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N-substituted benzyl tetrahydropyridine with indole and preparation method and application thereof

A technology of benzyl tetrahydropyridine linkage and indole, which is applied in the directions of organic chemistry, drug combination, anti-tumor drugs, etc.

Inactive Publication Date: 2013-08-07
SHANGHAI NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the number of new anti-cancer drugs on the market in my country and the number of candidate drugs in preclinical research is very small, especially the number of candidate drugs with my country's independent intellectual property rights is even smaller

Method used

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  • N-substituted benzyl tetrahydropyridine with indole and preparation method and application thereof
  • N-substituted benzyl tetrahydropyridine with indole and preparation method and application thereof
  • N-substituted benzyl tetrahydropyridine with indole and preparation method and application thereof

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Experimental program
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Effect test

Embodiment 1～21

[0029] 1. Examples 1-21: The preparation method of N-substituted benzyl (ethyl)tetrahydropyridin-5-substituted indole of general formula (Ia-u):

[0030] 1) At room temperature, dissolve 0.04mol of the compound of formula (1) (substituted benzylamine or substituted phenylethylamine) in 4mL of methanol solution, and add dropwise to a mixed solution of 0.16mol of methyl acrylate and 7mL of methanol under stirring. Not exceeding 50°C. After the dropwise addition is completed, heat to reflux for 6-7 hours, the reflux temperature is 60-65°C, and the reaction progress is tracked by thin-layer chromatography (TLC). After the reaction is finished, methanol and unreacted methyl acrylate are recovered and distilled under reduced pressure to obtain a light yellow oily liquid as the compound of formula (2).

[0031] 2) Dissolve 0.04mol of the compound of formula (2) in 20mL of anhydrous toluene, and then drop into 15mL of anhydrous toluene and 0.122mol of metallic sodium solution under s...

Embodiment 1

[0034] Example 1 3-(N-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (Ia)

[0035] Yield: 75%; yellow crystals; melting point: 180-182°C; 1 H NMR (400MHz, DMSO-d 6 )δ11.10(s, 1H), 7.79(d, J=8.0Hz, 1H), 7.56-6.78(m, 9H), 6.11(s, 1H), 3.67(s, 2H), 3.02(s, 2H ), 2.65 (t, J=5.5Hz, 2H), 2.49 (s, 2H); 820, 760cm -1 ;Anal.calcd.forC 20 h 20 N 2C% 83.30, H% 6.79, N% 9.71; Found: C% 82.15, H% 6.90, N% 9.80.

Embodiment 2

[0036] Example 2 3-(N-(4-chlorobenzyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (Ib)

[0037] Yield: 72%; yellow crystals; melting point: 184-186°C; 1 H NMR (400MHz, DMSO-d 6 )δ11.02(s, 1H), 7.72(d, J=8.0Hz, 1H), 7.43-6.80(m, 8H), 6.02(s, 1H), 3.49(s, 2H), 3.02(d, J =2.7Hz, 2H), 2.59(t, J=5.6Hz, 2H), 2.48(s, 2H); IR(KBr): 3072, 3059, 2920, 2852, 1657, 1604, 1575, 1510, 1322, 1287 , 1103, 935, 815, 760cm -1 ;Anal.calcd.for C 20 h 19 ClN 2 C% 74.41, H% 5.93, N% 8.68; Found: C% 74.55, H% 6.01, N% 8.50.

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Abstract

The invention discloses a N-substituted benzyl tetrahydropyridine with -5-substituted indole and preparation method and application thereof, and the structure is shown in the general formula (I): substituted benzene methylamine (ethylamine) and methyl acrylate are raw materials, and an intermediate N-substituted benzylpiperidine (phenylethylpiperidine)-4-ketone is obtained by three steps of reaction such as Michael addition, Dieckmann condensation and hydrolysis decarboxylation or the like in sequence, and the object (I) is obtained by condensation reaction of the intermediate and 5-substituted indole. The compound (I) can effectively inhibit proliferation of human leukemia K562, Jurkat, U937, THP-1 cell line, the human esophagus cancer ECA-109 cell line, human liver cancer SMMC-7721 cell line, human ovary cancer HO-8910 cell line, human breast cancer MCF-7 cell line, breast cancer MDA-MB-231 cell line; the compound has a good metabolism stability in the human and rat liver microsomes; The compound does not have mechanical inhibition effects for five enzymes of human liver microsomes such as CYP3A4, CYP 2D6, CYP2C9, CYP1A2 and CYP2C19 or the like; the compound can induce the cell cycle G2 / M retardance and promote cancer cell apoptosis and inhibit cancer cell propagation.

Description

technical field [0001] The invention relates to a class of lead compounds of anticancer drugs with high efficiency, broad anticancer spectrum and stable metabolism: N-substituted benzyltetrahydropyridine-5-substituted indole, its preparation method and application. technical background [0002] Cancer is the number one killer of human beings and one of the diseases with the highest mortality rate in the world today. According to the estimates of the World Health Organization, there are more than 3 million cancer patients in my country, and 1.6 to 2 million people are newly diagnosed every year, and the rate of increase is 3%, and the trend is younger. For example, leukemia, a blood cell cancer, is more likely to occur in adolescents, and its incidence rate ranks first among adolescent tumors, so its harm to humans is more obvious and prominent. Primary liver cancer among malignant tumors is one of the most common malignant tumors in the world. Due to the large number of pat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04A61P35/00
Inventor 孙传文郝志兵刘海燕李萍薛思佳肖笛
Owner SHANGHAI NORMAL UNIVERSITY
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