US 9,540,389 B2 · Antimicrobial potentiators

Abstract

Novel compounds are disclosed having the structure of Formula I: wherein, n is an integer from 1 to 5; X is —CN, —F, —Cl, —Br, —I, —NO2; W is S, SO, SO2, O, NH, or NR5; R5 is alkyl, aralkyl, alkenyl, or alkynyl; Y is O, S; Z is NR1R2 or heterocycloalkyl; R1, R2 are, independently, hydrogen, alkyl, aralkyl, alkenyl, alkynyl, or cycloalkyl and may be optionally substituted with halo, hydroxy, alkoxy, amino, alkylamino, carboxy, alkoxycarbonyl, or nitrile groups; R3 and R4 are, independently, hydrogen, alkyl, aralkyl, alkenyl, alkynyl, or cycloalkyl and may be optionally substituted with halo, hydroxy, alkoxy, amino, alkylamino, carboxy, alkoxycarbonyl, or nitrile groups, and may together form a cyclic structure; and Ar is mono-, di-, or tri-substituted phenyl or heteroaryl, a pharmaceutically acceptable salts thereof. The compounds are potent bacterial efflux pump inhibitors (EPIs). Such compounds are useful to potentiate the antimicrobial activity of antimicrobial compounds such as beta-lactam antibiotics and quinolone antibiotics against Gram-negative bacteria.

Claims17

Dependent claims

A bacterial efflux inhibitor compound having the structure of Formula I, or a pharmaceutically acceptable salt thereof:

wherein,
n is an integer from 1 to 5;
X is —CN, —F, —Cl, —Br, —I, —NO2;
W is S, SO, SO2, O, NH, or NR5;
R5 is alkyl, aralkyl, alkenyl, or alkynyl;
Y is O, S;
Z is NR1R2 or heterocycloalkyl;
R1, R2 are, independently, hydrogen, alkyl, aralkyl, alkenyl, alkynyl, or cycloalkyl and may be optionally substituted with halo, hydroxy, alkoxy, amino, alkylamino, carboxy, alkoxycarbonyl, or nitrile groups;
R3 and R4 are, independently, hydrogen, alkyl, aralkyl, alkenyl, alkynyl, or cycloalkyl and may be optionally substituted with halo, hydroxy, alkoxy, amino, alkylamino, carboxy, alkoxycarbonyl, or nitrile groups, and may together form a cyclic structure;
and
Ar is mono-, di-, or tri-substituted phenyl or heteroaryl.

8 more elements

A method of inhibiting bacterial efflux pumps in a mammal comprising administering an effective amount of at least one compound having the structure of Formula I:

wherein,
n is an integer from 1 to 5;
X is —CN, —F, —Cl, —Br, —I, —NO2;
W is S, SO, SO2, O, NH, or NR5;
R5 is alkyl, aralkyl, alkenyl, or alkynyl;
Y is O, S;
Z is NR1R2 or heterocycloalkyl;
R1, R2 are, independently, hydrogen, alkyl, aralkyl, alkenyl, alkynyl, or cycloalkyl and may be optionally substituted with halo, hydroxy, alkoxy, amino, alkylamino, carboxy, alkoxycarbonyl, or nitrile groups;
R3 and R4 are, independently, hydrogen, alkyl, aralkyl, alkenyl, alkynyl, or cycloalkyl and may be optionally substituted with halo, hydroxy, alkoxy, amino, alkylamino, carboxy, alkoxycarbonyl, or nitrile groups, and may together form a cyclic structure;
and
Ar is mono-, di-, or tri-substituted phenyl or heteroaryl.

8 more elements

A method, for treating a bacterial infection in a mammal comprising administering to said mammal a composition comprising a compound having the structure of Formula I:

wherein,
n is 1, 2, 3, 4 or 5;
X is —CN, —F, —Cl, —Br, —I, —NO2;
W is S, SO, SO2, O, NH, or NR5;
R5 is alkyl, aralkyl, alkenyl, or alkynyl;
Y is O, S;
Z is NR1R2 or heterocycloalkyl;
R1, R2 are, independently, hydrogen, alkyl, aralkyl, alkenyl, alkynyl, or cycloalkyl and may be optionally substituted with halo, hydroxy, alkoxy, amino, alkylamino, carboxy, alkoxycarbonyl, or nitrile groups;
R3 and R4 are, independently, hydrogen, alkyl, aralkyl, alkenyl, alkynyl, or cycloalkyl and may be optionally substituted with halo, hydroxy, alkoxy, amino, alkylamino, carboxy, alkoxycarbonyl, or nitrile groups, and may together form a cyclic structure;
and
Ar is mono-, di-, or tri-substituted phenyl or heteroaryl.

8 more elements

Dependencies are inferred from the claim text.

Antimicrobial potentiators

Life of this patent

Antimicrobial potentiators

Life of this patent

Abstract

Claims17