1-Phenyl-4-benzylpiperazines dopamine receptor subtype specific ligands

Abstract

Disclosed are compounds of the formula: or the pharmaceutically acceptable addition salts thereof wherein: R 1 is halogen or C 1 -C 4 alkyl; and R 2 and R 3 are the same or different and represent hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, alkylthio, hydroxy, amino, mono(C 1 -C 4 )alkylamino, di(C 1 -C 4 )alkylamino, or R 2 and R 3 together represent a 4 carbon alkenylene moiety that together with the phenyl ring to which they are attached form a naphthyl moiety, which compounds are useful in the treatment of neuropsycological diseases such as schizophrenia, psychotic depression and mania.

What is claimed is:  
     
         1 . A compounds of the formula:  
       
         
           
           
               
               
           
         
       
       or the pharmaceutically acceptable acid salts thereof wherein: 
 R 1  is halogen or C 1 -C 4  alkyl;  
 R 2  and R 3  are the same or different and represent hydrogen, halogen, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, alkylthio, hydroxy, amino, monoalkylamino or dialkylamino,  
  with the proviso that R 2  and R 3  may not be 2-isopropoxyl and hydrogen respectively when R 1  is bromo.  
 
     
     
         2 . A compound according to  claim 1 , wherein R 1  is methyl.  
     
     
         3 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       or the pharmaceutically acceptable salts thereof wherein 
 R x  is fluorine, chlorine, bromine, or iodine; and  
 R 2  and R 3  are the same or different and represent hydrogen, halogen, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, alkylthio, hydroxy, amino, monoalkylamino or dialkylamino.  
 
     
     
         4 . A compound according to  claim 3 , wherein R 2  and R 3  may not be 2-isopropoxyl and hydrogen, respectively, when R 1  is bromo.  
     
     
         5 . A compound according to  claim 3 , wherein R x  is chloride; R 2  and R 3  may not be 2-isopropoxyl and hydrogen, respectively, when R 1  is bromo; R 2  is chloride, methyl or methoxy; and R 3  is hydrogen or methyl.  
     
     
         6 . A compound according to  claim 5 , wherein the phenyl group substituted with R 2  and R 3  is selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
     
     
         7 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       or the pharmaceutically acceptable salts thereof wherein 
 R a  is C 1 -C 4  alkyl; and  
 R 2  and R 3  are the same or different and represent hydrogen, halogen, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, alkylthio, hydroxy, amino, monoalkylamino or dialkylamino.  
 
     
     
         8 . A compound according to  claim 7 , wherein R 1  is methyl.  
     
     
         9 . A compound of according to  claim 1 , wherein R 2  is chloride, fluoride, methyl or methoxy; and R 3  is hydrogen or methyl.  
     
     
         10 . A compound according to  claim 8 , wherein the phenyl group substituted with R 2  and R 3  is selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
     
     
         11 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       or the pharmaceutically acceptable salts thereof wherein: 
 R 1  is C 1 -C 4  alkyl or halogen.  
 
     
     
         12 . A compound according to  claim 11 , wherein R 1  is chloro.  
     
     
         13 . A compound according to  claim 1 , which is 1-(3-chlorophenyl)-4-(4-chlorobenzyl)piperazine.  
     
     
         14 . A compound according to  claim 1 , which is 1-(2-chlorophenyl)-4-(4-chlorobenzyl)piperazine.  
     
     
         15 . A compound according to  claim 1 , which is 1-3,4-dichlorophenyl)-4-(4-chlorobenzyl)piperazine.  
     
     
         16 . A compound according to  claim 1 , which is 1-(4-methylphenyl)-4-(4-chlorobenzyl)piperazine.  
     
     
         17 . A compound according to  claim 1 , which is 1-3-methylphenyl)-4-(4-chlorobenzyl)piperazine.  
     
     
         18 . A compound according to  claim 1 , which is 1-(2-methylphenyl)-4-(4-chlorobenzyl)piperazine.  
     
     
         19 . A compound according to  claim 1 , which is 1-(3,4-dimethylphenyl)-4-(4-chlorobenzyl)piperazine dihydrobromide.  
     
     
         20 . A compound according to  claim 1 , which is 14-methoxyphenyl)-4-(4-chlorobenzyl)piperazine dihydrobromide.  
     
     
         21 . A compound according to  claim 1 , which is 1-(3-methoxyphenyl)-4-(4-chlorobenzyl)piperazine.  
     
     
         22 . A compound according to  claim 1 , which is 1-(2-methoxyphenyl)-4-(4-chlorobenzyl)piperazine.  
     
     
         23 . A compound according to  claim 1 , which is 1-(4-ethoxyphenyl)-4-(4-chlorobenzyl)piperazine.  
     
     
         24 . A compound according to  claim 1 , which is 1-(2-ethoxyphenyl)-4-(4-chlorobenzyl)piperazine.  
     
     
         25 . A compound according to  claim 1 , which is 1-phenyl-4-(4-chlorobenzyl)piperazine.  
     
     
         26 . A compound according to  claim 1 , which is 1-(4-chlorophenyl)-4-(4-fluorobenzyl)piperazine.  
     
     
         27 . A compound according to  claim 1 , which is 1-(4-chlorophenyl)-4-(4-methylbenzyl)piperazine.  
     
     
         28 . A compound according to  claim 1 , which is 1-(3-chlorophenyl)-4-(4-methylbenzyl)piperazine.  
     
     
         29 . A compound according to  claim 1 , which is 1-(3,4-dichlorophenyl)-4-(4-ethylbenzyl)piperazine.  
     
     
         30 . A compound according to  claim 1 , which is 1-(4-methylphenyl)-4-(4-methylbenzyl)piperazine.  
     
     
         31 . A compound according to  claim 1 , which is 1-(2-methylphenyl)-4-(4-methylbenzyl)piperazine.  
     
     
         32 . A compound according to  claim 1 , which is 1-(4-methoxyphenyl)-4-(4-methylbenzyl)piperazine.  
     
     
         33 . A compound according to  claim 1 , which is 1-(2-methoxyphenyl)-4-(4-methylbenzyl)piperazine.  
     
     
         34 . A method for treating or preventing neuropsychological disorders which comprises administering to a patient in need of such treatment a compound selected from the group consisting of 
 (a) 1-(3-chlorophenyl)-4-(4-chlorobenzyl)piperazine;    (b)-(2-chlorophenyl)-4-(chlorobenzyl)piperazine;    (c) 1-(3,4-dichlorophenyl)-4-chlorobenzyl)piperazine;    (d) 1-(4-methylphenyl)-4-(4-chlorobenzyl)piperazine;    (e) 1-(3-methylphenyl)-4-(4-chlorobenzyl)piperazine;    (f) 1-(2-methylphenyl)-4-(4-chlorobenzyl)piperazine;    (g) 1-(3,4-dimethylphenyl)-4-(chlorobenzyl)piperazine;    (h) 1-(4-methoxyphenyl)-4-(4-chlorobenzyl)piperazine;    (i) 1-(3-methoxyphenyl)-4-(4-chlorobenzyl)piperazine;    (j) 1-(2-methoxyphenyl)-4-(4-chlorobenzyl)piperazine;    (k) 1-(4-ethoxyphenyl)-4-(4-chlorobenzyl)piperazine;    (l) 1-(2-ethoxyphenyl)-4-(4-chlorobenzyl)piperazine;    (m) 1-phenyl-4-4-chlorobenzyl)piperazine;    (n) 1-(4-chlorophenyl)-4-(4-fluorobenzyl)piperazine;    (o) 1-(4-chlorophenyl)-4-(4-methylbenzyl)piperazine;    (p) 1-(3-chlorophenyl)-4-(4-methylbenzyl)piperazine;    (q) 1-(4-chlorophenyl)-4-(4-methylbenzyl)piperazine;    (r) 1-(3,4-dichlorophenyl)-4-(4-methylbenzyl)piperazine;    (s) 1-(4-methylphenyl)-4-(4-methylbenzyl)piperazine;    (t) 1-(2-methylphenyl)-4-(4-methylbenzyl)piperazine;    (u)-methoxyphenyl)-4-(methylbenzyl)piperazine;    (v)-methoxyphenyl)-4-(4-methylbenzyl)piperazine;    (w) 1-(4-chlorophenyl)-4-chlorobenzyl)piperazine dihydrochloride; and    (x)-(2-isopropoxyphenyl)-4-(4-bromobenzyl)piperazine.    
     
     
         35 . A compound according to  claim 1 , which is 1-Naphthyl-4-(4-chlorobenzyl)piperazine.