Pyridine amine compound pharmaceutical composition and application thereof in ROS1-positive non-small cell lung cancer

Abstract

A pyridine amine compound pharmaceutical composition and an application thereof in ROS1-positive non-small cell lung cancer. Specifically, a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, filler, lubricating agent, and disintegrating agent, wherein the water content of the filler is ≤ 2 wt%. The pharmaceutical composition has good stability and fluidity, and is suitable for industrial production. Use of the compound of Formula (I) or the pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention or treatment of ROS1-positive non-small cell lung cancer.

Description

Pharmaceutical Compositions of Pyridineamine Compounds and Their Application in ROS1-Positive Non-Small Cell Lung Cancer

[0001] Cross-references to related applications

[0002] This application claims the benefit and priority of Chinese Patent Application No. 201910427849.X, filed with the State Intellectual Property Office of the People's Republic of China on May 22, 2019, and Chinese Patent Application No. 201910427881.8, filed with the State Intellectual Property Office of the People's Republic of China on May 22, 2019, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This application belongs to the pharmaceutical field, specifically relating to pharmaceutical compositions of pyridineamine compounds, their preparation methods and applications, and the application of pyridineamine compounds in the treatment of ROS1-positive non-small cell lung cancer. Background Technology

[0004] Protein tyrosine kinases (PTKs) play a crucial role in intracellular signal transduction pathways. They are involved in the regulation, signal transduction, and development of normal cells, and are also closely related to the proliferation, differentiation, migration, and apoptosis of tumor cells. Therefore, inhibiting the activity of tyrosine kinases has a positive effect on the inhibition and treatment of tumors. The tyrosine kinase family has several subtypes, including epidermal growth factor receptor subtype (EGFR), vascular endothelial growth factor receptor subtype (VEGFR), platelet-derived growth factor receptor subtype (PDGFR), and anaplastic lymphoma kinase (ALK). Studies have found abnormal activation and expression of ALK kinases in various tumor cells, such as non-small cell lung cancer (NSCLC), breast cancer, and malignant glioma. In NSCLC, a fusion of the ROS1 gene has also been found. The ROS1 gene was initially discovered in avian sarcoma virus (UR2) and has a gene sequence with unique oncogenic effects. The human ROS1 gene is located on chromosome 6q21 and belongs to the tyrosine kinase insulin receptor gene family. It consists of three parts: an intracellular tyrosine kinase active domain, a transmembrane domain, and an extracellular domain, encoding a chimeric protein with tyrosine kinase activity. In NSCLC, the ROS1 gene mainly fuses with SLC34A2 and CD74, continuously activating the ROS1 tyrosine kinase domain and downstream signaling pathways such as JAK / STAT, PI3K / AKT, and RAS / MAPK, thereby leading to tumorigenesis.

[0005] CN102850328A discloses a pyridineamine compound with the chemical structure shown in formula (I), which has good ALK kinase inhibitory activity and can be used to prevent or treat tumor growth and metastasis.

[0006]

[0007] CN104557870A discloses the fumarate of compound (I), with the specific structure shown in formula (II), which can be used to treat anaplastic lymphoma kinase (ALK)-positive primary or metastatic non-small cell lung cancer.

[0008]

[0009] Invention Overview

[0010] One of the purposes of this application is to find a pharmaceutical composition of a long-term stable, clinically applicable compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0011] One of the purposes of this application is to provide the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of ROS1-positive non-small cell lung cancer.

[0012] On one hand, this application provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a filler, a lubricant, and a disintegrant, wherein the moisture content of the filler is ≤2 wt%.

[0013]

[0014] On the other hand, this application provides a method for preparing the above-mentioned pharmaceutical composition, comprising:

[0015] a) A pulverized (I) compound or a pharmaceutically acceptable salt thereof;

[0016] b) Mix the compound of formula (I) obtained in step a) or its pharmaceutically acceptable salt, filler, disintegrant, and partial lubricant, and sieve; and

[0017] c) Add the remaining lubricant and mix.

[0018] On the other hand, this application provides the use of the above-mentioned pharmaceutical composition in the preparation of a medicament for the prevention or treatment of non-small cell lung cancer.

[0019] On the other hand, this application provides a method for treating non-small cell lung cancer in mammals, comprising administering a therapeutically effective amount of the above-mentioned pharmaceutical composition to a mammal, preferably a human, in need of the treatment.

[0020] On the other hand, this application provides the use of the above-mentioned pharmaceutical composition in the prevention or treatment of non-small cell lung cancer.

[0021] On the other hand, this application provides the above-mentioned pharmaceutical composition for the prevention or treatment of non-small cell lung cancer.

[0022] In another aspect, this application provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of ROS1-positive non-small cell lung cancer.

[0023] On the other hand, this application provides a method for treating ROS1-positive non-small cell lung cancer in mammals, comprising administering to a mammal, preferably a human, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0024] On the other hand, this application provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the prevention or treatment of ROS1-positive non-small cell lung cancer.

[0025] On the other hand, this application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for the prevention or treatment of ROS1-positive non-small cell lung cancer. Attached Figure Description

[0026] Figure 1 shows brain target lesion images at the end of cycles C0 and C1 for subject 4.

[0027] Figure 2 shows images of non-target lesions in the brain of subject 5 at the end of cycles C0 and C1.

[0028] Invention Details

[0029] The pharmaceutical composition of this application

[0030] This application provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, a filler, a lubricant, and a disintegrant, wherein the filler has a moisture content ≤2 wt%.

[0031]

[0032] In some embodiments, the moisture content of the filler is ≤1.5wt%.

[0033] In some embodiments, a pharmaceutically acceptable salt of the compound of formula (I) is shown as that of formula (II).

[0034]

[0035] In some embodiments, the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 20 wt% to 60 wt%, preferably 35 wt% to 55 wt%, more preferably 40 wt% to 50 wt%. In some embodiments, the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 30 wt% to 60 wt%.

[0036] In some embodiments, the filler is selected from one or a mixture of several of lactose, starch, pregelatinized starch, mannitol, microcrystalline cellulose, glucose, and anhydrous dicalcium phosphate. In some embodiments, the filler is selected from one or a mixture of several of mannitol, microcrystalline cellulose, starch, and anhydrous dicalcium phosphate. In some embodiments, the filler is microcrystalline cellulose and / or anhydrous dicalcium phosphate. In some embodiments, the filler is microcrystalline cellulose and anhydrous dicalcium phosphate, and the mass ratio of microcrystalline cellulose to anhydrous dicalcium phosphate is 1:5 to 5:1, preferably 1:4 to 4:1. In some embodiments, the filler is microcrystalline cellulose and anhydrous dicalcium phosphate, and the mass ratio of microcrystalline cellulose to anhydrous dicalcium phosphate is 3:1 to 5:1, preferably 3.5:1 to 4.5:1. In some embodiments, the mass ratio of microcrystalline cellulose to anhydrous dicalcium phosphate is 1:4. In some embodiments, the mass ratio of microcrystalline cellulose to anhydrous dicalcium phosphate is 1:1. In some embodiments, the mass ratio of microcrystalline cellulose to anhydrous dicalcium phosphate is 4:1.

[0037] In some embodiments, the filler content is 20 wt% to 60 wt%, preferably 35 wt% to 55 wt%, and more preferably 40 wt% to 50 wt%. In some embodiments, the filler content is 30 wt% to 60 wt%.

[0038] In some embodiments, the disintegrant is selected from one or a mixture of several of sodium carboxymethyl starch, crospovidone, crospovidone sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, dry starch, hydroxypropyl starch, polysorbate 80, and sodium alginate. In some embodiments, the disintegrant is selected from one or a mixture of several of crospovidone, crospovidone sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, dry starch, hydroxypropyl starch, polysorbate 80, and sodium alginate. In some embodiments, the disintegrant is selected from one or a mixture of several of sodium carboxymethyl starch, crospovidone, and crospovidone sodium carboxymethyl cellulose. In some embodiments, the disintegrant is selected from one or a mixture of two of crospovidone and crospovidone sodium carboxymethyl cellulose. In some embodiments, the disintegrant is crospovidone sodium carboxymethyl cellulose. In some embodiments, the disintegrant does not include sodium carboxymethyl starch.

[0039] In some embodiments, the content of the disintegrant is 1 wt% to 8 wt%, preferably 2 wt% to 7 wt%, and more preferably 3.5 wt% to 6.5 wt%.

[0040] In some embodiments, the lubricant is selected from one or a mixture of several of silica, hydrogenated castor oil, talc, polyethylene glycol, glyceryl behenate, sodium lauryl sulfate, and magnesium lauryl sulfate. In some embodiments, the lubricant is silica and / or hydrogenated castor oil. In some embodiments, the lubricant is silica and hydrogenated castor oil. In some embodiments, the lubricant is silica and hydrogenated castor oil, and the mass ratio of silica to hydrogenated castor oil is 10:1 to 1:1. In some embodiments, the lubricant is silica and hydrogenated castor oil, and the mass ratio of silica to hydrogenated castor oil is 7:1 to 4:1, preferably 6.5:1 to 5:1. In some embodiments, the mass ratio of silica to hydrogenated castor oil is 10:1. In some embodiments, the mass ratio of silica to hydrogenated castor oil is 35:6. In some embodiments, the mass ratio of silica to hydrogenated castor oil is 5:3. In some implementations, the lubricant does not include magnesium stearate.

[0041] In some embodiments, the lubricant content is 0.5wt% to 8wt%, preferably 1wt% to 6wt%, and more preferably 2.5wt% to 4.5wt%.

[0042] In some embodiments, the pharmaceutical composition further comprises one or more of a binder, sweetener, colorant, and opacifier.

[0043] In some embodiments, the binder is selected from starch, pregelatinized starch, gelatin, sucrose, gum arabic, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, sodium carboxymethyl cellulose, ethylcellulose, and hydroxypropyl methylcellulose. In some embodiments, the sweetener is selected from steviol glycosides and aspartame. In some embodiments, the colorant is selected from iron oxide yellow, iron oxide red, and titanium dioxide. In some embodiments, the opacifier is selected from titanium dioxide, barium sulfate, and precipitated calcium carbonate.

[0044] In some embodiments, the pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, croscarmellose sodium, silica, and hydrogenated castor oil, wherein the moisture content of the microcrystalline cellulose is ≤2 wt%, preferably ≤1.5 wt%.

[0045] In some embodiments, the pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, anhydrous dicalcium phosphate, croscarmellose sodium, silica, and hydrogenated castor oil, wherein the moisture content of the microcrystalline cellulose and anhydrous dicalcium phosphate is ≤2 wt%. In some embodiments, the moisture content of the microcrystalline cellulose and anhydrous dicalcium phosphate is ≤1.5 wt%.

[0046] In some embodiments, the pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, anhydrous dicalcium phosphate, croscarmellose sodium cellulose, silica, and hydrogenated castor oil, wherein the moisture content of the microcrystalline cellulose and / or anhydrous dicalcium phosphate is ≤2 wt%, preferably less than ≤1.5 wt%.

[0047] In some embodiments, the pharmaceutical composition comprises 40 wt% to 50 wt% of a compound of formula (I) or a pharmaceutically acceptable salt thereof, 8 wt% to 40 wt% of microcrystalline cellulose, 8 wt% to 40 wt% of anhydrous dicalcium phosphate, 2.5 wt% to 6.5 wt% of croscarmellose sodium, 0.5 wt% to 6 wt% of silica, and 0.1 wt% to 1 wt% of hydrogenated castor oil, wherein the moisture content of the microcrystalline cellulose and / or anhydrous dicalcium phosphate is ≤2 wt%, preferably less than ≤1.5 wt%.

[0048] In some embodiments, the pharmaceutical composition comprises 40 wt% to 50 wt% of a compound of formula (I) or a pharmaceutically acceptable salt thereof, 8 wt% to 40 wt% of microcrystalline cellulose, 8 wt% to 40 wt% of anhydrous dicalcium phosphate, 3.5 wt% to 5.5 wt% of croscarmellose sodium, 0.5 wt% to 6 wt% of silica, and 0.1 wt% to 1 wt% of hydrogenated castor oil. In some embodiments, the moisture content of the microcrystalline cellulose and / or anhydrous dicalcium phosphate in the pharmaceutical composition is ≤2 wt%, preferably less than ≤1.5 wt%.

[0049] In some embodiments, the pharmaceutical composition comprises 43 wt% to 50 wt% of a compound of formula (II), 35 wt% to 38 wt% of microcrystalline cellulose, 8.5 wt% to 9.5 wt% of anhydrous dicalcium phosphate, 3 wt% to 5 wt% of croscarmellose sodium, 2.5 wt% to 4 wt% of silica, and 0.4 wt% to 0.6 wt% of hydrogenated castor oil. In some embodiments, the moisture content of the microcrystalline cellulose and / or anhydrous dicalcium phosphate in the pharmaceutical composition is ≤2 wt%, preferably less than ≤1.5 wt%.

[0050] In some embodiments, the pharmaceutical composition comprises: 50 parts by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof, 10-40 parts by weight of microcrystalline cellulose, 10-40 parts by weight of anhydrous dicalcium phosphate, 3-7 parts by weight of croscarmellose sodium, 1-6 parts by weight of silica and 0.6 parts by weight of hydrogenated castor oil, wherein the moisture content of the microcrystalline cellulose and / or anhydrous dicalcium phosphate is ≤2 wt%, preferably less than ≤1.5 wt%.

[0051] In some embodiments, the pharmaceutical composition comprises: 50 parts by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof, 40 parts by weight of microcrystalline cellulose, 10 parts by weight of anhydrous dicalcium phosphate, 5 parts by weight of croscarmellose sodium, 3.5 parts by weight of silica and 0.6 parts by weight of hydrogenated castor oil, wherein the moisture content of the microcrystalline cellulose and / or anhydrous dicalcium phosphate is ≤2 wt%, preferably less than ≤1.5 wt%.

[0052] In some embodiments, the moisture content of the compound of formula (I) or its pharmaceutically acceptable salt in the pharmaceutical composition of this application is ≤1%.

[0053] In some embodiments, the moisture content of the lubricant and disintegrant in the pharmaceutical composition of this application is ≤2%, preferably less than ≤1.5wt%.

[0054] In some embodiments, the X of the compound of formula (I) or a pharmaceutically acceptable salt thereof 90 ≤180 μm. In some embodiments, the X of the compound of formula (I) or a pharmaceutically acceptable salt thereof... 90 ≤100 μm. In some embodiments, the X of the compound of formula (I) or a pharmaceutically acceptable salt thereof... 90 ≤70μm.

[0055] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt is mechanically pulverized to control the particle size range.

[0056] In some implementations, the above-mentioned pharmaceutical composition is in oral form.

[0057] In some embodiments, the dosage form of the above pharmaceutical composition may be selected from tablets, capsules, granules, or microgranules. In some embodiments, the above pharmaceutical composition is a capsule. In some embodiments, the capsule is a gelatin capsule or a hydroxypropyl methylcellulose capsule. In some embodiments, the capsule is a hydroxypropyl methylcellulose capsule. In some embodiments, the moisture content of the capsule shell is ≤5 wt%.

[0058] In some embodiments, the above-described pharmaceutical composition is a unit dose pharmaceutical composition. In one embodiment, the mass of the compound of formula (I) in each unit dose composition is 10 mg to 200 mg, preferably 25 mg to 150 mg, and most preferably 50 mg to 125 mg. In another embodiment, the mass of the compound of formula (I) in each unit dose composition is 50 mg, 100 mg, or 125 mg.

[0059] In one embodiment, each unit dose of the pharmaceutical composition comprises 50 mg of compound (I) or 61.8 mg of compound (II), 40.0 mg of microcrystalline cellulose, 10.0 mg of anhydrous dicalcium phosphate, 5.0 mg of croscarmellose sodium, 3.5 mg of silica, and 0.6 mg of hydrogenated castor oil, wherein the moisture content of the microcrystalline cellulose is ≤1.5 wt%.

[0060] In one embodiment, each unit dose of the pharmaceutical composition comprises 100 mg of compound (I) or 123.6 mg of compound (II), 80.0 mg of microcrystalline cellulose, 20.0 mg of anhydrous dicalcium phosphate, 10.0 mg of croscarmellose sodium, 7.0 mg of silica, and 1.2 mg of hydrogenated castor oil, wherein the moisture content of the microcrystalline cellulose is ≤1.5 wt%.

[0061] In one embodiment, each unit dose of the pharmaceutical composition comprises 125 mg of compound (I) or 154.5 mg of compound (II), 100.0 mg of microcrystalline cellulose, 25.0 mg of anhydrous dicalcium phosphate, 12.5 mg of croscarmellose sodium, 8.75 mg of silica, and 1.5 mg of hydrogenated castor oil, wherein the moisture content of the microcrystalline cellulose is ≤1.5 wt%.

[0062] In some implementations, "several" in "a mixture of one or more" refers to 2, 3, 4, 5, or 6 kinds.

[0063] On the other hand, this application relates to a method for preparing the above-mentioned pharmaceutical composition, comprising:

[0064] a) A pulverized (I) compound or a pharmaceutically acceptable salt thereof;

[0065] b) Mix the compound of formula (I) obtained in step a) or its pharmaceutically acceptable salt, filler, disintegrant and partial lubricant, and sieve;

[0066] c) Add the remaining lubricant and mix.

[0067] The lubricant in step b) above and the remaining lubricant in step c) above can be the same lubricant or different lubricants.

[0068] In some embodiments, the pulverization in step a) above is selected from air jet milling or mechanical milling, preferably mechanical milling.

[0069] In some implementations, the lubricant added in step b) above is silica, and the remaining lubricant added in step c) above is hydrogenated castor oil.

[0070] In some embodiments, prior to step b) above, the moisture content of the filler is reduced to ≤2 wt%, preferably ≤1.5 wt%, by drying.

[0071] In some embodiments, in step b) above, the sieving is performed through a sieve with a mesh size of 0.6–1.2 mm. In some embodiments, in step b) above, the sieving is performed through a sieve with a mesh size of 0.8 mm.

[0072] In some implementations, the ambient relative humidity for steps b) and c) above is ≤40%.

[0073] In some embodiments, the above preparation method further includes step d): filling the mixture obtained in step c) into capsule shells. In some embodiments, in step d), the mixture obtained in step c) is filled into hydroxypropyl methylcellulose capsule shells. In some embodiments, the relative humidity in step d) is ≤40%.

[0074] On the other hand, this application relates to the use of pharmaceutical compositions comprising the aforementioned compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of non-small cell lung cancer.

[0075] On the other hand, this application relates to a method for treating non-small cell lung cancer in mammals, comprising administering to a mammal, preferably a human, a therapeutically effective amount of the aforementioned compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0076] On the other hand, this application relates to the use of pharmaceutical compositions comprising the aforementioned compound of formula (I) or a pharmaceutically acceptable salt thereof in the prevention or treatment of non-small cell lung cancer.

[0077] On the other hand, this application relates to pharmaceutical compositions of the aforementioned inclusion compound (I) or its pharmaceutically acceptable salts for the prevention or treatment of non-small cell lung cancer.

[0078] In some embodiments, the non-small cell lung cancer refers to ROS1-positive non-small cell lung cancer. In some embodiments, the non-small cell lung cancer refers to ROS1-positive locally advanced or metastatic non-small cell lung cancer. In some embodiments, the non-small cell lung cancer refers to ROS1-positive non-small cell lung cancer with brain metastases.

[0079] In this application, unless otherwise specified, the moisture content is determined by a halogen rapid moisture analyzer.

[0080] In this application, unless otherwise specified, "RH" refers to relative humidity.

[0081] In this application, unless otherwise specified, the mass and percentage of pharmaceutically acceptable salts of formula (I) compounds (e.g., formula (II) compounds) are calculated in their free base form (i.e., formula (I) compounds).

[0082] In this application, unless otherwise specified, "wt%" refers to the percentage of the weight of a component relative to the total weight of the pharmaceutical composition (wherein the total weight of the pharmaceutically acceptable salt of the compound of formula (I) is expressed as its free base weight).

[0083] The preparation method of the pharmaceutical composition provided in this application is simple to operate, and the obtained pharmaceutical composition has good stability and flowability, making it suitable for industrial production. The applicant found that when the moisture content of the filler exceeds 2 wt%, the impurity content of the pharmaceutical composition increases significantly during storage. Furthermore, the applicant found that when sodium carboxymethyl starch is used as the disintegrant, the impurity content of the pharmaceutical composition containing compound (I) or its salt also increases, and when magnesium stearate is used as the lubricant, the active ingredient in the pharmaceutical composition containing compound (I) or its salt is significantly degraded, and clumping occurs.

[0084] The use of the compound of formula (I) of this application or a pharmaceutically acceptable salt thereof

[0085] On the one hand, this application provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of ROS1-positive non-small cell lung cancer.

[0086]

[0087] On the other hand, this application provides a method for treating ROS1-positive non-small cell lung cancer, comprising administering to a patient in need of the treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0088] On the other hand, this application also provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the prevention or treatment of ROS1-positive non-small cell lung cancer.

[0089] On the other hand, this application also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for the prevention or treatment of ROS1-positive non-small cell lung cancer.

[0090] In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is a compound of formula (II).

[0091]

[0092] In some implementations, the ROS1-positive non-small cell lung cancer is ROS1-positive locally advanced or metastatic non-small cell lung cancer.

[0093] In some implementations, the ROS1-positive non-small cell lung cancer is ROS1-positive brain metastatic non-small cell lung cancer.

[0094] In some embodiments, the ROS1-positive non-small cell lung cancer is ROS1-positive lung adenocarcinoma; in some embodiments, the ROS1-positive non-small cell lung cancer is ROS1-positive poorly differentiated lung adenocarcinoma.

[0095] In some implementations, the ROS1-positive non-small cell lung cancer is a ROS1-positive locally advanced or metastatic poorly differentiated lung adenocarcinoma.

[0096] In some embodiments, patients with ROS1-positive non-small cell lung cancer receive treatment with a compound of formula (I) or a pharmaceutically acceptable salt thereof, which may reduce the incidence and / or likelihood of side effects. In some embodiments, the side effects include elevated transaminase levels and / or visual impairment.

[0097] In some implementations, patients with the ROS1-positive non-small cell lung cancer have previously received anti-tumor drug treatment.

[0098] In some embodiments, patients with the ROS1-positive non-small cell lung cancer have not received or have received one or more prior treatment regimens. In some embodiments, patients with the ROS1-positive non-small cell lung cancer have not received or have received one, two, three, four, or five prior treatment regimens.

[0099] In some implementations, the prior treatment regimen includes radiation therapy, radical cancer surgery, or antitumor drug therapy.

[0100] In some embodiments, the antitumor drug is selected from bevacizumab, camrelizumab, tislelizumab, trastuzumab, nimotuzumab, panitumumab, cetuximab, racotumomab, mogamulizumab, pertuzumab, ipilimumab, cannabinumab, denosumab, atezolizumab, olamarumab, daratumumab, nexituzumab, lambrolizumab, nivolumab, etc. One or more of the following: toripalimab, sintilimab, cemiplimab, avelumab, aflibercept, ramucirumab, durvalumab, cisplatin, carboplatin, nedaplatin, cycloplatin, oxaliplatin, lobaplatin, raltitrexed, pemetrexed, pralatrexate, methotrexate, edaraxate, aminopterin, vinorelbine, paclitaxel, gemcitabine, docetaxel, gefitinib, erlotinib, icotinib, and endostatin.

[0101] In some embodiments, the antitumor drug treatment is selected from the following chemotherapy regimens: NP, TP, GP, DP, AP, anti-angiogenic drugs including endostatin, targeted therapy drugs including one or more selected from gefitinib, erlotinib, icotinib, docetaxel, or pemetrexed. In some embodiments, the antitumor drug treatment includes the following first-line chemotherapy regimens: NP, TP, GP, DP, or AP. In some embodiments, the antitumor drug treatment includes the following second-line chemotherapy regimens: docetaxel or pemetrexed.

[0102] In some embodiments, the antitumor drug is selected from one or a combination of several of bevacizumab, carboplatin, and pemetrexed.

[0103] In some embodiments, the antitumor drug is selected from a combination of bevacizumab, carboplatin, and pemetrexed.

[0104] In some embodiments, the antitumor drug is selected from one or a combination of several of nedaplatin, pemetrexed, bevacizumab, paclitaxel, carboplatin, and cisplatin.

[0105] In some embodiments, the antitumor drug is selected from a combination of nedaplatin and pemetrexed.

[0106] In some embodiments, the antitumor drug is selected from a combination of bevacizumab, paclitaxel, and carboplatin.

[0107] In some embodiments, the antitumor drug is selected from a combination of cisplatin and pemetrexed.

[0108] In some embodiments, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 50 mg to 1000 mg / day. In some embodiments, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 200 to 800 mg / day. In some embodiments, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 500 mg / day. In some embodiments, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 250 mg twice daily. In some embodiments, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 600 mg / day. In some embodiments, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 300 mg twice daily. In some embodiments, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 400 mg / day. In some embodiments, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 200 mg twice daily.

[0109] In this application, the dosage of pharmaceutically acceptable salts of compound (I) is based on compound (I).

[0110] In some embodiments, the administration period of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 28 days.

[0111] Compounds of formula (I) or pharmaceutically acceptable salts thereof may be administered via a variety of routes, including but not limited to oral, rectal, local, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration, preferably oral administration.

[0112] Compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered once or more daily. In some embodiments, compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice daily.

[0113] The method of administration can be determined based on a comprehensive consideration of drug activity, side effects, and patient tolerability, with the preferred method being continuous administration of the compound of formula (I) or its pharmaceutically acceptable salt.

[0114] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is used as a single active agent.

[0115] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof as described above.

[0116] In this application, unless otherwise specified, ROS1 positivity refers to the presence of ROS1 gene rearrangement or abnormal expression of fusion protein, as determined by an FDA or CFDA-approved detection method, such as reverse transcription-polymerase chain reaction (RT-PCR) technology.

[0117] In this application, unless otherwise specified, the reverse transcription-polymerase chain reaction (RT-PCR) technique uses the NMPA-approved ROS1 RT-PCR assay kit.

[0118] In this application, the NP regimen is vinorelbine in combination with cisplatin, the TP regimen is paclitaxel in combination with cisplatin or carboplatin, the GP regimen is gemcitabine in combination with cisplatin or carboplatin, the DP regimen is docetaxel in combination with cisplatin or carboplatin, and the AP regimen is pemetrexed in combination with cisplatin or carboplatin. For the specific meanings of each regimen, please refer to the Chinese Guidelines for the Diagnosis and Treatment of Primary Lung Cancer (2015 Edition).

[0119] In this application, unless otherwise specified, the clinical staging is based on the TNM staging system of the Union for International Cancer Control.

[0120] definition

[0121] Unless otherwise stated, the following terms as used in this application shall have the following meanings. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0122] The term "treatment" means administering the compound or preparation described in this application to improve or eliminate a disease or one or more symptoms related to said disease, and includes:

[0123] (i) Suppress the disease or disease state, that is, curb its development;

[0124] (ii) Relieve the disease or disease state, even if the disease or disease state subsides.

[0125] The term “prevention” means administering the compound or formulation described in this application to prevent the occurrence of a disease or disease state in a mammal, particularly when such mammals are susceptible to the disease state but have not yet been diagnosed with the disease state.

[0126] The term “therapeutic effective amount” means (i) the amount of the compound of this application used to treat or prevent a particular disease, condition or disorder, (ii) to reduce, improve or eliminate one or more symptoms of a particular disease, condition or disorder, or (iii) to prevent or delay the onset of one or more symptoms of a particular disease, condition or disorder described herein.

[0127] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0128] As pharmaceutically acceptable salts, for example, metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, and salts formed with basic or acidic amino acids may be mentioned.

[0129] The word “comprise” or “include” and its English variants such as comprises or comprising should be understood in an open, non-exclusive sense, meaning “including but not limited to”.

[0130] Term "X" 90"≤Xi" means that in the sample being tested, particles with a diameter smaller than Xi account for no less than 90% of the total volume. Xi represents a certain particle size value. In this application, the particle size distribution is determined using a laser diffraction particle size analyzer.

[0131] The term "CR" refers to complete remission, specifically the disappearance of all target lesions, and the short axis value of any pathological lymph node (whether or not it is a target lesion) must be less than 10 mm.

[0132] The term "PR" refers to partial remission, specifically a reduction of at least 30% in the total radius of all target lesions, with the total radius of the critical lesion as a reference.

[0133] The term "SD" refers to stable lesions, specifically those that, based on the minimum sum of the studied (target lesion radius) values, do not meet either the criteria for mitigation or the criteria for worsening.

[0134] The term "bid" means administering the medication twice a day.

[0135] The term "po" refers to oral administration.

[0136] In this application, compound (I) can be prepared according to Example 1 of WO2016169030A1, and compound (II) can be prepared according to Example 2 of WO2016169030A1. For clarity, the invention is further illustrated by examples, but these examples are not intended to limit the scope of this application. All reagents used in this application are commercially available and can be used without further purification. If the commercially available anhydrous calcium hydrogen phosphate has a water content of less than 1%, dehydration treatment is not required. Specific Implementation

[0137] Example 1 Pharmaceutical composition of compound (II)

[0138]

[0139] Note: The weight of compound (II) in the table is based on the weight of compound (I). For example, 50 mg of compound (II) in prescription 1 in the table means that the weight of compound (I) in compound (II) is 50 mg.

[0140] Preparation process:

[0141] 1) Mechanically pulverized (II) compounds to X 90 Microcrystalline cellulose with a particle size ≤180μm was dried at 105℃ until the moisture content was ≤1.5wt%.

[0142] 2) In an environment with relative humidity ≤40%, the compound of formula (II), microcrystalline cellulose, anhydrous dicalcium phosphate, cross-linked sodium carboxymethyl cellulose, and silica are placed in a hopper mixer and mixed (15 rpm, 5 min). The mixed product is then passed through a 0.8 mm sieve.

[0143] 3) Place the mixture obtained in step 2) and hydrogenated castor oil in a hopper mixer and mix (15 rpm, 10 min).

[0144] 4) Fill with hydroxypropyl methylcellulose empty capsules.

[0145] Example 2 Stability Experiment

[0146] According to the General Chapter 9001 of the 2015 edition of the Chinese Pharmacopoeia, the capsules obtained from Formula 1 in Example 1 were placed in high-density polyethylene bottles, sealed, and placed under the conditions of 40°C and relative humidity RH 75% (Table 1) and 25°C ± 2°C and relative humidity 60% ± 10% (Table 2).

[0147] Table 1

[0148] Conditional impurity content (%) 0 months 1.28 1 month 1.38 2 months 1.39

[0149] Table 2

[0150]

[0151] Dissolution test method: Take the capsules obtained from Formula 1 of Example 1, and perform the dissolution and release test according to the method (Chinese Pharmacopoeia 2015 Edition, Part IV, General Chapter 0931, Method 1), using 1000 ml of 0.1 mol / L hydrochloric acid solution as the dissolution medium, and rotate at 100 rpm. After 30 minutes, filter the solution, accurately measure the filtrate, dilute it with the dissolution medium and shake well, and measure the absorbance at a wavelength of 337 nm according to the ultraviolet-visible spectrophotometry method (Chinese Pharmacopoeia 2015 Edition, Part IV, General Chapter 0401). Take an appropriate amount of compound (II) reference standard, accurately weigh it, dissolve and dilute it with the dissolution medium, and measure it in the same way. Calculate the amount of dissolution per capsule.

[0152] HPLC detection conditions: The test was conducted according to the high performance liquid chromatography method (Chinese Pharmacopoeia 2015 Edition, Part IV, General Chapter 0512), using octadecylsilane-bonded silica gel as the stationary phase; 0.02 mol / L ammonium formate buffer as mobile phase A, methanol as mobile phase B, flow rate of 1.0 ml / min, linear gradient elution; column temperature of 40℃; detection wavelength of 264 nm.

[0153] Example 3 Clinical Trial - Study of Compound (II) on ROS1-Positive Poorly Differentiated Lung Adenocarcinoma

[0154] (1) Patient's medical history

[0155] Female, 47 years old, with adenocarcinoma of the left lung, metastasizing to the left supraclavicular, left hilar and mediastinal lymph nodes. Pathological classification is poorly differentiated lung adenocarcinoma, and clinical stage is IIIB (cT3N3M0).

[0156] The patient had previously received combination therapy with bevacizumab, carboplatin, and pemetrexed. After genetic testing showed that the patient was ROS1 positive, the patient started oral administration of 250 mg (calculated as compound (I)) of compound (II) capsules (capsules of formulation 1 in Example 1) twice a day for 28 consecutive days as one cycle.

[0157] (2) The CT scan and evaluation results after enrollment are as follows:

[0158]

[0159] During treatment with compound (II), no progression of non-target lesions was observed. Adverse reactions were generally tolerable during treatment, with the main adverse events being elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST). No drug-related cardiotoxicity was observed.

[0160] Example 4: Clinical Trial - Safety and Efficacy Study of Compound (II) in ROS1-Positive Non-Small Cell Lung Cancer

[0161] 1. Investigational drug and dosing regimen

[0162] 1) Test drug: Capsules of the compound of formula (II) prepared in Example 1 (Formula 1)

[0163] 2) Method of administration:

[0164] 300 mg twice daily orally, taken on an empty stomach in the morning and evening, with an interval of 10-12 hours between doses. One cycle consists of 28 days of continuous administration, until the subject experiences disease progression or adverse events that are intolerable after treatment.

[0165] 3) Dosage adjustment:

[0166] If a subject experiences an adverse event of grade 3 or higher severity as defined by the National Cancer Institute CTCAE (version 5.0), the dose may be adjusted as follows: First dose reduction: Dosage regimen: 250 mg, bid, po; Second dose reduction: Dosage regimen: 200 mg, bid, po.

[0167] 2. Main inclusion criteria

[0168] 1) Age ≥ 18 years;

[0169] 2) ECOG physical condition: 0-1 point; expected survival period exceeds 3 months;

[0170] 3) Major organ functions are normal;

[0171] 4) Diagnosis of locally advanced or metastatic NSCLC confirmed by histology or cytology (based on the 8th edition of the TNM staging criteria);

[0172] 5) A confirmed diagnosis of ROS1 positivity via pathology and / or cytology;

[0173] 6) Those who have previously received no more than two chemotherapy regimens. If more than two chemotherapy regimens have been used, a biopsy must be performed again during the screening period, and the test result must be confirmed as ROS1 positive (using the ROS1 RT-PCR test kit approved by NMPA).

[0174] 7) Within 28 days prior to the first study drug administration, there is at least one evaluable target lesion other than a brain lesion, as confirmed by imaging (evaluated according to RECIST 1.1 criteria).

[0175] 3. Evaluation Criteria

[0176] Efficacy evaluation criteria: RECIST 1.1 criteria were used for evaluation; the main efficacy evaluation endpoint was the objective response rate (ORR), which is (number of CR + PR cases) / total number of cases, including complete response (CR) and partial response (PR).

[0177] Safety evaluation criteria: The adverse reactions of the drug are evaluated using the NCI-CTC AE5.0 standard.

[0178] 4. Test Results

[0179] 1) Security

[0180] Among the 22 patients enrolled, the adverse reactions occurring in >20% of the study and their incidence rates are as follows:

[0181] Incidence of adverse reactions: Vomiting 54.55%, Elevated transaminase 45.45%, Nausea 36.36%, Diarrhea 27.27%.

[0182] 2) Effectiveness

[0183] A total of 45 patients were enrolled. Five patients did not reach the time for their first imaging evaluation, and one patient was discharged without receiving a response evaluation. Of the remaining 39 patients, 34 achieved partial response (PR) or complete response (CR) after imaging evaluation at the sub-center, resulting in an objective response rate (ORR) of 85%.

[0184] The following are representative cases:

[0185]

[0186]

[0187] Note: "-" indicates that the data has not yet been obtained.

[0188] During the efficacy evaluation, subjects 3, 4 and 5 were patients with brain metastases, and compound (II) was found to have significant efficacy on their brain metastases.

[0189] Subject 3: Baseline: Left frontal lobe mass 21.8 mm; End of C1 cycle: Left frontal lobe mass shrank to 15.2 mm; End of C3 cycle: Left frontal lobe mass shrank to 8 mm; End of C5 cycle: Left frontal lobe mass shrank to 5 mm; The brain metastases are currently stable, and the subject has been in the group for more than 36 weeks and is still in the group.

[0190] Subject 4: At the end of the C1 cycle, the target lesion in the brain was smaller than the baseline, as shown in Figure 1.

[0191] Subject 5: Non-target lesions in the brain disappeared at the end of the C1 cycle, see Figure 2.

Claims

1. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, a filler, a lubricant, and a disintegrant, wherein, The moisture content of the filler is ≤2wt%.

2. The pharmaceutical composition of claim 1, wherein, The moisture content of the filler is ≤1.5wt%.

3. The pharmaceutical composition according to claim 1 or 2, wherein, Pharmaceutically acceptable salts of the compound of formula (I) are shown in formula (II).

4. The pharmaceutical composition according to any one of claims 1-3, wherein, The filler is selected from one or a mixture of several of lactose, starch, pregelatinized starch, mannitol, microcrystalline cellulose, glucose, and anhydrous dicalcium phosphate, preferably a mixture of one or a mixture of several of mannitol, microcrystalline cellulose, starch, and anhydrous dicalcium phosphate, more preferably microcrystalline cellulose and / or anhydrous dicalcium phosphate, and most preferably microcrystalline cellulose and anhydrous dicalcium phosphate.

5. The pharmaceutical composition according to any one of claims 1-4, wherein, The disintegrant is selected from one or a mixture of several of crospovidone, crospovidone sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, dry starch, hydroxypropyl starch, polysorbate 80, and sodium alginate, preferably one or a mixture of two of crospovidone and crospovidone sodium carboxymethyl cellulose, and more preferably crospovidone sodium carboxymethyl cellulose.

6. The pharmaceutical composition according to any one of claims 1-5, wherein, The lubricant is selected from one or a mixture of several of the following: silica, hydrogenated castor oil, talc, polyethylene glycol, glyceryl behenate, sodium lauryl sulfate, and magnesium lauryl sulfate, preferably silica and / or hydrogenated castor oil, and more preferably silica and hydrogenated castor oil.

7. The pharmaceutical composition according to any one of claims 1-6, wherein, The content of the compound of formula (I) or its pharmaceutically acceptable salt is 20 wt% to 60 wt%, preferably 35 wt% to 55 wt%, more preferably 40 wt% to 50 wt%; The content of the filler is 20wt% to 60wt%, preferably 35wt% to 55wt%, more preferably 40wt% to 50wt%; The content of the disintegrant is 1 wt% to 8 wt%, preferably 2 wt% to 7 wt%, more preferably 3.5 wt% to 6.5 wt%; The content of the lubricant is 0.5wt% to 8wt%, preferably 1wt% to 6wt%, and more preferably 2.5wt% to 4.5wt%.

8. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, croscarmellose sodium, silicon dioxide, and hydrogenated castor oil, wherein, The moisture content of microcrystalline cellulose and / or anhydrous dicalcium phosphate is ≤2 wt%.

9. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition comprises 43 wt% to 50 wt% of a compound of formula (II), 35 wt% to 38 wt% of microcrystalline cellulose, 8.5 wt% to 9.5 wt% of anhydrous dicalcium phosphate, 3 wt% to 5 wt% of croscarmellose sodium, 2.5 wt% to 4 wt% of silica, and 0.4 wt% to 0.6 wt% of hydrogenated castor oil, wherein the moisture content of the microcrystalline cellulose and / or anhydrous dicalcium phosphate is ≤2 wt%, preferably less than ≤1.5 wt%.

10. Use of the pharmaceutical composition according to any one of claims 1-9 in the preparation of a medicament for the prevention or treatment of non-small cell lung cancer.

11. A method for preparing the pharmaceutical composition according to any one of claims 1-9, comprising: a) A pulverized (I) compound or a pharmaceutically acceptable salt thereof; b) Mix the compound of formula (I) obtained in step a) or its pharmaceutically acceptable salt, filler, disintegrant and partial lubricant, and sieve; c) Add the remaining lubricant and mix.

12. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of ROS1-positive non-small cell lung cancer.

13. The use as described in claim 12, wherein, The pharmaceutically acceptable salt of the compound of formula (I) is the compound of formula (II).

14. The use as described in claim 12 or 13, wherein, The ROS1-positive non-small cell lung cancer is ROS1-positive locally advanced or metastatic non-small cell lung cancer; preferably, it is ROS1-positive brain metastatic non-small cell lung cancer.

15. The use as described in any one of claims 12-14, wherein, Patients with ROS1-positive non-small cell lung cancer have not received or have received one or more prior treatment regimens, preferably prior treatment regimens including radiotherapy, radical cancer surgery, or antitumor drug therapy.