Nucleoside phosphonate salts
Inventors
Almond, Merrick • Lampert, Bernhard • Lanier, Ernest Randall • Ware, Roy W.
Assignees
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Publication Number
US-9006218-B2
Publication Date
2015-04-14
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: (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 document describes nucleoside phosphonate antiviral salts of CMX157, identified as Formula I, where the compound includes a cation M+ selected from Na+, Li+, K+, Ca2+, Mg2+, or an NRcRdReRf+ group. The variable substituents Rc-Rf are described as hydrogen or C1-5 alkyl, including stereoisomers, and the salt forms are contrasted with the free CMX157 acid, which is described as unstable.
The problem addressed is the instability of free CMX157 acid and the resulting need for salt forms that provide improved physical properties. The document reports improved stability at 40°C for four weeks, reduced hygroscopicity, and improved filtration processability for the CMX157 salts, with emphasis on the potassium salt.
Beyond the physical-property improvements, the disclosure broadly covers pharmaceutical formulations that include these stable crystalline forms of CMX157 salts together with pharmaceutically acceptable carriers or excipients. The document also provides routes and use contexts for treating viral diseases, including retroviruses such as XMRV, and includes combinations with other therapeutic agents and use in topical microbicidal contexts.
Claims Coverage
The document contains two independent claims covering stable crystalline forms of a Formula I CMX157 nucleoside phosphonate salt and, in the second case, a pharmaceutical composition containing such a stable crystalline form. Both independent claims incorporate a purity requirement and retention of purity after storage at about 40°C for about four weeks.
Stable crystalline form with defined cation and retained purity
A stable crystalline form of a compound of formula I (or a stereoisomer, diastereomer, enantiomer or racemate thereof), wherein M+ is selected from Na+, Li+, K+, Ca2+, Mg2+, or NRcRdReRf+ (with Rc, Rd, Re and Rf each independently hydrogen or C1-5 alkyl), and wherein the crystalline form is greater than 95% pure and retains greater than 95% purity after being kept at about 40°C for four weeks.
Pharmaceutical composition with stable crystalline form and defined cation
A pharmaceutical composition comprising a stable crystalline form of a compound of formula I (or a stereoisomer, diastereomer, enantiomer or racemate thereof) and a pharmaceutically acceptable adjuvant, diluent, carrier, or excipient, wherein M+ is selected from Na+, Li+, K+, Ca2+, Mg2+, or NRcRdReRf+ (with Rc, Rd, Re and Rf each independently hydrogen or C1-5 alkyl), and wherein the crystalline form is greater than 95% pure and retains purity greater than 95% after being kept at 40°C for about four weeks.
Overall, the claim coverage centers on stable crystalline forms of Formula I CMX157 nucleoside phosphonate salts defined by specific cations (M+) and alkyl/hydrogen substituents (Rc-Rf), together with strict purity (>95%) and retention of that purity after storage at about 40°C for about four weeks. The second independent claim extends this crystalline form requirement to pharmaceutical compositions that include pharmaceutically acceptable adjuvant/diluent/carrier/excipient.
Stated Advantages
Improved stability at 40°C for four weeks for CMX157 salts.
Reduced hygroscopicity of CMX157 salts.
Improved filtration processability for CMX157 salts.
Documented Applications
Treating viral diseases, including retroviruses such as XMRV, using pharmaceutical formulations that include CMX157 salts.
Use in treatment contexts described for chronic fatigue syndrome.
Use in treatment contexts described for prostate cancer.
Combination therapy contexts are described in relation to treating the above conditions/viral diseases.
Topical microbicidal use is described for the disclosed compositions.
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