Manage your formulary budget
Drug patents …
… from Kazakhstan to Kalamazoo
Proactively manage your pharmacy inventory
Deep knowledge on
small-molecule drugs and
the 110,000 global patents
Find generic entry opportunities
Anticipate generic drug launch
Upgrade to enjoy subscriber-only features like email alerts and data export. See the Plans and Pricing
|Title:||Nucleotide analog composition and synthesis method|
|Abstract:||The invention provides a composition comprising bis(POC)PMPA and fumaric acid (1:1). The composition is useful as an intermediate for the preparation of antiviral compounds, or is useful for administration to patients for antiviral therapy or prophylaxis. The composition is particularly useful when administered orally. The invention also provides methods to make PMPA and intermediates in PMPA synthesis. Embodiments include lithium t-butoxide, 9-(2-hydroxypropyl) adenine and diethyl p-toluenesulfonylmethoxyphosphonate in an organic solvent such as DMF. The reaction results in diethyl PMPA preparations containing an improved by-product profile compared to diethyl PMPA made by prior methods.|
|Inventor(s):||Munger, Jr.; John D. (Alviso, CA), Rohloff; John C. (Mountain View, CA), Schultze; Lisa M. (San Carlos, CA)|
|Assignee:||Gilead Sciences, Inc. (Foster City, CA)|
1. A composition of formula (1) ##STR4## wherein B is adenin-9-yl and R independently is --H or --CH.sub.2 --O--C(O)--O--CH(CH.sub.3).sub.2, but at least one R is --CH.sub.2
2. The composition of claim 1 wherein both R are --CH.sub.2 --O--C(O)--O--CH(CH.sub.3).sub.2.
3. The composition of claim 1 wherein the composition is a crystalline solid.
4. The composition of claim 1 wherein the compound is enriched or resolved at the carbon atom chiral center (*).
5. The composition of claim 1 having an X-ray powder diffraction spectrum peak using Cu-K.alpha. radiation, expressed in degrees 2.theta. at about 25.0.
6. A composition comprising the composition of claim 1 and an acceptable excipient.
7. A composition comprising a lithium alkoxide and a 9-(2-hydroxypropyl)adenine solution.
8. A composition comprising an (R,S)-PMPA solution at a pH of about 2.7-3.5 wherein the solution has less than about 0.1 g/mL (R,S)-PMPA and wherein about 90-94% of the PMPA is in the (R) configuration.
9. A method comprising orally administering to a patient infected with virus or at risk to viral infection a therapeutically effective amount of a composition of claim 1.
10. A method comprising contacting bis(POC)PMPA with fumaric acid.
11. The method of claim 10 wherein the fumaric acid is dissolved in 2-propanol.
12. A method comprising mixing a lithium alkoxide with a 9-(2-hydroxypropyl)adenine solution.
13. The method of claim 12 wherein the lithium alkoxide is an alkoxide selected from the group consisting of methoxide, ethoxide, n-propoxide, i-propoxide, n-butoxide, i-butoxide, t-butoxide, neopentoxide, n-pentoxide, i-pentoxide or n-hexoxide, n-heptoxide, 2-heptoxide, n-octoxide, 2-octoxide, typically t-butoxide or i-propoxide.
14. The method of claim 13 wherein the lithium alkoxide is lithium t-butoxide or lithium i-propoxide.
15. A method comprising adjusting the pH of a solution comprising less than about 0.08 g/mL (R,S)-PMPA wherein about 90-94% of the PMPA is in the (R) configuration to a pH of about 2.7-3.5.
16. A composition comprising a tablet containing 9-[2-(R)-[[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphinoyl]methoxy]propyl ]-adenine.fumaric acid (1:1), pregelatinized starch, croscarmellose sodium, lactose monohydrate and magnesium stearate.
17. The composition of claim 16 wherein the 9-[2-(R)-[[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphinoyl]methoxy]propyl ]-adenine.fumaric acid (1:1) is crystalline.
18. The composition of claim 16 wherein the tablet contains 75 mg 9-[2-(R)-[[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphinoyl]methoxy]propyl ]-adenine.fumaric acid (1:1), 11 mg pregelatinized starch, 8.8 mg croscarmellose sodium, 123.6 mg lactose monohydrate and 2.2 mg magnesium stearate.
19. A product produced by the process of preparing wet granules from a mixture comprising a liquid, 9-[2-(R)-[[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphinoyl]methoxy]propyl ]-adenine.fumaric acid (1:1) and a pharmaceutically acceptable excipient.
20. The product of claim 19 wherein the liquid is water and the process optionally further comprises drying the wet granules.
Drugs may be covered by multiple patents or regulatory protections. All trademarks and applicant names are the property of their respective owners or licensors. Although great care is taken in the proper and correct provision of this service, thinkBiotech LLC does not accept any responsibility for possible consequences of errors or omissions in the provided data. The data presented herein is for information purposes only. There is no warranty that the data contained herein is error free. thinkBiotech performs no independent verifification of facts as provided by public sources nor are attempts made to provide legal or investing advice. Any reliance on data provided herein is done solely at the discretion of the user. Users of this service are advised to seek professional advice and independent confirmation before considering acting on any of the provided information. thinkBiotech LLC reserves the right to amend, extend or withdraw any part or all of the offered service without notice.