Boronic acid derivatives and therapeutic uses thereof
Inventors
Reddy, Raja K. • Glinka, Tomasz • TOTROV, MAXIM • Hecker, Scott • Rodny, Olga
Assignees
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Publication Number
US-10206937-B2
Publication Date
2019-02-19
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 disclosure concerns compounds having the structure of Formula I-(1) or Formula (I-2), including pharmaceutically acceptable salts. The scaffold is defined by variable atoms and substituents, including Y and G, as well as J, L, and M and Y′ and M′, with additional substituent definitions for R, R7, R10, R11, and related groups. The structure constraints specify selectable chemical substituents and optional substitution patterns within defined chemical groups.
Y is selected from —S—, —S(O)—, —S(O)2—, —O—, —CH2—, and —NR2—, and G is selected from a broad set of heteroatom-containing and ring-containing groups, including amide, thioether, ether, carbonyl-containing groups, and multiple ring and heteroring classes optionally substituted by enumerated R10 groups. J, L, and M are each independently selected from CR7 and N, and each R7 is independently selected from H, OH, halogen, alkyl, alkoxy(C1-C6)alkyl, mercapto, cyano, and (CH2)m—Y′—(CH2)pM′.
The document further defines Y′ and M′ to constrain the core scaffold and substitution pattern, and specifies X, Z, R, R1, R2, R1a, and R2a through enumerated substituent sets. In the provided examples context, the document characterizes benzo[e][1,2]oxaborinine carboxylic acid derivatives and related benzoxaborinine-8-carboxylic acid derivatives with heteroarylthio substituents, including methylthio and methoxy substitution patterns and other aromatic substitution patterns such as difluoro and chloro.
The examples report substituted benzoxaborinine-thiadiazole sulfide scaffold compounds, a sulfonamide-containing analog, and multiple prodrug precursors and ester prodrugs derived from an alcohol-bearing boronic acid scaffold. The document also reports biochemical evaluation of inhibition of carbapenemases including NDM-1 and VIM-1, broader carbapenemase/β-lactamase inhibition across class A/B/D enzymes, potentiation of carbapenems against engineered and clinical bacterial isolates, and serum hydrolysis stability data and oral pharmacokinetics/bioavailability for the prodrugs in rats.
Claims Coverage
The independent claim defines a broad compound class by Formula I-(1) or Formula (I-2) with pharmaceutically acceptable salts, using multiple structural variables constrained by enumerated groups. Dependent claims narrow or specify sub-forms and include a pharmaceutical composition limitation.
Formula I-(1) or Formula I-(2) scaffold with defined Y and G
A compound having the structure of Formula I-(1) or Formula I-(2), including pharmaceutically acceptable salts, wherein Y is selected from —S—, —S(O)—, —S(O)2—, —O—, —CH2—, and —NR2—, and G is selected from the enumerated heteroatom/carbonyl-containing and ring-based groups.
Variable core definitions via J, L, and M
J, L, and M are each independently selected from CR7 and N, where each R7 is independently selected from H, OH, halogen, CH3, CF3, alkyl/alkenyl/alkynyl, carbocyclyl/heterocyclyl/aryl/heteroaryl, cyano, alkoxyalkyl, aryloxy, sulfhydryl, and (CH2)m—Y′—(CH2)p—M′ forms.
Defined Y′ and M′ substituent groups
Y′ is selected from —S—, —S(O)—, —S(O)2—, —O—, —CR5R6—, and —NR1—, and M′ is selected from carbonyl/amide-related options including C(O)NR1R2, C(O)NR1OR3, NR1C(O)R5, NR1C(O)NR2R1a, NR1C(O)OR3, NR1S(O)2R3, and related variants.
Constrained X, Z and R substituent families
X is hydrogen or optionally substituted C1-9 alkyl; Z is selected from optionally substituted cycloalkyl, heterocyclyl, aryl, and heteroaryl; and R, R1, R2, R1a, and R2a are defined by enumerated optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl options.
Pharmaceutical composition with excipient
A pharmaceutical composition includes a therapeutically effective amount of the compound together with a pharmaceutically acceptable excipient.
Formula (Ig) or Formula (Ih) sub-form
The compound of formula (I) has the specific structural form of either formula (Ig) or formula (Ih).
Claim coverage centers on a Formula I-(1)/Formula (I-2) compound family with constrained Y, G, J/L/M, Y′, M′, X, Z, and R-substituent options, plus dependent narrowing to specific sub-forms and a pharmaceutical composition.
Stated Advantages
Inhibition of carbapenemases including NDM-1 and VIM-1.
Broader carbapenemase/β-lactamase inhibition across class A/B/D enzymes, including KPC-2, OXA-48, and NDM-1.
Potentiation of carbapenems against engineered and clinical bacterial isolates.
Serum hydrolysis stability data and oral pharmacokinetics/bioavailability for the prodrugs in rats.
Documented Applications
Treating or preventing bacterial infections.
Therapeutic use against bacterial infections associated with β-lactamases and multidrug-resistant bacteria, with reference to carbapenemases.
Use in pharmaceutical compositions including a therapeutically effective amount of the compound together with a pharmaceutically acceptable excipient.
Use in a formulation including a monosaccharide/monosaccharide-derivative complex.
Biochemical evaluation of inhibition of carbapenemases and β-lactamases.
Potentiation of carbapenems against engineered and clinical bacterial isolates.
Oral prodrugs derived from an alcohol-bearing boronic acid scaffold.
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