Sophoridine amine derivative, preparation method thereof and application

A compound and solvate technology, applied in the field of medicine, can solve problems such as less research on structure-activity relationship

Active Publication Date: 2017-09-15
MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The structure of sophoridine (structure shown below) is different from that of existing anticancer chemotherapeutic dru

Method used

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  • Sophoridine amine derivative, preparation method thereof and application
  • Sophoridine amine derivative, preparation method thereof and application
  • Sophoridine amine derivative, preparation method thereof and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0107] Example 1 Synthesis of 12-N-p-chlorobenzyl sophoridin aldehyde (Q08)

[0108]

[0109] Step 1: Sophoridine (4.96g, 20mmol) was uniformly dispersed in 50mL 6N HCl aqueous solution, and refluxed for 4 hours. After TLC detected that the raw material disappeared, the reaction was stopped, and the solvent was evaporated to dryness under reduced pressure to obtain a yellow oil, and 50mL of anhydrous Methanol was stirred at room temperature for two hours, TLC detected that the reaction was complete, and the solvent was evaporated to dryness under reduced pressure to obtain a white solid, which was separated and purified by silica gel column chromatography using dichloromethane / methanol as the mobile phase to obtain a white solid Z0A.

[0110] Step 2: Suspend the above white solid ZOA (2.81g, 10.0mmol) in 50mL 1,2-dichloroethane, add triethylamine (2.8mL, 20.0mmol), stir until dissolved, add p-chlorobenzaldehyde ( 2.1g, 15.0mmol), after reflux for 2 hours, slowly add sodi...

Embodiment 2

[0113] Example 2 Synthesis of 12-N-p-chlorobenzyl-4'-(3,4,5-trimethoxyphenyl)sophoridine (A08A)

[0114]

[0115] Dissolve Q08 (1.1g, 3.0mmol) in 50mL of anhydrous methanol, add 3,4,5-trimethoxyaniline (0.8g, 4.5mmol), and after refluxing for 4 hours, slowly add sodium cyanoborohydride (0.9 g, 4.5mmol), continue to reflux for 4 hours, after cooling to room temperature, evaporate the reaction system to dryness under reduced pressure, add 50mL of dichloromethane, wash with 30mL water and 30mL saturated ammonium chloride solution successively, and evaporate the organic phase to dryness under reduced pressure , using dichloromethane / methanol as the mobile phase, separated and purified by silica gel column chromatography to obtain a white solid (1.1 g, 67%). Melting point: 77-79°C; 1 H NMR (500MHz, DMSO-d 6 )δ7.43–7.25(m,4H),5.86(s,2H),3.70(s,6H),3.62–3.54(m,1H),3.53(s,3H),3.50–3.44(m,1H) ,3.09–2.63(m,6H),2.50–2.37(m,3H),2.30–2.12(m,1H),2.13–1.84(m,3H),1.81–1.60(m,3H),1.61–1...

Embodiment 3

[0116] Example 3 Synthesis of 12-N-p-chlorobenzyl-4'-(N-morpholinyl)sophoridine (A08B)

[0117]

[0118] Dissolve Q08 (1.1g, 3.0mmol) in 50mL of anhydrous methanol, add 4-aminomorpholine (0.43mL, 4.5mmol), reflux for 4 hours, cool to room temperature, evaporate the reaction system to dryness under reduced pressure, add 50mL di After methyl chloride, wash with 30mL water and 30mL saturated ammonium chloride solution successively, evaporate the organic phase to dryness under reduced pressure, use dichloromethane / methanol as the mobile phase, and separate and purify by silica gel column chromatography to obtain a white solid (1.0g, 74 %). Melting point: 59-61°C; 1 H NMR (500MHz, DMSO-d 6 )δ7.38–7.30(m,4H),6.93(t,J=5.2Hz,1H),3.73–3.65(m,4H),3.61–3.44(m,2H),3.01–2.89(m,1H) ,2.88–2.75(m,6H),2.71–2.60(m,1H),2.50–2.35(m,2H),2.25–1.87(m,6H),1.82–1.62(m,3H),1.58–1.37( m,5H),1.31–1.21(m,2H),1.17–1.10(m,1H),1.01(dd,J=20.5,11.7Hz,1H); 13 C NMR (125MHz, DMSO-d 6 )δ140.4, 139.7, ...

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Abstract

The invention relates to a sophoridine amine derivative, a preparation method thereof and an application, in particular to a compound as shown in a formula I, an optical isomer of the compound, a solvate of the compound or pharmaceutically acceptable salt of the compound. The compound is novel in structure and has excellent anti-tumor activity and good inhibitory activity for cancers such as liver cancer, lung adenocarcinoma, breast cancer, stomach cancer, colon cancer, cervical cancer, ovarian cancer, lymphoma, glioma, brain glioma and melanoma.

Description

technical field [0001] The invention relates to the field of medicine, in particular to sophoridine derivatives and their preparation methods and applications. Background technique [0002] Sophoridine is an alkaloid monomer extracted from Sophora sophora, a leguminous plant, which has a wide range of pharmacological effects, such as anti-tumor, anti-virus, anti-inflammatory and so on. Sophoridine Hydrochloride Injection was approved for marketing in 2005 for the treatment of trophoblastic carcinoma. The structure of sophoridine (structure shown below) is different from that of existing anticancer chemotherapeutic drugs. It is a new type of new anticancer drug. There is still a huge demand for novel and highly active anticancer drugs. [0003] Contents of the invention [0004] The inventors of the present invention took sophoridine as the lead compound, and obtained a class of novel structural sophoridine derivatives with excellent anti-tumor activity by transforming...

Claims

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Application Information

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IPC IPC(8): C07D471/16A61K31/4375A61K31/5377A61K31/496A61P35/00
CPCC07D471/16
Inventor 宋丹青毕重文李迎红唐胜范田运蒋建东邓洪斌叶程
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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