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Edaravone prodrug compound and pharmaceutical use thereof in treatment or alleviation of neurodegenerative or motor neuron disease

A compound and drug technology, applied in the field of edaravone prodrug compound and its medical use in the treatment or improvement of neurodegenerative or motor neuron diseases, can solve the problem of insufficient improvement of the bioavailability of edaravone , Undisclosed or implied Edaravone plasma concentration, undisclosed pharmacokinetics and other issues

Pending Publication Date: 2021-04-27
J2H BIOTECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the aforementioned patents do not disclose the pharmacokinetic aspects of in vivo administration of the compound, nor do they disclose or imply plasma levels of edaravone produced from the prodrug
[0009] The results confirmed by the inventors through personal experiments, the prodrugs disclosed in the Chinese patents are not enough to improve the bioavailability of Edaravone, therefore, the inventors determined that there is a need for a significantly improved absorption rate and bioavailability drug

Method used

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  • Edaravone prodrug compound and pharmaceutical use thereof in treatment or alleviation of neurodegenerative or motor neuron disease
  • Edaravone prodrug compound and pharmaceutical use thereof in treatment or alleviation of neurodegenerative or motor neuron disease
  • Edaravone prodrug compound and pharmaceutical use thereof in treatment or alleviation of neurodegenerative or motor neuron disease

Examples

Experimental program
Comparison scheme
Effect test

reference example 1

[0058] Reference Example 1: 3-methyl-1-phenyl-1H-pyrazol-5-yl 4-methylpiperazine-1-carboxylate hydrochloride

[0059]

[0060] 1.0 g of 1-methylpiperazine was dissolved in 10 ml of dichloromethane, and 1.2 ml of pyridine (1.5 eq.) was added. The reaction solution was cooled to below 0° C. under an argon atmosphere, and then 3.5 g (1.2 eq.) of triphosgene diluted in 15 ml of dichloromethane was slowly added thereto. After stirring at room temperature for 2 hours, it was washed with 25 ml of saturated brine, and the organic layer was separated. After drying over anhydrous magnesium sulfate, it was concentrated under reduced pressure to obtain a yellow oil. After complete dissolution by adding 10 ml of acetonitrile, 1.74 g (1.0 eq.) of edaravone and 9.76 g (3 eq.) of cesium carbonate were added thereto. After stirring at room temperature for 4 hours, the reaction solution was filtered using celite, and the filtrate was recovered and concentrated under reduced pressure. The ...

preparation example 1

[0063]

[0064] After dissolving the benzyl piperazine-1-carboxylated derivative in 10 times the volume of methylene chloride, 1.2 equivalents of triethylamine and 1.1 equivalents of the active ester compound were added. The mixture was stirred at room temperature under an argon atmosphere for 2 hours, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran, 5% of palladium adsorbed on carbon of 10 wt% purity was added thereto, and then stirred at room temperature under normal pressure of hydrogen. After the reaction is completed, the reaction solution is filtered, and the filtrate is recovered and concentrated under reduced pressure. Purification by silica gel column chromatography (eluent: a mixed solution of dichloromethane and methanol) afforded an acylated piperazine intermediate. 10 times the volume of dichloromethane was added thereto to dissolve, and 1.5 equivalents o...

preparation example 2

[0066]

[0067] Dissolve benzyl piperazine-1-carboxylate derivative in 5 times volume of dichloromethane and 5 times volume of N-methyl-2-pyrrolidone (N-methyl-2 -pyrrolidone, NMP), then add 1.0 equivalent of amino acid whose amino group is protected by t-butoxycarbonyl (Boc), 1.1 equivalent of diisopropylcarbodiimide (diisopropylcarbodiimide, DIPC) and 1.2 equivalent of three Ethylamine. The mixture was stirred at room temperature under an argon atmosphere for 2 hours, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran, 5% palladium adsorbed on 10 wt% pure carbon, and stirred at room temperature under atmospheric pressure of hydrogen. After the reaction was completed, the reaction solution was filtered, and the filtrate was recovered and concentrated under reduced pressure. Purification by silica gel column chromatography (eluent: a mixed solution of dichloromethane an...

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Abstract

The present invention provides a novel prodrug of an edaravone compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising same as an active ingredient, and a use thereof in treatment or alleviation of neurodegenerative and / or motor neuron disease.

Description

technical field [0001] The present invention relates to novel prodrugs (prodrugs) or pharmaceutically acceptable salts thereof of edaravone (edaravone) compound, and edaravone is known to be useful in treating or ameliorating neurodegenerative and motor neuron diseases, such as Lu - Lou Gehrig's disease. The present invention also relates to a pharmaceutical composition comprising this novel prodrug or a pharmaceutically acceptable salt thereof as an active ingredient. The invention also relates to the medical use of such prodrugs or pharmaceutically acceptable salts thereof. Background technique [0002] Currently, there are very limited clinical applications of therapeutic agents for degenerative brain diseases or motor neuron diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease disease), Lou Gehrig's disease (Lou Gehrig's disease, Amyotrophic lateral sclerosis), or multiple sclerosis. For the treatment of this disease or the improvement of...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/20A61K31/496A61P25/28
CPCC07D231/20A61P25/28C07D403/12C07D231/22
Inventor 金载善柳炯喆林智雄姜恩妃金赫敏梁铉俊张德浩金东奎柳柄焕吴龙镐
Owner J2H BIOTECH
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