WO2007124498A2 - Procede de traitement des malignites de la lignee hematopoietique - Google Patents

Procede de traitement des malignites de la lignee hematopoietique Download PDF

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WO2007124498A2
WO2007124498A2 PCT/US2007/067241 US2007067241W WO2007124498A2 WO 2007124498 A2 WO2007124498 A2 WO 2007124498A2 US 2007067241 W US2007067241 W US 2007067241W WO 2007124498 A2 WO2007124498 A2 WO 2007124498A2
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chloro
compound
lymphoma
use according
naphtalen
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PCT/US2007/067241
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WO2007124498A3 (fr
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Chris Pleiman
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Myriad Genetics, Inc.
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Publication of WO2007124498A2 publication Critical patent/WO2007124498A2/fr
Publication of WO2007124498A3 publication Critical patent/WO2007124498A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide

Definitions

  • the invention generally relates to a pharmaceutical composition and methods of use thereof, and particularly to an anti-cancer composition and methods of using the composition for treating cancer and malignancies.
  • Hematological malignancies are cancers affecting blood, bone marrow and lymph nodes. These three are intimately connected through the immune system. As such, hematological cancers form a distinct subset of cancers. Particularly, hematological cancers have some unique features that are not common in solid tumors. For example, chromosomal translocations are a common cause of hematological cancers, but relatively rare in solid tumors. Thus, it is not surprising that the approaches in the diagnosis and treatment of hematological malignancies can be distinct from those for solid tumors.
  • the compounds were shown via binding assay tests, to promote displacement of BH3 from a BcI-XL fusion protein.
  • the compounds were also shown to have apoptotic cytotoxicity when applied to Jurkat T lymphoma cells.
  • the apoptotic cytotoxicity of the compounds quantitatively paralleled their in vitro BcI-XL binding activities.
  • PCT publication WO 2004/006858 also discloses a genus of compounds of salicylic acid derivatives. Such compounds are generally disclosed to be useful in treating cancer.
  • the present invention provides a method for treating hematological malignancies using the compound, 5-chloro-N-[2-(4-chloro-naphtalen-l-yloxy)-5- trifluoromethyl-phenyl]-2-hydroxy-benzamide, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
  • the compound, 5- chloro-N-[2-(4-chloro-naphtalen-l-yloxy)-5-trifluoromethyl-phenyl]-2-hydroxy- benzamide while is generally useful in inducing cell apoptosis and treating cancer, is unexpectedly significantly more effective in killing hematological cancer cells than other types of cancer cells.
  • the compounds of the present invention are particularly useful in treating hematological malignancies.
  • the method is used in a first line or second line or third line therapy for treating leukemia selected from acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL) and hairy cell leukemia.
  • ALL acute lymphoblastic leukemia
  • AML acute myelogenous leukemia
  • CML chronic myelogenous leukemia
  • CLL chronic lymphocytic leukemia
  • hairy cell leukemia selected from acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL) and hairy cell leukemia.
  • ALL acute lymphoblastic leukemia
  • AML acute myelogenous leukemia
  • CML chronic myelogenous leukemia
  • CLL chronic lymphocytic leukemia
  • the method is used in a first line or second line or third line therapy for treating lymphoma such as Hodgkin's disease and non-Hodgkin lymphoma.
  • the method is used in a first line or second line or third line therapy for treating multiple myeloma.
  • the method is used in a first line or second line or third line therapy for treating hematological malignancies selected from myelodysplastic syndrome (MDS), myelofibrosis, myeloproliferative disease such as polycythemia vera (PV) and essential thrombocytosis (ET), and amyloid due to light- chain disease.
  • MDS myelodysplastic syndrome
  • PV polycythemia vera
  • ET essential thrombocytosis
  • the present invention provides the use of the compound, 5-chloro-N- [2-(4-chloro-naphtalen-l-yloxy)-5-trifluoromethyl-phenyl]-2-hydroxy-benzamide, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for the manufacture of a medicament for use in treating one or more of the above hematological malignancies.
  • the present invention also provides a combination therapy comprising treating a patient having a hematological malignancy as disclosed herein with the compound, 5-chloro-N-[2-(4-chloro-naphtalen-l-yloxy)-5-trifluoromethyl-phenyl]-2- hydroxy-benzamide, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and also with one or more other agents selected from immunomodulatory agents such as thalidomide and derivatives thereof (e.g., lenalidomide), demetylating agents such as 5- azacytidine and decitabine, antimetabolites (e.g., folic acid analogues, purine analogues, and pyrimidine analogues), anthracyclines, alkylating agents, interferon alfa, steroids, tyrosine kinase inhibitors, anti-CD22 antibodies, anti-CD25 antibodies, anti- CD52 antibodies, tubulin inhibitors, anti
  • the present invention is based in part on the surprising discovery that the compound 5-chloro-N-[2-(4-chloro-naphtalen-l-yloxy)-5-trifluoromethyl-phenyl]-2- hydroxy-benzamide is significantly more effective in inducing apoptosis in cancer cells of hematopoietic lineage than in cancer cells that are not of hematopoietic lineage.
  • the present invention provides a method of treating cancers of hematopoietic lineage or hematological neoplasm comprising treating a patient in need of such treatment with an effective amount of 5-chloro-N-[2-(4-chloro-naphtalen-l- yloxy)-5-trifluoromethyl-phenyl]-2-hydroxy-benzamide
  • patients in need of treatment i.e., having one or more hematological cancers, are identified, and treated with a therapeutically effective amount of the title compound or a pharmaceutically acceptable salt, or solvate or prodrug thereof.
  • the compound or a pharmaceutically acceptable salt or solvate or prodrug thereof is in a pharmaceutical composition having the compound and pharmaceutically acceptable carriers.
  • the method is used for treating lymphoma.
  • the method of the invention can be used in treating lymphomas of B- lymphocytic lineage, including but not limited to, follicular lymphomas, small non- cleaved lymphomas (e.g., endemic Burkitt's lymphoma, sporadic Burkitt's lymphoma and non-Burkitt's lymphoma), marginal zone lymphoma (e.g., extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) type, monocytoid B-cell lymphoma (nodal) and splenic lymphoma with villous lymphocytes), Mantle cell lymphoma, large cell lymphoma (diffuse large cell lymphoma, diffuse mixed cell lymphoma, immunoblastic lymphoma, primary mediastinal B-cell lymphoma and angiocentric lymphoma
  • MALT mucosa-
  • Lymphomas of T-lymphocytic lineage can also be treated with the method of the present invention.
  • T-lymphocytic lineage lymphomas include, but are not limited to, precursor T-lymphoblastic lymphoma/leukaemia, blastic NK lymphoma, nasal type extranodal NK/T-cell lymphoma, enteropathy-type T-cell lymphoma, hepatosplenic gamma-delta T-cell lymphoma, subcutaneous paanicultis-like T-cell lymphoma, T/null cell primary cutaneous anaplastic large cell lymphoma, peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma, and T/null cell primary systemic anaplastic large cell lymphoma.
  • the method is used for treating Hodgkin's lymphoma. In another embodiment, the method is used for treating non-Hodgkin's lymphoma.
  • the method is used for treating leukaemia.
  • the method of the invention can be used in treating adult acute lymphoblastic leukaemia, childhood acute lymphoblastic leukaemia, adult acute myeloid leukaemia, childhood acute myeloid leukaemia, chronic lymphocytic leukaemia, chronic myelogeous leukaemia, and hairy cell leukaemia.
  • leukaemias that can be treated with the present invention include, but are not limited to, B-cell chronic lymphocytic leukaemia, B-cell prolymphocytic leukaemia, hairy cell leukaemia, minimally differentiated acute myeloid leukaemia, acute myeloid leukaemia without maturation, acute myeloid leukaemia with maturation, acute myeloid leukaemia with maturation with t(8;21), acute promyelocytic leukaemia (hypergranular type or microgranular type), acute myelomonocytic leukaemia, acute monocytic leukaemia (acute monoblastic leukaemia or acute monocytic leukaemia with maturation), erythroleukaemia (erythroid /myeloid, or pure erythroid malignancy), acute megakaryoblastic leukaemia (e.g., acute megakaryoblastic leukaemia associated with t(l;22)
  • leukaemias that can be treated with the present invention include, but are not limited to, precursor B cell acute lymphoblastic leukaemia, "precursor" T cell acute lymphoblastic leukaemia, B-cell acute lymphoblastic leukaemia, precursor B-cell lymphoblastic lymphoma/leukaemia, "precursor” T-cell lymphoblastic lymphoma/leukaemia and biphenotypic acute leukaemia.
  • the method is used for treating acute myeloid leukaemias, including but not limited to, AML with recurrent cytogenetic abnormalities (e.g., AML with t(8;21)(q22;q22), (AML1/ETO); AML with inv(16)(pl3q22) or t(16; 16)(pl 3;q22), (CBFbeta/MYHl 1); AML with t(15; 17)(q22; 12), (PML/RARalpha) and variants; AML with I lq23 (MLL) abnormalities), AML with multilineage dysplasia (e.g., AML with prior myelodysplastic syndrome and AML without prior myelodysplastic syndrome), therapy related AML and MDS (e.g., Alkylating agent related AML and MDS and Topoisomerase II inhibitor-related AML and MDS), Acute leukaemia of ambiguous lineage, and AML with recurrent cyto
  • the method is used for treating plasma cell myelomas, including but not limited to, monoclonal gammopathy of undetermined significance (MGUS), indolent myeloma, smoldering myeloma, osteosclerotic myeloma (POEMS syndrome), plasma cell leukemia, non-secretory myeloma, plasmacytomas (e.g., solitary plasmacytoma of bone extramedullary plasmacytoma) and Waldenstrom's macroglobulinemia.
  • MGUS monoclonal gammopathy of undetermined significance
  • indolent myeloma indolent myeloma
  • smoldering myeloma smoldering myeloma
  • osteosclerotic myeloma POEMS syndrome
  • plasma cell leukemia e.g., solitary plasmacytoma of bone extramedullary plasmacytoma
  • the method is used for treating myelodysplastic syndromes (MDS), including but not limited to, refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory cytopenia with multilineage dysplasia, myelodysplastic syndrome associated with isolated del(5q) chromosome abnormality, and unclassifiable myelodysplastic syndrome.
  • MDS myelodysplastic syndromes
  • the method is used for treating chronic myeloproliferative diseases, including but not limited to, chronic myelogenous leukaemia with t(9;22)(q34;ql 1), (BCR/ABL); chronic neutrophilic leukaemia; chronic eosinophilic leukaemia/hypereosinophilic syndrome; polycythaemia vera; chronic idiopathic myelofibrosis; and essential thrombocythaemia; unclassifiable chronic myeloproliferative disease.
  • chronic myeloproliferative diseases including but not limited to, chronic myelogenous leukaemia with t(9;22)(q34;ql 1), (BCR/ABL); chronic neutrophilic leukaemia; chronic eosinophilic leukaemia/hypereosinophilic syndrome; polycythaemia vera; chronic idiopathic myelofibrosis; and essential thrombocythaemia; unclass
  • the method is used for treating myelodysplastic/myeloproliferative diseases, including but not limited to, chronic myelomonocytic leukaemia, atypical chronic myeloid leukaemia, juvenile myelomonocytic leukaemia and unclassifiable myelodysplastic/myeloproliferative diseases.
  • myelodysplastic/myeloproliferative diseases including but not limited to, chronic myelomonocytic leukaemia, atypical chronic myeloid leukaemia, juvenile myelomonocytic leukaemia and unclassifiable myelodysplastic/myeloproliferative diseases.
  • the method is used for treating B-cell neoplasms, including but not limited to, precursor B-cell neoplasm (precursor B lymphoblastic lymphoma/leukaemia); mature B-cell neoplasms (e.g., chronic lymphocytic leukaemia/small lymphocytic lymphoma, B-cell prolymphocytic leukaemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, hairy cell leukaemia, plasma cell myeloma, solitary plasmacytoma of bone, extraosseous plasmacytoma, extra-nodal marginal zone B-cell lymphoma of mucosa-associated (MALT) lymphoid tissue, nodal marginal zone B-cell lymphoma, follicular lymphoma, Mantle cell lymphoma, diffuse large B-cell lymphoma, mediastinal (thymic) large B-cell lymphom
  • the method is used for treating T-lymphocytic lineage and NK- lymphocytic lineage neoplasms, including but not limited to, precursor T-cell neoplasms (e.g., precursor T lymphoblastic lymphoma/leukaemia); mature T-cell and NK-cell neoplasms (e.g., T-cell prolymphocytic leukaemia, T-cell LGL leukaemia, aggressive NK cell leukaemia, adult T-cell leukaemia/lymphoma, nasal type extranodal NK/T cell lymphoma, enteropathy-type T-cell lymphoma, hepatosplenic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, mycosis fungoides, Sezary syndrome, primary cutaneous anaplastic large cell lymphoma, unspecified peripheral T- cell lymphoma, angioimmunoblastic T-
  • the method is used for treating T-cell and NK-cell Hodgkin lymphoma, including but not limited to, nodular lymphocyte predominant Hodgkin lymphoma, classical Hodgkin lymphoma, nodular sclerosis classical Hodgkin lymphoma, lymphocyte-rich classical Hodgkin lymphoma, mixed cellularity classical Hodgkin lymphoma and lymphocyte-depleted classical Hodgkin lymphoma.
  • the method is used for treating histiocytic and dendritic-cell neoplasms, including but not limited to, macrophage/histiocytic neoplasm (e.g., histiocytic sarcoma), dendritic cell neoplasms (e.g., langerhans cell histiocytosis, langerhans cell sarcoma, interdigitating dendritic cell sarcoma/tumor, and follicular dendritic cell sarcoma/tumor),
  • macrophage/histiocytic neoplasm e.g., histiocytic sarcoma
  • dendritic cell neoplasms e.g., langerhans cell histiocytosis, langerhans cell sarcoma, interdigitating dendritic cell sarcoma/tumor, and follicular dendritic cell
  • the method is used for treating mastocytosis, including but not limited to, cutaneous mastocytosis; indolent systemic mastocytosis; systemic mastocytosis with associated clonal, haematological non-mast cell linegae disease; aggressive systemic mastocytosis; mast cell leukaemia/sarcoma; and extracutaneous mastocytoma.
  • mastocytosis including but not limited to, cutaneous mastocytosis; indolent systemic mastocytosis; systemic mastocytosis with associated clonal, haematological non-mast cell linegae disease; aggressive systemic mastocytosis; mast cell leukaemia/sarcoma; and extracutaneous mastocytoma.
  • the method of the present invention comprises identifying a patient having a hematological cancer chosen from T-cell acute lymphoblastic leukaemia, T-cell lymphoma, acute promylocytic leukaemia, Burkitt's B lymphoblastic lymphoma, and plasmocytoma (e.g., nonsecretory plasmocytoma), and treating the patient with a therapeutically effective amount of 5-chloro-N-[2-(4-chloro- naphtalen-l-yloxy)-5-trifluoromethyl-phenyl]-2-hydroxy-benzamide or a salt thereof.
  • a hematological cancer chosen from T-cell acute lymphoblastic leukaemia, T-cell lymphoma, acute promylocytic leukaemia, Burkitt's B lymphoblastic lymphoma, and plasmocytoma (e.g., nonsecretory plasmocytoma)
  • the phrase "treating a patient with ... 5-chloro-N-[2-(4- chloro-naphtalen-l-yloxy)-5-trifluoromethyl-phenyl]-2-hydroxy-benzamide” means either administering 5-chloro-N-[2-(4-chloro-naphtalen-l-yloxy)-5-trifluoromethyl- phenyl]-2-hydroxy-benzamide to an animal, directly, or administering to a patient another agent (e.g., prodrugs) that causes or results in the formation of 5-chloro-N-[2- (4-chloro-naphtalen-l-yloxy)-5-trifluoromethyl-phenyl]-2-hydroxy-benzamide inside the patient's body.
  • another agent e.g., prodrugs
  • combination treatments are also contemplated and encompassed in the method of the present invention.
  • a patient identified as having a hematological cancer as disclosed above for which the compound of the present invention is useful can be treated with the compound and one or more other anticancer agents.
  • the compound 5-chloro-N-[2-(4-chloro-naphtalen-l-yloxy)-5- trifluoromethyl-phenyl]-2-hydroxy-benzamide, or a salt or prodrug thereof can be administered, together with or separately from, one or more other anticancer agents, to the same patient in need of treatment, in the same treatment regimen.
  • Such other anticancer agents can be chosen from alkylating agents, antimitotic agents, tubulin inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, RNA/DNA antimetabolites, DNA antimetabolites, tyrosine kinase inhibitors (e.g., an EGFR inhibitor), HSP90 inhibitors, angiogenesis inhibitors, anti-CD20 antibodies such as rituximab, interferon alpha, anti-CD52 antibodies, anti-CD22 antibodies and anti-CD25 antibodies, anti-CD33 antibodies, arsenic trioxide, tretinoin, farnesyltransferase inhibitors, and proteosome inhibitors, and some combinations thereof.
  • alkylating agents e.g., antimitotic agents, tubulin inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, RNA/DNA antimetabolites, DNA antimetabolites, tyrosine kinase inhibitors (e.g., an EGFR
  • the present invention also provides a pharmaceutical composition having the compound 5- chloro-N-[2-(4-chloro-naphtalen-l-yloxy)-5-trifluoromethyl-phenyl]-2-hydroxy- benzamide, or a salt or prodrug thereof, and one or more such anticancer agents, and a pharmaceutically acceptable carrier.
  • the present invention provides a method of treating an acute myelogenous leukemia (AML) comprising treating a patient identified as having one of the AML types with the compound 5-chloro-N-[2-(4-chloro-naphtalen-l-yloxy)- 5-trifluoromethyl-phenyl]-2-hydroxy-benzamide, and one or more other anticancer agents selected from antimetabolites (including folic acid analogues such as methotrexate, pemetrexed, raltitrexed; purine analogues such as mercaptopurine, tioguanine, clofarabine and fludarabine; and pyrimidine analogues such as 5- fluorouracil, floxuridine, cytosine arabinoside (cytarabine) and gemcitabine); anthracyclines (e.g., daunorubicin, idarubicin, doxorubicin, epirub
  • AML acute mye
  • the compound 5-chloro-N-[2-(4-chloro- naphtalen-l-yloxy)-5-trifluoromethyl-phenyl]-2-hydroxy-benzamide is preferably used in combination with at least tretinoin and/or arsenic trioxide.
  • the present invention also provides a pharmaceutical composition having the compound 5-chloro- N-[2-(4-chloro-naphtalen-l-yloxy)-5-trifluoromethyl-phenyl]-2-hydroxy-benzamide, or a salt or prodrug thereof, and one or more such anticancer agents, and a pharmaceutically acceptable carrier.
  • a patient having an AML is treated with 5- chloro-N-[2-(4-chloro-naphtalen-l-yloxy)-5-trifluoromethyl-phenyl]-2-hydroxy- benzamide, and cytarabine (ara-C) and/or an anthracycline.
  • the present invention provides a method of treating a chronic myelogenous leukemia (CML) comprising treating a patient identified as having one of the CML types with the compound 5-chloro-N-[2-(4-chloro-naphtalen-l-yloxy)- 5-trifluoromethyl-phenyl]-2-hydroxy-benzamide, and one or more other anticancer agents selected from antimetabolites, alkylating agents, interferon alfa, steroids, and tyrosine kinase inhibitors.
  • CML chronic myelogenous leukemia
  • a patient having a CML is treated with the compound 5-chloro-N-[2-(4-chloro-naphtalen-l-yloxy)-5-trifluoromethyl- phenyl]-2-hydroxy-benzamide and a tyrosine kinase inhibitor (e.g., imatinib, dasatinib, and nilotinib).
  • a tyrosine kinase inhibitor e.g., imatinib, dasatinib, and nilotinib.
  • the present invention also provides a pharmaceutical composition having the compound 5-chloro-N-[2-(4-chloro-naphtalen-l-yloxy)-5-trifluoromethyl- phenyl]-2-hydroxy-benzamide, or a salt or prodrug thereof, and one or more such anticancer agents, and a pharmaceutically acceptable carrier.
  • the present invention provides a method of treating an chronic lymphocytic leukemia (CLL) comprising treating a patient identified as having one of the CLL types with the compound 5-chloro-N-[2-(4-chloro-naphtalen- l-yloxy)-5-trifluoromethyl-phenyl]-2-hydroxy-benzamide, and one or more other anticancer agents selected from antimetabolites (e.g., purine analogues such as fludarabine), cyclophosphamide, anti-CD20 antibodies such as rituximab, steroids, anthracyclines, tubulin inhibitors, and anti-CD52 antibodies.
  • CLL chronic lymphocytic leukemia
  • a patient having a CLL is treated with the compound 5-chloro-N-[2-(4-chloro- naphtalen-l-yloxy)-5-trifluoromethyl-phenyl]-2-hydroxy-benzamide and one or more anticancer agents selected from fludarabine, cyclophosphamide and rituximab, doxorubicin, vincristine and prednisolone.
  • one or more anticancer agents selected from fludarabine, cyclophosphamide and rituximab, doxorubicin, vincristine and prednisolone.
  • the present invention also provides a pharmaceutical composition having the compound 5-chloro-N-[2-(4-chloro-naphtalen-l- yloxy)-5-trifluoromethyl-phenyl]-2-hydroxy-benzamide, or a salt or prodrug thereof, and one or more such anticancer agents, and a pharmaceutically acceptable carrier.
  • the present invention provides a method of treating a hairy cell leukemia comprising treating a patient with the compound 5-chloro- N-[2-(4-chloro-naphtalen-l-yloxy)-5-trifluoromethyl-phenyl]-2-hydroxy-benzamide, and one or more other anticancer agents selected from purine analogues, anti-CD20 antibodies such as rituximab, interferon alpha, anti-CD52 antibodies, anti-CD22 antibodies and anti-CD25 antibodies.
  • the patient is treated with the compound 5-chloro-N-[2-(4-chloro-naphtalen-l-yloxy)-5-trifluoromethyl- phenyl]-2-hydroxy-benzamide, and one or more anticancer agents selected from cladribine, pentostatin, rituximab, alemtuzumab, ibritumomab tiuxetan, 1-131 tositumomab and interferon alpha.
  • one or more anticancer agents selected from cladribine, pentostatin, rituximab, alemtuzumab, ibritumomab tiuxetan, 1-131 tositumomab and interferon alpha.
  • the present invention also provides a pharmaceutical composition having the compound 5-chloro-N-[2-(4-chloro-naphtalen-l- yloxy)-5-trifluoromethyl-phenyl]-2-hydroxy-benzamide, or a salt or prodrug thereof, and one or more such anticancer agents, and a pharmaceutically acceptable carrier.
  • the present invention provides a method of treating a Hodgkin's lymphoma comprising treating a patient identified as having one of the Hodgkin's lymphoma types with the compound 5-chloro-N-[2-(4-chloro- naphtalen-l-yloxy)-5-trifluoromethyl-phenyl]-2-hydroxy-benzamide, and one or more anticancer agents selected from adriamycin, bleomycin, vinblastine, dacarbazine, mechlorethamine, doxorubicin, vincristine, etoposide, and prednisone.
  • the compound is used in combination with an ABVD chemotherapy regimen (adriamycin, bleomycin, vinblastine, and dacarbazine), a Standford V chemotherapy regimen (mechlorethamine, doxorubicin, vinblastine, vincristine, bleomycin, etoposide, prednisone) or a BEACOPP chemotherapy regimen.
  • an ABVD chemotherapy regimen adriamycin, bleomycin, vinblastine, and dacarbazine
  • a Standford V chemotherapy regimen mechlorethamine, doxorubicin, vinblastine, vincristine, bleomycin, etoposide, prednisone
  • BEACOPP a BEACOPP chemotherapy regimen.
  • the present invention also provides a pharmaceutical composition having the compound 5- chloro-N-[2-(4-chloro-naphtalen-l-yloxy)-5-trifluoromethyl-phenyl]-2-hydroxy- benzamide, or
  • the present invention provides a method of treating a non-Hodgkin's lymphoma comprising treating a patient identified as having one of the non-Hodgkin's lymphoma types with the compound 5-chloro-N-[2-(4-chloro- naphtalen-l-yloxy)-5-trifluoromethyl-phenyl]-2-hydroxy-benzamide, and one or more anticancer agents selected from Cytoxan, hydroxyrubicin vincristine, prednisone and rituximab.
  • the patient is treated with the compound, in combination with a CHOP (Cytoxan, hydroxyrubicin (adriamycin), Oncovin (vincristine), prednisone) or COP (Cytoxan, Oncovin (vincristine), prednisone) chemotherapy regimen, with or without rituximab.
  • CHOP Cytoxan, hydroxyrubicin (adriamycin), Oncovin (vincristine), prednisone
  • COP Cytoxan, Oncovin (vincristine), prednisone
  • the present invention also provides a pharmaceutical composition having the compound 5-chloro-N-[2-(4-chloro- naphtalen-l-yloxy)-5-trifluoromethyl-phenyl]-2-hydroxy-benzamide, or a salt or prodrug thereof, and one or more such anticancer agents, and a pharmaceutically acceptable carrier.
  • the present invention provides a method of treating a multiple myeloma comprising treating a patient identified as having multiple myeloma with the compound 5-chloro-N-[2-(4-chloro-naphtalen-l-yloxy)-5- trifluoromethyl-phenyl]-2-hydroxy-benzamide, and one or more anticancer agents selected from dexamethasone, thalidomide, and vincristine, doxorubicin, bortezomib, and lenalidomide.
  • the present invention also provides a pharmaceutical composition having the compound 5-chloro-N-[2-(4-chloro-naphtalen-l-yloxy)-5- trifluoromethyl-phenyl]-2-hydroxy-benzamide, or a salt or prodrug thereof, and one or more such anticancer agents, and a pharmaceutically acceptable carrier.
  • the present invention provides a method of treating a myelodysplastic syndrome (MDS) comprising treating a patient identified as having MDS with the compound 5-chloro-N-[2-(4-chloro-naphtalen-l-yloxy)-5- trifluoromethyl-phenyl]-2-hydroxy-benzamide, and one or more anticancer agents selected from demethylating agents (e.g., 5-azacytidine, decitabine) and immunomodulatory agents such as thalidomide and lenalidomide.
  • demethylating agents e.g., 5-azacytidine, decitabine
  • immunomodulatory agents such as thalidomide and lenalidomide.
  • the present invention also provides a pharmaceutical composition having the compound 5-chloro- N-[2-(4-chloro-naphtalen-l-yloxy)-5-trifluoromethyl-phenyl]-2-hydroxy-benzamide, or a salt or prodrug thereof, and one or more such anticancer agents, and a pharmaceutically acceptable carrier.
  • the treatment with the compound 5-chloro-N-[2-(4-chloro-naphtalen-l-yloxy)-5-trifluoromethyl-phenyl]-2-hydroxy- benzamide can be a first line treatment, i.e., the patient has not completed any treatment cycle with another anticancer agent.
  • the patient treated with the compound can be patient who is refractory, reflective or resistant to another anticancer agent.
  • the active compound is desirably administered in a therapeutically effective amount, i.e., in an amount sufficient to promote/induce apoptosis and/or to reduce the proliferation of abnormal cells.
  • the dosage for the treatment is preferably from about 5 mg 5-chloro-N-[2-(4-chloro-naphtalen-l-yloxy)-5- trifluoromethyl-phenyl]-2-hydroxy-benzamide, or a salt thereof, per kg of body weight to about 250 mg/kg, and more preferably from about 5 mg/kg to about 100 mg/kg, per treatment.
  • the amount can vary with the body weight of the patient treated and the state of disease conditions.
  • the active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at predetermined intervals of time.
  • Each treatment cycle can be treatment at everyday, or treatment once every other day, treatment every week, one treatment every two weeks or one treatment per month.
  • Preferred dosages and dosing regimens for humans will be perfected following clinical trials using methods well known to those of ordinary skill in the art of clinical trials, and will be further optimized for particular types and stages of cancers.
  • a therapeutically effective amount of another therapeutic compound can be administered in a separate pharmaceutical composition, or alternatively included in the pharmaceutical composition according to the present invention.
  • the pharmacology and toxicology of other therapeutic compositions are known in the art. See e.g., Physicians Desk Reference, Medical Economics, Montvale, NJ; and The Merck Index, Merck & Co., Rahway, NJ.
  • the therapeutically effective amounts and suitable unit dosage ranges of such compounds used in art can be equally applicable in the present invention.
  • the therapeutically effective amount for each active compound can vary with factors including but not limited to the stability of the active compound in the patient's body, the severity of the conditions to be alleviated, the total weight of the patient treated, the route of administration, the ease of absorption, distribution, and excretion of the active compound by the body, the age and sensitivity of the patient to be treated, and the like, as will be apparent to a skilled artisan.
  • the amount of administration can also be adjusted as the various factors change over time.

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Abstract

La présente invention concerne un procédé de traitement d'une hémopathie maligne ou d'un cancer des cellules sanguines par l'administration à un patient qui a besoin d'un tel traitement d'une quantité efficace de 5-chloro-N-[2-(4-chloro-naphtalén-1-yloxy)-5-trifluorométhyl-phényl]-2-hydroxy-benzamide ou d'un sel ou d'un promédicament pharmaceutiquement acceptable de celui-ci.
PCT/US2007/067241 2006-04-21 2007-04-23 Procede de traitement des malignites de la lignee hematopoietique WO2007124498A2 (fr)

Applications Claiming Priority (2)

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US79387806P 2006-04-21 2006-04-21
US60/793,878 2006-04-21

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WO2007124498A2 true WO2007124498A2 (fr) 2007-11-01
WO2007124498A3 WO2007124498A3 (fr) 2008-08-07

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004006858A2 (fr) * 2002-07-15 2004-01-22 Myriad Genetics, Inc Composes, compositions et methodes d'utilisation de ces derniers
WO2006060580A1 (fr) * 2004-11-30 2006-06-08 Myriad Genetics, Inc. Preparations therapeutiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004006858A2 (fr) * 2002-07-15 2004-01-22 Myriad Genetics, Inc Composes, compositions et methodes d'utilisation de ces derniers
WO2006060580A1 (fr) * 2004-11-30 2006-06-08 Myriad Genetics, Inc. Preparations therapeutiques

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