Cyclic boronic acid ester derivatives and therapeutic uses thereof

• US 10,561,675 B2
• Filed: 03/15/2013
• Issued: 02/18/2020
• Est. Priority Date: 06/06/2012
• Status: Active Grant

• Current Assignee: Melinta Therapeutics, Inc.
• Original Assignee: Rempex Pharmaceuticals, Inc (Melinta Therapeutics, Inc.)
• Inventors: Griffith, David C., Dudley, Michael N., Rodny, Olga
• Primary Examiner(s): Wang, Shengjun
• Application Number:
  US13/843,579
• Publication Number:
  US 20130331355A1
• Time in Patent Office: 2,531 Days
• Field of Search: 514 64, 51421012
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/403 condensed with carbocyclic rings, e.g. carbazole
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61K 31/4196 1,2,4-Triazoles
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Method of treating or ameliorating a bacterial infection comprising administering a composition comprising a cyclic boronic acid ester compound in combination with a carbapenem antibacterial agent such as Biapenem, and the pharmacokinetics studies thereof are provided.

Claims

1. A method for treating a bacterial infection in a human, comprising administering to a subject in need thereof a composition comprising Compound I or a pharmaceutically acceptable salt thereof and a carbapenem antibacterial agent to achieve an in vivo Compound I plasma concentration C_max from about 50 mg/L to about 200 mg/L, wherein Compound I has the structure:

2. The method of claim 1, wherein the carbapenem antibacterial agent is selected from the group consisting of Imipenem, Biapenem, Doripenem, Meropenem, and Ertapenem.

3. The method of claim 2, wherein the carbapenem antibacterial agent is Biapenem.

4. The method of claim 1, wherein the composition is administered intravenously.

5. The method of claim 1, wherein the infection is caused by a bacteria selected from Pseudomonas aeruginosa, Pseudomonas aeruginosa, Pseudomonas fluorescens, Stenotrophomonas maltophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Moraxella, Bacteroides fragilis, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, and Bacteroides splanchnicus..

6. The method of claim 1, wherein the composition further comprises an additional medicament selected from an antibacterial agent, antifungal agent, an antiviral agent, an anti-inflammatory agent, or an anti-allergic agent.

7. The method of claim 2, wherein the carbapenem antibacterial agent is meropenem.

8. A method for treating a bacterial infection in a human, comprising administering to a subject in need thereof a composition comprising Compound I or a pharmaceutically acceptable salt thereof and a carbapenem antibacterial agent to achieve an in vivo Compound I 24 h AUC from about 45 mg*h/L to about 500 mg*h/L, wherein Compound I has the structure:

9. The method of claim 8, wherein the carbapenem antibacterial agent is selected from the group consisting of Imipenem, Biapenem, Doripenem, Meropenem, and Ertapenem.

10. The method of claim 9, wherein the carbapenem antibacterial agent is Biapenem.

11. The method of claim 8, wherein the composition is administered intravenously.

12. The method of claim 8, wherein the infection is caused by a bacteria selected from Pseudomonas aeruginosa, Pseudomonas aeruginosa, Pseudomonas fluorescens, Stenotrophomonas maltophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Moraxella, Bacteroides fragilis, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, and Bacteroides splanchnicus.

13. The method of claim 8, wherein the composition further comprises an additional medicament selected from an antibacterial agent, antifungal agent, an antiviral agent, an anti-inflammatory agent, or an anti-allergic agent.

14. The method of claim 9, wherein the carbapenem antibacterial agent is meropenem.