US20020052391A1 - Tetrahydroquinoline derivatives as glycine antagonists - Google Patents
Tetrahydroquinoline derivatives as glycine antagonists Download PDFInfo
- Publication number
- US20020052391A1 US20020052391A1 US09/990,513 US99051301A US2002052391A1 US 20020052391 A1 US20020052391 A1 US 20020052391A1 US 99051301 A US99051301 A US 99051301A US 2002052391 A1 US2002052391 A1 US 2002052391A1
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- US
- United States
- Prior art keywords
- group
- phenyl
- chloro
- solution
- compound
- 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.)
- Granted
Links
- 229940127337 Glycine Antagonists Drugs 0.000 title 1
- 125000000147 tetrahydroquinolinyl group Chemical class N1(CCCC2=CC=CC=C12)* 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 166
- -1 hydroxy, methoxy, amino Chemical group 0.000 claims abstract description 68
- 239000001257 hydrogen Substances 0.000 claims abstract description 38
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 38
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 35
- 150000003839 salts Chemical class 0.000 claims abstract description 34
- 238000000034 method Methods 0.000 claims abstract description 32
- 150000002148 esters Chemical class 0.000 claims abstract description 29
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims abstract description 7
- 125000004663 dialkyl amino group Chemical group 0.000 claims abstract description 5
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 5
- 150000002367 halogens Chemical class 0.000 claims abstract description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 38
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 30
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 19
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- 125000006239 protecting group Chemical group 0.000 claims description 16
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 15
- 229920006395 saturated elastomer Polymers 0.000 claims description 15
- 231100000252 nontoxic Toxicity 0.000 claims description 13
- 230000003000 nontoxic effect Effects 0.000 claims description 13
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 claims description 11
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 claims description 11
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 11
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 11
- 230000000694 effects Effects 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- 239000000460 chlorine Substances 0.000 claims description 9
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 7
- 239000005864 Sulphur Chemical group 0.000 claims description 7
- 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 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 230000002461 excitatory amino acid Effects 0.000 claims description 6
- 239000003257 excitatory amino acid Substances 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 5
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 229910052740 iodine Chemical group 0.000 claims description 5
- 159000000000 sodium salts Chemical class 0.000 claims description 5
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 125000001246 bromo group Chemical group Br* 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 3
- 125000006164 6-membered heteroaryl group Chemical group 0.000 claims description 3
- DGJFOKSXPJLLMX-UHFFFAOYSA-N 7-chloro-4-(2,5-dioxo-1-phenylimidazolidin-4-ylidene)-2,3-dihydro-1h-quinoline-2-carboxylic acid Chemical compound C12=CC=C(Cl)C=C2NC(C(=O)O)CC1=C(C1=O)NC(=O)N1C1=CC=CC=C1 DGJFOKSXPJLLMX-UHFFFAOYSA-N 0.000 claims description 3
- NEUYJSROPOLVLU-UHFFFAOYSA-N 7-chloro-4-(2-oxo-1-phenylpiperidin-3-ylidene)-2,3-dihydro-1h-quinoline-2-carboxylic acid Chemical compound C12=CC=C(Cl)C=C2NC(C(=O)O)CC1=C(C1=O)CCCN1C1=CC=CC=C1 NEUYJSROPOLVLU-UHFFFAOYSA-N 0.000 claims description 3
- XDKRVNKVAKCFGW-UHFFFAOYSA-N 7-chloro-4-(2-oxo-1-phenylpyrrolidin-3-ylidene)-2,3-dihydro-1h-quinoline-2-carboxylic acid Chemical compound C12=CC=C(Cl)C=C2NC(C(=O)O)CC1=C(C1=O)CCN1C1=CC=CC=C1 XDKRVNKVAKCFGW-UHFFFAOYSA-N 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- FCMZVVRKJTVTQK-UHFFFAOYSA-N 5,7-dichloro-4-(2-oxo-1-phenylpyrrolidin-3-ylidene)-2,3-dihydro-1h-quinoline-2-carboxylic acid Chemical compound C12=C(Cl)C=C(Cl)C=C2NC(C(=O)O)CC1=C(C1=O)CCN1C1=CC=CC=C1 FCMZVVRKJTVTQK-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 claims description 2
- OSJVTYVKQNOXPP-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline-2-carboxylic acid Chemical compound C1=CC=C2NC(C(=O)O)CCC2=C1 OSJVTYVKQNOXPP-UHFFFAOYSA-N 0.000 claims 2
- 150000001721 carbon Chemical group 0.000 claims 2
- 241000124008 Mammalia Species 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- 238000002955 isolation Methods 0.000 claims 1
- 238000000926 separation method Methods 0.000 claims 1
- 229940124597 therapeutic agent Drugs 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 abstract description 8
- 125000003545 alkoxy group Chemical group 0.000 abstract 4
- 125000000623 heterocyclic group Chemical group 0.000 abstract 3
- 125000003282 alkyl amino group Chemical group 0.000 abstract 2
- 125000003118 aryl group Chemical group 0.000 abstract 2
- 125000004093 cyano group Chemical group *C#N 0.000 abstract 2
- 125000000547 substituted alkyl group Chemical group 0.000 abstract 2
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 abstract 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 306
- 239000000243 solution Substances 0.000 description 146
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 134
- 239000000203 mixture Substances 0.000 description 100
- 239000000543 intermediate Substances 0.000 description 84
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 68
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 66
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 66
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 65
- 239000007787 solid Substances 0.000 description 61
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 60
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 60
- 238000005481 NMR spectroscopy Methods 0.000 description 54
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 51
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 51
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 50
- 229910001868 water Inorganic materials 0.000 description 44
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 43
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- 239000012267 brine Substances 0.000 description 39
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 39
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 37
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 35
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 35
- 239000012074 organic phase Substances 0.000 description 29
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 25
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 25
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 25
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
- 238000004440 column chromatography Methods 0.000 description 20
- 229960004132 diethyl ether Drugs 0.000 description 20
- 235000019441 ethanol Nutrition 0.000 description 20
- 239000003921 oil Substances 0.000 description 20
- 235000019198 oils Nutrition 0.000 description 20
- 238000003756 stirring Methods 0.000 description 19
- 239000012047 saturated solution Substances 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- 125000004432 carbon atom Chemical group C* 0.000 description 17
- 238000003818 flash chromatography Methods 0.000 description 17
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 16
- 239000012043 crude product Substances 0.000 description 16
- 238000000746 purification Methods 0.000 description 15
- 239000000725 suspension Substances 0.000 description 15
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 14
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 12
- 235000019270 ammonium chloride Nutrition 0.000 description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 12
- 239000012045 crude solution Substances 0.000 description 12
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- QMGVPVSNSZLJIA-FVWCLLPLSA-N strychnine Chemical compound O([C@H]1CC(N([C@H]2[C@H]1[C@H]1C3)C=4C5=CC=CC=4)=O)CC=C1CN1[C@@H]3[C@]25CC1 QMGVPVSNSZLJIA-FVWCLLPLSA-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
- 239000012299 nitrogen atmosphere Substances 0.000 description 11
- 0 *c1cc(C)c2c(c1)N([H])C(C(=O)O)C*2[Y]1**N(C)C1=O Chemical compound *c1cc(C)c2c(c1)N([H])C(C(=O)O)C*2[Y]1**N(C)C1=O 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 10
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- MPXAPULVRLDXGU-YOZOHBORSA-N (3R)-2-(5-chloro-2-iodoanilino)-3-methyl-4-[(2-methylpropan-2-yl)oxy]-4-oxo-2-(2-oxoethyl)butanoic acid Chemical compound C[C@@H](C(=O)OC(C)(C)C)C(CC=O)(C(=O)O)NC1=C(C=CC(=C1)Cl)I MPXAPULVRLDXGU-YOZOHBORSA-N 0.000 description 9
- 108090001060 Lipase Proteins 0.000 description 9
- 102000004882 Lipase Human genes 0.000 description 9
- 239000004480 active ingredient Substances 0.000 description 9
- 239000003826 tablet Substances 0.000 description 9
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 8
- 239000004471 Glycine Substances 0.000 description 8
- 239000004367 Lipase Substances 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- 208000002193 Pain Diseases 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 229940040461 lipase Drugs 0.000 description 8
- 235000019421 lipase Nutrition 0.000 description 8
- YSILGYNNTSDLPH-FAQQKDIKSA-N 2-(5-chloro-2-iodoanilino)-2-[(2R)-1-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]pent-4-enoic acid Chemical compound C[C@@H](C(=O)OC(C)(C)C)C(CC=C)(C(=O)O)NC1=C(C=CC(=C1)Cl)I YSILGYNNTSDLPH-FAQQKDIKSA-N 0.000 description 7
- 241000228245 Aspergillus niger Species 0.000 description 7
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- QMGVPVSNSZLJIA-UHFFFAOYSA-N Nux Vomica Natural products C1C2C3C4N(C=5C6=CC=CC=5)C(=O)CC3OCC=C2CN2C1C46CC2 QMGVPVSNSZLJIA-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 241001279009 Strychnos toxifera Species 0.000 description 6
- NKRFGTUOGIUDLV-UHFFFAOYSA-N ethyl 7-chloro-4-(2-oxo-1-phenylpyrrolidin-3-ylidene)-2,3-dihydro-1h-quinoline-2-carboxylate Chemical compound C12=CC=C(Cl)C=C2NC(C(=O)OCC)CC1=C(C1=O)CCN1C1=CC=CC=C1 NKRFGTUOGIUDLV-UHFFFAOYSA-N 0.000 description 6
- QJIPWGTVZXAHBS-UHFFFAOYSA-N ethyl 7-chloro-4-(2-oxo-1-pyridin-3-ylpyrrolidin-3-ylidene)-2,3-dihydro-1h-quinoline-2-carboxylate Chemical compound C12=CC=C(Cl)C=C2NC(C(=O)OCC)CC1=C(C1=O)CCN1C1=CC=CN=C1 QJIPWGTVZXAHBS-UHFFFAOYSA-N 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 6
- 229960005453 strychnine Drugs 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 5
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- 150000007530 organic bases Chemical class 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical class C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 4
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- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 239000005557 antagonist Substances 0.000 description 4
- 239000000010 aprotic solvent Substances 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000003389 potentiating effect Effects 0.000 description 4
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- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical class CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000020374 simple syrup Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- VYPDUQYOLCLEGS-UHFFFAOYSA-M sodium;2-ethylhexanoate Chemical compound [Na+].CCCCC(CC)C([O-])=O VYPDUQYOLCLEGS-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 208000020431 spinal cord injury Diseases 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000003019 stabilising effect Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- WIVYTYZCVWHWSH-UHFFFAOYSA-N tert-butyl n-(4-aminophenyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=C(N)C=C1 WIVYTYZCVWHWSH-UHFFFAOYSA-N 0.000 description 1
- CJIIUHXNKIOWLT-UHFFFAOYSA-N tert-butyl n-[4-(2,4-dibromobutanoylamino)phenyl]carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=C(NC(=O)C(Br)CCBr)C=C1 CJIIUHXNKIOWLT-UHFFFAOYSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- MPVGERFLOBRUPY-UHFFFAOYSA-M tributyl-(2-oxo-1-pyridin-3-ylpyrrolidin-3-yl)phosphanium;bromide Chemical compound [Br-].O=C1C([P+](CCCC)(CCCC)CCCC)CCN1C1=CC=CN=C1 MPVGERFLOBRUPY-UHFFFAOYSA-M 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229910009112 xH2O Inorganic materials 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
-
- 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
- C07D401/14—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 three or more hetero rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- This invention relates to 1, 2, 3, 4 tetrahydroquinoline derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.
- it relates to 1, 2, 3, 4 tetrahydroquinoline derivatives which are potent and specific antagonists of excitatory amino acids.
- WO 97112870 and WO 98107704 describe novel 4-substituted-2-carboxy-tetrahydroquinoline derivatives which not only have a good in vitro affinity for the strychnine insensitive glycine binding site associated with the NMDA receptor complex but also have good in vivo activity when administered intravenously (iv).
- Y represents a carbon atom
- Z is the group CH which is linked to the group Y via a double bond
- X is CH or Z is methylene or NR 11 and X is a carbon atom linked to the group Y via a double bond;
- R represents a halogen atom or C 1-4 alkyl group
- R 1 represents a hydrogen, a halogen atom or C 1-4 alkyl group
- R 2 represents phenyl which may be substituted with up to 3 groups selected from halogen, hydrogen, or (CH 2 ) n R 3 wherein R 3 is COR 4 , NR 6 R 5 , NHCOR 7 , NHCONR 9 R 8 or NH SO2 R 10 group or R 2 is a 5 membered heteroaryl group containing 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen; or 6 membered heteroaryl group containing 1 to 3 nitrogen atoms
- R 4 represents an amino, a hydroxyl or C 1-4 alkoxy group
- R 5 and R 6 each independently represents hydrogen or C 1-4 alkyl group or
- R 5 and R 6 together with the nitrogen atom to which they are attached represent a saturated 5-7 membered heterocyclic group optionally containing an additional heroatom selected from oxygen, sulphur or nitrogen
- R 7 represents a hydrogen atom or C 1-4 alkyl, C 1-4 alkoxy, or phenyl
- R 8 represents hydrogen or C 1-4 alkyl group
- R 9 represents hydrogen, optionally substituted C 1-4 alkyl (optionally substituted by one or more hydroxy carboxyl and amino group), phenyl;
- R 11 represents hydrogen or C 1-4 alkyl group
- R 10 represents hydrogen, C 1-4 alkyl or a nitrogen protecting group.
- n is zero or an integer from 1 to 2;
- a further embodiment of the invention provides compounds of formula (I) or a salt or a non toxic metabolically labile esters thereof, wherein
- Y represents a carbon atom
- Z is the group CH which is linked to the group Y via a double bond
- X is CH or Z is methylene or NR 11 and X is a carbon atom linked to the group Y via a double bond;
- R represents a halogen atom
- R1 represents a hydrogen or a halogen atom
- R 2 represents phenyl which may be substituted with up to 3 groups selected from halogen, hydrogen, or (CH 2 ) n R 3 wherein R 3 is COR 4 , NR 6 R 5 , NHCOR 7 , NHCONR 9 R 8 or NH SO2 R 10 group or R 2 is a 5 membered heteroaryl group containing 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen; or 6 membered heteroaryl group containing 1 to 3 nitrogen atoms
- R 4 represents an amino or a hydroxyl
- R 5 and R 6 each independently represents hydrogen or C 1-4 alkyl group or
- R 5 and R 6 together with the nitrogen atom to which they are attached represent a saturated 5-7 membered heterocyclic group optionally containing an additional heroatom selected from oxygen, sulphur or nitrogen
- R 7 represents a hydrogen atom or C 1-4 alkyl, C 1-4 alkoxy, or phenyl
- R 8 represents hydrogen or C 1-4 alkyl group
- R 9 represents hydrogen, optionally substituted C 1-4 alkyl (optionally substituted by one or more hydroxy carboxyl and amino group), phenyl;
- R 11 represents hydrogen or C 1-4 alkyl group
- R 10 represents hydrogen, C 1-4 alkyl or a nitrogen protecting group
- n is zero or an integer from 1 to 2 with the proviso that when X is a carbon atom linked to the group Y via a double bond then R 1 is hydrogen;
- salts of the compounds of formula (I) will be physiologically acceptable thereof.
- Other salts may be useful in the preparation of the compounds of formula (I) or physiologically acceptable salts thereof. Therefore, unless otherwise stated, references to salts include both physiologically acceptable salts and non-physiologically acceptable salts of compounds of formula (I).
- Suitable physiologically acceptable salts of compounds of the invention include base addition salts and, where appropriate, acid addition salts.
- Suitable physiologically acceptable base addition salts of compounds of formula (I) include alkali metal or alkaline metal salts such as sodium, potassium, calcium, magnesium and ammonium salts, formed with amino acids (e.g. lysine and arginine) and organic bases (e.g. procaine, phenylbenzylamine, ethanolamine diethanolamine and N-methyl glucosamine).
- the compounds of formula (I) and/or salts thereof may form solvates (e.g. hydrates) and the invention includes all such solvates.
- halogen refers to a fluorine, chlorine, bromine or iodine atom.
- C 1-4 alkyl as used herein as a group or part of a group refers to a straight or branched chain alkyl group containing from 1 to 4 carbon atom, examples of such groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, secondary butyl or tertiary butyl.
- R 2 is a 5 or 6 membered heteroaryl group this may be for example furanyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, pyridyl or pyrimidinyl.
- R 5 and R 6 together with the nitrogen atom to which they are attached form a saturated 5-7 membered heterocyclic group optionally containing an additional heroatom selected from oxygen, sulphur or nitrogen this may be morpholino, 2,6 dimethylmorpholino, thiomorpholino, piperidino, pyrrolidino, piperazino or N-methylpiperazino.
- R 2 is a substituted phenyl group this is conveniently a mono substituted phenyl group.
- the substituent is conveniently in the meta position or more conveniently in the para position.
- the compounds of formula (I) possess at least one asymmetric carbon atom (namely the carbon atom occupying the 2 position of the 1, 2, 3, 4 tetrahydroquinoline ring system) and other asymmetric carbon atoms are possible in the group R 2 . It is to be understood that all enantiomers and diastereomers and mixtures thereof are encompassed within the scope of the present invention.
- the compounds of formula (I) possess at least two asymmetric carbon atoms (namely the carbon atom occupying the 2 and 4 position of the 1, 2, 3, 4 tetrahydroquinoline ring system) and these may be represented by the formulae (1a, 1b, 1c and 1d).
- the solid wedge shaped bond indicates that the bond is above the plane of the paper and is referred to as the ⁇ configuration.
- the broken indicates that the bond is below the plane of the paper and is referred to as ⁇ configuration.
- Non-toxic metabolically labile esters of compound of formula (I) are esters of compounds of formula (I) that are hydrolysed in vivo to afford said compound of formula I and a physiologically acceptable alcohol.
- Non toxic metabolically esters of compound of formula (I) may be formed by esterification, for example of any of the carboxylic acid groups in the parent compound of general formula (I) with, where appropriate, prior protection of any other reactive groups present in the molecule, followed by deprotection if required.
- Examples of such metabolically labile esters include C 1-4 alkyl esters e.g. methyl or ethyl esters, substituted or unsubstituted aminoalkyl esters (e.g.
- pivaloyloxymethyl 1-pivaloyloxyethyl, acetoxymethyl, 1-acetoxyethyl, 1-(1-methoxy-1-methyl)ethylcarbonyloxyethyl, 1-benzoyloxyethyl, isopropoxycarbonyloxymethyl, 1-isopropoxycarbonyloxyethyl, cyclohexylcarbonyloxymethyl, 1-cyclohexylcarbonyloxyethyl ester, cyclohexyloxycarbonyloxymethyl, 1-cyclohexyloxycarbonyloxyethyl, 1-(4-tetrahydropyranyloxy)carbonyloxyethyl or 1-(4-tetrahydropyranyl)carbonyloxyethyl.
- the group R is conveniently chlorine.
- the group R 1 is conveniently a hydrogen or a chlorine atom.
- a preferred class of compounds of formula (I) is that wherein R is chlorine and R 1 is a hydrogen or a chlorine atom.
- a further preferred class of compounds of formula (I) is that wherein R is chlorine and R 1 is a hydrogen atom.
- a preferred class of compounds of formula (I) is that in which the carbon atom in 4 position is ⁇ configuration and the carbon atom in 2 position is in a configuration (1a) and that in which the carbon atom in 4 position is a configuration and the carbon atom in 2 position is in ⁇ configuration (1c).
- A is an optionally substituted C 1-2 alkylene chain this may be, for example, methylene, ethylene or C ⁇ O.
- a preferred class of compounds of formula (I) includes those wherein A is a chain selected from —CH2—, —(CH2)2—, C ⁇ O.
- Z is a group NR 11 this is conveniently the group NH.
- a preferred class of compounds of formula (I) includes those wherein Z is CH which is linked to the group Y via a double bond, a methylene or a NH group.
- R 2 is an optionally substituted phenyl group this is conveniently phenyl substituted by a single substituent selected from (CH 2 ) n NR 6 R 5 in which R 5 is hydrogen and R 6 is hydrogen, C 1-4 alkyl (e.g. methyl, ethyl) or NR 6 R 5 represents a saturated 6 membered ring containing oxygen e.g. morpholino; (CH 2 ) n NHCOR 7 wherein R 7 is hydrogen, alkyl e.g.
- R 2 isopropyl, isobutyl, phenyl; (CH 2 ) n NHCONHR 9 wherein R 9 is hydrogen; (CH 2 )nNH SO2 R 10 in which R 10 is alkyl e.g. methyl. n is zero or an integer from 1 to 2;
- R 2 groups include phenyl (optionally substituted by amino, t-butoxycarbonylamino, acetylamino or methanesulphonylamino)
- R 2 is substituted phenyl the substituents are conveniently in the meta or more preferably in the para position.
- R 2 is a 5 or 6 membered heteroaryl group as above defined this is conveniently pyridyl e.g. 3-pyridyl.
- a preferred class of compounds of formula (I) is that wherein R 2 represents phenyl (optionally substituted by acetylamino, methanesulphonylamino) or 3-pyridyl. Within this class those wherein R 2 is phenyl are particularly preferred.
- a further preferred class of compounds of formula (I) is that wherein X is a carbon atom linked to the group Y via a double bond.
- a preferred group of compounds of formula (I) is that wherein A is is a chain selected from —CH 2 — or —(CH 2 ) 2 —, Z is a group CH which is linked to the group Y via a double bond or a methylene group, or A is the chain CO and Z is an NH group, R is chlorine, R 1 is chlorine or hydrogen and R 2 is phenyl (optionally substituted by acetylamino or methanesulphonylamino) or 3-pyridyl.
- physiologically acceptable salts e.g. sodium salt
- physiologically acceptable salts e.g. sodium salt
- (+) Sodium 7-chloro-4-(1-phenyl- ⁇ 3 -pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2carboxylate.
- physiologically acceptable salts e.g. sodium salts
- non-toxic metabolically labile esters or enantiomers thereof e.g. sodium salts
- the compounds of formula (I) and/or physiologically acceptable salts thereof are excitatory amino acid antagonists. More particularly they are potent antagonists at the strychnine insensitive glycine binding site associated with the NMDA receptor complex. As such they are potent antagonists of the NMDA receptor complex. These compounds are therefore useful in the treatment or prevention of neurotoxic damage or neurodegenerative diseases. Thus the compounds are useful for the treatment of neurotoxic injury which follows cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospam, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia cardiac arrest.
- the compounds are useful in the treatment of chronic neurodegenerative diseases such as: Huntingdon's disease, Alzheimer's senile dementia, amyotrophic lateral sclerosis, Glutaric Acidaemia type, multi-infarct dementia, status epilecticus, contusive injuries (e.g. spinal cord injury and head injury), viral infection induced neurodegeration (e.g.
- AIDS, encephalopaties), Down syndrome ocular neurodegeneration (e.g glaucoma), epilepsy, schizophrenia, depression, migraine, headaches including cluster headaches and or tension headaches, anxiety, pain (e.g inflamatory pain and neuropathic pain), neurogenic bladder, emesis irritative bladder disturbances, drug dependency, including withdrawal symptoms from alcohol, cocaine, opiates, nicotine (e.g. smoking cessation) benzodiazepines and, inhibition of tolerance induced by opioids (i.e morphine).
- opioids i.e morphine
- the potent and selective action of the compound of the invention at the strychnine-insensitive glycine binding site present on the NMDA receptor complex may be readily determined using conventional test procedures.
- the ability to bind at the strychnine insensitive glycine binding site was determined using the procedure of Kishimoto H et al., J Neurochem 1981, 37, 1015-1024.
- the selectivity of the action of compounds of the invention for the strychnine insensitive glycine site was confirmed in studies at other ionotropic known excitatory amino acid receptors.
- Compounds of the invention may be found found to inhibit NMDA induced convulsions in mice using the procedure Chiamulera C et al., Psychopharmacology (1990), 102, 551-552.
- the neuroprotective activity of the compounds of the invention may be demonstrated in the middle cerebral artery occlusion preparation in mice, using the procedure described by Chiamulera C. et al., European Journal of Pharmacology, 216 (1992) pp. 335-336.
- the invention therefore provides for the use of a compound of formula (I) and/or physiologically acceptable salts or non-toxic metabolically labile esters thereof for use in therapy and in particular use as medicine for antagonising the effects of excitatory amino acids upon the NMDA receptor complex.
- the invention also provides for the use of a compound of formula (I) and/or a physiologically acceptable salt or non-toxic metabolically labile esters thereof for the manufacture of a medicament for antagonising the effects of excitatory amino acids upon the NMDA receptor complex.
- the invention also provides for a method for antagonising the effects of excitatory amino acids upon the NMDA receptor complex, comprising administering to a patient in need thereof an antagonistic amount of a compound of formula (I) and/or a physiologically acceptable salt thereof.
- a compound of the invention required for use in treatment will vary with the nature of the condition being treated, the route of administration and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician. In general however doses employed for adult human treatment will typically be in the range of 2 to 800 mg per day, dependent upon the route of administration.
- a daily dose will typically be in the range 20-100 mg, preferably 60-80 mg per day.
- a daily dose will typically be within the range 200-800 mg, e.g. 400-600 mg per day.
- the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.
- a compound of the invention may be administered as the raw chemical, it is preferable to present the active ingredient as a pharmaceutical formulation.
- the invention thus further provides a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt or non-toxic metabolically labile esters thereof together with one or more pharmaceutically acceptable carriers thereof and, optionally, other therapeutic and/or prophylactic ingredients.
- the carrier(s) must be ‘acceptable’ in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- compositions of the invention include those in a form especially formulated for oral, buccal, parenteral, inhalation or insufflaflon, implant or rectal administration.
- Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone; fillers, for example, lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch or sodium starch glycollate, or wetting agents such as sodium lauryl sulphate.
- the tablets may be coated according to methods well known in the art.
- Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.
- Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-leate or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; solubilizers such as surfactants for example polysorbates or other agents such as cyclodextrins; and preservatives, for example, methyl or propyl p-hydroxybenzoates
- composition may take the form of tablets or lozenges formulated in conventional manner.
- composition according to the invention may be formulated for parenteral administration by injection or continuous infusion.
- Formulations for injection may be presented in unit dose form in ampoules, or in multi-dose containers with an added preservative.
- the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
- the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
- the compounds according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurised packs, with the use of a suitable propellant, such as dichlorodifluoromethane, tirchlorofluoromethane, dichloro-tetrafluoroethane, carbon dioxide or other suitable propellants, such as dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane, carbon dioxide or other suitable gases, or from a nebuliser.
- a suitable propellant such as dichlorodifluoromethane, tirchlorofluoromethane, dichloro-tetrafluoroethane, carbon dioxide or other suitable propellants, such as dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane, carbon dioxide or other suitable gases, or from a nebuliser.
- a suitable propellant such as dichlor
- the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable carrier such as lactose or starch.
- the powder composition may be presented in unit dosage form in, for example, capsules or cartridges of e.g. gelatin, or blister packs from which the powder may be administered with the aid of an inhaler or insufflator.
- composition according to the invention may also be formulated as a depot preparation.
- Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
- the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
- compositions according to the invention may contain between 0.1-99% of the active ingredient, conveniently from 30-95% for tablets and capsules and 3-50% for liquid preparations.
- Compounds of formula (I) and enantiomers thereof may be prepared by the cyclisation of a compound of formula (II) in which R 12 is a carboxylic protecting group, R 13 represents a bromine or iodine atom, R 14 represents hydrogen or a nitrogen protecting group.
- the reaction may be carried out using a catalytic amount of a Palladium (O) complex such as tetrakis(triphenylphosphine)palladium and a suitable organic base such as trialkylamine e.g. triethylamine or inorganic base, e.g. potassium carbonate.
- a Palladium (O) complex such as tetrakis(triphenylphosphine)palladium
- a suitable organic base such as trialkylamine e.g. triethylamine or inorganic base, e.g. potassium carbonate.
- reaction is conveniently carded out in an aprotic polar solvent such as acetonitrile, dimethylformamide or in aprotic apolar solvent such as hydrocarbon (ie toluene, xilene, hexane) at a temperature within the range of 60° C. to 150° C. followed, where necessary or desired, by subsequent removal of the carboxyl protecting group R 12 and any protecting group R 14 .
- aprotic polar solvent such as acetonitrile, dimethylformamide
- aprotic apolar solvent such as hydrocarbon (ie toluene, xilene, hexane)
- the reaction is carried out using a catalytic amount of a Pd(II) salt such as: palladium acetate or palladium dichloride in the presence of a suitable organic base such as trialkyl amine e.g. triethylamine and of a triarylphosphine such as triphenylphosphine.
- a Pd(II) salt such as: palladium acetate or palladium dichloride
- a suitable organic base such as trialkyl amine e.g. triethylamine and of a triarylphosphine such as triphenylphosphine.
- reaction is carried out in an aprotic solvent such as acetonitrile or dimethylformamide and preferably with heating followed, where necessary or desired, by subsequent removal of the carboxyl protecting group R 12 and any nitrogen protecting group R 14 .
- an aprotic solvent such as acetonitrile or dimethylformamide
- Compounds of formula (I) wherein X-Y is a double bond may be regioselectively prepared by carring out the cyclisation reaction in an aprotic apolar solvent such as toluene in the presence of catalytic amount of a Palladium (O) complex such as tetrakis(triphenylphosphine)palladium and a suitable organic base such as trialkylamine e.g. triethylamine or inorganic base, e.g. potassium carbonate.
- an aprotic apolar solvent such as toluene
- a Palladium (O) complex such as tetrakis(triphenylphosphine)palladium
- a suitable organic base such as trialkylamine e.g. triethylamine or inorganic base, e.g. potassium carbonate.
- Compounds of formula (I) wherein X-Y is a single bond may be prepared by carring out the reaction the cyclisation reaction in an aprotic polar solvent (such as acetonitrile, dimethylformamide) in the presence of a catalytic amount of a Pd(II) salt such as: palladium acetate or palladium dichloride in the presence of a suitable organic base such as trialkyl amine e.g. triethylamine and of a triarylphosphine such as triphenylphosphine.
- an aprotic polar solvent such as acetonitrile, dimethylformamide
- Pd(II) salt such as: palladium acetate or palladium dichloride
- a suitable organic base such as trialkyl amine e.g. triethylamine and of a triarylphosphine such as triphenylphosphine.
- Suitable carboxyl protecting groups R 12 for use in this reaction include alkyl, such as ethyl, trichloroalkyl, trialkylsilylalkyl, or arylmethyl groups such as benzyl, nitrobenzyl or trityl.
- carboxyl protecting groups are those having a chiral group derived from chiral alcohols such as (+)-S-indanol, (+)-S-methyl mandelate, chiral (C 1-4 )alkyl lactate: i.e. (+)-R- or ( ⁇ )-S-methly lactate, (+)-R-t-butyl lactate, (+)-R- or ( ⁇ )-S-ethyl lactate, ( ⁇ )-S-isopropyl lactate, ( ⁇ )-S-butyl lactate, (+)-R-isobutyl lactate or chiral aralkyl lactate (i.e.
- chiral alcohols such as (+)-S-indanol, (+)-S-methyl mandelate, chiral (C 1-4 )alkyl lactate: i.e. (+)-R- or ( ⁇ )-S-methly lactate, (+)-R-t-butyl lactate, (+)-R- or
- R 12 is preferably an ethyl, benzyl group or a group derived from a chiral(C 1-4 ) alkyl lactate alcohol (eg (+)-(R)-t-butyl lactate ( ⁇ )-S-butyl lactate, (+)-R-isobutyl lactate alcohol).
- a chiral(C 1-4 ) alkyl lactate alcohol eg (+)-(R)-t-butyl lactate ( ⁇ )-S-butyl lactate, (+)-R-isobutyl lactate alcohol.
- R 14 is nitrogen protecting examples of suitable groups include alkoxycarbonyl e.g. t-butoxycarbonyl, arylsulphonyl e.g. phenysulphonyl or 2-trimethylsilyiethoxymethyl.
- Compounds of formula (II) may be prepared from compound of formula (III) in which R 12 is a carboxyl protecting group and R 14 is hydrogen or a nitrogen protecting group as defined in formula (II) and R 13 represents a bromine or iodine atom.
- reaction may be carried out using a phoshorus ylide of formula (IV)
- R 15 is an alkyl or phenyl group.
- reaction is carried out in an aprotic solvent such as acetonitrile or dimethylformamide at a temperature ranging from ⁇ 20° C. to the reflux temperature of the solvent.
- aprotic solvent such as acetonitrile or dimethylformamide
- a convenient method for preparing compounds of formula (III) is reacting compound of formula (V) in which R 12 is a carboxyl protecting group and R 14 is hydrogen or a nitrogen protecting group as defined in formula (II) and R 13 represents a bromine or iodine atom with an allyltintrihalide. (VI) followed by ozonization reaction
- the reaction conveniently takes place in a solvent such as hydrocarbon e.g. Toluene or halogenated hydrocarbon (e.g. dichforo methane at a temperature ranging from ⁇ 78° C. to room temperature).
- a solvent such as hydrocarbon e.g. Toluene or halogenated hydrocarbon (e.g. dichforo methane at a temperature ranging from ⁇ 78° C. to room temperature).
- the ozonization may be carried out by passing a stream of ozone into a solution in the presence of dimethyl sulphide or triphenylphosphine in a suitable solvent such as halohydrocarbon (e.g dicholoromethane) at low temperature e.g. ⁇ 78° C.
- compounds (III) may be prepared by aldolic reaction of the imino compound (V) with the enol ether (VII), wherein R 16 is a C 1-4 alkyl group.
- the reaction may be carried out in a solvent such as methylene cloruro or acetonitrile in the presence of a Lewis acid such as Ytterbium triflate.
- a solvent such as methylene cloruro or acetonitrile
- a Lewis acid such as Ytterbium triflate.
- the carboxyl protecting group may be removed by conventional procedures known for removing such groups.
- R 12 is a benzyl, ethyl or (+)-R- or ( ⁇ )-S-t-butyl lactate group
- R 12 is a benzyl, ethyl or (+)-R- or ( ⁇ )-S-t-butyl lactate group
- R 12 is a benzyl, ethyl or (+)-R- or ( ⁇ )-S-t-butyl lactate group
- a suitable solvent such as ethanol or isopropanol, water or mixtures thereof
- a suitable acid e.g. hydrochloric acid
- the nitrogen protecting group may be removed by conventional procedures known for removing such groups, for example by acid or base hydrolysis.
- R 14 is alkoxycarbonyl e.g. t-butoxycarbonyl or phenylsulphonyl it may be removed by alkaline hydrolysis using for example lithium hydroxide in a suitable solvent such as tetrahydrofuran or an alkanol e.g. isopropanol.
- the alkoxycarbonyl group may be removed by acid hydrolysis.
- Physiologically acceptable salts of compounds of formula (I) may be prepared by treating the corresponding acid with an appropriate base in a suitable solvent.
- the sodium or potassium salt may be prepared by treating a solution of the corresponding acid of a compound of formula (I) with sodium or potassium 2-ethylhexanoate with alkali or alkaline metal hydroxide, or the corresponding carbonate or bicarbonate thereof.
- alkali or alkaline metal salts may be prepared by direct hydrolysis of carboxyl protected derivatives of compounds of formula (I) with the appropriate alkali or alkaline metal hydroxide.
- Metabolically labile esters of compounds of formula (I) may be prepared by esterification of the carboxylic acid group or a salt thereof or by trans esterfication using conventional procedures.
- acyloxyalkyl esters may be prepared by reacting the free carboxylic acid or a salt thereof with the appropriate acyloxylalkyl halide in a suitable solvent such as dimethylformamide.
- a suitable solvent such as dimethylformamide.
- this reaction is preferably carried out in the presence of a quaternary ammonium halide such as tetrabutylammonium chloride or benzyltriethylammonium chloride.
- the enantiomers may be prepared by esterification of the corresponding racemic compounds of formula (I) with a suitable chiral alcohol, separating the resultant diastereomeric esters by conventional means e.g. chromatography or crystallisation followed by hydrolysis of the diastereomeric esters.
- Suitable chiral alcohols for use in the process include (+)-S-indanol, (+)-S-methyl mandelate, chiral (C 1-4 )alkyl lactate: i.e. (+)-R- or ( ⁇ )-S-methly lactate, (+)-R-t-butyl lactate, (+)-R- or ( ⁇ )-S-ethyl lactate, ( ⁇ )-S-isopropyl lactate, ( ⁇ )-S-butyl lactate, (+)-R-isobutyl lactate or chiral aralkyl lactate (i.e.
- the diastereomeric esters of compounds of formula (I) may be prepared by conventional means such as reaction of the chiral alcohol with an activated derivative of a compound of formula (I) in an aprotic solvent such as ether e.g. tetrahydrofuran.
- the activated derivative of a compound of formula (I) may be prepared from compounds (I) using conventional means for preparing activated derivatives of a carboxylic acid groups such as those conveniently used in peptide synthesis.
- a particularly convenient method of preparing the diastereomeric esters of compounds (I) is to prepare the activated derivative of compounds (I) in the presence of the chiral alcohol.
- racemic mixture of compounds (I) may be treated with the Mitsunobu combination of reagents, i.e. a dialkyl azo-dicarboxylate such as diethylazodicarboxylate and a triarylphosphine e.g. triphenylphosphine or trialkylphoshine (i.e. tributylphosphine) in the presence of the chiral alcohol.
- reagents i.e. a dialkyl azo-dicarboxylate such as diethylazodicarboxylate and a triarylphosphine e.g. triphenylphosphine or trialkylphoshine (i.e. tributylphosphine)
- the reaction conveniently takes place in the presence of a suitable solvent such as an ether (e.g. diethylether or tetrahydrofuran), a halohydrocarbon (e.g. dichloromethane) or a nitrile (e.g. acetonitrile) or a mixture thereof at a temperature ranging from 0-30° C.
- a suitable solvent such as an ether (e.g. diethylether or tetrahydrofuran), a halohydrocarbon (e.g. dichloromethane) or a nitrile (e.g. acetonitrile) or a mixture thereof at a temperature ranging from 0-30° C.
- the required single diastereomeric ester of compounds (I) may be obtained from the mixture thereof by conventional means, for example by the use of conventional chromatographic procedures such as preparative HPLC or by fractional crystallization.
- Specific enantiomers of compounds of formula (I) may be prepared from the corresponding single diastereomeric ester of compounds (I) by hydrolysis e.g. alkaline hydrolysis.
- the hydrolysis may be carried using an alkali metal hydroxide e.g. sodium hydroxide or lithium hydroxide in a solvent such as an ether e.g. tetrahydrofuran and water.
- R 17 is a carboxyl protecting group
- Suitable carboxyl protecting group R 17 for use in this reaction include C 1-4 alkyl such as methyl, ethyl, propyl, butyl, or arylmethyl groups such as benzyl, nitrobenzyl or trityl.
- Suitable enzymes for use in this reaction are lipase enzymes such as Aspergillus niger (AP-12) lLipase-DS ( Aspergillus niger, Amano), Candida rugosa lipase (Amano), Candida cylindracea lipase (Amano), Alcaligenes sp. lipase, Rhizopus arrhizus lipase (Biotal), Wheat germ lipase (Sigma), Rhizopus niveus lipase (Amano), Promod 21 5-P protease (Biocatalyst), lipase E-7 (Themogen), lipase E-17 (Thermogen). Further suitable enzymes which may be used in this reaction are porcine pancreatic lipase, alpha-chymotrypsin or trypsin.
- lipase enzymes such as Aspergillus niger (AP-12) lLipase-DS ( Aspergillus n
- a particular preferred enzyme for use in this reaction is Aspergillus niger (AP-12).
- Resting cells of the following organisms may also be used in this reaction Aspergillus ochraceus, Aspergillus niger, Aspergillus chevalieri & Aspergillus cervinus.
- reaction is conveniently carried out in an aprotic solvent such as DMSO, tetrahydrofuran in the presence of a suitable aqueous buffer (i.e. phosphate buffer or CaCl2. If required a solubilising agent such as Tween-80 may be added to the reaction mixture.
- aprotic solvent such as DMSO, tetrahydrofuran
- a suitable aqueous buffer i.e. phosphate buffer or CaCl2.
- a solubilising agent such as Tween-80 may be added to the reaction mixture.
- the enzyme may be immobilized and the reaction is carried out in essentially “neat” water-saturated organic solvents such as methyl tert-butyl ether or tert-amyl alcohol.
- EA ethyl acetate
- CH cyclohexane
- DCM diichloromethane
- THF tetrahydrofuran
- TFA trifluoroacebc acid
- TEA triethylamine
- DMF dimethylformamide
- ACO acetic anhydride
- PPA polyphosphoric acid
- DBU 1,8-diazobicyclo [5,4,0]undec-7-ene
- DMSO dimethylsulphoxide
- IMS mixtureture of Ethanol with 5% of methanol
- LHDMS Lithiumbis(trimethylsilyl)amide.
- DIPEA diisopropylethylamine
- Tlc thin layer chromatography on silica plates, and dried refers to a solution dried over anhydrous sodium sulphate; r.t. (RT) refers to room temperature.
- Enantiomer A or diastereoisomer A refer to a single enatiomer or a single diastereoisomer respectively whose absolute stereochemistry was not characterized.
- N,N,N 1 N 1 -Tetramethylethylene diamine (23.3 ml) was added to a solution of N-phenylpyrrolidinone (5 g) in dichloromethane (50 ml). The solution was cooled to 0-5° and trimethylsilyl triflate (8.4 ml) was added over ca 20 mins maintaining the temperature in the range 0-5°. The resultant solution was stirred for 10 mins and a solution of pyridinium bromide perbromide (13 g) in acetonitrile (20 ml) was added over ca 20 mins maintaining the temperature in the range 0-10°. The resultant suspension was stirred at 0-5° for ca 60 mins.
- Aqueous sodium bicarbonate solution (50 ml) was added, cautiously. The mixture was stirred for ca 5 mins and the layers are separated. The aqueous phase was diluted with water (20 ml) and back extracted with dichloromethane (20 ml). The combined organic phases were washed with further sodium bicarbonate solution (50 ml), 2M hydrochloric acid (2 ⁇ 50 ml) and water (50 ml), back extracting each wash with dichloromethane (10 ml). The organic solution was dried (MgSO 4 ) and concentrated on a rotavapor.
- IR (CDCl3) (cm ⁇ 1 ) 3370, 1738, 1697, 1671.
- T.l.c. EA R f 0.289.
- 125 g of Aspergillus niger lipase (Amano AP12) were suspended in 650 ml of 100 mM calcium chloride solution in a stirred reactor. The suspension was cooled to 15° C. 50 g of example 31b were then dissolved in dimethyl sulphoxide (350 ml) and this solution added to the reactor. The reactor was then heated to 37° C. and the mixture stirred for 24 hours.
- the reactor temperature was then lowered to 20° C. and 1 liter of 0.2M hydrochloric acid was slowly added to the reactor.
- the reactor was then emptied and 50 g of filter aid (Dicalite) were added to the reaction mixture.
- the mixture was then filtered and the filter cake washed with water, before being dried.
- a 20 g sample of dried filter cake was dispersed in 390 ml of methyl t-butyl ether and 10 ml of 2M hydrochloric acid were added. This was stirred for 3 hours and filtered, the filter cake was washed with 100 ml of methyl t-butyl ether.
- the product was back extracted from the methyl t-butyl ether 500 into ml of 0.05M sodium hydroxide solution.
- the aqueous layer was then separated, acidified with 6 ml of 5M hydrochloric acid and the product extracted into 500 ml ethyl acetate.
- the ethyl acetate was removed by evaporation and the residue dissolved in IMS (80 ml).
- the title compound was identified in this solution by HPLC assay as follows:
- IR:3411 (NH,), 1692, 1651-1583 (C ⁇ O), (C ⁇ C), 1306-1154 (SO 2 ) cm ⁇ 1 .
- the active ingredient is blended with the other excipients.
- the blend can be used to fill gelatin capsules or compressed to form tablets using appropriate punches.
- the tablets can be coated using conventional techniques and coatings.
- the active ingredient is blended with lactose, microcrystalline cellulose and part of the croscarmellose sodium.
- the blend is granulated with povidone after dispersing in a suitable solvent (i.e. water).
- a suitable solvent i.e. water
- the granule, after drying and comminution is blended with the remaining excipients.
- the blend can be compressed using appropriate punches and the tablets coated using conventional techniques and coatings.
- the formulation may be packed in glass ampoules or vials and syringes with a rubber stopper and a plastic/metal overseal (vials only).
- the formulation may be packed in glass vials or plastic bag.
- the dose required to reduce the licking time by 50% expressed as mg/kg is referred to as the ED 50s value.
Abstract
Compounds of formula (I) or a salt, or metabolically labile ester thereof wherein R represents a group selected from halogen, alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, SO2R2 or COR2 wherein R2 represents hydroxy, methoxy, amino, alkylamino or dialkylamino; m is zero or an integer 1 or 2; R1 represents a group (CH2)nCN, —CH═CHR3, (CH2)nNHCOCH2R4 or O(CH2)pNR5R6; R3 represents cyano or the group COR7; R4 represents alkoxy or a group NHCOR8; R5 and R6 each represent independently hydrogen or alkyl, or R5 and R6 together with the nitrogen atom to which they are attached represent a heterocyclic group, or R5 is hydrogen and R6 is the group COR9; R7 represents an alkoxy, amino or hydroxyl group; R8 represents a hydrogen atom or optionally substituted alkyl, alkoxy, aryl or heterocyclic group; R9 is the group R8 or the group NR10R11 wherein R10 represents hydrogen or alkyl group; R11 represents optionally substituted alkyl, aryl, heterocyclic or cycloalkyl group; n is zero or an integer from 1 to 4; p is an integer from 2 to 4, processes for their preparation and to their use in medicine.
Description
- This invention relates to 1, 2, 3, 4 tetrahydroquinoline derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine. In particular, it relates to 1, 2, 3, 4 tetrahydroquinoline derivatives which are potent and specific antagonists of excitatory amino acids.
- Carling et al., Bioorganic and Medicinal Chemistry Letters, Vol. 13 pp. 65-70, 1993, teaches 4-substituted-2-carboxy tetrahydroquinolines having good in vitro affinity for the glycine modulatory site of the NMDA receptor complex but at best only weak in vivo activity. More particularly, it teaches that such derivatives substituted at the 4 position by the group CH2CO2H or CH2CONHPh have little or no in vivo activity when administered systemically (ip).
- WO 97112870 and WO 98107704 describe novel 4-substituted-2-carboxy-tetrahydroquinoline derivatives which not only have a good in vitro affinity for the strychnine insensitive glycine binding site associated with the NMDA receptor complex but also have good in vivo activity when administered intravenously (iv).
- We have now discovered a novel group of 4-substituted-2-carboxy tetrahydroquinoline having a particularly useful profile of activity as selective antagonists for the strychnine insensitive glycine binding site associated with the NMDA receptor complex.
-
- or a salt or a non toxic metabolically labile esters thereof, wherein
- Y represents a carbon atom;
- Z is the group CH which is linked to the group Y via a double bond and
- X is CH or Z is methylene or NR11 and X is a carbon atom linked to the group Y via a double bond;
- A represents a C1-2 alkylene chain and which chain may be substituted by one or two groups selected from C1-6 alkyl optionally substituted by hydroxy, amino, C1-4 alkyl amino or C1-4 dialkyl amino or which chain may be substituted by the group=0;
- R represents a halogen atom or C1-4 alkyl group;
- R1 represents a hydrogen, a halogen atom or C1-4alkyl group;
- R2 represents phenyl which may be substituted with up to 3 groups selected from halogen, hydrogen, or (CH2)nR3 wherein R3 is COR4, NR6R5, NHCOR7, NHCONR9R8 or NH SO2 R10 group or R2 is a 5 membered heteroaryl group containing 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen; or 6 membered heteroaryl group containing 1 to 3 nitrogen atoms
- R4 represents an amino, a hydroxyl or C1-4 alkoxy group;
- R5 and R6 each independently represents hydrogen or C1-4 alkyl group or
- R5 and R6 together with the nitrogen atom to which they are attached represent a saturated 5-7 membered heterocyclic group optionally containing an additional heroatom selected from oxygen, sulphur or nitrogen
- R7 represents a hydrogen atom or C1-4 alkyl, C1-4 alkoxy, or phenyl;
- R8 represents hydrogen or C1-4alkyl group;
- R9 represents hydrogen, optionally substituted C1-4 alkyl (optionally substituted by one or more hydroxy carboxyl and amino group), phenyl;
- R11 represents hydrogen or C1-4 alkyl group;
- R10 represents hydrogen, C1-4 alkyl or a nitrogen protecting group.
- n is zero or an integer from 1 to 2;
- A further embodiment of the invention provides compounds of formula (I) or a salt or a non toxic metabolically labile esters thereof, wherein
- Y represents a carbon atom;
- Z is the group CH which is linked to the group Y via a double bond and
- X is CH or Z is methylene or NR11 and X is a carbon atom linked to the group Y via a double bond;
- A represents a C1-2 alkylene chain and which chain may be substituted by one or two groups selected from C1-6 alkyl optionally substituted by hydroxy, amino, C1-4 alkyl amino or C1-4 dialkyl amino or which chain may be substituted by the group=0;
- R represents a halogen atom;
- R1 represents a hydrogen or a halogen atom;
- R2 represents phenyl which may be substituted with up to 3 groups selected from halogen, hydrogen, or (CH2)nR3 wherein R3 is COR4, NR6R5, NHCOR7, NHCONR9R8 or NH SO2 R10 group or R2 is a 5 membered heteroaryl group containing 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen; or 6 membered heteroaryl group containing 1 to 3 nitrogen atoms
- R4 represents an amino or a hydroxyl;
- R5 and R6 each independently represents hydrogen or C1-4 alkyl group or
- R5 and R6 together with the nitrogen atom to which they are attached represent a saturated 5-7 membered heterocyclic group optionally containing an additional heroatom selected from oxygen, sulphur or nitrogen
- R7 represents a hydrogen atom or C1-4 alkyl, C1-4 alkoxy, or phenyl;
- R8 represents hydrogen or C1-4 alkyl group;
- R9 represents hydrogen, optionally substituted C1-4 alkyl (optionally substituted by one or more hydroxy carboxyl and amino group), phenyl;
- R11 represents hydrogen or C1-4 alkyl group;
- R10 represents hydrogen, C1-4 alkyl or a nitrogen protecting group;
- n is zero or an integer from 1 to 2 with the proviso that when X is a carbon atom linked to the group Y via a double bond then R1 is hydrogen;
- For use in medicine the salts of the compounds of formula (I) will be physiologically acceptable thereof. Other salts however may be useful in the preparation of the compounds of formula (I) or physiologically acceptable salts thereof. Therefore, unless otherwise stated, references to salts include both physiologically acceptable salts and non-physiologically acceptable salts of compounds of formula (I).
- Suitable physiologically acceptable salts of compounds of the invention include base addition salts and, where appropriate, acid addition salts. Suitable physiologically acceptable base addition salts of compounds of formula (I) include alkali metal or alkaline metal salts such as sodium, potassium, calcium, magnesium and ammonium salts, formed with amino acids (e.g. lysine and arginine) and organic bases (e.g. procaine, phenylbenzylamine, ethanolamine diethanolamine and N-methyl glucosamine).
- The compounds of formula (I) and/or salts thereof may form solvates (e.g. hydrates) and the invention includes all such solvates.
- The term halogen refers to a fluorine, chlorine, bromine or iodine atom. The term C1-4 alkyl as used herein as a group or part of a group refers to a straight or branched chain alkyl group containing from 1 to 4 carbon atom, examples of such groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, secondary butyl or tertiary butyl.
- When R2 is a 5 or 6 membered heteroaryl group this may be for example furanyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, pyridyl or pyrimidinyl.
- When R5 and R6 together with the nitrogen atom to which they are attached form a saturated 5-7 membered heterocyclic group optionally containing an additional heroatom selected from oxygen, sulphur or nitrogen this may be morpholino, 2,6 dimethylmorpholino, thiomorpholino, piperidino, pyrrolidino, piperazino or N-methylpiperazino.
- When R2 is a substituted phenyl group this is conveniently a mono substituted phenyl group. The substituent is conveniently in the meta position or more conveniently in the para position.
- When X-Y represents a double bond, the compounds of formula (I) possess at least one asymmetric carbon atom (namely the carbon atom occupying the 2 position of the 1, 2, 3, 4 tetrahydroquinoline ring system) and other asymmetric carbon atoms are possible in the group R2. It is to be understood that all enantiomers and diastereomers and mixtures thereof are encompassed within the scope of the present invention.
-
- The solid wedge shaped bond indicates that the bond is above the plane of the paper and is referred to as the β configuration. The broken indicates that the bond is below the plane of the paper and is referred to as α configuration.
- Further other asymmetric carbon atoms are possible in the groups R2. It is to be understood that all enantiomers and diastereomers and mixtures thereof are encompassed within the scope of the present invention.
- Non-toxic metabolically labile esters of compound of formula (I) are esters of compounds of formula (I) that are hydrolysed in vivo to afford said compound of formula I and a physiologically acceptable alcohol. Non toxic metabolically esters of compound of formula (I) may be formed by esterification, for example of any of the carboxylic acid groups in the parent compound of general formula (I) with, where appropriate, prior protection of any other reactive groups present in the molecule, followed by deprotection if required. Examples of such metabolically labile esters include C1-4alkyl esters e.g. methyl or ethyl esters, substituted or unsubstituted aminoalkyl esters (e.g. aminoethyl, 2-(N,N-diethylamino) ethyl, or 2-(4-morpholino)ethyl esters or acloxyalkyl esters such as, acyloxymethyl or 1-acyloxyethyl e.g. pivaloyloxymethyl, 1-pivaloyloxyethyl, acetoxymethyl, 1-acetoxyethyl, 1-(1-methoxy-1-methyl)ethylcarbonyloxyethyl, 1-benzoyloxyethyl, isopropoxycarbonyloxymethyl, 1-isopropoxycarbonyloxyethyl, cyclohexylcarbonyloxymethyl, 1-cyclohexylcarbonyloxyethyl ester, cyclohexyloxycarbonyloxymethyl, 1-cyclohexyloxycarbonyloxyethyl, 1-(4-tetrahydropyranyloxy)carbonyloxyethyl or 1-(4-tetrahydropyranyl)carbonyloxyethyl.
- The group R is conveniently chlorine. The group R1 is conveniently a hydrogen or a chlorine atom.
- A preferred class of compounds of formula (I) is that wherein R is chlorine and R1 is a hydrogen or a chlorine atom.
- A further preferred class of compounds of formula (I) is that wherein R is chlorine and R1 is a hydrogen atom.
- When X-Y is a single bound, a preferred class of compounds of formula (I) is that in which the carbon atom in 4 position is β configuration and the carbon atom in 2 position is in a configuration (1a) and that in which the carbon atom in 4 position is a configuration and the carbon atom in 2 position is in β configuration (1c).
- When A is an optionally substituted C1-2 alkylene chain this may be, for example, methylene, ethylene or C═O.
- A preferred class of compounds of formula (I) includes those wherein A is a chain selected from —CH2—, —(CH2)2—, C═O.
- When Z is a group NR11 this is conveniently the group NH.
- A preferred class of compounds of formula (I) includes those wherein Z is CH which is linked to the group Y via a double bond, a methylene or a NH group.
- When R2 is an optionally substituted phenyl group this is conveniently phenyl substituted by a single substituent selected from (CH2)nNR6R5 in which R5 is hydrogen and R6 is hydrogen, C1-4 alkyl (e.g. methyl, ethyl) or NR6R5 represents a saturated 6 membered ring containing oxygen e.g. morpholino; (CH2)nNHCOR7 wherein R7 is hydrogen, alkyl e.g. methyl, isopropyl, isobutyl, phenyl; (CH2)nNHCONHR9 wherein R9 is hydrogen; (CH2)nNH SO2 R10 in which R10 is alkyl e.g. methyl. n is zero or an integer from 1 to 2; Examples of such R2 groups include phenyl (optionally substituted by amino, t-butoxycarbonylamino, acetylamino or methanesulphonylamino)
- When R2 is substituted phenyl the substituents are conveniently in the meta or more preferably in the para position.
- When R2 is a 5 or 6 membered heteroaryl group as above defined this is conveniently pyridyl e.g. 3-pyridyl.
- A preferred class of compounds of formula (I) is that wherein R2 represents phenyl (optionally substituted by acetylamino, methanesulphonylamino) or 3-pyridyl. Within this class those wherein R2 is phenyl are particularly preferred.
- A further preferred class of compounds of formula (I) is that wherein X is a carbon atom linked to the group Y via a double bond.
- A preferred group of compounds of formula (I) is that wherein A is is a chain selected from —CH2— or —(CH2)2—, Z is a group CH which is linked to the group Y via a double bond or a methylene group, or A is the chain CO and Z is an NH group, R is chlorine, R1 is chlorine or hydrogen and R2 is phenyl (optionally substituted by acetylamino or methanesulphonylamino) or 3-pyridyl.
- Specific preferred compounds of the invention include:
- (±)7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinoline carboxylic acid,
- (±)7-chloro-4-(1-phenyl-Δ3-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydro-2-quinoline carboxylic acid,
- and physiologically acceptable salts (e.g. sodium salt) non-toxic metabolically labile esters or enantiomers thereof.
- (−)-Sodium 7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylate.
- (−)Sodium 7-chloro-4-(1-phenyl-Δ3-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylate,
- (+)Sodium 7-chloro-4-(1-phenyl-Δ3-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2carboxylate.
- Further specific preferred compounds of the invention include:
- (±)-7-chloro-4-(1-(3-pyridin)-Δ3-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
- (±)-7-chloro-4-(1-phenyl-Δ3-5,6-dihydro-pyridin-2one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxlic acid,
- (±)-5,7-dichloro-4-(1-phenyl-Δ3-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
- (+/−)-7-chloro-4-(1-(4-acetylamino)-1-phenyl-Δ3-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
- (+/−)7-chloro-4-(1-(4-methanesulfonylamino)-1-phenyl-Δ3-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
- (±)-7-chloro-4-(2-oxo-1-phenyl-3-piperidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid,
- (±)-7-chloro-4-(2,5dioxo-1-phenyl-imidazolidin-4-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid,
- (±)-7-chloro-4-(2-oxo-1-(pyridin-3yl)-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylate,
- (±)-7-chloro-4-(2-oxo-1-(4-acetylamino)phenyl-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid,
- (±)7-chloro-4-(2-oxo-1-((4-methanesulfonyl amino)phenyl-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid,
- 5,7-dichloro-4-(2-oxo-1-(phenyl)-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinoline carboxylic acid (enantiomer A);
- 5,7-dichloro-4-(2-oxo-1-phenyl-Δ3-pyrrolin-2-one-3-yl)-1,2,3,4-tetrahydro-quinoline-2-carboxylic acid (enatiomer A);
- and physiologically acceptable salts (e.g. sodium salts), non-toxic metabolically labile esters or enantiomers thereof.
- The compounds of formula (I) and/or physiologically acceptable salts thereof are excitatory amino acid antagonists. More particularly they are potent antagonists at the strychnine insensitive glycine binding site associated with the NMDA receptor complex. As such they are potent antagonists of the NMDA receptor complex. These compounds are therefore useful in the treatment or prevention of neurotoxic damage or neurodegenerative diseases. Thus the compounds are useful for the treatment of neurotoxic injury which follows cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospam, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia cardiac arrest. The compounds are useful in the treatment of chronic neurodegenerative diseases such as: Huntingdon's disease, Alzheimer's senile dementia, amyotrophic lateral sclerosis, Glutaric Acidaemia type, multi-infarct dementia, status epilecticus, contusive injuries (e.g. spinal cord injury and head injury), viral infection induced neurodegeration (e.g. AIDS, encephalopaties), Down syndrome, ocular neurodegeneration (e.g glaucoma), epilepsy, schizophrenia, depression, migraine, headaches including cluster headaches and or tension headaches, anxiety, pain (e.g inflamatory pain and neuropathic pain), neurogenic bladder, emesis irritative bladder disturbances, drug dependency, including withdrawal symptoms from alcohol, cocaine, opiates, nicotine (e.g. smoking cessation) benzodiazepines and, inhibition of tolerance induced by opioids (i.e morphine).
- The potent and selective action of the compound of the invention at the strychnine-insensitive glycine binding site present on the NMDA receptor complex may be readily determined using conventional test procedures. Thus the ability to bind at the strychnine insensitive glycine binding site was determined using the procedure of Kishimoto H et al., J Neurochem 1981, 37, 1015-1024. The selectivity of the action of compounds of the invention for the strychnine insensitive glycine site was confirmed in studies at other ionotropic known excitatory amino acid receptors. Thus compounds of the invention were found to show little or no affinity for the kainic acid (kainate) receptor, a-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA) receptor or at the NMDA binding site.
- Compounds of the invention may be found found to inhibit NMDA induced convulsions in mice using the procedure Chiamulera C et al., Psychopharmacology (1990), 102, 551-552.
- The neuroprotective activity of the compounds of the invention may be demonstrated in the middle cerebral artery occlusion preparation in mice, using the procedure described by Chiamulera C. et al., European Journal of Pharmacology, 216 (1992) pp. 335-336.
- The ability of compounds of the invention to alleviate withdrawal symptoms from nicotine following smoking cessation may be demonstrated in conventional tests of nicotine induced relapse using the procedure described in C. Chiamulera et al., Arch. Pharmacol., 358, 1998.
- The invention therefore provides for the use of a compound of formula (I) and/or physiologically acceptable salts or non-toxic metabolically labile esters thereof for use in therapy and in particular use as medicine for antagonising the effects of excitatory amino acids upon the NMDA receptor complex.
- The ability of compounds of the invention to inhibit pain may be demonstrated in conventional analgesic screen such as those described by Dubuisson and Dennis,Pain, 1977, 4:161-174; J. J. Bennett and J. K Xue, Pain, 1988, 41, 87-107.
- The invention also provides for the use of a compound of formula (I) and/or a physiologically acceptable salt or non-toxic metabolically labile esters thereof for the manufacture of a medicament for antagonising the effects of excitatory amino acids upon the NMDA receptor complex.
- According to a further aspect, the invention also provides for a method for antagonising the effects of excitatory amino acids upon the NMDA receptor complex, comprising administering to a patient in need thereof an antagonistic amount of a compound of formula (I) and/or a physiologically acceptable salt thereof.
- It will be appreciated by those skilled in the art that reference herein to treatment extends to prophylactics as well as the treatment of established diseases or symptoms.
- It will further be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated, the route of administration and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician. In general however doses employed for adult human treatment will typically be in the range of 2 to 800 mg per day, dependent upon the route of administration.
- Thus for parenteral administration a daily dose will typically be in the range 20-100 mg, preferably 60-80 mg per day. For oral administration a daily dose will typically be within the range 200-800 mg, e.g. 400-600 mg per day.
- The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.
- While it is possible that, for use in therapy, a compound of the invention may be administered as the raw chemical, it is preferable to present the active ingredient as a pharmaceutical formulation.
- The invention thus further provides a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt or non-toxic metabolically labile esters thereof together with one or more pharmaceutically acceptable carriers thereof and, optionally, other therapeutic and/or prophylactic ingredients. The carrier(s) must be ‘acceptable’ in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- The compositions of the invention include those in a form especially formulated for oral, buccal, parenteral, inhalation or insufflaflon, implant or rectal administration.
- Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone; fillers, for example, lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch or sodium starch glycollate, or wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-leate or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; solubilizers such as surfactants for example polysorbates or other agents such as cyclodextrins; and preservatives, for example, methyl or propyl p-hydroxybenzoates or ascorbic acid. The compositions may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa buffer or other glycerides.
- For buccal administration the composition may take the form of tablets or lozenges formulated in conventional manner.
- The composition according to the invention may be formulated for parenteral administration by injection or continuous infusion. Formulations for injection may be presented in unit dose form in ampoules, or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
- For administration by inhalation the compounds according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurised packs, with the use of a suitable propellant, such as dichlorodifluoromethane, tirchlorofluoromethane, dichloro-tetrafluoroethane, carbon dioxide or other suitable propellants, such as dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane, carbon dioxide or other suitable gases, or from a nebuliser. In the case of a pressurised aerosol the dosage unit may be determined by providing a valve to deliver a metered amount.
- Alternatively, for administration by inhalation or insufflation, the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable carrier such as lactose or starch. The powder composition may be presented in unit dosage form in, for example, capsules or cartridges of e.g. gelatin, or blister packs from which the powder may be administered with the aid of an inhaler or insufflator.
- The composition according to the invention may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus for example, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
- The compositions according to the invention may contain between 0.1-99% of the active ingredient, conveniently from 30-95% for tablets and capsules and 3-50% for liquid preparations.
- Compounds of general formula (I) enantiomers and salts thereof may be prepared by the general methods outlined hereinafter. In the following description, the groups R, R1, R2, A, Z, X and Y are as defined for the compounds of formula (I) unless otherwise stated.
-
- followed where necessary or desired by removal of one or more protecting groups.
- In one embodiment of this process the reaction may be carried out using a catalytic amount of a Palladium (O) complex such as tetrakis(triphenylphosphine)palladium and a suitable organic base such as trialkylamine e.g. triethylamine or inorganic base, e.g. potassium carbonate.
- The reaction is conveniently carded out in an aprotic polar solvent such as acetonitrile, dimethylformamide or in aprotic apolar solvent such as hydrocarbon (ie toluene, xilene, hexane) at a temperature within the range of 60° C. to 150° C. followed, where necessary or desired, by subsequent removal of the carboxyl protecting group R12 and any protecting group R14.
- In a further embodiment of the process the reaction is carried out using a catalytic amount of a Pd(II) salt such as: palladium acetate or palladium dichloride in the presence of a suitable organic base such as trialkyl amine e.g. triethylamine and of a triarylphosphine such as triphenylphosphine.
- The reaction is carried out in an aprotic solvent such as acetonitrile or dimethylformamide and preferably with heating followed, where necessary or desired, by subsequent removal of the carboxyl protecting group R12 and any nitrogen protecting group R14.
- Compounds of formula (I) wherein X-Y is a double bond may be regioselectively prepared by carring out the cyclisation reaction in an aprotic apolar solvent such as toluene in the presence of catalytic amount of a Palladium (O) complex such as tetrakis(triphenylphosphine)palladium and a suitable organic base such as trialkylamine e.g. triethylamine or inorganic base, e.g. potassium carbonate.
- Compounds of formula (I) wherein X-Y is a single bond may be prepared by carring out the reaction the cyclisation reaction in an aprotic polar solvent (such as acetonitrile, dimethylformamide) in the presence of a catalytic amount of a Pd(II) salt such as: palladium acetate or palladium dichloride in the presence of a suitable organic base such as trialkyl amine e.g. triethylamine and of a triarylphosphine such as triphenylphosphine.
- Suitable carboxyl protecting groups R12 for use in this reaction include alkyl, such as ethyl, trichloroalkyl, trialkylsilylalkyl, or arylmethyl groups such as benzyl, nitrobenzyl or trityl.
- Further convenient carboxyl protecting groups are those having a chiral group derived from chiral alcohols such as (+)-S-indanol, (+)-S-methyl mandelate, chiral (C1-4)alkyl lactate: i.e. (+)-R- or (−)-S-methly lactate, (+)-R-t-butyl lactate, (+)-R- or (−)-S-ethyl lactate, (−)-S-isopropyl lactate, (−)-S-butyl lactate, (+)-R-isobutyl lactate or chiral aralkyl lactate (i.e. benzyl lactate), (−)-S-perillyl alcohol, (−)-methyl-(R)-3-hydroxy-2-methylpropionate, (−)-(R)-2-butanol, (−)-(S)-2-methyl-1-butanol.
- R12 is preferably an ethyl, benzyl group or a group derived from a chiral(C1-4) alkyl lactate alcohol (eg (+)-(R)-t-butyl lactate (−)-S-butyl lactate, (+)-R-isobutyl lactate alcohol).
- When R14 is nitrogen protecting examples of suitable groups include alkoxycarbonyl e.g. t-butoxycarbonyl, arylsulphonyl e.g. phenysulphonyl or 2-trimethylsilyiethoxymethyl.
-
-
- followed, where necessary or desired, by removal of the carboxyl protecting group R12 and nitrogen protecting group R13.
-
- wherein R15 is an alkyl or phenyl group.
- The reaction is carried out in an aprotic solvent such as acetonitrile or dimethylformamide at a temperature ranging from −20° C. to the reflux temperature of the solvent.
- Compounds of formula (III) and (IV) are either known compounds or may be prepared by analogous methods to those used for known compounds.
-
- The reaction conveniently takes place in a solvent such as hydrocarbon e.g. Toluene or halogenated hydrocarbon (e.g. dichforo methane at a temperature ranging from −78° C. to room temperature). The ozonization may be carried out by passing a stream of ozone into a solution in the presence of dimethyl sulphide or triphenylphosphine in a suitable solvent such as halohydrocarbon (e.g dicholoromethane) at low temperature e.g. −78° C.
-
- The reaction may be carried out in a solvent such as methylene cloruro or acetonitrile in the presence of a Lewis acid such as Ytterbium triflate.
- In any of the above reactions the carboxyl protecting group may be removed by conventional procedures known for removing such groups. Thus compounds where R12 is a benzyl, ethyl or (+)-R- or (−)-S-t-butyl lactate group may be removed by hydrolysis using an alkali metal hydroxide e.g. lithium hydroxide or sodium hydroxide in a suitable solvent such as ethanol or isopropanol, water or mixtures thereof, followed, where desired or necessary, by that addition of a suitable acid e.g. hydrochloric acid to give the corresponding free carboxylic acid.
- In any of the above reactions the nitrogen protecting group may be removed by conventional procedures known for removing such groups, for example by acid or base hydrolysis. Thus when R14 is alkoxycarbonyl e.g. t-butoxycarbonyl or phenylsulphonyl it may be removed by alkaline hydrolysis using for example lithium hydroxide in a suitable solvent such as tetrahydrofuran or an alkanol e.g. isopropanol. Alternatively the alkoxycarbonyl group may be removed by acid hydrolysis.
- Physiologically acceptable salts of compounds of formula (I) may be prepared by treating the corresponding acid with an appropriate base in a suitable solvent. For example the sodium or potassium salt may be prepared by treating a solution of the corresponding acid of a compound of formula (I) with sodium or potassium 2-ethylhexanoate with alkali or alkaline metal hydroxide, or the corresponding carbonate or bicarbonate thereof. Alternatively alkali or alkaline metal salts may be prepared by direct hydrolysis of carboxyl protected derivatives of compounds of formula (I) with the appropriate alkali or alkaline metal hydroxide.
- Metabolically labile esters of compounds of formula (I) may be prepared by esterification of the carboxylic acid group or a salt thereof or by trans esterfication using conventional procedures. Thus, for example, acyloxyalkyl esters may be prepared by reacting the free carboxylic acid or a salt thereof with the appropriate acyloxylalkyl halide in a suitable solvent such as dimethylformamide. For the esterification of the free carboxyl group this reaction is preferably carried out in the presence of a quaternary ammonium halide such as tetrabutylammonium chloride or benzyltriethylammonium chloride.
- Specific enantiomers of the compounds of formula (I) may also be obtained from corresponding racemic compounds of formula (I) using chiral HPLC procedure.
- Alternatively the enantiomers may be prepared by esterification of the corresponding racemic compounds of formula (I) with a suitable chiral alcohol, separating the resultant diastereomeric esters by conventional means e.g. chromatography or crystallisation followed by hydrolysis of the diastereomeric esters.
- Suitable chiral alcohols for use in the process include (+)-S-indanol, (+)-S-methyl mandelate, chiral (C1-4)alkyl lactate: i.e. (+)-R- or (−)-S-methly lactate, (+)-R-t-butyl lactate, (+)-R- or (−)-S-ethyl lactate, (−)-S-isopropyl lactate, (−)-S-butyl lactate, (+)-R-isobutyl lactate or chiral aralkyl lactate (i.e. benzyl lactate), (−)-S-perillyl alcohol, (−)-methyl-(R)-3-hydroxy-2-methylpropionate, (−)-(R)-2-butanol, (−)-(S)-2-methyl-1-butanol.
- The diastereomeric esters of compounds of formula (I) may be prepared by conventional means such as reaction of the chiral alcohol with an activated derivative of a compound of formula (I) in an aprotic solvent such as ether e.g. tetrahydrofuran.
- The activated derivative of a compound of formula (I) may be prepared from compounds (I) using conventional means for preparing activated derivatives of a carboxylic acid groups such as those conveniently used in peptide synthesis.
- A particularly convenient method of preparing the diastereomeric esters of compounds (I) is to prepare the activated derivative of compounds (I) in the presence of the chiral alcohol.
- Thus for example racemic mixture of compounds (I) may be treated with the Mitsunobu combination of reagents, i.e. a dialkyl azo-dicarboxylate such as diethylazodicarboxylate and a triarylphosphine e.g. triphenylphosphine or trialkylphoshine (i.e. tributylphosphine) in the presence of the chiral alcohol.
- The reaction conveniently takes place in the presence of a suitable solvent such as an ether (e.g. diethylether or tetrahydrofuran), a halohydrocarbon (e.g. dichloromethane) or a nitrile (e.g. acetonitrile) or a mixture thereof at a temperature ranging from 0-30° C.
- The required single diastereomeric ester of compounds (I) may be obtained from the mixture thereof by conventional means, for example by the use of conventional chromatographic procedures such as preparative HPLC or by fractional crystallization.
- Alternatively the required single diastereomeric ester of compound of formula (I) may be obtained using a suitable chiral protecting group R12 as defined in formula (II).
- Specific enantiomers of compounds of formula (I) may be prepared from the corresponding single diastereomeric ester of compounds (I) by hydrolysis e.g. alkaline hydrolysis. Thus, for example, the hydrolysis may be carried using an alkali metal hydroxide e.g. sodium hydroxide or lithium hydroxide in a solvent such as an ether e.g. tetrahydrofuran and water.
-
- Wherein R17 is a carboxyl protecting group Suitable carboxyl protecting group R17 for use in this reaction include C1-4 alkyl such as methyl, ethyl, propyl, butyl, or arylmethyl groups such as benzyl, nitrobenzyl or trityl.
- Suitable enzymes for use in this reaction are lipase enzymes such asAspergillus niger (AP-12) lLipase-DS (Aspergillus niger, Amano), Candida rugosa lipase (Amano), Candida cylindracea lipase (Amano), Alcaligenes sp. lipase, Rhizopus arrhizus lipase (Biotal), Wheat germ lipase (Sigma), Rhizopus niveus lipase (Amano), Promod 21 5-P protease (Biocatalyst), lipase E-7 (Themogen), lipase E-17 (Thermogen). Further suitable enzymes which may be used in this reaction are porcine pancreatic lipase, alpha-chymotrypsin or trypsin.
- A particular preferred enzyme for use in this reaction isAspergillus niger (AP-12).
- Resting cells of the following organisms may also be used in this reactionAspergillus ochraceus, Aspergillus niger, Aspergillus chevalieri & Aspergillus cervinus.
- The reaction is conveniently carried out in an aprotic solvent such as DMSO, tetrahydrofuran in the presence of a suitable aqueous buffer (i.e. phosphate buffer or CaCl2. If required a solubilising agent such as Tween-80 may be added to the reaction mixture.
- In a further process the enzyme may be immobilized and the reaction is carried out in essentially “neat” water-saturated organic solvents such as methyl tert-butyl ether or tert-amyl alcohol.
- In order that the invention may be more fully understood the following examples are given by way of illustration only.
- In the Intermediates and Examples unless otherwise stated:
- Melting points (m.p.) were determined on a Gallenkamp m.p. apparatus and are uncorrected. All temperatures refer to ° C. Infrared spectra were measured on a FT-IR instrument. Proton Magnetic Resonance (1H-NMR) spectra were recorded at 400 MHz, chemical shifts are reported in ppm downfield (d) from Me4Si, used as internal standard, and are assigned as singlets (s), doublets (d), doublets of doublets (dd), triplets (t), quartets (q) or multiplets (m). Column chromathography was carried out over silica gel (Merck AG Darmstaadt, Germany). The following abbreviations are used in text: EA=ethyl acetate, CH=cyclohexane, DCM=dichloromethane, THF=tetrahydrofuran, TFA=trifluoroacebc acid, TEA=triethylamine, DMF=dimethylformamide, ACO=acetic anhydride, PPA=polyphosphoric acid, DBU=1,8-diazobicyclo [5,4,0]undec-7-ene, DMSO=dimethylsulphoxide, IMS=mixture of Ethanol with 5% of methanol, LHDMS=Lithiumbis(trimethylsilyl)amide. DIPEA=diisopropylethylamine Tlc refers to thin layer chromatography on silica plates, and dried refers to a solution dried over anhydrous sodium sulphate; r.t. (RT) refers to room temperature.
- Enantiomer A or diastereoisomer A refer to a single enatiomer or a single diastereoisomer respectively whose absolute stereochemistry was not characterized.
- Intermediate 1
- (±)-Ethyl 2-(5-chloro-2-iodoanilino)-4-pentenoate
- To a solution of 2-iodo 4 chloro aniline (9.1 g) in dry toluene (150 ml) ethyl glyoxylate (50% solution in toluene, 14.6 ml) and MgSO4 (2 g) were added and the resulting suspension was refluxed overnight. It was then filtered and concentrated to dryness under high vacuum at 50° C. for 1.5 h. The resulting brown oil was dissolved in dichloromethane (150 ml) cooled to −78° C. and TiCl4 (99.995% purity, 4 ml) was added via syringe.
- The suspension was stirred 15 min at −78° C., then allowed to warm to rt over 15 min before being cooled again to −78° C. Allyltributyltin (17 ml) was then added and the reaction allowed to proceed for 1 h. The black solution was poured into 200 ml of ethyl acetate and washed first with a saturated solution of NH4Cl (2×150 ml), then with water and brine. The organic phase was dried and concentrated to give the crude product, which was purified by column chromatography (cyclohexane, then cyclohexanelethyl acetate 98/2) to give the title compound (10.4 g) as a colourless oil.
- NMR (CDCl3) δ (ppm) 7.57 (d, 1H), 6.49 (dd, 1H), 6.45 (dd, 1H), 5.79 (m, 1H), 5.25 (dd, 1H) 5.24 (dd, 1H), 4.83 (d, 1H), 4.25 (q, 2H), 4.13 (m, 1H), 2.66 (m, 2H), 1.30 (t, 3H)
- Intermediate 2
- (±)-Ethyl 2-(5-chloro-2-iodoanilino)-4-oxobutanoate
- A solution of intermediate 1 (5.2 g) in dichloromethane (150 ml) was cooled to −78° C. and ozone was bubbled through it until the clear solution became brick-red. At this point the flux of ozone was interrupted and the solution was purged with nitrogen for a few minutes. Triphenyl phosphine (7.1 g) was added and stirring continued for 1.5 h, without control of the temperature. The resulting solution was poured into 200 ml of ethyl acetate and washed first with a saturated solution of NH4Cl (2×150 ml), then with water and brine. The organic phase was dried and concentrated to give the crude product, which was purified by column chromatography (cyclohexanelethyl acetate 80/20) to give the title compound (2.4 g) as a colourless oil.
- NMR (DMSO) δ (ppm) 9.80 (t, 1H), 7.57 (d, 1H), 6.55 (d, 1H), 6.51 (dd, 1H), 4.99 (d, 1H), 4.46 (m, 1H), 4.24 (q, 2H), 3.08 (m, 2H), 1.28 (t, 3H)
- Intermediate 2a
- (±) Ethyl 2-(3,5-dichloro-2-iodoanilino)-4-oxobutanoate
- A solution of ethyl glyoxylate (50% solution in toluene, 1 ml) and MgSO4 (7 g) in toluene (30 ml) was refluxed in Dean-Stark apparatus for 0.5 hrs.
- Then, 3,5,-chloro-2iodoaniline was added, and the mixture refluxed for 1 hr. Then mixture was cooled, filtered through celite to eliminate the MgSO4, and concentrated. The resulting brown oil was dissolved in dichloromethane (15 ml) cooled to −78° C. and Yb(OTf)3xH2O (0.186 g) was added. The suspension was stirred for 5 mins at −78° C., then the vinyloxytrimethylsilane (0.29 g) was added and the temperature was risen to 20° C. After 1 hr at that temperature a saturated solution of NH4Cl (20 cc) was added followed by ethyl acetate (30 ml). The organic phase was washed with brine (20 ml) and dried over sodium sulphate and concentrated to give the crude product, which was purified by column chromatography (cyclohexane, then cyclohexane/ethyl acetate 85/15) to give the title compound (0.562 g) as a colourless oil.
- NMR (CDCl3) δ (ppm) 9.65 (s, 1H), 7.00 (d, 1H), 6.70 (d, 1H), 5.60 (d, 1H), 4.80 (m, 1H) 4.10 (q, 2H), 3.10 (m, 2H), 1.15 (t, 3H).
- Intermediate 3
- Tributyl (2oxo-1-phenylpyrrolidin-1-yl) phosphonium Bromide
- N,N,N1N1-Tetramethylethylene diamine (23.3 ml) was added to a solution of N-phenylpyrrolidinone (5 g) in dichloromethane (50 ml). The solution was cooled to 0-5° and trimethylsilyl triflate (8.4 ml) was added over ca 20 mins maintaining the temperature in the range 0-5°. The resultant solution was stirred for 10 mins and a solution of pyridinium bromide perbromide (13 g) in acetonitrile (20 ml) was added over ca 20 mins maintaining the temperature in the range 0-10°. The resultant suspension was stirred at 0-5° for ca 60 mins. Aqueous sodium bicarbonate solution (50 ml) was added, cautiously. The mixture was stirred for ca 5 mins and the layers are separated. The aqueous phase was diluted with water (20 ml) and back extracted with dichloromethane (20 ml). The combined organic phases were washed with further sodium bicarbonate solution (50 ml), 2M hydrochloric acid (2×50 ml) and water (50 ml), back extracting each wash with dichloromethane (10 ml). The organic solution was dried (MgSO4) and concentrated on a rotavapor. The red/brown solid was stirred with ethyl acetate (50 ml) and warmed to give a solution which was then cooled and tributylphosphine (8.5 ml) was added. The solution was heated to reflux and maintained at reflux for 2.5 hours. The solution was allowed to cool to room temperature and was then cooled to 0-5°. The resulting suspension was aged at 0-5° for ca 60 min. The product was isolated by vacuum filtration and then washed with ethyl acetate:t-butyimethylether (1:1, 40 ml) and dried in a vacuum oven at 45° to give the title compound as a white crystalline solid (10.12 g), mp 127-128°.
- Intermediate 4
- (±) E-Ethyl 2-(5-chloro-2-iodoanilino)-4-(2-oxo-1-phenyl-3-pyrrolidinylidene) butanoate (4a);(±)-Z-Ethyl 2-(5-chloro-2-iodoanilino)-4-(2oxo-1-phenyl-3-pyrrolidinylidene) Butanoate(4b)
- To a solution of intermediate 2 (2.4 g) in acetonitrile (100 ml) at r.t. intermediate 3 (3.7 g) and DBU (13 ml) were added and stirring was continued overnight at −20° C. The crude solution was poured into 200 ml of ethyl acetate and washed with a saturated solution of NH4Cl (2×150 ml), then with water and brine. The organic phase was dried and concentrated to give the crude product as a 4/1 mixture of 4a/4b compounds. Purification by column chromatography (cyclohexanelethyl acetate 80/20) gave the title 4a (2.16 g) and the 4b (0.5 g) compounds as colourless oils.
- Intermediate 4a
- NMR (CDCl3) δ (ppm) 7.72 (d, 2H), 7.56 (d, 1H), 7.38 (t, 2H), 7.16 (t, 1H), 6.6 (m, 1H), 6.50 (dd, 1H), 6.49 (d, 1H), 4.88 (d, 1H), 4.26 (m, 3H), 3.87 (t, 2H), 2.79 (m, 4H), 1.30 (t, 3H)
- Intermediate 4b
- NMR (CDCl3) δ (ppm) 7.69 (d, 2H), 7.52 (d, 1H), 7.38 (t, 2H), 7.17 (t, 1H), 6.47 (d, 1H), 6.44 (dd, 1H), 5.98 (m, 1H), 5.00 (d, 1H), 4.22 (m, 2H), 4.13 (m, 1H), 3.84 (t, 2H), 3.2-3.6 (m, 2H), 2.85 (m, 2H), 1.26 (t, 3H)
- Intermediate 5
- (1R)-2-(tert-butoxy)-1-methyl-2-oxoethyl-2-(5-chloro-2-iodoanilino)-4-pentenoate (5a) and (1R)-2-(tert-butoxy)-1-methyl-2-oxoethyl-2-(5-chloro-2-iodoanilino)-4-pentenoate (5b)
- A solution of intermediate 1-tert-butyl-(R)-2(oxoacetoxy)-2-methyl acetate (4.1 g) in toluene (200 ml) was refluxed in a Dean-Stark apparatus for 2 hrs. After cooling to room temperature, 5-chloro-2-iodoaniline (4.3 g) was added, and the solution refluxed in the presence of MgSO4 for 3 hrs. The clear solution was cooled, filtered through cotton to eliminate the MgSO4, concentrated to dryness and re-dissolved in dichloromethane (150 ml). The solution was cooled to −78° C., and TiCl4 (1.9 ml) was added slowly from a syringe. After 15 min, allyl tributyltin (7.9 ml) was added, and the resulting black suspension was stirred for 1 hr. It was then poured onto ethyl acetate (300 ml), and saturated NH4Cl (150 ml) was added. The organic phase was separated, washed with water and brine, dried and concentrated. Final purification by column chromatography (cyclohexanelethyl acetate 95/5) afforded the title compound (4.1 g) (65/35 mixture of diastereomers) as a colourless oil (7.01 g)
- NMR (CDCl3) δ (ppm) 7.54 (1H), 6.46 (dd, 1H), 5.86 (m, 1H), 5.3-5.2 (m, 2H), 5.03 (m, 1H), 4.77 (bd, 1H), 4.16 (m, 1H), 2.8-2.68 (m, 2H), 1.50 (d, 3H), 1.45 (s, 9H)
- Intermediate 5a
- (1R)-2-(tert-butoxy)-1-methyl-2-oxoethyl-2-(5-chloro-2-iodoanilino)-4-pentenoate
- To a solution of allyltributyl tin (3.3 g) in dry DCM (100 ml) a 1M solution in DCM of SnCl4 (10 ml) was added at −78° C. The mixture was stirred for 20 min, then intermediate 2-[2-(5-Chloro-2-iodo-phenylimino)-acetoxy]-1-(R)-methyl-acetic acid terbutyl ester (2.39 g) in dry DCM (50 ml) was added. The reaction was allowed to react at −78° C. for 20 min, then a saturated solution of NH4Cl was added and the resulting mixture was extracted with ethyl acetate (2×200 ml). The organic layer was washed with a solution of KF 10% in water, then diethyl ether was added and the resulting solid was filtered.
- The solution was dried and evaporated under vacuum. Final purification by flash chromatography (CH/EA 95:5) give the title compound as pure diastereomer as a colourless oil (1.3 g).
- NMR (CDCl3): 7.55 (d, 1H); 6.47 (d, 1H); 6.43 (d, 1H); 5.88 (m, 1H); 5.27 (m, 2H); 5.05 (q, 1H); 4.78 (d, 1H); 4.18 (m, 1H0; 2.74 (m, 2H); 1.52 (d, 3H); 1.67 (s, 9H).
- IR (CDCl3): 3379, 1740
- Intermediate 6
- (1R)-2-(tert-butoxy)-1-methyl-2-oxoethyl-2-(5-chloro-2-iodoanilino)-4-oxobutanoate (6a) and (1R)-2-(tert-butoxy)-1-methyl-2-oxoethyl-2(5-chloro-2-iodoanilino)-4-oxobutanoate (6b)
- A solution of intermediate 5 (7.1 g) in dichloromethane (200 ml) was cooled to −78° C. and ozone was bubbled through it until the solution turned red. Triphenylphosphine (8 g) was then added, and the reaction allowed to stir for 2 hrs, without control of the temperature. The crude mixture was evaporated to dryness and purified repeatedly by column chromatography ((cyclohexanelethyl acetate 85/15) to afford the title compound 6a (2.75 g) and 6b (0.87 g) as colourless oils.
- compound 6a:
- NMR (CDCl3) δ (ppm) 9.85 (t, 1H), 7.57 (d, 1H), 6.58 (d, 1H), 6.51 (dd, 1H), 5.04 (q, 1H), 4.96 (d, 1H), 4.62 (m, 1H), 3.13 (dd, 2H), 1.55-1.42 (m, 12 H)
- IR (CDCl3) (cm−1) 1740
- compound 6b:
- NMR (CDCl3) δ (ppm) 9.81 (t, 1H), 7.57 (d, 1H), 6.60 (d,1H), 6.52 (dd, 1H), 5.02 (q, 1H), 4.95 (d, 1H), 4.55 (m, 1H), 3.11 (m, 2H), 1.55-1.43 (m, 12H).
- IR (CDCl3) (cm−1) 1740
- Intermediate 6a
- (1R)-2-(tert-butoxy)-1-methyl-2-oxoethyl-2-(5-chloro-2-iodoanilino)-4-oxobutanoate
- The title compound was obtained starting from intermediate 5a following the same procedure described for intermediate 6.
- Intermediate 7
- (E)-(1R)-2-(tert-butoxy)-1-methyl-2-oxoethyl 2-(5-chloro-2-iodoanilino)-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)butanoate (Diastereoisomer A)
- To a solution of intermediate 6a (2.7 g) in acetonitrile (60 ml) 2b (3 g) and DBU (1 ml) were added and the mixture was reacted at −20° C. overnight. It was then taken up with ethyl acetate (300 ml) and washed with 1N HCl, water and brine, dried and concentrated. Final purification by column chromatography (cyclohexanelethyl acetate 85/15) afforded the title compound (2.1 g) as a white solid.
- m.p. 36-39°, [α]D 22° (c=0.160% w/v in DMSO)
- NMR (CDCl3) δ (ppm) 7.72 (d, 2H), 7.55 (d, 1H), 7.38 (t, 2H), 7.15 (t, 1H), 6.66 (m, 1H), 6.49 (dd, 1H), 6.48 (d, 1H), 5.05 (m, 1H), 4.81 (d, 1H), 4.30 (m, 1H), 3.87 (t, 2H), 3.0 (m, 2H), 2.75 (m, 2H), 1.51 (d, 3H), 1.45 (s, 9H).
- Intermediate 8
- (−)-(1R)-2-(tert-butoxy)-1-methyl-2-oxoethyl 7-chloro-4-(1-phenyl-Δ3-pyrrolin-2one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylate (8a)
- (−)7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinoline 2-carboxylic acid, [1-(R)-(1-tert-butoxycarbonyl)]ethyl Ester (8b)
- To a solution of intermediate 7 (2.1 g) in DMF (40 ml) Pd(PPh3)4 (0.393 g) and triethylamine (0.95 ml) were added and the mixture was heated to 150° C. for 1 hr. The crude solution was taken up with ethyl acetate and washed with 1N HCl, water and brine, dried and evaporated. Final purification by column chromatography (cyclohexane/dichloromethanelethyl acetate 50/40/10) afforded the title compound 8a (0.7 g) as a white solid.
- m.p.=69-73° C.
- [α]D−70.1° (c=0.190% w/v in DMSO)
- NMR (DMSO) δ (ppm) 7.80 (m, 2H), 7.39 (m, 2H), 7.12 (m, 1H), 6.82 (d, 1H), 6.77 (d, 1H), 6.70 (m, 1H), 6.49 (dd, 1H), 6.46 (bs, 1H), 4.93 (q, 1H), 4.49 (m, 2H), 4.02 (m, 1H), 3.87 (m, 1H), 2.44 (m, 1H), 2.00 (m, 1H), 1.39 (s, 9H), 1.38 (d, 3H).
- IR (Nujol) (cm−1) 3380, 1741, 1681, 1601 and the title compound 8b (0.8 g) as a yellow solid.
- m.p.=59-64° C.
- [α]D−76.2° (c=0.510% w/v in DMSO)
- NMR (DMSO) δ (ppm) 7.73 (m, 2H), 7.36 (m, 2H), 7.21 (d, 1H), 7.11 (m, 1H), 6.98 (da, 1H), 6.75 (d, 1H), 6.57 (dd, 1H), 4.70 (q, 1H), 4.24 (m, 2H), 3.84 (m, 1H), 3.75 (m, 1H), 3.18 (m, 1H), 3.05 (m, 1H), 2.94 (m, 1H), 1.25 (s, 9H), 1.23 (d, 3H)
- Intermediate 9
- (±)-E-Ethyl 2-(5-chloro-2-iodoanilino)-4-(2-oxo-1-phenyl piperidinylidene) Butanoate
- To a solution of tributyl-3-(1-phenyl-2-piperidinone) phosphonium bromide (0.83 g) in acetonitrile (20 ml) DBU (0.27 ml) was added and after 15 min a solution of the intermediate 2 (0.35 g) in acetonitrile (20 ml). The reaction mixture was stirred for 30 min, then diluted with ethyl acetate and washed with a 1N solution of HCl and brine. The organic phase was dried and concentrated to give the crude product which was purified by flash column chromatography to obtain the title compound (0.29 g) as pale yellow foam.
- NMR (CDCl3) δ (ppm) 7.56 (dd, 1H), 7.38 (dd, 2H), 7.27 (dd, 2H), 7.24 (t, 1H), 6.93 (t, 1H), 6.50-6.47 (m, 2H), 4.85 (d, 1H), 4.25 (q, 2H), 4.22 (m, 1H), 3.71 (m, 2H), 2.76, (m, 2H), 2.59 (m, 2H), 2.01 (m, 2H), 1.29 (t, 3H)
- Intermediate 10
- (±)-Ethyl 2-(5-chloro-2-iodoanilino)-4-(2-oxo-1-(pyridin-3-yl)-pyrrolidin-3-ylidene)butanoate
- To a solution of the (1-(pyridin-3-yl)-2-oxo-pyrrolidin-3-yl) tributylphosphonium bromide (0.93 g) in acetonitrile (10 ml) DBU (0.22 ml) was added and after 10 min a solution of the intermediate 2 (0.46 g) in acetonitrile (10 ml). The reaction mixture was stirred for 3 hr. then diluted with ethyl acetate and washed with a saturated solution of NH4Cl and brine. The organic phase was dried and concentrated to give the crude product which was purified by flash column chromatography to obtain the title compound (0.47 g) as a mixture of E/Z isomer (80/20)
- MS (m/z) 526
- Intermediate 11
- (±)-E-Ethyl 2-(3,5-dichloro-2-iodoanilino)-4-(2-oxo-1-phenyl-3-pyrrolidinylidene) Butanoate (11a);(±)-Z-Ethyl 2-(3,5-dichloro-2-iodoanilino)-4-(2-oxo-1-phenyl-3-pyrrolidinylidene) Butanoate (11b)
- To a solution of intermediate 2a in acetonitrile (10 ml) at r.t 2b (0.726 g) and DBU (0.33 ml) were added and stirring was continued overnight at −20° C. The crude solution was poured into 20 ml of ethyl acetate and washed first with a saturated solution of NH4Cl (2×15 ml), then with water and brine. The organic phase was dried and concentrated to give the crude product as a 4/1 mixture of Z/E isomers. Purification by column chromatography (cyclohexane/ethyl acetate 85/15) gave the title compound 11a (0.498 g) and the title compound 11b (0.122 g) as colourless oils.
- intermediate 11a
- NMR (CDCl3) δ (ppm) 7.78 (d, 2H), 7.39 (t, 2H), 7.16 (t, 1H), 6.90 (d, 1H), 6.58 (m, 1H), 6.36 (d, 1H), 5.22 (d, 1H), 4.26 (m, 3H), 3.87 (t, 2H), 2.79 (m, 4H), 1.30 (t, 3H)
- IR (CDCl3) (cm−1) 3370, 1738, 1697, 1671.
- MS (m/z) 559.
- intermediate 11b
- NMR (CDCl3) δ (ppm) 7.69 (d, 2H), 7.38 (t, 2H), 7.17 (t, 1H), 6.84 (d, 1H), 6.34 (d, 1H), 5.96 (m, 1H), 5.34 (d, 1H), 4.22 (m, 2H), 4.12 (m, 1H), 3.84 (t, 2H), 3.63-3.27 (m, 2H), 2.85 (t, 2H), 1.26 (t, 3H)
- IR (CDCl3) (cm−1) 1733, 1685.
- MS (m/z) 559.
- Intermediate 12
- -(1R)-2-(tert-butoxy)-1-methyl-2-oxoethyl 2-(5-chloro-2-iodoanilino)-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)butanoate (Diastereoisomer B)
- To a solution of intermediate 6b (0.87 g) in acetonitrile (20 ml) tributyl-3-(N-phenyl-1-pyrrolidonyl)phosphonium bromide (1.6 g) and DBU (0.33 ml) were added and the mixture was reacted at −20° C. overnight. It was then taken up with ethyl acetate (100 ml) and washed with 1N HCl, water and brine, dried and concentrated. Final purification by column chromatography (cyclohexanelethyl acetate 85/15) afforded the title compound (0.47 g) as a white solid oil.
- m.p.=38-42° C.
- NMR (CDCl3) δ (ppm) 7.72 (d, 2H), 7.55 (d, 1H), 7.38 (t, 2H), 7.16 (t, 1H), 6.60 (m, 1H), 6.56 (d, 1H), 6.49 (dd, 1H), 5.03 (q, 1H), 4.80 (d, 1H), 4.33 (m, 1H), 3.88 (t, 2H), 2.9 (m, 2H), 2.75 (m, 2H), 1.48 (d, 3H), 1.44 (s, 9H).
- IR (CDCl3) (cm−1) 3375, 1738, 1693, 1665
- Intermediate 13
- -(1R)-2-(tert-butoxy)-1-methyl-2-oxoethyl 7-chloro-4-(1-phenyl-Δ3-pyrrolin-2one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylate (diastereoisomer B)
- To a solution of intermediate 12 (0.46 g) in DMF (8 ml) Pd(PPh3)4 (0.043 g) and triethylamine (0.21 ml) were added and the mixture was heated to 150° C. for 1 hr. The crude solution was taken up with ethyl acetate and washed with 1N HCl, water and brine, dried and evaporated. Final purification by column chromatography (cyclohexane/dichloromethane/ethyl acetate 50/40/10) afforded the title compound (0.114 g) as a white solid.
- m.p.=62-67° C.
- NMR (DMSO) δ (ppm) 7.79 (m, 2H), 7.38 (m, 2H), 7.11 (t, 1H), 6.81 (d, 1H), 6.77 (d, 1H), 6.70 (d, 1H), 6.55 (bs, 1H), 6.48 (dd, 1H), 4.90 (q, 1H), 4.5 (m, 2H), 3.99 (m, 1H), 3.84 (t, 1H), 2.35 (m 1H), 2.02 (m, 1H), 1.39 (s, 12H).
- Intermediate 14
- 2,4-dibromo-N-(4-(tert-butoxycarbonylamino)phenyl)-butyramide
- To the derivative 2,4-dibromobutyryl bromide (3.1 g) in dry dichloromethane (60 ml) pyridine (3.2 ml) was added, the mixture was kept at 0° C. under a nitrogen atmosphere for 10 minutes and then the N-t-butoxy carbonyl-1,4 phenylene diamine (2.08 g) was dropped. After 1 hour the mixture was poured into a saturated solution of NH4Cl (200 ml) extracted with EA (3×150 ml) and the organic phase washed with brine (200 ml), dried and concentrated in vacuum, the crude was purified by flash chromatography (eluting with CH/EA 80: 20) to give of the title compound as a yellow foam (3.5 g). T.l.c. CH/EA 8:2, Rf=0.53.
-
- Intermediate 15
- 3-bromo-1-(4-(tert-butoxyarbonylamino)phenyl-2-oxo-pyrrolidine
- To a solution of intermediate 14 (3.5 g) in dry THF (50 ml) cooled (0° C.), a solution of LHMDS (9.6 ml of a 1M solution in tetrahydrofuran) was added drop-wise. The mixture was stirred under nitrogen until the temperature reached r.t for 2 hours. Then it was quenched into a saturated solution of NH4Cl (200 ml) extracted with EA (3×150 ml) and the organic extracts were washed with brine (200 ml), dried and concentrated in vacuum. The mixture was purified by flash chromatography (eluting with CH/EA 8:2) to give the title compound (2.6 g). T.l.c. CH/EA 8:2, Rf=0.31. 1H-NMR: 7.57 (d); 7.39 (d); 6.49 (sa); 4.59 (m); 4.03 (m); 3.81 (m); 2.73 (m); 2.46 (m); 1.53(s).
- Intermediate 16
- (+/−)-Z-Ethyl2-(5-chloro-2-iodoanilino)-4-(2-oxo-1-(4-tert-butoxycarbonylamino)phenyl-pyrrolidin-3-ylidene)butanoate
- A solution of intermediate 15 (2.6 g) in dry DMF (100 ml) and tributylphosphine was refluxed at 110° C. under a nitrogen atmosphere for 4 h, until reaction completion (TLC). The mixture was concentrated in vacuum to give the crude 1-(4-tert-butoxycarbonylamino)phenyl-2-oxo-pyrrolidin-3-yl-tributylphosphonium bromide (1.75 g) which was dissolved in dry CH3CN (100 ml) was cooled at −30° C. and stirred under a nitrogen atmosphere, then DBU (0.44 ml) and intermediate 2 (1.0 g) were added. The mixture was stirred for 1 h then was poured into a saturated solution of NH4Cl (200 ml) extracted with EA (3×150 ml) and the organic extracts were washed with brine (200 ml), dried and concentrated in vacuum to give a yellow oil which was purified by flash chromatography (eluting with CH/EA 80:20) to give the title compound (0.085 g) as a white solid. T.l.c. CH-EA (7:3), Rf=0.23 IR: 1727 and 1695 (C═O) cm−1. 1H-NMR: 7.64 (d); 7.53 (d); 7.38 (d); 6.48 (d); 6.47 (sa); 6.45 (dd); 5.97(m); 5.02(d); 4.23 (m); 4.14 (m); 3.8(t); 3.6 (m); 3.3 (m); 2.85 (m); 1.53(s); 1.27(t).
- Intermediate 17
- (±)-Z-Benzyl 2-(5-chloro-2-iodoanilino)-4-(2,5-dioxo-1-phenyl-imidazolidin-4-ylidene)butanoate
- To a solution of the derivative N-(phenylaminocarbonyl)α-phosphonoglycine-trimethyl ester (0.1 g) in acetonitrile (10 ml) DBU (0.1 ml) was added and after 10 min a solution of the (+/−)-2-(5-Chloro-2-iodo-phenylamino)-4-oxo-butyric acid benzyl ester (0.1 g) in acetonitrile (2 ml). The reaction mixture was stirred for 1½ hr, then diluted with ethyl acetate and washed with a 1N solution of HCl and brine. The organic phase was dried and concentrated to give the crude product which was purified by flash column chromatography to obtain the title compound (0.065 g)
- NMR (DMSO) δ (ppm) 10.80 (s, 1H), 7.65 (d, 1H), 7.7-7.3 (m, 10H), 6.75 (d, 1H), 6.55 (dd, 1H), 5.70 (t, 1H), 5.20 (s, 2H), 5.07 (d, 1H), 4.72 (m, 1H), 2.86 (t, 2H
- IR (Nujol) (cm−1) 3339, 3160, 1768, 1721, 1691
- Intermediate 18
- (±)-Benzyl 7-chloro-4-(2,5-dioxo-1-phenyl-imidazolidin-4-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylate
- To a solution of intermediate 17 (0.065 g) in DMF (5 ml) Pd(PPh3)4 (16 mg) and TEA (0.05 ml) were added and the resulting solution was heated to 110° C. for 1 h. The crude solution was poured into ethyl acetate and washed with a 1N solution of HCl and brine. The organic phase was dried and concentrated to give the crude product which was purified by flash column chromatography to obtain the title compound (0.015 g) as yellow powder.
- m.p.>220° C.
- NMR (DMSO) δ (ppm) 10.5 (s, 1H), 7.5-7.2 (m, 11H), 7.16 (bd, 1H), 6.75 (d, 1H), 6.58 (dd, 1H), 5.2-5.01 (dd, 2H), 4.40 (m, 1H), 4.25 (dd, 1H), 2.83 (dd, 1H).
- IR (Nujol) (cm−1) 3378, 1752, 1728, 1704
- Intermediate 19
- 2-[2-(5-Chloro-2-iodo-phenylimino)-acetoxy]-1-(R)-methyl-acetic Acid Isobutyl Ester
- To a solution of acrylic acid 1-isobutoxycarbonyl-1-(R)-methyl-methyl ester (3.7 g) in THF/H2O OsO4 4% in H20 (4 ml) was added. The black suspension was then treated with NalO4 (10.5 g) by portions. After 5 hrs, the solution was taken up with ethyl acetate (2×50 ml) and washed with water (2×50 ml). The organic phase evaporated under vacuum and the crude mixture was purified by flash chromatography (CH/EA 1:1) to afford 2-(2-Oxo-acetoxy)-1-(R)-methyl-acetic acid isobutyl ester as colourless oil (3 g). 24.8 g of 2-(2-Oxo-acetoxy)-1-(R)-methyl-acetic acid isobutyl ester was dissolved in toluene (1000 ml) and refluxed in a Dean-Stark apparatus for 2 hrs. After cooling to room temperature, 5-chloro-2-iodoaniline (22 g) was added, and the solution refluxed in the presence of MgSO4 for 3 hrs. The clear solution was cooled, filtered through cotton to eliminate the MgSO4, concentrated to dryness to obtain the title compound (38 g) as a yellow oil.
- NMR (CDCl3) δ (ppm) 7.83 (1H, d), 7.79 (s 1H), 7.02(dd, 1H), 6.96 (d, 1H), 5.373 (q 1H), 4.00 (m, 2H), 2.00 (m, 1H), 1.67 (d, 3H), 0.96 (2d, 6H)
- IR (CDCl3): 1749, 1730
- Intermediate 20
- 2-(5-Chloro-2-iodo-phenylamino)-4-oxo-butyric Acid 1-isobutoxycarbonyl-1(R)-methyl-methyl Ester (20a and 20b)
- A solution of intermediate 19 (38 g) in toluene (1 ml) was cooled to −20° C. and Yb(OTf)3 (16.5 g) was added and, after a few minutes, vinyloxy trimethylsilane (12.5 g) dissolved in toluene (50 ml) was added drop-wise. The bath was removed and the reaction allowed to stir for 2 hrs. The crude mixture was taken up with ethyl acetate (500 ml) and the organic phase was washed with a saturated solution of ammonium chloride (300 ml) and evaporated. Then, the mixture was purified by column chromatography (cyclohexanelethyl acetate 85/15) to afford the title compounds 20a (14 g) and 20b (4 g) as colourless oils.
- Intermediate 20a
- NMR (CDCl3) δ (ppm) 9.85 (s, 1H), 7.57 (d, 1H), 6.58 (d, 1H), 6.51 (dd, 1H), 5.19 (m, 1H), 4.97 (d, 1H), 4.63 (m, 1H), 3.93 (m, 2H), 3.24-3.04 (m, 2 H), 1.94 (m, 1H), 1.53 (d, 3H), 0.93 (dt, 3H); 0.91 (d, 3H).
- IR (CDCl3) (cm−1) 1742, 1740
- Intermediate 20b
- NMR (CDCl3) δ (ppm) 9.81 (s, 1H), 7.57 (d, 1H), 6.60 (d, 1H), 6.52 (dd, 1H), 5.17 (m, 1H), 4.95 (d, 1H), 4.57 (m, 1H), 3.92 (m, 2H), 3.11 (m, 2H); 1.92 (m, 1H); 1.50 (d, 3H); 0.90 (d, 6H).
- IR (CDCl3) (cm−1) 3375, 1734
- Intermediate 21
- (E)-2-(5-Chloro-2-iodo-phenylamino)-4-(2-oxo-1-phenyl-pyrrolidin-3-ylidene)-butyric acid 1-isobutoxycarbonyl-1-(R) methyl-methyl Ester
- To a solution of intermediate 3 (14.45 g) in acetonitrile (200 ml) DBU (4.43 ml) was added at room temperature and the mixture was stirred for 10 min. The mixture was then cooled at −25° C. and intermediate 31a (12.98 g) in 60 ml of CH3CN was added drop-wise in 15 min. Then the reaction was stirred at this temperature for 2 h. Then the mixture was taken up with ethyl acetate (100 ml) and the organic phase washed with a saturated solution of NH4Cl (150 ml), and HCl 2% (200 ml) and brine (2×200 ml). The solution was then dried and concentrated. Final purification by column chromatography (cyclohexanelethyl acetate/CH2C/2 7/0.5/2.5) afforded the title compound (11.04) as a white foam.
- NMR (CDCl3) δ (ppm) 7.73 (m, 2H), 7.56 (d, 1H), 7.38 (t, 2H), 7.16 (m, 1H), 6.67 (m, 1H), 6.50(dd, 1H), 6.49 (s, 1H), 5.20 (q, 1H), 4.81 (d, 1H), 4.33 (m, 1H), 3.94 (d, 2H), 3.88 (t, 2H), 3.0-2.74 (m, 4H), 1.94 (m, 1H), 1.57 (d, 3H); 0.91 (d, 6H).
- IR (CDCl3); 1696, 1670 cm−1
- Intermediate 22
- 7-Chloro-4-(2-oxo-1-phenyl-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-quinoline-2-carboxylic Acid, [1R)-methyl-1-isobutoxycarbonyl]-methyl Ester (Diastereoisomer A)
- To a solution of intermediate 21 (9.55 g) in toluene (130 ml), Pd(PPh3)4 (3.52 g) and triethylamine (5.1 ml) were added in portions and the mixture was heated to 110° C. for 3.5 hr. The crude solution was taken up with ethyl acetate (600 ml) and washed with NH4Cl and brine, dried and evaporated. Purification by column chromatography (cyclohexaneldichloromethane/ethyl acetate 6.5/3/0.5) afforded the title compound (6.08 g) as a yellow foam.
- NMR (DMSO) δ (ppm) 7.71 (d, 2H), 7.35 (t, 2H), 7.20 (d, 1H), 7.11 (t, 1H), 7.00 (s,1H), 6.74 (d, 1H), 6.57 (dd, 1H), 4.89 (q, 1H), 4.24 (m, 2H), 3.84-3.60 (m, 4H), 3.2-2.8 (m, 3H), 1.70 (m, 1H), 1.24 (d, 3H); 0.73 (d, 6H).
- IR (nujol): 3377, 1746, 1670
- Intermediate 23
- 7-Chloro-4-(2-oxo-1-phenyl-2,5-dihydro-1H-pyrrol-3-yl)-1,2,3,4-tetrahydro-quinoline-2-carboxylic Acid, [1-(R)-methyl-1-isobutoxycarbonyl]-methyl Ester
- To a solution of intermediate 22 (3.67 g) in DMF (50 ml) Pd(PPh3)4 (0.340 g) and triethylamine (2 ml) were added and the mixture was heated to 110° C. for 2 hrs. The crude solution was taken up with ethyl acetate (2×200 ml) and washed with NH4Cl and brine, dried and evaporated. Final purification by column chromatography (cyclohexane/dichloromethane/ethyl acetate 6.5/3/0.5) afforded the title compound (1.289 g) as a yellow foam.
- NMR (DMSO) δ (ppm) 7.79 (d, 2H), 7.38 (t, 2H), 7.11 (t, 1H), 6.79 (d, 1H), 6.57 (d, 1H), 6.74 (d, 1H); 6.47 (dd, 1H); 6.47 (m, 1H); 5.10 (q, 1H); 4.49 (m, 2H); 4.06 (m, 1H); 3.92-3.82 (m, 3H); 2.45 (m, 1H); 2.019 (m, 1H); 1.84 (m, 1H); 1.42 (d, 3H); 0.84 (d, 6H).
- IR (nujol): 3375, 1749, 1683.
- Intermediate 24
- 2-(3,5-Dichloro-2-iodo-phenylamino)-4-oxo-butyric Acid 1-n-butoxycarbonyl-1(S)-methyl-methyl Ester (24a and 24b)
- To a solution of intermediate Acrylic acid 1-n-butoxycarbonyl-1-(S)-methyl-methyl ester (4.9 g) in THF/H2O (100 ml, 2/1) OsO4 4% in H20 (2.8 g) was added. The black suspension was then treated with NalO4 (13 g) by portions. After 5 hrs, the solution was taken up with ethyl acetate (2×50 ml) and washed with water (2×50 ml). The organic phase evaporated under vacuum and the crude mixture was purified by flash chromatography (CH/EA 1:1) to afford the 2-(2-oxo-acetoxy)-1-(S)-methyl-acetic acid n-butyl ester as a colourless oil (4.85 g). (2.5 g) of which was dissolved in toluene (200 ml) and refluxed in a Dean-Stark apparatus for 2 hrs. After cooling to room temperature, 3,5-dichloro-2-iodoaniline (2.46 g) was added, and the solution refluxed in the presence of MgSO4 for 3 hrs. The clear solution was cooled, filtered through cotton to eliminate the MgSO4, concentrated to dryness to obtain (2-[2-(5-chloro-2-iodo-phenylimino)acetoxy]-1-(S)-methyl-acetic acid n butyl ester (4 g,) as a yellow oil.
- A solution of such a yellow oil in CH3CN (70 ml) was cooled to −30° C. and Yb(OTf)3 (2.1 g) was added and, after a few minutes, vinyloxy trimethylsilane (1.1 g) dissolved in CH3CN (20 ml) was added, drop-wise. The reaction was stirred for 10 min. The crude mixture was taken up with ethyl acetate (500 ml) and the organic phase was washed with a saturated solution of ammonium chloride (2×50 ml) and evaporated. Then, the mixture was purified by column chromatography (cyclohexanelethyl acetate 90/10) to afford the title compounds 24a (1.4 g) and 24b (0.7 g) as colourless oils.
- Intermediate 24a
- NMR (CDCl3) δ (ppm) 9.84 (t, 1H), 6.92 (d, 1H); 6.45 (d, 1H); 5.33 (da, 1H); 5.17 (q, 1H); 4.60 (m, 1H); 4.14 (m, 2H); 3.34-3.06 (m, 2H); 1.6 (m, 2H); 1.52 (d, 3H); 1.37 (m, 2H); 0.93 (t, 3H).
- IR (CDCl3) (cm−1) 3370, 1742
- Intermediate 24b
- NMR (CDCl3) δ (ppm) 9.80 (s, 1H), 6.92 (d, 1H); 6.47 (d, 1H); 5.3 (da, 1H); 5.15 (q, 1H); 4.55 (m, 1H); 4.14 (m, 2H); 3.13 (m, 2H); 1.57 (m, 2H); 1.49 (d, 3H); 1.34 (m, 2H); 0.91 (t, 3H).
- IR (CDCl3) (cm−1) 3370, 1744.
- Intermediate 25
- (E)-2-(3,5-Dichloro-2-iodo-phenylamino)-4-(2-oxo-1-phenyl-pyrrolidin-3-ylidene)-butyric acid 1-n-butoxycarbonyl-1-(S) methyl-methyl Ester (Diastereoisomer A)
- To a solution of intermediate 2a (0.893) in acetonitrile (20 ml) DBU (0.25 ml) was added at room temperature and the mixture was stirred for 10 min. The mixture was then cooled at −25° C. and intermediate 6b (0.8 g) in 10 ml of CH3CN was added drop-wise in 15 min. Then the reaction was stirred at this temperature for 30 min. Then the mixture was taken up with ethyl acetate (50 ml) and the organic phase washed with a saturated solution of NH4Cl (50 ml), and HCl 2% (10 ml) and brine (2×20 ml). The solution was then dried and concentrated. Final purification by column chromatography (cyclohexanelethyl acetate 8/2) afforded the title product (0.734 g) as a white foam.
- NMR (CDCl3) δ (ppm) 7.72 (d, 2H), 7.39 (t, 2H), 7.17 (t, 1H); 6.92 (d, 1H); 6.60 (m, 1H); 6.43 (d, 1H); 5.16 (q, 1H); 5.14 (d, 1H); 4.34 (d, 1H); 4.15 (m, 2H); 3.89 (t, 2H); 2.75-2.4 (m, 4H); 1.60 (m, 2H); 1.53 (d, 3H); 1.34 (m, 2H); 0.91 (t, 3H).
- IR (CDCl3); 3377, 1744, 1697, 1672 cm−1
- Intermediate 26
- 5,7-Dichloro-4-(2-oxo-1-phenyl-2,5-dihydro-1H-pyrrol-3-yl)-1,2,3,4-tetrahydro-quinoline-2-carboxylic Acid, [1(S)-methyl-1-n-butoxycarbonyl]-methyl Ester (26a)5,7-Dichloro-4(2-oxo-1-phenyl-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydroquinoline-2-carboxylic Acid, [1-(S)-methyl-1-n-butoxycarbonyl]-methyl Ester (26b)
- To a solution of intermediate 25 (0.734 g) in DMF (20 ml) Pd(OAc)2 (0.110 g) and triethylamine (0.37 ml) were added in portions, and the mixture was heated to 120° C. for 3 hr. The crude solution was taken up with ethyl acetate (1000 ml) and washed with NH4Cl and brine, dried and evaporated. Final purification by column chromatography (cyclohexaneldichloromethane/ethyl acetate 7/2.5/0.5) afforded the title compound 26a (0.35 g) and 26b (0.06 g) as a yellow foam.
- Intermediate 26a
- NMR (DMSO) δ (ppm) 7.80 (d, 2H); 7.38 (t, 2H); 7.11 (t, 1H); 6.89 (d, 1H); 6.83 (s, 1H); 6.68 (d, 1H); 6.47 (d, 1H); 5.07 (q, 1H); 4.48 (m, 2H); 4.11 (m, 1H); 4.06 (t, 2H); 3.8 (dd, 1H); 2.3-1.8 (m, 2H); 1.52 (m, 2H); 1.40 (d, 3H); 1.54 (m, 2H); 1.3 (m, 2H); 0.84 (t, 3H).
- IR (nujol): 3374, 1740, 1683 cm−1
- Intermediate 26b
- NMR (DMSO) δ (ppm) 7.69 (d, 2H); 7.39 (t, 2H); 7.33 (d, 1H); 7.15 (t, 1H); 6.71 (d, 1H); 6.62 (d, 1H); 4.72 (d, 1H); 4.40 (q, 1H); 4.40 (m, 1H); 3.94 (t, 2H); 3.76 (t, 1H); 3.60 (q, 1 H); 3.12 (m, 1H); 2.35 (m, 1H); 2.21 (dd, 1H); 1.42 (m, 2H); 1.21 (m, 2H); 0.97 (d, 3H); 0.82 (t, 3H).
- IR (nujol): 3377, 1746, 1684, 1594cm−1
- (±)-Sodium 7-chloro-4-(1-phenyl-Δ3-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylate
- To a solution of example 31a (540 mg) in IMS (5% methanol in absolute ethanol, 7 ml) NaOH (1N, 1.4 ml) was added and stirring continued for 2 hrs. The resulting solution was dried on the rotary evaporator and the resulting solid was triturated with diethyl ether. After filtration and drying the title compound (440 mg) was obtained as an off-white solid.
- m.p.>200° C.
- NMR (DMSO) δ (ppm) 7.80 (m, 2H), 7.39 (m, 2H), 7.11 (m, 1H), 6.80 (d, 1H), 6.72 (d, 1H), 6.36 (d, 1H), 6.34 (dd, 1H), 5.71 (s, 1H), 4.42 (m, 2H), 3.77 (m, 1H), 3.13 (m, 1H), 2.29 (m, 1H), 1.44 (m, 1H).
- IR (Nujol) (cm−1) 1672, 1600.
- (−)-Sodium 7-chloro-4-(1-phenyl-Δ3-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylate
- To a solution of intermediate 8a (690 mg) in THF/H2O (1/1) (14 ml) LiOH (65 mg) was added and stirring continued for 1 h. The resulting solution was concentrated to dryness, taken up with ethyl acetate and 1N HCl was added. After vigorous stirring, the organic phase was separated, washed with water and brine and concentrated. The resulting solid was dissolved in THF (15 ml) and treated with sodium ethylhexanoate (232 mg) for 30 min. After drying, the resulting solid was triturated with hot diethyl ether and filtered, to afford the title compound (160 mg) as a white solid.
- e.e.=99%
- [α]D=−102.3° (c=0.09% w/v in DMSO)
- m.p.>200° C.
- NMR (DMSO) δ (ppm) 7.80 (m, 2H), 7.39 (m, 2H), 7.11 (m, 1H), 6.80 (d, 1H), 6.72 (d, 1H), 6.36 (d, 1H), 6.34 (dd, 1H), 5.71 (s, 1H), 4.42 (m, 2H), 3.77 (m, 1H), 3.13 (m, 1H), 2.29 (m, 1H), 1.44 (m, 1H).
- IR (Nujol) (cm−1) 1672, 1600.
- (±)-Ethyl 7-chloro-4(1-phenyl-Δ3-5,6-dihydro-pyridin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylate (3a)
- (±)-Ethyl 7-chloro-4-(2-oxo-1-phenyl-3-piperidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylate (3b)
- To a solution of intermediate 9 (0.2 g) in DMF (5 ml) Pd(PPh3)4 (41 mg) and TEA (0.1 ml) were added and the resulting solution was heated to 110° C. for 2 hrs. The crude solution was poured into ethyl acetate and washed with a 1N solution of HCl and brine. The organic phase was dried and concentrated to give the crude product which was purified by flash column chromatography to obtain the title compound 3a (0.085 g) as a white powder.
- m.p.=131-133° C.
- NMR (DMSO) δ (ppm) 7.4-7.3 (m, 4H), 7.20 (t, 1H), 6.78 (d, 1H), 6.75 (d, 1H), 6.48 (dd, 1 H), 6.34 (bs, 1H), 5.99 (t, 1H), 4.13 (m, 2H), 3.97 (t, 1H), 3.93 (dd, 1H), 3.77 (m, 2H), 2.45 (m, 2H), 2.15 (m, 1H), 1.85 (m, 1H), 1.19 (t, 3H).
- IR (Nujol) (cm−1) 3392, 1723, 1659 and the title compound 3b (0.055 g) as pale yellow powder.
- m.p.=99-101° C.
- NMR (DMSO) δ (ppm) 7.4-7.2 (m, 5H), 7.01 (d, 1H), 6.93 (d, 1H), 6.68 (d, 1H), 6.52 (dd, 1H), 4.20 (m, 1H), 4.16-3.96 (m, 2H), 3.74-3.60, 3.40 (m, 2H), 2.9-2.5 (m, 3H), 2.0-1.6 (m, 2H), 1.14 (t, 3H).
- (±)-Ethyl 7-chloro-4-(1-pyridin-Δ3-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylate (4a)
- (±)-Ethyl 7-chloro-4-(2oxo-1-(pyridin-3-yl)-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylate (4b)
- To a solution of example 3 (0.47 g) in DMF (20 ml) Pd(PPh3)4 (100 mg) and TEA (0.38 ml) were added and the resulting solution was heated to 110° C. for 1½ h. The crude solution was poured into ethyl acetate and washed with a saturated solution of NH4Cl and brine. The organic phase was dried and concentrated to give the crude mixture which was dissolved in ethyl acetate (2 ml) and treated with petroleum (2 ml) the solid was filtered to give the title compound 4a (0.08 g) as a white powder.
- m.p.=132-134° C.
- NMR (DMSO) δ (ppm) 8.99 (d, 1H), 8.32 (dd, 1H), 8.21 (m, 1H), 7.41 (dd, 1H), 6.80 (d, 1H), 6.77 (m, 1H), 6.75 (d, 1H), 6.47 (dd, 1H), 6.45 (m, 1H), 4.56 (m, 1H), 4.50 (m, 1H), 4.2-4.02 (m, 2H), 3.99 (m, 1H), 3.81 (t, 1H), 2.31 (m, 1H), 1.97 (m, 1H), 1.18 (t, 3H).
- IR (Nujol) (cm−1) 3391, 1728, 1679
- The mother liquor was purified by flash chromatography to obtain a product which was triturated in cyclohexane to obtain title compound 4b (0.067 g, yellow powder).
- NMR (DMSO) δ (ppm) 8.94 (d, 1H), 8.34 (dd, 1H), 8.14 (m, 1H), 7.41 (dd, 1H), 7.19 (d, 1H), 7.00 (d, 1H), 6.73 (d, 1H), 6.56 (dd, 1H), 4.27 (m, 1H), 4.20 (m, 1H), 4.00 (m, 1H), 3.89 (m, 1H), 3.85 (m, 1H), 3.72 (m, 1H), 3.21 (m, 1H), 2.93 (m, 1H), 2.84 (m, 1H), 0.90 (t, 3H).
- IR (Nujol) (cm−1) 3366, 1734, 1676.
- (±)-Ethyl 5,7-dichloro-4-(1-phenyl-Δ3-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylate
- To a solution of intermediate 11 a (0.430 g) in DMF (10 ml) Pd(OAc)2 (11.6 mg) and TEA (0.12 ml) were added and the resulting solution was heated to 130° C. for 2 h. The crude solution was poured into 20 ml of ethyl acetate and washed first with a saturated solution of NH4Cl (2×15 ml), then with water and brine. The organic phase was dried with Na2SO4 and concentrated to give the crude product. Purification by column chromatography (cyclohexane/dichloromethane/ethyl acetate 60/30/10) gave the title compound (0.087 g) as an off-white solid.
- NMR (DMSO) δ (ppm) 7.81 (m, 2H), 7.40 (m, 2H), 7.13 (m, 1H), 6.91 (d, 1H), 6.75 (Sa, 1H), 6.68 (d, 1H), 6.45 (m, 1H), 4.46 (m, 2H), 4.17-4.10 (m, 3H), 3.79 (dd, 1H), 2.31 (m, 1H), 1.84 (m, 1H), 1.20 (t, 3H)
- IR (Nujol) (cm−1) 3390, 1724, 1678.
- (+/−)-Ethyl 7-chloro-4-(1-(4-tert-butoxycarbonylamino)-phenyl-Δ3-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylate
- A solution of intermediate 16 (0.085 g) in dry DMF (5ml) was stirred in the presence of TEA (0.018 ml) and Pd(OAc)2 (0.0015 g) under a nitrogen atmosphere at 110° C. for 1 h. The mixture was diluted with a saturated aqueous ammonium chloride solution (100 ml), and EA (100 ml); the organic layer was washed with brine (100 ml), dried and concentrated in vacuum. The crude mixture was purified by flash chromatography (eluting with CH/EA 8:2) to give the title compound as a yellow solid (0.050 g).
- T.l.c. CH-EA (8:2) Rf=0.30. 1H-NMR:9.30 (sa); 7.64 (d); 7.43 (d); 6.80 (d); 6.75 (d); 6.63 (m); 6.46 (dd); 6.42 (sa); 4.40 (m); 4.13 (m); 3.92 (m); 3.78 (m); 2.31 (m); 1.94 (m); 1.45 (s); 1.18(t).
- (+/−)-Ethyl 7-chloro-4-(1-(4-amino)-phenyl-Δ3-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylate
- To a solution of example 6 (0.070 g) in ethyl acetate (35 ml) HCl conc. (2.0 ml) was added. The mixture was stirred a r.t. under nitrogen atmosphere for 1 h. The mixture was poured into a saturated aqueous solution of NaHCO3 (100 ml) and extracted with EA (200 ml); the organic layer was dried and concentrated in vacuum. The crude mixture was purified by flash chromatography (eluting with CH/EA 1:1) to give the title compound as a yellow solid (0.043 g).
- T.l.c. EA Rf=0.289. IR:3388 (NH), 3161(NH2), 1718 and 1670 (C═O) cm−1.
-
- (+/−)-Ethyl 7-chloro-4-(1-(4-acetylamino)-phenyl-Δ3-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylate
- To a solution of example 7 (0.030 g) in pyridine dry (1 ml) Ac2O (0.012 ml) was added. The mixture was stirred at r.t. under nitrogen atmosphere for 30 minutes. The mixture was poured into a saturated aqueous solution of NH4Cl (50 ml) and extracted with EA (50 ml), the organic layer was dried and concentrated in vacuum. The crude mixture was triturated with EA to give the title compound as a white solid (0.025 g)
- T.l.c. CH/EA (1:1) Rf=0.33. IR:3401(NH), 1730, 1675, 1651 (C═O) cm−1. d
-
- (+/−)-Ethyl 7-chloro-4-(1-(4-methanesulfonylamino)-phenyl-Δ3-pyrrolin-2one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylate
- To a solution of example 7 (0.040 g) in CH2Cl2 dry (10 ml) DIPEA (0.021 ml) and CH3SO2Cl (0.008 ml) were added. The mixture was stirred at r.t. under nitrogen atmosphere for 1 h. The mixture was poured onto a saturated aqueous solution of NH4Cl (50 ml) and extracted with EA (50 ml), the organic layer was dried and concentrated in vacuum. The crude mixture was purified by flash chromatography (eluting with CH/EA (1:1) to give the title compound as a yellow solid (0.027 g).
- T.l.c. CH/EA (1:1) Rf=0.63. IR:3394(NH, 1726, 1680, 1635 (C═O), (C═C) cm−1.
-
- (+)-Ethyl 7-chloro-4-(2-oxo-1-((4-tert-butoxycarbonylamino) phenyl-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylate
- A solution of intermediate 16 (1.02 g) in dry DMF (100 ml) was stirred in the presence of TEA (0.018 ml) and Pd(PPh3)4 (0.184 g) under a nitrogen atmosphere at 110° C. for 2 h until reaction completion (TLC). The mixture was diluted with a saturated aqueous ammonium chloride solution (100 ml) and EA (200 ml); the organic layer was washed with brine (200 ml), dried and concentrated in vacuum. The crude mixture was purified by flash chromatography (eluting with CH/DCM/EA 5:4:1) to give the title compound (280 mg).
- IR:3350 (NH), 1718 and 1670 (C═O) cm−1. 1H-NMR: 9.32 (sa); 759 (d); 7.43 (d); 7.17 (d); 6.94 (d); 6.72 (m); 6.55 (dd); 4.26 (dd); 4.19(m); 4.04-3.88 (m); 3.8-3.6 (m); 3.18(m); 2.94-2.86 (m); 1.46 (s); 0.92 (t).
- (+)-Ethyl 7-chloro-4-(2-oxo-1-(4-amino)phenyl-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylate
- To a solution of example 10 (0.280 g) in ethyl acetate (100 ml) HCl conc. (9.5 ml) was added. The mixture was stirred a r.t. under nitrogen atmosphere for 1 h until reaction completion (Tlc). The mixture was poured onto a saturated aqueous solution of NaHCO3 (100 ml) and extracted with EA (200 ml); the organic layer was dried and concentrated in vacuum. The crude mixture was triturated with CH/EA 1:1 to give the title compound as a yellow solid (0.191 g).
- T.l.c. EA Rf=0.33. IR:3464-3406(NH), 3364(NH2), 1730, 1658 and 1633 (C═O) cm−1.
-
- (+)-Ethyl 7-chloro-4-(2-oxo-1-(4-acetylamino)phenyl-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylate
- To a solution of intermediate 19 dry pyridine (1 ml) Ac2O (0.010 ml) was added. The mixture was stirred a r.t. under nitrogen atmosphere for 30 minutes. The mixture was poured onto a saturated aqueous solution of NH4Cl (50 ml) and extracted with EA (50 ml), the organic layer was dried and concentrated in vacuum. The crude mixture was triturated with EA to give the title compound as a yellow solid (0.027 g).
- T.l.c. CH/EA (1:1) Rf=0.63 IR:3396-3325(NH), 1724-1685 (C═O) cm−1.
-
- (+)-Ethyl 7-chloro-4-(2-oxo-1-((4-methanesulfonyl-amino)phenyl-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylate
- To a solution of example 12 (0.040 g) in dry CH2Cl2 (10 ml) DIPEA (0.021 ml) and CH3SO2Cl (0.008 ml) were added. The mixture was stirred a r.t. under nitrogen atmosphere for 1 h (Tlc). The mixture was poured onto a saturated aqueous solution of NH4Cl (50 ml) and extracted with EA (50 ml), the organic layer was dried and concentrated in vacuum. The crude mixture was crystallised with CH/EA (1:1) to give the title compound as a yellow solid (0.023 g). T.l.c. CH/EA (1:1) Rf=0.63.
- IR:3384(NH), 1734, 1683 (C═O), 1600 (C═C) cm−1.
-
- (±)-Sodium 7-chloro-4-(1-(3-pyridin)-Δ3-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylate
- To a solution of example 4a (70 mg) in IMS (5% of methanol in ethanol) (10 ml) a 1N solution of NaOH (0.18 ml) was added and reaction mixture was stirred for 1½ hr. The solvent was evaporated and the crude product was first triturated in methanol/ethyl acetate 05 ml/2 ml then in isopropyl alcohol (3 ml) to yield the title compound (40 mg) as a pale yellow solid.
- m.p.>220° C.
- NMR (DMSO) δ (ppm) 8.98 (d, 1H), 8.31 (dd, 1H), 8.21 (m, 1H), 7.41 (m, 1H), 6.79 (d, 1H), 6.72 (d, 1H), 6.42 (d, 1H), 6.33 (dd, 1H), 5.71 (s, 1H), 4.50 (m, 1H), 4.44 (m, 1H), 3.76 (m, 1H), 3.11 (m, 1H), 2.27 (m, 1H), 1.43 (m, 1H).
- IR (Nujol) (cm−1) 3300, 1684.
- (±)-Sodium 7-chloro-4-(1-phenyl-Δ3-5,6-dihydro-pyridin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylate
- To a solution of example 3a (80 mg) in IMS (5% of methanol in ethanol) (6 ml) a 0.1N solution of NaOH (2.9 ml) was added and reaction mixture was stirred for 1 hr. The solution was poured into ethyl acetate and washed with a 1N solution of HCl and brine. The organic phase was dried with Na2SO4 and concentrated to give the crude acid compound. The latter was suspended in ethyl acetate (2 ml) and sodium 2-ethylhexanoate (35 mg) was added obtaining a solution. Diethyl ether (4 ml) and petroleum (3 ml) was added to precipitate the title compound (42 mg) as a white solid.
- m.p.>163-166° C.
- NMR (DMSO) δ (ppm) 7.4-7.34 (m, 4H), 7.19 (m, 1H), 6.72 (d, 1H), 6.67 (d, 1H), 6.32 (d, 1H), 6.32 (dd, 1H), 5.71 (t, 1H), 5.64 (s, 1H), 3.96 (m, 1H), 3.8-3.65 (m, 2H), 3.17 (dd, 1H), 2.4 (m, 2H), 2.08 (1H), 1.3 (m, 1H)
- IR (Nujol) (cm−1) 3373, 1658, 1653
- (±)-Sodium 5,7-dichloro-4-(1-phenyl-Δ3-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylate
- To a solution of example 5 (87 mg) in IMS (5% methanol in absolute ethanol, 5 ml) NaOH (1N, 0.22 ml) was added and stirring continued for. 3 hrs. The resulting solution was dried on the rotary evaporator and the resulting solid was triturated with diethyl ether. After filtration and drying the title compound (78 mg) was obtained as an off-white solid.
- NMR (DMSO) δ (ppm) 7.80 (m, 2H), 7.38 (t, 2H), 7.10 (t, 1H), 6.82 (d, 1H), 6.46 (d, 1H), 6.37 (s, 1H), 6.11 (s, 1H), 4.42 (s, 2H), 3.98 (d, 1H), 3.05 (dd, 1H), 2.24 (dd, 1 H), 1.34 (m, 1H).
- IR (Nujol) (cm−1) 3385, 1663, 1591, 1555
- (+)Sodium-7-chloro-4-(1-phenyl-Δ3-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylate
- Method A
- To a solution of intermediate 13 (110 mg) in THF/H2O (1/1) (3 ml) LiOH (11 mg) was added and stirring continued for 1 h. The resulting solution was concentrated to dryness, taken up with ethyl acetate and 1N HCl was added. After vigorous stirring, the organic phase was separated, washed with water and brine and concentrated. The resulting solid was dissolved in THF (15 ml) and treated with sodium ethylhexanoate (39 mg) for 30 min. After drying, the resulting solid was triturated with hot diethyl ether and filtered, to afford the title compound (69 mg) as a white solid.
- e.r.=98%
- [α]D=92.5° (c=0.420% w/v in DMSO)
- m.p.>200° C.
- NMR (DMSO) δ (ppm) 7.80 (m, 2H), 7.39 (m, 2H), 7.11 (m, 1H), 6.80 (d, 1H), 6.72 (d, 1H), 6.36 (d, 1H), 6.34 (dd, 1H), 5.71 (s, 1H), 4.42 (m, 2H), 3.77 (m, 1H), 3.13 (m, 1H), 2.29 (m, 1H), 1.44 (m, 1H).
- IR (Nujol) (cm−1) 1672, 1600.
- Method B
- Starting from Example 28 using the procedure as described for Example 21 (Method B).
- (+/−)-7-chloro-4-(1-(4-acetylamino)-phenyl-Δ3-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylic Acid
- To a solution of example 8 (0.023 g) in IMS (5 ml) NaOH (0.150 ml) was added and the mixture was stirred at r.t. for 1 h.
- The mixture was poured onto a solution of HCl 6 N (50 ml) and extracted with EA (50 ml), the organic layer was washed with brine (30 ml), dried and concentrated in vacuum. The crude mixture was triturated with Et2O to give the title compound as a yellow solid (0.019g). T.l.c. EA Rf=0.2.
- IR:3401(NH, OH), 1734, 1651 (C═O) cm−1.
- 1H-NMR:12.84 (bs); 9.9 (s); 7.69(d); 7.56 (d); 6.80 (d); 6.76 (d);6.6 (d); 6.45 (dd);6.33 (sa); 4.42(m); 3.84-3.78(m); 3.70 (m); 2.3 (m); 2.017 (s); 1.9 (m).
- To a solution of example 9 (0.027 g) in IMS (5 ml) was added NaOH (0.142 ml). The mixture was stirred a r.t. for 2 h.
- The mixture was poured onto a solution of HCl 6N (50 ml) and extracted with EA (50 ml), the organic layer was washed with brine (30 ml), dried and concentrated in vacuum. The crude mixture was crystallized with CH/EA (1:1) to give the title compound as a yellow solid (0.015 g). T.l.c. EA Rf=0.2. IR:3446(NH,), 1732-(C═O), 1337-1154 (SO2) cm−1.
-
- (±)-Sodium 7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylate
- To a solution of example 31b (540 mg) in IMS (5% methanol in absolute ethanol, 7 ml) NaOH (1N, 1.4 ml) was added and stirring continued for 2 hrs. The resulting suspension was filtered and the solid was washed with small portions of diethyl ether. After drying, the title compound (450 mg) was obtained as a yellow solid.
- m.p.>200° C.
- NMR (DMSO) δ (ppm) 7.74 (d, 2H), 7.37 (t, 2H), 7.11 (t, 1H), 7.12 (d, 1H), 6.77 (d, 1H), 6.38 (dd, 1H), 6.13 (bs, 1H), 4.48 (dd, 1H), 3.78 (m, 2H), 3.2-3.4 (m, 2H), 2.90 (m, 1H), 1.98 (m, 1H)
- (−)-Sodium 7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylate
- Method A
- To a solution of intermediate 8b (790 mg) in THF/H2O (1/1) (16 ml) LiOH (73 mg) was added and stirring continued for 1 hr. The resulting solution was concentrated to dryness, taken up with ethyl acetate and 1N HCl was added. After vigorous stirring, the organic phase was separated, washed with water and brine and concentrated. The resulting solid was dissolved in THF (15 ml) and treated with sodium ethylhexanoate (265 mg) for 30 mins. After drying, the resulting solid was triturated with hot ethyl acetate and filtered to afford the title compound (400 mg) as a yellow solid.
- ee=88.8%
- [α]D−603.7° (c=0.316% w/v in DMSO)
- m.p.>200° C.
- NMR (DMSO) δ (ppm) 7.74 (d, 2H), 7.37 (t, 2H), 7.11 (t, 1H), 7.12 (d, 1H), 6.77 (d, 1H), 6.38 (dd, 1H), 6.13 (bs, 1H), 4.48 (dd, 1H), 3.78 (m, 2H), 3.2-3.4 (m, 2H), 2.90 (m, 1H), 1.98 (m, 1H)
- IR (Nujol) (cm−1) 3425, 1666, 1592
- Method B
- To a solution of example 27 (3.18 g) in IMS (5% of methanol in ethanol) (100 ml) a 1N solution of NaOH (8.64 ml) was added: the sodium salt precipitates after 5 min. To the resulting suspension diethyl ether was added (50 ml) and the solid was filtered.
- The solution was evaporated and the solid obtained was mixed to the previous one and triturated with diethylether to afford the title sodium salt (3.2 g) as yellow solid.
- m.p.>220° C.
- NMR (DMSO) δ (ppm) 7.74 (d, 2H), 7.37 (t, 2H), 7.11 (t, 1H); 7.11 (d, 1H); 6.76 (d, 1H); 6.38 (dd, 1H); 6.11 (s, 1H); 4.48 (dd, 1H); 3.78 (m, 2H); 3.4-3.2 (m, 2H); 2.9 (m, 1H); 1.95 (m, 1H).
- IR (Nujol) (cm−1) 3392, 1669.
- [α]−603.7° (c=0.316% w/v in DMSO)
- e.e.: 96%
- Method C
- 125 g ofAspergillus niger lipase (Amano AP12) were suspended in 650 ml of 100 mM calcium chloride solution in a stirred reactor. The suspension was cooled to 15° C. 50 g of example 31b were then dissolved in dimethyl sulphoxide (350 ml) and this solution added to the reactor. The reactor was then heated to 37° C. and the mixture stirred for 24 hours.
- The reactor temperature was then lowered to 20° C. and 1 liter of 0.2M hydrochloric acid was slowly added to the reactor. The reactor was then emptied and 50 g of filter aid (Dicalite) were added to the reaction mixture. The mixture was then filtered and the filter cake washed with water, before being dried. A 20 g sample of dried filter cake was dispersed in 390 ml of methyl t-butyl ether and 10 ml of 2M hydrochloric acid were added. This was stirred for 3 hours and filtered, the filter cake was washed with 100 ml of methyl t-butyl ether. The product was back extracted from the methyl t-butyl ether 500 into ml of 0.05M sodium hydroxide solution. The aqueous layer was then separated, acidified with 6 ml of 5M hydrochloric acid and the product extracted into 500 ml ethyl acetate. The ethyl acetate was removed by evaporation and the residue dissolved in IMS (80 ml). The title compound was identified in this solution by HPLC assay as follows:
- 0.5 ml reaction mixture diluted into 2 mls DMSO and mixed to dissolve. 5 ul of this further diluted ino 1 ml of mobile phase (70% acetonitrile in 20 mM Ammonium acetate pH 3.0), Column: Spherisorb C6 50×4.6 mm, Flow rate: 1 ml/min, Detection: uv adsorbance at 254 nm, Injection vol: 10 ul, Retention time: 0.8 min.
- The solution was diluted to 96 ml with IMS and stirred while 10 ml of 1 M sodium hydroxide were added drop-wise over 15 minutes. 40 ml of diethyl ether were added over 10 minutes and stirring continued for 1 hour. The mixture was then placed in the fridge for 1 hour and the product filtered, washed with 50 ml of cold diethyl ether before being dried overnight under vacuum to obtain the title compound (3.3 g). HPLC analyses: the title compound was dissolved in DMSO at 1 mg/ml. 10 ul of this diluted into 990 ul of mobile phase.
- Column: Phenomenex Luna Phenyl hexyl 150×4.6 mm, Injection vol: 50 ul, Retention time: 3.4 min.
- (±)-Sodium 7-chloro-4-(2oxo-1-(pyridn-3yl)-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylate
- To a solution of example 4b (55 mg) in IMS (5% of methanol in ethanol) (10 ml) a 1N solution of NaOH (0.145 ml) was added and reaction mixture was stirred for 1½ hr. The solvent was evaporated and the crude product was triturated in ethyl acetate 2 ml to yield the title compound (38 mg) as a yellow solid.
- m.p.>220° C.
- NMR (DMSO) δ (ppm) 8.96 (d, 1H), 8.32 (dd, 1H), 8.18 (m, 1H), 7.40 (m, 1H), 7.12 (d, 1H), 6.78 (d, 1H), 6.38 (dd, 1H), 6.15 (s, 1H), 4.46 (m, 1H), 3.83 (m, 2H), 3.3-3.2 (m, 2H), 2.92 (m, 1H), 1.97 (m, 1H).
- IR (Nujol) (cm−1) 3361, 1669.
- (±)-7-chloro-4-(2-oxo-1-phenyl-3-piperidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylic Acid
- To a solution of example 3b (48 mg) in IMS (5% of methanol in ethanol) (2 ml) a 0.1N solution of NaOH (1.2 ml) was added and reaction mixture was stirred for 2½ hr. The solution was poured into ethyl acetate and washed with a 1N solution of HCl and brine. The organic phase was dried and concentrated to give the crude product which was triturated in ethyl acetate/petroleum 2 ml/5 ml, to yield the title compound (14 mg) as a yellow solid.
- m.p.>130-133° C.
- NMR (DMSO) δ (ppm) 12.64 (s, 1H), 7.38 (t, 2H), 7.30 (d, 2H), 7.22 (t, 1H), 6.99 (d, 1H), 6.87 (bd, 1 H), 6.67 (d, 1H), 6.50 (dd, 1H), 4.08 (m, 1H), 3.54 (m, 2H), 3.43 (m, 1H), 2.83 (m, 1H), 2.72 (m, 1H), 2.58 (1H), 1.93-1.8 (m, 2H)
- IR (Nujol) (cm−1) 3348, 1732, 1717
- MS (m/z) 383
- (±)-7-chloro-4-(2,5-dioxo-1-phenyl-imidazolidin-4-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylic Acid
- To a solution of intermediate 18 (10 mg) in CH2Cl2 (5 ml) a 1M solution of BCl3 in hexane (0.1 ml) was added at −78° C. and reaction mixture was stirred for 1½ hr maintaining the temperature between −20 and −10° C. The solution was poured into ethyl acetate and washed with a 3N solution of HCl and brine. The organic phase was dried with Na2SO4 and concentrated to give the crude product which was triturated in diethyl ether/petroleum (1 ml/3 ml), to yield the title compound (6 mg) as a yellow solid.
- m.p.>190° C. deg.
- NMR (DMSO) δ (ppm) 12.75 (bs, 1H), 10.50 (bs, 1H), 7.50-7.39 (m, 6H), 6.99 (bs, 1H), 6.76 (d, 1H), 6.57 (dd, 1H), 4.15 (m, 1H), 3.77.(m, 1H). 3.17 (dd, 1H),.
- IR (Nujol) (cm−1) 3400, 2800, 1746, 1701
- (+/−)-7-chloro-4-(2-oxo-1-(4-acetylamino)phenyl-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylic Acid
- To a solution of example 12 (0.027 g) in THF H2O (3:1) (10 ml) was added LiOH (0.010 g). The mixture was stirred a r.t. for 1 h. The mixture was poured onto a saturated aqueous solution of NH4Cl (50 ml) and extracted with EA (50 ml), the organic layer was washed with brine (30 ml), dried and concentrated in vacuum. The crude mixture was triturated with EA to give the title compound as a yellow solid (0.020 g). T.l.c. CH/EA (1:1) Rf=0.2. IR:3400-2700 (NH, OH), 1660 (C═O) cm−1.
-
- (+/−)7-chloro-4-(2-oxo-1-((4-methanesulfonyl amino)phenyl-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylic Acid
- To a solution of example 13 (0.023 g) in IMS (5 ml) NaOH (0.120 ml) was added. The mixture was stirred a r.t. for 2 h. The mixture was poured onto a solution of HCl 6N (50 ml) and extracted with EA (50 ml), the organic layer was washed with brine (30 ml), dried and concentrated in vacuum. The crude mixture was chromatographed with Et2O to give the title compound as a yellow solid (0.007 g). T.l.c. CH/EA (1:1) Rf=0.2.
- IR:3411 (NH,), 1692, 1651-1583 (C═O), (C═C), 1306-1154 (SO2) cm−1.
-
- 7chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylic Acid (Enantiomer A)
- To a solution of intermediate 22 (6.2 g) in THF/H2O (100 ml, 3/1) at room temperature LiOH (1 g) was added and stirring continued for 1 hr. The THF was evaporated and H2O (100 ml) was added. The resulting solution was washed with diethylether (2×50 ml). The aqueous phase was acidified until pH=4 with HCl 10% and the product extracted with ethyl acetate (2×100 ml) The organic phase was washed with water and brine, dried and evaporated to afford the title compound (4.2 g) as a yellow solid. m.p.>200° C.
- NMR (DMSO) δ (ppm) 12.62 (bs, 1H); 7.72 (d, 2H), 7.38 (t, 2H), 7.20 (d, 1H), 7.13 (t, 1H), 6.86 (d, 1H), 6.74 (d, 1H), 6.54 (dd, 1H), 4.06 (m, 1H), 3.86-3.68 (m, 3H), 3.3 (m, 1H), 3.18-2.88 (m, 2H).
- IR (nujol): 3356, 1724
- 7-Chloro-4-(2-oxo-1-phenyl-Δ3-pyrrolin-2-one-3-yl)-1,2,3,4-tetrahydro-quinoline-2-carboxylic Acid; (Enantiomer A)
- To a solution of intermediate 10 (1.289 g) in THF/H2O (30 ml, 3/1) at room temperature LiOH (0.24 g) was added and stirring continued for 1 hr. The THF was evaporated and H2O (80 ml) was added. The resulting solution was washed with diethylether (2×50 ml). The aqueous phase was acidified until pH=4 with HCl 10% and the product was filtered and washed with water (10 ml). The product was dried under vacuum at 60C for 12 hrs to obtain 0.734 g as white solid.
- m.p.: 190° C.
- e.e.: 100%
- NMR (DMSO) δ (ppm) 12.86 (bs, 1H); 7.79 (d, 2H), 7.38 (t, 2H), 7.11 (d, 1H), 6.81 (d, 1H), 6.77 (d, 1H), 6.64 (s, 1H), 6.46 (dd, 1H); 6.34 (s, 1H); 4.46 (m, 1H), 3.82-3.79 (m, 2H), 2.34 (m,1 H); 1.92 (m, 1 H).
- IR (nujol): 3356, 1724
- Sodium, 5,7-Dichloro-4-(2-oxo-1-phenyl-Δ3-pyrrolin-2-one-3-yl)-1,2,3,4-tetrahydro-quinoline-2-carboxylic Acid; (Enatiomer A)
- To a solution of intermediate 26a (0.35 g) in THF/H2O (10 ml, 3/1) at room temperature LiOH (0.06 g) was added and stirring continued for 30 min. The THF was evaporated and H2O (5 ml) was added. The resulting solution was washed with diethylether (2×50 ml). The aqueous phase was acidified until pH=4 with HCl 10% and the product filtered and dried under vacuum at 60 C for 12 hrs to afford the title compound (0.134 g) as white solid.
- The solid was dissolved in IMS (5% of methanol in ethanol) (10 ml) and a 1N solution of NaOH (0.33 ml) was added. To the resulting suspension diethyl ether was added (10ml) and the solid was filtered, washed with diethyl ether (10 ml) and dried under vacuum for 12 hrs to give the title compound (0.082 g) as a white solid.
- m.p.>220° C.
- NMR (D2O) δ (ppm) 7.49 (d, 2H); 7.40(t, 2H); 7.23 (t, 1H); 6.74 (d, 1H); 6.70 (d, 1H): 6.51 (m, 1H); 4.40-4.35 (m, 2H); 4.11 (m, 1H); 3.53 (dd, 1H); 2.18 (m, 1H); 1.74 (td, 1H)
- HPLC Column: Cyclobond I, R,S-Hydroxypropyl ether 25 cm×4.6 mm; Mobile Phase: Methanol=50 20 mM Ammonium Acetate buffer pH 5=50% by volume; Flow rate: 1 ml/min; Retention time: 12 mins.
- Sodium 5,7-dichloro-4(2-oxo-1-(phenyl)-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinoline Carboxylate (Enatiomer A)
- To a solution of intermediate 26b (0.052 g) in THF/H2O (4 ml, 3/1) at room temperature LiOH (0.01 g) was added and stirring continued for 30 min. The THF was evaporated and H2O (2 ml) was added. The resulting solution was washed with diethylether (2×50 ml). The aqueous phase was acidified until pH=4 with HCl 10% and the product was filtered and washed with water (10 ml) and was dried under vacuum at 60° C. for 12 hrs to obtain 5,7-dichloro-4-(2-oxo-1-(pyridn-3yl)-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinoline carboxylic acid 0.033 g as a yellow solid. The solid was dissolved in IMS (5% of methanol in ethanol) (5 ml) and a 1N solution of NaOH (0.08 ml) was added. After 5 min, the solvent was evaporated and the solid triturated with diethyl ether (5 ml), filtered, dried under vacuum for 12 hrs to give the title compound (0.01 g) as a yellow solid.
- m.p.: >200°
- NMR (DMSO) δ (ppm) 7.74 (d, 2H); 7.39 (t, 2H); 7.15 (t, 1H); 6.76 (d, 1H); 6.51 (d, 1H); 6.20 (m, 1H); 4.63 (dd, 1H); 3.78 (m, 2H); 3.41 (dd, 1H); 3.18 (m, 1H); 2.35 (dd, 1H); 1.81 (t, 1H).
- IR (nujol): 3363, 1688, 1630, 1586 cm−1
- (±)-Ethyl 7-chloro-4-(1-phenyl-Δ3-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylate (31a)
- (±)-Ethyl 7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylate (31b)
- To a solution of intermediate 4 (2.2 g) in DMF (50 ml) Pd(PPh3)4 (244 mg) and TEA (1.2 ml) were added and the resulting solution was heated to 110° C. for 2 h. The crude solution was poured into 200 ml of ethyl acetate and washed first with a saturated solution of NH4Cl (2×150 ml), then with water and brine. The organic phase was dried and concentrated to give the crude product. Purification by column chromatography (cyclohexane/dichloromethane/ethyl acetate 50/40/10) Rf=0.41 gave the title compound 31a (540 mg) as an off-white solid.
- m.p.=150-153° C.
- NMR (DMSO) δ (ppm) 7.80 (m, 2H), 7.39 (m, 2H), 7.12 (m, 1H), 6.83 (d, 1H), 6.77 (d, 1H), 6.69 (m, 1H), 6.48 (dd, 1H), 6.45 (s, 1H), 4.48 (m, 2H), 4.15 (m, 2H), 3.94 (m, 1H), 3.82 (m, 1H), 2.34 (m, 1H), 1.97 (m, 1H), 1.20 (t, 3H)
- IR (Nujol) (cm−1) 3385, 1728, 1680
- and the title compound 31b (475 mg) Rf=0.29 as a yellow solid.
- m.p.=152-156° C.
- NMR (DMSO) δ (ppm) 7.72 (m, 2H), 7.39 (m, 2H), 7.20 (d, 1H), 7.16 (m, 1H), 6.98 (d, 1H), 6.74 (d, 1H), 6.57 (dd, 1H), 4.29 (dd, 1H), 4.21 (m, 1H), 4.02 (m, 1H), 3.93 (m, 1H), 3.82 (m, 1H), 3.69 (m, 1H), 3.20 (m, 1H), 2.92 (m, 2H), 0.93 (t, 3H)
- (±)-Ethyl 7-chloro-4-(1-phenyl-Δ3-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylate
- To a solution of intermediate 4a (0.1 g) in dry DMF (5 ml) Pd(OAc)2 (10 mg) and TEA (0.026 ml) were added. The mixture was heated at 110° C. for 2 hrs, then diluted with a saturated solution of NH4Cl and extracted with ethyl acetate (2×10 ml).
- The solvent was evaporated and the crude purified by flash chromatography (Cyclohexane/EA 8:2) to afford the title compound as a white solid (40 mg).
- (±)-Ethyl 7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylate
- To a solution of intermediate 4b (370 g) in toluene (5.2 lit), Triethylamine (248 ml), Triphenilphosphine (7.4 g) and PdCl2 (2.52 g) were added. The resulting solution was warmed to 100° C. and stirred for 2 h. The suspension was chilled to 20-25° C. and toluene (2.6 ml) was added. The reaction mixture was washed with NH4Cl 8% (3×5.2 lit) and water (5.2 lit). The organic layer was filtered over a celite pad and it was washed with toluene (1 lit); then it was distilled under vacuum (T=50° C.; P=60 mbar) to reach 6.3 lit. After cooling to T=20-25° C., isooctane (5.2 lit) was dropped over 30 min. The precipitate was stirred for 2 h 30 min then it was filtered and washed with a mixture toluene/isooctane 1/1 (1.85 lit). The yellow solid was dried in vacuum at T=40° C. for 18 h to obtain the title compound as a yellow solid 210 g.
- m.p. 160-162° C.
- NMR (DMSO): 7.72 (m, 2H); 7.39 (m, 2H); 7.20 (d, 2H); 7.15 (m, 2H); 6.96 (dd, 1H); 6.74 (d, 1H); 6.57 (dd, 1H); 4.29 (dd, 1H); 4.21 (m, 1H); 4.02 (m, 1H); 3.93 (m, 1H); 3.82 (m, 1H); 3.69 (m, 1H); 3.20 (m, 1H). 2.92 (m, 2H); 2.92 (m, 2H); 0.93 (t, 3H).
- A. Capsules/Tablets
Active ingredient 20.0 mg Starch 1500 2.5 mg Microcrystalline 200.0 mg Cellulose Croscarmellose Sodium 6.0 mg Magnesium Stearate 1.5 mg - The active ingredient is blended with the other excipients. The blend can be used to fill gelatin capsules or compressed to form tablets using appropriate punches. The tablets can be coated using conventional techniques and coatings.
- B. Tablets
Active ingredient 20.0 mg Lactose 200.0 mg Microcrystalline 70.0 mg Cellulose Povidone 25.0 mg Croscarmellose Sodium 6.0 mg Magnesium Stearate 1.5 mg - The active ingredient is blended with lactose, microcrystalline cellulose and part of the croscarmellose sodium. The blend is granulated with povidone after dispersing in a suitable solvent (i.e. water). The granule, after drying and comminution is blended with the remaining excipients. The blend can be compressed using appropriate punches and the tablets coated using conventional techniques and coatings.
- c) Bolus
Active ingredient 0.1-32 mg/ml Sodium phosphate 1.0-50.0 mg/ml water for injection qs to 1 ml - The formulation may be packed in glass ampoules or vials and syringes with a rubber stopper and a plastic/metal overseal (vials only).
- D) Infusion
Active ingredient 0.01-3.2 mg/ml 5% dextrose injection qs to 100 ml - The formulation may be packed in glass vials or plastic bag.
- The affinity of the compound of the invention for the strychnine insensitive glycine binding site was determined using procedure of Kishimoto H. et al J.
- The pki values obtained with representative compounds of the invention are given in the following table:
Example No pki 1 8.1 14 7.9 15 7.73 16 7.8 17 8.7 18 7.78 19 8.9 21 7.1 22 7.9 24 7.8 25 7.15 30 7.7 29 8.7 - The ability of compounds of the invention to inhibit pain in mouse has been assessed in the formalin test as described by Dubuisson and Dennis (Pain, 1977, 4:161-174). In this test 20 μl of 1% formalin was injected into the plantar surface of the mouse left hind paw. The amount of time, in seconds, the animals spent licking the injected paw for the first 5 minutes (early phase) and then from 20 to 60 minutes (late phase) after formalin was used as measurement of the intensity of pain.
- The compounds of the invention were administered orally 1 hour before formalin injection.
- From these results the dose required to reduce the licking time by 50% expressed as mg/kg is referred to as the ED50s value.
- Representative results obtained for compounds of the invention when given by oral administration are given in the following table:
Ex No ED50 (mg/kg po) 21 0.14 17 0.3 2 0.03 - No untoward effects have been observed when compounds of the invention have been administered to mice at pharmacologically active doses.
Claims (20)
1. A compound of formula (I)
or a salt or a non toxic metabolically labile esters thereof, wherein
Y represents a carbon atom;
Z is the group CH which is linked to the group Y via a double bond and X is CH or Z is methylene or NR11 and X is a carbon atom linked to the group Y via a double bond;
A represents a C1-2 alkylene chain and which chain may be substituted by one or two groups selected from C1-6 alkyl optionally substituted by hydroxy, amino, C1-4alkyl amino or C1-4 dialkyl amino or which chain may be substituted by the group=0;
R represents a halogen atom or C1-4 alkyl group;
R1 represents a hydrogen, a halogen atom or C1-4 alkyl group;
R2 represents phenyl which may be substituted with up to 3 groups selected from halogen, hydrogen, or (CH2)nR3 wherein R3 is COR4, NR6R5, NHCOR7, NHCONR9R8 or NH SO2 R10 group or R2 is a 5 membered heteroaryl group containing 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen; or 6 membered heteroaryl group containing 1 to 3 nitrogen atoms
R4 represents an amino, a hydroxyl or C1-4 alkoxy group;
R5 and R6 each independently represents hydrogen or C1-4 alkyl group or
R5 and R6 together with the nitrogen atom to which they are attached represent a saturated 5-7 membered heterocyclic group optionally containing an additional heroatom selected from oxygen, sulphur or nitrogen
R7 represents a hydrogen atom or C1-4alkyl, C1-4alkoxy, or phenyl;
R8 represents hydrogen or C1-4 alkyl group;
R9 represents hydrogen, optionally substituted C1-4 alkyl (optionally substituted by one or more hydroxy carboxyl and amino group), phenyl;
R11 represents hydrogen or C1-4 alkyl group;
R10 represents hydrogen, C1-4 alkyl or a nitrogen protecting group.
n is zero or an integer from 1 to 2.
2. A compound as claimed in claim 1 wherein R is chlorine and Rf is hydrogen or a chlorine atom.
3. A compound as claimed in claims 1 or 2 wherein A is a chain selected from —CH2—, —(CH2)2— or C═O.
4. A compound as claimed in any of the claims 1-3 wherein Z is CH which is linked to the group Y via a double bond, a methylene or a NH group.
5. A compound as claimed in any of the claims 14 wherein R2 is a group selected from phenyl (optionally substituted by acetylamino, methanesulphonylamino) or 3-pyridyl.
6. A compound as claimed in any of the claims 1-5 wherein R2 represents phenyl.
7. A compound as claimed in any of the claims 1-6 wherein A is a chain selected from —CH2—, —(CH2)2—, and Z is the group CH which is linked to the group Y via a double bond, or a methylene group, or A is C═O and Z is a NH group, R is chlorine, Rf is chlorine or hydrogen and R2 is phenyl (optionally substituted by acetylamino or methanesulphonylamino) or 3-pyridyl.
8. (±)7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinoline carboxylic acid, physiologically acceptable salts or non toxic metabolically labile esters thereof.
9. Sodium (±) 7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene) 1,2,3,4-tetrahydro-2-quinolinecarboxylate.
10. (−) Sodium 7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene) 1,2,3,4-tetrahydro-2-quinolinecarboxylate.
11. (±)7-chloro-4-(1-phenyl-Δ3-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydro-2-quinoline carboxylic acid, physiologically acceptable salts or non toxic metabolically labile esters thereof.
12. Sodium (±)7-chloro-4-(1-phenyl-Δ3-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydro-2-quinolinecarboxylate.
13. (−)Sodium 7-chloro-4-(1-phenyl-Δ3-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydro-2-quinolinecarboxylate.
14. (+) Sodium 7-chloro-4-(1-phenyl-Δ3-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydro-2-quinolinecarboxylate.
15. A compound selected from:
(±)-7-chloro-4-(1-(3-pyridin)-Δ3-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
(±)-7-chloro-4-(1-phenyl-Δ3-5,6-dihydro-pyridin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxlic acid,
(±)-5,7-dichloro-4-(1-phenyl-Δ3-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
(+/−)-7-chloro-4-(1-(4-acetylamino)-1-phenyl-Δ3-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
(+/−)7-chloro-4-(1-(4-methanesulfonylamino)-1-phenyl-Δ3-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid,
(±)-7-chloro-4-(2-oxo-1-phenyl-3-piperidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid,
(±)-7-chloro-4-(2,5-dioxo-1-phenyl-imidazolidin-4-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid,
(±)-7-chloro-4-(2-oxo-1-pyridin-3yl)-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylate,
(±)-7-chloro-4-(2-oxo-1-(4-acetylamino)phenyl-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid,
(±)7-chloro-4-(2-oxo-1-((4-methanesulfonyl amino)phenyl-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid,
5,7-dichloro-4-(2-oxo-1-(phenyl)-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinoline carboxylic acid,
5,7-dichloro-4-(2-oxo-1-phenyl-Δ3-pyrrolin-2-one-3-yl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid;
and physiologically acceptable salts (e.g. sodium salts), non-toxic metabolically labile esters or enantiomers thereof.
16. A compound as claimed in any of claims 1-15 for use in therapy.
17. The use of a compound as claimed in any of claims 1-15 in the manufacturing of a therapeutic agent for antagonising the effects of excitatory amino acids on the NMDA receptor complex.
18. A pharmaceutical composition comprising a compound as claimed in any of claims 1-15 in admixture with one or more physiologically acceptable carriers or excipients.
19. A method of treatment of a mammal including man for conditions where antagonising the effects of excitatory amino acids on the NMDA receptor complex is of therapeutic benefit comprising administration of an effective amount of a compound as claimed in any of claims 1 to 16 .
20. A process for the preparation of compounds as claimed in any of the claims 1-15 which comprises cyclising a compound of formula (II) in which R, R1, R2, A, X, Y, Z have the meanings defined in claim 1 and R12 is a carboxylic protecting group, R13 represents a bromine or iodine atom, R14 represents hydrogen or a nitrogen protecting group,
followed where necessary or desired by one or more of the following steps:
(i) removal of a protecting group,
(ii) isolation of the compound as a salt thereof;
(iii) conversion of a compound of formula (I) or a salt thereof into a metabolically labile ester thereof,
(iv) separation of a compound of formula (I) or a derivative thereof into the enantiomers thereof.
Priority Applications (2)
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US09/990,513 US6413985B1 (en) | 1998-06-10 | 2001-11-16 | Tetrahydroquinoline derivatives as glycine antagonists |
US10/145,258 US6495566B2 (en) | 1998-06-10 | 2002-05-14 | Tetrahydroquinoline derivatives as glycine antagonists |
Applications Claiming Priority (8)
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GBGB9812410.0A GB9812410D0 (en) | 1998-06-10 | 1998-06-10 | Heterocyclic derivatives |
GB9812410.0 | 1998-06-10 | ||
GB9812410 | 1998-06-10 | ||
GB9812408 | 1998-06-10 | ||
GB9812408.4 | 1998-06-10 | ||
GBGB9812408.4A GB9812408D0 (en) | 1998-06-10 | 1998-06-10 | Heterocyclic compounds |
US09/719,188 US6362199B1 (en) | 1998-06-10 | 1999-06-08 | Tetrahydroquinoline derivatives as glycine antagonists |
US09/990,513 US6413985B1 (en) | 1998-06-10 | 2001-11-16 | Tetrahydroquinoline derivatives as glycine antagonists |
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US09/719,188 Continuation US6362199B1 (en) | 1998-06-10 | 1999-06-08 | Tetrahydroquinoline derivatives as glycine antagonists |
PCT/EP1999/003936 Continuation WO1999064411A1 (en) | 1998-06-10 | 1999-06-08 | Tetrahydroquinoline derivatives as glycine antagonists |
US09719118 Continuation | 2001-02-28 |
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US10/145,258 Continuation US6495566B2 (en) | 1998-06-10 | 2002-05-14 | Tetrahydroquinoline derivatives as glycine antagonists |
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US20020052391A1 true US20020052391A1 (en) | 2002-05-02 |
US6413985B1 US6413985B1 (en) | 2002-07-02 |
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US09/719,188 Expired - Fee Related US6362199B1 (en) | 1998-06-10 | 1999-06-08 | Tetrahydroquinoline derivatives as glycine antagonists |
US09/990,513 Expired - Fee Related US6413985B1 (en) | 1998-06-10 | 2001-11-16 | Tetrahydroquinoline derivatives as glycine antagonists |
US10/145,258 Expired - Fee Related US6495566B2 (en) | 1998-06-10 | 2002-05-14 | Tetrahydroquinoline derivatives as glycine antagonists |
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US09/719,188 Expired - Fee Related US6362199B1 (en) | 1998-06-10 | 1999-06-08 | Tetrahydroquinoline derivatives as glycine antagonists |
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US10/145,258 Expired - Fee Related US6495566B2 (en) | 1998-06-10 | 2002-05-14 | Tetrahydroquinoline derivatives as glycine antagonists |
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EP (1) | EP1086093B1 (en) |
JP (1) | JP2002517492A (en) |
KR (1) | KR100586762B1 (en) |
CN (1) | CN1173970C (en) |
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IL (2) | IL140062A0 (en) |
IS (1) | IS5746A (en) |
MY (1) | MY125037A (en) |
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Cited By (1)
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US6855826B2 (en) | 2000-08-09 | 2005-02-15 | Magnesium Diagnostics, Inc. | Antagonists of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states |
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MY125037A (en) * | 1998-06-10 | 2006-07-31 | Glaxo Wellcome Spa | 1,2,3,4 tetrahydroquinoline derivatives |
GB9929037D0 (en) * | 1999-12-08 | 2000-02-02 | Glaxo Wellcome Spa | Heterocyclic derivatives |
DE10000311A1 (en) | 2000-01-05 | 2001-07-12 | Gruenenthal Gmbh | Aminomethyl-phonyl-cyclohexanone derivatives |
DE10005302A1 (en) * | 2000-02-07 | 2002-01-17 | Gruenenthal Gmbh | Substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivatives |
DE10137488A1 (en) * | 2001-08-03 | 2003-02-20 | Gruenenthal Gmbh | New salts of tetrahydroisoquinoline-carboxylic acid derivatives, are N-methyl-D-aspartate (NMDA) receptor antagonists useful e.g. for treating anxiety, depression, epilepsy, Alzheimer's disease, cardiovascular disease or especially pain |
DE10137487A1 (en) * | 2001-08-03 | 2003-03-27 | Gruenenthal Gmbh | Substituted 5,6,6a, 11b-tetrahydro-7-oxa-6-aza-benzo [c] fluorene-6-carboxylic acid derivatives |
US7504508B2 (en) * | 2002-10-04 | 2009-03-17 | Millennium Pharmaceuticals, Inc. | PGD2 receptor antagonists for the treatment of inflammatory diseases |
WO2004032848A2 (en) * | 2002-10-04 | 2004-04-22 | Millennium Pharmaceuticals, Inc. | Pgd2 receptor antagonists for the treatment of inflammatory diseases |
US20090181966A1 (en) * | 2002-10-04 | 2009-07-16 | Millennium Pharmaceuticals, Inc. | PGD2 receptor antagonists for the treatment of inflammatory diseases |
GB0327912D0 (en) * | 2003-12-02 | 2004-01-07 | Glaxo Group Ltd | Medicament |
RU2007135224A (en) * | 2005-02-24 | 2009-03-27 | Милленниум Фармасьютикалз, Инк. (Us) | PGD2 RECEPTOR ANTAGONISTS FOR TREATMENT OF INFLAMMATORY DISEASES |
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RU2024516C1 (en) * | 1989-02-02 | 1994-12-15 | Яманути Фармасьютикал Ко., Лтд. | Method of synthesis of tetrahydrobenzimidazole derivative or its pharmaceutically acceptable salt |
US4902695A (en) * | 1989-02-13 | 1990-02-20 | Eli Lilly And Company | Excitatory amino acid receptor antagonists |
US5231102A (en) * | 1989-03-08 | 1993-07-27 | Merck Sharp & Dohme, Ltd. | Tetrahydroquinoline derivatives useful for neurodegenerative disorders |
ATE147732T1 (en) * | 1989-03-08 | 1997-02-15 | Merck Sharp & Dohme | TETRAHYDROQUINOLINE DERIVATIVES USABLE IN NEURODEGENERATIVE DISEASES |
US5529999A (en) | 1994-03-04 | 1996-06-25 | Eli Lilly And Company | Antitumor compositions and methods of treatment |
US5977136A (en) | 1995-09-29 | 1999-11-02 | Glaxo Wellcome Spa | Tetrahydroquinolines as NMDA antagonists |
GB9617305D0 (en) * | 1996-08-17 | 1996-09-25 | Glaxo Wellcome Spa | Heterocyclic compounds |
MY125037A (en) * | 1998-06-10 | 2006-07-31 | Glaxo Wellcome Spa | 1,2,3,4 tetrahydroquinoline derivatives |
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US6855826B2 (en) | 2000-08-09 | 2005-02-15 | Magnesium Diagnostics, Inc. | Antagonists of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states |
US20050096279A1 (en) * | 2000-08-09 | 2005-05-05 | Magnesium Diagnostics, Inc. | Antagonists of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states |
US20060069259A1 (en) * | 2000-08-09 | 2006-03-30 | Magnesium Diagnostics, Inc. | Antagonists of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states |
US7041829B2 (en) | 2000-08-09 | 2006-05-09 | Magnesium Diagnostics, Inc. | Antagonists of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states |
US7132537B2 (en) | 2000-08-09 | 2006-11-07 | Magnesium Diagnostics, Inc. | Antagonists of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states |
US7211667B2 (en) | 2000-08-09 | 2007-05-01 | Magnesium Diagnostics, Inc. | Antagonists of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states |
US20070197659A1 (en) * | 2000-08-09 | 2007-08-23 | Magnesium Diagnostics, Inc. | Antagonist of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states |
US7405311B2 (en) | 2000-08-09 | 2008-07-29 | Magnesium Diagnostics, Inc. | Antagonist of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states |
US20090030080A1 (en) * | 2000-08-09 | 2009-01-29 | Magnesium Diagnostics, Inc. | Antagonists of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states |
US7619097B2 (en) | 2000-08-09 | 2009-11-17 | Magnesium Diagnostics, Inc. | Antagonists of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states |
US7795450B2 (en) | 2000-08-09 | 2010-09-14 | Magnesium Diagnostics, Inc. | Antagonist of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states |
US7982048B2 (en) | 2000-08-09 | 2011-07-19 | Magnesium Diagnostics, Inc. | Antagonists of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states |
US8129545B2 (en) | 2000-08-09 | 2012-03-06 | Magnesium Diagnostics, Inc. | Antagonists of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states |
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