US4477464A
Expired / Lapsed
US
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Hetero-benzazepine derivatives and their pharmaceutical use
Assignee: Novartis Corp
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Filing: 1983-02-10
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Granted: 1984-10-16
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Expires: 2003-02-10
Abstract
Abstract Disclosed are variously substituted 3-(carboxymethylamino)-(1,5-benzothiazepin-4-one, 1,5-benzoxazepin-4-one and 1,5-benzodiazepin-4-one)-5-alkanoic acids and derivatives as angiotensin-converting enzyme inhibitors and antihypertensive agents. Their synthesis, pharmaceutical compositions thereof, and methods of threatment utilizing such compounds are included.
Inventors
- 👤 Joel Slade
- 👤 James L. Stanton
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-05 21:02
CPC Classifications
C; C07; C07D; C07D281/00; C07D281/02; C07D281/04; C07D281/08; C07D281/10; C07D243/00; C07D243/06; C07D243/10; C07D243/12; C07D267/00; C07D267/02; C07D267/08; C07D267/12; C07D267/14
Claims Analysis
Total Claims: 20
Claim 1
Independent Claim
268 words
A compound of the formula ##STR20## wherein R 1 is hydrogen, lower alkyl, amino-lower alkyl, acylamino-lower alkyl, aryl, aryl-lower alkyl, cycloalkyl or cycloalkyl-lower alkyl; R 2 is hydrogen or lower alkyl; R 3 and R 4 , each independently, represent hydrogen, lower alkyl, lowr alkoxy, lower alkanoyloxy, hydroxy, halogen or trifluoromethyl; or R 3 and R 4 taken together represent lower alkylenedioxy; R 5 is hydrogen or lower alkyl; R 6 and R 7 represent independently hydroxy; lower alkoxy; (amino, mono- or di-lower alkylamino)-substituted lower alkoxy; carboxy-substituted lower alkoxy; lower alkoxycarbonyl-substituted lower alkoxy; aryl-substituted lower alkoxy; (hydroxy, lower alkanoyloxy or lower alkoxy)-substituted lower alkoxy; (hydroxy, lower alkanoyloxy or lower alkoxy)-substituted lower alkoxymethoxy; bicyclo[2,2,1]-heptyloxycarbonyl-substituted lower alkoxy; 3-phthalidoxy; (lower alkyl, lower alkoxy, halo)-substituted 3-phthalidoxy; amino; lower alkylamino; di-lower alkylamino; pyrrolidino, piperidino or perhydroazepino; (amino or acylamino)-substituted lower alkylamino; α-(carboxy or lower alkoxycarbonyl)-substituted lower alkylamino; aryl-substituted lower alkylamino which can be substituted on the α-carbon by carboxy or lower alkoxycarbonyl; X represents S(O) p , N--R 8 or O, in which radicals R 8 represents hydrogen, lower alkyl or aryl, and p represents zero, one or two; and wherein the carbocylic ring may also be hexahydro; and wherein within the above definitions acylamino represents lower alkanoylamino; lower alkoxycarbonylamino; aryl-lower alkanoylamino; aryl-lower alkoxycarbonylamino; or aroylamino in which aroyl represents benzoyl or benzoyl substituted by lower alkyl, lower alkoxy or halogen, or nicotinoyl; and wherein within the above definitions aryl represents phenyl unsubstituted or mono- or di-substituted by lower alkyl, lower alkoxy, lower alkylenedioxy, lower alkanoyloxy, hydroxy, halogen or trifluoromethyl; and cycloalkyl contains 3 to 8 carbons; or a pharmaceutically acceptable salt thereof.
Claim 2
Dependent Claim
268 words
A compound of the formula ##STR20## wherein R 1 is hydrogen, lower alkyl, amino-lower alkyl, acylamino-lower alkyl, aryl, aryl-lower alkyl, cycloalkyl or cycloalkyl-lower alkyl; R 2 is hydrogen or lower alkyl; R 3 and R 4 , each independently, represent hydrogen, lower alkyl, lowr alkoxy, lower alkanoyloxy, hydroxy, halogen or trifluoromethyl; or R 3 and R 4 taken together represent lower alkylenedioxy; R 5 is hydrogen or lower alkyl; R 6 and R 7 represent independently hydroxy; lower alkoxy; (amino, mono- or di-lower alkylamino)-substituted lower alkoxy; carboxy-substituted lower alkoxy; lower alkoxycarbonyl-substituted lower alkoxy; aryl-substituted lower alkoxy; (hydroxy, lower alkanoyloxy or lower alkoxy)-substituted lower alkoxy; (hydroxy, lower alkanoyloxy or lower alkoxy)-substituted lower alkoxymethoxy; bicyclo[2,2,1]-heptyloxycarbonyl-substituted lower alkoxy; 3-phthalidoxy; (lower alkyl, lower alkoxy, halo)-substituted 3-phthalidoxy; amino; lower alkylamino; di-lower alkylamino; pyrrolidino, piperidino or perhydroazepino; (amino or acylamino)-substituted lower alkylamino; α-(carboxy or lower alkoxycarbonyl)-substituted lower alkylamino; aryl-substituted lower alkylamino which can be substituted on the α-carbon by carboxy or lower alkoxycarbonyl; X represents S(O) p , N--R 8 or O, in which radicals R 8 represents hydrogen, lower alkyl or aryl, and p represents zero, one or two; and wherein the carbocylic ring may also be hexahydro; and wherein within the above definitions acylamino represents lower alkanoylamino; lower alkoxycarbonylamino; aryl-lower alkanoylamino; aryl-lower alkoxycarbonylamino; or aroylamino in which aroyl represents benzoyl or benzoyl substituted by lower alkyl, lower alkoxy or halogen, or nicotinoyl; and wherein within the above definitions aryl represents phenyl unsubstituted or mono- or di-substituted by lower alkyl, lower alkoxy, lower alkylenedioxy, lower alkanoyloxy, hydroxy, halogen or trifluoromethyl; and cycloalkyl contains 3 to 8 carbons; or a pharmaceutically acceptable salt thereof.
Claim 3
Dependent Claim
136 words
A compound of claim 1 wherein R 1 is lower alkyl, amino-lower alkyl or aryl-lower alkyl; R 2 and R 5 independently represent hydrogen or lower alkyl; R 3 and R 4 represent independently hydrogen, lower alkyl, lower alkoxy, lower alkanoyloxy, hydroxy, halogen or trifluoromethyl; or R 3 and R 4 taken together represent lower alkylenedioxy; R 6 and R 7 represent independently hydroxy, amino, mono- or di-lower alkylamino, lower alkoxy, benzyloxy, pyridylmethoxy, pivaloyloxymethoxy, bicyclo[2,2,1]heptyloxy-substituted methoxy, α-carboxyethoxy or α-lower alkoxycarbonylethoxy; X represents O, S(O) p wherein p represents zero, 1 or 2, or N--R 8 wherein R 8 represents hydrogen or lower alkyl; R 6 and R 7 , have meaning as defined in said claim; and wherein said definitions aryl and acylamino have meaning as defined in said claim; or a pharmaceutically acceptable salt thereof.
Claim 4
Dependent Claim
171 words
A compound having the formula ##STR21## wherein R 1 is hydrogen, lower alkyl, amino-lower alkyl, acylamino-lower alkyl, aryl, aryl-lower alkyl, or cycloalkyl-lower alkyl; R 2 and R 5 represent hydrogen or lower alkyl; R 3 and R 4 represent hydrogen, lower alkyl, lower alkoxy, lower alkanoyloxy, hydroxy, halogen or trifluoromethyl; or R 3 and R 4 taken together represent lower alkylenedioxy; p represents zero, one or two; R 6 and R 7 independently represent hydroxy, amino, mono- or di-lower alkylamino, lower alkoxy, aryl-lower alkoxy, lower alkanoyloxymethoxy, (amino, mono- or di-lower alkylamino, carboxy, lower alkoxycarbonyl or bicyclo [2,2,1]-heptyloxycarbonyl)-lower alkoxy; and wherein within the above definitions acylamino represents lower alkanoylamino; lower alkoxycarbonylamino; aryl(lower)alkanoylamino; aryl(lower)alkoxycarbonylamino; or aroylamino in which aroyl represents benzoyl or benzoyl substituted by lower alkyl, lower alkoxy or halogen, or nicotinoyl; and wherein within the above definitions aryl represents phenyl unsubstituted or mono- or di-substituted by lower alkyl, lower alkoxy, lower alkylenedioxy, lower alkanoyloxy, hydroxy, halogen or trifluoromethyl; and cycloalkyl contains 3 to 8 carbons; or a pharmaceutically acceptable salt thereof.
Claim 5
Dependent Claim
171 words
A compound having the formula ##STR21## wherein R 1 is hydrogen, lower alkyl, amino-lower alkyl, acylamino-lower alkyl, aryl, aryl-lower alkyl, or cycloalkyl-lower alkyl; R 2 and R 5 represent hydrogen or lower alkyl; R 3 and R 4 represent hydrogen, lower alkyl, lower alkoxy, lower alkanoyloxy, hydroxy, halogen or trifluoromethyl; or R 3 and R 4 taken together represent lower alkylenedioxy; p represents zero, one or two; R 6 and R 7 independently represent hydroxy, amino, mono- or di-lower alkylamino, lower alkoxy, aryl-lower alkoxy, lower alkanoyloxymethoxy, (amino, mono- or di-lower alkylamino, carboxy, lower alkoxycarbonyl or bicyclo [2,2,1]-heptyloxycarbonyl)-lower alkoxy; and wherein within the above definitions acylamino represents lower alkanoylamino; lower alkoxycarbonylamino; aryl(lower)alkanoylamino; aryl(lower)alkoxycarbonylamino; or aroylamino in which aroyl represents benzoyl or benzoyl substituted by lower alkyl, lower alkoxy or halogen, or nicotinoyl; and wherein within the above definitions aryl represents phenyl unsubstituted or mono- or di-substituted by lower alkyl, lower alkoxy, lower alkylenedioxy, lower alkanoyloxy, hydroxy, halogen or trifluoromethyl; and cycloalkyl contains 3 to 8 carbons; or a pharmaceutically acceptable salt thereof.
Claim 6
Dependent Claim
107 words
A compound of claim 3 wherein R 1 is hydrogen, lower alkyl, amino-lower alkyl, acylamino-lower alkyl, aryl-lower alkyl where aryl represents phenyl unsubstituted or mono- or disubstituted by lower alkyl, hydroxy, lower alkoxy, lower alkylenedioxy, lower alkanoyloxy, halogen or trifluoromethyl; R 2 and R 5 are hydrogen or lower alkyl; R 3 and R 4 are hydrogen, lower alkoxy, lower alkyl, halogen or trifluoromethyl; or R 3 and R 4 taken together represent alkylenedioxy; p represents zero, one or two; R 6 and R 7 independently represent hydroxy, amino, lower alkoxy, phenyl-lower alkoxy, pyridyl-lower alkoxy, lower alkanoyloxymethoxy, lower alkoxycarbonyl-lower alkoxy, or bicyclo[2,2,1]heptyloxycarbonylmethoxy; a pharmaceutically acceptable salt thereof.
Claim 7
Dependent Claim
69 words
A compound of claim 3 having the formula ##STR22## wherein n represents an integer from 1 to 4; p is zero, one or two; R 9 is hydrogen, amino, benzyloxycarbonylamino, phenyl unsubstituted or monosubstituted by lower alkyl, lower alkoxy, lower alkanoyloxy, halogen, hydroxy, or trifluoromethyl; R 6 and R 7 independently represent hydroxy, lower alkoxy of up to 4 carbon atoms, benzyloxy, amino; or a pharmaceutically acceptable salt thereof.
Claim 8
Dependent Claim
70 words
A compound of claim 5 and formula III wherein C n H 2n represents ethylene; R 9 represents phenyl or phenyl monosubstituted by lower alkoxy with up to 4 carbon atoms, lower alkyl with up to 4 carbon atoms, halogen or trifluoromethyl; p is zero or one; R 6 and R 7 independently represent hydroxy or lower alkoxy with up to 4 carbon atoms; or a pharmaceutically acceptable salt thereof.
Claim 9
Dependent Claim
61 words
A compound of claim 1 having the formula ##STR23## n represents an integer from 1 to 4; R 9 is hydrogen, amino, benzyloxycarbonylamino, phenyl unsubstituted or monosubstituted by lower alkyl, lower alkoxy, lower alkanoyloxy, halogen, hydroxy, or trifluoromethyl; R 6 and R 7 independently represent hydroxy or lower alkoxy of up to 4 carbon atoms; or a pharmaceutically acceptable salt thereof.
Claim 10
Dependent Claim
65 words
A compound of claim 7 and formula IV wherein C n H 2n represents ethylene; R 9 represents phenyl or phenyl mono-substituted by lower alkoxy with up to 4 carbon atoms, lower alkyl with up to 4 carbon atoms, halogen or trifluoromethyl; R 6 and R 7 independently represent hydroxy or lower alkoxy with up to 4 carbon atoms; or a pharmaceutically acceptable salt thereof.
Claim 11
Dependent Claim
31 words
A compound of claim 3 wherein the ring carbon atom 3 is of the R-configuration and the side chain carbon atom is of the S-configuration; or a pharmaceutically acceptable salt thereof.
Claim 12
Dependent Claim
21 words
A compound of claim 7 wherein both the ring carbon atom 3 and the side chain carbon atom are of S-configuration.
Claim 13
Dependent Claim
17 words
A compound as claimed in claim 5 being 3-[N-(1-carboethoxy-3-phenylpropyl)amino]-5-carboxymethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, a stereoisomer or a pharmaceutically acceptable salt thereof.
Claim 14
Dependent Claim
17 words
A compound as claimed in claim 5 being 3-[N-(1-carboxy-3-phenylpropyl)amino]-5-carboxymethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, a stereoisomer or a pharmaceutically acceptable salt thereof.
Claim 15
Dependent Claim
17 words
A compound as claimed in claim 5 being 3-[N-(1-carboxy-3-phenylpropyl)amino]-5-carboxymethyl-2,3-dihydro-1-oxo-1,5-benzothiazepin-4(5H)-one, a stereoisomer or a pharmaceutically acceptable salt thereof.
Claim 16
Dependent Claim
17 words
A compound as claimed in claim 7 being 3-[N-(1-carboxy-3-phenylpropyl)amino]-5-carboxymethyl-2,3-dihydro-1,5-benzoxa-zepin-4(5H)-one, a stereoisomer or a pharmaceutically acceptable salt thereof.
Claim 17
Dependent Claim
17 words
A compound as claimed in claim 5 being 3-[N-(1-carboxy-5-aminopentyl)amino]-5-carboxymethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, a stereoisomer or a pharmaceutically acceptable salt thereof.
Claim 18
Dependent Claim
43 words
A pharmaceutical composition suitable for oral or parenteral administration to mammals for the treatment or prevention of diseases responsive to inhibition of angiotensin-converting enzyme comprising an effective amount of a compound of claim 1 in combination with one or more pharmaceutically acceptable carriers.
Claim 19
Dependent Claim
28 words
A method of treating hypertensive or cardiac conditions in mammals which comprises administering to a mammal in need thereof an effective amount of a composition of claim 16.
Claim 20
Dependent Claim
24 words
A method of inhibiting angiotensin-converting enzyme which comprises administering to a mammal in need thereof an effective amount of a composition of claim 16.
References Cited (Backward Citations)
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USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1987-10-16 | 1988-04-16 | 1988-10-16 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1991-10-16 | 1992-04-16 | 1992-10-16 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1995-10-16 | 1996-04-16 | 1996-10-16 | $7700.00 | Window Closed / Lapsed |