Claims
- 1. A phosphonate compound selected from the group consisting of a phosponoglyoxylamide ester, an α-keto phosphonophosphinate ester, a carbonylbisphosphonate analog of a nucleotide, and a diazomethylenebisphosphonate analog of a nucleotide.
- 2. The phosphonoglyoxylamide ester of claim 1 having formula I:
- 3. The phosphonophosphinate ester of claim 1 having formula II:
- 4. The phosphonate compound of claim 1, wherein the compound is a carbonylbisphosphonate or diazomethylenebisphosphonate analog of nucleotide of formula
- 5. The compound of claim 4, wherein R3 includes a modified purine or pyrimidine base residue.
- 6. The compound of claim 4, wherein R3 includes a modified ribosyl or deoxyribosyl residue.
- 7. The compound of claim 4 wherein the nucleosidyl analog moiety is 3′-azido-3′deoxythymidinyl.
- 8. The compound of claim 4, said compound having antiviral activity.
- 9. The compound of claim 4, said compound having anticancer activity.
- 10. The compound of claim 4, wherein Y is oxygen a the reactivity of Y is determined by the pH.
- 11. A method of preparing α-keto phosphonates comprising:
i) forming a reaction mixture comprising an a rhodium(II) catalyst, an oxygen donor and an α-diazo phosphonate having formula IV: 27wherein X is selected from the group consisting of —C(═O)OR3, —C(═O)N(R4)(R5), and —P(═O)(OR6)(R7), wherein R1, R2 R3, R4, R5 and R6 and each independently selected from the group consisting of alkyl, and aryl; R7 is selected from the group consisting of alkyl, aryl, and OR8, wherein R8 is selected from the group consisting of alkyl, aryl and nucleosidyl; and ii) oxidizing the α-diazo phosphonate to form an α-keto phosphonate.
- 12. The method of claim 11 wherein the oxygen donor is an alkene oxide.
- 13. The method of claim 11 wherein the oxygen donor is selected from the group consisting of propylene oxide, 1,2-epoxybutane, 1,2-expoxyhexane and styrene oxide.
- 14. The method of claim 11 wherein X is —C(═O)N(R4)(R5) and the oxygen donor is styrene oxide.
- 15. The method of claim 11 wherein the catalyst is selected from the group consisting of Rh2(NHCOC3F7)4, Rh2(OCOCH3)4, Rh2(NHCOCF3)4, and Rh2(NHCOCH3)4.
- 16. The method of claim 11 wherein the catalyst is Rh2(OCOCH3)4 and X is —C(═O)N(R4)(R5).
- 17. The method of claim 11 wherein the catalyst is Rh2(NHCOC3F7)4.
- 18. A method of preparing α-keto phosphonates comprising:
i) forming a reaction mixture comprising tert-butyl hypochlorite, a polar aprotic solvent and an α-diazo phosphonate having formula VI: 28wherein X is selected from the group consisting —C(═O)NR4R5, and —P(═O)OR6R7, wherein R1, R2 R3, R4, R5 and R6 and each independently selected from the group consisting of alkyl, and aryl; R7 is selected from the group consisting of alkyl, aryl, and OR8, wherein R8 is a nucleosidyl moiety; and ii) adding an effective amount of water to said reaction mixture, whereby the α-diazo phosphonate is converted to an α-keto phosphonate.
- 19. A method of preparing a nucleotide analog, comprising:
i) forming a monosalt of an α-diazomethylene bisphosphonate; and ii) coupling a nucleoside and the monosalt to form a nucleotide analog having formula VII: 29wherein R1, R2 and R4 are each independently alkyl or aryl and R3 is a nucleosidyl moiety joined to the bisphosphonate via a 5′ester linkage.
- 20. The method of claim 19, further comprising the step of oxidizing the diazomethylene bisphosphonate to form a carbonylbisphosphonate.
- 21. The method of claim 19, wherein said monosalt is formed by monodealkylating a tetralkyl ester of the α-diazomethylene bisphosphonate using sodium iodide.
- 22. The method of claim 19, wherein said coupling step includes:
i) converting the monosalt to a free acid; and
a) forming a reaction mixture of the free acid, the nucleoside and either; b) (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (pyBOP) and diisopropylethylamine (DIEA), or c) triphenyl phosphine (PPh3) and diisopropyl azodicarboxylate (DIAD).
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. provisional application No. 60/308,909 filed on Jul. 30, 2001
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
PCT/US02/24213 |
7/30/2002 |
WO |
|
Provisional Applications (1)
|
Number |
Date |
Country |
|
60308909 |
Jul 2001 |
US |