9-aminoacyl tetracycline compounds and methods of use thereof

1. A compound of formula (I):

wherein:

R represents hydrogen, halogen, or C 1-6 alkyl;

R 1 represents hydrogen, C 1-6 alkyl or together R 1 and R 3 represent a CH 2 moiety;

R 2 represents hydrogen, —OC 1-6 alkyl, —O(O)C 1-6 alkyl or hydroxy;

R 3 represents hydrogen, hydroxy or together R 3 and R 1 represent a CH 2 moiety;

R 4 represents hydrogen or C 1-6 alkyl;

R 5 represents hydrogen, C 1-6 alkyl or C 1-6 alkoxycarbonyl;

X represents NRxRy or —OC 1-6 alkyl optionally substituted by one or more groups selected from hydroxy, methoxy, halogen, amino and trifluoromethyl;

Ra and Rb independently represent hydrogen or C 1-6 alkyl;

Rx and Ry independently represent hydrogen, benzyl, C 3-6 cycloalkyl, C 3-6 alkenyl, C 3-6 alkynyl, or C 1-6 alkyl optionally substituted by one or more groups selected from hydroxy, methoxy, halogen, NRaRb and trifluoromethyl, —C 1-6 alkylcycloalkyl, C 1-6 alkylamino and C 1-6 alkylthio and pharmaceutically acceptable derivatives and solvates thereof.

2. A compound of claim 1 for use in medical therapy.

3. The compound of claim 1 wherein R, R 3 , R 4 and R 5 are each hydrogen, R 1 is methyl and R 2 is hydroxyl.

4. The compound of claim 3 , wherein X is NRxRy and Rx and Ry are each independently hydrogen, benzyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 3-6 alkenyl, or substituted or unsubstituted C 1-6 alkyl.

5. The compound of claim 4 , wherein said substituted C 3-6 cycloalkyl, substituted C 3-6 alkenyl and substituted C 1-6 alkyl are substituted by one or more groups selected from hydroxy, methoxy, and NRaRb, —C 1-3 alkylcycloalkyl, C 1-6 alkylamino and C 1-6 alkylthio.

6. The compound of claim 5 , wherein X is NRxRy and NRxRy is selected from the group consisting of MeNH, Me 2 N, EtNH, CH 2 CHCH 2 NH, CH 3 OCH 2 CH 2 NH, n-PrNH, i-PrNH, n-HexNH, (CH 3 ) 2 NCH 2 CH 2 NH, CH 3 (CH 3 ) 2 CHCH 2 CH 2 NH, cyclopropyl-NH, cyclobutyl-NH, cyclopentyl-NH, cyclohexylNH, propenyl-NH, and benzyl-NH.

7. The compound of claim 1 , wherein R, R 1 , R 2 , R 3 , R 4 and R 5 are each hydrogen.

8. The compound of claim 7 , wherein X is NRxRy and Rx and Ry are each independently hydrogen, benzyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 3-6 alkenyl, substituted or unsubstituted C 1-6 alkyl.

9. The compound of claim 8 , wherein said substituted C 3-6 cycloalkyl, substituted C 3-6 alkenyl and substituted C 1-6 alkyl are substituted by one or more groups selected from hydroxy, methoxy, and NRaRb, —C 1-3 alkylcycloalkyl, C 1-6 alkylamino and C 1-6 alkylthio.

10. The compound of claim 9 , wherein X is NRxRy and NRxRy is selected from the group consisting of MeNH, Me 2 N, EtNH, CH 2 CHCH 2 NH, CH 3 OCH 2 CH 2 NH, n-PrNH, i-PrNH, n-HexNH, (CH 3 ) 2 NCH 2 CH 2 NH, CH 3 (CH 3 ) 2 CHCH 2 CH 2 NH, cyclopropyl-NH, cyclobutyl-NH, cyclopentyl-NH, cyclohexylNH, propenyl-NH, benzyl-NH.

11. The compound of claim 3 , wherein X is substituted or unsubstituted —OC 1-6 alkyl.

12. The compound of claim 11 , wherein said substituted —OC 1-6 alkyl is substituted by one or more groups selected from hydroxy, methoxy, halogen, amino and trifluoromethyl.

13. The compound of claim 7 , wherein X is substituted or unsubstituted —OC 1-6 alkyl.

14. The compound of claim 13 , wherein said substituted —OC 1-6 alkyl is substituted by one or more groups selected from hydroxy, methoxy, halogen, amino and trifluoromethyl.

15. The compound of claim 1 , wherein the compound is [4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[1-(ethoxycarbonyl)ethyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naplitacenecarboxamide.

16. A compound of formula (I):

wherein:

R represents NRaRb;

R 1 represents hydrogen, C 1-6 alkyl or together R 1 and R 3 represent a CH 2 moiety;

R 2 represents hydrogen, —OC 1-6 alkyl, —O(O)C 1-6 alkyl or hydroxy;

R 3 represents hydrogen, hydroxy or together R 3 and R 1 represent a CH 2 moiety;

R 4 represents hydrogen or C 1-6 alkyl;

R 5 represents C 1-6 alkoxycarbonyl;

X represents NRxRy or —OC 1-6 alkyl optionally substituted by one or more groups selected from hydroxy, methoxy, halogen, amino and trifluoromethyl;

Ra and Rb represents hydrogen or C 1-6 alkyl;

Rx and Ry independently represent hydrogen, benzyl, C 3-6 cycloalkyl, C 3-6 alkenyl, C 3-6 alkynyl, or C 1-6 alkyl optionally substituted by one or more groups selected from hydroxy, methoxy, halogen, NRaRb and trifluoromethyl, —C 1-6 alkylcycloalkyl, C 1-6 alkylamino and C 1-6 alkylthio and pharmaceutically acceptable derivatives and solvates thereof.

17. The compound of claim 16 wherein R 3 and R 4 are each hydrogen, R 1 is methyl and R 2 is hydroxyl.

18. The compound of claim 17 , wherein X is NRxRy and Rx and Ry are each independently hydrogen, benzyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 3-6 alkenyl, or substituted or unsubstituted C 1-6 alkyl.

19. The compound of claim 18 , wherein said substituted C 3-6 cycloalkyl, substituted C 3-6 alkenyl and substituted C 1-6 alkyl are substituted by one or more groups selected from hydroxy, methoxy, and NRaRb, —C 1-3 alkylcycloalkyl, C 1-6 alkylamino and C 1-6 alkylthio.

20. The compound of claim 19 , wherein X is NRxRy and NRxRy is selected from the group consisting of MeNH, Me 2 N, EtNH, CH 2 CHCH 2 NH, CH 3 OCH 2 CH 2 NH, n-PrNH, i-PrNH, n-HexNH, (CH 3 ) 2 NCH 2 CH 2 NH, CH 3 (CH 3 ) 2 CHCH 2 CH 2 NH, cyclopropyl-NH, cyclobutyl-NH, cyclopentyl-NH, cyclohexylNH, propenyl-NH, and benzyl-NH.

21. The compound of claim 16 , wherein R 1 , R 2 , R 3 and R 4 are each hydrogen.

22. The compound of claim 21 , wherein X is NRxRy and Rx and Ry are each independently hydrogen, benzyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 3-6 alkenyl, substituted or unsubstituted C 1-6 alkyl.

23. The compound of claim 22 , wherein said substituted C 3-6 cycloalkyl, substituted C 3-6 atkenyl and substituted C 1-6 alkyl are substituted by one or more groups selected from hydroxy, methoxy, and NRaRb, —C 1-3 alkylcycloalkyl, C 1-6 alkylamino and C 1-6 alkylthio.

24. The compound of claim 23 , wherein X is NRxRy and NRxRy is selected from the group consisting of MeNH, Me 2 N, EtNH, CH 2 CHCH 2 NH, CH 3 OCH 2 CH 2 NH, n-PrNH, i-PrNH, n-HexNH, (CH 3 ) 2 NCH 2 CH 2 NH, CH 3 (CH 3 ) 2 CHCH 2 CH 2 NH, cyclopropyl-NH, cyclobutyl-NH, cyclopentyl-NH, cyclohexylNH, propenyl-NH, benzyl-NH.

25. The compound of claim 17 , wherein X is substituted or unsubstituted —OC 1-6 alkyl.

26. The compound of claim 25 , wherein said substituted —OC 1-6 alkyl is substituted by one or more groups selected from hydroxy, methoxy, halogen, amino and trifluoromethyl.

27. The compound of claim 21 , wherein X is substituted or unsubstituted —OC 1-6 alkyl.

28. The compound of claim 27 , wherein said substituted —OC 1-6 alkyl is substituted by one or more groups selected from hydroxy, methoxy, halogen, amino and trifluoromethyl.

29. The compound of claim 16 , wherein the compound is [4S-(4a,5a,12a)]-4,7-Bis(dimethylamino)-9-[(N,N-dimethylaminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtacenecarboxamide.

30. The compound of claim 1 , wherein said compound is [4S-(4a,5, 5a,6,12a)]-4-(Dimethylamino)-9-[(ethoxycarbonyl) methyl]amino- 1,4,4a,5 ,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl- 1,11-dioxo-2-naphtacenecarboxamide.

31. The compound of claim 1 , wherein said compound is [4S-(4a,5,5 a,6,12a)]-4-(Dimethylamino)-9-[(N,N-dimethylaminocarbonyl) methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3 ,5,10,12,12a-pentahydroxy-6-methyl- 1,11-dioxo-2-naphtacenecarboxamide.

32. The compound of claim 1 , wherein said compound is [4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(N-isopropylaminocarbonyl) methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide.

33. The compound of claim 1 , wherein said compound is [4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(N-(2-propenyl) aminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide.

34. The compound of claim 1 , wherein said compound is [4S-(4a,5,5a,6, 12a)]-4-(Dimethylamino)-9-[(iso-propoxycarbonyl) methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl- 1,11-dioxo-2-naphtacenecarboxamide.

35. The compound of claim 1 , wherein said compound is [4S-(4a,5,5 a,6,12a)]-4-(Dimethylamino)-9-[(N-benzylaminocarbonyl) methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide.

36. The compound of claim 1 , wherein said compound is [4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(N-ethylaminocarbonyl) methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide.

37. The compound of claim 1 , wherein said compound is [4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(N-cyclohexylaminocarbonyl) methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide.

38. The compound of claim 1 , wherein said compound is [4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(N-(2-methoxyethyl) amino-carbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,1 2a-pentahydroxy-6-methyl- 1,11-dioxo-2-naphtacenecarboxamide.

39. The compound of claim 1 , wherein said compound is [4S-(4a, 5 , 5 a,6,12a)]-4-(Dimethylamino)-9-[(N-cyclobutylaminocarbonyl) methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl- 1,11-dioxo-2-naphtacenecarboxamide.

40. The compound of claim 1 , wherein said compound is [4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(N-(3,3-dimethylbutyl) aminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl- 1,11-dioxo-2-naphtacenecarboxamide.

41. The compound of claim 1 , wherein said compound is [4S-(4a,5,5a6,12a)]-4-(Dimethylamino)-9-[(N-methylaminocarbonyl) methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide.

42. The compound of claim 1 , wherein said compound is [4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(N-cyclopropylaminocarbonyl) methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide.

43. The compound of claim 1 , wherein said compound is [4S-(4a,5a,12a)]-4-(Dimethylamino)-9-[(N,N-dimethylaminocarbonyl) methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtacenecarboxamide.

44. The compound of claim 1 , wherein said compound is [4S-(4a,5a,12a)]-4-(Dimethylamino)-9[(N-isopropylaminocarbonyl) methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtacenecarboxamide.

45. The compound of claim 1 , wherein said compound is [4S-(4a,5a,12a)]-4-(Dimethylamino)-9-[(N-ethylaminocarbonyl)methyl]amino- 1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtacenecarboxamide.

46. The compound of claim 1 , wherein said compound is [4S-(4a,5a,12a)]-4-(Dimethylamino)-9-[(N-(2-N′,N′-dimethylaminoethyl)aminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtacenecarboxamide.

47. The compound of claim 1 , wherein said compound is [4S-(4a,5a,12a)]-4-(Dimethylamino)-9-[(N-cyclopropylaminocarbonyl)methyl]amino-1,4,4a,5 ,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtacenecarboxamide.

48. The compound of claim 1 , wherein said compound is [4S-(4a,5a,12a)]-4-(Dimethylamino)-9-[(N-cyclopentylaminocarbonyl)methyl]amino- 1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtacenecarboxamide.

49. The compound of claim 1 , wherein said compound is [4S-(4a,5a,12a)]-4-(Dimethylamino)-9-[(N-(2-propenyl)aminocarbonyl) methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtacenecarboxamide.

50. The compound of claim 1 , wherein said compound is [4S-(4a,5a,12a)]-4-(Dimethylamino)-9-[(N-methylaminocarbonyl) methyl]amino-1,4,4a,5,5a,6, 11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtacenecarboxamide.

51. The compound of claim 1 , wherein said compound is [4S-(4a,5a,12a)]-4-(Dimethylamino)-9-[(N-benzylaminocarbonyl) methyllamino- 1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtacenecarboxamide.

52. The compound of claim 1 , wherein said compound is [4S-(4a,5a,12a)]-4-(Dimethylamino)-9-[(N-cyclobutylaminocarbonyl) methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphtacenecarboxamide.

53. The compound of claim 1 , wherein said compound is [4S-(4α, 5α, 5a α, 6α12α)-4-(dimethylamino)-9- [(ethoxycarbonyl)-2-propyl-methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-1,11-dioxo-6-methyl-2-naphthacenecarboxamide.

54. The compound of claim 1 , wherein said compound is [4S-(4α, 5α, 5aα,6α, 12aα)-4-(dimethylamino)-9- [(ethoxycarbonyl)-2-carbonylethoxy methyllamino-1,4,4a,5,5a,6,11,12a-octahydro-3, 5,10,12,12a-pentahydroxy-1,11-dioxo-6-methyl-2-naphthacenecarboxamide.

55. A pharmaceutical formulation comprising a compound of claims 1 or 16 and one or more pharmaceutically acceptable carriers.