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 compound represented by Formula I: 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts, stereoisomers, and N-oxides thereof; wherein 
         T is, independently for each occurrence, CR 4 R 4  , and n is 0, 1, 2 or 3; 
         A is optionally present and is selected from 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 1 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, 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 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 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 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 . The compound of  claim 1 , represented by: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is C(O)—C 2 -C 4 alkyl, wherein C 2 -C 4 alkyl is substituted at one carbon with NH 2  or —N-carbobenzyloxy and at a different carbon by hydroxyl. 
 
     
     
         3 . The compound of  claim 1 , wherein R 1  is C(O)—O—C 1- C 4 alkyl, wherein C 1 -C 4 alkyl is substituted by phenyl. 
     
     
         4 . The compound of  claim 3 , wherein R 1  is carbobenzyloxy. 
     
     
         5 . The compound of  claim 1 , wherein R 1  is: 
       
         
           
           
               
               
           
         
       
       wherein:
 X is N; 
 R 5 ′ is H; and 
 R 8  is C(O)—C 2 -C 4 alkyl, wherein C 2 -C 4 alkyl is substituted at one carbon with NH 2  or —N-carbobenzyloxy and at a different carbon by hydroxyl. 
 
     
     
         6 . The compound of  claim 1 , wherein R 3  is phenyl. 
     
     
         7 . The compound of  claim 1 , wherein R 3  is H. 
     
     
         8 . The compound of  claim 1 , wherein R 2  is —C(O)—C 2 -C 4 alkyl, substituted at one carbon with NH 2  and another carbon with hydroxyl. 
     
     
         9 . The compound of  claim 1 , wherein C 1 -C 4 alkyl is selected from the group consisting of methyl, ethyl, propyl, n-butyl or t-butyl, and wherein said C 1 -C 4 alkyl is optionally substituted by one, two, or three substituents selected from the group consisting of F, Cl, or Br. 
     
     
         10 . The compound of  claim 1 , wherein the compound is represented by: 
       
         
           
           
               
               
           
         
       
     
     
         11 . A compound represented by formula II: 
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts, stereoisomers and N-oxides thereof; wherein
 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; R 7 , or 
 
       
         
           
           
               
               
           
         
         X is CH or N; 
         R 3  and R 3 ′ are each 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 Ra; 
         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  is selected from 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 6  is selected from 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 1, 2 or 3 substituents selected from R a ; 
         R 7  is selected from 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 ; or 
         or R 1  and R 6 , taken together with formula II form: 
       
       
         
           
           
               
               
           
         
         R 8  is selected from 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. 
       
     
     
         12 . The compound of  claim 1 , wherein R 1  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound of claiml represented by: 
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         15 . A compound of  claim 1 , which is capable of generating an enhanced single shock evoked NMDA receptor-gated single neuron conductance (I NMDA ) in hippocampal CA1 pyramidal neurons at concentrations of 100 nM to 1 μM. 
     
     
         16 . A non-peptidyl compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts, stereoisomers and N-oxides thereof. 
     
     
         17 . A method for treating a cognitive disorder comprising administering to an patient in need thereof an effective amount of a compound of  claim 1 . 
     
     
         18 . The method of  claim 17 , wherein the cognitive disorder is associated with memory loss or impaired learning. 
     
     
         19 . The method of  claim 19 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         20 . The method of  claim 19 , wherein the compound is administered orally. 
     
     
         21 . A pharmaceutically acceptable composition comprising a compound of any one of  claims 1 - 16 , and a pharmaceutically acceptable excipient. 
     
     
         22 . The composition of  claim 21 , wherein the composition is suitable for oral administration to a patient. 
     
     
         23 . A method for treating neuropathic pain in a patient in need thereof comprising administering an effective amount of a compound of  claim 1 . 
     
     
         24 . A method for treating depression, obsessive-compulsive disorder, or schizophrenia in a patient in need thereof comprising administering an effective amount of a compound of  claim 1 . 
     
     
         25 . A method for treating post traumatic stress disorder, an alcohol dependency disorder, or an addiction to an addictive drug in a patient in need thereof comprising administering an effective amount of a compound of  claim 1 . 
     
     
         26 . The compound represented by: 
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts, stereoisomers, and N-oxides thereof. 
     
     
         27 . A composition comprising the compound of  claim 26 , and a pharmaceutically acceptable carrier.