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Substituted 1,2,3 triazole diarylpyrimidine derivative as well as preparation method and application thereof

A technology of triazole diarylpyrimidine and its derivatives, which is applied in the field of medicine, can solve the problems of restricting wide application, toxic side effects, accompanying skin, etc., and achieve the effect of high application value

Active Publication Date: 2019-02-22
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As a new generation of NNRTIs, they have high inhibitory activity against a variety of drug-resistant strains, but their low water solubility and poor membrane permeability lead to low bioavailability, increased oral doses, causing toxic side effects and crossover Drug resistance and other issues
For example, etravirine requires multiple daily doses and is associated with severe allergic skin reactions
The pharmacokinetic properties of rilpivirine have improved, but there are still toxic and side effects such as depression, insomnia, acute respiratory distress syndrome, headache and rash, which limit its wide application

Method used

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  • Substituted 1,2,3 triazole diarylpyrimidine derivative as well as preparation method and application thereof
  • Substituted 1,2,3 triazole diarylpyrimidine derivative as well as preparation method and application thereof
  • Substituted 1,2,3 triazole diarylpyrimidine derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Embodiment 1: the preparation of intermediate 4-((4-chloropyrimidin-2-yl) amino) benzonitrile

[0052] Weigh 2-(methylthio)pyrimidin-4(3H)-one (3g, 21mmol) and 4-aminobenzonitrile (2.99g, 25mmol) in a 50mL round-bottom flask, nitrogen protection, and slowly heat up to 180°C, Reaction 8h. After the reaction was cooled, 20 mL of acetonitrile was added for sonication, filtered, the filter cake was washed with acetonitrile, no 4-aminobenzonitrile residue was detected by TLC, and the filter cake was dried to obtain a pale yellow solid which was 4-((4-oxo-1,6 -Dihydropyrimidin-2-yl)amino)benzonitrile, yield 73.6%, ESI-MS: m / z 213.3[M+H] + ,C 11 h 8 N 4 O(212.12).

[0053] Accurately weigh 4-((4-oxo-1,6-dihydropyrimidin-2-yl)amino)benzonitrile (0.80g, 3.8mmol), add 5mL phosphorus oxychloride, stir and reflux at 100°C for 0.5h . After the reaction was cooled, the mixture was slowly added dropwise to 50 mL of ice-water mixture, vigorously stirred, filtered, and the obtain...

Embodiment 2

[0054] Example 2: 4-((4-(4-ethynyl-2,6-dimethylphenoxy)pyrimidin-2-yl)amino)benzonitrile

[0055]

[0056] Weigh 4-iodo-2,6-dimethylphenol (0.05g, 0.21mmol), 4-((4-chloropyrimidin-2-yl)amino)benzonitrile (0.049g, 0.21mmol), potassium carbonate ( 0.035g, 0.25mmol) was dissolved in N,N-dimethylformamide, and reacted at 100°C for 10h. After the reaction was completed, 30 mL of saturated brine was added to the residual substrate, washed three times with 10 mL of ethyl acetate, and the organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. Flash column chromatography gave 4-((4-(4-iodo-2,6-dimethylphenoxy)pyrimidin-2-yl)amino)benzonitrile. Yield 83.8%.

[0057] Weigh 4-((4-(4-iodo-2,6-dimethylphenoxy)pyrimidin-2-yl)amino)benzonitrile (0.5g, 1.13mmol), trimethylsilylacetylene (0.33 g, 3.39mmol), bistriphenylphosphine palladium dichloride (0.039g, 0.056mmol), cuprous iodide (0.022g, 0.11mmol), triethylamine (0.34g, 3.39mmol) dissolved in a...

Embodiment 3

[0059] Embodiment 3: the preparation of compound IA-1-1

[0060] Weigh the important intermediate 4-((4-(4-ethynyl-2,6-dimethylphenoxy)pyrimidin-2-yl)amino)benzonitrile (0.1g, 0.29mmol), azide substituent (0.043g, 0.32mmol), copper sulfate pentahydrate (0.022g, 0.088mmol), sodium ascorbate (0.035g, 0.18mmol) were dissolved in a tetrahydrofuran / water mixed solvent, and reacted at room temperature for 4-6h. After the reaction was detected by TLC, extracted with ethyl acetate, 30 mL of ethyl acetate was added to the residual substrate, washed with saturated saline solution 3 times, 10 mL each time, the organic layer was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column. The target product IA-1-1 was obtained after recrystallization from ethyl acetate / petroleum ether.

[0061] With different azide substituents and 4-((4-(4-ethynyl-2,6-dimethylphenoxy)pyrimidin-2-yl)amino)benzonitrile (6) were prepared by the above method The target p...

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Abstract

The invention discloses a substituted 1,2,3 triazole diarylpyrimidine derivative as well as a preparation method and application thereof. The substituted 1,2,3 triazole diarylpyrimidine derivative orpharmaceutically acceptable salts or prodrugs thereof have the following structure shown as a formula I. The invention further provides a preparation method of the substituted 1,2,3 triazole diarylpyrimidine derivative and application of a composition containing one or more compounds in preparing drugs for treating and preventing human immunodeficiency virus (HIV). (The formula I is shown in the description).

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a substituted 1,2,3 triazole-type diarylpyrimidine derivative. The invention also relates to a preparation method of the derivative and its anti-human immunodeficiency virus (HIV) Application of inhibitors. Background technique [0002] AIDS (AIDS) is a disease that seriously damages the human immune system and endangers human life and health. It is caused by HIV infection. Among anti-AIDS drugs, HIV-1 non-nucleoside reverse transcriptase inhibitors (Non-nucleoside Reverse Transcriptase Inhibitors, NNRTIs) play an important role because of their high selectivity, high activity, low toxicity and other advantages. However, due to the high variability of HIV-1 virus, the frequent emergence of drug-resistant strains has become a major problem in clinical treatment. In addition, the problems of poor drug resistance, strong side effects and poor pharmacokinetics of NNRTI...

Claims

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Application Information

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IPC IPC(8): C07D403/12C07D409/14A61P31/18A61K31/506
CPCA61P31/18C07D403/12C07D409/14
Inventor 刘新泳周忠霞展鹏
Owner SHANDONG UNIV
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