TWI460161B - １－苯基吡咯化合物 - Google Patents
１－苯基吡咯化合物 Download PDFInfo
- Publication number
- TWI460161B TWI460161B TW098134159A TW98134159A TWI460161B TW I460161 B TWI460161 B TW I460161B TW 098134159 A TW098134159 A TW 098134159A TW 98134159 A TW98134159 A TW 98134159A TW I460161 B TWI460161 B TW I460161B
- Authority
- TW
- Taiwan
- Prior art keywords
- phenyl
- methyl
- pyrrole
- carboxamide
- compound
- Prior art date
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- 150000005356 1-phenylpyrroles Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 271
- 239000000203 mixture Substances 0.000 claims description 90
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 68
- 239000003795 chemical substances by application Substances 0.000 claims description 51
- -1 2-hydroxypropyl Chemical group 0.000 claims description 45
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 21
- 206010020772 Hypertension Diseases 0.000 claims description 21
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 21
- 208000017169 kidney disease Diseases 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 230000000694 effects Effects 0.000 claims description 19
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 18
- 229940126585 therapeutic drug Drugs 0.000 claims description 18
- 102000003979 Mineralocorticoid Receptors Human genes 0.000 claims description 17
- 108090000375 Mineralocorticoid Receptors Proteins 0.000 claims description 17
- 125000005843 halogen group Chemical group 0.000 claims description 17
- 206010019280 Heart failures Diseases 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 16
- 230000000069 prophylactic effect Effects 0.000 claims description 16
- 150000001412 amines Chemical class 0.000 claims description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
- 229940043274 prophylactic drug Drugs 0.000 claims description 14
- AHFINSWGYAZBOZ-UHFFFAOYSA-N 4-chloro-2-(trifluoromethyl)benzaldehyde Chemical group FC(F)(F)C1=CC(Cl)=CC=C1C=O AHFINSWGYAZBOZ-UHFFFAOYSA-N 0.000 claims description 13
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 12
- 206010016654 Fibrosis Diseases 0.000 claims description 12
- 239000004480 active ingredient Substances 0.000 claims description 12
- 230000004761 fibrosis Effects 0.000 claims description 12
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 11
- 208000011775 arteriosclerosis disease Diseases 0.000 claims description 11
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 10
- 208000004476 Acute Coronary Syndrome Diseases 0.000 claims description 10
- 206010002383 Angina Pectoris Diseases 0.000 claims description 10
- 229940083712 aldosterone antagonist Drugs 0.000 claims description 10
- 206010008118 cerebral infarction Diseases 0.000 claims description 10
- 208000026106 cerebrovascular disease Diseases 0.000 claims description 10
- 239000000460 chlorine Substances 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- 241001465754 Metazoa Species 0.000 claims description 8
- 206010030113 Oedema Diseases 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 8
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 8
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 8
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- FLBDMCCVBXITAO-ZDUSSCGKSA-N 1-(2,4-dichlorophenyl)-5-[(2s)-2-hydroxypropyl]-2-methyl-n-(4-methylsulfonylphenyl)pyrrole-3-carboxamide Chemical compound CC=1N(C=2C(=CC(Cl)=CC=2)Cl)C(C[C@@H](O)C)=CC=1C(=O)NC1=CC=C(S(C)(=O)=O)C=C1 FLBDMCCVBXITAO-ZDUSSCGKSA-N 0.000 claims description 6
- QANHVYSEDAJLHZ-ZDUSSCGKSA-N 1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-[(2s)-2-hydroxypropyl]-2-methyl-n-(4-methylsulfonylphenyl)pyrrole-3-carboxamide Chemical compound CC=1N(C=2C(=CC(F)=CC=2)C(F)(F)F)C(C[C@@H](O)C)=CC=1C(=O)NC1=CC=C(S(C)(=O)=O)C=C1 QANHVYSEDAJLHZ-ZDUSSCGKSA-N 0.000 claims description 6
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 6
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 6
- KJUMMWCOFRQVML-ZDUSSCGKSA-N 1-(2-chloro-4-fluorophenyl)-5-[(2s)-2-hydroxypropyl]-2-methyl-n-(4-methylsulfonylphenyl)pyrrole-3-carboxamide Chemical compound CC=1N(C=2C(=CC(F)=CC=2)Cl)C(C[C@@H](O)C)=CC=1C(=O)NC1=CC=C(S(C)(=O)=O)C=C1 KJUMMWCOFRQVML-ZDUSSCGKSA-N 0.000 claims description 5
- YQXGVUQFXVJXSP-ZDUSSCGKSA-N 1-[4-chloro-2-(difluoromethoxy)phenyl]-5-[(2s)-2-hydroxypropyl]-2-methyl-n-(4-methylsulfonylphenyl)pyrrole-3-carboxamide Chemical compound CC=1N(C=2C(=CC(Cl)=CC=2)OC(F)F)C(C[C@@H](O)C)=CC=1C(=O)NC1=CC=C(S(C)(=O)=O)C=C1 YQXGVUQFXVJXSP-ZDUSSCGKSA-N 0.000 claims description 5
- IVDMGYRTLPRBSE-ZDUSSCGKSA-N 1-[4-chloro-2-(trifluoromethoxy)phenyl]-5-[(2s)-2-hydroxypropyl]-2-methyl-n-(4-methylsulfonylphenyl)pyrrole-3-carboxamide Chemical compound CC=1N(C=2C(=CC(Cl)=CC=2)OC(F)(F)F)C(C[C@@H](O)C)=CC=1C(=O)NC1=CC=C(S(C)(=O)=O)C=C1 IVDMGYRTLPRBSE-ZDUSSCGKSA-N 0.000 claims description 5
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 5
- DUNDTSFOUCXJOA-AWEZNQCLSA-N 1-(2-chloro-4-fluorophenyl)-2-ethyl-5-[(2s)-2-hydroxypropyl]-n-(4-methylsulfonylphenyl)pyrrole-3-carboxamide Chemical compound CCC1=C(C(=O)NC=2C=CC(=CC=2)S(C)(=O)=O)C=C(C[C@H](C)O)N1C1=CC=C(F)C=C1Cl DUNDTSFOUCXJOA-AWEZNQCLSA-N 0.000 claims description 4
- YKDRJUVCOIOBKA-ZDUSSCGKSA-N 1-[2-(difluoromethyl)-4-fluorophenyl]-5-[(2s)-2-hydroxypropyl]-2-methyl-n-(4-methylsulfonylphenyl)pyrrole-3-carboxamide Chemical compound CC=1N(C=2C(=CC(F)=CC=2)C(F)F)C(C[C@@H](O)C)=CC=1C(=O)NC1=CC=C(S(C)(=O)=O)C=C1 YKDRJUVCOIOBKA-ZDUSSCGKSA-N 0.000 claims description 4
- FZPJYKNUNFUEGS-ZDUSSCGKSA-N 1-[4-chloro-2-(trifluoromethyl)phenyl]-5-[(2s)-2-hydroxypropyl]-2-methyl-n-(4-methylsulfonylphenyl)pyrrole-3-carboxamide Chemical compound CC=1N(C=2C(=CC(Cl)=CC=2)C(F)(F)F)C(C[C@@H](O)C)=CC=1C(=O)NC1=CC=C(S(C)(=O)=O)C=C1 FZPJYKNUNFUEGS-ZDUSSCGKSA-N 0.000 claims description 4
- GFILFLBJFUSGFU-ZDUSSCGKSA-N 1-[4-fluoro-2-(trifluoromethoxy)phenyl]-5-[(2s)-2-hydroxypropyl]-2-methyl-n-(4-methylsulfonylphenyl)pyrrole-3-carboxamide Chemical compound CC=1N(C=2C(=CC(F)=CC=2)OC(F)(F)F)C(C[C@@H](O)C)=CC=1C(=O)NC1=CC=C(S(C)(=O)=O)C=C1 GFILFLBJFUSGFU-ZDUSSCGKSA-N 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- FBTPYIWUMJFLLF-NSHDSACASA-N n-(3-chloro-4-sulfamoylphenyl)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-[(2s)-2-hydroxypropyl]-2-methylpyrrole-3-carboxamide Chemical compound CC=1N(C=2C(=CC(F)=CC=2)C(F)(F)F)C(C[C@@H](O)C)=CC=1C(=O)NC1=CC=C(S(N)(=O)=O)C(Cl)=C1 FBTPYIWUMJFLLF-NSHDSACASA-N 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- AIIMYNRWFVAVON-HNNXBMFYSA-N 1-(4-chloro-2-methylphenyl)-5-[(2s)-2-hydroxypropyl]-2-methyl-n-(4-methylsulfonylphenyl)pyrrole-3-carboxamide Chemical compound CC=1N(C=2C(=CC(Cl)=CC=2)C)C(C[C@@H](O)C)=CC=1C(=O)NC1=CC=C(S(C)(=O)=O)C=C1 AIIMYNRWFVAVON-HNNXBMFYSA-N 0.000 claims description 3
- PSZCHIZBNFBDFN-INIZCTEOSA-N 1-(4-fluoro-2-methylphenyl)-5-[(2s)-2-hydroxypropyl]-2-methyl-n-(3-methyl-4-methylsulfonylphenyl)pyrrole-3-carboxamide Chemical compound CC=1N(C=2C(=CC(F)=CC=2)C)C(C[C@@H](O)C)=CC=1C(=O)NC1=CC=C(S(C)(=O)=O)C(C)=C1 PSZCHIZBNFBDFN-INIZCTEOSA-N 0.000 claims description 3
- VTXSOQMOHSONEK-ZDUSSCGKSA-N 1-[2-(difluoromethoxy)-4-fluorophenyl]-5-[(2s)-2-hydroxypropyl]-2-methyl-n-(4-methylsulfonylphenyl)pyrrole-3-carboxamide Chemical compound CC=1N(C=2C(=CC(F)=CC=2)OC(F)F)C(C[C@@H](O)C)=CC=1C(=O)NC1=CC=C(S(C)(=O)=O)C=C1 VTXSOQMOHSONEK-ZDUSSCGKSA-N 0.000 claims description 3
- LNRCOLUXWSJHNJ-CYBMUJFWSA-N 1-[4-chloro-2-(trifluoromethyl)phenyl]-5-[(2r)-2-fluoropropyl]-2-methyl-n-(4-methylsulfonylphenyl)pyrrole-3-carboxamide Chemical compound CC=1N(C=2C(=CC(Cl)=CC=2)C(F)(F)F)C(C[C@H](F)C)=CC=1C(=O)NC1=CC=C(S(C)(=O)=O)C=C1 LNRCOLUXWSJHNJ-CYBMUJFWSA-N 0.000 claims description 3
- KIYWDCNTYBVXFR-ZDUSSCGKSA-N 1-[4-fluoro-2-(trifluoromethyl)phenyl]-5-[(2s)-2-hydroxypropyl]-2-methyl-n-(3-methyl-4-sulfamoylphenyl)pyrrole-3-carboxamide Chemical compound CC=1N(C=2C(=CC(F)=CC=2)C(F)(F)F)C(C[C@@H](O)C)=CC=1C(=O)NC1=CC=C(S(N)(=O)=O)C(C)=C1 KIYWDCNTYBVXFR-ZDUSSCGKSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 230000002401 inhibitory effect Effects 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- MJGXNSYWRGMXJC-HNNXBMFYSA-N 1-(4-fluoro-2-methylphenyl)-5-[(2s)-2-hydroxypropyl]-2-methyl-n-(4-methylsulfonylphenyl)pyrrole-3-carboxamide Chemical compound CC=1N(C=2C(=CC(F)=CC=2)C)C(C[C@@H](O)C)=CC=1C(=O)NC1=CC=C(S(C)(=O)=O)C=C1 MJGXNSYWRGMXJC-HNNXBMFYSA-N 0.000 claims description 2
- KCGARYQTZZSKBQ-AWEZNQCLSA-N 1-[2-(difluoromethoxy)-4-fluorophenyl]-2-ethyl-5-[(2s)-2-hydroxypropyl]-n-(4-methylsulfonylphenyl)pyrrole-3-carboxamide Chemical compound CCC1=C(C(=O)NC=2C=CC(=CC=2)S(C)(=O)=O)C=C(C[C@H](C)O)N1C1=CC=C(F)C=C1OC(F)F KCGARYQTZZSKBQ-AWEZNQCLSA-N 0.000 claims description 2
- OWWNPKCCJAMTKQ-CYBMUJFWSA-N 1-[4-chloro-2-(difluoromethoxy)phenyl]-5-[(2r)-2-fluoropropyl]-2-methyl-n-(4-methylsulfonylphenyl)pyrrole-3-carboxamide Chemical compound CC=1N(C=2C(=CC(Cl)=CC=2)OC(F)F)C(C[C@H](F)C)=CC=1C(=O)NC1=CC=C(S(C)(=O)=O)C=C1 OWWNPKCCJAMTKQ-CYBMUJFWSA-N 0.000 claims description 2
- IHWDSEPNZDYMNF-UHFFFAOYSA-N 1H-indol-2-amine Chemical compound C1=CC=C2NC(N)=CC2=C1 IHWDSEPNZDYMNF-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 230000001404 mediated effect Effects 0.000 claims description 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims description 2
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 2
- GUKPXCNCKVJPOE-UHFFFAOYSA-N 1-[4-chloro-2-(trifluoromethyl)phenyl]-5-(2-hydroxyethyl)-2-methyl-n-(4-methylsulfonylphenyl)pyrrole-3-carboxamide Chemical compound CC1=C(C(=O)NC=2C=CC(=CC=2)S(C)(=O)=O)C=C(CCO)N1C1=CC=C(Cl)C=C1C(F)(F)F GUKPXCNCKVJPOE-UHFFFAOYSA-N 0.000 claims 1
- 239000002904 solvent Substances 0.000 description 268
- 238000004128 high performance liquid chromatography Methods 0.000 description 226
- JXMQGRHLXOEQJI-UHFFFAOYSA-N ethanol;hexane;methanol Chemical compound OC.CCO.CCCCCC JXMQGRHLXOEQJI-UHFFFAOYSA-N 0.000 description 155
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 154
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 149
- 238000000132 electrospray ionisation Methods 0.000 description 148
- 238000005160 1H NMR spectroscopy Methods 0.000 description 136
- 238000004896 high resolution mass spectrometry Methods 0.000 description 83
- 239000003480 eluent Substances 0.000 description 76
- 230000000052 comparative effect Effects 0.000 description 70
- 235000019439 ethyl acetate Nutrition 0.000 description 67
- 239000000243 solution Substances 0.000 description 65
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 63
- 238000006243 chemical reaction Methods 0.000 description 62
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 52
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
- 238000004587 chromatography analysis Methods 0.000 description 51
- 238000000926 separation method Methods 0.000 description 51
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 42
- ZYBWTEQKHIADDQ-UHFFFAOYSA-N ethanol;methanol Chemical compound OC.CCO ZYBWTEQKHIADDQ-UHFFFAOYSA-N 0.000 description 40
- 230000002829 reductive effect Effects 0.000 description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 38
- 238000000034 method Methods 0.000 description 31
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 28
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 229910052938 sodium sulfate Inorganic materials 0.000 description 27
- 235000011152 sodium sulphate Nutrition 0.000 description 27
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 26
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 25
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 20
- 125000003396 thiol group Chemical class [H]S* 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- WRHZVMBBRYBTKZ-UHFFFAOYSA-N pyrrole-2-carboxylic acid Chemical class OC(=O)C1=CC=CN1 WRHZVMBBRYBTKZ-UHFFFAOYSA-N 0.000 description 16
- 239000011541 reaction mixture Substances 0.000 description 16
- 229920006395 saturated elastomer Polymers 0.000 description 16
- 239000012044 organic layer Substances 0.000 description 15
- 238000012360 testing method Methods 0.000 description 15
- 101100441092 Danio rerio crlf3 gene Proteins 0.000 description 14
- 238000000524 positive electrospray ionisation mass spectrometry Methods 0.000 description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
- 150000001448 anilines Chemical class 0.000 description 11
- 239000007810 chemical reaction solvent Substances 0.000 description 11
- 238000001514 detection method Methods 0.000 description 11
- 239000011734 sodium Substances 0.000 description 11
- 239000007864 aqueous solution Substances 0.000 description 10
- 238000010531 catalytic reduction reaction Methods 0.000 description 10
- 238000001816 cooling Methods 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- GCFHZZWXZLABBL-UHFFFAOYSA-N ethanol;hexane Chemical compound CCO.CCCCCC GCFHZZWXZLABBL-UHFFFAOYSA-N 0.000 description 9
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- 238000009835 boiling Methods 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 6
- RNOVGJWJVRESAA-UHFFFAOYSA-N 4-fluoro-2-(trifluoromethyl)phenol Chemical group OC1=CC=C(F)C=C1C(F)(F)F RNOVGJWJVRESAA-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 125000005594 diketone group Chemical group 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- 230000037361 pathway Effects 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 6
- APOYTRAZFJURPB-UHFFFAOYSA-N 2-methoxy-n-(2-methoxyethyl)-n-(trifluoro-$l^{4}-sulfanyl)ethanamine Chemical compound COCCN(S(F)(F)F)CCOC APOYTRAZFJURPB-UHFFFAOYSA-N 0.000 description 5
- 108060001084 Luciferase Proteins 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 208000019622 heart disease Diseases 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- SAVQQRYWWAGSQW-UHFFFAOYSA-N n-methyl-n-(trifluoro-$l^{4}-sulfanyl)methanamine Chemical compound CN(C)S(F)(F)F SAVQQRYWWAGSQW-UHFFFAOYSA-N 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 230000000144 pharmacologic effect Effects 0.000 description 5
- 230000036470 plasma concentration Effects 0.000 description 5
- 210000002706 plastid Anatomy 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical compound CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 239000004215 Carbon black (E152) Substances 0.000 description 4
- 206010007558 Cardiac failure chronic Diseases 0.000 description 4
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
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- 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
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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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
- 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
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/42—Nitro radicals
-
- 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
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Diabetes (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Endocrinology (AREA)
- Physical Education & Sports Medicine (AREA)
- Biomedical Technology (AREA)
- Hospice & Palliative Care (AREA)
- Vascular Medicine (AREA)
- Emergency Medicine (AREA)
- Obesity (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10380408P | 2008-10-08 | 2008-10-08 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| TW201028376A TW201028376A (en) | 2010-08-01 |
| TWI460161B true TWI460161B (zh) | 2014-11-11 |
Family
ID=41328965
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW098134159A TWI460161B (zh) | 2008-10-08 | 2009-10-08 | １－苯基吡咯化合物 |
| TW103129290A TWI532717B (zh) | 2008-10-08 | 2009-10-08 | １-苯基吡咯化合物 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW103129290A TWI532717B (zh) | 2008-10-08 | 2009-10-08 | １-苯基吡咯化合物 |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US8642640B2 (OSRAM) |
| EP (1) | EP2349996B1 (OSRAM) |
| JP (2) | JP5767587B2 (OSRAM) |
| KR (1) | KR101671868B1 (OSRAM) |
| CN (1) | CN102177137B (OSRAM) |
| AU (1) | AU2009302375B2 (OSRAM) |
| BR (1) | BRPI0920551B1 (OSRAM) |
| CA (1) | CA2736930C (OSRAM) |
| ES (1) | ES2453500T3 (OSRAM) |
| IL (1) | IL212171A (OSRAM) |
| TW (2) | TWI460161B (OSRAM) |
| WO (1) | WO2010042626A1 (OSRAM) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2349996B1 (en) * | 2008-10-08 | 2014-01-01 | Exelixis, Inc. | 1-phenylpyrrole compounds |
| CN104447484B (zh) * | 2015-01-13 | 2016-06-08 | 佛山市赛维斯医药科技有限公司 | 含烷氧苯基和二烯金刚烷结构的化合物、其制备方法和用途 |
| CN104478781A (zh) * | 2015-01-13 | 2015-04-01 | 佛山市赛维斯医药科技有限公司 | 二烯金刚烷类化合物、其制备方法和用途 |
| CN104447485A (zh) * | 2015-01-13 | 2015-03-25 | 佛山市赛维斯医药科技有限公司 | 一种含腈基苯和二烯金刚烷结构的化合物、其制备方法和用途 |
| CN104478782B (zh) * | 2015-01-13 | 2016-03-16 | 佛山市赛维斯医药科技有限公司 | 一类含烷氧苯基和二烯氟代金刚烷结构的化合物和用途 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006012642A2 (en) * | 2004-07-30 | 2006-02-02 | Exelixis, Inc. | Pyrrole derivatives as pharmaceutical agents |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008126831A1 (ja) * | 2007-04-09 | 2008-10-23 | Daiichi Sankyo Company, Limited | ピロール誘導体のアトロプ異性体 |
| EP2349996B1 (en) * | 2008-10-08 | 2014-01-01 | Exelixis, Inc. | 1-phenylpyrrole compounds |
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2009
- 2009-10-07 EP EP09793339.4A patent/EP2349996B1/en active Active
- 2009-10-07 BR BRPI0920551-9A patent/BRPI0920551B1/pt active IP Right Grant
- 2009-10-07 ES ES09793339.4T patent/ES2453500T3/es active Active
- 2009-10-07 CA CA2736930A patent/CA2736930C/en active Active
- 2009-10-07 WO PCT/US2009/059852 patent/WO2010042626A1/en not_active Ceased
- 2009-10-07 JP JP2011531142A patent/JP5767587B2/ja active Active
- 2009-10-07 KR KR1020117010429A patent/KR101671868B1/ko active Active
- 2009-10-07 AU AU2009302375A patent/AU2009302375B2/en active Active
- 2009-10-07 CN CN200980139825.9A patent/CN102177137B/zh active Active
- 2009-10-07 US US13/122,239 patent/US8642640B2/en active Active
- 2009-10-08 TW TW098134159A patent/TWI460161B/zh active
- 2009-10-08 TW TW103129290A patent/TWI532717B/zh active
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2011
- 2011-04-06 IL IL212171A patent/IL212171A/en active IP Right Grant
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2014
- 2014-07-22 JP JP2014148863A patent/JP5837655B2/ja active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006012642A2 (en) * | 2004-07-30 | 2006-02-02 | Exelixis, Inc. | Pyrrole derivatives as pharmaceutical agents |
Also Published As
| Publication number | Publication date |
|---|---|
| JP5767587B2 (ja) | 2015-08-19 |
| CN102177137B (zh) | 2015-03-18 |
| CA2736930C (en) | 2016-11-22 |
| EP2349996A1 (en) | 2011-08-03 |
| AU2009302375A1 (en) | 2010-04-15 |
| CA2736930A1 (en) | 2010-04-15 |
| HK1155162A1 (en) | 2012-05-11 |
| WO2010042626A1 (en) | 2010-04-15 |
| ES2453500T3 (es) | 2014-04-08 |
| TWI532717B (zh) | 2016-05-11 |
| BRPI0920551B1 (pt) | 2021-12-14 |
| JP5837655B2 (ja) | 2015-12-24 |
| IL212171A0 (en) | 2011-06-30 |
| EP2349996B1 (en) | 2014-01-01 |
| BRPI0920551A2 (pt) | 2020-08-11 |
| AU2009302375B2 (en) | 2015-03-26 |
| JP2014196366A (ja) | 2014-10-16 |
| JP2012505226A (ja) | 2012-03-01 |
| KR101671868B1 (ko) | 2016-11-03 |
| CN102177137A (zh) | 2011-09-07 |
| US20110263544A1 (en) | 2011-10-27 |
| US8642640B2 (en) | 2014-02-04 |
| IL212171A (en) | 2015-11-30 |
| KR20110091664A (ko) | 2011-08-12 |
| TW201028376A (en) | 2010-08-01 |
| TW201514144A (zh) | 2015-04-16 |
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