β-d-2′-deoxy-2′-α-fluoro-2′-β-c-substituted-2-modified-n6-substituted purine nucleotides for HCV treatment
Inventors
Sommadossi, Jean-Pierre • Moussa, Adel
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-10875885-B2
Publication Date
2020-12-29
Expiration Date
Abstract
A compound of the structure: or a pharmaceutically acceptable salt or composition thereof for the treatment of a host infected with or exposed to an HCV virus or other disorders more fully described herein.
Core Innovation
The disclosure concerns fluorinated purine nucleoside phosphoramidate compounds and prodrugs of Formulas I through VII, including substituted beta-D-2'-deoxy-2'-alpha-fluoro-2'-beta-C-substituted, N6-substituted purine nucleotide compounds, 2'-fluoro-2'-ethynyl purine nucleosides, and stabilized phosphate or thiophosphoramidate prodrug variants. These compounds encompass beta-D and beta-L configurations with modified purine bases, fluorinated sugars, and specified phosphorus stereochemistry, with certain embodiments enriched to be at least 90% free of the opposite phosphorus S-enantiomer.
Prodrug forms are metabolized through nucleotide intermediates to a common monophosphate and active guanine triphosphate NS5B inhibitors for HCV treatment. Evaluated compounds demonstrate potent anti-HCV activity, inhibit HCV NS5B genotype 1b polymerase, and outperform parent nucleosides and comparator sofosbuvir across tested genotypes and resistance variants, showing low cytotoxicity in cell assays and favorable human hepatocyte findings relative to comparator compounds.
Claims Coverage
The independent claims identify three inventive features directed to compounds of the recited formula, compounds meeting phosphorus stereoisomer purity thresholds, and pharmaceutical compositions containing the stereoisomer-enriched compounds.
Compound of the recited formula
Independent claim 1 covers a compound of the recited formula or a pharmaceutically acceptable salt thereof. Dependent claims define pharmaceutical compositions comprising an effective therapeutic amount in a pharmaceutically acceptable carrier, including oral, parenteral, and intravenous formulations.
Compound enriched for a phosphorus stereoisomer
Independent claim 11 covers a compound of the recited formula, or a pharmaceutically acceptable salt thereof, wherein the compound is at least 90% free of the opposite phosphorus S-enantiomer. Dependent claims further specify enantiomeric purity thresholds of at least 98% and at least 99%.
Pharmaceutical composition containing a phosphorus-stereoisomer-enriched compound
Independent claim 14 covers a pharmaceutical composition comprising an effective therapeutic amount of the recited compound or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier, wherein the compound is at least 90% free of the opposite phosphorus S-enantiomer. Related dependent claims specify higher purity thresholds as well as oral, intravenous, or parenteral formulations.
The independent claims cover the recited chemical compounds and salts, phosphorus stereoisomer-enriched compounds, and pharmaceutical compositions containing the enriched compounds. Dependent claims further specify purity thresholds and oral, parenteral, or intravenous formulations.
Stated Advantages
In vitro screening results report EC50 values of 4 to 5 nM and therapeutic indices above 25,000, including Compound 5-2 and Compound 25, compared with sofosbuvir's reported EC50 of 53 nM and therapeutic index greater than 1,920.
Compounds show substantially greater activity than parent nucleosides and comparator sofosbuvir, generally outperforming sofosbuvir across tested genotypes and resistance variants.
The beta-D methyl-guanine triphosphate inhibits HCV NS5B genotype 1b polymerase, with no detected cross-resistance to specified NS5B variants.
The evaluated compounds show low cytotoxicity across several cell assays.
Human hepatocyte findings are favorable relative to sofosbuvir and INX-189.
Documented Applications
Treatment of HCV.
HCV prophylaxis.
Combination treatment for HCV.
Pharmaceutical compositions containing an effective therapeutic amount of the compound or its pharmaceutically acceptable salt in a pharmaceutically acceptable carrier, formulated as oral tablets, suspensions, or solutions, or as parenteral or intravenous formulations.
Evaluation of anti-HCV activity through HCV replication inhibition in Huh7 cells.
Interested in licensing this patent?