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A kind of compound and its preparation method and application

A compound and basic substance technology, applied in the field of compound and its preparation, can solve problems such as poor prognosis of surgery, late clinical symptoms, and difficulties in early diagnosis

Active Publication Date: 2021-01-08
SHANDONG NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Due to the insidious onset of cholangiocarcinoma, early diagnosis is difficult, and clinical symptoms appear late. Epidemiological studies have shown that only 10-15% of patients may be cured by surgery, and many patients are found to be in the late stage, but the postoperative recurrence rate is still high. 50-60%, five-year survival rate is only 30%
At present, the treatment principle of cholangiocarcinoma still adopts the comprehensive treatment plan based on surgical resection, but only 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
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

Method used

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  • A kind of compound and its preparation method and application
  • A kind of compound and its preparation method and application
  • A kind of compound and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050]Weigh 4.2 g of diosgenin and 0.5 g of sodium hydride, dissolve in 500 mL of 100 mL of absolute ethanol in a three-necked flask, then add 1.5 g of 2-chloropyrrole, stir and freeze to -20°C, and heat and stir to react for 72 hours. TLC : Petroleum ether-ethyl acetate (1:1), color developer: 5% phosphomolybdic acid ethanol solution) Detect all diosgenin reactions, distill the ethanol, cool to room temperature, add 50mL water, and extract 3 times with dichloromethane (60mL×3), the dichloromethane was recovered from the extract, and TLC followed the separation and purification process of the reaction and the product. The solid was dried at 60°C for 4h to obtain 3.2g of a pale yellow powder. The melting point of the target product: 192.5-194.5°C,13C NMR(CDCl3,100MHz)δ143.56,140.83,121.85,119.64,118.34,108.61,107.92,82.95,82.33,66.94,62.82,56.64,50.81,42.15,40.71,40.13,39.24,37.73,37.52,32.86,32.26,32.05,31.31, ,29.14,28.86,21.13,19.37,17.56,15.50,14.82. TOF-HRMS: M / e(479.6925), mole...

Embodiment 2

[0053]Weigh 4.2g diosgenin and 1.0g potassium hydride dissolved in 100mL methanol 500mL in a three-necked flask, then add 1.5g 2-methyl-3-chloro-pyrrole, stir and heat at 25°C, and keep stirring for 36h. TLC( Developing agent: petroleum ether-ethyl acetate (1:1), developer: 5% phosphomolybdic acid ethanol solution) to detect all the diosgenin reactions, distilling out methanol, cooling to room temperature, adding 50 mL of water, and extracting with dichloromethane Three times (60 mL×3), the extract was recovered with dichloromethane, TLC followed the separation and purification process of the reaction and the product, and the solid was dried at 60° C. for 4 hours to obtain 3.4 g of a light yellow powder. The melting point of the target product: 191.7-193.9°C,13C NMR(CDCl3,100MHz)δ140.80,129.86,121.82,119.61,118.05,108.21,107.83,82.92,82.50,66.91,62.79,56.61,50.78,42.12,40.68,40.10,39.21,37.70,37.49,32.83,32.20,32.02,31.28 ,29.11,28.83,21.10,19.34,17.53,15.47,14.79,11.95. TOF-HRMS: M...

Embodiment 3

[0056]Weigh 4.2g diosgenin and 0.8g sodium ethoxide, dissolve 100mL n-propanol in a 500mL three-necked flask, then add 1.5g 2-chloroimidazole, stir and heat at 75°C, and keep stirring for 48h, TLC (developer: petroleum Ether-ethyl acetate (1:1), developer: 5% phosphomolybdic acid ethanol solution) to detect all diosgenin reactions, distill out n-propanol, cool to room temperature, separate with silica gel chromatography, ethyl acetate -Ethanol (such as 10:1) eluent, collect the product fractions, and spin off the solvent to obtain a solid. TLC follows the reaction and the separation and purification process of the product. Drying at 60°C for 4 hours, the product is a pale yellow powder 3.5g. The melting point of the target product: 195.1-196.8°C,13C NMR(CDCl3,100MHz) δ150.11,140.81,127.84,127.81,121.83,119.62,82.93,81.28,66.92,62.80,56.62,50.79,42.13,40.69,40.11,39.22,37.71,37.50,32.84,32.21,32.03,31.29,30.33 ,28.84,21.11,19.35,17.54,15.48,14.80. TOF-HRMS: M / e(480.6806), molecular f...

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Abstract

The invention provides a compound, and a preparation method and application thereof. The compound has a structure shown in a formula (I), wherein R is an unsubstituted nitrogen-containing heterocyclicgroup or a nitrogen-containing heterocyclic group substituted by a substituent, the nitrogen-containing heterocyclic group is a five-membered or six-membered nitrogen-containing aliphatic heterocyclic ring or nitrogen-containing aromatic heterocyclic ring, and the substituent is selected from alkyl, haloalkyl, carboxyl and halogen. The invention also provides a pharmaceutically acceptable salt ofthe compound shown in the formula (I). The compound provided by the invention has better inhibition activity on proliferation of cholangiocarcinoma cells QBC-939 and human pancreatic cancer cells PANC-1. The inhibition rates of the compound at 0.2 ug / mL provided by the invention on proliferation of the cholangiocarcinoma cells QBC-939 and the human pancreatic cancer cells PANC-1 are generally 80%or higher, and activity is far higher than that of fluorouracil in clinical applications.

Description

Technical field[0001]The invention relates to the field of biomedicine, in particular to a compound and its preparation method and application.Background technique[0002]Disclosure of the background information is only intended to increase the understanding of the overall background of the present invention, and is not necessarily regarded as an acknowledgement or in any form suggesting that the information constitutes the prior art known to those of ordinary skill in the art.[0003]Cholangiocarcinoma is a common malignant tumor of the biliary tract with a high degree of malignancy and a very poor prognosis. Its morbidity and mortality are increasing year by year (Wang Xiangyu, et al. Progress in clinical treatment of hilar cholangiocarcinoma[J], China Liver Surgery Electronics Magazine, 2018, 7(4):253-257). The commonly used chemotherapeutic drugs in the clinic of cholangiocarcinoma are 5-fluorouracil and cisplatin. 5-Fluorouracil has a good effect on the growth inhibition of human c...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J71/00A61K31/58A61P35/00
CPCA61P35/00C07J71/0005
Inventor 刘玉法高修正吕绪涛高翔宇孙彬
Owner SHANDONG NORMAL UNIV