CN111821302A

CN111821302A - Quinolines for the combined treatment of chondrosarcoma

Info

Publication number: CN111821302A
Application number: CN202010305976.5A
Authority: CN
Inventors: 湛筱乐; 屠礼凡; 杨朝强; 张喜全; 王训强
Original assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Current assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority date: 2019-04-18
Filing date: 2020-04-17
Publication date: 2020-10-27

Abstract

The invention belongs to the field of medicines, provides a quinoline compound or a pharmaceutically acceptable salt thereof for combined treatment of chondrosarcoma, and particularly relates to application of a therapeutically effective amount of 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine or a pharmaceutically acceptable salt thereof and a second therapeutic agent in combination preparation of a combined medicine for treating chondrosarcoma.

Description

Quinolines for the combined treatment of chondrosarcoma

Technical Field

The invention belongs to the field of medicines, belongs to the technical field of pharmaceutical preparations, and particularly relates to a quinoline compound or pharmaceutically acceptable salt thereof for combined treatment of chondrosarcoma.

Background

Chondrosarcoma is the second largest malignancy after osteosarcoma. The etiology is unknown, mainly occurs from chondrocytes or mesenchymal leaf tissues, and originates from any bone of the chondrogenic bone of the body, possibly associated with chromosomal abnormalities, experimental pathology suggests that chondrosarcoma is associated with viral infection, while borderline chondrosarcoma is associated with genetic factors.

Chondrosarcoma can occur in any part of the skeleton, preferably in the long bones, pelvis, and humerus, as well as in the vertebrae, sacrum, clavicle, scapula, and foot bones. Chondrosarcoma can occur at any age, most in adults, less common under 30 years of age, with increasing incidence after 40 years of age, and more in men than women.

Chondrosarcoma is histologically classified as hyaline, mucoid, fibrocartilage, mixed and hyaline cell. Generally, the hyaline type is considered to have a low degree of malignancy, while the fibroid type, fibrocartilage type, and mixed type are considered to be highly malignant. The chondrosarcoma is divided into two main types of primary and secondary types in terms of onset, wherein the primary type has sarcoma characteristics from the beginning, and the secondary type is derived from benign chondrosarcosis tumors such as teratogenic osteitis, fibrous dysplasia, solitary bone cyst, Maffucci syndrome, Ollier disease, multiple hereditary bone warts, chondroblastoma, cartilage mucoid fibroma and the like, and is one of the reasons for the late onset. Regionally, chondrosarcoma is divided into central and limbic; there are also pericortical or periosteal chondrosarcomas, and extraosseous mucinous chondrosarcomas. In addition, there are chondrosarcoma generally, chondrosarcoma mesenchymal, and chondrosarcoma hyaline.

Most of chondrosarcoma have large tumor bodies, and the maximum diameter of the tumor generally exceeds 4cm, and the maximum diameter can reach more than 20 cm. The patient feels discomfort to the affected part in the early stage, swelling and lumps appear after several days or weeks, and varicose veins, local skin temperature rise and redness appear in the late stage. Patients experience periarticular pain, which is initially intermittent and then gradually worsens, turning into persistent pain, which is more pronounced at night and ineffective as a pain killer. The joint movement of the patient is limited, and joint effusion and even pathological fracture can occur in some patients.

The most effective treatment for chondrosarcoma is surgical resection. Chondrosarcoma has been considered in the past to be insensitive to radiation therapy, and so radiation therapy alone has rarely been used to treat chondrosarcoma. In recent years, researches show that a part of chondrosarcoma has certain sensitivity to radiotherapy and can be used as an auxiliary treatment means for treating the chondrosarcoma. However, chondrosarcoma has poor blood supply and lymphatic circulation and is not sensitive to traditional chemotherapeutic drugs. Thus, until now, there has been no effective chemotherapeutic regimen for treating chondrosarcoma. Thus, current treatments for chondrosarcoma are, as the case may be, considered as partial massive resection, segmental resection or amputation. Most chondrosarcomas are surgically stressed with a partial, thorough resection, with amputation or joint amputation in relapsers or cases of high primary malignancy and rapid progression. The commonly used auxiliary drugs for chondrosarcoma are compound cyclophosphamide tablets, methotrexate tablets, cisplatin injection, zaltoprofen, diclofenac, indomethacin, oxaprozin, acetaminophen, ketoprofen and the like.

Based on the lack of current treatment options, the necessity and urgency to provide new options based on traditional treatments for chondrosarcoma has been suggested.

Disclosure of Invention

Compound I in one aspect, the present invention provides the use of a therapeutically effective amount of compound I, or a pharmaceutically acceptable salt thereof, having the chemical name 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine, having the structural formula:

in another aspect, the invention provides a method of treating chondrosarcoma, comprising administering to a patient in need thereof a therapeutically effective amount of compound I, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a second therapeutic agent.

In a further aspect, the invention provides a combination for the treatment of chondrosarcoma comprising a therapeutically effective amount of compound I, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a second therapeutic agent.

Chondrosarcoma

The chondrosarcoma described herein is a primary chondrosarcoma and/or a secondary chondrosarcoma.

In some embodiments, the chondrosarcoma is a dedifferentiated chondrosarcoma and/or a hyperdifferentiated chondrosarcoma.

In some embodiments, the chondrosarcoma is a centrochondrosarcoma, a limbic chondrosarcoma, a paraspinal chondrosarcoma, an periosteal chondrosarcoma, or an extraosseous mucinous chondrosarcoma.

In some embodiments, the chondrosarcoma is a low-grade malignant chondroblastoma, a moderate-grade malignant chondroblastoma, or a high-grade malignant chondroblastoma.

In some embodiments, the chondrosarcoma is chondrosarcoma generally, chondrosarcoma mesenchymal, chondrosarcoma hyaline.

In some embodiments, the chondrosarcoma is advanced and/or metastatic chondrosarcoma.

In some embodiments, the chondrosarcoma includes, but is not limited to, chondrosarcoma with failure of prior treatment; preferably, the chondrosarcoma is a chondrosarcoma that has failed a radiotherapy and/or chemotherapy treatment. In some embodiments, the chondrosarcoma is selected from a chondrosarcoma that has failed methotrexate, ifosfamide, cisplatin, and/or doxorubicin therapy. In some embodiments, the subject with chondrosarcoma has progressed following chemotherapy and/or radiation therapy. In some embodiments, the chondrosarcoma is a chondrosarcoma that has previously undergone surgical resection. The chondrosarcoma is a chondrosarcoma that has not previously been surgically excised.

A second therapeutic agent

In some embodiments, the second therapeutic agent is a chemotherapeutic agent, including but not limited to one or more of an alkylating agent, a podophyllum, a topoisomerase inhibitor, a taxoid, an antimetabolite, an antibiotic antineoplastic agent,

examples that may be enumerated include, but are not limited to, platinum drugs (e.g., oxaliplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin), fluoropyrimidine derivatives (e.g., gemcitabine, capecitabine, fluorouracil, difurofluorouracil, doxifluridine, tegafur, carmofur, trifluridine), taxanes (e.g., paclitaxel, albumin-bound paclitaxel, and docetaxel), topoisomerase I inhibitors (e.g., camptothecin and its derivatives, hydroxycamptothecin, irinotecan, topotecan), topoisomerase ii inhibitors (e.g., etoposide (etoposide), teniposide), vinblastines (vinorelbine, vinblastine, vincristine, vindesine, vinblastine (vinflunine)), pirarubicin, pemetrexed, mitomycin, ifosfamide, azacitidine, pirarubicin, mitomycin, doxorabicistrine, and the like, Amrubicin, methotrexate, bendamustine, epirubicin, doxorubicin, temozolomide, LCL-161, KML-001, Sapacitabine, plinabulin (plinabulin), troosufan (treosulfan), dipivefrin hydrochloride (tipiracil hydrochloride),¹⁵³One or more of Sm-EDTMP, tegafur and encequidar.

In some embodiments, the chemotherapeutic agent is selected from one or more of methotrexate, cyclophosphamide, ifosfamide, doxorubicin, irinotecan, platins, etoposide, tinib platinum glycoside, camptothecin, hydroxycamptothecin, gemcitabine, paclitaxel, docetaxel, vinblastine, cyclophosphamide, mitomycin. In a specific embodiment, the chemotherapeutic agent is gemcitabine.

In some embodiments, the second therapeutic agent is a small molecule targeted anti-tumor drug, including but not limited to protein kinase inhibitors. Wherein, the protein kinase inhibitor includes but is not limited to tyrosine kinase inhibitor, serine and/or threonine kinase inhibitor, the target of the inhibitor includes but is not limited to EGFR (epidermal growth factor receptor), Anaplastic Lymphoma (ALK), MET gene, ROS1 gene, HER2 gene, RET gene, BRAF gene, PI3K signal path, DDR2 (discoid death receptor 2) gene, FGFR1 (fibroblast growth factor receptor 1), NTRK1 (neurotrophic tyrosine kinase type 1 receptor) gene, KRAS gene; the target of the small molecule targeted antitumor drug also comprises COX-2 (cyclooxygenase-2), APE1 (depurination and depyrimidinization endonuclease), 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 activation adhesion factor), HSP, JIP1, GSK-3 beta (glycogen synthesis kinase 3 beta), CyclinD1 (cell cycle regulatory protein), 4 (cyclin dependent kinase), TIMP1 (tissue metalloproteinase inhibitor), THBS3, PTHR1 (parathyroid hormone related protein receptor 1), CDK 7 (human tumor vascular endothelial marker 7), COPS3, CDK 3 (tumor endothelial marker 7), CDK-associated protein receptor 1), and the like, Cathepsin K. Examples of small molecule targeted antineoplastic agents include, but are not limited to, Erlotinib (Erlotinib), Afatinib (Afatinib), Crizotinib (Crizotinib), Ceritinib (Ceritinib), Vemurafenib (Vemurafenib), Dabrafenib (Dabrafenib), Cabozantinib (Cabozantinib), Gefitinib (Gefitinib), Dacomitinib (Dacomitinib), oxitinib (ositinib), ibrutinib (ositinib), lanotinib (larotinib), tracinib (mettinib), larotinib (larotitinib), Erlotinib (icotinib), icotinib (icotinib), Lapatinib), Vandetanib (vatinib), seritinib (seritinib), lanitinib (emtinib), lesatinib (oertitinib), lesatinib (ovatinib), nilotinib (oetinib), valtinib (ovatinib), nilotinib (oetinib), nilotinib (ovatinib (oetinib), valtinib (ovatinib), valtinib (oetinib (valtinib), valtinib (oetinib), valtinib (oetinib), valtinib (oetinib (oenotinib (oetinib), valtinib (oetinib), val, Acertinib (Axitinib), lenalinib (Neratinib), cobitinib (Cobimetinib), acacetinib (Acalabastinib), Famitinib (Famitiniib), Masitinib (Masitinib), Ibrutinib (Ibrutinib), rociletinib, nintedanib, lenalidomide, Evemosis, LOXO-292, Vorolanib, bemcentinib, caplatib, entestinib, TAK-931, ALT-803, palbociclib, Famitinib L-malacoplate, LTT-462, BLU-667, ninetinib, tiparenib, pozitinib, DS-1205, capivatilib, SH-1028, dimethyleritib, BLU-42047, sunitinib, PLIIB-1028, PLIIb-1028, PLIbratisella-101, PLIbL-1028, PLIbratisnib-1, PSIbratisnib-1, PSIbraticib-101, PSIbraticib-223, PSIbraticib-358, PSIbratisnib, PSIbratisella-223, PSIb-358, PSIbratisella-351, PSIb, PSIbticib, PSIb, PSIbratisella-8, PSIb-358-103, PSIbratisella-103, PSIb, PSIbratisella-358, PSIb, PSIbratisb, PSIb, PSIbratisella-358, PSIb, PSIbratisella-4, PSIbratisb, PSIbratisella-4, simotinib, GSK-3368715, TAS-0728, malitinib, tepotinib, HS-10296, AZD-4547, merestib, olaptested peg, galiniservib, ASN-003, gedatolib, defatinib, lazerttinib, CKI-27, S-49076, BPI-9016M, RF-A-089, RMC-4630, AZD-3759, antroquinol, SAF-189, AT-101, TTI-101, naputinib, LNP-3794, SCC-244, ASK-120067, CT-707, epitinib succinate, tesetatinib, SPH-1188-11, BPI-15000, copuliib, mirabilib, velutinib, velostat, patatinib, tablet, or tablet, tablet-281, tablet-1000 tablet. In some embodiments, the small molecule targeted antineoplastic agent is one or more of sorafenib, ibrutinib, erlotinib, afatinib, crizotinib, ceritinib, vemurafenib, dabrafenib, cabozantinib, gefitinib, dacomitinib, ocitinib, brertinib, lorartinib, trametinib, larotinib, erlotinib, lapatinib, vandetanib, semertinib, tematinib, wallitinib, enritinib, dasatinib, enzatinib, lenvatinib, itatinib, pirertinib, bimetinib, erlotinib, axitinib, lenatinib, bivatinib, famitinib, masitinib, imatinib, ibrutinib, nilotinib, nicartinib, acartinib, famitinib, masitinib, imatinib, and ninib.

In the application, the use, the method or the combined medicament can further contain chemotherapy auxiliary medicaments, wherein the chemotherapy auxiliary medicaments comprise but are not limited to leucovorin Calcium (CF), aldehydo-folic acid, mesna, bisphosphonate, amifostine, hematopoietic cell Colony Stimulating Factors (CSFs) and ondansetron. In some embodiments, the chemotherapeutic adjuvant is calcium leucovorin (CF), mesna, aldehydic acid.

Compound I

Compound I can be administered in its free base form, as well as in the form of its salts, hydrates, and prodrugs, which convert in vivo to the free base form of compound I. For example, pharmaceutically acceptable salts of compound I are within the scope of the invention, which salts can be produced from various organic and inorganic acids according to methods well known in the art.

In some embodiments, the pharmaceutically acceptable salt thereof 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.

In some embodiments, compound I is administered as the hydrochloride salt of compound I. In some embodiments, compound I is administered as the monohydrochloride salt of compound I. In some embodiments, compound I is administered as the dihydrochloride salt. In some embodiments, the compound I is administered as a crystalline form of the hydrochloride salt of compound I. In a particular embodiment, compound I dihydrochloride is administered as a crystalline form. In some embodiments, compound I is administered as the maleate salt of compound I.

In some embodiments, the amount of compound I or a pharmaceutically acceptable salt thereof administered in a combination can be determined based on the severity of the disease, the response to the disease, any treatment-related toxicities, the age and health of the patient. In some embodiments, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is from 3 mg to 30 mg. In some embodiments, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is from 5 mg to 20 mg. In some embodiments, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is from 8 mg to 16 mg. In some embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof administered is from 8 mg to 14 mg. In a particular embodiment, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is 8 mg. In a particular embodiment, compound I or a pharmaceutically acceptable salt thereof is administered in a daily dose of 10 mg. In a particular embodiment, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is 12 mg.

Compound I or a pharmaceutically acceptable salt thereof may be administered one or more times daily. In some embodiments, compound I, or a pharmaceutically acceptable salt thereof, is administered once daily.

The method of administration of compound I can be determined comprehensively on the basis of the activity, toxicity of the drug, tolerance of the patient, and the like.

Preferably, compound I or a pharmaceutically acceptable salt thereof is administered in a spaced-apart manner. The intermittent administration includes a dosing period during which compound I or a pharmaceutically acceptable salt thereof may be administered one or more times per day and a rest period. For example, compound I or a pharmaceutically acceptable salt thereof is administered daily during a dosing period, then the administration is stopped for a period of time during a rest period, followed by a dosing period, then a rest period, and so on, which may be repeated multiple times. Wherein the ratio of the administration period to the withdrawal period in days is 2: 0.5-5, preferably 2: 0.5-3, more preferably 2: 0.5-2, and still more preferably 2: 0.5-1.

In some embodiments, compound I or a pharmaceutically acceptable salt thereof is administered at intervals of 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.

Wherein, the compound I or the pharmaceutically acceptable salt thereof with the effective treatment amount is preferably suitable for oral preparations, including tablets, capsules, powder, granules, dripping pills, pastes, powders and the like, preferably tablets and capsules. Wherein the tablet can be common tablet, dispersible tablet, effervescent tablet, sustained release tablet, controlled release tablet or enteric coated tablet, and the capsule can be common capsule, sustained release capsule, controlled release capsule or enteric coated capsule. The oral preparation can be prepared by a conventional method using a pharmaceutically acceptable carrier well 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, and the like; the absorbent comprises calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; wetting agents include water, ethanol, and the like; the binder comprises hypromellose, polyvidone, microcrystalline cellulose, etc.; the disintegrating agent comprises croscarmellose sodium, crospovidone, surfactant, low-substituted hydroxypropyl cellulose, etc.; the lubricant comprises magnesium stearate, pulvis Talci, polyethylene glycol, sodium laurylsulfate, silica gel micropowder, pulvis Talci, etc. The medicinal adjuvants also include colorant, sweetener, etc.

In the present application, the combination of chondrosarcoma is a formulation suitable for any administration form, oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intralipid, intraarticular, intraperitoneal or intrathecal.

Preferably, the therapeutically effective amount of compound I or a pharmaceutically acceptable salt thereof, and the therapeutically effective amount of the second therapeutic agent are administered separately, either simultaneously, intermittently or sequentially. Compared with the prior art, the combined use of the invention can help to:

(1) the compound I or the pharmaceutically acceptable salt thereof can obviously enhance the killing effect of medicaments, especially chemotherapeutic medicaments, on chondrosarcoma and enhance the curative effect;

(2) the compound I or the pharmaceutically acceptable salt thereof can reduce the dosage of chemotherapeutic drugs, thereby reducing side effects;

(3) inhibiting lung metastasis of chondrosarcoma;

(4) better efficacy in reducing tumor growth or even eliminating tumors than either drug of the combination administered alone;

(5) provides for administration of a smaller amount than the administration of a single drug in the combination;

(6) providing a treatment that is well tolerated in patients with fewer adverse reactions and/or complications than a single administration of the drug;

(7) provide better disease control rates among treated patients;

(8) providing a patient treated with longer survival (e.g., median survival, progression-free survival, or overall survival); or provide a longer duration of disease remission (DOR). Unless otherwise indicated, the following terms used in the specification and claims shall have the following meanings for the purposes of this application.

By "patient" is meant a mammal, preferably a human. Herein, "patient", "subject" or "subject" are used interchangeably.

As used herein, the term "combination pharmaceutical composition" refers to a combination of two or more active ingredients (administered as the respective active ingredients themselves, or as their respective pharmaceutically acceptable salts or esters, derivatives, prodrugs or compositions) that are administered simultaneously or sequentially. The terms "combination pharmaceutical composition", "combination drug" and "drug combination" are used interchangeably herein.

As used herein, "in combination" or "in combination" means that two or more active substances may each be administered to a subject simultaneously as a single formulation, or sequentially in any order each as a single formulation.

By "pharmaceutically acceptable" is meant that it is used to prepare pharmaceutical compositions that are generally safe, non-toxic, and neither biologically nor otherwise undesirable, and include that they are acceptable for human pharmaceutical use.

"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; or with organic acids such as acetic, trifluoroacetic, propionic, hexanoic, heptanoic, cyclopentanepropionic, glycolic, pyruvic, lactic, malonic, succinic, malic, maleic, fumaric, tartaric, citric, benzoic, cinnamic, mandelic, methanesulfonic, ethanesulfonic, 1, 2-ethanedisulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, p-chlorobenzenesulfonic, p-toluenesulfonic, 3-phenylpropionic, trimethylacetic, t-butylacetic, dodecylsulfuric, gluconic, glutamic, hydroxynaphthoic, salicylic, stearic acid and the like.

By "therapeutically effective amount" is meant an amount of a compound that, when administered to a human for the treatment of a disease, is sufficient to effect control of the disease.

By "treatment" is meant any administration of a therapeutically effective amount of a compound and includes:

(1) inhibiting the disease (i.e., arresting further development of the pathology and/or symptomatology) in a human experiencing or exhibiting the pathology or symptomatology of the disease, or

(2) Ameliorating the disease (i.e., reversing the pathology and/or symptomatology) in a human experiencing or exhibiting the pathology or symptomatology of the disease.

In this document, unless otherwise indicated, the terms "comprises, comprising and including" or equivalents thereof, are open-ended and mean that elements, components and steps other than those listed may be included.

All patents, patent applications, and other established publications are herein expressly incorporated by reference for the purpose of description and disclosure. These publications are provided solely for their disclosure prior to the filing date of the present application. All statements as to the date of these documents or representation as to the contents of these documents is based on the information available to the applicant and does not constitute any admission as to the correctness of the dates of these documents or the contents of these documents. Moreover, any reference to such publications in this specification does not constitute an admission that the publications form part of the common general knowledge in the art in any country.

Detailed Description

The following is a further illustration of the invention with reference to specific examples and experimental examples. These examples are only illustrative and not intended to limit the scope of the present invention. The experimental methods of the following examples, in which the specific experimental conditions are not specified, were carried out according to the usual conditions.

Example 11- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine dihydrochloride

1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine prepared by the procedure described in example 24 of WO2008112407 and then the title compound was prepared by the procedure described in the description of WO2008112407 in "example of salt form".

Or prepared by referring to the method disclosed in Chinese patent application CN 102344438A.

Example preparation of a Capsule of 21- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine dihydrochloride (dihydrochloride of Compound I)

Crushing dihydrochloride of the compound I, and sieving the crushed dihydrochloride with a 80-mesh sieve; then mixing with mannitol and hydroxypropyl cellulose uniformly; then adding microcrystalline cellulose in the prescription amount, mixing uniformly, and sieving by a 0.8mm sieve; finally, adding magnesium stearate with the prescription amount, mixing uniformly, and filling capsules.

Capsules of other contents of dihydrochloride salt of compound I can be prepared with reference to the same proportions and formula as described above.

Example 3 in vitro experiments

Cell lines:

human chondromas cell line CAL-78, SW1353 (source: ATCC).

The tested drugs are:

1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine dihydrochloride (compound I dihydrochloride for short); methotrexate; cyclophosphamide; oxaprozin.

The preparation method comprises the following steps:

all the samples are dissolved by dimethyl sulfoxide to prepare a mother solution with the concentration of 100mmol/L, and the mother solution is stored at the temperature of minus 20 ℃ for later use. When in use, the required concentration is prepared by DMEM serum culture solution. And the dihydrochloride diluent of the compound I is respectively mixed with methotrexate, cyclophosphamide and oxaprozin diluent to determine whether the dihydrochloride of the compound I has better effect after combination.

Cell culture:

the test cells were cultured in a medium containing 10% fetal bovine serum and 0.1g/L streptomycin and penicillin (final concentration: 100U. mL)^-1) The DMEM complete culture solution is placed in 5% CO at constant temperature of 37 DEG C₂Culturing in an incubator. When the cell fusion degree reaches about 85 percent, mixing and digesting the cells by 0.02 EDTA% +0.25 percent trypsin, collecting the cells, centrifuging the cells at 1000r/min, and subculturing the cells.

The test method comprises the following steps:

1. effect of the dihydrochloride salt of Compound I in combination with a second therapeutic agent on inhibition of chondrosarcoma cell proliferation

The IC50 value can be measured by a method generally used in the art (e.g., MTT method), or by the following method (MTT method):

cells in logarithmic growth phase were seeded in 96-well culture plates (180. mu.l/well, 10)⁵Individual cells/well). After growth at 37 ℃ under 5% CO2 for 24 hours, cells were cultured by adding the dihydrochloride of Compound I (gradient 0, 0.5, 1, 3, 6, 8, 10, 12, 16, 30. mu.g/ml solutions) in combination with 10. mu.g/ml methotrexate, 40. mu.g/ml oxaprozin, and 150. mu.g/ml cyclophosphamide, respectively, in two wells per concentration, 20. mu.L of each well, and a saline vehicle control and a cell-free zeroing well at the corresponding concentration.

Tumor cells were incubated at 37 ℃ with 5% CO₂The culture was further incubated under the conditions for 24 hours (i.e., 48 hours in total). After the drug effect is finished, MTT working solution is added into each hole, after 4 hours, the triple solution is dissolved and stays overnight at 37 ℃. The next day, OD values were measured at 570nm and 630nm using a microplate reader (SPECTRA max 190) (all OD values measured at 570nm were calculated after subtracting OD value at 630nm from that at the control wavelength), and the cell growth inhibition ratio was calculated by the following formula:

inhibition ═ OD value (OD value vs control well-OD value dosing well)/OD value control well x 100%

Half maximal inhibitory concentration IC50 was calculated using GraphPad Prism 5 software based on the inhibition rate at each concentration to determine whether compound I dihydrochloride combination had a better effect.

2. Effect of the dihydrochloride salt of Compound I in combination with a pharmaceutical second therapeutic agent for the treatment of chondrosarcoma on apoptosis of chondrosarcoma cells

Flow cytometry detection of apoptosis CAL-78, SW1353 cells were added to 0, 0.5, 1, 3, 6, 8, 10, 12, 16, 30. mu.g/ml of Compound I dihydrochloride + 10. mu.g/ml methotrexate; 0. 0.5, 1, 3, 6, 8, 10, 12, 16, 30 μ g/ml of the dihydrochloride salt of compound I +150 μ g/ml cyclophosphamide; 0. culturing in 0.5, 1, 3, 6, 8, 10, 12, 16, 30 μ g/ml compound I dihydrochloride +40 μ g/ml oxaprozin culture solution, collecting cells after 24h, centrifuging at 1000r/min for 3-5min, and washing with PBS. Then using Annexin-V-FITC/PI apoptosis detection kit to detect the apoptosis condition, adding cells into 100 mu L1 xBinding buffer solution for resuspension, adding 5 mu LannexinV-FITC and 2.5 mu LPI dye, shaking and mixing uniformly in a dark place, reacting at room temperature for 15min, then adding 300 mu L1 xBinding buffer solution, mixing uniformly, and detecting by an up-flow cytometer. The experiment was repeated 3 times.

And (3) test results:

1. dihydrochloride salt of compound I + methotrexate; dihydrochloride salt of compound I + cyclophosphamide; the in vitro pharmacodynamic action of the dihydrochloride of the compound I and the oxaprozin on chondrosarcoma cell strains shows that the dihydrochloride of the compound I and the medicine for treating chondrosarcoma have clear inhibition effect on the proliferation of CAL-78 and SW1353 cells.

2. The result of a classical Annexin-V-FITC/PI cell apoptosis detection method shows that dihydrochloride of the compound I with different concentrations can respectively and remarkably enhance apoptosis of a chondrosarcoma cell line caused by methotrexate, cyclophosphamide and oxaprozin.

EXAMPLE 4 clinical trial

Clinical trials of compound I dihydrochloride capsules in combination with a second therapeutic agent were developed in chondrosarcoma patients with measurable lesions (according to RECIST 1.1).

Compound I or a pharmaceutically acceptable salt thereof is administered orally at a dose of 12mg once daily for 2 weeks, and is administered for 2 weeks; methotrexate is administered orally at a daily dose of 5-10 mg once a day, 1-2 times a week.

Compound I or a pharmaceutically acceptable salt thereof is administered orally at a dose of 12mg once daily for 2 weeks, with 1 week off; cyclophosphamide is administered orally in a daily dose of 150mg once or more times daily.

Oral administration of compound I or a pharmaceutically acceptable salt thereof at a dose of 12mg once daily for 5 days and 2 days off; oxaprozin is administered orally in a daily dose of 600mg, once or more times daily.

The evaluation indexes comprise the following curative effect indexes: progression Free Survival (PFS), Objective Remission Rate (ORR), duration of remission (DOR), Stable Disease (SD) rate, Clinical Benefit Rate (CBR), Overall Survival (OS), and the like; the safety index is as follows: incidence and severity of adverse reactions; quality of life, etc.

The clinical test results are as follows:

the dihydrochloride of the compound I is combined with the medicine to be effective in treating chondrosarcoma, and can prolong the total survival time and the like.

Claims

1. The use of a therapeutically effective amount of compound I or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of a second therapeutic agent in the manufacture of a combination medicament for the treatment of chondrosarcoma,

2. the use of claim 1, wherein the chondrosarcoma is a primary chondrosarcoma and/or a secondary chondrosarcoma.

3. The use of claim 1, wherein the chondrosarcoma is a centrochondrosarcoma, a limbic chondrosarcoma, a pericarpal parachondroosarcoma, an periosteal chondrosarcoma, or an extraosseous mucinous chondrosarcoma.

4. The use of claim 1, wherein the chondrosarcoma is a low-grade malignant chondroblastoma, a moderate-grade malignant chondroblastoma, or a high-grade malignant chondroblastoma.

5. The use of claim 1, wherein the chondrosarcoma is chondrosarcoma generally, chondrosarcoma mesenchymal, chondrosarcoma hyaline.

6. The use according to any one of claims 1 to 5, wherein the second therapeutic agent is a chemotherapeutic agent and/or a non-steroidal anti-inflammatory drug and/or a small molecule targeted anti-neoplastic drug;

preferably, the chemotherapeutic drug is one or more of alkylating agent, podophyllum, topoisomerase inhibitor, taxus, antimetabolite and antibiotic antineoplastic drug;

more preferably, the chemotherapeutic agent is a platinum-based agent, fluoropyrimidine derivative, taxane, topoisomerase I inhibitor, topoisomerase II inhibitor, vinblastine, pemetrexed, mitomycin, ifosfamide, cyclophosphamide, azacitidine, pirarubicin, amrubicin, methotrexate, bendamustine, epirubicin, doxorubicin, temozolomide, LCL-161, KML-001, Sapacitabine, plinabulin, troxsufen, dipivefrin hydrochloride, dipyridamole, doxorubicin,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 topoisomerase I inhibitor is one or more of camptothecin and its derivatives, hydroxycamptothecin, irinotecan and topotecan, the topoisomerase ii inhibitor is one or more of etoposide and teniposide, and the vinblastine is one or more of vinorelbine, vinblastine, vincristine, vindesine and vinblastine;

preferably, the non-steroidal anti-inflammatory drug is one or more of zaltoprofen, diclofenac, indomethacin, oxaprozin, acetaminophen and ketoprofen;

preferably, the small molecule targeted antitumor drug is a protein kinase inhibitor;

more preferably, the small molecule targeted antitumor drug 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, ematinib, enratinib, lenvatinib, itacintinib, pyrrole, bimatinib, erlotinib, axitinib, lenatinib, cobitinib, acartitinib, famitinib 931, masitinib, irotinib, rociletinib, naridanib, lenalidomide, elvalidomide, elvucidomide, elvucinostrilatinib, loxacinitrosol, loxapitinib, tamicinib, tamici, 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, SANYPervicib, AZT-3, SALXylanib-0796, AZ-4596, SANzyrtib-077, SANYLASN-3, SANgrain-3, SANTI-3, SANTI-3, SANTI-3, SANTI-3, SANTI, 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, Siremaddin, Telaglenastat, MP-0250, GLG-801, ABTL-0812, bortezomib, panobistat, tucidinostat, vorinostat, reminiostat, epatadost, tametat, metenostat, entastatin, mocetinostat, and quisiteostat;

still further preferably, the small molecule targeted antitumor drug is one or more of sorafenib, ibrutinib, erlotinib, afatinib, crizotinib, ceritinib, vemurafenib, dabrafenib, cabozantinib, gefitinib, dacomitinib, oxitinib, erlotinib, brigatinib, luratinib, tremitinib, laratinib, lapatinib, vandetanib, sematinib, voritinib, furaquitinib, enretinib, dasatinib, enratinib, lenvatinib, itatinib, pyrrole, bimetinib, erlotinib, acotinib, lenatinib, fibatinib, acartinib, famitinib, masitinib, imatinib, ibrutinib, and darinib.

7. The use according to any one of claims 1 to 6, wherein the pharmaceutically acceptable salt thereof 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.

8. The use according to any one of claims 1 to 7, wherein the daily dose for the administration of compound I or a pharmaceutically acceptable salt thereof is from 3 mg to 30 mg, preferably from 5 mg to 20 mg, more preferably from 8 mg to 16 mg, even more preferably from 8 mg to 14 mg, most preferably 8 mg, 10mg, 12 mg.

9. The use according to any one of claims 1 to 8, wherein the therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt thereof, and the therapeutically effective amount of the second therapeutic agent are administered simultaneously, separately or sequentially.

10. The use according to any one of claims 1 to 9, wherein the combination is a formulation suitable for any administration form, oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intralipid, intraarticular, intraperitoneal or intrathecal.