Combination of triazine derivatives and insulin sensitisers

Abstract

The present invention relates to combinations of triazine derivatives and of insulin sensitisers.

1 . Pharmaceutical composition comprising, as active principle:
 i) an insulin sensitiser, wherein the insulin sensitiser is a glitazone (TZD), and   ii) a compound of the formula (I)   
       in combination with one or more pharmaceutically acceptable excipients 
       
         
           
           
               
               
           
         
       
       in which: 
       R1, R2, R3 and R4 are independently chosen from the following groups:
 H, 
 (C1-C20)alkyl optionally substituted by (C1-C5)alkyl, 
 (C2-C20)alkenyl, or 
 (C6-C14)aryl(C1-C20)alkyl, 
 or R1 and R2, on the one hand, and R3 and R4, on the other hand, possibly forming with the nitrogen atom an n-membered ring with n being between 3 and 8, 
 R5 and R6 are independently chosen from the following groups: 
 H, 
 (C1-C20)alkyl optionally substituted by hydroxyl, halogen, (C1-C5)alkyl or trifluoromethyl, 
 (C3-C8)cycloalkyl, 
 (C6-C14)aryl optionally substituted by hydroxyl or (C1-C5)alkoxy, 
 (C1-C13)heteroaryl bearing one or more heteroatoms chosen from N, O and S, or 
 (C6-C14)aryl(C1-C5)alkyl, 
 or R5 and R6 possibly forming with the carbon atom to which they are attached an m-membered ring with m being between 3 and 8, optionally containing one or more heteroatoms chosen from N, O and S and optionally being substituted by hydroxyl, (C1-C5)alkyl, or (C6-C14)aryl(C1-C5)alkoxy, 
 
       or R5 and R6 forming with the carbon atom a C10-C30 polycyclic residue optionally substituted by hydroxyl, (C1-C5)alkyl, carboxyl, carboxymethyl or carboxyethyl,
 or a racemic form, tautomer, enantiomer, diastereoisomer, epimer or polymorph thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . The pharmaceutical composition according to  claim 1 , comprising a compound of the formula (I) in which R5 is hydrogen. 
     
     
         3 . The pharmaceutical composition according to  claim 1 , comprising a compound of the formula (I) in which R5 and R6 are independently chosen from H and (C1-C20)alkyl groups optionally substituted by hydroxyl, halogen, (C1-C5)alkyl, (C6-C14)aryloxy or trifluoromethyl. 
     
     
         4 . The pharmaceutical composition according to  claim 1 , wherein R1, R2, R3 and R4 are independently chosen from H and (C1-C20)alkyl groups optionally substituted by (C1-C5)alkyl. 
     
     
         5 . (canceled) 
     
     
         6 . The pharmaceutical composition according to  claim 1 , comprising a compound of the formula (I) in which R1 and R2 are a methyl group and R3 and R4 represent a hydrogen. 
     
     
         7 . The pharmaceutical composition according to  claim 1 , wherein the compound of formula (I) is 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine, or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The pharmaceutical composition according to  claim 1 , wherein the compound of formula (I) is (−)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine, or a pharmaceutically acceptable salt thereof. 
     
     
         9 . The pharmaceutical composition according to  claim 1 , wherein the compound of formula (I) is (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine, or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The pharmaceutical composition according to  claim 1 , wherein the compound of the formula (I) is in the form of a hydrochloride salt. 
     
     
         11 - 12 . (canceled) 
     
     
         13 . The pharmaceutical composition according to  claim 1 , wherein the insulin sensitiser is selected from the group consisting of rosiglitazone and pioglitazone. 
     
     
         14 . (canceled) 
     
     
         15 . The pharmaceutical composition according to  claim 1 , wherein the insulin sensitiser is in the form of a pharmaceutically acceptable salt. 
     
     
         16 . The pharmaceutical composition according to  claim 1 , wherein the composition contains between 0.5 mg and 50 mg of insulin sensitiser. 
     
     
         17 . The pharmaceutical composition according to  claim 1 , wherein the composition contains between 200 mg and 2000 mg of compound of the formula (I). 
     
     
         18 . The pharmaceutical composition according to  claim 1 , wherein the weight ratio of insulin sensitiser to the compound of the formula (I) is between 1/2 and 1/2000. 
     
     
         19 . The pharmaceutical composition according to  claim 1 , wherein the insulin sensitiser is rosiglitazone and the compound of the formula (I) is (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine, or its hydrochloride salt. 
     
     
         20 . The pharmaceutical composition according to  claim 1 , wherein the insulin sensitiser is pioglitazone and the compound of the formula (I) is (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine or its hydrochloride salt. 
     
     
         21 - 22 . (canceled) 
     
     
         23 . The pharmaceutical composition according to  claim 1 , which is suitable for oral administration, in which the pharmaceutical composition is a powder, a coated tablet, a gel capsule, a sachet, a solution, a suspension or an emulsion. 
     
     
         24 . A method for the treatment of diabetes comprising administering an insulin sensitiser, wherein the insulin sensitiser is a glitazone (TZD) in combination with a compound of the formula (I) according to  claim 1 . 
     
     
         25 . The method according to  claim 24 , for the treatment of non-insulin-dependent diabetes. 
     
     
         26 . A method for the treatment of at least one of the pathologies associated with insulin resistance syndrome, selected from the group consisting of dyslipidaemia, obesity, arterial hypertension, and microvascular and macrovascular complications, comprising administering an insulin sensitiser, wherein the insulin sensitiser is a glitazone (TZD), in combination with a compound of formula (I) according to  claim 1 . 
     
     
         27 . The method according to  claim 24 , wherein the insulin sensitiser is selected from the group consisting of rosiglitazone and pioglitazone. 
     
     
         28 . (canceled) 
     
     
         29 . The method according to  claim 24 , wherein the administration of the compound of formula (I) and that of the insulin sensitiser are simultaneous, separate or sequential. 
     
     
         30 . A kit comprising a compound of the formula (I) and an insulin sensitiser, for simultaneous, separate or sequential administration wherein the insulin sensitiser is a glitazone and formula (I) is as follows: 
       
         
           
           
               
               
           
         
       
       in which: 
       R1, R2. R3 and R4 are independently chosen from the following groups:
 H, 
 C1-C20)alkyl optionally substituted by (C1-C5)alkyl, 
 (C2-C20)alkenyl, 
 (C6-C14)aryl(C1-C20)alkyl, 
 or R1 and R2, on the one hand, and R3 and R4, on the other hand, possibly forming with the nitrogen atom an n-membered ring with n being between 3 and 8, 
 R5 and R6 are independently chosen from the following groups: 
 H, 
 (C1-C20)alkyl optionally substituted by hydroxyl, halogen, (C1-C5)alkyl or trifluoromethyl, 
 (C3-C8)cycloalkyl, 
 (C6-C14)aryl optionally substituted by hydroxyl or (C1-C5)alkoxy, 
 (C1-C13)heteroaryl bearing one or more heteroatoms chosen from N, O and S or 
 (C6-C14)aryl(C1-C5)alkyl, 
 or R5 and R6 possibly forming with the carbon atom to which they are attached an m-membered ring with m being between 3 and 8, optionally containing one or more heteroatoms chosen from N, O and S and optionally being substituted by hydroxyl, (C1-C5)alkyl, or (C6-C14)aryl(C1-C5)alkoxy, 
 
       or R5 and R6 forming with the carbon atom a C10-C30 polycyclic residue optionally substituted by hydroxyl, (C1-C5)alkyl, carboxyl, carboxymethyl or carboxyethyl,
 or a racemic form, tautomer, enantiomer, diastereoisomer, epimer or polymorph thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof.