WO2019188456A1 - Novel anti-tumor agent - Google Patents

Novel anti-tumor agent Download PDF

Info

Publication number
WO2019188456A1
WO2019188456A1 PCT/JP2019/011009 JP2019011009W WO2019188456A1 WO 2019188456 A1 WO2019188456 A1 WO 2019188456A1 JP 2019011009 W JP2019011009 W JP 2019011009W WO 2019188456 A1 WO2019188456 A1 WO 2019188456A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
ring
synthesis
nmr
mhz
Prior art date
Application number
PCT/JP2019/011009
Other languages
French (fr)
Japanese (ja)
Inventor
山内　明
臣成 町支
Original Assignee
学校法人 川崎学園
学校法人 福山大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 学校法人 川崎学園, 学校法人 福山大学 filed Critical 学校法人 川崎学園
Priority to JP2020510676A priority Critical patent/JPWO2019188456A1/en
Publication of WO2019188456A1 publication Critical patent/WO2019188456A1/en
Priority to JP2023115386A priority patent/JP2023134657A/en

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Definitions

  • the present invention relates to a compound having antitumor activity and cancer metastasis inhibitory activity, in particular, a pyrazole derivative and a pyrimidine derivative, and an antitumor agent containing the compound as an active ingredient.
  • pancreatic cancer drugs that focus on cell proliferation are the mainstream as therapeutic drugs for cancer and exert their effects by inhibiting the division and proliferation of cancer cells.
  • the standard therapeutic agent for pancreatic cancer is gemcitabine, which is combined with several anticancer agents.
  • immune checkpoint inhibitors have emerged and have been approved for skin cancer and lung cancer, and have been effective in several cancer diseases by increasing the cytotoxic activity of cancer cells by eliminating the mechanism by which cancer cells escape cell damage. ing.
  • Cancer is often fatal due to metastasis, but existing anticancer agents target cell growth inhibition and have little effect of suppressing cancer metastasis itself. Also, cancer therapeutic agents that target cancer metastasis itself are not currently used as therapeutic agents. However, if further metastasis can be suppressed in both early stage and advanced cancer, 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.
  • Ring A represents an optionally substituted 5- to 6-membered ring
  • R 1 and R 4 each independently represents 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.
  • Each of the benzene ring B and the benzene ring C may further have a 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 each independently represents 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.
  • R 2 and R 3 together represent an oxo group or a hydroxyimino group.
  • a salt thereof sometimes abbreviated as “compound (1)” in the present specification).
  • Ring A represents an optionally substituted 5- to 6-membered ring
  • R 1 and R 4 each independently represents 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.
  • Each of the benzene ring B and the benzene ring C may further have a 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 each independently represents 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.
  • R 2 and R 3 together represent an oxo group.
  • a salt thereof sometimes abbreviated as “compound (1)” in the present specification).
  • R 1 and R 4 are each independently a chlorine atom, bromine atom or methoxy group
  • ring A is a pyrazole ring or pyrimidine ring optionally having a methyl group
  • R 2 The compound according to any one of [1] to [4] and [1 ′], wherein R 3 and R 3 are together an oxo group.
  • a compound having antitumor activity and cancer metastasis inhibiting activity particularly a pyrazole derivative and a pyrimidine derivative, and an antitumor agent containing the compound as an active ingredient.
  • 6 is a graph showing the results of Test Example 1.
  • 6 is a graph showing the results of Test Example 2. It is a graph which shows the result (change of body weight (it is set as 1 at the time of transplant)) of the test example 3.
  • FIG. 10 is a graph showing the results of Test Example 3 (number of individuals in which metastasis was observed). It is a graph which shows the result (comparison of the amount of fluorescence from a tumor) of Experimental example 3. It is a graph which shows the result of Experiment 4 (suppression of the speed of movement among chemotaxis components).
  • each substituent used in the present specification will be described in detail. Unless otherwise specified, each substituent has the following definition.
  • examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • examples of the “C 1-6 alkyl group” include 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.
  • 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”.
  • examples of the “C 3-10 cycloalkyl group” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2. 2] Octyl, bicyclo [3.2.1] octyl, and adamantyl.
  • examples of the “C 1-6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
  • examples of the “C 6-14 aryl group” include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, and 9-anthryl.
  • the “5- to 14-membered aromatic heterocyclic group” contains, for example, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring constituent atom.
  • Examples include 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic groups, and preferable examples include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, 5- to 6-membered monocyclic such as pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl An aromatic heterocyclic group; Benzothiophenyl, benzofuranyl, benzoimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imi
  • examples of the “5- to 6-membered ring” include, for example, a 5- to 6-membered ring containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom. And aromatic or non-aromatic heterocycles.
  • Suitable examples of the “5- to 6-membered aromatic heterocycle” include thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2 , 4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, triazine and the like.
  • Suitable examples of the “5- to 6-membered non-aromatic heterocycle” include tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole, Examples include tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridine, dihydrothiopyran, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine and the like.
  • Ring A represents a 5- to 6-membered ring optionally having a substituent.
  • the “5- to 6-membered ring” of the “optionally substituted 5- to 6-membered ring” 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 “optionally substituted 5- to 6-membered ring” may have 1 to 3 substituents at substitutable positions, and the number of substituents is 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, methyl group), more preferably a methyl group.
  • the “substituent” is preferably an optionally substituted C 1-6 alkyl group (eg, methyl group, ethyl group, isopropyl group), optionally substituted.
  • a C 3-10 cycloalkyl group eg, cyclohexyl group
  • an optionally substituted C 6-14 aryl group eg, phenyl, naphthyl
  • an optionally substituted 5- to 14-membered aromatic heterocycle eg, , Pyridyl.
  • Ring A is preferably a 5- to 6-membered aromatic heterocyclic ring (eg, pyrazole ring) optionally having 1 to 3 substituents selected from a C 1-6 alkyl group (eg, methyl group). More preferably a pyrazole ring or a pyrimidine ring, each of which may have 1 to 3 methyl groups.
  • ring A is preferably an optionally substituted C 1-6 alkyl group (eg, a methyl group, an ethyl group, an isopropyl group), an 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)
  • a 5- to 6-membered aromatic heterocyclic ring eg, pyrazole ring, pyrimidine ring
  • substituents selected from: (1) hydroxyl group and C A C 1-6 alkyl group (eg, a methyl group, an ethyl group, an isopropyl group) optionally having 1 to 3 substituents selected from 6-14 aryl groups (eg, phenyl), (2) C 3-10 cyclo Alkyl group (
  • R 1 and R 4 each independently represents 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.
  • R 1 and R 4 are preferably each independently a halogen atom (eg, chlorine atom, bromine atom) or a C 1-6 alkoxy group (eg, methoxy group), more preferably each independently.
  • R 1 and R 4 are preferably each independently a hydrogen atom, a nitro group, a cyano group, a halogen atom (eg, a chlorine atom, a bromine atom), or a substituted group.
  • a good C 1-6 alkyl group (eg, methyl group) or an optionally substituted C 1-6 alkoxy group (eg, methoxy group) more preferably each independently 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 further have 1 to 4 substituents other than R 1 and R 4 at substitutable positions.
  • the benzene ring B and the benzene ring C preferably have no further substituent other than R 1 and R 4 , respectively.
  • the benzene ring C may preferably have a halogen atom (eg, chlorine atom) in addition to R 4 .
  • the benzene ring BC (R 2 ) (R 3 ) group and the benzene ring C are each bonded to separate carbon atoms 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 that each constitute the ring A.
  • R 2 and R 3 each independently represents 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. Or R 2 and R 3 together represent an oxo group. R 2 and R 3 are preferably taken together to form an oxo group.
  • R 2 and R 3 each independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a cyano group, a C 1-6 alkyl group, or a halogenated C 1-6 alkyl group. Or a C 1-6 alkoxy group, or R 2 and R 3 together represent an oxo group or a hydroxyimino group.
  • R 2 and R 3 are each independently a hydrogen atom or a hydroxyl group, or R 2 and R 3 together are an oxo group or a hydroxyimino group.
  • Ring A is a 5- to 6-membered aromatic heterocyclic ring (eg, pyrazole ring, pyrimidine ring) optionally having 1 to 3 substituents selected from C 1-6 alkyl groups (eg, methyl group) ); R 1 and R 4 are each independently a halogen atom (eg, chlorine atom, bromine atom) or a C 1-6 alkoxy group (eg, methoxy group); Benzene ring B and benzene ring C have no further substituents other than R 1 and R 4 , respectively; The benzene ring BC (R 2 ) (R 3 ) group and the benzene ring C are each bonded to separate adjacent carbon atoms that constitute ring A; R 2 and R 3 together are an oxo group; Compound (1).
  • Ring A is a 5- to 6-membered aromatic heterocyclic ring (eg, pyrazole ring, pyrimidine ring) optionally having 1 to 3 substituents selected from C
  • Ring A is a pyrazole ring or a pyrimidine ring each optionally having 1 to 3 methyl groups; R 1 and R 4 are each independently a chlorine atom, a bromine atom or a methoxy group; Benzene ring B and benzene ring C have no further substituents other than R 1 and R 4 , respectively; The benzene ring BC (R 2 ) (R 3 ) group and the benzene ring C are each bonded to separate adjacent carbon atoms that constitute ring A; R 2 and R 3 together are an oxo group; Compound (1).
  • Ring A is an optionally substituted C 1-6 alkyl group (eg, methyl group, ethyl group, isopropyl group), an optionally substituted C 3-10 cycloalkyl group (eg, cyclohexyl group), substituted Having 1 to 3 substituents selected from an optionally substituted C 6-14 aryl group (eg, phenyl, naphthyl) and an optionally substituted 5- to 14-membered aromatic heterocycle (eg, pyridyl).
  • C 1-6 alkyl group eg, methyl group, ethyl group, isopropyl group
  • C 3-10 cycloalkyl group eg, cyclohexyl group
  • substituents selected from an optionally substituted C 6-14 aryl group (eg, phenyl, naphthyl) and an optionally substituted 5- to 14-membered aromatic heterocycle (eg, pyridyl).
  • R 1 and R 4 are each independently a hydrogen atom, nitro group, cyano group, halogen atom (eg, chlorine atom, bromine atom), optionally substituted C 1-6 alkyl group (eg, methyl group) Or an optionally substituted C 1-6 alkoxy group (eg, a methoxy group);
  • the benzene ring B has no further substituents other than R 1 ;
  • the benzene ring C may further have a halogen atom (eg, chlorine atom) in addition to R 4 ;
  • the benzene ring BC (R 2 ) (R 3 ) group and the benzene ring C are each bonded to separate adjacent carbon atoms that constitute ring A;
  • R 2 and R 3 are each independently a hydrogen atom or a hydroxyl group, or R 2 and R 3 together are an oxo group or a hydroxyi
  • Ring A may each have (1) a C 1-6 alkyl group (eg, methyl group) optionally having 1 to 3 substituents selected from a hydroxyl group and a C 6-14 aryl group (eg, phenyl) , 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 C 6-14 aryl group (eg, phenyl, naphthyl) optionally having 1 to 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 pyrimidine ring optionally having 1 to 3 substituents selected from 5- to 14-membered aromatic heterocycles (eg, pyridyl); R 1
  • examples of such a salt include 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.
  • the salt with an inorganic base 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.
  • the salt with an organic base include trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris (hydroxymethyl) methylamine], tert-butylamine, cyclohexylamine, benzylamine, And salts with dicyclohexylamine and N, N-dibenzylethylenediamine.
  • salt with inorganic acid include salts with hydrogen chloride, hydrogen bromide, nitric acid, sulfuric acid and phosphoric acid.
  • salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, and benzenesulfonic acid And salts with p-toluenesulfonic acid.
  • salts with basic amino acids include salts with arginine, lysine and ornithine.
  • salt with acidic amino acid include salts with aspartic acid and glutamic acid.
  • Pharmaceutically acceptable salts include, for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or the like when the compound has a basic functional group; or acetic acid, phthalic acid And salts with organic acids such as fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid and p-toluenesulfonic acid.
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or the like when the compound has a basic functional group
  • acetic acid phthalic acid
  • salts with organic acids such as fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid and p-toluenesulfonic acid.
  • inorganic salts such as alkali metal salts (eg, sodium salts, potassium salts, etc.) and alkaline earth metal salts (eg, calcium salts, magnesium salts, barium salts, etc.) An ammonium salt and the like.
  • ring A is a pyrazole ring or pyrimidine ring which may have a methyl group or the like, and benzene ring B and benzene ring C have no further substituent other than R 1 and R 4 , respectively.
  • a benzene ring BC (R 2 ) (R 3 ) group and a benzene ring C are bonded to separate adjacent carbon atoms constituting the ring A, and R 2 and R 3 are each independently
  • the production method of the compound (1) which is a hydrogen atom or a hydroxyl group, or R 2 and R 3 together form an oxo group or a hydroxyimino group will be described below.
  • N, N-dimethylaminomethylene-dibenzoylmethane (IV ) A dimethylformamide dimethyl acetal solution of dibenzoylmethane (III) is heated to reflux in a nitrogen stream for 6 hours. After cooling to room temperature, water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is subjected to silica gel column chromatography, and N, N-dimethylaminomethylene (IV) is obtained from the ethyl acetate-hexane stream.
  • Compound (1) has antitumor activity and cancer metastasis inhibitory activity, and antitumor agents containing compound (1) as an active ingredient are various malignant tumors (eg, pancreatic cancer, lung cancer, colon cancer, breast cancer, Ovarian cancer, cervical cancer, prostate cancer, malignant melanoma, gastric cancer, hepatocellular carcinoma, bile duct cancer, oral cancer, esophageal cancer, bladder cancer, nerve tumor, testicular tumor, leiomyosarcoma, liposarcoma, rhabdomyosarcoma, Malignant fibrous histiocytoma, chondroma, osteosarcoma, leukemia, lymphoma, mesothelioma).
  • malignant tumors eg, pancreatic cancer, lung cancer, colon cancer, breast cancer, Ovarian cancer, cervical cancer, prostate cancer, malignant melanoma, gastric cancer, hepatocellular carcinoma, bile duct cancer, oral cancer, esophage
  • the antitumor agent containing the compound (1) of the present invention as an active ingredient may contain only the compound (1), or a pharmacologically acceptable carrier (excipient, binder, Disintegrating agents, flavoring agents, flavoring agents, emulsifiers, diluents, solubilizing agents, and the like).
  • a pharmacologically acceptable carrier excipient, binder, Disintegrating agents, flavoring agents, flavoring agents, emulsifiers, diluents, solubilizing agents, and the like.
  • the antitumor agent containing the compound (1) of the present invention as an active ingredient is pharmacologically combined with the compound (1) according to a method known per se (eg, a method described in the Japanese Pharmacopoeia) as a method for producing a pharmaceutical preparation.
  • 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 It is about 100% by weight, preferably about 0.01 to 10% by weight, and more preferably about 0.1 to 1% by weight.
  • parenteral means subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip method or local administration (intra-articular administration, transdermal administration, ophthalmic administration, transpulmonary administration, bronchial administration) , Nasal administration or rectal 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 subject, administration route, and symptoms, and is not particularly limited.
  • the compound (1) is, for example, 0.1 to 1000 mg / kg body weight once a week, preferably 1 to 500 mg / kg body weight once a week, more preferably 10 to 100 mg once a week. / Kg body weight may be administered. This amount can be administered in 1 to 3 divided doses per day.
  • Example 5 The following pyrimidine derivatives were synthesized according to the method of Example 1.
  • Example 6 The following pyrazole derivatives were synthesized according to the method of Example 4.
  • Test example 1 Pancreatic cancer cell chemotaxis inhibitory effect (in vitro) Real-time cell kinetic analysis method 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 chemotaxis / invasion ability in pancreatic cancer cells, and the compounds synthesized in Examples 1 to 4 were chemotactic for pancreatic cancer cells. The inhibitory effect of was evaluated. The result is shown in FIG. As can be seen from FIG.
  • the compounds synthesized in Examples 1 to 4 suppress the chemotaxis of pancreatic cancer cell line BxPC-3 to fetal bovine serum, in particular, the speed of migration, and the speed is determined by the chemotactic factor. It was suppressed to almost the same speed as the cells without.
  • Test example 2 Pancreatic cancer cell growth inhibitory effect (in vivo) 1 ⁇ 10 6 human pancreatic cancer cell lines BxPC-3 were suspended in 100 ⁇ L of phosphate buffer and inoculated subcutaneously on the back of 5-week-old nude mice. After confirming engraftment 7 days after the inoculation, 1 mg (corresponding to 40 mg / kg body weight) of the compound synthesized in Example 4 per mouse was orally administered once a week. At the time of administration, 30 mg / mL of a compound dissolved in dimethyl sulfoxide was diluted to 1 mg / 100 ⁇ L with olive oil and forcibly administered orally using a stomach tube. The result is shown in FIG. As can be seen from FIG. 3, the compound synthesized in Example 4 suppressed the increase of pancreatic cancer cell line BxPC-3 inoculated on the back of nude mice, compared with 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) proliferated after subcutaneous implantation of GFP-labeled human pancreatic cancer cell line BxPC-3 (4.0 ⁇ 10 6 in 200 ⁇ l PBS) The tumor tissue was excised, and a mass (4 mm 3 ) excised from the separated tumor was transplanted into the pancreas of another 16 mice. Two weeks after transplantation, the mice were divided into 4 groups (4 animals / group), and drugs were administered every week. The amount of fluorescence and the number of tumors were measured from the body surface every week.
  • Group 1 No drug
  • Group 2 Gemcitabine (ip)
  • Group 3 Compound of Example 4 (stock solution: 100 mM in DMSO)
  • Group 4 gemcitabine (ip) + compound of Example 4 (stock solution: 100 mM in DMSO) (po)
  • the results are shown in FIGS.
  • Test example 4 Pancreatic cancer cell chemotaxis inhibitory effect (in vitro)
  • the compounds synthesized in Example 5 and Example 6 were evaluated for the inhibitory effect on pancreatic cancer cell chemotaxis.
  • the results are shown in FIGS.
  • the compounds synthesized in Example 5 and Example 6 significantly suppressed the speed of migration among the chemotactic components of fetal bovine serum of pancreatic cancer cell line BxPC-3.
  • the compounds synthesized in Example 5 and Example 6 significantly suppressed the directionality of the chemotactic component of fetal bovine serum of pancreatic cancer cell line BxPC-3.
  • FIG. 7 the compounds synthesized in Example 5 and Example 6 significantly suppressed the speed of migration among the chemotactic components of fetal bovine serum of pancreatic cancer cell line BxPC-3.
  • the compounds synthesized in Example 5 and Example 6 significantly suppressed the directionality of the chemotactic component of fetal bovine serum of pancreatic cancer cell line BxPC
  • Example 5 and Example 6 significantly suppressed the migration speed among the chemotactic components of the pancreatic cancer cell line BxPC-3 with respect to fetal calf serum.
  • the compounds synthesized in Example 5 and Example 6 significantly suppressed the directionality of the chemotactic component of fetal bovine serum of pancreatic cancer cell line BxPC-3.
  • pancreatic cancer The number of cases of pancreatic cancer in Japan is about 33,000 (2010), accounting for 7-9% of all cancers, the number of deaths is about 30,000 (2012), and the number of cases worldwide is every year. About 277,000 people, 2.2% of all cancers.
  • the 5-year survival rate (all stages) is about 7% between 1981 and 1990, and about 13% between 2001 and 2007, but treatment results are improving but still poor.
  • new drugs and surgical methods have progressed, but far from overcoming pancreatic cancer. If the present invention reaches clinical application, the effect of dramatically improving the prognosis of these patients is expected.
  • pancreatic cancer not only pancreatic cancer but also the in vitro cell kinetic analysis method on which the present invention is based has established chemotaxis assay systems for lung cancer, colon cancer, breast cancer cells, ovarian cancer, and sarcoma cells. It is possible to evaluate a wide range of cancer metastasis inhibitory effects including cancers of The total number of cancer cases is approximately 980,000 in Japan (2015 estimate), 14 million in the world (2012 estimate), and the number of deaths in Japan is approximately 370,000 (2015 estimate). It is 8.2 million (2012 estimate). Some of these cancer patients are expected to have therapeutic effects. Further, as shown in FIG. 2, since the cytotoxicity seen with the existing drug gemcitabine is small, it is expected to have fewer side effects than the existing drug in clinical application. Currently, there are cases where it is unavoidable to abandon medication due to side effects in cancer treatment, and therefore an effect of avoiding interruption or discontinuation of treatment is also expected.
  • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Provided are: a compound having an anti-tumor activity and a cancer metastasis inhibiting activity; and an anti-tumor agent containing the compound as an active ingredient. A compound represented by formula (1) (wherein the ring A represents a 5- to 6-membered ring which may have a substituent; R1 and R4 independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a cyano group, a C1-6 alkyl group, a halogenated C1-6 alkyl group or a C1-6 alkoxy group; each of the benzene ring B and the benzene ring C may further have a substituent; the (benzene ring B)-C(R2)(R3) group and the benzene ring C are bonded to different carbon atoms constituting the ring A, respectively; and R2 and R3 independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitro 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) or a salt thereof.

Description

新規抗腫瘍剤New antitumor agent
　本発明は、抗腫瘍活性および癌転移抑制活性を有する化合物、特にピラゾール誘導体およびピリミジン誘導体、ならびに当該化合物を有効成分として含有する抗腫瘍剤に関する。 The present invention relates to a compound having antitumor activity and cancer metastasis inhibitory activity, in particular, a pyrazole derivative and a pyrimidine derivative, and an antitumor agent containing the compound as an active ingredient.
　現在、癌治療薬としては細胞増殖に的を絞った薬剤が主流であり、癌細胞の***および増殖を抑制することでその効果を発揮する。例えば、膵癌に対する標準治療薬はゲムシタビンであり、これにいくつかの抗癌剤が併用される。近年は、免疫チェックポイント阻害剤が登場し、皮膚癌と肺癌で認可されており、癌細胞が細胞障害を免れる機構を絶ち自身の細胞傷害活性を増すことによりいくつかの癌疾患で効果を上げている。 Currently, drugs that focus on cell proliferation are the mainstream as therapeutic drugs for cancer and exert their effects by inhibiting the division and proliferation of cancer cells. For example, the standard therapeutic agent for pancreatic cancer is gemcitabine, which is combined with several anticancer agents. In recent years, immune checkpoint inhibitors have emerged and have been approved for skin cancer and lung cancer, and have been effective in several cancer diseases by increasing the cytotoxic activity of cancer cells by eliminating the mechanism by which cancer cells escape cell damage. ing.
　癌は転移を起こすことにより致命的になることが多いが、既存の抗癌剤は細胞増殖阻害をターゲットとしており、癌転移そのものを抑える効果はほとんどない。また、癌転移そのものをターゲットとした癌治療薬は現在、治療薬としては用いられていない。しかしながら、早期・進行癌のいずれにしてもさらなる転移を抑えることができれば、手術によって癌を取り除くことができ、予後の大幅な改善が期待できる。 Cancer is often fatal due to metastasis, but existing anticancer agents target cell growth inhibition and have little effect of suppressing cancer metastasis itself. Also, cancer therapeutic agents that target cancer metastasis itself are not currently used as therapeutic agents. However, if further metastasis can be suppressed in both early stage and advanced cancer, cancer can be removed by surgery, and a significant improvement in prognosis can be expected.
　本発明の目的は、抗腫瘍活性および癌転移抑制活性を有する化合物、ならびに当該化合物を有効成分として含有する抗腫瘍剤を提供することである。 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.
　本発明者らは上記課題を解決すべく鋭意検討した結果、下記の式（１）で示される化合物が抗腫瘍活性および癌転移抑制活性を有することを見出し、本発明を完成するに至った。
　すなわち、本発明は以下の通りである。
［１］式（１）： As a result of intensive studies to solve the above problems, the present inventors have found that a compound represented by the following formula (1) has an antitumor activity and a cancer metastasis suppressing activity, and has completed the present invention.
That is, the present invention is as follows.
[1] Formula (1):
Figure JPOXMLDOC01-appb-C000002
Figure JPOXMLDOC01-appb-C000002
（式中、
　環Ａは、置換基を有していてもよい５ないし６員環を示し、
　Ｒ１およびＲ４は、それぞれ独立して、水素原子、ハロゲン原子、水酸基、ニトロ基、シアノ基、Ｃ１－６アルキル基、ハロゲン化Ｃ１－６アルキル基またはＣ１－６アルコキシ基を示し、
　ベンゼン環Ｂおよびベンゼン環Ｃは、それぞれさらに置換基を有していてもよく、
　ベンゼン環Ｂ－Ｃ（Ｒ２）（Ｒ３）基およびベンゼン環Ｃは、それぞれ環Ａを構成する別個の炭素原子に結合しており、
　Ｒ２およびＲ３は、それぞれ独立して、水素原子、ハロゲン原子、水酸基、ニトロ基、シアノ基、Ｃ１－６アルキル基、ハロゲン化Ｃ１－６アルキル基またはＣ１－６アルコキシ基を示すか、あるいはＲ２およびＲ３は一緒になってオキソ基またはヒドロキシイミノ基を示す。）
で表される化合物（本明細書中、「化合物（１）」と略記する場合がある）またはその塩。
［１’］式（１）： (Where
Ring A represents an optionally substituted 5- to 6-membered ring,
R 1 and R 4 each independently represents 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. ,
Each of the benzene ring B and the benzene ring C may further have a 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 each independently represents 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. R 2 and R 3 together represent an oxo group or a hydroxyimino group. )
Or a salt thereof (sometimes abbreviated as “compound (1)” in the present specification).
[1 ′] Formula (1):
Figure JPOXMLDOC01-appb-C000003
Figure JPOXMLDOC01-appb-C000003
（式中、
　環Ａは、置換基を有していてもよい５ないし６員環を示し、
　Ｒ１およびＲ４は、それぞれ独立して、水素原子、ハロゲン原子、水酸基、ニトロ基、シアノ基、Ｃ１－６アルキル基、ハロゲン化Ｃ１－６アルキル基またはＣ１－６アルコキシ基を示し、
　ベンゼン環Ｂおよびベンゼン環Ｃは、それぞれさらに置換基を有していてもよく、
　ベンゼン環Ｂ－Ｃ（Ｒ２）（Ｒ３）基およびベンゼン環Ｃは、それぞれ環Ａを構成する別個の炭素原子に結合しており、
　Ｒ２およびＲ３は、それぞれ独立して、水素原子、ハロゲン原子、水酸基、ニトロ基、シアノ基、Ｃ１－６アルキル基、ハロゲン化Ｃ１－６アルキル基またはＣ１－６アルコキシ基を示すか、あるいはＲ２およびＲ３は一緒になってオキソ基を示す。）
で表される化合物（本明細書中、「化合物（１）」と略記する場合がある）またはその塩。
［２］Ｒ１およびＲ４が、それぞれ独立して、塩素原子、臭素原子またはメトキシ基である、［１］または［１’］に記載の化合物。
［３］環Ａが、メチル基を有していてもよいピラゾール環またはピリミジン環である、［１］、［１’］または［２］に記載の化合物。
［４］Ｒ２およびＲ３が一緒になってオキソ基である、［１］～［３］および［１’］のいずれか１に記載の化合物。
［５］Ｒ１およびＲ４が、それぞれ独立して、塩素原子、臭素原子またはメトキシ基であり、環Ａが、メチル基を有していてもよいピラゾール環またはピリミジン環であり、かつＲ２およびＲ３が一緒になってオキソ基である、［１］～［４］および［１’］のいずれか１に記載の化合物。
［６］5-(4-メトキシベンゾイル)-4-(4-メトキシフェニル)-2-メチルピリミジン、4-(4-メトキシベンゾイル)-5-(4-メトキシフェニル)-1-メチルピラゾール、4-(4-ブロモベンゾイル)-5-(4-ブロモフェニル)-1-メチルピラゾールまたは4-(4-クロロベンゾイル)-5-(4-クロロフェニル)-1-メチルピラゾールである、［５］に記載の化合物。
［７］抗腫瘍活性および癌転移抑制活性を有する、［１］～［６］および［１’］のいずれか１に記載の化合物。 (Where
Ring A represents an optionally substituted 5- to 6-membered ring,
R 1 and R 4 each independently represents 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. ,
Each of the benzene ring B and the benzene ring C may further have a 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 each independently represents 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. Or R 2 and R 3 together represent an oxo group. )
Or a salt thereof (sometimes abbreviated as “compound (1)” in the present specification).
[2] The compound according to [1] or [1 ′], wherein R 1 and R 4 are each independently a chlorine atom, a bromine atom or a methoxy group.
[3] The compound according to [1], [1 ′] or [2], wherein ring A is a pyrazole ring or a pyrimidine ring optionally having a methyl group.
[4] The compound according to any one of [1] to [3] and [1 ′], wherein R 2 and R 3 are together an oxo group.
[5] R 1 and R 4 are each independently a chlorine atom, bromine atom or methoxy group, ring A is a pyrazole ring or pyrimidine ring optionally having a methyl group, and R 2 The compound according to any one of [1] to [4] and [1 ′], wherein R 3 and R 3 are together an oxo group.
[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 described compound.
[7] The compound according to any one of [1] to [6] and [1 ′], which has antitumor activity and cancer metastasis inhibiting activity.
　本発明によれば、抗腫瘍活性および癌転移抑制活性を有する化合物、特にピラゾール誘導体およびピリミジン誘導体、ならびに当該化合物を有効成分として含有する抗腫瘍剤を提供することができる。 According to the present invention, it is possible to provide a compound having antitumor activity and cancer metastasis inhibiting activity, particularly a pyrazole derivative and a pyrimidine derivative, and an antitumor agent containing the compound as an active ingredient.
試験例１で用いたリアルタイム細胞動態解析法（TAXIScan法）を説明する図である。It is a figure explaining the real-time cell dynamics analysis method (TAXIScan method) used in Test example 1. 試験例１の結果を示すグラフである。6 is a graph showing the results of Test Example 1. 試験例２の結果を示すグラフである。6 is a graph showing the results of Test Example 2. 試験例３の結果（体重の変化（移植時を１とする））を示すグラフである。It is a graph which shows the result (change of body weight (it is set as 1 at the time of transplant)) of the test example 3. FIG. 試験例３の結果（転移が見られた個体数）を示すグラフである。10 is a graph showing the results of Test Example 3 (number of individuals in which metastasis was observed). 試験例３の結果（腫瘍からの蛍光量の比較）を示すグラフである。It is a graph which shows the result (comparison of the amount of fluorescence from a tumor) of Experimental example 3. 試験例４の結果（走化性の成分のうち移動の速さの抑制）を示すグラフである。It is a graph which shows the result of Experiment 4 (suppression of the speed of movement among chemotaxis components). 試験例４の結果（走化性の成分のうち方向性の抑制）を示すグラフである。It is a graph which shows the result (control of directionality among chemotaxis components) of test example 4. 試験例４の結果（走化性の成分のうち移動の速さの抑制）を示すグラフである。It is a graph which shows the result of Experiment 4 (suppression of the speed of movement among chemotaxis components). 試験例４の結果（走化性の成分のうち方向性の抑制）を示すグラフである。It is a graph which shows the result (control of directionality among chemotaxis components) of test example 4.
　以下、本明細書中で用いられる各置換基の定義について詳述する。特記しない限り各置換基は以下の定義を有する。 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.
　本明細書中、「ハロゲン原子」としては、例えば、フッ素原子、塩素原子、臭素原子、ヨウ素原子が挙げられる。
　本明細書中、「Ｃ１－６アルキル基」としては、例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ペンチル、イソペンチル、ネオペンチル、１－エチルプロピル、ヘキシル、イソヘキシル、１，１－ジメチルブチル、２，２－ジメチルブチル、３，３－ジメチルブチル、２－エチルブチルが挙げられる。
　本明細書中、「ハロゲン化Ｃ１－６アルキル基」としては、例えば、１ないし５個の上記「ハロゲン原子」で置換された上記「Ｃ１－６アルキル基」が挙げられる。
　本明細書中、「Ｃ３－１０シクロアルキル基」としては、例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル、ビシクロ［２．２．１］ヘプチル、ビシクロ［２．２．２］オクチル、ビシクロ［３．２．１］オクチル、アダマンチルが挙げられる。
　本明細書中、「Ｃ１－６アルコキシ基」としては、例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ｔｅｒｔ－ブトキシ、ペンチルオキシ、ヘキシルオキシが挙げられる。
　本明細書中、「Ｃ６－１４アリール基」としては、例えば、フェニル、１－ナフチル、２－ナフチル、１－アントリル、２－アントリル、９－アントリルが挙げられる。
　本明細書中、「５ないし１４員芳香族複素環基」としては、例えば、環構成原子として炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれる１ないし４個のヘテロ原子を含有する５ないし１４員（好ましくは５ないし１０員）の芳香族複素環基が挙げられ、好適な例としては、チエニル、フリル、ピロリル、イミダゾリル、ピラゾリル、チアゾリル、イソチアゾリル、オキサゾリル、イソオキサゾリル、ピリジル、ピラジニル、ピリミジニル、ピリダジニル、１，２，４－オキサジアゾリル、１，３，４－オキサジアゾリル、１，２，４－チアジアゾリル、１，３，４－チアジアゾリル、トリアゾリル、テトラゾリル、トリアジニルなどの５ないし６員単環式芳香族複素環基；
ベンゾチオフェニル、ベンゾフラニル、ベンゾイミダゾリル、ベンゾオキサゾリル、ベンゾイソオキサゾリル、ベンゾチアゾリル、ベンゾイソチアゾリル、ベンゾトリアゾリル、イミダゾピリジニル、チエノピリジニル、フロピリジニル、ピロロピリジニル、ピラゾロピリジニル、オキサゾロピリジニル、チアゾロピリジニル、イミダゾピラジニル、イミダゾピリミジニル、チエノピリミジニル、フロピリミジニル、ピロロピリミジニル、ピラゾロピリミジニル、オキサゾロピリミジニル、チアゾロピリミジニル、ピラゾロトリアジニル、ナフト［２，３－ｂ］チエニル、フェノキサチイニル、インドリル、イソインドリル、１Ｈ－インダゾリル、プリニル、イソキノリル、キノリル、フタラジニル、ナフチリジニル、キノキサリニル、キナゾリニル、シンノリニル、カルバゾリル、β－カルボリニル、フェナントリジニル、アクリジニル、フェナジニル、フェノチアジニル、フェノキサジニルなどの８ないし１４員縮合多環式（好ましくは２または３環式）芳香族複素環基が挙げられる。 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, examples of the “C 1-6 alkyl group” include 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, examples of the “C 3-10 cycloalkyl group” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2. 2] Octyl, bicyclo [3.2.1] octyl, and adamantyl.
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-anthryl.
In the present specification, the “5- to 14-membered aromatic heterocyclic group” contains, for example, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring constituent atom. Examples include 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic groups, and preferable examples include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, 5- to 6-membered monocyclic such as pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl An aromatic heterocyclic group;
Benzothiophenyl, benzofuranyl, benzoimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolo Pyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl, naphtho [2,3 -B] thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quina And 8- to 14-membered condensed polycyclic (preferably 2 or 3 ring) aromatic heterocyclic groups such as linyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl .
　本明細書中、「５ないし６員環」としては、例えば、環構成原子として炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれる１ないし４個のヘテロ原子を含有する５ないし６員の芳香族または非芳香族複素環が挙げられる。
　該「５ないし６員の芳香族複素環」の好適な例としては、チオフェン、フラン、ピロール、イミダゾール、ピラゾール、チアゾール、イソチアゾール、オキサゾール、イソオキサゾール、ピリジン、ピラジン、ピリミジン、ピリダジン、１，２，４－オキサジアゾール、１，３，４－オキサジアゾール、１，２，４－チアジアゾール、１，３，４－チアジアゾール、トリアゾール、テトラゾール、トリアジンなどが挙げられる。
　該「５ないし６員の非芳香族複素環」の好適な例としては、テトラヒドロチオフェン、テトラヒドロフラン、ピロリン、ピロリジン、イミダゾリン、イミダゾリジン、オキサゾリン、オキサゾリジン、ピラゾリン、ピラゾリジン、チアゾリン、チアゾリジン、テトラヒドロイソチアゾール、テトラヒドロオキサゾール、テトラヒドロイソオキサゾール、ピペリジン、ピペラジン、テトラヒドロピリジン、ジヒドロピリジン、ジヒドロチオピラン、テトラヒドロピリミジン、テトラヒドロピリダジン、ジヒドロピラン、テトラヒドロピラン、テトラヒドロチオピラン、モルホリン、チオモルホリンなどが挙げられる。 In the present specification, examples of the “5- to 6-membered ring” include, for example, a 5- to 6-membered ring containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom. And aromatic or non-aromatic heterocycles.
Suitable examples of the “5- to 6-membered aromatic heterocycle” include thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2 , 4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, triazine and the like.
Suitable examples of the “5- to 6-membered non-aromatic heterocycle” include tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole, Examples include tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridine, dihydrothiopyran, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine and the like.
　以下に、式（１）中の各記号の定義について詳述する。 Hereinafter, the definition of each symbol in formula (1) will be described in detail.
　環Ａは、置換基を有していてもよい５ないし６員環を示す。
　該「置換基を有していてもよい５ないし６員環」の「５ないし６員環」は、好ましくは５ないし６員の芳香族複素環（例、ピラゾール環、ピリミジン環）であり、より好ましくはピラゾール環またはピリミジン環である。
　該「置換基を有していてもよい５ないし６員環」の「５ないし６員環」は、置換可能な位置に１～３個の置換基を有していてもよく、置換基数が２個以上の場合、各置換基は同一であっても異なっていてもよい。該「置換基」は、好ましくはＣ１－６アルキル基（例、メチル基）であり、より好ましくはメチル基である。
　本発明の別の実施態様において、該「置換基」は、好ましくは、置換されていてもよいＣ１－６アルキル基（例、メチル基、エチル基、イソプロピル基）、置換されていてもよいＣ３－１０シクロアルキル基（例、シクロヘキシル基）、置換されていてもよいＣ６－１４アリール基（例、フェニル、ナフチル）、置換されていてもよい５ないし１４員芳香族複素環（例、ピリジル）である。
　環Ａは、好ましくは、Ｃ１－６アルキル基（例、メチル基）から選ばれる１～３個の置換基を有していてもよい５ないし６員の芳香族複素環（例、ピラゾール環、ピリミジン環）であり、より好ましくは、それぞれ１～３個のメチル基を有していてもよいピラゾール環またはピリミジン環である。
　本発明の別の実施態様において、環Ａは、好ましくは、置換されていてもよいＣ１－６アルキル基（例、メチル基、エチル基、イソプロピル基）、置換されていてもよいＣ３－１０シクロアルキル基（例、シクロヘキシル基）、置換されていてもよいＣ６－１４アリール基（例、フェニル、ナフチル）および置換されていてもよい５ないし１４員芳香族複素環（例、ピリジル）から選ばれる１～３個の置換基を有していてもよい５ないし６員の芳香族複素環（例、ピラゾール環、ピリミジン環）であり、より好ましくは、それぞれ、（１）水酸基およびＣ６－１４アリール基（例、フェニル）から選ばれる１～３個の置換基を有していてもよいＣ１－６アルキル基（例、メチル基、エチル基、イソプロピル基）、（２）Ｃ３－１０シクロアルキル基（例、シクロヘキシル基）、（３）ハロゲン原子（例、塩素原子、臭素原子）、シアノ基、ニトロ基、Ｃ１－６アルキル基（例、メチル基）およびＣ１－６アルコキシ基（例、メトキシ基）から選ばれる１～３個の置換基を有していてもよいＣ６－１４アリール基（例、フェニル、ナフチル）および（４）５ないし１４員芳香族複素環（例、ピリジル）から選ばれる１～３個の置換基を有していてもよい、ピラゾール環またはピリミジン環である。 Ring A represents a 5- to 6-membered ring optionally having a substituent.
The “5- to 6-membered ring” of the “optionally substituted 5- to 6-membered ring” 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 “optionally substituted 5- to 6-membered ring” may have 1 to 3 substituents at substitutable positions, and the number of substituents is 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, methyl group), more preferably a methyl group.
In another embodiment of the present invention, the “substituent” is preferably an optionally substituted C 1-6 alkyl group (eg, methyl group, ethyl group, isopropyl group), optionally substituted. A C 3-10 cycloalkyl group (eg, cyclohexyl group), an optionally substituted C 6-14 aryl group (eg, phenyl, naphthyl), an optionally substituted 5- to 14-membered aromatic heterocycle (eg, , Pyridyl).
Ring A is preferably a 5- to 6-membered aromatic heterocyclic ring (eg, pyrazole ring) optionally having 1 to 3 substituents selected from a C 1-6 alkyl group (eg, methyl group). More preferably a pyrazole ring or a pyrimidine ring, each of which may have 1 to 3 methyl groups.
In another embodiment of the present invention, ring A is preferably an optionally substituted C 1-6 alkyl group (eg, a methyl group, an ethyl group, an isopropyl group), an 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) A 5- to 6-membered aromatic heterocyclic ring (eg, pyrazole ring, pyrimidine ring) optionally having 1 to 3 substituents selected from: (1) hydroxyl group and C A C 1-6 alkyl group (eg, a methyl group, an ethyl group, an isopropyl group) optionally having 1 to 3 substituents selected from 6-14 aryl groups (eg, phenyl), (2) C 3-10 cyclo Alkyl group (e.g., cyclohexyl group), (3) a halogen atom (e.g., chlorine atom, bromine atom), a cyano group, a nitro group, C 1-6 alkyl group (e.g., methyl) and C 1-6 alkoxy groups ( C 6-14 aryl group (eg, phenyl, naphthyl) optionally having 1 to 3 substituents selected from (eg, methoxy group) and (4) 5- to 14-membered aromatic heterocycle (eg, A pyrazole ring or a pyrimidine ring optionally having 1 to 3 substituents selected from pyridyl).
　Ｒ１およびＲ４は、それぞれ独立して、水素原子、ハロゲン原子、水酸基、ニトロ基、シアノ基、Ｃ１－６アルキル基、ハロゲン化Ｃ１－６アルキル基またはＣ１－６アルコキシ基を示す。
　Ｒ１およびＲ４は、好ましくは、それぞれ独立して、ハロゲン原子（例、塩素原子、臭素原子）またはＣ１－６アルコキシ基（例、メトキシ基）であり、より好ましくは、それぞれ独立して、塩素原子、臭素原子またはメトキシ基である。
　本発明の別の実施態様において、Ｒ１およびＲ４は、好ましくは、それぞれ独立して、水素原子、ニトロ基、シアノ基、ハロゲン原子（例、塩素原子、臭素原子）、置換されていてもよいＣ１－６アルキル基（例、メチル基）または置換されていてもよいＣ１－６アルコキシ基（例、メトキシ基）であり、より好ましくは、それぞれ独立して、水素原子、ニトロ基、シアノ基、ハロゲン原子（例、塩素原子、臭素原子）、Ｃ１－６アルキル基（例、メチル基）またはＣ１－６アルコキシ基（例、メトキシ基）である。 R 1 and R 4 each independently represents 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. .
R 1 and R 4 are preferably each independently a halogen atom (eg, chlorine atom, bromine atom) or a C 1-6 alkoxy group (eg, methoxy group), more preferably each independently. , A chlorine atom, a bromine atom or a methoxy group.
In another embodiment of the present invention, R 1 and R 4 are preferably each independently a hydrogen atom, a nitro group, a cyano group, a halogen atom (eg, a chlorine atom, a bromine atom), or a substituted group. A good C 1-6 alkyl group (eg, methyl group) or an optionally substituted C 1-6 alkoxy group (eg, methoxy group), more preferably each independently 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).
　ベンゼン環Ｂおよびベンゼン環Ｃは、それぞれ置換可能な位置にＲ１およびＲ４以外にさらに１～４個の置換基を有していてもよい。
　ベンゼン環Ｂおよびベンゼン環Ｃは、好ましくは、それぞれＲ１およびＲ４以外にさらに置換基を有していていない。
　本発明の別の実施態様において、ベンゼン環Ｃは、好ましくは、Ｒ４以外にさらにハロゲン原子（例、塩素原子）を有していてもよい。 The benzene ring B and the benzene ring C may further have 1 to 4 substituents other than R 1 and R 4 at substitutable positions.
The benzene ring B and the benzene ring C preferably have no further substituent other than R 1 and R 4 , respectively.
In another embodiment of the present invention, the benzene ring C may preferably have a halogen atom (eg, chlorine atom) in addition to R 4 .
　ベンゼン環Ｂ－Ｃ（Ｒ２）（Ｒ３）基およびベンゼン環Ｃは、それぞれ環Ａを構成する別個の炭素原子に結合している。
　ベンゼン環Ｂ－Ｃ（Ｒ２）（Ｒ３）基およびベンゼン環Ｃは、好ましくは、それぞれ環Ａを構成する別個の互いに隣接した炭素原子に結合している。 The benzene ring BC (R 2 ) (R 3 ) group and the benzene ring C are each bonded to separate carbon atoms 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 that each constitute the ring A.
　Ｒ２およびＲ３は、それぞれ独立して、水素原子、ハロゲン原子、水酸基、ニトロ基、シアノ基、Ｃ１－６アルキル基、ハロゲン化Ｃ１－６アルキル基またはＣ１－６アルコキシ基を示すか、あるいはＲ２およびＲ３は一緒になってオキソ基を示す。
　Ｒ２およびＲ３は、好ましくは一緒になってオキソ基である。 R 2 and R 3 each independently represents 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. Or R 2 and R 3 together represent an oxo group.
R 2 and R 3 are preferably taken together to form an oxo group.
　本発明の別の実施態様において、Ｒ２およびＲ３は、それぞれ独立して、水素原子、ハロゲン原子、水酸基、ニトロ基、シアノ基、Ｃ１－６アルキル基、ハロゲン化Ｃ１－６アルキル基またはＣ１－６アルコキシ基を示すか、あるいはＲ２およびＲ３は一緒になってオキソ基またはヒドロキシイミノ基を示す。好ましくは、Ｒ２およびＲ３は、それぞれ独立して、水素原子または水酸基であるか、あるいは、Ｒ２およびＲ３は、一緒になってオキソ基またはヒドロキシイミノ基である。 In another embodiment of the present invention, R 2 and R 3 each independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a cyano group, a C 1-6 alkyl group, or a halogenated C 1-6 alkyl group. Or 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 each independently a hydrogen atom or a hydroxyl group, or R 2 and R 3 together are an oxo group or a hydroxyimino group.
　化合物（１）の好適な例としては、以下の化合物が挙げられる。
［化合物１－１］
　環Ａが、Ｃ１－６アルキル基（例、メチル基）から選ばれる１～３個の置換基を有していてもよい５ないし６員の芳香族複素環（例、ピラゾール環、ピリミジン環）であり；
　Ｒ１およびＲ４が、それぞれ独立して、ハロゲン原子（例、塩素原子、臭素原子）またはＣ１－６アルコキシ基（例、メトキシ基）であり；
　ベンゼン環Ｂおよびベンゼン環Ｃが、それぞれＲ１およびＲ４以外にさらに置換基を有しておらず；
　ベンゼン環Ｂ－Ｃ（Ｒ２）（Ｒ３）基およびベンゼン環Ｃが、それぞれ環Ａを構成する別個の互いに隣接した炭素原子に結合しており；
　Ｒ２およびＲ３が、一緒になってオキソ基である；
化合物（１）。 Preferable examples of compound (1) include the following compounds.
[Compound 1-1]
Ring A is a 5- to 6-membered aromatic heterocyclic ring (eg, pyrazole ring, pyrimidine ring) optionally having 1 to 3 substituents selected from C 1-6 alkyl groups (eg, methyl group) );
R 1 and R 4 are each independently a halogen atom (eg, chlorine atom, bromine atom) or a C 1-6 alkoxy group (eg, methoxy group);
Benzene ring B and benzene ring C have no further substituents other than R 1 and R 4 , respectively;
The benzene ring BC (R 2 ) (R 3 ) group and the benzene ring C are each bonded to separate adjacent carbon atoms that constitute ring A;
R 2 and R 3 together are an oxo group;
Compound (1).
［化合物１－２］
　環Ａが、それぞれ１～３個のメチル基を有していてもよいピラゾール環またはピリミジン環であり；
　Ｒ１およびＲ４が、それぞれ独立して、塩素原子、臭素原子またはメトキシ基であり；
　ベンゼン環Ｂおよびベンゼン環Ｃが、それぞれＲ１およびＲ４以外にさらに置換基を有しておらず；
　ベンゼン環Ｂ－Ｃ（Ｒ２）（Ｒ３）基およびベンゼン環Ｃが、それぞれ環Ａを構成する別個の互いに隣接した炭素原子に結合しており；
　Ｒ２およびＲ３が、一緒になってオキソ基である；
化合物（１）。 [Compound 1-2]
Ring A is a pyrazole ring or a pyrimidine ring each optionally having 1 to 3 methyl groups;
R 1 and R 4 are each independently a chlorine atom, a bromine atom or a methoxy group;
Benzene ring B and benzene ring C have no further substituents other than R 1 and R 4 , respectively;
The benzene ring BC (R 2 ) (R 3 ) group and the benzene ring C are each bonded to separate adjacent carbon atoms that constitute ring A;
R 2 and R 3 together are an oxo group;
Compound (1).
［化合物１－３］
　5-(4-メトキシベンゾイル)-4-(4-メトキシフェニル)-2-メチルピリミジン、
　4-(4-メトキシベンゾイル)-5-(4-メトキシフェニル)-1-メチルピラゾール、
　4-(4-ブロモベンゾイル)-5-(4-ブロモフェニル)-1-メチルピラゾール、または
　4-(4-クロロベンゾイル)-5-(4-クロロフェニル)-1-メチルピラゾール。 [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.
［化合物１－４］
　環Ａが、置換されていてもよいＣ１－６アルキル基（例、メチル基、エチル基、イソプロピル基）、置換されていてもよいＣ３－１０シクロアルキル基（例、シクロヘキシル基）、置換されていてもよいＣ６－１４アリール基（例、フェニル、ナフチル）および置換されていてもよい５ないし１４員芳香族複素環（例、ピリジル）から選ばれる１～３個の置換基を有していてもよい５ないし６員の芳香族複素環（例、ピラゾール環、ピリミジン環）であり；
　Ｒ１およびＲ４が、それぞれ独立して、水素原子、ニトロ基、シアノ基、ハロゲン原子（例、塩素原子、臭素原子）、置換されていてもよいＣ１－６アルキル基（例、メチル基）または置換されていてもよいＣ１－６アルコキシ基（例、メトキシ基）であり；
　ベンゼン環Ｂが、Ｒ１以外にさらに置換基を有しておらず；
　ベンゼン環Ｃが、Ｒ４以外にさらにハロゲン原子（例、塩素原子）を有していてもよく；
　ベンゼン環Ｂ－Ｃ（Ｒ２）（Ｒ３）基およびベンゼン環Ｃが、それぞれ環Ａを構成する別個の互いに隣接した炭素原子に結合しており；
　Ｒ２およびＲ３が、それぞれ独立して、水素原子または水酸基であるか、あるいは、Ｒ２およびＲ３が、一緒になってオキソ基またはヒドロキシイミノ基である；
化合物（１）。 [Compound 1-4]
Ring A is an optionally substituted C 1-6 alkyl group (eg, methyl group, ethyl group, isopropyl group), an optionally substituted C 3-10 cycloalkyl group (eg, cyclohexyl group), substituted Having 1 to 3 substituents selected from an optionally substituted C 6-14 aryl group (eg, phenyl, naphthyl) and an optionally substituted 5- to 14-membered aromatic heterocycle (eg, pyridyl). An optionally substituted 5- to 6-membered aromatic heterocycle (eg, pyrazole ring, pyrimidine ring);
R 1 and R 4 are each independently a hydrogen atom, nitro group, cyano group, halogen atom (eg, chlorine atom, bromine atom), optionally substituted C 1-6 alkyl group (eg, methyl group) Or an optionally substituted C 1-6 alkoxy group (eg, a methoxy group);
The benzene ring B has no further substituents other than R 1 ;
The benzene ring C may further have a halogen atom (eg, chlorine atom) in addition to R 4 ;
The benzene ring BC (R 2 ) (R 3 ) group and the benzene ring C are each bonded to separate adjacent carbon atoms that constitute ring A;
R 2 and R 3 are each independently a hydrogen atom or a hydroxyl group, or R 2 and R 3 together are an oxo group or a hydroxyimino group;
Compound (1).
［化合物１－５］
　環Ａが、それぞれ、（１）水酸基およびＣ６－１４アリール基（例、フェニル）から選ばれる１～３個の置換基を有していてもよいＣ１－６アルキル基（例、メチル基、エチル基、イソプロピル基）、（２）Ｃ３－１０シクロアルキル基（例、シクロヘキシル基）、（３）ハロゲン原子（例、塩素原子、臭素原子）、シアノ基、ニトロ基、Ｃ１－６アルキル基（例、メチル基）およびＣ１－６アルコキシ基（例、メトキシ基）から選ばれる１～３個の置換基を有していてもよいＣ６－１４アリール基（例、フェニル、ナフチル）および（４）５ないし１４員芳香族複素環（例、ピリジル）から選ばれる１～３個の置換基を有していてもよい、ピラゾール環またはピリミジン環であり；
　Ｒ１およびＲ４が、それぞれ独立して、水素原子、ニトロ基、シアノ基、ハロゲン原子（例、塩素原子、臭素原子）、Ｃ１－６アルキル基（例、メチル基）またはＣ１－６アルコキシ基（例、メトキシ基）であり；
　ベンゼン環Ｂが、Ｒ１以外にさらに置換基を有しておらず；
　ベンゼン環Ｃが、Ｒ４以外にさらにハロゲン原子（例、塩素原子）を有していてもよく；
　ベンゼン環Ｂ－Ｃ（Ｒ２）（Ｒ３）基およびベンゼン環Ｃが、それぞれ環Ａを構成する別個の互いに隣接した炭素原子に結合しており；
　Ｒ２およびＲ３が、それぞれ独立して、水素原子または水酸基であるか、あるいは、Ｒ２およびＲ３が、一緒になってオキソ基またはヒドロキシイミノ基である；
化合物（１）。 [Compound 1-5]
Ring A may each have (1) a C 1-6 alkyl group (eg, methyl group) optionally having 1 to 3 substituents selected from a hydroxyl group and a C 6-14 aryl group (eg, phenyl) , 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 C 6-14 aryl group (eg, phenyl, naphthyl) optionally having 1 to 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 pyrimidine ring optionally having 1 to 3 substituents selected from 5- to 14-membered aromatic heterocycles (eg, pyridyl);
R 1 and R 4 are each independently a 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 An alkoxy group (eg, methoxy group);
The benzene ring B has no further substituents other than R 1 ;
The benzene ring C may further have a halogen atom (eg, chlorine atom) in addition to R 4 ;
The benzene ring BC (R 2 ) (R 3 ) group and the benzene ring C are each bonded to separate adjacent carbon atoms that constitute ring A;
R 2 and R 3 are each independently a hydrogen atom or a hydroxyl group, or R 2 and R 3 together are an oxo group or a hydroxyimino group;
Compound (1).
　化合物（１）が塩である場合、このような塩としては、例えば、無機塩基との塩、有機塩基との塩、無機酸との塩、有機酸との塩、塩基性または酸性アミノ酸との塩などが挙げられる。 When the compound (1) is a salt, examples of such a salt include 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.
　無機塩基との塩の好適な例としては、ナトリウム塩、カリウム塩等のアルカリ金属塩；カルシウム塩、マグネシウム塩等のアルカリ土類金属塩；アルミニウム塩；アンモニウム塩が挙げられる。 Preferable examples of the salt with an inorganic base 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.
　有機塩基との塩の好適な例としては、トリメチルアミン、トリエチルアミン、ピリジン、ピコリン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、トロメタミン［トリス（ヒドロキシメチル）メチルアミン］、ｔｅｒｔ－ブチルアミン、シクロヘキシルアミン、ベンジルアミン、ジシクロヘキシルアミン、Ｎ，Ｎ－ジベンジルエチレンジアミンとの塩が挙げられる。 Preferable examples of the salt with an organic base include trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris (hydroxymethyl) methylamine], tert-butylamine, cyclohexylamine, benzylamine, And salts with dicyclohexylamine and N, N-dibenzylethylenediamine.
　無機酸との塩の好適な例としては、塩化水素、臭化水素、硝酸、硫酸、リン酸との塩が挙げられる。 Preferable examples of the salt with inorganic acid include salts with hydrogen chloride, hydrogen bromide, nitric acid, sulfuric acid and phosphoric acid.
　有機酸との塩の好適な例としては、ギ酸、酢酸、トリフルオロ酢酸、フタル酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、リンゴ酸、メタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸との塩が挙げられる。 Preferable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, and benzenesulfonic acid And salts with p-toluenesulfonic acid.
　塩基性アミノ酸との塩の好適な例としては、アルギニン、リジン、オルニチンとの塩が挙げられる。 Preferable examples of salts with basic amino acids include salts with arginine, lysine and ornithine.
　酸性アミノ酸との塩の好適な例としては、アスパラギン酸、グルタミン酸との塩が挙げられる。 Preferable examples of the salt with acidic amino acid include salts with aspartic acid and glutamic acid.
　これらの塩のなかでも、薬学的に許容し得る塩が好ましい。薬学的に許容し得る塩としては、化合物内に塩基性官能基を有する場合には、例えば塩酸、臭化水素酸、硝酸、硫酸、リン酸等の無機酸との塩；または酢酸、フタル酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、メタンスルホン酸、ｐ－トルエンスルホン酸等の有機酸との塩が挙げられる。また、化合物内に酸性官能基を有する場合には、アルカリ金属塩（例、ナトリウム塩、カリウム塩等）、アルカリ土類金属塩（例、カルシウム塩、マグネシウム塩、バリウム塩等）等の無機塩；アンモニウム塩等が挙げられる。 Among these salts, pharmaceutically acceptable salts are preferable. Pharmaceutically acceptable salts include, for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or the like when the compound has a basic functional group; or acetic acid, phthalic acid And salts with organic acids such as fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid and p-toluenesulfonic acid. In addition, when the compound has an acidic functional group, inorganic salts such as alkali metal salts (eg, sodium salts, potassium salts, etc.) and alkaline earth metal salts (eg, calcium salts, magnesium salts, barium salts, etc.) An ammonium salt and the like.
　化合物（１）の製造方法について以下に説明する。一例として、環Ａがメチル基等を有していてもよいピラゾール環またはピリミジン環であり、ベンゼン環Ｂおよびベンゼン環Ｃが、それぞれＲ１およびＲ４以外にさらに置換基を有しておらず、ベンゼン環Ｂ－Ｃ（Ｒ２）（Ｒ３）基およびベンゼン環Ｃが、それぞれ環Ａを構成する別個の互いに隣接した炭素原子に結合しており、Ｒ２およびＲ３が、それぞれ独立して水素原子または水酸基であるか、あるいはＲ２およびＲ３が一緒になってオキソ基またはヒドロキシイミノ基である化合物（１）の製造方法について以下に説明する。 The method for producing compound (1) will be described below. As an example, ring A is a pyrazole ring or pyrimidine ring which may have a methyl group or the like, and benzene ring B and benzene ring C have no further substituent other than R 1 and R 4 , respectively. , A benzene ring BC (R 2 ) (R 3 ) group and a benzene ring C are bonded to separate adjacent carbon atoms constituting the ring A, and R 2 and R 3 are each independently The production method of the compound (1) which is a hydrogen atom or a hydroxyl group, or R 2 and R 3 together form an oxo group or a hydroxyimino group will be described below.
Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000004
　1) ジベンゾイルメタン（ＩＩＩ）の合成
　窒素気流中、水素化ナトリウムと安息香酸エステル（Ｉ）の無水ベンゼン懸濁液にアセトフェノン（ＩＩ）の無水ベンゼン溶液を滴下後、加熱還流する。室温まで冷却後、反応液に１０％塩酸水溶液を加え、酢酸エチル抽出する。有機層を飽和食塩水で水洗後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去する。残留物をエタノールにて再結晶、あるいはシリカゲルカラムクロマトグラフィーに付し、酢酸エチル－ヘキサン流分よりジベンゾイルメタン（ＩＩＩ）を得る。
参考文献：T. Choshi, S. Horimoto, C.Y. Wang, H. Nagase, M. Ichikawa, E. Sugino, S. Hibino, Chem. Pharm. Bull., 40, 1047-1049 (1992). 1) Synthesis of dibenzoylmethane (III ) An anhydrous benzene solution of acetophenone (II) is dropped into an anhydrous benzene suspension of sodium hydride and benzoate (I) in a nitrogen stream, and then heated to reflux. After cooling to room temperature, 10% aqueous hydrochloric acid solution is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is recrystallized with ethanol or subjected to silica gel column chromatography to obtain dibenzoylmethane (III) from a fraction of ethyl acetate-hexane.
References: T. Choshi, S. Horimoto, CY Wang, H. Nagase, M. Ichikawa, E. Sugino, S. Hibino, Chem. Pharm. Bull., 40, 1047-1049 (1992).
　2) N,N-ジメチルアミノメチレン-ジベンゾイルメタン（ＩＶ）の合成
　窒素気流中、ジベンゾイルメタン（ＩＩＩ）のジメチルホルムアミドジメチルアセタール溶液を６時間加熱環流する。室温まで冷却後、反応液に水を加え、酢酸エチル抽出する。有機層を飽和食塩水で水洗後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去する。残留物をシリカゲルカラムクロマトグラフィーに付し、酢酸エチル－ヘキサン流分よりN,N-ジメチルアミノメチレン（ＩＶ）を得る。 2) Synthesis of N, N-dimethylaminomethylene-dibenzoylmethane (IV ) A dimethylformamide dimethyl acetal solution of dibenzoylmethane (III) is heated to reflux in a nitrogen stream for 6 hours. After cooling to room temperature, water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is subjected to silica gel column chromatography, and N, N-dimethylaminomethylene (IV) is obtained from the ethyl acetate-hexane stream.
　3) 5-ベンゾイル-4-フェニル-2-メチルピリミジン（Ｖ）の合成
　N,N-ジメチルアミノメチレン（ＩＶ）、アセトアミジン、および炭酸カリウムのエタノール懸濁液を４時間加熱環流する。室温まで冷却後、反応液に水を加え、酢酸エチル抽出する。有機層を飽和食塩水で水洗後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去する。残留物をシリカゲルカラムクロマトグラフィーに付し、酢酸エチル-ヘキサン流分より油状物の5-ベンゾイル-4-フェニル-2-メチルピリミジン（Ｖ）を得る。 3) Synthesis of 5-benzoyl-4-phenyl-2-methylpyrimidine (V) A ethanol suspension of N, N-dimethylaminomethylene (IV), acetamidine, and potassium carbonate is heated to reflux for 4 hours. After cooling to room temperature, water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is subjected to silica gel column chromatography, and oily 5-benzoyl-4-phenyl-2-methylpyrimidine (V) is obtained from an ethyl acetate-hexane stream.
　4) 4-ベンゾイル-5-フェニル-1-メチルピラゾール（ＶＩ）の合成
　N,N-ジメチルアミノメチレン（ＩＶ）、およびメチルヒドラジンのエタノール溶液を室温で１２時間撹拌する。反応終了後、エタノールを減圧留去する。残留物をシリカゲルカラムクロマトグラフィーに付し、酢酸エチル-ヘキサン流分より4-ベンゾイル-5-フェニル-1-メチルピラゾール（ＶＩ）とその次の流出物として異性体（ＶＩＩ）を得る。 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 give 4-benzoyl-5-phenyl-1-methylpyrazole (VI) and isomer (VII) as the next effluent from an ethyl acetate-hexane stream.
　化合物（１）は抗腫瘍活性および癌転移抑制活性を有しており、当該化合物（１）を有効成分として含有する抗腫瘍剤は、各種悪性腫瘍（例、膵癌、肺癌、大腸癌、乳癌、卵巣癌、子宮頸癌、前立腺癌、悪性黒色腫、胃癌、肝細胞癌、胆管癌、口腔癌、食道癌、膀胱癌、神経腫瘍、精巣腫瘍、平滑筋肉腫、脂肪肉腫、横紋筋肉腫、悪性線維製組織球腫、軟骨腫、骨肉腫、白血病、リンパ腫、中皮腫）の予防または治療薬として用いることができる。 Compound (1) has antitumor activity and cancer metastasis inhibitory activity, and antitumor agents containing compound (1) as an active ingredient are various malignant tumors (eg, pancreatic cancer, lung cancer, colon cancer, breast cancer, Ovarian cancer, cervical cancer, prostate cancer, malignant melanoma, gastric cancer, hepatocellular carcinoma, bile duct cancer, oral cancer, esophageal cancer, bladder cancer, nerve tumor, testicular tumor, leiomyosarcoma, liposarcoma, rhabdomyosarcoma, Malignant fibrous histiocytoma, chondroma, osteosarcoma, leukemia, lymphoma, mesothelioma).
　本発明の化合物（１）を有効成分として含有する抗腫瘍剤は、化合物（１）のみを含有するものであってもよいし、薬理学的に許容され得る担体（賦形剤、結合剤、崩壊剤、矯味剤、矯臭剤、乳化剤、希釈剤、溶解補助剤など）を含有してもよい。
　本発明の化合物（１）を有効成分として含有する抗腫瘍剤は、医薬製剤の製造法として自体公知の方法（例、日本薬局方記載の方法等）に従って、化合物（１）と薬理学的に許容され得る担体とを混合し、各種剤形（例、錠剤、丸剤、散剤、顆粒剤、カプセル剤、液剤、乳剤、懸濁剤、注射剤、点滴剤など）に製剤化して得られ、経口的又は非経口的に投与することができる。 The antitumor agent containing the compound (1) of the present invention as an active ingredient may contain only the compound (1), or a pharmacologically acceptable carrier (excipient, binder, Disintegrating agents, flavoring agents, flavoring agents, emulsifiers, diluents, solubilizing agents, and the like).
The antitumor agent containing the compound (1) of the present invention as an active ingredient is pharmacologically combined with the compound (1) according to a method known per se (eg, a method described in the Japanese Pharmacopoeia) as a method for producing a pharmaceutical preparation. It is obtained by mixing with an acceptable carrier and formulating it into various dosage forms (eg, tablets, pills, powders, granules, capsules, solutions, emulsions, suspensions, injections, drops, etc.) It can be administered orally or parenterally.
　本発明の化合物（１）を有効成分として含有する抗腫瘍剤における化合物（１）の含有量は、抗腫瘍剤の剤形によって相違するが、通常、抗腫瘍剤全体に対して０．００１～１００重量％、好ましくは０．０１～１０重量％、さらに好ましくは０．１～１重量％程度である。 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 It is about 100% by weight, preferably about 0.01 to 10% by weight, and more preferably about 0.1 to 1% by weight.
　本明細書において非経口とは、皮下注射、静脈内注射、筋肉内注射、腹腔内注射、点滴法あるいは局所投与（関節内投与、経皮的投与、経眼的投与、経肺・気管支的投与、経鼻的投与又は経直腸的投与など）などを含むものである。 In this specification, parenteral means subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip method or local administration (intra-articular administration, transdermal administration, ophthalmic administration, transpulmonary administration, bronchial administration) , Nasal administration or rectal administration, etc.).
　本発明の化合物（１）を有効成分として含有する抗腫瘍剤の投与量は、投与対象、投与ルート、症状によっても異なり得、特に限定されないが、例えば膵癌の成人患者（成人、体重４０～８０ｋｇ、例えば６０ｋｇ）に経口投与する場合、化合物（１）として、例えば週１回０．１～１０００ｍｇ／ｋｇ体重、好ましくは週１回１～５００ｍｇ／ｋｇ体重、さらに好ましくは週１回１０～１００ｍｇ／ｋｇ体重で投与し得る。この量を１日１回～３回に分けて投与し得る。 The dose of the antitumor agent containing the compound (1) of the present invention as an active ingredient may vary depending on the administration subject, administration route, and symptoms, and is not particularly limited. In the case of oral administration to eg 60 kg), the compound (1) is, for example, 0.1 to 1000 mg / kg body weight once a week, preferably 1 to 500 mg / kg body weight once a week, more preferably 10 to 100 mg once a week. / Kg body weight may be administered. This amount can be administered in 1 to 3 divided doses per day.
　以下、実施例および試験例を用いて本発明をより詳しく説明するが、これらの例は本発明を限定するものではない。 Hereinafter, the present invention will be described in more detail with reference to examples and test examples, but these examples do not limit the present invention.
実施例１
5-(4-メトキシベンゾイル)-4-(4-メトキシフェニル)-2-メチルピリミジンの合成
1) ジ(4-メトキシベンゾイル)メタンの合成
　窒素気流中、水素化ナトリウム(0.84 g, 20.9 mmol)と4-メトキシ安息香酸エチル(3.6 g, 20.0 mmol)の無水ベンゼン(40 mL)懸濁液に4-メトキシアセトフェノン(2.7 g, 18.2 mmol) の無水ベンゼン(10 mL)溶液を滴下後、5時間加熱還流した。室温まで冷却後、反応液に10%塩酸水溶液を加え、酢酸エチル抽出（100 mL×3回）した。有機層を飽和食塩水で水洗後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残留物をエタノールから再結晶しジベンゾイルメタン体(2.83 g, 56%)を得た。
mp 126-127 ℃. 1H-NMR (300 MHz, CDCl3)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). Example 1
Synthesis of 5- (4-methoxybenzoyl) -4- (4-methoxyphenyl) -2-methylpyrimidine
1) Synthesis of di (4-methoxybenzoyl) methane Suspension of anhydrous benzene (40 mL) with sodium hydride (0.84 g, 20.9 mmol) and ethyl 4-methoxybenzoate (3.6 g, 20.0 mmol) in a nitrogen stream A solution of 4-methoxyacetophenone (2.7 g, 18.2 mmol) in anhydrous benzene (10 mL) was added dropwise, and the mixture was heated to reflux for 5 hours. After cooling to room temperature, 10% aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 3 times). 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 obtain a dibenzoylmethane compound (2.83 g, 56%).
mp 126-127 ° C. 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) N,N-ジメチルアミノメチレン-ジ(4-メトキシベンゾイル)メタンの合成
　窒素気流中、ジ(4-メトキシベンゾイル)メタン(1.0 g, 3.5 mmol)のジメチルホルムアミドジメチルアセタール(6 mL)溶液を5時間加熱環流した。室温まで冷却後、反応液に水を加え、酢酸エチル抽出（50 mL×3回）した。有機層を飽和食塩水で水洗後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残留物をシリカゲルカラムクロマトグラフィー(50 g) に付し、酢酸エチル-ヘキサン(70:30 v/v)流分より油状物のN,N-ジメチルアミノメチレン体(1.09 g, 92%)を得た。
1H-NMR (300 MHz, CDCl3)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). 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 to reflux for 5 hours. After cooling to room temperature, water was added to the reaction solution, followed by extraction with ethyl acetate (50 mL × 3 times). 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 an oily N, N-dimethylaminomethylene (1.09 g, 92%) was obtained from the ethyl acetate-hexane (70:30 v / v) fraction. It was.
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) 5-(4-メトキシベンゾイル)-4-(4-メトキシフェニル)-2-メチルピリミジン（以下、「１４－５３」と略記する場合がある）の合成
　N,N-ジメチルアミノメチレン体(2.3 g, 6.78 mmol)、アセトアミジン塩酸塩(0.96 g, 8.13 mmol)、および炭酸カリウム(1.12 g, 8.13 mmol)のエタノール(40 mL)懸濁液を4時間加熱環流した。室温まで冷却後、反応液に水を加え、酢酸エチル抽出（50 mL×3回）した。有機層を飽和食塩水で水洗後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残留物をシリカゲルカラムクロマトグラフィー(50 g)に付し、酢酸エチル-ヘキサン(30:70 v/v)流分より油状物の5-(4-メトキシベンゾイル)-4-(4-メトキシフェニル)-2-メチルピリミジン(1.88 g, 83%)を得た。
1H-NMR (300 MHz, CDCl3)δ: 2.86 (3H, s), 3.76 (3H, s), 3.83 (3H, s), 6.81 (2H, d, J = 8.7 Hz), 6.82 (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). 3) Synthesis of 5- (4-methoxybenzoyl) -4- (4-methoxyphenyl) -2-methylpyrimidine (hereinafter sometimes abbreviated as “14-53”) N, N-dimethylaminomethylene ( A suspension of 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) was heated to reflux for 4 hours. After cooling to room temperature, water was added to the reaction solution, followed by extraction with ethyl acetate (50 mL × 3 times). 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 an oily 5- (4-methoxybenzoyl) -4- (4-methoxyphenyl) was obtained from the ethyl acetate-hexane (30:70 v / v) fraction. -2-Methylpyrimidine (1.88 g, 83%) was obtained.
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, 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).
実施例２
4-(4-メトキシベンゾイル)-5-(4-メトキシフェニル)-1-メチルピラゾール（以下、「１４－６１」と略記する場合がある。）の合成
　N,N-ジメチルアミノメチレン体(380 mg, 1.1 mmol)、およびメチルヒドラジン(72 mg, 1.6 mmol)のエタノール(3 mL)溶液を室温で12時間撹拌した。反応終了後、エタノールを減圧留去した。残留物をシリカゲルカラムクロマトグラフィー(20 g)に付し、酢酸エチル-ヘキサン(15:85 v/v)流分より油状物の4-(4-メトキシベンゾイル)-5-(4-メトキシフェニル)-1-メチルピラゾール(137 mg, 38%)とその次の流出物として異性体4-(4-メトキシベンゾイル)-3-(4-メトキシフェニル)-1-メチルピラゾール(109 mg, 30%)を得た。
1H-NMR (300 MHz, CDCl3)δ: 3.82 (3H, s), 3.84 (3H, s), 3.85 (3H, s), 6.88 (2H, d, J = 8.6 Hz), 6.96 (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 2
Synthesis of 4- (4-methoxybenzoyl) -5- (4-methoxyphenyl) -1-methylpyrazole (hereinafter sometimes abbreviated as “14-61”) N, N-dimethylaminomethylene (380 mg, 1.1 mmol) and methyl hydrazine (72 mg, 1.6 mmol) in ethanol (3 mL) were 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 an oily 4- (4-methoxybenzoyl) -5- (4-methoxyphenyl) was obtained from the ethyl acetate-hexane (15:85 v / v) fraction. -1-Methylpyrazole (137 mg, 38%) and the isomer 4- (4-methoxybenzoyl) -3- (4-methoxyphenyl) -1-methylpyrazole (109 mg, 30%) as the next effluent Got.
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, 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).
実施例３
4-(4-ブロモベンゾイル)-5-(4-ブロモフェニル)-1-メチルピラゾールの合成
1) ジ(4-ブロモベンゾイル)メタンの合成
　窒素気流中、水素化ナトリウム(1.0 g, 25.1 mmol)と4-ブロモ安息香酸エチル(5.5 g, 24.0 mmol)の無水ベンゼン(40 mL)懸濁液に4-ブロモアセトフェノン(4.3 g, 21.8 mmol)の無水ベンゼン(10 mL)溶液を滴下後、1時間加熱還流した。室温まで冷却後、反応液に10%塩酸水溶液を加え、酢酸エチル抽出（100 mL×3回）した。有機層を飽和食塩水で水洗後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残留物をエタノールから再結晶しジベンゾイルメタン体(4.5 g, 54%)を得た。
mp 195-196 ℃. 1H-NMR (300 MHz, CDCl3)δ: 6.77 (1H, s), 7.63 (4H, d, J= 8.4 Hz), 7.85 (4H, d, J = 8.4 Hz). Example 3
Synthesis of 4- (4-bromobenzoyl) -5- (4-bromophenyl) -1-methylpyrazole
1) Synthesis of di (4-bromobenzoyl) methane 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, and the mixture was heated to reflux for 1 hour. After cooling to room temperature, 10% aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 3 times). 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 obtain a dibenzoylmethane compound (4.5 g, 54%).
mp 195-196 ° C. 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) N,N-ジメチルアミノメチレン-ジ(4-ブロモベンゾイル)メタンの合成
　窒素気流中、ジ(4-ブロモベンゾイル)メタン(2.5 g, 6.54 mmol)のジメチルホルムアミドジメチルアセタール(15 mL)溶液を6時間加熱環流した。室温まで冷却後、反応液に水を加え、酢酸エチル抽出（100 mL×3回）した。有機層を飽和食塩水で水洗後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残留物をシリカゲルカラムクロマトグラフィー(50 g)に付し、酢酸エチル-ヘキサン(40:60 v/v) 流分より油状物のN,N-ジメチルアミノメチレン体(1.66 g, 58%)を得た。
1H-NMR (300 MHz, CDCl3)δ: 2.77 (3H, br s), 3.31 (3H, br s), 7.32-7.51 (8H, m), 7.64 (1H, s). 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 to reflux for 6 hours. After cooling to room temperature, water was added to the reaction solution, followed by extraction with ethyl acetate (100 mL × 3 times). 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 N, N-dimethylaminomethylene (1.66 g, 58%) as an oily substance was obtained from the ethyl acetate-hexane (40:60 v / v) stream. It was.
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) 4-(4-ブロモベンゾイル)-5-(4-ブロモフェニル)-1-メチルピラゾールの合成
　N,N-ジメチルアミノメチレン体(600 mg, 1.4 mmol)、およびメチルヒドラジン(74 mg, 1.6 mmol)のエタノール(4 mL)溶液を室温で2時間撹拌した。反応終了後、エタノールを減圧留去した。残留物をシリカゲルカラムクロマトグラフィー(50 g)に付し、酢酸エチル-ヘキサン(15:85 v/v)流分より油状物の4-(4-ブロモベンゾイル)-5-(4-ブロモフェニル)-1-メチルピラゾール（以下、「１４－６７」と略記する場合がある）(420 mg, 73%)とその次の流出物として異性体4-(4-ブロモベンゾイル)-3-(4-ブロモフェニル)-1-メチルピラゾール(以下、「１４-６８」と略記する場合がある)(95 mg, 16%)を得た。
4-(4-ブロモベンゾイル)-5-(4-ブロモフェニル)-1-メチルピラゾール:1H-NMR (300 MHz, CDCl3)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-ブロモベンゾイル)-3-(4-ブロモフェニル)-1-メチルピラゾール: 1H-NMR (300 MHz, CDCl3)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). 3) Synthesis of 4- (4-bromobenzoyl) -5- (4-bromophenyl) -1-methylpyrazole 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 an oily 4- (4-bromobenzoyl) -5- (4-bromophenyl) was obtained from the ethyl acetate-hexane (15:85 v / v) fraction. -1-methylpyrazole (hereinafter sometimes abbreviated as “14-67”) (420 mg, 73%) and the isomer 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) 4-(4-クロロベンゾイル)-5-(4-クロロフェニル)-1-シクロヘキシルピラゾール（以下、「１４－１１２」と略記する場合がある）の合成
　N,N-ジメチルアミノメチレン体(200 mg, 0.57 mmol)、シクロヘキシルヒドラジン塩酸塩(76 mg, 1.09 mmol)、および炭酸カリウム(236 mg, 1.71 mmol)のエタノール(6 mL)溶液を60℃で1時間撹拌した。反応終了後、エタノールを減圧留去した。残留物に水を加え、酢酸エチル抽出（50 mL×3回）した。有機層を飽和食塩水で水洗後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。粗結晶をエタノールにて再結晶し4-(4-クロロベンゾイル)-5-(4-クロロフェニル)-1-シクロヘキシルピラゾール(200 mg, 87%)を得た。
1H-NMR (300 MHz, CDCl3)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). 4) Synthesis of 4- (4-chlorobenzoyl) -5- (4-chlorophenyl) -1-cyclohexylpyrazole (hereinafter sometimes abbreviated as “14-112”) 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) were stirred at 60 ° C. for 1 hour. After completion of the reaction, ethanol was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate (3 x 50 mL). 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 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) 4-クロロフェニル-[5-(4-クロロフェニル)-1-メチルピラゾール-4-イル]メタノール（以下、「１４－１２０」と略記する場合がある）の合成
　4-ベンゾイル-5-フェニル-1-メチルピラゾール (VI) (132 mg, 0.40 mmol)、および水素化ほう素ナトリウム (30 mg, 0.79 mmol)のメタノール(5 mL)溶液を室温で3時間撹拌した。反応終了後、メタノールを減圧留去した。残留物に水を加え、酢酸エチル抽出（50 mL×3回）した。有機層を飽和食塩水で水洗後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。粗結晶をメタノールにて再結晶し4-クロロフェニル-[5-(4-クロロフェニル)-1-メチルピラゾール-4-イル]メタノール(118 mg, 89%)を得た。
1H-NMR (300 MHz, DMSO-d6)δ: 3.66 (3H, s), 5.41 (1H, d, J = 4.0 Hz), 5.75 (1H, d, J = 4.0 Hz), 7.23 (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). 5) Synthesis of 4-chlorophenyl- [5- (4-chlorophenyl) -1-methylpyrazol-4-yl] methanol (hereinafter sometimes abbreviated as “14-120”) 4-benzoyl-5-phenyl- A solution of 1-methylpyrazole (VI) (132 mg, 0.40 mmol) and sodium borohydride (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 the mixture was extracted with ethyl acetate (3 x 50 mL). 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-methylpyrazol-4-yl] methanol (118 mg, 89%).
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, 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) 4-クロロベンジル-5-(4-クロロフェニル)-1-メチルピラゾール(IX)（以下、「１４－１２１」と略記する場合がある）の合成
　4-クロロフェニル-[5-(4-クロロフェニル)-1-メチルピラゾール-4-イル]メタノール(112 mg, 0.34 mmol)のトリフルオロ酢酸(5 mL)溶液に氷冷下トリエチルシラン(62 μL, 0.39 mmol)を滴下後、室温で10分撹拌した。反応終了後、トリフルオロ酢酸を減圧留去した。残留物に水を加え、酢酸エチル抽出（100 mL×3回）した。有機層を飽和炭酸水素ナトリウム水溶液および飽和食塩水で水洗後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残留物をシリカゲルカラムクロマトグラフィーに付し、酢酸エチル-ヘキサン(20:80 v/v)流分より油状物の4-クロロベンジル-5-(4-クロロフェニル)-1-メチルピラゾール(103 mg, 97%)を得た。
1H-NMR (300 MHz, CDCl3)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). 6) Synthesis of 4-chlorobenzyl-5- (4-chlorophenyl) -1-methylpyrazole (IX) (hereinafter sometimes abbreviated as “14-121”) 4-chlorophenyl- [5- (4-chlorophenyl) ) -1-Methylpyrazol-4-yl] methanol (112 mg, 0.34 mmol) in trifluoroacetic acid (5 mL) was added dropwise triethylsilane (62 μL, 0.39 mmol) under ice-cooling and stirred at room temperature for 10 minutes. did. After completion of the reaction, trifluoroacetic acid was distilled off under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate (100 mL × 3 times). 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.From the ethyl acetate-hexane (20:80 v / v) fraction, oily 4-chlorobenzyl-5- (4-chlorophenyl) -1-methylpyrazole (103 mg, 97%).
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) 4-クロロベンゾイル-5-(4-クロロフェニル)-1-メチルピラゾールオキシム(X)(以下、「１４－１２２」と略記する場合がある)の合成
　4-ベンゾイル-5-フェニル-1-メチルピラゾール (VI) (65 mg, 0.20 mmol)、塩酸ヒドロキシルアミン(41 mg, 0.59 mmol)および炭酸カリウム(138 mg, 1.0 mmol)のエタノール(3 mL)懸濁液を80℃で5時間加熱撹拌した。室温まで冷却後、反応液に水を加え、酢酸エチル抽出（100 mL×3回）した。有機層を飽和食塩水で水洗後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残留物をシリカゲルカラムクロマトグラフィーに付し、酢酸エチル-ヘキサン(30:70 v/v) 流分よりジアステレオマー混合物(1 : 3)として油状物の4-クロロベンゾイル-5-(4-クロロフェニル)-1-メチルピラゾールオキシム(60 mg, 88%)を得た。
1H-NMR (300 MHz, CDCl3)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). 7) Synthesis of 4-chlorobenzoyl-5- (4-chlorophenyl) -1-methylpyrazole oxime (X) (hereinafter sometimes abbreviated as “14-122”) 4-benzoyl-5-phenyl-1- A suspension of 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) is heated and stirred at 80 ° C for 5 hours. did. After cooling to room temperature, water was added to the reaction solution, followed by extraction with ethyl acetate (100 mL × 3 times). 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 ethyl acetate-hexane (30:70 v / v) was used as an oily 4-chlorobenzoyl-5- (4-chlorophenyl) diastereomer mixture (1: 3) from the fraction. ) -1-methylpyrazole oxime (60 mg, 88%) was obtained.
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).
原料(III)と原料(IV)の合成
ジ(4-フルオロベンゾイル)メタン
　実施例１の1)の合成法に従い、4-フルオロ安息香酸メチルと4-フルオロアセトフェノンを反応させ目的物を収率52%で得た。
1H-NMR (300 MHz, CDCl3)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). 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 and 4-fluoroacetophenone were reacted to obtain the desired product in a yield of 52 Obtained in%.
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-ジメチルアミノメチレン-ジ(4-フルオロベンゾイル)メタン
　実施例１の2)の合成法に従い、ジ(4-フルオロベンゾイル)メタンとジメチルホルムアミドジメチルアセタールを反応させ目的物を収率66%で得た。
1H-NMR (300 MHz, CDCl3)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). 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 obtain the desired product in a yield of 66%. I got it.
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).
ジ(3-クロロベンゾイル)メタン
　実施例１の1)の合成法に従い、3-クロロ安息香酸エチルと3-クロロアセトフェノンを反応させ目的物を収率58%で得た。
1H-NMR (300 MHz, CDCl3)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). Di (3-chlorobenzoyl) methane According to the synthesis method of 1) of Example 1, ethyl 3-chlorobenzoate was reacted with 3-chloroacetophenone to obtain the desired product in a yield of 58%.
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-ジメチルアミノメチレン-ジ(3-クロロベンゾイル)メタン
　実施例１の2)の合成法に従い、ジ(3-クロロベンゾイル)メタンとジメチルホルムアミドジメチルアセタールを反応させ目的物を収率57%で得た。
1H-NMR (300 MHz, CDCl3)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). 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 obtain the desired product in a yield of 57%. I got it.
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).
ジ(2-クロロベンゾイル)メタン
　実施例１の1)の合成法に従い、2-クロロ安息香酸メチルと2-クロロアセトフェノンを反応させ目的物を収率51%で得た。
1H-NMR (300 MHz, CDCl3)δ: 7.31-7.42 (3H, s), 7.41-7.53 (4H, s),8.02 (2H, d, J = 8.2 Hz). Di (2-chlorobenzoyl) methane According to the synthesis method of 1) of Example 1, methyl 2-chlorobenzoate and 2-chloroacetophenone were reacted to obtain the desired product in a yield of 51%.
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-ジメチルアミノメチレン-ジ(2-クロロベンゾイル)メタン
　実施例１の2)の合成法に従い、ジ(2-クロロベンゾイル)メタンとジメチルホルムアミドジメチルアセタールを反応させ目的物を収率48%で得た。
1H-NMR (300 MHz, CDCl3)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). N, N-dimethylaminomethylene-di (2-chlorobenzoyl) methane According to the synthesis method of Example 1, 2), di (2-chlorobenzoyl) methane was reacted with dimethylformamide dimethyl acetal to obtain the desired product in a yield of 48%. I got it.
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).
ジ(4-メチルベンゾイル)メタン
　実施例１の1)の合成法に従い、4-メチル安息香酸エチルと4-メチルアセトフェノンを反応させ目的物を収率66%で得た。
1H-NMR (300 MHz, CDCl3)δ: 6.82 (1H, s), 7.29 (4H, d, J = 8.0 Hz), 7.89 (4H, d, J = 8.0 Hz). Di (4-methylbenzoyl) methane According to the synthesis method of 1) of Example 1, ethyl 4-methylbenzoate was reacted with 4-methylacetophenone to obtain the desired product in a yield of 66%.
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-ジメチルアミノメチレン-ジ(4-メチルベンゾイル)メタン
　実施例１の2)の合成法に従い、ジ(4-メチルベンゾイル)メタンとジメチルホルムアミドジメチルアセタールを反応させ目的物を収率98%で得た。
1H-NMR (300 MHz, CDCl3)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). 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 obtain the desired product in a yield of 98%. I got it.
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).
ジ(2-メトキシベンゾイル)メタン
　実施例１の1)の合成法に従い、2-メトキシ安息香酸エチルと4-フルオロアセトフェノンを反応させ目的物を収率45%で得た。
1H-NMR (300 MHz, CDCl3)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). Di (2-methoxybenzoyl) methane According to the synthesis method of 1) of Example 1, ethyl 2-methoxybenzoate and 4-fluoroacetophenone were reacted to obtain the desired product in a yield of 45%.
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-ジメチルアミノメチレン-ジ(2-メトキシベンゾイル)メタン
　実施例１の2)の合成法に従い、ジ(2-メトキシベンゾイル)メタンとジメチルホルムアミドジメチルアセタールを反応させ目的物を収率51%で得た。
1H-NMR (300 MHz, CDCl3)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). 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 obtain 51% yield. I got it.
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).
実施例４
　4-(4-クロロベンゾイル)-5-(4-クロロフェニル)-1-メチルピラゾールの合成
1) ジ(4-クロロベンゾイル)メタンの合成
　窒素気流中、水素化ナトリウム(0.9 g, 22.5 mmol)と4-クロロ安息香酸エチル(4.1 g, 22 mmol)の無水ベンゼン(40 mL)懸濁液に4-クロロアセトフェノン(3.1 g, 20 mmol)の無水ベンゼン(20 mL)溶液を滴下後、3時間加熱還流した。室温まで冷却後、反応液に10%塩酸水溶液を加え、酢酸エチル抽出（100 mL×3回）した。有機層を飽和食塩水で水洗後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残留物をエタノールから再結晶しジベンゾイルメタン体(2.4 g, 41%)を得た。
mp 157.5-159.5 ℃. 1H-NMR (300 MHz, CDCl3)δ: 6.77 (1H, s), 7.48 (4H, d, J= 8.9 Hz), 7.93 (4H, d, J = 8.9 Hz). Example 4
Synthesis of 4- (4-chlorobenzoyl) -5- (4-chlorophenyl) -1-methylpyrazole
1) Synthesis of di (4-chlorobenzoyl) methane Suspension of anhydrous benzene (40 mL) with sodium hydride (0.9 g, 22.5 mmol) and ethyl 4-chlorobenzoate (4.1 g, 22 mmol) in a nitrogen stream A solution of 4-chloroacetophenone (3.1 g, 20 mmol) in anhydrous benzene (20 mL) was added dropwise, and the mixture was heated to reflux for 3 hours. After cooling to room temperature, 10% aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 3 times). 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 obtain a dibenzoylmethane compound (2.4 g, 41%).
mp 157.5-159.5 ° C. 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) N,N-ジメチルアミノメチレン-ジ(4-クロロベンゾイル)メタンの合成
　窒素気流中、ジ(4-クロロベンゾイル)メタン(400 mg, 1.36 mmol)のジメチルホルムアミドジメチルアセタール(10 mL)溶液を室温で4時間撹拌した。室温まで冷却後、反応液に水を加え、酢酸エチル抽出（50 mL×3回）した。有機層を飽和食塩水で水洗後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残留物をシリカゲルカラムクロマトグラフィー(50 g)に付し、酢酸エチル-ヘキサン(80:20 v/v)流分より油状物のN,N-ジメチルアミノメチレン体(384 mg, 81%)を得た。
1H-NMR (300 MHz, CDCl3)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). 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. Stir at room temperature for 4 hours. After cooling to room temperature, water was added to the reaction solution, followed by extraction with ethyl acetate (50 mL × 3 times). 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 an oily N, N-dimethylaminomethylene (384 mg, 81%) was obtained from the ethyl acetate-hexane (80:20 v / v) fraction. It was.
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) 4-(4-クロロベンゾイル)-5-(4-クロロフェニル)-1-メチルピラゾールの合成
　N,N-ジメチルアミノメチレン体(380 mg, 1.09 mmol)、およびメチルヒドラジン(50 mg, 1.09 mmol)のエタノール(10 mL)溶液を室温で12時間撹拌した。反応終了後、エタノールを減圧留去した。残留物をシリカゲルカラムクロマトグラフィー(20 g)に付し、酢酸エチル-ヘキサン(15:85 v/v) 流分より油状物の4-(4-クロロベンゾイル)-5-(4-クロロフェニル)-1-メチルピラゾール(197 mg, 55%)とその次の流出物として異性体(39 mg, 11%)を得た。
1H-NMR (300 MHz, CDCl3)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). 3) Synthesis of 4- (4-chlorobenzoyl) -5- (4-chlorophenyl) -1-methylpyrazole 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 ethyl acetate-hexane (15:85 v / v) 4- (4-chlorobenzoyl) -5- (4-chlorophenyl)- 1-methylpyrazole (197 mg, 55%) and the isomer (39 mg, 11%) were obtained as the next effluent.
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).
実施例５
　実施例1の方法に準じて以下のピリミジン誘導体を合成した。 Example 5
The following pyrimidine derivatives were synthesized according to the method of Example 1.
1) 5-(4-メチルベンゾイル)-4-(4-メチルフェニル)ピリミジン（以下、「５－１０６」と略記する場合がある）の合成
　実施例１の3)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(4-メチルベンゾイル)メタンとホルムアミジン酢酸塩を反応させ目的物を収率85%で得た。
1H-NMR (300 MHz, CDCl3)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). 1) Synthesis of 5- (4-methylbenzoyl) -4- (4-methylphenyl) pyrimidine (hereinafter sometimes 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 obtain the desired product in a yield of 85%.
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) 2-アミノ-5-(4-メチルベンゾイル)-4-(4-メチルフェニル)ピリミジン（以下、「５－１０７」と略記する場合がある）の合成
　実施例１の3)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(4-メチルベンゾイル)メタンとグアニジン塩酸塩を反応させ目的物を収率91%で得た。
1H-NMR (300 MHz, CDCl3)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). 2) Synthesis of 2-amino-5- (4-methylbenzoyl) -4- (4-methylphenyl) pyrimidine (hereinafter sometimes abbreviated as “5-107” ) Synthesis method of Example 1 3) According to the above, N, N-dimethylaminomethylene-di (4-methylbenzoyl) methane was reacted with guanidine hydrochloride to obtain the desired product in a yield of 91%.
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) 2-アミノ-5-(4-クロロベンゾイル)-4-(4-クロロフェニル)ピリミジン（以下、「５－１０２」と略記する場合がある）の合成
　実施例１の3)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(4-クロロベンゾイル)メタンとグアニジン塩酸塩を反応させ目的物を収率97%で得た。
1H-NMR (300 MHz, CDCl3)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). 3) Synthesis of 2-amino-5- (4-chlorobenzoyl) -4- (4-chlorophenyl) pyrimidine (hereinafter sometimes 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 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) 5-(2-メトキシベンゾイル)-4-(2-メトキシフェニル)-2-メチルピリミジン（以下、「５－１０９」と略記する場合がある）の合成
　実施例１の3)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(2-メトキシベンゾイル)メタンとアセトアミジン塩酸塩を反応させ目的物を収率99%で得た。
1H-NMR (300 MHz, CDCl3)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). 4) Synthesis of 5- (2-methoxybenzoyl) -4- (2-methoxyphenyl) -2-methylpyrimidine (hereinafter sometimes abbreviated as “5-109” ) Synthesis method of Example 1 3) Then, 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) 5-(2-メトキシベンゾイル)-4-(2-メトキシフェニル)ピリミジン（以下、「５－１０８」と略記する場合がある）の合成
　実施例１の3)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(2-メトキシベンゾイル)メタンとホルムアミジン酢酸塩を反応させ目的物を収率42%で得た。
1H-NMR (300 MHz, CDCl3)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). 5) Synthesis of 5- (2-methoxybenzoyl) -4- (2-methoxyphenyl) pyrimidine (hereinafter sometimes 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 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) 2-アミノ-5-(2-メトキシベンゾイル)-4-(2-メトキシフェニル)ピリミジン（以下、「５－１１０」と略記する場合がある）の合成
　実施例１の3)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(2-メトキシベンゾイル)メタンとグアニジン塩酸塩を反応させ目的物を収率83%で得た。
1H-NMR (300 MHz, CDCl3)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, dd, J = 1.4, 7.3 Hz), 7.46 (1H, dd, J = 1.4, 7.3 Hz), 8.58 (1H, s). 6) Synthesis of 2-amino-5- (2-methoxybenzoyl) -4- (2-methoxyphenyl) pyrimidine (hereinafter sometimes abbreviated as “5-110” ) Synthesis method of Example 1 3) According to the above, N, N-dimethylaminomethylene-di (2-methoxybenzoyl) methane was reacted with guanidine hydrochloride to obtain the desired product in a yield of 83%.
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, dd, J = 1.4, 7.3 Hz), 7.46 (1H, dd, J = 1.4, 7.3 Hz), 8.58 (1H, s).
実施例６
　実施例4の方法に準じて以下のピラゾール誘導体を合成した。 Example 6
The following pyrazole derivatives were synthesized according to the method of Example 4.
1) 4-ベンゾイル-1-メチル-5-フェニルピラゾール（以下、「１４－６０」と略記する場合がある）の合成
　実施例４の3)の合成法に従い、N,N-ジメチルアミノメチレン-ジベンゾイルメタンとフェニルヒドラジンを反応させ目的物を収率67%で得た。
1H-NMR (300 MHz, CDCl3)δ: 3.82 (3H, s), 7.30-7.52 (8H, m), 7.75 (2H, d, J = 8.5 Hz), 7.87 (1H, s). 1) Synthesis of 4-benzoyl-1-methyl-5-phenylpyrazole (hereinafter sometimes abbreviated as “14-60” ) According to the synthesis method of Example 4 3), N, N-dimethylaminomethylene- Dibenzoylmethane and phenylhydrazine were reacted to obtain the desired product in a yield of 67%.
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) 4-(4-メチルベンゾイル)-5-(4-メチルフェニル)-1-メチルピラゾール（以下、「１４－６３」と略記する場合がある）の合成
　実施例４の3)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(4-メチルベンゾイル)メタンとメチルヒドラジンを反応させ目的物を収率56%で得た。
1H-NMR (300 MHz, CDCl3)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). 2) Synthesis of 4- (4-methylbenzoyl) -5- (4-methylphenyl) -1-methylpyrazole (hereinafter sometimes abbreviated as “14-63” ) Synthesis method of Example 4-3 ) Then, N, N-dimethylaminomethylene-di (4-methylbenzoyl) methane was reacted with methylhydrazine to obtain the desired product in a yield of 56%.
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) 4-(4-メチルベンゾイル)-3-(4-メチルフェニル)-1-メチルピラゾール（以下、「１４－６４」と略記する場合がある）の合成
　実施例４の3)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(4-メチルベンゾイル)メタンとメチルヒドラジンを反応させ異性体として目的物を収率25%で得た。
1H-NMR (300 MHz, CDCl3)δ: 2.33 (3H, s), 2.39 (3H, s), 3.95 (3H, s), 7.12 (2H, d, J = 8.8 Hz), 7.18 (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). 3) Synthesis of 4- (4-methylbenzoyl) -3- (4-methylphenyl) -1-methylpyrazole (hereinafter sometimes abbreviated as “14-64” ) Synthesis method of Example 4 3) Then, 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 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, 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) 4-(4-フルオロベンゾイル)-5-(4-フルオロフェニル)-1-メチルピラゾール（以下、「１４－１００F」と略記する場合がある）の合成
　実施例４の3)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(4-フルオロベンゾイル)メタンとメチルヒドラジンを反応させ目的物を収率23%で得た。
1H-NMR (300 MHz, CDCl3)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). 4) Synthesis of 4- (4-fluorobenzoyl) -5- (4-fluorophenyl) -1-methylpyrazole (hereinafter sometimes abbreviated as “14-100F” ) Synthesis method of Example 4-3 ) Then, N, N-dimethylaminomethylene-di (4-fluorobenzoyl) methane was reacted with methylhydrazine to obtain the desired product in a yield of 23%.
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) 4-(3-クロロベンゾイル)-5-(3-クロロフェニル)-1-メチルピラゾール（以下、「１４－１１８」と略記する場合がある）の合成
　実施例４の3)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(3-クロロベンゾイル)メタンとメチルヒドラジンを反応させ目的物を収率69%で得た。
1H-NMR (300 MHz, CDCl3)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). 5) Synthesis of 4- (3-chlorobenzoyl) -5- (3-chlorophenyl) -1-methylpyrazole (hereinafter sometimes abbreviated as “14-118” ) According to the synthesis method of Example 4 3) N, N-dimethylaminomethylene-di (3-chlorobenzoyl) methane and methylhydrazine were reacted to obtain the desired product in a yield of 69%.
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) 4-(2-クロロベンゾイル)-5-(2-クロロフェニル)-1-メチルピラゾール（以下、「１４－１１９」と略記する場合がある）の合成
　実施例４の3)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(2-クロロベンゾイル)メタンとメチルヒドラジンを反応させ目的物を収率57%で得た。
1H-NMR (300 MHz, CDCl3)δ: 3.68 (3H, s), 7.11-7.39 (8H, m), 7.91 (1H, s). 6) Synthesis of 4- (2-chlorobenzoyl) -5- (2-chlorophenyl) -1-methylpyrazole (hereinafter sometimes abbreviated as “14-119” ) According to the synthesis method of Example 4 3) N, N-dimethylaminomethylene-di (2-chlorobenzoyl) methane and methylhydrazine were reacted to obtain the desired product in a yield of 57%.
1 H-NMR (300 MHz, CDCl 3 ) δ: 3.68 (3H, s), 7.11-7.39 (8H, m), 7.91 (1H, s).
7) 4-(4-クロロベンゾイル)-5-(4-クロロフェニル)ピラゾール（以下、「１４－１２３」と略記する場合がある）の合成
　実施例４の3)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(4-クロロベンゾイル)メタンとヒドラジンを反応させ目的物を収率66%で得た。
1H-NMR (300 MHz, CDCl3)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). 7) Synthesis of 4- (4-chlorobenzoyl) -5- (4-chlorophenyl) pyrazole (hereinafter sometimes abbreviated as “14-123” ) According to the synthesis method of Example 4 3), N, N -Dimethylaminomethylene-di (4-chlorobenzoyl) methane and hydrazine were reacted to obtain the desired product in a yield of 66%.
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) 4-(4-クロロベンゾイル)-5-(4-クロロフェニル)-1-イソプロピルピラゾール（以下、「１４－１１１」と略記する場合がある）の合成
　実施例４の4)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(4-クロロベンゾイル)メタンとイソプロピルヒドラジン塩酸塩を反応させ目的物を収率76%で得た。
1H-NMR (300 MHz, CDCl3)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). 8) Synthesis of 4- (4-chlorobenzoyl) -5- (4-chlorophenyl) -1-isopropylpyrazole (hereinafter sometimes abbreviated as “14-111” ) According to the synthesis method of Example 4 4) N, N-dimethylaminomethylene-di (4-chlorobenzoyl) methane and isopropylhydrazine hydrochloride were reacted to obtain the desired product in a yield of 76%.
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) 4-(4-クロロベンゾイル)-5-(4-クロロフェニル)-1-(2-ヒドロキシエチル)ピラゾール（以下、「１４－１１３」と略記する場合がある）の合成
　実施例４の4)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(4-クロロベンゾイル)メタンと2-ヒドロキシエチルヒドラジン塩酸塩を反応させ目的物を収率85%で得た。
1H-NMR (300 MHz, CDCl3)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, 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). 9) Synthesis of 4- (4-chlorobenzoyl) -5- (4-chlorophenyl) -1- (2-hydroxyethyl) pyrazole (hereinafter sometimes abbreviated as “14-113”) ) 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 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, 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) 4-(4-クロロベンゾイル)-5-(4-クロロフェニル)-1-フェニルピラゾール（以下、「１４－１１７」と略記する場合がある）の合成
　実施例４の3)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(4-クロロベンゾイル)メタンとフェニルヒドラジンを反応させ目的物を収率98%で得た。
1H-NMR (300 MHz, CDCl3)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). 10) Synthesis of 4- (4-chlorobenzoyl) -5- (4-chlorophenyl) -1-phenylpyrazole (hereinafter sometimes abbreviated as “14-117” ) According to the synthesis method of Example 4 3) N, N-dimethylaminomethylene-di (4-chlorobenzoyl) methane and phenylhydrazine were reacted to obtain the desired product in a yield of 98%.
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) 4-(4-クロロベンゾイル)-5-(4-クロロフェニル)-1-(2-ピリジル)ピラゾール（以下、「１４－１１６」と略記する場合がある）の合成
　実施例４の4)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(4-クロロベンゾイル)メタンと2-ピリジルヒドラジンを反応させ目的物を収率97%で得た。
1H-NMR (300 MHz, CDCl3)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, 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). 11) Synthesis of 4- (4-chlorobenzoyl) -5- (4-chlorophenyl) -1- (2-pyridyl) pyrazole (hereinafter sometimes abbreviated as “14-116”), Example 4-4 ) According to the above synthesis method, N, N-dimethylaminomethylene-di (4-chlorobenzoyl) methane and 2-pyridylhydrazine were reacted to obtain the desired product in a yield of 97%.
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, 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) 4-(4-クロロベンゾイル)-5-(4-クロロフェニル)-1-(4-メチルフェニル)ピラゾール（以下、「１４－１２９」と略記する場合がある）の合成
　実施例４の4)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(4-クロロベンゾイル)メタンと4-メチルフェニルヒドラジン塩酸塩を反応させ目的物を収率29%で得た。
1H-NMR (300 MHz, CDCl3)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). 12) Synthesis of 4- (4-chlorobenzoyl) -5- (4-chlorophenyl) -1- (4-methylphenyl) pyrazole (hereinafter sometimes abbreviated as “14-129”) 4 of Example 4 ), N, N-dimethylaminomethylene-di (4-chlorobenzoyl) methane and 4-methylphenylhydrazine hydrochloride were reacted to obtain the desired product in a yield of 29%.
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) 4-(4-クロロベンゾイル)-1,5-ジ(4-クロロフェニル)ピラゾール（以下、「１４－１３０」と略記する場合がある）の合成
　実施例４の4)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(4-クロロベンゾイル)メタンと4-クロロフェニルヒドラジン塩酸塩を反応させ目的物を収率29%で得た。 
1H-NMR (300 MHz, CDCl3)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). 13) Synthesis of 4- (4-chlorobenzoyl) -1,5-di (4-chlorophenyl) pyrazole (hereinafter sometimes 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 29% of the desired product.
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) 4-(4-クロロベンゾイル)-5-(4-クロロフェニル)-1-(2-ニトロフェニル)ピラゾール（以下、「１４－１３２」と略記する場合がある）の合成
　実施例４の3)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(4-クロロベンゾイル)メタンと2-ニトロフェニルヒドラジン塩酸塩を反応させ目的物を収率36%で得た。
1H-NMR (300 MHz, CDCl3)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). 14) Synthesis of 4- (4-chlorobenzoyl) -5- (4-chlorophenyl) -1- (2-nitrophenyl) pyrazole (hereinafter sometimes abbreviated as “14-132”) ), N, N-dimethylaminomethylene-di (4-chlorobenzoyl) methane and 2-nitrophenylhydrazine hydrochloride were reacted to obtain the desired product in a yield of 36%.
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) 4-(4-クロロベンゾイル)-5-(4-クロロフェニル)-1-(1-ナフチル)ピラゾール（以下、「１４－１３３」と略記する場合がある）の合成
　実施例４の4)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(4-クロロベンゾイル)メタンと1-ナフチルヒドラジン塩酸塩を反応させ目的物を収率78%で得た。
1H-NMR (300 MHz, CDCl3)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). 15) Synthesis of 4- (4-chlorobenzoyl) -5- (4-chlorophenyl) -1- (1-naphthyl) pyrazole (hereinafter sometimes abbreviated as “14-133” ) According to the above synthesis method, N, N-dimethylaminomethylene-di (4-chlorobenzoyl) methane and 1-naphthylhydrazine hydrochloride were reacted to obtain the desired product in a yield of 78%.
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) 4-(4-クロロベンゾイル)-5-(4-クロロフェニル)-1-(4-メトキシフェニル)ピラゾール（以下、「１４－１３４」と略記する場合がある）の合成
　実施例４の4)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(4-クロロベンゾイル)メタンと4-メトキシフェニルヒドラジン塩酸塩を反応させ目的物を収率36%で得た。
1H-NMR (300 MHz, CDCl3)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). 16) Synthesis of 4- (4-chlorobenzoyl) -5- (4-chlorophenyl) -1- (4-methoxyphenyl) pyrazole (hereinafter sometimes abbreviated as “14-134”) ), N, N-dimethylaminomethylene-di (4-chlorobenzoyl) methane and 4-methoxyphenylhydrazine hydrochloride were reacted to obtain the desired product in a yield of 36%.
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) 4-(4-クロロベンゾイル)-5-(4-クロロフェニル)-1-(3,4-ジクロロフェニル)ピラゾール（以下、「１４－１３９」と略記する場合がある）の合成
　実施例４の4)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(4-クロロベンゾイル)メタンと3,4-ジクロロフェニルヒドラジン塩酸塩を反応させ目的物を収率43%で得た。
1H-NMR (300 MHz, CDCl3)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). 17) Synthesis of 4- (4-chlorobenzoyl) -5- (4-chlorophenyl) -1- (3,4-dichlorophenyl) pyrazole (hereinafter sometimes abbreviated as “14-139”) According to the synthesis method of 4), N, N-dimethylaminomethylene-di (4-chlorobenzoyl) methane and 3,4-dichlorophenylhydrazine hydrochloride were reacted to obtain the target 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) 1-ベンジル-4-(4-クロロベンゾイル)-5-(4-クロロフェニル)ピラゾール（以下、「１４－１１５」と略記する場合がある）の合成
　実施例４の4)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(4-クロロベンゾイル)メタンとベンジルヒドラジン塩酸塩を反応させ目的物を収率93%で得た。
1H-NMR (300 MHz, CDCl3)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). 18) Synthesis of 1-benzyl-4- (4-chlorobenzoyl) -5- (4-chlorophenyl) pyrazole (hereinafter sometimes abbreviated as “14-115” ) According to the synthesis method of Example 4 4) N, N-dimethylaminomethylene-di (4-chlorobenzoyl) methane and benzylhydrazine hydrochloride were reacted to obtain the desired product in a yield of 93%.
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) 4-(4-ブロモベンゾイル)-5-(4-ブロモフェニル)-1-(4-メチルフェニル)ピラゾール（以下、「１４－１４０」と略記する場合がある）の合成
　実施例４の4)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(4-ブロモベンゾイル)メタンと4-メチルフェニルヒドラジン塩酸塩を反応させ目的物を収率55%で得た。
1H-NMR (300 MHz, CDCl3)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). 19) Synthesis of 4- (4-bromobenzoyl) -5- (4-bromophenyl) -1- (4-methylphenyl) pyrazole (hereinafter sometimes abbreviated as “14-140”) 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 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) 4-(4-ブロモベンゾイル)-5-(4-ブロモフェニル)-1-(2-クロロフェニル)ピラゾール（以下、「１４－１４２」と略記する場合がある）の合成
　実施例４の4)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(4-ブロモベンゾイル)メタンと2-クロロフェニルヒドラジン塩酸塩を反応させ目的物を収率27%で得た。
1H-NMR (300 MHz, CDCl3)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, d, J = 8.5 Hz), 8.05 (1H, s). 20) Synthesis of 4- (4-bromobenzoyl) -5- (4-bromophenyl) -1- (2-chlorophenyl) pyrazole (hereinafter sometimes abbreviated as “14-142”) ) 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 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, d, J = 8.5 Hz), 8.05 (1H, s).
21) 4-(4-ブロモベンゾイル)-5-(4-ブロモフェニル)-1-(2-ニトロフェニル)ピラゾール（以下、「１４－１４３」と略記する場合がある）の合成
　実施例４の3)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(4-ブロモベンゾイル)メタンと2-ニトロフェニルヒドラジン塩酸塩を反応させ目的物を収率55%で得た。
1H-NMR (300 MHz, CDCl3)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). 21) Synthesis of 4- (4-bromobenzoyl) -5- (4-bromophenyl) -1- (2-nitrophenyl) pyrazole (hereinafter sometimes abbreviated as “14-143”) According to the synthesis method of 3), N, N-dimethylaminomethylene-di (4-bromobenzoyl) methane and 2-nitrophenylhydrazine hydrochloride were reacted to obtain the desired product in a yield of 55%.
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) 4-(4-ブロモベンゾイル)-5-(4-ブロモフェニル)-1-(1-ナフチル)ピラゾール（以下、「１４－１４４」と略記する場合がある）の合成
　実施例４の4)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(4-ブロモベンゾイル)メタンと1-ナフチルヒドラジン塩酸塩を反応させ目的物を収率30%で得た。
1H-NMR (300 MHz, CDCl3)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). 22) Synthesis of 4- (4-bromobenzoyl) -5- (4-bromophenyl) -1- (1-naphthyl) pyrazole (hereinafter sometimes abbreviated as “14-144”) ), N, N-dimethylaminomethylene-di (4-bromobenzoyl) methane and 1-naphthylhydrazine hydrochloride were reacted to obtain the desired product in a yield of 30%.
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) 4-(4-ブロモベンゾイル)-5-(4-ブロモフェニル)-1-(4-シアノフェニル)ピラゾール（以下、「１４－１４６」と略記する場合がある）の合成
　実施例４の4)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(4-ブロモベンゾイル)メタンと4-シアノフェニルヒドラジン塩酸塩を反応させ目的物を収率18%で得た。
1H-NMR (300 MHz, CDCl3)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). 23) Synthesis of 4- (4-bromobenzoyl) -5- (4-bromophenyl) -1- (4-cyanophenyl) pyrazole (hereinafter sometimes abbreviated as “14-146”) According to the synthesis method of 4), N, N-dimethylaminomethylene-di (4-bromobenzoyl) methane and 4-cyanophenylhydrazine hydrochloride were reacted to obtain the desired product in a yield of 18%.
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) 1-ベンジル-4-(4-ブロモベンゾイル)-5-(4-ブロモフェニル)ピラゾール（以下、「１４－１７３」と略記する場合がある）の合成
　実施例４の4)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(4-ブロモベンゾイル)メタンとベンジルヒドラジン塩酸塩を反応させ目的物を収率36%で得た。
1H-NMR (300 MHz, CDCl3)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). 25) Synthesis of 1-benzyl-4- (4-bromobenzoyl) -5- (4-bromophenyl) pyrazole (hereinafter sometimes abbreviated as “14-173” ) Synthesis method of Example 4-4 ) Then, N, N-dimethylaminomethylene-di (4-bromobenzoyl) methane was reacted with benzylhydrazine hydrochloride to obtain the target product in a yield of 36%.
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) 4-(4-ブロモベンゾイル)-5-(4-ブロモフェニル)-1-(3,4-ジクロロフェニル)ピラゾール（以下、「１４－１５０」と略記する場合がある）の合成
　実施例４の4)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(4-ブロモベンゾイル)メタンと3,4-ジクロロフェニルヒドラジン塩酸塩を反応させ目的物を収率45%で得た。
1H-NMR (300 MHz, CDCl3)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). 26) Synthesis Example 4 of 4- (4-bromobenzoyl) -5- (4-bromophenyl) -1- (3,4-dichlorophenyl) pyrazole (hereinafter sometimes abbreviated as “14-150”) According to the synthesis method of 4), 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 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) 1-(2-クロロフェニル)-4-(4-メチルベンゾイル)-5-(4-メチルフェニル)ピラゾール（以下、「１４－１５３」と略記する場合がある）の合成
　実施例４の4)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(4-メチルベンゾイル)メタンと2-クロロフェニルヒドラジン塩酸塩を反応させ目的物を収率55%で得た。
1H-NMR (300 MHz, CDCl3)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). 27) Synthesis of 1- (2-chlorophenyl) -4- (4-methylbenzoyl) -5- (4-methylphenyl) pyrazole (hereinafter sometimes abbreviated as “14-153”) Example 4-4 ), N, N-dimethylaminomethylene-di (4-methylbenzoyl) methane and 2-chlorophenylhydrazine hydrochloride were reacted to obtain the desired product in a yield of 55%.
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) 4-(4-メチルベンゾイル)-5-(4-メチルフェニル)-1-(1-ナフチル)ピラゾール（以下、「１４－１５５」と略記する場合がある）の合成
　実施例４の4)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(4-メチルベンゾイル)メタンと1-ナフチルヒドラジン塩酸塩を反応させ目的物を収率30%で得た。
1H-NMR (300 MHz, CDCl3)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). 28) Synthesis of 4- (4-methylbenzoyl) -5- (4-methylphenyl) -1- (1-naphthyl) pyrazole (hereinafter sometimes abbreviated as “14-155”) 4 of Example 4 ), N, N-dimethylaminomethylene-di (4-methylbenzoyl) methane and 1-naphthylhydrazine hydrochloride were reacted to obtain the desired product in a yield of 30%.
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) 4-(4-メチルベンゾイル)-5-(4-メチルフェニル)-1-(4-メトキシフェニル)ピラゾール（以下、「１４－１５６」と略記する場合がある）の合成
　実施例４の4)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(4-メチルベンゾイル)メタンと4-メトキシフェニルヒドラジン塩酸塩を反応させ目的物を収率55%で得た。
1H-NMR (300 MHz, CDCl3)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). 29) Synthesis of 4- (4-methylbenzoyl) -5- (4-methylphenyl) -1- (4-methoxyphenyl) pyrazole (hereinafter sometimes abbreviated as “14-156”) 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 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) 1-(4-シアノシフェニル)-4-(4-メチルベンゾイル)-5-(4-メチルフェニル)ピラゾール（以下、「１４－１５７」と略記する場合がある）の合成
　実施例４の4)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(4-メチルベンゾイル)メタンと4-シアノシフェニルヒドラジン塩酸塩を反応させ目的物を収率36%で得た。
1H-NMR (300 MHz, CDCl3)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). 30) Synthesis Example 1 of 1- (4-cyanosiphenyl) -4- (4-methylbenzoyl) -5- (4-methylphenyl) pyrazole (hereinafter sometimes abbreviated as “14-157”) According to the synthesis method of 4), N, N-dimethylaminomethylene-di (4-methylbenzoyl) methane and 4-cyanocyphenylhydrazine hydrochloride were reacted to obtain the desired product in a yield of 36%.
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) 1-ベンジル-4-(4-メチルベンゾイル)-5-(4-メチルフェニル)ピラゾール（以下、「１４－１７４」と略記する場合がある）の合成
　実施例４の4)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(4-メチルベンゾイル)メタンとベンジルヒドラジン塩酸塩を反応させ目的物を収率77%で得た。
1H-NMR (300 MHz, CDCl3)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). 31) Synthesis of 1-benzyl-4- (4-methylbenzoyl) -5- (4-methylphenyl) pyrazole (hereinafter sometimes abbreviated as “14-174” ) Synthesis method of Example 4-4 ) Then, N, N-dimethylaminomethylene-di (4-methylbenzoyl) methane was reacted with benzylhydrazine hydrochloride to obtain the desired product in a yield of 77%.
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) 4-(2-メトキシベンゾイル)-5-(2-メトキシフェニル)-1-(4-メチルフェニル)ピラゾール（以下、「１４－１６２」と略記する場合がある）の合成
　実施例４の4)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(2-メトキシベンゾイル)メタンと4-メチルフェニルヒドラジン塩酸塩を反応させ目的物を収率34%で得た。
1H-NMR (300 MHz, CDCl3)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). 32) Synthesis of 4- (2-methoxybenzoyl) -5- (2-methoxyphenyl) -1- (4-methylphenyl) pyrazole (hereinafter sometimes abbreviated as “14-162”) According to the synthesis method of 4), N, N-dimethylaminomethylene-di (2-methoxybenzoyl) methane and 4-methylphenylhydrazine hydrochloride were reacted to obtain the desired product in a yield of 34%.
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) 1-(4-クロロフェニル)-4-(2-メトキシベンゾイル)-5-(2-メトキシフェニル)ピラゾール（以下、「１４－１６３」と略記する場合がある）の合成
　実施例４の4)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(2-メトキシベンゾイル)メタンと4-クロロフェニルヒドラジン塩酸塩を反応させ目的物を収率41%で得た。
1H-NMR (300 MHz, CDCl3)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). 33) Synthesis of 1- (4-chlorophenyl) -4- (2-methoxybenzoyl) -5- (2-methoxyphenyl) pyrazole (hereinafter sometimes abbreviated as “14-163”) ), N, N-dimethylaminomethylene-di (2-methoxybenzoyl) methane and 4-chlorophenylhydrazine hydrochloride were reacted to obtain the desired product in a yield of 41%.
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) 4-(2-メトキシベンゾイル)-5-(2-メトキシフェニル)-1-(4-メトキシフェニル)ピラゾール（以下、「１４－１６７」と略記する場合がある）の合成
　実施例４の4)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(2-メトキシベンゾイル)メタンと4-メトキシフェニルヒドラジン塩酸塩を反応させ目的物を収率48%で得た。
1H-NMR (300 MHz, CDCl3)δ: 3.47 (3H, s), 3.65 (3H, s), 3.76 (3H, s), 6.60 (1H, d, J = 8.3 Hz), 6.63 (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). 34) Synthesis of 4- (2-methoxybenzoyl) -5- (2-methoxyphenyl) -1- (4-methoxyphenyl) pyrazole (hereinafter sometimes abbreviated as “14-167”) According to the synthesis method of 4), N, N-dimethylaminomethylene-di (2-methoxybenzoyl) methane and 4-methoxyphenylhydrazine hydrochloride were reacted to obtain the desired product in a yield of 48%.
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, 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) 1-(4-シアノフェニル)-4-(2-メトキシベンゾイル)-5-(2-メトキシフェニル)ピラゾール（以下、「１４－１６８」と略記する場合がある）の合成
　実施例４の4)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(2-メトキシベンゾイル)メタンと4-シアノフェニルヒドラジン塩酸塩を反応させ目的物を収率90%で得た。
1H-NMR (300 MHz, CDCl3)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). 35) Synthesis of 1- (4-cyanophenyl) -4- (2-methoxybenzoyl) -5- (2-methoxyphenyl) pyrazole (hereinafter sometimes abbreviated as “14-168”) According to the synthesis method of 4), N, N-dimethylaminomethylene-di (2-methoxybenzoyl) methane and 4-cyanophenylhydrazine hydrochloride were reacted to obtain the desired product in a yield of 90%.
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) 1-(3,4-ジメチルフェニル)-4-(2-メトキシベンゾイル)-5-(2-メトキシフェニル)ピラゾール（以下、「１４－１６９」と略記する場合がある）の合成
　実施例４の4)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(2-メトキシベンゾイル)メタンと3,4-ジメチルフェニルヒドラジン塩酸塩を反応させ目的物を収率48%で得た。
1H-NMR (300 MHz, CDCl3)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). 36) Synthesis example of 1- (3,4-dimethylphenyl) -4- (2-methoxybenzoyl) -5- (2-methoxyphenyl) pyrazole (hereinafter sometimes abbreviated as “14-169”) According to the synthesis method of 4-4), N, N-dimethylaminomethylene-di (2-methoxybenzoyl) methane and 3,4-dimethylphenylhydrazine hydrochloride were reacted to obtain the desired product in a yield of 48%.
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) 1-(4-ブロモフェニル)-4-(2-メトキシベンゾイル)-5-(2-メトキシフェニル)ピラゾール（以下、「１４－１７０」と略記する場合がある）の合成
　実施例４の4)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(2-メトキシベンゾイル)メタンと4-ブロモフェニルヒドラジン塩酸塩を反応させ目的物を収率55%で得た。
1H-NMR (300 MHz, CDCl3)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). 37) Synthesis of 1- (4-bromophenyl) -4- (2-methoxybenzoyl) -5- (2-methoxyphenyl) pyrazole (hereinafter sometimes abbreviated as “14-170”) According to the synthesis method of 4), N, N-dimethylaminomethylene-di (2-methoxybenzoyl) methane and 4-bromophenylhydrazine hydrochloride were reacted to obtain the desired product in a yield of 55%.
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) 1-(3,4-ジクロロフェニル)-4-(2-メトキシベンゾイル)-5-(2-メトキシフェニル)ピラゾール（以下、「１４－１７２」と略記する場合がある）の合成
　実施例４の4)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(2-メトキシベンゾイル)メタンと3,4-ジクロロフェニルヒドラジン塩酸塩を反応させ目的物を収率66%で得た。
1H-NMR (300 MHz, CDCl3)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). 38) Synthesis Example 1 of 1- (3,4-dichlorophenyl) -4- (2-methoxybenzoyl) -5- (2-methoxyphenyl) pyrazole (hereinafter sometimes abbreviated as “14-172”) According to the synthesis method of 4), N, N-dimethylaminomethylene-di (2-methoxybenzoyl) methane and 3,4-dichlorophenylhydrazine hydrochloride were reacted to obtain the desired product in a yield of 66%.
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) 1-ベンジル-4-(2-メトキシベンゾイル)-5-(2-メトキシフェニル)ピラゾール（以下、「１４－１７５」と略記する場合がある）の合成
　実施例４の4)の合成法に従い、N,N-ジメチルアミノメチレン-ジ(2-メトキシベンゾイル)メタンとベンジルヒドラジン塩酸塩を反応させ目的物を収率75%で得た。
1H-NMR (300 MHz, CDCl3)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). 39) Synthesis of 1-benzyl-4- (2-methoxybenzoyl) -5- (2-methoxyphenyl) pyrazole (hereinafter sometimes abbreviated as “14-175” ) Synthesis method of Example 4-4 ) Then, N, N-dimethylaminomethylene-di (2-methoxybenzoyl) methane was reacted with benzylhydrazine hydrochloride to obtain the desired product in a yield of 75%.
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).
試験例１
　膵癌細胞走化性抑制効果（in vitro）
　画像解析に基づいたリアルタイム細胞動態解析法（TAXIScan法）（J Immunol. Methods. 282:1, 2003、J Immunol. Methods. 320:55, 2007、J Immunol. Methods. 404:59, 2014およびBMC cancer.17:234, 2017を参照）（図１）を用いて、膵癌細胞で走化能・浸潤能を評価する系を構築し、実施例１～４で合成した化合物について膵癌細胞の走化性の抑制効果を評価した。その結果を図２に示す。
　図２から分かるように、実施例１～４で合成した化合物は、膵癌細胞株BxPC-3のウシ胎児血清に対する走化性、特に移動の速さを抑制し、その速さは走化性因子無しの細胞とほぼ同じ速さまで抑制された。 Test example 1
Pancreatic cancer cell chemotaxis inhibitory effect (in vitro)
Real-time cell kinetic analysis method 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 chemotaxis / invasion ability in pancreatic cancer cells, and the compounds synthesized in Examples 1 to 4 were chemotactic for pancreatic cancer cells. The inhibitory 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 suppress the chemotaxis of pancreatic cancer cell line BxPC-3 to fetal bovine serum, in particular, the speed of migration, and the speed is determined by the chemotactic factor. It was suppressed to almost the same speed as the cells without.
試験例２
　膵癌細胞増殖抑制効果（in vivo）
　１ｘ１０６個のヒト膵癌細胞株BxPC-3を１００μＬのリン酸緩衝液に懸濁し、５週齢のヌードマウスの背部の皮下に接種した。接種７日後に生着を確認後、マウス１匹あたり１ｍｇ（４０ｍｇ/ｋｇ体重に相当）の実施例４で合成した化合物を週１回経口投与した。投与時はジメチルスルホキシドに溶解した化合物３０ｍｇ／ｍＬをオリーブ油にて１ｍｇ／１００μＬに希釈し、胃ゾンデを用いて強制的に経口投与した。
　その結果を図３に示す。
　図３から分かるように、実施例４で合成した化合物は、既存薬のゲムシタビンよりも、ヌードマウスの背部に接種した膵癌細胞株BxPC-3の増大を抑制した。 Test example 2
Pancreatic cancer cell growth inhibitory effect (in vivo)
1 × 10 6 human pancreatic cancer cell lines BxPC-3 were suspended in 100 μL of phosphate buffer and inoculated subcutaneously on the back of 5-week-old nude mice. After confirming engraftment 7 days after the inoculation, 1 mg (corresponding to 40 mg / kg body weight) of the compound synthesized in Example 4 per mouse was orally administered once a week. At the time of administration, 30 mg / mL of a compound dissolved in dimethyl sulfoxide was diluted to 1 mg / 100 μL with olive oil and forcibly administered orally using a stomach tube.
The result is shown in FIG.
As can be seen from FIG. 3, the compound synthesized in Example 4 suppressed the increase of pancreatic cancer cell line BxPC-3 inoculated on the back of nude mice, compared with the existing drug gemcitabine.
試験例３
　膵癌細胞転移抑制効果（in vivo）
　ヌードマウス（系統名：BALB/c Ajcl-nu/nu；5-6週齢）にGFPラベル-ヒト膵癌細胞株BxPC-3を皮下移植（200 μl PBS中4.0 x 106）した後、増殖した腫瘍組織を切除し、分離した腫瘍から切り出した塊（4mm3）を別のマウス１６匹の膵臓内へ移植した。移植２週間後に４グループに分け（４匹／グループ）、毎週薬物を投与し、毎週体表から蛍光量、腫瘍の個数を計測した。５０日（約７週間）後に安楽死させて、開腹し、蛍光量を直接計測した。統計は、ノンパラメトリックな方法を用いて、Kruskal-Wallis testにて有意差を検討し、p<0.05を有意とした。
　グループ１：薬剤なし
　グループ２：ゲムシタビン（i.p.）
　グループ３：実施例４の化合物（ストック溶液：ＤＭＳＯ中１００ｍＭ）（p.o.）
　グループ４：ゲムシタビン（i.p.）＋実施例４の化合物（ストック溶液：ＤＭＳＯ中１００ｍＭ）（p.o.）
　その結果（体重の変化（移植時を１とする）、転移が見られた個体数、および腫瘍からの蛍光量の比較）を、それぞれ図４～６に示す。
　図４から分かるように、グループ１（薬剤なし）以外は体重が増加した。
　図５から分かるように、グループ１（薬剤なし）は２２日後に、グループ２（ゲムシタビン投与）は３６日後に転移が観られたが、グループ３（実施例４の化合物投与）およびグループ４（ゲムシタビン＋実施例４の化合物投与）は転移が観られなかった。
　図６から分かるように、グループ４（ゲムシタビン＋実施例４の化合物投与）ではグループ１（薬剤なし）と比べて有意に蛍光量が少なく、腫瘍増大が抑えられた。 Test example 3
Pancreatic cancer cell metastasis inhibitory effect (in vivo)
Nude mice (strain name: BALB / c Ajcl-nu / nu; 5-6 weeks old) proliferated after subcutaneous implantation of GFP-labeled human pancreatic cancer cell line BxPC-3 (4.0 × 10 6 in 200 μl PBS) The tumor tissue was excised, and a mass (4 mm 3 ) excised from the separated tumor was transplanted into the pancreas of another 16 mice. Two weeks after transplantation, the mice were divided into 4 groups (4 animals / group), and drugs were administered every week. The amount of fluorescence and the number of tumors were measured from the body surface every week. After 50 days (approximately 7 weeks), the animals were euthanized, opened, and the fluorescence was measured directly. For statistics, a non-parametric method was used to examine significant differences with 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 (changes in body weight (1 at the time of transplantation), the number of individuals in which metastasis was observed, and comparison of the amount of fluorescence from the tumor) are shown in FIGS. 4 to 6, respectively.
As can be seen from FIG. 4, body weight increased except for Group 1 (no drug).
As can be seen from FIG. 5, metastasis was observed after 22 days for group 1 (no drug) and after 36 days for group 2 (administered gemcitabine), whereas group 3 (administration of the compound of Example 4) and group 4 (gemcitabine). + No administration of the compound of Example 4 was observed.
As can be seen from FIG. 6, group 4 (gemcitabine + administration of the compound of Example 4) had significantly less fluorescence than group 1 (no drug), and tumor growth was suppressed.
試験例４
　膵癌細胞走化性抑制効果（in vitro）
　試験例１と同様にして、実施例５及び実施例６で合成した化合物について膵癌細胞の走化性の抑制効果を評価した。その結果を図７～１０に示す。
　図７から分かるように、実施例５及び実施例６で合成した化合物は、膵癌細胞株BxPC-3のウシ胎児血清に対する走化性の成分のうち移動の速さを有意に抑制した。
　図８から分かるように、実施例５及び実施例６で合成した化合物は、膵癌細胞株BxPC-3のウシ胎児血清に対する走化性の成分のうち方向性を有意に抑制した。
　図９から分かるように、実施例５及び実施例６で合成した化合物は、膵癌細胞株BxPC-3のウシ胎児血清に対する走化性の成分のうち移動の速さを有意に抑制した。
　図１０から分かるように、実施例５及び実施例６で合成した化合物は、膵癌細胞株BxPC-3のウシ胎児血清に対する走化性の成分のうち方向性を有意に抑制した。 Test example 4
Pancreatic cancer cell chemotaxis inhibitory effect (in vitro)
In the same manner as in Test Example 1, the compounds synthesized in Example 5 and Example 6 were evaluated for the inhibitory effect on pancreatic cancer cell chemotaxis. The results are shown in FIGS.
As can be seen from FIG. 7, the compounds synthesized in Example 5 and Example 6 significantly suppressed the speed of migration among the chemotactic components of fetal bovine serum of pancreatic cancer cell line BxPC-3.
As can be seen from FIG. 8, the compounds synthesized in Example 5 and Example 6 significantly suppressed the directionality of the chemotactic component of fetal bovine serum of pancreatic cancer cell line BxPC-3.
As can be seen from FIG. 9, the compounds synthesized in Example 5 and Example 6 significantly suppressed the migration speed among the chemotactic components of the pancreatic cancer cell line BxPC-3 with respect to fetal calf serum.
As can be seen from FIG. 10, the compounds synthesized in Example 5 and Example 6 significantly suppressed the directionality of the chemotactic component of fetal bovine serum of pancreatic cancer cell line BxPC-3.
　国内の膵癌の罹患数は年間約３万３千人（２０１０年）で全癌の７～９％を占め、死亡者数は年間約３万人（２０１２年）、全世界の罹患数は毎年約２７万７千人で、全癌の２．２％である。５年生存率（全ステージ）は１９８１～１９９０年で約７％、２００１～２００７年で約１３％程度と治療成績は向上しつつもいまだに不良である。この間、新薬や手術方法が進歩してきたが、膵癌の克服には程遠い。本発明が臨床応用に至れば、これらの患者の予後を劇的に改善できる効果が期待される。
　膵癌のみならず、本発明の基となっているin vitro細胞動態解析法では、肺癌、大腸癌、乳癌細胞、卵巣癌、肉腫系細胞でも走化性アッセイ系を確立しており、今後、これらの癌を含めた広範囲な癌転移抑制効果の評価が可能である。全ての癌罹患数は国内約９８万人（２０１５年推計）、全世界では１４００万人（２０１２年推計）で、死亡者数は国内約３７万人（２０１５年推計）、全世界では年間約８２０万（２０１２年推計）である。これらの癌患者の中でも一部で治療効果が期待される。
　また、図２で示された通り、既存薬のゲムシタビンで見られる細胞毒性が少ないことから、臨床応用の際に既存薬よりも副作用が少ないことが期待される。現在、癌治療において副作用により投薬を断念せざるを得ない場合もあるので、治療の中断や中止を避けることができる効果も期待される。 The number of cases of pancreatic cancer in Japan is about 33,000 (2010), accounting for 7-9% of all cancers, the number of deaths is about 30,000 (2012), and the number of cases worldwide is every year. About 277,000 people, 2.2% of all cancers. The 5-year survival rate (all stages) is about 7% between 1981 and 1990, and about 13% between 2001 and 2007, but treatment results are improving but still poor. During this time, new drugs and surgical methods have progressed, but far from overcoming pancreatic cancer. If the present invention reaches clinical application, the effect of dramatically improving the prognosis of these patients is expected.
Not only pancreatic cancer but also the in vitro cell kinetic analysis method on which the present invention is based has established chemotaxis assay systems for lung cancer, colon cancer, breast cancer cells, ovarian cancer, and sarcoma cells. It is possible to evaluate a wide range of cancer metastasis inhibitory effects including cancers of The total number of cancer cases is approximately 980,000 in Japan (2015 estimate), 14 million in the world (2012 estimate), and the number of deaths in Japan is approximately 370,000 (2015 estimate). It is 8.2 million (2012 estimate). Some of these cancer patients are expected to have therapeutic effects.
Further, as shown in FIG. 2, since the cytotoxicity seen with the existing drug gemcitabine is small, it is expected to have fewer side effects than the existing drug in clinical application. Currently, there are cases where it is unavoidable to abandon medication due to side effects in cancer treatment, and therefore an effect of avoiding interruption or discontinuation of treatment is also expected.
　本発明は、抗腫瘍活性および癌転移抑制活性を有する化合物、ならびに当該化合物を有効成分として含有する抗腫瘍剤を提供することができる。 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.
　本出願は、日本で出願された特願２０１８－０５９０７４を基礎としており、その内容は本明細書にすべて包含されるものである。 This application is based on Japanese Patent Application No. 2018-059074 filed in Japan, the contents of which are incorporated in full herein.

Claims (7)

  1. 　式（１）：
    Figure JPOXMLDOC01-appb-C000001
     （式中、
    　環Ａは、置換基を有していてもよい５ないし６員環を示し、
    　Ｒ１およびＲ４は、それぞれ独立して、水素原子、ハロゲン原子、水酸基、ニトロ基、シアノ基、Ｃ１－６アルキル基、ハロゲン化Ｃ１－６アルキル基またはＣ１－６アルコキシ基を示し、
    　ベンゼン環Ｂおよびベンゼン環Ｃは、それぞれさらに置換基を有していてもよく、
    　ベンゼン環Ｂ－Ｃ（Ｒ２）（Ｒ３）基およびベンゼン環Ｃは、それぞれ環Ａを構成する別個の炭素原子に結合しており、
    　Ｒ２およびＲ３は、それぞれ独立して、水素原子、ハロゲン原子、水酸基、ニトロ基、シアノ基、Ｃ１－６アルキル基、ハロゲン化Ｃ１－６アルキル基またはＣ１－６アルコキシ基を示すか、あるいはＲ２およびＲ３は一緒になってオキソ基またはヒドロキシイミノ基を示す。）
    で表される化合物またはその塩。     Formula (1):
    Figure JPOXMLDOC01-appb-C000001
     (Where
    Ring A represents an optionally substituted 5- to 6-membered ring,
    R 1 and R 4 each independently represents 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. ,
    Each of the benzene ring B and the benzene ring C may further have a 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 each independently represents 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. R 2 and R 3 together represent an oxo group or a hydroxyimino group. )
    Or a salt thereof.
  2. 　Ｒ１およびＲ４が、それぞれ独立して、塩素原子、臭素原子またはメトキシ基である、請求項１に記載の化合物。 The compound according to claim 1, wherein R 1 and R 4 are each independently a chlorine atom, a bromine atom or a methoxy group.
  3. 　環Ａが、メチル基を有していてもよいピラゾール環またはピリミジン環である、請求項１または２に記載の化合物。 The compound according to claim 1 or 2, wherein ring A is a pyrazole ring or pyrimidine ring optionally having a methyl group.
  4. 　Ｒ２およびＲ３が一緒になってオキソ基である、請求項１～３のいずれか１項に記載の化合物。 The compound according to any one of claims 1 to 3, wherein R 2 and R 3 together are an oxo group.
  5. 　Ｒ１およびＲ４が、それぞれ独立して、塩素原子、臭素原子またはメトキシ基であり、環Ａが、メチル基を有していてもよいピラゾール環またはピリミジン環であり、かつＲ２およびＲ３が一緒になってオキソ基である、請求項１～４のいずれか１項に記載の化合物。 R 1 and R 4 are each independently a chlorine atom, bromine atom or methoxy group, ring A is a pyrazole ring or pyrimidine ring optionally having a methyl group, and R 2 and R 3 The compound according to any one of claims 1 to 4, wherein together are an oxo group.
  6. 　5-(4-メトキシベンゾイル)-4-(4-メトキシフェニル)-2-メチルピリミジン、4-(4-メトキシベンゾイル)-5-(4-メトキシフェニル)-1-メチルピラゾール、4-(4-ブロモベンゾイル)-5-(4-ブロモフェニル)-1-メチルピラゾールまたは4-(4-クロロベンゾイル)-5-(4-クロロフェニル)-1-メチルピラゾールである、請求項５に記載の化合物。 5- (4-methoxybenzoyl) -4- (4-methoxyphenyl) -2-methylpyrimidine, 4- (4-methoxybenzoyl) -5- (4-methoxyphenyl) -1-methylpyrazole, 4- (4 6. The compound according to claim 5, which is -bromobenzoyl) -5- (4-bromophenyl) -1-methylpyrazole or 4- (4-chlorobenzoyl) -5- (4-chlorophenyl) -1-methylpyrazole .
  7. 　癌転移抑制活性および腫瘍増殖抑制活性を有する、請求項１～６のいずれか１項に記載の化合物。 The compound according to any one of claims 1 to 6, which has cancer metastasis inhibitory activity and tumor growth inhibitory activity.
PCT/JP2019/011009 2018-03-26 2019-03-15 Novel anti-tumor agent WO2019188456A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2020510676A JPWO2019188456A1 (en) 2018-03-26 2019-03-15 New antitumor agent
JP2023115386A JP2023134657A (en) 2018-03-26 2023-07-13 Novel anti-tumor agent

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2018059074 2018-03-26
JP2018-059074 2018-03-26

Publications (1)

Publication Number Publication Date
WO2019188456A1 true WO2019188456A1 (en) 2019-10-03

Family

ID=68058828

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2019/011009 WO2019188456A1 (en) 2018-03-26 2019-03-15 Novel anti-tumor agent

Country Status (2)

Country Link
JP (2) JPWO2019188456A1 (en)
WO (1) WO2019188456A1 (en)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07165724A (en) * 1993-12-13 1995-06-27 Nkk Corp Pyrazole derivative and anticoagulant
WO1999028301A1 (en) * 1997-12-03 1999-06-10 E.I. Du Pont De Nemours And Company Substituted pyrimidine and pyridine herbicides
JP2011524422A (en) * 2008-06-16 2011-09-01 ユニバーシティ オブ テネシー リサーチ ファウンデーション Compounds for treating cancer
JP2013538213A (en) * 2010-08-24 2013-10-10 ジーティーエックス・インコーポレイテッド Compounds for the treatment of cancer
WO2015026646A1 (en) * 2013-08-20 2015-02-26 E. I. Du Pont De Nemours And Company Fungicidal pyrazoles
WO2018111904A1 (en) * 2016-12-12 2018-06-21 Vettore, LLC Heterocyclic inhibitors of mct4

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07165724A (en) * 1993-12-13 1995-06-27 Nkk Corp Pyrazole derivative and anticoagulant
WO1999028301A1 (en) * 1997-12-03 1999-06-10 E.I. Du Pont De Nemours And Company Substituted pyrimidine and pyridine herbicides
JP2011524422A (en) * 2008-06-16 2011-09-01 ユニバーシティ オブ テネシー リサーチ ファウンデーション Compounds for treating cancer
JP2013538213A (en) * 2010-08-24 2013-10-10 ジーティーエックス・インコーポレイテッド Compounds for the treatment of cancer
WO2015026646A1 (en) * 2013-08-20 2015-02-26 E. I. Du Pont De Nemours And Company Fungicidal pyrazoles
WO2018111904A1 (en) * 2016-12-12 2018-06-21 Vettore, LLC Heterocyclic inhibitors of mct4

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
CHEN, JIANJUN, J. MED. CHEM., vol. 53, 2010, pages 7414 - 7427 *
LIU, XIN-HUA: "Design and synthesis of N-phenylacetyl (sulfonyl) 4,5-dihydropyrazole derivatives as potential antitumor agents", BIOORG. MED. CHEM. LETT., vol. 21, no. 10, 23 March 2011 (2011-03-23), pages 2916 - 2920, XP028208748 *
LU , YAN, J. MED. CHEM., vol. 52, 2009, pages 1701 - 1711 *
NICULESCU-DUVAZ, DAN: "Novel tricyclic pyrazole BRAF inhibitors with imidazole or furan central scaffolds", BIOORG. MED. CHEM., vol. 18, no. 18, 15 June 2010 (2010-06-15) - 15 September 2010 (2010-09-15), pages 6934 - 6952, XP027252795 *
YAMAMOTO, SATOSHI: "Design, synthesis, and biological evaluation of 4-arylmethyl-1-phenylpyrazole and 4-aryloxy-1-phenylpyrazole derivatives as novel androgen receptor antagonists", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 20, no. 7, 10 February 2012 (2012-02-10), pages 2338 - 2352, XP055639373 *
YANG, GONGMING: "Facile synthesis of pyrimidines via iminium catalyzed [4+2] reaction of α,β-unsaturated ketones with 1,3,5-triazines", TETRAHEDRON LETT., vol. 56, no. 43, 8 September 2015 (2015-09-08), pages 5889 - 5891, XP029283065 *
ZHAI,MIN'AI: "Synthesis and biological evaluation of (1-aryl-1H-pyrazol-4-yl) (3,4,5-trimethoxyphenyl)methanone derivatives as tubulin inhibitors", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 156, 2 June 2018 (2018-06-02) - August 2018 (2018-08-01), pages 137 - 147, XP055639390 *

Also Published As

Publication number Publication date
JPWO2019188456A1 (en) 2021-03-18
JP2023134657A (en) 2023-09-27

Similar Documents

Publication Publication Date Title
JP5702392B2 (en) Novel compound effective as xanthine oxidase inhibitor, process for producing the same, and pharmaceutical composition containing the same
CA2274594C (en) Aminopyrazole derivatives
RU2293733C2 (en) Novel 1,2,4-triazole compounds, methods for their preparing and medicaments containing thereof
CN101636397A (en) Urea compounds, preparation methods and pharmaceutical uses thereof
US20080064734A1 (en) Anilinopyrazole derivatives useful for the treatment of diabetes
PT1024138E (en) Pyrazole derivatives
WO2001060819A1 (en) Novel isoxazole and thiazole compounds and use thereof as drugs
CA2273102A1 (en) Urea derivatives
EA026674B1 (en) Compounds useful as medicaments
AU1998501A (en) 5-aryl-1h-1,2,4-triazole compounds as inhibitors of cyclooxygenase-2 and pharmaceutical compositions containing them
JP2009506127A (en) Anilinopyrazole derivatives useful for the treatment of diabetes
CZ20032637A3 (en) Kinase inhibitors
JPWO2005087749A1 (en) 2-Aminoquinazoline derivatives
TW201125865A (en) Oxadiazole derivative having inhibion activity on endothelial lipase
TWI772309B (en) Compounds and their use for reducing uric acid levels
US20090111860A1 (en) Sulfonamide compounds useful as adg receptor modulators
JP2022521081A (en) Amide derivatives useful in the treatment of HBV infections or HBV-induced diseases
EA018900B1 (en) Compounds modulating cannabinoid cb1 receptor activity, compositions based thereon and use thereof
TW200914438A (en) 3-disubstituted indol-2-one derivatives, preparation thereof and therapeutic application thereof
US7019144B2 (en) 1,2,4-Triazole derivative, method for preparing the same, and pharmaceutical composition containing the same
FR2965262A1 (en) NICOTINAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
WO2015075051A1 (en) Allosteric inhibitors of atypical protein kinases c
WO2019188456A1 (en) Novel anti-tumor agent
TW200533637A (en) Aryl- and heteroarylalkylcarbamate derivatives, their preparation and their application in therapeutics
RU2542980C2 (en) Substituted 3-benzofuranyl-indol-2-one-3-acetamidopiperazines derivatives, preparing and using them in therapy

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19777517

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2020510676

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19777517

Country of ref document: EP

Kind code of ref document: A1