Acyclic nucleoside phosphonate diesters
Inventors
Hostetler, Karl Y. • Beadle, James R. • Valiaeva, Nadejda
Assignees
Office of General Counsel of VA • University of California San Diego UCSD
Publication Number
US-10076532-B2
Publication Date
2018-09-18
Expiration Date
2034-03-14
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Abstract
The present disclosure relates, inter alia, to compositions and methods for treating viral diseases and cancer. There are disclosed lipophilic antiviral and anticancer acyclic nucleoside phosphonate diesters, preparation thereof, and methods of using the compounds to treat viral diseases and cancer.
Core Innovation
The invention relates to lipophilic antiviral and anticancer acyclic nucleoside phosphonate diesters, their preparation, and methods for using these compounds to treat viral diseases and cancer. The compounds feature structures of Formula (I) and Formula (Ia), which comprise a naturally occurring or analog purine or pyrimidine base, lipophilic promoieties such as substituted or unsubstituted alkyl, heteroalkyl, or O-substituted glyceryl groups, and other substituents designed to enhance pharmacokinetic properties and tissue targeting.
The problem addressed is that acyclic nucleoside phosphonates (ANPs), although effective antiviral agents, exhibit poor oral bioavailability due to their molecular weight and double negative charge on the phosphonate moiety. This limits their uptake from the gastrointestinal tract and access to certain target tissues such as the central nervous system (CNS). Monoester prodrugs of ANPs, while improving absorption, may cause local toxicity in intestinal enterocytes due to enzymatic cleavage and anabolic phosphorylation. Therefore, improved compounds are needed to enhance uptake, reduce gastrointestinal toxicity, and increase selective toxicity toward transformed or infected cells, including CNS viral infections and various cancers.
The disclosed lipophilic acyclic nucleoside phosphonate diesters mask both negative charges on the phosphonate group, which is anticipated to reduce cleavage in the small intestine, thereby decreasing gastrointestinal side effects while increasing systemic drug levels. Furthermore, this masking also increases penetration into the CNS for treatment of CNS viral infections and brain cancers. The compounds selectively inhibit DNA synthesis and cell division in transformed or cancer cells, such as leukemias, lymphomas, glioblastoma, and cervical cancer cells, with less effect on non-malignant cells. Additionally, diester compounds provide enhanced topical uptake for treatment of HPV-related lesions and viral skin infections, offering efficacious treatment for infections including high-risk human papillomavirus types associated with cervical and other cancers.
Claims Coverage
The patent presents multiple inventive features across its independent claims, focusing on novel compounds, their compositions, methods of treatment, and synthetic methods.
Compounds of Formula (Ia) with defined substituents
The patent claims compounds of Formula (Ia), including pharmaceutically acceptable salts, hydrates, solvates, or crystalline forms. BNuc(a) includes naturally occurring or non-naturally occurring purine or pyrimidine bases. La is an unsubstituted C12-24 alkyl, C13-29 heteroalkyl, or a substituted glyceryl moiety with further substituents. Ra includes unsubstituted C1-6 alkyl, aryl (including substituted or unsubstituted), heteroaryl, heterocycloalkyl, or alkylated derivatives thereof. Xa is hydrogen, unsubstituted or substituted alkyl or alkoxy, including halogen or hydroxy substituted groups.
Pharmaceutical compositions comprising the claimed compounds
Compositions include a compound of Formula (Ia) or a pharmaceutically acceptable salt, hydrate, solvate or crystalline form thereof combined with a pharmaceutically acceptable excipient.
Methods of treating viral diseases and cancer
Methods include administering a therapeutically effective amount of compounds of Formula (Ia) to treat viral diseases such as HIV and hepatitis B, specific HPV infections, or cancers including cervical cancer, as well as to inhibit growth of virus-transformed cells.
Methods of synthesis for compounds of Formula (I) and (Ia)
Synthetic methods encompass: reacting protected nucleosides with specific esters in the presence of strong bases to afford monoesters, followed by coupling with alcohols (L-OH or La-OH) using coupling agents like PYBOP®, and alternative methods involving direct coupling of suitably protected nucleosides with diesters bearing leaving groups under basic conditions.
The independent claims establish inventive features covering novel lipophilic acyclic nucleoside phosphonate diester compounds with specific substituents, their pharmaceutical compositions, therapeutic methods for treating viral diseases and cancers, and defined synthetic pathways employing coupling agents and protected intermediates.
Stated Advantages
Reduced gastrointestinal side effects due to decreased cleavage of diesters in the small intestine compared to monoester prodrugs.
Improved oral bioavailability and higher systemic drug levels resulting from effective masking of phosphonate charges.
Enhanced penetration into the central nervous system for treatment of CNS viral infections and brain cancers.
Selective cytotoxicity towards transformed or cancer cells with substantially lesser effects on non-malignant cells.
Effective topical uptake and treatment efficacy for HPV-related infections and proliferative disorders such as cervical intraepithelial neoplasia and skin cancers.
Documented Applications
Treatment of viral diseases including human papilloma virus, HIV, hepatitis B virus, hepatitis C virus, variola virus, vaccinia virus, adenovirus, cytomegalovirus, herpes simplex virus types 1 and 2, Epstein Barr virus, BK virus, JC virus, feline leukemia virus, and feline immunodeficiency virus.
Treatment of cancers including cervix cancer and cancers caused by viral infections such as HPV-associated cancers.
Inhibition of growth of cells transformed by viruses, including those listed for viral diseases.
Use in treating proliferative disorders caused by HPV, such as cervical, vaginal, anal intraepithelial neoplasia, vulvar intraepithelial neoplasia, penile and venereal warts.
Topical, oral, intravenous, intravitreal, and other routes of administration for delivering therapeutically effective amounts for antiviral and anticancer effects.
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