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Diarylpyrimidines HIV-1 reverse transcriptase inhibitor as well as preparation method and application thereof

A technology of reverse transcriptase inhibition and diarylpyrimidines, which is applied in the field of organic compound synthesis and pharmaceutical applications, can solve the problems of restricting wide application, poor water solubility, cross-drug resistance, etc., and achieve high application value

Active Publication Date: 2018-03-09
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the disadvantages of poor water solubility and poor membrane permeability caused by its own rigid structure, its bioavailability is low, and the oral dose is increased, which in turn causes problems such as toxic side effects and cross-drug resistance.
For example, etravirine requires multiple daily doses and can cause severe allergic skin reactions
Rilpivirine can easily cause side effects such as depression, insomnia, acute respiratory distress syndrome, headache, and rash, and a mutant strain resistant to the second-generation NNRTIs has been found clinically, which limits their wide application

Method used

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  • Diarylpyrimidines HIV-1 reverse transcriptase inhibitor as well as preparation method and application thereof
  • Diarylpyrimidines HIV-1 reverse transcriptase inhibitor as well as preparation method and application thereof
  • Diarylpyrimidines HIV-1 reverse transcriptase inhibitor as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Example 1: 2-((4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)pyrimidin-5-yl)mercapto)acetic acid Preparation of methyl ester (PP-3)

[0040]

[0041]Weigh 2,4-dichloropyrimidine (1g, 6.7mmol) and 4-hydroxy-3,5-dimethylbenzonitrile (1.18g, 8mmol) and dissolve in 20mL N,N-dimethylformamide, add K 2 CO 3 (8mmol, 1.10g), stirred overnight at room temperature, filtered and concentrated, dissolved in ethyl acetate, washed 3 times with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried in a vacuum oven to obtain a white solid which is compound 6 , yield 86%, melting point: 195-197°C.

[0042] Weigh palladium acetate (0.112g, 0.5mmol) and 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (0.289g, 0.5mmol) and dissolve in 15mL of 1,4-dioxane , and stirred at room temperature for 15 min. Then compound 6 (3.12 g, 0.012 mol) and cesium carbonate (4.89 g, 0.015 mol) were added and stirred for another 15 min. Finally, the raw m...

Embodiment 2

[0047] Example 2: 3-((4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)pyrimidin-5-yl)mercapto)propane Preparation of acid methyl ester (PP-4)

[0048]

[0049] Weigh PP-2 (1.00g, 4.55mmol), methyl mercaptopropionate (0.547g, 4.55mmol), tris(dibenzylideneacetone) dipalladium (208mg, 0.227mmol), bis(2-diphenyl Phosphino)ether (245mg, 0.455mmol) and potassium tert-butoxide (561mg, 5.00mmol) were dissolved in toluene (20mL), heated to 100°C under nitrogen protection and stirred for 3h. After cooling the reaction mixture to room temperature, the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. Dichloromethane (80mL) was dissolved, washed with water (20mL×3), washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered and separated by silica gel column chromatography to obtain the target compound 3-((4-(4-cyano- 2,6-Dimethylphenoxy)-2-((4-cyanophenyl)amino)pyrimidin-5-yl)mercapto)propanoic acid methyl e...

Embodiment 3

[0052] Example 3: 2-((4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)pyrimidin-5-yl)sulfonyl) Preparation of methyl acetate (PP-3-5)

[0053]

[0054] Weigh 2-((4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)pyrimidin-5-yl)thio)acetic acid methyl The ester (100 mg, 0.22 mmol) was dissolved in dichloromethane (10 mL), m-chloroperoxybenzoic acid (132.5 mg, 0.77 mmol) was added and stirred overnight at room temperature. The reaction solution was extracted with dichloromethane (50 mL), washed with saturated sodium bisulfite (30 mL), water (2×20 mL), brine (20 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness, then recrystallized with ethyl acetate / petroleum ether to obtain the target product 2-((4-(4-cyano-2,6-dimethylphenoxy )-methyl 2-((4-cyanophenyl)amino)pyrimidin-5-yl)sulfonyl)acetate.

[0055] The product is a white solid, yield: 62%, melting point 240-241°C.

[0056] 1 H NMR(400MHz,DMSO-d6):δ11.02(s,1H,NH),8.7...

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Abstract

The invention relates to a diarylpyrimidines HIV-1 reverse transcriptase inhibitor as well as a preparation method and application thereof. The diarylpyrimidines HIV-1 reverse transcriptase inhibitorhas a structure shown as a formula I. The invention further relates to a pharmaceutical composition containing the compound with the structure formula I. The invention further provides application ofthe compound and the composition containing one or more compounds to preparation of medicines for treating and preventing human immunodeficiency virus (HIV).

Description

technical field [0001] The invention belongs to the technical field of organic compound synthesis and medical application, and in particular relates to a diarylpyrimidine HIV-1 reverse transcriptase inhibitor and its preparation method and application. Background technique [0002] AIDS (Acquired Immune Deficiency Syndrome, AIDS) is a major infectious disease mainly caused by Human Immunodeficiency Virus Type 1 (Human Immunodeficiency Virus Type 1, HIV-1), which endangers human life and health. Although the implementation of highly active antiretroviral therapy (Highly Active Antiretroviral Therapy, HAART) has significantly prolonged the survival time of patients and improved the quality of life of patients, problems such as drug resistance, drug side effects, and high costs of long-term medication have greatly This reduces the efficacy of the therapy and limits the application of the therapy, which in turn forces researchers to develop new anti-AIDS drugs that are more effi...

Claims

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Application Information

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IPC IPC(8): C07D239/56C07D401/12C07D405/12C07D403/12A61K31/505A61K31/5377A61K31/506A61K31/541A61P31/18
Inventor 刘新泳霍志鹏展鹏康东伟
Owner SHANDONG UNIV
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