IL100416A - 7-[(carboxy-3-phenylpropyl) amino]- 1,2,3,4,6,7,8, 12b-octahydro-6- oxo-amino or nitro containing tricyclic benzazepine derivatives and pharmaceutical compositions containing them as inhibitors of ace - Google Patents

7-[(carboxy-3-phenylpropyl) amino]- 1,2,3,4,6,7,8, 12b-octahydro-6- oxo-amino or nitro containing tricyclic benzazepine derivatives and pharmaceutical compositions containing them as inhibitors of ace

Info

Publication number: IL100416A
Authority: IL; Israel
Prior art keywords: amino; nitro; carboxylic acid; compound; phenylpropyl
Prior art date: 1990-12-21

Application number

IL10041691A

Other languages

English (en)

Other versions

IL100416A0 (en

Original Assignee

Merrell Dow Pharma

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.)

1990-12-21

Filing date

1991-12-18

Publication date

1995-11-27

1991-12-18 Application filed by Merrell Dow Pharma filed Critical Merrell Dow Pharma

1992-09-06 Publication of IL100416A0 publication Critical patent/IL100416A0/xx

1995-11-27 Publication of IL100416A publication Critical patent/IL100416A/en

Links

125000002924 primary amino group Chemical group [H]N([H])* 0.000 title claims abstract description 130
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 title claims abstract description 18
239000008194 pharmaceutical composition Substances 0.000 title claims description 16
239000003112 inhibitor Substances 0.000 title abstract description 7
-1 carboxy-3-phenylpropyl Chemical group 0.000 title description 114
150000008038 benzoazepines Chemical class 0.000 title description 2
150000001875 compounds Chemical class 0.000 claims abstract description 125
239000001257 hydrogen Substances 0.000 claims abstract description 33
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 33
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 14
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 11
150000002431 hydrogen Chemical group 0.000 claims abstract description 10
125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 9
125000000217 alkyl group Chemical group 0.000 claims abstract description 7
125000003118 aryl group Chemical group 0.000 claims abstract description 6
125000000008 (C1-C10) alkyl group Chemical group 0.000 claims abstract description 5
101150047265 COR2 gene Proteins 0.000 claims abstract description 5
101100467189 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) QCR2 gene Proteins 0.000 claims abstract description 5
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 5
150000003839 salts Chemical class 0.000 claims abstract description 5
229910052717 sulfur Inorganic materials 0.000 claims abstract description 5
239000011593 sulfur Substances 0.000 claims abstract description 5
WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims abstract description 4
CMIRWXFQPVROKZ-UHFFFAOYSA-N 5h-2-benzazepine-4-carboxylic acid Chemical compound C1C(C(=O)O)=CN=CC2=CC=CC=C21 CMIRWXFQPVROKZ-UHFFFAOYSA-N 0.000 claims description 79
230000002401 inhibitory effect Effects 0.000 claims description 11
239000000546 pharmaceutical excipient Substances 0.000 claims description 9
206010020772 Hypertension Diseases 0.000 claims description 5
239000003937 drug carrier Substances 0.000 claims description 5
239000001301 oxygen Substances 0.000 claims description 4
229910052760 oxygen Inorganic materials 0.000 claims description 4
206010007559 Cardiac failure congestive Diseases 0.000 claims description 3
206010019280 Heart failures Diseases 0.000 claims description 3
230000001684 chronic effect Effects 0.000 claims description 3
125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 2
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 abstract description 23
102000004270 Peptidyl-Dipeptidase A Human genes 0.000 abstract description 23
108090000882 Peptidyl-Dipeptidase A Proteins 0.000 abstract description 23
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 249
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 96
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 62
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 39
239000002904 solvent Substances 0.000 description 38
238000003756 stirring Methods 0.000 description 38
XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 31
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 28
238000010898 silica gel chromatography Methods 0.000 description 27
150000001732 carboxylic acid derivatives Chemical class 0.000 description 26
239000000243 solution Substances 0.000 description 26
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
239000008346 aqueous phase Substances 0.000 description 20
238000000034 method Methods 0.000 description 19
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
239000012300 argon atmosphere Substances 0.000 description 18
239000002253 acid Substances 0.000 description 17
239000012074 organic phase Substances 0.000 description 17
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
239000000376 reactant Substances 0.000 description 16
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 15
239000000203 mixture Substances 0.000 description 15
RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 14
125000006308 propyl amino group Chemical group 0.000 description 14
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
238000005192 partition Methods 0.000 description 12
239000000284 extract Substances 0.000 description 10
QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 10
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
238000006243 chemical reaction Methods 0.000 description 9
239000006260 foam Substances 0.000 description 9
150000004702 methyl esters Chemical group 0.000 description 9
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
ITLHXEGAYQFOHJ-UHFFFAOYSA-N [diazo(phenyl)methyl]benzene Chemical compound C=1C=CC=CC=1C(=[N+]=[N-])C1=CC=CC=C1 ITLHXEGAYQFOHJ-UHFFFAOYSA-N 0.000 description 7
239000012298 atmosphere Substances 0.000 description 7
239000000706 filtrate Substances 0.000 description 7
UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 7
239000012299 nitrogen atmosphere Substances 0.000 description 7
NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 6
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
235000008504 concentrate Nutrition 0.000 description 6
239000012141 concentrate Substances 0.000 description 6
IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 6
239000003960 organic solvent Substances 0.000 description 6
229920006395 saturated elastomer Polymers 0.000 description 6
239000002002 slurry Substances 0.000 description 6
102400000345 Angiotensin-2 Human genes 0.000 description 5
101800000733 Angiotensin-2 Proteins 0.000 description 5
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 description 5
CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 5
239000004480 active ingredient Substances 0.000 description 5
229950006323 angiotensin ii Drugs 0.000 description 5
239000000010 aprotic solvent Substances 0.000 description 5
YOYHXRDYEOKWSG-OAQYLSRUSA-N benzhydryl (2r)-4-phenyl-2-(trifluoromethylsulfonyl)butanoate Chemical compound C([C@@H](S(=O)(=O)C(F)(F)F)C(=O)OC(C=1C=CC=CC=1)C=1C=CC=CC=1)CC1=CC=CC=C1 YOYHXRDYEOKWSG-OAQYLSRUSA-N 0.000 description 5
239000003795 chemical substances by application Substances 0.000 description 5
201000010099 disease Diseases 0.000 description 5
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
238000004128 high performance liquid chromatography Methods 0.000 description 5
229910052943 magnesium sulfate Inorganic materials 0.000 description 5
125000001424 substituent group Chemical group 0.000 description 5
MJHVVXOHJFVLEB-SECBINFHSA-N (2r)-4-phenyl-2-(trifluoromethylsulfonyl)butanoic acid Chemical compound FC(F)(F)S(=O)(=O)[C@@H](C(=O)O)CCC1=CC=CC=C1 MJHVVXOHJFVLEB-SECBINFHSA-N 0.000 description 4
NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 4
WMYRYTHPUNNJQO-AWEZNQCLSA-N 2-[[(1s)-1-carboxy-2-phenylethyl]carbamoyl]benzoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)C=1C(=CC=CC=1)C(O)=O)C1=CC=CC=C1 WMYRYTHPUNNJQO-AWEZNQCLSA-N 0.000 description 4
239000005541 ACE inhibitor Substances 0.000 description 4
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 4
SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 4
229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 4
239000002775 capsule Substances 0.000 description 4
239000000969 carrier Substances 0.000 description 4
230000000694 effects Effects 0.000 description 4
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
230000005764 inhibitory process Effects 0.000 description 4
239000000463 material Substances 0.000 description 4
CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
238000002360 preparation method Methods 0.000 description 4
239000011780 sodium chloride Substances 0.000 description 4
239000000725 suspension Substances 0.000 description 4
ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 4
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 3
COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical class OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 3
DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
229940124572 antihypotensive agent Drugs 0.000 description 3
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
125000004432 carbon atom Chemical group C* 0.000 description 3
239000003814 drug Substances 0.000 description 3
238000001704 evaporation Methods 0.000 description 3
230000008020 evaporation Effects 0.000 description 3
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
239000005526 vasoconstrictor agent Substances 0.000 description 3
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
OFBSPGYFQJUDHF-UHFFFAOYSA-N Cl.Cl.C1=NC=C(CC2=C1C=CC=C2)C(=O)O Chemical compound Cl.Cl.C1=NC=C(CC2=C1C=CC=C2)C(=O)O OFBSPGYFQJUDHF-UHFFFAOYSA-N 0.000 description 2
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
229930006000 Sucrose Natural products 0.000 description 2
CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
239000002671 adjuvant Substances 0.000 description 2
238000004458 analytical method Methods 0.000 description 2
239000006286 aqueous extract Substances 0.000 description 2
229910052786 argon Inorganic materials 0.000 description 2
ODXRLCORPKTWCY-OAQYLSRUSA-N benzhydryl (2r)-2-hydroxy-4-phenylbutanoate Chemical compound C([C@@H](O)C(=O)OC(C=1C=CC=CC=1)C=1C=CC=CC=1)CC1=CC=CC=C1 ODXRLCORPKTWCY-OAQYLSRUSA-N 0.000 description 2
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
CWBHKBKGKCDGDM-UHFFFAOYSA-N bis[(2,2,2-trifluoroacetyl)oxy]boranyl 2,2,2-trifluoroacetate Chemical compound FC(F)(F)C(=O)OB(OC(=O)C(F)(F)F)OC(=O)C(F)(F)F CWBHKBKGKCDGDM-UHFFFAOYSA-N 0.000 description 2
ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
239000001569 carbon dioxide Substances 0.000 description 2
229910002092 carbon dioxide Inorganic materials 0.000 description 2
208000010877 cognitive disease Diseases 0.000 description 2
150000002081 enamines Chemical class 0.000 description 2
150000002148 esters Chemical class 0.000 description 2
125000004494 ethyl ester group Chemical group 0.000 description 2
239000000796 flavoring agent Substances 0.000 description 2
235000003599 food sweetener Nutrition 0.000 description 2
238000007327 hydrogenolysis reaction Methods 0.000 description 2
125000004356 hydroxy functional group Chemical group O* 0.000 description 2
230000001631 hypertensive effect Effects 0.000 description 2
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
ANSUDRATXSJBLY-VKHMYHEASA-N methyl (2s)-2-amino-3-hydroxypropanoate Chemical compound COC(=O)[C@@H](N)CO ANSUDRATXSJBLY-VKHMYHEASA-N 0.000 description 2
OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 2
WPHGSKGZRAQSGP-UHFFFAOYSA-N methylenecyclohexane Natural products C1CCCC2CC21 WPHGSKGZRAQSGP-UHFFFAOYSA-N 0.000 description 2
LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
125000001624 naphthyl group Chemical group 0.000 description 2
229910017604 nitric acid Inorganic materials 0.000 description 2
229910052757 nitrogen Inorganic materials 0.000 description 2
230000000269 nucleophilic effect Effects 0.000 description 2
239000003921 oil Substances 0.000 description 2
239000003791 organic solvent mixture Substances 0.000 description 2
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
239000006187 pill Substances 0.000 description 2
229920001223 polyethylene glycol Polymers 0.000 description 2
229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
235000015497 potassium bicarbonate Nutrition 0.000 description 2
239000011736 potassium bicarbonate Substances 0.000 description 2
TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
229940086066 potassium hydrogencarbonate Drugs 0.000 description 2
230000002035 prolonged effect Effects 0.000 description 2
239000005720 sucrose Substances 0.000 description 2
HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 2
239000003765 sweetening agent Substances 0.000 description 2
235000020357 syrup Nutrition 0.000 description 2
239000006188 syrup Substances 0.000 description 2
239000003826 tablet Substances 0.000 description 2
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 description 2
125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 2
JNJCEALGCZSIGB-SECBINFHSA-N (2r)-2-hydroxy-4-phenylbutanoic acid Chemical class OC(=O)[C@H](O)CCC1=CC=CC=C1 JNJCEALGCZSIGB-SECBINFHSA-N 0.000 description 1
UOJLGCAIQSQACY-UHFFFAOYSA-N 11-nitro-6-oxo-2,3,4,7,8,12b-hexahydro-1H-pyrido[2,1-a][2]benzazepine-4-carboxylic acid Chemical compound [N+](=O)([O-])C1=CC2=C(CCC(N3C2CCCC3C(=O)O)=O)C=C1 UOJLGCAIQSQACY-UHFFFAOYSA-N 0.000 description 1
KGLPWQKSKUVKMJ-UHFFFAOYSA-N 2,3-dihydrophthalazine-1,4-dione Chemical compound C1=CC=C2C(=O)NNC(=O)C2=C1 KGLPWQKSKUVKMJ-UHFFFAOYSA-N 0.000 description 1
125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 description 1
125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 description 1
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ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
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Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/022—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
- C07K5/0222—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2 with the first amino acid being heterocyclic, e.g. Pro, Trp
- 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
- 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
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides

Landscapes

Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Medicinal Chemistry (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
General Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
General Chemical & Material Sciences (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Chemical Kinetics & Catalysis (AREA)
Pharmacology & Pharmacy (AREA)
Animal Behavior & Ethology (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Heart & Thoracic Surgery (AREA)
Cardiology (AREA)
Biochemistry (AREA)
Urology & Nephrology (AREA)
Biophysics (AREA)
Genetics & Genomics (AREA)
Molecular Biology (AREA)
Proteomics, Peptides & Aminoacids (AREA)
Vascular Medicine (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Preparation Of Compounds By Using Micro-Organisms (AREA)
Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

IL10041691A 1990-12-21 1991-12-18 7-[(carboxy-3-phenylpropyl) amino]- 1,2,3,4,6,7,8, 12b-octahydro-6- oxo-amino or nitro containing tricyclic benzazepine derivatives and pharmaceutical compositions containing them as inhibitors of ace IL100416A (en)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
US63357290A	1990-12-21	1990-12-21
US77762591A	1991-10-23	1991-10-23

Publications (2)

Publication Number	Publication Date
IL100416A0 IL100416A0 (en)	1992-09-06
IL100416A true IL100416A (en)	1995-11-27

Family

ID=27091923

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
IL10041691A IL100416A (en)	1990-12-21	1991-12-18	7-[(carboxy-3-phenylpropyl) amino]- 1,2,3,4,6,7,8, 12b-octahydro-6- oxo-amino or nitro containing tricyclic benzazepine derivatives and pharmaceutical compositions containing them as inhibitors of ace

Country Status (18)

Country	Link
EP (1)	EP0492369B1 (de)
JP (1)	JP3112327B2 (de)
KR (2)	KR100220880B1 (de)
CN (1)	CN1040985C (de)
AT (1)	ATE158303T1 (de)
AU (1)	AU642321B2 (de)
CA (1)	CA2057786C (de)
DE (1)	DE69127681T2 (de)
DK (1)	DK0492369T3 (de)
ES (1)	ES2108027T3 (de)
FI (1)	FI95800C (de)
GR (1)	GR3025622T3 (de)
HU (1)	HU210167B (de)
IE (1)	IE914507A1 (de)
IL (1)	IL100416A (de)
NO (1)	NO180196C (de)
NZ (1)	NZ241023A (de)
PT (1)	PT99849B (de)

Families Citing this family (22)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US5308841A (en) *	1990-12-21	1994-05-03	Merrell Dow Pharmaceuticals Inc.	Amino and nitro containing tricyclic compounds useful as inhibitors of ACE
US5455242A (en) *	1991-09-27	1995-10-03	Merrell Dow Pharmaceuticals Inc.	Carboxyalkyl tricyclic derivatives useful as inhibitors of enkephalinase and ace
ZA927211B (en) *	1991-09-27	1993-03-24	Merrell Dow Pharma	Novel carboxyalkyl derivatives useful as inhibitors of enkephalinase and ACE.
US5457196A (en) *	1991-09-27	1995-10-10	Merrell Dow Pharmaceuticals Inc.	2-substituted indane-2-carboxyalkyl derivatives useful as inhibitors of enkephalinase and ACE
AU657793B2 (en) *	1991-09-27	1995-03-23	Merrell Pharmaceuticals Inc.	Novel 2-substituted indane-2-carboxyalkyl derivatives useful as inhibitors of enkephalinase and ACE
CA2078758C (en) *	1991-09-27	2003-12-09	Alan M. Warshawsky	2-substituted indane-2-mercaptoacetylamide derivatives useful as inhibitors of enkephalinase and ace
DK0640086T3 (da) *	1992-05-15	1999-12-06	Merrell Pharma Inc	Mercaptoacetylamido-pyridazo[1,2-a][1,2]diazepin-derivateranvendelige som enkephalinase- og ACE-inhibitorer
PT669936E (pt) *	1992-10-30	2001-04-30	Merrell Pharma Inc	Derivados de lactama biciclica de mercaptoacetilamida uteis como inibidores de encefalinase e de ace
US5362727A (en) *	1993-07-26	1994-11-08	Bristol-Myers Squibb	Substituted azepino[2,1-a]isoquinoline compounds
US5525723A (en) *	1993-11-18	1996-06-11	Bristol-Myers Squibb Co.	Compounds containing a fused multiple ring lactam
CA2183313C (en) *	1994-02-14	2001-01-02	Gary A. Flynn	Novel indane-2-mercaptoacetylamide disulfide derivatives useful as inhibitors of enkephalinase
US5530013A (en) *	1994-02-14	1996-06-25	American Home Products Corporation	Venlafaxine in the inducement of cognition enhancement
CA2183314C (en) *	1994-02-14	1999-08-31	Gary A. Flynn	Novel 2-substituted indane-2-mercaptoacetylamide disulfide derivatives useful as inhibitors of enkephalinase and ace
JPH09508906A (ja) *	1994-02-14	1997-09-09	メレルファーマスーティカルズインコーポレーテッド	エンケファリナーゼ及びａｃｅの阻害剤として有用な新規なメルカプトアセチルアミド１，３，４，５−テトラヒドロベンゾ［ｃ］アゼピン−３−オンジスルフィド誘導体類
WO1995021839A1 (en) *	1994-02-14	1995-08-17	Merrell Pharmaceuticals Inc.	Novel mercaptoacetylamide disulfide derivatives useful as inhibitors of enkephalinase and ace
US5484783A (en) *	1994-03-24	1996-01-16	Merrell Dow Pharmaceuticals Inc.	Hypocholesterolemic, antiatherosclerotic and hypotriglyceridemic mercaptoacetylamide and benzazapine derivatives
FI963784A0 (fi) *	1994-03-24	1996-09-23	Merrell Pharma Inc	Hypokolesteroleemisiä, antiateroskleroottisia ja hypotriglyserideemisiä merkaptoasetyyliamididisulfidijohdannaisia
NZ282568A (en) *	1994-03-24	1997-07-27	Merrell Pharma Inc	Use of condensed aminoacetylmercaptobenzazepines in treating elevated cholesterol levels, atherosclerosis, and hypotriglyceridemia
DK0800527T3 (da) *	1994-12-21	2000-06-05	Aventis Pharma Inc	Nye fremgangsmåder til fremstilling af mellemprodukter for inhibitorer af enkephalinase og angiotensinomdannende enzym og m
US5641880A (en) *	1994-12-21	1997-06-24	Hoechst Marion Roussel, Inc.	Processes for preparing intermediates of inhibitors of enkephalinase and angiotensin converting enzyme and intermediates thereof
US7078225B2 (en)	2000-06-02	2006-07-18	Nippon Shokubai Co., Ltd.	Method for enzymatically producing an optically active cyanohydrin
GB0119305D0 (en)	2001-04-12	2001-10-03	Aventis Pharma Gmbh	Mercaptoacetylamide derivatives,a process for their preparation and their use

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US4584294A (en) *	1984-11-07	1986-04-22	Merck & Co., Inc.	Fused tricyclic lactams as angiotensin converting enzyme inhibitors and as antihypertensive agents
CA1337654C (en) *	1986-06-13	1995-11-28	Gary A. Flynn	Fused tricyclic lactams as antihypertensive agents
AU636101B2 (en) *	1987-04-10	1993-04-22	Monash University	1,2,3,4,10,14b-hexahydrodibenzo(c,f)pyrazino-(1,2-a)azepino derivatives and 10-aza, 10-oxa and 10-thia analogues
US4824832A (en) *	1987-12-30	1989-04-25	Merrell Dow Pharmaceuticals Inc.	Sulfhydryl containing tricyclic lactams and their pharmacological methods of use
CA2053340C (en) *	1990-10-18	2002-04-02	Timothy P. Burkholder	Mercaptoacetylamide derivatives useful as inhibitors of enkephalinase and ace

1991
- 1991-12-17 AT AT91121638T patent/ATE158303T1/de not_active IP Right Cessation
- 1991-12-17 DK DK91121638.0T patent/DK0492369T3/da active
- 1991-12-17 ES ES91121638T patent/ES2108027T3/es not_active Expired - Lifetime
- 1991-12-17 CA CA002057786A patent/CA2057786C/en not_active Expired - Fee Related
- 1991-12-17 DE DE69127681T patent/DE69127681T2/de not_active Expired - Fee Related
- 1991-12-17 NZ NZ241023A patent/NZ241023A/en unknown
- 1991-12-17 EP EP91121638A patent/EP0492369B1/de not_active Expired - Lifetime
- 1991-12-17 AU AU89819/91A patent/AU642321B2/en not_active Ceased
- 1991-12-18 IL IL10041691A patent/IL100416A/en not_active IP Right Cessation
- 1991-12-18 PT PT99849A patent/PT99849B/pt not_active IP Right Cessation
- 1991-12-19 FI FI916017A patent/FI95800C/fi active IP Right Grant
- 1991-12-20 KR KR1019910023702A patent/KR100220880B1/ko not_active Expired - Fee Related
- 1991-12-20 CN CN91111735A patent/CN1040985C/zh not_active Expired - Fee Related
- 1991-12-20 HU HU914092A patent/HU210167B/hu not_active IP Right Cessation
- 1991-12-20 NO NO915068A patent/NO180196C/no unknown
- 1991-12-20 JP JP03354999A patent/JP3112327B2/ja not_active Expired - Fee Related
- 1991-12-20 IE IE450791A patent/IE914507A1/en not_active IP Right Cessation
1997
- 1997-12-10 GR GR970403274T patent/GR3025622T3/el unknown
1999
- 1999-03-27 KR KR1019990010649A patent/KR100220879B1/ko not_active Expired - Fee Related

Also Published As

Publication number	Publication date
NZ241023A (en)	1994-10-26
NO915068D0 (no)	1991-12-20
HU210167B (en)	1995-02-28
NO915068L (no)	1992-06-22
DE69127681D1 (de)	1997-10-23
HUT60271A (en)	1992-08-28
CN1062729A (zh)	1992-07-15
CA2057786C (en)	2002-06-18
ES2108027T3 (es)	1997-12-16
IL100416A0 (en)	1992-09-06
KR920012082A (ko)	1992-07-25
HU914092D0 (en)	1992-03-30
IE914507A1 (en)	1992-07-01
DK0492369T3 (da)	1997-10-13
AU642321B2 (en)	1993-10-14
EP0492369A1 (de)	1992-07-01
FI95800C (fi)	1996-03-25
KR100220879B1 (ko)	2000-03-15
PT99849B (pt)	1999-06-30
PT99849A (pt)	1992-11-30
FI95800B (fi)	1995-12-15
KR100220880B1 (ko)	1999-09-15
JPH04342588A (ja)	1992-11-30
NO180196B (no)	1996-11-25
JP3112327B2 (ja)	2000-11-27
GR3025622T3 (en)	1998-03-31
ATE158303T1 (de)	1997-10-15
EP0492369B1 (de)	1997-09-17
CA2057786A1 (en)	1992-06-22
FI916017A0 (fi)	1991-12-19
NO180196C (no)	1997-03-05
FI916017L (fi)	1992-06-22
DE69127681T2 (de)	1998-01-15
AU8981991A (en)	1992-06-25
CN1040985C (zh)	1998-12-02

Legal Events

Date	Code	Title
1996-05-14	FF	Patent granted
1998-04-05	KB	Patent renewed
2002-02-10	KB	Patent renewed
2006-09-05	MM9K	Patent not in force due to non-payment of renewal fees

Publication	Publication Date	Title
EP0492369B1 (de)	1997-09-17	Neue trizyklische Amino- und Nitro Verbindungen mit ACE-hemmenden Eigenschaften
US5208230A (en)	1993-05-04	Amino and nitro containing tricyclic compounds useful as inhibitors of ACE
US5529996A (en)	1996-06-25	2-substituted indane-2-mercaptoacetylamide derivatives useful as inhibitors of enkephalinase and ace
AU657794B2 (en)	1995-03-23	Novel carboxyalkyl derivatives useful as inhibitors of enkephalinase and ACE
EP0534396B1 (de)	1996-10-09	2-Substituierte Indane-2-Carboxyalkyl-Verbindungen mit Enkephalinase und ACE-Hemmwirkung
CA2146238C (en)	2001-03-13	Novel mercaptoacetylamide bicyclic lactam derivatives useful as inhibitors of enkephalinase and ace
IL99769A (en)	1998-12-27	Mercaptoacetamido derivatives of tricyclic benz (c) azepinones useful as inhibitors of enkephalinase and ace and pharmaceutical compositions containing them
EP0026640B1 (de)	1984-03-14	Über längere Zeit wirksame Agonisten und Antagonisten des das luteinisierende Hormon freisetzenden Hormons und sie enthaltende Zusammensetzungen
US5591739A (en)	1997-01-07	2-substituted indane-2-carboxyalkyl derivatives useful as inhibitors of enkephalinase and ACE
EP0728746B1 (de)	2003-05-28	Azepinonverbindungen zur Anwendung bei der Hemmung von ACE und NEP
US5308841A (en)	1994-05-03	Amino and nitro containing tricyclic compounds useful as inhibitors of ACE
US5488047A (en)	1996-01-30	Carboxyalkyl tricylic derivatives useful as inhibitors of enkephalinase and ace
US4493934A (en)	1985-01-15	2(3-Amino-2-oxopyrrolidin-1-yl) acetic acid and n-acylated derivatives thereof
EP0297815A2 (de)	1989-01-04	Fluor enthaltende Renin-Inhibitoren
KR960003549B1 (ko)	1996-03-15	글루타민산 유도체