Penicillin-binding protein inhibitors
Inventors
Burns, Christopher J. • DAIGLE, Denis • Chu, Guo-Hua • Jackson, Randy W. • HAMRICK, Jodie • Lucas, Matthew • Boyd, Steven A. • Yao, Jiangchao • Mesaros, Eugen F.
Assignees
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Publication Number
US-11267826-B2
Publication Date
2022-03-08
Expiration Date
Abstract
Described herein are certain boron-containing compounds, compositions, preparations and their use as modulators of the transpeptidase function of bacterial penicillin-binding proteins and as antibacterial agents. In some embodiments, the compounds described herein inhibit penicillin-binding proteins. In certain embodiments, the compounds described herein are useful in the treatment of bacterial infections.
Core Innovation
The invention relates to compounds of Formula (IIa) or (IIb), or pharmaceutically acceptable salts, solvates, stereoisomers, tautomers, N-oxides, dimers, or trimers thereof. The compounds are defined by a boron-containing scaffold with Ring A selected from cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, together with variable substituents including L1 and L2, R groups, Z, T, and Q, and structural indices such as n, m, p, q, v, and w. The specification provides extensive substituent options while maintaining the overall Formula (IIa)/(IIb) framework.
The structural definition further includes variable substitution rules for R1, R2, R5, R10, R11, R12, R13, and related substituent families, including hydrogen, halogen, optionally substituted alkyl, hydroxyl, alkoxy, thioalkyl, amino-related groups, and carbonyl-containing substituents. It also permits cases where R1 and R2 are taken together to form an optionally substituted cycloalkyl, and where other adjacent substituent pairs are taken together to form optionally substituted cycloalkyl or heterocycloalkyl. The boron-related region includes X1 and X2, which are independently hydroxyl, alkoxy, or fluoro, or can be taken together with the boron atom to form a cyclic boronate ester.
The specification also defines Z as hydrogen or various oxy- and alkyl-related motifs, T as pyridin-1-yl, pyrimidin-1-yl, or thiazol-3-yl, and Q as a pharmaceutically acceptable counterion. It further describes explicit exclusions of listed (Z)-configured benzo[e][1,2]oxaborinine-8-carboxylic acid and corresponding boronoethyl analogs. Example compounds and characterized derivatives are described, including oxime-ether diastereomer mixtures, (R,Z)-configured oxime/propanamido variants, and biologically evaluated boron-containing derivatives.
Claims Coverage
The consolidated claim coverage centers on claim 1, which defines a broad genus of compounds of Formula (IIa) or (IIb) and related pharmaceutically acceptable forms. The claim space is organized around the Formula (IIa)/(IIb) scaffold, Ring A selection, linker and substituent definitions, defined T and Q elements, and explicit exclusions. In total, the merged claim coverage reflects 5 core inventive features.
Formula (IIa)/(IIb) compound framework with pharmaceutically acceptable forms
A compound of Formula (IIa) or (IIb), or a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, N-oxide, dimer, or trimer thereof.
Ring A selection and linker-based scaffold definition
Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and L1 and L2 are defined as (CR1R2)n- and (CR1R2)m- within the overall scaffold.
Combinatorial substitution rules for R groups
R1, R2, R5, R10, R11, R12, R13, and related groups are independently defined over broad substituent sets including hydrogen, halogen, optionally substituted alkyl, hydroxyl, alkoxy, thioalkyl, amino-related groups, carbonyl-containing substituents, and optional ring-forming combinations.
Boron-related substituent framework with Z, X1/X2, T, and Q
Z is defined by hydrogen or various oxy- and alkyl-related motifs, X1 and X2 are hydroxyl, alkoxy, or fluoro or form a cyclic boronate ester with boron, T is pyridin-1-yl, pyrimidin-1-yl, or thiazol-3-yl, and Q is a pharmaceutically acceptable counterion.
Explicit exclusion of listed (Z)-configured embodiments
The compound is expressly not the listed (Z)-configured benzo[e][1,2]oxaborinine-8-carboxylic acid compounds and corresponding boronoethyl analogs, as set out in the claim exclusions.
Claim 1 defines a broad Formula (IIa)/(IIb) compound genus with selectable Ring A and linker patterns, extensive R-group and boron-related substitution rules, defined T and Q elements, and explicit exclusions of listed (Z)-configured embodiments.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating a bacterial infection in a subject by administering an effective amount of a compound of claim 1 or a pharmaceutically acceptable derivative of that compound.
Inhibiting bacterial penicillin-binding protein in a human infected subject.
Treating antibiotic-resistant infections.
Biological assay evaluation of PBP binding and antibacterial MIC testing.
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