Glutamine antagonists for the treatment of cognitive deficits and psychiatric disorders

Abstract

The disclosure provides compounds having formula (I): and the pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 2 ′, and X are as defined as set forth in the specification, for use in treating cognitive deficits and/or psychiatric disorders, such as those associated with neurological or neurodegenerative disorders, psychiatric or mood disorders, and HIV-associated neurocognitive disorders (HAND). Compounds having formula (I) are prodrugs that release glutamine analogs, e.g., 6-diazo-5-oxo-L-norleucine (DON).

That which is claimed: 
     
         1 . A method for treating a subject having a cognitive deficit or psychiatric disorder, the method comprising administering to the subject a compound having formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         X is selected from the group consisting of a bond, —O—, and —(CH 2 ) n —, wherein n is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8; 
         R 1  is selected from the group consisting of C 1-6  alkyl and substituted C 1-6  alkyl; 
         R 2  is —C(═O)—O—(CR 3 R 4 ) m —O—C(═O)—R 10 ; 
         R 2 ′ is selected from the group consisting of H, C 1 -C 6  alkyl, and substituted C 1 -C 6  alkyl; 
         each R 3  and R 4  is independently H, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, aryl, substituted aryl, —(CR 3 R 4 ) m —NR 5 R 6 , or 
       
       
         
           
           
               
               
           
         
         m is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8; 
         R 5  and R 6  is independently H or alkyl; and 
         R 10  is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, monosaccharide, acylated monosaccharide, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, 
         in an amount effective to treat the cognitive deficit or psychiatric disorder. 
       
     
     
         2 . The method of  claim 1 , wherein X is —CH 2 —. 
     
     
         3 . The method of  claim 1 , wherein X is —O—. 
     
     
         4 . The method of  claim 1 , wherein R 1  is selected from the group consisting of methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, trimethylammonium, triethylammonium, tri(hydroxyethyl)ammonium, tripropylammonium, and tri(hydroxypropyl)ammonium. 
     
     
         5 . The method of  claim 1 , wherein:
 m is 1;   each R 3  and R 4  are independently H, C 1 -C 6  alkyl, aryl or substituted aryl; and   R 10  is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.   
     
     
         6 . The method of  claim 1 , wherein the compound having formula (I) is a compound having formula (II): 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is selected from the group consisting of H and C 1-6  alkyl; 
         R 3  and R 4  are independently selected from the group consisting of H, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, aryl, and substituted aryl; and 
         R 10  is C 1-6  alkyl. 
       
     
     
         7 . The method of  claim 6 , wherein R 1  is selected from the group consisting of methyl, ethyl, and isopropyl. 
     
     
         8 . The method of  claim 6 , wherein R 3  is H and R 4  is selected from the group consisting of methyl and phenyl. 
     
     
         9 . The method of  claim 6 , wherein R 10  is selected from the group consisting of isopropyl and tert-butyl. 
     
     
         10 . The method of  claim 1 , wherein the compound having formula (I) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         11 . The method of  claim 10 , wherein the compound having formula (I) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The method of  claim 1  for treating a subject having a cognitive deficit. 
     
     
         13 . The method of  claim 12 , wherein the cognitive deficit is characterized by impairment of the mental processes of perception, learning, memory, judgment, and/or reasoning. 
     
     
         14 . The method of  claim 12 , wherein the cognitive deficit is due to a viral infection. 
     
     
         15 . The method of  claim 14 , wherein the cognitive deficit is due to the human immunodeficiency virus (HIV). 
     
     
         16 . The method of  claim 15 , wherein the virus is latent. 
     
     
         17 . The method of  claim 12 , wherein the cognitive deficit is selected from the group consisting of asymptomatic neurocognitive impairment (ANI) and mild neurocognitive disorder (MND). 
     
     
         18 . The method of  claim 12 , wherein the cognitive deficit is associated with a neurodegenerative disorder. 
     
     
         19 . The method of  claim 12 , wherein the cognitive deficit is associated with a psychiatric disorder. 
     
     
         20 . The method of  claim 12 , wherein the cognitive deficit is associated with multiple sclerosis. 
     
     
         21 . The method of  claim 1  for treating a subject having a psychiatric disorder.