Beta-lactamase inhibitor compounds
Inventors
McGuire, Helen • Bist, Shanta • Bifulco, Neil • Zhao, Liang • Wu, Ye • Huynh, Hoan • Xiong, Hui • Comita-Prevoir, Janelle • Dussault, Daemian • Geng, Bolin • Chen, Brendan • Durand-Reville, Thomas • Guler, Satenig
Assignees
AstraZeneca UK Ltd • Entasis Therapeutics Ltd • AstraZeneca Pharmaceuticals LP
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Publication Number
US-9309245-B2
Publication Date
2016-04-12
Expiration Date
Abstract
The present invention is directed to compounds which are beta-lacatamase inhibitors. The compounds and their pharmaceutically acceptable salts, are useful in combination with beta-lactam antibiotics, or alone, for the treatment of bacterial infections, including infections caused by drug resistant organisms, including multi-drug resistant organisms. The present invention includes compounds according to formula (Ia): or a pharmaceutically acceptable salt thereof, wherein the values of R1, R2, R3 and R4 are described herein.
Core Innovation
The invention relates to compounds according to formula (Ia), or pharmaceutically acceptable salts thereof. The compounds are defined by substituent selections for R1, R2, and R3, including CONR′R″, CN, OH, NR′R″, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, halo, heterocycle, and heteroaryl options, with additional optional substitution patterns on the substituted groups.
The definition includes explicit compatibility constraints: R2 and R3 are not both hydrogen, and when R1 is C(O)NR′R″, neither of R2 nor R3 is C(O)NR′R″. The disclosed compound family further includes pharmaceutically acceptable salts, including sulfate, hydrogen sulfate, sodium sulfate, and hydrogen sulfate sodium salt forms.
The document also describes specific stereodefined 1,6-diazabicyclo[3.2.1]oct-3-en derivatives and related intermediates. These examples include carbamoyl-, hydroxymethyl-, cyano-, amino-oxoethyl-, methyl-, ethyl-, and isopropyl-substituted members, as well as compounds linked through deprotection, ion-exchange, and chromatographic purification to isolated salt forms.
Claims Coverage
The consolidated claim coverage includes one broad independent claim to a compound according to formula (Ia) or a pharmaceutically acceptable salt thereof, together with additional claim coverage to specific compounds or pharmaceutically acceptable salts thereof. The inventive features center on the formula (Ia) scaffold, defined substituent classes for R1, R2, and R3, and explicit compatibility constraints.
Compound according to formula (Ia)
A compound according to formula (Ia) or a pharmaceutically acceptable salt thereof, wherein R1 is CONR′R″, CN, OH, NR′R″, or a C1-C3 alkyl substituted with C1-C3 alkoxy, OH, CN, NR′R″, or CONR′R″; and R2 and R3 are independently selected from H, halo, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 alkoxy, CONR′R″, or C(O)2R′, with optional substitution on the alkyl, alkenyl, cycloalkyl, and alkoxy groups.
Substituent compatibility constraints
R2 and R3 are not both hydrogen; and when R1 is C(O)NR′R″, neither of R2 nor R3 is C(O)NR′R″.
Specific compound or pharmaceutically acceptable salt thereof
Specific compounds and pharmaceutically acceptable salts thereof, including specific stereodefined 1,6-diazabicyclo[3.2.1]oct-3-en derivatives and sulfate or sodium sulfate salt forms.
The claim coverage is directed to the formula (Ia) compound family with broad but explicitly constrained substituent scope, plus specific compound or salt embodiments. The recurring inventive features are the defined R1, R2, and R3 options, the non-hydrogen and amide compatibility exclusions, and the specific disclosed salt-form compounds.
Stated Advantages
Beneficial pharmacologic properties.
Inhibits beta-lactamase, including Class A/C/D serine enzymes and optionally Class D plus A/C.
Used to treat Gram-negative and other bacterial infections, including drug resistant organisms and multidrug resistant (MDR) bacteria.
Documented Applications
Treatment of Gram-negative and other bacterial infections, including infections caused by drug resistant organisms and multidrug resistant (MDR) bacteria.
Use as a beta-lactamase inhibitor alone or in combination with beta-lactam antibiotics, and sometimes other antibiotic classes, to inhibit beta-lactamase enzymes.
Combination use with beta-lactam antibiotics and/or penicillin-binding protein inhibitors for therapeutic infection indications.
Minimum Inhibitory Concentrations against multiple bacteria are reported for formula (I) compounds using broth microdilution and CLSI.
Synergy with β-lactams is reported, including synergy with β-lactamase-mediated organisms, with synergy quantified as a ≥4-fold MIC reduction.
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