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5-fluorouracil iodized oil derivative as well as preparation method and application thereof

A technology for fluorouracil and derivatives is applied in the field of novel 5-fluorouracil lipiodol derivatives and their preparation, and achieves the effects of improving curative effect, inhibiting tumor cell proliferation and high yield

Inactive Publication Date: 2012-06-20
TENTH PEOPLES HOSPITAL OF TONGJI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are no reports about 5-fluorouracil lipiodol derivatives with physical embolism and direct killing of liver cancer cells.

Method used

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  • 5-fluorouracil iodized oil derivative as well as preparation method and application thereof
  • 5-fluorouracil iodized oil derivative as well as preparation method and application thereof
  • 5-fluorouracil iodized oil derivative as well as preparation method and application thereof

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Experimental program
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Embodiment 1

[0027] Embodiment 1 Compound of the present invention and preparation method thereof

[0028] Please refer to the attached figure 1 , the general chemical structure formula of novel 5-fluorouracil iodized oil derivative of the present invention is as follows:

[0029]

[0030] Wherein, n is 2, 3, 4, 5 or 6.

[0031] (1) Preparation of 1-hydroxyalkyl-5-fluorouracil, intermediate 2

[0032] 5-Fluorouracil reacts with the corresponding bromine-substituted alcohol in aqueous sodium hydroxide solution to obtain the corresponding 1-hydroxyalkyl-substituted 5-fluorouracil, namely intermediate 2. Please refer to the attached figure 2 , with figure 2 is the reaction scheme for the preparation of Intermediate 2.

[0033] (2) Preparation of 9,12-octadecadienoic acid [3-(5-fluorouracil-1-yl)] ester, intermediate 3

[0034] Intermediate 2 was reacted with dicyclohexylcarbodiimide (DCC), 4-dimethylaminopyridine (DMAP) in anhydrous acetonitrile at 0-5°C for 15 minutes, and then ...

Embodiment 2

[0038] (1) Preparation of 1-hydroxypropyl-5-fluorouracil (intermediate 2):

[0039] 5-Fu (1.30 g, 10 mmol), KOH (1.61 g, 30 mmol), H 2 O 10 ml, after stirring at room temperature for a while, the temperature was raised to 40 °C, and 3-bromo-1-propanol (2.87 g, 20 mmol) was slowly added dropwise, monitored by TLC. (Developer: DCM / MeOH (v / v=10:1). After the reaction is completed, the reaction solution is adjusted to PH to 6~7 with 6 mol / L hydrochloric acid, the solvent is distilled under reduced pressure, and dehydrated alcohol is added after evaporating to dryness. The insoluble matter was filtered off, the filtrate was concentrated under reduced pressure, and the product was separated and purified by column chromatography. (DCM / MeOH was used as the eluent (v / v) = 40:1), to obtain product 2, a white solid, with a yield of 30%.

[0040] 1 H NMR (600 MHz, MeOD) δ 7.81 (1H, d , J = 6.3 Hz), 3.82 (2H, t , J = 7.0 Hz), 3.60 (2H, t , J = 6.0 Hz), 1.96 – 1.84 (2H, m )...

Embodiment 3

[0050] Embodiment 3 Pharmacological experiments of compounds of the present invention

[0051] 1. Pharmacodynamic experiment

[0052] Cell line: human liver cancer HepG2 cell line

[0053] Drugs: 5-fluorouracil iodized oil derivatives, 5-fluorouracil

[0054] Operation method: 24 hours after the cells were plated, the drug-containing medium prepared with different concentrations of 5-fluorouracil iodized oil derivatives, 5-FU and blank was replaced, and each drug was inoculated in 3 duplicate wells, and a blank medium control group was set. The culture plate was cultured in a CO2 incubator, and the culture plate was taken out at 1, 2, 4, 8 and 24 hours respectively, the medium was discarded, and the culture medium was continued to 72 hours at the respective pH values. Take out all the culture plates, and measure the tumor cell inhibition rate by MTT method: cell inhibition rate (%)=(1-A value of the drug group / A value of the control group)×100%.

[0055] Experimental re...

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Abstract

The invention relates to a 5-fluorouracil iodized oil derivative and a salt thereof. The 5-fluorouracil iodized oil derivative and the salt thereof have the chemical structure shown in the following chemical general formula (described in the specification), wherein n is 2, 3, 4 or 5. The invention also provides a preparation method and application of the 5-fluorouracil iodized oil derivative and the salt thereof. According to the invention, a novel 5-fluorouracil iodized oil derivative is provided for preparation of a liver cancer resisting medicament. The preparation method has the advantage of high yield; the 5-fluorouracil iodized oil derivative has the advantages of good tumor resisting effect, targeting, low toxicity and the like; primary pharmacodynamic and toxicological experiments indicate that the novel iodized oil derivative can cause tumor vessel embolization and can release 5-fluorouracil to inhibit the proliferation of cancer cells simultaneously.

Description

technical field [0001] The present invention relates to a compound and its preparation method and use, in particular, a novel 5-fluorouracil lipiodol derivative and its preparation method and use. Background technique [0002] Malignant tumor is an important disease that threatens human health and has become the second leading cause of human death. According to statistics, the top five cancers in my country that die from malignant tumors are: gastric cancer, liver cancer, lung cancer, esophageal cancer and colorectal cancer. The main methods for the treatment of solid tumors include surgery, intravenous chemotherapy, radiotherapy, interventional therapy, and molecular targeted therapy. Clinical studies have found that transarterial chemoembolization (TACE) interventional therapy is the non-surgical preferred method for the treatment of solid tumors. TACE emulsifies chemotherapy drugs with iodized oil, injects them directly into the tumor through the blood supply artery of t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/553A61K31/513A61P35/00
Inventor 李茂全吴秋业蔡国君赵庆杰曹传武黄生军廖俊邹燕胡宏岗俞世冲柴晓云
Owner TENTH PEOPLES HOSPITAL OF TONGJI UNIV
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