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5-fluorouracil derivative and preparation method and application thereof

A technology of fluorouracil and reaction, applied in the field of 5-fluorouracil derivatives, can solve the problems of poor curative effect and inability of cancer drugs to penetrate, and achieve high anti-tumor effect

Inactive Publication Date: 2019-02-26
NANJING YOUYI MEDICAL TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] According to reports in the literature, one of the reasons for the poor efficacy of many cancer treatment drugs is that these drugs cannot penetrate into the high-pressure environment inside solid tumors. Cause (Christopher C. DuFort et al, Biophysical Journal 110, 2106-2119, May 10, 2016.)

Method used

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  • 5-fluorouracil derivative and preparation method and application thereof
  • 5-fluorouracil derivative and preparation method and application thereof
  • 5-fluorouracil derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0102] Example 1. Synthesis of 1-{4-[3-(1,2-dithiolane)]-butylamino}formyl-5-fluorouracil (YY-003)

[0103](1) Synthesis of 4-[3-(1,2-dithiolane)]-butyl isocyanate

[0104] The reaction formula is as follows:

[0105]

[0106] Experimental steps:

[0107] In a 100mL round bottom flask, add 1.0g (4.85mmol) lipoic acid and 10ml dry toluene, stir to dissolve, add 0.4g powdered 4A molecular sieve, and then add 2.105g (7.65mmol) phosphoric acid azide to the solution Diphenyl ester (DPPA) and 0.773g (7.65mmol) of triethylamine were stirred at room temperature until the reaction was complete (about 2 hours), and about 30ml of saturated NaHCO was added to the reaction solution 3 aqueous solution, stirred for 2-3 minutes, added ethyl acetate (30ml×3) for extraction three times, combined the organic phases, and washed with anhydrous Na 2 SO 4 After drying and column separation, 200-300 mesh silica gel was used as the stationary phase, and a mixture of dichloromethane and petroleu...

Embodiment 2

[0116] Example 2. Synthesis of 1-{4-[3-(1,2-dithiolane)]-butylamino}formyl-5-fluorouracil (YY-003)

[0117] (1) Synthesis of 4-[3-(1,2-dithiolane)]-butyl isocyanate

[0118] The reaction formula is as follows:

[0119]

[0120] In a 100mL round bottom flask, add 1.0g (4.85mmol) of lipoic acid and 5ml of acetone, stir to dissolve, add 0.539g (5.335mmol) of triethylamine, cool to 0 to -5°C in an ice-salt bath, and add to the solution A solution of 0.578 g (3.616 mmol) of ethyl chloroformate in acetone (2 ml) was slowly added dropwise, and after the drop was completed, stirring was continued at 0 to -5°C for 30 minutes. Then, 0.630 g (9.70 mmol) of an aqueous solution of sodium azide (2 ml) was slowly added dropwise to the solution, and stirring was continued at 0 to -5° C. for 30 minutes. Add 30ml of ice water to the solution, pour the mixture into a separatory funnel, add 50ml of toluene to the separatory funnel in four times to extract the reaction product, combine the to...

Embodiment 3

[0123] Example 3. Synthesis of 1-{4-[3-(1,2-dithiolane)]-butylamino}formyl-5-fluorouracil (YY-003)

[0124] (1) Synthesis of 4-[3-(1,2-dithiolane)]-butyl isocyanate

[0125] The reaction formula is as follows:

[0126]

[0127] In a 100ml flask, add 1.0g (4.85mmol) lipoic acid, 30ml chloroform and 2-3 drops of DMF, stir, 1.150g (9.7mmol) thionyl chloride (MW: 119), stir at room temperature for 4 hours under nitrogen protection , reacted at reflux for 1 hour, and removed the solvent and excess thionyl chloride under reduced pressure to obtain 4-[3-(1,2-dithiolane)]-pentanoyl chloride.

[0128] Add 0.630 g (9.70 mmol) of sodium azide and 10 ml of anhydrous tetrahydrofuran into a 100 ml flask, heat and stir until reflux. Dissolve the 4-[3-(1,2-dithiolane)]-pentanoyl chloride obtained above in 10ml of tetrahydrofuran and add it to the constant pressure dropping funnel. After reflux occurs, start to add 4-[3 -(1,2-Dithiolane)]-pentanoyl chloride was dissolved in 10ml of tetra...

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Abstract

The invention discloses an antitumor drug compound having a structure of a formula I: 1-{4-[3-(1,2-dithiolane)]butyrylamino}formyl-5-fluorouracil and a preparation method thereof. The drug compound ofthe present invention contains a lipoic acid structure having strong penetrating ability to cells, and contains a 5-fluorouracil precursor structure capable of inhibiting deoxythymidylate synthase, the molecular metabolite 5-fluorouracil can inhibit and kill cancer cells, the 5-fluorouracil derivative has good anticancer activity, and can be used for preparing drugs for treating blood system cancer, solid tumor cancer, sarcoma, skin cancer or glioma.

Description

technical field [0001] The present invention relates to a 5-fluorouracil derivative, in particular to a compound 1-{4-[3-(1,2-dithiolane)]-butylamino}formyl-5- Fluorouracil, its preparation method, and its application as an antitumor drug. Background technique [0002] Tumor is a kind of disease that seriously endangers human life and health. Under the action of carcinogenic factors, a certain cell in a local tissue loses normal regulation of its growth at the gene level, resulting in abnormal clonal proliferation. It manifests as excessive cell proliferation and abnormal differentiation. At present, cancer has become the first cause of death for human beings and poses the most serious threat to human survival. [0003] Drug therapy plays an important role in the treatment of tumors, and there are many kinds of anticancer drugs with different mechanisms of action. The mechanism of action of most anti-tumor drugs is mainly to prevent the synthesis of deoxyribonucleic acid ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/12A61K31/513A61P35/00
CPCC07D409/12
Inventor 张跃华赵梦尧
Owner NANJING YOUYI MEDICAL TECH CO LTD
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