CN100376567C - 作为vegf抑制剂的喹唑啉衍生物 - Google Patents
作为vegf抑制剂的喹唑啉衍生物 Download PDFInfo
- Publication number
- CN100376567C CN100376567C CNB008153108A CN00815310A CN100376567C CN 100376567 C CN100376567 C CN 100376567C CN B008153108 A CNB008153108 A CN B008153108A CN 00815310 A CN00815310 A CN 00815310A CN 100376567 C CN100376567 C CN 100376567C
- Authority
- CN
- China
- Prior art keywords
- methoxyl group
- quinazoline
- compound
- formula
- fluoroanilino
- 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.)
- Expired - Lifetime
Links
- 239000002525 vasculotropin inhibitor Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 174
- 150000003839 salts Chemical class 0.000 claims abstract description 85
- 238000000034 method Methods 0.000 claims abstract description 54
- 230000000694 effects Effects 0.000 claims abstract description 29
- 238000002360 preparation method Methods 0.000 claims abstract description 23
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims abstract description 3
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 103
- -1 salt salt Chemical class 0.000 claims description 66
- 238000006243 chemical reaction Methods 0.000 claims description 36
- 239000003513 alkali Substances 0.000 claims description 22
- 239000002253 acid Substances 0.000 claims description 18
- 241001465754 Metazoa Species 0.000 claims description 16
- 241001597008 Nomeidae Species 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 230000008728 vascular permeability Effects 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 10
- 239000004037 angiogenesis inhibitor Substances 0.000 claims description 9
- VEEGZPWAAPPXRB-BJMVGYQFSA-N (3e)-3-(1h-imidazol-5-ylmethylidene)-1h-indol-2-one Chemical compound O=C1NC2=CC=CC=C2\C1=C/C1=CN=CN1 VEEGZPWAAPPXRB-BJMVGYQFSA-N 0.000 claims description 8
- 229940121369 angiogenesis inhibitor Drugs 0.000 claims description 8
- 125000006239 protecting group Chemical group 0.000 claims description 7
- 238000010511 deprotection reaction Methods 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000003386 piperidinyl group Chemical group 0.000 claims description 5
- 230000000259 anti-tumor effect Effects 0.000 claims description 2
- 206010028980 Neoplasm Diseases 0.000 abstract description 26
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 abstract description 24
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 abstract description 24
- 238000011282 treatment Methods 0.000 abstract description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 8
- 125000003342 alkenyl group Chemical group 0.000 abstract description 7
- 201000010099 disease Diseases 0.000 abstract description 7
- 125000000304 alkynyl group Chemical group 0.000 abstract description 6
- 201000011510 cancer Diseases 0.000 abstract description 6
- 230000008569 process Effects 0.000 abstract description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 abstract description 4
- 125000001424 substituent group Chemical group 0.000 abstract description 3
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 abstract description 2
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 abstract description 2
- 125000005843 halogen group Chemical group 0.000 abstract 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 abstract 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract 1
- 239000004480 active ingredient Substances 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 113
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 93
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 70
- 239000000243 solution Substances 0.000 description 61
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- 238000001228 spectrum Methods 0.000 description 52
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
- 238000005160 1H NMR spectroscopy Methods 0.000 description 45
- 239000000203 mixture Substances 0.000 description 42
- 239000007787 solid Substances 0.000 description 36
- 238000001291 vacuum drying Methods 0.000 description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 31
- 238000012360 testing method Methods 0.000 description 31
- 238000003756 stirring Methods 0.000 description 27
- 239000002994 raw material Substances 0.000 description 26
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 23
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 23
- 238000005406 washing Methods 0.000 description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- VBUBADWLHFZFDK-UHFFFAOYSA-N quinazoline;hydrochloride Chemical compound Cl.N1=CN=CC2=CC=CC=C21 VBUBADWLHFZFDK-UHFFFAOYSA-N 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- 235000019439 ethyl acetate Nutrition 0.000 description 19
- 238000001704 evaporation Methods 0.000 description 19
- 230000008020 evaporation Effects 0.000 description 19
- 238000001914 filtration Methods 0.000 description 19
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 18
- 229940093499 ethyl acetate Drugs 0.000 description 17
- 239000012044 organic layer Substances 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 238000004458 analytical method Methods 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 15
- 238000001556 precipitation Methods 0.000 description 15
- 239000000725 suspension Substances 0.000 description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 13
- 230000012010 growth Effects 0.000 description 13
- 229910052799 carbon Inorganic materials 0.000 description 12
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 12
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 11
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 11
- 239000012895 dilution Substances 0.000 description 11
- 238000010790 dilution Methods 0.000 description 11
- 239000012442 inert solvent Substances 0.000 description 11
- 241000700159 Rattus Species 0.000 description 10
- 230000008859 change Effects 0.000 description 10
- 238000001816 cooling Methods 0.000 description 10
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 10
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 102000004190 Enzymes Human genes 0.000 description 9
- 108090000790 Enzymes Proteins 0.000 description 9
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 9
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 9
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 9
- 125000003545 alkoxy group Chemical group 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- 229940088598 enzyme Drugs 0.000 description 9
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 9
- 239000010410 layer Substances 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- 229940002612 prodrug Drugs 0.000 description 9
- 239000000651 prodrug Substances 0.000 description 9
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 9
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 230000004862 vasculogenesis Effects 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
- 210000004349 growth plate Anatomy 0.000 description 7
- 238000001727 in vivo Methods 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 235000011121 sodium hydroxide Nutrition 0.000 description 7
- CTEDVGRUGMPBHE-UHFFFAOYSA-N tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate Chemical class CC(C)(C)OC(=O)N1CCC(CO)CC1 CTEDVGRUGMPBHE-UHFFFAOYSA-N 0.000 description 7
- 210000004204 blood vessel Anatomy 0.000 description 6
- 150000001721 carbon Chemical group 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
- 238000004440 column chromatography Methods 0.000 description 6
- UQLDLKMNUJERMK-UHFFFAOYSA-L di(octadecanoyloxy)lead Chemical compound [Pb+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O UQLDLKMNUJERMK-UHFFFAOYSA-L 0.000 description 6
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Chemical compound CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- CNFDGXZLMLFIJV-UHFFFAOYSA-L manganese(II) chloride tetrahydrate Chemical compound O.O.O.O.[Cl-].[Cl-].[Mn+2] CNFDGXZLMLFIJV-UHFFFAOYSA-L 0.000 description 6
- 239000002953 phosphate buffered saline Substances 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- 239000012312 sodium hydride Substances 0.000 description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 235000019253 formic acid Nutrition 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- 238000007363 ring formation reaction Methods 0.000 description 5
- 210000002303 tibia Anatomy 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 231100000027 toxicology Toxicity 0.000 description 5
- 210000000689 upper leg Anatomy 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 4
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-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
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- 102000013275 Somatomedins Human genes 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 230000033228 biological regulation Effects 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 235000015320 potassium carbonate Nutrition 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 241000701447 unidentified baculovirus Species 0.000 description 4
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 206010003210 Arteriosclerosis Diseases 0.000 description 3
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- SKTKSJPHMKCYGX-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CCC(CC1)COS(=O)(=O)C1=CC=C(C=C1)CN Chemical class C(C)(C)(C)OC(=O)N1CCC(CC1)COS(=O)(=O)C1=CC=C(C=C1)CN SKTKSJPHMKCYGX-UHFFFAOYSA-N 0.000 description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 3
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 3
- 201000004681 Psoriasis Diseases 0.000 description 3
- 238000000692 Student's t-test Methods 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 108091008605 VEGF receptors Proteins 0.000 description 3
- 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 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229940098773 bovine serum albumin Drugs 0.000 description 3
- 210000000845 cartilage Anatomy 0.000 description 3
- 229960001681 croscarmellose sodium Drugs 0.000 description 3
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000003810 ethyl acetate extraction Methods 0.000 description 3
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 229930182817 methionine Natural products 0.000 description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 3
- 235000010755 mineral Nutrition 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 230000026731 phosphorylation Effects 0.000 description 3
- 238000006366 phosphorylation reaction Methods 0.000 description 3
- 229910052697 platinum Inorganic materials 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000000452 restraining effect Effects 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 229960001866 silicon dioxide Drugs 0.000 description 3
- 239000001488 sodium phosphate Substances 0.000 description 3
- 229910000162 sodium phosphate Inorganic materials 0.000 description 3
- 238000010025 steaming Methods 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 231100000820 toxicity test Toxicity 0.000 description 3
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 3
- 206010055031 vascular neoplasm Diseases 0.000 description 3
- 239000008215 water for injection Substances 0.000 description 3
- KJZLJGZZDNGGCA-UHFFFAOYSA-N (1-methylpiperidin-4-yl)methanol Chemical compound CN1CCC(CO)CC1 KJZLJGZZDNGGCA-UHFFFAOYSA-N 0.000 description 2
- XNMQEEKYCVKGBD-UHFFFAOYSA-N 2-butyne Chemical compound CC#CC XNMQEEKYCVKGBD-UHFFFAOYSA-N 0.000 description 2
- ZQEXBVHABAJPHJ-UHFFFAOYSA-N 2-fluoro-4-methylaniline Chemical compound CC1=CC=C(N)C(F)=C1 ZQEXBVHABAJPHJ-UHFFFAOYSA-N 0.000 description 2
- GHCZTIFQWKKGSB-UHFFFAOYSA-N 2-hydroxypropane-1,2,3-tricarboxylic acid;phosphoric acid Chemical class OP(O)(O)=O.OC(=O)CC(O)(C(O)=O)CC(O)=O GHCZTIFQWKKGSB-UHFFFAOYSA-N 0.000 description 2
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- GZRMNMGWNKSANY-UHFFFAOYSA-N 4-bromo-2-fluoroaniline Chemical compound NC1=CC=C(Br)C=C1F GZRMNMGWNKSANY-UHFFFAOYSA-N 0.000 description 2
- AKDPHEYBBWDWCM-UHFFFAOYSA-N 4-chloro-2,6-difluoroaniline Chemical compound NC1=C(F)C=C(Cl)C=C1F AKDPHEYBBWDWCM-UHFFFAOYSA-N 0.000 description 2
- CSFDTBRRIBJILD-UHFFFAOYSA-N 4-chloro-2-fluoroaniline Chemical compound NC1=CC=C(Cl)C=C1F CSFDTBRRIBJILD-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 102400000068 Angiostatin Human genes 0.000 description 2
- 108010079709 Angiostatins Proteins 0.000 description 2
- 206010051113 Arterial restenosis Diseases 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 206010013908 Dysfunctional uterine bleeding Diseases 0.000 description 2
- 201000009273 Endometriosis Diseases 0.000 description 2
- 102400001047 Endostatin Human genes 0.000 description 2
- 108010079505 Endostatins Proteins 0.000 description 2
- MWAYRGBWOVHDDZ-UHFFFAOYSA-N Ethyl vanillate Chemical compound CCOC(=O)C1=CC=C(O)C(OC)=C1 MWAYRGBWOVHDDZ-UHFFFAOYSA-N 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 241000238631 Hexapoda Species 0.000 description 2
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 206010027514 Metrorrhagia Diseases 0.000 description 2
- 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 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CWHJIJJSDGEHNS-MYLFLSLOSA-N Senegenin Chemical compound C1[C@H](O)[C@H](O)[C@@](C)(C(O)=O)[C@@H]2CC[C@@]3(C)C(CC[C@]4(CCC(C[C@H]44)(C)C)C(O)=O)=C4[C@@H](CCl)C[C@@H]3[C@]21C CWHJIJJSDGEHNS-MYLFLSLOSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 2
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 230000001154 acute effect Effects 0.000 description 2
- 208000038016 acute inflammation Diseases 0.000 description 2
- 230000006022 acute inflammation Effects 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 229930013930 alkaloid Natural products 0.000 description 2
- 150000003797 alkaloid derivatives Chemical class 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 125000000129 anionic group Chemical group 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- FZCSTZYAHCUGEM-UHFFFAOYSA-N aspergillomarasmine B Natural products OC(=O)CNC(C(O)=O)CNC(C(O)=O)CC(O)=O FZCSTZYAHCUGEM-UHFFFAOYSA-N 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 229910052728 basic metal Inorganic materials 0.000 description 2
- 150000003818 basic metals Chemical class 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 125000001589 carboacyl group Chemical group 0.000 description 2
- 235000011089 carbon dioxide Nutrition 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 238000011262 co‐therapy Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 230000000994 depressogenic effect Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 210000002889 endothelial cell Anatomy 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 210000003559 hypertrophic chondrocyte Anatomy 0.000 description 2
- 230000001969 hypertrophic effect Effects 0.000 description 2
- 208000017169 kidney disease Diseases 0.000 description 2
- 108020001756 ligand binding domains Proteins 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 210000005075 mammary gland Anatomy 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000005905 mesyloxy group Chemical group 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 150000002828 nitro derivatives Chemical class 0.000 description 2
- 150000007524 organic acids Chemical group 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 210000002307 prostate Anatomy 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 210000001210 retinal vessel Anatomy 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- YKLJGMBLPUQQOI-UHFFFAOYSA-M sodium;oxidooxy(oxo)borane Chemical compound [Na+].[O-]OB=O YKLJGMBLPUQQOI-UHFFFAOYSA-M 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 229910052722 tritium Inorganic materials 0.000 description 2
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 2
- 238000007738 vacuum evaporation Methods 0.000 description 2
- 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 2
- 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 2
- YJGVMLPVUAXIQN-LGWHJFRWSA-N (5s,5ar,8ar,9r)-5-hydroxy-9-(3,4,5-trimethoxyphenyl)-5a,6,8a,9-tetrahydro-5h-[2]benzofuro[5,6-f][1,3]benzodioxol-8-one Chemical class COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-LGWHJFRWSA-N 0.000 description 1
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 1
- 125000004825 2,2-dimethylpropylene group Chemical group [H]C([H])([H])C(C([H])([H])[H])(C([H])([H])[*:1])C([H])([H])[*:2] 0.000 description 1
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Substances CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 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
- GXVUZYLYWKWJIM-UHFFFAOYSA-N 2-(2-aminoethoxy)ethanamine Chemical compound NCCOCCN GXVUZYLYWKWJIM-UHFFFAOYSA-N 0.000 description 1
- HDECRAPHCDXMIJ-UHFFFAOYSA-N 2-methylbenzenesulfonyl chloride Chemical compound CC1=CC=CC=C1S(Cl)(=O)=O HDECRAPHCDXMIJ-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 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
- 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
- QZFWATQEEPAGAF-UHFFFAOYSA-N 4-chloro-2,6-difluoroaniline;hydrochloride Chemical compound Cl.NC1=C(F)C=C(Cl)C=C1F QZFWATQEEPAGAF-UHFFFAOYSA-N 0.000 description 1
- SGOOQMRIPALTEL-UHFFFAOYSA-N 4-hydroxy-N,1-dimethyl-2-oxo-N-phenyl-3-quinolinecarboxamide Chemical compound OC=1C2=CC=CC=C2N(C)C(=O)C=1C(=O)N(C)C1=CC=CC=C1 SGOOQMRIPALTEL-UHFFFAOYSA-N 0.000 description 1
- FUFZNHHSSMCXCZ-UHFFFAOYSA-N 5-piperidin-4-yl-3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole Chemical compound FC(F)(F)C1=CC=CC(C=2N=C(ON=2)C2CCNCC2)=C1 FUFZNHHSSMCXCZ-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
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 1
- 229940122815 Aromatase inhibitor Drugs 0.000 description 1
- 102000015790 Asparaginase Human genes 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-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
- 108010059108 CD18 Antigens Proteins 0.000 description 1
- 241000208328 Catharanthus Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 1
- ZQZFYGIXNQKOAV-OCEACIFDSA-N Droloxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 ZQZFYGIXNQKOAV-OCEACIFDSA-N 0.000 description 1
- 102000001301 EGF receptor Human genes 0.000 description 1
- 108060006698 EGF receptor Proteins 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 108090000386 Fibroblast Growth Factor 1 Proteins 0.000 description 1
- 102100031706 Fibroblast growth factor 1 Human genes 0.000 description 1
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 1
- 102000003974 Fibroblast growth factor 2 Human genes 0.000 description 1
- 101150048336 Flt1 gene Proteins 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 108010069236 Goserelin Proteins 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 101000904173 Homo sapiens Progonadoliberin-1 Proteins 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- JJKOTMDDZAJTGQ-DQSJHHFOSA-N Idoxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN2CCCC2)=CC=1)/C1=CC=C(I)C=C1 JJKOTMDDZAJTGQ-DQSJHHFOSA-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
- 102100022337 Integrin alpha-V Human genes 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 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
- 102000005741 Metalloproteases Human genes 0.000 description 1
- 108010006035 Metalloproteases Proteins 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-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
- ZSEMWHCVIJETNE-UHFFFAOYSA-N N1=CC=CC2=CC(=C3C=CC=NC3=C12)S(=O)(=O)O.C(C)N1CSC2=C1C=CC=C2 Chemical compound N1=CC=CC2=CC(=C3C=CC=NC3=C12)S(=O)(=O)O.C(C)N1CSC2=C1C=CC=C2 ZSEMWHCVIJETNE-UHFFFAOYSA-N 0.000 description 1
- 229930182507 Neplanocin Natural products 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 235000016408 Podocarpus macrophyllus Nutrition 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 102100024028 Progonadoliberin-1 Human genes 0.000 description 1
- 102000004278 Receptor Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000873 Receptor Protein-Tyrosine Kinases Proteins 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 229940123934 Reductase inhibitor Drugs 0.000 description 1
- 229940121742 Serine/threonine kinase inhibitor Drugs 0.000 description 1
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 description 1
- 241000256251 Spodoptera frugiperda Species 0.000 description 1
- 101000996723 Sus scrofa Gonadotropin-releasing hormone receptor Proteins 0.000 description 1
- 244000162450 Taxus cuspidata Species 0.000 description 1
- 235000009065 Taxus cuspidata Nutrition 0.000 description 1
- 108020005038 Terminator Codon Proteins 0.000 description 1
- 108010022394 Threonine synthase Proteins 0.000 description 1
- 102000005497 Thymidylate Synthase Human genes 0.000 description 1
- IVTVGDXNLFLDRM-HNNXBMFYSA-N Tomudex Chemical compound C=1C=C2NC(C)=NC(=O)C2=CC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)S1 IVTVGDXNLFLDRM-HNNXBMFYSA-N 0.000 description 1
- 101710183280 Topoisomerase Proteins 0.000 description 1
- 102000016549 Vascular Endothelial Growth Factor Receptor-2 Human genes 0.000 description 1
- 102000016663 Vascular Endothelial Growth Factor Receptor-3 Human genes 0.000 description 1
- 108020005202 Viral DNA Proteins 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 description 1
- AIWRTTMUVOZGPW-HSPKUQOVSA-N abarelix Chemical compound C([C@@H](C(=O)N[C@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)N(C)C(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 AIWRTTMUVOZGPW-HSPKUQOVSA-N 0.000 description 1
- 108010023617 abarelix Proteins 0.000 description 1
- 229960002184 abarelix Drugs 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 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 1
- 239000000556 agonist Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000005910 alkyl carbonate group Chemical group 0.000 description 1
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001413 amino acids Chemical group 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 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
- 229960001220 amsacrine Drugs 0.000 description 1
- 229960002932 anastrozole Drugs 0.000 description 1
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 1
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 150000001454 anthracenes Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000000708 anti-progestin effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 239000003080 antimitotic agent Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003418 antiprogestin Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 239000003886 aromatase inhibitor Substances 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
- 238000003556 assay Methods 0.000 description 1
- OHDRQQURAXLVGJ-HLVWOLMTSA-N azane;(2e)-3-ethyl-2-[(e)-(3-ethyl-6-sulfo-1,3-benzothiazol-2-ylidene)hydrazinylidene]-1,3-benzothiazole-6-sulfonic acid Chemical compound [NH4+].[NH4+].S/1C2=CC(S([O-])(=O)=O)=CC=C2N(CC)C\1=N/N=C1/SC2=CC(S([O-])(=O)=O)=CC=C2N1CC OHDRQQURAXLVGJ-HLVWOLMTSA-N 0.000 description 1
- 238000000498 ball milling Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 229960000997 bicalutamide Drugs 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 229960002092 busulfan Drugs 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
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- QNEFNFIKZWUAEQ-UHFFFAOYSA-N carbonic acid;potassium Chemical compound [K].OC(O)=O QNEFNFIKZWUAEQ-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 229950010118 cellacefate Drugs 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- GGRHYQCXXYLUTL-UHFFFAOYSA-N chloromethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCCl GGRHYQCXXYLUTL-UHFFFAOYSA-N 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- LGZKGOGODCLQHG-UHFFFAOYSA-N combretastatin Natural products C1=C(O)C(OC)=CC=C1CC(O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-UHFFFAOYSA-N 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 1
- 229940021171 curative drug Drugs 0.000 description 1
- 229960000978 cyproterone acetate Drugs 0.000 description 1
- UWFYSQMTEOIJJG-FDTZYFLXSA-N cyproterone acetate Chemical compound C1=C(Cl)C2=CC(=O)[C@@H]3C[C@@H]3[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 UWFYSQMTEOIJJG-FDTZYFLXSA-N 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- 230000006378 damage Effects 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
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229950004203 droloxifene Drugs 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 229960001776 edrecolomab Drugs 0.000 description 1
- 230000035616 enchondral ossification Effects 0.000 description 1
- 210000003725 endotheliocyte Anatomy 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- LBAQSKZHMLAFHH-UHFFFAOYSA-N ethoxyethane;hydron;chloride Chemical compound Cl.CCOCC LBAQSKZHMLAFHH-UHFFFAOYSA-N 0.000 description 1
- CHDFNIZLAAFFPX-UHFFFAOYSA-N ethoxyethane;oxolane Chemical compound CCOCC.C1CCOC1 CHDFNIZLAAFFPX-UHFFFAOYSA-N 0.000 description 1
- GSQLMBQLTPEPHD-UHFFFAOYSA-N ethyl 3-methoxybenzoate Chemical compound CCOC(=O)C1=CC=CC(OC)=C1 GSQLMBQLTPEPHD-UHFFFAOYSA-N 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 229960005420 etoposide Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 229960000255 exemestane Drugs 0.000 description 1
- 210000000521 femorotibial joint Anatomy 0.000 description 1
- 230000008175 fetal development Effects 0.000 description 1
- 230000008442 fetal wound healing Effects 0.000 description 1
- DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 description 1
- 229960004039 finasteride Drugs 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- 229960002074 flutamide Drugs 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- XLXSAKCOAKORKW-UHFFFAOYSA-N gonadorelin Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 XLXSAKCOAKORKW-UHFFFAOYSA-N 0.000 description 1
- 229960003690 goserelin acetate Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 229950002248 idoxifene Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 150000002485 inorganic esters Chemical class 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound 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 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 235000012204 lemonade/lime carbonate Nutrition 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 1
- 239000008263 liquid aerosol Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 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
- OCSMOTCMPXTDND-OUAUKWLOSA-N marimastat Chemical compound CNC(=O)[C@H](C(C)(C)C)NC(=O)[C@H](CC(C)C)[C@H](O)C(=O)NO OCSMOTCMPXTDND-OUAUKWLOSA-N 0.000 description 1
- 229950008959 marimastat Drugs 0.000 description 1
- 108010082117 matrigel Proteins 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- RTWNYYOXLSILQN-UHFFFAOYSA-N methanediamine Chemical compound NCN RTWNYYOXLSILQN-UHFFFAOYSA-N 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 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
- 229960004857 mitomycin Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000002969 morbid Effects 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 229940087004 mustargen Drugs 0.000 description 1
- BLCLNMBMMGCOAS-UHFFFAOYSA-N n-[1-[[1-[[1-[[1-[[1-[[1-[[1-[2-[(carbamoylamino)carbamoyl]pyrrolidin-1-yl]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amin Chemical compound C1CCC(C(=O)NNC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)C(COC(C)(C)C)NC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 BLCLNMBMMGCOAS-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 description 1
- 229960002653 nilutamide Drugs 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- OSTGTTZJOCZWJG-UHFFFAOYSA-N nitrosourea Chemical compound NC(=O)N=NO OSTGTTZJOCZWJG-UHFFFAOYSA-N 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 239000012053 oil suspension Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- PTMHPRAIXMAOOB-UHFFFAOYSA-N phosphoramidic acid Chemical compound NP(O)(O)=O PTMHPRAIXMAOOB-UHFFFAOYSA-N 0.000 description 1
- 229940061584 phosphoramidic acid Drugs 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- JPMRTCFFXGDMRI-UHFFFAOYSA-N quinazolin-3-ium 2,2,2-trifluoroacetate Chemical compound OC(=O)C(F)(F)F.c1ccc2ncncc2c1 JPMRTCFFXGDMRI-UHFFFAOYSA-N 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 229960004622 raloxifene Drugs 0.000 description 1
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
- 229960004432 raltitrexed Drugs 0.000 description 1
- 229920005604 random copolymer Polymers 0.000 description 1
- 229960000460 razoxane Drugs 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
- 239000011541 reaction mixture Substances 0.000 description 1
- 229940124617 receptor tyrosine kinase inhibitor Drugs 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229960003522 roquinimex Drugs 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 108091008601 sVEGFR Proteins 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000005204 segregation Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- CMZUMMUJMWNLFH-UHFFFAOYSA-N sodium metavanadate Chemical compound [Na+].[O-][V](=O)=O CMZUMMUJMWNLFH-UHFFFAOYSA-N 0.000 description 1
- ZOFJBHYCGASUQK-UHFFFAOYSA-N sodium;trimethylsilylazanide Chemical compound [Na+].C[Si](C)(C)[NH-] ZOFJBHYCGASUQK-UHFFFAOYSA-N 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 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 1
- 229940063683 taxotere 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
- 239000009871 tenuigenin Substances 0.000 description 1
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 1
- 229940048102 triphosphoric acid Drugs 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 210000003606 umbilical vein Anatomy 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 230000007998 vessel formation Effects 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 229960001771 vorozole Drugs 0.000 description 1
- XLMPPFTZALNBFS-INIZCTEOSA-N vorozole Chemical compound C1([C@@H](C2=CC=C3N=NN(C3=C2)C)N2N=CN=C2)=CC=C(Cl)C=C1 XLMPPFTZALNBFS-INIZCTEOSA-N 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 238000002689 xenotransplantation Methods 0.000 description 1
- 229910000166 zirconium phosphate Inorganic materials 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
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- 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
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- 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
- 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
- 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
-
- 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
- A61P35/00—Antineoplastic agents
-
- 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
-
- 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
- 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
- A61P9/10—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
Abstract
本发明涉及式(I)的喹唑啉衍生物及其盐,其中m是1至3的整数;R1表示卤素或C1-3烷基;X1表示-O-;R2选自如下三组之一:1)C1-5烷基R3(其中R3是哌啶-4-基,其可以带有一个或两个选自羟基、卤素、C1-4烷基、C1-4羟基烷基和C1-4烷氧基的取代基);2)C2-5链烯基R3(其中R3如上所定义);3)C2-5链炔基R3(其中R3如上所定义);并且其中的烷基、链烯基或链炔基均可以带有一个或多个选自羟基、卤素和氨基的取代基;其制备方法、含有式(I)化合物或其可药周盐作为活性成分的药物组合物。式I化合物及其可药用盐可以抑制VEGF的作用,该特性可用于治疗多种疾病状态,包括癌症和类风湿性关节炎。
Description
本发明涉及喹唑啉衍生物、其制备方法、含有该化合物作为活性成分的药物组合物、治疗与血管生成和/或血管通透性增加有关的疾病状态的方法、该化合物作为药物的用途及其在生产用于在温血动物例如人中产生抗血管生成和/或降低血管通透性作用的药物中的用途。
正常的血管生成在许多过程,包括胚胎发育、伤口愈合以及女性生殖功能的多种成分中起重要作用。不希望的或病理性的血管生成与糖尿病性视网膜病、牛皮癣、癌症、类风湿性关节炎、动脉粥样化、卡波济氏肉瘤和血管瘤等疾病状态有关(Fan等,1995,TrendsPharmacol.Sci.16:57-66;Folkman,1995,Nature Medicine 1:27-31)。血管通透性的改变被认为在正常的和病理性的生理学过程中均起作用(Cullinan-Bove等,1993,Endocrinology 133:829-837;Senger等,1993,Cancer and Metastasis Reviews,12:303-324)。已经确定了多种具有体外内皮细胞生长促进活性的多肽,包括酸性和碱性成纤维细胞生长因子(aFGF&bFGF)和血管内皮生长因子(VEGF)。由于VEGF受体的限制性表达,VEGF的生长因子活性与FGF相比对内皮细胞的特异性相对较强。最近的证据表明,VEGF是正常的以及病理性血管生成(Jakeman等,1993,Endocrinology,133 848-859;Kolch等,1995,Breast Cancer Research and Treatment,36:139-155)和血管通透性(Connolly等,1989,J.Biol.Chem.264:20017-20024)的重要刺激物。通过用抗体隔离VEGF来拮抗VEGF的作用可以引起肿瘤生长抑制(Kim等,1993,Nature 362:841-844)。
受体酪氨酸激酶(RTK)在生物化学信号的跨细胞质膜传导中是非常重要的。这些跨膜分子特征性地构成了细胞外的配体结合结构域,该配体结合结构域通过质膜内的部分与细胞内的酪氨酸激酶结构域相连。配体与受体的结合引起对受体相关性酪氨酸激酶活性的刺激,从而引起受体和其它细胞内分子上的酪氨酸残基的磷酸化。这些酪氨酸磷酸化的改变可以引发导致各种细胞应答的信号级联。迄今为止,已证实了至少19种不同的RTK亚族,这些亚族是根据氨基酸序列的同源性定义的。其中的一个亚族目前包括fms-类酪氨酸激酶受体Flt或Flt1、含有激酶插入结构域的受体、KDR(也称为Flk-1)和另一种fms-类酪氨酸激酶受体Flt4。这些相关的RTK,Flt和KDR中的两种显示出能够以高亲和性与VEGF结合(De Vries等,1992,Science 255:989-991;Terman等,1992,Biochem.Biophys.Res.Comm.1992,187:1579-1586)。VEGF与这些表达在异种细胞上的受体的结合与细胞蛋白的酪氨酸磷酸化状态改变以及钙流有关。
在国际专利申请公开号WO 97/30035和WO 98/13354中记载了是VEGF受体酪氨酸激酶抑制剂的喹唑啉衍生物。在WO 97/30035和WO98/13354中,记载了具有抗VEGF受体酪氨酸激酶活性并同时具有一定的抗EGF受体酪氨酸激酶活性的化合物。
本发明的化合物包括在WO 97/30035和WO 98/13354的一般性公开的宽范围之内。我们发现,本发明的化合物对VEGF受体酪氨酸激酶具有非常好的抑制活性。所测试的本发明化合物对小鼠的多种肿瘤异种移植物显示出体内活性。当对大鼠进行14天的测试时,本发明的化合物显示出良好的毒理学特性。本发明的化合物对VEGF受体酪氨酸激酶具有非常好的抑制活性,对小鼠的多种肿瘤异种移植物显示出体内活性,并且当对大鼠进行14天的测试时,具有良好的毒理学特性。
本发明的化合物抑制VEGF的作用,该特性可用于治疗与血管生成和/或血管通透性增加有关的疾病状态,例如癌症、糖尿病、牛皮癣、类风湿性关节炎、卡波济氏肉瘤、血管瘤、急性和慢性肾病、动脉粥样化、动脉再狭窄、自身免疫疾病、急性炎症、过度疤痕形成和粘连、子宫内膜异位、机能障碍性子宫出血和存在视网膜血管增生的眼病。
本发明的化合物具有良好的抗VEGF受体酪氨酸激酶活性并同时具有一定的抗EGF受体酪氨酸激酶活性。
此外,某些本发明的化合物对VEGF受体酪氨酸激酶的效力明显高于对EGF受体酪氨酸激酶或FGF R1受体酪氨酸激酶的效力。不希望受到理论的束缚,这些化合物可用于例如治疗与VEGF有关的肿瘤,特别是那些在其生长中依赖VEGF的肿瘤。此外还确信,这些化合物可用于治疗与VEGF和EGF均有关的肿瘤,特别是当患者所患的肿瘤在其生长中同时依赖VEGF和EGF时。
一方面,本发明提供了式I的喹唑啉衍生物:
其中:
m是1至3的整数;
R1表示卤素或C1-3烷基;
X1表示-O-;
R2选自如下三组之一:
1)C1-5烷基R3(其中R3是哌啶-4-基,其可以带有一个或两个选自羟基、卤素、C1-4烷基、C1-4羟基烷基和C1-4烷氧基的取代基);
2)C2-5链烯基R3(其中R3如上所定义);
3)C2-5链炔基R3(其中R3如上所定义);
并且其中的烷基、链烯基或链炔基均可以带有一个或多个选自羟基、卤素和氨基的取代基;
或其盐或其前药。
优选m是2。
优选带有(R1)m的苯基选自2-氟-4-甲基苯基、4-氯-2,6-二氟苯基、4-溴-2,6-二氟苯基、4-氯-2-氟苯基和4-溴-2-氟苯基。
更优选带有(R1)m的苯基选自4-氯-2-氟苯基和4-溴-2-氟苯基。
首选带有(R1)m的苯基是4-溴-2-氟苯基。
优选R2是C1-5烷基R3(其中R3如上所定义)。
更优选R2是C1-3烷基R3(其中R3如上所定义)。
具体地讲,R2是哌啶-4-基甲基,其中的哌啶环可以带有一个或两个如上所定义的取代基。
更具体地讲,R2是哌啶-4-基甲基,其中的哌啶环可以带有一个或两个选自C1-4烷基的取代基。
特别优选R2是1-甲基哌啶-4-基甲基。
另一方面,本发明提供了式II的喹唑啉衍生物:
其中:ma是1至3的整数;
R1a表示卤素或C1-3烷基;
X1a表示-O-;
R2a选自如下三组之一:
1)C1-5烷基R3(其中R3如上所定义);
2)C2-5链烯基R3(其中R3如上所定义);
3)C2-5链炔基R3(其中R3如上所定义);
或其盐或其前药。
优选ma是2。
优选带有(R14)ma的苯基选自2-氟-4-甲基苯基、4-氯-2,6-二氟苯基、4-溴-2,6-二氟苯基、4-氯-2-氟苯基和4-溴-2-氟苯基。
更优选带有(R1a)ma的苯基选自4-氯-2-氟苯基和4-溴-2-氟苯基。
首选带有(R1a)ma的苯基是4-溴-2-氟苯基。
优选R2a是C1-5烷基R3(其中R3如上所定义)。
更优选R2a是C1-3烷基R3(其中R3如上所定义)。
具体地讲,R2a是哌啶-4-基甲基,其中的哌啶环可以带有一个或两个如上所定义的取代基。
更具体地讲,R2a是哌啶-4-基甲基,其中的哌啶环可以带有一个或两个选自C1-4烷基的取代基。
特别优选R2a是1-甲基哌啶-4-基甲基。
优选的本发明化合物包括:
4-(4-氯-2-氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉,
4-(2-氟-4-甲基苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉,
4-(4-溴-2-氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉,
4-(4-氯-2,6-二氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉,
4-(4-溴-2,6-二氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉,
4-(4-氯-2-氟苯氨基)-6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉,
4-(2-氟-4-甲基苯氨基)-6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉,
4-(4-溴-2-氟苯氨基)-6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉,
4-(4-氯-2,6-二氟苯氨基)-6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉,和
4-(4-溴-2,6-二氟苯氨基)-6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉及其盐、特别是其盐酸盐。
更优选的本发明化合物包括:
4-(4-氯-2-氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉,
4-(4-溴-2-氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉,
4-(4-氯-2,6-二氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉,
4-(4-溴-2,6-二氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉,
4-(4-氯-2-氟苯氨基)-6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉,
4-(4-溴-2-氟苯氨基)-6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉,
4-(4-氯-2,6-二氟苯氨基)-6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉,和
4-(4-溴-2,6-二氟苯氨基)-6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉及其盐、特别是其盐酸盐。
特别优选的本发明化合物包括:
4-(4-氯-2-氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉,
4-(4-溴-2-氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉,
4-(4-氯-2,6-二氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉,和
4-(4-溴-2,6-二氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉及其盐、特别是其盐酸盐。
更特别优选的本发明化合物包括:
4-(4-氯-2-氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉和
4-(4-溴-2-氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉及其盐、特别是其盐酸盐。
尤其优选的本发明化合物是4-(4-溴-2-氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉及其盐、特别是其盐酸盐。
为了避免误解,应当理解,当在本说明书中提到某个基团“如上所定义”时,所述的基团包括了首次出现的和最宽的定义以及对于该基团的各个和所有的优选定义。类似的规定也适用于“如下所定义的”。
在本说明书中,若无另外说明,术语“烷基”包括直链和支链的烷基,但对于单指的烷基例如“丙基”,则特指直链的形式。类似的规定还适用于其它类属的术语。若无另外说明,术语“烷基”主要是指含有1-5个碳原子的烷基链,优选1-3个碳原子。若无另外说明,文中所用的术语“烷氧基”包括“烷基”-O-基团,其中的“烷基”如上所定义。若无另外说明,文中所用的术语“芳基”包括C6-10芳基,如需要,该基团还可以带有一个或多个选自卤素、烷基、烷氧基、硝基、三氟甲基和氰基的取代基,其中的烷基和烷氧基如上所定义。若无另外说明,文中所用的术语“芳氧基”包括“芳基”-O-基团,其中的“芳基”如上所定义。文中所用的术语“磺酰氧基”是指烷基磺酰氧基和芳基磺酰氧基,其中的“烷基”和“芳基”如上所定义。若无另外说明,文中所用的术语“链烷酰基”包括甲酰基和烷基C=O基团,其中的“烷基”如上所定义,例如,C2链烷酰基是乙酰基,是指CH3C=O,C1链烷酰基是甲酰基,指CHO。在本说明书中,若无另外说明,术语“链烯基”包括直链和支链的链烯基,但对于单指的链烯基例如2-丁烯基,则特指直链的形式。若无另外说明,术语“链烯基”主要是指含有2-5个碳原子、优选3-5个碳原子的链。在本说明书中,若无另外说明,术语“链炔基”包括直链和支链的链炔基,但对于单指的链炔基例如2-丁炔基,则特指直链的形式。若无另外说明,术语“链炔基”主要是指含有2-5个碳原子、优选3-5个碳原子的链。
在以上定义的式I中,氢可以存在于喹唑啉基团的2、5和8位。
在本发明中,应当理解,式I化合物或其盐可以表现出互变异构现象,在本说明书中所画出的结构式仅代表了其中一种可能的互变异构体形式。应当理解,本发明包括所有可以抑制VEGF受体酪氨酸激酶活性的互变异构体形式,并不仅限于结构式图中所采用的任何一种互变异构体形式。
还应当理解,某些式I化合物及其盐可以以溶剂化物以及非溶剂化物的形式、例如水合物的形式存在。应当理解,本发明包括所有可以抑制VEGF受体酪氨酸激酶活性的溶剂化物形式。
为了避免误解,应当理解,在式I化合物中,当R2是例如式C2-5链烯基R3的基团时,是链烯基部分与X1相连,类似的规定也适用于其它基团。当R2是基团1-R3丙-1-烯-3-基时,基团R3与第一个碳相连,X1与第三个碳相连,同样,当R2是基团2-R3戊-3-烯-5-基时,基团R3与第二个碳相连,X1与第五个碳相连,类似的规定也适用于其它基团。
式I化合物可以以前药的形式给药,所述前药可以在人或动物体内分解产生式I化合物。前药的例子包括可以在体内水解的式I化合物的酯。
各种形式的前药是现有技术中已知的。所述前药衍生物的例子可以参见:
a)Design of Prodrugs,H.Bundgaard编,(Elsevier,1985)和Method sin Enzymology,42卷,309-396页,K.Widder等编(Academic Press,1985);
b)A Textbook of Drug Design and Development,Krogsgaard-Larsen和H.Bundgaard编,第5章“前药的设计和应用”,H.Bundgaard,113-191页(1991);
c)H.Bundgaard,Advanced Drug Delivery Reviews,8,1-38(1992);
d)H.Bundgaard等,Journal of Pharmaceutical Sciences,77,285(1988);和
e)N.Kakeya等,Chem Pharm Bull,32692(1984)。
含羟基式I化合物的可以在体内水解的酯包括无机酯例如磷酸酯(包括氨基磷酸的环状酯)和a-酰氧基烷基醚以及可以由于酯在体内的水解而分解产生母体羟基的相关化合物。a-酰氧基烷基醚的例子包括乙酰氧基甲氧基和2,2-二甲基丙酰氧基-甲氧基。可以使羟基形成可在体内水解的酯的基团包括链烷酰基、苯甲酰基、苯乙酰基和取代的苯甲酰基和苯乙酰基、烷氧基羰基(生成烷基碳酸酯)、二烷基氨基甲酰基和N-(二烷基氨基乙基)-N-烷基氨基甲酰基(生成氨基甲酸酯)、二烷基氨基乙酰基和羧基乙酰基。苯甲酰基上的取代基的例子包括由环氮原子通过亚甲基连接在苯甲酰基环的3-或4-位上的吗啉代和1-哌嗪基。
本发明涉及以上所定义的式I化合物及其盐。用于药物组合物的盐应是可药用盐,但其它的盐可用于制备式I化合物及其可药用盐。本发明的可药用盐可以包括例如具有足够的碱性以形成盐的以上所定义的式I化合物的酸加成盐。所述酸加成盐包括例如与可以提供可药用阴离子的无机或有机酸形成的盐,例如与氢卤酸(特别是盐酸或氢溴酸,特别优选盐酸)、硫酸、磷酸、三氟乙酸、柠檬酸或马来酸形成的盐。此外,当式I化合物具有足够的酸性时,还可与可以提供可药用阳离子的无机或有机碱形成盐。与无机或有机碱形成的盐包括,例如碱金属盐例如钠或钾盐、碱土金属盐例如钙或镁盐、铵盐或例如与甲胺、二甲胺、三甲胺、哌啶、吗啉或三-(2-羟基乙基)胺形成的盐。
式I化合物或其盐以及本发明的其它化合物(如下所定义)可以通过已知可用于制备化学上相关的化合物的任何方法来制备。所述方法包括,例如欧洲专利申请公开号0520722、0566226、0602851和0635498以及国际专利中请公开号WO 97/22596、WO 97/30035、WO97/32856和WO 98/13354中描述的方法。这些方法构成了本发明的另一个特点并且将在下文中进行描述。所需的原料可以通过常规的有机化学方法得到。在所附的非限定性实施例中描述了所述原料的制备。其它所需的原料可以通过与所描述的方法类似的方法制得,这是一般的有机化学家所熟知的。
因此,如下方法(a)至(d)和(i)至(iv)构成了本发明的另一个特点
式I化合物的合成
(a)式I化合物及其盐可以通过将式III化合物:
(其中R2和X1如上所定义,和L1是可置换的部分)与式IV化合物V反应制得:
(其中R1和m如上所定义),由此得到式I化合物及其盐。适宜的可置换部分L1是例如卤素、烷氧基(优选C1-4烷氧基)、芳氧基或磺酰氧基,例如氯、溴、甲氧基、苯氧基、甲磺酰氧基或甲苯-4-磺酰氧基。
该反应优选在酸或碱的存在下进行。所述的酸是,例如无水的无机酸例如氯化氢。所述的碱是,例如有机胺碱,例如吡啶、2,6-二甲基吡啶、三甲吡啶、4-二甲基氨基吡啶、三乙胺、吗啉、N-甲基吗啉或二氮杂双环[5.4.0]十一碳-7-烯,或是例如碱金属或碱土金属碳酸盐或氢氧化物,例如碳酸钠、碳酸钾、碳酸钙、氢氧化钠或氢氧化钾。或者,所述的碱可以是例如碱金属氢化物例如氢化钠或碱金属或碱土金属氨化物例如氨基钠或二(三甲基硅烷基)氨基钠。反应优选在惰性溶剂或稀释剂的存在下进行,例如醇或酯例如甲醇、乙醇、2-丙醇或乙酸乙酯、卤代溶剂例如二氯甲烷、氯仿或四氯化碳、醚例如四氢呋喃或1,4-二氧六环、芳香烃溶剂例如甲苯或极性非质子溶剂例如N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷-2-酮或二甲亚砜。反应通常在例如10至150℃、优选20至80℃的温度范围内进行。
本发明的化合物可以通过该方法以游离碱的形式得到,或者可以以与H-L1的酸的盐形式得到,其中的L1具有上述含义。如果需要从盐制备游离碱,可将盐用如上所定义的碱通过常规方法处理。
(b)式I化合物及其盐可以通过将式V化合物:
(其中m、X1和R1如上所定义)与式VI化合物在以上所定义的碱的存在下反应方便地制备:
R2-L1(VI)
(其中R2和L1如上所定义);L1是可置换的部分例如卤素或磺酰氧基例如溴或甲磺酰氧基。
L1可以是基团O-+P(Y)3(其中Y是丁基或苯基),在该情况下,式VI化合物通常可以就地形成。该反应优选在碱(如以上方法(a)中所定义)的存在下并且最好在惰性溶剂或稀释剂(如以上方法(a)中所定义)的存在下、有利地在例如10至150℃的温度范围内、通常在约50℃下进行。
(c)式I化合物及其盐可以通过将式VII化合物:
与式VIII化合物反应制得:
R2-X1-H (VIII)
(其中L1、R1、R2、m和X1均如上所定义)。该反应通常在碱(如以上方法(a)中所定义)的存在下并且最好在惰性溶剂或稀释剂(如以上方法(a)中所定义)的存在下、在例如10至150℃的温度范围内、通常在约100℃下进行。
(d)式I化合物及其盐可以通过将式IX化合物脱保护制得:
其中R1、m和X1均如上所定义,R4表示保护了的R2基团,其中R2如上所定义但另外带有一个或多个保护基P2。对保护基P2的选择是有机化学家的一般常识,例如在常规教科书例如“Protective Groups inOrganic Synthesis”T.W.Greene和R.G.M.Wuts,第2版,Wiley1991中所记载的。优选P2是保护基例如氨基甲酸酯(烷氧基羰基)(例如,叔丁氧羰基、叔戊氧羰基、环丁氧羰基、丙氧羰基、甲氧羰基、乙氧羰基、异丙氧羰基、烯丙氧羰基或苄氧羰基)。更优选P2是叔丁氧羰基。该反应优选在酸的存在下进行。所述的酸是,例如无机酸,例如氯化氢、溴化氢或有机酸例如三氟乙酸、三氟甲磺酸。反应可以在惰性溶剂例如二氯甲烷、氯仿以及痕量水的存在下进行。反应通常在例如10-100℃、优选20-80℃的范围内进行。
中间体的合成
(i)其中L1是卤素的式III化合物及其盐可以通过例如将式X化合物的卤化来制备:
(其中R2和X1如上所定义)。
常用的卤化试剂包括无机酸卤化物,例如亚硫酰氯、三氯化磷(III)、三氯氧磷(V)和五氯化磷(V)。卤化反应通常在惰性溶剂或稀释剂例如卤代溶剂如二氯甲烷、氯仿或四氯化碳或芳香烃溶剂例如苯或甲苯的存在下进行。反应通常在例如10至150℃、优选40至100℃的温度范围内进行。
式X化合物及其盐可以通过例如将式XI化合物:
(其中L1如上所定义)与以上所定义的式VIII化合物反应制得。该反应通常在碱(如以上方法(a)中所定义)的存在下并且最好在惰性溶剂或稀释剂(如以上方法(a)中所定义)的存在下、在例如10至150℃的温度范围内、通常在约100℃下进行。
式X化合物及其盐还可以通过将式XII的化合物环化制得:
(其中R2和X1如上所定义,A1是羟基、烷氧基(优选C1-4烷氧基)或氨基),由此形成式X化合物或其盐。环化反应可以通过将其中A1是羟基或烷氧基的式XII化合物与甲酰胺或者可以引起环化从而得到式X化合物或其盐的甲酰胺的等同物例如[3-(二甲基氨基)-2-氮杂亚丙-2-烯基]二甲基氯化铵反应来进行。环化反应在存在甲酰胺作为溶剂或在惰性溶剂或稀释剂例如醚,例如1,4-二氧六环的存在下进行。环化反应通常在升高的温度下进行,优选在80至200℃之间。式X化合物还可以通过将其中A1是氨基的式XII化合物用甲酸或者可以引起环化从而得到式X化合物或其盐的甲酸的等同物环化来制备。可以引起环化的甲酸的等同物包括例如三-C1-4烷氧基甲烷,例如三乙氧基甲烷和三甲氧基甲烷。环化反应通常在催化量的无水酸例如磺酸如对甲苯磺酸和惰性溶剂或稀释剂例如卤代溶剂例如二氯甲烷、氯仿或四氯化碳、醚例如乙醚或四氢呋喃或芳香烃溶剂例如甲苯的存在下进行。环化反应通常在例如10至100℃、优选20至50℃的温度范围内进行。
式XII化合物及其盐还可以通过例如将式XIII化合物中的硝基还原来制备:
(其中R2、X1和A1如上所定义),得到如上所定义的式XII化合物。硝基的还原可以通过已知用于该转化的任何方法来进行。例如,还原可以通过将硝基化合物的溶液在以上所定义的惰性溶剂或稀释剂的存在下、在可以有效催化氢化反应的金属例如钯或铂的存在下氢化来进行。另一种还原剂是活化的金属例如活化的铁(通过例如将铁粉用酸例如盐酸的稀溶液洗涤制得)。因此,还原反应可以通过例如将硝基化合物和活化的金属在溶剂或稀释剂例如水和醇例如甲醇或乙醇的混合物的存在下加热至例如50至150℃,通常是约70℃来进行。
式XIII化合物及其盐可以通过例如将式XIV化合物:
(其中L1和A1如上所定义)与以上所定义的式VIII化合物反应来制备,得到式XIII的化合物。式XIV化合物和式VIII化合物的反应通常在以上方法(c)中所描述的条件下进行。
式XIII化合物及其盐还可以通过将式XV化合物:
(其中X1和A1如上所定义)与以上所定义的式VI化合物反应来制备,得到以上所定义的式XIII化合物。式XV和VI化合物的反应通常在以上方法(b)中所描述的条件下进行。
式III化合物及其盐还可以通过将式XVI化合物:
(其中X1如上所定义,L2表示可置换的保护基部分)与以上所定义的式VI化合物反应来制备,由此得到式III化合物,其中L1是由L2表示。
可以使用其中L2表示苯氧基的式XVI化合物,如需要,所述苯氧基可以带有最多5个、优选最多2个选自卤素、硝基和氰基的取代基。该反应可以在以上方法(b)中所描述的条件下进行。
以上所定义的式XVI化合物及其盐可以通过例如将式XVII化合物脱保护制得:
(其中X1和L2如上所定义,P1表示酚羟基保护基)。对酚羟基保护基P1的选择是有机化学家的一般常识,例如在常规教科书例如“ProtectiveGroups in Organic Synthesis”T.W.Greene和R.G.M.Wuts,第2版,Wiley 1991中所记载的,包括醚(例如甲基、甲氧基甲基、烯丙基和苄基以及被最多两个选自C1-4烷氧基和硝基的取代基取代的苄基)、硅烷基醚(例如叔丁基二苯基硅烷基和叔丁基二甲基硅烷基)、酯(例如乙酸酯和苯甲酸酯)和碳酸酯(例如甲基、苄基和被最多两个选自C1-4烷氧基和硝基的取代基取代的苄基)。脱保护可以通过文献中已知的方法来进行,例如,当P1表示苄基时,脱保护可以通过氢解或用三氟乙酸处理来完成。
所述酚羟基保护基的脱除可以通过已知用于所述转化的任何方法来进行,包括在常规教科书例如上文中所给出的反应条件,或者通过相关的方法来进行。优选的反应条件可以产生羟基衍生物而不会在原料或产物化合物的其它部位发生不希望的反应。例如,当保护基P1是乙酸酯时,转化可以通过将喹唑啉衍生物用以上所定义的碱,包括氨及其单和二烷基化的衍生物处理来完成,反应优选在质子溶剂或助溶剂例如水或醇例如甲醇或乙醇的存在下进行。该反应可以在以上所定义的另外的惰性溶剂或稀释的存在下、在0至50℃、通常在约20℃下进行。
如需要,可将一种式III化合物转化成另一种其中的L1部分不同的式III化合物。因此,例如,其中的L1不是卤素(例如是任选取代的苯氧基)的式III化合物可以通过如下方法转化成其中L1是卤素的式III化合物:将式III化合物(其中的L1不是卤素)水解得到如上所定义的式X化合物,然后向所得到的如上所定义的式X化合物中引入卤化物,得到其中L1表示卤素的式III化合物。
(ii)如上所定义的式V化合物及其盐可以通过将式XIII化合物用例如以上(i)中所描述的方法脱保护制得:
(其中R1、P1、X1和m如上所定义)。
式XVIII化合物及其盐可以通过将以上所定义的式XVII和IV化合物在以上(a)中所描述的条件下反应进行制备,得到式XVIII化合物或其盐。
(iii)以上所定义的式VII化合物及其盐可以通过将式XIX化合物:
(其中L1如上所定义,并且在4-和7-位的L1可以相同或不同)与以上所定义的式IV化合物反应制得,反应通过以上(a)中描述的方法进行。
(iv)式IX化合物可以通过将如上所定义的式V化合物与式XX化合物在以上(b)中描述的条件下反应进行制备:
R4-L1(XX)
其中R4和L1如上所定义,得到式IX化合物或其盐。该反应优选在碱(如以上方法(a)中所定义)的存在下、并且最好在惰性溶剂或稀释剂(如以上方法(a)中所定义)的存在下、在例如10至150℃、通常是20-50℃的温度范围内进行。
当需要式I化合物的可药用盐时,该可药用盐可以通过将所述化合物与例如含有可药用阴离子的酸用常规方法反应制得,或者可以通过将所述化合物与碱通过常规方法反应制得。
需要对可以有效抑制与VEGF受体例如Flt和/或KDR有关的酪氨酸激酶活性以及可以抑制血管生成和/或血管通透性增加的化合物进行鉴定,这也是本发明的主题。这些性质可以用例如以下提出的一种或多种方法进行评估:
(a)体外受体酪氨酸激酶抑制试验
该试验测定测试化合物抑制酪氨酸激酶活性的能力。编码VEGF或表皮生长因子(EGF)受体细胞质结构域的DNA可以通过全基因合成(Edwards M,International Biotechnology Lab5(3),19-25,1987)或通过克隆得到。然后可将其在适当的表达系统中表达以得到具有酪氨酸激酶活性的多肽。例如,发现通过在昆虫细胞中表达重组蛋白得到的VEGF和EGF受体细胞质结构域显示固有的酪氨酸激酶活性。在VEGF受体Flt(基因库登记号X51602)的情况下,从cDNA分离Shibuya等(Oncogene,1990,5:519-524)所描述的编码大部分细胞质结构域、从蛋氨酸783开始并且包含终止密码子的1.7kb的DNA片段然后克隆到杆状病毒置换型载体(例如pAcYM1(参见The BaculovirusExpression System:A Laboratory Guide,L.A.King和R.D.Possee,Chapman和Hall,1992)或pAc360或pBlueBacHis(可从Invitrogen Corporation得到))中。将该重组构建体和病毒DNA(例如Pharmingen BaculoGold)共转染到昆虫细胞(例如草地夜蛾21(Sf21))内以制备重组杆状病毒。(关于装配重组DNA分子以及制备和使用重组杆状病毒的方法的详细描述可以参见常规的教科书例如Sambrook等,1989,Molecular cloning-A Laboratory Manual,第2版,Cold Spring Harbour Laboratory Press,以及O′Reilly等,1992,Baculovirus Expression Vectors-A Laboratory Manual,W.H.Freeman和Co,New York)。关于其它用于试验的酪氨酸激酶,可以克隆从蛋氨酸806(KDR,基因库登记号L04947)和蛋氨酸668(EGF受体,基因库登记号X00588)开始的细胞质片段并以类似的方式表达。
对于cFlt酪氨酸激酶活性的表达,将Sf21细胞用噬斑纯的cFlt重组病毒感染,感染重复数为3,并在48小时后进行收集。将收集的细胞用冰冷的磷酸缓冲盐溶液(PBS)(10mM磷酸钠pH7.4,138mM氯化钠,2.7mM氯化钾)洗涤,然后用1ml HNTG/PMSF每1000万个细胞重新悬浮在冰冷的HNTG/PMSF(20mM Hepes pH7.5,150mM氯化钠,10%v/v甘油,1%v/v Triton X100,1.5mM氯化镁,1mM乙二醇-二(β-氨基乙基醚)N,N,N′,N′-四乙酸(EGTA),1mM PMSF(苯基甲磺酰氟);PMSF在临用前以新制备的100mM甲醇溶液的形式加入)中。将悬浮液以13,000rpm在4℃下离心10分钟,取出上清液(酶储备液)并以等分试样的形式于-70℃下保存。通过用酶稀释液(100mM Hepes pH7.4,0.2mM正钒酸钠,0.1%v/v Triton X100,0.2mM二硫苏糖醇)稀释对每一批新的酶储备液进行滴定。对于一般的批次,将酶储备液用酶稀释液以1∶2000进行稀释,然后将50μl稀释的酶用于各试验孔。
用含有酪氨酸的无规共聚物例如聚(Glu,Ala,Tyr)6∶3∶1(Sigma P3899)制备底物溶液的储备液,以1mg/ml在PBS中的储备液的形式于-20℃下保存,然后用PBS以1比500进行稀释用于平板涂覆。
在试验前一天,将100μl稀释的底物溶液分别加入试验平板(Nuncmaxisorp 96孔免疫平板)的所有的孔中,将孔密封然后于4℃放置过夜。
在试验的当天,弃去底物溶液并将试验平板的孔用PBST(含有0.05%v/v Tween 20的PBS)洗涤一次,然后用50mM Hepes pH 7.4洗涤一次。
将试验化合物用10%二甲亚砜(DMSO)稀释并将25μl稀释了的化合物转移到洗涤过的试验平板的孔中。“总”对照孔含有10%DMSO代替化合物。将25μl含有8μM腺苷-5′-三磷酸(ATP)的40mM氯化锰(II)加入到所有的试验孔中,“空白”对照孔除外,“空白”对照孔含有不含ATP的氯化锰(II)。为了开始反应,将50μl新稀释的酶加入各孔中并将平板在室温下保温20分钟。然后除去液体并将各孔用PBST洗涤两次。向各孔中加入100μl小鼠IgG抗-磷酸酪氨酸抗体(UpstateBiotechnology Inc.产品05-321,以1比6000用含有0.5%w/v牛血清白蛋白(BSA)的PBST稀释)并将平板在室温下保温1小时,然后除去液体并将各孔用PBST洗涤两次。加入100μl辣根过氧化物酶(HRP)-键接的绵羊抗小鼠Ig抗体(Amersham产品NXA 931,以1比500用含有0.5%w/v BSA的PBST稀释)并将平板在室温下保温1小时,然后除去液体并将各孔用PBST洗涤两次。向各孔中加入100μl新制备的2,2′-连氮-二(3-乙基苯并噻唑啉-6-磺酸)(ABTS)溶液(用一粒50mg的ABTS片(Boehringer 1204521)在50ml新制备的50mM磷酸盐-柠檬酸盐缓冲液pH 5.0+0.03%过硼酸钠(用1粒含有过硼酸钠的磷酸盐柠檬酸盐缓冲(PCSB)胶囊(Sigma P4922)在100ml蒸馏水中制备)中制备)。然后将平板在室温下保温20-60分钟,直至“总”对照孔的光密度值约为1.0(用平板读数分光光度计在405nm下测定)。用“空白”(无ATP)和“总”(无化合物)对照值测定对酶的活性产生50%抑制的测试化合物的稀释范围。
(b)体外HUVEC增殖试验
该试验测定测试化合物抑制生长因子刺激的人脐静脉内皮细胞(HUVEC)增殖的能力。
将HUVEC细胞分离于MCDB 131(Gibco BRL)+7.5%v/v胎牛血清(FCS)中然后以1000个细胞/孔的浓度在96孔板上在MCDB 131+2%v/v FCS+3μg/ml肝素+1μg/ml氢化可的松中铺平板(2~8代)。最少在4小时后,向其中加入适宜的生长因子(即VEGF 3ng/ml、EGF3ng/ml或b-FGF 0.3ng/ml)和化合物。然后将培养物在37℃及7.5%二氧化碳下保温4天。在第4天,将培养物用1μCi/孔的氚代-胸腺嘧啶核甙(Amersham产品TRA 61)刺激并保温4小时。用96孔平板收集器(Tomtek)收集细胞然后用β平板计数器测定氚的掺入量。用掺入细胞的放射性(用cpm表示)测定化合物对生长因子刺激的细胞增殖的抑制作用。
(c)体内实体瘤疾病模型
该试验测定化合物抑制实体瘤生长的能力。
通过皮下注射在100μl 50%(v/v)Matrigel的无血清培养基溶液中的1x 106 CaLu-6细胞/小鼠在雌性无胸腺Swiss nu/nu小鼠的胁腹建立CaLu-6肿瘤异种移植。细胞移植10天后,将小鼠分成8-10组,以获得可比较的组平均体积。用游标卡尺测量肿瘤并按照如下方法计算体积:(1xw)x√(1xw)x(π/6),其中1是最长的直经,w是与最长的直径垂直的直径。将测试化合物每天一次口服给药至少21天,对照动物接受化合物的稀释剂。每周测量肿瘤两次。通过将对照组的平均肿瘤体积与治疗组相比计算出生长抑制水平,并用学生t试验和/或Mann-Whitney秩和试验确定统计学显著性。当p<0.05时,认为化合物的抑制作用具有显著性。
本发明化合物的毒理学特性可以用例如下文描述的大鼠14天研究来评估。
(d)大鼠的14天毒性试验
该试验测定化合物增加远侧股骨和近侧胫骨的股骨骺生长板的肥大区的活性,并评估其它组织的组织病理学改变。
血管生成是长骨伸长过程中软骨骨化的必需事件,曾有人提出生长板的血管侵入依赖于肥大软骨细胞生产VEGF。在用可以特异性结合VEGF的物质治疗后,例如,(i)用可溶性VEGF受体嵌合蛋白(Flt-(1-3)-IgG)在小鼠中(Gerber,H-P.,Vu,T.H.,Ryan,A.M.,Kowalski,J.,Werb,Z.和Ferrara,N.VEGF将软骨成骨形成过程中的肥大软骨改造、骨化和血管生成联系起来,Nature Med.,5:623-628,1999)和(ii)用重组人源化的抗-VEGF单克隆IgGI抗体在Cynomologus猴中(Ryan,A.M.,Eppler,D.B.,Hagler,K.E.,Bruner,R.H.,Thomford,P.J.,Hall,R.L.,Shopp,G.M.和O′Niell,C.A.rhuMAbVEGF-一种抗血管生成的人源化单克隆抗体-的临床前安全性评估,Tox.Path.,27:78-86,1999),证实了肥大软骨细胞区的扩展和血管生成的抑制。
因此,VEGF受体酪氨酸激酶活性的抑制剂应当还可以抑制软骨的血管侵入,并且在生长的动物中增加远侧股骨和近侧胫骨的股骨骺生长板的肥大区。
将化合物通过用球磨于4℃下研磨过夜(至少15小时)悬浮在1%(v/v)聚氧乙烯(20)脱水山梨醇一油酸酯的去离子水溶液中。在临给药前,通过搅拌使化合物重新悬浮。通过管饲法每日一次向幼小的Alderley Park大鼠(得自Wistar,体重135-150g,4至8周龄,每组5-6只)口服给药化合物(0.25ml/100g体重)或赋形剂,连续给药14天。在第15天,用高浓度的二氧化碳处死动物并进行尸体剖检。收集包括股胫关节的一系列组织,然后通过常规的组织学技术进行加工以制备石蜡切片。将组织学切片用苏木精和曙红进行染色并通过光学显微镜进行组织病理学检查。用形态测定图像分析测定股骨和胫骨切片中远侧股骨和近侧胫骨的股骨骺生长板面积。通过将对照组的平均骺生长板面积与治疗组相比较确定出肥大区域的增加,并用单尾的学生t试验确定统计学显著性。当p<0.05时,认为化合物的抑制作用具有显著性。
虽然式I化合物的药理学特性随着结构的改变而改变,但通常可以在如下浓度或剂量下在一个或多个以上的试验(a)、(b)、(c)和(d)中证实式I化合物所具有的活性:
试验(a):-IC50在例如<5μM的范围内;
试验(b):-IC50在例如0.001-5μM的范围内;
试验(c):-活性在例如0.1-100mg/kg的范围内;
试验(d):-活性在例如0.1-100mg/kg的范围内。
根据本发明的一个方面,在大鼠的14天毒性试验中评估时,式I化合物具有优于国际专利申请公开号WO 98/13354范围内的其它化合物的毒理学特性。
根据本发明的另一个方面,在大鼠的14天毒性试验中评估时,式I化合物具有优于国际专利申请公开号WO 97/30035范围内的其它化合物的毒理学特性。
虽然式I化合物的药理学特性随着结构的改变而改变并且在不同物种之间有所不同,但在大鼠中,在可以使远侧股骨和/或近侧胫骨的股骨骺生长板面积产生具有统计学显著性的增加的式I化合物的剂量下、优选在小于或等于150mg/kg的剂量下、更优选在小于或等于100mg/kg的剂量下、特别是在小于或等于50mg/kg剂量下,在我们所进行的试验(d)中,不会在其它组织中产生不可接受的组织病理学改变。
因此,例如,化合物4-(4-溴-2-氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉(实施例2),在按照上述(a)、(b)、(c)和(d)进行试验时,给出如下结果:
(a)Flt-IC50为1.6μM
KDR-IC50为0.04μM
EGFR-IC50为0.5μM
(b)VEGF-IC50为0.06μM
EGF-IC50为0.17μM
基础-IC50>3μM
(c)在50mg/kg的剂量下,对肿瘤生长的抑制为78%;p<0.001(Mann-Whitney秩和试验);
(d)在100mg/kg/天的剂量下,在雌性大鼠中引起骺生长板肥大增加了75%;p<0.001(单尾的学生t试验)。
根据本发明的另一个方面,本发明提供了含有如上所定义的式I化合物或其可药用盐以及可药用赋形剂或载体的组合物。
该组合物可以是适于口服给药的形式(例如片剂、锭剂、硬或软胶囊、水或油混悬剂、乳剂、可分散的粉末或颗粒剂、糖浆或酏剂)、适于吸入给药的形式(例如细分散的粉末或液体气雾剂)、适于吹入给药的形式(例如细分散的粉末)、适于胃肠外注射的形式(例如,用于静脉内、皮下、肌肉内、血管内或输注给药的无菌溶液剂、混悬剂或乳剂)、适于局部给药的形式(例如霜剂、软膏、凝胶或水或油溶液或混悬液)或适于直肠给药的形式(例如栓剂)。上述组合物可以用常规赋形剂以常规方式制得。
本发明的组合物优选以单位剂量形式存在。通常将化合物以5-5000mg/平方米动物体面积、即约0.1-100mg/kg范围内的单位剂量向温血动物给药。可以采用例如1-100mg/kg、优选1-50mg/kg范围内的单位剂量,该单位剂量通常可以提供治疗有效剂量。单位剂量形式例如片剂或胶囊通常含有例如1-250mg活性成分。
根据本发明的另一个方面,本发明提供了如上所定义的式I化合物或其可药用盐用于治疗人或动物体的方法。
我们发现,本发明的化合物可以抑制VEGF受体酪氨酸激酶活性,因此,它们的抗血管生成作用和/或其引起血管通透性降低的能力是值得注意的。
本发明的另一个特点是式I化合物或其可药用盐用作药物,优选式I化合物或其可药用盐用作用于在温血动物例如人中产生抗血管生成和/或降低血管通透性作用的药物。
因此,根据本发明的另一方面,本发明提供了式I化合物或其可药用盐在生产用于在温血动物例如人中产生抗血管生成和/或降低血管通透性作用的药物中的用途。
根据本发明的另一个特点,本发明提供了在需要治疗的温血动物例如人中产生抗血管生成和/或降低血管通透性作用的方法,该方法包括,向所述动物施用有效量的上文中所定义的式I化合物或其可药用盐。
如上所述,治疗或预防具体疾病所需的剂量的大小需要根据所治疗的对象、给药途径和所治疗疾病的严重程度而改变。优选采用1-50mg/kg的每日剂量。但是,每日剂量需要根据所治疗的对象、具体的给药途径和所治疗疾病的严重程度而改变。因此,最佳的剂量应由治疗具体患者的医生来确定。
以上所定义的抗血管生成和/或降低血管通透性的治疗可以作为单一疗法应用,或者除了本发明的化合物外还可以涉及一种或多种其它物质和/或疗法。所述的联合治疗可以通过同时、顺序或分别给药单独的治疗成分来实现。在医学肿瘤学领域,通常采用不同形式治疗方法的联合来治疗癌症患者。在医学肿瘤学中,除上文中所定义的抗血管生成和/或降低血管通透性疗法之外,所述联合疗法的其它内容可以是手术、放疗或化疗。所述化疗可以包括5种主要的治疗剂:
(i)通过与以上定义不同的机制起作用的其它抗血管生成剂(例如linomide,整联蛋白αvβ3功能的抑制剂、血管抑制素(angiostatin)、内皮抑制素(endostatin)、razoxin、沙利度胺),包括血管靶向剂(例如combretastatin磷酸酯和国际专利申请公开号WO 99/02166中记载的血管损伤剂(例如N-乙酰基colchinol-O-磷酸酯),该专利申请所公开的内容全文引入本文作为参考);
(ii)细胞抑制剂例如抗雌激素(例如他莫昔芬、托瑞米芬、雷洛昔芬、屈洛昔芬、艾多昔芬)、孕激素(例如醋酸甲地孕酮)、芳香酶抑制剂(例如anastrozole、来曲唑、伏氯唑、依西美坦)、抗孕激素、抗雄激素(例如氟他胺、尼鲁米特、比卡鲁胺、醋酸环丙孕酮)、LHRH激动剂和拮抗剂(例如醋酸戈舍瑞林、luprolide、abarelix)、睾酮5α-二氢还原酶抑制剂(例如非那雄胺)、抗侵入剂(例如金属蛋白酶抑制剂例如marimastat和尿激酶纤溶酶原激活物受体功能抑制剂)以及生长因子功能抑制剂(所述生长因子包括例如血小板衍生的生长因子和肝细胞生长因子,所述抑制剂包括生长因子抗体、生长因子受体抗体、酪氨酸激酶抑制剂和丝氨酸/苏氨酸激酶抑制剂);
(iii)生物学响应调节剂(例如干扰素);
(iv)抗体(例如edrecolomab);和
(v)医学肿瘤学中所用的抗增殖/抗肿瘤药物及其联合形式,例如抗代谢剂(例如抗叶酸剂例如甲氨蝶呤、氟嘧啶类例如5-氟尿嘧啶、嘌呤和腺苷类似物、阿糖胞苷);抗肿瘤抗生素(例如蒽环类例如阿霉素、柔红霉素、表阿霉素和去甲氧柔红霉素、丝裂霉素-C、放线菌素D、光辉霉素);铂衍生物(例如顺铂、碳铂);烷化剂(例如氮芥、美法仑、苯丁酸氮芥、白消安、环磷酰胺、异环磷酰胺、亚硝脲类、噻替派);抗有丝分裂剂(例如长春花属生物碱例如长春新碱和紫杉生物碱(taxoids)例如紫杉酚、泰索帝);酶(例如天冬酰胺酶);胸苷酸合成酶抑制剂(例如raltitrexed);拓扑异构酶抑制剂(例如表鬼臼毒素类例如依托泊苷和替尼泊苷、安吖啶、托泊替堪、伊立替康)。
例如,所述联合疗法可以通过同时、顺序或分别给药以上所定义的式I化合物例如4-(4-溴-2-氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉或其盐、特别是其盐酸盐和WO 99/02166中所记载的血管靶向剂例如N-乙酰基colchinol-O-磷酸酯(WO 99/02166的实施例1)来实现。
如上所述,本发明所定义的化合物的价值在于其抗血管生成和/或降低血管通透性的作用。预期所述的本发明化合物可用于多种疾病状态,包括癌症、糖尿病、牛皮癣、类风湿性关节炎、卡波济氏肉瘤、血管瘤、急性和慢性肾病、动脉粥样化、动脉再狭窄、自身免疫疾病、急性炎症、过度疤痕形成和粘连、子宫内膜异位、机能障碍性子宫出血和存在视网膜血管增生的眼病。具体地讲,预期所述的本发明化合物可延缓原发和复发的结肠、乳腺、前列腺、肺和皮肤等的实体瘤的生长。更具体地讲,预期所述的本发明化合物可以抑制与VEGF有关的原发和复发实体瘤的生长,特别是那些在其生长和扩散中明显依赖于VEGF的肿瘤,包括例如某些结肠、乳腺、前列腺、肺、女阴和皮肤的肿瘤。
在本发明的另一方面,预期式I化合物可以抑制与EGF有关的原发和复发实体瘤的生长,特别是那些在其生长和扩散中明显依赖于EGF的肿瘤。
在本发明的另一方面,预期式I化合物可以抑制与VEGF和EGF均有关的原发和复发实体瘤的生长,特别是那些在其生长和扩散中明显依赖于VEGF和EGF的肿瘤。
除了在治疗性药物中的应用外,式I化合物及其可药用盐还可在评估VEGF受体酪氨酸激酶活性的抑制剂在实验室动物例如猫、狗、兔子、猴、大鼠和小鼠中的作用的体外和体内试验系统的开发和标准化中用作药理学工具,作为寻找新的治疗剂的一部分。
应当理解,本说明书中使用的术语“醚”特指乙醚。
通过如下实施例对本发明进行举例说明,但本发明并不受这些实施例的限定,其中,若无另外说明:
(i)蒸发通过真空旋转蒸发来完成并且在通过过滤除去残余的固体例如干燥剂后进行;
(ii)操作在室温(即18-25℃)下、在惰性气氛例如氩气氛下进行;
(iii)柱色谱(通过快速色谱法)和中压液相色谱(MPLC)在来自E.Merck,Darmstadt(德国)的Merck Kieselgel硅胶(Art.9385)或Merck Lichroprep RP-18(Art.9303)反相硅胶上进行;
(iv)给出的收率仅仅是说明性的,并不一定是可以达到的最大值;
(v)熔点用Mettler SP62自动熔点仪、油浴装置或Koffler热板仪测定,未校正。
(vi)式I终产物的结构通过核(通常是质子)磁共振(NMR)和质谱技术来证实;质子磁共振化学位移值用δ表示,峰的多重性用如下方式表示:s,单峰;d,二重峰;t,三重峰;m,多重峰;br,宽峰;q,四重峰;NMR波谱在400MHz的仪器上于24℃下测定。
(vii)对中间体一般未进行完全地鉴定,纯度通过薄层色谱(TLC)、高效液相色谱(HPLC)、红外(IR)或NMR分析来评估;
(viii)使用了如下缩写:
DMF N,N-二甲基甲酰胺
DMSO 二甲亚砜
THF 四氢呋喃
TFA 三氟乙酸
NMP 1-甲基-2-吡咯烷酮。
实施例1
将TFA(3ml)加入到4-(4-溴-2-氟苯氨基)-7-(1-(叔丁氧羰基)哌啶-4-基甲氧基)-6-甲氧基喹唑啉(673mg,1.2mmol)的二氯甲烷(10ml)悬浮液中。室温下搅拌1小时后,真空蒸除挥发性物质。将残余物用水/乙醚的混合物研磨。分出有机层。将水层再次用乙醚洗涤。用2N氢氧化钠水溶液将水层调至pH l0。将水层用二氯甲烷萃取。将有机层干燥(硫酸镁)然后真空蒸除溶剂。将固体用乙醚/石油醚(1/1)的混合物研磨,过滤,用乙醚洗涤然后真空干燥得到4-(4-溴-2-氟苯氨基)-6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉(390mg,70.5%)。MS-ESI:461-463[MH]+
1H NMR波谱:(DMSOd6)1.13-1.3(m,2H),1.75(d,2H),1.87-2.0(m,1H),2.5(d,2H),3.0(d,2H),3.96(s,3H),3.98(d,2H),7.2(s,1H),7.5(dd,1H),7.55(t,1H),7.68(dd,1H),7.80(s,1H),8.36(s,1H),9.55(br s,1H)
元素分析: 实测值C 54.5 H 4.9 N 12.1
C21H22N4O2BrF 理论值C 54.7 H 4.8 N 12.1%
原料的制备如下:
将7-苄氧基-4-氯-6-甲氧基喹唑啉盐酸盐(8.35g,27.8mmol)(按照例如WO 97/22596,实施例1的描述制备)和4-溴-2-氟苯胺(5.65g,29.7mmol)的2-丙醇(200ml)溶液加热回流4小时。过滤收集形成的沉淀,依次用2-丙醇和乙醚洗涤然后真空干燥得到7-苄氧基-4-(4-溴-2-氟苯氨基)-6-甲氧基喹唑啉盐酸盐(9.46g,78%)。1H NMR波谱:(DMSOd6;CD3COOD)4.0(s,3H);5.37(s,2H);7.35-7.5(m,4H);7.52-7.62(m,4H);7.8(d,1H);8.14(s,1H);8.79(s,1H)
MS-ESI:456[MH]+
元素分析: 实测值:C 54.0 H 3.7 N 8.7
C22H17N3O2BrF0.9HCl 理论值 C 54.2 H 3.7 N 8.6%
将7-苄氧基-4-(4-溴-2-氟苯氨基)-6-甲氧基喹唑啉盐酸盐(9.4g,19.1mmol)的TFA(90ml)溶液加热回流50分钟。将混合物冷却然后倒在冰上。过滤收集形成的沉淀然后溶于甲醇(70ml)。用浓氨水将溶液调至pH 9-10。将混合物通过蒸发浓缩至原体积的一半。过滤收集形成的沉淀,依次用水和乙醚洗涤然后真空干燥得到4-(4-溴-2-氟苯氨基)-7-羟基-6-甲氧基喹唑啉(5.66g,82%)。1H NMR波谱:(DMSOd6;CD3COOD)3.95(s,3H);7.09(s,1H);7.48(s,1H);7.54(t,1H);7.64(d,1H);7.79(s,1H);8.31(s,1H)
MS-ESI:366[MH]u
元素分析: 实测值:C 49.5 H 3.1 N 11.3
C15H11N3O2BrF 理论值 C 49.5 H 3.0 N 11.5%
将二碳酸二叔丁酯(41.7g,0.19mol)的乙酸乙酯(75ml)溶液分批加入到冷却至5℃的4-哌啶甲酸乙酯(30g,0.19mol)的乙酸乙酯(150ml)溶液中,并保持温度在0-5℃。室温搅拌48小时后,将混合物倒入水(300ml)中。分出有机层,依次用水(200ml)、0.1N盐酸(200ml)、饱和碳酸氢钠(200ml)和盐水(200ml)洗涤,干燥(MgSO4)然后蒸发得到4-(1-(叔丁氧羰基)哌啶)甲酸乙酯(48g,98%)。1H NMR波谱:(CDCl3)1.25(t,3H);1.45(s,9H);1.55-1.70(m,2H);1.8-2.0(d,2H);2.35-2.5(m,1H);2.7-2.95(t,2H);3.9-4.1(br s,2H);4.15(q,2H)
将1M氢化锂铝的THF溶液(133ml,0.133mol)分批加入到冷却至0℃的4-(1-(叔丁氧羰基)哌啶)甲酸乙酯(48g,0.19mol)的干燥THF(180ml)溶液中。于0℃下搅拌2小时后,加入水(30ml),然后加入2N氢氧化钠(10ml)。用硅藻土过滤除去沉淀并用乙酸乙酯洗涤。将滤液用水、盐水洗涤,干燥(MgSO4)然后蒸发得到1-(叔丁氧羰基)-4-羟基甲基哌啶(36.3g,89%)。
MS (EI):215[M]+
1H NMR波谱:(CDCl3)1.05-1.2(m,2H);1.35-1.55(m,10H);1.6-1.8(m,2H);2.6-2.8(t,2H);3.4-3.6(t,2H);4.0-4.2(brs,2H)
将1,4-二氮杂二环[2.2.2]辛烷(42.4g,0.378mol)加入到1-(叔丁氧羰基)-4-羟基甲基哌啶(52.5g,0.244mol)的叔丁基甲基醚(525ml)溶液中。室温搅拌15分钟后,将混合物冷却至5℃,在2小时时间分批加入甲苯磺酰氯(62.8g,0.33mmol)的叔丁基甲基醚(525ml)溶液,同时保持温度在0℃。室温搅拌1小时后,加入石油醚(1升)。过滤除去沉淀。将滤液蒸发得到固体。将固体溶于乙醚并依次用0.5N盐酸(2x500ml)、水、饱和碳酸氢钠和盐水洗涤,干燥(MgSO4)然后蒸发得到1-(叔丁氧羰基)-4-(4-甲基苯基磺酰氧基甲基)哌啶(76.7g,85%)。
MS (ESI):392[MNa]+
1H NMR波谱:(CDCl3)1.0-1.2(m,2H);1.45(s,9H);1.65(d,2H);1.75-1.9(m,2H);2.45(s,3H);2.55-2.75(m,2H);3.85(d,1H);4.0-4.2(br s,2H);7.35(d,2H);7.8(d,2H)
将碳酸钾(414mg,3mmol)加入到4-(4-溴-2-氟苯氨基)-7-羟基-6-甲氧基喹唑啉(546mg,1.5mmol)的DMF(5ml)悬浮液中。室温搅拌10分钟后,加入1-(叔丁氧羰基)-4-(4-甲基苯基磺酰氧基甲基)哌啶(636mg,1.72mmol)并将混合物于95℃加热2小时。冷却后,将混合物倒入冷水(20ml)中。过滤收集沉淀,用水洗涤然后真空干燥得到4-(4-溴-2-氟苯氨基)-7-(1-(叔丁氧羰基)哌啶-4-基甲氧基)-6-甲氧基喹唑啉(665mg,79%)。
MS-ESI:561-563[MH]+
1H NMR波谱:(DMSOd6)1.15-1.3(m,2H),1.46(s,9H),1.8(d,2H),2.0-2.1(m,1H),2.65-2.9(m,2H),3.95(s,3H),4.02(brs,2H),4.05(d,2H),7.2(s,1H),7.48(d,1H),7.55(t,1H),7.65(d,1H),7.8(s,1H),8.35(s,1H),9.55(br s,1H)
实施例2a
将37%的甲醛水溶液(50μl,0.6mmol)和氰基硼氢化钠(23mg,0.36mmol)依次加入到4-(4-溴-2-氟苯氨基)-6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉(139mg,0.3mmol)(按照实施例1中的描述制备)在THF/甲醇(1.4ml/1.4ml)混合物中的溶液中。室温搅拌1小时后,加入水并真空蒸除挥发性物质。将残余物用水研磨,过滤,用水洗涤然后真空干燥。将固体通过中性氧化铝色谱进行纯化,用二氯甲烷→二氯甲烷/乙酸乙酯(1/1)→二氯甲烷/乙酸乙酯/甲醇(50/45/5)洗脱。将含有预期产物的馏份真空蒸发。将得到的白色固体溶于二氯甲烷/甲醇(3ml/3ml)并加入3N氯化氢的乙醚溶液(0.5ml)。真空蒸除挥发性物质。将固体用乙醚研磨,过滤,用乙醚洗涤然后真空干燥得到4-(4-溴-2-氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉盐酸盐(120mg,69%)。
MS-ESI:475-477[MH]+
4-(4-溴-2-氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉盐酸盐的质子化形式的NMR波谱显示存在A和B两种形式,A∶B的比例约为9∶1。
1H NMR波谱:(DMSOd6;CF3COOD)1.55-1.7(m,A形式2H);1.85-2.0(m,B形式4H);2.03(d,A形式2H);2.08-2.14(br s,A形式1H);2.31-2.38(br s,B形式1H);2.79(s,A形式3H);2.82(s,B形式3H);3.03(t,A形式2H);3.21(br s,B形式2H);3.30(br s,B形式2H);3.52(d,A形式2H);4.02(s,3H);4.12(d,A形式2H);4.30(d,B形式2H);7.41(s,1H);7.5-7.65(m,2H);7.81(d,1H);8.20(s,1H);8.88(s,1H)
元素分析: 实测值C 46.0 H 5.2 N 9.6
C22H24N4O2BrF 0.3H2O 2.65HCl 理论值C 45.8 H 4.8 N 9.7%
实施例2b
将37%的甲醛水溶液(3.5ml,42mmol)加入到4-(4-溴-2-氟苯氨基)-7-(1-(叔丁氧羰基)哌啶-4-基甲氧基)-6-甲氧基喹唑啉(3.49g,6.22mmol)(按照实施例1中关于原料的描述进行制备)的甲酸(35ml)溶液中。于95℃加热4小时后,真空蒸除挥发性物质。将残余物悬浮在水中并缓慢加入2N氢氧化钠溶液将混合物调至pH 10.5。将悬浮液用乙酸乙酯萃取。将有机层用盐水洗涤,干燥(MgSO4)然后蒸发得到4-(4-溴-2-氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉(2.61g,88%)。
MS-ESI:475-477[MH]+
1H NMR波谱:(DMSOd6)1.3-1.45(m,2H),1.8(d,2H),1.7-1.9(m,1H),1.95(t,2H),2.2(s,3H),2.85(d,2H),3.96(s,3H),4.05(d,2H),7.19(s,1H),7.5(d,1H),7.55(t,1H),7.67(d,1H),7.81(s,1H),8.37(s,1H),9.54(s,1H)
元素分析: 实测值C 55.4 H 5.1 N 11.6
C22H24N4O2BrF 理论值C 55.6 H 5.1 N 11.8%
实施例2c
将4-氯-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉(200mg,0.62mmol)和4-溴-2-氟苯胺(142mg,0.74mmol)在含有6N氯化氢的异丙醇溶液(110μl,0.68ml)的异丙醇(3ml)中的悬浮液加热回流1.5小时。冷却后,过滤收集沉淀,依次用异丙醇和乙醚洗涤然后真空干燥得到4-(4-溴-2-氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉盐酸盐(304mg,90%)。
元素分析: 实测值C 47.9 H 4.9 N 10.0
C22H22N4O2BrF 0.5H2O 理论值C 48.2 H 5.0 N 10.1%
1.8HCl 0.08异丙醇
4-(4-溴-2-氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉盐酸盐的质子化形式的NMR波谱显示存在A和B两种形式,A∶B的比例约为9∶1。
1H NMR波谱:(DMSOd6)1.6-1.78(m,A形式2H);1.81-1.93(br s,B形式4H);1.94-2.07(d,A形式2H);2.08-2.23(br s,A形式1H);2.29-2.37(br s,B形式1H);2.73(d,A形式3H);2.77(d,B形式3H);2.93-3.10(q,A形式2H);3.21(br s,B形式2H);3.27(br s,B形式2H);3.42-3.48(d,A形式2H);4.04(s,3H);4.10(d,A形式2H);4.29(d,B形式2H);7.49(s,1H);7.53-7.61(m,2H);7.78(d,1H);8.47(s,1H);8.81(s,1H);10.48(br s,A形式1H);10.79(br s,B形式1H);11.90(br s,1H)
对于其它NMR读数,可向上述4-(4-溴-2-氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉盐酸盐的DMS O溶液中加入少量固体碳酸钾以在NMR管中释放出游离碱。然后再次记录NMR波谱并且仅显示出如下一种形式:
1H NMR波谱:(DMSOd6;固体碳酸钾)1.3-1.45(m,2H);1.75(d,2H);1.7-1.9(m,1H);1.89(t,2H);2.18(s,3H);2.8(d,2H);3.98(s,3H);4.0(d,2H);7.2(s,1H);7.48(d,1H);7.55(t,1H);7.68(d,1H);7.8(s,1H);8.35(s,1H);9.75(s,1H)
按照如下描述从4-(4-溴-2-氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉盐酸盐(按照以上描述制备)生成4-(4-溴-2-氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉(游离碱):
将4-(4-溴-2-氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉盐酸盐(50mg)悬浮在二氯甲烷(2ml)中并用饱和碳酸氢钠洗涤。将二氯甲烷溶液干燥(硫酸镁)然后通过蒸发除去挥发性物质得到4-(4-溴-2-氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉(游离碱)。所生成的游离碱的NMR仅显示如下-种形式:
1H NMR波谱:(DMSOd6)1.3-1.45(m,2H);1.76(d,2H);1.7-1.9(m,1H);1.9(t,2H);2.19(s,3H);2.8(d,2H);3.95(s,3H);4.02(d,2H);7.2(s,1H);7.48(d,1H);7.55(t,1H);7.68(dd,1H);7.8(s,1H);8.38(s,1H);9.55(br s,1H)
对于其它NMR读数,可向上述4-(4-溴-2-氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉(游离碱)的NMR DMSO溶液中加入少量CF3COOD然后再次记录NMR波谱。所得到的4-(4-溴-2-氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉三氟乙酸盐的质子化形式的波谱显示存在A和B两种形式,A∶B的比例约为9∶1。
1H NMR波谱:(DMSOd6;CF3COOD)1.5-1.7(m,A形式2H);1.93(brs,B形式4H);2.0-2.1(d,A形式2H);2.17(br s,A形式1H);2.35(br s,B形式1H);2.71(s,A形式3H);2.73(s,B形式3H);2.97-3.09(t,A形式2H);3.23(br s,B形式2H);3.34(brs,B形式2H);3.47-3.57(d,A形式2H);4.02(s,3H);4.15(d,A形式2H);4.30(d,B形式2H);7.2(s,1H);7.3-7.5(m,2H);7.6(d,1H);7.9(s,1H);8.7(s,1H)
原料按照如下描述制备:
将1-(叔丁氧羰基)-4-(4-甲基苯基磺酰氧基甲基)哌啶(40g,0.11mol)(按照实施例1中关于原料的描述制备)加入到4-羟基-3-甲氧基苯甲酸乙酯(19.6g,0.1mol)和碳酸钾(28g,0.2mol)的干燥DMF(200ml)悬浮液中。于95℃下搅拌2.5小时后,将混合物冷却至室温然后在水和乙酸乙酯/乙醚之间进行分配。将有机层用水、盐水洗涤,干燥(MgSO4)然后蒸发。将得到的油用石油醚结晶并将该悬浮液于5℃下存放过夜。过滤收集固体,用石油醚洗涤然后真空干燥得到4-(1-(叔丁氧羰基)哌啶-4-基甲氧基)-3-甲氧基苯甲酸乙酯(35g,89%)。
m.p.81-83℃
MS(ESI):416[MNa]+
1H NMR波谱:(CDC13)1.2-1.35(m,2H);1.4(t,3H);1.48(s,9H);1.8-1.9(d,2H);2.0-2.15(m,2H);2.75(t,2H);3.9(d,2H);3.95(s,3H);4.05-4.25(br s,2H);4.35(q,2H);6.85(d,1H);7.55(s,1H);7.65(d,1H)
元素分析: 实测值C63.4 H 8.0 N 3.5
C21H31NO6 0.3H2O 理论值C63.2 H 8.0 N 3.5%
将甲醛(12M,37%水溶液,35ml,420mmo1)加入到4-(1-(叔丁氧羰基)哌啶-4-基甲氧基)-3-甲氧基苯甲酸乙酯(35g,89mmo1)的甲酸(35m1)溶液中。于95℃下搅拌3小时后,通过蒸发除去挥发性物质。将残余物溶于二氯甲烷并加入3M氯化氢的乙醚溶液(40ml,120mmol)。用乙醚稀释后,将混合物研磨直至有固体形成。过滤收集固体,用乙醚洗涤然后于50℃下真空干燥过夜得到3-甲氧基-4-(1-甲基哌啶-4-基甲氧基)苯甲酸乙酯(30.6g,定量)。
MS(ESI):308[MH]+
1H NMR波谱:(DMSOd6)1.29(t,3H);1.5-1.7(m,2H);1.95(d,2H);2.0-2.15(br s,1H);2.72(s,3H);2.9-3.1(m,2H);3.35-3.5(br s,2H);3.85(s,3H);3.9-4.05(br s,2H);4.3(q,2H);7.1(d,1H);7.48(s,1H);7.6(d,1H)
将3-甲氧基-4-(1-甲基哌啶-4-基甲氧基)苯甲酸乙酯(30.6g,89mmol)的二氯甲烷(75m1)溶液冷却至0-5℃。加入TFA(37.5ml),然后在15分钟内滴加24N发烟硝酸(7.42ml,178mmol)的二氯甲烷(15m1)溶液。加料完成后,将溶液升温至室温并在室温下搅拌2小时。真空蒸除挥发性物质并将残余物溶于二氯甲烷(50ml)。将溶液冷却至0-5℃然后加入乙醚。过滤收集沉淀然后于50℃下真空干燥。将固体溶于二氯甲烷(500ml),依次加入3M氯化氢的乙醚溶液(30ml)和乙醚(500ml)。过滤收集固体然后于50℃下真空干燥得到3-甲氧基-4-(1-甲基哌啶-4-基甲氧基)-6-硝基苯甲酸乙酯(28.4g,82%)。
MS(ESI):353[MH]+
1H NMR波谱:(DMSOd6)1.3(t,3H);1.45-1.65(m,2H);1.75-2.1(m,3H);2.75(s,3H);2.9-3.05(m,2H);3.4-3.5(d,2H);3.95(s,3H);4.05(d,2H);4.3(q,2H);7.32(s,1H);7.66(s,1H)
将3-甲氧基-4-(1-甲基哌啶-4-基甲氧基)-6-硝基苯甲酸乙酯(3.89g,10mmol)在含有10%铂/活性炭(50%润湿的)(389mg)的甲醇(80ml)中的溶液在1.8大气压下氢化直至氢气的摄取停止。将混合物过滤并将滤液蒸发。将残余物溶于水(30ml)并用饱和碳酸氢钠溶液调至pH 10。将混合物用乙酸乙酯/乙醚(1/1)稀释然后分出有机层。将水层再次用乙酸乙酯/乙醚萃取并将有机层合并。将有机层用水、盐水洗涤,干燥(MgSO4)。过滤然后蒸发。将得到的固体在乙醚/石油醚的混合物中研磨,过滤,用石油醚洗涤然后于60℃下真空干燥得到6-氨基-3-甲氧基-4-(1-甲基哌啶-4-基甲氧基)苯甲酸乙酯(2.58g,80%)。
m.p.111-112℃
MS (ESI):323[MH]+
1H NMR波谱:(CDCl3)1.35(t,3H);1.4-1.5(m,2H);1.85(m,3H);1.95(t,2H);2.29(s,3H);2.9(d,2H);3.8(s,3H);3.85(d,2H);4.3(q,2H);5.55(br s,2H);6.13(s,1H);7.33(s,1H)
元素分析: 实测值C 62.8 H 8.5 N 8.3
C17H26N2O4 0.2H2O 理论值C 62.6 H 8.2 N 8.6%
将6-氨基-3-甲氧基-4-(1-甲基哌啶-4-基甲氧基)苯甲酸乙酯(16.1g,50mmol)在含有乙酸甲脒(5.2g,50mmol)的2-甲氧基乙醇(160ml)中的溶液于115℃下加热2小时。在4小时的时间内分批加入乙酸甲脒(10.4g,100mmol),每30分钟加入一次。在最后一次加料后继续加热30分钟。冷却后,真空蒸除挥发性物质。将固体溶于乙醇(100ml)和二氯甲烷(50ml)。过滤除去沉淀并将滤液浓缩至最终体积为100ml。将该悬浮液冷却至5℃然后过滤收集固体,用冷的乙醇洗涤,然后用乙醚洗涤并于60℃下真空干燥过夜得到6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)-3,4-二氢喹唑啉-4-酮(12.7g,70%)。
MS(ESI):304[MH]+
1H NMR波谱:(DMSOd6)1.25-1.4(m,2H);1.75(d,2H);1.9(t,1H);1.9(s,3H);2.16(s,2H);2.8(d,2H);3.9(s,3H);4.0(d,2H);7.11(s,1H);7.44(s,1H);7.97(s,1H)
将6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)-3,4-二氢喹唑啉-4-酮(2.8g,9.24mmol)在含有DMF(280μl)的亚硫酰氯(28ml)中的溶液于85℃加热回流1小时。冷却后,蒸除挥发性物质。将沉淀用乙醚研磨,过滤,用乙醚洗涤然后真空干燥。将固体溶于二氯甲烷然后加入饱和碳酸氢钠水溶液。分出有机层,用水、盐水洗涤,干燥(MgSO4)然后蒸发得到4-氯-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉(2.9g,98%)。
MS (ESI):322[MH]+
1H NMR波谱:(DMSOd6)1.3-1.5(m,2H);1.75-1.9(m,3H);2.0(t,1H);2.25(s,3H);2.85(d,2H);4.02(s,3H);4.12(d,2H);7.41(s,1H);7.46(s,1H);8.9(s,1H)
或者,6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)-3,4-二氢喹唑啉-4-酮可以按照如下方法制备:
将氢化钠(1.44g 60%矿物油悬浮体,36mmol)用20分钟分批加入到7-苄氧基-6-甲氧基-3,4-二氢喹唑啉-4-酮(8.46g,30mmol)(例如按照WO 97/22596中实施例1的描述制备)的DMF(70ml)溶液中并将该混合物搅拌1.5小时。分批加入新戊酸氯甲酯(5.65g,37.5mmol)并将混合物室温搅拌2小时。将混合物用乙酸乙酯(100ml)稀释然后倒入冰/水(400ml)和2N盐酸(4ml)中。分出有机层并将水层用乙酸乙酯萃取,将合并的萃取液用盐水洗涤,干燥(MgSO4)然后蒸除溶剂。将残余物用乙醚和石油醚的混合物研磨,过滤收集固体然后真空干燥得到7-苄氧基-6-甲氧基-3-((新戊酰氧基)甲基)-3,4-二氢喹唑啉-4-酮(10g,84%)。
1H NMR波谱:(DMSOd6)1.11(s,9H);3.89(s,3H);5.3(s,2H);5.9(s,2H);7.27(s,1H);7.35(m,1H);7.47(t,2H);7.49(d,2H);7.51(s,1H);8.34(s,1H)
将7-苄氧基-6-甲氧基-3-((新戊酰氧基)甲基)-3,4-二氢喹唑啉-4-酮(7g,17.7mmol)和10%钯/炭催化剂(700mg)在乙酸乙酯(250ml)、DMF(50ml)、甲醇(50ml)和乙酸(0.7ml)中的混合物在常压的氢气下搅拌40分钟。过滤除去催化剂并通过蒸发从滤液中除去溶剂。将残余物用乙醚研磨,过滤收集固体然后真空干燥得到7-羟基-6-甲氧基-3-((新戊酰氧基)甲基)-3,4-二氢喹唑啉-4-酮(4.36g,80%)。
1H NMR波谱:(DMSOd6)1.1(s,9H);3.89(s,3H);5.89(s,2H);7.0(s,1H);7.48(s,1H);8.5(s,1H)
将三苯基膦(1.7g,6.5mmol)在氮气氛下加入到7-羟基-6-甲氧基-3-((新戊酰氧基)甲基)-3,4-二氢喹唑啉-4-酮(1.53g,5mmol)的二氯甲烷(20ml)悬浮液中,然后加入1-(叔丁氧羰基)-4-(羟基甲基)哌啶(1.29g,6mmol)(按照实施例1中关于原料的描述进行制备)和偶氮二甲酸二乙酯(1.13g,6.5mmol)的二氯甲烷(5ml)溶液。室温搅拌30分钟后,将反应混合物倒在硅胶柱上并用乙酸乙酯/石油醚洗脱(1/1,然后是6/5、6/4和7/3)。将含有预期产物的馏份蒸发得到油,其在用戊烷研磨后结晶。过滤收集固体然后真空干燥得到7-(1-(叔丁氧羰基)哌啶-4-基甲氧基)-6-甲氧基-3-((新戊酰氧基)甲基)-3,4-二氢喹唑啉-4-酮(232g,92%)。
MS-ESI:526[MNa]+
1H NMR波谱:(CDCl3)1.20(s,9H),1.2-1.35(m,2H),1.43(s,9H),1.87(d,2H),2.05-2.2(m,1H),2.75(t,2H),3.96(d,2H),3.97(s,3H),4.1-4.25(b r s,2H),5.95(s,2H),7.07(s,1H),7.63(s,1H),8.17(s,1H)
元素分析: 实测值C 61.8 H 7.5 N 8.3
C26H37N3O7 理论值C 62.0 H 7.4 N 8.3%
将7-(1-(叔丁氧羰基)哌啶-4-基甲氧基)-6-甲氧基-3-((新戊酰氧基)甲基)-3,4-二氢喹唑啉-4-酮(2.32g,4.6mmol)在含有TFA(5ml)的二氯甲烷(23ml)中的溶液室温搅拌1小时。真空蒸除挥发性物质。将残余物在乙酸乙酯和碳酸氢钠之间进行分配。真空蒸除有机溶剂并将残余物过滤。将沉淀用水洗涤然后真空干燥。将固体与甲苯共沸然后真空干燥得到6-甲氧基-7-(哌啶-4-基甲氧基)-3-((新戊酰氧基)甲基)-3,4-二氢喹唑啉-4-酮(1.7g,92%)。
MS-ESI:404[MH]+
1H NMR波谱:(DMSOd6;CF3COOD)1.15(s,9H),1.45-1.6(m,2H),1.95(d,2H),2.1-2.25(m,1H),2.95(t,2H),3.35(d,2H),3.95(s,3H),4.1(d,2H),5.95(s,2H),7.23(s,1H),7.54(s,1H),8.45(s,1H)
将37%的甲醛水溶液(501μl,6mmol)和氰基硼氢化钠(228mg,3.6mmol)依次分批加入到6-甲氧基-7-(哌啶-4-基甲氧基)-3-((新戊酰氧基)甲基)-3,4-二氢喹唑啉-4-酮(1.21g,3mmol)在THF/甲醇(10ml/10ml)的混合物中的溶液中。室温搅拌30分钟后,真空蒸除有机溶剂并将残余物在二氯甲烷和水之间进行分配。分出有机层,用水和盐水洗涤,干燥(MgSO4)然后蒸除挥发性物质。将残余物用乙醚研磨并通过过滤收集形成的固体,用乙醚洗涤然后真空干燥得到6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)-3-((新戊酰氧基)甲基)-3,4-二氢喹唑啉-4-酮(1.02g,82%)。
MS-ESI:418[MH]+
1H NMR波谱:(CDCl3)1.19(s,9H),1.4-1.55(m,2H),1.9(d,2H),2.0(t,2H),1.85-2.1(m,1H),2.3(s,3H),2.92(d,2H),3.96(s,3H),3.99(d,2H),5.94(s,2H),7.08(s,1H),7.63(s,1H),8.17(s,1H)
将饱和的氨/甲醇溶液(14ml)加入到6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)-3-((新戊酰氧基)甲基)-3,4-二氢喹唑啉-4-酮(1.38g,3.3mmol)的甲醇(5ml)溶液中。室温下搅拌20小时后,将悬浮液用二氯甲烷(10ml)稀释。将溶液过滤。将滤液真空蒸发并将残余物用乙醚研磨,过滤收集固体,用乙醚洗涤然后真空干燥得到6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)-3,4-二氢喹唑啉-4-酮(910mg,83%)。
MS-ESI:304[MH]+
1H NMR波谱:(DMSOd6)1.3-1.45(m,2H),1.75(d,2H),1.7-1.85(m,1H),1.9(t,2H),2.2(s,3H),2.8(d,2H),3.9(s,3H),4.0(d,2H),7.13(s,1H),7.45(s,1H),7.99(s,1H)
实施例3a
将3.5M氯化氢的乙醇溶液(75μl,0.26mmol)加入到4-氯-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉(80mg,0.25mmol)(按照实施例2c中关于原料的描述制备)的异丙醇(3ml)悬浮液中,将混合物加热至50℃并加入4-氯-2-氟苯胺(44mg,0.3mmol)。将混合物加热回流30分钟。冷却后,将混合物用乙醚(3ml)稀释。过滤收集沉淀,用乙醚洗涤然后真空干燥得到4-(4-氯-2-氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉盐酸盐(105mg,82%)。
MS-ESI:431-433[MH]+
4-(4-氯-2-氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉盐酸盐的质子化形式的NMR波谱显示存在A和B两种形式,A∶B的比例约为9∶1。
1H NMR波谱:(DMSOd6;CF3COOD)1.55-1.7(m,A形式2H),1.85-2.0(m,B形式4H),2.05(d,A形式2H),2.1-2.2(m,A形式1H),2.35(s,3H);2.79(s,A形式3H),2.82(s,B形式3H),3.03(t,A形式2H),3.2-3.3(m,B形式2H);3.3-3.4(m,B形式2H),3.52(d,A形式2H),4.02(s,3H),4.13(d,A形式2H),4.3(d,B形式2H),7.41(s,1H),7.47(dd,1H),7.63(t,1H),7.69(dd,1H),8.19(s,1H),8.88(s,1H)
元素分析: 实测值C 51.8 H 5.6 N 10.9
C22H24N4O2ClF 0.4H2O 2HCl 理论值C 51.7 H 5.3 N 11.0%
实施例3b
另一种制备方法如下:
将三苯基膦(615mg,2.3mmol)和偶氮二甲酸二乙酯(369μl,2.3mmol)依次加入到4-羟基甲基-1-甲基哌啶(151mg,1.1mmol)(JMed.Chem 1973,16,156)和4-(4-氯-2-氟苯氨基)-7-羟基-6-甲氧基喹唑啉(250mg,0.78mmol)(按照实施例7中关于原料的描述进行制备)的二氯甲烷(5ml)溶液中。室温搅拌30分钟后,加入4-羟基甲基-1-甲基哌啶(51mg,0.39mmol)、三苯基膦(102mg,0.39mmol)和偶氮二甲酸二乙酯(61μl,0.39mmol)。搅拌15分钟后,真空蒸除挥发性物质并将残余物通过柱色谱纯化,用二氯甲烷/乙腈/甲醇洗脱(70/10/20,然后是75/5/20和80/0/20)。合并含有预期产物的馏份然后蒸除挥发性物质。将残余物溶于二氨甲烷和甲醇的混合物然后加入5M氯化氢的异丙醇溶液。将悬浮液浓缩,过滤收集固体,用乙醚洗涤然后真空干燥得到4-(4-氯-2-氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉盐酸盐(16mg,4%)。
实施例4
氩气氛下,将氢化钠(60%,372mg,9.3mmol)加入到4-溴-2,6-二氟苯胺(1.67g,8.08mmol)的DMF溶液中。室温搅拌30分钟后,加入4-氯-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉(1.3g,4.04mmol)并继续搅拌20小时。将混合物倒入水(130ml)中并用乙酸乙酯萃取。将有机层用水、盐水洗涤,干燥(MgSO4)然后蒸除挥发性物质。将残余物通过硅胶柱色谱纯化,依次用二氯甲烷/甲醇(95/5)和含有氨(1%)的二氯甲烷/甲醇(90/10)洗脱。合并含有预期产物的级份然后蒸发。将残余物用乙醚研磨,通过过滤进行收集,用乙醚洗涤然后于50℃下真空干燥得到4-(4-溴-2,6-二氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉(1.4g,70%)。
MS-ESI:493-495[MH]+
1HNMR波谱:(DMSOd6)1.3-1.45(m,2H),1.8(d,2H),1.7-1.9(m,1H),1.9(t,2H),2.17(s,3H),2.8(d,2H),3.95(s,3H),4.02(d,2H),7.2(s,1H),7.63(s,1H),7.6(s,1H),7.82(s,1H),8.35(s,1H)
元素分析: 实测值C 53.8 H 4.8 N 11.3
C22H23N4O2BrF2 理论值C 53.6 H 4.7 N 11.4%
实施例5
采用与实施例4中所述类似的方法,将4-氯-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉(246mg,0.764mmol)(按照实施例2c中关于原料的描述制备)与4-氯-2,6-二氟苯胺(250mg,1.53mmol)(参见WO 97/30035实施例15)在DMF(9ml)中、在氢化钠(60%,76.5mg,1.9mmol)的存在下反应得到4-(4-氯-2,6-二氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉(210mg,61%)。
MS-ESI:449-451[MH]+
1H NMR波谱:(DMSOd6)1.3-1.45(m,2H),1.8(d,2H),1.7-1.9(m,1H),1.9(t,2H),2.2(s,3H),2.8(d,2H),3.96(s,3H),4.02(d,2H),7.21(s,1H),7.52(s,1H),7.54(s,1H),7.82(s,1H),8.35(s,1H)
元素分析: 实测值C 59.0 H 5.3 N 12.5
C22H23N4O2ClF2 理论值C 58.9 H 5.2 N 12.5%
原料按照如下描述制备:
将4-氯-2,6-二氟苯胺盐酸盐(参见WO 97/30035实施例15)在二氯甲烷和水之间进行分配并加入碳酸氢钠水溶液直至水层的pH达到约9。分出有机层,用盐水洗涤,干燥(MgSO4)然后蒸发得到4-氯-2,6二氟苯胺游离碱。
实施例6
将4-氯-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉(200mg,0.622mmol)(按照实施例2c中关于原料的描述进行制备)和2-氟-4-甲基苯胺(94mg,0.764mmol)在含有6.2M氯化氢的异丙醇溶液(110μl)的异丙醇(5ml)中的悬浮液于80℃下搅拌1.5小时。冷却后,过滤收集沉淀,用异丙醇洗涤,然后用乙醚洗涤并真空干燥。将固体通过柱色谱纯化,用二氯甲烷/甲醇(90/10)洗脱,然后用5%氨的甲醇/二氯甲烷(10/90)溶液洗脱。将含有预期产物的级份蒸发得到4-(2-氟-4-甲基苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉(170mg,61%)。
MS-ESI:411[MH]+
1H NMR波谱:(DMSOd6)1.3-1.45(m,2H),1.8(d,2H),1.7-1.9(m,1H),1.9(t,2H),2.2(s,3H),2.35(s,3H),2.8(d,2H),3.95(s,3H),4.01(d,2H),7.1(d,1H),7.13(d,1H),7.16(s,1H),7.4(t,1H),7.81(s,1H),8.32(s,1H),9.4(s,1H)
元素分析: 实测值C 66.5 H 6.7 N 13.7
C23H27N4O2F 0.3H2O 理论值C 66.4 H 6.7 N 13.5%
实施例7
将1-叔丁氧羰基-4-羟基甲基哌啶(590mg,2.75mmol)(按照实施例1中关于原料的描述进行制备)、三苯基膦(1.2g,4.58mmol)和偶氮二甲酸二乙酯(0.72ml,4.58mmol)依次加入到4-(4-氯-2-氟苯氨基)-7-羟基-6-甲氧基喹唑啉(585mg,1.83mmol)的二氯甲烷(20ml)溶液中。室温搅拌1小时后,补加三苯基膦(239mg,0.91mmol)和偶氮二甲酸二乙酯(0.14ml,0.91mmol)。搅拌1.5小时后,真空蒸除挥发性物质并将残余物通过柱色谱纯化,用乙酸乙酯/二氯甲烷(1/1)洗脱。将粗产物直接用于下一步骤。
将粗产物在含有TFA(4.5ml)的二氯甲烷(15ml)中的溶液室温搅拌1.5小时。真空蒸除挥发性物质。将残余物在水和乙酸乙酯之间进行分配。将水层用2N氢氧化钠调至pH9.5。分出有机层,依次用水和盐水洗涤,干燥(MgSO4)然后蒸发得到4-(4-氯-2-氟苯氨基)-6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉。
MS-ESI:417-419[MH]+
1H NMR波谱:(DMSOd6)1.1-1.3(m,2H),1.75(d,2H),1.85-2.0(br s,1H),2.55(d,2H),2.95(d,2H),3.95(s,3H),4.0(d,2H),7.2(s,1H),7.35(dd,1H),7.55(dd,1H),7.6(t,1H),7.8(s,1H),8.35(s,1H),9.55(s,1H)
盐酸盐按照如下描述制备:
将4-(4-氯-2-氟苯氨基)-6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉溶于甲醇/二氯甲烷的混合物然后加入6M氯化氢的乙醚溶液。真空蒸除挥发性物质,将残余物用乙醚研磨,通过过滤进行收集,用乙醚洗涤然后真空干燥得到4-(4-氯-2-氟)-6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉盐酸盐(390mg,2步的收率47%)。
元素分析: 实测值C 50.4 H 5.2 N 11.0
C21H22O2N4ClF 2.25HCl 理论值C 50.6 H 4.9 N 11.2%
原料按照如下描述制备:
将7-苄氧基-4-氯-6-甲氧基喹唑啉盐酸盐(1.2g,4mmol)(按照W097/22596实施例1中的描述制备)和4-氯-2-氟苯胺(444μl,4mmol)的2-丙醇(40ml)溶液加热回流1.5小时。冷却后,过滤收集沉淀,依次用2-丙醇和乙醚洗涤然后真空干燥得到7-苄氧基-4-(4-氯-2-氟苯氨基)-6-甲氧基喹唑啉盐酸盐(1.13g,64%)。
m.p.239-242℃
1H NMR波谱:(DMSOd6)4.0(s,3H);5.36(s,2H);7.39-7.52(m,9H);8.1(s,1H);8.75(s,1H)
MS-ESI:410[MH]+
元素分析: 实测值C 59.2 H 4.3 N 9.4
C22H17N3O2ClF 1HCl 理论值C 59.2 H 4.1 N 9.4%
将7-苄氧基-4-(4-氯-2-氟苯氨基)-6-甲氧基喹唑啉盐酸盐(892mg,2mmol)的TFA(10ml)溶液加热回流50分钟。冷却后,将混合物倒在冰上。过滤收集沉淀,溶于甲醇(10ml)并用氨水碱化至pH11。通过蒸发浓缩后,过滤收集固体产物,依次用水和乙醚洗涤然后真空干燥得到黄色固体状4-(4-氯-2-氟苯氨基)-7-羟基-6-甲氧基喹唑啉(460mg,72%)。
m.p.141-143℃
MS-ESI:320-322[MH]+
1H NMR波谱:(DMSOd6)3.95(s,3H);7.05(s,1H);7.35(d,1H);7.54-7.59(m,2H);7.78(s,1H);8.29(s,1H)
实施例8
将7-(1-(叔丁氧羰基)哌啶-4-基甲氧基)-4-(2-氟-4-甲基苯氨基)-6-甲氧基喹唑啉(318mg,0.64mmol)在含有TFA(2.5ml)的二氯甲烷(5ml)中的溶液室温搅拌2小时。真空蒸除挥发性物质并将残余物在二氯甲烷和水之间进行分配。将水层调至pH 10-11。分出有机层,用水、盐水洗涤,干燥(MgSO4)然后蒸除挥发性物质得到4-(2-氟-4-甲基苯氨基)-6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉(220mg,87%)。
MS-ESI:397[MH]+
1H NMR波谱:(DMSOd6)1.15-1.3(m,2H);1.75(d,2H);1.85-2.0(m,1H);2.4(s,3H);3.0(d,2H);3.3-3.4(d,2H);3.95(s,3H);4.0(d,2H);7.04(d,1H);7.15(d,1H);7.17(s,1H);7.4(t,1H);7.8(s,1H);8.3(s,1H);9.4(s,1H)
原料按照如下描述制备:
采用与实施例6所述类似的方法,将7-苄氧基-4-氯-6-甲氧基喹唑啉盐酸盐(1.55g,5.15mmol)(按照WO 97/22596实施例1的描述制备)与2-氟-4-甲基苯胺(700mg,5.67mmol)在含有6.2M氯化氢的异丙醇溶液(80μl,0.51mmol)的异丙醇(90ml)中反应得到7-苄氧基-4-(2-氟-4-甲基苯氨基)-6-甲氧基喹唑啉盐酸盐(2g,91%)。
MS-ESI:390[MH]+
1H NMR波谱:(DMSOd6)2.4(s,3H),4.01(s,3H),7.15(d,1H),7.25(d,1H),7.35-7.6(m,7H),8.3(s,1H),8.78(s,1H)
将7-苄氧基-4-(2-氟-4-甲基苯氨基)-6-甲氧基喹唑啉盐酸盐(2g,4.7mmol)的TFA(20mml)溶液于80℃加热5小时然后室温搅拌过夜。真空蒸除挥发性物质并将残余物悬浮在水(50ml)中。加入固体碳酸氢钠直至pH达到7左右。过滤收集沉淀,用水洗涤然后真空干燥。将固体通过柱色谱纯化,用甲醇/二氯甲烷(5/95)洗脱。蒸除溶剂后,将固体用乙醚研磨,过滤收集固体,用乙醚洗涤然后真空干燥得到4-(2-氟-4-甲基苯氨基)-7-羟基-6-甲氧基喹唑啉(1.04g,74%)。
MS-ESI:300[MH]+
1H NMR波谱:(DMSOd6)2.4(s,3H),4.0(s,3H),7.15(d,1H),7.22(s,1H),7.25(d,1H),7.41(t,1H),8.05(s,1H),8.7(s,1H),11.0(s,1H),11.5-11.8(br s,1H)
将三苯基膦(2.19g,8.36mmol)加入到于0℃下冷却的4-(2-氟-4-甲基苯氨基)-7-羟基-6-甲氧基喹唑啉(1g,3.34mmol)的二氯甲烷(10ml)悬浮液中,然后加入1-(叔丁氧羰基)-4-羟基甲基哌啶(1.08g,5.01mmol)(按照实施例1中关于原料的描述进行制备)和偶氮二甲酸二乙酯(1.31ml,8.36mmol)。室温搅拌2小时后,真空蒸除挥发性物质。将残余物通过柱色谱纯化,用二氯甲烷/甲醇(2/98)洗脱。蒸除溶剂后,将残余物用乙醚研磨,过滤收集固体,用乙醚洗涤然后真空干燥得到7-(1-(叔丁氧羰基)哌啶-4-基甲氧基)-4-(2-氟-4-甲基苯氨基)-6-甲氧基喹唑啉(327mg,20%)。
MS-ESI:497[MH]+
1H NMR波谱:(DMSOd6)1.15-1.3(m,2H);1.45(s,9H);1.8(d,2H);2.0-2.1(m,1H);2.4(s,3H);2.75-2.9(br s,2H);3.95(s,3H);4.0(br s,2H);4.05(d,2H);7.1(d,1H);7.15(d,1H);7.2(s,1H);7.4(t,1H);7.85(t,1H);8.32(s,1H);9.45(s,1H)
实施例9
将4-(4-溴-2,6-二氟苯氨基)-7-(1-(叔丁氧羰基)哌啶-4-基甲氧基)-6-甲氧基喹唑啉(578mg,1mmol)在含有TFA(4ml)的二氯甲烷(10ml)中的溶液室温搅拌2小时。真空蒸除挥发性物质并将残余物悬浮在水中。将水层调至约pH 10并用二氯甲烷萃取。将有机层用水、盐水洗涤,干燥(MgSO4)然后蒸除挥发性物质。将残余物用乙醚研磨然后真空干燥得到4-(4-溴-2,6-二氟苯氨基)-6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉(10mg,23%)。
MS-ESI:479-481[MH]+
1H NMR波谱:(DMSOd6)1.15-1.3(m,2H);1.75(d,2H);1.85-2.0(br s,1H);2.5(d,2H);3.0(d,2H);3.97(s,3H);4.0(d,2H);7.2(s,1H);7.62(d,2H);7.82(s,1H);8.35(s,1H)
1H NMR波谱:(DMSOd6;CF3COOD)1.5-1.65(m,2H);2.0(d,2H);2.15-2.3(br s,1H);3.0(t,2H);3.4(d,2H);4.02(s,3H);4.15(d,2H);7.4(s,1H);7.75(d,2H);8.1(s,1H);8.92(s,1H)
原料按照如下描述制备:
将氢化钠(60%,612mg,15.3mmol)加入到4-溴-2,6-二氟苯胺(2.77g,6.65mmol)的DMF(80ml)溶液中。室温搅拌30分钟后,加入7-苄氧基-4-氯-6-甲氧基喹唑啉(2g,6.65mmol)(按照WO97/22596实施例1的描述制备,但游离碱在临用前生成)并继续搅拌4小时。将混合物在乙酸乙酯和水(200ml)之间进行分配。分出有机层,用水、盐水洗涤,干燥(MgSO4)然后蒸除挥发性物质。将残余物用异丙醇研磨,过滤收集固体,用乙醚洗涤然后真空干燥得到7-苄氧基-4-(4-溴-2,6-二氟苯氨基)-6-甲氧基喹唑啉(1.95g,62%)。
MS-ES I:472-474[MH]+
1H NMR波谱:(DMSOd6)3.94(s,3H),5.3(s,2H),7.3(s,1H),7.4(d,1H),7.45(t,2H),7.5(s,1H),7.55(d,1H),7.65(d,2H),7.85(s,1H),8.35(s,1H),9.4-9.6(br s,1H)
采用与合成实施例8的原料所述类似的方法,将7-苄氧基-4-(4-溴-2,6-二氟苯氨基)-6-甲氧基喹唑啉(1.9g,4.02mmol)与TFA(20ml)反应得到4-(4-溴-2,6-二氟苯氨基)-7-羟基-6-甲氧基喹唑啉(1.5g,98%)。
1H NMR波谱:(DMSOd6)3.95(s,3H),7.1(s,1H),7.6(s,1H),7.65(s,1H),7.8(s,1H),8.3(s,1H),9.45(br s,1H),10.5(br s,1H)
采用与制备实施例8的原料所述类似的方法,将4-(4-溴-2,6-二氟苯氨基)-7-羟基-6-甲氧基喹唑啉(1g,2.62mmol)与1-(叔丁氧羰基)-4-羟基甲基哌啶(845mg,3.93mmol)(按照实施例1中关于原料的描述进行制备)反应得到4-(4-溴-2,6-二氟苯氨基)-7-(1-(叔丁氧羰基)哌啶-4-基甲氧基)-6-甲氧基喹唑啉(620mg,41%)。
MS-ESI:579-581[MH]+
1H NMR波谱:(DMSOd6)1.15-1.3(m,2H);1.45(s,9H);1.8(d,2H);2.0-2.1(m,1H);2.7-2.9(m,2H);3.95(s,3H);4.0(brs,2H);4.05(d,2H);7.22(s,1H);7.65(d,2H);7.85(s,1H);8.35(s,1H);9.4-9.6(br s,1H)
实施例10
采用与实施例9所述类似的方法,将7-(1-(叔丁氧羰基)哌啶-4-基甲氧基)-4-(4-氯-2,6-二氟苯氨基)-6-甲氧基喹唑啉(95mg,0.2mmol)的二氯甲烷(2ml)溶液用TFA(800μl)处理得到4-(4-氯-2,6-二氟苯氨基)-6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉(20mg,26%)。
MS-ESI:435-437[MH]+
1H NMR波谱:(DMSOd6)1.2-1.3(m,2H);1.75(d,2H);1.85-2.0(br s,1H);2.5(d,2H);3.0(d,2H);3.97(s,3H);4.0(d,2H);7.2(s,1H);7.52(d,2H);7.85(s,1H);8.35(s,1H)
原料可以按照如下描述制备:
采用与制备实施例9的原料所述类似的方法,将7-苄氧基4-氯-6-甲氧基喹唑啉(184mg,0.61mmol)(按照WO 97/22596实施例1的描述制备,但游离碱在临用前生成)与4-氯-2,6-二氟苯胺(200mg,1.22mmol)在氢化钠(60%,87mg,1.4mmol)的存在下在DMF(8ml)中反应得到7-苄氧基-4-(4-氯-2,6-二氟苯氨基)-6-甲氧基喹唑啉(212mg,74%)。
MS-ESI:428[MH]+
1H NMR波谱:(DMSOd6)3.96(s,3H);5.31(s,2H);7.32(s,1H);7.4(d,1H);7.45(t,2H);7.5-7.6(m,4H);7.85(s,1H);8.35(br s,1H);9.55(br s,1H)
将7-苄氧基-4-(4-氯-2,6-二氟苯氨基)-6-甲氧基喹唑啉(200mg,0.47mmol)的TFA(3ml)溶液于80℃下搅拌3小时。冷却后,真空蒸除挥发性物质并将残余物溶于含有5%甲醇的水中。用碳酸氢钠将pH调至8,然后过滤收集固体并用水洗涤。将固体溶于乙酸乙酯/甲醇/二氯甲烷(47/6/47)的混合物。真空蒸除挥发性物质得到4-(4-氯-2,6-二氟苯氨基)-7-羟基-6-甲氧基喹唑啉(126mg,80%)。
MS-ESI:338[MH]+
1H NMR波谱:(DMSOd6)3.95(s,3H);7.1(s,1H);7.55(d,2H);7.8(s,1H);8.3(s,1H);9.42(br s,1H)
采用与制备实施例9的原料所述类似的方法,将4-(4-氯-2,6-二氟苯氨基)-7-羟基-6-甲氧基喹唑啉(150mg,0.44mmol)与1-(叔丁氧羰基)-4-羟基甲基哌啶(150mg,0.88mmol)(按照实施例1中关于原料的描述进行制备)反应得到7-(1-(叔丁氧羰基)哌啶-4-基甲氧基)-4-(4-氯-2,6-二氟苯氨基)-6-甲氧基喹唑啉(113mg,59%)。
MS-ESI:535[MH]+
1H NMR波谱:(DMSOd6)1.15-1.3(m,2H);1.45(s,9H);1.8(d,2H);2.0-2.1(m,1H);2.7-2.9(m,2H);3.95(s,3H);4.0(brs,2H);4.05(d,2H);7.2(s,1H);7.6(m,2H);7.8(s,1H);8.35(s,1H);9.4-9.6(br s,1H)
实施例11
以下举例说明了用于人的治疗或预防性应用的含有式I化合物或其可药用盐(以下称为化合物X)的代表性药物剂型:
(a)片剂I mg/片
化合物X 100
乳糖Ph.Eur 182.75
交联羧甲基纤维素钠 12.0
玉米淀粉糊(5%w/v糊) 2.25
硬脂酸镁 3.0
(b)片剂II mg/片
化合物X 50
乳糖Ph.Eur 223.75
交联羧甲基纤维素钠 6.0
玉米淀粉 15.0
聚乙烯吡咯烷酮(5%w/v糊)2.25
硬脂酸镁 3.0
(c)片剂III mg/片
化合物X 1.0
乳糖Ph.Eur 93.25
交联羧甲基纤维素钠 4.0
玉米淀粉糊(5%w/v糊) 0.75
硬脂酸镁 1.0
(d)胶囊 mg/胶囊
化合物X 10
乳糖Ph.Eur 488.5
硬脂酸镁 1.5
(e)注射液I (50mg/ml)
化合物X 5.0%w/v
1M氢氧化钠溶液 15.0%v/v
0.1M盐酸(调节pH至7.6)
聚乙二醇400 4.5%w/v
注射用水至100%
(f)注射液II (10mg/ml)
化合物X 1.0%w/v
磷酸钠BP 3.6%w/v
0.1M氢氧化钠溶液 15.0%v/v
注射用水至100%
(g)注射液III (1mg/mL,缓冲至pH6)
化合物X 0.1%w/v
磷酸钠BP 2.26%w/v
柠檬酸 0.38%w/v
聚乙二醇400 3.5%w/v
注射用水至100%
注
以上制剂可以通过制药领域公知的常规方法制得。片剂(a)-(c)可以通过常规方法进行肠溶包衣,例如提供乙酸邻苯二甲酸纤维素包衣。
Claims (12)
2.权利要求1所述的喹唑啉衍生物,其中带有(R1)m的苯基选自2-氟-4-甲基苯基、4-氯-2,6-二氟苯基、4-溴-2,6-二氟苯基、4-氯-2-氟苯基和4-溴-2-氟苯基。
3.权利要求1或2所述的喹唑啉衍生物,其中R2是哌啶-4-基甲基,或R2是其中的哌啶环带有一个选自C1-4烷基的取代基的哌啶-4-基甲基。
4.如权利要求1所述的喹唑啉衍生物,选自:
4-(4-氯-2-氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉,
4-(2-氟-4-甲基苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉,
4-(4-溴-2-氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉,
4-(4-氯-2,6-二氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉,
4-(4-溴-2,6-二氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉,
4-(4-氯-2-氟苯氨基)-6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉,
4-(2-氟-4-甲基苯氨基)-6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉,
4-(4-溴-2-氟苯氨基)-6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉,
4-(4-氯-2,6-二氟苯氨基)-6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉,和
4-(4-溴-2,6-二氟苯氨基)-6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉及其盐。
5.如权利要求1所述的喹唑啉衍生物,选自:
4-(4-氯-2-氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉,
4-(4-溴-2-氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉,
4-(4-氯-2,6-二氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉,和
4-(4-溴-2,6-二氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉及其盐。
6.如权利要求1所述的喹唑啉衍生物,选自:
4-(4-溴-2-氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉及其盐。
7.可药用盐形式的权利要求1所述的喹唑啉衍生物。
8.权利要求1所定义的式I的喹唑啉衍生物或其可药用盐的制备方法,该方法包括:
(a)将式III化合物:
其中R2和X1如权利要求1所定义,L1是可置换的部分,与式IV化合物反应:
其中R1和m如权利要求1所定义;
(b)将式V化合物:
其中m、X1和R1如权利要求1所定义,与式VI化合物反应:
R2-L1 (VI)
其中R2如权利要求1所定义,L1如上所定义;
(c)将式VII化合物:
与式VIII化合物反应:
R2-X1-H (VIII)
其中R1、R2、m和X1如权利要求1所定义,L1如上所定义;或(d)将式IX化合物脱保护:
其中R1、m和X1如权利要求1所定义,R4表示保护了的R2基团,其中R2如权利要求1所定义但另外带有一个或多个保护基P2;并且当需要式I的喹唑啉衍生物的可药用盐时,将所得到的化合物与酸或碱反应得到所需的可药用盐。
9.含有权利要求1所定义的式I化合物或其可药用盐作为活性成分以及可药用赋形剂或载体的药物组合物。
10.权利要求1所定义的式I化合物或其可药用盐在生产用于在温血动物中产生抗血管生成和/或降低血管通透性作用的药物中的用途。
11.如权利要求10所述的用途,其中所述温血动物是人。
12.权利要求1所定义的式I化合物或其可药用盐在生产用于在温血动物中产生抗癌作用的药物中的用途。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP99402759 | 1999-11-05 | ||
EP99402759.7 | 1999-11-05 | ||
EP99402877.7 | 1999-11-19 | ||
EP99402877 | 1999-11-19 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA2008100037759A Division CN101219145A (zh) | 1999-11-05 | 2000-11-01 | 作为vegf抑制剂的喹唑啉衍生物 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1387527A CN1387527A (zh) | 2002-12-25 |
CN100376567C true CN100376567C (zh) | 2008-03-26 |
Family
ID=26153696
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB008153108A Expired - Lifetime CN100376567C (zh) | 1999-11-05 | 2000-11-01 | 作为vegf抑制剂的喹唑啉衍生物 |
CNA2008100037759A Pending CN101219145A (zh) | 1999-11-05 | 2000-11-01 | 作为vegf抑制剂的喹唑啉衍生物 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA2008100037759A Pending CN101219145A (zh) | 1999-11-05 | 2000-11-01 | 作为vegf抑制剂的喹唑啉衍生物 |
Country Status (36)
Country | Link |
---|---|
US (9) | US7173038B1 (zh) |
EP (2) | EP1244647B1 (zh) |
JP (1) | JP3522727B2 (zh) |
KR (3) | KR100881105B1 (zh) |
CN (2) | CN100376567C (zh) |
AR (1) | AR033499A1 (zh) |
AT (2) | ATE398120T1 (zh) |
AU (1) | AU769222B2 (zh) |
BE (1) | BE2012C036I2 (zh) |
BG (1) | BG65861B1 (zh) |
BR (2) | BRPI0015203B8 (zh) |
CA (1) | CA2389767C (zh) |
CY (3) | CY1106166T1 (zh) |
CZ (1) | CZ301689B6 (zh) |
DE (2) | DE60029007T2 (zh) |
DK (2) | DK1244647T3 (zh) |
EE (1) | EE05330B1 (zh) |
ES (2) | ES2265998T3 (zh) |
FR (1) | FR12C0048I2 (zh) |
HK (2) | HK1049664B (zh) |
HU (1) | HU229414B1 (zh) |
IL (2) | IL149034A0 (zh) |
IS (2) | IS2284B (zh) |
LU (1) | LU92057I2 (zh) |
MX (1) | MXPA02004366A (zh) |
NO (2) | NO322298B1 (zh) |
NZ (1) | NZ518028A (zh) |
PL (1) | PL203782B1 (zh) |
PT (2) | PT1676845E (zh) |
RU (1) | RU2291868C2 (zh) |
SI (2) | SI1676845T1 (zh) |
SK (1) | SK287401B6 (zh) |
TW (1) | TWI287540B (zh) |
UA (1) | UA72946C2 (zh) |
WO (1) | WO2001032651A1 (zh) |
ZA (1) | ZA200202775B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106397401A (zh) * | 2016-08-30 | 2017-02-15 | 山东罗欣药业集团股份有限公司 | 一种抗癌药物的晶体化合物及其制备方法 |
Families Citing this family (216)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9718972D0 (en) * | 1996-09-25 | 1997-11-12 | Zeneca Ltd | Chemical compounds |
SI1676845T1 (sl) | 1999-11-05 | 2008-10-31 | Astrazeneca Ab | Novi kinazolinski derivati |
GB0008269D0 (en) * | 2000-04-05 | 2000-05-24 | Astrazeneca Ab | Combination chemotherapy |
GB0126879D0 (en) * | 2001-11-08 | 2002-01-02 | Astrazeneca Ab | Combination therapy |
WO2003063904A2 (en) * | 2002-01-29 | 2003-08-07 | Vlaams Interuniversitair Instituut Voor Biotechnologie Vzw | Tissue adhesion formation control |
KR101093345B1 (ko) | 2002-02-01 | 2011-12-14 | 아스트라제네카 아베 | 퀴나졸린 화합물 |
US6924285B2 (en) | 2002-03-30 | 2005-08-02 | Boehringer Ingelheim Pharma Gmbh & Co. | Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them |
CA2491191C (en) | 2002-07-15 | 2014-02-04 | Exelixis, Inc. | Receptor-type kinase modulators and methods of use |
WO2004014383A1 (en) * | 2002-08-09 | 2004-02-19 | Astrazeneca Ab | Combination of zd6474, an inhibitor of the vascular endothelial growth factor receptor, with radiotherapy in the treatment of cancer |
DE10237423A1 (de) | 2002-08-16 | 2004-02-19 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verwendung von LCK-Inhibitoren für die Behandlung von immunologischen Erkrankungen |
GB0223380D0 (en) * | 2002-10-09 | 2002-11-13 | Astrazeneca Ab | Combination therapy |
WO2004041829A1 (en) * | 2002-11-04 | 2004-05-21 | Astrazeneca Ab | Quinazoline derivatives as src tyrosine kinase inhibitors |
DK1592423T3 (da) * | 2003-02-13 | 2011-06-27 | Astrazeneca Ab | Kombinationsterapi af ZD6474 med 5-FU og/eller CPT-11 |
US20050043233A1 (en) * | 2003-04-29 | 2005-02-24 | Boehringer Ingelheim International Gmbh | Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells or angiogenesis |
KR20120093411A (ko) * | 2003-07-10 | 2012-08-22 | 아스트라제네카 아베 | 백금 화합물 및 임의적으로 이온화 방사능과 조합된 퀴나졸린 유도체 zd6474의 혈관신생 및/또는 증가된 혈관 투과성 관련 질환 치료 용도 |
GB0316176D0 (en) * | 2003-07-10 | 2003-08-13 | Astrazeneca Ab | Combination therapy |
TW201319088A (zh) | 2003-07-18 | 2013-05-16 | Amgen Inc | 對肝細胞生長因子具專一性之結合劑 |
GB0317665D0 (en) | 2003-07-29 | 2003-09-03 | Astrazeneca Ab | Qinazoline derivatives |
GB0318423D0 (en) * | 2003-08-06 | 2003-09-10 | Astrazeneca Ab | Chemical compounds |
SI1667991T1 (sl) * | 2003-09-16 | 2008-10-31 | Astrazeneca Ab | Kinazolinski derivati kot inhibitorji tirozin kinaze |
US20070043010A1 (en) * | 2003-09-25 | 2007-02-22 | Astrazeneca Uk Limited | Quinazoline derivatives |
GB0330002D0 (en) * | 2003-12-24 | 2004-01-28 | Astrazeneca Ab | Quinazoline derivatives |
CN1914182B (zh) | 2004-02-03 | 2011-09-07 | 阿斯利康(瑞典)有限公司 | 喹唑啉衍生物 |
GB0421438D0 (en) * | 2004-09-27 | 2004-10-27 | Astrazeneca Ab | Combination therapy |
US20080119479A1 (en) * | 2004-04-01 | 2008-05-22 | Stephen Robert Wedge | Combination Comprising Zd6474 And Imatinib |
GB0411378D0 (en) | 2004-05-21 | 2004-06-23 | Astrazeneca Ab | Pharmaceutical compositions |
WO2006002422A2 (en) * | 2004-06-24 | 2006-01-05 | Novartis Vaccines And Diagnostics Inc. | Compounds for immunopotentiation |
GB0424339D0 (en) * | 2004-11-03 | 2004-12-08 | Astrazeneca Ab | Combination therapy |
MX2007006230A (es) | 2004-11-30 | 2007-07-25 | Amgen Inc | Quinolinas y analogos de quinazolinas y su uso como medicamentos para tratar cancer. |
NZ556029A (en) | 2004-12-21 | 2010-04-30 | Astrazeneca Ab | Antibodies directed to angiopoietin-2 and uses thereof |
CN1854130B (zh) * | 2005-04-15 | 2011-04-20 | 中国医学科学院药物研究所 | 喹唑啉衍生物、及其制法和药物组合物与用途 |
DK1922307T3 (da) | 2005-05-18 | 2012-04-02 | Array Biopharma Inc | Heterocykliske inhibitorer af MEK og fremgangsmåder til anvendelse heraf |
GB0519879D0 (en) | 2005-09-30 | 2005-11-09 | Astrazeneca Ab | Chemical process |
AU2011203358B2 (en) * | 2005-09-30 | 2013-05-30 | Genzyme Corporation | Chemical process |
GB0519878D0 (en) * | 2005-09-30 | 2005-11-09 | Astrazeneca Ab | Chemical compound |
US20080108664A1 (en) | 2005-12-23 | 2008-05-08 | Liu Belle B | Solid-state form of AMG 706 and pharmaceutical compositions thereof |
JO2660B1 (en) | 2006-01-20 | 2012-06-17 | نوفارتيس ايه جي | Pi-3 inhibitors and methods of use |
AR059066A1 (es) * | 2006-01-27 | 2008-03-12 | Amgen Inc | Combinaciones del inhibidor de la angiopoyetina -2 (ang2) y el inhibidor del factor de crecimiento endotelial vascular (vegf) |
ATE489380T1 (de) | 2006-02-10 | 2010-12-15 | Amgen Inc | Hydratformen von amg706 |
AR060358A1 (es) | 2006-04-06 | 2008-06-11 | Novartis Vaccines & Diagnostic | Quinazolinas para la inhibicion de pdk 1 |
TW200813091A (en) | 2006-04-10 | 2008-03-16 | Amgen Fremont Inc | Targeted binding agents directed to uPAR and uses thereof |
US20070293491A1 (en) | 2006-04-19 | 2007-12-20 | Novartis Vaccines And Diagnostics, Inc. | Indazole compounds and methods for inhibition of cdc7 |
PE20080403A1 (es) | 2006-07-14 | 2008-04-25 | Amgen Inc | Derivados heterociclicos fusionados y metodos de uso |
US8217177B2 (en) | 2006-07-14 | 2012-07-10 | Amgen Inc. | Fused heterocyclic derivatives and methods of use |
CL2007002225A1 (es) | 2006-08-03 | 2008-04-18 | Astrazeneca Ab | Agente de union especifico para un receptor del factor de crecimiento derivado de plaquetas (pdgfr-alfa); molecula de acido nucleico que lo codifica; vector y celula huesped que la comprenden; conjugado que comprende al agente; y uso del agente de un |
TW200817409A (en) | 2006-08-04 | 2008-04-16 | Takeda Pharmaceutical | Fused heterocyclic derivative and use thereof |
MX2009001946A (es) | 2006-08-23 | 2009-03-05 | Kudos Pharm Ltd | Derivados de 2-metilmorfolin-pirido-, pirazo- y pirimido- pirimidina como inhibidores de mtor. |
JP2010504949A (ja) | 2006-09-29 | 2010-02-18 | アストラゼネカ アクチボラグ | Zd6474とベバシズマブの癌療法のための組合せ |
US8883790B2 (en) | 2006-10-12 | 2014-11-11 | Astex Therapeutics Limited | Pharmaceutical combinations |
US8916552B2 (en) | 2006-10-12 | 2014-12-23 | Astex Therapeutics Limited | Pharmaceutical combinations |
WO2008046242A1 (fr) * | 2006-10-16 | 2008-04-24 | Institute Of Mataria Medica, Chinese Academy Of Medical Sciences | Nouveaux dérivés quinazolines, leurs procédés de préparation et leurs utilisations |
EP1921070A1 (de) | 2006-11-10 | 2008-05-14 | Boehringer Ingelheim Pharma GmbH & Co. KG | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstelllung |
US7687522B2 (en) | 2006-12-20 | 2010-03-30 | Amgen Inc. | Substituted pyridines and pyrimidines and their use in treatment of cancer |
EP2118069B1 (en) | 2007-01-09 | 2014-01-01 | Amgen Inc. | Bis-aryl amide derivatives useful for the treatment of cancer |
AU2008212999A1 (en) | 2007-02-06 | 2008-08-14 | Boehringer Ingelheim International Gmbh | Bicyclic heterocycles, drugs containing said compounds, use thereof, and method for production thereof |
US20080190689A1 (en) * | 2007-02-12 | 2008-08-14 | Ballard Ebbin C | Inserts for engine exhaust systems |
CA2676173A1 (en) | 2007-02-16 | 2008-08-28 | Amgen Inc. | Nitrogen-containing heterocyclyl ketones and their use as c-met inhibitors |
PE20081887A1 (es) | 2007-03-20 | 2009-01-16 | Dainippon Sumitomo Pharma Co | Nuevo compuesto de adenina |
EP2138497A4 (en) | 2007-03-20 | 2012-01-04 | Dainippon Sumitomo Pharma Co | NEW ADENINE CONNECTION |
US8914063B2 (en) | 2007-05-15 | 2014-12-16 | Lg Electronics Inc. | Mobile terminal equipped with mode setting key and method of controlling the mobile terminal |
US8304557B2 (en) | 2007-06-05 | 2012-11-06 | Takeda Pharmaceutical Company Limited | Fused heterocycle derivatives and use thereof |
SG10201500328QA (en) | 2007-08-21 | 2015-03-30 | Amgen Inc | Human c-fms antigen binding proteins |
JP5270553B2 (ja) | 2007-08-23 | 2013-08-21 | 武田薬品工業株式会社 | 複素環化合物およびその用途 |
NZ585261A (en) | 2007-10-11 | 2011-10-28 | Astrazeneca Ab | Pyrrolo [2, 3 -d] pyrimidin derivatives as protein kinase b inhibitors |
CA2706571C (en) | 2007-12-19 | 2012-11-27 | Genentech, Inc. | 5-anilinoimidazopyridines and methods of use |
CN101952282A (zh) | 2007-12-20 | 2011-01-19 | 诺瓦提斯公司 | 用作pi 3激酶抑制剂的噻唑衍生物 |
CA2708176A1 (en) | 2007-12-21 | 2009-07-02 | Genentech, Inc. | Azaindolizines and methods of use |
US8609673B2 (en) * | 2008-01-22 | 2013-12-17 | Concert Pharmaceuticals, Inc. | Vandetanib derivatives |
EP2245026B1 (de) | 2008-02-07 | 2012-08-01 | Boehringer Ingelheim International GmbH | Spirocyclische heterocyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung |
EP2262504A1 (en) * | 2008-02-21 | 2010-12-22 | AstraZeneca AB | Combination therapy 238 |
NZ589883A (en) | 2008-05-13 | 2012-06-29 | Astrazeneca Ab | Fumarate salt of 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [1- (n-methylcarbamoylmethyl) piperidin- 4-yl] oxy} quinazoline |
CA2729303A1 (en) | 2008-06-30 | 2010-01-14 | Angioblast Systems, Inc. | Treatment of eye diseases and excessive neovascularization using a combined therapy |
US8648191B2 (en) | 2008-08-08 | 2014-02-11 | Boehringer Ingelheim International Gmbh | Cyclohexyloxy substituted heterocycles, pharmaceutical compositions containing these compounds and processes for preparing them |
KR20110057244A (ko) | 2008-09-19 | 2011-05-31 | 메디뮨 엘엘씨 | Dll4에 대한 항체 및 이의 용도 |
US8697874B2 (en) | 2008-12-01 | 2014-04-15 | Takeda Pharmaceutical Company Limited | Heterocyclic compound and use thereof |
JO3101B1 (ar) | 2008-12-02 | 2017-09-20 | Takeda Pharmaceuticals Co | مشتقات بنزوثيازول كعوامل مضادة للسرطان |
UY32351A (es) | 2008-12-22 | 2010-07-30 | Astrazeneca Ab | Compuestos de pirimidinil indol para uso como inhibidores de atr |
WO2010072740A2 (en) | 2008-12-23 | 2010-07-01 | Astrazeneca Ab | TARGETED BINDING AGENTS DIRECTED TO α5β1 AND USES THEREOF |
US8426402B2 (en) | 2009-02-05 | 2013-04-23 | Immunogen, Inc. | Benzodiazepine derivatives |
WO2010103094A1 (en) | 2009-03-13 | 2010-09-16 | Cellzome Limited | PYRIMIDINE DERIVATIVES AS mTOR INHIBITORS |
WO2010108503A1 (en) | 2009-03-24 | 2010-09-30 | Life & Brain Gmbh | Promotion of neuronal integration in neural stem cell grafts |
US20120040955A1 (en) | 2009-04-14 | 2012-02-16 | Richard John Harrison | Fluoro substituted pyrimidine compounds as jak3 inhibitors |
US8293753B2 (en) | 2009-07-02 | 2012-10-23 | Novartis Ag | Substituted 2-carboxamide cycloamino ureas |
US20120172385A1 (en) | 2009-09-11 | 2012-07-05 | Richard John Harrison | Ortho substituted pyrimidine compounds as jak inhibitors |
AR078675A1 (es) | 2009-10-20 | 2011-11-23 | Cellzome Ltd | Derivados de pirazolo[3,4-d]pirimidina inhibidores de jak quinasas, composiciones farmaceuticas que los comprenden, metodo para prepararlos y uso de los mismos para el tratamiento o profilaxis de trastornos inmunologicos, inflamatorios y autoinmunes. |
CN102070608A (zh) * | 2009-11-19 | 2011-05-25 | 天津药物研究院 | 4-取代苯胺基-7-取代烷氧基-喹唑啉衍生物、其制备方法和用途 |
HUE037159T2 (hu) | 2009-11-24 | 2018-08-28 | Medimmune Ltd | Targetált kötõdõ ágensek B7-H1 ellen |
JP2013512859A (ja) | 2009-12-03 | 2013-04-18 | 大日本住友製薬株式会社 | トール様受容体(tlr)を介して作用するイミダゾキノリン |
JP5841072B2 (ja) | 2010-02-10 | 2016-01-06 | イミュノジェン・インコーポレーテッド | Cd20抗体およびその使用 |
EP2542536B1 (en) | 2010-03-04 | 2015-01-21 | Cellzome Limited | Morpholino substituted urea derivatives as mtor inhibitors |
EP2566867A1 (en) | 2010-04-30 | 2013-03-13 | Cellzome Limited | Pyrazole compounds as jak inhibitors |
SA111320519B1 (ar) | 2010-06-11 | 2014-07-02 | Astrazeneca Ab | مركبات بيريميدينيل للاستخدام كمثبطات atr |
WO2011161217A2 (en) | 2010-06-23 | 2011-12-29 | Palacký University in Olomouc | Targeting of vegfr2 |
US20130143915A1 (en) | 2010-07-01 | 2013-06-06 | Cellzome Limited | Triazolopyridines as tyk2 inhibitors |
AR082418A1 (es) | 2010-08-02 | 2012-12-05 | Novartis Ag | Formas cristalinas de 1-(4-metil-5-[2-(2,2,2-trifluoro-1,1-dimetil-etil)-piridin-4-il]-tiazol-2-il)-amida de 2-amida del acido (s)-pirrolidin-1,2-dicarboxilico |
WO2012022681A2 (en) | 2010-08-20 | 2012-02-23 | Cellzome Limited | Heterocyclyl pyrazolopyrimidine analogues as selective jak inhibitors |
DK2612151T3 (en) | 2010-08-31 | 2017-10-02 | Genentech Inc | BIOMARKETS AND METHODS OF TREATMENT |
AU2011328237A1 (en) | 2010-11-09 | 2013-05-23 | Cellzome Limited | Pyridine compounds and aza analogues thereof as TYK2 inhibitors |
CN102532103B (zh) * | 2010-12-20 | 2014-07-09 | 天津药物研究院 | 喹唑啉芳基脲衍生物及其制备方法和用途 |
TW201309700A (zh) | 2011-01-31 | 2013-03-01 | Novartis Ag | 新穎雜環衍生物 |
WO2012112708A1 (en) | 2011-02-15 | 2012-08-23 | Immunogen, Inc. | Cytotoxic benzodiazepine derivatives and methods of preparation |
JP5937112B2 (ja) | 2011-02-17 | 2016-06-22 | カンサー・セラピューティクス・シーアールシー・プロプライエタリー・リミテッドCancer Therapeutics Crc Pty Limited | 選択的fak阻害剤 |
US20130324532A1 (en) | 2011-02-17 | 2013-12-05 | Cancer Therapeutics Crc Pty Limited | Fak inhibitors |
ES2543569T3 (es) | 2011-03-23 | 2015-08-20 | Amgen Inc. | Inhibidores duales tricíclicos condensados de CDK 4/6 y FLT3 |
JP2014510122A (ja) | 2011-04-04 | 2014-04-24 | セルゾーム リミテッド | mTOR阻害剤としてのジヒドロピロロピリミジン誘導体 |
WO2012143320A1 (en) | 2011-04-18 | 2012-10-26 | Cellzome Limited | (7h-pyrrolo[2,3-d]pyrimidin-2-yl)amine compounds as jak3 inhibitors |
CN103781780B (zh) | 2011-07-28 | 2015-11-25 | 赛尔佐姆有限公司 | 作为jak抑制剂的杂环基嘧啶类似物 |
WO2013017479A1 (en) | 2011-07-29 | 2013-02-07 | Cellzome Limited | Pyrazolo[4,3-c]pyridine derivatives as jak inhibitors |
WO2013017480A1 (en) | 2011-07-29 | 2013-02-07 | Cellzome Limited | Pyrazolo[4,3-c]pyridine derivatives as jak inhibitors |
WO2013025939A2 (en) | 2011-08-16 | 2013-02-21 | Indiana University Research And Technology Corporation | Compounds and methods for treating cancer by inhibiting the urokinase receptor |
JP2014531449A (ja) | 2011-09-20 | 2014-11-27 | セルゾーム リミティッド | キナーゼ阻害剤としてのピラゾロ[4,3―c]ピリジン誘導体 |
CN103917530B (zh) | 2011-09-21 | 2016-08-24 | 塞尔佐姆有限公司 | 作为mtor抑制剂的吗啉代取代的脲或氨基甲酸衍生物 |
CN103946222B (zh) | 2011-10-07 | 2016-12-28 | 塞尔佐姆有限公司 | 作为mtor抑制剂的吗啉代取代的双环嘧啶脲或氨基甲酸衍生物 |
MX340452B (es) | 2011-10-28 | 2016-07-08 | Novartis Ag | Novedosos derivados de purina y su uso en el tratamiento de enfermedades. |
JP2015500862A (ja) | 2011-12-23 | 2015-01-08 | セルゾーム リミティッド | キナーゼ阻害剤としてのピリミジン−2,4−ジアミン誘導体 |
AR090263A1 (es) | 2012-03-08 | 2014-10-29 | Hoffmann La Roche | Terapia combinada de anticuerpos contra el csf-1r humano y las utilizaciones de la misma |
AU2013263043B2 (en) | 2012-05-16 | 2016-06-16 | Novartis Ag | Dosage regimen for a PI-3 kinase inhibitor |
US9738724B2 (en) | 2012-06-08 | 2017-08-22 | Sutro Biopharma, Inc. | Antibodies comprising site-specific non-natural amino acid residues, methods of their preparation and methods of their use |
EP2863955B1 (en) | 2012-06-26 | 2016-11-23 | Sutro Biopharma, Inc. | Modified fc proteins comprising site-specific non-natural amino acid residues, conjugates of the same, methods of their preparation and methods of their use |
EP2885291A4 (en) | 2012-08-17 | 2015-11-04 | Cancer Therapeutics Crc Pty Ltd | INHIBITORS OF VEGFR3 |
EP2887965A1 (en) | 2012-08-22 | 2015-07-01 | ImmunoGen, Inc. | Cytotoxic benzodiazepine derivatives |
WO2014036022A1 (en) | 2012-08-29 | 2014-03-06 | Amgen Inc. | Quinazolinone compounds and derivatives thereof |
SI3584255T1 (sl) | 2012-08-31 | 2022-05-31 | Sutro Biopharma, Inc | Modificirane aminokisline, ki vsebujejo azido skupino |
WO2014041349A1 (en) | 2012-09-12 | 2014-03-20 | Cancer Therapeutics Crc Pty Ltd | Tetrahydropyran-4-ylethylamino- or tetrahydropyranyl-4-ethyloxy-pyrimidines or -pyridazines as isoprenylcysteincarboxymethyl transferase inhibitors |
WO2014045101A1 (en) | 2012-09-21 | 2014-03-27 | Cellzome Gmbh | Tetrazolo quinoxaline derivatives as tankyrase inhibitors |
WO2014074517A1 (en) | 2012-11-08 | 2014-05-15 | Emory University | Cellular compositions used to restore stem cell or progenitor cell function and methods related thereto |
JP2016509045A (ja) | 2013-02-22 | 2016-03-24 | エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト | がんを治療し、薬剤耐性を防止する方法 |
EP2961435B1 (en) | 2013-02-28 | 2019-05-01 | ImmunoGen, Inc. | Conjugates comprising cell-binding agents and cytotoxic agents |
WO2014134483A2 (en) | 2013-02-28 | 2014-09-04 | Immunogen, Inc. | Conjugates comprising cell-binding agents and cytotoxic agents |
JP2016510751A (ja) | 2013-03-06 | 2016-04-11 | ジェネンテック, インコーポレイテッド | 抗がん剤耐性を治療及び予防する方法 |
EP2968565A2 (en) | 2013-03-14 | 2016-01-20 | Genentech, Inc. | Methods of treating cancer and preventing cancer drug resistance |
AR095443A1 (es) | 2013-03-15 | 2015-10-14 | Fundación Centro Nac De Investig Oncológicas Carlos Iii | Heterociclos condensados con acción sobre atr |
MX2015011899A (es) | 2013-03-15 | 2016-05-05 | Genentech Inc | Metodos para el tratamiento de cáncer y prevención de resistencia a los fármacos para el cáncer. |
WO2014194030A2 (en) | 2013-05-31 | 2014-12-04 | Immunogen, Inc. | Conjugates comprising cell-binding agents and cytotoxic agents |
ES2658039T3 (es) | 2013-07-10 | 2018-03-08 | Sutro Biopharma, Inc. | Anticuerpos que comprenden múltiples residuos de aminoácidos no naturales sitio-específicos, métodos para su preparación y métodos de uso |
WO2015031604A1 (en) | 2013-08-28 | 2015-03-05 | Crown Bioscience, Inc. | Gene expression signatures predictive of subject response to a multi-kinase inhibitor and methods of using the same |
CN103483276B (zh) * | 2013-09-22 | 2018-04-17 | 南京恒道医药科技有限公司 | 一种凡德他尼杂质的制备方法 |
WO2015054658A1 (en) | 2013-10-11 | 2015-04-16 | Sutro Biopharma, Inc. | Modified amino acids comprising tetrazine functional groups, methods of preparation, and methods of their use |
TN2016000179A1 (en) | 2013-12-06 | 2017-10-06 | Novartis Ag | Dosage regimen for an alpha-isoform selective phosphatidylinositol 3-kinase inhibitor. |
BR112016021383A2 (pt) | 2014-03-24 | 2017-10-03 | Genentech Inc | Método para identificar um paciente com câncer que é susceptível ou menos susceptível a responder ao tratamento com um antagonista de cmet, método para identificar um paciente apresentando câncer previamente tratado, método para determinar a expressão do biomarcador hgf, antagonista anti-c-met e seu uso, kit de diagnóstico e seu método de preparo |
WO2016112111A1 (en) | 2015-01-08 | 2016-07-14 | The Board Of Trustees Of The Leland Stanford Junior University | Factors and cells that provide for induction of bone, bone marrow, and cartilage |
GB201510019D0 (en) | 2015-06-09 | 2015-07-22 | Cancer Therapeutics Crc Pty Ltd | Compounds |
CN106317022A (zh) * | 2015-06-25 | 2017-01-11 | 中美华世通生物医药科技(武汉)有限公司 | 化合物的制备方法和用途 |
MX2018005298A (es) | 2015-11-02 | 2018-06-22 | Novartis Ag | Regimen de dosificacion para un inhibidor de fosfatidilinositol 3-quinasa. |
CN105254614B (zh) * | 2015-11-16 | 2017-08-15 | 山东罗欣药业集团股份有限公司 | 一种凡德他尼化合物的合成方法 |
CA3011455A1 (en) | 2016-01-27 | 2017-08-03 | Sutro Biopharma, Inc. | Anti-cd74 antibody conjugates, compositions comprising anti-cd74 antibody conjugates and methods of using anti-cd74 antibody conjugates |
WO2017139417A1 (en) | 2016-02-08 | 2017-08-17 | Vitrisa Therapeutics, Inc. | Compositions with improved intravitreal half-life and uses thereof |
CN106349231A (zh) * | 2016-08-09 | 2017-01-25 | 浙江医药高等专科学校 | 一类含卤代噻吩磺酰胺结构的苯并喹唑啉类酪氨酸激酶抑制剂 |
CN106349230A (zh) * | 2016-08-09 | 2017-01-25 | 浙江医药高等专科学校 | 一种含硝基噻吩磺酰胺结构的苯并喹唑啉类酪氨酸激酶抑制剂及用途 |
CN106317040A (zh) * | 2016-08-09 | 2017-01-11 | 浙江医药高等专科学校 | 含噻吩磺酰胺结构的苯并喹唑啉类酪氨酸激酶抑制剂、制备方法及用途 |
CN106279135A (zh) * | 2016-08-09 | 2017-01-04 | 浙江医药高等专科学校 | 一种噻吩磺酰胺结构的苯并喹唑啉类酪氨酸激酶抑制剂 |
CN106317039A (zh) * | 2016-08-09 | 2017-01-11 | 浙江医药高等专科学校 | 一种含噻吩磺酰胺结构的乙氧苯并喹唑啉类酪氨酸激酶抑制剂、制备方法及用途 |
CN106478598B (zh) * | 2016-08-30 | 2018-11-13 | 山东罗欣药业集团股份有限公司 | 一种凡德他尼水合物晶体及其制备方法 |
AU2017321973A1 (en) | 2016-09-02 | 2019-03-07 | Dana-Farber Cancer Institute, Inc. | Composition and methods of treating B cell disorders |
WO2018060833A1 (en) | 2016-09-27 | 2018-04-05 | Novartis Ag | Dosage regimen for alpha-isoform selective phosphatidylinositol 3-kinase inhibitor alpelisib |
ES2906439T3 (es) | 2016-12-05 | 2022-04-18 | Apros Therapeutics Inc | Compuestos de pirimidina que contienen grupos ácidos |
US10786502B2 (en) | 2016-12-05 | 2020-09-29 | Apros Therapeutics, Inc. | Substituted pyrimidines containing acidic groups as TLR7 modulators |
ES2894255T3 (es) | 2016-12-22 | 2022-02-14 | Amgen Inc | Derivados de benzoisotiazol, isotiazolo[3,4-b]piridina, quinazolina, ftalazina, pirido[2,3-d]piridazina y derivados de pirido[2,3-d]pirimidina como inhibidores de KRAS G12C para tratar el cáncer de pulmón, pancreático o colorrectal |
JOP20190272A1 (ar) | 2017-05-22 | 2019-11-21 | Amgen Inc | مثبطات kras g12c وطرق لاستخدامها |
EP3658588A1 (en) | 2017-07-26 | 2020-06-03 | Sutro Biopharma, Inc. | Methods of using anti-cd74 antibodies and antibody conjugates in treatment of t-cell lymphoma |
SG11202001499WA (en) | 2017-09-08 | 2020-03-30 | Amgen Inc | Inhibitors of kras g12c and methods of using the same |
KR20200051802A (ko) | 2017-09-18 | 2020-05-13 | 서트로 바이오파마, 인크. | 항-엽산 수용체 알파 항체 접합체 및 이의 용도 |
NL2019801B1 (en) | 2017-10-25 | 2019-05-02 | Univ Leiden | Delivery vectors |
EP3788053A1 (en) | 2018-05-04 | 2021-03-10 | Amgen Inc. | Kras g12c inhibitors and methods of using the same |
WO2019213516A1 (en) | 2018-05-04 | 2019-11-07 | Amgen Inc. | Kras g12c inhibitors and methods of using the same |
MA52564A (fr) | 2018-05-10 | 2021-03-17 | Amgen Inc | Inhibiteurs de kras g12c pour le traitement du cancer |
AU2019278998B2 (en) | 2018-06-01 | 2023-11-09 | Amgen Inc. | KRAS G12C inhibitors and methods of using the same |
WO2019236496A1 (en) | 2018-06-04 | 2019-12-12 | Apros Therapeutics, Inc. | Pyrimidine compounds containing acidic groups useful to treat diseases connected to the modulation of tlr7 |
AU2019284472A1 (en) | 2018-06-11 | 2020-11-26 | Amgen Inc. | KRAS G12C inhibitors for treating cancer |
EP3807276A2 (en) | 2018-06-12 | 2021-04-21 | Amgen Inc. | Kras g12c inhibitors encompassing a piperazine ring and use thereof in the treatment of cancer |
GB201810092D0 (en) | 2018-06-20 | 2018-08-08 | Ctxt Pty Ltd | Compounds |
GB201810581D0 (en) | 2018-06-28 | 2018-08-15 | Ctxt Pty Ltd | Compounds |
WO2020060944A1 (en) | 2018-09-17 | 2020-03-26 | Sutro Biopharma, Inc. | Combination therapies with anti-folate receptor antibody conjugates |
JP2020090482A (ja) | 2018-11-16 | 2020-06-11 | アムジエン・インコーポレーテツド | Kras g12c阻害剤化合物の重要な中間体の改良合成法 |
EP3883565A1 (en) | 2018-11-19 | 2021-09-29 | Amgen Inc. | Kras g12c inhibitors and methods of using the same |
JP7377679B2 (ja) | 2018-11-19 | 2023-11-10 | アムジエン・インコーポレーテツド | がん治療のためのkrasg12c阻害剤及び1種以上の薬学的に活性な追加の薬剤を含む併用療法 |
WO2020132651A1 (en) | 2018-12-20 | 2020-06-25 | Amgen Inc. | Kif18a inhibitors |
JP2022513971A (ja) | 2018-12-20 | 2022-02-09 | アムジエン・インコーポレーテツド | Kif18a阻害剤として有用なヘテロアリールアミド |
AU2019404576A1 (en) | 2018-12-20 | 2021-06-24 | Amgen Inc. | Heteroaryl amides useful as KIF18A inhibitors |
JP7407196B2 (ja) | 2018-12-20 | 2023-12-28 | アムジエン・インコーポレーテツド | Kif18a阻害剤 |
CA3124330A1 (en) | 2018-12-21 | 2020-06-25 | Daiichi Sankyo Company, Limited | Combination of antibody-drug conjugate and kinase inhibitor |
US20230148450A9 (en) | 2019-03-01 | 2023-05-11 | Revolution Medicines, Inc. | Bicyclic heteroaryl compounds and uses thereof |
SG11202109422WA (en) | 2019-03-01 | 2021-09-29 | Revolution Medicines Inc | Bicyclic heterocyclyl compounds and uses thereof |
EP3962951A1 (en) | 2019-05-03 | 2022-03-09 | Sutro Biopharma, Inc. | Anti-bcma antibody conjugates |
EP3738593A1 (en) | 2019-05-14 | 2020-11-18 | Amgen, Inc | Dosing of kras inhibitor for treatment of cancers |
AU2020280024A1 (en) | 2019-05-21 | 2021-12-09 | Amgen Inc. | Solid state forms |
MX2022001302A (es) | 2019-08-02 | 2022-03-02 | Amgen Inc | Inhibidores de kif18a. |
AU2020326627A1 (en) | 2019-08-02 | 2022-03-17 | Amgen Inc. | KIF18A inhibitors |
EP4007756A1 (en) | 2019-08-02 | 2022-06-08 | Amgen Inc. | Kif18a inhibitors |
CN114401953A (zh) | 2019-08-02 | 2022-04-26 | 美国安进公司 | Kif18a抑制剂 |
AU2020335054A1 (en) | 2019-08-31 | 2022-03-24 | Etern Biopharma (Shanghai) Co., Ltd. | Pyrazole derivative for FGFR inhibitor and preparation method therefor |
CA3155857A1 (en) | 2019-10-24 | 2021-04-29 | Amgen Inc. | PYRIDOPYRIMIDINE DERIVATIVES USEFUL AS KRAS G12C AND KRAS G12D INHIBITORS IN THE TREATMENT OF CANCER |
AU2020377925A1 (en) | 2019-11-04 | 2022-05-05 | Revolution Medicines, Inc. | Ras inhibitors |
BR112022008534A2 (pt) | 2019-11-04 | 2022-08-09 | Revolution Medicines Inc | Compostos, composição farmacêutica, conjugado e métodos para tratar câncer e para tratar um distúrbio relacionado à proteína ras |
JP2022553858A (ja) | 2019-11-04 | 2022-12-26 | レボリューション メディシンズ インコーポレイテッド | Ras阻害剤 |
CN116425742A (zh) | 2019-11-08 | 2023-07-14 | 锐新医药公司 | 双环杂芳基化合物及其用途 |
EP4058432A1 (en) | 2019-11-14 | 2022-09-21 | Amgen Inc. | Improved synthesis of kras g12c inhibitor compound |
AR120457A1 (es) | 2019-11-14 | 2022-02-16 | Amgen Inc | Síntesis mejorada del compuesto inhibidor de g12c de kras |
JP2023505100A (ja) | 2019-11-27 | 2023-02-08 | レボリューション メディシンズ インコーポレイテッド | 共有ras阻害剤及びその使用 |
CN114929279A (zh) | 2020-01-07 | 2022-08-19 | 锐新医药公司 | Shp2抑制剂给药和治疗癌症的方法 |
EP4114852A1 (en) | 2020-03-03 | 2023-01-11 | Sutro Biopharma, Inc. | Antibodies comprising site-specific glutamine tags, methods of their preparation and methods of their use |
MX2022016355A (es) | 2020-06-18 | 2023-04-03 | Revolution Medicines Inc | Metodos para retardar, prevenir, y tratar la resistencia adquirida a inhibidores de ras. |
WO2022053130A1 (en) | 2020-09-09 | 2022-03-17 | Sid Alex Group, S.R.O. | Antago-mir-155 for treatment of v-src, c-src-tyrosine kinase-induced cancers |
WO2022060836A1 (en) | 2020-09-15 | 2022-03-24 | Revolution Medicines, Inc. | Indole derivatives as ras inhibitors in the treatment of cancer |
CA3203111A1 (en) | 2020-12-22 | 2022-06-30 | Kailiang Wang | Sos1 inhibitors and uses thereof |
PE20240089A1 (es) | 2021-05-05 | 2024-01-16 | Revolution Medicines Inc | Inhibidores de ras para el tratamiento del cancer |
KR20240004960A (ko) | 2021-05-05 | 2024-01-11 | 레볼루션 메디슨즈, 인크. | Ras 억제제 |
EP4334324A1 (en) | 2021-05-05 | 2024-03-13 | Revolution Medicines, Inc. | Covalent ras inhibitors and uses thereof |
AR127308A1 (es) | 2021-10-08 | 2024-01-10 | Revolution Medicines Inc | Inhibidores ras |
TW202340214A (zh) | 2021-12-17 | 2023-10-16 | 美商健臻公司 | 做為shp2抑制劑之吡唑并吡𠯤化合物 |
EP4227307A1 (en) | 2022-02-11 | 2023-08-16 | Genzyme Corporation | Pyrazolopyrazine compounds as shp2 inhibitors |
WO2023172940A1 (en) | 2022-03-08 | 2023-09-14 | Revolution Medicines, Inc. | Methods for treating immune refractory lung cancer |
WO2023228095A1 (en) | 2022-05-24 | 2023-11-30 | Daiichi Sankyo Company, Limited | Dosage regimen of an anti-cdh6 antibody-drug conjugate |
WO2023240263A1 (en) | 2022-06-10 | 2023-12-14 | Revolution Medicines, Inc. | Macrocyclic ras inhibitors |
US20240058465A1 (en) | 2022-06-30 | 2024-02-22 | Sutro Biopharma, Inc. | Anti-ror1 antibody conjugates, compositions comprising anti ror1 antibody conjugates, and methods of making and using anti-ror1 antibody conjugates |
WO2024081916A1 (en) | 2022-10-14 | 2024-04-18 | Black Diamond Therapeutics, Inc. | Methods of treating cancers using isoquinoline or 6-aza-quinoline derivatives |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0566226A1 (en) * | 1992-01-20 | 1993-10-20 | Zeneca Limited | Quinazoline derivatives |
WO1997030035A1 (en) * | 1996-02-13 | 1997-08-21 | Zeneca Limited | Quinazoline derivatives as vegf inhibitors |
WO1998013354A1 (en) * | 1996-09-25 | 1998-04-02 | Zeneca Limited | Quinazoline derivatives and pharmaceutical compositions containing them |
CN1116286C (zh) * | 1996-03-05 | 2003-07-30 | 曾尼卡有限公司 | 4-苯胺基喹唑啉衍生物 |
Family Cites Families (122)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3266990A (en) | 1963-09-24 | 1966-08-16 | Warner Lambert Pharmaceutical | Derivatives of quinazoline |
US3870725A (en) | 1971-03-30 | 1975-03-11 | Lilly Industries Ltd | Nitrothiazole derivatives |
JPS542327A (en) | 1977-06-07 | 1979-01-09 | Sankyo Co Ltd | Agricultural and horticultural pesticide |
JPS5538325A (en) | 1978-09-11 | 1980-03-17 | Sankyo Co Ltd | 4-anilinoquinazoline derivative and its preparation |
US4343940A (en) | 1979-02-13 | 1982-08-10 | Mead Johnson & Company | Anti-tumor quinazoline compounds |
GB2160201B (en) | 1984-06-14 | 1988-05-11 | Wyeth John & Brother Ltd | Quinazoline and cinnoline derivatives |
IL81307A0 (en) | 1986-01-23 | 1987-08-31 | Union Carbide Agricult | Method for reducing moisture loss from plants and increasing crop yield utilizing nitrogen containing heterocyclic compounds and some novel polysubstituted pyridine derivatives |
ATE110071T1 (de) | 1988-01-23 | 1994-09-15 | Kyowa Hakko Kogyo Kk | Pyridazinon-derivate und diese enthaltende pharmazeutische zubereitungen. |
US5411963A (en) | 1988-01-29 | 1995-05-02 | Dowelanco | Quinazoline derivatives |
IL89029A (en) | 1988-01-29 | 1993-01-31 | Lilly Co Eli | Fungicidal quinoline and cinnoline derivatives, compositions containing them, and fungicidal methods of using them |
DE9290018U1 (de) | 1991-02-20 | 1993-10-14 | Pfizer | 2,4-Diaminochinazolin-Derivate zur Verbesserung der Antitumor-Aktivität |
IL101291A0 (en) | 1991-03-22 | 1992-11-15 | Nippon Soda Co | 2-pyridine derivatives,their preparation and their use as fungicides |
US5721237A (en) | 1991-05-10 | 1998-02-24 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Protein tyrosine kinase aryl and heteroaryl quinazoline compounds having selective inhibition of HER-2 autophosphorylation properties |
US5710158A (en) | 1991-05-10 | 1998-01-20 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Aryl and heteroaryl quinazoline compounds which inhibit EGF and/or PDGF receptor tyrosine kinase |
ES2108120T3 (es) | 1991-05-10 | 1997-12-16 | Rhone Poulenc Rorer Int | Compuestos bis arilicos y heteroarilicos mono- y biciclicos que inhiben tirosina quinasa receptora de egf y/o pdgf. |
US6645969B1 (en) | 1991-05-10 | 2003-11-11 | Aventis Pharmaceuticals Inc. | Aryl and heteroaryl quinazoline compounds which inhibit CSF-1R receptor tyrosine kinase |
US5480883A (en) | 1991-05-10 | 1996-01-02 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Bis mono- and bicyclic aryl and heteroaryl compounds which inhibit EGF and/or PDGF receptor tyrosine kinase |
US5714493A (en) | 1991-05-10 | 1998-02-03 | Rhone-Poulenc Rorer Pharmaceuticals, Inc. | Aryl and heteroaryl quinazoline compounds which inhibit CSF-1R receptor tyrosine kinase |
NZ243082A (en) | 1991-06-28 | 1995-02-24 | Ici Plc | 4-anilino-quinazoline derivatives; pharmaceutical compositions, preparatory processes, and use thereof |
DE4208254A1 (de) | 1992-03-14 | 1993-09-16 | Hoechst Ag | Substituierte pyrimidine, verfahren zu ihrer herstellung und ihre verwendung als schaedlingsbekaempfungsmittel und fungizid |
US5270466A (en) | 1992-06-11 | 1993-12-14 | American Cyanamid Company | Substituted quinazoline fungicidal agents |
US6177401B1 (en) | 1992-11-13 | 2001-01-23 | Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften | Use of organic compounds for the inhibition of Flk-1 mediated vasculogenesis and angiogenesis |
US5792771A (en) | 1992-11-13 | 1998-08-11 | Sugen, Inc. | Quinazoline compounds and compositions thereof for the treatment of disease |
US5712395A (en) | 1992-11-13 | 1998-01-27 | Yissum Research Development Corp. | Compounds for the treatment of disorders related to vasculogenesis and/or angiogenesis |
GB9323290D0 (en) | 1992-12-10 | 1994-01-05 | Zeneca Ltd | Quinazoline derivatives |
GB9314893D0 (en) | 1993-07-19 | 1993-09-01 | Zeneca Ltd | Quinazoline derivatives |
GB9314884D0 (en) | 1993-07-19 | 1993-09-01 | Zeneca Ltd | Tricyclic derivatives |
WO1995006648A1 (en) | 1993-09-03 | 1995-03-09 | Kyowa Hakko Kogyo Co., Ltd. | Imidazoquinazoline derivative |
JPH07126165A (ja) | 1993-10-29 | 1995-05-16 | Masao Oguro | 腫瘍治療剤 |
US5656643A (en) | 1993-11-08 | 1997-08-12 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Bis mono-and bicyclic aryl and heteroaryl compounds which inhibit EGF and/or PDGF receptor tyrosine kinase |
GB9325217D0 (en) | 1993-12-09 | 1994-02-09 | Zeneca Ltd | Pyrimidine derivatives |
US5700823A (en) | 1994-01-07 | 1997-12-23 | Sugen, Inc. | Treatment of platelet derived growth factor related disorders such as cancers |
IL112248A0 (en) | 1994-01-25 | 1995-03-30 | Warner Lambert Co | Tricyclic heteroaromatic compounds and pharmaceutical compositions containing them |
IL112249A (en) | 1994-01-25 | 2001-11-25 | Warner Lambert Co | Pharmaceutical compositions containing di and tricyclic pyrimidine derivatives for inhibiting tyrosine kinases of the epidermal growth factor receptor family and some new such compounds |
CZ288955B6 (cs) | 1994-02-23 | 2001-10-17 | Pfizer Inc. | Substituované chinazolinové deriváty, jejich pouľití a farmaceutické prostředky na jejich bázi |
WO1995024190A2 (en) | 1994-03-07 | 1995-09-14 | Sugen, Inc. | Receptor tyrosine kinase inhibitors for inhibiting cell proliferative disorders and compositions thereof |
ES2109796T3 (es) | 1994-05-03 | 1998-01-16 | Ciba Geigy Ag | Derivados de pirrolopirimidilo con efecto antiproliferante. |
TW414798B (en) | 1994-09-07 | 2000-12-11 | Thomae Gmbh Dr K | Pyrimido (5,4-d) pyrimidines, medicaments comprising these compounds, their use and processes for their preparation |
DE19503151A1 (de) | 1995-02-01 | 1996-08-08 | Thomae Gmbh Dr K | Pyrimido[5,4-d]pyrimidine, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
GB9510757D0 (en) | 1994-09-19 | 1995-07-19 | Wellcome Found | Therapeuticaly active compounds |
TW321649B (zh) | 1994-11-12 | 1997-12-01 | Zeneca Ltd | |
GB9424233D0 (en) | 1994-11-30 | 1995-01-18 | Zeneca Ltd | Quinazoline derivatives |
AU5108196A (en) | 1995-03-20 | 1996-10-08 | Dr. Karl Thomae Gmbh | Imidazoquinazolines, drugs containing these compounds, their use and process for their preparation |
IL117620A0 (en) | 1995-03-27 | 1996-07-23 | Fujisawa Pharmaceutical Co | Heterocyclic compounds processes for the preparation thereof and pharmaceutical compositions containing the same |
WO1996030347A1 (en) | 1995-03-30 | 1996-10-03 | Pfizer Inc. | Quinazoline derivatives |
ES2150113T3 (es) | 1995-04-03 | 2000-11-16 | Novartis Ag | Derivados de pirazol y procedimientos para la preparacion de los mismos. |
JPH11507329A (ja) | 1995-04-27 | 1999-06-29 | ゼネカ リミテッド | キナゾリン誘導体 |
GB9508535D0 (en) | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quinazoline derivative |
GB9508565D0 (en) | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quiazoline derivative |
GB9508537D0 (en) | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quinazoline derivatives |
GB9508538D0 (en) | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quinazoline derivatives |
IL117923A (en) | 1995-05-03 | 2000-06-01 | Warner Lambert Co | Anti-cancer pharmaceutical compositions containing polysubstituted pyrido¬2,3-d¾pyrimidine derivatives and certain such novel compounds |
WO1996035689A1 (en) | 1995-05-12 | 1996-11-14 | Neurogen Corporation | Novel deazapurine derivatives; a new class of crf1 specific ligands |
TW334434B (en) | 1995-05-16 | 1998-06-21 | Kanebo Ltd | Novel quinazoline compound and anti-tumor agent |
US5639757A (en) | 1995-05-23 | 1997-06-17 | Pfizer Inc. | 4-aminopyrrolo[2,3-d]pyrimidines as tyrosine kinase inhibitors |
US5747498A (en) | 1996-05-28 | 1998-05-05 | Pfizer Inc. | Alkynyl and azido-substituted 4-anilinoquinazolines |
JPH11507052A (ja) | 1995-06-07 | 1999-06-22 | スージェン・インコーポレーテッド | キナゾリンおよび医薬組成物 |
US5773459A (en) | 1995-06-07 | 1998-06-30 | Sugen, Inc. | Urea- and thiourea-type compounds |
DK0831829T3 (da) | 1995-06-07 | 2003-12-15 | Pfizer | Heterocykliske, ringkondenserede pyrimidinderivater |
US5650415A (en) | 1995-06-07 | 1997-07-22 | Sugen, Inc. | Quinoline compounds |
TR199800012T1 (xx) | 1995-07-06 | 1998-04-21 | Novartis Ag | Piroloprimidinler ve preparasyon i�in tatbikler. |
GB9514265D0 (en) | 1995-07-13 | 1995-09-13 | Wellcome Found | Hetrocyclic compounds |
AR004010A1 (es) | 1995-10-11 | 1998-09-30 | Glaxo Group Ltd | Compuestos heterociclicos |
GB9520822D0 (en) | 1995-10-11 | 1995-12-13 | Wellcome Found | Therapeutically active compounds |
UA57002C2 (uk) | 1995-10-13 | 2003-06-16 | Мерк Фросст Кенада Енд Ко./Мерк Фросст Кенада Енд Сі. | Похідне (метилсульфоніл)феніл-2-(5н)-фуранону, фармацевтична композиція та спосіб лікування |
WO1997016435A1 (en) | 1995-10-30 | 1997-05-09 | Merck Frosst Canada Inc. | 3,4-diaryl-2-hydroxy-2,5-dihydrofurans as prodrugs to cox-2 inhibitors |
AU7340096A (en) | 1995-11-07 | 1997-05-29 | Kirin Beer Kabushiki Kaisha | Quinoline derivatives and quinazoline derivatives inhibiting autophosphorylation of growth factor receptor originating in platelet and pharmaceutical compositions containing the same |
EA000072B1 (ru) | 1995-11-14 | 1998-06-25 | Фармация Энд Апджон С.П.А. | Бициклическое конденсированное пиримидиновое соединение и его применение в качестве терапевтического агента |
GB9624482D0 (en) | 1995-12-18 | 1997-01-15 | Zeneca Phaema S A | Chemical compounds |
CH690773A5 (de) | 1996-02-01 | 2001-01-15 | Novartis Ag | Pyrrolo(2,3-d)pyrimide und ihre Verwendung. |
US5760041A (en) | 1996-02-05 | 1998-06-02 | American Cyanamid Company | 4-aminoquinazoline EGFR Inhibitors |
GB9603097D0 (en) | 1996-02-14 | 1996-04-10 | Zeneca Ltd | Quinazoline compounds |
GB9603095D0 (en) | 1996-02-14 | 1996-04-10 | Zeneca Ltd | Quinazoline derivatives |
GB9604361D0 (en) | 1996-02-29 | 1996-05-01 | Pharmacia Spa | 4-Substituted pyrrolopyrimidine compounds as tyrosine kinase inhibitors |
DE19608631A1 (de) | 1996-03-06 | 1997-09-11 | Thomae Gmbh Dr K | 4-Amino-pyrimidin-Derivate, diese Verbindungen enthaltende Arnzeimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
DE19608653A1 (de) | 1996-03-06 | 1997-09-11 | Thomae Gmbh Dr K | Pyrimido[5,4-d]pyrimidine, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
DE19608588A1 (de) | 1996-03-06 | 1997-09-11 | Thomae Gmbh Dr K | Pyrimido [5,4-d]pyrimidine, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
DE19629652A1 (de) | 1996-03-06 | 1998-01-29 | Thomae Gmbh Dr K | 4-Amino-pyrimidin-Derivate, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
AU2103097A (en) | 1996-03-15 | 1997-10-10 | Zeneca Limited | Cinnoline derivatives and use as medicine |
WO1997037999A1 (en) | 1996-04-04 | 1997-10-16 | University Of Nebraska Board Of Regents | Synthetic triple helix-forming compounds |
BR9708640B1 (pt) | 1996-04-12 | 2013-06-11 | inibidores irreversÍveis de tirosina-cinases e composiÇço farmacÊutica compreendendo os mesmo. | |
GB9607729D0 (en) | 1996-04-13 | 1996-06-19 | Zeneca Ltd | Quinazoline derivatives |
DE19614718A1 (de) | 1996-04-15 | 1997-10-16 | Hoechst Schering Agrevo Gmbh | Substituierte Pyridine/Pyrimidine, Verfahren zu ihrer Herstellung, und ihre Verwendung als Schädlingsbekämpfungsmittel |
GB9707800D0 (en) | 1996-05-06 | 1997-06-04 | Zeneca Ltd | Chemical compounds |
GB9613021D0 (en) | 1996-06-21 | 1996-08-28 | Pharmacia Spa | Bicyclic 4-aralkylaminopyrimidine derivatives as tyrosine kinase inhibitors |
CA2258548C (en) | 1996-06-24 | 2005-07-26 | Pfizer Inc. | Phenylamino-substituted tricyclic derivatives for treatment of hyperproliferative diseases |
DE69716916T2 (de) | 1996-07-13 | 2003-07-03 | Glaxo Group Ltd | Kondensierte heterozyklische verbindungen als protein kinase inhibitoren |
ID19430A (id) | 1996-07-13 | 1998-07-09 | Glaxo Group Ltd | Senyawa senyawa heterosiklik |
HRP970371A2 (en) | 1996-07-13 | 1998-08-31 | Kathryn Jane Smith | Heterocyclic compounds |
DE69738468T2 (de) | 1996-08-23 | 2009-01-08 | Novartis Ag | Substituierte pyrrolopyrimidine und verfahren zu ihrer herstellung |
CA2265630A1 (en) | 1996-09-13 | 1998-03-19 | Gerald Mcmahon | Use of quinazoline derivatives for the manufacture of a medicament in the treatment of hyperproliferative skin disorders |
CN1252054C (zh) | 1996-09-25 | 2006-04-19 | 曾尼卡有限公司 | 抑制生长因子的作用的喹啉衍生物 |
CA2239227C (en) | 1996-10-01 | 2007-10-30 | Kenji Matsuno | Nitrogen-containing heterocyclic compounds |
EP0837063A1 (en) | 1996-10-17 | 1998-04-22 | Pfizer Inc. | 4-Aminoquinazoline derivatives |
KR20000057228A (ko) | 1996-11-27 | 2000-09-15 | 디. 제이. 우드, 스피겔 알렌 제이 | 축합된 비사이클릭 피리미딘 유도체 |
CO4950519A1 (es) | 1997-02-13 | 2000-09-01 | Novartis Ag | Ftalazinas, preparaciones farmaceuticas que las comprenden y proceso para su preparacion |
US6002008A (en) | 1997-04-03 | 1999-12-14 | American Cyanamid Company | Substituted 3-cyano quinolines |
UA73073C2 (uk) | 1997-04-03 | 2005-06-15 | Уайт Холдінгз Корпорейшн | Заміщені 3-ціанохіноліни, спосіб їх одержання та фармацевтична композиція |
US5929080A (en) | 1997-05-06 | 1999-07-27 | American Cyanamid Company | Method of treating polycystic kidney disease |
CN1195521C (zh) | 1997-05-06 | 2005-04-06 | 惠氏控股公司 | 喹唑啉化合物在治疗多囊肾病中的应用 |
ZA986732B (en) | 1997-07-29 | 1999-02-02 | Warner Lambert Co | Irreversible inhibitiors of tyrosine kinases |
ZA986729B (en) | 1997-07-29 | 1999-02-02 | Warner Lambert Co | Irreversible inhibitors of tyrosine kinases |
TW436485B (en) | 1997-08-01 | 2001-05-28 | American Cyanamid Co | Substituted quinazoline derivatives |
AR016817A1 (es) | 1997-08-14 | 2001-08-01 | Smithkline Beecham Plc | Derivados de fenilurea o feniltiourea, procedimiento para su preparacion, coleccion de compuestos, compuestos intermediarios, composicion farmaceutica,metodo de tratamiento y uso de dichos compuestos para la manufactura de un medicamento |
US6294532B1 (en) | 1997-08-22 | 2001-09-25 | Zeneca Limited | Oxindolylquinazoline derivatives as angiogenesis inhibitors |
DE19742379C1 (de) * | 1997-09-25 | 1999-02-11 | Siemens Ag | Verfahren zum Betrieb eines Ultraschall-Therapiegeräts sowie entsprechendes Gerät |
ES2241324T3 (es) | 1998-10-08 | 2005-10-16 | Astrazeneca Ab | Derivados de quinazolina. |
DK1154774T3 (da) * | 1999-02-10 | 2005-09-26 | Astrazeneca Ab | Quinazolinderivater som angiogenesisinhibitorer |
US20030086924A1 (en) * | 1999-06-25 | 2003-05-08 | Genentech, Inc. | Treatment with anti-ErbB2 antibodies |
SI1676845T1 (sl) * | 1999-11-05 | 2008-10-31 | Astrazeneca Ab | Novi kinazolinski derivati |
DE60112268T2 (de) | 2000-03-06 | 2006-05-24 | Astrazeneca Ab | Verwendung von quinazolinderivate als inhibitoren der angiogenese |
GB0008269D0 (en) | 2000-04-05 | 2000-05-24 | Astrazeneca Ab | Combination chemotherapy |
SI1274692T1 (sl) | 2000-04-07 | 2006-12-31 | Astrazeneca Ab | Kinazolinske spojine |
AU2001276521B2 (en) | 2000-08-09 | 2006-05-25 | Astrazeneca Ab | Cinnoline compounds |
AU7993801A (en) | 2000-08-09 | 2002-02-18 | Astrazeneca Ab | Chemical compounds |
IL153947A0 (en) | 2000-08-09 | 2003-07-31 | Astrazeneca Ab | Quinoline derivatives having vegf inhibiting activity |
GB0126879D0 (en) | 2001-11-08 | 2002-01-02 | Astrazeneca Ab | Combination therapy |
KR101093345B1 (ko) | 2002-02-01 | 2011-12-14 | 아스트라제네카 아베 | 퀴나졸린 화합물 |
WO2004014383A1 (en) | 2002-08-09 | 2004-02-19 | Astrazeneca Ab | Combination of zd6474, an inhibitor of the vascular endothelial growth factor receptor, with radiotherapy in the treatment of cancer |
GB0218526D0 (en) | 2002-08-09 | 2002-09-18 | Astrazeneca Ab | Combination therapy |
GB0223380D0 (en) | 2002-10-09 | 2002-11-13 | Astrazeneca Ab | Combination therapy |
DK1592423T3 (da) | 2003-02-13 | 2011-06-27 | Astrazeneca Ab | Kombinationsterapi af ZD6474 med 5-FU og/eller CPT-11 |
-
2000
- 2000-11-01 SI SI200031001T patent/SI1676845T1/sl unknown
- 2000-11-01 CN CNB008153108A patent/CN100376567C/zh not_active Expired - Lifetime
- 2000-11-01 KR KR1020087004070A patent/KR100881105B1/ko active IP Right Grant
- 2000-11-01 ES ES00974667T patent/ES2265998T3/es not_active Expired - Lifetime
- 2000-11-01 SK SK612-2002A patent/SK287401B6/sk not_active IP Right Cessation
- 2000-11-01 US US10/129,336 patent/US7173038B1/en not_active Expired - Lifetime
- 2000-11-01 RU RU2002114809/04A patent/RU2291868C2/ru active Protection Beyond IP Right Term
- 2000-11-01 DE DE60029007T patent/DE60029007T2/de not_active Expired - Lifetime
- 2000-11-01 BR BRPI0015203A patent/BRPI0015203B8/pt unknown
- 2000-11-01 DK DK00974667T patent/DK1244647T3/da active
- 2000-11-01 UA UA2002064594A patent/UA72946C2/uk unknown
- 2000-11-01 NZ NZ518028A patent/NZ518028A/en not_active IP Right Cessation
- 2000-11-01 AU AU12886/01A patent/AU769222B2/en active Active
- 2000-11-01 DK DK06004921T patent/DK1676845T3/da active
- 2000-11-01 ES ES06004921T patent/ES2306306T3/es not_active Expired - Lifetime
- 2000-11-01 EP EP00974667A patent/EP1244647B1/en not_active Expired - Lifetime
- 2000-11-01 PT PT06004921T patent/PT1676845E/pt unknown
- 2000-11-01 IL IL14903400A patent/IL149034A0/xx unknown
- 2000-11-01 PT PT00974667T patent/PT1244647E/pt unknown
- 2000-11-01 HU HU0203453A patent/HU229414B1/hu active Protection Beyond IP Right Term
- 2000-11-01 JP JP2001534802A patent/JP3522727B2/ja not_active Expired - Lifetime
- 2000-11-01 WO PCT/GB2000/004181 patent/WO2001032651A1/en active IP Right Grant
- 2000-11-01 EE EEP200200237A patent/EE05330B1/xx active Protection Beyond IP Right Term
- 2000-11-01 BR BR0015203-0A patent/BR0015203A/pt not_active IP Right Cessation
- 2000-11-01 SI SI200030877T patent/SI1244647T1/sl unknown
- 2000-11-01 MX MXPA02004366A patent/MXPA02004366A/es active IP Right Grant
- 2000-11-01 AT AT06004921T patent/ATE398120T1/de active
- 2000-11-01 CA CA2389767A patent/CA2389767C/en not_active Expired - Lifetime
- 2000-11-01 DE DE60039206T patent/DE60039206D1/de not_active Expired - Lifetime
- 2000-11-01 KR KR1020077022543A patent/KR100881104B1/ko active IP Right Grant
- 2000-11-01 EP EP06004921A patent/EP1676845B1/en not_active Expired - Lifetime
- 2000-11-01 PL PL355942A patent/PL203782B1/pl not_active IP Right Cessation
- 2000-11-01 AT AT00974667T patent/ATE330954T1/de active
- 2000-11-01 CZ CZ20021526A patent/CZ301689B6/cs unknown
- 2000-11-01 KR KR1020027005814A patent/KR100849151B1/ko active Protection Beyond IP Right Term
- 2000-11-01 CN CNA2008100037759A patent/CN101219145A/zh active Pending
- 2000-11-03 AR ARP000105821A patent/AR033499A1/es active IP Right Grant
- 2000-11-29 TW TW089125343A patent/TWI287540B/zh active
-
2002
- 2002-04-08 IL IL149034A patent/IL149034A/en active Protection Beyond IP Right Term
- 2002-04-09 IS IS6335A patent/IS2284B/is unknown
- 2002-04-09 ZA ZA200202775A patent/ZA200202775B/xx unknown
- 2002-04-26 BG BG106659A patent/BG65861B1/bg unknown
- 2002-05-03 NO NO20022139A patent/NO322298B1/no not_active IP Right Cessation
-
2003
- 2003-03-07 HK HK03101686.4A patent/HK1049664B/zh not_active IP Right Cessation
-
2006
- 2006-09-21 CY CY20061101355T patent/CY1106166T1/el unknown
- 2006-12-08 HK HK06113553A patent/HK1092804A1/xx unknown
- 2006-12-21 US US11/642,979 patent/US20070265286A1/en not_active Abandoned
-
2007
- 2007-09-04 IS IS8673A patent/IS2556B/is unknown
-
2008
- 2008-08-12 CY CY20081100853T patent/CY1108256T1/el unknown
-
2010
- 2010-04-15 US US12/761,105 patent/US8642608B2/en not_active Expired - Lifetime
-
2012
- 2012-08-07 NO NO2012014C patent/NO2012014I1/no unknown
- 2012-08-07 LU LU92057C patent/LU92057I2/fr unknown
- 2012-08-09 FR FR12C0048C patent/FR12C0048I2/fr active Active
- 2012-08-09 BE BE2012C036C patent/BE2012C036I2/fr unknown
- 2012-08-14 CY CY2012026C patent/CY2012026I1/el unknown
-
2014
- 2014-01-03 US US14/146,954 patent/US9040548B2/en not_active Expired - Fee Related
-
2015
- 2015-05-22 US US14/719,779 patent/US20160130249A1/en not_active Abandoned
-
2017
- 2017-06-19 US US15/626,576 patent/US20180099946A1/en not_active Abandoned
- 2017-12-28 US US15/856,235 patent/US10457664B2/en not_active Expired - Fee Related
-
2019
- 2019-09-25 US US16/582,469 patent/US20200262811A1/en not_active Abandoned
-
2021
- 2021-01-15 US US17/150,856 patent/US20210276972A1/en not_active Abandoned
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0566226A1 (en) * | 1992-01-20 | 1993-10-20 | Zeneca Limited | Quinazoline derivatives |
WO1997030035A1 (en) * | 1996-02-13 | 1997-08-21 | Zeneca Limited | Quinazoline derivatives as vegf inhibitors |
CN1116286C (zh) * | 1996-03-05 | 2003-07-30 | 曾尼卡有限公司 | 4-苯胺基喹唑啉衍生物 |
WO1998013354A1 (en) * | 1996-09-25 | 1998-04-02 | Zeneca Limited | Quinazoline derivatives and pharmaceutical compositions containing them |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106397401A (zh) * | 2016-08-30 | 2017-02-15 | 山东罗欣药业集团股份有限公司 | 一种抗癌药物的晶体化合物及其制备方法 |
CN106397401B (zh) * | 2016-08-30 | 2018-11-13 | 山东罗欣药业集团股份有限公司 | 一种抗癌药物的晶体化合物及其制备方法 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN100376567C (zh) | 作为vegf抑制剂的喹唑啉衍生物 | |
EP1005470B1 (en) | Oxindolylquinazoline derivatives as angiogenesis inhibitors | |
US7087602B2 (en) | Cinnoline derivatives and use as medicine | |
CA2362715C (en) | Quinazoline derivatives as angiogenesis inhibitors | |
AU2001276536B9 (en) | Quinoline derivatives having vegf inhibiting activity | |
EP1309587B1 (en) | Cinnoline compounds | |
US20060148819A1 (en) | Chemical compounds | |
AU2001276536A1 (en) | Quinoline derivatives having vegf inhibiting activity | |
AU2001276521A1 (en) | Cinnoline compounds |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C41 | Transfer of patent application or patent right or utility model | ||
TR01 | Transfer of patent right |
Effective date of registration: 20160722 Address after: Massachusetts, USA Patentee after: Genzyme Corp Address before: Swedish Sodertalje Patentee before: Astra Zeneca Aktiebolag |
|
CX01 | Expiry of patent term |
Granted publication date: 20080326 |
|
CX01 | Expiry of patent term |