Heterocyclic compounds and their use in preventing or treating bacterial infections
Inventors
BRIAS, Julie • Caravano, Audrey • Chasset, Sophie • Chevreuil, Francis • Faivre, Fabien • Ledoussal, Benoît • Le Strat, Frédéric • Richard, Sébastien • Simon, Christophe • VOMSCHEID, Sophie
Assignees
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Publication Number
US-10570131-B2
Publication Date
2020-02-25
Expiration Date
Abstract
The present invention relates to heterocyclic compounds, their process of preparation, pharmaceutical compositions comprising these compounds and use thereof, optionally in combination with other antibacterial agents and/or beta-lactam compounds, for the prevention or treatment of bacterial infections. The present invention also relates to the use of these compounds as β-lactamase inhibitors and/or as antibacterial agents.
Core Innovation
The invention relates to compounds of formula (I), including racemates, enantiomers, diastereoisomers, geometric isomers, and pharmaceutically acceptable salts. Formula (I) specifies extensive structural variability through substituents R1, R2, and R3, ring and linker groups Q1 to Q7, and functional-group options for T1 to T3, with optional oxidation of carbon atoms to a C(=O) group and sulphur atoms to S(=O) groups or S(O)2 groups.
The structural definitions further allow optional quaternization of a nitrogen atom within a heterocycle or within a tertiary amino group by a methyl group. The disclosed scope also includes specific selections and linkages for Q1 and Q2, Q3 and Q4, and Q5, together with defined ranges for m, n, p, and q, and optional subclasses defined by formula sets A1, A2, B1, and B2.
The disclosed use includes prevention and treatment of bacterial infections, including infections caused by beta-lactamase-producing bacteria. The compounds are characterized as antibacterial agents and/or beta-lactamase inhibitors, and the pharmaceutical embodiments include compositions and kits comprising the compounds and pharmaceutically acceptable excipients or carriers, including combination use with beta-lactam antibiotics such as ceftazidime.
Claims Coverage
One independent claim is provided. It covers a compound of formula (I) with extensive structural variability in R1, R2, and R3, and in Q1 to Q7 and T1 to T3, together with optional oxidation, optional methyl quaternization, and stereochemical or salt forms. The provided material also includes narrower structural selections and pharmaceutical composition embodiments.
Compound of formula (I)
A compound of formula (I) wherein R1, R2, R3, and the groups Q1 to Q7 and T1 to T3 are selected according to the specified structural definitions, including optional carbon and sulphur oxidation, optional methyl quaternization of a nitrogen atom, and racemate, enantiomer, diastereoisomer, geometric isomer, or pharmaceutically acceptable salt forms.
Specific formula set selection
Selection from the group consisting of formulae A1, A2, B1, and B2.
Pharmaceutical composition including the formula (I) compound
A pharmaceutical composition comprising the compound of formula (I).
Combination pharmaceutical composition
A pharmaceutical composition further including an antibacterial compound selected from aminoglycosides, beta-lactams, glycylcyclines, tetracyclines, quinolones, fluoroquinolones, glycopeptides, lipopeptides, macrolides, ketolides, lincosamides, streptogramins, oxazolidinones, polymyxins, and combinations thereof.
The claim coverage centers on compounds of formula (I) with broad substituent definitions and allowed oxidation, methyl quaternization, and stereochemical or salt forms, and extends to pharmaceutical compositions and combination compositions with additional antibacterial compounds.
Stated Advantages
b2-lactamase inhibitory activity, with IC50 values reported for compounds alone and in combination with ceftazidime.
Antibacterial activity represented by MIC results for compounds alone and in combination with ceftazidime against multiple resistant Gram-negative strains.
Synergy and combination effects presented in synergy and combination tables for MIC combinations with ceftazidime.
Prevention or treatment of bacterial infections.
Antibacterial activity and/or beta-lactamase inhibition.
Ability to address beta-lactamase-producing bacteria.
Compatibility with combination use with other antibacterial agents, including beta-lactam antibacterial agents such as ceftazidime.
Documented Applications
b2-lactamase inhibitory activity and MIC evaluation against resistant Gram-negative strains, including testing for compounds alone and in combination with ceftazidime against TEM-1, SHV-1/11/12, CTX-M-15, KPC-2/3, P99 AmpC, CMY-37/CMY-2, OXA-1/11/15/48, and P. aeruginosa strains.
Therapeutic use for preventing or treating bacterial infections, including infections involving beta-lactamase-producing bacteria.
Use in pharmaceutical compositions for treatment of bacterial infections.
Use in kits comprising a compound composition together with an additional antibacterial or beta-lactam composition.
Combination use with other antibacterial agents, including beta-lactam antibacterial agents such as ceftazidime.
Use for urinary tract infection and pyelonephritis.
Use for community-acquired pneumonia, hospital-acquired pneumonia, ventilator associated pneumonia, intra-abdominal pneumonia, sepsis, and catheter-related sepsis.
Antibacterial control against gram-positive bacteria and gram-negative bacteria.
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