Pharmaceutical compositions comprising cyclic boronic acid ester derivatives

• US 10,172,874 B2
• Filed: 03/26/2018
• Issued: 01/08/2019
• Est. Priority Date: 08/10/2010
• Status: Active Grant

• Current Assignee: Melinta Therapeutics, Inc.
• Original Assignee: Rempex Pharmaceuticals, Inc (Melinta Therapeutics, Inc.)
• Inventors: Hirst, Gavin, Reddy, Raja, Hecker, Scott, Totrov, Maxim, Griffith, David C., Rodny, Olga, Dudley, Michael N., Boyer, Serge
• Primary Examiner(s): Shameem, Golam M
• Application Number:
  US15/935,862
• Publication Number:
  US 20180207183A1
• Time in Patent Office: 288 Days
• 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 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61K 31/4196 1,2,4-Triazoles
• CPC Class Codes: A61K 31/427 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/546 containing further heterocyclic rings, e.g. cephalothin
• 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: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• 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

Disclosed herein are antimicrobial compounds compositions, pharmaceutical compositions, the use and preparation thereof. Some embodiments relate to cyclic boronic acid ester derivatives and their use as therapeutic agents.

Claims

1. A pharmaceutical composition comprising a compound of Formula (I) and an additional medicament selected from the group consisting of an antibacterial agent, antifungal agent, an antiviral agent, an anti-inflammatory agent, and an anti-allergic agent, wherein Formula (I) has the structure:

2. The pharmaceutical composition of claim 1, having the structure of formula II:

3. The pharmaceutical composition of claim 2, wherein n is 1.

4. The pharmaceutical composition of claim 2, wherein R², R³, R⁴, and R⁵ are hydrogen.

5. The pharmaceutical composition of claim 1, wherein the compound has the structure of formula Ma, IIIb, IVa, IVb, or IVc:

6. The pharmaceutical composition of claim 1, wherein R¹ is —

NHC(═

O)C_1-9alkylR¹¹.

7. The pharmaceutical composition of claim 6, wherein R¹¹ is optionally substituted aryl or optionally substituted heteroaryl.

8. The pharmaceutical composition of claim 7, wherein R¹¹ is thien-2-yl.

9. The pharmaceutical composition of claim 1, wherein m is 1.

10. The pharmaceutical composition of claim 1, wherein R⁶ and each R⁷ and R⁸ is hydrogen.

11. The pharmaceutical composition of claim 1, wherein X is —

CO₂H.

12. The pharmaceutical composition of claim 1, having a structure selected from the group consisting of:

13. The pharmaceutical composition of claim 1, wherein the compound is:

14. The pharmaceutical composition of claim 1, wherein the additional medicament is a β

-lactam antibacterial agent.

15. The pharmaceutical composition of claim 14, wherein the β

-lactam antibacterial agent is a carbapenem selected from the group consisting of simipenem, biapenem, doripenem, meropenem, and ertapenem.

16. The pharmaceutical composition of claim 15, wherein the carbapenem is meropenem.

17. The pharmaceutical composition of claim 14, wherein the β

-lactam antibacterial agent is selected from the group consisting of Amoxicillin, Ampicillin, Pivampicillin, Hetacillin, Bacampicillin, Metampicillin, Talampicillin, Epicillin, Carbenicillin, Carindacillin, Ticarcillin, Temocillin, Azlocillin, Piperacillin, Mezlocillin, Mecillinam, Pivmecillinam, Sulbenicillin, Benzylpenicillin (G), Clometocillin, Benzathine benzylpenicillin, Procaine benzylpenicillin, Azidocillin, Penamecillin, Phenoxymethylpenicillin (V), Propicillin, Benzathine phenoxymethylpenicillin, Pheneticillin, Cloxacillin, Dicloxacillin, Flucloxacillin, Oxacillin, Meticillin, Nafcillin, Faropenem, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, Panipenem, Tomopenem, Razupenem, Cefazolin, Cefacetrile, Cefadroxil, Cefalexin, Cefaloglycin, Cefalonium, Cefaloridine, Cefalotin, Cefapirin, Cefatrizine, Cefazedone, Cefazaflur, Cefradine, Cefroxadine, Ceftezole, Cefaclor, Cefamandole, Cefminox, Cefonicid, Ceforanide, Cefotiam, Cefprozil, Cefbuperazone, Cefuroxime, Cefuzonam, Cefoxitin, Cefotetan, Cefmetazole, Loracarbef, Cefixime, Ceftazidime, Ceftriaxone, Cefcapene, Cefdaloxime, Cefdinir, Cefditoren, Cefetamet, Cefmenoxime, Cefodizime, Cefoperazone, Cefotaxime, Cefpimizole, Cefpiramide, Cefpodoxime, Cefsulodin, Cefteram, Ceftibuten, Ceftiolene, Ceftizoxime, Flomoxef, Latamoxef, Cefepime, Cefozopran, Cefpirome, Cefquinome, Ceftobiprole, Ceftaroline, CXA-101, RWJ-54428, RWJ-333441, ME1036, BAL30072, BAL19764, Ceftiofur, Cefquinome, Cefovecin, Aztreonam, Tigemonam, Carumonam, RWJ-442831, RWJ-333441, and RWJ-333442.

18. The pharmaceutical composition of claim 1, in a solid form.

19. The pharmaceutical composition of claim 1, further comprising sodium carbonate.

20. The pharmaceutical composition of claim 1, further comprising saline.

21. A pharmaceutical composition in a solid form comprising a compound and meropenem, the compound having the structure:

22. The pharmaceutical composition of claim 21, further comprising sodium carbonate.

23. A pharmaceutical composition comprising a compound, meropenem, sodium carbonate and saline, the compound having the structure:

24. A pharmaceutical composition comprising a compound and meropenem, the compound having the structure: