Methods of treating leukemia

Abstract

The present invention provides a novel method for treating leukemia and more particularly acute myelogenous leukemia (AML) in a host comprising administering to the host a therapeutically effective amount of a compound having the formula I: wherein B is cytosine or 5-fluorocytosine and R is selected from the group comprising H, monophosphate, diphosphate, triphosphate, carbonyl substituted with a C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, and wherein each Rc is independently selected from the group comprising H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and an hydroxy protecting group; and wherein said compound is substantially in the form of the enantiomer.

1 - 10  (Cancelled)  
     
     
         11 . A method for treating leukemia in a host comprising administering to the host having leukemia a therapeutically effective amount of cytarabine and at least one compound of general formula I  
       
         
           
           
               
               
           
         
       
       wherein B is cytosine or 5-fluorocytosine and R is selected from the group comprising H, monophosphate, diphosphate, triphosphate, carbonyl substituted with a C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-10  aryl, and  
       
         
           
           
               
               
           
         
       
       wherein each Rc is independently selected from the group comprising H, C 1-4  alkyl, C 2-6  alkenyl, C 2-6  alkynyl and hydroxy protecting groups, and wherein said compound is substantially in the form of the (−) enantiomer.  
     
     
         12 . A method according to  claim 11 , wherein the leukemia is chronic myelogenous leukemia.  
     
     
         13 . A method according to  claim 11 , wherein the leukemia is acute myelogenous leukemia.  
     
     
         14 . A method according to  claim 11 , further comprising the step of administering a multidrug resistance reversing agent or a biological response modifier.  
     
     
         15 . A method according to  claim 14 , wherein the multidrug resistance agent is PSC 833.  
     
     
         16 . A method according to  claim 14 , wherein the biological response modifiers are selected from the group consisting of monoclonal antibodies and cytokines.  
     
     
         17 . A method according to  claim 14 , wherein the cytokines are selected from the group consisting of interferons, interleukins and colony-stimulating factors.  
     
     
         18 . A method according to  claim 14 , wherein the biological response modifiers are selected from the group consisting of Rituxan, CMA-676, Interferon-alpha recombinant, Interleukin-2, Interleukin-3, Erythropoetin, Epoetin, G-CSF, GM-CSF, Filgrastim, Sargramostim and Thrombopoietin.  
     
     
         19 . A method according to  claim 11 , wherein the compound of formula I and cytarabine are administered sequentially.  
     
     
         20 . A method according to  claim 11 , wherein the compound of formula I and cytarabine are administered simultaneously.  
     
     
         21 . A method according to  claim 11 , wherein said compound is (−)-β-L-Dioxolane-Cytidine (β-L-oddC) or a pharmaceutically acceptable salt thereof.  
     
     
         22 . A method according to  claim 21 , wherein said compound is (−)-β-Dioxolane-5-fluoro-Cytidine (5-FddC).  
     
     
         23 . A method according to  claim 11 , wherein said compound is at least 97% free of the corresponding (+) enantiomer.  
     
     
         24 . A method according to  claim 11 , wherein said compound is at least 99% free of the corresponding (+) enantiomer.  
     
     
         25 . A method according to  claim 21 , wherein said compound is at least 97% free of the corresponding (+) enantiomer.  
     
     
         26 . A method according to  claim 21 , wherein said compound is at least 99% free of the corresponding (+) enantiomer.  
     
     
         27 . A pharmaceutical composition comprising cytarabine and at least one compound of formula I  
       
         
           
           
               
               
           
         
       
       wherein 
 B is cytosine or 5-fluorocytosine,  
 R is H, monophosphate, diphosphate, triphosphate, carbonyl substituted with a C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-10  aryl, or Rc is in each case independently H, C 1-6    
                     
  alkyl, C 2-6  alkenyl, C 2-6  alkynyl or a hydroxy protecting group, and wherein said compound is substantially in the form of the (−) enantiomer.  
 
     
     
         28 . A composition according to  claim 27 , further comprising a pharmaceutically acceptable carrier.  
     
     
         29 . A composition according to  claim 27 , further comprising a multidrug resistance reversing agent or a biological response modifier.  
     
     
         30 . A composition according to  claim 29 , wherein the multidrug resistance agent is PSC 833.  
     
     
         31 . A composition according to  claim 29 , wherein said biological response modifier is a monoclonal antibody or a cytokine.  
     
     
         32 . A composition according to  claim 31 , wherein said cytokine is an interferon, an interleukin or a colony-stimulating factor.  
     
     
         33 . A composition according to  claim 29 , wherein the biological response modifier is Rituxan, CMA-676, Interferon-alpha recombinant, Interleukin-2, Interleukin-3, Erythropoetin, Epoetin, G-CSF, GM-CSF, Filgrastim, Sargramostim or Thrombopoietin.  
     
     
         34 . A composition according to  claim 27 , wherein said compound is (−)-β-L-Dioxolane-Cytidine (β-L-oddC) or a pharmaceutically acceptable salt thereof.  
     
     
         35 . A composition according to  claim 28 , wherein said compound is (−)-β-L-Dioxolane-Cytidine (β-L-oddC) or a pharmaceutically acceptable salt thereof.  
     
     
         36 . A composition according to  claim 34 , wherein said compound is (−)-β-Dioxolane-5-fluoro-Cytidine (5-FddC) or a pharmaceutically acceptable salt thereof.  
     
     
         37 . A composition according to  claim 35 , wherein said compound is (−)-β-L-Dioxolane-Cytidine (β-L-oddC).  
     
     
         38 . A composition according to  claim 27 , wherein said compound is at least 97% free of the corresponding (+) enantiomer.  
     
     
         39 . A composition according to  claim 27 , wherein said compound is at least 99% free of the corresponding (+) enantiomer.  
     
     
         40 . A composition according to  claim 28 , wherein said compound is at least 97% free of the corresponding (+) enantiomer.  
     
     
         41 . A composition according to  claim 28 , wherein said compound is at least 99% free of the corresponding (+) enantiomer.  
     
     
         42 . A composition according to  claim 34 , wherein said compound is at least 97% free of the corresponding (+) enantiomer.  
     
     
         43 . A composition according to  claim 34 , wherein said compound is at least 99% free of the corresponding (+) enantiomer.  
     
     
         44 . A composition according to  claim 35 , wherein said compound is at least 97% free of the corresponding (+) enantiomer.  
     
     
         45 . A composition according to  claim 35 , wherein said compound is at least 99% free of the corresponding (+) enantiomer.  
     
     
         46 . A composition according to  claim 27 , wherein said composition is in unit dosage and contains 10 to 1500 mg of said compound per unit dosage form.  
     
     
         47 . A composition according to  claim 27 , wherein said composition is in unit dosage and contains 20 to 1000 mg of said compound per unit dosage form.  
     
     
         48 . A composition according to  claim 27 , wherein said composition is in unit dosage and contains 50 to 700 mg of said compound per unit dosage form.  
     
     
         49 . A pharmaceutical combination comprising cytarabine and at least one compound of formula  
       
         
           
           
               
               
           
         
       
       wherein 
 B is cytosine or 5-fluorocytosine,  
 R is H, monophosphate, diphosphate, triphosphate, carbonyl substituted with a C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-10  aryl, or  
                     
 Rc is in each case independently H, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl or a hydroxy protecting group, and wherein said compound is substantially in the form of the (−) enantiomer.  
 
     
     
         50 . A combination according to  claim 49 , wherein said compound of formula I is (−)-β-L-Dioxolane-Cytidine (β-L-oddC) or a pharmaceutically acceptable salt thereof.