JP2015117182A - Anticancer agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an anticancer agent having excellent anticancer activity.SOLUTION: The present invention provides: a compound represented by the formula (I), where Aris phenyl or 4-hydroxy-3-methoxyphenyl and Aris substituted or unsubstituted phenyl, or a salt thereof; and an anticancer agent containing the compound or salt thereof.

Description

  The present invention relates to an anticancer agent.

  TrkA, TrkB and TrkC, which are Trk family receptor tyrosine kinases, are signal receptors having a neurotrophic factor as a ligand. Neurotrophic factors include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), NT-3, and NT-4 / 5, but BDNF and NT-4 / 5 act on TrkB. BDNF is generally reported to regulate the proliferation, differentiation and survival of nerve cells (Patent Document 1).

  Normally, adherent cells regulate survival and proliferation through interaction with the extracellular matrix that is used as the scaffold, but apoptosis is induced when the interaction is lost. Such a phenomenon is called “Anoikis”. In recent years, it has been reported that anoikis of cells are specifically suppressed by activation of TrkB (Non-patent Document 1). This document suggests that human tumors that overexpress TrkB and have anoikis resistance may metastasize through infiltration into lymph vessels and blood vessels.

  Neuroblastoma is known as a kind of tumor that excessively expresses TrkB. Neuroblastoma is a tumor of the sympathetic nervous system and is the most common solid tumor other than the head of a child. Neuroblastomas expressing TrkB are highly progressive and in some cases fatal. TrkB-expressing tumors are known to secrete BDNF themselves or have a paracrine survival circuit, thereby causing prolonged tumor survival, drug resistance, and angiogenesis.

  Currently, surgical treatment and chemotherapy are used as treatment methods for neuroblastoma. Anticancer drugs used in chemotherapy are mainly vincristine, cyclophosphamide, ifosfamide, doxorubicin, pirarubicin, cisplatin, carboplatin, etoposide, etc., depending on the degree of cancer progression and malignancy. Combined multidrug therapy is being used.

  On the other hand, development of a novel compound targeting neuroblastoma and the like has also been attempted, and Patent Document 1 discloses a TrkB inhibitor.

  The present inventors have previously found that specific arylthioacetamide derivatives and aryloxyacetamide derivatives have an anticancer action and have filed patent applications (Patent Document 2).

Special table 2008-543762 JP 2013-95743 A

Nature, 2004 Aug 26: 430 (7003): 973-974; 1034-1039

  An object of the present invention is to provide an anticancer agent having a more excellent action by chemically modifying the compound described in Patent Document 2.

で示される化合物（Ｎ−（２−メトキシフェニル）−２−［［５−（４−クロロフェニル）−４−（１Ｈ−ピロール−１−イル）−４Ｈ−１，２，４−トリアゾール−３−イル］チオ］アセトアミド）の１，２，４−トリアゾール環の５位に結合している４−クロロフェニル基をフェニル基又は４−ヒドロキシ−３−メトキシフェニル基に置き換えると、抗癌作用が著しく向上することを見出し、本発明を完成するに至った。即ち、本発明は以下の発明を包含する。 The inventors have the following formula (A) described in Patent Document 2:

(N- (2-methoxyphenyl) -2-[[5- (4-chlorophenyl) -4- (1H-pyrrol-1-yl) -4H-1,2,4-triazole-3- Replacing the 4-chlorophenyl group bonded to the 5-position of the 1,2,4-triazole ring of [yl] thio] acetamide) with a phenyl group or 4-hydroxy-3-methoxyphenyl group, the anticancer activity is significantly improved. As a result, the present invention has been completed. That is, the present invention includes the following inventions.

（式中、Ａｒ^１はフェニル基又は４−ヒドロキシ−３−メトキシフェニル基であり、Ａｒ^２は置換又は非置換のフェニル基である。）
で示される化合物又はその塩。
（２）前記式（Ｉ）においてＡｒ^２が、少なくともオルト位がメトキシ基で置換されているフェニル基である前記（１）に記載の化合物又はその塩。
（３）前記（１）又は（２）に記載の化合物又はその塩を含有する抗癌剤。
（４）癌が神経芽腫、肺癌、大腸癌、子宮癌又は乳癌である前記（３）に記載の抗癌剤。
（５）癌が神経芽腫である前記（３）に記載の抗癌剤。
（６）癌の進展及び／又は転移の抑制のための前記（３）〜（５）のいずれかに記載の抗癌剤。 (1) The following formula (I)

(In the formula, Ar ¹ is a phenyl group or a 4-hydroxy-3-methoxyphenyl group, and Ar ² is a substituted or unsubstituted phenyl group.)
Or a salt thereof.
(2) The compound or salt thereof according to (1), wherein Ar ² in formula (I) is a phenyl group substituted at least in the ortho position with a methoxy group.
(3) The anticancer agent containing the compound or its salt as described in said (1) or (2).
(4) The anticancer agent according to (3), wherein the cancer is neuroblastoma, lung cancer, colon cancer, uterine cancer or breast cancer.
(5) The anticancer agent according to (3), wherein the cancer is neuroblastoma.
(6) The anticancer agent according to any one of (3) to (5), which is for suppressing cancer progression and / or metastasis.

  ADVANTAGE OF THE INVENTION According to this invention, the anticancer agent which has the outstanding anticancer action can be provided.

  Hereinafter, the present invention will be described in detail.

In the formula (I), the phenyl group represented by Ar ² is, for example, a C _1-6 -alkoxy group, a C _1-6 -alkyl group, a C _2-6 -alkenyl group, a C _2-6 -alkynyl group, an aromatic From group, acyl group, hydroxyl group, carboxyl group, cyano group, halogen atom, aralkyl group, aralkyloxy group, nitro group, amino group, C _1-6 -alkylamino group, diC _1-6 -alkylamino group, etc. It may be substituted with one or more selected substituents.

Examples of the C _1-6 -alkoxy group include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, preferably a methoxy group.

Examples of the C _1-6 -alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and cyclopropyl. Group, cyclobutyl group, cyclopentyl group, and cyclohexyl group.

The C _1-6 -alkyl group is an aromatic group, acyl group, hydroxyl group, carboxyl group, halogen atom, C _1-6 -alkoxy group, amino group, C _1-6 -alkylamino group, di-C _1-6. -It may be substituted with one or more substituents selected from alkylamino groups and the like.

Examples of the C _2-6 -alkenyl group include a vinyl group, 1-propenyl group, allyl group, 1-butenyl group, 2-butenyl group, pentenyl group, and hexenyl group.

Examples of the C _2-6 -alkynyl group include ethynyl group, 1-propynyl group, 2-propynyl (propargyl) group, 3-butynyl group, pentynyl group, and hexynyl group.

  Examples of aromatic groups include aromatic hydrocarbon groups such as phenyl, tolyl, and naphthyl groups; furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, Examples thereof include aromatic heterocyclic groups such as triazolyl groups (1,2,3-triazolyl groups, 1,2,4-triazolyl groups), pyridyl groups, pyrimidinyl groups, pyridazinyl groups, pyrazinyl groups, quinolyl groups, and isoquinolyl groups.

The aromatic group includes a C _1-6 -alkyl group, a C _2-6 -alkenyl group, a C _2-6 -alkynyl group, an aromatic group, an acyl group, a hydroxyl group, a carboxyl group, a cyano group, a halogen atom, and C _1. Substituted with one or more substituents selected from a _-6 -alkoxy group, an aralkyl group, an aralkyloxy group, a nitro group, an amino group, a C _1-6 -alkylamino group, a diC _1-6 -alkylamino group, and the like. May be.

Examples of the acyl group include a C _1-6 -aliphatic acyl group such as a formyl group, an acetyl group, a propionyl group (propanoyl group), a butyryl group (butanoyl group), a valeryl group (pentanoyl group), and a hexanoyl group; An aromatic acyl group (aroyl group) such as a toluoyl group can be mentioned.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
Examples of the aralkyl group include a benzyl group and a phenethyl group.

Examples of the aralkyloxy group include a benzyloxy group and a phenethyloxy group.
The aralkyl group and aralkyloxy group are an aromatic group, acyl group, hydroxyl group, carboxyl group, halogen atom, C _1-6 -alkoxy group, amino group, C _1-6 -alkylamino group, di-C _1-6-. It may be substituted with one or more substituents selected from alkylamino groups and the like.

The Ar ^2, at least _{C 1-6} - substituted with an alkoxy group and a halogen atom - a phenyl group substituted with an alkoxy group _{(e.g., the C 1-6} - a phenyl group substituted with an alkoxy _{group, C 1-6} A phenyl group (for example, 2-methoxyphenyl group, 4-fluoro-2-methoxyphenyl group, 5-fluoro-2-methoxyphenyl group) substituted at least in the ortho position with a methoxy group. Further preferred.

  The salt of the compound represented by the formula (I) is preferably a pharmaceutically acceptable salt. For example, hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, nitric acid, pyrosulfuric acid, metaphosphoric acid Or a salt with an organic acid such as citric acid, benzoic acid, acetic acid, propionic acid, fumaric acid, maleic acid, sulfonic acid (for example, methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid) Can be mentioned. Moreover, when it has a phenolic hydroxyl group or a carboxyl group, it can also be used as alkali metal salts, such as a sodium salt and potassium salt.

（式中、Ａｒ^１はフェニル基又は４−ヒドロキシ−３−メトキシフェニル基であり、Ａｒ^２は置換又は非置換のフェニル基である。） The compound of the present invention represented by the formula (I) can be produced, for example, by the method shown below.

(In the formula, Ar ¹ is a phenyl group or a 4-hydroxy-3-methoxyphenyl group, and Ar ² is a substituted or unsubstituted phenyl group.)

  Ethyl chloroacetate and sodium hydroxide are added to an ethanol solution of the thiol compound (1) and reacted to obtain ethyl triazolylthioacetate (2). Ethyl triazolylthioacetate (2) is reacted with dimethoxytetrahydrofuran in the presence of iron (III) chloride and acetic acid to give ethyl 4- (1-pyrrolyl) triazolylthioacetate (3). Next, compound (I) of the present invention can be produced by reacting compound (3) with an aniline compound in the presence of 1-hydroxybenzotriazole and carbodiimide.

  In order to purify the product obtained as described above, a commonly used technique such as column chromatography using silica gel or the like as a carrier or a recrystallization method using methanol, ethanol, chloroform, dimethyl sulfoxide, water or the like is used. You can do it. Examples of the column chromatography elution solvent include methanol, ethanol, chloroform, acetone, hexane, dichloromethane, ethyl acetate, and mixed solvents thereof.

  The anticancer agent of the present invention can be used in combination with other commonly used anticancer agents, immunosuppressive agents, and the like in consideration of the desired therapeutic effect. In this case, the dose described later can be increased or decreased as necessary.

The type of cancer to which the anticancer agent of the present invention is applied is not particularly limited. For example, malignant melanoma, malignant lymphoma, lung cancer, esophageal cancer, stomach cancer, colon cancer, rectal cancer, colon cancer, ureteral tumor, gallbladder cancer, bile duct Cancer, biliary tract cancer, breast cancer, liver cancer (liver cancer), pancreatic cancer, testicular tumor, maxillary cancer, tongue cancer, lip cancer, oral cancer, pharyngeal cancer, laryngeal cancer, kidney cancer, ovarian cancer, uterine cancer, prostate cancer, thyroid gland Cancer, brain tumor, Kaposi's sarcoma, hemangioma, leukemia, polycythemia vera, neuroblastoma, retinoblastoma, myeloma, cystoma, sarcoma, osteosarcoma, myoma, skin cancer, basal cell carcinoma, skin appendage cancer , Skin metastatic cancer, cutaneous melanoma and the like. Preferred is neuroblastoma, lung cancer, colon cancer, uterine cancer or breast cancer, and particularly preferred is neuroblastoma.
The anticancer agent of the present invention can also be used for progression of various cancers and / or suppression of metastasis.

Hereinafter, the dosage and formulation of the compound (I) of the present invention will be described.
Compound (I) of the present invention can be administered to animals and humans as it is or together with a conventional pharmaceutical carrier. The dosage form is not particularly limited, and is appropriately selected and used as necessary. Tablets, capsules, granules, fine granules, powders, sustained-release preparations, suspensions, emulsions, syrups, elixirs And oral preparations such as pills, and parenteral preparations such as injections, suppositories, coatings, and patches.

  The oral preparation is produced according to a conventional method using, for example, starch, lactose, sucrose, mannitol, carboxymethylcellulose, corn starch, inorganic salts and the like.

  In this type of preparation, a binder, a disintegrant, a surfactant, a lubricant, a fluidity promoter, a corrigent, a colorant, a fragrance and the like can be appropriately used in addition to the above-mentioned excipients.

  Examples of the binder include starch, dextrin, gum arabic powder, gelatin, hydroxypropyl starch, methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, and macrogol.

  Examples of the disintegrant include starch, hydroxypropyl starch, carboxymethylcellulose sodium, carboxymethylcellulose calcium, carboxymethylcellulose, and low-substituted hydroxypropylcellulose.

  Examples of the surfactant include sodium lauryl sulfate, soybean lecithin, sucrose fatty acid ester, and polysorbate 80.

  Examples of the lubricant include talc, waxes, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, and polyethylene glycol.

  Examples of the fluidity promoter include light anhydrous silicic acid, dry aluminum hydroxide gel, synthetic aluminum silicate, and magnesium silicate.

  Injectables are produced according to conventional methods, and generally used as diluents are distilled water for injection, physiological saline, aqueous glucose solution, olive oil, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol and the like. Furthermore, you may add a disinfectant, antiseptic | preservative, and a stabilizer as needed. In addition, from the viewpoint of stability, the injection can be frozen after filling into a vial or the like, the water can be removed by a normal freeze-drying technique, and the liquid can be re-prepared from the freeze-dried product immediately before use. Furthermore, an isotonic agent, stabilizer, preservative, soothing agent and the like may be added as necessary.

  Examples of other parenteral preparations include coating solutions for external use, ointments and the like, patches, suppositories for rectal administration, and the like, which are produced according to a conventional method.

  The preparation of the present invention varies depending on the dosage form, administration route and the like, and can be administered from 1 to several times to 1 to several times / week to month.

  In order to exert the desired effect as an oral preparation, it varies depending on the patient's age, body weight, and degree of disease, but usually 1 to 200 mg of the weight of compound (I) is taken in several times a day for adults. Is appropriate.

  In order to exert the desired effect as a parenteral preparation, it varies depending on the age, body weight, and degree of disease of the patient, but usually 1-50 mg / day intravenously or intravenously as the weight of compound (I) in adults. Subcutaneous injection and intramuscular injection are suitable.

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples, but the scope of the present invention is not limited thereto.

[Example 1] N- (2-methoxyphenyl) -2-[[5-phenyl-4- (1H-pyrrol-1-yl) -4H-1,2,4-triazol-3-yl] thio] Synthesis of acetamide (compound 1)

(1) Synthesis of ethyl 2- (4-amino-5-phenyl-4H-1,2,4-triazol-3-yl) thioacetate 4-amino-5-phenyl-4H-1,2,4-triazole After adding ethyl chloroacetate (1.37 ml, 12.8 mmol) and sodium hydroxide (0.4 g, 10 mmol) to an ethanol (100 ml) solution of -3-thiol (2.06 g, 10.7 mmol), the mixture was brought to room temperature. And stirred for 3 hours. The reaction solution was suction filtered and recrystallized with ethanol to give ethyl 2- (4-amino-5-phenyl-4H-1,2,4-triazol-3-yl) thioacetate (1.62 g, 54%). Was obtained as a white solid.

(2) Synthesis of ethyl 2-[[5-phenyl-4- (1H-pyrrol-1-yl) -4H-1,2,4-triazol-3-yl] thio] acetate 2- (4-amino- 5-phenyl-4H-1,2,4-triazol-3-yl) ethyl thioacetate (1.62 g, 5.8 mmol) to iron (III) chloride (0.90 g, 5.5 mmol), water (5 ml) , Acetic acid (0.1 ml) and dimethoxytetrahydrofuran (0.90 ml, 7.0 mmol) were sequentially added, and the mixture was heated at 60 ° C. for 2 hours. Then, ethyl acetate and distilled water were added and extracted. Further, the aqueous layer was extracted twice with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with a column (hexane: ethyl acetate = 3: 2) to give 2-[[5-phenyl-4- (1H-pyrrol-1-yl) -4H-1 , 2,4-Triazol-3-yl] thio] ethyl acetate (0.75 g, 40%) was obtained as a brown solid.

(3) Synthesis of 2-[[5-phenyl-4- (1H-pyrrol-1-yl) -4H-1,2,4-triazol-3-yl] thio] acetic acid Distilled water (4 ml) and methanol ( 12-ml) ethyl 2-[[5-phenyl-4- (1H-pyrrol-1-yl) -4H-1,2,4-triazol-3-yl] thio] acetate (360 mg, 1.1 mmol). ) And sodium hydroxide (0.2 g, 5 mmol) were added, and the mixture was stirred at room temperature for 90 minutes. The reaction solution was neutralized with 1N hydrochloric acid, extracted with ethyl acetate and distilled water. Further, the aqueous layer was extracted twice with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 2-[[5-phenyl-4- (1H-pyrrol-1-yl) -4H-1,2,4-triazol-3-yl] thio] acetic acid (0.24 g). 73%) as a white solid.

(4) N- (2-methoxyphenyl) -2-[[5-phenyl-4- (1H-pyrrol-1-yl) -4H-1,2,4-triazol-3-yl] thio] acetamide ( Synthesis of Compound 1) 2-[[5-Phenyl-4- (1H-pyrrol-1-yl) -4H-1,2,4-triazol-3-yl] thio] acetic acid (0.15 g, 0.5 mmol) ), 1-hydroxybenzotriazole (0.07 g, 0.5 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.1 g, 0.5 mmol) in N, N-dimethylformamide ( To the solution, triethylamine (0.14 ml, 1 mmol) and 2-methoxyaniline (0.07 ml, 0.6 mmol) were added and stirred at room temperature for 16 hours. The reaction solution was extracted by adding an aqueous sodium hydrogen carbonate solution and ethyl acetate, and the aqueous layer was further extracted twice with ethyl acetate. The organic layer was acidified with 1N hydrochloric acid and extracted, and the aqueous layer was extracted twice with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with a column (hexane: ethyl acetate = 1: 3-1: 5) to give N- (2-methoxyphenyl) -2-[[5-phenyl-4- ( 1H-pyrrol-1-yl) -4H-1,2,4-triazol-3-yl] thio] acetamide (60 mg, 30%) was obtained as a light brown solid.

¹ H-NMR (400 MHz, DMSO-D ₆ ) 4.07 (s, 3H), 4.23 (s, 2H), 6.54 (dd, J = 2.2Hz, 2H), 6.95 (dd, J = 2.2Hz, 2H) , 7.01 (bd, 1H), 7.09 (bt, 1H), 7.20 (bt, 1H), 7.48-7.59 (m, 5H), 8.48 (bd, 1H), 9.80 (s, 1H)
¹³ C-NMR (100 MHz, CDCl ₃ ) 35.42, 55.83, 110,10, 110.52, 120.05, 120.86, 124.06, 124.38, 126.25, 127.71, 129.06, 130.94, 148.54, 165.83

[Example 2] N- (2-methoxyphenyl) -2-[[5- (4-hydroxy-3-methoxyphenyl) -4- (1H-pyrrol-1-yl) -4H-1,2,4 -Triazol-3-yl] thio] acetamide (Compound 2) synthesis

(1) Synthesis of 4-hydroxy-3-methoxybenzoic acid hydrazide Methyl 4-hydroxy-3-methoxybenzoate (3.64 g, 20 mmol) was added to hydrazine monohydrate (2.5 ml) at 60 ° C. After heating for 15 minutes, ethanol (10 ml) was added and the mixture was further heated to reflux at 80 ° C. for 4 hours. After the solvent of the reaction solution was distilled off under reduced pressure, the residue was cooled in an ice bath and suction filtered with ice water. Furthermore, 4-hydroxy-3-methoxybenzoic acid hydrazide was obtained as a white solid by recrystallization from ethanol.

(2) Synthesis of 4-amino-5- (4-hydroxy-3-methoxyphenyl) -4H-1,2,4-triazole-3-thiol Ethanol of 4-hydroxy-3-methoxybenzoic acid hydrazide (20 mmol) To the (125 ml) solution, carbon disulfide (1.82 ml, 30 mmol) was added dropwise, potassium hydroxide (1.7 g, 30 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Diethyl ether (200 ml) was added to the reaction solution, and suction filtration was performed to obtain a white solid. To this solid was added hydrazine monohydrate (6 ml) and distilled water (4 ml), and the mixture was heated to reflux at 113 ° C. for 3 hours. The reaction solution was cooled in an ice bath and concentrated hydrochloric acid was added to precipitate a white solid. This was suction filtered and recrystallized with ethanol to give 4-amino-5- (4-hydroxy-3-methoxyphenyl) -4H-1,2,4-triazole-3-thiol (2.23 g, 47 %) As a white solid.

(3) Synthesis of ethyl 2-[[4-amino-5- (4-hydroxy-3-methoxyphenyl) -4H-1,2,4-triazol-3-yl] thio] acetate 4-amino-5- Sodium hydroxide (0.4 g, 10 mmol) was added to a solution of (4-hydroxy-3-methoxyphenyl) -4H-1,2,4-triazole-3-thiol (2.23 g, 9.4 mmol) in ethanol (50 ml). And ethyl chloroacetate (1.2 ml, 11.3 mmol) were added and stirred at room temperature for 3 hours. The reaction solution was suction filtered and recrystallized from ethanol to give 2-[[4-amino-5- (4-hydroxy-3-methoxyphenyl) -4H-1,2,4-triazol-3-yl] thio. Ethyl acetate (1.47 g, 48%) was obtained as a white solid.

(4) 2-[[5- (4-Hydroxy-3-methoxyphenyl) -4- (1H-pyrrol-1-yl) -4H-1,2,4-triazol-3-yl] thio] ethyl acetate Synthesis of 2- [4-amino-5- (4-hydroxy-3-methoxyphenyl) -4H-1,2,4-triazol-3-yl] thioacetate (1.47 g, 4.5 mmol) in chloride Iron (III) (0.72 g, 4.4 mmol), water (16 ml), acetic acid (0.2 ml) and dimethoxytetrahydrofuran (0.86 ml, 6.5 mmol) were added in this order and heated at 60 ° C. for 3 hours. Then, ethyl acetate and distilled water were added and extracted. Further, the aqueous layer was extracted twice with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 2-[[5- (4-hydroxy-3-methoxyphenyl) -4- (1H-pyrrol-1-yl) -4H-1,2,4-triazole-3- [Il] thio] ethyl acetate (0.84 g, 49%) was obtained as an oil.

(5) 2-[[5- (4-Hydroxy-3-methoxyphenyl) -4- (1H-pyrrol-1-yl) -4H-1,2,4-triazol-3-yl] thio] acetic acid Synthesis To a mixed solution of distilled water (4 ml) and methanol (12 ml) was added 2-[[5- (4-hydroxy-3-methoxyphenyl) -4- (1H-pyrrol-1-yl) -4H-1,2, 4-Triazol-3-yl] thio] ethyl acetate (0.84 g, 2.24 mmol) and sodium hydroxide (0.2 g, 5 mmol) were added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was neutralized with 1N hydrochloric acid, extracted with ethyl acetate and distilled water. Further, the aqueous layer was extracted twice with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 2-[[5- (4-hydroxy-3-methoxyphenyl) -4- (1H-pyrrol-1-yl) -4H-1,2,4-triazole-3- [Il] thio] acetic acid (621 mg, 80%) was obtained as an oil.

(6) N- (2-methoxyphenyl) -2-[[5- (4-hydroxy-3-methoxyphenyl) -4- (1H-pyrrol-1-yl) -4H-1,2,4-triazole Synthesis of -3-yl] thio] acetamide (Compound 2) 2-[[5- (4-Hydroxy-3-methoxyphenyl) -4- (1H-pyrrol-1-yl) -4H-1,2,4 -Triazol-3-yl] thio] acetic acid (200 mg, 0.58 mmol), 1-hydroxybenzotriazole (80 mg, 0.6 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (120 mg, 0.6 mmol) in N, N-dimethylformamide (4 ml) and triethylamine (0.18 ml, 1.2 mmol) and 2-methoxyaniline (0.08 ml, 0.7 mmol) was added and stirred at room temperature for 16 hours. The reaction solution was extracted with 1N hydrochloric acid and ethyl acetate. Further, the aqueous layer was extracted twice with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with a column (hexane: ethyl acetate = 1: 3-1: 5) to give N- (2-methoxyphenyl) -2-[[5- (4-hydroxy- 3-Methoxyphenyl) -4- (1H-pyrrol-1-yl) -4H-1,2,4-triazol-3-yl] thio] acetamide (48 mg, 18%) was obtained as a light brown solid.

¹ H-NMR (400 MHz, DMSO-D ₆ ) 3.75 (s, 2H), 3.99 (s, 2H), 4.33 (s, 2H), 6.49 (dd, J = 2.3Hz), 6.80-7.26 (m, 6H), 7.38 (dd, J = 2.3Hz), 8.13 (bd, 1H), 9.77 (s, 1H), 9.79 (s, 1H)
¹³ C-NMR (100 MHz, CDCl ₃ ) 35.50, 55.79, 55.91, 108.30, 110.13, 110.51, 114.95, 116.29, 120.11, 120.21, 120.99, 121.03, 124.17, 127.62, 146.64, 148.05, 148.53, 153.53, 165.81

Example 3 N- (5-Fluoro-2-methoxyphenyl) -2-[[5-phenyl-4- (1H-pyrrol-1-yl) -4H-1,2,4-triazole-3- Synthesis of [Il] thio] acetamide (Compound 3)

  2-[[5-Phenyl-4- (1H-pyrrol-1-yl) -4H-1,2,4-triazol-3-yl] thio] acetic acid (90 mg, obtained in Example 1 (3) 0.3 mmol), 1-hydroxybenzotriazole (40 mg, 0.3 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (60 mg, 0.3 mmol) in N, N-dimethylformamide (2 ml) ) Triethylamine (0.09 ml, 0.6 mmol) and 5-fluoro-2-methoxyaniline (0.04 ml, 0.36 mmol) were added to the solution and stirred at room temperature for 16 hours. The reaction solution was extracted by adding an aqueous sodium hydrogen carbonate solution and ethyl acetate, and the aqueous layer was further extracted twice with ethyl acetate. The organic layer was acidified with 1N hydrochloric acid and extracted, and the aqueous layer was extracted twice with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with a column (hexane: ethyl acetate = 1: 3-1: 5) to give N- (5-fluoro-2-methoxyphenyl) -2-[[5-phenyl. -4- (1H-pyrrol-1-yl) -4H-1,2,4-triazol-3-yl] thio] acetamide (20 mg, 16%) was obtained as a light brown solid.

¹ H-NMR (400 MHz, DMSO-D ₆ ) 4.01 (s, 3H), 4.36 (s, 2H), 6.48 (dd, J = 2.3Hz, 2H), 6.90-7.14 (m, 2H), 7.40 ( dd, J = 2.3Hz, 2H), 7.46 (d, 2H), 7.55 (dd, 2H), 7.62 (dd, 1H), 8.06 (dd, 1H), 9.84 (s, 1H)

Example 4 N- (5-Fluoro-2-methoxyphenyl) -2-[[5- (4-hydroxy-3-methoxyphenyl) -4- (1H-pyrrol-1-yl) -4H-1 , 2,4-Triazol-3-yl] thio] acetamide (Compound 4)

  2-[[5- (4-Hydroxy-3-methoxyphenyl) -4- (1H-pyrrol-1-yl) -4H-1,2,4-triazole-3 obtained in Example 2 (5) -Yl] thio] acetic acid (200 mg, 0.58 mmol), 1-hydroxybenzotriazole (80 mg, 0.6 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (120 mg, 0.6 mmol) To a solution of N, N-dimethylformamide (4 ml), triethylamine (0.18 ml, 1.2 mmol) and 5-fluoro-2-methoxyaniline (0.08 ml, 0.7 mmol) were added and stirred at room temperature for 16 hours. . The reaction solution was extracted with 1N hydrochloric acid and ethyl acetate. Further, the aqueous layer was extracted twice with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with a column (hexane: ethyl acetate = 1: 3-1: 5) to give N- (5-fluoro-2-methoxyphenyl) -2-[[5- ( 4-Hydroxy-3-methoxyphenyl) -4- (1H-pyrrol-1-yl) -4H-1,2,4-triazol-3-yl] thio] acetamide (30 mg, 11%) as a pale brown solid Got as.

¹ H-NMR (400 MHz, DMSO-D ₆ ) 3.74 (s, 3H), 4.00 (s, 3H), 4.35 (s, 2H), 6.48 (dd, J = 2.3Hz, 2H), 6.81-7.21 ( m, 4H), 7.38 (dd, J = 2.3Hz, 2H), 8.08 (bd, 1H), 9.78 (s, 1H), 9.97 (s, 1H)

Example 5 N- (4-Fluoro-2-methoxyphenyl) -2-[[5- (4-hydroxy-3-methoxyphenyl) -4- (1H-pyrrol-1-yl) -4H-1 , 2,4-Triazol-3-yl] thio] acetamide (Compound 5)

  2-[[5- (4-Hydroxy-3-methoxyphenyl) -4- (1H-pyrrol-1-yl) -4H-1,2,4-triazole-3 obtained in Example 2 (5) -Yl] thio] acetic acid (100 mg, 0.29 mmol), 1-hydroxybenzotriazole (40 mg, 0.3 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (60 mg, 0.3 mmol) Triethylamine (0.09 ml, 0.6 mmol) and 4-fluoro-2-methoxyaniline (0.04 ml, 0.35 mmol) were added to a solution of N, N-dimethylformamide (2 ml) and stirred at room temperature for 16 hours. . The reaction solution was extracted with 1N hydrochloric acid and ethyl acetate. Further, the aqueous layer was extracted twice with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with a column (hexane: ethyl acetate = 1: 3-1: 5) to give N- (4-fluoro-2-methoxyphenyl) -2-[[5- ( 4-Hydroxy-3-methoxyphenyl) -4- (1H-pyrrol-1-yl) -4H-1,2,4-triazol-3-yl] thio] acetamide (45 mg, 33%) as a black solid Obtained.

¹ H-NMR (400 MHz, DMSO-D ₆ ) 3.75 (s, 3H), 4.00 (s, 3H), 4.31 (s, 2H), 6.48 (dd, J = 2.3Hz, 2H), 6.82-7.13 ( m, 3H), 7.38 (dd, J = 2.3Hz, 2H), 7.56-7.86 (m, 2H), 9.77 (s, 1H), 9.80 (s, 1H)
¹³ C-NMR (100MHz, CDCl ₃ ) 35.35, 55.92, 56.02, 105.73, 108.27, 110.55, 112.01, 114.96, 120.22, 120.94, 124.59, 125.58, 146.67, 148.02, 148.18, 160.89, 160.97, 174.52

[Example 6]
The test compounds shown in Table 1 were allowed to act on human neuroblastoma-derived cells, SH-SY5Y / TrkB cells, and the IC _{50 of} each compound was determined. SH-SY5Y / TrkB cells are cell lines in which TrkB is overexpressed in SH-SY5Y cells. The test method is as follows.

SH-SY5Y / TrkB cells cultured in 10% FBS RPMI1640 medium were prepared so that 1 × 10 ⁴ cells were contained in 1 mL of the medium, and seeded in a 24-well plate. The cells were cultured overnight, and each test compound was dissolved in a DMSO solution, diluted with a medium, and treated with cultured cells at a concentration of each compound ranging from 0 to 0.3 μM. After 6 days (7 days for compounds 3 to 5), the number of cells was measured with a cell counter and IC ₅₀ was determined from a logarithmic graph (Table 1).

As can be seen from Table 1, the compound of the present invention has 6 times or more anticancer activity as compared with Compound 6 described in Patent Document 2. Further, since Compound 7, Ar ¹ in the formula (I) even though the same as compound 1 and 3 of the present invention, Ar ² in formula (I) is not substituted or unsubstituted phenyl group, Anticancer activity is extremely inferior.

Claims (6)

Formula (I)

(In the formula, Ar ¹ is a phenyl group or a 4-hydroxy-3-methoxyphenyl group, and Ar ² is a substituted or unsubstituted phenyl group.)
Or a salt thereof. The compound or a salt thereof according to claim 1, wherein Ar ² in the formula (I) is a phenyl group substituted at least in the ortho position with a methoxy group.   The anticancer agent containing the compound or its salt of Claim 1 or 2.   The anticancer agent according to claim 3, wherein the cancer is neuroblastoma, lung cancer, colon cancer, uterine cancer or breast cancer.   The anticancer agent according to claim 3, wherein the cancer is neuroblastoma.   The anticancer agent according to any one of claims 3 to 5, which is used for suppressing cancer progression and / or metastasis.