Substituted indoline derivatives as dengue viral replication inhibitors
Inventors
Bardiot, Dorothée Alice Marie-Eve • Kesteleyn, Bart Rudolf Romanie • Bonfanti, Jean-François • Raboisson, Pierre Jean-Marie Bernard • Marchand, Arnaud Didier M
Assignees
CISTIM LEUVEN VZW • Katholieke Universiteit Leuven • Janssen Pharmaceutica NV • Janssen Pharmaceuticals Inc
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Publication Number
US-11179368-B2
Publication Date
2021-11-23
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 compounds of formula (I) and any stereochemically isomeric form thereof. The formula (I) is defined by substituent selections in which R1 is fluoro or chloro, R2 is —CH2CH2OH or —(CH2)3COOH, R3 is trifluoromethyl or trifluoromethoxy, and R4 is hydrogen or methoxy. The scope additionally includes pharmaceutically acceptable salts, solvates, and polymorphs.
The disclosure describes stereoisomeric forms and reported stereochemical properties for chiral compounds, including optical rotation [α]D, chiral purity, melting points, LC-MS retention times, and characterization of separated enantiomers. Preparative chiral SFC separation is explicitly used to produce stereochemically distinct forms for multiple compounds.
The disclosure further relates to installation of ether substituents on substituted phenylacetic acid esters, conversion to bromoacetate derivatives, coupling with substituted anilines via HATU-mediated bond formation, and subsequent deprotection or hydrolysis to carboxylic acids. The resulting intermediates are described as being condensed with indoline cores to form final compounds, with examples also reporting alternative indoline substituents including trifluoromethyl and trifluoromethoxy and phenyl substitution patterns including fluoro and chloro.
Claims Coverage
The claim coverage centers on a chemical compound class of formula (I) with specified substituent options and stereochemically isomeric forms, together with pharmaceutically acceptable salts, solvates, or polymorphs. The inventive features further include stereochemical characterization, inhibition of Dengue virus replication, treatment of Dengue infection or Dengue-associated disease, targeting DENV-1 to DENV-4, and pharmaceutical compositions.
Compounds of formula (I) with defined substituent pattern
A compound of formula (I), including any stereochemically isomeric form thereof, wherein R1 is fluoro or chloro, R2 is —CH2CH2OH or —(CH2)3COOH, R3 is trifluoromethyl or trifluoromethoxy, and R4 is hydrogen or methoxy, together with a pharmaceutically acceptable salt, solvate, or polymorph thereof.
(+ ) specific rotation stereochemical characterization
The compound of claim 1 is characterized by having the (+) specific rotation.
Inhibition of Dengue virus replication by administration
A method that inhibits Dengue virus replication in an animal cell by administering to a subject an effective amount of a compound according to claim 1.
Treatment of Dengue infection or Dengue-associated disease by administration
A method of treating Dengue infection, or a related Dengue-associated disease, by administering an effective amount of the compound from claim 1 to a subject in need.
Dengue serotype targeting (DENV-1 to DENV-4)
The method is specified such that Dengue infection is caused by viruses of the DENV-1, DENV-2, DENV-3, or DENV-4 strains.
Pharmaceutical composition with pharmaceutically acceptable excipients
A pharmaceutical composition that includes the compound of claim 1 together with one or more pharmaceutically acceptable excipients, diluents, or carriers.
Overall, the claim coverage centers on a defined formula (I) scaffold with specific R1–R4 substituent options, including stereoisomers and pharmaceutically acceptable salts, solvates, or polymorphs. Dependent coverage further specifies (+) specific rotation, method-of-use for inhibiting Dengue virus replication, treating Dengue infection or Dengue-associated disease, targeting DENV-1 through DENV-4, and inclusion of the compound in pharmaceutical compositions.
Stated Advantages
Inhibits dengue viral replication.
Prevents and/or treats dengue infections in humans.
Treats Dengue infection or a disease associated with Dengue infection.
Provides a pharmaceutical composition with pharmaceutically acceptable excipients, diluents, or carriers.
Documented Applications
Preventing and/or treating dengue infections in humans using the substituted indoline derivatives as dengue antiviral agents, including inhibition of dengue viral replication.
Treatment of Dengue infection or a disease associated with Dengue infection in subjects in need thereof.
Dengue infection caused by viruses of the DENV-1, DENV-2, DENV-3, or DENV-4 strains.
Use of pharmaceutical compositions comprising the substituted indoline derivatives together with pharmaceutically acceptable excipients, diluents, or carriers.
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