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Aminomethyl substituted silybin derivative and preparation method and application thereof

A technology of silibinin and dehydrosilibinin, which is applied in the field of compounds, can solve the problems of not synthesizing aminomethylated derivatives, etc., and achieve the effects of improving bioavailability, protecting liver damage, and improving water solubility

Active Publication Date: 2019-10-11
TIANJIN TASLY PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in the research process of silibinin, there is no report on the synthesis of aminomethylated derivatives, whether silybin compounds are suitable for the synthesis of aminomethylated derivatives, and whether the synthesized aminomethylated derivatives can be Improved properties of silybin-like compounds, none of which are known

Method used

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  • Aminomethyl substituted silybin derivative and preparation method and application thereof
  • Aminomethyl substituted silybin derivative and preparation method and application thereof
  • Aminomethyl substituted silybin derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Embodiment 1: Preparation of 8-(N-methylenepiperidinyl) silibinin (I-1) and its hydrochloride

[0060]

[0061] Ⅰ-1 hydrochloride

[0062]

[0063] Put silibinin (5.0 g, 10.4 mmol), 37% aqueous formaldehyde (0.48 g, 5.2 mmol), and piperidine (0.44 g, 5.2 mmol) in 50 mL of methanol and stir at room temperature. TLC (dichloromethane:methanol=10:1) tracked the reaction, and the reaction was complete within 24 hours, and the reaction was terminated. Spin-dry under reduced pressure to obtain 5.7 g of crude product, add 100 ml of ethyl acetate to make slurry for 2 h, filter under reduced pressure, and separate by silica gel column chromatography (CH2Cl2-CH3OH=10:1-8:1) to obtain 0.9 g of (I-1) (yield rate 30%). The prepared (I-1) was dissolved in methanol-hydrochloric acid solution (100ml), stirred for 0.5h, concentrated and dried to obtain 0.95g of (I-1) hydrochloride. 1 H NMR (400MHz, DMSO-d 6 )δ: 7.02~6.82(6H,m), 5.62(1H,s), 4.99~4.94(1H,m), 4.93~4.90(1H,m), 4.56...

Embodiment 2

[0064] Embodiment 2: Preparation of 6,8-bis(N-methylenepiperidinyl) silibinin (I-2) and its hydrochloride

[0065]

[0066] I-2 hydrochloride

[0067]

[0068] Silibinin (5.0g, 10.4mmol), 37% formaldehyde aqueous solution (3.38g, 41.7mmol), piperidine (3.55g, 41.7mmol) were placed in 25mL methanol, stirred at room temperature, TLC (dichloromethane: methanol =10:1) Follow up the reaction, complete the reaction within 24 hours, and terminate the reaction. Spin-dried under reduced pressure to obtain 6.5 g of the crude product, which was slurried with 100 ml of ethanol for 2 hours, then filtered under reduced pressure, and the solid was dried to obtain 3.7 g of (I-2) (yield 52.9%). The prepared (I-2) was dissolved in methanol-hydrochloric acid solution (100ml), stirred for 0.5h, concentrated and dried to obtain 3.9g of (I-2) hydrochloride. 1H NMR(400MHz,DMSO-d6)δ7.12-6.80(6H,m), 4.99-4.94(1H,m), 4.93-4.90(1H,m), 4.66-4.46(1H,m), 4.18-4.15 (1H,m), 3.78(3H,s), 3.60(4H,m), 3...

Embodiment 3

[0069] Embodiment 3: Preparation of 8-(N-methylenediethylamino) silibinin (I-3) and its hydrochloride

[0070]

[0071] I-3 hydrochloride

[0072]

[0073] Put silibinin (10.0 g, 20.8 mmol), 37% formaldehyde aqueous solution (1.0 g, 10.4 mmol), diethylamine (0.76 g, 10.4 mmol) in 80 mL of methanol, and stir at room temperature. TLC (dichloromethane:methanol=10:1) tracked the reaction, and the reaction was complete within 24 hours, and the reaction was terminated. The crude product was spin-dried under reduced pressure to obtain 10.3 g, which was slurried by adding 100 mL of ethyl acetate for 2 h, filtered under reduced pressure, and separated by silica gel column chromatography (CH2Cl2-CH3OH=10:1-8:1) to obtain 2.1 g of (I-3) (yield rate 19%). The prepared (I-3) was dissolved in methanol-hydrochloric acid solution (100 mL), stirred for 0.5 h, concentrated and dried to obtain 2.12 g of (I-3) hydrochloride. 1 H NMR (400MHz, DMSO-d 6 )δ: 7.07~6.82(6H,m), 5.54(1H,s), 4.9...

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Abstract

The invention relates to an aminomethyl substituted silybin derivative as shown in formula (I) and pharmaceutical salt or solvate thereof. The invention further relates to a preparation method and medical application of the compound as shown in formula (I) and a pharmaceutical composition of the compound. The compound has effects of treating liver injury, resisting oxidation and regulating dyslipidemia and can be used as medicine for treating diseases such as liver injury, non-alcoholic fatty liver disease, hepatitis B, hepatitis C, hepatic fibrosis and liver cancer.

Description

technical field [0001] The invention relates to the field of compounds, in particular to an aminomethyl-substituted silibinin derivative and its preparation method and application. Background technique [0002] Silymarin is extracted from the seeds and fruits of the Compositae plant Silybum marianum (L.) Gaertn. Standardized extract composed of flavonoid lignan isomers. The content of silybin (Silybin) is about 50%-70%, which belongs to flavonoid lignin compounds. [0003] Silibinin has been used in the treatment of liver diseases for two thousand years. It is a natural hepatoprotective drug. Its mechanism of action is mainly anti-oxidation, anti-lipid peroxidation, scavenging free radicals and stabilizing cell membranes. The silibinin preparations currently used clinically include Shuilinjia (silybin capsules, Tasly Pharmaceutical Group Co., Ltd.), Yiganling (silybin meglumine tablets, Fosun Zhaohui Pharmaceutical Co., Ltd.) , celipide (silymarin and lecithin complex cap...

Claims

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Application Information

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IPC IPC(8): C07D407/04C07D405/14A61P1/16A61P39/06A61P3/06A61P35/00A61K31/357A61K31/496A61K31/4545A61K31/453A61K31/4025
CPCC07D407/04C07D405/14A61P1/16A61P39/06A61P3/06A61P35/00C07B2200/07
Inventor 韩民何毅王保军曹晶靳元鹏王根辈王媛媛马晓慧周水平
Owner TIANJIN TASLY PHARMA CO LTD
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