3-(phenylsulfonyl)-[1,2,3]triazolo[1,5A]quinazolin-5(4H)-one derivatives
Inventors
BOUROTTE, Marilyne • Pieren, Michel • Lociuro, Sergio • Gitzinger, Marc • Kemmer, Christian • Schellhorn, Birgit • SCHILL, Julian • Schneider, Peter
Assignees
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Publication Number
US-12509462-B2
Publication Date
2025-12-30
Expiration Date
Abstract
The present invention relates to a compound according to formula (I)wherein R1 to R9 are as described herein;and pharmaceutically acceptable salts, stereoisomers, enantiomers, tautomers of the compounds of formula (I) as well as pharmaceutical compositions thereof and their uses in methods of reducing the virulence of bacteria that express AgrA, in methods for preventing or treating diseases caused or exacerbated by bacteria, preferably by Staphylococcus aureus, such as skin or lung infections or atopic dermatitis.
Core Innovation
The invention relates to substituted 4H-triazolo[1,5-a]quinazolin-5-one sulfonyl derivatives of formula (I), including pharmaceutically acceptable salts, stereoisomers, enantiomers, and tautomers, with variables R1-R18 defined by allowable substituent types. The compounds are exemplified by named triazolo[1,5-a]quinazolin-5-one sulfonyl compounds bearing halogen, hydroxyl, methoxy, hydroxyethoxy, ether/alkoxy, azetidinyl/amine side chains, and other specified substituent patterns.
The formula (I) framework includes a conditional constraint that if R3 is methyl and R1 is methyl, then at least one of R2, R4 to R9 is not H. The disclosed subject matter also includes specific embodiments and examples of Formula (I) compounds, together with intermediates and late-stage formation of triazolo compound systems.
The examples describe substituted quinazolin-5-one sulfonyl compounds and related intermediate structures that are characterized by 1H NMR and ESI-MS or ES-MS. The specification presents multiple exemplars within the formula (I) family, including sulfonylacetonitrile intermediates and related aromatic sulfonyl nitriles, as well as exemplified triazolo[1,5-a]quinazolin-5-one sulfonamide compounds with variants on the phenyl sulfonyl group and quinazolinyl ring.
Claims Coverage
The provided claim set centers on one broad independent claim for formula (I), with dependent claims refining substituent selections and extending to pharmaceutical compositions and bacterial-genus context. In total, the provided claims identify five inventive feature groupings: the formula (I) compound, a conditional substituent constraint, a refined substituent pattern, a pharmaceutical composition with a pharmaceutically acceptable excipient, and a composition context with bacteria selected from specified genera.
Formula (I) substituted triazolo[1,5-a]quinazolin-5-one sulfonyl compounds
A compound of formula (I) in which R1-R18 are defined by the specified selections for halogen, hydroxyl, NO2, CN, C1-C6-alkyl and C1-C6-alkoxy, cycloalkyl, sulfonyl, ether/alkoxy, amide, and heterocycle options, together with pharmaceutically acceptable salts, stereoisomers, enantiomers, and tautomers.
Conditional substituent constraint relating R1 and R3
A constraint that if R3 is methyl and R1 is methyl, then at least one of said R2, R4 to R9 is not H.
Refined substituent pattern with fixed R2 and R4
A compound of formula (I) in which R2 and R4 are H, R1 is selected from C1-C3 alkyl optionally substituted with R11, halogen, or C1-C3 alkoxy, and exactly one of R6 to R9 is not H.
Pharmaceutical composition with pharmaceutically acceptable excipient
A pharmaceutical composition comprising at least one compound of formula (I), or its pharmaceutically acceptable salts, stereoisomers, enantiomers, or tautomers, together with a pharmaceutically acceptable excipient.
Pharmaceutical composition with specified bacterial genera
A pharmaceutical composition in which the bacteria is from a genus selected from Staphylococcus, Streptococcus, or Clostridium.
The claims cover a broadly defined formula (I) compound class with extensive substituent variability, a conditional restriction on the R1/R3 methyl combination, a narrower substituent pattern fixing R2 and R4 and requiring exactly one non-H among R6-R9, and pharmaceutical compositions including an excipient and a specified bacterial-genus context.
Stated Advantages
Reducing virulence by inhibiting RNAIII and PSMα expression.
Reducing RNAIII/psmα expression and RBC hemolysis more effectively than Savirin.
Being non-antibacterial.
Being non-cytotoxic.
Antibacterial anti-virulence activity by inhibiting quorum sensing via AgrA in Gram-positive bacteria.
Prevention or treatment of infections, including Staphylococcus aureus infections.
Prevention or treatment of inflammatory skin diseases, including atopic dermatitis.
Documented Applications
Anti-virulence/quorum-sensing therapy targeting bacteria expressing AgrA and orthologs, preferably in Staphylococcus aureus.
Use as an antibacterial anti-virulence agent targeting quorum sensing via AgrA in Gram-positive bacteria, including inhibition of virulence factors.
Prevention or treatment of bacterial skin and lung infections.
Treatment of inflammatory diseases such as atopic dermatitis or psoriasis.
Prevention or treatment of Staphylococcus aureus infections.
Prevention or treatment of inflammatory skin diseases including atopic dermatitis.
Pharmaceutical composition applications incorporating at least one formula (I) compound with pharmaceutically acceptable excipient, and optionally combining with antibiotics and/or anti-inflammatory agents.
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