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Bisbenzylisoquinoline quaternary ammonium salt as well as preparation method and application thereof in preparing antitumor drug

A technology of bisbenzylisoquinoline and quaternary ammonium salts, which is applied in the direction of antineoplastic drugs, drug combinations, and pharmaceutical formulations, and can solve problems such as lack of access

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

These compounds are mainly alkaloid derivatives, and have not achieved ideal effects in anti-cancer, especially liver cancer and pancreatic cancer.

Method used

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  • Bisbenzylisoquinoline quaternary ammonium salt as well as preparation method and application thereof in preparing antitumor drug
  • Bisbenzylisoquinoline quaternary ammonium salt as well as preparation method and application thereof in preparing antitumor drug
  • Bisbenzylisoquinoline quaternary ammonium salt as well as preparation method and application thereof in preparing antitumor drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Weigh 6.10g of 7-hydroxybisbenzylisoquinoline (general formula ⅡX=OH), 3mL of methyl 2-chloroacetate and 1.50g of potassium carbonate, dissolve them in 200mL of ethanol, add them to a 500mL three-necked flask, heat and stir until boiling, And insulated and stirred for 24 hours, evaporated ethanol under reduced pressure, cooled to room temperature, added 50mL of water, neutralized to neutral with 10% hydrochloric acid, extracted 3 times with chloroform (50mL×3), traced the separation and purification process of reaction and product by TLC, extracted Anhydrous Na for liquid 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 5.87 g of a light yellow powder. The melting point of the target product: 147-148°C, 13 C NMR (75MHz, DMSO-d 6 ): δ21.61(C-4), 23.12(C-4’), 35.63(C-15), 41.67(C-15’), 49.72(-COO * CH 3 ), 53.48 (NCH 3 ), 54.12 (N'CH 3 ), 56.16(C-3), 56.24(C-3'), 59.70(6-OCH 3 ), 59.74 (6'-OCH ...

Embodiment 2

[0036] Weigh 6.10 g of 7-hydroxybisbenzylisoquinoline (general formula IIX=OH), 5 mL of methyl 2-chloropropionate and 1.50 g of sodium carbonate, dissolve them in 200 mL of propanol, add them to a 500 mL three-necked flask, heat and stir until Boil, keep warm and stir for 12 hours, evaporate the solvent under reduced pressure, cool down to room temperature, add 50mL of water, neutralize to neutral with 10% hydrochloric acid, and extract 3 times with acetone (60mL×3), trace the separation and purification process of reaction and 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 5.65 g of a light yellow powder. The melting point of the target product: 145-146°C, 13 CNMR experiment, time-of-flight mass spectrometry: M / e (348.1077), molecular formula C 41 h 48 o 8 N 2 Cl 2 , namely compound 7 in Table 1.

Embodiment 3

[0038] Weigh 6.10g of 7-hydroxybisbenzylisoquinoline (general formula ⅡX=OH), 10.00g of methyl 2-iodooctadecanoate, measure 200mL of ethyl acetate and 10mL of triethylamine, and add them to a 500mL three-necked flask. Stir, keep the reaction at -20°C for 72 hours, neutralize with dilute hydroiodic acid until neutral, separate the liquids, evaporate the ethyl acetate phase under reduced pressure until the liquid volume is reduced to 1 / 4, cool to 5°C to crystallize overnight, and filter , TLC traced the separation and purification process of the reaction and the product, and the solid was dried at 60° C. for 4 hours to obtain 1.52 g of a pale yellow powder. The melting point of the target product: 77-78°C, 13 CNMR experiment, time-of-flight mass spectrometry: M / e (453.2880), molecular formula C 56 h 78 o 8 N 2 I 2 , namely compound 16 in Table 1.

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Abstract

The invention relates to bisbenzylisoquinoline quaternary ammonium salt as well as a preparation method and an application thereof in preparing an antitumor drug. A structure of the bisbenzylisoquinoline quaternary ammonium salt is shown in a general formula (I) described in the specification and a substituent group is shown in the specification. The bisbenzylisoquinoline quaternary ammonium salt disclosed by the invention is applied to preparation of an antitumor drug. The compound disclosed by the invention, which has a bisbenzylisoquinoline parent nucleus structure and has the characteristics of ester quaternary ammonium salt, has achieved a pancreatic cancer cell SW1990 proliferation inhibiting rate above 50% and a hepatoma cell line HepG2 inhibiting rate above 50% as well when the compound is 0.5ug / ml, and activity of the compound is much higher than that of an existing tetrandrine compound.

Description

technical field [0001] The invention relates to a novel anti-tumor bisbenzylisoquinoline quaternary ammonium salt, a preparation method thereof and an application in medicine, belonging to the technical field of medicine synthesis. Background technique [0002] Pancreatic cancer is a common pancreatic tumor. It is a highly malignant tumor of the digestive tract that is difficult to diagnose and treat. The 5-year survival rate is <1%. Pancreatic cancer is one of the malignant tumors with the worst prognosis due to its low diagnosis rate and high surgical mortality rate. At present, the main therapeutic drugs are fluorouracil, doxorubicin, ifosfamide, semustine, paclitaxel, gemcitabine, cisplatin, etc., but the clinical cure rate is very low. Cancer drugs are very necessary. [0003] Liver cancer is one of the common malignant tumors in my country. It has a high incidence in adults, and most of them are late when discovered, with a high mortality rate. It is commonly know...

Claims

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Application Information

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IPC IPC(8): C07D491/18A61K31/4748A61P35/00
CPCC07D491/18
Inventor 刘玉法吴国梁顾巧莲张萌王锐
Owner SHANDONG NORMAL UNIV
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