Cinnamic acid derivatives

A pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula ##STR309## or a pharmaceutically acceptable salt thereof, wherein A is ##STR310## wherein Y.sup.1 is selected from the group consisting of N--R.sup.2, O, and S;

• R.sup.2 is selected from the group consisting of H;
• alkyl;
• aryl;
• hydroxy;
• alkoxy;
• cyano;
• nitro;
• amino;
• aminocarbonyl;
• alkenyl;
• alkynyl;
• alkyl optionally substituted with one or more substituent selected from lower alkyl, halogen, hydroxyl, haloalkyl, cyano, nitro, carboxyl, amino, alkoxy, aryl or aryl optionally substituted with one or more halogen, haloalkyl, lower alkyl, alkoxy, cyano, alkylsulfonyl, alkylthio, nitro, carboxyl, amino, hydroxyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, or fused monocyclic heterocycles;
• aryl optionally substituted with one or more substituent selected from halogen, haloalkyl, hydroxy, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, cyano, nitro, alkylthio, alkylsulfonyl, sulfonic acid, sulfonamide, carboxyl derivatives, amino, aryl, fused aryl, monocyclic heterocycles and fused monocyclic heterocycle;
• monocyclic heterocycles;
• and monocyclic heterocycles optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, amino, nitro, hydroxy, carboxyl derivatives, cyano, alkylthio, alkylsulfonyl, sulfonic acid, sulfonamide, aryl or fused aryl;
• or
• R.sup.2 taken together with R.sup.7 forms a 4-12 membered dinitrogen containing heterocycle optionally substituted with one or more substituent selected from the group consisting of lower alkyl, hydroxy, carboxyl derivatives and phenyl;
• or R.sup.2 taken together with R.sup.7 forms a 5 membered heteroaromatic ring;
• or R.sup.2 taken together with R.sup.7 forms a 5 membered heteroaromatic ring fused with a phenyl group;
• R.sup.7 (when not taken together with R.sup.2) and R.sup.8 are independently selected from the group consisting of H;
• alkyl;
• alkenyl;
• alkynyl;
• aralkyl;
• cycloalkyl;
• bicycloalkyl;
• aryl;
• acyl;
• benzoyl;
• alkyl optionally substituted with one or more substituent selected from lower alkyl, halogen, hydroxy, haloalkyl, cyano, nitro, carboxyl derivatives, amino, alkoxy, thio, alkylthio, sulfonyl, aryl, aralkyl, aryl optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, carboxyl derivatives, aryloxy, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethyl, sulfonyl, alkylsulfonyl, haloalkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, fused monocyclic heterocycles;
• aryl optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, carboxyl derivatives, aryloxy, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethylsulfonyl, alkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, or fused monocyclic heterocycles;
• monocyclic heterocycles;
• monocyclic heterocycles optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, aryloxy, amino, nitro, hydroxy, carboxyl derivatives, cyano, alkylthio, alkylsulfonyl, aryl, fused aryl;
• monocyclic and bicyclic heterocyclicalkyls;
• --SO.sub.2 R.sup.10 wherein R.sup.10 is selected from the group consisting of alkyl, aryl and monocyclic heterocycles, all optionally substituted with one or more substituent selected from the group consisting of halogen, haloalkyl, alkyl, alkoxy, cyano, nitro, amino, acylamino, trifluoroalkyl, amido, alkylaminosulfonyl, alkylsulfonyl, alkylsulfonylamino, alkylamino, dialkylamino, trifluoromethylthio, trifluoroalkoxy, trifluoromethylsulfonyl, aryl, aryloxy, thio, alkylthio, and monocyclic heterocycles;
• and ##STR311## wherein R.sup.10 is defined above;
• or NR.sup.7 and R.sup.8 taken together form a 4-12 membered mononitrogen containing monocyclic or bicyclic ring optionally substituted with one or more substituent selected from lower alkyl, carboxyl derivatives, aryl or hydroxy and wherein said ring optionally contains a heteroatom selected from the group consisting of O, N and S;
• R.sup.5 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, benzyl, and phenethyl;
• or ##STR312## A is wherein y.sup.2 is selected from the group consisting of alkyl;
• cycloalkyl;
• bicycloalkyl;
• aryl;
• monocyclic heterocycles;
• alkyl optionally substituted with aryl which can also be optionally substituted with one or more substituent selected from halo, haloalkyl, alkyl, nitro, hydroxy, alkoxy, aryloxy, aryl, or fused aryl;
• aryl optionally substituted with one or more substituent selected from halo, haloalkyl, hydroxy, alkoxy, aryloxy, aryl, fused aryl, nitro, methylenedioxy, ethylenedioxy, or alkyl;
• alkynyl;
• alkenyl;
• --S--R.sup.9 and --O--R.sup.9 wherein R.sup.9 is selected from the group consisting of H;
• alkyl;
• aralkyl;
• aryl;
• alkenyl;
• and alkynyl;
• or R.sup.9 taken together with R.sup.7 forms a 4-12 membered mononitrogen containing sulfur or oxygen containing heterocyclic ring;
• and
• R.sup.5 and R.sup.7 are as defined above;
• or y.sup.2 (when y.sup.2 is carbon) taken together with R.sup.7 forms a 4-12 membered mononitrogen containing ring optionally substituted with alkyl, aryl or hydroxy;
• z.sup.1, Z.sup.2, Z.sup.4 and Z.sup.5 are independently selected from the group consisting of H;
• alkyl;
• hydroxy;
• alkoxy;
• aryloxy;
• arylalkoxy;
• halogen;
• haloalkyl;
• haloalkoxy;
• nitro;
• amino;
• aminoalkyl;
• alkylamino;
• dialkylamino;
• cyano;
• alkylthio;
• alkylsulfonyl;
• carboxyl derivatives;
• carboxylalkenyl;
• alkoxycarbonylalkenyl;
• alkoxycarbonylamino;
• acetamide;
• aryl;
• fused aryl;
• cycloalkyl;
• thio;
• monocyclic heterocycles;
• fused monocyclic heterocycles;
• and A, wherein A is defined above;
• B is selected from the group consisting of ##STR313## wherein p is an integer selected from the group consisting of 0, 1 and 2;
• wherein R.sup.11 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, benzyl and phenethyl;
• wherein n is an integer selected from the group consisting of 0, 1, 2 and 3;
• or B is CONR" wherein R" together with Z.sup.4 forms a 5 or 6-membered ring fused to the phenyl;
• l is an integer 0, 1, 2, or 3;
• t is an integer 0, 1 or 2;
• R.sup.50 is selected from the group consisting of H, alkyl, aryl and aryl optionally substituted with one or more substituent selected from the group consisting of halo, haloalkyl, hydroxy, alkoxy, aryloxy, aryl, nitro and alkyl;
• R is X-R.sup.3 wherein X is selected from the group consisting of O, S and NR.sup.4, wherein R.sup.3 and R.sup.4 are independently selected from the group consisting of hydrogen;
• alkyl;
• alkenyl;
• alkynyl;
• haloalkyl;
• dialkylaminocarbonylalkoxy;
• aryl;
• arylalkyl;
• sugars;
• steroids and in the case of the free acid, all pharmaceutically acceptable salts thereof;
• y.sup.3 and Z.sup.3 are independently selected from the group consisting of H, alkyl, aryl, cycloalkyl and aralkyl;
• R.sup.1 is selected from the group consisting of hydrogen;
• alkyl;
• amino, ##STR314## R.sup.12 is selected from the group consisting of H, alkyl, cycloalkyl, alkylaryl and aryl;
• R.sup.52 is selected from the group consisting of ##STR315## wherein R.sup.12 is as defined above;
• R.sup.51 is selected from the group consisting of N-substituted pyrrolidinyl, piperidinyl, phenyl and morpholinyl;
• R.sup.13 is selected from the group consisting of hydrogen;
• alkyl;
• alkenyl;
• alkynyl;
• aryl;
• carboxyl derivatives;
• haloalkyl;
• monocyclic heterocycles;
• monocyclic heterocycles optionally substituted with alkyl, halogen, haloalkyl, cyano, hydroxy, aryl, fused aryl, nitro, alkoxy, aryloxy, alkylsulfonyl, arylsulfonyl, sulfonamide, thio, alkylthio, carboxyl derivatives, amino, amido;
• alkyl optionally substituted with halo, haloalkyl, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, alkylsulfoxide, alkylsulfonyl, arylsulfoxide, arylsulfonyl, cyano, nitro, amino, alkylamino, dialkylamino, alkylsulfonamide, arylsulfonamide, acylamide, carboxyl derivatives, sulfonamide, sulfonic acid, phosphonic acid derivatives, phosphinic acid derivatives, aryl, arylthio, arylsulfoxide, or arylsulfone all optionally substituted on the aryl ring with halo, haloalkyl, cyano, nitro, hydroxy, carboxyl derivatives, alkoxy, aryloxy, amino, alkylamino, dialkylamino, amido, aryl, fused aryl, monocyclic heterocycles;
• and fused monocyclic heterocycles, monocyclic heterocyclicthio, monocyclic heterocyclicsulfoxide, and monocyclic heterocyclic sulfone, which can be optionally substituted with halo, haloalkyl, nitro, hydroxy, alkoxy, fused aryl, or alkyl;
• aryl optionally substituted in one or more positions with halo, haloalkyl, alkyl, alkoxy, aryloxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, carboxyl derivatives, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethylsulfonyl, alkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles and fused monocyclic heterocycles;
• and ##STR316## wherein R.sup.7 and R.sup.7 are as defined above and provided that taken together with the nitrogen, R.sup.7 and R.sup.8 comprise an amino acid;
• and
• a pharmaceutically acceptable carrier.

A method for treating conditions mediated by the .alpha..sub.v .beta..sub.3 integrin in a mammal in need of such treatment comprising administering a therapeutically effective .alpha..sub.v .beta..sub.3 inhibiting amount of a compound of the formula ##STR317## or a pharmaceutically acceptable salt thereof, wherein A is ##STR318## wherein Y.sup.1 is selected from the group consisting of N--R.sup.2, O, and S;

• R.sup.2 is selected from the group consisting of H;
• alkyl;
• aryl;
• hydroxy;
• alkoxy;
• cyano;
• nitro;
• amino;
• aminocarbonyl;
• alkenyl;
• alkynyl;
• alkyl optionally substituted with one or more substituent selected from lower alkyl, halogen, hydroxyl, haloalkyl, cyano, nitro, carboxyl, amino, alkoxy, aryl or aryl optionally substituted with one or more halogen, haloalkyl, lower alkyl, alkoxy, cyano, alkylsulfonyl, alkylthio, nitro, carboxyl, amino, hydroxyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, or fused monocyclic heterocycles;
• aryl optionally substituted with one or more substituent selected from halogen, haloalkyl, hydroxy, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, cyano, nitro, alkylthio, alkylsulfonyl, sulfonic acid, sulfonamide, carboxyl derivatives, amino, aryl, fused aryl, monocyclic heterocycles and fused monocyclic heterocycle;
• monocyclic heterocycles;
• and monocyclic heterocycles optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, amino, nitro, hydroxy, carboxyl derivatives, cyano, alkylthio, alkylsulfonyl, sulfonic acid, sulfonamide, aryl or fused aryl;
• or
• R.sup.2 taken together with R.sup.7 forms a 4-12 membered dinitrogen containing heterocycle optionally substituted with one or more substituent selected from the group consisting of lower alkyl, hydroxy, carboxyl derivatives and phenyl;
• or R.sup.2 taken together with R.sup.7 forms a 5 membered heteroaromatic ring;
• or R.sup.2 taken together with R.sup.7 forms a 5 membered heteroaromatic ring fused with a phenyl group;
• R.sup.7 (when not taken together with R.sup.2) and R.sup.8 are independently selected from the group consisting of H;
• alkyl;
• alkenyl;
• alkynyl;
• aralkyl;
• cycloalkyl;
• bicycloalkyl;
• aryl;
• acyl;
• benzoyl;
• alkyl optionally substituted with one or more substituent selected from lower alkyl, halogen, hydroxy, haloalkyl, cyano, nitro, carboxyl derivatives, amino, alkoxy, thio, alkylthio, sulfonyl, aryl, aralkyl, aryl optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, carboxyl derivatives, aryloxy, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethyl, sulfonyl, alkylsulfonyl, haloalkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, fused monocyclic heterocycles;
• aryl optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, carboxyl derivatives, aryloxy, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethylsulfonyl, alkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, or fused monocyclic heterocycles;
• monocyclic heterocycles;
• monocyclic heterocycles optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, aryloxy, amino, nitro, hydroxy, carboxyl derivatives, cyano, alkylthio, alkylsulfonyl, aryl, fused aryl;
• monocyclic and bicyclic heterocyclicalkyls;
• --SO.sub.2 R.sup.10 wherein R.sup.10 is selected from the group consisting of alkyl, aryl and monocyclic heterocycles, all optionally substituted with one or more substituent selected from the group consisting of halogen, haloalkyl, alkyl, alkoxy, cyano, nitro, amino, acylamino, trifluoroalkyl, amido, alkylaminosulfonyl, alkylsulfonyl, alkylsulfonylamino, alkylamino, dialkylamino, trifluoromethylthio, trifluoroalkoxy, trifluoromethylsulfonyl, aryl, aryloxy, thio, alkylthio, and monocyclic heterocycles;
• and ##STR319## wherein R.sup.10 is defined above;
• or NR.sup.7 and R.sup.8 taken together form a 4-12 membered mononitrogen containing monocyclic or bicyclic ring optionally substituted with one or more substituent selected from lower alkyl, carboxyl derivatives, aryl or hydroxy and wherein said ring optionally contains a heteroatom selected from the group consisting of O, N and S;
• R.sup.5 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, benzyl, and phenethyl;
• or ##STR320## A is wherein y.sup.2 is selected from the group consisting of alkyl;
• cycloalkyl;
• bicycloalkyl;
• aryl;
• monocyclic heterocycles;
• alkyl optionally substituted with aryl which can also be optionally substituted with one or more substituent selected from halo, haloalkyl, alkyl, nitro, hydroxy, alkoxy, aryloxy, aryl, or fused aryl;
• aryl optionally substituted with one or more substituent selected from halo, haloalkyl, hydroxy, alkoxy, aryloxy, aryl, fused aryl, nitro, methylenedioxy, ethylenedioxy, or alkyl;
• alkynyl;
• alkenyl;
• --S--R.sup.9 and --O--R.sup.9 wherein R.sup.9 is selected from the group consisting of H;
• alkyl;
• aralkyl;
• aryl;
• alkenyl;
• and alkynyl;
• or R.sup.9 taken together with R.sup.7 forms a 4-12 membered mononitrogen containing sulfur or oxygen containing heterocyclic ring;
• and
• R.sup.5 and R.sup.7 are as defined above;
• or y.sup.2 (when y.sup.2 is carbon) taken together with R.sup.7 forms a 4-12 membered mononitrogen containing ring optionally substituted with alkyl, aryl or hydroxy;
• Z.sup.1, Z.sup.2, Z.sup.4 and Z5 are independently selected from the group consisting of H;
• alkyl;
• hydroxy;
• alkoxy;
• aryloxy;
• arylalkoxy;
• halogen;
• haloalkyl;
• haloalkoxy;
• nitro;
• amino;
• aminoalkyl;
• alkylamino;
• dialkylamino;
• cyano;
• alkylthio;
• alkylsulfonyl;
• carboxyl derivatives;
• carboxylalkenyl;
• alkoxycarbonylalkenyl;
• alkoxycarbonylamino;
• acetamide;
• aryl;
• fused aryl;
• cycloalkyl;
• thio;
• monocyclic heterocycles;
• fused monocyclic heterocycles;
• and A, wherein A is defined above;
• B is selected from the group consisting of ##STR321## wherein p is an integer selected from the group consisting of 0, 1 and 2;
• wherein R.sup.11 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, benzyl and phenethyl;
• wherein n is an integer selected from the group consisting of 0, 1, 2 and 3;
• or B is CONR" wherein R" together with Z.sup.4 forms a 5 or 6-membered ring fused to the phenyl;
• l is an integer 0, 1, 2, or 3;
• t is an integer 0, 1 or 2;
• R.sup.50 is selected from the group consisting of H, alkyl, aryl and aryl optionally substituted with one or more substituent selected from the group consisting of halo, haloalkyl, hydroxy, alkoxy, aryloxy, aryl, nitro and alkyl;
• R is X--R.sup.3 wherein X is selected from the group consisting of O, S and NR.sup.4, wherein R.sup.3 and R.sup.4 are independently selected from the group consisting of hydrogen;
• alkyl;
• alkenyl;
• alkynyl;
• haloalkyl;
• dialkylaminocarbonylalkoxy;
• aryl;
• arylalkyl;
• sugars;
• steroids and in the case of the free acid, all pharmaceutically acceptable salts thereof;
• Y.sup.3 and Z.sup.3 are independently selected from the group consisting of H, alkyl, aryl, cycloalkyl and aralkyl;
• R.sup.1 is selected from the group consisting of hydrogen;
• alkyl;
• amino, ##STR322## R.sup.12 is selected from the group consisting of H, alkyl, cycloalkyl, alkylaryl and aryl;
• R.sup.52 is selected from the group consisting of ##STR323## wherein R.sup.12 is as defined above;
• R.sup.51 is selected from the group consisting of N-substituted pyrrolidinyl, piperidinyl, phenyl and morpholinyl;
• R.sup.13 is selected from the group consisting of hydrogen;
• alkyl;
• alkenyl;
• alkynyl;
• aryl;
• carboxyl derivatives;
• haloalkyl;
• monocyclic heterocycles;
• monocyclic heterocycles optionally substituted with alkyl, halogen, haloalkyl, cyano, hydroxy, aryl, fused aryl, nitro, alkoxy, aryloxy, alkylsulfonyl, arylsulfonyl, sulfonamide, thio, alkylthio, carboxyl derivatives, amino, amido;
• alkyl optionally substituted with halo, haloalkyl, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, alkylsulfoxide, alkylsulfonyl, arylsulfoxide, arylsulfonyl, cyano, nitro, amino, alkylamino, dialkylamino, alkylsulfonamide, arylsulfonamide, acylamide, carboxyl derivatives, sulfonamide, sulfonic acid, phosphonic acid derivatives, phosphinic acid derivatives, aryl, arylthio, arylsulfoxide, or arylsulfone all optionally substituted on the aryl ring with halo, haloalkyl, cyano, nitro, hydroxy, carboxyl derivatives, alkoxy, aryloxy, amino, alkylamino, dialkylamino, amido, aryl, fused aryl, monocyclic heterocycles;
• and fused monocyclic heterocycles, monocyclic heterocyclicthio, monocyclic heterocyclicsulfoxide, and monocyclic heterocyclic sulfone, which can be optionally substituted with halo, haloalkyl, nitro, hydroxy, alkoxy, fused aryl, or alkyl;
• aryl optionally substituted in one or more positions with halo, haloalkyl, alkyl, alkoxy, aryloxy, methylenedioxy, ethylenedioxy, alkylthio, aloalkylthio, thio, hydroxy, cyano, nitro, carboxyl derivatives, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethylsulfonyl, alkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles and fused monocyclic heterocycles;
• and ##STR324## wherein R.sup.7 and R.sup.8 are as defined above and provided that taken together with the nitrogen, R.sup.7 and R.sup.8 comprise an amino acid.