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Triazole-ring-containing diaryl pyrimidine HIV-1 inhibitor as well as preparation method and application of triazole-ring-containing diaryl pyrimidine HIV-1 inhibitor

A technology of diarylpyrimidines and HIV-1, which is applied in the field of organic compound synthesis and pharmaceutical application, can solve the problems of drug resistance, toxic and side effects, poor pharmacokinetic properties, etc., and achieve high application value

Inactive Publication Date: 2018-09-28
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the problems of drug resistance, toxic side effects and poor pharmacokinetic properties of NNRTIs in clinical treatment limit their clinical application to a certain extent.

Method used

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  • Triazole-ring-containing diaryl pyrimidine HIV-1 inhibitor as well as preparation method and application of triazole-ring-containing diaryl pyrimidine HIV-1 inhibitor
  • Triazole-ring-containing diaryl pyrimidine HIV-1 inhibitor as well as preparation method and application of triazole-ring-containing diaryl pyrimidine HIV-1 inhibitor
  • Triazole-ring-containing diaryl pyrimidine HIV-1 inhibitor as well as preparation method and application of triazole-ring-containing diaryl pyrimidine HIV-1 inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Example 1: Preparation of 4-((2-chlorothieno[3,2-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile (6)

[0036]

[0037] Weigh 4-hydroxy-3,5-dimethylbenzonitrile (1.5g, 10mmol) and potassium carbonate (1.7g, 12mmol) in 30mL DMF, stir at room temperature for 15 minutes, and then add 2,4-dichlorothiophene And [3,2-d]pyrimidine 1 (1.9g, 10mmol) was stirred at room temperature for 2h (TLC detects the completion of the reaction). When a large amount of white solid is formed, 100 mL of ice water is slowly added to it, filtered, dried in vacuum, and recrystallized from ethanol to obtain Intermediate 6. White solid, yield 93.8%, melting point 258-260°C. ESI-MS: m / z316.3[M+1] + .C 15 H 10 ClN 3 OS(315.02).

Embodiment 2

[0038] Example 2: 3,5-Dimethyl-4-((2-(piperidin-4-ylamino)thieno[3,2-d]pyrimidin-4-yl)oxy)benzonitrile (8) Preparation

[0039]

[0040] 6 (0.95g, 3.17mmol), N-Boc-4-aminopiperidine (0.83g, 3.80mmol) and potassium carbonate (0.87g, 6.33mmol) were added to 20mL of DMF, and then heated to reflux for 10h (TLC Detection). After the reaction was cooled to room temperature, the reaction solution was slowly added dropwise to 50 mL of water, and a large amount of yellow solid was formed. After standing for 30 min, filter and vacuum dry to obtain crude product. Weigh the crude product (1.26g, 2.53mmol) and dissolve it in 4mL of dichloromethane, add 2.22mL of trifluoroacetic acid (30mmol), and stir at room temperature for 3-5h (TLC detection). Then the pH of the reaction solution was adjusted to 9 with saturated sodium bicarbonate solution, extracted with dichloromethane (3×5 mL), washed with saturated sodium chloride solution, and the organic layer was dried with anhydrous sodium sulfa...

Embodiment 3

[0041] Example 3: 3,5-Dimethyl-4-((2-((1-(prop-2-yn-1-yl)piperidin-4-yl)amino)thieno[3,2-d ]Pyrimidine-4-yl)oxy)benzonitrile (9)

[0042]

[0043] Weigh Intermediate 8 (0.5mmol, 0.19g) in 5mL DMF, then add anhydrous potassium carbonate (1.0mmol, 0.14g) and bromopropyne (0.6mmol, 0.07g) in sequence, and react at room temperature (TLC detection The reaction is complete). After the reaction was completed, 20 mL of saturated brine was added to the reaction solution, washed with ethyl acetate (3 x 15 mL), the organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated. Fast column chromatography separation, and then recrystallization from ethyl acetate-petroleum ether to obtain the target compound 9. 1 H NMR(400MHz, DMSO-d 6 )δ8.20(d,J=5.3Hz,1H,C 6 -thienopyrimidine-H),7.72(s,2H, C 3 ,C 5 -Ph-H), 7.27(s, 1H, C 7 -thienopyrimidine-H), 6.88(s,1H,NH), 3.69(s,1H), 3.22(s,2H, N-CH 2 ), 3.13 (s, 1H, CH ≡), 2.74 (s, 2H), 2.12 (s, 6H), 1.90-1.30 (m, 6H). 13 C NMR(100MHz...

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Abstract

The invention relates to a triazole-ring-containing diaryl pyrimidine HIV-1 inhibitor as well as a preparation method and application of the triazole-ring-containing diaryl pyrimidine HIV-1 inhibitor.The compound has a structure as shown in a formula I. The invention further relates to a pharmaceutical composition containing the compound with the structure as shown in the formula I. The inventionfurther provides an application of the compound and a composition containing one or more of the compound to preparation of a drug for treating and preventing a human immunodeficiency virus (HIV).

Description

Technical field [0001] The invention belongs to the technical field of organic compound synthesis and medical application, and specifically relates to a diarylpyrimidine HIV-1 inhibitor containing a triazole ring, and a preparation method and application thereof. Background technique [0002] AIDS, also known as Acquired Immunodeficiency Syndrome (AIDS), is a very harmful infectious disease caused by human immunodeficiency virus (HIV) infection. After an infected person is infected, the body's immune barrier is usually severely damaged and is prone to various opportunistic infections and tumors as well as their own chronic diseases. Therefore, AIDS has become one of the chronic diseases with a high mortality rate. [0003] HIV-1 reverse transcriptase (RT) plays a key role in the replication cycle of the virus, making it an important target for the development of anti-HIV-1 drugs. Inhibitors acting on RT are mainly divided into nucleoside reverse transcriptase inhibitors (Nucleosi...

Claims

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Application Information

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IPC IPC(8): C07D495/04A61P31/18A61K31/5377A61K31/519
CPCA61P31/18C07D495/04Y02P20/55
Inventor 刘新泳康东伟展鹏武高禅
Owner SHANDONG UNIV
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