Methods and compositions for the treatment of BCR-ABL positive lymphoblastic leukemias

Abstract

In one aspect, the invention relates to compositions comprising BCR-ABL tyrosine kinase inhibitors and artemisinin analogs, derivatives thereof, or related compounds, which are useful as in treating Philadelphia chromosome positive leukemias; pharmaceutical compositions comprising the compounds; and methods of treating disorders of uncontrolled cellular proliferation associated with BCR-ABL dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

What is claimed: 
     
       1. A method for the treatment of a Philadelphia chromosome positive leukemia comprising the step of administering to a patient having a Philadelphia chromosome leukemia with a mutation in the kinase domain in the BCR-ABL gene a therapeutically effective amount of a BCR-ABL kinase inhibitor and a therapeutically effective amount of at least one artemisinin analogue having a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein R 1a  and R 1b  together are (C═O) or wherein each of R 1a  and R 1b  are independently selected from hydrogen, hydroxyl, —NH 2 , C1-C8 alkyl, C1-C8 alkoxy, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)(C1-C6 alkyl), C2-C5 heterocycloalkyl, C3-C6 cycloalkyl, —O(C1-C8 alkyl)C3-C6 cycloalkyl, —O(C1-C8 alkyl)-(C═O)OH, —O(C═O)(C1-C6 alkyl)-(C═O)OH, —O(C1-C8 alkyl)-(C═O)O(C1-C6 alkyl), —O(C═O)(C1-C6 alkyl)-(C═O)O(C1-C6 alkyl), —O(C1-C8 alkyl)-aryl, and —O-aryl; 
         wherein each of aryl, C2-C5 heterocycloalkyl, C3-C6 cycloalkyl, and —O(C1-C8 alkyl)C3-C6 cycloalkyl, when present, is substituted with 0-3 groups selected from halogen, hydroxyl, —NH 2 , —(C═O)OH, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)(C1-C6 alkyl), —(C1-C6 alkyl)-NH(C1-C6 alkyl), and —(C1-C6 alkyl)-N(C1-C6 alkyl)(C1-C6 alkyl); 
         wherein R 2a  and R 2b  together are (C═CR 5a R 5b ) or wherein each of R 2a  and R 2b  are independently selected from hydrogen, C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, —(C1-C8 alkyl)-(C═O)OH, and —O(C═O)(C1-C6 alkyl)-(C═O)O(C1-C6 alkyl); 
         wherein each of R 5a  and R 5b  are independently selected from hydrogen, C1-C6 alkyl, C1-C6 monohaloalkyl, and C1-C6 polyhaloalkyl; 
         wherein each of R 3a  and R 3b  are independently selected from hydrogen, C1-C8 alkyl, C1-C8 monohaloalkyl, and C1-C8 polyhaloalkyl; and 
         wherein R 4  is selected from hydrogen, C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, —(C1-C8 alkyl)-(C═O)OH, and —O(C═O)(C1-C6 alkyl)-(C═O)O(C1-C6 alkyl), or a pharmaceutically acceptable salt thereof, 
         wherein the BCR-ABL tyrosine kinase inhibitor is administered in a first period; and the BCR-ABL tyrosine kinase inhibitor and the artemisinin analogue are co-administered in a second period. 
       
     
     
       2. The method of  claim 1 , wherein the artemisinin analogue is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       3. The method of  claim 1 , wherein the Philadelphia chromosome positive leukemia during the first treatment period becomes refractory to treatment by the BCR-ABL tyrosine kinase inhibitor. 
     
     
       4. The method of  claim 1 , wherein the Philadelphia chromosome positive leukemia mutation comprises a mutation selected from H201L, Y232S, M237V, I242T, M244V, L248V, del248-274, G250E, G250V, Q252H, Y253F, Y253H, E255K, E255V, E258D, L273M, D276G, E279K, E281X, V289I, E292V, L298V, V299L, F311I, F311L, T315I, F317L, Y342H, M351T, E355G, F359C, F359I, F359V, D363Y, L364I, A365V, A366G, V379I, L384M, L387M, M388L, Y393C, H396P, H396R, A397P, S417Y, I418S, I418V, S438C, P441L, E450A, E450G, E450K, E450V, E453K, E453V, E459G, E459K, M472I, P480L, F486S, D504D, G514S, T240T, K247R, F311V, and E499E. 
     
     
       5. The method of  claim 1 , wherein the BCR-ABL tyrosine kinase inhibitor is selected from imatinib, dasatinib, nilotinib, bosutinib, ponatinib, bafetinib, saracatinib, tozasertib and rebastinib. 
     
     
       6. The method of  claim 1 , wherein the patient has been diagnosed with a need for treatment of a Philadelphia chromosome positive leukemia prior to the administering step. 
     
     
       7. A method for the treatment of a Philadelphia chromosome positive leukemia comprising the step of administering to a patient having a Philadelphia chromosome leukemia with a mutation in the kinase domain in the BCR-ABL gene a therapeutically effective amount of a BCR-ABL kinase inhibitor and a therapeutically effective amount of at least one artemisinin analogue having a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein R 1a  and R 1b  together are (C═O) or wherein each of R 1a  and R 1b  are independently selected from hydrogen, hydroxyl, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)(C1-C6 alkyl), C2-C5 heterocycloalkyl, C3-C6 cycloalkyl, —O(C1-C8 alkyl)C3-C6 cycloalkyl, —O(C1-C8 alkyl)-(C═O)OH, —O(C═O)(C1-C6 alkyl)-(C═O)OH, —O(C1-C8 alkyl)-(C═O)O(C1-C6 alkyl), —O(C═O)(C1-C6 alkyl)-(C═O)O(C1-C6 alkyl), —O(C1-C8 alkyl)-aryl, and —O-aryl; 
         wherein each of aryl, C2-C5 heterocycloalkyl, C3-C6 cycloalkyl, and —O(C1-C8 alkyl)C3-C6 cycloalkyl, when present, is substituted with 0-3 groups selected from halogen, hydroxyl, —NH 2 , —(C═O)OH, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)(C1-C6 alkyl), —(C1-C6 alkyl)-NH(C1-C6 alkyl), and —(C1-C6 alkyl)-N(C1-C6 alkyl)(C1-C6 alkyl); 
         wherein R 2a  and R 2b  together are (C═CR 5a R 5b ) or wherein each of R 2a  and R 2b  are independently selected from hydrogen, C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, —(C1-C8 alkyl)-(C═O)OH, and —O(C═O)(C1-C6 alkyl)-(C═O)O(C1-C6 alkyl); 
         wherein each of R 5a  and R 5b  are independently selected from hydrogen, C1-C6 alkyl, C1-C6 monohaloalkyl, and C1-C6 polyhaloalkyl; 
         wherein each of R 3a  and R 3b  are independently selected from hydrogen, C1-C8 alkyl, C1-C8 monohaloalkyl, and C1-C8 polyhaloalkyl; and 
         wherein R 4  is selected from hydrogen, C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, —(C1-C8 alkyl)-(C═O)OH, and —O(C═O)(C1-C6 alkyl)-(C═O)O(C1-C6 alkyl), or a pharmaceutically acceptable salt thereof, 
         wherein the Philadelphia chromosome positive leukemia mutation comprises a mutation selected from H201L, Y232S, M237V, I242T, M244V, L248V, del248-274, G250E, G250V, Q252H, Y253F, Y253H, E255K, E255V, E258D, L273M, D276G, E279K, E281X, V289I, E292V, L298V, V299L, F311I, F311L, T315I, F317L, Y342H, M351T, E355G, F359C, F359I, F359V, D363Y, L364I, A365V, A366G, V379I, L384M, L387M, M388L, Y393C, H396P, H396R, A397P, S417Y, I418S, I418V, S438C, P441L, E450A, E450G, E450K, E450V, E453K, E453V, E459G, E459K, M472I, P480L, F486S, D504D, G514S, T240T, K247R, F311V, and E499E. 
       
     
     
       8. The method of  claim 7 , wherein the mutation is T315I. 
     
     
       9. The method of  claim 7 , wherein the artemisinin analogue is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       10. The method of  claim 7 , wherein the BCR-ABL tyrosine kinase inhibitor is selected from imatinib, dasatinib, nilotinib, bosutinib, ponatinib, bafetinib, saracatinib, tozasertib and rebastinib. 
     
     
       11. The method of  claim 7 , wherein the patient has been diagnosed with a need for treatment of a Philadelphia chromosome positive leukemia prior to the administering step. 
     
     
       12. A method for the treatment of a Philadelphia chromosome positive leukemia comprising the step of administering to a patient having a Philadelphia chromosome leukemia with a mutation in the kinase domain in the BCR-ABL gene a therapeutically effective amount of a BCR-ABL kinase inhibitor and a therapeutically effective amount of at least one artemisinin analogue having a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein R 1a  and R 1b  together are (C═O) or wherein each of R 1a  and R 1b  are independently selected from hydrogen, hydroxyl, —NH 2 , C1-C8 alkyl, C1-C8 alkoxy, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)(C1-C6 alkyl), C2-C5 heterocycloalkyl, C3-C6 cycloalkyl, —O(C1-C8 alkyl)C3-C6 cycloalkyl, —O(C1-C8 alkyl)-(C═O)OH, —O(C═O)(C1-C6 alkyl)-(C═O)OH, —O(C1-C8 alkyl)-(C═O)O(C1-C6 alkyl), —O(C═O)(C1-C6 alkyl)-(C═O)O(C1-C6 alkyl), —O(C1-C8 alkyl)-aryl, and —O-aryl; 
         wherein each of aryl, C2-C5 heterocycloalkyl, C3-C6 cycloalkyl, and —O(C1-C8 alkyl)C3-C6 cycloalkyl, when present, is substituted with 0-3 groups selected from halogen, hydroxyl, —NH 2 , —(C═O)OH, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)(C1-C6 alkyl), —(C1-C6 alkyl)-NH(C1-C6 alkyl), and —(C1-C6 alkyl)-N(C1-C6 alkyl)(C1-C6 alkyl); 
         wherein R 2a  and R 2b  together are (C═CR 5a R 5b ) or wherein each of R 2a  and R 2b  are independently selected from hydrogen, C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, —(C1-C8 alkyl)-(C═O)OH, and —O(C═O)(C1-C6 alkyl)-(C═O)O(C1-C6 alkyl); 
         wherein each of R 5a  and R 5b  are independently selected from hydrogen, C1-C6 alkyl, C1-C6 monohaloalkyl, and C1-C6 polyhaloalkyl; 
         wherein each of R 3a  and R 3b  are independently selected from hydrogen, C1-C8 alkyl, C1-C8 monohaloalkyl, and C1-C8 polyhaloalkyl; and 
         wherein R 4  is selected from hydrogen, C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, —(C1-C8 alkyl)-(C═O)OH, and —O(C═O)(C1-C6 alkyl)-(C═O)O(C1-C6 alkyl), or a pharmaceutically acceptable salt thereof, 
         wherein the BCR-ABL tyrosine kinase inhibitor is selected from imatinib, dasatinib, nilotinib, bosutinib, ponatinib, bafetinib, saracatinib, tozasertib and rebastinib. 
       
     
     
       13. The method of  claim 12 , wherein the artemisinin analogue is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       14. The method of  claim 12 , wherein the Philadelphia chromosome positive leukemia mutation comprises a mutation selected from H201L, Y232S, M237V, I242T, M244V, L248V, del248-274, G250E, G250V, Q252H, Y253F, Y253H, E255K, E255V, E258D, L273M, D276G, E279K, E281X, V289I, E292V, L298V, V299L, F311I, F311L, T315I, F317L, Y342H, M351T, E355G, F359C, F359I, F359V, D363Y, L364I, A365V, A366G, V379I, L384M, L387M, M388L, Y393C, H396P, H396R, A397P, S417Y, I418S, I418V, S438C, P441L, E450A, E450G, E450K, E450V, E453K, E453V, E459G, E459K, M472I, P480L, F486S, D504D, G514S, T240T, K247R, F311V, and E499E. 
     
     
       15. The method of  claim 12 , wherein the BCR-ABL tyrosine kinase inhibitor is imatinib. 
     
     
       16. The method of  claim 12 , wherein the BCR-ABL tyrosine kinase inhibitor is dasatinib. 
     
     
       17. The method of  claim 12 , wherein the patient has been diagnosed with a need for treatment of a Philadelphia chromosome positive leukemia prior to the administering step. 
     
     
       18. A method for the treatment of a Philadelphia chromosome positive leukemia comprising the step of administering to a patient having a Philadelphia chromosome leukemia with a mutation in the kinase domain in the BCR-ABL gene a therapeutically effective amount of a BCR-ABL kinase inhibitor and a therapeutically effective amount of at least one artemisinin analogue having a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein R 1a  and R 1b  together are (C═O) or wherein each of R 1a  and R 1b  are independently selected from hydrogen, hydroxyl, —NH 2 , C1-C8 alkyl, C1-C8 alkoxy, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)(C1-C6 alkyl), C2-C5 heterocycloalkyl, C3-C6 cycloalkyl, —O(C1-C8 alkyl)C3-C6 cycloalkyl, —O(C1-C8 alkyl)-(C═O)OH, —O(C═O)(C1-C6 alkyl)-(C═O)OH, —O(C1-C8 alkyl)-(C═O)O(C1-C6 alkyl), —O(C═O)(C1-C6 alkyl)-(C═O)O(C1-C6 alkyl), —O(C1-C8 alkyl)-aryl, and —O-aryl; 
         wherein each of aryl, C2-C5 heterocycloalkyl, C3-C6 cycloalkyl, and —O(C1-C8 alkyl)C3-C6 cycloalkyl, when present, is substituted with 0-3 groups selected from halogen, hydroxyl, —NH 2 , —(C═O)OH, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)(C1-C6 alkyl), —(C1-C6 alkyl)-NH(C1-C6 alkyl), and —(C1-C6 alkyl)-N(C1-C6 alkyl)(C1-C6 alkyl); 
         wherein R 2a  and R 2b  together are (C═CR 5a R 5b ) or wherein each of R 2a  and R 2b  are independently selected from hydrogen, C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, —(C1-C8 alkyl)-(C═O)OH, and —O(C═O)(C1-C6 alkyl)-(C═O)O(C1-C6 alkyl); 
         wherein each of R 5a  and R 5b  are independently selected from hydrogen, C1-C6 alkyl, C1-C6 monohaloalkyl, and C1-C6 polyhaloalkyl; 
         wherein each of R 3a  and R 3b  are independently selected from hydrogen, C1-C8 alkyl, C1-C8 monohaloalkyl, and C1-C8 polyhaloalkyl; and 
         wherein R 4  is selected from hydrogen, C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, —(C1-C8 alkyl)-(C═O)OH, and —O(C═O)(C1-C6 alkyl)-(C═O)O(C1-C6 alkyl), or a pharmaceutically acceptable salt thereof, 
         wherein the patient has been diagnosed with a need for treatment of a Philadelphia chromosome positive leukemia prior to the administering step. 
       
     
     
       19. The method of  claim 18 , wherein the artemisinin analogue is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       20. The method of  claim 18 , wherein the Philadelphia chromosome positive leukemia mutation comprises a mutation selected from H201L, Y232S, M237V, I242T, M244V, L248V, del248-274, G250E, G250V, Q252H, Y253F, Y253H, E255K, E255V, E258D, L273M, D276G, E279K, E281X, V289I, E292V, L298V, V299L, F311I, F311L, T315I, F317L, Y342H, M351T, E355G, F359C, F359I, F359V, D363Y, L364I, A365V, A366G, V379I, L384M, L387M, M388L, Y393C, H396P, H396R, A397P, S417Y, I418S, I418V, S438C, P441L, E450A, E450G, E450K, E450V, E453K, E453V, E459G, E459K, M472I, P480L, F486S, D504D, G514S, T240T, K247R, F311V, and E499E. 
     
     
       21. The method of  claim 18 , wherein the BCR-ABL tyrosine kinase inhibitor is selected from imatinib, dasatinib, nilotinib, bosutinib, ponatinib, bafetinib, saracatinib, tozasertib and rebastinib. 
     
     
       22. The method of  claim 18 , further comprising the step of identifying a patient in need of treatment of a Philadelphia chromosome positive leukemia. 
     
     
       23. The method of  claim 18 , wherein the patient has been diagnosed with a Philadelphia chromosome positive leukemia refractory prior to treatment with a BCR-ABL kinase inhibitor.