Methods and compositions for the treatment of BCR-ABL positive lymphoblastic leukemias
AssigneeSt. Jude Children's Research Hospital
InventorsHarpreet Singh, Richard T. Williams, Kiplin R. Guy
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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.
Claims23
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 R1a and R1b together are (C═O) or wherein each of R1a and R1b are independently selected from hydrogen, hydroxyl, —NH2, 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, —NH2, —(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 R2a and R2b together are (C═CR5aR5b) or wherein each of R2a and R2b 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 R5a and R5b are independently selected from hydrogen, C1-C6 alkyl, C1-C6 monohaloalkyl, and C1-C6 polyhaloalkyl;
- wherein each of R3a and R3b are independently selected from hydrogen, C1-C8 alkyl, C1-C8 monohaloalkyl, and C1-C8 polyhaloalkyl;
- and
- wherein R4 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.
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 R1a and R1b together are (C═O) or wherein each of R1a and R1b 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, —NH2, —(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 R2a and R2b together are (C═CR5aR5b) or wherein each of R2a and R2b 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 R5a and R5b are independently selected from hydrogen, C1-C6 alkyl, C1-C6 monohaloalkyl, and C1-C6 polyhaloalkyl;
- wherein each of R3a and R3b are independently selected from hydrogen, C1-C8 alkyl, C1-C8 monohaloalkyl, and C1-C8 polyhaloalkyl;
- and
- wherein R4 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.
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 R1a and R1b together are (C═O) or wherein each of R1a and R1b are independently selected from hydrogen, hydroxyl, —NH2, 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, —NH2, —(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 R2a and R2b together are (C═CR5aR5b) or wherein each of R2a and R2b 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 R5a and R5b are independently selected from hydrogen, C1-C6 alkyl, C1-C6 monohaloalkyl, and C1-C6 polyhaloalkyl;
- wherein each of R3a and R3b are independently selected from hydrogen, C1-C8 alkyl, C1-C8 monohaloalkyl, and C1-C8 polyhaloalkyl;
- and
- wherein R4 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.
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 R1a and R1b together are (C═O) or wherein each of R1a and R1b are independently selected from hydrogen, hydroxyl, —NH2, 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, —NH2, —(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 R2a and R2b together are (C═CR5aR5b) or wherein each of R2a and R2b 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 R5a and R5b are independently selected from hydrogen, C1-C6 alkyl, C1-C6 monohaloalkyl, and C1-C6 polyhaloalkyl;
- wherein each of R3a and R3b are independently selected from hydrogen, C1-C8 alkyl, C1-C8 monohaloalkyl, and C1-C8 polyhaloalkyl;
- and
- wherein R4 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.
Dependencies are inferred from the claim text.