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-10765662-B2
Publication Date
2020-09-08
Expiration Date
Abstract
The present invention concerns mono- or di-substituted indole compounds, methods to prevent or treat dengue viral infections by using said compounds and also relates to said compounds for use 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 concerns compounds of formula (I) consisting of a mono- or di-substituted indole group, together with a stereo-isomeric form, a pharmaceutically acceptable salt, solvate or polymorph thereof. The substitution pattern is constrained such that R1 can be H, CH3, F, CF3 or OCF3, R2 can be H, F, Cl or OCH3, and R3 can be H or CH3, with the allowed combinations reflected in the formula (I).
The disclosed subject matter includes indole-based intermediates and final compounds, including Compound 11 and Compound 12, with enantiomeric forms separated into Enantiomer 11A/11B and Enantiomer 12A/12B. It reports racemic mixtures for Compound 11 prior to chiral separation, and chiral normal-phase separation for Compound 12 into enantiomers. The separation approaches are explicitly linked to chiral SFC and normal phase chiral separation, and chiral purity is addressed through reported characterization.
Purification and analytical characterization are included in the disclosed description for the prepared intermediates and final compounds, using LC/MS, NMR, optical rotation, and chiral purity determinations. The document also provides antiviral testing workflows and tabulated results, including EC50/CC50/SI calculations, with assays described as RT-qPCR antiviral assays across multiple dengue serotypes.
Claims Coverage
The independent claim is directed to a compound of formula (I) with specific substitution constraints on a mono- or di-substituted indole group, optionally as a stereo-isomeric form, pharmaceutically acceptable salt, solvate or polymorph. Additional claim coverage extends to pharmaceutical compositions and methods for treating dengue infection. Overall, the claims cover one independent structural feature with formulation and therapeutic use embodiments.
Compound of formula (I) with mono- or di-substituted indole substitution constraints
A compound of formula (I), or a stereo-isomeric form, a pharmaceutically acceptable salt, solvate or polymorph thereof, consisting of a mono- or di-substituted indole group, wherein R1, R2 and R3 take the specified allowed combinations.
Pharmaceutical composition including the compound
A pharmaceutical composition including the compound together with one or more pharmaceutically acceptable excipients, diluents, or carriers.
Treatment of dengue infection with an effective amount
A method for treating dengue infection by administering an effective amount of the pharmaceutical composition to a patient who needs it.
Combination with another antiviral agent
The treatment method further includes administering another antiviral agent to the patient.
Claim coverage is anchored by the structural Markush scope of formula (I) for mono- or di-substituted indole compounds with defined R1/R2/R3 substitution options. Additional claims cover pharmaceutical compositions containing the compound and methods of treating dengue infection, including a variant that adds another antiviral agent.
Stated Advantages
Prevention or treatment of dengue infections in humans.
Use of pharmaceutically acceptable salts, solvates and polymorphs and defined stereo-isomeric forms including chiral stability.
Provision of combination regimens including another antiviral agent.
Documented Applications
Use to prevent or treat dengue infections in humans via pharmaceutical compositions containing the indole derivative.
Use in combination preparations for treatment in which another antiviral agent is administered.
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