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
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Publication Number
US-10870672-B2
Publication Date
2020-12-22
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 invention discloses beta-D-2'-deoxy-2'-alpha-fluoro-2'-beta-C-substituted, N6-substituted purine nucleotide compounds and stabilized phosphate prodrugs, including phosphoramidates and thiophosphoramidates, for the treatment of HCV. Examples include fluorinated, methylated nucleoside cores with varied purine substituents, amino-acid-derived prodrug groups, ethynyl-substituted analogs, and phosphorus stereoisomers. Independent claims cover pharmaceutical compositions comprising an effective therapeutic amount of the compound or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier.
The prodrugs convert through mono-, di-, and triphosphate nucleotide metabolites to active guanine triphosphate, which inhibits HCV NS5B polymerase with an IC50 of 0.15 uM. Metabolite data demonstrate that compounds converge on a common guanine monophosphate before further phosphorylation to the active triphosphate. Selected compounds exhibit reported EC50 values of 4 nM, TC50 values above 100 uM, and therapeutic indices exceeding 25,000, outperforming sofosbuvir in comparative evaluations.
Claims Coverage
The claims include two independent claims, claims 1 and 19, which cover substantially the same type of pharmaceutical composition. Two inventive features are identified across the claims.
Pharmaceutical composition containing the compound or its salt
Independent claims 1 and 19 each recite a pharmaceutical composition comprising an effective therapeutic amount of a compound of the formula, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.
Dosage forms of the pharmaceutical composition
Dependent claims specify dosage forms for the pharmaceutical composition, including solid, solid oral, tablet, and capsule forms.
Independent claims 1 and 19 cover pharmaceutical compositions containing an effective therapeutic amount of the compound or its pharmaceutically acceptable salt in a pharmaceutically acceptable carrier. Dependent claims further define solid, solid oral, tablet, and capsule dosage forms.
Stated Advantages
The specification states that the compounds or their metabolites have anti-HCV activity.
Selected compounds show a 4 nM replicon EC50 and therapeutic indices above 25,000, substantially improving on parent nucleosides.
Compounds 5-2, 25, and 27 show greater in-vitro anti-HCV activity than sofosbuvir across the tested genotypes.
No cross-resistance is observed for compounds 5-2 and 25 against the tested NS5B variants.
The compounds show low cytotoxicity in several cell assays, with compound 5-2 being less cytotoxic to human hepatocyte co-cultures than sofosbuvir and INX-189.
Documented Applications
Treatment or prophylaxis of HCV, including inhibition of HCV replication.
Use of the compounds alone or in optional combination antiviral therapy.
Pharmaceutical compositions containing the claimed compound or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier, including solid, solid oral, tablet, and capsule dosage forms.
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