Back to results
US 6,831,199 B1Granted
Pyrimidine compounds and derivatives thereof
AssigneeG. D. Searle & Co.
InventorsPeter Gerrard Ruminski, Michael Clare, Paul Waddell Collins, Bipinchandra Nanubhai Desai, Richard John Lindmark, Joseph Gerace Rico, Thomas Edward Rogers, Mark Andrew Russell
Life of this patent
Estimating the term…
Abstract
The present invention relates to a class of compounds represented by the Formula I or a pharmaceutically acceptable salt thereof, wherein A is pharmaceutical compositions thereof and methods of using such compounds and compositions as αvβ3 antagonists.
Claims20
A compound of the formula
- or a pharmaceutically acceptable salt thereof, wherein
- A is
- wherein Y1 is N—R2;
- R2 taken together with R7 forms a 6 membered dinitrogen containing heterocycle optionally substituted with one or more substituent selected from the group consisting of lower alkyl, hydroxy, keto, alkoxy, halo, phenyl, amino, carboxyl or carboxyl ester, and fused phenyl;
- R5 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, benyl, and phenethyl;
- R8 and R8′ are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aralkyl, amino, alkylamino, hydroxy, alkoxy, arylamino, amido, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkylcarbonyl, aryloxy, haloalkoxycarbonyl, alkylthiocarbonyl, arylthiocarbonyl, acyloxymethoxycarbonyl, cycloalkyl, bicycloalkyl, aryl, acyl, benzolyl, 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, arylkyl, aryl optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alcoxy, 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, aryl optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, alkylthio, haloalkylthio, thio hydroxy, cyano, nitro, carboxyl derivatives aryloxy, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkyoxy, trifluoromethylsulfonyl, alkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, SO2R10 wherein R10 is selected from the group consisting of alkyl and, aryl and
- wherein R10 is selected from the group consisting of alkyl and aryl;
- Z1 is one or more substituent selected from the group consisting of H;
- alkyl;
- hydroxy;
- alkoxy;
- aryloxy;
- halogen;
- haloalkyl;
- haloalkoxy;
- nitro;
- amino;
- alkylamino;
- acylamino;
- dialkylamino;
- cyano;
- alkylthio;
- alkylsulfonyl;
- carboxyl derivatives;
- trihaloacetamide;
- acetamide;
- aryl;
- fused aryl;
- cycloalkyl;
- thio;
- V is selected from the group consisting of —N—(R6)— wherein R6 is selected from the group consisting of H;
- lower alkyl;
- cycloalkyl;
- aralkyl;
- and aryl;
- Y, Y3, Z and Z3 are independently selected from the group consisting of hydrogen;
- alkyl;
- aryl;
- and cycloalkyl;
- or Y and Z taken together form a cycloalkyl;
- or Y3 and Z3 taken together form a cycloalkyl;
- n is an integer 1, 2, or 3;
- t is 0;
- p is an integer 0, 1, 2, or 3;
- R is X—R3 wherein X is selected from the group consisting of O, S and NR4, wherein R3 and R4 are independently selected from the group consisting of hydrogen;
- alkyl;
- alkenyl;
- alkynyl;
- haloalkyl;
- aryl;
- arylalkyl;
- polyalkylethers;
- alkylamido;
- alkyl N,N-dialkylamido;
- pivaloyloxymethyl;
- and in the case of the free acid, all pharmaceutically acceptable salts thereof;
- R1 is selected from the group consisting of hydrogen;
- alkyl;
- alkenyl;
- alkynyl;
- aryl;
- carboxyl derivatives;
- haloalkyl;
- alkyl optionally substituted with one or more of halo, haloalkyl, hydroxy, alkoxy, aryloxy, thio, alkylthio, alkynyl, alkenyl, alkyl, 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, alkyl, haloalkyl, cyano, nitro, hydroxy, carboxyl derivatives, alkoxy, aryloxy, amino, alkylamino, dialkylamino, amido, aryl, fused aryl,
- alkylcarbonyl, haloalkylcarbonyl, and arylcarbonyl;
- aryl optionally substituted in one or more positions with halo, haloalkyl, alkyl, alkoxy, aryloxy, alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, acyloxy, carboxyl derivatives, carboxyalkoxy, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethylsulfonyl, alkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, and
- wherein R8″l and R8 are as defined above;
- and
- R11 is selected from the group consisting of H, alkyl, aralkyl, alkenyl, alkynyl, haloalkyl or haloalkynyl.
66 more elements
A pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula
- or a pharmaceutically acceptable salt thereof, wherein A is
- wherein Y1 is N—R2;
- R2 taken together with R7 forms a 6 membered dinitrogen containing heterocycle optionally substituted with one or more substituent selected from the group consisting of lower alkyl, hydroxy, keto, alkoxy, halo, phenyl, amino, carboxyl or carboxyl ester, and fused phenyl;
- R5 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, benyl, and phenethyl;
- R8 and R8″ are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aralkyl, amino, alkylamino, hydroxy, alkoxy, arylamino, amido, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkylcarbonyl, aryloxy, haloalkoxycarbonyl, alkylthiocarbonyl, arylthiocarbonyl, acyloxymethoxycarbonyl, cycloalkyl, bicycloalkyl, aryl, acyl, benzolyl, 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, arylkyl, aryl optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alcoxy, 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, aryl optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl alkoxy, alkylthio, haloalkylthio, thio hydroxy, cyano, nitro, carboxyl derivatives aryloxy, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkyoxy, trifluoromethylsulfonyl, alkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, SO2R10 wherein R10 is selected from the group consisting of alkyl and, aryl and
- wherein R10 is selected from the group consisting of alkyl and aryl;
- Z1 is one or more substituent selected from the group consisting of H;
- alkyl;
- hydroxy;
- alkoxy;
- aryloxy;
- halogen;
- haloalkyl;
- haloalkoxy;
- nitro;
- amino;
- alkylamino;
- acylamino;
- dialkylamino;
- cyano;
- alkylthio;
- alkylsulfonyl;
- carboxyl derivatives;
- trihaloacetamide;
- acetamide;
- aryl;
- fused aryl;
- cycloalkyl;
- thio;
- V is selected from the group consisting of —N—(R6— wherein R6 is selected from the group consisting of H;
- lower alkyl;
- cycloalkyl;
- aralkyl;
- and aryl;
- Y, Y3, Z and Z3 are independently selected from the group consisting of hydrogen;
- alkyl;
- aryl;
- and cycloalkyl;
- or Y and Z taken together form a cycloalkyl;
- or Y3 and Z3 taken together form a cycloalkyl;
- n is an integer 1, 2, or 3;
- t is 0;
- p is an integer 0, 1, 2, or 3;
- R is X—R3 wherein X is selected from the group consisting of O, S and NR4, wherein R3 and R4 are independently selected from the group consisting of hydrogen;
- alkyl;
- alkenyl;
- alkynyl;
- haloalkyl;
- aryl;
- arylalkyl;
- polyalkylethers;
- alkylamido;
- alkyl N,N-dialkylamido;
- pivaloyloxymethyl;
- and in the case of the free acid, all pharmaceutically acceptable salts thereof;
- R1 is selected from the group consisting of hydrogen;
- alkyl;
- alkenyl;
- alkynyl;
- aryl;
- carboxyl derivatives;
- haloalkyl;
- alkyl optionally substituted with one or more of halo, haloalkyl, hydroxy, alkoxy, aryloxy, thio, alkylthio, alkynyl, alkenyl, alkyl, 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, alkyl, haloalkyl, cyano, nitro, hydroxy, carboxyl derivatives, alkoxy, aryloxy, amino, alkylamino, dialkylamino, amido, aryl, fused aryl, alkylcarbonyl, haloalkylcarbonyl, and arylcarbonyl;
- aryl optionally substituted in one or more positions with halo, haloalkyl, alkyl, alkoxy, aryloxy, alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, acyloxy, carboxyl derivatives, carboxyalkoxy, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethylsulfonyl, alkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, and
- wherein R8″ and R8 are as defined above;
- and
- R11 is selected from the group consisting of H, alkyl, aralkyl, alkenyl, alkynyl, haloalkyl or haloalkynyl and a pharmaceutically acceptable carrier.
64 more elements
A method for treating conditions mediated by the αvβ3 integrin in a mammal in need of such treatment comprising administering an effective αvβ3 inhibiting amount of a compound of the formula
- or a pharmaceutically acceptable salt thereof, wherein A is
- wherein Y1 is N—R2;
- R2 taken together with R7 forms a 6 membered dinitrogen containing heterocycle optionally substituted with one or more substituent selected from the group consisting of lower alkyl, hydroxy, keto, alkoxy, halo, phenyl, amino, carboxyl or carboxyl ester, and fused phenyl;
- R5 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, benyl, and phenethyl;
- R8 and R8″ are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aralkyl, amino, alkylamino, hydroxy, alkoxy, arylamino, amido, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkylcarbonyl, aryloxy, haloalkoxycarbonyl, alkylthiocarbonyl, arylthiocarbonyl, acyloxymethoxycarbonyl, cycloalkyl, bicycloalkyl, aryl, acyl, benzolyl, 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, arylkyl, aryl optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alcoxy, 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, aryl optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, alkylthio, haloalkylthio, thio hydroxy, cyano, nitro, carboxyl derivatives aryloxy, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkyoxy, trifluoromethylsulfonyl, alkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, SO2R10 wherein R10 is selected from the group consisting of alkyl and, aryl and
- wherein R10 is selected from the group consisting of alkyl and aryl;
- Z1 is one or more substituent selected from the group consisting of H;
- alkyl;
- hydroxy;
- alkoxy, aryloxy;
- halogen;
- haloalkyl;
- haloalkoxy;
- nitro;
- amino;
- alkylamino;
- acylamino;
- dialkylamino;
- cyano;
- alkylthio;
- alkylsulfonyl;
- carboxyl derivatives;
- trihaloacetamide;
- acetamide;
- aryl;
- fused aryl;
- cycloalkyl;
- thio;
- V is selected from the group consisting of —N—(R6)— wherein R6 is selected from the group consisting of H;
- lower alkyl;
- cycloalkyl;
- aralkyl;
- and aryl;
- Y, Y3, Z and Z3 are independently selected from the group consisting of hydrogen;
- alkyl;
- aryl;
- and cycloalkyl;
- or Y and Z taken together form a cycloalkyl;
- or Y3 and Z3 taken together form a cycloalkyl;
- n is an integer 1, 2, or 3;
- t is 0;
- p is an integer 0, 1, 2, or 3;
- R is X—R3 wherein X is selected from the group consisting of O, S and NR4, wherein R3 and R4 are independently selected from the group consisting of hydrogen;
- alkyl;
- alkenyl;
- alkynyl;
- haloalkyl;
- aryl;
- arylalkyl;
- polyalkylethers;
- alkylamido;
- alkyl N,N-dialkylamido;
- pivaloyloxymethyl;
- and in the case of the free acid, all pharmaceutically acceptable salts thereof;
- R1 is selected from the group consisting of hydrogen;
- alkyl;
- alkenyl;
- alkynyl;
- aryl;
- carboxyl derivatives;
- haloalkyl;
- alkyl optionally substituted with one or more of halo, haloalkyl, hydroxy, alkoxy, aryloxy, thio, alkylthio, alkynyl, alkenyl, alkyl, 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, alkyl, haloalkyl, cyano, nitro, hydroxy, carboxyl derivatives, alkoxy, aryloxy, amino, alkylamino, dialkylamino, amido, aryl, fused aryl, alkylcarbonyl, haloalkylcarbonyl, and arylcarbonyl;
- aryl optionally substituted in one or more positions with halo, haloalkyl, alkyl, alkoxy, aryloxy, alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, acyloxy, carboxyl derivatives, carboxyalkoxy, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethylsulfonyl, alkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, and
- wherein R8″ and R8 are as defined above;
- and
- R11 is selected from the group consisting of H, alkyl, aralkyl, alkenyl, alkynyl, haloalkyl or haloalkynyl.
63 more elements
Dependencies are inferred from the claim text.