Tenofovir cyclic phosphonate compound and pharmaceutically acceptable salt thereof, and preparation methods and applications thereof

A technology of vircyclondronate and compounds, applied in the field of chemical pharmaceuticals, to achieve the effect of avoiding kidney toxicity, high safety, and good antiviral effect

Inactive Publication Date: 2015-06-17
ANHUI BIOCHEM UNITED PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Metabolic by-product aryl vinyl ketone can quickly undergo 1,4-addition to glutathione, which is abundant in liver cells and has anti-oxidation and anti-free radical effects, and is eliminated. No side effects have been found for this addition product to report

Method used

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  • Tenofovir cyclic phosphonate compound and pharmaceutically acceptable salt thereof, and preparation methods and applications thereof
  • Tenofovir cyclic phosphonate compound and pharmaceutically acceptable salt thereof, and preparation methods and applications thereof
  • Tenofovir cyclic phosphonate compound and pharmaceutically acceptable salt thereof, and preparation methods and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] Example 1 The preparation of formula I compound

[0067] The preparation method of formula I compound comprises the following steps:

[0068] 1) Slowly add 150 ml of oxalyl chloride dropwise under nitrogen protection at 15-25°C with stirring to a mixture consisting of 150 g of tenofovir, 60 g of N,N-diethylformamide and 2 liters of dichloromethane. In the mixture, stir and reflux for 4 to 6 hours, then cool to 15 to 25°C for later use;

[0069] 2) Add 62 ml of titanium tetrachloride dropwise to 100 g of (S)-1-(3-chlorophenyl)-1,3-propanediol and 2 liters of In the solution that methyl chloride was formed, after adding dropwise 310 milliliters of triethylamine, stirred for 30 minutes, obtained reaction mixture;

[0070] 3) Add the reaction mixture prepared in step 2) to the reaction mixture prepared in step 1), stir at 20-25°C for 1-2 hours, then add 2 liters of saturated saline, and stir for 30 minutes , static layering, the aqueous layer was extracted five times w...

Embodiment 2

[0074] Example 2 Preparation of formula I compound mesylate

[0075] The preparation method of formula I compound mesylate may further comprise the steps:

[0076] 1) Add 85 grams of methanesulfonic acid and 900 milliliters of ethanol to the distillation residue obtained in Step 4) of Example 1, heat to reflux until clarified, cool down to 50°C, stir for 4-6 hours, and then stir at 0-5°C After 1-2 hours, filter under reduced pressure to obtain the crude product of the compound mesylate of formula I;

[0077] 2) Add 500 ml of ethanol to the obtained crude mesylate of the compound of formula I, heat to reflux until completely dissolved, cool down to 50°C, stir for 4-6 hours, then cool down to 5°C and stir for 1-2 hours, filter under reduced pressure , washed with cold ethanol, and dried at 45-50°C to obtain 175 g of the mesylate salt of the compound of formula I as a light yellow solid; cis / trans: 99.6:0.4.

[0078] δ( 1 HNMR, DMSO-d 6 ): 1.28 (d, J=7.5Hz, 3H), 1.95-2.20 (...

Embodiment 3

[0079] Example 3 Preparation of formula I compound fumarate

[0080] The preparation method of formula I compound fumarate, comprises the steps:

[0081] 1) Add 90 g of fumaric acid and 900 ml of ethanol to the distillation residue obtained in Step 4) of Example 1, heat to reflux until clarified, cool down to 50°C and stir for 4-6 hours, then cool down to 0-5°C Stir for 1-2 hours, and filter under reduced pressure to obtain the crude product of compound fumarate of formula I;

[0082] 2) Add 500 ml of ethanol to the obtained crude product of compound fumarate of formula I, heat to reflux until completely dissolved, cool down to 50°C and stir for 4-6 hours, then cool down to 5°C and stir for 1-2 hours, filter under reduced pressure , washed with cold ethanol, and dried at 45-50°C to obtain 182 grams of fumarate salt of the compound of formula I as a light yellow solid; cis / trans: 99.5:0.5.

[0083] δ( 1 HNMR, DMSO-d 6 ): 1.28 (d, J=7.5Hz, 3H), 1.95-2.20 (m, 2H), 2.68-2.75 (...

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PUM

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Abstract

The invention relates to a tenofovir cyclic phosphonate compound having a structure represented by a formula I and a pharmaceutically acceptable salt thereof, and preparation methods and applications thereof, wherein the compound represented by the formula I is a tenofovir pro-drug having a liver targeting character and is used for treatment of hepatitis B and resistance of human immunodeficiency virus infection.

Description

technical field [0001] The invention relates to the field of chemical pharmacy, in particular to a tenofovir cyclodronate compound and a pharmaceutically acceptable salt thereof, a preparation method and an application thereof. Background technique [0002] Tenofovir is a nucleoside reverse transcriptase inhibitor with the strongest antiviral activity and low nephrotoxicity so far. It is used for the treatment of hepatitis B and anti-HIV infection. The phosphonic acid in tenofovir is highly negatively charged at physiological pH, and has poor intestinal penetration, poor cell penetration, limited tissue distribution, short plasma half-life, poor oral bioavailability, and renal and gastrointestinal toxicity. Defects such as large side effects limit its clinical application and scope of application. Tenofovir disoproxil is a prodrug of tenofovir, and its antiviral active part is tenofovir. Tenofovir disoproxil enters the body and is converted into tenofovir by ester hydrolas...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6574A61K31/675A61P31/20A61P31/18A61P31/14
Inventor 岳祥军钟晓锋田磊邹春伟陈小峰王志邦
Owner ANHUI BIOCHEM UNITED PHARMA CO LTD
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