Details for Patent: 8,754,065

Title:	Tenofovir alafenamide hemifumarate
Abstract:	A hemifumarate form of 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]- methoxy]propyl]adenine (tenofovir alafenamide), and antiviral therapy using tenofovir alafenamide hemifumarate (e.g., anti-HIV and anti-HBV therapies).
Inventor(s):	Liu; Dazhan (Alberta, CA), Shi; Bing (Foster City, CA), Wang; Fang (Foster City, CA), Yu; Richard Hung Chiu (San Francisco, CA)
Assignee:	Gilead Sciences, Inc. (CA)
Filing Date:	Aug 15, 2012
Application Number:	13/586,358
Claims:	1. Tenofovir alafenamide hemifumarate. 2. The hemifumarate of claim 1 that has a differential scanning calorimetry (DSC) onset endotherm of 131.+-.2.degree. C. 3. The hemifumarate of claim 2 that has a DSC onset endotherm of 131.+-.1.degree. C. 4. Tenofovir alafenamide hemifumarate, having an X-ray powder diffraction (XRPD) pattern comprises 2theta values of 6.9.+-.0.2.degree. and 8.6.+-.0.2.degree.. 5. The hemifumarate of claim 4, wherein the XRPD pattern comprises 2theta values of 6.9.+-.0.2.degree., 8.6.+-.0.2.degree., 11.0.+-.0.2.degree., 15.9.+-.0.2.degree., and 20.2.+-.0.2.degree.. 6. A composition comprising tenofovir alafenamide hemifumarate according to claim 1, wherein the ratio of fumaric acid to tenofovir alafenamide in said composition is 0.5.+-.0.1. 7. The composition of claim 6, wherein the ratio of fumaric acid to tenofovir alafenamide is 0.5.+-.0.05. 8. The composition of claim 6, wherein the ratio of fumaric acid to tenofovir alafenamide is 0.5.+-.0.01. 9. The composition of claim 6, wherein the ratio of fumaric acid to tenofovir alafenamide is about 0.5. 10. The composition of claim 6, which is a solid. 11. A pharmaceutical composition comprising the hemifumarate of claim 1 and a pharmaceutically acceptable excipient. 12. The pharmaceutical composition of claim 11, further comprising an additional therapeutic agent. 13. The pharmaceutical composition of claim 12, wherein the additional therapeutic agent is selected from the group consisting of human immunodeficiency virus (HIV) protease inhibiting compounds, HIV nonnucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, and CCR5 inhibitors. 14. The composition of claim 7, which is a solid. 15. The composition of claim 8, which is a solid. 16. The composition of claim 9, which is a solid. 17. A method for treating a human immunodeficiency virus (HIV) infection comprising administering to a subject in need thereof a therapeutically effective amount of the hemifumarate of claim 1. 18. A method for treating an HIV infection comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 11. 19. The method for treating an HIV infection of claim 17, further comprising administering to the subject one or more additional therapeutic agents selected from the group consisting of HIV protease inhibiting compounds, HIV nonnucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, and CCR5 inhibitors. 20. A method for treating a hepatitis B virus (HBV) infection comprising administering to a subject in need thereof a therapeutically effective amount of the hemifumarate of claim 1. 21. A method for treating an HBV infection comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 11. 22. The method for treating an HIV infection of claim 17, wherein the hemifumarate is administered in multiple daily doses. 23. The method for treating an HIV infection of claim 17, wherein the hemifumarate is administered in a single daily dose. 24. The method for treating an HBV infection of claim 20, wherein the hemifumarate is administered in multiple daily doses. 25. The method for treating an HBV infection of claim 20, wherein the hemifumarate is administered in a single daily dose. 26. A method for preparing a pharmaceutical composition comprising combining the hemifumarate of claim 1 and a pharmaceutically acceptable excipient to provide the pharmaceutical composition. 27. A method for preparing tenofovir alafenamide hemifumarate comprising admixing a) aprotic organic solvent; b) fumaric acid; c) tenofovir alafenamide; and d) one or more seeds of tenofovir alafenamide hemifumarate; and crystallizing additional tenofovir alafenamide hemifumarate. 28. The method of claim 27, wherein the solvent comprises acetonitrile. 29. The method of claim 27, wherein the solution is subjected to a temperature in the range of from about 0.degree. C. to about 75.degree. C. 30. A method for preparing tenofovir alafenamide hemifumarate, comprising the steps of: admixing a) a solvent comprising water, isopropyl alcohol, acetone, acetonitrile, toluene, ethyl acetate, isopropyl acetate, heptane, tetrahydrofuran, 2-methyl tetrahydrofuran, methyl ethyl ketone, methyl isobutyl ketone or mixtures thereof; b) fumaric acid; c) tenofovir alafenamide; and d) one or more seeds of tenofovir alafenamide hemifumarate; and crystallizing additional tenofovir alafenamide hemifumaratre at a temperature from about 0.degree. C. to about 70.degree. C. 31. The method of claim 30, wherein the solvent comprises acetonitrile and up to about 50% by volume methylene chloride.