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A kind of isosorbide mononitrate derivative and its preparation method and application

A technology of isosorbide dinitrate and its derivatives, which is applied in the field of isosorbide mononitrate derivatives and its preparation and application, can solve the problems of high water solubility and poor skin permeability of isosorbide mononitrate, and achieve enhanced anticancer efficacy , The effect of improving fat solubility

Active Publication Date: 2015-10-07
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, isosorbide mononitrate is highly water-soluble, and it is difficult to load it into nanocarriers to prepare a drug-loaded nano-drug delivery system; and the skin permeability is poor, and there is no report on its combination with anticancer drugs for the treatment of solid tumors.

Method used

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  • A kind of isosorbide mononitrate derivative and its preparation method and application
  • A kind of isosorbide mononitrate derivative and its preparation method and application
  • A kind of isosorbide mononitrate derivative and its preparation method and application

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Effect test

Embodiment 1

[0032] The preparation of embodiment 1 isosorbide mononitrate acetic acid derivative (ISMN-2)

[0033] Weigh 955mg (5mmol) of isosorbide mononitrate (ISMN for short), place it in a 100mL round bottom flask, add 50ml of anhydrous dichloromethane to dissolve; then add 612mg (6mmol) of acetic anhydride and 67mg of 4-N , N-dimethylaminopyridine (DMAP), magnetically stirred, and reacted at room temperature for 15 hours. The reaction solution was washed with 250mL saturated NaHCO 3 Solution was washed 3 times, 250mL deionized water was washed 3 times, the organic layer was collected, and then washed with anhydrous Na 2 CO 3 Remove the moisture in the organic layer, filter to remove Na 2 CO 3 , The organic solvent was removed by rotary evaporation of the filtrate under reduced pressure to obtain 779 mg of product with a yield of 49.7%, which was designated as ISMN-2.

Embodiment 2

[0034] The preparation of embodiment 2 isosorbide mononitrate lauric acid derivatives (ISMN-12)

[0035] Weigh 955mg (5mmol) of isosorbide mononitrate (ISMN), place in a 100mL round bottom flask, add 50ml of anhydrous dichloromethane to dissolve; then add 1.2g (6mmol) of lauric acid, 67mg of 4-N , N-dimethylaminopyridine (DMAP) and 1.1g of dehydrating agent 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), magnetic stirring, room temperature for 10 hours . The reaction solution was washed with 250mL saturated NaHCO 3 Solution was washed 3 times, 250mL deionized water was washed 3 times, the organic layer was collected, and then washed with anhydrous Na 2 CO 3 Remove the moisture in the organic layer, filter to remove Na 2 CO 3 , The organic solvent was removed by rotary evaporation of the filtrate under reduced pressure to obtain 1.6 g of the product with a yield of 76.5%, which was designated as ISMN-12.

Embodiment 3

[0036] The preparation of embodiment 3 isosorbide mononitrate stearic acid derivatives (ISMN-18)

[0037] Weigh 955mg (5mmol) of isosorbide 5-mononitrate (ISMN), place in a 100mL round bottom flask, add 50ml of anhydrous dichloromethane to dissolve; then add 1.7g (6mmol) of stearic acid, 67mg of 4-N,N-dimethylaminopyridine (DMAP) and 1.1 g of dehydrating agent 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), magnetic stirring, room temperature React for 12 hours. The reaction solution was washed with 250mL saturated NaHCO 3 Solution was washed 3 times, 250mL deionized water was washed 3 times, the organic layer was collected, and then washed with anhydrous Na 2 CO 3 Remove the moisture in the organic layer, filter to remove Na 2 CO 3 , The organic solvent was removed by rotary evaporation of the filtrate under reduced pressure to obtain 1.7 g of the product with a yield of 64.6%, which was designated as ISMN-18.

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Abstract

The invention discloses an isosorbide mononitrate derivative, a preparation method thereof and an application thereof to tumor combined treatment as shown in the formula (II). Ester is formed by isosorbide mononitrate and fatty acid through an esterification reaction, so that lipid solubility can be improved, and then a lipid nanoparticle passive targeting drug delivery system is further prepared. Afterwards, the drug combination is conducted by lipid nanoparticles of an isosorbide mononitrate fatty acid derivative and nano targeting anticancer drugs, and the therapeutic effect of chemotherapeutic drugs is improved.

Description

1. Technical field [0001] The invention relates to an isosorbide mononitrate derivative, a preparation method thereof and an application in tumor treatment. 2. Background technology [0002] During the growth process of solid tumors, when the tumor diameter reaches 0.2mm, in order to obtain the nutrients and oxygen needed for rapid growth, the formation of new blood vessel supply system has been induced spontaneously. Different from normal tissues, the microvascular wall of tumor tissue is missing, the endothelial cells are loosely arranged, the intercellular space is large, and there is no lymphatic drainage system, so that the passive and active targets of macromolecules or colloidal carriers such as liposomes, nanoparticles, micelles, etc. Carriers can pass through the gap between tumor vascular endothelial cells to reach tumor tissue, and the residence time is longer than molecular drugs, which is the so-called enhanced permeability and retention effect (EPR), which has ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D493/04A61K31/34A61K9/16A61P35/00
Inventor 熊素彬王铁闯卢琳尹小东
Owner ZHEJIANG UNIV OF TECH
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