Piperidine Derivatives

Abstract

The present invention relates to piperidine derivatives of formula (I) R represents halogen or C 1-4 alkyl; R 1 represents C 1-4 alkyl; R 2 or R 3 independently represent hydrogen or C 1-4 alkyl; R 4 represents trifluoromethyl, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethoxy or halogen; R 5 represents hydrogen, C 1-4 alkyl or C 3-7 cycloalkyl; R 6 is hydrogen and R 7 is a radical of formula (W): or R 6 is a radical of formula (W) and R 7 is hydrogen; X represents CH 2 , NR 5 or O; Y represents Nitrogen and Z is CH or Y represents CH and Z is Nitrogen; A represents C(O) or S(O)q, provided that when Y is nitrogen and Z is CH, A is not S(O)q; m is zero or an integer from 1 to 3; n is an integer from 1 to 3; p and q are independently an integer from 1 to 2; and pharmaceutically acceptable salts and solvates thereof. The process for their preparation and their use in the treatment of condition mediated by tachykinins.

1 . A compound of formula (I) 
     
       
         
         
             
             
         
       
       R represents halogen or C 1-4  alkyl; 
       R 1  represents C 1-4  alkyl; 
       R 2  or R 3  independently represent hydrogen or C 1-4  alkyl; 
       R 4  represents trifluoromethyl, C 1-4  alkyl, C 1-4  alkoxy, trifluoromethoxy or halogen; 
       R 5  represents hydrogen, C 1-4  alkyl or C 3-7  cycloalkyl; 
       R 6  is hydrogen and R 7  is a radical of formula (W): 
     
     
       
         
         
             
             
         
       
       or R 6  is a radical of formula (W) and R 7  is hydrogen; 
       X represents CH 2 , NR 5  or O; 
       Y represents Nitrogen and Z is CH or Y represents CH and Z is Nitrogen; 
       A represents C(O) or S(O)q, provided that when Y is nitrogen and Z is CH, A is not S(O)q; 
       m is zero or an integer from 1 to 3; 
       n is an integer from 1 to 3; 
       p and q are independently an integer from 1 to 2; 
     
     and pharmaceutically acceptable salts and solvates thereof. 
   
   
       2 . A compound as claimed in  claim 1  in which R 6  is hydrogen, R 7  is a radical of formula (W) and Y is CH and Z is nitrogen or wherein R 6  is a radical of formula (W), R 7  is a hydrogen and Y is nitrogen and Z is CH. 
   
   
       3 . A compound as claimed in  claim 1  or  claim 2  wherein A is C(O). 
   
   
       4 . A compound as claimed in any claims from  1  to  3  wherein X is CH 2 . 
   
   
       5 . A compound as claimed in any claims from  1  to  4  wherein p is 1. 
   
   
       6 . A compound as claimed in any claims from  1  to  5  wherein each R 4  is independently trifluoromethyl group or halogen (e.g. chlorine) and n is 2. 
   
   
       7 . A compound as claimed in any claims from  1  to  6  wherein each R is independently a halogen (e.g. fluorine) or a C 1-4  alkyl (e.g. methyl) group, wherein m is 0, 1 or 2. 
   
   
       8 . A compound as claimed in any claims from  1  to  7  in which R 6  is hydrogen, R 7  is a radical of formula (W) and Y is CH and Z is nitrogen or wherein R 6  is a radical of formula (W), R 7  is a hydrogen and Y is nitrogen and Z is CH; A is C(O) and X is CH 2 . 
   
   
       9 . A compound as claimed in any claims from  1  to  8  in which R 6  is hydrogen, R 7  is a radical of formula (W) and Y is CH and Z is nitrogen or wherein R 6  is a radical of formula (W), R 7  is a hydrogen and Y is nitrogen and Z is CH, A is C(O), X is CH 2 , R is independently a halogen (e.g. fluorine) or a C 1-4  alkyl (e.g. methyl) group; R 4  is a trifluoromethyl group; m is 1 or 2; n is 2 and p is 1. 
   
   
       10 . A compound selected from:
 2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-(6-oxo-hexahydro-pyrrolo[1,2-a]-pyrazin-2-yl)-piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methylamide;   2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-(6-oxo-hexahydro-pyrrolo[1,2-a]-pyrazin-2-yl)-piperidine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;   1-(4-Fluoro-2-methyl-phenyl)-4-(6-oxo-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-piperidine-2-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide;   
     and enantiomers, diastereoisomers pharmaceutically acceptable salts (e.g. hydrochloride, methanesulphonate or maleate) and solvates thereof. 
   
   
       11 . A compound selected from:
 2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-((8aS)-6-oxo-hexahydro-pyrrolo[1,2-M-pyrazin-2-ylypiperidine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl]-ethyl]-methylamide;   2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-((8aR)-6-oxo-hexahydro-pyrrolo[1,2-a]-pyrazin-2-ylypiperidine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;   
     and amorphous and crystalline forms thereof and pharmaceutically acceptable salts (e.g. hydrochloride or maleate) and solvates thereof. 
   
   
       12 . A compound as claimed in any claims from  1  to  11  for use in therapy. 
   
   
       13 . The use of a compound as claimed in any claims from  1  to  11  in the preparation of a medicament for use in the treatment of conditions mediated by tachykinins, including substance P and other neurokinins. 
   
   
       14 . The use of a compound as claimed in any claims from  1  to  11  in the treatment of conditions mediated by tachykinins, including substance P and other neurokinins. 
   
   
       15 . A pharmaceutical composition comprising a compound as claimed in any claims from  1  to  11  in admixture with one or more pharmaceutically acceptable carriers or excipients. 
   
   
       16 . A method for the treatment of a mammal, including man, in particular in the treatment of conditions mediated by tachykinins, including substance P and other neurokinins, comprising administration of an effective amount of a compound as claimed in any claims from  1  to  11 . 
   
   
       17 . A process for the preparation of a compound as claimed in any claims from  1  to  11 , which comprises reacting a compound of formula (II),), wherein R 8  is ═O and R 9  is hydrogen or R 8  is hydrogen and R 9  is ═O 
     
       
         
         
             
             
         
       
     
     with compound of formula (III) or a salt thereof in the presence of a suitable metal reducing agent, followed where necessary or desired by one or more of the following steps:
 i) removal of any protecting group; 
 ii) isolation of the compound as a salt or a solvate thereof; 
 iii) separation of a compound of formula (I) or derivative thereof into the enantiomers thereof.