7-pyrazolyl tetracycline compounds and methods of use thereof
View Patent ↗The present invention provides compounds of Formula (I) and related methods and formulations: wherein: A represents a pyrazole ring optionally substituted by one or more R groups.
1. A compound of Formula (I):
wherein:
A represents a pyrazole ring 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, and 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, and —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, —OC(O)C 1-6 alkyl or hydroxy;
R 3 represents hydrogen, hydroxy or together R 3 and R 1 represent a CH 2 moiety, or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein R 1 , R 2 and R 3 are each hydrogen.
3. The compound of claim 1 , wherein R 1 , R 2 and R 3 are each hydrogen and further wherein A is unsubstituted.
4. The compound of claim 1 , wherein A is substituted with ethoxycarbonyl, carboxaldehyde, cyano, dimethylaminomethyl, oxime or methyloxime.
5. 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 claim 1 , wherein the infection is caused by S. pneumoniae, S. aureus, H. influenzae, M catarrhalis, E. coli, pneumococci, salmonella , or E. faecalis.
6. The method of claim 5 , wherein said subject is a human.
7. A pharmaceutical formulation comprising a compound of claim 1 and one or more pharmaceutically acceptable carriers.
8. The compound of claim 1 , wherein R 1 is C 1-6 alkyl, R 2 is hydroxy and R 3 is hydrogen.
9. The compound of claim 1 , wherein R 1 is C 1-6 alkyl, R 2 is hydroxy, R 3 is hydrogen, and further wherein A is unsubstituted.
10. The compound of claim 1 , wherein R 1 is C 1-6 alkyl, R 2 is hydrogen and R 3 is hydroxy.
11. The compound of claim 1 , wherein R 1 is C 1-6 alkyl, R 2 is hydrogen, R 3 is hydroxy, and further wherein A is unsubstituted.
12. The compound of claim 1 , wherein R is selected from: halogen and —NRaRb.
13. The compound of claim 1 , wherein R is selected from: C 2-6 alkenyl and C 3-6 alkynyl.
14. The compound of claim 1 , wherein R is selected from: aryl and heteroaryl.
15. The compound of claim 1 , wherein R is selected from: hydroxy, —OC 1-6 alkyl, and formyl.
16. The compound of claim 1 , wherein R is selected from: cyano and trifluoromethyl.
17. The compound of claim 1 , wherein R is selected from: —CHNORa, —CO 2 Ra, —CONRaRb, —NRaC(O)Ra and —NRaC(O)ORa.
18. The compound of claim 1 , wherein R is selected from: —OC(O)NRaRb, —OC(O)Ra and —OC(O)ORa.
19. The compound of claim 1 , wherein R is C 1-6 alkyl.
20. The compound of claim 1 , wherein R is 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, and —OC(O)ORa.