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Cucoline derivative as well as salts, preparation method and application thereof

A technology of sinomenine and its derivatives, which is applied in the field of medicine, and can solve problems such as large medicinal doses, anaphylactic shock, and slow onset of action

Active Publication Date: 2012-01-04
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, sinomenine has shortcomings such as short biological half-life, large medicinal dose, slow onset of action, instability to light and heat, and side effects such as skin rash and anaphylactic shock caused by the release of histamine (Li Le, Zhang Cailing, Song Biwei

Method used

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  • Cucoline derivative as well as salts, preparation method and application thereof
  • Cucoline derivative as well as salts, preparation method and application thereof
  • Cucoline derivative as well as salts, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0096] Example 1: Preparation of Class A sinomenine derivatives 1-bromo-substituted benzyl sinomenine ether

[0097] (1) Preparation of intermediate 1-bromosinomenine

[0098] Mix 200mg (0.61mmol) of sinomenine, 130mg (0.73mmol) of N-bromosuccinimide (NBS), and 30ml of chloroform in an eggplant-shaped bottle, reflux and stir for 4 hours, concentrate the appropriate amount of the reaction solution, and stir The sample was applied to a silica gel column (eluent: dichloromethane) to obtain 227 mg of pure product with a yield of 91%. 1 H NMR (300MHz, CDCl 3 ): 6.93 (1H, s, H-2), 5.43-5.44 (2H, m, H-8), 2.47-4.36 (2H, dd, J=15.9Hz, H-5), 3.81 (3H, s, CH 3 O-3), 3.50 (3H, s, CH 3 O-7), 3.16-3.44 (2H, m, H-10), 2.99-3.05 (1H, m, H-9), 2.59-2.73 (2H, m, H-16), 2.55 (3H, s, H-17), 2.06-2.10 (1H, m, H-14), 1.97-1.99 (2H, m, H-15).

[0099] (2) Preparation of 1-bromo-4-methylbenzyl sinomenine ether

[0100] Dissolve 200mg (0.48mmol) of 1-bromosinomenine in 40ml of absolute ethanol...

Embodiment 2

[0102] Example 2: Preparation of Class B sinomenine derivatives 1-bromo-6(S)-hydroxyl-substituted benzyl sinomenine phenol ether

[0103] (1) Preparation of intermediate 6(S)-hydroxyl-sinomenine

[0104] Add 5 g (0.015 mol) of sinomenine to absolute ethanol, add 4.6 g (0.12 mol) of sodium borohydride in batches, reflux for 6 hours, evaporate ethanol under reduced pressure after cooling, and pour the oil into 40 ml of ice water , chloroform extraction (120ml×3), combined chloroform solution, concentrated to 100mL, added anhydrous sodium sulfate to dry for 6 hours, filtered, the filtrate was decompressed to remove chloroform, dissolved with ethyl acetate / petroleum ether, dropped a few drops of methanol, static Placed overnight, square crystals were precipitated, totaling 3.4 g, yield 67%. 1 H NMR (300MHz, CDCl 3 ): 6.55-6.71 (2H, dd, J=8.4Hz, H-1, H-2), 4.49 (1H, s, H-8), 3.04-4.18 (2H, m, H-5), 3.83 ( 3H, s, CH 3 O-3), 3.65-3.70 (1H, m, H-6), 3.45 (3H, s, CH 3 O-7), 2.75-2...

Embodiment 3

[0110] Example 3: Preparation of C-type sinomenine derivatives 1-substituted benzyl-1,2,3-triazole-4-methylene-sinomenine phenol ether

[0111] (1) Preparation of intermediate propynyl sinomenine phenol ether

[0112]Fully dissolve 3.29g (0.01mol) of sinomenine in a three-necked flask with 80ml of acetonitrile, add 1.12g (0.01mol) of potassium tert-butoxide, stir for 1 hour, then slowly drop in propyne bromide dissolved in 50ml of acetonitrile 3.57g (0.03mol), reacted for 2 hours. After the reaction was completed, it was concentrated to an appropriate amount, and the mixed sample was applied to a silica gel column (eluent: chloroform-methanol) to obtain 2.34 g of pure product with a yield of 64%. 1 H NMR (300MHz, CDCl 3 ): 6.72-6.79 (2H, dd, J=8.4Hz, H-1, H-2), 5.42-5.43 (1H, m, H-8), 4.74-4.89 (2H, m, H-18), 2.51-4.18 (2H, dd, J=15.6Hz, H-5), 3.79 (3H, s, CH 3 O-3), 3.46 (3H, s, CH 3 O-7), 3.40-3.48 (2H, m, H-10), 2.99-3.01 (2H, m, H-16), 2.84-2.87 (1H, m, H-9), 2.57 (3H...

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Abstract

The invention relates to the technical field of medicine, and in particular relates to a cucoline derivative as well as salts, a preparation method and application thereof. According to the invention, 1, 4, 6 and 17 positions in a cucoline structure are modified so as to obtain the cucoline derivative the structural general formula of which is as follows (shown in the specification); the salts of the cucoline derivative comprise hydrochloride, sulfate, bisulfate, hydrobromide, oxalate, citrate and mesylate; and the inhibition activity of partial compounds of the invention on NF-kappa B are obviously superior to that of cucoline, and the cucoline derivative and salts thereof are used for preparing anti-inflammatory medicaments.

Description

technical field [0001] The invention relates to the technical field of medicine, specifically, sinomenine derivatives, their salts and their preparation methods and uses. Background technique [0002] Sinomenine is an alkaloid monomer extracted from the dry canes of the plants of the family Menispermaceae (Menispermaceae) and the dry cane of Ivy, and its hydrochloride is mostly used in medicine. [0003] Sinomenine has anti-inflammatory, immunosuppressive, analgesic and anti-tumor biological activities. Sinomenine is mainly used clinically for diseases such as rheumatism and rheumatoid arthritis. Its mechanism of action is by inhibiting the inflammatory substance prostaglandin F of macrophages 2α Synthesize with leukotriene, reduce the level of nitric oxide; and can reduce the level of inflammatory factors (IL-1, TNF); in addition, sinomenine also concentration-dependently inhibits the activity of NF-κB in the nucleus of dendritic cells , resulting in blocked differentiat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D221/28C07D401/06C07D401/12A61K31/485A61P29/00
Inventor 陶霞管忠俊高守红陆文铨柴晓云赵庆杰罗剑飞
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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