Application and preparation method of berberine compound

A compound and application technology, applied in the fields of medicinal chemistry and pharmacotherapeutics, can solve the problem of no quaternary ammonium berberine analgesic activity and the like, and achieve the effects of abundant synthetic raw materials, long-term analgesic effect and easy preparation

Active Publication Date: 2014-05-28
DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In addition to the tertiary amine type berberine, Corydalis Corydalis also contains many quaternary ammonium type berberine compounds, such as dehydrocorydine, palmatine, berberine, jatrorrhizine, etc. These compounds have anti-gastric ulcer, There are many reports on antibacterial, hypoglycemic, antitumor and other activities, but so far, there is no report that quaternary ammonium berberine has analgesic activity

Method used

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  • Application and preparation method of berberine compound
  • Application and preparation method of berberine compound
  • Application and preparation method of berberine compound

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0042] Preparation of compound 2:

[0043] Dissolve 5 g of berberine hydrochloride in 400 mL of methanol, add 5 g of anhydrous potassium carbonate, dropwise add 6 ml of 5% sodium hydroxide solution (containing 0.4 g of sodium borohydride), stir and react at room temperature for one hour, filter out the precipitate, and use 30 % ethanol, washed with 80% ethanol, and recrystallized in methanol to obtain dihydroberberine (3.5 g, 76%). Dissolve dihydroberberine in 100mL of 80% ethanol and glacial acetic acid mixture, add 40ml of formaldehyde solution, reflux reaction at 85-95°C for 4-5 hours, remove the organic solvent by rotary evaporation, add an appropriate amount of concentrated hydrochloric acid to the residue, and leave at room temperature Under stirring for one hour, the solid was filtered out, washed with a small amount of water and methanol, and recrystallized in methanol to obtain compound 2 (3.6g, 90%)

[0044] Compound 2, C 21 h 20 NO 4 Cl, MW: 385.5 yellow crystal...

Embodiment 1

[0119] Activity Example 1: Using a cell receptor model, the effects of some compounds of the present invention on analgesia-related receptors were preliminarily evaluated in vitro.

[0120] Experimental protocol: The cells expressing mu opioid receptors used in this study were stably transfected human embryonic kidney 293T cells (HEK293T); the dopamine receptors used were transiently transfected HEK293T cells. Part of the berberine derivatives obtained in the present invention were added to cells expressing the corresponding receptors, and FLIPR (Fluorometric Imaging Plate Reader; Molecular Devices Corp) was used for functional screening and identification. Specifically: inoculate 80,000 cells per well in a poly-D-lysine-coated 96-well cell culture plate, remove the medium after 24 hours, and add 100 μl of fluorescent dye solution (2 μM Fluo-4AM first dissolves in each well) In pluronic acid, then dissolved in a buffer consisting of 1 times Hank's buffer and 20mM HEPES, pH 7.4...

Embodiment 2

[0122] Activity Example 2: Comparison of dose-effect curves of dehydrocorydine (DHCB) to different receptor activities

[0123] The experimental scheme is the same as that in Example 1, except that when the test substance is added, the test substance is first diluted to different concentrations with a buffer to detect the response at different doses. In this way, the effects of DHCB on μ-opioid receptors and 5 kinds of dopamine receptors were detected, and the results are as follows: image 3 and shown in Table 1. Experiments have shown that DHCB is not only a weak agonist of μ-opioid receptors, but also an antagonist of various dopamine receptors (D1, D2, D3, D4, D5), which are not only related to pain, but also to Schizophrenia, depression and other mental diseases are related, suggesting that the compound also has certain therapeutic application value in this respect. In addition, the weak synergy of μ-opioid receptors can also enhance the analgesic effect of DHCB.

[01...

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Abstract

The invention provides application of a compound with the structure as shown in the formula (I) in the specification, or a medical salt, a hydrate or a solvate, of the compound, in preparation of a medicine for treating nervous system diseases relevant to the dopamine receptor, and a preparation method of the compound with the structure as shown in the formula (I) in the specification or the medical salt, the hydrate or the solvate, of the compound. The compound has multiple pharmacologic functions such as mu-opioid receptor excitation and dopamine D2 receptor blocking, and has good physicochemical properties and oral bioavailability, and integral animal experiment shows that the compound has remarkable and long-lasting analgesia and calm activity and can be applied to treatment on pain and other mental diseases.

Description

technical field [0001] The present invention relates to the fields of medicinal chemistry and pharmacotherapeutics, more specifically, the use of a class of quaternary ammonium berberine derivatives in the preparation of drugs for treating nervous system diseases and their preparation methods. Background technique [0002] Pain is a symptom of many diseases, and it is a response of the body to adverse stimulation or damage, which can protect the body from damage. However, severe pain, such as myocardial infarction, advanced cancer and trauma, not only makes patients suffer, but also causes serious disturbance of physiological functions, and even shock and death. Therefore, painkillers must be used rationally to reduce injuries and improve the quality of life of patients. [0003] Analgesics currently used clinically can be mainly divided into two categories: narcotic analgesics (opioid analgesics) and non-narcotic analgesics (antipyretic analgesics). The former has a stron...

Claims

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Application Information

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IPC IPC(8): A61K31/4375A61P25/00A61P25/04A61P25/24C07D455/03
Inventor 梁鑫淼王超然张秀莉张岩王志伟奥利维尔·希维利柯燕雄王藜恩
Owner DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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