Five-membered heterocyclyl tetracycline compounds and methods of use thereof
View Patent ↗The present invention describes methods of treating bacterial infections with 7-pyrrolyl tetracycline compounds of formula (I):
1. A method of ameliorating a bacterial infection in a subject in need thereof, which comprises administering to the subject an effective amount of a compound of Formula (I):
wherein:
A represents a heterocycle optionally substituted by one or more R groups, wherein R is selected from: halogen, —NRaRb, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 alkynyl, aryl, heteroaryl, hydroxy, —OC 1-6 alkyl, formyl, cyano, trifluoromethyl, CHNORa, —CO 2 Ra, —CONRaRb, —NRaC(O)Ra, —NRaC(O)ORa, —OC(O)NRaRb, —OC(O)Ra, —OC(O)ORa, or a C 1-6 alkyl group substituted by one or more groups selected from: hydroxy, —NRaRb, —OC 1-6 alkyl, —SRa, —CHNORa, —CO 2 Ra, —CONRaRb, —NRaC(O)Ra, —NRaC(O)ORa, —OC(O)NRaRb, —OC(O)Ra, —OC(O)ORa, wherein:
Ra and Rb independently represent hydrogen 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, and
further wherein said bacterial infection is selected from the group consisting of: S. pneumoniae, S. aureus, H. influenzae, M. catarrhalis, E. coli, pneumococci, salmonella, and E. faecalis.
2. The method of claim 1 , wherein said subject is a human.
3. The method of claim 1 , wherein A is tetrazole.
4. The method of claim 3 , wherein R is hydrogen.
5. The method of claim 1 , wherein A is triazole.
6. The method of claim 5 , wherein said triazole is 1, 2, 3-triazole.
7. The method of claim 6 , wherein R is CO 2 Ra.
8. The method of claim 7 , wherein Ra is C 1-6 alkyl.
9. The method of claim 1 , wherein A is pyrrolyl.
10. The method of claim 9 , wherein R is formyl.
11. The method of claim 9 , wherein R is cyano.
12. The method of claim 9 , wherein R is CHNORa.
13. The method of claim 12 , wherein Ra is hydrogen.
14. The method of claim 12 , wherein Ra is methyl.
15. The method of claim 1 , wherein R 1 , R 2 , and R 3 are each hydrogen.
16. The method of claim 1 , wherein the compound is: [4(R,S)-(4aα,5aα,12aα)]-4-(Dimethylamino)-7-(1H-Tetrazol-1-yl)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide.
17. The method of claim 1 , wherein the compound is: [4-S-(4aα,5aα,12aα)]-4-(Dimethylamino)-7-[(4-ethoxycarbonyl)-1H-triazol-1-yl]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide.
18. The method of claim 1 , wherein the compound is: [4-S-(4aα,5aα,12aα)]-4-(Dimethylamino)-7-[(5-ethoxycarbonyl)-1H-triazol-1-yl 1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide.
19. The method of claim 1 , wherein the compound is: [4S-(4aα,5aαα,12aα)]-4-(Dimethylamino)-7-(1H-pyrrol-1-yl-3-carboxaldehyde)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide.
20. The method of claim 1 , wherein the compound is: [4S-(4aα,5aαα, 12aα)]-4-(Dimethylamino)-7-(3-((hydroxymino)-methyl)-1H-pyrrol-1-yl)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide.
21. The method of claim 1 , wherein the compound is: [4S-(4aα,5aαα,12aα)]-7-(3-Cyanopyrrol-1-yl)-4-(dimethylamino)-1,4,4a,5,5a,6, 11,12a -octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide.
22. The method of claim 1 , wherein the compound is: [4S-(4aα,5aα,12aα)]-4-(Dimethylamino)-7-(3-((methyloxymino)methyl)-1H-pyrrol-1-yl)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide.