Substituted 1-(piperidin-4-YL)-3-(aryl)-isothioureas, their preparation and therapeutic use

Abstract

The invention concerns compounds of formula (I) wherein: R1 and R2, identical or different, represent a saturated or unsaturated alkyl radical, branched or not and containing 1 to 7 carbon atoms; R3 to R8, identical or different, represent a hydrogen, an alkyl branched or not and containing 1 to 5 carbon atoms, an acyloxy, branched or not and containing 1 to 5 carbon atoms, a halogeno, nitro, hydroxy, acyl or alkoxy group containing 1 to 5 carbon atoms, a dialkylamino group containing 1 to 5 carbon atoms, a trifluoromethyl or trifluoro methoxyl group; Z represents an oxygen or sulphur atom or methylene; m represents an integer between 0 and 4 inclusively; n represents an integer between 2 and 7 inclusively; and their pure enantiomers and mixtures, the therapeutically acceptable mineral or organic salts of the compounds of formula (I) and their possible hydrates.

1 . Novel 1,2-dialkyl-1-[1-(aryl(alkyl)oxyalkyl)-piperidin-4-yl]-3-arylisothiourea of formula I:  
       
         
           
           
               
               
           
         
       
       in which: 
 R 1  and R 2 , which are identical or different, represent a saturated or unsaturated and branched or unbranched alkyl radical having from 1 to 7 carbon atoms,  
 R 3  to R 8 , which are identical or different, represent: 
 a hydrogen,  
 a branched or unbranched alkyl having 1 to 5 carbon atoms,  
 a branched or unbranched alkyloxy having 1 to 5 carbon atoms,  
 a halo group,  
 a nitro group,  
 a hydroxyl group,  
 an acyl or acyloxy group comprising 1 to 5 carbon atoms,  
 a dialkylamino group having 1 to 5 carbon atoms,  
 a trifluoromethyl or trifluoromethoxyl group,  
 
 Z represents an oxygen or sulfur atom or a methylene,  
 m represents an integer varying from 0 to 4 inclusive,  
 n represents an integer of between 2 and 7 inclusive;  
 and their pure enantiomers and their mixtures, and the therapeutically acceptable organic or inorganic salts of the compounds of formula I and their possible hydrates.  
 
     
     
         2 . Compound according to  claim 1 , characterized in that it is chosen from the following compounds: 
 1,2-Dimethyl-3-phenyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]isothiourea hydrogen fumarate.    2-Ethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-1-methyl-3-phenylisothiourea hydrogen fumarate.    1-Ethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-2-methyl-3-phenylisothiourea hydrogen fumarate.    1-Isobutyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-2-methyl-3-phenylisothiourea hydrogen fumarate.    1,2-Dimethyl-1-[1-[5-(3,4-difluorophenoxy)pentyl]piperidin-4-yl]-3-phenylisothiourea hydrogen fumarate.    1,2-Dimethyl-1-[1-[3-(3,4-difluorophenoxy)propyl]piperidin-4-yl]-3-phenylisothiourea hydrogen fumarate.    1,2-Dimethyl-1-[1-[4-(4-fluorophenoxy)butyl]piperidin-4-yl]-3-phenylisothiourea hydrogen fumarate.    1,2-Dimethyl-1-[1-[2-(4-fluorophenoxy)ethyl]piperidin-4-yl]-3-phenylisothiourea hydrogen fumarate.    1,2-Dimethyl-1-[1-[4-(4-methoxyphenoxy)butyl]piperidin-4-yl]-3-phenylisothiourea hydrogen fumarate.    1,2-Dimethyl-1-[1-[4-(3,4-dimethylphenoxy)butyl]piperidin-4-yl]-3-phenylisothiourea hydrogen fumarate.    1,2-Dimethyl-1-[1-[4-(2-methoxy-4-chlorophenoxy)butyl]piperidin-4-yl]-3-phenylisothiourea hydrogen fumarate.    1,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(2-fluorophenyl)isothiourea hydrogen fumarate.    1,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(4-fluorophenyl)isothiourea hydrogen fumarate.    1,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(4-chlorophenyl)isothiourea hydrogen fumarate.    1,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(4-methylphenyl)isothiourea hydrogen fumarate.    1,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(4-methoxyphenyl)isothiourea hydrogen fumarate.    1,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(2,6-dimethylphenyl)isothiourea hydrogen fumarate.    1,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-[2,6-diisopropylphenyl]isothiourea hydrogen fumarate.    1,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(3-fluorophenyl)isothiourea hydrogen fumarate.    1,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(4-nitrophenyl)isothiourea hydrogen fumarate.    1,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(2,6-difluorophenyl)isothiourea hydrogen fumarate.    1,2-Dimethyl-1-[1-[3-[2-(4-fluorophenyl)ethoxy]propyl]piperidin-4-yl]-3-phenylisothiourea hydrogen fumarate.    
     
     
         3 . Process for the preparation of the chemical compounds of formula I according to claims  1  and  2 , characterized in that an isothiocyanate of formula (III):  
       
         
           
           
               
               
           
         
       
       is reacted with a diamine of formula (II):  
       
         
           
           
               
               
           
         
       
       in a protic solvent, such as ethanol, or an aprotic solvent, such as THF or dioxane, by heating or not heating at reflux, to give the intermediate thiourea of formula (IV):  
       
         
           
           
               
               
           
         
       
       which is subsequently S-alkylated with a halide R 1 Br or R 1 I or an alkyl sulfate (R 1 ) 2 SO 4  in a protic solvent, such as alcohol, or an aprotic solvent, such as THF, DMF or ethyl acetate, in the presence or in the absence of lime at a temperature of between 20 and 60° C., to give the compound I of the present invention. 
 In the formulae II, III and IV, the R 1  to R 8  and Z radicals and the numbers m and n have the same values as in  claim 1 .  
 
     
     
         4 . As novel of medicaments, the compounds defined according to either are claims  1  and  2 .  
     
     
         5 . Pharmaceutical composition, characterized in that it comprises, as active principle, at least one compound according to claims  1 ,  2  and  4  in combination with an inert pharmaceutical excipient or other pharmaceutically acceptable vehicles which may or may not be used in combination with another medicament.  
     
     
         6 . Pharmaceutical composition according to  claim 5  of use in the prophylactic treatment of myocardial ischemia, such as crises of chronic stable angina, unstable and Prinzmetal's angina, silent ischemia, reinfarctus, reocclusion and restenosis.  
     
     
         7 . Pharmaceutical composition according to  claim 5 , of use in cerebral ischemia, strokes, transitory ischemic attack and neurodegenerative diseases.  
     
     
         8 . Pharmaceutical composition according to  claim 5 , characterized in that it makes it possible to prevent and to treat atherosclerosis.  
     
     
         9 . Pharmaceutical composition according to  claim 5 , characterized in that it makes it possible to treat cardiac insufficiency and hypertension.  
     
     
         10 . Pharmaceutical composition according to  claim 5 , characterized in that it makes it possible to treat epilepsy, migraine and pain.