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Lamivudin stearate and synthesis method and application

A technology of lamivudine stearate and lamivudine, which is applied in the field of drug synthesis, can solve problems such as difficult loading and limited drug loading capacity, and achieve the effects of increasing drug concentration, reducing distribution, and increasing uptake

Inactive Publication Date: 2010-08-18
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, graft micelles also have some potential limitations, such as limited drug loading capacity, difficulty in encapsulating hydrophilic drugs, etc.

Method used

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  • Lamivudin stearate and synthesis method and application
  • Lamivudin stearate and synthesis method and application
  • Lamivudin stearate and synthesis method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Embodiment 1: the synthesis of the prodrug lamivudine stearate of lamivudine

[0023] Accurately weighed dry 1.29g lamivudine, 2.778g dicyclohexylcarbodiimide and 142mg 4-dimethylaminopyridine were dissolved in 50mL anhydrous dichloromethane; accurately weighed 3.18g stearic acid Dissolve in 50mL of anhydrous dichloromethane. Under the condition of 400rpm magnetic stirring, the stearic acid organic solution was added dropwise to the mixed organic solution of lamivudine, and heated to reflux at 30° C. for 4 days under nitrogen protection. After the reaction was completed, the solvent dichloromethane was distilled off to obtain a crude product. Using methanol / dichloromethane (1:20, v / v) as eluent, the crude product was separated and purified by silica gel column chromatography to obtain the target product lamivudine stearate (I). figure 1 It is the nuclear magnetic resonance spectrum of lamivudine stearate, lamivudine, and stearic acid, and the synthesis of lamivudine s...

Embodiment 2

[0024] Embodiment 2: the preparation of lamivudine stearate chitosan stearic acid micelles

[0025] 1) Synthesis of chitosan stearic acid graft

[0026] Weigh 2.0g of chitosan oligosaccharide with a molecular weight of 1.8KDa, add 50mL of deionized water and stir to dissolve; and weigh 0.8g of stearic acid and 5.5g of carbodiimide and dissolve in 40ml of ethanol. The chitosan oligosaccharide solution was heated to 80° C., and the stearic acid solution was added dropwise with stirring. The reaction temperature was maintained at 80° C., and the reaction was performed for 5 h under the condition of magnetic stirring at 400 rpm. The final reaction solution was placed in a dialysis bag (molecular weight: 7 kDa), and dialyzed against deionized water for 24 hours to remove residual carbodiimide and reaction by-product isourea. The dialysate was freeze-dried to obtain chitooligosaccharide stearic acid graft. figure 1 D is the H NMR spectrum of the chitosan stearic acid graft.

[0...

Embodiment 3

[0036] Embodiment 3: the preparation of the graft micelles of loading lamivudine stearate

[0037] 1) Synthesis of chitosan stearic acid graft

[0038] Weigh 2.0g of chitosan oligosaccharide with a molecular weight of 1.8KDa, add 50mL of deionized water and stir to dissolve; and weigh 0.8g of stearic acid and 5.5g of carbodiimide and dissolve in 40ml of ethanol. The chitosan oligosaccharide solution was heated to 80° C., and the stearic acid solution was added dropwise with stirring. The reaction temperature was maintained at 80° C., and the reaction was performed for 5 h under the condition of magnetic stirring at 400 rpm. The final reaction solution was placed in a dialysis bag (molecular weight: 7 kDa), and dialyzed against deionized water for 24 hours to remove residual carbodiimide and reaction by-product isourea. The dialysate was freeze-dried to obtain chitooligosaccharide stearic acid graft. figure 1 D is the H NMR spectrum of the chitosan stearic acid graft.

[00...

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Abstract

The invention provides lamivudin stearate. The lamivudin stearate is characterized in that the lamivudin stearate is synthesized through lipophilicity modification of lamivudin, which is favorable for medicinal loads of targeted carrier materials; chitosan-stearate graft micelles having efficient cell intake and low toxicity are used for encapsulating antiviral medicaments of molecular targets incells so as to greatly increase medicament intake of viral cells and medicament concentration at the medicinal molecular targets; the increased medicament intake of the viral cells is favorable for reducing the distribution of the medicaments in normal tissues or cells and toxic and side effects of the medicaments; the increased medicament concentration at the medicinal molecular targets is favorable for improving the effects of the antiviral medicaments; and the lamivudin stearate can be applied to preparing the medicaments having efficient anti-HBV activity. The lamivudin stearate has the following chemical structural formula.

Description

technical field [0001] The invention belongs to drug synthesis, and relates to a synthesis method and application of lamivudine prodrug, in particular to a synthesis method of lamivudine stearic acid and its application in the preparation of anti-hepatitis B virus drugs. Background technique [0002] As an infectious disease, viral diseases have become one of the main threats to human health. Chronic hepatitis B is a serious viral infectious disease and the main cause of liver fibrosis, liver cirrhosis and liver cancer. More than 500,000 people die from primary liver cancer every year in the world, and as many as 80% of the primary liver cancers are caused by chronic hepatitis B. Since the existing antiviral drugs cannot completely inhibit and clear the virus, there are problems of large dosage, low curative effect, toxic side effects and easy drug resistance. Therefore, for the treatment of viral diseases, especially the treatment of chronic viral infections Still a medic...

Claims

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Application Information

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IPC IPC(8): C07D411/04A61K31/513A61K47/36A61P31/20A61P1/16
Inventor 胡富强杜永忠袁弘李茜
Owner ZHEJIANG UNIV
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