Denibulin di-hydrochloride

Abstract

MN-029 di-hydrochloride (MN-029.2HCl, Formula 2) is a potent vascular targeting agent. The present invention focuses on the synthesis and characterization of the di-hydrochloride salt MN-029 and the preparation of pharmaceutically acceptable formulations thereof. Methods are disclosed of using the compound and formulations thereof in the treatment of diseases that rely on the generation of neovasculature by angiogenesis for disease progression.

What is claimed is: 
     
         1 . A pharmaceutical composition for in vivo targeting of vasculature comprising:
 (a) a compound according to Formula 2:   
       
         
           
           
               
               
           
         
       
       wherein the compound in solid form has an X-ray powder diffraction pattern having the following peaks that are obtained using CuKα as the source of radiation and are expressed in degrees 2θ comprising: 15.01, 20.98, 21.49, 22.52, 23.15, 24.27, 25.80 and 26.57, and
 (b) a pharmaceutically acceptable carrier. 
 
     
     
         2 . The pharmaceutical composition for in vivo targeting of vasculature according to  claim 1 , in which the X-ray powder diffraction pattern further exhibits the following peaks expressed in degrees 2θ: 11.10, 15.9, 18.03, 21.25 and 27.43. 
     
     
         3 . The pharmaceutical composition for in vivo targeting of vasculature according to  claim 1 , wherein the compound according to Formula 2 is provided as a lyophillized powder. 
     
     
         4 . The pharmaceutical composition for in vivo targeting of vasculature according to  claim 1 , wherein the composition inhibits the formation of neovasculature or slows down the progression of vasculature associated with a cell proliferative disease selected from the group consisting of solid tumors, psoriasis, rheumatoid arthritis, macular degeneration and atherosclerotic plaques. 
     
     
         5 . The pharmaceutical composition for in vivo targeting of vasculature according to  claim 1 , further comprising an additional chemotherapeutic agent. 
     
     
         6 . The pharmaceutical composition for in vivo targeting of vasculature according to  claim 5 , wherein the chemotherapeutic agent is selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating agents and anti-hormones. 
     
     
         7 . The pharmaceutical composition for in vivo targeting of vasculature according to  claim 1 , wherein the pharmaceutically acceptable carrier is aqueous citric acid or a citrate buffer. 
     
     
         8 . The pharmaceutical composition for in vivo targeting of vasculature according to  claim 1 , wherein the composition is administered in combination with radiation therapy. 
     
     
         9 . A method for damaging vasculature in vivo comprising:
 (a) administering to a subject diagnosed with a cell proliferative disease a therapeutically effective amount of denibulin dihydrochloride or its tautomer, and   (b) inhibiting the formation of neovasculature or the progression of vasculature in the subject suffering from a cell proliferative disease condition.   
     
     
         10 . The method according to  claim 9 , wherein denibulin dihydrochloride or its tautomer is a compound according to Formula 2: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The method according to  claim 10 , wherein the compound according to Formula 2 in solid form has an X-ray powder diffraction pattern having the following peaks, obtained using CuKα as the source of radiation and expressed in degrees 2θ comprising: 15.01, 20.98, 21.49, 22.52, 23.15, 24.27, 25.80 and 26.57. 
     
     
         12 . The method according to  claim 9 , wherein denibulin dihydrochloride or its tautomer is provided as a lyophillized powder that is reconstituted with a pharmaceutically acceptable carrier prior to administration to the subject. 
     
     
         13 . The method according to  claim 12 , wherein the pharmaceutically acceptable carrier selected from the group consisting of sterile water, hydroxypropyl-β-cyclodextrin, aqueous citric acid or a citrate buffer. 
     
     
         14 . The method according to  claim 9 , wherein denibulin dihydrochloride or its tautomer is provided in a unit dosage form. 
     
     
         15 . The method according to  claim 14 , wherein the unit dose comprises from 0.1 mg/kg to 15 mg/kg of denibulin dihydrochloride or its tautomer. 
     
     
         16 . The method according to  claim 9 , wherein denibulin dihydrochloride or its tautomer is administered as a single daily dose, as multiple daily doses, or as a single dose/week. 
     
     
         17 . The method according to  claim 9 , wherein denibulin dihydrochloride or its tautomer is administered orally or intravenously. 
     
     
         18 . The method according to  claim 9 , wherein the cell proliferative disease is a condition selected from the group consisting of solid tumors, psoriasis, rheumatoid arthritis, macular degeneration and atherosclerotic plaques. 
     
     
         19 . The method according to  claim 18 , wherein the cell proliferative disease is solid tumor.