Antibacterial agents: salinamide derivatives

Patent metadata

Field	Value
Publication number	US-2016200771-A1
Application number	US-201514973554-A
Country	US
Kind code	A1
Filing date	Dec 17, 2015
Priority date	Dec 12, 2012
Publication date	Jul 14, 2016
Grant date	—

Abstract

The invention provides compounds of formula (I):

and salts thereof, wherein X and Y have any of the values defined herein. The compounds inhibit bacterial RNA polymerase, inhibit bacterial growth, and have applications in, analysis of RNA polymerase structure and function, control of bacterial gene expression, control of bacterial growth, antibacterial chemistry, antibacterial therapy, and drug discovery.

First claim

1 - 24 . (canceled)

25 . A method of synthesis of a compound of formula (I):

wherein:
X is one of —Br, —I, —OR, —SR, and —NHR; and Y is OH;
each R is independently H or a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 3 to 15 carbon atoms, wherein one or more of the carbon atoms is optionally replaced by (—O—) or (—NR a —), and wherein the chain is optionally substituted on carbon with one or more substituents independently selected from the group consisting of (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, azido, cyano, nitro, halo, hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl, heteroaryloxy, a hydrogen-bonding group, and a negatively charged functional group; and
each R a is independently H or (C 1 -C 6 )alkyl;
or a salt thereof, comprising reacting:
a) salinamide A with HX in the presence of an acid; or
b) salinamide A with HX in the presence of a base; or
c) salinamide A with Y′X, wherein Y′ is a cation; or
d) salinamide B with HX in the optional presence of a base; or
e) salinamide B with Y′X, wherein Y′ is a cation.

26 . The method of claim 25 , comprising reacting salinamide A with HX in the presence of an acid.

27 . The method of claim 25 , comprising reacting salinamide A with HX in the presence of a base.

28 . The method of claim 25 , comprising reacting salinamide A with Y′X, wherein Y′ is a cation.

29 . The method of claim 25 , comprising reacting salinamide B with HX in the optional presence of a base.

30 . The method of claim 25 , comprising reacting salinamide B with Y′X, wherein Y′ is a cation.

31 . A method comprising deprotecting a compound:

to provide a corresponding deprotected amine:

32 . A method comprising deprotecting a compound:

to provide a corresponding deprotected amine:

33 . A compound selected from:

34 . A method to inhibit a bacterial RNA polymerase comprising contacting a bacterial RNA polymerase with a compound of formula (I):

wherein:
X is one of —Br, —I, —OR, —SR, and —NHR; Y is one of —Br, —I, —OR, —SR, and —NHR; and at least one of X and Y is OH;
each R is independently H or a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 3 to 15 carbon atoms, wherein one or more of the carbon atoms is optionally replaced by (—O—) or (—NR a —), and wherein the chain is optionally substituted on carbon with one or more substituents independently selected from the group consisting of (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, azido, cyano, nitro, halo, hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl, heteroaryloxy, a hydrogen-bonding group, and a negatively charged functional group; and
each R a is independently H or (C 1 -C 6 )alkyl;
or a salt thereof.

35 . A method to treat a bacterial infection in an animal comprising administering a compound of formula (I):

wherein:
X is one of —Br, —I, —OR, —SR, and —NHR; Y is one of —Br, —I, —OR, —SR, and —NHR; and at least one of X and Y is OH;
each R is independently H or a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 3 to 15 carbon atoms, wherein one or more of the carbon atoms is optionally replaced by (—O—) or (—NR a —), and wherein the chain is optionally substituted on carbon with one or more substituents independently selected from the group consisting of (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, azido, cyano, nitro, halo, hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl, heteroaryloxy, a hydrogen-bonding group, and a negatively charged functional group; and
each R a is independently H or (C 1 -C 6 )alkyl;

or a pharmaceutically acceptable salt thereof, to the animal.

36 . An assay for inhibition of a RNA polymerase comprising contacting a bacterial RNA polymerase with a compound of formula (I):

wherein:
X is one of —Br, —I, —OR, —SR, and —NHR; Y is one of —Br, —I, —OR, —SR, and —NHR; and at least one of X and Y is OH;
each R is independently H or a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 3 to 15 carbon atoms, wherein one or more of the carbon atoms is optionally replaced by (—O—) or (—NR a —), and wherein the chain is optionally substituted on carbon with one or more substituents independently selected from the group consisting of (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, azido, cyano, nitro, halo, hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl, heteroaryloxy, a hydrogen-bonding group, and a negatively charged functional group; and
each R a is independently H or (C 1 -C 6 )alkyl;
or a salt thereof.

37 . An assay for potential antibacterial activity comprising contacting a bacterium with a compound of formula (I):

wherein:
X is one of —Br, —I, —OR, —SR, and —NHR; Y is one of —Br, —I, —OR, —SR, and —NHR; and at least one of X and Y is OH;
each R is independently H or a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 3 to 15 carbon atoms, wherein one or more of the carbon atoms is optionally replaced by (—O—) or (—NR a —), and wherein the chain is optionally substituted on carbon with one or more substituents independently selected from the group consisting of (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, azido, cyano, nitro, halo, hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl, heteroaryloxy, a hydrogen-bonding group, and a negatively charged functional group; and
each R a is independently H or (C 1 -C 6 )alkyl;
or a salt thereof.

Assignees

• Univ Rutgers

Inventors

• Ebright Richard H
• Ebright Yon W
• Feng Yu
• Degen David

Classifications

• C07K1/062

  for alpha- or omega-carboxy functions · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• G01N2333/91255

  DNA-directed RNA polymerase (2.7.7.6) · CPC title

• C07K11/02 Primary

  cyclic, e.g. valinomycins {; Derivatives thereof} · CPC title