US2006105999A1PendingUtilityA1
Novel inhibitors of beta-lactamase
Est. expiryNov 22, 2022(expired)· nominal 20-yr term from priority
C07F 9/6524C07F 9/65312C07F 9/58C07F 9/65586C07F 9/65583C07F 9/425C07F 9/655354C07F 9/65515C07F 9/6541C07F 9/6506C07F 9/4084C07F 9/4006C07F 9/5728C07F 9/4407C07F 9/6539C07F 9/3808C07F 9/65395C07F 9/572C07F 9/65517A61P 31/04C07F 9/655345C07F 9/60C07F 9/2491
43
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Claims
Abstract
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 β-lactam pharmacophore. The invention also provides pharmaceutical compositions and methods for inhibiting bacterial growth.
Claims
exact text as granted — not AI-modified1 . A compound of the following formula:
or a pharmaceutically acceptable salt thereof, wherein
R 1 is phenyl or thien-2-yl, each optionally substituted;
L is a covalent bond, —CH 2 O—, —C(O)—, or —C(═N—OCH 3 )—; and
R 5 is -halo or —OR 10 wherein R 10 is phenyl, pyridinyl, or quinolinyl, each optionally substituted,
provided that when L is —CH 2 O—, R 5 is not —F or p-nitrophenyl.
2 . The compound according to claim 1 wherein the substituents are independently selected from —NO 2 , —CO 2 H, and halo.
3 . The compound according to claim 1 wherein R 1 is unsubstituted.
4 . The compound according to claim 1 wherein R 5 is selected from:
5 . The compound according to claim 1 wherein R 1 —L and R 5 are selected from the following combinations:
R 1 —L—
R 5
PNP
PNP
PNP
PNP
and
—OH
6 . The compound according to claim 1 wherein the phosphonate moiety is replaced with a thiophosphonate moiety, provided that when R 1 —L— is benzyloxy, R 5 is not —O—PNP.
7 . 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) s , 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—C(O)—, —C(O)—NH—, or heteroaryl;
B is —H, 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 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 -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.
8 . The compound according to claim 7 wherein R 3 is H and R 1 is
9 . The compound according to claim 7 wherein R 3 is —CO 2 Et and R 1 is
10 . The compound according to claim 7 wherein L 1 is —O— and A is phenyl or pyridinyl, each optionally substituted, R 3 is H and R 1 is
11 . The compound according to claim 10 wherein A is pyridin-3-yl.
12 . The compound according to claim 11 wherein s is 0.
13 . The compound according to claim 11 wherein s 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.
14 . The compound according to claim 13 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 .
15 . The compound according to claim 8 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.
16 . The compound according to to claim 9 , wherein R 6 is phenyl or p-nitro phenyl.
17 . The compound according to claim 8 selected from those in which —O—R 6 is
18 . A compound of formula:
or a pharmaceutically acceptable salt thereof, wherein
R 1 is
optionally substituted with 1-3 moieties independently selected from the group consisting of —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) s , 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—C(O)—, —C(O)—NH—, or heteroaryl;
B is —H, 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 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.
19 . The compound according to claim 18 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.
20 . The compound according to claim 19 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.
21 . The compound according to claim 20 wherein R 1 is
22 . The compound according to claim 19 wherein R 6 is phenyl optionally substituted with 1 or 2 moieties independently selected from the group consisting of halo, —CF 3 , and CN.
23 . The compound according to claim 22 wherein the compound is selected from those in which —O—R 6 is;
24 . The compound according to claim 18 having the structure:
25 . The compound according to claim 18 having the structure:
26 . The compound according to claim 18 having the structure:
27 . The compound according to claim 18 having the structure:
28 . The compound according to claim 18 having the structure:
29 . The compound according to claim 18 having the structure:
30 . The compound according to claim 18 having the structure:
31 . A composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.
32 . A method of inhibiting β-lactamase, the method comprising contacting a cell with a compound according to claim 1.Join the waitlist — get patent alerts
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