JPWO2019188456A1 - New antitumor agent - Google Patents

Abstract

To provide a compound having antitumor activity and cancer metastasis inhibitory activity, and an antitumor agent containing the compound as an active ingredient. Formula (1): (In the formula, ring A represents a 5- to 6-membered ring which may have a substituent, and R1 and R4 are independently hydrogen atom, halogen atom, hydroxyl group and nitro group, respectively. , Cyan group, C1-6 alkyl group, halogenated C1-6 alkyl group or C1-6 alkoxy group, and the benzene ring B and the benzene ring C may each have a further substituent, and the benzene ring B may have a substituent. The −C (R2) (R3) group and the benzene ring C are each bonded to a separate carbon atom constituting the ring A, and R2 and R3 are independently hydrogen atom, halogen atom, hydroxyl group, and nitro. It represents a group, a cyano group, a C1-6 alkyl group, a halogenated C1-6 alkyl group or a C1-6 alkoxy group, or R2 and R3 together represent an oxo group or a hydroxyimino group). Compound or salt thereof.

Description

The present invention relates to compounds having antitumor activity and cancer metastasis inhibitory activity, particularly pyrazole derivatives and pyrimidine derivatives, and antitumor agents containing the compounds as active ingredients.

Currently, the mainstream cancer therapeutic agents are those focusing on cell proliferation, and their effects are exerted by suppressing the division and proliferation of cancer cells. For example, the standard treatment for pancreatic cancer is gemcitabine, which is combined with several anticancer drugs. In recent years, immune checkpoint inhibitors have emerged and are approved for skin and lung cancers, and are effective in several cancer diseases by breaking the mechanism by which cancer cells escape cytotoxicity and increasing their own cytotoxic activity. ing.

Cancer is often fatal by causing metastasis, but existing anticancer drugs target cell growth inhibition and have little effect in suppressing cancer metastasis itself. In addition, cancer therapeutic agents targeting cancer metastasis itself are not currently used as therapeutic agents. However, if further metastasis can be suppressed in both early and advanced cancers, the cancer can be removed by surgery, and a significant improvement in prognosis can be expected.

An object of the present invention is to provide a compound having antitumor activity and cancer metastasis inhibitory activity, and an antitumor agent containing the compound as an active ingredient.

As a result of diligent studies to solve the above problems, the present inventors have found that the compound represented by the following formula (1) has antitumor activity and cancer metastasis inhibitory activity, and have completed the present invention.
That is, the present invention is as follows.
[1] Equation (1):

(During the ceremony,
Ring A represents a 5- to 6-membered ring that may have a substituent,
R ¹ and R ⁴ independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a cyano group, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group or a C _1-6 alkoxy group, respectively. ,
The benzene ring B and the benzene ring C may each have a further substituent.
The benzene ring BC (R ² ) (R ³ ) group and the benzene ring C are each bonded to a separate carbon atom constituting the ring A.
R ² and R ³ independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a cyano group, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group or a C _1-6 alkoxy group, respectively. Alternatively, R ² and R ³ together represent an oxo or hydroxyimino group. )
(In the present specification, it may be abbreviated as "Compound (1)") or a salt thereof.
[1'] Equation (1):

(During the ceremony,
Ring A represents a 5- to 6-membered ring that may have a substituent,
R ¹ and R ⁴ independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a cyano group, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group or a C _1-6 alkoxy group, respectively. ,
The benzene ring B and the benzene ring C may each have a further substituent.
The benzene ring BC (R ² ) (R ³ ) group and the benzene ring C are each bonded to a separate carbon atom constituting the ring A.
R ² and R ³ independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a cyano group, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group or a C _1-6 alkoxy group, respectively. Alternatively, R ² and R ³ together represent an oxo group. )
(In the present specification, it may be abbreviated as "Compound (1)") or a salt thereof.
[2] The compound according to [1] or [1'], wherein ^{R 1} and R ^{4 are independently chlorine atoms, bromine atoms or methoxy groups, respectively.}
[3] The compound according to [1], [1'] or [2], wherein the ring A is a pyrazole ring or a pyrimidine ring which may have a methyl group.
[4] The compound according to any one of [1] to [3] and [1'], wherein ^{R 2} and R ^{3 are together as an oxo group.}
[5] R ¹ and R ⁴ are independently chlorine atoms, bromine atoms or methoxy groups, and ring A is a pyrazole ring or a pyrimidine ring which may have a methyl group, and R ² and R ³ together are an oxo group, [1] to [4] and the compound according to any one of [1 '].
[6] 5- (4-methoxybenzoyl) -4- (4-methoxyphenyl) -2-methylpyrimidine, 4- (4-methoxybenzoyl) -5- (4-methoxyphenyl) -1-methylpyrazole, 4 -(4-Bromobenzoyl) -5- (4-bromophenyl) -1-methylpyrazole or 4- (4-chlorobenzoyl) -5- (4-chlorophenyl) -1-methylpyrazole, in [5] The compound described.
[7] The compound according to any one of [1] to [6] and [1'], which has antitumor activity and cancer metastasis inhibitory activity.

According to the present invention, it is possible to provide a compound having antitumor activity and cancer metastasis inhibitory activity, particularly a pyrazole derivative and a pyrimidine derivative, and an antitumor agent containing the compound as an active ingredient.

It is a figure explaining the real-time cell dynamics analysis method (TAXIScan method) used in Test Example 1. It is a graph which shows the result of Test Example 1. It is a graph which shows the result of Test Example 2. It is a graph which shows the result of Test Example 3 (change of body weight (1 at the time of transplantation)). It is a graph which shows the result of Test Example 3 (the number of individuals which metastasis was observed). It is a graph which shows the result of Test Example 3 (comparison of the amount of fluorescence from a tumor). It is a graph which shows the result of Test Example 4 (suppression of the speed of movement among chemotaxis components). It is a graph which shows the result of Test Example 4 (suppression of directionality among chemotaxis components). It is a graph which shows the result of Test Example 4 (suppression of the speed of movement among chemotaxis components). It is a graph which shows the result of Test Example 4 (suppression of directionality among chemotaxis components).

Hereinafter, the definition of each substituent used in the present specification will be described in detail. Unless otherwise specified, each substituent has the following definition.

In the present specification, examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
In the present specification, the "C _1-6 alkyl group" includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl. , Isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl.
In the present specification _{, examples of the "halogenated C 1-6 alkyl group" include the above "C 1-6} alkyl group" substituted with 1 to 5 of the above "halogen atoms".
In the present specification, the "C _3-10 cycloalkyl group" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2. 2] Octyl, bicyclo [3.2.1] Octyl, Adamantyl can be mentioned.
In the present specification _{, examples of the "C 1-6} alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy.
In the present specification _{, examples of the "C 6-14} aryl group" include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, and 9-antryl.
In the present specification, the "5- to 14-membered aromatic heterocyclic group" contains, for example, 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom as a ring-constituting atom. Examples include 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic groups, with preferred examples being thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl, pyridyl, pyrazinyl. 5- to 6-membered monocyclics such as pyrimidinyl, pyridadinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl, etc. Aromatic heterocyclic group;
Benzothiophenyl, benzofuranyl, benzoimidazolyl, benzoxazolyl, benzoisooxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, imidazolypyridinyl, thienopyridinyl, flopyridinyl, pyroropyridinyl, pyrazolopyridinyl, oxazolo Pyridinyl, thiazolopyridinyl, imidazolopyridinyl, imidazolipyrimidinyl, thienopyrimidinyl, flopyrimidinyl, pyrrolopyrimidinyl, pyrazoropyrimidinyl, oxazoropyrimidinyl, thiazolopyrimidinyl, pyrazorotriadinyl, naphtho -B] Thienyl, phenoxatinyl, indrill, isoindrill, 1H-indazolyl, prynyl, isoquinolyl, quinolyl, phthalazinyl, naphthyldinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, pheno Examples thereof include 8- to 14-membered fused polycyclic (preferably 2- or 3-cyclic) aromatic heterocyclic groups such as thiazinyl and phenoxadinyl.

In the present specification, the term "5- to 6-membered ring" refers to, for example, 5 to 6-membered ring-constituting atom containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom. Aromatic or non-aromatic heterocycles can be mentioned.
Preferable examples of the "5- to 6-membered aromatic heterocycle" include thiophene, furan, pyrrol, imidazole, pyrazole, thiazole, isothiazole, oxazole, isooxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1, 2 , 4-Oxazole, 1,3,4-Oxazole, 1,2,4-Thiadiazole, 1,3,4-Thiadiazole, Triazole, Tetrazole, Triazine and the like.
Preferable examples of the "5- to 6-membered non-aromatic heterocycle" include tetrahydropyran, tetrahydrofuran, pyrrolin, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazolin, thiazolidine, tetrahydroisothiazole, Examples thereof include tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridine, dihydrothiopyran, tetrahydropyramidine, tetrahydropyrandazine, dihydropyran, tetrahydropyran, tetrahydropyran, morpholine and thiomorpholin.

The definition of each symbol in the equation (1) will be described in detail below.

Ring A represents a 5- to 6-membered ring that may have a substituent.
The "5- to 6-membered ring" of the "5- to 6-membered ring which may have a substituent" is preferably a 5- to 6-membered aromatic heterocycle (eg, pyrazole ring, pyrimidine ring). More preferably, it is a pyrazole ring or a pyrimidine ring.
The "5- to 6-membered ring" of the "5- to 6-membered ring which may have a substituent" may have 1 to 3 substituents at substituent positions, and the number of substituents is high. In the case of two or more, each substituent may be the same or different. The "substituent" is preferably a C _1-6 alkyl group (eg, a methyl group), more preferably a methyl group.
In another embodiment of the invention, the "substituent" is preferably a optionally substituted C _1-6 alkyl group (eg, methyl group, ethyl group, isopropyl group), optionally substituted. C _3-10 cycloalkyl groups (eg, cyclohexyl groups), optionally substituted C _6-14 aryl groups (eg, phenyl, naphthyl), optionally substituted 5- to 14-membered aromatic heterocycles (eg, eg). , Pyridil).
Ring A is preferably a 5- to 6-membered aromatic heterocycle (eg, pyrazole ring) which may have 1 to 3 substituents selected from _{C 1-6 alkyl groups (eg, methyl groups).} , Pyrimidine ring), more preferably a pyrazole ring or a pyrimidine ring, each of which may have 1 to 3 methyl groups.
In another embodiment of the invention, ring A is preferably an optionally substituted C _1-6 alkyl group (eg, methyl group, ethyl group, isopropyl group), optionally substituted C _{3-. 10} cycloalkyl groups (eg, cyclohexyl groups), optionally substituted C _6-14 aryl groups (eg, phenyl, naphthyl) and optionally substituted 5- to 14-membered aromatic heterocycles (eg, pyridyl). It is a 5- to 6-membered aromatic heterocycle (eg, pyrazole ring, pyrimidine ring) which may have 1 to 3 substituents selected from, and more preferably (1) hydroxyl group and C, respectively. _{C 1-6} alkyl groups (eg, methyl group, ethyl group, isopropyl group), (2) C, _{which may have 1-3 substituents selected from 6-14} aryl groups (eg, phenyl). _3-10 Cycloalkyl group (eg, cyclohexyl group), (3) Halogen atom (eg, chlorine atom, bromine atom), cyano group, nitro group, C _1-6 alkyl group (eg, methyl group) and C _{1- C 6-14} aryl groups (eg, phenyl, naphthyl) which may have 1-3 substituents selected from ₆ alkoxy groups (eg, methoxy groups) and (4) 5- to 14-membered aromatic complex It is a pyrazole ring or a pyrimidine ring which may have 1 to 3 substituents selected from the ring (eg, pyridyl).

R ¹ and R ⁴ independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a cyano group, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group or a C _1-6 alkoxy group, respectively. ..
R ¹ and R ⁴ are preferably independent halogen atoms (eg, chlorine atom, bromine atom) or C _1-6 alkoxy groups (eg, methoxy group), and more preferably independent of each other. , Chlorine atom, bromine atom or methoxy group.
In another embodiment of the invention, R ¹ and R ⁴ are preferably independently substituted with a hydrogen atom, a nitro group, a cyano group, a halogen atom (eg, a chlorine atom, a bromine atom), respectively. A good C _1-6 alkyl group (eg, methyl group) or an optionally substituted C _1-6 alkoxy group (eg, methoxy group), more preferably independently of a hydrogen atom, a nitro group, A cyano group, a halogen atom (eg, chlorine atom, bromine atom), a C _1-6 alkyl group (eg, methyl group) or a C _1-6 alkoxy group (eg, methoxy group).

The benzene ring B and the benzene ring C may have 1 to 4 substituents in addition ^{to R 1} and R ^{4, respectively, at substitutable positions.}
Benzene ring B and benzene ring C preferably have no further substituents other than ^{R 1} and R ^{4, respectively.}
In another embodiment of the present invention, the benzene ring C is preferably further halogen atoms other than R ⁴ (eg, chlorine atom) may have.

The benzene ring BC (R ² ) (R ³ ) group and the benzene ring C are each bonded to a separate carbon atom constituting the ring A.
The benzene ring BC (R ² ) (R ³ ) group and the benzene ring C are preferably bonded to separate adjacent carbon atoms constituting ring A, respectively.

R ² and R ³ independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a cyano group, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group or a C _1-6 alkoxy group, respectively. Alternatively, R ² and R ³ together represent an oxo group.
R ² and R ³ are preferably together as an oxo group.

In another embodiment of the invention, R ² and R ³ independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a cyano group, a C _1-6 alkyl group, and a halogenated C _1-6 alkyl group. Alternatively, it represents a C _1-6 ^{alkoxy group, or R 2} and R ³ together represent an oxo group or a hydroxyimino group. Preferably, R ² and R ³ are independent hydrogen atoms or hydroxyl groups, or R ² and R ³ together are oxo or hydroxyimino groups.

Preferable examples of the compound (1) include the following compounds.
[Compound 1-1]
Ring A _{may have 1 to 3 substituents selected from C 1-6} alkyl groups (eg, methyl groups) and may have 5 to 6 membered aromatic heterocycles (eg, pyrazole ring, pyrimidine ring). ) And;
R ¹ and R ⁴ are independently halogen atoms (eg, chlorine atom, bromine atom) or C _1-6 alkoxy groups (eg, methoxy group);
Benzene ring B and benzene ring C have no additional substituents other than ^{R 1} and R ^{4, respectively;}
The benzene ring BC (R ² ) (R ³ ) groups and the benzene ring C are each bonded to separate adjacent carbon atoms that make up ring A;
R ² and R ³ are together an oxo group;
Compound (1).

[Compound 1-2]
Ring A is a pyrazole ring or a pyrimidine ring, each of which may have 1 to 3 methyl groups;
R ¹ and R ⁴ are independently chlorine, bromine or methoxy groups;
Benzene ring B and benzene ring C have no additional substituents other than ^{R 1} and R ^{4, respectively;}
The benzene ring BC (R ² ) (R ³ ) groups and the benzene ring C are each bonded to separate adjacent carbon atoms that make up ring A;
R ² and R ³ are together an oxo group;
Compound (1).

[Compound 1-3]
5- (4-Methoxybenzoyl) -4- (4-Methoxyphenyl) -2-methylpyrimidine,
4- (4-Methoxybenzoyl) -5- (4-Methoxyphenyl) -1-methylpyrazole,
4- (4-Bromobenzoyl) -5- (4-Bromophenyl) -1-methylpyrazole, or
4- (4-Chlorobenzoyl) -5- (4-chlorophenyl) -1-methylpyrazole.

[Compound 1-4]
Ring A may be substituted C _1-6 alkyl group (eg, methyl group, ethyl group, isopropyl group), optionally substituted C _3-10 cycloalkyl group (eg, cyclohexyl group), substituted. _Has 1-3 substituents selected from C 6-14 aryl groups (eg, phenyl, naphthyl) which may be substituted and 5- to 14-membered aromatic heterocycles (eg, pyridyl) which may be substituted. It is a 5- to 6-membered aromatic heterocycle (eg, pyrazole ring, pyrimidine ring) which may be used;
R ¹ and R ⁴ are independently hydrogen atom, nitro group, cyano group, halogen atom (eg, chlorine atom, bromine atom) and optionally substituted C _1-6 alkyl group (eg, methyl group). ) Or optionally substituted C _1-6 alkoxy group (eg, methoxy group);
Benzene ring B is, does not have a further substituent in addition to R ^1;
Benzene ring C is further halogen atom (e.g., chlorine atom) in addition to R ⁴ may have;
The benzene ring BC (R ² ) (R ³ ) groups and the benzene ring C are each bonded to separate adjacent carbon atoms that make up ring A;
R ² and R ³ are independently hydrogen atoms or hydroxyl groups, or R ² and R ³ together are oxo or hydroxyimino groups;
Compound (1).

[Compound 1-5]
Ring A may have 1-3 substituents selected from (1) hydroxyl groups and C _6-14 aryl groups (eg, phenyl) _{, respectively, C 1-6} alkyl groups (eg, methyl groups). , Ethyl group, isopropyl group), (2) C _3-10 cycloalkyl group (eg, cyclohexyl group), (3) halogen atom (eg, chlorine atom, bromine atom), cyano group, nitro group, C _{1-6 A C 6-14} aryl group (eg, phenyl, naphthyl) which may have 1-3 substituents selected from an alkyl group (eg, methyl group) and a C _1-6 alkoxy group (eg, methoxy group). ) And (4) a pyrazole ring or a pyrimidine ring, which may have 1-3 substituents selected from 5- to 14-membered aromatic heterocycles (eg, pyridyl);
R ¹ and R ⁴ are independently hydrogen atom, nitro group, cyano group, halogen atom (eg, chlorine atom, bromine atom), C _1-6 alkyl group (eg, methyl group) or C _1-6. It is an alkoxy group (eg, a methoxy group);
Benzene ring B is, does not have a further substituent in addition to R ^1;
Benzene ring C is further halogen atom (e.g., chlorine atom) in addition to R ⁴ may have;
The benzene ring BC (R ² ) (R ³ ) groups and the benzene ring C are each bonded to separate adjacent carbon atoms that make up ring A;
R ² and R ³ are independently hydrogen atoms or hydroxyl groups, or R ² and R ³ together are oxo or hydroxyimino groups;
Compound (1).

When the compound (1) is a salt, such salts include, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, and a basic or acidic amino acid. Examples include salt.

Preferable examples of salts with inorganic bases include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt; ammonium salt.

Preferable examples of salts with organic bases include trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris (hydroxymethyl) methylamine], tert-butylamine, cyclohexylamine, benzylamine, Examples thereof include salts with dicyclohexylamine and N, N-dibenzylethylenediamine.

Preferable examples of salts with inorganic acids include salts with hydrogen chloride, hydrogen bromide, nitric acid, sulfuric acid and phosphoric acid.

Preferable examples of salts with organic acids are formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid. , Salt with p-toluenesulfonic acid.

Preferable examples of salts with basic amino acids include salts with arginine, lysine and ornithine.

Preferable examples of the salt with an acidic amino acid include a salt with aspartic acid and glutamic acid.

Among these salts, pharmaceutically acceptable salts are preferable. Pharmaceutically acceptable salts include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitrate, sulfuric acid, phosphoric acid, etc., if the compound has a basic functional group; or acetic acid, phthalic acid. , Fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid and other salts with organic acids. If the compound has an acidic functional group, it is an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt, etc.), an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium salt, etc.). ; Ammonium salt and the like can be mentioned.

The method for producing the compound (1) will be described below. As an example, the ring A is a pyrazole ring or a pyrimidine ring which may have a methyl group or the like, and the benzene ring B and the benzene ring C do not have a substituent other than ^{R 1} and R ^{4, respectively.} , The benzene ring BC (R ² ) (R ³ ) group and the benzene ring C are bonded to separate adjacent carbon atoms constituting the ring A, respectively, and R ² and R ³ are independent of each other. The method for producing a compound (1) which is a hydrogen atom or a hydroxyl group, or which is an oxo group or a hydroxyimino group in which ^{R 2} and R ^{3 are combined, will be described below.}

1) Synthesis of dibenzoylmethane (III) A solution of acetophenone (II) in anhydrous benzene is added dropwise to an anhydrous benzene suspension of sodium hydride and benzoate ester (I) in a nitrogen stream, and then heated to reflux. After cooling to room temperature, a 10% aqueous hydrochloric acid solution is added to the reaction solution, and ethyl acetate is extracted. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is recrystallized from ethanol or subjected to silica gel column chromatography to obtain dibenzoylmethane (III) from an ethyl acetate-hexane fraction.
References: T. Choshi, S. Horimoto, CY Wang, H. Nagase, M. Ichikawa, E. Sugino, S. Hibino, Chem. Pharm. Bull., 40, 1047-1049 (1992).

2) Synthesis of N, N-dimethylaminomethylene-dibenzoylmethane (IV) In a nitrogen stream, a dimethylformamide dimethylacetal solution of dibenzoylmethane (III) is heated and recirculated for 6 hours. After cooling to room temperature, water is added to the reaction solution and ethyl acetate is extracted. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is subjected to silica gel column chromatography to obtain N, N-dimethylaminomethylene (IV) from the ethyl acetate-hexane fraction.

3) Synthesis of 5-benzoyl-4-phenyl-2-methylpyrimidine (V)
An ethanol suspension of N, N-dimethylaminomethylene (IV), acetoamidine, and potassium carbonate is heated and recirculated for 4 hours. After cooling to room temperature, water is added to the reaction solution and ethyl acetate is extracted. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is subjected to silica gel column chromatography to obtain an oily 5-benzoyl-4-phenyl-2-methylpyrimidine (V) from an ethyl acetate-hexane fraction.

4) Synthesis of 4-benzoyl-5-phenyl-1-methylpyrazole (VI)
An ethanol solution of N, N-dimethylaminomethylene (IV) and methylhydrazine is stirred at room temperature for 12 hours. After completion of the reaction, ethanol is distilled off under reduced pressure. The residue is subjected to silica gel column chromatography to obtain 4-benzoyl-5-phenyl-1-methylpyrazole (VI) from the ethyl acetate-hexane fraction and the isomer (VII) as the next effluent.

Compound (1) has antitumor activity and cancer metastasis inhibitory activity, and antitumor agents containing the compound (1) as an active ingredient include various malignant tumors (eg, pancreatic cancer, lung cancer, colon cancer, breast cancer, etc.). Ovarian cancer, cervical cancer, prostate cancer, malignant melanoma, gastric cancer, hepatocellular carcinoma, bile duct cancer, oral cancer, esophageal cancer, bladder cancer, nerve tumor, testis tumor, smooth muscle tumor, liposarcoma, horizontal print myoma, It can be used as a prophylactic or therapeutic agent for malignant fibrous histiocytoma, chondroma, osteosarcoma, leukemia, lymphoma, mesenteric tumor).

The antitumor agent containing the compound (1) of the present invention as an active ingredient may contain only the compound (1), or may be a pharmacologically acceptable carrier (excipient, binder, etc.). Disintegrants, flavoring agents, odorants, emulsifiers, diluents, solubilizers, etc.) may be included.
The antitumor agent containing the compound (1) of the present invention as an active ingredient is pharmacologically different from the compound (1) according to a method known per se as a method for producing a pharmaceutical preparation (eg, a method described in the Japanese Pharmacopoeia, etc.). It is obtained by mixing with an acceptable carrier and formulating it into various dosage forms (eg, tablets, pills, powders, granules, capsules, liquids, emulsions, suspensions, injections, infusions, etc.). It can be administered orally or parenterally.

The content of the compound (1) in the antitumor agent containing the compound (1) of the present invention as an active ingredient varies depending on the dosage form of the antitumor agent, but is usually 0.001 to 1 with respect to the entire antitumor agent. It is 100% by weight, preferably 0.01 to 10% by weight, and more preferably about 0.1 to 1% by weight.

In the present specification, parenteral means subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, infusion method or local administration (intra-articular administration, percutaneous administration, intraocular administration, transpulmonary / bronchial administration). , Nasal administration or transrectal administration, etc.).

The dose of the antitumor agent containing the compound (1) of the present invention as an active ingredient may vary depending on the administration target, administration route, and symptoms, and is not particularly limited. For example, an adult patient with pancreatic cancer (adult, body weight 40 to 80 kg). , For example, 60 kg), as compound (1), for example, once a week 0.1 to 1000 mg / kg body weight, preferably once a week 1 to 500 mg / kg body weight, more preferably 10 to 100 mg once a week. Can be administered at / kg body weight. This amount can be administered in 1 to 3 divided doses daily.

Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but these examples are not limited to the present invention.

Example 1
Synthesis of 5- (4-Methoxybenzoyl) -4- (4-Methoxyphenyl) -2-methylpyrimidine
1) Synthesis of di (4-methoxybenzoyl) methane A suspension of sodium hydride (0.84 g, 20.9 mmol) and ethyl 4-methoxybenzoate (3.6 g, 20.0 mmol) in anhydrous benzene (40 mL) in a nitrogen stream. A solution of 4-methoxyacetophenone (2.7 g, 18.2 mmol) in anhydrous benzene (10 mL) was added dropwise to the mixture, and the mixture was heated under reflux for 5 hours. After cooling to room temperature, a 10% aqueous hydrochloric acid solution was added to the reaction solution, and ethyl acetate extraction (100 mL × 3 times) was performed. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethanol to give a dibenzoylmethane compound (2.83 g, 56%).
mp 126-127 ℃. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.92 (6H, s), 6.81 (1H, s), 7.29 (4H, d, J = 8.3 Hz), 7.89 (4H, d) , J = 8.3 Hz).

2) Synthesis of N, N-dimethylaminomethylene-di (4-methoxybenzoyl) methane A solution of di (4-methoxybenzoyl) methane (1.0 g, 3.5 mmol) in dimethylformamide dimethylacetal (6 mL) in a nitrogen stream. Heated and recirculated for 5 hours. After cooling to room temperature, water was added to the reaction solution, and ethyl acetate extraction (50 mL × 3 times) was performed. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (50 g) to obtain an oily N, N-dimethylaminomethylene compound (1.09 g, 92%) from an ethyl acetate-hexane (70:30 v / v) stream. It was.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 2.94 (6H, br s), 3.83 (6H, s), 5.85 (1H, s), 6.86 (2H, d, J = 8.8 Hz), 6.94 (2H) , d, J = 8.8 Hz), 7.18 (2H, d, J = 8.8 Hz), 7.86 (2H, d, J = 8.8 Hz).

3) Synthesis of 5- (4-methoxybenzoyl) -4- (4-methoxyphenyl) -2-methylpyrimidine (hereinafter, may be abbreviated as "14-53")
A suspension of N, N-dimethylaminomethylene (2.3 g, 6.78 mmol), acetamidine hydrochloride (0.96 g, 8.13 mmol), and potassium carbonate (1.12 g, 8.13 mmol) in ethanol (40 mL) for 4 hours. Heated recirculation. After cooling to room temperature, water was added to the reaction solution, and ethyl acetate extraction (50 mL × 3 times) was performed. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (50 g) and oiled 5- (4-methoxybenzoyl) -4- (4-methoxyphenyl) from the ethyl acetate-hexane (30:70 v / v) fraction. -2-Methylpyrimidine (1.88 g, 83%) was obtained.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 2.86 (3H, s), 3.76 (3H, s), 3.83 (3H, s), 6.81 (2H, d, J = 8.7 Hz), 6.82 (2H, 2H, d, J = 8.7 Hz), 7.61 (2H, d, J = 8.7 Hz), 7.69 (2H, d, J = 8.7 Hz), 8.65 (1H, s).

Example 2
Synthesis of 4- (4-methoxybenzoyl) -5- (4-methoxyphenyl) -1-methylpyrazole (hereinafter, may be abbreviated as "14-61")
A solution of N, N-dimethylaminomethylene (380 mg, 1.1 mmol) and methylhydrazine (72 mg, 1.6 mmol) in ethanol (3 mL) was stirred at room temperature for 12 hours. After completion of the reaction, ethanol was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (20 g) and oiled 4- (4-methoxybenzoyl) -5- (4-methoxyphenyl) from the ethyl acetate-hexane (15:85 v / v) fraction. -1-Methylpyrazole (137 mg, 38%) and its next effluent are isomers 4- (4-methoxybenzoyl) -3- (4-methoxyphenyl) -1-methylpyrazole (109 mg, 30%) Got
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 3.82 (3H, s), 3.84 (3H, s), 3.85 (3H, s), 6.88 (2H, d, J = 8.6 Hz), 6.96 (2H, 2H, d, J = 8.6 Hz), 7.32 (2H, d, J = 8.6 Hz), 7.79 (2H, d, J = 8.6 Hz), 7.83 (1H, s).

Example 3
Synthesis of 4- (4-Bromobenzoyl) -5- (4-Bromophenyl) -1-methylpyrazole
1) Synthesis of di (4-bromobenzoyl) methane A suspension of sodium hydride (1.0 g, 25.1 mmol) and ethyl 4-bromobenzoate (5.5 g, 24.0 mmol) in anhydrous benzene (40 mL) in a nitrogen stream. A solution of 4-bromoacetophenone (4.3 g, 21.8 mmol) in anhydrous benzene (10 mL) was added dropwise to the mixture, and the mixture was heated under reflux for 1 hour. After cooling to room temperature, a 10% aqueous hydrochloric acid solution was added to the reaction solution, and ethyl acetate extraction (100 mL × 3 times) was performed. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethanol to give a dibenzoylmethane compound (4.5 g, 54%).
mp 195-196 ℃. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 6.77 (1H, s), 7.63 (4H, d, J = 8.4 Hz), 7.85 (4H, d, J = 8.4 Hz).

2) Synthesis of N, N-dimethylaminomethylene-di (4-bromobenzoyl) methane A solution of di (4-bromobenzoyl) methane (2.5 g, 6.54 mmol) in dimethylformamide dimethylacetal (15 mL) in a nitrogen stream. Heated and recirculated for 6 hours. After cooling to room temperature, water was added to the reaction solution, and ethyl acetate extraction (100 mL × 3 times) was performed. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (50 g) to obtain an oily N, N-dimethylaminomethylene compound (1.66 g, 58%) from an ethyl acetate-hexane (40:60 v / v) stream. It was.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 2.77 (3H, br s), 3.31 (3H, br s), 7.32-7.51 (8H, m), 7.64 (1H, s).

3) Synthesis of 4- (4-bromobenzoyl) -5- (4-bromophenyl) -1-methylpyrazole
A solution of N, N-dimethylaminomethylene (600 mg, 1.4 mmol) and methylhydrazine (74 mg, 1.6 mmol) in ethanol (4 mL) was stirred at room temperature for 2 hours. After completion of the reaction, ethanol was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (50 g) and oiled 4- (4-bromobenzoyl) -5- (4-bromophenyl) from the ethyl acetate-hexane (15:85 v / v) fraction. -1-Methylpyrazole (hereinafter sometimes abbreviated as "14-67") (420 mg, 73%) and its next effluent are isomers 4- (4-bromobenzoyl) -3- (4-) Bromophenyl) -1-methylpyrazole (hereinafter sometimes abbreviated as "14-68") (95 mg, 16%) was obtained.
4- (4-Bromobenzoyl) -5- (4-Bromophenyl) -1-methylpyrazole: ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.82 (3H, s), 7.27 (2H, d, J) = 8.5 Hz), 7.57 (2H, d, J = 8.5 Hz), 7.61 (2H, d, J = 8.5 Hz), 7.65 (2H, d, J = 8.5 Hz), 7.83 (1H, s).
4- (4-Bromobenzoyl) -3- (4-Bromophenyl) -1-methylpyrazole: ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.99 (3H, s), 7.47 (2H, d, J) = 8.8 Hz), 7.55 (4H, d, J = 8.8 Hz), 7.64 (2H, d, J = 8.8 Hz), 7.73 (1H, s).

4) Synthesis of 4- (4-chlorobenzoyl) -5- (4-chlorophenyl) -1-cyclohexylpyrazole (hereinafter, may be abbreviated as "14-112")
A solution of N, N-dimethylaminomethylene (200 mg, 0.57 mmol), cyclohexylhydrazine hydrochloride (76 mg, 1.09 mmol), and potassium carbonate (236 mg, 1.71 mmol) in ethanol (6 mL) at 60 ° C. 1 Stirred for hours. After completion of the reaction, ethanol was distilled off under reduced pressure. Water was added to the residue, and ethyl acetate extraction (50 mL × 3 times) was performed. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The crude crystals were recrystallized from ethanol to obtain 4- (4-chlorobenzoyl) -5- (4-chlorophenyl) -1-cyclohexylpyrazole (200 mg, 87%).
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 1.21-1.27 (3H, m), 1.59-2.05 (7H, m), 3.90-3.98 (1H, m), 7.28 (2H, d, J = 8.7 Hz) ), 7.39 (2H, d, J = 8.9 Hz), 7.45 (2H, d, J = 8.9 Hz), 7.72 (2H, d, J = 8.7 Hz), 7.84 (1H, s).

5) Synthesis of 4-chlorophenyl- [5- (4-chlorophenyl) -1-methylpyrazole-4-yl] methanol (hereinafter, may be abbreviated as "14-120")
A solution of 4-benzoyl-5-phenyl-1-methylpyrazole (VI) (132 mg, 0.40 mmol) and sodium hydride (30 mg, 0.79 mmol) in methanol (5 mL) was stirred at room temperature for 3 hours. .. After completion of the reaction, methanol was distilled off under reduced pressure. Water was added to the residue, and ethyl acetate extraction (50 mL × 3 times) was performed. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The crude crystals were recrystallized from methanol to obtain 4-chlorophenyl- [5- (4-chlorophenyl) -1-methylpyrazole-4-yl] methanol (118 mg, 89%).
^{1 1} H-NMR (300 MHz, DMSO-d ₆ ) δ: 3.66 (3H, s), 5.41 (1H, d, J = 4.0 Hz), 5.75 (1H, d, J = 4.0 Hz), 7.23 (2H, 2H, d, J = 8.5 Hz), 7.25 (1H, s), 7.29 (2H, d, J = 8.5 Hz), 7.46 (2H, d, J = 7.7 Hz), 7.57 (2H, d, J = 7.7 Hz) ..

6) Synthesis of 4-chlorobenzyl-5- (4-chlorophenyl) -1-methylpyrazole (IX) (hereinafter, may be abbreviated as "14-121")
4-Chlorophenyl- [5- (4-chlorophenyl) -1-methylpyrazole-4-yl] Methanol (112 mg, 0.34 mmol) in trifluoroacetic acid (5 mL) solution with ice-cooled triethylsilane (62 μL, 0.39) After the dropwise addition of mmol), the mixture was stirred at room temperature for 10 minutes. After completion of the reaction, trifluoroacetic acid was distilled off under reduced pressure. Water was added to the residue, and ethyl acetate extraction (100 mL × 3 times) was performed. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and oiled 4-chlorobenzyl-5- (4-chlorophenyl) -1-methylpyrazole (103 mg,) from the ethyl acetate-hexane (20:80 v / v) fraction. 97%) was obtained.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 3.67 (2H, s), 3.75 (3H, s), 7.00 (2H, d, J = 8.5 Hz), 7.16 (2H, d, J = 8.7 Hz) , 7.20 (2H, d, J = 8.5 Hz), 7.35 (1H, s), 7.43 (2H, d, J = 8.7 Hz).

7) Synthesis of 4-chlorobenzoyl-5- (4-chlorophenyl) -1-methylpyrazole oxime (X) (hereinafter sometimes abbreviated as "14-122")
4-Benzoyl-5-Phenyl-1-methylpyrazole (VI) (65 mg, 0.20 mmol), hydroxylamine hydrochloride (41 mg, 0.59 mmol) and potassium carbonate (138 mg, 1.0 mmol) in ethanol (3 mL) suspension. The turbid liquid was heated and stirred at 80 ° C. for 5 hours. After cooling to room temperature, water was added to the reaction solution, and ethyl acetate extraction (100 mL × 3 times) was performed. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and oiled 4-chlorobenzoyl-5- (4-chlorophenyl) as a diastereomer mixture (1: 3) from the ethyl acetate-hexane (30:70 v / v) stream. )-1-Methylpyrazole oxime (60 mg, 88%) was obtained.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 3.72 (3 / 4H, s), 3.85 (9 / 4H, s), 7.10-7.38 (8H, m), 7.51 (1 / 4H, s), 7.76 (3 / 4H, s).

Synthesis of raw material (III) and raw material (IV) Di (4-fluorobenzoyl) methane According to the synthesis method of Example 1-1), methyl 4-fluorobenzoate is reacted with 4-fluoroacetophenone to obtain the desired product in a yield of 52. Obtained in%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 3.88 (2H, s), 7.14 (2H, d, J = 8.7 Hz), 7.17 (2H, d, J = 8.7 Hz), 8.12 (2H, d, J = 8.7 Hz), 8.15 (2H, d, J = 8.7 Hz).

N, N-Dimethylaminomethylene-di (4-fluorobenzoyl) methane According to the synthesis method of Example 1-2), di (4-fluorobenzoyl) methane was reacted with dimethylformamide dimethylacetal to produce the desired product in a yield of 66%. I got it in.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 2.81 (3H, br s), 3.32 (3H, br s), 6.88 (4H, t, J = 7.8 Hz), 7.50-7.65 (4H, m), 7.67 (1H, s).

Di (3-chlorobenzoyl) methane According to the synthesis method of Example 1-1), ethyl 3-chlorobenzoate was reacted with 3-chloroacetophenone to obtain the desired product in a yield of 58%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 6.77 (1H, s), 7.44 (2H, t, J = 8.5 Hz), 7.50-7.58 (2H, m), 7.82-7.88 (2H, m), 7.94-7.99 (2H, m).

N, N-Dimethylaminomethylene-di (3-chlorobenzoyl) methane According to the synthesis method of Example 1-2), di (3-chlorobenzoyl) methane was reacted with dimethylformamide dimethylacetal to produce the desired product in a yield of 57%. I got it in.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 2.79 (3H, br s), 3.34 (3H, br s), 7.14 (2H, t, J = 7.8 Hz), 7.25 (2H, d, J = 7.8) Hz), 7.41 (2H, d, J = 7.8 Hz), 7.52 (2H, br s), 7.69 (1H, s).

Di (2-chlorobenzoyl) methane According to the synthesis method of Example 1-1), methyl 2-chlorobenzoate was reacted with 2-chloroacetophenone to obtain the desired product in a yield of 51%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 7.31-7.42 (3H, s), 7.41-7.53 (4H, s), 8.02 (2H, d, J = 8.2 Hz).

N, N-Dimethylaminomethylene-di (2-chlorobenzoyl) methane According to the synthesis method of Example 1-2), di (2-chlorobenzoyl) methane was reacted with dimethylformamide dimethylacetal to produce the desired product in a yield of 48%. I got it in.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 2.78 (3H, br s), 3.30 (3H, br s), 7.20 (4H, d, J = 8.2 Hz), 7.51 (4H, br d, J = 7.9 Hz), 7.64 (1H, s).

Di (4-methylbenzoyl) methane According to the synthesis method of Example 1-1), ethyl 4-methylbenzoate was reacted with 4-methylacetophenone to obtain the desired product in a yield of 66%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 6.82 (1H, s), 7.29 (4H, d, J = 8.0 Hz), 7.89 (4H, d, J = 8.0 Hz).

N, N-Dimethylaminomethylene-di (4-methylbenzoyl) methane According to the synthesis method of Example 1-2), di (4-methylbenzoyl) methane was reacted with dimethylformamide dimethylacetal to produce the desired product in a yield of 98%. I got it in.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 2.27 (6H, s), 2.80-3.20 (6H, br s), 7.03 (4H, d, J = 8.2 Hz), 7.53 (4H, d, J = 8.2 Hz), 7.67 (1H, s).

Di (2-methoxybenzoyl) methane According to the synthesis method of 1) of Example 1, ethyl 2-methoxybenzoate was reacted with 4-fluoroacetophenone to obtain the desired product in a yield of 45%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 3.94 (6H, s), 6.92-67.10 (4H, m), 7.31 (1H, s), 7.43-7.52 (2H, m), 7.86-7.94 (2H) , m).

N, N-Dimethylaminomethylene-di (2-methoxybenzoyl) methane According to the synthesis method of Example 1-2), di (2-methoxybenzoyl) methane was reacted with dimethylformamide dimethyl acetal to produce the desired product in a yield of 51%. I got it in.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 2.92 (3H, br s), 3.44 (3H, br s), 3.67 (6H, s), 6.49 (2H, d, J = 8.5 Hz), 6.71 ( 2H, t, J = 8.5 Hz), 7.10 (2H, t, J = 8.5 Hz), 7.26 (2H, d, J = 8.5 Hz), 7.98 (1H, s).

Example 4
Synthesis of 4- (4-chlorobenzoyl) -5- (4-chlorophenyl) -1-methylpyrazole
1) Synthesis of di (4-chlorobenzoyl) methane A suspension of sodium hydride (0.9 g, 22.5 mmol) and ethyl 4-chlorobenzoate (4.1 g, 22 mmol) in anhydrous benzene (40 mL) in a nitrogen stream. A solution of 4-chloroacetophenone (3.1 g, 20 mmol) in anhydrous benzene (20 mL) was added dropwise to the mixture, and the mixture was heated under reflux for 3 hours. After cooling to room temperature, a 10% aqueous hydrochloric acid solution was added to the reaction solution, and ethyl acetate extraction (100 mL × 3 times) was performed. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethanol to give a dibenzoylmethane compound (2.4 g, 41%).
mp 157.5-159.5 ℃. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 6.77 (1H, s), 7.48 (4H, d, J = 8.9 Hz), 7.93 (4H, d, J = 8.9 Hz).

2) Synthesis of N, N-dimethylaminomethylene-di (4-chlorobenzoyl) methane A solution of di (4-chlorobenzoyl) methane (400 mg, 1.36 mmol) in dimethylformamide dimethylacetal (10 mL) in a nitrogen stream. The mixture was stirred at room temperature for 4 hours. After cooling to room temperature, water was added to the reaction solution, and ethyl acetate extraction (50 mL × 3 times) was performed. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (50 g) to obtain an oily N, N-dimethylaminomethylene compound (384 mg, 81%) from an ethyl acetate-hexane (80: 20 v / v) stream. It was.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 2.77 (3H, br s), 3.32 (3H, br s), 7.20 (4H, d, J = 8.6 Hz), 7.35-7.60 (4H, m), 7.64 (1H, s).

3) Synthesis of 4- (4-chlorobenzoyl) -5- (4-chlorophenyl) -1-methylpyrazole
A solution of N, N-dimethylaminomethylene (380 mg, 1.09 mmol) and methylhydrazine (50 mg, 1.09 mmol) in ethanol (10 mL) was stirred at room temperature for 12 hours. After completion of the reaction, ethanol was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (20 g) and oiled 4- (4-chlorobenzoyl) -5- (4-chlorophenyl)-from the ethyl acetate-hexane (15:85 v / v) stream. 1-Methylpyrazole (197 mg, 55%) and the isomer (39 mg, 11%) were obtained as the next effluent.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 3.81 (3H, s), 7.33 (2H, d, J = 8.5 Hz), 7.39 (2H, d, J = 8.5 Hz), 7.44 (2H, d, J = 8.5 Hz), 7.61 (2H, d, J = 8.5 Hz), 7.82 (1H, s).

Example 5
The following pyrimidine derivatives were synthesized according to the method of Example 1.

1) Synthesis of 5- (4-methylbenzoyl) -4- (4-methylphenyl) pyrimidine (hereinafter, may be abbreviated as "5-106" ) According to the synthesis method of Example 1-3), N, N-Dimethylaminomethylene-di (4-methylbenzoyl) methane was reacted with formamidine acetate to give the desired product in a yield of 85%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 2.29 (3H, s), 2.36 (3H, s), 7.11 (2H, d, J = 8.0 Hz), 7.17 (2H, d, J = 8.0 Hz) , 7.54 (2H, d, J = 8.0 Hz), 7.62 (2H, d, J = 8.0 Hz), 8.77 (1H, br s), 9.36 (1H, s).

2) Synthesis of 2-amino-5- (4-methylbenzoyl) -4- (4-methylphenyl) pyrimidine (hereinafter, may be abbreviated as "5-107" ) Synthesis method of Example 1-3) According to this, N, N-dimethylaminomethylene-di (4-methylbenzoyl) methane was reacted with guanidine hydrochloride to obtain the desired product in a yield of 91%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 2.28 (3H, s), 2.35 (3H, s), 5.67 (2H, br s), 7.06 (2H, d, J = 8.0 Hz), 7.13 (2H) , d, J = 8.0 Hz), 7.40 (2H, d, J = 8.0 Hz), 7.62 (2H, d, J = 8.0 Hz), 8.45 (1H, s).

3) Synthesis of 2-amino-5- (4-chlorobenzoyl) -4- (4-chlorophenyl) pyrimidine (hereinafter, may be abbreviated as "5-102" ) According to the synthesis method of Example 1-3). , N, N-Dimethylaminomethylene-di (4-chlorobenzoyl) methane was reacted with guanidine hydrochloride to obtain the desired product in a yield of 97%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 5.73 (2H, br s), 7.25 (2H, d, J = 8.4 Hz), 7.30 (2H, d, J = 8.6 Hz), 7.42 (2H, d) , J = 8.4 Hz), 7.61 (2H, d, J = 8.6 Hz), 8.53 (1H, s).

4) Synthesis of 5- (2-methoxybenzoyl) -4- (2-methoxyphenyl) -2-methylpyrimidine (hereinafter, may be abbreviated as "5-109" ) Synthesis method of Example 1-3) Therefore, N, N-dimethylaminomethylene-di (2-methoxybenzoyl) methane was reacted with acetamidine hydrochloride to obtain the desired product in a yield of 99%.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.85 (3H, s), 3.53 (6H, s), 6.51 (1H, d, J = 8.6 Hz), 6.58 (1H, d, J = 8.6 Hz) , 6.88 (1H, dt, J = 0.8, 8.0 Hz), 6.93 (1H, dt, J = 0.8, 8.0 Hz), 7.17 (1H, dt, J = 0.8, 8.6 Hz), 7.27 (1H, dt, J) = 0.8, 8.6 Hz), 7.48 (1H, dd, J = 1.8, 7.6 Hz), 7.56 (1H, dd, J = 1.8, 7.6 Hz), 8.81 (1H, s).

5) Synthesis of 5- (2-methoxybenzoyl) -4- (2-methoxyphenyl) pyrimidine (hereinafter, may be abbreviated as "5-108" ) According to the synthesis method of Example 1-3), N, N-Dimethylaminomethylene-di (2-methoxybenzoyl) methane was reacted with formamidine acetate to obtain the desired product in a yield of 42%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 3.51 (3H, s), 3.55 (3H, s), 6.54 (1H, d, J = 8.5 Hz), 6.58 (1H, d, J = 8.5 Hz) , 6.90 (1H, dt, J = 1.0, 7.4 Hz), 6.95 (1H, dt, J = 1.0, 7.4 Hz), 7.17-7.32 (2H, m), 7.53 (1H, dd, J = 1.6, 7.2 Hz) ), 7.61 (1H, dd, J = 1.6, 7.2 Hz), 8.89 (1H, s), 9.34 (1H, s).

6) Synthesis of 2-amino-5- (2-methoxybenzoyl) -4- (2-methoxyphenyl) pyrimidine (hereinafter, may be abbreviated as "5-110" ) Synthesis method of Example 1-3) According to this, N, N-dimethylaminomethylene-di (2-methoxybenzoyl) methane was reacted with guanidine hydrochloride to obtain the desired product in a yield of 83%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 3.57 (3H, s), 3.60 (3H, s), 5.55 (2H, br s), 6.52 (1H, d, J = 8.3 Hz), 6.57 (1H) , d, J = 7.8 Hz), 6.85 (1H, dt, J = 0.8, 7.8 Hz), 6.92 (1H, dt, J = 0.8, 7.8 Hz), 7.14-7.26 (2H, m), 7.38 (1H, m) dd, J = 1.4, 7.3 Hz), 7.46 (1H, dd, J = 1.4, 7.3 Hz), 8.58 (1H, s).

Example 6
The following pyrazole derivatives were synthesized according to the method of Example 4.

1) Synthesis of 4-benzoyl-1-methyl-5-phenylpyrazole (hereinafter, may be abbreviated as "14-60" ) According to the synthesis method of Example 4-3), N, N-dimethylaminomethylene- Dibenzoylmethane was reacted with phenylhydrazine to obtain the desired product in a yield of 67%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 3.82 (3H, s), 7.30-7.52 (8H, m), 7.75 (2H, d, J = 8.5 Hz), 7.87 (1H, s).

2) Synthesis of 4- (4-methylbenzoyl) -5- (4-methylphenyl) -1-methylpyrazole (hereinafter, may be abbreviated as "14-63" ) Synthesis method of Example 4-3) According to this, N, N-dimethylaminomethylene-di (4-methylbenzoyl) methane was reacted with methylhydrazine to obtain the desired product in a yield of 56%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 2.40 (6H, s), 3.82 (3H, s), 7.20 (2H, d, J = 8.8 Hz), 7.23-7.29 (4H, m), 7.69 ( 2H, d, J = 8.8 Hz), 7.84 (1H, s).

3) Synthesis of 4- (4-methylbenzoyl) -3- (4-methylphenyl) -1-methylpyrazole (hereinafter, may be abbreviated as "14-64" ) Synthesis method of Example 4-3) Therefore, N, N-dimethylaminomethylene-di (4-methylbenzoyl) methane was reacted with methylhydrazine to obtain the desired product as an isomer in a yield of 25%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 2.33 (3H, s), 2.39 (3H, s), 3.95 (3H, s), 7.12 (2H, d, J = 8.8 Hz), 7.18 (2H, 2H, d, J = 8.8 Hz), 7.54 (2H, d, J = 8.8 Hz), 7.69 (2H, d, J = 8.8 Hz), 7.70 (1H, s).

4) Synthesis of 4- (4-fluorobenzoyl) -5- (4-fluorophenyl) -1-methylpyrazole (hereinafter, may be abbreviated as "14-100F" ) Synthesis method of Example 4-3) According to this, N, N-dimethylaminomethylene-di (4-fluorobenzoyl) methane was reacted with methylhydrazine to obtain the desired product in a yield of 23%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 3.82 (3H, s), 7.08 (2H, dd, J = 8.7, 8.7 Hz), 7.15 (2H, dd, J = 8.7, 8.7 Hz), 7.38 ( 2H, dd, J = 8.7, 5.6 Hz), 7.80 (2H, d, J = 8.7, 5.6 Hz), 7.84 (1H, s).

5) Synthesis of 4- (3-chlorobenzoyl) -5- (3-chlorophenyl) -1-methylpyrazole (hereinafter, may be abbreviated as "14-118" ) According to the synthesis method of Example 4-3). , N, N-Dimethylaminomethylene-di (3-chlorobenzoyl) methane was reacted with methylhydrazine to obtain the desired product in a yield of 69%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 3.82 (3H, s), 7.20-7.26 (1H, m), 7.29-7.47 (5H, m), 7.59-7.63 (1H, m), 7.66-7.68 (1H, m), 7.87 (1H, s).

6) Synthesis of 4- (2-chlorobenzoyl) -5- (2-chlorophenyl) -1-methylpyrazole (hereinafter, may be abbreviated as "14-119" ) According to the synthesis method of Example 4-3). , N, N-Dimethylaminomethylene-di (2-chlorobenzoyl) methane was reacted with methylhydrazine to obtain the desired product in a yield of 57%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 3.68 (3H, s), 7.11-7.39 (8H, m), 7.91 (1H, s).

7) Synthesis of 4- (4-chlorobenzoyl) -5- (4-chlorophenyl) pyrazole (hereinafter, may be abbreviated as "14-123" ) N, N according to the synthesis method of Example 4-3). -Dimethylaminomethylene-di (4-chlorobenzoyl) Methane was reacted with hydrazine to obtain the desired product in a yield of 66%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 7.36 (2H, d, J = 8.8 Hz), 7.41 (2H, d, J = 8.8 Hz), 7.59 (2H, d, J = 8.8 Hz), 7.75 (2H, d, J = 8.8 Hz). 7.93 (1H, br s).

8) Synthesis of 4- (4-chlorobenzoyl) -5- (4-chlorophenyl) -1-isopropylpyrazole (hereinafter, may be abbreviated as "14-111" ) According to the synthesis method of Example 4-4). , N, N-Dimethylaminomethylene-di (4-chlorobenzoyl) methane was reacted with isopropylhydrazine hydrochloride to obtain the desired product in a yield of 76%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 1.48 (6H, d, J = 6.6 Hz), 4.40 (1H, sep, J = 6.6 Hz), 7.29 (2H, d, J = 8.7 Hz), 7.39 (2H, d, J = 8.7 Hz), 7.45 (2H, d, J = 8.7 Hz), 7.73 (2H, d, J = 8.7 Hz). 7.86 (1H, s).

9) Synthesis of 4- (4-chlorobenzoyl) -5- (4-chlorophenyl) -1- (2-hydroxyethyl) pyrazole (hereinafter, may be abbreviated as "14-113") Synthesis Example 4-4 ) Was reacted with N, N-dimethylaminomethylene-di (4-chlorobenzoyl) methane and 2-hydroxyethylhydrazine hydrochloride to obtain the desired product in a yield of 85%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 3.13 (1H, t, J = 7.7 Hz), 4.00-4.05 (2H, m), 4.14 (2H, t, J = 4.2 Hz), 7.34 (2H, 2H, d, J = 8.6 Hz), 7.39 (2H, d, J = 8.6 Hz), 7.43 (2H, d, J = 8.6 Hz), 7.71 (2H, d, J = 8.6 Hz). 7.87 (1H, s) ..

10) Synthesis of 4- (4-chlorobenzoyl) -5- (4-chlorophenyl) -1-phenylpyrazole (hereinafter, may be abbreviated as "14-117" ) According to the synthesis method of Example 4-3). , N, N-Dimethylaminomethylene-di (4-chlorobenzoyl) methane was reacted with phenylhydrazine to obtain the desired product in a yield of 98%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 7.20 (2H, d, J = 8.5 Hz), 7.22-7.29 (4H, m), 7.34-7.39 (3H, m), 7.42 (2H, d, J) = 8.5 Hz), 7.78 (2H, d, J = 8.5 Hz), 8.00 (1H, s).

11) Synthesis of 4- (4-chlorobenzoyl) -5- (4-chlorophenyl) -1- (2-pyridyl) pyrazole (hereinafter, may be abbreviated as "14-116") Example 4-4) The desired product was obtained in a yield of 97% by reacting N, N-dimethylaminomethylene-di (4-chlorobenzoyl) methane with 2-pyridylhydrazine according to the above synthetic method.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.21-7.31 (5H, m), 7.41 (2H, d, J = 8.8 Hz), 7.45 (1H, d, J = 7.9 Hz), 7.85 (2H, 2H, d, J = 8.6 Hz), 7.75-7.82 (1H, m), 8.02 (1H, s), 8.38 (1H, dd, J = 5.3, 2.0 Hz).

12) Synthesis of 4- (4-chlorobenzoyl) -5- (4-chlorophenyl) -1- (4-methylphenyl) pyrazole (hereinafter, may be abbreviated as "14-129") Example 4-4-4 ) Was reacted with N, N-dimethylaminomethylene-di (4-chlorobenzoyl) methane and 4-methylphenylhydrazine hydrochloride to obtain the desired product in a yield of 29%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 2,36 (3H, s), 7.09-7.13 (4H, m), 7.19 (2H, d, J = 8.7 Hz), 7.26-7.28 (2H, m) ), 7.42 (2H, d, J = 8.7 Hz), 7.77 (2H, d, J = 8.7 Hz), 7.98 (1H, s).

13) Synthesis of 4- (4-chlorobenzoyl) -1,5-di (4-chlorophenyl) pyrazole (hereinafter, may be abbreviated as "14-130" ) According to the synthesis method of Example 4-4). N, N-Dimethylaminomethylene-di (4-chlorobenzoyl) methane was reacted with 4-chlorophenylhydrazine hydrochloride to obtain the desired product in a yield of 29%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 7.18 (2H, d, J = 8.8 Hz), 7.19 (2H, d, J = 8.5 Hz), 7.31 (2H, d, J = 8.5 Hz), 7.33 (2H, d, J = 8.8 Hz), 7.42 (2H, d, J = 8.5 Hz), 7.76 (2H, d, J = 8.5 Hz), 8.00 (1H, s).

14) Synthesis of 4- (4-chlorobenzoyl) -5- (4-chlorophenyl) -1- (2-nitrophenyl) pyrazole (hereinafter, may be abbreviated as "14-132") Synthesis Example 4-3 ) Was reacted with N, N-dimethylaminomethylene-di (4-chlorobenzoyl) methane and 2-nitrophenylhydrazine hydrochloride to obtain the desired product in a yield of 36%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 7.25-7.28 (6H, m), 7.42 (2H, d, J = 8.5 Hz), 7.58-7.62 (2H, m), 7.78 (2H, d, J) = 8.5 Hz), 8.02 (1H, s).

15) Synthesis of 4- (4-chlorobenzoyl) -5- (4-chlorophenyl) -1- (1-naphthyl) pyrazole (hereinafter, may be abbreviated as "14-133") Example 4-4) N, N-dimethylaminomethylene-di (4-chlorobenzoyl) methane was reacted with 1-naphthylhydrazine hydrochloride according to the above synthetic method to obtain the desired product in a yield of 78%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 7.09 (4H, s), 7.26-7.29 (1H, m), 7.39-7.46 (3H, m), 7.51-7.61 (3H, m), 7.85 (2H) , d, J = 8.5 Hz), 7.92 (2H, d, J = 8.1 Hz), 8.14 (1H, s).

16) Synthesis of 4- (4-chlorobenzoyl) -5- (4-chlorophenyl) -1- (4-methoxyphenyl) pyrazole (hereinafter, may be abbreviated as "14-134") Synthesis Example 4-4 ) Was reacted with N, N-dimethylaminomethylene-di (4-chlorobenzoyl) methane and 4-methoxyphenylhydrazine hydrochloride to obtain the desired product in a yield of 36%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 3.82 (3H, s), 6.85 (2H, d, J = 8.8 Hz), 7.16 (2H, d, J = 8.8 Hz), 7.19 (2H, d, J = 8.4 Hz), 7.27 (2H, d, J = 8.4 Hz), 7.42 (2H, d, J = 8.4 Hz), 7.77 (2H, d, J = 8.4 Hz), 7.97 (1H, s).

17) Synthesis of 4- (4-chlorobenzoyl) -5- (4-chlorophenyl) -1- (3,4-dichlorophenyl) pyrazole (hereinafter, may be abbreviated as "14-139") of Example 4 According to the synthesis method of 4), N, N-dimethylaminomethylene-di (4-chlorobenzoyl) methane was reacted with 3,4-dichlorophenylhydrazine hydrochloride to obtain the desired product in a yield of 43%.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 6.95 (1H, dd, J = 8.7, 2.3 Hz), 7.21 (2H, d, J = 8.4 Hz), 7.34 (2H, d, J = 8.4 Hz) , 7.37 (1H, d, J = 8.7 Hz), 7.43 (2H, d, J = 8.7 Hz), 7.54 (1H, d, J = 2.3 Hz), 7.76 (2H, d, J = 8.7 Hz), 8.00 (1H, s).

18) Synthesis of 1-benzyl-4- (4-chlorobenzoyl) -5- (4-chlorophenyl) pyrazole (hereinafter, may be abbreviated as "14-115" ) According to the synthesis method of Example 4-4). , N, N-Dimethylaminomethylene-di (4-chlorobenzoyl) methane was reacted with benzylhydrazine hydrochloride to obtain the desired product in a yield of 93%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 4.83 (2H, br s), 7.22 (1H, d, J = 8.4 Hz), 7.33 (2H, d, J = 8.4 Hz), 7.40-7.44 (4H) , m), 7.76 (2H, d, J = 8.4 Hz), 7.92 (2H, d, J = 8.4 Hz), 7.76 (2H, d, J = 8.6 Hz), 8.04 (1H, s).

19) Synthesis of 4- (4-bromobenzoyl) -5- (4-bromophenyl) -1- (4-methylphenyl) pyrazole (hereinafter, may be abbreviated as "14-140") of Example 4 According to the synthesis method of 4), N, N-dimethylaminomethylene-di (4-bromobenzoyl) methane was reacted with 4-methylphenylhydrazine hydrochloride to obtain the desired product in a yield of 55%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 2.36 (3H, s), 7.09-7.16 (6H, m), 7.43 (2H, d, J = 8.6 Hz), 7.59 (2H, d, J = 8.6) Hz), 7.70 (2H, d, J = 8.7 Hz), 7.98 (1H, s).

20) Synthesis of 4- (4-bromobenzoyl) -5- (4-bromophenyl) -1- (2-chlorophenyl) pyrazole (hereinafter, may be abbreviated as "14-142") Synthesis Example 4-4 ) Was reacted with N, N-dimethylaminomethylene-di (4-bromobenzoyl) methane and 2-chlorophenylhydrazine hydrochloride to obtain the desired product in a yield of 27%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 7.12 (2H, d, J = 8.7 Hz), 7.35-7.44 (6H, m), 7.59 (2H, d, J = 8.7 Hz), 7.71 (2H, 2H, d, J = 8.5 Hz), 8.05 (1H, s).

21) Synthesis of 4- (4-bromobenzoyl) -5- (4-bromophenyl) -1- (2-nitrophenyl) pyrazole (hereinafter, may be abbreviated as "14-143") of Example 4 According to the synthesis method of 3), N, N-dimethylaminomethylene-di (4-bromobenzoyl) methane was reacted with 2-nitrophenylhydrazine hydrochloride to obtain the desired product in a yield of 55%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 7.19 (2H, d, J = 8.6 Hz), 7.23-7.29 (1H, m), 7.41 (2H, d, J = 8.3 Hz), 7.57-7.62 ( 4H, m), 7.70 (2H, d, J = 8.3 Hz), 7.97-8.00 (1H, m), 8.01 (1H, s).

22) Synthesis of 4- (4-bromobenzoyl) -5- (4-bromophenyl) -1- (1-naphthyl) pyrazole (hereinafter, may be abbreviated as "14-144") Synthesis Example 4-4 ) Was reacted with N, N-dimethylaminomethylene-di (4-bromobenzoyl) methane and 1-naphthylhydrazine hydrochloride to obtain the desired product in a yield of 30%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 7.02 (2H, d, J = 8.6 Hz), 7.23-7.29 (2H, m), 7.42 (1H, t, J = 7.4 Hz), 7.50-7.57 ( 4H, m), 7.62 (2H, d, J = 8.3 Hz), 7.77 (2H, d, J = 8.3 Hz), 7.93 (2H, d, J = 8.3 Hz), 8.13 (1H, s).

23) Synthesis of 4- (4-bromobenzoyl) -5- (4-bromophenyl) -1- (4-cyanophenyl) pyrazole (hereinafter, may be abbreviated as "14-146") of Example 4 According to the synthesis method of 4), N, N-dimethylaminomethylene-di (4-bromobenzoyl) methane was reacted with 4-cyanophenylhydrazine hydrochloride to obtain the desired product in a yield of 18%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 7.14 (2H, d, J = 8.3 Hz), 7.39 (2H, d, J = 8.3 Hz), 7.50 (2H, d, J = 8.5 Hz), 7.59 (2H, d, J = 8.5 Hz), 7.65 (2H, d, J = 6.3 Hz), 7.68 (2H, d, J = 6.3 Hz), 8.03 (1H, s).

25) Synthesis of 1-benzyl-4- (4-bromobenzoyl) -5- (4-bromophenyl) pyrazole (hereinafter, may be abbreviated as "14-173" ) Synthesis method of Example 4-4) Therefore, N, N-dimethylaminomethylene-di (4-bromobenzoyl) methane was reacted with benzylhydrazine hydrochloride to obtain the desired product in a yield of 36%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 5.24 (2H, s), 7.05-7.08 (2H, m), 7.15 (2H, d, J = 8.4 Hz), 7.29-7.32 (3H, m), 7.53 (2H, d, J = 8.6 Hz), 7.56 (2H, d, J = 8.8 Hz), 7.65 (2H, d, J = 8.8 Hz), 7.89 (1H, s).

26) Synthesis Example 4 of 4- (4-bromobenzoyl) -5- (4-bromophenyl) -1- (3,4-dichlorophenyl) pyrazole (hereinafter, may be abbreviated as "14-150") According to the synthesis method of 4) above, N, N-dimethylaminomethylene-di (4-bromobenzoyl) methane was reacted with 3,4-dichlorophenylhydrazine hydrochloride to obtain the desired product in a yield of 45%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 6.95 (1H, dd, J = 8.8, 2.8 Hz), 7.15 (2H, d, J = 8.2 Hz), 7.38 (1H, d, J = 8.8 Hz) , 7. 49 (2H, d, J = 8.2 Hz), 7.55 (1H, d, J = 2.8 Hz), 7.59 (2H, d, J = 8.2 Hz), 7.68 (2H, d, J = 8.2 Hz) , 8.00 (1H, s).

27) Synthesis of 1- (2-chlorophenyl) -4- (4-methylbenzoyl) -5- (4-methylphenyl) pyrazole (hereinafter, may be abbreviated as "14-153") Example 4-4-4 ) Was reacted with N, N-dimethylaminomethylene-di (4-methylbenzoyl) methane and 2-chlorophenylhydrazine hydrochloride to obtain the desired product in a yield of 55%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 2,33 (3H, s), 2,41 (3H, s), 7.01 (2H, d, J = 8.1 Hz), 7.12 (2H, d, J) = 8.0 Hz), 7.22 (2H, d, J = 8.1 Hz), 7.29-7.38 (3H, m), 7.42-7.45 (1H, m), 7.77 (2H, d, J = 8.4 Hz), 8.05 (1H) , s).

28) Synthesis of 4- (4-methylbenzoyl) -5- (4-methylphenyl) -1- (1-naphthyl) pyrazole (hereinafter, may be abbreviated as "14-155") Example 4-4-4 ) Was reacted with N, N-dimethylaminomethylene-di (4-methylbenzoyl) methane and 1-naphthylhydrazine hydrochloride to obtain the desired product in a yield of 30%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 2.18 (3H, s), 2.42 (3H, s), 6.88 (2H, d, J = 8.4 Hz), 7.03 (2H, t, J = 8.1 Hz) , 7.23-7.29 (3H, m), 7.39 (1H, t, J = 8.1 Hz), 7.49-7.60 (3H, m), 7.82 (2H, d, J = 7.9 Hz), 7.89 (2H, d, J) = 7.8 Hz), 8.13 (1H, s).

29) Synthesis of 4- (4-methylbenzoyl) -5- (4-methylphenyl) -1- (4-methoxyphenyl) pyrazole (hereinafter, may be abbreviated as "14-156") of Example 4 According to the synthesis method of 4), N, N-dimethylaminomethylene-di (4-methylbenzoyl) methane was reacted with 4-methoxyphenylhydrazine hydrochloride to obtain the desired product in a yield of 55%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 2,31 (3H, s), 2,41 (3H, s), 3.80 (3H, s), 6.83 (2H, d, J = 8.7 Hz), 7.07 (2H, d, J = 8.3 Hz), 7.14 (2H, d, J = 8.0 Hz), 7.18 (2H, d, J = 8.7 Hz), 7.22 (2H, d, J = 8.0 Hz), 7.75 ( 2H, d, J = 8.3 Hz), 7.97 (1H, s).

30) Synthesis Example 4 of 1- (4-cyanosiphenyl) -4- (4-methylbenzoyl) -5- (4-methylphenyl) pyrazole (hereinafter, may be abbreviated as "14-157") According to the synthesis method of 4) above, N, N-dimethylaminomethylene-di (4-methylbenzoyl) methane was reacted with 4-cyanocyphenylhydrazine hydrochloride to obtain the desired product in a yield of 36%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 2,35 (3H, s), 2,41 (3H, s), 7.14 (4H, s), 7.23 (2H, d, J = 8.7 Hz), 7.40 (2H, d, J = 8.5 Hz), 7.61 (2H, d, J = 8.7 Hz), 7.73 (2H, d, J = 8.5 Hz), 8.03 (1H, s).

31) Synthesis of 1-benzyl-4- (4-methylbenzoyl) -5- (4-methylphenyl) pyrazole (hereinafter, may be abbreviated as "14-174" ) Synthesis method of Example 4-4) According to this, N, N-dimethylaminomethylene-di (4-methylbenzoyl) methane was reacted with benzylhydrazine hydrochloride to obtain the desired product in a yield of 77%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 2,38 (3H, s), 2,39 (3H, s), 5.29 (2H, s), 7.08-7.11 (2H, m), 7.18-7.21 (6H, m), 7.29-7.32 (3H, m), 7.70 (2H, d, J = 8.6 Hz), 7.92 (1H, s).

32) Synthesis of 4- (2-methoxybenzoyl) -5- (2-methoxyphenyl) -1- (4-methylphenyl) pyrazole (hereinafter, may be abbreviated as "14-162") of Example 4 According to the synthesis method of 4), N, N-dimethylaminomethylene-di (2-methoxybenzoyl) methane was reacted with 4-methylphenylhydrazine hydrochloride to obtain the desired product in a yield of 34%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 2,29 (3H, s), 3.45 (3H, s), 3.65 (3H, s), 6.61 (1H, d, J = 8.4 Hz), 6.62 ( 1H, d, J = 8.4 Hz), 6.74 (1H, t, J = 7.5 Hz), 6.83 (1H, t, J = 7.5 Hz), 6.98 (1H, dd, J = 2.0, 7.5 Hz), 7.04 ( 2H, d, J = 8.6 Hz), 7.10 (2H, d, J = 8.6 Hz), 7.15-7.18 (1H, m), 7.20-7.23 (1H, m), 7.26-7.29 (1H, m), 8.10 (1H, s).

33) Synthesis of 1- (4-chlorophenyl) -4- (2-methoxybenzoyl) -5- (2-methoxyphenyl) pyrazole (hereinafter, may be abbreviated as "14-163") Example 4-4-4 ) Was reacted with N, N-dimethylaminomethylene-di (2-methoxybenzoyl) methane and 4-chlorophenylhydrazine hydrochloride to obtain the desired product in a yield of 41%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 3.45 (3H, s), 3.64 (3H, s), 6.62 (1H, d, J = 8.4 Hz), 6.63 (1H, d, J = 8.4 Hz) , 6.75 (1H, dt, J = 7.5, 1.0 Hz), 6.84 (1H, dt, J = 7.5, 1.0 Hz), 7.00 (1H, dd, J = 7.5, 1.7 Hz), 7.14-7.29 (7H, m) ), 8.11 (1H, s).

34) Synthesis of 4- (2-methoxybenzoyl) -5- (2-methoxyphenyl) -1- (4-methoxyphenyl) pyrazole (hereinafter, may be abbreviated as "14-167") of Example 4 According to the synthesis method of 4), N, N-dimethylaminomethylene-di (2-methoxybenzoyl) methane was reacted with 4-methoxyphenylhydrazine hydrochloride to obtain the desired product in a yield of 48%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 3.47 (3H, s), 3.65 (3H, s), 3.76 (3H, s), 6.60 (1H, d, J = 8.3 Hz), 6.63 (1H, 1H, d, J = 8.3 Hz), 6.71-6.78 (3H, m), 6.83 (1H, t, J = 7.5 Hz), 6.98 (1H, dd, J = 7.5, 1.7 Hz), 7.10-7.28 (5H, m) ), 8.09 (1H, s).

35) Synthesis of 1- (4-cyanophenyl) -4- (2-methoxybenzoyl) -5- (2-methoxyphenyl) pyrazole (hereinafter, may be abbreviated as "14-168") of Example 4 According to the synthesis method of 4), N, N-dimethylaminomethylene-di (2-methoxybenzoyl) methane was reacted with 4-cyanophenylhydrazine hydrochloride to obtain the desired product in a yield of 90%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 3.42 (3H, s), 3.64 (3H, s), 3.76 (3H, s), 6.61-6.64 (2H, m), 6.76 (1H, t, J) = 7.5 Hz), 6.84 (1H, t, J = 7.5 Hz), 7.02 (1H, dd, J = 7.5, 1.8 Hz), 7.18-7.25 (2H, m), 7.29-7.34 (3H, m), 7.71 (2H, d, J = 8.7 Hz), 8.15 (1H, s).

36) Examples of Synthesis of 1- (3,4-Dimethylphenyl) -4- (2-Methoxybenzoyl) -5- (2-Methoxyphenyl) Pyrazole (hereinafter, may be abbreviated as "14-169") According to the synthesis method of 4-4), N, N-dimethylaminomethylene-di (2-methoxybenzoyl) methane was reacted with 3,4-dimethylphenylhydrazine hydrochloride to obtain the desired product in a yield of 48%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 2.16 (3H, s), 2.19 (3H, s), 3.47 (3H, s), 3.65 (3H, s), 6.61 (1H, d, J = 8.3) Hz), 6.63 (1H, d, J = 8.3 Hz), 6.74 (1H, t, J = 7.6 Hz), 6.80-6.87 (2H, m), 6.93-6.99 (2H, m), 7.10-7.29 (4H) , m), 8.10 (1H, s).

37) Synthesis of 1- (4-bromophenyl) -4- (2-methoxybenzoyl) -5- (2-methoxyphenyl) pyrazole (hereinafter, may be abbreviated as "14-170") of Example 4 According to the synthesis method of 4), N, N-dimethylaminomethylene-di (2-methoxybenzoyl) methane was reacted with 4-bromophenylhydrazine hydrochloride to obtain the desired product in a yield of 55%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 3.45 (3H, s), 3.64 (3H, s), 6.62 (1H, d, J = 8.3 Hz), 6.64 (1H, d, J = 8.3 Hz) , 6.76 (1H, t, J = 7.7 Hz), 6.84 (1H, t, J = 7.7 Hz), 7.00 (1H, dd, J = 7.7, 1.8 Hz), 7.10 (2H, d, J = 8.8 Hz) , 7.18-7.31 (3H, m), 7.38 (2H, d, J = 8.8 Hz), 8.12 (1H, s).

38) Synthesis Example 4 of 1- (3,4-dichlorophenyl) -4- (2-methoxybenzoyl) -5- (2-methoxyphenyl) pyrazole (hereinafter, may be abbreviated as "14-172") According to the synthesis method of 4) above, N, N-dimethylaminomethylene-di (2-methoxybenzoyl) methane was reacted with 3,4-dichlorophenylhydrazine hydrochloride to obtain the desired product in a yield of 66%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 3.48 (3H, s), 3.64 (3H, s), 6.62 (1H, d, J = 8.6 Hz), 6.65 (1H, d, J = 8.6 Hz) , 6.78 (1H, t, J = 7.5 Hz), 6.84 (1H, t, J = 7.5 Hz), 6.97-7.02 (2H, m), 7.19-7.30 (4H, m), 7.47 (1H, d, J) = 2.5 Hz), 8.12 (1H, s).

39) Synthesis of 1-benzyl-4- (2-methoxybenzoyl) -5- (2-methoxyphenyl) pyrazole (hereinafter, may be abbreviated as "14-175" ) Synthesis method of Example 4-4) According to this, N, N-dimethylaminomethylene-di (2-methoxybenzoyl) methane was reacted with benzylhydrazine hydrochloride to obtain the desired product in a yield of 75%.
^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 3.57 (3H, s), 3.64 (3H, s), 5.11 (2H, q, J = 8.2 Hz), 6.58 (1H, d, J = 8.2 Hz) , 6.68 (1H, d, J = 7.5 Hz), 6.76 (1H, d, J = 7.5 Hz), 6.81 (1H, d, J = 7.5 Hz), 6.95-7.02 (3H, m), 7.13-7.24 ( 6H, m), 8.04 (1H, s).

Test Example 1
Pancreatic cancer cell chemotaxis inhibitory effect (in vitro)
Real-time cytodynamic analysis based on image analysis (TAXIScan method) (J Immunol. Methods. 282: 1, 2003, J Immunol. Methods. 320:55, 2007, J Immunol. Methods. 404: 59, 2014 and BMC cancer .17: 234, 2017) (Fig. 1) was used to construct a system for evaluating the chemotactic and infiltrating ability of pancreatic cancer cells, and the chemotactic properties of pancreatic cancer cells were obtained for the compounds synthesized in Examples 1 to 4. The suppressive effect of was evaluated. The result is shown in FIG.
As can be seen from FIG. 2, the compounds synthesized in Examples 1 to 4 suppressed the chemotaxis of the pancreatic cancer cell line BxPC-3 to fetal bovine serum, particularly the speed of migration, and the speed was a chemotaxis factor. It was suppressed to about the same rate as the cells without.

Test Example 2
Pancreatic cancer cell growth inhibitory effect (in vivo)
1x10 ⁶ human pancreatic cancer cell lines BxPC-3 were suspended in 100 μL phosphate buffer and inoculated subcutaneously on the back of 5-week-old nude mice. After confirming engraftment 7 days after inoculation, the compound synthesized in Example 4 of 1 mg (corresponding to 40 mg / kg body weight) per mouse was orally administered once a week. At the time of administration, 30 mg / mL of the compound dissolved in dimethyl sulfoxide was diluted with olive oil to 1 mg / 100 μL, and the compound was forcibly orally administered using a gastric sonde.
The result is shown in FIG.
As can be seen from FIG. 3, the compound synthesized in Example 4 suppressed the increase of the pancreatic cancer cell line BxPC-3 inoculated on the back of nude mice more than the existing drug gemcitabine.

Test Example 3
Pancreatic cancer cell metastasis inhibitory effect (in vivo)
Nude mice (strain name: BALB / c Ajcl-nu / nu; 5-6 weeks old) were subcutaneously transplanted with GFP-labeled human pancreatic cancer cell line BxPC-3 (4.0 x 10 ⁶ in 200 μl PBS) and then proliferated. The tumor tissue was excised, and a mass (4 mm ³ ) cut out from the isolated tumor was transplanted into the pancreas of 16 other mice. Two weeks after transplantation, the cells were divided into 4 groups (4 animals / group), drugs were administered weekly, and the amount of fluorescence and the number of tumors were measured from the body surface every week. After 50 days (about 7 weeks), the patient was euthanized, the abdomen was opened, and the fluorescence amount was directly measured. For statistics, a non-parametric method was used, and significant differences were examined by the Kruskal-Wallis test, and p <0.05 was considered significant.
Group 1: No drug Group 2: Gemcitabine (ip)
Group 3: Compound of Example 4 (stock solution: 100 mM in DMSO) (po)
Group 4: Gemcitabine (ip) + compound of Example 4 (stock solution: 100 mM in DMSO) (po)
The results (comparison of changes in body weight (assuming 1 at the time of transplantation), the number of individuals with metastasis, and the amount of fluorescence from the tumor) are shown in FIGS. 4 to 6, respectively.
As can be seen from FIG. 4, weight gained except in Group 1 (no drug).
As can be seen from FIG. 5, metastasis was observed in group 1 (without drug) after 22 days and in group 2 (administered with gemcitabine) after 36 days, but in group 3 (compound administration of Example 4) and group 4 (administered gemcitabine). + No metastasis was observed in (compound administration of Example 4).
As can be seen from FIG. 6, the amount of fluorescence in Group 4 (gemcitabine + compound administration of Example 4) was significantly lower than that in Group 1 (without drug), and tumor growth was suppressed.

Test Example 4
Pancreatic cancer cell chemotaxis inhibitory effect (in vitro)
In the same manner as in Test Example 1, the effect of suppressing the chemotaxis of pancreatic cancer cells was evaluated for the compounds synthesized in Examples 5 and 6. The results are shown in FIGS. 7-10.
As can be seen from FIG. 7, the compounds synthesized in Examples 5 and 6 significantly suppressed the speed of migration of the chemotactic components of the pancreatic cancer cell line BxPC-3 to fetal bovine serum.
As can be seen from FIG. 8, the compounds synthesized in Examples 5 and 6 significantly suppressed the directionality of the chemotactic components of the pancreatic cancer cell line BxPC-3 with respect to fetal bovine serum.
As can be seen from FIG. 9, the compounds synthesized in Examples 5 and 6 significantly suppressed the speed of migration of the chemotactic components of the pancreatic cancer cell line BxPC-3 to fetal bovine serum.
As can be seen from FIG. 10, the compounds synthesized in Examples 5 and 6 significantly suppressed the directionality of the chemotactic components of the pancreatic cancer cell line BxPC-3 with respect to fetal bovine serum.

The number of pancreatic cancers in Japan is about 33,000 per year (2010), accounting for 7-9% of all cancers, the number of deaths is about 30,000 per year (2012), and the number of cases worldwide is every year. There are about 277,000 people, which is 2.2% of all cancers. The 5-year survival rate (all stages) is about 7% from 1981 to 1990 and about 13% from 2001 to 2007, and the treatment results are improving but still poor. During this time, new drugs and surgical methods have advanced, but it is far from overcoming pancreatic cancer. If the present invention reaches clinical application, it is expected to have an effect of dramatically improving the prognosis of these patients.
In the in vitro cytodynamic analysis method which is the basis of the present invention as well as pancreatic cancer, a chemotactic assay system has been established for lung cancer, colon cancer, breast cancer cells, ovarian cancer, and sarcomatous cells. It is possible to evaluate a wide range of cancer metastasis inhibitory effects including cancer. The total number of cancer cases is about 980,000 in Japan (2015 estimate), 14 million worldwide (2012 estimate), and the number of deaths is about 370,000 in Japan (2015 estimate), about annually in the world. It is 8.2 million (2012 estimate). A therapeutic effect is expected in some of these cancer patients.
In addition, as shown in FIG. 2, since the cytotoxicity observed with the existing drug gemcitabine is low, it is expected that there are fewer side effects than the existing drug in clinical application. Currently, in cancer treatment, medication may have to be abandoned due to side effects, so it is expected to have the effect of avoiding interruption or discontinuation of treatment.

The present invention can provide a compound having antitumor activity and cancer metastasis inhibitory activity, and an antitumor agent containing the compound as an active ingredient.

This application is based on Japanese Patent Application No. 2018-059074 filed in Japan, the contents of which are incorporated herein by reference in its entirety.

Claims (7)

Equation (1):

(During the ceremony,
Ring A represents a 5- to 6-membered ring that may have a substituent,
R ¹ and R ⁴ independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a cyano group, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group or a C _1-6 alkoxy group, respectively. ,
The benzene ring B and the benzene ring C may each have a further substituent.
The benzene ring BC (R ² ) (R ³ ) group and the benzene ring C are each bonded to a separate carbon atom constituting the ring A.
R ² and R ³ independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a cyano group, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group or a C _1-6 alkoxy group, respectively. Alternatively, R ² and R ³ together represent an oxo or hydroxyimino group. )
A compound represented by or a salt thereof. The compound according to claim 1, wherein R ¹ and R ⁴ are independently chlorine atoms, bromine atoms or methoxy groups. The compound according to claim 1 or 2, wherein the ring A is a pyrazole ring or a pyrimidine ring which may have a methyl group. The compound according to any one of claims 1 to 3, wherein R ² and R ^{3 are together as an oxo group.} R ¹ and R ⁴ are independently chlorine atoms, bromine atoms or methoxy groups, ring A is a pyrazole ring or pyrimidine ring which may have a methyl group, and R ² and R ^{3 are} The compound according to any one of claims 1 to 4, wherein the compound is an oxo group together. 5- (4-methoxybenzoyl) -4- (4-methoxyphenyl) -2-methylpyrimidine, 4- (4-methoxybenzoyl) -5- (4-methoxyphenyl) -1-methylpyrazole, 4- (4) The compound according to claim 5, which is -bromobenzoyl) -5- (4-bromophenyl) -1-methylpyrazole or 4- (4-chlorobenzoyl) -5- (4-chlorophenyl) -1-methylpyrazole. .. The compound according to any one of claims 1 to 6, which has a cancer metastasis inhibitory activity and a tumor growth inhibitory activity.

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