ANTIBACTERIAL AGENTS
Compounds of formula (I) have antibacterial activity: wherein R represents hydrogen or 1, 2 or 3 optional substituents; W is ═C(R 1 )— or ═N—; R 1 is hydrogen or an optional substituent and R 2 is hydrogen, methyl, or fluorine; or R 1 and R 2 taken together are —CH 2 —, —CH 2 CH 2 —, —O—, or, in either orientation, —O—CH 2 — or —OCH 2 CH 2 —; R 3 is a radical of formula -(Alk 1 ) m -(Z) p -(Alk 2 ) n -Q wherein m, p and n are independently 0 or 1, provided that at least one of m, p and n is 1, Z is —O—, —S—, —S(O)—, —S(O 2 )—, —NH—, —N(CH 3 )—, —N(CH 2 CH 3 )—, —C(═O)—, —O—(C═O)—, —C(═O)—O—, or an optionally substituted divalent monocyclic carbocyclic or heterocyclic radical having 3 to 6 ring atoms; or an optionally substituted divalent bicyclic heterocyclic radical having 5 to 10 ring atoms; Alk 1 and Alk 2 are optionally substituted C 1 -C 6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene radicals, which may optionally terminate with or be interrupted by —O—, —S—, —S(O)—, —S(O 2 )—, —NH—, —N(CH 3 )—, or —N(CH 2 CH 3 )—; and Q is hydrogen, halogen, nitrile, or hydroxyl or an optionally substituted monocyclic carbocyclic or heterocyclic radical having 3 to 6 ring atoms; or an optionally substituted bicyclic heterocyclic radical having 5 to 10 ring atoms.
1 . A substituted benzamide or pyridylamide compound of formula (I) or a salt, hydrate, or solvate thereof, for use in treating bacterial infection:
wherein
R represents hydrogen or 1, 2 or 3 optional substituents;
W is ═C(R 1 )—;
R 1 is hydrogen and R 2 is hydrogen, methyl, or fluorine; or R 1 and R 2 taken together are —CH 2 —, —CH 2 CH 2 —, —O—, or, in either orientation, —O—CH 2 — or —OCH 2 CH 2 —;
R 3 is a radical of formula -(Alk 1 ) m -(Z) p -(Alk 2 ) n -Q wherein
m, p and n are independently 0 or 1, provided that at least one of m, p and n is 1,
Z is —O—, —S—, —S(O)—, —S(O 2 )—, —NH—, —N(CH 3 )—, —N(CH 2 CH 3 )—, —C(═O)—, —O—(C═O)—, —C(═O)—O—, or an optionally substituted divalent monocyclic carbocyclic or heterocyclic radical having 3 to 6 ring atoms; or an optionally substituted divalent bicyclic heterocyclic radical having 5 to 10 ring atoms;
Alk 1 and Alk 2 are optionally substituted C 1 -C 6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene radicals, which may optionally terminate with or be interrupted by —O—, —S—, —S(O)—, —S(O 2 )—, —NH—, —N(CH 3 )—, or —N(CH 2 CH 3 )—; and
Q is hydrogen, halogen, nitrile, or hydroxyl or an optionally substituted monocyclic carbocyclic or heterocyclic radical having 3 to 6 ring atoms; or an optionally substituted bicyclic heterocyclic radical having 5 to 10 ring atoms.
2 . The compound as claimed in claim 1 wherein the compound has formula (IA)
wherein R 4 and R 5 are independently fluoro or chloro, or one of R 4 and R 5 is hydrogen while the other is fluoro or chloro, and R 1 , R 2 and R 3 are as defined in claim 1 .
3 . The compound as claimed in claim 1 wherein R 1 and R 2 are hydrogen.
4 . The compound as claimed in claim 1 wherein p is 0, and m and/or n is 1.
5 . The compound as claimed in claim 1 wherein p is 1, and Z is an optionally substituted heteroaryl radical having 3 to 6 ring atoms or an optionally substituted bicyclic heteroaryl radical having 5 to 10 ring atoms, which is linked to the -(Alk 1 ) m part of R 3 and to the -(Alk 2 ) n -Q part of R 3 via ring carbon or nitrogen atoms.
6 . The compound as claimed in claim 5 wherein the divalent radical Z is selected from the following, optionally substituted, in either orientation:
7 . The compound as claimed in claim 5 wherein the divalent radical Z is selected from the following, optionally substituted, in either orientation:
8 . The compound as claimed in claim 5 wherein the divalent radical Z is selected from the following, optionally substituted, in either orientation:
9 . The compound as claimed in claim 1 wherein p is 1, and Z is an optionally substituted monocyclic non-aromatic carbocyclic or heterocyclic radical having 3 to 6 ring atoms or an optionally substituted bicyclic non-aromatic carbocyclic or heterocyclic having 5 to 10 ring atoms, which is linked to the -(Alk 1 ) m part of R 3 and to the -(Alk 2 ) n -Q part of R 3 via ring carbon or nitrogen atoms.
10 . The compound as claimed in claim 9 wherein the divalent radical Z is selected from the following, optionally substituted, in either orientation:
11 . The compound as claimed in claim 1 wherein Q is hydrogen.
12 . The compound as claimed in claim 1 wherein Q is a radical selected from any of the divalent radicals specified in any of claims 6 to 9 with one of the unsatisfied valencies thereof satisfied with hydrogen or an optional substituent.
13 . The compound as claimed in claim 5 wherein n is 0.
14 . The compound as claimed in claim 5 wherein m is 0.
15 . The compound as claimed in claim 1 wherein the length of the radical R 3 does not exceed the length of an unbranched saturated hydrocarbon chain of 14 carbon atoms.
16 . The compound as claimed in claim 1 wherein the length of the radical R 3 is equivalent to that of an unbranched saturated hydrocarbon chain of from 6 to 12, or 9 to 12 carbon atoms.
17 . The compound as claimed in claim 1 wherein Alk 1 and Alk 2 , when present, are optionally substituted straight chain C 1 -C 6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene radicals, each of which may optionally terminate with or be interrupted by —O—, —S—, —S(O)—, —S(O 2 )—, —NH—, —N(CH 3 )—, or —N(CH 2 CH 3 )—, —C(═O)—, —O—(C═O)—, —C(═O)—O—.
18 . The compound as claimed in claim 1 wherein any optional substituents R and any optional substituents present in Alk 1 , Alk 2 , Z and Q are selected from methyl, ethyl, cyclopropyl, oxo, hydroxyl, halogen, cyano, acetyl, amino, methylamino, dimethylamino, acetylamino, carbamate and CH 2 OH.
19 . The compound as claimed in claim 2 wherein R 2 is hydrogen and R 3 is a radical selected from those of formulae A-H:
wherein Q is as defined in claim 1 , and wherein any unsubstituted ring carbon is optionally substituted.
20 . The compound as claimed in claim 19 wherein Q is hydrogen or optionally substituted phenyl.
21 . The compound as claimed in claim 19 wherein R 2 is hydrogen, and R 3 is optionally substituted quinolin-2-yl, benzothiazol-2-yl, thiazolopyridin-2-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxadiazol-3-yl or oxadiazol-5-yl.
22 . The compound as claimed in claim 21 wherein R 3 is substituted by optionally substituted phenyl.
23 . The compound as claimed in claim 19 wherein any optional substituents in R 3 are selected from methyl, —OCH 3 , —CF 3 , —OCF 3 , ethyl, cyclopropyl, oxo, hydroxyl, —F, —Cl, —Br, cyano, acetyl, amino, methylamino, dimethylamino, acetylamino, carbamate, —CONH 2 , nitro, —COOH and —CH 2 OH.
24 . A compound which is a substituted benzamide or pyridylamide of formula
(IC) or a salt, hydrate or solvate thereof:
wherein W is ═C(R 1 )—;
R 1 is hydrogen and R 2 is hydrogen, methyl, or fluoro; or R 1 and R 2 taken together are —CH 2 —, —CH 2 CH 2 —, —O—, or, in either orientation, —O—CH 2 — or —OCH 2 CH 2 —;
R 4 and R 5 are independently fluoro or chloro, or one of R 4 and R 5 is hydrogen while the other is fluoro or chloro;
R 3 is a radical selected from those of the following formulae A-H, in which any vacant ring position is optionally substituted:
wherein Q is hydrogen, halogen, nitrile, or hydroxyl; or an optionally substituted monocyclic carbocyclic or heterocyclic radical having 3 to 6 ring atoms; or an optionally substituted bicyclic heterocyclic radical having 5 to 10 ring atoms.
25 . A compound as claimed in claim 24 wherein W is ═CH— and R 2 is hydrogen.
26 . A compound as claimed in claim 24 wherein Q in radical R 3 is hydrogen or optionally substituted phenyl.
27 . A compound as claimed in claim 24 wherein R 3 is optionally substituted quinolin-2-yl, benzothiazol-2-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxadiazol-3-yl, oxadiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl or thiazolopyridin-2-yl.
28 . A compound as claimed in claim 27 wherein R 3 is substituted by optionally substituted phenyl.
29 . A compound as claimed in claim 24 wherein any optional substituents in R 3 are selected from methyl, —OCH 3 , —CF 3 , —OCF 3 , ethyl, cyclopropyl, oxo, hydroxyl, —F, —Cl, —Br, cyano, acetyl, amino, methylamino, dimethylamino, acetylamino, carbamate, —CONH 2 , nitro, —COOH and —CH 2 OH.
30 . A pharmaceutical composition comprising a compound as claimed in claim 24 , together with a pharmaceutically acceptable carrier.
31 . An antibacterial composition comprising a compound as claimed in claim 24 in an amount effective to inhibit bacterial growth, together with a pharmaceutically acceptable carrier.
32 . A method of treating bacterial infection in a subject suffering such infection comprising administering to the subject an amount of a compound as defined in claim 1 sufficient to inhibit bacterial growth.
33 . A method of treating bacterial contamination of a substrate comprising applying to the site of such contamination an amount of a compound as defined in claim 1 sufficient to inhibit bacterial growth.