WO2020211860A1 - 用于治疗尤因肉瘤的喹啉类化合物或其药学上可接受的盐 - Google Patents

用于治疗尤因肉瘤的喹啉类化合物或其药学上可接受的盐 Download PDF

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WO2020211860A1
WO2020211860A1 PCT/CN2020/085552 CN2020085552W WO2020211860A1 WO 2020211860 A1 WO2020211860 A1 WO 2020211860A1 CN 2020085552 W CN2020085552 W CN 2020085552W WO 2020211860 A1 WO2020211860 A1 WO 2020211860A1
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acid
ewing sarcoma
sarcoma
ewing
compound
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PCT/CN2020/085552
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English (en)
French (fr)
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湛筱乐
屠礼凡
杨朝强
张喜全
王训强
许婕
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正大天晴药业集团股份有限公司
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Priority to AU2020259565A priority Critical patent/AU2020259565A1/en
Priority to CN202080019229.3A priority patent/CN113710658B/zh
Priority to CA3137204A priority patent/CA3137204A1/en
Priority to JP2021562183A priority patent/JP2022529295A/ja
Priority to KR1020217037623A priority patent/KR20220003560A/ko
Priority to US17/603,886 priority patent/US20220193067A1/en
Priority to EP20790646.2A priority patent/EP3957631A4/en
Publication of WO2020211860A1 publication Critical patent/WO2020211860A1/zh

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention belongs to the field of medicine, and specifically relates to quinoline compounds or pharmaceutically acceptable salts thereof for treating Ewing sarcoma, and quinoline compounds or pharmaceutically acceptable salts thereof for combined treatment of Ewing sarcoma.
  • Ewing's sarcoma is recognized as an independent bone tumor, defined as a small round cell tumor originating in the bone or soft tissue of the neuroectoderm. Ewing sarcoma accounts for 6%-8% of all primary bone tumors and 10%-14.2% of malignant bone tumors. It is second only to osteosarcoma and chondrosarcoma. It is the most common malignant primary bone tumor in children and adolescents. , And there are slightly more men than women.
  • Ewing's sarcoma The most common early symptoms of Ewing's sarcoma are pain and swelling. More than 60% of patients have intermittent pain in the early stage of the disease, and the painful part spreads as the tumor spreads. As the pain intensified, local lumps appeared, and the lumps were tender. Secondly, there are symptoms of nerve damage such as nerve root and spinal cord. Some patients have a fever of 38°C to 40°C, and the serum high-density lipoprotein, cholesterol, and red blood cell sedimentation rate are significantly increased, accompanied by an increase in white blood cell count and anemia. The lesion can produce larger soft tissue masses. Because Ewing's sarcoma has a high degree of malignancy and rapid metastasis, surgery, radiotherapy or single-agent chemotherapy alone have unsatisfactory results, and the 5-year survival rate does not exceed 10%.
  • Ewing's sarcoma the most effective treatment for Ewing's sarcoma is comprehensive therapy, that is, radiotherapy plus chemotherapy plus surgery or no surgery.
  • chemotherapy is mostly combined with multiple drugs.
  • multi-drug combination chemotherapy for Ewing’s sarcoma can significantly improve the 5-year survival rate, because Ewing’s sarcoma mostly metastasizes within 2 years, chemotherapy generally takes 2 years, and long-term chemotherapy brings accumulation of toxic side effects. For example, complications of hematopoietic system, respiratory system, cardiovascular system, nervous system, urinary system, etc. Therefore, there is an urgent need to develop a new treatment plan for Ewing's sarcoma.
  • the present invention provides the use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating Ewing's sarcoma.
  • compound I 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy Yl]methyl]cyclopropylamine, which has the following structural formula:
  • the Ewing sarcoma is intraosseous Ewing sarcoma, extraosseous Ewing sarcoma, or periosteal Ewing sarcoma.
  • the Ewing sarcoma is osteolytic Ewing sarcoma, sclerosing Ewing sarcoma, mixed Ewing sarcoma.
  • the Ewing sarcoma is advanced Ewing sarcoma.
  • advanced Ewing sarcoma refers to a primary tumor or a locally recurring tumor that cannot be cured by surgery or other local treatments, or the patient refuses surgery or other local treatments.
  • advanced Ewing's sarcoma refers to Ewing's sarcoma in which distant metastases have occurred, but the metastases cannot be cured by surgery or other local treatments, or the patient refuses surgery or other local treatments.
  • the Ewing sarcoma is Ewing sarcoma that has failed prior treatment.
  • the Ewing sarcoma is Ewing sarcoma that has failed radiotherapy and/or chemotherapy. More preferably, the Ewing sarcoma is Ewing sarcoma that has received the following chemotherapeutic agents and has failed treatment selected from the group consisting of cyclophosphamide, ifosfamide, doxorubicin, pirarubicin, doxorubicin, dactinomycin, One or more of bleomycin, vincristine, carmustine, etoposide, actinomycin D, methotrexate, and cisplatin.
  • the chemotherapeutic agent that the subject of Ewing's sarcoma has received is selected from one of cyclophosphamide, ifosfamide, doxorubicin, pirarubicin, vincristine, etoposide, or Many kinds.
  • the compound I described in this application can be administered in its free base form, or in the form of its salts, hydrates and prodrugs, which are converted into the free base form of compound I in vivo.
  • a pharmaceutically acceptable salt of Compound I is within the scope of the present invention, and the salt can be produced from different organic acids and inorganic acids according to methods known in the art.
  • the pharmaceutically acceptable salt of Compound I includes, but is not limited to, the salt formed by Compound I and any of the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, Propionic acid, caproic acid, heptanoic acid, cyclopentane propionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamon Acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, p-toluenesulfonic acid, 3-phenylpropionic acid , Trimethyl
  • the administration is in the form of Compound I hydrochloride. In some embodiments, the administration is in the form of Compound I monohydrochloride. In some embodiments, the administration is in the form of Compound I dihydrochloride. In some embodiments, the administration is in the crystalline form of Compound I hydrochloride. In a specific embodiment, it is administered in the crystal form of Compound I dihydrochloride. In some embodiments, the administration is in the form of Compound I maleate.
  • the present invention provides a method for treating Ewing's sarcoma, the method comprising administering to a patient in need of treatment a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof.
  • Compound I or a pharmaceutically acceptable salt thereof can be administered by various routes, including but not limited to a route selected from the group consisting of oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, Sublingual, intramuscular, rectal, transbuccal, intranasal, inhalation, vagina, intraocular, topical administration, subcutaneous, intra-fat, intra-articular, intraperitoneal or intrathecal. In a specific embodiment, it is administered orally.
  • the method of administration of Compound I can be comprehensively determined according to the activity, toxicity, and patient tolerance of the drug.
  • Compound I or a pharmaceutically acceptable salt thereof may be provided in the following forms: suitable for oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal , Buccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intra-fat, intra-articular, intraperitoneal or intrathecal formulations; preferably formulations suitable for oral administration.
  • Compound I or a pharmaceutically acceptable salt thereof may be preferably provided in the form of a tablet, capsule, powder, granule, dripping pill, paste or powder, more preferably a tablet or capsule Agent.
  • the administration amount of Compound I or a pharmaceutically acceptable salt thereof can be determined based on the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health of the patient.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof may be 3 mg to 30 mg, preferably 5 mg to 20 mg, more preferably 8 mg to 16 mg; The dosage is 8 mg to 14 mg; most preferably 8 mg, 10 mg or 12 mg.
  • Compound I or a pharmaceutically acceptable salt thereof is administered at intervals.
  • the interval administration includes an administration period and a drug withdrawal period.
  • Compound I or a pharmaceutically acceptable salt thereof can be administered one or more times a day.
  • Compound I or its pharmaceutically acceptable salt is administered every day during the administration period, and then the administration is stopped for a period of time during the withdrawal period, followed by the administration period, and then the withdrawal period, which can be repeated many times.
  • the ratio of the administration period and the drug withdrawal period in terms of days is 2:0.5-5, preferably 2:0.5-3, more preferably 2:0.5-2, and even more preferably 2:0.5-1.
  • the interval administration can be selected from one of the following ways: continuous administration for 2 weeks and withdrawal for 2 weeks, continuous administration for 2 weeks and withdrawal for 1 week or continuous administration for 5 days The drug was stopped for 2 days; the interval administration method can be repeated many times.
  • the present invention provides a pharmaceutical composition for treating Ewing's sarcoma, the pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • the pharmaceutical composition includes, but is not limited to, suitable for oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, inhalation, vagina, intraocular, Preparations for topical, subcutaneous, intra-fat, intra-articular, intraperitoneal or intrathecal administration; preparations suitable for oral administration, including tablets, capsules, powders, granules, dripping pills, pastes, powders, etc. , Preferably tablets and capsules.
  • the tablets can be ordinary tablets, dispersible tablets, effervescent tablets, sustained-release tablets, controlled-release tablets or enteric-coated tablets
  • capsules can be ordinary capsules, sustained-release capsules, controlled-release capsules or enteric-coated capsules.
  • the oral preparation can be prepared by conventional methods using pharmaceutically acceptable carriers known in the art.
  • Pharmaceutically acceptable carriers include fillers, absorbents, wetting agents, binders, disintegrants, lubricants and the like.
  • Fillers include starch, lactose, mannitol, microcrystalline cellulose, etc.; absorbents include calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; wetting agents include water, ethanol, etc.; binders include hypromellose, poly Vividone, microcrystalline cellulose, etc.; disintegrants include croscarmellose sodium, crospovidone, surfactants, low-substituted hydroxypropyl cellulose, etc.; lubricants include magnesium stearate, talc Powder, polyethylene glycol, sodium lauryl sulfate, micro-powder silica gel, talc, etc. Pharmaceutical excipients also include colorants, sweeteners and so on.
  • the pharmaceutical composition is a solid preparation suitable for oral administration.
  • the composition may be in the form of tablets or capsules, for example.
  • the pharmaceutical composition is a capsule.
  • the pharmaceutically acceptable carrier of the oral solid preparation includes mannitol, microcrystalline cellulose, hydroxypropyl cellulose, and magnesium stearate.
  • the present invention provides the use of Compound I or a pharmaceutically acceptable salt thereof in combination with a second therapeutic agent in the preparation of a combination drug for the treatment of Ewing's sarcoma.
  • the Ewing sarcoma includes, but is not limited to, intraosseous Ewing sarcoma, extraosseous Ewing sarcoma, and periosteal Ewing sarcoma.
  • the Ewing sarcoma includes, but is not limited to, osteolytic Ewing sarcoma, sclerosing Ewing sarcoma, and mixed Ewing sarcoma.
  • the Ewing sarcoma is advanced Ewing sarcoma.
  • advanced Ewing sarcoma refers to a primary tumor or a locally recurring tumor that cannot be cured by surgery or other local treatments, or the patient refuses surgery or other local treatments.
  • advanced Ewing's sarcoma refers to Ewing's sarcoma in which distant metastases have occurred, but the metastases cannot be cured by surgery or other local treatments, or the patient refuses surgery or other local treatments.
  • the Ewing sarcoma includes, but is not limited to, Ewing sarcoma that has failed prior treatment.
  • the Ewing sarcoma is Ewing sarcoma that has failed radiotherapy and/or chemotherapy.
  • the chemotherapeutic agent that the subject of the Ewing sarcoma has received is selected from cyclophosphamide, ifosfamide, doxorubicin, pirarubicin, doxorubicin, dactinomycin, bleomycin One or more of, vincristine, carmustine, etoposide, actinomycin D, methotrexate, and cisplatin.
  • the chemotherapeutic agent that the subject of Ewing's sarcoma has received is selected from one of cyclophosphamide, ifosfamide, doxorubicin, pirarubicin, vincristine, etoposide, or Many kinds.
  • the second therapeutic agent is a chemotherapeutic drug, including but not limited to one of alkylating agents, podophyllum, camptothecins, taxanes, antimetabolites, and antibiotic antitumor drugs Or multiple.
  • chemotherapeutic drugs such as oxaliplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin
  • fluoropyrimidine derivatives such as gemcitabine, capecitabine, fluorouracil, Difurfurouracil, deoxyfluridine, tegafur, carmofur, trifluorouridine
  • taxanes e.g.
  • paclitaxel paclitaxel, albumin-bound paclitaxel and docetaxel
  • camptothecins e.g. hi Vinblastine, hydroxycamptothecin, irinotecan, topotecan
  • vinblastines vinorelbine, vinblastine, vincristine, vindesine, vinflunine
  • pemetrexed card Nitrogen mustard, etoposide (etoposide), tenibin, mitomycin, ifosfamide, cyclophosphamide, azacitidine, doxorubicin, pirarubicin, amrubicin Star, Methotrexate, Bendamustine, Epirubicin, Adriamycin, Actinomycin D, Dactinomycin, Bleomycin, Temozolomide, LCL-161, KML-001, Sapacitabine, General One or more of plinabulin, treosulfan, tipiracil hydrochloride, 153Sm-EDTMP
  • the chemotherapeutic agent is selected from the group consisting of vincristine, cyclophosphamide, ifosfamide, doxorubicin, dactinomycin, bleomycin, carmustine, etoposide (etoposide ), one or more of actinomycin D, methotrexate, and cisplatin.
  • the second therapeutic agent can be further used in combination with chemotherapy adjuvant drugs.
  • the chemotherapeutic adjuvant drugs include but are not limited to calcium leucovorin (CF), folate, mesna, bisphosphonates, amifostine, hematopoietic cell colony stimulating factors (CSFs).
  • the chemotherapeutic adjuvant is calcium leucovorin (CF), mesna, and aldofolate.
  • the second therapeutic agent is a combination of camptothecin and vinblastine compounds. In some embodiments, the second therapeutic agent is a combination of one of camptothecins and one of vinblastine compounds. In some embodiments, the camptothecin compound is one or more selected from camptothecin, hydroxycamptothecin, irinotecan, and topotecan; the vinblastine compound is selected from vinblastine One or more of rebine, vinblastine, vincristine, vindesine, and vinblastine.
  • the second therapeutic agent is a combination of a vinblastine compound and one selected from camptothecin, hydroxycamptothecin, irinotecan, and topotecan. In some embodiments, the second therapeutic agent is a combination of a camptothecin compound and one selected from the group consisting of vinorelbine, vinblastine, vincristine, vindesine, and vinblastine. In some specific embodiments, the second therapeutic agent is a combination of irinotecan and vindesine.
  • the second therapeutic agent is the VAC-1 regimen, specifically vincristine, cyclophosphamide, and actinomycin D.
  • the second therapeutic agent is the VAC-2 regimen, specifically vincristine, cyclophosphamide, and doxorubicin.
  • the second therapeutic agent is a T9 regimen, specifically adriamycin, methotrexate, cyclophosphamide, actinomycin D, bleomycin, vincristine.
  • the second therapeutic agent is an IE regimen, specifically ifosfamide and etoposide.
  • the second therapeutic agent is an AC regimen, specifically doxorubicin and cyclophosphamide.
  • the second therapeutic agent is a small molecule targeted anti-tumor drug, including but not limited to protein kinase inhibitors.
  • the protein kinase inhibitor includes but is not limited to tyrosine kinase inhibitor, serine and/or threonine kinase inhibitor, poly ADP ribose polymerase (PARP, poly ADP-ribose polymerase) inhibitor; the inhibitor
  • the targets of the agent include but are not limited to EGFR (epidermal growth factor receptor), anaplastic lymphoma (ALK), MET gene, ROS1 gene, HER2 gene, RET gene, BRAF gene, PI3K signaling pathway, DDR2 (disc death receptor) Body 2) gene, FGFR1 (fibroblast growth factor receptor 1), NTRK1 (neurotrophic tyrosine kinase type 1 receptor) gene, KRAS gene.
  • EGFR epigallocate kinase inhibitor
  • ALK aplastic lymphom
  • the targets of the small molecule targeted anti-tumor drugs also include COX-2 (cyclooxygenase-2), APE1 (apurinic and apyrimidinic endonuclease), and VEGFR-2 (vascular endothelial growth factor receptor-2) , CXCR-4 (chemokine receptor-4), MMP (matrix metalloproteinase), IGF-1R (insulin-like growth factor receptor), Ezrin, PEDF (pigment epithelium-derived factor), AS, ES, OPG (bone Protective factor), Src, IFN, ALCAM (leukocyte activating adhesion factor), HSP, JIP1, GSK-3 ⁇ (glycogen synthesis kinase 3 ⁇ ), CyclinD1 (cell cycle regulatory protein), CDK4 (cyclin-dependent kinase), TIMP1 (Tissue inhibitor of metalloproteinase), THBS3, PTHR1 (Parathyroid hormone related protein receptor 1), TEM7 (Human tumor vascular endo
  • the small molecule targeted anti-tumor drugs that can be enumerated include but are not limited to Erlotinib, Afatinib, Crizotinib, Ceritinib, Verofenib (Vemurafenib), Dabrafenib (Dabrafenib), Cabozantinib (Cabozantinib), Gefitinib (Gefitinib), Dacomitinib (Dacomitinib), Osimertinib, Alectinib ), brigatinib (Brigatinib), lorlatinib (Lorlatinib), trametinib (Trametinib), larotrectinib (Larotrectinib), icotinib (icotinib), lapatinib (Lapatinib), Vandetanib, Selumetinib, Sorafenib, Olmutinib, Savolitinib, Fru
  • the small molecule targeted anti-tumor drug is sorafenib, everolimus, erlotinib, afatinib, crizotinib, ceritinib, velofenib , Dalafini, cabozantinib, gefitinib, dacomitinib, osimertinib, alectinib, brigatinib, loratinib, trametinib, larotinib , Icotinib, Lapatinib, Vandetanib, Smeltinib, Omotinib, Volitinib, Fruquintinib, Entratinib, Dasatinib, Ensatinib , Levatinib, itacitinib, pyrrotinib, bimetinib, erdatinib, axitinib, lenatinib, cobitinib, a
  • the administration amount of Compound I or a pharmaceutically acceptable salt thereof in the combination drug can be determined according to the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health of the patient.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 3 mg to 30 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 5 mg to 20 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 8 mg to 16 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 8 mg to 14 mg. In a specific embodiment, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 8 mg. In a specific embodiment, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 10 mg. In a specific embodiment, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 12 mg.
  • Compound I or a pharmaceutically acceptable salt thereof can be administered one or more times a day. In some embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered once a day.
  • the method of administration of Compound I can be comprehensively determined according to the activity, toxicity, and patient tolerance of the drug.
  • Compound I or a pharmaceutically acceptable salt thereof is administered at intervals.
  • the interval administration includes an administration period and a drug withdrawal period.
  • Compound I or a pharmaceutically acceptable salt thereof can be administered one or more times a day.
  • Compound I or its pharmaceutically acceptable salt is administered every day during the administration period, and then the administration is stopped for a period of time during the withdrawal period, followed by the administration period, and then the withdrawal period, which can be repeated many times.
  • the ratio of the administration period and the drug withdrawal period in terms of days is 2:0.5-5, preferably 2:0.5-3, more preferably 2:0.5-2, and even more preferably 2:0.5-1.
  • Compound I or a pharmaceutically acceptable salt thereof is administered in one of the following ways at intervals: continuous administration for 2 weeks and withdrawal for 2 weeks, continuous administration for 2 weeks and withdrawal for 1 week or continuous administration
  • the medicine is discontinued for 5 days for 2 days; the interval administration mode can be repeated many times.
  • Compound I or a pharmaceutically acceptable salt thereof, and the second therapeutic agent are administered simultaneously, sequentially or sequentially. In some embodiments, Compound I or a pharmaceutically acceptable salt thereof, and the second therapeutic agent are separately prepared into a pharmaceutical composition and then administered.
  • the combination drugs for the treatment of Ewing's sarcoma include, but are not limited to, suitable for oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, and transdermal Buccal, intranasal, inhalation, vagina, intraocular, topical, subcutaneous, intra-fat, intra-articular, intraperitoneal or intrathecal preparations for any administration method.
  • compound I or a pharmaceutically acceptable salt thereof is preferably a preparation suitable for oral administration, including tablets, capsules, powders, granules, dripping pills, pastes, powders, etc., preferably tablets and capsules.
  • the tablets can be ordinary tablets, dispersible tablets, effervescent tablets, sustained-release tablets, controlled-release tablets or enteric-coated tablets; capsules can be ordinary capsules, sustained-release capsules, controlled-release capsules or enteric-coated capsules.
  • the oral preparation can be prepared by conventional methods using pharmaceutically acceptable carriers known in the art.
  • Pharmaceutically acceptable carriers include fillers, absorbents, wetting agents, binders, disintegrants, lubricants and the like.
  • Fillers include starch, lactose, mannitol, microcrystalline cellulose, etc.; absorbents include calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; wetting agents include water, ethanol, etc.; binders include hypromellose, poly Vividone, microcrystalline cellulose, etc.; disintegrants include croscarmellose sodium, crospovidone, surfactants, low-substituted hydroxypropyl cellulose, etc.; lubricants include magnesium stearate, talc Powder, polyethylene glycol, sodium lauryl sulfate, micro-powder silica gel, talc, etc. Pharmaceutical excipients also include colorants, sweeteners and so on.
  • irinotecan is used for intravenous injection at a dosage of 10-40 mg/m 2 each time; meanwhile, compound I or a pharmaceutically acceptable salt thereof is selected from but not limited to 3-30 mg per day.
  • the dose is administered orally once or multiple times, with continuous administration for 2 weeks and withdrawal for 1 week.
  • irinotecan is used for intravenous injection, with a dosage of 10-40 mg/m 2 each time; vindesine, with a dosage of 1 to 4 mg/m 2 each time; and compound I or its pharmaceutically acceptable
  • the accepted salt is administered orally at a dose selected from, but not limited to, 3-30 mg per day, one or more times, with continuous administration for 2 weeks and drug withdrawal for 1 week.
  • the dosage of irinotecan is 10-40 mg/m 2 per dosage; the dosage of vindesine is 1 to 4 mg/m 2 per dosage; and the compound I or its pharmaceutically acceptable salt per dosage A daily dose of 8-12 mg is administered orally, with continuous administration for 2 weeks and withdrawal for 1 week.
  • the dosage of irinotecan is 10, 15, 20, 25 , 30, 35, or 40 mg/m 2 each time; the dosage of vindesine is 1, 2, 3, or 4 mg/m 2 each time;
  • compound I or its pharmaceutically acceptable salt is administered orally at a dose of 8-12 mg per day, with continuous administration for 2 weeks and drug withdrawal for 1 week
  • every three weeks is a treatment cycle, in which irinotecan is administered on days 1-5 and 8-10 of each cycle; vindesine is administered on the first Administration on day 1 and day 8; and Compound I or its pharmaceutically acceptable salt is administered on day 1-14 of each cycle.
  • every three weeks is a treatment cycle, in which irinotecan is administered on days 1-5 and 8-10 of each cycle, once a day, and the dosage is 10, 15 or 20 mg/m 2 ; Vindesine is administered once a day on the 1st and 8th day of each cycle, and the dosage is 2, 3 or 4 mg/m 2 each time; and Compound I or its The pharmaceutically acceptable salt is administered on days 1-14 of each cycle, once a day, with a dose of 8-12 mg each time.
  • actinomycin D 450 ⁇ g/m 2 intravenously, 1 time/day ⁇ 5; on the 15th and 29th day, start adriamycin 20mg/m 2 intravenously, 1 time/day ⁇ 3; On the 43rd day, start vincristine 1.5mg/m 2 intravenous injection, 1 time/week ⁇ 4 and cyclophosphamide 1200 mg/m 2 intravenous injection, 1 time/2 weeks ⁇ 2;
  • Compound I or its pharmaceutically acceptable The salt of is selected from but not limited to 3-30 mg per day orally administered one or more times, in a continuous administration for 2 weeks, and the drug is stopped for 1 week.
  • Compound I or a pharmaceutically acceptable salt thereof is used in combination with the VAC-1 regimen.
  • the method is: vincristine 2 mg, intravenous injection on the first day; actinomycin D 2 mg/m 2 intravenously on the first day; cyclophosphamide 1200 mg/m 2 intravenously on the first day; compound I or its pharmacy
  • the acceptable salt is administered orally at a dose selected from but not limited to 3-30 mg per day, one or more times, with continuous administration for 2 weeks and withdrawal for 2 weeks, 28 days as a cycle.
  • Compound I or a pharmaceutically acceptable salt thereof is used in combination with the VAC-2 regimen.
  • the method is: vincristine 2 mg, intravenous injection on the first day; doxorubicin 75 mg/m 2 intravenously on the first day; cyclophosphamide 1200 mg/m 2 intravenously on the first day; compound I or its pharmaceutically acceptable
  • the salt is selected from but not limited to 3-30 mg per day for oral administration one or more times, continuous administration for 5 days and withdrawal for 2 days; 7 days as a cycle.
  • Compound I or a pharmaceutically acceptable salt thereof is used in combination with the T9 regimen.
  • the method is: doxorubicin 20mg/m 2 , intravenous infusion on day 1 to 3 and 42 to 44; methotrexate 12 mg/m 2 , intravenous infusion on day 1 to 3 and 42 to 44; cyclophosphate Amide 1.2g/m 2 , intravenous infusion on day 1 and 42; Actinomycin D 0.5mg/m 2 , intravenous infusion on day 21-23; Bleomycin 10mg/m 2 , day 21-23 Intravenous infusion; vincristine 1.5mg/m 2 , intravenous infusion on the 1, 7, 14, 21 and 30 days; compound I or a pharmaceutically acceptable salt thereof is selected from but not limited to 3-30 mg per day once Or multiple oral administration, continuous administration for 5 days and stop for 2 days.
  • Compound I or a pharmaceutically acceptable salt thereof is used in sequential combination therapy with IE regimen and AC regimen.
  • the method is as follows: ifosfamide 1.6g/m 2 intravenous infusion on the 1st to 5th day; etoposide 100mg/m 2 intravenous infusion on the 15th day; 21 days a cycle, 3 cycles after adriamycin 35mg/ m 2 , intravenous infusion on day 8; cyclophosphamide 1.50 g/m 2 orally on day 1 to 7; compound I or a pharmaceutically acceptable salt thereof is selected from but not limited to a dose of 3 to 30 mg per day once or Multiple oral administrations were given in a manner of continuous administration for 2 weeks and withdrawal for 1 week.
  • the present invention provides a method for treating Ewing’s sarcoma, which comprises administering simultaneously, intermittently or sequentially to a patient in need of treatment a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof, and treatment An effective amount of the second therapeutic agent.
  • the present invention provides a combined pharmaceutical composition for treating Ewing's sarcoma, the combined pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt thereof, and a second therapeutic agent.
  • the present invention has the beneficial effects that: the present invention uses compound I or its pharmaceutically acceptable salt for the treatment of Ewing’s sarcoma, with significant curative effect; the present invention combines compound I or its pharmaceutically acceptable salt with In combination with the second therapeutic agent, Compound I or its pharmaceutically acceptable salt can significantly enhance the killing effect of drugs, especially chemotherapeutics, on Ewing's sarcoma, while enhancing the curative effect, reducing the dosage of the chemotherapeutic drugs, thereby reducing side effects.
  • the invention provides a new idea for the treatment of Ewing's sarcoma, especially for the second-line treatment of Ewing's sarcoma that has failed prior radiotherapy and chemotherapy.
  • the dosages and ranges of Compound I or its pharmaceutically acceptable salts provided herein are based on the molecular weight of the free base of Compound I.
  • Patient refers to mammals, preferably humans.
  • patient refers to mammals, preferably humans.
  • subject refers to mammals, preferably humans.
  • subject refers to mammals, preferably humans.
  • subject refers to mammals, preferably humans.
  • subject refers to mammals, preferably humans.
  • subject refers to mammals, preferably humans.
  • subject refers to mammals, preferably humans.
  • subject refers to mammals, preferably humans.
  • subject refers to mammals, preferably humans.
  • subject refers to mammals, preferably humans.
  • combined pharmaceutical composition refers to two or more active ingredients administered simultaneously or sequentially (administered in the form of the respective active ingredients themselves, or in their respective pharmaceutically acceptable salts). Or esters and other derivatives, prodrugs or compositions).
  • combination drug composition “combination drug” and “drug combination” are used interchangeably.
  • combination or “combination” means that two or more active substances can each be administered to a subject simultaneously as a single formulation, or each as a single formulation sequentially in any order.
  • “Pharmaceutically acceptable” means that it is used to prepare a pharmaceutical composition that is generally safe, non-toxic, and neither biologically or otherwise undesirable, and includes its use in human medicine. Accepted.
  • “Pharmaceutically acceptable salts” include, but are not limited to, acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or with organic acids such as acetic acid, trifluoroacetic acid, and propionic acid.
  • “Therapeutically effective amount” refers to an amount sufficient to control the disease when the compound is administered to a human.
  • Treatment means any administration of a therapeutically effective amount of a compound, and includes:
  • the dihydrochloride of compound I was dissolved in water to reach a concentration of 25 mg/mL, and was further diluted with distilled water to 250 ⁇ g/ml.
  • mice BALB/cA-nude nude mice, rearing environment: SPF level.
  • Nude mice were subcutaneously inoculated with human Ewing sarcoma cells A673, and after the tumor grew to 100-250 mm 3 , the animals were randomly divided into groups (d0).
  • Compound I dihydrochloride was administered orally to animals at a dose of 6.25 mg/kg at a volume of 10 ml/kg daily for 14 consecutive days, the tumor volume was measured 2-3 times a week, the mouse was weighed, and the data was recorded.
  • V tumor volume
  • T/C(%) (T-T0)/(C-C0) ⁇ 100%, where T and C respectively represent the tumor volume of mice in the administration group and the control group (ie solvent group) at the end of the experiment; T0 and C0 respectively represent the tumor volume of mice in the administration group and the control group (ie, the solvent group) at the time of group administration (d0).
  • RTV relative tumor volume
  • TV represents the tumor volume at each measurement after the administration
  • TV0 represents the tumor at the time of group administration (d0) volume).
  • the tested drugs were all dissolved in dimethyl sulfoxide, prepared into a 100mmol/L mother liquor, and stored at -20°C for later use.
  • Human Ewing sarcoma cell line A673 was cultured in DMEM complete culture medium containing 10% fetal bovine serum, 0.1g/L streptomycin and penicillin (final concentration 100U ⁇ mL -1 ), kept at 37°C in 5% CO 2 incubator. When the cell confluence reaches about 85%, it is digested with 0.02% EDTA+0.25% trypsin, the cells are collected, centrifuged at 1000 r/min, and subcultured.
  • the IC 50 value can be determined according to the usual method in the art (for example, the MTT method), or the following method (MTT method):
  • Logarithmic phase cells were seeded in 96-well culture plate (180 L / well, 105 cells / well); grown for 2 hours at 37 °C, 5% CO 2 conditions, were added to the dihydrochloride salt of compound I (gradient (0, 0.005, 0.1, 0.05, 0.1, 0.5, 1.5, 4, 12, 30 ⁇ g/ml concentration solution) combined with 2 ⁇ g/ml vincristine + 75 ⁇ g/ml adriamycin + 500 ⁇ g/ml cyclophosphamide Culture, set up two replicate wells for each concentration, add 20 ⁇ L to each well, and set up the corresponding concentration of normal saline solvent control and cell-free zeroing hole; the tumor cells were cultured for another 24 hours under the conditions of 37°C and 5% CO 2 (ie 48 hours in total); after the drug action is over, add MTT working solution to each well, 4 hours later, the triple solution will dissolve at 37°C overnight.
  • compound I grade (0, 0.005, 0.1, 0.05,
  • Inhibition rate (OD value control hole-OD value administration hole)/OD value control hole ⁇ 100%
  • Annexin-V-FITC/PI cell apoptosis detection kit to detect its apoptosis, add the cells to 100 ⁇ L 1 ⁇ Binding buffer to resuspend, add 5 ⁇ L AnnexinV-FITC and 2.5 ⁇ LPI dye, shake and mix in the dark, React at room temperature for 15 minutes, then add 300 ⁇ L of 1 ⁇ Binding buffer, mix well, and perform detection on a flow cytometer. Repeat the test 3 times.
  • the results show that the dihydrochloride of compound I at different concentrations can significantly enhance vincristine + adriamycin + cyclophosphamide (VAC-2 protocol) Ewing's sarcoma cell line apoptosis caused by the protocol.
  • a clinical trial of compound I dihydrochloride capsules combined with a second therapeutic agent (VAC-2 regimen) was carried out in patients with measurable lesions (according to RECIST 1.1) with Ewing’s sarcoma.
  • the patients in the patient group included the previous Patients who have undergone chemotherapy and those who have not received chemotherapy are given compound I dihydrochloride capsules 12 mg orally once a day (two consecutive weeks and one week stop is a treatment cycle), and the VAC-2 regimen: Changchunxin Alkali 2mg, intravenous injection on the first day; Doxorubicin 75mg/m 2 intravenously on the first day; cyclophosphamide 1200mg/m 2 intravenously on the first day (28 days as a cycle).
  • Evaluation indicators include curative effect indicators: Progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), stable disease (SD) rate, clinical benefit rate (CBR), overall survival (OS), etc.; safety indicators: poor Reaction incidence and severity; quality of life, etc. Clinical trial results:
  • the combination of compound I dihydrochloride and VAC-2 regimen is effective in the treatment of Ewing's sarcoma, and can prolong overall survival.
  • the CT scan showed that the total diameter of the measurable target lesion (lower left lung nodule) was 16mm. After the administration, CT scan was performed regularly. After 10 cycles of treatment, The total diameter of the target lesions was reduced to 10mm, and the curative effect was evaluated as partial response (PR), which was reduced by 37.5%. After 16 cycles of treatment, the total diameter of the target lesions was reduced to 9mm, the curative effect was evaluated as PR, and no new lesions appeared. During the treatment period, the overall tolerance was good and is still under treatment.
  • PR partial response
  • CT scan showed that the sum of the measurable target lesion diameters was 36mm (right lower lobe 36mm). After each treatment cycle, a CT scan was performed immediately. The results are shown in Table 1. The subject has been taking the medicine for 20 cycles. After the doctor's assessment, it is recommended to continue taking the medicine. During the treatment, the overall tolerance is good.
  • Treatment cycle Sum of target lesion diameter Efficacy evaluation Second cycle 20mm PR Sixth cycle 19.3mm PR Eighth cycle 19mm PR Tenth cycle 19.6mm PR Twelfth cycle 18.6mm PR Fourteenth cycle 16.8mm PR Sixteenth cycle 18.5mm PR 20th cycle 18.5mm PR
  • a and B Patients with advanced Ewing sarcoma who failed the previous treatment were divided into two groups: A and B.
  • a total of 23 patients over 16 years of age in group A were given an oral 12mg dose of Anlotinib dihydrochloride capsules d1-d14 once a day (2 consecutive weeks and 1 week as a treatment cycle) + once a day intravenous injection Irinotecan 15mg/m 2 d1-d5, d8-d10 (3 weeks is a treatment cycle) + Vindesine 3mg/m 2 (d1, d8 administration, every 3 weeks is a treatment cycle);
  • Group B has a total of 12 A patient younger than 16 years old was given Anlotinib dihydrochloride capsules once a day (2 consecutive weeks and 1 week as a treatment cycle.
  • the dose is allocated according to body surface area (BSA) as follows: BSA ⁇ 1.0m 2 , 8mg, d1-d14; BSA ⁇ 1.0m 2 , 12mg, d1-d14) + once a day intravenous injection of irinotecan 20mg/m 2 d1-d5, d8-d10 (3 weeks is a treatment cycle) + Changchun Desine 3mg/m 2 d1, d8 (3 weeks is a treatment cycle).
  • BSA body surface area

Abstract

本发明属于医药领域，提供用于治疗尤因肉瘤的喹啉类化合物或其药学上可接受的盐，具体涉及化合物I或其药学上可接受的盐在制备用于治疗尤因肉瘤的药物中的应用，以及化合物I或其药学上可接受的盐与第二治疗剂联合在制备用于治疗尤因肉瘤的联用药物中的应用，化合物I的化学名称为1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺。

Description

用于治疗尤因肉瘤的喹啉类化合物或其药学上可接受的盐
相关申请的交叉引用
本申请要求于2019年04月19日向中国国家知识产权局提交的第201910315417.X号中国专利申请的优先权和权益，所述申请公开的内容通过引用整体并入本文中。
技术领域
本发明属于医药领域，具体涉及用于治疗尤因肉瘤的喹啉类化合物或其药学上可接受的盐，以及用于联合治疗尤因肉瘤的喹啉类化合物或其药学上可接受的盐。
背景技术
目前，尤因肉瘤被公认是一种独立的骨肿瘤，定义为起源于神经外胚层的骨或软组织的小圆细胞肿瘤。尤因肉瘤占所有原发性骨肿瘤的6％～8％，占恶性骨肿瘤的10％～14.2％，仅次于骨肉瘤及软骨肉瘤，是儿童和青少年最常见的恶性原发性骨肿瘤，且男性稍多于女性。
尤因肉瘤最常见的早期症状为疼痛和肿胀，60％以上患者在患病早期出现间歇性疼痛，且疼痛部位随肿瘤的扩散而蔓延。随疼痛的加剧而出现局部肿块，肿块压痛显著。其次是出现神经根及脊髓等神经功能损伤症状，部分患者发热38℃～40℃，血清高密度脂蛋白、胆固醇和红细胞沉降率明显升高，伴有白细胞计数增多和贫血。病变可产生较大的软组织肿块。由于尤因肉瘤恶性程度高，且转移快，单独采用手术、放疗或者单药化疗治疗，效果均不理想，5年生存率不超过10％。
目前，尤因肉瘤较有效治疗方法为综合疗法，即放疗加化疗加手术或不加手术的综合治疗方法，其中化疗多采用多药联合的化疗。虽然研究显示，多药联合化疗治疗尤因肉瘤等能够显著提高5年生存率，但由于尤因肉瘤大多在2年内发生转移，因此化疗一般需持续2年，长期化疗带来毒副作用的积累，例如造血系统、呼吸系统、心血管系统、神经系统、泌尿系统等的并发症。因此，急需开发尤因肉瘤的治疗新方案。
发明内容
第一方面，本发明提供了化合物I或其药学上可接受的盐在制备用于治疗尤因肉瘤的药物中的应用。
其中，化合物I的化学名称为1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺，其具有如下的结构式：
Figure PCTCN2020085552-appb-000001
在一些实施方案中，所述尤因肉瘤为骨内型尤因肉瘤、骨外型尤因肉瘤、骨膜型尤因肉瘤。
在一些实施方案中，所述尤因肉瘤为溶骨型尤因肉瘤、硬化型尤因肉瘤、混合型尤因肉瘤。
在一些实施方案中，所述尤因肉瘤为进展期尤因肉瘤。在一些实施方案中，进展期尤因肉瘤是指原发肿瘤或局部复发肿瘤，无法通过手术或其它局部治疗手段根治，或患者拒绝手术或其它局部治疗的尤因肉瘤。在一些实施方案中，进展期尤因肉瘤是指已出现远处转移时，转移瘤无法通过手术或其它局部治疗手段根治，或患者拒绝手术或其它局部治疗的尤因肉瘤。
在一些实施方案中，所述尤因肉瘤为在先治疗失败的尤因肉瘤。优选地，所述尤因肉瘤为放疗和/或化疗药物治疗失败的尤因肉瘤。更优选地，所述尤因肉瘤为接受以下化疗剂治疗失败的尤因肉瘤选自：环磷酰胺、异环磷酰胺、多柔比星、吡柔比星、阿霉素、更生霉素、博来霉素、长春新碱、卡氮芥、依托泊苷、 放线菌素D、甲氨蝶呤、顺铂中的一种或多种。最优选地，所述尤因肉瘤的主体已接受过的化疗剂选自环磷酰胺、异环磷酰胺、多柔比星、吡柔比星、长春新碱、依托泊苷中的一种或多种。
本申请所述的化合物I可以以它的游离碱形式给药，也可以以其盐、水合物和前药的形式给药，该前药在体内转换成化合物I的游离碱形式。例如，化合物I药学上可接受的盐在本发明的范围内，可按照本领域公知的方法由不同的有机酸和无机酸产生所述盐。
在一些实施方案中，所述化合物I的药学上可接受的盐包括但不限于化合物I与任意如下酸所形成的盐：盐酸、氢溴酸、硫酸、硝酸、磷酸、乙酸、三氟乙酸、丙酸、己酸、庚酸、环戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙二磺酸、2-羟基乙磺酸、苯磺酸、对氯苯磺酸、对甲苯磺酸、3-苯基丙酸、三甲基乙酸、叔丁基乙酸、十二烷基硫酸、葡糖酸、谷氨酸、羟基萘甲酸、水杨酸、硬脂酸。在本发明中，所述化合物I的药学上可接受的盐优选为盐酸盐或马来酸盐的形式，更优选为二盐酸盐。
在一些实施方案中，以化合物I盐酸盐的形式给药。在一些实施方案中，以化合物I一盐酸盐的形式给药。在一些实施方案中，以化合物I二盐酸盐的形式给药。在一些实施方案中，以化合物I盐酸盐的晶体形式给药。在特定的实施方案中，以化合物I二盐酸盐的晶体形式给药。在一些实施方案中，以化合物I马来酸盐的形式给药。
另一方面，本发明提供了一种用于治疗尤因肉瘤的方法，所述方法包括给予需要治疗的患者治疗有效量的化合物I或其药学上可接受的盐。
化合物I或其药学上可接受的盐可通过多种途径给药，所述给药途径包括但不限于选自以下的途径：口服、肠胃外、腹膜内、静脉内、动脉内、透皮、舌下、肌内、直肠、透颊、鼻内、经吸入、阴道、眼内、经局部给药、皮下、脂肪内、关节内、腹膜内或鞘内。在一个特定的实施方案中，通过口服给药。
化合物I给药的方法可根据药物的活性、毒性以及患者的耐受性等来综合确定。
在一些实施方案中，可将化合物I或其药学上可接受的盐以以下的形式提供：适于口服、肠胃外、腹膜内、静脉内、动脉内、透皮、舌下、肌内、直肠、透颊、鼻内、经吸入、阴道、眼内、经局部给药、皮下、脂肪内、关节内、腹膜内或鞘内任一给药方式的制剂；优选适于口服的制剂。在一些实施方案中，可将化合物I或其药学上可接受的盐优选以以下的形式提供：片剂、胶囊剂、粉剂、颗粒剂、滴丸、糊剂或散剂，更优选片剂或胶囊剂。
在一些实施方案中，化合物I或其药学上可接受的盐的给予量可根据疾病的严重程度、疾病的响应、任何治疗相关的毒性、患者的年龄和健康状态来确定。在一些实施方案中，给予所述化合物I或其药学上可接受的盐的日剂量可为3毫克至30毫克，优选为5毫克至20毫克，更优选为8毫克至16毫克；进一步优选日剂量为8毫克至14毫克；最优选为8毫克、10毫克或12毫克。
优选地，以间隔给药的方式给予化合物I或其药学上可接受的盐。所述间隔给药包括给药期和停药期，在给药期内可以每天一次或多次给予化合物I或其药学上可接受的盐。例如在给药期内每天给予化合物I或其药学上可接受的盐，然后停药期内停止给药一段时间，接着给药期，然后停药期，如此可以反复进行多次。其中，给药期和停药期的以天数计的比值为2:0.5～5，优选2:0.5～3，较优选2:0.5～2，更优选2:0.5～1。
作为更进一步优选的间隔给药方式，所述间隔给药可选自如下方式中的一种：连续给药2周停药2周、连续给药2周停药1周或连续给药5天停药2天；所述间隔给药方式可以反复进行多次。
再一方面，本发明提供了一种治疗尤因肉瘤的药物组合物，所述药物组合物包含化合物I或其药学上可接受的盐，以及至少一种药学上可接受的载体。
所述药物组合物包括但不限于适于口服、肠胃外、腹膜内、静脉内、动脉内、透皮、舌下、肌内、直肠、透颊、鼻内、经吸入、阴道、眼内、经局部给药、皮下、脂肪内、关节内、腹膜内或鞘内给药的制剂；优选适于口服的制剂，包括片剂、胶囊剂、粉剂、颗粒剂、滴丸、糊剂、散剂等，优选片剂和胶囊剂。其中片剂可以是普通片剂、分散片、泡腾片、缓释片、控释片或肠溶片，胶囊剂可以是普通胶囊、缓释胶囊、控释胶囊或肠溶胶囊。所述口服制剂可使用本领域公知的药学上可接受的载体通过常规方法制得。药学上可接受的载体包括填充剂、吸收剂、润湿剂、粘合剂、崩解剂、润滑剂等。填充剂包括淀粉、乳糖、甘露 醇、微晶纤维素等；吸收剂包括硫酸钙、磷酸氢钙、碳酸钙等；润湿剂包括水、乙醇等；粘合剂包括羟丙甲纤维素、聚维酮、微晶纤维素等；崩解剂包括交联羧甲基纤维素钠、交联聚维酮、表面活性剂、低取代羟丙基纤维素等；润滑剂包括硬脂酸镁、滑石粉、聚乙二醇、十二烷基硫酸钠、微粉硅胶、滑石粉等。药用辅料还包括着色剂、甜味剂等。
在一个实施方案中，该药物组合物是适于口服的固体制剂。该组合物例如可以是片剂或胶囊的形式。在一个特定的实施方案中，该药物组合物是胶囊。在本发明的一个特定实施方案中，口服固体制剂的药学上可接受的载体包括甘露醇、微晶纤维素、羟丙纤维素、硬脂酸镁。
在另一方面，本发明提供了化合物I或其药学上可接受的盐与第二治疗剂联合在制备用于治疗尤因肉瘤的联用药物中的应用。
在一些实施方案中，所述尤因肉瘤包括但不限于骨内型尤因肉瘤、骨外型尤因肉瘤、骨膜型尤因肉瘤。
在一些实施方案中，所述尤因肉瘤包括但不限于溶骨型尤因肉瘤、硬化型尤因肉瘤、混合型尤因肉瘤。
在一些实施方案中，所述尤因肉瘤为进展期尤因肉瘤。在一些实施方案中，进展期尤因肉瘤是指原发肿瘤或局部复发肿瘤，无法通过手术或其它局部治疗手段根治，或患者拒绝手术或其它局部治疗的尤因肉瘤。在一些实施方案中，进展期尤因肉瘤是指已出现远处转移时，转移瘤无法通过手术或其它局部治疗手段根治，或患者拒绝手术或其它局部治疗的尤因肉瘤。
在一些实施方案中，所述尤因肉瘤包括但不限于在先治疗失败的尤因肉瘤。优选地，所述尤因肉瘤为放疗和/或化疗药物治疗失败的尤因肉瘤。更优选地，所述尤因肉瘤的主体已接受过的化疗剂选自环磷酰胺、异环磷酰胺、多柔比星、吡柔比星、阿霉素、更生霉素、博来霉素、长春新碱、卡氮芥、依托泊苷、放线菌素D、甲氨蝶呤、顺铂中的一种或多种。最优选地，所述尤因肉瘤的主体已接受过的化疗剂选自环磷酰胺、异环磷酰胺、多柔比星、吡柔比星、长春新碱、依托泊苷中的一种或多种。
在一些实施方案中，所述第二治疗剂为化疗药物，包括但不限于烷化剂、鬼臼类、喜树碱类、紫杉类、抗代谢类、抗生素类抗肿瘤药物中的一种或多种。可以列举的实例包括但不限于铂类药物(例如奥沙利铂、顺铂、卡铂、奈达铂、双环铂(dicycloplatin))、氟嘧啶衍生物(例如吉西他滨、卡培他滨、氟尿嘧啶、双呋氟尿嘧啶、去氧氟尿苷、替加氟、卡莫氟、三氟尿苷)、紫杉烷类(例如紫杉醇、白蛋白结合的紫杉醇以及多烯紫杉醇)、喜树碱类(例如喜树碱、羟基喜树碱、伊立替康、拓扑替康)、长春碱类(长春瑞滨、长春碱、长春新碱、长春地辛、长春富宁(vinflunine))、培美曲塞、卡氮芥、依托泊苷(足叶乙苷)、替尼铂苷、丝裂霉素、异环磷酰胺、环磷酰胺、阿扎胞苷、多柔比星、吡柔比星、氨柔比星、甲氨蝶呤、苯达莫司汀、表阿霉素、阿霉素、放线菌素D、更生霉素、博来霉素、替莫唑胺、LCL-161、KML-001、Sapacitabine、普那布林(plinabulin)、曲奥舒凡(treosulfan)、地匹福林盐酸盐(tipiracil hydrochloride)、153Sm-EDTMP、替吉奥和encequidar中的一种或多种。在一些实施方案中，所述化疗药物选自长春新碱、环磷酰胺、异环磷酰胺、阿霉素、更生霉素、博来霉素、卡氮芥、依托泊苷(足叶乙苷)、放线菌素D、甲氨蝶呤、顺铂中的一种或多种。
视需要，所述第二治疗剂还可进一步联合化疗辅助药物使用。所述化疗辅助药物包括但不限于甲酰四氢叶酸钙(CF)、醛氢叶酸、美司钠、双膦酸盐、氨磷汀、造血细胞集落刺激因子(CSFs)。在一些实施方案中，所述化疗辅助药物为甲酰四氢叶酸钙(CF)、美司钠、醛氢叶酸。
在一些实施方案中，所述第二治疗剂为喜树碱类和长春碱类化合物的组合。在一些实施方案中，所述第二治疗剂为喜树碱类中的一种和长春碱类化合物中的一种的组合。在一些实施方案中，所述喜树碱类化合物为选自喜树碱、羟基喜树碱、伊立替康、拓扑替康中的一种或多种；所述长春碱类化合物为选自长春瑞滨、长春碱、长春新碱、长春地辛、长春富宁中的一种或者几种。
在一些实施方案中，所述第二治疗剂为长春碱类化合物与选自喜树碱、羟基喜树碱、伊立替康和拓扑替康中的一种的组合。在一些实施方案中，所述第二治疗剂为喜树碱类化合物与选自长春瑞滨、长春碱、长春新碱、长春地辛、长春富宁中的一种的组合。在一些具体的实施方案中，所述第二治疗剂为伊立替康和长春地辛的组合。
在一些实施方案中，所述第二治疗剂为VAC-1方案，具体为长春新碱、环磷酰胺、以及放线菌素D。
在一些实施方案中，所述第二治疗剂为VAC-2方案，具体为长春新碱、环磷酰胺、以及阿霉素。
在一些实施方案中，所述第二治疗剂为T9方案，具体为阿霉素、甲氨蝶呤、环磷酰胺、放线菌素D、博来霉素、长春新碱。
在一些实施方案中，所述第二治疗剂为IE方案，具体为异环磷酰胺、足叶乙苷。
在一些实施方案中，所述第二治疗剂为AC方案，具体为阿霉素、环磷酰胺。
在一些实施方案中，所述第二治疗剂为小分子靶向抗肿瘤药物，包括但不限于蛋白激酶抑制剂。其中，所述蛋白激酶抑制剂包括但不限于酪氨酸激酶抑制剂、丝氨酸和/或苏氨酸激酶抑制剂、聚ADP核糖聚合酶(PARP，poly ADP-ribose polymerase)抑制剂；所述抑制剂的靶点包括但不限于EGFR(表皮生长因子受体)、间变性淋巴瘤(ALK)、MET基因、ROS1基因、HER2基因、RET基因、BRAF基因、PI3K信号通路、DDR2(盘状死亡受体2)基因、FGFR1(成纤维生长因子受体1)、NTRK1(神经营养酪氨酸激酶1型受体)基因、KRAS基因。所述小分子靶向抗肿瘤药物的靶点还包括COX-2(环氧酶-2)、APE1(脱嘌呤脱嘧啶核酸内切酶)、VEGFR-2(血管内皮生长因子受体-2)、CXCR-4(趋化因子受体-4)、MMP(基质金属蛋白酶)、IGF-1R(胰岛素样生长因子受体)、Ezrin、PEDF(色素上皮衍生因子)、AS、ES、OPG(骨保护因子)、Src、IFN、ALCAM(白细胞活化黏附因子)、HSP、JIP1、GSK-3β(糖原合成激酶3β)、CyclinD1(细胞周期调节蛋白)、CDK4(细胞周期素依赖性激酶)、TIMP1(组织金属蛋白酶抑制物)、THBS3、PTHR1(甲状旁腺素相关蛋白受体1)、TEM7(人肿瘤血管内皮标志物7)、COPS3、组织蛋白酶K。可以列举的小分子靶向抗肿瘤药物包括但不限于厄洛替尼(Erlotinib)、阿法替尼(Afatinib)、克唑替尼(Crizotinib)、色瑞替尼(Ceritinib)、威罗菲尼(Vemurafenib)、达拉菲尼(Dabrafenib)、卡博替尼(Cabozantinib)、吉非替尼(Gefitinib)、达可替尼(Dacomitinib)、奥希替尼(Osimertinib)、艾乐替尼(Alectinib)、布格替尼(Brigatinib)、劳拉替尼(Lorlatinib)、曲美替尼(Trametinib)、拉罗替尼(Larotrectinib)、埃克替尼(icotinib)、拉帕替尼(Lapatinib)、凡德他尼(Vandetanib)、司美替尼(Selumetinib)、索拉非尼(Sorafenib)、奥莫替尼(Olmutinib)、沃利替尼(Savolitinib)、呋喹替尼(Fruquintinib)、恩曲替尼(Entrectinib)、达沙替尼(Dasatinib)、恩沙替尼(Ensartinib)、乐伐替尼(Lenvatinib)、itacitinib、吡咯替尼(Pyrotinib)、比美替尼(Binimetinib)、厄达替尼(Erdafitinib)、阿西替尼(Axitinib)、来那替尼(Neratinib)、考比替尼(Cobimetinib)、阿卡替尼(Acalabrutinib)、法米替尼(Famitinib)、马赛替尼(Masitinib)、伊布替尼(Ibrutinib)、rociletinib、尼达尼布(nintedanib)、来那度胺、依维莫斯、LOXO-292、Vorolanib、bemcentinib、capmatinib、entrectinib、TAK-931、ALT-803、palbociclib、famitinib L-malate、LTT-462、BLU-667、ningetinib、tipifarnib、poziotinib、DS-1205c、capivasertib、SH-1028、二甲双胍、seliciclib、OSE-2101、APL-101、berzosertib、idelalisib、lerociclib、ceralasertib、PLB-1003、tomivosertib、AST-2818、SKLB-1028、D-0316、LY-3023414、allitinib、MRTX-849、AP-32788、AZD-4205、lifirafenib、vactosertib、mivebresib、napabucasin、sitravatinib、TAS-114、molibresib、CC-223、rivoceranib、CK-101、LXH-254、simotinib、GSK-3368715、TAS-0728、masitinib、tepotinib、HS-10296、AZD-4547、merestinib、olaptesed pegol、galunisertib、ASN-003、gedatolisib、defactinib、lazertinib、CKI-27、S-49076、BPI-9016M、RF-A-089、RMC-4630、AZD-3759、antroquinonol、SAF-189s、AT-101、TTI-101、naputinib、LNP-3794、HH-SCC-244、ASK-120067、CT-707、epitinib succinate、tesevatinib、SPH-1188-11、BPI-15000、copanlisib、niraparib、olaparib、veliparib、talazoparib tosylate、DV-281、Siremadlin、Telaglenastat、MP-0250、GLG-801、ABTL-0812、bortezomib、帕比司他(panobinostat)、tucidinostat、vorinostat、resminostat、epacadostat、tazemetostat、entinostat、mocetinostat和quisinostat中的一种或者多种。在一些实施方案中，所述小分子靶向抗肿瘤药物为索拉非尼、依维莫斯、厄洛替尼、阿法替尼、克唑替尼、色瑞替尼、威罗菲尼、达拉菲尼、卡博替尼、吉非替尼、达可替尼、奥希替尼、艾乐替尼、布格替尼、劳拉替尼、曲美替尼、拉罗替尼、埃克替尼、拉帕替尼、凡德他尼、司美替尼、奥莫替尼、沃利替尼、呋喹替尼、恩曲替尼、达沙替尼、恩沙替尼、乐伐替尼、itacitinib、吡咯替尼、比美替尼、厄达替尼、阿西替尼、来那替尼、考比替尼、阿卡替尼、法米替尼、马赛替尼、伊布替尼、尼达尼布中的一种或者多种。
在一些实施方案中，联用药物中的化合物I或其药学上可接受的盐的给予量可根据疾病的严重程度、疾病的响应、任何治疗相关的毒性、患者的年龄和健康状态来确定。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为3毫克至30毫克。在一些实施方案中，给予化合物I或其药学上可接受的 盐的日剂量为5毫克至20毫克。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为8毫克至16毫克。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为8毫克至14毫克。在一个特定的实施方案中，给予化合物I或其药学上可接受的盐的日剂量为8毫克。在一个特定的实施方案中，给予化合物I或其药学上可接受的盐的日剂量为10毫克。在一个特定的实施方案中，给予化合物I或其药学上可接受的盐的日剂量为12毫克。
化合物I或其药学上可接受的盐可以每日施用一次或多次。在一些实施方案中，每天一次给予化合物I或其药学上可接受的盐。
化合物I给药的方法可根据药物的活性、毒性以及患者的耐受性等来综合确定。
优选地，以间隔给药的方式给予化合物I或其药学上可接受的盐。所述间隔给药包括给药期和停药期，在给药期内可以每天一次或多次给予化合物I或其药学上可接受的盐。例如在给药期内每天给予化合物I或其药学上可接受的盐，然后停药期内停止给药一段时间，接着给药期，然后停药期，如此可以反复进行多次。其中，给药期和停药期的以天数计的比值为2:0.5～5，优选2:0.5～3，较优选2:0.5～2，更优选2:0.5～1。
在一些实施方案中，化合物I或其药学上可接受的盐采用如下方式间隔给药方式中的一种：连续给药2周停药2周、连续给药2周停药1周或连续给药5天停药2天；所述间隔给药方式可以反复进行多次。
在一些实施方案中，化合物I或其药学上可接受的盐，以及第二治疗剂采用同时给药、序贯给药或先后给药。在一些实施方案中，化合物I或其药学上可接受的盐，以及第二治疗剂分别制备成药物组合物后给药。
在一些实施方案中，所述用于治疗尤因肉瘤的联用药物包括但不限于适于口服、肠胃外、腹膜内、静脉内、动脉内、透皮、舌下、肌内、直肠、透颊、鼻内、吸入、阴道、眼内、局部、皮下、脂肪内、关节内、腹膜内或鞘内任意给药方式的制剂。
其中，化合物I或其药学上可接受的盐优选适于口服的制剂，包括片剂、胶囊剂、粉剂、颗粒剂、滴丸、糊剂、散剂等，优选片剂和胶囊剂。其中片剂可以是普通片剂、分散片、泡腾片、缓释片、控释片或肠溶片；胶囊剂可以是普通胶囊、缓释胶囊、控释胶囊或肠溶胶囊。所述口服制剂可使用本领域公知的药学上可接受的载体通过常规方法制得。药学上可接受的载体包括填充剂、吸收剂、润湿剂、粘合剂、崩解剂、润滑剂等。填充剂包括淀粉、乳糖、甘露醇、微晶纤维素等；吸收剂包括硫酸钙、磷酸氢钙、碳酸钙等；润湿剂包括水、乙醇等；粘合剂包括羟丙甲纤维素、聚维酮、微晶纤维素等；崩解剂包括交联羧甲基纤维素钠、交联聚维酮、表面活性剂、低取代羟丙基纤维素等；润滑剂包括硬脂酸镁、滑石粉、聚乙二醇、十二烷基硫酸钠、微粉硅胶、滑石粉等。药用辅料还包括着色剂、甜味剂等。
在某些特定的实施方案中，采用伊立替康静脉注射，每次用量为10～40mg/m 2；同时化合物I或其药学上可接受的盐以选自但不限于每日3～30mg的剂量一次或多次口服给药，以连续给药2周，停药1周的给药方式给药。
在某些特定的实施方案中，采用伊立替康静脉注射，每次用量为10～40mg/m 2；长春地辛，每次用量为1～4mg/m 2；同时化合物I或其药学上可接受的盐以选自但不限于每日3～30mg的剂量一次或多次口服给药，以连续给药2周，停药1周的给药方式给药。
在某些特定的实施方案中，伊立替康每次用量为10～40mg/m 2；长春地辛每次用量为1～4mg/m 2；和化合物I或其药学上可接受的盐以每日8～12mg的剂量口服给药，以连续给药2周，停药1周的给药方式给药。在一些特定的实施方案中，伊立替康每次用量为10、15、20、25、30、35或40mg/m 2；长春地辛每次用量为1、2、3或4mg/m 2；和化合物I或其药学上可接受的盐以每日8～12mg的剂量口服给药，以连续给药2周，停药1周的给药方式给药
在某些特定的实施方案中，每三周为一个治疗周期，其中，伊立替康在每个周期的第1-5天和第8-10天给药；长春地辛在每个周期的第1天和第8天给药；和化合物I或其药学上可接受的盐在每个周期的第1-14天给药。
在一个特定的实施方案中，每三周为一个治疗周期，其中，伊立替康在每个周期的第1-5天和第8-10天给药，每天给药一次，每次的用量为10、15或20mg/m 2；长春地辛在每个周期的第1天和第8天给药 每天给药一次，每次的用量为2、3或4mg/m 2；和化合物I或其药学上可接受的盐在每个周期的第1-14天给药，每天给药一次，每次剂量为8-12mg。
在某些特定的实施方案中，采用长春新碱1.5mg/m 2静脉注射，每周1次；环磷酰胺500mg/m 2静脉注射，每周1次，共6周，与长春新碱一起应用；6周后，用上述两种化疗药物的同样剂量静脉注射，每周1次；同时化合物I或其药学上可接受的盐以选自但不限于每日3～30mg的剂量一次或多次口服给药，以连续给药2周，停药1周的给药方式给药，配合根治手术。
在某些特定的实施方案中，放线菌素D 450μg/m 2静脉注射，1次/日×5；第15和29天各开始阿霉素20mg/m 2静脉注射，1次/日×3；第43天开始长春新碱1.5mg/m 2静脉注射，1次/周×4和环磷酰胺1200mg/m 2静脉注射，1次/2周×2；化合物I或其药学上可接受的盐以选自但不限于每日3～30mg的剂量一次或多次口服给药，以连续给药2周，停药1周的给药方式给药。
在某些特定的实施方案中，采用化合物I或其药学上可接受的盐与VAC-1方案联用。方法为：长春新碱2mg，第1天静脉注射；放线菌素D 2mg/m 2，第1天静脉点滴；环磷酰胺1200mg/m 2，第1天静脉点滴；化合物I或其药学上可接受的盐以选自但不限于每日3～30mg的剂量一次或多次口服给药，以连续给药2周，停药2周的给药方式给药，28天为一周期。
在某些特定的实施方案中，采用化合物I或其药学上可接受的盐与VAC-2方案联用。方法为：长春新碱2mg，第1天静脉注射；阿霉素75mg/m 2，第1天静脉点滴；环磷酰胺1200mg/m 2，第1天静脉点滴；化合物I或其药学上可接受的盐以选自但不限于每日3～30mg的剂量一次或多次口服给药，连续给药5天停药2天；7天为一周期。
在某些特定的实施方案中，采用化合物I或其药学上可接受的盐与T9方案联用。方法为：阿霉素20mg/m 2，第1～3天、第42～44天静脉点滴；甲氨蝶呤12mg/m 2，第1～3天、第42～44天静脉点滴；环磷酰胺1.2g/m 2，第1天、第42天静脉点滴；放线菌素D 0.5mg/m 2，第21～23天静脉点滴；博来霉素10mg/m 2，第21～23天静滴；长春新碱1.5mg/m 2，第1、7、14、21、30天静滴；化合物I或其药学上可接受的盐以选自但不限于每日3～30mg的剂量一次或多次的口服给药，连续给药5天停药2天。
在某些特定的实施方案中，采用化合物I或其药学上可接受的盐与IE方案、AC方案序贯联用治疗。方法为：异环磷酰胺1.6g/m 2第1～5天静脉滴注；足叶乙苷100mg/m 2第15天静脉滴注；21天一周期，3周期后接阿霉素35mg/m 2，第8天静脉滴注；环磷酰胺1.50g/m 2第1～7天口服；化合物I或其药学上可接受的盐以选自但不限于每日3～30mg的剂量一次或多次口服给药，以连续给药2周，停药1周的给药方式给药。
另一方面，本发明提供一种治疗尤因肉瘤的方法，所述方法包括向需要治疗的患者同时给予、间隔给予或依次给予治疗有效量的化合物I或其药学上可接受的盐，以及治疗有效量的第二治疗剂。
再一方面，本发明提供一种治疗尤因肉瘤的联用药物组合物，该联用药物组合物包括化合物I或其药学上可接受的盐，以及第二治疗剂。
与现有技术相比，本发明有益效果在于：本发明将化合物I或其药学上可接受的盐用于治疗尤因肉瘤，疗效显著；本发明将化合物I或其药学上可接受的盐与第二治疗剂联合应用，化合物I或其药学上可接受的盐能够明显增强药物尤其是化疗药物对尤因肉瘤的杀伤作用，增强疗效的同时，降低化疗药物的使用剂量，从而降低副作用。本发明为尤因肉瘤治疗，特别是对在先放疗、化疗药物治疗失败的尤因肉瘤的二线治疗提供了新的思路。
除非另有说明，为本申请的目的，本说明书和权利要求书中所用的下列术语应具有下述含义。
本申请中，凡是涉及安罗替尼，其活性成分均是指化合物I。
本申请中，除非另有说明，这里提供的涉及化合物I或其药学上可接受的盐的剂量及其范围，均是基于化合物I游离碱的分子量。
“患者”是指哺乳动物，优选人。在本文中，“患者”、“受试者”或“主体”可互换使用。
如文本所用，术语“联用药物组合物”是指同时或先后施用的两种或两种以上的活性成分(以各自的活性成分本身的形式施用，或者以其各自的药学上可接受的盐或酯等衍生物、前药或组合物的形式施用)的组合。在本文中，术语“联用药物组合物”、“联用药物”和“药物组合”可互换使用。
如本文所用，“联用”或“联合使用”意指两种或更多种活性物质可以各自作为单一制剂同时地、或各自作为单一制剂以任何顺序依次地施用于受试者。
“药学上可接受的”是指其用于制备药物组合物，该药物组合物通常是安全、无毒的并且既不在生物学上或其它方面不合乎需要，并且包括其对于人类药物使用是可接受的。
“药学上可接受的盐”包括，但不限于与无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸等等形成的酸加成盐；或者与有机酸如乙酸、三氟乙酸、丙酸、己酸、庚酸、环戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙二磺酸、2-羟基乙磺酸、苯磺酸、对氯苯磺酸、对甲苯磺酸、3-苯基丙酸、三甲基乙酸、叔丁基乙酸、十二烷基硫酸、葡糖酸、谷氨酸、羟基萘甲酸、水杨酸、硬脂酸等形成的酸加成盐。
“治疗有效量”意指化合物被给予人用于治疗疾病时，足以实现对该疾病控制的使用量。
“治疗”意指治疗上有效量的化合物的任何施用，并且包括：
(1)抑制正经历或显示出所述疾病的病理学或症状学的人体中的该疾病(即，阻止所述病理学和/或症状学的进一步发展)，或
(2)改善正经历或显示出所述疾病的病理学或症状学的人体中的该疾病(即逆转所述病理学和/或症状学)。
在本文中，除非另有说明，否则术语“包含、包括和含有(comprise、comprises和comprising)”或等同物为开放式表述，意味着除所列出的要素、组分和步骤外，还可涵盖其它未指明的要素、组分和步骤。
为了描述和公开的目的，以引用的方式将所有的专利、专利申请和其它已确定的出版物在此明确地并入本文。这些出版物仅因为它们的公开早于本申请的申请日而提供。所有关于这些文件的日期的声明或这些文件的内容的表述是基于申请者可得的信息，并且不构成任何关于这些文件的日期或这些文件的内容的正确性的承认。而且，在任何国家，在本中对这些出版物的任何引用并不构成关于该出版物成为本领域的公知常识的一部分的认可。
具体实施方式
下述是结合具体实施例和实验例，进一步阐述本发明。但这些实施例仅限于说明本发明而不是用于限制本发明的范围。下列实施例中未注明具体实验条件的实验方法，按照常规条件。
实施例1 1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺二盐酸盐(化合物I的二盐酸盐)
Figure PCTCN2020085552-appb-000002
参照WO2008112407中实施例24的方法制备得到1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺，然后参照WO2008112407说明书中“盐形式的实施例”的制备方法，制备得到标题化合物。
或者参照中国专利申请CN102344438A中公开的方法制备得到。
实施例2 1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺二盐酸盐(化合物Ⅰ的二盐酸盐)的胶囊的制备
Figure PCTCN2020085552-appb-000003
将化合物Ⅰ的二盐酸盐粉碎，过80目筛；然后与甘露醇、羟丙纤维素混合均匀；接着加入处方量的微晶纤维素，混合均匀，过0.8mm筛网；最后加入处方量的硬脂酸镁混合均匀，并填充胶囊。
对于化合物I的二盐酸盐为其它含量的胶囊，可参照上述相同的比例和处方制备得到。
实施例3药效实验
受试药物：
1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺二盐酸盐(简称化合物I的二盐酸盐)；长春新碱；阿霉素；环磷酰胺。
1.化合物I的二盐酸盐对于尤因肉瘤生长的影响
配制方法：
化合物I的二盐酸盐溶解于水中达到25mg/mL浓度，并且进一步采用蒸馏水稀释成250μg/ml。
实验动物准备：
BALB/cA-nude裸小鼠，饲养环境：SPF级。裸小鼠皮下接种人尤因肉瘤细胞A673，待肿瘤生长至100-250mm 3后，将动物随机分组(d0)。
实验过程：
化合物I的二盐酸盐以6.25mg/kg的剂量，每日经口给予动物10ml/kg的体积连续14天，每周测2-3次瘤体积，称鼠重，记录数据。
肿瘤体积(V)计算公式为：V＝1/2×a×b 2，其中a、b分别表示长、宽。
T/C(％)＝(T-T0)/(C-C0)×100％，其中，T、C分别表示实验结束时的给药组和对照组(即溶剂组)小鼠的肿瘤体积；T0、C0分别表示分组给药时(d0)给药组和对照组(即溶剂组)小鼠的肿瘤体积。
给药后的相对肿瘤体积(relative tumor volume,RTV)，计算公式为：RTV＝TV/TV0(TV表示给药后的每次测量时的肿瘤体积，TV0表示分组给药时(d0)的肿瘤体积)。
实验结果显示，1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺二盐酸盐(化合物Ⅰ的二盐酸盐)能够显著抑制尤因肉瘤的生长。
2.化合物I的二盐酸盐与第二治疗剂联合对于尤因肉瘤细胞增殖的影响
配制方法：
受试药物均用二甲基亚砜溶解，配成100mmol/L的母液，于-20℃保存，备用。使用时用DMEM血清培养液配制成所需浓度，并将长春新碱、阿霉素、环磷酰胺混合(VAC-2方案)，以及化合物I的二盐酸盐稀释液与长春新碱、阿霉素、环磷酰胺混合。
细胞培养：
人尤因肉瘤细胞株A673培养于含10％胎牛血清和0.1g/L链霉素与青霉素(终浓度为100U·mL -1)的DMEM完全培养液中，恒温37℃置于5％CO 2培养箱中培养。待细胞融合度达到85％左右时，用0.02％EDTA+0.25％胰蛋白酶混合消化，收集细胞，1000r/min离心，传代培养。
实验过程：
可按照本领域通常的方法(例如MTT法)来测定IC 50值，也可按照如下的方法(MTT法)来测定：
接种的对数生长期细胞于96孔培养板(180μL/孔，10 5个细胞/孔)；在37℃、5％CO 2条件下生长2小时，分别加入化合物I的二盐酸盐(梯度为0、0.005、0.1、0.05、0.1、0.5、1.5、4、12、30μg/ml浓度的溶液)联合2μg/ml的长春新碱+75μg/ml阿霉素+500μg/ml的环磷酰胺进行培养，每个浓度设两复孔，每孔加20μL，同时设相应浓度的生理盐水溶媒对照及无细胞调零孔；将肿瘤细胞在37℃、5％CO 2条件下再培养24小时(即总共48小时)；药物作用结束后，每孔加入MTT工作液，4小时后，三联液溶解，37℃过夜。次日，用酶标仪(SPECTRA max 190)在570nm和630nm波长下测定OD值(所有在570nm波长下测得的OD值，减去对照波长630nm波长OD值后再计算)，以下列公式计算细胞生长抑制率：
抑制率＝(OD值对照孔－OD值给药孔)/OD值对照孔×100％
根据各浓度抑制率，采用GraphPad Prism 5软件计算半数抑制浓度IC 50。
实验结果：
化合物I的二盐酸盐+长春新碱+阿霉素+环磷酰胺以及阳性对照长春新碱+阿霉素+环磷酰胺对人尤因肉瘤A673细胞的体外药效学作用显示，化合物I的二盐酸盐与第二治疗剂联合，对人尤因肉瘤A673细胞的增殖有明确的抑制作用。
3.化合物I的二盐酸盐与第二治疗剂联合对尤因肉瘤细胞凋亡的影响
采用流式细胞仪检测细胞凋亡
将处于对数生长期的人尤因肉瘤A673细胞以10 5个细胞/孔分别加入到含有2μg/ml的长春新碱+75μg/ml阿霉素+500μg/ml的环磷酰胺的DMEM完全培养液，以及含有0、0.005、0.1、0.05、0.1、0.5、1.5、4、12、30μg/ml浓度的溶液)浓度的化合物I的二盐酸盐+2μg/ml的长春新碱+75μg/ml阿霉素+500μg/ml的环磷酰胺的DMEM完全培养液中进行培养，24h后收集细胞，1000r/min离心3-5min，PBS清洗。然后使用Annexin-V-FITC/PI细胞凋亡检测试剂盒检测其凋亡情况，将细胞加入到100μL1×Binding缓冲液中重悬，添加5μLAnnexinV-FITC和2.5μLPI染料，进行避光振荡混匀，室温反应15min，然后再加入300μL1×Binding缓冲液，混匀，上流式细胞仪进行检测。重复试验3次。
试验结果：
采用经典的Annexin-V-FITC/PI细胞凋亡检测方法，结果表明，不同浓度的化合物I的二盐酸盐能够显著的增强长春新碱+阿霉素+环磷酰胺(VAC-2方案)方案引起的尤因肉瘤细胞系的凋亡。
实施例4临床试验
在有可测量病灶(根据RECIST 1.1)的尤因肉瘤患者中开展化合物I的二盐酸盐胶囊与第二治疗剂(VAC-2方案)联用的临床试验，患者组中的患者包括之前接受过化疗的患者，以及未接受过化疗的患者，给予化合物I的二盐酸盐胶囊每日一次口服12mg(连续用2周停1周为一个治疗周期)，同时给予VAC-2方案：长春新碱2mg，第1天静脉注射；阿霉素75mg/m 2，第1天静脉点滴；环磷酰胺1200mg/m 2，第1天静脉点滴(28天为一个周期)，评价指标包括疗效指标：无进展生存期(PFS)、客观缓解率(ORR)、缓解持续时间(DOR)、疾病稳定(SD)率、临床获益率(CBR)、总生存期(OS)等；安全性指标：不良反应发生率及严重程度；生活质量等。临床试验结果：
化合物I的二盐酸盐与VAC-2方案联合对尤因肉瘤的治疗有效，可延长总生存期等。
实施例5
患者，男，29岁，2014年11月左耻骨穿刺活检，病理诊断提示：小圆细胞恶性肿瘤。临床诊断：左侧耻骨尤因肉瘤术后化疗后，双肺转移。
2014年11月-2018年10月期间，先后分别累计接受长春新碱(VCR)+阿霉素(ADM)+环磷酰胺(CTX)治疗9周期，异环磷酰胺(IFO)+依托泊苷(VP-16)治疗10周期，化疗期间多次出现III度骨髓抑制。并于2015年3月全麻下行“骨盆巨大肿瘤切除术+髋关节旷置半骨盆截肢术”。术后病理：(左髋部)小细胞恶性肿瘤，结合免疫表型及分子检测结果，首先考虑尤因肉瘤。2018年12月起再次接受“长春新碱+多柔吡星+环磷酰胺”化疗2周期，2019年3月CT等检查结果表明，肺部较前进展，化疗效果不理想。 之后患者开始了每日一次口服12mg(连续用2周停1周为一个治疗周期)剂量的安罗替尼二盐酸盐胶囊(其活性成分为化合物I)的治疗。
在给予安罗替尼二盐酸盐胶囊治疗前一周，CT扫描显示：可测量的靶病灶(左下肺结节)直径之和为16mm，给药后，定期进行CT扫描，治疗10周期后，靶病灶直径之和降至10mm，疗效评价为部分缓解(partial response，PR)，降低达到37.5％。治疗16周期时靶病灶直径之和降低至9mm，疗效评价为PR，未出现新发病灶。治疗期间，总体耐受性良好，目前仍在接受治疗中。
实施例6
患者，男，28岁。2016年行穿刺活检术，病理诊断为外周原始神经外胚层肿瘤。临床诊断骶骨尤因肉瘤/原始神经外胚层肿瘤术后，化疗后双肺转移。
2016年5月至2016年7月期间，先后接受了脂质体多柔比星40mg d1+环磷酰胺1g d1；异环磷酰胺4g d1-3+足叶乙苷100mg d1-3；脂质体多柔比星40mg d1+环磷酰胺1g d1；异环磷酰胺4g d1-3+足叶乙苷100mg d1-3的治疗。2016年8月，患者在全麻下行“后路骶骨肿瘤切除坚固定术”，术后病理骶骨小圆细胞恶性肿瘤，倾向尤因肉瘤/原始神经外胚层肿瘤。术后化疗五周期，依次为表阿霉素110mg d1+环磷酰胺1g d1；异环磷酰胺4g d1-3+足叶乙苷100mg d1-3；表阿霉素110mg d1+环磷酰胺1g d1+长春地辛3mg d1；异环磷酰胺4g d1-3+足叶乙苷100mg d1-3；表阿霉素110mg d1+环磷酰胺1g d1+长春地辛3mg d1；化疗后出现II度骨抑制，末次化疗时间为2017年2月。2017年8月，先后给予伊立替康40mg d1-4+替莫唑胺140mg d1-5；以及伊立替康40mg。2017年9月起，依次给予伊立替康40mg d1-4+替莫唑胺140mg d1-5；伊立替康40mg；伊立替康40mg d1-4+环磷酰胺500mg d1-4；伊立替康40mg d1-4+替莫唑胺140mg d1-5的治疗。
2019年1月患者开始每日一次口服12mg(连续用2周停1周为一个治疗周期)剂量的安罗替尼二盐酸盐胶囊的治疗。
在给予以安罗替尼二盐酸盐胶囊的前3天，CT扫描显示，可测量的靶病灶直径之和为36mm(右肺下叶36mm)。各治疗周期结束后，随即进行CT扫描，结果如下表1所示，受试者目前已服药20周期，医生评估后，建议仍可继续服药，治疗期间，总体耐受性良好。
表1
治疗周期 靶病灶直径之和 疗效评价
第二周期 20mm PR
第六周期 19.3mm PR
第八周期 19mm PR
第十周期 19.6mm PR
第十二周期 18.6mm PR
第十四周期 16.8mm PR
第十六周期 18.5mm PR
第二十周期 18.5mm PR
实施例7
对于在先治疗失败的进展期尤因肉瘤患者，分为A、B两组。A组共有23例16岁以上的患者，给予每日一次口服12mg剂量的安罗替尼二盐酸盐胶囊d1-d14(连续用2周停1周为一个治疗周期)+每日一次静脉注射伊立替康15mg/m 2d1-d5，d8-d10(3周为一个治疗周期)+长春地辛3mg/m 2(d1，d8给药，每3周为一个治疗周期)；B组共有12例年龄小于16岁的患者，给予每日一次口服的安罗替尼二盐酸盐胶囊(连续用2周停1周为一个治疗周期，剂量按体表面积(BSA)分配如下：BSA<1.0m 2，8mg，d1-d14；BSA≥1.0m 2，12mg，d1-d14)+每日一次静脉注射伊立替康20mg/m 2d1-d5，d8-d10(3周为一个治疗周期)+长春地辛3mg/m 2d1，d8(3周为一个治疗周期)。
12周时评价A、B组的研究结果：2组患者12周的ORR分别为62.5％和83.3％，23例16岁以上的患者中1例发生了完全缓解(complete response，CR)。

Claims (15)

  1. 化合物I或其药学上可接受的盐在制备用于治疗尤因肉瘤的药物中的应用，
    Figure PCTCN2020085552-appb-100001
  2. 根据权利要求1所述的应用，其特征在于，所述尤因肉瘤为骨内型尤因肉瘤、骨外型尤因肉瘤、骨膜型尤因肉瘤；
    或者，所述尤因肉瘤为溶骨型尤因肉瘤、硬化型尤因肉瘤、混合型尤因肉瘤；
    或者，所述尤因肉瘤为在先治疗失败的尤因肉瘤，优选地，所述尤因肉瘤为放疗和/或化疗药物治疗失败的尤因肉瘤。
  3. 化合物I或其药学上可接受的盐与第二治疗剂联合在制备用于治疗尤因肉瘤的联用药物中的应用，
    Figure PCTCN2020085552-appb-100002
  4. 根据权利要求3所述的应用，其特征在于，
    所述尤因肉瘤为骨内型尤因肉瘤、骨外型尤因肉瘤、骨膜型尤因肉瘤；
    或者，所述尤因肉瘤为溶骨型尤因肉瘤、硬化型尤因肉瘤、混合型尤因肉瘤；
    或者，所述尤因肉瘤为在先治疗失败的尤因肉瘤，优选地，所述尤因肉瘤为放疗和/或化疗药物治疗失败的尤因肉瘤。
  5. 根据权利要求3或4所述的应用，其特征在于，所述第二治疗剂为化疗药物和/或小分子靶向抗肿瘤药物；优选地，所述化疗药物为烷化剂、鬼臼类、喜树碱类、紫杉类、抗代谢类、抗生素类抗肿瘤药物中的一种或多种；
    更优选地，所述化疗药物为铂类药物、氟嘧啶衍生物、紫杉烷类、喜树碱类、长春碱类、培美曲塞、卡氮芥、依托泊苷(足叶乙苷)、替尼铂苷、丝裂霉素、异环磷酰胺、环磷酰胺、阿扎胞苷、吡柔比星、氨柔比星、甲氨蝶呤、苯达莫司汀、表阿霉素、阿霉素、放线菌素D、更生霉素、博来霉素、替莫唑胺、LCL-161、KML-001、Sapacitabine、普那布林、曲奥舒凡、地匹福林盐酸盐、 153Sm-EDTMP、替吉奥和encequidar中 的一种或多种；
    进一步优选地，所述铂类药物为奥沙利铂、顺铂、卡铂、奈达铂、双环铂中的一种或多种，所述氟嘧啶衍生物为吉西他滨、卡培他滨、氟尿嘧啶、双呋氟尿嘧啶、去氧氟尿苷、替加氟、卡莫氟、三氟尿苷中的一种或多种，所述紫杉烷类为紫杉醇、白蛋白结合的紫杉醇以及多烯紫杉醇中的一种或多种，所述喜树碱类为喜树碱、羟基喜树碱、伊立替康、拓扑替康中的一种或多种，所述长春碱类为长春瑞滨、长春碱、长春新碱、长春地辛、长春富宁中的一种或多种；
    优选地，所述小分子靶向抗肿瘤药物为蛋白激酶抑制剂；
    更优选地，所述小分子靶向抗肿瘤药物为酪氨酸激酶抑制剂、丝氨酸和/或苏氨酸激酶抑制剂；
    进一步优选地，所述小分子靶向抗肿瘤药物为厄洛替尼、阿法替尼、克唑替尼、色瑞替尼、威罗菲尼、达拉菲尼、卡博替尼、吉非替尼、达可替尼、奥希替尼、艾乐替尼、布格替尼、劳拉替尼、曲美替尼、拉罗替尼、埃克替尼、拉帕替尼、凡德他尼、司美替尼、索拉非尼、奥莫替尼、沃利替尼、呋喹替尼、恩曲替尼、达沙替尼、恩沙替尼、乐伐替尼、itacitinib、吡咯替尼、比美替尼、厄达替尼、阿西替尼、来那替尼、考比替尼、阿卡替尼、法米替尼、马赛替尼、伊布替尼、rociletinib、尼达尼布、来那度胺、依维莫斯、LOXO-292、Vorolanib、bemcentinib、capmatinib、entrectinib、TAK-931、ALT-803、palbociclib、famitinib L-malate、LTT-462、BLU-667、ningetinib、tipifarnib、poziotinib、DS-1205c、capivasertib、SH-1028、二甲双胍、seliciclib、OSE-2101、APL-101、berzosertib、idelalisib、lerociclib、ceralasertib、PLB-1003、tomivosertib、AST-2818、SKLB-1028、D-0316、LY-3023414、allitinib、MRTX-849、AP-32788、AZD-4205、lifirafenib、vactosertib、mivebresib、napabucasin、sitravatinib、TAS-114、molibresib、CC-223、rivoceranib、CK-101、LXH-254、simotinib、GSK-3368715、TAS-0728、masitinib、tepotinib、HS-10296、AZD-4547、merestinib、olaptesedpegol、galunisertib、ASN-003、gedatolisib、defactinib、lazertinib、CKI-27、S-49076、BPI-9016M、RF-A-089、RMC-4630、AZD-3759、antroquinonol、SAF-189s、AT-101、TTI-101、naputinib、LNP-3794、HH-SCC-244、ASK-120067、CT-707、epitinib succinate、tesevatinib、SPH-1188-11、BPI-15000、copanlisib、niraparib、olaparib、veliparib、talazoparibtosylate、DV-281、Siremadlin、Telaglenastat、MP-0250、GLG-801、ABTL-0812、bortezomib、帕比司他、tucidinostat、vorinostat、resminostat、epacadostat、tazemetostat、entinostat、mocetinostat和quisinostat中的一种或者多种；
    更进一步优选地，所述小分子靶向抗肿瘤药物为索拉非尼、依维莫斯、厄洛替尼、阿法替尼、克唑替尼、色瑞替尼、威罗菲尼、达拉菲尼、卡博替尼、吉非替尼、达可替尼、奥希替尼、艾乐替尼、布格替尼、劳拉替尼、曲美替尼、拉罗替尼、埃克替尼、拉帕替尼、凡德他尼、司美替尼、奥莫替尼、沃利替尼、呋喹替尼、恩曲替尼、达沙替尼、恩沙替尼、乐伐替尼、itacitinib、吡咯替尼、比美替尼、厄达替尼、阿西替尼、来那替尼、考比替尼、阿卡替尼、法米替尼、马赛替尼、伊布替尼、尼达尼布中的一种或者多种。
  6. 根据权利要求3-5中任一项所述的应用，其特征在于，所述第二治疗剂为长春新碱、环磷酰胺、以及放线菌素D的组合；
    或者，所述第二治疗剂为长春新碱、环磷酰胺、以及阿霉素的组合；
    或者，所述第二制剂为阿霉素、甲氨蝶呤、环磷酰胺、放线菌素D、博来霉素、长春新碱的组合；
    或者，所述第二治疗剂为长春新碱、环磷酰胺、放线菌素D和/或阿霉素的组合；
    或者，所述第二治疗剂为异环磷酰胺、足叶乙苷的组合；
    或者，所述第二治疗剂为阿霉素、环磷酰胺的组合；
    或者，所述第二治疗剂为长春新碱、环磷酰胺的组合。
  7. 根据权利要求3-5中任一项所述的应用，其特征在于，所述第二治疗剂为VAC方案、T9方案、IE方案或AC方案中的一种。
  8. 根据权利要求1-7中任一项所述的应用，其特征在于，所述化合物I的药学上可接受的盐为化合物I与任意如下酸所形成的盐：盐酸、氢溴酸、硫酸、硝酸、磷酸、乙酸、三氟乙酸、丙酸、己酸、庚酸、环戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙二磺酸、2-羟基乙磺酸、苯磺酸、对氯苯磺酸、对甲苯磺酸、3- 苯基丙酸、三甲基乙酸、叔丁基乙酸、十二烷基硫酸、葡糖酸、谷氨酸、羟基萘甲酸、水杨酸、硬脂酸；优选为盐酸盐或马来酸盐的形式，更优选为二盐酸盐。
  9. 根据权利要求1-8中任一项所述的应用，其特征在于，给予所述化合物I或其药学上可接受的盐的日剂量为3毫克至30毫克，优选为5毫克至20毫克，更优选为8毫克至16毫克，进一步优选为8毫克至14毫克，最优选为8毫克、10毫克或12毫克；
    优选地，所述化合物I或其药学上可接受的盐以给药期和停药期间隔的给药方式；优选地，给药期和停药期以天数计的比值为2:0.5～5，更优选2:0.5～3，较优选2:0.5～2，进一步优选2:0.5～1；作为更进一步优选的间隔给药方式，所述给药方式为如下方式中的一种：连续给药2周停药2周、连续给药2周停药1周或连续给药5天停药2天；所述间隔给药方式可以反复进行多次。
  10. 根据权利要求3-9中任一项所述的应用，其特征在于，所述化合物I或其药学上可接受的盐以及第二治疗剂采用同时给药、序贯给药或不分次序先后给药。
  11. 根据权利要求1-10任一项所述的应用，其特征在于，所述用于治疗尤因肉瘤的药物和/或联用药物为适于口服、肠胃外、腹膜内、静脉内、动脉内、透皮、舌下、肌内、直肠、透颊、鼻内、经吸入、阴道、眼内、经局部给药、皮下、脂肪内、关节内、腹膜内或鞘内任意给药方式的制剂。
  12. 一种用于治疗尤因肉瘤的方法，所述方法包括向需要治疗的受试者给予治疗有效量的化合物I或其药学上可接受的盐。
  13. 根据权利要求12所述的方法，其中，所述尤因肉瘤为骨内型尤因肉瘤、骨外型尤因肉瘤、骨膜型尤因肉瘤；
    或者，所述尤因肉瘤为溶骨型尤因肉瘤、硬化型尤因肉瘤、混合型尤因肉瘤；
    或者，所述尤因肉瘤为在先治疗失败的尤因肉瘤，优选地，所述尤因肉瘤为放疗和/或化疗药物治疗失败的尤因肉瘤。
  14. 一种用于治疗尤因肉瘤的药物组合物，所述药物组合物含有化合物I或其药学上可接受的盐。
  15. 一种用于治疗尤因肉瘤的联用药物组合物，所述药物组合物含有化合物I或其药学上可接受的盐以及第二治疗剂。
PCT/CN2020/085552 2019-04-19 2020-04-20 用于治疗尤因肉瘤的喹啉类化合物或其药学上可接受的盐 WO2020211860A1 (zh)

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CA3137204A CA3137204A1 (en) 2019-04-19 2020-04-20 Quinoline compound or pharmaceutically acceptable salt thereof for treating ewing's sarcoma
JP2021562183A JP2022529295A (ja) 2019-04-19 2020-04-20 ユーイング肉腫治療用キノリン系化合物又はその薬学的に許容される塩
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US17/603,886 US20220193067A1 (en) 2019-04-19 2020-04-20 Quinoline compound or pharmaceutically acceptable salt thereof for treating ewing's sarcoma
EP20790646.2A EP3957631A4 (en) 2019-04-19 2020-04-20 QUINOLINE COMPOUND OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF FOR THE TREATMENT OF EWING'S SARCOMA

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CN112358467A (zh) * 2020-10-29 2021-02-12 苏州富士莱医药股份有限公司 一种吡咯替尼的制备工艺
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