4-Pyrazin-2-ylmethyl-morpholine derivatives and the use thereof as medicament

Abstract

Disclosed are 4-pyrazin-2-ylmethyl-morpholines of formula Aand pharmaceutically acceptable salts thereof, wherein R1 and R2 are defined herein. Also disclosed are processes for their preparation, pharmaceutical compositions containing the compounds, and their use in therapy, particularly in the treatment or prevention of conditions having an association with NR2B negative allosteric modulating properties.

What is claimed is: 
     
         1 . A method for treating acute and chronic pain which is related to neuropathy, a physiological process or physical disorder, or a disease of the musculoskeletal system and connective tissue, or a nerve, a nerve root or a plexus disorder, the method comprising administering to a patient in need thereof a pharmaceutically effective amount of a compound of formula A 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         R 1  is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, cyclopropyl, H 3 C—CH 2 —CH 2 —CH 2 —, and cyclobutyl; 
         R 2  is phenyl which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of fluoro, chloro, methyl, ethyl, and cyclopropyl. 
       
     
     
         2 . The method according to  claim 1 , wherein:
 the neuropathy is diabetic neuropathy or polyneuropathy;   the physiological process or physical disorder is low back pain or pain in the joints;   the disease of the musculoskeletal system and connective tissue is rheumatism, myalgia; and   the nerve disorder is phantom limb syndrome with pain or carpal tunnel syndrome.   
     
     
         3 . The method according to  claim 1 , wherein
 R 1  is methyl or ethyl;   R 2  is selected from the group consisting of   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         4 . The method according to  claim 1 , wherein the compound of formula A is an (S)-enantiomer selected from the group consisting of: 
       
         
           
                 
                 
                 
               
                     
                 
                     
                   Ex. 
                     
                 
                     
                 
                     
                    1 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                    2 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                    3 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                    4 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                    5 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                    6 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                    7 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                    8 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                    9 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   18 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   30 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   31 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   33 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   34 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   35 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   36 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         5 . The method according to  claim 1 , wherein the compound of formula A is a pharmaceutically acceptable salt. 
     
     
         6 . A method for treating acute and chronic pain which is related to neuropathy, a physiological process or physical disorder, or a disease of the musculoskeletal system and connective tissue, or a nerve, a nerve root or a plexus disorder, the method comprising administering to a patient in need thereof a pharmaceutical composition comprising a compound of formula A 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         R 1  is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, cyclopropyl, H 3 C—CH 2 —CH 2 —CH 2 —, and cyclobutyl; 
         R 2  is phenyl which is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of fluoro, chloro, methyl, ethyl, and cyclopropyl 
         in admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier. 
       
     
     
         7 . A method for treating acute and chronic pain which is related to neuropathy, a physiological process or physical disorder, or a disease of the musculoskeletal system and connective tissue, or a nerve, a nerve root or a plexus disorder, the method comprising administering to a patient in need thereof a pharmaceutically effective amount of an (S)-enantiomer of a compound having the structure: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The method according to  claim 4 , wherein the (S)-enantiomer of the compound of formula A has the structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         9 . A method for treating acute and chronic pain which is related to neuropathy, a physiological process or physical disorder, or a disease of the musculoskeletal system and connective tissue, or a nerve, a nerve root or a plexus disorder, the method comprising administering to a patient in need thereof a pharmaceutically effective amount of an (S)-enantiomer of a compound having the structure: 
       
         
           
           
               
               
           
         
       
     
     
         10 . The method according to  claim 4 , wherein the (S)-enantiomer of the compound of formula A has the structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         11 . A method for treating acute and chronic pain which is related to neuropathy, a physiological process or physical disorder, or a disease of the musculoskeletal system and connective tissue, or a nerve, a nerve root or a plexus disorder, the method comprising administering to a patient in need thereof a pharmaceutically effective amount of an (S)-enantiomer of a compound having the structure: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The method according to  claim 4 , wherein the (S)-enantiomer of the compound of formula A has the structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         13 . A method for treating acute and chronic pain which is related to neuropathy, a physiological process or physical disorder, or a disease of the musculoskeletal system and connective tissue, or a nerve, a nerve root or a plexus disorder, the method comprising administering to a patient in need thereof a pharmaceutically effective amount of an (S)-enantiomer of a compound having the structure: 
       
         
           
           
               
               
           
         
       
     
     
         14 . The method according to  claim 4 , wherein the (S)-enantiomer of the compound of formula A has the structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         15 . A method for treating acute and chronic pain which is related to neuropathy, a physiological process or physical disorder, or a disease of the musculoskeletal system and connective tissue, or a nerve, a nerve root or a plexus disorder, the method comprising administering to a patient in need thereof a pharmaceutically effective amount of an (S)-enantiomer of a compound having the structure: 
       
         
           
           
               
               
           
         
       
     
     
         16 . The method according to  claim 4 , wherein the (S)-enantiomer of the compound of formula A has the structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         17 . A method for treating acute and chronic pain which is related to neuropathy, a physiological process or physical disorder, or a disease of the musculoskeletal system and connective tissue, or a nerve, a nerve root or a plexus disorder, the method comprising administering to a patient in need thereof a pharmaceutically effective amount of an (S)-enantiomer of a compound having the structure: 
       
         
           
           
               
               
           
         
       
     
     
         18 . The method according to  claim 4 , wherein the (S)-enantiomer of the compound of formula A has the structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         19 . A method for treating acute and chronic pain which is related to neuropathy, a physiological process or physical disorder, or a disease of the musculoskeletal system and connective tissue, or a nerve, a nerve root or a plexus disorder, the method comprising administering to a patient in need thereof a pharmaceutically effective amount of an (S)-enantiomer of a compound having the structure: 
       
         
           
           
               
               
           
         
       
     
     
         20 . The method according to  claim 4 , wherein the (S)-enantiomer of the compound of formula A has the structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         21 . A method for treating acute and chronic pain which is related to neuropathy, a physiological process or physical disorder, or a disease of the musculoskeletal system and connective tissue, or a nerve, a nerve root or a plexus disorder, the method comprising administering to a patient in need thereof a pharmaceutically effective amount of an (S)-enantiomer of a compound having the structure: 
       
         
           
           
               
               
           
         
       
     
     
         22 . The method according to  claim 4 , wherein the (S)-enantiomer of the compound of formula A has the structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         23 . A method for treating acute and chronic pain which is related to neuropathy, a physiological process or physical disorder, or a disease of the musculoskeletal system and connective tissue, or a nerve, a nerve root or a plexus disorder, the method comprising administering to a patient in need thereof a pharmaceutically effective amount of an (S)-enantiomer of a compound having the structure: 
       
         
           
           
               
               
           
         
       
     
     
         24 . The method according to  claim 4 , wherein the (S)-enantiomer of the compound of formula A has the structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         25 . A method for treating acute and chronic pain which is related to neuropathy, a physiological process or physical disorder, or a disease of the musculoskeletal system and connective tissue, or a nerve, a nerve root or a plexus disorder, the method comprising administering to a patient in need thereof a pharmaceutically effective amount of an (S)-enantiomer of a compound having the structure: 
       
         
           
           
               
               
           
         
       
     
     
         26 . The method according to  claim 4 , wherein the (S)-enantiomer of the compound of formula A has the structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof.