Inclusion Compounds of Fumagillol Derivative or its Salt, and Pharmaceutical Compositions Comprising the Same

Abstract

The present invention relates to an inclusion compound of fumagillol derivative or its salt with hydroxypropyl-β-cyclodextrin or sulfobutylether-7-β-cyclodextrin, and pharmaceutical compositions comprising the same. The inclusion compound according to the present invention has superior water solubility and stability while exhibiting low toxicity, rendering it valuable as an anticancer agent or inhibitor of tumor metastasis.

1 . An inclusion compound of fumagillol derivative of the following Formula 1 or its salt with hydroxypropyl-β-cyclodextrin or sulfobutylether-7-β-cyclodextrin 
       
         
           
           
               
               
           
         
       
       Wherein,
 X is hydroxy, Y is halogen, or X and Y together forms oxirane ring; 
 B is O or H 2 ; and 
 R 1 , R 2 , R 3 , R 4  and R 5  independently represent hydrogen, hydroxy, acetoxy, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminoalkoxy, alkylaminoalkoxy, dialkylaminoalkoxy, halogen, cyano, trifluoromethyl, nitro, formyl, acetamido, methyleneoxycarboxy, methylenedioxy or ethylenedioxy group, 
 provided that R 1 , R 2 , R 3 , R 4  and R 5  cannot be hydrogen at the same time. 
 
     
     
         2 . The inclusion compound in  claim 1  characterized in that said fumagillol derivative or its salt is the following compounds:
 O-(4-chlorocinnamoyl)fumagillol; 
 O-(4-aminocinnamoyl)fumagillol; 
 O-(4-dimethylaminoethoxycinnamoyl)fumagillol; 
 O-(4-methoxycinnamoyl)fumagillol; 
 O-(4-dimethylaminocinnamoyl)fumagillol; 
 O-(4-hydroxycinnamoyl)fumagillol; 
 O-(3,4-dimethoxycinnamoyl)fumagillol; 
 O-(3,4-methylenedioxycinnamoyl)fumagillol; 
 O-(3,4,5-trimethoxycinnamoyl)fumagillol; 
 O-(4-nitrocinnamoyl)fumagillol; 
 O-(3,4-dimethoxy-6-aminocinnamoyl)fumagillol; 
 O-(4-acetoxy-3,5-dimethoxycinnamoyl)fumagillol; 
 O-(4-ethylaminocinnamoyl)fumagillol; 
 O-(4-ethylaminoethoxycinnamoyl)fumagillol; 
 O-(3-dimethylaminomethyl-4-methoxycinnamoyl)fumagillol; 
 O-(4-trifluoromethylcinnamoyl)fumagillol; 
 O-(3,4-dimethoxy-6-nitrocinnamoyl)fumagillol; 
 O-(4-acetoxycinnamoyl)fumagillol; 
 O-(4-cyanocinnamoyl)fumagillol; 
 4-(4-methoxycinnamoyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol; 
 O-(3,4,5-trimethoxycinnamyl)fumagillol; 
 O-(4-dimethylaminocinnamyl)fumagillol; 
 O-(3,4,5-trimethoxycinnamoyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol; 
 O-(4-dimethylaminocinnamoyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol; 
 O-(3,5-dimethoxy-4-hydroxycinnamoyl)fumagillol; or a salt thereof. 
 
     
     
         3 . The inclusion compound in  claim 1  characterized in that said fumagillol derivative or its salt is the following compounds:
 (4-methoxycinnamoyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol; 
 O-(4-methoxycinnamoyl)fumagillol; 
 O-(3,5-dimethoxy-4-hydroxycinnamoyl)fumagillol; 
 O-(4-dimethylaminoethoxycinnamoyl)fumagillol; 
 O-(3,4,5-trimethoxycinnamoyl)fumagillol; 
 O-(3,4-dimethoxy-6-aminocinnamoyl)fumagillol; or a salt thereof. 
 
     
     
         4 . The inclusion compound in  claim 1  characterized in that said fumagillol derivative or its salt is O-(4-dimethylaminoethoxycinnamoyl)fumagillol or O-(3,4,5-trimethoxycinnamoyl)fumagillol. 
     
     
         5 . The inclusion compound of  claim 1  characterized in that said fumagillol derivative salt is selected from a group consisting of salts of fumagillol derivative with hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, fumaric acid, tartaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid or para-toluenesulfonic acid. 
     
     
         6 . The inclusion compound in  claim 1  characterized in preparing by dissolving hydroxypropyl-β-cyclodextrin or sulfobutylether-7-β-cyclodextrin in distilled water, and adding fumagillol derivative or its salt under stirring. 
     
     
         7 . The inclusion compound in  claim 1  characterized in that the inclusion compound is prepared by dissolving hydroxypropyl-β-cyclodextrin or sulfobutylether-7-β-cyclodextrin in distilled water, and adding fumagillol derivative or its salt under stirring after adjusting the solution pH in a range of 6-8 with dilute hydrochloric acid or sodium hydroxide solution. 
     
     
         8 . The inclusion compound in  claim 1  characterized in that the inclusion compound is prepared by dissolving hydroxypropyl-β-cyclodextrin or sulfobutylether-7-β-cyclodextrin in buffer solution which pH was pre-adjusted in a range of 6-8 with phosphate, and adding fumagillol derivative or its salt under stirring. 
     
     
         9 . The inclusion compound in  claim 6  characterized in that the inclusion compound is obtained by further lyophilization step for the final solution obtained after stirring. 
     
     
         10 . The inclusion compound in  claim 6  characterized in that molar ratio of fumagillol derivative or its salt to hydroxypropyl-β-cyclodextrin or sulfobutylether-7-β-cyclodextrin is 1:1 to 1:10. 
     
     
         11 . A pharmaceutical composition comprising the inclusion compound in  claim 1  and pharmaceutically acceptable additives. 
     
     
         12 . The pharmaceutical composition in  claim 11  characterized in that the pharmaceutically acceptable additive is at least one selected from a group consisting of pharmaceutically acceptable diluents, buffers, flavors, binders, thickening agent, lubricants and preservatives. 
     
     
         13 . The pharmaceutical composition in  claim 12  characterized in that said buffer is phosphate buffer. 
     
     
         14 . The pharmaceutical composition in  claim 11  characterized in that it is formulated in oral or parenteral preparation. 
     
     
         15 . The pharmaceutical composition in  claim 14  characterized in that said parenteral preparation is injection. 
     
     
         16 . The pharmaceutical composition in  claim 11  characterized in that it is formulated in sustained-release dosage form. 
     
     
         17 . An anti-tumor agent comprising the inclusion compound of  claim 1  as active component. 
     
     
         18 . A tumor metastasis inhibitor comprising the inclusion compound of  claim 1  as active component.