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US 12,637,481 B2Granted
Boronic acid derivatives and therapeutic uses thereof
AssigneeQpex Biopharma, Inc.
InventorsRaja K. Reddy, David C. Griffith, Emily Rigsbee, Serge Henri Boyer, Scott J. Hecker, Matthew Jonathan Jones
Life of this patent
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Abstract
Disclosed herein are antimicrobial compounds, polymorphic forms, compositions, pharmaceutical compositions, the method of use and preparation thereof. Some embodiments relate to boronic acid derivatives and their use as therapeutic agents, for example, β-lactamase inhibitors (BLIs). The boronic acid derivatives disclosed herein can be used in combination with various antibiotics to treat resistant bacteria.
Claims30
A crystalline form of Compound II′:
- or a solvate thereof, wherein the crystalline form exhibits an X-ray powder diffraction pattern comprising at least three characteristic peaks, wherein said characteristic peaks are selected from approximately 4.3, 7.0, 7.2, 8.3, 11.0, 12.5, 15.0, 16.7, 17.5, 18.2, 19.1, 20.3, 22.3, 22.7, and 25.6 degrees 2θ.
A compound having the structure of
- or a pharmaceutically acceptable salt of any of the foregoing.
A method of preparing crystalline Form A or B of Compound II′
- wherein crystalline Form A exhibits an X-ray powder diffraction pattern comprising at least three characteristic peaks, wherein said characteristic peaks are selected from approximately 4.3, 7.0, 7.2, 8.3, 11.0, 12.5, 15.0, 16.7, 17.5, 18.2, 19.1, 20.3, 22.3, 22.7, and 25.6 degrees 2θ;
- wherein crystalline Form B exhibits an X-ray powder diffraction pattern comprising at least three characteristic peaks, wherein said characteristic peaks are selected from approximately 5.1, 7.0, 9.9, 11.0, 11.1, 14.1, 16.4, 17.1, 21.1, 22.3, 22.6, 26.9, and 28.3 degrees 2θ;
- the method comprising the steps of:
- (a) dissolving Compound II′ in a solvent system to form a crystallization solution, wherein the solvent system consists of isopropyl acetate;
- (b) heating the crystallization solution;
- (c) adding heptane to the crystallization solution;
- and
- (d) adding seed crystals of crystalline Form A of Compound II′ to the crystallization solution;
- or
- the method comprising the steps of:
- (a) dissolving Compound II′ in a solvent system to form a crystallization solution, wherein the solvent system consists of isopropyl acetate and isopropanol;
- (b) adding heptane to the crystallization solution;
- and
- (c) adding seed crystals of crystalline Form B of Compound II′ to the crystallization solution;
- or
- the method comprising the steps of:
- (a) dissolving Compound II′ in a solvent system to form a crystallization solution, wherein the solvent system consists of hexanes and ethyl acetate;
- (b) heating the crystallization solution;
- (c) initially cooling the crystallization solution;
- (d) stirring the crystallization solution;
- (e) further cooling the crystallization solution to room temperature;
- and
- (f) allowing the crystallization mixture to stand at room temperature;
- or
- the method comprising the steps of
- (a) dissolving Compound II′ in isopropanol to form a crystallization solution;
- (b) heating the crystallization solution;
- and
- cooling the crystallization solution to room temperature;
- or
- the method comprising the steps of
- (c) dissolving Compound II′ in isopropanol to form a crystallization solution;
- (d) heating the crystallization solution;
- and
- (e) cooling the crystallization solution to room temperature.
32 more elements
A method of preparing Compound II′
- comprising the steps of:
- combining Compound I
- or a salt thereof, a halomethyl isobutyrate, and a base in a polar organic solvent to form a reaction mixture 1;
- wherein the base is an inorganic base containing sodium;
- and
- heating the reaction mixture to a temperature of from about 50° C. to about 80° C. for a period of 0.5 to 24 hours.
3 more elements
A crystalline form of Compound II′:
- or a solvate thereof, wherein the crystalline form exhibits an X-ray powder diffraction pattern comprising at least three characteristic peaks, wherein said characteristic peaks are selected from approximately 5.1, 7.0, 9.9, 11.0, 11.1, 14.1, 16.4, 17.1, 21.1, 22.3, 22.6, 26.9, and 28.3 degrees 2θ.
Dependencies are inferred from the claim text.