,, H C v \OH
CI
37 \ ~ ~ \ 38 ~ ~ °
F \H/ --~OH
F H v \OH
F
M ,~ ~ ~-~~ ~ ~
N~. ~,~ ~~~~~~~~, ;
~-~~ STRLICT~U~R,E~N.r O ;,, ~ , "~ r STRI~TUC URE
ON
O
O-O p 55 '56 w \ p \N ~7~\~
H ~~OH
OH ~,, .:~, iii' OH
s z r.
~z;
57 a OH ~:~'7~:
or pharmaceutically acceptable salts thereof.
Pharmaceutical compositions comprising a therapeutically effective amount of a prodrug, active metabolite, or pharmaceutically acceptable salt of a compound of Formula I, as well as pharmaceutically acceptable salts of such active metabolites, are also provided herein.
Methods of treating a neoplasia comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising a compound of Formula I are provided herein. In some embodiments, the neoplasia is a hematological cancer. In other embodiments, the neoplasia is selected from leukemias such as chronic lymphocytic leukemia, myelomas such as multiple myeloma, and lymphomas. In still other embodiments, the cancer is selected from brain cancer, bone cancer, basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, mouth cancer, esophageal cancer, small bowel cancer, stomach cancer, colon cancer, liver cancer, bladder cancer, 1 S pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer, skin cancer, prostate cancer, and renal cell carcinoma.
Methods for treating cancer by administering a composition comprising a therapeutically effective amount of a composition of Formula I given in combination with another antineoplastic agent are provided herein. In some embodiments, the antineoplastic agent is an alkylating agent. In other embodiments, the alkylating agent is selected from the group consisting of bendamustine, chlorambucil, cyclophosphamide and melphalan.
In still other embodiments, the antineoplastic agent is a glucocorticoid. In yet other embodiments, the glucocoritcoid is prednisone. In some embodiments, the glucocorticoid is given in combination with additional antineoplastic agents.
Methods for treating a disease mediated by ~i-catenin in a subject in need of such therapy wherein a therapeutically effective amount of a compound of Formula I
is administered to the subj ect, are provided herein.
Methods for treating a disease mediated by Cyclin D1 in a subject in need of such therapy wherein a therapeutically effective amount of a compound of Formula I
is administered to the subject, are also provided herein.
Methods for reducing or preventing the development of Alzheimer's disease comprising administering to a subject in thereof a therapeutically effective amount of a composition comprising a compound of Formula I are provided herein. In some embodiments, the method comprises administering to a mammal in need of such treatment a therapeutically effective amount of: (a) at least one compound, pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite of Formula I; and (b) at least one agent selected from the group consisting of estrogen, risperidone, a thiobenzodiazepine, ampakine, [N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide, DM9384, a cholinesterase inhibitor, donepezil hydrochloride, rivastigmine tartrate, galantamine, NGF, and metrifonate.
Methods for treating a disease in a mammal treatable by administration of a COX-1 and/or COX-2 inhibitor comprising administering to the mammal a therapeutically effective amount of a compound of Formula I which inhibits one or both of COX-1 or COX-2 are provided herein. In some embodiments, the disease is an inflammatory disease.
Methods for treating a hyperplastic disease in a mammal comprising administration to the mammal a therapeutically effective amount of a compound of Formula I are provided herein.
Methods for inhibiting or delaying the onset of a neoplasia in a mammal in need of such treatment comprising administration to the mammal a therapeutically effective amount of a compound of Formula I are provided herein. In some embodiments, the neoplasia is selected from the group consisting of adenomatous polyps, gastrointestinal cancer, liver cancer, bladder cancer, cervical cancer, prostate cancer, lung cancer, breast cancer, and skin cancer.
Methods for treating, inhibiting or delaying the onset of uncontrolled or abnormal angiogenesis in a subject in need of such treatment, inhibition or delay, wherein the uncontrolled or abnormal angiogenesis is selected from the group consisting of metastasis, corneal graft rejection, ocular neovascularization, retinal neovascularization, diabetic retinopathy, retrolental fibroplasia, neovascular glaucoma, gastric ulcer, infantile hemaginomas, angiofibroma of the nasopharynx, avascular necrosis of bone, and endometriosis, and the method comprises treating the subject with a therapeutically effective amount of a compound of Formula I are provided herein.
Pharmaceutical compositions for the treatment of one or more conditions selected from the group consisting of arthritis, fever, common cold, dysmenorrhea, menstrual cramps, inflammatory bowel disease, Crohn's disease, emphysema, acute respiratory distress syndrome, asthma, bronchitis, chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer, tissue ulceration, peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis, recurrent gastrointestinal lesion, gastrointestinal bleeding, coagulation, anemia, synovitis, gout, ankylosing spondylitis, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, loosening of artificial joint implants, atherosclerosis, aortic aneurysm, periarteritis nodosa, congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neuralgia, neuro-degenerative disorders, autoimmune disorders, Huntington's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain, gingivitis, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, conjunctivitis, abnormal wound healing, muscle or joint sprains or strains, tendonitis, skin disorders, myasthenia gravis, polymyositis, myositis, bursitis, bums, diabetes, tumor invasion, tumor growth, tumor metastasis, corneal scarnng, scleritis, immunodeficiency diseases, sepsis, premature labor, hypoprothrombinemia, hemophilia, thyroiditis, sarcoidosis, Behcet's syndrome, hypersensitivity, schizophrenia, kidney disease, Rickettsial infections, Protozoan diseases, reproductive disorders, obesity, and septic shock in a mammal, comprising an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof effective in such treatments and a pharmaceutically acceptable carrier are provided herein.
Methods of treating a neoplasia in a subject in need of treatment where the subject is treated with a composition comprising a compound of Formula I. Neoplasms that can be treated include, but are not limited to, hematological cancers, such as leukemias, myelomas and lymphomas, brain cancer, bone cancer, epithelial cell derived neoplasia (epithelial carcinoma) such as basal cell carcinoma, adenocarcinoma, gastrointestinal cancer such as lip cancer, mouth cancer, esophageal cancer, small bowel cancer, stomach cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer, skin cancer such as squamous cell and basal cell cancers, prostate cancer, renal cell carcinoma, and other known cancers that effect epithelial cells throughout the body and cancers of the bone marrow.
Methods for treating one or more conditions selected from the group consisting of arthritis, fever, common cold, dysmenorrhea, menstrual cramps, inflammatory bowel disease, Crohn's disease, emphysema, acute respiratory distress syndrome, obesity, asthma, bronchitis, chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer, tissue ulceration, peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis, recurrent gastrointestinal lesion, gastrointestinal bleeding, coagulation, anemia, synovitis, gout, ankylosing spondylitis, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, loosening of artificial joint implants, atherosclerosis, aortic aneurysm, periarteritis nodosa, congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neuralgia, neuro-degenerative disorders, autoimmune disorders, Huntington's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain, gingivitis, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, conjunctivitis, abnormal wound healing, muscle or joint sprains or strains, tendonitis, skin disorders, myasthenia gravis, polymyositis, myositis, bursitis, burns, diabetes, tumor invasion, tumor growth, tumor metastasis, corneal scarring, scleritis, immunodeficiency diseases, sepsis, premature labor, hypoprothrombinemia, hemophilia, thyroiditis, sarcoidosis, Behcet's syndrome, hypersensitivity, schizophrenia, kidney disease, Rickettsial infections, Protozoan diseases, reproductive disorders, and septic shock in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof effective in treating such a condition, are provided herein.
In some embodiments, methods for treating a hyperplastic disease in a mammal by administering to the mammal a therapeutically effective amount of a compound of Formula I.
In other embodiments, methods for treating, inhibiting, or delaying the onset of uncontrolled or abnormal angiogenesis in a subject in need of such treatment, inhibition, or delay by administering a therapeutically effective amount of a compound of Formula I, are provided. In one embodiment of this method, the uncontrolled or abnormal angiogenesis to be treated is selected from the group including, but not limited to, metastasis, corneal graft rejection, ocular neovascularization, retinal neovascularization, diabetic retinopathy, retrolental fibroplasia, neovascular glaucoma, gastric ulcer, infantile hemaginomas, angiofibroma of the nasopharynx, avascular necrosis of bone, and endometriosis.
In still other embodiments, methods for selecting a subject for treatment of a disease or condition mediated by (3-catenin where the method involves obtaining a sample of the subject's tumor, determining if (3-catenin is activated in the tumor, and treating the subject with an agent that modulates (3-catenin activity. In one related method, (3-catenin activation is determined with immunohistochemical methods.
In still other embodiments, methods for selecting a subject for treatment of a disease or condition mediated by Cyclin Dl where the method involves obtaining a sample of the subject's tumor, determining if Cyclin D1 is overexpressed in the tumor, and treating the subject with an agent that modulates Cyclin D1 activity.
Preferred compounds for use in the method are compounds of Formula I. In one related method, Cyclin D1 overexpression is determined using quantitative PCR.
BRIEF DESCRIPTION OF THE DRAWINGS
FIGURE 1 shows inhibition of (3-catenin:TOP flash by R-etodolac and compounds of the invention.
FIGURE 2 shows inhibition of Cyclin D1 mRNA expression by R-etodolac and compounds of the invention.
DETAILED DESCRIPTION OF THE INVENTION
To more readily facilitate an understanding of the invention and its preferred embodiments, the meanings of terms used herein will become apparent from the context of this specification in view of common usage of various terms and the explicit definitions of other terms provided in the glossary below or in the ensuing description.
Glossary of Terms As used herein, the terms "comprising," "including," and "such as" are used in their open, non-limiting sense.
As used herein and in the appended claims, the singular forms "a", "an", and "the"
include plural reference unless the context clearly dictates otherwise.
../
In accordance with a convention used in the art, %~w is used in structural formulae herein to depict the bond that is the point of attachment of the moiety or substituent to the core or backbone structure.
In accordance with a convention used in the art, the symbol ~ represents a methyl group, ~ represents an ethyl group, ~ represents a cyclopentyl group, etc.
The term "alkyl" as used herein refers to a straight- or branched-chain alkyl group having one to twelve carbon atoms. Exemplary alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and the like. The term "lower alkyl" designates an alkyl having from 1 to 6 carbon atoms (a C1_6-alkyl).
The term "heteroalkyl" as used herein refers to straight- and branched-chain alkyl groups having from one to twelve atoms containing one or more heteroatoms selected from S, O, and N. The term "lower heteroalkyl" designates a heteroalkyl having from 1 to 6 carbon atoms (a Cl_6-heteroalkyl).
The term "alkenyl" means an alkyl radical having one or more double bonds and two to twelve carbon atoms. Alkenyl groups containing three or more carbon atoms may be straight or branched. Alkenyl groups as used herein include either the cis or trans configurations. Illustrative alkenyl groups include prop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, hex-2-enyl, and the like. The term "lower alkenyl"
designates an alkyl having from 1 to 6 carbon atoms (a C1_6-alkenyl).
The term "allyloxy" refers to an alkenyloxy group which is CHZ=CHCHZ-O-.
The term "alkynyl" means an alkyl radical having one or more triple bonds and two to twelve carbon atoms. Alkynyl groups containing three or more carbon atoms may be straight or branched. Alkynyl groups as used herein include either the cis or traps configurations. Illustrative alkynyl groups include prop-2-ynyl, but-2-ynyl, but-3-ynyl, 2-methylbut-2-ynyl, hex-2-ynyl, and the like. The term "lower alkynyl"
designates an alkyl having from 1 to 6 carbon atoms (a CI_6-alkynyl).
The term "aryl" (Ar) refers to a monocyclic, or fused or spiro polycyclic, aromatic carbocycle (ring structure having ring atoms that are all carbon) having from three to twelve ring atoms per ring. Illustrative examples of aryl groups include the following moieties:
\ \ I \ \ \ I ~\ I \ \
~ ~ ~ , ~ ~ , ~ ~ , and the like.
The term "heteroaryl" (heteroAr) refers to a monocyclic, or fused or spiro polycyclic, aromatic heterocycle (ring structure having ring atoms selected from carbon atoms as well as nitrogen, oxygen, and sulfur heteroatoms) having from three to twelve ring atoms per ring. Illustrative examples of heteroaryl groups include the following moieties:
N~N N~N I ~ ~ I ~ O I ~ N\
~N ~ NON , / , / ~ , / N// , N S O ,O N S ,S
W , W , ~~ ~ N~ ~ , ~ ~ ~ ~~ N~ ~ , N N N
N~N O INS N ~ INS INN
,, " , ~ . c~ . .
~N ~ N > > S
s o \ /
I N \ \ ~N ~ O
S~ ~ I / N~ ~ I / ~, I / , and the like.
The term "cycloalkyl" refers to a saturated or partially saturated, monocyclic or fused or spiro polycyclic, carbocycle having from three to twelve ring atoms per ring.
Illustrative examples of cycloalkyl groups include the following moieties:
> > , , ~~ a > > > >
~ ~ ~, ~
to > > > > >
and the like.
A "heterocycloalkyl" refers to a monocyclic, or fused or spiro polycyclic, ring structure that is saturated or partially saturated and has from three to twelve ring atoms per ring selected from C atoms and N, O, and S heteroatoms. Illustrative examples of 1 S heterocycloalkyl groups include:
O O O O O O
~S~ N
S N~N N O O O
U
, ,~ ~ , N N~ O O C N
O
U ~ ~ , U , ~N , , U , N-N , N
O
O S II
I I N N ~O O
n c~ c~
, n N , N ~ ~ c ~ , N N N ~ , O
N_S O N N I \ O S
N , , ~ ~ ~ U, , O and the hke.
The term "alkoxy" refers to O-alkyl. Illustrative examples include methoxy, ethoxy, propoxy, and the like.
The term "halogen" represents chlorine, fluorine, bromine or iodine. The term "halo" represents chloro, fluoro, bromo or iodo.
Unless otherwise defined, the term "substituted" as used herein means at least one hydrogen atom is replaced with a suitable substituent.
The term "unsubstituted" means that the specified group bears no substituents.
The term "lower" when refernng to a group such as an alkyl, alkenyl, alkynyl, alkoxy or other group refers to such a group having up to 6 carbon atoms.
As used herein "tumors" or "neoplasms" include growths of tissue cells wherein multiplication of cells is uncontrolled and progressive. Some such growths are benign, but others are termed malignant and can lead to death of the organism. Malignant neoplasms, or cancers are distinguished from benign growths in that in addition to exhibiting aggressive cellular proliferation can invade surrounding tissues and metastasize.
Malignant neoplasms may be characterized by showing a greater loss of differentiation and organization relative to one another and surrounding tissues.
"Hyperplasia" refers to the abnormal multiplication or increase in the number of normal cells in normal arrangement in a tissue.
The term "subject" for purposes of treatment includes any human or animal subject who has any one of the known diseases or conditions described herein, e.g., cancer, hyperplasia, inflammation, Alzheimer's, and abnormal angiogenesis. For methods of prevention, the subject is any human or animal subject, and preferably is a human subject who is at risk for the disease or conditions described herein, e.g., cancer.
The subject may be at risk due to a genetic predisposition, and/or exposure to various agents, including chemicals and viral agents. Besides being useful for human treatment, the compounds described herein are also useful for veterinary treatment of mammals, including companion animals and farm animals, such as horses, dogs, cats, cows, sheep and pigs.
Preferably, subject means a human.
As used herein "a disease mediated by a-catenin" means a disease that is associated with changes in (3-catenin regulation such that the its levels, distribution and/or association with other proteins in the cytoplasm and nucleus differ from that found in normal cells. Changes in ~3-catenin levels, associations, and/or distribution, e.g., nuclear accumulation may result from mutations in ~3 -catenin, APC, axin or other proteins involved in the trafficking of ~i-catenin. ,Q -catenin accumulation, levels and/or distribution may also be affected by changes in the wnt/fzd signaling pathway. ~i-catenin accumulation in the nucleus may lead to the transcription of genes involved in tumorgenesis, such as cyclin Dl and c-myc.
As used herein "activated ~i-catenin" represents ~3-catenin that is not marked for degradation.
As used herein "a disease mediated by Cyclin D1" means a disease that is associated with changes in Cyclin D1 expression such that the its levels, distribution and/or association with other proteins in the cell differ from that found in normal cells.
As used herein "angiogenesis" is the development of new blood vessels into a tissue or organ. Under normal conditions, angiogenesis is observed in wound healing and embryonal development. Uncontrolled or abnormal angiogenesis is associated with neoplastic disease, tumor metastasis and other angiogenesis-related diseases.
"A pharmaceutically acceptable salt" is intended to mean a salt that retains the biological effectiveness of the free acids and bases of the specified compound and that is not biologically or otherwise undesirable.
As used herein a "pharmaceutically acceptable prodrug" is a compound that may be converted under physiological conditions or by solvolysis to the specified compound or to a pharmaceutically acceptable salt of such compound.
The term "a pharmaceutically active metabolite" is intended to mean a pharmacologically active product produced through metabolism in the body of a specified compound or salt thereof.
An "effective amount" is intended to mean that amount of an agent that, when administered to a subject in need of such treatment, is sufficient to effect treatment for a disease and/or condition associated with (3-catenin, COX, PPAR, Cyclin D
and/or A(342.
Thus, e.g., a therapeutically effective amount of a compound of the Formula I, salt, active metabolite or prodrug thereof is a quantity sufficient to modulate, regulate, or inhibit the activity of (3-catenin, COX, PPAR, Cyclin D and/or A(342 such that a disease and/or condition which is mediated by that activity is reduced or alleviated.
The terms "treating", "treat" and "treatment" refer to any treatment of a COX, ~i-catenin, PPAR, or amyloid-[3 mediated disease and/or condition in a mammal, particularly a human, and include: (i) preventing the disease or condition from occurring in a subject which may be predisposed to the condition, for example subjects with accumulated A~3 peptides, such that the treatment constitutes prophylactic treatment for the pathologic condition; (ii) modulating or inhibiting the disease or condition, i.e., arresting its development; (iii) relieving the disease or condition, i.e., causing regression of the disease or condition; or (iv) relieving and/or alleviating disease or condition or the symptoms resulting from the disease or condition, e.g., relieving an inflammatory response without addressing the underlining disease or condition.
By "efficacious levels" is meant levels in which the effects of (3-catenin, COX, PPAR, Cyclin D and/or A(342 activity or amounts are, at a minimum, regulated.
The phrase "conjunctive therapy" (or "combination therapy"), in defining use of a compound of the invention and another pharmaceutical agent, is intended to embrace administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended as well to embrace co-administration of these agents in a substantially simultaneous manner, such as in a single formulation having a fixed ratio of these active agents, or in multiple, separate formulations for each agent.
COMPOUNDS
Applicants have discovered compounds, as represented by Formulas I, which possess COX inhibitory activity, ~3-catenin inhibitory activity, cyclin D1 activity, and/or are cytotoxic to cancer cell lines.
Provided herein are compounds represented by Formulas I:
o Rz or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt thereof, wherein Rl-Rlo, X, Y, Z and n are as defined herein.
The compounds of Formula I may exhibit the phenomenon of tautomerism. While Formulas I cannot expressly depict all possible tautomeric forms, it is to be understood that Formula I are intended to represent any tautomeric form of the depicted compound and are not to be limited merely to a specific compound form depicted by the formula drawings.
The compounds of Formula I may have one or more asymmetric centers depending upon the nature of the various substituents on the molecule. As a consequence of these asymmetric centers, the compounds of Formulas I may exist as single stereoisomers (i.e., essentially free of other stereoisomers), racemates, and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present invention. Preferably, the inventive compounds that are optically active are used in optically pure form.
As generally understood by those skilled in the art, an optically pure compound having one chiral center (i.e., one asymmetric carbon atom) is one that consists essentially of one of the two possible enantiomers (i.e., is enantiomerically pure), and an optically pure compound having more than one chiral center is one that is both diastereomerically pure and enantiomerically pure. The compounds of the present invention can be used in a R9 rormwa i form that is at least 90% optically pure, that is, a form that contains at least 90% of a single isomer (80% enantiomeric excess ("e.e.") or diastereomeric excess ("d.e.")). In some cases, e.g., to reduce toxicity, the compounds can be used in a form that contains at least 95% (90% e.e. or d.e.), even more preferably at least 97.5% (95% e.e. or d.e.), and S most preferably at least 99% (98% e.e. or d.e.) of a single isomer e.e. or d.e.
Additionally, Formula I are intended to cover solvated as well as unsolvated forms of the identified structures. For example, Formula I include compounds of the indicated structure in both hydrated and non-hydrated forms. Other examples of solvates include the structures in combination with isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.
In addition to compounds of Formula I, the invention includes pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts of such compounds and metabolites.
Prodrugs and active metabolites of a compound may be identified using routine techniques known in the art. See, e.g., Bertolini et al., J. Med. Chem., 40, (1997); Shan, et al., J. Pharm. Sci., 86 (7), 765-767; Bagshawe, Drug Dev.
Res., 34, 220-230 (1995); Bodor, Advances in Drug Res., 13, 224-331 (1984); Bundgaard, Design of Prodrugs (Elsevier Press 1985); Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991); Dear et al., J. Chromatogr. B, 748, 281-293 (2000); Spraul et al., J.
Pharmaceutical & Biomedical Analysis, 10, 601-605 (1992); and Prox et al., Xenobiol., 3, 103-112 (1992).
A compound of the invention may possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. Exemplary pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an inorganic base, such as salts including sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, g-hydroxybutyrates, glycolates, tartrates, methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.
If the inventive compound is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, malefic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
If the inventive compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
In the case of agents that are solids, it is understood by those skilled in the art that the inventive compounds and salts may exist in different crystal or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulas.
Therapeutically effective amounts of the agents of the invention may be used to treat or prevent diseases and/or conditions mediated by modulation or regulation of ~3-catenin, COX, A(342, and PPAR.
The amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the subject in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
The active agents of the invention may be formulated into pharmaceutical compositions as described below. Pharmaceutical compositions of this invention comprise S an effective modulating, regulating, or inhibiting amount of a compound of Formula I and an inert, pharmaceutically acceptable carrier or diluent. In one embodiment of the pharmaceutical compositions, efficacious levels of the inventive agents are provided so as to provide therapeutic benefits involving modulation of (3-catenin, COX, PPAR, and/or A(342. These compositions are prepared in unit-dosage form appropriate for the mode of administration, e.g., parenteral or oral administration.
An inventive agent can be administered in conventional dosage form prepared by combining a therapeutically effective amount of an agent (e.g., a compound of Formula I) as an active ingredient with appropriate pharmaceutical carriers or diluents according to conventional procedures. These procedures may involve mixing, granulating and 1 S compressing or dissolving the ingredients as appropriate to the desired preparation.
The pharmaceutical carrier employed may be either a solid or liquid. Exemplary of solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may include time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate and the like.
A variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge. The amount of solid carrier may vary, but generally will be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation will be in the form of syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial or non-aqueous liquid suspension.
To obtain a stable water-soluble dose form, a pharmaceutically acceptable salt of an inventive agent is dissolved in an aqueous solution of an organic or inorganic acid, such as 0.3M solution of succinic acid or citric acid. If a soluble salt form is not available, the agent may be dissolved in a suitable cosolvent or combinations of cosolvents.
Examples of suitable cosolvents include, but are not limited to, alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, gylcerin and the like in concentrations ranging from 0-60% of the total volume. In an exemplary embodiment, a compound of Formula I
is dissolved in DMSO and diluted with water. The composition may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle such as water or isotonic saline or dextrose solution.
It will be appreciated that the actual dosages of the agents used in the compositions of this invention will vary according to the particular complex being used, the particular composition formulated, the mode of administration and the particular site, host and disease and/or condition being treated. Optimal dosages for a given set of conditions can be ascertained by those skilled in the art using conventional dosage-determination tests in view of the experimental data for an agent. For oral administration, an exemplary daily dose generally employed is from about 0.001 to about 3000 mg/kg of body weight, with courses of treatment repeated at appropriate intervals. In some embodiments, the daily dose is from about 1 to 3000 mg/kg of body weight.
Typical daily doses in a pateint may be anywhere between about 500 mg to about 3000 mgs, given once or twice daily, e.g., 3000 mg can be given twice daily for a total dose of 6000 mg.. In one embodiment, the dose is between about 1000 to about 3000 mgs.
In another embodiment, the dose is between about 1500 to about 2800 mgs. In other embodiments, the dose is between about 2000 to about 3000 mgs.
Plasma concentrations in the subjects may be between about 100 p,M to about ~M. In some embodiments, the plasma concentration may be between about 200 ~,M
to about 800 pM. In other embodiments, the concentration is about 300 ~M to about ~M. In still other embodiments the plasma concentration may be between about 400 to about 800 ~M. Administration of prodrugs is typically dosed at weight levels, which are chemically equivalent to the weight levels of the fully active form.
The compositions of the invention may be manufactured using techniques generally known for preparing pharmaceutical compositions, e.g., by conventional techniques such as mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing. Pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers, which may be selected from excipients and auxiliaries that facilitate processing of the active compounds into preparations, which can be used pharmaceutically.
Proper formulation is dependent upon the route of administration chosen. For injection, the agents of the invention may be formulated into aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers known in the art. Such Garners enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurnes, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained using a solid excipient in admixture with the active ingredient (agent), optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include:
fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as crosslinked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active agents.
Pharmaceutical preparations, which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the active agents may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.
For administration intranasally or by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of 1 S gelatin for use in an inhaler or insufflator and the like may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit-dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active agents may be prepared as appropriate oily injection suspensions.
Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents, which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
In addition to the formulations described above, the compounds may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion-exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
An exemplary pharmaceutical carrier for hydrophobic compounds is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. The cosolvent system may be a VPD co-solvent system.
VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol. The VPD co-solvent system (VPD:SW) contains VPD diluted 1:1 with a 5%
dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration.
Naturally, the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied;
other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may be substituted for dextrose.
Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are known examples of delivery vehicles or Garners for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity.
Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
Various sustained-release materials have been established and are known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.
The pharmaceutical compositions also may comprise suitable solid- or gel-phase Garners or excipients. Examples of such Garners or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
Some of the compounds of the invention may be provided as salts with pharmaceutically compatible counter ions. Pharmaceutically compatible salts may be formed with many acids, including hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free-base forms.
The administration of the present invention may be for either prevention or treatment purposes. When used for the treatment and/or prevention of neoplasia, or Alzheimer's, or for the treatment of diseases treatable by inhibiting COX, the methods and compositions described herein may be used alone or in conjunction with additional therapies known to those skilled in the art. Alternatively, the methods and compositions described herein may be used as conjunctive therapy. By way of example, the compounds described herein may be administered alone or in conjunction with other antineoplastic agents, glucocorticoids or other growth inhibiting agents or other drugs or nutrients.
There are large numbers of antineoplastic agents available in commercial use, in clinical evaluation and in pre-clinical development, which could be selected for treatment of neoplasia by combination drug chemotherapy. Such antineoplastic agents fall into several major categories, namely, antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, including glucocorticoids such as prednisone and dexamethasone, immunological agents, interferon-type agents and a category of miscellaneous agents. Alternatively, other anti-neoplastic agents, such as metallomatrix proteases (MMP), SOD mimics or alpha" beta3 inhibitors may be used.
One family of antineoplastic agents which may be used in combination with the compounds of the inventions consists of antimetabolite-type antineoplastic agents.
Suitable antimetabolite antineoplastic agents may be selected from the group consisting of alanosine, AG2037 (Pfizer), S-FU-fibrinogen, acanthifolic acid, aminothiadiazole, brequinar sodium, carmofur, Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabine phosphate stearate, cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC, dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC, doxifluridine, Wellcome EHNA, Merck & Co. EX-015, fazarabine, floxuridine, fludarabine phosphate, 5-fluorouracil, N-(2'-furanidyl)-5-fluorouracil, Daiichi Seiyaku FO-152, isopropyl pyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim, methotrexate, Wellcome MZPES, norspermidine, NCI NSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA, pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, Takeda TAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, tyrosine kinase inhibitors, tyrosine protein kinase inhibitors, Taiho UFT
and uricytin.
A second family of antineoplastic agents which may be used in combination with the compounds of the invention consists of alkylating-type antineoplastic agents. Suitable alkylating-type antineoplastic agents may be selected from the group consisting of Shionogi 254-S, aldo-phosphamide analogues, altretamine, anaxirone, Boehringer Mannheim BBR-2207, bendamustine, bestrabucil, budotitane, Wakunaga CA-102, carboplatin, carmustine, Chinoin-139, Chinoin-153, chlorambucil, cisplatin, cyclophosphamide, American Cyanamid CL-286558, Sanofi CY-233, cyplatate, Degussa D-19-384, Sumimoto DACHP(Myr)2, diphenylspiromustine, diplatinum cytostatic, Erba distamycin derivatives, Chugai DWA-21148, ITI E09, elmustine, Erbamont FCE-24517, estramustine phosphate sodium, fotemustine, Unimed G-6-M, Chinoin GYKI-17230, hepsul-fam, ifosfamide, iproplatin, lomustine, mafosfamide, melphalan, mitolactol, Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC-342215, oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-119, ranimustine, semustine, SmithKline SK&F-101772, Yakult Honsha SN-22, spiromustine, Tanabe Seiyaku TA-077, tauromustine, temozolomide, teroxirone, tetraplatin and trimelamol.
Another family of antineoplastic agents which may be used in combination with the compounds of the invention consists of antibiotic-type antineoplastic agents. Suitable antibiotic-type antineoplastic agents may be selected from the group consisting of Taiho 4181-A, aclarubicin, actinomycin D, actinoplanone, alanosine, Erbamont ADR-456, aeroplysinin derivative, Ajinomoto AN-201-II, Ajinomoto AN-3, Nippon Soda anisomycins, anthracycline, azino-mycin-A, bisucaberin, Bristol-Myers BL-6859, Bristol-Myers BMY-25067, Bristol-Myers BMY-25551, Bristol-Myers BMY-26605, Bristol-Myers BMY-27557, Bristol-Myers BMY-28438, bleomycin sulfate, bryostatin-1, Taiho C-1027, calichemycin, chromoximycin, dactinomycin, daunorubicin, Kyowa Hakko DC-102, Kyowa Hakko DC-79, Kyowa Hakko DC-88A, Kyowa Hakko DC89-Al, Kyowa Hakko DC92-B, ditrisarubicin B, Shionogi DOB-41, doxorubicin, doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin, esorubicin, esperamicin-Al, esperamicin-Alb, Erbamont FCE-21954, Fujisawa FK-973, fostriecin, Fujisawa FR-900482, glidobactin, gregatin-A, grincamycin, herbimycin, idarubicin, illudins, kazusamycin, kesarirhodins, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, American Cyanamid LL-D49194, Meiji Seika ME 2303, menogaril, mitomycin, mitoxantrone, SmithKline M-TAG, neoenactin, Nippon Kayaku NK-313, Nippon Kayaku NKT-O1, SRI International NSC-357704, oxalysine, oxaunomycin, peplomycin, pilatin, pirarubicin, porothramycin, pyrindamycin A, Tobishi RA-I, rapamycin, rhizoxin, rodorubicin, sibanomicin, siwenmycin, Sumitomo SM-5887, Snow Brand SN-706, Snow Brand SN-07, sorangicin-A, sparsomycin, SS
Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS Pharmaceutical SS-9816B, steffimycin B, Taiho 4181-2, talisomycin, Takeda TAN-868A, terpentecin, thrazine, tricrozarin A, Upjohn U-73975, Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024 and zorubicin.
A fourth family of antineoplastic agents which may be used in combination with the compounds of the invention include a miscellaneous family of antineoplastic agents selected from the group consisting of alpha-carotene, alpha-difluoromethyl-arginine, acitretin, arsenic trioxide, Avastin ~ (bevacizumab), Biotec AD-5, Kyorin AHC-52, alstonine, amonafide, amphethinile, amsacrine, Angiostat, ankinomycin, anti-neoplaston A10, antineoplaston A2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, Henkel APD, aphidicolin glycinate, asparaginase, Avarol, baccharin, batracylin, benfluron, benzotript, Ipsen-Beaufour BIM-23015, bisantrene, Bristo-Myers BMY-40481, Vestar boron-10, bromofosfamide, Wellcome BW-502, Wellcome BW-773, caracemide, carmethizole hydrochloride, Ajinomoto CDAF, chlorsulfaquinoxalone, Chemes CHX-2053, Chemex CHX-100, Warner-Lambent CI-921, Warner-Lambent CI-937, Warner-Lambert CI-941, Warner-Lambert CI-958, clanfenur, claviridenone, ICN compound 1259, ICN compound 4711, Contracan, Yakult Honsha CPT-11, crisnatol, curaderm, cytochalasin B, cytarabine, cytocytin, Merz D-609, DABIS maleate, dacarbazine, datelliptinium, didemnin- B, dihaematoporphyrin ether, dihydrolenperone, dinaline, distamycin, Toyo Pharmar DM-341, Toyo Pharmar DM-75, Daiichi Seiyaku DN-9693, elliprabin, elliptinium acetate, epothionesTsumura EPMTC, erbitux, ergotamine, erlotnib, etoposide, etretinate, fenretinide, Fujisawa FR-57704, gallium nitrate, genkwadaphnin, Glivec (imatnib), Chugai GLA-43, Glaxo GR-63178, gefitinib, grifolan NMF-SN, hexadecylphosphocholine, Green Cross HO-221, homoharringtonine, hydroxyurea, BTG
ICRF-187, indanocine, ilmofosine, isoglutamine, isotretinoin, Otsuka JI-36, Ramot K-477, Otsuak K-76COONa, Kureha Chemical K-AM, MECT Corp KI-8110, American Cyanamid L-623, leukoregulin, lonidamine, Lundbeck LU-23-112, Lilly LY-186641, NCI
(US) MAP, marycin, mefloquine, Merrel Dow MDL-27048, Medco MEDR-340, merbarone, merocyanine derivatives, methylanilinoacridine, Molecular Genetics MGI-136, minactivin, mitonafide, mitoquidone, mopidamol, motretinide, Zenyaku Kogyo MST-16, N-(retinoyl)amino acids, Nisshin Flour Milling N-021, N- acylated-dehydroalanines, nafazatrom, Taisho NCU-190, nocodazole derivative, Normosang, NCI
NSC-145813, NCI NSC-361456, NCI NSC-604782, NCI NSC-95580, octreotide, Ono ONO-112, oquizanocine, Akzo Org-10172, paclitaxel, pancratistatin, pazelliptine, Warner-Lambert PD-111707, Warner-Lambert PD-115934, Warner-Lambert PD-131141, Pierre Fabre PE-1001, ICRT peptide D, piroxantrone, polyhaematoporphyrin, polypreic acid, Efamol porphyrin, probimane, procarbazine, proglumide, Invitron protease nexin I, Tobishi RA-700, razoxane, Sapporo Breweries RBS, restrictin-P, retelliptine, retinoic acid, Rhone-Poulenc RP-49532, Rhone-Poulenc RP-56976, Rituxan~ (and other anti CD20 antibodies, e.g. Bexxar~, Zevalin~), SmithKline SK&F-104864, statins (Lipitor~
etc.), Sumitomo SM-108, Kuraray SMANCS, SeaPharm SP-10094, spatol, spirocyclopropane derivatives, spirogermanium, Unimed, SS Pharmaceutical SS-554, strypoldinone, Stypoldione, Suntory SUN 0237, Suntory SUN 2071, superoxide dismutase, Thalidomide, Toyama T-506, Toyama T-680, taxol, Teijin TEI-0303, teniposide, thaliblastine, Eastman Kodak TJB-29, tocotrienol, Topostin, Teijin TT-82, Kyowa Hakko UCN-Ol, Kyowa Hakko UCN-1028, ukrain, Eastman Kodak USB-006, vinblastine sulfate, vincristine, vindesine, vinestramide, vinorelbine, vintriptol, vinzolidine, withanolides and Yamanouchi YM-534, zometa.
Examples of radioprotective agents which may be used in the combination chemotherapy of this invention are AD-S, adchnon, amifostine analogues, detox, dimesna, 1-102, MM-159, N-acylated-dehydroalanines, TGF-Genentech, tiprotimod, amifostine, WR-151327, FUT-187, ketoprofen transdermal, nabumetone, superoxide dismutase (Chiron) and superoxide dismutase Enzon.
Methods for preparation of the antineoplastic agents described above may be found in the literature. Methods for preparation of doxorubicin, for example, are described in U.S. Pat. Nos. 3,590,028 and 4,012,448. Methods for preparing metallomatrix protease inhibitors are described in EP 780386. Methods for preparing SOD mimics are described in EP 524,101. Methods for preparing .alpha,, .beta3 inhibitors are described in W097/08174.
Additionally, the compounds of Formula I may be administered either alone or in combination with other compounds effective for treating Alzheimer's or dementia. For example, the compounds of the invention may be administered in combination with other 1 S agents used to treat amyloid-(3-mediated diseases or conditions, such as estrogen, risperidone, a thiobenzodiazepine, ampakine, [N-(2,6-dimethylphenyl)-2-(2-oxo-pyrrolidinyl)acetamide, DM9384, a cholinesterase inhibitor, donepezil hydrochloride, rivastigmine tartrate, galantamine, NGF, and metrifonate.
COX INHIBITORS
The compounds of Formula I described herein or pharmaceutically acceptable salts may possess COX-inhibiting activity and possess anti-inflammatory, antipyretic, analgesic, antithrombotic, and anti-cancer activities. The compounds of Formula I and pharmaceutically acceptable salt thereof, therefore, are useful for treating and/or preventing COX-mediated diseases, inflammatory conditions, pain, fever, rheumatic fever, collagen diseases, autoimmune diseases, various immunological diseases, thrombosis, cancer and neurodegenerative diseases in human beings or animals by using administered systemically or topically. More particularly, the compounds and pharmaceutically acceptable salts thereof are useful for treating and/or preventing inflammation and acute or chronic joint and muscle pain [e.g. rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, juvenile arthritis, etc.], inflammatory skin condition [e.g.
sunburn, burns, eczema, dermatitis, etc.], inflammatory eye condition (e.g.
conjunctivitis, etc.], lung disorder in which inflammation is involved [e.g. asthma, bronchitis, pigeon fancier's disease, farmer's lung, etc.], conditions of the gastrointestinal tract associated with inflammation [e.g. aphthous ulcer, Crohn's disease, atopic gastritis, gastritis varialoforme, ulcerative colitis, coeliac disease, regional ileitis, irntable bowel syndrome, etc.], gingivitis, inflammation, pain and tumescence after operation or injury, pyrexia, pain and other conditions associated with inflammation, particularly those in which lipoxygenase and cyclooxygenase products are a factor, systemic lupus erythematosus, scleroderma, polymyositis, tendonitis, bursitis, periarteritisnodose, rheumatic fever, Sjogren's syndrome, Behcet disease, thyroiditis, type I diabetes, nephrotic syndrome, aplastic anemia, myasthenia gravis, uveitis contact dermatitis, psoriasis, Kawasaki disease, sarcoidosis, Hodgkin's disease, Alzheimer's disease, Parkinson's disease, symptoms associated with influenza and other viral infections, common cold, low back and neck pain, dysmenorrheal, headache, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis including rheumatoid arthritis, degenerative joint disease or osteoarthritis, gout, ankylosing spondylitis, bursitis, injuries following surgical and dental procedures, bone loss, or the like. Additionally, the compounds disclosed herein or a salt thereof is expected to be useful as therapeutical and/or preventive agents for cardiovascular or cerebrovascular diseases, the diseases caused by hyperglycemia and hyperlipemia.
The anti-inflammatory activity of the compounds of this invention may be assayed by measuring the ability of the compound to inhibit COX-l and COX-2.
Techniques for measuring COX inhibition is described herein and in the literature, for example, see US
Patent Application No. 2002/0107280; Winter et al. 1962 Proc. Soc. Exp. Biol.
Med.
111:544 both incorporated herein by reference.
In still other embodiments preferred compounds of Formula 1 are those compound with no or little COX activity.
CANCER
Neoplasms treatable by the present invention include solid tumors, i.e., carcinomas and sarcomas. Carcinomas include malignant neoplasms derived from epithelial cells which infiltrate surrounding tissues and give rise to metastases.
Adenocarcinomas are carcinomas derived from glandular tissue, or from tissues that form recognizable glandular structures. Another broad category of cancers includes sarcomas, which are tumors whose cells are embedded in a fibrillar or homogeneous substance, like embryonic connective tissue. The invention also enables treatments of cancer of the myeloid or lymphoid systems, including leukemias, such as CLL, myelomas, such as multiple myeloma, lymphomas, and other cancers that typically are not present as a tumor mass, but are distributed in the vascular or lymphoreticular systems.
Cancers that may be treated using the compounds described herein include, without limitation, brain cancer, bone cancer, epithelial cell derived neoplasia (epithelial carcinoma) such as basal cell carcinoma, adenocarcinoma, gastrointestinal cancer such as lip cancer, mouth cancer, esophageal cancer, small bowel cancer, stomach cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer, skin cancer such as squamous cell and basal cell cancers, prostate cancer, renal cell carcinoma, and other known cancers that effect epithelial cells throughout the body.
The activity of compounds of Formula I against various cancers can be tested using assays known in the art, e.g., MTT assay to cancer cell lines in vitro and animal tumor models-see, for example, Romijn et al., 1988 Prostate 12:99-110.
Cancers amenable to treatment with the compounds of the invention include those mentioned above and those mediated by (3-catenin. Exemplary cancers would include those having mutations in APC, the wnt/fzd signaling pathway, axin and/or ~i-catenin resulting in [3-catenin deregulation and a subsequent increase in free (3-catenin in the cytoplasm and nucleus.
The identification of cancers mediated by (3-catenin can be determined using a variety of techniques known in the art. For example, the expression of wnt and/or fzd RNA can be measured in cancer cells and compared to normal cells as described in International Publications Nos. WO 02/092635 and WO 02/088081 (both incorporated herein by reference in their entireties). Cancers that overexpress wnt and/or fzd would be expected to have deregulated ~3-catenin.
Deregulation of (3-catenin can also be shown by analyzing the subcellular localization of ~3-catenin, e.g., cytoplasmic, nuclear and/or plasma membrane in cancer cells as compared to normal cells of the same type. Such characterization can be done using techniques know in the art including immunohistochemistry, confocal microscopy, and immunoblot analysis.
Samples for (3-catenin analysis can be obtained using standard procedures know to those of skill in the art and include generally known biopsy methods including fine-needle aspiration, surgical biopsy, and core-needle biopsy. Samples for analysis can also be fixed and embedded in such materials as paraffin.
For a review of immunological and immunoassay procedures in general, see Stites et al. (eds.) (1991) Basic and Clinicallmmunology (7th ed.). Immunoassays to detect (3-catenin can be performed in any of several configurations, which are reviewed extensively in Maggio (ed.) (1980) Enzyme Immunoassay CRC Press, Boca Raton, Fla.; Tijan (1985) "Practice and Theory of Enzyme Immunoassays," Laboratory Techniques in Biochemistry and Molecular Biology, Elsevier Science Publishers B. V., Amsterdam; and Harlow and Lane Antibodies, A Laboratory Manual, supra, each of which is incorporated herein by reference. See also Chan (ed.) (1987) Immunoassay: A Practical C'ruide Academic Press, Orlando, Fla.; Price et al. (eds.) (1997) Principles and Practice oflmmunoassay (2°a ed), Groves Dictionaries, Inc.; Boenisch (ed.) (2001) Handbooklmmunochemical Staining Methods DAKO Corp. Carpinteria, CA, USA; and Ngo (ed.). (1988) Non-isotopic Immunoassays Plenum Press, NY; all incorporated herein by reference.
In general, immunoassay design considerations include preparation of antibodies (e.g., monoclonal or polyclonal) having sufficiently high-binding specificity for their antigen so the specifically bound antibody-antigen complex can be distinguished reliably from nonspecific interactions. Polyclonal and monoclonal antibodies that detect (3-catenin are known in the art and are commercially available, e.g., Upstate Cell Signaling Solutions, Charlottesville, VA-catalogue nos. 06-734; 05-601; and 05-482.
Western blot analysis can be used to quantitate the amount of ~3-catenin protein in a sample. Electrophoresis is carried out, e.g., on a tissue sample suspected of containing the protein. Following electrophoresis to separate the proteins, and transfer of the proteins to a suitable solid support such as a nitrocellulose filter, the solid support is incubated with an antibody reactive with the denatured protein. This antibody may be labeled, or alternatively may be it may be detected by subsequent incubation with a second labeled antibody that binds the primary antibody.
A preferred method for identifying cancers that have deregulated (3-catenin is immunohistochemistry (IHC). Immunohistochemistry allows for the evaluation of micro-anatomical detail and heterogeneity in tissues and tumors.
Immunohistochemistry is advantageous over other methods of analyses because it is the only method that can S directly localize proteins to individual cell types and specific cell locations, e.g., plasma membrane, cytoplasm, and/or nucleus. Differences among gene expression of normal and tumor tissue can be detected while simultaneously noting the changes in cell number and composition. In contrast, techniques, such as Western blotting require the use of cell extracts; therefore, a possibility exists of contamination of different cell types. For IHC, a primary (3-catenin antibody that recognizes (3-catenin protein is introduced to a biological specimen. ABer incubation with the primary antibody, a wash can be performed to remove unbound antibody. Then, a secondary antibody, directed against the primary antibody and labeled with an enzyme, can be incubated with the biological specimen.
During incubation, the secondary antibody will bind to the primary antibody.
Alternatively, the second antibody may lack a label, but it may, in turn, be bound by a labeled third antibody specific to antibodies of the species from which the second antibody is derived.
The primary antibody can be labeled with an enzyme thus eliminating the need for a second antibody. Alternatively, the labeled (3-catenin antibody can be labeled with biotin rather than an enzyme. Then, in an additional step, enzyme-labeled avidin or streptavidin is introduced to the sample and allowed to bind to the biotinylated antibody.
For immunohistochemistry, the tissue sample may be fresh or frozen or may be embedded, for example, in paraffin or other waxes, nitrocellulose, carbowax (also known as water soluble polyethylene glycol (see, Gao ed. (1993) "Polyethylene Glycol as an Embedment for Microscopy and Histochemistry," CRC Press, Inc. Boca Raton, Fl.), plastic, including resins such as acrylic and epoxy resins, or OCT embedded frozen blocks. Preferably, the samples are embedded in paraffin or other waxes, nictrocellulose, carbowax, or plastic. The samples can be fixed with a preservative, such as formalin, for example.
Samples for immunohistochemistry can be obtained from surgical biopsies, fine-needle biopsies, fine-needle aspiration biopsies, core-needle biopsies, effusions from body cavities, such as the abdominal cavity, the pleural cavities and the pericardial cavity, and cells collected from other bodily fluids, such as blood and urine and the like. Methods of obtaining such samples are known in the art. For example, an effusion sample can be collected by puncturing the chest wall or abdominal wall with a needle and evacuating the fluid. Samples from fine-needle aspirations, effusions or other bodily fluids can be spun onto slides using conventional centrifugation or Cytospin~ (Shandon, Runcorn, U.K.) or smeared onto an appropriate slide for staining and/or fixation. Cell blocks can also be prepared from such samples by concentrating the cells contained therein. For example, cells can be concentrated, e.g., by centrifugation. After concentration, the cells can be fixed in a suitable fixing agent, such as formalin or alcohol and then embedded into paraffin or other suitable material as done for tissue in surgical pathology.
Concentrated cells can also be processed for ThinPrep~ preparation using, for example, a Cytyc Thin Prep processor (Cytyc Corp Boxborough, MA).
Yet another technique for detecting (3-catenin is Flow Cytometry (FACS). The theory of Flow Cytometry is discussed in Ormerod (ed) Flow Cytometry: A
Practical Approach (IRL Press, Oxford. 1994); Shapiro, Practical Flow Cytometry. 3rd Edition;
(Alan R Liss, Inc.). Givan, Flow Cytometry. First Principles (Whey-Liss, New York, 1992.); Robinson (ed.) Handbook o. f Flow Cytometry Methods. (Wiley-Liss, New York, 1993) FACs provides the means of scanning individual cells for the presence of deregulated /3-catenin.
Antibodies reactive with a particular protein can also be measured by a variety of immunoassay methods, as discussed herein. For reviews of immunological and immunoassay procedures applicable to the measurement of antibodies by immunoassay techniques, see, e.g., Stites and Terr (eds.) Basic and Clinical Immunology (7th ed.) supra;
Maggio (ed.) Enzyme Immunoassay, supra; and Harlow and Lane Antibodies, A
Laboratory Manual, supra.
Techniques for determining (3-catenin localization in cells using immunoassays are known in the art, for example, see Wakita et al. 2001 Cancer Res. 61:854-858;
Carayol et al. 2002 Am J. Respir Cell Mol Biol. 26:341-347; Lim et al 2002 Oncology Reports 9:915-928; and Sakai et al. 2002 Int. J. Oncology 21:547-552; all incorporated herein by reference.
OTHER CONDITIONS AND DISEASES
Other conditions and disease processes amenable to treatment with the compounds described herein include, e.g., benign prostatic hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, fibrosis which occurs S with radiation therapy, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, hypertrophic scar formation, inflammatory bowel disease, transplantation rejection, endotoxic shock, and fungal infections; and defective apoptosis-associated conditions, such as cancers (including, but not limited to, those types mentioned herein above), viral infections (including, but not limited to, HIV, human papilloma virus, herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), prevention of AIDS development in HIV-infected individuals, autoimmune diseases (including, but not limited to, systemic lupus erythematosus, rheumatoid arthritis, psoriasis, autoimmune mediated glomerulonephritis, inflammatory bowel disease and autoimmune diabetes mellitus), neurodegenerative disorders (including, but not limited to, Alzheimer's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, Parkinson's disease, AIDS-related dementia, spinal muscular atrophy and cerebellar degeneration), myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol related liver diseases, hematological diseases (including, but not limited to, chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including, but not limited to, osteroporosis and arthritis), aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, schizophrenia, kidney diseases, abnormal angiogenesis, and cancer pain.
Compounds that inhibit uncontrolled or abnormal angiogenesis are useful for treatment of neoplasia, including metastasis; ophthalmological conditions such as corneal graft rejection, ocular neovascularization, retinal neovascularization including neovascularization following injury or infection, diabetic retinopathy, retrolental fibroplasia and neovascular glaucoma; ulcerative diseases such as gastric ulcer;
pathological, but non-malignant, conditions such as hemangiomas, including infantile hemaginomas, angiofibroma of the nasopharynx and avascular necrosis of bone;
and disorders of the female reproductive system such as endometriosis.
PREPARATION OF COMPOUNDS OF THE INVENTION
Compounds of the present invention may be synthesized using standard synthetic techniques known to those of skill in the art or using methods known in the art in combination with methods described herein. See, e.g., March, ADVANCED ORGANIC
CHEMISTRY 4th Ed., (Whey 1992); Caret' and Sundberg, ADVANCED ORGANIC
CHEMISTRY
S 3ra Ed., Vols. A and B (Plenum 1992), and Green and Wuts, PROTECTIVE GROUPS
IN
ORGANIC SYNTHESIS 2°a Ed. (Whey 1991). General methods for the preparation of compound as disclosed herein may be derived from known reactions in the field, and the reactions may be modified by the use of appropriate reagents and conditions, as would be recognized by the skilled person, for the introduction of the various moieties found in the formulae as provided herein.
Selected examples of covalent linkages and precursor functional groups which yield them are given in the Table entitled "Examples of Covalent Linkages and Precursors Thereof." Precursor functional groups are shown as electrophilic groups and nucleophilic groups. The functional group on the organic substance may be attached directly, or 1 S attached via any useful spacer or linker as defined below.
Examples of Covalent Linkages and Precursors Thereof .~ ,,z ,._ .r: ~~_._. Nucleo hale., ..Covalent~Ltnka a Procluct~ .~ ; :Electi=o __ h~le ~ ~
Carboxamides Activated esters amines/anilines Carboxamides acyl azides amines/anilines Carboxamides acyl halides amines/anilines Esters acyl halides alcohols/phenols Esters acyt nitrites alcohols/ henols Carboxamides ac 1 nitrites amines/anilines Imines Aldehydes amines/anilines Hydrazones aldehydes or ketonesHydrazines Oximes aldehydes or ketonesHydroxylamines Alkyl amines alkyl halides amines/anitines Esters alkyl halides carboxylic acids Thioethers alkyl halides Thiols Ethers alkyl halides alcohots/ henols Thioethers alkyl sulfonates Thiols Esters alkyl sulfonates carboxylic acids Ethers alkyl sulfonates alcohots/phenots Esters Anhydrides alcohots/phenols Carboxamides Anhydrides amines/anitines Thiophenols aryl halides Thiols Aryl amines aryl halides Amines m ,w ~ ;,, -_ , .T.. Nucleo bile ' ,: .. ..... =~.~~Electro hyhe~
~,~ Covalenf~Lwka a Product Thioethers Azindines Thiols Boronate esters Boronates Glycols Carboxamides carboxylic acids amines/anilines Esters carboxylic acids Alcohols Hydrazines Hydrazides carboxylic acids N-acylureas or Anhydrides carbodiimides carbox lic acids Esters diazoalkanes carboxylic acids Thioethers Epoxides Thiols Thioethers haloacetamides Thiols Ammotriazines halotriazines amines/anilines Triazinyl ethers halotriazines alcohols/phenols Amidines imido esters amines/anilines Ureas Isocyanates amines/anilines Urethanes Isocyanates alcohols/ henols Thioureas isothiocyanates amines/anilines Thioethers Maleimides Thiols Phosphite esters phos horamidites Alcohols Silyl ethers silyl halides Alcohols Alkyl amines sulfonate esters amines/anilines Thioethers sulfonate esters Thiols Esters sulfonate esters carboxylic acids Ethers sulfonate esters Alcohols Sulfonamides sulfonyl halides amines/anilines Sulfonate esters sulfonyl halides phenols/alcohols In general, carbon electrophiles are susceptible to attack by complementary nucleophiles, including carbon nucleophiles, wherein an attacking nucleophile brings an electron pair to the carbon electrophile in order to form a new bond between the nucleophile and the carbon electrophile.
Suitable carbon nucleophiles include, but are not limited to alkyl, alkenyl, aryl and alkynyl Grignard, organolithium, organozinc, alkyl-, alkenyl , aryl- and alkynyl-tin reagents (organostannanes), alkyl-, alkenyl-, aryl- and alkynyl-borane reagents (organoboranes and organoboronates); these carbon nucleophiles have the advantage of being kinetically stable in water or polar organic solvents. Other carbon nucleophiles include phosphorus ylids, enol and enolate reagents; these carbon nucleophiles have the advantage of being relatively easy to generate from precursors well known to those skilled in the art of synthetic organic chemistry. Carbon nucleophiles, when used in conjunction with carbon electrophiles, engender new carbon-carbon bonds between the carbon nucleophile and carbon electrophile.
Non-carbon nucleophiles suitable for coupling to carbon electrophiles include but are not limited to primary and secondary amines, thiols, thiolates, and thioethers, alcohols, alkoxides, azides, semicarbazides, and the like. These non-carbon nucleophiles, when used in conjunction with carbon electrophiles, typically generate heteroatom linkages (C-X-C), wherein X is a hetereoatom, e. g, oxygen or nitrogen.
The term "protecting group" refers to chemical moieties that block some or all reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. It is preferred that each protective group be removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal. Protective groups can be removed by acid, base, and hydrogenolysis. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and may be used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile.
Carboxylic acid and hydroxy reactive moieties may be blocked with base labile groups such as, without limitation, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as t-butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable.
Carboxylic acid and hydroxy reactive moieties may also be blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids may be blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties may be protected by conversion to simple ester derivatives as exemplified herein, or they may be blocked with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while co-existing amino groups may be blocked with fluoride labile silyl carbamates.
Allyl blocking groups are useful in then presence of acid- and base-protecting groups since the former are stable and can be subsequently removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid can be deprotected with a Pdo-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate may be attached. As long as the residue is attached to the resin, that functional group is blocked and cannot react. Once released from the resin, the functional group is available to react.
Typically blocking/protecting groups may be selected from:
HZ H O
i C~ , C~ H ,O
H C C~C~C\ ~ I ~ ~ O~ H2C~C'H ~ H3Ci allyl Bn Cbz alloc Me H3C~ CH3 H O
z f-/3C~C~ ~H3C)3C~ (H3C~3C,SI~ ~Cl..ls)3C~SI~O
Et t-butyl TBDMS Teoc O
O
O / C~ O HzC
UH3~3C ~ ~ ~C6H5~3C~ H
Boc pMBn trityl acetyl Fmoc Other protecting groups are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, which is incorporated herein by reference in its entirety.
In various embodiments, the compounds of the present invention can be prepared according to the following reaction schemes and examples, or modifications thereof.
Starting materials can be purchased or made from procedures known in the art or as illustrated. In these reactions, one skilled in the art can make use of variations that are not described in greater detail. Other methods for preparing compounds of the invention will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. For example, the synthesis of non-exemplified compounds according to the invention may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or generally known in the art will be recognized as having applicability for preparing other compounds of the invention. Unless otherwise indicated, the variables are as defined above.
The abbreviations employed throughout the application have the following meaning unless otherwise indicated: EtOH: ethyl alcohol; NHZOH.HCI:
hydroxylamine;
CC13CH(OH)2: chloral hydrate; H2S04: sulfuric acid; LiBH4: lithium borohydride;
C1COCOCI: oxalyl chloride; HCI: Hydrochloric acid; NaOH: sodium hydroxide;
S BF3.Etz0: boron trifluoride etherate; CHZCIz: dichloromethane; [R]: partial reduction.
General Scheme lA shows the preparation of pyranoindol-1-yl alcohols from starting material 1.
General Scheme 1 1A.
X X X O X
CCI3CH(OH)z I ~ ~ H2S04 / \ LiBH4 r ~NOH / \ \ 1)CICOCOCI
~
NHz NHZOH HCI R H R N O Rte' 2) EtOH
N
I II III H IV H
X O
O LiBH4 X / \ OH + Oj~ Ou BF3 X / \ O
j \ ~ OEt ~ Et O ~ r ~ R~~(CHz)~OEt \ O ~
R R CHzCIz R
N N
OEt CH
V H H z)n VI H R~ ( VII
X Ar LiBH4 R~ \ \ O ArB(OH)z ~ \ \ O
Pd(L)n R
VIII H R~ (CHz)o OH IX H R' (CHz)/_OH
Rz-(CHz)n Rz (CHz)n Pd(L)m / O
R H R~ (CHz)/~OH
X
[R) Rz-(CHz)n Rz (CH2)n~
/ \
Pd(L)m R ~ ~ O
H R~ (CHz)~OH
XI
In General Scheme 1, 1,3,4,9-tetrahydro-pyrano[3,4-bJindole of this invention may be prepared by techniques well known to those skilled in the art of organic synthesis. The substituted tryptophols (VI) may be prepared by the appropriate segment of the pathway illustrated in General Scheme lA, starting with an aniline (I), an isatin (III), or an indole (IV). The suitable starting materials are commercially available anilines with the desired R or may be readily prepared. The aniline may be converted into a corresponding isatin 1 S (III) by treatment of aniline with chloral hydrate and hydroxylamine, followed by heating with sulfuric acid. The indole (IV) may be obtained by reduction of isatin with lithium borohydride or other reducing agents. The tryptophol (VI) may be prepared by acylation at 3-position of indole (IV) with a suitable reagent, e.g., oxalyl chloride, followed by reduction of glyoxylate (V) with lithium borohydride. The substituted tryptopholes (VI) may be condensed with an appropriate ketone or aldehyde, in the presence of an acid catalyst, to provide 1,3,4,9-tetradydro-pyrano[3,4-b]indole (VII). After the ester (VII) is reduced by an appropriate reducing reagent, e.g., lithium borohydride, the title compounds (IX) may be prepared from (VIII) by displacement of the halogen with an appropriately activated Ar moiety. For example, in the presence of an appropriate Pd(L)m catalyst, Ar-boronic acids may be coupled via a Suzuki reaction to give the title compounds (IX).
Compounds (X) and (XI) may be prepared, via Heck reaction, from suitable alkyne and alkene precursors in the presence of an appropriate Pd(L)m catalyst. The cis isomer of (XI) may also be prepared by partial reduction of (X) by hydrogenation over palladium on activated carbon that has been treated with quinoline.
General Scheme 1B shows the preparation of pyranoindol-1-yl alkylsulfonamides from starting material 6.
Scheme 1B.
X X
/ \ OH ~O BF3 EtzO / \ Ar R/ ~ N~ + R~~(CHp)n SOzY CHzCIz R/ ~ N\ O ~SOZY A~(OH~ / \
O
H H R~ (CHz)" Pd(L)m R\~ ~SOzY
VI XII H R~ (CHz)n XIII
R-(CHz)"
R (CHz)n = \\
Y=H, OH, NHz, NHR, NRR, R /
X= Br,l Pd(L)m / ~ O
R=unsubstituted or substituted alkyl, aryl, alkenyl, or alkynyl R N ,SOzY
Ar= unsubstituted or substituted aryl H R~ (CHz)"
R~= hydrogen, lower alkyl, lower alkenyl, lower alkynyl, XIV
lower alkoxy, lower cycloalkyl, phenyl, benzyl and 2-thienyl n=0 to 6 [R]
R-(CHz)"
R-(CHz)n~ \
/ ~ O
Pd(L)m R/ ~ SOzY
H R~ (CHz)n XV
Scheme 1B illustrates syntheses of the title compounds (XIII), (XIV), or (XV) wherein -(CHZ)nSOZY is substituted at 1-position of 1,3,4,9-tetradydro-pyrano[3,4-b]indole. The compounds (XIII) may be prepared by condensation of tryptophols (VI) with an appropriate ketone or aldehyde bearing -SOZY in the presence of a suitable acid, followed by coupling reactions, which may be via Suzuki reaction with a suitable activated Ar moiety in the presence of an appropriate Pd(L)m catalyst.
Analogously, compounds (XIV) and (XV) may be prepared, via Heck reaction, from suitable alkyne and alkene in the presence of an appropriate Pd(L)m catalyst.
General Scheme 2 illustrates the additional embodiment wherein R]o is lower alkyl, lower alkenyl, lower alkynyl, or aryl. The nitrogen of compound (VII) may be alkylated with an appropriate alkyl halide in the presence of a suitable base. After the ester is reduced to the alcohol (XVII) by a suitable reducing reagent, e.g., lithium borohydride, the title compounds (XVIII), (XIX), or (XX) may be prepared by coupling reactions, e.g., Suzuki reaction or Heck reaction.
General Scheme 2 X
X
~~~0 O td~~base X
R N ~ R j \ \ O ~ LiBH4 / ~ Ar8(OH)z Ar H Rt (CHz)n OEt R Rto Rt (CHz)n OEt R/ ~ N\ 0 OOH ~ / ~ \ 0 VII R Rt (CHz)n Pd(L)m R~ /'~OI
XVI Rto Rt (CHz) XVII XVIII
R-(CHz)~
R-(CHz)n = \\
/' \ \ l0 Pd(L)m R N Rt (CHz)~OH
Rto Rto= lower alkyl, lower alkenyl, lower alkynyl, benzyl, or aryl X= Br, I XIX
[R]
R-(CHz)n R-(CHz)n~ /
Pd(L)m O
R
N Rt (CHz)~OH
Rto XX
General Scheme 3 illustrates the synthesis of compounds where R7 is substituted, R9 is an isopropyl group, Rl is ethyl, and Y-Z is ethylalcohol.
Scheme 3 y HCI / \ HyS04 / \ O
+ CI3CCH(OH)2 + NHZOH HCI
NHZ HZO NHCOCH=NOH H20 N O AcOH,heat Na2S04 H
Br Br Br O Br \ O LiBH4 / \ CIEt200C1 / \ CpZEt LiBH4 / \ BF3~Et20 ~O THF \ EtOH ~ THF \ OH
N N N CHZCIZ
H H H
Br Br EtO2C
\ LiBH4 / \ ~CO2Et \ Hp _ ~ O /
H\ 0 COZEt THF H\ OH Pd(L)n I H\ O OH
EtO2C HOZC HO
/ \ LiOH \ LAH \
\ p ~ ~ \ \O / \ \O
H OH H~pH ! H~OH
TBDMSiCI
EtO2C 1 HO
LAH
/ \ \ O ~ / \ \ O ~ / \ \ O
H~OSiTBDM H~OSiTBDM H~OH
General Scheme 4 illustrates the synthesis of of pyranoindol-1-yl alcohols.
Scheme 4 NHNHp R s \ OH Rte \
Rt i / + ~~ t ~ ~ + RZCO(CHZ)nC02R ~ ~ ~ O
H H Rp (CHZ)nCOpR
Ros \ ~ O Ry \ ~ O
H RZ (CHz)nCO2H H Rz (CHz)nCH20H
EXAMPLES
EXAMPLE 1: SYNTHESIS OF COMPOUNDS
COMPOiJND l: 2-(1,H-DIETHYL-E-PHENYL-1,3,4,9-TETRAHYDRO-PYRAN0~3,4-B~INDOL-1-YL~-ETHANOL
l.A. Synthesis of N (4-Bromo-2-ethyl phenyl)-2-hydroximino-acetoamide To a suspension of 4-bromo-2-ethylaniline (50.0 g, 250 mmol) in water (1000 mL) was added concentrated hydrochloric acid (25 mL), sodium sulfate (220 g), and S hydroxylamine hydrochloride (56.25 g), followed by addition of chloral hydrate (44.0 g).
The reaction mixture was heated to 90°C using an oil bath for 1 hour.
After cooling down to room temperature, it was extracted with ethyl acetate. Extract was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (31.1 g, 46% yield). 1H NMR (DMSO-db) 8 12.24 (s, 1H), 9.56 (s, 1H), 7.68 (s, 1H), 7.41 (m, 3H), 2.58 (q, 2H), 1.11 (t, 3H).
LB. Synthesis of S-Bromo-7-ethyl-IH indole-2,3-dione To a solution of sulfuric acid (100 mL) and water (10 mL) at 80°C (oil bath) was added N-(4-bromo-2-ethyl-phenyl)-2-hydroximino-acetoamide (61.0 g, 225 mmol) in small portions over 20 minutes. The reaction mixture was heated at 80°C
(oil bath) for 15 minutes. After cooling to room temperature, ice-water (500 mL) was added and the mixture was extracted with ethyl acetate. Extracts were washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (42.3 g, 74% yield). 1H NMR (DMSO-d6) 8 8.87 (s, 1H), 7.75 (d, 1H), 7.71 (d, 1H), 2.75 (q, 2H), 1.44 (t, 3H).
LC. Synthesis of (S-Bromo-7-ethyl-IH indol-3 yl)-oxo-acetic acid ethyl ester To a solution of 5-bromo-7-ethyl-1H-indole-2,3-dione (36.g, 144 mmol) in tetrahydrofuran (120 mL) at room temperature was dropped a 2.0 M solution of lithium borohydride in tetrahydrofuran. The reaction mixture was stirred at 90°C (oil bath) for S
hours. After cooling down to room temperature, it was quenched with 5%
hydrochloric acid solution until the excess lithium borohydride was destroyed. To the mixture was added saturated sodium bicarbonate solution (300 mL) and extracted with ethyl acetate.
Extracts were dried over magnesium sulfate and concentrated under reduced pressure to give the crude product of 5-bromo-7-ethyl-1H-indole, which went to next reaction without further purification.
To a solution of 5-bromo-7-ethyl-1H-indole in ethyl ether (400 mL) at room temperature under nitrogen was added a 2.0 M solution of oxalyl chloride in dichloromethane. After the reaction mixture was stirred at room temperature for 6 hours, the solvents were removed under reduce pressure. To the residue was added ethyl alcohol (400 mL) and stirred at room temperature overnight. After ethyl alcohol was removed under reduce pressure, to the residue was added saturated sodium bicarbonate solution (300 mL) and extracted with ethyl acetate. Extract was dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 30-50% ethyl acetatelhexane) to give the title compound (14.5 g, 31% yield). ES-MS (m/z) 324 [M+1]+, 322 [M-1]-.
LD. Synthesis of (6-Bromo-1,8-diethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1-yl)-acetic acid ethyl ester To a solution of (5-bromo-7-ethyl-1H-indol-3-yl)-oxo-acetic acid ethyl ester (1.55 g, 4.8 mmol) in tetrahydrofuran at room temperature under nitrogen was dropped a 2.0 M
solution of lithium borohydride in tetrahydrofuran. The reaction mixture was heated at 90°C oil bath for 5 hours. After cooling to room temperature, it was quenched with 5%
hydrochloric acid solution until the excess lithium borohydride was destroyed.
To the mixture was added saturated sodium bicarbonate solution and extracted with ethyl acetate.
Extracts were dried over magnesium sulfate and concentrated under reduced pressure to give the crude product of 2-(S-bromo-7-ethyl-1H-indol-3-yl)-ethanol, which went to the next reaction without further purification.
To a solution of 2-(S-bromo-7-ethyl-1H-indol-3-yl)-ethanol in dichloromethane at room temperature under nitrogen was added boron trifluoride diethyl etherate (0.809 g, 5.7 mmol), followed by ethyl propionylacetate (1.038 g, 7.2 mmol). The reaction mixture was stirred at room temperature for 5 hours. It was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 15-20% ethyl acetate/hexane) to give the title compound (0.994 g, 53% yield). ES-MS (m/z) 394 [M+1]+, 392 [M-1]-.
LE. Synthesis of 2-(6-Bromo-1,8-diethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-ethanol To a solution of (6-bromo-1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester (5.2 g, 13.2 mmol) in tetrhydrofuran at room temperature under nitrogen was dropped a 2.0 M solution of lithium borohydride in tetrahydrofuran. The reaction mixture was heated at 90°C (oil bath) for 5 hours. After cooling to room temperature, it was quenched with 5% hydrochloric acid solution until the excess lithium borohydride was destroyed. Water was added and the mixture extracted with ethyl acetate. Extracts were dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 50%
ethyl acetate/hexane) to give the title compound (3.80 g, 82% yield). 1H NMR
(CDC13) 8 8.07 (s, 1H), 7.64 (d, 1H), 7.26 (d, 1H), 4.17 (m, 2H), 3.86 (m, 2H), 2.94 (m, 3H), 2.87 (dt, 1H), 2.76 (t, br, 1H), 2.36 (m, 1H), 2.24 (m, 1H), 2.13 (m, 2H), 1.49 (t, 3H), 1.08 (t, 3H).
ES-MS (m/z) 352 [M+1]+, 350 [M-1]-.
LF. Synthesis of 2-(1,8-Diethyl-6 phenyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-ethanol To a solution of 2-(6-bromo-1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-yl)-ethanol (3.8 g, 10.8 mmol) in ethylene glycol dimethyl ether (50 mL) was added potassium phosphate (6.37 g, 30 mmol), phenylboronic acid (1.83 g, 15 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane.
The reaction mixture was heated at 90°C (oil bath) overnight. It was quenched with water and extracted with ethyl acetate. Extracts were dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 50% ethyl acetate/hexane, followed by Sephadex LH-20, 50%
chloroform/hexane) to give the title compound (0.75 g, 20% yield).'H NMR
(CDC13) 8 7.77 (s, 1H), 7.66 (d, 1H), 7.63 (m, 1H), 7.56 (d, 1H), 7.44 (m, 3H), 7.32 (m, 1H), 4.06 (m, 2H), 3.72 (m, 3H), 2.91 (m, 3H), 2.81 (dt, 1H), 2.65 (dd, 1H), 2.20 (m, 1H), 2.07 (m, 2H), 1.40 (t, 3H), 0.95 (t, 3H). ES-MS (m/z) 348 [M-1]-.
COMPOUND 2: 2-[1,8-DIETI-IYL-6-(4-METHOXY-PHENYL)-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL]- ETHANOL
The title compound is prepared in a manner analogous to Example 1, except using 4-methoxyphenylboronic acid in step 1.F.
COMPOUND 3: 2-~l,S-DIETHYL-C7-~3-TRIFLUOROMETHOXY-PHENYL-1,3,4,9-TETRAHYDRO-PYRANO ~3,4-B~ INDOL-1-YL~-ETHANOL
The title compound is prepared in a manner analogous to Example 1, except using 3-trifluoromethoxyphenylboronic acid in step 1.F.
COMPOUND 4: 2-~l,g-DIETHYL-6-(2-TRIFLUOROMETHYL-PHENYL-1,3,4,9-TETRAHYDRO-1 O PYRAN0~3,4-B~INDOL-1-YL~-ETHANOL
~ O
H/~OH
The title compound is prepared as described in Example 1, except using 2-trifluoromethylphenylboronic acid in step 1.F.
COMPOUND S: Z-~6-~2,4-DIFLUORO-PHENYL-1,g-DIETHYL-1,3,4,9-TETRAHYDRO-1 S PYRAN0~3,4-B~INDOL-1-YL~- ETHANOL
The title compound is prepared in a manner analogous to Example 1, except using 2,4-difluorophenylboronic acid in step l .F.
COMPOUND 6: 2-(1,H-DIETHYL-6-PYRIDIN-4-YL-1,3,4,9-TETRAHYDRO-PYRAN0~3,4-B~INDOL- I -YL~-ETHANOL
The title compound is prepared in a manner analogous to Example 1, except using pyridine-4-boronic acid in step 1.F.
COMPOUND H: 2-~6-~3-AMINO-PHENYL-1,8-DIETHYL-1,3,4,9-TETRAHYDRO-PYRAN0~3,4-B~INDOL-I-YL~-ETHANOL
NHS
1~
The title compound is prepared in a manner analogous to Example l, except using 3-aminophenylboronic acid in step 1.F.
COMPOUND 10: 2-[6-(3,4-DIFLUORO-PHENYL)-1,8-DIETHYL-1,3,4,9-TETRAHYDRO-PYRAN0~3,4-B~INDOL-1-YL~-ETHANOL
F
I$
The title compound is prepared in a manner analogous to Example 1, except using 3,4-difluorophenylboronic acid in step l.F.
COMPOUND 11: 2-[6-(5-CHLORO-THIOPHEN-2-YL)-1,8-DIETHYL-1,3,4,9-TETRAHYDRO-PYRAN0~3,4-B~INDOL-1-YL~-ETHANOL
CI / ' S
\ O
H/~~OH
The title compound is prepared in a manner analogous to Example 1, except using 5-chloro-2-thiopheneboronic acid in step 1.F.
COMPOUND 12: 2-(1-ETHYL-6-ISOPROPYL-8-PHENYL-1,3,4,9-TETRAHYDRO-PYRAN0~3,4-B~INDOL-1-YL)-ETHANOL
12.A. Synthesis of N (2-Bromo-4-isopropyl phenyl)-2-hydroximino-acetoamide The title compound is prepared in a manner analogous to Example l, except using 2-bromo 4-aminoaniline in step 1.A.
12.B. Synthesis of 7-Bromo-5-isopropyl-IH indole-2,3-dione The title compound is prepared in a manner analogous to Example 1, except using N-(2-bromo-4-isopropyl-phenyl)-2-hydroximino-acetoamide in step 1.B.
12. C. Synthesis of (7-Bromo-S-isopropyl-IH indol-3 yl)-oxo-acetic acid ethyl ester The title compound is prepared in a manner analogous to Example 1, except using 7-bromo-5-isopropyl-1H-indole-2,3-dione in step 1.C.
12.D. Synthesis of (8-Bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid ethyl ester The title compound is prepared in a manner analogous to Example 1, except using (7-bromo-5-isopropyl-1H-indol-3-yl)-oxo-acetic acid ethyl ester in step 1.D.
12.B. Synthesis of 7-Bromo-5-isopropyl-IH indole-2,3-dione The title compound is prepared in a manner analogous to Example 1, except using N-(2-bromo-4-isopropyl-phenyl)-2-hydroximino-acetoamide in step 1.B.
12. C. Synthesis of (7-Bromo-S-isopropyl-IH indol-3 yl)-oxo-acetic acid ethyl ester The title compound is prepared in a manner analogous to Example 1, except using 7-bromo-5-isopropyl-1H-indole-2,3-dione in step 1.C.
12.D. Synthesis of (8-Bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid ethyl ester The title compound is prepared in a manner analogous to Example 1, except using (7-bromo-5-isopropyl-1H-indol-3-yl)-oxo-acetic acid ethyl ester in step 1.D.
12.E. Synthesis of 2-(8-Bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano~3,4-bJindol-1 yl)-ethanol The title compound is prepared in a manner analogous to Example 1, except using (8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester in step 1.E.
12.F. Synthesis of 2-(1-Ethyl-6-isopropyl-8 phenyl-1,3,4,9-tetrahydro-pyrano~3,4-bJindol-1 yl)-ethanol The title compound is prepared in a manner analogous to Example l, except using 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol in step 1.F.
COMPOUND 13: 2-[8-(3-CYANO-PHENYL)-1-ETHYL-6-ISOPROPYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL]-ETHANOL
H
The title compound is prepared in a manner analogous to Example 1, except using 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol and 3-cyanophenylboronic acid in step 1.F.
COMPOUND 14: 2-[8-(S-BROMO-2-METHOXY-PHENYL)-1-ETHYL-6-ISOPROPYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]1NDOL-1-YL]-ETHANOL
The title compound is prepared in a manner analogous to Example 1, except using 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol and 2-bromo-3-methoxyphenylboronic acid in step 1.F.
COMPOUND 15: 2-[1-ETHYL-8-(2-FLUORO-BIPHENYL-4-YL)-6-ISOPROPYL-1,3,4,9 TETRAHYDRO-PYRANO [ 3,4-B] INDOL-1-YL]-ETHANOL
The title compound is prepared in a manner analogous to Example 1, except using 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol and 2-fluorobiphenyl-4-boronic acid in step 1.F.
COMPOUND 1C7: 4-[1-ET'HYL-1-(Z-HYDROXY-ETHYL)-6-ISOPROPYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-8-YL]-BENZOIC ACID
H
The title compound is prepared in a manner analogous to Example 1, except using 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol and 4-carboxylphenylboronic acid in step 1.F.
COMPOUND 17: 3-[1-ETHYL-1-(2-HYDROXY-ETHYL)-6-ISOPROPYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-8-YL]-BENZALDEHYDE
H
The title compound is prepared in a manner analogous to Example 1, except using 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol and 3-formylphenylboronic acid in step 1.F.
COMPOUND 18: 2-[8-(3,S-DIMETHYL-PHENYL)-1-ETHYL-6-ISOPROPYL-1,3,4,9-TETRAHYDRO-PYRANO [3,4-B] INDOL-1-YL]-ETHANOL
H
The title compound is prepared in a manner analogous to Example 1, except using 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol and 3,5-dimethylphenylboronic acid in step 1.F.
COMPOUND 19: 2-(8-DIBENZOFURAN-3-YL-1-ETHYL-6-ISOPROPYL-1,3,4,9-TETRAHYDRO-PYRANO [3,4-B] INDOL-1-YL)-ETHANOL
The title compound is prepared in a manner analogous to Example 1, except using 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol and 4-dibenzofuranboronic acid in step 1.F.
COMPOUND 20: 2-(1-ETHYL-6-ISOPROPYL-8-STYRYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B] INDOL-1-YL)-ETHANOL
20.A. Synthesis of2-(1-Ethyl-6-isopropyl-8-styryl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-ethanol The title compound is prepared according to the following procedure. To solution of 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol (1.0 mmol) in dried acetonitril (10 mL) at under nitrogen is added triethylamine (1.5 mL), tri-o-tolylphosphine (0.4 mmol), styrene (2.0 mmol), and tri(debenzylideneacetone)dipalladiumn (0) (0.1 mmol). The reaction mixture is heated at 90°C (oil bath) overnight. It is quenched with water and extracted with ethyl acetate.
Extracts are dried over magnesium sulfate and concentrated under reduced pressure. The chromatography (silica gel) gives the title compound.
COMPOUND 21: 2-(1-ETHYL-6-ISOPROPYL-8-PHENYLETHYNYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
The title compound is prepared in a manner analogous to Example 20.A, except using phenylacetylene.
COMPOUND 22: (1-ETHYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
H v OOH
The title compound is prepared in a manner analogous to the procedure outlined below:
NHNHz R ~ \ ' \
R~ ~ / + ~ ~ ~ ~ ~ ~ OH + RZCO(CHz)nCOzR ' R~'~ ~ O
N
H H Rz ( Ros \ ~ O R~s \ ~ O
H Rz (CHz)nCOzH ~ H Rz (CHz)nCHzOH
22.A. Synthesis of (I-Ethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-I yl)-acetic acid ethyl ester A mixture of tryptophol (1.612 g, 10 mmol), ethyl propionylacetate (1.730 g, mmol), andp-toluenesulfonic acid monohydrate (0.20 g) in benzene (70 mL) was heated to reflux for 5 hours. It was quenched with ethyl acetate and washed with saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate, evaporated to dryness.
Flash chromatography on silica gel provided 1.943 g (68%) of the title compound as a solid. mp<80 °C. 1H NMR (300 MHz, CDC13) 8 9.06 (br, 1H), 7.50 (d, 1H), 7.36 (d, 1H), 7.14 (t, 1 H), 7.12 (t, 1 H), 4.18 (q, 2H), 4.03 (m, 1 H), 3.94 (m, 1 H), 2.99 (d, 1 H), 2.88 (d, 1H), 2.78 (m, 2H), 2.14 (m, 1H), 2.01 (m, 1H), 1.25 (t, 3H), 0.82 (t, 3H); ESI
(+) MS
m/e=288 (MH+), ESI (-) MS m/e=286 (MH-) 22.B. .Synthesis of (1-Ethyl-1,3,4,9-tetrahydro pyrano(3,4-bJindol-1 yl)-acetic acid To a solution of (1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester (2.50 g, 8.7 mmol) in 1,4-dioxane was added a solution of lithium hydroxide monohydrate (1.50 g, 35.7 mmol) in water (5 mL). The mixture was stirred at room temperature overnight. It was neutralized with 5% HCl solution and extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulfate, and evaporated to dryness. Flash chromatography on silica gel provided 0.954 g (42%) of the title compound as a solid. mp. 135-136 °C. 1H NMR (500 MHz, CDCl3) 8 10.0 (br, 1H), 8. S S (br, 1 H), 7.51 (d, 1 H), 7.34 (d, 1 H), 7.18 (t, 1 H), 7.12 (t, 1 H), 4.12 (m, 1 H), 4.06 (m, 1 H), 3.01 (d, 1 H), 2.99 (d, 1 H), 2.85 (m, 2H), 2.10 (m, 1 H), 2.03 (m, 1 H), 0.86 (t, 3H);
ESI (+) MS m/e=260 (MH+), ESI (-) MS m/e=258 (MII-).
22. C. Synthesis of (1-Ethyl-1, 3, 4, 9-tetrahydro pyrano(3, 4-bJindol-I yl)-ethanol To solution of (1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid (0.52 g, 2.0 mmol) in tetrahydrofuran (10 mL) was added lithium aluminum hydride (0.114 g, 3.0 mmol) in several small portions. The mixture was stirred at room temperature for 6 hours. It was quenched with ethyl acetate carefully and washed with water. The organic layer was dried over magnesium sulfate and evaporated to dryness.
Flash chromatography on silica gel provided 0.389 g (79%) of the title compound as an oil. 'H NMR (500 MHz, CDC13) 8 7.82 (br, 1H), 7.52 (d, 1H), 7.34 (d, 1H), 7.18 (td, 1H), 7.13 (td, 1 H), 4.07 (m, 1 H), 4.01 (m, 1 H), 3 .70 (m, 1 H), 3 .64 (m, 1 H), 2. 89 (m, 1 H), 2.77 (dt, 1 H), 2.71 (br, 1 H), 2.20 (m, 1 H), 2.05 (m, 1 H), 2.00 (m, 1 H), 1.90 (m, 1 H), 0.94 (t, 3H); ESI (+) MS m/e=246 (MH+), ESI (-) MS m/e=244 (MIT-).
1$ COMPOUND 23: 2-(1-ETHYL-6-METHOXY-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
/o / o OH
N
H
23.A. Synthesis of (1-Ethyl-6-methoxy-1, 3, 4, 9-tetrahydro pyrano~3, 4-bJindol-1-yl)-acetic acid ethyl ester The title compound was synthesized in a manner analogous to step 22, using 5-methoxytrypotophol as the 3-indolethanol component in step 22.A. 'H NMR (300 MHz, CDC13) 8 8.93 (br, 1H), 7.25 (d, 1H), 6.95 (d, 1H), 6.90 (dd, 1H), 4.17 (q, 2H), 4.03 (m, 1H), 3.94 (m, 1H), 3.86 (s, 3H), 2.99 (d, 1H), 2.90 (d, 1H), 2.74 (m, 2H), 2.12 (m, 1H), 2.00 (m, 1H), 1.27 (t, 3H), 0.82 (t, 3H); ESI (+) MS m/e=318 (MH+), ESI (-) MS
m/e=316 (MH-).
23.B. Synthesis of (1-Ethyl-6-methoxy-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1-yl)-acetic acid The title compound was synthesized in a manner analogous to step 22, using (1-ethyl-6-methoxy-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the ester component in step 22.B., afforded the title compound as a solid. mp. 169 °C. 1H
NMR (300 MHz, CDC13) 8 8.38 (br, 1H), 7.22 (d, 1H), 6.94 (d, 1H), 6.84 (dd, 1H), 4.08 (m, 2H), 3.85 (s, 3H), 2.97 (m, 2H), 2.81 (m, 2H), 2.02 (m, 2H), 0.85 (t, 3H);
ESI (+) MS
m/e=290 (MH+), ESI (-) MS m/e=288 (MH-).
23. C. Synthesis of 2-(1-Ethyl-6-methoxy-1,3,4,9-tetrahydro pyrano~3,4-bJindol-I yl)-ethanol The title compound was synthesized in a manner analogous to step 22, using ( 1-ethyl-6-methoxy-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid as the carboxylic acid component in step 22.C., afforded the title compound as a solid. 1H NMR
(500 MHz, CDCl3) 8 7.71 (br, 1H), 7.22 (d, 1H), 6.97 (d, 1H), 6.83 (dd, 1H), 4.08 (m, 1H), 4.00 (m, 1H), 3.86 (s, 3H), 3.69 (m, 1H), 3.64 (m, 1H), 2.85 (m, 1H), 2.73 (dt, 1H), 2.19 (m, 1H), 2.05 (br, 1H), 2.03 (m, 1H), 1.98 (m, 1H), 1.89 (m, 1H), 0.93 (t, 3H); ESI (+) MS m/e=276 (MH+), ESI (-) MS m/e=274 (MIi-).
COMPOUND 24: 2-(1-ETHYL-6-METHYL-1,3,4,9-T'ETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
OH
N
H
24.A. Synthesis of 2-(5-Methyl-1H indol-3 yl)-ethanol To a suspension of 4-methylphenylhydrazine hydrochloride (2.50 g, 15.7 mmol) in 1,4-dioxane (25 mL) and water (1.5 mL) was dropped neat 2,3-dihydrofuran (1.66 g, 23.6 mmol). After the addition, the mixture was heated at 95 °C for 4 hours.
After cooling to room temperature, it was poured into ethyl ether, dried over magnesium sulfate, evaporated to dryness. Flash chromatography on silica gel provided 0.485 g (18%) of the title compound as a solid. 1H NMR (500 MHz, CDC13) 6 7.95 (br, 1H), 7.41 (s, 1H), 7.27 (d, 1H), 7.05 (m, 2H), 3.90 (dd, 2H), 3.01 (t, 2H), 2.46 (s, 3H), 1.50 (t, br, 1H).
24.B. Synthesis of (1-Ethyl-6-methyl-1, 3, 4, 9-tetrahydro pyrano~3, 4-bJindol-1 yl)-S acetic acid ethyl ester To a solution of 2-(5-methyl-1H-indol-3-yl)-ethanol (0.48 g, 2.7 mmol) in dichloromethane (10 mL) was added boron trifluoride diethyl etherate (0.468 g, 3.3 mmol), followed by ethyl propionylacetate (0.649 g, 4.5 mmol). The mixture was stirred at room temperature for 5 hours. It was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layer was dried over magnesium sulfate and evaporated to dryness. Flash chromatography on silica gel provided 0.421 g (52%) of the title compound as an oil. 1H NMR (500 MHz, CDC13) b 8.90 (br, 1H), 7.28 (s, 1H), 7.24 (d, 1 H), 6.99 (d, 1 H), 4.16 (m, 2H), 4.03 (m, 1 H), 3.94 (m, 1 H), 2.98 (d, 1 H), 2.88 (d, 1H), 2.80 (m, 1H), 2.73 (m, 1H), 2.44 (s, 3H), 2.12 (m, 1H), 1.98 (m, 1H), 1.25 (t, 3H), 0.80 (t, 3H); ESI (-) MS m/e=300 (MII-).
24. C. Synthesis of (1-Ethyl-6-methyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid The title compound was synthesized in a manner analogous to step 22.B., using (1-ethyl-6-methyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the ester component afforded the title compound as a solid. mp. 158-159 °C.
1H NMR (500 MHz, CDC13) 8 9.70 (br, 1H), 8.33 (br, 1H), 7.29 (s, 1H), 7.22 (d, 1H), 7.00 (d, 1H), 4.10 (m, 1H), 4.05 (m, 1H), 2.99 (d, 1H), 2.98 (d, 1H), 2.81 (q, 2H), 2.44 (s, 3H), 2.07 (m, 1H), 2.01 (m, 1H), 0.85 (t, 3H); ESI (+) MS m/e=274 (MH+), ESI (-) MS m/e=272 (MH-).
24.D. Synthesis of 2-(1-Ethyl-6-methyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1-yl)-ethanol The title compound was synthesized in a manner analogous to step 22.C., using (1-ethyl-6-methyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid as the carboxylic acid component afforded the title compound as a solid. mp. 114-11 S °C.
'H NMR (500 MHz, CDC13) 8 7.70 (br, 1H), 7.30 (s, 1H), 7.21 (d, 1H), 7.00 (dd, 1H), 4.06 (m, 1H), 3.97 (m, 1 H), 3.67 (m, 1 H), 3.62 (m, 1 H), 2.84 (m, 1 H), 2.73 (m, 1 H), 2.71 (br, 1 H), 2.45 (s, 3H), 2.17 (m, 1H), 2.04 (m, 1H), 1.96 (m, 1H), 1.86 (m, 1H), 0.92 (t, 3H); ESI
(+) MS
m/e=260 (MH+), ESI (-) MS m/e=258 (MH-).
COMPOUND 2S: 2-(1-ETHYL-8-METHYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-S ETHANOL
25.A. Synthesis of 2-(7-Methyl-IH indol-3 yl)-ethanol.
Following the procedure of example 24.A. except using 2-methylphenylhydrazine hydrochloride as the hydrazine component afforded the title compound as a solid. 1H
NMR (500 MHz, CDCl3) 8 7.97 (br, 1H), 7.49 (d, 1H), 7.11 (d, 1H), 7.07 (t, 1H), 7.03 (d, 1H), 3.91 (t, 2H and br, 1H), 3.04 (t, 2H), 2.49 (s, 3H).
25.8. Synthesis of (1-Ethyl-8-methyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid ethyl ester.
Following the procedure of example 23.B. except using 2-(7-methyl-1H indol-3-yl)-ethanol as the 3-indolethanol component afforded the title compound as solid. mp. 77-78 °C. 1H NMR (S00 MHz, CDC13) 8 9.04 (br, 1H), 7.36 (d, 1H), 7.02 (t, 1H), 6.97 (d, 1 H), 4.19 (m, 2H), 4.04 (m, 1 H), 3.94 (m, 1 H), 2.98 (d, 1 H), 2.90 (d, 1 H), 2.81 (m, 1 H), 2.75 (dt, 1H), 2.49 (s, 3H), 2.15 (m, 1H), 2.02 (m, 1H), 1.27 (t, 3H), 0.83 (t, 3H); ESI (-) MS m/e=300 (MIA).
25. C. Synthesis of2-(1-Ethyl-8-methyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1-yl)-ethanol.
Following the procedure of example 22.C. except using (1-ethyl-8-methyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the carboxylic acid component afforded the title compound as a solid. mp. 68 °C. 'H NMR
(500 MHz, CDC13) 8 7.68 (br, 1H), 7.37 (d, 1H), 7.05 (t, 1H), 6.98 (d, 1H), 4.06 (m, 1H), 3.98 (m, 1 H), 3.70 (m, 1 H), 3.65 (m, 1 H), 2.88 (m, 1 H), 2.76 (t, 1 H), 2.72 (m, 1 H), 2.47 (s, 3H), 2.21 (m, 1H), 2.07 (m, 1H), 2.00 (m, 1H), 1.91 (m, 1H), 0.94 (t, 3H); ESI (+) MS m/e=260 (MH+), ESI (-) MS m/e=258 (MH-).
COMPOUND 26: 2-(1-ETHYL-8-FLUORO-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
N
H ~~\OH
26.A. Synthesis oft-(7-Fluoro-IH indol-3 yl)-ethanol Following the procedure of example 24.A. except using 2-fluorophenylhydrazine hydrochloride as the hydrazine component afforded the title compound as an oil.
26.B. Synthesis of (1-Ethyl-8 fluoro-1,3,4,9-tetrahydro pyrano(3,4-bJindol-1 yl)-acetic acid ethyl ester Following the procedure of 24.B. except using 2-(7-fluoro-1H indol-3-yl)-ethanol as the 3-indolethanol component afforded the title compound as an oil.
26. C. Synthesis of 2-(1-Ethyl-8 f luoro-1, 3, 4, 9-tetrahydro pyrano~3, 4-bJindol-1-yl)-ethanol Following the procedure of example 22.C. except using (1-ethyl-8-fluoro-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the carboxylic acid component afforded the title compound as a solid. 1H NMR (500 MHz, CDC13) 8 8.18 (br, 1 H), 7.27 (d, 1 H), 7.02 (m, 1 H), 6. 89 (dd, 1 H), 4.07 (m, 1 H), 3 .99 (m, 1 H), 3 .71 (m, 1 H), 3.65 (m, 1 H), 2.8 8 (m, 1 H), 2.78 (dt, 1 H), 2.76 (br, 1 H), 2.22 (m, 1 H), 2.07 (m, 1 H), 1.99 (m, 1H), 1.91 (m, 1H), 0.94 (t, 3H); ESI (+) MS m/e=264 (MH+), ESI (-) MS
m/e=262 (MHO.
COMPOUND 27: 2-(8-CHLORO-1-ETHYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-27.A. Synthesis of 2-(7-Chloro-IH indol-3 yl)-ethanol Following the procedure of 24.A. except using 2-chlorophenylhydrazine hydrochloride as the hydrazine component afforded the title compound as an oil. 1H NMR
(500 MHz, CDC13) 8 8.26 (br, 1H), 7.52 (d, 1H), 7.21 (d, 1H), 7.15 (d, 1H), 7.06 (t, 1H), 3.91 (t, 2H), 3.02 (t, 2H), 1.48 (br, 1H).
27.B. Synthesis of (8-Chloro-1-ethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid ethyl ester Following the procedure of 24.B. except using 2-(7-chloro-1H indol-3-yl)-ethanol as the 3-indolethanol component afforded the title compound as a solid. 1H NMR
(500 MHz, CDC13) ~ 9.28 (br, 1H), 7.39 (d, 1H), 7.16 (d, 1H), 7.02 (t, 1H), 4.18 (m, 2H), 4.05 (m, 1H), 3.94 (m, 1H), 2.98 (d, 1H), 2.88 (d, 1H), 2.82 (m, 1H), 2.75 (dt, 1H), 2.15 (m, 1H), 2.03 (m, 1H), 1.27 (t, 3H), 0.84 (t, 3H); ESI (-) MS m/e=230 (MH-).
27. C. Synthesis of (8-Chloro-1-ethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid Following the procedure of example 22.B. except using (8-chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the ester component afforded the title compound as a solid. 'H NMR (500 MHz, CDC13) b 8.81 (br, 1H), 7.40 (d, 1H), 7.17 (d, 1 H), 7.04 (t, 1 H), 4.09 (m, 1 H), 4.03 (m, 1 H), 3.05 (d, 1 H), 3.02 (d, 1 H), 2.82 (m, 2H), 2.13 (m, 1H), 2.06 (m, 1H), 0.88 (t, 3H); ESI (+) MS m/e=294 (MH+), ESI (-) MS
m/e=292 (MH-).
27.D. Synthesis of2-(8-Chloro-1-ethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1-yl)-ethanol Following the procedure of example 22.C. except using (8-chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid as the carboxylic acid component afforded the title compound as a solid. 1H NMR (500 MHz, CDCl3) 8 8.05 (br, 1H), 7.41 (d, 1H), 7.17 (d, 1 H), 7.05 (t, 1 H), 4.07 (m, 1 H), 4.00 (m, 1 H), 3.72 (m, 1 H), 3.67 (m, 1 H), 2.87 (m, 1 H), 2.76 (dt, 1 H), 2.70 (br, 1 H), 2.23 (m, 1 H), 2.03 (m, 1 H), 1.91 (m, 1 H), 0.94 (t, 3H); ESI (+) MS m/e=280 (MH+), ESI (-) MS m/e=278 (MH-).
COMPOUND 28: 2-(8-BROMO-1-ETHYL-1,3,4,9-TETRa,HYDRO-PYRANO[3,4-B]arDOL-1-YL)-ETHANOL
i O
\ N OH
H
Br 28.A. Synthesis of 2-(7-Bromo-IH indol-3 yl)-ethanol Following the procedure of example 24.A. except using 2-bromophenylhydrazine hydrochloride as the hydrazine component afforded the title compound as an oil.
28.B. Synthesis of (8-Bromo-1-ethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid ethyl ester Following the procedure of 24.B. except using 2-(7-bromo-1H indol-3-yl)-ethanol as the 3-indolethanol component afforded the title compound as an oil.
28. C. Synthesis of2-(8-Bromo-1-ethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1-yl)-ethanol To a solution of (8-bromo-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester (1.03 g, 2.8 mmol) in tetrahydrofuran at room temperature was added 2.0 M solution of lithium borohydride in tetrahydrofuran. The mixture was heated to reflux for 5 hours. It was quenched with 5% HCl solution, followed by saturated sodium bicarbonate. It was extracted with ethyl acetate, extracts were dried over magnesium sulfate, and it was evaporated to dryness. Crystallization with diethyl ether afforded 0.682 g (75%) of the title compound as a solid. 'H NMR (500 MHz, CDC13) 8 8.01 (br, 1H), 7.45 (d, 1 H), 7.32 (d, 1 H), 7.00 (t, 1 H), 4.07 (m, 1 H), 3.99 (m, 1 H), 3.72 (m, 1 H), 3.67 (m, 1 H), 2.87 (m, 1 H), 2.75 (dt, 1 H), 2.68 (dd, 1 H), 2.24 (m, 1 H), 2.08 (m, 1 H), 2.02 (m, 1 H), 1.93 (m, 1H), 0.94 (t, 3H); ESI (+) MS m/e=324 (MH+), ESI (-) MS m/e=322 (MH-).
COMPOUND 29: 2-(8-ETHYL-1-METHYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
N
OH
29.A. Synthesis of 2-(7-Ethyl-IH indol-3 yl)-ethanol Following the procedure of example 24.A. except using 2-ethylphenylhydrazine hydrochloride as the hydrazine component afforded the title compound as a solid. 1H
NMR (500 MHz, CDC13) 8 8.05 (br, 1H), 7.50 (d, 1H), 7.08 (m, 3H), 3.92 (m, 2H), 3.04 (m, 2H), 2.86 (m, 2H), 2.06 (br, 1H), 1.35 (t, 3H); ESI (+) MS m/e=190 (MH+), ESI (-) MS m/e=188 (MIA) 29.B. Synthesis of (8-Ethyl-1-methyl-1,3,4,9-tetrahydro pyrano(3,4-bJindol-1 yl)-acetic acid ethyl ester Following the procedure of example 22.A. except using 2-(7-ethyl-1H indol-3-yl)-ethanol as the 3-indolethanol component and the ethyl acetoacetate as ketone component afforded the title compound as an oil. 1H NMR (500 MHz, CDC13) b 9.16 (br, 1H), 7.35 (d, 1H), 7.01 (m, 2H), 4.17 (m, 2H), 4.02 (m, 2H), 2.85 (m, 6H), 1.57 (t, 3H), 1.36 (t, 3H), 1.29 (t, 3H); ESI (+) MS m/e=302 (MH+), ESI (-) MS m/e=300 (MIA).
29. C. Synthesis of (8-Ethyl-1-methyl-1, 3, 4, 9-tetrahydro pyrano~3, 4-bJindol-I yl)-acetic acid Following the procedure of example l, step (b) except using (8-ethyl-1-methyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the ester component afforded the title compound as a solid. ESI (-) MS m/e=272 (MIA).
29.D. Synthesis of 2-(8-Ethyl-1-methyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1-yl)-ethanol Following the procedure of example 22.C. except using (8-ethyl-1-methyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid as the carboxylic acid component afforded the title compound as a solid. 1H NMR (500 MHz, CDC13) 8 7.74 (br, 1H), 7.37 (d, 1H), 7.09 (m, 1 H), 7.03 (d, 1 H), 4.12 (m, 1 H), 3.98 (m, 1 H), 3.70 (m, 2H), 2.92 (m, 1 H), 2.85 (m, 2H), 2.74 (m, 2H), 2.15 (m, 2H), 1.56 (s, 3H), 1.36 (t, 3H); ESI (+) MS
m/e=282 (MNa+), ESI (-) MS m/e=258 (MIA) COMPOUND 30: 2-(8-ETHYL-1-PROPYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
30.A. Synthesis of (8-Ethyl-1 propyl-1,3,4,9-tetrahydro pyrano(3,4-bJindol-1 yl)-acetic acid ethyl ester Following the procedure of example 1, step (a) except using 2-(7-ethyl-1H
indol-3-yl)-ethanol as the 3-indolethanol component and the ethyl butyrylacetate as ketone component afforded the title compound as a solid. 1H NMR (500 MHz, CDCl3) 8 9.10 (br, 1 H), 7.34 (d, 1 H), 7.03 (m, 2H), 4.17 (m, 2H), 4.02 (m, 1 H), 3.92 (m, 1 H), 2.99 (d, 1 H), 2.84 (m, 3H), 2.73 (dt, 1H), 2.09 (m, 1H), 1.96 (m, 1H), 1.35 (t, 3H), 1.26 (t, 3H), 1.19 (m, 2H), 0.85 (t, 3H); ESI (+) MS m/e=330 (MH+), ESI (-) MS m/e=328 (MH-).
30.B. Synthesis of (8-Ethyl-1 propyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid Following the procedure of example 22.B. except using (8-ethyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the ester component afforded the title compound as a solid.
30. C. Synthesis of 2-(8-Ethyl-1 propyl-1, 3, 4, 9-tetrahydro pyrano~3, 4-bJindol-1-yl)-ethanol Following the procedure of example 22.C. except using (8-ethyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid as the carboxylic acid component afforded the title compound as a solid. 1H NMR (500 MHz, CDC13) 8 7.73 (br, 1H), 7.36 (d, 1H), 7.09 (t, 1 H), 7.02 (m, 1 H), 4.05 (m, 1 H), 4.01 (m, 1 H), 3.72 (m, 1 H), 3.67 (m, 1 H), 2.85 (m, 2H), 2.76 (dt, 1H), 2.68 (br, 1H), 2.20 (m, 1H), 2.09 (m, 1H), 1.90 (m, 2H), 1.48 (m, 1H), 1.36 (t, 3H), 1.32 (m, 1H), 0.91 (t, 3H); ESI (+) MS m/e=288 (MH+), ESI (-) MS
m/e=286 (MH-).
COMPOUND 31: 2-(8-ETHYL-1-ISOPROPYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
i H
OH
31.A. Synthesis of (8-Ethyl-1-isopropyl-1,3,4,9-tetrahydro pyrano(3,4-bJindol-yl)-acetic acid ethyl ester Following the procedure of example 22.A. except using 2-(7-ethyl-1H indol-3-yl)-ethanol as the 3-indolethanol component and ethyl iso-butyrylacetate as ketone component afforded the title compound as a solid.'H NMR (500 MHz, CDCl3) 8 9.12 (br, 1H), 7.36 (d, 1H), 7.07 (m, 2H), 4.13 (m, 3H), 3.81 (m, 1H), 3.04 (q, 2H), 2.87 (m, 3H), 2.66 (m, 1H), 2.56 (m, 1H), 1.37 (t, 3H), 1.25 (t, 3H), 1.05 (d, 3H), 0.69 (d, 3H).
31.B. Synthesis of (8-Ethyl-1-isopropyl-1, 3, 4, 9-tetrahydro pyrano~3, 4-bJindol-1-yl)-acetic acid Following the procedure of example 24.B. except using (8-ethyl-1-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the ester component afforded the title compound as a solid. 1H NMR (500 MHz, CDCl3) 8 9.70 (br, 1H), 8.55 (br, 1 H), 7.3 6 (d, 1 H), 7.07 (dd, 1 H), 7.01 (d, 1 H), 4.18 (m, 1 H), 3.94 (m, 1 H), 3.10 (q, 2H), 2.82 (m, 4H), 2.52 (m, 1H), 1.32 (t, 3H), 1.06 (d, 3H), 0.82 (d, 3H); ESI
(+) MS
m/e=302 (MH+), ESI (-) MS m/e=300 (MH-) 31.C. Synthesis of2-(8-Ethyl-I-isopropyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-ethanol Following the procedure of example 22.C. except using (8-ethyl-1-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid as the carboxylic acid component afforded the title compound as a solid. 1H NMR (500 MHz, CDC13) 8 7.68 (br, 1H), 7.38 (d, 1H), 7.09 (dd, 1H), 7.03 (d, 1H), 4.06 (m, 2H), 3.65 (m, 2H), 2.87 (m, 3H), 2.77 (dt, 1H), 2.68 (br, 1H), 2.32 (m, 1H), 2.23 (m, 1H), 2.05 (m, 1H), 1.35 (t, 3H), 1.05 (d, 3H), 1.00 (d, 3H); ESI (+) MS m/e=288 (MH+), ESI (-) MS m/e=286 (MH-).
COMPOUND 32: 2-(8-Ethyl-1-phenyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol 32.A. Synthesis of (8-Ethyl-I phenyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid ethyl ester S Following the procedure of example 22.A. except using 2-(7-ethyl-1H indol-3-yl)-ethanol as the 3-indolethanol component and ethyl benzoylacetate as ketone component afforded the title compound as a solid.'H NMR (500 MHz, CDC13) 8 10.05 (br, 1H), 7.42 (d, 1H), 7.28 (m, SH), 7.12 (m, 2H), 3.96 (m, 3H), 3.60 (m, 1H), 3.43 (d, 1H), 3.22 (d, 1H), 3.05 (m, 3H), 2.65 (dd, 1H), 1.42 (d, 3H), 1.03 (t, 3H); ESI (-) MS
m/e=362 (MII-).
32.B. Synthesis of (8-Ethyl-1 phenyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid Following the procedure of example 22.B. except using (8-ethyl-1-phenyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the ester component afforded the title compound as a solid.'H NMR (500 MHz, CDCl3) 8 9.25 (br, 1H), 7.41 (d, 1H), 7.31 (m, SH), 7.10 (t, 1 H), 7.06 (d, 1 H), 4.08 (m, 1 H), 3.70 (m, 1 H), 3.42 (d, 1 H), 3.22 (d, 1H), 3.03 (m, 1H), 2.83 (m, 2H), 2.68(m, 1H), 1.33 (t, 3H); ESI (+) MS m/e=358 (MNa+).
ESI (-) MS m/e=334 (MIi-).
32. C. Synthesis of 2-(8-Ethyl-1 phenyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-yl)-ethanol Following the procedure of example 22.C. except using (8-ethyl-1-phenyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid as the carboxylic acid component afforded the title compound as a solid. 1H NMR (500 MHz, CDCl3) 8 8.27 (br, 1H), 7.38 (m, 3H), 7.32 (m, 3H), 7.12 (t, 1 H), 7.08 (d, 1 H), 4.12 (m, 2H), 3.99 (dd, 1 H), 3.61 (ddd, 1 H), 3.01 (m, 1H), 2.94 (q, 2H), 2.61 (m, 2H), 2.47(m, 1H), 1.39 (t, 3H).
COMPOUND 34: [8'-ETHYL-4',9'-DIHYDRO-3'H SPIRO(CYCLOHEXANE-1,1'-PYRANO[3,4-B]INDOL)-4-YL]-METHANOL
34.A. Synthesis of 8'-Ethyl-4 ;9'-dihydro-3'H spiro(cyclohexane-1,1 '-$ pyrano~3,4-bJindole)-4-carboxylic acid ethyl ester Following the procedure of example 24.A. except using 2-(7-ethyl-1H indol-3-yl)-ethanol as the 3-indolethanol component and 4-oxo-cyclohexane carboxylic acid ethyl ester as ketone component afforded the title compound as an oil. ESI (+) MS
m/e=342 (MH+), ESI (-) MS m/e=340 (MH-).
34.B. Synthesis of 8'-Ethyl-4',9'-dihydro-3'H spiro(cyclohexane-1,1 '-pyrano~3,4-bJindole)-4-carboxylic acid Following the procedure of example 22.B. except using 8'-ethyl-4',9'-dihydro-3'H spiro(cyclohexane-1,1'-pyrano[3,4-b]indole)-4-carboxylic acid ethyl ester as the ester component afforded the title compound as a solid. ESI (+) MS m/e=314 (MH+), ESI (-) 1$ MS m/e=312 (MHO.
34. C. Synthesis of (8'-Ethyl-4',9'-dihydro-3 FI spiro(cyclohexane-1,1 '-pyrano~3,4-bJindol)-4 ylJ-methanol Following the procedure of example 22.C. except using 8'-ethyl-4',9'-dihydro-3'H spiro(cyclohexane-1,1'-pyrano[3,4-b]indole)-4-carboxylic acid as the carboxylic acid component afforded the title compound as a solid. 1H NMR ($00 MHz, CDC13) 8 7.$1 (br, 1H), 7.33 (d, 1H), 7.06 (t, 1H), 7.00 (d, 1H), 3.97 (t, 2H), 3.$4 (t, 2H), 2.84 (q, 2H), 2.78 (t, 2H), 2.12 (br, 1 H), 2.09 (m, t, 1 H), 1.69 (m, 4H), 1.60 (m, 1 H), 1. $2 (m, 3H), 1.3 $ (t, 3H); ESI (+) MS m/e=300 (NIH+), ESI (-) MS m/e=298 (MH-).
COMPOUND 3$: R-2-(1,8-DIETHYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-2$ ETHANOL
~~ii~
OH
35.A. Synthesis ofR-2-(1,8-Diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol Following the procedure of example 22, except using R-(1,8-Diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid as the carboxylic acid component in step 22.C. afforded the title compound as a solid. 1H NMR (500 MHz, CDCl3) 8 7.74 (br, 1H), 7.37 (d, 1 H), 7.09 (t, 1 H), 7.03 (d, 1 H), 4.07 (m, 1 H), 3.98 (m, 1 H), 3.68 (m, 2H), 2.86 (m, 3H), 2.76 (dt, 1 H), 2.69 (br, t, 1 H), 2.21 (m, 1 H), 2.07 (m, 1 H), 2.00 (m, 1 H), 1.91 (m, 1H), 1.35 (t, 3H), 0.94 (t, 3H); ESI (+) MS m/e=274 (MH+), ESI (-) MS m/e=272 (MH-).
COMPOUND 36: 2-(1-ETHYL-8-ISOPROPYL-1,3,4,9-TETR.AHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
i \N~ \ ~
H V \OH
36.A. Synthesis of 2-Hydroxyimino-N (2-isopropyl phenyl)-acetamide A mixture of 2-isopropylaniline (4.7 g, 35 mmol), Na2S04 (30.0 g), concentrated hydrochloride (3 mL), chloral hydrate (6.5 g), hydroxylamine hydrochloride (8.00 g) in water (150 mL) was heated at 85 °C for 40 minutes. After cooling to room temperature, it was extracted with ethyl acetate. The extracts were dried over magnesium sulfate and evaporated to dryness. Flash chromatography on silica gel provided 4.357 g (54%) of the title compound as solid.
36.B. Synthesis of 7-Isopropyl-IH indole-2,3-dione To concentrated sulfuric acid at 80 °C was added 2-hydroxyimino-N-(2-isopropyl-phenyl)-acetamide in several small portions over 10 minutes. After addition it was heated at 80 °C for 30 minutes., then poured into ice. Filtration, washing with water, and drying under vacuum over P205 provided 2.974 g (84%) of the title compound as a solid. ESI (-) MS m/e=188 (MH-).
36. C. Synthesis of (7-Isopropyl-IH indol-3 yl)-oxo-acetic acid ethyl ester To a solution of 7-isopropyl-1H-indole-2,3-dione (2.97 g, 15.7 mmol) in tetrahydrofuran (20 mL) was dropped 2.0 M solution of lithium borohydride in tetrahydrofuran (15 mL, 30 mmol). The mixture was heated at 90 °C for 4 hours. It was quenched with 5% HCI, followed by saturated sodium bicarbonate. It was extracted with ethyl acetate. The extracts were dried over magnesium sulfate and evaporated to dryness to provide a crude 7-isopropyl-1H-indole. To a solution of the crude 7-isopropyl-1H-indole in diethyl ether (40 mL) was dropped 2.0 M solution of oxalyl chloride in dichloromethane (15 mL, 30 mmol). After stirring at room temperature for 5 hours, it was evaporated to dryness. Ethanol was added to the residue and it was stirred at room temperature overnight. After the ethanol was evaporated, flash chromatography on silica gel provided 0.972 g (24%) of the title compound as solid. ESI (-) MS m/e=258 (MH-).
36.D. Synthesis of (1-Ethyl-8-isopropyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-yl)-acetic acid ethyl ester To a solution of (7-isopropyl-1H-indol-3-yl)-oxo-acetic acid ethyl ester (0.97 g. 3.7 mmol) in tetrahydrofuran was added 2.0 M solution of lithium borohydride in tetrahydrofuran. The mixture was heated at 90 °C for 5 hours. It was quenched with 5%
HCI, followed by saturated sodium bicarbonate. It was extracted with ethyl acetate. The extracts were dried over magnesium sulfate and evaporated to dryness to provide a crude 2-(7- isopropyl -1H-indol-3-yl)-ethanol. ESI (+) MS m/e=204 (MH+), ESI (-) MS
m/e=202 (MH-).
Following the procedure of example 24.B. except using 2-(7-isopropyl-1H-indol-yl)-ethanol as the 3-indolethanol component afforded the title compound as an oil. ESI (+) MS m/e=330 (MH+), ESI (-) MS m/e=328 (MH-).
36.E. Synthesis of (1-Ethyl-8-isopropyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-yl)-acetic acid Following the procedure of example 22.B. except using (1-ethyl-8-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the ester component afforded the title compound as a solid. mp. 158-159 °C. 1H NMR (500 MHz, CDCl3) S
9.50 (br, 1H), 8.58 (br, 1H), 7.36 (d, 1H), 7.08 (m, 2H), 4.09 (m, 1H), 4.04 (m, 1H), 3.20 S (m, 1 H), 3 .05 (d, 1 H), 3 .02 (d, 1 H), 2.84 (m, 2H), 2.13 (m, 1 H), 2.04 (m, 1 H), 1.3 8 (d, 3H), 1.35 (d, 3H), 0.88 (t, 3H); ESI (+) MS m/e=302 (MH+), ESI (-) MS m/e=300 (MII-) 36.F. Synthesis of 2-(1-Ethyl-8-isopropyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-ethanol Following the procedure of example 22.C. except using (1-ethyl-8-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid as the carboxylic acid component afforded the title compound as a oil. 1H NMR (500 MHz, CDC13) 8 7.78 (br, 1H), 7.36 (d, 1 H), 7.11 (t, 1 H), 7.07 (d, 1 H), 4.07 (m, 1 H), 3.99 (m, 1 H), 3.71 (m, 2H), 3.20 (m, 1 H), 2.90 (m, 1 H), 2.76 (dt, 1 H), 2.65 (br, 1 H), 2.22 (m, 1 H), 2.06 (m, 1 H), 2.03 (m, 1 H), 1.92 (m, 1H), 1.38 (d, 6H), 0.88 (t, 3H); ESI (+) MS m/e=288 (MH+), ESI (-) MS
m/e=286 (MHO
COMPOUND 37: 2-(1-ETHYL-8-TRIFLUOROMETHYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
i F H v \OH
F
F
37.A. Synthesis of 2-Hydroxyimino-N (2-trifluoromethyl phenyl)-acetamide Following the procedure of example 36.A. except using 2-trifluoromethylaniline as the aniline component afforded the title compound as a solid.
37.B. Synthesis of 7-Trifluoromethyl-IH indole-2,3-dione Following the procedure of example 36.B. except using 2-hydroxyimino-N-(2-trifluoromethyl-phenyl)-acetamide as the acetamide component afforded the title compound as a solid. ESI (-) MS m/e=214 (MH-).
37. C. Synthesis of (7-Trifluoromethyl-IH indol-3 yl)-oxo-acetic acid ethyl ester Following the procedure of example 36.C. except using 7-trifluoromethyl-1H-indole-2,3-dione as the dione component afforded the title compound as a solid.
37.D. Synthesis of 2-(1-Ethyl-8-trifluoromethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-ethanol Following the procedure of example 28.C. except using (1-ethyl-8-trifluoromethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the ester component afforded the title compound as a solid. 1H NMR (500 MHz, CDCl3) 8 8.42 (br, 1H), 7.67 (d, 1 H), 7.41 (d, 1 H), 7.18 (t, 1 H), 4.07 (m, 1 H), 4.00 (m, 1 H), 3.71 (m, 2H), 2.89 (m, 1 H), 2.78 (dt, 1H), 2.64 (br, 1H), 2.23 (m, 1H), 2.07 (m, 1H), 2.02 (m, 1H), 1.93 (m, 1H), 0.93 (t, 3H); ESI (+) MS m/e=314 (MH+), ESI (-) MS m/e=312 (MII-).
COMPOUND 38: 2-($-CHLORO-1-ETHYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
38.A. Synthesis of (4-Chloro-1H indol-3 yl)-oxo-acetic acid ethyl ester Following the procedure of example 36.C. except using 4-chloro-1H-indole as the indole component afforded the title compound as a solid.
38.B. Synthesis of S-Chloro-1-ethyl-1, 3, 4, 9-tetrahydro pyrano~3, 4-bJindol-1 yl)-acetic acid ethyl ester Following the procedure of example 36.D. except using (4-chloro-1H-indol-3-yl)-oxo-acetic acid ethyl ester as the ester component afforded the title compound as an oil.
1H NMR (008-08) MS. ESI (+) MS m/e=322 (MH+), ESI (-) MS m/e=320 (MIi-).
38. C. Synthesis of (S-Chloro-1-ethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid Following the procedure of example 22.B except using (5-chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the ester component afforded the title compound as a solid. ESI (+) MS m/e=294 (MH+), ESI (-) MS m/e=292 (MII-).
38.D. Synthesis of 2-(5-Chloro-1-ethyl-1, 3, 4, 9-tetrahydro pyrano~3, 4-bJindol-1-yl)-ethanol Following the procedure of example 22.C. except using (5-chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid as the carboxylic acid component afforded the title compound as a solid. IH NMR (500 MHz, CDC13) 8 8.04 (br, 1H), 7.20 (dd, 1H), 7.04 (m, 2H), 4.05 (m, 1 H), 3.97 (m, 1 H), 3.68 (m, 2H), 3.16 (m, 2H), 2.19 (m, 1 H), 2.04 (m, 1H), 1.98 (m, 1H), 1.89 (m, 1H), 0.92 (t, 3H); ESI (-) MS m/e=278 (MII-).
COMPOUND 39: 2-(1-ETHYL-S-FLUORO-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
39.A. Synthesis of (4-Fluoro-IH indol-3 yl)-oxo-acetic acid ethyl ester Following the procedure of example 36.C. except using 4-fluoro-1H-indole as the indole component afforded the title compound as a solid.
39.B. Synthesis of (1-Ethyl-5 fluoro-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid ethyl ester Following the procedure of example 36.D. except using (4-fluoro-1H-indol-3-yl)-oxo-acetic acid ethyl ester as the ester component afforded the title compound as an oil.
ESI (-) MS m/e=304 (MH-).
39. C. (1-Ethyl-5 fluoro-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid Following the procedure of example 22.B. except using (1-ethyl-5-fluoro-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the ester component afforded the title compound as a solid. 1H NMR (500 MHz, CDC13) ~ 9.70 (br, 1H), 8.75 (br, 1H), 7.06 (m, 2H), 6.73 (dd, 1 H), 4.08 (m, 1 H), 4.04 (m, 1 H), 3.00 (m, 4H), 2.10 (m, 1 H), 2.01 (m, 1H), 0.86 (t, 3H); ESI (+) MS m/e=278 (MH+), ESI (-) MS m/e=276 (MH-).
39.D. Synthesis of 2-(1-Ethyl-5 fluoro-1,3,4,9-tetrahydro pyrano(3,4-bJindol-1-yl)-ethanol Following the procedure of example 22.C. except using (1-ethyl-S-fluoro-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid as the carboxylic acid component afforded the title compound as a solid. 1H NMR (500 MHz, CDC13) 8 7.97 (br, 1H), 7.08 (d, 1H), 7.04 (ddd, 1 H), 6.75 (dd, 1 H), 4.04 (m, 1 H), 3.98 (m, 1 H), 3.67 (m, 2H), 3.04 (m, 1 H), 2.93 (m, 1 H), 2.61 (br, 1 H), 2.19 (m, 1 H), 2.03 (m, 1 H), 2.01 (m, 1 H), 1.
89 (m, 1 H), 0.92 (t, 3H); ESI (+) MS m/e=264 (MH+), ESI (-) MS m/e=262 (MH-) COMPOUND 40: 2-(1-ETHYL-6-FLUORO-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
40.A. Synthesis of (5-Fluoro-IH indol-3 yl)-oxo-acetic acid ethyl ester Following the procedure of example 36.C. except using 5-fluoro-1H-indole as the indole component afforded the title compound as a solid.
40.B. Synthesis of (1-Ethyl-6 fluoro-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1-yl)-acetic acid ethyl ester Following the procedure of example 36.D. except using (5-fluoro-1H-indol-3-yl)-oxo-acetic acid ethyl ester as the ester component afforded the title compound as an oil.
40. C. Synthesis of 2-(1-Ethyl-6 fluoro-1,3,4,9-tetrahydro pyrano~3,4-bJindol-yl)-ethanol Following the procedure of example 22.C. except using (1-ethyl-6-fluoro-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the carboxylic acid component afforded the title compound as a solid. IH NMR (500 MHz, CDC13) 8 7.91 (br, 1 H), 7.22 (dd, 1 H), 7.14 (dd, 1 H), 6.90 (ddd, 1 H), 4.05 (m, 1 H), 4.00 (m, 1 H), 3.68 (m, 2H), 2.71 (dt, 1 H), 2.69 (br, 1 H), 2.18 (m, 1 H), 2.04 (m, 1 H), 1.97 (m, 1 H), 1.89 (m, 1H), 0.92 (t, 3H); ESI (+) MS m/e=264 (MH+), ESI (-) MS m/e=262 (MHO.
S COMPOUND 41: 2-(6-CHLORO-1-ETHYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
ci 41.A. Synthesis of (5-Chloro-IH indol-3 yl)-oxo-acetic acid ethyl ester Following the procedure of example 36.C. except using S-chloro-1H-indole as the indole component afforded the title compound as a solid. 1H NMR(500 MHz, DMSO-d6) 8 12.54 (br, 1H), 8.50 (d, 1H), 8.12 (d, 1H), 7.56 (d, 1H), 7.30 (dd, 1H), 4.36 (q, 2H), 2.48 (t, br, 1H), 1.32 (t, 3H); APCI (-) MS m/e=250 (MH-).
41.B. Synthesis of (6-Chloro-1-ethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid ethyl ester Following the procedure of example 36.D. except using (5-chloro-1H-indol-3-yl)-oxo-acetic acid ethyl ester as the ester component afforded the title compound as an oil.
1H NMR (500 MHz, CDC13) 8 9.18 (br, 1H), 7.46 (d, 1H), 7.26 (d, 1H), 7.11 (dd, 1H), 4.19 (m, 2H), 4.03 (m, 1H), 3.93 (m, 1H), 2.99 (d, 1H), 2.90 (d, 1H), 2.77 (m, 1H), 2.72 (m, 1H), 2.11 (m, 1H), 1.98 (m, 1H), 1.27 (t, 3H), 0.81 (t, 3H); APCI (+) MS
m/e=322 (MH+), APCI (-) MS m/e=320(MH-) 41.C Synthesis of (6-Chloro-1-ethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid Following the procedure of example 22.B. except using (6-chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the ester component afforded the title compound as a solid. 'H NMR (500 MHz, CDCl3) 8 9.50 (br, 1H), 8.68 (br, 1H), 7.46 (s, 1 H), 7.23 (d, 1 H), 7.12 (d, 1 H), 4.09 (m, 1 H), 4.03 (m, 1 H), 3 .03 (d, 1 H), 2.99 (d, 1H), 2.79 (m, 2H), 2.10 (m, 1H), 2.01 (m, 1H), 0.86 (t, 3H); ESI (+) MS
m/e=294 (MH+), ESI (-) MS m/e=292 (MII-).
41.D. Synthesis of2-(6-Chloro-1-ethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1-yl)-ethanol Following the procedure of example 22.C. except using (6-chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid as the carboxylic acid component afforded the title compound as a solid. 1H NMR (S00 MHz, CDCl3) 8 8.01 (br, 1H), 7.46 (s, 1H), 7.22 (d, 1 H), 7.12 (d, 1 H), 4.05 (m, 1 H), 3.99 (m, 1 H), 3.67 (m, 2H), 2.83 (m, 1 H), 2.72 (m, 1H), 2.65 (br, 1H), 2.19 (m, 1H), 2.00 (m, 2H), 1.88 (m, 1H), 0.92 (t, 3H); APCI (+) MS m/e=280 (MH+), APCI (-) MS m/e=278 (MII-) COMPOUND 42: 2-(6-BROMO-1-ET'HYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
Br 42.A. Synthesis of (S-Bromo-1H indol-3 yl)-oxo-acetic acid ethyl ester Following the procedure of example 36, step (c) except using 5-bromo-1H-indole as the indole component afforded the title compound as a solid.
42.B. Synthesis of (6-Bromo-1-ethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid ethyl ester Following the procedure of example 36.B. except using (5-bromo-1H-indol-3-yl)-oxo-acetic acid ethyl ester as the ester component afforded the title compound as an oil.
42. C. Synthesis of 2-(6-Bromo-1-ethyl-1, 3, 4, 9-tetrahydro pyrano~3, 4-bJindol-1-yl)-ethanol Following the procedure of example 28.C. except using (6-bromo-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the ester component afforded the title compound as a solid. 1H NMR (500 MHz, CDC13) b 7.95 (br, 1H), 7.62 (d, 1H), 7.24 (dd, 1 H), 7.19 (d, 1 H), 4.05 (m, 1 H), 3.97 (m, 1 H), 3.67 (m, 2H), 2.
84 (m, 1 H), 2.71 (m, 1 H), 2. 5 5 (br, 1 H), 2.19 (m, 1 H), 2.03 (m, 1 H), 1.97 (m, 1 H), 1. 8 8 (m, 1 H), 0.91 (t, 3H); ESI (+) MS m/e=324 (MH+), ESI (-) MS m/e=322 (MH-).
COMPOUND 43: 2-(1-ETHYL-7-FLUORO-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
43.A. Synthesis of (6-Fluoro-1 H indol-3 yl)-oxo-acetic acid ethyl ester Following the procedure of example 36.C. except using 6-fluoro-1H-indole as the indole component afforded the title compound as a solid. 'H NMR (500 MHz, CDC13) b 8.75 (br, 1H), 8.48 (d, 1H), 8.39 (dd, 1H), 7.12 (m, 2H), 4.41 (q, 2H), 1.43 (t, 3H); ESI (-) MS m/e=234(MI-~).
43.B. Synthesis of (1-Ethyl-7 fluoro-1,3,4,9-tetrahydro pyrano~3,4-bJindol-I
yl)-acetic acid ethyl ester Following the procedure of example 36.D. except using (6-fluoro-1H-indol-3-yl)-oxo-acetic acid ethyl ester as the ester component afforded the title compound as an oil.
43.G Synthesis of (1-Ethyl-7 fluoro-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid Following the procedure of example 22.B. except using (1-ethyl-7-fluoro-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the ester component afforded the title compound as a solid.'H NMR (500 MHz, CDC13) 8 11.8 (br, 1H), 9.53 (br, 1H), 7.29 (dd, 1 H), 6.93 (dd, 1 H), 6.74 (ddd, 1 H), 3.94 (m, 1 H), 3.89 (m, 1 H), 2. 86 (d, 1 H), 2.82 (d, 1H), 2.69 (m, 1H), 2.66 (m, 1H), 2.03 (m, 1H), 1.95 (m, 1H), 0.74 (t, 3H); ESI (+) MS m/e=278 (MH+), ESI (-) MS m/e=276 (MH-) 43.D. Synthesis of 2-(1-Ethyl-7 fluoro-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1-yl)-ethanol Following the procedure of example 22.C. except using (1-ethyl-7-fluoro-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid as the carboxylic acid component afforded the title compound as a solid. 'H NMR (500 MHz, CDC13) b 7.95 (br, 1H), 7.40 (dd, 1H), 7.00 (dd, 1 H), 6.88 (ddd, 1 H), 4.06 (m, 1 H), 3.99 (m, 1 H), 3.65 (m, 2H), 2. 85 (m, 1 H), 2.71 (m, br, 2H), 2.18 (m, 1H), 2.02 (m, 1H), 1.98 (m, 1H), 1.88 (m, 1H), 0.92 (t, 3H); ESI
(+) MS m/e=264 (MH+), ESI (-) MS m/e=262 (MII-) COMPOUND 44: 2-(7-CHLORO-1-ETHYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
r ci \ / \ o H v \OH
44.A. Synthesis of (6-Chloro-IH indol-3 yl)-oxo-acetic acid ethyl ester Following the procedure of example 36.c. except using 6-chloro-1H-indole as the indole component afforded the title compound as a solid. 1H NMR (500 MHz, CDC13) 8 11.50 (br, 1 H), 8.3 0 (d, 1 H), 8.21 (d, 1 H), 7.3 7 (d, 1 H), 7.15 (dd, 1 H), 4.31 (q, 2H), 1.3 3 (t, 3H); ESI (+) MS m/e=252 (MH+), ESI (-) MS m/e=250 (MII-) 44.B. Synthesis of (7-Chloro-1-ethyl-1,3,4,9-tetrahydro pyrano(3,4-bJindol-1 yl)-acetic acid ethyl ester Following the procedure of example 22.D. except using (6-chloro-1H-indol-3-yl)-oxo-acetic acid ethyl ester as the ester component afforded the title compound as an oil.
44.G Synthesis of (7-Chloro-1-ethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid Following the procedure of example 22.B. except using (7-chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the ester component afforded the title compound as a solid. 1H NMR (500 MHz, CDC13) 8 11.80 (br, 1H), 9.57 (br, 1H), 7.30 (d, 1 H), 7.24 (d, 1 H), 6.95 (dd, 1 H), 3.97 (m, 1 H), 3.8 8 (m, 1 H), 2.8 8 (d, 1 H), 2.80 (d, 1 H), 2.71 (m, 1 H), 2.66 (dt, 1 H), 2.04 (m, 1 H), 1.96 (m, 1 H), 0.74 (t, 3H); ESI (+) MS
m/e=294 (MH~, ESI (-) MS m/e=292 (MH-).
44.D. Synthesis of 2-(7-Chloro-1-ethyl-1, 3, 4, 9-tetrahydro pyrano~3, 4-bJindol-1-yl)-ethanol Following the procedure of example 22.C. except using (7-chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid as the carboxylic acid component afforded the title compound as a solid. 1H NMR (500 MHz, CDC13) 8 8.02 (br, 1H), 7.40 (d, 1H), 7.30 (d, 1H), 7.08 (dd, 1H), 4.05 (m, 1H), 3.99 (m, 1H), 3.66 (m, 2H), 2.73 (dt, 1H), 2.71 (br, 1H), 2.11 (m, 1H), 2.02 (m, 1H), 1.96 (m, 1H), 1.88 (m, 1H), 0.91 (t, 3H); ESI (+) MS
m/e=280 (MH+), ESI (-) MS m/e=278 (MH-) COMPOUND 45: 2-(1-ETHYL-6,S-DIMETHYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]lrrDOL-1-YL)-ETHANOL
45.A. Synthesis of 5,7-Dimethyl-1H indole To solution of 5,7-dimethyl-1H-indole-2,3-dione in tetrahydrofuran at 0 °C was added 1.0 M solution of borane-tetrahydrofuran complex in tetrahydrofuran (40 mL).
After stirred at room temperature overnight, a 5% HCl solution was added to the mixture and it was stirred 20 minutes. It was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate. Extracts were dried over magnesium sulfate and evaporated to dryness to afford the title compound as oil.
45.B. Synthesis of (5, 7-Dimethyl-1H indol-3 yl)-oxo-acetic acid ethyl ester Following the procedure of example 36.C. except using 5,7-dimethyl-1H-indole as the indole component afforded the title compound as a solid. ESI (+) MS
m/e=246 (MH+) 45. C. Synthesis of (1-Ethyl-6, 8-dimethyl-1, 3, 4, 9-tetrahydro pyrano~3, 4-bJindol-1 yl)-acetic acid ethyl ester Following the procedure of example 36.D. except using (5,7-dimethyl-1H-indol-3-yl)-oxo-acetic acid ethyl ester component afforded the title compound as an oil.
45.D. Synthesis of (1-Ethyl-6,8-dimethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid Following the procedure of example 22.B. except using (1-ethyl-6,8-dimethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the ester component afforded the title compound as a solid. 'H NMR (500 MHz, CDC13) 8 9.50 (br, 1H), 8.28 (br, 1H), 7.14 (s, 1H), 6.82 (s, 1H), 4.10 (m, 1H), 4.06 (m, 1H), 3.02 (d, 2H), 3.01 (d, 1H), 2.81 (m, 2H), 2.41 (s, 3H), 2.40 (s, 3H), 2.10 (m, 1H), 2.03 (m, 1H), 0.87 (t, 3H); ESI (+) MS m/e=288 (MH+), ESI (-) MS m/e=286 (MH-).
45.E. Synthesis of 2-(1-Ethyl-6,8-dimethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-ethanol Following the procedure of example 22.C. except using (1-ethyl-6,8-dimethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid as the carboxylic acid component afforded the title compound as a solid. 1H NMR (500 MHz, CDCl3) 8 7.51 (br, 1H), 7.15 (s, 1H), 6.83 (s, 1H), 4.06 (m, 1H), 3.98 (m, 1H), 3.67 (m, 2H), 2.85 (m, 1H), 2.72 (dt, 1H), 2.69 (br, 1H), 2.43 (s, 3H), 2.42 (s, 3H), 2.20 (m, 1H), 2.06 (m, 1H), 2.03 (m, 1H), 1.89 (m, 1H), 0.95 (t, 3H); ESI (+) MS m/e=274 (MH+), ESI (-) MS m/e=272 (MH-) COMPOUND 46: 2-(6,8-DICHLORO-1-ETHYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
a 46.A. Synthesis of S, 7-Dichloro-1 H indole Following the procedure of example 45.A. except using 5,7-dichloro-1H-indole-2,3-dione as the dione component afforded the title compound as a oil.
46.B. Syntehsis of (5,7-Dichloro-IH indol-3 yl)-oxo-acetic acid ethyl ester Following the procedure of example 36.C. except using 5,7-dichloro-1H-indole as the indole component afforded the title compound as a solid.
46. G Synthesis of (6, 8-Dichloro-1-ethyl-1, 3, 4, 9-tetrahydro pyrano~3, 4-bJindol-1 yl)-acetic acid ethyl ester Following the procedure of example 36.D. except using (5,7-dichloro-1H-indol-3-yl)-oxo-acetic acid ethyl ester component afforded the title compound as an oil.
46.D. Synthesis of (6,8-Dichloro-1-ethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid Following the procedure of example 22.B. except using (6,8-dichloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the ester component afforded the title compound as a solid. 1H NMR (500 MHz, CDC13) 8 9.07 (br, 1H), 7.03 (d, 1 H), 6.97 (d, 1 H), 4.07 (m, 1 H), 4.01 (m, 1 H), 3 .15 (t, 2H), 3 .10 (d, 1 H), 3.03 (d, 1 H), 2.15 (m, 1H), 2.05 (m, 1H), 0.88 (t, 3H); ESI (+) MS m/e=328 (MH+), ESI (-) MS
m/e=326 (MH-).
46.E. Synthesis of 2-(6, 8-Dichloro-1-ethyl-1, 3, 4, 9-tetrahydro pyrano~3, 4-bJindol-1-yl)-ethanol Following the procedure of example 22.C. except using (6,8-dichloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid as the carboxylic acid component afforded the title compound as a solid. 1H NMR (500 MHz, CDC13) 8 8.25 (br, 1H), 7.03 (d, 1 H), 6.98 (d, 1 H), 4.03 (m, 1 H), 3.99 (m, 1 H), 3.71 (m, 2H), 3.13 (rn, 2H), 2.57 (br, 1H), 2.23 (m, 1H), 2.07 (m, 1H), 2.04 (m, 1H), 1.92 (m, 1H), 0.93 (t, 3H); ESI
(+) MS
m/e=314 (MH+), ESI (-) MS m/e=312 (MII-).
COMPOUND 47: 2-(6-BItOMO-1,8-DIETHYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
47.A. Synthesis of N (4-Bromo-2-ethyl phenyl)-2-hydroxyimino-acetamide Following the procedure of example 36.A. except using 4-bromo-2-ethylaniline as the aniline component afforded the title compound as a solid. ESI (-) MS
m/e=269 (MH-).
S 47.B. Synthesis of 5-Bromo-7-ethyl-1H indole-2,3-dione Following the procedure of example 36.B. except using N-(4-Bromo-2-ethyl-phenyl)-2-hydroxyimino-acetamide as the acetamide component afforded the title compound as a solid. ESI (-) MS m/e=252 (MH-).
47. C. Synthesis of (5-Bromo-7-ethyl-1 H indol-3 yl)-oxo-acetic acid ethyl ester Following the procedure of example 36.C. except using S-Bromo-7-ethyl-1H
indole-2,3-dione as the dione component afforded the title compound as a solid. ESI (+) MS m/e=324 (MH+), ESI (-) MS m/e=322 (MH-).
47.D. Synthesis of (6-Bromo-1,8-diethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-yl)-acetic acid ethyl ester Following the procedure of example 36.D. except using (S-bromo-7-ethyl-1H
indol-3-yl)-oxo-acetic acid ethyl ester as the ester component afforded the title compound as a solid.
47.E. Synthesis of 2-(6-Bromo-1,8-diethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-ethanol Following the procedure of example 28.C. except using (6-bromo-1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the ester component afforded the title compound as a solid. 1H NMR (500 MHz, CDC13) 8 7.89 (br, 1H), 7.48 (d, 1H), 7.11 (d, 1H), 4.05 (m, 1H), 3.99 (m, 1H), 3.70 (m, 2H), 2.80 (m, 3H), 2.71 (dt, 1H), 2.55 (br, t, 1H), 2.19 (m, 1H), 2.05 (m, 1H), 2.01 (m, 1H), 1.90 (m, 1H), 1.33 (t, 3H), 0.92 (t, 3H); ESI (+) MS m/e=352 (MH+), ESI (-) MS m/e=350 (MH-).
COMPOUND 48: 2-(1,8-DIETHYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-N,N-DIMETHYL-ACETAMIDE
\N/
H ~ ~O
2-( 1, 8-Diethyl-1,3,4, 9-tetrahydro-pyrano [ 3,4-b] indo 1-1-yl)-N,N-dimethyl-acetamide. Following the procedure of example 27 except using dimethylamine as the amine component afforded the title compound as a solid. 1H NMR (500 MHz, CDCl3) 8 9.39 (br, 1H), 7.35 (d, 1H), 7.05 (t, 1H), 6.99 (d, 1H), 6.19 (m, 1H), 4.06 (m, 1H), 3.98 (m, 1H), 2.84 (s, m, 9H), 2.11 (m, 1H), 2.01 (m, 1H), 1.36 (t, 3H), 0.85 (t, 3H);
ESI (-) MS
m/e=299 (MH~).
COMPOUND 49: 2-(9-BENZYL-1,8-DIETHYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
Compound 49 was synthesized according to the following scheme:
/ ~
~ o -(CHZ)nC02H N~(CHZ)nC02H
OH2)nCH
49.A. Synthesis of (9-Benzyl-1,8-diethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-yl)-acetic acid To a solution of (1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid (0.51 g, 1.8 mmol) in tetrahydrofuran at room temperature was added sodium hydride (60% dispersion in mineral oil, 0.4 g). After being heated at 50 °C for 2 hours, benzyl bromide (0.6 g, 3.5 mmol) was added and the solution was stirred for another 2 hours. It was quenched with ethyl acetate and washed with water. The ethyl acetate layer was dried over magnesium sulfate and evaporated to dryness. Flash chromatography on silica gel provided 0.486 g (73%) of the title compound as a solid.'H NMR (500 MHz, CDC13) 8 7.13 (m, 3H), 6.97 (d, 1 H), 6.74 (d, 1 H), 6.68 (t, 1 H), 6.21 (d, 1 H), 3.90 (s, 1 H), 3.63 (m, 1 H), 3.3 5 (td, 1 H), 3.18 (d, 1 H), 3 .00 (d, 1 H), 2.67 (q, 2H), 2.44 (q, 2H), 2.10 (m, 1 H), 1.85 (d, 1H), 1.52 (m, 1H), 1.41 (m, 1H), 1.16 (t, 3H), 0.75 (t, 3H); ESI (+) MS m/e=278 (MH+).
49.B. Synthesis of 2-(9-Benzyl-1,8-diethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-I yl)-ethanol To a solution of (9-benzyl-1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid (0.45 g, 1.2 mmol) in tetrahydrofuran at room temperature was added 1.0 M
solution of borane-tetrahydrofuran complex in tetrahydrofuran and it was stirred at 90 °C
for 4 hours. The mixture was quenched with 5% HCl solution and stirred at room temperature for 20 minutes. It was extracted with ethyl acetate and washed with saturated sodium bicarbonate. The extracts were dried over magnesium sulfate and evaporated to dryness. Flash chromatography on silica gel provided 0.321 g (74%) of the title compound as a solid. 1H NMR (500 MHz, CDCl3) 8 7.17 (m, 3H), 6.94 (d, 1H), 6.84 (m, 2H), 6.70 (t, 1 H), 6.56 (d, 1 H), 3.87 (m, 1 H), 3.79 (m, 1 H), 3.68 (dt, 1 H), 3.64 (br, 1 H), 3.41 (td, 1 H), 2.93 (q, 2H), 2.43 (q, 2H), 2.04 (m, 1 H), 1.93 (dt, 1 H), 1.86 (m, 1 H), 1.77 (m, 1 H), 1.49 (m, 1H), 1.38 (m, 1H), 1.17 (t, 3H), 0.70 (t, 3H).
COMPOUND SO: 2-(1,8-DIETHYL-9-METHYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
i - ~ ~ ~oH
SO.A. Synthesis of 2-(1,8-Diethyl-9-methyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid Following the procedure of example 49.A. except using (1,8-Diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid as the indole component afforded the title compound as an oil.
SO.B. Synthesis of 2-(1,8-Diethyl-9-methyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-ethanol Following the procedure of example 49.B. except using 2-(1,8-diethyl-9-methyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid as the carboxylic acid component afforded the title compound as a solid. 1H NMR (500 MHz, CDCl3) 8 7.35 (dd, 1H), 7.03 (t, 1H), 6.98 (d, 1H), 4.04 (m, 1H), 3.93 (m, 1H), 3.91 (s, 3H), 3.75 (m, 1H), 3.63 (m, 1H), 3.11 (q, 2H), 2.87 (m, 1 H), 2.76 (dt, 1 H), 2.68 (br, 1 H), 2.27 (m, 1 H), 2.22 (m, 1 H), 2.12 (m, 1H), 1.97 (m, 1H), 1.35 (t, 3H), 0.94 (t, 3H); ESI (+) MS m/e=288 (MH+) COMPOUND 51: 2-(7-BROMO-1,8-DIETHYL-1,3,4,9-TETRAHYDROPYRANO[3,4-B]INDOL-1-YL)ETHANOL
v \OH
O .2HBr Br2, CHCI3 I ~ \ LiOH
~ o ~ ~.j ~ COpEt '' I / N~COzEt "60 C Br H
/H
O ~ BHZ
\ \
Br I ~ N COzH ~ Br I ~ H OH
H / THF
90°C
SLA. Synthesis ofEthyl2-(7-bromo-1,8-diethyl-1,3,4,9-tetrahydropyrano~3,4-bJindol-1-yl)acetate.
(R,S)-Etodolac ethyl ester (5 g, 15.8 mmol) was dissolved in chloroform (50 ml) and cooled to -60°C with a dry ice/acetone bath. To this solution was added dropwise a solution of bromine (2.53 g, 15.8 mmol) in chloroform (50 ml) during 2hr.
After the addition, the reaction mixture was allowed to warm to -20'C and triethylamine (5 ml) was added dropwise followed by silica gel (~20 g). The mixture was stirred for 10 min, filtered through silica gel (~10 g), and the filtrate evaporated to dryness.
The crude product was recrystallized in hexane/dichloromethane (60 ml/20 ml) to give (4.5 g g, 72%) of product. 1H NMR (300 MHz, CDC13) 8 9.23 (b, NH), 7.45 (d, 1H), 7.15 (d, 1H), 4.21 (qrt, 2H), 4.15 (m, 1H), 3.95 (m, 1H), 3.25 (dd, 2H), 2.94 (m, 2H), 2.25 (m, 1H), 2.1 (m, 1H), 1.45 (t, 3H), 1.15 (t, 3H), 0.85 (t, 3H).
SLB. Synthesis of2-(7-Bromo-1,8-diethyl-1,3,4,9-tetrahydropyrano~3,4-bJindol-1-yl)acetic acid To a stirred solution of ethyl 2-(7-bromo-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetate (2.8 g, 5 mmol) in dioxane (40 ml) was added lithium hydroxide monohydrate (2.8g, 67 mmol) and water (30 ml). The mixture was stirred at room temperature overnight. It was concentrated under reduced pressure, neutralized with 5%
HCI, extracted with CHZCl2, dried over MgS04, and concentrated. The crude product was recrystallized in dichloromethane/hexane (60 ml/ 20 ml) to give a white solid (980 mg, 53 %). 1H NMR (300 MHz, CDCl3) 8 8.68 (br, NH)), 7.27 (d, 1H), 7.19 (d, 1H), 4.06 (m, 2H), 3.04 (qrt, 2H), 2.95 (qrt, 2H), 2.80 (m, 2H), 2.09 (m, 2H), 1.24 (t, 3H), 0.874 (t, 3H).
SL C. Synthesis of2-(7-Bromo-1,8-diethyl-1,3,4,9-tetrahydropyrano~3,4-bJindol-yl)ethanol To a stirred solution of 2-(7-Bromo-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid (0.87 g, 2.4 mmol) in THF (5 ml), was added dropwise via syringe borane-tetrahydrofuran complex, 1.0 M solution in tetrahydrofuran (3.6 ml, 3.6 mmol) during 30 min. The mixture was stirred at 90 C for 8 hr, cooled, quenched with distilled water and 5 % HCI, extracted with EtOAc. The organic phases collected, washed with brine, dried over MgS04, and evaporated to give a residue which was chromatographed on silica gel. Elution with hexane-EtOAc (l:l) gave the product which was father recrystallized in hexane/dichloromethane to give the product (0.64g, 76 %). 1H
NMR (300 MHz, CDC13) 8 7.91 (b, NH), 7.28 (d, 1H), 7.20 (d, 1H), 4.02 (m, 2H), 3.71 (m, 2H), 2.95 (qrt, 1 H), 2.81 (m, 1 H), 2.75 (t, 1 H), 2.69 (t, 1 H), 2. S 8 (t, 1 H), 2.19 (m, 1 H), 2.04 (m, 2H), 1.26(t, 3H), 0.93 (t, 3H).
COMPOUND 54: 2-(6-BROMO-1-ETHYL-1,3,4,9-TETRAHYDRO-8-ISOPROPYLPYRANO[3,4-B]INDOL-1-YL)ETHANOL
e~
v OOH
w HCI ~ \ HZS04 / \ O Br~
+ CI3CCH(OH)Z + NHZOH HCI ~
NHZ HZO ' NHCOCH=NOH H20 N'_O AcOH, heat NaZS04 H
Br O
O Br CICOCOCI Br COzEt B
\ LiBH4 / \ _Et20 / \ LiBH4 / \ OH BF3-Et20 N~O THF ~ EtOH ~ THF CHZCIZ
H H H H
Br Br Compound \ LiBH4 / \ 54 v O
N O COzEt THF
H ~V H ' ~OH
54.A. Synthesis of 2-(Hydroxyimino)-N (2-isopropylphenyl)acetamide.
In a 2-1 round-bottomed flask are placed water (1000m1), followed by chloral hydrate (49g, 0.30 mol), anhydrous sodium sulfate (225 g), 2-isopropylaniline (50 g, 0.37mo1), concentrated hydrochloric acid (22 ml, 0.26 mol), hydroxylamine hydrochloride (57 g, 0.81 mol). The solution was boiled for 3 hr, cooled, quenched with water, and extracted with ethyl acetate. The extracts were dried over MgS04, and evaporated. The residue was purified by elution from a silica gel column with hexane/ EtOAc (7:3) to afford the product (26.7g, 35%). 1H NMR (300 MHz, CDC13) 8 8.28 (br, NH), 7.88 (dd, 1H ), 7.82 (b, NOH), 7.63 (s, N=CH), 7.24 (m, 3H), 3.04 (m, 1H), 1.27 (d, 6H);
ESI (+) MS m/e = 207 (MH+), ESI (-) MS m/e = 205 (MH-).
54.B. Synthesis of 7-Isopropylindoline-2,3-dione To a stirred solution of concentrated HzS04 (210 ml) and H20 (SOmI), was added over 20 min (26.7 g, 0.13 mol) of 2-(hydroxyimino)-N (2-isopropylphenyl)acetamide. The mixture was stirred at 75°C for 2 hr, cooled and poured onto cracked ice. After standing for 15 min, it was extracted with EtOAc, washed with water, dried over MgS04, and concentrated. Air drying afforded (23.8 g, 97%) of crude product). tH NMR (300 MHz, CDCl3) b 8.15 (b, NH), 7.49 (d, 2H), 7.11 (t, 1H), 2.87(m, 1H), 1.30 (d, 6H);
ESI (+) MS
m/e =190 (MH+), ESI (-) MS m/e = 188 (MH-) 54. C. Synthesis of 5-Bromo-7-isopropylindoline-2,3-dione 7-isopropylindoline-2,3-dione (23.8 g, .12 mol) was added to a stirred solution of glacial acetic acid (700 ml). To this solution was added, via additional funnel bromine (7.8 ml, 0.15mo1) in glacial acetic acid (300m1) during 30 min. After the addition, the combined mixture was stirred at 75°C for 3 hr, cooled, and extracted with EtOAc. The organic extracts were washed with brine, dried over MgS04, and evaporated in vacuo; air dried to give (31.8 g, 94%) of crude product. 1H NMR (300 MHz, CDCl3) b 8.04 (b, NH), 7.59 (dd 2H), 2.84 (m, 1H), 1.31 (d, 6H); ESI (+) MS m/e = 269 (MH+), ESI (-) MS m/e =
267(MH-) 54.D. Synthesis of 5-Bromo-7-isopropyl-1H indole To a stirred solution of 5-bromo-7-isopropylindoline-2,3-dione (45.1 g, .17 mol) in THF ( 275 ml) at room temperature under a nitrogen atmosphere, was added, via syringe, 2.0 M solution of LiBH4/THF ( 215 ml) over 30min. The reaction mixture was stirred at 90° C for 1 hr, cooled, quenched with distilled water and 5% HCI, and extracted with EtOAc. The extracts were washed with brine, dried over MgS04, and concentrated under reduced pressure. The crude product was purified by elution from a silica gel column with hexane/ EtOAc (9:1) to give (14.5g, 36%) of the product. 1H NMR (300 MHz, CDC13) 8 8.18 (b, NH), 7.62 (d, 1 H), 7.21 (t, 1 H), 7.16 (d, 1 H), 6. 51 (dd, 1 H), 3 .20 (m, 1 H), 1.3 8 (d, 6H); ESI (+) MS m/e = 239 (MH+), ESI (-) MS m/e = 237 (MH-) 54.E. Synthesis ofEthyl2-(S-Bromo-7-isopropyl-1H indol-3 yl)-2-oxoacetate A 2.0 M solution of oxalyl dichloride in dichloromethane ( 60 ml, 0.12mo1) was added dropwise during 10 min to a solution of 5-Bromo-7-isopropyl-1H indole (14.5 g, 0.061 mol) in Et20 (220 ml) at room temperature under a nitrogen atmosphere.
The mixture was stirred for 4.5 hr. The Et20 was removed by evaporation and absolute EtOH
(220 ml) was added. The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight. The EtOH was evaporated, and EtOAc was added to the residue and washed with sat. NaHC03 and brine. The organic layers were dried over MgS04, concentrated, and dried under vaccume to give a crude product (13.8 g, 67 %). 1H
NMR (300 MHz, CDCl3) b 8.85 (b, NH), 8.46 (dd, 2H), 7.33 (d, 1H), 4.42 (qrt, 2H), 3.21 (m, 1H), 1.44 (t, 3 H), 1.38 (d, 6H), ESI (+) MS m/e = 339 (MH+), ESI (-) MS
m/e = 337 54.F. Synthesis of 2-(S-Bromo-7-isopropyl-IH indol-3 yl)ethanol. Ethyl 2-(5-bromo-7-isopropyl-1H indol-3-yl)-2-oxoacetate(13.8 g, 0.04mo1) in THF (300 ml) was reduced with 2.0 M solution of LiBH4 in THF (50 ml, 0.1 mol) by refluxing under nitrogen atmosphere for 5 hr, cooled, quenched with distilled water and 5 %
HCI, and extracted with EtOAc. The extracts were washed with brine, dried over MgS04, and concentrated. The crude product was purified by eluting from silica gel with hexane/EtOAc to obtain (4.5 g, 39 %) of product. 1H NMR (300 MHz, CDC13) 8 8.05 (b, NH), 7.59 (d, 1H), 7.17 (d, 1H), 7.10 (d, 1H), 3.89 (t, 2H), 3.18 (m, 1H), 2.98 (t, 2 H), 1.37 (d, 6H); ESI (+) MS m/e = 283 (MH+), ESI (-) MS m/e = 281 (MH-).
54. G. Synthesis ofEthyl2-(6-Bromo-1-ethyl-1,3,4,9-tetrahydro-8-isopropylpyrano(3,4-bJindol-1 yl)acetate To a suspension of 2-(S-bromo-7-isopropyl-1H indol-3-yl)ethanol (4.5 g, 0.016 mol) under nitrogen atmosphere was added boron trifluoride diethyl etherate (2.2 ml, 0.18 mol), followed by dropwise addition of ethyl propionyl acetate (3.4 ml, 0.024 mol) over ten minutes. The mixture was stirred at room temperature for 1.5 hr.
Dichloromethane was added to the mixture and the organic layer was washed with sat. NaHC03 and water, and dried over MgS04. The solvent was concentrated and air dried to give a crude product (6 g, 92%). ESI (+) MS m/e = 409 (MH+), ESI (-) MS m/e = 407 (MH-).
54.F. Synthesisof2-(6-Bromo-1-ethyl-1,3,4,9-tetrahydro-8-isopropylpyrano~3,4-bJindol-1 yl)ethanol To a stirred solution of ethyl 2-(6-bromo-1-ethyl-1,3,4,9-tetrahydro-8-isopropylpyrano[3,4-b]indol-1-yl)acetate (6.0 g, 0.015 mol) in THF (120 ml), was added 2.0 M solution of LiBH~/THF (20 ml, 0.30mo1) via syringe during 30min under a nitrogen atmosphere at room temperature. The mixture was refluxed for 10 hr, cooled, quenched with water and S% HCI, and extracted with EtOAc. The organic phases were combined and washed with brine, dried over MgS04, and evaporated to give a residue, which was chromatographed on silica gel. Elution with hexane-EtOAc (7:3) gave the product (4.3 g, 80 %). 1H NMR (300 MHz, CDC13) b 8.18 (b, NH), 0.92 (t, 3H), 1.35 (d, 6H), 1.98 (m, 3H), 2.19 (m, 1H), 2.54 (t, 1H), 2.75 (m, 2H), 3.17 (m, 1H), 3.71 (t, 1H), 4.03(m, 2H), 7.13 (dd, 1H), 7.45 (d, 1H), 7.96 (b, NH). ESI (+) MS m/e = 367 (MH+), ESI (-) MS m/e =
365 (MH-).
COMPOUND SS: ETHYL 3-(1-ETHYL-1,3,4,9-TETRAHYDRO-1-(2-HYDROXYETHYL)-8-ISOPROPYLPYRANO[3,4-B]INDOL-6-YL)PROPANOATE
Br Compound EtO2C EtO2C Com oun / ~ \ O 54 ~COZEt I / ~ O HZ / ~ O 55 H~~OH Pd(L)n H
N~OH H~OH
SS.A. Synthesis of (E)-ethyl 3-(1-Ethyl-1,3,4,9-tetrahydro-1-(2-hydroxyethyl)-isopropylpyrano~3,4-bJindol-6 yl)acrylate A suspension of Pd(OAc)2 (0.2 g, 0.8 mmol), P(o-tolyl)3 (0.25 g, 0.8 mmol), 2-(6-bromo-1-ethyl-1,3,4,9-tetrahydro-8-isopropylpyrano[3,4-b]indol-1-yl)ethanol (1.5 g, 4.lmmol), triethylamine (1.5 ml, 11 mmol), and ethyl acrylate (l.8ml, 16 mmol) in acetonitrile (45 ml) and stirred under a nitrogen atmosphere at 100' C for 24 hr. The mixture was allowed to cool, quenched with water, worked-up with dichloromethane, and washed with brine. The organic layers were dried over MgS04 and concentrated under reduced pressure. The crude product was chromatographed on silica hexane/EtOAc (6:4) to give the product (0.9 g, 56 %). %). 1H NMR (300 MHz, CDC13) 8 8.07 (br, NH), 7.83 (d, 1H), 7.53 (d, 1H), 7.28 (d, 1H), 6.43 (d, 1H), 4.27 (m, 2H), 4.04 (m, 2H), 3.73 (m, 2H), 3.19 (m, 1 H), 2. 84 (m, 1 ), 2.77 (d, 1 H), 2.52 (br, 1 H), 2.20 (m, 1 H), 2.09 (m, 1 H), 1.92 (m, 1H), 1.38 (d, 6H), 1.35 (t, 3H), 0.95 (t, 3H); ESI (+) MS m/e = 386 (MH+), ESI (-) MS
m/e = 384 (MH-).
SS.B. Synthesis of Ethyl 3-(1-Ethyl-I , 3, 4, 9-tetrahydro-1-(2-hydroxyethyl)-isopropylpyrano~3,4-bJindol-6-yl)propanoate To a suspension of (E)-ethyl 3-(1-ethyl-1,3,4,9-tetrahydro-1-(2-hydroxyethyl)-isopropylpyrano[3,4-b]indol-6-yl)acrylate (0.8 g, 2.3 mmol) in 2% HCl in EtOH
(80 ml) was added palladium on carbon (10%, O.Sg). The mixture was stirred under an atmoshphere of hydrogen (1 am) at room temperature for 24 hr. The catalyst filtered through celite. The filtrate was evaporated at reduced pressure. The residue was neutralized with sat. NaHC03, extracted with EtOAc, and dried over MgS04. The solvent was concentrated under reduced pressure and purified by silica gel flash column chromatography hexane/EtOAc (6:4) to give the product (0.33g, 38%). tH NMR
(300 MHz, CDCl3) 8 7.72 (br, NH), 7.18 (d, 1H), 6.91 (d, 1H), 4.15 (qrt, 2H), 4.02 (m, 2H), 3.70 (m, 2H), 3.17 (m, 1H), 3.04 (t, 2H), 2.83 (m, 1H), 2.68 (m, 3H), 2.18 (m, 1H), 2.05 (m, 1H), 1.96 (m, 2H), 1.36 (d, 6H), 1.26 (t, 3H), 0.94 (t, 3H); ESI (+) MS
m/e = 388 (MFI+), ESI (-) MS m/e = 386 (MH-).
COMPOUND 56: 3-(1-ETHYL-1,3,4,9-TETRAHYDRO-1-(2-HYDROXYETHYL)-$-ISOPROPYLPYRANO[3,4-B]INDOL-6-YL)PROPANOIC ACID
EtOZC Com55und HOzC Compounc LiOH / ~ 56 \ O \ O
N
H OH H/~OH
56.A. Synthesis of 3-(1-Ethyl-1,3,4,9-tetrahydro-1-(2-hydroxyethyl)-8-isopropylpyrano~3,4-bJindol-6 yl)propanoicAcid To a stirred solution of ethyl 3-(1-ethyl-1,3,4,9-tetrahydro-1-(2-hydroxyethyl)-8-isopropylpyrano[3,4-b]indol-6-yl)propanoate (0.28 g, 0.72 mmol) in dioxane (6 ml) was added lithium hydroxide monohydrate (0.18 g, 4.3 mmol) and water (3 ml). The mixture was stirred at room temperature for 8 hr. It was concentrated under reduced pressure, neutralized with 5% HCI, extracted with EtOAc, and dried over MgS04. The solvent concentrated and purified by silica gel flash column chromatography dichloromethane/methanol (8:2) to give the product (0.09 g, 35%). IH NMR (300 MHz, CDCl3) 8 7.77 (br, NH)), 7.19 (d, 1H), 6.91 (d, 1H), 4.04 (m, 2H), 3.68 (m, 2H), 3.16 (m, 1H), 3.06 (t, 2H), 2.85 (m, 1H), 2.74 (m, 3H), 2.18 (m, 1H), 1.98 (m, 3H), 1.35 (d, 6H), 0.94 (t, 3H); ESI (+) MS m/e = 360 (MH+), ESI (-) MS m/e = 358 (MH-).
COMPOUND 57: 3-(1-ETHYL-1,3,4,9-TETRAHYDRO-1-(2-HYDROXYETHYL)-8-ISOPROPYLPYRANO[3,4-B]INDOL-6-YL)PROPAN-1-OL
HOZC Compound HO
56 Compound LAH / ~ 57 \ O ~ ~ \ O
N N
H OH H OH
57.A. Synthesis of 3-(1-ethyl-1, 3, 4, 9-tetrahydro-1-(2-hydroxyethyl)-8-isopropylpyrano~3,4-bJindol-6 yl)propan-1-of A solution of ethyl 3-(1-ethyl-1,3,4,9-tetrahydro-1-(2-hydroxyethyl)-8-isopropylpyrano[3,4-b]indol-6-yl)propanoate(0.18 g, 0.46 mmol) in anhydrous diethyl ether (15 ml) was stirred at room temperature under a nitrogen atmosphere.
LiAlH4 (0.09 g, 2.4 mmol) was slowly added to the solution. The mixture was stirred for 18 hr, quenched with water and 5% HCI, extracted with EtOAc, dried over MgS04, and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography hexane/EtOAc (4:6) twice to give (31 mg) of the product (0.031 g, 20%). 1H NMR (300 MHz, CDCl3) 8 7.70 (br, NH), 7.18 (d, 1H), 6.91 (d, 1H), 4.03 (m, 2H), 3.73 (m, 4H), 3.17 (m, 1H), 2.80 (m, 6H), 2.18 (m, 1H), 1.98 (m, 3H), 1.37 (d, 6H), 1.26 (br, 1H), 0.94 (t, 3H); ESI (+) MS m/e = 346 (MH+), ESI (-) MS m/e =
(MH-).
EXAMPLE 2: BIOLOGICAL DATA
Cox-1 Test compound and/or vehicle is incubated with human platelets (10g/ml) containing the phospholipase inhibitor MLnFP (100 pM) for 15 minutes at 37°C.
Arachidonic acid (100 pM) is then added for a further 15 minute incubation period. The reaction is stopped by addition of 1 N HCl and neutralized with 1N NaOH. PGE2 levels in the supernatant are determined using the Amersham EIA kit. Compounds are screened at pM. Cox assays are described in Chan et al. 1999 JPharmacol Exp Ther. 290:551-560;
and Swinney et al. 1997, JBiol Chem. 272:12393-12398; both incorporated herein by 10 reference.
Cox-2 Cyclooxygenase-2 (human recombinant, expressed in Sf~ cell, Cayman 60122) is used. Test compound and/or vehicle is pre-incubated with 0.11 U cyclooxygenase-2, 1 mM reduced glutathione (GSH), 500 pM phenol and 1 pM hematin for 15 minutes at 1 S 37°C. The reaction is initiated by addition of 0.3 pM arachidonic acid as substrate in Tris-HCl pH 7.7 and terminated after a 5 minute incubation at 37°C by addition of 1N HCI.
Following centrifugation, substrate conversion to PGEZ is measured by an Amersham EIA
kit. Compounds are screened at 10 pM. COX-2 assays are described in Riendeau, D., et al., 1997 Can. J. Physiol. Pharmacol. 75:1088-1095; and Warner, J.D., et al., 1999 Proc.
Natl. Acad. Sci. U.S.A. 96: 7563-7568; both incorporated herein by reference.
Provided below in Table I are exemplary results for COX-1 and COX-2 inhibition by compounds described herein:
TahlP T
.. ~ ".:.
":.."~s ,'"~, Yw, ,: " ;< ...,'.f,".
. ;,~.: '~.~ , '""g~ ', ' . ~>..m~: 7~ ~_ y;",: 's ",~3 , ::. ~:.COX-1 CC1X 1.' : ~;;,": ~ COX 2.
~~ CS(1rn = COX_2~ C50 un -~ : ..~. ~'.
Gom o d ;Y'.. ,K,.. a ,'M~ '~,~nk~ ", ~ K
Y P, ~ ., ,~',r;..., k.. '~Y~~ ,:, I., ''..'.
~ $u , ~. u~"~.'.Y3~;H.,.
~ ~.'.; 3 i., ' .
i " F."- ,;a .a .,s.c,.;-m.., ~ ,."
~o ~
l~T ~v_ Y I ~ition~.
Irihibitlon ~ ~
: - Tnhib / ~ /
~."~~ ~t~~ ~ :' o _ ~::~~M~_~, o~ .~ .' o ~ . ~M ~ ~~. ._ ~~
y ~:.,.
Etodolac >300 -25 >300 -14 1 <10 96 <10 100 27 >300 24 >300 3 35 >300 -69 >300 -10 36 >300 -4 >300 18 :. . x~ .~. ,. . .....y p...,.,.",-~-., ~Com ound ~.~.., .._~ ," COX~ 2~(IC50~COX2 per" COX-1 ~ .C50~ CU:X-1 -.:~ ~- ~ CI ~ ~~~~.-~:_. o v .
No: ' ~~~ ~ 11~ ~ to Iuhib~tion /o Inhibitivon ~
47 68.6 45 >100 78 Inhibition of ~Catenin Inhibition of (3-catenin was measured using a reporter assay based on the assay described in Korinek et al. 1997 Science 275:1784-1787 and employing the reporter plasmid TOPFLASH.
On Day 1, HEK-293 cells (ATCC) were plated in 24-well plates (VWR) at 40,000 cells per well in 450 ~L DMEM + l OX FBS media and incubated overnight at 37°C, $%C02.
On Day 2, TOPFLASH plasmid (Upstate Cell Signaling Solutions, VA), pGL3 control vector (Promega), and a plasmid encoding for constitutively expressed human (3-catenin (Hans Clevers) were separately diluted to 0.1 ~g/~L in TE Buffer.
Transfections were done using FuGene 6 Transfection Reagent (Roche). Transfection mixtures included either 8 ~l of 0.1 ~g/~l pGL3 in 400 ~l serum free media (DMEM, Gibco) and 9.6 ~.1 FuGene, or 8 pl of 0.1 ~g/~1 TOPFLASH and 16 ~1 of 0.1 ~3-catenin plasmid in 400 ~1 serum free media (DMEM, Gibco) and 9.6 ~l FuGene. The transfection mixtures were gently mixed and incubated for 1 S-30 min at room temperature. Fifty ~1 of the appropriate transfection mixture was added dropwise to the 293 cells and the cells incubated overnight at 37°C, 5% CO2.
On Day 3, the compounds to be tested were diluted to 0.25M in dimethylsulfoxide (DMSO). This solution was then used to make a 3X dilution of compound into DMEM +
10% FBS, e.g., 100 ~m to 300 Vim. Two-hundred and fifty ~1 of the 3X diluted compound was added drop-wise to an appropriate well containing 500 ~l of media. This was swirled gently. After mixing, 250 ~1 of the diluted 3X compound was added to another well and the procedure followed until the compound was diluted down three times. Plates were incubated for 24 hrs at 37°C, 5% CO2. Experiments were performed in duplicate.
On Day 4, Luciferase activity was measured using a Promega Steady-Glo~
luciferase assay system (Promega Cat. No. EC251) according to the manufactures instructions. The cells and Glo Lysis buffer were equilibrated to room temperature. Ten mls of Glo Lysis~ Buffer was added to reconstitute the Steady-Glo~ Assay Reagent.
Five hundred ~l of the Glo Lysis Buffer~/Assay Reagent were added to each well. The reaction was incubated for 5 min on a shaker at room temperature. 100 ~1 of lysate was transferred to a white 96-well plate and read on a Tecan (Research Triangle Park, NC) GENios microplate reader, using the luminescence setting.
Inhibition of (3-catenin:TOP flash by some compounds of the invention is shown in Fig. 1.
Cell Cytotoxicity Normal prostate cells (PREC, Cambrex East Rutherford New Jersey), prostate cancer cell line (LNCaP, ATCC), PBL (peripheral blood leukocytes- buffy coat San Diego Blood Bank), and primary CLL cells were incubated for one to two days in RPMI-and 10% FBS (fetal bovine serum). They were plated in 96-well plates at 100,000 cells/well. Titrated concentrations of the compound to be tested were added to the culture medium. The cells were incubated three days at 37° C, S% C02. Viability of the cells was assayed by standard MTT assay. Each drug concentration was done in duplicate.
MTT assay: 10 ~1 of 12 mM 3,[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) (Sigma) was added to each well. The cells were incubated at 37°C, S%
COZ for 4 hours. 100 ~1 of 20% SDS, O.O15M HCl was added to each well and the cells were incubated overnight. The plates were read at absorbance 595nM.
Cytotoxicty results are shown in Table II and Table III.
Table II
.: ._ ~ ....
.gin ~ ~ .- , . ~,- r~ ;~-:, ~a ~.:.~ m ~ t:~ H, ~ ~:..: .
.~°~ ~.,~ ~ .
~~ ~ ~ ;:: .
m.Cnm ound =NCa PREC~ CSOM'',~ C'om oand. ,~M.. L~N.Ca RE.C ~C50~
~P P , ~ PM ~ .> P. . ' ~' <:
.., ~-;
:~ ,..._ ~~ ..
:.N ~ I ' 0~ nm ~°~ riin. :~ ,:. Nio: ~:,I 50 nrri: am;
o.. C5 ~( .. . ) ' (. . , . ) .~ ~ : C ~(-, ) ( ~, ".'s, ~; .~'w "''~.~"-,.~~.," '"~.rF.. ...,.." .,a, ~ , ~. ~'~'."~.
....,.~~-x..,~~..x.°.'r ~~~
. ~..__ < ~.,."" ~ " ' ., ....,.. ":, .., Vii.. ~ . - ,...", , ,..,w . <.., .,..... _ ~ , . _ Etodolac 122 416 37 60 r.~o 1 14 53 '=~' 38 23 7 12 Vim' 39 46 22 163 -: 41 51 . ,..~~
Compound .NCa PREC IC50Compound~~ T3 LNCap w PREC :C50 No. ~TC~-50 ~nm) (nm) - No IC50'(nm) ~nm) ~.... -.:s_ ~. ~_.~ a. ..........3 , ~ ~ ..
28 25 '! 47 9 14 30 100 ~' 51 10 34 20 "~' S5 18 35 68 220 ~° 56 235 36 30 160 '~_~ 57 110 Table III
;..,.w ~.:;: a~.-,rc-~._._ r ~ ~, ~C ~ P$~ . _ ~ CLL ~ '~
B' ~.~ mCom ou-n _~
~ . . P L -N Corii P d LL.~u~~.
ound ~~ ~ . ~ .
~~-.~.
P ~
~~ , a .. , :: . ,.
~.~ ._~ .:
IC50 rIC50 nm ~ w. :-5 ~nm N nin No .~ICSO~ ~I
) ( ) . nm ,v C 0 ( ( ( ) ) .~ .~~ : . . .. , a ~ .~ M " M.: , ~, ~ ~._. , ~~ ~
~
Etodolac 200 350 _35 100 140 27 52 150 -~40 185 36 50 160 ~r47 21 60 Selected analogs were tested and compared in several tumor cell lines and their multidrug-resistant (MDR) sublines. The MDR cell lines used in these experiments have been extensively characterized in the literature and are resistant to several widely used anti-cancer drugs, such as doxorubicin, paclitaxel, etoposide, and others. As shown in Table IV, Table V and Table VI, the selected analogs were found to be about 10-20-fold more potent when compared to Etodolac. In addition, no appreciable loss of activity was observed in the multidrug resistant sub-lines, when compared to the parental cells.
Table IV
--, _ .., m W~~ m~: w. _ , : ~. ,.- ~W . - w., ,M
:Hr 5 ,. Ovarian ~. ~ -Leukemia ~::;
_-.
w- Ovarian ~ -Breast Breast~~ ~,HLeakeimaa~. o :n ~ ..,, '~Com ounil ~ MSS ~ ~ _~.. HL-a P
7 ~ CF-7 L- 0 = MES-SA MCF ~~ M H 6 ~~ ~- :- . ..: ' . ' m~.~. _ :: =,~ , . , - -. ;
No: SA/Dx5 60/ADR
m ~~ , ~. ; , arental = ;~ . ~ ::~-~ mr.;: . arental arental arental ~:.;.~ ....~~~-.
'(p ) :~ resistant ~ ~ ~ (P ) ~~' ) =::resistant ~.. _. ~ : , w . w ~ ).: . .. ~ ~~ = ~ , N., _- . _ _.. _ Etodolac 700 430 ~ 625 >1000 300 550 Table V
_.~.
~, . ._..
.u:: : w~~
m ~~...r Kiilne ~.- ~:Golon ~.~ ~
~:. . ... ~ ~s H.
:~ . Colon Prci 'fate Y ~ Pr -t~ P - tate~>
..;_~ .
Coin ound. . ~ 'n -. os ate s ros ... Luri Colo P
.~~~ g ; .. s .. p .~ HEK -~ HT ,..~ . ~:.
.a ~H.~T ~.
~, -Ul4 P .=: L , a No. ~ A54 SW480 , ~..D .r.H...;
~. T, 5. ,. C3 NC
9.: :~
. p :~
. ... ..
x~ _. ~ _2 ~ ~ ~-.. . ... ~_. ~. m;
~-... .: . . .~ .rt _.. -. ..
w~ . . ~-~ -w 6 2 ~ - ~ . , a-~. . . ~~.
_ _ _ ~ ~ ~ ~w . __ . ~,..
9 .3~-. .. - g ., . _ ~ . _ _ ~ T
. _~ 1 ~ ~
-.
-_s .
Etodolac 900 ' 800 ~'355 195 750 ~'266 240 93 1 23 10 ~ 23 17 30 48 40 11 47 47 ' 26 16 8 25 <20 <20 <20 Table VI
Compoun,d ~RMPI8226 -_~Compound RMP~8226 --No micromolar~ ~ _No micromolar -~ ~~.;
H ~
~
Etodolac 140 55 37 Antiangiogenic Assay To determine the effects of COX inhibitors on angiogenesis in vivo, selective compounds will be tested in the mouse and rat corneal micropocket assay. The mouse corneal neovascularization micropocket model is performed with materials, reagents and procedures essentially as described by Muthukkauppah et al., 1982 J. Natl.
Cancer Inst., 69, 699-708. In this assay, a pellet containing basic fibroblast growth factor (FGF) is implanted into the corneal stroma of the mouse and the newly formed vessels are measured using a slit lamp. In this model, COX-2 is expressed in the endothelial cells of the newly developed blood vessels. The ability of a compound of the invention to inhibit FGF-induced angiogenesis in the mouse will be tested using the above method.
The inhibitory effects of the compounds of the invention in the mouse cornea model will be tested using another angiogenic stimulus, vascular endotherlial growth factor (VEGF).
Cyclin DI
Cyclin D1 Transcript Expression Levels as measured by quantitative PCR assay.
LNCaP cells were cultured at 37° C, 5% C02 for 24 hours untreated or in the presence of R-etodolac (200 ~,M), compound 42 (50 ~,M), compound 36 (100 ~M), or compound 1 (20 ~M) (see Table II for structures). Cells were harvested by trypsinization, washed with PBS, and stored at -80° C. Total cellular RNA was prepared from cell pellets using the RNEasyC~ Mini kit (Qiagen, Inc., Valencia, CA). RNA was quantified by spectrophotometer. Approximately 2 ~g of RNA was used to prepare cDNA using the ThermoScriptTM RT-PCR System (Invitrogen, Carlsbad, CA).
The levels of cyclin Dl transcripts in the cDNA samples were measured using a quantitative PCR (qPCR) assay specific for cyclin D1. The cyclin Dl transcript was amplified using the following primer pair:
Cyclin Dl for: 5'- AATGACCCCGACCGATT-3' (SEQ ID NO:1) Cyclin D1 rev: 5'- GCACAAGAGGCAACGAAG G-3' (SEQ ID N0:2) The cyclin Dl primers are described in a manuscript from Takayasu et al. (2001 Clin. Cancer Res. 7:901-908). All assays were performed in duplicate. All qPCR
assays were performed and analyzed using a Bio-Rad iCycler (Bio-Rad, Hercules, CA).
The levels of cyclin D1 transcripts were normalized for total input cDNA by performing a separate assay to detect the levels of a housekeeping gene (18s) using the following primer pair:
18s for: 5'-CGCCGCTAGAGGTGAAATTC-3' (SEQ ID N0:3) 18s rev: 5'-TTGGCAAATGCTTTCGCTC-3' (SEQ ID N0:4) The samples were normalized for 18s transcript levels using the method of Livak et al. (2001 Methods 25:402-408). The level of cyclin D1 transcripts in the control sample was set to 1. FIG. 2 represents the averaged normalized cyclin D 1 transcripts ~ standard deviation for three independent experiments (two independent experiments for compound 1 ). The data show that compound 42, compound 36, and compound 1 inhibit cyclin D 1 mRNA expression.
Western blot analysis of LNCaP cell lysates from cells treated with R-etodolac, compound 42, compound 36, or compound 1 using a monoclonal antibody specific for Cyclin D 1 (BD Pharmingen) confirmed that the compounds reduced Cyclin D 1 protein expression.
Other Cyclin D proteins have been shown to be dependent on the Wnt/beta-catenin pathway (e.g., cyclin D2- Briata et al. 2003 Mol. Cell 12:1201-11) and would be expected to be affected by the compounds of the invention in a similar way as Cyclin D
1. The inhibition of cyclin D expression by the compounds of the invention can also be used as a biomarker of the efficacy of these compounds.
EXAMPLE 3: DAUDI LYMPHOMA MURINE XENOGRAFT MODEL MICE STUDIES
Materials Male SC>D mice, 6-8 weeks of age, obtained from Simonsen Laboratories, Inc.
(Gilroy, CA) were housed in groups of five.
The Daudi human Burkitt Lymphoma cells were obtained from American Type Culture Collection and were inoculated subcutaneously (l.Ox 107 cells/mouse) on the flanks of SCID mice. After the tumors reached approximately 100 mm3 treatment was initiated.
Body weights and tumor volume of all mice were measured and recorded twice weekly. Tumors were measured in three dimensions and volume calculated using the formula: 4 37rr3. Time for the tumors (days) to grow to 4X and 8X the initial volume at dosing were assessed. Study compounds were administered at 125 or 250 mg/kg/day (M-F) via oral gavage until the end of the study.
Efficacy The efficacy of chlorambucil (2 and 3 mg/kg/d), (R-etodoalc) (400 mg/kg/d) and compound 47 (250 mg/kg/d), compound 26 (250 mg/kg/d), and compound 1 (125 mg/kg/d) against Daudi derived tumors in male SCm mice were studied. R-etodolac and compounds 1, 26 and 47 were prepared in sesame oil. Both chlorambucil (ip, 0.1 ml) and compounds of the invention (per os [p.o.], 0.31m1) were dosed daily (Monday to Friday) for two weeks. SDX-101 (0.31m1) was dosed p.o. daily until the end of the study. Slight body weight loss (<3%) was observed at the beginning of the study in chlorambucil (2 mg/kg/d), compounds 47 and 36 treated groups. However, all treated mice recovered after Day 2 and maintained their weights. There was no body weight loss observed in other treatment groups. At termination of the study, the control group mean tumor volume was 1583 mm3. The mean tumor volume of chlorambucil treated groups were 864 and mm3 with 2 and 3 mg/kg/d chlorambucil treatment, respectively. The mean tumor volume S of R-etodolac and compounds 1, 36 and 47 were 802, 996, 1011, and 1157 mm3 with compounds 47, 36, 1 and R-etodolac treatment, respectively. Analysis of variance (ANOVA) of tumor volume of control and chlorambucil groups on Day 20 showed a p-value of 0.001 and 0.0003 between the control group vs 2 and 3 mg/kg/d chlorambucil treated groups, respectively. ANOVA also showed a p-value of 0.007 and 0.03 between the control group vs compound 47 and compound groups, respectively. At termination of the study, tumor samples along with liver, kidney, and spleen samples from each group were collected and fixed in 10% buffered formalin for histopathology.
Histological analysis of all liver, spleen and kidney tissues indicated that all tissues appeared normal.
Table VII shows the time for the tumors to grow to 4X and 8X the initial volume when mice were administered chlorambucil, R-etodolac and compounds 1, 36 and 47.
These data indicate that the compounds of the invention inhibit tumor growth in the Daudi mouse model.
Table VII
.Grou -: 4X Growth (d __.w~' 8X Growth d) _ 8.9 14.5 Control Chlorambucil 16 21 R-etodolac 11 17 Compound 47 16 21.5 Compound 1 15.8 21.1 Com ound 36 13.5 20.8 All patents and documents referenced herein are incorporated by reference.
The invention is not limited to those embodiments described herein, but may encompass modification and variations which do not depart from the spirit of the invention. While the invention has been described in connection with specific embodiments thereof, those of ordinary skill in the art will understand that further modifications are within the scope of the following claims. In addition, where features or aspects of the invention are described in terms of Markush groups or other grouping of alternatives, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group or genus, and exclusions of individual members as appropriate.
Indole Derivatives ST25.txt SEQUENCE LISTING
<110> Salmedix, Inc <120> Indole Derivatives <130> 028 <150> us 60/556,599 <151> 2004-03-26 <160> 4 <170> Patentln version 3.3 <210> 1 <211> 17 <212> DNA
<213> artificial sequence <220>
<223> primers <400> 1 aatgaccccg accgatt 17 <210> 2 <211> 19 <212> DNA
<213> artificial sequence <220>
<223> primer <400> 2 gcacaagagg caacgaagg 19 <210> 3 <211> 20 <212> DNA
<213> artificial sequence <220>
<223> primer <400> 3 cgccgctaga ggtgaaattc 20 <210> 4 <211> 19 <212> DNA
<213> artificial sequence <220>
<223> primer <400> 4 ttggcaaatg ctttcgctc 19
12.F. Synthesis of 2-(1-Ethyl-6-isopropyl-8 phenyl-1,3,4,9-tetrahydro-pyrano~3,4-bJindol-1 yl)-ethanol The title compound is prepared in a manner analogous to Example l, except using 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol in step 1.F.
COMPOUND 13: 2-[8-(3-CYANO-PHENYL)-1-ETHYL-6-ISOPROPYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL]-ETHANOL
H
The title compound is prepared in a manner analogous to Example 1, except using 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol and 3-cyanophenylboronic acid in step 1.F.
COMPOUND 14: 2-[8-(S-BROMO-2-METHOXY-PHENYL)-1-ETHYL-6-ISOPROPYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]1NDOL-1-YL]-ETHANOL
The title compound is prepared in a manner analogous to Example 1, except using 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol and 2-bromo-3-methoxyphenylboronic acid in step 1.F.
COMPOUND 15: 2-[1-ETHYL-8-(2-FLUORO-BIPHENYL-4-YL)-6-ISOPROPYL-1,3,4,9 TETRAHYDRO-PYRANO [ 3,4-B] INDOL-1-YL]-ETHANOL
The title compound is prepared in a manner analogous to Example 1, except using 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol and 2-fluorobiphenyl-4-boronic acid in step 1.F.
COMPOUND 1C7: 4-[1-ET'HYL-1-(Z-HYDROXY-ETHYL)-6-ISOPROPYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-8-YL]-BENZOIC ACID
H
The title compound is prepared in a manner analogous to Example 1, except using 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol and 4-carboxylphenylboronic acid in step 1.F.
COMPOUND 17: 3-[1-ETHYL-1-(2-HYDROXY-ETHYL)-6-ISOPROPYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-8-YL]-BENZALDEHYDE
H
The title compound is prepared in a manner analogous to Example 1, except using 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol and 3-formylphenylboronic acid in step 1.F.
COMPOUND 18: 2-[8-(3,S-DIMETHYL-PHENYL)-1-ETHYL-6-ISOPROPYL-1,3,4,9-TETRAHYDRO-PYRANO [3,4-B] INDOL-1-YL]-ETHANOL
H
The title compound is prepared in a manner analogous to Example 1, except using 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol and 3,5-dimethylphenylboronic acid in step 1.F.
COMPOUND 19: 2-(8-DIBENZOFURAN-3-YL-1-ETHYL-6-ISOPROPYL-1,3,4,9-TETRAHYDRO-PYRANO [3,4-B] INDOL-1-YL)-ETHANOL
The title compound is prepared in a manner analogous to Example 1, except using 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol and 4-dibenzofuranboronic acid in step 1.F.
COMPOUND 20: 2-(1-ETHYL-6-ISOPROPYL-8-STYRYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B] INDOL-1-YL)-ETHANOL
20.A. Synthesis of2-(1-Ethyl-6-isopropyl-8-styryl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-ethanol The title compound is prepared according to the following procedure. To solution of 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol (1.0 mmol) in dried acetonitril (10 mL) at under nitrogen is added triethylamine (1.5 mL), tri-o-tolylphosphine (0.4 mmol), styrene (2.0 mmol), and tri(debenzylideneacetone)dipalladiumn (0) (0.1 mmol). The reaction mixture is heated at 90°C (oil bath) overnight. It is quenched with water and extracted with ethyl acetate.
Extracts are dried over magnesium sulfate and concentrated under reduced pressure. The chromatography (silica gel) gives the title compound.
COMPOUND 21: 2-(1-ETHYL-6-ISOPROPYL-8-PHENYLETHYNYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
The title compound is prepared in a manner analogous to Example 20.A, except using phenylacetylene.
COMPOUND 22: (1-ETHYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
H v OOH
The title compound is prepared in a manner analogous to the procedure outlined below:
NHNHz R ~ \ ' \
R~ ~ / + ~ ~ ~ ~ ~ ~ OH + RZCO(CHz)nCOzR ' R~'~ ~ O
N
H H Rz ( Ros \ ~ O R~s \ ~ O
H Rz (CHz)nCOzH ~ H Rz (CHz)nCHzOH
22.A. Synthesis of (I-Ethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-I yl)-acetic acid ethyl ester A mixture of tryptophol (1.612 g, 10 mmol), ethyl propionylacetate (1.730 g, mmol), andp-toluenesulfonic acid monohydrate (0.20 g) in benzene (70 mL) was heated to reflux for 5 hours. It was quenched with ethyl acetate and washed with saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate, evaporated to dryness.
Flash chromatography on silica gel provided 1.943 g (68%) of the title compound as a solid. mp<80 °C. 1H NMR (300 MHz, CDC13) 8 9.06 (br, 1H), 7.50 (d, 1H), 7.36 (d, 1H), 7.14 (t, 1 H), 7.12 (t, 1 H), 4.18 (q, 2H), 4.03 (m, 1 H), 3.94 (m, 1 H), 2.99 (d, 1 H), 2.88 (d, 1H), 2.78 (m, 2H), 2.14 (m, 1H), 2.01 (m, 1H), 1.25 (t, 3H), 0.82 (t, 3H); ESI
(+) MS
m/e=288 (MH+), ESI (-) MS m/e=286 (MH-) 22.B. .Synthesis of (1-Ethyl-1,3,4,9-tetrahydro pyrano(3,4-bJindol-1 yl)-acetic acid To a solution of (1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester (2.50 g, 8.7 mmol) in 1,4-dioxane was added a solution of lithium hydroxide monohydrate (1.50 g, 35.7 mmol) in water (5 mL). The mixture was stirred at room temperature overnight. It was neutralized with 5% HCl solution and extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulfate, and evaporated to dryness. Flash chromatography on silica gel provided 0.954 g (42%) of the title compound as a solid. mp. 135-136 °C. 1H NMR (500 MHz, CDCl3) 8 10.0 (br, 1H), 8. S S (br, 1 H), 7.51 (d, 1 H), 7.34 (d, 1 H), 7.18 (t, 1 H), 7.12 (t, 1 H), 4.12 (m, 1 H), 4.06 (m, 1 H), 3.01 (d, 1 H), 2.99 (d, 1 H), 2.85 (m, 2H), 2.10 (m, 1 H), 2.03 (m, 1 H), 0.86 (t, 3H);
ESI (+) MS m/e=260 (MH+), ESI (-) MS m/e=258 (MII-).
22. C. Synthesis of (1-Ethyl-1, 3, 4, 9-tetrahydro pyrano(3, 4-bJindol-I yl)-ethanol To solution of (1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid (0.52 g, 2.0 mmol) in tetrahydrofuran (10 mL) was added lithium aluminum hydride (0.114 g, 3.0 mmol) in several small portions. The mixture was stirred at room temperature for 6 hours. It was quenched with ethyl acetate carefully and washed with water. The organic layer was dried over magnesium sulfate and evaporated to dryness.
Flash chromatography on silica gel provided 0.389 g (79%) of the title compound as an oil. 'H NMR (500 MHz, CDC13) 8 7.82 (br, 1H), 7.52 (d, 1H), 7.34 (d, 1H), 7.18 (td, 1H), 7.13 (td, 1 H), 4.07 (m, 1 H), 4.01 (m, 1 H), 3 .70 (m, 1 H), 3 .64 (m, 1 H), 2. 89 (m, 1 H), 2.77 (dt, 1 H), 2.71 (br, 1 H), 2.20 (m, 1 H), 2.05 (m, 1 H), 2.00 (m, 1 H), 1.90 (m, 1 H), 0.94 (t, 3H); ESI (+) MS m/e=246 (MH+), ESI (-) MS m/e=244 (MIT-).
1$ COMPOUND 23: 2-(1-ETHYL-6-METHOXY-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
/o / o OH
N
H
23.A. Synthesis of (1-Ethyl-6-methoxy-1, 3, 4, 9-tetrahydro pyrano~3, 4-bJindol-1-yl)-acetic acid ethyl ester The title compound was synthesized in a manner analogous to step 22, using 5-methoxytrypotophol as the 3-indolethanol component in step 22.A. 'H NMR (300 MHz, CDC13) 8 8.93 (br, 1H), 7.25 (d, 1H), 6.95 (d, 1H), 6.90 (dd, 1H), 4.17 (q, 2H), 4.03 (m, 1H), 3.94 (m, 1H), 3.86 (s, 3H), 2.99 (d, 1H), 2.90 (d, 1H), 2.74 (m, 2H), 2.12 (m, 1H), 2.00 (m, 1H), 1.27 (t, 3H), 0.82 (t, 3H); ESI (+) MS m/e=318 (MH+), ESI (-) MS
m/e=316 (MH-).
23.B. Synthesis of (1-Ethyl-6-methoxy-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1-yl)-acetic acid The title compound was synthesized in a manner analogous to step 22, using (1-ethyl-6-methoxy-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the ester component in step 22.B., afforded the title compound as a solid. mp. 169 °C. 1H
NMR (300 MHz, CDC13) 8 8.38 (br, 1H), 7.22 (d, 1H), 6.94 (d, 1H), 6.84 (dd, 1H), 4.08 (m, 2H), 3.85 (s, 3H), 2.97 (m, 2H), 2.81 (m, 2H), 2.02 (m, 2H), 0.85 (t, 3H);
ESI (+) MS
m/e=290 (MH+), ESI (-) MS m/e=288 (MH-).
23. C. Synthesis of 2-(1-Ethyl-6-methoxy-1,3,4,9-tetrahydro pyrano~3,4-bJindol-I yl)-ethanol The title compound was synthesized in a manner analogous to step 22, using ( 1-ethyl-6-methoxy-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid as the carboxylic acid component in step 22.C., afforded the title compound as a solid. 1H NMR
(500 MHz, CDCl3) 8 7.71 (br, 1H), 7.22 (d, 1H), 6.97 (d, 1H), 6.83 (dd, 1H), 4.08 (m, 1H), 4.00 (m, 1H), 3.86 (s, 3H), 3.69 (m, 1H), 3.64 (m, 1H), 2.85 (m, 1H), 2.73 (dt, 1H), 2.19 (m, 1H), 2.05 (br, 1H), 2.03 (m, 1H), 1.98 (m, 1H), 1.89 (m, 1H), 0.93 (t, 3H); ESI (+) MS m/e=276 (MH+), ESI (-) MS m/e=274 (MIi-).
COMPOUND 24: 2-(1-ETHYL-6-METHYL-1,3,4,9-T'ETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
OH
N
H
24.A. Synthesis of 2-(5-Methyl-1H indol-3 yl)-ethanol To a suspension of 4-methylphenylhydrazine hydrochloride (2.50 g, 15.7 mmol) in 1,4-dioxane (25 mL) and water (1.5 mL) was dropped neat 2,3-dihydrofuran (1.66 g, 23.6 mmol). After the addition, the mixture was heated at 95 °C for 4 hours.
After cooling to room temperature, it was poured into ethyl ether, dried over magnesium sulfate, evaporated to dryness. Flash chromatography on silica gel provided 0.485 g (18%) of the title compound as a solid. 1H NMR (500 MHz, CDC13) 6 7.95 (br, 1H), 7.41 (s, 1H), 7.27 (d, 1H), 7.05 (m, 2H), 3.90 (dd, 2H), 3.01 (t, 2H), 2.46 (s, 3H), 1.50 (t, br, 1H).
24.B. Synthesis of (1-Ethyl-6-methyl-1, 3, 4, 9-tetrahydro pyrano~3, 4-bJindol-1 yl)-S acetic acid ethyl ester To a solution of 2-(5-methyl-1H-indol-3-yl)-ethanol (0.48 g, 2.7 mmol) in dichloromethane (10 mL) was added boron trifluoride diethyl etherate (0.468 g, 3.3 mmol), followed by ethyl propionylacetate (0.649 g, 4.5 mmol). The mixture was stirred at room temperature for 5 hours. It was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layer was dried over magnesium sulfate and evaporated to dryness. Flash chromatography on silica gel provided 0.421 g (52%) of the title compound as an oil. 1H NMR (500 MHz, CDC13) b 8.90 (br, 1H), 7.28 (s, 1H), 7.24 (d, 1 H), 6.99 (d, 1 H), 4.16 (m, 2H), 4.03 (m, 1 H), 3.94 (m, 1 H), 2.98 (d, 1 H), 2.88 (d, 1H), 2.80 (m, 1H), 2.73 (m, 1H), 2.44 (s, 3H), 2.12 (m, 1H), 1.98 (m, 1H), 1.25 (t, 3H), 0.80 (t, 3H); ESI (-) MS m/e=300 (MII-).
24. C. Synthesis of (1-Ethyl-6-methyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid The title compound was synthesized in a manner analogous to step 22.B., using (1-ethyl-6-methyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the ester component afforded the title compound as a solid. mp. 158-159 °C.
1H NMR (500 MHz, CDC13) 8 9.70 (br, 1H), 8.33 (br, 1H), 7.29 (s, 1H), 7.22 (d, 1H), 7.00 (d, 1H), 4.10 (m, 1H), 4.05 (m, 1H), 2.99 (d, 1H), 2.98 (d, 1H), 2.81 (q, 2H), 2.44 (s, 3H), 2.07 (m, 1H), 2.01 (m, 1H), 0.85 (t, 3H); ESI (+) MS m/e=274 (MH+), ESI (-) MS m/e=272 (MH-).
24.D. Synthesis of 2-(1-Ethyl-6-methyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1-yl)-ethanol The title compound was synthesized in a manner analogous to step 22.C., using (1-ethyl-6-methyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid as the carboxylic acid component afforded the title compound as a solid. mp. 114-11 S °C.
'H NMR (500 MHz, CDC13) 8 7.70 (br, 1H), 7.30 (s, 1H), 7.21 (d, 1H), 7.00 (dd, 1H), 4.06 (m, 1H), 3.97 (m, 1 H), 3.67 (m, 1 H), 3.62 (m, 1 H), 2.84 (m, 1 H), 2.73 (m, 1 H), 2.71 (br, 1 H), 2.45 (s, 3H), 2.17 (m, 1H), 2.04 (m, 1H), 1.96 (m, 1H), 1.86 (m, 1H), 0.92 (t, 3H); ESI
(+) MS
m/e=260 (MH+), ESI (-) MS m/e=258 (MH-).
COMPOUND 2S: 2-(1-ETHYL-8-METHYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-S ETHANOL
25.A. Synthesis of 2-(7-Methyl-IH indol-3 yl)-ethanol.
Following the procedure of example 24.A. except using 2-methylphenylhydrazine hydrochloride as the hydrazine component afforded the title compound as a solid. 1H
NMR (500 MHz, CDCl3) 8 7.97 (br, 1H), 7.49 (d, 1H), 7.11 (d, 1H), 7.07 (t, 1H), 7.03 (d, 1H), 3.91 (t, 2H and br, 1H), 3.04 (t, 2H), 2.49 (s, 3H).
25.8. Synthesis of (1-Ethyl-8-methyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid ethyl ester.
Following the procedure of example 23.B. except using 2-(7-methyl-1H indol-3-yl)-ethanol as the 3-indolethanol component afforded the title compound as solid. mp. 77-78 °C. 1H NMR (S00 MHz, CDC13) 8 9.04 (br, 1H), 7.36 (d, 1H), 7.02 (t, 1H), 6.97 (d, 1 H), 4.19 (m, 2H), 4.04 (m, 1 H), 3.94 (m, 1 H), 2.98 (d, 1 H), 2.90 (d, 1 H), 2.81 (m, 1 H), 2.75 (dt, 1H), 2.49 (s, 3H), 2.15 (m, 1H), 2.02 (m, 1H), 1.27 (t, 3H), 0.83 (t, 3H); ESI (-) MS m/e=300 (MIA).
25. C. Synthesis of2-(1-Ethyl-8-methyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1-yl)-ethanol.
Following the procedure of example 22.C. except using (1-ethyl-8-methyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the carboxylic acid component afforded the title compound as a solid. mp. 68 °C. 'H NMR
(500 MHz, CDC13) 8 7.68 (br, 1H), 7.37 (d, 1H), 7.05 (t, 1H), 6.98 (d, 1H), 4.06 (m, 1H), 3.98 (m, 1 H), 3.70 (m, 1 H), 3.65 (m, 1 H), 2.88 (m, 1 H), 2.76 (t, 1 H), 2.72 (m, 1 H), 2.47 (s, 3H), 2.21 (m, 1H), 2.07 (m, 1H), 2.00 (m, 1H), 1.91 (m, 1H), 0.94 (t, 3H); ESI (+) MS m/e=260 (MH+), ESI (-) MS m/e=258 (MH-).
COMPOUND 26: 2-(1-ETHYL-8-FLUORO-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
N
H ~~\OH
26.A. Synthesis oft-(7-Fluoro-IH indol-3 yl)-ethanol Following the procedure of example 24.A. except using 2-fluorophenylhydrazine hydrochloride as the hydrazine component afforded the title compound as an oil.
26.B. Synthesis of (1-Ethyl-8 fluoro-1,3,4,9-tetrahydro pyrano(3,4-bJindol-1 yl)-acetic acid ethyl ester Following the procedure of 24.B. except using 2-(7-fluoro-1H indol-3-yl)-ethanol as the 3-indolethanol component afforded the title compound as an oil.
26. C. Synthesis of 2-(1-Ethyl-8 f luoro-1, 3, 4, 9-tetrahydro pyrano~3, 4-bJindol-1-yl)-ethanol Following the procedure of example 22.C. except using (1-ethyl-8-fluoro-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the carboxylic acid component afforded the title compound as a solid. 1H NMR (500 MHz, CDC13) 8 8.18 (br, 1 H), 7.27 (d, 1 H), 7.02 (m, 1 H), 6. 89 (dd, 1 H), 4.07 (m, 1 H), 3 .99 (m, 1 H), 3 .71 (m, 1 H), 3.65 (m, 1 H), 2.8 8 (m, 1 H), 2.78 (dt, 1 H), 2.76 (br, 1 H), 2.22 (m, 1 H), 2.07 (m, 1 H), 1.99 (m, 1H), 1.91 (m, 1H), 0.94 (t, 3H); ESI (+) MS m/e=264 (MH+), ESI (-) MS
m/e=262 (MHO.
COMPOUND 27: 2-(8-CHLORO-1-ETHYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-27.A. Synthesis of 2-(7-Chloro-IH indol-3 yl)-ethanol Following the procedure of 24.A. except using 2-chlorophenylhydrazine hydrochloride as the hydrazine component afforded the title compound as an oil. 1H NMR
(500 MHz, CDC13) 8 8.26 (br, 1H), 7.52 (d, 1H), 7.21 (d, 1H), 7.15 (d, 1H), 7.06 (t, 1H), 3.91 (t, 2H), 3.02 (t, 2H), 1.48 (br, 1H).
27.B. Synthesis of (8-Chloro-1-ethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid ethyl ester Following the procedure of 24.B. except using 2-(7-chloro-1H indol-3-yl)-ethanol as the 3-indolethanol component afforded the title compound as a solid. 1H NMR
(500 MHz, CDC13) ~ 9.28 (br, 1H), 7.39 (d, 1H), 7.16 (d, 1H), 7.02 (t, 1H), 4.18 (m, 2H), 4.05 (m, 1H), 3.94 (m, 1H), 2.98 (d, 1H), 2.88 (d, 1H), 2.82 (m, 1H), 2.75 (dt, 1H), 2.15 (m, 1H), 2.03 (m, 1H), 1.27 (t, 3H), 0.84 (t, 3H); ESI (-) MS m/e=230 (MH-).
27. C. Synthesis of (8-Chloro-1-ethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid Following the procedure of example 22.B. except using (8-chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the ester component afforded the title compound as a solid. 'H NMR (500 MHz, CDC13) b 8.81 (br, 1H), 7.40 (d, 1H), 7.17 (d, 1 H), 7.04 (t, 1 H), 4.09 (m, 1 H), 4.03 (m, 1 H), 3.05 (d, 1 H), 3.02 (d, 1 H), 2.82 (m, 2H), 2.13 (m, 1H), 2.06 (m, 1H), 0.88 (t, 3H); ESI (+) MS m/e=294 (MH+), ESI (-) MS
m/e=292 (MH-).
27.D. Synthesis of2-(8-Chloro-1-ethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1-yl)-ethanol Following the procedure of example 22.C. except using (8-chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid as the carboxylic acid component afforded the title compound as a solid. 1H NMR (500 MHz, CDCl3) 8 8.05 (br, 1H), 7.41 (d, 1H), 7.17 (d, 1 H), 7.05 (t, 1 H), 4.07 (m, 1 H), 4.00 (m, 1 H), 3.72 (m, 1 H), 3.67 (m, 1 H), 2.87 (m, 1 H), 2.76 (dt, 1 H), 2.70 (br, 1 H), 2.23 (m, 1 H), 2.03 (m, 1 H), 1.91 (m, 1 H), 0.94 (t, 3H); ESI (+) MS m/e=280 (MH+), ESI (-) MS m/e=278 (MH-).
COMPOUND 28: 2-(8-BROMO-1-ETHYL-1,3,4,9-TETRa,HYDRO-PYRANO[3,4-B]arDOL-1-YL)-ETHANOL
i O
\ N OH
H
Br 28.A. Synthesis of 2-(7-Bromo-IH indol-3 yl)-ethanol Following the procedure of example 24.A. except using 2-bromophenylhydrazine hydrochloride as the hydrazine component afforded the title compound as an oil.
28.B. Synthesis of (8-Bromo-1-ethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid ethyl ester Following the procedure of 24.B. except using 2-(7-bromo-1H indol-3-yl)-ethanol as the 3-indolethanol component afforded the title compound as an oil.
28. C. Synthesis of2-(8-Bromo-1-ethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1-yl)-ethanol To a solution of (8-bromo-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester (1.03 g, 2.8 mmol) in tetrahydrofuran at room temperature was added 2.0 M solution of lithium borohydride in tetrahydrofuran. The mixture was heated to reflux for 5 hours. It was quenched with 5% HCl solution, followed by saturated sodium bicarbonate. It was extracted with ethyl acetate, extracts were dried over magnesium sulfate, and it was evaporated to dryness. Crystallization with diethyl ether afforded 0.682 g (75%) of the title compound as a solid. 'H NMR (500 MHz, CDC13) 8 8.01 (br, 1H), 7.45 (d, 1 H), 7.32 (d, 1 H), 7.00 (t, 1 H), 4.07 (m, 1 H), 3.99 (m, 1 H), 3.72 (m, 1 H), 3.67 (m, 1 H), 2.87 (m, 1 H), 2.75 (dt, 1 H), 2.68 (dd, 1 H), 2.24 (m, 1 H), 2.08 (m, 1 H), 2.02 (m, 1 H), 1.93 (m, 1H), 0.94 (t, 3H); ESI (+) MS m/e=324 (MH+), ESI (-) MS m/e=322 (MH-).
COMPOUND 29: 2-(8-ETHYL-1-METHYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
N
OH
29.A. Synthesis of 2-(7-Ethyl-IH indol-3 yl)-ethanol Following the procedure of example 24.A. except using 2-ethylphenylhydrazine hydrochloride as the hydrazine component afforded the title compound as a solid. 1H
NMR (500 MHz, CDC13) 8 8.05 (br, 1H), 7.50 (d, 1H), 7.08 (m, 3H), 3.92 (m, 2H), 3.04 (m, 2H), 2.86 (m, 2H), 2.06 (br, 1H), 1.35 (t, 3H); ESI (+) MS m/e=190 (MH+), ESI (-) MS m/e=188 (MIA) 29.B. Synthesis of (8-Ethyl-1-methyl-1,3,4,9-tetrahydro pyrano(3,4-bJindol-1 yl)-acetic acid ethyl ester Following the procedure of example 22.A. except using 2-(7-ethyl-1H indol-3-yl)-ethanol as the 3-indolethanol component and the ethyl acetoacetate as ketone component afforded the title compound as an oil. 1H NMR (500 MHz, CDC13) b 9.16 (br, 1H), 7.35 (d, 1H), 7.01 (m, 2H), 4.17 (m, 2H), 4.02 (m, 2H), 2.85 (m, 6H), 1.57 (t, 3H), 1.36 (t, 3H), 1.29 (t, 3H); ESI (+) MS m/e=302 (MH+), ESI (-) MS m/e=300 (MIA).
29. C. Synthesis of (8-Ethyl-1-methyl-1, 3, 4, 9-tetrahydro pyrano~3, 4-bJindol-I yl)-acetic acid Following the procedure of example l, step (b) except using (8-ethyl-1-methyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the ester component afforded the title compound as a solid. ESI (-) MS m/e=272 (MIA).
29.D. Synthesis of 2-(8-Ethyl-1-methyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1-yl)-ethanol Following the procedure of example 22.C. except using (8-ethyl-1-methyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid as the carboxylic acid component afforded the title compound as a solid. 1H NMR (500 MHz, CDC13) 8 7.74 (br, 1H), 7.37 (d, 1H), 7.09 (m, 1 H), 7.03 (d, 1 H), 4.12 (m, 1 H), 3.98 (m, 1 H), 3.70 (m, 2H), 2.92 (m, 1 H), 2.85 (m, 2H), 2.74 (m, 2H), 2.15 (m, 2H), 1.56 (s, 3H), 1.36 (t, 3H); ESI (+) MS
m/e=282 (MNa+), ESI (-) MS m/e=258 (MIA) COMPOUND 30: 2-(8-ETHYL-1-PROPYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
30.A. Synthesis of (8-Ethyl-1 propyl-1,3,4,9-tetrahydro pyrano(3,4-bJindol-1 yl)-acetic acid ethyl ester Following the procedure of example 1, step (a) except using 2-(7-ethyl-1H
indol-3-yl)-ethanol as the 3-indolethanol component and the ethyl butyrylacetate as ketone component afforded the title compound as a solid. 1H NMR (500 MHz, CDCl3) 8 9.10 (br, 1 H), 7.34 (d, 1 H), 7.03 (m, 2H), 4.17 (m, 2H), 4.02 (m, 1 H), 3.92 (m, 1 H), 2.99 (d, 1 H), 2.84 (m, 3H), 2.73 (dt, 1H), 2.09 (m, 1H), 1.96 (m, 1H), 1.35 (t, 3H), 1.26 (t, 3H), 1.19 (m, 2H), 0.85 (t, 3H); ESI (+) MS m/e=330 (MH+), ESI (-) MS m/e=328 (MH-).
30.B. Synthesis of (8-Ethyl-1 propyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid Following the procedure of example 22.B. except using (8-ethyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the ester component afforded the title compound as a solid.
30. C. Synthesis of 2-(8-Ethyl-1 propyl-1, 3, 4, 9-tetrahydro pyrano~3, 4-bJindol-1-yl)-ethanol Following the procedure of example 22.C. except using (8-ethyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid as the carboxylic acid component afforded the title compound as a solid. 1H NMR (500 MHz, CDC13) 8 7.73 (br, 1H), 7.36 (d, 1H), 7.09 (t, 1 H), 7.02 (m, 1 H), 4.05 (m, 1 H), 4.01 (m, 1 H), 3.72 (m, 1 H), 3.67 (m, 1 H), 2.85 (m, 2H), 2.76 (dt, 1H), 2.68 (br, 1H), 2.20 (m, 1H), 2.09 (m, 1H), 1.90 (m, 2H), 1.48 (m, 1H), 1.36 (t, 3H), 1.32 (m, 1H), 0.91 (t, 3H); ESI (+) MS m/e=288 (MH+), ESI (-) MS
m/e=286 (MH-).
COMPOUND 31: 2-(8-ETHYL-1-ISOPROPYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
i H
OH
31.A. Synthesis of (8-Ethyl-1-isopropyl-1,3,4,9-tetrahydro pyrano(3,4-bJindol-yl)-acetic acid ethyl ester Following the procedure of example 22.A. except using 2-(7-ethyl-1H indol-3-yl)-ethanol as the 3-indolethanol component and ethyl iso-butyrylacetate as ketone component afforded the title compound as a solid.'H NMR (500 MHz, CDCl3) 8 9.12 (br, 1H), 7.36 (d, 1H), 7.07 (m, 2H), 4.13 (m, 3H), 3.81 (m, 1H), 3.04 (q, 2H), 2.87 (m, 3H), 2.66 (m, 1H), 2.56 (m, 1H), 1.37 (t, 3H), 1.25 (t, 3H), 1.05 (d, 3H), 0.69 (d, 3H).
31.B. Synthesis of (8-Ethyl-1-isopropyl-1, 3, 4, 9-tetrahydro pyrano~3, 4-bJindol-1-yl)-acetic acid Following the procedure of example 24.B. except using (8-ethyl-1-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the ester component afforded the title compound as a solid. 1H NMR (500 MHz, CDCl3) 8 9.70 (br, 1H), 8.55 (br, 1 H), 7.3 6 (d, 1 H), 7.07 (dd, 1 H), 7.01 (d, 1 H), 4.18 (m, 1 H), 3.94 (m, 1 H), 3.10 (q, 2H), 2.82 (m, 4H), 2.52 (m, 1H), 1.32 (t, 3H), 1.06 (d, 3H), 0.82 (d, 3H); ESI
(+) MS
m/e=302 (MH+), ESI (-) MS m/e=300 (MH-) 31.C. Synthesis of2-(8-Ethyl-I-isopropyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-ethanol Following the procedure of example 22.C. except using (8-ethyl-1-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid as the carboxylic acid component afforded the title compound as a solid. 1H NMR (500 MHz, CDC13) 8 7.68 (br, 1H), 7.38 (d, 1H), 7.09 (dd, 1H), 7.03 (d, 1H), 4.06 (m, 2H), 3.65 (m, 2H), 2.87 (m, 3H), 2.77 (dt, 1H), 2.68 (br, 1H), 2.32 (m, 1H), 2.23 (m, 1H), 2.05 (m, 1H), 1.35 (t, 3H), 1.05 (d, 3H), 1.00 (d, 3H); ESI (+) MS m/e=288 (MH+), ESI (-) MS m/e=286 (MH-).
COMPOUND 32: 2-(8-Ethyl-1-phenyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol 32.A. Synthesis of (8-Ethyl-I phenyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid ethyl ester S Following the procedure of example 22.A. except using 2-(7-ethyl-1H indol-3-yl)-ethanol as the 3-indolethanol component and ethyl benzoylacetate as ketone component afforded the title compound as a solid.'H NMR (500 MHz, CDC13) 8 10.05 (br, 1H), 7.42 (d, 1H), 7.28 (m, SH), 7.12 (m, 2H), 3.96 (m, 3H), 3.60 (m, 1H), 3.43 (d, 1H), 3.22 (d, 1H), 3.05 (m, 3H), 2.65 (dd, 1H), 1.42 (d, 3H), 1.03 (t, 3H); ESI (-) MS
m/e=362 (MII-).
32.B. Synthesis of (8-Ethyl-1 phenyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid Following the procedure of example 22.B. except using (8-ethyl-1-phenyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the ester component afforded the title compound as a solid.'H NMR (500 MHz, CDCl3) 8 9.25 (br, 1H), 7.41 (d, 1H), 7.31 (m, SH), 7.10 (t, 1 H), 7.06 (d, 1 H), 4.08 (m, 1 H), 3.70 (m, 1 H), 3.42 (d, 1 H), 3.22 (d, 1H), 3.03 (m, 1H), 2.83 (m, 2H), 2.68(m, 1H), 1.33 (t, 3H); ESI (+) MS m/e=358 (MNa+).
ESI (-) MS m/e=334 (MIi-).
32. C. Synthesis of 2-(8-Ethyl-1 phenyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-yl)-ethanol Following the procedure of example 22.C. except using (8-ethyl-1-phenyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid as the carboxylic acid component afforded the title compound as a solid. 1H NMR (500 MHz, CDCl3) 8 8.27 (br, 1H), 7.38 (m, 3H), 7.32 (m, 3H), 7.12 (t, 1 H), 7.08 (d, 1 H), 4.12 (m, 2H), 3.99 (dd, 1 H), 3.61 (ddd, 1 H), 3.01 (m, 1H), 2.94 (q, 2H), 2.61 (m, 2H), 2.47(m, 1H), 1.39 (t, 3H).
COMPOUND 34: [8'-ETHYL-4',9'-DIHYDRO-3'H SPIRO(CYCLOHEXANE-1,1'-PYRANO[3,4-B]INDOL)-4-YL]-METHANOL
34.A. Synthesis of 8'-Ethyl-4 ;9'-dihydro-3'H spiro(cyclohexane-1,1 '-$ pyrano~3,4-bJindole)-4-carboxylic acid ethyl ester Following the procedure of example 24.A. except using 2-(7-ethyl-1H indol-3-yl)-ethanol as the 3-indolethanol component and 4-oxo-cyclohexane carboxylic acid ethyl ester as ketone component afforded the title compound as an oil. ESI (+) MS
m/e=342 (MH+), ESI (-) MS m/e=340 (MH-).
34.B. Synthesis of 8'-Ethyl-4',9'-dihydro-3'H spiro(cyclohexane-1,1 '-pyrano~3,4-bJindole)-4-carboxylic acid Following the procedure of example 22.B. except using 8'-ethyl-4',9'-dihydro-3'H spiro(cyclohexane-1,1'-pyrano[3,4-b]indole)-4-carboxylic acid ethyl ester as the ester component afforded the title compound as a solid. ESI (+) MS m/e=314 (MH+), ESI (-) 1$ MS m/e=312 (MHO.
34. C. Synthesis of (8'-Ethyl-4',9'-dihydro-3 FI spiro(cyclohexane-1,1 '-pyrano~3,4-bJindol)-4 ylJ-methanol Following the procedure of example 22.C. except using 8'-ethyl-4',9'-dihydro-3'H spiro(cyclohexane-1,1'-pyrano[3,4-b]indole)-4-carboxylic acid as the carboxylic acid component afforded the title compound as a solid. 1H NMR ($00 MHz, CDC13) 8 7.$1 (br, 1H), 7.33 (d, 1H), 7.06 (t, 1H), 7.00 (d, 1H), 3.97 (t, 2H), 3.$4 (t, 2H), 2.84 (q, 2H), 2.78 (t, 2H), 2.12 (br, 1 H), 2.09 (m, t, 1 H), 1.69 (m, 4H), 1.60 (m, 1 H), 1. $2 (m, 3H), 1.3 $ (t, 3H); ESI (+) MS m/e=300 (NIH+), ESI (-) MS m/e=298 (MH-).
COMPOUND 3$: R-2-(1,8-DIETHYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-2$ ETHANOL
~~ii~
OH
35.A. Synthesis ofR-2-(1,8-Diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol Following the procedure of example 22, except using R-(1,8-Diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid as the carboxylic acid component in step 22.C. afforded the title compound as a solid. 1H NMR (500 MHz, CDCl3) 8 7.74 (br, 1H), 7.37 (d, 1 H), 7.09 (t, 1 H), 7.03 (d, 1 H), 4.07 (m, 1 H), 3.98 (m, 1 H), 3.68 (m, 2H), 2.86 (m, 3H), 2.76 (dt, 1 H), 2.69 (br, t, 1 H), 2.21 (m, 1 H), 2.07 (m, 1 H), 2.00 (m, 1 H), 1.91 (m, 1H), 1.35 (t, 3H), 0.94 (t, 3H); ESI (+) MS m/e=274 (MH+), ESI (-) MS m/e=272 (MH-).
COMPOUND 36: 2-(1-ETHYL-8-ISOPROPYL-1,3,4,9-TETR.AHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
i \N~ \ ~
H V \OH
36.A. Synthesis of 2-Hydroxyimino-N (2-isopropyl phenyl)-acetamide A mixture of 2-isopropylaniline (4.7 g, 35 mmol), Na2S04 (30.0 g), concentrated hydrochloride (3 mL), chloral hydrate (6.5 g), hydroxylamine hydrochloride (8.00 g) in water (150 mL) was heated at 85 °C for 40 minutes. After cooling to room temperature, it was extracted with ethyl acetate. The extracts were dried over magnesium sulfate and evaporated to dryness. Flash chromatography on silica gel provided 4.357 g (54%) of the title compound as solid.
36.B. Synthesis of 7-Isopropyl-IH indole-2,3-dione To concentrated sulfuric acid at 80 °C was added 2-hydroxyimino-N-(2-isopropyl-phenyl)-acetamide in several small portions over 10 minutes. After addition it was heated at 80 °C for 30 minutes., then poured into ice. Filtration, washing with water, and drying under vacuum over P205 provided 2.974 g (84%) of the title compound as a solid. ESI (-) MS m/e=188 (MH-).
36. C. Synthesis of (7-Isopropyl-IH indol-3 yl)-oxo-acetic acid ethyl ester To a solution of 7-isopropyl-1H-indole-2,3-dione (2.97 g, 15.7 mmol) in tetrahydrofuran (20 mL) was dropped 2.0 M solution of lithium borohydride in tetrahydrofuran (15 mL, 30 mmol). The mixture was heated at 90 °C for 4 hours. It was quenched with 5% HCI, followed by saturated sodium bicarbonate. It was extracted with ethyl acetate. The extracts were dried over magnesium sulfate and evaporated to dryness to provide a crude 7-isopropyl-1H-indole. To a solution of the crude 7-isopropyl-1H-indole in diethyl ether (40 mL) was dropped 2.0 M solution of oxalyl chloride in dichloromethane (15 mL, 30 mmol). After stirring at room temperature for 5 hours, it was evaporated to dryness. Ethanol was added to the residue and it was stirred at room temperature overnight. After the ethanol was evaporated, flash chromatography on silica gel provided 0.972 g (24%) of the title compound as solid. ESI (-) MS m/e=258 (MH-).
36.D. Synthesis of (1-Ethyl-8-isopropyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-yl)-acetic acid ethyl ester To a solution of (7-isopropyl-1H-indol-3-yl)-oxo-acetic acid ethyl ester (0.97 g. 3.7 mmol) in tetrahydrofuran was added 2.0 M solution of lithium borohydride in tetrahydrofuran. The mixture was heated at 90 °C for 5 hours. It was quenched with 5%
HCI, followed by saturated sodium bicarbonate. It was extracted with ethyl acetate. The extracts were dried over magnesium sulfate and evaporated to dryness to provide a crude 2-(7- isopropyl -1H-indol-3-yl)-ethanol. ESI (+) MS m/e=204 (MH+), ESI (-) MS
m/e=202 (MH-).
Following the procedure of example 24.B. except using 2-(7-isopropyl-1H-indol-yl)-ethanol as the 3-indolethanol component afforded the title compound as an oil. ESI (+) MS m/e=330 (MH+), ESI (-) MS m/e=328 (MH-).
36.E. Synthesis of (1-Ethyl-8-isopropyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-yl)-acetic acid Following the procedure of example 22.B. except using (1-ethyl-8-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the ester component afforded the title compound as a solid. mp. 158-159 °C. 1H NMR (500 MHz, CDCl3) S
9.50 (br, 1H), 8.58 (br, 1H), 7.36 (d, 1H), 7.08 (m, 2H), 4.09 (m, 1H), 4.04 (m, 1H), 3.20 S (m, 1 H), 3 .05 (d, 1 H), 3 .02 (d, 1 H), 2.84 (m, 2H), 2.13 (m, 1 H), 2.04 (m, 1 H), 1.3 8 (d, 3H), 1.35 (d, 3H), 0.88 (t, 3H); ESI (+) MS m/e=302 (MH+), ESI (-) MS m/e=300 (MII-) 36.F. Synthesis of 2-(1-Ethyl-8-isopropyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-ethanol Following the procedure of example 22.C. except using (1-ethyl-8-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid as the carboxylic acid component afforded the title compound as a oil. 1H NMR (500 MHz, CDC13) 8 7.78 (br, 1H), 7.36 (d, 1 H), 7.11 (t, 1 H), 7.07 (d, 1 H), 4.07 (m, 1 H), 3.99 (m, 1 H), 3.71 (m, 2H), 3.20 (m, 1 H), 2.90 (m, 1 H), 2.76 (dt, 1 H), 2.65 (br, 1 H), 2.22 (m, 1 H), 2.06 (m, 1 H), 2.03 (m, 1 H), 1.92 (m, 1H), 1.38 (d, 6H), 0.88 (t, 3H); ESI (+) MS m/e=288 (MH+), ESI (-) MS
m/e=286 (MHO
COMPOUND 37: 2-(1-ETHYL-8-TRIFLUOROMETHYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
i F H v \OH
F
F
37.A. Synthesis of 2-Hydroxyimino-N (2-trifluoromethyl phenyl)-acetamide Following the procedure of example 36.A. except using 2-trifluoromethylaniline as the aniline component afforded the title compound as a solid.
37.B. Synthesis of 7-Trifluoromethyl-IH indole-2,3-dione Following the procedure of example 36.B. except using 2-hydroxyimino-N-(2-trifluoromethyl-phenyl)-acetamide as the acetamide component afforded the title compound as a solid. ESI (-) MS m/e=214 (MH-).
37. C. Synthesis of (7-Trifluoromethyl-IH indol-3 yl)-oxo-acetic acid ethyl ester Following the procedure of example 36.C. except using 7-trifluoromethyl-1H-indole-2,3-dione as the dione component afforded the title compound as a solid.
37.D. Synthesis of 2-(1-Ethyl-8-trifluoromethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-ethanol Following the procedure of example 28.C. except using (1-ethyl-8-trifluoromethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the ester component afforded the title compound as a solid. 1H NMR (500 MHz, CDCl3) 8 8.42 (br, 1H), 7.67 (d, 1 H), 7.41 (d, 1 H), 7.18 (t, 1 H), 4.07 (m, 1 H), 4.00 (m, 1 H), 3.71 (m, 2H), 2.89 (m, 1 H), 2.78 (dt, 1H), 2.64 (br, 1H), 2.23 (m, 1H), 2.07 (m, 1H), 2.02 (m, 1H), 1.93 (m, 1H), 0.93 (t, 3H); ESI (+) MS m/e=314 (MH+), ESI (-) MS m/e=312 (MII-).
COMPOUND 38: 2-($-CHLORO-1-ETHYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
38.A. Synthesis of (4-Chloro-1H indol-3 yl)-oxo-acetic acid ethyl ester Following the procedure of example 36.C. except using 4-chloro-1H-indole as the indole component afforded the title compound as a solid.
38.B. Synthesis of S-Chloro-1-ethyl-1, 3, 4, 9-tetrahydro pyrano~3, 4-bJindol-1 yl)-acetic acid ethyl ester Following the procedure of example 36.D. except using (4-chloro-1H-indol-3-yl)-oxo-acetic acid ethyl ester as the ester component afforded the title compound as an oil.
1H NMR (008-08) MS. ESI (+) MS m/e=322 (MH+), ESI (-) MS m/e=320 (MIi-).
38. C. Synthesis of (S-Chloro-1-ethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid Following the procedure of example 22.B except using (5-chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the ester component afforded the title compound as a solid. ESI (+) MS m/e=294 (MH+), ESI (-) MS m/e=292 (MII-).
38.D. Synthesis of 2-(5-Chloro-1-ethyl-1, 3, 4, 9-tetrahydro pyrano~3, 4-bJindol-1-yl)-ethanol Following the procedure of example 22.C. except using (5-chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid as the carboxylic acid component afforded the title compound as a solid. IH NMR (500 MHz, CDC13) 8 8.04 (br, 1H), 7.20 (dd, 1H), 7.04 (m, 2H), 4.05 (m, 1 H), 3.97 (m, 1 H), 3.68 (m, 2H), 3.16 (m, 2H), 2.19 (m, 1 H), 2.04 (m, 1H), 1.98 (m, 1H), 1.89 (m, 1H), 0.92 (t, 3H); ESI (-) MS m/e=278 (MII-).
COMPOUND 39: 2-(1-ETHYL-S-FLUORO-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
39.A. Synthesis of (4-Fluoro-IH indol-3 yl)-oxo-acetic acid ethyl ester Following the procedure of example 36.C. except using 4-fluoro-1H-indole as the indole component afforded the title compound as a solid.
39.B. Synthesis of (1-Ethyl-5 fluoro-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid ethyl ester Following the procedure of example 36.D. except using (4-fluoro-1H-indol-3-yl)-oxo-acetic acid ethyl ester as the ester component afforded the title compound as an oil.
ESI (-) MS m/e=304 (MH-).
39. C. (1-Ethyl-5 fluoro-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid Following the procedure of example 22.B. except using (1-ethyl-5-fluoro-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the ester component afforded the title compound as a solid. 1H NMR (500 MHz, CDC13) ~ 9.70 (br, 1H), 8.75 (br, 1H), 7.06 (m, 2H), 6.73 (dd, 1 H), 4.08 (m, 1 H), 4.04 (m, 1 H), 3.00 (m, 4H), 2.10 (m, 1 H), 2.01 (m, 1H), 0.86 (t, 3H); ESI (+) MS m/e=278 (MH+), ESI (-) MS m/e=276 (MH-).
39.D. Synthesis of 2-(1-Ethyl-5 fluoro-1,3,4,9-tetrahydro pyrano(3,4-bJindol-1-yl)-ethanol Following the procedure of example 22.C. except using (1-ethyl-S-fluoro-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid as the carboxylic acid component afforded the title compound as a solid. 1H NMR (500 MHz, CDC13) 8 7.97 (br, 1H), 7.08 (d, 1H), 7.04 (ddd, 1 H), 6.75 (dd, 1 H), 4.04 (m, 1 H), 3.98 (m, 1 H), 3.67 (m, 2H), 3.04 (m, 1 H), 2.93 (m, 1 H), 2.61 (br, 1 H), 2.19 (m, 1 H), 2.03 (m, 1 H), 2.01 (m, 1 H), 1.
89 (m, 1 H), 0.92 (t, 3H); ESI (+) MS m/e=264 (MH+), ESI (-) MS m/e=262 (MH-) COMPOUND 40: 2-(1-ETHYL-6-FLUORO-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
40.A. Synthesis of (5-Fluoro-IH indol-3 yl)-oxo-acetic acid ethyl ester Following the procedure of example 36.C. except using 5-fluoro-1H-indole as the indole component afforded the title compound as a solid.
40.B. Synthesis of (1-Ethyl-6 fluoro-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1-yl)-acetic acid ethyl ester Following the procedure of example 36.D. except using (5-fluoro-1H-indol-3-yl)-oxo-acetic acid ethyl ester as the ester component afforded the title compound as an oil.
40. C. Synthesis of 2-(1-Ethyl-6 fluoro-1,3,4,9-tetrahydro pyrano~3,4-bJindol-yl)-ethanol Following the procedure of example 22.C. except using (1-ethyl-6-fluoro-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the carboxylic acid component afforded the title compound as a solid. IH NMR (500 MHz, CDC13) 8 7.91 (br, 1 H), 7.22 (dd, 1 H), 7.14 (dd, 1 H), 6.90 (ddd, 1 H), 4.05 (m, 1 H), 4.00 (m, 1 H), 3.68 (m, 2H), 2.71 (dt, 1 H), 2.69 (br, 1 H), 2.18 (m, 1 H), 2.04 (m, 1 H), 1.97 (m, 1 H), 1.89 (m, 1H), 0.92 (t, 3H); ESI (+) MS m/e=264 (MH+), ESI (-) MS m/e=262 (MHO.
S COMPOUND 41: 2-(6-CHLORO-1-ETHYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
ci 41.A. Synthesis of (5-Chloro-IH indol-3 yl)-oxo-acetic acid ethyl ester Following the procedure of example 36.C. except using S-chloro-1H-indole as the indole component afforded the title compound as a solid. 1H NMR(500 MHz, DMSO-d6) 8 12.54 (br, 1H), 8.50 (d, 1H), 8.12 (d, 1H), 7.56 (d, 1H), 7.30 (dd, 1H), 4.36 (q, 2H), 2.48 (t, br, 1H), 1.32 (t, 3H); APCI (-) MS m/e=250 (MH-).
41.B. Synthesis of (6-Chloro-1-ethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid ethyl ester Following the procedure of example 36.D. except using (5-chloro-1H-indol-3-yl)-oxo-acetic acid ethyl ester as the ester component afforded the title compound as an oil.
1H NMR (500 MHz, CDC13) 8 9.18 (br, 1H), 7.46 (d, 1H), 7.26 (d, 1H), 7.11 (dd, 1H), 4.19 (m, 2H), 4.03 (m, 1H), 3.93 (m, 1H), 2.99 (d, 1H), 2.90 (d, 1H), 2.77 (m, 1H), 2.72 (m, 1H), 2.11 (m, 1H), 1.98 (m, 1H), 1.27 (t, 3H), 0.81 (t, 3H); APCI (+) MS
m/e=322 (MH+), APCI (-) MS m/e=320(MH-) 41.C Synthesis of (6-Chloro-1-ethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid Following the procedure of example 22.B. except using (6-chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the ester component afforded the title compound as a solid. 'H NMR (500 MHz, CDCl3) 8 9.50 (br, 1H), 8.68 (br, 1H), 7.46 (s, 1 H), 7.23 (d, 1 H), 7.12 (d, 1 H), 4.09 (m, 1 H), 4.03 (m, 1 H), 3 .03 (d, 1 H), 2.99 (d, 1H), 2.79 (m, 2H), 2.10 (m, 1H), 2.01 (m, 1H), 0.86 (t, 3H); ESI (+) MS
m/e=294 (MH+), ESI (-) MS m/e=292 (MII-).
41.D. Synthesis of2-(6-Chloro-1-ethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1-yl)-ethanol Following the procedure of example 22.C. except using (6-chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid as the carboxylic acid component afforded the title compound as a solid. 1H NMR (S00 MHz, CDCl3) 8 8.01 (br, 1H), 7.46 (s, 1H), 7.22 (d, 1 H), 7.12 (d, 1 H), 4.05 (m, 1 H), 3.99 (m, 1 H), 3.67 (m, 2H), 2.83 (m, 1 H), 2.72 (m, 1H), 2.65 (br, 1H), 2.19 (m, 1H), 2.00 (m, 2H), 1.88 (m, 1H), 0.92 (t, 3H); APCI (+) MS m/e=280 (MH+), APCI (-) MS m/e=278 (MII-) COMPOUND 42: 2-(6-BROMO-1-ET'HYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
Br 42.A. Synthesis of (S-Bromo-1H indol-3 yl)-oxo-acetic acid ethyl ester Following the procedure of example 36, step (c) except using 5-bromo-1H-indole as the indole component afforded the title compound as a solid.
42.B. Synthesis of (6-Bromo-1-ethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid ethyl ester Following the procedure of example 36.B. except using (5-bromo-1H-indol-3-yl)-oxo-acetic acid ethyl ester as the ester component afforded the title compound as an oil.
42. C. Synthesis of 2-(6-Bromo-1-ethyl-1, 3, 4, 9-tetrahydro pyrano~3, 4-bJindol-1-yl)-ethanol Following the procedure of example 28.C. except using (6-bromo-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the ester component afforded the title compound as a solid. 1H NMR (500 MHz, CDC13) b 7.95 (br, 1H), 7.62 (d, 1H), 7.24 (dd, 1 H), 7.19 (d, 1 H), 4.05 (m, 1 H), 3.97 (m, 1 H), 3.67 (m, 2H), 2.
84 (m, 1 H), 2.71 (m, 1 H), 2. 5 5 (br, 1 H), 2.19 (m, 1 H), 2.03 (m, 1 H), 1.97 (m, 1 H), 1. 8 8 (m, 1 H), 0.91 (t, 3H); ESI (+) MS m/e=324 (MH+), ESI (-) MS m/e=322 (MH-).
COMPOUND 43: 2-(1-ETHYL-7-FLUORO-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
43.A. Synthesis of (6-Fluoro-1 H indol-3 yl)-oxo-acetic acid ethyl ester Following the procedure of example 36.C. except using 6-fluoro-1H-indole as the indole component afforded the title compound as a solid. 'H NMR (500 MHz, CDC13) b 8.75 (br, 1H), 8.48 (d, 1H), 8.39 (dd, 1H), 7.12 (m, 2H), 4.41 (q, 2H), 1.43 (t, 3H); ESI (-) MS m/e=234(MI-~).
43.B. Synthesis of (1-Ethyl-7 fluoro-1,3,4,9-tetrahydro pyrano~3,4-bJindol-I
yl)-acetic acid ethyl ester Following the procedure of example 36.D. except using (6-fluoro-1H-indol-3-yl)-oxo-acetic acid ethyl ester as the ester component afforded the title compound as an oil.
43.G Synthesis of (1-Ethyl-7 fluoro-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid Following the procedure of example 22.B. except using (1-ethyl-7-fluoro-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the ester component afforded the title compound as a solid.'H NMR (500 MHz, CDC13) 8 11.8 (br, 1H), 9.53 (br, 1H), 7.29 (dd, 1 H), 6.93 (dd, 1 H), 6.74 (ddd, 1 H), 3.94 (m, 1 H), 3.89 (m, 1 H), 2. 86 (d, 1 H), 2.82 (d, 1H), 2.69 (m, 1H), 2.66 (m, 1H), 2.03 (m, 1H), 1.95 (m, 1H), 0.74 (t, 3H); ESI (+) MS m/e=278 (MH+), ESI (-) MS m/e=276 (MH-) 43.D. Synthesis of 2-(1-Ethyl-7 fluoro-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1-yl)-ethanol Following the procedure of example 22.C. except using (1-ethyl-7-fluoro-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid as the carboxylic acid component afforded the title compound as a solid. 'H NMR (500 MHz, CDC13) b 7.95 (br, 1H), 7.40 (dd, 1H), 7.00 (dd, 1 H), 6.88 (ddd, 1 H), 4.06 (m, 1 H), 3.99 (m, 1 H), 3.65 (m, 2H), 2. 85 (m, 1 H), 2.71 (m, br, 2H), 2.18 (m, 1H), 2.02 (m, 1H), 1.98 (m, 1H), 1.88 (m, 1H), 0.92 (t, 3H); ESI
(+) MS m/e=264 (MH+), ESI (-) MS m/e=262 (MII-) COMPOUND 44: 2-(7-CHLORO-1-ETHYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
r ci \ / \ o H v \OH
44.A. Synthesis of (6-Chloro-IH indol-3 yl)-oxo-acetic acid ethyl ester Following the procedure of example 36.c. except using 6-chloro-1H-indole as the indole component afforded the title compound as a solid. 1H NMR (500 MHz, CDC13) 8 11.50 (br, 1 H), 8.3 0 (d, 1 H), 8.21 (d, 1 H), 7.3 7 (d, 1 H), 7.15 (dd, 1 H), 4.31 (q, 2H), 1.3 3 (t, 3H); ESI (+) MS m/e=252 (MH+), ESI (-) MS m/e=250 (MII-) 44.B. Synthesis of (7-Chloro-1-ethyl-1,3,4,9-tetrahydro pyrano(3,4-bJindol-1 yl)-acetic acid ethyl ester Following the procedure of example 22.D. except using (6-chloro-1H-indol-3-yl)-oxo-acetic acid ethyl ester as the ester component afforded the title compound as an oil.
44.G Synthesis of (7-Chloro-1-ethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid Following the procedure of example 22.B. except using (7-chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the ester component afforded the title compound as a solid. 1H NMR (500 MHz, CDC13) 8 11.80 (br, 1H), 9.57 (br, 1H), 7.30 (d, 1 H), 7.24 (d, 1 H), 6.95 (dd, 1 H), 3.97 (m, 1 H), 3.8 8 (m, 1 H), 2.8 8 (d, 1 H), 2.80 (d, 1 H), 2.71 (m, 1 H), 2.66 (dt, 1 H), 2.04 (m, 1 H), 1.96 (m, 1 H), 0.74 (t, 3H); ESI (+) MS
m/e=294 (MH~, ESI (-) MS m/e=292 (MH-).
44.D. Synthesis of 2-(7-Chloro-1-ethyl-1, 3, 4, 9-tetrahydro pyrano~3, 4-bJindol-1-yl)-ethanol Following the procedure of example 22.C. except using (7-chloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid as the carboxylic acid component afforded the title compound as a solid. 1H NMR (500 MHz, CDC13) 8 8.02 (br, 1H), 7.40 (d, 1H), 7.30 (d, 1H), 7.08 (dd, 1H), 4.05 (m, 1H), 3.99 (m, 1H), 3.66 (m, 2H), 2.73 (dt, 1H), 2.71 (br, 1H), 2.11 (m, 1H), 2.02 (m, 1H), 1.96 (m, 1H), 1.88 (m, 1H), 0.91 (t, 3H); ESI (+) MS
m/e=280 (MH+), ESI (-) MS m/e=278 (MH-) COMPOUND 45: 2-(1-ETHYL-6,S-DIMETHYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]lrrDOL-1-YL)-ETHANOL
45.A. Synthesis of 5,7-Dimethyl-1H indole To solution of 5,7-dimethyl-1H-indole-2,3-dione in tetrahydrofuran at 0 °C was added 1.0 M solution of borane-tetrahydrofuran complex in tetrahydrofuran (40 mL).
After stirred at room temperature overnight, a 5% HCl solution was added to the mixture and it was stirred 20 minutes. It was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate. Extracts were dried over magnesium sulfate and evaporated to dryness to afford the title compound as oil.
45.B. Synthesis of (5, 7-Dimethyl-1H indol-3 yl)-oxo-acetic acid ethyl ester Following the procedure of example 36.C. except using 5,7-dimethyl-1H-indole as the indole component afforded the title compound as a solid. ESI (+) MS
m/e=246 (MH+) 45. C. Synthesis of (1-Ethyl-6, 8-dimethyl-1, 3, 4, 9-tetrahydro pyrano~3, 4-bJindol-1 yl)-acetic acid ethyl ester Following the procedure of example 36.D. except using (5,7-dimethyl-1H-indol-3-yl)-oxo-acetic acid ethyl ester component afforded the title compound as an oil.
45.D. Synthesis of (1-Ethyl-6,8-dimethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid Following the procedure of example 22.B. except using (1-ethyl-6,8-dimethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the ester component afforded the title compound as a solid. 'H NMR (500 MHz, CDC13) 8 9.50 (br, 1H), 8.28 (br, 1H), 7.14 (s, 1H), 6.82 (s, 1H), 4.10 (m, 1H), 4.06 (m, 1H), 3.02 (d, 2H), 3.01 (d, 1H), 2.81 (m, 2H), 2.41 (s, 3H), 2.40 (s, 3H), 2.10 (m, 1H), 2.03 (m, 1H), 0.87 (t, 3H); ESI (+) MS m/e=288 (MH+), ESI (-) MS m/e=286 (MH-).
45.E. Synthesis of 2-(1-Ethyl-6,8-dimethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-ethanol Following the procedure of example 22.C. except using (1-ethyl-6,8-dimethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid as the carboxylic acid component afforded the title compound as a solid. 1H NMR (500 MHz, CDCl3) 8 7.51 (br, 1H), 7.15 (s, 1H), 6.83 (s, 1H), 4.06 (m, 1H), 3.98 (m, 1H), 3.67 (m, 2H), 2.85 (m, 1H), 2.72 (dt, 1H), 2.69 (br, 1H), 2.43 (s, 3H), 2.42 (s, 3H), 2.20 (m, 1H), 2.06 (m, 1H), 2.03 (m, 1H), 1.89 (m, 1H), 0.95 (t, 3H); ESI (+) MS m/e=274 (MH+), ESI (-) MS m/e=272 (MH-) COMPOUND 46: 2-(6,8-DICHLORO-1-ETHYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
a 46.A. Synthesis of S, 7-Dichloro-1 H indole Following the procedure of example 45.A. except using 5,7-dichloro-1H-indole-2,3-dione as the dione component afforded the title compound as a oil.
46.B. Syntehsis of (5,7-Dichloro-IH indol-3 yl)-oxo-acetic acid ethyl ester Following the procedure of example 36.C. except using 5,7-dichloro-1H-indole as the indole component afforded the title compound as a solid.
46. G Synthesis of (6, 8-Dichloro-1-ethyl-1, 3, 4, 9-tetrahydro pyrano~3, 4-bJindol-1 yl)-acetic acid ethyl ester Following the procedure of example 36.D. except using (5,7-dichloro-1H-indol-3-yl)-oxo-acetic acid ethyl ester component afforded the title compound as an oil.
46.D. Synthesis of (6,8-Dichloro-1-ethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid Following the procedure of example 22.B. except using (6,8-dichloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the ester component afforded the title compound as a solid. 1H NMR (500 MHz, CDC13) 8 9.07 (br, 1H), 7.03 (d, 1 H), 6.97 (d, 1 H), 4.07 (m, 1 H), 4.01 (m, 1 H), 3 .15 (t, 2H), 3 .10 (d, 1 H), 3.03 (d, 1 H), 2.15 (m, 1H), 2.05 (m, 1H), 0.88 (t, 3H); ESI (+) MS m/e=328 (MH+), ESI (-) MS
m/e=326 (MH-).
46.E. Synthesis of 2-(6, 8-Dichloro-1-ethyl-1, 3, 4, 9-tetrahydro pyrano~3, 4-bJindol-1-yl)-ethanol Following the procedure of example 22.C. except using (6,8-dichloro-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid as the carboxylic acid component afforded the title compound as a solid. 1H NMR (500 MHz, CDC13) 8 8.25 (br, 1H), 7.03 (d, 1 H), 6.98 (d, 1 H), 4.03 (m, 1 H), 3.99 (m, 1 H), 3.71 (m, 2H), 3.13 (rn, 2H), 2.57 (br, 1H), 2.23 (m, 1H), 2.07 (m, 1H), 2.04 (m, 1H), 1.92 (m, 1H), 0.93 (t, 3H); ESI
(+) MS
m/e=314 (MH+), ESI (-) MS m/e=312 (MII-).
COMPOUND 47: 2-(6-BItOMO-1,8-DIETHYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
47.A. Synthesis of N (4-Bromo-2-ethyl phenyl)-2-hydroxyimino-acetamide Following the procedure of example 36.A. except using 4-bromo-2-ethylaniline as the aniline component afforded the title compound as a solid. ESI (-) MS
m/e=269 (MH-).
S 47.B. Synthesis of 5-Bromo-7-ethyl-1H indole-2,3-dione Following the procedure of example 36.B. except using N-(4-Bromo-2-ethyl-phenyl)-2-hydroxyimino-acetamide as the acetamide component afforded the title compound as a solid. ESI (-) MS m/e=252 (MH-).
47. C. Synthesis of (5-Bromo-7-ethyl-1 H indol-3 yl)-oxo-acetic acid ethyl ester Following the procedure of example 36.C. except using S-Bromo-7-ethyl-1H
indole-2,3-dione as the dione component afforded the title compound as a solid. ESI (+) MS m/e=324 (MH+), ESI (-) MS m/e=322 (MH-).
47.D. Synthesis of (6-Bromo-1,8-diethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-yl)-acetic acid ethyl ester Following the procedure of example 36.D. except using (S-bromo-7-ethyl-1H
indol-3-yl)-oxo-acetic acid ethyl ester as the ester component afforded the title compound as a solid.
47.E. Synthesis of 2-(6-Bromo-1,8-diethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-ethanol Following the procedure of example 28.C. except using (6-bromo-1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as the ester component afforded the title compound as a solid. 1H NMR (500 MHz, CDC13) 8 7.89 (br, 1H), 7.48 (d, 1H), 7.11 (d, 1H), 4.05 (m, 1H), 3.99 (m, 1H), 3.70 (m, 2H), 2.80 (m, 3H), 2.71 (dt, 1H), 2.55 (br, t, 1H), 2.19 (m, 1H), 2.05 (m, 1H), 2.01 (m, 1H), 1.90 (m, 1H), 1.33 (t, 3H), 0.92 (t, 3H); ESI (+) MS m/e=352 (MH+), ESI (-) MS m/e=350 (MH-).
COMPOUND 48: 2-(1,8-DIETHYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-N,N-DIMETHYL-ACETAMIDE
\N/
H ~ ~O
2-( 1, 8-Diethyl-1,3,4, 9-tetrahydro-pyrano [ 3,4-b] indo 1-1-yl)-N,N-dimethyl-acetamide. Following the procedure of example 27 except using dimethylamine as the amine component afforded the title compound as a solid. 1H NMR (500 MHz, CDCl3) 8 9.39 (br, 1H), 7.35 (d, 1H), 7.05 (t, 1H), 6.99 (d, 1H), 6.19 (m, 1H), 4.06 (m, 1H), 3.98 (m, 1H), 2.84 (s, m, 9H), 2.11 (m, 1H), 2.01 (m, 1H), 1.36 (t, 3H), 0.85 (t, 3H);
ESI (-) MS
m/e=299 (MH~).
COMPOUND 49: 2-(9-BENZYL-1,8-DIETHYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
Compound 49 was synthesized according to the following scheme:
/ ~
~ o -(CHZ)nC02H N~(CHZ)nC02H
OH2)nCH
49.A. Synthesis of (9-Benzyl-1,8-diethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-yl)-acetic acid To a solution of (1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid (0.51 g, 1.8 mmol) in tetrahydrofuran at room temperature was added sodium hydride (60% dispersion in mineral oil, 0.4 g). After being heated at 50 °C for 2 hours, benzyl bromide (0.6 g, 3.5 mmol) was added and the solution was stirred for another 2 hours. It was quenched with ethyl acetate and washed with water. The ethyl acetate layer was dried over magnesium sulfate and evaporated to dryness. Flash chromatography on silica gel provided 0.486 g (73%) of the title compound as a solid.'H NMR (500 MHz, CDC13) 8 7.13 (m, 3H), 6.97 (d, 1 H), 6.74 (d, 1 H), 6.68 (t, 1 H), 6.21 (d, 1 H), 3.90 (s, 1 H), 3.63 (m, 1 H), 3.3 5 (td, 1 H), 3.18 (d, 1 H), 3 .00 (d, 1 H), 2.67 (q, 2H), 2.44 (q, 2H), 2.10 (m, 1 H), 1.85 (d, 1H), 1.52 (m, 1H), 1.41 (m, 1H), 1.16 (t, 3H), 0.75 (t, 3H); ESI (+) MS m/e=278 (MH+).
49.B. Synthesis of 2-(9-Benzyl-1,8-diethyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-I yl)-ethanol To a solution of (9-benzyl-1,8-diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid (0.45 g, 1.2 mmol) in tetrahydrofuran at room temperature was added 1.0 M
solution of borane-tetrahydrofuran complex in tetrahydrofuran and it was stirred at 90 °C
for 4 hours. The mixture was quenched with 5% HCl solution and stirred at room temperature for 20 minutes. It was extracted with ethyl acetate and washed with saturated sodium bicarbonate. The extracts were dried over magnesium sulfate and evaporated to dryness. Flash chromatography on silica gel provided 0.321 g (74%) of the title compound as a solid. 1H NMR (500 MHz, CDCl3) 8 7.17 (m, 3H), 6.94 (d, 1H), 6.84 (m, 2H), 6.70 (t, 1 H), 6.56 (d, 1 H), 3.87 (m, 1 H), 3.79 (m, 1 H), 3.68 (dt, 1 H), 3.64 (br, 1 H), 3.41 (td, 1 H), 2.93 (q, 2H), 2.43 (q, 2H), 2.04 (m, 1 H), 1.93 (dt, 1 H), 1.86 (m, 1 H), 1.77 (m, 1 H), 1.49 (m, 1H), 1.38 (m, 1H), 1.17 (t, 3H), 0.70 (t, 3H).
COMPOUND SO: 2-(1,8-DIETHYL-9-METHYL-1,3,4,9-TETRAHYDRO-PYRANO[3,4-B]INDOL-1-YL)-ETHANOL
i - ~ ~ ~oH
SO.A. Synthesis of 2-(1,8-Diethyl-9-methyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-acetic acid Following the procedure of example 49.A. except using (1,8-Diethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid as the indole component afforded the title compound as an oil.
SO.B. Synthesis of 2-(1,8-Diethyl-9-methyl-1,3,4,9-tetrahydro pyrano~3,4-bJindol-1 yl)-ethanol Following the procedure of example 49.B. except using 2-(1,8-diethyl-9-methyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid as the carboxylic acid component afforded the title compound as a solid. 1H NMR (500 MHz, CDCl3) 8 7.35 (dd, 1H), 7.03 (t, 1H), 6.98 (d, 1H), 4.04 (m, 1H), 3.93 (m, 1H), 3.91 (s, 3H), 3.75 (m, 1H), 3.63 (m, 1H), 3.11 (q, 2H), 2.87 (m, 1 H), 2.76 (dt, 1 H), 2.68 (br, 1 H), 2.27 (m, 1 H), 2.22 (m, 1 H), 2.12 (m, 1H), 1.97 (m, 1H), 1.35 (t, 3H), 0.94 (t, 3H); ESI (+) MS m/e=288 (MH+) COMPOUND 51: 2-(7-BROMO-1,8-DIETHYL-1,3,4,9-TETRAHYDROPYRANO[3,4-B]INDOL-1-YL)ETHANOL
v \OH
O .2HBr Br2, CHCI3 I ~ \ LiOH
~ o ~ ~.j ~ COpEt '' I / N~COzEt "60 C Br H
/H
O ~ BHZ
\ \
Br I ~ N COzH ~ Br I ~ H OH
H / THF
90°C
SLA. Synthesis ofEthyl2-(7-bromo-1,8-diethyl-1,3,4,9-tetrahydropyrano~3,4-bJindol-1-yl)acetate.
(R,S)-Etodolac ethyl ester (5 g, 15.8 mmol) was dissolved in chloroform (50 ml) and cooled to -60°C with a dry ice/acetone bath. To this solution was added dropwise a solution of bromine (2.53 g, 15.8 mmol) in chloroform (50 ml) during 2hr.
After the addition, the reaction mixture was allowed to warm to -20'C and triethylamine (5 ml) was added dropwise followed by silica gel (~20 g). The mixture was stirred for 10 min, filtered through silica gel (~10 g), and the filtrate evaporated to dryness.
The crude product was recrystallized in hexane/dichloromethane (60 ml/20 ml) to give (4.5 g g, 72%) of product. 1H NMR (300 MHz, CDC13) 8 9.23 (b, NH), 7.45 (d, 1H), 7.15 (d, 1H), 4.21 (qrt, 2H), 4.15 (m, 1H), 3.95 (m, 1H), 3.25 (dd, 2H), 2.94 (m, 2H), 2.25 (m, 1H), 2.1 (m, 1H), 1.45 (t, 3H), 1.15 (t, 3H), 0.85 (t, 3H).
SLB. Synthesis of2-(7-Bromo-1,8-diethyl-1,3,4,9-tetrahydropyrano~3,4-bJindol-1-yl)acetic acid To a stirred solution of ethyl 2-(7-bromo-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetate (2.8 g, 5 mmol) in dioxane (40 ml) was added lithium hydroxide monohydrate (2.8g, 67 mmol) and water (30 ml). The mixture was stirred at room temperature overnight. It was concentrated under reduced pressure, neutralized with 5%
HCI, extracted with CHZCl2, dried over MgS04, and concentrated. The crude product was recrystallized in dichloromethane/hexane (60 ml/ 20 ml) to give a white solid (980 mg, 53 %). 1H NMR (300 MHz, CDCl3) 8 8.68 (br, NH)), 7.27 (d, 1H), 7.19 (d, 1H), 4.06 (m, 2H), 3.04 (qrt, 2H), 2.95 (qrt, 2H), 2.80 (m, 2H), 2.09 (m, 2H), 1.24 (t, 3H), 0.874 (t, 3H).
SL C. Synthesis of2-(7-Bromo-1,8-diethyl-1,3,4,9-tetrahydropyrano~3,4-bJindol-yl)ethanol To a stirred solution of 2-(7-Bromo-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetic acid (0.87 g, 2.4 mmol) in THF (5 ml), was added dropwise via syringe borane-tetrahydrofuran complex, 1.0 M solution in tetrahydrofuran (3.6 ml, 3.6 mmol) during 30 min. The mixture was stirred at 90 C for 8 hr, cooled, quenched with distilled water and 5 % HCI, extracted with EtOAc. The organic phases collected, washed with brine, dried over MgS04, and evaporated to give a residue which was chromatographed on silica gel. Elution with hexane-EtOAc (l:l) gave the product which was father recrystallized in hexane/dichloromethane to give the product (0.64g, 76 %). 1H
NMR (300 MHz, CDC13) 8 7.91 (b, NH), 7.28 (d, 1H), 7.20 (d, 1H), 4.02 (m, 2H), 3.71 (m, 2H), 2.95 (qrt, 1 H), 2.81 (m, 1 H), 2.75 (t, 1 H), 2.69 (t, 1 H), 2. S 8 (t, 1 H), 2.19 (m, 1 H), 2.04 (m, 2H), 1.26(t, 3H), 0.93 (t, 3H).
COMPOUND 54: 2-(6-BROMO-1-ETHYL-1,3,4,9-TETRAHYDRO-8-ISOPROPYLPYRANO[3,4-B]INDOL-1-YL)ETHANOL
e~
v OOH
w HCI ~ \ HZS04 / \ O Br~
+ CI3CCH(OH)Z + NHZOH HCI ~
NHZ HZO ' NHCOCH=NOH H20 N'_O AcOH, heat NaZS04 H
Br O
O Br CICOCOCI Br COzEt B
\ LiBH4 / \ _Et20 / \ LiBH4 / \ OH BF3-Et20 N~O THF ~ EtOH ~ THF CHZCIZ
H H H H
Br Br Compound \ LiBH4 / \ 54 v O
N O COzEt THF
H ~V H ' ~OH
54.A. Synthesis of 2-(Hydroxyimino)-N (2-isopropylphenyl)acetamide.
In a 2-1 round-bottomed flask are placed water (1000m1), followed by chloral hydrate (49g, 0.30 mol), anhydrous sodium sulfate (225 g), 2-isopropylaniline (50 g, 0.37mo1), concentrated hydrochloric acid (22 ml, 0.26 mol), hydroxylamine hydrochloride (57 g, 0.81 mol). The solution was boiled for 3 hr, cooled, quenched with water, and extracted with ethyl acetate. The extracts were dried over MgS04, and evaporated. The residue was purified by elution from a silica gel column with hexane/ EtOAc (7:3) to afford the product (26.7g, 35%). 1H NMR (300 MHz, CDC13) 8 8.28 (br, NH), 7.88 (dd, 1H ), 7.82 (b, NOH), 7.63 (s, N=CH), 7.24 (m, 3H), 3.04 (m, 1H), 1.27 (d, 6H);
ESI (+) MS m/e = 207 (MH+), ESI (-) MS m/e = 205 (MH-).
54.B. Synthesis of 7-Isopropylindoline-2,3-dione To a stirred solution of concentrated HzS04 (210 ml) and H20 (SOmI), was added over 20 min (26.7 g, 0.13 mol) of 2-(hydroxyimino)-N (2-isopropylphenyl)acetamide. The mixture was stirred at 75°C for 2 hr, cooled and poured onto cracked ice. After standing for 15 min, it was extracted with EtOAc, washed with water, dried over MgS04, and concentrated. Air drying afforded (23.8 g, 97%) of crude product). tH NMR (300 MHz, CDCl3) b 8.15 (b, NH), 7.49 (d, 2H), 7.11 (t, 1H), 2.87(m, 1H), 1.30 (d, 6H);
ESI (+) MS
m/e =190 (MH+), ESI (-) MS m/e = 188 (MH-) 54. C. Synthesis of 5-Bromo-7-isopropylindoline-2,3-dione 7-isopropylindoline-2,3-dione (23.8 g, .12 mol) was added to a stirred solution of glacial acetic acid (700 ml). To this solution was added, via additional funnel bromine (7.8 ml, 0.15mo1) in glacial acetic acid (300m1) during 30 min. After the addition, the combined mixture was stirred at 75°C for 3 hr, cooled, and extracted with EtOAc. The organic extracts were washed with brine, dried over MgS04, and evaporated in vacuo; air dried to give (31.8 g, 94%) of crude product. 1H NMR (300 MHz, CDCl3) b 8.04 (b, NH), 7.59 (dd 2H), 2.84 (m, 1H), 1.31 (d, 6H); ESI (+) MS m/e = 269 (MH+), ESI (-) MS m/e =
267(MH-) 54.D. Synthesis of 5-Bromo-7-isopropyl-1H indole To a stirred solution of 5-bromo-7-isopropylindoline-2,3-dione (45.1 g, .17 mol) in THF ( 275 ml) at room temperature under a nitrogen atmosphere, was added, via syringe, 2.0 M solution of LiBH4/THF ( 215 ml) over 30min. The reaction mixture was stirred at 90° C for 1 hr, cooled, quenched with distilled water and 5% HCI, and extracted with EtOAc. The extracts were washed with brine, dried over MgS04, and concentrated under reduced pressure. The crude product was purified by elution from a silica gel column with hexane/ EtOAc (9:1) to give (14.5g, 36%) of the product. 1H NMR (300 MHz, CDC13) 8 8.18 (b, NH), 7.62 (d, 1 H), 7.21 (t, 1 H), 7.16 (d, 1 H), 6. 51 (dd, 1 H), 3 .20 (m, 1 H), 1.3 8 (d, 6H); ESI (+) MS m/e = 239 (MH+), ESI (-) MS m/e = 237 (MH-) 54.E. Synthesis ofEthyl2-(S-Bromo-7-isopropyl-1H indol-3 yl)-2-oxoacetate A 2.0 M solution of oxalyl dichloride in dichloromethane ( 60 ml, 0.12mo1) was added dropwise during 10 min to a solution of 5-Bromo-7-isopropyl-1H indole (14.5 g, 0.061 mol) in Et20 (220 ml) at room temperature under a nitrogen atmosphere.
The mixture was stirred for 4.5 hr. The Et20 was removed by evaporation and absolute EtOH
(220 ml) was added. The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight. The EtOH was evaporated, and EtOAc was added to the residue and washed with sat. NaHC03 and brine. The organic layers were dried over MgS04, concentrated, and dried under vaccume to give a crude product (13.8 g, 67 %). 1H
NMR (300 MHz, CDCl3) b 8.85 (b, NH), 8.46 (dd, 2H), 7.33 (d, 1H), 4.42 (qrt, 2H), 3.21 (m, 1H), 1.44 (t, 3 H), 1.38 (d, 6H), ESI (+) MS m/e = 339 (MH+), ESI (-) MS
m/e = 337 54.F. Synthesis of 2-(S-Bromo-7-isopropyl-IH indol-3 yl)ethanol. Ethyl 2-(5-bromo-7-isopropyl-1H indol-3-yl)-2-oxoacetate(13.8 g, 0.04mo1) in THF (300 ml) was reduced with 2.0 M solution of LiBH4 in THF (50 ml, 0.1 mol) by refluxing under nitrogen atmosphere for 5 hr, cooled, quenched with distilled water and 5 %
HCI, and extracted with EtOAc. The extracts were washed with brine, dried over MgS04, and concentrated. The crude product was purified by eluting from silica gel with hexane/EtOAc to obtain (4.5 g, 39 %) of product. 1H NMR (300 MHz, CDC13) 8 8.05 (b, NH), 7.59 (d, 1H), 7.17 (d, 1H), 7.10 (d, 1H), 3.89 (t, 2H), 3.18 (m, 1H), 2.98 (t, 2 H), 1.37 (d, 6H); ESI (+) MS m/e = 283 (MH+), ESI (-) MS m/e = 281 (MH-).
54. G. Synthesis ofEthyl2-(6-Bromo-1-ethyl-1,3,4,9-tetrahydro-8-isopropylpyrano(3,4-bJindol-1 yl)acetate To a suspension of 2-(S-bromo-7-isopropyl-1H indol-3-yl)ethanol (4.5 g, 0.016 mol) under nitrogen atmosphere was added boron trifluoride diethyl etherate (2.2 ml, 0.18 mol), followed by dropwise addition of ethyl propionyl acetate (3.4 ml, 0.024 mol) over ten minutes. The mixture was stirred at room temperature for 1.5 hr.
Dichloromethane was added to the mixture and the organic layer was washed with sat. NaHC03 and water, and dried over MgS04. The solvent was concentrated and air dried to give a crude product (6 g, 92%). ESI (+) MS m/e = 409 (MH+), ESI (-) MS m/e = 407 (MH-).
54.F. Synthesisof2-(6-Bromo-1-ethyl-1,3,4,9-tetrahydro-8-isopropylpyrano~3,4-bJindol-1 yl)ethanol To a stirred solution of ethyl 2-(6-bromo-1-ethyl-1,3,4,9-tetrahydro-8-isopropylpyrano[3,4-b]indol-1-yl)acetate (6.0 g, 0.015 mol) in THF (120 ml), was added 2.0 M solution of LiBH~/THF (20 ml, 0.30mo1) via syringe during 30min under a nitrogen atmosphere at room temperature. The mixture was refluxed for 10 hr, cooled, quenched with water and S% HCI, and extracted with EtOAc. The organic phases were combined and washed with brine, dried over MgS04, and evaporated to give a residue, which was chromatographed on silica gel. Elution with hexane-EtOAc (7:3) gave the product (4.3 g, 80 %). 1H NMR (300 MHz, CDC13) b 8.18 (b, NH), 0.92 (t, 3H), 1.35 (d, 6H), 1.98 (m, 3H), 2.19 (m, 1H), 2.54 (t, 1H), 2.75 (m, 2H), 3.17 (m, 1H), 3.71 (t, 1H), 4.03(m, 2H), 7.13 (dd, 1H), 7.45 (d, 1H), 7.96 (b, NH). ESI (+) MS m/e = 367 (MH+), ESI (-) MS m/e =
365 (MH-).
COMPOUND SS: ETHYL 3-(1-ETHYL-1,3,4,9-TETRAHYDRO-1-(2-HYDROXYETHYL)-8-ISOPROPYLPYRANO[3,4-B]INDOL-6-YL)PROPANOATE
Br Compound EtO2C EtO2C Com oun / ~ \ O 54 ~COZEt I / ~ O HZ / ~ O 55 H~~OH Pd(L)n H
N~OH H~OH
SS.A. Synthesis of (E)-ethyl 3-(1-Ethyl-1,3,4,9-tetrahydro-1-(2-hydroxyethyl)-isopropylpyrano~3,4-bJindol-6 yl)acrylate A suspension of Pd(OAc)2 (0.2 g, 0.8 mmol), P(o-tolyl)3 (0.25 g, 0.8 mmol), 2-(6-bromo-1-ethyl-1,3,4,9-tetrahydro-8-isopropylpyrano[3,4-b]indol-1-yl)ethanol (1.5 g, 4.lmmol), triethylamine (1.5 ml, 11 mmol), and ethyl acrylate (l.8ml, 16 mmol) in acetonitrile (45 ml) and stirred under a nitrogen atmosphere at 100' C for 24 hr. The mixture was allowed to cool, quenched with water, worked-up with dichloromethane, and washed with brine. The organic layers were dried over MgS04 and concentrated under reduced pressure. The crude product was chromatographed on silica hexane/EtOAc (6:4) to give the product (0.9 g, 56 %). %). 1H NMR (300 MHz, CDC13) 8 8.07 (br, NH), 7.83 (d, 1H), 7.53 (d, 1H), 7.28 (d, 1H), 6.43 (d, 1H), 4.27 (m, 2H), 4.04 (m, 2H), 3.73 (m, 2H), 3.19 (m, 1 H), 2. 84 (m, 1 ), 2.77 (d, 1 H), 2.52 (br, 1 H), 2.20 (m, 1 H), 2.09 (m, 1 H), 1.92 (m, 1H), 1.38 (d, 6H), 1.35 (t, 3H), 0.95 (t, 3H); ESI (+) MS m/e = 386 (MH+), ESI (-) MS
m/e = 384 (MH-).
SS.B. Synthesis of Ethyl 3-(1-Ethyl-I , 3, 4, 9-tetrahydro-1-(2-hydroxyethyl)-isopropylpyrano~3,4-bJindol-6-yl)propanoate To a suspension of (E)-ethyl 3-(1-ethyl-1,3,4,9-tetrahydro-1-(2-hydroxyethyl)-isopropylpyrano[3,4-b]indol-6-yl)acrylate (0.8 g, 2.3 mmol) in 2% HCl in EtOH
(80 ml) was added palladium on carbon (10%, O.Sg). The mixture was stirred under an atmoshphere of hydrogen (1 am) at room temperature for 24 hr. The catalyst filtered through celite. The filtrate was evaporated at reduced pressure. The residue was neutralized with sat. NaHC03, extracted with EtOAc, and dried over MgS04. The solvent was concentrated under reduced pressure and purified by silica gel flash column chromatography hexane/EtOAc (6:4) to give the product (0.33g, 38%). tH NMR
(300 MHz, CDCl3) 8 7.72 (br, NH), 7.18 (d, 1H), 6.91 (d, 1H), 4.15 (qrt, 2H), 4.02 (m, 2H), 3.70 (m, 2H), 3.17 (m, 1H), 3.04 (t, 2H), 2.83 (m, 1H), 2.68 (m, 3H), 2.18 (m, 1H), 2.05 (m, 1H), 1.96 (m, 2H), 1.36 (d, 6H), 1.26 (t, 3H), 0.94 (t, 3H); ESI (+) MS
m/e = 388 (MFI+), ESI (-) MS m/e = 386 (MH-).
COMPOUND 56: 3-(1-ETHYL-1,3,4,9-TETRAHYDRO-1-(2-HYDROXYETHYL)-$-ISOPROPYLPYRANO[3,4-B]INDOL-6-YL)PROPANOIC ACID
EtOZC Com55und HOzC Compounc LiOH / ~ 56 \ O \ O
N
H OH H/~OH
56.A. Synthesis of 3-(1-Ethyl-1,3,4,9-tetrahydro-1-(2-hydroxyethyl)-8-isopropylpyrano~3,4-bJindol-6 yl)propanoicAcid To a stirred solution of ethyl 3-(1-ethyl-1,3,4,9-tetrahydro-1-(2-hydroxyethyl)-8-isopropylpyrano[3,4-b]indol-6-yl)propanoate (0.28 g, 0.72 mmol) in dioxane (6 ml) was added lithium hydroxide monohydrate (0.18 g, 4.3 mmol) and water (3 ml). The mixture was stirred at room temperature for 8 hr. It was concentrated under reduced pressure, neutralized with 5% HCI, extracted with EtOAc, and dried over MgS04. The solvent concentrated and purified by silica gel flash column chromatography dichloromethane/methanol (8:2) to give the product (0.09 g, 35%). IH NMR (300 MHz, CDCl3) 8 7.77 (br, NH)), 7.19 (d, 1H), 6.91 (d, 1H), 4.04 (m, 2H), 3.68 (m, 2H), 3.16 (m, 1H), 3.06 (t, 2H), 2.85 (m, 1H), 2.74 (m, 3H), 2.18 (m, 1H), 1.98 (m, 3H), 1.35 (d, 6H), 0.94 (t, 3H); ESI (+) MS m/e = 360 (MH+), ESI (-) MS m/e = 358 (MH-).
COMPOUND 57: 3-(1-ETHYL-1,3,4,9-TETRAHYDRO-1-(2-HYDROXYETHYL)-8-ISOPROPYLPYRANO[3,4-B]INDOL-6-YL)PROPAN-1-OL
HOZC Compound HO
56 Compound LAH / ~ 57 \ O ~ ~ \ O
N N
H OH H OH
57.A. Synthesis of 3-(1-ethyl-1, 3, 4, 9-tetrahydro-1-(2-hydroxyethyl)-8-isopropylpyrano~3,4-bJindol-6 yl)propan-1-of A solution of ethyl 3-(1-ethyl-1,3,4,9-tetrahydro-1-(2-hydroxyethyl)-8-isopropylpyrano[3,4-b]indol-6-yl)propanoate(0.18 g, 0.46 mmol) in anhydrous diethyl ether (15 ml) was stirred at room temperature under a nitrogen atmosphere.
LiAlH4 (0.09 g, 2.4 mmol) was slowly added to the solution. The mixture was stirred for 18 hr, quenched with water and 5% HCI, extracted with EtOAc, dried over MgS04, and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography hexane/EtOAc (4:6) twice to give (31 mg) of the product (0.031 g, 20%). 1H NMR (300 MHz, CDCl3) 8 7.70 (br, NH), 7.18 (d, 1H), 6.91 (d, 1H), 4.03 (m, 2H), 3.73 (m, 4H), 3.17 (m, 1H), 2.80 (m, 6H), 2.18 (m, 1H), 1.98 (m, 3H), 1.37 (d, 6H), 1.26 (br, 1H), 0.94 (t, 3H); ESI (+) MS m/e = 346 (MH+), ESI (-) MS m/e =
(MH-).
EXAMPLE 2: BIOLOGICAL DATA
Cox-1 Test compound and/or vehicle is incubated with human platelets (10g/ml) containing the phospholipase inhibitor MLnFP (100 pM) for 15 minutes at 37°C.
Arachidonic acid (100 pM) is then added for a further 15 minute incubation period. The reaction is stopped by addition of 1 N HCl and neutralized with 1N NaOH. PGE2 levels in the supernatant are determined using the Amersham EIA kit. Compounds are screened at pM. Cox assays are described in Chan et al. 1999 JPharmacol Exp Ther. 290:551-560;
and Swinney et al. 1997, JBiol Chem. 272:12393-12398; both incorporated herein by 10 reference.
Cox-2 Cyclooxygenase-2 (human recombinant, expressed in Sf~ cell, Cayman 60122) is used. Test compound and/or vehicle is pre-incubated with 0.11 U cyclooxygenase-2, 1 mM reduced glutathione (GSH), 500 pM phenol and 1 pM hematin for 15 minutes at 1 S 37°C. The reaction is initiated by addition of 0.3 pM arachidonic acid as substrate in Tris-HCl pH 7.7 and terminated after a 5 minute incubation at 37°C by addition of 1N HCI.
Following centrifugation, substrate conversion to PGEZ is measured by an Amersham EIA
kit. Compounds are screened at 10 pM. COX-2 assays are described in Riendeau, D., et al., 1997 Can. J. Physiol. Pharmacol. 75:1088-1095; and Warner, J.D., et al., 1999 Proc.
Natl. Acad. Sci. U.S.A. 96: 7563-7568; both incorporated herein by reference.
Provided below in Table I are exemplary results for COX-1 and COX-2 inhibition by compounds described herein:
TahlP T
.. ~ ".:.
":.."~s ,'"~, Yw, ,: " ;< ...,'.f,".
. ;,~.: '~.~ , '""g~ ', ' . ~>..m~: 7~ ~_ y;",: 's ",~3 , ::. ~:.COX-1 CC1X 1.' : ~;;,": ~ COX 2.
~~ CS(1rn = COX_2~ C50 un -~ : ..~. ~'.
Gom o d ;Y'.. ,K,.. a ,'M~ '~,~nk~ ", ~ K
Y P, ~ ., ,~',r;..., k.. '~Y~~ ,:, I., ''..'.
~ $u , ~. u~"~.'.Y3~;H.,.
~ ~.'.; 3 i., ' .
i " F."- ,;a .a .,s.c,.;-m.., ~ ,."
~o ~
l~T ~v_ Y I ~ition~.
Irihibitlon ~ ~
: - Tnhib / ~ /
~."~~ ~t~~ ~ :' o _ ~::~~M~_~, o~ .~ .' o ~ . ~M ~ ~~. ._ ~~
y ~:.,.
Etodolac >300 -25 >300 -14 1 <10 96 <10 100 27 >300 24 >300 3 35 >300 -69 >300 -10 36 >300 -4 >300 18 :. . x~ .~. ,. . .....y p...,.,.",-~-., ~Com ound ~.~.., .._~ ," COX~ 2~(IC50~COX2 per" COX-1 ~ .C50~ CU:X-1 -.:~ ~- ~ CI ~ ~~~~.-~:_. o v .
No: ' ~~~ ~ 11~ ~ to Iuhib~tion /o Inhibitivon ~
47 68.6 45 >100 78 Inhibition of ~Catenin Inhibition of (3-catenin was measured using a reporter assay based on the assay described in Korinek et al. 1997 Science 275:1784-1787 and employing the reporter plasmid TOPFLASH.
On Day 1, HEK-293 cells (ATCC) were plated in 24-well plates (VWR) at 40,000 cells per well in 450 ~L DMEM + l OX FBS media and incubated overnight at 37°C, $%C02.
On Day 2, TOPFLASH plasmid (Upstate Cell Signaling Solutions, VA), pGL3 control vector (Promega), and a plasmid encoding for constitutively expressed human (3-catenin (Hans Clevers) were separately diluted to 0.1 ~g/~L in TE Buffer.
Transfections were done using FuGene 6 Transfection Reagent (Roche). Transfection mixtures included either 8 ~l of 0.1 ~g/~l pGL3 in 400 ~l serum free media (DMEM, Gibco) and 9.6 ~.1 FuGene, or 8 pl of 0.1 ~g/~1 TOPFLASH and 16 ~1 of 0.1 ~3-catenin plasmid in 400 ~1 serum free media (DMEM, Gibco) and 9.6 ~l FuGene. The transfection mixtures were gently mixed and incubated for 1 S-30 min at room temperature. Fifty ~1 of the appropriate transfection mixture was added dropwise to the 293 cells and the cells incubated overnight at 37°C, 5% CO2.
On Day 3, the compounds to be tested were diluted to 0.25M in dimethylsulfoxide (DMSO). This solution was then used to make a 3X dilution of compound into DMEM +
10% FBS, e.g., 100 ~m to 300 Vim. Two-hundred and fifty ~1 of the 3X diluted compound was added drop-wise to an appropriate well containing 500 ~l of media. This was swirled gently. After mixing, 250 ~1 of the diluted 3X compound was added to another well and the procedure followed until the compound was diluted down three times. Plates were incubated for 24 hrs at 37°C, 5% CO2. Experiments were performed in duplicate.
On Day 4, Luciferase activity was measured using a Promega Steady-Glo~
luciferase assay system (Promega Cat. No. EC251) according to the manufactures instructions. The cells and Glo Lysis buffer were equilibrated to room temperature. Ten mls of Glo Lysis~ Buffer was added to reconstitute the Steady-Glo~ Assay Reagent.
Five hundred ~l of the Glo Lysis Buffer~/Assay Reagent were added to each well. The reaction was incubated for 5 min on a shaker at room temperature. 100 ~1 of lysate was transferred to a white 96-well plate and read on a Tecan (Research Triangle Park, NC) GENios microplate reader, using the luminescence setting.
Inhibition of (3-catenin:TOP flash by some compounds of the invention is shown in Fig. 1.
Cell Cytotoxicity Normal prostate cells (PREC, Cambrex East Rutherford New Jersey), prostate cancer cell line (LNCaP, ATCC), PBL (peripheral blood leukocytes- buffy coat San Diego Blood Bank), and primary CLL cells were incubated for one to two days in RPMI-and 10% FBS (fetal bovine serum). They were plated in 96-well plates at 100,000 cells/well. Titrated concentrations of the compound to be tested were added to the culture medium. The cells were incubated three days at 37° C, S% C02. Viability of the cells was assayed by standard MTT assay. Each drug concentration was done in duplicate.
MTT assay: 10 ~1 of 12 mM 3,[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) (Sigma) was added to each well. The cells were incubated at 37°C, S%
COZ for 4 hours. 100 ~1 of 20% SDS, O.O15M HCl was added to each well and the cells were incubated overnight. The plates were read at absorbance 595nM.
Cytotoxicty results are shown in Table II and Table III.
Table II
.: ._ ~ ....
.gin ~ ~ .- , . ~,- r~ ;~-:, ~a ~.:.~ m ~ t:~ H, ~ ~:..: .
.~°~ ~.,~ ~ .
~~ ~ ~ ;:: .
m.Cnm ound =NCa PREC~ CSOM'',~ C'om oand. ,~M.. L~N.Ca RE.C ~C50~
~P P , ~ PM ~ .> P. . ' ~' <:
.., ~-;
:~ ,..._ ~~ ..
:.N ~ I ' 0~ nm ~°~ riin. :~ ,:. Nio: ~:,I 50 nrri: am;
o.. C5 ~( .. . ) ' (. . , . ) .~ ~ : C ~(-, ) ( ~, ".'s, ~; .~'w "''~.~"-,.~~.," '"~.rF.. ...,.." .,a, ~ , ~. ~'~'."~.
....,.~~-x..,~~..x.°.'r ~~~
. ~..__ < ~.,."" ~ " ' ., ....,.. ":, .., Vii.. ~ . - ,...", , ,..,w . <.., .,..... _ ~ , . _ Etodolac 122 416 37 60 r.~o 1 14 53 '=~' 38 23 7 12 Vim' 39 46 22 163 -: 41 51 . ,..~~
Compound .NCa PREC IC50Compound~~ T3 LNCap w PREC :C50 No. ~TC~-50 ~nm) (nm) - No IC50'(nm) ~nm) ~.... -.:s_ ~. ~_.~ a. ..........3 , ~ ~ ..
28 25 '! 47 9 14 30 100 ~' 51 10 34 20 "~' S5 18 35 68 220 ~° 56 235 36 30 160 '~_~ 57 110 Table III
;..,.w ~.:;: a~.-,rc-~._._ r ~ ~, ~C ~ P$~ . _ ~ CLL ~ '~
B' ~.~ mCom ou-n _~
~ . . P L -N Corii P d LL.~u~~.
ound ~~ ~ . ~ .
~~-.~.
P ~
~~ , a .. , :: . ,.
~.~ ._~ .:
IC50 rIC50 nm ~ w. :-5 ~nm N nin No .~ICSO~ ~I
) ( ) . nm ,v C 0 ( ( ( ) ) .~ .~~ : . . .. , a ~ .~ M " M.: , ~, ~ ~._. , ~~ ~
~
Etodolac 200 350 _35 100 140 27 52 150 -~40 185 36 50 160 ~r47 21 60 Selected analogs were tested and compared in several tumor cell lines and their multidrug-resistant (MDR) sublines. The MDR cell lines used in these experiments have been extensively characterized in the literature and are resistant to several widely used anti-cancer drugs, such as doxorubicin, paclitaxel, etoposide, and others. As shown in Table IV, Table V and Table VI, the selected analogs were found to be about 10-20-fold more potent when compared to Etodolac. In addition, no appreciable loss of activity was observed in the multidrug resistant sub-lines, when compared to the parental cells.
Table IV
--, _ .., m W~~ m~: w. _ , : ~. ,.- ~W . - w., ,M
:Hr 5 ,. Ovarian ~. ~ -Leukemia ~::;
_-.
w- Ovarian ~ -Breast Breast~~ ~,HLeakeimaa~. o :n ~ ..,, '~Com ounil ~ MSS ~ ~ _~.. HL-a P
7 ~ CF-7 L- 0 = MES-SA MCF ~~ M H 6 ~~ ~- :- . ..: ' . ' m~.~. _ :: =,~ , . , - -. ;
No: SA/Dx5 60/ADR
m ~~ , ~. ; , arental = ;~ . ~ ::~-~ mr.;: . arental arental arental ~:.;.~ ....~~~-.
'(p ) :~ resistant ~ ~ ~ (P ) ~~' ) =::resistant ~.. _. ~ : , w . w ~ ).: . .. ~ ~~ = ~ , N., _- . _ _.. _ Etodolac 700 430 ~ 625 >1000 300 550 Table V
_.~.
~, . ._..
.u:: : w~~
m ~~...r Kiilne ~.- ~:Golon ~.~ ~
~:. . ... ~ ~s H.
:~ . Colon Prci 'fate Y ~ Pr -t~ P - tate~>
..;_~ .
Coin ound. . ~ 'n -. os ate s ros ... Luri Colo P
.~~~ g ; .. s .. p .~ HEK -~ HT ,..~ . ~:.
.a ~H.~T ~.
~, -Ul4 P .=: L , a No. ~ A54 SW480 , ~..D .r.H...;
~. T, 5. ,. C3 NC
9.: :~
. p :~
. ... ..
x~ _. ~ _2 ~ ~ ~-.. . ... ~_. ~. m;
~-... .: . . .~ .rt _.. -. ..
w~ . . ~-~ -w 6 2 ~ - ~ . , a-~. . . ~~.
_ _ _ ~ ~ ~ ~w . __ . ~,..
9 .3~-. .. - g ., . _ ~ . _ _ ~ T
. _~ 1 ~ ~
-.
-_s .
Etodolac 900 ' 800 ~'355 195 750 ~'266 240 93 1 23 10 ~ 23 17 30 48 40 11 47 47 ' 26 16 8 25 <20 <20 <20 Table VI
Compoun,d ~RMPI8226 -_~Compound RMP~8226 --No micromolar~ ~ _No micromolar -~ ~~.;
H ~
~
Etodolac 140 55 37 Antiangiogenic Assay To determine the effects of COX inhibitors on angiogenesis in vivo, selective compounds will be tested in the mouse and rat corneal micropocket assay. The mouse corneal neovascularization micropocket model is performed with materials, reagents and procedures essentially as described by Muthukkauppah et al., 1982 J. Natl.
Cancer Inst., 69, 699-708. In this assay, a pellet containing basic fibroblast growth factor (FGF) is implanted into the corneal stroma of the mouse and the newly formed vessels are measured using a slit lamp. In this model, COX-2 is expressed in the endothelial cells of the newly developed blood vessels. The ability of a compound of the invention to inhibit FGF-induced angiogenesis in the mouse will be tested using the above method.
The inhibitory effects of the compounds of the invention in the mouse cornea model will be tested using another angiogenic stimulus, vascular endotherlial growth factor (VEGF).
Cyclin DI
Cyclin D1 Transcript Expression Levels as measured by quantitative PCR assay.
LNCaP cells were cultured at 37° C, 5% C02 for 24 hours untreated or in the presence of R-etodolac (200 ~,M), compound 42 (50 ~,M), compound 36 (100 ~M), or compound 1 (20 ~M) (see Table II for structures). Cells were harvested by trypsinization, washed with PBS, and stored at -80° C. Total cellular RNA was prepared from cell pellets using the RNEasyC~ Mini kit (Qiagen, Inc., Valencia, CA). RNA was quantified by spectrophotometer. Approximately 2 ~g of RNA was used to prepare cDNA using the ThermoScriptTM RT-PCR System (Invitrogen, Carlsbad, CA).
The levels of cyclin Dl transcripts in the cDNA samples were measured using a quantitative PCR (qPCR) assay specific for cyclin D1. The cyclin Dl transcript was amplified using the following primer pair:
Cyclin Dl for: 5'- AATGACCCCGACCGATT-3' (SEQ ID NO:1) Cyclin D1 rev: 5'- GCACAAGAGGCAACGAAG G-3' (SEQ ID N0:2) The cyclin Dl primers are described in a manuscript from Takayasu et al. (2001 Clin. Cancer Res. 7:901-908). All assays were performed in duplicate. All qPCR
assays were performed and analyzed using a Bio-Rad iCycler (Bio-Rad, Hercules, CA).
The levels of cyclin D1 transcripts were normalized for total input cDNA by performing a separate assay to detect the levels of a housekeeping gene (18s) using the following primer pair:
18s for: 5'-CGCCGCTAGAGGTGAAATTC-3' (SEQ ID N0:3) 18s rev: 5'-TTGGCAAATGCTTTCGCTC-3' (SEQ ID N0:4) The samples were normalized for 18s transcript levels using the method of Livak et al. (2001 Methods 25:402-408). The level of cyclin D1 transcripts in the control sample was set to 1. FIG. 2 represents the averaged normalized cyclin D 1 transcripts ~ standard deviation for three independent experiments (two independent experiments for compound 1 ). The data show that compound 42, compound 36, and compound 1 inhibit cyclin D 1 mRNA expression.
Western blot analysis of LNCaP cell lysates from cells treated with R-etodolac, compound 42, compound 36, or compound 1 using a monoclonal antibody specific for Cyclin D 1 (BD Pharmingen) confirmed that the compounds reduced Cyclin D 1 protein expression.
Other Cyclin D proteins have been shown to be dependent on the Wnt/beta-catenin pathway (e.g., cyclin D2- Briata et al. 2003 Mol. Cell 12:1201-11) and would be expected to be affected by the compounds of the invention in a similar way as Cyclin D
1. The inhibition of cyclin D expression by the compounds of the invention can also be used as a biomarker of the efficacy of these compounds.
EXAMPLE 3: DAUDI LYMPHOMA MURINE XENOGRAFT MODEL MICE STUDIES
Materials Male SC>D mice, 6-8 weeks of age, obtained from Simonsen Laboratories, Inc.
(Gilroy, CA) were housed in groups of five.
The Daudi human Burkitt Lymphoma cells were obtained from American Type Culture Collection and were inoculated subcutaneously (l.Ox 107 cells/mouse) on the flanks of SCID mice. After the tumors reached approximately 100 mm3 treatment was initiated.
Body weights and tumor volume of all mice were measured and recorded twice weekly. Tumors were measured in three dimensions and volume calculated using the formula: 4 37rr3. Time for the tumors (days) to grow to 4X and 8X the initial volume at dosing were assessed. Study compounds were administered at 125 or 250 mg/kg/day (M-F) via oral gavage until the end of the study.
Efficacy The efficacy of chlorambucil (2 and 3 mg/kg/d), (R-etodoalc) (400 mg/kg/d) and compound 47 (250 mg/kg/d), compound 26 (250 mg/kg/d), and compound 1 (125 mg/kg/d) against Daudi derived tumors in male SCm mice were studied. R-etodolac and compounds 1, 26 and 47 were prepared in sesame oil. Both chlorambucil (ip, 0.1 ml) and compounds of the invention (per os [p.o.], 0.31m1) were dosed daily (Monday to Friday) for two weeks. SDX-101 (0.31m1) was dosed p.o. daily until the end of the study. Slight body weight loss (<3%) was observed at the beginning of the study in chlorambucil (2 mg/kg/d), compounds 47 and 36 treated groups. However, all treated mice recovered after Day 2 and maintained their weights. There was no body weight loss observed in other treatment groups. At termination of the study, the control group mean tumor volume was 1583 mm3. The mean tumor volume of chlorambucil treated groups were 864 and mm3 with 2 and 3 mg/kg/d chlorambucil treatment, respectively. The mean tumor volume S of R-etodolac and compounds 1, 36 and 47 were 802, 996, 1011, and 1157 mm3 with compounds 47, 36, 1 and R-etodolac treatment, respectively. Analysis of variance (ANOVA) of tumor volume of control and chlorambucil groups on Day 20 showed a p-value of 0.001 and 0.0003 between the control group vs 2 and 3 mg/kg/d chlorambucil treated groups, respectively. ANOVA also showed a p-value of 0.007 and 0.03 between the control group vs compound 47 and compound groups, respectively. At termination of the study, tumor samples along with liver, kidney, and spleen samples from each group were collected and fixed in 10% buffered formalin for histopathology.
Histological analysis of all liver, spleen and kidney tissues indicated that all tissues appeared normal.
Table VII shows the time for the tumors to grow to 4X and 8X the initial volume when mice were administered chlorambucil, R-etodolac and compounds 1, 36 and 47.
These data indicate that the compounds of the invention inhibit tumor growth in the Daudi mouse model.
Table VII
.Grou -: 4X Growth (d __.w~' 8X Growth d) _ 8.9 14.5 Control Chlorambucil 16 21 R-etodolac 11 17 Compound 47 16 21.5 Compound 1 15.8 21.1 Com ound 36 13.5 20.8 All patents and documents referenced herein are incorporated by reference.
The invention is not limited to those embodiments described herein, but may encompass modification and variations which do not depart from the spirit of the invention. While the invention has been described in connection with specific embodiments thereof, those of ordinary skill in the art will understand that further modifications are within the scope of the following claims. In addition, where features or aspects of the invention are described in terms of Markush groups or other grouping of alternatives, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group or genus, and exclusions of individual members as appropriate.
Indole Derivatives ST25.txt SEQUENCE LISTING
<110> Salmedix, Inc <120> Indole Derivatives <130> 028 <150> us 60/556,599 <151> 2004-03-26 <160> 4 <170> Patentln version 3.3 <210> 1 <211> 17 <212> DNA
<213> artificial sequence <220>
<223> primers <400> 1 aatgaccccg accgatt 17 <210> 2 <211> 19 <212> DNA
<213> artificial sequence <220>
<223> primer <400> 2 gcacaagagg caacgaagg 19 <210> 3 <211> 20 <212> DNA
<213> artificial sequence <220>
<223> primer <400> 3 cgccgctaga ggtgaaattc 20 <210> 4 <211> 19 <212> DNA
<213> artificial sequence <220>
<223> primer <400> 4 ttggcaaatg ctttcgctc 19
Claims (68)
1. A compound of Formula I:
wherein:
(a) X is C, S or O;
(b) R1 is hydrogen; halogen; -CN; -OH; -SH; -NO2; or an unsubstituted or substituted moiety selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl, wherein the substituted groups are substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, -CN, -NO2, -OH, -SH, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted heteroalkyl, unsubstituted haloalkyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted heteroaryl, and -(CH2)2CN where z is an integer from 0 to 6;
(c) R2, R3, R4 and R5 are each independently hydrogen; halogen; -CN; -OH; -SH;
NO2; or an unsubstituted or substituted moiety selected from lower alkyl, lower alkynyl, lower alkenyl, alkoxy, haloalkyl, aryl, and heteroaryl;
(d) R6, R8 and R9 are each independently hydrogen; halogen; -CN; -OH; -SH; -NO2;
or an unsubstituted or substituted moiety selected from alkyl, alkenyl, alkynyl, alkoxy, allyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;
(e) R7 is hydrogen; halogen; -CN; -OH; -SH; -NO2; or an unsubstituted or substituted moiety selected from alkyl, alkenyl, and alkynyl.
(f) R10 is hydrogen; or an unsubstituted or substituted moiety selected from lower alkyl, lower alkenyl, lower alkynyl, aryl; heteroaryl, heterocycloalkyl, and cycloalkyl;
(g) Y is an unsubstituted or substituted moiety selected from alkyl, alkenyl, and alkynyl; wherein the substituted moiety is substituted with one, two or three substitutents each independently selected from halogen; -CN; -OH; -SH; -NO2;
unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls; and (h) Z is an unsubstituted moiety selected from -OH, -SH and -OC(O)NH2;
wherein R1 and Y may cyclize to form an unsubstituted or substituted cycloalkyl group or an unsubstituted or substituted heterocycloalkyl group; and wherein:
(i) at least one of R6, R7, R8 and R9 is not hydrogen;
(ii) when R1 is propyl, Y-Z is ethoxy and R9 is fluorine, R6 is not substituted with a -C(O)-heterocycloalkyl group;
(iii) when Y-Z is propoxy and R9 is ethyl, R1 is not CN;
(iv) when R1 is ethyl and R9 is ethyl, Y-Z is not unsubstituted or substituted methoxy or unsubstituted or substituted ethoxy;
(v) when R1 is methyl and R9 is methyl, Y-Z is not methoxy or ethoxy;
(vi) when Y-Z is ethoxy and R9 is ethyl, R1 is not ethoxy; and (vii) when Z is a substituted amide or a substituted amine; R6 is not methyl or chloro; and R7 is not hydroxy, alkoxy-phenyl or methoxy;
or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt thereof.
wherein:
(a) X is C, S or O;
(b) R1 is hydrogen; halogen; -CN; -OH; -SH; -NO2; or an unsubstituted or substituted moiety selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl, wherein the substituted groups are substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, -CN, -NO2, -OH, -SH, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted heteroalkyl, unsubstituted haloalkyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted heteroaryl, and -(CH2)2CN where z is an integer from 0 to 6;
(c) R2, R3, R4 and R5 are each independently hydrogen; halogen; -CN; -OH; -SH;
NO2; or an unsubstituted or substituted moiety selected from lower alkyl, lower alkynyl, lower alkenyl, alkoxy, haloalkyl, aryl, and heteroaryl;
(d) R6, R8 and R9 are each independently hydrogen; halogen; -CN; -OH; -SH; -NO2;
or an unsubstituted or substituted moiety selected from alkyl, alkenyl, alkynyl, alkoxy, allyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;
(e) R7 is hydrogen; halogen; -CN; -OH; -SH; -NO2; or an unsubstituted or substituted moiety selected from alkyl, alkenyl, and alkynyl.
(f) R10 is hydrogen; or an unsubstituted or substituted moiety selected from lower alkyl, lower alkenyl, lower alkynyl, aryl; heteroaryl, heterocycloalkyl, and cycloalkyl;
(g) Y is an unsubstituted or substituted moiety selected from alkyl, alkenyl, and alkynyl; wherein the substituted moiety is substituted with one, two or three substitutents each independently selected from halogen; -CN; -OH; -SH; -NO2;
unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls; and (h) Z is an unsubstituted moiety selected from -OH, -SH and -OC(O)NH2;
wherein R1 and Y may cyclize to form an unsubstituted or substituted cycloalkyl group or an unsubstituted or substituted heterocycloalkyl group; and wherein:
(i) at least one of R6, R7, R8 and R9 is not hydrogen;
(ii) when R1 is propyl, Y-Z is ethoxy and R9 is fluorine, R6 is not substituted with a -C(O)-heterocycloalkyl group;
(iii) when Y-Z is propoxy and R9 is ethyl, R1 is not CN;
(iv) when R1 is ethyl and R9 is ethyl, Y-Z is not unsubstituted or substituted methoxy or unsubstituted or substituted ethoxy;
(v) when R1 is methyl and R9 is methyl, Y-Z is not methoxy or ethoxy;
(vi) when Y-Z is ethoxy and R9 is ethyl, R1 is not ethoxy; and (vii) when Z is a substituted amide or a substituted amine; R6 is not methyl or chloro; and R7 is not hydroxy, alkoxy-phenyl or methoxy;
or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt thereof.
2. A compound or pharmaceutically acceptable salt according to claim 1.
3. A compound or pharmaceutically acceptable salt according to claim 1, wherein the compound has an IC50 of greater than about 100 for at least one of COX-1 or COX-2.
4. A compound according to claim 1, wherein the substituted groups in R2, R3, R4, R5, R6, R7, R8, R9 and R10 are substituted with one, two or three suitable substituents independently selected from the group consisting of: halogens, =O, =S, -CN, -NO2, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2)z CN where z is an integer from 0 to 6, =NH, -NHOH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -OC(O)OC(O)H, -OOH, -C(NH)NH2, -NHC(NH)NH2, -C(S)NH2, -NHC(S)NH2, -NHC(O)NH2, -S(O2)H, -S(O)H, -NH2, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(O)NHC(O)H, -OS(O2)H, -OS(O)H, -OSH, -SC(O)H, -S(O)C(O)OH, -SO2C(O)OH, -NHSH, -NHS(O)H, -NHSO2H, -C(O)SH, -C(O)S(O)H, -C(O)S(O2)H, -C(S)H, -C(S)OH,-C(SO)OH, -C(SO2)OH, -NHC(S)H, -OC(S)H,-OC(S)OH, -OC(SO2)H, -S(O2)NH2, -S(O)NH2, -SNH2,-NHCS(O2)H, -NHC(SO)H, -NHC(S)H, and -SH groups unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, =O, -NO2, -CN, -OH, -SH, -(CH2)z-CN
where z is an integer from 0 to 6, -OR c, -NR c OR c, -NR c R c, -C(O)NR c, -C(O)OR c, -C(O)R c, -NR c C(O)NR c R c, -NR c C(O)R c, -OC(O)OR c, -OC(O)NR c R c, -SR
c, unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls, where R c is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted heteroaryl, or two or more R c groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group.
where z is an integer from 0 to 6, -OR c, -NR c OR c, -NR c R c, -C(O)NR c, -C(O)OR c, -C(O)R c, -NR c C(O)NR c R c, -NR c C(O)R c, -OC(O)OR c, -OC(O)NR c R c, -SR
c, unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls, where R c is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted heteroaryl, or two or more R c groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group.
5. A compound or pharmaceutically acceptable salt according to claim 1, wherein X
is S or O.
is S or O.
6. A compound or pharmaceutically acceptable salt according to claim 1, wherein R1 is hydrogen; or an unsubstituted moiety selected from lower alkyl, lower alkyl-hydroxy, lower alkenyl, lower alkenyl-hydroxy, lower alkynyl, lower alkynyl-hydroxy, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl.
7. A compound or pharmaceutically acceptable salt according to claim 1, wherein R1 cyclizes with Y to from a substituted or unsubstitued cycloalkyl or heterocycloalkyl group.
8. A compound or pharmaceutically acceptable salt according to claim 1, wherein R2, R3, R4 and R5 are each independently hydrogen; or an unsubstituted moiety selected from lower alkyl, lower alkynyl, lower alkenyl, alkoxy, haloalkyl, aryl, and heteroaryl.
9. A compound or pharmaceutically acceptable salt according to claim 1, wherein R2, R3, R4 and R5 are each independently hydrogen.
10. A compound or pharmaceutically acceptable salt according to claim 1, wherein R6, R8 and R9 are each independently hydrogen; or an unsubstituted or substituted moiety selected from alkyl, alkenyl, alkynyl, alkoxy, allyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein at least one of R6, R8 and R9 is not hydrogen.
11. A compound or pharmaceutically acceptable salt according to claim 10, wherein the substituted moieties are each independently selected from the group consisting of halogen, -CN, alkyl, alkoxy, -NH2, -O-haloalkyl, -CH(O), haloalkyl, aryl, heteroaryl, heterocycloalkyl, alkenyl, alkynyl, -OH, -C(O)2-alkyl, and -C(O)2H.
12. A compound or pharmaceutically acceptable salt according to claim 1, wherein R7 is hydrogen; halogen; or an unsubstituted or substituted moiety selected from alkyl and alkoxy, wherein the substituted moiety is substituted with one, two or three substituents independently selected from the group consisting of OH, C(O)2-alkyl, C(O)2H, alkoxy, O-haloalkyl, halogen, alkyl, haloalkyl, and NH2.
13. A compound or pharmaceutically acceptable salt according to claim 1, wherein R7 is hydrogen; halogen; -CN; -OH; -SH; -NO2; unsubstituted lower alkyl, unsubstituted lower alkenyl, unsubstituted lower alkynyl, lower alkyl-C(O)2H, lower alkyl-C(O)2-lower alkyl, or lower alkoxy.
14. A compound or pharmaceutically acceptable salt according to claim 1 wherein R7 is not hydrogen.
15. A compound or pharmaceutically acceptable salt according to claim 1, wherein R6 is hydrogen or halogen.
16. A compound or pharmaceutically acceptable salt according to claim 1, wherein R8 is hydrogen or halogen.
17. A compound or pharmaceutically acceptable salt according to claim 1, wherein R9 is hydrogen; halogen; or an unsubstituted or substituted moiety selected from alkyl, aryl, heteroaryl, heterocycloalkyl, haloalkyl, alkynyl, alkenyl, haloalkyl, wherein the substituted moiety is substituted with one, two or three substitutents independently selected from the group consisting of alkyl, -C(O)H, -CN, halogen, alkoxy, aryl, and -C(O)2H.
18. A compound or pharmaceutically acceptable salt according to claim 1, wherein R10 is hydrogen, alkyl, or alkyl-aryl.
19. A compound or pharmaceutically acceptable salt according to claim 1, wherein X
is O.
is O.
20. A compound or pharmaceutically acceptable salt according to claim 1, wherein Y
is lower alkyl.
is lower alkyl.
21. A compound or pharmaceutically acceptable salt according to claim 1, wherein Z
is hydroxy.
is hydroxy.
22. A compound or pharmaceutically acceptable salt according to claim 1, wherein Z
is -OC(O)NH2.
is -OC(O)NH2.
23. A compound or pharmaceutically acceptable salt according to claim 1, wherein Z
is SH.
is SH.
24. A compound or pharmaceutically acceptable salt according to claim 1, wherein the substituted groups in R2, R3, R4, R5, R6, R7, R8, R9 and R10 are substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, =O, =S, -CN, -NO2, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2)2CN where z is an integer from 0 to 6, =NH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -C(NH)NH2, -NHC(O)NH2, -S(O)H, -NH2, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(S)H, and -SH groups unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, =O, -NO2, -CN, -OH, -SH, -(CH2)z-CN where z is an integer from 0 to 6, unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls.
25. A compound or pharmaceutically acceptable salt according to claim 1 wherein:
(a) X is S or O;
(b) R1 is hydrogen; or an unsubstituted moiety selected from lower alkyl, lower alkyl-hydroxy, lower alkenyl, lower alkenyl-hydroxy, lower alkynyl, lower alkynyl-hydroxy, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl;
(c) R2, R3, R4 and R5 are each independently hydrogen; or an unsubstituted moiety selected from lower alkyl, lower alkynyl, lower alkenyl, alkoxy, haloalkyl, aryl, and heteroaryl;
(d) R6, R8 and R9 are each independently hydrogen; or an unsubstituted or substituted moiety selected from alkyl, alkenyl, alkynyl, alkoxy, allyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein the substituted moieties are each independently selected from the group consisting of halogen, -CN, alkyl, alkoxy, -NH2, -O-haloalkyl, -CH(O), haloalkyl, aryl, heteroaryl, heterocycloalkyl, alkenyl, alkynyl, -OH, -C(O)2-alkyl, and -C(O)2H;
(e) R7 is hydrogen; halogen; -CN; -OH; -SH; -NO2; unsubstituted lower alkyl, unsubstituted lower alkenyl, unsubstituted lower alkynyl, alkyl-C(O)2H, alkyl-C(O)2-alkyl, or lower alkoxy; and (f) R10 is hydrogen; or an unsubstituted moiety selected from lower alkyl, lower alkenyl, lower alkynyl, aryl, benzyl, heteroaryl, heterocycloalkyl, and cycloalkyl.
(a) X is S or O;
(b) R1 is hydrogen; or an unsubstituted moiety selected from lower alkyl, lower alkyl-hydroxy, lower alkenyl, lower alkenyl-hydroxy, lower alkynyl, lower alkynyl-hydroxy, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl;
(c) R2, R3, R4 and R5 are each independently hydrogen; or an unsubstituted moiety selected from lower alkyl, lower alkynyl, lower alkenyl, alkoxy, haloalkyl, aryl, and heteroaryl;
(d) R6, R8 and R9 are each independently hydrogen; or an unsubstituted or substituted moiety selected from alkyl, alkenyl, alkynyl, alkoxy, allyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein the substituted moieties are each independently selected from the group consisting of halogen, -CN, alkyl, alkoxy, -NH2, -O-haloalkyl, -CH(O), haloalkyl, aryl, heteroaryl, heterocycloalkyl, alkenyl, alkynyl, -OH, -C(O)2-alkyl, and -C(O)2H;
(e) R7 is hydrogen; halogen; -CN; -OH; -SH; -NO2; unsubstituted lower alkyl, unsubstituted lower alkenyl, unsubstituted lower alkynyl, alkyl-C(O)2H, alkyl-C(O)2-alkyl, or lower alkoxy; and (f) R10 is hydrogen; or an unsubstituted moiety selected from lower alkyl, lower alkenyl, lower alkynyl, aryl, benzyl, heteroaryl, heterocycloalkyl, and cycloalkyl.
26. A compound or pharmaceutically acceptable salt according to claim 1 wherein:
(a) X is O;
(b) R1 is an unsubstituted alkyl group or unsubstituted aryl group;
(c) R2, R3, R4 and R5 are each hydrogen;
(d) R7 is hydrogen, halogen, unsubstituted lower alkyl, lower alkyl-C(O)2H, lower alkyl-C(O)2-lower alkyl, or lower alkyl-hydroxy; and (e) R10 is hydrogen.
(a) X is O;
(b) R1 is an unsubstituted alkyl group or unsubstituted aryl group;
(c) R2, R3, R4 and R5 are each hydrogen;
(d) R7 is hydrogen, halogen, unsubstituted lower alkyl, lower alkyl-C(O)2H, lower alkyl-C(O)2-lower alkyl, or lower alkyl-hydroxy; and (e) R10 is hydrogen.
27. A compound or pharmaceutically acceptable salt according to claim 1 wherein:
(a) R9 is hydrogen, halogen or an unsubstituted alkyl group;
(b) Y is an unsubstitued alkyl group; and (c) Z is hydroxyl.
(a) R9 is hydrogen, halogen or an unsubstituted alkyl group;
(b) Y is an unsubstitued alkyl group; and (c) Z is hydroxyl.
28. A compound or pharmaceutical salt according to claim 1, wherein at least one of R6, R8 and R9 is an aryl group unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of:
halogens, =O, =S, -CN, -NO2, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2)z CN where z is an integer from 0 to 6, =NH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -C(NH)NH2, -NHC(O)NH2,-S(O)H, -NH2, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(S)H, and -SH groups unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, =O, -NO2, -CN, -OH, -SH, -(CH2)z-CN where z is an integer from 0 to 6, unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls.
halogens, =O, =S, -CN, -NO2, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2)z CN where z is an integer from 0 to 6, =NH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -C(NH)NH2, -NHC(O)NH2,-S(O)H, -NH2, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(S)H, and -SH groups unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, =O, -NO2, -CN, -OH, -SH, -(CH2)z-CN where z is an integer from 0 to 6, unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls.
29. A compound or pharmaceutical salt according to claim 1, wherein at least one of R6, R8 and R9 is a heteroaryl group unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of: halogens, =O, =S, -CN, -NO2, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2)z CN where z is an integer from 0 to 6, =NH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -C(NH)NH2, -NHC(O)NH2,-S(O)H, -NH2, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(S)H, and -SH groups unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, =O, -NO2, -CN, -OH, -SH, -(CH2)z-CN where z is an integer from 0 to 6, unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls.
30. A compound or pharmaceutical salt according to claim 1, wherein at least one of R6, R8 and R9 is a heterocycloalkyl group unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, =O, =S, -OH, -SH, -CN, -NO2, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2)z CN
where z is an integer from 0 to 6, =NH, -OH, C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -C(NH)NH2, -NHC(O)NH2,-S(O)H, -NH2, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(S)H, and -SH groups unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, =O, -NO2, -OH, -SH, -CN, -(CH2)z-CN where z is an integer from 0 to 6, unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls.
where z is an integer from 0 to 6, =NH, -OH, C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -C(NH)NH2, -NHC(O)NH2,-S(O)H, -NH2, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(S)H, and -SH groups unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, =O, -NO2, -OH, -SH, -CN, -(CH2)z-CN where z is an integer from 0 to 6, unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls.
31. A compound or pharmaceutically acceptable salt according to claim 1 wherein:
(a) X is O or S;
(b) R1 is an unsubstituted lower alkyl group;
(c) R2, R3, R4 and R5 are each hydrogen;
(d) R6 is hydrogen or halogen;
(e) R7 is halogen, unsubstituted lower alkyl, lower alkyl-C(O)2H, lower alkyl-C(O)2-lower alkyl, or lower alkoxy;
(f) R8 is hydrogen or halogen;
(g) R9 is hydrogen; or an unsubstituted or substituted moiety selected from alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; and (h) R10 is hydrogen.
(a) X is O or S;
(b) R1 is an unsubstituted lower alkyl group;
(c) R2, R3, R4 and R5 are each hydrogen;
(d) R6 is hydrogen or halogen;
(e) R7 is halogen, unsubstituted lower alkyl, lower alkyl-C(O)2H, lower alkyl-C(O)2-lower alkyl, or lower alkoxy;
(f) R8 is hydrogen or halogen;
(g) R9 is hydrogen; or an unsubstituted or substituted moiety selected from alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; and (h) R10 is hydrogen.
32. A compound or pharmaceutically acceptable salt according to claim 31 wherein Y
is an unsubstituted lower alkyl group and Z is hydroxyl.
is an unsubstituted lower alkyl group and Z is hydroxyl.
33. A compound or pharmaceutically acceptable salt according to claim 1 wherein:
(a) X is O;
(b) R1 is an unsubstituted moiety selected from aryl, alkyl, and lower-alkoxy;
(c) R2, R3, R4, and R5 are each hydrogen;
(d) R6 and R8 are each hydrogen or halogen;
(e) R7 is halogen, unsubstituted lower alkyl, lower alkyl-C(O)2H, lower alkyl-C(O)2-lower alkyl, or lower alkoxy;
(f) R9 is an unsubstituted branched alkyl group; and (g) R10 is hydrogen;
wherein the substituted groups in R7 are substituted with one, two or three suitable substituents independently selected from the group consisting of halogens, =O, =S, -CN, -NO2, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2)z CN where z is an integer from 0 to 6, =NH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -C(NH)NH2, -NHC(O)NH2, -S(O)H, -NH2, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(S)H, and -SH groups unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, =O, -NO2, -CN, -OH, -SH, -(CH2)z-CN where z is an integer from 0 to 6, unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls.
(a) X is O;
(b) R1 is an unsubstituted moiety selected from aryl, alkyl, and lower-alkoxy;
(c) R2, R3, R4, and R5 are each hydrogen;
(d) R6 and R8 are each hydrogen or halogen;
(e) R7 is halogen, unsubstituted lower alkyl, lower alkyl-C(O)2H, lower alkyl-C(O)2-lower alkyl, or lower alkoxy;
(f) R9 is an unsubstituted branched alkyl group; and (g) R10 is hydrogen;
wherein the substituted groups in R7 are substituted with one, two or three suitable substituents independently selected from the group consisting of halogens, =O, =S, -CN, -NO2, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -(CH2)z CN where z is an integer from 0 to 6, =NH, -OH, -C(O)H, -OC(O)H, -C(O)OH, -OC(O)OH, -C(NH)NH2, -NHC(O)NH2, -S(O)H, -NH2, -C(O)NH2, -OC(O)NH2, -NHC(O)H, -NHC(O)OH, -C(S)H, and -SH groups unsubstituted or substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, =O, -NO2, -CN, -OH, -SH, -(CH2)z-CN where z is an integer from 0 to 6, unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls.
34. A compound or pharmaceutically acceptable salt according to claim 33 wherein:
(a) Y is an unsubstituted lower alkyl group; and (b) Z is hydroxyl.
(a) Y is an unsubstituted lower alkyl group; and (b) Z is hydroxyl.
35. A compound or pharmaceutically acceptable salt according to claim 1 wherein R9 is a branched alkyl.
36. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
or a pharmaceutically acceptable salt thereof.
37. A compound having the following structure:
or a pharmaceutically acceptable salt thereof.
or a pharmaceutically acceptable salt thereof.
38. A compound having the following structure:
or a pharmaceutically acceptable salt thereof.
or a pharmaceutically acceptable salt thereof.
39. A compound having the following structure:
or a pharmaceutically acceptable salt thereof.
or a pharmaceutically acceptable salt thereof.
40. A compound having the following structure:
or a pharmaceutically acceptable salt thereof.
or a pharmaceutically acceptable salt thereof.
41. A pharmaceutical composition comprising a therapeutically effective amount of an agent selected from the group consisting of compounds and salts as defined in claim 1 and a pharmaceutically acceptable carrier.
42. A pharmaceutical composition comprising a therapeutically effective amount of an agent selected from the group consisting of compounds and salts as defined in claim 36 and a pharmaceutically acceptable carrier.
43. A method of treating a neoplasia comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising a compound of claim 1.
44. A method according to claim 43 wherein the neoplasia is a hematological cancer.
45. A method according to claim 44 wherein the neoplasia is selected from leukemias, myelomas and lymphomas.
46. A method according to claim 43, wherein the neoplasia is selected from brain cancer, bone cancer, basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, mouth cancer, esophageal cancer, small bowel cancer, stomach cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer, skin cancer, prostate cancer, and renal cell carcinoma.
47. A method according to claim 43, wherein the compound is given in combination with at least one other antineoplastic agent.
48. A method according to claim 47, wherein the antineoplastic agent is an alkylating agent.
49. A method according to claim 48, wherein the alkylating agent is selected from the group consisting of bendamustine, chlorambucil, cyclophosphamide and melphalan.
50. A method according to claim 48, wherein the alkylating agent is bendamustine.
51. A method according to 47, wherein the antineoplastic agent is a glucocorticoid.
52. A method according to 51, wherein the glucocoritcoid is prednisone or dexmethasone.
53. A method according to claim 51, wherein the glucocorticoid is given in combination with additional antineoplastic agents.
54. A method of reducing or preventing the development of Alzheimer's disease comprising administering to a subject in thereof a therapeutically effective amount of a composition comprising a compound of claim 1.
55. A method of treating Alzheimer's disease in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of:
(a) at least one compound, pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite defined in claim 1;
and (b) at least one agent selected from the group consisting of estrogen, risperidone, a thiobenzodiazepine, ampakine, [N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide, DM9384, a cholinesterase inhibitor, donepezil hydrochloride, rivastigmine tartrate, galantamine, NGF, and metrifonate.
(a) at least one compound, pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite defined in claim 1;
and (b) at least one agent selected from the group consisting of estrogen, risperidone, a thiobenzodiazepine, ampakine, [N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide, DM9384, a cholinesterase inhibitor, donepezil hydrochloride, rivastigmine tartrate, galantamine, NGF, and metrifonate.
56. A method of treating a disease mediated by .beta.-catenin in a mammal by administering to a mammal in need of such treatment a therapeutically effective amount of at least one compound, pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite as defined in claim 1.
57. A method of treatment of a hyperplastic disease in a mammal comprising administration to the mammal a therapeutically effective amount of a compound of claim 1.
58. A method of inhibiting or delaying the onset of a neoplasia in a mammal in need of such treatment comprising administration to the mammal a therapeutically effective amount of a compound of claim 1.
59. A method according to claim 58 wherein said neoplasia is selected from the group consisting of adenomatous polyps, gastrointestinal cancer, liver cancer, bladder cancer, cervical cancer, prostate cancer, lung cancer, breast cancer, and skin cancer.
60. A method for treating, inhibiting or delaying the onset of uncontrolled or abnormal angiogenesis in a subject in need of such treatment, inhibition or delay, wherein the uncontrolled or abnormal angiogenesis is selected from the group consisting of metastasis, corneal graft rejection, ocular neovascularization, retinal neovascularization, diabetic retinopathy, retrolental fibroplasia, neovascular glaucoma, gastric ulcer, infantile hemaginomas, angiofibroma of the nasopharynx, avascular necrosis of bone, and endometriosis, and the method comprises treating the subject with a therapeutically effective amount of a compound of claim 1.
61. A method for treating a condition selected from the group consisting of arthritis, fever, common cold, dysmenorrhea, menstrual cramps, inflammatory bowel disease, Crohn's disease, emphysema, acute respiratory distress syndrome, asthma, bronchitis, chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer, tissue ulceration, peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis, recurrent gastrointestinal lesion, gastrointestinal bleeding, coagulation, anemia, synovitis, gout, ankylosing spondylitis, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, loosening of artificial joint implants, atherosclerosis, aortic aneurysm, periarteritis nodosa, congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neuralgia, neuro-degenerative disorders, autoimmune disorders, Huntington's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain, gingivitis, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, conjunctivitis, abnormal wound healing, muscle or joint sprains or strains, tendonitis, skin disorders, myasthenia gravis, polymyositis, myositis, bursitis, burns, diabetes, tumor invasion, tumor growth, tumor metastasis, corneal scarring, scleritis, immunodeficiency diseases, sepsis, premature labor, hypoprothrombinemia, hemophilia, thyroiditis, sarcoidosis, Behcet's syndrome, hypersensitivity, schizophrenia, kidney disease, Rickettsial infections, Protozoan diseases, myelodymyelodysplastic syndrome, reproductive disorders, obesity, and septic shock in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof effective in treating such a condition.
62. A pharmaceutical composition comprising a compound of Formula I:
wherein:
(a) X is C, S or O;
(b) R1 is hydrogen; halogen; -CN; -OH; -SH; -NO2; or an unsubstituted or substituted moiety selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl, wherein the substituted groups are substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, -CN, -NO2, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted heteroalkyl, unsubstituted haloalkyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted heteroaryl, and -(CH2)z CN where z is an integer from 0 to 6;
(c) R2, R3, R4 and R5 are each independently hydrogen; halogen; -CN; -OH; -SH;
-NO2; or an unsubstituted or substituted moiety selected from lower alkyl, lower alkynyl, lower alkenyl, alkoxy, haloalkyl, aryl, and heteroaryl;
(d) R6, R8 and R9 are each independently hydrogen; halogen; -CN; -OH; -SH; -NO2;
or an unsubstituted or substituted moiety selected from alkyl, alkenyl, alkynyl, alkoxy, allyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;
(e) R7 is hydrogen; halogen; -CN; -OH; -SH; -NO2; or an unsubstituted or substituted moiety selected from alkyl, alkenyl, and alkynyl.
(f) R10 is hydrogen; or an unsubstituted or substituted moiety selected from lower alkyl, lower alkenyl, lower alkynyl, aryl; heteroaryl, heterocycloalkyl, and cycloalkyl;
(g) Y is an unsubstituted or substituted moiety selected from alkyl, alkenyl, and alkynyl; wherein the substituted moiety is substituted with one, two or three substitutents each independently selected from halogen; -CN; -OH; -SH; -NO2;
unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls; and (h) Z is a moiety selected from -OH, -SH, -OC(O)NH2;
wherein R1 and Y may cyclize to form an unsubstituted or substituted cycloalkyl group or an unsubstituted or substituted heterocycloalkyl group; and at least one of R6, R7, R8 and R9 is not hydrogen;
or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt thereof.
wherein:
(a) X is C, S or O;
(b) R1 is hydrogen; halogen; -CN; -OH; -SH; -NO2; or an unsubstituted or substituted moiety selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl, wherein the substituted groups are substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, -CN, -NO2, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted heteroalkyl, unsubstituted haloalkyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted heteroaryl, and -(CH2)z CN where z is an integer from 0 to 6;
(c) R2, R3, R4 and R5 are each independently hydrogen; halogen; -CN; -OH; -SH;
-NO2; or an unsubstituted or substituted moiety selected from lower alkyl, lower alkynyl, lower alkenyl, alkoxy, haloalkyl, aryl, and heteroaryl;
(d) R6, R8 and R9 are each independently hydrogen; halogen; -CN; -OH; -SH; -NO2;
or an unsubstituted or substituted moiety selected from alkyl, alkenyl, alkynyl, alkoxy, allyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;
(e) R7 is hydrogen; halogen; -CN; -OH; -SH; -NO2; or an unsubstituted or substituted moiety selected from alkyl, alkenyl, and alkynyl.
(f) R10 is hydrogen; or an unsubstituted or substituted moiety selected from lower alkyl, lower alkenyl, lower alkynyl, aryl; heteroaryl, heterocycloalkyl, and cycloalkyl;
(g) Y is an unsubstituted or substituted moiety selected from alkyl, alkenyl, and alkynyl; wherein the substituted moiety is substituted with one, two or three substitutents each independently selected from halogen; -CN; -OH; -SH; -NO2;
unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls; and (h) Z is a moiety selected from -OH, -SH, -OC(O)NH2;
wherein R1 and Y may cyclize to form an unsubstituted or substituted cycloalkyl group or an unsubstituted or substituted heterocycloalkyl group; and at least one of R6, R7, R8 and R9 is not hydrogen;
or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt thereof.
63. A pharmaceutical composition according to claim 62, wherein:
(a) X is S or O;
(b) R1 is hydrogen; or an unsubstituted moiety selected from lower alkyl, lower alkyl-hydroxy, lower alkenyl, lower alkenyl-hydroxy, lower alkynyl, lower alkynyl-hydroxy, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl;
(c) R2, R3, R4 and R5 are each independently hydrogen; or an unsubstituted moiety selected from lower alkyl, lower alkynyl, lower alkenyl, alkoxy, haloalkyl, aryl, and heteroaryl;
(d) R6, R8 and R9 are each independently hydrogen; or an unsubstituted or substituted moiety selected from alkyl, alkenyl, alkynyl, alkoxy, allyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein the substituted moieties are each independently selected from the group consisting of halogen, -CN, alkyl, alkoxy, -NH2, -O-haloalkyl, -CH(O), haloalkyl, aryl, heteroaryl, heterocycloalkyl, alkenyl, alkynyl, -OH, -C(O)2-alkyl, and -C(O)2H;
(e) R7 is hydrogen; halogen; -CN; -OH; -SH; -NO2; unsubstituted lower alkyl, unsubstituted lower alkenyl, unsubstituted lower alkynyl, alkyl-C(O)2H, alkyl-C(O)2-alkyl, or alkyl-hydroxy; and R10 is hydrogen; or an unsubstituted moiety selected from lower alkyl, lower alkenyl, lower alkynyl, aryl, benzyl, heteroaryl, heterocycloalkyl, and cycloalkyl.
(a) X is S or O;
(b) R1 is hydrogen; or an unsubstituted moiety selected from lower alkyl, lower alkyl-hydroxy, lower alkenyl, lower alkenyl-hydroxy, lower alkynyl, lower alkynyl-hydroxy, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl;
(c) R2, R3, R4 and R5 are each independently hydrogen; or an unsubstituted moiety selected from lower alkyl, lower alkynyl, lower alkenyl, alkoxy, haloalkyl, aryl, and heteroaryl;
(d) R6, R8 and R9 are each independently hydrogen; or an unsubstituted or substituted moiety selected from alkyl, alkenyl, alkynyl, alkoxy, allyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein the substituted moieties are each independently selected from the group consisting of halogen, -CN, alkyl, alkoxy, -NH2, -O-haloalkyl, -CH(O), haloalkyl, aryl, heteroaryl, heterocycloalkyl, alkenyl, alkynyl, -OH, -C(O)2-alkyl, and -C(O)2H;
(e) R7 is hydrogen; halogen; -CN; -OH; -SH; -NO2; unsubstituted lower alkyl, unsubstituted lower alkenyl, unsubstituted lower alkynyl, alkyl-C(O)2H, alkyl-C(O)2-alkyl, or alkyl-hydroxy; and R10 is hydrogen; or an unsubstituted moiety selected from lower alkyl, lower alkenyl, lower alkynyl, aryl, benzyl, heteroaryl, heterocycloalkyl, and cycloalkyl.
64. A pharmaceutical composition according to claim 62, wherein (a) X is O;
(b) R1 is an unsubstituted alkyl group;
(c) R2, R3, R4 and R5 are each hydrogen;
(d) R7 is hydrogen, halogen, unsubstituted lower alkyl, alkyl-C(O)2H, alkyl-C(O)2-alkyl, or alkyl-hydroxy; and (e) R10 is hydrogen.
(b) R1 is an unsubstituted alkyl group;
(c) R2, R3, R4 and R5 are each hydrogen;
(d) R7 is hydrogen, halogen, unsubstituted lower alkyl, alkyl-C(O)2H, alkyl-C(O)2-alkyl, or alkyl-hydroxy; and (e) R10 is hydrogen.
65. A pharmaceutical composition according to claim 62, wherein:
(a) R9 is hydrogen, halogen or an unsubstituted alkyl group;
(b) Y is an unsubstitued alkyl group; and (c) Z is hydroxyl.
(a) R9 is hydrogen, halogen or an unsubstituted alkyl group;
(b) Y is an unsubstitued alkyl group; and (c) Z is hydroxyl.
66. A compound or pharmaceutically acceptable salt according to claim 62, wherein:
(a) X is O or S;
(b) R1 is an unsubstituted lower alkyl group or unsubstituted aryl group;
(c) R2, R3, R4 and R5 are each hydrogen;
(d) R6 is hydrogen or halogen;
(e) R7 is hydrogen, halogen, unsubstituted lower alkyl, alkyl-C(O)2H, alkyl-C(O)2-alkyl, or alkyl-hydroxy;
(f) R8 is hydrogen or halogen;
(g) R9 is hydrogen; or an unsubstituted or substituted moiety selected from alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; and (h) R10 is hydrogen.
(a) X is O or S;
(b) R1 is an unsubstituted lower alkyl group or unsubstituted aryl group;
(c) R2, R3, R4 and R5 are each hydrogen;
(d) R6 is hydrogen or halogen;
(e) R7 is hydrogen, halogen, unsubstituted lower alkyl, alkyl-C(O)2H, alkyl-C(O)2-alkyl, or alkyl-hydroxy;
(f) R8 is hydrogen or halogen;
(g) R9 is hydrogen; or an unsubstituted or substituted moiety selected from alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; and (h) R10 is hydrogen.
67. A compound of Formula I:
wherein:
(a) X is C, S or O;
(b) R1 is hydrogen; halogen; -CN; -OH; -SH; -NO2; or an unsubstituted or substituted moiety selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl, wherein the substituted groups are substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, -CN, -NO2, -OH, -SH, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted heteroalkyl, unsubstituted haloalkyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted heteroaryl, and -(CH2)2CN where z is an integer from 0 to 6;
(c) R2, R3, R4 and R5 are each independently hydrogen; halogen; -CN; -OH; -SH;
-NO2; or an unsubstituted or substituted moiety selected from lower alkyl, lower alkynyl, lower alkenyl, alkoxy, haloalkyl, aryl, and heteroaryl;
(d) R6, R8 and R9 are each independently hydrogen; halogen; -CN; -OH; -SH; -NO2;
or an unsubstituted or substituted moiety selected from alkyl, alkenyl, alkynyl, alkoxy, allyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;
(e) R7 is hydrogen; halogen; -CN; -OH; -SH; -NO2; or an unsubstituted or substituted moiety selected from alkyl, alkenyl, and alkynyl.
(f) R10 is hydrogen; or an unsubstituted or substituted moiety selected from lower alkyl, lower alkenyl, lower alkynyl, aryl; heteroaryl, heterocycloalkyl, and cycloalkyl;
(g) Y is an unsubstituted or substituted moiety selected from alkyl, alkenyl, and alkynyl; wherein the substituted moiety is substituted with one, two or three substitutents each independently selected from halogen; -CN; -OH; -SH; -NO2;
unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls; and (h) Z is -OH; -SH; or a moiety selected from -OC(O)NH2, -SO2H, -SO2OH, -S(O)H, -SO2NH2 -NH2 unsubstituted or substituted with one or two suitable substituents selected from the group consisting of alkyl, haloalkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl each independently substituted with one, two or three suitable substituents;
wherein R1 and Y may cyclize to form an unsubstituted or substituted cycloalkyl group or an unsubstituted or substituted heterocycloalkyl group; and wherein:
(i) at least one of R6, R7, R8 and R9 is not hydrogen;
(ii) when R1 is propyl, Y-Z is ethoxy and R9 is fluorine, R6 is not substituted with a -C(O)-heterocycloalkyl group;
(iii) when Y-Z is propoxy and R9 is ethyl, R1 is not CN;
(iv) when R1 is ethyl and R9 is ethyl, Y-Z is not unsubstituted or substituted methoxy or unsubstituted or substituted ethoxy;
(v) when R1 is methyl and R9 is methyl, Y-Z is not methoxy or ethoxy; and (vi) when Z is a substituted amide or a substituted amine; R6 is not methyl or chloro; and R7 is not hydroxy, alkoxy-phenyl or methoxy;
or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt thereof.
wherein:
(a) X is C, S or O;
(b) R1 is hydrogen; halogen; -CN; -OH; -SH; -NO2; or an unsubstituted or substituted moiety selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl, wherein the substituted groups are substituted with one, two or three suitable substituents each independently selected from the group consisting of halogens, -CN, -NO2, -OH, -SH, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted heteroalkyl, unsubstituted haloalkyl, unsubstituted alkynyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted heteroaryl, and -(CH2)2CN where z is an integer from 0 to 6;
(c) R2, R3, R4 and R5 are each independently hydrogen; halogen; -CN; -OH; -SH;
-NO2; or an unsubstituted or substituted moiety selected from lower alkyl, lower alkynyl, lower alkenyl, alkoxy, haloalkyl, aryl, and heteroaryl;
(d) R6, R8 and R9 are each independently hydrogen; halogen; -CN; -OH; -SH; -NO2;
or an unsubstituted or substituted moiety selected from alkyl, alkenyl, alkynyl, alkoxy, allyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;
(e) R7 is hydrogen; halogen; -CN; -OH; -SH; -NO2; or an unsubstituted or substituted moiety selected from alkyl, alkenyl, and alkynyl.
(f) R10 is hydrogen; or an unsubstituted or substituted moiety selected from lower alkyl, lower alkenyl, lower alkynyl, aryl; heteroaryl, heterocycloalkyl, and cycloalkyl;
(g) Y is an unsubstituted or substituted moiety selected from alkyl, alkenyl, and alkynyl; wherein the substituted moiety is substituted with one, two or three substitutents each independently selected from halogen; -CN; -OH; -SH; -NO2;
unsubstituted alkyls, unsubstituted alkenyls, unsubstituted alkynyls, unsubstituted heteroalkyls, unsubstituted haloalkyls, unsubstituted aryls, unsubstituted cycloalkyls, unsubstituted heterocycloalkyls, and unsubstituted heteroaryls; and (h) Z is -OH; -SH; or a moiety selected from -OC(O)NH2, -SO2H, -SO2OH, -S(O)H, -SO2NH2 -NH2 unsubstituted or substituted with one or two suitable substituents selected from the group consisting of alkyl, haloalkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl each independently substituted with one, two or three suitable substituents;
wherein R1 and Y may cyclize to form an unsubstituted or substituted cycloalkyl group or an unsubstituted or substituted heterocycloalkyl group; and wherein:
(i) at least one of R6, R7, R8 and R9 is not hydrogen;
(ii) when R1 is propyl, Y-Z is ethoxy and R9 is fluorine, R6 is not substituted with a -C(O)-heterocycloalkyl group;
(iii) when Y-Z is propoxy and R9 is ethyl, R1 is not CN;
(iv) when R1 is ethyl and R9 is ethyl, Y-Z is not unsubstituted or substituted methoxy or unsubstituted or substituted ethoxy;
(v) when R1 is methyl and R9 is methyl, Y-Z is not methoxy or ethoxy; and (vi) when Z is a substituted amide or a substituted amine; R6 is not methyl or chloro; and R7 is not hydroxy, alkoxy-phenyl or methoxy;
or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt thereof.
68. A method of treating a disease mediated by PPAR in in a mammal by administering to a mammal in need of such treatment a therapeutically effective amount of at least one compound, pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite as defined in claim 1.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US50859203P | 2003-10-02 | 2003-10-02 | |
US60/508,592 | 2003-10-02 | ||
US55659904P | 2004-03-26 | 2004-03-26 | |
US60/556,599 | 2004-03-26 | ||
PCT/US2004/032185 WO2005033113A2 (en) | 2003-10-02 | 2004-10-01 | Indole derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2540343A1 true CA2540343A1 (en) | 2005-04-14 |
Family
ID=34426060
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002540343A Abandoned CA2540343A1 (en) | 2003-10-02 | 2004-10-01 | Indole derivatives |
CA002540289A Abandoned CA2540289A1 (en) | 2003-10-02 | 2004-10-01 | Substituted indole derivatives |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002540289A Abandoned CA2540289A1 (en) | 2003-10-02 | 2004-10-01 | Substituted indole derivatives |
Country Status (7)
Country | Link |
---|---|
US (2) | US7446122B2 (en) |
EP (2) | EP1673373A2 (en) |
JP (2) | JP2007507524A (en) |
CA (2) | CA2540343A1 (en) |
MX (1) | MXPA06003758A (en) |
TW (2) | TW200526668A (en) |
WO (2) | WO2005033112A2 (en) |
Families Citing this family (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10252667A1 (en) | 2002-11-11 | 2004-05-27 | Grünenthal GmbH | New spiro-((cyclohexane)-tetrahydropyrano-(3,4-b)-indole) derivatives, are ORL1 receptor ligands useful e.g. for treating anxiety, depression, epilepsy, senile dementia, withdrawal symptoms or especially pain |
WO2005033112A2 (en) * | 2003-10-02 | 2005-04-14 | Cephalon, Inc. | Substituted indole derivatives |
DE102004039382A1 (en) * | 2004-08-13 | 2006-02-23 | Grünenthal GmbH | Spirocyclic cyclohexane derivatives |
DE102006046745A1 (en) * | 2006-09-29 | 2008-04-03 | Grünenthal GmbH | Use of spirocyclic cyclohexane-derivative exhibiting an affinity for opioid-receptor and opioid receptor-like-1-receptor, for producing a medicament e.g. for treating diabetic neuropathy, for narcosis or for analgesia during narcosis |
US20110251144A1 (en) * | 2008-09-16 | 2011-10-13 | Massachusetts Institute Of Technology | Molecular modulators of the wnt/beta-catenin pathway |
MX2013001858A (en) | 2010-08-18 | 2013-09-13 | Del Mar Pharmaceuticals | Compositions and methods to improve the therapeutic benefit of suboptimally administered chemical compounds including substituted hexitols such as dianhydrogalactitol and diacetyldianhydrogalactitol. |
EP2758043A4 (en) | 2011-08-17 | 2016-02-24 | Dennis M Brown | Compositions and methods to improve the therapeutic benefit of suboptimally administered chemical compounds including substituted hexitols such as dibromodulcitol |
EP2804602A4 (en) | 2012-01-20 | 2016-08-10 | Dennis Brown | Use of substituted hexitols including dianhydrogalactitol and analogs to treat neoplastic disease and cancer stem cells including glioblastoma multforme and medulloblastoma |
WO2013142817A2 (en) | 2012-03-23 | 2013-09-26 | Dennis Brown | Compositions and methods to improve the therapeutic benefit of indirubin and analogs thereof, including meisoindigo |
WO2013169600A1 (en) | 2012-05-09 | 2013-11-14 | Delmar Pharmaceuticals | Veterinary use of dianhydrogalactitol, diacetyldianhydrogalactitol, and dibromodulcitol to treat malignancies |
AU2013280644B2 (en) | 2012-06-26 | 2018-08-02 | Jeffrey A. BACHA | Methods for treating tyrosine-kinase-inhibitor-resistant malignancies in patients with genetic polymorphisms or AHI1 dysregulations or mutations employing dianhydrogalactitol, diacetyldianhydrogalactitol, dibromodulcitol, or analogs or derivatives thereof |
EP2738173A1 (en) * | 2012-11-28 | 2014-06-04 | Commissariat A L'energie Atomique Et Aux Energies Alternatives | Heterocyclic compounds as inhibitors of the sodium iodide symporter |
CN103864803A (en) * | 2012-12-07 | 2014-06-18 | 天津科技大学 | Preparation of 1-(phenyl)-1, 3, 4, 9-tetrahydropyrano[3, 4-b]indole derivative and application in antitumor drugs |
CA2928568A1 (en) | 2013-07-26 | 2015-01-29 | Update Pharma Inc. | Combinatorial methods to improve the therapeutic benefit of bisantrene |
KR102359214B1 (en) | 2014-04-04 | 2022-02-07 | 델 마 파마슈티컬스 | Use of dianhydrogalactitol and analogs or derivatives thereof to treat non-small-cell carcinoma of the lung and ovarian cancer |
EP4119542A1 (en) * | 2019-11-01 | 2023-01-18 | FMC Corporation | An efficient process for the synthesis of 2-amino-5-chloro-n,3-dimethylbenzamide |
Family Cites Families (36)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
YU33730B (en) * | 1967-04-18 | 1978-02-28 | Farmaceutici Italia | Process for preparing a novel antibiotic substance and salts thereof |
US3843681A (en) | 1971-06-01 | 1974-10-22 | American Home Prod | 1-carboxamido pyrano(thiopyrano)(3,4-6)indole derivatives |
US3939178A (en) | 1971-06-01 | 1976-02-17 | American Home Products Corporation | Certain pyrano [3,4-b]indoles and thiopyrano[3,4-b]indoles |
US4070371A (en) * | 1972-05-16 | 1978-01-24 | American Home Products Corporation | Derivatives of 1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid |
DE2226703A1 (en) | 1972-05-25 | 1973-12-13 | Schering Ag | NEW TETRAHYDROCARBAZOLE DERIVATIVES AND THE PROCESS FOR THEIR PRODUCTION |
US4056537A (en) * | 1974-09-18 | 1977-11-01 | Ayerst Mckenna And Harrison Ltd. | Process for making pyrano- and thiopyranoindole derivatives |
US4041169A (en) * | 1975-03-05 | 1977-08-09 | Ayerst Mckenna And Harrison Ltd. | Pharmaceutical method for using pyrano-and thiopyranoindole derivatives |
US4012448A (en) * | 1976-01-15 | 1977-03-15 | Stanford Research Institute | Synthesis of adriamycin and 7,9-epiadriamycin |
US4179503A (en) | 1978-05-08 | 1979-12-18 | American Home Products Corp. | 1-Hydroxyalkanamine pyrano[3,4-b]indole derivatives |
US4686213A (en) | 1986-08-15 | 1987-08-11 | American Home Products Corporation | Substituted 1,3,4,9-tetrahydropyrano(3,4-b)indole-1-acetic acids |
US4748252A (en) * | 1986-08-15 | 1988-05-31 | American Home Products Corporation | Substituted 1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acids |
CA1299577C (en) * | 1987-01-09 | 1992-04-28 | John W. Gillard | Tetrahydrocarbazole 1-alkanoic acids |
US5420289A (en) * | 1989-10-27 | 1995-05-30 | American Home Products Corporation | Substituted indole-, indene-, pyranoindole- and tetrahydrocarbazole-alkanoic acid derivatives as inhibitors of PLA2 and lipoxygenase |
DE69328838T2 (en) | 1992-03-13 | 2000-10-12 | Sepracor Inc | ANTIPYRETIC AND ANALGETIC METHODS AND COMPOSITIONS CONTAINING OPTICALLY PURE R-ETODOLAC |
US5955504A (en) * | 1995-03-13 | 1999-09-21 | Loma Linda University Medical Center | Colorectal chemoprotective composition and method of preventing colorectal cancer |
US6255347B1 (en) | 1996-06-21 | 2001-07-03 | Advanced Research And Technology Institute | Methods and compositions comprising R-ibuprofen |
US5776967A (en) * | 1996-07-26 | 1998-07-07 | American Home Products Corporation | Pyranoindole inhibitors of COX--2 |
US5830911A (en) | 1996-08-14 | 1998-11-03 | American Home Products Corporation | Pyranoindole and tetrahydrocarbazole inhibitors of COX-2 |
US6552055B2 (en) | 1996-12-11 | 2003-04-22 | Dana-Farber Cancer Institute | Methods and pharmaceutical compositions for inhibiting tumor cell growth |
US5972986A (en) | 1997-10-14 | 1999-10-26 | G.D. Searle & Co. | Method of using cyclooxygenase-2 inhibitors in the treatment and prevention of neoplasia |
US6025353A (en) * | 1997-11-19 | 2000-02-15 | G.D. Searle & Co. | Method of using cyclooxygenase-2 inhibitors as anti-angiogenic agents |
DK1104297T3 (en) * | 1998-07-09 | 2006-05-29 | Cephalon Inc | Compositions for the treatment of chronic lymphocytic leukemia |
US7105560B1 (en) * | 1999-07-23 | 2006-09-12 | The Regents Of The University Of California | Use of etodolac in the treatment of multiple myeloma |
US7361680B2 (en) * | 1999-07-23 | 2008-04-22 | The Regents Of The University Of California | Indole compounds useful for the treatment of cancer |
US6545034B1 (en) * | 1999-07-23 | 2003-04-08 | The Regents Of The University Of California | Use of etodolac for the treatment of chronic lymphocytic leukemia |
US7129262B2 (en) * | 1999-07-23 | 2006-10-31 | The Regents Of The University Of California | Indole compounds useful for the treatment of cancer |
US7151100B1 (en) * | 1999-07-23 | 2006-12-19 | The Regents Of The University Of California | Indole compounds useful for the treatment of cancer |
US20020015943A1 (en) * | 2000-07-31 | 2002-02-07 | Mariann Bienz | Assays, methods and means relating to the modulation of levels of nuclear beta-catenin |
AU8322401A (en) | 2000-08-09 | 2002-02-18 | Univ California | Indole compounds useful for the treatment of cancer |
JP4212892B2 (en) * | 2000-12-05 | 2009-01-21 | エフ.ホフマン−ラ ロシュ アーゲー | Benzofuran and benzothiophene derivatives |
US20030064384A1 (en) | 2001-04-02 | 2003-04-03 | Mien-Chie Hung | Beta-catenin is a strong and independent prognostic factor for cancer |
US7682607B2 (en) | 2001-05-01 | 2010-03-23 | The Regents Of The University Of California | Wnt and frizzled receptors as targets for immunotherapy in head and neck squamous cell carcinomas |
US20030044409A1 (en) | 2001-05-01 | 2003-03-06 | Carson Dennis A. | Immunologic compositions and methods for studying and treating cancers expressing frizzled antigens |
AU2003295336A1 (en) * | 2002-09-19 | 2004-04-08 | Dennis A. Carson | Use of etodoclac to treat hyperplasia |
JP4908215B2 (en) * | 2003-09-12 | 2012-04-04 | エリクサー ファーマスーティカルズ インコーポレイテッド | Treatment of disease |
WO2005033112A2 (en) * | 2003-10-02 | 2005-04-14 | Cephalon, Inc. | Substituted indole derivatives |
-
2004
- 2004-10-01 WO PCT/US2004/032184 patent/WO2005033112A2/en not_active Application Discontinuation
- 2004-10-01 EP EP04793917A patent/EP1673373A2/en not_active Withdrawn
- 2004-10-01 WO PCT/US2004/032185 patent/WO2005033113A2/en active Search and Examination
- 2004-10-01 JP JP2006534104A patent/JP2007507524A/en active Pending
- 2004-10-01 TW TW093129905A patent/TW200526668A/en unknown
- 2004-10-01 CA CA002540343A patent/CA2540343A1/en not_active Abandoned
- 2004-10-01 EP EP04809825A patent/EP1680428A2/en not_active Withdrawn
- 2004-10-01 US US10/956,668 patent/US7446122B2/en not_active Expired - Fee Related
- 2004-10-01 US US10/957,039 patent/US7314886B2/en active Active
- 2004-10-01 JP JP2006534103A patent/JP2007507523A/en active Pending
- 2004-10-01 MX MXPA06003758A patent/MXPA06003758A/en not_active Application Discontinuation
- 2004-10-01 CA CA002540289A patent/CA2540289A1/en not_active Abandoned
- 2004-10-01 TW TW093129929A patent/TW200524940A/en unknown
Also Published As
Publication number | Publication date |
---|---|
WO2005033113A3 (en) | 2005-06-30 |
WO2005033113A2 (en) | 2005-04-14 |
WO2005033112A2 (en) | 2005-04-14 |
TW200524940A (en) | 2005-08-01 |
TW200526668A (en) | 2005-08-16 |
JP2007507523A (en) | 2007-03-29 |
US7446122B2 (en) | 2008-11-04 |
JP2007507524A (en) | 2007-03-29 |
EP1680428A2 (en) | 2006-07-19 |
US20070244180A1 (en) | 2007-10-18 |
EP1673373A2 (en) | 2006-06-28 |
MXPA06003758A (en) | 2006-08-11 |
CA2540289A1 (en) | 2005-04-14 |
WO2005033112A3 (en) | 2005-06-09 |
US20060160876A1 (en) | 2006-07-20 |
US7314886B2 (en) | 2008-01-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7314886B2 (en) | Tetrahydropyrano-indole derivatives | |
NL1028308C2 (en) | Benzopyran compounds useful for treating inflammatory conditions. | |
US20060166947A1 (en) | Multiple myeloma treatments | |
EP1104760B1 (en) | Sulfamoylheteroaryl pyrazole compounds as anti-inflammatory/analgesic agents | |
CA2313122C (en) | Bicycliccarbonyl indole compounds as anti-inflammatory/analgesic agents | |
CA2854936A1 (en) | Modulating certain tyrosine kinases | |
SK285931B6 (en) | Substituted benzopyran derivatives, their use and pharmaceutical composition comprising the same | |
US20220380367A1 (en) | Modified carbazoles as therapeutic agents | |
JP3962425B2 (en) | Substituted pyrazinone compounds for the treatment of inflammation | |
MXPA06003756A (en) | Indole derivatives | |
US20150336915A1 (en) | Structures of proteasome inhibitors and methods for synthesizing and use thereof | |
EP1065206B1 (en) | Tetrazolylalkyl indole compounds as anti-inflammatory and analgesic agents | |
JP2004509096A (en) | 2-Amino-2-alkyl-3heptenoic acid and heptinoic acid derivatives useful as nitric oxide synthase inhibitors | |
JP2006519835A (en) | Crystalline salt of S- [2-[(1-Iminoethyl) amino] ethyl] -2-methyl-L-cysteine salicylic acid monohydrate | |
CZ367399A3 (en) | Substituted benzopyran derivatives for treating inflammation |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
FZDE | Discontinued |