WO2016091165A1

WO2016091165A1 - Quinoline derivative for treating non-small cell lung cancer

Info

Publication number: WO2016091165A1
Application number: PCT/CN2015/096770
Authority: WO
Inventors: 王训强; 缪亚东; 周敏; 王善春; 杨玲; 施伟
Original assignee: 正大天晴药业集团股份有限公司
Priority date: 2014-12-09
Filing date: 2015-12-09
Publication date: 2016-06-16
Also published as: CN115590852A; CN114831988A; CN112057451A; CN106999484A; CN114767680A; CN112057452A; CN114652723A

Abstract

Provided in the present application is a quinoline derivative for treating non-small cell lung cancer. 1-[[[4-(4-fluoro-2-methyl-1H-indole-5-yl)oxy-6-methoxyquinoline-7-yl]oxy]methyl]cyclopropylamine or a pharmaceutically acceptable salt thereof as provided in the present application can be used for treating a patient with non-small cell long cancer who is not suitable for EGFR-TKI therapy, and with respect to placebos, can significantly increase the progression-free survival of the patient with non-small cell long cancer who is not suitable for EGFR-TKI therapy.

Description

Quinoline derivative for the treatment of non-small cell lung cancer

Cross-reference to related applications

The present application claims priority to and the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the present disclosure.

Technical field

This application belongs to the field of medical technology, and the present application relates to the use of quinoline derivatives for antitumor. In particular, the present application relates to the use of a quinoline derivative for the treatment of non-small cell lung cancer.

Background technique

Non-small cell lung cancer (NSCLC) is the most malignant tumor with morbidity and mortality in China. Its main histological types include adenocarcinoma, squamous cell carcinoma (SCC) and large cell carcinoma. . Based on cell morphology, adenocarcinoma is a common histological type of NSCLC. Surgical resection combined with chemotherapy is the main means of treatment. However, most patients have lost the opportunity for surgery in the late stage of diagnosis. Most patients undergoing surgery also need adjuvant chemotherapy. Therefore, chemotherapy is the most important method of treatment. Traditional chemotherapeutic drugs have been limited in clinical application due to their poor specificity and toxic side effects. Choosing the right drug and targeting individualized treatment is the development direction of cancer treatment. Tumor molecular targeted drug therapy is becoming the mainstream of clinical cancer individual chemotherapy because of its specificity and small side effects. Many epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) have shown beneficial effects in the treatment of non-small cell lung cancer, such as gefitinib and erlotinib. , ectinib (icotinib), etc.; EGFR-TKI inhibits the activation and phosphorylation of the enzyme by binding to the ATP binding site of the EGFR tyrosine kinase domain, so that the activation signal can not be transmitted downward, inhibit tumor cell proliferation, and initiate Apoptosis. Clinical applications in recent years have found that there are individual differences in the treatment of NSCLC patients with EGFR-TKI. Therefore, there is an urgent need for further research on non-small cell lung cancer in order to develop effective therapeutic drugs, improve survival rate, and bring substantial benefits to patients.

Summary of invention

In one aspect, the application provides a method of treating non-small cell lung cancer that is not EGFR-TKI-treated, the method comprising administering to a patient in need of treatment a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, having the formula

Compound I.

In another aspect, the application provides the use of Compound 1, or a pharmaceutically acceptable salt thereof, having the above formula, for the manufacture of a medicament for the treatment of non-small cell lung cancer for which EGFR-TKI therapy is not applicable.

In a further aspect, the application provides a compound I or a pharmaceutical composition having the above formula, wherein the pharmaceutical composition comprises Compound I or a pharmaceutically acceptable salt thereof, and a non-small cell lung cancer that is not suitable for treatment with EGFR-TKI At least one pharmaceutically acceptable carrier.

Detailed description of the invention

In one aspect, the application provides a method of treating non-small cell lung cancer that is not EGFR-TKI-treated, the method comprising administering to a patient in need of treatment a therapeutically effective amount of Compound I having the following structural formula or a pharmaceutically acceptable thereof salt,

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 EGFR-TKI treated, the method comprising administering to a patient in need of treatment a therapeutically effective amount Compound I or a pharmaceutically acceptable salt thereof.

Compound I can be administered in the form of its free base or it can be administered in the form of its salts, hydrates and prodrugs which are converted in vivo to the free base form of Compound I. For example, a pharmaceutically acceptable salt of Compound I is within the scope of the present application and can be produced from different organic and inorganic acids by methods well known in the art.

In some embodiments, the administration is in the form of Compound I hydrochloride. In some embodiments, the administration is in the form of Compound I monohydrochloride. In some embodiments, the administration is in the form of Compound I dihydrochloride. In some embodiments, the administration is in the form of a crystal of Compound I hydrochloride. In a particular embodiment, it is administered in the form of a crystal of Compound I dihydrochloride.

The chemical name of Compound I is 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy] Methyl]cyclopropylamine having the following structural formula:

Compound I.

Compound 1, or a pharmaceutically acceptable salt thereof, can be administered by a variety of routes including, but not limited to, those selected from the group consisting of oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, Intramuscular, rectal, buccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intrahepatic, intra-articular, intraperitoneal, and intrathecal. In a particular embodiment, it is administered orally.

The amount of Compound I or a pharmaceutically acceptable salt thereof administered can be determined based on the severity of the disease, the response to the disease, any treatment-related toxicity, the age and health of the patient. In some embodiments, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from 3 mg to 30 mg. In some embodiments, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from 5 mg to 20 mg. In some embodiments, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from 8 mg to 16 mg. In some embodiments, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from 10 mg to 14 mg. In a specific embodiment, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is 8 mg. In a specific embodiment, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is 10 mg. In a specific embodiment, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is 12 mg.

Compound I or a pharmaceutically acceptable salt thereof can be administered one or more times a day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once daily. In one embodiment, the oral solid preparation is administered once a day.

In the above treatment methods, the method of administration can be comprehensively determined based on the activity, toxicity, and tolerance of the patient. Preferably, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in a separate manner. The interval administration includes a administration period and a withdrawal period, and Compound I or a pharmaceutically acceptable salt thereof may be administered one or more times a day during the administration period. For example, Compound I or a pharmaceutically acceptable salt thereof is administered daily during the administration period, and then the administration is stopped for a certain period of time during the withdrawal period, followed by the administration period, and then the withdrawal period, which can be repeated a plurality of times. The ratio of the administration period to the withdrawal period in days is 2:0.5 to 5, preferably 2:0.5 to 3, more preferably 2:0.5 to 2, still more preferably 2:0.5 to 1.

In some embodiments, the continuous administration is discontinued for 2 weeks for 2 weeks. In some embodiments, the drug is administered once a day for 14 days, then for 14 days; then once a day for 14 days, then for 14 days, so The interval administration method in which the administration is continued for 2 weeks and the drug is stopped for 2 weeks can be repeated a plurality of times.

In some embodiments, the continuous administration is discontinued for 2 weeks for 1 week. In some embodiments, administration once a day for 14 days, followed by 7 days of withdrawal; followed by 1 administration per day for 14 days, followed by 7 days of discontinuation, such continuous administration for 2 weeks The interval of administration of the drug for one week can be repeated a plurality of times.

In some embodiments, the administration is continued for 5 days for 2 days. In some embodiments, the drug is administered once a day for 5 days, then for 2 days; then once a day for 5 days, then for 2 days, such continuous administration for 5 days. The two-day interval administration method can be repeated multiple times.

In certain specific embodiments, the oral administration is administered once daily at a dose of 12 mg, administered continuously for 2 weeks, and administered for 1 week.

In one embodiment, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to a patient as the sole active ingredient.

In another aspect, the present application also provides the use of Compound 1, 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 therapy is not applicable.

In some embodiments of the present application, Compound 1, or a pharmaceutically acceptable salt thereof, is provided 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 therapy is not applicable. the use of.

Compound I may be in its free base form, or it may be in the form of its salts, hydrates and prodrugs which are converted in vivo to the free base form of Compound I. For example, a pharmaceutically acceptable salt of Compound I is within the scope of the present application and can be produced from different organic and inorganic acids by methods well known in the art.

In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is the hydrochloride salt form of Compound I. In some embodiments, is in the form of Compound I monohydrochloride. In some embodiments, is in the form of Compound I dihydrochloride. In some embodiments, is the crystalline form of the hydrochloride salt of Compound I. In a particular embodiment, it is the crystalline form of Compound I dihydrochloride.

The amount of Compound I or a pharmaceutically acceptable salt thereof can be determined depending on the severity of the disease, the response of the disease, any treatment-related toxicity, the age of the patient, and the state of health. In some embodiments, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from 3 mg to 30 mg. In some embodiments, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from 5 mg to 20 mg. In some embodiments, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from 8 mg to 16 mg. In some embodiments, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from 10 mg to 14 mg.

In a further aspect, the present application provides a Compound I or a pharmaceutical composition for treating non-small cell lung cancer that is not suitable for EGFR-TKI treatment, wherein the pharmaceutical composition comprises Compound 1, or a pharmaceutically acceptable salt thereof, and at least A pharmaceutically acceptable carrier.

In some embodiments of the present application, there is provided a Compound I or pharmaceutical composition for treating advanced non-small cell lung cancer and/or metastatic non-small cell lung cancer that is not suitable for 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 can be determined depending on the severity of the disease, the response of the disease, any treatment-related toxicity, the age of the patient, and the state of health. In some embodiments, the above pharmaceutical compositions contain from 3 mg to 30 mg of Compound 1, or a pharmaceutically acceptable salt thereof, on a unit dosage basis. In some embodiments, the above pharmaceutical compositions contain 5 mg to 20 mg of Compound 1, or a pharmaceutically acceptable salt thereof, on a unit dosage basis. In some embodiments, the above pharmaceutical compositions contain from 8 mg to 16 mg of Compound 1, or a pharmaceutically acceptable salt thereof, on a unit dosage basis. In some embodiments, the above pharmaceutical compositions contain 10 mg to 14 mg of Compound 1, or a pharmaceutically acceptable salt thereof, on a unit dosage basis. In the present application, for example, for a tablet or a capsule, "containing 12 mg of Compound I on a unit dose basis" means that 12 mg of Compound I is contained per tablet or capsule per capsule.

In some particular embodiments, wherein the pharmaceutical composition contains 8, 10 or 12 mg of Compound 1, or a pharmaceutically acceptable salt thereof, on a unit dosage basis.

In some embodiments, Compound I is formulated for oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, inhalation, vaginal, ocular Formulations for internal, topical, subcutaneous, intra-, intra-articular, intraperitoneal, and intrathecal administration; preferably suitable for oral administration, including tablets, capsules, powders, granules, pills, pastes, Powders and the like, preferably tablets and capsules. The tablet may be a common tablet, a dispersible tablet, an effervescent tablet, a sustained release tablet, a controlled release tablet or an enteric coated tablet, and the capsule may be a general capsule, a sustained release capsule, a controlled release capsule or an enteric coated capsule. The oral preparations can be prepared by conventional methods using pharmaceutically acceptable carriers well known in the art. Pharmaceutically acceptable carriers include fillers, absorbents, wetting agents, binders, disintegrants, lubricants, and the like. Filling agents include starch, lactose, mannitol, microcrystalline cellulose, etc.; absorbents include calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; wetting agents include water, ethanol, etc.; binders include hypromellose, poly Retardone, microcrystalline cellulose, etc.; disintegrants include croscarmellose sodium, crospovidone, surfactant, low-substituted hydroxypropyl cellulose, etc.; lubricants include magnesium stearate, talc Powder, polyethylene glycol, Sodium lauryl sulfate, micronized silica gel, talc, and the like. Pharmaceutical excipients also include coloring agents, sweeteners, and the like.

The pharmaceutical composition may be suitable for oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, inhalation, vaginal, intraocular, meridian Formulations for topical administration, subcutaneous, intra-, intra-articular, intraperitoneal and intrathecal administration; preferably suitable for oral administration, including tablets, capsules, powders, granules, dropping pills, pastes, powders, etc. Preference is given to tablets and capsules. The tablet may be a common tablet, a dispersible tablet, an effervescent tablet, a sustained release tablet, a controlled release tablet or an enteric coated tablet, and the capsule may be a general capsule, a sustained release capsule, a controlled release capsule or an enteric coated capsule. The oral preparations can be prepared by conventional methods using pharmaceutically acceptable carriers well known in the art. Pharmaceutically acceptable carriers include fillers, absorbents, wetting agents, binders, disintegrants, lubricants, and the like. Filling agents include starch, lactose, mannitol, microcrystalline cellulose, etc.; absorbents include calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; wetting agents include water, ethanol, etc.; binders include hypromellose, poly Retardone, microcrystalline cellulose, etc.; disintegrants include croscarmellose sodium, crospovidone, surfactant, low-substituted hydroxypropyl cellulose, etc.; lubricants include magnesium stearate, talc Powder, polyethylene glycol, sodium lauryl sulfate, micronized silica gel, talcum powder, and the like. Pharmaceutical excipients also include coloring agents, sweeteners, and the like.

Preferably, Compound I or the above pharmaceutical composition is administered in a separate manner. The interval administration includes a administration period and a withdrawal period, and the compound I or the above pharmaceutical composition may be administered one or more times a day during the administration period. For example, Compound I or the above-mentioned pharmaceutical composition is administered daily during the administration period, and then the administration is stopped for a certain period of time during the withdrawal period, followed by the administration period, and then the withdrawal period, which can be repeated a plurality of times. The ratio of the administration period to the withdrawal period in days is 2:0.5 to 5, preferably 2:0.5 to 3, more preferably 2:0.5 to 2, still more preferably 2:0.5 to 1.

In some embodiments, the continuous administration is discontinued for 2 weeks for 2 weeks. In some embodiments, administration once a day for 14 days, followed by 14 days of withdrawal; followed by 1 administration per day for 14 days, followed by 14 days of discontinuation, such continuous administration for 2 weeks The two-week interval administration method can be repeated a plurality of times.

In some embodiments, Compound I or the above pharmaceutical composition can be administered one or more times a day. In some embodiments, Compound I or a pharmaceutical composition described above is administered once a day. In one embodiment, the oral solid preparation is administered once a day.

It will be understood by those skilled in the art that the EGFR-TKI described herein is an epidermal growth factor receptor tyrosine kinase inhibitor, and examples thereof include, but are not limited to, gefitinib (Iressa), Ero Tinie (Troquet), Ektorini (Kemena).

As used herein, "late" refers to the staging of non-small cell lung cancer based on the extent of the lesion and concurrent disease, such as stage III-IV non-small cell lung cancer according to the TNM classification of the AJCC cancer staging manual lung cancer staging system. In some embodiments, the advanced non-small cell lung cancer is a stage IIIB-IV non-small cell lung cancer.

As used herein, "EGFR" refers to the epidermal growth factor receptor.

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

Herein, the dosages and ranges provided herein are calculated based on the molecular weight of the free form of Compound I, unless otherwise indicated.

Herein, the amount of Compound I administered can be determined based on the severity of the disease, the response to the disease, any treatment-related toxicity, the age of the patient, and the state of health. The period of administration can be comprehensively determined based on the activity, toxicity, and tolerance of the patient.

In this article, non-small cell lung cancer not treated with EGFR-TKI includes: non-small cell lung cancer treated with EGFR-TKI first, such as non-small cell lung cancer with negative EGFR mutation; and resistance or intolerance to EGFR-TKI Non-small cell lung cancer, after treatment with EGFR-TKI, benefits from initial treatment, and continues to use non-small cell lung cancer with progression of the disease or non-small cell lung cancer in patients with toxic side effects that are unlikely to be tolerated. Non-small cell lung cancer that is not suitable for EGFR-TKI treatment includes non-small cell lung cancer that is not sensitive to EGFR-TKI, that is, non-small cell lung cancer that does not benefit from treatment with EGFR-TKI and whose disease is still progressing. Here, "benefit" means that the disease has no progress.

Unless otherwise stated, the following terms used in the specification and claims shall have the following meanings for the purposes of the present application.

"Patient" means a mammal, preferably a human.

"Pharmaceutically acceptable" means that it is used in the preparation of a pharmaceutical composition which is generally safe, non-toxic and neither biologically or otherwise undesirable, and which includes its use for human pharmaceutical use. Accepted.

"Pharmaceutically acceptable salt" includes, but is not limited to, acid addition salts 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 acid, trifluoroacetic acid, propionic acid , hexanoic acid, heptanoic acid, cyclopentane propionic acid, B Alkyd, 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, t-butyl acetic acid, dodecyl An acid addition salt formed by sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid or the like.

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

"Treatment" means any administration of a therapeutically effective amount of a compound and includes:

(1) inhibiting the disease in a human being that is experiencing or exhibiting the pathology or symptomology of the disease (ie, preventing further progression of the pathology and/or symptomology), or

(2) improving the disease in a human being (or reversing the pathology and/or symptomology) that is undergoing or exhibiting the pathology or symptomology of the disease.

In this paper, progression-free survival P50 refers to the time when no disease progresses in 50% of patients participating in the statistics; progression-free survival P75 refers to the time when no disease progresses in 25% of the patients participating in the statistics; Mean survival progression mean the mean value of progression-free survival in patients who participated in the outcome statistics.

Specific embodiment

The technical solutions of the present application are described in the following specific embodiments, but the scope of protection of the present application is not limited to the scope of the embodiments described.

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

1-[[[4-(4-Fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl) was prepared according to the method of Example 24 in WO2008112407 The oxy]methyl]cyclopropylamine is then prepared according to the preparation of the examples in the salt form of the specification to give the title compound.

Example 21-[[[4-(4-Fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl] ring Preparation of capsules of propylamine dihydrochloride (dihydrochloride salt of compound I)

The dihydrochloride salt of Compound I is pulverized and passed through a 80 mesh sieve; then uniformly mixed with mannitol and hydroxypropylcellulose; then a prescribed amount of microcrystalline cellulose is added, uniformly mixed, and passed through a 0.8 mm sieve; The magnesium stearate is mixed evenly and filled with capsules.

Example 3

Randomized, in patients with measurable lesions diagnosed as advanced non-small cell lung cancer, treated with second-line or higher or intolerant treatment, and receiving other cytotoxic drugs, radiation therapy, or surgery for more than four weeks. A double-blind, placebo-controlled, multicenter, phase II clinical trial study. In this study, the efficacy of Compound II dihydrochloride capsules in the treatment of advanced non-small cell lung cancer was initially evaluated in comparison with placebo. The primary indicator of evaluation was disease progression-free survival (PFS). A total of 117 patients were enrolled in the study, of whom 57 were randomized to placebo and randomized to 60 patients in the hydrochloride group, aged 18-70 years.

The above eligible non-small cell lung cancer patients received a compound I dihydrochloride/placebo for clinical trials. According to the dose of 12mg/0mg once a day, the continuous medication for 2 weeks, 1 week, that is, 3 weeks (21 days) is a cycle program; until the researchers believe that the patient is not suitable for continued medication or efficacy evaluation for disease progression (PD) When the medication is over.

RESULTS: A total of 117 patients with non-small cell lung cancer were enrolled. Of these, 57 were randomized to placebo, 60 were randomized to the compound I dihydrochloride group, and 43 were in the placebo group. There were 32 cases in the compound I dihydrochloride group. The rest of the cases were still in the interview because they were detached or rejected during the test or the subjects were not out of the group, and were not included in the statistics. During the study, for non-small cell lung cancer that was not treated with EGFR-TKI, stratified analysis was performed according to whether the previous EGFR-TKI benefited. The benefit here is that the disease has no progress. The statistical results are shown in the following table:

Based on the above results, the dihydrochloride salt of Compound I can significantly prolong the progression-free survival of patients with non-small cell lung cancer who are not treated with EGFR-TKI.

Example 4

A) medical history

A 41-year-old woman was admitted to the hospital in February 2012 for “cough for one week”. She underwent chest CT to show right lung mass, and on February 24, she underwent right lower lobe resection. Postoperative pathology: right lower lobe dorsal segment and basal segment Invasive mucinous adenocarcinoma, moderately differentiated. Postoperative chest X-ray on March 17, 2013 showed postoperative changes. From March 28 to July 6, 2012, NP (vinorelbine and cisplatin) regimen was used for 4 cycles of chemotherapy. In September 2012, due to chest pain and discomfort, a review of chest CT revealed multiple small nodules in both lungs. After 11 days of treatment with cefotiam, the increase of small nodules in both lungs was observed. November 6, 2012, December 8, 2012 Chemotherapy was performed twice with A (pemetrex) regimen; disease progression was performed on January 23, 2013 using GP (gemcitabine and cisplatin); D (docetaxel) was used from March 2013 to April 2013 The regimen of chemotherapy one cycle, the efficacy of PD (disease progression); June 1st - July 31st, 2013, given Kemena (Ektorinib hydrochloride) treatment, the efficacy of PD (disease progression). Two cycles of chemotherapy using IE (ifosfamide + etoposide) regimen from August 12 to September 30, 2013, the effect is unknown. No history of radiotherapy, accompanied by fatty liver, left kidney and kidney milk sign.

On November 21, 2013, a dose of Compound I dihydrochloride capsule was administered orally once a day at a dose of 12 mg (continuous with 2 weeks for 1 week).

B) CT results

In the CT scan before administration of Compound I dihydrochloride, the sum of the diameters of the two large measurable lesions was 71.51 mm (there was a cavity in the right upper lung lesion, 33.34 mm in diameter, and 38.17 mm in the right lower lung lesion). In the subsequent CT scan of Compound I dihydrochloride treatment, the sum of the diameters of the first cycle (2013-12-11) after treatment with Compound I dihydrochloride was reduced to 68.65 mm (the right upper lung cavity was changed). Large, thin wall; void in the right lower lung solid lesion); the sum of the diameters of the second cycle (2014-1-1) is 70.29 mm (the upper lung cavity continues to enlarge, the wall becomes thinner; the right lower lung cavity becomes larger) ), the fourth cycle (2014-2-12) the sum of the diameters is 74.2mm (the cavity continues to increase) to the sixteenth cycle. CT examination suggests that the cavity present in the right upper lobe during the screening continues to increase during the treatment, the wall Thinning; the solid lesion in the right lower lobe appeared in the first cycle after the cavity, after which the cavity continued to increase; non-target lesions did not progress, and no new lesions appeared. As of December 4, 2014, the patient had received Compound I dihydrochloride for one year and one month, and still took Compound I dihydrochloride capsules during the nineteenth treatment cycle. The tumor continued to respond and the clinical performance was better. it is good.

C) Tolerance

Treatment with Compound I dihydrochloride was generally well tolerated. There was no significant change in blood routine, and no drug-related cardiotoxicity was observed during treatment.

Example 5

A) medical history

A 66-year-old retired woman with no history of smoking and a uterine myomectomy in 1990. In 2007, lymph node dissection was performed in the outpatient department, and the pathological suggestion (right-locked) lymph node metastatic carcinoma was poorly differentiated adenocarcinoma. Combined with imaging findings, clinical diagnosis: right upper lobe adenocarcinoma, bilateral lung metastasis, mediastinal lymph node metastasis, right supraclavicular lymph node metastasis (T4N3M1, stage IV), no other history of disease. From January 4, 2008 to March 13, 2008, he received 4 cycles of NP (vinorelbine + cisplatin) + Endo regimen chemotherapy, the best efficacy PR (partial remission), May 19, 2008 to 2008 On June 17th, the Ener + Ai Su regime was used. In July 2008, the treatment with Endo single drug was started. On July 28, 2008, the chest CT was reviewed, suggesting that the infiltration of the right upper lobe tumor was more than before. Progress, starting on August 5, 2008, gemcitabine + cisplatin regimen, best efficacy SD (stable disease), started taking Iressa (gefitinib) treatment in September 2008, reexamination of CT showed right upper lobe mass Compared with the previous reduction, the right pleural effusion disappeared. On March 3, 2009, after two cycles of pemetrexed + cisplatin + Endo, oral Iressa (gefitinib) was continued. In July 2009, CT showed double lung nodules, September 2009. On the 21st, Pemetrexed + Cisplatin 3 cycles, on March 6, 2010, oral erlotinib for 3 months, the efficacy of PD (disease progression). In July 2010, Pemetrexed + Oxaliplatin 3 cycles, on January 19, 2011, oral apafitini mesylate, PD progression; continued pemetrexed + oxaliplatin, disease progression after 16 cycles On April 1, 2013, the disease progressed after 2 cycles of Theliatinib. After oral administration of gefitinib in July 2013, CT showed a double nodular nodule and enlarged mass in December 2013. . The tumor marker CEA test results were abnormal, 7.25 ng / mL.

On December 18, 2013, a dose of Compound I dihydrochloride capsule was administered once daily at a dose of 12 mg (continuous administration for 2 weeks for 1 week).

B) CT results

There is a considerable reduction in the sum of the long-term diameters of tumor target lesions in patients treated with Compound I dihydrochloride. In the CT scan of the day before taking Compound I dihydrochloride, the sum of the diameters of the two large measurable target lesions was 142 mm (72 mm in the anterior segment of the right upper lobe and 70 mm in the right lung lesion). In the subsequent CT scan of Compound I dihydrochloride treatment, the sum of the target lesion diameters decreased to 108 mm and decreased by 23.9% (the right upper lobe) at 3 weeks after treatment with Compound I dihydrochloride. The lesion in the anterior segment was 48 mm, and the lesion in the right lung was 60 mm. When the drug was administered for 14 days, the dose was reduced to 10 mg. The 6-week CT results showed that the sum of the diameters of the two large measurable target lesions was 114 mm, which was decreased by 21.1% (52 mm in the anterior segment of the right upper lobe). The right lung lesion was 62 mm, and the imaging showed a cavity in the tumor. As of December 4, 2014, the patient had received Compound I dihydrochloride for 351 days, and still took Compound I dihydrochloride at the 16th treatment cycle. The tumor continues to respond and the clinical performance is still good.

C) Tolerance

Treatment with Compound I dihydrochloride was generally well tolerated and no drug-related cardiotoxicity was observed during treatment.

Example 6

A 62-year-old female patient with left lung cancer, bilateral lung metastases, double hilar and mediastinum, right supraclavicular lymph node metastasis, and ECT suggesting bone metastases, and cranial MRI suggesting left frontal metastases on June 2, 2014 . CT-guided pulmonary puncture was confirmed as non-small cell lung cancer adenocarcinoma. The gene detection EML4-ALK fusion gene was not mutated, and the EGFR gene was not mutated.

From June 9th, 2014 to September 25th, 2014, cisplatin and pemetrexed chemotherapy were given for 6 cycles. The best effect was PR. There was a second degree gastrointestinal reaction and no bone marrow suppression. Oral Tiggio capsules were taken orally for 2 weeks from October 17, 2014 to November 1, 2014. The cough was relieved and mild chest tightness was observed. On January 27, 2015, the disease was found to be inspected. From January 31, 2015 to June 21, 2015, Ecetinib plus docetaxel chemotherapy was given for 6 cycles. The best effect was SD. On July 8, 2015, he participated in the clinical study of Compound I Dihydrochloride Capsules, and started the oral administration of 12 mg (continuous administration for 2 weeks for 1 week for one treatment cycle) at a dose of Compound I dihydrochloride capsule. treatment.

On July 29, 2015, the patient received treatment for 1 cycle. Enhanced CT showed left upper lobe cancer with obstructive inflammation, bilateral lung metastasis, interlobular septal thickening in the lower lung, left hilar and mediastinal lymph node metastasis, right The supraclavicular lymph nodes were enlarged, and the bilateral pleural metastases were considered. Some of them were better, and some of them were not significant. The best effect was evaluated by RECIST1.1.

On August 20, 2015, the patient's head enhanced CT showed that the left temporal lobe nodule was slightly smaller than the baseline.

On November 12, 2015, enhanced CT showed that the condition was continuously controlled, and the confirmed effect was still PR. As of the filing date, the patient's adverse reactions were basically tolerable and continued to receive treatment.

Example 7

A 62-year-old man was diagnosed with non-small cell lung cancer squamous cell carcinoma by CT-guided lung puncture in March 2013. Cranial MRI suggested left frontal lobe metastasis. The gene detection EML4-ALK fusion gene has no mutation, and the EGFR gene has no mutation.

Cisplatin and gemcitabine were given from March 26, 2013 to June 5, 2013. The best effect was SD for 4 cycles of chemotherapy. After the above chemotherapy, the local radiotherapy was performed for one cycle, and the adverse reactions were mild. Two cycles of chemotherapy with cisplatin and gemcitabine were given from September 9, 2013 to October 6, 2013. The CT was reviewed in December 2013, suggesting that the disease progressed. On March 24, 2014, a dose of docetaxel chemotherapy was given. After chemotherapy, bone marrow suppression, oral infection, and pneumonia occurred, and the symptomatic treatment improved. On December 10, 2014, the CT examination revealed: 1. The soft tissue shadow of the right upper hilar was increased earlier; 2. The multiple lungs of the lungs were less changed than before; 3. The inflammation of the lungs was narrower than before; Lymph nodes on the left clavicle, mediastinum, and right hilar, slightly larger than before. Gemcitabine and nedaplatin (NDP) were given from January 7, 2015 to January 29, 2015. After the chemotherapy, there was a third degree of myelosuppression, which was restored after whitening. On March 4, 2015, a CT scan showed that the right lung mass increased earlier. Oral treatment with oral dioxin on March 6, 2015. On May 27, 2015, the CT review progressed. Pathological diagnosis tips on June 2, 2015: right After chemoradiotherapy for lung squamous cell carcinoma, (right lung) poorly differentiated cancer.

On June 4, 2015, a capsule of 12 mg of Compound I dihydrochloride was orally administered once a day (continuous administration for 1 week for 1 week for one treatment cycle). On June 25, 2015, the patient received treatment for 1 cycle, and enhanced CT showed a soft tissue density tumor of the right hilar, which was slightly smaller than the previous one; the left clavicle, mediastinum, and right hilar multiple lymph nodes; lung inflammation, the range was changed before Large, double lung multiple lung vesicles, less change than before; according to RECIST1.1 evaluation of SD (small), the total target lesion is 66mm, 10mm smaller than the baseline.

On July 15, 2015, the patient's enhanced CT showed a soft tissue density tumor of the right hilar, which was slightly smaller than before. The total target lesion was 63mm; on September 8, 2015, enhanced CT showed that the lesion was further reduced, and the total target lesion was 57mm. On October 16, 2015, enhanced CT showed that the lesion was reduced, which was not changed much before, and the total target lesion was 56mm. The patient's adverse reactions are basically tolerable and continue to be treated.

Claims

A method of treating EGFR-TKI-treated non-small cell lung cancer, the method comprising administering to a patient in need of treatment a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, having the formula
The method of claim 1, wherein the non-small cell lung cancer that is not EGFR-TKI-treated is advanced non-small cell lung cancer and/or metastatic non-small cell lung cancer.
The method according to any one of claims 1 to 2, wherein the compound I or a pharmaceutically acceptable salt thereof is the hydrochloride salt of the compound I, preferably the monohydrochloride or dihydrochloride salt of the compound I. .
The method according to any one of claims 1 to 3, wherein the daily dose of the compound I or a pharmaceutically acceptable salt thereof is from 3 mg to 30 mg, preferably from 5 mg to 20 mg, more preferably It is 8 mg to 16 mg, further preferably 10 mg to 14 mg, and most preferably 8 mg, 10 mg or 12 mg.
The method according to any one of claims 1 to 4, wherein the compound I or a pharmaceutically acceptable salt thereof is administered in a divided manner, preferably in a ratio of days of administration to withdrawal period of 2 0.5 to 5, preferably 2: 0.5 to 3, more preferably 2: 0.5 to 2, still more preferably 2: 0.5 to 1.
The method according to any one of claims 1 to 5, wherein the compound I or a pharmaceutically acceptable salt thereof is continuously administered for 2 weeks for 2 weeks, or continuously for 2 weeks for 1 week. Or discontinuous administration for 5 days for 2 days.
The method according to any one of claims 1 to 6, wherein the treatment is continued for 2 weeks and stopped for 1 week every 3 weeks for one treatment cycle.
The method according to any one of claims 1 to 7, wherein the administration route of the compound I or a pharmaceutically acceptable salt thereof comprises oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal , sublingual, intramuscular, rectal, buccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intra-, intra-articular, intraperitoneal, and intrathecal, preferably oral.
The method according to any one of claims 1 to 8, wherein the compound I or a pharmaceutically acceptable salt thereof is administered one or more times a day, preferably once a day, more preferably as an oral solid preparation per day. Dosing once.
The method according to any one of claims 1 to 9, wherein the compound I or a pharmaceutically acceptable salt thereof is The dose of 12 mg once a day was orally administered, and the administration was continued for 2 weeks, and the administration was stopped for 1 week.
Use of Compound I or a pharmaceutically acceptable salt thereof having the following structural formula for the preparation of a medicament for the treatment of non-small cell lung cancer which is not suitable for EGFR-TKI treatment,
The use according to claim 11, wherein the non-small cell lung cancer which is not suitable for EGFR-TKI treatment is advanced non-small cell lung cancer and/or metastatic non-small cell lung cancer.
The use according to any one of claims 11 to 12, wherein the compound I or a pharmaceutically acceptable salt thereof is the hydrochloride salt of the compound I, preferably the monohydrochloride or dihydrochloride salt of the compound I. .
A compound I or a pharmaceutical composition having the following structural formula which is not suitable for EGFR-TKI-treated non-small cell lung cancer, wherein the pharmaceutical composition comprises Compound 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable Carrier,
The compound I or the pharmaceutical composition according to claim 14, wherein the non-small cell lung cancer which is not suitable for EGFR-TKI treatment is advanced non-small cell lung cancer and/or metastatic non-small cell lung cancer.
The compound I or the pharmaceutical composition according to any one of claims 14 to 15, wherein the compound I or a pharmaceutically acceptable salt thereof is the hydrochloride salt of the compound I, preferably the monohydrochloride salt of the compound I. Or dihydrochloride.
The compound I or the pharmaceutical composition according to any one of claims 14 to 16, wherein the pharmaceutical composition contains 3 mg to 30 mg of the compound I or a pharmaceutically acceptable salt thereof on a unit dosage basis, preferably 5 mg to 20 mg, more preferably 8 mg to 16 mg, further preferably 10 mg to 14 mg, most preferably 8 mg, 10 mg or 12 mg.
The compound I or the pharmaceutical composition according to any one of claims 14-17, wherein the compound I is formulated for oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, muscular Internal, rectal, buccal, intranasal, menstrual Formulation for inhalation, vaginal, intraocular, topical administration, subcutaneous, intra-, intra-articular, intraperitoneal, and intrathecal administration, preferably a preparation suitable for oral administration; or the pharmaceutical composition is suitable for oral administration, parenteral administration , intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, by inhalation, vaginal, intraocular, topical, subcutaneous, intrahepatic, intra-articular, intraperitoneal And a formulation for intrathecal administration; preferably a formulation suitable for oral administration.
The compound I or the pharmaceutical composition according to claim 18, wherein the preparation is a tablet, a capsule, a powder, a granule, a dropping pill, a paste or a powder, preferably a tablet and a capsule.
The compound I or the pharmaceutical composition according to any one of claims 14 to 19, wherein the compound I or the pharmaceutical composition is administered in a divided manner, and the ratio of the administration period and the withdrawal period in days is 2: 0.5 to 5, preferably 2: 0.5 to 3, more preferably 2: 0.5 to 2, still more preferably 2: 0.5 to 1.
The compound I or the pharmaceutical composition according to any one of claims 14 to 20, wherein the compound I or the pharmaceutical composition is administered continuously for 2 weeks for 2 weeks, or continuously for 2 weeks for 1 week. , or continuous administration for 5 days to stop the drug for 2 days.
The compound I or the pharmaceutical composition according to any one of claims 14 to 21, wherein the compound I or the pharmaceutical composition is administered one or more times a day, preferably once a day, more preferably as an oral solid preparation. Dosing once a day.
The compound I or the pharmaceutical composition according to any one of claims 14 to 22, wherein the compound I or the pharmaceutical composition is orally administered at a dose of 12 mg once a day for 2 weeks, and is stopped for 1 week. Drug administration.