Phosphoramidates for the treatment of hepatitis B virus
Inventors
De La Rosa, Abel • BLUEMLING, Gregory R.
Assignees
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Publication Number
US-12595280-B2
Publication Date
2026-04-07
Expiration Date
Abstract
Disclosed are compounds to the treatment of infectious diseases and methods of treating such diseases. The compounds are derivatives of clevudine.
Core Innovation
The invention relates to compounds having a specified chemical formula, or pharmaceutically acceptable salts thereof, including phosphonate-containing compound class and clevudine-derived phosphoramidate prodrugs. The structure is defined by enumerated selections for Y, Y1, Y2, aryl, R1, R3, R4, R5, and R6, with Y constrained to O or S, Y1 and Y2 constrained to OH, OAryl, OAlkyl, or BH3−M+, and aryl defined as aromatic or heteroaromatic.
The disclosed subject matter includes substituted embodiments in which R3, R4, R5, and R6 are selected from defined sets of substituents, including halogenated, alkyl, substituted amino, hydroxymethyl, cyano, azido, lipid, and heteroaryl substituent classes. The patent text also includes broad methods of use for treating or preventing DNA-virus infection by administering an effective amount of the compound or a pharmaceutically acceptable salt thereof to a host in need, further limited to hepadnavirus infection.
The document further describes clevudine phosphoramidate derivatives as intended to deliver clevudine monophosphate to the liver, reducing systemic clevudine exposure and addressing skeletal myopathy. It also states that HBV reverse transcriptase is the antiviral target associated with clevudine activity, and that (S,S) and (S,R) clevudine phosphoramidate diastereomers show anti-HBV activity similar to clevudine, with the (S,S) diastereomer slightly more potent.
Claims Coverage
The claim coverage centers on one independent compound claim defining a formula with multiple enumerated substituent selections, supported by dependent claims that narrow the structure and add therapeutic method-of-use limitations. Across the provided items, the inventive features include the compound definition and the treatment or prevention of DNA-virus infection, including hepadnavirus.
Defined compound formula with enumerated substituents and O/S selection
A compound having the formula, or a pharmaceutically acceptable salt thereof, wherein R1 is independently selected from one of the formulae; Y is O or S; Y1 is OH, OAryl, OAlkyl, or BH3−M+; Y2 is OH or BH3−M+; aryl is aromatic or heteroaromatic; R3 is hydrogen, deuterium, fluoromethyl, difluoromethyl, trifluoromethyl, alkyl, alkenyl, alkynyl, amino, fluoro, chloro, bromo, iodo, hydroxyl, cyano, formyl, acyl, substituted amino, or hydroxymethyl; R4 is alkyl, branched alkyl, cycloalkyl, or lipid; R5 is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C1-22 alkoxy, C1-22 alkyl, C2-22 alkenyl, C2-22 alkynyl, or substituted heteroaryl; and R6 is methyl, ethyl, tert-butyl, C1-22 alkoxy, C1-22 alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy.
R3 fixed to fluoro
The compound of claim 1 is defined by having R3 equal to fluoro.
R4 restricted to selected alkyl and cycloalkyl options
The claimed compound is defined by having R4 selected from methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, or neopentyl.
Treatment or prevention of DNA virus infection
A method for treating or preventing a DNA-virus infection by administering an effective amount of the compound or a pharmaceutically acceptable salt thereof to a host in need.
Treatment or prevention of hepadnavirus infection
The method further limits the DNA virus to a hepadnavirus.
The provided claims define a broadly substituted compound class and narrow it through dependent substituent selections, while also covering methods for treating or preventing DNA virus infection, including hepadnavirus infection.
Stated Advantages
The clevudine phosphoramidate prodrugs are intended to deliver clevudine monophosphate to the liver.
The clevudine phosphoramidate prodrugs are intended to reduce systemic clevudine exposure.
The clevudine phosphoramidate prodrugs are intended to address skeletal myopathy.
(S,S) and (S,R) clevudine phosphoramidate diastereomers show anti-HBV activity similar to clevudine, and the (S,S) diastereomer is slightly more potent.
Documented Applications
Treating or preventing a DNA-virus infection by administering an effective amount of the compound or a pharmaceutically acceptable salt thereof to a host in need.
Treating or preventing hepadnavirus infection.
Treating or preventing hepatitis B virus (HBV), including antiviral use in the context of HBV activity involving cccDNA and pgRNA.
Optionally further administering a second antiviral agent selected from a specified list of antiviral drugs or combinations thereof.
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