TREATMENT OF 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.