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Seven-membered-ring berberine analogue and pharmaceutical composition, preparation method and application thereof

A technology of berberine and analogues, applied in the fields of medicinal chemistry and pharmacotherapeutics, can solve the problems of low oral bioavailability of berberine, large dosage, poor fat-solubility and water-solubility of compounds, etc.

Active Publication Date: 2016-10-05
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Abstract
  • Description
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AI Technical Summary

Problems solved by technology

A careful comparison of the data on the antitumor activity of berberine reported in the literature found that the effective dose of its in vivo and in vitro activity tests is too large compared with the current clinically used antitumor drugs
The main reason for this problem is the low oral bioavailability of berberine
In order to solve this problem, pharmacists have come up with many methods, such as liposomes, cyclodextrin inclusion complexes and combined administration with absorption enhancers, etc., but it is difficult to fundamentally solve the problem.
It is speculated that the unique structural features of berberine are the key to this problem. Its parent body can be regarded as a four-membered ring system composed of two isoquinoline basic units, and the whole system is in a nearly planar state. , plus the polar C=N in the molecule + bond, resulting in poor fat solubility and water solubility of the compound, thereby affecting bioavailability

Method used

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  • Seven-membered-ring berberine analogue and pharmaceutical composition, preparation method and application thereof
  • Seven-membered-ring berberine analogue and pharmaceutical composition, preparation method and application thereof
  • Seven-membered-ring berberine analogue and pharmaceutical composition, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0126] Preparation of Compound 2

[0127]

[0128] Method 1: Compound 1 (refer to the method of Chinese Patent Application No. 201010537594.1 for specific preparation) is dissolved in methanol, a catalytic amount of 10% palladium carbon is added, hydrogen gas is introduced, and the reaction is carried out at room temperature until the raw materials are completely reacted. The reaction solution was filtered with celite, and the filtrate was evaporated to dryness under reduced pressure to obtain 2 as a white solid with a yield of 95%.

[0129] Method 2: Compound 1 (1.0eq.) was dissolved in methanol, a catalytic amount of 10% palladium on carbon was added, and ammonium formate (10 equivalents) was added, and the reaction was heated under reflux until the reaction of the raw materials was complete. The reaction solution was filtered with celite, the filtrate was evaporated to dryness under reduced pressure, and separated on a silica gel column (PE / EA=2:1) ​​to obtain 2 as a whi...

Embodiment 2

[0132] Preparation of Compounds 3a-3d

[0133]

[0134] Preparation of 3a: Compound 2 (1.0eq.) was dissolved in carbon tetrachloride, under nitrogen protection, added NBS (nitrobromosuccinimide, 1.2eq.), heated to 50°C for 5 hours, filtered, tetrachloro After washing with carbon dioxide, the filtrate was evaporated to dryness under reduced pressure, and separated on a silica gel column (PE / EA=2:1) ​​to obtain a white solid 3a with a yield of 80%.

[0135] 1 H NMR (400MHz, CDCl 3 )δ7.94–7.82(d,J=9.1Hz,1H),7.47–7.38(d,J=9.0Hz,1H),7.11(s,1H),6.76(s,1H),6.08(s,1H ),6.05(s,1H),5.17–5.03(m,1H),4.03(s,3H),4.00(s,3H),3.05–2.94(m,1H),2.67–2.49(m,2H), 2.39–2.27(m,1H),1.84–1.72(m,1H). 13 C NMR (126MHz, CDCl 3 )δ159.09,152.24,149.23,148.72,145.52,139.44,133.28,130.74,127.08,123.21,120.06,118.32,111.96,108.53,101.47,99.65,77.24,61.60,56.65,42.41,29.47,28.66.MS(ESI)m / z[M+H] + 444.1.

[0136] Preparation of 3b: Compound 2 (1.0eq.) was dissolved in carbon tetrachloride, under nitr...

Embodiment 3

[0143] Preparation of Compound 4

[0144]

[0145] Compound 3a (1.0eq.) was dissolved in dichloromethane, added 10% solution volume of concentrated hydrochloric acid, stirred and reacted for 2 hours, the reaction solution was diluted with water, extracted with dichloromethane, separated organic phase, washed with water, washed with saturated sodium chloride, no Dry over sodium sulfate and evaporate to dryness under reduced pressure to obtain white solid 4 with a yield of 93%.

[0146] 1 H NMR (400MHz, CDCl 3 )δ13.48(s,1H),7.52–7.41(m,1H),7.41–7.32(m,1H),7.12(s,1H),6.75(s,1H),6.12(s,1H),6.05 (s,1H),5.11–4.94(m,1H),4.01(s,3H),3.12–2.96(m,1H),2.73–2.58(m,1H),2.59–2.47(m,1H),2.36 –2.18(m,1H),1.88–1.74(m,1H). 13 C NMR (126MHz, CDCl 3 )δ164.60,150.46,148.95,145.99,145.69,138.14,133.14,129.22,126.35,118.31,116.41,112.09,110.97,108.57,102.76,101.57,77.24,56.53,41.90,29.34,28.55.MS(ESI)m / z [M+H] + 430.2.

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Abstract

The invention relates to a seven-membered-ring berberine analogue and a pharmaceutically acceptable salt thereof. Particularly, the analogue has a structure in a formula A, wherein definitions of all substituent groups are described in the description. The invention further provides a preparation method of the seven-membered-ring berberine analogue as shown in the formula A and application of the seven-membered-ring berberine analogue in preparing drugs for preventing or treating tumors or cancers. Please see the formula in the description.

Description

technical field [0001] The invention relates to the fields of medicinal chemistry and drug therapeutics, in particular to a seven-membered ring berberine analogue for treating tumors, a pharmaceutical composition, a preparation method and a medical application thereof. Background technique [0002] Traditional Chinese medicine is the treasure of the Chinese nation. Therefore, the development of modern innovative drug research based on active natural products is a research field that Chinese new drug research and development workers should pay close attention to. There are many active natural products extracted from Chinese herbal medicines that have been widely used, and berberine is one of them. Berberine, an isoquinoline alkaloid with the trade name of berberine, is mainly used to treat intestinal bacterial infections and is the main active ingredient in Chinese medicine Coptis chinensis. [0003] [0004] Coptis chinensis Franch (Coptis chinensis Franch), Coptis delto...

Claims

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Application Information

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IPC IPC(8): C07D491/147A61K31/55A61P35/00A61P35/02
CPCA61K31/55C07D223/16
Inventor 朱维良缪泽鸿李波宋姗姗徐志建张勇蔡婷婷陈凯先
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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