Fluorouracil prodrug with low cytotoxicity and preparation method and application thereof

A fluorouracil and cytotoxic technology, which is applied to fluorouracil prodrugs with low cytotoxicity and the fields of preparation and application thereof, can solve the problems of strong toxic and side effects, hinder DNA synthesis, high cytotoxicity, etc., and achieve the effect of good effect and lower killing rate.

Pending Publication Date: 2020-04-03
HEILONGJIANG FUHE HUAXING PHARMA GROUP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] 5-Fluorouracil is a commonly used antibacterial drug in clinical practice. It has certain antibacterial activity against Candida and Cryptococcus. Proliferation, because it blocks the metabolism of tumor cells and normal cells at the same time, it is highly toxic to normal cells, has strong toxic and side effects, and brings more pain to patients

Method used

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  • Fluorouracil prodrug with low cytotoxicity and preparation method and application thereof
  • Fluorouracil prodrug with low cytotoxicity and preparation method and application thereof
  • Fluorouracil prodrug with low cytotoxicity and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Example 1 Preparation of 2-(5-fluorouracil-1-carboxamide)acetic acid

[0023] The preparation method of 2-(5-fluorouracil-1-carboxamide) acetic acid is as follows:

[0024] S1: Add 140 mg of fluorouracil, 118.8 mg of phosgene, 103 mg of glycine ethyl ester shown in formula 2-1 and 20 mL of methanol into the reaction flask, add 136 mg of sodium acetate under stirring conditions, and stir the reaction in an oil bath at 80 °C for 2 h. Monitor After the reaction was completed, methanol was evaporated under reduced pressure, and the concentrate was purified by using petroleum ether / ethyl acetate as the mobile phase with silica gel column to obtain the intermediate product 2-(5-fluorouracil-1-carboxamide) ethyl acetate (formula 3- 1), the yield is 65.4%;

[0025] S2: Add the intermediate product formula 3-1 to 20 mL of 0.2M sodium hydroxide aqueous solution, stir at 10°C, monitor the completion of the reaction, adjust the pH to 7 with 0.2M hydrochloric acid, then add ethanol...

Embodiment 2

[0027] Example 2 Preparation of 2-(N-n-propyl-N-n-propyl-5-fluorouracil-1-carboxamide)acetic acid

[0028] The preparation method of 2-(N-n-propyl-5-fluorouracil-1-carboxamide) acetic acid is as follows:

[0029] S1: Add 140 mg of fluorouracil, 118.8 mg of phosgene, 145 mg of N-n-propylglycine ethyl ester shown in formula 2-2 and 20 mL of methanol into the reaction flask, add 136 mg of sodium acetate under stirring conditions, and put it in an oil bath at 80 °C. The reaction was stirred for 2 h, and after monitoring the completion of the reaction, methanol was evaporated under reduced pressure, and the concentrate was purified by using petroleum ether / ethyl acetate as the mobile phase with silica gel column to obtain the intermediate product 2-(N-n-propyl-5-fluorouracil-1 -Carboxamide) ethyl acetate (formula 3-2), the yield is 62.2%;

[0030] S2: Add the intermediate product formula 3-2 to 20 mL of 0.2M sodium hydroxide aqueous solution, stir at 10°C, monitor the completion o...

Embodiment 3

[0032] Example 3 Preparation of 2-(N-isopropyl-N-isopropyl-5-fluorouracil-1-carboxamide)acetic acid

[0033] The preparation method of 2-(N-isopropyl-5-fluorouracil-1-carboxamide) acetic acid is as follows:

[0034] S1: Add 140 mg of fluorouracil, 118.8 mg of phosgene, 145 mg of N-isopropylglycine ethyl ester shown in formula 2-3 and 20 mL of methanol into the reaction flask, add 136 mg of sodium acetate under stirring conditions, and put it in an oil bath at 80 °C. The reaction was stirred for 2 h, and after monitoring the completion of the reaction, methanol was evaporated under reduced pressure, and the concentrate was purified by using petroleum ether / ethyl acetate as the mobile phase with silica gel column to obtain the intermediate product 2-(N-isopropyl-5-fluorouracil-1 -Carboxamide) ethyl acetate (formula 3-3), yield 62.9%;

[0035] S2: Add the intermediate product formula 3-3 to 20 mL of 0.2M sodium hydroxide aqueous solution, stir at 10°C, monitor the completion of ...

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Abstract

The invention provides a fluorouracil prodrug with low cytotoxicity. The prodrug has a structure represented by a formula I, the structure represented by the formula I is shown in the specification, and the fluorouracil prodrug is high in selectivity, capable of reducing the killing rate of normal cells and better in cancer or tumor treatment effect.

Description

technical field [0001] The invention relates to a derivative used for antitumor drugs, in particular to a fluorouracil prodrug with low cytotoxicity and a preparation method and application thereof. Background technique [0002] 5-Fluorouracil is a commonly used antibacterial drug in clinical practice, and has certain antibacterial activity against Candida and Cryptococcus. Proliferation, because it blocks the metabolism of tumor cells and also blocks the metabolism of normal cells, it is more toxic to normal cells and has stronger side effects, which brings more pain to patients. SUMMARY OF THE INVENTION [0003] In order to solve the above technical problems, the present invention uses the difference between the enzyme systems of normal cells and tumor cells to transform the chemical structure of 5-fluorouracil, so that 5-fluorouracil is combined with small molecular amino acids to prepare a prodrug, which is used in tumors. Under the action of intracellular plasmin, th...

Claims

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Application Information

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IPC IPC(8): C07D239/28A61K31/513A61P35/00
CPCC07D239/28A61P35/00
Inventor 吴光彦
Owner HEILONGJIANG FUHE HUAXING PHARMA GROUP
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