JP2004507531A - シトクロムp450rai阻害剤としての活性を有する化合物 - Google Patents
シトクロムp450rai阻害剤としての活性を有する化合物 Download PDFInfo
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- JP2004507531A JP2004507531A JP2002523479A JP2002523479A JP2004507531A JP 2004507531 A JP2004507531 A JP 2004507531A JP 2002523479 A JP2002523479 A JP 2002523479A JP 2002523479 A JP2002523479 A JP 2002523479A JP 2004507531 A JP2004507531 A JP 2004507531A
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- Prior art keywords
- carbon atoms
- compound
- alkyl
- phenyl
- mmol
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- 150000001875 compounds Chemical class 0.000 title claims description 571
- 239000003112 inhibitor Substances 0.000 title abstract description 12
- 102100039282 Cytochrome P450 26A1 Human genes 0.000 title abstract description 6
- 101710130818 Cytochrome P450 26A1 Proteins 0.000 title abstract description 6
- 230000000694 effects Effects 0.000 title description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims description 282
- 125000000217 alkyl group Chemical group 0.000 claims description 197
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 86
- -1 3,4-dihydro-4,4-dimethylspiro [2H-1-benzopyran-2,1′-cyclopropane] -6-yl Chemical group 0.000 claims description 84
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 65
- 150000003839 salts Chemical class 0.000 claims description 46
- 229910052801 chlorine Inorganic materials 0.000 claims description 45
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 45
- 229910052794 bromium Inorganic materials 0.000 claims description 44
- 229910052740 iodine Inorganic materials 0.000 claims description 44
- 238000006243 chemical reaction Methods 0.000 claims description 42
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 40
- 239000000203 mixture Substances 0.000 claims description 38
- 229910052731 fluorine Inorganic materials 0.000 claims description 37
- 125000001072 heteroaryl group Chemical group 0.000 claims description 33
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 31
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 31
- 125000003545 alkoxy group Chemical group 0.000 claims description 27
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 27
- 229910052736 halogen Inorganic materials 0.000 claims description 27
- 150000002367 halogens Chemical class 0.000 claims description 27
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 26
- 125000004076 pyridyl group Chemical group 0.000 claims description 26
- 229910052799 carbon Inorganic materials 0.000 claims description 25
- 150000001768 cations Chemical class 0.000 claims description 25
- 125000002541 furyl group Chemical group 0.000 claims description 25
- 125000001624 naphthyl group Chemical group 0.000 claims description 25
- 125000001544 thienyl group Chemical group 0.000 claims description 25
- 229910052760 oxygen Inorganic materials 0.000 claims description 23
- 125000004414 alkyl thio group Chemical group 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- 125000002883 imidazolyl group Chemical group 0.000 claims description 16
- 125000002971 oxazolyl group Chemical group 0.000 claims description 16
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 claims description 16
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 16
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 16
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 16
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 16
- 125000000335 thiazolyl group Chemical group 0.000 claims description 16
- 239000005711 Benzoic acid Substances 0.000 claims description 15
- 150000002148 esters Chemical class 0.000 claims description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 235000010233 benzoic acid Nutrition 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229960003424 phenylacetic acid Drugs 0.000 claims description 7
- FRFBANPMURAGSX-UHFFFAOYSA-N spiro[chromene-2,1'-cyclopropane]-6-carboxylic acid Chemical compound C1=CC2=CC(C(=O)O)=CC=C2OC21CC2 FRFBANPMURAGSX-UHFFFAOYSA-N 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- NSTREUWFTAOOKS-UHFFFAOYSA-N 2-fluorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1F NSTREUWFTAOOKS-UHFFFAOYSA-N 0.000 claims description 4
- 150000007513 acids Chemical class 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- PGAUVHNCULESQT-UHFFFAOYSA-N 2-[4-[2-[3-ethyl-4-(1-phenylmethoxycyclopropyl)phenyl]ethynyl]phenyl]acetic acid Chemical compound CCC1=CC(C#CC=2C=CC(CC(O)=O)=CC=2)=CC=C1C1(OCC=2C=CC=CC=2)CC1 PGAUVHNCULESQT-UHFFFAOYSA-N 0.000 claims description 3
- CVJNXBWYODEEOO-UHFFFAOYSA-N 4-[2-[5-[cyclopropyl(methyl)amino]-8,8-dimethyl-6,7-dihydro-5h-naphthalen-2-yl]ethynyl]-2-fluorobenzoic acid Chemical compound C1CC(C)(C)C2=CC(C#CC=3C=C(F)C(C(O)=O)=CC=3)=CC=C2C1N(C)C1CC1 CVJNXBWYODEEOO-UHFFFAOYSA-N 0.000 claims description 3
- JBKIUXYXZUSWPS-UHFFFAOYSA-N 2-[4-(8,8-dimethyl-5-oxo-6,7-dihydronaphthalene-2-carbonyl)oxyphenyl]acetic acid Chemical compound C1=C2C(C)(C)CCC(=O)C2=CC=C1C(=O)OC1=CC=C(CC(O)=O)C=C1 JBKIUXYXZUSWPS-UHFFFAOYSA-N 0.000 claims description 2
- ITXFQVKXIVKNHH-UHFFFAOYSA-N 2-[4-[2-(2,2,4,4-tetramethyl-3h-chromen-6-yl)ethynyl]phenyl]acetic acid Chemical compound C=1C=C2OC(C)(C)CC(C)(C)C2=CC=1C#CC1=CC=C(CC(O)=O)C=C1 ITXFQVKXIVKNHH-UHFFFAOYSA-N 0.000 claims description 2
- AZLHHZTWOKNMGH-UHFFFAOYSA-N 2-[4-[2-(2-cyclopropyl-4,4-dimethyl-1,3-dihydroisoquinolin-6-yl)ethynyl]-2-fluorophenyl]acetic acid Chemical compound C1=C2C(C)(C)CN(C3CC3)CC2=CC=C1C#CC1=CC=C(CC(O)=O)C(F)=C1 AZLHHZTWOKNMGH-UHFFFAOYSA-N 0.000 claims description 2
- ZLYPJYBYWIRJKY-UHFFFAOYSA-N 2-[4-[2-(2-cyclopropyl-4,4-dimethyl-1,3-dihydroisoquinolin-6-yl)ethynyl]phenyl]acetic acid Chemical compound C1=C2C(C)(C)CN(C3CC3)CC2=CC=C1C#CC1=CC=C(CC(O)=O)C=C1 ZLYPJYBYWIRJKY-UHFFFAOYSA-N 0.000 claims description 2
- LWCBOTGILHXRHK-UHFFFAOYSA-N 2-[4-[2-(8,8-dimethyl-5-oxo-6,7-dihydronaphthalen-2-yl)ethynyl]-2-fluorophenyl]acetic acid Chemical compound C1=C2C(C)(C)CCC(=O)C2=CC=C1C#CC1=CC=C(CC(O)=O)C(F)=C1 LWCBOTGILHXRHK-UHFFFAOYSA-N 0.000 claims description 2
- LYOAHZUZZNMLNC-UHFFFAOYSA-N 2-[4-[2-(8-cyclopropyl-2,2,4,4-tetramethyl-3h-chromen-6-yl)ethynyl]-2-fluorophenyl]acetic acid Chemical compound C=12OC(C)(C)CC(C)(C)C2=CC(C#CC=2C=C(F)C(CC(O)=O)=CC=2)=CC=1C1CC1 LYOAHZUZZNMLNC-UHFFFAOYSA-N 0.000 claims description 2
- FKURZNWAFOUMKK-UHFFFAOYSA-N 2-[4-[2-(8-cyclopropyl-2,2,4,4-tetramethyl-3h-chromen-6-yl)ethynyl]phenyl]acetic acid Chemical compound C=12OC(C)(C)CC(C)(C)C2=CC(C#CC=2C=CC(CC(O)=O)=CC=2)=CC=1C1CC1 FKURZNWAFOUMKK-UHFFFAOYSA-N 0.000 claims description 2
- YFWAMPGMERJYRF-UHFFFAOYSA-N 2-[4-[2-(8-cyclopropyl-4,4-dimethylspiro[3h-chromene-2,1'-cyclopropane]-6-yl)ethynyl]-2-fluorophenyl]acetic acid Chemical compound O1C2=C(C3CC3)C=C(C#CC=3C=C(F)C(CC(O)=O)=CC=3)C=C2C(C)(C)CC21CC2 YFWAMPGMERJYRF-UHFFFAOYSA-N 0.000 claims description 2
- UBXQMNPDZOGDSY-UHFFFAOYSA-N 2-[4-[2-(8-ethyl-2,2,4,4-tetramethyl-3h-chromen-6-yl)ethynyl]phenyl]acetic acid Chemical compound C=1C(C(CC(C)(C)O2)(C)C)=C2C(CC)=CC=1C#CC1=CC=C(CC(O)=O)C=C1 UBXQMNPDZOGDSY-UHFFFAOYSA-N 0.000 claims description 2
- FNIQAQQYKWQMEP-UHFFFAOYSA-N 2-[4-[2-[3-methyl-4-(1-phenylmethoxycyclopropyl)phenyl]ethynyl]phenyl]acetic acid Chemical compound CC1=CC(C#CC=2C=CC(CC(O)=O)=CC=2)=CC=C1C1(OCC=2C=CC=CC=2)CC1 FNIQAQQYKWQMEP-UHFFFAOYSA-N 0.000 claims description 2
- RKSQOVLLZSFLAE-UHFFFAOYSA-N 2-[4-[2-[3-methyl-4-(1-propan-2-yloxycyclopropyl)phenyl]ethynyl]phenyl]acetic acid Chemical compound C=1C=C(C#CC=2C=CC(CC(O)=O)=CC=2)C=C(C)C=1C1(OC(C)C)CC1 RKSQOVLLZSFLAE-UHFFFAOYSA-N 0.000 claims description 2
- ISZHVGGVKUAHGB-UHFFFAOYSA-N 2-[4-[2-[4-(1-methoxycyclopropyl)phenyl]ethynyl]phenyl]acetic acid Chemical compound C=1C=C(C#CC=2C=CC(CC(O)=O)=CC=2)C=CC=1C1(OC)CC1 ISZHVGGVKUAHGB-UHFFFAOYSA-N 0.000 claims description 2
- QBNPHNDDPBUIQE-UHFFFAOYSA-N 2-[4-[2-[4-(1-phenylmethoxycyclopropyl)phenyl]ethynyl]phenyl]acetic acid Chemical compound C1=CC(CC(=O)O)=CC=C1C#CC1=CC=C(C2(CC2)OCC=2C=CC=CC=2)C=C1 QBNPHNDDPBUIQE-UHFFFAOYSA-N 0.000 claims description 2
- HQOZXBGCEKMVTO-UHFFFAOYSA-N 2-[4-[2-[4-(1-propan-2-yloxycyclopropyl)phenyl]ethynyl]phenyl]acetic acid Chemical compound C=1C=C(C#CC=2C=CC(CC(O)=O)=CC=2)C=CC=1C1(OC(C)C)CC1 HQOZXBGCEKMVTO-UHFFFAOYSA-N 0.000 claims description 2
- QLUKNAMQMQFMKP-UHFFFAOYSA-N 2-[4-[2-[4-[1-(2,2-dimethylpropoxy)cyclopropyl]-3-methylphenyl]ethynyl]phenyl]acetic acid Chemical compound CC1=CC(C#CC=2C=CC(CC(O)=O)=CC=2)=CC=C1C1(OCC(C)(C)C)CC1 QLUKNAMQMQFMKP-UHFFFAOYSA-N 0.000 claims description 2
- ZFDGDSDFJCLIBX-UHFFFAOYSA-N 2-[4-[2-[5-[cyclopropyl(methyl)amino]-8,8-dimethyl-6,7-dihydro-5h-naphthalen-2-yl]ethynyl]-2-fluorophenyl]acetic acid Chemical compound C1CC(C)(C)C2=CC(C#CC=3C=C(F)C(CC(O)=O)=CC=3)=CC=C2C1N(C)C1CC1 ZFDGDSDFJCLIBX-UHFFFAOYSA-N 0.000 claims description 2
- WNJLJQKQEKVIJT-UHFFFAOYSA-N 2-fluoro-4-[2-(2,2,4,4-tetramethyl-3h-chromen-6-yl)ethynyl]benzoic acid Chemical compound C=1C=C2OC(C)(C)CC(C)(C)C2=CC=1C#CC1=CC=C(C(O)=O)C(F)=C1 WNJLJQKQEKVIJT-UHFFFAOYSA-N 0.000 claims description 2
- HFSKVLVQPKQVFD-UHFFFAOYSA-N 4-[2-(1-cyclopropyl-4,4-dimethyl-2,3-dihydroquinolin-6-yl)ethynyl]benzoic acid Chemical compound C12=CC=C(C#CC=3C=CC(=CC=3)C(O)=O)C=C2C(C)(C)CCN1C1CC1 HFSKVLVQPKQVFD-UHFFFAOYSA-N 0.000 claims description 2
- VSHLPGYGJSORKV-UHFFFAOYSA-N 4-[2-(8,8-dimethyl-5-oxo-6,7-dihydronaphthalen-2-yl)ethynyl]-2-fluorobenzoic acid Chemical compound C1=C2C(C)(C)CCC(=O)C2=CC=C1C#CC1=CC=C(C(O)=O)C(F)=C1 VSHLPGYGJSORKV-UHFFFAOYSA-N 0.000 claims description 2
- QELVCKRITXHFTQ-UHFFFAOYSA-N 4-[2-(8-cyclopropyl-2,2,4,4-tetramethyl-3h-chromen-6-yl)ethynyl]benzoic acid Chemical compound C=12OC(C)(C)CC(C)(C)C2=CC(C#CC=2C=CC(=CC=2)C(O)=O)=CC=1C1CC1 QELVCKRITXHFTQ-UHFFFAOYSA-N 0.000 claims description 2
- APJKXYNFLYDWJW-UHFFFAOYSA-N 4-[2-(8-cyclopropyl-4,4-dimethylspiro[3h-chromene-2,1'-cyclopropane]-6-yl)ethynyl]-2-fluorobenzoic acid Chemical compound O1C2=C(C3CC3)C=C(C#CC=3C=C(F)C(C(O)=O)=CC=3)C=C2C(C)(C)CC21CC2 APJKXYNFLYDWJW-UHFFFAOYSA-N 0.000 claims description 2
- CODXXKPMKMZJPB-UHFFFAOYSA-N 4-[2-[3-ethyl-4-(1-phenylmethoxycyclopropyl)phenyl]ethynyl]benzoic acid Chemical compound CCC1=CC(C#CC=2C=CC(=CC=2)C(O)=O)=CC=C1C1(OCC=2C=CC=CC=2)CC1 CODXXKPMKMZJPB-UHFFFAOYSA-N 0.000 claims description 2
- IVAZIDXFVDVVCY-UHFFFAOYSA-N 4-[2-[3-methyl-4-(1-phenylmethoxycyclopropyl)phenyl]ethynyl]benzoic acid Chemical compound CC1=CC(C#CC=2C=CC(=CC=2)C(O)=O)=CC=C1C1(OCC=2C=CC=CC=2)CC1 IVAZIDXFVDVVCY-UHFFFAOYSA-N 0.000 claims description 2
- ZIUKLJTWFKPKDQ-UHFFFAOYSA-N 4-[2-[3-methyl-4-(1-propan-2-yloxycyclopropyl)phenyl]ethynyl]benzoic acid Chemical compound C=1C=C(C#CC=2C=CC(=CC=2)C(O)=O)C=C(C)C=1C1(OC(C)C)CC1 ZIUKLJTWFKPKDQ-UHFFFAOYSA-N 0.000 claims description 2
- VNIVFNHKLXHLGL-UHFFFAOYSA-N 4-[2-[4-(1-methoxycyclopropyl)phenyl]ethynyl]benzoic acid Chemical compound C=1C=C(C#CC=2C=CC(=CC=2)C(O)=O)C=CC=1C1(OC)CC1 VNIVFNHKLXHLGL-UHFFFAOYSA-N 0.000 claims description 2
- GYAFAFMCFDHMGV-UHFFFAOYSA-N 4-[2-[4-(1-phenylmethoxycyclopropyl)phenyl]ethynyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C#CC1=CC=C(C2(CC2)OCC=2C=CC=CC=2)C=C1 GYAFAFMCFDHMGV-UHFFFAOYSA-N 0.000 claims description 2
- ZLTXPVVWEWNZSO-UHFFFAOYSA-N 4-[2-[4-(1-propan-2-yloxycyclopropyl)phenyl]ethynyl]benzoic acid Chemical compound C=1C=C(C#CC=2C=CC(=CC=2)C(O)=O)C=CC=1C1(OC(C)C)CC1 ZLTXPVVWEWNZSO-UHFFFAOYSA-N 0.000 claims description 2
- GGZDTLRYODNTCH-UHFFFAOYSA-N 4-[2-[4-[1-(2,2-dimethylpropoxy)cyclopropyl]-3-methylphenyl]ethynyl]benzoic acid Chemical compound CC1=CC(C#CC=2C=CC(=CC=2)C(O)=O)=CC=C1C1(OCC(C)(C)C)CC1 GGZDTLRYODNTCH-UHFFFAOYSA-N 0.000 claims description 2
- 125000005907 alkyl ester group Chemical group 0.000 claims 30
- 125000002619 bicyclic group Chemical group 0.000 claims 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 3
- ZGWVVSCCYFKFBE-UHFFFAOYSA-N 2-[4-[2-(3,5-ditert-butyl-4-methoxyphenyl)ethynyl]phenyl]acetic acid Chemical compound C1=C(C(C)(C)C)C(OC)=C(C(C)(C)C)C=C1C#CC1=CC=C(CC(O)=O)C=C1 ZGWVVSCCYFKFBE-UHFFFAOYSA-N 0.000 claims 1
- GNPNJKBHUSKWND-UHFFFAOYSA-N 2-[4-[2-(4-imidazol-1-yl-2,3-dimethylphenyl)ethynyl]phenyl]acetic acid Chemical compound CC1=C(C)C(N2C=NC=C2)=CC=C1C#CC1=CC=C(CC(O)=O)C=C1 GNPNJKBHUSKWND-UHFFFAOYSA-N 0.000 claims 1
- ZPLGNBCEQJWHPT-UHFFFAOYSA-N 2-[4-[2-(4-imidazol-1-yl-2-methyl-3-propan-2-ylphenyl)ethynyl]phenyl]acetic acid Chemical compound CC(C)C1=C(C)C(C#CC=2C=CC(CC(O)=O)=CC=2)=CC=C1N1C=CN=C1 ZPLGNBCEQJWHPT-UHFFFAOYSA-N 0.000 claims 1
- RABWFFBPJKCGCA-UHFFFAOYSA-N 2-[4-[2-(4-imidazol-1-yl-2-methyl-3-propan-2-ylphenyl)ethynyl]phenyl]benzoic acid Chemical compound CC(C)C1=C(C)C(C#CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C(O)=O)=CC=C1N1C=CN=C1 RABWFFBPJKCGCA-UHFFFAOYSA-N 0.000 claims 1
- DGFTWCCCWFYBFB-UHFFFAOYSA-N 2-[4-[2-(5-imidazol-1-yl-8,8-dimethyl-6,7-dihydro-5h-naphthalen-2-yl)ethynyl]phenyl]acetic acid Chemical compound C1=C2C(C)(C)CCC(N3C=NC=C3)C2=CC=C1C#CC1=CC=C(CC(O)=O)C=C1 DGFTWCCCWFYBFB-UHFFFAOYSA-N 0.000 claims 1
- QUEYASYTUGEKAJ-UHFFFAOYSA-N 2-[4-[2-[4-[(1-methylcyclopropyl)oxymethyl]-3-propan-2-ylphenyl]ethynyl]phenyl]acetic acid Chemical compound CC(C)C1=CC(C#CC=2C=CC(CC(O)=O)=CC=2)=CC=C1COC1(C)CC1 QUEYASYTUGEKAJ-UHFFFAOYSA-N 0.000 claims 1
- JWGMJVCTCINGQN-UHFFFAOYSA-N 2-[4-[2-[4-[[cyclopropyl(ethyl)amino]methyl]-3-methylphenyl]ethynyl]phenyl]acetic acid Chemical compound C1CC1N(CC)CC(C(=C1)C)=CC=C1C#CC1=CC=C(CC(O)=O)C=C1 JWGMJVCTCINGQN-UHFFFAOYSA-N 0.000 claims 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims 1
- YNJIMZKUXOYINQ-UHFFFAOYSA-N 4-[2-(4-imidazol-1-yl-2,3-dimethylphenyl)ethynyl]benzoic acid Chemical compound CC1=C(C)C(N2C=NC=C2)=CC=C1C#CC1=CC=C(C(O)=O)C=C1 YNJIMZKUXOYINQ-UHFFFAOYSA-N 0.000 claims 1
- LTWKGLUJOILBLP-UHFFFAOYSA-N 4-[2-[4-[1-(2-phenylethylamino)cyclopropyl]phenyl]ethynyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C#CC1=CC=C(C2(CC2)NCCC=2C=CC=CC=2)C=C1 LTWKGLUJOILBLP-UHFFFAOYSA-N 0.000 claims 1
- QICQZRSZHVZUNX-UHFFFAOYSA-N 4-[2-[4-[1-(benzylamino)cyclopropyl]phenyl]ethynyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C#CC1=CC=C(C2(CC2)NCC=2C=CC=CC=2)C=C1 QICQZRSZHVZUNX-UHFFFAOYSA-N 0.000 claims 1
- ZTHZFYAFRKPOFL-UHFFFAOYSA-N 4-[2-[4-[1-(dibenzylamino)cyclopropyl]phenyl]ethynyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C#CC1=CC=C(C2(CC2)N(CC=2C=CC=CC=2)CC=2C=CC=CC=2)C=C1 ZTHZFYAFRKPOFL-UHFFFAOYSA-N 0.000 claims 1
- ODDUJFDAXPFOJC-UHFFFAOYSA-N 4-[2-[4-[1-(dipropylamino)cyclopropyl]phenyl]ethynyl]benzoic acid Chemical compound C=1C=C(C#CC=2C=CC(=CC=2)C(O)=O)C=CC=1C1(N(CCC)CCC)CC1 ODDUJFDAXPFOJC-UHFFFAOYSA-N 0.000 claims 1
- PBMNEISYXMSEQQ-UHFFFAOYSA-N 4-[2-[4-[1-(propylamino)cyclopropyl]phenyl]ethynyl]benzoic acid Chemical compound C=1C=C(C#CC=2C=CC(=CC=2)C(O)=O)C=CC=1C1(NCCC)CC1 PBMNEISYXMSEQQ-UHFFFAOYSA-N 0.000 claims 1
- GIYYNVDLOYBHRM-UHFFFAOYSA-N 4-[2-[4-[[cyclopropyl(ethyl)amino]methyl]-3-methylphenyl]ethynyl]benzoic acid Chemical compound C1CC1N(CC)CC(C(=C1)C)=CC=C1C#CC1=CC=C(C(O)=O)C=C1 GIYYNVDLOYBHRM-UHFFFAOYSA-N 0.000 claims 1
- ZNNVLFPXIQFABK-UHFFFAOYSA-N 4-[2-[4-[[cyclopropyl(ethyl)amino]methyl]-3-propan-2-ylphenyl]ethynyl]benzoic acid Chemical compound C1CC1N(CC)CC(C(=C1)C(C)C)=CC=C1C#CC1=CC=C(C(O)=O)C=C1 ZNNVLFPXIQFABK-UHFFFAOYSA-N 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 238000011282 treatment Methods 0.000 abstract description 33
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 abstract description 25
- 229930002330 retinoic acid Natural products 0.000 abstract description 25
- 229960001727 tretinoin Drugs 0.000 abstract description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 20
- 201000010099 disease Diseases 0.000 abstract description 17
- 102000004190 Enzymes Human genes 0.000 abstract description 6
- 108090000790 Enzymes Proteins 0.000 abstract description 6
- 230000001939 inductive effect Effects 0.000 abstract description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 460
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 424
- 239000000543 intermediate Substances 0.000 description 264
- 238000005160 1H NMR spectroscopy Methods 0.000 description 231
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 213
- 238000000034 method Methods 0.000 description 194
- 235000019439 ethyl acetate Nutrition 0.000 description 163
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 162
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- NBBLVSSVECGEJY-UHFFFAOYSA-N methyl 2-[4-[2-[4-(1-phenylmethoxycyclopropyl)phenyl]ethynyl]phenyl]acetate Chemical compound C1=CC(CC(=O)OC)=CC=C1C#CC1=CC=C(C2(CC2)OCC=2C=CC=CC=2)C=C1 NBBLVSSVECGEJY-UHFFFAOYSA-N 0.000 description 2
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Classifications
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- C07C59/40—Unsaturated compounds
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
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- C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
- C07C65/28—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups having unsaturation outside the aromatic rings
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Enzymes And Modification Thereof (AREA)
- Medicines Containing Plant Substances (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Quinoline Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
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Applications Claiming Priority (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US09/651,004 US6369261B1 (en) | 2000-08-29 | 2000-08-29 | Compounds having activity as inhibitors of cytochrome P450RAI |
| US09/651,001 US6291677B1 (en) | 2000-08-29 | 2000-08-29 | Compounds having activity as inhibitors of cytochrome P450RAI |
| US09/651,564 US6380256B1 (en) | 2000-08-29 | 2000-08-29 | Compounds having activity as inhibitors of cytochrome P450RAI |
| US09/651,235 US6252090B1 (en) | 2000-08-29 | 2000-08-29 | Compounds having activity as inhibitors of cytochrome P450RAI |
| US09/651,234 US6387951B1 (en) | 2000-08-29 | 2000-08-29 | Compounds having activity as inhibitors of cytochrome P450RAI |
| US09/651,566 US6369225B1 (en) | 2000-08-29 | 2000-08-29 | Compounds having activity as inhibitors of cytochrome P450RAI |
| US09/651,003 US6303785B1 (en) | 2000-08-29 | 2000-08-29 | Compounds having activity as inhibitors of cytochrome P450RAI |
| PCT/US2001/025443 WO2002018361A2 (en) | 2000-08-29 | 2001-08-14 | Compounds having activity as inhibitors of cytochrome p450rai |
Publications (2)
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| JP2004507531A true JP2004507531A (ja) | 2004-03-11 |
| JP2004507531A5 JP2004507531A5 (enExample) | 2008-10-02 |
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| JP2002523479A Pending JP2004507531A (ja) | 2000-08-29 | 2001-08-14 | シトクロムp450rai阻害剤としての活性を有する化合物 |
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| Country | Link |
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| EP (1) | EP1366036B1 (enExample) |
| JP (1) | JP2004507531A (enExample) |
| AT (1) | ATE315558T1 (enExample) |
| AU (2) | AU8647101A (enExample) |
| CA (1) | CA2420869A1 (enExample) |
| DE (1) | DE60116642T2 (enExample) |
| ES (1) | ES2256288T3 (enExample) |
| WO (1) | WO2002018361A2 (enExample) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2017537140A (ja) * | 2014-10-10 | 2017-12-14 | ハイ フォース リサーチ リミテッド | 蛍光合成レチノイド |
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| US6313107B1 (en) * | 2000-08-29 | 2001-11-06 | Allergan Sales, Inc. | Methods of providing and using compounds having activity as inhibitors of cytochrome P450RAI |
| US7482366B2 (en) | 2001-12-21 | 2009-01-27 | X-Ceptor Therapeutics, Inc. | Modulators of LXR |
| JP5082033B2 (ja) | 2001-12-21 | 2012-11-28 | エグゼリクシス パテント カンパニー エルエルシー | Lxrのモジュレーター |
| US6740676B2 (en) * | 2002-03-19 | 2004-05-25 | Allergan, Inc. | 4-[(8-ethynyl, 8-vinyl or 8-ethynyl-methyl)-6-chromanoyl]-benzoic and 2-[4-[(8-ethynyl, 8-vinyl or 8-ethynyl-methyl)-6-chromanoyl]-phenyl]-acetic acid, their esters and salts having cytochrome p450rai inhibitory activity |
| US7504508B2 (en) | 2002-10-04 | 2009-03-17 | Millennium Pharmaceuticals, Inc. | PGD2 receptor antagonists for the treatment of inflammatory diseases |
| MXPA05003456A (es) | 2002-10-04 | 2005-07-05 | Millennium Pharm Inc | Antagonistas del receptor de pgd2 para el tratamiento de enfermedades inflamatorias. |
| GB0302094D0 (en) | 2003-01-29 | 2003-02-26 | Pharmagene Lab Ltd | EP4 receptor antagonists |
| BRPI0413923A (pt) | 2003-08-29 | 2006-11-07 | Ono Pharmaceutical Co | composto capaz de ligar o receptor de s1p e uso farmacêutico do mesmo |
| GB0324269D0 (en) | 2003-10-16 | 2003-11-19 | Pharmagene Lab Ltd | EP4 receptor antagonists |
| US7226951B2 (en) | 2003-12-17 | 2007-06-05 | Allergan, Inc. | Compounds having selective cytochrome P450RAI-1 or selective cytochrome P450RAI-2 inhibitory activity and methods of obtaining the same |
| PL1826197T3 (pl) | 2004-12-13 | 2012-06-29 | Ono Pharmaceutical Co | Pochodna kwasu aminokarboksylowego i jej zastosowanie lecznicze |
| AU2005316739A1 (en) | 2004-12-13 | 2006-06-22 | Galileo Pharmaceuticals, Inc. | Spiro derivatives as lipoxygenase inhibitors |
| CA2598133A1 (en) | 2005-02-24 | 2006-08-31 | Millennium Pharmaceuticals, Inc. | Pgd2 receptor antagonists for the treatment of inflammatory diseases |
| CN103402986A (zh) | 2010-11-24 | 2013-11-20 | 阿勒根公司 | S1p受体的调节剂 |
| CA2848540A1 (en) | 2011-09-15 | 2013-03-21 | Arizona Board Of Regents, A Body Corporate Of The State Of Arizona Acting For And On Behalf Of Arizona State University | Therapeutic compounds |
| WO2015109318A2 (en) | 2014-01-17 | 2015-07-23 | Arizona Board Of Regents, A Body Corporate Of The State Of Arizona, Acting For And On Behalf Of Arizona State University | Therapeutic methods |
| US10238655B2 (en) | 2017-01-23 | 2019-03-26 | Arizona Board Of Regents On Behalf Of Arizona State University | Dihydroindene and tetrahydronaphthalene compounds |
| US10238626B2 (en) | 2017-01-23 | 2019-03-26 | Arizona Board Of Regents On Behalf Of Arizona State University | Therapeutic compounds |
| US10231947B2 (en) | 2017-01-23 | 2019-03-19 | Arizona Board Of Regents On Behalf Of Arizona State University | Isochroman compounds and methods of use thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6323868A (ja) * | 1986-07-11 | 1988-02-01 | イー・アイ・デュポン・ドゥ・ヌムール・アンド・カンパニー | アンギオテンシン2受容体遮断性イミダゾ−ル |
| WO1996020930A1 (en) * | 1994-12-29 | 1996-07-11 | Allergan | Acetylenes disubstituted with a 5 or 8 substituted tetrahydronaphthyl or dihydronaphthyl group and with an aryl or heteroaryl groups having retinoid-like biological activity |
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| DE3475305D1 (en) * | 1983-07-05 | 1988-12-29 | Pfizer | Carboxylic acid derivatives useful for inhibiting the degradation of cartilage |
| US5089509A (en) * | 1988-09-15 | 1992-02-18 | Allergan, Inc. | Disubstituted acetylenes bearing heteroaromatic and heterobicyclic groups having retinoid like activity |
| US5015658A (en) * | 1988-06-29 | 1991-05-14 | Allergan, Inc. | Thiochroman esters of phenols and terephthallates having retinoid-like activity |
| US5045551A (en) * | 1989-09-19 | 1991-09-03 | Allergan, Inc. | Acetylenes disubstituted with a heteroaromatic group and a 2-substituted chromanyl, thiochromanyl or 1,2,3,4-tetrahydroquinolinyl group having retinoid-like activity |
| US5023341A (en) * | 1989-09-19 | 1991-06-11 | Allergan, Inc. | Compounds having a disubstituted acetylene moiety and retinoic acid-like biological activity |
| US5202471A (en) * | 1990-02-06 | 1993-04-13 | Allergan, Inc. | Alkyl, alkoxy and thioalkoxy substituted diphenyl acetylenes having retinoid like activity |
| US5134159A (en) * | 1991-03-26 | 1992-07-28 | Allergan, Inc. | 7-chromanyl esters of phenols and benzoic acids having retinoid-like activity |
| US5489584A (en) * | 1994-12-29 | 1996-02-06 | Allergan, Inc. | Acetylenes disubstituted with a 5-amino or substituted 5-amino substituted tetrahydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity |
| US5498795A (en) * | 1994-12-29 | 1996-03-12 | Allergan, Inc. | Acetylenes disubstituted with hydroxyaryl and aryl or heteroaryl groups having retinoid-like biological activity |
| US5965606A (en) * | 1995-12-29 | 1999-10-12 | Allergan Sales, Inc. | Methods of treatment with compounds having RAR.sub.α receptor specific or selective activity |
| US5739338A (en) * | 1996-11-05 | 1998-04-14 | Allergan | N-aryl substituted tetrahydroquinolines having retinoid agonist, retinoid antagonist or retinoid inverse agonist type biological activity |
-
2001
- 2001-08-14 ES ES01965920T patent/ES2256288T3/es not_active Expired - Lifetime
- 2001-08-14 DE DE60116642T patent/DE60116642T2/de not_active Expired - Fee Related
- 2001-08-14 AT AT01965920T patent/ATE315558T1/de not_active IP Right Cessation
- 2001-08-14 AU AU8647101A patent/AU8647101A/xx active Pending
- 2001-08-14 WO PCT/US2001/025443 patent/WO2002018361A2/en not_active Ceased
- 2001-08-14 EP EP01965920A patent/EP1366036B1/en not_active Expired - Lifetime
- 2001-08-14 JP JP2002523479A patent/JP2004507531A/ja active Pending
- 2001-08-14 CA CA002420869A patent/CA2420869A1/en not_active Abandoned
- 2001-08-14 AU AU2001286471A patent/AU2001286471B2/en not_active Ceased
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6323868A (ja) * | 1986-07-11 | 1988-02-01 | イー・アイ・デュポン・ドゥ・ヌムール・アンド・カンパニー | アンギオテンシン2受容体遮断性イミダゾ−ル |
| WO1996020930A1 (en) * | 1994-12-29 | 1996-07-11 | Allergan | Acetylenes disubstituted with a 5 or 8 substituted tetrahydronaphthyl or dihydronaphthyl group and with an aryl or heteroaryl groups having retinoid-like biological activity |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2017537140A (ja) * | 2014-10-10 | 2017-12-14 | ハイ フォース リサーチ リミテッド | 蛍光合成レチノイド |
| US10759762B2 (en) | 2014-10-10 | 2020-09-01 | High Force Research Limited | Fluorescent synthetic retinoids |
| JP7178781B2 (ja) | 2014-10-10 | 2022-11-28 | ハイ フォース リサーチ リミテッド | 蛍光合成レチノイド |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1366036A2 (en) | 2003-12-03 |
| DE60116642T2 (de) | 2006-11-09 |
| HK1059439A1 (en) | 2004-07-02 |
| ES2256288T3 (es) | 2006-07-16 |
| WO2002018361A3 (en) | 2003-07-31 |
| DE60116642D1 (de) | 2006-04-06 |
| WO2002018361A2 (en) | 2002-03-07 |
| ATE315558T1 (de) | 2006-02-15 |
| CA2420869A1 (en) | 2002-03-07 |
| AU2001286471B2 (en) | 2006-09-07 |
| AU8647101A (en) | 2002-03-13 |
| EP1366036B1 (en) | 2006-01-11 |
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