NL8920642A - Benzazepine- en benzothiazepinederivaten. - Google Patents

Benzazepine- en benzothiazepinederivaten. Download PDF

Info

Publication number: NL8920642A
Authority: NL; Netherlands
Prior art keywords: compound; methoxyphenyl; hydroxy; benzazepin; tetrahydro
Prior art date: 1988-06-20

Application number

NL8920642A

Other languages

English (en)

Dutch (nl)

Original Assignee

Squibb & Sons Inc

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

1988-06-20

Filing date

1989-05-23

Publication date

1990-06-01

1989-05-23 Application filed by Squibb & Sons Inc filed Critical Squibb & Sons Inc

1990-06-01 Publication of NL8920642A publication Critical patent/NL8920642A/nl

Links

DQFQCHIDRBIESA-UHFFFAOYSA-N 1-benzazepine Chemical compound N1C=CC=CC2=CC=CC=C12 DQFQCHIDRBIESA-UHFFFAOYSA-N 0.000 title description 5
150000007657 benzothiazepines Chemical class 0.000 title description 5
229940085242 benzothiazepine derivative selective calcium channel blockers with direct cardiac effects Drugs 0.000 title description 2
150000001875 compounds Chemical class 0.000 claims description 391
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 167
-1 cyano, hydroxyl Chemical group 0.000 claims description 124
125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 112
229910052739 hydrogen Inorganic materials 0.000 claims description 56
239000001257 hydrogen Substances 0.000 claims description 55
VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 46
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 44
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 43
125000000217 alkyl group Chemical group 0.000 claims description 36
150000002431 hydrogen Chemical group 0.000 claims description 27
125000003545 alkoxy group Chemical group 0.000 claims description 24
VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 24
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 23
239000001530 fumaric acid Substances 0.000 claims description 22
150000003839 salts Chemical class 0.000 claims description 22
238000000034 method Methods 0.000 claims description 19
125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 18
GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 claims description 18
125000000753 cycloalkyl group Chemical group 0.000 claims description 17
125000004104 aryloxy group Chemical group 0.000 claims description 15
125000003118 aryl group Chemical group 0.000 claims description 14
229910052799 carbon Inorganic materials 0.000 claims description 13
125000003710 aryl alkyl group Chemical group 0.000 claims description 12
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
125000003342 alkenyl group Chemical group 0.000 claims description 9
125000001072 heteroaryl group Chemical group 0.000 claims description 9
229910052757 nitrogen Inorganic materials 0.000 claims description 9
125000005129 aryl carbonyl group Chemical group 0.000 claims description 8
125000001589 carboacyl group Chemical group 0.000 claims description 8
150000001721 carbon Chemical group 0.000 claims description 8
229910052736 halogen Inorganic materials 0.000 claims description 8
150000002367 halogens Chemical group 0.000 claims description 8
125000005223 heteroarylcarbonyl group Chemical group 0.000 claims description 8
125000002757 morpholinyl group Chemical group 0.000 claims description 8
125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
125000003386 piperidinyl group Chemical group 0.000 claims description 8
125000000719 pyrrolidinyl group Chemical group 0.000 claims description 8
125000002102 aryl alkyloxo group Chemical group 0.000 claims description 7
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
125000004423 acyloxy group Chemical group 0.000 claims description 5
125000003282 alkyl amino group Chemical group 0.000 claims description 5
125000004663 dialkyl amino group Chemical group 0.000 claims description 5
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
HDFJYHCLMAGOGD-GHTZIAJQSA-N (3r,4s)-1-(4,5-dihydro-1h-imidazol-2-ylmethyl)-3-hydroxy-7-methoxy-4-(4-methoxyphenyl)-4,5-dihydro-3h-1-benzazepin-2-one Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](O)C(=O)N(CC=2NCCN=2)C2=CC=C(OC)C=C2C1 HDFJYHCLMAGOGD-GHTZIAJQSA-N 0.000 claims description 4
XTHOIFAGDPGJPZ-PQQJDVFMSA-N (e,2r,3r,4s,5r)-n-(2,3-dihydro-1h-inden-2-yl)-3,4,5-trihydroxy-2-methoxy-8,8-dimethylnon-6-enamide Chemical compound C1=CC=C2CC(NC(=O)[C@@H]([C@H](O)[C@@H](O)[C@H](O)\C=C\C(C)(C)C)OC)CC2=C1 XTHOIFAGDPGJPZ-PQQJDVFMSA-N 0.000 claims description 4
VSHUQLRHTJOKTA-XBXARRHUSA-N N-cis-Caffeoyltyramine Chemical compound C1=CC(O)=CC=C1CCNC(=O)\C=C\C1=CC=C(O)C(O)=C1 VSHUQLRHTJOKTA-XBXARRHUSA-N 0.000 claims description 4
125000000304 alkynyl group Chemical group 0.000 claims description 4
125000002393 azetidinyl group Chemical group 0.000 claims description 4
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
BFIFXQXZCRZRSP-HTAPYJJXSA-N [(3r,4s)-1-(4,5-dihydro-1h-imidazol-2-ylmethyl)-4-(4-methoxyphenyl)-2-oxo-6-(trifluoromethyl)-4,5-dihydro-3h-1-benzazepin-3-yl] acetate Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CC=2NCCN=2)C(C=CC=C2C(F)(F)F)=C2C1 BFIFXQXZCRZRSP-HTAPYJJXSA-N 0.000 claims description 3
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
229940124549 vasodilator Drugs 0.000 claims description 2
239000003071 vasodilator agent Substances 0.000 claims description 2
JRFXMBVSOFDOSL-NQIIRXRSSA-N (3s,4r)-1-(4,5-dihydro-1h-imidazol-2-ylmethyl)-3-hydroxy-4-(4-methoxyphenyl)-7-methyl-4,5-dihydro-3h-1-benzazepin-2-one Chemical compound C1=CC(OC)=CC=C1[C@@H]1[C@H](O)C(=O)N(CC=2NCCN=2)C2=CC=C(C)C=C2C1 JRFXMBVSOFDOSL-NQIIRXRSSA-N 0.000 claims 1
GARHCDOTUULBOQ-PKNBQFBNSA-N 4-{(1e)-3-oxo-3-[(2-phenylethyl)amino]prop-1-en-1-yl}-1,2-phenylene diacetate Chemical compound C1=C(OC(C)=O)C(OC(=O)C)=CC=C1\C=C\C(=O)NCCC1=CC=CC=C1 GARHCDOTUULBOQ-PKNBQFBNSA-N 0.000 claims 1
PNUKFZYTHSYPAL-NZQKXSOJSA-N [(3r,4s)-1-(4,5-dihydro-1h-imidazol-2-ylmethyl)-7-methoxy-4-(4-methoxyphenyl)-2-oxo-4,5-dihydro-3h-1-benzazepin-3-yl] acetate Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CC=2NCCN=2)C2=CC=C(OC)C=C2C1 PNUKFZYTHSYPAL-NZQKXSOJSA-N 0.000 claims 1
201000010099 disease Diseases 0.000 claims 1
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 606
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 527
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 315
239000000243 solution Substances 0.000 description 296
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 234
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 211
235000019439 ethyl acetate Nutrition 0.000 description 202
239000007787 solid Substances 0.000 description 193
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 158
239000000460 chlorine Substances 0.000 description 155
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 149
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 139
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 115
229910001868 water Inorganic materials 0.000 description 112
239000000203 mixture Substances 0.000 description 111
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 78
239000012267 brine Substances 0.000 description 75
238000004458 analytical method Methods 0.000 description 73
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 72
229910000041 hydrogen chloride Inorganic materials 0.000 description 72
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 66
239000011541 reaction mixture Substances 0.000 description 66
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 65
239000000741 silica gel Substances 0.000 description 64
229910002027 silica gel Inorganic materials 0.000 description 64
229910052943 magnesium sulfate Inorganic materials 0.000 description 63
235000019341 magnesium sulphate Nutrition 0.000 description 63
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 60
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 56
239000003921 oil Substances 0.000 description 52
235000019198 oils Nutrition 0.000 description 52
238000006243 chemical reaction Methods 0.000 description 50
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 49
239000006260 foam Substances 0.000 description 48
239000012458 free base Substances 0.000 description 47
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 45
239000000706 filtrate Substances 0.000 description 43
238000003756 stirring Methods 0.000 description 42
239000012044 organic layer Substances 0.000 description 40
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 39
239000000284 extract Substances 0.000 description 39
229910000104 sodium hydride Inorganic materials 0.000 description 39
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 37
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 36
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 36
239000012312 sodium hydride Substances 0.000 description 36
239000000725 suspension Substances 0.000 description 36
239000010410 layer Substances 0.000 description 35
239000000047 product Substances 0.000 description 35
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 32
239000002904 solvent Substances 0.000 description 31
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 30
229920006395 saturated elastomer Polymers 0.000 description 30
KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 26
239000000377 silicon dioxide Substances 0.000 description 25
WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 24
229910000027 potassium carbonate Inorganic materials 0.000 description 24
235000011181 potassium carbonates Nutrition 0.000 description 24
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 23
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 23
239000000463 material Substances 0.000 description 23
150000002825 nitriles Chemical class 0.000 description 23
239000012074 organic phase Substances 0.000 description 23
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 22
238000010828 elution Methods 0.000 description 21
230000002829 reductive effect Effects 0.000 description 21
229960000583 acetic acid Drugs 0.000 description 20
125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 20
238000003818 flash chromatography Methods 0.000 description 20
YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 18
229910052786 argon Inorganic materials 0.000 description 18
ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 16
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 16
229910004298 SiO 2 Inorganic materials 0.000 description 16
TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 16
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 16
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 16
238000004809 thin layer chromatography Methods 0.000 description 16
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 15
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 15
239000003054 catalyst Substances 0.000 description 15
235000015497 potassium bicarbonate Nutrition 0.000 description 15
229910000028 potassium bicarbonate Inorganic materials 0.000 description 15
239000011736 potassium bicarbonate Substances 0.000 description 15
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 14
238000010438 heat treatment Methods 0.000 description 14
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 14
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 14
238000001816 cooling Methods 0.000 description 13
ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 12
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
239000012230 colorless oil Substances 0.000 description 12
239000012043 crude product Substances 0.000 description 12
239000007788 liquid Substances 0.000 description 12
239000002244 precipitate Substances 0.000 description 12
238000004587 chromatography analysis Methods 0.000 description 11
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 10
229910000024 caesium carbonate Inorganic materials 0.000 description 10
125000004432 carbon atom Chemical group C* 0.000 description 10
239000003480 eluent Substances 0.000 description 10
239000004533 oil dispersion Substances 0.000 description 10
229910052763 palladium Inorganic materials 0.000 description 10
VEPTXBCIDSFGBF-UHFFFAOYSA-M tetrabutylazanium;fluoride;trihydrate Chemical compound O.O.O.[F-].CCCC[N+](CCCC)(CCCC)CCCC VEPTXBCIDSFGBF-UHFFFAOYSA-M 0.000 description 10
VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 9
238000002425 crystallisation Methods 0.000 description 9
230000008025 crystallization Effects 0.000 description 9
239000012071 phase Substances 0.000 description 9
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 9
BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 9
QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 8
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
239000002585 base Substances 0.000 description 8
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 8
OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 8
238000001704 evaporation Methods 0.000 description 8
230000008020 evaporation Effects 0.000 description 8
239000012362 glacial acetic acid Substances 0.000 description 8
238000002360 preparation method Methods 0.000 description 8
235000017557 sodium bicarbonate Nutrition 0.000 description 8
229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 8
PVWGKGMXHFBABQ-UHFFFAOYSA-N 3-(trifluoromethyl)-1-benzazepin-2-one Chemical compound O=C1C(C(F)(F)F)=CC=C2C=CC=CC2=N1 PVWGKGMXHFBABQ-UHFFFAOYSA-N 0.000 description 7
150000001412 amines Chemical class 0.000 description 7
229910052681 coesite Inorganic materials 0.000 description 7
229910052906 cristobalite Inorganic materials 0.000 description 7
KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 7
PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 7
238000010992 reflux Methods 0.000 description 7
MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 7
235000012239 silicon dioxide Nutrition 0.000 description 7
229910052682 stishovite Inorganic materials 0.000 description 7
RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 7
238000002560 therapeutic procedure Methods 0.000 description 7
229910052905 tridymite Inorganic materials 0.000 description 7
230000002378 acidificating effect Effects 0.000 description 6
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
239000002024 ethyl acetate extract Substances 0.000 description 6
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
239000012065 filter cake Substances 0.000 description 6
125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 6
229940086066 potassium hydrogencarbonate Drugs 0.000 description 6
229910000029 sodium carbonate Inorganic materials 0.000 description 6
235000017550 sodium carbonate Nutrition 0.000 description 6
239000011780 sodium chloride Substances 0.000 description 6
229910052938 sodium sulfate Inorganic materials 0.000 description 6
235000011152 sodium sulphate Nutrition 0.000 description 6
239000003039 volatile agent Substances 0.000 description 6
XRJMPABWIZHNQA-UHFFFAOYSA-N 8-amino-1,3,4,5-tetrahydro-1-benzazepin-2-one Chemical compound C1CCC(=O)NC2=CC(N)=CC=C21 XRJMPABWIZHNQA-UHFFFAOYSA-N 0.000 description 5
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 5
229910004373 HOAc Inorganic materials 0.000 description 5
WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 5
239000012346 acetyl chloride Substances 0.000 description 5
239000002253 acid Substances 0.000 description 5
235000019270 ammonium chloride Nutrition 0.000 description 5
239000007864 aqueous solution Substances 0.000 description 5
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
238000001035 drying Methods 0.000 description 5
238000001914 filtration Methods 0.000 description 5
238000005187 foaming Methods 0.000 description 5
125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 5
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CEIPQQODRKXDSB-UHFFFAOYSA-N ethyl 3-(6-hydroxynaphthalen-2-yl)-1H-indazole-5-carboximidate dihydrochloride Chemical compound Cl.Cl.C1=C(O)C=CC2=CC(C3=NNC4=CC=C(C=C43)C(=N)OCC)=CC=C21 CEIPQQODRKXDSB-UHFFFAOYSA-N 0.000 description 1
238000000605 extraction Methods 0.000 description 1
239000003527 fibrinolytic agent Substances 0.000 description 1
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RGUQWGXAYZNLMI-UHFFFAOYSA-N flumethiazide Chemical compound C1=C(C(F)(F)F)C(S(=O)(=O)N)=CC2=C1NC=NS2(=O)=O RGUQWGXAYZNLMI-UHFFFAOYSA-N 0.000 description 1
125000001153 fluoro group Chemical group F* 0.000 description 1
125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 description 1
125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
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229960002490 fosinopril Drugs 0.000 description 1
229960003883 furosemide Drugs 0.000 description 1
ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
125000002541 furyl group Chemical group 0.000 description 1
239000007789 gas Substances 0.000 description 1
229940093915 gynecological organic acid Drugs 0.000 description 1
150000005826 halohydrocarbons Chemical class 0.000 description 1
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125000005842 heteroatom Chemical group 0.000 description 1
125000000623 heterocyclic group Chemical group 0.000 description 1
239000002035 hexane extract Substances 0.000 description 1
RBBOWEDMXHTEPA-UHFFFAOYSA-N hexane;toluene Chemical compound CCCCCC.CC1=CC=CC=C1 RBBOWEDMXHTEPA-UHFFFAOYSA-N 0.000 description 1
238000004128 high performance liquid chromatography Methods 0.000 description 1
239000008240 homogeneous mixture Substances 0.000 description 1
229960002003 hydrochlorothiazide Drugs 0.000 description 1
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DMDGGSIALPNSEE-UHFFFAOYSA-N hydroflumethiazide Chemical compound C1=C(C(F)(F)F)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O DMDGGSIALPNSEE-UHFFFAOYSA-N 0.000 description 1
238000005984 hydrogenation reaction Methods 0.000 description 1
230000007062 hydrolysis Effects 0.000 description 1
238000006460 hydrolysis reaction Methods 0.000 description 1
SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 1
230000001631 hypertensive effect Effects 0.000 description 1
206010020871 hypertrophic cardiomyopathy Diseases 0.000 description 1
125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 description 1
125000002883 imidazolyl group Chemical group 0.000 description 1
239000002198 insoluble material Substances 0.000 description 1
238000007918 intramuscular administration Methods 0.000 description 1
238000001990 intravenous administration Methods 0.000 description 1
239000011630 iodine Substances 0.000 description 1
229910052740 iodine Inorganic materials 0.000 description 1
LSACYLWPPQLVSM-UHFFFAOYSA-N isobutyric acid anhydride Chemical compound CC(C)C(=O)OC(=O)C(C)C LSACYLWPPQLVSM-UHFFFAOYSA-N 0.000 description 1
150000002576 ketones Chemical class 0.000 description 1
201000006370 kidney failure Diseases 0.000 description 1
GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
JYJKFDHLEYMLDX-NEPJUHHUSA-N methyl (2s,4r)-1-benzyl-4-hydroxypyrrolidine-2-carboxylate Chemical compound COC(=O)[C@@H]1C[C@@H](O)CN1CC1=CC=CC=C1 JYJKFDHLEYMLDX-NEPJUHHUSA-N 0.000 description 1
ZORHSASAYVIBLY-UHNVWZDZSA-N methyl (2s,4r)-4-hydroxypyrrolidine-2-carboxylate Chemical compound COC(=O)[C@@H]1C[C@@H](O)CN1 ZORHSASAYVIBLY-UHNVWZDZSA-N 0.000 description 1
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208000010125 myocardial infarction Diseases 0.000 description 1
KFIGICHILYTCJF-UHFFFAOYSA-N n'-methylethane-1,2-diamine Chemical compound CNCCN KFIGICHILYTCJF-UHFFFAOYSA-N 0.000 description 1
210000000653 nervous system Anatomy 0.000 description 1
238000006386 neutralization reaction Methods 0.000 description 1
239000012053 oil suspension Substances 0.000 description 1
239000010502 orange oil Substances 0.000 description 1
235000005985 organic acids Nutrition 0.000 description 1
239000003960 organic solvent Substances 0.000 description 1
125000002971 oxazolyl group Chemical group 0.000 description 1
TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
229910052760 oxygen Inorganic materials 0.000 description 1
238000007911 parenteral administration Methods 0.000 description 1
125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
229950008492 pentopril Drugs 0.000 description 1
239000000546 pharmaceutical excipient Substances 0.000 description 1
238000005191 phase separation Methods 0.000 description 1
UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
239000010452 phosphate Substances 0.000 description 1
125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 1
229960005483 polythiazide Drugs 0.000 description 1
229920000046 polythiazide Polymers 0.000 description 1
230000003389 potentiating effect Effects 0.000 description 1
238000001556 precipitation Methods 0.000 description 1
239000003755 preservative agent Substances 0.000 description 1
230000002335 preservative effect Effects 0.000 description 1
VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
208000020016 psychiatric disease Diseases 0.000 description 1
208000002815 pulmonary hypertension Diseases 0.000 description 1
125000000168 pyrrolyl group Chemical group 0.000 description 1
229960001455 quinapril Drugs 0.000 description 1
JSDRRTOADPPCHY-HSQYWUDLSA-N quinapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2=CC=CC=C2C1)C(O)=O)CC1=CC=CC=C1 JSDRRTOADPPCHY-HSQYWUDLSA-N 0.000 description 1
229960003401 ramipril Drugs 0.000 description 1
HDACQVRGBOVJII-JBDAPHQKSA-N ramipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 HDACQVRGBOVJII-JBDAPHQKSA-N 0.000 description 1
238000006268 reductive amination reaction Methods 0.000 description 1
230000021014 regulation of cell growth Effects 0.000 description 1
229910052703 rhodium Inorganic materials 0.000 description 1
239000010948 rhodium Substances 0.000 description 1
YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
229960001860 salicylate Drugs 0.000 description 1
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239000012047 saturated solution Substances 0.000 description 1
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239000012056 semi-solid material Substances 0.000 description 1
238000000926 separation method Methods 0.000 description 1
238000010898 silica gel chromatography Methods 0.000 description 1
239000002002 slurry Substances 0.000 description 1
QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
239000003381 stabilizer Substances 0.000 description 1
239000008174 sterile solution Substances 0.000 description 1
239000012258 stirred mixture Substances 0.000 description 1
238000007920 subcutaneous administration Methods 0.000 description 1
239000000126 substance Substances 0.000 description 1
229940086735 succinate Drugs 0.000 description 1
KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
229910052717 sulfur Inorganic materials 0.000 description 1
229940095064 tartrate Drugs 0.000 description 1
BTKHBQQDRKITJL-LSDHHAIUSA-N tert-butyl (2s,4r)-2-(bromomethyl)-4-phenylmethoxypyrrolidine-1-carboxylate Chemical compound C1[C@@H](CBr)N(C(=O)OC(C)(C)C)C[C@@H]1OCC1=CC=CC=C1 BTKHBQQDRKITJL-LSDHHAIUSA-N 0.000 description 1
IMCGHZIGRANKHV-AJNGGQMLSA-N tert-butyl (3s,5s)-2-oxo-5-[(2s,4s)-5-oxo-4-propan-2-yloxolan-2-yl]-3-propan-2-ylpyrrolidine-1-carboxylate Chemical compound O1C(=O)[C@H](C(C)C)C[C@H]1[C@H]1N(C(=O)OC(C)(C)C)C(=O)[C@H](C(C)C)C1 IMCGHZIGRANKHV-AJNGGQMLSA-N 0.000 description 1
XIRUXUKRGUFEKC-UHFFFAOYSA-N tert-butyl 2-(hydroxymethyl)azetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC1CO XIRUXUKRGUFEKC-UHFFFAOYSA-N 0.000 description 1
VSVOPDINJSHSBZ-UHFFFAOYSA-N tert-butyl 2-[(4-methylphenyl)sulfonyloxymethyl]pyrrolidine-1-carboxylate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCC1N(C(=O)OC(C)(C)C)CCC1 VSVOPDINJSHSBZ-UHFFFAOYSA-N 0.000 description 1
QOUUPLAWNNIBFW-NBGIEHNGSA-N tert-butyl 2-[[(3r,4s)-3-acetyloxy-4-(4-methoxyphenyl)-2-oxo-6-(trifluoromethyl)-4,5-dihydro-3h-1-benzazepin-1-yl]methyl]-4,5-dihydroimidazole-1-carboxylate Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CC=2N(CCN=2)C(=O)OC(C)(C)C)C(C=CC=C2C(F)(F)F)=C2C1 QOUUPLAWNNIBFW-NBGIEHNGSA-N 0.000 description 1
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
125000000335 thiazolyl group Chemical group 0.000 description 1
125000001544 thienyl group Chemical group 0.000 description 1
229960000103 thrombolytic agent Drugs 0.000 description 1
230000002537 thrombolytic effect Effects 0.000 description 1
231100000886 tinnitus Toxicity 0.000 description 1
125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 description 1
PMMYEEVYMWASQN-IMJSIDKUSA-N trans-4-Hydroxy-L-proline Natural products O[C@@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-IMJSIDKUSA-N 0.000 description 1
230000007704 transition Effects 0.000 description 1
229960001288 triamterene Drugs 0.000 description 1
229960004813 trichlormethiazide Drugs 0.000 description 1
LMJSLTNSBFUCMU-UHFFFAOYSA-N trichlormethiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC(C(Cl)Cl)NS2(=O)=O LMJSLTNSBFUCMU-UHFFFAOYSA-N 0.000 description 1
125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
JOHWNGGYGAVMGU-UHFFFAOYSA-N trifluorochlorine Chemical compound FCl(F)F JOHWNGGYGAVMGU-UHFFFAOYSA-N 0.000 description 1
229960005356 urokinase Drugs 0.000 description 1
238000001291 vacuum drying Methods 0.000 description 1
238000007738 vacuum evaporation Methods 0.000 description 1
208000019553 vascular disease Diseases 0.000 description 1
230000000304 vasodilatating effect Effects 0.000 description 1
238000010626 work up procedure Methods 0.000 description 1
229960002769 zofenopril Drugs 0.000 description 1
IAIDUHCBNLFXEF-MNEFBYGVSA-N zofenopril Chemical compound C([C@@H](C)C(=O)N1[C@@H](C[C@@H](C1)SC=1C=CC=CC=1)C(O)=O)SC(=O)C1=CC=CC=C1 IAIDUHCBNLFXEF-MNEFBYGVSA-N 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- 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
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D281/02—Seven-membered rings
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- 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
- C07D401/06—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 carbon chain containing only aliphatic carbon 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
- C07D403/06—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 carbon chain containing only aliphatic carbon atoms
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
Pharmacology & Pharmacy (AREA)
Veterinary Medicine (AREA)
Public Health (AREA)
General Health & Medical Sciences (AREA)
Animal Behavior & Ethology (AREA)
Life Sciences & Earth Sciences (AREA)
Medicinal Chemistry (AREA)
Cardiology (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
General Chemical & Material Sciences (AREA)
Chemical Kinetics & Catalysis (AREA)
Heart & Thoracic Surgery (AREA)
Bioinformatics & Cheminformatics (AREA)
Engineering & Computer Science (AREA)
Epidemiology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Plural Heterocyclic Compounds (AREA)
Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Hydrogenated Pyridines (AREA)

NL8920642A 1988-06-20 1989-05-23 Benzazepine- en benzothiazepinederivaten. NL8920642A (nl)

Applications Claiming Priority (6)

Application Number	Priority Date	Filing Date	Title
US20852188A	1988-06-20	1988-06-20
US20852188		1988-06-20
US07/353,806 US4902684A (en)	1988-06-20	1989-05-22	Benzazepine and benzothiazepine derivatives
US35380689		1989-05-22
US8902270		1989-05-23
PCT/US1989/002270 WO1989012633A1 (en)	1988-06-20	1989-05-23	Benzazepine and benzothiazepine derivatives

Publications (1)

Publication Number	Publication Date
NL8920642A true NL8920642A (nl)	1990-06-01

Family

ID=26903265

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
NL8920642A NL8920642A (nl)	1988-06-20	1989-05-23	Benzazepine- en benzothiazepinederivaten.

Country Status (29)

Country	Link
US (1)	US4902684A (it)
JP (1)	JP2793674B2 (it)
KR (1)	KR970002633B1 (it)
CN (1)	CN1027262C (it)
AT (1)	AT398567B (it)
AU (1)	AU614399B2 (it)
BE (1)	BE1003305A4 (it)
CA (1)	CA1336975C (it)
CH (1)	CH681723A5 (it)
EG (1)	EG19071A (it)
ES (1)	ES2016467A6 (it)
FI (1)	FI94246C (it)
FR (1)	FR2632953B1 (it)
GB (1)	GB2231329B (it)
GR (1)	GR1002099B (it)
HU (1)	HU210929B (it)
IE (1)	IE64242B1 (it)
IL (1)	IL90515A (it)
IT (1)	IT1230884B (it)
LU (1)	LU87865A1 (it)
NL (1)	NL8920642A (it)
NO (1)	NO179449C (it)
NZ (1)	NZ229612A (it)
PL (1)	PL162313B1 (it)
PT (1)	PT90914B (it)
RU (1)	RU2090562C1 (it)
SE (1)	SE9004060L (it)
WO (1)	WO1989012633A1 (it)
YU (1)	YU121389A (it)

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US5008284A (en) *	1989-02-15	1991-04-16	E. R. Squibb & Sons, Inc.	Method of reducing pre- and post-ischemic myocardial arrhythmias and fibrillation
US4946840A (en) *	1989-04-06	1990-08-07	E. R. Squibb & Sons, Inc.	Benzazepine and benzothiazepine derivatives
US4963671A (en) *	1989-11-20	1990-10-16	E. R. Squibb & Sons, Inc.	Process for resolving chiral intermediates used in making calcium channel blockers
US5112969A (en) *	1990-04-02	1992-05-12	Merrell Dow Pharmaceuticals Inc.	Cyano esters and azepinones
IT1240686B (it) *	1990-04-27	1993-12-17	Luso Farmaco Inst	Derivati 1,5-benzotiazepinonici, loro preparazione e uso farmaceutico
IT1244878B (it) *	1990-12-11	1994-09-12	Lusochimica Spa	Processo per la preparazione del (+)-cis-3-(acetossi)-5-!2-( dimetilammino)etil!-2,3-diidro-2-(4-metossifenil)-1,5-benzotiazepin- 4-(5h)-one cloridrato
AU666318B2 (en) *	1991-06-28	1996-02-08	Smithkline Beecham Corporation	Bicyclic fibrinogen antagonists
IT1255545B (it) *	1992-10-23	1995-11-09		Procedimento per la preparazione di diltiazem
CA2098446A1 (en) *	1992-09-30	1994-03-31	Eckard Weber	2,5-dihydro-2,5-dioxo-1h-azepines and 2,5-dihydro-2-oxo-1h-azepines and the use thereof as excitatory amino acid and glycine receptor antagonists
ATE216580T1 (de) *	1993-07-16	2002-05-15	Merck & Co Inc	Benzoxazinon- und benzopyrimidinon- piperidinyl- verbindungen als tokolytische oxytocin-rezeptor- antagonisten
US6174917B1 (en)	1993-09-08	2001-01-16	Pharmacy And Therapeutic Advisory Consultancy Ltd.	Method of treating liver disease and like indications with vasodilating agents
US5854233A (en) *	1993-09-08	1998-12-29	Pharmacy And Therapeutic Advisory Consultancy Ltd.	Method of treating liver disease and like indications with vasodilating agents
AU688012B2 (en) *	1994-03-24	1998-03-05	Merrell Pharmaceuticals Inc.	Hypocholesterolemic, antiatherosclerotic and hypotriglyceridemic mercaptoacetylamide disulfide derivatives
US5580867A (en) *	1994-09-09	1996-12-03	Universite De Montreal	Myocardial protection during ischemia and reperfusion
GB9423172D0 (en)	1994-11-17	1995-01-04	Wellcom Foundation The Limited	Hypolipidemic benzothiazepines
CA2698384C (en) *	1996-12-10	2012-05-01	Abbott Laboratories	3-pyridyl enantiomers and their use as analgesics
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US6472533B1 (en)	1999-04-08	2002-10-29	The Texas A & M University System	Ligands for chiral catalysis
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- 1989-05-22 US US07/353,806 patent/US4902684A/en not_active Expired - Lifetime
- 1989-05-23 RU SU895011155A patent/RU2090562C1/ru active
- 1989-05-23 HU HU894298A patent/HU210929B/hu not_active IP Right Cessation
- 1989-05-23 CH CH615/90A patent/CH681723A5/fr not_active IP Right Cessation
- 1989-05-23 WO PCT/US1989/002270 patent/WO1989012633A1/en not_active Ceased
- 1989-05-23 NL NL8920642A patent/NL8920642A/nl not_active Application Discontinuation
- 1989-05-23 AT AT0901089A patent/AT398567B/de not_active IP Right Cessation
- 1989-05-23 JP JP1507318A patent/JP2793674B2/ja not_active Expired - Lifetime
- 1989-05-23 AU AU38593/89A patent/AU614399B2/en not_active Ceased
- 1989-05-26 CA CA000600891A patent/CA1336975C/en not_active Expired - Fee Related
- 1989-06-02 IL IL9051589A patent/IL90515A/en not_active IP Right Cessation
- 1989-06-14 YU YU01213/89A patent/YU121389A/xx unknown
- 1989-06-16 IE IE195789A patent/IE64242B1/en not_active IP Right Cessation
- 1989-06-19 ES ES8902132A patent/ES2016467A6/es not_active Expired - Lifetime
- 1989-06-19 NZ NZ229612A patent/NZ229612A/en unknown
- 1989-06-20 PT PT90914A patent/PT90914B/pt not_active IP Right Cessation
- 1989-06-20 BE BE8900666A patent/BE1003305A4/fr not_active IP Right Cessation
- 1989-06-20 GR GR890100410A patent/GR1002099B/el not_active IP Right Cessation
- 1989-06-20 EG EG30389A patent/EG19071A/xx active
- 1989-06-20 IT IT8920933A patent/IT1230884B/it active
- 1989-06-20 PL PL89280122A patent/PL162313B1/pl unknown
- 1989-06-20 CN CN89104877A patent/CN1027262C/zh not_active Expired - Fee Related
- 1989-06-20 FR FR898908204A patent/FR2632953B1/fr not_active Expired - Fee Related
1990
- 1990-02-06 GB GB9002587A patent/GB2231329B/en not_active Expired - Fee Related
- 1990-02-19 KR KR90700338A patent/KR970002633B1/ko not_active Expired - Fee Related
- 1990-02-19 FI FI900813A patent/FI94246C/fi not_active IP Right Cessation
- 1990-12-19 SE SE9004060A patent/SE9004060L/xx not_active Application Discontinuation
- 1990-12-19 NO NO905485A patent/NO179449C/no not_active IP Right Cessation
- 1990-12-19 LU LU87865A patent/LU87865A1/de unknown

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Also Published As

Publication number	Publication date
JP2793674B2 (ja)	1998-09-03
IE891957L (en)	1989-12-20
HU210929B (en)	1995-09-28
FR2632953B1 (fr)	1992-05-29
IL90515A0 (en)	1990-01-18
YU121389A (en)	1991-04-30
NO179449C (no)	1996-10-09
AT398567B (de)	1994-12-27
PT90914A (pt)	1989-12-29
GB9002587D0 (en)	1990-08-29
AU3859389A (en)	1990-01-12
CN1027262C (zh)	1995-01-04
PT90914B (pt)	1994-12-30
IT1230884B (it)	1991-11-08
ES2016467A6 (es)	1990-11-01
EG19071A (en)	1994-07-30
GB2231329B (en)	1992-10-21
CA1336975C (en)	1995-09-12
JPH04502002A (ja)	1992-04-09
LU87865A1 (de)	1991-12-16
AU614399B2 (en)	1991-08-29
SE9004060D0 (sv)	1990-12-19
FI94246B (fi)	1995-04-28
US4902684A (en)	1990-02-20
GB2231329A (en)	1990-11-14
GR890100410A (el)	1990-05-11
IE64242B1 (en)	1995-07-26
BE1003305A4 (fr)	1992-02-25
NO179449B (no)	1996-07-01
GR1002099B (en)	1995-12-28
KR920700207A (ko)	1992-02-19
CH681723A5 (it)	1993-05-14
IT8920933A0 (it)	1989-06-20
KR970002633B1 (en)	1997-03-06
FI900813A0 (fi)	1990-02-19
CN1039585A (zh)	1990-02-14
RU2090562C1 (ru)	1997-09-20
ATA901089A (de)	1994-05-15
HU894298D0 (en)	1991-01-28
NO905485L (no)	1991-02-19
WO1989012633A1 (en)	1989-12-28
NO905485D0 (no)	1990-12-19
SE9004060L (sv)	1992-06-20
PL162313B1 (pl)	1993-09-30
IL90515A (en)	1994-07-31
HUT59908A (en)	1992-07-28
NZ229612A (en)	1992-07-28
FR2632953A1 (fr)	1989-12-22
FI94246C (fi)	1995-08-10

Legal Events

Date	Code	Title	Description
2003-02-03	BV	The patent application has lapsed

Publication	Publication Date	Title
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