CN114652723A

CN114652723A - Quinoline derivatives for treating non-small cell lung cancer

Info

Publication number: CN114652723A
Application number: CN202210460116.8A
Authority: CN
Inventors: 王训强; 缪亚东; 周敏; 王善春; 杨玲; 施伟
Original assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Current assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority date: 2014-12-09
Filing date: 2015-12-09
Publication date: 2022-06-24
Also published as: WO2016091165A1; CN112057451A; CN106999484A; CN114831988A; CN112057452A; CN115590852A; CN114767680A

Abstract

The application provides a quinoline derivative for treating non-small cell lung cancer. The 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine or a pharmaceutically acceptable salt thereof provided by the application can be used for treating non-small cell lung cancer patients who are not suitable for EGFR-TKI treatment, and can remarkably improve the progression-free survival of non-small cell lung cancer patients who are not suitable for EGFR-TKI treatment relative to a placebo.

Description

Quinoline derivatives for treating non-small cell lung cancer

The application is a divisional application of Chinese patent application with application number 201580066135.0 (international application number PCT/CN2015/096770), application date 2015, 12 months and 09, and invented name quinoline derivative for treating non-small cell lung cancer.

Cross Reference to Related Applications

This application claims priority and benefit to chinese patent application No. 201410747455, filed on 2014, 12, 09 and 2014 to the chinese intellectual property office, No. X, the disclosure of which is incorporated herein by reference in its entirety.

Technical Field

The application belongs to the technical field of medicines, and relates to an antitumor application of a quinoline derivative. In particular, the application relates to the use of quinoline derivatives for the treatment of non-small cell lung cancer.

Background

Non-small cell lung cancer (NSCLC) is the most common malignancy in our country with its major histological types including adenocarcinoma, Squamous Cell Carcinoma (SCC) and large cell carcinoma. Adenocarcinoma is a common histological type of NSCLC based on cell morphology. Surgical resection with chemotherapy is the primary means of treatment. However, most patients lose the chance of surgery due to late stage diagnosis, and most patients receiving surgery also need adjuvant chemotherapy, so chemotherapy is the most important mode of treatment. The traditional chemotherapy drugs are greatly limited in clinical application due to poor specificity and large toxic and side effects. The selection of appropriate drugs and the targeted individualized treatment are the development direction of tumor treatment. The tumor molecule targeted drug therapy is gradually becoming the mainstream of clinical tumor individual chemotherapy due to good specificity and small side effect. A number of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) show beneficial effects in the treatment of non-small cell lung cancer, such as gefitinib, erlotinib (icotinib), etc.; the EGFR-TKI inhibits activation and phosphorylation of EGFR tyrosine kinase domain ATP binding site, prevents downward transmission of activation signal, inhibits tumor cell proliferation, and initiates apoptosis. Recent clinical applications have found that EGFR-TKI treatment of NSCLC patients varies from individual to individual. Therefore, further research on non-small cell lung cancer is urgently needed to develop effective therapeutic drugs, improve survival rate and bring substantial benefits to patients.

Disclosure of Invention

In one aspect, the present application provides a method for treating non-small cell lung cancer that is refractory to EGFR-TKI treatment, comprising administering to a patient in need thereof a therapeutically effective amount of Compound I, having the structural formula or a pharmaceutically acceptable salt thereof,

in some embodiments of the present application, there is provided a method of treating advanced non-small cell lung cancer and/or metastatic non-small cell lung cancer that is not amenable to treatment with EGFR-TKI, comprising administering to a patient in need thereof a therapeutically effective amount of compound I, or a pharmaceutically acceptable salt thereof.

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 present application and can be produced from various organic and inorganic acids according to methods well known in the art.

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.

Compound I has the chemical name 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine, which has the following structural formula:

compound I or a pharmaceutically acceptable salt thereof may be administered by a variety of routes including, but not limited to, a route selected from: oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intralipid, intraarticular, intraperitoneal, and intrathecal. In a particular embodiment, administration is by oral administration.

The amount of compound I or a pharmaceutically acceptable salt thereof administered may be determined according to 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 10mg 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. In one embodiment, the oral solid formulation is administered once daily.

In the above-mentioned therapeutic methods, the administration method can be comprehensively determined depending on the activity and toxicity of the drug, the tolerance of the patient, and the like. Preferably, compound I or a pharmaceutically acceptable salt thereof is administered at intervals. 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, the administration is discontinued for 2 weeks. In some embodiments, administration is 1 time per day for 14 days followed by 14 days off; followed by 1 administration per day for 14 days and then 14 days, so that the administration may be repeated several times at 2-week intervals.

In some embodiments, the administration is discontinued for 1 week for 2 weeks. In some embodiments, administration is 1 time per day for 14 days followed by 7 days of discontinuation; the administration is then 1 time per day for 14 days and then 7 days off, so that the administration may be repeated a number of times at 1 week intervals with 2 weeks off for continuous administration.

In some embodiments, the administration is continued for 5 days and discontinued for 2 days. In some embodiments, administration is 1 time per day for 5 days, followed by 2 days off; the administration is followed 1 time per day for 5 days and then discontinued for 2 days, and the administration may be repeated multiple times at intervals of 5 consecutive days and 2 discontinued days.

In certain particular embodiments, the administration is oral at a dose of 12mg once daily for 2 weeks with 1 week rest.

In one embodiment, compound I or a pharmaceutically acceptable salt thereof is administered alone to the patient as the sole active ingredient.

In another aspect, the present application also provides the use of compound I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of non-small cell lung cancer for which EGFR-TKI is not indicated.

In some embodiments of the present application, there is provided a use of compound I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating advanced non-small cell lung cancer and/or metastatic non-small cell lung cancer that is not amenable to EGFR-TKI treatment.

Compound I may be in its free base form, or 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 present application and can be produced from various organic and inorganic acids according to methods well known in the art.

In some embodiments, compound I or a pharmaceutically acceptable salt thereof is the hydrochloride salt form of compound I. In some embodiments, in the form of compound I monohydrochloride. In some embodiments, in the form of the dihydrochloride salt of compound I. In some embodiments, is a crystalline form of the hydrochloride salt of compound I. In a particular embodiment, is a crystalline form of compound I dihydrochloride.

The amount of compound I or a pharmaceutically acceptable salt thereof may be determined according to 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 10mg to 14 mg.

In yet another aspect, the present application provides compound I or a pharmaceutical composition for treating non-small cell lung cancer that is not amenable to treatment with EGFR-TKI, wherein the pharmaceutical composition comprises compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

In some embodiments of the present application, there is provided compound I or a pharmaceutical composition for treating advanced non-small cell lung cancer and/or metastatic non-small cell lung cancer that is not amenable to EGFR-TKI treatment, wherein the pharmaceutical composition comprises compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

The amount of compound I or a pharmaceutically acceptable salt thereof may be determined according to 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 above pharmaceutical compositions contain 3 mg to 30 mg of compound I, or a pharmaceutically acceptable salt thereof, on a unit dose basis. In some embodiments, the above pharmaceutical compositions contain 5 mg to 20 mg of compound I, or a pharmaceutically acceptable salt thereof, on a unit dose basis. In some embodiments, the above pharmaceutical compositions contain 8 mg to 16 mg of compound I, or a pharmaceutically acceptable salt thereof, on a unit dose basis. In some embodiments, the above pharmaceutical compositions contain 10mg to 14 mg of compound I, or a pharmaceutically acceptable salt thereof, on a unit dose basis. In this application, for example, with respect to tablets or capsules, "12 mg of compound I on a unit dose basis" means that each tablet or each capsule ultimately produced contains 12mg of compound I.

In certain embodiments, the pharmaceutical composition comprises 8, 10 or 12mg of compound I or a pharmaceutically acceptable salt thereof on a unit dose basis.

In some embodiments, compound I is formulated in a formulation suitable for oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intralipid, intraarticular, intraperitoneal, and intrathecal administration; preferably suitable for oral administration, including tablet, capsule, powder, granule, dripping pill, paste, powder, etc., preferably tablet and capsule. 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.

The pharmaceutical composition may be a formulation suitable for oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, inhalational, vaginal, intraocular, topical, subcutaneous, intraadipogenic, intraarticular, intraperitoneal and intrathecal administration; preferably suitable for oral administration, including tablet, capsule, powder, granule, dripping pill, paste, powder, etc., preferably tablet and capsule. 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.

Preferably, compound I or the above pharmaceutical composition is administered in an intermittent manner. The interval administration comprises an administration period and a drug stopping period, and the pharmaceutical composition can be administered once or more times per day in the administration period. For example, the above-mentioned pharmaceutical composition is administered daily during a dosing period, followed by a discontinuation period in which the administration is stopped for a certain period of time, followed by a dosing period, followed by a discontinuation period, and so on may be repeated several 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, the administration is continued for 5 days and discontinued for 2 days. In some embodiments, administration is 1 time per day for 5 days, followed by 2 days off; the administration is then 1 time per day for 5 days and then 2 days off, so that the administration may be repeated a plurality of times at intervals of 5 consecutive days off for 2 days.

In some embodiments, compound I or the above pharmaceutical compositions may be administered one or more times daily. In some embodiments, compound I or the above pharmaceutical composition is administered once daily. In one embodiment, the oral solid formulation is administered once daily.

It will be appreciated by those skilled in the art that the EGFR-TKI described herein are epidermal growth factor receptor tyrosine kinase inhibitors, and examples that may be listed include, but are not limited to, gefitinib (Iressa), erlotinib (Tarceva), and erlotinib (Caimer).

Herein, "advanced stage" refers to staging non-small cell lung cancer according to the extent of the lesion and the concurrent disease, such as stage iii-iv non-small cell lung cancer according to TNM classification in the AJCC cancer staging system, and in some embodiments, advanced non-small cell lung cancer is stage iii B-iv non-small cell lung cancer.

Herein, "EGFR" refers to the epidermal growth factor receptor.

"EGFR mutation-negative" generally means that EGFR gene mutation is not detected according to the usual gene detection methods for clinical diagnosis, as is known to those skilled in the art. The EGFR mutation status can be detected by various methods, DNA mutation detection is the first method for detecting the EGFR status, various DNA mutation detection analyses can be used for detecting the EGFR mutation status of tumor cells, the most common EGFR mutation of non-small cell lung cancer patients is exon 19 deletion and exon 21 mutation, and direct DNA sequencing of exons 18-21 (or only exons 19 and 21) is a reasonable choice.

In this context, unless otherwise indicated, the dosages and ranges provided herein are based on the molecular weight calculation of the free base form of compound i.

Herein, the amount of compound i administered may 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. The period of administration can be determined comprehensively according to the activity and toxicity of the drug, the tolerance of the patient, and the like.

Herein, non-small cell lung cancers that are not amenable to EGFR-TKI treatment include: non-small cell lung cancer that is not recommended to be treated first with EGFR-TKI, e.g., EGFR mutation-negative non-small cell lung cancer; and EGFR-TKI resistant or intolerant non-small cell lung cancer, i.e., non-small cell lung cancer that develops disease progression or a patient develops an intolerable toxic side effect, after treatment with EGFR-TKI, the initial treatment benefits. Non-small cell lung cancers that are not amenable to treatment with EGFR-TKI also include: non-small cell lung cancer that is not sensitive to EGFR-TKI, i.e., non-small cell lung cancer that does not benefit from treatment with EGFR-TKI and in which the disease is still progressing. Here, "benefit" means no progression of the disease.

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.

By "pharmaceutically acceptable" is meant that it is used to prepare a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and includes that it is 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 treatment for 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.

Herein, progression-free survival P50 refers to the time to progression-free disease in 50% of patients participating in the statistics; progression-free survival P75 refers to the time to progression-free disease in 25% of patients participating in the statistics; the progression-free survival mean refers to the mean value of the progression-free survival of the patients involved in the outcome statistics.

DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION

The technical solutions of the present invention are described below with specific examples, but the scope of the present invention is not limited to the described examples.

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 method of example 24 in WO2008112407 and then the title compound was prepared by the methods of preparation of the examples in salt form in the specification.

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; and finally, adding magnesium stearate with the prescription amount, mixing uniformly, and filling capsules.

Example 3

Randomized, double-blind, placebo-controlled, multicenter phase II clinical trial studies were conducted in patients with pathologically confirmed advanced non-small cell lung cancer with measurable lesions, who received two or more lines of treatment or were intolerant of treatment, and who received other cytotoxic drugs, radiation therapy or surgery for more than four weeks. In this study, compound i dihydrochloride capsules were initially evaluated for effectiveness in treating advanced non-small cell lung cancer, as compared to placebo control. The primary indicator evaluated was Progression Free Survival (PFS). There were 117 patients enrolled in the study, with 57 randomized placebo and 60 randomized hydrochloride, and these patients were between 18-70 years of age.

Eligible non-small cell lung cancer patients received compound i dihydrochloride/placebo for clinical trials. The medicine is continuously taken for 2 weeks and is stopped for 1 week according to the dosage of 12mg/0mg every time 1 time every day, namely 3 weeks (21 days) are taken as a periodic scheme; until the study concluded that the patient was considered unsuitable for further use or that efficacy was assessed as disease Progression (PD).

The research result is as follows: 117 patients with non-small cell lung cancer were enrolled in a cohort of 57 randomized cohorts of placebo, 60 randomized cohorts of compound i dihydrochloride, 43 cohorts of the current data statistics, 32 cohorts of compound i dihydrochloride, and the remaining cases remained in the visit and not included in the data statistics due to subject shedding or culling during the trial or subjects not yet in the cohort. In the research process, the non-small cell lung cancer which is not suitable for being treated by the EGFR-TKI is subjected to hierarchical analysis according to whether the EGFR-TKI is taken before to benefit, wherein the benefit refers to no progress of the disease. The statistical results are shown in the following table:

according to the results, the dihydrochloride salt of the compound I can remarkably prolong the progression-free survival of the non-small cell lung cancer patients which are not applicable to the EGFR-TKI treatment.

Example 4

A) Medical history

A 41 year old woman admitted to the hospital for "one week cough" at month 2 of 2012, with chest CT showing right lung occupancy, and right lobe resection at day 24 of month 2, postoperative pathology: the dorsal segment of the right lung inferior lobe and basal segment invade and differentiate in the mucus adenocarcinoma. Post-operative changes were indicated by reviewing chest radiographs 3 and 17 days 2013. Chemotherapy was performed for 4 cycles using NP (vinorelbine with cisplatin) regimen from 3 months 28 days to 7 months 6 days 2012. In 9 months in 2012, due to chest pain discomfort, the repeated examination of chest CT indicates that two lungs have multiple nodules, and the increased size of the two lung nodules is repeatedly examined 11 days after cefotiam treatment; chemotherapy with a (pemetrexed) regimen 2 times on day 11/6 in 2012 and on day 12/8 in 2012, disease progression; cycle of chemotherapy with GP (gemcitabine and cisplatin) on 23/1/2013; chemotherapy with a cycle of D (docetaxel) regimen for 3 months in 2013 to 4 months in 2013 with PD (disease progression) effect; treatment with keimenin (icotinib hydrochloride) was given in 2013 on 1/6/7/31/month for therapeutic PD (disease progression). Two cycles of chemotherapy with IE (ifosfamide + etoposide) regimen for 12 days in 2013 and 8 months to 30 months, the curative effect is unknown. No history of radiotherapy is available, and the treatment is accompanied by symptoms of fatty liver, left kidney and kidney breast.

Treatment with a dose of 12mg (2 weeks off for 1 week with one treatment cycle) of compound i dihydrochloride once daily started on 21/11/2013 was performed.

B) CT result

The sum of the two large measurable lesions in the CT scan before compound I dihydrochloride was 71.51mm (void in the right upper lung lesion, 33.34mm in diameter, 38.17mm in the right lower lung lesion). In the subsequent CT scan with compound i dihydrochloride treatment, the sum of the diameters in the first cycle (2013-12-11) after starting treatment with compound i dihydrochloride dropped to 68.65mm (right upper lung cavity became larger, wall became thinner; right lower lung cavity appeared); the sum of the diameters of the second period (2014-01-01) is 70.29mm (upper lung cavity continues to become larger and thinner; right lower lung cavity becomes larger), and the sum of the diameters of the fourth period (2014-02-12) is 74.2mm (cavity continues to increase) to the sixteenth period CT examination prompt: the cavity existing in the upper right lobe during screening is continuously enlarged in the treatment process, and the wall is thinned; the parenchymal lesions of the right inferior lobe develop a cavity at the first cycle thereafter, after which the cavity continues to grow; none of the non-target lesions progressed and no new lesions appeared. By 12/4 days 2014, patients had received compound i dihydrochloride treatment for one year and one month, and were still taking compound i dihydrochloride capsules at the nineteenth treatment cycle, tumors continued to respond and clinical performance was better.

C) Tolerance to stress

Overall tolerability was good with compound i dihydrochloride treatment. The blood routine change is not obvious, and the cardiotoxicity related to the medicine is not seen during the treatment period.

Example 5

A) Medical history

A66 years old retired woman with no history of smoking, and was subjected to hysteromyomectomy in 1990. In 2007, lymph node dissection was performed at the clinic, and the pathology suggested (right supraclavicular) lymph node metastatic cancer to be poorly differentiated adenocarcinoma. Combined with the results of the imaging examination, clinical diagnosis: right suprapulmonary adenocarcinoma, bipulmonary metastasis, mediastinal lymph node metastasis, right supraclavicular lymph node metastasis (T4N3M1, stage iv), with no history of other diseases. 4 cycles of NP (vinorelbine + cisplatin) + enidol regimen chemotherapy are received from 4 days at 2008 and 3 and 13 days at 2008, the best-performing PR (partial remission) is obtained, the enidol + artemisinin regimen is used from 19 days at 2008 and 19 days at 5 and 17 days at 2008, the maintenance treatment with enidol is started at 7 months at 2008, the breast CT is reviewed at 28 days at 2008, so that the infiltration of the suprapulmonary lobes is increased earlier, the gemcitabine + cisplatin regimen is started at 5 days at 2008, 8 and 5 days at 2008, the best-performing SD (stable disease) is obtained, the treatment with iressa (gefitinib) is started at 9 months at 2008, and the review CT shows that the suprapulmonary lobes are reduced earlier and the pleural effusion disappears at the right side. Oral administration of iressa (gefitinib) is continued after two cycles of 3/2009 pemetrexed + cisplatin + enidegree, CT in 7/2009 shows an increase in diplopone nodules earlier, pemetrexed + cisplatin 3 cycles in 9/21/2009, oral administration of erlotinib for 3 months in 3/2010 and 6/2010, and therapeutic effect PD (disease progression). Pemetrexed + oxaliplatin cycle 7/2010, apatinib mesylate taken orally on 19/1/2011, PD progressed; pemetrexed + oxaliplatin was continued, disease progressed after 16 cycles, disease progressed after 2 cycles of using castanea casticifolia (thelitanib) 4/1/2013, and after oral gefitinib 7/2013, CT 12/2013 suggested that double lungs were more prone to nodules and tumors were increased earlier. The tumor marker CEA test result is abnormal, 7.25 ng/mL.

Treatment with a dose of 12mg (2 weeks off for 1 week with one treatment cycle) of compound i dihydrochloride once daily oral administration started on 18/12/2013.

B) CT result

There was a considerable reduction in the sum of the major diameters of the tumor target lesions in patients treated with compound i dihydrochloride. The sum of the 2 large measurable target lesion diameters in the CT scan the day before compound i dihydrochloride was administered was 142mm (72 mm for the anterior segment of the right lung superior lobe, 70mm for the right lung lesion). In the subsequent CT scanning carried out in the treatment process of the compound I dihydrochloride, the diameter sum of target lesions is reduced to 108mm and is reduced by 23.9 percent (48 mm of the anterior segment lesion of the right superior lobe and 60mm of the right lung lesion) at 3 weeks after the start of the treatment with the compound I dihydrochloride, the dosage is reduced to 10mg at 14 days after the administration, and the CT result at 6 weeks shows that the diameter sum of 2 large measurable target lesions is 114mm and is reduced by 21.1 percent (52 mm of the anterior segment lesion of the right superior lobe and 62mm of the right lung lesion, and the imaging indicates that the tumor is empty); by 12/4 days 2014, patients had received compound i dihydrochloride treatment for 351 days, with compound i dihydrochloride remaining at the 16 th treatment cycle, with continued tumor response and good clinical performance.

C) Tolerance to stress

The overall tolerability of treatment with compound i dihydrochloride was good, and no drug-related cardiotoxicity was seen during the treatment period.

Example 6

A62-year-old female patient was found to have left lung cancer, double lung metastasis, double-lung portal and mediastinal and right supraclavicular lymph node metastasis by CT examination at 6/2/2014, with ECT suggesting bone metastasis and cranial MRI suggesting left frontal lobe metastasis. Under the guidance of CT, lung puncture is confirmed to diagnose as non-small cell lung cancer adenocarcinoma, and the gene detection EML4-ALK fusion gene has no mutation and EGFR gene has no mutation.

Cisplatin and pemetrexed chemotherapy are given for 6 cycles from 6/9/2014 to 9/25/2014, with the best effect PR, during which there is a II-degree gastrointestinal reaction, without bone marrow suppression. The tegafur capsule is orally taken for 2 weeks during the period of discharge from 10 and 17 days 2014 to 11 and 1 days 2014, the cough is relieved, and the chest is slightly stuffy. Disease progression was observed on day 27/1/2015, and 6 cycles of chemotherapy with icotinib in combination with docetaxel was given on day 31/1/2015 to day 21/6/2015 for optimal efficacy SD. Clinical studies of compound i dihydrochloride capsules were performed on 7/8 days 2015, and treatment was initiated on the day by oral administration of a dose of 12mg (2 weeks on continuous administration and 1 week off for a treatment period) of compound i dihydrochloride capsules once daily.

The patient receives treatment for 1 period on 29 days 7 months 7 in 2015, CT is enhanced to indicate that left superior lung lobe cancer is accompanied with obstructive inflammation, double lung metastasis, interval thickening between double lower lobes of the double lung, left pulmonary portal and mediastinal lymph node metastasis and right supraclavicular lymph node swelling, pleural metastasis between the double side lobes is considered, part of metastasis is better, part of change is not obvious, and the optimal curative effect reaches PR according to RECIST1.1 evaluation.

Patient head enhancement CT on day 8, month 20 of 2015 suggests a slight reduction in left temporal lobe nodule foci from baseline.

Enhancement of CT in 11/12/2015 suggests that the disease condition is continuously controlled, and the therapeutic effect is still PR. By the date of the application, the patient is substantially tolerant of adverse events and continues to receive treatment.

Example 7

A62-year-old male was diagnosed with non-small cell lung cancer squamous carcinoma by lung puncture under the guidance of 3-menstruation CT in 2013, and left frontal lobe metastasis was suggested by cranial MRI. The gene detection EML4-ALK fusion gene has no mutation, and the EGFR gene has no mutation.

Cisplatin and gemcitabine are given in 26 days in 3 and 3 months in 2013 to 5 days in 6 and 3 months in 2013, the chemotherapy is carried out for 4 periods and the optimal curative effect SD is achieved, and a period of local radiotherapy of the lung is carried out after the chemotherapy is finished, and adverse reactions are light in the period. Cisplatin and gemcitabine chemotherapy was given for 2 cycles from 9 months 9 to 6 months 10 months 2013. CT is reviewed in 2013 in 12 months to prompt the progress of the disease. Docetaxel chemotherapy is given for a cycle in 24 days in 3 months in 2014, bone marrow suppression, oral infection and pneumonia appear after chemotherapy, and the treatment on symptoms is improved. Check CT prompt for 12 months and 10 days in 2014: 1. the soft tissue shadow of the right upper lung portal is enlarged compared with the front; 2. the double lung is mostly foamed with large bubbles, and the change is not large compared with the former; 3. inflammation of both lungs, narrowing the range; 4. the supraclavicular, mediastinal and right pulmonary lymph nodes on the left side are slightly enlarged compared to the anterior. Gemcitabine and Nedaplatin (NDP) were administered from 1/7/2015 to 1/29/2015, with III-degree myelosuppression occurring after chemotherapy and recovery after leukogenic administration. A review of CT 3, 4, 2015 suggested a more advanced enlargement of the right lung mass. Tegafur was orally administered 3/6/2015. CT was reviewed on day 5, month 5, day 27 in 2015 to indicate progress. Pathological diagnosis on 6 months and 2 days in 2015 suggests that: after radiotherapy and chemotherapy of squamous carcinoma of right lung, hypo-differentiated carcinoma of right lung.

Treatment was carried out starting on day 4/6 of 2015 by orally administering 12mg of compound I dihydrochloride capsule once daily (2 weeks for 1 week for a treatment period). The patient receives treatment for 1 cycle in 2015, 6 months and 25 days, and the CT is enhanced to prompt that the density of the soft tissue of the right lung is swollen and slightly reduced compared with the previous case; multiple lymph nodes on the left clavicle, in the mediastinum and right hilum; inflammation of both lungs, which has a range which is not changed greatly compared with the former, and both lungs are mostly provided with large pulmonary alveoli which are not changed greatly compared with the former; SD (small) was assessed by RECIST1.1, the total target lesion was 66mm, and a 10mm reduction from baseline.

Enhanced CT in 2015 for 07, 15 days suggests that the soft tissue density of the right lung is swollen and slightly reduced compared with the former. The total target focus is 63 mm; enhancement of CT at 9/8/2015 suggests that the lesion is further contracted, and the total target lesion is 57 mm; enhancement of CT at 10 months and 16 days in 2015 indicates that the focus is reduced, the change is not large compared with the previous focus, and the total target focus is 56 mm; by the date of the application, the patient is substantially tolerant of adverse events and continues to receive treatment.

Claims

1. Use of compound I having the structural formula: (1) EGFR mutation negative non-small cell lung cancer, and/or (2) EGFR-TKI resistant non-small cell lung cancer, and/or (3) EGFR-TKI intolerant non-small cell lung cancer, and/or (4) EGFR-TKI insensitive non-small cell lung cancer,

2. the use according to claim 1, wherein the non-small cell lung cancer is a non-small cell lung cancer whose disease has progressed or recurred after having been treated with chemotherapy, preferably a non-small cell lung cancer whose disease has progressed or recurred after having been treated with at least 2 kinds of chemotherapy.

3. The use of any one of claims 1 or 2, wherein the nsclc is a nsclc in which the disease has progressed following treatment with EGFR-TKI.

4. The use of any one of claims 1 or 2, wherein the EGFR-TKI comprises gefitinib, erlotinib and erlotinib.

5. The use according to any one of claims 1 or 2, wherein the compound I or the pharmaceutically acceptable salt thereof is the hydrochloride salt of compound I, preferably the mono-or di-hydrochloride salt of compound I.

6. The use according to any one of claims 1 or 2, wherein the compound I or the pharmaceutically acceptable salt thereof is administered in a daily dose of 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 10mg to 14 mg, most preferably 8 mg, 10mg or 12 mg.

7. The use according to any one of claims 1 or 2, wherein the compound I or the pharmaceutically acceptable salt thereof is administered at intervals, preferably at a ratio of administration period to rest period of 2:0.5 to 5, preferably 2:0.5 to 3, more preferably 2:0.5 to 2, more preferably 2:0.5 to 1, in days.

8. The use according to any one of claims 1 or 2, wherein the compound I or the pharmaceutically acceptable salt thereof is administered for 2 weeks off for 2 weeks, or for 2 weeks off for 1 week, or for 5 days off for 2 days.

9. The use as claimed in any one of claims 1 or 2, wherein every 3 weeks is a treatment cycle with 2 weeks of continuous administration and 1 week of rest.

10. The use according to any one of claims 1 or 2, wherein the compound I or the pharmaceutically acceptable salt thereof is administered orally at a dose of 12mg once daily for 2 weeks, and for 1 week.