Deuterated O-sulfated beta lactam hydroxamic acids and deuterated N-sulfated beta lactams
Provided herein are deuterated O-sulfated beta-lactam hydroxamic acids and deuterated N-sulfated beta-lactams, pharmaceutical compositions thereof and methods of treating infectious disease with deuterated compounds or pharmaceutical compositions thereof.
1. A compound of Formula (II):
or a pharmaceutically acceptable salt, hydrate, or solvate, thereof, wherein:
each of X and Y is independently selected from —CH 3 and —CD 3 ;
at least one of X and Y is —CD 3 ;
each of R 15 , R 17 , and R 18 is independently selected from hydrogen and deuterio; and
the level of deuterium enrichment at each position denoted D is at least 50%.
2. The compound of claim 1 , wherein R 15 is deuterio and each of R 17 and R 18 is hydrogen.
3. The compound of claim 1 , wherein R 17 is deuterio and each of R 15 and R 18 is hydrogen.
4. The compound of claim 1 , wherein R 18 is deuterio and each of R 15 and R 17 is hydrogen.
5. The compound of claim 1 , wherein each of R 15 and R 17 is deuterio, and R 18 is hydrogen.
6. The compound of claim 1 , wherein each of R 15 and R 18 is deuterio, and R 17 is hydrogen.
7. The compound of claim 1 , wherein each of R 17 and R 18 is deuterio, and R 15 is hydrogen.
8. The compound of claim 1 , wherein each of R 15 , R 17 , and R 18 is deuterio.
9. The compound of claim 1 , wherein X is —CD 3 and Y is —CH 3 .
10. The compound of claim 1 , wherein each of X and Y is —CD 3 .
11. The compound of claim 1 , wherein the level of deuterium enrichment at each position denoted D in moiety X and Y is at least 70%.
12. The compound of claim 1 , wherein the level of deuterium enrichment at each position denoted D in moiety X and Y is at least 90%.
13. The compound of claim 1 , wherein the level of deuterium enrichment at each position denoted D in moiety X and Y is at least 98%.
14. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and a pharmaceutically acceptable excipient.
15. The pharmaceutical composition of claim 14 , wherein the pharmaceutical composition comprises an oral formulation.
16. An oral dosage form comprising the pharmaceutical composition of claim 15 .
17. An oral dosage form comprising the compound of claim 1 or a pharmaceutically acceptable salt, hydrate, or solvate, thereof.
18. A method of treating a gram negative bacterial infection in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt, hydrate, or solvate, thereof.
19. The method of claim 18 , wherein the method further comprises administering to the patient a therapeutically effective amount of a β-lactamase inhibitor, a carbapenemase inhibitor, or a combination thereof.
20. The method of claim 18 , wherein the method further comprises administering to the patient a therapeutically effective amount of clavulanic acid, sulbactam, avibactam, tazobactam, relebactam, vaborbactam, ETX 2514 ((2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl hydrogen sulfate), RG6068, or a combination of any of the foregoing.
21. The method of claim 18 , wherein the method further comprises administering to the patient a therapeutically effective amount of avibactam.
22. The method of claim 18 , wherein the method further comprises administering to the patient a therapeutically effective amount of lindamycin, erythromycin, metronidazole, a penicillin, vancomycin, or a combination of any of the foregoing.
23. A method of treating a bacterial infection in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt, hydrate, or solvate, thereof, wherein the bacterial infection can be treated by administering tigemonam to a patient.
24. A method of treating a gram negative bacterial infection in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt, hydrate, or solvate, thereof, wherein each of X and Y is —CD 3 , and each of each of R 15 , R 17 , and R 18 is hydrogen.
25. A method of treating a bacterial infection in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt, hydrate, or solvate, thereof, wherein the bacterial infection can be treated by administering tigemonam to a patient, and wherein each of X and Y is —CD 3 , and each of each of R 15 , R 17 , and R 18 is hydroqen.