Substituted indoline derivatives as dengue viral replication inhibitors
Inventors
Kesteleyn, Bart Rudolf Romanie • Raboisson, Pierre Jean-Marie Bernard • Bonfanti, Jean-François • 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-10689340-B2
Publication Date
2020-06-23
Expiration Date
Abstract
The present invention concerns substituted indoline derivatives, 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 relates to substituted indoline derivatives described as dengue virus replication inhibitors. The disclosure provides compounds defined by formula (I) and a group of specified compounds, including stereoisomeric forms, pharmaceutically acceptable salts, solvates, and polymorphs. The compounds include enantiomeric and racemic forms, with characterization data such as 1H NMR, LC/MS, optical rotation, melting point, chiral purity, and retention times.
The invention addresses the use of the indoline derivatives as medicines for preventing or treating dengue virus infections, including DENV-1 to DENV-4. The compounds are presented in pharmaceutical compositions and are associated with crystalline form, amorphous form, and un-solvated form, as part of the claimed subject matter. The disclosure also includes synthetic routes, intermediates, and characterization of fluorinated, substituted indolinyl phenoxyacetic acid scaffold compounds.
The disclosure further evaluates the compounds against dengue virus using cellular assays. Activity is quantified using EC50, CC50, and selectivity index in a DENV-2 eGFP fluorescence assay and in an RT-qPCR assay targeting dengue virus RNA, with results reported across DENV-1, DENV-2, DENV-3, and DENV-4 and compared to prior-art WO-2013/045516 compounds (56) and (170).
Claims Coverage
The independent claim covers a compound selected from a specified group and its stereoisomeric forms, including pharmaceutically acceptable salts, solvates, or polymorphs. Across the dependent claims, inventive coverage is refined by a pharmaceutical composition context, specific solid-state forms, and a formula-based compound limitation.
Compound selected from the group comprising stereoisomeric forms
A compound selected from the group consisting of the specified compounds and stereoisomeric forms, including pharmaceutically acceptable salts, solvates, or polymorphs thereof.
Pharmaceutical composition with pharmaceutically acceptable excipients
A pharmaceutical composition comprising the compound and one or more pharmaceutically acceptable excipients, diluents, or carriers.
Crystalline form variant
A compound or stereoisomer, together with its pharmaceutically acceptable salt, solvate, or polymorph, provided in a crystalline form.
Amorphous form variant
A compound or stereoisomer together with its pharmaceutically acceptable salt, solvate, or polymorph, specified to be in an amorphous form.
Un-solvated form variant
A compound or stereoisomer, including a pharmaceutically acceptable salt, solvate, or polymorph, specifically in an unsolvated form.
Formula-based compound limitation
A compound corresponding to formula (I) or the formula of claim 1, including stereoisomeric forms, pharmaceutically acceptable salts, solvates, or polymorphs.
Overall claim coverage centers on the disclosed compound group together with stereoisomeric forms, with further scope extending to pharmaceutically acceptable salts, solvates, and polymorphs, specific solid-state forms, a pharmaceutical composition embodiment, and a formula-based definition.
Stated Advantages
Used as dengue virus replication inhibitors.
Used for preventing or treating dengue virus infections, including DENV-1 to DENV-4, as medicines.
Documented Applications
Prevention or treatment of dengue virus infections using formula (I) compounds as medicines.
Use of the compounds in pharmaceutical compositions.
DENV-2 antiviral evaluation using an eGFP fluorescence assay with EC50, CC50, and selectivity index (SI).
Dengue virus serotype antiviral evaluation (DENV-1 to DENV-4) using an RT-qPCR assay targeting dengue 3'UTR RNA with reported EC50, CC50, and selectivity index (SI).
Comparison to prior-art WO-2013/045516 compounds (56) and (170) using reported DENV-2 activity (EC50, CC50, SI).
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