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7-substituted cyclohexyl quinazoline derivatives and preparing method and uses thereof

A technology of quinazoline and cyclohexyl, applied in the preparation of antitumor drugs, 7-substituted cyclohexylquinazoline derivatives and its preparation field, can solve the problems of cardiac toxicity and side effects, prolonged cardiac QT time, etc.

Inactive Publication Date: 2014-05-21
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] ZD6474 has a good anti-tumor effect and has been successfully marketed. However, it is found clinically that this product is prone to prolong the cardiac QT time. With the increase of the dose, the probability of occurrence of this symptom also increases, and it will recover naturally after stopping the drug.
The main reason for this side effect is that ZD6474 can significantly inhibit the activity of hEGR (the human ether-a-go-go-relatedgene) potassium ion channel, IC 50 About 0.5umol, easy to cause toxic side effects on the heart

Method used

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  • 7-substituted cyclohexyl quinazoline derivatives and preparing method and uses thereof
  • 7-substituted cyclohexyl quinazoline derivatives and preparing method and uses thereof
  • 7-substituted cyclohexyl quinazoline derivatives and preparing method and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] The preparation of embodiment 1 cyclohexenyl p-toluenesulfonate (IV)

[0050] In a 250mL three-necked flask, add 15g of 4-cyclohexenemethanol (13.4mmol), 90ml of pyridine, stir at room temperature, add 61.4g (32.2mmol) of p-toluenesulfonyl chloride, stir at room temperature for 5 hours, the reaction is complete, add 200ml In water, use concentrated hydrochloric acid to adjust the pH value to 7, wash twice with water, extract with ethyl acetate, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure until exhausted to obtain a yellow oil, which is directly carried out to the next reaction.

Embodiment 24

[0051] Example 2 Preparation of 4-(2-fluoro-4-bromophenyl)-6-methoxy-7-(3-cyclohexenyl)methoxy)quinazoline (VI-1)

[0052] Add IV (1g, 3.76mmol), 4-((4-bromo-2-fluorophenyl)amino)-6-methoxy-7-hydroxyquinazoline (1g, 2.89mmol) to a 50ml round bottom flask , anhydrous potassium carbonate (0.8g, 5.78mmol), DMF (20ml), reacted at 80°C for 2 hours, cooled to room temperature, added 25ml of water under stirring, and precipitated a large amount of green solid. After the precipitation was complete, filtered to obtain a green solid. A white solid (0.68 g, yield 52.3%) was obtained by rapid preparative liquid chromatography column separation.

[0053] 1 H NMR (400MHz, DMSO-d 6 ):δ1.39(m,1H),1.88(m,2H),2.07(m,3H),2.49(d,1H),3.94(s,3H),4.03(m,2H),5.70(d, 2H),7.19(s,1H),7.45(d,1H),7.52(t,1H),7.64(d,1H),7.78(s,1H),8.34(s,1H),9.51(s,1H ). ESI-MS: m / z 457[M+H] + .

[0054] Using the same method to prepare 4-(2-fluoro-3-chlorophenyl)-6-methoxy-7-(3-cyclohexenyl)methoxy-quinazoline (VI-2...

Embodiment 34

[0055] Example 34-(2-fluoro-4-bromophenyl)-6-methoxy-7-(3,4-dihydroxy-cyclohexyl)methoxy)quinazoline (I-1)

[0056] Take 1g (2.19mmol) of VI-1, put it into a 50ml round bottom flask, add 10ml of THF, stir at room temperature, and dissolve it; take 0.52g (3.28mmol) of KMnO 4 , 20ml of distilled water, add an appropriate amount of NaOH to make the pH of the aqueous solution 7-8, and then start to add KMnO dropwise to the round bottom flask 4 The aqueous solution was added dropwise in 20 minutes, and the color of the reaction solution gradually changed from light yellow clear to brownish yellow turbid liquid. The reaction was continued at room temperature for 2 hours, followed by TLC until the reaction of the raw materials was completed, and the insoluble brown-yellow solid MnO was filtered off. 2 , concentrated the filtrate, and the remaining mixed solution was extracted 3 times with ethyl acetate 15ml, the organic layers were combined, anhydrous MgSO 4 Dry, filter, and concen...

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Abstract

The invention belongs to the technical field of pharmaceutical chemistry, and relates to quinazoline derivatives of a formula I. R1, R2 and R3 have meanings defined in a description. The invention relates to a preparation method of the derivatives, physiologically acceptable salts formed by the derivatives and inorganic or organic acid or alkali, and pharmaceutical compositions containing the derivatives. The compounds have valuable pharmacological properties, and in particular can obviously inhibit signal transduction caused by tyrosine kinase, and have an obvious effect on preventing and treating malignant tumors. The invention further comprises the uses of preventing and treating the malignant tumors.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to 7-substituted cyclohexylquinazoline derivatives and a preparation method thereof, pharmaceutical compositions containing these derivatives and their application in preparing antitumor drugs. Background technique [0002] Tumor is a series of diseases characterized by the uncontrolled proliferation and spread of abnormal cells, which seriously threatens human life and health. According to statistics, the total number of cancer deaths in the world is about 7.9 million every year, and the number of cancer patients in my country is about 1.6 million. It has become the number one cause of death of the urban population. In recent years, with the continuous development of molecular biotechnology, medicine has confirmed that cell functional activities are regulated by complex signaling pathways, and abnormal signal transduction can easily cause tumor cell growth and proliferat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/94A61K31/517A61P35/00
CPCC07D239/94
Inventor 李祎亮石玉张士俊商倩邹美香徐为人汤立达
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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