JPH06211846A - ベンゾフラン誘導体 - Google Patents
ベンゾフラン誘導体Info
- Publication number
- JPH06211846A JPH06211846A JP4148890A JP14889092A JPH06211846A JP H06211846 A JPH06211846 A JP H06211846A JP 4148890 A JP4148890 A JP 4148890A JP 14889092 A JP14889092 A JP 14889092A JP H06211846 A JPH06211846 A JP H06211846A
- Authority
- JP
- Japan
- Prior art keywords
- group
- methyl
- phenyl
- imidazole
- benzofuranyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000001907 coumarones Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 250
- -1 (substituted) phenyl group Chemical group 0.000 claims abstract description 78
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 72
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 48
- 150000003839 salts Chemical class 0.000 claims abstract description 48
- 150000002148 esters Chemical class 0.000 claims abstract description 33
- 125000005843 halogen group Chemical group 0.000 claims abstract description 31
- 239000012453 solvate Substances 0.000 claims abstract description 27
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 24
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 15
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims abstract description 14
- 206010020772 Hypertension Diseases 0.000 claims abstract description 6
- 230000000694 effects Effects 0.000 claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- 125000002883 imidazolyl group Chemical group 0.000 claims abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 104
- 239000000203 mixture Substances 0.000 claims description 92
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 88
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 77
- 238000000034 method Methods 0.000 claims description 63
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 45
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 45
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 40
- 239000000126 substance Substances 0.000 claims description 37
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 36
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 33
- 238000006243 chemical reaction Methods 0.000 claims description 28
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 24
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 claims description 14
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 13
- 102000005862 Angiotensin II Human genes 0.000 claims description 13
- 101800000733 Angiotensin-2 Proteins 0.000 claims description 13
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 claims description 13
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 13
- 229950006323 angiotensin ii Drugs 0.000 claims description 13
- 125000006239 protecting group Chemical group 0.000 claims description 13
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 12
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 12
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 11
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 10
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical group C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 9
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 7
- 229910021529 ammonia Inorganic materials 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 229940124597 therapeutic agent Drugs 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 230000004913 activation Effects 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 125000002560 nitrile group Chemical group 0.000 claims description 5
- 230000036454 renin-angiotensin system Effects 0.000 claims description 5
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 4
- 206010019280 Heart failures Diseases 0.000 claims description 4
- 208000001647 Renal Insufficiency Diseases 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 claims description 4
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 4
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 4
- 201000006370 kidney failure Diseases 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 150000001540 azides Chemical class 0.000 claims description 3
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 claims description 2
- ZBNZAJFNDPPMDT-UHFFFAOYSA-N 1h-imidazole-5-carboxamide Chemical compound NC(=O)C1=CNC=N1 ZBNZAJFNDPPMDT-UHFFFAOYSA-N 0.000 claims description 2
- UKYSONBAJBLFOD-UHFFFAOYSA-N 3-[[3-bromo-2-[2-(2h-tetrazol-5-yl)phenyl]-1-benzofuran-5-yl]methyl]-5-(cyclopropylmethyl)-2-ethylimidazole-4-carboxylic acid Chemical compound OC(=O)C=1N(CC=2C=C3C(Br)=C(OC3=CC=2)C=2C(=CC=CC=2)C2=NNN=N2)C(CC)=NC=1CC1CC1 UKYSONBAJBLFOD-UHFFFAOYSA-N 0.000 claims description 2
- VXXBNGSRGUWFTR-UHFFFAOYSA-N 3-[[3-bromo-2-[2-(2h-tetrazol-5-yl)phenyl]-1-benzofuran-5-yl]methyl]-5-cyclobutyl-2-ethylimidazole-4-carboxylic acid Chemical compound OC(=O)C=1N(CC=2C=C3C(Br)=C(OC3=CC=2)C=2C(=CC=CC=2)C2=NNN=N2)C(CC)=NC=1C1CCC1 VXXBNGSRGUWFTR-UHFFFAOYSA-N 0.000 claims description 2
- ICLFISNVDHVULF-UHFFFAOYSA-N 3-[[3-bromo-2-[2-(2h-tetrazol-5-yl)phenyl]-1-benzofuran-5-yl]methyl]-5-cyclopropyl-2-ethylimidazole-4-carboxylic acid Chemical compound OC(=O)C=1N(CC=2C=C3C(Br)=C(OC3=CC=2)C=2C(=CC=CC=2)C2=NNN=N2)C(CC)=NC=1C1CC1 ICLFISNVDHVULF-UHFFFAOYSA-N 0.000 claims description 2
- ZVHUSJOGBRWGCR-UHFFFAOYSA-N 3-[[3-bromo-2-[2-(trifluoromethylsulfonylamino)phenyl]-1-benzofuran-5-yl]methyl]-5-(cyclopropylmethyl)-2-ethyl-n-methylimidazole-4-carboxamide Chemical compound CNC(=O)C=1N(CC=2C=C3C(Br)=C(OC3=CC=2)C=2C(=CC=CC=2)NS(=O)(=O)C(F)(F)F)C(CC)=NC=1CC1CC1 ZVHUSJOGBRWGCR-UHFFFAOYSA-N 0.000 claims description 2
- TVUWISBVVWFASM-UHFFFAOYSA-N 3-[[3-bromo-2-[2-(trifluoromethylsulfonylamino)phenyl]-1-benzofuran-5-yl]methyl]-5-(cyclopropylmethyl)-2-ethylimidazole-4-carboxamide Chemical compound NC(=O)C=1N(CC=2C=C3C(Br)=C(OC3=CC=2)C=2C(=CC=CC=2)NS(=O)(=O)C(F)(F)F)C(CC)=NC=1CC1CC1 TVUWISBVVWFASM-UHFFFAOYSA-N 0.000 claims description 2
- FWWLWNQJAYHTMG-UHFFFAOYSA-N 3-[[3-bromo-2-[2-(trifluoromethylsulfonylamino)phenyl]-1-benzofuran-5-yl]methyl]-5-(cyclopropylmethyl)-n,2-diethylimidazole-4-carboxamide Chemical compound N1=C(CC)N(CC=2C=C3C(Br)=C(OC3=CC=2)C=2C(=CC=CC=2)NS(=O)(=O)C(F)(F)F)C(C(=O)NCC)=C1CC1CC1 FWWLWNQJAYHTMG-UHFFFAOYSA-N 0.000 claims description 2
- HOVPCXWALSSBGA-UHFFFAOYSA-N 3-[[3-bromo-2-[2-(trifluoromethylsulfonylamino)phenyl]-1-benzofuran-5-yl]methyl]-5-chloro-2-ethoxy-n-ethylimidazole-4-carboxamide Chemical compound CCNC(=O)C1=C(Cl)N=C(OCC)N1CC1=CC=C(OC(=C2Br)C=3C(=CC=CC=3)NS(=O)(=O)C(F)(F)F)C2=C1 HOVPCXWALSSBGA-UHFFFAOYSA-N 0.000 claims description 2
- YTGCRALAOPELLH-UHFFFAOYSA-N 3-[[3-bromo-2-[2-(trifluoromethylsulfonylamino)phenyl]-1-benzofuran-5-yl]methyl]-5-cyclobutyl-2-ethyl-n-methylimidazole-4-carboxamide Chemical compound CNC(=O)C=1N(CC=2C=C3C(Br)=C(OC3=CC=2)C=2C(=CC=CC=2)NS(=O)(=O)C(F)(F)F)C(CC)=NC=1C1CCC1 YTGCRALAOPELLH-UHFFFAOYSA-N 0.000 claims description 2
- BYNAJWQGAOURNE-UHFFFAOYSA-N 3-[[3-bromo-2-[2-(trifluoromethylsulfonylamino)phenyl]-1-benzofuran-5-yl]methyl]-5-cyclobutyl-n,2-diethylimidazole-4-carboxamide Chemical compound CCNC(=O)C1=C(C2CCC2)N=C(CC)N1CC(C=C1C=2Br)=CC=C1OC=2C1=CC=CC=C1NS(=O)(=O)C(F)(F)F BYNAJWQGAOURNE-UHFFFAOYSA-N 0.000 claims description 2
- AAODMQBTFSFVGS-UHFFFAOYSA-N 3-[[3-bromo-2-[2-(trifluoromethylsulfonylamino)phenyl]-1-benzofuran-5-yl]methyl]-5-cyclopropyl-2-ethyl-n-methylimidazole-4-carboxamide Chemical compound CNC(=O)C=1N(CC=2C=C3C(Br)=C(OC3=CC=2)C=2C(=CC=CC=2)NS(=O)(=O)C(F)(F)F)C(CC)=NC=1C1CC1 AAODMQBTFSFVGS-UHFFFAOYSA-N 0.000 claims description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 2
- 208000024827 Alzheimer disease Diseases 0.000 claims description 2
- 208000019901 Anxiety disease Diseases 0.000 claims description 2
- 201000001320 Atherosclerosis Diseases 0.000 claims description 2
- 208000012904 Bartter disease Diseases 0.000 claims description 2
- 208000010062 Bartter syndrome Diseases 0.000 claims description 2
- 206010007556 Cardiac failure acute Diseases 0.000 claims description 2
- 206010007558 Cardiac failure chronic Diseases 0.000 claims description 2
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 2
- 206010012289 Dementia Diseases 0.000 claims description 2
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 2
- 206010018364 Glomerulonephritis Diseases 0.000 claims description 2
- 208000018262 Peripheral vascular disease Diseases 0.000 claims description 2
- 208000003782 Raynaud disease Diseases 0.000 claims description 2
- 208000012322 Raynaud phenomenon Diseases 0.000 claims description 2
- DUEWVPTZCSAMNB-UHFFFAOYSA-N Saprisartan Chemical compound NC(=O)C=1N(CC=2C=C3C(Br)=C(OC3=CC=2)C=2C(=CC=CC=2)NS(=O)(=O)C(F)(F)F)C(CC)=NC=1C1CC1 DUEWVPTZCSAMNB-UHFFFAOYSA-N 0.000 claims description 2
- 206010039710 Scleroderma Diseases 0.000 claims description 2
- 230000001154 acute effect Effects 0.000 claims description 2
- 150000004703 alkoxides Chemical class 0.000 claims description 2
- 208000015114 central nervous system disease Diseases 0.000 claims description 2
- 229960003920 cocaine Drugs 0.000 claims description 2
- 208000010877 cognitive disease Diseases 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 2
- 208000010125 myocardial infarction Diseases 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 230000000269 nucleophilic effect Effects 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 201000001474 proteinuria Diseases 0.000 claims description 2
- 201000000980 schizophrenia Diseases 0.000 claims description 2
- 230000002792 vascular Effects 0.000 claims description 2
- WOBINWGBDIMJLA-UHFFFAOYSA-N 3-[[3-bromo-2-[2-(trifluoromethylsulfonylamino)phenyl]-1-benzofuran-5-yl]methyl]-5-cyclobutyl-2-ethylimidazole-4-carboxamide Chemical compound NC(=O)C=1N(CC=2C=C3C(Br)=C(OC3=CC=2)C=2C(=CC=CC=2)NS(=O)(=O)C(F)(F)F)C(CC)=NC=1C1CCC1 WOBINWGBDIMJLA-UHFFFAOYSA-N 0.000 claims 1
- 210000001765 aortic valve Anatomy 0.000 claims 1
- 230000036523 atherogenesis Effects 0.000 claims 1
- 206010012601 diabetes mellitus Diseases 0.000 claims 1
- 208000017169 kidney disease Diseases 0.000 claims 1
- 230000035479 physiological effects, processes and functions Effects 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 claims 1
- 201000010099 disease Diseases 0.000 abstract description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 5
- 239000000543 intermediate Substances 0.000 description 208
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 157
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 149
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 87
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 78
- 238000004809 thin layer chromatography Methods 0.000 description 78
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 75
- 239000000243 solution Substances 0.000 description 75
- 239000007787 solid Substances 0.000 description 72
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
- 239000002904 solvent Substances 0.000 description 58
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 52
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 48
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 48
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 45
- 239000000047 product Substances 0.000 description 44
- 235000019441 ethanol Nutrition 0.000 description 40
- 238000003756 stirring Methods 0.000 description 40
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 38
- 238000010992 reflux Methods 0.000 description 35
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- 239000012299 nitrogen atmosphere Substances 0.000 description 30
- 239000006260 foam Substances 0.000 description 27
- 239000000284 extract Substances 0.000 description 26
- 239000000725 suspension Substances 0.000 description 24
- 239000000843 powder Substances 0.000 description 20
- 239000012267 brine Substances 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- 239000002585 base Substances 0.000 description 16
- 238000003818 flash chromatography Methods 0.000 description 16
- 239000008346 aqueous phase Substances 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 14
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 13
- 238000002844 melting Methods 0.000 description 13
- 230000008018 melting Effects 0.000 description 13
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 12
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 11
- 239000004480 active ingredient Substances 0.000 description 11
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 11
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 9
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 description 9
- 239000003826 tablet Substances 0.000 description 9
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
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- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- LYRCQNDYYRPFMF-UHFFFAOYSA-N trimethyltin Chemical compound C[Sn](C)C LYRCQNDYYRPFMF-UHFFFAOYSA-N 0.000 description 1
- JEJAMASKDTUEBZ-UHFFFAOYSA-N tris(1,1,3-tribromo-2,2-dimethylpropyl) phosphate Chemical compound BrCC(C)(C)C(Br)(Br)OP(=O)(OC(Br)(Br)C(C)(C)CBr)OC(Br)(Br)C(C)(C)CBr JEJAMASKDTUEBZ-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 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
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- 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
- A61K31/415—1,2-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/20—Hypnotics; Sedatives
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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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
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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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
- A61P9/08—Vasodilators for multiple indications
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- A—HUMAN NECESSITIES
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- 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
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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
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole 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
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Psychiatry (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Urology & Nephrology (AREA)
- Addiction (AREA)
- Ophthalmology & Optometry (AREA)
- Vascular Medicine (AREA)
- Hospice & Palliative Care (AREA)
- Pain & Pain Management (AREA)
- Anesthesiology (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9110636.9 | 1991-05-16 | ||
| GB919110636A GB9110636D0 (en) | 1991-05-16 | 1991-05-16 | Chemical compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH06211846A true JPH06211846A (ja) | 1994-08-02 |
Family
ID=10695121
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4148890A Pending JPH06211846A (ja) | 1991-05-16 | 1992-05-15 | ベンゾフラン誘導体 |
Country Status (21)
| Country | Link |
|---|---|
| US (2) | US5332831A (enExample) |
| EP (1) | EP0514198B1 (enExample) |
| JP (1) | JPH06211846A (enExample) |
| KR (1) | KR920021541A (enExample) |
| AP (1) | AP318A (enExample) |
| AT (1) | ATE169297T1 (enExample) |
| AU (2) | AU1692692A (enExample) |
| BG (1) | BG98216A (enExample) |
| CA (1) | CA2068766A1 (enExample) |
| CZ (1) | CZ243093A3 (enExample) |
| DE (1) | DE69226472D1 (enExample) |
| FI (1) | FI935036A7 (enExample) |
| GB (1) | GB9110636D0 (enExample) |
| IL (1) | IL101882A0 (enExample) |
| IS (1) | IS1609B (enExample) |
| MX (1) | MX9202281A (enExample) |
| NO (1) | NO921944L (enExample) |
| OA (1) | OA09841A (enExample) |
| SK (1) | SK112893A3 (enExample) |
| TW (1) | TW221998B (enExample) |
| WO (1) | WO1992020674A1 (enExample) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008120800A1 (ja) | 2007-04-03 | 2008-10-09 | Shikoku Chemicals Corporation | ２－ハロイミダゾール化合物の製造方法 |
Families Citing this family (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9218449D0 (en) | 1992-08-29 | 1992-10-14 | Boots Co Plc | Therapeutic agents |
| US5336779A (en) * | 1992-10-08 | 1994-08-09 | Nippon Gohsei Kagaku Kogyo Kabushiki Kaisha | Method of producing formylimidazoles |
| DK0853477T3 (da) * | 1995-10-06 | 2003-02-10 | Novartis Ag | AT1-receptor-antagonister til forebyggelse og behandling af postiskæmisk nyresvigt og til beskyttelse af iskæmiske nyrer |
| JP4369994B2 (ja) | 1996-02-29 | 2009-11-25 | ノバルティス アクチエンゲゼルシャフト | アポトーシスの刺激のためのａｔ▲下１▼レセプターアンタゴニスト |
| KR100567183B1 (ko) * | 1997-11-14 | 2006-06-13 | 론자 아게 | 포르밀이미다졸의제조방법 |
| US6465502B1 (en) | 1998-12-23 | 2002-10-15 | Novartis Ag | Additional therapeutic use |
| RU2271809C2 (ru) | 1998-12-23 | 2006-03-20 | Новартис Аг | Применение антагониста рецептора at-1 или модулятора рецептора ат-2 для лечения болезней, связанных с увеличением содержания рецепторов ат-1 или ат-2 |
| CN101011390A (zh) | 1999-01-26 | 2007-08-08 | 诺瓦提斯公司 | 血管紧张素ⅱ受体拮抗剂在治疗急性心肌梗塞中的应用 |
| US6211217B1 (en) | 1999-03-16 | 2001-04-03 | Novartis Ag | Method for reducing pericardial fibrosis and adhesion formation |
| DE60037192T2 (de) * | 1999-07-21 | 2008-05-15 | Takeda Pharmaceutical Co. Ltd. | Mittel zur verbesserung der erkrankungen nach zerebralen durchblutungsstörungen sowie zur verhinderung deren fortschreitens |
| SE9903028D0 (sv) | 1999-08-27 | 1999-08-27 | Astra Ab | New use |
| US6794405B2 (en) * | 2000-08-17 | 2004-09-21 | Merck & Co., Inc. | Alicyclic imidazoles as H3 agents |
| DE10335027A1 (de) | 2003-07-31 | 2005-02-17 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verwendung von Angiotensin II Rezeptor Antagonisten |
| ES2560247T3 (es) * | 2006-05-05 | 2016-02-18 | Dow Global Technologies Llc | Complejos de hafnio de ligandos orgánicos heterocíclicos |
| AU2007292155B2 (en) | 2006-09-05 | 2012-11-01 | Kyowa Kirin Co., Ltd. | Imidazole derivative |
| EP1908469A1 (en) | 2006-10-06 | 2008-04-09 | Boehringer Ingelheim Vetmedica Gmbh | Angiotensin II receptor antagonist for the treatment of systemic diseases in cats |
| US8969514B2 (en) | 2007-06-04 | 2015-03-03 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
| CA2688161C (en) | 2007-06-04 | 2020-10-20 | Kunwar Shailubhai | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
| EP2328910B1 (en) | 2008-06-04 | 2014-08-06 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
| US9616097B2 (en) | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
| WO2014151206A1 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
| HK1220611A1 (zh) | 2013-03-15 | 2017-05-12 | Bausch Health Ireland Limited | 用於治疗胃肠道病症的组成物 |
| CN113388007A (zh) | 2013-06-05 | 2021-09-14 | 博士医疗爱尔兰有限公司 | 鸟苷酸环化酶c的超纯激动剂、制备和使用所述激动剂的方法 |
| SI3648761T1 (sl) | 2017-07-07 | 2024-07-31 | Boehringer Ingelheim Vetmedica Gmbh | Telmisartan za profilakso ali zdravljenje hipertenzije pri mačkah |
| CN110256382A (zh) * | 2019-06-06 | 2019-09-20 | 武汉药明康德新药开发有限公司 | 一种2-(5-甲基苯并呋喃-2-基)苯甲腈的合成方法 |
| CN121175053A (zh) | 2023-05-24 | 2025-12-19 | 勃林格殷格翰动物保健有限公司 | 包含一或多种sglt-2抑制剂及替米沙坦的非人类哺乳动物中肾脏疾病和/或高血压的组合治疗和/或预防 |
| WO2025125409A1 (en) | 2023-12-15 | 2025-06-19 | Boehringer Ingelheim Vetmedica Gmbh | Angiotensin ii receptor antagonist for the prevention of systemic diseases in cats |
Family Cites Families (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1389827A (en) * | 1971-07-23 | 1975-04-09 | Fisons Ltd | Tetrazolyl benzopyrans |
| JPS54148788A (en) * | 1978-05-15 | 1979-11-21 | Takeda Chem Ind Ltd | 1,2-disubstituted-4-halogenoimidazole-5-acetic acid derivative and its preparation |
| US4526896A (en) * | 1978-12-26 | 1985-07-02 | Riker Laboratories, Inc. | Tetrazol-5-yl 2-nitro-3-phenylbenzofurans and antimicrobial use thereof |
| JPS5671073A (en) * | 1979-11-12 | 1981-06-13 | Takeda Chem Ind Ltd | Imidazole derivative |
| JPS5671074A (en) * | 1979-11-12 | 1981-06-13 | Takeda Chem Ind Ltd | 1,2-disubstituted-4-halogenoimidazole-5-acetic acid derivative |
| ZA824343B (en) * | 1981-07-01 | 1983-04-27 | Upjohn Co | Pyridinyl- and imidazolyl-benzofurane and benzothiophenes |
| JPS6163671A (ja) * | 1984-09-05 | 1986-04-01 | Shionogi & Co Ltd | ２，３−ジヒドロベンゾフラン−５−スルホンアミド誘導体および降圧利尿剤 |
| CA1334092C (en) * | 1986-07-11 | 1995-01-24 | David John Carini | Angiotensin ii receptor blocking imidazoles |
| US4916129A (en) * | 1989-01-19 | 1990-04-10 | E. I. Du Pont De Nemours And Company | Combination β-blocking/angiotensin II blocking antihypertensives |
| EP0403159B1 (en) * | 1989-06-14 | 2000-03-01 | Smithkline Beecham Corporation | Imidazolyl-alkenoic acids |
| WO1991000277A1 (en) * | 1989-06-30 | 1991-01-10 | E.I. Du Pont De Nemours And Company | Substituted imidazoles |
| KR950009860B1 (ko) * | 1989-06-30 | 1995-08-29 | 이. 아이. 듀퐁 드 네모아 앤드 캄파니 | 융합된 환 아릴 치환된 이미다졸과 약제학적으로 허용되는 이의 염, 이들의 제조방법 및 이들을 함유하는 약제학적 조성물 |
| JPH03204875A (ja) * | 1989-10-03 | 1991-09-06 | Wakamoto Pharmaceut Co Ltd | テトラゾール酢酸誘導体、及び該誘導体を有効成分とするアルドースレダクターゼ阻害剤 |
| CA2027937A1 (en) * | 1989-10-25 | 1991-04-26 | Richard M. Keenan | Substituted 5-¬ (tetrazolyl)alkenyl|imidazoles |
| CA2028925A1 (en) * | 1989-11-06 | 1991-05-07 | Gerald R. Girard | Substituted n-(imidazolyl)alkyl alanine derivatives |
| GB8927277D0 (en) * | 1989-12-01 | 1990-01-31 | Glaxo Group Ltd | Chemical compounds |
| US5190942A (en) * | 1991-04-22 | 1993-03-02 | E. R. Squibb & Sons, Inc. | Benzoxazole and related heterocyclic substituted imidazole and benzimidazole derivatives |
| IL101888A0 (en) * | 1991-05-16 | 1992-12-30 | Glaxo Group Ltd | Benzofuran derivatives,their preparation and pharmaceutical compositions containing them |
| DE4140519A1 (de) * | 1991-12-09 | 1993-06-17 | Merck Patent Gmbh | Benzofurane |
-
1991
- 1991-05-16 GB GB919110636A patent/GB9110636D0/en active Pending
-
1992
- 1992-05-15 NO NO92921944A patent/NO921944L/no unknown
- 1992-05-15 MX MX9202281A patent/MX9202281A/es unknown
- 1992-05-15 IL IL101882A patent/IL101882A0/xx unknown
- 1992-05-15 US US07/883,378 patent/US5332831A/en not_active Expired - Fee Related
- 1992-05-15 AP AP9200389A patent/AP318A/en active
- 1992-05-15 TW TW081103782A patent/TW221998B/zh active
- 1992-05-15 WO PCT/GB1992/000888 patent/WO1992020674A1/en not_active Ceased
- 1992-05-15 AU AU16926/92A patent/AU1692692A/en not_active Abandoned
- 1992-05-15 CA CA002068766A patent/CA2068766A1/en not_active Abandoned
- 1992-05-15 CZ CS932430A patent/CZ243093A3/cs unknown
- 1992-05-15 AU AU16321/92A patent/AU654350B2/en not_active Ceased
- 1992-05-15 DE DE69226472T patent/DE69226472D1/de not_active Expired - Lifetime
- 1992-05-15 KR KR1019920008241A patent/KR920021541A/ko not_active Ceased
- 1992-05-15 IS IS3865A patent/IS1609B/is unknown
- 1992-05-15 AT AT92304420T patent/ATE169297T1/de not_active IP Right Cessation
- 1992-05-15 EP EP92304420A patent/EP0514198B1/en not_active Expired - Lifetime
- 1992-05-15 SK SK1128-93A patent/SK112893A3/sk unknown
- 1992-05-15 JP JP4148890A patent/JPH06211846A/ja active Pending
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1993
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- 1993-11-12 BG BG98216A patent/BG98216A/xx unknown
- 1993-11-15 FI FI935036A patent/FI935036A7/fi not_active Application Discontinuation
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1994
- 1994-03-31 US US08/220,698 patent/US5498722A/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008120800A1 (ja) | 2007-04-03 | 2008-10-09 | Shikoku Chemicals Corporation | ２－ハロイミダゾール化合物の製造方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2068766A1 (en) | 1992-11-17 |
| EP0514198A1 (en) | 1992-11-19 |
| NO921944D0 (no) | 1992-05-15 |
| EP0514198B1 (en) | 1998-08-05 |
| US5332831A (en) | 1994-07-26 |
| TW221998B (enExample) | 1994-04-01 |
| FI935036A0 (fi) | 1993-11-15 |
| BG98216A (en) | 1994-08-15 |
| FI935036A7 (fi) | 1993-11-15 |
| NO921944L (no) | 1992-11-17 |
| GB9110636D0 (en) | 1991-07-03 |
| DE69226472D1 (de) | 1998-09-10 |
| AU654350B2 (en) | 1994-11-03 |
| WO1992020674A1 (en) | 1992-11-26 |
| AP318A (en) | 1994-02-15 |
| MX9202281A (es) | 1992-11-01 |
| IL101882A0 (en) | 1992-12-30 |
| SK112893A3 (en) | 1994-11-09 |
| AU1692692A (en) | 1992-12-30 |
| ATE169297T1 (de) | 1998-08-15 |
| OA09841A (en) | 1994-08-15 |
| IS3865A (is) | 1992-11-17 |
| KR920021541A (ko) | 1992-12-18 |
| AU1632192A (en) | 1993-03-11 |
| US5498722A (en) | 1996-03-12 |
| CZ243093A3 (en) | 1994-03-16 |
| IS1609B (is) | 1996-10-18 |
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