Aminothiazole derivatives, process for preparing them and pharmaceutical compositions containing them

Abstract

The subject of the invention is the compounds of formula: in which R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in Claim 1. The compounds have a high affinity for the CRF receptors.

1 . Compound of formula:  
       
         
           
           
               
               
           
         
       
       in which 
 R 1  and R 2 , which are identical or different, each represent independently a halogen atom; a (C 1 -C 5 )hydroxyalkyl; a (C 1 -C 5 )alkyl; an aralkyl in which the aryl part is a (C 6 -C 8 ) and the alkyl part is a (C 1 -C 4 ); a (C 1 -C 5 )alkoxy; a trifluoromethyl group; a nitro group; a nitrile group; a group —SR in which R represents hydrogen, a (C 1 -C 5 )alkyl or an aralkyl in which the aryl part is a (C 6 -C 8 ) and the alkyl part is a (C 1 -C 4 ); a group —S—CO—R in which R represents a (C 1 -C 5 )alkyl radical or an aralkyl in which the aryl part is a (C 6 -C 8 ) and the alkyl part is a (C 1 -C 4 ); a group —COORa in which Ra represents hydrogen or a (C 1 -C 5 )alkyl; a group —CONRaRb with Ra and Rb as defined above for Ra; a group —NRaRb with Ra and Rb as defined above for Ra; a group —CONRcRd or —NRcRd in which Rc and Rd constitute, with the nitrogen atom to which they are attached, a 5- to 7-membered heterocycle; or a group —NHCO—NRaRb with Ra and Rb as defined above for Ra;  
 R 3  represents hydrogen or is as defined above for R 1  and R 2 ;  
 R 4  represents a (C 1 -C 5 )alkyl; a hydroxymethyl group; a formyl group; or a halogen atom;  
 R 5  represents a (C 1 -C 5 )alkyl; a cycloalkylalkyl group in which the cycloalkyl is a (C 3 -C 7 ) and the alkyl is a (C 1 -C 5 ); an alkenyl of 3 to 6 carbon atoms; a (C 1 -C 5 )hydroxyalkyl; an alkylcarbonyloxyalkyl group in which the alkyls are a (C 1 -C 5 ); or an alkynyl group of 3 to 6 carbon atoms;  
 R 6  represents a phenyl substituted with one or more substituents Z as defined below; a monocyclic heteroaromatic C 5 -C 7  group substituted with one or more radicals Z as defined below; or a bicyclic C 9 -C 10  group consisting of an aromatic monocycle optionally comprising one or more heteroatoms selected from O, N and S, condensed with a cycloalkyl group optionally comprising in the ring one or more heteroatoms selected from O, N and S, which bicyclic group is substituted with one or more substituents Z as defined below and which is attached to the nitrogen by the ring of an aromatic nature, it being understood that R 6  does not represent a substituted indan and that the substituent Z represents a radical selected from: a halogen atom, a nitro group, a hydroxyl group, a trifluoromethyl group, a (C 1 -C 5 )alkyl, a (C 1 -C 5 )thioalkyl, a group —NRaRb with Ra and Rb as defined above for Ra, a (C 1 -C 5 )hydroxyalkyl, a (C 1 -C 5 )alkoxy, a trifluoromethyloxy group, an alkoxyalkyl in which the alkyls are a (C 1 -C 5 ), a group —COORa with Ra as defined above, a group —CONRaRb with Ra and Rb as defined above for Ra, a carboxy-(C 1 -C 5 )alkyl, an alkoxycarbonylalkyl in which the alkyls are a (C 1 -C 5 ), a (C 1 -C 5 )alkylcarbonyl, an alkylcarbonylalkyl in which the alkyls are a (C 1 -C 5 ), a morpholinocarbonyl or morpholinocarbonyl(C 1 -C 5 )alkyl group, or a group —NRaCOORb with Ra and Rb as defined above, a group —NHCORc in which Rc represents a (C 1 -C 8 )alkyl, a cycloalkylcarbonyl in which the cycloalkyl is a (C 3 -C 6 ), a cycloalkylalkylcarbonyl in which the cycloalkyl is a (C 3 -C 6 ) and the alkyl a (C 1 -C 3 ), a benzoyl, a phenyl which is unsubstituted or substituted with a (C 1 -C 5 )alkyl, with a (C 1 -C 5 )alkoxy, with a halogen atom, with a nitro group, with a hydroxyl group or with a trifluoromethyl group;  
 their stereoisomers, their addition salts, their hydrates and/or their solvates.  
 
     
     
         2 . Compound of formula (I) according to  claim 1 , in which R 6  represents a phenyl or tetrahydronaphthyl group substituted with one or more substituents Z as defined for (I), R 1 , R 2 , R 3 , R 4 , and R 5  also being as defined for (I), one of their stereoisomers, one of their salts, one of their hydrates and/or one of their solvates.  
     
     
         3 . Compound of formula (I) according to claims  1  and  2 , in which R 4  represents a methyl, R 1 , R 2 , R 3  and R 5  being as defined for (I), one of their stereoisomers, one of their hydrates and/or one of their solvates.  
     
     
         4 . Compound of formula (I) according to  claim 3 , in which R 1  and/or R 2  represents a halogen, a trifluoromethyl, a (C 1 -C 5 )alkyl or a (C 1 -C 5 )alkoxy, R 4  represents a methyl, R 6  represents a phenyl at least substituted at the 2 position with a substituent Z as defined for (I), R 3  and R 5  are as defined for (I), one of their stereoisomers, one of their salts, one of their hydrates and/or one of their solvates.  
     
     
         5 . Compounds of formula: 
 4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-ethoxycarbonyl -2-methoxyphenyl)-N-propylamino]thiazole    4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-chloro -2-methylphenyl)-N-propylamino]thiazole    4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-trifluoromethylphenyl)-N-propylamino]thiazole    4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-methoxyphenyl)-N-propylamino]thiazole    4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2,6-dichlorophenyl)-N-propylamino]thiazole    4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2,5-dichlorophenyl)-N-propylamino]thiazole    4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-chloro -5-methylphenyl)-N-propylamino]thiazole    4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-chloro -5-trifluoromethylphenyl)-N-propylamino]thiazole    4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-chloro -5-methoxyphenyl)-N-propylamino]thiazole    4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-chloro -2-methoxyphenyl)-N-propylamino]thiazole    4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-chloro -2-ethoxyphenyl)-N-propylamino]thiazole    4-(2-Chloro-4-methoxphenyl)-5-methyl-2-[N-(2-methoxy-5-methylphenyl)-N-propylamino]thiazole    4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2,5-dimethylphenyl)-N-propylamino]thiazole    4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2,5-difluoromethylphenyl)-N-propylamino]thiazole    4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-methoxy-5-trifluoromethylphenyl)-N-propylamino]thiazole    4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2,5-dimethoxyphenyl)-N-propylamino]thiazole    4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-methoxy-5-methoxycarbonylphenyl)-N-propylamino]thiazole    4-(2,4-Dichlorophenyl)-5-methyl-2-[N-(2,5-dichlorophenyl)-N-propylamino]thiazole    4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-acetyl -2-methoxyphenyl)-N-propylamino]thiazole    4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-(methoxy)-5-(phenyl)phenyl)-N-propylamino]thiazole    4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2,6-dimethoxyphenyl)-N-propylamino]thiazole    4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-methoxy-6-methylphenyl)-N-propylamino]thiazole    4-(2,4-Dichlorophenyl)-5-methyl-2-[N-(2-methoxy-6-methylphenyl)-N-propylamino]thiazole    4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-ethyl-2-methoxyphenyl)-N-propylamino]thiazole    4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-bromo-2-methoxyphenyl)-N-propylamino]thiazole    4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-methoxy-5-o-tolylphenyl)-N-propylamino]thiazole    4-(2,4,6-Trichlorophenyl)-5-methyl-2-[N-2,5-ditrifluoromethylphenyl)-N-propylamino]thiazole    4-(2,4-Dichlorophenyl)-5-methyl-2-[N-(2,5-ditrifluoromethylphenyl)-N-propylamino]thiazole    4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-methoxy-5-nitrophenyl)-N-propylamino]thiazole    4-(2,4-Dichlorophenyl)-5-methyl-2-[N-(2,6-dichloro-5-methylphenyl)-N-propylamino]thiazole    4-(2,4-Dichlorophenyl)-5-methyl-2-[N-(2-methoxy-6-methylphenyl)-N-propylamino]thiazole    4-(2,4-Dichlorophenyl)-5-methyl-2-[N-(5-chloro-2-methylphenyl)-N-propylamino]thiazole    4-(4-Chloro-2-trifluoromethylphenyl)-5-methyl-2-[N-(5-chloro-2-methylphenyl)-N-propylamino]thiazole    4-(2-Chloro-4-methoxy-5-methylphenyl)-5-methyl-2-[N-(2-methoxy-5-methylphenyl)-N-propylamino]thiazole    4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-methyl-thio-5-trifluoromethylphenyl)-N-propylamino]thiazole    4-(2,4-Dichloro-5-methylphenyl)-5-methyl-2-[N-(2-methoxy-5-methylphenyl)-N-propylamino]thiazole    4-(2-Chloro-4,5-dimethylphenyl)-5-methyl-2-[N-(2-methoxy-5-methylphenyl)-N-propylamino]thiazole    4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-methoxy-5-methoxycarbonylphenyl)-N-propylamino]thiazole    4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-chloro-2-methylphenyl)-N-prop-2-ynylamino]thiazole one of their stereoisomers, one of their salts, one of their hydrates and/or one of their solvates.    
     
     
         6 . Process for the preparation of the compounds of formula (I) according to  claim 1 , characterized in that alpha-halogenated derivative of formula (III)  
       
         
           
           
               
               
           
         
       
       in which R 1 , R 2 , R 3  and R 4  are as defined for (I) and Hal represents a halogen, preferably bromine or chlorine, atom, is reacted 
 either with a thiourea (ROUTE A) of formula:  
                     
 in which R 6  is as defined for (I) in order to obtain a compound of formula (II)  
                     
 in which R 1 , R 2 , R 3 , R 4  and R 6  are as defined for (I) in order to then subject it to an alkylation reaction in order to provide the compound (I),  
 or with a thiourea (ROUTE B) of formula  
                     
 in which R 5  and R 6  are as defined for (I) in order to give directly the compound (I),  
 and, where appropriate, the compounds of formula (I) thus obtained are then optionally separated into their possible stereoisomers and/or salified in order to form the corresponding salts.  
 
     
     
         7 . Use of the compounds of formula (I) according to any one of  claims 1  to  7 , for the preparation of a medicament which can be used in the treatment of diseases requiring modulation of the action of corticopropin releasing factor.  
     
     
         8 . Pharmaceutical composition containing, as active ingredient, at least one compound according to any one of  claims 1  to  7 , in the form of a base or in the form of a salt with a pharmaceutically acceptable inorganic or organic acid, in combination with or mixed with a pharmaceutically acceptable nontoxic inert excipient.  
     
     
         9 . Pharmaceutical composition according to  claim 10 , in the form of dosage units, in which the active ingredient is mixed with at least one pharmaceutical excipient.  
     
     
         10 . Composition according to  claim 11 , in which each dosage unit contains from 0.5 to 800 mg of active ingredient.  
     
     
         11 . Composition according to  claim 12 , in which each dosage unit contains from 0.5 to 200 mg of active ingredient.  
     
     
         12 . Pharmaceutical composition containing a compound according to  claims 1  to  7  in combination with another anxiolytic, antidepressant or anorexigenic active ingredient.