3-Amino-[1]-benzazepin-2-one-1-alkanoic acids

Claim 2

A compound of the formula ##STR25## wherein R A and R B are radicals of the formula ##STR26## respectively, in which R o is carboxy or functionally modified carboxy represented by COR 6 in radical R A and represented by COR 7 in radical R B wherein one or both of R 6 and R 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; 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; R 1 is hydrogen, lower alkyl, amino (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, lower alkoxy, lower alkanoyloxy, hydroxy, halogen, trifluoromethyl, or R 3 and R 4 taken together represent lower alkylenedioxy; R 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.

Claim 3

A compound of claim 1 having the formula ##STR27## wherein R 1 is hydrogen, lower alkyl, amino (lower) alkyl, aryl, aryl (lower) alkyl, 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, trifluoromethyl; or R 3 and R 4 taken together represent lower alkylenedioxy; X represents oxo, two hydrogens or one hydroxy group and one hydrogen; R 6 and R 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.

Claim 4

A compound of claim 2 wherein R 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 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; X represents oxo, one hydroxy and one hydrogen, or 2 hydrogens; R 6 and R 7 independently represent hydroxy, amino, lower alkoxy, phenyl(lower)alkoxy, lower alkoxycarbonyl(lower)alkoxy; or a pharmaceutically acceptable salt thereof.

Claim 5

A compound of claim 2 wherein R 1 is hydrogen, lower alkyl, ω-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 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 lower alkylenedioxy; X represents oxo, one hydroxy and one hydrogen, or 2 hydrogens; R 6 and R 7 independently represent hydroxy, amino, lower alkoxy, phenyl(lower)alkoxy, lower alkoxycarbonyl (lower) alkoxy; or a pharmaceutically acceptable salt thereof.

Claim 6

A compound of claim 2 wherein R 1 is hydrogen, lower alkyl, ω-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 2 and R 5 are hydrogen or lower alkyl; R 3 is hydrogen; R 4 is hydrogen, lower alkoxy, lower alkyl, halogen, or trifluoromethyl; X represents oxo, one hydroxy and one hydrogen, or 2 hydrogens; R 6 and R 7 independently represent hydroxy, amino, lower alkoxy, phenyl (lower) alkoxy, lower alkoxycarbonyl (lower) alkoxy; or a pharmaceutically acceptable salt thereof.

Claim 7

A compound of claim 2 wherein R 1 is hydrogen, methyl, ethyl, isopropyl, ω-aminopropyl, ω-aminobutyl, aryl(methyl, ethyl, propyl) where aryl represents phenyl unsubstituted or substituted by one methyl, hydroxy, methoxy, methylenedioxy, acetyloxy, chloro or trifluoromethyl group. R 2 and R 5 are hydrogen or methyl; R 3 and R 4 represent hydrogen, methoxy, methyl, chloro or trifluoromethyl; X represents oxo, one hydroxy and one hydrogen or 2 hydrogens; R 6 and R 7 independently represent hydroxy, amino, ethoxy, methoxy, benzyloxy, ethoxycarbonylmethoxy or pivaloyloxymethoxy; or a pharmaceutically acceptable salt thereof.

Claim 8

A compound of claim 2 corresponding to the formula ##STR28## wherein n represents an integer from 1 to 4; R 8 is hydrogen, 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 9

A compound as claimed in claim 7 wherein C n H 2n represents ethylene, R 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 6 and R 7 independently represent hydroxy or lower alkoxy with up to 4 carbon atoms; or a pharmaceutically acceptable salt thereof.

Claim 10

A compound as claimed in claim 7 being 1-carboxymethyl-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.

Claim 11

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.

Claim 12

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.

Claim 13

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

Claim 14

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.

Claim 15

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.

Claim 16

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.

Claim 17

A compound of claim 7 being 1-ethoxycarbonylmethyl-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.

Claim 18

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

Claim 19

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.

Claim 20

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.

Claim 21

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

Claim 22

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 B , R 3 , R 4 and R 5 have the meanings given in said claim, with a compound of the formula R.sub.1 --CO--R.sub.o (IV) wherein R 1 and R 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 B , R 1 , R 3 , R 4 and R 5 .

Claim 23

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 3 , R 4 and R 5 have the meanings given in said claim and R A' is R A as defined in said claim with a compound of the formula R.sub.B --Z (IIIB) wherein Z is a reactive esterified hydroxyl group and R 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 A , R B , R 3 , R 4 and R 5 .

Claim 24

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 B , R 3 and R 4 have the meanings given in said claim, with an amine of the formula R.sub.A --NH--R.sub.5 (VII) wherein R A and R 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.

Claim 25

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 3 ' and R 4 ' represent hydrogen, lower alkyl, lower alkoxy, lower alkanoyloxy, halogen, trifluoromethyl or R 3 ' and R 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 9 is amino, lower alkylamino, azido or acylamino with a compound of the formula ##STR33## wherein R 2 ' represents hydrogen or lower alkyl; Z represents reactively esterified hydroxy and R 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 3 ', R 4 ', X' are as defined for formula XI; R 2 ' and R 5 ' represent hydrogen or lower alkyl, R 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 1 ' is hydrogen, lower alkyl, acylated amino (lower) alkyl, aryl, aryl (lower) alkyl, cycloalkyl (lower) alkyl; and R 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 1 ', R 6 ' and R 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.

Claim 26

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 3 ' and R 4 ' represent hydrogen, lower alkyl, lower alkoxy, lower alkanoyloxy, halogen, trifluoromethyl; or R 3 ' and R 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 5 ' is hydrogen or lower alkyl; with a compound of the formula IV ##STR37## wherein R 1 ' and R 6 ' have meanings as previously defined, or under alkylation conditions with a compound of formula III'A ##STR38## wherein R 1 ', R 6 ' and Z have meanings as previously deined to obtain a compound of the formula V' ##STR39## wherein R 1 ', R 3 ', R 4 ', R 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 2 ' and R 7 ' and Z have meanings as previously defined; (c) optionally hydrolyzing the resulting product; and wherein within the above definitions of R 1 ', R 6 ' and R 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.

Claim 27

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 1 " is hydrogen, lower alkyl, acylated amino (lower) alkyl, aryl, aryl (lower) alkyl, cycloalkyl (lower) alkyl; R 5 " represents hydrogen or lower alkyl; and R 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 2 " represents hydrogen or lower alkyl; R 3 " and R 4 " represent hydrogen, lower alkyl, lower alkoxy, lower alkanoyloxy, halogen, trifluoromethyl or R 3 " and R 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 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 1 ", R 6 " and R 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.

Claim 28

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 29

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.

Claim 30

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.