Fluoro-pyridinone phosphates and boronates useful as antibacterial agents
The present invention is directed to a new fluoro-pyridinone hydroxamic acid phosphates and boronates of Formulae I, II and III wherein Q is selected from the group consisting of —P(O)(OH) 2 , —P(O)(OH)(O − M + ), —P(O)(O − M + ) 2 and —P(O)(O − ) 2 M 2+ ; M + at each occurrence is a pharmaceutically acceptable monovalent cation; and M 2+ is a pharmaceutically acceptable divalent cation and their use as LpxC inhibitors and, more specifically, their use to treat bacterial infections.
1. A compound of Formula I:
wherein Q is selected from the group consisting of —P(O)(OH) 2 , —P(O)(OH)(O − M + ), —P(O)(O − M + ) 2 and —P(O)(O − ) 2 M 2+ ;
M + at each occurrence is a pharmaceutically acceptable monovalent cation; and
M 2+ is a pharmaceutically acceptable divalent cation.
2. The compound according to claim 1 of Formula Ia:
3. The compound according to claim 2 wherein Q is —P(O)(OH) 2 .
4. The compound according to claim 2 wherein Q is —P(O)(OH)(O − M + ),
or —P(O)(O − M + ) 2 .
5. The compound according to claim 4 wherein Q is —P(O)(O − M + ) 2 .
6. The compound according to claim 2 wherein Q is —P(O)(O − ) 2 M 2+ .
7. The compound according to claim 4 wherein M + at each occurrence is independently selected from the group consisting of Li + , K + and Na + .
8. The compound according to claim 4 wherein M + at each occurrence is a pharmaceutically acceptable monovalent cation independently selected from ammonium, (C 1 -C 12 alkyl)ammonium, (C 1 -C 12 alkyl) 2 ammonium, (C 1 -C 12 alkyl) 3 ammonium, (C 1 -C 12 alkyl) 4 ammonium, (C 3 -C 6 cycloalkyl)ammonium, (C 3 -C 6 cycloalkyl) 2 ammonium, (C 3 -C 6 cycloalkyl) 3 ammonium, (C 3 -C 6 cycloalkyl) 4 ammonium, pyrrolidinium, piperidinium and pyridinium; wherein each of the (C 1 -C 12 alkyl) or (C 3 -C 6 cycloalkyl) moieties are optionally substituted with one to three hydroxy or halo.
9. The compound according to claim 4 wherein M + at each occurrence is a pharmaceutically acceptable monovalent cation independently selected from the group consisting of glycinium, alaninium, β-alaninium, valinium, lysinium, isoleucinium, leucinium, methioninium, threoninium, asparaginium, glutaminium, histidinium, argininium, ornithinium, tryptophanium, prolinium, glutaminium, cysteinium, phenylalaninium, tyrosinium and serinium.
10. The compound according to claim 4 of the formula
11. The compound according to claim 4 of the formula
12. The compound according to claim 4 of the formula
13. The compound according to claim 4 of the formula
14. The compound according to claim 4 of the formula
15. The compound according to claim 4 of the formula
16. The compound according to claim 6 wherein M 2+ is selected from the group consisting of Ca 2+ , Mg 2+ and Zn 2+ .
17. A pharmaceutical composition comprising a compound according to claim 1 in admixture with at least one pharmaceutically acceptable excipient.
18. A method for a treating a Gram-negative bacterial infection in a patient, the method comprising administering a therapeutically effective amount of a compound according to claim 1 to a patient in need thereof.