Derivative of Butylphthalide and Preparation Method and Use Thereof

Abstract

(−)-(S)-3-(3′-hydroxy)-butylphthalide (a compound shown by Formula I) and an ester formed of the same and an acid are proved by experiments to be applicable to treatment and prevention of cerebral ischemic diseases and have a sleep-improving function. The acid refers to a pharmaceutically acceptable inorganic or organic acid. The inorganic acid refers to nitric acid, sulfuric acid, or phosphoric acid. In addition to an acid radical, the organic acid at least comprises at least one of an amino group, a hydroxyl group, and a carboxyl group. None of the compound shown by Formula I and the ester thereof is water-soluble. An ester generated from the compound and the acid further react with an acid or a base to generate a salt which is water-soluble and is used to prepare injection preparation. The experiment proves that the salt does not stimulate vessels.

1 . A compound for preventing or treating cerebral ischemic disease, the compound having formula I below: 
       
         
           
           
               
               
           
         
       
       or having the chemical name: (−)-(S)-3-(3′-hydroxy)-butylphthalide. 
     
     
         2 . An ester obtained by reacting the compound according to  claim 1  with an acid, said acid selected from a pharmaceutically acceptable inorganic acid or organic acid. 
     
     
         3 . The ester according to  claim 2 , wherein the inorganic acid is selected from the group consisting of nitric acid, sulfuric acid or phosphoric acid; the organic acid is selected from the group consisting of amino acid: glycine, alanine, lysine, arginine, serine, phenylalanine, proline, tyrosine, aspartic acid, glutamic acid, histidine, lecine, methionine, threonine, pyroglutamic acid, tryptophan or valine; dibasic acid: camphoric acid, malic acid, citric acid, maleic acid, succinic acid, oxalic acid, glutaric acid, ethanedioic acid, lactic acid or malonic acid; pamoic acid, hydroxynaphthoic acid, gentisic acid, salicylic acid, hydroxyacetic acid, mandelic acid, lactic acid, 4-acetamidobenzoic acid or nicotinic acid. 
     
     
         4 . The ester according to  claim 2 , wherein the acid is glycine, succinic acid, phosphoric acid, and wherein the ester has formula II, III or IV below: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The ester according to  claim 2 , which is in the form of salt, wherein the ester in the form of salt is obtained by reacting the compound of formula I with an amino acid to obtain an ester, which is further reacted with sulfuric acid, phosphoric acid, sulphonic acid or hydrochloric acid; or obtained by reacting the compound of formula I with a dibasic acid to obtain an ester, which is further reacted with sodium, potassium, magnesium, tromethamine, diethanolamine, triethanolamine, glycine, lysine or arginine; or obtained by reacting the compound of formula 1 with phosphoric acid to obtain an ester, which is further reacted with sodium, potassium, magnesium, lysine, glycine, arginine, tromethamine, diethanolamine or triethanolamine. 
     
     
         6 . The ester in the form of salt according to  claim 5 , having formula V, VI or VII below: 
       
         
           
           
               
               
           
         
       
     
     
         7 . A method of treating cerebral ischemic diseases comprising administrating an effective amount of the compound according to  claim 1  to a subject in need thereof. 
     
     
         8 . A method of improving sleep comprising administrating an effective amount of the compound according to  claim 1  to a subject in need thereof. 
     
     
         9 . A method of treating cerebral ischemic diseases and improving sleep comprising administrating an effective amount of the ester according to  claim 2  to a subject in need thereof. 
     
     
         10 . A method of treating cerebral ischemic diseases and improving sleep comprising administrating an effective amount of the ester according to  claim 4  to a subject in need thereof. 
     
     
         11 . A pharmaceutical composition, comprising an effective amount of the compound according to  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         12 . A pharmaceutical composition, comprising an effective amount of the ester according to  claim 2 , and a pharmaceutically acceptable carrier.