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2-polysubstituted aromatic ring-pyrimidine derivative and preparation and medical application

A technology of derivatives and pyrimidines, used in pharmaceutical formulations, drug combinations, anti-tumor drugs, etc., can solve problems such as poor selectivity, toxic and side effects, etc.

Active Publication Date: 2017-04-26
ZHEJIANG UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to its poor selectivity, it will cause a variety of toxic and side effects, and obvious drug resistance will occur during treatment.

Method used

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  • 2-polysubstituted aromatic ring-pyrimidine derivative and preparation and medical application
  • 2-polysubstituted aromatic ring-pyrimidine derivative and preparation and medical application
  • 2-polysubstituted aromatic ring-pyrimidine derivative and preparation and medical application

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0152] Preparation Example 1.N 4 -Methyl-5-(1-methyl-1H-pyrazol-4-yl)-N 2 -(1-methyl-5-(piperidin-4-oxyl)pyrazol-3-yl)-2,4-diaminopyrimidine (compound 1)

[0153]

[0154] Step 1. Synthesis of N-tert-butoxycarbonyl-4-((3-bromo-1-methyl-1H-pyrazol-5-yl)oxy)piperidine (Intermediate 1-2)

[0155]

[0156]Dissolve N-tert-butoxycarbonyl-4-hydroxypiperidine (460mg, 2.29mmol) in anhydrous THF (7.2mL), and add 60% sodium hydride (108mg, 4.5mmol) in batches under ice-cooling. Stir for 10 min. Raise the temperature to 35°C and stir for 10 minutes. 3-Bromo-1-methyl-5-nitropyrazole (360mg, 1.75mmol) was placed in a 50mL three-necked flask, and anhydrous THF (4.8mL) was added under nitrogen protection, and the sodium salt prepared above was slowly Add it dropwise to the reaction solution (the dropwise addition is completed in about 20 minutes), and stir at room temperature for 1 hour. The reaction was quenched by adding saturated ammonium chloride solution, and the solvent was r...

preparation Embodiment 2

[0169] Preparation Example 2.N 4 -Methyl-5-(1-methyl-1H-pyrazol-4-yl)-N 2 -(3-(piperidin-4-oxyl)isoxazol-5-yl)-2,4-diaminopyrimidine (compound 2)

[0170]

[0171] Step 1. Synthesis of N-tert-butoxycarbonyl-4-((5-bromo-isoxazol-3-yl)oxy)piperidine (Intermediate 1-8)

[0172]

[0173] Synthetic steps Reference Example 1 Step 1. Compound 1-8 was prepared from 5-bromo-3-nitropyrazole (compound 1-7) by a synthetic method similar to compound 1-2. Yield: 63%; LCMS: m / z=348[M+1] + .

[0174] Step 2.N 4 -Methyl-5-(1-methyl-1H-pyrazol-4-yl)-N 2 Synthesis of -(3-(piperidin-4-oxyl)isoxazol-5-yl)-2,4-diaminopyrimidine (Compound 2)

[0175]

[0176] For the synthesis steps, refer to step 5 of Example 1. Using a synthesis method similar to compound 1, using intermediates 1-8 and 1-6 as raw materials, compound 2 was prepared. Yield: 65%; LCMS: m / z=371[M+1] + .

preparation Embodiment 3

[0177] Preparation Example 3.N 4 -Methyl-5-(1-methyl-1H-pyrazol-4-yl)-N 2 -(1-methyl-2-(piperidin-4-oxyl)imidazol-4-yl)-2,4-diaminopyrimidine (Compound 3)

[0178]

[0179] Step 1. Synthesis of N-tert-butoxycarbonyl-4-((4-bromo-1-methyl-1H-imidazol-2-yl)oxy)piperidine (Intermediate 1-10)

[0180]

[0181] Synthesis steps Reference Example 1 Step 1. Compound 1-10 was prepared from 4-bromo-1-methyl-2-nitroimidazole (compound 1-9) by a method similar to that of compound 1-2. Yield: 67%; LCMS: m / z=361[M+1] + .

[0182] Step 2.N 4 -Methyl-5-(1-methyl-1H-pyrazol-4-yl)-N 2 Synthesis of -(1-methyl-2-(piperidin-3-oxyl)imidazol-4-yl)-2,4-diaminopyrimidine (Compound 3)

[0183]

[0184] For the synthesis steps, refer to step 5 of Example 1. Compound 3 was prepared by using a synthesis method similar to compound 1, using intermediates 1-10 and 1-6 as raw materials. Yield: 65%; LCMS: m / z=384[M+1] + .

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Abstract

The invention provides a 2-polysubstituted aromatic ring-pyrimidine derivative, an optical isomer of the derivative or a medically acceptable salt or solvate of the derivative, and application of the compound, the optical isomer of the derivative or the medically acceptable salt or solvate of the derivative in preparing antineoplastic medicine. According to the 2-polysubstituted aromatic ring-pyrimidine derivative, by adopting N-substituted pyridine-2-minopyrimidine as a lead compound obtained based on virtual screening of a structure, a series of brand new small molecule Chk1 inhibitors are designed and synthesized, and a Chk1 kinase inhibitory activity test of a molecular level is conducted on the compound. Experiments prove that the compound is a Chk1 inhibitor with a strong antitumous effect, Chk1 kinase inhibitory activity and a prospect, and new cancer treating medicine, and can be used for treating solid tumor or leukemia related with human or animal cell proliferation. The 2-polysubstituted aromatic ring-pyrimidine derivative has a structure shown in the general formula I.

Description

technical field [0001] The invention relates to the field of medicine, in particular to 2-multi-substituted aromatic ring-pyrimidine derivatives and their optical isomers or their pharmaceutically acceptable salts or solvates, pharmaceutical compositions containing them and their anti-tumor applications Applications. Background technique [0002] With the change of human living environment and the aging of population, malignant tumors are seriously threatening human life, and malignant tumors have become the leading cause of death in my country. Traditional cancer treatment methods mainly include surgery, radiation therapy and drug chemotherapy, among which drug chemotherapy is the most important. In recent years, with the gradual elucidation of tumor molecular targets, many targeted anti-tumor drugs have entered clinical application. However, due to the complexity and genetic diversity of tumors, a single targeted drug is not enough to cure tumors. Traditional chemotherap...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07D413/14C07D417/14C07D409/14C07D405/14A61K31/506A61P35/00
CPCC07D401/14C07D405/14C07D409/14C07D413/14C07D417/14A61P35/00A61P35/02
Inventor 刘滔李佳胡永洲高安慧董晓武周宇波宋品饶童乐仙
Owner ZHEJIANG UNIV
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