Use of phthalide derivatives for the treatment and prevention of diabetes mellitus

Abstract

The present invention relates to the use of a compound as effective agent for the prevention or treatment of diabetes mellitus in a mammal. Said compounds being selected from the group of phthalide derivatives and exhibit excellent blood glucose lowering effects and thus are effective agents in the prevention or treatment of diabetes mellitus in mammals.

1 - 10 . (canceled)  
   
   
       11 . A method of preventing or treating diabetes mellitus in mammals comprising: 
 administering to a mammal an effective dose of compound represented by formula (I),                          wherein    the dotted line is an optional bond;    R 1  is butyl or butyryl if R 2  is hydroxyl but is butyl if R 2  is hydrogen; or R 1  and R 2  taken together are 1-butylidene optionally substituted by hydroxyl, methyl, or 3-(α,β-dimethylacrylyloxy)-pentylidenyl;    X is a residue selected from the group consisting of X1, X2, X3, X4, and X5;                          wherein    X is X2, X3 or X5 if the dotted line does not signify a bond in formula (I) above and X is X1, X4 or X5 if the dotted line signifies a bond in formula (I) above;    R 3  is hydroxyl or butyryl; and    n is 1 or 2.    
   
   
       12 . A method according to  claim 11  wherein the compound is selected from the group consisting of (E)-senkyunolide E; senkyunolide C; senkyunolide B; 3-butyl-4,5,6,7-tetrahydro-3,6,7-trihydroxy-1(3H)-isobenzofuranone; 3-butyl-1(3H)-isobenzofuranone; 3-butylphthalide; 3-butylidenephthalide; chuangxinol; ligustilidiol; senkyunolide F; 3-hydroxy-senkyunolide A; angeloylsenkyunolide F; senkyunolide M; 3-hydroxy-8-oxo-senkyunolide A; ligustilide; 6,7-dihydro-(6S,7R)-dihydroxyligustilide; 3a,4-dihydro-3-(3-methylbutylidene)-1(3H)-isobenzofuranone; sedanolide; and cnidilide.  
   
   
       13 . A compound represented by formula (I):  
     
       
         
         
             
             
         
       
     
     wherein 
 the dotted line is an optional bond;  
 R 1  is butyl or butyryl if R 2  is hydroxyl but is butyl if R 2  is hydrogen; or R 1  and R 2  taken together are 1-butylidene optionally substituted by hydroxyl, methyl, or 3-(α,β-dimethylacrylyloxy)-pentylidenyl;  
 X is a residue selected from the group consisting of X1, X2, X3, X4, and X5;  
                     
 wherein  
 X is X2, X3 or X5 if the dotted line does not signify a bond in formula (I) above and X is X1, X4 or X5 if the dotted line signifies a bond in formula (I) above;  
 R 3  is hydroxyl or butyryl; and  
 n is 1 or 2.  
 
   
   
       14 . A method of making a pharmaceutical or dietary composition for the prevention or treatment of diabetes mellitus comprising: 
 admixing a compound represented by formula (I)                          wherein    the dotted line is an optional bond;    R 1  is butyl or butyryl if R 2  is hydroxyl but is butyl if R 2  is hydrogen; or R 1  and R 2  taken together are 1-butylidene optionally substituted by hydroxyl, methyl, or 3-(α,β-dimethylacrylyloxy)-pentylidenyl;    X is a residue selected from the group consisting of X1, X2, X3, X4, and. X5;                          wherein    X is X2, X3 or X5 if the dotted line does not signify a bond in formula (I) above and X is X1, X4 or X5 if the dotted line signifies a bond in formula (I) above;    R 3  is hydroxyl or butyryl; and    n is 1 or 2, 
 with a pharmaceutically acceptable carrier, an excipient, a diluent, a fortified food or feed, or a beverage.  
   
   
   
       15 . A pharmaceutical or dietary composition for the treatment or prevention of diabetes mellitus comprising an effective amount of a compound of formula (I),  
     
       
         
         
             
             
         
       
     
     wherein 
 the dotted line is an optional bond;  
 R 1  is butyl or butyryl if R 2  is hydroxyl but is butyl if R2 is hydrogen; or R 1  and R 2  taken together are 1-butylidene optionally substituted by hydroxyl, methyl, or 3-(α,β-dimethylacrylyloxy)-pentylidenyl;  
 X is a residue selected from the group consisting of X1, X2, X3, X4, and X5;  
                     
 wherein  
 X is X2, X3 or X5 if the dotted line does not signify a bond in formula (I) above and X is X1, X4 or X5 if the dotted line signifies a bond in formula (I) above;  
 R 3  is hydroxyl or butyryl; and  
 n is 1 or 2.  
 
   
   
       16 . A composition according to  claim 15  comprising a compound selected from the group consisting of (E)-senkyunolide E; senkyunolide C; senkyunolide B; 3-butyl-4,5,6,7-tetrahydro-3,6,7-trihydroxy-1(3H)-isobenzofuranone; 3-butyl-1 (3H)-isobenzofuranone; 3-butylphthalide; 3-butylidenephthalide; chuangxinol; ligustilidiol; senkyunolide F; 3-hydroxy-senkyunolide A; angeloylsenkyunolide F; senkyunolide M; 3-hydroxy-8-oxo-senkyunolide A; ligustilide; 6,7-dihydro-(6S,7R)-dihydroxyligustilide; 3a,4-dihydro-3-(3-methylbutylidene)-1(3H)-isobenzofuranone; sedanolide; and cnidilide.  
   
   
       17 . A composition according to  claim 15  comprising a compound selected from the group consisting of ligustilide, 3-butylphthalide, 3-butylidenephthalide, and sedanolide.  
   
   
       18 . A composition according to  claim 15  further comprising a pharmaceutically acceptable carrier, excipient, or diluent.  
   
   
       19 . A composition according to  claim 16  further comprising a pharmaceutically acceptable carrier, excipient, or diluent.  
   
   
       20 . A composition according to  claim 17  further comprising a pharmaceutically acceptable carrier, excipient, or diluent.  
   
   
       21 . A composition according to  claim 15  in a form selected from the group consisting of a fortified food or feed, a beverage, a tablet, a granule, a capsule, a paste, and an effervescent formulation.  
   
   
       22 . A composition according to  claim 16  in a form selected from the group consisting of a fortified food or feed, a beverage, a tablet, a granule, a capsule, a paste, and an effervescent formulation.  
   
   
       23 . A composition according to  claim 17  in a form selected from the group consisting of a fortified food or feed, a beverage, a tablet, a granule, a capsule, a paste, and an effervescent formulation.  
   
   
       24 . A composition according to  claim 18  in a form selected from the group consisting of a fortified food or feed, a beverage, a tablet, a granule, a capsule, a paste, and an effervescent formulation.  
   
   
       25 . A method for the prevention or treatment of diabetes mellitus in mammals, said method comprising: 
 (a) preparing a composition comprising an effective amount of a compound of formula (I),                          wherein    the dotted line is an optional bond;    R 1  is butyl or butyryl if R 2  is hydroxyl but is butyl if R2 is hydrogen; or R 1  and R 2  taken together are 1-butylidene optionally substituted by hydroxyl, methyl, or 3-(α,β-dimethylacrylyloxy)-pentylidenyl;    X is a residue selected from the group consisting of X1, X2, X3, X4, and X5;                          wherein    X is X2, X3 or X5 if the dotted line does not signify a bond in formula (I) above and X is X1, X4 or X5 if the dotted line signifies a bond in formula (I) above;    R 3  is hydroxyl or butyryl; and    n is 1 or 2, and 
 (b) administering an effective dose of said composition to a mammal which is in need thereof.  
   
   
   
       26 . A method according to  claim 25  wherein the compound of formula 1 is selected from the group consisting of (E)-senkyunolide E; senkyunolide C; senkyunolide B; 3-butyl-4,5,6,7-tetrahydro-3,6,7-trihydroxy-1(3H)-isobenzofuranone; 3-butyl-1(3H)-isobenzofuranone; 3-butylphthalide; 3-butylidenephthalide; chuangxinol; ligustilidiol; senkyunolide F; 3-hydroxy-senkyunolide A; angeloylsenkyunolide F; senkyunolide M; 3-hydroxy-8-oxo-senkyunolide A; ligustilide; 6,7-dihydro-(6S,7R)-dihydroxyligustilide; 3a,4-dihydro-3-(3-methylbutylidene)-1(3H)-isobenzofuranone; sedanolide; and cnidilide.  
   
   
       27 . A method according to  claim 25  wherein the compound of formula 1 is selected from the group consisting of ligustilide, 3-butylphthalide, 3-butylidenephthalide, and sedanolide.  
   
   
       28 . A method according to  claim 25  wherein the composition further comprises a pharmaceutically acceptable carrier, excipient, or diluent.  
   
   
       29 . A method according to  claim 25  wherein the composition is in a form selected from the group consisting of a fortified food or feed, a beverage, a tablet, a granule, a capsule, a paste, and an effervescent formulation.