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Oxime group-containing diarylpyrimidine HIV-1 reverse transcriptase inhibitor, and preparation method and application thereof

A technology of reverse transcriptase inhibition and arylpyrimidines, which is applied in the field of medicine, can solve the problems of restricting wide application, cross-drug resistance, low water solubility, etc., and achieve the effect of high application value

Active Publication Date: 2020-09-18
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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  • Oxime group-containing diarylpyrimidine HIV-1 reverse transcriptase inhibitor, and preparation method and application thereof
  • Oxime group-containing diarylpyrimidine HIV-1 reverse transcriptase inhibitor, and preparation method and application thereof
  • Oxime group-containing diarylpyrimidine HIV-1 reverse transcriptase inhibitor, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Example 1: N-(2-(2-(aminooxy)acetamido)ethyl)-4-(4-cyano-2,6-dimethylphenoxy)-2-((4- Preparation of cyanophenyl)amino)pyrimidine-5-carboxamide (A1).

[0041]

[0042] Dissolve ethyl 2,4-dichloro-5-pyrimidinecarboxylate (0.25g, 1.13mmol) and 4-hydroxy-3,5-dimethylbenzonitrile (0.20g, 1.36mmol) in 30mL DMF, add K 2 CO 3 (0.19g, 1.36mmol), stirred at room temperature for 6h, and detected the reaction by TLC. After the reaction, extract with dichloromethane (10mL×3), combine the organic layers, wash with saturated brine (30mL) once, anhydrous Na 2 SO 4 Dry for 5 hours, filter, mix the sample, separate by column, and recrystallize from ethyl acetate / petroleum ether to obtain white solid I-2.

[0043] Palladium acetate (0.028g, 0.125mmol) and 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (0.073g, 0.13mmol) were dissolved in dioxane (15mL), stirred at room temperature After activation for 15 min, I-2 (1.0 g, 3.0 mmol) and cesium carbonate (1.2 g, 3.68 mmol) were added ...

Embodiment 2

[0054] Embodiment 2: the preparation of target compound

[0055] Dissolve dominant hydroxylamine fragment A1 (0.1g, 0.20mmol), pyridine-2-carbaldehyde (22.8μL, 0.24mmol) in ethanol (10mL), add AcOH (13.7μL, 0.24mmol), reflux at 60°C for 4h, and detect by TLC reaction. After the reaction was complete, the sample was mixed directly, and the head compound A1Q4 was obtained by silica gel column separation.

[0056]

[0057] The product is a white solid, yield: 72%, melting point: 235-237°C.

[0058] 1 H NMR (400MHz, DMSO-d 6 ):δ10.54(s,1H),8.92(s,1H),8.60(d,J=2.8Hz,1H,C 6 -pyrimidine-H),8.30(s,1H),8.24(s,1H),8.08(s,1H),7.80(s,3H),7.72(d,J=7.6Hz,0H),7.47–7.41( m,5H),4.56(s,2H),3.46–3.45(m,2H),3.41–3.34(m,2H),2.14(s,6H,2CH 3 ). 13 C NMR (100MHz, DMSO-d 6):δ169.27,165.22,162.88,162.44,159.81,153.80,151.48,150.92,150.16,144.13,137.38,133.33,133.05,125.18,121.11,119.64,119.06,119.02,109.24,106.06,104.01,73.48,38.83,16.30. HRMS m / z C 31 h 27 N 9 o 4 :calcd 589.22,found 5...

Embodiment 3

[0067] Embodiment 3: In vitro anti-HIV activity test experiment of the target compound

[0068] Test principle:

[0069] The anti-HIV activity of compounds was screened in vitro by MTT method. The full name of MTT is bromide-3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium nitrogen (trade name: thiazolium blue), which can be used to detect the survival and growth of cells. The detection principle is:

[0070] MTT can be combined with succinate dehydrogenase in living cells to be reduced to water-insoluble blue-purple crystalline formazan and deposited in cells, while dead cells do not have this function. Dimethyl sulfoxide can dissolve formazan in cells, and its absorbance (A) value at 590 nm can indirectly reflect the number of living cells by using a microplate reader. Within a certain cell number range, the amount of MTT crystal formation is proportional to the cell number.

[0071] Because the MT-4 cell that HIV infects can take place lesion within a certain period...

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Abstract

The invention discloses an oxime group-containing diarylpyrimidine HIV-1 reverse transcriptase inhibitor, and a preparation method and application thereof. The oxime group-containing diaryl pyrimidineHIV-1 reverse transcriptase inhibitor or pharmaceutically acceptable salt or prodrug thereof has a structure represented by general formula I. The invention also discloses the preparation method of the oxime group-containing diarylpyrimidine HIV-1 reverse transcriptase inhibitor and application of a composition containing one or more compounds in preparation of medicines for treating and preventing human immunodeficiency virus (HIV). The structure of the diarylpyrimidine HIV-1 reverse transcriptase inhibitor is represented by general formula I in the specification.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a diarylpyrimidine HIV-1 reverse transcriptase inhibitor containing an oxime group. The invention also relates to a preparation method of this type of inhibitor and its anti-human immunodeficiency virus ( HIV) inhibitor application. 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...

Claims

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Application Information

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IPC IPC(8): C07D401/12A61K31/506A61P31/18
CPCA61P31/18C07D401/12
Inventor 展鹏左晓芳刘新泳康东伟荆兰兰
Owner SHANDONG UNIV
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