US5504080A
Expired / Lapsed
US
⏱️ 0.0 years remaining
Benzo-fused lactams
Assignee: Bristol Myers Squibb Co
•
Filing: 1993-09-22
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Granted: 1996-04-02
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Expires: 2013-09-22
Abstract
Abstract Compounds of the formula ##STR1## wherein A is ##STR2## are useful as ACE and NEP inhibitors and those wherein A is ##STR3## are useful as ACE inhibitors. Methods of preparation and intermediates are also disclosed.
Inventors
- 👤 Donald S. Karanewsky
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-05 16:26
CPC Classifications
C; C07; C07D; C07D471/00; C07D471/02; C07D471/04; A; A61; A61P; A61P13/00; A61P13/12; A61P27/00; A61P27/02; A61P27/06; A61P43/00; A61P9/00; A61P9/12; C07D487/00; C07D487/02; C07D487/06; C07K; C07K5/00; C07K5/02; C07K5/022; C07K5/0222; C07K5/04; C07K5/06; C07K5/06139; A61K; A61K38/00
Claims Analysis
Total Claims: 34
Claim 1
Independent Claim
242 words
A compound of the formula ##STR62## including a pharmaceutically acceptable salt thereof wherein: ##STR63## R 1 and R 12 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, substituted alkyl, substituted alkenyl, aryl, substituted aryl, heteroaryl, cycloalkyl-alkylene-, aryl-alkylene-, substituted aryl-alkylene-, and heteroaryl-alkylene- or R 1 and R 12 taken together with the carbon to which they are attached complete a cycloalkyl ring or a benzofused cycloalkyl ring; R 2 is hydrogen, ##STR64## or R 11 --S--; R 3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl-(CH 2 ) p --, substituted aryl-(CH 2 ) p --, heteroaryl-(CH 2 ) p -- ##STR65## R 6 is alkyl, substituted alkyl, cycloalkyl-(CH 2 ) p --, aryl-(CH 2 ) p --, substituted aryl-(CH 2 ) p --, or heteroaryl-(CH 2 ) p --; R 8 is hydrogen, lower alkyl, cycloalkyl, or phenyl; R 9 is hydrogen, lower alkyl, lower alkoxy, or phenyl; R 10 is lower alkyl or aryl-(CH 2 ) p --; R 11 is alkyl, substituted alkyl, cycloalkyl-(CH 2 ) p --, aryl-(CH 2 ) p --, substituted aryl-(CH 2 ) p --, heteroaryl-(CH 2 ) p --, or --S--R 11 completes a symmetrical disulfide wherein R 11 is ##STR66## m is one or two; n is zero or one; p is zero or an integer from 1 to 6; and the dashed line - - - represents an optional double bond between the two carbons.
Claim 2
Dependent Claim
242 words
A compound of the formula ##STR62## including a pharmaceutically acceptable salt thereof wherein: ##STR63## R 1 and R 12 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, substituted alkyl, substituted alkenyl, aryl, substituted aryl, heteroaryl, cycloalkyl-alkylene-, aryl-alkylene-, substituted aryl-alkylene-, and heteroaryl-alkylene- or R 1 and R 12 taken together with the carbon to which they are attached complete a cycloalkyl ring or a benzofused cycloalkyl ring; R 2 is hydrogen, ##STR64## or R 11 --S--; R 3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl-(CH 2 ) p --, substituted aryl-(CH 2 ) p --, heteroaryl-(CH 2 ) p -- ##STR65## R 6 is alkyl, substituted alkyl, cycloalkyl-(CH 2 ) p --, aryl-(CH 2 ) p --, substituted aryl-(CH 2 ) p --, or heteroaryl-(CH 2 ) p --; R 8 is hydrogen, lower alkyl, cycloalkyl, or phenyl; R 9 is hydrogen, lower alkyl, lower alkoxy, or phenyl; R 10 is lower alkyl or aryl-(CH 2 ) p --; R 11 is alkyl, substituted alkyl, cycloalkyl-(CH 2 ) p --, aryl-(CH 2 ) p --, substituted aryl-(CH 2 ) p --, heteroaryl-(CH 2 ) p --, or --S--R 11 completes a symmetrical disulfide wherein R 11 is ##STR66## m is one or two; n is zero or one; p is zero or an integer from 1 to 6; and the dashed line - - - represents an optional double bond between the two carbons.
Claim 3
Dependent Claim
9 words
A compound of claim 1 of the formula ##STR67##
Claim 4
Dependent Claim
9 words
A compound of claim 2 of the formula ##STR68##
Claim 5
Dependent Claim
99 words
A compound of claim 2 wherein: R 2 is hydrogen ##STR69## or R 11 --S--; R 3 is hydrogen or lower alkyl of 1 to 4 carbons; n is zero or one; R 12 is hydrogen; R 11 is lower alkyl or 1 to 4 carbons; R 1 is aryl-CH 2 --, substituted aryl-CH 2 --, heteroaryl-CH 2 --, cycloalkyl-CH 2 -- wherein cycloalkyl is of 5 to 7 carbons, or straight or branched chain alkyl of 1 to 7 carbons; R 6 is lower alkyl of 1 to 4 carbons or phenyl; and m is one or two.
Claim 6
Dependent Claim
15 words
A compound of claim 4 wherein: R 2 is hydrogen; and R 1 is benzyl.
Claim 7
Dependent Claim
13 words
The compound of claim 5 wherein: n is zero; and m is one.
Claim 8
Dependent Claim
10 words
The compound of claim 6, 2S- 2α,5α(R*)!!-1,2,4,5,6,7-hexahydro-5- (2-mercapto-1-oxo-3-phenylpropyl)amino!-4-oxoazepino 3,2,1-hi!indole-2-carboxylic acid.
Claim 9
Dependent Claim
13 words
The compound of claim 5 wherein: n is one; and m is one.
Claim 10
Dependent Claim
10 words
The compound of claim 8, 2S- 2α,5α(R*)!!-1,2,4,5,6,7-hexahydro-5- 2-(mercaptomethyl)-1-oxo-3-phenylpropyl!amino!-4-oxoazepino 3,2,1-hi!indole-2-carboxylic acid.
Claim 11
Dependent Claim
13 words
The compound of claim 5 wherein: n is zero; and m is two.
Claim 12
Dependent Claim
10 words
The compound of claim 10, 3S- 3α,6α(R*)!!-2,3,5,6,7,8-hexahydro-6- (2-mercapto-1-oxo-3-phenylpropyl)amino!-5-oxo-1H-azepino 3,2,1-ij!quinoline-3-carboxylic acid.
Claim 13
Dependent Claim
15 words
A compound of claim 4 wherein: R 2 is hydrogen; and R 1 is 1-naphthyl.
Claim 14
Dependent Claim
13 words
The compound of claim 12 wherein: n is zero; and m is one.
Claim 15
Dependent Claim
9 words
The compound of claim 13, 2S-(2α,5α)!!-1,2,4,5,6,7-hexahydro-5- 2-mercapto-1-oxo-3-(1-naphthalenyl)propyl!amino!-4-oxoazepino 3,2,1-hi!indole-2-carboxylic acid.
Claim 16
Dependent Claim
9 words
A compound of claim 2 of the formula ##STR70##
Claim 17
Dependent Claim
99 words
A compound of claim 15 wherein: R 2 is hydrogen, ##STR71## or R 11 --S--; R 3 is hydrogen or lower alkyl of 1 to 4 carbons; n is zero or one; R 12 is hydrogen; R 11 is lower alkyl or 1 to 4 carbons; R 1 is aryl-CH 2 --, substituted aryl-CH 2 --, heteroaryl-CH 2 --, cycloalkyl-CH 2 -- wherein cycloalkyl is of 5 to 7 carbons, or straight or branched chain alkyl of 1 to 7 carbons; R 6 is lower alkyl of 1 to 4 carbons or phenyl; and m is one or two.
Claim 18
Dependent Claim
15 words
A compound of claim 16 wherein: R 2 is hydrogen; and R 1 is benzyl.
Claim 19
Dependent Claim
13 words
The compound of claim 17 wherein: n is zero; and m is one.
Claim 20
Dependent Claim
10 words
The compound of claim 18, 2S- 2α,5α(R*)-1,2,4,5-tetrahydro-5- (2-mercapto-1-oxo-3-phenylpropyl)amino!-4-oxoazepino 3,2,1-hi!indole-2-carboxylic acid.
Claim 21
Dependent Claim
13 words
The compound of claim 17 wherein: n is one; and m is one.
Claim 22
Dependent Claim
10 words
The compound of claim 20, 2S- 2α,5α(R*)!!-1,2,4,5-tetrahydro-5- 2-(mercaptomethyl)-1-oxo-3-phenylpropyl!amino!-4-oxoazepino 3,2,1-hi!indole-2-carboxylic acid.
Claim 23
Dependent Claim
53 words
A pharmaceutical composition useful in the treatment of cardiovascular disease such as hypertension and congestive heart failure comprising a pharmaceutically acceptable carrier and one or more compounds of the formula ##STR72## including a pharmaceutically acceptable salt thereof wherein m, A, R 3 , and the dashed line are as defined in claim 1.
Claim 24
Dependent Claim
29 words
A method of treating cardiovascular diseases such as hypertension and congestive heart failure in a mammalian species which comprises administering an effective amount of the composition of claim 22.
Claim 25
Dependent Claim
165 words
A compound of the formula ##STR73## including a pharmaceutically acceptable salt thereof wherein: A is ##STR74## R 1 is hydrogen, alkyl, cycloalkyl-(CH 2 ) p --, substituted alkyl, aryl-(CH 2 ) p --, substituted aryl-(CH 2 ) p --, or heteroaryl-(CH 2 ) r --; R 2 is hydrogen or ##STR75## R 3 is hydrogen, lower alkyl, aryl-(CH 2 ) r --, ##STR76## R 6 is alkyl, substituted alkyl, cycloalkyl-(CH 2 ) p --, aryl-(CH 2 ) p --, substituted aryl-(CH 2 ) p --, or heteroaryl-(CH 2 ) p --; R 8 is hydrogen, lower alkyl, cycloalkyl, or phenyl; R 9 is hydrogen, lower alkyl, lower alkoxy, or phenyl; R 10 is lower alkyl or aryl-(CH 2 ) r --; m is one or two; n is zero or one, p is zero or an integer from 1 to 6; r is an integer from 1 to 6; and the dashed line - - - represents an optional double bond between the two carbons.
Claim 26
Dependent Claim
165 words
A compound of the formula ##STR73## including a pharmaceutically acceptable salt thereof wherein: A is ##STR74## R 1 is hydrogen, alkyl, cycloalkyl-(CH 2 ) p --, substituted alkyl, aryl-(CH 2 ) p --, substituted aryl-(CH 2 ) p --, or heteroaryl-(CH 2 ) r --; R 2 is hydrogen or ##STR75## R 3 is hydrogen, lower alkyl, aryl-(CH 2 ) r --, ##STR76## R 6 is alkyl, substituted alkyl, cycloalkyl-(CH 2 ) p --, aryl-(CH 2 ) p --, substituted aryl-(CH 2 ) p --, or heteroaryl-(CH 2 ) p --; R 8 is hydrogen, lower alkyl, cycloalkyl, or phenyl; R 9 is hydrogen, lower alkyl, lower alkoxy, or phenyl; R 10 is lower alkyl or aryl-(CH 2 ) r --; m is one or two; n is zero or one, p is zero or an integer from 1 to 6; r is an integer from 1 to 6; and the dashed line - - - represents an optional double bond between the two carbons.
Claim 27
Dependent Claim
54 words
A compound of the formula ##STR77## including a salt thereof wherein: R 3 is hydrogen, lower alkyl, or aryl-(CH 2 ) p --; p is zero or an integer from 1 to 6; m is one or two; and the dashed line - - - represents an optional double bond between the two carbons.
Claim 28
Dependent Claim
54 words
A compound of the formula ##STR77## including a salt thereof wherein: R 3 is hydrogen, lower alkyl, or aryl-(CH 2 ) p --; p is zero or an integer from 1 to 6; m is one or two; and the dashed line - - - represents an optional double bond between the two carbons.
Claim 29
Dependent Claim
9 words
A compound of claim 25 of the formula ##STR78##
Claim 30
Dependent Claim
18 words
The compound of claim 26 ##STR79## wherein: R 3 is lower alkyl; and m is one or two.
Claim 31
Dependent Claim
14 words
The compound of claim 27 wherein R 3 is ethyl; and m is one.
Claim 32
Dependent Claim
14 words
The compound of claim 27 wherein R 3 is methyl; and m is two.
Claim 33
Dependent Claim
18 words
The compound of claim 26 ##STR80## wherein: R 3 is lower alkyl; and m is one or two.
Claim 34
Dependent Claim
14 words
The compound of claim 30 wherein: R 3 is ethyl; and m is one.
References Cited (Backward Citations)
US4339600A
Cited
US4053651A
Cited
US4105776A
Cited
US4374829A
Cited
US4461896A
Cited
US4684660A
Cited
US4680392A
Cited
GB2086390A
Cited
US4337201A
Cited
US4432972A
Cited
US4432971A
Cited
US4410520A
Cited
US4873235A
Cited
US4487716A
Cited
US4460579A
Cited
US4567177A
Cited
US5238924A
Cited
US4584294A
Cited
US4816466A
Cited
US4871842A
Cited
US4954625A
Cited
DE3708484A1
Cited
US4749688A
Cited
US5061710A
Cited
US4801609A
Cited
US5262436A
Cited
US4801609B1
Cited
GB2207351A
Cited
US5075302A
Cited
EP0481522A1
Cited
EP0524553A1
Cited
EP0534396A2
Cited
EP0534363A2
Cited
EP0534492A2
Cited
US5366973A
Cited
EP0599444A1
Cited
WO1994010193A1
Cited
WO1994026719A1
Cited
EP0629627A2
Cited
US5362727A
Cited
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1999-04-02 | 1999-10-02 | 2000-04-02 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2003-04-02 | 2003-10-02 | 2004-04-02 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2007-04-02 | 2007-10-02 | 2008-04-02 | $7700.00 | Window Closed / Lapsed |