CN115590852A - Quinoline derivatives for treating non-small cell lung cancer - Google Patents

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/CN 2015/096770), 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.X filed on month 09 of 2014 12 to the chinese intellectual property office, 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 proper 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 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 of treating 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 having the 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, which salts 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, compound I is administered as a crystalline form of the hydrochloride salt of compound I. In particular embodiments, 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 treatment methods, the method of administration 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 for a dosing period, followed by a rest period for a period of time, followed by a dosing period, followed by a rest period, which may be repeated multiple times. Wherein the ratio in days of the administration period and the withdrawal period is 2.5 to 5, preferably 2.5 to 3, more preferably 2.5 to 2, and still more preferably 2.

In some embodiments, the administration is discontinued for 2 weeks. In some embodiments, the 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, the administration is 1 time per day for 14 days followed by 7 days of rest; the administration is followed 1 time per day for 14 days and then discontinued for 7 days, so that the administration is repeated multiple times at 1 week intervals for 2 weeks of 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 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 certain particular embodiments, the 12mg dose is administered orally once daily for 2 weeks with 1 week rest.

In one embodiment, compound I or a pharmaceutically acceptable salt thereof is administered to the patient alone 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 the use of compound I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of advanced non-small cell lung cancer and/or metastatic non-small cell lung cancer for which EGFR-TKI is not indicated.

Compound I may be in its free base form, or in the form of its salts, hydrates, and prodrugs, which convert to the free base form of compound I in vivo. 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.

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, is the form of compound I dihydrochloride. 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 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, for tablets or capsules, "12 mg of compound I on a unit dose basis" means that each tablet or 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, inhalation, vaginal, intraocular, topical, subcutaneous, intraadipogenic, intraarticular, intraperitoneal, and intrathecal administration; preferably oral preparation, 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 hydrophosphate, calcium carbonate and the like; 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 pharmaceutic adjuvant also comprises a coloring agent, a sweetening agent and the like.

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.

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; the administration is then 1 time per day for 14 days and then 14 days off, so that the administration may be repeated a plurality of times at 2-week intervals with 2 weeks off for 2 consecutive administrations.

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 followed 1 time per day for 14 days and then discontinued for 7 days, so that the administration is repeated multiple times at 1 week intervals for 2 weeks of continuous administration.

In some embodiments, the administration is continued for 5 days and discontinued for 2 days. In some embodiments, the 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 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.

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

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.

For those skilled in the art, "EGFR mutation negative" generally means that no EGFR gene mutation is detected according to the gene detection method commonly used in clinical diagnosis. 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.

As used herein, the amount of compound I administered will be determined by 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 non-small cell lung cancer which is resistant or intolerant to EGFR-TKI, namely the non-small cell lung cancer which is subjected to disease progression or has intolerable toxic and side effects is continuously used after EGFR-TKI treatment, and initial treatment benefits are obtained. Non-small cell lung cancers for which EGFR-TKI therapy is not indicated also include: non-small cell lung cancer which is insensitive to EGFR-TKI, namely non-small cell lung cancer which does not benefit and still progresses when treated by EGFR-TKI. 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 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 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 average number of progression free survivors for patients who participated in 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 1- [ [ [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 reference to WO2008112407 and then the title compound was prepared by the method of preparation of the example as a salt in reference to the description.

Example 2 preparation of a capsule of 1- [ [ [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 the microcrystalline cellulose with the prescription amount, uniformly mixing, 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 measurable lesions, pathologically confirmed advanced non-small cell lung cancer, who received two and 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). In this study 117 patients were enrolled, with 57 randomized placebo enrolled and 60 randomized hydrochloride enrolled, and the patients were aged between 18-70 years.

Eligible non-small cell lung cancer patients received compound i dihydrochloride/placebo for clinical trials. The dosage of 12mg/0mg is 1 time per day, and the drug is continuously taken for 2 weeks and is stopped for 1 week, namely 3 weeks (21 days) is taken as a periodic scheme; until the time when the investigator deems the patient unsuitable for continued medication or when the efficacy is evaluated 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 time of the non-small cell lung cancer patients which are not suitable for EGFR-TKI treatment.

Example 4

A) Medical history

A 41 year old woman admitted in 2 months 2012 with a "cough for one week", with chest CT showing right lung occupancy, and 24 days 2 with right lung hypolobutomy, postoperative pathology: the dorsal and basal segments of the right lung inferior lobe invade and differentiate into myxoma. 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 2012, due to chest pain and discomfort in 9 months, the repeated examination of chest CT suggests that nodules occur frequently in both lungs, and the increased increase of nodules in both lungs is repeatedly examined 11 days after cefotiam treatment; chemotherapy with a (pemetrexed) regimen 2 times on days 11/6/2012 and 8/12/2012, with 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 fatty liver, left kidney and breast symptoms are accompanied when the composition is used.

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 results

The sum of the two large measurable lesions in the CT scan before compound I dihydrochloride was 71.51mm (a 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 of the first cycle (2013-12-11) after starting treatment with compound I dihydrochloride decreased to 68.65mm (the right upper lung cavity became larger, the wall became thinner; the right lower lung parenchymal lesion became hollow); the sum of the diameters of the second period (2014-01-01) is 70.29mm (the upper lung cavity is continuously enlarged and the wall is thinned; the right lower lung cavity is enlarged), and the sum of the diameters of the fourth period (2014-02-12) is 74.2mm (the cavity is continuously enlarged) 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; a cavity appears in the solid lesion of the right inferior lobe 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, the patient had received zero-month of compound i dihydrochloride treatment for one year, and was still taking compound i dihydrochloride capsules at the nineteenth treatment cycle, with continued response and better clinical performance of the tumor.

C) Tolerance to stress

Overall tolerability was good with compound i dihydrochloride treatment. The routine change of blood 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. And combining the results of the imaging examination, and clinically diagnosing: right lung upper lobe adenocarcinoma, bipulmonary metastasis, mediastinal lymph node metastasis, right supraclavicular lymph node metastasis (T4N 3M1, stage iv), no history of other diseases. 4 cycles of NP (vinorelbine + cisplatin) + enidegree regimen chemotherapy were received from 4 days at 2008 to 3 and 13 days at 2008, best performing PR (partial remission), enidegree + artemisinin regimen was used from 19 days at 2008 to 17 days at 2008, the maintenance therapy with enidegree single drug was started at 2008 and 7 months, the breast CT was reviewed at 28 days at 2008, indicating more advanced infiltration of upper right lung lobes, the gemcitabine + cisplatin regimen was started at 2008 and 8 and 5 days at 8 and 2008, best performing SD (stable disease), treatment with iressa (gefitinib) was started at 2008 and 9 months, reviewing CT showed that upper right lung lobes were reduced earlier and right pleural effusion disappeared. Oral administration of iressa (gefitinib) is continued after two cycles of 3/2009 pemetrexed + cisplatin + enidegree, CT in 7/2009 shows an increase in double lung nodules earlier, CT in 2009 shows 21/9/3 cycles pemetrexed + cisplatin, and erlotinib is administered 3/2010-3/6/3 months, with 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 chaetotinib (thelitatinib) used in 4 months and 1 day in 2013, and after gefitinib was orally taken in 7 months in 2013, CT in 12 months in 2013 suggested that double lungs were multiple nodules and tumors were enlarged earlier. The tumor marker CEA has abnormal detection result, 7.25ng/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 diameters of the 2 large measurable target lesions in the CT scan the day before compound i dihydrochloride was taken was 142mm (72 mm for anterior segment lesion of right superior lung, 70mm for right lung). In the subsequent CT scanning in the treatment process of the compound I dihydrochloride, the sum of the diameters of target lesions is reduced to 108mm and 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 when the medicine is taken for 14 days, the sum of the diameters of 2 large measurable target lesions is 114mm at the CT result of 6 weeks, and the reduction is 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 day 4/12 of 2014, the patient had received compound i dihydrochloride treatment for 351 days, with compound i dihydrochloride remaining at the 16 th treatment cycle, with the tumor continuing to respond and the clinical performance remaining good.

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 is subjected to CT examination on 6-month and 2-day menstruation in 2014 to find left lung cancer, double-lung metastasis, lymph node metastasis on double lungs, mediastinum and right clavicle, ECT (emission computed tomography) prompt bone metastasis and cranial MRI prompt 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 administered for 6 cycles from 6/9/2014 to 25/9/2014, with optimal PR effect, gastrointestinal reaction at level II, and no 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 detected by examination on day 27/1/2015, and best SD treatment was given by 6 cycles of icotinib in combination with docetaxel chemotherapy on day 31/1/2015 to day 21/6/2015. 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.

A patient receives treatment for 1 cycle in 7 months and 29 days in 2015, CT is enhanced to prompt that left superior pulmonary lobe cancer is accompanied with obstructive inflammation, double lung metastasis, interval thickening between lower lobes of double lungs, metastasis of lymph nodes of left hilum and mediastinum, and enlargement of upper collarbone lymph nodes on the right side, the metastasis of pleura between the double lateral lobes is considered, part of the metastasis is better, part of the change is not obvious, and the optimal curative effect evaluated according to RECIST1.1 reaches PR.

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 filing, patients were substantially tolerant of adverse events and continued 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 detects that the 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 between 9/9 in 2013 and 6/10 in 2013. CT is reviewed in 12 months in 2013, and the progress of the disease is prompted. 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 two lungs are mostly developed with large lung bleb, 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 given on days 1/7 2015 to 29/2015, with III-degree myelosuppression following 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.

A capsule of 12mg of compound I dihydrochloride (2 weeks on continuous dosing and 1 week off for one treatment cycle) was administered orally once daily beginning 6/4 days 2015 for treatment. 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 supraclavicular, in the mediastinum and right hilum; inflammation of both lungs, the range of which is not changed much than before, and both lungs are mostly foamed with large lung bubbles and are not changed much than before; SD (small) was assessed by RECIST1.1, and the sum of target lesions was 66mm, which was 10mm smaller than 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 63mm; enhancement of CT at 9/8/2015 suggests that the lesion is further contracted, and the total target lesion is 57mm; enhancement of CT on 10 months and 16 days in 2015 suggests that the lesion size is reduced, the change is not large, and the total target lesion size is 56mm; by the date of filing, patients were substantially tolerant of adverse events and continued to receive treatment.

Claims (10)

1. Use of compound I having the structural formula or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of advanced non-small cell lung cancer and/or metastatic non-small cell lung cancer, which is non-small cell lung cancer intolerant to EGFR-TKI,

2. the use of claim 1, wherein the nsclc is one that benefits initial treatment after EGFR-TKI treatment and continues to exhibit intolerable toxic side effects.

3. The use according to any one of claims 1 or 2, wherein the non-small cell lung cancer is a non-small cell lung cancer whose disease has progressed or recurred after having been subjected to chemotherapy, preferably a non-small cell lung cancer whose disease has progressed or recurred after having been subjected to chemotherapy at least two times.

4. The use according to any 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 in an intermittent manner, preferably the ratio of the administration period to the rest period in days is 2.

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

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.