Piperazine derivatives as 5-HT1B antagonists

Abstract

Piperazine derivatives of formula (I) processes for their preparation, pharmaceutical compositions containing them and to their use in therapy as 5-HT 1B antagonists. W,Y,R a -R e are so defined in the application.

1 . A compound of formula (I) or a pharmaceutically acceptable salt thereof:  
       
         
           
           
               
               
           
         
         in which R a  is a group of formula (i)  
         
           
             
             
                 
                 
             
           
         
          wherein P 1  is phenyl, naphthyl or heteroaryl;  
         R 1  is halogen, C 1-6 alkyl, C 3-6 cycloalkyl, COC 1-6 alkyl, C 1-6 alkoxy, hydroxy, hydroxyC 1-6 alkyl, nitro, CF 3 , cyano, SR 6 , SOR 6 , SO 2 R 6 , SO 2 NR 6 R 7 , CO 2 R 6 , CONR 6 R 7 , OCONR 6 R 7 , NR 6 R 7 , NR 6 CO 2 R 7 , NR 6 CONR 7 R 8 , CR 6 ═NOR 7  where R 6 , R 7  and R 8  are independently hydrogen or C 1-6 alkyl;  
         a is 0, 1, 2 or 3;  
         or R a  is a group of formula (ii)  
         
           
             
             
                 
                 
             
           
         
          wherein  
         P 2  is phenyl, naphthyl, heteroaryl or a 5 to 7 membered heterocyclic ring;  
         P 3  is phenyl, naphthyl or heteroaryl;  
         A is a bond or oxygen, carbonyl, CH 2  or NR 4  where R 4  is hydrogen or C 1-6 alkyl;  
         R 2  is as defined above for R 1  in formula (i) or R 2  is heteroaryl optionally substituted by C 1-6 alkyl, halogen or COC 1-6 alkyl or is a 5-7 membered heterocyclic ring optionally substituted by oxo;  
         R 3  is halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, COC 1-6 alkyl, hydroxy, nitro, CF 3 , cyano, CO 2 R 6 , CONR 6 R 7 , NR 6 R 7  where R 6  and R 7  are as defined above;  
         b and c are independently 0, 1, 2 or 3;  
         Y is a single bond, CH 2 , O or NR 5  where R 5  is hydrogen or C 1-6 alkyl;  
         W is —(CR 9 R 10 ) t — where t is 2, 3 or 4 and R 9  and R 10  are independently hydrogen or C 1-6 alkyl or W is a group —CH═CH—;  
         R b  is hydrogen, halogen, hydroxy, C 1-6 alkyl, CF 3  , COC 1-6 alkyl, cyano or C 1-6 alkoxy;  
         R c  is hydrogen or C 1-6 alkyl;  
         R d  and R e  are independently C 1-4 alkyl.  
       
     
     
         2 . A compound according to  claim 1  in which R a  is a group of formula (i) wherein P 1  is phenyl.  
     
     
         3 . A compound according to  claim 2  in which R 1  is halogen, C 1-6 alkyl, nitro, CF 3  or cyano.  
     
     
         4 . A compound according to any of the preceding claims in which Y is CH 2 .  
     
     
         5 . A compound according to  claim 1  in which R a  is a group of formula (ii) wherein A is a single bond, P 3  is phenyl or naphthyl and P 2  is phenyl, pyridyl, pyrazinyl, oxadiazolyl, oxazolyl or piperidinyl.  
     
     
         6 . A compound according to any of the preceding claim in which W is —CH 2 —CH 2 — or —CH═CH—.  
     
     
         7 . A compound according to any of the preceding claims in which R c  is hydrogen or methyl.  
     
     
         8 . A compound according to any of the preceding claims in which R d  and R e  are both methyl.  
     
     
         9 . A compound according to  claim 1  which is a compound E1-E73 (as described above) or a pharmaceutically acceptable salt thereof.  
     
     
         10 . A compound according to  claim 1  which is 
 cis-1-[(2-chloro-3-trifluoromethylphenyl)acetyl]-6-(3,4,5-trimethylpiperazin-1-yl)indole,  
 cis-1-[(2-fluoro-3-trifluoromethylphenyl)acetyl]-5-methoxy-6-(3,4,5-trimethylpiperazin-1-yl)indoline,  
 cis-1-[(2,3-dichlorophenyl)acetyl]-6-(3,5-dimethylpiperazin-1-yl)-5-methoxyindoline  
 cis-6-(3,5-dimethylpiperazin-1-yl)-5-methoxy-1-[4-(2-methyl-6-(2-oxopyrrolidin-1-yl)pyridin-3-yl)benzoyl]-indoline,  
 cis-1-[(3-chloro-2-fluorophenyl)acetyl]-6-(3,5-dimethylpiperazin-1-yl)-5-methoxyindole,  
 cis-1-[(2-fluoro-3-trifluoromethylphenyl)acetyl]-5-fluoro-6-(3,4,5-trimethylpiperazin-1-yl)indole,  
 cis-1-[2-chloro-3-(trifluoromethyl)phenyl)aminocarbonyl]-5-methyl-6-(3,4,5-trimethylpiperazin-1-yl)indoline  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         11 . A process for the preparation of a compound of formula (I) according to  claim 1  or a pharmaceutically acceptable salt thereof which comprises: 
 (a) where Y is NH, coupling a compound of formula (II): 
 R a —N—(C═O)  (II) 
  in which R a  is as defined in formula (I) with a compound of formula (III):  
                     
  in which W, R b , R c , R d  and R e  are as defined in formula (I); or  
 (b) where Y is NR 5 , reacting a compound of formula (IV) 
 R a —NR 5 H  (IV) 
  in which R a  and R 5  are as defined in formula (I) with a compound of formula (III) as defined above together with an appropriate urea forming agent; or  
 (c) where Y is a single bond, CH 2  or O, reacting a compound of formula (V) 
 R a —Y—(C═O)-L  (V) 
  in which R a  is as defined in formula (I) and L is an appropriate leaving group, with a compound of formula (III) as defined above; and optionally thereafter for process (a), (b) or (c):  
 removing any protecting groups,  
 converting a compound of formula (I) into another compound of formula (I),  
 forming a pharmaceutically acceptable salt.  
 
     
     
         12 . A compound according to any one of  claims 1  to  10  for use in therapy.  
     
     
         13 . A compound according to any one of  claims 1  to  10  for use in the treatment of depression.  
     
     
         14 . A pharmaceutical composition which comprises a compound according to any of  claims 1  to  10  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.  
     
     
         15 . A compound of formula (I) as defined in any one of  claims 1  to  10  or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of diseases or disorders where an antagonist of the 5-HT 1B  receptor is beneficial.  
     
     
         16 . The use of a compound of formula (I) as defined in any one of  claims 1  to  10  or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of diseases or disorders where an antagonist of the 5-HT 1B  receptor is beneficial.