Method for treating hematopoietic neoplasms

Abstract

This invention relates to methods for treating a hematopoietic neoplasm comprising administering a therapeutically effective amount of a combretastatin compound, or a pharmaceutically acceptable salt thereof, to a subject having a hematological malignancy, wherein the combretastatin compound comprises a catechol or quinone moiety and is capable of forming a reactive oxygen species (ROS) in vivo. The method may further comprise co-administering a second chemotherapeutic agent.

1 . A method of treating a hematopoietic neoplasm comprising administering a therapeutically effective amount of a combretastatin compound, or a pharmaceutically acceptable salt thereof, to a subject having a hematological malignancy, wherein the combretastatin compound comprises a catechol or quinone moiety and is capable of forming a reactive oxygen species (ROS) in vivo. 
   
   
       2 . The method of  claim 1 , wherein the catechol or quinone moiety is an ortho-catechol or ortho-quinone moiety. 
   
   
       3 . The method of  claim 1 , wherein the combretastatin compound is a compound of the Formula I: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein
 each R 1  independently is selected from C 1-6  alkoxy, halogen and halo-substituted C 1-6  alkyl; 
 each R 2  independently is selected from C 1-6  alkoxy, halogen and halo-substituted C 1-6  alkyl; 
 p is 1, 2, 3, or 4; 
 q is 0, 1 or 2; 
 R 3  and R 4  each independently is selected from hydroxyl or 
 
     
       
         
         
             
             
         
       
       
         wherein 
         each Y independently is OR 5  or NHR 5 , or O − , wherein each R 5  independently is selected from hydrogen and C 1-6  alkyl; 
         Z is or S. 
       
     
   
   
       4 . The method of  claim 3 , wherein the compound is a pharmaceutically acceptable salt of the compound of Formula I, wherein each of R 3  and R 4  is a phosphate: 
     
       
         
         
             
             
         
       
     
     wherein the cation of the salt can be either a divalent cation or two monovalent cations. 
   
   
       5 . The method of  claim 4 , wherein, the divalent cation is a divalent metal cation. 
   
   
       6 . The method of  claim 4 , wherein, the monovalent cation is an alkali metal, an aliphatic amine or an ammonium. 
   
   
       7 . The method of  claim 4 , wherein, the monovalent cation is selected from the group consisting of sodium, TRIS, histidine, ethanolamine, diethanolamine, ethylenediamine, diethylamine, triethanolamine, glucamine, N-methylglucamine, ethylenediamine, 2-(4-imidazolyl)-ethylamine, choline, and hydrabamine. 
   
   
       8 . The method of  claim 1 , wherein the combretastatin compound is a compound of Formula II: 
     
       
         
         
             
             
         
       
     
     wherein
 each R 1  independently is selected from C 1-6  alkoxy, halogen and halo-substituted C 1-6  alkyl; 
 R 2  is selected from C 1-6  alkoxy, halogen and halo-substituted C 1-6  alkyl; 
 R 3  and R 4  each independently is selected from hydroxyl or 
 
     
       
         
         
             
             
         
       
       
         wherein 
         each Y independently is OR 5  or NHR 5 , or O − , wherein each R 5  independently is selected from hydrogen and C 1-6  alkyl; 
         Z is or S. 
       
     
   
   
       9 . The method of  claim 8 , wherein, the compound is combretastatin A-1 diphosphate (CA1dP): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       10 . The method of  claim 1 , wherein the hematopoietic neoplasm is a myeloid neoplasm. 
   
   
       11 . The method of  claim 10 , wherein the hematopoietic neoplasm is an acute myeloid leukemia (AML). 
   
   
       12 . The method of  claim 1 , wherein the hematopoietic neoplasm is a lymphoid neoplasm. 
   
   
       13 . The method of  claim 1 , wherein the hematopoietic neoplasm is a refractory organ-infiltrating leukemia. 
   
   
       14 . The method of  claim 1 , wherein the pharmaceutically acceptable salt is a potassium salt of combretastatin A-1 diphosphate. 
   
   
       15 . The method of  claim 1 , further comprising co-administering a chemotherapeutic agent to the subject having a hematological malignancy. 
   
   
       16 . The method of  claim 15 , wherein the chemotherapeutic agent is Ara-C, etoposide, thioguanine or cyclophosphamide.