N-hydroxyl heterocycle pyrimindine diketone derivative and preparation method and application thereof

A technology of pyrimidine diketones and derivatives, which can be used in pharmaceutical formulations, medical preparations containing active ingredients, organic chemistry, etc., and can solve problems such as poor therapeutic effects

Active Publication Date: 2016-06-15
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Cidofovir is currently the most ideal drug for the treatment of adenovirus infection, but its therapeutic effect is very poor for patients receiving hematopoietic stem cell transplantation

Method used

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  • N-hydroxyl heterocycle pyrimindine diketone derivative and preparation method and application thereof
  • N-hydroxyl heterocycle pyrimindine diketone derivative and preparation method and application thereof
  • N-hydroxyl heterocycle pyrimindine diketone derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Example 1. Synthesis of key intermediate 3-benzyloxy-6-ethynyl-1-alkylquinazoline-2,4(1H,3H)-dione (5a, 5b)

[0055] The starting material 2-amino-5-iodobenzoic acid (1) (15mmol, 4.0g) was added to 15mL of anhydrous methanol solution, and then 3M concentrated sulfuric acid with a mass fraction of 70% was added to the solution. Heated to reflux for 6h, then stirred at room temperature for 12h. After the reaction was completed, the solvent was distilled off under reduced pressure, and then 100 mL of saturated sodium bicarbonate solution was added to the residue in the bottle, and extracted with ethyl acetate (3×30 mL). The organic layer was separated, washed with saturated brine (3×20 mL), and the organic phase was separated and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated to dryness under reduced pressure to obtain 3.96 g of crude product of methyl 2-amino-5-iodobenzoate (2), yield: 94.5%, mp: 70-73°C. 1 HNMR (400MHz, DMSO-d6, ppm) ...

Embodiment 2

[0063] Embodiment 2. the synthesis of target product M01-M13 and E01-E13

[0064] The key intermediate 3-benzyloxy-6-ethynyl-1-alkylquinazoline-2,4(1H,3H)-dione (5a, 5b) (0.65mmol) and prepared by substituted benzyl halide Azide (0.65 mmol) was added to a mixed solvent of tert-butanol and water (v / v=1:1, 15 mL). Then, 1M freshly prepared aqueous solution of sodium ascorbate (0.195mmol, 0.04g) and 7.5% aqueous solution of copper sulfate pentahydrate (0.065mmol, 0.017g) were added to this solution. The mixed solution was heated to 65°C and stirred vigorously for 4-12h (TLC detection). After the reaction was completed, a large amount of precipitates were formed, the filter cake was filtered, washed with water, and then recrystallized in methanol to obtain intermediates 6a01-6a13, 6b01-6b13 of the target product.

[0065] Then for different target products, the present invention adopts different synthetic methods. The target products M01-M12 and E01-E12 used method one, while t...

Embodiment 3

[0120] Example 3. In vitro anti-pox virus and anti-adenovirus virus activity test (HEL cell) experiment of the target compound

[0121] Test Principle

[0122] Viruses can only replicate and proliferate in susceptible live animals, chicken embryos or cells. Therefore, animals, chicken embryos or cells can be used to carry out virus culture and drug antiviral tests. Drugs can be judged by observing changes in the pH of cell culture fluid, virus cytopathic effect (CPE), virus titer (PFU), changes in viral genome mRNA levels, changes in chicken embryo allantoic fluid or animal serum, etc. Antiviral test effect.

[0123] Virus CCID 50 Titration principle: After most viruses infect cells cultured in vitro, they often cause changes in cell morphology, such as cell shrinkage, lysis, and cell swelling. This change is called cytopathic effect (CPE), which can be directly measured by Microscopic observation can also be identified and judged by staining. The degree of CPE can indire...

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PUM

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Abstract

The invention discloses a quinazoline ketone derivative and a preparation method and application thereof.The compound is of the structure as shown in the general formula (I).The invention further relates to a drug composition containing the compound in the formula (I).Activity screening experiments show that the compound has good anti-acne-virus and anti-adenovirus activity, and therefore application of the compound to preparing anti-acne-virus and anti-adenovirus drugs is also provided.Please see the formula (I) in the description.

Description

technical field [0001] The invention belongs to the technical field of organic compound synthesis and medical application, and specifically relates to an N-hydroxy heterocyclic pyrimidine diketone derivative, a preparation method thereof and an application as an antiviral inhibitor. Background technique [0002] Poxviruses are the largest class of DNA viruses with complex structures. Poxviridae is divided into six genera based on antigenic and morphological differences. Among them, several poxvirus genera that cause human infection mainly include: smallpox, molluscum contagiosum, vaccinia, milking artificial nodules, and contagious pustular dermatitis (pustular dermatitis) virus. Among them, smallpox was once one of the greatest human diseases. Although the World Health Organization announced in 1979 that the smallpox virus had been eradicated globally, the vaccination against smallpox was interrupted, resulting in a gradual increase in the number of people susceptible to ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04A61K31/517A61P31/20
CPCC07D403/04
Inventor 刘新泳展鹏康东伟
Owner SHANDONG UNIV
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