Quinoline compounds or pharma- ceutical acceptable salts thereof for treating Ewing's sarcoma

Abstract

The present invention relates to the pharmaceutical field and provides a quinoline compound or a pharmaceutically acceptable salt thereof for the treatment of Ewing's sarcoma, specifically to the use of the compound represented by Formula I or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of Ewing's sarcoma, and the use of the compound represented by Formula I or a pharmaceutically acceptable salt thereof in combination with a second therapeutic agent for the preparation of a combination medicament for the treatment of Ewing's sarcoma. The chemical name of the compound represented by Formula I is 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropylamine.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from Chinese Patent Application No. 201910315417.X, filed with the State Intellectual Property Office of the People's Republic of China on April 19, 2019, the entire disclosure of which is incorporated herein by reference. [Technical field]

[0002] The present invention relates to the pharmaceutical field, specifically to a quinoline compound or a pharmaceutically acceptable salt thereof for the treatment of Ewing's sarcoma, and a quinoline compound or a pharmaceutically acceptable salt thereof for the combination therapy of Ewing's sarcoma. [Background technology]

[0003] Ewing's sarcoma is recognized as a type of isolated bone tumor and is defined as a small round cell tumor originating from the neuroectodermal bone or soft tissue. It accounts for 6% to 8% of primary bone tumors and 10% to 14.2% of malignant bone tumors, and is the most common malignant primary bone tumor in children and adolescents after osteosarcoma and chondrosarcoma, and is more common in men than in women.

[0004] Pain and swelling are the most common early symptoms of Ewing's sarcoma. More than 60% of patients experience intermittent pain in the early stages, and the area of ​​pain spreads as the tumor spreads. As the pain intensifies, a localized mass is formed, which is accompanied by significant tenderness. After that, symptoms of nerve dysfunction appear in the nerve roots and spinal cord, and some patients experience a fever of 38°C to 40°C, a clear increase in high-density lipoprotein, cholesterol, and red blood cell sedimentation rate, an increase in white blood cell count, and anemia. Large lumps may appear in the soft tissue of the affected area. Because Ewing's sarcoma is highly malignant and prone to metastasis, surgery, radiation therapy, and single-agent chemotherapy alone are not very effective, and the 5-year survival rate is less than 10%.

[0005] For the time being, effective treatment for Ewing's sarcoma is multidisciplinary therapy, which may or may not involve surgery followed by radiation therapy and chemotherapy. Most chemotherapy is a combination of multiple drugs. Although related research has already shown that the 5-year survival rate is significantly improved when Ewing's sarcoma is treated with chemotherapy using a combination of multiple drugs, chemotherapy generally lasts for two years because most Ewing's sarcomas metastasize within two years. Prolonged chemotherapy can cause toxicity and side effects, including complications in the hematopoietic, respiratory, cardiovascular, nervous, and urinary systems. Therefore, the development of new treatments for Ewing's sarcoma is necessary. Summary of the Invention

[0006] In a first aspect of the present invention, there is provided the use of a compound of formula I or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of Ewing's sarcoma.

[0007] The compound of formula I has the chemical name 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropylamine and the structural formula is: [ka]

[0008] In some embodiments, the Ewing's sarcoma is intraosseous, extraosseous, or periosteal.

[0009] In some embodiments, the Ewing's sarcoma is osteolytic Ewing's sarcoma, sclerosing Ewing's sarcoma, or mixed Ewing's sarcoma.

[0010] In some embodiments, the Ewing's sarcoma is advanced stage Ewing's sarcoma. In some embodiments, advanced stage Ewing's sarcoma refers to Ewing's sarcoma in a primary tumor or a locally recurrent tumor that has not been cured by surgery or other localized treatments, or in which the patient is unwilling to undergo surgery or other localized treatments. In some embodiments, advanced stage Ewing's sarcoma refers to Ewing's sarcoma in which distant metastasis has already occurred, in which the metastatic tumor has not been cured by surgery or other localized treatments, or in which the patient is unwilling to undergo surgery or other localized treatments.

[0011] In some embodiments, the Ewing's sarcoma is a Ewing's sarcoma that has failed previous treatments. Preferably, the Ewing's sarcoma is a Ewing's sarcoma that has failed radiation therapy and / or chemotherapy. More preferably, the Ewing's sarcoma is a Ewing's sarcoma that has failed treatment with a chemotherapy agent selected from one or more of cyclophosphamide, ifosfamide, doxorubicin, pirarubicin, adriamycin, dactinomycin, bleomycin, vincristine, carmustine, etoposide, actinomycin D, methotrexate, and cisplatin. Most preferably, the chemotherapy agent used on the subject of the Ewing's sarcoma is selected from one or more of cyclophosphamide, ifosfamide, doxorubicin, pirarubicin, vincristine, and etoposide.

[0012] The compounds of formula I described herein may be administered in the form of their free base or in the form of their salts, hydrates or prodrugs, which are converted in vivo to the free base form of the compounds of formula I. For example, pharma- ceutically acceptable salts of the compounds of formula I may be prepared from different organic or inorganic acids by methods well known in the art without departing from the scope of the present disclosure.

[0013] In some embodiments, the pharma- ceutically acceptable salt of the compound of Formula I is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, caproic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic 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, trimethylacetic acid, tert-butyl ... This includes, but is not limited to, salts formed from any of the following acids: t-butyl acetate, dodecyl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, and stearic acid, and the compound represented by formula I. In the present invention, the pharma- ceutically acceptable salt form of the compound represented by formula I is preferably a hydrochloride or maleate, and more preferably a dihydrochloride.

[0014] In some embodiments, the compound represented by formula I is administered in the form of a hydrochloride salt. In some embodiments, the compound represented by formula I is administered in the form of a monohydrochloride salt. In some embodiments, the compound represented by formula I is administered in the form of a dihydrochloride salt. In some embodiments, the compound represented by formula I is administered in the form of a crystalline hydrochloride salt. In certain embodiments, the compound represented by formula I is administered in the form of a crystalline dihydrochloride salt. In some embodiments, the compound represented by formula I is administered in the form of a maleate salt.

[0015] In a second aspect of the invention, there is provided a method for treating Ewing's sarcoma, comprising the step of administering to a patient in need of treatment a therapeutically effective amount of a compound of formula I, or a pharma- ceutically acceptable salt thereof.

[0016] The compound of formula I or a pharma- ceutically acceptable salt thereof may be administered in a number of ways, including, but not limited to, oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intraadipose, intraarticular, and intrathecal. In certain embodiments, the compound is administered orally.

[0017] The method of administration of the compound represented by formula I may be determined comprehensively based on the activity, toxicity, and tolerability of the drug.

[0018] In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof may be provided in a formulation suitable for any of oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intraadipose, intraarticular, and intrathecal administration.Preferably, the formulation is suitable for oral administration.In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof is preferably provided in a tablet, capsule, powder, granule, drop pill, paste, or powder, more preferably in a tablet or capsule.

[0019] In some embodiments, the dosage of the compound represented by formula I or a pharma- ceutically acceptable salt thereof is determined based on the severity of the disease, the response to the disease, any treatment-related toxicities, and the age and health of the patient. In some embodiments, the daily dose of the compound represented by formula I or a pharma- ceutically acceptable salt thereof is 3 mg to 30 mg, preferably 5 mg to 20 mg, more preferably 8 mg to 16 mg, even more preferably 8 mg to 14 mg, and most preferably 8 mg, 10 mg, or 12 mg.

[0020] Preferably, the compound represented by formula I or a pharma- ceutically acceptable salt thereof is administered at intervals. The interval administration includes an administration period and a rest period, and the compound represented by formula I or a pharma- ceutically acceptable salt thereof is administered once or multiple times daily during the administration period. For example, the compound represented by formula I or a pharma- ceutical acceptable salt thereof is administered daily during the administration period, and then the administration is stopped for a certain period during the rest period, followed by the administration period, and then the rest period. This can be repeated multiple times. However, the ratio of the administration period to the rest period based on the number 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.

[0021] More preferably, the interval administration method is any cycle selected from two weeks of continuous administration followed by two weeks of rest, two weeks of continuous administration followed by one week of rest, or five days of continuous administration followed by two days of rest, and the interval administration method can be repeated multiple times.

[0022] In a third aspect of the present invention, there is provided a pharmaceutical composition for treating Ewing's sarcoma comprising a compound of formula I, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable carrier.

[0023] The pharmaceutical composition includes, but is not limited to, formulations suitable for oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intraadipose, intraarticular, and intrathecal administration.Preferably, the formulations are suitable for oral administration, including tablets, capsules, powders, granules, drop pills, pastes, powders, etc., and are preferably tablets and capsules.The tablets may be normal tablets, dispersible tablets, effervescent tablets, sustained release tablets, controlled release tablets, or enteric-coated tablets, and the capsules may be normal capsules, sustained release capsules, controlled release capsules, or enteric-coated capsules.The oral formulations may be prepared by conventional methods using pharma-ceutically acceptable carriers well known in the art.The pharma-ceutically acceptable carriers include fillers, absorbents, wetting agents, binders, disintegrants, lubricants, etc. 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 hydroxypropyl methylcellulose, povidone, microcrystalline cellulose, etc., disintegrants include croscarmellose sodium, crospovidone, surfactants, low-substituted hydroxypropyl cellulose, etc., lubricants include magnesium stearate, talc, polyethylene glycol, sodium dodecyl sulfate, aerosil, talc, etc. Pharmaceutical additives further include colorants, sweeteners, etc.

[0024] In one embodiment, the pharmaceutical composition is a solid formulation suitable for oral administration. The composition is, for example, in the form of a tablet or capsule. In a particular embodiment, the pharmaceutical composition is a capsule. In a particular embodiment of the present invention, the pharma- ceutically acceptable carrier in the oral solid formulation includes mannitol, microcrystalline cellulose, hydroxypropyl cellulose, magnesium stearate.

[0025] In a fourth aspect of the present invention, there is provided the use of a compound of formula I, or a pharma- ceutically acceptable salt thereof, in combination with a second therapeutic agent for the manufacture of a medicinal combination for the treatment of Ewing's sarcoma.

[0026] In some embodiments, Ewing's sarcoma includes, but is not limited to, intraosseous Ewing's sarcoma, extraosseous Ewing's sarcoma, and periosteal Ewing's sarcoma.

[0027] In some embodiments, Ewing's sarcoma includes, but is not limited to, osteolytic Ewing's sarcoma, sclerosing Ewing's sarcoma, and mixed Ewing's sarcoma.

[0028] In some embodiments, the Ewing's sarcoma is advanced stage Ewing's sarcoma. In some embodiments, advanced stage Ewing's sarcoma refers to Ewing's sarcoma in a primary tumor or a locally recurrent tumor that has not been cured by surgery or other localized treatments, or in which the patient is unwilling to undergo surgery or other localized treatments. In some embodiments, advanced stage Ewing's sarcoma refers to Ewing's sarcoma in which distant metastasis has already occurred, in which the metastatic tumor has not been cured by surgery or other localized treatments, or in which the patient is unwilling to undergo surgery or other localized treatments.

[0029] In some embodiments, the Ewing's sarcoma is a Ewing's sarcoma that has failed previous treatments. The present invention includes, but is not limited to, Ewing's sarcoma. Preferably, the Ewing's sarcoma is a Ewing's sarcoma that has failed radiation therapy and / or chemotherapy. More preferably, the chemotherapeutic agent administered to the subject with Ewing's sarcoma is selected from one or more of cyclophosphamide, ifosfamide, doxorubicin, pirarubicin, adriamycin, dactinomycin, bleomycin, vincristine, carmustine, etoposide, actinomycin D, methotrexate, and cisplatin. Most preferably, the chemotherapeutic agent administered to the subject with Ewing's sarcoma is selected from one or more of cyclophosphamide, ifosfamide, doxorubicin, pirarubicin, vincristine, and etoposide.

[0030] In some embodiments, the second therapeutic agent is a chemotherapeutic agent, including, but not limited to, one or more of alkylating agents, podophyllums, camptothecins, taxanes, antimetabolites, and antibiotic antitumor agents, examples of which include platinum-based drugs (e.g., oxaliplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin), fluoropyrimidine derivatives (e.g., gemcitabine, capecitabine, fluorouracil, tegadiful, doxifluridine, tegafur, carmofur, trifluridine), taxanes (e.g., paclitaxel, albumin-bound paclitaxel, docetaxel), camptothecins (e.g., camptothecin, hydroxycamptothecin, irinotecan, topotecan), vinblastines (vinorelbine, vinblastine, vincristine, vinsulfamethoxazole ... desine, vinflunine, pemetrexed, carmustine, etoposide (lastet), teniposide, mitomycin, ifosfamide, cyclophosphamide, azacytidine, doxorubicin, pirarubicin, amrubicin, methotrexate, bendamustine, epirubicin, adriamycin, actinomycin D, dactinomycin, bleomycin, temozolomide, LCL-161, KML-001, sapacitabine, plinabulin, treosulfan, tipiracil hydrochloride, 153 In some embodiments, the chemotherapeutic agent is selected from one or more of the following: Sm-EDTMP, tegafur-gimeracil-oteracil potassium, and encequidar. In some embodiments, the chemotherapeutic agent is selected from one or more of the following: vincristine, cyclophosphamide, ifosfamide, adriamycin, dactinomycin, bleomycin, carmustine, etoposide (lastet), actinomycin D, methotrexate, and cisplatin.

[0031] Optionally, the second therapeutic agent may be used in combination with a chemotherapy adjuvant, including but not limited to calcium folinate (CF), folinic acid, mesna, bisphosphonate, amifostine, and colony-stimulating factor (CSF). In some embodiments, the chemotherapy adjuvant is calcium folinate (CF), mesna, or folinic acid.

[0032] In some embodiments, the second therapeutic agent is a combination of a camptothecin and a vinblastine compound. In some embodiments, the second therapeutic agent is a combination of a camptothecin and a vinblastine compound. In some embodiments, the camptothecin compound is selected from one or more of camptothecin, hydroxycamptothecin, irinotecan, and topotecan, and the vinblastine compound is selected from one or more of vinorelbine, vinblastine, vincristine, vindesine, and vinflunine.

[0033] In some embodiments, 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 vinorelbine, vinblastine, vincristine, vindesine, and vinflunine. In some specific embodiments, the second therapeutic agent is a combination of irinotecan and vindesine.

[0034] In some embodiments, the second therapeutic agent is VAC-1 therapy, specifically vincristine, cyclophosphamide, and actinomycin D.

[0035] In some embodiments, the second therapeutic agent is VAC-2 therapy, specifically vincristine, cyclophosphamide, and adriamycin.

[0036] In some embodiments, the second therapeutic agent is T9 therapy, specifically adriamycin, methotrexate, cyclophosphamide, actinomycin D, bleomycin, and vincristine.

[0037] In some embodiments, the second therapeutic agent is an IE therapy, specifically ifosfamide and lastet.

[0038] In some embodiments, the second therapeutic agent is AC therapy, specifically adriamycin and cyclophosphamide.

[0039] In some embodiments, the second therapeutic agent is a small molecule targeted anti-tumor drug, including but not limited to a protein kinase inhibitor, wherein the protein kinase inhibitor includes but is not limited to a tyrosine kinase inhibitor, a serine and / or threonine kinase inhibitor, and a poly ADP-ribose polymerase (PARP) inhibitor, and the targets of the inhibitor include but are not limited to EGFR (epidermal growth factor receptor), anaplastic lymphoma kinase (ALK), MET gene, ROS1 gene, HER2 gene, RET gene, BRAF gene, PI3K signaling pathway, DDR2 (discrete death receptor 2) gene, FGFR1 (fibroblast growth factor receptor 1), NTRK1 (neurotrophin tyrosine kinase receptor type 1) gene, and KRAS gene. The targets of the small molecule targeted antitumor drugs further include COX-2 (cyclooxygenase-2), APE1 (purine / apyrimidinium endonuclease 1), 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 molecule), Src, IFN, ALCAM (activated leukocyte adhesion molecule), HSP, JIP1, GSK-3β (glycogen synthase kinase 3β), CyclinD1 (cyclin D), CDK4 (cyclin-dependent kinase), TIMP1 (tissue inhibitor of metalloproteinase), THBS3, PTHR1 (parathyroid hormone-related peptide 1), TEM7 (human tumor endothelial marker 7), COPS3, cathepsin K.Examples of small molecule targeted antitumor drugs include erlotinib, afatinib, crizotinib, ceritinib, vemurafenib, dabrafenib, cabozantinib, gefitinib, dacomitinib, and osimertinib. b), Alectinib, Brigatinib, Lorlatinib, Trametinib, Larotrectinib, Icotinib, Lapatinib, Vandetanib, Selumetinib, Sorafenib, Olmutinib. nib), Savolitinib, Fruquintinib, Entrectinib, Dasatinib, Ensartinib, Lenvatinib, Itacitinib, Pyrotinib, Binimetinib, Erdafitinib, Axitinib, Neratinib, Cobimetinib, Acalabrutinib calabrutinib, famitinib, masitinib, ibrutinib, rociletinib, nintedanib, lenalidomide, everolimus, LOXO-292, vorolanib, bemcentinib, capmatinib, entrectinib, TAK-931, ALT-803, palbociclib, famitinib L-malateL-malate, LTT-462, BLU-667, ningetinib, tipifarnib, poziotinib, DS-1205c, capivasertib, SH-1028, metformin, 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, anthroquinonol, SAF-189s, AT-101, TTI-101, naputinib, LNP-3794, HH-SCC-244, ASK-120067, CT-707, epitinib succinatesuccinate, tesevatinib, SPH-1188-11, BPI-15000, copanlisib, niraparib, olaparib, veliparib, talazoparib tosylate, DV-281, siremadlin, telaglenstat, MP-0250, GLG-801, ABTL-0812, bortezomib In some embodiments, the small molecule targeted anti-tumor drug is one or more of sorafenib, everolimus, erlotinib, afatinib, crizotinib, ceritinib, vemurafenib, cemetin ... The drug is one or more of the following: phenib, dabrafenib, cabozantinib, gefitinib, dacomitinib, osimertinib, alectinib, brigatinib, lorlatinib, trametinib, larotrectinib, icotinib, lapatinib, vandetanib, selumetinib, olmutinib, savolitinib, fruquintinib, entrectinib, dasatinib, ensartinib, lenvatinib, itacitinib, pyrotinib, binimetinib, erdafitinib, axitinib, neratinib, cobimetinib, acalabrutinib, famitinib, masitinib, ibrutinib, and nintedanib.

[0040] In some embodiments, the dosage of the compound represented by formula I or a pharma- ceutically acceptable salt thereof in the combined drug is determined based on the severity of the disease, the response to the disease, any treatment-related toxicity, and the age and health of the patient. In some embodiments, the daily dose of the compound represented by formula I or a pharma- ceutically acceptable salt thereof is 3 mg to 30 mg. In some embodiments, the daily dose of the compound represented by formula I or a pharma- ceutically acceptable salt thereof is 5 mg to 20 mg. In some embodiments, the daily dose of the compound represented by formula I or a pharma- ceutically acceptable salt thereof is 8 mg to 16 mg. In some embodiments, the daily dose of the compound represented by formula I or a pharma- ceutically acceptable salt thereof is 8 mg to 14 mg. In certain embodiments, the daily dose of the compound represented by formula I or a pharma- ceutically acceptable salt thereof is 8 mg. In certain embodiments, the daily dose of the compound represented by formula I or a pharma- ceutically acceptable salt thereof is 10 mg. In certain embodiments, the daily dosage of the compound of formula I or a pharma- ceutically acceptable salt thereof is 12 mg.

[0041] The compound of formula I, or a pharma- ceutically acceptable salt thereof, is administered one or more times daily. In some embodiments, the compound of formula I, or a pharma- ceutically acceptable salt thereof, is administered once daily.

[0042] The method of administration of the compound represented by formula I may be determined comprehensively based on the activity, toxicity, and tolerability of the drug.

[0043] Preferably, the compound represented by formula I or a pharma- ceutically acceptable salt thereof is administered at intervals. The interval administration includes an administration period and a rest period, and the compound represented by formula I or a pharma- ceutically acceptable salt thereof is administered once or multiple times daily during the administration period. For example, the compound represented by formula I or a pharma- ceutical acceptable salt thereof is administered daily during the administration period, and then the administration is stopped for a certain period during the rest period, followed by the administration period, and then the rest period. This can be repeated multiple times. However, the ratio of the administration period to the rest period based on the number 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.

[0044] In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof is administered in an interval dosing regimen of 2 weeks of consecutive dosing followed by 2 weeks of rest, 2 weeks of consecutive dosing followed by 1 week of rest, or 5 days of consecutive dosing followed by 2 days of rest, which may be repeated multiple times.

[0045] In some embodiments, the compound of formula I, or a pharma- ceutically acceptable salt thereof, and the second therapeutic agent are administered simultaneously, sequentially, or sequentially, hi some embodiments, the compound of formula I, or a pharma- ceutically acceptable salt thereof, and the second therapeutic agent are each prepared and administered as a pharmaceutical composition.

[0046] In some embodiments, the combination drug for treating Ewing's sarcoma is administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, buccally, intranasally, by inhalation, vaginally, or intraocularly. These include, but are not limited to, formulations suitable for any method of administration, including topical, subcutaneous, intraadipose, intraarticular, and intrathecal.

[0047] The compound represented by formula I or its pharma- ceutically acceptable salt is preferably in the form of a preparation suitable for oral administration, including tablets, capsules, powders, granules, drop pills, pastes, powders, etc., and is preferably in the form of tablets and capsules. The tablets may be normal tablets, dispersible tablets, effervescent tablets, sustained-release tablets, controlled-release tablets, or enteric-coated tablets, and the capsules may be normal capsules, sustained-release capsules, controlled-release capsules, or enteric-coated capsules. The oral preparations may be prepared by conventional methods using pharma- ceutically acceptable carriers well known in the art. The pharma- ceutically acceptable carriers include fillers, absorbents, wetting agents, binders, disintegrants, lubricants, etc. 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 hydroxypropyl methylcellulose, povidone, microcrystalline cellulose, etc., disintegrants include croscarmellose sodium, crospovidone, surfactants, low-substituted hydroxypropyl cellulose, etc., lubricants include magnesium stearate, talc, polyethylene glycol, sodium dodecyl sulfate, aerosil, talc, etc. Pharmaceutical additives further include colorants, sweeteners, etc.

[0048] In certain embodiments, irinotecan is administered intravenously at a dose of 10 to 40 mg / m 2 and simultaneously administering the compound represented by formula I or a pharma- ceutically acceptable salt thereof orally once or multiple times at a dose selected, but not limited to, from 3 to 30 mg daily, for two consecutive weeks followed by a one-week break.

[0049] In certain embodiments, irinotecan is administered intravenously at a dose of 10 to 40 mg / m 2 and the dose is 1-4 mg / m 2 vindesine is administered at 400 mg / kg / day, and simultaneously, a compound represented by formula I or a pharma- ceutically acceptable salt thereof is orally administered once or multiple times at a dose selected, but not limited to, from 3 to 30 mg daily, for two consecutive weeks followed by a one-week break.

[0050] In certain embodiments, each dose of irinotecan is 10 to 40 mg / m 2 and the daily dose of vindesine is 1-4 mg / m 2 and the compound of formula I or a pharma- ceutical acceptable salt thereof is orally administered at a dose of 8-12 mg daily for 2 weeks of continuous administration and 1 week of rest. In certain embodiments, each dose of irinotecan is 10, 15, 20, 25, 30, 35, or 40 mg / m 2 and each dose of vindesine is 1, 2, 3 or 4 mg / m 2 The compound represented by formula I or a pharma- ceutical acceptable salt thereof is orally administered at a dose of 8-12 mg daily, with 2 weeks of continuous administration and 1 week of rest.

[0051] In certain embodiments, a treatment cycle lasts for 3 weeks, where irinotecan is administered on days 1-5 and days 8-10 of each cycle, vindesine is administered on days 1 and 8 of each cycle, and a compound of formula I, or a pharma- ceutical acceptable salt thereof, is administered on days 1-14 of each cycle.

[0052] In certain embodiments, one treatment cycle is 3 weeks, where irinotecan is administered on days 1-5 and days 8-10 of each cycle, once daily, with each dose being 10, 15, or 20 mg / m 2 and vindesine was administered once daily on days 1 and 8 of each cycle at doses of 2, 3, or 4 mg / m 2 and the compound of formula I or a pharma- ceutically acceptable salt thereof is administered once daily on days 1 to 14 of each cycle, with each dose being 8 to 12 mg.

[0053] In some specific embodiments, vincristine is administered at 1.5 mg / m 2 Inject intravenously with , once a week, and cyclophosphamide 500 mg / m 2After 6 weeks, the two chemotherapy drugs are intravenously administered at the same dose once a week, and the compound represented by formula I or a pharmaceutically acceptable salt thereof is orally administered once or multiple times at a dose selected from, but not limited to, 3-30 mg per day, for 2 weeks of continuous administration and 1 week of rest, and then radical surgery is performed at the same time.

[0054] In some specific embodiments, actinomycin D is 450 μg / m 2 The patients were intravenously injected with 20 mg / m2 of adriamycin once daily for 5 days. 2 Intravenous infusion was started, 1x / day × 3, and on day 43, vincristine 1.5 mg / m 2 Intravenous administration was started once a week × 4, and cyclophosphamide was administered at 1200 mg / m 2 The compound represented by formula I or a pharma- ceutical acceptable salt thereof is orally administered once or multiple times at a dose selected, but not limited to, from 3 to 30 mg daily, for two consecutive weeks followed by a one-week rest.

[0055] In some specific embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof is used in combination with VAC-1 therapy, with details as follows: 2 mg vincristine is administered intravenously on the first day, and 2 mg / m actinomycin D is administered intravenously on the second day. 2 On the first day, cyclophosphamide was administered intravenously at 1200 mg / m 2 On the first day, the compound represented by formula I or a pharma- ceutical acceptable salt thereof is administered orally once or multiple times at a dose selected from, but not limited to, 3 to 30 mg per day, with two weeks of continuous administration and two weeks of rest, making one cycle of 28 days.

[0056] In some specific embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof is used in combination with VAC-2 therapy, with details as follows: 2 mg vincristine is administered intravenously on the first day, and 75 mg / m adriamycin is administered intravenously on the second day. 2On the first day, cyclophosphamide was administered intravenously at 1200 mg / m 2 On the first day, the compound represented by formula I or a pharma- ceutical acceptable salt thereof is administered orally once or multiple times at a dose selected from, but not limited to, 3 to 30 mg per day, with 5 consecutive days of administration followed by 2 days of rest, making one cycle of 7 days.

[0057] In some specific embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof is used in combination with T9 therapy, the details of which are as follows: Adriamycin at 20 mg / m 2 on days 1-3 and 42-44, and methotrexate was administered intravenously at 12 mg / m 2 on days 1-3 and 42-44, and cyclophosphamide 1.2 g / m 2 On the first and 42nd days, actinomycin D was administered intravenously at 0.5 mg / m 2 on days 21-23, and bleomycin was administered intravenously at 10 mg / m 2 on days 21-23, and vincristine at 1.5 mg / m 2 The compound represented by formula I or a pharma- ceutical acceptable salt thereof is orally administered once or multiple times at a dose selected, but not limited to, from 3 to 30 mg daily for 5 consecutive days followed by a 2-day rest period.

[0058] In some specific embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof is used in combination with IE and AC therapy in sequential treatment, with details as follows: Ifosfamide at 1.6 g / m 2 on days 1-5, and Lastet was administered intravenously at 100 mg / m 2 on the 15th day, and adriamycin was administered intravenously for 21 days. After the 3rd cycle, adriamycin was administered at 35 mg / m 2 on the 8th day, cyclophosphamide was administered intravenously at 1.50 g / m 2on days 1 to 7, and the compound represented by formula I or a pharma- ceutical acceptable salt thereof is orally administered once or multiple times daily at a dose selected, but not limited to, from 3 to 30 mg, for two consecutive weeks followed by a one-week rest.

[0059] In a fifth aspect of the invention, a patient in need of treatment is administered an effective amount of a compound of formula I, or a pharma- ceutically acceptable salt thereof, and a therapeutically effective amount of a second therapeutic agent, either simultaneously, at intervals, or sequentially. The present invention provides a method for treating Ewing's sarcoma comprising administering a therapeutically effective amount of

[0060] In a sixth aspect of the present invention, there is provided a combination pharmaceutical composition for the treatment of Ewing's sarcoma comprising a compound of formula I, or a pharma- ceutically acceptable salt thereof, and a second therapeutic agent. Effect of the Invention

[0061] The present invention has the following beneficial effects compared to the prior art. In the present invention, the compound represented by formula I or a pharma- ceutically acceptable salt thereof is used in the treatment of Ewing's sarcoma, and a remarkable effect is obtained. In the present invention, the compound represented by formula I or a pharma- ceutically acceptable salt thereof is used in combination with a second therapeutic agent, and the compound represented by formula I or a pharma- ceutically acceptable salt thereof enhances the killing effect of drugs, particularly chemotherapeutic drugs, against Ewing's sarcoma, enhancing the effect, while reducing the amount of chemotherapeutic drugs used, thereby reducing side effects. The present invention shows a new direction in the treatment of Ewing's sarcoma, especially in the secondary treatment of Ewing's sarcoma for which previous radiation therapy and chemotherapy have failed.

[0062] For purposes of this application, unless otherwise stated, terms used in the specification and claims have the following meanings:

[0063] In this application, when anlotinib is referred to, the active ingredient is the compound of formula I.

[0064] In this application, all dosages and ranges of the compound of Formula I, or a pharma- ceutically acceptable salt thereof, are based on the molecular weight of the free base of the compound of Formula I, unless otherwise stated.

[0065] A "patient" refers to a mammal, preferably a human. As used herein, the terms "patient," "subject," and "subject" are used interchangeably.

[0066] The term "combination pharmaceutical composition" as used herein refers to a combination of two or more active ingredients (each active ingredient may be administered as it is, or may be administered in the form of a derivative, prodrug, or composition, such as a pharma- ceutically acceptable salt or ester) administered simultaneously or sequentially. The terms "combination pharmaceutical composition," "combination drug," and "drug combination" are used interchangeably herein.

[0067] As used herein, the terms "co-administration" and "use in combination" refer to the administration of two or more active ingredients to a subject simultaneously, each in its own formulation, or sequentially, in any order, each in its own formulation.

[0068] "Pharmaceutically acceptable" refers to the use for the manufacture of a pharmaceutical composition, which is generally safe, non-toxic, and free of biological or other incompatibilities, and which is approved for use in human medicines, including those that contain it.

[0069] "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, and the like, and acid addition salts formed with organic acids such as acetic acid, trifluoroacetic acid, propionic acid, caproic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic 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, trimethylacetic acid, tert-butylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and the like.

[0070] "Therapeutically effective amount" refers to the amount of a compound that, when administered to a human for treating a disease, is sufficient to bring about remission of the disease.

[0071] "Treatment" refers to the administration of a therapeutically effective amount of a compound by any method, including the following: (1) inhibiting a disease (i.e., reducing the progression of the pathology and / or symptomatology) in a human who is pathologically or symptomatically afflicted with or affected by the disease; or (2) Amelioration of the disease (i.e., reversal of pathology and / or symptomology) in a human pathologically or symptomatically manifesting or afflicted by the disease.

[0072] In this specification, unless otherwise stated, the terms "comprise," "comprises," "comprising," or equivalent terms are used in an open-ended manner and mean that the present invention may include unspecified elements, ingredients, or steps in addition to the stated elements, ingredients, or steps.

[0073] Any patents, patent applications, or existing publications are incorporated herein for the purposes of illustration and disclosure. These publications are available because they were published prior to the filing date of this application. Any statement as to the disclosure date of such documents or any representation as to their contents is based on the information known to the applicants and does not constitute an admission as to the correctness of the disclosure dates of such documents or the contents thereof. Furthermore, the incorporation of such publications by reference in any country does not constitute an admission that such publications constitute common general knowledge in the art. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0074] The present invention will now be further described in conjunction with specific examples and experimental examples. These examples are merely illustrative of the present invention and do not limit the scope of the present invention. In the following examples, the experimental methods not shown in specific experimental conditions are carried out under normal conditions.

[0075] Example 1: 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropylamine dihydrochloride (the dihydrochloride salt of the compound represented by formula I) [ka]

[0076] 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropylamine was prepared by referring to the method of Example 24 of International Patent WO2008112407, and then the title compound was prepared by referring to the preparation method of "Example of salt form" in the specification of International Patent WO2008112407.

[0077] Or, it may be prepared by referring to the method described in Chinese Patent Application No. CN102344438A. good.

[0078] Example 2: Preparation of 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropylamine dihydrochloride (dihydrochloride of the compound represented by formula I) capsules The names of the ingredients and carriers and their amounts used (per 1,000 tablets) are as follows: 14.16 g of the dihydrochloride of the compound represented by formula I (equivalent to 12 g of the compound represented by formula I), 89 g of mannitol, 138.4 g of microcrystalline cellulose, 5.9 g of hydroxypropyl cellulose, and 0.99 g of magnesium stearate.

[0079] The dihydrochloride salt of the compound represented by formula I was pulverized and passed through a 80 mesh sieve. It was then uniformly mixed with mannitol and hydroxypropyl cellulose, and then the formulation amount of microcrystalline cellulose was added, uniformly mixed, and passed through a 0.8 mm sieve. Finally, the formulation amount of magnesium stearate was added, uniformly mixed, and filled into capsules.

[0080] Capsules having a different content of the dihydrochloride salt of the compound of formula I than those described above may be prepared with reference to the above ratios and formulations.

[0081] Example 3: Pharmacodynamics Experiments Test drug: 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropylamine dihydrochloride (abbreviated as dihydrochloride of the compound represented by formula I), vincristine, adriamycin, cyclophosphamide.

[0082] 1. Effect of the dihydrochloride salt of the compound of formula I on the growth of Ewing's sarcoma Preparation procedure: The dihydrochloride salt of compound of formula I was dissolved in water to a concentration of 25 mg / mL and then diluted to 250 μg / mL with distilled water.

[0083] Animal Care: BALB / cA-nude mice were used, and the breeding standard was SPF. Human Ewing sarcoma cells A673 were subcutaneously inoculated into the nude mice, and tumors were grown to 100-250 mm 3 Once grown to maturity, animals were randomly assigned to groups (d0).

[0084] Testing Procedure: The dihydrochloride salt of the compound of formula I was orally administered to the animals at a dose of 6.25 mg / kg at 10 mL / kg daily for 14 consecutive days, and the tumor volumes were measured 2-3 times a week, and the mice were weighed and the values ​​were recorded.

[0085] The formula for calculating tumor volume (V) is V = 1 / 2 × a × b 2 In the formula, a represents the length and b represents the width.

[0086] T / C(%)=(T-T0) / (C-C0)×100%. In the formula, T is the tumor volume of the mice in the treatment group at the end of the experiment, and C is the tumor volume of the mice in the control group (solvent group). T0 is the tumor volume of the mice in the treatment group at the time of group administration (d0), and C0 is the tumor volume of the mice in the control group (solvent group).

[0087] The formula for calculating the relative tumor volume (RTV) after administration was RTV=TV / TV0 (TV is the tumor volume measured at each time after administration, and TV0 is the tumor volume measured by group). (Tumor volume at the time of administration (d0) is shown).

[0088] The experimental results showed that 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropylamine dihydrochloride (the dihydrochloride of the compound represented by formula I) could significantly inhibit the growth of Ewing's sarcoma.

[0089] 2. The effect of the dihydrochloride salt of the compound of formula I in combination with a second therapeutic agent on Ewing's sarcoma cell proliferation Preparation procedure: All test drugs were dissolved in dimethyl sulfoxide to prepare a 100 mmol / L mother solution, which was stored at -20° C. When used, the drugs were adjusted to the desired concentrations in DMEM serum liquid medium, and mixed with vincristine, adriamycin, and cyclophosphamide (VAC-2 therapy), and also mixed with a dilute solution of the dihydrochloride of the compound represented by formula I, vincristine, adriamycin, and cyclophosphamide.

[0090] Cell culture: Human Ewing's sarcoma cell line A673 was cultured in DMEM complete liquid medium containing 10% fetal bovine serum and 0.1 g / L streptomycin and penicillin (final concentration 100 U / mL) and cultured in a 5% CO2 incubator at a constant temperature of 37°C. When the cell confluence reached about 85%, the cells were collected by digestion with a mixture of 0.02% EDTA + 0.25% trypsin, centrifuged at 1000 r / min, and subcultured.

[0091] Testing Procedure: IC by methods commonly used in the field (e.g., MTT method) 50 The value may be measured or may be measured by the procedure described below (MTT method). The logarithmic growth phase cells were cultured in a 96-well culture plate (180 μL / well, 10 5Cells were seeded in 1000 μg / well of the tumor cells. After 2 hours of growth at 37°C and 5% CO2, the dihydrochloride salt of the compound of formula I (concentration gradients of 0, 0.005, 0.1, 0.05, 0.1, 0.5, 1.5, 4, 12, and 30 μg / mL solutions) and 2 μg / mL vincristine + 75 μg / mL adriamycin + 500 μg / mL cyclophosphamide were added and incubated. Each concentration was replicated in duplicate, with 20 μL added to each well, and corresponding concentrations of saline solvent control and no apoptosis wells were also included. The tumor cells were again incubated at 37°C and 5% CO2 for 24 hours (48 hours in total). When the drug effect disappeared, MTT working solution was added to each well, and after 4 hours, the wells were dissolved in triple solution and kept at 37°C overnight. The next day, the OD values ​​were measured at wavelengths of 570 nm and 630 nm using a microplate reader (SPECTRA max 190) (calculated by subtracting the OD value at a control wavelength of 630 nm from the OD value measured at a wavelength of 570 nm). The cell growth inhibition rate was calculated using the following formula. Inhibition rate = (OD value of control well - OD value of treatment well) / OD value of control well x 100%.

[0092] From the inhibition rate of each concentration, the half inhibitory concentration IC was calculated using the software GraphPad Prism 5. 50 was calculated.

[0093] Test Results: The in vitro pharmacodynamics results of the dihydrochloride of compound represented by formula I + vincristine + adriamycin + cyclophosphamide and the positive control vincristine + adriamycin + cyclophosphamide on human Ewing sarcoma A673 cells showed that the combination of the dihydrochloride of compound represented by formula I and a second therapeutic agent had obvious inhibitory effect on the proliferation of human Ewing sarcoma A673 cells.

[0094] 3. The effect of the dihydrochloride salt of the compound of formula I in combination with a second therapeutic agent on cell apoptosis in Ewing's sarcoma Detection of cell apoptosis by flow cytometry: Human Ewing sarcoma A673 cells in logarithmic growth phase were cultured for 105 The cells were cultured in a DMEM complete liquid medium containing 2 μg / mL vincristine + 75 μg / mL adriamycin + 500 μg / mL cyclophosphamide at 100 cells / well, and in a DMEM complete liquid medium containing the dihydrochloride salt of the compound represented by formula I + 2 μg / mL vincristine + 75 μg / mL adriamycin + 500 μg / mL cyclophosphamide at concentrations of 0, 0.005, 0.1, 0.05, 0.1, 0.5, 1.5, 4, 12, and 30 μg / mL, respectively, and the cells were collected after 24 hours, centrifuged at 1000 r / min for 3 to 5 minutes, and washed with PBS. Then, apoptosis was detected using Annexin-V-FITC / PI cell apoptosis detection kit, the cells were resuspended in 100μL of 1× binding buffer, 5μL of AnnexinV-FITC and 2.5μL of PI dye were added, and the cells were mixed uniformly by shaking in the dark, and reacted at room temperature for 15 minutes, and then 300μL of 1× binding buffer was added and mixed uniformly, and detection was performed by flow cytometry. The test was repeated three times.

[0095] Test results: Using the classical Annexin-V-FITC / PI cell apoptosis detection method, it was found that different concentrations of the dihydrochloride salt of compound represented by formula I could significantly enhance the apoptosis of Ewing's sarcoma cell line induced by vincristine + adriamycin + cyclophosphamide (VAC-2 therapy).

[0096] Example 4: Clinical Trials A clinical trial was conducted on patients with Ewing's sarcoma with measurable lesions (RECIST 1.1 criteria) using a combination of a dihydrochloride capsule of the compound represented by formula I and a second treatment agent (VAC-2 therapy). The patient group included patients who had already received chemotherapy and patients who had not received chemotherapy. The dihydrochloride capsule of the compound represented by formula I was orally administered at 12 mg once daily (one treatment cycle consisted of two consecutive weeks of administration and one week of rest). At the same time, 2 mg of vincristine was administered intravenously on the first day and 75 mg / m of adriamycin was administered intravenously as VAC-2 therapy. 2On the first day, cyclophosphamide was administered intravenously at 1200 mg / m 2 The drug was administered intravenously on the first day (one cycle lasted 28 days). Evaluation indicators included efficacy indicators such as progression-free survival (PFS), objective response rate (ORR), duration of remission (DOR), stable disease (SD) rate, clinical benefit rate (CBR), and overall survival (OS), safety indicators such as incidence and severity of adverse events, and quality of life.

[0097] Clinical Trial Results: The dihydrochloride salt of the compound of formula I in combination with VAC-2 therapy was effective in treating Ewing's sarcoma, including improving overall survival.

[0098] Example 5: A 29-year-old male patient underwent a left pubic bone puncture biopsy in November 2014, and the pathological diagnosis was small round cell malignant tumor. The clinical diagnosis was left pubic bone Ewing sarcoma, with metastases to both lungs after chemotherapy.

[0099] From November 2014 to October 2018, the patient underwent a total of nine cycles of vincristine (VCR) + adriamycin (ADM) + cyclophosphamide (CTX) treatment and a total of ten cycles of ifosfamide (IFO) + etoposide (VP-16) treatment, during which he experienced grade III bone marrow suppression several times. In March 2015, he underwent chemotherapy under general anesthesia. The patient underwent a pelvic giant tumor resection + total hip replacement and hemipelvectomy. Postoperative pathological examination revealed a small cell malignant tumor in the left hip joint, and in conjunction with the immunophenotype and molecular test results, it was initially diagnosed as Ewing's sarcoma. From December 2018, the patient underwent two cycles of chemotherapy with vincristine + doxorubicin + cyclophosphamide, and in March 2019, CT scans and other examination results showed that the disease had progressed in the lungs and that chemotherapy was not very effective. After that, the patient began oral administration of anlotinib dihydrochloride capsules (active ingredient is a compound represented by formula I) at a dose of 12 mg once daily (one treatment cycle is two weeks of continuous administration and one week of rest).

[0100] One week before the administration of anlotinib dihydrochloride capsules, a CT scan showed that the sum of the diameters of the measurable target lesions (lower left lung field nodules) was 16 mm. After administration, CT scans were performed periodically. After 10 cycles of treatment, the sum of the diameters of the target lesions had decreased to 10 mm, and the efficacy evaluation showed a partial response (PR), with a reduction rate of 37.5%. After 16 cycles of treatment, the sum of the diameters of the target lesions had decreased to 9 mm, and the efficacy evaluation showed a PR, with no new lesions. During the treatment period, the treatment was generally well tolerated, and treatment is continuing for the time being.

[0101] Example 6: A 28-year-old male patient underwent a fine needle biopsy in 2016, and the pathological diagnosis was primitive neuroectodermal tumor. The clinical diagnosis was sacral Ewing sarcoma / primitive neuroectodermal tumor, with metastases to both lungs after chemotherapy following surgery.

[0102] From May 2016 to July 2016, liposomal doxorubicin 40mg d1 + cyclophosphamide 1g d1, ifosfamide 4g d1~3 + lastet 100mg He has been treated with 100mg d1, liposomal doxorubicin 40mg d1 + cyclophosphamide 1g d1, ifosfamide 4g d1-3 + lastet 100mg d1-3. In August 2016, the patient underwent "posterior sacral tumor resection and fixation" under general anesthesia, and the postoperative pathological examination revealed a small round cell malignant tumor in the sacrum, likely Ewing's sarcoma / primitive neuroectodermal tumor. After surgery, the patient received five cycles of chemotherapy: epirubicin 110mg d1 + cyclophosphamide 1g d1, ifosfamide 4g d1-3 + lastet 100mg d1-3, epirubicin 110mg d1 + cyclophosphamide 1g d1 + vindesine 3mg d1, ifosfamide 4g d1-3 + lastet 100mg d1-3, epirubicin 110mg d1 + cyclophosphamide 1g d1 + vindesine 3mg d1. After chemotherapy, the patient experienced grade II bone marrow suppression, and the last chemotherapy was in February 2017. In August 2017, the patient received irinotecan 40mg d1-4 + temozolomide 140mg d1-5, and irinotecan 40mg d1. From September 2017, the patient received successive treatments of irinotecan 40 mg on days 1-4 + temozolomide 140 mg on days 1-5, irinotecan 40 mg, irinotecan 40 mg on days 1-4 + cyclophosphamide 500 mg on days 1-4, and irinotecan 40 mg on days 1-4 + temozolomide 140 mg on days 1-5.

[0103] In January 2019, oral administration of anlotinib dihydrochloride capsules was started at a dose of 12 mg once daily (one treatment cycle consisted of two weeks of continuous administration followed by one week of rest).

[0104] Three days before administration of anlotinib dihydrochloride capsules, a CT scan showed that the sum of the diameters of the measurable target lesions was 36 mm (right lower lung field 36 mm). CT scans were performed immediately after the completion of each treatment cycle, and the results are shown in Table 1. The subject had received 20 cycles to date and was deemed fit to continue taking the drug by the physician. Treatment was generally well tolerated. [Table 1]

[0105] Example 7: Patients with advanced Ewing sarcoma who had failed previous treatments were divided into two groups, A and B. Group A consisted of 23 patients aged 16 years or older, and was treated with anlotinib dihydrochloride capsules at a dose of 12 mg once daily on d1-d14 (2 weeks of continuous administration and 1 week of rest constituted one treatment cycle) plus irinotecan 15 mg / m once daily. 2 Intravenous injection on days 1-5 and 8-10 (each treatment cycle lasts 3 weeks) + vindesine 3 mg / m 2 In group B, 12 patients were aged 16 years or younger and were orally administered anlotinib dihydrochloride capsules once daily (2 weeks of continuous administration and 1 week of rest were considered as one treatment cycle, and the dose was set based on body surface area (BSA) as follows: BSA < 1.0 m 2 If the patient is 6-8 years of age, 8 mg should be administered on days 1-14, and BSA should be ≥ 1.0 mg. 2 12 mg, d1-d14 if ≥ 12 mg / mL + irinotecan 20 mg / mL once daily 2 Intravenous injection on days 1-5 and 8-10 (each treatment cycle lasts 3 weeks) + vindesine 3 mg / m 2 The treatment cycle was d1 and d8 (3 weeks was one treatment cycle).

[0106] The results of the study were evaluated over 12 weeks in groups A and B. The 12-week ORRs for patients in the two groups were 62.5% and 83.3%, respectively, and one of 23 patients aged 16 years or older achieved a complete response (CR).

Claims

1. 2. Use of a compound of formula I or a pharma- ceutical acceptable salt thereof in combination with a second therapeutic agent for the manufacture of a combination drug for the treatment of Ewing's sarcoma, comprising: The second therapeutic agent is a combination of a vinblastine compound and irinotecan, and the vinblastine compound is selected from one or more of vinorelbine, vinblastine, vincristine, vindesine, and vinflunine. 【Chemistry 1】

2. The Ewing's sarcoma is intraosseous Ewing's sarcoma, extraosseous Ewing's sarcoma, or periosteal Ewing's sarcoma; or the Ewing's sarcoma is osteolytic Ewing's sarcoma, sclerosing Ewing's sarcoma, or mixed Ewing's sarcoma; 2. The use of claim 1, wherein the Ewing's sarcoma has failed previous treatments.

3. The Ewing's sarcoma is a Ewing's sarcoma that has failed radiation therapy and / or chemotherapy.

3. The use according to claim 2, characterized in that

4. The use according to any one of claims 1 to 3, characterized in that the second therapeutic agent is a combination of irinotecan and vindesine.

5. The use according to any one of claims 1 to 4, wherein the pharma- ceutically acceptable salt of the compound represented by formula I is a salt formed between the compound represented by formula 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, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic 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, trimethylacetic acid, tert-butylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, and stearic acid.

6. The use according to any one of claims 1 to 5, characterized in that the pharma- ceutically acceptable salt of the compound of formula I is in the form of a hydrochloride or maleate salt.

7. 7. The use according to claim 6, wherein the pharma- ceutically acceptable salt of the compound of formula I is the dihydrochloride salt.

8. The daily dose of the compound of formula I or a pharma- ceutical acceptable salt thereof is selected from 3 mg to 30 mg, 5 mg to 20 mg, 8 mg to 16 mg, 8 mg to 14 mg, 8 mg, 10 mg, or 12 mg; Alternatively, the compound of formula I or a pharma- ceutically acceptable salt thereof is administered by an interval dosing method in which an administration period and a rest period are alternately repeated, and the ratio of the administration period to the rest period in terms of days is selected from 2:0.5-5, 2:0.5-3, 2:0.5-2, 2:0.5-1, and the interval dosing method is any one of a cycle of 2 weeks of continuous administration and 2 weeks of rest, 2 weeks of continuous administration and 1 week of rest, or 5 days of continuous administration and 2 days of rest, and the cycle can be repeated multiple times.

9. The use according to any one of claims 1 to 8, wherein the compound of formula I or a pharma- ceutically acceptable salt thereof and the second therapeutic agent are administered simultaneously, sequentially or in any order with no particular order.

10. The use according to any one of claims 1 to 9, wherein the therapeutic drug for Ewing's sarcoma and / or the concomitant drug is in a formulation suitable for any administration method, including oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intraadipose, intraarticular or intrathecal.

11. A combination pharmaceutical composition for the treatment of Ewing's sarcoma, comprising a compound represented by the following formula I or a pharma- ceutically acceptable salt thereof and a second therapeutic agent, wherein the second therapeutic agent is a combination of a vinblastine compound and irinotecan, and the vinblastine compound is selected from one or more of vinorelbine, vinblastine, vincristine, vindesine, and vinflunine. 【Chemistry 2】

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