Mono- or di-substituted indole derivatives as dengue viral replication inhibitors
Inventors
Kesteleyn, Bart Rudolf Romanie • Bonfanti, Jean-François • Jonckers, Tim Hugo Maria • Raboisson, Pierre Jean-Marie Bernard • Bardiot, Dorothée Alice Marie-Eve • Marchand, Arnaud Didier M
Assignees
CISTIM LEUVEN VZW • Katholieke Universiteit Leuven • Janssen Pharmaceutica NV • Janssen Cilag SAS • Janssen Pharmaceuticals Inc
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Publication Number
US-10696632-B2
Publication Date
2020-06-30
Expiration Date
Abstract
The present invention relates to mono- or di-substituted indole compounds, methods to prevent or treat dengue viral infections by using the compounds and also relates to use of the compounds as a medicine, more preferably for use as a medicine to treat or prevent dengue viral infections. The present invention furthermore relates to pharmaceutical compositions or combination preparations of the compounds, to the compositions or preparations for use as a medicine, more preferably for the prevention or treatment of dengue viral infections. The invention also relates to processes for preparation of the compounds.
Core Innovation
The invention is directed to mono- or di-substituted indole derivatives having formula (I) and to a compound having formula 9 or a stereoisomer thereof, together with pharmaceutically acceptable salts, solvates, and polymorphs. The disclosed subject matter includes enantiomeric forms, crystalline form, amorphous form, and unsolvated form, and presents specific compound embodiments corresponding to the disclosed formula.
The compounds are identified as dengue viral replication inhibitors and as active across all four DENV serotypes, DENV-1, DENV-2, DENV-3, and DENV-4. The disclosure states potent activity, improved pharmacokinetics, and improved chiral stability, including chiral stability data associated with at least one example embodiment.
The document provides structural representations and analytical characterization for stereochemical embodiments, including chiral separation using chiral SFC and characterization by LC/MS, optical rotation, 1H NMR, and melting point. Additional examples describe enantiomeric forms and related compounds prepared and separated, with chiral purity information reported for the separated stereoisomers.
Claims Coverage
The independent claim coverage centers on compounds having formula 9 or a stereoisomer, including pharmaceutically acceptable salts, solvates, and polymorphs. The claim set further includes crystalline and unsolvated forms, specific enantiomer embodiments characterized analytically, a method for treating Dengue viral infection, and pharmaceutical compositions. In total, the consolidated claim coverage reflects six inventive features.
Compound having formula 9
A compound having formula 9 or a stereoisomer, pharmaceutically acceptable salt, solvate or polymorph thereof.
Crystalline form of the compound or its variants
The compound (or a stereoisomer) and its pharmaceutically acceptable salt, solvate, or polymorph are provided in a crystalline form.
Unsolvated form of the compound or its variants
A compound (or stereoisomer) with pharmaceutically acceptable salt and/or polymorph forms, specifically in an unsolvated form or as a pharmaceutically acceptable salt.
Enantiomer specified by analytical characterization
A specific compound embodiment defined as Enantiomer 9A, including characterization by 1H NMR, LC/MS, optical rotation, and chiral SFC data with chiral purity.
Treatment of dengue viral infection by administration
A method for treating Dengue viral infection by administering to a patient in need thereof a compound according to claim 10.
Pharmaceutical composition with excipients, diluents, or carriers
A pharmaceutical composition includes the compound of claim 1 together with one or more pharmaceutically acceptable excipients, diluents, or carriers.
Overall, the claim coverage centers on formula 9 compounds and stereoisomers, with explicit scope for salts, solvates, polymorphs, crystalline and unsolvated forms, analytically characterized enantiomer embodiments, and use in treating Dengue viral infection as well as pharmaceutical compositions.
Stated Advantages
Potent activity as dengue viral replication inhibitors across all four DENV serotypes (DENV-1, DENV-2, DENV-3, and DENV-4).
Improved pharmacokinetics.
Improved chiral stability.
Documented Applications
Antiviral testing against DENV, including DENV-2 testing using an eGFP fluorescence assay with EC50/CC50/SI reporting.
Extended antiviral/serotype testing against DENV-1 to DENV-4 using RT-qPCR with EC50/CC50/SI reporting.
Cytotoxicity assessment using an MTS/PMS cytotoxicity assay with results tables.
Preventing or treating dengue infections in humans via administering the claimed compounds for dengue viral infection treatment.
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