JP2016537361A - 新規なヘテロ環化合物 - Google Patents
新規なヘテロ環化合物 Download PDFInfo
- Publication number
- JP2016537361A JP2016537361A JP2016530884A JP2016530884A JP2016537361A JP 2016537361 A JP2016537361 A JP 2016537361A JP 2016530884 A JP2016530884 A JP 2016530884A JP 2016530884 A JP2016530884 A JP 2016530884A JP 2016537361 A JP2016537361 A JP 2016537361A
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- JP
- Japan
- Prior art keywords
- methyl
- benzyl
- phenyl
- oxy
- ynoic acid
- 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
- 150000002391 heterocyclic compounds Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 76
- 102100026148 Free fatty acid receptor 1 Human genes 0.000 claims abstract description 51
- 238000000034 method Methods 0.000 claims abstract description 23
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 18
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 13
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- 101000912510 Homo sapiens Free fatty acid receptor 1 Proteins 0.000 claims abstract 3
- -1 unsaturated Polymers 0.000 claims description 137
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 34
- 125000000217 alkyl group Chemical group 0.000 claims description 31
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 31
- 239000002253 acid Substances 0.000 claims description 26
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
- 125000000623 heterocyclic group Chemical group 0.000 claims description 21
- 125000003118 aryl group Chemical group 0.000 claims description 20
- 201000010099 disease Diseases 0.000 claims description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 19
- 238000011282 treatment Methods 0.000 claims description 17
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 15
- 235000019253 formic acid Nutrition 0.000 claims description 15
- 125000001072 heteroaryl group Chemical group 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 239000011575 calcium Substances 0.000 claims description 13
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 12
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 125000002252 acyl group Chemical group 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 229910052791 calcium Inorganic materials 0.000 claims description 11
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 9
- 208000008589 Obesity Diseases 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 9
- 235000020824 obesity Nutrition 0.000 claims description 9
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 9
- VTZDPQGGOUEESD-UHFFFAOYSA-N 4-hexynoic acid Chemical class CC#CCCC(O)=O VTZDPQGGOUEESD-UHFFFAOYSA-N 0.000 claims description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 8
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 8
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 229920006395 saturated elastomer Polymers 0.000 claims description 8
- VEFJONBILXFNEH-QHCPKHFHSA-N (3S)-3-[4-[[3-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-ylmethyl)phenyl]methoxy]phenyl]hex-4-ynoic acid Chemical compound S1C=CC=2CN(CCC=21)CC=1C=C(COC2=CC=C(C=C2)[C@H](CC(=O)O)C#CC)C=CC=1 VEFJONBILXFNEH-QHCPKHFHSA-N 0.000 claims description 7
- YSLOKRXESKIMKW-DEOSSOPVSA-N (3S)-3-[4-[[3-[(2-methyl-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)methyl]phenyl]methoxy]phenyl]hex-4-ynoic acid Chemical compound CC1=CC=2CN(CCC=2S1)CC=1C=C(COC2=CC=C(C=C2)[C@H](CC(=O)O)C#CC)C=CC=1 YSLOKRXESKIMKW-DEOSSOPVSA-N 0.000 claims description 7
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 7
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 6
- 208000032928 Dyslipidaemia Diseases 0.000 claims description 6
- 208000017170 Lipid metabolism disease Diseases 0.000 claims description 6
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 125000004043 oxo group Chemical group O=* 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 5
- 235000019260 propionic acid Nutrition 0.000 claims description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
- WEORLDBOFNSZKQ-QHCPKHFHSA-N (3S)-3-[4-[[3-[(2-cyano-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)methyl]phenyl]methoxy]phenyl]hex-4-ynoic acid Chemical compound C(#N)C1=CC=2CN(CCC=2S1)CC=1C=C(COC2=CC=C(C=C2)[C@H](CC(=O)O)C#CC)C=CC=1 WEORLDBOFNSZKQ-QHCPKHFHSA-N 0.000 claims description 4
- UTNXOPBQWHYAJA-DEOSSOPVSA-N (3S)-3-[4-[[3-[(2-ethyl-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)methyl]phenyl]methoxy]phenyl]hex-4-ynoic acid Chemical compound C(C)C1=CC=2CN(CCC=2S1)CC=1C=C(COC2=CC=C(C=C2)[C@H](CC(=O)O)C#CC)C=CC=1 UTNXOPBQWHYAJA-DEOSSOPVSA-N 0.000 claims description 4
- HDPRAITYWQTHPH-DEOSSOPVSA-N (3S)-3-[4-[[3-[(2-propan-2-yl-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl)methyl]phenyl]methoxy]phenyl]hex-4-ynoic acid Chemical compound C(C)(C)N1N=C2C(=C1)CN(C2)CC=1C=C(COC2=CC=C(C=C2)[C@H](CC(=O)O)C#CC)C=CC=1 HDPRAITYWQTHPH-DEOSSOPVSA-N 0.000 claims description 4
- OKKQFOFAAKGVLQ-QHCPKHFHSA-N (3S)-3-[4-[[3-[[2-(methylcarbamoyl)-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl]methyl]phenyl]methoxy]phenyl]hex-4-ynoic acid Chemical compound CNC(=O)C1=CC=2CN(CCC=2S1)CC=1C=C(COC2=CC=C(C=C2)[C@H](CC(=O)O)C#CC)C=CC=1 OKKQFOFAAKGVLQ-QHCPKHFHSA-N 0.000 claims description 4
- ODFWOZMKEDFAAY-UHFFFAOYSA-N 3-cyano-3-[4-[[3-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-ylmethyl)phenyl]methoxy]phenyl]propanoic acid Chemical compound C(#N)C(CC(=O)O)C1=CC=C(C=C1)OCC1=CC(=CC=C1)CN1CC2=C(CC1)SC=C2 ODFWOZMKEDFAAY-UHFFFAOYSA-N 0.000 claims description 4
- RSBKMCMLWMAUOE-UHFFFAOYSA-N 3-cyano-3-[4-[[3-[(4-oxo-6,7-dihydrothieno[3,2-c]pyridin-5-yl)methyl]phenyl]methoxy]phenyl]propanoic acid Chemical compound C(#N)C(CC(=O)O)C1=CC=C(C=C1)OCC1=CC(=CC=C1)CN1C(C2=C(CC1)SC=C2)=O RSBKMCMLWMAUOE-UHFFFAOYSA-N 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 4
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 4
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- 125000001188 haloalkyl group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 150000003457 sulfones Chemical class 0.000 claims description 4
- RMHDPMQJYIFMLB-HSZRJFAPSA-N (3R)-3-[4-[[3-[(2-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridin-5-yl)methyl]phenyl]methoxy]phenyl]hex-4-ynoic acid Chemical compound CC=1SC=2CN(CCC2N1)CC=1C=C(COC2=CC=C(C=C2)[C@@H](CC(=O)O)C#CC)C=CC1 RMHDPMQJYIFMLB-HSZRJFAPSA-N 0.000 claims description 3
- XHKDSKNQBYHBLC-QHCPKHFHSA-N (3S)-3-[4-[[3-(1,4,6,7-tetrahydropyrrolo[3,2-c]pyridin-5-ylmethyl)phenyl]methoxy]phenyl]hex-4-ynoic acid Chemical compound N1C=CC=2CN(CCC=21)CC=1C=C(COC2=CC=C(C=C2)[C@H](CC(=O)O)C#CC)C=CC=1 XHKDSKNQBYHBLC-QHCPKHFHSA-N 0.000 claims description 3
- PSURUUIRCGNZPG-VWLOTQADSA-N (3S)-3-[4-[[3-(2,3-dihydroindol-1-ylmethyl)phenyl]methoxy]phenyl]hex-4-ynoic acid Chemical compound N1(CCC2=CC=CC=C12)CC=1C=C(COC2=CC=C(C=C2)[C@H](CC(=O)O)C#CC)C=CC=1 PSURUUIRCGNZPG-VWLOTQADSA-N 0.000 claims description 3
- BLBRNARYVDGZLD-SANMLTNESA-N (3S)-3-[4-[[3-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)phenyl]methoxy]phenyl]hex-4-ynoic acid Chemical compound C1N(CCC2=CC=CC=C12)CC=1C=C(COC2=CC=C(C=C2)[C@H](CC(=O)O)C#CC)C=CC=1 BLBRNARYVDGZLD-SANMLTNESA-N 0.000 claims description 3
- JZRCFFNNRCZNJO-SANMLTNESA-N (3S)-3-[4-[[3-(3,4-dihydro-2H-quinolin-1-ylmethyl)phenyl]methoxy]phenyl]hex-4-ynoic acid Chemical compound N1(CCCC2=CC=CC=C12)CC=1C=C(COC2=CC=C(C=C2)[C@H](CC(=O)O)C#CC)C=CC=1 JZRCFFNNRCZNJO-SANMLTNESA-N 0.000 claims description 3
- AGLLWUOWQJPCNE-NRFANRHFSA-N (3S)-3-[4-[[3-(4,6-dihydro-1H-pyrrolo[3,4-c]pyrazol-5-ylmethyl)phenyl]methoxy]phenyl]hex-4-ynoic acid Chemical compound N1N=CC2=C1CN(C2)CC=1C=C(COC2=CC=C(C=C2)[C@H](CC(=O)O)C#CC)C=CC=1 AGLLWUOWQJPCNE-NRFANRHFSA-N 0.000 claims description 3
- WDCHVGAGCDEDAH-QFIPXVFZSA-N (3S)-3-[4-[[3-(4,6-dihydrothieno[2,3-c]pyrrol-5-ylmethyl)phenyl]methoxy]phenyl]hex-4-ynoic acid Chemical compound S1C=CC2=C1CN(C2)CC=1C=C(COC2=CC=C(C=C2)[C@H](CC(=O)O)C#CC)C=CC=1 WDCHVGAGCDEDAH-QFIPXVFZSA-N 0.000 claims description 3
- RQFWJFKHMWJZAU-QFIPXVFZSA-N (3S)-3-[4-[[3-(6,7-dihydro-4H-triazolo[1,5-a]pyrazin-5-ylmethyl)phenyl]methoxy]phenyl]hex-4-ynoic acid Chemical compound N1=NC=C2N1CCN(C2)CC=1C=C(COC2=CC=C(C=C2)[C@H](CC(=O)O)C#CC)C=CC=1 RQFWJFKHMWJZAU-QFIPXVFZSA-N 0.000 claims description 3
- PFBQZFHQPCQPLD-QFIPXVFZSA-N (3S)-3-[4-[[3-(6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-ylmethyl)phenyl]methoxy]phenyl]hex-4-ynoic acid Chemical compound N=1N=CN2C=1CN(CC2)CC=1C=C(COC2=CC=C(C=C2)[C@H](CC(=O)O)C#CC)C=CC=1 PFBQZFHQPCQPLD-QFIPXVFZSA-N 0.000 claims description 3
- JAIDNXGKEULERX-KHRZNOOSSA-N (3S)-3-[4-[[3-(6-oxa-3-azabicyclo[3.1.1]heptan-3-ylmethyl)phenyl]methoxy]phenyl]hex-4-ynoic acid Chemical compound C12CN(CC(O1)C2)CC=2C=C(COC1=CC=C(C=C1)[C@H](CC(=O)O)C#CC)C=CC2 JAIDNXGKEULERX-KHRZNOOSSA-N 0.000 claims description 3
- VBYOBSFNBUCTBF-DEOSSOPVSA-N (3S)-3-[4-[[3-(7,8-dihydro-5H-1,6-naphthyridin-6-ylmethyl)phenyl]methoxy]phenyl]hex-4-ynoic acid Chemical compound N1=CC=CC=2CN(CCC1=2)CC=1C=C(COC2=CC=C(C=C2)[C@H](CC(=O)O)C#CC)C=CC=1 VBYOBSFNBUCTBF-DEOSSOPVSA-N 0.000 claims description 3
- IVGJYMKWXXJVAM-QHCPKHFHSA-N (3S)-3-[4-[[3-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-ylmethyl)phenyl]methoxy]phenyl]hex-4-ynoic acid Chemical compound N1=CN=CC2=C1CCN(C2)CC=1C=C(COC2=CC=C(C=C2)[C@H](CC(=O)O)C#CC)C=CC=1 IVGJYMKWXXJVAM-QHCPKHFHSA-N 0.000 claims description 3
- IJCJWPAXMABADM-DEOSSOPVSA-N (3S)-3-[4-[[3-[(1-methyl-6,7-dihydro-4H-pyrrolo[3,2-c]pyridin-5-yl)methyl]phenyl]methoxy]phenyl]hex-4-ynoic acid Chemical compound CN1C=CC=2CN(CCC=21)CC=1C=C(COC2=CC=C(C=C2)[C@H](CC(=O)O)C#CC)C=CC=1 IJCJWPAXMABADM-DEOSSOPVSA-N 0.000 claims description 3
- KLUBVAXROISNDZ-DEOSSOPVSA-N (3S)-3-[4-[[3-[(2-acetamido-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)methyl]phenyl]methoxy]phenyl]hex-4-ynoic acid Chemical compound CC#C[C@@H](CC(O)=O)C1=CC=C(OCC2=CC(CN3CCC4=C(C3)C=C(NC(C)=O)S4)=CC=C2)C=C1 KLUBVAXROISNDZ-DEOSSOPVSA-N 0.000 claims description 3
- IIMUJVLMAYWRCT-DEOSSOPVSA-N (3S)-3-[4-[[3-[(2-acetyl-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)methyl]phenyl]methoxy]phenyl]hex-4-ynoic acid Chemical compound C(C)(=O)C1=CC=2CN(CCC=2S1)CC=1C=C(COC2=CC=C(C=C2)[C@H](CC(=O)O)C#CC)C=CC=1 IIMUJVLMAYWRCT-DEOSSOPVSA-N 0.000 claims description 3
- QKGOQPAWBMAJRY-NRFANRHFSA-N (3S)-3-[4-[[3-[(2-amino-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridin-5-yl)methyl]phenyl]methoxy]phenyl]hex-4-ynoic acid Chemical compound NC=1SC=2CN(CCC=2N=1)CC=1C=C(COC2=CC=C(C=C2)[C@H](CC(=O)O)C#CC)C=CC=1 QKGOQPAWBMAJRY-NRFANRHFSA-N 0.000 claims description 3
- GODBKWUFDKFTET-NRFANRHFSA-N (3S)-3-[4-[[3-[(2-bromo-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridin-5-yl)methyl]phenyl]methoxy]phenyl]hex-4-ynoic acid Chemical compound BrC=1SC=2CN(CCC=2N=1)CC=1C=C(COC2=CC=C(C=C2)[C@H](CC(=O)O)C#CC)C=CC=1 GODBKWUFDKFTET-NRFANRHFSA-N 0.000 claims description 3
- XBJAGGJZEDDFRU-QFIPXVFZSA-N (3S)-3-[4-[[3-[(2-bromo-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)methyl]phenyl]methoxy]phenyl]hex-4-ynoic acid Chemical compound BrC1=CC=2CN(CCC=2S1)CC=1C=C(COC2=CC=C(C=C2)[C@H](CC(=O)O)C#CC)C=CC=1 XBJAGGJZEDDFRU-QFIPXVFZSA-N 0.000 claims description 3
- VJJSVXQXNNIUHP-QFIPXVFZSA-N (3S)-3-[4-[[3-[(2-carbamoyl-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)methyl]phenyl]methoxy]phenyl]hex-4-ynoic acid Chemical compound C(N)(=O)C1=CC=2CN(CCC=2S1)CC=1C=C(COC2=CC=C(C=C2)[C@H](CC(=O)O)C#CC)C=CC=1 VJJSVXQXNNIUHP-QFIPXVFZSA-N 0.000 claims description 3
- JBMKLWNSSOZECX-NRFANRHFSA-N (3S)-3-[4-[[3-[(2-chloro-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridin-5-yl)methyl]phenyl]methoxy]phenyl]hex-4-ynoic acid Chemical compound ClC=1SC=2CN(CCC=2N=1)CC=1C=C(COC2=CC=C(C=C2)[C@H](CC(=O)O)C#CC)C=CC=1 JBMKLWNSSOZECX-NRFANRHFSA-N 0.000 claims description 3
- XMPBOQQJDNRKEL-DEOSSOPVSA-N (3S)-3-[4-[[3-[(2-cyclopropyl-6,7-dihydro-4H-[1,3]oxazolo[4,5-c]pyridin-5-yl)methyl]phenyl]methoxy]phenyl]hex-4-ynoic acid Chemical compound C1(CC1)C=1OC2=C(CN(CC2)CC=2C=C(COC3=CC=C(C=C3)[C@H](CC(=O)O)C#CC)C=CC=2)N=1 XMPBOQQJDNRKEL-DEOSSOPVSA-N 0.000 claims description 3
- BUMIDNYDIWSPIS-QHCPKHFHSA-N (3S)-3-[4-[[3-[(2-methoxy-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)methyl]phenyl]methoxy]phenyl]hex-4-ynoic acid Chemical compound COC=1N=CC2=C(N=1)CCN(C2)CC=1C=C(COC2=CC=C(C=C2)[C@H](CC(=O)O)C#CC)C=CC=1 BUMIDNYDIWSPIS-QHCPKHFHSA-N 0.000 claims description 3
- ZCUHEXUKWVTMNP-QHCPKHFHSA-N (3S)-3-[4-[[3-[(2-methoxycarbonyl-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)methyl]phenyl]methoxy]phenyl]hex-4-ynoic acid Chemical compound COC(=O)C1=CC=2CN(CCC=2S1)CC=1C=C(COC2=CC=C(C=C2)[C@H](CC(=O)O)C#CC)C=CC=1 ZCUHEXUKWVTMNP-QHCPKHFHSA-N 0.000 claims description 3
- CUHNYJDLOGHOKS-QHCPKHFHSA-N (3S)-3-[4-[[3-[(2-methyl-6,7-dihydro-4H-[1,3]thiazolo[4,5-c]pyridin-5-yl)methyl]phenyl]methoxy]phenyl]hex-4-ynoic acid Chemical compound CC#C[C@@H](CC(O)=O)c1ccc(OCc2cccc(CN3CCc4sc(C)nc4C3)c2)cc1 CUHNYJDLOGHOKS-QHCPKHFHSA-N 0.000 claims description 3
- RMHDPMQJYIFMLB-QHCPKHFHSA-N (3S)-3-[4-[[3-[(2-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridin-5-yl)methyl]phenyl]methoxy]phenyl]hex-4-ynoic acid Chemical compound CC=1SC=2CN(CCC=2N=1)CC=1C=C(COC2=CC=C(C=C2)[C@H](CC(=O)O)C#CC)C=CC=1 RMHDPMQJYIFMLB-QHCPKHFHSA-N 0.000 claims description 3
- HCOUBYPLWQFVHI-DEOSSOPVSA-N (3S)-3-[4-[[3-[(2-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)methyl]phenyl]methoxy]phenyl]hex-4-ynoic acid Chemical compound CC1=NN2C(CN(CC2)CC=2C=C(COC3=CC=C(C=C3)[C@H](CC(=O)O)C#CC)C=CC=2)=C1 HCOUBYPLWQFVHI-DEOSSOPVSA-N 0.000 claims description 3
- BMHVJBRCVASEBC-QHCPKHFHSA-N (3S)-3-[4-[[3-[(2-methylsulfonyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)methyl]phenyl]methoxy]phenyl]hex-4-ynoic acid Chemical compound CS(=O)(=O)C=1N=CC2=C(N=1)CCN(C2)CC=1C=C(COC2=CC=C(C=C2)[C@H](CC(=O)O)C#CC)C=CC=1 BMHVJBRCVASEBC-QHCPKHFHSA-N 0.000 claims description 3
- UTIXBFSVGAPTRG-QFIPXVFZSA-N (3S)-3-[4-[[3-[(2-nitro-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)methyl]phenyl]methoxy]phenyl]hex-4-ynoic acid Chemical compound [N+](=O)([O-])C1=CC=2CN(CCC=2S1)CC=1C=C(COC2=CC=C(C=C2)[C@H](CC(=O)O)C#CC)C=CC=1 UTIXBFSVGAPTRG-QFIPXVFZSA-N 0.000 claims description 3
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- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- RBTVSNLYYIMMKS-UHFFFAOYSA-N tert-butyl 3-aminoazetidine-1-carboxylate;hydrochloride Chemical compound Cl.CC(C)(C)OC(=O)N1CC(N)C1 RBTVSNLYYIMMKS-UHFFFAOYSA-N 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000004055 thiomethyl group Chemical group [H]SC([H])([H])* 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- 150000005671 trienes Chemical class 0.000 description 1
- RXJKFRMDXUJTEX-UHFFFAOYSA-N triethylphosphine Chemical compound CCP(CC)CC RXJKFRMDXUJTEX-UHFFFAOYSA-N 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000006496 vascular abnormality Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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Abstract
Description
Q-L1-P-L2-M-X-L3-A
を有する化合物、医薬組成物、及び方法を開示している。
本発明の主な目的は、一般式(I)で表される新規なGPR40アゴニスト、それらの互変異性体、それらの立体異性体、それらの医薬として許容可能な塩、及びそれら又はそれらの混合物を含む医薬組成物を提供することである。
したがって、本発明は下記一般式(I)の化合物、それらの互変異性体、それらの立体異性体、それらの医薬として許容可能な塩、及びそれらを含む医薬組成物に関する。
「A」は、3〜7員の、部分的に飽和、不飽和か、又は飽和環であって、O、S、もしくはNから選択される1つ又は1つより多いヘテロ原子をさらに有していてもよい環から選択され;
「E」及び「D」の各々は、独立に、窒素又は炭素のいずれかであってよく;
「F」は、C、N、又はOから選択することができ;
「G」は存在するか又は存在せず、存在する場合には結合を表すか又はO、S、NRaから選択され、「Ra」は直鎖又は分岐(C1-C6)アルキルを表し;
m=1〜3であり;「n」、「r」、「p」、及び「s」のそれぞれは独立に、0〜6の範囲の整数を表し;
q=0〜4であり;
「X」は、存在するか又は存在せず、存在する場合には、CH2、O、S、及びNRa、SO2NHから選択され; Raは前に定義したとおりであり;
「T」は、酸素、-NH、S、SO、SO2、又はNRaから選択され、Ra は先に定義したとおりであり;
R7及びR8の各々は独立に、(C2-C4)アルキン、ニトリル、又はシクロアルキルから選択され; あるいはR7及びR8は、それらが結合している炭素原子と一緒に組み合わされて3〜7員環を形成していてもよく、この環はさらに任意選択によりS、N、又はOから選択される1つ又は1つより多いヘテロ原子を有していてもよく;
R9及びR10は、水素、アルキル、アルコキシ、及びハロゲン基から選択することができる。
「A」は、3〜7員の、部分的に飽和、不飽和か、又は飽和環であって、O、S、もしくはNから選択される1つ又は1つより多いヘテロ原子をさらに有していてもよい環から選択され;
「E」及び「D」の各々は、独立に、窒素又は炭素のいずれかであってよく;
「F」は、C、N、又はOから選択することができ;
「n」、「r」、及び「s」のそれぞれは独立に、0〜6の範囲の整数を表し;
R5及びR6の各々は独立に、(C2-C4)アルキン、ニトリル、又はシクロアルキルから選択してもよく; あるいはR5及びR6は、それらが結合している炭素原子と一緒に組み合わされて3〜7員環を形成していてもよく、この環はさらに任意選択によりS、N、又はOから選択される1つ又は1つより多いヘテロ原子を有していてもよい。
(S)-3-(4-((3-((6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸 (1);
3-(4-((3-((4H-フロ[3,4-c]ピロール-5(6H)-イル)メチル)ベンジル)オキシ)フェニル)-3-シアノプロパン酸リチウム;
3-シアノ-3-(4-((3-((4-オキソ-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)イル)メチル)ベンジル)オキシ)フェニル)プロパン酸;
3-シアノ-3-(4-((3-((3-(トリフルオロメチル)-5,6-ジヒドロ-[1,2,4]トリアゾロ[4,3-a]ピラジン-7(8H)-イル)メチル)ベンジル)オキシ)フェニル)プロパン酸リチウム;
3-シアノ-3-(4-((3-((2,2-ジオキシド-1H-チエノ[3,4-c]ピロール-5(3H,4H,6H)-イル)メチル)ベンジル)オキシ)フェニル)プロパン酸;
3-シアノ-3-(4-((3-((6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)プロパン酸;
(S)-3-(4-((3-((2-メチル-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((1-(tert-ブトキシカルボニル)-6,7-ジヒドロ-1H-ピロロ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((6,7-ジヒドロ-1H-ピロロ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-メチル-6,7-ジヒドロチアゾロ[5,4-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((3-(トリフルオロメチル)-5,6-ジヒドロ-[1,2,4]トリアゾロ[4,3-a]ピラジン-7(8H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-(イソインドリン-2-イルメチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((3,4-ジヒドロキノリン-1(2H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-ブロモ-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((3,4-ジヒドロイソキノリン-2(1H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-メチル-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸 (S)-3-(4-((3-((2-メチル-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸 カルシウム;
(S)-3-(4-((3-((2-メチル-6,7-ジヒドロチアゾロ[4,5-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸 (S)-3-(4-((3-((2-メチル-6,7-ジヒドロチアゾロ[4,5-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸 カルシウム;
(S)-3-(4-((3-((2-(ジフルオロメチル)-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-ブロモ-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸カルシウム;
(S)-3-(4-((3-((3,4-ジヒドロイソキノリン-2(1H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸カルシウム;
(S)-3-(4-((3-((7,8-ジヒドロピリド[4,3-d]ピリミジン-6(5H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((1-メチルピロロ[3,4-c]ピラゾール-5(1H,4H,6H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(3S)-3-(4-((3-(6-オキサ-3-アザビシクロ[3.1.1]ヘプタン-3-イルメチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-(インドリン-1-イルメチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((5,6-ジヒドロ-[1,2,4]トリアゾロ[4,3-a]ピラジン-7(8H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-シクロプロピル-6,7-ジヒドロオキサゾロ[4,5-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
ギ酸と組み合わされた(3S)-3-(4-((3-((5-ベンジルヘキサヒドロピロロ[3,4-c]ピロール-2(1H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸化合物;
(S)-3-(4-((3-((4H-チエノ[2,3-c]ピロール-5(6H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
6-(3-((4-((S)-1-カルボキシペンタ-3-イン-2-イル)フェノキシ)メチル)ベンジル)-6,7-ジヒドロ-5H-ピロロ[3,4-d]ピリミジン-6-イウム ホルマート(formate);
1-(3-((4-((S)-1-カルボキシペンタ-3-イン-2-イル)フェノキシ)メチル)ベンジル)-7-メトキシ-1,2,3,4-テトラヒドロキノリン-1-イウム ホルマート;
(S)-3-(4-((3-((2-クロロ-6,7-ジヒドロチアゾロ[5,4-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-ブロモ-6,7-ジヒドロチアゾロ[5,4-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-(ピロロ[3,4-c]ピラゾール-5(1H,4H,6H)-イルメチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-(ヒドロキシメチル)-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-5-(3-((4-(1-カルボキシペンタ-3-イン-2-イル)フェノキシ)メチル)ベンジル)-4,5,6,7-テトラヒドロチエノ[3,2-c]ピリジン-2-カルボン酸;
3-シクロプロピル-3-(3-((3-((2-メチル-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)プロパン酸;
(S)-3-(4-((3-((1-メチル-6,7-ジヒドロ-1H-ピロロ[3,2-c]ピリジン-5(4H)-イル)メチル) ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-アミノ-6,7-ジヒドロチアゾロ[5,4-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ) フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-クロロ-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸カルシウム;
(S)-3-(4-((3-((2-カルバモイル-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
((S)-3-(4-((3-((2-イソプロピルピロロ[3,4-c]ピラゾール-5(2H,4H,6H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-(メトキシカルボニル)-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-シアノ-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-ホルミル-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-メチル-6,7-ジヒドロピラゾロ[1,5-a]ピラジン-5(4H)-イル)メチル)ベンジル) オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-(メチルカルバモイル)-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-(ジメチルカルバモイル)-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(3S)-3-(4-((3-((2-メチル-5-(4-(メチルスルホニル)フェニル)ピロリジン-1-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-(メチルスルホニル)-7,8-ジヒドロピリド[4,3-d]ピリミジン-6(5H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-メトキシ-7,8-ジヒドロピリド[4,3-d]ピリミジン-6(5H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(3S)-3-(4-((3-((2-フェニルピロリジン-1-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
ギ酸と組み合わされた(S)-3-(4-((3-(ピロリジン-1-イルメチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸化合物;
ギ酸と組み合わされた(S)-3-(4-((3-(ピペリジン-1-イルメチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸化合物;
ギ酸と組み合わされた(S)-3-(4-((3-((1-イソプロピルピロロ[3,4-c]ピラゾール-5(1H,4H,6H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸化合物;
(R)-3-(4-((3-((2-メチル-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(R)-3-(4-((3-((2-メチル-6,7-ジヒドロチアゾロ[5,4-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((6,7-ジヒドロ-[1,2,3]トリアゾロ[1,5-a]ピラジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
3-(4-((3-((2-メチル-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
3-(4-((3-((2-メチル-6,7-ジヒドロチアゾロ[5,4-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-クロロ-6,7-ジヒドロチアゾロ[5,4-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸カルシウム;
(S)-3-(4-((3-((2-(シクロプロピルカルバモイル)-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-(ピロリジン-1-カルボニル)-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-アセトアミド-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-シクロプロピル-6,7-ジヒドロオキサゾロ[4,5-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸カルシウム;
(S)-3-(4-((3-((2-ニトロ-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
2,2,2-トリフルオロ酢酸と組み合わされた(S)-3-(4-((3-((2-(ジメチルアミノ)-7,8-ジヒドロピリド[4,3-d]ピリミジン-6(5H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸化合物;
2,2,2-トリフルオロ酢酸と組み合わされた(S)-3-(4-((3-((2-アミノ-7,8-ジヒドロピリド[4,3-d]ピリミジン-6(5H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸化合物;
(S)-3-(4-((3-((7,8-ジヒドロ-1,6-ナフチリジン-6(5H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
2,2,2-トリフルオロ酢酸と組み合わされた(S)-3-(4-((3-((2-シクロプロピル-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸化合物;
2,2,2-トリフルオロ酢酸と組み合わされた(S)-3-(4-((3-((2-アセトアミド-6,7-ジヒドロチアゾロ[5,4-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸化合物;
(S)-3-(4-((3-((2-エチル-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-アセチル-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
2,2,2-トリフルオロ酢酸と組み合わされた(S)-3-(4-((3-((2-((メチルアミノ)メチル)-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸化合物。
例において示した1H NMRスペクトルデータ(以下を参照)は、400 MHz分光器(Brucker AVANCE-400)を使用して記録し、δ単位で報告する。別途言及していない限り、NMRに使用した溶媒はCDCl3である。
i. メチル 3-(4,5,6,7-テトラヒドロチエノ[3,2-c]ピリジン-5-カルボニル)ベンゾエート(中間体3)
3-(メトキシカルボニル)安息香酸中間体1(10 g, 55.5 mmol)に、塩化チエニル(16.21 mL, 222 mmol)を少量ずつ25℃で添加し、次に1滴のジメチルホルミアミドを添加した。反応混合物を還流下で3時間撹拌した。過剰の塩化チエニルを減圧下、100℃で蒸発させた。4,5,6,7-テトラヒドロチエノ[3,2-c]ピリジン塩酸塩中間体2(12.19 g, 69.4 mmol)を100 mLの水に溶かし、そこへ25 mLの水中の水酸化ナトリウム(4.44 g, 111 mmol)の溶液を添加した。4,5,6,7-テトラヒドロチエノ[3,2-c]ピリジンのフリー塩基をジクロロメタン(75 mL)中に抽出し、無水炭酸カリウム上で乾燥させた。酸塩化物を無水ジクロロメタン(75 mL)に溶かし、0℃に冷やした。
この反応混合物に、トリエチルアミン(15.47 mL, 111 mmol)を滴下により添加し、次にジクロロメタン(75 mL)中の4,5,6,7-テトラヒドロチエノ[3,2-c]ピリジンの溶液を0℃で一滴ずつ添加した。反応混合物を25℃に温め、3時間撹拌した。反応の進行はTLCによって観察した。反応混合物を氷水(125 mL)に注ぎ、10%HClでpHを約4に調節し、ジクロロメタン(3 x 100 mL)で抽出した。一緒にした有機フラクションを5%水酸化ナトリウム(100 mL)、次に食塩水(100 mL)で洗い、無水Na2SO4上で乾燥させ、減圧下、ロータリーエバポレーターで蒸発させて、未精製アミド中間体3を得た。未精製生成物を、固定相として230〜400メッシュのシリカゲルを、移動相として10〜50%酢酸エチル−ヘキサンを用いるフラッシュカラムクロマトグラフィーによって精製して、純粋なメチル 3-(4,5,6,7-テトラヒドロチエノ[3,2-c]ピリジン-5-カルボニル)ベンゾエート(12 g, 39.8 mmol, 71.7 %収率)を得た。
無水THF(100 mL)中のメチル 3-(4,5,6,7-テトラヒドロチエノ[3,2-c]ピリジン-5-カルボニル)ベンゾエート中間体3(12 g, 39.8 mmol)の溶液に、LiAlH4(3.02 g, 80 mmol))を少量ずつ25℃で添加した。反応混合物を還流下で3時間撹拌した。反応の進行は、移動相としてヘキサン中30%酢酸エチルを用いるTLCによって観察した。硫酸ナトリウムの水懸濁液を反応混合物に滴下して添加して、過剰のLiAlH4を失活させた。反応混合物に酢酸エチル(150 mL)を添加し、30分間還流させ、酢酸エチルをデカンテーションし、この工程を3回繰り返して、硫酸リチウム及び水酸化アルミニウムの白色スラグ中に生成物が全くないことを確実にした。一緒にした有機フラクションを無水Na2SO4上で乾燥させ、減圧下、ロータリーエバポレーターで蒸発させて、中間体4の未精製生成物を淡黄色の粘着性物質として得た。
この未精製アルコール中間体4を、固定相として230〜400メッシュのシリカゲル、移動相として10〜50%酢酸エチル-ヘキサンを用いるフラッシュカラムクロマトグラフィーによって精製して、純粋な(3-((6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)フェニル)メタノール中間体4(5.41 g, 20.86 mmol, 52.4%収率)を得た。
5 mLの無水テトラヒドロフラン中の(3-((6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)フェニル)メタノール中間体4(0.16g, 0.617 mmol)の溶液に、トリエチルアミン(0.258 ml, 1.851 mmol)、次にメタンスルホニルクロリド(141 mg, 1.234 mmol)を0℃にて添加した。反応混合物を25℃で1時間撹拌した。反応の進行はTLCで観察した。反応混合物を氷水(25 mL)に注ぎ、ジクロロメタン(3 x 25 mL)で抽出した。一緒にした有機フラクションを無水Na2SO4上で乾燥させ、減圧下、ロータリーエバポレーターで蒸発させて、3-((6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジルメシレート中間体(5)を淡黄色の粘着性物質として得た。
アセトニトリル(5.00 mL)中の(S)-メチル 3-(4-ヒドロキシフェニル)ヘキサ-4-イノエート中間体6(162 mg, 0.740 mmol)の溶液に、炭酸セシウム(603 mg, 1.851 mmol)、次に2 mLのアセトニトリル中の3-((6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジルメシレート5の溶液を25℃で添加した。反応混合物を3時間、75℃で撹拌した。反応の進行をTLCで観察した。反応の終了後、揮発成分を減圧下で蒸発させて除去した。反応混合物を氷水(25 mL)に注ぎ、生成物をジクロロメタン(3 x 25 mL)で抽出した。一緒にした有機フラクションを無水Na2SO4上で乾燥させ、減圧下、ロータリーエバポレーターで蒸発させて、生成物を淡黄色の粘着性物質として得た。塩化水素のエーテル溶液をその未精製生成物に添加し、エーテルを蒸発させて除去し、残留物を酢酸エチルと一緒にすり潰して、65 mgの(S)-メチル 3-(4-((3-((6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イノエート塩酸塩中間体(7)を得た。エステル塩酸塩中間体7(60 mg, 0.121 mmol)を、THF(2 mL)及びMeOH(1 mL)の混合物を用い、水(1 mL)中のNaOH(24.19 mg, 0.605 mmol)を添加して加水分解した。反応混合物を12時間、25℃で撹拌した。反応の進行はTLCで観察した。反応の終了後、揮発成分を蒸発させて除去し、残留物を氷水で処理し、pH約4に調節(1N HCl)し、ジクロロメタン(3 x 25 mL)で抽出し、無水Na2SO4上で乾燥させた。減圧下、ロータリーエバポレーターで溶媒を蒸発させて、未精製生成物を得た。未精製の酸を分取TLCで精製して、(S)-3-(4-((3-((6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸 1 (42 mg, 0.094 mmol, 78 %収率)を得た。
1H NMR (DMSO-d6, 400 MHz) δ: 7.42 (s, 1H), 7.37-7.24 (m, 6H), 6.94 (d, J = 8.4 Hz, 2H), 6.75 (d, J = 5.2 Hz, 1H), 5.07 (s, 2H), 3.94 (m, 1H), 3.68 (s, 2H), 3.43 (s, 2H), 2.78-2.72 (m, 4H), 2.57-2.55 (m, 2H), 1.77 (d, J = 1.6 Hz, 3H); ESIMS: 446.2 (M+H)+。
3-(4-((3-((4H-フロ[3,4-c]ピロール-5(6H)-イル)メチル)ベンジル)オキシ)フェニル)-3-シアノプロパン酸 リチウム
4H), 2.53-2.41 (m, 1H), 2.33-2.32 (m, 1H)
3-シアノ-3-(4-((3-((4-オキソ-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)プロパン酸
3-シアノ-3-(4-((3-((3-(トリフルオロメチル)-5,6-ジヒドロ-[1,2,4]トリアゾロ[4,3-a]ピラジン-7(8H)-イル)メチル)ベンジル)オキシ)フェニル)プロパン酸リチウム
3-シアノ-3-(4-((3-((2,2-ジオキシド-1H-チエノ[3,4-c]ピロール-5(3H,4H,6H)-イル)メチル)ベンジル)オキシ)フェニル)プロパン酸
3-シアノ-3-(4-((3-((6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)プロパン酸
(S)-3-(4-((3-((2-メチル-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
(S)-3-(4-((3-((1-(tert-ブトキシカルボニル)-6,7-ジヒドロ-1H-ピロロ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
(S)-3-(4-((3-((6,7-ジヒドロ-1H-ピロロ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
(S)-3-(4-((3-((2-メチル-6,7-ジヒドロチアゾロ[5,4-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
(S)-3-(4-((3-((3-(トリフルオロメチル)-5,6-ジヒドロ-[1,2,4]トリアゾロ[4,3-a]ピラジン-7(8H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
(S)-3-(4-((3-(イソインドリン-2-イルメチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸 トリフルオロ酢酸
(S)-3-(4-((3-((3,4-ジヒドロキノリン-1(2H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
(S)-3-(4-((3-((2-ブロモ-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
(S)-3-(4-((3-((3,4-ジヒドロイソキノリン-2(1H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
(S)-3-(4-((3-((2-メチル-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸(S)-3-(4-((3-((2-メチル-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸カルシウム
(S)-3-(4-((3-((2-メチル-6,7-ジヒドロチアゾロ[4,5-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸(S)-3-(4-((3-((2-メチル-6,7-ジヒドロチアゾロ[4,5-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸カルシウム
(S)-3-(4-((3-((2-(ジフルオロメチル)-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
2.4 Hz, 3H)。
(S)-3-(4-((3-((2-ブロモ-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸カルシウム
(S)-3-(4-((3-((3,4-ジヒドロイソキノリン-2(1H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸カルシウム
(S)-3-(4-((3-((7,8-ジヒドロピリド[4,3-d]ピリミジン-6(5H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
(S)-3-(4-((3-((1-メチルピロロ[3,4-c]ピラゾール-5(1H,4H,6H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
(3S)-3-(4-((3-(6-Oxa-3-アザビシクロ[3.1.1]ヘプタン-3-イルメチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
(S)-3-(4-((3-(インドリン-1-イルメチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
(S)-3-(4-((3-((5,6-ジヒドロ-[1,2,4]トリアゾロ[4,3-a]ピラジン-7(8H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
(S)-3-(4-((3-((2-シクロプロピル-6,7-ジヒドロオキサゾロ[4,5-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
ギ酸と組み合わされた(3S)-3-(4-((3-((5-ベンジルヘキサヒドロピロロ[3,4-c]ピロール-2(1H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸化合物
(S)-3-(4-((3-((4H-チエノ[2,3-c]ピロール-5(6H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
6-(3-((4-((S)-1-カルボキシペンタ-3-イン-2-イル)フェノキシ)メチル)ベンジル)-6,7-ジヒドロ-5H-ピロロ[3,4-d]ピリミジン-6-イウム ホルメート
1-(3-((4-((S)-1-カルボキシペンタ-3-イン-2-イル)フェノキシ)メチル)ベンジル)-7-メトキシ-1,2,3,4-テトラヒドロキノリン-1-イウム ホルメート
(S)-3-(4-((3-((2-クロロ-6,7-ジヒドロチアゾロ[5,4-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
(S)-3-(4-((3-((2-ブロモ-6,7-ジヒドロチアゾロ[5,4-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
(S)-3-(4-((3-(ピロロ[3,4-c]ピラゾール-5(1H,4H,6H)-イルメチル)ベンジル)オキシ)フェニル) ヘキサ-4-イン酸
(S)-3-(4-((3-((2-(ヒドロキシメチル)-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
(S)-5-(3-((4-(1-カルボキシペンタ-3-イン-2-イル)フェノキシ)メチル)ベンジル)-4,5,6,7-テトラヒドロチエノ[3,2-c]ピリジン-2-カルボン酸
3-シクロプロピル-3-(3-((3-((2-メチル-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)プロパン酸
(S)-3-(4-((3-((1-メチル-6,7-ジヒドロ-1H-ピロロ[3,2-c]ピリジン-5(4H)-イル)メチル) ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
(S)-3-(4-((3-((2-アミノ-6,7-ジヒドロチアゾロ[5,4-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
(S)-3-(4-((3-((2-クロロ-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸カルシウム
(S)-3-(4-((3-((2-カルバモイル-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
((S)-3-(4-((3-((2-イソプロピルピロロ[3,4-c]ピラゾール-5(2H,4H,6H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
(S)-3-(4-((3-((2-(メトキシカルボニル)-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
(S)-3-(4-((3-((2-シアノ-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
(S)-3-(4-((3-((2-ホルミル-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
(S)-3-(4-((3-((2-メチル-6,7-ジヒドロピラゾロ[1,5-a]ピラジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
(S)-3-(4-((3-((2-(メチルカルバモイル)-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
(S)-3-(4-((3-((2-(ジメチルカルバモイル)-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
(3S)-3-(4-((3-((2-メチル-5-(4-(メチルスルホニル)フェニル)ピロリジン-1-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
(S)-3-(4-((3-((2-(メチルスルホニル)-7,8-ジヒドロピリド[4,3-d]ピリミジン-6(5H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
(S)-3-(4-((3-((2-メトキシ-7,8-ジヒドロピリド[4,3-d]ピリミジン-6(5H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
(3S)-3-(4-((3-((2-フェニルピロリジン-1-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
ギ酸と組み合わされた(S)-3-(4-((3-(ピロリジン-1-イルメチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸化合物
ギ酸と組み合わされた(S)-3-(4-((3-(ピペリジン-1-イルメチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸化合物
ギ酸と組み合わされた(S)-3-(4-((3-((1-イソプロピルピロロ[3,4-c]ピラゾール-5(1H,4H,6H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸化合物
(R)-3-(4-((3-((2-メチル-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル) オキシ)フェニル)ヘキサ-4-イン酸
(R)-3-(4-((3-((2-メチル-6,7-ジヒドロチアゾロ[5,4-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
(S)-3-(4-((3-((6,7-ジヒドロ-[1,2,3]トリアゾロ[1,5-a]ピラジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
3-(4-((3-((2-メチル-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル) オキシ)フェニル)ヘキサ-4-イン酸
3-(4-((3-((2-メチル-6,7-ジヒドロチアゾロ[5,4-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
(S)-3-(4-((3-((2-クロロ-6,7-ジヒドロチアゾロ[5,4-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸カルシウム
(S)-3-(4-((3-((2-(シクロプロピルカルバモイル)-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
(S)-3-(4-((3-((2-(ピロリジン-1-カルボニル)-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
(S)-3-(4-((3-((2-アセトアミド-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
(S)-3-(4-((3-((2-シクロプロピル-6,7-ジヒドロオキサゾロ[4,5-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸カルシウム
(S)-3-(4-((3-((2-ニトロ-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル) オキシ)フェニル)ヘキサ-4-イン酸
2,2,2-トリフルオロ酢酸と組み合わされた(S)-3-(4-((3-((2-(ジメチルアミノ)-7,8-ジヒドロピリド[4,3-d]ピリミジン-6(5H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸化合物
2,2,2-トリフルオロ酢酸と組み合わされた(S)-3-(4-((3-((2-アミノ-7,8-ジヒドロピリド[4,3-d]ピリミジン-6(5H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸化合物
7.30 (dd, J = 6.8, 1.6 Hz, 2H), 6.96 (d, J = 6.8, 1.6 Hz, 2H), 5.17 (s, 2H), 4.52 (s, 2H), 4.25 (s, 2H), 4.01-3.99 (m, 1H), 3.63 (s, 2H), 3.09-3.05 (m, 2H), 2.70-2.58 (m, 2H), 1.80 (d, J = 2.4 Hz, 3H)。
(S)-3-(4-((3-((7,8-ジヒドロ-1,6-ナフチリジン-6(5H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
2,2,2-トリフルオロ酢酸と組み合わされた(S)-3-(4-((3-((2-シクロプロピル-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸化合物
2,2,2-トリフルオロ酢酸と組み合わされた(S)-3-(4-((3-((2-アセトアミド-6,7-ジヒドロチアゾロ[5,4-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸化合物
(S)-3-(4-((3-((2-エチル-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル) オキシ)フェニル)ヘキサ-4-イン酸
(S)-3-(4-((3-((2-アセチル-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸
2,2,2-トリフルオロ酢酸と組み合わされた(S)-3-(4-((3-((2-((メチルアミノ)メチル)-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸化合物
本発明の化合物の生物学的活性をここに述べる以下のインビトロ及びインビボモデルにおいて試験をした。
蛍光アッセイ(FLIPR)を用いる、細胞内Ca2+フラックスに対する、化合物のEC50の決定
GPR40を発現している安定な細胞を25,000個/ウェルで蒔き、50μL/ウェルのアッセイ緩衝液(20 mM HEPES+1X HBSS)をその細胞に添加し、その細胞を20分間37℃で培養した。細胞に50μL/ウェルのカルシウム5染料を負荷し、45分間37℃で培養した。
細胞に、1000 nM(1:3漸減希釈-10点)の最高濃度において化合物を負荷させた。細胞内カルシウムフラックスをScreen Works 3.1ツールを使用して評価し、統計解析をGraph Pad Prism 4を使用して行った。
本発明の化合物の多くが、蛍光(FLIPR)アッセイを使用して測定した場合に、細胞内Ca2+フラックスに対するナノモルでの効能及び顕著な%刺激を実証した。
これらの化合物は、ナノモル範囲で有効性を示した(表1)。
GPR40活性化を、GPR40 cDNA(ChemiBrite細胞株、Millipore, USから)で安定にトランスフェクトしたHEK293細胞で測定した。これらの細胞は、規格化対照としてのβガラクトシダーゼプラスミドで、ルシフェラーゼ遺伝子のクローン化5′、5XSRE配列を有するpGL2(Promega Inc.)プラスミドで過渡的にトランスフェクトされた。手短に、35000細胞/ウェルを96ウェルプレートに播いた。37℃において夜通しインキュベーションした後、その細胞をPBSで洗い、その5XSRE-ルシフェラーゼプラスミド及びβガラクトシダーゼプラスミドでトランスフェクトした。形質移入6時間後、培養液を取り除き、さまざまな濃度の薬剤を伴う新しい培養液で置き換え、さらに16時間インキュベートした。細胞を、次に50μLのGlo-Lysis緩衝液(Promega)中で30分間室温において溶解させた。細胞を次に遠心分離にかけ、可溶化液を集めた。20μLの可溶化液中に100μLのルシフェラーゼ基質を添加し、ルミノメーター中で発光を測定することにより、ルシフェラーゼ活性を測定した。20μLの可溶化液に20μLのβガラクトシダーゼ緩衝液(Promega)を添加し、415 nmでの吸光度を観測することによって、βガラクトシダーゼ活性も測定した。ルシフェラーゼ値をβガラクトシダーゼ値で除して、トランスフェクションの効率を規格化した(表2)。
n-STZラットモデルにおけるGRP40アゴニスト試験化合物のための一次スクリーニング手順(プロトコル)
1〜2日齢のウィスターラットの仔に、腹腔内経路で120 mg/kg用量でストレプトゾトシン(STZ)を注入した。全ての仔を正常に生育させ、12〜14週の年齢で、グルコメーターを使用するテールクリップ法による経口グルコース耐容試験を行うことにより、グルコース不寛容についてスクリーニングをした。グルコース不寛容を示す動物を、試験化合物の評価のために選択した。3〜7日の休息期間のあいだ、動物を夜間絶食に保った。次の日の朝、グルコメーターを使用して血糖値を測定し、動物の予備処置のグルコース値がグループ同士の間で顕著に異ならないように、動物をグループ分けした。動物に試験化合物を投与し、次に化合物投与「0」分後15〜60分に血糖値を測定し、直ちに2g/kgのグルコース負荷を経口投与した。グルコメーターを使用するテールクリップ法によってグルコース負荷後30、60、及び120分に血糖値を測定した。また、グルコース負荷後10分に、インスリン値の測定のために血液も集めた。曲線(AUC)の下のグルコース面積を、グラフ・パッド・プリズムソフトウェア(Graph Pad Prism software)を使用して計算し、賦形剤処置した対照に対するAUCグルコースの%低下を計算した(表3)。
Claims (11)
- 下記一般式(I′)の化合物、それらの互変異性体、それらの立体異性体、それらの医薬として許容可能な塩、並びにそれらを含む医薬組成物。
「A」は、3〜7員の、部分的に飽和、不飽和か、又は飽和環であり、O、S、もしくはNから選択される1つ又は1つより多いヘテロ原子をさらに有している環から選択され;
「E」及び「D」の各々は、独立に、窒素又は炭素のいずれかであり;
「F」は、C、N、又はOから選択され;
「n」、「r」、及び「s」のそれぞれは独立に、0〜6の範囲の整数を表し;
R5及びR6の各々は独立に、(C2-C4)アルキン、ニトリル、又はシクロアルキルから選択され; あるいはR5及びR6は、それらが結合している炭素原子と一緒に組み合わされて3〜7員環を形成しており、前記環はさらに任意選択によりS、N、又はOから選択される1つ又は1つより多いヘテロ原子を有していてもよい。 - R1からR6の任意の基が1つ以上の基で置換されており、前記置換基が独立に、ヒドロキシル、オキソ、ハロ、チオ、ニトロ、アミノ、シアノ、ホルミル;あるいは、以下のものから選択される置換もしくは非置換基:アミジノ、アルキル、ハロアルキル、アルコキシ、ハロアルコキシ、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、ビシクロアルキル、ビシクロアルケニル、アルコキシ、アルケノキシ、シクロアルコキシ、アリール、アリールオキシ、アラルキル、アラルコキシ、ヘテロシクリル、ヘテロアリール、ヘテロシクリルアルキル、ヘテロアラルキル、ヘテロアリールオキシ、ヘテロアラルコキシ、ヘテロシクリルオキシ、ヘテロシクリルアルコキシ、ヘテロシクリルアルコキシアシル、アシル、アシルオキシ、アシルアミノ、一置換もしくは二置換アミノ、アリールアミノ、アラルキルアミノ、カルボン酸、及びエステル及びアミドから選択されるカルボン酸誘導体、カルボニルアミノ、ヒドロキシアルキル、アミノアルキル、アルコキシアルキル、アリールオキシアルキル、アラルコキシアルキル、アルキルチオ、チオアルキル、アリールチオ、アルキルスルホニルアミノ、アルキルスルホニルオキシ、アルコキシカルボニルアミノ、アリールオキシカルボニルアミノ、アラルキルオキシカルボニルアミノ、アミノカルボニルアミノ、アルキルアミノカルボニルアミノ、アルコキシアミノ、ヒドロキシルアミノ、スルフェニル誘導体、スルホニル誘導体、スルホン酸及びその誘導体からなる基から選択される、請求項1に記載の化合物。
- ヘテロアリール基が、ピリジル、チエニル、フリル、ピロリル、オキサゾリル、チアゾリル、イソチアゾリル、イミダゾリル、イソオキサゾリル、オキサジアゾリル、チアジアゾリル、トリアゾリル、テトラゾリル、ベンゾピラニル、ベンゾピラノニル、ベンゾフラニル、ベンゾチエニル、インドリニル、インドリル、アザインドリル、アザインドリニル、ベンゾジヒドロフラニル、ベンゾジヒドロチエニル、ピラゾロピリミジニル、ピラゾロピリミドニル、アザキナゾリニル、アザキナゾリノイル、ピリドフラニル、ピリドチエニル、チエノピリミジル、チエノピリミドニル、キノリニル、ピリミジニル、ピラゾリル、キナゾリニル、キナゾロニル、ピリミドニル、ピリダジニル、トリアジニル、ベンゾオキサジニル、ベンゾオキサジノニル、ベンゾチアジニル、ベンゾチアジノニル、 ベンゾオキサゾリル、ベンゾチアゾリル、ベンゾイミダゾリル、ベンゾトリアゾリル、フタラジニル、ナフチリジニル、プリニル、カルバゾリル、フェノチアジニル、フェノキサジニル基から選択される、請求項1に記載の化合物。
- ヘテロシクリル基が、アジリジニル、アゼチジニル、ピロリジニル、イミダゾリジニル、ピペリジニル、ピペラジニル、2-オキソピペリジニル、4-オキソピペリジニル、2-オキソピペラジニル、3-オキソピペラジニル、モルホリニル、チオモルホリニル、2-オキソモルホリニル、アゼピニル、ジアゼピニル、オキサピニル、チアゼピニル、オキサゾリジニル、チアゾリジニルなどから選択され、部分的飽和へテロ環基の例には、ジヒドロチオフェン、ジヒドロピラン、ジヒドロフラン、ジヒドロチアゾール基が含まれる、請求項1に記載の化合物。
- 以下のものからなる群から選択される請求項1に記載の化合物。
(S)-3-(4-((3-((6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
3-(4-((3-((4H-フロ[3,4-c]ピロール-5(6H)-イル)メチル)ベンジル)オキシ)フェニル)-3-シアノプロパン酸リチウム;
3-シアノ-3-(4-((3-((4-オキソ-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)イル)メチル)ベンジル)オキシ)フェニル)プロパン酸;
3-シアノ-3-(4-((3-((3-(トリフルオロメチル)-5,6-ジヒドロ-[1,2,4]トリアゾロ[4,3-a]ピラジン-7(8H)-イル)メチル)ベンジル)オキシ)フェニル)プロパン酸リチウム;
3-シアノ-3-(4-((3-((2,2-ジオキシド-1H-チエノ[3,4-c]ピロール-5(3H,4H,6H)-イル)メチル)ベンジル)オキシ)フェニル)プロパン酸;
3-シアノ-3-(4-((3-((6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)プロパン酸;
(S)-3-(4-((3-((2-メチル-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((1-(tert-ブトキシカルボニル)-6,7-ジヒドロ-1H-ピロロ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((6,7-ジヒドロ-1H-ピロロ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-メチル-6,7-ジヒドロチアゾロ[5,4-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((3-(トリフルオロメチル)-5,6-ジヒドロ-[1,2,4]トリアゾロ[4,3-a]ピラジン-7(8H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-(イソインドリン-2-イルメチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((3,4-ジヒドロキノリン-1(2H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-ブロモ-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((3,4-ジヒドロイソキノリン-2(1H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-メチル-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸(S)-3-(4-((3-((2-メチル-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸カルシウム;
(S)-3-(4-((3-((2-メチル-6,7-ジヒドロチアゾロ[4,5-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸(S)-3-(4-((3-((2-メチル-6,7-ジヒドロチアゾロ[4,5-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸カルシウム;
(S)-3-(4-((3-((2-(ジフルオロメチル)-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-ブロモ-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸カルシウム;
(S)-3-(4-((3-((3,4-ジヒドロイソキノリン-2(1H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸カルシウム;
(S)-3-(4-((3-((7,8-ジヒドロピリド[4,3-d]ピリミジン-6(5H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((1-メチルピロロ[3,4-c]ピラゾール-5(1H,4H,6H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(3S)-3-(4-((3-(6-オキサ-3-アザビシクロ[3.1.1]ヘプタン-3-イルメチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-(インドリン-1-イルメチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((5,6-ジヒドロ-[1,2,4]トリアゾロ[4,3-a]ピラジン-7(8H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-シクロプロピル-6,7-ジヒドロオキサゾロ[4,5-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
ギ酸と組み合わされた(3S)-3-(4-((3-((5-ベンジルヘキサヒドロピロロ[3,4-c]ピロール-2(1H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸化合物;
(S)-3-(4-((3-((4H-チエノ[2,3-c]ピロール-5(6H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
6-(3-((4-((S)-1-カルボキシペンタ-3-イン-2-イル)フェノキシ)メチル)ベンジル)-6,7-ジヒドロ-5H-ピロロ[3,4-d]ピリミジン-6-イウム ホルマート;
1-(3-((4-((S)-1-カルボキシペンタ-3-イン-2-イル)フェノキシ)メチル)ベンジル)-7-メトキシ-1,2,3,4-テトラヒドロキノリン-1-イウム ホルマート;
(S)-3-(4-((3-((2-クロロ-6,7-ジヒドロチアゾロ[5,4-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-ブロモ-6,7-ジヒドロチアゾロ[5,4-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-(ピロロ[3,4-c]ピラゾール-5(1H,4H,6H)-イルメチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-(ヒドロキシメチル)-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-5-(3-((4-(1-カルボキシペンタ-3-イン-2-イル)フェノキシ)メチル)ベンジル)-4,5,6,7-テトラヒドロチエノ[3,2-c]ピリジン-2-カルボン酸;
3-シクロプロピル-3-(3-((3-((2-メチル-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)プロパン酸;
(S)-3-(4-((3-((1-メチル-6,7-ジヒドロ-1H-ピロロ [3,2-c]ピリジン-5(4H)-イル)メチル) ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-アミノ-6,7-ジヒドロチアゾロ [5,4-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ) フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-クロロ-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸カルシウム;
(S)-3-(4-((3-((2-カルバモイル-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
((S)-3-(4-((3-((2-イソプロピルピロロ[3,4-c]ピラゾール-5(2H,4H,6H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-(メトキシカルボニル)-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-シアノ-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-ホルミル-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-メチル-6,7-ジヒドロピラゾロ [1,5-a]ピラジン-5(4H)-イル)メチル)ベンジル) オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-(メチルカルバモイル)-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-(ジメチルカルバモイル)-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(3S)-3-(4-((3-((2-メチル-5-(4-(メチルスルホニル)フェニル)ピロリジン-1-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-(メチルスルホニル)-7,8-ジヒドロピリド[4,3-d]ピリミジン-6(5H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-メトキシ-7,8-ジヒドロピリド[4,3-d]ピリミジン-6(5H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(3S)-3-(4-((3-((2-フェニルピロリジン-1-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
ギ酸と組み合わされた(S)-3-(4-((3-(ピロリジン-1-イルメチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸化合物;
ギ酸と組み合わされた(S)-3-(4-((3-(ピペリジン-1-イルメチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸化合物;
ギ酸と組み合わされた(S)-3-(4-((3-((1-イソプロピルピロロ[3,4-c]ピラゾール-5(1H,4H,6H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸化合物;
(R)-3-(4-((3-((2-メチル-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(R)-3-(4-((3-((2-メチル-6,7-ジヒドロチアゾロ[5,4-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((6,7-ジヒドロ-[1,2,3]トリアゾロ[1,5-a]ピラジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
3-(4-((3-((2-メチル-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
3-(4-((3-((2-メチル-6,7-ジヒドロチアゾロ[5,4-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-クロロ-6,7-ジヒドロチアゾロ[5,4-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸カルシウム;
(S)-3-(4-((3-((2-(シクロプロピルカルバモイル)-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-(ピロリジン-1-カルボニル)-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-アセトアミド-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-シクロプロピル-6,7-ジヒドロオキサゾロ[4,5-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸カルシウム;
(S)-3-(4-((3-((2-ニトロ-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
2,2,2-トリフルオロ酢酸と組み合わされた(S)-3-(4-((3-((2-(ジメチルアミノ)-7,8-ジヒドロピリド[4,3-d]ピリミジン-6(5H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸化合物;
2,2,2-トリフルオロ酢酸と組み合わされた(S)-3-(4-((3-((2-アミノ-7,8-ジヒドロピリド[4,3-d]ピリミジン-6(5H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸化合物;
(S)-3-(4-((3-((7,8-ジヒドロ-1,6-ナフチリジン-6(5H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
2,2,2-トリフルオロ酢酸と組み合わされた(S)-3-(4-((3-((2-シクロプロピル-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸化合物;
2,2,2-トリフルオロ酢酸と組み合わされた(S)-3-(4-((3-((2-アセトアミド-6,7-ジヒドロチアゾロ[5,4-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸化合物;
(S)-3-(4-((3-((2-エチル-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
(S)-3-(4-((3-((2-アセチル-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸;
2,2,2-トリフルオロ酢酸と組み合わされた(S)-3-(4-((3-((2-((メチルアミノ)メチル)-6,7-ジヒドロチエノ[3,2-c]ピリジン-5(4H)-イル)メチル)ベンジル)オキシ)フェニル)ヘキサ-4-イン酸化合物。 - 治療上有効量の請求項1〜7のいずれか一項に記載した式(I)の化合物を含み、かつ任意選択により1以上の医薬として許容可能な担体、希釈剤、又は賦形剤を含んでもよい、医薬組成物。
- GPR40受容体によって媒介される疾患を治療する方法であって、それを必要とする患者に、請求項1〜7のいずれか一項に記載した式(I)の化合物の有効量、又はその適切な医薬組成物を投与することを含む方法。
- 請求項1〜7のいずれか一項に記載した式(I)の化合物を好適な賦形剤とともに含み、脂質異常症、肥満などに関連するさまざまな疾患を治療するために適した医薬組成物。
- 哺乳動物において、GPR40受容体機能に関連する病状の予防又は治療のための医薬の調製における、請求項1〜7のいずれか一項に記載の化合物の使用。
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JP6352415B2 (ja) | 2018-07-04 |
KR20160077213A (ko) | 2016-07-01 |
IL245301A0 (en) | 2016-06-30 |
CA2928097A1 (en) | 2015-07-02 |
CN105722841A (zh) | 2016-06-29 |
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TW201531459A (zh) | 2015-08-16 |
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US10011609B2 (en) | 2018-07-03 |
US20160257701A1 (en) | 2016-09-08 |
MX2016006337A (es) | 2016-09-06 |
AR098432A1 (es) | 2016-05-26 |
MA38999A1 (fr) | 2018-01-31 |
IN2013MU03577A (ja) | 2015-07-31 |
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