Metallo-beta-lactamase inhibitors and methods of use thereof

Patent metadata

Field	Value
Publication number	US-11207312-B2
Application number	US-201816631673-A
Country	US
Kind code	B2
Filing date	Jul 12, 2018
Priority date	Jul 17, 2017
Publication date	Dec 28, 2021
Grant date	Dec 28, 2021

Abstract

The present invention relates to metallo-β-lactamase inhibitor compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein Z, RA, X1, X2 and R1 are as defined herein. The present invention also relates to compositions which comprise a metallo-β-lactamase inhibitor compound of the invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, optionally in combination with a beta lactam antibiotic and/or a beta-lactamase inhibitor. The invention further relates to methods for treating a bacterial infection comprising administering to a patient a therapeutically effective amount of a compound of the invention, in combination with a therapeutically effective amount of one or more β-lactam antibiotics and optionally in combination with one or more beta-lactamase inhibitor compounds. The compounds of the invention are useful in the methods described herein for overcoming antibiotic resistance.

First claim

What is claimed:

1. A compound having the structure:

or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition which comprises a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

3. A pharmaceutical composition according to claim 2 , which further comprises an effective amount of a beta-lactam antibiotic.

4. The pharmaceutical composition according to claim 2 which further comprises an effective amount of one or more beta-lactamase inhibitor compounds.

5. The pharmaceutical composition according to claim 4 , wherein the beta-lactamase inhibitor compound is selected from the group consisting of: relebactam or a pharmaceutically acceptable salt thereof, avibactam or a pharmaceutically acceptable salt thereof, vaborbactam or a pharmaceutically acceptable salt thereof, tazobactam or a pharmaceutically acceptable salt thereof, sulbactam or a pharmaceutically acceptable salt thereof, and clavulanic acid or a pharmaceutically acceptable salt thereof.

6. The pharmaceutical composition according to claim 5 , wherein the beta-lactamase inhibitor compound is relebactam or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition according to claim 3 , wherein the beta-lactam antibiotic is selected from the group consisting of: (a) imipenem, (b) ertapenem, (c) meropenem, (d) doripenem, (e) biapenem, (f) panipenem, (g) ticarcillin, (h) ampicillin, (i) amoxicillin, (j) carbenicillin, (k) piperacillin, (l) azlocillin, (m) mezlocillin, (n) cefoperazone, (o) cefotaxime, (p) ceftriaxone, (q) cefipime, (r) ceftolozane, (s) ceftazidime, and (t) a pharmaceutically acceptable salt of any of (a) through (s).

8. The pharmaceutical composition according to claim 7 , wherein the beta-lactam antibiotic is imipenem or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical composition according to claim 8 , further comprising cilastatin or a pharmaceutically acceptable salt thereof.

10. A method for inhibiting beta-lactamase in a subject which comprises administering to the subject an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, optionally in combination with a beta-lactam antibiotic.

11. A method for treating a bacterial infection which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, in combination with a beta-lactam antibiotic.

12. The method of claim 10 , wherein the beta-lactam antibiotic is selected from the group consisting of: (a) imipenem, (b) ertapenem, (c) meropenem, (d) doripenem, (e) biapenem, (f) panipenem, (g) ticarcillin, (h) ampicillin, (i) amoxicillin, (j) carbenicillin, (k) piperacillin, (l) azlocillin, (m) mezlocillin, (n) cefoperazone, (o) cefotaxime, (p) ceftriaxone, (q) cefipime, (r) ceftolozane, (s) ceftazidime, and (t) a pharmaceutically acceptable salt of any of (a) through (s).

13. The method of claim 11 , wherein the beta-lactam antibiotic is imipenem or a pharmaceutically acceptable salt thereof.

14. A method for treating a bacterial infection which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of imipenem or a pharmaceutically acceptable salt thereof, cilastatin or a pharmaceutically acceptable salt thereof, and relebactam or a pharmaceutically acceptable salt thereof.

Assignees

• Merck Sharp & Dohme

Inventors

• Pasternak Alexander
• Dong Shuzhi
• Scott Jack D
• Tang Haiqun
• Zhao Zhiqiang
• Yang Dexi
• Gu Xin
• Jiang Jinlong
• Xiao Li

Classifications

• C07D403/14

  containing three or more hetero rings · CPC title

• C07D403/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D257/02

  not condensed with other rings · CPC title

• C07D471/10

  Spiro-condensed systems · CPC title

• C07D498/04

  Ortho-condensed systems · CPC title