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Silybin derivative containing carbamic acid structure and application of silybin derivative

A technology of silibinin and carbamate, applied in the field of medicine, can solve the problems of limiting the anti-tumor application of silibinin, poor water solubility and fat solubility of silibinin, and less than 5% bioavailability, etc. Social and economic benefits, low cost and low pollution

Pending Publication Date: 2022-06-24
董金付
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it has been reported that due to the poor water-solubility and fat-solubility of silibinin, the bioavailability of silybin raw materials in the human body is less than 5%.
This severely limits the application of silibinin in antitumor

Method used

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  • Silybin derivative containing carbamic acid structure and application of silybin derivative
  • Silybin derivative containing carbamic acid structure and application of silybin derivative
  • Silybin derivative containing carbamic acid structure and application of silybin derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Synthesis of Compound 1

[0034]

[0035] At room temperature, silibinin (465.9 mg, 0.97 mmol, 1.0 eq) and tetrahydrofuran (7.0 mL, 15.0 vol) were added to a 5 mL three-necked round-bottom flask, and the argon was replaced 6 times. The stirring was turned on, and the system was cooled to 0 -5°C, N,N-diisopropylethylamine (249.6mg, 1.93mmol, 2.0eq) and 4-dimethylaminopyridine (23.6mg, 0.19mmol, 0.2eq) were added to the reaction flask, and argon was replaced 6 times, [1,4']bipiperidine-1'-formyl chloride (234.0 mg, 1.01 mmol, 1.05 eq) was added to the reaction flask, argon was replaced 6 times, and the temperature of the system was controlled at 0-5 °C to stir the reaction 24 hours. After the reaction was detected by TLC, 30 mL of water and 30 mL of ethyl acetate were added to the system, stirred for 10 min, and allowed to stand for 10 min. All the organic phases were washed by adding 50 mL of water, the organic phase was separated, 50 mL of brine was added to wash, ...

Embodiment 2

[0038] Synthesis of Compound 2

[0039]

[0040] At room temperature, silibinin (241.2 mg, 0.50 mmol, 1.0 eq) and tetrahydrofuran (3.6 mL, 15.0 vol) were added to a 5 mL three-necked round-bottomed flask, and the argon was replaced 6 times. The stirring was turned on, and the system was cooled to 0 -5°C, N,N-diisopropylethylamine (193.8mg, 1.50mmol, 3.0eq) and 4-dimethylaminopyridine (18.3mg, 0.15mmol, 0.3eq) were added to the reaction flask, and argon was replaced 6 times, diisopropylcarbamoyl chloride (163.7 mg, 1.00 mmol, 2.0 eq) was added to the reaction flask, argon was replaced 6 times, and the temperature of the system was controlled at 0-5 °C and stirred for 24 hours. After TLC detected the reaction, add 20 mL of water and 20 mL of ethyl acetate to the system, stir for 10 min, let stand for 10 min, separate the organic phase for temporary storage, add 20 mL of ethyl acetate to the aqueous phase, stir for 10 min, let stand for 10 min, separate and combine All organi...

Embodiment 3

[0043] Synthesis of Compound 3

[0044]

[0045] At room temperature, silibinin (241.2 mg, 0.50 mmol, 1.0 eq) and tetrahydrofuran (3.6 mL, 15.0 vol) were added to a 5 mL three-necked round-bottomed flask, and the argon was replaced 6 times. The stirring was turned on, and the system was cooled to 0 -5°C, N,N-diisopropylethylamine (129.2mg, 1.0mmol, 2.0eq) and 4-dimethylaminopyridine (12.2mg, 0.10mmol, 0.2eq) were added to the reaction flask, and argon was replaced 6 times, diethylcarbamoyl chloride (71.2 mg, 0.53 mmol, 1.05 eq) was added to the reaction flask, argon was replaced 6 times, and the temperature of the system was controlled at 0-5 °C and stirred for 24 hours. After TLC detected the reaction, add 20 mL of water and 20 mL of ethyl acetate to the system, stir for 10 min, let stand for 10 min, separate the organic phase for temporary storage, add 20 mL of ethyl acetate to the aqueous phase, stir for 10 min, let stand for 10 min, separate and combine All organic pha...

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Abstract

The invention aims to provide a silibinin derivative containing a carbamic acid structure as well as a preparation method and application thereof, the structure is shown as a general formula I, in the general formula I, R1 and R2 are independently selected from hydrogen atoms, amino, acyl, alkyl, alkoxy, alkenyl, alkynyl, isotope, halogenated alkenyl, hetero-alkyl, aryl and hetero-aryl, and R1 and R2 are independently selected from hydrogen atoms, amino, acyl, alkyl, alkoxy, alkenyl, alkynyl, isotope, halogenated alkenyl, hetero-alkyl, aryl and hetero-aryl. R3, R4 and R5 are respectively and independently selected from a hydrogen atom, alkyl, heteroalkyl, alkenyl, alkynyl, aryl alkyl, cycloalkyl, aryl, heteroaryl, heteroaryl alkyl, heterocycloalkyl, alkyl amino carbonyl, cycloalkyl amino carbonyl, heteroaryl amino carbonyl and heteroaryl amino carbonyl. Compared with silibinin, the compound provided by the invention has a better drug effect.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a carbamate-containing silibinin derivative and use thereof. Background technique [0002] Cancer is a highly lethal malignant disease caused by abnormal proliferation of human cells. It is estimated that there will be approximately 19.3 million new cancer cases globally in 2020, and this number will surge to 28.4 million by 2040. Natural products have been extensively studied due to their molecular diversity and novelty and eventually developed into drugs, especially anticancer chemotherapeutics. [0003] Silymarin is an active extract isolated from the seeds of the silymarin plant, which contains approximately 65-80% of the flavonoid lignans (silybin, isosilybin, silymarin, silymarin) Jinin, 2,3-dehydrosilibinin), as well as small amounts of flavonoids and about 20-30% of unidentified polymeric phenolic constituents. Silybinin, the main active ingredient in silymarin, is a ...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D407/04A61P35/00
CPCC07D401/14C07D407/04A61P35/00
Inventor 董金付吴秋婵曾江
Owner 董金付
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