Pyrrolidine bicyclic compounds and its derivatives, compositions and methods of use
N-[1-oxo-(optionally 2-aza)-2-alkyl-3-(carboxyl or thiol or hydroxyaminocarbonyl or N-hydroxyformamido)-propyl]-(aryl or heteroaryl)-azacyclo 4-7 alkanes or thiazacyclo 4-7 alkanes, salts or prodrugs thereof have interesting properties, e.g., in the treatment or prevention of disorders amenable to treatment by PDF inhibitors, such as treatment of bacterial infections.
1. An N-[1-oxo-(optionally 2-aza)-2-alkyl-3-(carboxyl or thiol or hydroxyaminocarbonyl or N-hydroxyformamido)-propyl]-(aryl or heteroaryl)-azacyclo 4-7 alkane or thiazacyclo 4-7 alkane, a pharmaceutically acceptable salt thereof, or a prodrug thereof.
2. A compound according to claim 1 of formula (I):
wherein:
R 1 is an aryl or heteroaryl which is linked to either the α-or β-position to the ring nitrogen;
R 2 is hydrogen, halogen or hydroxy;
R 3 is hydrogen, halogen, C 1-10 alkyl, C 1-10 heteroalkyl or (R 2 and R 3 ) collectively form a C 4-7 cycloalkyl, provided that when R 3 is halogen, R 2 is not hydroxy;
X is —CH 2 —;
W is NR 5 or CR 4 R 5 , wherein R 4 is hydrogen, halogen, C 1-10 alkyl, or C 1-10 heteroalkyl and R 5 is C 1-10 alkyl or (R 4 and R 5 ) collectively form a C 4-7 cycloalkyl, provided that when W is NR 5 , R 2 and R 3 are hydrogen, C 1-10 alkyl or heteroalkyl;
Y is —COOH, —SH, —N(OH)—CHO or —CO—NH(OH), provided that when Y is —N(OH)CHO or —SH, R 2 is hydrogen and R 3 is hydrogen, C 1-10 alkyl or C 1-10 heteroalkyl;
n is 1;
a pharmaceutically acceptable salt thereof or a prodrug thereof.
3. The compound of formula (I) according to claim 2 , wherein Y is —CO—NH(OH).
4. The compound of formula (I) according to claim 2 , wherein X is —CH 2 —, R 3 and R 4 are hydrogen, R 5 is lower alkyl and n is 1.
5. The compound of formula (I) according to claim 2 , wherein R 1 is hydroxy.
6. The compound of formula (I) according to claim 2 , wherein R 5 is n-butyl.
7. The compound of formula (I) according to claim 2 , wherein R 1 is heteroaryl.
8. The compound of formula (I) according to claim 2 , wherein the heteroaryl is oxazolyl, thiazolyl, pyridinyl and benzimidazolyl.
9. The compound of formula (I) according to claim 2 , wherein the heteroaryl is linked to the α-position to the nitrogen of the azacycloalkane represented in formula (I).
10. The compound of formula (I) according to claim 2 , wherein the heteroaryl is oxazolyl.
11. The compound of formula (I) according to claim 2 , wherein oxazolyl is substituted by one or two lower alkyl.
12. The compound of formula (I) according to claim 2 , wherein the heteroaryl is thiazolyl.
13. The compound of formula (I) according to claim 12 , wherein the thiazolyl is substituted by one or two substituents selected from the group consisting of lower alkyl and phenyl.
14. The compound of formula (I) according to claim 2 , wherein the heteroaryl is pyridinyl.
15. The compound of formula (I) according to claim 2 , wherein the heteroaryl is benzimidazolyl.
16. The compound of formula (I) according to claim 2 , wherein R 2 is hydrogen and W is N.
17. The compound of formula (I) according to claim 16 , wherein R 5 is a substituted lower alkyl.
18. The compound of formula (I) according to claim 16 , wherein R 1 is a heteroaryl.
19. The compound of formula (I) according to claim 16 , wherein the heteroaryl is oxazolyl and thiaazolyl.
20. The compound of formula (I) according to claim 16 , wherein the heteroaryl is linked to the α-position of the azacycloalkane represented in formula (I).
21. The compound of formula (I) according to claim 16 , wherein the heteroaryl is oxazolyl.
22. The compound of formula (I) according to claim 16 , wherein the heteroaryl is thiazolyl.
23. The compound of formula (I) according to claim 22 , wherein the thiazolyl is substituted with phenyl.
24. The compound of formula (I) according to claim 2 , wherein R 1 is an aryl.
25. The compound of formula (I) according to claim 24 , wherein the aryl is a phenyl.
26. The compound of formula (I) according to claim 2 , wherein R 1 is halogen.
27. The compound of formula (I) according to claim 26 , wherein the halogen is fluorine.
28. The compound of formula (I) according to claim 2 , wherein X is —N(OH)—CHO.
29. The compound of formula (I) according to claim 28 , wherein X is —CH 2 —, W is carbon, n is 1, R 2 , R 3 , R 4 are independently H or lower alkyl, and R 5 is lower alkyl.
30. The compound of formula (I) according to claim 28 , wherein R 2 , R 3 and R 4 are each hydrogen.
31. The compound of formula (I) according to claim 28 , wherein R 1 is a heteroaryl.
32. The compound of formula (I) according to claim 28 , wherein the heteroaryl is oxazolyl or pyridinyl.
33. The compound of formula (I) according to claim 28 , wherein the heteroaryl is linked at the α-position of the azacycloalkane represented in formula (I).
34. The compound of formula (I) according to claim 2 wherein the compound is selected from the group consisting of 2(S)-hydroxy-3(R)-[2(S)-oxazol-2-yl-pyrrolidine-1-carbonyl)-heptanoic acid hydroxamide, N-hydroxy-N-[2-(2-oxazol-2-yl-pyrrolidine-1-carbonyl)-hexyl]-formamide, 2(S)-hydroxy-3 (R)-[2(S)-(5 -methyl-oxazol-2-yl-pyrrolidine-1-carbonyl)-heptanoic acid hydroxamide, and 2(S)-fluoro-3-(R)-[2-S-(5-methyloxazol-2-yl-pyrrolidine-1-carbonyl)-heptanoic acid hydroxamide.
35. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
36. A method for inhibiting bacteria comprising contacting said bacteria with a bacteria inhibiting amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.