WO2014002922A1 - Method for treating cancer by combined use of anti-cancer agent - Google Patents

Abstract

[Problem] To provide a novel combination of an anti-cancer agent, which enables the potentiation of an anti-tumor activity. [Solution] The present invention relates to a pharmaceutical composition for treating cancer, which can be used in combination with an existing specific anti-cancer agent or a specific anti-cancer agent that is currently under development and contains N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)- piperidin-1-yl]phenyl}-N'-[2-(propane-2-sulfonyl)phenyl]- 1,3,5-triazine-2,4-diamine or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition enables the achievement of a potentiated anti-tumor activity compared with an anti-tumor activity achieved when each of the anti-cancer agents is used singly.

Description

Cancer treatment method in combination with anticancer drug

The present invention relates to pharmaceuticals, in particular pharmaceutical compositions for the treatment of cancer, in particular N- {2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N '-[2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine or a pharmaceutically acceptable salt thereof as an active ingredient and other anticancer agents The present invention relates to a pharmaceutical composition for cancer treatment for combined use. N- {2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N '-[2- (propane-2-sulfonyl) phenyl] -1 , 3,5-triazine-2,4-diamine or a pharmaceutically acceptable salt thereof, and a combination therapy with other anticancer agents.

ALK (Anaplastic Lymphoma Kinase) is a receptor tyrosine kinase, a protein having a transmembrane region in the center, a tyrosine kinase region on the carboxyl terminal side, and an extracellular region on the amino terminal side. So far, it has been reported that full-length ALK is expressed in cancer cells originating from several ectoderm, such as neuroblastoma, glioblastoma, breast cancer, melanoma and the like. In some cases of human malignant lymphoma, as a result of chromosomal translocation, ALK gene is fused with other genes (for example, NPM gene, CLTCL gene, TFG gene), and fused tyrosine kinase with carcinogenic potential is used. (Science, vol.263, p.1281-1284, 1994; Blood, vol.86, p.1954-1960, 1995; Blood, vol.95, p.3204-3207, 2000; Blood, vol.94, p.3265-3268, 1999). In inflammatory myofibroblastic tumors (Inflammatory Myofibroblastic Tumor), it is known that other gene such as CARS gene and SEC31L1 gene fuse with ALK gene as a result of chromosomal translocation to form fused tyrosine kinase. (Laboratory Investigation, vol.83, p.1255-1265, 2003; International Journal of Cancer, vol.118, p.1181-1186, 2006). In 2007, it was reported that EML4 (echinoderm microtubule associated protein like-4) gene and ALK gene were fused in non-small cell lung cancer (Nature 448, p.561-566, 2007). It has been shown that TPM4-ALK fusion protein and FN1-ALK fusion protein are also present in cancer (World Journal of Gastroenterology, vol.12, p.7104-7112, 2006; Journal of Molecular Medicine, vol .85, p.863-875, 2007, Cancer Research, OnlineFirst on May 8, 2012). Many partner molecules that fuse with ALK, including EML4, have a complex formation domain, and the fusion itself is thought to form a complex. This complex formation controls the tyrosine kinase activity of ALK. It is thought to cause canceration as a result of abnormal activation of intracellular signals (Cellular and Molecular Life Science, vol.61, p.2939-2953, 2004; Nature Reviews Cancer, vol.8, p.11-23, 2008).

An ALK inhibitor is thought to inhibit the growth of cells expressing the above ALK fusion gene and exhibit an antitumor effect. Crizotinib, which is actually known as an ALK inhibitor, has shown remarkable effectiveness in patients with non-small cell lung cancer expressing an ALK fusion gene and is used as a therapeutic agent. The overall response rate in clinical trials of crizotinib was more than 50%, but many patients who responded had partial remission and duration of efficacy was approximately 10 months (Journalourof Clinical Oncology, vol. 30, suppl, abstr.7553, 2012). As factors of resistance to crizotinib, secondary ALK mutation and activation of alternative pathways such as KRAS, KIT, and EGFR are known (see, for example, Non-Patent Document 1 or Non-Patent Document 2).

In general, when an anticancer agent is administered alone in chemotherapy of a tumor, particularly a malignant tumor, its effect is limited in terms of side effects, and sufficient antitumor action is often not obtained. Therefore, multi-drug combination therapy combining two or more drugs with different mechanisms of action is performed in clinical settings. This combination therapy combines anticancer drugs with different mechanisms of action to 1) reduce insensitive cell populations, 2) prevent or delay the emergence of drug resistance, and 3) disperse toxicity by combining drugs with different toxicities. The purpose is to enhance the antitumor action and reduce side effects. However, combination therapy with a combination of anticancer drugs with different mechanisms of action does not always result in an increase in antitumor activity, and sometimes only an increase in toxicity is seen, indicating a higher antitumor effect Combinations of anticancer agents are being studied.

In crizotinib-resistant cells, it has been reported that a combination of crizotinib and an EGFR (Epidermal growth factor receptor) inhibitor exhibits a cell growth inhibitory effect (see, for example, Non-Patent Document 3). In addition, in crizotinib-resistant patients, EGFR mutation and increased phosphorylation have been observed (see, for example, Non-Patent Document 1 or Non-Patent Document 2). In clinical trials, the combination of crizotinib and EGFR inhibitor erlotinib is being studied, which is related to MET (c-MET, hepatocyte growth factor receptor) in the resistance of EGFR inhibitors in non-small cell lung cancer. Therefore, crizotinib that also has a MET inhibitory action is used in combination with an EGFR inhibitor (see, for example, Non-Patent Document 4).
Pemetrexed has been reported to be effective in ALK fusion gene-positive patients (see, for example, Non-Patent Document 5). In addition, in two patients with non-small cell lung cancer with meningeal lesions, the combination of crizotinib and pemetrexed shows progression-free survival of 10 months and 6 months, respectively (see, for example, Non-Patent Document 6).
Non-Patent Document 7 describes the kinase inhibitory activity of GSK1838705A, which is an IGF-1R / IR / ALK inhibitor, and the growth inhibitory effect of non-small cell lung cancer cells. However, comparison with ALK inhibitors or IGF-1R / IR inhibitors has not been studied.
Patent Documents 1 and 2 disclose IGF-1R / ALK inhibitors, but do not disclose specific ALK inhibitory activity of the compounds.
Non-Patent Document 8 discloses an antitumor effect when crizotinib and paclitaxel are used in combination in a mouse model of oral squamous cell carcinoma.

N- {2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N ′-[2- (propane-2-sulfonyl) phenyl] -1,3 , 5-triazine-2,4-diamine or a pharmaceutically acceptable salt thereof has an ALK inhibitory action and an inhibitory action on the kinase activity of EML4-ALK fusion protein and mutant EGFR protein (Patent Document 3). . Patent Document 3 discloses that the compound is a single agent, a therapeutic agent for cancer, lung cancer, non-small cell lung cancer, or small cell lung cancer, or an EML4-ALK fusion polynucleotide positive and / or mutant EGFR polynucleotide positive cancer, It is also disclosed that it is useful as a therapeutic agent for lung cancer, non-small cell lung cancer, or small cell lung cancer. The chemical structure of this compound is as follows, and its free form is disclosed in Example 23 of Patent Document 3.

Patent Document 3 exemplifies cisplatin, carboplatin, paclitaxel, docetaxel, gemcitabine, irinotecan, vinorelbine, and bevacizumab as drugs that can be used in combination, but there is no disclosure of a specific combination effect.
Patent Document 4 discloses a crystal polymorph of the compound represented by the above structural formula.
Further, Patent Document 5 describes an intermediate of the compound represented by the above structural formula and a production method.

International Publication No. 2009/158431 Pamphlet International Publication No. 2010/002655 Pamphlet International Publication No. 2009/008371 Pamphlet International Publication No. 2011/145548 Pamphlet International Publication No. 2012/102393 Pamphlet

When a plurality of anticancer agents are used in combination, side effects are often increased together with the antitumor action, and it is not easy to combine two or more anticancer agents. Therefore, a new combination of anticancer agents capable of exerting an antitumor action without increasing side effects is desired.

The inventors have surprisingly found that N- {2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N '-[2- (propane- 2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (hereinafter referred to as “compound A”) is not effective in combination with a certain anticancer agent, while a specific anticancer agent The present invention was completed by finding that the antitumor action is enhanced by the combined use with A.

That is, the present invention relates to the following.
[1] Compound A or a pharmaceutically acceptable thereof characterized by being used in combination with one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906 A pharmaceutical composition for the treatment of cancer comprising a salt as an active ingredient,
[2] Contains Compound A or a pharmaceutically acceptable salt thereof as an active ingredient, which is used in combination with one or more compounds selected from the group consisting of erlotinib and OSI-906 [1] ] The pharmaceutical composition for cancer treatment as described in the above,
[3] The pharmaceutical composition for cancer treatment according to [1], containing Compound A or a pharmaceutically acceptable salt thereof as an active ingredient, which is used in combination with erlotinib,
[4] The pharmaceutical composition for cancer treatment according to [1], comprising Compound A or a pharmaceutically acceptable salt thereof as an active ingredient, which is used in combination with OSI-906,
[5] The pharmaceutical composition for cancer treatment according to [1], wherein the pharmaceutical composition is administered simultaneously, separately, sequentially or at intervals.
[6] For producing a pharmaceutical composition for treating cancer, characterized by being used in combination with one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906 Of compound A or a pharmaceutically acceptable salt thereof,
[7] The use according to [6], which is used in combination with one or more compounds selected from the group consisting of erlotinib and OSI-906,
[8] The use according to [6], characterized by being used in combination with erlotinib,
[9] The use according to [6], characterized by being used in combination with OSI-906,
[10] Compound A or a combination thereof, characterized by being used in combination with one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906 for cancer treatment A pharmaceutically acceptable salt,
[11] Compound A or a pharmaceutically acceptable salt thereof according to [10], which is used in combination with one or more compounds selected from the group consisting of erlotinib and OSI-906,
[12] Compound A or a pharmaceutically acceptable salt thereof according to [10], which is used in combination with erlotinib,
[13] Compound A or a pharmaceutically acceptable salt thereof according to [10], which is used in combination with OSI-906,
[14] Compound A or a pharmaceutically acceptable combination thereof in combination with one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906 for the treatment of cancer Salt used,
[15] The use according to [14], used in combination with one or more compounds selected from the group consisting of erlotinib and OSI-906,
[16] The use according to [14], in combination with erlotinib,
[17] Use according to [14], used in combination with OSI-906,
[18] (a) Compound A or a pharmaceutically acceptable salt thereof, and (b) one or more selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906 A pharmaceutical composition for treating cancer comprising a compound as an active ingredient,
[19] The active ingredient is (a) compound A or a pharmaceutically acceptable salt thereof, and (b) one or more compounds selected from the group consisting of erlotinib and OSI-906. The pharmaceutical composition for cancer treatment as described above,
[20] The pharmaceutical composition for cancer treatment according to [18], comprising (a) compound A or a pharmaceutically acceptable salt thereof, and (b) erlotinib as an active ingredient,
[21] The pharmaceutical composition for cancer treatment according to [18], comprising (a) Compound A or a pharmaceutically acceptable salt thereof, and (b) OSI-906, as an active ingredient,
[22] a therapeutically effective dose of one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906, and a compound A or a pharmaceutically acceptable salt thereof A method for treating cancer, comprising administering to a subject a combination of therapeutically effective doses;
[23] The method for treating cancer according to [22], wherein the method is administered to a subject simultaneously, separately, continuously or at intervals.
[24] The method for treating cancer according to [22], wherein a therapeutically effective dose of one or more compounds selected from the group consisting of erlotinib and OSI-906 is administered to the subject,
[25] The method for treating cancer according to [22], wherein a therapeutically effective dose of erlotinib is administered to the subject,
[26] The method for treating cancer according to [22], wherein a therapeutically effective dose of OSI-906 is administered to the subject,
[27] According to one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906, containing compound A or a pharmaceutically acceptable salt thereof as an active ingredient A pharmaceutical composition for cancer treatment for treating a subject undergoing anticancer treatment;
[28] The pharmaceutical composition for cancer treatment according to [27], for treating a subject undergoing anticancer treatment with one or more compounds selected from the group consisting of erlotinib and OSI-906,
[29] The pharmaceutical composition for cancer treatment according to [27], for treating a subject undergoing anticancer treatment with erlotinib,
[30] The pharmaceutical composition for cancer treatment according to [27], for treating a subject undergoing anticancer treatment with OSI-906,
[31] The pharmaceutical composition according to [1]-[5], [18]-[21], [27]-[30] for treatment of lung cancer, non-small cell lung cancer, or small cell lung cancer,
[32] [1]-[5], [18]-[21], [27]-[30], [19] for the treatment of EML4-ALK fusion polynucleotide positive and / or mutant EGFR polynucleotide positive cancer 31],
[33] The pharmaceutical composition according to [1]-[5], [18]-[21], [27]-[30], [31], [32] for treatment of ALK inhibitor resistant cancer ,
[34] The pharmaceutical composition according to [33], wherein the ALK inhibitor-resistant cancer is crizotinib-resistant cancer,
[35] One or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906, containing compound A or a pharmaceutically acceptable salt thereof as an active ingredient Anti-cancer action enhancer,
[36] The anticancer effect enhancer of one or more compounds selected from the group consisting of erlotinib and OSI-906 according to [35],
[37] The anticancer effect enhancer of erlotinib according to [35],
[38] OSI-906 anticancer activity enhancer according to [35],
[39] (a) Compound A or a pharmaceutically acceptable salt thereof, and (b) one or more selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906 A kit comprising a combination of compounds,
[40] The kit according to [39], comprising one or more compounds selected from the group consisting of erlotinib and OSI-906,
[41] The kit according to [39], which includes erlotinib,
[42] The kit according to [39], which includes OSI-906,
[43] (a) Compound A or a pharmaceutically acceptable salt thereof, and (c) one or more selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906 A medicinal product for cancer treatment comprising a package insert indicated to be used in combination with the compound,
[44] The medicament for treating cancer according to [43], comprising a package insert indicated to be used in combination with one or more compounds selected from the group consisting of erlotinib and OSI-906,
[45] The cancer therapeutic drug according to [43], comprising a package insert indicated to be used in combination with erlotinib,
[46] The cancer therapeutic drug according to [43], comprising a package insert indicated to be used in combination with OSI-906,
About.
The “subject” is a human or other animal that needs the prevention or treatment, and as a certain aspect, it is a human that needs the prevention or treatment.

According to the present invention, it is possible to provide a new combination of anticancer agents capable of exerting an enhanced antitumor action. That is, the combined use with Compound A and a specific anti-cancer agent under development or development can provide a high anti-tumor effect even for a subject that cannot obtain a sufficient anti-tumor effect by itself.

FIG. 1 is a graph showing the results of Example 1 in which Compound A (Comp A) and paclitaxel (PTX) were administered in combination. (a) is a graph showing tumor volume (Tumor Volume (mm ³ )), and (b) is a graph showing body weight (Body Weight (g)). The horizontal axis represents the number of days after the start of drug administration (Days). Untreated represents an untreated group. FIG. 2 is a graph showing the results of Example 1 in which Compound A (Comp A) and carboplatin (CBDCA) were administered in combination. (a) is a graph showing tumor volume (Tumor Volume (mm ³ )), and (b) is a graph showing body weight (Body Weight (g)). The horizontal axis represents the number of days after the start of drug administration (Days). Untreated represents an untreated group. FIG. 3 is a graph showing the results of Example 1 in which Compound A (Comp A) and erlotinib were administered in combination. (a) is a graph showing tumor volume (Tumor Volume (mm ³ )), and (b) is a graph showing body weight (Body Weight (g)). The horizontal axis represents the number of days after the start of drug administration (Days). Control represents a control group. FIG. 4 is a graph showing the results of Example 1 in which Compound A (Comp A) and pemetrexed (MTA) were administered in combination. (a) is a graph showing tumor volume (Tumor Volume (mm ³ )), and (b) is a graph showing body weight (Body Weight (g)). The horizontal axis represents the number of days after the start of drug administration (Days). Control represents a control group. FIG. 5 is a graph showing the results of Example 3 in which the cell growth inhibitory effect of Compound A alone and the cell growth inhibitory effect of Compound A in the presence of OSI-906 on crizotinib-resistant H2228 cell line were examined. . The horizontal axis represents the concentration of compound A (Comp A), and the vertical axis represents the cell viability when the control (DMSO added group) is 100%.

The cancer in the “pharmaceutical composition for cancer treatment” of the present invention includes all solid cancers and lymphomas. Some embodiments include skin cancer, bladder cancer, breast cancer, uterine cancer, ovarian cancer, prostate cancer, lung cancer, colon cancer, pancreatic cancer, kidney cancer, stomach cancer, etc., and other embodiments include lung cancer, non-small cell lung cancer, Or it is small cell lung cancer. Moreover, non-small cell lung cancer is mentioned as another aspect.
Another embodiment includes cancer that is EML4-ALK fusion polynucleotide positive and / or mutant EGFR polynucleotide positive. In still another aspect, lung cancer that is EML4-ALK fusion polynucleotide positive and / or mutant EGFR polynucleotide positive, lung cancer non-small cell lung cancer that is EML4-ALK fusion polynucleotide positive and / or mutant EGFR polynucleotide positive, Alternatively, lung cancer small cell lung cancer that is EML4-ALK fusion polynucleotide positive and / or mutant EGFR polynucleotide positive may be mentioned. Another aspect includes non-small cell lung cancer that is EML4-ALK fusion polynucleotide positive and / or mutant EGFR polynucleotide positive.
Another embodiment includes a cancer that is positive for an EML4-ALK fusion polynucleotide. Still another embodiment includes lung cancer positive for EML4-ALK fusion polynucleotide, non-small cell lung cancer positive for EML4-ALK fusion polynucleotide, or small cell lung cancer positive for EML4-ALK fusion polynucleotide. . Another embodiment includes non-small cell lung cancer that is EML4-ALK fusion polynucleotide positive.
Another embodiment includes an ALK inhibitor resistant cancer, another embodiment includes a compound A resistant cancer or a crizotinib resistant cancer, and yet another embodiment includes a compound A resistant cancer. Examples of this include crizotinib-resistant cancer. Another embodiment includes lung cancer that is resistant to ALK inhibitors, non-small cell lung cancer that is resistant to ALK inhibitors, or small cell lung cancer that is resistant to ALK inhibitors. Yet another embodiment includes non-small cell lung cancer that is resistant to ALK inhibitors. Another aspect includes EML4-ALK fusion polynucleotide positive and / or mutant EGFR polynucleotide positive cancer that is ALK inhibitor resistant, and yet another aspect is ALK inhibitor resistant. EML4-ALK fusion polynucleotide positive cancer is mentioned. Another embodiment includes EML4-ALK fusion polynucleotide positive non-small cell lung cancer that is ALK inhibitor resistant.
Another embodiment includes EML4-ALK fusion polynucleotide positive non-small cell lung cancer that is Compound A resistant. Another embodiment includes EML4-ALK fusion polynucleotide positive non-small cell lung cancer that is resistant to crizotinib.

An “ALK inhibitor-resistant cancer” is a cancer that has acquired resistance by administration of an ALK inhibitor and has reduced the anticancer effect of the drug. The ALK inhibitor in ALK inhibitor resistant cancer is not particularly limited, and examples thereof include compound A, crizotinib, LDK378, CH5424802, AP26113, CEP-28122, X-396 and the like. Or crizotinib. Another embodiment includes compound A, and another embodiment includes crizotinib. Cancers in ALK inhibitor resistant cancer include all solid cancers and lymphomas, and specifically include the various cancers described above.
A “compound A resistant cancer” is a cancer that has acquired resistance by administration of compound A and has reduced anticancer activity by compound A. The cancer includes all solid cancers and lymphomas, and specifically includes the various cancers described above.
A “crizotinib-resistant cancer” is a cancer that has acquired resistance by administration of crizotinib and has reduced the anticancer effect of crizotinib. The cancer includes all solid cancers and lymphomas, and specifically includes the various cancers described above.

Compound A or a pharmaceutically acceptable salt thereof, which is an active ingredient of the pharmaceutical composition of the present invention, can be easily obtained, for example, by the method described in Patent Documents 3 to 5 or a modified method thereof.
OSI-906 in the present invention can be easily obtained by, for example, the method described in WO 2005/097800 pamphlet or a modification thereof. The chemical structure of OSI-906 is as follows.

AZD-4547 in the present invention can be easily obtained by, for example, the method described in WO2008 / 075068, the method obvious to those skilled in the art, or a modification thereof. The chemical structure of AZD-4547 is as follows.

Paclitaxel (Paclitaxel: PTX), erlotinib (Erlotinib), pemetrexed (MTA), lapatinib (Lapatinib) can be purchased commercially and prepared based on the attached materials (for example, information on pharmaceuticals in Japan) Homepage (see http://www.info.pmda.go.jp/) These compounds can be easily obtained by publicly known information, methods obvious to those skilled in the art, or modifications thereof. For example, erlotinib can be readily obtained by the method described in WO 1996/30347, or by methods obvious to those skilled in the art, or modifications thereof. Chemistry Letters, vol.16 p.4686-4691, 2006, or methods obvious to those skilled in the art, or variations thereof. It is available on the easy.

“Compound A or a pharmaceutically acceptable salt thereof” means a salt described in Patent Document 3 (WO 2009/008371 pamphlet), specifically, hydrochloric acid, hydrobromic acid, Inorganic acids such as hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl Tartaric acid, ditoluoyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid and other acid addition salts with sodium, potassium, magnesium, calcium, aluminum, etc. Inorganic bases, salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine, acetyl leuco Salts or ammonium salts with various amino acids and amino acid derivatives such emissions, and the like.
“One or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906” can also include pharmaceutically acceptable salts thereof. These pharmaceutically acceptable salts may form acid addition salts or salts with bases depending on the type of substituent. Specifically, the salt mentioned above is mentioned. For example, erlotinib can include hydrochloride, pemetrexed can include sodium salt, and lapatinib can include oxalate or mesylate.

“Compound A or a pharmaceutically acceptable salt thereof” may be various hydrates, solvates, and crystalline polymorphic substances, all of which are active ingredients of the pharmaceutical composition of the present invention. Is included. In addition, “one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906” refers to various hydrates, solvates, and crystalline polymorphic substances. The compound to contain may be sufficient.
The present invention also encompasses pharmaceutical compositions containing compounds labeled with various radioactive or non-radioactive isotopes.

The pharmaceutical composition of the present invention can be prepared by a commonly used method using an excipient usually used in the art, that is, a pharmaceutical excipient or a pharmaceutical carrier.
Administration is orally by tablets, pills, capsules, granules, powders, solutions, etc., or injections such as intra-articular, intravenous, intramuscular, suppositories, eye drops, ophthalmic ointments, transdermal solutions, Any form of parenteral administration such as an ointment, a transdermal patch, a transmucosal liquid, a transmucosal patch, and an inhalant may be used.

As a solid composition for oral administration, tablets, powders, granules and the like are used. In such solid compositions, one or more active ingredients are mixed with at least one inert excipient. The composition may contain an inert additive such as a lubricant, a disintegrant, a stabilizer and a solubilizing agent according to a conventional method. If necessary, tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance.
Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like, and commonly used inert diluents such as purified water. Or it contains ethanol. The liquid composition may contain solubilizers, wetting agents, auxiliaries such as suspending agents, sweeteners, flavors, fragrances and preservatives in addition to the inert diluent.

The injection for parenteral administration contains a sterile aqueous or non-aqueous solution, suspension or emulsion. Examples of the aqueous solvent include distilled water for injection or physiological saline. Non-aqueous solvents include alcohols such as ethanol. Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.

When one or more compounds selected from the group consisting of Compound A or a pharmaceutically acceptable salt thereof, or paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906 are usually administered orally The daily dose is about 0.001 to 100 mg / kg, preferably 0.1 to 30 mg / kg, more preferably 0.1 to 10 mg / kg per body weight. Divide into 4 doses. When administered intravenously, the appropriate daily dose is about 0.0001 to 10 mg / kg per body weight, and is administered once to several times a day. As a transmucosal agent, about 0.001 to 100 mg / kg per body weight is administered once to several times a day. The dose is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like.

In another embodiment when Compound A or a pharmaceutically acceptable salt thereof is orally administered, the daily dose is about 100 to 600 mg / day, which is once or twice to three times Divide into two doses. In another embodiment, the daily dose is 150 to 600 mg. In still another embodiment, it is 150 to 550 mg, 200 to 600 mg, 200 to 550 mg, or 200 to 525 mg. In yet another embodiment, the dose is 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 525 mg, 550 mg, 575 mg, or 600 mg. The dose is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like.

Depending on the administration route, dosage form, administration site, excipient and additive type, the pharmaceutical composition of the present invention contains 0.01 to 100% by weight, and in one embodiment 0.01 to 50% by weight of the active ingredient.

In the present invention, the anticancer agent that can be used in combination with Compound A or a pharmaceutically acceptable salt thereof is one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906. Can be mentioned. Yet another embodiment includes one or more compounds selected from the group consisting of erlotinib, AZD-4547, OSI-906, and lapatinib. Yet another embodiment includes one or more compounds selected from the group consisting of erlotinib, AZD-4547, and OSI-906. Another embodiment includes erlotinib or OSI-906. Yet another embodiment is OSI-906. Another embodiment includes erlotinib.

Of the above-mentioned anticancer agents already in clinical use, the method of obtaining them, the route of administration, and the dosage are apparent to those skilled in the art. The appropriate dosage and administration (Dosage and Administration) varies depending on the type of cancer, symptoms, and concomitant drugs. Detailed information is available in various databases provided by the FDA, such as “Approved Oncology Drugs” (http: //www.accessdata .fda.gov / scripts / cder / drugsatfda /), "Orange Book" (http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm) http://www.info.pmda.go.jp/). Information on each anticancer agent in these databases is incorporated in the present application.

The following is an excerpt of some of the usages and dosages for each anticancer agent disclosed on the website for providing information on pharmaceuticals and medicines in Japan. It will be appreciated that the following administration conditions are examples and that complete information should be referred to for actual administration.

Paclitaxel (PTX): Applicable cancer types are ovarian cancer, non-small cell lung cancer, breast cancer, stomach cancer, endometrial cancer, head and neck cancer with relapse or distant metastasis, esophageal cancer with relapse or distant metastasis, angiosarcoma, Advanced or recurrent cervical cancer. Depending on each cancer type, it is usually administered at one of the following dosages. At least 3 weeks of rest dispensed once 210mg / m ² (body surface area) over 3 hours drip infusion daily, once daily 100 mg / m ² (body surface area) for 1 hour over drip dispensed week Take one dose for 6 weeks and then take a rest for at least 2 weeks. Once a day, 80 mg / m ² (body surface area) is infused intravenously over 1 hour and administered once a week for 3 weeks, or 1 day A dosage regimen of 135 mg / m ² (body surface area) at a time for intravenous infusion over 24 hours and resting for at least 3 weeks.
Erlotinib: Applicable cancer types include unresectable, recurrent / progressive non-small cell lung cancer that has progressed after cancer chemotherapy, or unresectable pancreatic cancer. Erlotinib is administered orally at a dose of 100 to 150 mg once a day at least 1 hour before meal or 2 hours after meal. The dose should be reduced according to the patient's symptoms.
Pemetrexed (MTA): Applicable cancer types include malignant pleural mesothelioma and unresectable advanced / recurrent non-small cell lung cancer. Depending on each cancer type, one of the following dosages is usually used. In combination with cisplatin, 500 mg / m ² (body surface area) of pemetrexed once a day is infused intravenously over 10 minutes, and the drug is withdrawn for at least 20 days. This is one course and the administration is repeated. As pemetrexed, 500 mg / m ² (body surface area) is administered intravenously over 10 minutes once a day, and the drug is withdrawn for at least 20 days. This is one course and the administration is repeated. In either case, the dose may be reduced as appropriate according to the patient's condition.
Lapatinib (Lapatinib): Applicable cancer types include inoperable or recurrent breast cancer with confirmed HER2 overexpression. In combination with capecitabine, for adults, 1250 mg of lapatinib is usually given orally once daily, at least 1 hour before meal or 1 hour after meal. The dose may be reduced according to the patient's condition.

Examples of dosage and administration for AZD-4547 and OSI-906 are listed below.
AZD-4547: For the administration route and dosage, reference can be made to the dosages described in WO 2008/075068 pamphlet. Specifically, for example, the dose is administered in divided doses if necessary so as to obtain a daily dose in the range of 0.1 mg to 1000 mg of active ingredient per kg body weight. However, the daily dose may be adjusted according to the patient's condition and administration route. In some embodiments, when a parenteral route is used, it is administered at a low dose. Intravenous administration includes, for example, a dose ranging from 0.1 mg to 30 mg of active ingredient per kg body weight. In another embodiment, the pharmaceutical composition for oral administration includes, for example, 0.1 mg to 2 g of active ingredient per kg of body weight.
OSI-906: For the administration route and dosage, reference can be made to the dosages described in WO 2005/097800 pamphlet. Specifically, for example, about 0.01 mg / kg to 150 mg / kg per day, in another embodiment, about 0.5 mg / patient to 7 g / patient, and in another embodiment, 1 day. In another embodiment, it is about 0.5 mg / patient to 3.5 mg / patient per day. As another aspect, Journal of Clinical Oncology, vol.28, Abstract 2530, 2010; Journal of Clinical Oncology, vol.28, Abstract 2531, 2010; Journal of Clinical Oncology., Vol.28, Abstract 3016,2010; Journal Reference can be made to the dosages described in of Clinical Oncology, vol. 27, Abstract 2559, 2009, etc.

The “therapeutically effective dose” in the present invention, when used in combination therapy, depends on the route of administration normally administered, the same dose as that usually administered alone or a lower dose, for example, when administered alone. 0.10-0.99 times the highest dose. In the case of a pharmaceutical composition administered in a certain administration cycle, it is preferable to appropriately adjust the administration cycle so as to be suitable for combined use with Compound A. Specific administration frequency, dosage, infusion administration time, administration cycle, and the like are appropriately determined according to individual cases in consideration of patient symptoms, age, sex, and the like.

(a) Compound A or a pharmaceutically acceptable salt thereof, and (b) one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906 The dosage form for administration is not particularly limited as long as the administration route, administration frequency, and dosage suitable for each are adopted, but administration can be performed simultaneously, separately, continuously, or at desired time intervals. May be. The simultaneous administration preparation may be a compounding agent or may be separately formulated.
Specifically, for example, (1) (a) Compound A or a pharmaceutically acceptable salt thereof, and (b) a group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906 Administration as a combination comprising one or more compounds selected from the above in the same formulation, and (2) (a) and (b) in the same administration route of two types of formulations obtained separately Simultaneous administration, (3) (a) and (b) are obtained by separately formulating two formulations obtained at the same administration route at intervals of time (for example, (b) (b) ) Administration in the order of () or administration in the reverse order), (4) simultaneous administration of two preparations obtained by separately formulating (a) and (b) by different administration routes, ( 5) Administration of two types of preparations obtained by separately formulating (a) and (b) at different intervals (for example, (a) followed by (b) Administration in or in the reverse order) and the like. Another embodiment includes a method in which two preparations obtained by separately formulating (a) and (b) are administered at the same administration route and administration frequency at the same time or at intervals. It is done.
In addition, in the case of administration with a time interval, it can be administered at an interval sufficient to enhance the antitumor action. If drug interaction with Compound A is a concern, it can be administered at intervals necessary to avoid the interaction.

“(A) Compound A or a pharmaceutically acceptable salt thereof, and (b) one or more selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906” “A kit comprising a combination of the above-mentioned compounds” means that a preparation containing the active ingredient (a) (first preparation) and a preparation containing the active ingredient (b) (second preparation) are used in combination therapy of these active ingredients. It is included in combination so that it can be used. If desired, the kit of the present invention may be a packaged product that may contain an additional formulation or a display member that facilitates administration according to each administration time, such as a placebo.
The two types of preparations can be administered with the same or different administration routes under the administration conditions such as formulation formulation, administration route, administration frequency, etc. suitable for each formulation, taking into consideration the bioavailability, stability, etc. of each formulation. They are administered simultaneously or separately. Here, “simultaneously” means that the first formulation and the second formulation are administered together by the same administration route, and “separately” means that the first formulation and the second formulation are the same or different administration routes. It means that they are administered separately at the same or different dosing frequency or dosing interval.

“(A) Compound A or a pharmaceutically acceptable salt thereof, and (c) one or more selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906” A pharmaceutical product for cancer treatment comprising a package insert that is indicated to be used in combination with a compound of the following: a pharmaceutical composition containing a therapeutically effective dose of an active ingredient (a), paclitaxel, erlotinib, pemetrexed, lapatinib , AZD-4547, and a package insert (c) relating to a pharmaceutical composition containing said (a), which is indicated to be used in combination with one or more compounds selected from the group consisting of OSI-906 It means a medicine for cancer treatment packaged in a package.

One or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906, containing “compound A or a pharmaceutically acceptable salt thereof as an active ingredient” In the "pharmaceutical composition for cancer treatment for treating a subject undergoing anticancer treatment by", "the subject undergoing anticancer treatment" includes paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI- Any other anticancer agent may be administered as long as it is treated with one or more compounds selected from the group consisting of 906. “Subject” refers to one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906, compound A or a pharmaceutically acceptable salt thereof as an active ingredient It may be administered simultaneously, separately, continuously or at intervals with the pharmaceutical composition for treating cancer.

As shown in the examples of the present specification, it has been found that the combined use of Compound A and a specific anticancer agent enhances the antitumor action. That is, Compound A does not show enhanced anti-tumor effects when used in combination with axitinib or carboplatin, while anti-tumor when used in combination with paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, or OSI-906. It was confirmed that the effect was enhanced.
Among them, as shown in Example 2, in a test using Compound A-resistant non-small cell lung cancer cells, when Compound A was used in combination with erlotinib, lapatinib, AZD-4547, or OSI-906, synergistic anti-cancer Tumor action was demonstrated.
In particular, as shown in Example 1, in a cancer-bearing test using non-small cell lung cancer cells, when compound A is used in combination with erlotinib, a synergistic anti-tumor is carried out at a dose at which erlotinib does not exhibit an anti-tumor effect. It became clear to show an effect.

Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples.

In the following examples, paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, OSI-906, carboplatin, and axitinib were used as existing or developing anticancer agents used in combination with compound A.
Paclitaxel (PTX) and pemetrexed (MTA) were purchased from LCLabs. Erlotinib (EGFR inhibitor) was purchased from Chugai Pharmaceutical Co., Ltd. and extracted. Lapatinib (EGFR and HER2 inhibitor) was synthesized with reference to the method described in Bioorganic & Medicinal Chemistry Letters, vol.16 p.4686-4691, 2006. AZD-4547 (FGFR inhibitor) was synthesized with reference to the method described in International Publication No. 2008/075068. OSI-906 (IGF1 receptor and insulin receptor inhibitor) was synthesized with reference to the method described in WO 2005/097800. Carboplatin (CBDCA) was purchased from Sigma and Bristol Myers. Axitinib (PDGF receptor inhibitor) was synthesized with reference to WO 2006/048745.

Example 1. Anti-tumor test on NCI-H2228 cells (in vivo)
1. Experimental method NCI-H2228 cells suspended in PBS (non-small cell lung cancer cells expressing EML4-ALK fusion protein) (see Cell, vol.131, p.1190, 2007) About 3 × 10 ⁶ cells are male After transplanting subcutaneously on the back of NOD / SCID mice (Charles River Japan) and confirming tumor growth, administration of the test compound was started. The test was conducted in four groups: a control group or an untreated group, a compound A alone group, a combination agent alone group, and a combination group. A solvent (0.5% methylcellulose aqueous solution) was administered to the control group. In the untreated group, no solvent was administered. Compound A was orally administered as a 0.5% methylcellulose suspension at a dose of 10 mg / kg / day once daily. Paclitaxel was intravenously administered at 12 mg / kg / day for 5 days after the start of administration. Both drugs were administered to the combination group in the same manner as the single agent group. In another three trials, carboplatin (60 mg / kg / day once every 7 days, intravenously administered on days 0 and 7) and erlotinib (60 mg / kg / day daily) Oral administration) or pemetrexed (50 mg / kg / day intravenously once daily for 5 days). Body weight and tumor diameter were measured twice a week, and tumor volume was calculated by the following formula.
[Tumor volume (mm ³ )] = [Tumor major axis (mm)] × [Tumor minor axis (mm)] ² × 0.5

2. Results The results are shown in Figure 1-4.
In the combination test with carboplatin, Compound A and carboplatin each independently inhibited tumor growth, but the tumor volume in the combination group was similar to that of Compound A alone group.
On the other hand, in the combination test with paclitaxel (PTX), erlotinib (Erlotinib) or pemetrexed (MTA), the tumor volume in the combination group was smaller than that in each single group.
From the above, it was confirmed that the antitumor effect of Compound A in vivo in combination with paclitaxel, erlotinib or pemetrexed was confirmed.

Example 2 Growth inhibition test using compound A resistant H2228 cell line established from human non-small cell lung cancer cell line NCI-H2228 cell (EML4-ALK fusion protein expressing cell) (in vitro)
1. Experimental Method The compound A resistant H2228 cell line was established by culturing NCI-H2228 cells in the presence of 0.3 and 1 μmol / L of compound A for about 1 year.
NCI-H2228 cells or Compound A resistant H2228 cell lines were seeded in 96-well spheroid plates in RPMI1640 medium (Invitrogen) containing 10% fetal bovine serum. After overnight culture at 37 ° C. in the presence of 5% CO ₂ , the test compound or DMSO was added, and the cells were further cultured for 5 days. Thereafter, the number of cells was measured using a cell number measurement reagent (CellTiter-Glo ™ Luminescent Cell Viability Assay; Promega). The inhibition rate of the test compound was calculated assuming that the measured values in the medium alone and DMSO group were 100% inhibition and 0% inhibition, respectively, and the 50% inhibition concentration (IC ₅₀ value) was determined by the logistic regression method. As test compounds, Compound A, paclitaxel, carboplatin, axitinib, erlotinib, lapatinib, AZD-4547, and OSI-906 were used.

2. Results The results are shown in Tables 1 to 3. Table 1 shows the cell growth inhibitory effects of each compound as a single agent against NCI-H2228 cells and Compound A-resistant H2228 cells. Indicates. Table 2 shows “cell growth inhibitory effects of each compound against Compound A-resistant H2228 cells in the presence of 1” in the presence of 1 μmol / L of Compound A. μmol / L Compound A) is shown. Table 3 shows “Cell growth inhibitory effects of Compound A against Compound A-resistant H2228 cells in the presence of each compound”. . The numerical values in the table indicate IC ₅₀ and the unit is μmol / L.

As shown in Table 1, Compound A inhibited proliferation with IC ₅₀ values of 0.065 and 3.85 μmol / L against NCI-H2228 and Compound A resistant H2228 cell lines, respectively. Axitinib, erlotinib, AZD-4547, and OSI-906 did not inhibit the proliferation of both cells by 50% or more at 3 μmol / L. Lapatinib did not inhibit the growth of both cells by more than 50% at 1 μmol / L.
On the other hand, as shown in Table 2, in the presence of 1 μmol / L of compound A, erlotinib, lapatinib, AZD-4547, and OSI-906 have compounds with IC ₅₀ values of 0.48, 0.11, 0.028, and 0.49 μmol / L, respectively. Inhibition of growth of the A resistant H2228 cell line. However, Compound A did not affect the growth inhibitory effect of axitinib, paclitaxel, or carboplatin on the Compound A resistant H2228 cell line.
Conversely, as shown in Table 3, the compound A resistant H2228 cell line was cultured in the presence of 1, 1, 0.3, and 3 μmol / L of erlotinib, lapatinib, AZD-4547, and OSI-906, respectively. When the growth inhibitory action was evaluated, Compound A inhibited growth with IC ₅₀ values of 0.40, 0.72, 0.075, and 0.12 μmol / L, respectively.
From the above, it was confirmed that Compound A synergistically exhibits cell growth inhibitory action with erlotinib, lapatinib, AZD-4547, and OSI-906 in the compound A resistant H2228 cell line.

Example 3 Growth inhibition test using crizotinib-resistant H2228 cell line established from human non-small cell lung cancer cell line NCI-H2228 cell (EML4-ALK fusion protein expressing cell) (in vitro)
1. Experimental method The crizotinib-resistant H2228 cell line was established by culturing NCI-H2228 cells for about 2 months in the presence of 0.01-1 μmol / L of crizotinib.
A 96-well spheroid plate was seeded with crizotinib-resistant H2228 cell line in RPMI1640 medium (Invitrogen) containing 10% fetal bovine serum. After overnight culture at 37 ° C. in the presence of 5% CO ₂ , the test compound or DMSO was added, and the cells were further cultured for 5 days. Thereafter, the number of cells was measured using a cell number measurement reagent (CellTiter-Glo ™ Luminescent Cell Viability Assay; Promega). The inhibition rate of the test compound was calculated assuming that the measured values in the medium alone and DMSO group were 100% inhibition and 0% inhibition, respectively, and the 50% inhibition concentration (IC ₅₀ value) was determined by the logistic regression method. In addition, IC ₅₀ values in the presence of 1 μmol / L erlotinib or 3 μmol / L OSI-906 were determined in the same manner. As test compounds, compound A, crizotinib, erlotinib, and OSI-906 were used.

2. Results The results are shown in Table 4, Table 5, and FIG. Table 4 shows “Cell growth inhibitory effects of compound A and crizotinib as a single agent against crizotinib-resistant H2228 cells”. Table 5 shows “Cell growth inhibitory effects of compound A against crizotinib-resistant H2228 cells in the presence of erlotinib or OSI-906”. ). The numerical values in the table indicate IC ₅₀ and the unit is μmol / L. FIG. 5 shows representative examples of the cell growth inhibitory action of Compound A alone or Compound A in the presence of OSI-906 on the crizotinib-resistant H2228 cell line shown in Tables 4 and 5. Show.
Compound A and crizotinib inhibited proliferation against crizotinib resistant H2228 cell line with IC ₅₀ values of 0.54 and 2.19 μmol / L, respectively. Compound A also inhibited the growth of crizotinib-resistant H2228 cell line in the presence of 1 μmol / L erlotinib or 3 μmol / L OSI-906 with IC ₅₀ values of 0.11 and 0.065 μmol / L, respectively.
From the above, it was confirmed that in the crizotinib-resistant H2228 cell line, the combined use with compound A and erlotinib or OSI-906 enhanced the cell growth inhibitory action.

The present invention relates to a pharmaceutical, in particular, a pharmaceutical composition for treating cancer, particularly a pharmaceutical for treating cancer for use in combination with other anticancer agents containing Compound A or a pharmaceutically acceptable salt thereof as an active ingredient. Relates to the composition. Further, the present invention relates to a combination therapy of Compound A or a pharmaceutically acceptable salt thereof and an anticancer agent. According to the present invention, a new combination of anticancer agents capable of exerting an antitumor action can be provided. That is, the combined use with Compound A and a specific anti-cancer agent under development or development can provide a high anti-tumor effect even for a subject that cannot obtain a sufficient anti-tumor effect by itself.

Claims (13)

1. N- {2-methoxy-4- [4-, which is used in combination with one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906 (4-Methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N '-[2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine or its A pharmaceutical composition for treating cancer comprising a pharmaceutically acceptable salt as an active ingredient.
2. N- {2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidine, characterized by being used in combination with one or more compounds selected from the group consisting of erlotinib and OSI-906 -1-yl] phenyl} -N '-[2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine or a pharmaceutically acceptable salt thereof as an active ingredient The pharmaceutical composition for cancer treatment of Claim 1 contained as.
3. N for the manufacture of a pharmaceutical composition for treating cancer, characterized in that it is used in combination with one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906. -{2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N '-[2- (propane-2-sulfonyl) phenyl] -1,3, Use of 5-triazine-2,4-diamine or a pharmaceutically acceptable salt thereof.
4. N- {2-methoxy-, characterized in that it is used in combination with one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906 for the treatment of cancer 4- [4- (4-Methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N '-[2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2, 4-diamine or a pharmaceutically acceptable salt thereof.
5. N- {2-methoxy-4- [4- in combination with one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906 for the treatment of cancer (4-Methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N '-[2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine or its Use of pharmaceutically acceptable salts.
6. (a) N- {2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N '-[2- (propane-2-sulfonyl) phenyl]- 1,3,5-triazine-2,4-diamine or a pharmaceutically acceptable salt thereof, and (b) selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906 A pharmaceutical composition for treating cancer comprising one or more compounds as active ingredients.
7. (a) N- {2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N '-[2- (propane-2-sulfonyl) phenyl]- 1,3,5-triazine-2,4-diamine or a pharmaceutically acceptable salt thereof, and (b) one or more compounds selected from the group consisting of erlotinib and OSI-906, as active ingredients The pharmaceutical composition for cancer treatment according to claim 6.
8. A therapeutically effective dose of one or more compounds selected from the group consisting of paclitaxel, erlotinib, pemetrexed, lapatinib, AZD-4547, and OSI-906, and N- {2-methoxy-4- [4- (4-methyl) Piperazin-1-yl) piperidin-1-yl] phenyl} -N '-[2- (propan-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine or pharmaceutically A method for treating cancer, comprising administering to a subject a combination of therapeutically effective doses of an acceptable salt.
9. The method for treating cancer according to claim 8, wherein the method is administered to a subject simultaneously, separately, continuously or at intervals.
10. The pharmaceutical composition according to claim 1, 2, 6, or 7, which is used for treatment of lung cancer, non-small cell lung cancer, or small cell lung cancer.
11. The pharmaceutical composition according to claim 1, 2, 6, 7, or 10, which is used for treatment of EML4-ALK fusion polynucleotide positive and / or mutant EGFR polynucleotide positive cancer.
12. The pharmaceutical composition according to claim 1, 2, 6, 7, 10, or 11, which is used for treatment of ALK inhibitor-resistant cancer.
13. The pharmaceutical composition according to claim 12, wherein the ALK inhibitor-resistant cancer is crizotinib-resistant cancer.

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