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-10913716-B2
Publication Date
2021-02-09
Expiration Date
Abstract
The present invention concerns substituted indoline 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
Substituted indoline derivatives of formula (I) are described as dengue viral replication inhibitors and as medicines for preventing and/or treating dengue viral infections. The compounds include stereoisomeric forms, enantiomeric (+) and (−) forms, pharmaceutically acceptable salts, solvates, and polymorphs, and dengue virus proliferation/replication is stated to be inhibited by the compounds.
Formula (I) substituent constraints are specified using R1, R2, and R3, where R1 is CF3 or OCF3, R2 is H, F or OCH3, and R3 is H or CH3. The compounds are reported to show antiviral activity against all four dengue serotypes, including DENV-1, DENV-2, DENV-3, and DENV-4.
The description further covers pharmaceutical composition forms and mentions unit dosage forms and effective daily dose ranges. Analytical characterization and example data are provided, including chiral and non-chiral analytical methods such as LC/MS and SFC/MS, together with melting point and optical rotation/chiral purity reporting.
Claims Coverage
The independent claims cover one formula (I) compound with specific substituent constraints and optional stereochemical, salt, solvate, or polymorph forms, and methods centered on treating dengue infection and inhibiting dengue virus replication using the claimed compound in an effective amount. The claim scope also includes pharmaceutical compositions and optional co-administration of an additional therapeutic agent.
Substituted indoline derivatives with specified R1, R2 and R3
A compound having formula (I) in which R1 is CF3 or OCF3, R2 is H, F or OCH3, and R3 is H or CH3, wherein the compound is selected from stereoisomeric forms, pharmaceutically acceptable salts, solvates or polymorphs.
Treating dengue viral infection by administering an effective amount
A method for treating Dengue viral infection in a subject by administering a compound having formula (I) in a stereoisomeric form, pharmaceutically acceptable salt, solvate or polymorph, or a pharmaceutical composition, in an effective amount to treat the infection.
Inhibiting dengue virus replication by contacting with an effective amount
A method for inhibiting dengue virus replication in a biological sample or patient by contacting the virus with a compound having formula (I) in a stereoisomeric form, pharmaceutically acceptable salt, solvate or polymorph in an effective amount.
Co-administering an additional therapeutic agent
The treating or replication-inhibition method further includes co-administering an additional therapeutic agent, including an antiviral agent, a Dengue vaccine, or both.
The claim coverage is anchored on formula (I) substituted indoline derivatives with defined substituent constraints and optional stereochemical, salt, solvate, or polymorph forms, together with dengue-focused methods that administer or contact the compound in an effective amount to treat dengue infection and inhibit dengue virus replication. The scope also extends to pharmaceutical compositions and optional co-administration of an additional therapeutic agent.
Stated Advantages
Potent antiviral activity against all four dengue serotypes (DENV-1, DENV-2, DENV-3, DENV-4).
Inhibition of dengue virus proliferation/replication.
Prevention and/or treatment of dengue viral infections.
Addresses limitations of vaccination, including antibody-dependent enhancement (ADE), by providing pre-exposure antiviral compounds.
In vitro antiviral activity against dengue virus is supported by determination of EC50 for viral replication inhibition and CC50 for cytotoxicity, including selectivity index (SI) values.
Dengue virus replication inhibition is supported by RT-qPCR evaluation targeting 3′UTR with β-actin normalization across multiple dengue serotypes.
Documented Applications
Medicines for preventing and/or treating dengue viral infections by using substituted indoline derivatives of formula (I) as dengue viral replication inhibitors.
Treating Dengue viral infection in a subject by administering a compound or pharmaceutical composition in an effective amount.
Inhibiting dengue virus replication by contacting dengue virus in a biological sample or patient with the compound in an effective amount.
Use in methods that optionally co-administer an additional therapeutic agent, including an antiviral agent and/or a Dengue vaccine.
In vitro antiviral evaluation of invention compounds against dengue virus, including eGFP-based DENV-2 antiviral assay and measurement of EC50/CC50/SI.
RT-qPCR-based assessment of dengue virus replication across dengue serotypes DEN-1, DENV-2, DENV-3, and DENV-4 using 3′UTR targets and β-actin normalization.
Comparative in vitro testing of invention compounds against prior-art compounds from WO-2013/045516, including compounds labeled 56 and 170.
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