Prodrugs of modulators of the nmda receptor

Abstract

The present invention is directed to novel prodrugs of modulators of the NMDA receptor. Separate aspects of the inventions are directed to pharmaceutical compositions comprising said compounds and uses of the compounds to treat neurological disorders or neuropsychiatric disorders such as depression.

1 - 36 . (canceled) 
     
     
         37 . A method for the treatment of depression comprising the administration of a therapeutically effective amount of a compound having the formula Ia: 
       
         
           
           
               
               
           
         
         wherein: 
         R 5  is selected from the group consisting of C 1-5  alkyl, C 1-4  haloalkyl, hydroxyalkyl, C 1-4  hydroxyhaloalkyl, R 8 , WR 8 , and W(OR 9 ); 
         W is selected from the group consisting of C 1-3  alkylene and —CH 2 C(O)—; 
         R 8  is selected from the group consisting of C 3-6  cycloalkyl, phenyl, a 4, 5, or 6 membered heterocycle, and a 5 or 6 membered heteroaryl, wherein said cycloalkyl, phenyl, heterocycle or heteroaryl are independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, C 1-3  alkyl, C 1-3  alkoxy, wherein said C 1-3  alkyl and C 1-3  alkoxy are independently unsubstituted or substituted with 1, 2 or 3 F; and 
         R 9  is C 1-3  alkyl unsubstituted or substituted with 1, 2 or 3 F; 
         or pharmaceutically acceptable salt thereof, to a patient in need thereof. 
       
     
     
         38 . The method according to  claim 37 , wherein R 5  is selected from the group consisting of methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, —CH 2 -cyclopropyl, 2-methoxyethyl, isopentyl, benzyl, cyclohexyl, 2-oxo-2-(pyrrolidin-1-yl)ethyl, and phenyl. 
     
     
         39 . The method according to  claim 37 , wherein R 5  is C 1-5  alkyl. 
     
     
         40 . The method according to  claim 37 , wherein R 5  is selected from the group consisting of methyl, ethyl, propyl, butyl, and isopropyl. 
     
     
         41 . The method according to  claim 37 , wherein R 5  is selected from the group consisting of methyl, ethyl, propyl, and butyl. 
     
     
         42 . The method according to  claim 37 , wherein R 5  is selected from the group consisting of methyl and ethyl. 
     
     
         43 . The method according to  claim 37 , wherein R 5  is methyl. 
     
     
         44 . The method according to  claim 37 , wherein R 5  is ethyl. 
     
     
         45 . The method according to  claim 37 , wherein the compound is selected from the group consisting of:
 methyl (R)-2-amino-3-(7-methylthieno[3,2-b]pyridine-2-carboxamido)propanoate;   ethyl (R)-2-amino-3-(7-methylthieno[3,2-b]pyridine-2-carboxamido)propanoate;   propyl (R)-2-amino-3-(7-methylthieno[3,2-b]pyridine-2-carboxamido)propanoate;   isopropyl (R)-2-amino-3-(7-methylthieno[3,2-b]pyridine-2-carboxamido)propanoate;   cyclopropyl (R)-2-amino-3-(7-methylthieno[3,2-b]pyridine-2-carboxamido)propanoate;   butyl (R)-2-amino-3-(7-methylthieno[3,2-b]pyridine-2-carboxamido)propanoate;   isobutyl (R)-2-amino-3-(7-methylthieno[3,2-b]pyridine-2-carboxamido)propanoate;   cyclopropylmethyl (R)-2-amino-3-(7-methylthieno[3,2-b]pyridine-2-carboxamido)propanoate;   2-methoxyethyl (R)-2-amino-3-(7-methylthieno[3,2-b]pyridine-2-carboxamido)propanoate;   isopentyl (R)-2-amino-3-(7-methylthieno[3,2-b]pyridine-2-carboxamido)propanoate;   benzyl (R)-2-amino-3-(7-methylthieno[3,2-b]pyridine-2-carboxamido)propanoate;   cyclohexyl (R)-2-amino-3-(7-methylthieno[3,2-b]pyridine-2-carboxamido)propanoate; and   phenyl (R)-2-amino-3-(7-methylthieno[3,2-b]pyridine-2-carboxamido)propanoate; or a pharmaceutically acceptable salt thereof.   
     
     
         46 . The method according to  claim 37 , wherein the compound is selected from the group consisting of:
 methyl (R)-2-amino-3-(7-methylthieno[3,2-b]pyridine-2-carboxamido)propanoate;   ethyl (R)-2-amino-3-(7-methylthieno[3,2-b]pyridine-2-carboxamido)propanoate;   propyl (R)-2-amino-3-(7-methylthieno[3,2-b]pyridine-2-carboxamido)propanoate; and   isobutyl (R)-2-amino-3-(7-methylthieno[3,2-b]pyridine-2-carboxamido)propanoate; and   pharmaceutically acceptable salts thereof.   
     
     
         47 . The method according to  claim 37 , wherein the compound is methyl (R)-2-amino-3-(7-methylthieno[3,2-b]pyridine-2-carboxamido)propanoate, or a pharmaceutically acceptable salt thereof. 
     
     
         48 . The method according to  claim 37 , wherein the compound is ethyl (R)-2-amino-3-(7-methylthieno[3,2-b]pyridine-2-carboxamido)propanoate, or a pharmaceutically acceptable salt thereof. 
     
     
         49 . The method according to  claim 37 , wherein the compound is propyl (R)-2-amino-3-(7-methylthieno[3,2-b]pyridine-2-carboxamido)propanoate, or a pharmaceutically acceptable salt thereof. 
     
     
         50 . The method according to  claim 37 , wherein the compound is isobutyl (R)-2-amino-3-(7-methylthieno[3,2-b]pyridine-2-carboxamido)propanoate, or a pharmaceutically acceptable salt thereof. 
     
     
         51 . The method for the treatment of depression according to  claim 37 , wherein the depression is selected from the group consisting of major depressive disorder, treatment-resistant depression, catatonic depression, melancholic depression, atypical depression, psychotic depression, perinatal depression, postpartum depression, bipolar depression, including bipolar I depression and bipolar II depression, and mild, moderate or severe depression. 
     
     
         52 . The method for the treatment of depression according to  claim 47 , wherein the depression is selected from the group consisting of major depressive disorder, treatment-resistant depression, catatonic depression, melancholic depression, atypical depression, psychotic depression, perinatal depression, postpartum depression, bipolar depression, including bipolar I depression and bipolar II depression, and mild, moderate or severe depression. 
     
     
         53 . The method for the treatment of depression according to  claim 48 , wherein the depression is selected from the group consisting of major depressive disorder, treatment-resistant depression, catatonic depression, melancholic depression, atypical depression, psychotic depression, perinatal depression, postpartum depression, bipolar depression, including bipolar I depression and bipolar II depression, and mild, moderate or severe depression. 
     
     
         54 . The method for the treatment of depression according to  claim 49 , wherein the depression is selected from the group consisting of major depressive disorder, treatment-resistant depression, catatonic depression, melancholic depression, atypical depression, psychotic depression, perinatal depression, postpartum depression, bipolar depression, including bipolar I depression and bipolar II depression, and mild, moderate or severe depression. 
     
     
         55 . The method for the treatment of depression according to  claim 50 , wherein the depression is selected from the group consisting of major depressive disorder, treatment-resistant depression, catatonic depression, melancholic depression, atypical depression, psychotic depression, perinatal depression, postpartum depression, bipolar depression, including bipolar I depression and bipolar II depression, and mild, moderate or severe depression. 
     
     
         56 . A method of treatment of a condition selected from suicidal ideation, bipolar disorder (including bipolar depression), obsessive compulsive disorder and status epilepticus comprising the administration of a therapeutically effective amount of a compound having the formula Ia: 
       
         
           
           
               
               
           
         
         wherein: 
         R 5  is selected from the group consisting of C 1-5  alkyl, C 1-4  haloalkyl, hydroxyalkyl, C 1-4  hydroxyhaloalkyl, R 8 , WR 8 , and W(OR 9 ); 
         W is selected from the group consisting of C 1-3  alkylene and —CH 2 C(O)—; 
         R 8  is selected from the group consisting of C 3-6  cycloalkyl, phenyl, a 4, 5, or 6 membered heterocycle, and a 5 or 6 membered heteroaryl, wherein said cycloalkyl, phenyl, heterocycle or heteroaryl are independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, C 1-3  alkyl, C 1-3  alkoxy, wherein said C 1-3  alkyl and C 1-3  alkoxy are independently unsubstituted or substituted with 1, 2 or 3 F; and 
         R 9  is C 1-3  alkyl unsubstituted or substituted with 1, 2 or 3 F; 
         or pharmaceutically acceptable salt thereof, to a patient in need thereof.