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 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 of  claim 1  wherein said fumagillol derivative or its salt is selected from 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; 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-trimethoxycinnamoyl)fumagillol; O-(4-dimethylaminocinnamoyl)fumagillol; O-(3,4,5-trimethoxycinnamoyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-m-ethoxy-1-chloromethyl-1-cyclohexanol; O-(4-dimethylaminocinnamoyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-me-thoxy-1-chloromethyl-1-cyclohexanol; O-(3,5-dimethoxy-4-hydroxycinnamoyl)fumagillol; or a salt thereof. 
     
     
         3 . The inclusion compound of  claim 1  wherein said fumagillol derivative or its salt is selected from the group consisting of the following compounds: 4-(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 of  claim 1  wherein 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  wherein said fumagillol derivative salt is selected from the 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 .- 9 . (canceled) 
     
     
         10 . The inclusion compound of  claim 1  wherein the 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 of  claim 1  and a pharmaceutically acceptable additives. 
     
     
         12 . The pharmaceutical composition of  claim 11  wherein 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 of  claim 12  wherein said buffer is phosphate buffer. 
     
     
         14 . The pharmaceutical composition of  claim 11  formulated as an oral or parenteral preparation. 
     
     
         15 . The pharmaceutical composition of  claim 14  wherein said parenteral preparation is for injection. 
     
     
         16 . The pharmaceutical composition of  claim 11  formulated in sustained-release dosage form. 
     
     
         17 .- 18 . (canceled) 
     
     
         19 . The composition of  claim 11 , wherein said composition is more stable after 1 month of storage at 25° C., as compared to the fumagillol derivative or salt thereof alone. 
     
     
         20 . The composition of  claim 11 , wherein said composition is more stable after 12 months of storage at 25° C., as compared to the fumagillol derivative or salt thereof alone.