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

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

Water-soluble derivatives of edaravone and their preparation methods and applications technical field The invention relates to a series of water-soluble derivatives of edaravone and their preparation methods and applications. Background technique 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: 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...

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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

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