Nmda receptor modulators and uses thereof

Abstract

Disclosed are compounds having enhanced potency in the modulation of NMDA receptor activity. Such compounds are contemplated for use in the treatment of diseases and disorder such as learning, cognitive activities, and analgesia, particularly in alleviating and/or reducing neuropathic pain. Orally available formulations and other pharmaceutically acceptable delivery forms of the compounds, including intravenous formulations, are also disclosed.

1 . A method for treating neuropathic pain in a patient in need thereof comprising administering to the patient an effective amount of a pharmaceutically acceptable composition comprising a compound represented by Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, a stereoisomer, or an N-oxide thereof; and a pharmaceutically acceptable excipient; wherein
 T is, independently for each occurrence, CR 4 R 4 ′, and n is 0, 1, 2 or 3; 
 A is optionally present and phenyl or pyridine, wherein A is optionally substituted by one or more substituents selected from R a ; 
 R 1  is selected from the group consisting of H, hydroxyl, —S(O) 2 —C 1 -C 4 alkyl; —SO 2 , C 1 -C 4 alkyl, C 2 -C 4 alkenyl, phenyl, R 7 , or 
 
       
         
           
           
               
               
           
         
       
       wherein C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or phenyl is optionally substituted by one or more substituents selected from R a ;
 X is CH or N; 
 R 3  and R 3 ′ are independently selected from the group consisting of H, halogen, hydroxyl, phenyl, C 1 -C 4 alkyl, amido, amine, or C 2 -C 4 alkenyl, wherein C 1 -C 4 alkyl, C 2 -C 4 alkenyl and phenyl are optionally substituted by one or more substituents selected from R a ; 
 R 4  and R 4 ′ are independently selected from the group consisting of H, halogen, hydroxyl, phenyl, C 1 -C 4 alkyl, amido, amine, C 1 -C 4 alkoxy or C 2 -C 4 alkenyl, wherein C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 1 -C 4 alkoxy, and phenyl are optionally substituted by one or more substituents selected from R a ; 
 R 2  is selected from the group consisting of H, R 7 , —S(O) 2 , S(O) 2 —C 1 -C 4 alkyl, C 1 -C 4 alkyl, hydroxyl, or phenyl wherein C 1 -C 4 alkyl, C 2 -C 4  alkenyl and phenyl are optionally substituted by one or more substituents selected from R a ; 
 R 5  and R 5 ′ are each independently selected from the group consisting of H, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 2 -C 4 alkenyl, cyano, amino, phenyl, and hydroxyl, wherein C 1 -C 4 alkyl, C 2 -C 4 alkenyl and phenyl are optionally substituted by one or more substituents selected from R a ; 
 R 7  is selected from the group consisting of —C(O)—C 1 -C 4 alkyl or C(O)—O—C 1 -C 4 alkyl, wherein C 1 -C 4  alkyl is optionally substituted by 1, 2 or 3 substituents selected from R b ; 
 R 8  is selected from the group consisting of H, —C(O)—C 1 -C 4  alkyl or C(O)—O—C 1 -C 4  alkyl, wherein C 1 -C 4 alkyl is optionally substituted by 1, 2 or 3 substituents selected from R a ; 
 R a  is selected, independently for each occurrence, from carboxy, hydroxyl, halogen, amino, phenyl, C 1 -C 4  alkyl, and C 1 -C 4  alkoxy; 
 R b  is selected, independently for each occurrence, from the group consisting of carboxy, hydroxyl, halogen, amino, phenyl, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, and —NH—R c ; and 
 R c  is selected, independently for each occurrence, —C(O)—O—C 1 -C 4 alkyl; and —C(O)—C 1 -C 4 alkyl. 
 
     
     
         2 .- 12 . (canceled) 
     
     
         13 . The method of  claim 1 , wherein the compound is represented by: 
       
         
           
           
               
               
           
         
       
     
     
         14 . The method of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         15 .- 27 . (canceled)