Metallo-beta-lactamase inhibitors and methods of use thereof
View Patent ↗The present invention relates to metallo-β-lactamase inhibitor compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein Z, R A , X 1 , X 2 and R 1 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.
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.