Heterocyclic compounds and their use in preventing or treating bacterial infections
Inventors
Barbion, Julien • Caravano, Audrey • Chasset, Sophie • Chevreuil, Francis • Faivre, Fabien • LEBEL, Rémi • Lecointe, Nicolas • Ledoussal, Benoît • LE-STRAT, Frédéric • Simon, Christophe • OLIVEIRA, Chrystelle • Le Fralliec, Géraldine • BRIAS, Julie • FARESCOUR, Laurence • VOMSCHEID, Sophie • Richard, Sébastien
Assignees
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Publication Number
US-10722520-B2
Publication Date
2020-07-28
Expiration Date
Abstract
A compound of formula (I) or a racemate, an enantiomer, a diastereoisomer, a geometric isomer or a pharmaceutically acceptable salt thereof, and its use as antibacterial agent.
Core Innovation
The invention relates to compounds of formula (I) in which R1 represents a 5-membered heterocycle linked to the structure by a nitrogen atom, and the nitrogen atom may be quaternized. R2 is selected from —SO3H, —CFHCOOH, or —CF2COOH, and the compounds also include a broad set of substituent and heteroatom-bearing groups defined by T1, T2, X, Q1, Q2, Q3, Q4, m, n, p, and r.
The formula (I) scope further allows stereochemical variants and pharmaceutically acceptable salts, including racemates, enantiomers, diastereoisomers, and geometric isomers. The variable definitions also permit fluorine atom, heterocycle, alkyl, and fluoroalkyl patterns, with oxidation of carbon atoms to C=O, oxidation of sulfur atoms to S=O or S(O)2, and quaternization of nitrogen atoms by a methyl group.
The document also describes compounds and examples built on azabicyclic triazole, pyrazole, imidazole, thiazole, oxazole, pyridyl, and thiadiazolyl scaffolds, including sulfate, hydrogen sulfate, sodium sulfate, pyridinium, and triethylammonium forms. The examples reference sulfation, deprotection, and salt formation, and report MS and 1H NMR characterization data for the resulting compounds.
Claims Coverage
The consolidated claim coverage centers on formula (I) compounds with a nitrogen-linked 5-membered heterocycle that may be quaternized, a restricted R2 substituent set, and broad substituent, heteroatom, oxidation, and stereoisomer/salt definitions. A separate claim family defines a related formula with selectable Y substituents and a protective group PG.
Quaternizable nitrogen-linked 5-membered heterocycle scaffold
A compound of formula (I) wherein R1 represents a 5-membered heterocycle, optionally substituted by one or more T1, linked to the structure by a nitrogen atom, and the nitrogen atom may be quaternized.
Specified R2 acid substituent selection
A compound of formula (I) wherein R2 represents —SO3H, —CFHCOOH, or —CF2COOH.
Broad substitution framework for T1, T2, Q groups, X, and stereochemical or salt variants
In formula (I), T1 includes fluorine and other defined groups; T2 is —OH, —NH2, or —CONH2; Q1 and Q2 are hydrogen atom; Q3 and Q4 are hydrogen atom or (C1-C3)-alkyl; X is O, S, S(O), S(O)2, or N(Q3); and the compound may be a racemate, an enantiomer, a diastereoisomer, a geometric isomer, or a pharmaceutically acceptable salt.
Compound of formula with selectable Y group and protective group PG
A compound of formula wherein Y is selected from a halogen, —B(OR)2, and SnR3, and PG is a protective group selected from allyl, benzyl, tertbutyldimethylsilyl (TBDMS), or tert-butoxycarbonyl (Boc).
The independent claim coverage is centered on formula (I) compounds defined by a nitrogen-linked 5-membered heterocycle that may be quaternized, together with an R2 group restricted to —SO3H, —CFHCOOH, or —CF2COOH, and broad allowable substituent definitions. A separate independent claim defines a related formula with selectable Y substituents and a protective group PG.
Stated Advantages
Provides compounds and pharmaceutical compositions for preventing and treating bacterial infections.
Provides β-lactamase inhibitor activity for bacterial infection therapy.
Enables antibacterial use in combination with β-lactam antibiotics, including ceftazidime.
Documented Applications
Use in preventing and treating bacterial infections with β-lactamase inhibitor compounds of formula (I).
Use of the β-lactamase inhibitor compounds in combination with β-lactam antibiotics, including ceftazidime.
Treatment relevance is described for bacterial infections involving β-lactamase-producing bacteria and Gram-positive/Gram-negative bacteria.
β-lactamase inhibitory IC50 determinations using nitrocefin against multiple β-lactamases.
MIC and synergy testing versus ceftazidime across genotyped bacterial isolates, with MIC tables and ceftazidime-combination outcomes.
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