NEW TYROSINE DERIVATIVES AS PPARy MODULATORS

Abstract

Compounds of general formula I, and the salts and solvates thereof, wherein R1 represents the radical 2-benzoylphenylamino; R2 represents —(CH 2 ) s —N(COR3)-A-J-T or —(CH 2 ) s —N(R4)-B-J-T; and s, R3, R4, A, B, J and T have the meanings disclosed herein. These compounds are PPARγ modulators and, therefore, are useful for the treatment or prevention of a condition or a disease mediated by these receptors.

1 . A method for the treatment or prevention of diseases mediated by PPARγ comprising the administration to a mammal of an effective amount of a compound of formula I 
     
       
         
         
             
             
         
       
     
     its stereoisomers and mixtures thereof, its polymorphs and mixtures thereof, and the pharmaceutically acceptable solvates and addition salts of all of them, wherein
 R1 represents the radical 2-benzoylphenylamino; 
 R2 represents —(CH 2 ) s —N(COR3)-A-J-T or —(CH 2 ) s —N(R4)-B-J-T; 
 R3 represents —(C 1 -C 10 )alkyl optionally substituted by one or more substituents selected from —F, —Cl, —Br and —O(C 1 -C 4 )alkyl; —(C 2 -C 6 )alkenyl; —(C 2 -C 6 )alkynyl; —(C 1 -C 3 )alkylene-Y; —(C 2 -C 3 )alkenylene-Y; —(C 2 -C 3 )alkynylene-Y or —Y; 
 R4 represents —(C 4 -C 10 )alkyl optionally substituted by one or more substituents selected from —F, —Cl, —Br and —O(C 1 -C 4 )alkyl; —(C 2 -C 6 )alkenyl; —(C 2 -C 6 )alkynyl; —(C 1 -C 4 )alkylene-Y; —(C 2 -C 4 )alkenylene-Y; —(C 2 -C 4 )alkynylene-Y or —Y; 
 s represents 2 or 3; 
 A represents —(C 1 -C 4 )alkylene-; —(C 2 -C 4 )alkenylene-; —(C 2 -C 4 )alkynylene-; —(C 1 -C 4 )alkylene-Z-, wherein the alkylene part is attached to the N atom and Z is attached to J; or -Z-; 
 B represents —(C 4 )alkylene-; —(C 2 -C 4 )alkenylene-; —(C 2 -C 4 )alkynylene-; —(C 1 -C 4 )alkylene-Z-, wherein the alkylene part is attached to the N atom and Z is attached to J; or -Z-; 
 J represents a single bond or a biradical selected from the following groups:
 a) —(CH 2 ) 1-4 —, —O—, —S—, —SO—, —SO 2 —, —CO—, —OCO—, —COO—, —OCONR5-, —NR5COO—, —CONR5-, —NR5CO—, —NR5-, —NR5SO 2 —, —SO 2 NR5-; and 
 b) —O(C 1 -C 4 )alkyl-, —(C 1 -C 4 )alkyl-O—, —S(C 1 -C 4 )alkyl-, —(C 1 -C 4 )alkyl-S—, —SO(C 1 -C 4 )alkyl-, —(C 1 -C 4 )alkyl-SO—, —SO 2 (C 1 -C 4 )alkyl-, —(C 1 -C 4 )alkyl-SO 2 —, —OCO—(C 1 -C 4 )alkyl-, —COO—(C 1 -C 4 )alkyl-, —(C 1 -C 4 )alkyl-OCO—, —(C 1 -C 4 )alkyl-COO—, —OCONR5-(C 1 -C 4 )alkyl-, —NR5COO—(C 1 -C 4 )alkyl-, —(C 1 -C 4 )alkyl-OCONR5-, —(C 1 -C 4 )alkyl-NR5COO—, —CONR5-(C 1 -C 4 )alkyl-, —NR5CO—(C 1 -C 4 )alkyl-, —(C 1 -C 4 )alkyl-CONR5-, —(C 1 -C 4 )alkyl-NR5CO—, —NR5-(C 1 -C 4 )alkyl-, —(C 1 -C 4 )alkyl-NR5-, —SO 2 NR5-(C 1 -C 4 )alkyl-, —NR5SO 2 —(C 1 -C 4 )alkyl-, —(C 1 -C 4 )alkyl-SO 2 NR5-, —(C 1 -C 4 )alkyl-NR5SO 2 —; 
 
 T represents —H, —(C 1 -C 4 )alkyl, —(C 2 -C 4 )alkenyl, —(C 2 -C 4 )alkynyl or —Y; 
 Y represents a monoradical coming from a cycle selected from a (C 3 -C 6 )cycloalkane, cyclohexene, a heterocycle, benzene and a bicycle, wherein all these cycles can be optionally substituted with one or more substituents selected from the group —OH, —CHO, —SH, —NO 2 , —CN, —F, —Cl, —Br, —CO(C 1 -C 4 )alkyl, —COO(C 1 -C 4 )alkyl, —OCO(C 1 -C 4 )alkyl, —S(C 1 -C 4 )alkyl, —SO(C 1 -C 4 )alkyl, —SO 2 (C 1 -C 4 )alkyl, —SO 2 —O(C 1 -C 4 )alkyl, —O—SO 2 (C 1 -C 4 )alkyl, —NR5R6, —CONR5R6, —(C 1 -C 4 )alkyl optionally substituted by one or more —OH or —F and —O(C 1 -C 4 )alkyl optionally substituted by one or more —OH or —F, and wherein the cycles (C 3 -C 6 )cycloalkane, cyclohexene and bicycle can also be optionally substituted with one or more substituents oxo (═O); 
 Z represents a biradical coming from a cycle selected from a (C 3 -C 6 )cycloalkane, cyclohexene, a heterocycle, benzene and a bicycle, wherein all these cycles can be optionally substituted with one or more substituents selected from the group —OH, —CHO, —SH, —NO 2 , —CN, —F, —Cl, —Br, —CO(C 1 -C 4 )alkyl, —COO(C 1 -C 4 )alkyl, —OCO(C 1 -C 4 )alkyl, —S(C 1 -C 4 )alkyl, —SO(C 1 -C 4 )alkyl, —SO 2 (C 1 -C 4 )alkyl, —SO 2 —O(C 1 -C 4 )alkyl, —O—SO 2 (C 1 -C 4 )alkyl, —NR5R6, —CONR5R6, —(C 1 -C 4 )alkyl optionally substituted by one or more —OH or —F and —O(C 1 -C 4 )alkyl optionally substituted by one or more —OH or —F, and wherein the cycles (C 3 -C 6 )cycloalkane, cyclohexene and bicycle can also be optionally substituted with one or more substituents oxo (═O); 
 R5 and R6 independently represent —H or —(C 1 -C 4 )alkyl;
 a heterocycle in the above definitions represents a five- or six-membered aromatic ring containing from one to three heteroatoms independently selected from O, S and N, wherein said ring can be attached to the rest of the molecule through a carbon or a nitrogen atom; and 
 a bicycle in the above definitions represents a partially unsaturated, saturated or aromatic seven- to ten-membered ring optionally containing from one to three heteroatoms independently selected from O, S and N, wherein said ring or rings can be attached to the rest of the molecule through a carbon or a nitrogen atom. 
 
 
   
   
       2 . A method for the treatment or prevention of metabolic diseases comprising the administration to a mammal of an effective amount of a compound of formula I 
     
       
         
         
             
             
         
       
     
     its stereoisomers and mixtures thereof, its polymorphs and mixtures thereof, and the pharmaceutically acceptable solvates and addition salts of all of them, wherein
 R1 represents the radical 2-benzoylphenylamino; 
 R2 represents —(CH 2 ) s —N(COR3)-A-J-T or —(CH 2 ) s —N(R4)-B-J-T; 
 R3 represents —(C 1 -C 10 )alkyl optionally substituted by one or more substituents selected from —F, —Cl, —Br and —O(C 1 -C 4 )alkyl; —(C 2 -C 6 )alkenyl; —(C 2 -C 6 )alkynyl; —(C 1 -C 3 )alkylene-Y; —(C 2 -C 3 )alkenylene-Y; —(C 2 -C 3 )alkynylene-Y or —Y; 
 R4 represents —(C 4 -C 10 )alkyl optionally substituted by one or more substituents selected from —F, —Cl, —Br and —O(C 1 -C 4 )alkyl; —(C 2 -C 6 )alkenyl; —(C 2 -C 6 )alkynyl; —(C 1 -C 4 )alkylene-Y; —(C 2 -C 4 )alkenylene-Y; —(C 2 -C 4 )alkynylene-Y or —Y; 
 s represents 2 or 3; 
 A represents —(C 1 -C 4 )alkylene-; —(C 2 -C 4 )alkenylene-; —(C 2 -C 4 )alkynylene-; —(C 1 -C 4 )alkylene-Z-, wherein the alkylene part is attached to the N atom and Z is attached to J; or -Z-; 
 B represents —(C 4 )alkylene-; —(C 2 -C 4 )alkenylene-; —(C 2 -C 4 )alkynylene-; —(C 1 -C 4 )alkylene-Z-, wherein the alkylene part is attached to the N atom and Z is attached to J; or -Z-; 
 J represents a single bond or a biradical selected from the following groups:
 a) —(CH 2 ) 1-4 —, —O—, —S—, —SO—, —SO 2 —, —CO—, —OCO—, —COO—, —OCONR5-, —NR5COO—, —CONR5-, —NR5CO—, —NR5-, —NR5SO 2 —, —SO 2 NR5-; and 
 b) —O(C 1 -C 4 )alkyl-, —(C 1 -C 4 )alkyl-O—, —S(C 1 -C 4 )alkyl-, —(C 1 -C 4 )alkyl-S—, —SO(C 1 -C 4 )alkyl-, —(C 1 -C 4 )alkyl-SO—, —SO 2 (C 1 -C 4 )alkyl-, —(C 1 -C 4 )alkyl-SO 2 —, —OCO—(C 1 -C 4 )alkyl-, —COO—(C 1 -C 4 )alkyl-, —(C 1 -C 4 )alkyl-OCO—, —(C 1 -C 4 )alkyl-COO—, —OCONR5-(C 1 -C 4 )alkyl-, —NR5COO—(C 1 -C 4 )alkyl-, —(C 1 -C 4 )alkyl-OCONR5-, —(C 1 -C 4 )alkyl-NR5COO—, —CONR5-(C 1 -C 4 )alkyl-, —NR5CO—(C 1 -C 4 )alkyl-, —(C 1 -C 4 )alkyl-CONR5-, —(C 1 -C 4 )alkyl-NR5CO—, —NR5-(C 1 -C 4 )alkyl-, —(C 1 -C 4 )alkyl-NR5-, —SO 2 NR5-(C 1 -C 4 )alkyl-, —NR5SO 2 —(C 1 -C 4 )alkyl-, —(C 1 -C 4 )alkyl-SO 2 NR5-, —(C 1 -C 4 )alkyl-NR5SO 2 —; 
 
 T represents —H, —(C 1 -C 4 )alkyl, —(C 2 -C 4 )alkenyl, —(C 2 -C 4 )alkynyl or —Y; 
 Y represents a monoradical coming from a cycle selected from a (C 3 -C 6 )cycloalkane, cyclohexene, a heterocycle, benzene and a bicycle, wherein all these cycles can be optionally substituted with one or more substituents selected from the group —OH, —CHO, —SH, —NO 2 , —CN, —F, —Cl, —Br, —CO(C 1 -C 4 )alkyl, —COO(C 1 -C 4 )alkyl, —OCO(C 1 -C 4 )alkyl, —S(C 1 -C 4 )alkyl, —SO(C 1 -C 4 )alkyl, —SO 2 (C 1 -C 4 )alkyl, —SO 2 —O(C 1 -C 4 )alkyl, —O—SO 2 (C 1 -C 4 )alkyl, —NR5R6, —CONR5R6, —(C 1 -C 4 )alkyl optionally substituted by one or more —OH or —F and —O(C 1 -C 4 )alkyl optionally substituted by one or more —OH or —F, and wherein the cycles (C 3 -C 6 )cycloalkane, cyclohexene and bicycle can also be optionally substituted with one or more substituents oxo (═O); 
 Z represents a biradical coming from a cycle selected from a (C 3 -C 6 )cycloalkane, cyclohexene, a heterocycle, benzene and a bicycle, wherein all these cycles can be optionally substituted with one or more substituents selected from the group —OH, —CHO, —SH, —NO 2 , —CN, —F, —Cl, —Br, —CO(C 1 -C 4 )alkyl, —COO(C 1 -C 4 )alkyl, —OCO(C 1 -C 4 )alkyl, —S(C 1 -C 4 )alkyl, —SO(C 1 -C 4 )alkyl, —SO 2 (C 1 -C 4 )alkyl, —SO 2 —O(C 1 -C 4 )alkyl, —O—SO 2 (C 1 -C 4 )alkyl, —NR5R6, —CONR5R6, —(C 1 -C 4 )alkyl optionally substituted by one or more —OH or —F and —O(C 1 -C 4 )alkyl optionally substituted by one or more —OH or —F, and wherein the cycles (C 3 -C 6 )cycloalkane, cyclohexene and bicycle can also be optionally substituted with one or more substituents oxo (═O); 
 R5 and R6 independently represent —H or —(C 1 -C 4 )alkyl;
 a heterocycle in the above definitions represents a five- or six-membered aromatic ring containing from one to three heteroatoms independently selected from O, S and N, wherein said ring can be attached to the rest of the molecule through a carbon or a nitrogen atom; and 
 a bicycle in the above definitions represents a partially unsaturated, saturated or aromatic seven- to ten-membered ring optionally containing from one to three heteroatoms independently selected from O, S and N, wherein said ring or rings can be attached to the rest of the molecule through a carbon or a nitrogen atom. 
 
 
   
   
       3 . A method according to  claim 2 , wherein the metabolic disease is selected from non-insulin-dependent diabetes mellitus and obesity. 
   
   
       4 . A method for the treatment or prevention of cardiovascular diseases associated with metabolic syndrome, inflammatory diseases, cancer, bone diseases, skin wound healing, cutaneous disorders associated with an anomalous differentiation of epidermic cells and other disorders where insulin resistance is a component, comprising the administration to a mammal of an effective amount of a compound of formula I 
     
       
         
         
             
             
         
       
     
     its stereoisomers and mixtures thereof, its polymorphs and mixtures thereof, and the pharmaceutically acceptable solvates and addition salts of all of them, wherein
 R1 represents the radical 2-benzoylphenylamino; 
 R2 represents —(CH 2 ) s —N(COR3)-A-J-T or —(CH 2 ) s —N(R4)-B-J-T; 
 R3 represents —(C 1 -C 10 )alkyl optionally substituted by one or more substituents selected from —F, —Cl, —Br and —O(C 1 -C 4 )alkyl; —(C 2 -C 6 )alkenyl; —(C 2 -C 6 )alkynyl; —(C 1 -C 3 )alkylene-Y; —(C 2 -C 3 )alkenylene-Y; —(C 2 -C 3 )alkynylene-Y or —Y; 
 R4 represents —(C 4 -C 10 )alkyl optionally substituted by one or more substituents selected from —F, —Cl, —Br and —O(C 1 -C 4 )alkyl; —(C 2 -C 6 )alkenyl; —(C 2 -C 6 )alkynyl; —(C 1 -C 4 )alkylene-Y; —(C 2 -C 4 )alkenylene-Y; —(C 2 -C 4 )alkynylene-Y or —Y; 
 s represents 2 or 3; 
 A represents —(C 1 -C 4 )alkylene-; —(C 2 -C 4 )alkenylene-; —(C 2 -C 4 )alkynylene-; —(C 1 -C 4 )alkylene-Z-, wherein the alkylene part is attached to the N atom and Z is attached to J; or -Z-; 
 B represents —(C 4 )alkylene-; —(C 2 -C 4 )alkenylene-; —(C 2 -C 4 )alkynylene-; —(C 1 -C 4 )alkylene-Z-, wherein the alkylene part is attached to the N atom and Z is attached to J; or -Z-; 
 J represents a single bond or a biradical selected from the following groups:
 a) —(CH 2 ) 1-4 —, —O—, —S—, —SO—, —SO 2 —, —CO—, —OCO—, —COO—, —OCONR5-, —NR5COO—, —CONR5-, —NR5CO—, —NR5-, —NR5SO 2 —, —SO 2 NR5-; and 
 b) —O(C 1 -C 4 )alkyl-, —(C 1 -C 4 )alkyl-O—, —S(C 1 -C 4 )alkyl-, —(C 1 -C 4 )alkyl-S—, —SO(C 1 -C 4 )alkyl-, —(C 1 -C 4 )alkyl-SO—, —SO 2 (C 1 -C 4 )alkyl-, —(C 1 -C 4 )alkyl-SO 2 —, —OCO—(C 1 -C 4 )alkyl-, —COO—(C 1 -C 4 )alkyl-, —(C 1 -C 4 )alkyl-OCO—, —(C 1 -C 4 )alkyl-COO—, —OCONR5-(C 1 -C 4 )alkyl-, —NR5COO—(C 1 -C 4 )alkyl-, —(C 1 -C 4 )alkyl-OCONR5-, —(C 1 -C 4 )alkyl-NR5COO—, —CONR5-(C 1 -C 4 )alkyl-, —NR5CO—(C 1 -C 4 )alkyl-, —(C 1 -C 4 )alkyl-CONR5-, —(C 1 -C 4 )alkyl-NR5CO—, —NR5-(C 1 -C 4 )alkyl-, —(C 1 -C 4 )alkyl-NR5-, —SO 2 NR5-(C 1 -C 4 )alkyl-, —NR5SO 2 —(C 1 -C 4 )alkyl-, —(C 1 -C 4 )alkyl-SO 2 NR5-, —(C 1 -C 4 )alkyl-NR5SO 2 —; 
 
 T represents —H, —(C 1 -C 4 )alkyl, —(C 2 -C 4 )alkenyl, —(C 2 -C 4 )alkynyl or —Y; 
 Y represents a monoradical coming from a cycle selected from a (C 3 -C 6 )cycloalkane, cyclohexene, a heterocycle, benzene and a bicycle, wherein all these cycles can be optionally substituted with one or more substituents selected from the group —OH, —CHO, —SH, —NO 2 , —CN, —F, —Cl, —Br, —CO(C 1 -C 4 )alkyl, —COO(C 1 -C 4 )alkyl, —OCO(C 1 -C 4 )alkyl, —S(C 1 -C 4 )alkyl, —SO(C 1 -C 4 )alkyl, —SO 2 (C 1 -C 4 )alkyl, —SO 2 —O(C 1 -C 4 )alkyl, —O—SO 2 (C 1 -C 4 )alkyl, —NR5R6, —CONR5R6, —(C 1 -C 4 )alkyl optionally substituted by one or more —OH or —F and —O(C 1 -C 4 )alkyl optionally substituted by one or more —OH or —F, and wherein the cycles (C 3 -C 6 )cycloalkane, cyclohexene and bicycle can also be optionally substituted with one or more substituents oxo (═O); 
 Z represents a biradical coming from a cycle selected from a (C 3 -C 6 )cycloalkane, cyclohexene, a heterocycle, benzene and a bicycle, wherein all these cycles can be optionally substituted with one or more substituents selected from the group —OH, —CHO, —SH, —NO 2 , —CN, —F, —Cl, —Br, —CO(C 1 -C 4 )alkyl, —COO(C 1 -C 4 )alkyl, —OCO(C 1 -C 4 )alkyl, —S(C 1 -C 4 )alkyl, —SO(C 1 -C 4 )alkyl, —SO 2 (C 1 -C 4 )alkyl, —SO 2 —O(C 1 -C 4 )alkyl, —O—SO 2 (C 1 -C 4 )alkyl, —NR5R6, —CONR5R6, —(C 1 -C 4 )alkyl optionally substituted by one or more —OH or —F and —O(C 1 -C 4 )alkyl optionally substituted by one or more —OH or —F, and wherein the cycles (C 3 -C 6 )cycloalkane, cyclohexene and bicycle can also be optionally substituted with one or more substituents oxo (═O); 
 R5 and R6 independently represent —H or —(C 1 -C 4 )alkyl;
 a heterocycle in the above definitions represents a five- or six-membered aromatic ring containing from one to three heteroatoms independently selected from O, S and N, wherein said ring can be attached to the rest of the molecule through a carbon or a nitrogen atom; and 
 a bicycle in the above definitions represents a partially unsaturated, saturated or aromatic seven- to ten-membered ring optionally containing from one to three heteroatoms independently selected from O, S and N, wherein said ring or rings can be attached to the rest of the molecule through a carbon or a nitrogen atom.