β-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 Francois • Guler, Satenig
Assignees
AstraZeneca UK Ltd • Entasis Therapeutics Ltd • AstraZeneca Pharmaceuticals LP
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Publication Number
US-9623014-B2
Publication Date
2017-04-18
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 a method for treating a bacterial infection in a subject in need thereof by administering an effective amount of a compound of Formula (III) or a pharmaceutically acceptable salt thereof. The compound of Formula (III) is defined by substituent rules for R1, R2, and R3, including allowed choices for each substituent and constraints on which combinations are permitted. R2 and R3 are not both hydrogen, and when R1 is C(O)NR′R″, neither R2 nor R3 is C(O)NR′R″.
The disclosure additionally describes bicyclic aza-lactam or 1,6-diazabicyclo[3.2.1]octene scaffold examples, sulfate salt forms including hydrogen sulfate and sodium hydrogen sulfate salt forms, and compound preparation and characterization for intermediates and example products.
Additional content describes in vitro antimicrobial MIC results and synergy data with beta-lactams for examples against multiple bacterial species. The disclosure also states a purpose of treating bacterial infections, including Gram-negative infections and infections caused by Acinetobacter spp., and mentions combination therapy with an additional antibiotic agent.
Claims Coverage
The independent claim is a method claim directed to treating bacterial infection by administering an effective amount of a Formula (III) compound or a pharmaceutically acceptable salt. The claim defines multiple inventive features through substituent rules for R1, R2, and R3, with explicit compatibility constraints, and dependent claims refine the infection context and combination therapy.
Administering a Formula (III) compound for bacterial infection treatment
A method for treating a bacterial infection in a subject in need thereof comprising administering an effective amount of a compound of Formula (III) or a pharmaceutically acceptable salt thereof.
Formula (III) substituent selection and constraints for R1, R2, and R3
R1 is CONR′R″, CN, or C1-C3 alkyl substituted with C1-C3 alkoxy, OH, CN, NR′R″, or CONR′R″; 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′; and R2 and R3 are not both hydrogen, with an additional restriction that when R1 is C(O)NR′R″ neither R2 nor R3 is C(O)NR′R″.
Combination therapy with an additional antibiotic agent
The method further comprises administering an effective amount of an additional antibiotic agent.
Additional antibiotic selected from a listed group
The additional antibiotic agent is selected from a specified list of antibiotics.
Specific second-antibiotic subset
The additional antibiotic agent is selected from meropenem, aztreonam, or ceftazidime.
Gram-negative bacterial infection treatment
The bacterial infection is a Gram-negative bacterial infection.
Acinetobacter spp. infection
The bacterial infection is caused by Acinetobacter spp.
Claim coverage centers on administering a Formula (III) compound or pharmaceutically acceptable salt to treat bacterial infection, with the inventive scope defined by the R1, R2, and R3 substitution rules and explicit compatibility constraints. The dependent claims further narrow the method through additional antibiotic combination therapy and through Gram-negative and Acinetobacter spp. infection contexts.
Stated Advantages
Treating bacterial infections by inhibiting β-lactamase enzymes, including Class A/C/D (including Class D).
Addressing Gram-negative infections.
Addressing drug-resistant and multi-drug resistant (MDR) infections.
Providing combination therapy with β-lactam antibiotics, including optional additional β-lactamase inhibitors.
Documented Applications
Treating a bacterial infection in a subject by administering a compound of Formula (III) or a pharmaceutically acceptable salt.
Treatment targeted to Gram-negative bacterial infection.
Treatment targeted to Acinetobacter spp. caused bacterial infection.
Infection treatment medicaments made by manufacturing medicaments containing the disclosed compounds.
In vitro antimicrobial activity reported as MIC results, including synergy data with beta-lactams, for examples against multiple bacterial species.
Synergy with beta-lactams reported in examples including combinations associated with ceftazidime, ceftaroline, meropenem, aztreonam, cefepime, and avibactam.
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