Substituted indole compound derivatives as dengue viral replication inhibitors
Inventors
Kesteleyn, Bart Rudolf Romanie • Bonfanti, Jean-François • Raboisson, Pierre Jean-Marie Bernard • Bardiot, Dorothée Alice Marie-Eve • Marchand, Arnaud Didier M • Cosemans, Erwin
Assignees
CISTIM LEUVEN VZW • Katholieke Universiteit Leuven • Janssen Pharmaceutica NV • Janssen Cilag SAS • Janssen Pharmaceuticals Inc
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Publication Number
US-10730884-B2
Publication Date
2020-08-04
Expiration Date
Abstract
The present invention concerns 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 disclosure relates to substituted indole derivatives and indole-based compounds corresponding to formulas (Ia, Ib, II, III, IV), including stereoisomeric forms and pharmaceutically acceptable salts, solvates, and polymorphs. The core structure comprises a mono- or di-substituted indole group with specific substitution patterns, including cases where substituents are connected forming a heterocycle of 5 members having one oxygen atom.
The subject matter includes compound series such as Compound 13, Compound 14, and Compound 15, with intermediates, racemic compounds, chiral enantiomers, and deuterated analogs. The disclosure reports deuterium incorporation, separation into enantiomeric deuterated forms, and characterization data for the stereoisomeric and deuterated derivatives, including 1H NMR, LC/MS, optical rotation, retention times, and chiral purity.
The invention further encompasses pharmaceutical composition embodiments using the disclosed substituted indole compounds together with pharmaceutically acceptable excipients, carriers, and diluents. The described compounds are characterized as inhibiting dengue virus replication, and the disclosure includes analytical and example content consistent with identifying and differentiating stereoisomeric material.
Claims Coverage
The independent claims cover substituted indole compounds defined by formulas (Ia, Ib, II, or IV), pharmaceutical compositions including these compounds with pharmaceutically acceptable excipients, diluents, or carriers, and a method of inhibiting dengue virus replication by contacting dengue virus with the claimed compound. The claim set combines compound structure selection, formulation, and dengue virus replication inhibition.
Indole-containing compounds defined by formulas Ia, Ib, II or IV
A compound of formula (Ia, Ib, II or IV) comprising a mono- or di-substituted indole group, selected according to specified substitution combinations for the indole framework.
Stereoisomers with pharmaceutically acceptable salts, solvates or polymorphs
The compound is provided in a stereoisomeric form and includes pharmaceutically acceptable salts, solvates, or polymorphs.
Specific substitution patterns including connected 5-member heterocycles with one oxygen
The allowed indole substitution patterns include enumerated R-group combinations and cases where substituents are connected forming a heterocycle of 5 members having one oxygen atom.
Pharmaceutical composition with pharmaceutically acceptable excipients, diluents or carriers
A pharmaceutical composition comprising a compound of formula (Ia, Ib, II or IV) together with pharmaceutically acceptable excipients, diluents, or carriers.
Method of inhibiting dengue virus replication by contacting dengue virus
A method that inhibits dengue virus replication by contacting dengue virus with the claimed substituted indole compound.
The claims center on substituted indole compounds of formulas (Ia, Ib, II, or IV) with restricted substitution patterns and stereoisomeric/salt/solvate/polymorph forms, and further include pharmaceutical compositions and a dengue virus replication inhibition method.
Stated Advantages
The document reports dengue virus antiviral activity using EC50, CC50, and selectivity index (SI).
The document reports selectivity index (SI=CC50/EC50) for the disclosed compounds in DENV-2 and across a tetravalent DENV RT-qPCR format spanning DENV-1 to DENV-4.
Inhibits dengue virus replication.
Documented Applications
Antiviral activity testing against dengue virus, including DENV-2 using an eGFP-based assay format and a tetravalent DENV RT-qPCR assay spanning DENV-1 to DENV-4, with reported EC50/CC50/SI values.
Use of the disclosed compounds in a prior-art comparison against a WO-2013/045516 compound (350), including reported EC50/CC50/SI in an analogous DENV-2 assay.
Prevention and/or treatment in humans using substituted indole derivatives that inhibit dengue virus replication.
Use as dengue virus replication inhibitors, including all four serotypes.
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