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Crown ether cyclic quinazoline compound, preparation method therefor and application thereof in preparing tumor therapy and imaging drug

A technology of cycloquinazolines and cycloquinazolines, applied in the field of tumor treatment and imaging drugs, can solve the problems of high absorption, limited brain tumor imaging applications, false positives, etc., and achieve good anti-tumor activity, Good anticancer activity, less synthesis steps

Inactive Publication Date: 2016-03-09
BEIJING NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In terms of tumor diagnosis, [ 18 F]-FDG has high absorption in non-tumor and speech and behavior tissues, causing false positive results; high background absorption in normal brain tissue limits its application in brain tumor imaging

Method used

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  • Crown ether cyclic quinazoline compound, preparation method therefor and application thereof in preparing tumor therapy and imaging drug
  • Crown ether cyclic quinazoline compound, preparation method therefor and application thereof in preparing tumor therapy and imaging drug
  • Crown ether cyclic quinazoline compound, preparation method therefor and application thereof in preparing tumor therapy and imaging drug

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028]

[0029] The compound is N-[3-(2-fluoroethoxy)phenyl-(6,7-benzo-9-crown-3)]quinazolin-4-amine, and its synthetic route:

[0030] 1.1 Synthesis of diethylene glycol di-p-toluenesulfonate

[0031] Add 10mL (0.105mol) of diethylene glycol, 300ml of dichloromethane, 40g (0.21mol) of p-toluenesulfonyl chloride into a 500ml round-bottomed flask, and slowly add 47g (0.84mol) of hydroxide Potassium, the reaction is basically completed in 1.5h. The reaction solution was washed three times with water (3×100ml), and the organic layer was collected and dried over anhydrous sodium sulfate. Filtration and spin-drying of the solvent gave the crude product ethanol recrystallization to obtain 40 g of a white solid with a yield of 95%. The obtained spectrum is consistent with that reported in the literature.

[0032]

[0033] 1.23, Synthesis of ethyl 4-(benzo-9-crown-3)benzoate:

[0034] In a 250ml round bottom flask, add 6.68g (48.31mmol) of potassium carbonate, 50ml of DMF, h...

Embodiment 2

[0055]

[0056] The compound is N-[3-(2-fluoroethoxy)phenyl-(6,7-benzo-12-crown-4)]quinazolin-4-amine, its synthetic route:

[0057] 2.1 Synthesis of triethylene glycol di-p-toluenesulfonate

[0058] Add 10mL (0.075mol) of triethylene glycol, 300ml of dichloromethane, 28.6g (0.15mol) of p-toluenesulfonyl chloride into a 500ml round bottom flask, and slowly add 33.6g (0.6mol) of Potassium hydroxide, the reaction was basically completed in 8 hours. The reaction solution was washed three times with water (3×100ml), and the organic layer was collected and dried over anhydrous sodium sulfate. Filtration and spin-drying of the solvent gave the crude product methanol recrystallization to obtain 30 g of a white solid with a yield of 90%. The obtained spectrum is consistent with that reported in the literature.

[0059]

[0060] 2.23, Synthesis of ethyl 4-(benzo-12-crown-4)benzoate:

[0061] In a 250ml round bottom flask, add 10.02g (72.5mmol) of potassium carbonate and 50ml ...

Embodiment 3

[0082]

[0083] The compound is N-[3-(2-fluoroethoxy)phenyl-(6,7-benzo-15-crown-5)]quinazolin-4-amine, its synthetic route:

[0084] 3.1 Synthesis of tetraethylene glycol di-p-toluenesulfonate

[0085] Put 10mL (0.068mol) of tetraethylene glycol, 300ml of dichloromethane, 25.8g (0.136mol) of p-toluenesulfonyl chloride into a 500ml round bottom flask, and slowly add 30.4g (0.544mol) ) Potassium hydroxide, the reaction is basically completed in 1.5h. The reaction solution was washed three times with water (3×100ml), and the organic layer was collected and dried over anhydrous sodium sulfate. Filter and spin dry the solvent to obtain the crude product as an oil. Column chromatography (petroleum ether: ethyl acetate = 1:4) gave 34 g of light yellow oily liquid. The yield was 98%. The obtained spectrum is consistent with that reported in the literature.

[0086]

[0087] 3.23, Synthesis of ethyl 4-(benzo-15-crown-5)benzoate:

[0088] In a 250ml round bottom flask, add 1...

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Abstract

The invention relates to a crown ether cyclic quinazoline derivative and medicinal salts thereof using in tumor therapy and imaging. The crown ether cyclic quinazoline compound is characterized in that a 2-, 3-, 4- substituted aniline is disposed at one end; a 6-, 7- substituted crown ether cyclic quinazoline structure is disposed at the other end; the substituent group R1 is located on the fourth-position aniline of a quinazoline mother ring and is 2-, 3-, 4- substituted alkoxy; and the crown ether cycle is located at the 6, 7 position of the mother ring, and is a 9-crown-3, 12-crown-4 and 15-crown-5, and the structural formula is formula I. The experimental result of antitumor activity in vitro of nonradioactive isotope labeling compounds shows that the compounds are good in inhibitory effect for four kind of cancer cells namely HepG2, A549, sy5y and DU145, and have the potential as cancer treatment medicine; and the body distribution experiment of 18F or 125I labeling compounds show that the compounds are higher in ingestion and certain detention in tumors and faster in blood clearance and have potential applied to tumor imaging.

Description

Technical field: [0001] The invention relates to a new class of crown ether cyclic quinazoline compounds, a preparation method thereof, and an application as a tumor treatment and imaging drug. Background technique: [0002] According to the data released by our country's health department, the death rate of malignant tumors in my country's urban and rural areas has surpassed that of cardiovascular and cerebrovascular diseases, becoming the number one cause of death among Chinese residents, and cancer is also one of the main causes of death in the world. Early diagnosis, early detection, and early treatment are the three principles of cancer prevention and treatment. [0003] PET (Positron Emission Tomography) imaging is currently the highest level of nuclear medicine, and can reflect whether there are pathophysiological changes in the human body at the molecular level. PET can be used for the diagnosis of malignant tumors, the identification of benign and malignant tumors,...

Claims

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Application Information

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IPC IPC(8): C07D491/056A61P35/00A61K51/04A61K101/02
CPCC07D491/056A61K51/0459
Inventor 齐传民任红玉宁红玉常进赵明霞崇岩贺勇
Owner BEIJING NORMAL UNIVERSITY
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