Benzazepin-2-ones, process for their preparation, pharmaceutical preparations containing these compounds and the compounds for therapeutical use

Claim 2

A coumpound of formula I wherein R 1 is hydrogen, C 1-7 -alkyl, amino-C 1-7 -alkyl, aryl, phenyl which is mono- or disubstituted by C 1-7 - alkyl, C 1-7 -alkoxy, C 1-7 -alkylenedioxy, C 1-7 -alkanoyloxy, hydroxy, halogen or trifluoromethyl, or is aryl-C 1-7 -alkyl, phenyl-C 1-7 -alkyl which is mono- or disubstituted by C 1-7 -alkyl, C 1-7 -alkoxy, C 1-7 -al- kylenedioxy, C 1-7 -alkanoyloxy, hydroxy, halogen or trifluoromethyl, or is cycloalkyl-C 1-7 -alkyl; R 2 is hydrogen or C 1-7 -alkyl; R 3 and R 4 are each independently hydrogen, C 1-7 -alkyl, C 1 . 7 -alkoxy, C 1-7 -alkanoyloxy, hydroxy, halogen or trifluoromethyl or R 3 and R 4 together are C 1-7 -alkylenedioxy; R 5 is hydrogen or C 1-7 -alkyl; R 6 and R 7 are each independently hydroxy ; C 1-7 -alkoxy; ω-(amino, mono- or di-C 1-7 -alkylamino)-substituted C 2-4 -alkoxy; carboxy-substituted C 1-7 -alkoxy; C 1-7 -alkoxy-carbonyl-substituted C 1-7 -alkoxy ; aryl-substituted C 1-7 -alkoxy; phenyl-C 1-7 -alkoxy which is mono- or disubstituted by C 1-7 -alkyl, C 1-7 -alkoxy, C 1-7 -alkylenedioxy, C 1-7 -alkanoyloxy, hydroxy, halogen or trifluoromethyl ; or (hydroxy, C 1- 7 -alkanoyloxy or C 1-7 -alkoxy)-substituted C 1-7 -alkoxy; (hydroxy, C 1-7 -alkanoyloxy or C 1-7 -alkoxy)-substituted C 1-7 -alkoxymethoxy; bicycloalkylcarbonylsubstituted C 1-7 -alkoxy; 3-phthalidoxy ; (C 1-7 - alkyl, C 1-7 -alkoxy, halo)-substituted 3-phthalidoxy; amino ; C 1-7 -alkylamino; di-C 1-7 -alkylamino; di-C 1-7 - alkylamino in which the two alkyl moities are linked by a carbon carbon bond and, together with the amino nitrogen, form a 5-, 6-, or 7-membered heterocyclic ring ; a-(carboxy or C 1-7 -alkoxycarbonyl)-substituted C 1-7 -alkylamino; aryl-substituted C 1-7 -alkylamino which may be substituted at the a-carbon atom by carboxy or C 1-7 -alkoxycarbonyl; or phenyl-C 1-7 -alkylamino which is mono- or disubstituted by C 1-7 -alkyl, C 1-7 -alkoxy, C 1-7 -alkylenedioxy, C 1-7 -alkanoyloxy, hydroxy, halogen or trifluoromethyl and which may be substituted at the a-carbon atom by carboxy or C 1-7 -alkoxycarbonyl; and X is oxo, two hydrogen atoms or a hydrogen atom and a hydroxyl group ; and wherein the carbocyclic ring may also be hexahydro or 6,7,8,9-tetrahydro ; or a stereoisomer or a salt thereof.

Claim 3

A compound of formula I according to claim 1, wherein R 2 , R 3 , R 4 , R 5 and X are as defined in claim 1, R 1 is hydrogen, C 1-7 -alkyl, amino-C, 1-7 -alkyl, aryl, aryl-C 1-7 -alkyl, cycloalkyl-C 1-7 -alkyl, or is phenyl or phenyl-C 1-7 -alkyl, each mono- or disubstituted by C 1-7 -alkyl, C 1-7 -alkoxy, C 1-7 -alkylenedioxy. C 1-7 - alkanoyloxy, hydroxy, halogen or trifluoromethyl, and R 6 and R 7 are each independently hydroxy, amino, mono- or di-C 1-7 -alkylamino, C 1-7 -alkoxy, aryl-C 1-7 -alkoxy, C 1-7 -alkanoyloxymethoxy, ω-(amino, mono- or di-C 1-7 -alkylamino)-C 2-4 -alkoxy, (carboxy or C 1-7 -alkoxycarbonyl)-C 1-7 -alkoxy. or a salt thereof.

Claim 4

A compound of formula I according to claim 1, wherein R 2 , R 5 and X are as defined in claim 1, R, is hydrogen, C 1-7 -alkyl, amino-C 1-7 -alkyl, phenyl-C 1-7 -alkyl, or is phenyl-C 1-7 -alkyl which is mono- or disubstituted in the phenyl moiety by C 1-7 alkyl, hydroxy, C 1-7 alkoxy, C 1-7 alkylenedioxy, C 1-7 - alkanoyloxy, halogen or trifluoromethyl, R 3 and R 4 are hydrogen, C 1-7 -alkyl, halogen or trifluoromethyl, or R 3 and R 4 together are C 1-7 - alkylenedioxy, R 6 and R 7 are each independently hydroxy, amino, C 1-7 -alkoxy, phenyl-C 1-7 -alkoxy or C 1-7 - alkoxycarbonyl-C 1-7 -alkoxy, or a salt thereof.

Claim 5

A compound of formula IA wherein n is an integer from 1 to 4, R 8 is hydrogen, unsubstituted phenyl or phenyl which is monosubstituted by C 1-7 -alkyl, C 1-7 -alkoxy, C 1-7 -alkanoyloxy, halogen, hydroxy or trifluoromethyl, and R 6 and R 7 are each independently hydroxy, C 1-7 -alkoxy, benzyloxy or amino, or a pharmaceutically acceptable salt thereof.

Claim 6

A compound of formula IA wherein n is an integer from 1 to 4, R 8 is hydrogen, unsubstituted phenyl or phenyl which is monosubstituted by C 1-7 -alkyl, C 1-7 -alkoxy, C 1-7 -alkanoyloxy, halogen, hydroxy or trifluoromethyl, and R 6 and R 7 are each independently hydroxy, C 1-7 -alkoxy, benzyloxy or amino, or a pharmaceutically acceptable salt thereof.

Claim 7

A compound of formula IB wherein (S) is the chirality and n, R 6 , R 7 and R 8 are as defined in claim 4, or a pharmaceutically acceptable salt thereof.

Claim 8

1-Carboxymethyl-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1] benzazepin-2-one, or a stereoisomer or a salt thereof.

Claim 9

1-Carboxymethyl-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1] benzazepin-2-one, or a stereoisomer or a salt thereof.

Claim 10

The racemic compound which melts at 138 to 140 °C of the compound claimed in claim 6, or an enantiomer or a salt thereof.

Claim 11

The racemic compound which melts at 126 to 129 °C of the compound claimed in claim 6, or an enantiomer or a salt thereof.

Claim 12

1-Carboxymethyl-3S-(1S-ethoxycarbonyl-3-phenytpropylamino)-2,3,4,5-tetrahydro-1H-[1] benzazepin-2-one, or a salt thereof.

Claim 13

1-Carboxymethyl-3S-(1S-ethoxycarbonyl-3-phenytpropylamino)-2,3,4,5-tetrahydro-1H-[1] benzazepin-2-one, or a salt thereof.

Claim 14

1-Carboxymethyl-3-(1-carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1] benzazepin-2- one, or a stereoisomer or a salt thereof.

Claim 15

1-Carboxymethyl-3-(1-carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1] benzazepin-2- one, or a stereoisomer or a salt thereof.

Claim 16

1-Carboxymethy)-3S-(1S-carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-1.H-[1] benzazepin-2- one, or a salt thereof.

Claim 17

1-Carboxymethy)-3S-(1S-carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-1.H-[1] benzazepin-2- one, or a salt thereof.

Claim 18

1-Ethoxycarbonylmethyl-3-(1-carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1] benzazepin-2-one, or a stereoisomer or a salt thereof.

Claim 19

1-Ethoxycarbonylmethyl-3-(1-carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1] benzazepin-2-one, or a stereoisomer or a salt thereof.

Claim 20

The racemate which melts at 175-177 °C of the compound as claimed in claim 12, or a salt thereof.

Claim 21

The racemate of 1-carboxymethyl-7-chloro-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1] benzazepin-2-one, the hydrochloride of which melts at 149 to 151 °C, or a salt thereof.

Claim 22

The racemate of 1-carboxymethyl-7-chloro-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1] benzazepin-2-one, the hydrochloride of which melts at 149 to 151 °C, or a salt thereof.

Claim 23

3-(1-Benzyloxycarbonyl-3-phenylpropylamino)-1-carboxymethyl-2,3,4,5-tetrahydro-1H-[1] benzazepin-2-one, or a stereoisomer or a salt thereof.

Claim 24

3-(1-Benzyloxycarbonyl-3-phenylpropylamino)-1-carboxymethyl-2,3,4,5-tetrahydro-1H-[1] benzazepin-2-one, or a stereoisomer or a salt thereof.

Claim 25

A pharmaceutical composition containing a compound as claimed in any one of clams 2 and 4 to 10, together with a pharmaceuticaly acceptable carrier.

Claim 26

A pharmaceutical composition containing a compound as claimed in any one of claims 3 and 11 to 13, together with a pharmaceutically acceptable carrier.

Claim 27

A pharmaceutical composition containing a compound as claimed in any one of claims 1, 14 and 15, together with a pharmaceutically acceptable carrier.

Claim 28

Use of a compound as claimed in any one of claims 2 and 4 to 10 in a therapeutic method of treating the human or animal body.

Claim 29

Use of a compound as claimed in any one of claims 3 and 11 to 13 in a therapeutic method of treating the human or animal body.

Claim 30

Use of a compound as claimed in any one of claims 1, 14 and 15 in a therapeutic method of treating the human or animal body.

Claim 31

Use of a compound as claimed in any one of claims 2 and 4 to 10 as angiotensin-converting enzyme inhibitor.

Claim 32

Use of a compound as claimed in any one of claims 3 and 11 to 13 as angiotensin-converting enzyme inhibitor.

Claim 33

Use of a compound as claimed in any one of claims 1, 14 and 15 as angiotensin-converting enzyme inhibitor.

Claim 34

Use of a compound as claimed in any one of claims 2 and 4 to 10 for the preparation of a pharmaceutical composition.

Claim 35

Use of a compound as claimed in any one of claims 3 and 11 to 13 for the preparation of a pharmaceutical composition.

Claim 36

Use of a compound as claimed in any one of claims 1, 14 and 15 for the preparation of a pharmaceutical composition.

Claim 37

A process for the preparation of a compound of formula I as claimed in claim 1, or of a stereoisomer or a salt thereof, which process comprises a) introducing the radical ―CH(R 1 )COR 6 into a compound of formula II wherein the carbocyclic ring may also be hexahydro or 6,7,8,9-tetrahydro and wherein X, R 2 , R 3 , R 4 , R 5 and R 6 are as defined above, by alkylation with a compound of the formula R,-CH(Z)-COR6 (III A ), wherein Z is a reactive esterified hydroxyl group and R 1 and R 6 are as defined above, or with a compound of the formula R 1 ―CO―COR 6 (IV), wherein R 1 and R 6 are as defined above, in the presence of a reducing agent, with temporary protection of any primary and secondary amino groups and/or, optionally, hydroxyl and/or oxo groups, which may be present in any one of the radicals X, R,, R 3 , R 4 , R 6 and R 7 , or b) alkylating a compound of formula V wherein the carbocyclic ring may also be hexahydro or 6,7,8,9-tetrahydro and wherein X, R 3 , R 4 and R 5 are as defined above and R A is hydrogen or ―CH(R 1 )―COR 6 as defined above, with a compound of the formula R 2 ―CH(Z)―COR 7 (IIIB), wherein Z is a reactive esterified hydroxyl group and R 2 and R 7 are as defined above, while protecting temporarily any primary and secondary amino groups and/or, optionally, hydroxyl and/or oxo groups which may be present in any one of the radicals X, R 1 , R 3 , R 4 , R 6 and R 7 , or c) condensing a compound of formula VI wherein the carbocyclic group may also be hexahydro or 6,7,8,9-tetrahydro and wherein Y is oxo or a reactive esterified hydroxyl group Z and hydrogen, and X, R 2 , R 3 , R 4 and R 7 are as defined above, with an amine of formula VII wherein R 1 , R 5 and R 6 are as defined above, with the proviso that, if Y is oxo, the condensation is carried out in the presence of a reducing agent and with temporary protection of the oxo group which may be present as the substituent X, or d) in a compound of formula VIII wherein the carbocyclic ring may also be hexahydro or 6,7,8,9-tetrahydro and wherein X and R 1 to R 5 are as defined above, one of the symbols R' and R" is cyano and the other is also cyano or COR 6 or COR 7 as defined above, subjecting the cyano group or groups to solvolysis, or e) cyclising a compound of formula IX wherein the carbocyclic ring may also be hexahydro or 3,4,5,6-tetrahydro and wherein X and R 1 to R 7 are as defined above, or cyclising an ester thereof, or f) treating a compound which is structurally identical with a compound of formula I above, except for having an additional double bond in the C-3-position or between the exocyclic nitrogen atom and the adjacent carbon atom in the side chain, with a reducing agent in order to saturate this double bond, and, if desired, converting a resultant compound of formula I as defined above into another compound of formula I within its above-specified scope, and/or if desired, converting a resultant compound of formula I as defined above and having salt-forming properties into a salt thereof or liberating a free compound from such a salt, and/or, if desired, enriching an optical isomer which has a specific configuration with respect to at least one center of chirality from a mixture of stereoisomeric forms of a resultant compound of formula I.

Claim 38

A process for the preparation of a compound of formula I as claimed in claim 1, wherein X is oxo and R 1 to R 7 are as defined above, which process comprises condensing a compound of formula X i wherein the carbocyclic ring may also be hexahydro or 6,7,8,9-tetrahydro and wherein R 2 to R 4 and R 7 are as defined above, with an amine of formula VII wherein R 1' R 5 and R 6 are as defined above, and, if desired, converting a resultant compound of formula I as defined above into another compound of formula I within its above-specified scope, and/or, if desired, converting a resultant compound of formula I as defined above and having salt-forming properties into a salt thereof of liberating a free compound from such a salt, and/or, if desired, enriching an optical isomer which has a specific configuration with respect to at least one center of chirality from a mixture of stereoisomeric forms of a resultant compound of formula I.

Claim 39

A compound obtainable by the process according to claim 28.

Claim 40

A compound obtainable by the process according to claim 29.