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A peg modification of sinomenine and its derivatives and its preparation

A technology of sinomenine and its derivatives, which is applied in the field of PEG modification and its drug combination, and in the field of medicine, and can solve problems such as prolonging the half-life

Active Publication Date: 2019-05-28
CHENGDU YIPING MEDICAL SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there is no report on the modification of sinomenine monomers with polyethylene glycol at present. Through research, the inventors found that after the modification of sinomenine monomers with polyethylene glycol, it can effectively shield the immunogenic reaction. , avoid the release of mast cell histamine, reduce allergies and other serious toxic side effects, and prolong the half-life

Method used

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  • A peg modification of sinomenine and its derivatives and its preparation
  • A peg modification of sinomenine and its derivatives and its preparation
  • A peg modification of sinomenine and its derivatives and its preparation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0094] Example 1: PEG 20k -[-LYS-(-CO-CH 2 CH 2 -CO-O-Sinomenine) 2 ] 2 PEG20K-cyan

[0095]

[0096] (1) Synthesis of sinomenine-4-succinic acid monoester (A1)

[0097] Add sinomenine (3.3g, 10mmol), succinic anhydride (2g, 20mmol), 4-dimethylaminopyridine (DMAP, 300mg, 2.5mmol), dicyclohexylcarbodiimide (DCC, 2.1g, 10mmol) into 100ml In the single-necked bottle, 60ml of dichloromethane was added under the protection of nitrogen, the temperature was raised to 50° C. and the reaction was stirred for 48 hours, and the reaction was detected by thin-layer chromatography. The reaction solution was concentrated, and the residual solution was added to the ice-water mixture with stirring, stirred for 30 min, crystallized at 0°C overnight, filtered, the filter cake was washed with ice water, and the filter cake was dried to obtain 4.9 g of light yellow solid.

[0098] (2) Synthesis of Dilysyl-Polyethylene Glycol (A2)

[0099] In a one-mouth bottle, add successively, bisamin...

Embodiment 2

[0103] Example 2: mPEG 5k -CO-NHCH 2 -CO-O-Sinomenine Experimentally called PEG5K-cyan

[0104]

[0105] (1) Synthesis of sinomenine-4-glycine monoester (B1)

[0106] Sinomenine (3.3g, 10mmol), N-tert-butoxycarbonylglycine (8.7g, 50mmol), 4-dimethylaminopyridine (DMAP, 300mg, 2.5mmol), dicyclohexylcarbodiimide (DCC, 3.1 g (15 mmol) was added to a 250 ml single-necked bottle, and 100 ml of dichloromethane was added under nitrogen protection, and the reaction was stirred at room temperature for 48 hours, and the reaction was detected by thin-layer chromatography. Filtrate, concentrate the reaction solution, add 100ml of diethyl ether, stir for 30min, filter, and vacuum-dry to obtain 11g of white sinomenine-4-(N-tert-butoxycarbonyl)glycine monoester solid.

[0107] Add 10 g of sinomenine-4-(N-tert-butoxycarbonyl)glycine monoester from the previous step into a 250ml single-necked bottle, add 100ml of dichloromethane to dissolve, add 30ml of trifluoroacetic acid after complet...

Embodiment 3

[0110] Example 3: mPEG-6-sinomenine ether oxalate (sinomenine 6-(-3,6,9,12,15,18,21-heptaoxodocosane) ether oxalate experiment mPEG-6-cyan

[0111]

[0112] (1) Synthesis of 4-MEM-6-OH-sinomenine

[0113] Join sinomenine (10g, 30mmol) in the 500ml round bottom flask, add 300ml dichloromethane, then add DIPEA (23.5ml, 18.4g, 180mmol) and stir, add MEMCl (13.7ml, 14.9g, 120mmol) under ice-water bath ) after 30 min of dropwise addition, the temperature was naturally raised to room temperature, and the reaction was carried out overnight. The reaction solution was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate for 1 hour, filtered, and concentrated to obtain 12.01 g of 4-MEM-sinomenine product.

[0114]4-MEM-sinomenine, (12.01g, 28.8mmol) was added to a 500ml round bottom flask, then a mixed solution of 120ml acetonitrile and 120ml acetic acid was added, the temperature was lowered to -15°C, and tetramethylammonium triacetoxyborohydride ( 1...

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Abstract

Disclosed are PEGylated sinomenine and derivative thereof and a preparation method and use of the same. The PEGylated sinomenine or derivative thereof can significantly reduce immunogenic reactions or allergic reactions, extend the half-life of sinomenine, reduce bitter taste upon oral administration, reduce irritation to blood vessels upon injection, and / or reduce side effects of nausea and vomiting.

Description

technical field [0001] The invention relates to a pharmaceutical product, in particular to a PEG modification of sinomenine and its derivatives and a pharmaceutical combination thereof, as well as its preparation method and its application in anti-inflammatory, analgesic, immunosuppressive and other medical aspects. technical background [0002] Qingfengteng is the dried rhizome of Qingteng and Maoqingteng of Fangjiaceae plants. Qingfengteng has the functions of dredging collaterals, relieving pain, and dispelling rheumatism. In traditional Chinese medicine, Qingfengteng, as a Chinese herbal medicine for internal and external use, has been used for thousands of years to treat symptoms such as rheumatism and rheumatoid arthritis, joint swelling, numbness and pain. [0003] Sinomenine is a kind of alkaloid monomer obtained from S. sinensis through the extraction and separation technology of modern Chinese medicine. The structural formula is as follows: [0004] [0005] Ch...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C08G65/48C07D221/28A61K31/485A61K31/77A61P29/00A61P37/06A61K47/64A61K47/60
CPCC07D221/28C08G65/48
Inventor 不公告发明人
Owner CHENGDU YIPING MEDICAL SCI & TECH
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