Heterocyclic compounds and their use in preventing or treating bacterial infections
Inventors
Caravano, Audrey • Chasset, Sophie • Chevreuil, Francis • Faivre, Fabien • Lecointe, Nicolas • Ledoussal, Benoît • Le Strat, Frédéric • Richard, Sébastien • Simon, Christophe • VOMSCHEID, Sophie • BRIAS, Julie • Barbion, Julien
Assignees
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Publication Number
US-10072006-B2
Publication Date
2018-09-11
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 describes compounds of formula (I) defined by variable substituents R1, R2, and R3, where R1 is selected from carbon-linked 4-, 5-, or 6-member monocyclic heterocycles containing a nitrogen heteroatom and optionally further heteroatoms, and where R2 is a 4- to 10-member monocyclic or bicyclic heterocycle containing a nitrogen heteroatom and optionally further heteroatoms. R3 is selected from —SO3H, —CFHCOOH, or —CF2COOH, and the definition includes optional substitution by T1, T2, and T3, along with Q1, Q2, Q3, and Q4 selections and related saturation, oxidation, and quaternization variants.
The scope also includes pharmaceutically acceptable salts, corresponding zwitterions, optical isomers, racemates, diastereoisomers, enantiomers, and tautomers of formula (I). The document describes a pharmaceutical composition comprising at least one compound of formula (I) at an effective amount together with a pharmaceutically acceptable excipient, and additional context where the composition includes an antibacterial agent selected from defined antibiotic classes and combinations thereof.
The document further describes thiazolodiazabicycloocten-oxo intermediates and final salts, including specific protected intermediate and salt-forming intermediates used to reach guanidinomethyl and other salt forms. The disclosed compounds include specific final salt examples such as a guanidinomethyl hydrogen sulfate and a sodium and 2,2,2-trifluoroacetate disalt form of a thiazolodiazabicycloocten-oxo derivative.
Claims Coverage
The consolidated content identifies multiple independent claims across the input items, centered on a broad structural compound claim, narrower protected compound selections, and pharmaceutical composition and method claims. Overall, the inventive features cover defined chemical compound classes with specific substituent variables and, in one item, beta-lactamase-associated antibacterial use.
Compound of formula (I) defined by R1, R2, and R3 substituent classes
A compound of formula (I) wherein R1 is selected from carbon-linked 4- or 5- or 6-member monocyclic heterocycles with a nitrogen heteroatom and optionally further heteroatoms; R2 is a 4- to 10-member monocyclic or bicyclic heterocycle with a nitrogen heteroatom and optionally further heteroatoms; and R3 is selected from —SO3H, —CFHCOOH, or —CF2COOH, with optional substitution by T1 and detailed parameter selections for Q1–Q4 and T3.
Protective-group compound selection with X substituent and different protective groups
A compound selected from the group wherein X is selected from halogen, B(OR)2, —OTf, and —SnR3, with PG1 and PG2 being different protective groups.
Protected compound selection with a 5-member B(OR)2 linkage and two different protective groups
A compound selected from the group wherein X is selected from halogen, B(OR)2, —OTf, and —SnR3, where the B(OR)2 portion forms a cycle comprising 5 members, and where PG1 and PG2 are different protective groups selected from allyl, benzyl, tertbutyldimethylsilyl (TBDMS), and tert-butoxycarbonyl (Boc).
Pharmaceutical composition comprising an effective amount of the formula (I) compound
A pharmaceutical composition comprising at least one compound of formula (I) at an effective amount together with a pharmaceutically acceptable excipient.
Pharmaceutical composition further comprising a specified antibacterial agent
The pharmaceutical composition further includes an antibacterial agent selected from the listed antibiotic classes and combinations thereof.
Method for treating bacterial infections by administering the formula (I) compound
A method for treating bacterial infections in a patient by administering a therapeutically effective amount of a compound of formula (I).
Treatment of beta-lactamase-producing bacterial infections
The method applies to bacterial infections caused by bacteria producing one or more beta-lactamases.
Across the independent claims in the input items, the coverage centers on defined chemical compound classes: a general formula (I) with specified substituent classes and allowed parameter values, narrower compound selections defined by X substituents and the presence of two different protective groups, and pharmaceutical composition and method claims directed to antibacterial use against beta-lactamase-producing bacterial infections.
Stated Advantages
Provides beta-lactamase inhibitory activity against multiple beta-lactamase enzymes and variants as evaluated in the document.
Provides antibacterial activity as assessed by MIC determinations and reported combination results showing synergy with ceftazidime.
Documented Applications
Inhibition of beta-lactamases using thiazolodiazabicycloocten-oxo derivatives evaluated against enzymes and variants including TEM-1, SHV-1, CTX-M-15, KPC-2, P99, CMY-37, AmpC, and OXA variants.
Treatment or therapeutic relevance in bacterial infection contexts supported by MIC determinations and synergy testing with ceftazidime across genotyped Gram-negative bacterial strains.
Combination evaluation with ceftazidime to assess synergy using reported MIC and combination results for bacterial strains.
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