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A kind of pyrimidine derivative and its preparation method and application

A pyrimidine and drug technology, applied in the field of pyrimidine derivatives and their preparation, can solve the problems of no compound, large toxic and side effects, short half-life and the like, and achieve the effects of reducing drug dosage, good sustained release effect and easy operation

Active Publication Date: 2018-08-03
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] 5-fluorouracil (5-fluoro-2,4(1H,3H)pyrimidinedione, 5-FU) is a traditional and classic chemotherapy drug, widely used in the chemotherapy of head and neck tumors, digestive system tumors and breast cancer However, as a monomeric nucleoside drug, 5-fluorouracil has the disadvantages of rapid metabolism, large toxic and side effects, and short half-life. It is often necessary to increase the dosage of the drug and / or increase the frequency of administration to achieve a more ideal treatment Effect
[0004] At present, there is no relevant report of the compound represented by formula I of the present invention or its crystal form or salt as a drug carrier, especially, there is no report of the compound represented by formula I of the present invention or its crystal form or salt as 5-fluorouracil Related reports of monomeric nucleoside drugs or carriers

Method used

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  • A kind of pyrimidine derivative and its preparation method and application
  • A kind of pyrimidine derivative and its preparation method and application
  • A kind of pyrimidine derivative and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1, 1-(β-L-ribofuranose)-5-amino-pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione (compound 1)

[0042]

[0043] Among them, Ac represents an acetyl group.

[0044] 1-(2',3',5'-O-acetyl-β-L-ribofuranose)-5-amino-pyrimido[4,5-d]pyrimidine-2,4(1H,3H)- Diketone 120mg was dissolved in 10mL 0.1M NaOMe / MeOH, and reacted at 75°C for 20 minutes. After cooling to room temperature (25°C), neutralized with diluted glacial acetic acid, a precipitate was formed, filtered, and the precipitate was used Washed three times with methanol, washed once with water, and dried under vacuum to obtain white powder 1-(β-L-ribofuranose)-5-amino-pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione (70 mg, 82% yield, 99% purity).

[0045] 1-(β-L-ribofuranose)-5-amino-pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione:

[0046] 1 H NMR (DMSO-d 6 ,600MHz): δ3.55-3.63(1H,m,5'-H),3.76-3.79(1H,m,5'-H β ),3.92-3.96(1H,m,4′-H),4.07-4.09(1H,3′-H),4.13-4.15(1H,2′-H),5.09-5.11(1H,5′-OH ),5.26-5.30(t,1H,3′-OH),5.55-...

Embodiment 2

[0050] Embodiment 2, compound 1 forms nanoparticle structure by self-assembly

[0051] A certain amount of compound 1 was dissolved in water, heated to boiling, cooled, and left to stand at room temperature for 24 hours; the results of scanning electron microscopy (SEM) and dynamic laser light scattering (DLS) showed that compound 1 could form particles by self-assembly in aqueous solution. Granular nanostructures with uniform diameter (~150nm), such as figure 1 shown.

Embodiment 3

[0052] Example 3. Nanoparticles formed by self-assembly of compound 1 are used to encapsulate drug 5-fluorouracil

[0053] A certain amount of compound 1 was dissolved in PBS, heated to about 100°C, cooled to room temperature, and left to stand for 24 hours, then added with a certain amount of 5-fluorouracil, and then left to stand for another 24 hours; the results of scanning electron microscopy and dynamic laser light scattering after the drug was wrapped It shows that compound 1 of the present invention can effectively wrap 5-fluorouracil to form a granular structure with uniform particle size, such as figure 2 shown.

[0054] In order to illustrate the beneficial effects of the present invention, the present invention provides the following test examples.

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Abstract

A pyrimidine derivative and its preparation method and use. The invention discloses a compound represented by formula I or its crystal form and salt: wherein, R1 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, amino or substituted amino, and R2-R4 are respectively or At the same time, it is selected from hydrogen, alkali metals, and C1-C6 alkyl groups. The SNNP of compound 1 of the present invention is used as a drug carrier, which significantly improves the therapeutic effect of monomeric nucleoside drugs and / or oligonucleotide drugs, has a good sustained-release effect, enhances the therapeutic effect of drugs, and reduces the dosage of drugs and the frequency of administration, improve the bioavailability of the drug, reduce the toxic and side effects of the drug, and have good clinical application value; at the same time, the preparation method of the present invention has high yield, high purity, low energy consumption, few steps, and easy operation , low cost, environmental protection, safety and other advantages, very suitable for industrial applications.

Description

technical field [0001] The invention relates to a pyrimidine derivative and its preparation method and use. Background technique [0002] 5-fluorouracil (5-fluoro-2,4(1H,3H)pyrimidinedione, 5-FU) is a traditional and classic chemotherapy drug, widely used in the chemotherapy of head and neck tumors, digestive system tumors and breast cancer However, as a monomeric nucleoside drug, 5-fluorouracil has the disadvantages of rapid metabolism, large toxic and side effects, and short half-life. It is often necessary to increase the dosage of the drug and / or increase the frequency of administration to achieve a more ideal treatment Effect. [0003] Currently, the reported carrier materials for 5-fluorouracil mainly include: aliphatic polyester polymers, chitosan, n-butyl cyanoacrylate, porphyrin compounds, sulfadiazine, glucuronic acid glycosides, galactose, Kai diphosphoric acid, etc. (1. Ma Baohua Wang Shaohua Wang Hong Zhang Na. Research progress of 5-fluorouracil nano-scale dr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/23C07H1/00A61K47/26
Inventor 赵行江潞冯慧何杨刘江曾昕陈谦明
Owner SICHUAN UNIV
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