Morphic forms of marizomib and uses thereof

Abstract

The present invention relates to polymorphic forms of marizomib (e.g., Morphic Form I). The morphic forms can be used alone and in pharmaceutical compositions for the treatment of disease.

1 . Morphic Form I of marizomib, characterized by an X-ray powder diffraction pattern including peaks at about 7.2, 14.5, and 36.7°2° using Cu Kα radiation. 
     
     
         2 . The morphic Form of  claim 1 , further including X-ray powder diffraction peaks at about 18.1, 19.6, and 20.8°2θ using Cu Kα radiation. 
     
     
         3 . The morphic Form of any of the preceding claims, further including X-ray powder diffraction peaks at about 16.3, 19.8, and 20.5°2θ using Cu Kα radiation. 
     
     
         4 . The morphic Form of any of the preceding claims, further including X-ray powder diffraction peaks at about 15.2, 21.5, and 22.3°2θ using Cu Kα radiation. 
     
     
         5 . The morphic Form of any of the preceding claims, further including X-ray powder diffraction peaks at about 14.7, 29.2, and 30.0°2° using Cu Kα radiation. 
     
     
         6 . The morphic Form of any of the preceding claims, further including X-ray powder diffraction peaks at about 8.2, 14.8, and 27.7°2θ using Cu Kα radiation. 
     
     
         7 . The morphic Form of any of the preceding claims, further characterized by an X-ray powder diffraction pattern substantially similar to that set forth in  FIG. 1, 2 or 3 . 
     
     
         8 . The morphic Form of any of the preceding claims, further characterized by a degradation event at about 175° C. measured by thermogravimetric analysis. 
     
     
         9 . The morphic Form of any of the preceding claims, further characterized by two exotherms at about 150-180° C. as measured by differential scanning calorimetry at a rate of about 2° C. per minute. 
     
     
         10 . The morphic Form of any of the preceding claims, characterized by melting at about 160-175° C. as measured by hot stage microscopy. 
     
     
         11 . The morphic Form of any of the preceding claims, wherein the polymorph is at least about 98% pure as measured by HPLC. 
     
     
         12 . The morphic Form of  claim 11 , wherein the polymorph is at least about 99.1% pure as measured by HPLC. 
     
     
         13 . A pharmaceutical composition comprising a morphic Form of any of the preceding claims and a pharmaceutically acceptable carrier. 
     
     
         14 . A method of treating a disease, comprising administering to a subject in need thereof an effective amount of a morphic Form of any of  claims 1 - 12 . 
     
     
         15 . The method of  claim 14 , wherein the disease is cancer. 
     
     
         16 . Use of the morphic Form of any of  claims 1 - 12  for the treatment of a disease. 
     
     
         17 . Use of the morphic Form of any of  claims 1 - 12  for inhibiting a protease. 
     
     
         18 . Use of the morphic Form of any of  claims 1 - 12  in the manufacture of a medicament for the treatment of a disease. 
     
     
         19 . A method of preparing a morphic Form of marizomib characterized by an X-ray powder diffraction pattern including peaks at about 7.2, 14.5, and 36.7°2θ using Cu Kα radiation, comprising recrystallizing marizomib from a solvent. 
     
     
         20 . The method of  claim 19 , wherein the solvent is selected from the group consisting of n-heptane, ethyl acetate, methyl-isobutyl ketone, 2-propanol, acetone, chloroform, dimethyl sulfoxide, tert-butyl methyl ether, anisole, cumene, methyl ethyl ketone, isopropyl acetate, dimethylformamide, toluene, tetrahydrofuran, dichloromethane, acetonitrile, nitromethane, ethanol, and dimethylacetamide.