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Orthoester 5-fluorouracil prodrug molecule, preparation method and acid-sensitive nanoparticle and application thereof

A fluorouracil and orthoester technology, which can be used in pharmaceutical formulations, medical preparations without active ingredients, and medical preparations containing active ingredients, etc. The effect of reducing toxic and side effects, good acid degradation performance, and improving lipophilicity

Active Publication Date: 2019-02-22
ANHUI UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, traditional nano-preparations also have some shortcomings, mainly including low drug loading efficiency, poor stability, toxic and side effects related to carrier materials, crystallization and leakage of drugs during storage, etc.

Method used

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  • Orthoester 5-fluorouracil prodrug molecule, preparation method and acid-sensitive nanoparticle and application thereof
  • Orthoester 5-fluorouracil prodrug molecule, preparation method and acid-sensitive nanoparticle and application thereof
  • Orthoester 5-fluorouracil prodrug molecule, preparation method and acid-sensitive nanoparticle and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Preparation of 5-fluorouracil-1-acetic acid:

[0040] Weigh 10.07g of 5-fluorouracil (77.41mmol) into a 250ml round bottom bottle, then add 13.03gKOH (0.23mol), add a small amount of water, react at 100°C for half an hour and then the temperature drops to 60°C, weigh 10.97g of chlorine Acetic acid (0.12mol), dissolved with a small amount of water, placed in the dropping funnel and slowly dripped into the original bottom bottle, reacted for 6 hours, after the reaction, adjusted the pH to 5.0 with hydrochloric acid, cooled at 4°C for 4 hours, and used a sand core funnel Filter to remove the precipitate, adjust the pH to 2.0 with hydrochloric acid, cool in the refrigerator overnight, collect the precipitate, adjust the pH to 5.0 with saturated NaHCO3, cool for 4 hours, filter, adjust the pH of the filtrate to 2.0 with hydrochloric acid, and place in the refrigerator , the precipitate was collected and dried in a vacuum oven to obtain 14.3 g of a white solid product with a ...

Embodiment 2

[0042] Preparation of 2,2,2-trifluoro-N-(2-methoxy-[1,3]dipentane-4-methylene)acetamide:

[0043] (1) Under the protection of nitrogen, take a 250ml round-mouth reaction bottle as a reaction vessel, add 15.49g (0.17mol) 3-amino-1,2-propanediol to it, and dissolve it with 100ml of acetonitrile, ice-bath, and slowly add 36.23 g of ethyl trifluoroacetate, stirred and reacted at room temperature for 12h, after the reaction was completed, the solvent was removed by rotary evaporation, and then 300ml of ethyl acetate was added to dissolve the product after the rotary evaporation, and 100ml of 10% potassium ammonium sulfate solution and 100ml of saturated sodium chloride The solution was washed once respectively, the organic phase was collected, read-dried with anhydrous sulfuric acid, filtered, and the filtrate was concentrated under vacuum to obtain the colorless oily compound 2,2,2-trifluoro-N-(2,3-dihydroxypropane Alcohol) acetamide 26.53g, productive rate is 83.4%;

[0044] (2)...

Embodiment 3

[0046] (1) 2-octalkoxy-(1,3) dioxolane-4-methylamine (C 8- oe-NH 2 ) preparation:

[0047] Take 3.08g of n-octanol (23.65mmol), 8.12g of 2,2,2-trifluoro-N-(2-methoxy-[1,3]dipentane-4-methylene prepared in Example 2 Base) acetamide (35.5mmol) and 118.87mg pyridine p-toluenesulfonate (0.47mmol) were added to a 100ml round bottom reaction flask, reacted in a vacuum oil bath at 130°C for 8h, cooled to room temperature, and terminated by adding a few drops of triethylamine For the reaction, dissolve the reactant with a small amount of dichloromethane, settle in ethanol with a few drops of triethylamine, place it in a -20°C refrigerator for 1 hour, filter it with a sand core funnel, take the upper precipitate, and vacuumize to obtain a white reactant 7.34 g, yield 90.2%, put 7.34g of white reactant in a round-bottomed bottle, dissolve in THF with added triethylamine, dissolve 7.67g of NaOH (0.19mol) in 100ml of deionized water, add in THF after cooling and stir Overnight, remove ...

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Abstract

The invention discloses an orthoester 5-fluorouracil prodrug molecule. The orthoester 5-fluorouracil prodrug molecule is N-5-fluorouracil1-ethyl-2-carbonalkoxy-(1,3) dioxolane-4-methylformamide havinga structure as shown in formula (I) described in the specification, wherein n=2-32 and m=n+2. The invention further discloses a preparation method of the abovementioned prodrug molecule and a nanoparticle prepared therefrom and an application thereof. The orthoester 5-fluorouracil prodrug molecule, the preparation method and the nanoparticle and the application thereof have the advantages that the nanoparticle prepared by the orthoester 5-fluorouracil prodrug molecule not only has the advantages of a small molecule prodrug but also is endowed with the advantage of a nano drug delivery system(that is a drug carrier), the prodrug nanoparticle not only has excellent acid degradation property and reduced tumor cytotoxicity and realizes passive targeting enrichment of a drug in a tumor, the nanoparticle has high drug loading capacity because the drug is used as a main part of the carrier, and the nanoparticle is capable of loading other antitumor drugs and achieves the effect of cooperatively treating the tumor and thus has good application prospects in the field of tumor treatment.

Description

technical field [0001] The invention relates to the technical field of biomedicine, and more specifically relates to an orthoester 5-fluorouracil prodrug molecule, a preparation method thereof, acid-sensitive nanoparticles and applications thereof. Background technique [0002] At present, cancer has become one of the chief culprits that seriously threaten human health all over the world. According to the World Health Organization, an average of 8.2 million people die of cancer every year. Therefore, effectively treating cancer has become an urgent problem in the medical field. Among the many methods for treating cancer, chemical drug therapy (chemotherapy) is currently one of the most effective means for treating cancer. However, most of the antineoplastic drugs used in chemotherapy are cytotoxic drugs, and most of the drugs have disadvantages such as low solubility, poor stability, narrow therapeutic window and poor pharmacokinetic properties, resulting in poor therapeut...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/12A61K9/51A61K47/22A61K31/513A61K31/704A61P35/00
CPCA61K9/5123A61K31/513A61K31/704A61P35/00C07D405/12A61K2300/00
Inventor 唐汝培曾小丽王鑫杨霞
Owner ANHUI UNIVERSITY
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