Nucleoside phosphonate salts
Inventors
Almond, Merrick • Lampert, Bernhard • Lanier, Ernest Randall • Ware, Roy W.
Assignees
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Publication Number
US-9765100-B2
Publication Date
2017-09-19
Expiration Date
Abstract
The present invention relates to compounds and methods for treating viral diseases. Some compounds of the invention are described by Formula I:wherein M+ is Na+, Li+, K+, Ca2+, Mg2+, or NRcRdReRf+ and Rc, Rd, Re and Rf are each independently hydrogen or C1-5 alkyl, or a stereoisomer, a diastereomer, an enantiomer or racemate thereof.
Core Innovation
The invention concerns a stable crystalline form of a compound having the structure, or a stereoisomer, diastereomer, enantiomer or racemate thereof, with a counterion M+ where M+ is Na+, Li+, K+, Ca2+, Mg2+, or NRcRdReRf+. Rc, Rd, Re and Rf are each independently hydrogen or C1-5 alkyl. The crystalline form is greater than 95% pure and retains greater than 95% purity after being kept at about 40° C. for four weeks.
The description identifies nucleoside phosphonate salt forms of CMX157 using Formula I with defined cations M+, and describes the salt forms as stable crystalline forms with improved physical properties over the free acid. The free acid decomposes under elevated temperature conditions, while multiple high-purity salt forms retain greater than 95% purity under comparable conditions.
The stable crystalline forms are connected to antiviral use through pharmaceutical compositions. Specific salt embodiments are described for treating viral diseases including XMRV and other retroviruses, and also for chronic fatigue syndrome and prostate cancer.
Claims Coverage
The independent claim covers methods of treating hepatitis B (HBV) or HIV by administering a stable crystalline form of a defined compound with specific counterions and defined purity retention criteria. Three inventive features are identified, centered on the stable crystalline form, the disease target, and the treatment conditions.
Stable crystalline form with defined counterion and purity retention
A method of treating hepatitis B (HBV) or HIV in a subject comprising administering a stable crystalline form of a compound having the structure, or a stereoisomer, diastereomer, enantiomer or racemate thereof, wherein M+ is Na+, Li+, K+, Ca2+, Mg2+, or NRcRdReRf+, Rc, Rd, Re and Rf are each independently hydrogen or C1-5 alkyl, and the crystalline form is greater than 95% pure and retains greater than 95% purity after being kept at about 40° C. for four weeks.
Treatment targeting hepatitis B or HIV
A method of treating hepatitis B (HBV) or HIV in a subject by administering the stable crystalline form of the specified compound defined by the counterion and purity retention criteria.
Effective amount and inhibition of resistance to other antiviral compounds
The method administering the compound in an amount effective to treat hepatitis B (HBV) or HIV and to inhibit development of resistance to other antiviral compounds.
Subject without prior antiviral active agent
The method performed on a subject that has not previously been administered an antiviral active agent.
Overall, the claim coverage is directed to antiviral treatment methods (HBV or HIV) using a stable crystalline form characterized by defined counterions (M+) and defined purity retention after storage, with refinements directed to specific antiviral targeting, resistance inhibition, and prior antiviral exposure.
Stated Advantages
Improved physical properties and stability of nucleoside phosphonate salt forms of CMX157 over the free acid.
Crystalline form purity greater than 95% and retention greater than 95% after being kept at about 40° C. for four weeks.
Free acid decomposition under elevated temperature conditions contrasted with retained high purity for multiple salts under comparable conditions.
Improved therapeutic index in vitro for CMX157 potassium salt compared with tenofovir and other controls, as supported by anti-XMRV evaluation in the described cell assays.
Documented Applications
Treatment of hepatitis B (HBV) or HIV in a subject using the stable crystalline form with defined counterions and purity retention.
Treatment of viral diseases including XMRV and other retroviruses, as described in the provided summary.
Treatment of chronic fatigue syndrome (CFS), as described in the provided summary.
Treatment of prostate cancer, as described in the provided summary.
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