11a, 12-derivatives of tetracycline compounds

1. A compound of the formula (I):

wherein

R 1 is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylcarbonyl, arylcarbonyl, thiol, alkylthio, arylthio, heterocyclic, halogen or linked to R 2 to form a ring;

R 2 is hydrogen, alkyl, halogen, alkenyl, alkynyl, aryl, hydroxyl, thiol, cyano, nitro, acyl, formyl, alkoxy, amino, alkylamino, heterocyclic, absent or linked to R 1 to form a ring;

R 2′ , R 2″ , R 4a , and R 4b are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;

R 3 , R 10 , and R 12 are each hydrogen, alkyl, aryl, benzyl, arylalkyl, or a prodrug moiety;

R 4 is NR 4a R 4b , alkyl, alkenyl, alkynyl, hydroxyl, halogen, or hydrogen;

R 4′ is hydrogen;

R 5 and R 5′ are each independently hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl carbonyloxy, or aryl carbonyloxy;

R 6 and R 6′ are each independently hydrogen, methylene, absent, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;

R 7 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or —(CH 2 ) 0-3 (NR 7c ) 0-1 C(═W′)WR 7a ;

R 8 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or —(CH 2 ) 0-3 (NR 8c ) 0-1 C(=E′)ER 8a ;

R 9 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or —(CH 2 ) 0-3 (NR 9c ) 0-1 C(═Z)ZR 9a ;

R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 8a , R 8b , R 8c , R 8d , R 8e , R 8f , R 9a , R 9b , R 9c , R 9d , R 9e , and R 9f are each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;

R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;

E is CR 8d R 8e , S, NR 8b or O;

E′ is O, NR 8f , or S;

when Q is a double bond, then R 1′ and R 2 are absent;

when Q is a single bond, then R 1′ is hydrogen, alkyl, halogen, thiol, alkenyl, alkynyl, aryl, formyl, or heterocyclic;

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

W′ is O, NR 7f , or S;

X is CHC(R 13 Y′Y), C═CR 13 Y, CR 6′ R 6 , S, NR 6 , or O;

Y′ and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;

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

Z′ is O, S, or NR 9f , or a pharmaceutically acceptable salt, ester, prodrug, or enantiomer thereof.

2. The compound of claim 1 , wherein R 2′ , R 3 , R 10 and R 12 are each hydrogen or a prodrug moiety; R 4 is NR 4a R 4b ; R 4a and R 4b are each alkyl; X is CR 6′ R 6 ; and R 2″ , R 5 , R 5′ , R 6 , and R 6′ are each hydrogen.

3. The compound of claim 1 , wherein R 4 is NR 4a R 4b ; R 4a and R 4b are each alkyl; R 5 is hydroxyl; X is CR 6′ R 6 ; R 6 is methyl; and R 5′ and R 6′ are hydrogen.

4. The compound of claim 1 , wherein R 4 is NR 4a R 4b ; R 4a and R 4b are each alkyl; X is CR 6′ R 6 ; R 5 , R 5′ , R 6 and R 6′ are hydrogen atoms and R 7 is dimethylamino.

5. The compound of claim 1 , wherein R 9 is hydrogen.

6. The compound of claim 1 , wherein R 9 is substituted or unsubstituted aryl, substituted or unsubstituted alkyl, substituted or unsubstituted amino, nitro or halogen.

7. The compound of claim 6 , wherein R 9 is aminoalkyl.

8. The compound of claim 7 , wherein R 9 is aminomethyl.

9. The compound of claim 8 , wherein R 9 is alkylaminomethyl.

10. The compound of claim 1 , wherein R 7 is hydrogen, substituted or unsubstituted aryl, substituted or unsubstituted alkyl, substituted or unsubstituted amino, nitro or halogen.

11. The compound of claim 1 , wherein R 8 is hydrogen, substituted or unsubstituted aryl, substituted or unsubstituted alkyl, substituted or unsubstituted amino, nitro or halogen.

12. The compound of claim 1 , wherein R 3 , R 10 and R 12 are each hydrogen, alkyl, aryl, or arylalkyl.

13. The compound of claim 1 , wherein R 1 is hydrogen, halogen, thiol, alkyl, alkenyl, alkynyl, or aryl.

14. The compound of claim 1 , wherein Q is a single bond.

15. The compound of claim 14 , wherein R 1 , R 1′ and R 2 are each hydrogen.

16. The compound of claim 1 , wherein Q is a double bond.

17. The compound of claim 16 , wherein R 1 is hydrogen.

18. A compound selected from the group consisting of:

and pharmaceutically acceptable salts, esters, prodrugs and enantiomers thereof.

19. A pharmaceutical composition comprising compound of claim 1 and a pharmaceutically acceptable carrier.

20. The pharmaceutical composition of claim 19 , wherein said compound is present in an amount effective to ameliorate a disease selected from: bacterial infection, multiple sclerosis, central pontine myelinolysis, leukodystrophy, acute disseminated encephalomyelitis, progressive multifocal leukoencephalopathy, and subacute sclerosing panencephalitis.

21. A method for ameliorating a disease selected from: bacterial infection, multiple sclerosis, central pontine myelinolysis, leukodystrophy, acute disseminated encephalomyelitis, progressive multifocal leukoencephalopathy, and subacute sclerosing panencephalitis in a subject in need thereof, comprising administering to said subject an effective amount of a compound of claim 1 , such that said disease is ameliorated.

22. The method of claim 21 , wherein said subject is a mammal.

23. The method of claim 21 , wherein said subject is a human.

24. The method of claim 21 , wherein said disease is associated with bacterial infection.

25. The method of claim 21 , wherein said disease is central pontine myelinolysis.

26. The method of claim 21 , wherein said disease is leukodystrophy.

27. The method of claim 21 , wherein said disease is acute disseminated encephalomyelitis.

28. The method of claim 21 , wherein said disease is progressive multifocal leukoencephalopathy or subacute sclerosing panencephalitis.

29. The method of claim 21 , wherein said disease is multiple sclerosis.

30. The method of claim 29 , wherein said multiple sclerosis is relapsing or remitting multiple sclerosis, primary progressive multiple sclerosis, or secondary progressive multiple sclerosis.