WO2016091167A1

WO2016091167A1 - Quinoline derivative against squamous cell carcinoma of lung

Info

Publication number: WO2016091167A1
Application number: PCT/CN2015/096776
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: CN106999485A; CN106999485B

Abstract

Provided in the present application is a quinoline derivative against squamous cell carcinoma of the lung. 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 squamous cell carcinoma of the lung, and with respect to placebos, can significantly prolong the progression-free survival of a patient with squamous cell carcinoma of the lung.

Description

Quinoline derivative against lung squamous cell carcinoma

Cross-reference to related applications

Priority is claimed on Japanese Patent Application No. 201410748467.4, filed on Jan. 09,,,,,,,,,,,,

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 lung squamous cell carcinoma.

Background technique

Cancer is a major public health problem in many parts of the world. Non-small cell lung cancer is one of the most common causes of cancer death, and the incidence is also high. For non-small cell lung cancer (NSCLC), although platinum-containing chemotherapy can improve patient survival, the prognosis of advanced non-small cell lung cancer remains extremely poor, with a 5-year survival rate of less than 10%. It has been reported that increasing the survival rate requires further studies on the tumorigenesis and chemical resistance machinery of lung cancer (Jemal A et al, Cancer Statistics, CA Cancer. J. Clin., 56, 106-130, 2006). The main histological types of NSCLC include adenocarcinoma (AC), squamous cell carcinoma (SCC), and large cell carcinoma. Based on cell morphology, adenocarcinoma and squamous cell carcinoma are the most common histological types of NSCLC. Compared with lung adenocarcinoma, the targeted treatment of lung squamous cell carcinoma has progressed significantly. Targeted drugs for clinical efficacy of lung adenocarcinoma, such as: epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), echinoderma microtubule-associated protein-4 (echinodern microtubule-associated protein-like 4, EML4)-anaplastic lymphoma kinase (ALK) fusion gene inhibitors, etc., have poor efficacy in lung squamous cell carcinoma (Yuan Hong et al, lung squamous cell carcinoma targeted therapy research Current Situation, Chinese Journal of Lung Cancer, 2013, Issue 10).

The 2014 NCCN guidelines recommend platinum or cisplatin/vinorelbine plus cetuximab as first-line treatment options for lung squamous cell carcinoma. The cisplatin/gemcitabine regimen is superior to the cisplatin/pemetrexed regimen. Because lung squamous cell carcinoma has a very wide and complex genomic changes, there is no clear driver gene and targeted therapeutic drugs. Three-generation platinum-containing dual-agent chemotherapy is still the standard treatment for advanced lung squamous cell carcinoma. Therefore, the development of effective drugs to treat lung squamous cell carcinoma is the key and hot spot of current research.

Summary of invention

In one aspect, the application provides a method of treating lung squamous cell carcinoma, 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 structural formula below.

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 lung squamous cell carcinoma.

In a further aspect, the application provides a compound I or a pharmaceutical composition having the above formula, wherein the pharmaceutical composition comprises Compound 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable Carrier.

Detailed description of the invention

In some embodiments of the present application, a method of treating advanced lung squamous cell carcinoma and/or metastatic lung squamous cell carcinoma, the method comprising administering to a patient in need of treatment a therapeutically effective amount of Compound I or a pharmaceutically acceptable compound thereof Salt.

In some embodiments of the present application, a method of treating EGFR mutated negative lung squamous cell carcinoma, the method comprising administering to a patient in need of treatment a therapeutically effective amount of Compound 1, 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 In the case of the crystal form of the 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 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, 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, 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 another aspect, the present application also provides the use of Compound 1, or a pharmaceutically acceptable salt thereof, of the formula: for the manufacture of a medicament for the treatment of lung squamous cell carcinoma.

In some embodiments of the present application, there is provided the use of Compound 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of advanced lung squamous cell carcinoma and/or metastatic lung squamous cell carcinoma.

In some embodiments of the present application, there is provided the use of Compound 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of EGFR mutation-negative lung squamous cell carcinoma.

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, Compound 1, or a pharmaceutically acceptable thereof, is administered The daily dose of the salt received 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 having the following structural formula for treating lung squamous cell carcinoma, wherein the pharmaceutical composition comprises Compound 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable Acceptable carrier.

In some embodiments of the present application, there is provided a Compound I or a pharmaceutical composition for treating advanced lung squamous cell carcinoma and/or metastatic lung squamous cell carcinoma, wherein the pharmaceutical composition comprises Compound 1, or a pharmaceutically acceptable thereof a salt, and at least one pharmaceutically acceptable carrier.

In some embodiments of the present application, there is provided a Compound I or a pharmaceutical composition for treating EGFR mutation-negative lung squamous cell carcinoma, wherein the pharmaceutical composition comprises Compound 1, or a pharmaceutically acceptable salt thereof, and at least one A 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 on a unit dosage basis. Compound I or a pharmaceutically acceptable salt thereof. 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, talcum powder, 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. Wherein, the ratio of the number of days in the administration period and the withdrawal period is 2: 0.5 to 5, It is preferably 2: 0.5 to 3, more preferably 2: 0.5 to 2, still more preferably 2: 0.5 to 1.

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.

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.

As used herein, "late" refers to the staging of lung squamous cell carcinoma according to the extent of the lesion and concurrent disease, such as stage III-IV lung squamous cell carcinoma according to the TNM classification in the AJCC cancer staging manual lung cancer staging system, in some In an embodiment, the advanced lung squamous cell carcinoma is a stage IIIB-IV lung squamous cell carcinoma.

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.

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 , caproic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, Mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, p-toluenesulfonic acid, 3-phenylpropionic acid, three An acid addition salt formed by methyl acetic acid, t-butyl acetic acid, dodecyl 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 disease progression occurs in 50% of patients participating in the statistics; mean progression-free survival refers to the mean value of progression-free survival of patients participating 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 1 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) 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 2 contains 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl a capsule of cyclopropylamine 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, double-blind, in patients with measurable lesions diagnosed with lung squamous cell carcinoma, treated with second-line or higher or intolerant treatment, and receiving other cytotoxic drugs, radiation therapy, or surgery for more than four weeks , placebo parallel control clinical trial study. In this study, the efficacy of Compound I dihydrochloride capsules in the treatment of patients with lung squamous cell carcinoma was initially evaluated in comparison with placebo. The primary indicator of evaluation was disease progression-free survival (PFS). Thirteen patients with squamous cell carcinoma were enrolled in the study. Seven patients were randomized to receive a placebo group. Six patients were randomized to receive the dihydrochloride group of Compound I. These patients ranged in age from 18 to 70 years.

Patients with eligible lung squamous cell carcinoma above received clinical trials with Compound I dihydrochloride/placebo. According to the dose of 12mg/0mg once a day, the drug was stopped for 2 weeks, that is, 3 weeks (21 days) as a one-cycle program; until the researchers believe that the patient is not suitable for continued medication or the efficacy is evaluated as disease progression (PD) When the medication is over.

RESULTS: A total of 13 patients with squamous cell carcinoma were enrolled, 7 of whom were randomized to placebo, 6 were randomized to the compound I dihydrochloride group, and 6 were in the placebo group. There were 2 cases in the 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. The results showed that the progression-free survival P50 of the placebo group was 1.10 months, with a mean of 1.73 months. The progression-free survival P50 of the compound I dihydrochloride group was 7.80 months, with a mean of 6.53 months. Based on the above results, Compound I dihydrochloride can significantly prolong the progression-free survival of patients with squamous cell carcinoma.

Example 4

A) medical history

A 51-year-old male smoked for 32 years (70 pigs/day). On August 17, 2012, the pathological biopsy results in non-small cell lung cancer and squamous differentiation. Combined with imaging findings, clinical diagnosis: bronchogenic carcinoma, primary, central, left upper lobe, squamous, poorly differentiated, with hilar, mediastinal lymph node metastasis (C-T4N3M0, IIB). Combined with hepatitis B and small three-yang disease. On August 29, 2012, I received a cycle of NIP (Vin ribin + Isocyclic Phosphonamide + Cisplatin). The effect was stable. I took TC (Paclitaxel + Card) from September 1, 2013 to April 1, 2013. The platinum regimen continued the four cycles of chemotherapy, and the best effect was PR (partial remission). During the period from May 1, 2013 to July 1, 2013, GP (Gemcitabine + Cisplatin) regimen was given for 2 cycles, and the effect was stable. From August 1st, 2013 to September 1st, 2013, D (Docetaxel) regimen was given 2 cycles of chemotherapy, and the effect was stable. Radiation therapy was performed on the left upper lobe mass and mediastinum from December 10, 2012 to January 3, 2013. Radiotherapy was performed again on the left upper lobe mass from January 7, 2013 to January 19, 2013. From January 7th to January 21st, 2013, radiotherapy was performed on the left supraclavicular region. The specific effect is unknown. On September 23, 2013, in the imaging CT, the left upper lobe mass was found to have a long diameter of 90 mm, and the mediastinum and multiple hilar lymph nodes were enlarged. Compound I dihydrochloride capsules were administered once daily at a dose of 12 mg (continuously with 1 week for 1 week for one treatment cycle) starting on September 28, 2013.

B) CT results

After treatment with Compound I dihydrochloride, the long diameter of the left upper lobe lesion was slightly reduced at the end of the second cycle, with a value of 86 mm. The disease persisted for 10 cycles and the tumor response was good. At the 10th cycle, the lesion of the left upper lobe was reduced, the longest diameter was 81 mm, and the lesion showed obvious cavity necrosis.

C) Tolerance

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

Example 5

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. On June 2, 2015, pathological diagnosis revealed: right lung squamous cell carcinoma after radiotherapy and chemotherapy, (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 66, 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 lung squamous cell carcinoma, 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 said lung squamous cell carcinoma is advanced lung squamous cell carcinoma and/or metastatic lung squamous cell carcinoma.
The method of claim 1 wherein said lung squamous cell carcinoma is EGFR mutated negative lung squamous cell carcinoma.
The method according to any one of claims 1 to 3, 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 4, wherein the ratio of the compound I or a pharmaceutically acceptable salt thereof, preferably between the administration period and the withdrawal period, in days, is administered in a divided manner. 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 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 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 orally administered at a dose of 12 mg once a day for 2 weeks, and is administered for 1 week. Mode of administration.
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 lung squamous cell carcinoma,
The use according to claim 11, wherein the lung squamous cell carcinoma is advanced lung squamous cell carcinoma and/or metastatic lung squamous cell carcinoma.
The use according to claim 11, wherein the lung squamous cell carcinoma is squamous cell carcinoma of the EGFR mutation negative.
The use according to any one of claims 11 to 13, 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 for treating lung squamous cell carcinoma, 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 15, wherein the lung squamous cell carcinoma is EGFR mutated negative lung squamous cell carcinoma.
The compound I or the pharmaceutical composition according to claim 15, wherein the lung squamous cell carcinoma is advanced lung squamous cell carcinoma and/or metastatic lung squamous cell carcinoma.
The compound I or the pharmaceutical composition according to any one of claims 15 to 17, wherein the compound I or a pharmaceutically acceptable salt thereof is the hydrochloride salt of the compound I.
The compound I or the pharmaceutical composition according to claim 18, wherein the compound I or a pharmaceutically acceptable salt thereof is the dihydrochloride salt of the compound I.
The compound I or the pharmaceutical composition according to any one of claims 15 to 19, 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 It is 5 mg to 20 mg, more preferably 8 mg to 16 mg, further preferably 10 mg to 14 mg, and most preferably 8 mg, 10 mg or 12 mg.
The compound I or the pharmaceutical composition according to any one of claims 15 to 20, wherein the compound I is formulated as Suitable for oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, by inhalation, vaginal, intraocular, topical, subcutaneous, fat a formulation for intra-articular, intraperitoneal, and intrathecal administration, preferably a formulation suitable for oral administration; or the pharmaceutical composition is suitable for oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, Formulations for intramuscular, rectal, buccal, intranasal, by inhalation, vaginal, intraocular, topical, subcutaneous, intra-, intra-articular, intraperitoneal, and intrathecal administration; preferably formulations suitable for oral administration.
The compound I or the pharmaceutical composition according to claim 21, 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 15 to 22, 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 15 to 23, wherein the compound I or the pharmaceutical composition is continuously administered 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 15 to 24, 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 15 to 25, 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.