Beta-lactamase inhibitors
Inventors
Burns, Christopher J. • DAIGLE, Denis • Liu, Bin • McGarry, Daniel • Pevear, Daniel C. • TROUT, Robert E. Lee • Jackson, Randy W.
Assignees
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Publication Number
US-11414435-B2
Publication Date
2022-08-16
Expiration Date
Abstract
Described herein are compounds and compositions that modulate the activity of beta-lactamases. In some embodiments, the compounds described herein inhibit beta-lactamase. In certain embodiments, the compounds described herein are useful in the treatment of bacterial infections.
Core Innovation
The invention relates to compounds of Formula (I) or Formula (Ia), including pharmaceutically acceptable salts, polymorphs, solvates, prodrugs, N-oxides, and isomers thereof. The compounds are defined by structural variables including M, m, n, p, X1 and X2, Z, ArA, each Y, v, and substituent groups Ra, Rb, Rc, R1, R2, R3, Rd, R4, R5, R6, R7, R8, and R10, with boron-containing scaffold variants and open–closed boron forms.
The structural scope includes X1 and X2 independently selected from —OH, —OR8, —OR10, or F; Z selected from >C(O), >C(S), or >SO2; and ArA selected from an optionally substituted aromatic or 6-membered heteroaromatic ring system. Each Y is selected from fluoro, chloro, CN, optionally substituted C1–C6 alkyl, hydroxyl, alkoxy, amine-containing patterns, and sulfur-oxygen patterns, while further refinements constrain ArA, X1 and X2, Z, and related substituent positions.
The invention also describes the compounds in pharmaceutical forms and as isotopically labeled compounds, with stereoisomers, tautomers, cis/trans forms, diastereomers, enantiomers, epimers, and racemates explicitly listed. The document further addresses antibacterial activity in bacterial infections and pharmaceutical compositions, including beta-lactamase inhibitor functional use and combination therapy with beta-lactam antibiotics.
Claims Coverage
The consolidated claim coverage centers on a Formula (I) or Formula (Ia) compound claim, including pharmaceutically acceptable salts, polymorphs, solvates, prodrugs, N-oxides, and isomers, together with a bacterial infection treatment claim. The inventive features are the formula-defined scaffold, the specified variable constraints, the enumerated Y substituent set, boronate-related functionality, and the therapeutic use in bacterial infection treatment.
Formula (I) or Formula (Ia) compound scaffold including pharmaceutically acceptable forms
A compound of Formula (I) or Formula (Ia), including a pharmaceutically acceptable salt, polymorph, solvate, prodrug, N-oxide, or isomer thereof, defined by M, m, n, p, X1, X2, Z, ArA, each Y, v, and substituent groups Ra, Rb, Rc, R1, R2, R3, Rd, R4, R5, R6, R7, R8, and R10.
Structural variable constraints for X1, X2, Z, ArA, and Y
M is a bond; m is 0, 1, or 2; n is 0, 1, 2, or 3; p is 3; X1 and X2 are independently selected from —OH, —OR8, —OR10, or F; Z is selected from >C(O), >C(S), or >SO2; ArA is an optionally substituted aromatic or 6-membered heteroaromatic ring system; each Y is selected from the listed fluoro, chloro, CN, C1–C6 alkyl, hydroxyl, alkoxy, amine-containing, and sulfur-oxygen-containing substituent patterns; and v is 1–4.
Defined substituent patterns for Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, and R10
Ra, Rb, Rc, R1, and R2 are independently selected from hydrogen, halogen, optionally substituted C1–C6 alkyl, optionally substituted C3–C6 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OH, —OR10, —NR4R5, and —SR10, with R1 and R2 optionally taken together to form an oxo, oxime, or an optionally substituted carbocycle or heterocycle. R3 is hydrogen, optionally substituted C1–C6 alkyl, or a pharmaceutically acceptable prodrug; R4 and R5 and R6 and R7 are independently selected from the listed hydrogen, hydroxyl, cyano, alkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, ring, and saccharide/PEG options; R8 is optionally substituted C1–C6 alkyl, optionally substituted C3–C6 cycloalkyl, or a pharmaceutically acceptable boronate ester group; and R10 is optionally substituted C1–C6 alkyl or optionally substituted C3–C6 cycloalkyl.
Optional combination with beta-lactam antibiotics in bacterial infection treatment
A method of treating a bacterial infection in a subject by administering a pharmaceutical composition of the claimed scaffold, optionally together with a beta-lactam antibiotic.
Overall, the claim coverage is centered on a Formula (I) or Formula (Ia) boron-containing compound framework with explicit structural variable constraints, extensive substituent definitions, and inclusion of pharmaceutically acceptable derivatives and isomeric forms, together with an explicit bacterial infection treatment use optionally combined with a beta-lactam antibiotic.
Stated Advantages
Broad-spectrum beta-lactamase inhibition across Ambler classes A–D.
Potency against all four classes (A, B, C, and D).
Provides beta-lactamase enzyme inhibition across Ambler classes A–D with IC50 determination and reported inhibition categories.
Enables MIC potentiation against strains producing ESBLs, carbapenemases, and penicillinase in combination with beta-lactam antibiotic partners.
Documented Applications
Treatment of bacterial infections in a subject by administering a pharmaceutical composition containing a Formula (I) or Formula (Ia) compound, optionally together with a beta-lactam antibiotic.
Antibacterial and beta-lactamase inhibitor functional use in the context of antibacterial applications and beta-lactam antibiotic co-use.
Use against bacterial infections with explicitly named bacteria including Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, Streptococcus pneumoniae, Bacteroides fragilis, and Clostridium difficile.
Beta-lactamase enzyme inhibition evaluation using enzymes including SHV-5, KPC-2, p99 AmpC, OXA-1, and VIM-2, with IC50 values and inhibition categories reported across Ambler classes A–D.
In vitro MIC potentiation assays against strains producing ESBLs, carbapenemases, and penicillinase, with MIC interpretation categories reported in combination with beta-lactam antibiotic partners including ceftazidime, meropenem, and piperacillin.
Pharmaceutical formulation use cases including parenteral injection composition and oral tablets or hard-shell gelatin capsules using excipients described in the provided material.
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