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Phosphoryl N-fatty acyl nucleoside analogue for treating viral hepatitis and liver cancer

A technology for fatty acyl nucleosides and nucleoside analogs, applied in the field of phosphoryl N-fatty acyl nucleoside analogs, which can solve the problems of drug leakage into the external water phase and low encapsulation rate

Inactive Publication Date: 2014-12-17
ACADEMY OF MILITARY MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These factors determine that the encapsulation rate of most water-soluble drugs is low (<50%), sometimes very low (5%), and the encapsulated drugs may leak into the outer aqueous phase

Method used

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  • Phosphoryl N-fatty acyl nucleoside analogue for treating viral hepatitis and liver cancer
  • Phosphoryl N-fatty acyl nucleoside analogue for treating viral hepatitis and liver cancer
  • Phosphoryl N-fatty acyl nucleoside analogue for treating viral hepatitis and liver cancer

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Experimental program
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Effect test

Embodiment 1

[0033] Embodiment 1. the synthesis of phosphoryl N-fatty acyl gemcitabine

[0034] The structural formula of phosphoryl N-fatty acyl gemcitabine is:

[0035]

[0036] Wherein R is a single-chain aliphatic chain, and R=C 7 h 15 -, C 9 h 19 -, C 11 h 23 -, C 13 h 27 -, C 15 h 31 - or C 17 h 35 - 1-(3-Chlorophenyl)-1,3-propanediol is first synthesized. Weigh magnesium powder (6.3g, 0.26mol), add ethanol (27ml) and carbon tetrachloride (3ml), and stir under ice-bath conditions to obtain a white solid. A mixture of 33 ml of ethyl acetoacetate (0.26 mol), 40 ml of ethanol and 30 ml of diethyl ether was added dropwise. After 0.5h, m-chlorobenzoyl chloride (33ml, 0.26mol) was added dropwise, in an oil bath at 60°C for 2h, after the reaction liquid was cooled, it was poured into 150ml of cold water, and the pH value was adjusted to 4 with 3M hydrochloric acid solution. Take the organic phase and wash with 5% (w / v) NaHCO 3 and water three times respectively, dried and ...

Embodiment 2

[0041] Example 2.1-(3-chlorophenyl)-1,3-propanediol-N-dodecanoyl lamivudine phosphate

[0042] This product is the product of lamivudine and 1-(3-chlorophenyl)-1,3-propanediol to generate phosphate, and then amidation with dodecanoic acid. Molecular formula C 28 h 41 ClN 3 o 7 PS, molecular weight 642.14. First, 1-(3-chlorophenyl)-1,3-propanediol is synthesized, and the specific steps are as follows. Take magnesium powder (6.3g, 0.26mol) and add it to a round bottom flask, add ethanol (27ml) and carbon tetrachloride (3ml), and stir and mix under ice bath conditions. A solution of ethyl acetoacetate (33ml, 0.26mol) in ethanol (40ml) and diethyl ether (30ml) was added dropwise thereto. After reacting for 0.5h, the mixture was cooled to 0°C, and m-chlorobenzoyl chloride (33ml, 0.26mol) was added dropwise, reacted at 60°C for 2h, and cooled. The reaction solution was poured into cold water (150ml) and acidified to pH4 with hydrochloric acid solution. Separate the organic ph...

Embodiment 3

[0046] Embodiment 3. Preparation of phosphoryl N-lauroyl gemcitabine liposomes

[0047] Take phosphoryl N-lauroyl gemcitabine (25 mg) and soybean lecithin (0.1 g) in a 250 ml flask, dissolve them in 20 ml of dichloromethane, and evaporate under reduced pressure to obtain a layer of organic fat-soluble film, and add phosphoric acid with a pH of 7.4 Shake 10ml of saline buffer solution, most of the membranes fall off, sonicate at 50°C until a uniform suspension is obtained, and observe under a microscope, most of the particles are less than 1 micron in diameter, which are phosphoryl N-dodecanoyl gemcitabine liposomes.

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Abstract

The invention discloses a phosphoryl N-fatty acyl nucleoside analogue for treating viral hepatitis and liver cancer. The phosphoryl N-fatty acyl nucleoside analogue is characterized in that a nucleoside analogue is modified by a cyclophosphoryl group and then is connected to aliphatic chains having different numbers of carbon atoms. The phosphoryl N-fatty acyl nucleoside analogue can be used for convenient preparation of a nanometer transmission system and has obvious hepatocyte and tumor targeting. The nanometer transmission system comprises liposome, nonionic surfactant niosomes, nanoparticles, nano-emulsion and a self-assembled transmission system. The nucleoside analogue is selected from lamivudine, adenine arabinoside, cidofovir, gemcitabine, cytosine arabinoside, azacitidine and fludarabine. After intravenous administration, the nanometer transmission system of the phosphoryl N-fatty acyl nucleoside analogue has effects of targeting treatment on viral hepatitis and liver cancer.

Description

technical field [0001] The present invention relates to the fields of chemistry and biomedicine, in particular to a phosphoryl N-fatty acyl nucleoside analog, from which a nano delivery system can be prepared, including liposomes, nonionic surfactant vesicles, nanoparticles, nano milk, self-assembling delivery system. Background technique [0002] Liver tissue cells can be divided into hepatic parenchymal cells and non-parenchymal cells. Nonparenchymal cells mainly include Kupffer cells and other cells with phagocytic function, which belong to the mononuclear macrophage system (MPS). Liver malignant tumors include hepatocellular carcinoma (HCC, referred to as liver cancer), cholangiocarcinoma, intrahepatic angiosarcoma, and intrahepatic metastatic tumors, among which 90% are hepatic parenchymal carcinoma, which is the second most common cancer in the world except gastric cancer and esophageal cancer. 3 common tumors. my country is the country with the highest incidence ra...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/11C07F9/6574A61K47/48A61K9/127A61K9/14A61K9/107A61P1/16A61P31/12A61P35/00
Inventor 金义光杜丽娜汪珊
Owner ACADEMY OF MILITARY MEDICAL SCI
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