New 2-(alpha-hydroxypentyl) benzoates, their preparations and their uses

Abstract

The invention relates to new synthetic 2-(α-hydroxypentyl) benzoates, their preparation and pharmaceutical compositions containing such salts as active ingredients. The invention also relates to the use of the compounds for preventing and treating cardioischemia, cerebroischemia and cardiac or cerebral arterial occlusion (obstruction), etc.

1 . A compound of the following general formula (I): 
     
       
         
         
             
             
         
       
       wherein M is a monovalent metal ion, a divalent metal ion, or an organic base group and n is 1 or 2. 
     
   
   
       2 . The compound according to  claim 1 , wherein M is a potassium ion, a sodium ion, or a lithium ion. 
   
   
       3 . The compound according to  claim 1 , wherein M is a calcium ion, a magnesium ion, or a zinc ion. 
   
   
       4 . The compound according to  claim 1 , wherein M is an anilino group, a benzyl amino group, a morpholinyl group or a diethylamino group. 
   
   
       5 . A preparation method of the compound of general formula (I) according to  claim 1  wherein M is a monovalent metal ion, comprising:
 solving an equivalent racemic 3-n-butyl-isobenzofuran-1-(3H)-one in a hydrolysis and ring-opening reaction solvent medium, adding an equivalent or slightly excess amount of monovalent base, conducting hydrolysis and ring-opening reaction under the temperature of 10˜100° C., to afford the 2-(α-hydroxypentyl) benzoate of general formula (I) wherein M is a monovalent metal ion.   
   
   
       6 . The preparation method according to  claim 5 , wherein the solvent for the hydrolysis and ring-opening reaction is any one of methanol, ethanol, acetone, isopropanol, water or mixture of water-alcohol (ketone),
 the monovalent base is an inorganic base, such as sodium hydroxide, potassium hydroxide, or lithium hydroxide; or a chemically pure organic base, such as sodium (potassium) methoxide, sodium (potassium) ethoxide.   
   
   
       7 . A preparation method of the compound of general formula (I) according to  claim 1  wherein M is a divalent metal ion, comprising:
 solving 2-(α-Hydroxypentyl) benzoate of general formula (I) wherein M is a monovalent metal ion (sodium or potassium) in a solvent, adding an equivalent or slightly excess amount of chemically pure divalent metal salt and conducting an ion-exchange reaction under the temperature of 10-100° C., to afford the 2-(α-hydroxylpentyl) benzoate of general formula (I) wherein M is a divalent metal ion.   
   
   
       8 . The preparation method according to  claim 7 , wherein the reaction solvent medium is any one of methanol, ethanol, acetone, isopropanol, water or a mixture of water-alcohol (ketone); and the divalent metal salt is any one of magnesium chloride, calcium chloride, or zinc chloride. 
   
   
       9 . A preparation method of the compound of general formula (I) according to  claim 1 , comprising:
 (1) solving 2-(α-hydroxypentyl) benzoate of general formula (I) wherein M is a monovalent metal ion in a solvent medium, adding an inorganic acid to the solution and adjusting the pH value to 6.0˜2.0, allowing the 2-(α-hydroxypentyl) benzoate to react with the acid to afford 2-(α-hydroxypentyl) benzoic acid, at a temperature of −20˜20° C., preferably −20˜0° C.;   (2) adding an organic extraction solvent to the so-obtained benzoic acid solution and extracting free 2-(α-hydroxypentyl) benzoic acid to obtain an organic solution containing 2-(α-hydroxypentyl) benzoic acid, keeping the solution for use under the temperature of −20˜10° C., preferably −20˜0° C.;   (3) adding a solution which contains an equivalent or slightly excess amount of monovalent base to the 2-(α-hydroxypentyl) benzoic acid solution obtained in the above step under the temperature of −10˜0° C., to afford a 2-(α-hydroxylpentyl) benzoate of general formula (I) wherein M is a monovalent metal ion;   (4) adding a solution which contains an equivalent or slightly excess amount of divalent base or a divalent metal salt solution to the 2-(α-hydroxypentyl) benzoic acid solution obtained in step (2) under the temperature of −10˜0° C., to afford a 2-(α-hydroxypentyl) benzoate of general formula (I) wherein M is a divalent metal ion;   (5) adding a solution which contains an equivalent or slightly excess amount of organic base to the 2-(α-hydroxypentyl) benzoic acid solution obtained in step (2) under the temperature of −10˜0° C., to afford a 2-(α-hydroxypentyl) benzoate of general formula (I) wherein M is an organic base.   
   
   
       10 . The preparation method according to  claim 9 , wherein the acid used in the acidification reaction is any one of concentrated or diluted hydrochloric acid or sulfuric acid; the acidification reaction temperature is controlled within the range of −20˜+20° C.; the organic solvent to extract 2-(α-hydroxypentyl) benzoic acid is any one of ether, ethyl acetate, chloroform, dichloromethane, benzene, toluene, petroleum ether, n-hexane, or cyclohexane; the monovalent base is any one of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium (or potassium) methoxide, or sodium (or potassium) ethoxide; the divalent inorganic metal salt or divalent inorganic base is any one of magnesium chloride, magnesium carbonate, calcium chloride, calcium carbonate, zinc chloride, zinc carbonate, magnesium sulfate, magnesium hydroxide, or calcium hydroxide; the organic base is any one of aniline, benzyl amine, morpholine or diethylamine; the solvent is any one of methanol, ethanol, acetone, isopropanol, water or water-alcohol (ketone) or any one of ether, acetyl acetate, chloroform, dichloromethane, benzene, toluene, petroleum ether, n-hexane, or cyclohexane.