Substituted benzamidines as antibacterial agents
View Patent ↗Compounds of formula (IA) or (IB) have antibacterial activity: wherein W is ═C(H)— or ═N—; R 3 is a radical of formula -(Alk 1 ) m -(Z 1 ) 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 , Z1 is —O—, —S—, —S(O)—, —S(O 2 )—, —NH—, —N(CH 3 )—, —N(CH 2 CH 3 )—, —C(—O)—, —0—(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 carbocyclic or 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 carbocyclic or heterocyclic radical having 5 to 10 ring atoms; R 4 and R 5 are optional substituents; and R 2 , R 6 and R 7 are independently hydrogen or a radical of formula -(Alk 3 ) x -(Z 2 )y-(Alk 4 ) z -H wherein x, y and z are independently 0 or 1, Z 2 is —O—, —S—, —S(O)—, —S(O 2 )—, —NH—, —N(CH 3 )—, —N(CH 2 CH 3 )—, —C(—O)—, —0—(C═O)— or —C(═O)—O—; Alk 3 and Alk 4 are optionally substituted C 1 -C 3 alkylene, C 2 -C 3 alkenylene, or C 2 -C 3 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 )—.
1. A compound of formula (1A)′ or (IB), or a salt thereof:
wherein
W is ═CH— or ═N—;
R 3 is a radical selected from those of formulae A-J:
wherein K is (Alk 2 ) n -Q,
wherein 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
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 carbocyclic or heterocyclic radical having 5 to 10 ring atoms; and
wherein n is 0 or 1, and wherein any unsubstituted ring carbon is optionally substituted,
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 2 , R 6 and R 7 are independently hydrogen or a radical of formula -(Alk 3 )x-(Z 2 )y-(Alk 4 ) z -H wherein x, y and z are independently 0 or 1 ,
Z 2 is —O—, —S—, —S(O)—, —S(O 2 )—, —NH—, —N(CH 3 )—, —N(CH 2 CH 3 )—, —C(═O)—, —0—(C═O)— or —C(═O)—O—;
Alk 3 and Alk 4 are optionally substituted C 1 -C 3 alkylene, C 2 -C 3 alkenylene, or C 2 -C 3 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 )—.
2. A compound as claimed in claim 1 wherein W is ═CH—.
3. A compound as claimed in claim 1 wherein R 6 and R 7 are each hydrogen.
4. A compound as claimed in claim 1 wherein R 2 is —OR 8 , —OC(═O)R 8 or —SO 2 R 8 wherein R 8 is optionally substituted C 1 -C 3 alkyl or C 2 -C 3 alkenyl.
5. A compound as claimed in claim 1 wherein R 2 is hydrogen, —OH, —OCH 3 , —OC(═O)CH 3 Or —SO 2 CH 3 .
6. A 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.
7. A compound as claimed in claim 1 wherein the length of the radical R3 is equivalent to that of an unbranched saturated hydrocarbon chain of from 6 to 12, or 9 to 12 carbon atoms.
8. A compound as claimed in claim 1 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.
9. A compound as claimed in claim 1 wherein Q is optionally substituted phenyl.
10. A compound as claimed in claim 1 wherein Q is optionally substituted pyridin-2-yl or pyridin-3-yl.
11. A compound as claimed in claim 1 wherein any optional substituents in Q 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.
12. A compound selected from the group consisting of:
and salts thereof.
13. A pharmaceutical composition comprising a compound as claimed in claim 1 together with a pharmaceutically acceptable carrier.
14. An antibacterial composition comprising a compound as claimed in claim 1 in an amount effective to inhibit bacterial growth, together with a pharmaceutically acceptable carrier.
15. A compound as claimed in claim 1 , for use in a method of treatment of the human or animal body.