Inhibitors of bacterial growth

Patent metadata

Field	Value
Publication number	US-10695322-B2
Application number	US-201716073759-A
Country	US
Kind code	B2
Filing date	Jan 26, 2017
Priority date	Jan 29, 2016
Publication date	Jun 30, 2020
Grant date	Jun 30, 2020

Abstract

New antimicrobials targeting L,D-transpeptidases, non-classical cysteine peptidases, have been developed and their unique chemical structures identified. Carbapenems and penems of the present invention are unique among β-lactams as they acylate and inhibit L,D-transpeptidases, which likely results in their superior antimicrobial potency. These new antimicrobial agents can be used alone, or in combination with other classic antimicrobial agents that target D,D transpeptidases, when treating bacterial infections.

First claim

The invention claimed is:

1. A compound of Formula (I):

wherein:
R1 is —H or —CH3;
R2 is

R3 is H,

and
R4 is H,

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

2. The compound, salt, solvate, or stereoisomer of claim 1 , wherein the compound is one of the following:

3. A pharmaceutical composition comprising a compound, salt, solvate, or stereoisomer of claim 1 , and a pharmaceutically acceptable carrier.

4. A pharmaceutical composition comprising a compound, salt, solvate, or stereoisomer of claim 1 , and at least one or more other antimicrobial compounds.

5. A method of use of a compound, salt, solvate, or stereoisomer of claim 1 comprising administering to a subject having a bacterial infection an effective amount of a compound, salt, solvate, or stereoisomer of claim 1 and treating the bacterial infection in the subject.

6. The method of claim 5 wherein the bacterial infection is selected from the group consisting of M. tuberculosis, M. abscessus, A. baumannii, S. aureus, K. pneumoniae, E. cloacae, P. aeruginosa and E. faecalis or a combination thereof.

7. The method of claim 5 wherein the bacterial infection is one or more strains of bacteria that is resistant to antimicrobial agents directed to inactive D, D-transpeptidase.

8. A method of inhibiting the growth of a bacteria in vitro comprising contacting the bacteria with an effective amount of a compound, salt, solvate, or steroisomer of claim 1 wherein the bacteria stops growing than when the subject is not administered an effective amount of the compound.

9. A method of inhibiting L,D-transpeptidase activity in a subject with a bacterial infection, comprising administering to the subject an effective amount of a compound, salt, solvate, or stereoisomer of claim 1 wherein the L,D-transpeptidase activity is less than when the subject is not administered an effective amount of the compound.

10. A method of inhibiting L,D-transpeptidase activity in a subject with a bacterial infection, comprising administering to the subject comprising a bacteria with L,D-transpeptidase, an effective amount of a compound, salt, solvate, or stereoisomer of any one of the compounds selected from the group consisting of:

wherein the L,D-transpeptidase activity in the subject with the bacterial is less than when the subject is not administered an effective amount of any one of the compounds.

11. A pharmaceutical composition comprising a compound, salt, solvate, or stereoisomer of claim 2 , and a pharmaceutically acceptable carrier.

12. A pharmaceutical composition comprising a compound, salt, solvate, or stereoisomer of claim 2 , and at least one or more other antimicrobial compounds.

13. A method of use of a compound, salt, solvate, or stereoisomer of claim 2 comprising administering to a subject having a bacterial infection an effective amount of a compound, salt, solvate, or stereoisomer of claim 2 and treating the bacterial infection in the subject.

14. A method of inhibiting the growth of a bacteria in vitro comprising contacting the bacteria with an effective amount of a compound, salt, solvate, or steroisomer of claim 2 wherein the bacteria stops growing than when the subject is not administered an effective amount of the compound.

15. A method of inhibiting L,D-transpeptidase activity in a subject with a bacterial infection, comprising administering to the subject an effective amount of a compound, salt, solvate, or stereoisomer of the claim 2 wherein the L,D-transpeptidase activity is less than when the subject is not administered an effective amount of the compound.

Assignees

• Univ Johns Hopkins
• Univ Rutgers

Inventors

• Lamichhane Gyanu
• Townsend Craig A
• Lloyd Evan
• Kaushik Amit
• Kumar Pankaj
• Freundlich Joel
• Li Shaogang
• Ekins Sean
• Parrish Nicole

Classifications

• C07D499/893

  with a hetero ring or a condensed hetero ring system, directly attached in position 3 · CPC title

• C07D477/20

  Sulfur atoms · CPC title

• A61K31/546

  containing further heterocyclic rings, e.g. cephalothin · CPC title

• A61K31/43

  Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula [IMAGE cpc-sch-A61K-0952.gif], e.g. penicillins, penems · CPC title

• A61K31/427

  not condensed and containing further heterocyclic rings · CPC title