Serotonin 5-HT1A and dopamin D2 receptor ligands

Abstract

The present invention relates to a series of 4-phenylpiperazines of formula (I) wherein A is alkylene, alkenylene, alkynylene, and C 3-7 cycloalkylene; R 1 is a C 3-10 alkyl, alkenyl, or alkynyl group, cycloalk(en)yl, cycloalk(en)yl-alk(en/yn)yl, trifluoromethylsulfonyl, or alkylsulfonyl, R 2 -R 5 are optional substituents; R 9 and R 10 are hydrogen, alkyl or together form an ethylene or propylene bridge, W is O or S; V is O, S, CR 6 R 7 , or NR 8 wherein R 6 , R 7 , and R 8 are hydrogen or alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, optionally substituted arylalkyl or aryl, or R 6 and R 7 constitute a 3-7 membered spiro ring; Z is—(CH 2 ) m —; m being 2 or 3 or Z is —CH═CH—; which show effects on central serotonin 5-HT 1A and dopamine D 2 receptors. Thus the novel compounds are useful in the treatment of certain psychic and neurologic disorders, in particular psychosis.

What is claimed:  
     
         1 . A 4-phenylpiperazine compound of formula I:  
       
         
           
           
               
               
           
         
         wherein A is a spacer group selected from the group consisting of C 3-8  alkylene, C 3-8  alkenylene, C 3-8  alkynylene, and C 3-7  cycloalkylene, said spacer group being optionally substituted with lower alkyl, phenyl or hydroxy; wherein said alkylene, alkenylene and alkynylene groups can be branched or straight chains,  
         R 1  is branched C 3-10  alkyl, branched C 3-10  alkenyl, branched C 3-10  alkynyl, cycloalk(en)yl, cycloalk(en)yl-lower alk(en/yn)yl, trifluoromethylsulfonyl, or lower alkylsulfonyl,  
         R 2 -R 5  are independently selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, lower alkylthio, hydroxy, lower alkylsulfonyl, cyano, lower alkylcarbonyl, phenylcarbonyl, halogen substituted phenylcarbonyl, trifluoromethyl, trifluoromethylsulfonyloxy, cycloalkyl, cycloalkyl-lower alkyl, nitro, lower alkylamino, di-lower-alkylamino and trifluoromethylthio,  
         R 9  and R 10  are independently selected from the group consisting of hydrogen, and lower alkyl;  
         W is O or S;  
         V is O, S, CR 6 R 7 , or NR 8  wherein R 6 , R 7  and R 8  are independently selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, cycloalkyl, cycloalkyl-lower-alkyl, phenyl-lower alkyl and phenyl, or R 6  and R 7  are linked together to constitute a 3-7-membered spiro joined ring;  
         Z is —(CH 2 ) m —, m being 2 or 3 or Z is —CH═CH—;  
         any alkyl, cycloalkyl or cycloalkylalkyl group present can be optionally substituted with one or two hydroxy groups, which can be optionally esterified with an aliphatic or phenyl carboxylic acid; and any phenyl substituent present can be optionally substituted with halogen, lower alkyl, lower alkoxy, lower alkylthio, hydroxy, lower alkylsulfonyl, cyano, phenylcarbonyl, C 1-8  alkylcarbonyl, N′-(C 1-18 )alkylcarbonyl or N′,N′-di(C 1-18 )alkylcarbonyl, trifluoromethyl, trifluoromethylsulfonyloxy, cycloalkyl, cycloalkylalkyl or nitro;  
         or a pharmaceutically acceptable acid addition salt thereof.  
       
     
     
         2 . The compound of  claim 1 , wherein A is a —(CH 2 ) n — group wherein n is an integer from 3-8, inclusive.  
     
     
         3 . The compound of  claim 2 , wherein n is 4-6.  
     
     
         4 . The compound of  claim 3 , wherein n is 4.  
     
     
         5 . The compound of  claim 1 , wherein R 1  is branched C 3-6  alkyl, cycloalkyl, cycloalkyl-lower alkyl or trifluoromethylsulfonyl.  
     
     
         6 . The compound of  claim 5 , wherein R 1  is 2-propyl, 2-methyl-1-propyl, 2-butyl, 3-pentyl, 2,2-dimethyl-1-propyl, tert-butyl, cyclopentyl, cyclopropylmethyl, 2,4-dimethyl-3-pentyl or trifluoromethylsulfonyl.  
     
     
         7 . The compound of  claim 1 , wherein R 2 -R 5  are independently hydrogen, halogen or cyano.  
     
     
         8 . The compound of  claim 6 , wherein R 2 -R 5  are all hydrogen.  
     
     
         9 . The compound of  claim 6 , whrein one of R 2 -R 5  is halogen and the others are hydrogen.  
     
     
         10 . The compound of  claim 6 , wherein R 9  and R 10  are both hydrogen.  
     
     
         11 . The compound of  claim 1 , wherein Z is —CH 2 CH 2 — or —CH═CH— and V designates NR 8 , wherein R 8  is lower alkyl, cycloalkyl, phenyl or phenyl substituted with halogen.  
     
     
         12 . The compound of  claim 1 , wherein W is oxygen.  
     
     
         13 . A pharmaceutical composition comprising at least one compound of  claim 1  in a therapeutically effective amount and one or more pharmaceutically acceptable carriers or diluents.  
     
     
         14 . A method of treating psychosis, positive symptoms of schizophrenia, anxiety disorders, depression, impulse control disorders, alcohol abuse, aggression, EPS induced by conventional antipsychotic drugs, ischaemic disease states, senile dementia and cardiovascular disorders, comprising administering a compound of  claim 1  to a patient in need of said treatment.  
     
     
         15 . The method of  claim 14 , wherein said anxiety disorders are selected from the group consisting of generalized anxiety disorder, panic disorder and obsessive compulsive disorder.