Bacterial efflux pump inhibitors

Patent metadata

Field	Value
Publication number	US-9950993-B2
Application number	US-201615068113-A
Country	US
Kind code	B2
Filing date	Mar 11, 2016
Priority date	Mar 13, 2015
Publication date	Apr 24, 2018
Grant date	Apr 24, 2018

Abstract

Disclosed herein are compounds of formula I:

and salts thereof. Also disclosed are compositions comprising of compounds of formula I and methods using compounds of formula I.

First claim

The invention claimed is:

1. A compound of formula I:

R 1 is (C 3 -C 8 )alkyl substituted with two or more groups selected from —NR b1 R c1 ;
R 2 is hydrogen or (C 1 -C 3 )alkyl;
each R 3 is independently hydrogen, halo or (C 1 -C 4 )alkyl;
R 4 is aryl or aryl(C 1 -C 6 )alkyl- wherein any aryl or aryl(C 1 -C 6 )alkyl- of R 4 is optionally substituted with one or more groups independently selected from halo, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy and (C 1 -C 4 )haloalkoxy;
R 5 is hydrogen, (C 1 -C 3 )alkyl, aryl, or aryl(C 1 -C 6 )alkyl- wherein any aryl or aryl(C 1 -C 6 )alkyl- of R 5 is optionally substituted with one or more groups independently selected from halo, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy and (C 1 -C 4 )haloalkoxy, provided that when R 5 is hydrogen or (C 1 -C 3 )alkyl, and R 4 is optionally substituted phenyl, then n is not 0;
each R b1 and R c1 is independently hydrogen or (C 1 -C 4 )alkyl; and
n is 0 or 1;
or a salt thereof.

2. The compound of claim 1 , wherein R 2 is hydrogen and each R 3 is hydrogen.

3. The compound of claim 1 , wherein n is 0.

4. The compound of claim 1 , wherein n is 1.

5. The compound of claim 1 , wherein R 4 is phenyl or phenyl(C 1 -C 3 )alkyl- wherein any phenyl or phenyl(C 1 -C 3 )alkyl- of R 4 is optionally substituted with one or more groups independently selected from halo, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy and (C 1 -C 4 )haloalkoxy.

6. The compound of claim 1 , wherein R 5 is hydrogen, phenyl or phenyl(C 1 -C 6 )alkyl- wherein any phenyl or phenyl(C 1 -C 6 )alkyl- of R 5 is optionally substituted with one or more groups independently selected from halo, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy and (C 1 -C 4 )haloalkoxy provided that when R 5 is hydrogen and R 4 is optionally substituted phenyl, then n is not 0.

7. The compound of claim 1 , wherein R 5 is phenyl or phenyl(C 1 -C 6 )alkyl- wherein any phenyl or phenyl(C 1 -C 6 )alkyl- of R 5 is optionally substituted with one or more groups independently selected from halo, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy and (C 1 -C 4 )haloalkoxy.

8. The compound of claim 1 , wherein the moiety —(C(R 3 ) 2 ) n CHR 4 R 5 of the compound of formula I is:

9. The compound of claim 1 , wherein R 1 is (C 3 -C 8 )alkyl substituted with two groups independently selected from —NR b1 R c1 .

10. The compound of claim 1 , wherein R 1 is:

11. The compound of claim 1 which is:

or a salt thereof.

12. A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof as described in claim 1 , and a pharmaceutically acceptable vehicle.

13. A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof as described in claim 1 , one or more antibacterial agents and a pharmaceutically acceptable vehicle.

14. A method of inhibiting a bacterial efflux pump in an animal comprising administering to the animal a compound of formula I or a pharmaceutically acceptable salt thereof as described in claim 1 .

15. A method of treating or preventing a bacterial infection in an animal comprising co-administering to the animal a compound of formula I or a pharmaceutically acceptable salt thereof as described in claim 1 , and one or more antibacterial agents.

16. The method of claim 15 , wherein the animal is infected with bacteria.

17. The method of claim 16 wherein the bacterial infection is a Gram-negative bacterial strain infection.

18. The method of claim 17 , wherein the Gram-negative bacterial strain is selected from the group consisting of Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Acinetobacter lwoffi, Actinobacillus actinomycetemcomitans, Aeromonas hydrophilia, Aggregatibacter actinomycetemcomitans, Agrobacterium tumefaciens, Bacteroides distasonis, Bacteroides eggerthii, Bacteroides forsythus, Bacteroides fragilis, Bacteroides ovalus, Bacteroides splanchnicus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Bordetella bronchiseptica, Bordetella parapertussis, Bordetella pertussis, Borrelia burgdorferi, Branhamella catarrhalis, Burkholderia cepacia, Campylobacter coli, Campylobacter fetus, Campylobacter jejuni, Caulobacter crescentus, Chlamydia trachomatis, Citrobacter diversus, Citrobacter freundii, Enterobacter aerogenes, Enterobacter asburiae, Enterobacter cloacae, Enterobacter sakazakii, Escherchia coli, Francisella tularensis, Fusobacterium nucleatum, Gardnerella vaginalis, Haemophilus ducreyi, Haemophilus haemolyticus, Haemophilus influenzae, Haemophilus parahaemolyticus, Haemophilus parainfluenzae, Helicobacter pylori, Kingella denitrificans, Kingella indologenes, Kingella kingae, Kingella oralis, Klebsiella oxytoca, Klebsiella pneumoniae, Klebsiella rhinoscleromatis, Legionella pneumophila, Listeria monocytogenes, Moraxella bovis, Moraxella catarrhalis, Moraxella lacunata, Morganella morganii, Neisseria gonorrhoeae, Neisseria meningitidis, Pantoea agglomerans, Pasteurella canis, Pasteurella haemolytica, Pasteurella multocida, Pasteurella tularensis, Porphyromonas gingivalis, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Pseudomonas acidovorans, Pseudomonas aeruginosa, Pseudomonas alcaligenes, Pseudomonas fluorescens, Pseudomonas putida, Salmonella enteriditis, Salmonella paratyphi, Salmonella typhi, Salmonella typhimurium, Serratia marcescens, Shigella dysenteriae, Shigella jlexneri, Shigella sonnei, Stenotrophomonas maltophilla, Veillonella parvula, Vibrio cholerae, Vibrio parahaemolyticus, Yersinia enterocolitica, Yersinia intermedia, Yersinia pestis and Yersinia pseudotuberculosis.

19. The method of claim 16 , wherein the bacterial infection is a Gram-positive bacterial strain infection.

20. The method of claim 19 , wherein the Gram-positive bacterial strain is selected from the group consisting of Actinomyces naeslundii, Actinomyces viscosus, Bacillus anthracis, Bacillus cereus, Bacillus subtilis, Clostridium difficile, Corynebacterium diphtheriae, Corynebacterium ulcerans, Enterococcus faecalis, Enterococcus faecium, Micrococcus luteus, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Mycobacterium tuberculosis, Propionibacterium acnes, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus hyicus, Staphylococcus intermedius, Staphylococcus saccharolyticus, Staphylococcus saprophyticus, Streptococcus agalactiae, Streptococcus mutans, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus salivarius and Streptococcus sanguis.

Assignees

• Univ Rutgers

Inventors

• Lavoie Edmond J
• Blankson Gifty A
• Parhi Ajit K
• Kaul Malvika
• Pilch Daniel S

Classifications

• C07C235/34

  having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07C233/40 Primary

  having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings · CPC title