Nucleotide analog composition and synthesis method

• US 5,935,946 A
• Filed: 07/25/1997
• Issued: 08/10/1999
• Est. Priority Date: 07/25/1997
• Status: Expired due to Term

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Sciences Inc.
• Inventors: Rohloff, John C., Schultze, Lisa M., Munger, John D. Jr.
• Primary Examiner(s): Reamer, James H.
• Application Number:
  US08/900,752
• Time in Patent Office: 746 Days
• Field of Search: 514/81, 544/244
• US Class Current: 514/81
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: C07D 473/34 attached in position 6, e.g. adenine
• CPC Class Codes: C07F 9/65616 containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs

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.

Claims

1. A composition of formula (1) ##STR4## wherein B is adenin-9-yl and R independently is --H or --CH₂ --O--C(O)--O--CH(CH₃)₂, but at least one R is --CH₂ --O--C(O)--O--CH(CH₃)₂.

2. The composition of claim 1 wherein both R are --CH₂ --O--C(O)--O--CH(CH₃)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-Kα

radiation, expressed in degrees 2θ

at about 25.0.

6. A composition comprising the composition of claim 1 and an acceptable excipient.

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.

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.

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.