AU2014385276B2 - Isothiazole derivatives as GPR120 agonists for the treatment of Type II diabetes - Google Patents

Info

Publication number

AU2014385276B2

AU2014385276B2 AU2014385276A AU2014385276A AU2014385276B2 AU 2014385276 B2 AU2014385276 B2 AU 2014385276B2 AU 2014385276 A AU2014385276 A AU 2014385276A AU 2014385276 A AU2014385276 A AU 2014385276A AU 2014385276 B2 AU2014385276 B2 AU 2014385276B2

Authority

AU

Australia

Prior art keywords

methoxy

trifluoromethyl

chloro

phenyl

fluoro

Prior art date

2014-03-07

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Ceased

Links

• Espacenet
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• 102100040134 Free fatty acid receptor 4 Human genes 0.000 title claims abstract description 41
• 101000890672 Homo sapiens Free fatty acid receptor 4 Proteins 0.000 title claims abstract description 41
• 208000001072 type 2 diabetes mellitus Diseases 0.000 title claims description 44
• 238000011282 treatment Methods 0.000 title description 16
• 239000000556 agonist Substances 0.000 title description 9
• 150000003854 isothiazoles Chemical class 0.000 title description 3
• 150000001875 compounds Chemical class 0.000 claims abstract description 324
• 238000000034 method Methods 0.000 claims abstract description 203
• 239000000203 mixture Substances 0.000 claims abstract description 166
• 239000007787 solid Substances 0.000 claims description 258
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 248
• XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 201
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 169
• DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 claims description 129
• 235000019260 propionic acid Nutrition 0.000 claims description 129
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 120
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 106
• 125000001153 fluoro group Chemical group F* 0.000 claims description 94
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 90
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 81
• 125000001424 substituent group Chemical group 0.000 claims description 71
• -1 methoxy, fluoro, 1 fluoroethyl Chemical group 0.000 claims description 64
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 58
• 208000008589 Obesity Diseases 0.000 claims description 47
• 235000020824 obesity Nutrition 0.000 claims description 47
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 43
• 208000035475 disorder Diseases 0.000 claims description 40
• 150000003839 salts Chemical group 0.000 claims description 39
• 239000001257 hydrogen Substances 0.000 claims description 37
• 229910052739 hydrogen Inorganic materials 0.000 claims description 37
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 30
• 208000001145 Metabolic Syndrome Diseases 0.000 claims description 22
• 125000004076 pyridyl group Chemical group 0.000 claims description 20
• 239000008194 pharmaceutical composition Substances 0.000 claims description 18
• 206010022489 Insulin Resistance Diseases 0.000 claims description 17
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 17
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 16
• 125000004500 isothiazol-4-yl group Chemical group S1N=CC(=C1)* 0.000 claims description 16
• WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 15
• 239000008103 glucose Substances 0.000 claims description 15
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 15
• 208000024172 Cardiovascular disease Diseases 0.000 claims description 14
• 208000032928 Dyslipidaemia Diseases 0.000 claims description 14
• 208000017170 Lipid metabolism disease Diseases 0.000 claims description 14
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
• 125000000335 thiazolyl group Chemical group 0.000 claims description 14
• 239000003085 diluting agent Substances 0.000 claims description 13
• 201000010390 abdominal obesity-metabolic syndrome 1 Diseases 0.000 claims description 12
• 208000011661 metabolic syndrome X Diseases 0.000 claims description 12
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 12
• 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 11
• 125000006002 1,1-difluoroethyl group Chemical group 0.000 claims description 10
• 206010014486 Elevated triglycerides Diseases 0.000 claims description 10
• 206010061218 Inflammation Diseases 0.000 claims description 10
• 208000001132 Osteoporosis Diseases 0.000 claims description 10
• 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 10
• 230000001771 impaired effect Effects 0.000 claims description 10
• 230000004054 inflammatory process Effects 0.000 claims description 10
• 239000003937 drug carrier Substances 0.000 claims description 7
• 125000001786 isothiazolyl group Chemical group 0.000 claims description 6
• BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
• 239000000725 suspension Substances 0.000 claims description 6
• 125000001544 thienyl group Chemical group 0.000 claims description 6
• 125000001246 bromo group Chemical group Br* 0.000 claims description 5
• 239000003814 drug Substances 0.000 claims description 5
• 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 claims description 5
• GQJOCUJNVIBULK-UHFFFAOYSA-N 3-[3,5-difluoro-4-[[3-(1,2-thiazol-5-yl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]phenyl]propanoic acid Chemical compound FC=1C=C(C=C(C1OCC=1C(=NSC1C(F)(F)F)C1=CC=NS1)F)CCC(=O)O GQJOCUJNVIBULK-UHFFFAOYSA-N 0.000 claims description 3
• CSHPCGOCKUHMCH-UHFFFAOYSA-N 3-[3,5-difluoro-4-[[3-(5-methoxypyridin-2-yl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]phenyl]propanoic acid Chemical compound FC=1C=C(C=C(C1OCC=1C(=NSC1C(F)(F)F)C1=NC=C(C=C1)OC)F)CCC(=O)O CSHPCGOCKUHMCH-UHFFFAOYSA-N 0.000 claims description 3
• UYEQPRWGHIBZEO-UHFFFAOYSA-N 3-[4-[[3-(5-chloro-3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-3-fluorophenyl]-2-methylpropanoic acid Chemical compound ClC=1C=C(C(=NC1)C1=NSC(=C1COC1=C(C=C(C=C1)CC(C(=O)O)C)F)C(F)(F)F)F UYEQPRWGHIBZEO-UHFFFAOYSA-N 0.000 claims description 3
• VJWXNUJYSBEMQG-UHFFFAOYSA-N 3-[4-[[3-chloro-5-(2,4-dimethylphenyl)-1,2-thiazol-4-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid Chemical compound ClC1=NSC(=C1COC1=CC(=C(C=C1)CCC(=O)O)C(F)(F)F)C1=C(C=C(C=C1)C)C VJWXNUJYSBEMQG-UHFFFAOYSA-N 0.000 claims description 3
• JJAUKQBDNDYIQK-UHFFFAOYSA-N 3-[4-[[3-chloro-5-(2-chlorophenyl)-1,2-thiazol-4-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid Chemical compound ClC1=NSC(=C1COC1=CC(=C(C=C1)CCC(=O)O)C(F)(F)F)C1=C(C=CC=C1)Cl JJAUKQBDNDYIQK-UHFFFAOYSA-N 0.000 claims description 3
• BSMPDLWHEBDVSI-UHFFFAOYSA-N 3-[4-[[3-chloro-5-(2-methoxyphenyl)-1,2-thiazol-4-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid Chemical compound ClC1=NSC(=C1COC1=CC(=C(C=C1)CCC(=O)O)C(F)(F)F)C1=C(C=CC=C1)OC BSMPDLWHEBDVSI-UHFFFAOYSA-N 0.000 claims description 3
• ZDMNBTYNNWONNS-UHFFFAOYSA-N 3-[4-[[3-chloro-5-(2-methylphenyl)-1,2-thiazol-4-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid Chemical compound ClC1=NSC(=C1COC1=CC(=C(C=C1)CCC(=O)O)C(F)(F)F)C1=C(C=CC=C1)C ZDMNBTYNNWONNS-UHFFFAOYSA-N 0.000 claims description 3
• CRRPUBJWCVWNHT-UHFFFAOYSA-N 3-[4-[[3-chloro-5-(2-methylphenyl)-1,2-thiazol-4-yl]methoxy]-2-methylphenyl]propanoic acid Chemical compound ClC1=NSC(=C1COC1=CC(=C(C=C1)CCC(=O)O)C)C1=C(C=CC=C1)C CRRPUBJWCVWNHT-UHFFFAOYSA-N 0.000 claims description 3
• KBSDNYOVHLKZSE-UHFFFAOYSA-N 3-[4-[[3-chloro-5-(4-methylcyclohexen-1-yl)-1,2-thiazol-4-yl]methoxy]-2-(trifluoromethyl)phenyl]propanoic acid Chemical compound ClC1=NSC(=C1COC1=CC(=C(C=C1)CCC(=O)O)C(F)(F)F)C1=CCC(CC1)C KBSDNYOVHLKZSE-UHFFFAOYSA-N 0.000 claims description 3
• MDIISSRLFAQUKL-UHFFFAOYSA-N 3-[4-[[3-chloro-5-(4-methylphenyl)-1,2-thiazol-4-yl]methoxy]-2-(1-fluoroethyl)phenyl]propanoic acid Chemical compound ClC1=NSC(=C1COC1=CC(=C(C=C1)CCC(=O)O)C(C)F)C1=CC=C(C=C1)C MDIISSRLFAQUKL-UHFFFAOYSA-N 0.000 claims description 3
• 239000006188 syrup Substances 0.000 claims description 3
• 235000020357 syrup Nutrition 0.000 claims description 3
• UOYZSMXCWBVPFW-UHFFFAOYSA-N 3-[4-[[3-(4-chlorophenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-2-(difluoromethyl)phenyl]propanoic acid Chemical compound ClC1=CC=C(C=C1)C1=NSC(=C1COC1=CC(=C(C=C1)CCC(=O)O)C(F)F)C(F)(F)F UOYZSMXCWBVPFW-UHFFFAOYSA-N 0.000 claims description 2
• KEMJTSMZXNXNFK-UHFFFAOYSA-N 3-[4-[[3-(5-chloro-3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-3,5-difluorophenyl]-2-methylpropanoic acid Chemical compound ClC=1C=C(C(=NC1)C1=NSC(=C1COC1=C(C=C(C=C1F)CC(C(=O)O)C)F)C(F)(F)F)F KEMJTSMZXNXNFK-UHFFFAOYSA-N 0.000 claims description 2
• OKBOMPCMGSBYCO-UHFFFAOYSA-N 3-[4-[[3-chloro-5-(2,4-dimethylphenyl)-1,2-thiazol-4-yl]methoxy]phenyl]propanoic acid Chemical compound ClC1=NSC(=C1COC1=CC=C(C=C1)CCC(=O)O)C1=C(C=C(C=C1)C)C OKBOMPCMGSBYCO-UHFFFAOYSA-N 0.000 claims description 2
• IXMBSHPTLQWCGL-UHFFFAOYSA-N 3-[7-[[3-chloro-5-(4-methylphenyl)-1,2-thiazol-4-yl]methoxy]-3,3-difluoro-1,2-dihydroinden-4-yl]propanoic acid Chemical compound ClC1=NSC(=C1COC=1C=CC(=C2C(CCC12)(F)F)CCC(=O)O)C1=CC=C(C=C1)C IXMBSHPTLQWCGL-UHFFFAOYSA-N 0.000 claims description 2
• 238000004519 manufacturing process Methods 0.000 claims description 2
• 239000006186 oral dosage form Substances 0.000 claims description 2
• ZKRHLOKMNHLNFL-UHFFFAOYSA-N 3-[4-[[3-chloro-5-(4-methylphenyl)-1,2-thiazol-4-yl]methoxy]-2-(1,1-difluoroethyl)phenyl]propanoic acid Chemical compound CC1=CC=C(C=C1)C1=C(COC2=CC(=C(CCC(O)=O)C=C2)C(C)(F)F)C(Cl)=NS1 ZKRHLOKMNHLNFL-UHFFFAOYSA-N 0.000 claims 1
• GFTODUORRZARMN-UHFFFAOYSA-N methyl 3-[4-[[3-(4-chloro-2-fluorophenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-3,5-difluorophenyl]propanoate Chemical compound ClC1=CC(=C(C=C1)C1=NSC(=C1COC1=C(C=C(C=C1F)CCC(=O)OC)F)C(F)(F)F)F GFTODUORRZARMN-UHFFFAOYSA-N 0.000 claims 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 356
• 239000000243 solution Substances 0.000 description 250
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 192
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 180
• 239000000047 product Substances 0.000 description 169
• 238000001819 mass spectrum Methods 0.000 description 149
• 238000005481 NMR spectroscopy Methods 0.000 description 145
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 130
• 235000019439 ethyl acetate Nutrition 0.000 description 122
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 121
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 120
• 229940093499 ethyl acetate Drugs 0.000 description 112
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 104
• 230000007062 hydrolysis Effects 0.000 description 99
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• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 54
• 229910052757 nitrogen Inorganic materials 0.000 description 54
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• 238000003756 stirring Methods 0.000 description 35
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• 239000002253 acid Substances 0.000 description 29
• IJAFUGGGBHSCAW-UHFFFAOYSA-N ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate Chemical compound CCOC(=O)CCC1=CC(F)=C(O)C(F)=C1 IJAFUGGGBHSCAW-UHFFFAOYSA-N 0.000 description 28
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 28
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• MBABOKRGFJTBAE-UHFFFAOYSA-N methyl methanesulfonate Chemical compound COS(C)(=O)=O MBABOKRGFJTBAE-UHFFFAOYSA-N 0.000 description 21
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• 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 description 14
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• UKIVNXCBKLKXTH-UHFFFAOYSA-N ethyl 3-[3,5-difluoro-4-[[3-(4-methoxyphenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]phenyl]propanoate Chemical compound FC1=CC(CCC(=O)OCC)=CC(F)=C1OCC1=C(C(F)(F)F)SN=C1C1=CC=C(OC)C=C1 UKIVNXCBKLKXTH-UHFFFAOYSA-N 0.000 description 1
• GKSCRADUMPZZFY-UHFFFAOYSA-N ethyl 3-[3,5-difluoro-4-[[3-(6-methoxypyridin-3-yl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]phenyl]propanoate Chemical compound FC1=CC(CCC(=O)OCC)=CC(F)=C1OCC1=C(C(F)(F)F)SN=C1C1=CC=C(OC)N=C1 GKSCRADUMPZZFY-UHFFFAOYSA-N 0.000 description 1
• HGCBPCBAOXYHMU-UHFFFAOYSA-N ethyl 3-[3,5-difluoro-4-[[3-methoxy-5-(4-methoxyphenyl)-1,2-thiazol-4-yl]methoxy]phenyl]propanoate Chemical compound FC1=CC(CCC(=O)OCC)=CC(F)=C1OCC1=C(C=2C=CC(OC)=CC=2)SN=C1OC HGCBPCBAOXYHMU-UHFFFAOYSA-N 0.000 description 1
• QZFRHALSPMJCQW-UHFFFAOYSA-N ethyl 3-[4-[[3-(4-chlorophenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-2,3-difluorophenyl]propanoate Chemical compound FC1=C(F)C(CCC(=O)OCC)=CC=C1OCC1=C(C(F)(F)F)SN=C1C1=CC=C(Cl)C=C1 QZFRHALSPMJCQW-UHFFFAOYSA-N 0.000 description 1
• PYDDOVHNAUUIRG-UHFFFAOYSA-N ethyl 3-[4-[[3-(4-chlorophenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-3,5-difluoro-2-methylphenyl]propanoate Chemical compound FC1=C(C)C(CCC(=O)OCC)=CC(F)=C1OCC1=C(C(F)(F)F)SN=C1C1=CC=C(Cl)C=C1 PYDDOVHNAUUIRG-UHFFFAOYSA-N 0.000 description 1
• HRKMPTIDSLHPLL-UHFFFAOYSA-N ethyl 3-[4-[[3-(4-chlorophenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-3,5-difluorophenyl]-2-methylpropanoate Chemical compound FC1=CC(CC(C)C(=O)OCC)=CC(F)=C1OCC1=C(C(F)(F)F)SN=C1C1=CC=C(Cl)C=C1 HRKMPTIDSLHPLL-UHFFFAOYSA-N 0.000 description 1
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