Dihydro-1,3,5-triazine amine derivatives and their therapeutic uses

Abstract

The invention relates to the compounds of general formula (I): in which R1, R2, R3, R4, R5 and R6 are as defined in claim 1. These compounds can be used in the treatment of pathological conditions associated with the insulin-resistance syndrome.

1 . A method for inhibiting the formation of advanced glycosylation end products (AGE) in a patient that has and is being treated for a neurodegenerative disease, comprising: administering to said patient in need thereof an effective amount of a compound of formula (I)  
       
         
           
           
               
               
           
         
       
       in which:  
       R1 and R2 are chosen independently from the groups: 
 H,  
 (C 1 -C 20 )alkyl,  
 wherein R3 and R4 are chosen independently from the groups  
 H,  
 (C 1 -C 20 )alkyl,  
 (C 2 -C 20 ) alkenyl,  
 R3 and R4 can form with the nitrogen atom an n-membered ring (n between 3 and 8) optionally comprising one or more heteroatoms chosen from N, O, S,  
 R5 and R6 are chosen independently from the groups:  
 H,  
 (C 1 -C 20 )alkyl optionally substituted with hydroxyl,  
 (C 3 -C 8 )cycloalkyl optionally substituted with (C 6 -C 14 ) aryl (C 1 -C 5 ) alkoxy,  
 (C 3 -C 8 )heterocycloalkyl carrying one or more heteroatoms chosen from N, O, S,  
 (C 6 -C 14 )aryl optionally substituted with hydroxyl,  
 (C 1 -C 13 )heteroaryl carrying one or more heteroatoms chosen from N, O, S,  
 (C 6 -C 14 )aryl(C 1 -C 5 )alkyl,  
 wherein R5 and R6 can form with the carbon atom to which they are attached an m-membered ring (m between 3 and 8) optionally comprising one or more heteroatoms chosen from N, O, S and being capable of being substituted with hydroxyl, (C 1 -C 5 )alkyl, (C 6 -C 14 ) aryl(C 1 -C 5 )alkoxy,  
 wherein when R1 and R2 represent a hydrogen, or R3 and R4 represent a hydrogen, then R3 and R4 or R1 and R2 are defined as above with the exception of hydrogen, or a form selected from the group consisting of tautomeric, enantiomeric, diastereo-isomeric and epimeric or the pharmaceutically acceptable salt thereof.  
 
     
     
         2 . A method for treating a neurodegenerative disease, comprising: administering to a patient in the need thereof an effective amount of a compound of formula (I)  
       
         
           
           
               
               
           
         
       
       in which:  
       R1 and R2 are chosen independently from the groups: 
 H,  
 (C 1 -C 20 )alkyl,  
 wherein R3 and R4 are chosen independently from the groups  
 H,  
 (C 1 -C 20 )alkyl,  
 (C 2 -C 20 ) alkenyl,  
 R3 and R4 can form with the nitrogen atom an n-membered ring (n between 3 and 8) optionally comprising one or more heteroatoms chosen from N, O, S,  
 R5 and R6 are chosen independently from the groups:  
 H,  
 (C 1 -C 20 )alkyl optionally substituted with hydroxyl,  
 (C 3 -C 8 )cycloalkyl optionally substituted with (C 6 -C 14 ) aryl (C 1 -C 5 ) alkoxy,  
 (C 3 -C 8 )heterocycloalkyl carrying one or more heteroatoms chosen from N, O, S,  
 (C 6 -C 14 )aryl optionally substituted with hydroxyl,  
 (C 1 -C 13 )heteroaryl carrying one or more heteroatoms chosen from N, O, S,  
 (C 6 -C 14 )aryl(C 1 -C 5 )alkyl,  
 wherein R5 and R6 can form with the carbon atom to which they are attached an m-membered ring (m between 3 and 8) optionally comprising one or more heteroatoms chosen from N, O, S and being capable of being substituted with hydroxyl, (C 1 -C 5 )alkyl, (C 6 -C 14 ) aryl(C 1 -C 5 )alkoxy,  
 wherein when R1 and R2 represent a hydrogen, or R3 and R4 represent a hydrogen, then R3 and R4 or R1 and R2 are defined as above with the exception of hydrogen, or a form selected from the group consisting of tautomeric, enantiomeric, diastereo-isomeric and epimeric form or the pharmaceutically acceptable salt thereof.  
 
     
     
         3 . A method for treating neurodegenerative diseases wherein the formation of advanced glycosylation end products (AGE) is implicated in a patient, comprising administering to said patient in need thereof an effective amount of a compound of formula (I)  
       
         
           
           
               
               
           
         
       
       in which:  
       R1 and R2 are chosen independently from the groups: 
 H,  
 (C 1 -C 20 )alkyl,  
 wherein R3 and R4 are chosen independently from the groups  
 H,  
 (C 1 -C 20 )alkyl,  
 (C 2 -C 20 ) alkenyl,  
 R3 and R4 can form with the nitrogen atom an n-membered ring (n between 3 and 8) optionally comprising one or more heteroatoms chosen from N, O, S,  
 R5 and R6 are chosen independently from the groups:  
 H,  
 (C 1 -C 20 )alkyl optionally substituted with hydroxyl,  
 (C 3 -C 8 )cycloalkyl optionally substituted with (C 6 -C 14 ) aryl (C 1 -C 5 ) alkoxy,  
 (C 3 -C 8 )heterocycloalkyl carrying one or more heteroatoms chosen from N, O, S,  
 (C 6 -C 14 )aryl optionally substituted with hydroxyl,  
 (C 1 -C 13 )heteroaryl carrying one or more heteroatoms chosen from N, O, S,  
 (C 6 -C 14 )aryl(C 1 -C 5 )alkyl,  
 wherein R5 and R6 can form with the carbon atom to which they are attached an m-membered ring (m between 3 and 8) optionally comprising one or more heteroatoms chosen from N, O, S and being capable of being substituted with hydroxyl, (C 1 -C 5 )alkyl, (C 6 -C 14 ) aryl(C 1 -C 5 )alkoxy,  
 wherein when R1 and R2 represent a hydrogen, or R3 and R4 represent a hydrogen, then R3 and R4 or R1 and R2 are defined as above with the exception of hydrogen, or a form selected from the group consisting of tautomeric, enantiomeric, diastereo-isomeric and epimeric or the pharmaceutically acceptable salt thereof.  
 
     
     
         4 . The method according to  claim 1 , wherein the compound is 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5 triazine or a form selected from the group consisting of tautomeric, enantiomeric, diastereoisomeric and epimeric or the pharmaceutically acceptable salt thereof.  
     
     
         5 . The method according to  claim 2 , wherein the compound is 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5 triazine or a form selected from the group consisting of tautomeric, enantiomeric, diastereoisomeric and epimeric or the pharmaceutically acceptable salt thereof.  
     
     
         6 . The method according to  claim 3 , wherein the compound is 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5 triazine or a form selected from the group consisting of tautomeric, enantiomeric, diastereoisomeric and epimeric or the pharmaceutically acceptable salt thereof.  
     
     
         7 . The method according to  claim 3 , wherein compound is of general formula (I):  
       
         
           
           
               
               
           
         
       
       in which:  
       R1 and R2 are chosen independently from the(C1-C20)alkyl;  
       R3 and R4 are H;  
       R5 is H;  
       R6 is (C1-C20)alkyl;  
       as well as the tautomeric, enantiomeric, diastereoisomeric and epimeric forms and the pharmaceutically acceptable salts.  
     
     
         8 . The compound of formula (I) according to  claim 1 , in which R1 is methyl.  
     
     
         9 . The compound of formula (I) according to  claim 1 , in which R2 is methyl.  
     
     
         10 . The compound of formula (I) according to  claim 1 , in which R6 is methyl.  
     
     
         11 . The compound of formula (I) according to  claim 1 , in which R1=R2=R6=methyl, R3=R4=R5=H as well as the tautomeric, enantiomeric, diastereoisomeric and epimeric forms and the pharmaceutically acceptable salts.