Chemical Compounds

Abstract

The present invention provides a method for the treatment of emesis in a mammal being treated with an opiod analgesic

1 . A compound of formula (I) 
     
       
         
         
             
             
         
       
       wherein 
       R represents a halogen atom or a C 1-4  alkyl group; 
       R 1  represents a C 1-4  alkyl group; 
       R 2  represents hydrogen or a C 1-4  alkyl group; 
       R 3  represents hydrogen or C 1-4  alkyl group; 
       R 4  represents a trifluoromethyl group; 
       R 5  represents hydrogen, a C 1-4  alkyl group or C(O)R 6 ;
 R 6  represents C 1-4  alkyl, C 3-7  cycloalkyl, NH(C 1-4  alkyl) or N(C 1-4 alkyl) 2 , 
 m is zero or an integer from 1 to 3; 
 n is an integer from 1 to 3; 
 and pharmaceutically acceptable salts thereof. 
 
     
   
   
       2 . A compound as claimed in  claim 1  wherein the carbon atom at the 2-position in the piperidine ring is in the β configuration. 
   
   
       3 . A compound as claimed in  claim 1  wherein m is 1 or 2, each R is independently a halogen atom or a C 1-4  alkyl group at the 2 and/or 4-positions in the phenyl ring. 
   
   
       4 . A compound as claimed in  claim 1  wherein n is 2 and the groups R 4  are at the 3 and 5-positions in the phenyl ring. 
   
   
       5 . A compound as claimed in  claim 1  wherein each R is independently halogen or methyl at the 2 and/or 4 position in the phenyl ring, the R 4  groups are at the 3 and 5-positions, R 1  is methyl, R 2  and R 3  are independently hydrogen or methyl and R 5  is methyl, isopropyl, or a C(O)cyclopropyl, a C(O)CH 3 , a C(O)NHCH 3  or a C(O)N(CH 3 ) 2  group, m is 1 or 2 and n is 2. 
   
   
       6 . A compound selected from
 4-(R)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;   4-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;   4-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid, (3,5-bis-trifluoromethyl-benzyl)-methylamide;   4-(R)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid, (3,5-bis-trifluoromethyl-benzyl)-methylamide;   2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R,S)-(4-methyl-piperazin-1-yl)-piperidine-1-carboxylic acid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;   2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-piperazin-1-yl-piperidine-1-carboxylic acid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;   2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(R,S)-(4-methyl-piperazin-1-yl)-piperidine-1-carboxylic acid, (3,5-bis-trifluoromethyl-benzyl)-methylamide;   4-(S)-(4-Cyclopropanoyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide   4-(R)-(4-Cyclopropanoyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;   4-(S)-[4-(2-Methyl-propanoyl)-piperazin-1-yl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;   4-(R)-[4-(2-Methyl-propanoyl)-piperazin-1-yl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;   4-(S)-[1-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidin-4-yl]-piperazine-1-carboxylic acid, dimethylamide;   4-(S)-[1-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidin-4-yl]-1-carboxylic acid, methylamide;   4-(S)-[1-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidin-4-yl]-piperazine;   4-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-phenyl)-piperidine-1-carboxylic acid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;   4-(R)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-phenyl)-piperidine-1-carboxylic acid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide;   and pharmaceutically acceptable salts thereof.   
   
   
       7 . 4-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide methanesulphonate. 
   
   
       8 . A compound as claimed in any  claim 1  for use in therapy. 
   
   
       9 . (canceled) 
   
   
       10 . (canceled) 
   
   
       11 . A pharmaceutical composition comprising a compound as claimed in  claim 1  in admixture with one or more pharmaceutically acceptable carriers or excipients. 
   
   
       12 . 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  claim 1 . 
   
   
       13 . A process for the preparation of a compound as claimed in  claim 1 , which comprises reacting a compound of formula (II), 
     
       
         
         
             
             
         
       
     
     with a piperazine (III) in the presence of a suitable metal reducing agent, followed where necessary or desired by one or more of the following steps
 i) isolation of the compound as a salt or a solvate thereof; 
 ii) separation of a compound of formula (I) or derivative thereof into the enantiomers thereof.