Piperazine derivatives

Abstract

Compounds of general formula (I) in which R 1 and R 0 have any of the meanings given in the specification have affinity for sigma receptors and are useful in the treatment of disorders of the central nervous system.

1 . A compound of general formula (I) 
       
         
           
           
               
               
           
         
         in which: —
 R 0  represents phenyl or 4-fluorophenyl; and 
 R 1  represents: — 
 (i) a group of formula
   R 2 —(CH 2 ) n CH 2 —
 
 
 wherein: — 
 n is 1 or 2; and 
 R 2  represents a phenyl group that is substituted by one, two, or three substituents selected independently from (1-2C)alkylenedioxy, a halogen atom, a hydroxyl group, a (1-4C) alkyl group, a (3-6C)cycloalkyl group, a halo(1-4C) alkyl group, a (1-4C)alkoxy group and a halo(1-4C)alkoxy group, provided that when R 0  represents phenyl, R 2  is not 3,4,5-trimethoxyphenyl or phenyl substituted by two (1-4C) alkoxy groups; 
 (ii) a group of formula
   R 3 —(CH 2 ) m C(R 4a R 4b )—
 
 
 wherein: — 
 m is 1 or 2; 
 
         in which: —
 R 3  represents a phenyl group that is unsubstituted or substituted by one, two or three substituents selected independently from (1-2C)alkylenedioxy, a halogen atom, a hydroxyl group, a (1-4C) alkyl group, a (3-6C)cycloalkyl group, a halo(1-4C) alkyl group, a (1-4C)alkoxy group and a halo(1-4C)alkoxy group; and one or two of R 4a  and R 4b  represents a (1-4C) alkyl or a (1-4C)alkoxy(1-4C)alkyl group and any remainder represents a hydrogen atom; or 
 (iii) 1,2,3,4-tetrahydronaphth-1-yl or 1,2,3,4-tetrahydronaphth-1-yl, each of which may bear a hydroxyl substituent on a non-aromatic carbon atom; or (3-6C) cycloalkyl; 
 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . A compound of general formula (I) 
       
         
           
           
               
               
           
         
         in which: —
 R 0  represents phenyl or 4-fluorophenyl; and, 
 R 1  represents: 
 a group of formula
   R 2 —(CH 2 ) n CH 2 —
 
 
 wherein: 
 n is 1 or 2; and 
 R 2  represents a phenyl group that is substituted by one fluorine atom or phenyl substituted by one, two, or three substituents selected independently from (1-2C)alkylenedioxy, a hydroxyl group, a (1-4C) alkyl group, a (3-6C)cycloalkyl group, and a halo(1-4C) alkyl group. 
 
       
     
     
         3 . A compound of general formula (I) 
       
         
           
           
               
               
           
         
         in which: —
 R 0  represents phenyl or 4-fluorophenyl; and 
 R 1  represents a group of formula
   R 3 —(CH 2 ) m C(R 4a R 4b )—
 
 
 wherein: 
 m is 1 or 2; and 
 R 3  represents a phenyl group that is unsubstituted or substituted by one, two, or three substituents selected independently from (1-2C)alkylenedioxy, a halogen atom, a hydroxyl group, a (1-4C) alkyl group, a (3-6C)cycloalkyl group, a halo(1-4C) alkyl group, a (1-4C)alkoxy group, and a halo(1-4C)alkoxy group; and 
 one or both of R 4a  and R 4b  represents a (1-4C) alkyl or a (1-4C)alkoxy(1-4C)alkyl group, and any remainder represents a hydrogen atom. 
 
       
     
     
         4 . A compound according to  claim 2 , in which R 0  represents phenyl. 
     
     
         5 . A compound according to  claim 2 , in which R 0  represents 4-fluorophenyl. 
     
     
         6 . A compound according to  claim 2 , or  claim 4 , or  claim 5 , in which n is 1. 
     
     
         7 . A compound according to  claim 2 ,  claim 4 , or  claim 5 , in which R 2  represents 3,4-dihydroxyphenyl, 3,4-methylenedioxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-methylphenyl, or 3-trifluoromethylphenyl. 
     
     
         8 . A compound according to  claim 2 , in which n is 1, and R 2  represents 3,4-dihydroxyphenyl, 3,4-methylenedioxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-methylphenyl, or 3-trifluoromethylphenyl. 
     
     
         9 . A compound according to  claim 3 , in which m is 1. 
     
     
         10 . A compound according to  claim 3 , in which m is 2. 
     
     
         11 . A compound according to  claim 3 , or  claim 9 , or  claim 10 , in which R 3  represents a phenyl group. 
     
     
         12 . A compound according to  claim 3 , or  claim 9 , or  claim 10 , in which R 4a  represents a methoxymethyl group and R 4b  represents a hydrogen atom. 
     
     
         13 . A compound according to  claim 3 , or  claim 9 , or  claim 10 , in which R 3  represents a phenyl group and R 4a  represents a methoxymethyl group and R 4b  represents a hydrogen atom. 
     
     
         14 . A compound according to  claim 2 , which is selected from 1-[2-(2-fluorophenyl)ethyl]-4-(3-phenylpropyl)piperazine and pharmaceutically acceptable salts thereof and 1-[2-(3-methylphenyl)ethyl]-4-(3-phenylpropyl)piperazine and pharmaceutically acceptable salts thereof. 
     
     
         15 . A compound according to  claim 2 , which is 1-[2-(2-fluorophenyl)ethyl]-4-(3-phenylpropyl)piperazine, or a pharmaceutically acceptable salt thereof. 
     
     
         16 . A compound as claimed in  claim 2 , which is 1-[2-(2-fluorophenyl)ethyl]-4-(3-phenylpropyl)piperazine dihydrochloride. 
     
     
         17 . A pharmaceutical composition, which comprises a compound of general formula (I) 
       
         
           
           
               
               
           
         
         in which: —
 R 0  represents phenyl or 4-fluorophenyl; and, 
 R 1  represents: 
 a group of formula
   R 2 —(CH 2 ) n CH 2 —
 
 
 wherein: 
 n is 1 or 2; and 
 R 2  represents a phenyl group that is substituted by one fluorine atom or phenyl substituted by one, two, or three substituents selected independently from (1-2C)alkylenedioxy, a hydroxyl group, a (1-4C) alkyl group, a (3-6C)cycloalkyl group, and a halo(1-4C) alkyl group, 
 
         or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. 
       
     
     
         18 . A pharmaceutical composition, which comprises a compound selected from 1-[2-(2-fluorophenyl)ethyl]-4-(3-phenylpropyl)piperazine, 1-[2-(3-methylphenyl)ethyl]-4-(3-phenylpropyl)piperazine and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable diluent or carrier. 
     
     
         19 . A compound which is 1-(1R)-(1,2,3,4-Tetrahydronaphthalen-1-yl)-4-(3-phenylpropyl)piperazine or 1-(1S)-(1,2,3,4-Tetrahydronaphthalen-1-yl)-4-(3-phenylpropyl)piperazine, or a pharmaceutically acceptable salt thereof. 
     
     
         20 . A compound which is 1-Cyclopentyl-4-(3-phenylpropyl)piperazine, or 1-(1S,2S)-(2-Hydroxycyclopentyl)-4-(3-phenylpropyl)piperazine, or a pharmaceutically acceptable salt thereof. 
     
     
         21 . A compound according to  claim 2  which is
 1-(2-Benzo[1,3]dioxol-5-ylethyl)-4-(3-phenylpropyl)piperazine, 
 1-[2-(2-Fluorophenyl)ethyl]-4-(3-phenylpropyl)piperazine, 
 1-[2-(3-Fluorophenyl)ethyl]-4-(3-phenylpropyl)piperazine, 
 1-[2-(4-Fluorophenyl)ethyl]-4-(3-phenylpropyl)piperazine, 
 1-[2-(3-Methylphenyl)ethyl]-4-(3-phenylpropyl)piperazine, 
 1-[2-(3-Trifluoromethylphenyl)ethyl]-4-(3-phenylpropyl)piperazine, 
 1-[2-(3,4-Dihydroxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine, 
 1-[2-(2-Trifluoromethylphenyl)ethyl]-4-(3-phenylpropyl)piperazine, 
 1-[2-(4-Trifluoromethylphenyl)ethyl]-4-(3-phenyl propyl)piperazine, 
 1-[2-(7-Fluorobenzo[1,3]dioxol-5-yl)ethyl)-4-(3-phenylpropyl)piperazine, 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         22 . A compound according to  claim 3  which is 1-[(S)-(1-Methoxymethyl-2-phenyl)ethyl]-4-(3-phenylpropyl)piperazine or 1-[(R)-(1-Methoxymethyl-2-phenyl)ethyl]-4-(3-phenylpropyl)piperazine or a pharmaceutically acceptable salt thereof. 
     
     
         23 . The composition according to  claim 17 , in which the compound of general formula (I) is
 1-(2-Benzo[1,3]dioxol-5-ylethyl)-4-(3-phenylpropyl)piperazine,   1-[2-(2-Fluorophenyl)ethyl]-4-(3-phenylpropyl)piperazine,   1-[2-(3-Fluorophenyl)ethyl]-4-(3-phenylpropyl)piperazine,   1-[2-(4-Fluorophenyl)ethyl]-4-(3-phenylpropyl)piperazine,   1-[2-(3-Methylphenyl)ethyl]-4-(3-phenylpropyl)piperazine,   1-[2-(3-Trifluoromethylphenyl)ethyl]-4-(3-phenylpropyl)piperazine,   1-[2-(3,4-Dihydroxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine,   1-[2-(2-Trifluoromethylphenyl)ethyl]-4-(3-phenylpropyl)piperazine,   1-[2-(4-Trifluoromethylphenyl)ethyl]-4-(3-phenylpropyl)piperazine,   1-[2-(7-Fluorobenzo[1,3]dioxol-5-yl)ethyl)-4-(3-phenylpropyl)piperazine,   or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier.   
     
     
         24 . A pharmaceutical composition, which comprises a compound of general formula (I) 
       
         
           
           
               
               
           
         
         in which: —
 R 0  represents phenyl or 4-fluorophenyl; and 
 R 1  represents a group of formula
   R 3 —(CH 2 ) m C(R 4a R 4b )—
 
 
 wherein: 
 m is 1 or 2; and 
 R 3  represents a phenyl group that is unsubstituted or substituted by one, two, or three substituents selected independently from (1-2C)alkylenedioxy, a halogen atom, a hydroxyl group, a (1-4C) alkyl group, a (3-6C)cycloalkyl group, a halo(1-4C) alkyl group, a (1-4C)alkoxy group, and a halo(1-4C)alkoxy group; and 
 one or both of R 4a  and R 4b  represents a (1-4C) alkyl or a (1-4C)alkoxy(1-4C)alkyl group, and any remainder represents a hydrogen atom, 
 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. 
 
       
     
     
         25 . A pharmaceutical composition according to  claim 24 , in which the compound of general formula (I) is 1-[(S)-(1-Methoxymethyl-2-phenyl)ethyl]-4-(3-phenylpropyl)piperazine or 1-[(R)-(1-Methoxymethyl-2-phenyl)ethyl]-4-(3-phenylpropyl)piperazine or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier. 
     
     
         26 . A pharmaceutical composition which comprises 1-(1R)-(1,2,3,4-Tetrahydronaphthalen-1-yl)-4-(3-phenylpropyl)piperazine, or 1-(1S)-(1,2,3,4-Tetrahydronaphthalen-1-yl)-4-(3-phenylpropyl)piperazine, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier. 
     
     
         27 . A pharmaceutical composition which comprises 1-Cyclopentyl-4-(3-phenylpropyl)piperazine, and 1-(1S,2S)-(2-Hydroxycyclopentyl)-4-(3-phenylpropyl)piperazine, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier.