JPH0517470A - Pyrazole derivative - Google Patents

Abstract

PURPOSE:To obtain the subject new compounds useful as medicines such as antiphlogistics, anti-rheumatics, antimicrobial agents or antiviral agents. CONSTITUTION:A compound expressed by formula I [R<1> is pyridyl or (substituted)phenyl; R<2> is pyridyl or NHR<5> (R<5> is H, lower alkyl, formyl, etc.); R<3> is pyridyl; R<4> is H, lower alkanoyl, (phenyl)-lower alkoxycarbonyl; R<3> and R<4> together may form formula II ((n) is 1 or 2) or formula III (R<6> is H or lower alkyl,), e.g. 3-amino-4-(4-fluorophenyl)-5-(2-pyridyl)-pyrazole. The compound expressed by formula I is e.g. obtained by reacting a nitrile derivative expressed by the formula R<1>-CH2CN with a carboxylic acid ester expressed by the formula R<3a>COOR<7> (R<3a> is pyridyl; R<7> is lower alkyl) in the presence of a base in an inert solvent to afford a compound expressed by formula IV and subjecting the compound expressed by formula IV to cyclic reaction with hydrazine.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel pyrazole derivative.

[0002]

The compound of the present invention is a novel compound which has not been published in the literature.

[0003]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a compound useful as a medicine as described below.

[0004]

According to the present invention, a pyrazole derivative represented by the following general formula (1) is provided.

[0005]

[Chemical 4]

[Wherein R ¹ is a pyridyl group or a group selected from a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a halogen-substituted lower alkyl group, a halogen atom, a phenyl group, a phenylthio group and a methylenedioxy group as a substituent. A phenyl group which may have 1 to 3 R
² is a pyridyl group or a group -NHR ⁵ (R ⁵ is a hydrogen atom, a lower alkyl group, a lower alkanoyl group or a formyl group), R ³ is a pyridyl group, R ⁴ is a hydrogen atom, a lower alkanoyl group or a lower alkoxy. A carbonyl group or a phenyl lower alkoxycarbonyl group, respectively, and R
³ and R ⁴ are bonded to each other to form a group

[0007]

[Chemical 5]

(N is 1 or 2) or a group

[0009]

[Chemical 6]

(R ⁶ represents a hydrogen atom or a lower alkyl group) may be formed. ] The compound of the present invention represented by the above general formula (1) and salts thereof are anti-inflammatory, anti-rheumatic,
It exhibits antibacterial and antiviral pharmacological effects, and is therefore useful as a drug such as an anti-inflammatory agent, antirheumatic agent, antibacterial agent and antiviral agent.

In the present specification, examples of the lower alkyl group include methyl, ethyl, propyl, isopropyl,
Examples thereof include linear or branched lower alkyl groups such as butyl, isobutyl, tert-butyl, pentyl and hexyl groups.

Examples of the lower alkoxy group include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy and hexyloxy groups.

Examples of the lower alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl groups.

Examples of the phenyl lower alkoxycarbonyl group include benzyloxycarbonyl, β-phenethyloxycarbonyl, 3-phenylpropoxycarbonyl, 4-phenylbutoxycarbonyl, 5-phenylpentyloxycarbonyl and 6-phenylhexyloxycarbonyl groups. It can be illustrated.

Examples of the lower alkylthio group include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, pentylthio and hexylthio groups.

Examples of the halogen-substituted lower alkyl group include trifluoromethyl, pentafluoroethyl, heptafluoropropyl, nonafluorobutyl, undecafluoropentyl and tridecafluorohexyl groups.

Examples of the lower alkanoyl group include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, trimethylacetyl and hexanoyl groups.

The pyridyl group includes 2-pyridyl, 3-pyridyl and 4-pyridyl groups.

The halogen atom includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The pyrazole derivative of the present invention can be produced by various methods. A specific example is shown in the following reaction process formula.

<Reaction Process Formula-1>

[0022]

[Chemical 7]

[Wherein R ¹ is the same as above. R ^3a represents a pyridyl group and R ⁷ represents a lower alkyl group. The reaction of the nitrile derivative (2) represented by the above reaction process formula-1 with the carboxylic acid ester (3) is carried out in the presence of a base in a suitable inert solvent. Examples of the base used here include metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, and metal hydrides such as sodium hydride and lithium hydride. These bases are usually compound (2)
1 to 2.5 molar amount is used. Further, as the inert solvent, for example, N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), aromatic hydrocarbons such as benzene, toluene, xylene and the like can be preferably used. The reaction is generally 0 to 130 ° C.
It is carried out in a temperature range of about 1 to 20 hours.

The target compound (1a) can be obtained by subjecting the compound (4) thus obtained to a cyclization reaction with hydrazine. The cyclization reaction is carried out in acetic acid or in the presence of an acid catalyst such as acetic acid in an inert solvent such as benzene, toluene and xylene. When an acid catalyst is used, the amount used is preferably equimolar or more based on the compound (4). The reaction is generally completed in a temperature range of about 50 to 130 ° C. in about 1 to 20 hours.

<Reaction Process Formula-2>

[0026]

[Chemical 8]

[Wherein R ¹ and R ^3a are the same as defined above. ] The formylation reaction shown in the above reaction scheme-2 is carried out by the compound (1
It is carried out by treating a) with a formylating agent such as formic acid or formic acid-acetic anhydride. In this reaction, since the above-mentioned formylating agent also serves as a solvent, no particular solvent is required, but a suitable inert solvent can also be used, and examples of the inert solvent include dichloromethane, 1,2-dichloroethane and chloroform. Etc. can be illustrated. The reaction is generally performed under a condition of a temperature range of about 40 to 100 ° C. for about 2 to 12 hours, and thus the target compound (1b) can be obtained.

<Reaction Process Formula-3>

[0029]

[Chemical 9]

[In the formula, R ¹ and R ^3a are the same as defined above. R
^2a (= R ^3a ) represents a pyridyl group, and R ^4a and R ^5a each represent a lower alkanoyl group. In the above reaction process formula-3, the alkanoylation reaction of the compound (1a) can be carried out by reacting the starting compound with an acid anhydride in an inert solvent. As the above-mentioned inert solvent, for example, tetrahydrofuran (THF), diethyl ether, chloroform, dichloromethane, DMF and the like can be used. If necessary, a basic catalyst such as pyridine, collidine, lutidine, triethylamine and the like can be added and present in the reaction system. As the acid anhydride, for example, acetic anhydride, propionic anhydride, butyric anhydride, valeric anhydride,
Caproic anhydride, heptanoic anhydride, etc. can be used. The reaction is completed in about 1 to 24 hours under the temperature condition of 0 to 100 ° C., and thus the target compound (1c) and / or (1
d) is obtained.

<Reaction Process Formula-4>

[0032]

[Chemical 10]

[In the formula, R ¹ , R ^2a and R ^3b are the same as defined above.
R ^4b represents a lower alkoxycarbonyl group or a phenyl lower alkoxycarbonyl group, and X represents a halogen atom. The reaction of the compound (1a) represented by the above reaction scheme-4 with the haloformic acid ester derivative (5) is carried out in a suitable inert solvent in the presence of a deoxidizing agent. Examples of the inert solvent include dichloromethane, chloroform, DM
Examples include F, THF, dioxane and the like. The amount of the haloformic acid ester derivative (5) used is usually about 1 to 2.5 times the molar amount of the compound (1a). Examples of the deoxidizing agent include sodium hydride, potassium carbonate,
Sodium carbonate, triethylamine, diisopropylethylamine and the like can be preferably used, and the amount thereof used can be about 1 to 2.5 times the molar amount of the compound (1a). The reaction is carried out under the temperature condition of 0 to 50 ° C.
Is completed in about 24 hours, and thus the target compound (1e) is obtained.
Is obtained.

<Reaction Process Formula-5>

[0035]

[Chemical 11]

[In the formula, R ¹ and R ^3a are the same as defined above. ] The reduction reaction of the compound (1b) shown in the above reaction process formula-5 is carried out using a reducing agent such as lithium aluminum hydride or lithium borohydride in an inert solvent such as diethyl ether, THF or benzene. It The amount of the reducing agent used is usually an equimolar amount or more with respect to the compound (1b). The reaction is generally carried out under the temperature condition of about 0 to 70 ° C.
Is completed in about 24 hours, and thus the target compound (1f) is obtained.
Is obtained.

<Reaction Process Formula-6>

[0038]

[Chemical 12]

[In the formula, R ¹ , R ^3a and n are the same as defined above. R
⁸ represents a lower alkyl group, and Y represents a halogen atom. The cyclization reaction represented by the above reaction process formula-6 is carried out by reacting the compound (1a) with the halocarboxylic acid ester (6) in the presence of a base. Specific examples of the halocarboxylic acid ester (6) include ethyl bromoacetate, ethyl chloroacetate, ethyl 3-bromopropionate, and the like, and the amount thereof is about 1 to 3 times the molar amount of the compound (1a). It is good to say Examples of the base include inorganic salts such as calcium carbonate and sodium carbonate, sodium hydride, triethylamine and the like.
~ 2.5 times the molar amount is used. The reaction is carried out in an inert solvent such as DMF or dimethylacetamide (DMA) at 50
It is carried out under a temperature condition of about 130 ° C. for about 3 to 30 hours, and thus the target compound (1 g) can be obtained.

<Reaction Process Formula-7>

[0041]

[Chemical 13]

[In the formula, R ¹ , R ^2a and R ^3a are the same as defined above.
R ^6a and R ⁹ each represent a lower alkyl group. The reaction of the compound (1a) represented by the above reaction process formula-7 with the compound (7) is carried out by heat treatment in an inert solvent such as acetic acid, ethanol-acetic acid, benzene or toluene. The compound (7) is generally 1 to the compound (1a).
It is used in a double molar amount. The heating conditions are 80-150
It is preferable to set the temperature to about 1 to 24 hours. Thus, the target compound (1h) is obtained.

<Reaction Process Formula-8>

[0044]

[Chemical 14]

[In the formula, R ¹ , R ^2a and R ^6a are the same as defined above. ] The hydrolysis reaction of the compound (1a) shown in the above reaction process formula-8 is carried out using an alkaline aqueous solution such as an aqueous sodium hydroxide solution or an aqueous potassium hydroxide solution in an inert solvent such as methanol, ethanol, THF or dioxane. To be done. The reaction is carried out at room temperature to a boiling point of the solvent for about 1 to 15 hours. Thus, the target compound (1
i) is obtained.

The target compound obtained by the method shown in each of the above reaction schemes can be easily isolated and purified by a conventional separation means. Examples of the means include solvent extraction, recrystallization, column chromatography and the like.

The compound (1) of the present invention can be easily converted into a pharmaceutically acceptable acid addition salt by subjecting the compound (1) of the present invention to an addition reaction with an appropriate acidic compound according to a conventional method.
Examples of the acidic compound capable of forming the acid addition salt include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid, and oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, An organic acid such as benzenesulfonic acid can be exemplified.

The above acid addition salts have the same pharmacological activity as the compound of the present invention in a free form, and the present invention also includes such acid addition salts.

Among the pyrazole derivatives of the present invention, the compound represented by the following general formula (1j) may exist as a tautomer of the compound (1k) and the compound (1l) represented by the following formula. The present invention also includes these compounds.

[0050]

[Chemical 15]

[0051]

EXAMPLES In order to explain the present invention in more detail, production examples of the compound of the present invention will be given below as Examples.

[0052]

Example 1 Preparation of 3-amino-4- (4-fluorophenyl) -5- (2-pyridyl) -pyrazole 4-fluorophenylacetonitrile 27 g (0.2 mol), ethyl picolinate 32 g (0.21) Mol) and 23 g (0.43 mol) of sodium methoxide were suspended in 300 ml of toluene, and the mixture was heated and stirred at 90 ° C. for 2 hours.
After allowing the reaction solution to cool, the precipitated yellow crystals were filtered and washed with a small amount of toluene.

Next, the yellow crystals obtained above were mixed with acetic acid 20.
Suspend in 0 ml and add 40 g of hydrazine hydrate under ice cooling.
(0.8 mol) was added, and the mixture was stirred as it was for 30 minutes, then 90
The mixture was heated and stirred at ℃ for 1 hour. Pour the reaction solution into ice water,
The mixture was extracted with dichloromethane, the organic layer was washed successively with an aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The precipitate formed by concentration was collected by filtration and washed with ethyl acetate, and this was dissolved in 500 ml of ethanol-ethyl acetate (2: 3) and treated with activated carbon. Activated carbon was filtered off and the crystals formed after concentration under reduced pressure were collected by filtration and recrystallized from ethanol-ethyl acetate to obtain 11 g of the target compound.

The structure and physical properties of the obtained compound are shown in Table 1 as Compound 1.

[0055]

Examples 2 to 18 In the same manner as in Example 1, each compound shown in Table 1 (Compounds 2 to 18) was produced. The structure and physical properties of the obtained compound are also shown in Table 1.

[0056]

Example 19 Preparation of 3-amino-4- (4-methoxyphenyl) -5- (2-pyridyl) -pyrazole dihydrochloride 7.4 g (50 mmol) 4-methoxyphenylacetonitrile, ethyl picolinate 7. 6 g (50 mmol)
And sodium methoxide (5.7 g, 100 mmol)
Was suspended in 100 ml of toluene and heated and stirred at 90 ° C. for 1 hour. The reaction solution was allowed to cool and then dried under reduced pressure. Next, the residue was suspended in 60 ml of acetic acid, and hydrazine hydrate under ice cooling was used.
8 ml (200 mmol) was added, and the mixture was stirred as it was for 10 minutes and then heated and stirred at 90 ° C. for 1 hour. The reaction solution was poured into ice water and extracted with dichloromethane. The organic layer was washed successively with an aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 4N hydrochloric acid on the residue
Ethyl acetate was added, and the formed crystals were collected by filtration and recrystallized from methanol-diethyl ether to obtain 5 g of the target compound.

The structure and physical properties of the resulting compound are shown in Table 1 as Compound 19.

[0058]

Examples 20 to 24 In the same manner as in Example 1, each compound shown in Table 1 (Compounds 20 to 24) was produced. The structure and physical properties of the obtained compound are also shown in Table 1.

[0059]

Example 25 Preparation of 3-formamido-4- (3,4-dimethoxyphenyl) -5- (2-pyridyl) -pyrazole 2.26 g (7.6 mmol) of compound 14 was dissolved in 23 ml of dichloromethane, 3 ml of formic acid-acetic anhydride (5: 3, volume ratio) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, xylene was further added, and the mixture was concentrated under reduced pressure three times under azeotropic distillation, and the obtained residue was recrystallized from ethyl acetate and then methanol-ethyl acetate to give the desired compound
g was obtained.

The structure and physical properties of the obtained compound are shown in Table 1 as Compound 25.

[0061]

Example 26 In the same manner as in Example 25, the compound 26 shown in Table 1 was prepared. The structure and physical properties of the obtained compound are also shown in Table 1.

The above compound 26 can also be produced by the following method. That is, 9.5 ml of formic acid was added to 5.4 g (21.2 mmol) of compound 1, and the temperature was adjusted to 10 at about 60 minutes.
After raising the temperature to 0 ° C and heating at 100 ° C overnight, after completion of the reaction, excess formic acid was distilled off under reduced pressure, xylene was further added, and the mixture was concentrated twice under azeotropic distillation under reduced pressure, and the obtained residue was diluted with ethyl acetate and then with dichloromethane. -Recrystallized from methanol-ethyl acetate. Thus, 5.3 g of compound 26 was obtained.

[0063]

Examples 27-28 3-Acetamido-4- (4-fluorophenyl) -5- (2-pyridyl) -pyrazole and 1-acetyl-5-amino-4- (4-fluorophenyl) -3- ( Preparation of 2-pyridyl) pyrazole 5.0 g (19.7 mmol) of compound 1 was dissolved in 15 ml of chloroform, and 2.01 g of acetic anhydride (19.7).
(Mmol) and added, and reacted at room temperature for 3 days. The reaction solution was concentrated under reduced pressure, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from diethyl ether and then ethyl acetate-diethyl ether to obtain 1.27 g of the desired compound (Compound 27).

The residue obtained by concentrating the mother liquor of the above recrystallization is subjected to silica gel column chromatography (elution solvent ...
Dichloromethane-methanol = 50: 1), and the target fraction was recrystallized from diethyl ether and then ethyl acetate to give the target compound (compound 28) (1.05 g).
Got

Table 1 shows the structures and physical properties of the obtained compounds.

[0066]

Example 29 5-Amino-1-benzyloxycarbonyl-4- (3,4-dimethoxyphenyl) -3- (2
Preparation of -pyridyl) -pyrazole 1.0 g (2.7 mmol) of compound 14 was dissolved in 20 ml of dichloromethane and 0.74 ml of triethylamine was dissolved.
(5.31 mmol) was added, and 0.4 ml (2.78 mmol) of benzyl chloroformate was further added dropwise under ice cooling.
After stirring for 3 hours at room temperature, benzyl chloroformate 0.2m
1 was added and reacted overnight. Water was added to the reaction solution, extraction was performed with dichloromethane, the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (elution solvent ... dichloromethane-methanol = 50: 1), the target fraction is concentrated under reduced pressure, and further recrystallized with diethyl ether and then dichloromethane-ethyl acetate to obtain the target. 380 mg of the compound are obtained.

The structure and physical properties of the obtained compound are shown in Table 1 as Compound 29.

[0068]

Example 30 5-Amino-4- (4-fluorophenyl) -1-methoxycarbonyl-3- (2-pyridyl)
-Production of pyrazole In a suspension of 1.0 g of sodium hydride in 40 ml of DMF,
5.0 g (19.7 mmol) of Compound 1 DMF (4
(0 ml) solution was added dropwise at room temperature, and the mixture was further stirred at room temperature for 1 hour. There, 1.68 ml of methyl chloroformate (21.7
(Mmol) and added and stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction solution for extraction, the organic layer was washed 3 times with water,
It was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was recrystallized from diethyl ether-ethyl acetate to obtain 3.15 g of the objective compound.

The structure and physical properties of the obtained compound are shown in Table 1 as compound 30.

[0070]

Example 31 4- (4-fluorophenyl) -3-
Preparation of Methylamino-5- (2-pyridyl) -pyrazole 0.8 g lithium aluminum hydride, 30 ml THF
A suspension of 2.0 g (7.09 mmol) of compound 26 in THF (20 ml) was added dropwise to the suspension prepared in (1) under ice cooling.
After stirring overnight at room temperature, 1 ml of water and 1 ml of 5% aqueous sodium hydroxide solution were added to the reaction solution and the mixture was stirred for several minutes, and 3 ml of water was further added and stirred. After sufficient insoluble matter was formed, this was filtered off with Celite, and dichloromethane and water were added to the filtrate for extraction. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the obtained residue was recrystallized from ethyl acetate-diethyl ether and then dichloromethane-diethyl ether to obtain 0.94 g of the target compound.

The structure and physical properties of the obtained compound are shown in Table 1 as Compound 31.

[0072]

Example 32 Preparation of 6,7-dihydro-3- (4-fluorophenyl) -2- (2-pyridyl) -4H-pyrazolo [1,5-a] -pyrimidin-5-one Compound 1 1 0.0 g (3.93 mmol), ethyl 3-bromopropionate 0.56 ml (4.33 mmol)
And anhydrous potassium carbonate 543 mg (3.93 mmol)
Was added to 20 ml of DMF and heated at 110 ° C. for 5 hours.
Then, ethyl 3-bromopropionate and anhydrous potassium carbonate were added in an amount of 1 equivalent each, and the mixture was heated at 110 ° C. overnight. After completion of the reaction, the mixture was allowed to cool, and water and ethyl acetate were added for extraction. The ethyl acetate layer was washed twice with saturated saline,
It was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was recrystallized from diethyl ether to obtain 400 mg of the target compound.

The structure and physical properties of the obtained compound are shown in Table 1 as Compound 32.

[0074]

Example 33 Ethyl 3- (4-fluorophenyl)-
Preparation of 7-hydroxy-2- (2-pyridyl) -pyrazolo [1,5-a] -pyrimidine-6-carboxylate 5 g (19.7 mmol) of compound 1 and 4.5 g (2
50 ml of acetic acid was added to (0.8 mmol) diethyl ethoxymethylenemalonate, and the mixture was heated under reflux for 7 hours. After the reaction, the reaction mixture was concentrated under reduced pressure, the produced crystals were collected by filtration, and washed with diethyl ether to obtain 6.5 g of the objective compound.

The structure and physical properties of the obtained compound are shown in Table 1 as Compound 33.

[0076]

Example 34 3- (4-Fluorophenyl) -7-hydroxy-2- (2-pyridyl) -pyrazolo [1,5-
a] -Production of pyrimidine-6-carboxylic acid 4.5 g (11.9 mmol) of Compound 1 was dissolved in 60 ml of ethanol, 40 ml of 12.5% sodium hydroxide aqueous solution was added, and the mixture was heated at 80 ° C for 4 hours. The reaction solution was allowed to cool, hydrochloric acid was added dropwise to adjust the pH to about 4, and the resulting precipitate was collected by filtration and washed with methanol and then diethyl ether to obtain 3.6 g of the target compound.

The structure and physical properties of the obtained compound are shown in Table 1 as compound 34.

[0078]

Example 35 Compound 35 shown in Table 1 was produced in the same manner as in Example 1. The structure and physical properties of the obtained compound are also shown in Table 1.

[0079]

Example 36 In the same manner as in Example 25, the compound 36 shown in Table 1 was prepared. The structure and physical properties of the obtained compound are also shown in Table 1.

[0080]

Example 37 In the same manner as in Example 31, the compound 37 shown in Table 1 was prepared. The structure and physical properties of the obtained compound are also shown in Table 1.

[0081]

[Embodiments 38 and 39]
Compound 38 and compound 39 shown in the table were produced. The structure and physical properties of the obtained compound are also shown in Table 1.

[0082]

[Table 1]

[0083]

[Table 2]

[0084]

[Table 3]

[0085]

[Table 4]

[0086]

[Table 5]

[0087]

[Table 6]

[0088]

[Table 7]

[0089]

[Table 8]

[0090]

[Table 9]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical indication location A61K 31/505 7252-4C C07D 401/14 231 8829-4C 405/14 8829-4C 487/04 142 7019-4C // (C07D 487/04 231: 00 6701-4C 239: 00) 7038-4C (72) Inventor Masatoshi Inai 1 of 554, Oza-gun, Dosei-cho, Itano-gun, Tokushima Prefecture

Claims (1)

What is claimed is: 1. A general formula: [Wherein R ¹ is a pyridyl group or a substituent selected from a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a halogen-substituted lower alkyl group, a halogen atom, a phenyl group, a phenylthio group and a methylenedioxy group.
R ² is a pyridyl group or a group —NHR ⁵ (R ⁵ is a hydrogen atom, a lower alkyl group, a lower alkanoyl group or a formyl group),
³ represents a pyridyl group, R ⁴ represents a hydrogen atom, a lower alkanoyl group, a lower alkoxycarbonyl group or a phenyl lower alkoxycarbonyl group, and R ³ and R
⁴ are bonded to each other to form a group (N is 1 or 2) or a group (R ⁶ represents a hydrogen atom or a lower alkyl group) may be formed. ] The pyrazole derivative represented by these.