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Details for Patent: 4,473,575

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Details for Patent: 4,473,575

Title: 3-Amino-(1)-benzazepin-2-one-1-alkanoic acids
Abstract:Variously substituted 1-carboxymethyl-3-(carboxymethylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin -2-ones and functional derivatives are angiotensin converting enzyme inhibitors and are useful as antihypertensive agents. Synthesis of, compositions and methods of treatment utilizing such compounds are included.
Inventor(s): Watthey; Jeffrey W. H. (Chappaqua, NY)
Assignee: Ciba-Geigy Corporation (Ardsley, NY)
Filing Date:Feb 10, 1983
Application Number:06/465,695
Claims:1. A compound having the formula ##STR25## wherein the carbocyclic ring may also be hexahydro; R.sub.1 is hydrogen, lower alkyl, amino(lower)alkyl, aryl, aryl(lower)alkyl, cycloalkyl or cycloalkyl(lower)alkyl;

R.sub.2 and R.sub.5 represent hydrogen or lower alkyl;

R.sub.3 and R.sub.4 represent hydrogen, lower alkyl, lower alkoxy, lower alkanoyloxy, hydroxy, halogen, trifluoromethyl; or R.sub.3 and R.sub.4 taken together represent lower alkylenedioxy;

X represents one acylated hydroxy group and one hydrogen;

R.sub.6 and R.sub.7 independently represent hydroxy, amino, mono- or di-(lower)alkylamino, lower alkoxy, aryl(lower)alkoxy, lower alkanoyloxymethoxy, (amino, mono- or di-lower alkylamino, carboxy, or lower alkoxycarbonyl)-lower alkoxy; and

wherein within the above definitions acylated hydroxy represents lower alkanoyloxy, nicotinoyloxy, benzoyloxy or benzoyloxy substituted on the phenyl ring by lower alkyl, halogen or lower alkoxy; 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.

2. A compound having the formula ##STR26## wherein the carbocyclic ring may also be hexahydro; R.sub.1 is indolyl(lower)alkyl, mono- or di-(lower)alkylamino(lower)alkyl, lower alkylthio(lower)alkyl, hydroxy(lower)alkyl, aryloxy(lower)alkyl, arylthio(lower)alkyl, aryl-N-(lower)alkylamino(lower)alkyl or arylamino(lower)alkyl; or R.sub.1 is etherified hydroxy(lower)alkyl in which etherified hydroxy represents lower alkoxy or benzyloxy; or R.sub.1 is acylated hydroxy(lower)alkyl; or

R.sub.1 represents carboxy(lower)alkyl, esterified carboxy(lower)alkyl, carbamoyl(lower)alkyl, N-substituted carbamoyl (lower)alkyl wherein carboxy, esterified carboxy, carbamoyl and N-substituted carbamoyl are as represented by COR.sub.6 and COR.sub.7 ; or

R.sub.1 is acylamino(lower)alkyl in which 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;

R.sub.2 and R.sub.5 represent hydrogen or lower alkyl;

R.sub.3 and R.sub.4 represent hydrogen, lower alkyl, lower alkoxy, lower alkanoyloxy, hydroxy, halogen, trifluoromethyl; or R.sub.3 and R.sub.4 taken together represent lower alkylenedioxy;

X represents oxo, two hydrogens, or one hydroxy or acylated hydroxy group and one hydrogen;

R.sub.6 and R.sub.7 independently represent hydroxy, amino, mono- or di-(lower)alkylamino, lower alkoxy, aryl(lower)alkoxy, lower alkanoyloxymethoxy, (amino, mono- or di-lower alkylamino, carboxy or lower alkoxycarbonyl)-lower alkoxy; 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

wherein within the above definitions acylated hydroxy represents lower alkanoyloxy, nicotinoyloxy, benzoyloxy or benzoyloxy substituted on the phenyl ring by lower alkyl, halogen or lower alkoxy;

or a pharmaceutically acceptable salt thereof.

3. A compound as claimed in claim 2 wherein R.sub.1 is indolyl(lower)alkyl, carboxy(lower)alkyl, lower alkoxycarbonyl(lower)alkyl, hydroxy(lower)alkyl, lower alkylthio(lower)alkyl, acylamino(lower)alkyl, aryloxy(lower)alkyl or arylthio(lower)alkyl; and in which aryl, acylamino, X and R.sub.2 to R.sub.7 are as defined in said claim; or a pharmaceutically acceptable salt thereof; or any said compound wherein the carbocyclic ring is hexahydro.

4. A compound as claimed in claim 2 whrein R.sub.1 is acylamino(lower)alkyl in which acylamino represents lower alkanoylamino, lower alkoxycarbonylamino, phenyl(lower)alkoxycarbonylamino or benzoylamino;

R.sub.2 and R.sub.5 are hydrogen or lower alkyl;

R.sub.3 and R.sub.4 are hydrogen, lower alkoxy, lower alkyl, halogen or trifluoromethyl; or R.sub.3 and R.sub.4 taken together represent alkylenedioxy;

X represents oxo, one hydroxy or lower alkanoyloxy and one hydrogen, or 2 hydrogens;

R.sub.6 and R.sub.7 independently represent hydroxy, amino, lower alkoxy, phenyl(lower)alkoxy, lower alkoxycarbonyl(lower)alkoxy; or a pharmaceutically acceptable salt thereof; or any said compound wherein the carbocyclic ring is hexahydro.

5. A compound as claimed in claim 2 wherein

R.sub.1 is aryl(lower)alkoxycarbonylamino-(lower)alkyl wherein aryl represents phenyl unsubstituted or mono-substituted by lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, halogen or trifluoromethyl;

R.sub.2 and R.sub.5 are hydrogen or lower alkyl;

R.sub.3 and R.sub.4 are hydrogen, lower alkoxy, lower alkyl, halogen, or trifluoromethyl; or R.sub.3 and R.sub.4 taken together represent lower alkylenedioxy;

X represents oxo, one hydroxy or lower alkanoyloxy and one hydrogen, or 2 hydrogens;

R.sub.6 and R.sub.7 independently represent hydroxy, amino, lower alkoxy, phenyl(lower)alkoxy or lower alkoxycarbonyl(lower)alkoxy; or a pharmaceutically acceptable salt thereof.

6. A compound of claim 1 and formula IA wherein R.sub.1 is .omega.-arylmethoxycarbonylamino-(lower) alkyl where aryl represents phenyl unsubstituted or mono-substituted by lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, halogen or trifluoromethyl;

R.sub.2 and R.sub.5 are hydrogen or lower alkyl;

R.sub.3 is hydrogen;

R.sub.4 is hydrogen, lower alkoxy, lower alkyl, halogen, or trifluoromethyl; 7

X represents oxo, one hydroxy or lower alkanoyloxy and one hydrogen, or 2 hydrogens;

R.sub.6 and R.sub.7 independently represent hydroxy, amino, lower alkoxy, phenyl(lower)alkoxy, lower alkoxycarbonyl(lower)alkoxy;

or a pharmaceutically acceptable salt thereof; or any said compound wherein the carbocyclic ring is hexahydro.

7. A compound having the formula ##STR27## wherein the carboxylic ring may also be hexahydro; n represents an integer from 1 to 4;

R.sub.8 is amino, benzyloxycarbonylamino;

R.sub.6 and R.sub.7 independently represent hydroxy, lower alkoxy of up to 4 carbon atoms, benzyloxy, amino; or a pharmaceutically acceptable salt thereof.

8. A compound as claimed in claim 7 wherein C.sub.n H.sub.2n represents n-propylene or n-butylene; R.sub.8 represents amino or benzyloxycarbonylamino; R.sub.6 and R.sub.7 independently represent hydroxy or lower alkoxy with up to 4 carbon atoms; or a pharmaceutically acceptable salt thereof; or any said compound wherein the carboxyclic ring is hexahydro.

9. A compound of claim 7 being 3-[(5-benzyloxycarbonylamino-1-carboxy)pentylamino]-1-carboxymethyl-2,3,4, 5-tetrahydro-1H-[1]benzazepin-2-one, a stereoisomer or a pharmaceutically acceptable salt thereof.

10. A compound of claim 1 being 5-acetoxy-1-carboxymethyl-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5 -tetrahydro-1H-[1]benzazepin-2-one, a stereoisomer or a pharmaceutically acceptable salt thereof.

11. 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 2 in combination with one or more pharmaceutically acceptable carriers.

12. 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 11.

13. A method of inhibiting angiotensin-converting enzyme which comprises administering to a mammal in need thereof an effective amount of a composition of claim 11.

14. A compound according to claim 7 being 3-(5-amino-1-carboxypentylamino)-1-carboxymethyl-2,3,4,5-tetrahydro-1H-[1] benzazepin-2-one, a stereoisomer or a pharmaceutically acceptable salt thereof.

15. 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.

16. 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 15.

17. A method of inhibiting angiotensin-converting enzyme which comprises administering to a mammal in need thereof an effective amount of a composition of claim 15.

18. 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 7 in combination with one or more pharmaceutically acceptable carriers.

19. 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 18.

20. A method of inhibiting angiotensin-converting enzyme which comprises administering to a mammal in need thereof an effective amount of a composition of claim 18.

21. A compound according to claim 7 having the formula ##STR28## wherein S represents the chirality, n represents an integer from 1 to 4;

R.sub.8 is amino or benzyloxycarbonylamino;

R.sub.6 and R.sub.7 independently represent hydroxy, lower alkoxy of up to 4 carbon atoms, benzyloxy or amino; or a pharmaceutically acceptable salt thereof.

22. A compound according to claim 21 being the S,S-stereoisomer of 3-(5-amino-1-carboxypentylamino)-1-carboxymethyl-2,3,4,5-tetrahydro-1H-[1] -benzazepin-2-one or a pharmaceutically acceptable salt thereof.
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