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EP-3565561-B1 - PHOSPHAPLATIN COMPOUNDS AS THERAPEUTIC AGENTS FOR TREATMENT OF BONE BLOOD CANCERS

EP3565561B1EP 3565561 B1EP3565561 B1EP 3565561B1EP-3565561-B1

Inventors

  • PRICE, MATTHEW
  • AMES, Tyler

Dates

Publication Date
20260506
Application Date
20180105

Claims (15)

  1. A phosphaplatin compound having a structure of formula II: or a pharmaceutically acceptable salt thereof, for use in the treatment of a bone or blood cancer selected from the group consisting of osteosarcoma, chondrosarcoma, Ewing tumor, malignant fibrous histiocytoma (MFH), fibrosarcoma, giant cell tumor, chordoma, spindle cell sarcomas, multiple myeloma, leukemia, childhood acute myelogenous leukemia (AML), chronic myelomonocytic leukaemia (CMML), hairy cell leukaemia, juvenile myelomonocytic leukaemia (JMML), myelodysplastic syndromes, myelofibrosis, myeloproliferative neoplasms, polycythaemia vera, and thrombocythaemia, or a cancer that has metastasized to bone in a subject, wherein R 3 is selected from aliphatic diamines and aromatic diamines and coordinated to Pt through two amino (NH 2 ) groups.
  2. The phosphaplatin compound for use of claim 1, wherein R 3 is selected from 1,2-ethylenediamine and cyclohexane-1,2-diamine.
  3. The phosphaplatin compound for use of claim 1, wherein the phosphaplatin compound is selected from the group consisting of: pharmaceutically acceptable salts, and mixtures thereof.
  4. The phosphaplatin compound for use of claim 1, wherein the phosphaplatin compound is (R,R)-1,2-cyclohexanediamine-(dihydrogen pyrophosphato) platinum(II) (or "PT-112"), or a pharmaceutically acceptable salt thereof.
  5. A phosphaplatin compound having a structure of formula IV: or a pharmaceutically acceptable salt thereof, for use in the treatment of a bone or blood cancer selected from the group consisting of osteosarcoma, chondrosarcoma, Ewing tumor, malignant fibrous histiocytoma (MFH), fibrosarcoma, giant cell tumor, chordoma, spindle cell sarcomas, multiple myeloma, leukemia, childhood acute myelogenous leukemia (AML), chronic myelomonocytic leukaemia (CMML), hairy cell leukaemia, juvenile myelomonocytic leukaemia (JMML), myelodysplastic syndromes, myelofibrosis, myeloproliferative neoplasms, polycythaemia vera, and thrombocythaemia, or a cancer that has metastasized to bone in a subject, wherein R 3 is selected from aliphatic diamines and aromatic diamines and coordinated to Pt through two amino (NH 2 ) groups.
  6. The phosphaplatin compound for use of claim 5, wherein R 3 is selected from 1,2-ethylenediamine and cyclohexane-1,2-diamine.
  7. The phosphaplatin compound for use of claim 5, wherein the monomeric platinum (IV) pyrophosphate complex has a formula (IV), wherein R 3 is 1,2-ethylene-diamine or cyclohexane-1,2-diamine.
  8. The phosphaplatin compound for use of claim 5, wherein the phosphaplatin compound is selected from the group consisting of: pharmaceutically acceptable salts, and mixtures thereof.
  9. The phosphaplatin compound for use of any one of claims 1 to 7, wherein the compound is for administration by intravenous or intraperitoneal injection.
  10. The phosphaplatin compound for use of any one of claims 1 to 9, wherein the dose of pyrophosphate platinum complex is in the range of from about 1 mg and to about 200 mg/Kg based on body weight of the subject.
  11. The phosphaplatin compound for use of any one of claims 1 to 10, wherein the bone or blood cancer is selected from the group consisting of childhood acute myelogenous leukemia (AML), chronic myelomonocytic leukaemia (CMML), hairy cell leukaemia, juvenile myelomonocytic leukaemia (JMML), myelodysplastic syndromes, myelofibrosis, myeloproliferative neoplasms, polycythaemia vera, and thrombocythaemia.
  12. The phosphaplatin compound for use of claim 11, wherein the bone or blood cancer is selected from the group consisting of osteosarcoma, chondrosarcoma, Ewing tumor, malignant fibrous histiocytoma (MFH), fibrosarcoma, giant cell tumor, chordoma, spindle cell sarcomas, multiple myeloma, and leukemia.
  13. The phosphaplatin compound for use of any one of claims 1 to 12, wherein the compound is for administration in conjunction with a second anti-cancer agent.
  14. The phosphaplatin compound for use of claim 13, wherein the second anti-cancer agent is selected from the group consisting of alkylating agents, glucocorticoids, immunomodulatory drugs (IMiDs) and proteasome inhibitors.
  15. Phosphaplatin compound (R,R)-1,2-cyclohexanediamine-(dihydrogen pyrophosphato) platinum(II) (or "PT-112"), or a pharmaceutically acceptable salt thereof, for use in the treatment of a bone or blood cancer selected from osteosarcoma, chondrosarcoma, Ewing tumor, malignant fibrous histiocytoma (MFH), fibrosarcoma, giant cell tumor, chordoma, spindle cell sarcomas, multiple myeloma, leukemia, childhood acute myelogenous leukemia (AML), chronic myelomonocytic leukaemia (CMML), hairy cell leukaemia, juvenile myelomonocytic leukaemia (JMML), myelodysplastic syndromes, myelofibrosis, myeloproliferative neoplasms, polycythaemia vera, and thrombocythaemia, or a cancer that has metastasized to bones.

Description

TECHNICAL FIELD OF THE INVENTION This invention relates to use of phosphaplatin compounds as therapeutic agents for the treatment of bone or blood cancers. BACKGROUND OF THE INVENTION Bones are made up of osteoid (hard), cartilaginous (tough and flexible), and fibrous (threadlike) tissues, as well as elements of bone marrow. Bone cancer can start in any bone in the body and in any type of bone tissues. If discovered early, bone cancer could be treated by surgery to remove the tumor and the cancerous cells, which would be ideal especially if the tumor and cancerous cells have not spread and can be removed cleanly. More often the treatment needs a combination of surgery with other treatments, such as stem cell transplantation, chemotherapy, radiation therapy, etc. A targeted chemotherapy for the treatment of bone cancers, in principle, requires that the chemotherapy agent, after systemic administration, accumulate in the cancerous bone tissues. This requirement, in addition to the large variety of bone cancers, renders development of bone cancer therapies a challenging task. Hematologic (or blood) cancer is a close relative to bone cancer since it begins in blood-forming tissue, such as the bone marrow, or in the cells of the immune system. Examples of hematologic cancer are leukemia, lymphoma, and multiple myeloma. In particular, multiple myeloma, a neoplastic plasma-cell disorder characterized by clonal proliferation of malignant plasma cells in the bone marrow microenvironment, monoclonal protein in the blood or urine, and associated organ dysfunction, accounts for approximately 1% of neoplastic diseases and 13% of hematologic cancers. (Palumbo, A. and Anderson, K.; "Multiple Myeloma," New. Engl. J. Med., 2011, 364(11): 1046-1060). Although treatments have been developed for multiple myeloma, including alkylating agents, glucocorticoids, immunomodulatory drugs (IMiDs), and proteasome inhibitors, see Chesi, M., et al., Blood, 2012, 120(2), 376-385, multiple myeloma is still considered a fatal B cell malignancy. US 2013/0281377A1. The platinum-based antineoplastic agents, such as cisplatin, carboplatin, and oxaliplatin, though without an alkyl group, are sometimes described as "alkylating-like" due to their similar effects to those of alkylating antineoplastic agents. Cruet-Hennequart, S., et al. DNA Repair (Amst.), 2008, 7 (4): 582-596. They have been used for treating a variety of cancers, such as ovarian cancer, testicular cancer, small-cell lung cancer, and colorectal cancer. A new class of platinum-based antitumor agents disclosed in U.S. Patent Nos. 7,700,649 and 8,034,964, both to R. Bose, namely "phosphaplatin" complexes (because they contain a pyrophosphate group), function as anti-cancer agents without reliance on covalently binding DNA. These phosphaplatin complexes exhibit significantly different anticancer properties compared to the classical platinum drugs such as cisplatin, carboplatin, and oxaliplatin. See Lu Yang, et al., "Insights into the anti-angiogenic properties of phosphaplatins"; J. Inorg. Biochem., 2016, vol. 164, pages 5-16. As a result, they have been found to be efficacious in the treatment of various cisplatin and carboplatin-resistant cancers. These phosphaplatin compounds harbor a pyrophosphate moiety within their composition, which we posit may render these anti-cancer agents selective to targeting cancers that originate in, reside in, or metastasize to the bone. Yang, L., et al, Insights into the anti-angiogenic properties of phosphaplatins, Journal of Inorganic Biochemistry, 164, pp.5-16 discloses that Pt(II) and Pt(IV) phosphaplatins possess diverse antitumor properties.Examples of such diseases include prostate or other solid tumor cancers that have a propensity to metastasize to bone, and multiple myeloma or other hematological malignancies that originate in bone. SUMMARY OF THE INVENTION This application discloses a phosphaplatin compound for use in a method of treating a bone or blood cancer selected from the group consisting of osteosarcoma, chondrosarcoma, Ewing tumor, malignant fibrous histiocytoma (MFH), fibrosarcoma, giant cell tumor, chordoma, spindle cell sarcomas, multiple myeloma, leukemia, childhood acute myelogenous leukemia (AML), chronic myelomonocytic leukaemia (CMML), hairy cell leukaemia, juvenile myelomonocytic leukaemia (JMML), myelodysplastic syndromes, myelofibrosis, myeloproliferative neoplasms, polycythaemia vera, and thrombocythaemia, or a cancer that has metastasized to bone in a subject, using phosphaplatin compounds, based on a surprising discovery that these pyrophosphato-platinum complexes can accumulate in bone tissues in treated mice and can effectively reduce M-spike levels in an established multiple myeloma mice model. The phosphaplatin compound for use in the method comprises, or consists essentially of, administration to a subject having a bone or blood cancer a therapeutically effective amount of a compound according to formulae II or