Compounds
Inventors
PORRAS DE FRANCISCO, Esther • Remuiñan-Blanco, Modesto Jesús • BOUROTTE, Marilyne • Deprez, Benoit • Willand, Nicolas
Assignees
Bioversys AG • GlaxoSmithKline Intellectual Property Development Ltd
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Publication Number
US-11254689-B2
Publication Date
2022-02-22
Expiration Date
Abstract
The invention relates to compounds of Formula (I) and their use in therapy, for example in the treatment of mycobacterial infections or in the treatment of diseases caused by mycobacterium, such as tuberculosis.
Core Innovation
The invention relates to novel spirocyclic compounds of Formula (I), or pharmaceutically acceptable salts thereof, including fluorinated diazaspiro[4.5]dec-2-en compounds and related spiroisoxazoline, alkoxyspiro, and alkylspiro variants. The compound family is defined by an R1 substituent selected from halogen, cyano, C1-6 straight alkyl, C3-4 branched alkyl, C1-6 straight alkoxy, C3-4 branched alkoxy, methyl substituted by one or more fluoro, ethyl substituted by one or more fluoro, methoxy substituted by one or more fluoro, or ethoxy substituted by one or more fluoro.
The document frames these compounds in relation to mycobacterial infections, particularly tuberculosis, including multidrug-resistant and ethionamide-resistant tuberculosis. It describes the compounds as potentiators of ethionamide and as agents with biological activity in tuberculosis-related assays, including EthA-activatable activity and thioamide-related activity.
The document further describes therapeutic use through combination therapy, including combining Formula (I) compounds with thioamides such as ethionamide and prothionamide to potentiate activity. It also describes combination regimens with other anti-tuberculosis agents and optional antiviral or antiretroviral agents for relevant patient populations.
Claims Coverage
The provided claim coverage centers on Formula (I) compounds defined by the specified R1 substituent class, with pharmaceutically acceptable salt coverage and composition coverage. The inventive features are the Formula (I) spirocyclic compound definition, specific named fluorinated members, and pharmaceutical composition with a pharmaceutically acceptable excipient.
Formula (I) spirocyclic compound with R1 substituent class
A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is selected from halogen; cyano; C1-6 straight alkyl; C3-4 branched alkyl; C1-6 straight alkoxy; C3-4 branched alkoxy; methyl substituted by one or more fluoro; ethyl substituted by one or more fluoro; methoxy substituted by one or more fluoro; or ethoxy substituted by one or more fluoro.
Named Formula (I) member as a specific fluorinated diazaspiro compound
A specific compound of Formula (I) or a pharmaceutically acceptable salt thereof, defined as a named fluorinated diazaspiro structure, including a 4,4,4-trifluoro-1-(3-(trifluoromethyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-en-8-yl)butan-1-one member.
Pharmaceutical composition with pharmaceutically acceptable excipient
A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable excipient.
The claims focus on Formula (I) spirocyclic compounds defined by the specified R1 substituent class, with pharmaceutically acceptable salts covered as well. Additional coverage includes specific named fluorinated spiro/diazaspiro members and pharmaceutical compositions comprising the claimed compound plus a pharmaceutically acceptable excipient.
Stated Advantages
Potentiation of ethionamide for mycobacterial activity.
Activity in tuberculosis-related assays, including EC50 and intracellular IC50 readouts.
Use in EthA-activatable combination therapy for ethionamide-resistant tuberculosis.
Documented Applications
Potentiation of ethionamide evaluated using M. tuberculosis H37Rv-GFP strains with EC50 measurements, with additional intracellular IC50 results using THP-1 for selected examples.
Therapy of mycobacterial infections, including tuberculosis, including multidrug-resistant and ethionamide-resistant tuberculosis.
Treatment of tuberculosis via combination therapy including combination with thioamides such as ethionamide and prothionamide in an EthA-activatable manner to potentiate activity.
Combination therapy with other anti-tuberculosis agents.
Combination therapy optionally including antiviral/antiretroviral agents.
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