Nucleotide compound in halogenating adenine class, synthetic method, medical appliction

A nucleoside compound, halogenated adenine technology, applied in the field of 8-halogenated adenine nucleoside compounds, can solve problems such as the strong hydrophilic effect of tenofovir, and achieve good application prospects and good fat solubility. Effect

Active Publication Date: 2007-07-25
ZHEJIANG AUSUN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the strong hydrophilicity of tenofovir affects its clinical drug application

Method used

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  • Nucleotide compound in halogenating adenine class, synthetic method, medical appliction
  • Nucleotide compound in halogenating adenine class, synthetic method, medical appliction
  • Nucleotide compound in halogenating adenine class, synthetic method, medical appliction

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Example 1.8-bromo-9-(2-dipivaloyloxymethoxyphosphonomethoxy)-ethyl-adenine (compound 11):

[0045]

[0046] Take 9-(2-dipivaloyloxymethoxyphosphonomethoxy)-ethyl-adenine (3.0 g, 6.0 mmol), dissolve it in 30 ml of acetic acid, add sodium acetate (3 g), add Br 2 0.5mL, 9.7mmol). Stir for 2 hours, the raw material point disappears, add ethyl acetate (150ml), water 120ml in turn, add saturated sodium bisulfite (NaHSO 3 ) until the mixture becomes colorless and static, separate the organic phase, adjust the pH of the aqueous phase to 8.0-8.5, extract with ethyl acetate (2 × 100mL), combine the organic phases, and wash with saturated aqueous sodium chloride, anhydrous sodium sulfate After drying, the organic solvent was distilled off to obtain 3.10 g of the title compound. mp.99℃,FAB HRMS[M+H + ]calcd for C 20 h 32 BrN 5 o 8 P 581.3740.found 581.3747.

Embodiment 2

[0047] Example 2.8-bromo-9-(2-(R)-diisopropoxycarbonyloxymethoxyphosphonomethoxy)-propyladenine-fumaric acid (compound 6):

[0048]

[0049] (1) 8-bromo-9-(2-(R)-diisopropoxycarbonyloxymethoxyphosphonomethoxy)-propyladenine (compound 5):

[0050] Take 9-(2-(R)-diisopropoxycarbonyloxymethoxyphosphonomethoxy)-propyladenine (3.3 g, 6.3 mmol), dissolve it in 30 ml of acetic acid, add sodium acetate (1.0 g ), add Br 2 (0.50mL, 9.7mmol). Stir for 2 hours, the raw material point disappears, add ethyl acetate (180ml), water (150ml) in turn, add saturated sodium bisulfite (NaHSO 3 ) until the mixture becomes colorless and static, separate the organic phase, adjust the pH of the aqueous phase to 8.0-8.5, extract with ethyl acetate (280mL), combine the organic phases, wash with saturated aqueous sodium chloride, and dry over anhydrous sodium sulfate. The organic solvent was distilled off to obtain viscous compound 5. 1 H NMR (CD 3 OD) δppm8.19(s, 1H), 6.75(s, 2H, CH 2 ), 5.56-5.4...

Embodiment 3

[0053] Example 3.8-chloro-9-(2-(R)-diisopropoxycarbonyloxymethoxyphosphonomethoxy)-propyladenine-fumaric acid

[0054] (1) 8-chloro-9-(2-(R)-diisopropoxycarbonyloxymethoxyphosphonomethoxy)-propyladenine

[0055] Take 9-(2-(R)-diisopropoxycarbonyloxymethoxyphosphonomethoxy)-propyladenine (3.0 g), dissolve it in 50 ml of acetic acid, add sodium acetate (3.0 g), and stir Chlorine gas was introduced at the bottom, and stirred for 2 hours. When TLC detected that the raw material point disappeared, ethyl acetate (100ml) and water 150ml were added successively, and 5% sodium bisulfite (NaHSO4) was added under stirring. 3 ) until the mixture is detected by starch potassium iodide test paper and does not turn blue, static layering, separating the organic phase, adjusting the pH of the aqueous phase to 8.0-8.5, extracting with ethyl acetate (2 × 60mL), combining the organic phases, and using saturated sodium chloride After washing with aqueous solution and drying over anhydrous sodium ...

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PUM

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Abstract

This invention discloses a method for preparing compounds shown in formula I, 8-halogen-9-(2-pivoxilmethoxyphosphonyl methoxyl)ethyl-adenine, 8-halogen-9-(2-(R)-dipropoxyl methoxyphosphonyl methoxyl)propyyl-adenine, and their organic acid salts. Wherein, X is F, Cl or Br; R1 is H, -CH2OCOC (CH3)3 or -CH2OCOOCH (CH3)2; when R is H, R1 is -CH2OCOC (CH3)3; when R is CH3, R1 is -CH2OCOOCH (CH3)2. The organic acid is allomaleic acid, fumaric acid or citric acid. The compounds can be used to treat HIV and HBV.

Description

technical field [0001] The invention relates to a series of nucleoside compounds, in particular to 8-halogenated adenine nucleoside compounds, a synthesis method and a pharmaceutical use thereof. Background technique [0002] Adefovir (adefovir, ADV) is an antiviral drug developed by Gilead Sciences, which has been clinically proven to have anti-HBV activity (including HBV resistant to lamivudine). The chemical structure of ADV is adenine-9-ethoxymethyl phosphate, with low oral availability and severe allergic reactions. Adefovir dipivoxil (adefovir dipivoxiil) is the prodrug of ADV, with improved lipophilicity, 10-fold increase in intestinal epithelial penetration than ADV, and improved bioavailability. [0003] Tenofovir (PMPA) is an adenine noncyclic nucleoside antiviral compound that has a strong inhibitory effect on retroviruses and has no cross-resistance with other nucleoside antiviral drugs used in clinical practice sex. However, the strong hydrophilicity of tenof...

Claims

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Application Information

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IPC IPC(8): C07F9/6561A61K31/675A61P31/12C07D473/32
Inventor 常俊标程森祥王利敏郝佳王强郭晓河
Owner ZHEJIANG AUSUN PHARMA
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