Inhibitors of β-lactamase
View Patent ↗The intention relates to bacterial antibiotic resistance and, in particular, to compositions and methods for overcoming bacterial antibiotic resistance. The invention provides novel β-lactamase inhibitors, which are structurally unrelated to the natural product and semi-synthetic β-lactamase inhibitors presently available, and which do not require a β-lactam pharmacophore. The invention also provides pharmaceutical compositions and methods for inhibiting bacterial growth.
1. A compound of formula:
or a pharmaceutically acceptable salt thereof, wherein
R 1 is
R 3 is —H or —CO 2 R 9 , wherein R 9 is —C 1 -C 3 -alkyl;
R 6 is —L 1 —A—(L 2 —B) 5 , wherein
L 1 is C 0 -C 3 -alkyl optionally mono- to per -halogenated;
A is C 3 -C 6 -cycloalkyl, aryl, or heteroaryl;
L 2 is a covalent bond or (C 0 -C 3 -hydrocarbyl)-X 1 —(C 0 -C 3 -hydrocarbyl), wherein X 1 is —C(O)—, —NH—, —NH—, —NH—C(O)—, —C(O)—NH—, or heteroaryl;
B is —H, halo, C 3 -C 6 -cycloalkyl, aryl, or heteroaryl; and
S is 0 or 1;
wherein when s is 0, (L 2 B) S is —H or halo, and wherein A and B are independently optionally substituted with 1-3 moieties independently selected from the group consisting of halo, —NO 2 , —CO 2 H, —CN, —C(O)—NH 2 , —SO 2 —NH 2 , or hydrocarbyl-Y—(C 1 -C 3 -hydrocarbyl) wherein Y is a covalent bond, —O—C(O)—, —C(O)—, —O—, —S—, —SO 2 —, —C(O)—NH—, or —NH—C(O)—; and
each alkyl moiety is optionally mono- to per-halogenated.
2. The compound according to claim 1 wherein R 3 is H and R 1 is
3. The compound according to claim 1 wherein R 3 is —CO 2 Et and R 1 is
4. The compound according claim 1 wherein L 1 is —O— and A is phenyl or
5. The compound according to claim 4 wherein A is pyridin-3-yl.
6. The compound according to claim 5 wherein s is 0.
7. The compound according to claim 5 is 1 and L 2 is —C(O)—, —C(O)NH—, —NH—, 1,2,4-oxadiazolyl, or 1,3,4-oxadiazolyl and B is phenyl, pyridinyl, cyclopropyl, or thienyl, wherein B is optionally substituted.
8. The compound according to claim 7 wherein the substituents on the A and B rings are independently selected from —F, —Cl, —Br, —CO 2 H, —C(O)O—CH 3 , —CF 3 , —OCH 3 , —OCF 3 , —CH 3 , —CN, —C(O)NH 2 , —S—CF 3 —SO 2 CH 3 , —NO 2 , —CF 3 CF 3 , —SO 2 CF 3 , —SO 2 CF 3 CF 3 , and —SO 2 NH 2 .
9. The compound according to claim 2 wherein one or both of the following are true:
a. A is selected from phenyl and pyridinyl;
b. B is selected from phenyl, tetraazolyl, cyclopropyl, pyridinyl, and thienyl.
10. The compound according to claim 3 wherein R 6 is phenyl or p-nitro phenyl.
11. The compound according to selected from those in which —O—R 6 is
12. A composition comprising the compound according to any one of claim 1 to 11 and a pharmaceutically acceptable carrier or diluent.
13. A method of treating a bacterial infection comprising administering to an infected patient an effective anti-bacterial amount of a β-lactamase inhibitor according to any one of claim 1 to 11 .
14. A method of treating a bacterial infection comprising administering to an infected patient an effective antibacterial amount of a composition according to claim 12 .