3,5-Disubsitituted and 3,5,7-trisubstituted-3H-oxazolo and 3H-thiazolo[4,5-d]pyrimidin-2-one compounds and prodrugs thereof
Inventors
Webber, Stephen E. • Haley, Gregory J. • Lennox, Joseph R. • Xiang, Alan X. • Rueden, Erik J.
Assignees
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Publication Number
US-7560544-B2
Publication Date
2009-07-14
Expiration Date
Abstract
The invention is directed to 3,5-disubstituted and 3,5,7-trisubstituted-3H-oxazolo and 3H-thiazolo[4,5-d]pyrimidin-2-one compounds and prodrugs thereof that have immunomodulatory activity. The invention is also directed to the therapeutic or prophylactic use of such compounds and pharmaceutical compositions containing them, and to methods of treating diseases and disorders described herein, by administering effective amounts of such compounds and prodrugs.
Core Innovation
The disclosure describes 3,5-disubstituted and 3,5,7-trisubstituted 3H-oxazolo and 3H-thiazolo[4,5-d]pyrimidin-2-one compounds, as well as thiazolo[4,5-d]pyrimidine nucleosides, nucleoside analog intermediates, prodrugs, metabolites, pharmaceutically acceptable salts, and pharmaceutically acceptable solvates. The compounds are also defined with variable groups and include stereoisomers and pharmaceutically acceptable salts, solvates, metabolites, tautomers, and prodrugs.
The document also describes sugar-modified variants and carbohydrate-conjugated thiazolopyrimidinone derivatives, including ribofuranosyl, xylosyl, deoxy, fluoro, azido, acetylated, alkoxy, acyloxy, and hydroxyl or methyl-modified derivatives, as well as non-sugar substituted analogs. Formula I and Formula II embodiments with defined substituent variables and illustrative structures are also presented.
The examples describe preparation and characterization of thiazolo[4,5-d]pyrimidine and related nucleoside compounds, including glycosylation, deprotection, and conversion to thione or oxo analogs, with reported yields and analytical data. The disclosure further includes antiviral and biological evaluation, metabolism studies in cynomolgus monkey hepatocytes with LC/MS/MS metabolite profiling, and IFN-α induction from human PBMCs using IFN-α ELISA.
Claims Coverage
The provided independent claims center on selected compounds, including pharmaceutically acceptable salts and, in some claims, tautomers, with pharmaceutical compositions and methods of treating hepatitis C virus infection by administering a therapeutically effective amount. Across the independent claims, the main inventive features are compound selection, salt or tautomer coverage, pharmaceutical composition coverage with a pharmaceutically acceptable carrier, and hepatitis C virus treatment by administration.
Compound selected from the group with pharmaceutically acceptable salt or tautomer
A compound selected from the group, or a pharmaceutically acceptable salt or tautomer thereof.
Compound with pharmaceutically acceptable salt or tautomer
A compound, or a pharmaceutically acceptable salt or tautomer thereof.
Compound or pharmaceutically acceptable salt selected from the group consisting of
A compound or pharmaceutically acceptable salt selected from the group consisting of, with the selection text incomplete in the provided excerpts.
Pharmaceutical composition including a pharmaceutically acceptable carrier
A pharmaceutical composition that includes a pharmaceutically acceptable carrier and the compound specified in the claim.
Treating hepatitis C virus infection by administering a therapeutically effective amount
A method for treating a hepatitis C virus infection by administering to a patient in need a therapeutically effective amount of the claimed compound.
The independent claims center on selected compounds with optional pharmaceutically acceptable salt or tautomer forms, together with pharmaceutical compositions and treatment methods for hepatitis C virus infection using a therapeutically effective amount.
Stated Advantages
Immune system-enhancing activity.
Immunomodulatory activity.
Antiviral activity.
Antitumor activity.
Documented Applications
Treating or preventing hepatitis C virus infection.
Using the compounds in pharmaceutical compositions including a pharmaceutically acceptable carrier.
Broad viral, bacterial, fungal, protozoal, and tumor indications.
Treatment of hepatitis C virus infection by administering a therapeutically effective amount of the claimed compound to a patient.
HCV treatment or prevention kit configurations.
Antiviral and biological evaluation, including metabolism studies in cynomolgus monkey hepatocytes and IFN-α induction from human PBMCs.
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