Thiazolylimidazole derivatives an their use as inhibitors of microsomal triglyceride transfer protein

Abstract

The present invention relates to thiazolylimidazole derivatives of the general formula (I) in which: G represents a bond or a divalent radical chosen from the groups g1, g2 and g3; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Y and Z are as defined in the description. Application of the compounds of the formula (I) to the treatment of hypertriglyceridaemia, hypercholesterolaemia and dyslipidaemia.

1 . A process for the preparation of a compound of formula (I): 
     
       
         
         
             
             
         
       
       in which:
 G represents a bond or a divalent radical chosen from the groups g1, g2 and g3 below: 
 
     
     
       
         
         
             
             
         
       
       
         R 1  is chosen from hydrogen and an alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcarbonyl or alkoxycarbonyl radical; 
         R 2  and R 3 , which may be identical or different, are chosen, independently of each other, from a hydrogen atom, an alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl radical and a radical —NRR′; 
         R 4 , R 5  and R 6 , which may be identical or different, are chosen, independently of each other, from a hydrogen atom and an alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl radical; 
         R and R′, which may be identical or different, represent, independently of each other, a hydrogen atom or a radical chosen from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; or together form, with the nitrogen atom that bears them, a heterocycle, or together form the double bond of an alken-1-yl radical; 
         Y represents an oxygen or sulfur atom; and 
         Z represents —NH— or an oxygen atom; 
       
       comprising reacting a compound of the formula (II): 
     
     
       
         
         
             
             
         
       
       in which T represents a labile protecting group, with ethyl R 3 -bromopyruvate, in a polar solvent, in the presence of an excess of base, at a suitable temperature, for a period ranging from 1 to 40 hours, 
       so as to form a thiazolyl ring and produce a compound of formula (III): 
     
     
       
         
         
             
             
         
       
       saponifying the compound of the formula (III) with an alkali metal or alkaline-earth metal hydroxide base, in polar medium, at room temperature, for a period of 1 to 12 hours, so as to form a salt of formula (IV): 
     
     
       
         
         
             
             
         
       
     
     in which M +  represents the alkali metal or alkaline-earth metal cation derived from the base that is used for the saponification reaction,
 hydrolyzing the compound of formula (IV) to a compound of formula (V): 
 
     
       
         
         
             
             
         
       
       converting the compound of formula (V) to a corresponding amide of formula (VI): 
     
     
       
         
         
             
             
         
       
       via the action of an amine of formula (VIa): 
     
     
       
         
         
             
             
         
       
       in the presence of a base, and a catalyst, in a polar aprotic solvent, at room temperature, for 1 to 50 hours, 
       deprotecting of the amine function of the piperidine ring of VI, via the action of an organic or mineral acid, in dichloromethane or dioxane medium, at room temperature, for a few minutes to several hours, to give a compound of formula (VII): 
     
     
       
         
         
             
             
         
       
       subjecting said compound VII to the action of: 
     
     
       
         
         
             
             
         
       
       in which X represents a halogen atom, 
       in the presence of a base, and a catalyst, in a polar aprotic solvent, at room temperature, for 1 to 50 hours, 
       to give a compound of the formula (VIII): 
     
     
       
         
         
             
             
         
       
       and subjecting VIII to a cyclization reaction to form an imidazole ring, in the presence of a cyclizing agent, acting as a solvent, at a suitable temperature, 
       to give a compound of the formula (I). 
     
   
   
       2 . The process according to  claim 1 , in which the radical R 2  represents hydrogen. 
   
   
       3 . The process according to  claim 1 , in which the radical R 3  represents hydrogen. 
   
   
       4 . The process according to  claim 1 , in which the radicals R 4  and R 5 , independently of each other, represent an alkyl radical. 
   
   
       5 . The process according to  claim 1 , in which the radical R 6  represents an aryl or heteroaryl radical. 
   
   
       6 . The process according to  claim 1 , in which in which the thiazolyl radical is branched in position 3 or in position 4 of the piperidine nucleus. 
   
   
       7 . The process according to  claim 1 , in which the thiazolyl radical is branched in position 4 of the piperidine nucleus. 
   
   
       8 . The process according to  claim 1 , in which G represents the radical g1. 
   
   
       9 . The process according to  claim 1 , in which G represents the radical g1 and Y represents an oxygen atom. 
   
   
       10 . The process according to  claim 1 , in which the radicals R 2  and R 3  each represent a hydrogen atom, the radicals R 4  and R 5  represent, independently of each other, an alkyl radical, the radical R 6  represents an aryl or heteroaryl radical, the thiazolyl radical is branched in position 4 of the piperidine nucleus, and G represents the radical g1 in which Y represents an oxygen atom. 
   
   
       11 . The process according to  claim 1 , in which R 1  represents an aryl radical, especially phenyl, substituted by one or more aryl and/or alkyl radicals. 
   
   
       12 . The process according to  claim 1 , in which R 1  represents a biphenyl radical, optionally substituted by one or more alkyl radicals, preferably methyl, ethyl or propyl, and/or with a perhaloalkyl or perhaloalkoxy radical. 
   
   
       13 . The process according to  claim 1 , in which G represents the radical g1, with Y representing an oxygen atom, R 1  represents a biphenyl radical, optionally substituted by one or more alkyl radicals. 
   
   
       14 . The process according  claim 1 , wherein the compound of formula I is
 {4-[4-(1,5-dimethyl-4-phenyl-1H-imidazol-2-yl)thiazol-2-yl]piperid-1-yl}(4′-trifluoromethylbiphenyl-2-yl)methanone;   {4-[4-(1-ethyl-5-methyl-4-phenyl-1H-imidazol-2-yl)thiazol-2-yl]piperid-1-yl}(4′-trifluoromethylbiphenyl-2-yl)methanone;   {3-[4-(1-ethyl-5-methyl-4-phenyl-1H-imidazol-2-yl)thiazol-2-yl]piperid-1-yl}(4′-trifluoromethylbiphenyl-2-yl)methanone;   {4-[4-(1-ethyl-5-methyl-4-phenyl-1H-imidazol-2-yl)thiazol-2-yl]piperid-1-yl}(6-methyl-4′-trifluoromethoxybiphenyl-2-yl)methanone;   {4-[4-(1-ethyl-5-methyl-4-(pyrid-3-yl)-1H-imidazol-2-yl)thiazol-2-yl]piperid-1-yl}(4′-trifluoromethylbiphenyl-2-yl)methanone;   {4-[4-(1-ethyl-5-methyl-4-(pyrid-2-yl)-1H-imidazol-2-yl)thiazol-2-yl]piperid-1-yl}(4′-trifluoromethylbiphenyl-2-yl)methanone; or   {4-[4-(1-ethyl-5-methyl-4-(pyrid-2-yl)-1H-imidazol-2-yl)thiazol-2-yl]piperid-1-yl}(6-methyl-4′-trifluoromethoxybiphenyl-2-yl)methanone.   
   
   
       15 . (canceled) 
   
   
       16 . (canceled) 
   
   
       17 . (canceled)