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A kind of 2,3-dehydrosilibinin derivative and its preparation method and application

A technology for dehydrosilibinin and derivatives, which can be used in pharmaceutical combinations, pharmaceutical formulations, medical preparations containing active ingredients, etc., and can solve the problems of low bioavailability, limited application, poor water solubility of silibinin, etc.

Inactive Publication Date: 2017-11-03
CENT SOUTH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Silybin has a wide range of biological activities, such as scavenging active oxygen, anti-lipid peroxidation, prevention and treatment of cardiovascular diseases, prevention of cerebral ischemia, inhibition of prostate cancer, lung cancer, colon cancer, bladder cancer and other cancers, However, silibinin has poor water solubility and low bioavailability, which limits its application in the pharmaceutical field.

Method used

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  • A kind of 2,3-dehydrosilibinin derivative and its preparation method and application
  • A kind of 2,3-dehydrosilibinin derivative and its preparation method and application
  • A kind of 2,3-dehydrosilibinin derivative and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Example 1: (Preparation of intermediate)

[0045] Preparation of 7-(2-bromo)ethoxy-2,3-dehydrosilybin

[0046]

[0047] The structural formula of 7-(2-bromo)ethoxy-2,3-dehydrosilybin

[0048] Dissolve 2.41 g (5 mmol) of silybin in 110 ml of acetone, then add 8.5 ml (100 mmol) of 1,2-dibromoethane and 0.345 g (2.5 mmol) of potassium carbonate at 45 ℃ The reaction was stirred for 2 d, monitored by TLC. After the reaction, stop the reaction, spin off the acetone, add 100 ml of water, extract with EA, wash the EA layer with water and saturated sodium chloride respectively, separate the organic layer, dry the organic layer with anhydrous sodium sulfate, filter, and concentrate the filtrate. The silica gel column was separated to obtain 0.63 g of yellow solid, the yield was 21.5%, mp 240.0-242.0°C. Structural identification data: 1 H NMR (400 MHz, DMSO-d 6 ): δ 3.35-3.39(m, 1H), 3.56-3.58 (m, 1H), 3.79 (s, 3H), 3.83 (t, J = 5.2 Hz, 2H), 4.26-4.30(m, 1H), 4.44 (t, J = 5.2 Hz, 2...

Embodiment 2

[0049] Example 2: (Preparation of intermediate)

[0050] Preparation of 7-(3-bromo)propoxy-2,3-dehydrosilybin

[0051]

[0052] The structural formula of 7-(3-bromo)propoxy-2,3-dehydrosilybin

[0053] According to Example 1, 1,3-dibromopropane was used instead of 1,2-dibromoethane to obtain a yellow solid with a yield of 10.2%, mp 214.0-215.0 °C. Structural identification data: 1 H NMR (DMSO-d 6 ): δ 2.25-2.29 (m, 2H), 3.35-3.40 (m,1H), 3.56-3.58 (m, 1H), 3.66 (t, J = 6.4 Hz, 2H), 3.80 (s, 3H), 4.19 (t, J =6.0 Hz, 2H), 4.25-4.28 (m, 1H), 4.96 (d, 1H), 6.35 (d, 1H), 6.81-6.83 (m,2H), 6.89 (d, J = 8.4Hz, 1H), 7.05 (br, 1H), 7.12 (d, J = 9.2 Hz, 1H), 7.80-7.82 (m, 2H).

Embodiment 3

[0055] Preparation of 7-(2-morpholinyl)ethoxy-2,3-dehydrosilybin (compound 1)

[0056]

[0057] Compound 1 structural formula

[0058] Dissolve 0.11 g (0.188 mmol) of 7-(2-bromo)ethoxy-2,3-dehydrosilybin in 4 ml of DMF, then add 33 mg (0.376 mmol) of morpholine, React at 50°C for 12 hours, monitored by TLC. After the reaction, stop the reaction, cool at room temperature, add 30 ml of water, extract with EA, separate the organic layer, wash the organic layer with water and saturated sodium chloride successively, separate the organic layer, dry with anhydrous sodium sulfate, filter, and filtrate Concentrate to obtain 0.11 g of yellow solid residue. Separate on a silica gel column to obtain 0.1 g of yellow solid, yield 90.1%, mp 229.3-232.6 ℃. 1 H NMR (DMSO-d 6 ): δ 2.47 (t, 4H), 2.70 (t, J = 5.6 Hz, 2H), 3.39-3.42 (m, 1H), 3.56-3.58 (m, 1H), 3.57 (t, 4H), 3.79(s, 3H), 4.19 (t, J = 5.6 Hz, 2H), 4.25-4.29 (m, 1H), 4.96 (s, 1H), 4.98(d, 1H), 6.33 (br.s, 1H), 6.81-6.83 (m, 2H), 6.88-...

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Abstract

The invention belongs to the field of preparation of new compounds, and specifically provides a 2,3-dehydrosilibinin derivative and its preparation method and application, the structure of which is shown in general formula I. Wherein R1 and R2 are independently selected from hydrogen, straight-chain or branched alkyl, cycloalkyl or unsaturated alkyl with 1-6 carbon atoms; R1R2 N is morpholinyl, piperidinyl or pyrrolyl ; R3, R6, R7, R8 are independently selected from hydrogen, saturated or unsaturated alkyl groups and acyl groups with 1-6 carbon atoms; R4, R5 are independently selected from hydrogen, and alkane with 1-6 carbon atoms Oxygen, alkyl with 1-6 carbon atoms, halogen atom, nitro, haloalkyl with 1-6 carbon atoms, alkyl or unsaturated alkyl with 1-6 carbon atoms, hydroxyl, acyl, Amino group, amido group, ester group; wherein n is 0, 1, 2 or 3. The invention also provides the application of 2,3-dehydrosilibinin derivatives and pharmaceutically acceptable salts thereof in the preparation of antitumor drugs. (1).

Description

Technical field [0001] The present invention relates to structural derivatives of silibinin, in particular to the introduction of nitrogen-containing amino side chains and their salts into the core aromatic ring of the 2,3-dehydrosilybin related structure, and its preparation method and application For anti-tumor applications. Background technique [0002] Silymarin (silymarin) is a flavonoid lignan compound isolated from the fruit or seeds of the compositae herb Silymarin. It is mainly composed of silibinin (silybin), isosilybin, It is composed of 7 compounds including silydianin and silychristin. Among silymarins, silybin has the highest content and is the main active ingredient. Natural silibinin is a mixture of equal amounts of two stereoisomers silibinin A (2R, 3R, 10R, 11R) and silibinin B (2R, 3R, 10S, 11S) . Silybin has a wide range of biological activities, such as removing active oxygen, anti-lipid peroxidation, preventing and treating cardiovascular diseases, preve...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D407/04A61K31/357A61K31/453A61K31/5377A61P35/00A61P35/02
Inventor 刘苏友罗志勇马大友曾江黄景嘉皮朝琼金芳刘丽君陈湘晖
Owner CENT SOUTH UNIV