3, 10, and 12a substituted tetracycline compounds

1. A compound of Formula I:

wherein:

X is CHC(R 13 Y′Y) or CR 6′ R 6 ;

R 2″ is —C(═O)NR 2 R 2′ or —CN;

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

R 3 , R 11 and R 12″ are each independently hydrogen, alkyl, alkenyl, aryl, alkynyl, arylalkyl, acetyl, alkylcarbonyl, alkenylcarbonyl, arylcarbonyl, alkynylcarbonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl, arylaminocarbonyl, alkylthiocarbonyl, alkenylthiocarbonyl, alkynylthiocarbonyl, arylthiocarbonyl, alkyloxythiocarbonyl, alkenyloxythiocarbonyl, alkynyloxythiocarbonyl, aryloxythiocarbonyl, alkylaminothiocarbonyl, alkenylaminothiocarbonyl, alkynylaminothiocarbonyl, arylaminothiocarbonyl, alkylthiothiocarbonyl, alkenylthiothiocarbonyl, alkynylthiothiocarbonyl or arylthiothiocarbonyl;

R 10 is hydrogen, alkenyl, aryl, alkynyl, arylalkyl, alkenylcarbonyl, arylcarbonyl, alkynylcarbonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl, arylaminocarbonyl, alkylthiocarbonyl, alkenylthiocarbonyl, alkynylthiocarbonyl, arylthiocarbonyl, alkyloxythiocarbonyl, alkenyloxythiocarbonyl, alkynyloxythiocarbonyl, aryloxythiocarbonyl, alkylaminothiocarbonyl, alkenylaminothiocarbonyl, alkynylaminothiocarbonyl, arylaminothiocarbonyl, alkylthiothiocarbonyl, alkenylthiothiocarbonyl, alkynylthiothiocarbonyl or arylthiothiocarbonyl;

R 12 is hydrogen, alkyl, alkenyl, aryl, alkynyl, arylalkyl, alkenylcarbonyl, alkynylcarbonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aryloxycarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl, alkylthiocarbonyl, alkenylthiocarbonyl, alkynylthiocarbonyl, arylthiocarbonyl, alkyloxythiocarbonyl, alkenyloxythiocarbonyl, alkynyloxythiocarbonyl, aryloxythiocarbonyl, alkylaminothiocarbonyl, alkenylaminothiocarbonyl, alkynylaminothiocarbonyl, arylaminothiocarbonyl, alkylthiothiocarbonyl, alkenylthiothiocarbonyl, alkynylthiothiocarbonyl or arylthiothiocarbonyl, provided that at least one of R 3 , R 10 , R 11 or R 12 is not hydrogen when R 12′ is OR 12 ;

R 4 and R 4′ are each independently NR 4a R 4b , alkyl, alkenyl, alkynyl, hydroxyl, halogen or hydrogen;

R 5 is 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, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino or arylalkyl;

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

R 12′ is OR 12 or NR 12 R 12″ ;

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

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

E′ is O, NR 8 or S;

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;

Z′ is O, S or NR 9f ; and

Y′ and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino or arylalkyl, or pharmaceutically acceptable salts, esters or enantiomers thereof.

2. The compound of claim 1 , wherein X is CR 6 R 6′ ; R 2 , R 2′ , R 6 , R 6′ , R 8 and R 11 are each hydrogen; and R 5 is hydroxyl or hydrogen.

3. The compound of claim 2 , wherein R 4 is dialkylamino; and R 4′ and R 5 are each hydrogen.

4. The compound of claim 1 , wherein R 3 is hydrogen, alkyl, alkenyl, aryl, acetyl, arylalkyl, alkynyl, alkylcarbonyl, alkenylcarbonyl, arylcarbonyl, alkynylcarbonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl, arylaminocarbonyl, alkylthiocarbonyl, alkenylthiocarbonyl, alkynylthiocarbonyl, arylthiocarbonyl, alkyloxythiocarbonyl, alkenyloxythiocarbonyl, alkynyloxythiocarbonyl, aryloxythiocarbonyl, alkylaminothiocarbonyl, alkenylaminothiocarbonyl, alkynylaminothiocarbonyl, arylaminothiocarbonyl, alkylthiothiocarbonyl, alkenylthiothiocarbonyl, alkynylthiothiocarbonyl or aryithiothiocarbonyl.

5. The compound of claim 4 , wherein R 3 is benzyl.

6. The compound of claim 4 , wherein R 3 is alkyl.

7. The compound of claim 4 , wherein R 3 is acetyl.

8. The compound of claim 4 , wherein R 3 is alkenyl.

9. The compound of claim 4 , wherein R 3 is hydrogen.

10. The compound of claim 1 , wherein R 10 is hydrogen, alkenyl, aryl, arylalkyl, alkynyl, alkenylcarbonyl, arylcarbonyl, alkynylcarbonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl, arylaminocarbonyl, alkylthiocarbonyl, alkenylthiocarbonyl, alkynylthiocarbonyl, arylthiocarbonyl, alkyloxythiocarbonyl, alkenyloxythiocarbonyl, alkynyloxythiocarbonyl, aryloxythiocarbonyl, alkylaminothiocarbonyl, alkenylaminothiocarbonyl, alkynylaminothiocarbonyl, arylaminothiocarbonyl, alkylthiothiocarbonyl, alkenylthiothiocarbonyl, alkynylthiothiocarbonyl or arylthiothiocarbonyl.

11. The compound of claim 10 , wherein R 10 is benzyl.

12. The compound of claim 10 , wherein R 10 is alkenyl.

13. The compound of claim 10 , wherein R 10 is hydrogen.

14. The compound of claim 1 , wherein R 12 is hydrogen, alkyl, alkenyl, aryl, arylalkyl, alkynyl, alkenylcarbonyl, alkynylcarbonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aryloxycarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl, alkylthiocarbonyl, alkenylthiocarbonyl, alkynylthiocarbonyl, arylthiocarbonyl, alkyloxythiocarbonyl, alkenyloxythiocarbonyl, alkynyloxythiocarbonyl, aryloxythiocarbonyl, alkylaminothiocarbonyl, alkenylaminothiocarbonyl, alkynylaminothiocarbonyl, arylaminothiocarbonyl, alkylthiothiocarbonyl, alkenylthiothiocarbonyl, alkynylthiothiocarbonyl or arylthiothiocarbonyl.

15. The compound of claim 14 , wherein R 12 is benzyl.

16. The compound of claim 14 , wherein R 12 is hydrogen.

17. A compound selected from the group consisting of:

or pharmaceutically acceptable salts, esters or enantiomers thereof.

18. A method for treating a tetracycline responsive state in a subject, comprising administering to said subject a compound of claim 1 or 17 , such that said tetracycline responsive state is treated.

19. The method of claim 18 , wherein said compound is non-antibacterial.

20. The method of claim 18 wherein said tetracycline responsive state is an inflammatory process associated state, a cancer, a lung injury, an eye disorder, a stroke or a neurological disorder.

21. The method of claim 20 , wherein said neurological disorder is Alzheimer's disease, Huntington's disease, Parkinson's disease, amylotropic lateral sclerosis or multiple sclerosis.

22. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or 17 , and a pharmaceutically acceptable carrier.

23. A compound selected from the group consisting of:

or pharmaceutically acceptable salts, esters or enantiomers thereof.

24. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 23 , and a pharmaceutically acceptable carrier.