Double-liver-targeting phosphoramidate and phosphonoamidate prodrugs
AssigneeNanjing Molecular Research, Inc.
InventorsJunbiao Chang, Qiang Huang, Runcong Liu, Zheng Wang
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Abstract
This application discloses phosphoramidate and phosphonoamidate prodrugs of alcohol-based therapeutic agents, such as nucleosides, nucleotides, acyclonucleosides, C-nucleosides, and C-nucleotides, and use of these prodrugs for treatment of diseases or disorders, including infectious diseases and cancers. This application also discloses a general method for enhancing bioavailability and/or liver-targeting property of alcohol drugs through converting the alcohol drugs to phosphoramidate or phosphonoamidate prodrugs, and methods of preparation of these prodrugs.
Claims20
A compound of formula:
- or a pharmaceutically acceptable salt or solvate thereof, wherein:
- X is oxygen (O) or —CH2—;
- Y is a nucleoside, acyclonucleoside, or C-nucleoside moiety;
- R′, R1, R2, and R3 are each independently selected from the group consisting of hydrogen and substituted or unsubstituted alkyl, aryl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, and heteroaryl groups, wherein said heterocyclyl and heteroaryl group each comprises one to three heteroatoms independently selected from O, S, and N, or alternatively, R2 and R3, together with the carbon atom to which they are attached, form an optionally substituted 3- to 8-membered ring;
- R4 is selected from the group consisting of hydrogen, and substituted or unsubstituted alkyl, aryl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, and heteroaryl groups, metal ions, and ammonium ions;
- Ar is substituted C6-C10 aryl or optionally substituted 5- to 10-membered heteroaryl comprising one to three heteroatoms independently selected from O, S, and N;
- and
- the “linker” is selected from a bond and optionally substituted C1-C3 alkylene, vinyl, ethynyl, arylene, and heteroarylene, wherein the heteroarylene comprises one to three heteroatoms independently selected from O, S, and N.
A method of enhancing bioavailability and/or liver-targeting property of an alcohol drug, comprising protecting at least one hydroxyl group of said alcohol-containing drug with a phosphoramidate moiety of formula:
- wherein:
- R′, R1, R2, and R3 are each independently selected from the group consisting of hydrogen and substituted or unsubstituted alkyl, aryl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, and heteroaryl groups, wherein the heterocyclyl and heteroaryl group each comprises one to three heteroatoms independently selected from O, S, and N, or, alternatively, R2 and R3 together with the carbon atom to which they are attached form an optionally substituted 3- to 8-membered ring;
- R4 is selected from the group consisting of hydrogen and substituted or unsubstituted alkyl, aryl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, and heteroaryl groups, metal ions, and ammonium ions;
- Ar is substituted C6-C10 aryl or optionally substituted 5- to 10-membered heteroaryl comprising one to three heteroatoms independently selected from O, S, and N;
- and
- the “linker” is selected from a bond and optionally substituted C1-C3 alkylene, vinyl, ethynyl, arylene and heteroarylene, wherein the heteroaryl comprises one to three heteroatoms independently selected from O, S, and N.
Dependencies are inferred from the claim text.