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Claims for Patent: 4,410,520

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Claims for Patent: 4,410,520

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 angiotension 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)
Application Number:06/398,241
Patent Claims: 1. A compound of the formula ##STR25## wherein R.sub.A and R.sub.B are radicals of the formula ##STR26## respectively, in which R.sub.o is carboxy or functionally modified carboxy represented by COR.sub.6 in radical R.sub.A and represented by COR.sub.7 in radical R.sub.B wherein one or both of R.sub.6 and R.sub.7 represent hydroxy; lower alkoxy; (amino- 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]heptyl-oxycarbonyl-substituted lower alkoxy; 3-phthalidoxy; (lower alkyl, lower alkoxy, halo)-substituted 3-phthalidoxy; amino; lower alkylamino; di-lower alkylamino; di-lower alkylamino in which both alkyl groups are linked by a carbon to carbon bond and together with the amino nitrogen form pyrrolidino, piperidino or perhydroazepino; (amino)-substituted lower alkylamino; .alpha.-(carboxy or lower alkoxycarbonyl)-substituted lower alkylamino; aryl-substituted lower alkylamino which can be substituted on the .alpha.-carbon by carboxy or lower alkoxycarbonyl;

R.sub.1 is hydrogen, lower alkyl, amino (lower) alkyl, aryl, aryl (lower) alkyl, cycloalkyl or cycloalkyl (lower) alkyl;

R.sub.2 is hydrogen or lower alkyl;

R.sub.3 and R.sub.4, each independently represent hydrogen, lower alkyl, lower alkoxy, lower alkanoyloxy, hydroxy, halogen, trifluoromethyl, or

R.sub.3 and R.sub.4 taken together represent lower alkylenedioxy;

R.sub.5 is hydrogen or lower alkyl, and

X represents oxo, two hydrogens, or one hydroxy together with one hydrogen; and wherein the carbocyclic ring may also be hexahydro or 6,7,8,9-tetrahydro;

and wherein within the above definitons 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 of claim 1 having the formula ##STR27## wherein R.sub.1 is hydrogen, lower alkyl, amino (lower) alkyl, aryl, aryl (lower) alkyl, 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 oxo, two hydrogens or one 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 alkanoyloxymethyl, (amino, mono- or di-loweralkylamino, carboxy, or lower alkoxycarbonyl) lower alkoxy;

and wherein 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.

3. A compound of claim 2 wherein R.sub.1 is hydrogen, lower alkyl, amino(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.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 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.

4. A compound of claim 2 wherein R.sub.1 is hydrogen, lower alkyl, .omega.-amino (lower) alkyl, aryl (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 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 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.

5. A compound of claim 2 wherein R.sub.1 is hydrogen, lower alkyl, .omega.-amino(lower)alkyl, aryl (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 is hydrogen;

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

X represents oxo, one hydroxy 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.

6. A compound of claim 2 wherein R.sub.1 is hydrogen, methyl, ethyl, isopropyl, .omega.-aminopropyl, .omega.-aminobutyl, aryl(methyl, ethyl, propyl) where aryl represents phenyl unsubstituted or substituted by one methyl, hydroxy, methoxy, methylenedioxy, acetyloxy, chloro or trifluoromethyl group.

R.sub.2 and R.sub.5 are hydrogen or methyl;

R.sub.3 and R.sub.4 represent hydrogen, methoxy, methyl, chloro or trifluoromethyl;

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

R.sub.6 and R.sub.7 independently represent hydroxy, amino, ethoxy, methoxy, benzyloxy, ethoxycarbonylmethoxy or pivaloyloxymethoxy; or a pharmaceutically acceptable salt thereof.

7. A compound of claim 2 corresponding to the formula ##STR28## wherein n represents an integer from 1 to 4;

R.sub.8 is hydrogen, phenyl unsubstituted or monosubstituted by lower alkyl, lower alkoxy, lower alkanoyloxy, halogen, hydroxy, or trifluoromethyl;

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 ethylene, R.sub.8 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.sub.6 and R.sub.7 independently represent hydroxy or lower alkoxy with up to 4 carbon atoms; or a pharmaceutically acceptable salt thereof.

9. A compound as claimed in claim 7 being 1-carboxymethyl-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydr o-1H-[1]benzazepin-2-one, a stereoisomer or a pharmaceutically acceptable acid addition, metal or ammonium salt thereof.

10. A compound according to claim 9, being the higher melting racemic stereoisomer of said compound, an enantiomer or a pharmaceutically acceptable acid addition, metal or ammonium salt thereof.

11. A compound as claimed in claim 9, being the lower melting racemic stereoisomer of said compound, an enantiomer or a pharmaceutically acceptable acid addition, metal or ammonium salt thereof.

12. A compound according to claim 9 being 1-carboxymethyl-3S-(1S-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahy dro-1H-[1]benzazepin-2-one or a pharmaceutically acceptable acid addition, metal or ammonium salt thereof.

13. A compound of claim 2 being 1-carboxymethyl-3-(1-carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1 ]benzazepin-2-one, a stereoisomer or a pharmaceutically acceptable acid addition, metal or ammonium salt thereof.

14. A compound as claimed in claim 13 being the racemic higher melting stereoisomer of 1-carboxymethyl-3-(1-carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1 ]benzazepin-2-one, an enantiomer or a pharmaceutically acceptable acid addition, metal or ammonium salt thereof.

15. A compound of claim 7 being 1-carboxymethyl-3S-(1S-carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H- [1]benzazepin-2-one or a pharmaceutically acceptable acid addition, metal or ammonium salt thereof.

16. A compound of claim 7 being 1-ethoxycarbonylmethyl-3-(1-carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydr o-1H-[1]benzazepin-2-one, a stereoisomer or a pharmaceutically acceptable acid addition, metal or ammonium salt thereof.

17. A compound of claim 7 being 3-(1-benzyloxycarbonyl-3-phenylpropylamino)-1-carboxymethyl-2,3,4,5-tetrah ydro-1H-[1]benzazepin-2-one, a stereoisomer or a pharmaceutically acceptable acid addition, metal or ammonium salt thereof.

18. A compound of claim 2 being 1-carboxymethyl-7-chloro-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5- tetrahydro-1H-[1]benzazepin-2-one, a stereoisomer or a pharmaceutically acceptable acid addition, metal or ammonium salt thereof.

19. A compound of claim 2 being 1-carboxymethyl-8-methoxy-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5 -tetrahydro-1H-[1]benzazepin-2-one, a stereoisomer or a pharmaceutically acceptable acid addition, metal or ammonium salt thereof.

20. A compound of claim 1 being 1-carboxymethyl-3S-(1-ethoxycarbonyl-3-phenylamino)-2,3,4,5,5a,6,7,9,9a-de cahydro-1H[1]benzazepin-2-one, a stereoisomer or a pharmaceutically acceptable acid addition, metal or ammonium salt thereof.

21. A process for the preparation of a compound of claim 1 which comprises:

alkylating a compound of the formula ##STR29## in which the carbocyclic ring may also be hexahydro or 6,7,8,9-tetrahydro, and wherein X, R.sub.B, R.sub.3, R.sub.4 and R.sub.5 have the meanings given in said claim, with a compound of the formula

wherein R.sub.1 and R.sub.o have meanings given in said claim, in the presence of a reducing agent with temporary protection of any primary and secondary amino groups and/or hydroxyl and/or oxo groups which may be present in any one of the substituents X, R.sub.B, R.sub.1, R.sub.3, R.sub.4 and R.sub.5.

22. A process for the preparation of a compound of claim 1 which comprises:

alkylating a compound of the formula ##STR30## in which the carboxylic ring may also be hexahydro or 6,7,8,9-tetrahydro, and wherein X, R.sub.3, R.sub.4 and R.sub.5 have the meanings given in said claim and R.sub.A' is R.sub.A as defined in said claim with a compound of the formula

wherein Z is a reactive esterified hydroxyl group and R.sub.B has the meanings given in said claim, while protecting temporarily any primary and secondary amino groups and/or hydroxyl and/or oxo groups which may be present in any one of the residues X, R.sub.A, R.sub.B, R.sub.3, R.sub.4 and R.sub.5.

23. A process for the preparation of a compound of claim 1 which comprises:

reacting a compound of the formula ##STR31## in which the carboxyclic ring may also be hexahydro or 6,7,8,9-tetrahydro and wherein Y is oxo, and X, R.sub.B, R.sub.3 and R.sub.4 have the meanings given in said claim, with an amine of the formula

wherein R.sub.A and R.sub.5 have the meanings given in said claim, in the presence of a reducing agent and with temporary protection of the oxo group which may be present as the substituent X.

24. A process for the preparation of a compound of claim 2 comprising the steps of:

(a) condensing under conditions of basic catalysis, a compound of the formula ##STR32## wherein R.sub.3 ' and R.sub.4 ' represent hydrogen, lower alkyl, lower alkoxy, lower alkanoyloxy, halogen, trifluoromethyl or R.sub.3 ' and R.sub.4 ' taken together represent lower alkylenedioxy;

X' presents 2 hydrogens, one hydrogen and one etherified or esterified hydroxy, oxo or oxo protected in form of a ketal or thioketal and R.sub.9 is amino, lower alkylamino, azido or acylamino with a compound of the formula ##STR33## wherein R.sub.2 ' represents hydrogen or lower alkyl;

Z represents reactively esterified hydroxy and

R.sub.7 ' represents hydroxy, di (lower) alkylamino, lower alkoxy, aryl (lower) alkoxy, lower alkanoyloxymethoxy or lower alkoxycarbonyl (lower) alkoxy;

(b) optionally reducing, hydrogenolyzing, hydrolyzing or alkylating the resulting intermediate to obtain a compound of the formula II' ##STR34## wherein R.sub.3 ', R.sub.4 ', X' are as defined for formula XI; R.sub.2 ' and R.sub.5 ' represent hydrogen or lower alkyl, R.sub.7 ' represents hydroxy, amino, mono- or di-(lower) alkylamino, lower alkoxy, aryl (lower) alkoxy, lower alkanoyloxymethoxy, di-(lower alkylamino) lower alkoxy or lower alkoxycarbonyl (lower) alkoxy;

(c) condensing compound of formula II' above under conditions of reductive alkylation with a compound of the formula IV' ##STR35## wherein R.sub.1 ' is hydrogen, lower alkyl, acylated amino (lower) alkyl, aryl, aryl (lower) alkyl, cycloalkyl (lower) alkyl; and R.sub.6 ' represents hydroxy, di(lower) alkylamino, lower alkoxy, aryl (lower) alkoxy, lower alkanoyloxymethoxy or lower alkoxycarbonyl (lower) alkoxy; and

(d) optionally hydrolyzing or derivatizing the resulting product;

and wherein within the above definitions of R.sub.1 ', R.sub.6 ' and R.sub.7 ' 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.

25. A process for the preparation of a compound of claim 2 comprising the steps of:

(a) Condensing under conditions of reductive alkylation a compound of the formula ##STR36## wherein R.sub.3 ' and R.sub.4 ' represent hydrogen, lower alkyl, lower alkoxy, lower alkanoyloxy, halogen, trifluoromethyl; or R.sub.3 ' and R.sub.4 ' taken together represent lower alkylenedioxy; X' represents 2 hydrogens, one hydrogen and one etherified or esterified hydroxy, oxo or oxo protected in form of a ketal or thioketal; and R.sub.5 ' is hydrogen or lower alkyl; with a compound of the formula IV ##STR37## wherein R.sub.1 ' and R.sub.6 ' have meanings as previously defined, or under alkylation conditions with a compound of formula III'A ##STR38## wherein R.sub.1 ', R.sub.6 ' and Z have meanings as previously deined to obtain a compound of the formula V' ##STR39## wherein R.sub.1 ', R.sub.3 ', R.sub.4 ', R.sub.5 ' and X' have meanings as previously defined,

(b) Condensing under conditions of basic catalysis a resulting compound of the formula V' with a compound of the formula III'B ##STR40## wherein R.sub.2 ' and R.sub.7 ' and Z have meanings as previously defined;

(c) optionally hydrolyzing the resulting product;

and wherein within the above definitions of R.sub.1 ', R.sub.6 ' and R.sub.7 ' 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.

26. A process for the preparation of compounds according to claim 2 comprising the steps of:

(a) condensing a compound of the formula VII' ##STR41## wherein R.sub.1 " is hydrogen, lower alkyl, acylated amino (lower) alkyl, aryl, aryl (lower) alkyl, cycloalkyl (lower) alkyl; R.sub.5 " represents hydrogen or lower alkyl; and R.sub.6 " represents hydroxy, di (lower) alkylamino, lower alkoxy, aryl (lower) alkoxy, lower alkanoyloxymethoxy or lower alkoxycarbonyl (lower) alkoxy- with a compound of the formula VI' ##STR42## wherein R.sub.2 " represents hydrogen or lower alkyl;

R.sub.3 " and R.sub.4 " represent hydrogen, lower alkyl, lower alkoxy, lower alkanoyloxy, halogen, trifluoromethyl or R.sub.3 " and R.sub.4 " taken together represent lower alkylenedioxy; X" represents 2 hydrogens, one hydrogen and one etherified or esterified hydroxy, oxo or oxo protected in the form of a ketal or thioketal; R.sub.7 " represents hydroxy, di (lower) alkylamino, lower alkoxy, aryl (lower) alkoxy, lower alkanoyloxymethoxy or lower alkoxycarbonyl (lower) alkoxy; and Y represents oxo under conditions of reductive N-alkylation; and

(b) optionally hydrolyzing the resulting product;

and wherein within the above definitions of R.sub.1 ", R.sub.6 " and R.sub.7 " 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.

27. 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.

28. 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 27.

29. A method of inhibiting antiotensin-converting enzyme which comprises administering to a mammal in need thereof an effective amount of a composition of claim 27.
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