PH26646A - Benzazepine and benzothiazepine derivatives - Google Patents

Benzazepine and benzothiazepine derivatives Download PDF

Info

Publication number: PH26646A
Authority: PH; Philippines
Prior art keywords: alkyl; solution; trifluoromethyl; methoxyphenyl; benzazepin
Prior art date: 1988-06-20

Application number

PH38739A

Other languages

English (en)

Inventor

David Floyd

John Thomas Hunt

Spencer David Kimball

John Krapcho

Jagabandhu Das

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

1989-06-02

Publication date

1992-09-04

1989-06-02 Application filed by Squibb & Sons Inc filed Critical Squibb & Sons Inc

1992-09-04 Publication of PH26646A publication Critical patent/PH26646A/en

Links

DQFQCHIDRBIESA-UHFFFAOYSA-N 1-benzazepine Chemical compound N1C=CC=CC2=CC=CC=C12 DQFQCHIDRBIESA-UHFFFAOYSA-N 0.000 title claims description 5
229940085242 benzothiazepine derivative selective calcium channel blockers with direct cardiac effects Drugs 0.000 title 1
150000007657 benzothiazepines Chemical class 0.000 title 1
150000001875 compounds Chemical class 0.000 claims description 107
229910052739 hydrogen Inorganic materials 0.000 claims description 33
239000001257 hydrogen Substances 0.000 claims description 32
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 27
-1 cyano, hydroxy Chemical group 0.000 claims description 26
125000000217 alkyl group Chemical group 0.000 claims description 25
150000002431 hydrogen Chemical class 0.000 claims description 17
125000003545 alkoxy group Chemical group 0.000 claims description 13
125000003118 aryl group Chemical group 0.000 claims description 12
125000000753 cycloalkyl group Chemical group 0.000 claims description 12
150000003839 salts Chemical class 0.000 claims description 12
229910052736 halogen Inorganic materials 0.000 claims description 11
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
150000002367 halogens Chemical class 0.000 claims description 9
229910052727 yttrium Inorganic materials 0.000 claims description 9
125000003710 aryl alkyl group Chemical group 0.000 claims description 8
125000003342 alkenyl group Chemical group 0.000 claims description 7
125000004104 aryloxy group Chemical group 0.000 claims description 7
125000001589 carboacyl group Chemical group 0.000 claims description 6
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
125000002102 aryl alkyloxo group Chemical group 0.000 claims description 5
125000005129 aryl carbonyl group Chemical group 0.000 claims description 5
229910052799 carbon Inorganic materials 0.000 claims description 5
125000001072 heteroaryl group Chemical group 0.000 claims description 5
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
125000004423 acyloxy group Chemical group 0.000 claims description 4
125000003282 alkyl amino group Chemical group 0.000 claims description 4
125000005223 heteroarylcarbonyl group Chemical group 0.000 claims description 4
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
238000000034 method Methods 0.000 claims description 4
125000002757 morpholinyl group Chemical group 0.000 claims description 4
229910052757 nitrogen Inorganic materials 0.000 claims description 4
125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
125000003386 piperidinyl group Chemical group 0.000 claims description 4
125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
125000000304 alkynyl group Chemical group 0.000 claims description 3
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
230000000304 vasodilatating effect Effects 0.000 claims description 3
125000002393 azetidinyl group Chemical group 0.000 claims description 2
229940124549 vasodilator Drugs 0.000 claims description 2
239000003071 vasodilator agent Substances 0.000 claims description 2
150000001721 carbon Chemical group 0.000 claims 3
101100536354 Drosophila melanogaster tant gene Proteins 0.000 claims 2
FHKKLQIBTXYWGR-UHFFFAOYSA-N 2-[[8-(1-methylindol-6-yl)quinoxalin-6-yl]amino]-N-(pyrimidin-5-ylmethyl)benzenesulfonamide Chemical compound CN1C=CC2=CC=C(C=C12)C=1C=C(C=C2N=CC=NC=12)NC1=C(C=CC=C1)S(=O)(=O)NCC=1C=NC=NC=1 FHKKLQIBTXYWGR-UHFFFAOYSA-N 0.000 claims 1
201000010099 disease Diseases 0.000 claims 1
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 1
210000002268 wool Anatomy 0.000 claims 1
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 182
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 131
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 123
239000000243 solution Substances 0.000 description 119
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 108
239000007787 solid Substances 0.000 description 84
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 81
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 67
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 62
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 60
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 56
239000000203 mixture Substances 0.000 description 41
QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 33
ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Natural products CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 32
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
238000002844 melting Methods 0.000 description 28
230000008018 melting Effects 0.000 description 28
239000000741 silica gel Substances 0.000 description 28
229910002027 silica gel Inorganic materials 0.000 description 28
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
229910052943 magnesium sulfate Inorganic materials 0.000 description 27
235000019341 magnesium sulphate Nutrition 0.000 description 27
239000012458 free base Substances 0.000 description 24
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 23
239000012312 sodium hydride Substances 0.000 description 23
229910000104 sodium hydride Inorganic materials 0.000 description 23
238000004458 analytical method Methods 0.000 description 22
239000011541 reaction mixture Substances 0.000 description 22
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 21
239000012267 brine Substances 0.000 description 21
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 21
239000003921 oil Substances 0.000 description 20
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 19
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 18
WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 17
239000000706 filtrate Substances 0.000 description 16
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 16
229910000041 hydrogen chloride Inorganic materials 0.000 description 16
239000000463 material Substances 0.000 description 15
239000000047 product Substances 0.000 description 15
239000000284 extract Substances 0.000 description 14
KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 14
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 14
239000000725 suspension Substances 0.000 description 14
229960000583 acetic acid Drugs 0.000 description 13
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 description 12
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
239000012074 organic phase Substances 0.000 description 11
239000000377 silicon dioxide Substances 0.000 description 11
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
125000004432 carbon atom Chemical group C* 0.000 description 10
238000006243 chemical reaction Methods 0.000 description 10
239000010410 layer Substances 0.000 description 10
229910000027 potassium carbonate Inorganic materials 0.000 description 10
235000011181 potassium carbonates Nutrition 0.000 description 10
238000010992 reflux Methods 0.000 description 10
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 9
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
238000003756 stirring Methods 0.000 description 9
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
239000000460 chlorine Substances 0.000 description 8
238000004587 chromatography analysis Methods 0.000 description 8
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
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 7
239000006260 foam Substances 0.000 description 7
KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 7
239000012044 organic layer Substances 0.000 description 7
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 7
230000002829 reductive effect Effects 0.000 description 7
MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 7
BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 7
238000004809 thin layer chromatography Methods 0.000 description 7
AYQMNFRCBKOMIA-UHFFFAOYSA-N 1-benzazepin-2-one Chemical compound O=C1C=CC=C2C=CC=CC2=N1 AYQMNFRCBKOMIA-UHFFFAOYSA-N 0.000 description 6
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
239000012043 crude product Substances 0.000 description 6
238000010828 elution Methods 0.000 description 6
238000001914 filtration Methods 0.000 description 6
239000004533 oil dispersion Substances 0.000 description 6
VEPTXBCIDSFGBF-UHFFFAOYSA-M tetrabutylazanium;fluoride;trihydrate Chemical compound O.O.O.[F-].CCCC[N+](CCCC)(CCCC)CCCC VEPTXBCIDSFGBF-UHFFFAOYSA-M 0.000 description 6
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
239000002585 base Substances 0.000 description 5
238000002425 crystallisation Methods 0.000 description 5
230000008025 crystallization Effects 0.000 description 5
238000001704 evaporation Methods 0.000 description 5
238000003818 flash chromatography Methods 0.000 description 5
238000010438 heat treatment Methods 0.000 description 5
DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 description 5
238000005245 sintering Methods 0.000 description 5
239000002904 solvent Substances 0.000 description 5
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
229910021529 ammonia Inorganic materials 0.000 description 4
235000019270 ammonium chloride Nutrition 0.000 description 4
238000001816 cooling Methods 0.000 description 4
125000004093 cyano group Chemical group *C#N 0.000 description 4
OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 4
230000008020 evaporation Effects 0.000 description 4
238000005187 foaming Methods 0.000 description 4
239000012362 glacial acetic acid Substances 0.000 description 4
230000007935 neutral effect Effects 0.000 description 4
239000002244 precipitate Substances 0.000 description 4
229920006395 saturated elastomer Polymers 0.000 description 4
LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 4
HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 4
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
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 4
238000010792 warming Methods 0.000 description 4
JNAYPRPPXRWGQO-UHFFFAOYSA-N 2-chloropropanenitrile Chemical compound CC(Cl)C#N JNAYPRPPXRWGQO-UHFFFAOYSA-N 0.000 description 3
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 3
QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
229910000102 alkali metal hydride Inorganic materials 0.000 description 3
150000008046 alkali metal hydrides Chemical class 0.000 description 3
VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 3
239000008346 aqueous phase Substances 0.000 description 3
SWEDETNNQUBIJG-LBPRGKRZSA-N benzyl (2s)-2-(bromomethyl)pyrrolidine-1-carboxylate Chemical compound BrC[C@@H]1CCCN1C(=O)OCC1=CC=CC=C1 SWEDETNNQUBIJG-LBPRGKRZSA-N 0.000 description 3
229960001760 dimethyl sulfoxide Drugs 0.000 description 3
HWJHWSBFPPPIPD-UHFFFAOYSA-N ethoxyethane;propan-2-one Chemical compound CC(C)=O.CCOCC HWJHWSBFPPPIPD-UHFFFAOYSA-N 0.000 description 3
239000002024 ethyl acetate extract Substances 0.000 description 3
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
239000012442 inert solvent Substances 0.000 description 3
238000012746 preparative thin layer chromatography Methods 0.000 description 3
FJODGURPPPXAOE-LLVKDONJSA-N (2r)-1-chloro-n,n-dimethyl-3-phenylpropan-2-amine Chemical compound CN(C)[C@@H](CCl)CC1=CC=CC=C1 FJODGURPPPXAOE-LLVKDONJSA-N 0.000 description 2
ZXEQVHDPCGPJSJ-ZCFIWIBFSA-N (2r)-2-(chloromethyl)-1-methylpyrrolidine Chemical compound CN1CCC[C@@H]1CCl ZXEQVHDPCGPJSJ-ZCFIWIBFSA-N 0.000 description 2
FJODGURPPPXAOE-NSHDSACASA-N (2s)-1-chloro-n,n-dimethyl-3-phenylpropan-2-amine Chemical compound CN(C)[C@H](CCl)CC1=CC=CC=C1 FJODGURPPPXAOE-NSHDSACASA-N 0.000 description 2
ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
WTDNWEITCUMXGW-UHFFFAOYSA-N 2-chlorobutanenitrile Chemical compound CCC(Cl)C#N WTDNWEITCUMXGW-UHFFFAOYSA-N 0.000 description 2
ZMLUHYJUTIZTOJ-UHFFFAOYSA-N 2-dimethylamino-2-methyl-1-chloro-ethane Natural products ClCC(C)N(C)C ZMLUHYJUTIZTOJ-UHFFFAOYSA-N 0.000 description 2
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 2
239000005541 ACE inhibitor Substances 0.000 description 2
CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
HVVNJUAVDAZWCB-RXMQYKEDSA-N D-prolinol Chemical compound OC[C@H]1CCCN1 HVVNJUAVDAZWCB-RXMQYKEDSA-N 0.000 description 2
KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
VCOJPHPOVDIRJK-ZCFIWIBFSA-N [(2r)-1-methylpyrrolidin-2-yl]methanol Chemical compound CN1CCC[C@@H]1CO VCOJPHPOVDIRJK-ZCFIWIBFSA-N 0.000 description 2
HVVNJUAVDAZWCB-YFKPBYRVSA-N [(2s)-pyrrolidin-2-yl]methanol Chemical compound OC[C@@H]1CCCN1 HVVNJUAVDAZWCB-YFKPBYRVSA-N 0.000 description 2
239000002253 acid Substances 0.000 description 2
125000004414 alkyl thio group Chemical group 0.000 description 2
238000005804 alkylation reaction Methods 0.000 description 2
150000001412 amines Chemical class 0.000 description 2
229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 2
239000003416 antiarrhythmic agent Substances 0.000 description 2
239000002220 antihypertensive agent Substances 0.000 description 2
229940030600 antihypertensive agent Drugs 0.000 description 2
229910052786 argon Inorganic materials 0.000 description 2
SWEDETNNQUBIJG-GFCCVEGCSA-N benzyl (2r)-2-(bromomethyl)pyrrolidine-1-carboxylate Chemical compound BrC[C@H]1CCCN1C(=O)OCC1=CC=CC=C1 SWEDETNNQUBIJG-GFCCVEGCSA-N 0.000 description 2
BJTNHGVCFWDNDP-GFCCVEGCSA-N benzyl (2r)-2-(hydroxymethyl)pyrrolidine-1-carboxylate Chemical compound OC[C@H]1CCCN1C(=O)OCC1=CC=CC=C1 BJTNHGVCFWDNDP-GFCCVEGCSA-N 0.000 description 2
BJTNHGVCFWDNDP-UHFFFAOYSA-N benzyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate Chemical compound OCC1CCCN1C(=O)OCC1=CC=CC=C1 BJTNHGVCFWDNDP-UHFFFAOYSA-N 0.000 description 2
HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 2
230000036772 blood pressure Effects 0.000 description 2
239000003054 catalyst Substances 0.000 description 2
239000003638 chemical reducing agent Substances 0.000 description 2
239000012230 colorless oil Substances 0.000 description 2
238000007796 conventional method Methods 0.000 description 2
125000004663 dialkyl amino group Chemical group 0.000 description 2
235000004879 dioscorea Nutrition 0.000 description 2
239000002934 diuretic Substances 0.000 description 2
LBAQSKZHMLAFHH-UHFFFAOYSA-N ethoxyethane;hydron;chloride Chemical compound Cl.CCOCC LBAQSKZHMLAFHH-UHFFFAOYSA-N 0.000 description 2
150000004678 hydrides Chemical class 0.000 description 2
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Landscapes

Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)

PH38739A 1988-06-20 1989-06-02 Benzazepine and benzothiazepine derivatives PH26646A (en)

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
US20852188A	1988-06-20	1988-06-20

Publications (1)

Publication Number	Publication Date
PH26646A true PH26646A (en)	1992-09-04

Family

ID=22774894

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
PH38739A PH26646A (en)	1988-06-20	1989-06-02	Benzazepine and benzothiazepine derivatives

Country Status (4)

Country	Link
DD (1)	DD284005A5 (de)
MX (1)	MX16514A (de)
PH (1)	PH26646A (de)
ZA (1)	ZA894315B (de)

1989
- 1989-06-02 PH PH38739A patent/PH26646A/en unknown
- 1989-06-07 ZA ZA894315A patent/ZA894315B/xx unknown
- 1989-06-19 MX MX1651489A patent/MX16514A/es unknown
- 1989-06-20 DD DD89329786A patent/DD284005A5/de not_active IP Right Cessation

Also Published As

Publication number	Publication date
DD284005A5 (de)	1990-10-31
MX16514A (es)	1994-03-31
ZA894315B (en)	1990-02-28

Publication	Publication Date	Title
CA1336975C (en)	1995-09-12	Benzazepine and benzothiazepine derivatives
KR0128210B1 (ko)	1998-04-02	1-인돌릴알킬-4-(치환-피리디닐)피페라진류
US4983608A (en)	1991-01-08	N-substituted-4-pyrimidinamines and pyrimidinediamines
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CA2022486C (en)	2001-04-03	1,3-dihydro-1-(pyridinylamino)-2h-indol-2-ones, a process for their preparation and their use as medicaments
KR900005014B1 (ko)	1990-07-16	1,2,3,4-테트라히드로-6-치환-4-아릴(또는 헤테로시클로)-3-[(치환 아미노)카르보닐]-2-티옥소(또는 옥소)-5-피리미딘 카르복실산 및 에스테르 및 그의 제조 방법
CA1302409C (en)	1992-06-02	Benzazepine derivatives
CZ224098A3 (cs)	1998-10-14	Derivát chinolin-2-(1H)-onu, způsob jeho přípravy a farmaceutický prostředek, který ho obsahuje
CA1300621C (en)	1992-05-12	3-substituted benzazepines
AU609169B2 (en)	1991-04-26	Benzazepines derivatives
US6358993B1 (en)	2002-03-19	Pharmaceutically active nitrogen ring compounds and methods of use thereof
PH26646A (en)	1992-09-04	Benzazepine and benzothiazepine derivatives
CZ915486A3 (en)	1994-01-19	Benzazepine derivatives and process for preparing thereof
CA2169112A1 (en)	1996-08-10	1-¬2-(substituted vinyl)\|-3,4-dihydro-5h-2,3-benzodiazepine derivatives
US4952692A (en)	1990-08-28	Benzazepine derivatives
CA1300620C (en)	1992-05-12	Benzazepine derivatives
AU733475B2 (en)	2001-05-17	Pharmaceutically active compounds containing 5-8 member N-hetero rings incorporating the linking group carboximidamide
US4946840A (en)	1990-08-07	Benzazepine and benzothiazepine derivatives
EP1086095B1 (de)	2002-10-23	Tetrahydroisochinolinderivate als modulatoren von dopamin d3 rezeptoren
HU204257B (en)	1991-12-30	Process for producing new substituted quinoline derivatives and pharmaceutical compositions containing them
US5686626A (en)	1997-11-11	1,3-dihydro-1-amino-2H-indol-2-ones
HU197726B (en)	1989-05-29	Process for production of derivatives of bensoic acid and medical compositions containing them