JP4976499B2 - キマーゼ阻害剤としてのビニル酸誘導体 - Google Patents
キマーゼ阻害剤としてのビニル酸誘導体 Download PDFInfo
- Publication number
- JP4976499B2 JP4976499B2 JP2009531810A JP2009531810A JP4976499B2 JP 4976499 B2 JP4976499 B2 JP 4976499B2 JP 2009531810 A JP2009531810 A JP 2009531810A JP 2009531810 A JP2009531810 A JP 2009531810A JP 4976499 B2 JP4976499 B2 JP 4976499B2
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- JP
- Japan
- Prior art keywords
- methyl
- phenyl
- alkyl
- indol
- hydroxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- 239000002253 acid Substances 0.000 title description 11
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 title description 6
- 229920002554 vinyl polymer Polymers 0.000 title description 5
- 239000003601 chymase inhibitor Substances 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 79
- 125000000217 alkyl group Chemical group 0.000 claims description 55
- -1 nitro, cyano, amino Chemical group 0.000 claims description 34
- 229910052739 hydrogen Inorganic materials 0.000 claims description 31
- 239000001257 hydrogen Substances 0.000 claims description 31
- 150000002431 hydrogen Chemical class 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 16
- 108090000227 Chymases Proteins 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 13
- 125000002947 alkylene group Chemical group 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 201000010099 disease Diseases 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 208000006673 asthma Diseases 0.000 claims description 7
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 6
- 206010003178 Arterial thrombosis Diseases 0.000 claims description 6
- 230000007214 atherothrombosis Effects 0.000 claims description 6
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 238000011282 treatment Methods 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- QMAUTFNEWXRLNC-UHFFFAOYSA-N n-[[2-[(2-hydroxy-3-methyl-4-oxo-3-phenylcyclobuten-1-yl)-phenylmethyl]-6-methyl-1h-indol-3-yl]methyl]acetamide Chemical compound N1C2=CC(C)=CC=C2C(CNC(=O)C)=C1C(C=1C=CC=CC=1)C(C1=O)=C(O)C1(C)C1=CC=CC=C1 QMAUTFNEWXRLNC-UHFFFAOYSA-N 0.000 claims description 4
- SOUCSSOLFNJFQE-UHFFFAOYSA-N 2-[(3,5-dimethyl-1h-indol-2-yl)-phenylmethyl]-3-hydroxy-4-methyl-4-(4-methylphenyl)cyclobut-2-en-1-one Chemical compound N1C2=CC=C(C)C=C2C(C)=C1C(C=1C=CC=CC=1)C(C1=O)=C(O)C1(C)C1=CC=C(C)C=C1 SOUCSSOLFNJFQE-UHFFFAOYSA-N 0.000 claims description 3
- VZGRBDSYNZLWFU-UHFFFAOYSA-N 2-[(3,5-dimethyl-1h-indol-2-yl)-phenylmethyl]-3-hydroxy-4-methyl-4-phenylcyclobut-2-en-1-one Chemical compound N1C2=CC=C(C)C=C2C(C)=C1C(C=1C=CC=CC=1)C(C1=O)=C(O)C1(C)C1=CC=CC=C1 VZGRBDSYNZLWFU-UHFFFAOYSA-N 0.000 claims description 3
- RJVVQLWSPYQPJH-UHFFFAOYSA-N 2-[(3,6-dimethyl-1h-indol-2-yl)-phenylmethyl]-3-hydroxy-4-methyl-4-(4-methylphenyl)cyclobut-2-en-1-one Chemical compound N1C2=CC(C)=CC=C2C(C)=C1C(C=1C=CC=CC=1)C(C1=O)=C(O)C1(C)C1=CC=C(C)C=C1 RJVVQLWSPYQPJH-UHFFFAOYSA-N 0.000 claims description 3
- QTHHJBJGTAYYNU-UHFFFAOYSA-N 2-[(3,6-dimethyl-1h-indol-2-yl)-phenylmethyl]-3-hydroxy-4-methyl-4-phenylcyclobut-2-en-1-one Chemical compound N1C2=CC(C)=CC=C2C(C)=C1C(C=1C=CC=CC=1)C(C1=O)=C(O)C1(C)C1=CC=CC=C1 QTHHJBJGTAYYNU-UHFFFAOYSA-N 0.000 claims description 3
- RUBQMWQIXBHKBP-UHFFFAOYSA-N 2-[(5-fluoro-3-methyl-1h-indol-2-yl)-phenylmethyl]-3-hydroxy-4-methyl-4-(4-methylphenyl)cyclobut-2-en-1-one Chemical compound N1C2=CC=C(F)C=C2C(C)=C1C(C=1C=CC=CC=1)C(C1=O)=C(O)C1(C)C1=CC=C(C)C=C1 RUBQMWQIXBHKBP-UHFFFAOYSA-N 0.000 claims description 3
- UGRNAGBVLKOUHP-UHFFFAOYSA-N 2-[(5-fluoro-3-methyl-1h-indol-2-yl)-phenylmethyl]-3-hydroxy-4-methyl-4-phenylcyclobut-2-en-1-one Chemical compound N1C2=CC=C(F)C=C2C(C)=C1C(C=1C=CC=CC=1)C(C1=O)=C(O)C1(C)C1=CC=CC=C1 UGRNAGBVLKOUHP-UHFFFAOYSA-N 0.000 claims description 3
- JMIRVKMNFKRUNH-UHFFFAOYSA-N 3-hydroxy-4-methyl-2-[(3-methyl-1h-indol-2-yl)-phenylmethyl]-4-(4-methylphenyl)cyclobut-2-en-1-one Chemical compound N1C2=CC=CC=C2C(C)=C1C(C=1C=CC=CC=1)C(C1=O)=C(O)C1(C)C1=CC=C(C)C=C1 JMIRVKMNFKRUNH-UHFFFAOYSA-N 0.000 claims description 3
- BWAIKMXVPWAMJB-UHFFFAOYSA-N 3-hydroxy-4-methyl-2-[(3-methyl-1h-indol-2-yl)-phenylmethyl]-4-phenylcyclobut-2-en-1-one Chemical compound N1C2=CC=CC=C2C(C)=C1C(C=1C=CC=CC=1)C(C1=O)=C(O)C1(C)C1=CC=CC=C1 BWAIKMXVPWAMJB-UHFFFAOYSA-N 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- XAUXLOOKCXOIPU-UHFFFAOYSA-N n-[1-[2-[(2-hydroxy-3-methyl-4-oxo-3-phenylcyclobuten-1-yl)-phenylmethyl]-6-methyl-1h-indol-3-yl]-2-methylpropan-2-yl]acetamide Chemical compound N1C2=CC(C)=CC=C2C(CC(C)(C)NC(=O)C)=C1C(C=1C=CC=CC=1)C(C1=O)=C(O)C1(C)C1=CC=CC=C1 XAUXLOOKCXOIPU-UHFFFAOYSA-N 0.000 claims description 3
- ZYCBSRUJFCNJOR-UHFFFAOYSA-N n-[[2-[[2-hydroxy-3-methyl-3-(4-methylphenyl)-4-oxocyclobuten-1-yl]-phenylmethyl]-6-methyl-1h-indol-3-yl]methyl]acetamide Chemical compound N1C2=CC(C)=CC=C2C(CNC(=O)C)=C1C(C=1C=CC=CC=1)C(C1=O)=C(O)C1(C)C1=CC=C(C)C=C1 ZYCBSRUJFCNJOR-UHFFFAOYSA-N 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 230000001225 therapeutic effect Effects 0.000 claims description 3
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 1
- 102000003858 Chymases Human genes 0.000 claims 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 1
- 230000001548 androgenic effect Effects 0.000 claims 1
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 54
- 238000000034 method Methods 0.000 description 52
- 239000007787 solid Substances 0.000 description 38
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 239000000203 mixture Substances 0.000 description 24
- OCDJXGDYEQQTMV-UHFFFAOYSA-N 2-methyl-2-phenylcyclobutane-1,3-dione Chemical compound C=1C=CC=CC=1C1(C)C(=O)CC1=O OCDJXGDYEQQTMV-UHFFFAOYSA-N 0.000 description 23
- 239000000243 solution Substances 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- REQGRJQLONTTLF-UHFFFAOYSA-N 3,6-dimethyl-1h-indole Chemical compound CC1=CC=C2C(C)=CNC2=C1 REQGRJQLONTTLF-UHFFFAOYSA-N 0.000 description 13
- 102100024539 Chymase Human genes 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
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- KJEWJGNNYWWWAH-UHFFFAOYSA-N 2-methyl-2-(4-methylphenyl)cyclobutane-1,3-dione Chemical compound C1=CC(C)=CC=C1C1(C)C(=O)CC1=O KJEWJGNNYWWWAH-UHFFFAOYSA-N 0.000 description 11
- 125000001072 heteroaryl group Chemical group 0.000 description 11
- 125000003107 substituted aryl group Chemical group 0.000 description 11
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- 239000012876 carrier material Substances 0.000 description 10
- 125000000623 heterocyclic group Chemical group 0.000 description 10
- 125000006413 ring segment Chemical group 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
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- 125000003118 aryl group Chemical group 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 125000005594 diketone group Chemical group 0.000 description 9
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- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
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- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 5
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 5
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- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 208000021328 arterial occlusion Diseases 0.000 description 1
- 230000003143 atherosclerotic effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000020411 cell activation Effects 0.000 description 1
- 239000001913 cellulose Chemical class 0.000 description 1
- 229920002678 cellulose Chemical class 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000006254 cycloalkyl carbonyl group Chemical group 0.000 description 1
- 125000005144 cycloalkylsulfonyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229960001008 heparin sodium Drugs 0.000 description 1
- 125000006517 heterocyclyl carbonyl group Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 229960004903 invert sugar Drugs 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- QTSCKHIROATUGX-UHFFFAOYSA-N n-(1h-indol-3-ylmethyl)acetamide Chemical compound C1=CC=C2C(CNC(=O)C)=CNC2=C1 QTSCKHIROATUGX-UHFFFAOYSA-N 0.000 description 1
- IBLCSVLVIJWGPG-UHFFFAOYSA-N n-[1-[2-[(3-benzyl-2-hydroxy-3-methyl-4-oxocyclobuten-1-yl)-phenylmethyl]-6-methyl-1h-indol-3-yl]-2-methylpropan-2-yl]acetamide Chemical compound N1C2=CC(C)=CC=C2C(CC(C)(C)NC(=O)C)=C1C(C=1C=CC=CC=1)C(C1=O)=C(O)C1(C)CC1=CC=CC=C1 IBLCSVLVIJWGPG-UHFFFAOYSA-N 0.000 description 1
- JNEFQSXORRMSDR-UHFFFAOYSA-N n-[[2-[[2-hydroxy-3-methyl-3-(4-methylphenyl)-4-oxocyclobuten-1-yl]-phenylmethyl]-1h-indol-3-yl]methyl]acetamide Chemical compound N1C2=CC=CC=C2C(CNC(=O)C)=C1C(C=1C=CC=CC=1)C(C1=O)=C(O)C1(C)C1=CC=C(C)C=C1 JNEFQSXORRMSDR-UHFFFAOYSA-N 0.000 description 1
- CRAHCIMBGRXVEU-UHFFFAOYSA-N n-[[2-[[2-hydroxy-3-methyl-3-(4-methylphenyl)-4-oxocyclobuten-1-yl]-phenylmethyl]-7-methyl-1h-indol-3-yl]methyl]acetamide Chemical compound N1C2=C(C)C=CC=C2C(CNC(=O)C)=C1C(C=1C=CC=CC=1)C(C1=O)=C(O)C1(C)C1=CC=C(C)C=C1 CRAHCIMBGRXVEU-UHFFFAOYSA-N 0.000 description 1
- RSQTVTAKQPTKRA-UHFFFAOYSA-N n-[[6-chloro-2-[[2-hydroxy-3-methyl-3-(4-methylphenyl)-4-oxocyclobuten-1-yl]-phenylmethyl]-1h-indol-3-yl]methyl]acetamide Chemical compound N1C2=CC(Cl)=CC=C2C(CNC(=O)C)=C1C(C=1C=CC=CC=1)C(C1=O)=C(O)C1(C)C1=CC=C(C)C=C1 RSQTVTAKQPTKRA-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- ZSRNGEOMMHRNAK-UHFFFAOYSA-N n-methyl-n-[(6-methyl-1h-indol-3-yl)methyl]formamide Chemical compound CC1=CC=C2C(CN(C)C=O)=CNC2=C1 ZSRNGEOMMHRNAK-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 229920001223 polyethylene glycol Chemical class 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical class CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Cardiology (AREA)
- Diabetes (AREA)
- Heart & Thoracic Surgery (AREA)
- Pulmonology (AREA)
- Hematology (AREA)
- Immunology (AREA)
- Urology & Nephrology (AREA)
- Rheumatology (AREA)
- Hospice & Palliative Care (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Endocrinology (AREA)
- Obesity (AREA)
- Pain & Pain Management (AREA)
- Vascular Medicine (AREA)
- Dermatology (AREA)
- Emergency Medicine (AREA)
- Physical Education & Sports Medicine (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Indole Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
[式中、
Aは、フェニル環であるか、又は
N、O及びSより選択される1もしくは2個の環ヘテロ原子を含み、残りの環原子がCである、5もしくは6個の環原子の単環式芳香族環である、ヘテロアリール環であるか、又は
N及びS(O)n(ここで、nは、0〜2の整数である)より選択される1もしくは2個の環ヘテロ原子を含み、残りの環原子がCであり、ヘテロシクリル環の環炭素原子の1つが場合によりカルボニル基で置き換えられている、5もしくは6個の環原子の非芳香族単環式環である、ヘテロシクリル環であり;
R1は、水素、ハロゲン、ニトロ、シアノ、アミノ、C1−6アルキル、ヘテロアルキル、C3−7シクロアルキル、C2−6アルケニル、C2−6アルキニル、ヒドロキシ、C1−6アルコキシ、
−NR’R”、−(C0−6アルキレン)−NR’R”(ここで、R’及びR”は、水素、C1−6アルキル、ヘテロアルキル、ホルミル、C1−6アルキルカルボニル、場合により置換されているC3−7シクロアルキルカルボニル、場合により置換されているアリールカルボニル、場合により置換されているヘテロアリールカルボニル、場合により置換されているヘテロシクリルカルボニル、C1−6アルキルスルホニル、場合により置換されているC3−7シクロアルキルスルホニル、場合により置換されているアリールスルホニル、場合により置換されているヘテロアリールスルホニル及び場合により置換されているヘテロシクリルスルホニルからなる群より独立して選択される)であるか、又は
−(C0−6アルキレン)−OR’(ここで、R’は、水素、C1−6アルキル、ヘテロアルキル、ホルミル又はC1−6アルキルカルボニルである)であり;
R2、R2’及びR2”は、独立して、水素、ハロゲン、シアノ、ニトロ、アミノ、モノ−もしくはジC1−6アルキル置換アミノ、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、ヘテロアルキル、ヒドロキシ又はC1−6アルコキシであり;
R3は、水素、ハロゲン、シアノ、ニトロ、アミノ、モノ−もしくはジC1−6アルキル置換アミノ、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、ヘテロアルキル、ヒドロキシ、C1−6アルコキシ、場合により置換されているC3−7シクロアルキル、場合により置換されているアリール、場合により置換されているヘテロアリール、場合により置換されているヘテロシクリル、場合により置換されているC3−7シクロアルキルC1−6アルキル、場合により置換されているアリールC1−6アルキル、場合により置換されているヘテロアリールC1−6アルキル又は場合により置換されているヘテロシクリルC1−6アルキルであり;
R4は、水素、ハロゲン、シアノ、ニトロ、アミノ、モノ−もしくはジC1−6アルキル置換アミノ、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、ヘテロアルキル、ヒドロキシ、C1−6アルコキシ、場合により置換されているC3−7シクロアルキル、場合により置換されているアリール、場合により置換されているヘテロアリール、場合により置換されているヘテロシクリル、場合により置換されているC3−7シクロアルキルC1−6アルキル、場合により置換されているアリールC1−6アルキル、場合により置換されているヘテロアリールC1−6アルキル又は場合により置換されているヘテロシクリルC1−6アルキルであり;
R5は、水素、ハロゲン又はC1−6アルキルであるか;あるいは
R4とR5は、それらが結合している炭素原子と共に、場合により置換されているC3−7シクロアルキル環又は場合により置換されているヘテロシクリル環を形成する]で示される新規なビニル酸誘導体、及びプロドラッグ及び薬学的に許容しうるその塩に関する。
N−(2−{2−[(2−ヒドロキシ−3−メチル−4−オキソ−3−フェニル−シクロブタ−1−エニル)−フェニル−メチル]−6−メチル−1H−インドール−3−イル}−1,1−ジメチル−エチル)−アセトアミド、
3−ヒドロキシ−4−メチル−2−[(3−メチル−1H−インドール−2−イル)−フェニル−メチル]−4−フェニル−シクロブタ−2−エノン、
2−[(3,5−ジメチル−1H−インドール−2−イル)−フェニル−メチル]−3−ヒドロキシ−4−メチル−4−フェニル−シクロブタ−2−エノン、
2−[(3,6−ジメチル−1H−インドール−2−イル)−フェニル−メチル]−3−ヒドロキシ−4−メチル−4−フェニル−シクロブタ−2−エノン、
2−[(5−フルオロ−3−メチル−1H−インドール−2−イル)−フェニル−メチル]−3−ヒドロキシ−4−メチル−4−フェニル−シクロブタ−2−エノン、
N−{2−[(2−ヒドロキシ−3−メチル−4−オキソ−3−フェニル−シクロブタ−1−エニル)−フェニル−メチル]−6−メチル−1H−インドール−3−イルメチル}−アセトアミド、
3−ヒドロキシ−4−メチル−2−[(3−メチル−1H−インドール−2−イル)−フェニル−メチル]−4−p−トリル−シクロブタ−2−エノン、
2−[(3,5−ジメチル−1H−インドール−2−イル)−フェニル−メチル]−3−ヒドロキシ−4−メチル−4−p−トリル−シクロブタ−2−エノン、
2−[(3,6−ジメチル−1H−インドール−2−イル)−フェニル−メチル]−3−ヒドロキシ−4−メチル−4−p−トリル−シクロブタ−2−エノン、
2−[(5−フルオロ−3−メチル−1H−インドール−2−イル)−フェニル−メチル]−3−ヒドロキシ−4−メチル−4−p−トリル−シクロブタ−2−エノン、
N−{2−[(2−ヒドロキシ−3−メチル−4−オキソ−3−p−トリル−シクロブタ−1−エニル)−フェニル−メチル]−6−メチル−1H−インドール−3−イルメチル}−アセトアミド又は
N−{2−[(2−ヒドロキシ−3−メチル−4−オキソ−3−p−トリル−シクロブタ−1−エニル)−フェニル−メチル]−6−メチル−1H−インドール−3−イルメチル}−N−メチル−ホルムアミドである。
1) Brand, Stephen et al., Organic Letters (2003), 5(13), 2343-2346.
2) Kreighbaum, William E. et al., J. Med. Chem. (1980), 23(3), 285-9.
3) Yang, Shyh-Chyun et al., Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry (1999), 38B(8), 897-904.
4) Tsuchiya, Michihiro et al., international patent application, WO8200032 (1982).
5) Hengartner, Urs et al., Journal of Organic Chemistry (1979), 44(22), 3741-7.
6) Somei, Masanori et al., Heterocycles (1992), 33(1), 77-80.
A1.
トルエン(10ml)中の酸VI(30mmole)の混合物を、塩化チオニル(90mmole)で処理し、ガスの発生が停止するまで、約1時間加熱還流した。混合物を蒸発乾固し、酸塩化物VIIを得て、それを更に精製しないで使用した。
ジエチルエーテル(70ml)中の酸塩化物VII(30mmole)及びエトキシアセチレン(ヘキサン中40%、60mmole)の撹拌した溶液に、22℃でトリエチルアミン(50mmole)を加え、撹拌を還流温度で20時間続けた。懸濁液を濾過し、濾液を蒸発させ、残留物をシリカのクロマトグラフィーに付して、エチルエステルVIIIを得た。
テトラヒドロフラン(2ml)中のエチルエステルVIII(2mmole)及び塩酸水溶液(25%、1.5ml)の混合物を、22℃で16時間撹拌した。混合物を蒸発させ、残留物を塩酸水溶液(1N)と酢酸エチルに分配した。有機層を乾燥させ、蒸発させ、シリカのクロマトグラフィーに付して、ジケトンIIを得た。
テトラヒドロフラン(150ml)中の2−ブロモナフタレン誘導体(10mmole)又はベンゾチオフェン誘導体(10mmole)の溶液に、n−ブチルリチウム(n−へキサン中1.6M、11mmole)を−78℃で加え、撹拌を−78℃で1時間続けた(ベンゾチオフェン誘導体の場合、撹拌を22℃で続け、続いて−78℃に冷却した)。混合物をテトラヒドロフラン(20ml)中のアルデヒドIII(10mmole)の溶液で処理し、撹拌を30分間続けた。混合物を飽和NH4Cl水溶液でクエンチし、酢酸エチルで抽出した。有機層を乾燥させ、蒸発させ、残留物をシリカのクロマトグラフィーに付して、アルコールVを得た。
酢酸(4ml)中のジケトンII(1mmole)、アルデヒドIII(1.3mmole)及びインドールIV(1mmole)の溶液を、22℃で16時間撹拌した。懸濁液を濾過し、残留物をペンタンで洗浄した。沈殿が起こらなければ、溶液を分取HPLC(RP−18、CH3CN/H2O、勾配)で精製して、ビニル酸Iを得た。
ジクロロメタン(2ml)中のジケトンII(0.2mmole)及びアルコールV(0.2mmole)の溶液に、トリフルオロ酢酸(0.4mmole)を加え、撹拌を22℃で6時間続けた。懸濁液を蒸発させ、残留物をn−ペンタンで洗浄した。沈殿が起こらなければ、溶液を分取HPLC(RP−18、CH3CN/H2O、勾配)で精製して、ビニル酸Iを得た。
N−(2−{2−[(2−ヒドロキシ−3−イソブチル−3−メチル−4−オキソ−シクロブタ−1−エニル)−フェニル−メチル]−6−メチル−1H−インドール−3−イル}−1,1−ジメチル−エチル)−アセトアミド
N−(2−{2−[(3−ベンジル−2−ヒドロキシ−3−メチル−4−オキソ−シクロブタ−1−エニル)−フェニル−メチル]−6−メチル−1H−インドール−3−イル}−1,1−ジメチル−エチル)−アセトアミド
N−(2−{2−[(2−ヒドロキシ−3−メチル−4−オキソ−3−フェニル−シクロブタ−1−エニル)−フェニル−メチル]−6−メチル−1H−インドール−3−イル}−1,1−ジメチル−エチル)−アセトアミド
N−(2−{2−[(2−ヒドロキシ−3−メチル−4−オキソ−3−p−トリル−シクロブタ−1−エニル)−フェニル−メチル]−6−メチル−1H−インドール−3−イル}−1,1−ジメチル−エチル)−アセトアミド
N−[2−(2−{[3−(4−クロロ−フェニル)−2−ヒドロキシ−3−メチル−4−オキソ−シクロブタ−1−エニル]−フェニル−メチル}−6−メチル−1H−インドール−3−イル)−1,1−ジメチル−エチル]−アセトアミド
3−ヒドロキシ−4−メチル−2−[(3−メチル−1H−インドール−2−イル)−フェニル−メチル]−4−フェニル−シクロブタ−2−エノン
2−[(3,5−ジメチル−1H−インドール−2−イル)−フェニル−メチル]−3−ヒドロキシ−4−メチル−4−フェニル−シクロブタ−2−エノン
2−[(3,6−ジメチル−1H−インドール−2−イル)−フェニル−メチル]−3−ヒドロキシ−4−メチル−4−フェニル−シクロブタ−2−エノン
2−[(5−フルオロ−3−メチル−1H−インドール−2−イル)−フェニル−メチル]−3−ヒドロキシ−4−メチル−4−フェニル−シクロブタ−2−エノン
N−{2−[(2−ヒドロキシ−3−メチル−4−オキソ−3−フェニル−シクロブタ−1−エニル)−フェニル−メチル]−6−メチル−1H−インドール−3−イルメチル}−アセトアミド
3−ヒドロキシ−4−メチル−2−[(3−メチル−1H−インドール−2−イル)−フェニル−メチル]−4−p−トリル−シクロブタ−2−エノン
2−[(3,5−ジメチル−1H−インドール−2−イル)−フェニル−メチル]−3−ヒドロキシ−4−メチル−4−p−トリル−シクロブタ−2−エノン
2−[(3,6−ジメチル−1H−インドール−2−イル)−フェニル−メチル]−3−ヒドロキシ−4−メチル−4−p−トリル−シクロブタ−2−エノン
2−[(5−フルオロ−3−メチル−1H−インドール−2−イル)−フェニル−メチル]−3−ヒドロキシ−4−メチル−4−p−トリル−シクロブタ−2−エノン
N−{2−[(2−ヒドロキシ−3−メチル−4−オキソ−3−p−トリル−シクロブタ−1−エニル)−フェニル−メチル]−1H−インドール−3−イルメチル}−アセトアミド
N−{6−クロロ−2−[(2−ヒドロキシ−3−メチル−4−オキソ−3−p−トリル−シクロブタ−1−エニル)−フェニル−メチル]−1H−インドール−3−イルメチル}−アセトアミド
N−{2−[(2−ヒドロキシ−3−メチル−4−オキソ−3−p−トリル−シクロブタ−1−エニル)−フェニル−メチル]−7−メチル−1H−インドール−3−イルメチル}−アセトアミド
N−{2−[(2−ヒドロキシ−3−メチル−4−オキソ−3−p−トリル−シクロブタ−1−エニル)−フェニル−メチル]−6−メチル−1H−インドール−3−イルメチル}−アセトアミド
N−{2−[(2−ヒドロキシ−3−メチル−4−オキソ−3−p−トリル−シクロブタ−1−エニル)−フェニル−メチル]−6−メチル−1H−インドール−3−イルメチル}−N−メチル−ホルムアミド
3−ヒドロキシ−4−メチル−2−(ナフタレン−2−イル−フェニル−メチル)−4−フェニル−シクロブタ−2−エノン
3−ヒドロキシ−2−[(6−メトキシ−ナフタレン−2−イル)−フェニル−メチル]−4−メチル−4−フェニル−シクロブタ−2−エノン
2−(ベンゾ[b]チオフェン−2−イル−フェニル−メチル)−3−ヒドロキシ−4−メチル−4−フェニル−シクロブタ−2−エノン
2−[(3,5−ジメチル−ベンゾ[b]チオフェン−2−イル)−フェニル−メチル]−3−ヒドロキシ−4−メチル−4−フェニル−シクロブタ−2−エノン
3−ヒドロキシ−4−メチル−2−[(3−メチル−ベンゾ[b]チオフェン−2−イル)−フェニル−メチル]−4−フェニル−シクロブタ−2−エノン
2−[(5−フルオロ−3−メチル−ベンゾ[b]チオフェン−2−イル)−フェニル−メチル]−3−ヒドロキシ−4−メチル−4−フェニル−シクロブタ−2−エノン
3−ヒドロキシ−4−メチル−2−[(5−メチル−ベンゾ[b]チオフェン−2−イル)−フェニル−メチル]−4−フェニル−シクロブタ−2−エノン
3−ヒドロキシ−4−メチル−2−[(6−メチル−ベンゾ[b]チオフェン−2−イル)−フェニル−メチル]−4−フェニル−シクロブタ−2−エノン
下記の成分を含有するフィルムコーティング錠は常法により製造することができる:
下記の成分を含有するカプセル剤は、常法により製造することができる:
注射液は下記の組成を有することができる:
下記の成分を含有する軟ゼラチンカプセル剤は常法により製造できる:
下記の成分を含有するサッシェは常法により製造できる:
Claims (13)
- 式(I):
下記式:
R1は、水素、C 1−6アルキル又は−(C0−6アルキレン)−NR’R”(ここで、R’及びR”は、水素、C1−6アルキル、ホルミル及びC1−6アルキルカルボニルからなる群より独立して選択される)であり;
R2、R2’及びR2”は、独立して、水素、ハロゲン、C 1−6アルキル又はC1−6アルコキシであり;
R3は、フェニルであり;
R4は、水素、C 1−6アルキル、場合により置換されているフェニル、又はフェニルC1−6アルキルであり;
R5は、水素又はC1−6アルキルである]で示される化合物、又は薬学的に許容しうるその塩
[ここで、他の定義のない限り、
用語「場合により置換されているフェニル」は、ハロゲン、ニトロ、シアノ、アミノ、C1−6アルキル、ヒドロキシ、C1−6アルコキシ及びモノ−もしくはジ−C1−6アルキル置換アミノからなる群より独立して選択される1個以上の置換基により場合により置換されている、フェニルを意味する]。 - R1が、C1−6アルキル、−(C2−6アルキレン)−NR’R”[ここで、R’及びR”は、水素、ホルミル及びアセチルからなる群より独立して選択される]である、請求項1又は2に記載の化合物。
- R1が、2−アミノエチル、2−アセチルアミノエチル、2−(N−ホルミル−N−メチルアミノ)エチル、2−アセチルアミノ−2,2−ジメチルエチル、メチル又はイソプロピルである、請求項1又は2に記載の化合物。
- R1が、メチル、2−アセチルアミノエチル、2−アセチルアミノ−2,2−ジメチルエチル又は2−(N−ホルミル−N−メチルアミノ)エチルである、請求項1又は2に記載の化合物。
- R2、R2’及びR2”のうちの二つが、水素であり、もう一方が、水素、ハロゲン、C1−6アルキル又はC1−6アルコキシである、請求項1又は2に記載の化合物。
- R2、R2’及びR2”のうちの二つが、水素であり、もう一方が、水素、クロロ、フルオロ、メチル、エチル又はメトキシである、請求項1又は2に記載の化合物。
- R2、R2’及びR2”のうちの二つが、水素であり、もう一方が、水素、フルオロ又はメチルである、請求項1又は2に記載の化合物。
- R4が、C1−6アルキル、場合により置換されているフェニル、又はフェニルC1−6アルキルであり、
R5が、C 1−6アルキルである、請求項1又は2に記載の化合物。 - R4が、フェニル又は4−メチルフェニルであり、
R5が、メチルである、請求項1又は2に記載の化合物。 - 下記:
N−(2−{2−[(2−ヒドロキシ−3−メチル−4−オキソ−3−フェニル−シクロブタ−1−エニル)−フェニル−メチル]−6−メチル−1H−インドール−3−イル}−1,1−ジメチル−エチル)−アセトアミド、
3−ヒドロキシ−4−メチル−2−[(3−メチル−1H−インドール−2−イル)−フェニル−メチル]−4−フェニル−シクロブタ−2−エノン、
2−[(3,5−ジメチル−1H−インドール−2−イル)−フェニル−メチル]−3−ヒドロキシ−4−メチル−4−フェニル−シクロブタ−2−エノン、
2−[(3,6−ジメチル−1H−インドール−2−イル)−フェニル−メチル]−3−ヒドロキシ−4−メチル−4−フェニル−シクロブタ−2−エノン、
2−[(5−フルオロ−3−メチル−1H−インドール−2−イル)−フェニル−メチル]−3−ヒドロキシ−4−メチル−4−フェニル−シクロブタ−2−エノン、
N−{2−[(2−ヒドロキシ−3−メチル−4−オキソ−3−フェニル−シクロブタ−1−エニル)−フェニル−メチル]−6−メチル−1H−インドール−3−イルメチル}−アセトアミド、
3−ヒドロキシ−4−メチル−2−[(3−メチル−1H−インドール−2−イル)−フェニル−メチル]−4−p−トリル−シクロブタ−2−エノン、
2−[(3,5−ジメチル−1H−インドール−2−イル)−フェニル−メチル]−3−ヒドロキシ−4−メチル−4−p−トリル−シクロブタ−2−エノン、
2−[(3,6−ジメチル−1H−インドール−2−イル)−フェニル−メチル]−3−ヒドロキシ−4−メチル−4−p−トリル−シクロブタ−2−エノン、
2−[(5−フルオロ−3−メチル−1H−インドール−2−イル)−フェニル−メチル]−3−ヒドロキシ−4−メチル−4−p−トリル−シクロブタ−2−エノン、
N−{2−[(2−ヒドロキシ−3−メチル−4−オキソ−3−p−トリル−シクロブタ−1−エニル)−フェニル−メチル]−6−メチル−1H−インドール−3−イルメチル}−アセトアミド又は
N−{2−[(2−ヒドロキシ−3−メチル−4−オキソ−3−p−トリル−シクロブタ−1−エニル)−フェニル−メチル]−6−メチル−1H−インドール−3−イルメチル}−N−メチル−ホルムアミドである、請求項1記載の化合物。 - 請求項1、2又は11のいずれか一項記載の化合物及び薬学的に許容しうる賦形剤を含む、アテローム血栓症又は喘息の治療及び/又は予防のための医薬組成物。
- 請求項1、2又は11のいずれか一項記載の化合物を含む、キマーゼに関連する疾患の治療的処置のための医薬であって、ここで疾患がアテローム血栓症又は喘息である、医薬。
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WO1982000032A1 (en) | 1980-06-25 | 1982-02-07 | Tsuchiya M | Process for preparing indoles |
US4443615A (en) * | 1981-11-10 | 1984-04-17 | Tanabe Seiyaku Co., Ltd. | Process for preparing indoles |
AU7855787A (en) | 1986-08-08 | 1988-02-24 | Upjohn Company, The | Asymmetric synthesis of enantiomerically pure monocyclic beta-lactam intermediates |
JPH0578250A (ja) | 1991-09-18 | 1993-03-30 | Fujisawa Pharmaceut Co Ltd | 肝炎または膵炎の予防・治療剤 |
ATE195530T1 (de) | 1992-05-20 | 2000-09-15 | Merck & Co Inc | 17-ether und thioether von 4-aza-steroiden |
CA2135173A1 (en) | 1992-05-20 | 1993-11-25 | Bruce E. Witzel | Ester derivatives of 4-aza-steroids |
GB9418762D0 (en) | 1994-09-16 | 1994-11-02 | Bayer Ag | Use of substituted cyclopentane-DI-and-triones |
US5814631A (en) * | 1995-09-28 | 1998-09-29 | Suntory Limited | Quinazoline derivatives and applications thereof |
AU723234B2 (en) * | 1996-09-06 | 2000-08-24 | Nippon Kayaku Kabushiki Kaisha | Novel acetamide derivatives and protease inhibitors |
ATE232521T1 (de) | 1998-03-27 | 2003-02-15 | Janssen Pharmaceutica Nv | Hiv hemmende pyrimidin derivate |
EP1099690A4 (en) | 1998-07-23 | 2001-10-17 | Shionogi & Co | MONOCYCLIC BETA LACTAM COMPOUNDS AND CHYMASE INHIBITORS THAT CONTAIN THEM |
EP1136488A4 (en) | 1998-12-01 | 2002-06-12 | Meiji Seika Kaisha | SF2809-I, II, III. VI, V AND VI COMPOUNDS WITH CHYMASE INHIBITING EFFECT |
IL142768A0 (en) | 1998-12-18 | 2002-03-10 | Du Pont Pharm Co | N-ureidoalkyl-piperidines as modulators of chemokine receptor activity |
WO2001053272A1 (fr) * | 2000-01-17 | 2001-07-26 | Teijin Limited | Inhibiteurs de chymase humaine |
US7205318B2 (en) | 2003-03-18 | 2007-04-17 | Bristol-Myers Squibb Company | Lactam-containing cyclic diamines and derivatives as a factor Xa inhibitors |
-
2007
- 2007-09-24 US US11/903,579 patent/US7705034B2/en not_active Expired - Fee Related
- 2007-10-04 JP JP2009531810A patent/JP4976499B2/ja not_active Expired - Fee Related
- 2007-10-04 AU AU2007306399A patent/AU2007306399B2/en not_active Expired - Fee Related
- 2007-10-04 MX MX2009003640A patent/MX2009003640A/es active IP Right Grant
- 2007-10-04 WO PCT/EP2007/060528 patent/WO2008043698A1/en active Application Filing
- 2007-10-04 KR KR1020097007357A patent/KR101122989B1/ko not_active IP Right Cessation
- 2007-10-04 NZ NZ575741A patent/NZ575741A/en not_active IP Right Cessation
- 2007-10-04 CA CA002665046A patent/CA2665046A1/en not_active Abandoned
- 2007-10-04 EP EP07820905A patent/EP2074090A1/en not_active Withdrawn
- 2007-10-04 CN CNA2007800376817A patent/CN101522615A/zh active Pending
- 2007-10-04 BR BRPI0719785-3A2A patent/BRPI0719785A2/pt not_active IP Right Cessation
- 2007-10-04 UA UAA200904015A patent/UA96610C2/ru unknown
- 2007-10-04 RU RU2009117707/04A patent/RU2451013C2/ru not_active IP Right Cessation
- 2007-10-09 TW TW096137881A patent/TWI337864B/zh not_active IP Right Cessation
- 2007-10-11 CL CL200702922A patent/CL2007002922A1/es unknown
- 2007-10-12 AR ARP070104527A patent/AR063269A1/es unknown
- 2007-10-12 PE PE2007001382A patent/PE20081176A1/es not_active Application Discontinuation
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2009
- 2009-03-20 CR CR10678A patent/CR10678A/es not_active Application Discontinuation
- 2009-03-23 IL IL197764A patent/IL197764A0/en unknown
- 2009-03-26 NO NO20091255A patent/NO20091255L/no not_active Application Discontinuation
- 2009-05-11 MA MA31862A patent/MA30882B1/fr unknown
Also Published As
Publication number | Publication date |
---|---|
CN101522615A (zh) | 2009-09-02 |
CA2665046A1 (en) | 2008-04-17 |
NZ575741A (en) | 2011-12-22 |
PE20081176A1 (es) | 2008-09-17 |
MA30882B1 (fr) | 2009-11-02 |
MX2009003640A (es) | 2009-04-22 |
RU2009117707A (ru) | 2010-11-20 |
WO2008043698A1 (en) | 2008-04-17 |
AR063269A1 (es) | 2009-01-14 |
CL2007002922A1 (es) | 2008-05-30 |
TW200824685A (en) | 2008-06-16 |
JP2010505900A (ja) | 2010-02-25 |
US7705034B2 (en) | 2010-04-27 |
AU2007306399A1 (en) | 2008-04-17 |
RU2451013C2 (ru) | 2012-05-20 |
AU2007306399B2 (en) | 2012-05-17 |
KR20090067165A (ko) | 2009-06-24 |
KR101122989B1 (ko) | 2012-03-13 |
TWI337864B (en) | 2011-03-01 |
NO20091255L (no) | 2009-04-27 |
UA96610C2 (ru) | 2011-11-25 |
CR10678A (es) | 2009-06-25 |
IL197764A0 (en) | 2009-12-24 |
US20080096953A1 (en) | 2008-04-24 |
EP2074090A1 (en) | 2009-07-01 |
BRPI0719785A2 (pt) | 2014-11-25 |
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