Beta-lactamase inhibitor compounds
Inventors
Comita-Prevoir, Janelle • Durand-Reville, Thomas Francois • Gauthier, Lise • O'Donnell, John • Romero, Jan • Tommasi, Ruben • Verheijen, Jeroen Cunera • Wu, Frank • Wu, Xiaoyun • Zhang, Jing
Assignees
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Publication Number
US-10800778-B2
Publication Date
2020-10-13
Expiration Date
Abstract
The present invention is directed to compounds which are beta-lactamase inhibitors. The compounds and their pharmaceutically acceptable salts are useful in combination with beta-lactam antibiotics, 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 (I): or a pharmaceutically acceptable salt thereof, wherein the values of R1, R2, R3, R4, R5 and R6 are described herein.
Core Innovation
The patent relates to compounds according to Formula (I), or pharmaceutically acceptable salts thereof, defined by extensive structural constraints on substituents R1 through R10 and R7/R8. The structural definition allows carbonyl/amine-like groups, cyano, phenyl, heteroaryl, and related heteroatom-containing substituent patterns, together with optional independent substitution on phenyl and heteroaryl groups by halo, hydroxyl, alkoxy, nitrile, amino-like, carboxamide-like, carboxyl, and related functional groups.
A key aspect is that at least one of R2 and R3 is other than hydrogen, while R4 and R5 are independently selected from hydrogen, halo, CN, CO2R9, C1-C3 alkyl, and C1-C3 haloalkyl. R6 is hydrogen or a substituted alkyl, alkoxy-containing, alkenyl, cycloalkyl, heteroaryl, or non-aromatic heterocyclyl group, and R7 and R8 are independently selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, phenyl, C3-C6 cycloalkyl, heterocyclyl, and heteroaryl, with additional optional substitution limits.
The disclosure also describes stereochemically defined examples centered on a 1,6-diazabicyclo[3.2.1]oct-3-ene or 7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en core linked to fluoroacetic acid or difluoroacetic acid derivatives, including ester, acid, lithium salt, and related side-chain variants. The compounds are described as orally bioavailable beta-lactamase inhibitor compounds, and the document includes pharmaceutical and combination contexts involving bacterial infection treatment together with a beta-lactam antibiotic.
Claims Coverage
The provided independent claims are centered on a Formula (I) compound, or a pharmaceutically acceptable salt thereof, with extensive substituent constraints across R1-R10 and R7/R8, and a proviso that at least one of R2 and R3 is other than hydrogen. Dependent claim coverage further includes pharmaceutical composition scope and a method for treating bacterial infection with a beta-lactam antibiotic.
Compound according to Formula (I) with defined substituent scope
A compound according to Formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 is selected from specified carbonyl/amine-like groups, nitrile, phenyl, heteroaryl, and alkyl-substituted options; R2 and R3 are independently selected from hydrogen, halo, C1-C3 alkyl, and C3-C6 cycloalkyl; R4 and R5 are independently selected from hydrogen, halo, CN, CO2R9, C1-C3 alkyl, and C1-C3 haloalkyl; R6 is hydrogen or specified substituted alkyl/alkoxy/alkenyl/cycloalkyl/heteroaryl/heterocyclyl options; and R7/R8, R9, and R10 are defined by additional allowed identities and optional substitution patterns.
At least one of R2 and R3 is not hydrogen
The compound of Formula (I), or a pharmaceutically acceptable salt thereof, is provided with the proviso that at least one of R2 and R3 is other than hydrogen.
Pharmaceutical composition with carrier, diluent, or excipient
A pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, diluent, or excipient.
Treating bacterial infection with beta-lactam antibiotic
A method for treating a bacterial infection in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a beta-lactam antibiotic, with cefpodoxime proxetil specified in the provided material.
Claim coverage centers on Formula (I) compounds defined by detailed R-group selections and optional substitution patterns, with the additional requirement that at least one of R2 and R3 is not hydrogen. The provided dependent scope further includes pharmaceutical compositions and combination treatment of bacterial infection with a beta-lactam antibiotic.
Stated Advantages
Orally bioavailable beta-lactamase inhibitor enabling oral therapy.
Broad-spectrum beta-lactamase inhibition across Class A/C/D and ESBL.
Ability to perform an oral switch after IV treatment.
Treatment strategies intended to reduce hospital stays.
Restores cefpodoxime and other oral beta-lactam activities via MIC shift assays in Enterobacteriaceae.
Reports beta-lactamase inhibition with IC50 values against TEM-1, AmpC, and OXA-48.
Dose-dependent maximal kill and reduction of bacterial burden in a mouse neutropenic thigh infection model with cefpodoxime proxetil plus an exemplar compound.
Reports metabolic stability/conversion in human and rat S9 with half-life measurements.
Reports rat pharmacokinetics including IV/PO exposure summarized by AUC and oral bioavailability.
Documented Applications
Oral therapy for treating bacterial infections using orally bioavailable beta-lactamase inhibitors, including oral switch therapy after IV treatment.
Use in combination therapy involving a beta-lactam antibiotic, with cefpodoxime proxetil identified as a beta-lactam antibiotic in the provided dependent claim context.
Treating a bacterial infection in a subject in need thereof using an effective amount of the compound of the formula together with a beta-lactam antibiotic.
Pharmaceutical compositions containing the claimed compound, or a pharmaceutically acceptable salt, with a pharmaceutically acceptable carrier, diluent, or excipient.
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