JP2012512178A - リゾホスファチジン酸受容体のアンタゴニスト - Google Patents

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Publication number

JP2012512178A

JP2012512178A JP2011540973A JP2011540973A JP2012512178A JP 2012512178 A JP2012512178 A JP 2012512178A JP 2011540973 A JP2011540973 A JP 2011540973A JP 2011540973 A JP2011540973 A JP 2011540973A JP 2012512178 A JP2012512178 A JP 2012512178A

Authority

JP

Japan

Prior art keywords

phenyl

methyl

compound

biphenyl

isoxazol

Prior art date

2008-12-15

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.)

Pending

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• 229940123977 Lysophosphatidic acid receptor antagonist Drugs 0.000 title abstract 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 305
• 238000000034 method Methods 0.000 claims abstract description 121
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 39
• 230000001404 mediated effect Effects 0.000 claims abstract description 26
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• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 108
• 241000124008 Mammalia Species 0.000 claims description 90
• 201000010099 disease Diseases 0.000 claims description 85
• -1 4 ′-{3-methyl-4- [1- (3-trifluoromethyl-phenyl) -ethoxycarbonylamino] -isoxazol-5-yl} -biphenyl-4-yl Chemical group 0.000 claims description 78
• 206010016654 Fibrosis Diseases 0.000 claims description 51
• 239000002253 acid Substances 0.000 claims description 47
• 230000004761 fibrosis Effects 0.000 claims description 47
• 229910052739 hydrogen Inorganic materials 0.000 claims description 43
• QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 34
• 229910052731 fluorine Inorganic materials 0.000 claims description 29
• 229910052801 chlorine Inorganic materials 0.000 claims description 28
• 239000000243 solution Substances 0.000 claims description 27
• 208000019425 cirrhosis of liver Diseases 0.000 claims description 25
• 150000003839 salts Chemical class 0.000 claims description 25
• 210000001519 tissue Anatomy 0.000 claims description 24
• 206010028980 Neoplasm Diseases 0.000 claims description 22
• 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 21
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• 210000000056 organ Anatomy 0.000 claims description 17
• XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 16
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• 229910052799 carbon Inorganic materials 0.000 claims description 15
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• TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 claims description 8
• 206010027476 Metastases Diseases 0.000 claims description 8
• 229940125851 compound 27 Drugs 0.000 claims description 8
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
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• YSGICPNQNJZMCE-UHFFFAOYSA-N 2-[4-[4-[4-[1-(2-fluorophenyl)ethoxycarbonylamino]-3-methyl-1,2-oxazol-5-yl]phenyl]phenyl]acetic acid Chemical compound C=1C=CC=C(F)C=1C(C)OC(=O)NC=1C(C)=NOC=1C(C=C1)=CC=C1C1=CC=C(CC(O)=O)C=C1 YSGICPNQNJZMCE-UHFFFAOYSA-N 0.000 claims description 7
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• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 6
• NQCJTTBAAFMHFN-UHFFFAOYSA-N 2-[4-[4-[4-[1-(2-methoxyphenyl)ethoxycarbonylamino]-3-methyl-1,2-oxazol-5-yl]phenyl]phenyl]acetic acid Chemical compound COC1=CC=CC=C1C(C)OC(=O)NC1=C(C=2C=CC(=CC=2)C=2C=CC(CC(O)=O)=CC=2)ON=C1C NQCJTTBAAFMHFN-UHFFFAOYSA-N 0.000 claims description 6
• 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 6
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• MRNRJQHRNSENIU-UHFFFAOYSA-N 2-[3-[4-[4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-methyl-1,2-oxazol-5-yl]phenyl]-4-methoxyphenyl]acetic acid Chemical compound COC1=CC=C(CC(O)=O)C=C1C1=CC=C(C2=C(C(C)=NO2)NC(=O)OC(C)C=2C(=CC=CC=2)Cl)C=C1 MRNRJQHRNSENIU-UHFFFAOYSA-N 0.000 claims description 5
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• 125000003831 tetrazolyl group Chemical group 0.000 claims description 4
• 125000002733 (C1-C6) fluoroalkyl group Chemical group 0.000 claims description 3
• WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 claims description 3
• KLPSKQJHAFYOFX-UHFFFAOYSA-N 2-[4-[4-[3-methyl-4-[1-[2-(trifluoromethyl)phenyl]ethoxycarbonylamino]-1,2-oxazol-5-yl]phenyl]phenyl]acetic acid Chemical compound C=1C=CC=C(C(F)(F)F)C=1C(C)OC(=O)NC=1C(C)=NOC=1C(C=C1)=CC=C1C1=CC=C(CC(O)=O)C=C1 KLPSKQJHAFYOFX-UHFFFAOYSA-N 0.000 claims description 3
• LNDDRUPAICPXIN-GOSISDBHSA-N 2-[4-[4-[3-methyl-4-[[(1r)-1-phenylethoxy]carbonylamino]-1,2-oxazol-5-yl]phenyl]phenyl]acetic acid Chemical compound O([C@H](C)C=1C=CC=CC=1)C(=O)NC=1C(C)=NOC=1C(C=C1)=CC=C1C1=CC=C(CC(O)=O)C=C1 LNDDRUPAICPXIN-GOSISDBHSA-N 0.000 claims description 3
• RCPPMKCYGLGOSN-UHFFFAOYSA-N 2-[4-[4-[4-[1-(2-chlorophenyl)ethoxycarbonylamino]-3-methyl-1,2-oxazol-5-yl]phenyl]phenyl]propanoic acid Chemical compound C=1C=CC=C(Cl)C=1C(C)OC(=O)NC=1C(C)=NOC=1C(C=C1)=CC=C1C1=CC=C(C(C)C(O)=O)C=C1 RCPPMKCYGLGOSN-UHFFFAOYSA-N 0.000 claims description 3
• XTIJUKFPBVYTEE-UHFFFAOYSA-N 2-[4-[4-[4-[1-(2-fluorophenyl)ethoxycarbonylamino]-3-methyl-1,2-oxazol-5-yl]phenyl]phenyl]propanoic acid Chemical compound C=1C=CC=C(F)C=1C(C)OC(=O)NC=1C(C)=NOC=1C(C=C1)=CC=C1C1=CC=C(C(C)C(O)=O)C=C1 XTIJUKFPBVYTEE-UHFFFAOYSA-N 0.000 claims description 3
• WWQTWEWAPUCDDZ-QGZVFWFLSA-N 2-[4-[4-[4-[[(1r)-1-(2-chlorophenyl)ethoxy]carbonylamino]-3-methyl-1,2-oxazol-5-yl]phenyl]phenyl]acetic acid Chemical compound O([C@H](C)C=1C(=CC=CC=1)Cl)C(=O)NC=1C(C)=NOC=1C(C=C1)=CC=C1C1=CC=C(CC(O)=O)C=C1 WWQTWEWAPUCDDZ-QGZVFWFLSA-N 0.000 claims description 3
• 208000031104 Arterial Occlusive disease Diseases 0.000 claims description 3
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• 206010035226 Plasma cell myeloma Diseases 0.000 claims description 3
• GGBQHSGLUNQRHB-GOSISDBHSA-N [(1r)-1-(2-fluorophenyl)ethyl] n-[5-[4-[4-(cyanomethyl)phenyl]phenyl]-3-methyl-1,2-oxazol-4-yl]carbamate Chemical compound O([C@H](C)C=1C(=CC=CC=1)F)C(=O)NC=1C(C)=NOC=1C(C=C1)=CC=C1C1=CC=C(CC#N)C=C1 GGBQHSGLUNQRHB-GOSISDBHSA-N 0.000 claims description 3
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• 230000027939 micturition Effects 0.000 claims description 3
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• ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 claims description 2
• UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 claims description 2
• AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 claims description 2
• ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 claims description 2
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• GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims description 2
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• VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 claims description 2
• WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 claims description 2
• STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 claims description 2
• QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 2
• IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 claims description 2
• UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 claims description 2
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• KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 claims description 2
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