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New acyclic nucleoside phosphate ester and its pharmaceutical use

A pharmaceutical and drug technology, applied in the field of acyclic nucleoside phosphonate derivatives, can solve the problems of toxicity and kidney production, and achieve strong anti-hepatitis B virus activity

Inactive Publication Date: 2011-05-11
FOSHAN YIBAOSHENG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the clinical application of adefovir dipivoxil can produce nephrotoxicity

Method used

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  • New acyclic nucleoside phosphate ester and its pharmaceutical use
  • New acyclic nucleoside phosphate ester and its pharmaceutical use
  • New acyclic nucleoside phosphate ester and its pharmaceutical use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1 2-amino-6-[(2,3-dihydrobenzofuran-5-yl)-thio]-9-[2-[bis(2,2,2-trifluoroethyl)phosphine Acylmethoxy]ethyl]-purine (I 1 )

[0028] 1.1 2-[bis(2,2,2-trifluoroethyl)-phosphonomethoxy]-ethyl chloride (III 1 )

[0029] Under stirring, 32 g of phosphorus trichloride was slowly added to 70 g of trifluoroethanol, and stirred at 85°C for 5 hours. Fractional distillation under reduced pressure collected the components at 120-125°C / 70-74 mmHg to obtain 62 grams of tris-(2,2,2-trifluoroethyl)phosphite.

[0030] Add 39 grams of 2-chloroethanol and 15 grams of paraformaldehyde to 80 ml of dichloromethane, cool in an ice bath; pass hydrogen chloride under stirring for 10 hours, and continue stirring overnight. Then the water layer was separated, the organic layer was dried with anhydrous calcium chloride, the solid was filtered off, the solvent was evaporated under reduced pressure, fractional distillation was carried out, and the components at 75-78°C / 24-26 mmHg were col...

Embodiment 2

[0038] Example 2 2-amino-6-[(benzo-1,3-dioxol-5-yl)-thio]-9-[2-[bis(2,2,2-trifluoroethane) base) phosphonomethoxy] ethyl] - purine (I 2 )

[0039] 2.1 (Benzo-1,3-dioxol-5-yl)-thiol (V 2 )

[0040] Add 2.54 milliliters of bromine dropwise to a solution of 4 grams of benzo-1,3-dioxolene in 44 milliliters of glacial acetic acid. After the addition, continue stirring for 2 hours, evaporate the reaction solution to dryness under pressure, and add ice water , extracted with ether, washed with aqueous sodium bicarbonate solution, dried with anhydrous sodium sulfate, and evaporated to dryness under pressure, the residue was fractionally distilled, and the fraction at 73°C / 0.1mmHg was collected to obtain 4.2 g of a colorless liquid.

[0041] Suspend 0.61 g of magnesium chips in 10 ml of anhydrous tetrahydrofuran, and add dropwise a solution of 4.2 g of 5-bromo-benzo-1,3-dioxolene in 10 ml of tetrahydrofuran under nitrogen within 1 hour. After the dropwise addition was completed, th...

Embodiment 3

[0045] Example 3 2-amino-6-[(benzo-1,4-dioxen-6-yl)-thio]-9-[2-[bis(2,2,2-trifluoroethane base) phosphonomethoxy] ethyl] - purine (I 3 )

[0046] 3.1 (Benzo-1,4-dioxan-6-yl)-thiol (V 3 )

[0047] Referring to Method 2.1, benzo-1,4-dioxene was reacted with bromine to obtain 6-bromo-benzo-1,4-dioxene; the latter was reacted with magnesium chips and sulfur to obtain V 3 .

[0048] 3.2 2-amino-6-[(benzo-1,4-dioxen-6-yl)-thio]-9-[2-[bis(2,2,2-trifluoroethyl) Phosphonomethoxy] ethyl] - purine (I 3 )synthesis

[0049] Refer to Method 1.4, V 3 with IV 1 condensation to produce I 3 . 1 HNMRδ (ppm, CDCl 3 ): 7.42(s, 1H); 6.96(d, 1H); 6.90(dd, 1H); 6.80(d, 1H); 4.75(b, 2H); 4.43(m, 4H); 4.25(m, 4H) ; 3.94(m, 2H); 3.72(t, 2H); 3.0(t, 2H).

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Abstract

The invention provides a compound of formula I and a pharmaceutically acceptable salt thereof. The compound can be used as antiviral remedy, especially for anti-hepatitis B virus, wherein R1 represents H or C1-C3 alkyl; R2 represents H, CH2CF3, OCH2OCOR3 or CH2OCOOR3; R3 represents iPr, tBu; X represents 0, CH2; and n equals to 1-3.

Description

Technical field: [0001] The present invention relates to a new acyclic nucleoside phosphonate derivative with high-efficiency anti-hepatitis B virus activity and low cytotoxicity and its application as medicine. Background technique: [0002] There are as many as 400 million hepatitis B virus carriers worldwide, and about 40 million people die of liver cirrhosis or liver cancer due to hepatitis B infection every year. Currently clinically effective anti-HBV drugs mainly include interferon, lamivudine and adefovir dipivoxil. However, the effective rate of interferon treatment is only 30-50%, and it is often accompanied by toxic side effects such as flu-like symptoms and leukopenia; lamivudine treatment is prone to drug resistance, and the incidence rate is as high as 40-50% after 2 years of continuous treatment . Nucleotide analogues such as adefovir dipivoxil do not require phosphorylation in cells, are not prone to drug resistance, and can overcome lamivudine drug resista...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/6561C07F9/20C07F9/48A61K31/675A61P1/16A61P31/20
Inventor 王进京
Owner FOSHAN YIBAOSHENG PHARMA CO LTD
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