Acyclic nucleoside phosphonate diesters

• US 9,775,852 B2
• Filed: 06/10/2016
• Issued: 10/03/2017
• Est. Priority Date: 03/15/2013
• Status: Active Grant

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Hostetler, Karl Y., Beadle, James R., Valiaeva, Nadejda
• Primary Examiner(s): Kifle, Bruck
• Application Number:
  US15/179,209
• Publication Number:
  US 20170002033A1
• Time in Patent Office: 480 Days
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/685 one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/0031 Rectum, anus
• CPC Class Codes: A61K 9/0034 Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: C07F 9/6512 having the nitrogen atoms in positions 1 and 3
• CPC Class Codes: C07F 9/65583 each of the hetero rings containing nitrogen as ring hetero atom
• CPC Class Codes: C07F 9/6561 containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
• 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
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present disclosure relates, inter alia, to compositions and methods for treating viral diseases and cancer. There are disclosed lipophilic antiviral and anticancer acyclic nucleoside phosphonate diesters, preparation thereof, and methods of using the compounds to treat viral diseases and cancer.

Claims

1. A process for preparing a compound of Formula I comprising combining an alcohol R—

OH, a coupling agent, a base, an organic solvent, and a compound of formula;

2. The process of claim 1, further comprising resolving the compound of Formula I to an optically active enantiomer or diastereomer of Formula I.

3. The process of claim 1, wherein R—

OH is benzyl alcohol.

4. The process of claim 1, wherein the coupling agent is (benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate.

5. The process of claim 1, wherein the base is N,N-diisopropylethylamine.

6. The process of claim 1, wherein the organic solvent is N,N-dimethylformamide.

28. The process of claim 1, wherein B_NUC is guanine.

7. A process for preparing a compound of Formula Ia comprising combining an alcohol R^a—

OH, a coupling agent, a base, an organic solvent, and a compound of formula;

8. The process of claim 7, further comprising resolving the compound of Formula Ia to obtain an optically active enantiomer or diastereomer of Formula Ia.

9. The process of claim 7, wherein R^a—

OH is benzyl alcohol.

10. The process of claim 7, wherein the coupling agent is (benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate.

11. The process of claim 7, wherein the base is N,N-diisopropylethylamine.

12. The process of claim 7, wherein the organic solvent is N,N-dimethylformamide.

29. The process of claim 7, wherein B_NUC is guanine.

30. The process of claim 29, wherein L^a is C₁₃-C₂₉ heteroalkyl.

31. The process of claim 30, wherein L^a is (CH₂)₂—

O—

(CH₂)₁₇CH₃.

32. The process of claim 31, wherein X^a is hydrogen.

13. A process for preparing a compound of Formula I comprising combining an alcohol L-OH, a coupling agent, a base, an organic solvent, and a compound of Formula 2-3

14. The process of claim 13, further comprising resolving the compound of Formula I to obtain an optically active enantiomer or diastereomer of Formula I.

15. The process of claim 13, wherein L-OH is 2-(octadecyloxy)ethan-1-ol.

16. The process of claim 13, wherein the coupling agent is (benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate.

17. The process of claim 13, wherein the base is N,N-diisopropylethylamine.

18. The process of claim 13, wherein the organic solvent is N,N-dimethylformamide.

33. The process of claim 13, wherein B_NUC is guanine.

19. A process for preparing a compound of Formula Ia comprising combining an alcohol L^a-OH, a coupling agent, a base, an organic solvent, and a compound of Formula 2-3a:

20. The process of claim 19, further comprising resolving the compound of Formula Ia to obtain an optically active enantiomer or diastereomer of Formula Ia.

21. The process of claim 19, wherein L^a-OH is 2-(octadecyloxy)ethan-1-ol.

22. The process of claim 19, wherein the coupling agent is (benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate.

23. The process of claim 19, wherein the base is N,N-diisopropylethylamine.

24. The process of claim 19, wherein the organic solvent is N,N-dimethylformamide.

34. The process of claim 19, wherein B_NUC is guanine.

35. The process of claim 34, wherein L^a is C₁₃-C₂₉ heteroalkyl.

36. The process of claim 35, wherein L^a is (CH₂)₂—

O—

(CH₂)₁₇CH₃.

37. The process of claim 36, wherein X^a is hydrogen.

25. A process for preparing a compound of Formula I comprising combining a strong base, an organic solvent, a compound of Formula 3-1:

26. The process of claim 25, further comprising resolving the compound of Formula I to obtain an optically active enantiomer or diastereomer of Formula I.

27. The process of claim 25, wherein Y is a leaving group selected from p-toluenesulfonyl, methanesulfonyl, trifluoromethanesulfonyl, bromo and iodo.

38. The process of claim 25, wherein B_NUC is guanine.

39. The process of claim 38, wherein L^a is C₁₃-C₂₉ heteroalkyl.

40. The process of claim 39, wherein L^a is (CH₂)₂—

O—

(CH₂)₁₇CH₃.

41. The process of claim 40, wherein X^a is hydrogen.

42. A process comprising combining benzyl alcohol, a coupling agent, a base, an organic solvent, and a compound of formula:

43. The process of claim 42, wherein the coupling agent is (benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate.

44. The process of claim 42, wherein the base is N,N-diisopropylethylamine.

45. The process of claim 42, wherein the organic solvent is N,N-dimethylformamide.