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Substituted benzofuran derivative, preparation and application thereof in preparing antitumor drug

A technology of benzofuran and derivatives, applied in the field of medicinal chemistry, can solve the problems of limited clinical application and high toxicity

Inactive Publication Date: 2018-12-11
SHANGHAI QINGDONG BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the literature shows that the median lethal dose of BNC105 to mice is 60mg / kg, indicating that its toxicity is still relatively high, and its clinical application is limited. Further modification is necessary to reduce its toxicity

Method used

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  • Substituted benzofuran derivative, preparation and application thereof in preparing antitumor drug
  • Substituted benzofuran derivative, preparation and application thereof in preparing antitumor drug
  • Substituted benzofuran derivative, preparation and application thereof in preparing antitumor drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Example 1, 6-methoxy-2-methyl-3-(1-(3,4,5-trimethoxyphenyl)allyl-2,2-dideuterium)-benzofuran-7 -phenol, the synthesis of compound 4 shown in formula one

[0061]

[0062] Take deuteromethyltriphenylphosphine bromide (3.57g, 10mmol) in a three-necked flask, add anhydrous tetrahydrofuran 30mL under the protection of argon, drop to about -70°C, drop n-butyllithium solution (5mL, 11mmol , 2.2M hexane solution), after 1 hour, drop into 30 mL of anhydrous THF solution of BNC105 (1.87 g, 5 mmol), naturally return to room temperature at 25 ° C, stir until TLC shows that the raw materials are completely consumed, then drop to about 0 ° C, drop Quenched by adding 60 mL of ammonium chloride aqueous solution, the reaction solution was extracted twice with 180 mL of ethyl acetate (90 mL*2 times), combined with the organic phase of ethyl acetate, washed once with 70 mL of water, dried over anhydrous sodium sulfate, filtered, 45 °C Concentrate under reduced pressure on a rotary ev...

Embodiment 2

[0063] Example 2, 3-(2,2-dichloro-1-(3,4,5-trimethoxyphenyl)ethyl)-6-methoxy-2-methylbenzofuran-7-ol , the synthesis of compound 4 shown in formula one

[0064]

[0065]Take diethyl trichloromethylphosphonate (2.56g, 10mmol) in a three-necked flask, add 30mL of anhydrous tetrahydrofuran under the protection of argon, cool down to about -80°C, drop n-butyllithium solution (5mL, 11mmol, 2.2M hexane solution), after 1 hour, drop into 30 mL of anhydrous tetrahydrofuran solution of BNC105 (3.72 g, 10 mmol), naturally return to room temperature at 25 ° C, heat to reflux until TLC shows that the raw materials are completely consumed, and then drop to about 0 ° C, Drop in 60 mL of ammonium chloride aqueous solution to quench, the reaction solution was extracted twice with 160 mL of ethyl acetate (80 mL*2 times), the organic phase of ethyl acetate was combined, washed once with 60 mL of water, dried over anhydrous sodium sulfate, filtered, 45 ℃, vacuum degree 0.1MPa rotary evaporat...

Embodiment 3

[0066] Example 3, 3-(2,2-dichloro-1-(3,4,5-trimethoxyphenyl)ethyl)-6-methoxy-2-methylbenzofuran-7-ol , the synthesis of compound 4 shown in formula one

[0067]

[0068] Take benzyltriphenylphosphine bromide (4.33g, 10mmol) in a three-necked flask, add 30mL of anhydrous tetrahydrofuran under the protection of argon, lower it to about -70°C, drop n-butyllithium solution (5mL, 11mmol, 2.2 M hexane solution), after 1 hour, drop into 30 mL of anhydrous tetrahydrofuran solution of BNC105 (1.87 g, 5 mmol), naturally return to room temperature at 25 ° C, stir until TLC shows that the raw materials are completely consumed, then drop to about 0 ° C, and drop into 60 mL Ammonium chloride aqueous solution was quenched, the reaction solution was extracted twice with 120 ml of ethyl acetate (60 ml*2 times), the organic phase of ethyl acetate was combined, washed once with 50 ml of water, dried over anhydrous sodium sulfate, filtered, and at 45°C, Concentrate under reduced pressure with...

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Abstract

The invention provides a substituted benzofuran derivative. A chemical structure of the derivative is as shown in general formula I. The invention further provides a preparation method of the formulaI, the preparation method is as shown in the following reaction formula described in the specification, wherein R and R' are defined the same as the specification. In-vitro proliferation inhibition experiment researches of human tumor cells show that the substituted benzofuran derivative has excellent inhibition effects on tumor cells such as human hepatoma cells HLF, human intestinal cancer cellsHCT116, human breast cancer cells MDA-MB-231, human prostate cancer cells DU145, human melanoma cells A375, human colon cancer cells Lovo, human kidney cancer cells 786-o, human chronic myeloid leukemia cells K562, human gastric cancer cells MGC-803, human pancreatic cancer cells PANC-1, can be used for preparing an anti-tumor drug, has low acute toxicity and good water solubility, and has good clinical application prospects. The preparation method provided by the invention is suitable for industrial production.

Description

technical field [0001] The present invention relates to medicinal chemistry, in particular to medicine and its preparation, in particular to a substituted benzofuran derivative, its preparation and its application in the preparation of antitumor medicine. Background technique [0002] Malignant tumors are frequently-occurring and common diseases that seriously endanger human life and health. Globally, malignant tumors have become the second leading cause of human death, and the incidence rate is still on the rise. Currently clinically applied tumor therapies include: surgical treatment, radiotherapy, chemotherapy and biological therapy, among which chemotherapy is still the mainstream treatment method, but the existing chemotherapy drugs have limited anti-tumor activity, large toxic and side effects, poor patient tolerance and price Expensive and other disadvantages. Therefore, searching for new, highly effective, and low-toxic antitumor compounds has become an important f...

Claims

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Application Information

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IPC IPC(8): C07D307/86C07F9/655A61K31/343A61K31/665A61P35/00
CPCC07D307/86C07F9/65517Y02P20/55
Inventor 孙青龑张卫东袁虎
Owner SHANGHAI QINGDONG BIOTECH CO LTD
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