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-11180512-B2
Publication Date
2021-11-23
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 invention relates to compounds having the structure of Formula IIIb or IVb, or pharmaceutically acceptable salts thereof. The compounds are defined by multiple independently variable substituent positions including J, L, M, R2, R3, R5, R6, K, and Y2 to Y6, with optional fused ring or ring system formation. The disclosure includes representative structures, salts, stereoisomers, resonance and tautomeric forms, and solvated forms.
The substituent scope includes R5 selected as —Y5—(CH2)t—G with t as 0 or 1, R6 as —C(O)OR or a carboxylic acid isostere, and R7 as OH or optionally substituted C1-6 alkoxy. The groups selected for Y2, Y3, Y4, Y5, Y6, and K include oxygen-, sulfur-, nitrogen-, amide-, and sulfonamide-related options, together with a wide range of cyclic, aryl, heteroaryl, alkyl, haloalkyl, alkoxy, hydroxy, cyano, amino, and halogen substituents. The compounds are described as antimicrobial agents and/or potentiators of antimicrobial agents.
Claims Coverage
One independent claim is explicitly provided, directed to a compound of Formula IIIb or IVb, or pharmaceutically acceptable salts thereof. The inventive scope is defined by extensive substituent variability across J, L, M, R2/R3, R5, R6, R7, Y2-Y6, K, and optional fused ring or ring system formation.
Formula IIIb or IVb compound scaffold
A compound having the structure of Formula IIIb or IVb, or pharmaceutically acceptable salts thereof.
Variable J, L, M and R2/R3 substituent framework
Each J, L, M is independently CR12 or N, and each of R2 and R3 is independently selected from extensive substituent groups, including options for fused ring or ring system formation.
R5 linker and G selection
R5 is —Y5—(CH2)t—G where t is 0 or 1, and G is selected from a listed group of substituents.
R6 as carboxylic acid isostere
R6 is —C(O)OR or a carboxylic acid isostere.
Defined Y2-Y6, K, and R7 options
Y2-Y6, K, and R7 are selected from their respective defined sets, including oxygen-, sulfur-, nitrogen-, amide-, and sulfonamide-related options and optional substituted C1-6 alkoxy for R7.
Claim coverage centers on structurally defined compounds of Formula IIIb or IVb, with the inventive features driven by the permitted substituent sets, linker definitions, and optional fused ring or ring system formation.
Stated Advantages
Compounds of Formulas III-V act as antimicrobial agents and/or potentiators of antimicrobial agents.
Potentiation of aztreonam and tigemonam using BLI/prodrug approaches.
Potentiation of biapenem and meropenem using BLI/prodrug approaches.
β-lactamase inhibitory activity assessment across classes A, C, D, and B, including metallo-β-lactamase activity.
Efflux assessment for Pseudomonas aeruginosa MexAB-OprM via an efflux index.
Prodrug stability and activation evaluation in human serum and human liver microsomes, including reported activation half-lives.
Documented Applications
Treatment of a bacterial infection by administering a compound of claim 1, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
Treatment of a bacterial infection caused by β-lactam antibacterial agent-resistant Enterobacteriaceae.
Treatment of a bacterial infection caused by carbapenem-resistant Enterobacteriaceae.
Potentiation of aztreonam and tigemonam using BLI/prodrug approaches (assays indicated as MPC4).
Potentiation of biapenem and meropenem using BLI/prodrug approaches (assays indicated as MPC1 and MPC8).
β-lactamase inhibitory activity assessment using a nitrocefin-based Ki across β-lactamase classes A, C, D, and B, including metallo-β-lactamase activity via imipenem.
Efflux assessment for Pseudomonas aeruginosa MexAB-OprM via an efflux index (EI).
Prodrug stability and activation evaluation in human serum and in human liver microsomes, including reported activation half-lives.
Interested in licensing this patent?