WO2011151436A2 - Nouveaux composés, procédé d'utilisation de ces composés et composition pharmaceutique les contenant - Google Patents
Nouveaux composés, procédé d'utilisation de ces composés et composition pharmaceutique les contenant Download PDFInfo
- Publication number
- WO2011151436A2 WO2011151436A2 PCT/EP2011/059181 EP2011059181W WO2011151436A2 WO 2011151436 A2 WO2011151436 A2 WO 2011151436A2 EP 2011059181 W EP2011059181 W EP 2011059181W WO 2011151436 A2 WO2011151436 A2 WO 2011151436A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- haloalkyl
- fluoro
- thiazol
- alkoxyalkyl
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 300
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 9
- 238000000034 method Methods 0.000 title description 41
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 15
- 208000018522 Gastrointestinal disease Diseases 0.000 claims abstract description 14
- 208000030159 metabolic disease Diseases 0.000 claims abstract description 14
- 230000002496 gastric effect Effects 0.000 claims abstract description 13
- 230000002757 inflammatory effect Effects 0.000 claims abstract description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 434
- 125000001153 fluoro group Chemical group F* 0.000 claims description 331
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 282
- -1 haloalkoxyalkoxy Chemical group 0.000 claims description 269
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 232
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 200
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 192
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 188
- 125000004994 halo alkoxy alkyl group Chemical group 0.000 claims description 188
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 186
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 130
- 125000001188 haloalkyl group Chemical group 0.000 claims description 118
- 125000003545 alkoxy group Chemical group 0.000 claims description 95
- 150000003839 salts Chemical class 0.000 claims description 80
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 73
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 73
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 70
- 125000004043 oxo group Chemical group O=* 0.000 claims description 70
- 125000000623 heterocyclic group Chemical group 0.000 claims description 66
- 125000001072 heteroaryl group Chemical group 0.000 claims description 65
- 125000003118 aryl group Chemical group 0.000 claims description 64
- 239000000651 prodrug Substances 0.000 claims description 61
- 229940002612 prodrug Drugs 0.000 claims description 61
- 239000012453 solvate Substances 0.000 claims description 59
- 125000005843 halogen group Chemical group 0.000 claims description 48
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 46
- 239000000203 mixture Substances 0.000 claims description 41
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 36
- 102100040133 Free fatty acid receptor 2 Human genes 0.000 claims description 34
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 34
- 125000003282 alkyl amino group Chemical group 0.000 claims description 30
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 30
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 30
- 125000001424 substituent group Chemical group 0.000 claims description 30
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 28
- 125000005112 cycloalkylalkoxy group Chemical group 0.000 claims description 26
- 239000003814 drug Substances 0.000 claims description 25
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 25
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 24
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 24
- 125000001691 aryl alkyl amino group Chemical group 0.000 claims description 24
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 24
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 24
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 24
- 125000004076 pyridyl group Chemical group 0.000 claims description 24
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 23
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 22
- 125000005842 heteroatom Chemical group 0.000 claims description 21
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims description 20
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 18
- 125000001769 aryl amino group Chemical group 0.000 claims description 16
- 125000004658 aryl carbonyl amino group Chemical group 0.000 claims description 16
- 125000004657 aryl sulfonyl amino group Chemical group 0.000 claims description 16
- 125000004104 aryloxy group Chemical group 0.000 claims description 16
- 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 16
- 125000005169 cycloalkylcarbonylamino group Chemical group 0.000 claims description 16
- 125000001475 halogen functional group Chemical group 0.000 claims description 16
- 125000005114 heteroarylalkoxy group Chemical group 0.000 claims description 16
- 125000005241 heteroarylamino group Chemical group 0.000 claims description 16
- 125000005224 heteroarylcarbonylamino group Chemical group 0.000 claims description 16
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 16
- 125000005419 heteroarylsulfonylamino group Chemical group 0.000 claims description 16
- 125000005844 heterocyclyloxy group Chemical group 0.000 claims description 16
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 16
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 15
- 125000005162 aryl oxy carbonyl amino group Chemical group 0.000 claims description 15
- 125000002619 bicyclic group Chemical group 0.000 claims description 15
- 125000005083 alkoxyalkoxy group Chemical group 0.000 claims description 14
- 125000006517 heterocyclyl carbonyl group Chemical group 0.000 claims description 14
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 14
- 239000000556 agonist Substances 0.000 claims description 11
- 239000004031 partial agonist Substances 0.000 claims description 10
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 9
- 230000000694 effects Effects 0.000 claims description 7
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 6
- 125000002947 alkylene group Chemical group 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 6
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- 101000890668 Homo sapiens Free fatty acid receptor 2 Proteins 0.000 claims description 4
- 239000004305 biphenyl Substances 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- JRGQSQMWPNWILM-LDQXTDLNSA-N 2-[(3s,4s,5r)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-5-hydroxy-2-oxo-4-phenylazepan-3-yl]acetic acid Chemical compound C([C@H]([C@@H]([C@H](CC(O)=O)C1=O)C=2C=CC=CC=2)O)CN1C(SC=1)=NC=1C1=CC=CC=C1Cl JRGQSQMWPNWILM-LDQXTDLNSA-N 0.000 claims description 3
- DBKXOROARXFDKF-SQBLYHGDSA-N 2-[(3s,4s,6s,7r)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-6,7-dihydroxy-2-oxo-4-phenylazocan-3-yl]acetic acid Chemical compound O=C([C@@H](CC(O)=O)[C@H](C[C@@H]([C@@H](C1)O)O)C=2C=CC=CC=2)N1C(SC=1)=NC=1C1=CC=CC=C1Cl DBKXOROARXFDKF-SQBLYHGDSA-N 0.000 claims description 3
- 125000005041 acyloxyalkyl group Chemical group 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 3
- 125000006699 (C1-C3) hydroxyalkyl group Chemical group 0.000 claims description 2
- HRLRLZMBNRAFAU-AEFFLSMTSA-N 2-[(3s,4r)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-4-(oxan-4-yl)-2-oxoazocan-3-yl]acetic acid Chemical compound C([C@@H]([C@@H](C1=O)CC(=O)O)C2CCOCC2)CCCN1C(SC=1)=NC=1C1=CC=CC=C1Cl HRLRLZMBNRAFAU-AEFFLSMTSA-N 0.000 claims description 2
- DMSADYSOEDUNSY-AEFFLSMTSA-N 2-[(3s,4r)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-4-cyclopentyl-2-oxoazocan-3-yl]acetic acid Chemical compound C([C@@H]([C@@H](C1=O)CC(=O)O)C2CCCC2)CCCN1C(SC=1)=NC=1C1=CC=CC=C1Cl DMSADYSOEDUNSY-AEFFLSMTSA-N 0.000 claims description 2
- YMWYDKBJFOTLIK-KNQAVFIVSA-N 2-[(3s,4r)-1-[4-[2-(6-methoxypyridin-3-yl)phenyl]-1,3-thiazol-2-yl]-2-oxo-4-propan-2-ylazocan-3-yl]acetic acid Chemical compound C1=NC(OC)=CC=C1C1=CC=CC=C1C1=CSC(N2C([C@@H](CC(O)=O)[C@@H](C(C)C)CCCC2)=O)=N1 YMWYDKBJFOTLIK-KNQAVFIVSA-N 0.000 claims description 2
- AORMPLXRPZFJGX-QPPBQGQZSA-N 2-[(3s,4r)-2-oxo-1-[4-[2-[6-(2-oxopyrrolidin-1-yl)pyridin-3-yl]phenyl]-1,3-thiazol-2-yl]-4-propan-2-ylazocan-3-yl]acetic acid Chemical compound O=C1[C@@H](CC(O)=O)[C@@H](C(C)C)CCCCN1C1=NC(C=2C(=CC=CC=2)C=2C=NC(=CC=2)N2C(CCC2)=O)=CS1 AORMPLXRPZFJGX-QPPBQGQZSA-N 0.000 claims description 2
- VYJWYJXSJUUEPW-BVAGGSTKSA-N 2-[(3s,4r)-4-cyclopentyl-2-oxo-1-[4-[2-[6-(2-oxopyrrolidin-1-yl)pyridin-3-yl]phenyl]-1,3-thiazol-2-yl]azocan-3-yl]acetic acid Chemical compound C([C@@H]([C@@H](C1=O)CC(=O)O)C2CCCC2)CCCN1C(SC=1)=NC=1C1=CC=CC=C1C(C=N1)=CC=C1N1CCCC1=O VYJWYJXSJUUEPW-BVAGGSTKSA-N 0.000 claims description 2
- BFBCTDBDUMCSCZ-NUJGCVRESA-N 2-[(3s,4r,7r)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-4-cyclopentyl-7-hydroxy-2-oxoazocan-3-yl]acetic acid Chemical compound C1([C@H]2CC[C@H](CN(C(=O)[C@H]2CC(O)=O)C=2SC=C(N=2)C=2C(=CC=CC=2)Cl)O)CCCC1 BFBCTDBDUMCSCZ-NUJGCVRESA-N 0.000 claims description 2
- IDXNTJRYIVPYML-FMKPAKJESA-N 2-[(3s,4r,7r)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-7-hydroxy-2-oxo-4-propan-2-ylazocan-3-yl]acetic acid Chemical compound O=C1[C@@H](CC(O)=O)[C@@H](C(C)C)CC[C@@H](O)CN1C1=NC(C=2C(=CC=CC=2)Cl)=CS1 IDXNTJRYIVPYML-FMKPAKJESA-N 0.000 claims description 2
- BFBCTDBDUMCSCZ-JZXOWHBKSA-N 2-[(3s,4r,7s)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-4-cyclopentyl-7-hydroxy-2-oxoazocan-3-yl]acetic acid Chemical compound C1([C@H]2CC[C@@H](CN(C(=O)[C@H]2CC(O)=O)C=2SC=C(N=2)C=2C(=CC=CC=2)Cl)O)CCCC1 BFBCTDBDUMCSCZ-JZXOWHBKSA-N 0.000 claims description 2
- LBTXWLSTRIQNJO-MSOLQXFVSA-N 2-[(3s,4s)-1-[4-(2,5-dichlorophenyl)-1,3-thiazol-2-yl]-2-oxo-4-phenylazocan-3-yl]acetic acid Chemical compound C([C@@H]([C@@H](C1=O)CC(=O)O)C=2C=CC=CC=2)CCCN1C(SC=1)=NC=1C1=CC(Cl)=CC=C1Cl LBTXWLSTRIQNJO-MSOLQXFVSA-N 0.000 claims description 2
- BVHCTICCDWFJED-MJGOQNOKSA-N 2-[(3s,4s)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-2,7-dioxo-4-phenylazocan-3-yl]acetic acid Chemical compound C([C@@H]([C@@H](C1=O)CC(=O)O)C=2C=CC=CC=2)CC(=O)CN1C(SC=1)=NC=1C1=CC=CC=C1Cl BVHCTICCDWFJED-MJGOQNOKSA-N 0.000 claims description 2
- HIFCURKONYPZMG-VRAFCGOGSA-N 2-[(3s,4s)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-2-oxo-4-phenyl-7-(propan-2-ylamino)azocan-3-yl]acetic acid Chemical compound O=C([C@@H](CC(O)=O)[C@H](CCC(C1)NC(C)C)C=2C=CC=CC=2)N1C(SC=1)=NC=1C1=CC=CC=C1Cl HIFCURKONYPZMG-VRAFCGOGSA-N 0.000 claims description 2
- ZFTJDJJVJIVUCC-AEFFLSMTSA-N 2-[(3s,4s)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-2-oxo-4-phenylazepan-3-yl]acetic acid Chemical compound C([C@@H]([C@@H](C1=O)CC(=O)O)C=2C=CC=CC=2)CCN1C(SC=1)=NC=1C1=CC=CC=C1Cl ZFTJDJJVJIVUCC-AEFFLSMTSA-N 0.000 claims description 2
- WTVUKACDKDBHHI-MJGOQNOKSA-N 2-[(3s,4s)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-2-oxo-4-phenylazocan-3-yl]acetic acid Chemical compound C([C@@H]([C@@H](C1=O)CC(=O)O)C=2C=CC=CC=2)CCCN1C(SC=1)=NC=1C1=CC=CC=C1Cl WTVUKACDKDBHHI-MJGOQNOKSA-N 0.000 claims description 2
- QBCHXFKQFCDTPG-KVJCIMDZSA-N 2-[(3s,4s)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-6-hydroxy-2-oxo-4-phenylazepan-3-yl]acetic acid Chemical compound O=C([C@@H](CC(O)=O)[C@H](CC(C1)O)C=2C=CC=CC=2)N1C(SC=1)=NC=1C1=CC=CC=C1Cl QBCHXFKQFCDTPG-KVJCIMDZSA-N 0.000 claims description 2
- LMPBOTCGEIMKNX-VITQDTLGSA-N 2-[(3s,4s)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-6-hydroxy-2-oxo-4-phenylazocan-3-yl]acetic acid Chemical compound C([C@@H]([C@H](CC(O)=O)C1=O)C=2C=CC=CC=2)C(O)CCN1C(SC=1)=NC=1C1=CC=CC=C1Cl LMPBOTCGEIMKNX-VITQDTLGSA-N 0.000 claims description 2
- SJHKLTOVMAPWRI-QIONWKSUSA-N 2-[(3s,4s)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-7-fluoro-2-oxo-4-phenylazocan-3-yl]acetic acid Chemical compound C([C@@H]([C@@H](C1=O)CC(=O)O)C=2C=CC=CC=2)CC(F)CN1C(SC=1)=NC=1C1=CC=CC=C1Cl SJHKLTOVMAPWRI-QIONWKSUSA-N 0.000 claims description 2
- PUUUMVZRVPHKSA-QIONWKSUSA-N 2-[(3s,4s)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-7-hydroxy-2-oxo-4-phenylazocan-3-yl]acetic acid Chemical compound O=C([C@@H](CC(O)=O)[C@H](CCC(C1)O)C=2C=CC=CC=2)N1C(SC=1)=NC=1C1=CC=CC=C1Cl PUUUMVZRVPHKSA-QIONWKSUSA-N 0.000 claims description 2
- GANHLDGJPGDPBM-QPPBQGQZSA-N 2-[(3s,4s)-1-[4-[2-(6-methoxypyridin-3-yl)phenyl]-1,3-thiazol-2-yl]-2-oxo-4-phenylazepan-3-yl]acetic acid Chemical compound C1=NC(OC)=CC=C1C1=CC=CC=C1C1=CSC(N2C([C@@H](CC(O)=O)[C@H](CCC2)C=2C=CC=CC=2)=O)=N1 GANHLDGJPGDPBM-QPPBQGQZSA-N 0.000 claims description 2
- XDVYEQCUICNRLD-NUJYYHISSA-N 2-[(3s,4s)-7-(benzylamino)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-2-oxo-4-phenylazocan-3-yl]acetic acid Chemical compound C([C@@H]([C@@H](C1=O)CC(=O)O)C=2C=CC=CC=2)CC(NCC=2C=CC=CC=2)CN1C(SC=1)=NC=1C1=CC=CC=C1Cl XDVYEQCUICNRLD-NUJYYHISSA-N 0.000 claims description 2
- PUUUMVZRVPHKSA-LMMKCTJWSA-N 2-[(3s,4s,7r)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-7-hydroxy-2-oxo-4-phenylazocan-3-yl]acetic acid Chemical compound O=C([C@@H](CC(O)=O)[C@H](CC[C@H](C1)O)C=2C=CC=CC=2)N1C(SC=1)=NC=1C1=CC=CC=C1Cl PUUUMVZRVPHKSA-LMMKCTJWSA-N 0.000 claims description 2
- PUUUMVZRVPHKSA-SCTDSRPQSA-N 2-[(3s,4s,7s)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-7-hydroxy-2-oxo-4-phenylazocan-3-yl]acetic acid Chemical compound O=C([C@@H](CC(O)=O)[C@H](CC[C@@H](C1)O)C=2C=CC=CC=2)N1C(SC=1)=NC=1C1=CC=CC=C1Cl PUUUMVZRVPHKSA-SCTDSRPQSA-N 0.000 claims description 2
- KLZQJNRTEJUPKT-IIFCEKJISA-N 2-[(3z,6s,7s)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-8-oxo-6-phenyl-2,5,6,7-tetrahydroazocin-7-yl]acetic acid Chemical compound C([C@@H]([C@@H](C1=O)CC(=O)O)C=2C=CC=CC=2)\C=C/CN1C(SC=1)=NC=1C1=CC=CC=C1Cl KLZQJNRTEJUPKT-IIFCEKJISA-N 0.000 claims description 2
- MRICGOKABUOYKK-QPPBQGQZSA-N 2-[(5s,6s)-1-[4-[2-(6-methoxypyridin-3-yl)phenyl]-1,3-thiazol-2-yl]-7-oxo-5-phenyl-5,6-dihydro-2h-azepin-6-yl]acetic acid Chemical compound C1=NC(OC)=CC=C1C1=CC=CC=C1C1=CSC(N2C([C@@H](CC(O)=O)[C@H](C=CC2)C=2C=CC=CC=2)=O)=N1 MRICGOKABUOYKK-QPPBQGQZSA-N 0.000 claims description 2
- GCQGMICAJCDECM-UHFFFAOYSA-N 2-[4-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-1-cyclopentyl-3,8-dioxo-1,4-diazocan-2-yl]acetic acid Chemical compound O=C1CCCN(C=2SC=C(N=2)C=2C(=CC=CC=2)Cl)C(=O)C(CC(=O)O)N1C1CCCC1 GCQGMICAJCDECM-UHFFFAOYSA-N 0.000 claims description 2
- XKTYXVDYIKIYJP-UHFFFAOYSA-N 3h-dioxole Chemical compound C1OOC=C1 XKTYXVDYIKIYJP-UHFFFAOYSA-N 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- XELOVLWJBPDZBE-RUZDIDTESA-N 2-[(2r)-1-cyclopentyl-3,8-dioxo-4-[4-[2-[6-(2-oxopyrrolidin-1-yl)pyridin-3-yl]phenyl]-1,3-thiazol-2-yl]-1,4-diazocan-2-yl]acetic acid Chemical compound N1([C@@H](C(N(C=2SC=C(N=2)C=2C(=CC=CC=2)C=2C=NC(=CC=2)N2C(CCC2)=O)CCCC1=O)=O)CC(=O)O)C1CCCC1 XELOVLWJBPDZBE-RUZDIDTESA-N 0.000 claims 1
- CAYSFMGHSUINCC-QGZVFWFLSA-N 2-[(2r)-4-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-1-(2-methylpropyl)-3,8-dioxo-1,4-diazocan-2-yl]acetic acid Chemical compound C1CCC(=O)N(CC(C)C)[C@H](CC(O)=O)C(=O)N1C1=NC(C=2C(=CC=CC=2)Cl)=CS1 CAYSFMGHSUINCC-QGZVFWFLSA-N 0.000 claims 1
- CNPIMYFUZSJAGH-LJQANCHMSA-N 2-[(2r)-4-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-1-(cyclopentylmethyl)-3,8-dioxo-1,4-diazocan-2-yl]acetic acid Chemical compound N1([C@@H](C(N(C=2SC=C(N=2)C=2C(=CC=CC=2)Cl)CCCC1=O)=O)CC(=O)O)CC1CCCC1 CNPIMYFUZSJAGH-LJQANCHMSA-N 0.000 claims 1
- RDABUATXYWJHJH-QGZVFWFLSA-N 2-[(2r)-4-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-1-cyclopentyl-3,7-dioxo-1,4-diazepan-2-yl]acetic acid Chemical compound N1([C@@H](C(N(C=2SC=C(N=2)C=2C(=CC=CC=2)Cl)CCC1=O)=O)CC(=O)O)C1CCCC1 RDABUATXYWJHJH-QGZVFWFLSA-N 0.000 claims 1
- MEMLLINOKKYJKT-MRXNPFEDSA-N 2-[(2r)-4-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-3,8-dioxo-1-propan-2-yl-1,4-diazocan-2-yl]acetic acid Chemical compound C1CCC(=O)N(C(C)C)[C@H](CC(O)=O)C(=O)N1C1=NC(C=2C(=CC=CC=2)Cl)=CS1 MEMLLINOKKYJKT-MRXNPFEDSA-N 0.000 claims 1
- OPXBAZYJFVUOKA-NOOIUNMQSA-N 2-[(2r,5s,6s)-5-cyclopentyl-2-(hydroxymethyl)-7-oxo-1-[4-[2-[6-(2-oxopyrrolidin-1-yl)pyridin-3-yl]phenyl]-1,3-thiazol-2-yl]-5,6-dihydro-2h-azepin-6-yl]acetic acid Chemical compound C1([C@H]2C=C[C@@H](N(C(=O)[C@H]2CC(O)=O)C=2SC=C(N=2)C=2C(=CC=CC=2)C=2C=NC(=CC=2)N2C(CCC2)=O)CO)CCCC1 OPXBAZYJFVUOKA-NOOIUNMQSA-N 0.000 claims 1
- YTGRTFRPPFJRII-VRPIGFSUSA-N 2-[(2s,3z,6r,7s)-6-cyclopentyl-2-(hydroxymethyl)-8-oxo-1-[4-[2-[6-(2-oxopyrrolidin-1-yl)pyridin-3-yl]phenyl]-1,3-thiazol-2-yl]-2,5,6,7-tetrahydroazocin-7-yl]acetic acid Chemical compound C1([C@H]2C\C=C/[C@H](N(C(=O)[C@H]2CC(O)=O)C=2SC=C(N=2)C=2C(=CC=CC=2)C=2C=NC(=CC=2)N2C(CCC2)=O)CO)CCCC1 YTGRTFRPPFJRII-VRPIGFSUSA-N 0.000 claims 1
- NJXROSMVRGASBX-SCTDSRPQSA-N 2-[(2s,5s,6s)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-2-(hydroxymethyl)-7-oxo-5-phenyl-5,6-dihydro-2h-azepin-6-yl]acetic acid Chemical compound O=C([C@@H](CC(O)=O)[C@H](C=C[C@H]1CO)C=2C=CC=CC=2)N1C(SC=1)=NC=1C1=CC=CC=C1Cl NJXROSMVRGASBX-SCTDSRPQSA-N 0.000 claims 1
- OPXBAZYJFVUOKA-FBILRYNDSA-N 2-[(2s,5s,6s)-5-cyclopentyl-2-(hydroxymethyl)-7-oxo-1-[4-[2-[6-(2-oxopyrrolidin-1-yl)pyridin-3-yl]phenyl]-1,3-thiazol-2-yl]-5,6-dihydro-2h-azepin-6-yl]acetic acid Chemical compound C1([C@H]2C=C[C@H](N(C(=O)[C@H]2CC(O)=O)C=2SC=C(N=2)C=2C(=CC=CC=2)C=2C=NC(=CC=2)N2C(CCC2)=O)CO)CCCC1 OPXBAZYJFVUOKA-FBILRYNDSA-N 0.000 claims 1
- CMMZMIIZMHGSBO-ZBFHGGJFSA-N 2-[(3S,4R)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-4-cyclopropyl-2-oxoazocan-3-yl]acetic acid Chemical compound OC(=O)C[C@H]1[C@H](CCCCN(c2nc(cs2)-c2ccccc2Cl)C1=O)C1CC1 CMMZMIIZMHGSBO-ZBFHGGJFSA-N 0.000 claims 1
- KPWMMFNGOUMHLH-OASJLCFRSA-N 2-[(3S,4R,8R)-4-cyclopentyl-8-(hydroxymethyl)-2-oxo-1-[4-[2-[6-(2-oxopyrrolidin-1-yl)pyridin-3-yl]phenyl]-1,3-thiazol-2-yl]azocan-3-yl]acetic acid Chemical compound OC[C@H]1CCC[C@H](C2CCCC2)[C@H](CC(O)=O)C(=O)N1c1nc(cs1)-c1ccccc1-c1ccc(nc1)N1CCCC1=O KPWMMFNGOUMHLH-OASJLCFRSA-N 0.000 claims 1
- UMNPHRHNKYMWJW-WBVHZDCISA-N 2-[(3s,4r)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-4-cyclobutyl-2-oxoazocan-3-yl]acetic acid Chemical compound C([C@@H]([C@@H](C1=O)CC(=O)O)C2CCC2)CCCN1C(SC=1)=NC=1C1=CC=CC=C1Cl UMNPHRHNKYMWJW-WBVHZDCISA-N 0.000 claims 1
- LRJIDOKKOHFEIN-XLIONFOSSA-N 2-[(3s,4r)-1-[4-[2-(5-methoxypyrazin-2-yl)phenyl]-1,3-thiazol-2-yl]-2-oxo-4-propan-2-ylazocan-3-yl]acetic acid Chemical compound C1=NC(OC)=CN=C1C1=CC=CC=C1C1=CSC(N2C([C@@H](CC(O)=O)[C@@H](C(C)C)CCCC2)=O)=N1 LRJIDOKKOHFEIN-XLIONFOSSA-N 0.000 claims 1
- ZORSIABRHJJLTE-RDGATRHJSA-N 2-[(3s,4r)-4-cyclobutyl-2-oxo-1-[4-[2-[6-(2-oxopyrrolidin-1-yl)pyridin-3-yl]phenyl]-1,3-thiazol-2-yl]azocan-3-yl]acetic acid Chemical compound C([C@@H]([C@@H](C1=O)CC(=O)O)C2CCC2)CCCN1C(SC=1)=NC=1C1=CC=CC=C1C(C=N1)=CC=C1N1CCCC1=O ZORSIABRHJJLTE-RDGATRHJSA-N 0.000 claims 1
- FUVJOJXXPHZEAV-KNQAVFIVSA-N 2-[(3s,4r)-4-cyclopentyl-1-[4-[2-(5-methoxypyrazin-2-yl)phenyl]-1,3-thiazol-2-yl]-2-oxoazocan-3-yl]acetic acid Chemical compound C1=NC(OC)=CN=C1C1=CC=CC=C1C1=CSC(N2C([C@@H](CC(O)=O)[C@@H](C3CCCC3)CCCC2)=O)=N1 FUVJOJXXPHZEAV-KNQAVFIVSA-N 0.000 claims 1
- IQOUQEYXSKYOPR-KNQAVFIVSA-N 2-[(3s,4r)-4-cyclopentyl-1-[4-[2-(6-methoxypyridazin-3-yl)phenyl]-1,3-thiazol-2-yl]-2-oxoazocan-3-yl]acetic acid Chemical compound N1=NC(OC)=CC=C1C1=CC=CC=C1C1=CSC(N2C([C@@H](CC(O)=O)[C@@H](C3CCCC3)CCCC2)=O)=N1 IQOUQEYXSKYOPR-KNQAVFIVSA-N 0.000 claims 1
- QDIBSAURKQRAOT-ZSQFBXSQSA-N 2-[(3s,4r)-4-cyclopentyl-1-[4-[2-[6-[(3r)-3-fluoro-2-oxopyrrolidin-1-yl]pyridin-3-yl]phenyl]-1,3-thiazol-2-yl]-2-oxoazocan-3-yl]acetic acid Chemical compound C([C@@H]([C@@H](C1=O)CC(=O)O)C2CCCC2)CCCN1C(SC=1)=NC=1C1=CC=CC=C1C(C=N1)=CC=C1N1CC[C@@H](F)C1=O QDIBSAURKQRAOT-ZSQFBXSQSA-N 0.000 claims 1
- PQVJHVRHYYHFPS-DBTWGZIYSA-N 2-[(3s,4r)-4-cyclopentyl-1-[4-[2-[6-[(3r)-3-methyl-2-oxopyrrolidin-1-yl]pyridin-3-yl]phenyl]-1,3-thiazol-2-yl]-2-oxoazocan-3-yl]acetic acid Chemical compound O=C1[C@H](C)CCN1C1=CC=C(C=2C(=CC=CC=2)C=2N=C(SC=2)N2C([C@@H](CC(O)=O)[C@@H](C3CCCC3)CCCC2)=O)C=N1 PQVJHVRHYYHFPS-DBTWGZIYSA-N 0.000 claims 1
- QDIBSAURKQRAOT-RZFJZAQRSA-N 2-[(3s,4r)-4-cyclopentyl-1-[4-[2-[6-[(3s)-3-fluoro-2-oxopyrrolidin-1-yl]pyridin-3-yl]phenyl]-1,3-thiazol-2-yl]-2-oxoazocan-3-yl]acetic acid Chemical compound C([C@@H]([C@@H](C1=O)CC(=O)O)C2CCCC2)CCCN1C(SC=1)=NC=1C1=CC=CC=C1C(C=N1)=CC=C1N1CC[C@H](F)C1=O QDIBSAURKQRAOT-RZFJZAQRSA-N 0.000 claims 1
- PQVJHVRHYYHFPS-WBWMCNGVSA-N 2-[(3s,4r)-4-cyclopentyl-1-[4-[2-[6-[(3s)-3-methyl-2-oxopyrrolidin-1-yl]pyridin-3-yl]phenyl]-1,3-thiazol-2-yl]-2-oxoazocan-3-yl]acetic acid Chemical compound O=C1[C@@H](C)CCN1C1=CC=C(C=2C(=CC=CC=2)C=2N=C(SC=2)N2C([C@@H](CC(O)=O)[C@@H](C3CCCC3)CCCC2)=O)C=N1 PQVJHVRHYYHFPS-WBWMCNGVSA-N 0.000 claims 1
- MUNMLSCCNPDWKI-RDGATRHJSA-N 2-[(3s,4r)-4-cyclopentyl-1-[5-fluoro-4-[2-[6-(2-oxopyrrolidin-1-yl)pyridin-3-yl]phenyl]-1,3-thiazol-2-yl]-2-oxoazocan-3-yl]acetic acid Chemical compound C([C@@H]([C@@H](C1=O)CC(=O)O)C2CCCC2)CCCN1C(SC=1F)=NC=1C1=CC=CC=C1C(C=N1)=CC=C1N1CCCC1=O MUNMLSCCNPDWKI-RDGATRHJSA-N 0.000 claims 1
- LYLQXYCBZIPAHT-RDGATRHJSA-N 2-[(3s,4r)-4-cyclopentyl-2-oxo-1-[3-[2-[6-(2-oxopyrrolidin-1-yl)pyridin-3-yl]phenyl]-1,2,4-thiadiazol-5-yl]azocan-3-yl]acetic acid Chemical compound C([C@@H]([C@@H](C1=O)CC(=O)O)C2CCCC2)CCCN1C(SN=1)=NC=1C1=CC=CC=C1C(C=N1)=CC=C1N1CCCC1=O LYLQXYCBZIPAHT-RDGATRHJSA-N 0.000 claims 1
- GSKAGODUUZUGDT-QPPBQGQZSA-N 2-[(3s,4r)-4-cyclopropyl-2-oxo-1-[4-[2-[6-(2-oxopyrrolidin-1-yl)pyridin-3-yl]phenyl]-1,3-thiazol-2-yl]azocan-3-yl]acetic acid Chemical compound C([C@@H]([C@@H](C1=O)CC(=O)O)C2CC2)CCCN1C(SC=1)=NC=1C1=CC=CC=C1C(C=N1)=CC=C1N1CCCC1=O GSKAGODUUZUGDT-QPPBQGQZSA-N 0.000 claims 1
- TXWAAMLBXDXYPD-SUMDDJOVSA-N 2-[(3s,4r,7r)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-4-cyclopentyl-7-(hydroxymethyl)-2-oxoazocan-3-yl]acetic acid Chemical compound C1([C@H]2CC[C@H](CN(C(=O)[C@H]2CC(O)=O)C=2SC=C(N=2)C=2C(=CC=CC=2)Cl)CO)CCCC1 TXWAAMLBXDXYPD-SUMDDJOVSA-N 0.000 claims 1
- RVCMWBPAAMCHBS-LMMKCTJWSA-N 2-[(3s,4r,7r)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-4-cyclopentyl-7-(methanesulfonamido)-2-oxoazocan-3-yl]acetic acid Chemical compound C1([C@H]2CC[C@H](CN(C(=O)[C@H]2CC(O)=O)C=2SC=C(N=2)C=2C(=CC=CC=2)Cl)NS(=O)(=O)C)CCCC1 RVCMWBPAAMCHBS-LMMKCTJWSA-N 0.000 claims 1
- YYWMSCQLCCRYMC-NOOIUNMQSA-N 2-[(3s,4r,7r)-4-cyclopentyl-7-(hydroxymethyl)-2-oxo-1-[4-[2-[6-(2-oxopyrrolidin-1-yl)pyridin-3-yl]phenyl]-1,3-thiazol-2-yl]azepan-3-yl]acetic acid Chemical compound C1([C@H]2CC[C@@H](N(C(=O)[C@H]2CC(O)=O)C=2SC=C(N=2)C=2C(=CC=CC=2)C=2C=NC(=CC=2)N2C(CCC2)=O)CO)CCCC1 YYWMSCQLCCRYMC-NOOIUNMQSA-N 0.000 claims 1
- PIMKFGKXLOAORF-RMXYQJDTSA-N 2-[(3s,4r,7r)-4-cyclopentyl-7-(hydroxymethyl)-2-oxo-1-[4-[2-[6-(2-oxopyrrolidin-1-yl)pyridin-3-yl]phenyl]-1,3-thiazol-2-yl]azocan-3-yl]acetic acid Chemical compound C1([C@H]2CC[C@H](CN(C(=O)[C@H]2CC(O)=O)C=2SC=C(N=2)C=2C(=CC=CC=2)C=2C=NC(=CC=2)N2C(CCC2)=O)CO)CCCC1 PIMKFGKXLOAORF-RMXYQJDTSA-N 0.000 claims 1
- JJBDVTSKRULZOM-HYZYYIOASA-N 2-[(3s,4r,7r)-4-cyclopentyl-7-(methanesulfonamido)-2-oxo-1-[4-[2-[6-(2-oxopyrrolidin-1-yl)pyridin-3-yl]phenyl]-1,3-thiazol-2-yl]azocan-3-yl]acetic acid Chemical compound C1([C@H]2CC[C@H](CN(C(=O)[C@H]2CC(O)=O)C=2SC=C(N=2)C=2C(=CC=CC=2)C=2C=NC(=CC=2)N2C(CCC2)=O)NS(=O)(=O)C)CCCC1 JJBDVTSKRULZOM-HYZYYIOASA-N 0.000 claims 1
- GXZWEDRUOMGLJX-GGPKGHCWSA-N 2-[(3s,4r,7r)-7-acetamido-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-4-cyclopentyl-2-oxoazocan-3-yl]acetic acid Chemical compound C1([C@H]2CC[C@H](CN(C(=O)[C@H]2CC(O)=O)C=2SC=C(N=2)C=2C(=CC=CC=2)Cl)NC(=O)C)CCCC1 GXZWEDRUOMGLJX-GGPKGHCWSA-N 0.000 claims 1
- ACVVNSMRMCHWSB-INOCPDNRSA-N 2-[(3s,4r,7r)-7-acetamido-4-cyclopentyl-2-oxo-1-[4-[2-[6-(2-oxopyrrolidin-1-yl)pyridin-3-yl]phenyl]-1,3-thiazol-2-yl]azocan-3-yl]acetic acid Chemical compound C1([C@H]2CC[C@H](CN(C(=O)[C@H]2CC(O)=O)C=2SC=C(N=2)C=2C(=CC=CC=2)C=2C=NC(=CC=2)N2C(CCC2)=O)NC(=O)C)CCCC1 ACVVNSMRMCHWSB-INOCPDNRSA-N 0.000 claims 1
- TXWAAMLBXDXYPD-WDYCEAGBSA-N 2-[(3s,4r,7s)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-4-cyclopentyl-7-(hydroxymethyl)-2-oxoazocan-3-yl]acetic acid Chemical compound C1([C@H]2CC[C@@H](CN(C(=O)[C@H]2CC(O)=O)C=2SC=C(N=2)C=2C(=CC=CC=2)Cl)CO)CCCC1 TXWAAMLBXDXYPD-WDYCEAGBSA-N 0.000 claims 1
- YYWMSCQLCCRYMC-FBILRYNDSA-N 2-[(3s,4r,7s)-4-cyclopentyl-7-(hydroxymethyl)-2-oxo-1-[4-[2-[6-(2-oxopyrrolidin-1-yl)pyridin-3-yl]phenyl]-1,3-thiazol-2-yl]azepan-3-yl]acetic acid Chemical compound C1([C@H]2CC[C@H](N(C(=O)[C@H]2CC(O)=O)C=2SC=C(N=2)C=2C(=CC=CC=2)C=2C=NC(=CC=2)N2C(CCC2)=O)CO)CCCC1 YYWMSCQLCCRYMC-FBILRYNDSA-N 0.000 claims 1
- PIMKFGKXLOAORF-BBVXACFBSA-N 2-[(3s,4r,7s)-4-cyclopentyl-7-(hydroxymethyl)-2-oxo-1-[4-[2-[6-(2-oxopyrrolidin-1-yl)pyridin-3-yl]phenyl]-1,3-thiazol-2-yl]azocan-3-yl]acetic acid Chemical compound C1([C@H]2CC[C@@H](CN(C(=O)[C@H]2CC(O)=O)C=2SC=C(N=2)C=2C(=CC=CC=2)C=2C=NC(=CC=2)N2C(CCC2)=O)CO)CCCC1 PIMKFGKXLOAORF-BBVXACFBSA-N 0.000 claims 1
- UPFMKXINPNFSNT-LMMKCTJWSA-N 2-[(3s,4r,8r)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-4-cyclopentyl-8-(hydroxymethyl)-2-oxoazocan-3-yl]acetic acid Chemical compound C1([C@H]2CCC[C@@H](N(C(=O)[C@H]2CC(O)=O)C=2SC=C(N=2)C=2C(=CC=CC=2)Cl)CO)CCCC1 UPFMKXINPNFSNT-LMMKCTJWSA-N 0.000 claims 1
- UPFMKXINPNFSNT-SCTDSRPQSA-N 2-[(3s,4r,8s)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-4-cyclopentyl-8-(hydroxymethyl)-2-oxoazocan-3-yl]acetic acid Chemical compound C1([C@H]2CCC[C@H](N(C(=O)[C@H]2CC(O)=O)C=2SC=C(N=2)C=2C(=CC=CC=2)Cl)CO)CCCC1 UPFMKXINPNFSNT-SCTDSRPQSA-N 0.000 claims 1
- KPWMMFNGOUMHLH-XFAFFCHDSA-N 2-[(3s,4r,8s)-4-cyclopentyl-8-(hydroxymethyl)-2-oxo-1-[4-[2-[6-(2-oxopyrrolidin-1-yl)pyridin-3-yl]phenyl]-1,3-thiazol-2-yl]azocan-3-yl]acetic acid Chemical compound C1([C@H]2CCC[C@H](N(C(=O)[C@H]2CC(O)=O)C=2SC=C(N=2)C=2C(=CC=CC=2)C=2C=NC(=CC=2)N2C(CCC2)=O)CO)CCCC1 KPWMMFNGOUMHLH-XFAFFCHDSA-N 0.000 claims 1
- RXWFXYLUUHGLFH-QDKIRNHSSA-N 2-[(3s,4s)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-7-(hydroxymethyl)-2-oxo-4-phenylazocan-3-yl]acetic acid Chemical compound O=C([C@@H](CC(O)=O)[C@H](CCC(C1)CO)C=2C=CC=CC=2)N1C(SC=1)=NC=1C1=CC=CC=C1Cl RXWFXYLUUHGLFH-QDKIRNHSSA-N 0.000 claims 1
- MBZXWVOIWYEUEK-VWNXMTODSA-N 2-[(3s,4s)-4-(2-chlorophenyl)-1-[4-(2-methoxyphenyl)phenyl]-2-oxoazocan-3-yl]acetic acid Chemical compound COC1=CC=CC=C1C1=CC=C(N2C([C@@H](CC(O)=O)[C@H](CCCC2)C=2C(=CC=CC=2)Cl)=O)C=C1 MBZXWVOIWYEUEK-VWNXMTODSA-N 0.000 claims 1
- WBVAUVQEIBUVHH-QIONWKSUSA-N 2-[(3s,4s)-7-amino-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-2-oxo-4-phenylazocan-3-yl]acetic acid Chemical compound O=C([C@@H](CC(O)=O)[C@H](CCC(C1)N)C=2C=CC=CC=2)N1C(SC=1)=NC=1C1=CC=CC=C1Cl WBVAUVQEIBUVHH-QIONWKSUSA-N 0.000 claims 1
- DBKXOROARXFDKF-OVQGTLEDSA-N 2-[(3s,4s,6r,7s)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-6,7-dihydroxy-2-oxo-4-phenylazocan-3-yl]acetic acid Chemical compound O=C([C@@H](CC(O)=O)[C@H](C[C@H]([C@H](C1)O)O)C=2C=CC=CC=2)N1C(SC=1)=NC=1C1=CC=CC=C1Cl DBKXOROARXFDKF-OVQGTLEDSA-N 0.000 claims 1
- DFBYENQXIUQXFI-GGPKGHCWSA-N 2-[(3s,4s,7r)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-7-(methanesulfonamido)-2-oxo-4-phenylazocan-3-yl]acetic acid Chemical compound O=C([C@@H](CC(O)=O)[C@H](CC[C@H](C1)NS(=O)(=O)C)C=2C=CC=CC=2)N1C(SC=1)=NC=1C1=CC=CC=C1Cl DFBYENQXIUQXFI-GGPKGHCWSA-N 0.000 claims 1
- OEBAPNBOQUUCKG-SBHAEUEKSA-N 2-[(3s,4s,7r)-7-acetamido-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-2-oxo-4-phenylazocan-3-yl]acetic acid Chemical compound O=C([C@@H](CC(O)=O)[C@H](CC[C@H](C1)NC(=O)C)C=2C=CC=CC=2)N1C(SC=1)=NC=1C1=CC=CC=C1Cl OEBAPNBOQUUCKG-SBHAEUEKSA-N 0.000 claims 1
- JCOBMHPNLBKAQB-MXTKCAFNSA-N 2-[(3z,6r,7s)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-6-cyclobutyl-8-oxo-2,5,6,7-tetrahydroazocin-7-yl]acetic acid Chemical compound C([C@@H]([C@@H](C1=O)CC(=O)O)C2CCC2)\C=C/CN1C(SC=1)=NC=1C1=CC=CC=C1Cl JCOBMHPNLBKAQB-MXTKCAFNSA-N 0.000 claims 1
- NDNPTDJRCPUIOB-ZRBYZBAOSA-N 2-[(3z,6r,7s)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-8-oxo-6-propan-2-yl-2,5,6,7-tetrahydroazocin-7-yl]acetic acid Chemical compound O=C1[C@@H](CC(O)=O)[C@@H](C(C)C)C\C=C/CN1C1=NC(C=2C(=CC=CC=2)Cl)=CS1 NDNPTDJRCPUIOB-ZRBYZBAOSA-N 0.000 claims 1
- INEWDSUFMPHIMW-TWSMFDHCSA-N 2-[(3z,6r,7s)-6-cyclopentyl-1-[4-[2-[6-[(3r)-3-methyl-2-oxopyrrolidin-1-yl]pyridin-3-yl]phenyl]-1,3-thiazol-2-yl]-8-oxo-2,5,6,7-tetrahydroazocin-7-yl]acetic acid Chemical compound O=C1[C@H](C)CCN1C1=CC=C(C=2C(=CC=CC=2)C=2N=C(SC=2)N2C([C@@H](CC(O)=O)[C@@H](C3CCCC3)C\C=C/C2)=O)C=N1 INEWDSUFMPHIMW-TWSMFDHCSA-N 0.000 claims 1
- INEWDSUFMPHIMW-VPODHVIVSA-N 2-[(3z,6r,7s)-6-cyclopentyl-1-[4-[2-[6-[(3s)-3-methyl-2-oxopyrrolidin-1-yl]pyridin-3-yl]phenyl]-1,3-thiazol-2-yl]-8-oxo-2,5,6,7-tetrahydroazocin-7-yl]acetic acid Chemical compound O=C1[C@@H](C)CCN1C1=CC=C(C=2C(=CC=CC=2)C=2N=C(SC=2)N2C([C@@H](CC(O)=O)[C@@H](C3CCCC3)C\C=C/C2)=O)C=N1 INEWDSUFMPHIMW-VPODHVIVSA-N 0.000 claims 1
- KXWJVJLTARCVRE-MGBKSAOESA-N 2-[(3z,6r,7s)-6-cyclopentyl-8-oxo-1-(4-phenyl-1,3-thiazol-2-yl)-2,5,6,7-tetrahydroazocin-7-yl]acetic acid Chemical compound C([C@@H]([C@@H](C1=O)CC(=O)O)C2CCCC2)\C=C/CN1C(SC=1)=NC=1C1=CC=CC=C1 KXWJVJLTARCVRE-MGBKSAOESA-N 0.000 claims 1
- MLOUECFPVUUYCB-KKSLTYSGSA-N 2-[(3z,6s,7s)-1-[4-(2,5-dichlorophenyl)-1,3-thiazol-2-yl]-8-oxo-6-phenyl-2,5,6,7-tetrahydroazocin-7-yl]acetic acid Chemical compound C([C@@H]([C@@H](C1=O)CC(=O)O)C=2C=CC=CC=2)\C=C/CN1C(SC=1)=NC=1C1=CC(Cl)=CC=C1Cl MLOUECFPVUUYCB-KKSLTYSGSA-N 0.000 claims 1
- VQKNLIXOUQWAMV-FHYYHZITSA-N 2-[(3z,6s,7s)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-6-(2-methylpropyl)-8-oxo-2,5,6,7-tetrahydroazocin-7-yl]acetic acid Chemical compound O=C1[C@@H](CC(O)=O)[C@@H](CC(C)C)C\C=C/CN1C1=NC(C=2C(=CC=CC=2)Cl)=CS1 VQKNLIXOUQWAMV-FHYYHZITSA-N 0.000 claims 1
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- 239000003208 petroleum Substances 0.000 description 1
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- 125000006239 protecting group Chemical group 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
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- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
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- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
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- 229940043131 pyroglutamate Drugs 0.000 description 1
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- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000004159 quinolin-2-yl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C([H])C(*)=NC2=C1[H] 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- YEENEYXBHNNNGV-XEHWZWQGSA-M sodium;3-acetamido-5-[acetyl(methyl)amino]-2,4,6-triiodobenzoate;(2r,3r,4s,5s,6r)-2-[(2r,3s,4s,5r)-3,4-dihydroxy-2,5-bis(hydroxymethyl)oxolan-2-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound [Na+].CC(=O)N(C)C1=C(I)C(NC(C)=O)=C(I)C(C([O-])=O)=C1I.O[C@H]1[C@H](O)[C@@H](CO)O[C@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 YEENEYXBHNNNGV-XEHWZWQGSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
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- 239000007929 subcutaneous injection Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
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- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- NNTYBUBZPCVRJL-VXNXHJTFSA-N tert-butyl (3s,4s)-3-[(4s)-4-benzyl-2-oxo-1,3-oxazolidine-3-carbonyl]-4-phenylhept-6-enoate Chemical compound C1([C@@H](CC=C)[C@H](CC(=O)OC(C)(C)C)C(=O)N2C(OC[C@@H]2CC=2C=CC=CC=2)=O)=CC=CC=C1 NNTYBUBZPCVRJL-VXNXHJTFSA-N 0.000 description 1
- NNTYBUBZPCVRJL-XAGPSQNTSA-N tert-butyl (4s)-3-[(4s)-4-benzyl-2-oxo-1,3-oxazolidine-3-carbonyl]-4-phenylhept-6-enoate Chemical compound C1([C@@H](CC=C)C(CC(=O)OC(C)(C)C)C(=O)N2C(OC[C@@H]2CC=2C=CC=CC=2)=O)=CC=CC=C1 NNTYBUBZPCVRJL-XAGPSQNTSA-N 0.000 description 1
- DJJIXKYZANDHOZ-OMQKAAQBSA-N tert-butyl 2-[(3S,4S)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-2-oxo-4-phenyl-7-(propan-2-ylamino)azocan-3-yl]acetate Chemical compound CC(C)NC1CC[C@@H]([C@H](CC(=O)OC(C)(C)C)C(=O)N(C1)c1nc(cs1)-c1ccccc1Cl)c1ccccc1 DJJIXKYZANDHOZ-OMQKAAQBSA-N 0.000 description 1
- RZBLCXAXAZEJJZ-VRAFCGOGSA-N tert-butyl 2-[(3S,4S)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-7-fluoro-2-oxo-4-phenylazocan-3-yl]acetate Chemical compound CC(C)(C)OC(=O)C[C@H]1[C@H](CCC(F)CN(c2nc(cs2)-c2ccccc2Cl)C1=O)c1ccccc1 RZBLCXAXAZEJJZ-VRAFCGOGSA-N 0.000 description 1
- JNXAGWCUBYJEMM-JDBUVZGPSA-N tert-butyl 2-[(3S,4S,6R,7S)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-6,7-dihydroxy-2-oxo-4-phenylazocan-3-yl]acetate Chemical compound CC(C)(C)OC(=O)C[C@H]1[C@H](C[C@@H](O)[C@@H](O)CN(c2nc(cs2)-c2ccccc2Cl)C1=O)c1ccccc1 JNXAGWCUBYJEMM-JDBUVZGPSA-N 0.000 description 1
- JNXAGWCUBYJEMM-CDPNLFKUSA-N tert-butyl 2-[(3S,4S,6S,7R)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-6,7-dihydroxy-2-oxo-4-phenylazocan-3-yl]acetate Chemical compound CC(C)(C)OC(=O)C[C@H]1[C@H](C[C@H](O)[C@H](O)CN(c2nc(cs2)-c2ccccc2Cl)C1=O)c1ccccc1 JNXAGWCUBYJEMM-CDPNLFKUSA-N 0.000 description 1
- CNSCUAYYHRJIRJ-VWPQPMDRSA-N tert-butyl 2-[(3S,4S,7S)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-7-hydroxy-2-oxo-4-phenylazocan-3-yl]acetate Chemical compound CC(C)(C)OC(=O)C[C@H]1[C@H](CC[C@H](O)CN(c2nc(cs2)-c2ccccc2Cl)C1=O)c1ccccc1 CNSCUAYYHRJIRJ-VWPQPMDRSA-N 0.000 description 1
- KMOLTTRBEWZKOS-ZTQYDYAKSA-N tert-butyl 2-[(3z,6s,7s)-1-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-8-oxo-6-phenyl-2,5,6,7-tetrahydroazocin-7-yl]acetate Chemical compound C([C@@H]([C@@H](C1=O)CC(=O)OC(C)(C)C)C=2C=CC=CC=2)\C=C/CN1C(SC=1)=NC=1C1=CC=CC=C1Cl KMOLTTRBEWZKOS-ZTQYDYAKSA-N 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000005307 thiatriazolyl group Chemical group S1N=NN=C1* 0.000 description 1
- 125000004305 thiazinyl group Chemical group S1NC(=CC=C1)* 0.000 description 1
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- FYZXEMANQYHCFX-UHFFFAOYSA-K tripotassium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxymethyl)amino]acetate Chemical compound [K+].[K+].[K+].OC(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O FYZXEMANQYHCFX-UHFFFAOYSA-K 0.000 description 1
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 210000000636 white adipocyte Anatomy 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D223/08—Oxygen atoms
- C07D223/10—Oxygen atoms attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D225/00—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom
- C07D225/02—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Definitions
- the present invention relates to novel compounds including their pharmaceutically acceptable salts, solvates, and prodrugs, which are modulators of G- protein coupled receptor 43 (GPR43) and are useful as therapeutic compounds, particularly in the treatment and/or prevention of inflammatory, gastrointestinal and/or metabolic disorders.
- GPR43 G- protein coupled receptor 43
- GPR43 (also named FFA2R) belongs to a subfamily of G-Protein-Coupled Receptors (GPCRs), including GPR40 and GPR41 that have been identified as receptor for Free Fatty Acids (FFAs) (Le Poul et al, J. Biol Chem. 278, 25481-489, 2003; Covington et al., Biochemical Society transaction 34, 770-773, 2006).
- GPCRs G-Protein-Coupled Receptors
- FFAs Free Fatty Acids
- the 3 family members share 30 to 40% sequences identity with specificity toward different fatty acids carbon chain lengths, with short chain fatty acids (SCFAs: six carbons molecules or shorter) activating GPR41 and GPR43 and medium and long chain fatty acids activating GPR40 (Rayasam et al., Expert Opinion on therapeutic targets, 1 1 661-671 , 2007 ).
- SCFAs short chain fatty acids
- GPR40 medium and long chain fatty acids activating GPR40 (Rayasam et al., Expert Opinion on therapeutic targets, 1 1 661-671 , 2007 ).
- C2 acetate and C3 propionate are the most potent activators of GPR43.
- GPR43 by immune cells (neutrophils, monocytes, peripheral blood mononuclear cells, B-lymphocytes and polymorphonuclear cells), in part of the gastro-intestinal tract and by white adipocytes cells as well as pancreatic ⁇ cells strongly suggested its potential as target in inflammatory, gastrointestinal and/or metabolic disorders (Milligan et al. BJP 158, ppl46-153, 2009; Regard et al, J. Clin. Inv., 117, pp40344043, 2007; Ahren Bo, Nature Reviews, 8, pp369-385, 2009). This potential is well supported by recent data. Using a GPR43 knockout mouse, Ge et al, (Endocrinology, 149, pp4519-
- GPR43 the major receptor for acetate and propionate
- new agonists or partial agonists of GPR43 may be of therapeutic value for the treatment and/or prevention of the above-mentioned disorders.
- the invention encompasses compounds of general Formula I, their pharmaceutically acceptable salts, solvates, and prodrugs as well as methods of use of such compounds or compositions comprising such compounds as modulators of GPR43 activity.
- the invention provides compounds of general formula I:
- Ar 1 is a C3-C6 alkyl, C3-C6 cycloalkyl, C4-C6 heterocyclyl, 6-membered aryl or 5 to 6- membered heteroaryl group, each of which being optionally substituted by one or more group(s) selected from halo, cyano, alkyl, haloalkyl, hydroxyl, alkoxy, phenyl or haloalkoxy;
- L 1 is a single bond, -CH 2 -, -CHCH3 or -C(CH 3 ) 2 ;
- Ar 2 is a 6-membered aryl group or a 5 to 6-membered heteroaryl group, each of which being optionally substituted by one or more halo or alkyl group(s);
- Ar 3 is a 5 to 6-membered aryl optionally substituted by one or more halo, cyano, alkyl, haloalkyl, hydroxyl, alkoxy or haloalkoxy group(s), by one aryl or heteoaryl group, each of said aryl or heteroaryl group may be further substituted by one or more substituent(s) selected from halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkylalkyloxy, aralkyloxy, alkoxyalkoxy optionally substituted by an alkoxy group, haloalkoxy, haloalkoxyalkoxy, amino, alkylamino, N,N-(cycloalkyl)(alkyl)amino, N,N-(aralkyl)(alkyl)amino, heterocyclyl, heterocyclylcarbonyl, heteroaryl, or fused to the aryl or heteroaryl group may
- R is a 7 to 9-membered heterocyclyl ring selected from the group consisting of:
- L 1 is attached to the ring at position a and Ar 2 is attached to the nitrogen atom at position b; the bonds represented by the dotted lines are independently a single bond, a double bond or a triple bond; at least one of the bonds represented by the dotted lines depicted as "c" and "d” in ring- VII is a single bond;
- R 1 is selected from H, fluoro, chloro, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxyl, hydroxy-Ci-C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, Ci- C 4 alkoxyalkyl or C 1 -C 4 haloalkoxyalkyl
- R 1 is selected from H, fluoro, chloro, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxy-Ci-C 4 alkyl, C 1 -C 4 alkoxyalkyl or C 1 -C 4 haloalkoxyalkyl
- R 2 is selected from H, fluoro, chloro, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclyl
- R 6 and R 6' are independently selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl;
- R 7 is selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl, hydroxy-Ci- C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl;
- R 7 is selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl, C1-C4 haloalkoxyalky
- R 8 is H or C1-C4 alkyl
- R 9 and R 9 are independently selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl;
- R 10 and R 10' are independently selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl; when the dotted line in ring-V is a single bond, R 11 is selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, Ci- C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl; R 11 is selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl,
- R 16 is selected from H, fluoro, chloro, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxyl, hydroxy-Ci- C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkoxyalkyl or C 1 -C 4 haloalkoxyalkyl;
- R 16 is selected from H, fluoro, chloro, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxy-Ci-C 4 alkyl, C 1 -C 4 alkoxyalkyl or C 1 -C 4 haloalkoxyalkyl, or R 16 forms together with R 16 an oxo moiety;
- R 17 and R 17' are independently selected from H, fluoro, chloro, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkoxyalkyl or C 1 -C 4 haloalkoxyalkyl; when the dotted lines depicted by "c" and "d” in ring- VII are both single bonds, R 18 is selected from H, fluoro, chloro, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxyl, hydroxy-Ci-C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkoxyalkyl or C 1 -C 4 haloalkoxyalkyl; R 18 is selected from H, fluoro, chloro, C 1
- L 3 is a single bond, or L 3 is a C 1 -C3 alkylene optionally substituted by one or more group(s) selected from fluoro, chloro, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxyl, hydroxy-Ci-C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkoxyalkyl or C 1 -C 4 haloalkoxyalkyl;
- R 21 is selected from H, fluoro, chloro, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxyl, hydroxy-Ci- C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkoxyalkyl or C 1 -C 4 haloalkoxyalkyl;
- R 21 is selected from H, fluoro
- R 23 is selected from H, fluoro, chloro, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxyl, hydroxy-Ci- C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkoxyalkyl or C 1 -C 4 haloalkoxyalkyl;
- R 23 is selected from H, fluoro, chloro, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxy-Ci-C 4 alkyl, C 1 -C 4 alkoxyalkyl or C 1 -C 4 haloalkoxyalkyl, or R 23 forms together with R 23 an oxo moiety;
- R 24 is H or Ci-C 4 alkyl
- R 25 and R 25 are independently selected from H, fluoro, chloro, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxy-Ci-C 4 alkyl, C 1 -C 4 alkoxyalkyl or C 1 -C 4 haloalkoxyalkyl;
- L 2 is a C 1 -C 2 alkylene optionally substituted by one or more methyl group(s);
- Z is selected from the group consisting of-COOR°, wherein R° is H or linear or branched alkyl, aryl, acyloxyalkyl, dioxolene, R is H, methyl or ethyl, and R" is hydroxyl -S0 2 CH 3i -S0 2 cyclopropyl or -S0 2 CF 3 .
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising at least one compound according to the invention or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
- the invention also relates to the use of the above compounds or their pharmaceutically acceptable salts and solvates or prodrugs as modulators of GPR43, preferably as agonists or partial agonists of GPR43.
- the invention further provides methods of treatment and/or prevention of inflammatory, gastrointestinal and/or metabolic disorders comprising the administration of a therapeutically effective amount of a compound or pharmaceutically acceptable salt, solvate, or prodrug of formula (I), to a patient in need thereof.
- the patient is a warm-blooded animal, more preferably a human.
- the invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof as a medicament.
- the medicament is used for the treatment and/or prevention of inflammatory, gastrointestinal and/or metabolic disorders.
- the invention relates to compounds of formula I, as well as their pharmaceutically acceptable salts, solvates, and prodrugs.
- Preferred compounds of formula I and pharmaceutically acceptable salts, solvates, and prodrugs thereof are those wherein
- Ar 1 is C 3 -C 6 alkyl, C 3 -C 6 cycloalkyl, tetrahydropyran-4-yl, 6-membered aryl or 5 membered heteroaryl group, each of which being optionally substituted by one or more group(s) selected from halo, alkyl, haloalkyl, alkoxy or haloalkoxy, preferably Ar 1 is C 3 -C 6 alkyl preferably isopropyl, isobutyl, C 3 -C 6 cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, more preferably cyclopentyl, tetrahydropyran-4-yl, 6-membered aryl preferably phenyl, or 5 membered heteroaryl preferably thiazolyl group; and/or L 1 is a single bond or -CH 2 -, preferably L 1 is a single bond; and/or
- Ar 2 is a 5 to 6-membered heteroaryl group optionally substituted by one or more halo or alkyl group(s), preferably Ar 2 is a thiazolyl, thiadiazolyl or pyridinyl group, more preferably Ar 2 is a thiazolyl group; and/or
- Ar 3 is a 5 to 6-membered aryl optionally substituted by one or more halo, cyano, alkyl, haloalkyl, hydroxyl, alkoxy or haloalkoxy group(s), by one aryl or heteoaryl group, each of said aryl or heteroaryl group may be further substituted by one or more substituent(s) selected from halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkylalkyloxy, aralkyloxy, alkoxyalkoxy optionally substituted by an alkoxy group, haloalkoxy, haloalkoxyalkoxy, amino, alkylamino, N,N-(cycloalkyl)(alkyl)amino, N,N-(aralkyl)(alkyl)amino, heterocyclyl, heterocyclylcarbonyl, heteroaryl, or fused to the aryl or heteroaryl group may
- R is selected from ring-I, ring-V, ring- VI and ring-VII, preferably R is ring-V or ring -VI, more preferably R is ring -V; wherein preferably when the dotted line in ring-I is a single bond, R 1 is selected from H, fluoro, Ci-C 3 alkyl, preferably methyl, Ci-C 2 haloalkyl preferably -CF 3 or -CHF 2 , hydroxyl, hydroxy-Ci-C 3 alkyl preferably hydroxymethyl, Ci-C 3 alkoxy, preferably methoxy, Ci-C 2 haloalkoxy preferably -OCF 3 or -OCHF 2 , Ci-C 3 alkoxyalkyl preferably methoxymethyl, more preferably R 1 is H; R 1 is selected from H, fluoro, Ci-C 3 alkyl preferably methyl, more preferably R 1 is H; R 2 is selected from H, fluoro, chloro, Ci-C 6 al
- R 3 is selected from H, fluoro, C 1 -C 2 alkyl preferably methyl, C 1 -C 2 haloalkyl preferably -CF 3 or -CHF 2 , hydroxyl, hydroxy-Ci-C 3 alkyl preferably hydroxymethyl, C 1 -C 2 alkoxy preferably methoxy, C 1 -C 2 haloalkoxy preferably - OCF 3 or -OCHF 2 , C 1 -C 3 alkoxyalkyl preferably methoxymethyl, more preferably R 3 is H; and/or
- R 3 is selected from H, fluoro, C 1 -C 3 alkyl preferably methyl, more preferably R 3 is H; and/or
- R 10 and R 10 ' are independently selected from H, fluoro, C 1 -C 2 alkyl preferably methyl, C 1 -C 2 haloalkyl preferably -CF 3 or -CHF 2 , hydroxyl, hydroxy-Ci-C 3 alkyl preferably hydroxymethyl, C 1 -C 2 alkoxy preferably methoxy, C 1 -C 2 haloalkoxy preferably -OCF 3 or -OCHF 2 , C 1 -C 3 alkoxyalkyl preferably methoxymethyl, more preferably R 10 and R 10 are H; and/or when the dotted line in ring-V is a single bond, R 11 is selected from H, fluoro, C 1 -C 3 alkyl, preferably methyl, C 1 -C 2 haloalkyl preferably -CF 3 or -CHF 2 , hydroxyl, hydroxy-Ci-C 3 alkyl preferably hydroxymethyl, C 1 -C 3 alkoxy, preferably
- R 13 is selected from H, fluoro, C 1 -C 2 alkyl preferably methyl, C 1 -C 2 haloalkyl preferably -CF 3 or -CHF 2 , hydroxyl, hydroxy-Ci-C 3 alkyl preferably hydroxymethyl, C 1 -C 2 alkoxy preferably methoxy, C 1 -C 2 haloalkoxy preferably - OCF 3 or -OCHF 2 , Ci-C 3 alkoxyalkyl preferably methoxymethyl, more preferably R 13 is H; and/or
- R 13 is selected from H, fluoro, Ci-C 3 alkyl preferably methyl, more preferably R 13 is H; and/or when the dotted line in ring- VI is a single bond, R 14 is selected from H, fluoro, chloro, Ci-C 2 alkyl preferably methyl, C 1 -C 2 haloalkyl preferably -CF 3 or -CHF 2 , hydroxyl, hydroxy-Ci-C 3 alkyl preferably hydroxymethyl, C 1 -C 2 alkoxy preferably methoxy, C 1 -C 2 haloalkoxy preferably -OCF 3 or -OCHF 2 , C 1 -C 3 alkoxyalkyl preferably methoxymethyl, more preferably R 14 is H; R 14 is selected from H, fluoro, Ci-C 2 alkyl preferably methyl, C 1 -C 2 haloalkyl preferably -CF 3 or -CHF 2 , hydroxy-Ci-C 3 alkyl preferably
- R 16 is selected from H, fluoro, C 1 -C 2 alkyl preferably methyl, C 1 -C 2 haloalkyl preferably -CF 3 or -CHF 2 , hydroxyl, hydroxy-Ci-C 3 alkyl preferably hydroxymethyl, C 1 -C 2 alkoxy preferably methoxy, C 1 -C 2 haloalkoxy preferably - OCF 3 or -OCHF 2 , C 1 -C 3 alkoxyalkyl preferably methoxymethyl, more preferably R 16 is H; and/or
- R 16 is selected from H, fluoro, C 1 -C 3 alkyl preferably methyl, more preferably R 16 is H; and/or
- R 17 and R 17 ' are independently selected from H, fluoro, C 1 -C 2 alkyl preferably methyl, C 1 -C 2 haloalkyl preferably -CF 3 or -CHF 2 , hydroxyl, hydroxy-Ci-C 3 alkyl preferably hydroxymethyl, C 1 -C 2 alkoxy preferably methoxy, C 1 -C 2 haloalkoxy preferably -OCF 3 or -OCHF 2 , C 1 -C 3 alkoxyalkyl preferably methoxymethyl, more preferably R 17 and R 17 are H; and/or when the dotted lines depicted by "c" and "d" in ring- VII are both single bonds, R 18 is selected from H, fluoro, chloro, C 1 -C 2 alkyl preferably methyl, C 1 -C 2 haloalkyl preferably -CF 3 or -CHF 2 , hydroxyl, hydroxy-Ci-C 3 alkyl preferably hydroxymethyl,
- R is H; R is absent; R and R are independently selected from H, fluoro, C 1 -C 2 alkyl preferably methyl, C 1 -C 2 haloalkyl preferably -CF 3 or -CHF 2 , hydroxy-Ci-C 3 alkyl preferably hydroxymethyl, C 1 -C3 alkoxyalkyl preferably methoxymethyl; more preferably R and R 20 are independently selected from H, fluoro, methyl, -CHF 2 , hydroxymethyl, methoxymethyl; still more preferably R 19 and R 20 are H; R 19 is absent; R 20 is selected from H, fluoro, chloro, C 1 -C4 alkyl preferably methyl, C 1 -C 2 haloalkyl preferably -CF 3 or -CHF 2 , hydroxy-Ci-C 3 alkyl preferably hydroxymethyl, Ci-C 3 alkoxyalkyl preferably methoxymethyl, or R 20 forms
- R 21 is selected from H, fluoro, C 1 -C 2 alkyl preferably methyl, C 1 -C 2 haloalkyl preferably -CF 3 or -CHF 2 , hydroxyl, hydroxy-Ci-C 3 alkyl preferably hydroxymethyl, C 1 -C 2 alkoxy preferably methoxy, C 1 -C 2 haloalkoxy preferably -
- Ci-C 3 alkoxyalkyl preferably methoxymethyl, more preferably R 21 is selected from H, fluoro, -CHF 2 , hydroxyl, hydroxymethyl, methoxy, methoxymethy, still more preferably R 21 is H; and/or
- R 21 is selected from H, fluoro, Ci-C 3 alkyl preferably methyl, more preferably R 21 is H; and/or
- L 3 is a single bond; and/or when R is selected from ring-II, ring III, ring IV and ring VIII
- R 4 , R 4' , R 5 and R 5 are H; and/or
- R 6 , R 6' , R 7 and R 7' are H; and/or R 8 , R 9 and R 9' are H; and/or
- R 22 , R 22' , R 23 , R 23' , R 24 , R 25 and R 25 are H; and/or
- L 2 is a methylene optionally substituted by one or more methyl group(s), preferably L 2 is CH 2 ; and/or
- Z is selected from the group consisting of -COOR 0 , wherein R° is H or linear or branched alkyl, preferably Z is -COOH.
- preferred compounds of Formula I are those of formula
- R is as defined above in respect to formula I, preferably R is selected from ring-I, ring-II, ring-V, ring- VI, ring- VII and ring- VIII, more preferably R is selected from ring-I, ring-V, ring VI and ring- VII, still more preferably R is ring-V or ring VI, even more preferably R is ring-V;
- Ar 1 is as defined above in respect to formula I, preferably Ar 1 is is isopropyl, butyl, tert-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-difluorocyclohexan-l-yl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, furanyl, thiophenyl or thiazolyl, each of which being optionally substituted by one or more group(s) selected from hal
- Y is CH or N, preferably Y is CH;
- heterocyclic group is substituted with Ar either in position 4 or 5 , preferably in position 4;
- R is H, methyl, F, CI, or CF 3 , more preferably R.
- o is H or F, still more R is preferably H; if Y is N, R 2b is absent.
- Preferred compounds of formula la are those of formula Ia-1
- R, Ar 1 , Ar 3 and R 26 are as defined above in respect to formula la, preferably R 26 is H or F, more preferably R 26 is H.
- Preferred compounds of formula Ia-1 are those of formula Ia-2
- R 27 is H, halo preferably chloro or fluoro, cyano, alkyl preferably methyl or isopropyl, haloalkyl preferably -CHF 2 or -CF 3 , hydroxyl, alkoxy preferably methoxy, haloalkoxy preferably -OCHF 2 or -OCF 3 , phenyl, pyridinyl, pyridazinyl or pyrazinyl, each of said phenyl, pyridinyl, pyridazinyl or pyrazinyl group may be further substituted by one or more substituent(s) selected from halo preferably chloro or fluoro, alkyl preferably methyl, haloalkyl preferably -CHF 2 or -CF 3 , hydroxyl, alkoxy preferably methoxy, cycloalkylalkyloxy preferably cyclopropylmethyloxy, aralkyloxy preferably benzyloxy, alk
- R 27' is H
- R 28 is H, halo, cyano, alkyl preferably methyl, haloalkyl, hydroxyl, alkoxy preferably methoxy, haloalkoxy, preferably R 28 is H, fluoro, chloro, cyano, -CHF 2 , -CF 3 or -OCF 3 more preferably R 28 is H;
- R 28' is H, halo, cyano, alkyl preferably methyl, haloalkyl, hydroxyl, alkoxy preferably methoxy, haloalkoxy, preferably R 28 is H, fluoro, chloro, -CF 3 , -OCHF 2 or -OCF 3 more preferably R 28 is H;
- R 29 is H, halo, cyano, alkyl, alkoxy, preferably R 29 is H, chloro, fluoro, methyl or methoxy more preferably R 29 is H.
- Preferred compounds of formula Ia-2 are those of formula Ia-3
- R 28 is as defined above in respect to formula Ia-2, preferably R 28 is H or fluoro, more preferably R 28 is H;
- R is as defined above in respect to formula Ia-2, preferably R is H, chloro or fluoro, more preferably R 28 is H;
- R 29 is as defined above in respect to formula Ia-2, preferably R 29 is H, chloro or fluoro, more preferably R 29 is H;
- R 30 is H, halo preferably chloro or fluoro, alkyl preferably methyl, haloalkyl preferably - CHF 2 or -CF 3 , hydro xyl, alkoxy preferably methoxy, preferably R 30 is H, chloro;
- R 31 is alkoxy preferably methoxy, cycloalkylalkyloxy preferably cyclopropylmethyloxy, aralkyloxy preferably benzyloxy, alkoxyalkoxy optionally substituted by an alkoxy group preferably (2-methoxyethyl)oxy, (2-ethoxyethyl)oxy, 2-(isopropyloxyethyl)oxy, (3- methoxybutan-2-yl) o xy , (1 -methoxy-2-methylpropan-2-yl)oxy, ((3 S)-3 -methoxybutan-2- yl)o xy , ( (3 R)-3-methoxybutan-2-yl)oxy, haloalkoxyalkoxy preferably (2-(2,2,2- trifluoroethoxy)ethyl) o x y , (2-(2-ethoxyethoxy)ethyl)oxy, alkylamino preferably dimethylamino, N
- R 30 and R 31 together form a heterocyclyl preferably pyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, or heteroaryl preferably pyrrolyl, pyrazolyl or triazolyl ring, thus forming a fused bicyclic system which may be substituted by one or more alkyl preferably methyl, halo preferably chloro or fluoro, or oxo group(s);
- X 1 is N or C-R 32 wherein R 32 is H;
- X is N or C-R wherein R is H or alkoxy preferably R is H or methoxy, more preferably R 32 is H, preferably X 2 is N or CH, more preferably X 2 is CH.
- Preferred compounds of formula Ia-3 are those wherein the moiety is selected from: H, X 2 is CH and R 31 is methoxy or 2-oxopyrrolidin-l-yl.
- R" and R i0 are as defined above in respect to formula Ia-2, preferably R and R are independently selected from H, halo, haloalkyl, haloalkoxy, preferably chloro, fluoro, -CF 3 , -CHF 2 , -OCF 3 or -OCHF 2 , more preferably R 27 is H, chloro or fluoro and R 28 is selected from H, halo, -CF 3 , -CHF 2 , -OCF 3 or -OCHF 2 , preferably chloro and fluoro, even more preferably R 27 is chloro or fluoro and R 28 is H, or R 27 is H and R 28' is -OCF 3 or -OCHF 2 , even more preferably R 27 is chloro or fluoro and R 28 is H.
- preferred compounds of Formula I are those of formula lb:
- R 33 and R 33' are independently selected from H, halo, cyano, hydro xyl, linear or branched C1-C 3 alkyl, C1-C 3 haloalkyl, preferably R 33 and R 33 are independently selected from H, F, CI, or CF 3 , more preferably R 33 and R 33' are H;
- preferred compounds of Formula I are those formula Ic:
- R, Ar 1 , Ar R ⁇ and R ⁇ are as defined above in respect to formula lb.
- preferred compounds of Formula I are those of formulae Id-1, Id-2, Id-3, Id-4, Id-5, Id-6, Id-7 and Id-8:
- R 3 is selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl, hydroxy-Ci- C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl;
- R 3 is selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl, or R 3 forms together with R 3 an oxo moiety; when the dotted line in formula Id-2 is absent, R 4 is selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl, hydroxy-Ci-C4 alkyl
- R 6 and R 6' are independently selected from H, fiuoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl;
- R 7 is selected from H, fiuoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl, hydroxy-Ci- C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl;
- R 7 is selected from H, fiuoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl, C1-C4 haloalkoxyalkyl, or R 7 forms together with R 7 an oxo moiety;
- R 8 is H or C1-C4 alkyl
- R 9 and R 9 are independently selected from H, fiuoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl;
- R 10 and R 10' are independently selected from H, fiuoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl; when the dotted line in formula Id-5 is absent, R 11 is selected from H, fiuoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, Ci- C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl; R 11 is selected from H, fiuoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl,
- R 13 is selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl, hydroxy-Ci- C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl; R 13 is selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl, or R 13 forms together with R 13 an oxo moiety; when the dotted line in formula Id-6 is absent, R 14 is selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl, hydroxy-Ci-C4 alkyl, C
- R 16 is selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl, hydroxy-Ci- C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl; R 16 is selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl, or R 16 forms together with R 16 an oxo moiety;
- R 17 and R 17' are independently selected from H, fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl; when the dotted lines depicted by "c" and "d” in formula Id-7 are both absent, R is selected from H, fluoro, chloro, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxyl, hydroxy-Ci-C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkoxyalkyl or C 1 -C 4 haloalkoxyalkyl; R 18 is selected from H, fluoro, chloro, C 1 -C 4 al
- R 21 is selected from H, fluoro, chloro, C 1 -C4 alkyl, C 1 -C4 haloalkyl, hydroxyl, hydroxy-Ci- C4 alkyl, C 1 -C4 alkoxy, C 1 -C4 haloalkoxy, C 1 -C4 alkoxyalkyl or C 1 -C4 haloalkoxyalkyl;
- R 21 is selected from H, fluoro, chloro, C 1 -C4 alkyl, C 1 -C4 haloalkyl, hydroxy-Ci-C4 alkyl, C 1 -C4 alkoxyalkyl or C 1 -C4 haloalkoxyalkyl, or R 21 forms together with R 21 an oxo moiety;
- R 22 and R 22' are independently selected from H, fluoro, chloro, C 1 -C4 alkyl, C 1 -C4 haloalkyl, hydroxyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkoxyalkyl or C 1 -C4 haloalkoxyalkyl;
- R 23 is selected from H, fluoro, chloro, C 1 -C4 alkyl, C 1 -C4 haloalkyl, hydroxyl, hydroxy-Ci- C4 alkyl, C 1 -C4 alkoxy, C 1 -C4 haloalkoxy, C 1 -C4 alkoxyalkyl or C 1 -C4 haloalkoxyalkyl;
- R 23 is selected from H, fluoro, chloro, C 1 -C4 alkyl, C 1 -C4 haloalkyl, hydroxy-Ci-C4 alkyl, C 1 -C4 alkoxyalkyl or C 1 -C4 haloalkoxyalkyl, or R 23 forms together with R 23 an oxo moiety;
- R 24 is H or Ci-C 4 alkyl
- R 25 and R 25 are independently selected from H, fluoro, chloro, C 1 -C4 alkyl, C 1 -C4 haloalkyl, hydroxy-Ci-C4 alkyl, C1-C4 alkoxyalkyl or C1-C4 haloalkoxyalkyl.
- compounds of formula Id-6 are those wherein the bond linking carbon to which L 2 -Z is attached and D is drawn as a solid wedge:
- Preferred compounds of formulae Id-1 , Id-2, Id-3, Id-4, Id-5, Id-6, Id-7 and Id-8 are those of formulae Ie-1, Ie-2, Ie-3, Ie-4, Ie-5, Ie-6, Ie-7 and Ie-8 respectively:
- le-7 le-8 harmaceutically acceptable salts, and solvates, or prodrugs thereof, wherein
- Ar 1 and Ar 3 are as defined above in respect to formula la;
- Ar 2 is as defined above in respect to formula I, preferably Ar 2 is a 5 to 6-membered heteroaryl group, preferably thiazolyl, thiadiazolyl or pyridinyl, each of which being optionally substituted by one or more halo, preferably fluoro, or alkyl, preferably methyl, group(s) preferably Ar 2 is a thiazolyl connected to the ring nitrogen at position 2 and to Ar 3 at position 4 and optionally substituted by a fluoro at position 5, preferably unsubstituted at position 5, or Ar 2 is a thiadiazolyl connected to the ring nitrogen at position 2 and to Ar 3 at position 5, more preferably Ar 2 is a thiazolyl connected to the ring nitrogen at position 2 and to Ar 3 at position 4;
- R 21 , R 21' , R 22 , R 22' , R 23 , R 23' , R 24 , R 25 , R 25 , and the dotted lines are as defined above in respect to formulae Id-1, Id-2, Id-3, Id-4, Id-5, Id-6, Id-7 and Id-8, preferably: when the dotted line in formula Ie-1 is absent, R 1 is selected from H, fluoro, C 1 -C 3 alkyl, preferably methyl, C 1 -C 2 haloalkyl preferably -CF 3 or -CHF 2 , hydroxyl, hydroxy-Ci-C 3 alkyl preferably hydroxymethyl, C 1 -C 3 alkoxy, preferably methoxy, Ci-C 2 haloalkoxy preferably -OCF 3 or -OCHF 2 , C 1 -C 3 alkoxyalkyl preferably methoxymethyl, more preferably R 1 is H; R 1 is selected from H, fluoro, C
- R 3 is selected from H, fluoro, Ci-C 3 alkyl preferably methyl, more preferably R 3 is H;
- R 4 , R 4' , R 5 and R 5 are H;
- R 6 , R 6' , R 7 and R 7' are H;
- R 8 , R 9 and R 9' are H;
- R 10 and R 10' are independently selected from H, fluoro, C 1 -C 2 alkyl preferably methyl, C 1 -C 2 haloalkyl preferably -CF 3 or -CHF 2 , hydroxyl, hydroxy-Ci-C 3 alkyl preferably hydroxymethyl, C 1 -C 2 alkoxy preferably methoxy, C 1 -C 2 haloalkoxy preferably -OCF 3 or -OCHF 2 , Ci-C 3 alkoxyalkyl preferably methoxymethyl, more preferably R 10 and R 10 are H; when the dotted line in formula Ie-5 is absent, R 11 is selected from H, fluoro, Ci-C 3 alkyl, preferably methyl, C 1 -C 2 haloalkyl preferably -CF 3 or -CHF 2 , hydroxyl, hydroxy-Ci-C 3 alkyl preferably hydroxymethyl, Ci-C 3 alkoxy, preferably methoxy, C 1 -C 2 halo
- R 13 is selected from H, fluoro, C 1 -C 2 alkyl preferably methyl, C 1 -C 2 haloalkyl preferably -CF 3 or -CHF 2 , hydroxyl, hydroxy-Ci-C 3 alkyl preferably hydroxymethyl, C 1 -C 2 alkoxy preferably methoxy, C 1 -C 2 haloalkoxy preferably - OCF 3 or -OCHF 2 , C 1 -C 3 alkoxyalkyl preferably methoxymethyl, more preferably R 13 is H;
- R 13 is selected from H, fluoro, C 1 -C 3 alkyl preferably methyl, more preferably R 13 is H; when the dotted line in formula Ie-6 is absent, R 14 is selected from H, fluoro, chloro, C 1 -C 2 alkyl preferably methyl, C 1 -C 2 haloalkyl preferably -CF 3 or -CHF 2 , hydroxyl, hydroxy-Ci-C 3 alkyl preferably hydroxymethyl, C 1 -C 2 alkoxy preferably methoxy, C 1 -C 2 haloalkoxy preferably -OCF 3 or -OCHF 2 , C 1 -C 3 alkoxyalkyl preferably methoxymethyl, more preferably R 14 is H; R 14 is selected from H, fluoro, C 1 -C 2 alkyl preferably methyl, C 1 -C 2 haloalkyl preferably -CF 3 or -CHF 2 , hydroxy-Ci-C 3 alkyl preferably
- R 16 is selected from H, fluoro, C 1 -C 2 alkyl preferably methyl, C 1 -C 2 haloalkyl preferably -CF 3 or -CHF 2 , hydroxyl, hydroxy-Ci-C 3 alkyl preferably hydroxymethyl, C 1 -C 2 alkoxy preferably methoxy, C 1 -C 2 haloalkoxy preferably - OCF 3 or -OCHF 2 , Ci-C 3 alkoxyalkyl preferably methoxymethyl, more preferably R 16 is H; R 16 is selected from H, fluoro, C 1 -C3 alkyl preferably methyl, more preferably R 16 is H;
- R 17 and R 17 ' are independently selected from H, fluoro, C 1 -C 2 alkyl preferably methyl, C 1 -C 2 haloalkyl preferably -CF 3 or -CHF 2 , hydroxyl, hydroxy-Ci-C 3 alkyl preferably hydroxymethyl, C 1 -C 2 alkoxy preferably methoxy, C 1 -C 2 haloalkoxy preferably -OCF 3 or -OCHF 2 , Ci-C 3 alkoxyalkyl preferably methoxymethyl, more preferably R 17 and R 17 are H; when the dotted lines depicted by "c" and "d” in formula Ie-7 are both absent, R 18 is selected from H, fluoro, chloro, C 1 -C 2 alkyl preferably methyl, C 1 -C 2 haloalkyl preferably -CF 3 or -CHF 2 , hydroxyl, hydroxy-Ci-C 3 alkyl preferably hydroxymethyl, C 1 -C 2
- R 21 is selected from H, fluoro, Ci-C 2 alkyl preferably methyl, Ci-C 2 haloalkyl preferably -CF 3 or -CHF 2 , hydroxyl, hydroxy-Ci-C 3 alkyl preferably hydroxymethyl, Ci-C 2 alkoxy preferably methoxy, Ci-C 2 haloalkoxy preferably - OCF 3 or -OCHF 2 , Ci-C 3 alkoxyalkyl preferably methoxymethyl, more preferably R 21 is selected from H, fluoro, -CHF 2 , hydroxyl, hydroxymethyl, methoxy, methoxymethy, still more preferably R 21 is H; R 21 is selected from H, fluoro, Ci-C 3 alkyl preferably methyl, more preferably R 21 is H;
- compounds of formula Ie-6 are those wherein the bond linking the carbon to which the carboxymethyl is attached and the adjacent carbonyl is drawn as a solid wedge:
- Preferred compounds of formulae Ie-1, Ie-2, Ie-3, Ie-4, Ie-5, Ie-6, Ie-7 and Ie-8 are those formulae If-1, If-2, If-3, If-4, If-5, If-6, If-7 and If-8 respectively:
- Ar 1 , Ar 3 , R 26 , X and Y are as defined above in respect to formula la;
- R 21 , R 21' , R 22 , R 22' , R 23 , R 23' , R 24 , R 25 and R 25 and the dotted lines are as defined above in respect to formulae Ie-1, Ie-2, Ie-3, Ie-4, Ie-5, Ie-6, Ie-7 and Ie-8.
- compounds of formula If-6 are those wherein the bond linking the carbon to which the carboxymethyl is attached and the adjacent carbonyl is drawn as a solid0 wedge:
- Preferred compounds of formulae If-l , If-2, If-3, If-4, If-5, If-6, If-7 and If-8 are those of formulae Ig-1 , Ig-2, Ig-3, Ig-4, Ig-5, Ig-6, Ig-7 and Ig-8 respectively:
- R 21 , R 21' , R 22 , R 22' , R 23 , R 23' , R 24 , R 25 and R 25 and the dotted lines are as defined above in respect to formulae If-1, If-2, If-3, If-4, If-5, If-6, If-7 and If-8.
- compounds of formula Ig-6 are those wherein the bond linking the carbon to which the carboxymethyl is attached and the adjacent carbonyl is drawn as a solid wedge:
- Preferred compounds of formulae Ig-1 , Ig-2, Ig-3, Ig-4, Ig-5, Ig-6, Ig-7 and Ig-8 are those of formulae Ih-1, Ih-2, Ih-3, Ih-4, Ih-5, Ih-6, Ih-7 and Ih-8 respectively: 52
- R 12 R 12' R 13 R 13' R 14 R 14' R 15 R 15' R 16 R 16' R 17 R 17' R 18 R 18' R 19 R 19' R 20 R 20' IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV . IV , R 21 , R 21' , R 22 , R 22' , R 23 , R 23' , R 24 , R 25 and R 25 and the dotted lines are as defined above in respect to formulae Ig-1, Ig-2, Ig-3, Ig-4, Ig-5, Ig-6, Ig-7 and Ig-8.
- compounds of formula Ih-6 are those wherein the bond linking the carbon to which the carboxymethyl is attached and the adjacent carbonyl is drawn as a solid wedge:
- Preferred compounds of formulae Ih-1 , Ih-2, Ih-3, Ih-4, Ih-5, Ih-6, Ih-7 and Ih-8 are those of formulae Ii-1, Ii-2, Ii-3, Ii-4, Ii-5, Ii-6, Ii-7 and Ii-8 respectively: 54
- Ar 1 , R 26 , R 27' , R 28 , R 28 , R 29 , R 30 , R 31 , X 1 and X 2 are as defined above in respect to formula Ia-3;
- R 21 , R 21' , R 22 , R 22' , R 23 , R 23' , R 24 , R 25 and R 25 and the dotted lines are as defined above in respect to formulae Ih-1, Ih-2, Ih-3, Ih-4, Ih-5, Ih-6, Ih-7 and Ih-8.
- compounds of formula Ii-6 are those wherein the bond linking the carbon to which the carboxymethyl is attached and the adjacent carbonyl is drawn as a solid 0 wedge:
- Preferred c mpounds of formulae Ii-l, Ii-2, Ii-3, Ii-4, Ii-5, Ii-6, Ii-7 and Ii-8 are those
- Ar 1 , R 26 , R 27 and R 28' are as defined above in respect to formula Ia-4;
- R 21 , R 21' , R 22 , R 22' , R 23 , R 23' , R 24 , R 25 and R 25 and the dotted lines are as defined above in respect to formulae Ii-1, Ii-2, Ii-3, Ii-4, Ii-5, Ii-6, Ii-7 and Ii-8.
- the compounds of formula I can be prepared by different ways with reactions known by the person skilled in the art. Reaction schemes as described in the example section illustrate by way of example different possible approaches.
- the invention further provides the use of the compounds of the invention or pharmaceutically acceptable salts, solvates, or prodrugs thereof as agonists or partial agonists of G-protein coupled receptor 43 (GPR43).
- GPR43 G-protein coupled receptor 43
- the invention relates to the use of compounds of formula I and subformulae in particular those of table 1 above, or pharmaceutically acceptable salts solvates, and prodrugs thereof, as GPR43 agonists or partial agonists.
- the compounds of the invention are therefore useful in the prevention and/or treatment of inflammatory, gastrointestinal and/or metabolic disorders.
- the invention also provides for a method for delaying in patient the onset of inflammatory, gastrointestinal and/or metabolic disorders comprising the administration of a pharmaceutically effective amount of a compound of formula (I) or pharmaceutically acceptable salt thereof to a patient in need thereof.
- the patient is a warm-blooded animal, more preferably a human.
- the invention further provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvates or prodrug thereof for treating and/or preventing inflammatory, gastrointestinal and/or metabolic disorders.
- the patient is a warm-blooded animal, more preferably a human.
- a method for modulating GPR43 receptor activity in a patient, preferably a warm blooded animal, and even more preferably a human, in need of such treatment, which comprises administering to said animal an effective amount of compound of the present invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
- the compounds of the invention, their pharmaceutical acceptable salts or solvates, or prodrugs may be administered as part of a combination therapy.
- a combination therapy comprising coadministration of, and compositions and medicaments which contain, in addition to a compound of the present invention, a pharmaceutically acceptable salt, solvate or prodrug thereof as active ingredient, additional therapeutic agents and/or active ingredients.
- Such multiple drug regimens often referred to as combination therapy, may be used in the treatment and/or prevention of any of the diseases or conditions mediated by or associated with GPR43 receptor modulation, particularly inflammatory, gastrointestinal and/or metabolic disorders.
- the use of such combinations of therapeutic agents is especially pertinent with respect to the treatment of the above-mentioned list of disorders within a patient in need of treatment or one at risk of becoming such a patient.
- Suitable supplementary therapeutic agents used for the purpose of auxiliary treatment include drugs which, instead of directly treating or preventing a disease or condition mediated by or associated with GPR43 receptor modulation, treat diseases or conditions which directly result from or indirectly accompany the basic or underlying GPR43 receptor modulated disease or condition.
- the methods of treatment and pharmaceutical compositions of the present invention may employ the compounds of Formula I or their pharmaceutical acceptable salts, solvates, or prodrugs thereof in the form of monotherapy, but said methods and compositions may also be used in the form of multiple therapy in which one or more compounds of Formula I or their pharmaceutically acceptable salts, solvates, or prodrugs are coadministered in combination with one or more other therapeutic agents.
- the compound of Formula I, a pharmaceutically acceptable salt or solvate thereof and other therapeutic active agents may be administered in terms of dosage forms either separately or in conjunction with each other, and in terms of their time of administration, either serially or simultaneously.
- the administration of one component agent may be prior to, concurrent with, or subsequent to the administration of the other component agent(s).
- the invention also provides pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant.
- the invention also covers pharmaceutical compositions which contain, in addition to a compound of the present invention, a pharmaceutically acceptable salt, solvate or prodrug thereof as active ingredient, additional therapeutic agents and/or active ingredients.
- Another object of this invention is a medicament comprising at least one compound of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as active ingredient.
- the invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof for the manufacture of a medicament.
- the medicament is used for the treatment and/or prevention of inflammatory, gastrointestinal and/or metabolic disorders.
- a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof for the manufacture of a medicament for modulating GPR43 receptor activity, in a patient, in need of such treatment, which comprises administering to said patient an effective amount of compound of the present invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
- the patient is a warm-blooded animal, more preferably a human.
- the medicament is used for the treatment and/or prevention of inflammatory, gastrointestinal and/or metabolic disorders
- the compounds of the invention, their pharmaceutically acceptable salts, solvates, or prodrugs may be used in monotherapy or in combination therapy.
- the invention provides the use of a compound of the invention for the manufacture of a medicament for at least one of the purposes described above, wherein said medicament is administered to a patient in need thereof, preferably a warm-blooded animal, and even more preferably a human, in combination with at least one additional therapeutic agent and/or active ingredient.
- a multiple drug regimen, possible administration regimens as well as suitable additional therapeutic agents and/or active ingredients are those described above.
- the compounds of the invention may be formulated as a pharmaceutical preparation comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant, and optionally one or more further pharmaceutically active compound(s).
- a formulation may be in a form suitable for oral administration, for parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), for topical administration (including ocular), for administration by inhalation, by a skin patch, by an implant, by a suppository, etc.
- Such suitable administration forms - which may be solid, semi-solid or liquid, depending on the manner of administration - as well as methods and carriers, diluents and excipients for use in the preparation thereof, will be clear to the skilled person; reference is made to the latest edition of Remington's Pharmaceutical Sciences.
- Such preparations include tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, cremes, lotions, soft and hard gelatin capsules, suppositories, drops, sterile injectable solutions and sterile packaged powders (which are usually reconstituted prior to use) for administration as a bolus and/or for continuous administration, which may be formulated with carriers, excipients, and diluents that are suitable per se for such formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, micro crystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methyl- and prop
- the formulations can optionally contain other substances that are commonly used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, desintegrants, bulking agents, fillers, preserving agents, sweetening agents, flavoring agents, flow regulators, release agents, etc..
- the compositions may also be formulated so as to provide rapid, sustained or delayed release of the active compound(s) contained therein.
- the pharmaceutical preparations of the invention are preferably in a unit dosage form, and may be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which may be properly labeled); optionally with one or more leaflets containing product information and/or instructions for use.
- unit dosages will contain between 0,05 and 1000 mg, and usually between 1 and 500 mg, of the at least one compound of the invention, e.g. about 10, 25, 50, 100, 200, 300 or 400 mg per unit dosage.
- the active compound of the invention will usually be administered between 0.01 to 100 mg per kilogram, more often between 0.1 and 50 mg, such as between 1 and 25 mg, for example about 0.5, 1, 5, 10, 15, 20 or 25 mg, per kilogram body weight of the patient per day, which may be administered as a single daily dose, divided over one or more daily doses, or essentially continuously, e.g. using a drip infusion.
- groups may be substituted, such groups may be substituted with one or more substituents, and preferably with one, two or three substituents.
- Substituents may be selected from but not limited to, for example, the group comprising halogen, hydroxyl, oxo, nitro, amido, carboxy, amino, cyano haloalkoxy, and haloalkyl.
- alkyl, aryl, or cycloalkyl each being optionally substituted with -- or "alkyl, aryl, or cycloalkyl, optionally substituted with -- encompasses “alkyl optionally substituted with?”, “aryl optionally substituted with?” and “cycloalkyl optionally substituted with... ".
- alkyl by itself or as part of another substituent refers to a hydrocarbyl radical of Formula C n H2 n +i wherein n is a number greater than or equal to 1.
- alkyl groups of this invention comprise from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, more preferably from 1 to 3 carbon atoms, still more preferably 1 to 2 carbon atoms.
- Alkyl groups may be linear or branched and may be substituted as indicated herein.
- Suitable alkyl groups include methyl, ethyl, n-propyl, /-propyl, n-butyl, /- butyl, 5-butyl and /-butyl, pentyl and its isomers (e.g. n-pentyl, iso-pentyl), and hexyl and its isomers (e.g. n-hexyl, /so-hexyl).
- Preferred alkyl groups include methyl, ethyl, n-propyl, /-propyl, n-butyl, /-butyl, s-butyl and /-butyl.
- alkylene When the suffix "ene” (“alkylene”) is used in conjunction with an alkyl group, this is intended to mean the alkyl group as defined herein having two single bonds as points of attachment to other groups.
- alkylene includes methylene, ethylene, methylmethylene, propylene, ethylethylene, and 1,2-dimethylethylene.
- alkenyl as used herein refers to an unsaturated hydrocarbyl group, which may be linear or branched, comprising one or more carbon-carbon double bonds. Suitable alkenyl groups comprise between 2 and 6 carbon atoms, preferably between 2 and 4 carbon atoms, still more preferably between 2 and 3 carbon atoms.
- alkenyl groups are ethenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2- hexenyl and its isomers, 2,4-pentanedienyl and the like.
- alkynyl refers to a class of monovalent unsaturated hydrocarbyl groups, wherein the unsaturation arises from the presence of one or more carbon-carbon triple bonds.
- Alkynyl groups typically, and preferably, have the same number of carbon atoms as described above in relation to alkenyl groups.
- Non limiting examples of alkynyl groups are ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl and its isomers, 2-hexynyl and its isomers-and the like.
- alkenylene and alkynylene respectively mean an alkenyl group or an alkinyl group as defined above having two single bonds as points of attachment to other groups.
- haloalkyl alone or in combination, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen as defined above.
- Non-limiting examples of such haloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1- trifluoro ethyl and the like.
- cycloalkyl as used herein is a cyclic alkyl group, that is to say, a monovalent, saturated, or unsaturated hydrocarbyl group having 1 or 2 cyclic structures.
- Cycloalkyl includes monocyclic or bicyclic hydrocarbyl groups. Cycloalkyl groups may comprise 3 or more carbon atoms in the ring and generally, according to this invention comprise from 3 to 10, more preferably from 3 to 8 carbon atoms still more preferably from 3 to 6 carbon atoms. Examples of cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, with cyclopropyl being particularly preferred.
- heterocycloalkyl where at least one carbon atom in a cycloalkyl group is replaced with a heteroatom, the resultant ring is referred to herein as "heterocycloalkyl” or “heterocyclyl”.
- heterocyclyl refers to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3 to 7 member monocyclic, 7 to 11 member bicyclic, or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom-containing ring.
- Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.
- heterocyclic group may be substituted by oxo (for example piperidone, pyrrolidinone).
- the heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows.
- the rings of multi-ring heterocycles may be fused, bridged and/or joined through one or more spiro atoms.
- Non limiting exemplary heterocyclic groups include oxetanyl, piperidinyl, azetidinyl, 2-imidazolinyl, pyrazolidinyl imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, 3H- indolyl, indolinyl, isoindolinyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2- pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro- 2H-pyranyl, 3-dioxolanyl, 1 ,4-dioxanyl, 2,5-dioximidazolidinyl, 2-oxopiperidiny
- aryl refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e. phenyl) or multiple aromatic rings fused together (e.g. naphtyl) or linked covalently, typically containing 5 to 12 atoms; preferably 6 to 10, wherein at least one ring is aromatic.
- the aromatic ring may optionally include one to two additional rings (either cycloalkyl, heterocyclyl or heteroaryl) fused thereto.
- Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated herein.
- Non-limiting examples of aryl comprise phenyl, biphenylyl, biphenylenyl, 5- or 6-tetralinyl, naphthalen-1- or -2-yl, 4-, 5-, 6 or 7-indenyl, 1- 2-, 3-, 4- or 5-acenaphtylenyl, 3-, 4- or 5-acenaphtenyl, 1- or 2-pentalenyl, 4- or 5-indanyl, 5-, 6-, 7- or 8-tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthyl, 1 ,4-dihydronaphthyl, 1-, 2-, 3-, 4- or 5- pyrenyl.
- arylene as used herein is intended to include divalent carbocyclic aromatic ring systems such as phenylene, biphenylylene, naphthylene, indenylene, pentalenylene, azulenylene and the like.
- Arylene is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthylene, 1,4- dihydronaphthylene and the like.
- heteroaryl ring where at least one carbon atom in an aryl group is replaced with a heteroatom, the resultant ring is referred to herein as a heteroaryl ring.
- heteroaryl refers but is not limited to 5 to 12 carbon-atom aromatic rings or ring systems containing 1 to 2 rings which are fused together or linked covalently, typically containing 5 to 6 atoms; at least one of which is aromatic, in which one or more carbon atoms in one or more of these rings is replaced by oxygen, nitrogen and/or sulfur atoms where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.
- Such rings may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring.
- Non-limiting examples of such heteroaryl include: furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,l-b][l,3]thiazolyl, thieno [3, 2-b] furanyl, thieno[3,2- b]thiophenyl, thieno[2,3-d][l,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[
- heteroarylene as used herein means divalent carbocyclic aromatic ring systems including pyridinylene and the like.
- X is selected from: X is selected from: X is selected from: Y is selected from:
- X is selected from: X is selected from:
- biaryl designates two aryl moieties as defined herein linked via a single bond.
- Non-limiting examples of such biaryl moieties include biphenyl.
- heteroaryl designates two heteroaryl moieties as defined herein or a heteroaryl moiety and an aryl moity as defined herein linked via a single bond.
- heterobiaryl moieties include pyridinylphenyl which is meant to include (2-pyridinyl)phenyl, (3-pyridinyl)phenyl and (4-pyridinyl)phenyl, bipyridinyl.
- alkylamino as used herein means an amino group substituted with one or two alkyl groups. This includes monoalkylamino and dialkylamino groups.
- the compounds of Formula I and subformulae thereof contain at least one asymmetric center and thus may exist as different stereoisomeric forms. Accordingly, the present invention includes all possible stereoisomers and includes not only racemic compounds but the individual enantiomers and their non racemic mixtures as well. When a compound is desired as a single enantiomer, such may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as each are known in the art.
- Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley- Interscience, 1994), incorporated by reference with regard to stereochemistry.
- the bonds from an asymmetric carbon in compounds of the present invention may be depicted herein using a solid line (— ), a zigzag line ( ⁇ ww ), a solid wedge ( ), or a dotted wedge ( ).
- the compounds of the invention may also contain more than one asymmetric carbon atom.
- the use of a solid line to depict bonds from asymmetric carbon atoms is meant to indicate that all possible stereoisomers are meant to be included, unless it is clear from the context that a specific stereoisomer is intended.
- the compounds of the invention may be in the form of pharmaceutically acceptable salts.
- Pharmaceutically acceptable salts of the compounds of formula I include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate
- Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, 2- (diethylamino)ethanol, ethanolamine, morpholine, 4-(2-hydroxyethyl)morpholine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
- Preferred, pharmaceutically acceptable salts include hydrochloride/chloride, hydrobromide/bromide, bisulphate/sulphate, nitrate, citrate, and acetate.
- the compounds of the invention may also form internal salts, and such compounds are within the scope of the invention.
- the compounds of the invention contain a hydrogen-donating heteroatom (e.g. NH, OH)
- the invention also covers salts and/or isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule.
- compositions of Formula I may be prepared by one or more of these methods:
- solvate is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
- solvent molecules for example, ethanol.
- 'hydrate' is employed when said solvent is water.
- the compounds of the invention include compounds of formula I as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) and iso topically- labeled compounds of formula I.
- salts of the compounds of the invention are preferred, it should be noted that the invention in its broadest sense also included non-pharmaceutically acceptable salts, which may for example be used in the isolation and/or purification of the compounds of the invention.
- non-pharmaceutically acceptable salts which may for example be used in the isolation and/or purification of the compounds of the invention.
- salts formed with optically active acids or bases may be used to form diastereo isomeric salts that can facilitate the separation of optically active isomers of the compounds of Formula I above.
- the invention also generally covers all pharmaceutically acceptable predrugs and prodrugs of the compounds of Formula I.
- prodrug means the pharmacologically acceptable derivatives of compounds of formula I such as esters whose in vivo biotransformation product is the active drug.
- Prodrugs are characterized by increased bio-availability and are readily metabolized into the active compounds in vivo.
- Suitable prodrugs for the purpose of the invention include carboxylic esters, in particular alkyl esters, aryl esters, acyloxyalkyl esters, and dioxolene carboxylic esters; ascorbic acid esters as well as compounds of formula I in which Z is a substituent selected from the table 2 below.
- predrug means any compound that will be modified to form a drug species, wherein the modification may take place either inside or outside of the body, and either before or after the predrug reaches the area of the body where administration of the drug is indicated.
- patient refers to a warm-blooded animal, more preferably a human, who/which is awaiting or receiving medical care or is or will be the object of a medical procedure.
- human refers to suject of both genders and at any stage of development (i.e. neonate, infant, juvenile, adolescent, adult).
- treat means to include alleviating or abrogating a condition or disease and/or its attendant symptoms.
- prevent refers to a method of delaying or precluding the onset of a condition or disease and/or its attendant symptoms, barring a patient from acquiring a condition or disease, or reducing a patient's risk of acquiring a condition or disease.
- terapéuticaally effective amount means the amount of active agent or active ingredient (e. g. GPR43 agonist or partial agonist) which is sufficient to achieve the desired therapeutic or prophylactic effect in the individual to which it is administered.
- administration means providing the active agent or active ingredient (e. g. a GPR43 agonist or partial agonist), alone or as part of a pharmaceutically acceptable composition, to the patient in whom/which the condition, symptom, or disease is to be treated or prevented.
- active agent or active ingredient e. g. a GPR43 agonist or partial agonist
- pharmaceutically acceptable is meant that the ingredients of a pharmaceutical composition are compatible with each other and not deleterious to the patient thereof.
- agonist means a ligand that activates an intracellular response when it binds to a receptor.
- An agonist according to the invention may promote internalization of a cell surface receptor such that the cell surface concentration of a receptor is decreased or remove.
- partial agonist means an agonist which is unable to induce maximal activation of a receptor, regardless of the amount of compound applied on the receptor.
- pharmaceutical vehicle means a carrier or inert medium used as solvent or diluent in which the pharmaceutically active agent is formulated and/or administered.
- pharmaceutical vehicles include creams, gels, lotions, solutions, and liposomes.
- inflammatory disorders are those pertaining to, characterized by, causing, resulting from or becoming affected by inflammation.
- inflammatory diseases include but are not limited to rheumatoid arthritis; inflammatory bowel disease (IBD) including but not limited to Crohn's disease, ulcerative colitis and colitis; Pagets disease; osteoporosis; multiple myeloma; uveitilis; acute and chronic myelogenous leukemia; pancreatic ⁇ cell destruction; rheumatoid spondylitis, osteoarthritis; gouty arthritis and other arthritis conditions; gout; adult respiratory distress syndrome (ARDS); chronic pulmonary inflammation diseases; silicosis; pulmonary sarcoidosis; psoriasis; allergic rhinitis; anaphylaxis; contact dermatitis; pancreatitis; non-alcoholic steatohepatitis (NASH); asthma; muscle degeneration; cachexia such as cachexia secondary to infection or malign
- metabolic disorders includes but is not limited to type I and type II diabetes, obesity, dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia hypertension, hyperlipoproteinemia, metabolic syndrome, syndrome X, thrombotic disorders, cardiovascular disease, atherosclerosis and its sequelae including angina, claudication, heart attack, stroke and others, kidney diseases, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, nonalcoholic fatty liver diseases such as steatosis or nonalcoholic steatohepatitis (NASH).
- dyslipidemia such as mixed or diabetic dyslipidemia
- hypercholesterolemia low HDL cholesterol, high LDL cholesterol
- hyperlipidemia hypertriglyceridemia
- hypoglycemia hyperglycemia
- glucose intolerance insulin resistance
- gastrointestinal disorders means diseases selected from the group consisting of gastrointestinal hypermotility disorders, including but not limited to any type of diarrhea, such as, cancer treatment-related diarrhea, cancer-induced diarrhea, chemotherapy-induced diarrhea, radiation enteritis, radiation-induced diarrhea, stress-induced diarrhea, chronic diarrhea, AIDS-related diarrhea, C. difficile associated diarrhea, traveller's diarrhea, diarrhea induced by graph versus host disease and other types of diarrhea; Irritable Bowel Syndrome (IBS); intestinal injury disorders such as short-bowel syndrome; diseases involving intestinal barrier dysfunction such as pancreatitis, proctitis and pouchitis.
- IBS Irritable Bowel Syndrome
- TLC thin layer chromatography
- the Agilent instrument includes an Autosampler 1200, a binary pump 1100, a 5 wave length detector 1100 and a 6100 Single Quad.
- the column used was an XBridge CI 8.
- Eluent was a mixture of solution A (0.1% TFA in H 2 0) and solution B (0.1% TFA in MeCN).
- Gradients used are as follows: gradient A (intermediates characterization): held the initial conditions of 5% solution B for 1 min, increased linearly to 95% solution B in 4 min, held at 95% during 1 min, returned to initial conditions in 0.5 min and maintained for 1 min; gradient B (examples characterization): held the initial conditions of 5% solution B for 1 min, increased linearly to 60% in 10 min, increased linearly to 95% in 0.5 min, held at 95% during 3 min, returned to initial conditions in 0.5 min and maintained for 1 min.
- enantiomeric excess was performed on an Agilent 1100 (binary pump and 5 wavelengths detector) with manual or automatic (Autosampler 1100) injection. Columns used were CHIRALPAK IA CHIRALPAK IB or CHIRALPAK IC in isocratic mode. Mixtures of eluents were selected depending on the separation obtained of enantiomers or diastereosiomers. Usual mixtures were:
- Solvents, reagents and starting materials were purchased from well known chemical suppliers such as for example Sigma Aldrich, Acros Organics, VWR Int., Sopachem or Polymer labs and the following abbreviations are used:
- HATU 0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tretramethyluronium hexafluorophosphate
- HMDS Hexamethyldisilazane
- NMM N-methylmorpholine
- NMO N-methylmorpholine-N-oxide
- PE Petroleum ether
- SIBX Stabilized 2-iodoxybenzoic acid
- R a is chloro and R b is isopropyl, isobutyl, cyclopropyl, cyclopentyl, tetrahydropyran-4-yl, phenyl, or biphen-4-yl; or
- R a is 2-methoxypyridin-5-yl and R b is isopropyl, cyclopentyl or phenyl; or
- R a is 2-methoxypyrazin-5-yl and R b is isopropyl; or
- R a is 2-(2-oxopyrrolidin-l-yl)pyridin-5-yl and R b is isopropyl, cyclopentyl or phenyl.
- Scheme 2 Selected methods to achieve ring substitutions for the compounds containg ring I, ring V or ring VII.
- Scheme 4 Suggested synthetic route for the compounds containing ring II.
- a suggested method for the synthesis of compounds of the invention containing ring III is outlined in scheme 5.
- Scheme 5 Suggested synthetic route for the compounds containing ring III.
- Scheme 6 Suggested method for the preparation of the compounds of the invention containg ring IV.
- R c is chloro and R d is cyclopentyl or phenyl; or R c is 2-methoxypyridin-5-yl and R d is isopropyl or cyclopentyl.
- Scheme 8 Suggested method for the preparation of the compounds of the invention containg ring VIII.
- Scheme 10 General scheme for the preparation of biaryl- or heterobiaryl-thiazole amine intermediates 10.3 using Suzuki approach.
- Scheme 11 Alternative general scheme for the preparation of biaryl- or heterobiaryl- thiazole amine intermediates 10.3 using Suzuki approach.
- Scheme 13 General scheme for the preparation of 4-aryl-2-amino-thiazole intermediates using Rudolph's synthetic approach.
- Acetophenone intermediates 12.1 can be prepared as described in Scheme 14.
- Step 1 synthesis of (S)-4-benzyl-3-cinnamoyloxazolidin-2-one.
- Step 3 synthesis of (3S,4S)-tert-butyl 3-((S)-4-benzyl-2-oxooxazolidine-3- carbonyl)-4-phenylhept-6-enoate.
- Step 4 synthesis of (2S,3S)-2-(2-(tert-butoxy)-2-oxoethyl)-3-phenylhex-5-enoic acid, intermediate la.
- Step 2 synthesis of (E)-3-cyclopentylacrylic acid.
- Step 3 synthesis of (E)-3-cyclopentylacryloyl chloride.
- Step 1 synthesis of 2-(2-(allylamino)thiazol-4-yl)phenylboronic acid.
- Step 2 synthesis of l-(5-(2-(2-(allylamino)thiazol-4-yl)phenyl)pyridin-2- yl)pyrrolidin-2-one, intermediate 2d.
- intermediate 2g N-allyl-4-(2-(6-methoxypyridin-3-yl)phenyl)thiazol-2-amine
- intermediate 21 4-(2-(6-methoxypyridin-3-yl)phenyl)thiazol-2-amine from intermediate 2j.
- Example 1 This general method is depicted with the synthesis of Example 1: compound n°6: 2-((3S,4S,Z)-l-(4-(2-chlorophenyl)thiazol-2-yl)-2-oxo-4- phenyl-l,2,3,4,5,8-hexahydroazocin-3-yl)acetic acid.
- Step 1 synthesis of (3S,4S)-tert-butyl 3-(allyl(4-(2-chlorophenyl)thiazol-2- yl)carbamoyl)-4-phenylhept-6-enoate.
- Step 2 synthesis of tert-butyl 2-((3S,4S,Z)-l-(4-(2-chlorophenyl)thiazol-2-yl)-2- oxo-4-phenyl-l,2, 3,4,5, 8-hexahydroazocin-3-yl)acetate.
- Step 3 synthesis of 2-((3S,4S,Z)-l-(4-(2-chlorophenyl)thiazol-2-yl)-2-oxo-4- phenyl-1,2, 3,4,5, 8-hexahydroazocin-3-yl)acetic acid, compound n°6.
- Step 1 synthesis of (R)-4-(tert-butoxy)-2-(cyclopentylamino)-4-oxobutanoic acid
- Step 2 synthesis of (R)-4-tert-butyl 1 -methyl 2-(cyclopentylamino)succinate.
- Preparation of the diazomethane solution (Organic Syntheses, Coll. Vol. 2, p.165 (1943); Vol. 15, p.3 (1935))
- Step 4 synthesis of (R)-4-tert-butyl 1-methyl 2-(N-cyclopentyl-4- oxobutanamido)succinate, intermediate 3a.
- intermediate 3b 4-tert-butyl 1 -methyl 2-(4-oxo-N-phenylbutanamido)succinate which was obtained from (R)-4-tert-butoxy-4-oxo-2-(phenylamino)butanoic acid which was synthesized as follows from (R)-2-amino-4-tert-butoxy-4-oxobutanoic acid:
- Example 2 compound n°32 2-(4-(4-(2-chlorophenyl)thiazol-2-yl)-l-cyclopentyl-3,8- dioxo- 1 ,4-diazocan-2-yl)acetic acid.
- Step 1 synthesis of 4-tert-butyl 1 -methyl 2-(4-((4-(2-chlorophenyl)thiazol-2- yl)amino)-N-cyclopentylbutanamido)succinate.
- Step 2 synthesis of 4-(tert-butoxy)-2-(4-((4-(2-chlorophenyl)thiazol-2- yl)amino)-N-cyclopentylbutanamido)-4-oxobutanoic acid.
- Step 3 synthesis of tert-buty l 2-(4-(4-(2-chlorophenyl)thiazol-2-yl)-l- cyclopentyl-3,8-dioxo-l,4-diazocan-2-yl)acetate.
- Step 4 synthesis of 2-(4-(4-(2-chlorophenyl)thiazol-2-yl)-l-cyclopentyl-3,8- dioxo-l,4-diazocan-2-yl)acetic acid, compound n°32.
- Example 3 compound n°l : 2-((3S,4S)-l-(4-(2-chlorophenyl)thiazol-2-yl)-2-oxo-4-phenyl- 2,3,4,7-tetrahydro-lH-azepin-3-yl)acetic acid was synthesized from intermediates lb and 2a using general method D.
- Example 4 compound n°2: 2-((3S,4R)-l-(4-(2-chlorophenyl)thiazol-2-yl)-2-oxo-4-phenyl- 2,3,4,7-tetrahydro-lH-azepin-3-yl)acetic acid was synthesized from intermediates lc and 2a using general method D.
- Example 5 compound n°3: 2-((3R,4S)-l-(4-(2-chlorophenyl)thiazol-2-yl)-2-oxo-4-phenyl- 2,3,4,7-tetrahydro-lH-azepin-3-yl)acetic acid was synthesized from intermediates Id and 2a using general method D.
- Example 6 compound n°4: 2-((3R,4R)-l-(4-(2-chlorophenyl)thiazol-2-yl)-2-oxo-4- phenyl-2,3,4,7-tetrahydro-lH-azepin-3-yl)acetic acid was synthesized from intermediates le and 2a using general method D.
- Example 7 compound n°5: 2-((3S,4S)-l-(4-(2-chlorophenyl)thiazol-2-yl)-2-oxo-4- phenylazepan-3-yl)acetic acid:
- Example 8 compound n°7: 2-((3S,4S)-l-(4-(2-chlorophenyl)thiazol-2-yl)-7-hydroxy-2- oxo-4-phenylazocan-3-yl)acetic acid:
- Step 1 synthesis of tert-butyl 2-((3S,4S)-l-(4-(2-chlorophenyl)thiazol-2-yl)-7- hydroxy-2-oxo-4-phenylazocan-3-yl)acetate.
- Step 2 synthesis of compound n°7.
- Example 9 c o m p o u n d n ° 9 : 2-((3S,4R,Z)-l-(4-(2-chlorophenyl)thiazol-2-yl)-4- cyclopentyl-2-oxo-l,2,3,4,5,8-hexahydroazocin-3-yl)acetic acid was synthesized from intermediates If and 2a using general method D.
- Example 10 compound n°l l : 2-((3S,4S,Z)-l-(4-(2-chlorophenyl)thiazol-2-yl)-2-oxo-4- phenyl-2,3,4,5,8,9-hexahydro-lH-azonin-3-yl)acetic acid was synthesized from intermediates la and 2b using general method D.
- Example 11 compound n°12: 2-((3S,4S)-l-(4-(2-chlorophenyl)thiazol-2-yl)-2-oxo-4- phenylazocan-3-yl)acetic acid was synthesized from compound n°6 using the hydrogenation procedure detailed for the synthesis of compound n°5.
- Example 12 compound n°13: 2-((3S,4S,Z)-l-(4-(2,5-dichlorophenyl)thiazol-2-yl)-2-oxo- 4-phenyl-l,2,3,4,5,8-hexahydroazocin-3-yl)acetic acid was synthesized from intermediates la and 2e using general method D.
- Example 13 compound n°14: 2-((3S,4S)-l-(4-(2-chlorophenyl)thiazol-2-yl)-6-hydroxy-2- oxo-4-phenylazepan-3-yl)acetic acid was synthesized from compound n°l using the hydroboration and TFA deprotection steps as described for the synthesis of compound n°7. 73 ⁇ 4rt-butyl 2-((3S,4S,5R)-l-(4-(2-chlorophenyl)thiazol-2-yl)-5-hydroxy-2-oxo-4- phenylazepan-3-yl)acetate was also recovered during the chromatography.
- Example 14 compound n°16: 2-((3S,4S)-l-(4-(2,5-dichlorophenyl)thiazol-2-yl)-2-oxo-4- phenylazocan-3-yl)acetic acid was synthesized from compound n°13 using the hydrogenation procedure detailed for the synthesis of compound n°5.
- Example 15 compound n°17: 2-((3S,4R,Z)-l-(4-(2-chlorophenyl)thiazol-2-yl)-2-oxo-4- (tetrahydro-2H-pyran-4-yl)-l,2, 3,4,5, 8-hexahydroazocin-3-yl)acetic acid was synthesized from intermediates lg and 2a using general method D.
- Example 16 compound n°18: 2-((3S,4R)-l-(4-(2-chlorophenyl)thiazol-2-yl)-2-oxo-4- (tetrahydro-2H-pyran-4-yl)azocan-3-yl)acetic acid was synthesized from compound n°17 using the hydrogenation procedure detailed for the synthesis of compound n°5.
- Example 17 compound n°19: 2-(4-(4-(2-chlorophenyl)thiazol-2-yl)-3,8-dioxo-l-phenyl- l,4-diazocan-2-yl)acetic acid was synthesized from intermediates 3b and 2f using general method F.
- Example 18 compound n°20: 2-((3S,4S)-l-(4-(2-chlorophenyl)thiazol-2-yl)-6-hydroxy-2- oxo-4-phenylazocan-3-yl)acetic acid:
- Example 19 c omp ound n°21 : 2-((3S,4S,5R)-l-(4-(2-chlorophenyl)thiazol-2-yl)-5- hydroxy-2-oxo-4-phenylazepan-3-yl)acetic acid:
- Example 20 compound n°22: 2-((3S,4S)-l-(4-(2-(6-methoxypyridin-3-yl)phenyl)thiazol- 2-yl)-2-oxo-4-phenyl-2,3,4,7-tetrahydro-lH-azepin-3-yl)acetic acid was synthesized from intermediates lb and 2g using general method D.
- Example 21 compound n°23: 2-((3S,4S)-l-(4-(2-(6-methoxypyridin-3-yl)phenyl)thiazol- 2-yl)-2-oxo-4-phenylazepan-3-yl)acetic acid was synthesized from compound n°22 using the hydrogenation procedure detailed for the synthesis of compound n°5.
- Example 22 compound n°24: 2-((3S,4S)-l-(4-(2-chlorophenyl)thiazol-2-yl)-7-fluoro-2- oxo-4-phenylazocan-3-yl)acetic acid:
- step 1 synthesis of tert-butyl 2-((3S,4S)-l-(4-(2-chlorophenyl)thiazol-2-yl)-7-fluoro-2-oxo- 4-phenylazocan-3-yl)acetate
- Step 2 synthesis of compound n°24
- Example 23 compound n°25: 2-((3S,4S,6S,7R)-l-(4-(2-chlorophenyl)thiazol-2-yl)-6,7- dihydroxy-2-oxo-4-phenylazocan-3-yl)acetic acid and compound n°26: 2-((3S,4S,6S,7R)- l-(4-(2-chlorophenyl)thiazol-2-yl)-6,7-dihydroxy-2-oxo-4-phenylazocan-3-yl)acetic acid: A solution of 4-methylmorpholine (1.336 mmol, 135 mg) and a catalytic amount of a 4wt% solution osmium tetroxide in distilled water (0.039 mmol, 0.240 mL) in distilled water (0.3 M, 230 ⁇ ) at RT was added slowly to a solution of tert-butyl 2-((3S,4S,Z)- 1 -(
- Example 24 c o m p o u n d n ° 2 7 : 2-((3S,4S,Z)-4-([l,l'-biphenyl]-4-yl)-l-(4-(2- chlorophenyl)thiazol-2-yl)-2-oxo- 1,2,3,4,5 , 8-hexahydroazocin-3 -y l) acetic acid was synthesized from intermediates lh and 2a using general method D.
- Example 25 compound n°29: 2-((3S,4S)-l-(4-(2-chlorophenyl)thiazol-2-yl)-2,7-dioxo- 4-phenylazocan-3-yl)acetic acid:
- Example 26 compound n°30: 2-((3S,4S,Z)-2-oxo-l-(4-(2-(6-(2-oxopyrrolidin-l- yl)pyridin-3-yl)phenyl)thiazol-2-yl)-4-phenyl-l,2,3,4,5,8-hexahydroazocin-3-yl)acetic acid was synthesized from intermediates la and 2d using general method D.
- Example 27 c omp o und n°31 : 2-((3S,4S)-l-(4-(2-chlorophenyl)thiazol-2-yl)-7- (isopropylamino)-2-oxo-4-phenylazocan-3-yl)acetic acid:
- step 1 synthesis of tert-butyl 2-((3S,4S)-l-(4-(2-chlorophenyl)thiazol-2-yl)-7- (isopropylamino)-2-oxo-4-phenylazocan-3-yl)acetate
- step 1 Intermediate obtained in step 1 was treated with TFA and DCM, as described in step 3 of general method D which provided title product.
- Example 28 compound n° 33 : 2-((3S,4S,7S)-l-(4-(2-chlorophenyl)thiazol-2-yl)-7- hydroxy-2-oxo-4-phenylazocan-3-yl)acetic acid
- Example 29 compound n°34 2-((3S,4R,Z)-l-(4-(2-chlorophenyl)thiazol-2-yl)-4- isopropyl-2-oxo-l,2,3,4,5,8-hexahydroazocin-3-yl)acetic acid was synthesized from intermediates li and 2a using general method D.
- Example 30 compound n°36: 2-((3S,4S,7R)-l-(4-(2-chlorophenyl)thiazol-2-yl)-7- hydroxy-2-oxo-4-phenylazocan-3-yl)acetic acid was obtained using the same procedure as for compound n°33.
- Example 31 compound n°37: 2-((3S,4R,7S)-l-(4-(2-chlorophenyl)thiazol-2-yl)-4- cyclopentyl-7-hydroxy-2-oxoazocan-3-yl)acetic acid and compound n° 38 : 2- ((3S,4R,7R)-l-(4-(2-chlorophenyl)thiazol-2-yl)-4-cyclopentyl-7-hydroxy-2-oxoazocan- 3-yl)acetic acid were synthesized from compound n°9 using the methodology described for the synthesis of compound n°7.
- Example 32 compound n°39 : 2-((3S,4S,Z)-l-(4-(2-chlorophenyl)thiazol-2-yl)-4- isobutyl-2-oxo-l,2,3,4,5,8-hexahydroazocin-3-yl)acetic acid was synthesized from intermediates lj and 2a using general method D.
- Example 33 compound n°40 : 2-((3S,4R,7R)-l-(4-(2-chlorophenyl)thiazol-2-yl)-7- hydroxy-4-isopropyl-2-oxoazocan-3-yl)acetic acid was synthesized from compound n°34 using the methodology described for the synthesis of compound n°7.
- Example 34 compound n°41 : 2-((3S,4R)-l-(4-(2-chlorophenyl)thiazol-2-yl)-4- cyclopentyl-2-oxoazocan-3-yl)acetic acid was synthesized from compound n°9 using the hydrogenation procedure detailed for the synthesis of compound n°5.
- Example 35 compound n°42 : 2-((3S,4R,Z)-4-cyclopentyl-2-oxo-l-(4-(2-(6-(2- oxopyrrolidin-l-yl)pyridin-3-yl)phenyl)thiazol-2-yl)-l,2,3,4,5,8-hexahydroazocin-3- yl)acetic acid was synthesized from intermediates If and 2d using general method D.
- Example 36 compound n°43: 2-((3S,4R)-4-cyclopentyl-2-oxo-l-(4-(2-(6-(2- oxopyrrolidin- 1 -yl)pyridin-3-yl)phenyl)thiazol-2-yl)azocan-3-yl)acetic acid was
- Example 37 compound n°44: 2-((3S,4R,Z)-4-cyclopentyl-2-oxo-l-(4-phenylthiazol-2- yl)-l,2, 3,4,5, 8-hexahydroazocin-3-yl)acetic acid was synthesized from intermediates If and 2h using general method D.
- Example 38 c omp ound n ° 45 : 2-((3S,4R,Z)-4-cyclopentyl-l-(4-(2- fluorophenyl)thiazol-2-yl)-2-oxo-l,2,3,4,5,8-hexahydroazocin-3-yl)acetic acid was synthesized from intermediates If and 2i using general method D.
- Example 39 compound n°46: 2-((3S,4R,Z)-4-cyclopentyl-l-(4-(2-(6-methoxypyridin- 3-yl)phenyl)thiazol-2-yl)-2-oxo-l,2,3,4,5,8-hexahydroazocin-3-yl)acetic acid was synthesized from intermediates If and 2g using general method D.
- Example 40 compound n°47: 2-((3S,4S)-7-(benzylamino)-l-(4-(2-chlorophenyl)thiazol-2- yl)-2-oxo-4-phenylazocan-3-yl)acetic acid was synthesized using the methodology used for the synthesis of compound n°31 , replacing isopropylamine with benzylamine.
- Example 41 compound n°48: 2-((3S,4R,Z)-4-isopropyl-l-(4-(2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)-2-oxo-l, 2,3,4,5, 8-hexahydroazocin-3-yl)acetic acid was synthesized from intermediates li and 2g using general method D.
- Example 42 compound n°49 : 2-((3S,4R,Z)-4-isopropyl-2-oxo-l-(4-(2-(6-(2- oxopyrrolidin-l-yl)pyridin-3-yl)phenyl)thiazol-2-yl)-l,2,3,4,5,8-hexahydroazocin-3- yl)acetic acid was synthesized from intermediates li and 2d using general method D.
- Example 43 compound n°50 : 2-((3S,4R,Z)-l-(4-(2-chlorophenyl)thiazol-2-yl)-4- cyclopropyl-2-oxo-l,2,3,4,5,8-hexahydroazocin-3-yl)acetic acid was synthesized from intermediates lk and 2a using general method D.
- Example 44 compound n° 62 : 2-((3S,4S,Z)-l-(4-(2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)-2-oxo-4-phenyl- 1 ,2,3 ,4,5 ,8-hexahydroazocin-3-y l)acetic acid was synthesized from intermediates la and 2g using general method D.
- Example 45 compound n° 63 : 2-((3S,4R)-4-isopropyl-2-oxo-l-(4-(2-(6-(2- oxopyrrolidin-l-yl)pyridin-3-yl)phenyl)thiazol-2-yl)azocan-3-yl)acetic acid was synthesized from compound n°49 using the hydrogenation procedure detailed for the synthesis of compound n°5.
- Example 46 compound n°64: 2-((3S,4R)-4-isopropyl-l-(4-(2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)-2-oxoazocan-3-yl)acetic acid was synthesized from compound n°62 using the hydrogenation procedure detailed for the synthesis of compound n°5.
- Example 47 c o m p o u n d n °116: 2-(l-isopropyl-4-(4-(2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)-3,8-dioxo-l,4-diazocan-2-yl)acetic acid was synthesized from intermediates 3c and 2g using general method F.
- Example 48 compound n°117: 2-((3S,4R,Z)-4-isopropyl-l-(4-(2-(5-methoxypyrazin-2- yl)phenyl)thiazol-2-yl)-2-oxo-l, 2,3,4,5, 8-hexahydroazocin-3-yl)acetic acid was synthesized from intermediates li and 2k using general method D.
- Example 49 compound n°118: 2-((3S,4R,Z)-4-isopropyl-l-(4-(2-(5-methoxypyrazin-2- yl)phenyl)thiazol-2-yl)-2-oxoazocan-3-yl)acetic acid was synthesized from compound n°l 17 using the hydrogenation procedure detailed for the synthesis of compound n°5.
- Example 50 c o m p o u n d n °119: 2-(l-cyclopentyl-4-(4-(2-(6-methoxypyridin-3- yl)phenyl)thiazol-2-yl)-3,8-dioxo-l,4-diazocan-2-yl)acetic acid was synthesized from intermediates 3a and 2g using general method F. BIOLOGY EXAMPLES
- Figure 1 represents the effect of compound 9 on GLP-1 release from rat lower intestinal GLP-1 secreting cells.
- Figure 2 represents the inhibition of in-vitro TNFa release from LPS-stimulated PBMC following the activation by the compounds of the invention.
- Figure 3 represents the inhibition of in-vivo lipolysis following the injection of compound 42 in mice.
- Membrane binding assay GTPyS binding assay.
- the following assay can be used for determination of GPR43 activation.
- a GPCR When a GPCR is in its active state, either as a result of ligand binding or constitutive activation, the receptor couples to a G protein and stimulates the release of GDP and subsequent binding of GTP to the G protein.
- the alpha subunit of the G protein-receptor complex acts as a GTPase and slowly hydrolyses the GTP to GDP, at which point the receptor normally is deactivated. Activated receptors continue to exchange GDP for GTP.
- the non- hydro lysable GTP analog, [ 35 S]GTPyS was used to demonstrate enhance binding of [ 35 S]GTPyS to membranes expressing receptors.
- the assay uses the ability of GPCR to stimulate [ 35 S]GTPyS binding to membranes expressing the relevant receptors.
- the assay can, therefore, be used in the direct identification method to screen candidate compounds to endogenous or not endogenous GPCR. Preparation of membrane extracts:
- Membrane extracts were prepared from cells expressing the human GPR43 receptor (hGPR43) as follows: the medium was aspirated and the cells were scraped from the plates in Ca ++ and Mg ++ -free Phosphate-buffered saline (PBS). The cells were then centrifuged for 3 min at 1500 g and the pellets were resuspended in buffer A (15 mM Tris-HCl pH 7.5, 2 mM MgCl 2 , 0.3 mM EDTA, 1 mM EGTA) and homogenized in a glass homogenizer. The crude membrane fraction was collected by two consecutive centrifugation steps at 40.000 x g for 25 min separated by a washing step in buffer A.
- buffer A 15 mM Tris-HCl pH 7.5, 2 mM MgCl 2 , 0.3 mM EDTA, 1 mM EGTA
- the final pellet was resuspended in 500 ⁇ . of buffer B (75 mM Tris-HCl pH 7.5, 12.5 mM MgCl 2 , 0.3 mM EDTA, lmM EGTA, 250 mM sucrose) and flash frozen in liquid nitrogen. Protein content was assayed by the Folin method.
- the assay was performed in the presence of SCFA, and was used to determine the activity of the compounds of the invention.
- the [ 35 S]GTPyS assay was incubated in 20 mM HEPES pH 7.4, 100 mM NaCl, 10 ⁇ g/ml saponin, 30 mM of MgCl 2 , 10 ⁇ of GDP, 5 ⁇ g membrane-expressing hGPR43, 250 ⁇ g of wheatgerm agglutinin beads (Amersham, ref: RPNQ001), a range concentration of compounds of the invention (from 30 ⁇ to 1 nM) in a final volume of 100 ⁇ for 30 min at room temperature.
- the SCFA propionate was used at 1 mM final concentration as positive control.
- Rat lower intestinal GLP-1 secreting cells were prepared from eight- week-old male Sprague-Dawley rat. Each well contained 5x 10 4 cells stimulated in assay buffer (DMEM- based medium) containing 5.6 mM glucose with increasing concentration of the compounds of the invention for 1 hour at 37°C in cell incubator. The supernatants were harvested and assessed for GLP-1 using an ELISA (Wako).
- assay buffer DMEM- based medium
- the blood glucose area under the curve (AUC) between time t-15 min and time tl20 min was calculated (GraphPad Prism software).
- preferred compounds of the invention When tested in the above-described assay, preferred compounds of the invention showed a % of AUC inhibition > 13%, indicating that the compounds of invention are able to significantly reduce the level of blood glucose.
- PBMC Peripheral blood mononuclear cells
- PBMC Peripheral blood mononuclear cells
- LPS 100 ng/ml
- Cell supernatants are recovered after centrifugation and human soluble TNFa .is quantified using ELISA assay (R&D system) according manufacturer's recommendation.
- mice Male C57BL/6N wild-type are housed one per cage in a room maintained on a 12h light/dark cycle under constant temperature (22-25°C) with ad libitum access to food and water.
- the anti-lipolytic effects of the compounds of the invention are studied in awake mice. Animals are fasted overnight before experimental use. On the day of the experiment, animals are put in metabolic cages and left undisturbed to acclimate to the environment for l-2h. Blood samples are taken at indicated time points from the intraorbital retrobulbar plexus. A 1% sodium citrate saline solution is used to flush the lines. A pre-treatment blood sample is obtained from each animal to determine baseline values for free fatty acids (FFA) and triglycerides (TG).
- FFA free fatty acids
- TG triglycerides
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Abstract
L'invention concerne de nouveaux composés de formule (I) : Ar1__L1__R__Ar2__Ar3 ainsi que leur utilisation pour traiter et/ou prévenir des troubles inflammatoires, gastro-intestinaux et/ou métaboliques.
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Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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WO2015078949A1 (fr) * | 2013-11-27 | 2015-06-04 | Euroscreen Sa | Composés, composition pharmaceutique et méthodes à utiliser dans le traitement de maladies inflammatoires |
US10710986B2 (en) | 2018-02-13 | 2020-07-14 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
US10774071B2 (en) | 2018-07-13 | 2020-09-15 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
US10899735B2 (en) | 2018-04-19 | 2021-01-26 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
WO2021018786A1 (fr) | 2019-07-26 | 2021-02-04 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Utilisation d'agonistes de ffar2 pour le traitement de surinfections bactériennes suite à une infection virale |
US11236085B2 (en) | 2018-10-24 | 2022-02-01 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
CN114685374A (zh) * | 2020-12-28 | 2022-07-01 | 山东道一医药科技有限公司 | 一种合成奥拉帕尼的新工艺 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005063725A1 (fr) * | 2003-12-26 | 2005-07-14 | Takeda Pharmaceutical Company Limited | Derives d'acide phenylpropanoique |
WO2005118573A1 (fr) * | 2004-05-28 | 2005-12-15 | Smithkline Beecham Corporation | Nouveaux composes de diazepine utilises comme ligands des recepteurs 1 et/ou 4 de la melanocortine |
GB2418427A (en) * | 2004-09-02 | 2006-03-29 | Univ Cambridge Tech | Ligands for G-protein coupled receptors |
US20060160869A1 (en) * | 2005-01-05 | 2006-07-20 | Rigel Pharmaceuticals, Inc. | Ubiquitin ligase inhibitors |
EP2215080A1 (fr) * | 2007-10-25 | 2010-08-11 | Boehringer Ingelheim International GmbH | Composés de diazépane qui modulent le récepteur cb2 |
-
2011
- 2011-06-03 WO PCT/EP2011/059181 patent/WO2011151436A2/fr active Application Filing
Non-Patent Citations (17)
Title |
---|
AHREN BO, NATURE REVIEWS, vol. 8, 2009, pages 369 - 385 |
BARTOLI ET AL., J. MED. CHEM., vol. 41, 1998, pages 1855 - 68 |
COVINGTON ET AL., BIOCHEMICAL SOCIETY TRANSACTION, vol. 34, 2006, pages 770 - 773 |
E. L. ELIEL, S. H. WILEN, L. N. MANDER: "Stereochemistry of Organic Compounds", 1994, WILEY- INTERSCIENCE |
FUSS, CURR DRUG TARGETS INFLAMM ALLERGY, vol. 2, 2003, pages 101 - 112 |
GE ET AL., ENDOCRINOLOGY, vol. 149, 2008, pages 4519 - 4526 |
LAROCK, R. C.: "Comprehensive Org Transf", 1999, WILEY, pages: 709 - 719 |
LE POUL ET AL., J. BIOL CHEM., vol. 278, 2003, pages 25481 - 489 |
MASLOWSKI ET AL., NATURE, vol. 461, no. 7268, 2009, pages 1282 - 1286 |
MILLIGAN ET AL., BJP, vol. 158, 2009, pages 146 - 153 |
RAYASAM ET AL., EXPERT OPINION ON THERAPEUTIC TARGETS, vol. 11, 2007, pages 661 - 671 |
REGARD ET AL., J. CLIN. INV., vol. 117, 2007, pages 4034 - 4043 |
RUDOLPH, J., TETRAHEDRON, vol. 56, 2000, pages 3161 |
SWAIN ET AL., J. MED. CHEM., vol. 34, 1991, pages 140 - 151 |
TEDELIND ET AL., WORLD J. GASTROENTEROL, vol. 13, no. 20, 2007, pages 2826 - 2832 |
TIWARI, CURRENT OPINION IN INVESTIGATIONAL DRUGS, vol. 11, no. 4, 2010, pages 385 - 393 |
WHITE ET AL., J. MED. CHEM., vol. 39, 1996, pages 4382 - 95 |
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