WO2010038428A1

WO2010038428A1 - Alternative agent to taxane anti-cancer agent

Info

Publication number: WO2010038428A1
Application number: PCT/JP2009/004992
Authority: WO
Inventors: 松本裕
Original assignee: 武田薬品工業株式会社
Priority date: 2008-09-30
Filing date: 2009-09-29
Publication date: 2010-04-08

Abstract

Disclosed is an alternative agent to a taxane anti-cancer agent such as paclitaxel, which enables the extension of the withdrawal period for the taxane anti-cancer agent while maintaining the therapeutic effect of the taxane anti-cancer agent. The alternative agent comprises a p38MAPK inhibitor. The alternative agent is administered to a patient who has a history of administration of the taxane anti-cancer agent at least two times over a period of 2 to 8 months for the purpose of potentiating an anti-cancer activity of the taxane anti-cancer agent and/or reducing adverse side effects of the taxane anti-cancer agent. During the period of 2 to 8 months, the taxane anti-cancer agent is not administered to the patient.

Description

Replacing taxane anticancer drugs

The present invention relates to a replacement drug for a taxane anticancer agent.

Paclitaxel, a taxane anticancer agent, is a microtubule depolymerization inhibitor and is a highly effective anticancer agent that is used as a therapeutic agent for many types of cancer such as breast cancer, lung cancer, and stomach cancer. It is. However, paclitaxel has to be administered by infusion over several hours with standard therapy, and it has significant side effects such as leukopenia, neutropenia, peripheral neuropathy, and nausea and vomiting, which can be very burdensome to patients. large. For this reason, it is necessary to take a drug holiday for at least 3 weeks.

If the drug withdrawal period can be extended while maintaining the therapeutic effect of paclitaxel, it is expected to significantly reduce side effects and improve the patient's QOL.
Therefore, the present invention provides a replacement agent for a taxane anticancer agent that can extend the drug withdrawal period of the taxane anticancer agent while maintaining the therapeutic effect of a taxane anticancer agent such as paclitaxel. The issue is to provide.

The present inventors have demonstrated that by using p38 MAPK (p38 mitogen-activated protein kinase) inhibitor, the drug withdrawal period can be extended while maintaining the cancer therapeutic effect of paclitaxel. I found it.
Furthermore, the present inventors have found that p38 MAPK inhibitors are useful for the prevention or treatment of non-small cell lung cancer.
Furthermore, the present inventors have found that there is an anchorage-independent cancer growth-specific inhibitory effect, which is promoted by the combined use with paclitaxel.
The present invention has been completed based on these findings.
That is, the present invention provides the following [1] to [17] and the like.
[1]
containing a p38 MAPK inhibitor;
2 or more times over a period of 2 to 8 months for patients with a history of administration of taxane anticancer drugs to enhance the anticancer effects and / or reduce side effects of taxane anticancer drugs A taxane anticancer agent is not administered during the period of 2 to 8 months.
Replacement drug for taxane anticancer drugs.
[2]
The p38 MAPK inhibitor is 5- (2,6-dichlorophenyl) -2-[(2,4-difluorophenyl) thio] -6H-pyrimido [1,6-b] pyridazin-6-one or 6-[(amino The pharmaceutical according to [1] above, which is carbonyl) (2,6-difluorophenyl) amino] -2- (2,4-difluorophenyl) -3-pyridinecarboxamide or a salt thereof.
[3]
The medicament according to [1] above, wherein the taxane anticancer agent is paclitaxel or a salt thereof.
[4]
A method of enhancing the anticancer action of a taxane anticancer agent in administration of a taxane anticancer agent to a patient by using a p38 MAPK inhibitor in combination with the taxane anticancer agent.
[5] A method for reducing side effects of a taxane anticancer agent in administration of a taxane anticancer agent to a patient by using a p38 MAPK inhibitor in combination with a taxane anticancer agent.
[6] The p38 MAPK inhibitor is 5- (2,6-dichlorophenyl) -2-[(2,4-difluorophenyl) thio] -6H-pyrimido [1,6-b] pyridazin-6-one or 6- The method according to [4] or [5] above, which is [(aminocarbonyl) (2,6-difluorophenyl) amino] -2- (2,4-difluorophenyl) -3-pyridinecarboxamide or a salt thereof.
[7]
The method according to [4] or [5] above, wherein the taxane anticancer agent is paclitaxel or a salt thereof.
[8] A method for treating cancer, comprising a single administration of a taxane anticancer agent to a patient;
Administration of the taxane anticancer agent followed by two or more administrations of the p38 MAPK inhibitor to the patient over a period of 2 to 8 months.
[9] The p38 MAPK inhibitor is 5- (2,6-dichlorophenyl) -2-[(2,4-difluorophenyl) thio] -6H-pyrimido [1,6-b] pyridazin-6-one or 6- The method according to [8] above, which is [(aminocarbonyl) (2,6-difluorophenyl) amino] -2- (2,4-difluorophenyl) -3-pyridinecarboxamide or a salt thereof.
[10]
The method according to [8] above, wherein the taxane anticancer agent is paclitaxel or a salt thereof.
[11] A medicament for preventing or treating non-small cell lung cancer, comprising a p38 MAPK inhibitor.
[12] The p38 MAPK inhibitor is 5- (2,6-dichlorophenyl) -2-[(2,4-difluorophenyl) thio] -6H-pyrimido [1,6-b] pyridazin-6-one or 6- The medicament according to [11] above, which is [(aminocarbonyl) (2,6-difluorophenyl) amino] -2- (2,4-difluorophenyl) -3-pyridinecarboxamide or a salt thereof.
[13]
An anchorage-independent cancer growth-specific inhibitor containing a p38 MAPK inhibitor.
[13a]
The anchorage-independent cancer growth-specific inhibitor according to [13] above, further comprising a taxane anticancer agent.
[13b]
(A) administering a taxane anticancer agent and a p38 MAPK inhibitor to a cancer cell over 3-7 days; and
(B) and then administering a p38 MAPK inhibitor to the cancer cell for a week or more and not administering a taxane anticancer agent to the cancer cell,
Specific suppression of anchorage-independent cancer growth.
[14]
The p38 MAPK inhibitor is 5- (2,6-dichlorophenyl) -2-[(2,4-difluorophenyl) thio] -6H-pyrimido [1,6-b] pyridazin-6-one or 6-[(amino The anchorage-independent cancer growth-specificity according to [13] above, which is carbonyl) (2,6-difluorophenyl) amino] -2- (2,4-difluorophenyl) -3-pyridinecarboxamide or a salt thereof. Inhibitor.
[15]
5- (2,6-dichlorophenyl) -2-[(2,4-difluorophenyl) thio] -6H-pyrimido [1,6-b] pyridazin-6-one or 6-[(aminocarbonyl) (2, 6-difluorophenyl) amino] -2- (2,4-difluorophenyl) -3-pyridinecarboxamide or a salt thereof and a taxane anticancer agent.
[16]
The medicament according to [15] above, wherein the taxane anticancer agent is paclitaxel or a salt thereof.
[17]
The medicine according to [15] above, which is a kit.
Furthermore, the present invention provides the following [18] and [19].
[18]
2 or more times over a period of 2 to 8 months for patients with a history of administration of taxane anticancer drugs to enhance the anticancer effects and / or reduce side effects of taxane anticancer drugs A taxane anticancer agent is not administered during the period of 2 to 8 months.
Use of a p38 MAPK inhibitor for the manufacture of a replacement drug for a taxane anticancer agent.
[19]
Use of a p38 MAPK inhibitor for an anchorage independent cancer growth specific inhibitor.

According to the replacement agent for the taxane anticancer agent of the present invention, the drug suspension period of the taxane anticancer agent can be extended while maintaining the therapeutic effect of the taxane anticancer agent.
Moreover, according to this invention, an anchorage independent cancer growth specific inhibitor is provided.
The present invention also provides a medicament for preventing or treating non-small cell lung cancer.

FIG. 1A is a graph showing the inhibitory effect of Compound 1 on the growth of A549 cell colonies, ie, anchorage-independent growth. (Test Example 1) FIG. 1B is a phase contrast micrograph showing the inhibitory action of Compound 1 on the growth of A549 cell colonies, ie, anchorage-independent growth. (Test Example 1) FIG. 2 is a graph showing changes in tumor volume of mice. (Test Example 2) FIG. 3 is a graph showing mouse body weight fluctuations. (Test Example 2) FIG. 4A is a graph showing tumor weight of mice. (Test Example 2) FIG. 4B is a graph showing the white blood cell count. (Test Example 2) FIG. 5A is a graph showing changes in tumor volume in mice. (Test Example 3) FIG. 5B is a graph showing the weight fluctuation of the mouse. (Test Example 3)

[Replacement agents for taxane anticancer agents]
The replacement agent for the taxane anticancer agent of the present invention contains a p38 MAPK inhibitor.
Examples of the p38 MAPK inhibitor used in the present invention include the following compounds or salts thereof.
SB203580 (Ishizuka et al., J. Immunol. 167 (4): 2298-304 (2001), Calbiochem), SB202190 (Karahashi et al., Biochim. Biophys. Acta 1502 (2): 207-23 (2000) ) (Calbiochem), SB220025 (Calbiochem),
EO-1428 (Leo Pharm),
SB239063 (Legos et al., 2001, Brain Res. 892: 70-77; Barone et al., 2001, Med Res Rev. 21 (2): 129-145),
SB-885653 (GlaxoSmithKline), SB-238039 (GlaxoSmithKline), SB-239065 (GlaxoSmithKline), SB-242235 (GlaxoSmithKline), SB-681323 (GlaSmiKline)
SCIO-323 (SCIOS),
SCIO-469 (2- [6-Chloro-5- [4- (4-fluorobenzyl) -2 (R), 5 (S) -dimethylpiperazin-1-ylcarbonyl] -1-methyl-1H-indole- 3-yl] -N, N-dimethyl-2-oxoacetamide) (Oncogene (2004), 23 (54): 8766) (SCIOS),
BMS-640994 (N- [2-methyl-5- (N-methylcarbamoyl) phenyl] -2- [1 (R) -methylpropylamino] thiazole-5-carboxamide) (Bioorg Med Chem Lett (2008), 18 (6): 1762) (Bristol-Myers Squibb), BMS-582949 (Bristol-Myers Squibb), PS-540446 (Bristol-Myers Squibb),
SD-06 (1- [4- [3- (4-chlorophenyl) -4- (4-pyrimidinyl) -1H-pyrazol-5-yl] piperidin-1-yl] -2-hydroxyethanone) (Drug Data Rep (2005), 27 (3): 276) (Pfizer), CP-808844 (6- [4- (4-fluorophenyl) oxazol-5-yl] -3-isopropyl [1,2,4] triazolo [4,3-a] pyridine) (J Med Chem (2005), 48 (18): 5728) (Pfizer), PH-79804 (Pfizer),
R-1503 / RO-4402257 (6- (2,4-difluorophenoxy) -2- [3-hydroxy-1- (2-hydroxyethyl) propylamino] -8-methylpyrido [2,3-d] pyrimidine- 7 (8H) -one) (WHO Drug Inf (2006), 20 (4): 293) (Roche),
RO-3201195 (1- [5-amino-1- (4-fluorophenyl) -1H-pyrazol-4-yl] -1- [3- [2 (S), 3-dihydroxypropoxy] phenyl] methanone) ( J Med Chem (2006), 49 (5): 1562) (Roche),
R-1503 / RO-4402257 (6- (2,4-difluorophenoxy) -2- [3-hydroxy-1- (2-hydroxyethyl) propylamino] -8-methylpyrido [2,3-d] pyrimidine- 7 (8H) -one) (WHO Drug Inf (2006), 20 (4): 293) (Roche), RO-3201195 (1- [5-amino-1- (4-fluorophenyl) -1H-pyrazole -4-yl] -1- [3- [2 (S), 3-dihydroxypropoxy] phenyl] methanone) (J Med Chem (2006), 49 (5): 1562) (Roche),
ARRY-797 (ARRAY), AR-00182263 (ARRAY), AR-00218343 (ARRAY),
MW01-2-069A-SRM (3-Phenyl-4- (4-pyridyl) -6- [4- (2-pyrimidinyl) piperazin-1-yl] pyridazine) (J Neuroinflamm (2007), 4 (21)) (Northwestern University & University Louis Pasteur),
KC-706 (Kemia), LEO-15520 (Leo Pharm), TA-5493 (Tanabe), AKP-001 (Aska Pharm), ABC-1 (Abbott),
HEP-689, RWJ-67657, RDP-58, RDP-58, AMG-548, SC-040, SC-XX906, CP-64131, CNI-1493, RDP-58, CNI-1493,
5- (2,6-dichlorophenyl) -2-[(2,4-difluorophenyl) thio] -6H-pyrimido [1,6-b] pyridazin-6-one (VX-745),
6-[(aminocarbonyl) (2,6-difluorophenyl) amino] -2- (2,4-difluorophenyl) -3-pyridinecarboxamide (VX-702),
RPR 20075A (Mclay L M et al, (2001), Bioorg Med Chem. 9 (2): 537-554),
N- (3-tert-butyl-1-methyl-5-pyrazolyl) -N ′-(4- (4-pyridinylmethyl) phenyl) urea (Dumas J, (2002), Bioorg Med Chem Lett 12 (12): 1559 -62),
PD169316 (Paine et al., J. Biol. Chem. 275 (15): 11284-290 (2000)),
FR167653 (Matsuoka et al., Am. J. Physiol. Lung Cell Mol. Phsiol. 283: L103-12 (2002), Nikken Chemical)
BIRB796BS (N- [3-tert-butyl-1- (4-methylphenyl) -1H-pyrazol-5-yl] -N ′-[4- [2- (4-morpholinyl) ethoxy] naphthalen-1-yl Urea) (Blood 101, 4446-4448 (2003)) (Nat Structure Biol (2002), 9 (4): 268) (Boehringer Ingelheim),
[Trans-1- (4-hydroxycyclohexyl) -4- (4-fluorophenyl) -5- (2-methoxypyrimidin-4-yl) imidazole) (Underwood et al., Am. J. Physiol. Lung Cell Mol. Physiol. 279 (5): L895-902 (2000)),
2- (4-chlorophenyl) -4-) 4-fluorophenyl) -5-pyridin-4-yl-1,2-dihydropyrazol-3-one (Calbiochem),
Anti-p38 MAPK activity neutralizing antibody and anti-phosphorylated p38 MAPK activity neutralizing antibody.
These compounds can be produced by known methods or can be obtained commercially.
In particular, 5- (2,6-dichlorophenyl) -2-[(2,4-difluorophenyl) thio] -6H-pyrimido [1,6-b] pyridazin-6-one or a salt thereof is disclosed in WO 98/58502. And can be produced by the method described in WO 98/58502 or a method analogous thereto.
In addition, 6-[(aminocarbonyl) (2,6-difluorophenyl) amino] -2- (2,4-difluorophenyl) -3-pyridinecarboxamide or a salt thereof is a known compound described in WO2007 / 103468. , And a method according to WO98 / 58502 or a method analogous thereto.
In addition, the p38 MAPK inhibitors used in the present invention include inhibitors of p38 MAPK gene expression.

Among these, preferably, for example, 5- (2,6-dichlorophenyl) -2-[(2,4-difluorophenyl) thio] -6H-pyrimido [1,6-b] pyridazin-6-one (in the present specification) In the text, it may be referred to as Compound 1.) or a salt thereof, and 6-[(aminocarbonyl) (2,6-difluorophenyl) amino] -2- (2,4-difluorophenyl) -3-pyridinecarboxamide (Sometimes referred to herein as Compound 2) or a salt thereof.
Among these, particularly preferably, for example, 5- (2,6-dichlorophenyl) -2-[(2,4-difluorophenyl) thio] -6H-pyrimido [1,6-b] pyridazin-6-one, and 6-[(aminocarbonyl) (2,6-difluorophenyl) amino] -2- (2,4-difluorophenyl) -3-pyridinecarboxamide.

In the present specification, examples of the “salt” include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. Preferable examples of the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like. Preferable examples of the salt with organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzyl. Examples include salts with ethylenediamine and the like. Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of the salt with organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzene Examples thereof include salts with sulfonic acid, p-toluenesulfonic acid and the like. Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Is mentioned.
Of these, pharmaceutically acceptable salts are preferred. For example, when the compound has an acidic functional group, an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt) or an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium salt), When the compound has a basic functional group, for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid And salts with organic acids such as oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, and p-toluenesulfonic acid.

The replacement agent for the taxane anticancer agent of the present invention can enhance the anticancer effect and / or reduce the side effects of the taxane anticancer agent for patients having a history of administration of the taxane anticancer agent. Therefore, it is administered more than once over a period of 2-8 months. During the period of 2 to 8 months, the taxane anticancer agent is not administered to the patient.

In the present specification, “taxane anticancer agent” includes paclitaxel: ANX-513, BMS-181339, DHP-107, DHP-208, DTS-301, NSC-125973, Nova- 12005, OAS-PAC-100, SDP-013, MPI-5018 (Trademarks: Taxol, Anzatax, Zenaxol, Genexol, Genexol-PM, Nanotaxel (Nanotax) OncoGel, Paclical, Pacligel, Paxceed, Paxene, Xorane, Taxane (Yewtaxan), Genetaxyl, ABI-007 (Nanoparticle albumin-bound paclitaxel) (Trademark: Abraxan / Abraxane), CT-2 (Polyglutamate paclitaxel)) (trademark: Opaxio, PG-TXL, Geotax), docetaxel: ANX-514, NSC-628503, RP-56976, SDP-014, XRP-76, XRP-76L (Taxotere)), RPR-116258A, TAX-258, XD-258, XRP-6258. (Trademark: Cabazitaxel (cabazitaxel)) and larotaxel (larotaxel) (XRP9881) or the like salts thereof Among them, preferably, paclitaxel or a salt thereof.
In this specification, the side effects of taxane anticancer agents include shock, anaphylaxis-like symptoms, bone marrow suppression such as leukopenia or neutropenia, peripheral neuropathy, nausea and vomiting, paralysis, interstitial pneumonia, lung fiber Disease, acute respiratory distress syndrome, myocardial infarction, congestive heart failure, cardiac conduction disorder, pulmonary embolism, thrombophlebitis, stroke, pulmonary edema, hearing loss, tinnitus, gastrointestinal necrosis, intestinal perforation, gastrointestinal bleeding, gastrointestinal ulcer, Severe enteritis, intestinal obstruction, intestinal palsy, liver dysfunction, jaundice, pancreatitis, acute renal failure, mucocutaneous ocular syndrome (Stevens-Johnson syndrome), toxic epidermal necrosis (Lyell syndrome), and disseminated intravascular coagulation Syndrome (DIC).

The replacement drug of the present invention is used for patients having a history of administration of taxane anticancer agents. That is, the patient is usually a patient suffering from cancer to which a taxane anticancer is applied. Examples of such cancer include ovarian cancer, non-small cell lung cancer, breast cancer, stomach cancer, head and neck cancer, prostate cancer, and endometrial cancer.
Since the replacement drug of the present invention contains a p38 MAPK inhibitor, the replacement drug of the present invention is based on the fact that the present inventors have newly found that the p38 MAPK inhibitor has an anchorage-independent cancer growth-specific suppressing effect. Is suitably applied to patients suffering from cancer that can exhibit anchorage-independent growth.
In addition, from the fact that the present inventors have newly found that a p38 MAPK inhibitor is useful for the prevention or treatment of non-small cell lung cancer, the replacement drug of the present invention is a patient suffering from non-small cell lung cancer. It is preferably applied to.

The replacement drug of the present invention is administered after the administration of the taxane anticancer agent.
Preferably, a set of one administration of a xanthine anticancer agent and two or more administrations of the replacement agent of the present invention is repeated and administered.
By administering the replacement agent of the present invention after the administration of the taxane anticancer agent, the cancer treatment effect can be maintained even after the administration of the taxane anticancer agent. As a result, the taxane anticancer agent is maintained. The drug withdrawal period can be extended.
The administration of the replacement drug of the present invention is preferably started within 0 to 28 days (more preferably within 0 to 1 day) after the administration of the taxane anticancer agent.
After the start of administration of the replacement drug of the present invention, the replacement drug of the present invention is administered at least once more (total of 2 or more times). The replacement agent of the present invention is preferably administered 1 to 4 times a day (more preferably 2 times a day).
The dose of the replacement drug of the present invention varies depending on the administration subject, administration route, and the like. For example, when administered orally to an adult (60 kg), the active ingredient is about 5 to about 20 mg / day, preferably about 10 mg / day.

Such administration of the replacement agent of the present invention is continued for a period of 2 to 8 months (preferably a period of 3 to 6 months).
The starting point of the period is the first administration of the replacement drug of the present invention after the administration of the taxane anticancer agent.
On the other hand, when the next taxane anticancer agent is administered to the patient, the end point of the period is the last administration of the replacement drug of the present invention before the next administration. When no further taxane anticancer agent is administered to the patient, the end point of the period is the last administration of the replacement drug of the present invention to the patient.
That is, as described above, during the “period”, the taxane anticancer agent is not administered to the patient.
It should be noted that the form in which the p38 MAPK inhibitor is administered during the administration period of the taxane anticancer agent is also within the scope of the present invention.

A single administration of a taxane anticancer agent to a patient, such as administration of a replacement agent of the present invention as described above;
A method for treating cancer comprising administering the taxane anticancer agent to the patient two or more times over a period of 2 to 8 months following administration of the taxane anticancer agent is also an aspect of the present invention. .
In the present specification, examples of the p38 MAPK inhibitor include those described above. Of these, compound 1 or a salt thereof, and compound 2 or a salt thereof are preferable. Of these, compound 1 and compound 2 are particularly preferable.
The administration method (administration regimen) of the p38 MAPK inhibitor may be performed according to the administration of the replacement drug of the present invention described in the present specification.
Examples of cancer to be treated by this method include ovarian cancer, non-small cell lung cancer, breast cancer, gastric cancer, and endometrial cancer.
“Method of treating cancer” also includes “method of suppressing cancer metastasis”.

The dosage form of the replacement drug of the present invention is not particularly limited, and is a pharmaceutical composition in which a p38 MAPK inhibitor is mixed with a pharmacologically acceptable carrier as it is or according to a method known per se, such as a tablet (sugar-coated tablet, film (Including coated tablets), powders, granules, capsules (including soft capsules), orally disintegrating tablets, orally disintegrating films, solutions, injections, suppositories, sustained-release preparations, patches, etc. Good. Such a preparation can be safely administered orally or parenterally (eg, topical, rectal, intravenous administration, etc.). In particular, it is suitably administered as an oral preparation as a tablet, granule, capsule or the like.
Examples of pharmacologically acceptable carriers that may be used in the production of the pharmaceutical composition of the present invention include various organic or inorganic carrier substances that are commonly used as pharmaceutical materials. Examples of the additives include binders, disintegrants, water-soluble polymers, basic inorganic salts; solvents, solubilizers, suspending agents, isotonic agents, buffers, soothing agents, etc. in liquid preparations. Further, if necessary, additives such as ordinary preservatives, antioxidants, colorants, sweeteners, sour agents, foaming agents, and fragrances can be used.

Examples of the “excipient” include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, titanium oxide and the like.
Examples of the “lubricant” include magnesium stearate, sucrose fatty acid ester, polyethylene glycol, talc, stearic acid and the like.
Examples of the “binder” include hydroxypropylcellulose, hydroxypropylmethylcellulose, crystalline cellulose, starch, polyvinylpyrrolidone, gum arabic powder, gelatin, pullulan, low-substituted hydroxypropylcellulose, and the like.
Examples of the “disintegrant” include (1) crospovidone, (2) disintegrants called super disintegrants such as croscarmellose sodium (FMC-Asahi Kasei), carmellose calcium (Gotoku Pharmaceutical), (3) carboxymethyl Examples include starch sodium (eg, Matsutani Chemical Co., Ltd.), (4) low-substituted hydroxypropylcellulose (eg, Shin-Etsu Chemical Co., Ltd.), (5) corn starch and the like. The “crospovidone” has a chemical name of 1-ethenyl-2-pyrrolidinone homopolymer, including those called polyvinylpolypyrrolidone (PVPP) and 1-vinyl-2-pyrrolidinone homopolymer. Specific examples include Kollidon CL (manufactured by BASF), Polyplastidone XL (manufactured by ISP), Polyplaston XL-10 (manufactured by ISP), and Polyplastidone. INF-10 (manufactured by ISP).
Examples of the “water-soluble polymer” include ethanol-soluble water-soluble polymers [for example, cellulose derivatives such as hydroxypropylcellulose (hereinafter sometimes referred to as HPC), polyvinylpyrrolidone, etc.], ethanol-insoluble water-soluble polymers Molecules [for example, hydroxypropylmethylcellulose (hereinafter sometimes referred to as HPMC), cellulose derivatives such as methylcellulose, sodium carboxymethylcellulose, sodium polyacrylate, polyvinyl alcohol, sodium alginate, guar gum, etc.] and the like.
Examples of the “basic inorganic salt” include basic inorganic salts of sodium, potassium, magnesium and / or calcium. Preferred is a basic inorganic salt of magnesium and / or calcium. More preferred is a basic inorganic salt of magnesium. Examples of the basic inorganic salt of sodium include sodium carbonate, sodium hydrogen carbonate, disodium hydrogen phosphate and the like. Examples of the basic inorganic salt of potassium include potassium carbonate and potassium hydrogen carbonate. Examples of the basic inorganic salt of magnesium include heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium metasilicate aluminate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite [Mg ₆ Al ₂ ( OH) ₁₆ · CO ₃ · 4H ₂ O] and alumina / magnesium hydroxide, preferably heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide and the like. Examples of the basic inorganic salt of calcium include precipitated calcium carbonate and calcium hydroxide.

Examples of the “solvent” include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
Examples of the “dissolution aid” include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
Examples of the “suspending agent” include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; And hydrophilic polymers such as polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.
Examples of the “isotonic agent” include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
Examples of the “buffering agent” include buffer solutions of phosphate, acetate, carbonate, citrate, and the like.
Examples of the “soothing agent” include benzyl alcohol.
Examples of the “preservative” include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
Examples of the “antioxidant” include sulfite, ascorbic acid, α-tocopherol and the like.
Examples of the “colorant” include edible pigments such as edible yellow No. 5, edible red No. 2, and edible blue No. 2; edible lake pigments, bengara and the like.
Examples of the “sweetening agent” include saccharin sodium, dipotassium glycyrrhizin, aspartame, stevia, thaumatin and the like.
Examples of the “sour agent” include citric acid (anhydrous citric acid), tartaric acid, malic acid and the like.
Examples of the “foaming agent” include sodium bicarbonate.
The “fragrance” may be a synthetic product or a natural product, and examples thereof include lemon, lime, orange, menthol, and strawberry.

The p38 MAPK inhibitor in the replacement drug of the present invention may be used in combination with another drug (concomitant drug) in addition to the taxane anticancer agent.
Examples of such concomitant drugs include hormone therapeutic agents, anticancer agents (for example, chemotherapeutic agents, immunotherapeutic agents, or agents that inhibit the action of cell growth factors and their receptors).
Examples of the “hormone therapeutic agent” include phosfestol, diethylstilbestrol, chlorotrianiserin, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, allylestrenol, gestrinone, Mepaltricin, raloxifene, olmeloxifen, levormeloxifene, antiestrogens (eg, tamoxifen citrate, toremifene citrate, etc.), pill formulations, mepithiostan, testrolactone, aminoglutethimide, LH-RH agonists (eg, goserelin acetate, Buserelin, leuprorelin, etc.), droloxifene, epithiostanol, ethinyl estradiol sulfonate, aromatase inhibitor (eg, fadrozole hydrochloride, anastrozole) Letrozole, exemestane, borozole, formestane, etc.), antiandrogens (eg, flutamide, bicalutamide, nilutamide, etc.), 5α-reductase inhibitors (eg, finasteride, epristeride, etc.), corticosteroids (eg, dexamethasone, prednisolone) , Betamethasone, triamcinolone, etc.), androgen synthesis inhibitors (eg, abiraterone), retinoids and drugs that delay the metabolism of retinoids (eg, riarosol), among others, LH-RH agonists (eg, goserelin acetate, buserelin) And leuprorelin) are preferred.
Examples of the “chemotherapeutic agent” include alkylating agents, antimetabolites, anticancer antibiotics, plant-derived anticancer agents and the like.
Examples of the “alkylating agent” include nitrogen mustard, nitrogen mustard hydrochloride-N-oxide, chlorambutyl, cyclophosphamide, ifosfamide, thiotepa, carbocon, improsulfan tosylate, busulfan, nimustine hydrochloride, mitoblonitol, Faran, dacarbazine, ranimustine, sodium estramustine phosphate, triethylenemelamine, carmustine, lomustine, streptozocin, piprobroman, etoglucid, altretamine, ambmustine, dibrospdium hydrochloride, fotemustine, predonimustine, pumitepa, ribomustine, temosofredomestre , Trophosphamide, Dinostatin styramer, Carbocon, Adzelesin, Systemustin, Vizeres , Platinum complexes (carboplatin, cisplatin, miboplatin, nedaplatin, such as oxaliplatin), and the like.
Examples of the “antimetabolite” include mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, enositabine, cytarabine, cytarabine okphosphat, ancitabine hydrochloride, 5-FU drugs (eg, fluorouracil, tegafur, UFT, Doxyfluridine, carmofur, garocitabine, emiteful, etc.), aminopterin, leucovorin calcium, tabloid, butosine, folinate calcium, levofolinate calcium, cladribine, emiteful, fludarabine, gemcitabine, hydroxycarbamide, pentostatin, pyritroxime, idoxyuridine, mitoxifridin , And ambamustine.
Examples of the “anticancer antibiotic” include anthracycline anticancer drugs (daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride), actinomycin D, actinomycin C, mitomycin C, chromomycin A3, Examples include bleomycin hydrochloride, bleomycin sulfate, pepromycin sulfate, neocartinostatin, misramycin, sarcomycin, carcinophylline, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride and the like.
Examples of the “plant-derived anticancer agent” include vinca alkaloid anticancer drugs (vinblastine sulfate, vincristine sulfate, vindesine sulfate), etoposide, etoposide phosphate, teniposide, vinorelbine, DJ-927, TZT-1027, and the like.
Examples of the “immunotherapeutic agent (BRM)” include picibanil, krestin, schizophyllan, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulating factor, granulocyte colony stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, coryne Examples include bacterial parvum, levamisole, polysaccharide K, and procodazole.
The “cell growth factor” in the “drug that inhibits the action of cell growth factor and its receptor” may be any substance that promotes cell growth, and usually has a molecular weight of 20,000. The following peptides include factors that exert their actions at low concentrations by binding to receptors. Specifically, (1) EGF (epidermal growth factor) or substantially the same activity as that (Eg, EGF, haregulin (HER2 ligand), etc.), (2) insulin or a substance having substantially the same activity (eg, insulin, IGF (insulin-like growth factor)) 1, IGF-2, etc.], (3) FGF (fibroblast growth factor) or a substance having substantially the same activity [eg, acidic FGF, basic FGF, KGF (keratinocyte growth factor), FGF-10 etc., (4) Other cell growth factors [eg, CSF (colony stimulating factor), EPO (erythropoietin), IL- 2 (interleukin-2), NGF (nerve growth factor), PDGF (platelet-derived growth factor), TGFβ (transforming growth factor β), HGF ( Hepatocyte growth factor), VEGF (vascular endothelial growth factor) and the like.
The “cell growth factor receptor” may be any receptor capable of binding to the above-mentioned cell growth factor, and specifically includes an EGF receptor, a haregulin receptor (HER2). Insulin receptor, IGF receptor, FGF receptor-1 or FGF receptor-2.
Examples of the “drug that inhibits the action of cell growth factor” include trastuzumab (trade name Herceptin (anti-HER2 antibody)), gefitinib (EGFR-TKI (epidermal growth factor receptor tyrosine kinase inhibitor); Iressa (Trademark)), ZD1839 or cetuximab (EGFR-TKI (epidermal growth factor receptor tyrosine kinase inhibitor)), imatinib mesylate (c-met, c-kit, abl inhibitor; Gleevec (trademark)) Etc. Also included are drugs that block the action of multiple cell growth factors with a single drug, and drugs that block intracellular information emitted by cell growth factors.
In addition to the above-mentioned drugs, L-asparaginase, acegraton, procarbazine hydrochloride, protoporphyrin / cobalt complex, mercury hematoporphyrin / sodium, topoisomerase I inhibitors (eg, irinotecan, topotecan, exatecan, DE-310 etc.), topoisomerase II inhibition Drugs (eg, sobuzoxane), differentiation inducers (eg, retinoids, vitamin Ds, etc.), angiogenesis inhibitors, α-blockers (eg, tamsulosin hydrochloride, etc.) can also be used.
In addition, such other drugs can be administered to a patient even during a period in which the above taxane anticancer drug is not administered. Therefore, the form of the combination of the replacement drug of the present invention and such a combination drug is not particularly limited, and such a combination drug may be formulated in the replacement drug of the present invention together with the p38 MAPK inhibitor.

That is, the administration mode of the combination of the p38 MAPK inhibitor and the concomitant drug in the replacement drug of the present invention is not particularly limited, as long as the p38 MAPK inhibitor and the concomitant drug are combined at the time of administration. More specifically as such a dosage form, for example,
(1) Administration of the replacement drug of the present invention as a single preparation obtained by simultaneously formulating a p38 MAPK inhibitor and a concomitant drug,
(2) Co-administration of two preparations obtained by separately formulating a p38 MAPK inhibitor and a concomitant drug by the same administration route,
(3) Administration of two types of preparations obtained by separately formulating a p38 MAPK inhibitor and a concomitant drug with a time difference in the same administration route,
(4) Simultaneous administration of two preparations obtained by separately formulating a p38 MAPK inhibitor and a concomitant drug through different administration routes,
(5) Two types of preparations obtained by separately formulating a p38 MAPK inhibitor and a concomitant drug are administered at different time intervals in different administration routes.

The concomitant drug and the replacement drug of the present invention may be administered at the same time, but after the administration of the concomitant drug, the replacement drug of the present invention may be administered, or after the administration of the replacement drug of the present invention, A drug may be administered. When administered at a time difference, the time difference varies depending on the active ingredient to be administered, the dosage form, and the administration method. For example, when administering a concomitant drug first, within 0 minute to 28 days after administration of the concomitant drug, preferably Examples include a method of administering the replacement drug of the present invention within 0 minute to 1 day, more preferably within 0 minute to 2 hours. When the replacement drug of the present invention is administered first, the concomitant drug is administered within 0 minutes to 1 day, preferably within 0 minute to 12 hours, more preferably within 0 minute to 6 hours after the replacement drug of the present invention is administered. The method of administering is mentioned.

As described above, the replacement drug of the present invention is used for enhancing the anticancer action and / or reducing side effects of the taxane anticancer drug.
These can enhance the anticancer effect of a taxane anticancer agent in administration of a taxane anticancer agent to a patient by using a p38 MAPK inhibitor in combination with a taxane anticancer agent, and
The p38 MAPK inhibitor is used in combination with a taxane anticancer agent, thereby reducing side effects of the taxane anticancer agent in the administration of the taxane anticancer agent to a patient.
That is,
(I) a method of enhancing the anticancer action of a taxane anticancer agent in administration of a taxane anticancer agent to a patient by using a p38 MAPK inhibitor in combination with a taxane anticancer agent; and (Ii) A method of reducing the side effects of a taxane anticancer agent in administration of a taxane anticancer agent to a patient by using a p38 MAPK inhibitor in combination with a taxane anticancer agent,
Each is one embodiment of the present invention.
The administration regime of such a p38 MAPK inhibitor is in accordance with the administration regime of the replacement drug of the present invention described above.

<Pharmaceutical containing compound 1 or compound 2 or a salt thereof and a taxane anticancer agent>
A medicament containing Compound 1 or Compound 2 or a salt thereof and a taxane anticancer agent is also an embodiment of the present invention.

Compound 1 or Compound 2 or a salt thereof and a taxane anticancer agent are mixed according to a method known per se, and one pharmaceutical composition (for example, tablet, powder, granule, capsule (including soft capsule)) , Solutions, injections, suppositories, sustained-release agents, etc.) may be formulated and used together, or each may be formulated separately and administered to the same subject simultaneously or with a time difference.
When compound 1 or compound 2 or a salt thereof is formulated separately, a medicament containing compound 1 or compound 2 or a salt thereof and a taxane anticancer agent is compound 1 or compound 2. Alternatively, it may be a kit having a preparation (B) containing a preparation (A) containing those salts and a taxane anticancer agent.

The administration form of Compound 1 or Compound 2 or a salt thereof and a taxane anticancer agent is not particularly limited, and Compound 1 or Compound 2 or a salt thereof and a taxane anticancer agent are combined at the time of administration. Just do it. More specifically as such a dosage form, for example,
(1) Administration of a single preparation obtained by simultaneously preparing Compound 1 or Compound 2 or a salt thereof and a taxane anticancer agent,
(2) Simultaneous administration by the same route of administration of two types of preparations obtained by separately formulating Compound 1 or Compound 2 or a salt thereof and a taxane anticancer agent,
(3) Administration of two types of preparations obtained by separately formulating Compound 1 or Compound 2 or a salt thereof and a taxane anticancer agent with a time difference in the same administration route,
(4) Simultaneous administration by different administration routes of two types of preparations obtained by separately formulating Compound 1 or Compound 2 or a salt thereof and a taxane anticancer agent,
(5) Administration of two types of preparations obtained by separately formulating Compound 1 or Compound 2 or a salt thereof and a taxane anticancer agent at different administration routes (for example, Compound 1 or Compound 2 or a salt thereof → administration in the order of taxane anticancer agent, or administration in the reverse order) is used. Hereinafter, these administration forms are collectively abbreviated as the combination agent of the present invention.

As described above, when administering the concomitant agent of the present invention, the taxane anticancer agent and Compound 1 or Compound 2 or a salt thereof may be administered at the same time. After administration, Compound 1 or Compound 2 or a salt thereof may be administered, or after administration of Compound 1 or Compound 2 or a salt thereof, a taxane anticancer agent may be administered. When administered at a time difference, the time difference varies depending on the active ingredient to be administered, dosage form, and administration method. For example, when a taxane anticancer agent is administered first, it is 0 after the taxane anticancer agent is administered. Examples include a method of administering Compound 1 or Compound 2 or a salt thereof within minutes to 28 days, preferably 0 minutes to 1 day, more preferably 0 minutes to 2 hours. When Compound 1 or Compound 2 or a salt thereof is administered first, 0 minutes to 1 day, preferably 0 minutes to 12 hours, more preferably 0 after administration of Compound 1 or Compound 2 or a salt thereof. Examples include a method of administering a taxane anticancer agent within minutes to 6 hours.

The daily dose of the taxane anticancer agent varies depending on the administration subject, administration route, symptom and the like. The daily dose of the taxane anticancer agent varies depending on the administration subject, administration route, symptom and the like. For example, when paclitaxel (trademark: Taxol) is administered to a patient (adult, body weight of about 60 kg) by infusion, 135 to 250 mg / m ² body surface area is usually infused intravenously once every 3 weeks (24 hours ), Preferably 135 to 175 mg / m ^{2 in} vivo surface area (24 hours), more preferably 175 to 200 mg / m ^{2 in} vivo surface area intravenous infusion (3 hours) once every 3 weeks, Preferably, intravenous infusion (1 hour) with a body surface area of 80 to 100 mg / m ² may be administered once a week.
In addition, when docetaxel (trademark: Taxotere) is administered to a patient (adult, body weight of about 60 kg) by infusion, 60 to 80 mg / m ² body surface area intravenous infusion (60 minutes) is usually performed once every 3 weeks. Preferably, intravenous infusion (60 minutes) of 60 to 75 mg / m ² body surface area is administered once every 3 weeks.
When Compound 1 or Compound 2 or a salt thereof is used in combination with a taxane anticancer agent, the amount of each agent can be reduced within a safe range in consideration of the opposite effect of these agents.

The combination agent of the present invention has low toxicity. For example, Compound 1 or Compound 2 or a salt thereof or (and) the above taxane anticancer agent is mixed with a pharmacologically acceptable carrier according to a known method. Pharmaceutical compositions such as tablets (including sugar-coated tablets and film-coated tablets), powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release agents, etc. Can be safely administered orally or parenterally (eg, topical, rectal, intravenous, etc.). The concomitant drug of the present invention may be further used in combination with other drugs (concomitant drugs). Examples of such concomitant drugs include those exemplified for the above-described replacement drug of the present invention.

As the pharmacologically acceptable carrier that may be used for the production of the concomitant drug of the present invention, the same carriers as those used for the pharmaceutical composition of the present invention described above can be used.

The compounding ratio of Compound 1 or Compound 2 or a salt thereof and the taxane anticancer agent in the combination agent of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
Two or more taxane anticancer agents may be used in combination at an appropriate ratio.
The dose of the taxane anticancer agent can be appropriately selected based on the clinically used dose. The content ratio of Compound 1 or Compound 2 or a salt thereof and the taxane anticancer agent can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination, etc. Alternatively, the taxane anticancer agent may be used in an amount of 0.0001 to 0.1 parts by weight, preferably 0.002 to 0.01 parts by weight, based on 1 part by weight of Compound 2 or a salt thereof.

For example, the content of Compound 1 or Compound 2 or a salt thereof in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to about 99.9% by weight with respect to the whole preparation The range is preferably from about 0.1 to about 90% by weight.

The content of the taxane anticancer agent in the concomitant drug of the present invention varies depending on the form of the preparation. For example, it is usually in the range of about 0.01 to about 99.9% by weight relative to the whole preparation, Is in the range of about 0.1 to about 90.0% by weight.

The content of an additive such as a carrier in the concomitant drug of the present invention varies depending on the form of the preparation. For example, it is usually in the range of about 0.01 to about 99.9% by weight relative to the whole preparation, The range is from about 0.1 to about 90% by weight.

The same content may be used when compound 1 or compound 2 or a salt thereof and a taxane anticancer agent are formulated separately.

As described above, since the dosage varies depending on various conditions, an amount smaller than the above dosage may be sufficient, and it may be necessary to administer beyond the range.

<Anchor-independent cancer growth-specific inhibitor>
The anchorage-independent cancer growth-specific inhibitor of the present invention contains a p38 MAPK inhibitor.
Examples of the p38 MAPK inhibitor include those described above. Of these, compound 1 or a salt thereof, and compound 2 or a salt thereof are preferable. Of these, compound 1 and compound 2 are particularly preferable.
The dosage form and production method of the anchorage-independent cancer growth-specific inhibitor of the present invention are in accordance with the above-described replacement drug of the present invention.
The dose of the anchorage-independent cancer growth-specific inhibitor of the present invention varies depending on the administration subject, administration route, and the like, but when administered orally to an adult (60 kg), for example, about 5 to About 20 mg / day, preferably about 10 mg / day.
The p38 MAPK inhibitor in the anchorage-independent cancer growth-specific inhibitor of the present invention may be used in combination with other drugs. Examples of such concomitant drugs include taxane anticancer agents and hormonal therapeutic agents, anticancer agents (for example, chemotherapeutic agents, immunotherapeutic agents, or agents that inhibit the action of cell growth factors and their receptors). It is done. Specific examples of the concomitant drug include those similar to the concomitant drug that can be used in combination with the p38 MAPK inhibitor in the above replacement drug. Examples of preferable concomitant drugs include taxane anticancer agents and gemcitabine (trademark: Gemzar).
The administration mode of the combination of the p38 MAPK inhibitor and the concomitant drug in the anchorage-independent cancer growth specific inhibitor of the present invention is not particularly limited, and it is sufficient that the p38 MAPK inhibitor and the concomitant drug are combined at the time of administration. . More specifically, such a dosage form conforms to the dosage form of a combination of a p38 MAPK inhibitor and a concomitant drug in the replacement drug of the present invention.
Specifically, preferably,
(A) administering a taxane anticancer agent and a p38 MAPK inhibitor to a cancer cell over 3-7 days; and
(B) Next, the form including administering a p38 MAPK inhibitor to the said cancer cell over a week or more and not administering a taxane type anticancer agent to the said cancer cell is mentioned.
According to such administration form, the p38 MAPK inhibitor enhances and / or maintains the anchorage-independent cancer growth-specific inhibitory action and the taxane-based anticancer agent anchorage-independent cancer growth-specific inhibitory action, respectively. can do.

<Pharmaceuticals for the prevention or treatment of non-small cell lung cancer>
The medicament for preventing or treating non-small cell lung cancer of the present invention contains a p38 MAPK inhibitor.
Examples of the p38 MAPK inhibitor include those described above. Of these, compound 1 or a salt thereof, and compound 2 or a salt thereof are preferable. Of these, compound 1 and compound 2 are particularly preferable.
The pharmaceutical dosage form and production method for the prevention or treatment of non-small cell lung cancer of the present invention are in accordance with the above-mentioned replacement drug of the present invention.
The dose of the pharmaceutical agent for preventing or treating non-small cell lung cancer of the present invention varies depending on the administration subject, administration route, etc., but for example, when administered orally to an adult (60 kg), about 5 to about 20 mg / day, preferably about 10 mg / day.
The p38 MAPK inhibitor in the medicament for preventing or treating non-small cell lung cancer of the present invention may be used in combination with other drugs. Examples of such concomitant drugs include taxane anticancer agents and hormonal therapeutic agents, anticancer agents (for example, chemotherapeutic agents, immunotherapeutic agents, or agents that inhibit the action of cell growth factors and their receptors). It is done. Specific examples of the concomitant drug include those similar to the concomitant drug that can be used in combination with the p38 MAPK inhibitor in the above replacement drug. Examples of preferable concomitant drugs include taxane anticancer agents and gemcitabine (trademark: Gemzar).
The administration mode of the combination of the p38 MAPK inhibitor and the concomitant drug in the medicament for the prevention or treatment of non-small cell lung cancer of the present invention is not particularly limited as long as the p38 MAPK inhibitor and the concomitant drug are combined at the time of administration. Good. More specifically, such a dosage form conforms to the dosage form of a combination of a p38 MAPK inhibitor and a concomitant drug in the replacement drug of the present invention.

Hereinafter, the present invention will be described in more detail with reference examples, test examples, and production examples, but the present invention is not limited thereto.

Reference Examples 1 and 2
As a p38 MAPK inhibitor, 5- (2,6-dichlorophenyl) -2-[(2,4-difluorophenyl) thio] -6H-pyrimido [1,6-b] pyridazin-6-one (compound 1), and 6-[(aminocarbonyl) (2,6-difluorophenyl) amino] -2- (2,4-difluorophenyl) -3-pyridinecarboxamide (Compound 2) was synthesized. Synthesis examples of

compounds

1 and 2 are shown in Reference Examples 1 and 2.

Reference example 1
Synthesis of 5- (2,6-dichlorophenyl) -2-[(2,4-difluorophenyl) thio] -6H-pyrimido [1,6-b] pyridazin-6-one (Compound 1)

(1-1)
2- (6-Chloropyrazin-3-yl) -2- (2,6-dichlorophenyl) acetonitrile

A suspension of sodium amide (90%, 6.8 g, 0.17 mol) in tetrahydrofuran (100 mL) was cooled to 0 ° C. To this suspension was added dropwise a solution of 2,6-dichlorophenylacetonitrile (25 g, 0.14 mol) in tetrahydrofuran (50 mL). After completion of the dropwise addition, the mixture was stirred at room temperature for 1 hour and then cooled to 0 ° C. To this reaction solution, a tetrahydrofuran solution (50 mL) of 3,6-dichloropyridazine (21 g, 0.14 mol) was added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water and extracted twice with ethyl acetate. The combined extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (filler Chromatorex NH DM1020 (trade name, manufactured by Fuji Silysia Chemical), hexane-ethyl acetate = 1: 3) to obtain the title compound (6.2 g, 15%).

(1-2)
2- (2,6-Dichlorophenyl) -2- {6-[(2,4-difluorophenyl) thio] pyridazin-3-yl} acetonitrile

Sodium hydride (60% paraffin dispersion, 1.6 g, 40 mmol) was washed twice with hexane and then suspended in tetrahydrofuran (70 mL). To this suspension, 2,4-difluorothiophenol (5.6 g, 38 mmol) obtained in (1-1) above was added dropwise. To this reaction solution was added dropwise a hot ethanol solution (150 mL) of 2- (6-chloropyrazin-3-yl) -2- (2,6-dichlorophenyl) acetonitrile (11 g, 37 mmol). After completion of the dropwise addition, the reaction solution was heated to reflux for 13 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. To the residue was added 1N aqueous sodium hydroxide solution, and the mixture was extracted twice with ethyl acetate. The combined extracts were washed with a saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the title compound (15 g, 99%).

(1-3)
2- (2,6-Dichlorophenyl) -2- {6-[(2,4-difluorophenyl) thio] pyrazin-3-yl} acetamide

2- (2,6-Dichlorophenyl) -2- {6-[(2,4-difluorophenyl) thio] pyridazin-3-yl} acetonitrile (3.0 g, 7. 3 mmol) and sulfuric acid (50 mL) were stirred at 100 ° C. for 2 hours. The reaction mixture was cooled to room temperature and adjusted to pH = 8 using 8N aqueous sodium hydroxide solution. The reaction mixture was extracted twice with ethyl acetate. The combined extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the title compound (2.3 g, 75%).

(1-4)
5- (2,6-Dichlorophenyl) -2-[(2,4-difluorophenyl) thio] -6H-pyrimido [1,6-b] pyridazin-6-one

2- (2,6-Dichlorophenyl) -2- {6-[(2,4-difluorophenyl) thio] pyrazin-3-yl} acetamide (1.5 g, 3. 5 mmol) in toluene (15 mL) was added N, N-dimethylformamide dimethyl acetal (1.4 mL, 11 mmol) and the mixture was stirred at 50 ° C. for 20 minutes. After the reaction mixture was cooled to room temperature, the resulting solid was collected by filtration and washed with toluene. The crude crystals were recrystallized from ethyl acetate to obtain the title compound (0.79 g, 52%).

Reference example 2
Synthesis of 6-[(aminocarbonyl) (2,6-difluorophenyl) amino] -2- (2,4-difluorophenyl) -3-pyridinecarboxamide

(2-1)
Ethyl 2- (2,4-difluorophenyl) pyridine-3-carboxylate

Under a nitrogen atmosphere, 2,4-difluorophenylboronic acid (11) was added to a suspension of ethyl 2-chloronicotinate (10.8 g, 58.1 mmol) and sodium carbonate (8.00 g, 75.6 mmol) in ethanol (235 mL). 0.0 g, 69.8 mmol) and tetrakis (triphenylphosphine) palladium (336 mg, 0.291 mmol) were sequentially added, and the mixture was stirred at 80 ° C. for 24 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The combined extracts were washed with saturated brine and dried over magnesium sulfate. The solution was filtered through Celite and concentrated under reduced pressure to give the title compound (16.5 g, quantitative) as a brown oil.

(2-2)
2- (2,4-Difluorophenyl) -3-pyridinecarboxylic acid ethyl 1-oxide

To a solution of ethyl 2- (2,4-difluorophenyl) pyridine-3-carboxylate (15.0 g, 57.0 mmol) obtained in (2-1) above in acetic acid (150 mL), a hydrogen peroxide-urea complex ( 21.4 g, 228 mmol) was added, and the mixture was stirred at 70 ° C. for 15 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and then poured onto ice. Ethyl acetate and sodium hydrogen carbonate (solid) were added to the reaction mixture to adjust to pH = 7, and the mixture was extracted with ethyl acetate. The combined extracts were washed twice with 5% aqueous sodium hydrogen carbonate solution and then twice with saturated brine. The solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (14.8 g, 93%) as a brown oil.

(2-3)
Ethyl 6-chloro-2- (2,4-difluorophenyl) -3-pyridinecarboxylate

2- (2,4-Difluorophenyl) -3-pyridinecarboxylic acid ethyl 1-oxide (15.0 g, 53.7 mmol) obtained in (2-2) above was added to phosphorus oxychloride (30.1 mL, 322 mmol). And stirred at 70 ° C. for 15 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was poured into ice. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (7.81 g, 49%) as a yellow oil.

(2-4)
Tert-Butyl (2,6-difluorophenyl) carbamate

To a solution of 2,6-difluoroaniline (20.0 g, 155 mmol) in tert-butanol (100 mL) is added dropwise a solution of di-tert-butyl dicarbonate (9.30 g, 42.60 mmol) in tert-butanol (100 mL) at room temperature. And stirred for 5 days. The mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude crystals were recrystallized from hexane to obtain the title compound (11.5 g, 32%) as a white powder.

(2-5)
Ethyl 6-[(tert-butoxycarbonyl) (2,6-difluorophenyl) amino] -2- (2,4-difluorophenyl) -3-pyridinecarboxylate

Ethyl 6-chloro-2- (2,4-difluorophenyl) -3-pyridinecarboxylate (4.90 g, 16.5 mmol) obtained in (2-3) above and cesium carbonate (14.7 g, 45.45). 3 mmol) of N-methylpyrrolidine (15 mL) was warmed to 65 ° C. and then tert-butyl (2,6-difluorophenyl) carbamate (5.85 g, 25) obtained in (2-4) above. 0.5 mmol) of N-methylpyrrolidine (10 mL) was added dropwise over 10 minutes, and the mixture was stirred at 65 ° C. for 15 hours, and further stirred at 75 ° C. for 24 hours. The reaction mixture was cooled to room temperature, poured into water, and stirred at room temperature for 15 hours. The precipitated solid was collected by filtration, washed with water and dried to give the title compound (7.54 g, 93%) as a brown powder.

(2-6)
2- (2,4-Difluorophenyl) -6-[(2,6-difluorophenyl) amino] pyridine-3-carboxylic acid ethyl hydrochloride

Ethyl 6-[(tert-butoxycarbonyl) (2,6-difluorophenyl) amino] -2- (2,4-difluorophenyl) -3-pyridinecarboxylate obtained in (2-5) above (7. To a suspension of (00 g, 14.3 mmol) in dichloromethane (40 mL) was added trifluoroacetic acid (3 mL), and the mixture was stirred for 15 hours. The reaction mixture was concentrated under reduced pressure, toluene was added to the residue, and the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, 4N hydrogen chloride-ethyl acetate solution (9 mL) and diethyl ether (45 mL) were added, and the mixture was stirred as it was for 5 hr. The precipitated solid was collected by filtration, washed with diethyl ether and dried to give the title compound (4.5 g, 74%) as a white powder.

(2-7)
2- (2,4-Difluorophenyl) -6-[(2,6-difluorophenyl) amino] -3-pyridinecarboxylic acid

2- (2,4-Difluorophenyl) -6-[(2,6-difluorophenyl) amino] -3-pyridinecarboxylic acid ethyl hydrochloride (4.30 g, 10.3) obtained in (2-6) above. 1 mmol) was dissolved in a mixed solution of tetrahydrofuran (40 mL), methanol (40 mL) and water (30 mL), 4N aqueous sodium hydroxide solution (10 mL, 40.0 mmol) was added, and the mixture was stirred at 80 ° C. for 15 hr. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the residue was extracted with 1N hydrochloric acid (30 mL), tetrahydrofuran and ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from diethyl ether to give the title compound (2.98 g, yield 82%) as a white powder.

(2-8)
2- (2,4-Difluorophenyl) -6-[(2,6-difluorophenyl) amino] -3-pyridinecarboxamide

2- (2,4-difluorophenyl) -6-[(2,6-difluorophenyl) amino] -3-pyridinecarboxylic acid (3.00 g, 8.28 mmol) obtained in (2-7) above and 1-Hydroxybenzotriazole (1.65 g, 10.77 mol) was dissolved in N, N-dimethylformamide (38 mL) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (2.06 g, 10 .77 mol) was added and stirred for 15 minutes. 28% aqueous ammonia (4.5 mL) was added, and the mixture was further stirred for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and water, and concentrated under reduced pressure. Ethyl acetate (30 mL) was added to the residue, and the mixture was stirred at 70 ° C. for 30 minutes, and then stirred at room temperature for 30 minutes. The crystallized product was collected by filtration and washed with diisopropyl ether to give the title compound (2.39 g, yield 80%) as a white powder.

(2-9)
6-[(Aminocarbonyl) (2,6-difluorophenyl) amino] -2- (2,4-difluorophenyl) -3-pyridinecarboxamide

2- (2,4-difluorophenyl) -6-[(2,6-difluorophenyl) amino] -3-pyridinecarboxamide (0.86 g, 2.4 mmol) obtained in (2-8) above was added to tetrahydrofuran. (20 mL) and a solution of trichloroacetyl isocyanate (0.49 g, 2.60 mmol) in tetrahydrofuran (3 mL) was added while stirring under ice cooling. After stirring for 30 minutes, 8N ammonia-methanol solution (10 mL) was added dropwise, and the mixture was stirred at 0-5 ° C. for 7 hours. The reaction solution was concentrated while maintaining the same temperature, and water was added to the residue. After stirring this for 5 minutes, the crystallized product was collected by filtration, washed with water and dried. The obtained white powder was recrystallized from tetrahydrofuran and further recrystallized from acetone-water (1: 1) to obtain the title compound (587 mg, yield 61%) as a white powder.

Test example 1
DMEM: F12 medium containing gel of DMEM: F12 medium (Invitrogen) containing 0.8 ml 0.7% agar (agar) in 12 well-plate (well plate) and 0.6 ml 0.35% agar And put the gel. In addition, 10,000 A549 NSCLC cells (ATCC CCL-185) were seeded in the gel containing 0.35% agar. The next day, together with 5 μM Compound 1 (solvent: DMSO) or an equal amount of DMSO, paclitaxel (Calbiochem # 580555) (solvent: DMSO) was developed to a total concentration of 10 points from 0 nM, 0.25 nM to 64 nM as shown in FIG. And added. After 11 days, the formed A549 cell colonies were stained with neutral red (neutral red) and photographed with a stereomicroscope. The volume of the stained colony in the image was digitized, and the percentage of colony formation inhibition of each sample was measured using a sample without addition of both agents as a control.
The results are shown in FIG. 1A. As is clear from FIG. 1A, treatment with Compound 1 alone inhibited nearly 90% of colony formation, and confirmed a specific inhibitory effect on anchorage-independent growth unique to malignant tumors. Moreover, the combined use of Compound 1 and paclitaxel was able to reduce the concentration of paclitaxel required for anchorage-independent growth inhibition. In FIG. 1A, in “Compound 1 (+) normalization”, when the colony volume (28.6% with respect to no addition) when 3.3 μM compound 1 is added at 0 nM paclitaxel is defined as 100%, each paclitaxel The percentage (%) of the colony volume when 3.3 μM compound 1 is added in the presence of concentration is shown.
As an additional test, a gel of DMEM: F12 medium containing 0.8 ml 0.7% agar and a gel of DMEM: F12 medium containing 0.6 ml 0.35% agar in 12 well-plate was added. . In addition, 10,000 A549 NSCLC cells were seeded in the gel containing 0.35% agar. The next day, 2 nM paclitaxel (Calbiochem # 580555) (solvent: DMSO) was added along with 3.3 μM compound 1 (solvent: DMSO) or an equal amount of DMSO. Seven days later, the gel was washed twice with DMEM: F12 medium to remove paclitaxel and Compound 1, and then 3.3 μM Compound 1 (solvent: DMSO) or an equivalent amount of DMSO was added again. After 14 days, the formed colonies of A549 cells were stained with neutral red and photographed with a phase contrast microscope.
The results are shown in FIG. 1B. Nearly 100% anchorage-independent growth inhibition (up to 1 cell) by co-addition of 3.3

μM compound

1,2 nM paclitaxel was maintained with 3.3 μM compound 1 alone after removal of paclitaxel. Therefore, if Compound 1 completely inhibited anchorage-independent growth for 1 week by co-addition with paclitaxel, it was possible to maintain the inhibition with Compound 1 alone even after removal of paclitaxel.

Test example 2
Mice subcutaneously transplanted with 5000000 A549 cells per animal 13 days later, administration of Compound 1 was started as follows, and the test was conducted for 20 days. Solvent (0.5 w / v% methylcellulose 400 solution (Wako)) administration, 100 mg / kg body weight Compound 1 (once / day, po (oral administration)) single agent administration, 100 mg / kg body weight Compound 1 (Once / day, po) and 30 mg / kg body weight Paclitaxel (Bristol-Myers 100 mg / 16.7 ml injection) (Day 1 and Day 4 (once each), ip (Intraperitoneal administration)), paclitaxel (on day 1 and day 4 (once each), ip), single agent administration, paclitaxel (once every 3 days, ip) Single agent administration. The tumor diameter was measured almost every two days, and the tumor volume and the body weight of the mouse were measured (FIGS. 2 and 3). On day 21, all mice were dissected and the tumor, liver, spleen mass, blood red blood cell, white blood cell, and platelet count were measured (FIG. 4A (tumor weight), FIG. 4B (white blood cell count)).
As is apparent from FIG. 2, 3 weeks after the start of administration, tumors in the group administered with 30 mg / kg body weight paclitaxel only on Day 1 (Day 1) and Day 4 (Day 4) were 58 tumors in the control group. The tumors in the group receiving 30 mg / kg paclitaxel on Day 1 and Day 4 and daily Compound 1 were up to 14.3% of the control group tumors, while remaining reduced to .9% Reduced.
As is clear from FIG. 3, weight loss, a significant side effect of paclitaxel, was suppressed by administration of Compound 1.
As is clear from FIGS. 4A and 4B, the decrease in white blood cell count, which is a significant side effect of paclitaxel, was suppressed by administration of Compound 1.

Test example 3
Mice subcutaneously transplanted with 5000000 A549 cells per animal 7 days later (Day 7), administration of Compound 2 was started as follows, and the test was conducted for 21 days.
Solvent (0.5 w / v% methylcellulose 400 solution (Wako Pure Chemical Industries)) administration, 100 mg / kg body weight Compound 2 (once / day, po) single agent administration, 30 mg / kg body weight Paclitaxel (Bristol Myers 100 mg / 16.7 ml injection solution (Day 1 and Day 4 (once each time), ip (intraperitoneal administration)), 100 mg / kg body weight Compound 2 (once / day, p.o.) and 30 mg / kg body weight paclitaxel (Bristol-Myers 100 mg / 16.7 ml injection) (Day 1 and Day 4 (once each time, ip)). The tumor diameter was measured approximately every 3 days, and the tumor volume and mouse body weight were measured (FIGS. 5A and 5B).
As is apparent from FIG. 5A, 3 weeks after the start of administration, the tumor of the group administered with 30 mg / kg body weight paclitaxel only on the first day and the fourth day was reduced to 26.1% of the tumor of the control group. Tumors in the group receiving 30 mg / kg body weight paclitaxel on day 1 and day 4 and compound 2 daily were -0.6% of the control group tumors. It was reduced to. Further, as is clear from FIG. 5B, weight loss, which is a significant side effect of paclitaxel, was suppressed by administration of Compound 2.

Formulation Example (1) Compound 1 10.0 g
(2) Lactose 70.0g
(3) Corn starch 50.0g
(4) 7.0g of soluble starch
(5) Magnesium stearate 3.0 g
Compound 1 (10.0 g) and magnesium stearate (3.0 g) are granulated with 70 ml of an aqueous solution of soluble starch (7.0 g as soluble starch), then dried and mixed with 70.0 g of lactose and 50.0 g of corn starch (lactose, Corn starch, soluble starch and magnesium stearate are all conforming to the 14th revised Japanese Pharmacopoeia). The mixture is compressed to obtain tablets.

Claims

containing a p38 MAPK inhibitor;
2 or more times over a period of 2 to 8 months for patients with a history of administration of taxane anticancer drugs to enhance the anticancer effects and / or reduce side effects of taxane anticancer drugs A taxane anticancer agent is not administered during the period of 2 to 8 months.
Replacement drug for taxane anticancer drugs.
The p38 MAPK inhibitor is 5- (2,6-dichlorophenyl) -2-[(2,4-difluorophenyl) thio] -6H-pyrimido [1,6-b] pyridazin-6-one or 6-[(amino The medicament according to claim 1, which is carbonyl) (2,6-difluorophenyl) amino] -2- (2,4-difluorophenyl) -3-pyridinecarboxamide or a salt thereof.
The medicament according to claim 1, wherein the taxane anticancer agent is paclitaxel or a salt thereof.
A method of enhancing the anticancer action of a taxane anticancer agent in administration of a taxane anticancer agent to a patient by using a p38 MAPK inhibitor in combination with the taxane anticancer agent.
A method for reducing side effects of a taxane anticancer agent in administration of a taxane anticancer agent to a patient by using a p38 MAPK inhibitor in combination with a taxane anticancer agent.
The p38 MAPK inhibitor is 5- (2,6-dichlorophenyl) -2-[(2,4-difluorophenyl) thio] -6H-pyrimido [1,6-b] pyridazin-6-one or 6-[(amino The method according to claim 4 or 5, which is carbonyl) (2,6-difluorophenyl) amino] -2- (2,4-difluorophenyl) -3-pyridinecarboxamide or a salt thereof.
The method according to claim 4 or 5, wherein the taxane anticancer agent is paclitaxel or a salt thereof.
A method of treating cancer, comprising administering a taxane anticancer agent to a patient once,
Administration of the taxane anticancer agent followed by two or more administrations of the p38 MAPK inhibitor to the patient over a period of 2 to 8 months.
The p38 MAPK inhibitor is 5- (2,6-dichlorophenyl) -2-[(2,4-difluorophenyl) thio] -6H-pyrimido [1,6-b] pyridazin-6-one or 6-[(amino The method according to claim 8, which is carbonyl) (2,6-difluorophenyl) amino] -2- (2,4-difluorophenyl) -3-pyridinecarboxamide or a salt thereof.
The treatment method according to claim 8, wherein the taxane anticancer agent is paclitaxel or a salt thereof.
A medicament for the prevention or treatment of non-small cell lung cancer, comprising a p38 MAPK inhibitor.
The p38 MAPK inhibitor is 5- (2,6-dichlorophenyl) -2-[(2,4-difluorophenyl) thio] -6H-pyrimido [1,6-b] pyridazin-6-one or 6-[(amino The medicament according to claim 11, which is carbonyl) (2,6-difluorophenyl) amino] -2- (2,4-difluorophenyl) -3-pyridinecarboxamide or a salt thereof.
An anchorage-independent cancer growth-specific inhibitor containing a p38 MAPK inhibitor.
The p38 MAPK inhibitor is 5- (2,6-dichlorophenyl) -2-[(2,4-difluorophenyl) thio] -6H-pyrimido [1,6-b] pyridazin-6-one or 6-[(amino The anchorage-independent cancer growth-specific inhibition according to claim 13, which is carbonyl) (2,6-difluorophenyl) amino] -2- (2,4-difluorophenyl) -3-pyridinecarboxamide or a salt thereof. medicine.
5- (2,6-dichlorophenyl) -2-[(2,4-difluorophenyl) thio] -6H-pyrimido [1,6-b] pyridazin-6-one or 6-[(aminocarbonyl) (2, 6-difluorophenyl) amino] -2- (2,4-difluorophenyl) -3-pyridinecarboxamide or a salt thereof and a taxane anticancer agent.
The medicament according to claim 15, wherein the taxane anticancer agent is paclitaxel or a salt thereof.
The medicine according to claim 15, which is a kit.