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AssigneeZhejiang Palo Alto Pharmaceuticals, Inc
InventorsZhijian XI, Huaqiang XU, Chunping LU, Zhongshan WU, Feng SUN
Estimating the term…
Disclosed herein are a liver specific delivery (LSD)-based antiviral prodrug nucleoside cyclophosphate compound and uses thereof. Specifically, this application provides a compound of formula (I), or an isomer, a pharmaceutically acceptable salt, a hydrate, a solvate or a pharmaceutical composition thereof. This application also provides an application of the compound alone or in combination with other antiviral drugs in the treatment for viruses, particularly hepatitis C virus (HCV).
A compound of formula (II) or formula (III)
Dependencies are inferred from the claim text.
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With the saccharide radical esterified by phosphoric or polyphosphoric acids: containing cyclic phosphate
Having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid: having two oxo groups directly attached to the…
Antivirals: for RNA viruses
Phosphorylation: introducing polyphosphoric acid radicals
Term end not estimated
The present invention relates to a preparation method and an application of a liver-specific delivery-based antiviral prodrug nucleoside cyclo-phosphate compound or an optical isomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
Hepatitis C virus (HCV) is a main human pathogen and there are about 200 million cases infected with HCV worldwide. Chronic HCV infection will develop into serious progressive liver diseases, including cirrhosis and hepatocellular carcinoma. Therefore, chronic HCV infection is the major cause of death worldwide in patients who suffer from liver diseases. According to the data released by the Health Planning Commission, the reported cases of hepatitis C virus infection in China has continuously increased in the past 10 years, and the general trend is still not optimistic.
HCV is a positive-strand RNA virus, and its genome consists of approximately 9,600 nucleotides, including non-coding regions at both ends, i.e., an internal ribosome entry site (IRES) and an open reading frame (ORF). HCV genome includes 10 genes that respectively express 10 structural proteins (a core protein, envelope proteins E1 and E2, an ion channel protein P7) and non-structural proteins (NS2, NS3, NS4A, NS4B, NS5A and NS5B), where NS5B has a RNA-dependent RNA polymerase activity and is involved in the replication of HCV genome.
FIG. 1 is a schematic diagram showing the action mechanism of a liver specific delivery-based compound.
FIG. 2 is a bar chart showing the change of concentration of the active triphosphorus molecule 2FM-UTP in the liver over time after intragastric administration of 30 mg/kg PA2020, PA2024, PA2029 and sofosbuvir to rats (ng/g, concentration/tissue weight).
FIG. 3 is a bar chart showing the change of concentration of the monophosphate metabolite 2FM-UMP in heart (A) and plasma (B) over time after intragastric administration of 30 mg/kg PA2020, PA2024, PA2029 and sofosbuvir (ng/g, concentration/tissue weight or ng/mL) to rats.
2-FM-UR: (2R)-2-deoxy-2-fluoro-2-methyl-uridine;
2-FM-UMP: (2R)-2-deoxy-2-fluoro-2-methyl-uridine-5-monophosphate; and
2-FM-UTP: (2R)-2-deoxy-2-fluoro-2-methyl-uridine-5-triphosphate.