Histone deacetylase inhibitors as therapeutics for neurological diseases

Abstract

The invention provides HDAC inhibitors that may be used as therapeutics for the treatment of a neurodegenerative or neuromuscular condition. The invention provides compounds of formula I: The invention also provides pharmaceutical compositions and articles of manufacture that include these compounds, as well as methods of treating and methods of preventing or delaying the onset of a neurodegenerative or neuromuscular condition.

1 . A compound of formula Ia:  
       
         
           
           
               
               
           
         
       
       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;  
 provided that when R 1  is phenyl and n is 3-6, R 2  is not 2-aminophenyl; and  
 provided that when R 1  is 2-aminophenyl and n is 3-6, R 2  is not phenyl.  
 
     
     
         2 . The compound of  claim 1 , wherein when R 1  is phenyl, R 2  is not 2-aminophenyl; and when R 1  is 2-aminophenyl, R 2  is not phenyl.  
     
     
         3 . The compound of  claim 1 , wherein R 1  is aryl or heteroaryl.  
     
     
         4 . The compound of  claim 1 , wherein R 1  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.  
     
     
         5 . The compound of  claim 1 , wherein R 2  is aryl or heteroaryl.  
     
     
         6 . The compound of  claim 1 , wherein 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.  
     
     
         7 . The compound of  claim 1 , wherein R 1  and R 2  are the same or are not the same.  
     
     
         8 . The compound of  claim 1 , wherein R a  is H, R b  is H, or both R a  and R b  are H's.  
     
     
         9 . The compound of  claim 1 , wherein R a  is a nitrogen protecting group; R b  is a nitrogen protecting group; or both are nitrogen protecting groups.  
     
     
         10 . The compound of  claim 1 , wherein n is 3 to 6.  
     
     
         11 . The compound of  claim 1 , wherein n is 4 to 5.  
     
     
         12 . The compound of  claim 1 , wherein n is 6.  
     
     
         13 . The compound of  claim 1 , wherein R 1 , R 2 , or both R 1  and R 2  are substituted with two amino groups or two methoxy groups.  
     
     
         14 . The compound of  claim 1  that has a structure selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       a salt of a basic compound thereof; and any combination thereof.  
     
     
         15 . The compound of  claim 1 , wherein the salt forming moiety is a mineral acid, an organic acid, an alkaline or alkaline earth base, an amine or ammonia.  
     
     
         16 . 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.  
 
     
     
         17 . The method of  claim 16 , wherein the one or more coupling agents comprise 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (EDC) and 1-hydroxy-7-azabenzotriazole (HOBt).  
     
     
         18 . The method of  claim 16 , wherein the compound of formula I is formed in the presence of one or more basic compounds.  
     
     
         19 . The method of  claim 18 , wherein the one or more basic compounds comprise an alkyl amine.  
     
     
         20 . The method of  claim 19 , wherein the alkyl amine is diisopropylethylamine.  
     
     
         21 . The method of  claim 16 , wherein the compound of formula I is formed in the presence of a solvent system.  
     
     
         22 . The method of  claim 21 , wherein the solvent system comprises dimethylformamide.  
     
     
         23 . The method of  claim 16 , further comprising purifying the compound of formula I.  
     
     
         24 . The method of  claim 23 , wherein the purification comprises one or more of precipitation, filtration, recrystallization, and chromatography.  
     
     
         25 . The method of  claim 16 , further comprising forming the compound of formula V by contacting a compound of formula III:  
       
         
           
           
               
               
           
         
       
       with a compound of formula IV:  
         R 1 -NH(R a )  (IV)  
       to provide the compound of formula V.  
     
     
         26 . The method of  claim 25 , wherein the compounds of formula III and IV are contacted in the presence of a solvent system.  
     
     
         27 . The method of  claim 26 , wherein the solvent system comprises an organic solvent.  
     
     
         28 . The method of  claim 27 , wherein the organic solvent comprises one or more of ether, tetrahydrofuran, and dioxane.  
     
     
         29 . The method of  claim 25 , further comprising forming the compound of formula III by contacting a compound of formula II:  
       
         
           
           
               
               
           
         
       
       with a dehydrating agent to provide the compound of formula III.  
     
     
         30 . The method of  claim 29 , wherein the dehydrating agent comprises a carboxylic anhydride.  
     
     
         31 . The method of  claim 30 , wherein the carboxylic anhydride is acetic anhydride.  
     
     
         32 . The method of  claim 29 , wherein the formation of the compound of formula III is carried out under anhydrous conditions.  
     
     
         33 . The method of  claim 29 , wherein the compound of formula II and the dehydrating agent are heated.  
     
     
         34 . 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.  
 
     
     
         35 . 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.  
 
     
     
         36 . The composition of  claim 35 , wherein when R 1  of the compound of formula I is phenyl, R 2  is not 2-aminophenyl; and when R 1  is 2-aminophenyl, R 2  is not phenyl.  
     
     
         37 . The composition of  claim 35 , wherein the composition is suitable for oral administration, parenteral administration, or intravenous administration.  
     
     
         38 . The composition of  claim 35 , wherein the composition is in the form of a tablet, capsule, elixir, or a sustained-release formulation.  
     
     
         39 . The composition of  claim 35 , wherein the compound of formula I is in an amount effective to increase frataxin mRNA levels in a cell.  
     
     
         40 . The composition of  claim 39 , wherein the cell is a mammalian cell.  
     
     
         41 . The composition of  claim 40 , wherein the mammalian cell is a human cell.  
     
     
         42 . The composition of  claim 41 , wherein the human cell is a lymphocyte, a cardiomyocyte or a neuronal cell.  
     
     
         43 . An article of manufacture comprising packaging material and, contained within the packaging material, the compound of formula I, wherein the packaging material comprises a label indicating that the compound of formula I can be used for treating Friedreich's ataxia, and wherein formula I is:  
       
         
           
           
               
               
           
         
       
       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.  
 
     
     
         44 . A method of treating, or preventing or delaying the onset of, a neurodegenerative or neuromuscular condition in a mammal comprising administering to the mammal a compound of formula I in an amount effective to alter the level of histone acetylation in the mammal, wherein formula I is:  
       
         
           
           
               
               
           
         
       
       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.  
 
     
     
         45 . The method of  claim 44 , further comprising identifying the mammal as one suffering from, or at risk for, a neurodegenerative or neuromuscular condition.  
     
     
         46 . The method of  claim 45 , wherein the neurodegenerative or neuromuscular condition is selected from the group consisting of Huntington's disease, spinocerebellar ataxia, Friedreich's ataxia, Fragile X syndrome, spinal muscular atrophy, Kennedy's disease, spinal and bulbar muscular atrophy, myotonic dystrophy, amyotrophic lateral sclerosis and Alzheimer's disease.  
     
     
         47 . A method of treating, or preventing or delaying the onset of, Friedreich's ataxia in a mammal comprising administering to the mammal a compound of formula I in an amount effective to increase fraxatin mRNA in the mammal, wherein formula I is:  
       
         
           
           
               
               
           
         
       
       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.  
 
     
     
         48 . The method of  claim 44  or  47 , wherein the mammal is a human.  
     
     
         49 . The method of  claim 44  or  47 , wherein the compound is administered orally or parenterally.  
     
     
         50 . The method of  claim 47 , further comprising identifying the mammal as one suffering from or at risk for Friedreich's ataxia.  
     
     
         51 . The method of  claim 50 , wherein the mammal suffering from or at risk for Friedreich's ataxia is identified by determining the extent of expansion of a GAA triplet repeat in intron 1 of the frataxin gene, the level of frataxin mRNA in the mammal, or the level of frataxin proteins in the mammal.  
     
     
         52 . A compound of  claim 1 , that is a histone deacetylase inhibitor.  
     
     
         53 . A pharmaceutical composition of  claim 35 , wherein the compound of formula I is a histone deacetylase inhibitor.  
     
     
         54 . A method of  claim 44  or  47 , wherein the compound of formula I is a histone deacetylase inhibitor.