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Publication Number
US-11813278-B2
Publication Date
2023-11-14
Expiration Date
Abstract
The present invention is the use of purine nucleotide phosphoramidates or pharmaceutically acceptable salts thereof administered in an effective amount for the treatment or prevention of COVID-19, an infection caused by the SARS CoV-2 virus in a host, for example a human, in need thereof.
Core Innovation
The invention relates to a method for the treatment of COVID-19 caused by the SARS-CoV-2 virus in a human host in need thereof by administering an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. The compounds are defined by specific substituent selections for R1 through R5 within Formula I, including R1 as methyl, R2 as aryl or aryl(C1-C4alkyl), R3 as hydrogen or C1-6alkyl, R4a and R4b as independently selected from hydrogen, C1-6alkyl, and C3-7cycloalkyl, and R5 as C1-6alkyl, C1-6haloalkyl, C3-7cycloalkyl, aryl(C1-C4alkyl)-, aryl, heteroaryl, or heteroalkyl.
The disclosure further includes embodiments with refined substituent patterns, stereochemical specificity for phosphoramidate in the Sp-configuration or Sp-/Rp-isomer forms with L-configuration, and pharmaceutically acceptable salt forms such as hemi-sulfate salts or 0.5 H2SO4. Additional embodiments describe Formula II, Formula IIIb, Formula IIIc, Formula IIId, Formula IIIe/IIIf, Formula IVa-IVf, Formula VI, and related example structures, supporting the use of these structurally defined compounds for treating or preventing COVID-19 caused by SARS-CoV-2.
The core invention also includes embodiments described as purine nucleotide phosphoramidate prodrugs and additional compound classes for COVID-19 treatment based on phosphates, including Formula VIII, Formula IX, Formula X, Formula XI, and Formula XII. These embodiments include alternative configurations, salt forms, oxygen protecting groups, and nested substituent definitions across the disclosed formulae.
Claims Coverage
The consolidated claim coverage centers on a COVID-19 treatment method using a Formula I compound or pharmaceutically acceptable salt, optionally in a pharmaceutically acceptable carrier, with one independent claim identified across the inputs. The inventive features repeatedly include structural definitions for R1-R5, and dependent refinements add specific substituent choices, phosphoramidate stereochemistry, dosage and administration constraints, and oral dosage form formulation.
Treatment of COVID-19 with a Formula I compound
A method for the treatment of COVID-19 caused by the SARS-CoV-2 virus in a human host in need thereof comprising administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.
Specific substituent definitions for Formula I
R1 is methyl; R2 is aryl, or aryl(C1-C4alkyl); R3 is hydrogen or C1-6alkyl; R4a and R4b are independently selected from hydrogen, C1-6alkyl, and C3-7cycloalkyl; and R5 is C1-6alkyl, C1-6haloalkyl, C3-7cycloalkyl, aryl(C1-C4alkyl)-, aryl, heteroaryl, or heteroalkyl.
Refined substituent pattern
The method further defines R2 as phenyl, R3 as hydrogen, R4a as methyl, and R4b as hydrogen.
Phosphoramidate stereochemical specification
The phosphoramidate is in the Sp-configuration, with additional embodiments describing Sp- or Rp-isomers with L-configuration.
Minimum administered amount constraint
The method is carried out by administering at least about 500 mg of the compound.
Administration frequency and treatment duration constraint
The compound is administered twice daily for about five days.
Oral dosage form formulation
Form I compounds or pharmaceutically acceptable salts are formulated with a pharmaceutically acceptable carrier into an oral dosage form.
Overall, the claim coverage is anchored in administering an effective amount of a Formula I compound or pharmaceutically acceptable salt to treat COVID-19 caused by SARS-CoV-2, with dependent claim refinements that narrow substituent selections, specify phosphoramidate stereochemistry, and constrain dose, dosing schedule, and oral formulation.
Stated Advantages
Treating COVID-19 caused by the SARS-CoV-2 virus in a human host.
Prophylactic prevention of COVID-19 is contemplated.
Reinfection minimization is referenced.
Broad coverage of chemical space through embodiments and representative chemical structures.
In vitro coronavirus antiviral potency is reported for Compound 1A and related comparators.
Supporting pharmacology and efficacy evidence is described through intracellular activation, non-human primate oral dosing, plasma PK, tissue triphosphate concentrations, and human lung triphosphate simulations.
Preventing COVID-19 caused by the SARS-CoV-2 virus.
Reported antiviral activity and potency in human airway epithelial cells.
Reported persistence of the active triphosphate metabolite in nasal/bronchial cells.
Reported lung over liver concentration of the active metabolite in primates.
Reported rationale of immunological or kinase-independent activity via differential activity among coronaviruses.
Documented Applications
Treatment of COVID-19 caused by the SARS-CoV-2 virus in a human host in need thereof.
Prophylactic prevention of COVID-19.
Prevention of COVID-19 caused by SARS-CoV-2 in a human host.
Oral dosage form formulation for Form I compounds or pharmaceutically acceptable salts.
Preventing COVID-19 caused by SARS-CoV-2.
Prophylactic prevention or minimization of COVID-19 in the described compounds.
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