Methods for treating spinal muscular atrophy using tetracycline compounds

1. A method for treating spinal muscular atrophy, comprising administering to a subject having spinal muscular atrophy an effective amount of a tetracycline compound; wherein said compound is of formula I:

wherein

X is CR 6′ R 6 ;

R 2 and R 2′ are each hydrogen;

R 3 , R 4a , R 11 and R 12 are each hydrogen;

R 4 is NR 4′ R 4″;

R 4′ and R 4″ are each alkyl;

R 5 and R 5′ are each hydrogen, alkyl, or hydroxyl;

R 6 and R 6′ are each hydrogen or alkyl;

R 7 is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl, heterocyclic or —(CH 2 ) 0-3 (NR 7c ) 0-1 C(=W′)WR 7a ;

R 8 is hydrogen;

R 9 is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl, heterocyclic or —(CH 2 ) 0-3 (NR 9c ) 0-1 C(=Z′)ZR 9a ;

R 10 is hydroxyl;

R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 9a , R 9b , R 9c , R 9d , R 9e , and R 9f are each independently hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic;

W is CR 7d R 7e , S, NR 7b or O;

W′ is O, NR 7f , or S;

Z is CR 9d R 9e , S, NR 9b or O; and

Z′ is O, S, or NR 9f ;

or a pharmaceutically acceptable salt, ester or enantiomer thereof.

2. The method of claim 1 , wherein R 5 , R 5 ′, R 6 , and R 6 ′ are each hydrogen and R 7 is amino.

3. The method of claim 2 , wherein said amino is dialkylamino.

4. The method of claim 3 , wherein said dialkylamino is dimethylamino.

5. The method of claim 1 , wherein R 9 is aryl, wherein said aryl is of formula II:

wherein

A 9g , A 9h , A 9i , A 9j and A 9k are each independently N or C; and

when A 9g , A 9h , A 9i , A 9j and A 9k are C, R 9g , R 9h , R 9i , R 9j and R 9k are each independently hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic; or

when A 9g , A 9h , A 9i , A 9j and A 9k is N, R 9g , R 9h , R 9i , R 9j and R 9k are absent.

6. The method of claim 5 , wherein A 9g , A 9h , A 9i , A 9j and A 9k are each C.

7. The method of claim 6 , wherein R 9g , R 9i , R 9j and R 9k are each hydrogen.

8. The method of claim 7 , wherein R 9h is carbonyl, wherein said carbonyl is of formula III:

wherein R 9l and R 9m may each be independently hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic or R 9l and R 9m are linked to form a 5- or 6-membered aryl, heterocyclic or aliphatic ring.

9. The method of claim 8 , wherein R 9m is hydrogen.

10. The method of claim 9 , wherein R 9l is alkyl, wherein said alkyl is of formula IV:

wherein

D 9 is O, N or CR 9′ ;

a is an integer from 0 to 10;

R 9′ is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic; and

when D 9 is N or CR 9′ , R 9n and R 9o are each hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic or R 9n and R 9o are linked to form a 5- or 6-membered aryl, heterocyclic or aliphatic ring; or

when D 9 is O, R 9n is hydrogen, alkyl, alkenyl, alkynyl, acyl, hydroxyl, alkoxy, halogen, thioether, sulfinyl, sulfonyl, amino, cyano, nitro, carbonyl, aryl or heterocyclic and R 9o is absent.

11. The method of claim 10 , wherein D 9 is N.

12. The method of claim 11 , wherein a is 2 or 3.

13. The method of claim 12 , wherein R 9n and R 9o are each alkyl.

14. The method of claim 13 , wherein said alkyl is methyl.

15. The method of claim 10 , wherein a is 0.

16. The method of claim 15 , wherein R 9n and R 9o are each hydrogen.

17. The method of claim 5 , wherein R 5 , R 5′ , R 6 , and R 6′ are each hydrogen and R 7 is amino.

18. The method of claim 17 , wherein said amino is dialkylamino.