Boronic acid derivatives and therapeutic uses thereof
Inventors
Reddy, Raja K. • Glinka, Tomasz • TOTROV, MAXIM • Hecker, Scott
Assignees
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Publication Number
US-9132140-B2
Publication Date
2015-09-15
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 as therapeutic agents.
Core Innovation
The invention discloses boronic-acid moiety compounds defined by Formula (I-1) and Formula (I-2), including pharmaceutically acceptable salts. The compounds include variable structural positions J, L, and M; Y; G; and a multiplicity and selection of R7, together with additional substituent variables including X, Z, R, and R1/R2/R3/R5/R6 and related definitions. The structure system also includes stereochemical variants and equilibrium between cyclic boronate monoesters and acyclic boronic acids, represented as I/I.1.
The structural definition further includes Y and Y' options such as S—, S(O)—, S(O)2—, O—, and CH2—, and G selected from defined heteroatom and carbonyl-containing groups including —NR1R2, —N3, —C(O)NR1R2, —S(O)2NR1R2, —SR3, —OR3, —CH2NR1C(O)R5, and related variants. X is hydrogen or optionally substituted C1-9 alkyl, and Z is selected from optionally substituted cycloalkyl, heterocyclyl, aryl, and heteroaryl groups. The compounds are also described with chemical complexes involving monosaccharides, including meglumine-containing complexes.
The document includes pharmaceutical compositions containing the compounds with pharmaceutically acceptable excipient(s), and related formats including prodrugs, metabolites, isomers, solvates, hydrates/polymorphs, and higher oligomeric forms including cyclic dimeric/trimeric/tetrameric forms. It also describes synthetic Scheme 3b to access substituted “VII-2” from a salicylic acid derivative through diallylated intermediates, Claisen rearrangement, ester hydrolysis, double-bond isomerization to a styryl aldehyde, diversification, and reduction, and it frames the compounds in the context of antimicrobial resistance and bacterial infection.
Claims Coverage
The claim coverage centers on one independent claim and broadens around Formula (I-1) or Formula (I-2) boronic-acid moiety compounds, with pharmaceutically acceptable salts and multiple defined structural variables. The inventive features are built from the J/L/M, Y, G, and R7 definitions, together with additional substituent-variable spaces for X, Z, and R1/R2/R3/R5/R6.
Formula (I-1)/Formula (I-2) boronic-acid moiety compound scaffold with variable structural positions
A compound having the structure of Formula (I-1) or Formula (I-2) or pharmaceutically acceptable salts thereof, with J, L, and M each independently selected from CR7 and N; Y selected from —S—, —S(O)—, —S(O)2—, —O—, and —CH2—; and G selected from the listed heteroatom and carbonyl-containing groups such as —NR1R2, —N3, —C(O)NR1R2, —S(O)2NR1R2, —SR3, —OR3, —CH2NR1C(O)R5, and related defined groups, with further definitions for X, Z, R7 occurrence and identity, and other substituent variables including Y' and M'.
R7 multiplicity and substituent identity constraints within the scaffold
R7 is present 1 to 5 times and each R7 is independently selected from the group consisting of —H, —OH, halogen, —CF3, alkenyl/alkynyl, heteroalkyl, carbocyclyl/heterocyclyl/aryl/heteroaryl, cyano, alkoxy(alkyl) groups, aryloxy, sulfhydryl (mercapto), and a specified —(CH2)m—Y'—(CH2)p—M' option, with m and p independently 0 to 3, and with Y' and M' selected from their respective explicitly listed groups.
Permitted substituent domains for core scaffold variables
X is hydrogen or optionally substituted C1-9 alkyl; Z is selected from optionally substituted cycloalkyl, heterocyclyl, aryl, and heteroaryl; and R is selected from —H, —C1-9 alkyl, and defined cyclic or heteroatom-substituted groups including CR5R6OC(O)C1-9 alkyl, CR5R6OC(O)OC1-9 alkyl, and with R1/R2/R1a/R2a and R3 and R5/R6/R8/R9 each independently selected from the explicitly defined sets of optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl/heterocyclyl, aryl, and heteroaryl options, including index constraints such as each n independently 0 to 3.
The claims broadly cover Formula (I-1) or Formula (I-2) boronic-acid moiety compounds, where the inventive scope is determined by selectable heteroatom/functional-group positions, constrained R7 occurrence and identity, and the explicitly defined substituent domains for X, Z, R, and the various substituent variables, with inclusion of pharmaceutically acceptable salts.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Administration/formulation in pharmaceutical compositions, including therapeutically effective dosage, routes of administration, and pharmaceutically acceptable carriers/excipients, for the described compounds.
Chemical complex formation with boronic acid oligomer formation using meglumine-containing anti-oligomer pharmaceutical complexes.
Methods of treating/preventing bacterial infection using the described compounds.
Combination use with β-lactam antibacterial agents and β-lactamase inhibitors, including class A/C/D inhibitors and class B inhibitor ME1071, as described in the partial content.
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