Pharmaceutical combinations for the treatment of cancer

Abstract

In accordance with the present invention there is provided a pharmaceutical combination useful for the treatment of cancer comprising at least one active compound of formula (I): and at least one further therapeutic agent chosen from a nucleoside analogue and/or a chemotherapeutic agents; and, a method of treating a patient having cancer comprising at least one active compound of formula (I), as defined above, and at least one further therapeutic agent chosen from a nucleoside analogue and/or a chemotherapeutic agents.

1 . A pharmaceutical combination comprising cytarabine and at least one active compound of formula (I):  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof,  
         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 a hydroxy protecting group;  
         wherein the ratio of the compound of formula (I) to cytarabine is 1:250 to 250:1.  
       
     
     
         2 . The pharmaceutical combination according to  claim 1 , wherein R is H.  
     
     
         3 . The pharmaceutical combination according to  claim 1 , wherein B is cytosine.  
     
     
         4 . The pharmaceutical combination according to  claim 1 , wherein R is H and B is cytosine.  
     
     
         5 . The pharmaceutical combination according to  claim 1 , wherein B is 5-fluorocytosine.  
     
     
         6 . The pharmaceutical combination according to  claim 1 , wherein said compound of formula I is (−)-β-L-Dioxolane-Cytidine (β-L-OddC).  
     
     
         7 . The pharmaceutical combination according to  claim 1 , wherein said compound of formula I is (−)-β-Dioxolane-5-fluoro-Cytidine ( 5 -FddC).  
     
     
         8 . The pharmaceutical combination according to  claim 1 , wherein the compound of formula I is substantially in the form of the (−) enantiomer.  
     
     
         9 . The pharmaceutical combination according to  claim 1 , wherein said compound of formula (I) is at least 97% free of the corresponding (+) enantiomer  
     
     
         10 . (Canceled)  
     
     
         11 . (Canceled)  
     
     
         12 . (Canceled)  
     
     
         13 . (Canceled)  
     
     
         14 . (Canceled)  
     
     
         15 . (Canceled)  
     
     
         16 . (Canceled)  
     
     
         17 . (Canceled)  
     
     
         18 . (Canceled)  
     
     
         19 . (Canceled)  
     
     
         20 . (Canceled)  
     
     
         21 . A pharmaceutical combination according to  claim 1 , wherein the compound of formula (1) and cytarabine are present in a ratio between about 1:50 to about 50:1.  
     
     
         22 . A pharmaceutical combination according to  claim 1 , wherein the compound of formula (I) and cytarabine are present in a ratio between about 1:20 to about 20:1.  
     
     
         23 . A pharmaceutical combination comprising cytarabine and at least one active compound of formula (I):  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof,  
         wherein B is cytosine or 5-fluorocytosine and R is selected from the group comprising H, monophosphate, diphosphate, triphosphate, carbonyl substituted with a C 1-9  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 a hydroxy protecting group;  
         wherein cytarabine and the compound of formula (I) are present in a synergistic ratio.  
       
     
     
         24 . A method of treating a patient having leukemia comprising administering to said patient a therapeutically effective amounts cytarabine and of a compound of formula I:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof,  
         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 a hydroxy protecting group;  
         wherein the ratio of the compound of formula (I) to cytarabine is 1:250 to 250:1.  
       
     
     
         25 . (Canceled)  
     
     
         26 . The method according to  claim 24 , wherein said patient has acute myelogenous leukemia or chronic myelogenous leukemia.  
     
     
         27 . The method according to  claim 24 , wherein said patient has chronic myelogenous leukemia in blastic phase.  
     
     
         28 . The method according to  claim 24 , wherein said patient has refractory/relapsed leukemia.  
     
     
         29 . The method according to  claim 24 , wherein the step of administering comprises administering to a patient who has refractory/relapsed leukemia and who has been previously treated with Cytarabine.  
     
     
         30 . (Canceled)  
     
     
         31 . (Canceled)  
     
     
         32 . A method of treating a patient having cancer, other than leukemia, comprising administering to said patient a therapeutically effective amounts of cytarabine and a compound of formula I:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof,  
         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 a hydroxy protecting group;  
         wherein the ratio of a said compound of formula I to cytarabine in 1:250 to 250:1.  
       
     
     
         33 . (Canceled)  
     
     
         34 . A method according to  claim 32 , wherein said cancer is selected from the group comprising lung cancer, prostate cancer, bladder cancer, colorectal cancer, pancreatic cancer, gastric cancer, breast cancer, ovarian cancer, soft tissue sarcoma, osteosarcoma, hepatocellular carcinoma, and lymphomas  
     
     
         35 . The method according to  claim 32 , wherein said patient has pancreatic cancer.  
     
     
         36 . (Canceled)  
     
     
         37 . (Canceled)  
     
     
         38 . (Canceled)  
     
     
         39 . (Canceled)  
     
     
         40 . The method according to  claim 32 , wherein R is H and B is cytosine.  
     
     
         41 . The method according to  claim 32 , wherein the β-L-dioxolane is at least 97% free of the corresponding (+) enantiomer.  
     
     
         42 . (Canceled)  
     
     
         43 . (Canceled)  
     
     
         44 . (Canceled)  
     
     
         45 . The method according to  claim 32 , wherein the compounds of formula (I) and cytarabine are administered to the mammal in need thereof sequentially.  
     
     
         46 . The method according to  claim 32 , wherein the compounds of formula (I) and cytarabine are administered to the mammal in need thereof simultaneously.  
     
     
         47 . (Canceled)  
     
     
         48 . (Canceled)  
     
     
         49 . The method according to  claim 32 , wherein the compound of formula (I) and cytarabine are present in a ratio between about 1:50 to about 50:1.  
     
     
         50 . The method according to  claim 32 , wherein the compound of formula (I) and cytarabine are present in a ratio between about 1:20 to about 20:1.  
     
     
         51 . A pharmaceutical composition comprising a pharmaceutical combination according to  claim 1  and at least one pharmaceutically acceptable carrier or excipient.  
     
     
         52 . (Canceled)  
     
     
         53 . A composition according to  claim 51 , wherein the compound of formula (I) is at least 97% free of the corresponding (+) enantiomer.  
     
     
         54 . (Canceled)  
     
     
         55 . (Canceled)  
     
     
         56 . (Canceled)  
     
     
         57 . (Canceled)  
     
     
         58 . A pharmaceutical combination according to  claim 1 , wherein the compound of formula (I) and cytarabine are present in a ratio of 2:1 to 25:1.  
     
     
         59 . A method according to  claim 24 , wherein the compound of formula (I) and cytarabine are present in a ratio of 2:1 to 25:1.  
     
     
         60 . A method according to  claim 32 , wherein the compound of formula (I) and cytarabine are present in a ratio of 2:1 to 25:1.  
     
     
         61 . A pharmaceutical composition comprising a pharmaceutical combination according to  claim 23  and at least one pharmaceutically acceptable carrier or excipient.  
     
     
         62 . A pharmaceutical combination comprising cytarabine and at least one active compound of formula (I):  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof,  
         wherein B is cytosine or 5-fluorocytosine and R is selected from the group comprising H, monophosphate, diphosphate, triphosphate, carbonyl substituted with a Cl  6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-10  aryl and  
         
           
             
             
                 
                 
             
           
         
         wherein cytarabine and said at least one compound of formula I are in a synergistic ratio.