Benzoylglycine derivatives and methods of making and using same

Patent metadata

Field	Value
Publication number	US-10550074-B2
Application number	US-201916270291-A
Country	US
Kind code	B2
Filing date	Feb 7, 2019
Priority date	Apr 25, 2016
Publication date	Feb 4, 2020
Grant date	Feb 4, 2020

Abstract

Disclosed are compounds of formulae:

and pharmaceutically acceptable salts thereof, wherein the variables, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , n, and m are defined herein. These compounds are useful for treating Gram-negative bacteria infections. Also disclosed are methods of making these compounds.

First claim

What is claimed is:

1. A compound which is
4-(cyclopropylbuta-1,3-diyn-1-yl)-N-((2S,3S)-4,4-difluoro-3-hydroxy-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)benzamide;
N-((2S,3S)-4,4-difluoro-3-hydroxy-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-((2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide;
4-((2-(aminomethyl)cyclopropyl)buta-1,3-diyn-1-yl)-N-((2S,3S)-4,4-difluoro-3-hydroxy-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)benzamide;
N-((2S,3S)-4,4-difluoro-3-hydroxy-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-((2-(methylsulfonamidomethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide;
N-((2S,3S)-4,4-difluoro-3-hydroxy-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-((2-(methoxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide;
N-((2S,3S)-4,4-difluoro-3-hydroxy-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-((2-((methylamino)methyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide;
N-((2S,3S)-4,4-difluoro-3-hydroxy-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-((2-(2-oxopropyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide;
4-((2-(2-amino-2-oxoethyl)cyclopropyl)buta-1,3-diyn-1-yl)-N-((2S,3S)-4,4-difluoro-3-hydroxy-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)benzamide;
4-((2-carbamoylcyclopropyl)buta-1,3-diyn-1-yl)-N-((2S,3S)-4,4-difluoro-3-hydroxy-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)benzamide;
4-((2-acetylcyclopropyl)buta-1,3-diyn-1-yl)-N-((2S,3S)-4,4-difluoro-3-hydroxy-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)benzamide;
or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, solvent, adjuvant or diluent.

3. A method of treating a Gram-negative bacterial infection, the method comprising administering to a subject in need of such treatment an effective amount of a compound according to claim 1 .

4. A method according to claim 3 , wherein the Gram-negative bacteria is Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Burkholderia cepacia, Alcaligenes xylosoxidans, Acinetobacter, Enterobacteriaceae, Haemophilus, Neisseria species, Francisella tularensis, Yersinia pestis, Burkholderia pseudomallei, Burkholderia mallei, Rickettsia prowazekii, Coxiella burnetti, Campylobacter jejuni, Shigella, Moraxella catarrhalis , or Chlamydia trachomatis.

5. A method according to claim 3 , wherein the Gram-negative bacteria is selected from the group consisting of Serratia, Proteus, Klebsiella, Enterobacter, Citrobacter, Salmonella, Providencia, Morganella, Cedecea, Edwardsiella, Escherichia coli, Enterobacter cloacae , and Enterobacter aerogenes.

6. A method of inhibiting a deacetylase enzyme in Gram-negative bacteria, the method comprising administering to a subject in need of such inhibition an effective amount of a compound according to claim 1 .

7. A method according to claim 6 , wherein deacetylase enzyme is LpxC.

Assignees

• Univ Duke
• Univ North Carolina Chapel Hill

Inventors

• Zhou Pei
• Toone Eric J
• Nicholas Robert A
• Gopalaswamy Ramesh
• Liang Xiaofei
• Navas Iii Frank

Classifications

• C07C317/44

  having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton · CPC title

• C07D335/02

  not condensed with other rings · CPC title

• C07D263/16

  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 ring carbon atoms · CPC title

• C07D309/04

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

• C07D277/40

  Unsubstituted amino or imino radicals · CPC title