Tetraphosphonate bicyclic trisanhydrides

• US 6,713,623 B2
• Filed: 11/13/2001
• Issued: 03/30/2004
• Est. Priority Date: 10/09/1996
• Status: Expired due to Fees

• Current Assignee: Gilead Pharmasset LLC (Gilead Sciences Inc.)
• Original Assignee: Pharmasset Incorporated (Gilead Sciences Inc.)
• Inventors: Pankiewicz, Krzysztof W., Watanabe, Kyoichi A., Lesiak, Krystyna
• Primary Examiner(s): Trinh, Ba K.
• Application Number:
  US10/008,572
• Publication Number:
  US 20020161220A1
• Time in Patent Office: 868 Days
• Field of Search: 536/26.3, 536/26.2, 536/26.23, 536/26.24, 536/26.4, 536/26.72, 536/26.74, 536/27.21, 536/27.3, 536/27.6, 536/27.7, 536/28.53, 536/29.2, 544/276, 544/277, 544/265, 558/87, 558/155
• US Class Current: 536/26.3
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07F 9/2495 containing the structure P(=X)n-N-P (X = O, S, Se; n = 0, 1)
• CPC Class Codes: C07F 9/3235 Esters of poly(thio)phosphinic acids
• CPC Class Codes: C07F 9/4025 Esters of poly(thio)phosphonic acids
• CPC Class Codes: C07F 9/4423 Amides of poly (thio)phosphonic acids
• CPC Class Codes: C07F 9/657172 the ring phosphorus atom and one oxygen atom being part of a (thio)phosphinic acid ester: (X = O, S)
• CPC Class Codes: C07F 9/657181 the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative
• CPC Class Codes: C07F 9/6581 having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/207 the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide

Abstract

Disclosed are novel bicyclic tris(anhydride)s useful as intermediates in the synthesis of biologically active compounds, and the compounds which may be synthesized from such intermediates.

Claims

1. A compound of formula I

wherein:

a) Z is 2′

,3′

-O-isopropylideneadenosine-5′

-yl; and

b) Z₁ is aralkyl.

41. A pharmaceutical composition comprising the compound of claim 1, 2, 4, 15, 21, 26, 29, or 34, in combination with a pharmaceutically acceptable carrier.

42. A method of treating a tumor in a human comprising administering compound of claim 1, 2, 4, 15, 21, 26, 29, or 34.

2. A compound of formula I

wherein:

a) Z is a nucleoside; and

b) Z₁ is aralkyl.

3. The compound of claim 2 wherein Z is a cytosinyl nucleoside.

4. A compound of formula I

wherein:

a) Z is a nucleoside;

b) Z₁ is benzamide riboside-5′

-yl; and

c) X is CH₂, CF₂, or CHF.

8. The compound of claim 4 wherein X is CH₂.

9. The compound of claim 4 wherein X is CHF.

10. The compound of claim 4 wherein X is CF₂.

11. The compound of claim 4 wherein Z is an adenosinyl nucleoside.

12. The compound of claim 4 wherein Z is adenosine-5′

-yl.

13. The compound of claim 4 wherein Z is defined by formula III:

a) each of R₁, R₂, R₃ and R₄ is independently H, OH or F;

b) each of W₁and W₂ is independently H, OH, ═

O, OR, SH, SR, NH₂, NHR or NR₂, wherein R is C₁-C₅ alkyl.

14. The compound of claim 13 wherein R₁ and R₂ are OH, and R₃ and R₄ are H.

5. P¹-(adenosine-5′

-yl)-P²-(benzamide riboside-5′

-yl)methylenebis(phosphonate).

6. P¹-(adenosine-5′

-yl)-P²-(benzamide riboside-5′

-yl)fluoromethylenbis(phosphonate).

7. P¹-(adenosine-5′

-yl)-P²-(benzamide riboside-5′

-yl)difluoromethylenebis(phosphonate).

15. A compound of formula I

wherein:

a) Z is a nucleoside;

b) Z₁ is a riboflavin residue; and

c) X is CH₂, CF₂, or CHF.

16. The compound of claim 15 wherein Z is an adenosinyl nucleoside.

17. The compound of claim 15 wherein Z is defined by formula III:

a) each of R₁, R₂, R₃ is independently H, OH or F;

b) each of W₁ and W₂ is independently H, OH, ═

O, OR, SH, SR, NH₂, NHR or NR₂, wherein R is C₁-C₅ alkyl.

18. The compound of claim 17 wherein R₁ and R₂ are OH, and R₃ and R₄ are H.

19. The compound of claim 15 wherein Z is adenosin-5′

-yl.

20. P¹-(adenosin-5′

-yl)-P²-(riboflavin-5′

-yl)methylenebis(phosphonate).

21. A compound of formula I

wherein:

a) Z is a nucleoside;

b) Z₁ is 1,2-diacyl-glycer-3-yl; and

c) X is CH₂, CF₂, or CHF.

22. P¹-(2′

,3′

-O-isopropylidenecytidine-5′

-yl)-P²-(1,2-diacyl-glycer-3-yl)methylenebis(phosphonate).

23. P¹-(cytidine-5′

-yl)-P²-(1,2-diacyl-glycer-3-yl)methylenebis(phosphonate).

24. P¹-(cytidine-5′

-yl)-P²-(1,2-diacyl-sn-glycer-3-yl)methylenebis(phosphonate).

25. P¹-(cytidine-5′

-yl)-P²-(1,2-dipalmitoyl-sn-glycer-3-yl)methylenebis(phosphonate).

26. A compound of formula I

wherein:

a) Z is a nucleoside;

b) Z₁ is N-acetylamino(ethyl); and

c) X is CH₂, CF₂, or CHF.

27. P¹-(2′

,3′

-O-isopropylidenecytidine-5′

-yl)-P²-[(N-acetylamino)ethyl]methylenebis(phosphonate).

28. P¹-(cytidine-5′

-yl)-P²-[(N-acetylamino)ethyl]methylenebis(phosphonate).

29. A compound of formula I

wherein:

a) Z is adenosine-5′

-yl;

b) Z₁ is aralkyl; and

c) X is CH₂, CHF, or CF₂.

30. The compound of claim 29 wherein Z₁ is the residue of a mycophenol.

31. The compound of claim 30 wherein X is CH₂.

32. The compound of claim 30 wherein X is CHF.

33. The compound of claim 30 wherein X is CF₂.

34. A compound of formula I

wherein:

a) Z is a nucleoside;

b) Z₁ is the residue of a mycophenol; and

c) X is CH₂, CHF, or CF₂.

35. The compound of claim 34 wherein Z is defined by formula III:

a) each of R₁, R₂, R₃ is independently H, OH or F;

b) each of W₁ and W₂ is independently H, OH, ═

O, OR, SH, SR, NH₂, NHR or NR₂, wherein R is C₁-C₅ alkyl.

36. The compound of claim 35 wherein R₁ and R₂ are OH, and R₃ and R₄ are H.

37. The compound of claim 34 wherein Z is an adenosinyl nucleoside.

38. The compound of claim 34 wherein X is CH₂.

39. The compound of claim 34 wherein X is CHF.

40. The compound of claim 34 wherein X is CF₂.