Boronic acid derivatives and therapeutic uses thereof
Inventors
Reddy, Raja K. • Hecker, Scott J.
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12016868-B2
Publication Date
2024-06-25
Expiration Date
Abstract
Disclosed herein are antimicrobial compounds, compositions, pharmaceutical compositions, the use and preparation thereof. Some embodiments relate to boronic acid derivatives and their use a therapeutic agents.
Core Innovation
The disclosure introduces boronic acid derivative antimicrobial compounds for therapeutic use against microbial infection, framed in relation to resistance mechanisms including b2-lactamases such as carbapenemases, efflux and permeability changes, and AmpC hyperproduction. The compounds are described by core structure Formulas (I), (II), (Ic), and (IIc), including stereochemical variants and equilibrium forms involving cyclic boronate monoesters and acyclic boronic acids, with extensive variable substituent definitions.
The document also describes synthesis and characterization of multiple oxaborinine-8-carboxylic acid boron-containing compounds, including Compounds 718, 9, 10, 11, 12, and 1317, together with stereoisomer separation by chiral HPLC and analytical characterization including LC-MS and 1H NMR data. It further reports structural derivatization and related chemical manipulations of the boron-containing scaffold to afford various hydroxymethyl, methoxymethyl, hydroxymethyl or amino, and methyltriazole substituents, together with formation of disodium salts for selected examples.
The disclosure further describes general synthetic approaches for carboxylic acid prodrugs, including ester prodrug moieties prepared from boronic-acid precursors of Formula (Ia), with coupling to chloro- or bromo-substituted prodrug moieties and an alternative route using boronate esters and trifluoroborates with subsequent deprotection to obtain prodrug-bearing carboxylic acids and derivatives. The prodrug formation is described in the context of specific carboxylic acid derivatives and stereoisomers, including benzoxaborinine carboxylic acid derivatives and salts corresponding to compounds such as Compounds 1-11 and related stereoisomers.
In addition, the document reports biological activity as potentiation of b2-lactam antibacterial agents by these boron-containing compounds. Aztreonam, tigemonam, biapenem, and meropenem are evaluated in potentiation assays, with minimum potentiating concentrations reported using MPC@4, MPC@1, and MPC@8 across bacterial strains expressing class A/C/D/B b2-lactamases.
Claims Coverage
The independent claim coverage centers on compounds having the structures of Formula (Ic) or Formula (IIc), or a pharmaceutically acceptable salt thereof, with constrained substituent selections. Dependent claims add pharmaceutical composition features and optional combination therapy with additional medicaments, including enumerated b2-lactam antibacterial agents.
Formula (Ic) or Formula (IIc) compound scaffold
A compound having the structure of Formula (Ic) or Formula (IIc), or a pharmaceutically acceptable salt thereof, with G, M, R7, R8, and R constrained to the recited selections.
Substituent selection for G, M, R7, R8, and R
G is selected from OH, OMe, OBn, CH2OH, N3, NH2, NHC(=O)H, NHC(=O)CH3, and M is selected from CR7 and N; R7 is selected from H, OR8, and halogen; R8 is C1-4 alkyl; and R is H.
Restricted G substituent options
G is selected to be either OH or OBn.
Restricted M substituent options
M is selected from CH, COMe, CF, or N.
Pharmaceutical composition with therapeutically effective amount and excipient
A pharmaceutical composition containing a therapeutically effective amount of a compound of claim 1 together with a pharmaceutically acceptable excipient.
Combination therapy composition with additional medicament categories
The pharmaceutical composition further comprises an additional medicament selected from antibacterial, antifungal, antiviral, anti-inflammatory, or anti-allergic agents.
Combination therapy composition with enumerated b2-lactam antibacterial agents
The composition further specifies that the b2-lactam antibacterial agent is selected from Ceftazidime, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, Tebipenem, Tebipenem pivoxil, Apapenem, or Panipenem.
Overall claim coverage centers on compounds having the structures of Formula (Ic) or Formula (IIc) with constrained substituent selections for G, M, R7, R8, and R, and extends to pharmaceutical compositions formulated with a therapeutically effective amount plus excipient, optionally combined with additional medicaments and further narrowed to an enumerated set of b2-lactam antibacterial agents.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treatment of bacterial infections.
Combination therapy with additional antibacterial agents, including b2-lactam antibacterial agents and b2-lactamase inhibitors, including class A/B/C/D inhibitors such as ME1071.
Use against representative bacterial species listed in the document, including Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli.
Interested in licensing this patent?