Boronic acid derivatives and therapeutic uses thereof
Inventors
Hecker, Scott J. • Reddy, Raja K. • Glinka, Tomasz • Rodny, Olga
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-10570159-B2
Publication Date
2020-02-25
Expiration Date
Abstract
Disclosed herein are antimicrobial compounds 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).
Core Innovation
The disclosure relates to boronic-acid-containing antimicrobial/potentiator compounds defined by multiple structural formulas, including Formula I/II and related Formula III/IV/V/VI variants and stereoisomeric forms. The compounds include boronic acid/boronate-containing fluorinated aromatic compounds and boron-containing cyclopropa-fused benzoxaborinine derivatives, with representative structures, numbered examples, and disodium salt forms.
The structural scope includes carbocyclyl, heterocyclyl, aryl, and heteroaryl ring systems, ring formation and fused or spiro variants, and pharmaceutically acceptable salts, including alkaline metal, ammonium, and sodium salts. The compounds may exist as enantiomers, diastereomers, racemates, crystalline forms, amorphous forms, polymorphs, solvates, hydrates, resonance forms, and tautomers, and cyclic boronate monoesters and acyclic boronic acid forms are convertible depending on the medium.
The invention also relates to cyclopropane-fused benzoxaborinino compounds and their preparation, including intermediates and example compounds described as disodium salts. The document provides chemical structures for multiple “Compound 13 prodrugs,” including compounds 25 through 43, together with NMR and LCMS characterization for the prepared compounds, and includes chloromethylcarbonate and chloromethylacyloxy ester prodrug precursor classes associated with the cyclopropane-fused benzoxaborinino framework.
Claims Coverage
The consolidated claim coverage includes independent claims to a specified boronic-acid-containing compound structure and pharmaceutically acceptable salts, together with treatment method claims for bacterial infections caused by beta-lactam antibacterial agent-resistant Enterobacteriaceae using pharmaceutical compositions combined with Meropenem or Ceftibuten. The inventive features center on the defined compound structures, salt forms, pharmaceutical compositions with excipient, and the therapeutic pairing with the named beta-lactam antibacterial agents.
Specified boronic-acid-containing compound structure
A compound having the specified structure, or a pharmaceutically acceptable salt thereof.
Alkaline metal, ammonium, and sodium salts
The pharmaceutically acceptable salt is an alkaline metal salt or an ammonium salt, including a sodium salt.
Pharmaceutical composition with excipient
A pharmaceutical composition comprising the compound of the structure, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient.
Treating beta-lactam antibacterial agent-resistant Enterobacteriaceae with Meropenem
A method of treating a bacterial infection caused by beta-lactam antibacterial agent-resistant Enterobacteriaceae by administering a pharmaceutical composition comprising therapeutically effective amounts of the compound and Meropenem, or pharmaceutically acceptable salts thereof, to a subject in need thereof.
Treating beta-lactam antibacterial agent-resistant Enterobacteriaceae with Ceftibuten
A method of treating a bacterial infection caused by beta-lactam antibacterial agent-resistant Enterobacteriaceae by administering a pharmaceutical composition comprising therapeutically effective amounts of the compound and Ceftibuten, or pharmaceutically acceptable salts thereof, to a subject in need thereof.
Overall, the claims focus on structurally defined boronic-acid-containing compounds, their pharmaceutically acceptable salt forms, and treatment methods that administer therapeutically effective pharmaceutical compositions containing the compound together with either Meropenem or Ceftibuten for beta-lactam antibacterial agent-resistant Enterobacteriaceae infections.
Stated Advantages
Not explicitly described in patent.
Documented Applications
NMR/LCMS characterization and reporting of chemical structures for multiple “Compound 13 prodrugs” (compounds 25 through 43).
Biological evaluation in potentiation assays against β-lactamase expressing strains.
Measurement of inhibitory activity against class A/C/D enzymes and metallo-β-lactamase inhibition.
Assessment of MexAB-OprM efflux dependence using an Efflux Index.
Assessment of stability and activation in human serum and human liver microsomes.
Treatment of bacterial infections caused by β-lactam antibacterial agent-resistant Enterobacteriaceae with the disclosed compound in a pharmaceutical composition containing Meropenem.
Treatment of bacterial infections caused by β-lactam antibacterial agent-resistant Enterobacteriaceae with the disclosed compound in a pharmaceutical composition containing Ceftibuten.
Interested in licensing this patent?