JPH05345768A - New triazol compound and antifungal agent containing the same compound as active ingredient - Google Patents

Abstract

PURPOSE:To obtain a new compound useful as an antifungal agent for treating fungal infection of human or animals. CONSTITUTION:A compound of formula I [R1 is phenyl substitutable with halogen; R2 is lower alkyl; R3 and R4 are H or lower alkyl; R5 is haloalkyl, lower alkynyl, OH, lower alkoxy, etc.; A is lower alkenylene, C(O), NHC(O), etc.; m is 0-2; n is 1-3], e.g. S-[(1RS,2RS)-2-(2,4-difluorophenyl)-2-hydroxy-1- methyl-3-(1,2,4-triazol-1-yl)-propyl]mercaptoacetic acid ethyl ester. The compound of formula I is obtained by reacting a compound of formula II with a compound of formula III in the presence of a base (e.g. NaOH), in a solvent (e.g. ethanol- water), at -20 deg.C to boiling point of the solvent for 0.5-48hr.

Description

Detailed Description of the Invention

[0001]

The present invention relates to general formula (I):

[Chemical 17] [In the formula, R ₁ represents a phenyl group which may be substituted with 1 to 3 halogen atoms, R ₂ represents a lower alkyl group, and R ₃ and R ₄ are the same or different and each is a hydrogen atom or a lower alkyl group. R ₅ is a haloalkyl group, a lower alkynyl group, a hydroxy group, a lower alkoxy group, a nitrile group, an optionally substituted phenyl group or the formula —NR ₆ R
₇ (In the formula, R ₆ and R ₇ are the same or different and each is a hydrogen atom,
A lower alkyl group, an optionally substituted phenyl group, a lower alkylcarbonyl group, an optionally substituted benzoyl group, or R ₆ and R _{7 taken} together are blocked by an oxygen atom or a nitrogen atom Represents an alkylene group which may be present. ) Is a group represented by the formula (A), A is a lower alkenylene group,

[Chemical 18] (In the formula, R ₈ represents a hydrogen atom or a lower alkyl group.)
Represents a group represented by or a single bond, m represents an integer of 0, 1 to 2, and n represents an integer of 1 to 3. ] It is related with the triazole compound represented by these, its manufacturing method, and the antifungal agent which uses this compound or the pharmaceutically acceptable salt of this compound as an active ingredient.

[0002]

2. Description of the Related Art The fact that a compound similar in structure to the compound of the present invention has antifungal activity is disclosed in JP-A-61-143368,
JP-A-61-85369, European Patent Application Publication No. 421
No. 210A2 (1990.9.22). However, not all of these conventionally known compounds are completely satisfactory.

[0003]

DISCLOSURE OF THE INVENTION Under the above circumstances, the present inventors have conducted earnest studies to provide an antifungal agent, and as a result, represented by the general formula (I) showing an antifungal action at a low dose. The present invention has been completed and the present invention has been completed. Furthermore, the compound of the present invention is also useful as an agricultural fungicide.

In the definition of the substituent of the general formula (I), the alkyl group means a methyl group, an ethyl group, an isopropyl group, an n-propyl group, an n-butyl group, an i-butyl group, s.
-Butyl group, n-pentyl group, n-hexyl group and the like, and the alkoxy group is methoxy group, ethoxy group, n-propoxy group, n-butoxy group, i-butoxy group, s-butoxy group, n-pentyloxy group. Group, n-hexyloxy group and the like.

In the compound represented by the general formula (I), when R ₃ and R ₄ are the same, the compound represented by the general formula (I) contains two asymmetric centers, so that a pair of It exists as a diastereomer, and each diastereomer is composed of a pair of enantiomers. Therefore, it exists as four types of stereoisomers. When R ₃ and R ₄ are different, since three asymmetric centers are included, eight kinds of stereoisomers are possible.
The compound represented by the general formula (I) of the present invention includes those in which these diastereomers and enantiomers are separated and a mixture thereof.

The compound represented by the general formula (I) of the present invention can be used as it is or in the form of an acid addition salt thereof as an antifungal agent. Examples of the acid used include hydrochloric acid, sulfuric acid, nitric acid and the like. Inorganic acids, organic acids such as oxalic acid and methanesulfonic acid.

The compound represented by the general formula (I) can be synthesized, for example, by the method shown below. Method A

[Chemical 19] (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , A, m and n
Is the same as above. )

That is, it can be obtained by reacting the compound represented by the general formula (II) with the compound represented by the general formula (III) in the presence of a base in an inert solvent. The organic solvent that can be used in this reaction may be any one that does not inhibit the progress of this reaction, for example, methanol, ethanol, acetonitrile, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, water and a combination of solvents selected from these. Mixed solvents can be used. As the base that can be used, sodium hydroxide, sodium hydride, calcium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide,
Tetrabutylammonium fluoride and the like can be mentioned, and these can be used as a solid or dissolved in a solvent. The amount of base used is the general formula
It may be used in an amount of 1 mol or more based on the compound represented by (III). The reaction temperature may be appropriately selected from -20 ° C to the boiling point range of the solvent. The reaction time varies depending on the reaction temperature and the reaction scale, but may be appropriately selected from the range of 0.5 to 48 hours. The molar ratio of the reaction reagents in carrying out this reaction is equimolar so that they may be used in equimolar amounts, but either one may be used in excess.

Method B

[Chemical 20] (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , A, m and n
Is the same as above, and X is a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group or the like. )

That is, it can be obtained by reacting the compound represented by the general formula (IV) with the compound represented by the general formula (V) in the presence of a base in an inert solvent. The organic solvent that can be used in this reaction may be any one that does not inhibit the progress of this reaction, for example, methanol, ethanol, acetonitrile, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, water and a combination of solvents selected from these. Mixed solvents can be used. As the base that can be used, sodium hydroxide, sodium hydride, calcium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide,
Tetrabutylammonium fluoride and the like can be mentioned, and these can be used as a solid or dissolved in a solvent. The amount of base used is the general formula
It may be used in an amount of 1 mol or more based on the compound represented by (IV). The reaction temperature may be appropriately selected from -20 ° C to the boiling point range of the solvent. The reaction time varies depending on the reaction temperature and the reaction scale, but may be appropriately selected from the range of 0.5 to 48 hours. The molar ratio of the reaction reagent in carrying out this reaction is equimolar, so it may be used equimolar.
Either one may be used in excess.

Method C

[Chemical 21] (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , A, X, m and n are the same as above.)

That is, it can be obtained by reacting the compound represented by the general formula (VI) with the compound represented by the general formula (III) in the presence of a base in an inert solvent. The organic solvent that can be used in this reaction may be any one that does not inhibit the progress of this reaction, for example, methanol, ethanol, acetonitrile, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, water and a combination of solvents selected from these. Mixed solvents can be used. As the base that can be used, sodium hydroxide, sodium hydride, calcium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide,
Tetrabutylammonium fluoride and the like can be mentioned, and these can be used as a solid or dissolved in a solvent. The amount of base used is the general formula
It may be used in an amount of 1 mol or more based on the compound represented by (III). The reaction temperature may be appropriately selected from -20 ° C to the boiling point range of the solvent. The reaction time varies depending on the reaction temperature and the reaction scale, but may be appropriately selected from the range of 0.5 to 48 hours. The molar ratio of the reaction reagents in carrying out this reaction is equimolar so that they may be used in equimolar amounts, but either one may be used in excess.

Method D

[Chemical formula 22] (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , A, m and n
Is the same as above. )

That is, it can be obtained by reacting the compound represented by the general formula (VII) with 1,2,4-triazole in the presence of a base in an inert solvent. The organic solvent that can be used in this reaction may be any one that does not inhibit the progress of this reaction, for example, methanol, ethanol, acetonitrile, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, water and a combination of solvents selected from these. Mixed solvents can be used. As the base that can be used, sodium hydroxide, sodium hydride, calcium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide,
Tetrabutylammonium fluoride and the like can be mentioned, and these can be used as a solid or dissolved in a solvent. The amount of base used is the general formula
It may be used in an amount of 1 mol or more based on the compound represented by (VII). The reaction temperature may be appropriately selected from -20 ° C to the boiling point range of the solvent. The reaction time varies depending on the reaction temperature and the reaction scale, but may be appropriately selected from the range of 0.5 to 48 hours. The molar ratio of the reaction reagents in carrying out this reaction is equimolar so that they may be used in equimolar amounts, but either one may be used in excess.

Method E

[Chemical formula 23] (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , A, m and n
Is the same as above)

In method A and method D, m =
In the case of 0, the product obtained is reacted with a suitable oxidizing agent to give a compound of m = 1,2. Examples of the oxidizing agent used in this reaction include hydrogen peroxide and peracids such as perbenzoic acid. Sodium tungstate or the like may be used as a catalyst to accelerate the reaction. The organic solvent that can be used in this reaction may be any one that does not inhibit the progress of this reaction, for example, methanol, ethanol, acetonitrile, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, water and a combination of solvents selected from these. Mixed solvents can be used.
As the base that can be used, sodium hydroxide, sodium hydride, calcium carbonate, sodium methoxide,
Sodium ethoxide, potassium tert-butoxide, tetrabutylammonium fluoride and the like can be mentioned, and these can be used as a solid or can be used after being dissolved in a solvent. Reaction temperature is -20
It may be appropriately selected from the range of ° C to the boiling point of the solvent. The reaction time varies depending on the reaction temperature and the reaction scale, but is 0.5
It may be appropriately selected from the range of 48 hours to 48 hours.

After completion of the reaction, the desired product is purified by a conventional method, but the diastereomers are separated by a conventional method such as fractional recrystallization or column chromatography.
Enantiomers are separated by a conventional method such as a column for separating optical isomers. General formula (II), (IV), (V
The compounds represented by I) and (VII) are described in European Patent Application Publication No. 4
21210A2, Chem. Pharm. Bull. (1990), 3
8 , 2476 to 2486, Chem. Pharm. Bull. (1990), 39 , 2241.
No. 2246, JP-A No. 03-128338.

Representative examples of the compound represented by formula (I) are shown in Table 1, but the present invention is not limited to these.

[Table 1]

[0019]

[Table 2]

[0020]

[Table 3]

[0021]

[Table 4]

[0022]

EXAMPLES Examples of the present invention are shown below, but the present invention is not limited to these.

Example 1 S-[(1RS, 2RS) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1,
Preparation of 2,4-triazol-1-yl) -propyl] mercaptoacetic acid ethyl ester (Compound No. 6) (2RS, 3RS) -2- (2,4-difluorophenyl) -3- (methylsulfonyloxy) -1- (1,
0.7 g of 2,4-triazol-1-yl) -butan-2-ol was dissolved in 20 ml of ethanol, 0.8 g of sodium ethoxide and 1.1 g of ethyl thioglycolate were added, and the mixture was refluxed for 3 hours. After cooling to room temperature,
It was poured into ice water and neutralized with dilute hydrochloric acid. The aqueous solution was extracted with ethyl acetate, the organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.5 g of the desired product as an oil.

Example 2 S-[(1RS, 2RS) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1,
Preparation of 2,4-triazol-1-yl) -propyl] mercaptoacetic acid (Compound No. 5) S-[(1RS, 2RS) -2- (2,4-difluorophenyl) -2-hydroxy-1- Methyl-3- (1,
2,4-Triazol-1-yl) -propyl] mercaptoacetic acid ethyl ester 1.5
g was dissolved in a mixed solvent of 20 ml of water and 10 ml of ethanol, 0.5 g of sodium hydroxide was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was neutralized with diluted hydrochloric acid and extracted with dichloromethane. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was crystallized with diethyl ether to obtain 1.0 g of the desired product. Melting point 146 ~
148 ° C.

Example 3 4- [S- (1RS, 2RS) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3-
(1,2,4-Triazol-1-yl) -propyl]
Preparation of mercaptoacetyl] morpholine (Compound No. 5) S-[(1RS, 2RS) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1,
2,4-triazol-1-yl) -propyl] mercaptoacetic acid 0.3 g was added to dioxane 10
Dissolve in ml, N-hydroxysuccinimide 0.15
g and 0.27 g of dicyclohexylcarbodiimide were added, and the mixture was stirred at room temperature for 19 hours. Next, 0.15 g of morpholine was added dropwise at room temperature and then stirred at room temperature for 1 hour. The insoluble matter was filtered off, and the filtrate was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.2 g of the desired product as an oil.

Example 4 S-((1RS, 2RS) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1,
Production of 2,4-triazol-1-yl) -propyl] mercaptoacetonitrile (Compound No. 20) (2RS, 3RS) -2- (2,4-difluorophenyl) -3-mercapto-1- (1,2,2) To 0.2 g of 4-triazol-1-yl) -butan-2-ol, 3.2 ml of a sodium methoxide solution prepared by adding 85 ml of methanol to 0.85 g of sodium and stirring until dissolved and 0.11 g of chloroacetonitrile were added. Two
Stir for hours. After completion of the reaction, the mixture was concentrated under reduced pressure, neutralized with 1N hydrochloric acid, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give the desired compound 0.16.
g was obtained as an oil.

Example 5 [(1RS, 2RS) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1,2,2
4-Triazol-1-yl) -propyl] sulfonylacetonitrile (Compound No. 17) S-((1RS, 2RS) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1 ，
2,4-triazol-1-yl) -propyl] mercaptoacetonitrile 0.32 g and methanol 10 ml
It is dissolved in a mixed solvent of 1 ml of water and water, 0.10 g of sodium tungstate is added, and 0.33 g of 31% hydrogen peroxide is added.
Was added dropwise, and the mixture was stirred at 55 ° C. for 5 hours. After cooling to room temperature 5
% Sodium thiosulfate 0.10 g was added.
Methanol was distilled off under reduced pressure, extracted with ethyl acetate, washed with water,
It was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained oil was purified by silica gel column chromatography to obtain 0.2 g of the desired product as an oil.

Example 6 N-2,4-difluorophenyl S-[(1RS, 2
RS) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1,2,4-triazol-1-yl) -propyl] mercaptoacetamide
(Compound No. 8) (2RS, 3RS) -2- (2,4
0.4 g of -difluorophenyl) -3-methylsulfonyloxy-1- (1,2,4-triazol-1-yl) -butan-2-ol is dissolved in 30 ml of ethanol and then with 0.55 g of sodium ethoxide. 0.93 g of 2,4-difluoroanilide thioglycolic acid was added at room temperature and refluxed for 5 hours. After cooling to room temperature, it was poured into ice water and neutralized with 6N hydrochloric acid water. It was extracted with dichloromethane, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained oily substance was purified by silica gel column chromatography to obtain 0.4 g of the desired product.
Melting point 126-128 [deg.] C.

The compounds of the present invention are antifungal agents useful in treating fungal infections of humans and animals. For example, they can be used for treating local fungal infections, mucosal infections and systemic fungal infections caused by Trichophyton, Candida, Aspergillus and the like. The compound of the present invention is a dosage form suitable for oral or parenteral administration of a composition consisting of an inert carrier or diluent which is singly or pharmaceutically acceptable, such as a solution, tablet, suppository, emulsifier, ointment, It is used after adjusting to creams, lotions, poultices, etc. The dose varies depending on symptoms, age, body weight, administration form, etc., but in the case of systemic treatment, it is usually 0.05 to 100 mg, preferably 0.5 to 50 mg once or several times per 1 kg of body weight per adult per day. It can be administered in divided doses. The concentration of the active ingredient in topical treatment is optimally 0.001% to 5%, preferably 0.1 to 2%.

Formulation examples are shown below, but the present invention is not limited thereto. In addition, a part represents a weight part. Formulation Example 1 0.01 part of the compound of the present invention was suspended in 99.9 parts of 0.5% carboxymethylcellulose aqueous solution to obtain a suspension. Formulation Example 2 The compound of the present invention 1 part Polyethylene glycol 400 99 parts was mixed and dissolved to obtain a coating liquid agent.

Formulation Example 3 Compound of the present invention 2 parts Polyethylene glycol 400 49 parts Polyethylene glycol 4000 49 parts were mixed and dissolved under heating and then cooled to obtain an ointment. Formulation Example 4 Compound of the present invention 3 parts 1,2 Propanediol 5 parts Glycerol stearate 5 parts Whale wax 5 parts Isopropyl myristate 10 parts Polysorbate 4 parts A mixture of warming, cooling and then stirring with water 68
Part was added to make a cream.

Formulation Example 5 Compound of the present invention 0.1 part Stearyl alcohol 5.0 parts Cetanol 5.0 parts Medium chain fatty acid triglyceride 10.0 parts Isopropyl myristate 5.0 parts Polysorbate 60 4.0 parts Sorbitan monostearate 1 0.0 part Methyl paraoxybenzoate 0.14 part Propyl paraoxybenzoate 0.06 part Dibutylhydroxytoluene 0.02 part Purified water The balance was adjusted according to a conventional method.

Test Example 1 Six-week-old male ddY mice were tested as a control group of 10 mice and a drug administration group of 5 mice per group. It was precultured at 37 ° C. for 24 hours in Candida GE medium (manufactured by Nissui Pharmaceutical Co., Ltd.). C. alb
Suspend icans IFO 1270 in physiological saline and 1 × 10 ⁸ c
Tail vein was administered at a dose of ells / kg. The reagent is 0.5
% Carboxymethylcellulose aqueous solution to a predetermined concentration and was orally administered 30 minutes before inoculation of the bacteria at a rate of 5 ml / kg. After that, it was orally administered once a day for 3 consecutive days. The survival number was investigated on the 10th day from the day of inoculation.
The results are shown in Table 2.

[0034]

[Table 5] Table 2 ──────────────────────── Compound number Survival rate (%) (dose 1 mg / kg) ─────── ───────────────── 7 80 9 100 100 10 80 11 11 100 12 80 13 100 100 18 100 20 20 100 21 100 100 23 100 ────────────── ─────────── Control group (no administration) 0 ────────────────────────

Test Example 2 Aspergillus fumigatus TIMM 0063 Conidia Solution 0.1
ml (10 ⁶ cells / ml, physiological saline supplemented with 0.1% Tween 80) was added to 9.8 ml of B-YNG medium L
Mold test tube. Next, 0.1 ml of a DMSO solution of the test compound diluted to a predetermined concentration was added, and the mixture was shake-cultured at 37 ° C. for 48 hours. Sterilize the culture by boiling and then use glass fiber fi
The cells were collected on the lter. The dry weight of the cells was measured to determine the growth inhibition rate relative to the control. The results are shown in Table 3.

[0036]

[Table 6] Table 3 ──────────────────────── Compound No. Survival rate (%) (Dose 1 mg / kg) ──────── ───────────────── 7 100 9 9 100 10 100 100 11 100 12 100 100 13 100 18 18 100 20 100 21 21 100 23 100 24 24 100 ─────────── ──────────────

[0037]

INDUSTRIAL APPLICABILITY The triazole derivative of the present invention is an antifungal agent useful for treating fungal infections of humans and animals.

Claims (5)

[Claims] 1. General formula (I): [In the formula, R ₁ represents a phenyl group which may be substituted with 1 to 3 halogen atoms, R ₂ represents a lower alkyl group, and R ₃ and R ₄ are the same or different and each is a hydrogen atom or a lower alkyl group. R ₅ is a haloalkyl group, a lower alkynyl group, a hydroxy group, a lower alkoxy group, a nitrile group,
An optionally substituted phenyl group or a formula —NR ₆ R ₇
(In the formula, R ₆ and R ₇ are the same or different and each represents a hydrogen atom, a lower alkyl group, an optionally substituted phenyl group, a lower alkylcarbonyl group, an optionally substituted benzoyl group, or R ₆ And R ₇ together represent an alkylene group which may be blocked by an oxygen atom or a nitrogen atom), and A is a lower alkenylene group, (In the formula, R ₈ represents a hydrogen atom or a lower alkyl group.)
Represents a group represented by or a single bond, m represents an integer of 0, 1 to 2, and n represents an integer of 1 to 3. ] The triazole compound represented by these. 2. General formula (II): (In the formula, R ₁ represents a phenyl group which may be substituted with 1 to 3 halogen atoms, and R ₂ represents a lower alkyl group.) And a compound represented by the general formula (III): ] [In the formula, R ₃ and R ₄ are the same or different and each represents a hydrogen atom or a lower alkyl group, and R ₅ is a haloalkyl group, a lower alkynyl group, a hydroxy group, a lower alkoxy group, a nitrile group or an optionally substituted phenyl group. Group or formula --NR ₆
R ₇ (wherein R ₆ and R ₇ are the same or different and each represents a hydrogen atom, a lower alkyl group, an optionally substituted phenyl group, a lower alkylcarbonyl group, an optionally substituted benzoyl group, or R ₆ and R ₇ together represent an alkylene group which may be blocked by an oxygen atom or a nitrogen atom), and A is a lower alkenylene group, (In the formula, R ₈ represents a hydrogen atom or a lower alkyl group.)
Represents a group represented by or a single bond, m represents an integer of 0, 1 to 2, and n represents an integer of 1 to 3. ] The compound represented by the general formula (I): (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , A, m and n
Is the same as above. The manufacturing method of the triazole compound represented by these. 3. General formula (IV): (In the formula, R ₁ represents a phenyl group which may be substituted with 1 to 3 halogen atoms, and R ₂ represents a lower alkyl group.) And a compound represented by the general formula (V): ] [In the formula, R ₃ and R ₄ are the same or different and each represents a hydrogen atom or a lower alkyl group, and R ₅ is a haloalkyl group, a lower alkynyl group, a hydroxy group, a lower alkoxy group, a nitrile group or an optionally substituted phenyl group. Group or formula --NR ₆
R ₇ (wherein R ₆ and R ₇ are the same or different and each represents a hydrogen atom, a lower alkyl group, an optionally substituted phenyl group, a lower alkylcarbonyl group, an optionally substituted benzoyl group, or R ₆ and R ₇ together represent an alkylene group which may be blocked by an oxygen atom or a nitrogen atom), and A is a lower alkenylene group, (In the formula, R ₈ represents a hydrogen atom or a lower alkyl group.)
Represents a group represented by or a single bond, m represents an integer of 0, 1 to 2, and n represents an integer of 1 to 3. ] The compound represented by the general formula (I): (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , A, m and n
Is the same as above. The manufacturing method of the triazole compound represented by these. 4. General formula (VI): (In the formula, R ₁ represents a phenyl group which may be substituted with 1 to 3 halogen atoms, R ₂ represents a lower alkyl group, X represents a halogen atom, a methanesulfonyloxy group, p
-Toluenesulfonyloxy group and the like are shown. ) And a compound represented by the general formula (III): [In the formula, R ₃ and R ₄ are the same or different and each represents a hydrogen atom or a lower alkyl group, and R ₅ is a haloalkyl group, a lower alkynyl group, a hydroxy group, a lower alkoxy group, a nitrile group or an optionally substituted phenyl group. Group or formula --NR ₆
R ₇ (wherein R ₆ and R ₇ are the same or different and each represents a hydrogen atom, a lower alkyl group, an optionally substituted phenyl group, a lower alkylcarbonyl group, an optionally substituted benzoyl group, or R ₆ and R ₇ together represent an alkylene group which may be blocked by an oxygen atom or a nitrogen atom), and A is a lower alkenylene group, (In the formula, R ₈ represents a hydrogen atom or a lower alkyl group.)
Represents a group or a single bond represented by, m represents an integer of 0, 1 to 2, and n represents an integer of 1 to 3. ] The compound represented by the general formula (I) characterized by reacting: (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , A, m and n
Is the same as above. The manufacturing method of the triazole compound represented by these. 5. General formula (I): (In the formula, R ₁ represents a phenyl group which may be substituted with 1 to 3 halogen atoms, R ₂ represents a lower alkyl group, and R ₃ and R ₄ are the same or different and are a hydrogen atom or a lower alkyl group. R ₅ is a haloalkyl group, a lower alkynyl group, a hydroxy group, a lower alkoxy group, a nitrile group, an optionally substituted phenyl group or the formula —NR ₆ R
₇ (In the formula, R ₆ and R ₇ are the same or different and each is a hydrogen atom,
A lower alkyl group, an optionally substituted phenyl group, a lower alkylcarbonyl group, an optionally substituted benzoyl group, or R ₆ and R ₇ together are blocked by an oxygen atom or a nitrogen atom Represents an alkylene group which may be present. ), A is a lower alkenylene group, (In the formula, R ₈ represents a hydrogen atom or a lower alkyl group.)
Represents a group represented by or a single bond, m represents an integer of 0, 1 to 2, and n represents an integer of 1 to 3. ] The antifungal agent containing the compound represented by these as an active ingredient.