Compounds with antimicrobial activity

Patent metadata

Field	Value
Publication number	US-11479529-B2
Application number	US-201916959142-A
Country	US
Kind code	B2
Filing date	Jan 8, 2019
Priority date	Jan 9, 2018
Publication date	Oct 25, 2022
Grant date	Oct 25, 2022

Abstract

This invention relates to compounds of formula 1, 2 or 3

a pharmaceutically acceptable salt, or solvate thereof, wherein X 1 , Y, R 1 , R 2 , R 3 , R 4 , and R 5 are as defined herein. The compounds are antimicrobial agents that may be used to treat various bacterial and protozoal infections and disorders related to such infections. The invention also relates to pharmaceutical compositions containing the compounds and to methods of treating bacterial and protozoal infections by administering the compounds of formula 1, 2 or 3.

First claim

What is claimed is:

1. A method of treating or preventing a bacterial or a protozoal infection in a subject, the method comprising: administering a therapeutically effective amount of a compound of Formula 1 to said subject, wherein said compound has the structure:

or a pharmaceutically acceptable salt or a solvate thereof, wherein:
X 1 is —NH—CH 2 ; and
R 1 is selected from the group consisting of hydrogen, acetyl, ethynyl, carboxy, carboxymethyl, hydroxymethyl, methoxy, methoxycarbonyl, aminosulfonyl, aminocarbonyl, cyano, tetrazolyl, dimethylaminosulfonylaminocarbonyl, cyanomethyl, acetylaminosulfonyl, methoxyaminocarbonyl, methylsulfonylaminocarbonyl, t-butyl, fluoro, chloro, bromo, phenyl, trifluoromethyl and benzo;
R 2 is selected from the group consisting of acetyl, ethynyl, carboxy, carboxymethyl, hydroxymethyl, methoxy, methoxycarbonyl, aminosulfonyl, aminocarbonyl, cyano, tetrazolyl, dimethylaminosulfonylaminocarbonyl, cyanomethyl, acetylaminosulfonyl, methoxyaminocarbonyl, methylsulfonylaminocarbonyl, t-butyl, fluoro, chloro, bromo, phenyl, trifluoromethyl and benzo;
R 3 is nitro;
R 4 is chloro, bromo, fluoro, cyano, cyanomethyl, carboxymethyl, methoxy, or nitro; and
R 5 is hydroxy.

2. The method of claim 1 , wherein said compound is administered through an oral, parenteral, topical, or rectal route.

3. The method of claim 1 , wherein said bacterial infection is caused by a bacterium selected from the group consisting of Enterococcus faecalis, Staphylococcus aureus, Acinetobacter baumannii , and Streptococcus pneumoniae.

4. The method of claim 1 , wherein said compound inhibits a NusB-NusE interaction.

5. The method of claim 4 , wherein said NusB-NusE interaction comprises the interaction of a NusB selected from the group consisting of NusB E81, NusB Y18 and NusB E75, and a NusE selected from the group consisting of NusE H15, NusE D19 and NusE R16.

6. The method of claim 1 , wherein said compound is selected from the group consisting of:

or a pharmaceutically acceptable salt or a solvate thereof.

7. The method of claim 1 , wherein said compound is selected from the group consisting of:

or a pharmaceutically acceptable salt or a solvate thereof.

8. The method of claim 1 , wherein said compound is selected from the group consisting of:

and

or a pharmaceutically acceptable salt or a solvate thereof.

9. The method of claim 1 , wherein the bacterial infection is a Staphylococcus aureus infection.

10. The method of claim 1 , wherein R 1 is t-butyl, ethynyl, phenyl, cyanomethyl, cyano, carboxymethyl, hydroxyl, methoxy, fluoro, chloro, or trifluoromethyl.

11. The method of claim 1 , wherein the compound has Formula 4:

a pharmaceutically acceptable salt, or a solvate thereof, wherein:
R 1 is selected from the group consisting of hydrogen, acetyl, ethynyl, carboxy, carboxymethyl, hydroxymethyl, methoxy, methoxycarbonyl, aminosulfonyl, aminocarbonyl, cyano, tetrazolyl, dimethylaminosulfonylaminocarbonyl, cyanomethyl, acetylaminosulfonyl, methoxyaminocarbonyl, methylsulfonylaminocarbonyl, t-butyl, fluoro, chloro, bromo, phenyl, trifluoromethyl and benzo;
R 2 is selected from the group consisting of acetyl, ethynyl, carboxy, carboxymethyl, hydroxymethyl, methoxy, methoxycarbonyl, aminosulfonyl, aminocarbonyl, cyano, tetrazolyl, dimethylaminosulfonylaminocarbonyl, cyanomethyl, acetylaminosulfonyl, methoxyaminocarbonyl, methylsulfonylaminocarbonyl, t-butyl, fluoro, chloro, bromo, phenyl, trifluoromethyl and benzo;

R 3 is nitro;
R 4 is chloro, bromo, fluoro, cyano, cyanomethyl, carboxymethyl, methoxy, and nitro; and
R 5 is hydroxy.

12. The method of claim 11 , wherein R 1 is t-butyl, ethynyl, phenyl, cyanomethyl, cyano, Carboxymethyl, methoxy, fluoro, chloro, or trifluoromethyl.

13. The method of claim 12 , wherein R 4 is nitro.

14. The method of claim 1 , wherein the compound has Formula 5:

a pharmaceutically acceptable salt, or a solvate thereof, wherein:
R 1 is selected from the group consisting of hydrogen, acetyl, ethynyl, carboxy, carboxymethyl, hydroxymethyl, methoxy, methoxycarbonyl, aminosulfonyl, aminocarbonyl, cyano, tetrazolyl, dimethylaminosulfonylaminocarbonyl, cyanomethyl, acetylaminosulfonyl, methoxyaminocarbonyl, methylsulfonylaminocarbonyl, t-butyl, fluoro, chloro, bromo, phenyl, trifluoromethyl and benzo;
R 2 is t-butyl, ethynyl, phenyl, cyanomethyl, cyano, carboxymethyl, methoxy, fluoro, chloro, or trifluoromethyl; and
R 4 is chloro, bromo, fluoro, cyano, cyanomethyl, carboxymethyl, methoxy, or nitro.

15. The method of claim 14 , wherein the bacterial infection is Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecalis , or Acinetobacter baumannii infection.

16. The method of claim 14 , wherein the bacterial infection is a Staphylococcus aureus infection.

Assignees

• Univ Hong Kong Polytechnic
• Univ Hong Kong Chinese

Inventors

• Ma Cong
• Yang Xiao

Classifications

• C07D231/20

  One oxygen atom attached in position 3 or 5 · CPC title

• C07C255/53

  containing cyano groups and hydroxy groups bound to the carbon skeleton · CPC title

• C07D307/88 Primary

  with one oxygen atom directly attached in position 1 or 3 · CPC title

• C07D257/04

  Five-membered rings · CPC title

• C07D231/42

  Benzene-sulfonamido pyrazoles · CPC title