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EP-3999056-B1 - PHARMACEUTICAL COMBINATION AND ITS USE IN THE PREVENTION AND TREATMENT OF CANCER

EP3999056B1EP 3999056 B1EP3999056 B1EP 3999056B1EP-3999056-B1

Inventors

  • ZHAI, YIFAN
  • YANG, DAJUN
  • FANG, DOUGLAS DONG
  • TANG, Qiuqiong

Dates

Publication Date
20260506
Application Date
20200716

Claims (9)

  1. A pharmaceutical combination comprising: substance M, wherein the substance M is a pharmaceutically acceptable salt thereof or a solvate thereof; and substance N, wherein the substance N is a pharmaceutically acceptable salt thereof or a solvate thereof
  2. The pharmaceutical combination as defined in claim 1, wherein, the substance M is a pharmaceutically acceptable salt thereof or a solvate thereof; and/or, the substance N is or or a solvate thereof.
  3. A single pharmaceutical composition comprising: substance M, a pharmaceutically acceptable salt thereof or a solvate thereof; substance N, a pharmaceutically acceptable salt thereof or a solvate thereof; and, a pharmaceutical excipient, wherein, the substance M and the substance N are as defined in claim 1 or 2.
  4. A kit for use in preventing and/or treating cancer, comprising: a first container comprising a first single pharmaceutical composition comprising substance M, a pharmaceutically acceptable salt thereof or a solvate thereof, and a pharmaceutical excipient; and, a second container comprising a second single pharmaceutical composition comprising substance N, a pharmaceutically acceptable salt thereof or a solvate thereof, and a pharmaceutical excipient; wherein, the substance M and the substance N are as defined in claim 1 or 2.
  5. The pharmaceutical combination as defined in claim 1 or 2 for use in a method for preventing and/or treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of substance M or a pharmaceutically acceptable salt thereof or a solvate thereof and substance N or a pharmaceutically acceptable salt thereof or a solvate thereof; wherein, the substance M and the substance N are as defined in claim 1 or 2.
  6. The pharmaceutical combination for use as defined in claim 5, wherein, the cancer is selected from the group consisting of adrenal cortical cancer, advanced cancer, anal cancer, aplastic anemia, bile duct cancer, bladder cancer, bone cancer, bone metastasis, brain/CNS tumors in adults, brain/CNS tumors in children, breast cancer, breast cancer in men, cancer in children, cancer of unknown primary, Castleman disease, cervical cancer, colon/rectum cancer, endometrial cancer, esophagus cancer, Ewing family of tumors, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumor, gestational trophoblastic disease, Hodgkin disease, Kaposi sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, acute lymphocytic leukemia in adults, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myelomonocytic leukemia, leukemia in children, liver cancer, lung cancer-non- small cell, lung cancer-small cell, lung carcinoid tumor, lymphoma of the skin, malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-Hodgkin lymphoma in children, oral cavity and oropharyngeal cancer, osteosarcoma, liposarcoma, leiomyosarcoma, alveolar and embryonal rhabdomyosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumors, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma-adult soft tissue cancer, skin cancer-basal and squamous cell, skin cancer-melanoma, small intestine cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, and Wilms tumor; e.g., the cancer is acute myeloid leukemia with wild type FLT3 gene or mutant FLT3 gene; e.g., the cancer is acute myeloid leukemia with mutant FLT3 gene comprising a mutation selected from the group consisting of ITD mutation, D835H mutation, D835Y mutation, K663Q mutation, N841I mutation and R834Q mutation; e.g., the cancer is acute myeloid leukemia with mutant FLT3 gene comprising an ITD mutation and wild type TP53 gene; and/or, the substance M and the substance N are administrated simultaneously or separately; and/or, the substance M is administrated orally or by injection such as intravenous injection, subcutaneous injection, or intramuscular injection; and/or, the substance N is administrated orally or by injection such as intravenous injection, subcutaneous injection, or intramuscular injection.
  7. The pharmaceutical combination for use as defined in claim 5 or 6, wherein, the substance M is administered at a dose based on the body weight of the subject, wherein the dose is 0.01 to 50 mg/kg, e.g., 0.05 mg/kg, 0.1 mg/kg, 0.2 mg/kg, 0.25 mg/kg, 0.3 mg/kg, 0.35 mg/kg, 0.4 mg/kg, 0.45 mg/kg, 0.5 mg/kg, 0.55 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg or 50 mg/kg; wherein the doses of the substance M can be administered to the subject in a frequency of QD, BID, TID, Q2D, QW, BIW or Q2W; or, the substance M is administered to the subject in a fixed dose to the subject, wherein the fixed dose is 0.1-1000 mg, e.g., 0.1, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475 or 500 mg; wherein the fixed doses of the substance M can be administrated to the subject in a frequency of QD, BID, TID, Q2D, QW, BIW or Q2W.
  8. The pharmaceutical combination for use as defined in any one of claims 5-7, wherein, the substance N is administered at a dose based on the body weight of the subject, wherein the dose is 0.01 to 50 mg/kg, e.g., 0.05 mg/kg, 0.1 mg/kg, 0.2 mg/kg, 0.25 mg/kg, 0.3 mg/kg, 0.35 mg/kg, 0.4 mg/kg, 0.45 mg/kg, 0.5 mg/kg, 0.55 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg or 50 mg/kg; wherein the doses of the substance N can be administered to the subject in a frequency of QD, BID, TID, Q2D, QW, BIW or Q2W; or, the substance N is administered to the subject in a fixed dose, wherein the fixed dose is 0.1-1000 mg, e.g., 0.1, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475 or 500 mg; wherein the fixed doses of the substance N can be administrated to the subject in a frequency of QD, BID, TID, Q2D, QW, BIW or Q2W.
  9. The pharmaceutical combination for use as defined in any one of claims 5-8, wherein, the substance M and the substance N are administrated in a weight ratio of 50:1 to 1:50, e.g. 50:1, 45:1, 40:1, 35:1, 30:1, 25:1, 20:1, 15:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:15, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45 or 1:50.

Description

Field of the invention The invention relates to a pharmaceutical composition and use thereof. The invention also relates to a combination therapy involving a MDM2 inhibitor and a FLT3-inhibitors for the treatment of a patient suffering from cancer, particular a cancer with internal tandem duplication of the FLT3 gene. Background of the invention Targeting the p53 antagonist MDM2 is a novel approach to restore the crucial p53 tumor suppressor function in AML cells (Kojima K, Konopleva M, Samudio IJ, et al. Blood. 2005, 106(9): 3150-3159). Acute myeloid leukemia (AML) is one of the most common types of leukemia among adults. The past decade has witnessed major advances in our comprehension of the biologic heterogeneity of AML. An internal tandem duplication (ITD) of FLT3 (Fms-like tyrosine kinase 3) gene has been found in AML (Kiyoi etc., H Internal tandem duplication (ITD) of FLT3 gene is a novel modality of elongation mutation which causes constitutive activation of the product, Leukemia (1998) 12, 1333-1337). In internal tandem duplication of FLT3 gene, a fragment of the JM domain-coding sequence, which primarily consists of exon 11 but sometimes includes intron 11 and exon 12, is arranged as a direct head-to-tail sequence. An internal tandem duplication of the FLT3 gene accounts for nearly 20% of acute myeloid leukemia (AML), and their prognosis is poor, particularly in unfit, refractory or relapsed patients, thus highlighting an unmet need for novel therapeutic approaches. Mutations within the tyrosine kinase domain (TKD) are the second most common type of FLT3 mutation in AML (occurring in up to 14% of adult patients with AML). Mutations within the TKD are primarily point mutations within the activation loop (e.g., residues D835, I836, and Y842) of the TKD2 and, to a lesser extent, within the TKD1 (e.g., residues N676 and F691). Other point mutations and smaller insertions/deletions have also been identified within the TKD and other domains (e.g., extracellular and juxtamembrane domains (occurring in about 2% of patients with AML)). The prognostic significance of FLT3-TKD mutations in the overall AML population and the impact of the FLT3-TKD allelic ratio are still debatable and may depend on additional mutations as well as the cytogenetic background (Patnaik etc., The importance of FLT3 mutational analysis in acute myeloid leukemia, Leukemia & Lymphoma (2018) 59, 2273-2286). FLT3 kinase is part of a family of proteins called receptor tyrosine kinases (RTKs). WO2012000304A1 (also published as EP2594567A1, US2013196985A1 and so on) discloses a series of heterocyclic benzene compounds of protein tyrosine kinase which have advanced into clinical trial, and some of them have been approved for clinical use and achieved excellent therapeutic effect. WO2015161032A1 discloses MDM2 inhibitors and their use in the treatment of cancer. However, the indications response to cancer therapy still remains a challenge. There is a continuing need for development of inhibitors on cancer treatment. Summary of the invention The invention relates to a novel pharmaceutical combination and use thereof, as defined in the appended claims. In one aspect, the disclosure provides a pharmaceutical combination comprising: substance M, wherein the substance M is a compound of formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof; andsubstance N, wherein the substance N is a compound of formula (II), a pharmaceutically acceptable salt thereof or a solvate thereof; wherein, is selected from the group consisting of ring B is a C4-7 carbocyclic ring;R1 is H, substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted 4 to 12-membered heterocycloalkyl, ORa, or NRaRb; the heteroatom of the heterocycloalkyl is independently selected from the group consisting of nitrogen, oxygen and sulfur, the number of the heteroatom is 1 to 4;n is 0, 1, or 2;R2, R3, R4, R5, R7, R8, R9, and R10 are independently selected from the group consisting of H, F, Cl, CH3 and CF3;R6 is each of Ra is independently H, or substituted or unsubstituted C1-4 alkyl;each of Rb is independently H, or substituted or unsubstituted C1-4 alkyl;Rc and Rd are substituents on one carbon atom of ring B, whereinRc is H, C1-3 alkyl, C1-3 alkylene-ORa, ORa, or halogen;Rd is H, C1-3 alkyl, C1-3 alkylene-ORa, ORa, or halogen;or, Rc and Rd are taken together with the carbon to which they are attached to form a 4 to 6-membered spiro substituent, optionally containing an oxygen atom;Re is -C(=O)ORa, -C(=O)NRaRb, or -C(=O)NHSO2CH3; wherein Z is CH or N;L1 is NH, -N= or CH;L2 is -CONH- or -NHCO-;R15 is H, C1-6 alkyl, C3-6 cycloalkyl, C1-5 alkyl substituted by one or two hydroxyl, or phenyl;or, R15 together with L1, the carbon to which L1 is attached, Z and ring A form a moiety having the structure wherein L1 is NH, -N= or CH; X, Y and Z are independently N or CH; ring D is an aromatic heterocycle containing 1 to