Substituted indoline derivatives as dengue viral replication inhibitors
Inventors
Kesteleyn, Bart Rudolf Romanie • Bonfanti, Jean-François • Coesemans, Erwin • Raboisson, Pierre Jean-Marie Bernard • Marchand, Arnaud Didier M • Bardiot, Dorothée Alice Marie-Eve
Assignees
CISTIM LEUVEN VZW • Katholieke Universiteit Leuven • Janssen Pharmaceutica NV • Janssen Cilag SAS • Janssen Pharmaceuticals Inc
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Publication Number
US-11083707-B2
Publication Date
2021-08-10
Expiration Date
Abstract
The present invention relates to 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 defined by formula (I), including specified substituent options R1-R5, and pharmaceutically acceptable salts, solvates and polymorphs of the formula (I) compounds. The compounds are described as dengue viral replication inhibitors in relation to Dengue virus, including DENV-1, DENV-2, DENV-3 and DENV-4.
The substituted indoline derivatives are described with defined stereoisomeric forms, including enantiomers designated by (+) and (-) specific rotation and racemic forms. The disclosure presents chemical structures, stereochemical characterization, and reported optical rotation [α]D20 values for the illustrated compounds.
The invention also provides pharmaceutical compositions comprising the formula (I) compounds and pharmaceutically acceptable excipients, diluents or carriers. Therapeutic use is described as treatment and prevention of Dengue, including inhibition of Dengue viral replication and Dengue virus proliferation across DENV-1 to DENV-4.
Claims Coverage
The independent claim coverage centers on a formula (I) family of substituted indoline derivatives with specific R1-R5 substituent selections, including pharmaceutically acceptable salts, solvates and polymorphs. The coverage further includes stereochemical and optical rotation features, selection of specific illustrated structures or variants, pharmaceutical compositions, and methods directed to inhibiting Dengue virus proliferation across DENV-1 to DENV-4.
Formula (I) substituted indoline derivatives with defined R1-R5 substituents
A compound having formula (I) wherein R1 is chloro or fluoro; R2 is —CH2CH2OH or C3-5 alkylCOOH; R3 is trifluoromethyl or trifluoromethoxy; R4 is hydrogen, fluoro, or methoxy; and R5 is hydrogen or methyl.
Pharmaceutically acceptable salts, solvates or polymorphs of the formula (I) compound
The compound of formula (I) is provided as or includes a pharmaceutically acceptable salt, solvate or polymorph thereof.
Compounds selected from specific illustrated chemical structures
A claimed compound, or its stereoisomer, pharmaceutically acceptable salt, solvate, or polymorph, is selected from a group of specific illustrated chemical structures shown in the claim images.
(+ ) specific rotation
The compound of claim 1 is defined as having a (+) specific rotation.
Pharmaceutical composition including the claim 1 compound
A pharmaceutical composition that includes a compound according to claim 1 and one or more pharmaceutically acceptable excipients, diluents, or carriers.
Inhibiting Dengue virus proliferation by administering the claim 1 compound
A method of inhibiting Dengue virus proliferation in an animal cell by administering an effective amount of the compound of claim 1 to a subject in need.
Targeting Dengue infection with DENV-1 to DENV-4 strains
The Dengue infection is caused by DENV-1, DENV-2, DENV-3, or DENV-4 viral strains.
The claim coverage is centered on formula (I) substituted indoline derivatives defined by specific R1-R5 substituent choices, including pharmaceutically acceptable salts, solvates and polymorphs. Dependent coverage further narrows to stereochemical and illustrated-structure selections, and extends the compounds into pharmaceutical compositions and methods administering an effective amount to inhibit Dengue virus proliferation, including DENV-1 through DENV-4.
Stated Advantages
Antiviral activity is demonstrated using DENV eGFP fluorescence assay and tetravalent RT-qPCR evaluation with EC50, CC50 and selectivity index tables.
Selectivity is reported via selectivity index values in the antiviral evaluations.
Documented Applications
Treatment and prevention of Dengue, including inhibition of Dengue viral replication and Dengue virus proliferation in connection with DENV-1 to DENV-4.
Inhibition of Dengue virus proliferation in an animal cell by administering an effective amount of the compound to a subject in need.
Inhibition of Dengue infection caused by DENV-1, DENV-2, DENV-3, or DENV-4 viral strains.
Use as part of a pharmaceutical composition including one or more pharmaceutically acceptable excipients, diluents, or carriers.
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