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Publication Number
US-11707480-B2
Publication Date
2023-07-25
Expiration Date
Abstract
The present invention is the use of a small group of purine nucleotide phosphoramidate disclosed herein or a pharmaceutically acceptable salt thereof in an effective amount for the treatment or prevention of the novel 2019 coronavirus disease (COVID-19) in a host, for example a human, in need thereof.
Core Innovation
The disclosed subject matter relates to selected purine nucleotide phosphoramidate small molecules and phosphate prodrug compounds, including Formula I, Formula II, Formula III, Formula IV, and Formula V, with pharmaceutically acceptable salts and representative compounds such as Compound 1/1A/1B, Compound 2/2A/2B, Compound 3/3A/3B, and Compound 4/4A/4B. The compounds include stabilized phosphate prodrug frameworks with defined substituents, stereochemical possibilities at the chiral phosphorus, isotopic substitution and/or enrichment, and enantiomeric enrichment at chiral phosphorous centers.
The compounds are described as nucleoside analog phosphate prodrugs and phosphate prodrug forms that metabolize in vivo to monophosphate, diphosphate, or triphosphate species. R5 and R6 are defined in terms of stabilized phosphate prodrug structures configured to metabolize in vivo, including phosphate chain motifs, HO-containing phosphate representations, linear or polyphosphate chain structures, and bisphosphoric acid motifs.
The disclosure frames the subject matter in the context of treatment or prophylaxis of COVID-19 caused by SARS-CoV-2 in a human in need thereof, and includes oral delivery and solid dosage form descriptions, including spray-dried solid dispersions and granulo-layered solid dispersions for oral delivery. It also reports activity and pharmacokinetic-related findings for the compounds and their intracellular metabolites, including triphosphate tissue concentrations, simulated human lung triphosphate concentrations, and in vitro antiviral activity data against HCoV-229E and HCoV-OC43 in Huh7 cells.
Claims Coverage
The provided material includes independent claim coverage for a method of treating COVID-19 in a human by delivering an effective amount of a compound of a defined formula or a pharmaceutically acceptable salt. The inventive features center on a stabilized phosphate prodrug metabolizing in vivo to a monophosphate, diphosphate, or triphosphate, with dependent claims refining R5 and related phosphate or polyphosphate motifs and selecting particular depicted compound structures. The coverage includes three inventive features.
COVID-19 treatment by delivery of a compound formula or salt
A method for the treatment of the 2019 coronavirus disease (COVID-19) caused by the SARS-CoV-2 virus in a human in need thereof comprising delivering an effective amount of a compound of the formula or a pharmaceutically acceptable salt thereof.
Stabilized phosphate prodrug metabolizing to monophosphate, diphosphate, or triphosphate
R6 is a stabilized phosphate prodrug that metabolizes in vivo to a monophosphate, diphosphate, or triphosphate.
Defined R5 substituent linked to phosphate motif structures
R5 is selected from the defined substituent options, including phosphate, polyphosphate, bisphosphoric acid, and depicted phosphate motifs including linear or polyphosphate chain structures.
The core inventive coverage is the delivery of a formula compound or pharmaceutically acceptable salt for treatment of COVID-19 caused by SARS-CoV-2, where the compound includes a defined R5 substituent and R6 is a stabilized phosphate prodrug that metabolizes in vivo to monophosphate, diphosphate, or triphosphate. Dependent claims further narrow the phosphate-related structural definitions and the selected depicted compound structures.
Stated Advantages
The stabilized phosphate prodrug metabolizes in vivo to a monophosphate, diphosphate, or triphosphate.
Enantiomer enrichment ranges are described as greater than 90% to 100% free of the opposite enantiomer for particular stereochemical variants.
The disclosure reports antiviral activity data, including CC50, EC50, EC90, and selectivity indices, for example compounds.
The disclosure includes triphosphate tissue concentrations and simulated human lung triphosphate concentrations.
Oral delivery is described using spray-dried solid dispersions and granulo-layered solid dispersions.
Documented Applications
Treatment of COVID-19 caused by SARS-CoV-2 in a human in need thereof, using delivery of an effective amount of a compound of the formula or a pharmaceutically acceptable salt.
Prophylaxis of COVID-19 is described in the document summary.
Treatment or prevention of SARS-CoV-2.
Oral delivery using solid dosage forms including spray-dried solid dispersions and granulo-layered solid dispersions.
Antiviral activity assessment against coronaviruses including SARS-CoV, SARS-CoV-2, HCoV-229E, and HCoV-OC43, with measurements including CC50, EC50, EC90, and selectivity index.
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