Substituted benzamidines as antibacterial agents

Inventors

Haydon, David John • Collins, Ian • Czaplewski, Lloyd George

Assignees

TAXIS PHARMACEUTICALS Inc

Abstract

Compounds of formula (IA) or (IB) have antibacterial activity: wherein W is ═C(H)— or ═N—; R3 is a radical of formula -(Alk1)m-(Z1)p-(Alk2)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(O2)—, —NH—, —N(CH3)—, —N(CH2CH3)—, —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; Alk1 and Alk2 are optionally substituted C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene radicals, which may optionally terminate with or be interrupted by —O—, —S—, —S(O)—, —S(O2)—, —NH—, —N(CH3)—, Or —N(CH2CH3)—; 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; R4 and R5 are optional substituents; and R2, R6 and R7 are independently hydrogen or a radical of formula -(Alk3)x-(Z2)y-(Alk4)z-H wherein x, y and z are independently 0 or 1, Z2 is —O—, —S—, —S(O)—, —S(O2)—, —NH—, —N(CH3)—, —N(CH2CH3)—, —C(—O)—, —0—(C═O)— or —C(═O)—O—; Alk3 and Alk4 are optionally substituted C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene radicals, which may optionally terminate with or be interrupted by —O—, —S—, —S(O)—, —S(O2)—, —NH—, —N(CH3)—, or —N(CH2CH3)—.

Core Innovation

The patent describes antibacterial substituted benzamidine, isonicotinamidine, phenyl-pyridyl oxadiazolone compounds defined by formula (1A)' or (1B), including salts, prodrugs and metabolites. The structural definition includes W as —CH— or —N—, R3 as a radical selected from formulae A-J, and K as (Alk2)n-Q, with Q, R4, R5, R2, R6 and R7 defined by specified allowable radicals and substitution rules, including optional substitution of ring carbons.

The compounds further include R2, R6 and R7 independently being hydrogen or a radical of the form -(Alk3)x-(Z2)y-(Alk4)z-H, where x, y and z are independently 0 or 1 and Z2 is selected from —O—, —S—, —S(O)—, —S(O2)—, —NH—, —N(CH3)—, —N(CH2CH3)—, —C(=O)—, —O—(C(=O)—), or —C(=O)—O—. Alk2, Alk3 and Alk4 are optionally substituted C1-C6 or C1-C3 alkylene, C2-C6 or C2-C3 alkenylene, or C2-C6 or C2-C3 alkynylene radicals, optionally terminated with or interrupted by the listed linkers.

The disclosure states that the compounds act by inhibiting bacterial cell division through binding to FtsZ. It also supports formulation with pharmaceutically acceptable carriers for treating infected subjects and treating bacterial contamination of substrates, and reports biological testing results using MIC measurements against Staphylococcus aureus ATCC29213 with activity categories A/B/C.

Claims Coverage

The provided claims center on a compound of formula (1A)' or (1B), or a salt thereof, defined by a large set of structural parameters. Dependent claims refine the independent claim by narrowing specific substituent classes and quantitative constraints on R3, and by defining antibacterial composition formulations that include the claimed compound at an effective amount with a pharmaceutically acceptable carrier.

Overall claim coverage centers on antibacterial benzamidine, isonicotinamidine, phenyl-pyridyl oxadiazolone-type compounds defined by the structural formula (1A)' or (1B) with specified allowances for W, R3, Q, n, fluoro/chloro substitution patterns at R4/R5, and optional Alk3/Z2/Alk4-linked substituent radicals at R2/R6/R7, including salts. Dependent refinements include explicit constraints on the length of R3, specific classes of R2 substituents, a constrained substituent set for Q, and an antibacterial composition embodiment using the claimed compounds.

Stated Advantages

Documented Applications