Inhibitors of β-lactamase
View Patent ↗The invention 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 therof, wheerein
R 1 is
optionally substituted with 1-3 moieties independently selected from the group consisting of —OH, —F, —Cl, —Br, —CO 2 H, —C(O)O—CH 3 , —CF 3 , —OCH 3 , —OCF 3 , —C 1 -C 6 alkyl, —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 ; R 6 is —L 1 -A-(L 2 -B) 5 , wherein
s is 0 or 1;
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—C(O)—, —C(O)—NH—, or heteroaryl;
B is —H, C 3 -C 6 -cycloalkyl, aryl, or heteroaryl;
or (L 2 -B) 2 togethre is —H or halo when s is 0; and
A and B are independently optionally substituted with 1-3 moieties independently selected from the group consisting of halo, —CF 3 , —NO 2 , —CO 2 H, —CN, —C(O)—NH 2 , —SO 2 —NH 2 , or —C 0 -C 3 -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. A compound according to claim 1 wherein R 6 is phenyl optionally substituted with 1-3 moieties independently selected from the group consisting of halo, —CF 3 , —NO 2 , —CO 2 H, —CN, —C(O)—NH 2 , —SO 2 —NH 2 , or —C 0 -C 3 -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.
3. A compound according to claim 2 wherein R 1 is optionally substituted with 1 or 2 moieties independently selected from the group consisting of F, Cl, Br and C 1 -C 6 alkyl.
4. A compound according to claim 3 wherein R 1 is
5. A compound according to claim 2 wherein R 6 is phenyl optionally substituted with 1 or 2 moieties independently selected from the group consisting of halo, —CF 3 , and CN.
6. A compound according to claim 5 wherein the compound is selected from those in which —O—R 6 is;
7. A compound according to claim 1 having the structure:
8. A compound according to claim 1 having the structure:
9. A compound according to claim 1 having the structure:
10. A compound according to claim 1 having the structure:
11. A compound according to claim 1 having the structure:
12. A compound according to claim 1 having the structure:
13. A compound according to claim 1 having the structure:
14. A composition comprising the compound according to any one of claims 1 to 13 and a pharmaceutically acceptable carrier or diluent.
15. A method of inhibiting bacterial growth, the method comprising contacting a bacterial cell with an effective bacterial growth-inhibiting amount of a compound according to any one of claims 1 to 13 .
16. A compound according to claim 1 wherein R 1 is
and R 6 is phenyl optionally substituted with 1-3 moieties independently selected from the group consisting of halo, —CF 3 , and —CN.
17. A compound according to claim 6 wherein R 1 is