Heterocyclic compounds and methods of use thereof
Inventors
Liang, Tsanyang • Hu, Zongyi • Marugan, Juan Jose • Southall, Noel Terrence • He, Shanshan • Hu, Xin • Xiao, Jingbo • Ferrer, Marc • Zheng, Wei • Frankowski, Kevin J. • Schoenen, Frank J. • Li, Kelin
Assignees
University of Kansas • US Department of Health and Human Services
Publication Number
US-10202367-B2
Publication Date
2019-02-12
Expiration Date
2035-06-12
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Abstract
Disclosed are compounds of formula (I), formula (II), and formula (III): wherein Ar, R1, A, and X are as defined in the specification. These compounds are antiviral agents and are contemplated for use in the treatment of viral infections, for example, hepatitis C. These compounds are also contemplated for use in treating or preventing cancers.
Core Innovation
The invention provides novel heterocyclic compounds of formula (I), formula (II), and formula (III), wherein various substituents such as Ar, R1, A, and X are defined within the specification. These compounds serve as antiviral agents, particularly contemplated for treating viral infections like hepatitis C, as well as for treating or preventing cancers.
The problem addressed by the invention stems from the significant global health burden of hepatitis C virus (HCV), which infects about 200 million people worldwide and leads to chronic liver diseases and liver cancer. Existing treatments such as peginterferon-α and ribavirin are only effective in approximately half of patients and have serious adverse effects, with a low treatment completion rate. Recent antivirals face issues of resistance and side effects and often require combination therapy with interferon and ribavirin for efficacy.
In response to these challenges, the invention discloses compounds that are structurally defined and can be used alone or in combination with other anti-hepatitis C compounds. Additionally, methods of treatment include administering these compounds for viral infections and cancers, including methods to synergistically enhance antiviral effects when used with other agents. Pharmaceutical compositions and kits comprising the compounds and other anti-hepatitis C agents are also provided.
Claims Coverage
The patent includes two sets of independent claims each covering compounds of different specified formulas and their pharmaceutical compositions and kits.
Compounds of formula (I)
The compounds have specific heterocyclic structures defined by formula (I) with substituents including optionally substituted C6-C14 aryl (Ar), oxygen or sulfur (X), hydrogen or C1-C6 alkyl or CF3 (R1), and a defined group A involving alkyl or heterocyclic amino substituents, including stereoisomers and pharmaceutically acceptable salts.
Pharmaceutical compositions containing compounds of formula (I)
Compositions comprising the compounds of formula (I), their salts or stereoisomers, combined with pharmaceutically acceptable carriers suitable for administration.
Kits comprising compounds of formula (I) with other anti-hepatitis C agents
Kits including a compound of formula (I) and at least one other anti-hepatitis C compound distinct from the compound of formula (I).
Compounds of formula (II)
Compounds characterized by formula (II), including variants with defined substituents analogous to formula (I), along with their stereoisomers and pharmaceutically acceptable salts.
Pharmaceutical compositions containing compounds of formula (II)
Pharmaceutical compositions comprising compounds of formula (II) or their salts or stereoisomers combined with pharmaceutically acceptable carriers.
Kits comprising compounds of formula (II) with other anti-hepatitis C agents
Kits containing a compound of formula (II) alongside at least one other anti-hepatitis C agent not including the compound of formula (II).
The claims broadly cover compounds of formula (I) and formula (II), their pharmaceutical compositions, and kits combined with other anti-hepatitis C agents, emphasizing their defined chemical structures, stereochemical forms, and therapeutic use in treating hepatitis C and related viral infections.
Stated Advantages
The compounds have robust stability and solubility under physiological conditions, including resistance to nucleophilic degradation.
The compounds exhibit potent antiviral activity against hepatitis C virus with low cytotoxicity, as demonstrated by EC50 and CC50 values in cellular assays.
The chemotypes show synergy with existing anti-hepatitis C drugs, indicating a novel mechanism and potential for combination therapy with reduced resistance risk.
Documented Applications
Treatment or prevention of hepatitis C virus infections in mammals, with methods including administration of the compounds alone or in combination with other anti-hepatitis C agents.
Treatment or prevention of various viral infections including viruses of the Flaviviridae family such as West Nile virus, yellow fever virus, Japanese encephalitis virus, dengue virus, as well as rhinovirus, polio virus, hepatitis A and B viruses, respiratory syncytial virus, SARS, and MERS-CoV.
Treatment or prevention of a wide range of cancers, including but not limited to non-small cell lung cancer, breast cancer, liver cancer, leukemia, lymphoma, melanoma, and other malignancies listed comprehensively in the specification.
Use in pharmaceutical kits combining the inventive compounds with other anti-hepatitis C drugs for improved therapeutic outcomes.
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