US4490369A
Expired / Lapsed
US
⏱️ 0.0 years remaining
Benzazepine derivatives, their pharmaceutical compositions and method of use
Assignee: Boehringer Ingelheim Pharma GmbH and Co KG
•
Filing: 1983-11-02
•
Granted: 1984-12-25
•
Expires: 2003-11-02
Abstract
Abstract Compounds of the formula <IMAGE> wherein A is -CH2-CH2-, -CH=CH-, -NH-CO-, -CH2-CO- or <IMAGE> where R7 is alkyl of 1 to 3 carbon atoms, and B is methylene, carbonyl or thiocarbonyl, or A is -CO-CO-, -N=CH-, <IMAGE> <IMAGE> where R8 is hydrogen or alkyl of 1 to 3 carbon atoms substituted by a phenyl, methoxyphenyl or dimethoxyphenyl, and B is methylene; E is n-alkylene of 2 to 4 carbon atoms optionally substituted by an alkyl of 1 to 3 carbon atoms, 2-hydroxy-n-propylene, 2-hydroxy-n-butylene or 3-hydroxy-n-butylene; G is n-alkylene of 1 to 5 carbon atoms optionally substituted by an alkyl of 1 to 3 carbon atoms, wherein one methylene group of an n-alkylene of 2 to 5 carbon atoms can be replaced by a carbonyl group, with the proviso that B represents a methylene or carbonyl group, or methylene-n-hydroxy-alkylene of 1 to 4 carbon atoms, where the methylene group is attached to the nitrogen atom; and R1 to R5 are simple substituents of various types; and non-toxic, pharmacologically acceptable acid addition salts thereof. The compounds as well as their salts are useful as bradycardiacs.
Inventors
- 👤 Manfred Reiffen
- 👤 Joachim Heider
- 👤 Norbert Hauel
- 👤 Volkhard Austel
- 👤 Wolfgang Eberlein
- 👤 Walter Kobinger
- 👤 Christian Lillie
- 👤 Klaus Noll
- 👤 Helmut Pieper
- 👤 Gerd Kruger
- 👤 Johannes Keck
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-02 19:28
CPC Classifications
C; C07; C07D; C07D223/00; C07D223/14; C07D223/16; C07C; C07C59/00; C07C59/40; C07C59/58; C07C59/64; C07D205/00; C07D205/02; C07D205/04; C07D243/00; C07D243/02; C07D243/04; C07D491/00; C07D491/02; C07D491/04
Claims Analysis
Total Claims: 17
Claim 1
Independent Claim
430 words
A compound of the formula ##STR50## wherein A is --CH 2 --CH 2 --, --CH═CH--, --NH--CO, --CH 2 CO-- or ##STR51## where R 7 is alkyl of 1 to 3 carbon atoms, and B is methylene, carbonyl or thiocarbonyl; or A is --CO--CO--, --N═CH--, ##STR52## where R 8 is hydrogen or alkyl of 1 to 3 carbon atoms substituted by a phenyl, methoxyphenyl or dimethoxyphenyl, and B is methylene; E is n-alkylene of 2 to 4 carbon atoms optionally substituted by an alkyl of 1 to 3 carbon atoms, 2-hydroxy-n-propylene, 2-hydroxy-n-butylene or 3-hydroxy-n-butylene; G is n-alkylene of 1 to 5 carbon atoms optionally substituted by an alkyl of 1 to 3 carbon atoms, wherein one methylene group of an n-alkylene of 2 to 5 carbon atoms can be replaced by a carbonyl group, with the proviso that B is methylene or carbonyl; or methylene-n-hydroxy-alkylene of 1 to 4 carbon atoms, where the methylene group is attached to the nitrogen atom; R 1 is hydrogen, fluorine, chlorine, bromine, trifluoromethyl, amino, hydroxyl, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, phenyl(alkoxy of 1 to 3 carbon atoms), (alkyl of 1 to 3 carbon atoms)amino or di(alkyl of 1 to 3 carbon atoms)amino; R 2 is hydrogen, fluorine, chlorine, bromine, hydroxyl, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms or phenyl(alkoxy of 1 to 3 carbon atoms); or R 1 and R 2 , together with each other, are alkylene of 1 to 2 carbon atoms)dioxy; R 3 is hydrogen, fluorine, chlorine, bromine, hydroxy, cyano, nitro, trifluoromethyl, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms; R 4 is hydrogen, alkyl of 1 to 3 carbon atoms, hydroxy, alkoxy of 1 to 3 carbon atoms, amino, (alkyl of 1 to 3 carbon atoms)amino, di(alkyl of 1 to 3 carbon atoms)amino, (alkanoyl of 1 to 3 carbon atoms)amino, (alkoxy of 1 to 3 carbon atoms)carbonylamino, bis[(alkoxy of 1 to 3 carbon atoms)carbonyl]amino, (trifluoromethyl-methyl)amino or (trifluoromethyl-ethyl)-amino; or R 3 and R 4 , together with each other, are (alkylene of 1 to 2 carbon atoms)dioxy; R 5 is hydrogen, chlorine, bromine, cyano, hydroxy, alkyl or alkoxy, where each alkyl moiety may contain 1 to 4 carbon atoms; and R 6 is hydrogen, alkyl of 1 to 3 carbon atoms, phenyl(alkyl of 1 to 3 carbon atoms), alkanoyl of 1 to 3 carbon atoms, (alkoxy of 1 to 3 carbon atoms)carbonyl or alkenyl of 3 to 5 carbon atoms; or a non-toxic, pharmacologically acceptable acid addition salt thereof.
Claim 2
Dependent Claim
430 words
A compound of the formula ##STR50## wherein A is --CH 2 --CH 2 --, --CH═CH--, --NH--CO, --CH 2 CO-- or ##STR51## where R 7 is alkyl of 1 to 3 carbon atoms, and B is methylene, carbonyl or thiocarbonyl; or A is --CO--CO--, --N═CH--, ##STR52## where R 8 is hydrogen or alkyl of 1 to 3 carbon atoms substituted by a phenyl, methoxyphenyl or dimethoxyphenyl, and B is methylene; E is n-alkylene of 2 to 4 carbon atoms optionally substituted by an alkyl of 1 to 3 carbon atoms, 2-hydroxy-n-propylene, 2-hydroxy-n-butylene or 3-hydroxy-n-butylene; G is n-alkylene of 1 to 5 carbon atoms optionally substituted by an alkyl of 1 to 3 carbon atoms, wherein one methylene group of an n-alkylene of 2 to 5 carbon atoms can be replaced by a carbonyl group, with the proviso that B is methylene or carbonyl; or methylene-n-hydroxy-alkylene of 1 to 4 carbon atoms, where the methylene group is attached to the nitrogen atom; R 1 is hydrogen, fluorine, chlorine, bromine, trifluoromethyl, amino, hydroxyl, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, phenyl(alkoxy of 1 to 3 carbon atoms), (alkyl of 1 to 3 carbon atoms)amino or di(alkyl of 1 to 3 carbon atoms)amino; R 2 is hydrogen, fluorine, chlorine, bromine, hydroxyl, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms or phenyl(alkoxy of 1 to 3 carbon atoms); or R 1 and R 2 , together with each other, are alkylene of 1 to 2 carbon atoms)dioxy; R 3 is hydrogen, fluorine, chlorine, bromine, hydroxy, cyano, nitro, trifluoromethyl, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms; R 4 is hydrogen, alkyl of 1 to 3 carbon atoms, hydroxy, alkoxy of 1 to 3 carbon atoms, amino, (alkyl of 1 to 3 carbon atoms)amino, di(alkyl of 1 to 3 carbon atoms)amino, (alkanoyl of 1 to 3 carbon atoms)amino, (alkoxy of 1 to 3 carbon atoms)carbonylamino, bis[(alkoxy of 1 to 3 carbon atoms)carbonyl]amino, (trifluoromethyl-methyl)amino or (trifluoromethyl-ethyl)-amino; or R 3 and R 4 , together with each other, are (alkylene of 1 to 2 carbon atoms)dioxy; R 5 is hydrogen, chlorine, bromine, cyano, hydroxy, alkyl or alkoxy, where each alkyl moiety may contain 1 to 4 carbon atoms; and R 6 is hydrogen, alkyl of 1 to 3 carbon atoms, phenyl(alkyl of 1 to 3 carbon atoms), alkanoyl of 1 to 3 carbon atoms, (alkoxy of 1 to 3 carbon atoms)carbonyl or alkenyl of 3 to 5 carbon atoms; or a non-toxic, pharmacologically acceptable acid addition salt thereof.
Claim 3
Dependent Claim
208 words
A compound of claim 1, where A is --CH 2 CH 2 --, --CH═CH--, ##STR53## and B is methylene, carbonyl or thiocarbonyl; or ##STR54## A is --CO--CO--, ##STR55## B is methylene; E is ethylene, n-propylene, n-butylene, 2-methyl-n-propylene or 2-hydroxy-n-propylene; G is methylenecarbonyl, with the proviso that B represents a methylene or carbonyl group; n-alkylene of 1 to 5 carbon atoms or methylene-n-hydroxyalkylene of 1 to 2 carbon atoms, where the methylene group is attached to the nitrogen atom; R 1 is hydrogen, chlorine, bromine, trifluoromethyl, methyl, hydroxyl, benzyloxy, alkoxy of 1 to 3 carbon atoms, amino, methylaino or dimethylamino; R 2 is hydrogen, chlorine, bromine, methyl, hydroxyl or methoxy; or R 1 and R 2 , together with each other, are methylenedioxy; R 3 is hydrogen, fluorine, chlorine, bromine, trifluoromethyl, nitro, cyano, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms; R 4 is hydrogen, methoxy, amino, methylamino, dimethylamino, acetylamino, ethoxycarbonylamino, bis(ethoxycarbonyl)amino or β,β,β-trifluoroethylamino; or R 3 and R 4 , together with each other, are methylenedioxy; R 5 is hydrogen, chlorine, bromine, methyl or methoxy; and R 6 is hydrogen, alkyl of 1 to 3 carbon atoms, benzyl, allyl, acetyl or ethoxycarbonyl; or a non-toxic, pharmacologically acceptable acid addition salt thereof.
Claim 4
Dependent Claim
133 words
A compound of claim 1, where A is --CH 2 --CH 2 --, --CH═CH-- or ##STR56## and B is carbonyl or thiocarbonyl; or A is --CH═CH--, ##STR57## or --CO--CO-- and B is methylene; E is n-propylene; G. is n-akylene of 2 to 5 carbon atoms, ##STR58## R 1 is hydroxy, methoxy, amino, methylamino or dimethylamino; R 2 is hydrogen or methoxy, or R 1 and R 2 , together with each other, are methylenedioxy; R 3 is hydrogen, fluorine, chlorine, bromine, trifluoromethyl, methyl, methoxy or nitro; R 4 is hydrogen, methoxy, amino or dimethylamine, or R 3 and R 4 , together with each other, are methylenedioxy; R 5 is hydrogen, chlorine or bromine; and R 6 is hydrogen, methyl, ethyl, n-propyl or allyl; or a non-toxic, pharmacologically acceptable acid addition salt thereof.
Claim 5
Dependent Claim
140 words
A compound of claim 1, which is of the formula ##STR59## wherein A is --CH 2 --CH 2 -- or --CH═CH-- and B is carbonyl or thiocarbonyl; or A is ##STR60## or --CO--CO-- and B is methylene; R 1 is methoxy, amino, methylamino or dimethylamino, R 2 is hydrogen or methoxy, or R 1 and R 2 , together with each other, are methylenedioxy; R 3 is hydrogen, fluorine, chlorine, bromine, methoxy or trifluoromethyl or nitro; R 4 is hydrogen, methoxy, amino, methylamino or dimethylamino, or chlorine, when R 6 is hydrogen, or R 3 and R 4 , together with each other, are methylenedioxy; R 5 is hydrogen, chlorine or bromine; R 6 is hydrogen, methyl or allyl, and G is n-alkylene of 2 to 5 carbon atoms or ##STR61## or a non-toxic, pharmacologically acceptable acid addition salt thereof.
Claim 6
Dependent Claim
27 words
A compound of claim 3, where A is --CH 2 CH 2 -- and B is carbonyl or thiocarbonyl, or A is ##STR62## and B is methylene;
Claim 7
Dependent Claim
64 words
R 1 and R 2 are each methoxy, or R 1 and R 2 are methylenedioxy; R 3 is hydrogen, chlorine or bromine or methoxy; R 4 is methoxy, amino or dimethylamino; R 5 is hydrogen or chlorine; R 6 is methyl, and G is n-alkylene of 2 to 5 carbon atoms or a ##STR63## group, or a non-toxic, pharmacologically acceptable addition salt thereof.
Claim 8
Dependent Claim
64 words
R 1 and R 2 are each methoxy, or R 1 and R 2 are methylenedioxy; R 3 is hydrogen, chlorine or bromine or methoxy; R 4 is methoxy, amino or dimethylamino; R 5 is hydrogen or chlorine; R 6 is methyl, and G is n-alkylene of 2 to 5 carbon atoms or a ##STR63## group, or a non-toxic, pharmacologically acceptable addition salt thereof.
Claim 9
Dependent Claim
17 words
A compound of claim 1, which is 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-[N-methyl-N-(2-{3,4-dimethoxy-phenyl}-ethyl)-amino]-propane or a non-toxic, pharmacologically acceptable acid addition salt thereof.
Claim 10
Dependent Claim
17 words
A compound of claim 1, which is 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-1,2-dione-3-yl]-3-[N-methyl-N-(2-{3,4-dimethoxy-phenyl}-ethyl)-amino]-propane or a non-toxic, pharmacologically acceptable acid addition salt thereof.
Claim 11
Dependent Claim
17 words
A compound of claim 1, which is 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl[-3-[N-methyl-N-(2-{4-amino-3,5-dichloro-phenyl}-ethyl)-amino]-propane or a non-toxic, pharmacologically acceptable acid addition salt thereof.
Claim 12
Dependent Claim
17 words
A compound of claim 1, which is 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-[N-methyl-N-(2-{4-methoxy-phenyl}-ethyl)-amino]-propane or a non-toxic, pharmacologically acceptable acid addition salt thereof.
Claim 13
Dependent Claim
17 words
A compound of claim 1, which is 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-[N-methyl-N-(3-{3,4-dimethoxy-phenyl}-propyl)-amino]-propane or a non-toxic, pharmacologically acceptable acid addition salt thereof.
Claim 14
Dependent Claim
17 words
A compound of claim 1, which is 1-1-hydroxy-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3yl]-3-[N-methyl-N-(3-{3,4-dimethoxy-phenyl}-propyl)amino]-propane or a non-toxic, pharmacologically acceptable acid addition salt thereof.
Claim 15
Dependent Claim
17 words
A compound of claim 1, which is 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl[-3-[N-methyl-N-(3-{4-amino-3,5-dichloro-phenyl}-propyl)amino]-propane or a non-toxic, pharmacologically acceptable acid addition salt thereof.
Claim 16
Dependent Claim
22 words
A bradycardiac pharmaceutical composition consisting essentially of an inert pharmaceutical carrier and an effective bradycardiac amount of a compound of claim 1.
Claim 17
Dependent Claim
34 words
The method of lowering the heart rate of a warm-blooded animal in need thereof, which comprises perorally, parenterally or rectally administering to said animal an effective bradycardiac amount of a compound of claim 1.
References Cited (Backward Citations)
US3474090A
Cited
US3719669A
Cited
US3780023A
Cited
US4210749A
Cited
DE2639718A1
Cited
US4137318A
Cited
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1987-12-25 | 1988-06-25 | 1988-12-25 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1991-12-25 | 1992-06-25 | 1992-12-25 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1995-12-25 | 1996-06-25 | 1996-12-25 | $7700.00 | Window Closed / Lapsed |