JP2017052800A - 置換フェニルアゾール誘導体 - Google Patents
置換フェニルアゾール誘導体 Download PDFInfo
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- JP2017052800A JP2017052800A JP2016247095A JP2016247095A JP2017052800A JP 2017052800 A JP2017052800 A JP 2017052800A JP 2016247095 A JP2016247095 A JP 2016247095A JP 2016247095 A JP2016247095 A JP 2016247095A JP 2017052800 A JP2017052800 A JP 2017052800A
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- IRTLROCMFSDSNF-UHFFFAOYSA-N 2-phenyl-1h-pyrrole Chemical class C1=CNC(C=2C=CC=CC=2)=C1 IRTLROCMFSDSNF-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 328
- 150000003839 salts Chemical class 0.000 claims abstract description 49
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 22
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 8
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims abstract description 7
- -1 5- {1- [4- (cyclopropylcarbonyl) phenoxy] ethyl} -1,3-thiazol-2-yl Chemical group 0.000 claims description 34
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 20
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 15
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 claims description 12
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 125000006255 cyclopropyl carbonyl group Chemical group [H]C1([H])C([H])([H])C1([H])C(*)=O 0.000 claims description 8
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 6
- 210000000496 pancreas Anatomy 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 5
- PSXSWYQVGRWDFF-UHFFFAOYSA-N 1-[4-[4-[1-[6-(cyclopropanecarbonyl)pyridin-3-yl]oxyethyl]-1,3-oxazol-2-yl]-2-fluorophenyl]-3-(2-hydroxyethyl)urea Chemical compound C=1OC(C=2C=C(F)C(NC(=O)NCCO)=CC=2)=NC=1C(C)OC(C=N1)=CC=C1C(=O)C1CC1 PSXSWYQVGRWDFF-UHFFFAOYSA-N 0.000 claims description 3
- AHROIPMLVNJYFH-UHFFFAOYSA-N 1-[4-[5-[1-[6-(cyclopropanecarbonyl)pyridin-3-yl]oxyethyl]-1,2,4-oxadiazol-3-yl]-2-fluorophenyl]-3-(2-hydroxyethyl)urea Chemical compound N=1C(C=2C=C(F)C(NC(=O)NCCO)=CC=2)=NOC=1C(C)OC(C=N1)=CC=C1C(=O)C1CC1 AHROIPMLVNJYFH-UHFFFAOYSA-N 0.000 claims description 3
- WOIOHDMQVPWGCC-UHFFFAOYSA-N 4-[4-[1-[6-(cyclopropanecarbonyl)pyridin-3-yl]oxyethyl]-1,3-oxazol-2-yl]-n-cyclopropyl-2-fluorobenzamide Chemical compound C=1OC(C=2C=C(F)C(C(=O)NC3CC3)=CC=2)=NC=1C(C)OC(C=N1)=CC=C1C(=O)C1CC1 WOIOHDMQVPWGCC-UHFFFAOYSA-N 0.000 claims description 3
- 208000008589 Obesity Diseases 0.000 claims description 3
- 235000020824 obesity Nutrition 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims 1
- 239000004202 carbamide Substances 0.000 claims 1
- 230000002218 hypoglycaemic effect Effects 0.000 abstract description 6
- 201000001421 hyperglycemia Diseases 0.000 abstract description 3
- 230000000069 prophylactic effect Effects 0.000 abstract description 3
- 230000001225 therapeutic effect Effects 0.000 abstract description 3
- 230000002159 abnormal effect Effects 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract description 2
- 230000004153 glucose metabolism Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 546
- 239000000243 solution Substances 0.000 description 291
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 273
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 212
- 239000000203 mixture Substances 0.000 description 208
- 239000002904 solvent Substances 0.000 description 160
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 134
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 123
- 238000005160 1H NMR spectroscopy Methods 0.000 description 115
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 108
- 238000010898 silica gel chromatography Methods 0.000 description 103
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 93
- 239000012044 organic layer Substances 0.000 description 91
- 238000003756 stirring Methods 0.000 description 80
- 239000011541 reaction mixture Substances 0.000 description 71
- 238000006243 chemical reaction Methods 0.000 description 70
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 68
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 67
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 66
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 58
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 57
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 50
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 49
- 238000001914 filtration Methods 0.000 description 42
- 229920006395 saturated elastomer Polymers 0.000 description 42
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 40
- 235000017557 sodium bicarbonate Nutrition 0.000 description 34
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 34
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 32
- 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 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 21
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 238000001816 cooling Methods 0.000 description 21
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 20
- 239000008280 blood Substances 0.000 description 18
- 210000004369 blood Anatomy 0.000 description 18
- 239000010410 layer Substances 0.000 description 17
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- 239000000725 suspension Substances 0.000 description 16
- 238000012360 testing method Methods 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 15
- 238000000926 separation method Methods 0.000 description 15
- QKSQWQOAUQFORH-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonylimino]carbamate Chemical compound CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C QKSQWQOAUQFORH-UHFFFAOYSA-N 0.000 description 15
- 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 description 14
- 238000000605 extraction Methods 0.000 description 14
- 239000008103 glucose Substances 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 10
- 235000019270 ammonium chloride Nutrition 0.000 description 10
- GVBHKNVCIKUPCZ-UHFFFAOYSA-N cyclopropyl-(4-hydroxyphenyl)methanone Chemical compound C1=CC(O)=CC=C1C(=O)C1CC1 GVBHKNVCIKUPCZ-UHFFFAOYSA-N 0.000 description 10
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 10
- 239000012267 brine Substances 0.000 description 9
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 9
- 239000007788 liquid Substances 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 230000003287 optical effect Effects 0.000 description 7
- 230000001681 protective effect Effects 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 239000012279 sodium borohydride Substances 0.000 description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 6
- BKMMTJMQCTUHRP-GSVOUGTGSA-N (2r)-2-aminopropan-1-ol Chemical compound C[C@@H](N)CO BKMMTJMQCTUHRP-GSVOUGTGSA-N 0.000 description 5
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 5
- QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Natural products COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 5
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 5
- 206010012601 diabetes mellitus Diseases 0.000 description 5
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 5
- YCCXQARVHOPWFJ-UHFFFAOYSA-M magnesium;ethane;chloride Chemical compound [Mg+2].[Cl-].[CH2-]C YCCXQARVHOPWFJ-UHFFFAOYSA-M 0.000 description 5
- 229940095102 methyl benzoate Drugs 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- 229940124597 therapeutic agent Drugs 0.000 description 5
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 4
- 239000004367 Lipase Substances 0.000 description 4
- 102000004882 Lipase Human genes 0.000 description 4
- 108090001060 Lipase Proteins 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 description 4
- MOTRZVVGCFFABN-UHFFFAOYSA-N hexane;2-propan-2-yloxypropane Chemical compound CCCCCC.CC(C)OC(C)C MOTRZVVGCFFABN-UHFFFAOYSA-N 0.000 description 4
- 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 4
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- 239000003755 preservative agent Substances 0.000 description 4
- 229940002612 prodrug Drugs 0.000 description 4
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- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- 210000003462 vein Anatomy 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 239000004925 Acrylic resin Substances 0.000 description 3
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- 208000002249 Diabetes Complications Diseases 0.000 description 3
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- 208000002705 Glucose Intolerance Diseases 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
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- 239000003795 chemical substances by application Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 3
- JMQGGPRJQOQKRT-UHFFFAOYSA-N diphenyl hydrogen phosphate;azide Chemical compound [N-]=[N+]=[N-].C=1C=CC=CC=1OP(=O)(O)OC1=CC=CC=C1 JMQGGPRJQOQKRT-UHFFFAOYSA-N 0.000 description 3
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- XIMFCGSNSKXPBO-UHFFFAOYSA-N ethyl 2-bromobutanoate Chemical compound CCOC(=O)C(Br)CC XIMFCGSNSKXPBO-UHFFFAOYSA-N 0.000 description 3
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
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- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 3
- 229920000609 methyl cellulose Polymers 0.000 description 3
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- DBNQIOANXZVWIP-UHFFFAOYSA-N n,n-dimethyl-1,1-bis[(2-methylpropan-2-yl)oxy]methanamine Chemical compound CC(C)(C)OC(N(C)C)OC(C)(C)C DBNQIOANXZVWIP-UHFFFAOYSA-N 0.000 description 3
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- 239000001632 sodium acetate Substances 0.000 description 3
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- BRHRGJUGWLPAQN-UHFFFAOYSA-N 1-[4-[3-[1-[6-(cyclopropanecarbonyl)pyridin-3-yl]oxyethyl]-1,2,4-oxadiazol-5-yl]-2-fluorophenyl]-3-(2-hydroxyethyl)urea Chemical compound N=1OC(C=2C=C(F)C(NC(=O)NCCO)=CC=2)=NC=1C(C)OC(C=N1)=CC=C1C(=O)C1CC1 BRHRGJUGWLPAQN-UHFFFAOYSA-N 0.000 description 2
- XEAGYBCOIAPRMG-CYBMUJFWSA-N 1-[4-[4-[(1r)-1-[6-(cyclopropanecarbonyl)pyridin-3-yl]oxyethyl]triazol-2-yl]-2-fluorophenyl]-3-(2-hydroxyethyl)urea Chemical compound O([C@H](C)C1=NN(N=C1)C=1C=C(F)C(NC(=O)NCCO)=CC=1)C(C=N1)=CC=C1C(=O)C1CC1 XEAGYBCOIAPRMG-CYBMUJFWSA-N 0.000 description 2
- CEZQXLQNJWSMTA-UHFFFAOYSA-N 1-[4-[4-[1-[4-(cyclopropanecarbonyl)phenoxy]propyl]triazol-2-yl]-2-fluorophenyl]-3-(2-hydroxyethyl)urea Chemical compound C1=NN(C=2C=C(F)C(NC(=O)NCCO)=CC=2)N=C1C(CC)OC(C=C1)=CC=C1C(=O)C1CC1 CEZQXLQNJWSMTA-UHFFFAOYSA-N 0.000 description 2
- 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 2
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- 230000004140 ketosis Effects 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 208000006443 lactic acidosis Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229940050906 magnesium chloride hexahydrate Drugs 0.000 description 1
- DHRRIBDTHFBPNG-UHFFFAOYSA-L magnesium dichloride hexahydrate Chemical compound O.O.O.O.O.O.[Mg+2].[Cl-].[Cl-] DHRRIBDTHFBPNG-UHFFFAOYSA-L 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- ZQDWYQDJDCIFKC-UHFFFAOYSA-N methanesulfonic acid;phosphoric acid Chemical compound CS(O)(=O)=O.OP(O)(O)=O ZQDWYQDJDCIFKC-UHFFFAOYSA-N 0.000 description 1
- ZPQRSJXZZPUAGY-VIFPVBQESA-N methyl (2S)-2-[(4-bromo-3-fluorobenzoyl)amino]-3-hydroxypropanoate Chemical compound COC(=O)[C@H](CO)NC(=O)c1ccc(Br)c(F)c1 ZPQRSJXZZPUAGY-VIFPVBQESA-N 0.000 description 1
- NDBQJIBNNUJNHA-DFWYDOINSA-N methyl (2s)-2-amino-3-hydroxypropanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CO NDBQJIBNNUJNHA-DFWYDOINSA-N 0.000 description 1
- UUMDEUHVQVJJFY-VIFPVBQESA-N methyl (4S)-2-(4-bromo-3-fluorophenyl)-4,5-dihydro-1,3-oxazole-4-carboxylate Chemical compound COC(=O)[C@@H]1COC(=N1)c1ccc(Br)c(F)c1 UUMDEUHVQVJJFY-VIFPVBQESA-N 0.000 description 1
- UEFHSHRIGSQCNH-UHFFFAOYSA-N methyl 2-(4-bromo-3-fluorophenyl)-1,3-oxazole-4-carboxylate Chemical compound COC(=O)c1coc(n1)-c1ccc(Br)c(F)c1 UEFHSHRIGSQCNH-UHFFFAOYSA-N 0.000 description 1
- ODFFWCFOFJZKJM-UHFFFAOYSA-N methyl 2-fluoro-4-(5-formyl-1,3-thiazol-2-yl)benzoate Chemical compound COC(=O)c1ccc(cc1F)-c1ncc(C=O)s1 ODFFWCFOFJZKJM-UHFFFAOYSA-N 0.000 description 1
- DKIWSNFQMGZNRH-UHFFFAOYSA-N methyl 2-fluoro-4-[5-(1-hydroxyethyl)-1,3-thiazol-2-yl]benzoate Chemical compound COC(=O)c1ccc(cc1F)-c1ncc(s1)C(C)O DKIWSNFQMGZNRH-UHFFFAOYSA-N 0.000 description 1
- QAFJIJWLEBLXHH-UHFFFAOYSA-N methyl 2-fluorobenzoate Chemical compound COC(=O)C1=CC=CC=C1F QAFJIJWLEBLXHH-UHFFFAOYSA-N 0.000 description 1
- AJLBRTMWHRHDST-UHFFFAOYSA-N methyl 4-(5-acetyltetrazol-2-yl)-2-fluorobenzoate Chemical compound COC(=O)c1ccc(cc1F)-n1nnc(n1)C(C)=O AJLBRTMWHRHDST-UHFFFAOYSA-N 0.000 description 1
- JOCBRFUPNIFGKB-UHFFFAOYSA-N methyl 4-[4-[1-[4-(cyclopropanecarbonyl)phenoxy]ethyl]triazol-2-yl]-2-fluorobenzoate Chemical compound COC(=O)c1ccc(cc1F)-n1ncc(n1)C(C)Oc1ccc(cc1)C(=O)C1CC1 JOCBRFUPNIFGKB-UHFFFAOYSA-N 0.000 description 1
- LGNNNXQTHGEYBY-UHFFFAOYSA-N methyl 4-[4-[1-[4-(cyclopropanecarbonyl)phenoxy]propyl]triazol-2-yl]-2-fluorobenzoate Chemical compound CCC(Oc1ccc(cc1)C(=O)C1CC1)c1cnn(n1)-c1ccc(C(=O)OC)c(F)c1 LGNNNXQTHGEYBY-UHFFFAOYSA-N 0.000 description 1
- RMFOGONFLMMXKJ-UHFFFAOYSA-N methyl 4-[5-[1-[4-(cyclopropanecarbonyl)phenoxy]ethyl]-1,3-thiazol-2-yl]-2-fluorobenzoate Chemical compound COC(=O)c1ccc(cc1F)-c1ncc(s1)C(C)Oc1ccc(cc1)C(=O)C1CC1 RMFOGONFLMMXKJ-UHFFFAOYSA-N 0.000 description 1
- AXBMAEDSXAKFHG-UHFFFAOYSA-N methyl 4-[5-[1-[4-(cyclopropanecarbonyl)phenoxy]propyl]tetrazol-2-yl]-2-fluorobenzoate Chemical compound CCC(Oc1ccc(cc1)C(=O)C1CC1)c1nnn(n1)-c1ccc(C(=O)OC)c(F)c1 AXBMAEDSXAKFHG-UHFFFAOYSA-N 0.000 description 1
- XJUIVNZQDWDZHB-UHFFFAOYSA-N methyl 4-[5-[1-[6-(cyclopropanecarbonyl)pyridin-3-yl]oxyethyl]-1,3-thiazol-2-yl]-2-fluorobenzoate Chemical compound COC(=O)c1ccc(cc1F)-c1ncc(s1)C(C)Oc1ccc(nc1)C(=O)C1CC1 XJUIVNZQDWDZHB-UHFFFAOYSA-N 0.000 description 1
- HPFKRCXRTJXFEK-UHFFFAOYSA-N methyl 4-[5-[1-[6-(cyclopropanecarbonyl)pyridin-3-yl]oxyethyl]tetrazol-2-yl]-2-fluorobenzoate Chemical compound COC(=O)c1ccc(cc1F)-n1nnc(n1)C(C)Oc1ccc(nc1)C(=O)C1CC1 HPFKRCXRTJXFEK-UHFFFAOYSA-N 0.000 description 1
- ZDCJFYFJXQCBSO-UHFFFAOYSA-N methyl 4-carbamothioyl-2-fluorobenzoate Chemical compound COC(=O)c1ccc(cc1F)C(N)=S ZDCJFYFJXQCBSO-UHFFFAOYSA-N 0.000 description 1
- BTSFXVSAECXZNJ-UHFFFAOYSA-N methyl 4-cyano-2-fluorobenzoate Chemical compound COC(=O)C1=CC=C(C#N)C=C1F BTSFXVSAECXZNJ-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000001333 moisturizer Effects 0.000 description 1
- 150000002780 morpholines Chemical class 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 239000006218 nasal suppository Substances 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000008203 oral pharmaceutical composition Substances 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical class CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 1
- 229960002218 sodium chlorite Drugs 0.000 description 1
- 229940074545 sodium dihydrogen phosphate dihydrate Drugs 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- WRVHPSSSTBDGRK-UHFFFAOYSA-N sodium;sulfane;hydrate Chemical compound O.[Na].S WRVHPSSSTBDGRK-UHFFFAOYSA-N 0.000 description 1
- 231100000240 steatosis hepatitis Toxicity 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- ZQEYQVPTKJFWMG-IBGZPJMESA-N tert-butyl 2-fluoro-4-[3-[(1S)-1-(4-methoxyphenoxy)propyl]-1,2,4-oxadiazol-5-yl]benzoate Chemical compound CC[C@H](Oc1ccc(OC)cc1)c1noc(n1)-c1ccc(C(=O)OC(C)(C)C)c(F)c1 ZQEYQVPTKJFWMG-IBGZPJMESA-N 0.000 description 1
- WIMVPGUMINTSFZ-LBPRGKRZSA-N tert-butyl 2-fluoro-4-[3-[(1S)-1-hydroxypropyl]-1,2,4-oxadiazol-5-yl]benzoate Chemical compound CC[C@H](O)c1noc(n1)-c1ccc(C(=O)OC(C)(C)C)c(F)c1 WIMVPGUMINTSFZ-LBPRGKRZSA-N 0.000 description 1
- VGELYYNHYILSDI-QMMMGPOBSA-N tert-butyl 2-fluoro-4-[5-[(1s)-1-hydroxyethyl]-1,2,4-oxadiazol-3-yl]benzoate Chemical compound O1C([C@@H](O)C)=NC(C=2C=C(F)C(C(=O)OC(C)(C)C)=CC=2)=N1 VGELYYNHYILSDI-QMMMGPOBSA-N 0.000 description 1
- WCGRFEGFFTVGMF-LBPRGKRZSA-N tert-butyl 2-fluoro-4-[5-[(1s)-1-hydroxypropyl]-1,2,4-oxadiazol-3-yl]benzoate Chemical compound O1C([C@@H](O)CC)=NC(C=2C=C(F)C(C(=O)OC(C)(C)C)=CC=2)=N1 WCGRFEGFFTVGMF-LBPRGKRZSA-N 0.000 description 1
- GZGKPLAINCFIGO-UHFFFAOYSA-N tert-butyl 2-fluoro-4-formylbenzoate Chemical compound CC(C)(C)OC(=O)C1=CC=C(C=O)C=C1F GZGKPLAINCFIGO-UHFFFAOYSA-N 0.000 description 1
- IENMNYGOVBTOTB-UHFFFAOYSA-N tert-butyl 4-[3-[1-[4-(cyclopropanecarbonyl)phenoxy]propyl]-1,2,4-oxadiazol-5-yl]-2-fluorobenzoate Chemical compound CCC(Oc1ccc(cc1)C(=O)C1CC1)c1noc(n1)-c1ccc(C(=O)OC(C)(C)C)c(F)c1 IENMNYGOVBTOTB-UHFFFAOYSA-N 0.000 description 1
- KJKZVXHBEHKQJC-AWEZNQCLSA-N tert-butyl 4-[5-[(1s)-1-acetyloxypropyl]-1,2,4-oxadiazol-3-yl]-2-fluorobenzoate Chemical compound O1C([C@@H](OC(C)=O)CC)=NC(C=2C=C(F)C(C(=O)OC(C)(C)C)=CC=2)=N1 KJKZVXHBEHKQJC-AWEZNQCLSA-N 0.000 description 1
- LXGZCNLIPFDAAM-UHFFFAOYSA-N tert-butyl 4-amino-2-fluoro-3-(hydroxyiminomethyl)benzoate Chemical compound NC1=C(C(=C(C(=O)OC(C)(C)C)C=C1)F)C=NO LXGZCNLIPFDAAM-UHFFFAOYSA-N 0.000 description 1
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 1
- 239000012414 tert-butyl nitrite Substances 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical class C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- 239000002562 thickening agent Substances 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
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 238000013293 zucker diabetic fatty rat Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
- C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole 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
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
-
- 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
-
- 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
- C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
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Abstract
Description
(1)一般式(I):
(2)環Aが、
(3)環Aが
(4)環Aが、
(5)環Aが、
(6)環Aが、
(7)一般式(II):
(8)一般式(III):
(9)以下:
1-[4-(4-{1-[4-(シクロプロピルカルボニル)フェノキシ]プロピル}-2H-1,2,3-トリアゾール-2-イル)-2-フルオロフェニル]-3-(2-ヒドロキシエチル)ウレア;
4-{4-[(1R)-1-{[6-(シクロプロピルカルボニル)ピリジン-3-イル]オキシ}エチル]-2H-1,2,3-トリアゾール-2-イル}-N-[(1R,2R)-2,3-ジヒドロキシ-1-メチルプロピル]-2-フルオロベンズアミド;
1-(4-{4-[(1R)-1-{[6-(シクロプロピルカルボニル)ピリジン-3-イル]オキシ}エチル]-2H-1,2,3-トリアゾール-2-イル}-2-フルオロフェニル)-3-(2-ヒドロキシエチル)ウレア;
4-(5-{1-[4-(シクロプロピルカルボニル)フェノキシ]プロピル}-2H-テトラゾール-2-イル)-2-フルオロ-N-[(1R)-2-ヒドロキシ-1-メチルエチル]ベンズアミド;
4-(5-{1-[4-(シクロプロピルカルボニル)フェノキシ]エチル}-1,3-チアゾール-2-イル)-2-フルオロ-N-[(1R)-2-ヒドロキシ-1-メチルエチル]ベンズアミド;
4-[4-(1-{[6-(シクロプロピルカルボニル)ピリジン-3-イル]オキシ}エチル)-1,3-オキサゾール-2-イル]-2-フルオロ-N-[(1R)-2-ヒドロキシ-1-メチルエチル]ベンズアミド;
N-シクロプロピル-4-[4-(1-{[6-(シクロプロピルカルボニル)ピリジン-3-イル]オキシ}エチル)-1,3-オキサゾール-2-イル]-2-フルオロベンズアミド;
1-{4-[4-(1-{[6-(シクロプロピルカルボニル)ピリジン-3-イル]オキシ}エチル)-1,3-オキサゾール-2-イル]-2-フルオロフェニル}-3-(2-ヒドロキシエチル)ウレア;
4-{5-[(1R)-1-{[6-(シクロプロピルカルボニル)ピリジン-3-イル]オキシ}エチル]-1,2,4-オキサジアゾール-3-イル}-2-フルオロ-N-[(1R)-2-ヒドロキシ-1-メチルエチル]ベンズアミド;
1-{4-[5-(1-{[6-(シクロプロピルカルボニル)ピリジン-3-イル]オキシ}エチル)-1,2,4-オキサジアゾール-3-イル]-2-フルオロフェニル}-3-(2-ヒドロキシエチル)ウレア;
4-[3-(1-{[6-(シクロプロピルカルボニル)ピリジン-3-イル]オキシ}エチル)-1,2,4-オキサジアゾール-5-イル]-2-フルオロ-N-[2-ヒドロキシ-1-(ヒドロキシメチル)エチル]ベンズアミド;および
1-{4-[3-(1-{[6-(シクロプロピルカルボニル)ピリジン-3-イル]オキシ}エチル)-1,2,4-オキサジアゾール-5-イル]-2-フルオロフェニル}-3-(2-ヒドロキシエチル)ウレア
からなる群より選択される化合物またはその薬学的に許容され得る塩;
(10)前記(1)〜(9)いずれか1項に記載の化合物またはその薬学的に許容され得る塩を有効成分として含有する医薬組成物;
(11)1型糖尿病、2型糖尿病または肥満を治療するための、前記(10)に記載の医薬組成物;
(12)β細胞または膵臓を保護するための、前記(10)に記載の医薬組成物;
(13)医薬組成物を製造するための、前記(1)〜(9)いずれか1項に記載の化合物またはその薬学的に許容され得る塩の使用;
(14)前記(1)〜(9)いずれか1項に記載の化合物またはその薬学的に許容され得る塩を哺乳動物に投与することを含む、疾病を治療する方法;ならびに
(15)哺乳動物がヒトである前記(14)に記載の方法;
を提供する。
1H-NMR (400MHz, CDCl3) δppm:
8.27 (1H, s), 8.13-7.98 (3H, m), 4.49 (2H, q, J = 7 Hz), 3.97 (3H, s), 1.45 (3H, t, J = 7 Hz).
1H-NMR (400MHz, DMSO-d6) δppm:
13.80 (1H, m), 8.63 (1H, s), 8.16-7.92 (3H, m), 3.90 (3H, s).
1H-NMR (400MHz, CDCl3) δppm:
8.25 (1H, s), 8.13-7.95 (3H, m), 3.97 (3H, s), 3.85 (3H, s), 3.46 (3H, br s).
1H-NMR (400MHz, CDCl3) δppm:
8.27 (1H, s), 8.14-8.10 (1H, m), 8.02-7.95 (2H, m), 3.98 (3H, s), 3.16-3.11 (2H, m), 1.29-1.25 (3H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.09-8.05 (1H, m), 7.93-7.85 (2H, m), 7.81 (1H, s), 4.94-4.89 (1H, m), 3.96 (3H, s), 2.20-2.19 (1H, m), 2.01-1.88 (2H, m), 1.05-1.02 (3H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.10-8.06 (1H, m), 7.98-7.86 (4H, m), 7.76 (1H, s), 7.01-6.99 (2H, m), 5.52-5.49 (1H, m), 3.96 (3H, s), 2.62-2.56 (1H, m), 2.21-2.07 (2H, m), 1.20-1.17 (2H, m), 1.10-1.06 (3H, m), 1.00-0.97 (2H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.19-8.15 (1H, m), 7.99-7.89 (4H, m), 7.78 (1H, s), 7.03-6.99 (2H, m), 5.53-5.50 (1H, m), 2.63-2.56 (1H, m), 2.22-2.06 (2H, m), 1.21-1.17 (2H, m), 1.11-1.07 (3H, m), 1.01-0.96 (2H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.26 (1H, s), 8.15-8.11 (1H, m), 8.03-7.95 (2H, m), 3.98 (3H, s), 2.71 (3H, s).
1H-NMR (400MHz, CDCl3) δppm:
8.10-8.05 (1H, m), 7.93-7.86 (2H, m), 7.83 (1H, s), 5.19-5.12 (1H, m), 3.96 (3H, s), 1.65 (3H, d, J = 7 Hz).
1H-NMR (400MHz, CDCl3) δppm:
8.10-8.06 (1H, m), 7.99-7.97 (2H, m), 7.93-7.86 (2H, m), 7.80 (1H, s), 7.04-7.00 (2H, m), 5.77-5.73 (1H, m), 3.96 (3H, s), 2.63-2.57 (1H, m), 1.80 (3H, d, J = 7 Hz), 1.21-1.18 (2H, m), 1.01-0.96 (2H, m).
1H-NMR (400MHz, DMSO-d6) δppm:
8.32 (1H, s), 8.12-8.01 (3H, m), 7.94-7.85 (2H, m), 7.18-7.16 (2H, m), 6.02-5.97 (1H, m), 2.87-2.80 (1H, m), 1.75 (3H, d, J = 6 Hz), 0.98-0.96 (4H, m).
1H-NMR (400MHz, DMSO-d6) δppm:
13.54 (1H, br s), 8.67 (1H, s), 8.15-8.11 (1H, m), 8.04-7.97 (2H, m), 3.16-3.10 (2H, m), 1.15-1.12 (3H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.26 (1H, s), 8.06-8.02 (1H, m), 7.98-7.90 (2H, m), 3.14 (2H, q, J = 7 Hz), 1.62 (9H, s), 1.27 (3H, t, J = 7 Hz).
1H-NMR (400MHz, CDCl3) δppm:
8.00-7.96 (1H, m), 7.89-7.81 (3H, m), 7.80 (3H, s), 4.93-4.89 (1H, m), 2.21-2.20 (1H, m), 2.01-1.88 (2H, m), 1.61 (9H, s), 1.06-1.02 (3H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.00-7.96 (1H, m), 7.89-7.81 (3H, m), 7.80 (3H, s), 4.93-4.89 (1H, m), 2.17-2.16 (1H, m), 2.00-1.90 (2H, m), 1.62 (9H, s), 1.06-1.02 (3H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.02-7.94 (3H, m), 7.89-7.81 (2H, m), 7.75 (1H, s), 7.03-6.99 (2H, m), 5.52-5.49 (1H, m), 2.62-2.56 (1H, m), 2.21-2.07 (2H, m), 1.62 (9H, s), 1.20-1.17 (2H, m), 1.10-1.07 (3H, m), 1.00-0.96 (2H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.19-8.15 (1H, m), 7.99-7.89 (4H, m), 7.78 (1H, s), 7.03-6.99 (2H, m), 5.53-5.50 (1H, m), 2.63-2.56 (1H, m), 2.22-2.06 (2H, m), 1.21-1.17 (2H, m), 1.11-1.07 (3H, m), 1.01-0.96 (2H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.26 (1H, s), 8.15-8.11 (1H, m), 8.03-7.95 (2H, m), 3.98 (3H, s).
1H-NMR (400MHz, CDCl3) δppm:
8.26 (1H, s), 8.06-7.91 (3H, m), 2.71 (3H, s), 1.63 (9H, s).
1H-NMR (400MHz, CDCl3) δppm:
8.01-7.97 (1H, m), 7.89-7.81 (3H, m), 5.18-5.12 (1H, m), 1.65 (3H, d, J = 6 Hz), 1.62 (9H, s).
1H-NMR (400MHz, CDCl3) δppm:
1H-NMR (CDCl3) δ: 8.01-7.97 (1H, m), 7.89-7.81 (3H, m), 5.18-5.12 (1H, m), 1.65 (4H, d, J = 6.4 Hz), 1.62 (9H, s).
1H-NMR (400MHz, CDCl3) δppm:
8.46 (1H, dd, J = 3, 1 Hz), 7.65 (1H, dd, J = 9, 1 Hz), 7.45 (1H, dd, J = 9, 3 Hz), 5.28 (2H, s), 3.50 (3H, s).
1H-NMR (400MHz, CDCl3) δppm:
8.32 (1H, dd, J = 3, 1 Hz), 8.00 (1H, d, J = 9, 1 Hz), 7.27 (1H, dd, J = 9, 3 Hz), 3.43-3.35 (1H, m), 1.26-1.21 (2H, m), 1.12-1.06 (2H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.42 (1H, d, J = 3 Hz), 8.02-7.98 (2H, m), 7.89-7.81 (3H, m), 7.37-7.34 (1H, m), 5.81-5.76 (1H, m), 3.45-3.38 (1H, m), 1.84 (3H, d, J= 7 Hz), 1.62 (9H, s), 1.22-1.18 (2H, m), 1.08-1.03 (2H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.45 (1H, d, J = 3 Hz), 8.18-8.14 (1H, m), 8.01 (1H, d, J= 9 Hz), 7.97-7.89 (2H, m), 7.85 (1H, s), 7.38-7.35 (1H, m), 5.83-5.78 (1H, m), 3.43-3.37 (1H, m), 1.85 (3H, d, J= 6 Hz), 1.22-1.19 (2H, m), 1.09-1.04 (2H, m).
上記の混合物(0.610g)のジクロロメタン(12mL)溶液に、室温にてトリフルオロ酢酸(6mL)を加えた。室温にて2時間攪拌後、反応液中の溶媒を減圧下、留去した。得られた残渣に飽和炭酸水素ナトリウム水溶液および水を加え、ジクロロメタンで抽出した。得られた有機層を無水硫酸ナトリウムで乾燥した。ろ別後、減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(25% 酢酸エチル/ヘキサン)で精製することにより、標記化合物(242mg、収率:52%)を得た。
1H-NMR (400MHz, CDCl3) δppm:
7.97-7.93 (2H, m), 7.72-7.69 (1H, m), 7.64-7.61 (2H, m), 7.03-6.99 (2H, m), 6.86-6.82 (1H, m), 5.49-5.45 (1H, m), 3.85 (2H, br s), 2.62-2.56 (1H, m), 2.20-2.04 (2H, m), 1.20-1.16 (2H, m), 1.09-1.05 (3H, m), 1.00-0.95 (2H, m).
上記の混合物(0.282g)のジクロロメタン(6mL)溶液に、室温にてトリフルオロ酢酸(3mL)を加えた。室温にて1時間攪拌後、反応液中の溶媒を減圧下、留去した。得られた残渣に飽和炭酸水素ナトリウム水溶液および水を加え、ジクロロメタンで抽出した。得られた有機層を無水硫酸ナトリウムで乾燥した。ろ別後、減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(30% 酢酸エチル/ヘキサン)で精製することにより、標記化合物(190mg、収率:99%)を得た。
1H-NMR (400MHz, CDCl3) δppm:
8.42 (1H, d, J = 3 Hz), 8.00-7.98 (1H, m), 7.72-7.68 (2H, m), 7.64-7.61 (1H, m), 7.39-7.36 (1H, m), 6.87-6.83 (1H, m), 5.78-5.73 (1H, m), 3.44-3.37 (1H, m), 1.82 (3H, d, J = 6 Hz), 1.21-1.18 (2H, m), 1.08-1.03 (2H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.22-8.18 (1H, m), 8.13-8.06 (2H, m), 4.62-4.57 (2H, m), 3.99 (3H, s), 1.52-1.49 (3H, m).
1H-NMR (400MHz, DMSO-d6) δppm:
8.23-8.10 (3H, m), 3.92 (3H, s).
1H-NMR (400MHz, CDCl3) δppm:
8.21-8.18 (1H, m), 8.11-8.02 (2H, m), 3.99 (3H, s), 3.93 (3H, s), 3.46 (3H, br s).
1H-NMR (400MHz, CDCl3) δppm:
8.22-8.18 (1H, m), 8.13-8.06 (2H, m), 4.00 (3H, s), 3.30-3.25 (2H, m), 1.34-1.31 (3H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.18-8.14 (1H, m), 8.05-7.97 (2H, m), 5.11-5.06 (1H, m), 3.99 (3H, s), 2.65-2.63 (1H, m), 2.18-1.99 (2H, m), 1.08-1.05 (3H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.17-8.13 (1H, m), 8.03-7.95 (4H, m), 7.08-7.05 (2H, m), 5.67-5.64 (1H, m), 3.98 (3H, s), 2.62-2.56 (1H, m), 2.38-2.21 (2H, m), 1.20-1.16 (2H, m), 1.13-1.09 (3H, m), 1.00-0.97 (2H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.25-8.21 (1H, m), 8.06-7.96 (4H, m), 7.08-7.06 (2H, m), 5.68-5.65 (1H, m), 2.62-2.56 (1H, m), 2.39-2.22 (2H, m), 1.21-1.17 (2H, m), 1.13-1.10 (3H, m), 1.00-0.97 (2H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.23-8.06 (3H, m), 4.00 (3H, s), 2.86 (3H, s).
1H-NMR (400MHz, CDCl3) δppm:
8.19-8.15 (1H, m), 8.05-7.97 (2H, m), 5.34-5.28 (1H, m), 3.99 (3H, s), 1.76 (3H, d, J = 7 Hz).
1H-NMR (400MHz, CDCl3) δppm:
8.47-8.46 (1H, m), 8.18-8.14 (1H, m), 8.03-7.95 (3H, m), 7.45-7.42 (1H, m), 5.96-5.91 (1H, m), 3.98 (3H, s), 3.45-3.38 (1H, m), 1.97 (3H, d, J = 7 Hz), 1.21-1.18 (2H, m), 1.08-1.03 (2H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.49 (1H, d, J = 3 Hz), 8.24-8.20 (1H, m), 8.06-7.98 (3H, m), 7.45 (1H, dd, J = 9, 3 Hz), 5.97-5.92 (1H, m), 3.42-3.36 (1H, m), 1.98 (3H, d, J = 7 Hz), 1.23-1.19 (2H, m), 1.09-1.04 (2H, m).
1H-NMR (500MHz, DMSO-d6) δppm:
10.21 (1H, s), 9.75 (1H, s), 7.94-7.90 (1H, m), 7.79-7.72 (2H, m), 3.88-3.87 (3H, m).
1H-NMR (500MHz, DMSO-d6) δppm:
10.12 (1H, m), 8.86-8.85 (1H, m), 8.05-8.02 (3H, m), 3.90-3.89 (3H, m).
1H-NMR (500MHz, CDCl3) δppm:
8.01-7.98 (1H, m), 7.73-7.71 (3H, m), 5.25-5.20 (1H, m), 3.96-3.95 (3H, m), 2.34-2.32 (1H, m), 1.67-1.65 (3H, m).
1H-NMR (500MHz, CDCl3) δppm:
8.01-7.96 (3H, m), 7.82 (1H, m), 7.72-7.71 (1H, m), 7.70-7.69 (1H, m), 7.02-6.98 (2H, m), 5.81-5.77 (1H, m), 3.95 (3H, s), 2.63-2.57 (1H, m), 1.83 (3H, d, J = 6 Hz), 1.21-1.18 (2H, m), 1.02-0.97 (2H, m).
1H-NMR (400MHz, DMSO-d6) δppm:
13.44 (1H, br s), 8.10 (1H, s), 8.02-7.93 (3H, m), 7.83-7.79 (2H, m), 7.19-7.15 (2H, m), 6.20-6.15 (1H, m), 2.86-2.80 (1H, m), 1.75-1.74 (3H, m), 0.98-0.96 (4H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.40 (1H, d, J = 3 Hz), 8.03-7.97 (2H, m), 7.84 (1H, s), 7.73-7.69 (2H, m), 7.32 (1H, dd, J = 9, 3 Hz), 5.82 (1H, q, J = 6 Hz), 3.95 (3H, s), 3.45-3.37 (1H, m), 1.86 (4H, d, J = 6 Hz), 1.22-1.17 (2H, m), 1.09-1.03 (2H, m).
1H-NMR (400MHz, CDCl3) δppm:
10.03 (1H, s), 7.94 (2H, d, J = 9 Hz), 7.31 (2H, d, J = 9 Hz), 7.26 (1H, s), 2.54 (3H, s).
1H-NMR (500MHz, CDCl3) δppm:
7.83 (2H, d, J = 9 Hz), 7.64 (1H, s), 7.28 (2H, d, J = 9 Hz), 4.90 (1H, dd, J = 7, 6 Hz), 2.52 (3H, s), 2.18 (1H, br s), 1.97-1.84 (2H, m), 1.00 (3H, t, J = 7 Hz).
1H-NMR (500MHz, CDCl3) δppm:
7.73 (1H, dd, J = 9, 1 Hz), 7.66 (1H, dd, J = 8, 1 Hz), 7.61 (1H, dd, J = 8, 6 Hz), 4.95 (1H, dd, J = 11, 8 Hz), 4.72 (1H, dd, J = 9, 8 Hz), 4.62 (1H, dd, J = 11, 9 Hz), 3.83 (3H, s).
1H-NMR (400MHz, CDCl3) δppm:
8.31 (1H, s), 7.87 (1H, dd, J = 9, 2 Hz), 7.80 (1H, td, J = 8, 2 Hz), 7.68 (1H, dd, J = 8, 7 Hz), 3.97 (3H, s).
1H-NMR (500MHz, CDCl3) δppm:
7.78 (1H, dd, J = 9, 2 Hz), 7.71 (1H, dd, J = 8, 2 Hz), 7.68 (1H, s), 7.65 (1H, dd, J = 8, 7 Hz), 4.69 (2H, d, J = 6 Hz), 2.06 (1H, br s).
1H-NMR (500MHz, CDCl3) δppm:
7.78 (1H, dd, J = 9, 2 Hz), 7.71 (1H, dd, J = 8, 2 Hz), 7.64 (1H, dd, J = 8, 7 Hz), 7.61 (1H, s), 4.95-4.88 (1H, m), 2.27 (1H, br s), 1.58 (3H, d, J = 6 Hz).
1H-NMR (500MHz, CDCl3) δppm:
8.03 (1H, dd, J = 8, 7 Hz), 7.87 (1H, dd, J = 8, 1 Hz), 7.81 (1H, dd, J = 11, 1 Hz), 7.65 (1H, s), 4.97-4.90 (1H, m), 3.96 (3H, s), 2.27 (1H, d, J = 5 Hz), 1.59 (3H, d, J= 8 Hz).
1H-NMR (400MHz, CDCl3)δppm:
8.18-8.05 (1H, m), 8.00 (2H, d, J = 9 Hz), 7.95-7.80 (2H, m), 7.66 (1H, s), 7.02 (2H, d, J = 9 Hz), 5.55 (1H, q, J = 6 Hz), 2.66-2.57 (1H, m), 1.76 (3H, d, J= 7 Hz), 1.23-1.18 (2H, m), 1.03-0.98 (2H, m).
1H-NMR (500MHz, CDCl3) δppm:
8.45 (1H, d, J = 3 Hz), 8.12 (1H, dd, J = 8, 7 Hz), 8.02 (1H, d, J = 9 Hz), 7.90 (1H, dd, J = 8, 2 Hz), 7.84 (1H, dd, J = 11, 2 Hz), 7.71 (1H, d, J = 1 Hz), 7.37 (1H, dd, J = 9, 3 Hz), 5.58 (1H, q, J = 7 Hz), 3.45-3.37 (1H, m), 1.81 (3H, d, J = 7 Hz), 1.24-1.19 (2H, m), 1.10-1.04 (2H, m).
1H-NMR (400MHz, CDCl3)δppm:
7.98 (2H, d, J = 9 Hz), 7.67-7.61 (2H, m), 7.51 (1H, s), 7.02 (2H, d, J = 7 Hz), 6.81 (1H, dd, J = 9, 8 Hz), 5.52 (1H, q, J = 6 Hz), 3.27 (2H, bs), 2.64-2.56 (1H, m), 1.74 (3H, d, J= 6 Hz), 1.22-1.18 (2H, m), 1.02-0.96 (2H, m).
1H-NMR (400MHz, CDCl3)δppm:
8.49-8.48 (1H, m), 8.02 (1H, d, J = 9 Hz), 7.65-7.60 (2H, m), 7.57 (1H, s), 7.43-7.39 (1H, m), 6.81 (1H, dd, J = 9, 9 Hz), 5.57 (1H, q, J = 6 Hz), 3.45-3.38 (1H, m), 1.78 (3H, d, J = 6 Hz), 1.25-1.20 (2H, m), 1.10-1.06 (2H, m).
1H-NMR (400MHz, CDCl3) δppm:
7.97 (1H, t, J = 8 Hz), 7.90 (1H, d, J = 8 Hz), 7.84 (1H, d, J = 5 Hz), 5.18 (1H, q, J = 7 Hz), 1.73 (4H, d, J = 7 Hz), 1.60 (9H, s);
MS (FAB) m/z: 309 [M+H]+.
1H-NMR (400MHz, CDCl3) δppm:
8.48 (1H, d, J = 3 Hz), 8.13 (1H, dd, J = 8, 7 Hz), 8.04 (1H, d, J = 9 Hz), 7.95 (1H, dd, J = 8, 2 Hz), 7.90 (1H, dd, J = 11, 2 Hz), 7.40 (1H, dd, J = 9, 3 Hz), 5.80 (1H, q, J = 7 Hz), 3.44-3.37 (1H,m), 1.97 (3H, d, J = 7 Hz), 1.24-1.19 (2H, m), 1.11-1.05 (2H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.31 (1H, d, J = 3 Hz), 8.00 (1H, d, J = 9 Hz), 7.31 (1H, dd, J = 9, 3 Hz), 4.05-3.98 (1H, m), 1.20 (6H, d, J = 7 Hz).
1H-NMR (400MHz, CDCl3) δppm:
8.35 (1H, d, J = 3 Hz), 8.05 (1H, d, J = 9 Hz), 7.26 (1H, d, J = 9, 3 Hz), 4.74 (1H, dd, J = 7, 5 Hz), 4.04-3.95 (1H, m), 2.17-2.03 (2H, m), 1.19 (6H, d, J = 7 Hz), 1.14 (3H, t, J = 7 Hz).
1H-NMR (500MHz, CDCl3) δppm:
8.42 (1H, d, J = 3 Hz), 8.05 (1H, dd, J = 8, 7 Hz), 8.03 (1H, d, J= 9 Hz), 7.92 (1H, dd, J = 8, 2 Hz), 7.86 (1H, dd, J = 11, 2 Hz), 7.36 (1H, dd, J = 9, 3 Hz), 5.54 (1H, dd, J = 7, 6 Hz), 4.07-4.00 (1H, m), 3.97 (3H, s), 2.38-2.24 (2H, m), 1.18 (6H, d, J = 7 Hz), 1.16 (3H, t, J = 7 Hz).
1H-NMR (500MHz, CDCl3) δppm:
8.45 (1H, d, J = 3 Hz), 8.14 (1H, dd, J = 8, 7 Hz), 8.05 (1H, d, J = 9 Hz), 7.96 (1H, dd, J = 8, 1 Hz), 7.90 (1H, dd, J = 11, 1 Hz), 7.38 (1H, dd, J = 9, 3 Hz), 5.56 (1H, dd, J = 7, 6 Hz), 4.08-3.98 (1H, m), 2.41-2.23 (2H, m), 1.18 (6H, d, J = 7 Hz), 1.17 (3H, t, J = 7 Hz).
1H-NMR (500MHz, CDCl3) δppm:
8.41 (1H, d, J = 3 Hz), 8.03 (1H, d, J = 9 Hz), 7.44 (1H, dd, J = 9, 3 Hz), 5.27 (2H, s), 3.50 (3H, s), 3.05 (2H, d, J = 7 Hz), 2.36-2.26 (1H, m), 0.99 (6H, d, J = 6 Hz).
1H-NMR (500MHz, CDCl3) δppm:
8.42 (1H, d, J = 3 Hz), 7.56 (1H, d, J = 9 Hz), 7.43 (1H, dd, J = 9, 3 Hz), 5.23 (2H, s), 3.50 (3H, s), 2.22 (2H, td, J = 18, 7 Hz), 1.93-1.84 (1H, m), 0.95 (6H, d, J= 7 Hz).
(500MHz, CDCl3) δppm:
8.27 (1H, d, J = 2 Hz), 7.54 (1H, d, J = 9 Hz), 7.25 (1H, dd, J = 9, 2 Hz), 2.20 (2H, td, J = 18, 7 Hz), 1.92-1.83 (1H, m), 0.94 (6H, d, J = 7 Hz).
1H-NMR (400MHz, CDCl3)δppm:
5.00 (1H, m), 2.15 (3H, s), 1.94-1.90 (2H, m), 1.03 (3H, t, J = 7 Hz);
MS (FAB) m/z: 147 [M+H]+.
1H-NMR (400MHz, CDCl3) δppm:
7.96 (1H, t, J = 8 Hz), 7.90 (1H, dd, J = 8, 2 Hz), 7.84 (1H, dd, J = 11, 2 Hz), 5.92 (1H, t, J = 7 Hz), 2.21 (3H, s), 2.16-2.08 (2H, m), 1.62 (9H, s), 1.05 (3H, t, J = 7 Hz);
MS (FAB) m/z: 365 [M+H]+.
1H-NMR (400MHz, CDCl3) δppm:
7.97 (1H, t, J = 8 Hz), 7.91 (1H, d, J = 8 Hz), 7.85 (1H, d, J = 11 Hz), 4.98 (1H, q, J = 6 Hz), 2.54 (1H, brs), 2.14-1.96 (2H, m), 1.62 (9H, s), 1.08 (3H, t, J = 7 Hz);
MS (FAB+) m/z: 323 [M+H]+.
1H-NMR (400MHz, CDCl3) δppm:
8.46 (1H, d, J = 3 Hz), 8.12 (1H, dd, J = 8, 7 Hz), 7.96 (1H, d, J = 8 Hz), 7.90 (1H, d, J = 11 Hz), 7.58 (1H, d, J = 9 Hz), 7.37 (1H, dd, J = 9, 3 Hz), 5.49 (1H, dd, J = 7, 6 Hz), 2.38-2.13 (4H, m), 1.91-1.82 (1H, m), 1.16 (3H, t, J = 7 Hz), 0.94 (6H, d, J = 7 Hz).
1H-NMR (500MHz, DMSO-d6)δppm:
9.35 (1H, s), 7.27 (1H, dd, J = 13, 2 Hz), 7.21 (1H, dd, J = 8, 2 Hz), 6.71 (1H, dd, J = 9, 8 Hz), 5.63 (2H, s), 5.33 (2H, s).
1H-NMR (500MHz, CDCl3) δppm:
7.74-7.66 (2H, m), 6.82 (1H, dd, J = 9, 8 Hz), 5.90 (1H, dd, J = 7, 6 Hz), 4.03 (1H, s), 2.19 (3H, d, J= 4 Hz), 2.16-2.04 (2H, m), 1.03 (2H, t, J= 8 Hz).
1H-NMR (500MHz, CDCl3) δppm:
7.74-7.66 (2H, m), 6.83 (1H, dd, J = 9, 8 Hz), 4.92 (1H, dd, J = 7, 6 Hz), 4.04 (2H, br s), 2.64 (1H, br s), 2.11-1.93 (2H, m), 1.06 (3H, t, J = 8 Hz).
1H-NMR (500MHz, CDCl3) δppm:
7.98 (2H, d, J = 9 Hz), 7.72-7.65 (2H, m), 7.03 (2H, d, J = 9 Hz), 6.81 (1H, dd, J = 9, 8 Hz), 5.47 (1H, dd, J = 7, 6 Hz), 4.04 (2H, s), 2.62-2.56 (1H, m), 2.33-2.16 (2H, m), 1.22-1.17 (2H, m), 1.12 (3H, t, J = 7 Hz), 1.01-0.96 (2H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.38 (1H, d, J = 3 Hz), 8.03 (1H, d, J = 9 Hz), 7.26 (1H, dd, J = 9, 2 Hz), 4.93 (1H, q, J = 7 Hz), 3.41-3.35 (1H, m), 1.74 (3H, d, J = 7 Hz), 1.25-1.20 (2H, m), 1.10-1.05 (2H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.46 (1H, d, J = 3 Hz), 8.02 (1H, d, J = 9 Hz), 7.69 (1H, dd, J = 12, 2 Hz), 7.67 (1H, dd, J = 8, 2), 7.38 (1H, dd, J = 9, 3 Hz), 6.82 (1H, dd, J = 9, 8 Hz), 5.73 (1H, q, J = 7 Hz), 4.06 (2H, s), 3.46-3.93 (1H, m), 1.93 (3H, d, J = 7 Hz), 1.23-1.19 (2H, m), 1.10-1.04 (2H, m).
1H-NMR (400MHz, CDCl3)δppm:
8.03 (2H, d, J= 9 Hz), 7.76-7.68 (2H, m), 7.10 (2H, d, J= 9 Hz), 6.85 (1H, dd, J = 9, 8 Hz), 5.49 (1H, t, J = 7 Hz), 4.08 (2H, bs), 3.34-3.24 (m, 1H), 2.38-2.20 (2H, m), 1.47 (6H, d, J = 7 Hz), 1.13 (3H, t, J = 8 Hz).
1H-NMR (400MHz, CDCl3)δppm:
8.00 (2H, d, J= 9 Hz), 7.73-7.65 (2H, m), 7.06 (2H, d, J= 9 Hz), 6.81 (1H, dd, J = 9, 8 Hz), 5.46 (1H, t, J = 7 Hz), 3.30-3.19 (m, 1H), 2.32-2.17 (2H, m), 1.43 (6H, d, J= 7 Hz), 1.13 (3H, t, J = 8 Hz).
1H-NMR (400MHz, CDCl3) δppm:
10.0 (1H, d, J = 2 Hz), 8.01 (1H, dd, J = 8, 7 Hz), 7.69 (1H, d, J = 8, 2 Hz), 7.61 (1H, dd, J = 10, 2 Hz), 1.61 (9H, s).
1H-NMR (400MHz, CDCl3) δppm:
7.97-7.89 (2H, m), 7.83 (1H, dd, J = 11, 1 Hz), 1.62 (9H, s).
1H-NMR (400MHz, CDCl3)δppm:
8.01-7.99 (2H, m), 6.95-6.93 (2H, m), 4.88 (2H, q, J = 7 Hz), 2.65-2.59 (1H, m), 1.70 (3H, d, J = 7 Hz), 1.24-1.20 (2H, m), 1.03-1.01 (2H, m).
1H-NMR (400MHz, CDCl3)δppm:
8.06 (2H, d, J= 9 Hz), 7.06 (2H, d, J = 9 Hz), 4.99 (1H, q, J = 7 Hz), 2.67-2.58 (1H, m), 1.84 (3H, d, J= 7 Hz), 1.39-1.32 (2H, m), 1.06-1.01 (2H, m).
1H-NMR (400MHz, CDCl3)δppm:
8.00 (2H, d, J= 9 Hz), 7.06 (2H, d, J = 9 Hz), 4.87 (1H, q, J =7 Hz), 4.68 (2H, bs), 2.64-2.57 (2H, m), 1.64 (3H, d, J = 7 Hz), 1.25-1.18 (2H, m), 1.04-0.98 (2H, m).
1H-NMR (400MHz, CDCl3)δppm:
8.20-8.14 (1H, m), 8.03-7.92 (4H, m), 7.08 (2H, d, J = 9 Hz), 5.72 (1H, q, J = 7 Hz), 2.63-2.56 (1H, m), 1.87 (3H, d, J = 6 Hz), 1.21-1.17 (2H, m), 1.01-0.96 (2H, m).
1H-NMR (400MHz, CDCl3)δppm:
7.98 (2H, d, J = 9 Hz), 7.76-7.72 (2H, m), 7.08 (2H, d, J = 9 Hz), 6.82 (1H, t, J = 9 Hz), 5.66 (1H, q, J = 7 Hz), 2.64-2.57 (1H, m), 1.84 (3H, d, J = 6 Hz), 1.21-1.17 (2H, m), 1.02-0.95 (2H, m).
1H-NMR (400MHz, CDCl3)δppm:
8.02 (2H, d, J= 9 Hz), 6.99 (2H, d, J = 9 Hz), 6.28 (1H, bs), 5.74 (1H, bs), 4.62 (1H, dd, J = 6, 5 Hz), 2.66-2.52 (1H, m), 2.10-1.95 (2H, m), 1.25-1.20 (2H, m), 1.10-1.00 (5H, m).
1H-NMR (400MHz, CDCl3)δppm:
8.05 (2H, d, J = 9 Hz), 7.07 (2H, d, J = 9 Hz), 4.83 (1H, t, J = 6 Hz), 2.67-2.60 (1H, m), 2.19-2.12 (2H, m), 1.28-1.17 (5H, m), 1.06-0.97 (2H, m).
1H-NMR (500MHz, CDCl3)δppm:
7.98 (2H, d, J= 9 Hz), 7.07 (2H, d, J = 9 Hz), 4.70 (2H, s), 4.62-4.55 (1H, m), 3.72 (1H, dq, J = 7, 6 Hz), 2.64-2.53 (1H, m), 2.08-1.82 (2H, m), 1.23-1.17 (2H, m), 1.09-0.92 (5H, m).
1H-NMR (400MHz, CDCl3)δppm:
8.02-7.92 (4H, m), 7.88 (1H, d, J= 9 Hz), 7.08 (2H, d, J = 9 Hz), 5.46 (1H, t, J = 7 Hz), 2.65-2.56 (1H, m), 2.36-2.12 (2H, m), 1.61 (9H, s), 1.23-1.17 (2H, m), 1.11 (3H, t, J = 7 Hz), 1.02-0.96 (2H, m).
1H-NMR (500MHz, CDCl3)δppm:
8.17 (1H, dd, J= 8, 7 Hz), 8.03-7.92 (4H, m), 7.08 (2H, d, J = 9 Hz), 5.47 (1H, t, J= 7 Hz), 2.63-2.56 (1H, m), 2.34-2.10 (2H, m), 1.22-1.15 (2H, m), 1.11 (3H, t, J = 8 Hz), 1.02-0.95 (2H, m).
1H-NMR (400MHz, CDCl3)δppm:
7.995 (2H, d, J = 9 Hz), 7.80-7.73 (2H, m), 7.08 (2H, d, J = 9 Hz), 6.82 (1H, t, J = 9 Hz), 5.39 (1H, t, J = 7 Hz), 4.24 (2H, s), 2.64-2.56 (1H, m), 2.34-2.10 (2H, m), 1.24-1.20 (2H, m), 1.09 (1H, t, J = 7 Hz), 1.04-0.96 (2H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.48 (1H, d, J = 3 Hz), 8.17 (1H, dd, J = 8, 7 Hz), 8.02 (1H, d, J = 9 Hz), 8.01 (1H, dd, J = 8, 2 Hz), 7.95 (1H, dd, J = 10, 2 Hz), 7.43 (1H, dd, J = 9, 3 Hz), 5.75 (1H, q, J = 6.5 Hz), 3.45-3.38 (1H,m), 1.91 (3H, d, J = 7 Hz), 1.22-1.17 (2H,m), 1.09-1.03 (2H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.47 (1H, d, J = 3 Hz), 8.34 (1H, t, J = 8 Hz), 8.00 (1H, d, J = 9 Hz), 7.90 (1H, dd, J = 8, 2 Hz), 7.83 (1H, dd, J = 11, 2 Hz), 7.42 (1H, dd, J = 9, 3 Hz), 6.98-6.94 (1H, m), 5.70 (1H, q, J = 7 Hz), 3.45-3.39 (1H, m), 1.89 (3H, d, J = 7 Hz), 1.54 (9H, s), 1.22-1.17 (2H, m), 1.09-1.03 (2H, m).
H-NMR (400MHz, CDCl3) δppm:
8.47 (1H, d, J = 3 Hz), 8.00 (1H, d, J = 9 Hz), 7.77-7.71 (2H, m), 7.42 (1H, dd, J = 9, 3 Hz), 6.82 (1H, t, J = 9 Hz), 5.67 (1H, q, J = 7 Hz), 4.25 (2H, s), 3.46-3.39 (1H, m), 1.87 (3H, d, J= 7 Hz), 1.22-1.17 (2H, m), 1.08-1.03 (2H, m).
1H-NMR (400MHz, CDCl3) δppm:
6.95-6.84 (4H, m), 6.49-6.35 (1H, m), 5.53-5.36 (1H, m), 4.45 (1H, dd, J = 7, 4 Hz), 3.80 (3H, s), 2.06-1.90 (2H, m), 1.08 (3H, t, J= 7 Hz).
1H-NMR (500MHz, CDCl3)δppm:
7.01 (2H, d, J= 9 Hz), 6.90 (2H, d, J = 9 Hz), 4.65 (1H, t, J = 7 Hz), 3.82 (3H, s), 2.10 (2H, dq, J = 7, 7 Hz), 1.22 (3H, t, J = 7 Hz).
1H-NMR (400MHz, CDCl3)δppm:
6.95 (2H, d, J= 9 Hz), 6.83 (2H, d, J = 9 Hz), 4.70 (2H, bs), 4.38 (1H, dd, J= 7, 6 Hz), 3.77 (3H, s), 2.02-1.80 (2H, m), 1.06 (3H, t, J = 7 Hz).
1H-NMR (400MHz, CDCl3)δppm:
8.03-7.89 (3H, m), 6.97 (2H, d, J = 9 Hz), 6.81 (2H, d, J = 9 Hz), 5.25 (1H, dd, J = 7, 6 Hz), 3.76 (3H, s), 2.30-2.07 (2H, m), 1.63 (9H, s), 1.10 (3H, t, J= 7 Hz).
1H-NMR (400MHz, CDCl3)δppm:
8.02 (1H, dd, J= 8, 7 Hz), 7.95 (1H, dd, J = 8, 2 Hz), 7.89 (1H, dd, J = 11, 1 Hz), 4.92-4.86 (1H, m), 2.40-2.32 (1H, m), 2.08-1.95 (2H, m), 1.62 (9H, s), 1.05 (3H, t, J = 7 Hz).
1H-NMR (400MHz, CDCl3)δppm:
8.20-8.13 (1H, m), 8.04-7.92 (4H, m), 7.08 (2H, d, J = 8 Hz), 5.50-5.44 (1H, m), 2.85-2.55 (1H, m), 2.38-2.10 (2H, m), 1.22-1.16 (2H, m), 1.11 (3H, t, J = 7 Hz), 1.04-0.96 (2H, m).
1H-NMR (400MHz, CDCl3)δppm:
8.02 (2H, d, J =9 Hz), 6.96 (2H, d, J =9 Hz), 5.39 (1H, br s).
1H-NMR (400MHz, CDCl3)δppm:
8.02 (2H, m), 7.02 (2H, d, J = 9 Hz).
1H-NMR (400MHz, CDCl3) δppm:
7.37-7.29 (4H, m), 7.28-7.21 (1H, m), 4.05-3.98 (2H, m), 3.93-3.85 (2H, m), 3.74 (1H, d, J = 13 Hz), 2.89-2.80 (1H, m), 1.71-1.29 (10H, m), 1.10 (3H, d, J = 6 Hz).
1H-NMR (400MHz, CDCl3) δppm:
3.99 (1H, dd, J = 7, 6 Hz), 3.93 (1H, td, J = 6, 5 Hz), 3.80 (1H, dd, J = 7, 6 Hz), 3.07 (1H, qd, J = 7, 5 Hz), 1.67-1.30 (10H, m), 1.07 (3H, dd, J = 7 Hz).
上記の化合物(306mg、0.543mmol)に酢酸(4.8mL)および水(1.2mL)を加え、80℃にて135分間攪拌した。室温に戻し、反応液中の溶媒を減圧下、留去した。得られた残渣に飽和炭酸水素ナトリウム水溶液および水を加え、ジクロロメタンで抽出した。得られた有機層を無水硫酸ナトリウムで乾燥した。ろ別後、減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(66%-99% 酢酸エチル/ヘキサン)で精製することにより、標記化合物(147mg、収率:56%)を得た。
1H-NMR (400MHz, CDCl3) δppm:
8.42 (1H, d, J = 2.7 Hz), 8.24-8.20 (1H, m), 8.01-7.97 (2H, m), 7.89-7.85 (1H, m), 7.83 (1H, s), 7.37-7.34 (1H, m), 6.88-6.83 (1H, m), 5.81-5.76 (1H, m), 4.26-4.21 (1H, m), 3.73-3.65 (2H, m), 3.51-3.47 (1H, m), 3.44-3.38 (1H, m), 3.23-3.19 (1H, m), 2.83-2.81 (1H, m), 1.84 (3H, d, J= 6.3 Hz), 1.42 (3H, d, J = 7.0 Hz), 1.22-1.18 (2H, m), 1.08-1.03 (2H, m);
MS (ES) m/z: 484 [M+H]+.
1H-NMR (400MHz, CDCl3) δppm:
8.23-8.19 (1H, m), 7.95 (2H, d, J= 8.6 Hz), 7.80-7.75 (2H, m), 7.67 (1H, s), 7.09 (1H, br s), 7.01 (2H, d, J = 9.0 Hz), 5.52-5.46 (2H, m), 3.81-3.78 (2H, m), 3.48-3.44 (2H, m), 2.63-2.56 (2H, m), 2.22-2.02 (2H, m), 1.19-1.16 (2H, m), 1.09-1.05 (3H, m), 0.99-0.97 (2H, m);
MS (ES) m/z: 468 [M+H]+.
1H-NMR (400MHz, CDCl3) δppm:
8.42 (1H, d, J = 2.7 Hz), 8.25-8.21 (1H, m), 7.99 (1H, d, J= 8.6 Hz), 7.82-7.76 (2H, m), 7.74 (1H, s), 7.38-7.35 (1H, m), 6.89 (1H, br s), 5.79-5.74 (1H, m), 5.28-5.24 (1H, m), 3.82-3.80 (2H, m), 3.50-3.46 (2H, m), 3.44-3.38 (1H, m), 2.35 (1H, m), 1.83 (3H, d, J = 6.7 Hz), 1.21-1.18 (2H, m), 1.08-1.03 (2H, m);
MS (ES) m/z: 455 [M+H]+.
参考例で得られた化合物または実施例で得られた化合物を使用して、上記実施例を参考に、下記表の化合物を得た。
1H-NMR (400MHz, CDCl3) δppm:
8.32-8.28 (1H, m), 8.08-8.05 (1H, m), 7.99-7.93 (3H, m), 7.09-7.05 (2H, m), 6.92-6.87 (1H, m), 5.67-5.64 (1H, m), 4.35 (1H, m), 3.85-3.80 (1H, m), 3.72-3.66 (1H, m), 2.62-2.56 (1H, m), 2.39-2.19 (3H, m), 1.33 (3H, d, J = 6.6 Hz), 1.20-1.16 (2H, m), 1.13-1.09 (3H, m), 1.01-0.96 (2H, m);
MS (FAB) m/z: 468 [M+H]+.
参考例で得られた化合物または実施例で得られた化合物を使用して、上記実施例を参考に、下記表の化合物を得た。
1H-NMR (400MHz, CDCl3) δppm:
8.16-8.12 (1H, m), 8.00-7.97 (2H, m), 7.81 (1H, s), 7.74 (1H, s), 7.72-7.71 (1H, m), 7.02-6.98 (2H, m), 6.93-6.88 (1H, m), 5.81-5.77 (1H, m), 4.35-4.31 (1H, m), 3.83-3.78 (1H, m), 3.70-3.65 (1H, m), 2.63-2.56 (2H, m), 1.83 (3H, d, J = 6.6 Hz), 1.31 (3H, d, J = 7.0 Hz), 1.21-1.18 (2H, m), 1.02-0.97 (2H, m).
MS (ES) m/z: 469 [M+H]+.
1H-NMR (400MHz, CDCl3) δppm:
8.40 (1H, d, J = 3 Hz), 8.15 (1H, t, J = 8 Hz), 8.00 (1H, d, J = 9 Hz), 7.83 (1H, s), 7.75-7.71 (2H, m), 7.32 (1H, dd, J = 9, 3 Hz), 6.93-6.85 (1H, m), 5.82 (1H, q, J= 6 Hz), 4.38-4.29 (1H, m), 3.83-3.77 (1H, m), 3.71-3.64 (1H, m), 3.45-3.37 (1H, m), 2.53 (1H, t, J = 6 Hz), 1.86 (3H, d, J = 6 Hz), 1.32 (3H, d, J = 7 Hz), 1.22-1.17 (2H, m), 1.09-1.03 (2H, m);
MS (ES) m/z: 470 [M+H]+.
1H-NMR (500MHz, CDCl3) δppm:
8.09 (2H, d, J = 8 Hz), 7.99 (2H, d, J = 8 Hz), 7.97 (2H, d, J = 9 Hz), 7.82 (1H, s), 7.02 (2H, d, J = 9 Hz), 5.49 (1H, dd, J = 7, 6 Hz), 3.28-3.22 (1H, m), 3.07 (3H, s), 2.26-2.17 (1H, m), 2.09-2.00 (1H, m), 1.43 (6H, d, J = 7 Hz), 1.09 (3H, t, J = 7 Hz).
MS (ES) m/z: 484 [M+H]+.
1H-NMR (400MHz, CDCl3) δppm:
8.43 (1H, d, J = 2 Hz), 8.19 (1H, t, J = 8 Hz), 8.01 (1H, d, J = 9 Hz), 7.92 (1H, dd, J = 8, 1 Hz), 7.80 (1H, dd, J = 12, 1 Hz), 7.68 (1H, s), 7.36 (1H, dd, J = 9, 2 Hz), 6.96-6.88 (1H, m), 5.56 (1H, q, J = 7 Hz), 4.39-4.30 (1H, m), 3.84-3.78 (1H, m), 3.71-3.65 (1H, m), 3.45-3.40 (1H, m), 2.51 (1H, t, J = 5 Hz), 1.80 (3H, d, J = 7 Hz), 1.32 (3H, d, J = 7 Hz), 1.22-1.19 (2H, m), 1.09-1.04 (2H, m).
MS (ES) m/z: 454 [M+H]+.
1H-NMR (400MHz, CDCl3)δppm:
8.42 (1H, d, J = 3 Hz), 8.21 (1H, dd, J = 8, 8 Hz), 8.01 (1H, d, J = 9 Hz), 7.91 (1H, dd, J = 8, 2 Hz), 7.78 (1H, dd, J = 13, 2 Hz), 7.67 (1H, s), 7.36 (1H, dd, J = 9, 3 Hz), 6.90-6.80 (1H, m), 5.56 (1H, q, J = 7 Hz), 3.47-3.40 (1H, m), 3.00-2.92 (1H, m), 1.79 (3H, d, J = 6 Hz), 1.23-1.18 (2H, m), 1.10-1.04 (2H, m), 0.93-0.88 (2H, m), 0.68-0.62 (2H, m).
MS (ES) m/z: 436 [M+H]+.
1H-NMR (400MHz, CDCl3)δppm:
8.42 (1H, d, J = 2 Hz), 8.27 (1H, dd J = 9, 8 Hz), 8.00 (1H, d, J = 9 Hz), 7.76 (1H, d, J = 9 Hz), 7.70 (1H, dd, J = 12, 2 Hz), 7.58 (1H, s), 7.36 (1H, dd, J = 9, 3 Hz), 7.15-7.04 (1H, m), 5.53 (1H, q, J = 6 Hz), 5.42-5.36 (1H, m), 3.85-3.76 (2H, m), 3.50-3.38 (3H, m), 2.46-2.39 (1H, m), 1.78 (3H, d, J = 7 Hz), 1.23-1.17 (2H, m), 1.09-1.02 (2H, m).
MS (FAB) m/z: 455 [M+H]+.
参考例で得られた化合物または実施例で得られた化合物を使用して、上記実施例を参考に、下記表の化合物を得た。
1H-NMR (400MHz, CDCl3) δppm:
8.47 (1H, d, J = 3 Hz), 8.21 (1H, t, J = 8 Hz), 8.03 (1H, d, J = 9 Hz), 7.98 (1H, dd, J = 8, 1 Hz), 7.85 (1H, dd, J = 12, 1 Hz), 7.39 (1H, dd, J = 9, 3 Hz), 6.97-6.85 (1H, m), 5.78 (1H, J = 7 Hz), 4.40-4.29 (1H, m), 3.81 (1H, dd, J = 11, 3 Hz), 3.68 (1H, dd, J = 11, 6 Hz), 3.47-3.37 (1H, m), 2.49 (1H, br s), 1.95 (3H, d, J = 7 Hz), 1.32 (3H, d, J = 7 Hz), 1.24-1.18 (2H, m), 1.10-1.04 (2H, m);
MS (ES) m/z: 455 [M+H]+.
参考例で得られた化合物または実施例で得られた化合物を使用して、上記実施例を参考に、下記表の化合物を得た。
1H-NMR (400MHz, DMSO-d6) δppm:
8.76 (1H, d, J = 3 Hz), 8.57 (1H, d, J = 3 Hz), 8.39 (1H, dd, J = 9, 8 Hz), 7.97 (1H, d, J = 9 Hz), 7.75-7.68 (3H, m), 6.93 (1H, t, J = 6 Hz), 6.28 (1H, q, J = 7 Hz), 4.79 (1H, t, J = 5 Hz), 3.46 (2H, q, J = 5 Hz), 3.43-3.38 (1H, m), 3.18 (2H, td, J = 6, 5 Hz), 1.84 (3H, d, J = 7 Hz), 1.09-0.98 (4H, m).
MS (ES) m/z: 456 [M+H]+.
参考例で得られた化合物または実施例で得られた化合物を使用して、上記実施例を参考に、下記表の化合物を得た。
(400MHz, CDCl3) δppm:
8.47 (1H, d, J = 3 Hz), 8.26 (1H, dd, J = 9, 8 Hz), 8.04 (1H, dd, J = 8, 1 Hz), 8.01 (1H, d, J = 9 Hz), 7.93 (1H, dd, J = 12, 1 Hz), 7.57-7.46 (1H, m), 7.43 (1H, dd, J= 9, 3 Hz), 5.74 (1H, q, J = 7 Hz), 4.28-4.22 (1H, m), 4.04-3.99 (2H, m), 3.97-3.91 (2H, m), 3.45-3.39 (1H, m), 2.46 (2H, dd, J = 7, 5 Hz), 1.91 (3H, d, J = 7 Hz), 1.22-1.17 (2H, m), 1.09-1.03 (2H, m);
MS (ES) m/z: 471 [M+H]+.
1H-NMR (400MHz, DMSO-d6) δppm:
8.92 (1H, d, J = 3 Hz), 8.52 (1H, d, J= 3 Hz), 8.48 (1H, t, J = 8 Hz), 7.94 (1H, d, J = 9 Hz), 7.91-7.85 (2H, m), 7.67 (1H, dd, J = 9, 3 Hz), 7.01 (1H, t, J = 5 Hz), 6.08 (1H, q, J = 7 Hz), 4.80 (1H, t, J = 5 Hz), 3.6 (2H, td, J = 6, 5 Hz), 3.42-3.37 (1H, m), 3.19 (2H, td, J = 6, 5 Hz), 1.77 (3H, d, J = 7 Hz), 1.07-0.98 (4H, m);
MS (ES) m/z: 456 [M+H]+.
参考例で得られた化合物または実施例で得られた化合物を使用して、上記実施例を参考に、下記表の化合物を得た。
実施例で得られた化合物5g、乳糖90g、トウモロコシデンプン34g、結晶セルロース20gおよびステアリン酸マグネシウム1gをブレンダーで混合した後、打錠機で打錠することにより、錠剤が得られる。
化合物の投与液は、0.5w/v%メチルセルロース溶液を用い、メノウ乳鉢で粉砕しながら1mg/mLの濃度になるように懸濁液を調製した。動物は、雄性C57/BL6Jマウス(日本チャールスリバー株式会社)を6週齢から8週齢で入荷し、9週齢から13週齢で使用した。試験日前日の17時から18時の間を目安に絶食を開始し、16時間から17時間程度の絶食下で試験を開始した。各群5匹ずつを用いた。尾静脈から採血を行った後、化合物懸濁液を10mg/kgとなるように経口投与した。陰性対照群には0.5w/v%メチルセルロース溶液を投与した。経口投与から25分後に尾静脈から採血を行い、経口投与から30分後に30w/v%グルコース溶液を10mL/kgで経口投与した。グルコース負荷から15分、30分、60分、120分後に尾静脈から採血を行った。採取した血液を遠心して血漿を分取し、Glucoroder-GXT(株式会社エイアンドティー)で血漿血糖値(mg/dL)を測定した。個体毎に、糖負荷5分前、糖負荷15分、30 分、60分、120分後の血糖値を用いてAUC(mg/dL・min)を算出した。群毎におけるAUC平均値を算出し、陰性対照群と比較したAUC低下率(%)を算出し、薬効の指標とした。
その結果、実施例で得られたすべての化合物は4%以上のAUC低下率を示した。
化合物を秤量し、溶媒(0.5w/v%メチルセルロースまたは20w/v%シクロデキストリン)中で1〜10mg/mLの濃度になるように懸濁し、投与液を調製する。必要に応じ、調製した投与液を前記溶媒を用いて順次希釈し、複数の用量の投与液を調製する。動物はZucker fatty ラット(日本チャールスリバー)またはZucker diabetic fatty(ZDF) ラット(日本チャールスリバー)、雄10〜18週齢を使用する。試験の2日前に血糖値、体重、血中インスリン値を測定し、各パラメータが均等になるように各群n=5から8に割り付ける。試験実施日の前日15時頃に絶食を行う。試験当日、ラットに前述の方法によって調製される化合物投与液を1〜5mL/kgで経口投与し、その30分後に25〜50w/v%グルコース溶液を4〜5mL/kgで経口投与する。採血は化合物投与前、グルコース投与5分前、グルコース投与30、60、120および180分後に、ラット尾静脈より行う。得られた血液を遠心後、プラズマを分離し、プラズマ血糖値をGlucoroder-GXT(株式会社エイアンドティー)で測定する。各群におけるグルコース投与後の血糖値のAUCを算出し、vehicle投与群の血糖値AUCに対する低下率(%)を化合物の薬効として表記する。
上述の方法で得られた血漿を被検化合物の血中濃度の測定に用いる。また、被検化合物の血中濃度を測定するために、投与後4時間から8時間、そして24時間後にも採血を行う。血漿を除タンパク処理した後、液体クロマトグラフィー・質量分析器に供して血中の化合物濃度を算出する。
Junko Ogawa, et al., Life Sciences Vol.65, No.12 pp.1287-1296 (1999) に記載の方法を参照して被検化合物のβ細胞(膵臓)保護作用を確認することができる。
Claims (11)
- 一般式(I):
環Aは、
Xは、CHまたはNであり、
R1は、-C(=O)-NH-R5、-NH-C(=O)-NH-R5または-S(=O)2-R5であり、
R2は、-Fまたは-Hであり、
R3は、-CH3または-C2H5であり、
R4は、
R5は、-H、あるいは、1〜3個の-OHで置換されていてもよい、C1〜C6アルキル基、C3〜C6シクロアルキル基または
で表される化合物またはその薬学的に許容され得る塩。 - 環Aが、
R1が、-C(=O)-NH-R5または-NH-C(=O)-NH-R5であり、
R2が、-Fであり、
R3が、-CH3であり、
R4が、
R5が、-H、あるいは、1〜3個の-OHで置換されていてもよい、C1〜C6アルキル基またはC3〜C6シクロアルキル基である、
請求項1に記載の化合物またはその薬学的に許容され得る塩。 - 環Aが、
R1が、-C(=O)-NH-R5または-NH-C(=O)-NH-R5であり、
R2が、-Fであり、
R4が、
R5が、-H、あるいは、1〜3個の-OHで置換されていてもよい、C1〜C6アルキル基またはC3〜C6シクロアルキル基である、
請求項1に記載の化合物またはその薬学的に許容され得る塩。 - 環Aが、
R1が、-C(=O)-NH-R5または-S(=O)2-R5であり、
R3が、-CH3であり、
R4が、
R5が、1〜3個の-OHで置換されていてもよいC1〜C6アルキル基である、
請求項1に記載の化合物またはその薬学的に許容され得る塩。 - 一般式(II):
R3は、-CH3または-C2H5であり、
R6は、1〜3個の-OHで置換されていてもよい、C1〜C6アルキル基またはC3〜C6シクロアルキル基であり、
R7は、
で表される化合物またはその薬学的に許容され得る塩。 - 一般式(III):
Xは、CHまたはNであり、
R3は、-CH3または-C2H5であり、
R8は、-H、または、置換基群αから選択される1〜3個の置換基で置換されていてもよいC1〜C6アルキル基であり、
R9は、
置換基群αは、-OH、-O-C(=O)-O-CH3または-O-C(=O)-NH-C2H5である)
で表される化合物またはその薬学的に許容され得る塩。 - 以下:
4-(5-{1-[4-(シクロプロピルカルボニル)フェノキシ]エチル}-1,3-チアゾール-2-イル)-2-フルオロ-N-[(1R)-2-ヒドロキシ-1-メチルエチル]ベンズアミド;
4-[4-(1-{[6-(シクロプロピルカルボニル)ピリジン-3-イル]オキシ}エチル)-1,3-オキサゾール-2-イル]-2-フルオロ-N-[(1R)-2-ヒドロキシ-1-メチルエチル]ベンズアミド;
N-シクロプロピル-4-[4-(1-{[6-(シクロプロピルカルボニル)ピリジン-3-イル]オキシ}エチル)-1,3-オキサゾール-2-イル]-2-フルオロベンズアミド;
1-{4-[4-(1-{[6-(シクロプロピルカルボニル)ピリジン-3-イル]オキシ}エチル)-1,3-オキサゾール-2-イル]-2-フルオロフェニル}-3-(2-ヒドロキシエチル)ウレア;
4-{5-[(1R)-1-{[6-(シクロプロピルカルボニル)ピリジン-3-イル]オキシ}エチル]-1,2,4-オキサジアゾール-3-イル}-2-フルオロ-N-[(1R)-2-ヒドロキシ-1-メチルエチル]ベンズアミド;
1-{4-[5-(1-{[6-(シクロプロピルカルボニル)ピリジン-3-イル]オキシ}エチル)-1,2,4-オキサジアゾール-3-イル]-2-フルオロフェニル}-3-(2-ヒドロキシエチル)ウレア;
4-[3-(1-{[6-(シクロプロピルカルボニル)ピリジン-3-イル]オキシ}エチル)-1,2,4-オキサジアゾール-5-イル]-2-フルオロ-N-[2-ヒドロキシ-1-(ヒドロキシメチル)エチル]ベンズアミド;および
1-{4-[3-(1-{[6-(シクロプロピルカルボニル)ピリジン-3-イル]オキシ}エチル)-1,2,4-オキサジアゾール-5-イル]-2-フルオロフェニル}-3-(2-ヒドロキシエチル)ウレア
からなる群より選択される化合物またはその薬学的に許容され得る塩。 - 請求項1〜7いずれか1項に記載の化合物またはその薬学的に許容され得る塩を有効成分として含有する医薬組成物。
- 1型糖尿病、2型糖尿病または肥満を治療するための、請求項8に記載の医薬組成物。
- β細胞または膵臓を保護するための、請求項8に記載の医薬組成物。
- 医薬組成物を製造するための、請求項1〜7いずれか1項に記載の化合物またはその薬学的に許容され得る塩の使用。
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002046174A1 (en) * | 2000-12-08 | 2002-06-13 | Glaxo Group Limited | 1, 2, 4-oxadiazole derivatives as hppar alpha agonists |
JP2008500357A (ja) * | 2004-05-25 | 2008-01-10 | メタボレックス インコーポレーティッド | Pparのモジュレーターとしての置換されたトリアゾールおよびこれらの調製方法 |
JP2009509989A (ja) * | 2005-09-29 | 2009-03-12 | サノフィ−アベンティス | フェニル基を有するフェニル−[1,2,4]−オキサジアゾール−5−オン誘導体、その製造方法、及び医薬品としてのその使用 |
JP2009532453A (ja) * | 2006-04-06 | 2009-09-10 | プロシディオン・リミテッド | ヘテロサイクリックgpcrアゴニスト |
WO2011016470A1 (ja) * | 2009-08-05 | 2011-02-10 | 第一三共株式会社 | スルホン誘導体 |
WO2011016469A1 (ja) * | 2009-08-05 | 2011-02-10 | 第一三共株式会社 | アミド誘導体 |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101154830B1 (ko) | 2003-12-24 | 2012-06-18 | 프로시디온 리미티드 | Gpcr 수용체 효능제로서의 헤테로사이클릭 유도체 |
WO2007003962A2 (en) | 2005-06-30 | 2007-01-11 | Prosidion Limited | Gpcr agonists |
WO2007003960A1 (en) | 2005-06-30 | 2007-01-11 | Prosidion Limited | Gpcr agonists |
GB0606913D0 (en) * | 2006-04-06 | 2006-05-17 | Prosidion Ltd | Compounds |
EP2185544B1 (en) * | 2007-07-19 | 2014-11-26 | Cymabay Therapeutics, Inc. | N-azacyclic substituted pyrrole, pyrazole, imidazole, triazole and tetrazole derivatives as agonists of the rup3 or gpr119 for the treatment of diabetes and metabolic disorders |
KR101536021B1 (ko) | 2007-10-16 | 2015-07-10 | 다이이찌 산쿄 가부시키가이샤 | 피리미딜 인돌린 화합물 |
EP2241558A1 (en) | 2009-04-03 | 2010-10-20 | Merck Serono SA | Oxadiazole derivatives |
WO2010119881A1 (ja) | 2009-04-15 | 2010-10-21 | 第一三共株式会社 | インドリン化合物 |
BR112013009043B8 (pt) | 2010-10-14 | 2019-09-17 | Daiichi Sankyo Co Ltd | composto, composição farmacêutica, e, uso de um composto |
BR112014001767A2 (pt) | 2011-07-29 | 2017-02-14 | Daiichi Sankyo Co Ltd | composto, composição farmaccêutica, uso de um composto, e, método para o tratamento de uma doença |
WO2013108800A1 (ja) | 2012-01-18 | 2013-07-25 | 第一三共株式会社 | 置換フェニルアゾール誘導体 |
-
2013
- 2013-01-17 WO PCT/JP2013/050710 patent/WO2013108800A1/ja active Application Filing
- 2013-01-17 EP EP13738825.2A patent/EP2805941B1/en not_active Not-in-force
- 2013-01-17 RU RU2014133738A patent/RU2014133738A/ru not_active Application Discontinuation
- 2013-01-17 EP EP15192148.3A patent/EP3009433B1/en not_active Not-in-force
- 2013-01-17 SG SG11201404026SA patent/SG11201404026SA/en unknown
- 2013-01-17 MX MX2014008790A patent/MX2014008790A/es unknown
- 2013-01-17 CA CA2861847A patent/CA2861847A1/en not_active Abandoned
- 2013-01-17 BR BR112014017656A patent/BR112014017656A2/pt not_active IP Right Cessation
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- 2013-01-17 TW TW102101765A patent/TWI551590B/zh not_active IP Right Cessation
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- 2013-01-17 ES ES13738825.2T patent/ES2602962T3/es active Active
- 2013-01-17 US US14/372,832 patent/US9233958B2/en not_active Expired - Fee Related
- 2013-01-17 AU AU2013210394A patent/AU2013210394A1/en not_active Abandoned
- 2013-01-17 CN CN201380014867.6A patent/CN104159892A/zh active Pending
- 2013-01-17 ES ES15192148.3T patent/ES2640667T3/es active Active
- 2013-01-17 KR KR1020147019737A patent/KR20140113688A/ko not_active Application Discontinuation
-
2014
- 2014-07-11 ZA ZA2014/05108A patent/ZA201405108B/en unknown
- 2014-07-17 PH PH12014501646A patent/PH12014501646A1/en unknown
- 2014-07-17 IL IL233682A patent/IL233682A0/en unknown
- 2014-07-31 CO CO14166876A patent/CO7020920A2/es unknown
-
2015
- 2015-02-05 HK HK15101292.6A patent/HK1200824A1/xx unknown
- 2015-02-05 HK HK16108406.3A patent/HK1220448A1/zh unknown
- 2015-12-01 US US14/956,240 patent/US9725438B2/en not_active Expired - Fee Related
- 2015-12-01 US US14/956,116 patent/US20160081993A1/en not_active Abandoned
-
2016
- 2016-12-20 JP JP2016247095A patent/JP2017052800A/ja active Pending
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002046174A1 (en) * | 2000-12-08 | 2002-06-13 | Glaxo Group Limited | 1, 2, 4-oxadiazole derivatives as hppar alpha agonists |
JP2008500357A (ja) * | 2004-05-25 | 2008-01-10 | メタボレックス インコーポレーティッド | Pparのモジュレーターとしての置換されたトリアゾールおよびこれらの調製方法 |
JP2009509989A (ja) * | 2005-09-29 | 2009-03-12 | サノフィ−アベンティス | フェニル基を有するフェニル−[1,2,4]−オキサジアゾール−5−オン誘導体、その製造方法、及び医薬品としてのその使用 |
JP2009532453A (ja) * | 2006-04-06 | 2009-09-10 | プロシディオン・リミテッド | ヘテロサイクリックgpcrアゴニスト |
WO2011016470A1 (ja) * | 2009-08-05 | 2011-02-10 | 第一三共株式会社 | スルホン誘導体 |
WO2011016469A1 (ja) * | 2009-08-05 | 2011-02-10 | 第一三共株式会社 | アミド誘導体 |
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