Antibacterial agents: salinamide derivatives

Patent metadata

Field	Value
Publication number	US-9605028-B2
Application number	US-201514973554-A
Country	US
Kind code	B2
Filing date	Dec 17, 2015
Priority date	Dec 12, 2012
Publication date	Mar 28, 2017
Grant date	Mar 28, 2017

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

What is claimed is:

1. 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.

2. The method of claim 1 , wherein the compound is a compound of formula (Ia):

or a salt thereof.

3. The method of claim 2 , wherein X is one of —Br, —I, —OR, and —SR; wherein R consists of a chain of about 3 to about 6 consecutively bonded non-hydrogen atoms, and contains a hydrogen-bonding or negatively charged functional group.

4. The method of claim 3 , wherein R consists of a chain of about 3 to about 4 consecutively bonded non-hydrogen atoms, and contains a hydrogen-bonding or negatively charged functional group.

5. The method of claim 1 , wherein R is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 3 to 8 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 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, halo, hydroxy, oxo, carboxy, aryl, aryloxy, a hydrogen-bonding group, and a negatively charged functional group.

6. The method of claim 1 , wherein X is one of —Br and —I.

7. The method of claim 1 , wherein X is one of —OR, —SR, and —NHR, and R is H or consists of a chain of about 3 to about 8 consecutively bonded non-hydrogen atoms and contains a hydrogen-bonding or negatively charged functional group.

8. The method of claim 7 , wherein R consists of a chain of about 3 to about 6 consecutively bonded non-hydrogen atoms and contains a hydrogen-bonding or negatively charged functional group.

9. The method of claim 1 , wherein the hydrogen-bonding group is selected from amine, hydroxyl, thiol, ether, thioether, carbonyl, thionyl, carboxyl, thiocarboxyl, amide, thioamide, ester, thioester, sulfonic acid sulfonic acid ester, sulfonamide, phosphoric acid, phosphoric acid ester, phosphonamide, boronic acid, boronic acid ester, pyrrole, pyrrolidine, carbazole, pyrroline, indole, isoindole, indoline, indolizine, furan, pyran, ben zofuran, thiophene, benzothiophene, pyridine, quinoline, isoquinoline, quinazoline, napthyridine, oxazole, isoxazole, benzoxazole, thiazole, isothiazole, benthiazole, oxadiazole, thiadiazole, imidazole, triazole, tetrazole, benzimidazole, pyrazole, pyrazine, pyridazine, pyrimidine, triazine, indazole, purine, pteridine, phthalazine, quinoxaline, quinazoline, cinnoline, acridine, phenazine, phenothiazine, phenoxazine, and ionized forms and salts thereof.

10. The method of claim 1 , wherein the negatively charged functional group is selected from carboxyl, thiocarboxyl, sulfonic acid, phosphoric acid, phosphoric acid ester, boronic acid, triazole, tetrazole, purine, and thiol, and ionized forms and salts thereof.

11. The method of claim 1 , wherein X is one of —O(CH 2 ) n C(OH)(R′)R″, —O(CH2) n C(O)R′, —O(CH 2 ) n C(O)OR′, —O(CH 2 ) n C(O)NR′R″, —O(CH 2 ) n OC(H)(R′)R″, —S(CH 2 ) n C(OH)(R′)R″, —S(CH 2 ) n C(O)R′, —S(CH 2 ) n C(O)OR′, —S(CH 2 ) n C(O)NR′R″, —S(CH 2 ) n OC(H)(R′)R″, —NH(CH 2 ) n C(OH)(R′)R″, —NH(CH 2 ) n C(O)R′, —NH(CH 2 ) n C(O)OR′, —NH(CH 2 ) n C(O)NR′″, and —NH(CH 2 ) n OC(H)(R′)R″; wherein n is 1, 2, 3, 4, 5, 6, or 7; and wherein R′ and R″ each independently is one of H, C 1 -C 3 alkyl, and C 1 -C 3 alkyl substituted by one or more halogen.

12. The method of claim 11 , wherein n is 1, 2, 3, 4, or 5.

13. The method of claim 1 , wherein the compound of formula (I) is selected from:

or salts thereof.

14. The method of claim 1 , wherein the compound of formula (I) is selected from

or salts thereof.

Assignees

• Univ Rutgers

Inventors

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

Classifications

• C12Q1/18

  Testing for antimicrobial activity of a material · CPC title

• C07K11/02 Primary

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

• G01N2500/04

  Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A) · 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

• C07K1/062

  for alpha- or omega-carboxy functions · CPC title