NO329777B1 - 2-aryltiazol-forbindelser, fremgangsmate for fremstilling av slike, farmasoytiske preparater inneholdende slike, slike forbindelser som terapeutisk aktive substanser samt anvendelse av slike for behandling av sykdom - Google Patents

2-aryltiazol-forbindelser, fremgangsmate for fremstilling av slike, farmasoytiske preparater inneholdende slike, slike forbindelser som terapeutisk aktive substanser samt anvendelse av slike for behandling av sykdom Download PDF

Info

Publication number: NO329777B1
Authority: NO; Norway
Prior art keywords: phenyl; ethoxy; methyl; propionic acid; thiazol
Prior art date: 2002-08-30

Application number

NO20050620A

Other languages

English (en)

Norwegian (no)

Other versions

NO20050620L (no

Inventor

Georges Hirth

Peter Mohr

Alfred Binggeli

Hans Hilpert

Markus Meyer

Hans-Peter Maerki

Grether Uwe

Original Assignee

Hoffmann La Roche

Priority date (The priority date 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 date listed.)

2002-08-30

Filing date

2005-02-03

Publication date

2010-12-13

2005-02-03 Application filed by Hoffmann La Roche filed Critical Hoffmann La Roche

2005-03-03 Publication of NO20050620L publication Critical patent/NO20050620L/no

2010-12-13 Publication of NO329777B1 publication Critical patent/NO329777B1/no

Links

150000001875 compounds Chemical class 0.000 title claims abstract description 172
201000010099 disease Diseases 0.000 title claims abstract description 17
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 17
238000000034 method Methods 0.000 title claims description 372
238000002360 preparation method Methods 0.000 title claims description 15
239000013543 active substance Substances 0.000 title claims description 6
230000008569 process Effects 0.000 title description 4
239000008194 pharmaceutical composition Substances 0.000 title 1
150000002148 esters Chemical class 0.000 claims abstract description 34
150000003839 salts Chemical class 0.000 claims abstract description 20
206010012601 diabetes mellitus Diseases 0.000 claims abstract description 9
229910052727 yttrium Inorganic materials 0.000 claims abstract description 8
XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 201
-1 3,5-dimethoxy-phenyl Chemical group 0.000 claims description 59
239000001257 hydrogen Substances 0.000 claims description 48
229910052739 hydrogen Inorganic materials 0.000 claims description 48
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 33
125000000217 alkyl group Chemical group 0.000 claims description 33
125000004432 carbon atom Chemical group C* 0.000 claims description 20
125000003545 alkoxy group Chemical group 0.000 claims description 18
102000000536 PPAR gamma Human genes 0.000 claims description 15
108010016731 PPAR gamma Proteins 0.000 claims description 14
150000002431 hydrogen Chemical class 0.000 claims description 14
102000023984 PPAR alpha Human genes 0.000 claims description 13
229910052736 halogen Inorganic materials 0.000 claims description 13
150000002367 halogens Chemical class 0.000 claims description 13
108091008725 peroxisome proliferator-activated receptors alpha Proteins 0.000 claims description 13
125000006239 protecting group Chemical group 0.000 claims description 13
208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 13
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
239000003814 drug Substances 0.000 claims description 9
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
125000001424 substituent group Chemical group 0.000 claims description 9
HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 8
125000006701 (C1-C7) alkyl group Chemical group 0.000 claims description 7
239000000556 agonist Substances 0.000 claims description 7
229910052757 nitrogen Inorganic materials 0.000 claims description 7
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
150000002632 lipids Chemical class 0.000 claims description 6
238000004519 manufacturing process Methods 0.000 claims description 6
239000000825 pharmaceutical preparation Substances 0.000 claims description 6
BJHFHRKGQFZRBM-UHFFFAOYSA-N 2-ethoxy-3-[2-methyl-4-[2-(5-methyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]phenyl]propanoic acid Chemical compound C1=C(C)C(CC(OCC)C(O)=O)=CC=C1OCCC1=C(C)SC(C=2C=CC=CC=2)=N1 BJHFHRKGQFZRBM-UHFFFAOYSA-N 0.000 claims description 5
229910052799 carbon Inorganic materials 0.000 claims description 5
125000000753 cycloalkyl group Chemical group 0.000 claims description 5
UUISXLDGYIHXKX-UHFFFAOYSA-N 2-ethoxy-3-[3-methyl-4-[[2-(4-propan-2-ylphenyl)-1,3-thiazol-4-yl]methoxy]phenyl]propanoic acid Chemical compound CC1=CC(CC(OCC)C(O)=O)=CC=C1OCC1=CSC(C=2C=CC(=CC=2)C(C)C)=N1 UUISXLDGYIHXKX-UHFFFAOYSA-N 0.000 claims description 4
OTUKSARQRIIQDU-UHFFFAOYSA-N 3-[4-[[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methoxy]-2-methylphenyl]-2-ethoxypropanoic acid Chemical compound C1=C(C)C(CC(OCC)C(O)=O)=CC=C1OCC1=CSC(C=2C=CC(Cl)=CC=2)=N1 OTUKSARQRIIQDU-UHFFFAOYSA-N 0.000 claims description 4
125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 4
208000032928 Dyslipidaemia Diseases 0.000 claims description 4
206010048554 Endothelial dysfunction Diseases 0.000 claims description 4
230000036772 blood pressure Effects 0.000 claims description 4
230000006806 disease prevention Effects 0.000 claims description 4
230000008694 endothelial dysfunction Effects 0.000 claims description 4
JGHIUSYNLMBQCA-IBGZPJMESA-N (2s)-3-[2-chloro-4-[[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methoxy]phenyl]-2-ethoxypropanoic acid Chemical compound C1=C(Cl)C(C[C@H](OCC)C(O)=O)=CC=C1OCC1=CSC(C=2C=CC(Cl)=CC=2)=N1 JGHIUSYNLMBQCA-IBGZPJMESA-N 0.000 claims description 3
IZKXAQPIMRIRJD-IBGZPJMESA-N (2s)-3-[4-[[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methoxy]-2-fluorophenyl]-2-ethoxypropanoic acid Chemical compound C1=C(F)C(C[C@H](OCC)C(O)=O)=CC=C1OCC1=CSC(C=2C=CC(Cl)=CC=2)=N1 IZKXAQPIMRIRJD-IBGZPJMESA-N 0.000 claims description 3
OTUKSARQRIIQDU-FQEVSTJZSA-N (2s)-3-[4-[[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methoxy]-2-methylphenyl]-2-ethoxypropanoic acid Chemical compound C1=C(C)C(C[C@H](OCC)C(O)=O)=CC=C1OCC1=CSC(C=2C=CC(Cl)=CC=2)=N1 OTUKSARQRIIQDU-FQEVSTJZSA-N 0.000 claims description 3
DSOBEFZGPISYQH-UHFFFAOYSA-N 2-[[4-[cyclopropyl-[4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]methoxy]-2-methylphenyl]methyl]butanoic acid Chemical compound C1=C(C)C(CC(CC)C(O)=O)=CC=C1OC(C1=C(N=C(S1)C=1C=CC(=CC=1)C(F)(F)F)C)C1CC1 DSOBEFZGPISYQH-UHFFFAOYSA-N 0.000 claims description 3
YJJKAPVQVUGMQK-UHFFFAOYSA-N 2-ethoxy-3-[2-methyl-4-[2-methyl-1-[4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]propoxy]phenyl]propanoic acid Chemical compound C1=C(C)C(CC(OCC)C(O)=O)=CC=C1OC(C(C)C)C1=C(C)N=C(C=2C=CC(=CC=2)C(F)(F)F)S1 YJJKAPVQVUGMQK-UHFFFAOYSA-N 0.000 claims description 3
208000001145 Metabolic Syndrome Diseases 0.000 claims description 3
201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 3
230000003143 atherosclerotic effect Effects 0.000 claims description 3
208000027866 inflammatory disease Diseases 0.000 claims description 3
201000010065 polycystic ovary syndrome Diseases 0.000 claims description 3
239000003805 procoagulant Substances 0.000 claims description 3
230000002062 proliferating effect Effects 0.000 claims description 3
UHFWEOUAYBXOSV-UHFFFAOYSA-N 2-ethoxy-3-[2-methyl-4-[1-[4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]ethoxy]phenyl]propanoic acid Chemical compound C1=C(C)C(CC(OCC)C(O)=O)=CC=C1OC(C)C1=C(C)N=C(C=2C=CC(=CC=2)C(F)(F)F)S1 UHFWEOUAYBXOSV-UHFFFAOYSA-N 0.000 claims description 2
125000004861 4-isopropyl phenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
239000002671 adjuvant Substances 0.000 claims description 2
239000003937 drug carrier Substances 0.000 claims description 2
125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 2
125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 258
RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 136
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 134
239000000203 mixture Substances 0.000 description 132
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 131
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 126
239000007787 solid Substances 0.000 description 105
239000002904 solvent Substances 0.000 description 105
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 96
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 87
FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 84
239000000243 solution Substances 0.000 description 83
239000007788 liquid Substances 0.000 description 82
NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 81
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 79
239000011734 sodium Substances 0.000 description 79
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 66
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 65
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 64
235000019260 propionic acid Nutrition 0.000 description 55
239000003921 oil Substances 0.000 description 52
235000019198 oils Nutrition 0.000 description 52
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 49
239000012230 colorless oil Substances 0.000 description 48
FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 47
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 45
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 45
SUNMBRGCANLOEG-UHFFFAOYSA-N 1,3-dichloroacetone Chemical compound ClCC(=O)CCl SUNMBRGCANLOEG-UHFFFAOYSA-N 0.000 description 44
238000006243 chemical reaction Methods 0.000 description 44
229910000024 caesium carbonate Inorganic materials 0.000 description 40
238000010992 reflux Methods 0.000 description 40
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 39
FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 39
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 37
SYIDEIWVKFMPNA-UHFFFAOYSA-N ethyl 2-ethoxy-3-(4-hydroxy-2-methylphenyl)propanoate Chemical compound CCOC(=O)C(OCC)CC1=CC=C(O)C=C1C SYIDEIWVKFMPNA-UHFFFAOYSA-N 0.000 description 37
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 35
230000002829 reductive effect Effects 0.000 description 32
239000000741 silica gel Substances 0.000 description 31
229910002027 silica gel Inorganic materials 0.000 description 31
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 30
239000002253 acid Substances 0.000 description 29
239000011541 reaction mixture Substances 0.000 description 29
229910052938 sodium sulfate Inorganic materials 0.000 description 28
235000011152 sodium sulphate Nutrition 0.000 description 28
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 26
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 26
DZEMOVISZADOLX-UHFFFAOYSA-N ethyl 2-ethoxy-3-(3-fluoro-4-hydroxyphenyl)propanoate Chemical compound CCOC(=O)C(OCC)CC1=CC=C(O)C(F)=C1 DZEMOVISZADOLX-UHFFFAOYSA-N 0.000 description 25
239000005457 ice water Substances 0.000 description 25
FKRCODPIKNYEAC-UHFFFAOYSA-N propionic acid ethyl ester Natural products CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 25
VLSDXINSOMDCBK-BQYQJAHWSA-N (E)-1,1'-azobis(N,N-dimethylformamide) Chemical compound CN(C)C(=O)\N=N\C(=O)N(C)C VLSDXINSOMDCBK-BQYQJAHWSA-N 0.000 description 22
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 22
239000013078 crystal Substances 0.000 description 22
238000001704 evaporation Methods 0.000 description 22
ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 22
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
239000012267 brine Substances 0.000 description 21
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 21
TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 21
238000004440 column chromatography Methods 0.000 description 20
230000008020 evaporation Effects 0.000 description 20
NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 20
239000000543 intermediate Substances 0.000 description 20
150000002989 phenols Chemical class 0.000 description 20
238000003756 stirring Methods 0.000 description 20
239000012300 argon atmosphere Substances 0.000 description 19
238000001816 cooling Methods 0.000 description 19
239000000725 suspension Substances 0.000 description 19
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
HCBQTGAZENNMLM-UHFFFAOYSA-N methyl 4-bromo-3-oxopentanoate Chemical compound COC(=O)CC(=O)C(C)Br HCBQTGAZENNMLM-UHFFFAOYSA-N 0.000 description 18
AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 18
239000012280 lithium aluminium hydride Substances 0.000 description 17
239000012044 organic layer Substances 0.000 description 17
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
239000002585 base Substances 0.000 description 16
238000003818 flash chromatography Methods 0.000 description 16
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 15
UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 15
QKSQWQOAUQFORH-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonylimino]carbamate Chemical group CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C QKSQWQOAUQFORH-UHFFFAOYSA-N 0.000 description 15
QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 14
239000010410 layer Substances 0.000 description 14
MMJCDOWKUCLEQX-UHFFFAOYSA-M (1,2-diethoxy-2-oxoethyl)-triphenylphosphanium;chloride Chemical compound [Cl-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C(C(=O)OCC)OCC)C1=CC=CC=C1 MMJCDOWKUCLEQX-UHFFFAOYSA-M 0.000 description 13
238000005160 1H NMR spectroscopy Methods 0.000 description 13
XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 13
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 13
150000001298 alcohols Chemical class 0.000 description 13
239000003054 catalyst Substances 0.000 description 13
229910000027 potassium carbonate Inorganic materials 0.000 description 13
235000011181 potassium carbonates Nutrition 0.000 description 13
229920006395 saturated elastomer Polymers 0.000 description 13
UZCXCVNBSPOTNE-LBPRGKRZSA-N (4s)-4-benzyl-3-(2-ethoxyacetyl)-1,3-oxazolidin-2-one Chemical compound C1OC(=O)N(C(=O)COCC)[C@H]1CC1=CC=CC=C1 UZCXCVNBSPOTNE-LBPRGKRZSA-N 0.000 description 12
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 12
239000003153 chemical reaction reagent Substances 0.000 description 12
238000004611 spectroscopical analysis Methods 0.000 description 12
NQWGWYXKBZSTFA-UHFFFAOYSA-N 2-[2-(4-tert-butylphenyl)-5-methyl-1,3-thiazol-4-yl]ethanol Chemical compound OCCC1=C(C)SC(C=2C=CC(=CC=2)C(C)(C)C)=N1 NQWGWYXKBZSTFA-UHFFFAOYSA-N 0.000 description 11
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 11
150000001299 aldehydes Chemical class 0.000 description 11
238000004587 chromatography analysis Methods 0.000 description 11
GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 10
UEJQTBKTWJQBRN-UHFFFAOYSA-N 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole Chemical compound ClCC1=CSC(C=2C=CC(Cl)=CC=2)=N1 UEJQTBKTWJQBRN-UHFFFAOYSA-N 0.000 description 10
KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 10
102000004877 Insulin Human genes 0.000 description 10
108090001061 Insulin Proteins 0.000 description 10
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
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MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 2
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229910052794 bromium Inorganic materials 0.000 description 2
229910002091 carbon monoxide Inorganic materials 0.000 description 2
238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
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238000006114 decarboxylation reaction Methods 0.000 description 2
230000005595 deprotonation Effects 0.000 description 2
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USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 2
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ZKSJQKFNOKHQMS-ZHZULCJRSA-N ethyl (z)-2-ethoxy-3-(4-phenylmethoxy-1-benzofuran-7-yl)prop-2-enoate Chemical compound C1=2C=COC=2C(/C=C(\OCC)C(=O)OCC)=CC=C1OCC1=CC=CC=C1 ZKSJQKFNOKHQMS-ZHZULCJRSA-N 0.000 description 2
GKNQMOJEPINFRF-UHFFFAOYSA-N ethyl 2-(4-tert-butylphenyl)-4-methyl-1,3-thiazole-5-carboxylate Chemical compound CC1=C(C(=O)OCC)SC(C=2C=CC(=CC=2)C(C)(C)C)=N1 GKNQMOJEPINFRF-UHFFFAOYSA-N 0.000 description 2
KBWCPINGYRFUKH-UHFFFAOYSA-N ethyl 2-[[4-[cyclopropyl-[4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]methoxy]-2-methylphenyl]methyl]butanoate Chemical compound C1=C(C)C(CC(CC)C(=O)OCC)=CC=C1OC(C1=C(N=C(S1)C=1C=CC(=CC=1)C(F)(F)F)C)C1CC1 KBWCPINGYRFUKH-UHFFFAOYSA-N 0.000 description 2
QRJKKAHZAFRLQA-UHFFFAOYSA-N ethyl 2-ethoxy-3-(4-hydroxynaphthalen-1-yl)propanoate Chemical compound C1=CC=C2C(CC(OCC)C(=O)OCC)=CC=C(O)C2=C1 QRJKKAHZAFRLQA-UHFFFAOYSA-N 0.000 description 2
DCZMZKXHSNSAJT-UHFFFAOYSA-N ethyl 2-ethoxy-3-[2-methyl-4-[(4-methyl-2-phenyl-1,3-thiazol-5-yl)methoxy]phenyl]propanoate Chemical compound C1=C(C)C(CC(OCC)C(=O)OCC)=CC=C1OCC1=C(C)N=C(C=2C=CC=CC=2)S1 DCZMZKXHSNSAJT-UHFFFAOYSA-N 0.000 description 2
RNPJONUYPCGURF-UHFFFAOYSA-N ethyl 2-ethoxy-3-[2-methyl-4-[1-[4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]but-3-enoxy]phenyl]propanoate Chemical compound C1=C(C)C(CC(OCC)C(=O)OCC)=CC=C1OC(CC=C)C1=C(C)N=C(C=2C=CC(=CC=2)C(F)(F)F)S1 RNPJONUYPCGURF-UHFFFAOYSA-N 0.000 description 2
VHCNKXDSUKHODZ-UHFFFAOYSA-N ethyl 2-ethoxy-3-[2-methyl-4-[2-(4-methyl-2-phenyl-1,3-thiazol-5-yl)ethoxy]phenyl]propanoate Chemical compound C1=C(C)C(CC(OCC)C(=O)OCC)=CC=C1OCCC1=C(C)N=C(C=2C=CC=CC=2)S1 VHCNKXDSUKHODZ-UHFFFAOYSA-N 0.000 description 2
HQLSNGHTBCSAAO-UHFFFAOYSA-N ethyl 2-ethoxy-3-[2-methyl-4-[[4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]-phenylmethoxy]phenyl]propanoate Chemical compound C1=C(C)C(CC(OCC)C(=O)OCC)=CC=C1OC(C=1C=CC=CC=1)C1=C(C)N=C(C=2C=CC(=CC=2)C(F)(F)F)S1 HQLSNGHTBCSAAO-UHFFFAOYSA-N 0.000 description 2
QKUGKPOTISEGCP-UHFFFAOYSA-N ethyl 3-[4-[3-(1,3-dioxan-2-yl)-1-[4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]propoxy]-2-methylphenyl]-2-ethoxypropanoate Chemical compound C1=C(C)C(CC(OCC)C(=O)OCC)=CC=C1OC(C1=C(N=C(S1)C=1C=CC(=CC=1)C(F)(F)F)C)CCC1OCCCO1 QKUGKPOTISEGCP-UHFFFAOYSA-N 0.000 description 2
KHALSYHBOMPJMH-UHFFFAOYSA-N ethyl 3-[4-[[2-(2-chlorophenyl)-4-methyl-1,3-thiazol-5-yl]methoxy]-2-methylphenyl]-2-ethoxypropanoate Chemical compound C1=C(C)C(CC(OCC)C(=O)OCC)=CC=C1OCC1=C(C)N=C(C=2C(=CC=CC=2)Cl)S1 KHALSYHBOMPJMH-UHFFFAOYSA-N 0.000 description 2
QIKXFPRSEANBNU-UHFFFAOYSA-N ethyl 3-[4-[cyclopentyl-[4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]methoxy]-2-methylphenyl]-2-ethoxypropanoate Chemical compound C1=C(C)C(CC(OCC)C(=O)OCC)=CC=C1OC(C1=C(N=C(S1)C=1C=CC(=CC=1)C(F)(F)F)C)C1CCCC1 QIKXFPRSEANBNU-UHFFFAOYSA-N 0.000 description 2
GZZZFAPAFHJOPU-UHFFFAOYSA-N ethyl 3-[4-[cyclopropyl-[4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]methoxy]-2-methylphenyl]-2-ethoxypropanoate Chemical compound C1=C(C)C(CC(OCC)C(=O)OCC)=CC=C1OC(C1=C(N=C(S1)C=1C=CC(=CC=1)C(F)(F)F)C)C1CC1 GZZZFAPAFHJOPU-UHFFFAOYSA-N 0.000 description 2
239000013613 expression plasmid Substances 0.000 description 2
238000000605 extraction Methods 0.000 description 2
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125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
238000006170 formylation reaction Methods 0.000 description 2
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125000002541 furyl group Chemical group 0.000 description 2
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102000037865 fusion proteins Human genes 0.000 description 2
108700039708 galantide Proteins 0.000 description 2
230000014509 gene expression Effects 0.000 description 2
125000005456 glyceride group Chemical group 0.000 description 2
VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 2
238000001727 in vivo Methods 0.000 description 2
230000002757 inflammatory effect Effects 0.000 description 2
150000002576 ketones Chemical class 0.000 description 2
CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 2
210000004185 liver Anatomy 0.000 description 2
NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
229910052751 metal Inorganic materials 0.000 description 2
239000002184 metal Substances 0.000 description 2
BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
GTBBGSMCSYZDPA-FQEVSTJZSA-N methyl (2s)-2-ethoxy-3-(2-ethyl-4-phenylmethoxyphenyl)propanoate Chemical compound C1=C(CC)C(C[C@H](OCC)C(=O)OC)=CC=C1OCC1=CC=CC=C1 GTBBGSMCSYZDPA-FQEVSTJZSA-N 0.000 description 2
FQGXIKADCCNRFX-NSHDSACASA-N methyl (2s)-2-ethoxy-3-(2-fluoro-4-hydroxyphenyl)propanoate Chemical compound CCO[C@H](C(=O)OC)CC1=CC=C(O)C=C1F FQGXIKADCCNRFX-NSHDSACASA-N 0.000 description 2
OTNSQUGJEAYJHI-SFHVURJKSA-N methyl (2s)-2-ethoxy-3-(2-fluoro-4-phenylmethoxyphenyl)propanoate Chemical compound C1=C(F)C(C[C@H](OCC)C(=O)OC)=CC=C1OCC1=CC=CC=C1 OTNSQUGJEAYJHI-SFHVURJKSA-N 0.000 description 2
NQYGKZLSBXLDMQ-LBPRGKRZSA-N methyl (2s)-2-ethoxy-3-(4-hydroxy-2-methoxyphenyl)propanoate Chemical compound CCO[C@H](C(=O)OC)CC1=CC=C(O)C=C1OC NQYGKZLSBXLDMQ-LBPRGKRZSA-N 0.000 description 2
WFEBVBHRVPNPPA-NRFANRHFSA-N methyl (2s)-2-ethoxy-3-[2-methyl-4-[[2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl]methoxy]phenyl]propanoate Chemical compound C1=C(C)C(C[C@H](OCC)C(=O)OC)=CC=C1OCC1=CSC(C=2C=CC(=CC=2)C(F)(F)F)=N1 WFEBVBHRVPNPPA-NRFANRHFSA-N 0.000 description 2
VUBMGFARWRVWEQ-FQEVSTJZSA-N methyl (2s)-3-(2,6-dimethyl-4-phenylmethoxyphenyl)-2-ethoxypropanoate Chemical compound C1=C(C)C(C[C@H](OCC)C(=O)OC)=C(C)C=C1OCC1=CC=CC=C1 VUBMGFARWRVWEQ-FQEVSTJZSA-N 0.000 description 2
ALYHNGPBSDTYQL-NSHDSACASA-N methyl (2s)-3-(2-chloro-4-hydroxyphenyl)-2-ethoxypropanoate Chemical compound CCO[C@H](C(=O)OC)CC1=CC=C(O)C=C1Cl ALYHNGPBSDTYQL-NSHDSACASA-N 0.000 description 2
PDYNGRHQWBHGTG-SFHVURJKSA-N methyl (2s)-3-(2-chloro-4-phenylmethoxyphenyl)-2-ethoxypropanoate Chemical compound C1=C(Cl)C(C[C@H](OCC)C(=O)OC)=CC=C1OCC1=CC=CC=C1 PDYNGRHQWBHGTG-SFHVURJKSA-N 0.000 description 2
QZZOBCFZOQICMN-QFIPXVFZSA-N methyl (2s)-3-[2,6-dimethyl-4-[[4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]methoxy]phenyl]-2-ethoxypropanoate Chemical compound C1=C(C)C(C[C@H](OCC)C(=O)OC)=C(C)C=C1OCC1=C(C)N=C(C=2C=CC(=CC=2)C(F)(F)F)S1 QZZOBCFZOQICMN-QFIPXVFZSA-N 0.000 description 2
PXWGWAYTIVICBH-FQEVSTJZSA-N methyl (2s)-3-[2-chloro-4-[[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methoxy]phenyl]-2-ethoxypropanoate Chemical compound C1=C(Cl)C(C[C@H](OCC)C(=O)OC)=CC=C1OCC1=CSC(C=2C=CC(Cl)=CC=2)=N1 PXWGWAYTIVICBH-FQEVSTJZSA-N 0.000 description 2
DZQUOLFNGUQJOL-NRFANRHFSA-N methyl (2s)-3-[4-[[2-(3-chloro-4-fluorophenyl)-1,3-thiazol-4-yl]methoxy]-2-methylphenyl]-2-ethoxypropanoate Chemical compound C1=C(C)C(C[C@H](OCC)C(=O)OC)=CC=C1OCC1=CSC(C=2C=C(Cl)C(F)=CC=2)=N1 DZQUOLFNGUQJOL-NRFANRHFSA-N 0.000 description 2
FHMJKWRJEFNCCR-QFIPXVFZSA-N methyl (2s)-3-[4-[[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methoxy]-2,6-dimethylphenyl]-2-ethoxypropanoate Chemical compound C1=C(C)C(C[C@H](OCC)C(=O)OC)=C(C)C=C1OCC1=CSC(C=2C=CC(Cl)=CC=2)=N1 FHMJKWRJEFNCCR-QFIPXVFZSA-N 0.000 description 2
HZWLSFIJENQWCB-QFIPXVFZSA-N methyl (2s)-3-[4-[[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methoxy]-2-ethylphenyl]-2-ethoxypropanoate Chemical compound C1=C(CC)C(C[C@H](OCC)C(=O)OC)=CC=C1OCC1=CSC(C=2C=CC(Cl)=CC=2)=N1 HZWLSFIJENQWCB-QFIPXVFZSA-N 0.000 description 2
MBJPCCXYVAHTLI-FQEVSTJZSA-N methyl (2s)-3-[4-[[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methoxy]-2-fluorophenyl]-2-ethoxypropanoate Chemical compound C1=C(F)C(C[C@H](OCC)C(=O)OC)=CC=C1OCC1=CSC(C=2C=CC(Cl)=CC=2)=N1 MBJPCCXYVAHTLI-FQEVSTJZSA-N 0.000 description 2
SKSFWAHGMVYAOR-NRFANRHFSA-N methyl (2s)-3-[4-[[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methoxy]-2-methoxyphenyl]-2-ethoxypropanoate Chemical compound C1=C(OC)C(C[C@H](OCC)C(=O)OC)=CC=C1OCC1=CSC(C=2C=CC(Cl)=CC=2)=N1 SKSFWAHGMVYAOR-NRFANRHFSA-N 0.000 description 2
DKWHCNBZQRWMFR-NRFANRHFSA-N methyl (2s)-3-[4-[[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methoxy]-2-methylphenyl]-2-ethoxypropanoate Chemical compound C1=C(C)C(C[C@H](OCC)C(=O)OC)=CC=C1OCC1=CSC(C=2C=CC(Cl)=CC=2)=N1 DKWHCNBZQRWMFR-NRFANRHFSA-N 0.000 description 2
FMFXYYXUSAJMQH-UXHICEINSA-N methyl (2s,3r)-2-ethoxy-3-(2-ethyl-4-phenylmethoxyphenyl)-3-hydroxypropanoate Chemical compound C1=C(CC)C([C@@H](O)[C@H](OCC)C(=O)OC)=CC=C1OCC1=CC=CC=C1 FMFXYYXUSAJMQH-UXHICEINSA-N 0.000 description 2
PJQUFHBXHMZCDH-MSOLQXFVSA-N methyl (2s,3r)-2-ethoxy-3-(2-fluoro-4-phenylmethoxyphenyl)-3-hydroxypropanoate Chemical compound C1=C(F)C([C@@H](O)[C@H](OCC)C(=O)OC)=CC=C1OCC1=CC=CC=C1 PJQUFHBXHMZCDH-MSOLQXFVSA-N 0.000 description 2
YDIVROVFFHTBIJ-MOPGFXCFSA-N methyl (2s,3r)-2-ethoxy-3-hydroxy-3-(2-methoxy-4-phenylmethoxyphenyl)propanoate Chemical compound C1=C(OC)C([C@@H](O)[C@H](OCC)C(=O)OC)=CC=C1OCC1=CC=CC=C1 YDIVROVFFHTBIJ-MOPGFXCFSA-N 0.000 description 2
JFFKMVOMSULECI-UXHICEINSA-N methyl (2s,3r)-3-(2,6-dimethyl-4-phenylmethoxyphenyl)-2-ethoxy-3-hydroxypropanoate Chemical compound C1=C(C)C([C@@H](O)[C@H](OCC)C(=O)OC)=C(C)C=C1OCC1=CC=CC=C1 JFFKMVOMSULECI-UXHICEINSA-N 0.000 description 2
CKECHJMAUZBBMK-MSOLQXFVSA-N methyl (2s,3r)-3-(2-chloro-4-phenylmethoxyphenyl)-2-ethoxy-3-hydroxypropanoate Chemical compound C1=C(Cl)C([C@@H](O)[C@H](OCC)C(=O)OC)=CC=C1OCC1=CC=CC=C1 CKECHJMAUZBBMK-MSOLQXFVSA-N 0.000 description 2
XNZMFRZTYQHFQS-UHFFFAOYSA-N methyl 2-[2-(4-propan-2-ylphenyl)-1,3-thiazol-4-yl]acetate Chemical compound COC(=O)CC1=CSC(C=2C=CC(=CC=2)C(C)C)=N1 XNZMFRZTYQHFQS-UHFFFAOYSA-N 0.000 description 2
UVPZRRHRZVFVDM-UHFFFAOYSA-N methyl 2-[[4-[cyclopropyl-[4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]methoxy]-2-methylphenyl]methyl]heptanoate Chemical compound C1=C(C)C(CC(CCCCC)C(=O)OC)=CC=C1OC(C1=C(N=C(S1)C=1C=CC(=CC=1)C(F)(F)F)C)C1CC1 UVPZRRHRZVFVDM-UHFFFAOYSA-N 0.000 description 2
FCYNWFZAMZKGGQ-UHFFFAOYSA-N methyl 2-[hydroxy-(2-methyl-4-phenylmethoxyphenyl)methyl]heptanoate Chemical compound C1=C(C)C(C(O)C(CCCCC)C(=O)OC)=CC=C1OCC1=CC=CC=C1 FCYNWFZAMZKGGQ-UHFFFAOYSA-N 0.000 description 2
OAAXEFKNVAPDMS-UHFFFAOYSA-N methyl 2-butoxy-3-[2-methyl-4-[[4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]methoxy]phenyl]propanoate Chemical compound C1=C(C)C(CC(OCCCC)C(=O)OC)=CC=C1OCC1=C(C)N=C(C=2C=CC(=CC=2)C(F)(F)F)S1 OAAXEFKNVAPDMS-UHFFFAOYSA-N 0.000 description 2
DDHALSCREICJDL-UHFFFAOYSA-N methyl 2-butoxy-3-hydroxy-3-(2-methyl-4-phenylmethoxyphenyl)propanoate Chemical compound C1=C(C)C(C(O)C(OCCCC)C(=O)OC)=CC=C1OCC1=CC=CC=C1 DDHALSCREICJDL-UHFFFAOYSA-N 0.000 description 2
KFFMOQYWYSAVTB-UHFFFAOYSA-N methyl 2-ethoxy-3-(4-hydroxy-1-benzothiophen-7-yl)propanoate Chemical compound CCOC(C(=O)OC)CC1=CC=C(O)C2=C1SC=C2 KFFMOQYWYSAVTB-UHFFFAOYSA-N 0.000 description 2
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238000002821 scintillation proximity assay Methods 0.000 description 2
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FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
230000001225 therapeutic effect Effects 0.000 description 2
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XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 2
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235000015112 vegetable and seed oil Nutrition 0.000 description 2
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VCGRFBXVSFAGGA-UHFFFAOYSA-N (1,1-dioxo-1,4-thiazinan-4-yl)-[6-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone Chemical compound CC=1ON=C(C=2C=CC(F)=CC=2)C=1COC(N=C1)=CC=C1C(=O)N1CCS(=O)(=O)CC1 VCGRFBXVSFAGGA-UHFFFAOYSA-N 0.000 description 1
FCRDIJHLAPKHSP-UHFFFAOYSA-M (1,2-dimethoxy-2-oxoethyl)-triphenylphosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C(C(=O)OC)OC)C1=CC=CC=C1 FCRDIJHLAPKHSP-UHFFFAOYSA-M 0.000 description 1
JZIAUYGVDIMTTR-NRFANRHFSA-N (2s)-2-ethoxy-3-[2-ethyl-4-[[4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]methoxy]phenyl]propanoic acid Chemical compound C1=C(CC)C(C[C@H](OCC)C(O)=O)=CC=C1OCC1=C(C)N=C(C=2C=CC(=CC=2)C(F)(F)F)S1 JZIAUYGVDIMTTR-NRFANRHFSA-N 0.000 description 1
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Classifications

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- C07D417/06—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 linked by a carbon chain containing only aliphatic carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/24—Radicals substituted by oxygen atoms
- 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
- C07D417/12—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 linked by a chain containing hetero atoms as chain links

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Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
General Health & Medical Sciences (AREA)
Pharmacology & Pharmacy (AREA)
Engineering & Computer Science (AREA)
Veterinary Medicine (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Bioinformatics & Cheminformatics (AREA)
Public Health (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
Diabetes (AREA)
Hematology (AREA)
Endocrinology (AREA)
Cardiology (AREA)
Heart & Thoracic Surgery (AREA)
Obesity (AREA)
Urology & Nephrology (AREA)
Reproductive Health (AREA)
Neurosurgery (AREA)
Neurology (AREA)
Biomedical Technology (AREA)
Gynecology & Obstetrics (AREA)
Pregnancy & Childbirth (AREA)
Emergency Medicine (AREA)
Rheumatology (AREA)
Psychiatry (AREA)
Dermatology (AREA)
Hospice & Palliative Care (AREA)
Pain & Pain Management (AREA)
Vascular Medicine (AREA)
Gastroenterology & Hepatology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Thiazole And Isothizaole Compounds (AREA)
Plural Heterocyclic Compounds (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

NO20050620A 2002-08-30 2005-02-03 2-aryltiazol-forbindelser, fremgangsmate for fremstilling av slike, farmasoytiske preparater inneholdende slike, slike forbindelser som terapeutisk aktive substanser samt anvendelse av slike for behandling av sykdom NO329777B1 (no)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
EP02019146		2002-08-30
PCT/EP2003/009281 WO2004020420A1 (en)	2002-08-30	2003-08-21	Novel 2-arylthiazole compounds as pparalpha and ppargama agonists

Publications (2)

Publication Number	Publication Date
NO20050620L NO20050620L (no)	2005-03-03
NO329777B1 true NO329777B1 (no)	2010-12-13

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NO20050620A NO329777B1 (no)	2002-08-30	2005-02-03	2-aryltiazol-forbindelser, fremgangsmate for fremstilling av slike, farmasoytiske preparater inneholdende slike, slike forbindelser som terapeutisk aktive substanser samt anvendelse av slike for behandling av sykdom

Country Status (30)

Country	Link
US (1)	US6809110B2 (zh)
EP (1)	EP1537091B1 (zh)
JP (2)	JP4533141B2 (zh)
KR (1)	KR100736955B1 (zh)
CN (1)	CN100475810C (zh)
AR (1)	AR041079A1 (zh)
AT (1)	ATE483699T1 (zh)
BR (1)	BR0313946A (zh)
CA (1)	CA2495942C (zh)
DE (1)	DE60334461D1 (zh)
DK (1)	DK1537091T3 (zh)
ES (1)	ES2350340T3 (zh)
GT (1)	GT200300183A (zh)
HK (1)	HK1082504A1 (zh)
HR (1)	HRP20050158A2 (zh)
IL (1)	IL166833A (zh)
MX (1)	MXPA05002115A (zh)
MY (1)	MY141020A (zh)
NO (1)	NO329777B1 (zh)
NZ (1)	NZ537897A (zh)
PA (1)	PA8581201A1 (zh)
PE (1)	PE20040982A1 (zh)
PL (1)	PL375779A1 (zh)
PT (1)	PT1537091E (zh)
RU (1)	RU2296754C2 (zh)
SI (1)	SI1537091T1 (zh)
TW (1)	TWI338686B (zh)
UY (1)	UY27959A1 (zh)
WO (1)	WO2004020420A1 (zh)
ZA (1)	ZA200501097B (zh)

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JP2009084156A (ja) *	2006-01-18	2009-04-23	Nissan Chem Ind Ltd	チアゾール置換アセトニトリルの製造方法
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KR20080082541A (ko) *	2007-03-07	2008-09-11	동아제약주식회사	퍼옥시좀 증식자-활성화 감마 수용체를 조절하는 신규한페닐프로판산 유도체의 제조방법 및 약학적 용도
DE102007038251A1 (de) *	2007-08-13	2009-02-19	Boehringer Ingelheim Pharma Gmbh & Co. Kg	Neues Herstellverfahren
CN101928259B (zh) *	2009-06-18	2012-10-03	南京海辰药业有限公司	2-芳基噻唑衍生物及其药物组合物
CN102285933B (zh) *	2010-06-18	2016-03-09	浙江海正药业股份有限公司	一种对亚型过氧化物酶增殖物激活受体具有激动作用的化合物、其制备方法和应用
CN102351852B (zh) *	2011-08-23	2014-06-18	上海交通大学	苯并呋喃类化合物及其制备方法、用途
EP2758041B1 (de)	2011-09-20	2021-01-13	Basf Se	Niedermolekulare modulatoren des kälte-menthol-rezeptors trpm8 und deren verwendung
EP3478297A1 (en)	2016-06-30	2019-05-08	INSERM (Institut National de la Santé et de la Recherche Médicale)	Methods and pharmaceutical compositions for the treatment of cardiomyopathies
CA3054452A1 (en) *	2017-03-14	2018-09-20	Dana-Farber Cancer Institute, Inc.	Small molecule sensitization of bax activation for induction of cell death
WO2020201263A1 (en)	2019-04-01	2020-10-08	INSERM (Institut National de la Santé et de la Recherche Médicale)	Methods and pharmaceutical compositions for the treatment and prevention of cardiac remodeling
CN115894379A (zh) *	2022-01-20	2023-04-04	中国药科大学	海因类化合物及其医药用途

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IL158589A0 (en) *	2001-05-15	2004-05-12	Hoffmann La Roche	Carboxylic acid substituted oxazole derivatives for use as ppar-alpha and -gamma activators in the treatment of diabetes
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WO2004020420A1 (en) *	2002-08-30	2004-03-11	F.Hoffmann-La Roche Ag	Novel 2-arylthiazole compounds as pparalpha and ppargama agonists

2003
- 2003-08-21 WO PCT/EP2003/009281 patent/WO2004020420A1/en active IP Right Grant
- 2003-08-21 SI SI200331904T patent/SI1537091T1/sl unknown
- 2003-08-21 NZ NZ537897A patent/NZ537897A/en not_active IP Right Cessation
- 2003-08-21 KR KR1020057003571A patent/KR100736955B1/ko not_active IP Right Cessation
- 2003-08-21 CA CA2495942A patent/CA2495942C/en not_active Expired - Fee Related
- 2003-08-21 MX MXPA05002115A patent/MXPA05002115A/es active IP Right Grant
- 2003-08-21 PL PL03375779A patent/PL375779A1/xx not_active Application Discontinuation
- 2003-08-21 JP JP2004532104A patent/JP4533141B2/ja not_active Expired - Fee Related
- 2003-08-21 AT AT03757762T patent/ATE483699T1/de active
- 2003-08-21 DK DK03757762.4T patent/DK1537091T3/da active
- 2003-08-21 RU RU2005109163/04A patent/RU2296754C2/ru not_active IP Right Cessation
- 2003-08-21 EP EP03757762A patent/EP1537091B1/en not_active Expired - Lifetime
- 2003-08-21 DE DE60334461T patent/DE60334461D1/de not_active Expired - Lifetime
- 2003-08-21 BR BR0313946-8A patent/BR0313946A/pt not_active IP Right Cessation
- 2003-08-21 CN CNB038205432A patent/CN100475810C/zh not_active Expired - Fee Related
- 2003-08-21 PT PT03757762T patent/PT1537091E/pt unknown
- 2003-08-21 ES ES03757762T patent/ES2350340T3/es not_active Expired - Lifetime
- 2003-08-26 PA PA20038581201A patent/PA8581201A1/es unknown
- 2003-08-26 TW TW092123445A patent/TWI338686B/zh not_active IP Right Cessation
- 2003-08-26 PE PE2003000873A patent/PE20040982A1/es not_active Application Discontinuation
- 2003-08-27 UY UY27959A patent/UY27959A1/es not_active Application Discontinuation
- 2003-08-27 GT GT200300183A patent/GT200300183A/es unknown
- 2003-08-28 MY MYPI20033266A patent/MY141020A/en unknown
- 2003-08-28 AR ARP030103120A patent/AR041079A1/es active IP Right Grant
- 2003-08-28 US US10/650,434 patent/US6809110B2/en not_active Expired - Fee Related
2005
- 2005-02-03 NO NO20050620A patent/NO329777B1/no not_active IP Right Cessation
- 2005-02-07 ZA ZA200501097A patent/ZA200501097B/en unknown
- 2005-02-10 IL IL166833A patent/IL166833A/en not_active IP Right Cessation
- 2005-02-18 HR HR20050158A patent/HRP20050158A2/xx not_active Application Discontinuation
2006
- 2006-04-03 HK HK06104073.6A patent/HK1082504A1/xx not_active IP Right Cessation
2010
- 2010-01-14 JP JP2010006072A patent/JP2010132671A/ja active Pending

Also Published As

Publication number	Publication date
KR20050057083A (ko)	2005-06-16
HK1082504A1 (en)	2006-06-09
DE60334461D1 (de)	2010-11-18
MY141020A (en)	2010-02-25
PE20040982A1 (es)	2004-12-30
TWI338686B (en)	2011-03-11
NZ537897A (en)	2007-08-31
MXPA05002115A (es)	2005-05-23
BR0313946A (pt)	2005-07-12
ES2350340T3 (es)	2011-01-21
CN100475810C (zh)	2009-04-08
WO2004020420A1 (en)	2004-03-11
GT200300183A (es)	2004-04-15
CN1678596A (zh)	2005-10-05
PA8581201A1 (es)	2004-09-16
AR041079A1 (es)	2005-04-27
AU2003273801A1 (en)	2004-03-19
JP2010132671A (ja)	2010-06-17
US20040110807A1 (en)	2004-06-10
TW200407133A (en)	2004-05-16
PT1537091E (pt)	2010-11-11
SI1537091T1 (sl)	2010-12-31
KR100736955B1 (ko)	2007-07-09
DK1537091T3 (da)	2010-11-08
JP4533141B2 (ja)	2010-09-01
HRP20050158A2 (en)	2006-11-30
JP2006502151A (ja)	2006-01-19
US6809110B2 (en)	2004-10-26
CA2495942C (en)	2010-03-23
IL166833A (en)	2010-12-30
RU2005109163A (ru)	2006-01-20
UY27959A1 (es)	2004-02-27
RU2296754C2 (ru)	2007-04-10
EP1537091B1 (en)	2010-10-06
EP1537091A1 (en)	2005-06-08
ZA200501097B (en)	2006-11-29
PL375779A1 (en)	2005-12-12
CA2495942A1 (en)	2004-03-11
NO20050620L (no)	2005-03-03
ATE483699T1 (de)	2010-10-15

Publication	Publication Date	Title
CA2503117C (en)	2010-12-21	Substituted 4-alkoxyoxazol derivatives as ppar agonists
JP2010132671A (ja)	2010-06-17	ＰＰＡＲα及びＰＰＡＲγアゴニストとしての新規２−アリールチアゾール化合物
KR100654516B1 (ko)	2006-12-05	당뇨병 치료에서 ｐｐａｒ-알파 및 -감마 활성제로서사용하기 위한 카복실산 치환된 옥사졸 유도체
CA2499721C (en)	2011-03-15	Chirale oxazole-arylpropionic acid derivatives and their use as ppar agonists
NZ537979A (en)	2007-08-31	N-substituted-1H-indol-5-propionic acid compounds as PPAR agonists useful for the treatment of diabetes
AU2003273801B2 (en)	2007-02-22	Novel 2-arylthiazole compounds as Pparalpha and Ppargama agonists
JP2006527175A (ja)	2006-11-30	アニリン誘導体

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