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

a technology ester derivatives, which is applied in the field of salts and polymorphs of cyclic boronic acid ester derivatives, can solve the problems of threatening the clinical utility of antibacterial therapy, higher morbidity and mortality, and long patient hospitalization

Active Publication Date: 2017-06-22
MELINTA SUBSIDIARY CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is about antimicrobial agents and potentiators thereof. Specifically, the invention discusses salts, polymorphs, compounds, compositions, and pharmaceutical compositions of cyclic boronic acid ester derivatives. The invention also includes a potassium salt of 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)acetic acid. The potassium salt is in a crystalline form and exhibits certain characteristic peaks on an X-ray powder diffraction pattern. The invention also includes a pharmaceutical composition comprising the potassium salt. The invention also includes a method of preventing bacterial infection by administering a composition described herein. The invention also includes a sterile container containing the pharmaceutical composition. The invention also includes a method of making the crystalline form of the potassium salt.

Problems solved by technology

However, in response to the pressure of antibiotic usage, multiple resistance mechanisms have become widespread and are threatening the clinical utility of anti-bacterial therapy.
The consequences of the increase in resistant strains include higher morbidity and mortality, longer patient hospitalization, and an increase in treatment costs
The rapid spread of bacterial resistance and the evolution of multi-resistant strains severely limits β-lactam treatment options available.
This has imposed a pressing threat to the effective use of drugs in that category to treat and prevent bacterial infections.
It has been particularly problematic in the New York City area, where several reports of spread within major hospitals and patient morbidity have been reported.
Treatment of resistant strains with carbapenems can be associated with poor outcomes.
Legacy β-lactamase inhibitors are largely ineffective against at least Class A carbapenemases, against the chromosomal and plasmid-mediated Class C cephalosporinases and against many of the Class D oxacillinases.

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

example 1

Salt Screening Study

Step 1. Purification and Characterization of Compound 1

[0083]Compound 1, 2-((3R, 6 S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)acetic acid, was found to often contain undesired NaCl salt. FIG. 6 shows the PXRD pattern of the NaCl, Compound 1 before purification and after purification. As shown in FIG. 6, the peak at 31.6° 2θ in the PXRD pattern is characteristic for the NaCl salt. The PXRD pattern for Compound 1 after purification shows significantly reduced or no presence of the NaCl salt.

[0084]During the purification process, compound 1 was combined with water (15.0 mL) and the suspension was stirred at room temperature for 4 hrs. The solids were isolated using a Buchner funnel and Whitman #1 filter paper. After filtration, the compound was air-dried for 15 hrs. The yield of the procedure was 87% by weight.

[0085]After the purification step, the purified compound was analyzed using HPLC, PXRD and TGA. The PXRD pattern of the purified compound...

example 2

Preparation of Potassium Salt at 50 mg Scale

[0098]48.7 mg of Compound 1 was combined with acetone (1.0 mL) in a 2-mL vial containing a stir bar. The suspension was stirred at 40° C. for 10 min and seeded with about 1 mg of potassium salt. 164.0 μL of potassium t-butoxide (1.0eq. of compound 1; 1.0M solution in t-BuOH) was added in five aliquots: 10 μL, 20 μL, 20 μL, 20 μL, 93 μL in every 5 min. Gum was formed upon the counterion addition. The sample was stirred for 15 hrs while the cycling temperature was maintained between 40° C.-45° C., during which the gum changed into a free-flowing suspension. The suspension was equilibrated at 5° C. for 30 min and the solids were isolated on a Buchner funnel under nitrogen blanket and allowed to dry for 30 min. The yield of this preparation procedure was 70% wt.

example 3

Preparation of Potassium Salt at 300 mg Scale

[0099]Compound 1 (302.6 mg) was combined with ACN (15.0 mL) in a 20-mL vial containing a stir bar. The suspension was stirred at 50° C. for 30 min and seeded with about 3 mg of potassium salt. 256.7 μL of potassium hydroxide (0.9 eq. of compound 1; 3.57M aqueous solution) was added in eight aliquots: 20 μL, 20 μL, 20 μL, 20 μL, 20 μL, 50 μL, 50 μL, 56.7 μL in every 15 min. Partial conversion to a gum upon the counterion addition was observed. The suspension was stirred at 50° C. for 60 min, cooled to 5° C. at 0.1° C. / min rate (7.5 hrs), and subjected to stirring while the cycling temperature was maintained between 40° C.-45° C. for 10 hrs. The temperature cycle involved holding at 40° C. for 1 hr followed by cooling at 0.5° C. / min, and then holding at 5° C. for 2 hrs followed by heating to 40° C. at a maximum rate. The suspension was equilibrated at 5° C. for 2 hrs. The solids were isolated on a Büchner funnel under nitrogen blanket, allo...

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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.

Description

BACKGROUND OF THE INVENTION[0001]Field of the Invention[0002]The present invention relates to salts and polymorphs of cyclic boronic acid ester derivatives, compositions, their use and preparation as therapeutic agents for treating bacterial infection. In particular, the present invention relates to a potassium salt of 2-((3R,6S)-2-hydroxy-3 -(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)acetic acid.[0003]Description of the Related Art[0004]Antibiotics have been effective tools in the treatment of infectious diseases during the last half-century. From the development of antibiotic therapy to the late 1980s there was almost complete control over bacterial infections in developed countries. However, in response to the pressure of antibiotic usage, multiple resistance mechanisms have become widespread and are threatening the clinical utility of anti-bacterial therapy. The increase in antibiotic resistant strains has been particularly common in major hospitals and care centers. The c...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/69A61K31/397A61K31/545C07F5/02
CPCA61K31/69C07F5/025A61K2300/00A61K31/545A61K2121/00A61K31/397A61P31/04A61P31/10Y02A50/30
Inventor BIS, JOANNA A.CHEN, PINGYUNKUSALAKUMARI SUKUMAR, SENTHIL KUMAR
Owner MELINTA SUBSIDIARY CORP
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