Adenosine derivative and pharmaceutical composition comprising the same
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Publication Number
US-12370208-B2
Publication Date
2025-07-29
Expiration Date
Abstract
Disclosed here is an adenosine derivative prodrug that can have reverse transcriptase inhibitor activity in vivo. This disclosure is also directed to a pharmaceutical composition comprising the adenosine derivative that can be used for the treatment of HIV infection or RNA virus infection.
Core Innovation
The invention relates to a compound of formula (4-A), including a pharmaceutically acceptable salt or stereoisomer thereof, and orally administered pharmaceutical compositions that contain the compound together with a pharmaceutically acceptable carrier. The disclosure also describes adenosine-derivative prodrugs and related fluorinated purine tetrahydrofuran intermediates, including carbonate, carbamate, and ester embodiments, stereoisomers, tautomers, and solvates.
The disclosed subject matter includes specific adenosine-derivative isomers and reverse transcriptase inhibitor compounds defined by multiple compound formulas and structural variants, including formula (1), (1a), (1b), and related variants with a 6-amino-2-fluoro purine scaffold and an ethynyl substituent. It further includes fluorinated purine-tetrahydrofuran-ethynyl scaffold derivatives and deuterated fluoro-purine nucleoside scaffold conversions, with protecting-group intermediates and compound formulas including (1)-(8), (1-A)-(8-A), (4-B), and (4-C).
The document further describes synthetic preparations and analytical characterization of multiple intermediates and derivatives using LCMS (ESI), 1H NMR, and 19F NMR. The disclosed adenosine derivatives are described as being converted in vivo to the target drug or to EFdA-like active reverse transcriptase inhibitors.
Claims Coverage
The independent claim coverage across the items centers on one core inventive feature: a compound of formula (4-A), including pharmaceutically acceptable salts or stereoisomers. The claims also cover orally administered pharmaceutical compositions that include the compound with a pharmaceutically acceptable carrier, with solid and liquid oral dosage form refinements.
Compound of formula (4-A)
A compound of formula (4-A), or a pharmaceutically acceptable salt or stereoisomer thereof.
Orally administered pharmaceutical composition with pharmaceutically acceptable carrier
An orally administered pharmaceutical composition containing the compound of formula (4-A) or a pharmaceutically acceptable salt or stereoisomer thereof together with a pharmaceutically acceptable carrier.
Oral solid dosage form
An orally administered pharmaceutical composition provided in a solid dosage form.
Oral liquid dosage form
A liquid, orally administered pharmaceutical composition.
Overall, the claim coverage is centered on the compound defined by formula (4-A), including pharmaceutically acceptable salts and stereoisomers, and on orally administered pharmaceutical compositions that include that compound with a pharmaceutically acceptable carrier, further limited to solid or liquid oral dosage forms.
Stated Advantages
Rapid conversion: more than 60% of adenosine derivatives are converted to the target drug within about 30 minutes in human plasma.
Higher EFdA exposure for prodrug formula 4-A versus dose-equivalent EFdA, including AUC0-24h and Cmax.
Plasma and liver S9 conversion and stability indicating conversion of named adenosine derivatives to parent EFdA.
Prolonged release versus dose-equivalent EFdA.
Reverse transcriptase inhibition/chain termination in vivo.
DNA translocation inhibition in vivo.
HIV antiviral activity.
Documented Applications
Treatment or prevention of HIV/AIDS and other RNA viral diseases, including HIV-1, HIV-2, multidrug resistant HIV, wild-type HIV, and RNA virus infection.
Administration by IM, SC, IV, oral, topical, or implant routes.
Co-administration with anti-HIV agents.
Therapeutic monitoring by measuring target drug levels in specimens, with possible dosage adjustment.
Biological performance evaluation including plasma and human liver S9 conversion/stability data indicating conversion to parent EFdA.
Oral pharmacokinetics in beagle dogs, including prodrug/EFdA plasma concentration and exposure tables comparing prodrug formula 4-A with dose-equivalent EFdA after oral administration.
Prevention and treatment of AIDS.
Prevention and treatment of wild-type HIV-1.
Prevention and treatment of NRTI-resistant HIV-1.
Prevention and treatment of HIV-2.
Prevention and treatment of HIV with M184V.
Prevention and treatment of HIV with K65R.
Prevention and treatment of multidrug resistant HIV.
Combination with anti-HIV agents for treatment use.
In vivo reverse transcriptase inhibition/chain termination.
In vivo DNA translocation inhibition.
HIV antiviral activity.
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