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Thieno miazines derivatives and preparation method and application thereof

A technology of pyrimidine and derivatives, applied in the field of organic compound synthesis and medical application, can solve the problems of poor water solubility and low oral bioavailability, and achieve the effect of high application value

Inactive Publication Date: 2015-09-23
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Etravirine (Etravirine) and Rilpivirine (Rilpivirine) in this class of drugs have been listed, but the water solubility of this class of compounds is poor, and the oral bioavailability is low, so the chemical structure of this class is further modified. New anti-HIV drugs with broad-spectrum high-efficiency, good bioavailability and independent intellectual property rights are of great significance

Method used

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  • Thieno miazines derivatives and preparation method and application thereof
  • Thieno miazines derivatives and preparation method and application thereof
  • Thieno miazines derivatives and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Example 1: 4-((2-(piperidin-4-amine)thieno[3,2-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile (10) preparation

[0054]

[0055] Weigh 4-hydroxy-3,5-dimethylbenzonitrile (0.15g, 1mmol) and potassium carbonate (0.17g, 1.2mmol) in 5mL of N,N-dimethylformamide (DMF) solution, room temperature Stir for 15 minutes, then add 2,4-dichlorothieno[3,2-d]pyrimidine (0.21g, 1mmol) and continue to stir at room temperature for 2h (TLC detects that the reaction is complete). At this time, a large amount of white solid was generated, and 25mL of ice water was slowly added thereto, filtered, and dried in a vacuum oven to obtain a white solid which was the compound 4-((2-chlorothieno[3,2-d]pyrimidine- 4-yl)oxy)-3,5-dimethylbenzonitrile, yield 93.8%, melting point 258-260°C.

[0056] Weigh the compound 4-((2-chlorothieno[3,2-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile (0.32g, 1.0mmol), N-Boc- 4-Aminopiperidine (0.24g, 1.2mmol) and potassium carbonate (0.28g, 2mmol) were dissolved...

Embodiment 2

[0058] Example 2: Preparation of 2-(piperidin-4-amine)-4-(2,4,6-trimethylphenoxy)thieno[3,2-d]pyrimidine (13)

[0059]

[0060] The operation steps are the same as in Example 1, except that the starting material is 2,4,6-trimethylphenol.

[0061] The product is a white solid. Yield 87.5%, 178-180°C.

[0062] 1 H NMR (400MHz, CDCl 3 -d6,ppm)δ:7.73(d,1H,J=5.4Hz,C 6 -thienopyrimidine-H), 7.19 (d, 1H, J=5.3Hz, C 7 -thienopyrimidine-H),6.90(s,2H,C 3 ,C 5 -Ph”-H), 4.89(d, 1H, J=7.4Hz, NH), 3.77(s, 1H, NH), 3.20(d, 2H, J=12.6Hz), 2.74-2.76(m, 2H) ,2.32(s,3H,C 4 -Ph"-CH 3 ),2.04-2.09(m,9H),1.46-1.54(m,2H).ESI-MS: m / z 369.5(M+1)C 20 h 24 N 4 OS(368.17)

Embodiment 3

[0063] Embodiment 3: the preparation of compound IA-1

[0064] Weigh compound 4-((2-(piperidin-4-amine)thieno[3,2-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile (10) (0.5 mmol) in 10mL DMF, stirred and dissolved at room temperature, then added anhydrous potassium carbonate (0.14g, 1.0mmol) and substituted benzyl chloride or benzyl bromide (0.6mmol), stirred at room temperature for 12h (reaction completed by TLC). The solvent was distilled off under reduced pressure, then 30ml of ethyl acetate was added to the residual substrate, washed with saturated saline solution 3 times, 10mL each time, the organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The target compound was separated by flash column chromatography, and then recrystallized in ethyl acetate-petroleum ether system to obtain the target compound IA-1.

[0065] With different substituted benzyl and 4-((2-(piperidin-4-amine)thieno[3,2-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile...

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Abstract

The invention discloses thieno miazines derivatives and a preparation method and application thereof. The thieno miazines derivatives are compounds of which the structures are shown in the general formula I or pharmaceutically acceptable salts, esters or prodrugs of the compounds. The invention further provides the preparation method of the compounds as well as application of composition of one or more of the compounds to preparation of medicines for treating and preventing human immunodeficiency virus (HIV) infection.

Description

technical field [0001] The invention belongs to the technical field of organic compound synthesis and medical application, and specifically relates to a thienopyrimidine derivative, a preparation method thereof and an application as an HIV-1 inhibitor. Background technique [0002] AIDS (Acquired Immune Deficiency Syndrome, AIDS) has become a major infectious disease that endangers human life and health, and its main pathogen is Human Immunodeficiency Virus Type 1 (Human Immunodeficiency Virus Type 1, HIV-1). Although the implementation of Highly Active Antiretroviral Therapy (HAART) significantly prolongs the survival time of patients, the problems of drug resistance, drug side effects, and the cost of long-term medication have forced researchers to develop new types of HIV with high efficiency and low toxicity. Inhibitors. HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) are an important part of HAART therapy. This type of drug has the advantages of high eff...

Claims

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Application Information

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IPC IPC(8): C07D495/04A61K31/519A61P31/18
CPCA61K31/519C07D495/04
Inventor 刘新泳康东伟展鹏方增军李震宇
Owner SHANDONG UNIV
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