Antimicrobial agents

Patent metadata

Field	Value
Publication number	US-9822108-B2
Application number	US-201314371950-A
Country	US
Kind code	B2
Filing date	Jan 11, 2013
Priority date	Jan 13, 2012
Publication date	Nov 21, 2017
Grant date	Nov 21, 2017

Abstract

The invention provides methods of treating a bacterial infection in a mammal comprising administering to the mammal a substituted bicyclic heteroaromatic ring compound of formula I: wherein two of X 1 to X 8 are N and the remaining of X 1 to X 8 are CH; or a pharmaceutically acceptable salt thereof, as well as novel compounds of formula I and salts thereof and pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof.

First claim

What is claimed is:

1. A method for treating a bacterial infection in a mammal comprising administering to the mammal an effective amount of a bicyclic heteroaromatic ring compound of formulae selected from:

Wherein:
R 1 is phenyl that is substituted with one or more groups independently selected from halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl, —C(═O)NR e R f , and phenyl that is optionally substituted with one or more halo, or (C 1 -C 6 )alkyl,
R 2 is —NR c R d , —N + (R 3 )Z − , or —NR a C(=NR a )—NR c R d , or R 2 is (C 1 -C 6 )alkyl that is substituted with —NR c R d , —N + (Ra) 3 Z − , —NR a C(═NR a )—NR c R d , or —NR a —C(═NR a )—R a ,
each R a is independently H, or (C 1 -C 6 )alkyl,
each R c and R d is independently selected from H, or (C 1 -C 6 )alkyl that is optionally substituted with one or more hydroxy or amino; or R c and R d togather with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino;
each R e and R f is independently selected from H, or (C 1 -C 6 )alkyl that is optionally substituted with one or more hydroxy or amino; or R e and R f togather with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino;
and each Z − is independently a suitable counter ion;
or a pharmaceutical acceptable salt thereof.

2. The method of claim 1 wherein R 1 is, 3-biphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl, 3-fluorophenyl, 3-methoxycarbonyl-5-(4-tert-butylphenyl)phenyl, 3-aminocarbonyl -5-(4-tert-butylphenyl)phenyl, 3-(N-(2-hydroxyethyl)aminocarbonyl)-5-(4-tert-butylphenyl)phenyl, or 3-methylphenyl.

3. The method of claim 1 wherein R 2 is guanadinomethyl, 2-aminoethylamino, aminomethyl, —CH 2 —NH—C(═NH)—CH 3 , or —CH 2 —N═C(NH 2 )—NH 2.

4. The method of claim 1 wherein the compound is selected from:

5. The method of claim 1 wherein the compound is:

or a pharmaceutically acceptable salt thereof.

6. A method for treating a bacterial infection in a mammal comprising administering to the mammal an effective amount of compound of formulae selected from:

7. The method of claim 1 or claim 5 wherein the bacterial infection is a Gram-negative bacterial strain infection.

8. The method of claim 7 wherein the Gram-negative bacterial strain is selected from the group consisting of Escherchia coli, Caulobacter crescentus, Pseudomonas aeruginosa, Agrobacterium tumefaciens, Branhamella catarrhalis, Citrobacter diversus, Enterobacter aerogenes, Enterobacter cloacae, Enterobacter sakazakii, Enterobacter asburiae, Pantoea agglomerans, Klebsiella pneumoniae, Klebsiella oxytoca, Klebsiella rhinoscleromatis, Proteus mirabilis, Salmonella typhimurium, Salmonella enteriditis, Serratia marcescens, Shigella sonnei, Neisseria gonorrhoeae, Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter lwoffi, Salmonella enteriditis, Fusobacterium nucleatum, Veillonella parvula, Bacteroides forsythus, Actinobacillus actinomycetemcomitans, Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Helicobacter pylori, Francisella tularensis, Yersinia pestis, Borrelia burgdorferi, Neisseria meningitidis and Haemophilus influenzae.

9. The method of claim 1 or claim 5 wherein the bacterial infection is a Gram-positive bacterial strain infection.

10. The method of claim 9 wherein the Gram-positive bacterial strain is selected from the group consisting of Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus pyogenes, Streptococcus faecalis, Enterococcus faecalis, Enterococcus faecium, Bacillus subtilis, Micrococcus luteus, Mycobacterium tuberculosis, Bacillus anthracis, Bacillus cereus, Clostridium difficile, Propionibacterium acnes, Streptococcus mutans, Actinomyces viscosus, Actinomyces naeslundii, Streptococcus sanguis, Streptococcus pneumoniae and Streptococcus salivarius.

11. The method of claim 1 or claim 5 wherein the bacterial infection is a multiple drug-resistant bacterial strain infection.

12. The method of claim 11 wherein the multiple drug-resistance bacterial strain is selected from the group consisting of methicillin-resistant Staphylococcus aureus , vancomycin-resistant Enterococcus , multiple drug-resistant tuberculosis and multidrug-resistant Clostridium difficile.

Assignees

• Univ Rutgers

Inventors

• Lavoie Edmond J
• Parhi Ajit
• Pilch Daniel S
• Kaul Malvika

Classifications

• A61K31/498

  Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine · CPC title

• C07D241/44

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring · CPC title

• A61K31/4375

  the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine · CPC title

• C07D241/42

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring · CPC title

• C07D237/30

  Phthalazines · CPC title