Boronic acid derivatives and therapeutic uses thereof
Inventors
Hecker, Scott J. • Reddy, Raja K. • Glinka, Tomasz • Rodny, Olga
Assignees
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Publication Number
US-11999759-B2
Publication Date
2024-06-04
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 boronic-acid-containing antimicrobial/potentiator compounds having the structure of Formula V and related variants, including stereochemical and isomeric forms. The disclosed scope also includes pharmaceutically acceptable salts, resonance forms and tautomers, and solid-form versatility including inclusion and solvates, while maintaining the core boronic acid/boronate motif.
The structural definition includes Y1 as N or CR4, Y2 as O, and multiple variable substituent positions including R1, R4, Ra, Rb, R5, R6, R7, Rc, Rd, Re, Rf, Rg, Rh, and Ri. R2 and R3 together with the atoms to which they are attached form a fused ring or ring system selected from C3-7 carbocyclyl and 3-10 membered heterocyclyl, each optionally substituted with one or more R5, and Rh and Ri may together form a spirocyclic ring or ring system.
R5 is defined as —Y5—(CH2)t—G, with Y5 selected from —S—, —S(O)—, —S(O)2—, —O—, —CRfRg—, and —NRg—, or absent, and G selected from broad hydrogen, amino, halogen, cyano, hydroxy, alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl options. R6 is defined as (CH2)nC(O)OR or a carboxylic acid isostere, R7 is selected from —OH, optionally substituted C1-6 alkoxy, amino, and —N(OR8)R9, and the document provides structural examples and stereochemical confirmation for representative compounds.
Claims Coverage
The consolidated claim coverage centers on one independent claim to a compound of Formula V, or pharmaceutically acceptable salts thereof. The claim uses multiple inventive structural features, including fused-ring formation, defined linker and substituent groups, and optional spirocyclic ring formation.
Formula V compound with pharmaceutically acceptable salts
A compound having the structure of Formula V, or pharmaceutically acceptable salts thereof, with Y1 as N or CR4, Y2 as O, and m and r as integers of 0 or 1.
Fused ring system defined by R2 and R3
R2 and R3 together with the atoms to which they are attached form a fused ring or ring system selected from C3-7 carbocyclyl and 3-10 membered heterocyclyl, each optionally substituted with one or more R5.
R5 linker pattern via Y5, (CH2)t, and G
R5 is —Y5—(CH2)t—G, wherein t is 0 or 1, Y5 is selected from —S—, —S(O)—, —S(O)2—, —O—, —CRfRg—, and —NRg—, or is absent, and G is selected from H, amino, halogen, cyano, hydroxy, and broad alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl options.
R6 side chain or carboxylic acid isostere
R6 is (CH2)nC(O)OR or a carboxylic acid isostere, with n selected from 0 to 6.
R7 terminal group definition
R7 is selected from —OH, optionally substituted C1-6 alkoxy, amino, and —N(OR8)R9, with R8 and R9 independently selected from H, halogen, and optionally substituted alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl groups.
Rh and Ri spirocyclic ring option
Each of Rh and Ri is independently selected from H, halogen, cyano, amino, C-amido, N-amido, and optionally substituted alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl groups, or Rh and Ri together with the atoms to which they are attached form a spirocyclic ring or ring system selected from C3-7 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl, and 5-10 membered heteroaryl, each optionally substituted with one or more R5.
The claim coverage is centered on Formula V compounds, or pharmaceutically acceptable salts, defined by a fused R2/R3 ring system, a Y5-linked R5 substituent pattern, an R6 side chain or carboxylic acid isostere, a defined R7 group, and optional spirocyclic ring formation via Rh and Ri.
Stated Advantages
The document states biological performance as β-lactamase inhibitors, including potentiation with aztreonam, tigemonam, biapenem, and meropenem, β-lactamase inhibition using nitrocefin, and imipenem hydrolysis for class B metallo-β-lactamases.
The document states in vitro stability and activation of Compound 13 prodrugs in human serum and human liver microsomes.
Documented Applications
Spectroscopic characterization and structures for Compounds 31–43, described as fluorinated cyclopropane-fused benzoxaborinine-4-carboxylate derivatives.
Biological evaluation as β-lactamase inhibitors and potentiators, including aztreonam, tigemonam, biapenem, and meropenem, and use in nitrocefin-based inhibition assays and imipenem hydrolysis for class B metallo-β-lactamases.
In vitro stability and activation evaluation of Compound 13 prodrugs in human serum and human liver microsomes.
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