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. A compound according to 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 S;
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 1-0 heteroalkyl;
n is 1;
or a pharmaceutically acceptable salt thereof.
2. The compound of formula (I) according to claim 1 , wherein Y is —CO—NH(OH).
3. The compound of formula (I) according to claim 1 , wherein X is S, R 3 and R 4 are hydrogen, R 5 is lower alkyl and n is 1.
4. The compound of formula (I) according to claim 1 , wherein R 1 is hydroxy.
5. The compound of formula (I) according to claim 1 , wherein R 5 is n-butyl.
6. The compound of formula (I) according to claim 1 , wherein R 1 is heteroaryl.
7. The compound of formula (I) according to claim 1 , wherein the heteroaryl is oxazolyl, thiazolyl, pyridinyl and benzimidazolyl.
8. The compound of formula (I) according to claim 1 , wherein the heteroaryl is linked to the α-position to the nitrogen of the azacycloalkane represented in formula (I).
9. The compound of formula (I) according to claim 1 , wherein the heteroaryl is oxazolyl.
10. The compound of formula (I) according to claim 1 , wherein oxazolyl is substituted by one or two lower alkyl.
11. The compound of formula (I) according to claim 1 , wherein the heteroaryl is thiazolyl.
12. The compound of formula (I) according to claim 11 , wherein the thiazolyl is substituted by one or two substituents selected from the group consisting of lower alkyl and phenyl.
13. The compound of formula (I) according to claim 1 , wherein the heteroaryl is pyridinyl.
14. The compound of formula (I) according to claim 1 , wherein the heteroaryl is benzimidazolyl.
15. The compound of formula (I) according to claim 1 , wherein R 2 is hydrogen and W is N.
16. The compound of formula (I) according to claim 15 , wherein R 5 is a substituted lower alkyl.
17. The compound of formula (I) according to claim 15 , wherein R 1 is a heteroaryl.
18. The compound of formula (I) according to claim 15 , wherein the heteroaryl is oxazolyl and thiaazolyl.
19. The compound of formula (I) according to claim 15 , wherein the heteroaryl is linked to the α-position of the azacycloalkane represented in formula (I).
20. The compound of formula (I) according to claim 15 , wherein the heteroaryl is oxazolyl.
21. The compound of formula (I) according to claim 15 , wherein the heteroaryl is thiazolyl.
22. The compound of formula (I) according to claim 21 , wherein the thiazolyl is substituted with phenyl.
23. The compound of formula (I) according to claim 1 , wherein R 1 is an aryl.
24. The compound of formula (I) according to claim 23 , wherein the aryl is a phenyl.
25. The compound of formula (I) according to claim 1 , wherein R 2 is halogen.
26. The compound of formula (I) according to claim 25 , wherein the halogen is fluorine.
27. The compound of formula (I) according to claim 1 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.
28. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
29. 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.