Salts and polymorphs of cyclic boronic acid ester derivatives and therapeutic uses thereof

• US 9,687,497 B1
• Filed: 04/29/2015
• Issued: 06/27/2017
• Est. Priority Date: 05/05/2014
• Status: Active Grant

• Current Assignee: Melinta Therapeutics, Inc.
• Original Assignee: Rempex Pharmaceuticals, Inc (Melinta Therapeutics, Inc.)
• Inventors: Bis, Joanna A., Kusalakumari Sukumar, Senthil Kumar, Chen, Pingyun
• Primary Examiner(s): BARKER, MICHAEL P
• Application Number:
  US15/309,425
• Publication Number:
  US 20170173055A1
• Time in Patent Office: 790 Days
• Field of Search: None
• CPC Class Codes: A61K 2121/00 Preparations for use in therapy
• 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 31/397 having four-membered rings, e.g. azetidine
• CPC Class Codes: A61K 31/545 Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula: , e.g. cephalosporins, cefaclor, or cephalexine
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• 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 is the crystalline form of the potassium salt of 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)acetic acid. The crystalline form maybe formulated for treating subjects with bacterial infection. Accordingly, some embodiments relate to compositions and methods of administering the potassium salt of 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)acetic acid.

Claims

1. A potassium salt of 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)acetic acid.

2. The potassium salt of claim 1, wherein the potassium salt is in a crystalline form exhibiting an X-ray powder diffraction pattern comprising at least three characteristic peaks selected from the group consisting of peaks at approximately 7.3°

, 13.9°

, 16.9°

, 19.1°

, 20.8°

, and 25.2°

2θ

.

3. The potassium salt of claim 2, exhibiting an X-ray powder diffraction pattern comprising at least peaks at approximately 7.3, 13.9°

, 16.9°

, 19.1°

, 20.8°

, and 25.2°

2θ

.

4. The potassium salt of claim 3, exhibiting an X-ray powder diffraction pattern comprising at least peaks at approximately 7.3°

, 13.9°

, 14.6°

, 16.9°

, 17.9°

, 19.1°

, 20.8°

, 21.3°

, 25.2°

, and 25.6°

2θ

.

5. The potassium salt of claim 1, wherein said crystalline form has a melting point of 199.0°

C.

6. The potassium salt of claim 1 having an X-ray powder diffraction pattern substantially the same as shown in FIG. 1.

7. A pharmaceutical composition comprising the potassium salt of claim 1 and a pharmaceutically acceptable excipient or a pharmaceutically acceptable liquid carrier.

8. The pharmaceutical composition of claim 7, further comprising an additional medicament selected from an antibacterial agent, antifungal agent, an antiviral agent, an antiinflammatory agent, or an anti-allergic agent.

9. The pharmaceutical composition of claim 8, wherein the additional medicament is a β

-lactam antibacterial agent selected from Ceftazidime, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, Panipenem, Aztreonam, Tigemonam, BAL30072, SYN 2416, or Carumonam.

10. The pharmaceutical composition of claim 7, comprising a unit dose from 0.1 mg to 5 g of the crystalline form of the potassium salt of 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)acetic acid.

11. A method of treating a bacterial infection, comprising administering to a subject in need thereof, a composition according to claim 7.

12. The method of claim 11, further comprising administering an additional medicament selected from an antibacterial agent, antifungal agent, an antiviral agent, an anti-inflammatory agent, or an anti-allergic agent.

13. The method of claim 12, wherein the additional medicament is a β

-lactam antibacterial agent selected from Ceftazidime, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, Panipenem, Aztreonam, Tigemonam, BAL30072, SYN 2416, or Carumonam.

14. The method of claim 11, wherein the subject is a mammal.

15. The method of claim 14, wherein the mammal is a human.

16. The method of claim 11, comprising administering the composition intravenously or orally to the subject.

17. A sterile container, comprising:

the composition according to claim 7.

18. A sterile container, comprising:

the potassium salt according to claim 1.

19. A method of preparing a pharmaceutical composition for administration, comprising reconstituting the contents of the sterile container of claim 17 using a pharmaceutically acceptable liquid carrier.

20. The method of any one of claim 19, wherein the liquid carrier is a saline solution or dextrose solution.

21. A process of making a crystalline form of a potassium salt of 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)acetic acid, comprising:

combining a purified 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)acetic acid with a solvent to form an intermediate solution;

intermixing a potassium ion with the intermediate solution; and

isolating the crystalline form of the potassium salt of 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)acetic acid.

22. The process of claim 21, wherein the potassium ion is from potassium hydroxide or potassium t-butoxide.

23. The process of claim 21, wherein the solvent is selected from the group consisting of tetrahydrofuran, 1, 4-dioxane, acenitrile, acetone, ethyl acetate, methyl tert-butyl ether, water, and any combinations thereof.

24. The process of claim 23, wherein the solvent is acetone or acenitrile.