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Water-soluble derivatives of edaravone, preparation method and application thereof

A technology of derivatives and synthesis methods, applied to water-soluble derivatives of edaravone and the fields of preparation and application thereof, can solve the problem of harsh process conditions, low oral bioavailability of edaravone, and water solubility of edaravone. It can improve the problems such as insignificant improvement, and achieve the effect of improving water solubility and improving drug bioavailability

Active Publication Date: 2015-01-07
ZHONGSHAN WANHAN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, Chinese patent documents CN1440749A, CN1493283A and CN101288650A all report methods for preparing Edaravone freeze-dried preparations, but these methods have harsh process conditions, and the water solubility of Edaravone is not significantly improved, and Edaravone is in The problem of being easily oxidized in the solution state has not been effectively solved
In addition, since Edaravone injection is currently undergoing Phase II clinical trials for amyotrophic sclerosis in Japan, and clinical research on chronic diseases such as endothelial dysfunction may also be carried out, Edaravone has the potential for long-term use to treat the above diseases , it is obvious that long-term injection administration will bring a lot of inconvenience
Animal experiments showed that rats were given 30mg / kg orally, which was equivalent to intravenous injection of 1.5mg / kg (Edaravone (3-Methyl-1-Phenyl-2-Pyrazolin-5-one), A Novel Free Radical Scavenger, for Treatment of Cardiovascular Diseases, Recent Patents on CardiovascularDrug Discovery, 2006,1,85-93), explain that the oral bioavailability of Edaravone is extremely low, so it is necessary to transform Edaravone, obtain the equivalent and Orally available compounds for clinical selection

Method used

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  • Water-soluble derivatives of edaravone, preparation method and application thereof
  • Water-soluble derivatives of edaravone, preparation method and application thereof
  • Water-soluble derivatives of edaravone, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Preparation of 1-piperazineformyl edaravone ester (compound 1)

[0035] in dry N 2 Flow down, add 15ml of dry dichloromethane, 2.0g of edaravone, 0.93g of anhydrous pyridine into a 50ml dry three-necked flask, and stir until completely dissolved. Dissolve 1.14g of triphosgene in 5ml of dry dichloromethane, add it dropwise slowly, and react at -10°C for 2-3 hours. After the reaction was completed, the pyridinium salt was filtered off, and the filtrate was placed in a constant pressure dropping funnel for subsequent use.

[0036] in dry N 2Flowing down, add 5ml of dry dichloromethane and 5.1g of cbz-piperazine into a 50ml dry three-necked flask, and stir until completely dissolved. Then the above filtrate was slowly dropped into it, and reacted at -5°C for 0.5 hours. After the reaction was completed, it was washed with acidic water at pH=1 until no cbz-piperazine was present in the organic phase. The liquid was separated, and then the dichloromethane was vacuum-dried ...

Embodiment 2

[0039] Preparation of 4-methyl-1-piperazinecarboyl edaravone ester (compound 2)

[0040] in dry N 2 Flowing down, add 20ml of dry chloroform, 2.0g of edaravone, and 1.5g of anhydrous pyridine into a 50ml dry three-necked flask, and stir until completely dissolved. Dissolve 1.5g of triphosgene in 5ml of dry chloroform, add it dropwise slowly, and react at -15°C for 2-3 hours. After the reaction was completed, the pyridinium salt was filtered off, and the filtrate was placed in a constant pressure dropping funnel for subsequent use.

[0041] in dry N 2 Add 10ml of dry chloroform and 3.0g of methylpiperazine to a 50ml dry three-necked flask, stir in an ice bath; then slowly drop the above filtrate into it, and react at 0°C for 0.5 hours. After the reaction, wash with water until there is no methylpiperazine in the organic phase, separate the layers, and evaporate chloroform to obtain an oily substance.

[0042] The above oil was dissolved in 20ml of ethyl acetate, and a satur...

Embodiment 3

[0044] Preparation of 4-methyl-1-piperazinecarboyl edaravone ester (compound 2)

[0045] in dry N 2 Add 20ml of dry dichloromethane, 2.0g of methylpiperazine, and 2.52g of sodium bicarbonate into a 50ml dry three-necked flask, and stir. Dissolve 1.97g of triphosgene in 10ml of dry dichloromethane, add it dropwise slowly, and react at -10°C for 1 hour. After filtration, the filtrate was evaporated to dryness under reduced pressure to obtain a light yellow solid.

[0046] in dry N 2 Add 30ml of dry dichloromethane, 3.5g of edaravone, and 1.9g of pyridine into a 100ml dry three-necked flask, and stir in an ice bath. Then 10 ml of the above solid dissolved in dichloromethane was slowly dropped into it, and reacted at 20° C. for 5 hours. After the reaction, wash with water until there is no pyridine in the organic phase, separate the layers, and evaporate dichloromethane to obtain an oily substance.

[0047] The above oil was dissolved in 30ml of acetone, and a saturated HCl s...

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Abstract

The invention discloses a series of amino carbonic ether derivatives of edaravone capable of reacting with acid salt to form water-soluble derivatives, and a preparation method thereof. The water-soluble derivatives are represented by the general formula (I), wherein R represents H, methyl, ethyl, propyl, isopropyl, butyl or benzyl, and HB represents the acid capable of reacting with organic groups containing nitrogen to form salt. The compound disclosed in the invention has favorable water-solubility and has the same cerebral protective effect in animals with edaravone.

Description

technical field [0001] The invention relates to a series of water-soluble derivatives of edaravone and their preparation methods and applications. Background technique [0002] Edaravone is a new generation of central nervous system drug developed by Mitsubishi Corporation, Japan. It is mainly used for neurological symptoms, daily life movement disorders and dysfunction in the acute stage of cerebral infarction. It can also be used for the treatment of subarachnoid hemorrhage. . Its chemical name is: 3-methyl-1-phenyl-2-pyrazolin-5-one, and its structural formula is: [0003] [0004] Edaravone is a brain protectant (free radical scavenger). Clinical studies suggest that N-acetylaspartic acid (NAA) is a specific marker of surviving nerve cells, and its content decreases sharply in the early stage of cerebral infarction. Giving edaravone to patients in the acute stage of cerebral infarction can inhibit the reduction of local cerebral blood flow around the infarction, an...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D231/26A61K31/496A61P25/00A61P39/06A61P7/10
Inventor 李勤耕谢守全甘永军王涛陈大海高宏伟徐璐
Owner ZHONGSHAN WANHAN PHARM CO LTD
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