阅读说明：本技术 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 (Quinolines or pharmaceutically acceptable salts thereof for the treatment of ewing's sarcoma ) 是由 湛筱乐 屠礼凡 杨朝强 张喜全 王训强 许婕 于 2020-04-20 设计创作，主要内容包括：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。(The invention belongs to the field of medicines, and provides a quinoline compound or a pharmaceutically acceptable salt thereof for treating Ewing's sarcoma, in particular relates to application of a compound I or a pharmaceutically acceptable salt thereof in preparation of a medicine for treating Ewing's sarcoma and application of the compound I or a pharmaceutically acceptable salt thereof in combination with a second therapeutic agent in preparation of a combined medicine for treating Ewing's sarcoma, wherein the chemical name of the compound I is 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine.)

The use of compound I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of ewing's sarcoma,

the use of claim 1, wherein said ewing sarcoma is endosteal ewing sarcoma, exo-osseous ewing sarcoma, periosteal ewing sarcoma;

or the Ewing sarcoma is osteolytic Ewing sarcoma, sclerosing Ewing sarcoma, mixed Ewing sarcoma;

alternatively, the Ewing's sarcoma is Ewing's sarcoma failed prior treatment, preferably, the Ewing's sarcoma is Ewing's sarcoma failed radiotherapy and/or chemotherapy treatment.

The use of compound I, or a pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent in the manufacture of a combination medicament for the treatment of Ewing's sarcoma,

use according to claim 3,

the Ewing sarcoma is intrabony Ewing sarcoma, exoskeletal Ewing sarcoma, periosteal Ewing sarcoma;

or the Ewing sarcoma is osteolytic Ewing sarcoma, sclerosing Ewing sarcoma, mixed Ewing sarcoma;

alternatively, the Ewing's sarcoma is Ewing's sarcoma failed prior treatment, preferably, the Ewing's sarcoma is Ewing's sarcoma failed radiotherapy and/or chemotherapy treatment.

The use of claim 3 or 4, wherein the second therapeutic agent is a chemotherapeutic drug and/or a small molecule targeted antineoplastic drug; preferably, the chemotherapeutic drug is one or more of alkylating agent, podophyllum, camptothecin, taxus, antimetabolite and antibiotic antineoplastic drug;

more preferably, the chemotherapeutic agent is a platinum-based agent, fluoropyrimidine derivative, taxane, camptothecin, vinblastine, pemetrexed, carmustine, etoposide (etoposide), teniposide, mitomycin, ifosfamide, cyclophosphamide, azacitidine, pirarubicin, amrubicin, methotrexate, bendamustine, epirubicin, doxorubicin, actinomycin D, dactinomycin, bleomycin, temozolomide, LCL-161, KML-001, Sapacitabine, plinabulin, trooshusuo, dipivefrin hydrochloride, fluvoxil hydrochloride, fluvoxil, fluvastatin, a,¹⁵³One or more of Sm-EDTMP, tegafur and encequidar;

further preferably, the platinum drug is one or more of oxaliplatin, cisplatin, carboplatin, nedaplatin and dicycloplatin, the fluoropyrimidine derivative is one or more of gemcitabine, capecitabine, fluorouracil, difurofluorouracil, doxifluridine, tegafur, carmofur and trifluridine, the taxane is one or more of paclitaxel, albumin-bound paclitaxel and docetaxel, the camptothecin is one or more of camptothecin, hydroxycamptothecin, irinotecan and topotecan, and the vinblastine is one or more of vinorelbine, vinblastine, vincristine, vindesine and vinblastine;

preferably, the small molecule targeted anti-tumor drug is a protein kinase inhibitor;

more preferably, the small molecule targeted antineoplastic agent is a tyrosine kinase inhibitor, a serine and/or threonine kinase inhibitor;

further preferably, the small molecule targeted antineoplastic agent is erlotinib, afatinib, crizotinib, ceritinib, vemurafenib, dabrafenib, cabozantinib, gefitinib, dacetinib, oxitinib, erlotinib, brigatinib, loratinib, treetinib, larotinib, erlotinib, lapatinib, vandetanib, sematinib, sorafenib, omotinib, voltinib, furacitinib, emtricitinib, dasatinib, emsatinib, ematinib, enratinib, lenvatinib, itacintinib, pyrrole, bimatinib, erlotinib, axitinib, lenatinib, cobitinib, acartitinib, famitinib 931, masitinib, irotinib, rociletinib, naridanib, lenalidomide, elvalidomide, elvucidomide, elvucinostrilatinib, loxacinitrosol, loxapitinib, tamicinib-803, tamicinib, tamicib, tamicinib, tamicib, tamicinib, tamicibut, LTT-462, BLU-667, nicetinib, tipifarnib, poziotiib, DS-1205c, capivastrib, SH-1028, metformin, selicib, OSE-2101, APL-101, berzostrib, idelalisib, lerociclib, ceralassib, PLB-1003, tomivotib, AST-2818, SKLB-1028, D-0316, LY-3023414, allitinib, MRTX-849, AP-32788, AZD-4205, lifirafenib, vacostrestib, mivebresib, napabusin, stravatinib, TAS-114, molibrib, CC-223, rivoceranib, CK-101, kaptis-254, movitine-497, SANcombustion, AZ-4596, AZ-077, AZ-20, SANzyrtib-077, AZ-3, SANzyrtib-3, SANYPERTINIB, SANZ-3, SANTRIVETIIB, SANTI-3, SANTI-3, SANTI, SANTIANTI, SANTI-3, SANTI-PII, SANTI-PII, SANTI-3, SANTI-3, SANTI-3, SANTI-3, SANTI-3, SANTI, SA, naputinib, LNP-3794, HH-SCC-244, ASK-120067, CT-707, epitinib succinate, tesevatinib, SPH-1188-11, BPI-15000, copanlisib, niraparib, olaparib, veliparib, talazoparatosylate, DV-281, Siremaddlin, Telaglenastat, MP-0250, GLG-801, ABTL-0812, bortezomib, panobinostat, tucidinostat, vorinostat, reminiostat, epadostat, tametat, tametostat, entinostat, mocetinostat, and quisitostat;

still further preferably, the small molecule targeted antineoplastic drug is one or more of sorafenib, ibrutinib, erlotinib, afatinib, crizotinib, ceritinib, vemurafenib, dabrafenib, cabozantinib, gefitinib, dacomitinib, oxitinib, erlotinib, brigatinib, luratinib, tremitinib, larotinib, erlotinib, lapatinib, vandetanib, sematinib, armotinib, wallitinib, enretinib, dasatinib, enratinib, lenvatinib, itatinib, pyrroltinib, bimetinib, erlotinib, acotinib, lenatinib, fibertinib, acartinib, famitinib, masitinib, ibrutinib, and dartinib.

The use of any one of claims 3-5, wherein the second therapeutic agent is a combination of vincristine, cyclophosphamide, and actinomycin D;

alternatively, the second therapeutic agent is a combination of vincristine, cyclophosphamide, and doxorubicin;

or the second preparation is a combination of adriamycin, methotrexate, cyclophosphamide, actinomycin D, bleomycin and vincristine;

alternatively, the second therapeutic agent is a combination of vincristine, cyclophosphamide, actinomycin D and/or doxorubicin;

alternatively, the second therapeutic agent is a combination of ifosfamide, etoposide;

alternatively, the second therapeutic agent is a combination of doxorubicin, cyclophosphamide;

alternatively, the second therapeutic agent is a combination of vincristine and cyclophosphamide.

The use of any one of claims 3-5, wherein the second therapeutic agent is one of a VAC regimen, a T9 regimen, an IE regimen, or an AC regimen.

The use according to any one of claims 1 to 7, wherein the pharmaceutically acceptable salt of compound I is a salt of compound I with any of the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, hexanoic 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; preferably in the form of the hydrochloride or maleate salt, more preferably the dihydrochloride salt.

The use according to any one of claims 1 to 8, wherein the compound I or the pharmaceutically acceptable salt thereof is administered in a daily dose of 3mg to 30mg, preferably 5mg to 20mg, more preferably 8 mg to 16 mg, even more preferably 8 mg to 14 mg, most preferably 8 mg, 10mg or 12 mg;

preferably, the compound I or a pharmaceutically acceptable salt thereof is administered at intervals between an administration period and a withdrawal period; preferably, the ratio of the administration period to the withdrawal period in days is 2: 0.5-5, more preferably 2: 0.5-3, more preferably 2: 0.5-2, and even more preferably 2: 0.5-1; as a further preferred mode of administration at intervals, the mode of administration is one of the following: stopping the drug for 2 weeks after 2 weeks of continuous administration, for 1 week after 2 weeks of continuous administration, or for 2 days after 5 days of continuous administration; the intermittent administration mode may be repeated a plurality of times.

The use according to any one of claims 3 to 9, wherein the compound I or the pharmaceutically acceptable salt thereof and the second therapeutic agent are administered simultaneously, sequentially or non-sequentially.

The use according to any one of claims 1 to 10, wherein the medicament and/or combination medicament for the treatment of ewing's sarcoma is a formulation suitable for any mode of administration, oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intraadipose, intraarticular, intraperitoneal or intrathecal.

A method for treating ewing's sarcoma, the method comprising administering to a subject in need thereof a therapeutically effective amount of compound I, or a pharmaceutically acceptable salt thereof.

The method of claim 12, wherein the ewing sarcoma is endosteal ewing sarcoma, exo-osseous ewing sarcoma, periosteal ewing sarcoma;

or the Ewing sarcoma is osteolytic Ewing sarcoma, sclerosing Ewing sarcoma, mixed Ewing sarcoma;

alternatively, the Ewing's sarcoma is Ewing's sarcoma failed prior treatment, preferably, the Ewing's sarcoma is Ewing's sarcoma failed radiotherapy and/or chemotherapy treatment.

A pharmaceutical composition for the treatment of ewing's sarcoma, comprising compound I or a pharmaceutically acceptable salt thereof.

A combination pharmaceutical composition for use in the treatment of ewing's sarcoma, comprising compound I, or a pharmaceutically acceptable salt thereof, and a second therapeutic agent.