Combination therapy for treating or managing acute myelocytic leukemia

Abstract

The present invention relates to methods and compositions designed for the treatment, management or prevention of cancer. The methods of the invention comprise the administration of an effective amount of one or more inhibitors of JNK in combination with the administration of an effective amount of one or more other agents useful for cancer therapy. The invention also provides pharmaceutical compositions comprising one or more inhibitors of JNK in combination with one or more other agents useful for cancer therapy. In particular, the invention is directed to methods of treatment and prevention of cancer by the administration of an effective amount of one or more inhibitors of JNK in combination with standard and experimental chemotherapies, hormonal therapies, bone marrow transplants, stem cell replacement therapies, biological therapies/immunotherapies and/or radiation therapies for treatment or prevention of cancer. Also included are methods of treatment of cancer by the administration of one or more inhibitors of JNK in combination with surgery, alone or in further combination with standard and experimental chemotherapies, hormonal therapies, bone marrow transplants, stem cell replacement therapies, biological therapies/immunotherapies and/or radiation therapies.

1 . A method for treating or managing acute myelocytic leukemia in a patient in need thereof, said method comprising administering to said patient an effective amount of one or more JNK inhibitors and an effective amount of cytarabine, wherein the JNK inhibitor is:  
     
       
         
         
             
             
         
       
     
     wherein: 
 -A-R 1  is phenyl, substituted with —O(CH 2 ) 2 NR 8 R 9 , and R 8  and R 9  taken together with the atom to which they are bonded form a heterocycle; and  
 R 2  is 3-triazolyl;  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       2 . The method of  claim 1 , wherein the JNK inhibitor is:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof.  
   
   
       3 . The method of  claim 1 , wherein the JNK inhibitor and cytarabine are administered concurrently.  
   
   
       4 . The method of  claim 1 , wherein the JNK inhibitor and cytarabine are administered sequentially.  
   
   
       5 . The method of  claim 1 , wherein the JNK inhibitor and cytarabine are administered orally, parenterally or mucosally.  
   
   
       6 . The method of  claim 5 , wherein the JNK inhibitor and cytarabine are administered intravenously.  
   
   
       7 . A method for treating or managing acute myelocytic leukemia in a patient in need thereof, said method comprising administering to said patient an effective amount of one or more JNK inhibitors and an effective amount of daunorubicin, wherein the JNK inhibitor is:  
     
       
         
         
             
             
         
       
     
     wherein: 
 -A-R 1  is phenyl, substituted with —O(CH 2 ) 2 NR 8 R 9 , and R 8  and R 9  taken together with the atom to which they are bonded form a heterocycle; and  
 R 2  is 3-triazolyl;  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       8 . The method of  claim 7 , wherein the JNK inhibitor is:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof.  
   
   
       9 . The method of  claim 7 , wherein the JNK inhibitor and daunorubicin are administered concurrently.  
   
   
       10 . The method of  claim 7 , wherein the JNK inhibitor and daunorubicin are administered sequentially.  
   
   
       11 . The method of  claim 7 , wherein the JNK inhibitor and daunorubicin are administered orally, parenterally or mucosally.  
   
   
       12 . The method of  claim 11 , wherein the JNK inhibitor and daunorubicin are administered intravenously.  
   
   
       13 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier, an effective amount of one or more JNK inhibitors and an effective amount of cytarabine or daunorubicin, wherein the JNK inhibitor is:  
     
       
         
         
             
             
         
       
     
     wherein: 
 (a) -A-R 1  is phenyl, substituted with —O(CH 2 ) 2 NR 8 R 9 , and R 8  and R 9  taken together with the atom to which they are bonded form a heterocycle; and  
 (b) R 2  is 3-triazolyl;  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       14 . The pharmaceutical composition of  claim 13 , wherein the JNK inhibitor is:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof.  
   
   
       15 . The pharmaceutical composition of  claim 13  suitable for oral, parenteral or mucosal administration.  
   
   
       16 . The pharmaceutical composition of  claim 15  suitable for intravenous administration.  
   
   
       17 . A single unit dosage form comprising an effective amount of one or more JNK inhibitors and an effective amount of cytarabine or daunorubicin, wherein the JNK inhibitor is:  
     
       
         
         
             
             
         
       
     
     wherein: 
 (a) -A-R 1  is phenyl, substituted with —O(CH 2 ) 2 NR 8 R 9 , and R 8  and R 9  taken together with the atom to which they are bonded form a heterocycle; and  
 (b) R 2  is 3-triazolyl;  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       18 . The single unit dosage form of  claim 17 , wherein the JNK inhibitor is:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof.  
   
   
       19 . The single unit dosage form of  claim 17  suitable for oral, parenteral or mucosal administration.  
   
   
       20 . The single unit dosage form of  claim 19  suitable for intravenous administration.