Bisbenzylisoquinoline glycine betaines as well as preparation method and application thereof in preparing anti-tumor medicines

A technology of bisbenzylisoquinoline and betaine, which is applied in the directions of antitumor drugs, drug combinations, and pharmaceutical formulations, can solve problems such as unsatisfactory curative effects, and achieve the effects of strong inhibitory activity, reduced toxicity, and improved affinity.

Active Publication Date: 2014-07-09
SHANDONG NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Nevertheless, most of the drugs currently used clinically in my country for the treatment of liver cancer are unsatisfactory in efficacy. Therefore, it is very necessary to research and develop new anti-hepatic tumor drugs with better efficacy.

Method used

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  • Bisbenzylisoquinoline glycine betaines as well as preparation method and application thereof in preparing anti-tumor medicines
  • Bisbenzylisoquinoline glycine betaines as well as preparation method and application thereof in preparing anti-tumor medicines
  • Bisbenzylisoquinoline glycine betaines as well as preparation method and application thereof in preparing anti-tumor medicines

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Weigh 5.92g of bisbenzylisoquinoline (general formula ⅡX=H), 2.50g of sodium 2-chloroacetate and 0.20g of sodium hydroxide, add them into a 500mL three-neck flask, dissolve in 200mL of ethanol, stir and heat to reflux, and keep warm for reaction 8h, distill off the solvent under reduced pressure, cool down to room temperature, neutralize to neutral with 10% HCl, add 50mL of water and extract 3 times with chloroform (60mL×3), track the separation and purification process of reaction and product by TLC, extract with anhydrous Na 2 SO 4 After drying for 8 hours, the chloroform was recovered, and the solid was dried at 60° C. for 4 hours to obtain 3.35 g of a yellow powder product. The melting point of the target product: 156-157°C, time-of-flight mass spectrum: M / e (326.1576), and the molecular formula is C 39 h 43 o 7 N 2 Cl, 13 CNMR showed a carbonyl peak at δ=167.01, X-ray diffraction single crystal structure, namely compound 1 in Table 1.

Embodiment 2

[0033] Weigh 6.60g of 7-hydroxybisbenzylisoquinoline (general formula ⅡX=OH), 10.00g of 2-bromoacetate sodium and 0.20g of potassium hydroxide, dissolve it in 150mL of n-butanol, add it to a 500mL three-necked flask, stir and heat Bring to a boil, keep stirring and react for 4 hours, distill off the solvent under reduced pressure, cool down to room temperature, neutralize to neutral with 5% HBr, add 50 mL of water and extract with acetone for 3 times (60 mL×3), track the separation and purification process of the reaction and the product by TLC , the extract was 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 4.25 g of a yellow powder product. The melting point of the target product: 151-152°C, time-of-flight mass spectrum: M / e (334.1550), and the molecular formula is C 39 h 43 o 8 N 2 Br, 13 C NMR (75MHz, DMSO-d6): δ21.61(C-4), 23.12(C-4'), 35.63(C-15), 41.67(C-15'), 3.48(NCH 3 ), 54.12 (N'CH ...

Embodiment 3

[0035] Weigh 6.26g of 7-chlorobisbenzylisoquinoline (general formula ⅡX=Cl), 3.00g of sodium 2-chloroacetate, 2.10g of anhydrous sodium carbonate, dissolve in 100mL of water, add to a 500mL three-neck flask, stir and freeze until 10°C, keep warm and stir for 24h, warm up to room temperature, neutralize with 10% HCl to neutral, distill water under reduced pressure until the liquid volume is reduced to half, crystallize at room temperature overnight, filter, and dry the obtained solid at 60°C After 4 hours, 2.12 g of a yellow powdery product was obtained. The melting point of the target product: 162-163°C, time-of-flight mass spectrum: M / e (343.1381), and the molecular formula is C 39 h 42 o 7 N 2 Cl 2 , 13 CNMR showed a carbonyl peak at δ=167.71, X-ray diffraction single crystal structure, namely compound 3 in Table 1.

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Abstract

The invention relates to bisbenzylisoquinoline glycine betaines as well as a preparation method thereof and an application in preparing anti-tumor medicines. The structural formula of the bisbenzylisoquinoline glycine betaines is as shown in a general formula (I); substituent groups in the formula are as shown in the specification; the bisbenzylisoquinoline glycine betaines are obtained by reacting bisbenzylisoquinoline or substitutes with a halogenated fatty acid salt in a solvent at a temperature ranging from minus 20 to 300 DEG C. The chemical structural of the bisbenzylisoquinoline glycine betaines enables the affinity to a receptor to be enhanced, and the bisbenzylisoquinoline glycine betaines have relatively high inhibition activity on the proliferation of the human hepatocarcinoma cell line HepG2 and the human colon cancer cells HT29. The anti-liver cancer activity of the bisbenzylisoquinoline glycine betaines is more than 20 times higher than that of the existing tetrandrine compounds, and therefore, the clinical dosage of the medicines can be reduced so that the toxic and side effects of the medicines can be reduced. The general formula is as shown in the specification. The general formula (I) is as shown in the specification.

Description

technical field [0001] The invention relates to a bisbenzylisoquinoline betaine, a preparation method thereof and an application in medicine, belonging to the technical field of medicine synthesis. Background technique [0002] BisBenzylisoquinoline compounds (bisBenzylisoquinoline compounds) have anti-cancer, antibacterial, anti-inflammatory, antihypertensive, muscle relaxation, and immune function regulation functions. Among them, the more important natural bisBenzylisoquinoline compounds include Fangji Tetrandrine, tetrandrine, berbamine, stephenine, chrysanthemum, curine, etc., such as Tetrandrine, also known as tetrandrine or tetrandrine, belongs to bisbenzyl isoquinone Phenyl compounds are mainly used clinically for rheumatic pain, arthralgia, neuralgia, and also for silicosis. Hanjisong (dimethyl iodide tetrandrine, the quaternary ammonium salt of tetrandrine) is a striated muscle relaxant, which can be used clinically to relax striated muscles during surgery. Exper...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/18A61K31/4748A61P35/00
CPCC07D491/18
Inventor 刘玉法赵树香张萌刘志先陈玉琴
Owner SHANDONG NORMAL UNIV
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