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Bisbenzylisoquinoline compound as well as preparation method and application thereof

A technology of bisbenzylisoquinoline and compound, applied in the field of medicine, can solve the problems of poor surgical prognosis, unsatisfactory effect of cholangiocarcinoma and the like

Active Publication Date: 2019-04-26
SHANDONG NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the principle of treatment for cholangiocarcinoma is still based on the comprehensive treatment plan of surgical resection, but less than 1 / 3 of the patients can be surgically resected at the time of diagnosis, and the prognosis of surgery is poor. The effect of combined chemotherapy on locally advanced or metastatic unresectable cholangiocarcinoma Not ideal, urgent need to develop new therapeutic drugs

Method used

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  • Bisbenzylisoquinoline compound as well as preparation method and application thereof
  • Bisbenzylisoquinoline compound as well as preparation method and application thereof
  • Bisbenzylisoquinoline compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0079] Weigh 6.23g of tetrandrine and 0.20g of potassium hydride, dissolve it in 200mL of methanol in a 500mL three-neck flask, add 3.00g of o-fluorobenzyl chloride, stir and heat to 65°C, and keep stirring for 8 hours. TLC detects the complete reaction of tetrandrine , cooled to room temperature, evaporated methanol, added 80 mL of water, extracted 3 times with dichloromethane (100 mL×3), traced the reaction and product separation and purification process by TLC, recovered dichloromethane from the extract, and dried the solid at 60°C for 4 hours , that is, 7.30 g of the product in the form of light yellow powder was obtained, and the yield was 80%. The melting point of the target product: 207.7-209.5°C, 13 C NMR (CDCl 3 ,100MHz)δ160.77,157.87,152.75,150.35,148.34,147.80,147.38,146.09,142.95,137.64,137.51,137.33,133.77,131.71,131.41,129.71,129.65,129.54,128.26,128.06,127.66,127.54,126.90,126.89 ,126.50,123.74,122.12,121.79,120.81,119.34,115.20,113.72,113.51,111.84,110.54,105...

Embodiment 2

[0081] Weigh 18.70g of tetrandrine and 0.20g of sodium ethoxide, dissolve it in 360mL of absolute ethanol in a 500mL three-necked flask, then add 9.00g of p-fluorobenzyl chloride, stir and heat to 78.5°C, and keep stirring for 36h. Alkali reacted completely, distilled out absolute ethanol, cooled to room temperature, added 100mL of water, extracted 3 times with chloroform (150mL×3), traced the separation and purification process of reaction and product by TLC, recovered chloroform from the extract, and the solid was in Dry at 60°C for 4 hours to obtain 16.55 g of a light yellow powder. The melting point of the target product: 208.5-209.9°C, 13 C NMR (CDCl 3 ,100MHz)δ163.55,161.11,153.75,151.39,149.43,148.78,148.52,147.13,143.95,137.41,137.29,136.98,135.12,133.61,133.54,132.65,132.55,132.43,130.09,130.01,128.65,128.43,128.26,127.96 ,127.83,127.26,127.11,122.82,121.91,120.23,116.14,114.89,114.68,112.94,111.59,106.04,73.62,64.07,61.51,56.16,55.93,55.83,55.63,45.65,44.54,44.29,4...

Embodiment 3

[0083] Weigh 6.23g of tetrandrine and 0.50g of potassium carbonate, dissolve in 100mL of propanol in a 500mL three-necked flask, then add 3.60g of 3,5-difluorobenzyl chloride, heat and stir to 98°C, and keep stirring for 24h, TLC Detect the entire reaction of tetrandrine, evaporate the solvent under reduced pressure, cool down to room temperature, add 100 mL of water, extract with acetone for 3 times (150 mL×3), trace the separation and purification process of the reaction and the product by TLC, and use anhydrous Na 2 SO 4 After drying for 8 hours, acetone was recovered, and the solid was dried at 60° C. for 4 hours to obtain 8.22 g of a light yellow powder. The melting point of the target product: 209.2-210.7°C, 13 C NMR (101MHz, CDCl 3 )δ153.87,151.33,151.20,151.04,149.53,148.84,148.74,148.57,147.19,143.91,136.45,135.43,134.98,134.85,134.77,134.56,132.76,130.24,128.86,128.73,128.55,124.02,123.40,122.91,122.00 ,120.28,117.12,116.97,116.74,116.68,116.64,116.62,116.34,113.0...

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Abstract

The invention provides a bisbenzylisoquinoline compound as well as a preparation method and application thereof. The bisbenzylisoquinoline compound has a structure shown in the formula (I), wherein R1and R2 represent same or different groups and are respectively selected from a methyl group; however, R1 and R2 do not represent the methyl group at the same time; R3 represents one or more substituent groups; the R3 group is selected from one or more of halogens, an alkyl group, an alkoxy group and a halogenated alkyl group, wherein R3 represents an F group when R3 is monosubstituted; R3 contains at least one F group or contains the F group when R3 is polysubstituted; Y represents an inorganic acid radical and an organic acid radical, and the value of n is equal to 1 or 2. The inhibition ratio of the type of compounds (concentration: 0.2mug / mL) on proliferation of bile duct carcinoma cells QBC-939 and human pancreatic cancer cells PANC-1 is generally higher than 60%, the inhibition ratioof most of the type of compounds is generally higher than 80%, and the activity of the type of compounds is much higher than that of fluorouracil for current clinical application.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a bisbenzylisoquinoline compound and a preparation method and application thereof. Background technique [0002] Bisbenzylisoquinoline compounds (Bisbenzylisoquinoline compounds) have anti-cancer, antibacterial, anti-inflammatory, antihypertensive, muscle relaxation, and immune function regulation effects, among which the more important natural bisbenzylisoquinoline compounds include Tetanus Alkali, tetrandrine, berbamine, stephenine, chrysanthemum, curine, etc., such as tetrandrine, also known as tetrandrine or tetrandrine, is mainly used clinically for rheumatic pain, arthralgia, Neuralgia, also used for silicosis. Hanjisong (dimethyl iodide tetrandrine) is a striated muscle relaxant, which can be used clinically to relax striated muscles during surgery. Experimental studies have proved that tetrandrine has certain effects on lung cancer, chronic myelogenous leukemia, liver cancer, ne...

Claims

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Application Information

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IPC IPC(8): C07D491/18A61P35/00A61K31/4748
CPCA61P35/00C07D491/18
Inventor 刘玉法高修正吕绪涛陈瑞敏庞茂启王萌萌安晓琪王坜雯
Owner SHANDONG NORMAL UNIV
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