9-aminoacyl tetracycline compounds and methods of use thereof

1. A compound of formula (I):

wherein:

R represents hydrogen or NRaRb;

R 1 represents hydrogen or C 1-6 alkyl;

R 2 represents hydrogen or hydroxy;

R 3 represents hydrogen;

R 4 represents hydrogen;

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

X represents NRxRy;

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

Rx and Ry independently represent hydrogen, benzyl, C 3-6 cycloalkyl, C 3-6 alkenyl, C 3-6 alkynyl, 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 alkylheterocycle, C 1-6 alkylamino and C 1-6 alkylthio or together Rx and Ry form a heterocycle; or a pharmaceutically acceptable salt thereof.

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

3. The compound of claim 2 , wherein R is NRaRb and further wherein Ra and Rb are each methyl.

4. The compound of claim 3 , wherein X is NRxRy and further wherein Rx and Ry are each methyl.

5. The compound of claim 4 , 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-naphthacenecarboxamide or a pharmaceutically acceptable salt thereof.

6. The compound of claim 2 , wherein R is hydrogen.

7. The compound of claim 6 , wherein X is NRxRy.

8. The compound of claim 7 , wherein the compound is [4S-(4a,5,5a,6,12a)]-4-(Dimethylamino)-9-[(N-(2-tetrahydrofurylmethyl)-aminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide or a pharmaceutically acceptable salt thereof.

9. The compound of claim 7 , wherein the compound is [4S-(4a,5a,12a)]-4-(Dimethylamino)-9-[(1-pyrrolidinoaminocarbonyl)methyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide or a pharmaceutically acceptable salt thereof.

10. A method for the treatment of a bacterial infection in a subject, which comprises administering to the subject an effective amount of a compound of formula (I):

wherein:

R represents hydrogen or NRaRb;

R 1 represents hydrogen or C 1-6 alkyl;

R 2 represents hydrogen or hydroxy;

R 3 represents hydrogen;

R 4 represents hydrogen;

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

X represents NRxRy;

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

Rx and Ry independently represent hydrogen, benzyl, C 3-6 cycloalkyl, C 3-6 alkenyl, C 3-6 alkynyl, 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 alkylheterocycle, C 1-6 alkylamino and C 1-6 alkylthio or together Rx and Ry form a heterocycle; or a pharmaceutically acceptable salt thereof.

11. The method of claim 10 , wherein said bacterial infection is a gram positive bacterium.

12. The method of claim 10 , wherein said bacterial infection is a gram negative bacterium.

13. The method of claim 10 , wherein said bacterial infection is S. pneumoniae or S. aureus.

14. The method of claim 10 , wherein said bacterial infection is H. influenzae, M. catarrhalis or E. coli.

15. A compound selected from the group consisting of: [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-naphthacenecarboxamide, 4S-(4aα,5α,5aα,6α,12aα)-4,7-(bis-dimethylamino)-9-[1-(ethoxycarbonyl)ethyl]amino-1,4,4a,5,5a,6,11,12a-octahydro-3, 10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide and pharmaceutically acceptable salts thereof.