Small molecules active against gram-negative bacteria

Patent metadata

Field	Value
Publication number	US-10995097-B2
Application number	US-201716084117-A
Country	US
Kind code	B2
Filing date	Mar 13, 2017
Priority date	Mar 11, 2016
Publication date	May 4, 2021
Grant date	May 4, 2021

Abstract

Disclosed are compounds that accumulate in Gram-negative bacteria. Also disclosed are method of antimicrobial treatment using the compounds.

First claim

The invention claimed is:

1. A compound represented by Formula (I) or a pharmaceutically acceptable salt thereof:

wherein, independently for each occurrence:
R 1 is heterocycloalkyl represented by Formula Ic:

wherein,
G 1 is CH or N;
G 2 is O;
R a is —((C 1 -C 6 )alkylene)N(R 5 ) m ;

R 2 is selected from the group consisting of halogen, (C 1 -C 6 )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, and —OR 5 ;
R 3 is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, cycloalkyl, and —OR 5 ; or
R 2 and R 3 , taken together, form a 5-10-membered heterocyclic or heteroaromatic ring comprising one N heteroatom and optionally further comprising one or two heteroatoms independently selected from the group consisting of O, N, and S;
R 4 is selected from the group consisting of hydrogen and (C 1 -C 6 )alkyl;
R 5 is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, and cycloalkyl;
n is an integer wherein the integer is 1, 3, or 4; and
m is an integer from 1-3;

wherein the compound has 15 or less rotatable bonds.

2. The compound of claim 1 wherein the compound has 10 or less rotatable bonds.

3. The compound of claim 1 wherein the compound has 8 or less rotatable bonds.

4. The compound of claim 1 wherein the compound has 6 or less rotatable bonds.

5. The compound of claim 1 wherein the compound of Formula (I) is represented by Formula (Ib) or a pharmaceutically acceptable salt thereof:

wherein, independently for each occurrence:
X is selected from the group consisting of CH 2 , O, NH, and S; and
q is an integer from 0-5.

6. The compound of claim 1 wherein R 1 is represented by Formula Ic:

wherein,
G 1 is CH or N;
G 2 is O;
R a is —((C 1 -C 6 )alkylene)N(R 5 ) m ;

R 2 is selected from the group consisting of halogen, (C 1 -C 6 )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, and —OR 5 ;
R 3 is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, cycloalkyl, and —OR 5 ;
R 4 is selected from the group consisting of hydrogen and (C 1 -C 6 )alkyl;
R 5 is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, and cycloalkyl;
n is an integer wherein the integer is 1, 3, or 4; and
m is an integer from 1-3;

wherein the compound has 15 or less rotatable bonds.

7. A compound selected from:

a pharmaceutically acceptable salt thereof.

8. A compound selected from:

a pharmaceutically acceptable salt thereof.

9. A method of antimicrobial treatment, comprising, administering to a subject in need thereof a therapeutically effective amount of a compound of claim 8 or a pharmaceutically acceptable salt thereof, thereby killing or inhibiting the growth of at least a portion of a plurality of microorganisms in the subject.

10. The method of claim 9 , wherein the microorganism is a bacterium, a virus, a fungus, or a parasite.

11. The method of claim 10 , wherein the microorganism is a bacterium.

12. The method of claim 11 , wherein the microorganism is a Gram-negative bacterium.

13. The method of claim 9 , wherein the microorganism is at least one bacterium selected from the group consisting of Acinetobacter , anthrax-causing bacteria, Bacilli, Bordetella, Borrelia , botulism-causing bacteria, Brucella, Burkholderia, Campylobacter, Chlamydia , cholera-causing bacteria, Clostridium, Conococcus, Corynebacterium , diptheria-causing bacteria, Enterobacter, Enterococcus, Erwinia, Escherichia, Francisella, Haemophilia, Heliobacter, Klebsiella, Legionella, Leptospira , leptospirosis-causing bacteria, Listeria , Lyme's disease-causing bacteria, meningococcus, Mycobacterium, Mycoplasma, Neisseria, Pasteurella, Pelobacter , plague-causing bacteria, Pneumonococcus, Proteus, Pseudomonas, Rickettsia, Salmonella, Serratia, Shigella, Staphylococcus, Streptococcus , tetanus, Treponema, Vibrio, Yersinia and Xanthomonas.

14. A method of antimicrobial treatment, comprising, administering to a subject in need thereof a therapeutically effective amount of a compound of claim 8 or a pharmaceutically acceptable salt thereof, thereby killing or inhibiting the growth of at least a portion of a plurality of microorganisms in the subject, wherein the microorganism is a bacterium.

15. The method of claim 14 , wherein the microorganism is at least one bacterium selected from the group consisting of Acinetobacter , anthrax-causing bacteria, Bacilli, Bordetella, Borrelia , botulism-causing bacteria, Brucella, Burkholderia, Campylobacter, Chlamydia , cholera-causing bacteria, Clostridium, Conococcus, Corynebacterium , diptheria-causing bacteria, Enterobacter, Enterococcus, Erwinia, Escherichia, Francisella, Haemophilia, Heliobacter, Klebsiella, Legionella, Leptospira , leptospirosis-causing bacteria, Listeria , Lyme's disease-causing bacteria, meningococcus, Mycobacterium, Mycoplasma, Neisseria, Pasteurella, Pelobacter , plague-causing bacteria, Pneumonococcus, Proteus, Pseudomonas, Rickettsia, Salmonella, Serratia, Shigella, Staphylococcus, Streptococcus , tetanus, Treponema, Vibrio, Yersinia and Xanthomonas.

Assignees

• Univ Illinois

Inventors

• Hergenrother Paul J
• Richter Michelle
• Riley Andrew
• Drown Bryon
• Chavez Martin
• Tasker Sarah
• Garcia Alfredo

Classifications

• C07D417/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D407/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07J21/008

  at position 17 · CPC title

• C07D413/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D407/12

  linked by a chain containing hetero atoms as chain links · CPC title