Benzoazepine derivative containing five-membered heterocycle as well as preparation method and application of derivative

A technology of phenyl and compound, applied in the field of compound with anti-tumor effect and its preparation, can solve the problems of damage, mutagenesis, toxic and side effects, etc.

Active Publication Date: 2014-06-18
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Chemotherapy is faster, but the cure rate is very low
At the same time, it is clinically found that many ant

Method used

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  • Benzoazepine derivative containing five-membered heterocycle as well as preparation method and application of derivative
  • Benzoazepine derivative containing five-membered heterocycle as well as preparation method and application of derivative
  • Benzoazepine derivative containing five-membered heterocycle as well as preparation method and application of derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 2

[0047] Intermediate Ⅲ-2

[0048]

[0049] In a reaction flask equipped with stirring, condenser and thermometer, add 1.9g (0.010mol) N,N-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine -5-amine (II), 2.0g (0.020mol) potassium bicarbonate and 30ml acetonitrile, add 2.78g (0.02mol) 3-bromopropanol dropwise under stirring, reflux reaction for 12h, TLC shows that the reaction is complete, filter the insoluble matter, The filtrate was poured into distilled water, extracted with ethyl acetate (15ml×3), the organic layers were combined, dried over anhydrous sodium sulfate, the solvent was evaporated, and the residue was separated by silica gel column chromatography to obtain a yellow solid with a yield of 82.5% and a purity of 97.5%. (HPLC normalization method), ESI-MS (m / z): 248.2.

Embodiment 3

[0051] Intermediate IV-1

[0052]

[0053] In a reaction flask equipped with stirring, condenser and thermometer, add 2.34g (0.01mol) of intermediate III-1, stir 50ml of pyridine to dissolve it, control the solution below -5°C, add 2.28g (0.012mol) in batches ) p-toluenesulfonyl chloride, reacted at 0°C for 10 hours, TLC showed that the reaction was complete, poured the reaction solution into cold water, solids precipitated, filtered, washed the filter cake with saturated brine (50ml×3), dried in vacuo, and obtained a white solid , yield 93.7%, purity 97.6% (HPLC normalization method), ESI-MS (m / z): 388.2.

[0054] Reference Example 4:

[0055] Intermediate Ⅳ-2

[0056]

[0057] Add 2.48g (0.01mol) of intermediate III-2, 50ml of N,N-dimethylformamide and 2.52g (0.025mol) of triethylamine into a reaction flask equipped with stirring, condenser and thermometer, and stir until It dissolves, and the solution is controlled below -5°C. Add 2.28g (0.012mol) p-toluenesulfon...

Embodiment 1

[0059] 3-(2-(5-(Dimethylamino)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)ethylamino)-1H-pyrrole- 2-Carboxylic acid ethyl ester (compound Ⅰ-1)

[0060]

[0061] In the reaction flask equipped with stirring, condenser and thermometer, add 3.88g (0.01mol) intermediate Ⅳ-1, 0.8g (0.02mol) sodium hydroxide, 30ml ethanol and 1.54g (0.01mol) 3-amino -1H-pyrrole-2-carboxylic acid ethyl ester, reflux reaction for 6h, TLC showed that the reaction was complete, filtered off the insoluble matter, evaporated the solvent, and the residue was separated by silica gel column chromatography to obtain compound Ⅰ-1: white solid, yield 78%, purity 99.4% (HPLC normalization method), HRMS(m / z)[M+H] + : 371.2442.

[0062] Example 2:

[0063] 2-(2-(5-(Dimethylamino)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)ethylamino)-1H-pyrrole- 3-carbonitrile (compound Ⅰ-2)

[0064]

[0065] In a reaction flask equipped with stirring, condenser and thermometer, add 3.88g (0.01mol) of intermediate IV-...

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PUM

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Abstract

The invention discloses a benzoazepine compound containing five-membered heterocycle with a structure shown in a formula I as well as a pharmaceutically acceptable salt of the derivative. In the formula I, n is equal to 1, 2, 3 or 4; X is N, O or S; R1 and R2 are simultaneously or separately hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, tertiary butyl, trifluoromethyl, methylalkoxyl, ethylalkoxyl, phenyl, fluorine, chlorine or bromine substituted phenyl, alkoxylphenyl, ester group, formyl, carboxyl and cyano. The invention also discloses a preparation method of the compound and discloses a medicinal composition with the compound or the pharmaceutically acceptable salt thereof as an active ingredient and application of the compound or the pharmaceutically acceptable salt thereof as anti-tumor medicaments, particularly application in preparation of medicaments for treating breast cancer, lung cancer and gastric cancer.

Description

technical field [0001] The invention belongs to the technical field of medicine, more specifically, relates to a class of compounds with anti-tumor effect and their preparation method and application. Background technique [0002] Cancer has become a major chronic disease that seriously endangers human health. According to statistics, there are 9 million people who suffer from cancer every year in the world, and 6 million patients die from cancer. Almost one cancer patient dies every second. The annual incidence of cancer in my country is about 1.2 million, the number of cancer deaths is as high as more than 900,000, and the number of patients waiting for treatment exceeds 1.5 million, and there is an increasing trend year by year. Therefore, cancer has become the second largest killer after cardiovascular disease. Clinically, tumors are treated in three major ways: surgery, radiotherapy, and chemotherapy. Although the chemotherapy method is quicker, the cure rate is very...

Claims

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Application Information

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IPC IPC(8): C07D403/12C07D405/12C07D409/12A61K31/55A61P35/00
CPCC07D403/12C07D405/12C07D409/12
Inventor 刘登科祁浩飞刘颖穆帅田军张力婉王景阳
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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