Heterocyclic compounds and their use in preventing or treating bacterial infections
Inventors
Barbion, Julien • Caravano, Audrey • Chasset, Sophie • Chevreuil, Francis • Lecointe, Nicolas • Le Strat, Frédéric • OLIVEIRA, Chrystelle • Simon, Christophe
Assignees
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Publication Number
US-11530227-B2
Publication Date
2022-12-20
Expiration Date
Abstract
The present invention relates to compounds of formula (I) and their use for treating or preventing a bacterial infection or as an antibacterial agent and/or as a β-lactamase inhibitor.
Core Innovation
The invention relates to compounds of formula (I) in which W is an 8- to 10-membered aromatic or partially unsaturated bicycle optionally having one or more heteroatoms selected from O, N, N(T2), and S. The compounds include extensive substituent variability defined for R1, R2, R3, R4, R5, Y1, Y2, Y3, Y4, and Y5, together with substituent groups T1, T2, and the optional substituent variables X1 to X4 and Z1 to Z4.
The structural definitions specify alternative choices for sulfonate and fluorinated acyl-type substituents, including Y1 being SO3H, CHFC(=O)Y2, CF2C(=O)Y2, or SO3(C1-C6)alkyl-C(=O)O(C1-C6)alkyl. The remaining variables define OH, O-alkyl, O-cycloalkyl, O-heterocyclyl, NY3Y4, and multiple alkyl, cycloalkyl, heterocyclyl, and heteroaryl options, with optional substitution by X4.
The compounds are described as having antibacterial activity and as functioning as β-lactamase inhibitor utilities. The scope includes pharmaceutically acceptable salts, inner zwitterionic salt forms, isotopically-labelled compounds, stereochemical forms, and optional sulfur oxidation and tertiary amino quaternization.
Claims Coverage
The claim set includes one independent compound claim with extensive structural variability and three dependent claim themes covering pharmaceutical composition, antibacterial co-agent selection, and treatment of β-lactamase-producing bacterial infection.
Compound of formula (I) with defined aromatic bicyclic system W
A compound of formula (I) in which W is an 8- to 10-membered aromatic or partially unsaturated bicycle optionally having heteroatoms selected from O, N, N(T2), and S, with extensive substituent definitions for R1, R2, R3, R4, R5, Y1, Y2, Y3, Y4, Y5, T1, T2, X1 to X4, and Z1 to Z4.
Variable groups Y1 to Y5 including sulfonate and fluorinated acyl options
Y1 is selected from SO3H, CHFC(=O)Y2, CF2C(=O)Y2, and SO3(C1-C6)alkyl-C(=O)O(C1-C6)alkyl; Y2 is selected from OH, O(C1-C6)alkyl, O-(C3-C11)cycloalkyl, O-(4 to 6-membered heterocyclyl), or NY3Y4.
Pharmaceutical composition including the defined compound and pharmaceutically acceptable excipient
A pharmaceutical composition that includes a compound as defined in claim 1 and a pharmaceutically acceptable excipient.
Antibacterial pharmaceutical composition with defined antibiotic co-agent selection
The antibacterial compound in the pharmaceutical composition is selected from aminoglycosides, β-lactams, glycylcyclines, tetracyclines, quinolones, fluoroquinolones, glycopeptides, lipopeptides, macrolides, ketolides, lincosamides, streptogramins, oxazolidinones, polymyxins, or mixtures thereof.
Treatment method for β-lactamase-producing bacterial infection
A method for treating a patient’s bacterial infection caused by β-lactamase-producing bacteria by administering an effective amount of a compound according to claim 1.
Coverage centers on a highly variable compound formula (I) defined by a specific bicyclic ring system W and multiple enumerated substituent variables, with dependent refinements covering pharmaceutical composition and β-lactamase-related therapeutic use.
Stated Advantages
Antibacterial activity.
β-lactamase inhibitor utility.
Use in pharmaceutical compositions and mixtures with β-lactam antibiotics, including ceftazidime.
Use as a kit.
Use for treatment and prevention.
Inhibition of beta-lactamases as assessed by nitrocefin (NCF) beta-lactamase inhibitory activity.
Antibacterial activity in MIC testing, including synergy testing in combination with ceftazidime against an E. coli isolate with described resistance mechanisms.
Documented Applications
Treatment of a patient’s bacterial infection caused by β-lactamase-producing bacteria by administering an effective amount of a compound according to claim 1.
Prevention and treatment via kit use.
Pharmaceutical compositions, including mixtures with β-lactam antibiotics, notably ceftazidime.
Example 1 for a specific sodium sulfate salt compound.
Beta-lactamase inhibitory activity testing using nitrocefin (NCF) with reported IC50 values across multiple beta-lactamase enzymes.
MIC and synergy testing of compounds alone and in combination with ceftazidime against an E. coli isolate with described resistance mechanisms.
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