2-substituted indane-2-mercaptoacetylamide disulfide derivatives useful as inhibitors of enkephalinase and ACE

A method of inhibiting ACE in a patient in need thereof comprising administering to said patient an effective ACE inhibitory amount of a compound of formula ##STR11## wherein n is an integer from 0 to 3;

• R.sub.1 and R.sub.2 are each time taken independently chosen from the group consisting of;
• hydrogen, hydroxy, --OR.sub.4 wherein R.sub.4 is a C.sub.1 -C.sub.4 alkyl or an Ar--Y-- group wherein Ar is a phenyl or naphthyl group unsubstituted or substituted with from one to three substituents selected from the group consisting of methylenedioxy, hydroxy, C.sub.1 -C.sub.4 alkoxy, fluoro and chloro;
• and Y is a C.sub.0 -C.sub.4 alkyl;
• or, where R.sub.1 and R.sub.2 are attached to adjacent carbon atoms, R.sub.1 and R.sub.2 can be taken together with said adjacent carbons to form a benzene ring or methylenedioxy;
• R.sub.3 is hydrogen, C.sub.1 -C.sub.4 alkyl, --CH.sub.2 O--C(O)C(CH.sub.3).sub.3 ;
• X is --(CH.sub.2).sub.p --, O, S, NR.sub.5, or NC(O)R.sub.6 wherein p is an integer 0 or 1, R.sub.5 is hydrogen, a C.sub.1 -C.sub.4 alkyl, or an Ar--Y-- group, and R.sub.6 is --CF.sub.3, C.sub.1 -C.sub.10 alkyl, or an Ar--Y-- group;
• Q is a alkylene radical chosen from the group ##STR12## wherein q is an integer from 1 to 5 and Z is O, S, NH;
• G is a radical chosen from the group;
• ##STR13## wherein m is an integer from 1 to 3;
• R.sub.7 is hydrogen, C.sub.1 -C.sub.6 alkyl, --CH.sub.2 CH.sub.2 S(O).sub.k CH.sub.3, or Ar--Y-- wherein k is an integer form 0 to 2;
• R.sub.8 is hydrogen, hydroxy, amino, C.sub.1 -C.sub.6 alkyl, N-methylamino, N,N-dimethylamino, --CO.sub.2 R.sub.3 --OC(O)R.sub.9 wherein R.sub.9 is hydrogen, C.sub.1 -C.sub.6 alkyl, or phenyl;
• R.sub.10 is 1 or 2 substituents independently chosen from the group consisting of;
• hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, or halogen;
• R.sub.11 is hydrogen, C.sub.1 -C.sub.6 alkyl, or Ar--Y-- group;
• V.sub.1 is O, S, or NH;
• V.sub.2 is N or CH;
• V.sub.3 is a direct bond or --C(O)--;
• or stereoisomers or pharmaceutically acceptable salts thereof.

A method of inhibiting smooth cell proliferation in a patient in need thereof comprising administering to said patient an effective smooth cell proliferation inhibitory amount of a compound of formula ##STR14## wherein n is an integer from 0 to 3;

• R.sub.1 and R.sub.2 are each time taken independently chosen from the group consisting of;
• hydrogen, hydroxy, --OR.sub.4 wherein R.sub.4 is a C.sub.1 -C.sub.4 alkyl or an Ar--Y-- group wherein Ar is a phenyl or naphthyl group unsubstituted or substituted with from one to three substituents selected from the group consisting of methylenedioxy, hydroxy, C.sub.1 -C.sub.4 alkoxy, fluoro and chloro;
• and Y is a C.sub.0 -C.sub.4 alkyl;
• or, where R.sub.1 and R.sub.2 are attached to adjacent carbon atoms, R.sub.1 and R.sub.2 can be taken together with said adjacent carbons to form a benzene ring or methylenedioxy;
• R.sub.3 is hydrogen, C.sub.1 -C.sub.4 alkyl, --CH.sub.2 O--C(O)C(CH.sub.3).sub.3 ;
• X is --(CH.sub.2).sub.p --, O, S, NR.sub.5, or NC(O)R.sub.6 wherein p is an integer 0 or 1, R.sub.5 is hydrogen, a C.sub.1 -C.sub.4 alkyl, or an Ar--Y-- group, and R.sub.6 is --CF.sub.3, C.sub.1 -C.sub.10 alkyl, or an Ar--Y-- group;
• Q is a alkylene radical chosen from the group ##STR15## wherein q is an integer from 1 to 5 and Z is O, S, NH;
• G is a radical chosen from the group;
• ##STR16## wherein m is an integer from 1 to 3;
• R.sub.7 is hydrogen, C.sub.1 -C.sub.6 alkyl, --CH.sub.2 CH.sub.2 S(O).sub.k CH.sub.3, or Ar--Y-- wherein k is an integer form 0 to 2;
• R.sub.8 is hydrogen, hydroxy, amino, C.sub.1 -C.sub.6 alkyl, N-methylamino, N,N-dimethylamino, --CO.sub.2 R.sub.3 --OC(O)R.sub.9 wherein R.sub.9 is hydrogen, C.sub.1 -C.sub.6 alkyl, or phenyl;
• R.sub.10 is 1 or 2 substituents independently chosen from the group consisting of;
• hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, or halogen;
• R.sub.11 is hydrogen, C.sub.1 -C.sub.6 alkyl, or Ar--Y-- group;
• V.sub.1 is O, S, or NH;
• V.sub.2 is N or CH;
• V.sub.3 is a direct bond or --C(O)--;
• or stereoisomers or pharmaceutically acceptable salts thereof.

A composition comprising an assayable amount of a compound of the the formula ##STR17## wherein n is an integer from 0 to 3;

• R.sub.1 and R.sub.2 are each time taken independently chosen from the group consisting of;
• hydrogen, hydroxy, --OR.sub.4 wherein R.sub.4 is a C.sub.1 -C.sub.4 alkyl or an Ar--Y-- group wherein Ar is a phenyl or naphthyl group unsubstituted or substituted with from one to three substituents selected from the group consisting of methylenedioxy, hydroxy, C.sub.1 -C.sub.4 alkoxy, fluoro and chloro;
• and Y is a C.sub.0 -C.sub.4 alkyl;
• or, where R.sub.1 and R.sub.2 are attached to adjacent carbon atoms, R.sub.1 and R.sub.2 can be taken together with said adjacent carbons to form a benzene ring or methylenedioxy;
• R.sub.3 is hydrogen, C.sub.1 -C.sub.4 alkyl, --CH.sub.2 O--C(O)C(CH.sub.3).sub.3 ;
• X is --(CH.sub.2).sub.p --, O, S, NR.sub.5, or NC(O)R.sub.6 wherein p is an integer 0 or 1, R.sub.5 is hydrogen, a C.sub.1 -C.sub.4 alkyl, or an Ar--Y-- group, and R.sub.6 is --CF.sub.3, C.sub.1 -C.sub.10 alkyl, or an Ar--Y-- group;
• Q is a alkylene radical chosen from the group ##STR18## wherein q is an integer from 1 to 5 and Z is O, S, NH;
• G is a radical chosen from the group;
• ##STR19## wherein m is an integer from 1 to 3;
• R.sub.7 is hydrogen, C.sub.1 -C.sub.6 alkyl, --CH.sub.2 CH.sub.2 S(O).sub.k CH.sub.3, or Ar--Y-- wherein k is an integer form 0 to 2;
• R.sub.8 is hydrogen, hydroxy, amino, C.sub.1 -C.sub.6 alkyl, N-methylamino, N,N-dimethylamino, --CO.sub.2 R.sub.3 --OC(O)R.sub.9 wherein R.sub.9 is hydrogen, C.sub.1 -C.sub.6 alkyl, or phenyl;
• R.sub.10 is 1 or 2 substituents independently chosen from the group consisting of;
• hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, or halogen;
• R.sub.11 is hydrogen, C.sub.1 -C.sub.6 alkyl, or Ar--Y-- group;
• V.sub.1 is O, S, or NH;
• V.sub.2 is N or CH;
• V.sub.3 is a direct bond or --C(O)--;
• or stereoisomers or pharmaceutically acceptable salts thereof;
• in admixture or otherwise in association with an inert carrier.

A pharmaceutical composition comprising an effective immunosuppressive amount of a compound of the the formula ##STR20## wherein n is an integer from 0 to 3;

• R.sub.1 and R.sub.2 are each time taken independently chosen from the group consisting of;
• hydrogen, hydroxy, --OR.sub.4 wherein R.sub.4 is a C.sub.1 -C.sub.4 alkyl or an Ar--Y-- group wherein Ar is a phenyl or naphthyl group unsubstituted or substituted with from one to three substituents selected from the group consisting of methylenedioxy, hydroxy, C.sub.1 -C.sub.4 alkoxy, fluoro and chloro;
• and Y is a C.sub.0 -C.sub.4 alkyl;
• or, where R.sub.1 and R.sub.2 are attached to adjacent carbon atoms, R.sub.1 and R.sub.2 can be taken together with said adjacent carbons to form a benzene ring or methylenedioxy;
• R.sub.3 is hydrogen, C.sub.1 -C.sub.4 alkyl, --CH.sub.2 O--C(O)C(CH.sub.3).sub.3 ;
• X is --(CH.sub.2).sub.p --, O, S, NR.sub.5, or NC(O)R.sub.6 wherein p is an integer 0 or 1, R.sub.5 is hydrogen, a C.sub.1 -C.sub.4 alkyl, or an Ar--Y-- group, and R.sub.6 is --CF.sub.3, C.sub.1 -C.sub.10 alkyl, or an Ar--Y-- group;
• Q is a alkylene radical chosen from the group ##STR21## wherein q is an integer from 1 to 5 and Z is O, S, NH;
• G is a radical chosen from the group;
• ##STR22## wherein m is an integer from 1 to 3;
• R.sub.7 is hydrogen, C.sub.1 -C.sub.6 alkyl, --CH.sub.2 CH.sub.2 S(O).sub.k CH.sub.3, or Ar--Y-- wherein k is an integer form 0 to 2;
• R.sub.8 is hydrogen, hydroxy, amino, C.sub.1 -C.sub.6 alkyl, N-methylamino, N,N-dimethylamino, --CO.sub.2 R.sub.3 --OC(O)R.sub.9 wherein R.sub.9 is hydrogen, C.sub.1 -C.sub.6 alkyl, or phenyl;
• R.sub.10 is 1 or 2 substituents independently chosen from the group consisting of;
• hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, or halogen;
• R.sub.11 is hydrogen, C.sub.1 -C.sub.6 alkyl, or Ar--Y-- group;
• V.sub.1 is O, S, or NH;
• V.sub.2 is N or CH;
• V.sub.3 is a direct bond or --C(O)--;
• or stereoisomers or pharmaceutically acceptable salts thereof;
• in admixture or otherwise in association with one or more pharmaceutically acceptable carriers or excipients.