Novel arylpiperazine derivatives

Abstract

Compounds of the general formula (I) below: are provided along with a process for preparing them, and these compounds may be used as therapeutic agents, e.g., for prevention and/or treatment of a neuropsychiatric illness or any illness involving the dopamine D3 receptor.

1 . Compounds of the formula (I): 
       
         
           
           
               
               
           
         
       
       in which:
 R1 represents a heteroaryl with five or six chain links, containing one or more heteroatoms, selected from among 2-pyridyl, 2-pyrimidinyl, 2-pyridazinyl, 2-pyrazinyl, 2-imidazolyl, 2-oxazolyl, 2-thiazolyl, 3-isoxazolyl, 3-isothiazolyl, 1,2,4-triazol-2-yl, 1,3,4-oxadiazol-2-yl, 1,3,4-thiadiazol-2-yl, optionally substituted, in addition to its two attachments, by one or more identical or different groups selected from among a halogen atom or a hydroxy, alkyl, monofluoroalkyl, polyfluoroalkyl, alkoxy, polyfluoroalkoxy, alkylsulfanyl, polyfluoroalkylsulfanyl group; 
 Ar is an aryl or heteroaryl fused with R1 and optionally substituted by one or more identical or different substituents selected from among a halogen atom or alkyl, monofluoroalkyl, polyfluoroalkyl, alkoxy, polyfluoroalkoxy, alkylsulfanyl, polyfluoroalkylsulfanyl, cyano, carbamoyl, dialkylcarbamoyl, alkyl-C(═O)—, alkyl-O—C(═O)—, HO—C(═O)—, (HO)alkyl group; 
 a=2, 3 or 4; 
 b and c, identical or different, represent 1 or 2; 
 R2, R3, R4, R5 and R6 each independently represent a hydrogen or halogen atom or a hydroxy, alkyl, monofluoroalkyl, polyfluoroalkyl, alkoxy, polyfluoroalkoxy, alkylsulfanyl, polyfluoroalkylsulfanyl, cyano, —NRR′, —COOR, —COR, —CONRR′ group or alternatively two adjacent R2, R3, R4, R5 and R6 are joined to one another to form a hydrocarbon cycle or a saturated or unsaturated heterocycle, fused to the phenyl nucleus to which they are attached; 
 where R, R′, identical or different, independently represent a hydrogen atom, or an alkyl group; 
 together with stereoisomers or mixtures thereof, the tautomeric forms thereof, the pharmaceutically acceptable salts thereof, 
 with the exception of those compounds for which: 
 R1 represents a 2-oxazolyl, 2-imidazolyl or 2-thiazolyl fused to the Ar group=optionally substituted phenyl, 
 and compounds for which: 
 R1 represents a 2-pyridyl group, fused to the Ar group=phenyl optionally substituted by Me in position 4 of the resultant quinoline cycle, a=2, b=c=1, R2=H, OMe and R3—R6=H or R2=R3=Me and R4—R6=H; 
 R1 represents a 2-pyrimidinyl group, fused to the Ar group=phenyl substituted by OMe in positions 6 and 7 and —OH in position 4 or 6 of the resultant quinazolinyl cycle, a=2, b=c=1, R2=R3=R4=R5=H and R6=OMe. 
 
     
     
         2 . Compounds according to  claim 1  such that R1 represents 2-pyridyl. 
     
     
         3 . Compounds according to  claim 1  such that Ar is an aryl fused with R1, and optionally substituted by one or more identical or different substituents selected from among a halogen atom or an alkyl group. 
     
     
         4 . Compounds according to  claim 1  such that a=3. 
     
     
         5 . Compounds according to  claim 1  such that b and c represent 1. 
     
     
         6 . Compounds according to  claim 1  such that R2, R3, R4, R5 and R6 each independently represent a hydrogen or halogen atom or a polyfluoroalkyl group. 
     
     
         7 . Compounds according to  claim 1  selected from among: 
       2-{4-[4-(3-trifluoromethylphenyl)piperazin-1-yl]butyl}aminoquinoline hydrochloride 
       1-{4-[4-(3-trifluoromethylphenyl)piperazin-1-yl]butyl}aminoisoquinoline hydrochloride 
       2-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl}aminoquinoline hydrochloride 
       1-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl}aminoisoquinoline hydrochloride, together with the stereoisomers or mixtures thereof, the tautomeric forms thereof, the pharmaceutically acceptable salts, free forms thereof. 
     
     
         8 . A process for preparing a compound according to  claim 1  comprising the step of preparing said compound using a starting compound corresponding to the compound of the formula (III): 
       
         
           
           
               
               
           
         
       
       where, in the formula (III), R2, R3, R4, R5, R6, a, b and c have the same meaning as in the formula (I). 
     
     
         9 . A process according to  claim 8  such that said compound of the formula (III) is coupled with a corresponding compound of the formula (II): 
       
         
           
           
               
               
           
         
       
       where Ar and R1 are as defined in the formula (I). 
     
     
         10 . A process according to  claim 9  such that said coupling reaction is performed by heating to 300-350° C. or by heating in a microwave oven. 
     
     
         11 . A process for preparing a compound according to  claim 1  comprising the step of preparing said compound using a starting compound corresponding to the compound of the formula (VI): 
       
         
           
           
               
               
           
         
       
       such that R1 as defined in the formula (I) is represented by the formula: 
       
         
           
           
               
               
           
         
       
       and A independently represents a carbon or nitrogen atom, 
       where Ar, R2, R3, R4, R5, R6, a, b, c are defined as in the formula (I). 
     
     
         12 . A process according to  claim 11 , such that the N-oxide function is reduced. 
     
     
         13 . A process according to  claim 8  further comprising the step of isolating the resultant product of the formula (I). 
     
     
         14 . A pharmaceutical composition, comprising a therapeutically effective quantity of at least one derivative according to  claim 1 , in the form of a pharmaceutically acceptable salt or free form r with a pharmaceutically acceptable vehicle or excipient. 
     
     
         15 . Use of a compound of the general formula (I): 
       
         
           
           
               
               
           
         
       
       in which:
 R1 represents a heteroaryl with five or six chain links, containing one or more heteroatoms, selected from among 2-pyridyl, 2-pyrimidinyl, 2-pyridazinyl, 2-pyrazinyl, 2-imidazolyl, 2-oxazolyl, 2-thiazolyl, 3-isoxazolyl, 3-isothiazolyl, 1,2,4-triazol-2-yl, 1,3,4-oxadiazol-2-yl, 1,3,4-thiadiazol-2-yl, optionally substituted, in addition to its two attachments, by one or more identical or different groups selected from among a halogen atom or a hydroxy, alkyl, monofluoroalkyl, polyfluoroalkyl, alkoxy, polyfluoroalkoxy, alkylsulfanyl, polyfluoroalkylsulfanyl group; 
 Ar is an aryl or heteroaryl fused with R1 and optionally substituted by one or more identical or different substituents selected from among a halogen atom or a hydroxy, alkyl, monofluoroalkyl, polyfluoroalkyl, alkoxy, polyfluoroalkoxy, alkylsulfanyl, polyfluoroalkylsulfanyl, cyano, carbamoyl, dialkylcarbamoyl, alkylC(═O)—, alkyl-O—C(═O)—, HO—C(═O)—, (HO)alkyl group, or Ar is an aryl or heteroaryl fused with a saturated, unsaturated or aromatic hydrocarbon cycle or heterocycle; 
 a=2, 3 or 4; 
 b and c, identical or different, represent 1 or 2; 
 R2, R3, R4, R5 and R6 each independently represent a hydrogen or halogen atom or a hydroxy, alkyl, monofluoroalkyl, polyfluoroalkyl, alkoxy, polyfluoroalkoxy, alkylsulfanyl, polyfluoroalkylsulfanyl, cyano, —NRR′, —COOR, —COR, —CONRR′ group or alternatively two adjacent R2, R3, R4, R5 and R6 are joined to one another to form a hydrocarbon cycle or a saturated or unsaturated heterocycle, fused to the phenyl nucleus to which they are attached; 
 where R, R′, identical or different, independently represent a hydrogen atom, or an alkyl group; 
 together with stereoisomers or mixtures thereof, the tautomeric forms thereof, the pharmaceutically acceptable salts thereof, 
 with the exception of those compounds for which: 
 R1 represents a 2-pyridyl group, fused to the group Ar=phenyl, a=2, b=c=1, R2=H, OMe and R3—R6=H or R2=R3=Me and R4—R6=H, 
 for the preparation of pharmaceutical compositions intended to act as a ligand for the dopamine D3 receptor. 
 
     
     
         16 . Use of a compound of the general formula (I) as defined according to  claim 1  for preparing pharmaceutical compositions intended for preventing and/or treating a neuropsychiatric illness. 
     
     
         17 . Use of a compound of the general formula (I) as defined according to  claim 1  for preparing pharmaceutical compositions intended for preventing and/or treating illnesses involving the dopamine D3 receptor. 
     
     
         18 . Use according to  claim 17  such that said illness is selected from among drug dependency, sexual disorders, motor disorders, Parkinson's disease, psychosis or psychotic states, depression or drug dependency. 
     
     
         19 . Use according to  claim 17 , such that said drug dependency comprises any state associated with drawal, abstinence and/or detoxification of an individual dependent on any agent, in particular therapeutically active agents; such as opioids, and/or drugs such as cocaine, heroin, or alternatively alcohol and/or nicotine. 
     
     
         20 . Use according to  claim 17  such that said sexual disorders comprise impotence, in particular male impotence. 
     
     
         21 . Use according to  claim 17  such that said prevention and/or treatment of Parkinson's disease is an adjunct therapy for Parkinson's disease. 
     
     
         22 . Use according to  claim 17 , such that said motor disorders comprise essential or iatrogenic dyskinesia, and/or essential or iatrogenic tremor.