Treatment of friedreich's ataxia using histone deacetylase inhibitors

Abstract

The invention provides methods of treating Friedreich's ataxia using histone deacetylase inhibitors.

1 . A method of treating or delaying the onset of Friedreich's ataxia in a mammal comprising administering to the mammal a histone deacetylase inhibitor in an amount effective to inhibit a histone deacetylase in the mammal. 
     
     
         2 . The method of  claim 1 , wherein the histone deacetylase inhibitor is administered to the mammal in an amount effective to increase the level of histone acetylation in the mammal. 
     
     
         3 . The method of  claim 1 , wherein the histone deacetylase inhibitor is administered to the mammal in an amount effective to increase frataxin mRNA in the mammal. 
     
     
         4 . The method of  claim 1 , wherein the histone deacetylase inhibitor interacts with a class I histone deacetylase. 
     
     
         5 . The method of  claim 4 , wherein the class I histone deacetylase is selected from the group consisting of a histone deacetylase 1, histone deacetylase 2, histone deacetylase 3, histone deacetylase 8, and a histone deacetylase that has a deacetylase domain exhibiting from 45% to 93% identity in amino acid sequence to deacetylase 1, histone deacetylase 2, histone deacetylase 3, and histone deacetylase 8. 
     
     
         6 . The method of  claim 4 , wherein the class 1 histone deacetylase is selected from the group consisting of a histone deacetylase 1, histone deacetylase 2, histone deacetylase 3, and histone deacetylase 8. 
     
     
         7 . The method of  claim 4 , wherein the class I histone deacetylase is a histone deacetylase 1. 
     
     
         8 . The method of  claim 4 , wherein the class I histone deacetylase is a histone deacetylase 2. 
     
     
         9 . The method of  claim 4 , wherein the class I histone deacetylase is a histone deacetylase 3. 
     
     
         10 . The method of  claim 4 , wherein the class I histone deacetylase is a histone deacetylase 8. 
     
     
         11 . The method of  claim 1 , wherein the mammal has a GAA triplet repeat in intron 1 of the frataxin gene. 
     
     
         12 . The method of  claim 1 , wherein the histone deacetylase inhibitor is a compound of formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 n is 2 to about 10; 
 R 1  is aryl or heteroaryl; 
 R 2  is aryl or heteroaryl; 
 R a  and R b  are each independently H, alkyl, aryl, heteroaryl, or a nitrogen protecting group; 
 wherein any alkyl, aryl or heteroaryl is unsubstituted or is substituted with 1 to 3 substituents selected from the group consisting of hydroxy, amino, nitro, cyano, halo, alkyl, trifluoromethyl, alkoxy, aryl, and NR c R d  or any combination thereof; 
 wherein R c  and R d  are each independently hydrogen, alkyl, or C(═O)OR e  wherein R e  is H or alkyl; 
 or a salt thereof. 
 
     
     
         13 . The method of  claim 12 , wherein R 1  or R 2  is phenyl; 2-methylphenyl; 3-methylphenyl; 4-methylphenyl; 2-aminophenyl; 3-aminophenyl; 4-aminophenyl; 2-methoxyphenyl; 3-methoxyphenyl; 4-methoxyphenyl; 2,4-dimethoxyphenyl; 3,5-dimethoxyphenyl; 3,4,5-trimethoxyphenyl; 2,4-diaminophenyl; 3,5-diaminophenyl; 3,4,5-triaminophenyl; 2-pyridinyl; 3-quinolinyl; or 8-quinolinyl. 
     
     
         14 . The method of  claim 12 , wherein R a  is H, R b  is H, or both R a  and R b  are H. 
     
     
         15 . The method of  claim 12 , wherein R a  is a nitrogen protecting group; R b  is a nitrogen protecting group; or both R a  and R b  are nitrogen protecting groups. 
     
     
         16 . The method of  claim 12 , wherein the compound of formula I has a structure selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       a salt of a basic compound thereof; and any combination thereof. 
     
     
         17 . A method for preparing a compound of formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 n is 2 to about 10; 
 R 1  is aryl or heteroaryl; 
 R 2  is aryl or heteroaryl; 
 R a  and R b  are each independently H, alkyl, aryl, heteroaryl, or a nitrogen protecting group; 
 wherein any alkyl, aryl or heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxy, amino, nitro, cyano, halo, alkyl, trifluoromethyl, alkoxy, aryl, and NR c R d ; 
 wherein R c  and R d  are each independently hydrogen, alkyl, or C(═O)OR e  wherein R e  is H or alkyl; 
 or a salt thereof; 
 comprising contacting a compound of formula V: 
 
       
         
           
           
               
               
           
         
       
       with one or more coupling agents and a compound of formula VI:
   R 2 —NH(R b )  (VI)
 
 
       to provide the compound of formula I. 
     
     
         18 . A method for preparing a compound of formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 n is 3 to about 10; 
 R 1  is aryl or heteroaryl; 
 R 2  is aryl or heteroaryl; 
 R a  and R b  are H, alkyl, aryl, heteroaryl, or a nitrogen protecting group; 
 wherein any alkyl, aryl or heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxy, amino, nitro, cyano, halo, alkyl, trifluoromethyl, alkoxy, aryl, and NR c R d ; 
 wherein R c  and R d  are each independently hydrogen, alkyl, or C(═O)OR e  wherein R e  is H or alkyl; 
 the method comprising: 
 (a) contacting a compound of formula II: 
 
       
         
           
           
               
               
           
         
       
       with a dehydrating agent to provide a compound of formula III: 
       
         
           
           
               
               
           
         
         (b) contacting the compound of formula III with a compound of formula IV:
   R 1 —NH(R a )  (IV)
 
 
       
       to provide a compound of formula V: 
       
         
           
           
               
               
           
         
         (c) contacting the compound of formula V with one or more coupling agents and a compound of formula VI:
   R 2 —NH(R b )  (VI)
 
 
       
       to provide the compound of formula I. 
     
     
         19 . A pharmaceutical composition comprising a compound of formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 n is 2 to about 10; 
 R 1  is aryl or heteroaryl; 
 R 2  is aryl or heteroaryl; 
 R a  and R b  are each independently H, alkyl, aryl, heteroaryl, or a nitrogen protecting group; 
 wherein any alkyl, aryl or heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxy, amino, nitro, cyano, halo, alkyl, trifluoromethyl, alkoxy, aryl, and NR c R d ; 
 wherein R c  and R d  are each independently hydrogen, alkyl, or C(═O)OR e  wherein R e  is H or alkyl; 
 or a salt thereof; 
 
       in combination with a pharmaceutically acceptable carrier. 
     
     
         20 . The composition of  claim 19 , wherein the composition is in the form of a tablet, capsule, elixir, or a sustained-release formulation. 
     
     
         21 . The composition of  claim 17 , wherein the compound of formula I is in an amount effective to inhibit a histone deacetylase or increase frataxin mRNA levels in a mammalian cell.