JPH09183769A - Azole compound and its use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new azole compound useful as an agricultural antifungal agent, having antifungal activity, useful for preventing and treating a mammalian fungus infection. SOLUTION: This compound is shown by formula I (Ar is phenyl which may be replaced; R<1> and R<2> are each H, a lower alkyl or R<1> and R<2> are bonded to form a lower alkylene; R<3> is H or an acyl; X is N or methylene; Y and Z are each N or methylene which may be replaced with a lower alkyl; (n) is 0-2; Az is azolyl which may be replaced) such as 1-[(1R,2R)-2-(2,4- difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3- [4-(1H-1,2,4- triazol-1-yl)phenyl]-2-imidazolidinone. The compound of formula I is obtained by reacting a compound of formula II with a compound of formula III in a solvent (e.g. DMF) preferably in the presence of a base (e.g. sodium hydride) at 0-150 deg.C and optionally acylating the reaction product.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an azole compound useful as a therapeutic agent for fungal diseases, a process for producing the same, and uses thereof.

[0002]

2. Description of the Related Art Various azole compounds having antifungal activity have been reported so far (for example, EP0122056A1 and EP0).
332387A1, EP0122693A1 and EP0567982A etc.).

[0003]

However, these azole compounds are not sufficiently satisfactory as pharmaceuticals in terms of antifungal activity, antifungal spectrum, side effects and pharmacokinetics of drugs. Compounds having higher safety, better absorbability in the body, and stronger antifungal activity have been demanded as therapeutic agents for mycosis.

[0004]

The present invention provides (1) general formula (I)

[0005]

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[In the formula, Ar represents an optionally substituted phenyl group, R ¹ and R ² are the same or different and each represents a hydrogen atom or a lower alkyl group, or R ¹ and R ² are combined to form a lower group. An alkylene group, R ³ is a hydrogen atom or an acyl group, X is a nitrogen atom or a methine group, and A is Y = Z.
(Y and Z are the same or different and each represents a methine group which may be substituted with a nitrogen atom or a lower alkyl group)
Or an ethylene group optionally substituted with a lower alkyl group, n is an integer of 0 to 2, and Az is an optionally substituted azolyl group] or a salt thereof,
(2) (i) Formula (II)

[0007]

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[Wherein Ar represents an optionally substituted phenyl group, R ¹ and R ² are the same or different and each represents a hydrogen atom or a lower alkyl group, or R ¹ and R ² are combined to form a lower group. An alkylene group, A is Y = Z (Y and Z
Are the same or different and each represents a methine group which may be substituted with a nitrogen atom or a lower alkyl group) or an ethylene group which may be substituted with a lower alkyl group, and n is 0.
Az is an optionally substituted azolyl group] or a salt thereof, and a compound of formula (III)

[0009]

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[Wherein X represents a nitrogen atom or a methine group] or a salt thereof is reacted with, and optionally acylated, or (ii) Formula (IV)

[0011]

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[Wherein, Ar is an optionally substituted phenyl group, R ¹ and R ² are the same or different and each is a hydrogen atom or a lower alkyl group, or R ¹ and R ² are combined to form a lower alkylene group. Group, X is a nitrogen atom or a methine group] or a salt thereof, and a compound of the formula (V ′)

[0013]

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[Wherein A "is -N = CH-, -CH = N
-Or-CH = CH-, n is an integer of 0 to 2, Az
Represents an optionally substituted azolyl group] or is reacted with a compound represented by the formula (I '')

[0015]

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[Wherein Ar is an optionally substituted phenyl group, R ¹ and R ² are the same or different and each is a hydrogen atom or a lower alkyl group, or R ¹ and R ² are combined to form a lower alkylene group. Group, R ³ is a hydrogen atom or an acyl group, X is a nitrogen atom or a methine group, n is an integer of 0 to 2, and Az is an optionally substituted azolyl group] or a compound thereof. Method for producing a compound of the above formula (I) or a salt thereof in which a salt is reduced and optionally acylated, and (3) an antifungal agent containing the azole compound represented by the above formula (I) or a salt thereof Alternatively, it provides a pharmaceutical composition and the like.

With respect to the general formula (I), preferable examples of the substituent in the "optionally substituted phenyl group" represented by Ar include halogen (eg, fluorine, chlorine, bromine,
Iodine, etc.), halogenated lower (C _1-4 ) alkyl group, halogenated lower (C _1-4 ) alkoxy group, lower (C _1-4 ) alkylsulfonyl group, halogenated lower (C _1-4 ) alkylsulfonyl group Groups and the like. The substituent is preferably halogen (eg, fluorine, chlorine, bromine, iodine, etc.), and particularly preferably fluorine. The number of substituents is preferably 1 to 3, and more preferably 1 to 2.

Preferred examples of Ar include a halogenophenyl group, a halogenated lower (C _1-4 ) alkylphenyl group, a halogenated lower (C _1-4 ) alkoxyphenyl group,
Examples thereof include lower (C _1-4 ) alkylsulfonylphenyl group and halogenated lower (C _1-4 ) alkylsulfonylphenyl group. Examples of the halogenophenyl group include 2,4-difluorophenyl, 2,4-dichlorophenyl, 4-chlorophenyl, 4-fluorophenyl and 2-
Examples thereof include chlorophenyl, 2-fluorophenyl, 2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, 2,4,6-trifluorophenyl and 4-bromophenyl.

Examples of the halogenated lower (C _1-4 ) alkylphenyl group include 4-trifluoromethylphenyl and the like. Examples of the halogenated lower (C _1-4 ) alkoxyphenyl group include 4-trifluoromethoxyphenyl, 4- (1,1,2,2-tetrafluoroethoxy) phenyl, 4- (2,2,2- Trifluoroethoxy) phenyl, 4- (2,2,3,3-tetrafluoropropoxy) phenyl, 4- (2,2,3,3,
3-pentafluoropropoxy) phenyl and the like can be mentioned.

Examples of the lower (C _1-4 ) alkylsulfonylphenyl group include 4-methanesulfonylphenyl and the like. Examples of the halogenated lower (C _1-4 ) alkylsulfonylphenyl group include 4- (2,2,2)
2-trifluoroethanesulfonyl) phenyl, 4-
Examples include (2,2,3,3-tetrafluoropropanesulfonyl) phenyl and 4- (2,2,3,3,3-pentafluoropropanesulfonyl) phenyl.

Specifically, Ar is a phenyl group substituted with 1 to 2 halogens, for example, 2,
4-difluorophenyl, 2,4-dichlorophenyl,
4-chlorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-fluorophenyl, 2-fluoro-4
-Chlorophenyl, 2-chloro-4-fluorophenyl, 4-bromophenyl and the like are preferable, and among them, 4
-Fluorophenyl, 2-fluorophenyl, 2,4-
Phenyl substituted with 1 or 2 fluorine atoms such as difluorophenyl is preferable, and more preferably 2-
Examples thereof include fluorophenyl and 2,4-difluorophenyl.

With respect to the general formula (I), preferred examples of the lower alkyl group represented by R ¹ or R ² include methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
Examples thereof include sec-butyl and tert-butyl linear or branched alkyl groups having 1 to 4 carbon atoms, of which methyl and the like are preferable. Both R ¹ and R ² are preferably a hydrogen atom, a hydrogen atom and methyl, a combination of methyl and methyl, and the like.

Examples of the lower alkylene group represented by R ¹ and R ^{2 in} combination include linear lower (C _2-4 ) alkylene groups such as ethylene, propylene and butylene, among which ethylene and the like. Is preferred. As R ¹ and R ² , one is preferably a hydrogen atom and the other is a C _1-4 alkyl group such as methyl.

With respect to the general formula (I), preferable examples of the acyl group represented by R ³ include an acyl group derived from an organic carboxylic acid, for example, an alkanoyl group, preferably an alkanoyl group having 1 to 7 carbon atoms. Groups (eg formyl,
Acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyl, etc.), particularly preferably an alkanoyl group having 1 to 3 carbon atoms; an arylcarbonyl group, preferably an arylcarbonyl group having 7 to 15 carbon atoms (eg, benzoyl, naphthalenecarbonyl) Etc.) Particularly preferably, an arylcarbonyl group having 7 to 11 carbon atoms;
Alkoxycarbonyl group, preferably an alkoxycarbonyl group having 2 to 7 carbon atoms (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, etc.), Particularly preferably an alkoxycarbonyl group having 2 to 4 carbon atoms; an aryloxycarbonyl group, preferably an aryloxycarbonyl group having 7 to 15 carbon atoms (eg, phenoxycarbonyl etc.), particularly preferably an aryloxycarbonyl group having 7 to 11 carbon atoms. Group; an aralkylcarbonyl group, preferably an aralkylcarbonyl group having 8 to 20 carbon atoms (eg, benzylcarbonyl, phenethylcarbonyl, phenylpropylcarbonyl, naphthylethylcarbonyl, etc.), particularly preferably An aralkylcarbonyl group having 8 to 14 carbon atoms and the like are preferable.

The above-mentioned acyl group is preferably one that can be hydrolyzed in vivo. Specific examples thereof include formyl, acetyl, benzoyl, benzylcarbonyl and the like. R ³ is preferably a hydrogen atom. Regarding the general formula (I), the nitrogen atom represented by X or the methine group is preferably a nitrogen atom. Regarding the general formula (I), A
When Y = Z, examples of the lower alkyl group in the “methine group optionally substituted with a lower alkyl group” represented by Y or Z include a straight chain or branched chain having 1 to 4 carbon atoms. Alkyl groups (methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t
ert-butyl), of which methyl is preferred.

[0026] Preferred examples of Y or a lower alkyl methine group optionally substituted with a group represented by Z, methine, ethylidyne _{(-C (CH 3) =)} , pro pyridine (-C (CH ₃ CH ₂ ) =), butyridine (-C (CH ₂
CH ₃ CH ₂ ) =) and the like, among which methine and ethylidin are particularly preferable, and methine and the like are particularly preferable. One of Y and Z is a nitrogen atom and the other is methine; both Y and Z are methine;
Both Y and Z are nitrogen atoms; it is preferable that one of Y and Z is a nitrogen atom and the other is ethylidin, etc. In particular, one of Y and Z is a nitrogen atom and the other is methine. Or both Y and Z are preferably methine.

In the general formula (I), when A is "ethylene group optionally substituted with lower alkyl group", examples of the lower alkyl group include straight or branched chain having 1 to 4 carbon atoms. Alkyl groups (methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl), among which methyl and ethyl are preferable, and methyl is more preferable.

Preferred examples of the ethylene group which may be substituted with a lower alkyl group represented by A include ethylene, 1-methylethylene, 1,1-dimethylethylene,
1,2-dimethylethylene, 1-ethylethylene, 1,
2-diethylethylene and the like can be mentioned, with ethylene and the like being particularly preferable. Specifically, as A, -N = CH-,
-CH = N-, -CH = CH-, -N = N-, -N = C
_{(CH 3) -, - C} (CH 3) = N -, - CH 2 -CH 2 -
And the like, especially -N = CH-, -CH = N-,
_{-CH = CH -, - CH 2} -CH 2 - and the like are preferable.

Regarding the general formula (I),

[0030]

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The group represented by

[0032]

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And the like are preferable, and

[0034]

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And the like are preferable, and

[0036]

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Etc. are preferred. The integer of 0 to 2 represented by n is preferably 0 or 1, and particularly preferably 0.

With respect to the general formula (I), examples of the azolyl group in the "optionally substituted azolyl group" represented by Az include 1 to 4 nitrogen atoms as ring-constituting atoms, and further contains sulfur. 5-membered aromatic heterocyclic groups which may contain a hetero atom selected from an atom and an oxygen atom as a ring-constituting atom, and specific examples thereof include pyrrolyl, pyrazolyl, imidazolyl, 1,2,3- Triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, flazanil, 1,3,4-thiadiazolyl, 1,
2,3-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,4-thiadiazolyl and the like can be mentioned.

Examples of the azolyl group include pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,
2,4-triazolyl, tetrazolyl and the like are preferable, more preferably 1H-pyrazol-1-yl,
1H-imidazol-1-yl, 1H-1,2,3-triazol-1-yl, 2H-1,2,3-triazol-2-yl, 1H-1,2,4-triazole-1-
Yl, 4H-1,2,4-triazol-4-yl, 1
H-tetrazol-1-yl, 2H-tetrazol-2-yl and the like, particularly preferably 1H-pyrazol-1-yl, 1H-1,2,3-triazol-1-yl, 2H-1,2,2. 3-triazol-2-yl, 1H
-1,2,4-triazol-1-yl, 1H-tetrazol-1-yl, 2H-tetrazol-2-yl and the like.

Examples of the substituent in the above-mentioned "azolyl group which may have a substituent" represented by Az are:
Hydroxyl group, carboxyl group that may be esterified (eg, C1-C6 alkoxycarbonyl such as carboxyl, methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, etc.), nitro group, amino group, acylamino group (eg, acetylamino) , Alkanoylamino having 1 to 10 carbon atoms such as propionylamino and butyrylamino), and an amino group mono- or di-substituted with an alkyl group having 1 to 10 carbon atoms (eg, methylamino, dimethylamino, diethylamino, dibutylamino, etc.) , Carbon number 1
6 alkyl groups (eg methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, pentyl, hexyl etc.), alkoxy groups having 1 to 6 carbon atoms (eg methoxy, ethoxy, butoxy etc.), Halogen atom (eg fluorine, chlorine, bromine, etc.), halogeno-C1
~ 6 alkyl groups (eg, trifluoromethyl, dichloromethyl, 2,2,2-trifluoroethyl, 2,2,2
3,3-tetrafluoropropyl, etc.), halogeno-alkoxy group having 1 to 6 carbon atoms (eg, trifluoromethoxy,
1,1,2,2-tetrafluoroethoxy, 2,2,2
-Trifluoroethoxy, 2,2,3,3-tetrafluoropropoxy, 2,2,3,3,3-pentafluoropropoxy, 2,2,3,3,4,4,5,5-octafluoropen Toxy, 2-fluoroethoxy, etc.), oxo group, thioxo group, mercapto group, alkylthio group having 1 to 6 carbon atoms (eg, methylthio, ethylthio, butylthio, etc.), alkylsulfonyl group having 1 to 6 carbon atoms (eg, methane) Sulfonyl, ethanesulfonyl, butanesulfonyl, etc.), alkanoyl group having 1 to 10 carbon atoms (eg, acetyl, formyl, propionyl, butyryl, etc.), phenyl group, phenyl group substituted by alkyl group having 1 to 6 carbon atoms (eg, : P-tolyl, mesityl, p-cumenyl, etc.), a phenyl group substituted with an alkoxy group having 1 to 6 carbon atoms (eg:
4-methoxyphenyl, 4-isopropoxyphenyl, etc.), a phenyl group substituted with a halogen atom (eg, 4-
Chlorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, etc.), a phenyl group substituted with a haloalkyl group having 1 to 6 carbon atoms (eg, 4-trifluoromethylphenyl, etc.), haloalkoxy having 1 to 6 carbon atoms. A phenyl group substituted with a group [eg, 4-trifluoromethoxyphenyl, 4- (2,2,3,3-tetrafluoropropoxy) phenyl, 4- (1,1,2,2-tetrafluoroethoxy) phenyl Etc.] etc. are mentioned. These substituents may be substituted on the ring-constituting carbon atom and / or the ring-constituting nitrogen atom of the azolyl group, and the number thereof is preferably 1 or 2.

Specifically, as Az,

[0042]

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Preferred are diazolyl, triazolyl, tetrazolyl and the like, and especially

[0044]

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And the like are preferred. Preferable examples of the compound (I) include compounds represented by the formula (I ′)

Embedded image [In the formula, Ar ′ is a monofluorophenyl (eg, 2-fluorophenyl, etc.) or difluorophenyl group (eg, 2,
4-difluorophenyl etc.) and A ′ is —N═CH
-, - CH = CH- or -CH ₂ -CH ₂ - and is, A
z ′ is an oxo group, a C _1-6 alkyl group (eg, methyl, ethyl, n-propyl, isopropyl, etc.), halogenated C
_1-6 alkyl group (eg trifluoromethyl, 2,2,2
- trifluoroethyl, 2,2,3,3-tetrafluoro propyl, etc.) and halogenated C _1-6 alkoxyphenyl group (e.g. 4-trifluoromethoxyphenyl, 4-
(2,2,3,3-tetrafluoropropoxy) phenyl, 4- (1,1,2,2-tetrafluoroethoxy)
And a salt thereof, which is a diazolyl, triazolyl, tetrazolyl, thiazolyl or oxazolyl group which may be substituted with 1 or 2 substituents selected from the group consisting of phenyl etc.). Especially A 'as the -CH ₂ -CH ₂ - are preferred, Az'
Is preferably triazolyl or tetrazolyl.
The compounds (I) and (I ′) are also used as salts. Such salts include pharmacologically acceptable salts, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid. Salt of
Examples thereof include salts with organic acids such as acetic acid, tartaric acid, citric acid, fumaric acid, maleic acid, toluenesulfonic acid and methanesulfonic acid. When the compound (I) has a carboxyl group as a substituent, it may be an alkali metal (sodium, potassium, etc.) salt.

The compound represented by the general formula (I) or a salt thereof (hereinafter abbreviated as the compound of the present invention) has one or more asymmetric carbon atoms in the molecule, and therefore has two or more stereoisomers. Although the body exists, any of its stereoisomers as well as a mixture thereof are included in the present invention. Especially R
^{When 1} is a hydrogen atom and R ² is a methyl group, both the carbon to which an optionally substituted phenyl group represented by Ar is bonded and the carbon to which R ² is bonded are in the (R) configuration. The body or the like is preferable.

The compound of the present invention has, for example, the general formula (II)

[0048]

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[Wherein the symbols have the same meanings as defined above] or a salt thereof, and a compound of the general formula (III)

[0050]

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It can be produced by reacting with a compound represented by the formula [wherein the symbols have the same meaning as defined above] or a salt thereof. By this reaction, the compound of the present invention in which R ³ is a hydrogen atom is obtained. This reaction is usually performed in a solvent that does not inhibit the reaction. Examples of the solvent that does not inhibit the reaction include water and ketones (eg:
Acetone etc.), Sulfoxides (eg dimethyl sulfoxide etc.), Ethers (eg diethyl ether, tetrahydrofuran, dioxane etc.), Nitriles (eg acetonitrile etc.), Aromatic hydrocarbons (eg benzene, toluene, xylene) Etc.), halogenated hydrocarbons (eg dichloromethane, chloroform, 1,2-dichloroethane etc.), esters (eg ethyl acetate etc.), amides (eg dimethylformamide, acetamide, dimethylacetamide, 1-methyl-). 2-pyrrolidinone and the like, ureylenes (eg, 1,3-dimethyl-2-imidazolidinone and the like) and the like are used. These may be used alone or as a mixture of two or more at an appropriate ratio.

In this reaction, for example, alkali metal hydroxide (eg, lithium hydroxide, potassium hydroxide, sodium hydroxide, etc.), alkali metal hydride (eg, potassium hydride,
Sodium hydride etc.), alkali metal carbonates (eg lithium carbonate, sodium hydrogen carbonate, cesium carbonate, potassium carbonate, sodium carbonate etc.), organic acid salts (eg sodium acetate etc.), alkali metal alcoholates (eg sodium methyl ester). Acid, potassium tert-butyrate, sodium tert-butyrate, etc.), and tetrabutylammonium fluoride, bis (trinormal butylstannyl) oxide, and other bases are preferably present.

The desired compound can also be produced by carrying out the reaction in the above solvent using a metal salt thereof (eg, an alkali metal such as sodium or potassium) instead of the compound (III). The amount of the base used is usually about 0.01 to 100 equivalents relative to compound (III) or a salt thereof,
It is preferably about 0.1 to 50 equivalents.

The compound (III) or a salt thereof is a compound (I
It is used in about 1 to 100 equivalents, preferably about 1 to 50 equivalents, relative to I) or a salt thereof. The reaction temperature is not particularly limited, but is usually about 0 to 150 ° C, preferably about 10 to 120 ° C. The reaction time is about several minutes to several tens of hours (for example, 5 minutes to 50 hours).

The compounds of the present invention are, for example, compounds of the general formula (IV)

[0056]

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[Wherein the symbols have the same meanings as defined above] or a salt thereof, and a compound of the general formula (V ′)

[0058]

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[Wherein A ″ is -N = CH-, -CH = N
-Or -CH = CH- and other symbols have the same meanings as described above] can be produced by reacting with a compound represented by the formula or a salt thereof. In the above reaction, as an example of the compound of formula (V ′), the compound of formula (V ″)

Embedded image [Wherein the symbols have the same meaning as defined above] are preferably used. By this reaction, in the compound of the present invention, A
Is Y = Z and R ³ is a hydrogen atom. This reaction is usually performed in a solvent that does not inhibit the reaction. Examples of the solvent which does not inhibit the reaction include water, ketones (eg, acetone, etc.), sulfoxides (eg, dimethyl sulfoxide, etc.), ethers (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), nitriles (eg, acetonitrile) ), Aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, 1,2-dichloroethane, etc.), esters (eg, ethyl acetate, etc.), amides (Eg, dimethylformamide, acetamide, dimethylacetamide, 1-methyl-2-pyrrolidinone, etc.) and ureylenes (eg, 1,3-dimethyl-2-imidazolidinone). These may be used alone or as a mixture of two or more at an appropriate ratio.

In this reaction, for example, alkali metal hydroxide (eg, lithium hydroxide, potassium hydroxide, sodium hydroxide, etc.), alkali metal hydride (eg, potassium hydride,
Sodium hydride etc.), alkali metal carbonates (eg lithium carbonate, sodium hydrogen carbonate, cesium carbonate, potassium carbonate, sodium carbonate etc.), organic acid salts (eg sodium acetate etc.), alkali metal alcoholates (eg sodium methyl ester). Acid, potassium tert-butyrate, sodium tert-butyrate, etc.), and tetrabutylammonium fluoride, bis (trinormal butylstannyl) oxide, and other bases are preferably present.

Further, instead of the compound (V ′) or (V ″), a metal (eg, alkali metal such as sodium or potassium) salt thereof is used to carry out a reaction in the above solvent to give a desired compound. It can be manufactured. The amount of base used is usually about 0.01 to 100 equivalents, preferably about 0.1 to 50 equivalents, relative to compound (V ′) or a salt thereof, or (V ″) or a salt thereof.

The compound (V ′) or (V ″) or its salt is about 1 to about 1 to the compound (IV) or its salt.
100 equivalents, preferably about 1 to 50 equivalents are used. The reaction temperature is not particularly limited, but is usually about 0 to 150 ° C,
It is preferably about 10 to 120 ° C. The reaction time is about several minutes to several tens of hours (for example, 5 minutes to 50 hours).

The compound of the present invention has, for example, the general formula (VI)

[0064]

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[Wherein L is a leaving group [eg: a halogen atom (chlorine, bromine, iodine, etc.) or R ⁴ SO ₃ (wherein, R ⁴ is a lower alkyl group having 1 to ⁴ carbon atoms or is substituted)] An optional phenyl group), and other symbols have the same meanings as defined above] and a salt thereof;

[0066]

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It can be produced by reacting with a compound represented by the formula [wherein the symbols have the same meaning as defined above] or a salt thereof. By this reaction, a compound in which R ³ is a hydrogen atom in the general formula (I) is obtained. Examples of the lower alkyl group having 1 to 4 carbon atoms represented by R ⁴ include methyl, ethyl, propyl, butyl, tert-
Butyl and the like. Examples of the optionally substituted phenyl group represented by R ⁴ include the same as the optionally substituted phenyl group represented by Ar. This reaction is usually performed in a solvent that does not inhibit the reaction. Examples of the solvent which does not inhibit the reaction include water, ketones (eg, acetone, etc.), sulfoxides (eg, dimethyl sulfoxide, etc.), ethers (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), nitriles (eg, acetonitrile) ), Aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, 1,2-dichloroethane, etc.), esters (eg, ethyl acetate, etc.), amides (Eg, dimethylformamide, acetamide, dimethylacetamide, 1-methyl-2-pyrrolidinone, etc.) and ureylenes (eg, 1,3-dimethyl-2-imidazolidinone). These may be used alone or as a mixture of two or more at an appropriate ratio.

In this reaction, for example, alkali metal hydroxide (eg, lithium hydroxide, potassium hydroxide, sodium hydroxide, etc.), alkali metal hydride (eg, potassium hydride,
Sodium hydride etc.), alkali metal carbonates (eg lithium carbonate, sodium hydrogen carbonate, cesium carbonate, potassium carbonate, sodium carbonate etc.), organic acid salts (eg sodium acetate etc.), alkali metal alcoholates (eg sodium methyl ester). Acid, potassium tert-butyrate, sodium tert-butyrate, etc.), and tetrabutylammonium fluoride, bis (trinormal butylstannyl) oxide, and other bases are preferably present.

The desired compound can also be prepared by carrying out the reaction in the above-mentioned solvent using a metal salt (eg, alkali metal such as sodium or potassium) instead of the compound (III). The amount of base used is usually about 2 to 100 equivalents, preferably about 2 to 50 equivalents, relative to compound (III) or a salt thereof.

Compound (III) or a salt thereof is a compound (V
It is used in about 1 to 100 equivalents, preferably about 1 to 50 equivalents, relative to I) or a salt thereof. The reaction temperature is not particularly limited, but is usually about 0 to 150 ° C, preferably about 10 to 120 ° C. The reaction time is about tens of minutes to tens of hours (for example, 30 minutes to 50 hours).

In the general formula (I), a compound in which A is an ethylene group optionally substituted with a lower alkyl group or a salt thereof is, for example, a compound of the general formula (I ″)

Embedded image [In the formula, symbols have the same meaning as described above] or a salt thereof,
Or a compound (I ′ ″) in which Y and Z in the general formula (I) are both methine groups optionally substituted with a lower alkyl group

[0072]

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[Wherein A ′ ″ is a vinylene group which may be substituted with a lower alkyl group, and other symbols have the same meanings] or a salt thereof is subjected to a catalytic reduction reaction to produce the compound. be able to. This reaction is usually carried out with water or an organic solvent which does not inhibit the reaction, such as ketones (eg acetone, methyl ethyl ketone etc.), alcohols (eg methanol, ethanol, propanol, isopropyl alcohol, butanol etc.), esters (eg acetic acid). Ethyl etc.), hydrocarbons (eg benzene, toluene, hexane, xylene etc.), organic carboxylic acids (eg acetic acid, propionic acid etc.) and the like in the presence of a single solvent or a mixed solvent. This reaction is usually performed in the presence of a catalyst. As the catalyst, for example, a suitable metal catalyst such as palladium-carbon is used. This reduction reaction is carried out at a temperature from room temperature to about 100 ° C. under normal pressure to a pressure of about 150 kg / cm ² .

The above raw material compounds (II), (IV), (VI),
As the salts of (I ″) and (I ′ ″), those similar to the salt of compound (I) are used. When a compound of the general formula (I) in which R ³ is a hydrogen atom or a salt thereof is obtained in the above reaction, a suitable acylating agent R ³ L ¹ [in the formula, R ³ Is an aliphatic or aromatic carboxylic acid residue (eg, acetyl, propionyl, butyryl, ethoxycarbonyl, benzoyl, substituted benzoyl, etc.),
L ¹ represents a group to be removed (eg, a halogen atom such as chlorine or bromine: an active ester group, etc.)] to give a compound of the general formula (I) in which R ³ is an acyl group. You can

This reaction is usually carried out in the presence or absence of a solvent which does not inhibit the reaction. Examples of solvents include
Ketones such as acetone; Sulfoxides such as dimethyl sulfoxide; Ethers such as diethyl ether, tetrahydrofuran, dioxane; Nitriles such as acetonitrile; Aromatic hydrocarbons such as benzene, toluene, xylene; Dichloromethane, Halogenated hydrocarbons such as chloroform, 1,2-dichloroethane; Esters such as ethyl acetate; Amides such as dimethylformamide, acetamide, dimethylacetamide; Like 1,3-dimethyl-2-imidazolidinone Ureilenes and the like. In order to promote the reaction, a base (eg, dimethylaminopyridine, pyridine, pyrroline, triethylamine) can be added to the reaction system.

The amount of base used is usually about 1 to 100 equivalents relative to compound (I) or a salt thereof. The compound of the present invention thus obtained is isolated from the reaction mixture by a means known per se, such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography, thin layer chromatography and the like. , Can be purified.
As described above, the compound of the present invention may have at least two stereoisomers, but if desired, these isomers can be individually produced. For example, the raw material compound (II),
A single isomer of each of (IV), (VI), (I ″) and (I ′ ″) or a salt thereof is used to carry out the above reaction to obtain a single compound of the present invention. The isomer of can be obtained. When the product is a mixture of two or more kinds of isomers, it is separated by an ordinary separation method, for example, a method of forming a salt with an optically active acid (eg, camphorsulfonic acid, tartaric acid, etc.) or various chromatographies. Alternatively, each isomer can be separated by a separation means such as fractional recrystallization.

The salt of compound (I) of the present invention can be produced by a means known per se, for example, by adding the above-mentioned inorganic acid or organic acid to compound (I). The starting compound (II) or a salt thereof according to the present invention, wherein R ¹ is a hydrogen atom, R ² is a methyl group, the carbon to which Ar is bound has the (S) configuration, and the carbon to which R ² is bound is the (R) configuration. (VII) or a salt thereof can be produced, for example, by the method represented by the following reaction formula.

[0078]

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[In the formula, Me represents a methyl group, Et represents an ethyl group, Pr represents a propyl group, Ph represents a phenyl group,
(R) and (S) each represent a marked carbon configuration, DMF means dimethylformamide, and other symbols have the same meanings as described above.] The starting compound (VIII) in the present reaction formula is For example, it can be produced by the method represented by the following reaction formula.

[0080]

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[In the formula, THP represents a tetrahydropyranyl group, Ts represents a p-toluenesulfonyl group, L ² represents a halogen atom (eg, chlorine, bromine, iodine, etc.), and DMSO represents dimethyl sulfoxide, Other symbols have the same meanings as described above.] The synthetic intermediate (IX) can be synthesized, for example, by the method represented by the following reaction formula.

[0082]

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[Wherein the symbols have the same meanings as defined above] In the starting compound (IV) of the present invention, R ¹ is a hydrogen atom, R ² is a methyl group, the carbon to which Ar is bonded is the (R) configuration, R is Compounds in which the ^two bonded carbons are in the (S) configuration (XVI
II)

[0084]

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[Wherein the symbols have the same meanings as described above]
Can be synthesized by, for example, the method described in EP0421210A, EP0548553A or EP0567982A or a method analogous thereto. In the starting compound (VI) or a salt thereof according to the present invention, R ¹ is a hydrogen atom, R ² is a methyl group, A
The carbon to which r is bound has the (S) configuration, the carbon to which R ² is bound has the (R) configuration, and L is a leaving group represented by R ⁴ SO ₃ (wherein R ⁴ is as defined above). R in a certain compound (XIX) or a salt thereof and a starting compound (II) or a salt thereof
^A compound (VII) or a salt thereof in which ¹ is a hydrogen atom, R ² is a methyl group, the carbon to which Ar is bonded has the (S) configuration, and the carbon to which R ² is bonded is the (R) configuration is represented by, for example, It can be manufactured by the method shown.

[0086]

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[Wherein L ³ , L ⁴ , L ⁵ , and L ⁶ each represent a halogen atom (eg, chlorine, bromine, iodine, etc., and other symbols have the same meanings as described above]] Compound (XX) or a salt thereof, and compound (XXVI) or a salt thereof in which L ³ is a chlorine atom in the starting compound (XXI) or a salt thereof can be produced, for example, by a method represented by the following reaction scheme, respectively. .

[0088]

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[In the formula, R ⁵ represents a lower (C _1-4 ) alkyl group, L ⁷ represents a halogen atom (eg, chlorine, bromine, iodine, etc.), and other symbols have the same meanings as above] The compound (XXXI) in the above formula or a salt thereof, wherein Ar is 2,4-difluorophenyl is synthesized by the following method.
It is described in JP-A-5-230038.

[0090]

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[Wherein, H ₂ / Pd-C means catalytic reduction of palladium carbon using a catalyst, and other symbols have the same meanings as described above] L ³ in the compound (XXI) or a salt thereof is a chlorine atom When the halogen atom is other than, in the above reaction formula,
Instead of (COCl) ₂ , each halogenating agent [eg:
Compound (XXI) can be produced by carrying out a reaction according to the above method using (COBr) ₂ , PBr _{3 and the} like].

In the starting compound (V) or a salt thereof according to the present invention, A is N = CH, CH = CH and CH ₂
Compounds (XXXVII), (XXXVIII) or salts thereof and (XXXIX) which are —CH ₂ can be produced, for example, by the methods shown in the following reaction schemes.

[0093]

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[Wherein the symbols have the same meanings as defined above] Furthermore, in the starting compound (V) or a salt thereof, a compound (XXXXIV) in which A is CH = N or a salt thereof is, for example, It can be manufactured by the method shown.

[0095]

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[Wherein the symbols have the same meaning as described above] The starting compound or synthetic intermediate obtained by the above-mentioned method can be obtained from the reaction mixture by a means known per se, for example, extraction, concentration, neutralization, filtration, recrystallization. , Column chromatography,
It can be isolated and purified by using a means such as thin layer chromatography. Alternatively, the reaction mixture may be used as it is as a raw material for the next step without isolation. The compound of the present invention has low toxicity and is a fungus, for example, Candida spp. (Eg Candida albicans, Candida utilis, Candida glabrata, etc.), Histoplasma spp. Fumigatus, etc.], Cryptococcus sp. [Example: Cryptococcus neoformans, etc.], Trichophyton sp. [Example: Malassezia furfa, etc.] has a strong antibacterial activity and a broad antifungal spectrum, etc., so it is possible to detect deep-seated and skin fungal infections (eg, Candida) in mammals (humans, livestock, poultry, etc.). Disease, Histopla Ma, aspergillosis, cryptococcosis, dermatomycosis, tinea versicolor, etc.), yet it can be used for prevention and treatment of atopic dermatitis. Further, the compound of the present invention can also be used as an agricultural antifungal agent.

When the compound of the present invention is administered to humans, it may be mixed with itself or with an appropriate pharmacologically acceptable carrier, excipient, diluent or the like, and then administered orally (eg, powder, granules,
Tablets, capsules, etc.), parenteral administration agents (eg injections, external preparations (eg nasal preparations, transdermal preparations etc.), suppositories (eg rectal suppositories, vaginal suppositories etc.) etc. Can be safely administered orally or parenterally. The compounding ratio of the compound of the present invention to the whole pharmaceutical composition is usually 5 to 10.
0% by weight, preferably 20 to 10 in oral administration
It is 0% by weight, and 5 to 30% by weight in parenteral administration.

These preparations can be manufactured by a method known per se which is generally used in the manufacturing process. For example, an injection may be prepared by dispersing the compound of the present invention in a dispersant (eg, Tween 80 (manufactured by Atlas Powder, USA), HCO60 (manufactured by Nikko Chemicals), carboxymethylcellulose, sodium alginate, etc.), a preservative (eg, methylparaben, Propylparaben, benzyl alcohol, chlorobutanol, etc.), tonicity agent (eg sodium chloride, glycerin, sorbitol, glucose, etc.)
Aqueous injection with vegetable oil (eg olive oil, sesame oil, peanut oil, cottonseed oil, corn oil, etc.),
It is produced by dissolving, suspending or emulsifying in propylene glycol or the like and molding into an oily injection.

The preparation for oral administration is obtained by adding the compound of the present invention to, for example, an excipient (eg lactose, sucrose, starch etc.) and a disintegrant (eg:
Starch, calcium carbonate, etc.), binder (eg starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, etc.)
Alternatively, a lubricant (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.) is added and compression-molded, and then, if necessary, a method known per se for the purpose of taste masking, enteric coating or sustainability. It can be manufactured by coating. As the coating agent, for example, hydroxypropylmethyl cellulose, ethyl cellulose, hydroxymethyl cellulose,
Hydroxypropyl cellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxymethyl cellulose acetate succinate, Eudragit (ROHM, West Germany, methacrylic acid / acrylic acid copolymerization) and titanium oxide , Pigments such as red iron oxide, etc. are used.

The compound of the present invention can also be used as a solid, semi-solid or liquid external preparation. For example, as a solid external preparation, the compound of the present invention can be used as it is or as an excipient (eg, glycol, mannitol, starch, microcrystalline cellulose, etc.), a thickener (eg, natural gums, cellulose derivatives, acrylic acid polymer) Etc.) and mixed to form a powdery composition. In the case of a semi-solid external preparation, it is preferably used as an aqueous or oily gel or ointment. Liquid external preparations are almost the same as in the case of injections, and are manufactured by using oily or aqueous suspensions. In addition to the above solid, semi-solid or liquid external preparations, pH adjusters (eg, carbonic acid, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, etc.), preservatives (eg, paraoxybenzoic acid esters, chlorobutanol) , Benzalkonium chloride, etc.). Specifically, for example, an ointment containing about 0.1 to 100 mg of the compound of the present invention per gram based on vaseline, lanolin or the like can be used for sterilization and disinfection of skin or mucous membranes.

The compound of the present invention is an oily or aqueous solid,
A semi-solid or liquid suppository can also be used. Examples of oily bases for producing suppositories include glycerides of higher fatty acids [eg: cacao butter, Witepsols (manufactured by Dynamite Nobel), etc.], intermediate fatty acids [eg: migliols (manufactured by Dynamite Nobel)] Etc.] or vegetable oil [eg: sesame oil, soybean oil, cottonseed oil, etc.] and the like. Examples of the aqueous base include polyethylene glycols, propylene glycol and the like, and examples of the aqueous gel base include natural gums, cellulose derivatives,
Examples thereof include vinyl polymers and acrylic acid polymers.

The dose of the compound of the present invention varies depending on the state of infection and administration route. For example, when it is administered to an adult (body weight 50 kg) patient for the purpose of treating Candida infection, it is orally administered in an amount of about 0.01 to 100 mg / kg / day, preferably about 0.1 to 50 mg / kg / day. More preferably, it is about 1 to 20 mg / kg / day. When the compound of the present invention is used as an antifungal agent for agriculture, the compound of the present invention is dissolved or dispersed in a suitable liquid carrier (eg, solvent), and a suitable solid carrier (eg, diluent, extender) is used. Mix or adsorb to it, and if necessary, further add an emulsifier, suspending agent, spreading agent, penetrating agent, wetting agent, thickener, stabilizer, etc., emulsion, wettable powder, powder It may be used as a dosage form such as granules. These preparations can be prepared by a method known per se. The amount of the compound of the present invention used is, for example, about 25 to 150 g, and more preferably about 40 to 80 g per 1 are of paddy field for controlling rice blast disease.

Examples of the liquid carrier include water, alcohols (eg, methyl alcohol, ethyl alcohol, n
-Propyl alcohol, isopropyl alcohol, ethylene glycol etc.), ethers (eg dioxane, tetrahydrofuran etc.), aliphatic hydrocarbons (eg kerosene, kerosene, fuel oil etc.), aromatic hydrocarbons (eg benzene, etc.) Toluenes), halogenated hydrocarbons (eg methylene chloride, chloroform etc.), acid amides (eg dimethylformamide, dimethylacetamide etc.), esters (eg ethyl acetate, butyl acetate etc.), nitriles (eg Acetonitrile, propionitrile, etc.) are used, and these can be used alone or in combination of two or more at an appropriate ratio.

As the solid carrier, vegetable powder (eg:
Soybean powder, tobacco powder, wheat flour, etc.), mineral powder (eg kaolin, bentonite, etc.), alumina, sulfur powder, activated carbon, etc. are used, and these are used alone or in admixture of two or more kinds in an appropriate ratio. can do.

[0105]

EXAMPLES Hereinafter, the present invention will be described in detail with reference to Reference Examples, Examples and Preparation Examples, but the present invention is not limited thereto. ^{The 1} H-NMR spectrum was measured using a Varian Gemini 200 using tetramethylsilane as an internal standard.
(200MHz) type spectrum meter
Values are given in ppm. The numerical values shown in parentheses in the mixed solvents are volume mixing ratios of the respective solvents. % Means percent by weight unless otherwise specified. Further, the ratio of the solvent in the silica gel chromatography indicates the volume ratio of the solvent to be mixed. The symbols in the examples have the following meanings. s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, tt:
Triple triplet, m: multiplet, br: wide range, J: coupling constant

Reference Example 1 2- (2,4-difluorophenyl) -2-[(1R)
-1- (3,4,5,6-tetrahydro-2H-pyran-2-yl) oxyethyl] oxirane (82 g) (synthesized by the method described in JP-A-4-74168) and pyridinium p-toluenesulfonate. (6.3 g) was dissolved in ethanol (600 ml), and the mixture was stirred at 55 ° C for 1 hr. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate (1 liter) and washed with water (200 ml × 2). The aqueous layer was extracted with ethyl acetate (100 ml × 2), the organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was chromatographed on silica gel (eluent: hexane / ethyl acetate = 10/1 → 8/1 → 3 /
When purified by subjecting to (1), (1R) -1- [2- (2,2
4-Difluorophenyl) -2-oxiranyl] ethanol (31.5 g) was obtained as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.14-1.23 (3H, m), 1.77, 2.22 (1
H), 2.80, 2.92 (1H), 3.27-3.32 (1H), 4.00-4.20 (1H,
m), 6.75-6.94 (2H, m), 7.36-7.48 (1H, m)

Reference Example 2 (1R) -1- [2- (2,4-difluorophenyl)
-2-oxiranyl] ethanol (31.5 g) and 3,
5-Dinitrobenzoyl chloride (40 g) was dissolved in methylene chloride (500 ml), and triethylamine (24.1 ml) was added dropwise under ice cooling. The reaction mixture was stirred at room temperature for 3.5 hours and then water (150 ml) was added, followed by 5% aqueous sodium hydrogen carbonate (1
It was washed with 50 ml), dried over magnesium sulfate and concentrated under reduced pressure. The precipitated crystals were filtered and washed with methylene chloride. The mother liquor and the washings were combined and evaporated under reduced pressure, ethyl acetate (25 ml) and methanol (300 ml) were added to the residue, and the mixture was ice-cooled. The precipitated crystals were collected by filtration and washed with ethyl acetate (25
((1R) -1-[(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethyl] 3, when recrystallized from a mixed solution of (ml) and methanol (250 ml).
5-Dinitrobenzoate (28.7 g) was obtained as colorless needles. Melting point: 104 to 107 ° C. (recrystallized from ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.46 (3H, dd, J = 6.6Hz, J = 1.2Hz),
3.01 (1H, d, J = 4.6Hz), 3.23 (1H, d, J = 4.6Hz), 5.3
3 (1H, q, J = 6.6Hz), 6.85-7.07 (2H, m), 7.54 (1H,
m), 9.13 (2H, d, J = 2.2Hz), 9.25 (1H, t, J = 2.2Hz)

Reference Example 3 [(1R) -1-[(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethyl] 3,5-
Dinitrobenzoate (50 g) was dissolved in methanol (2 liters), and 1N-sodium hydroxide (25
5 ml) was added dropwise. After stirring the reaction at room temperature for 1 hour,
The mixture was neutralized by adding 1N-hydrochloric acid (127 ml). Methanol was concentrated under reduced pressure and ethyl acetate (1 liter) was added to the residue.
And water (200 ml) were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine (200 ml), dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate / hexane = 1/3) to give (1R) -1-
[(2R) -2- (2,4-difluorophenyl) -2
-Oxiranyl] ethanol (25g) was obtained as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.17 (3H, dd, J = 6.6Hz, 1.2Hz),
1.83 (1H, d, J = 8Hz), 2.80 (1H, d, J = 5.2Hz), 3.30 (1
H, d, J = 5.2Hz), 4.01-4.17 (1H, m), 6.75-6.93 (2H,
m), 7.36-7.48 (1H, m)

Reference Example 4 (1R) -1-[(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethanol (16.1)
g) in tetrahydrofuran (320 ml) under ice cooling,
Triphenylphosphine (63.3 g), benzoic acid (2
9.5 g), diethyl azodicarboxylate (42.0 g)
Was added, and the mixture was stirred at room temperature for 6 hours under an argon atmosphere. Ethyl acetate (800 ml) and water (500 ml) were added to the reaction mixture to separate the layers, and the aqueous layer was extracted with ethyl acetate (200 ml).
The organic layers were combined, washed with water and saturated saline, dried over magnesium sulfate, and concentrated. The residue was chromatographed on silica gel (eluent: hexane / ethyl acetate = 15 /
1 → 7/1) and purified, [(1S) -1-
[(2R) -2- (2,4-difluorophenyl) -2
-Oxiranyl] ethyl] benzoate (19.2
g) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.37 (3H, d, J = 6.6Hz), 2.90 (1H,
d, J = 5.2Hz), 3.28 (1H, d, J = 5.2Hz), 5.36 (1H, q,
J = 6.6Hz), 6.74-6.94 (2H, m), 7.38-7.60 (4H, m), 7.
94-8.01 (2H, m) IRν _max ^neat _cm ^-1 : 1725, 1615, 1600, 1505, 1450, 1
425

[(1S) -1-[(2R) -2- (2,
4-Difluorophenyl) -2-oxiranyl] ethyl] benzoate (15.9 g) was added to methanol (80
0 ml), 28% sodium methylate-methanol solution (12.9 ml) was added under ice cooling, and the reaction mixture was stirred at room temperature for 6 hours. 1N hydrochloric acid (63.2 ml) was added to the reaction solution.
After adding, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 6/1 → 2/1), (1S) -1-
[(2R) -2- (2,4-difluorophenyl) -2
-Oxiranyl] ethanol (9.7 g) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, dd, J = 6.4Hz, 1Hz), 2.2
4 (1H, d, J = 2Hz), 2.92 (1H, d, J = 5Hz), 3.28 (1H,
d, J = 5Hz), 4.12 (1H, dq, J = 6.4Hz, 2Hz), 6.77-6.95
(2H, m), 7.32-7.44 (1H, m) IRν _max ^neat _cm ^-1 : 3420, 2980, 1615, 1600, 1500, 1
425

Reference Example 5 2- (2-Fluorophenyl) -2-[(1R) -1-
(3,4,5,6-tetrahydro-2H-pyran-2-
[(1R) -1-[(2R) -2- (2-fluorophenyl) -2-]) by the method shown in Reference Examples 1 and 2), and (yl) oxyethyl] oxirane (synthesized by the method described in EP0548553A). Oxiranyl] ethyl] 3,5-
Led to dinitrobenzoate. Colorless prism crystals (crystallized from ethyl acetate) Melting point: 183-184 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.47 (3H, dd, J = 6.6Hz, 1.6Hz),
3.03 (1H, d, J = 4.7Hz, 3.23 (1H, d, J = 4.7Hz), 5.35
(1H, q, J = 6.6Hz), 7.09-7.59 (4H, m), 9.13 (2H, d,
J = 2.2Hz), 9.23 (1H, t, J = 2.2Hz) [α] ²³ _D −24.7 ° (c = 1.0, in CHCl ₃ ) Elemental analysis value: Calculated value as C ₁₇ H ₁₃ FN ₂ O ₇ ( %): C, 54.26; H, 3.48; N, 7.44 Actual value (%): C, 54.23; H, 3.25; N, 7.41

Reference Example 6 [(1R) -1-[(2R) -2- (2-fluorophenyl) -2-oxiranyl] ethyl] 3,5-dinitrobenzoate was prepared by the method shown in Reference Example 3. (1R)-
1-[(2R) -2- (2-fluorophenyl) -2-
Oxilanyl] ethanol. Colorless oil ¹ H-NMR (CDCl ₃ ) δ: 1.17 (3H, dd, J = 6.6Hz, 1.0Hz),
1.78 (1H, d, J = 8.2Hz), 2.81 (1H, d, J = 5.3Hz), 3.32
(1H, d, J = 5.3Hz), 4.09-4.23 (1H, m), 6.99-7.47 (4
H, m)

Reference Example 7 (1R) -1-[(2R) -2- (2-fluorophenyl) -2-oxiranyl] ethanol was added to the method described in Reference Example 4 to obtain (1S) -1-[(2R ) -2- (2-Fluorophenyl) -2-oxiranyl] ethanol. Colorless oil ¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, d, J = 7Hz), 2.27 (1H,
d, J = 2Hz), 2.96 (1H, d, J = 5Hz), 3.30 (1H, d, J = 5H)
z), 4.16 (1H, dq, J = 7Hz, 2Hz), 7.03-7.44 (4H, m)

Reference Example 8 2- (2-Fluorophenyl) -2-[(1R) -1-
(3,4,5,6-tetrahydro-2H-pyran-2-
Yl) oxyethyl) oxirane (synthesized by the method described in EP0548553A) by the method shown in Reference Example 1
(1R) -1- [2- (2-fluorophenyl) -2-
Oxilanyl] ethanol. This product (34.77
g) in tetrahydrofuran (600 ml) under ice-cooling, triphenylphosphine (127.21 g), 3,
5-Dinitrobenzoic acid (102.88 g) and diethyl azodicarboxylate (84.47 g) were added, and the mixture was stirred at room temperature for 7 hours under an argon atmosphere. Ethyl acetate (6
(00 ml), diisopropyl ether (100 ml) and water (800 ml) were added for liquid separation, and the aqueous layer was separated with ethyl acetate (6
It was extracted with 00 ml, 400 ml). The organic layers were combined, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 5/1) and recrystallized from ethyl acetate to give [(1
S) -1-[(2R) -2- (2-fluorophenyl)
2-Oxiranyl] ethyl] 3,5-dinitrobenzoate (23.15 g) was obtained as colorless needles. ¹ H-NMR (CDCl ₃ ) δ: 1.47 (3H, d, J = 7Hz), 2.97 (1H,
d, J = 5Hz), 3.29 (1H, d, J = 5Hz), 5.43 (1H, q, J = 7H
z), 7.02-7.56 (4H, m), 9.06 (2H, d, J = 2Hz), 9.21
(1H, t, J = 2Hz)

This product (22.91 g) was added to methanol (70
0 ml), 1N-aqueous sodium hydroxide solution (146.5 ml) was added under ice cooling, and the reaction mixture was stirred at room temperature for 1 hr. After adding 1N-hydrochloric acid (85.5 ml) to the reaction solution,
The solvent was distilled off under reduced pressure, and the residue was washed with ethyl acetate (500 m
l) and water (500 ml) were added for liquid separation. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. Silica gel column chromatography of the residue (eluent: hexane / ethyl acetate = 3/1)
When purified by subjecting to (1S) -1-[(2R) -2-
(2-Fluorophenyl) -2-oxiranyl] ethanol (10.76 g) was obtained as a colorless oil. This product was identical to the compound obtained in Reference Example 7.

Reference Example 9 4-Fluoronitrobenzene (3.1 g), 4- [4-
(2,2,3,3-Tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone (5.8 g), potassium carbonate (13.8 g) and N,
A mixture of N-dimethylformamide (60 ml) was stirred at 80 ° C for 2 hours. The reaction was cooled and added to water (500ml). The obtained mixed solution was neutralized with hydrochloric acid, and the precipitated crystals were collected by filtration. The obtained crystals were dissolved in ethyl acetate (300 ml) and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was crystallized from a mixed solution of ethyl acetate and diisopropyl ether to give 2- (4-nitrophenyl) -4- [4- (2,2,3,3-tetrafluoro). Propoxy) phenyl] -3 (2H, 4H) -1,2,
4-Triazolone (5.5 g, 67%) was obtained as yellow powder crystals. Melting point: 161-162 ° C

Reference Examples 10 to 14 In the same manner as in Reference Example 9, the compounds shown in Table 1 were obtained.

[0118]

[Table 1]

Reference Example 15 4-Fluoronitrobenzene (21.g) and 1H-1,
2,3-triazole (12.4 g) was reacted in the same manner as in Reference Example 9. After cooling the reaction solution, water was added and the precipitated crystals were collected by filtration. The obtained crystals were purified by silica gel chromatography (eluent: dichloromethane → dichloromethane / acetone = 8/1). The first eluate was recrystallized from dichloromethane-diisopropyl ether to give 2- (4-nitrophenyl) -2H-1,2,3.
-Triazole (18.8g) was obtained as pale yellow prism crystals. Melting point: 183-184 ° C. ¹ H-NMR (CDCl ₃ ) δ: 7.90 (2H, s), 8.28 (2H, dt, J = 9.
4Hz, J = 2.4Hz), 8.38 (2H, dt, J = 9.4Hz, J = 2.4Hz)

Further, the second eluate was recrystallized from dichloromethane-diisopropyl ether to give 1- (4-nitrophenyl) -1H-1,2,3-triazole (6.
02g) was obtained as pale yellow prism crystals. Melting point: 205-206 ° C ¹ H-NMR (CDCl ₃ ) δ: 7.92 (1H, d, J = 1.4Hz), 8.00 (2H, 2H,
dt, J = 9Hz, J = 2.4Hz), 8.13 (1H, d, J = 1.4Hz), 8.44
(2H, dt, J = 9Hz, J = 2.4Hz)

Reference Example 16 2- (4-nitrophenyl) in methanol (200 ml)
-4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone (5.5 g) and 10% palladium-carbon (5
0% water content, 0.5 g) was added, and the catalytic reduction reaction was carried out at room temperature and atmospheric pressure. When the absorption of hydrogen stopped, dichloromethane (200 ml) was added to the reaction solution, and the catalyst was filtered off. The catalyst was washed with dichloromethane (50 ml), and the washing solution and the filtrate were combined and evaporated under reduced pressure to give 2- (4-aminophenyl) -4- [4- (2,2,3,3-tetrafluoropropoxy). Phenyl] -3 (2H, 4H) -1,
2,4-triazolone (4.6 g, 90%) was obtained as a white solid. This product was used in the next step without purification.

Reference Examples 17 to 21 In the same manner as in Reference Example 16, the compounds shown in Table 2 were obtained.

[0123]

[Table 2]

Reference Example 22 1- (4-nitrophenyl) -3- [4- (2,2,
3,3-Tetrafluoropropoxy) phenyl] -2
Ferric chloride (0.2 g) and activated carbon (2.0 g) were added to a solution of (1H, 3H) -imidazolone (20.5 g) in methanol (75 ml) -tetrahydrofuran (75 ml),
Then hydrazine hydrate (8.0 ml) was added dropwise over 10 minutes. After refluxing and stirring for 14 hours, ferric chloride (0.2 g), activated carbon (2.0 g) and hydrazine monohydrate (8.0 ml) were added to the reaction solution, and the mixture was further refluxed and stirred for 6 hours. Activated carbon was filtered off and washed with methanol (100 ml). The filtrate and washings were combined and evaporated under reduced pressure, and the obtained residue was dissolved in ethyl acetate (700 ml). The ethyl acetate layer was washed 4 times with water (200 ml), dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give 1- (4-aminophenyl) -3- [4- (2,2,3,3-tetra- Fluoropropoxy) phenyl] -2 (1H, 3H) -imidazolone (18.1 g, 95%) was obtained as a pale yellow powder. Melting point: 178 to 179 ° C. Elemental analysis value: Calculated as C ₁₈ H ₁₅ F ₄ N ₃ O ₂ (%): C, 56.70; H, 3.96; N, 11.02 Actual value (%): C, 56.58; H, 3.93; N, 11.21

Reference Example 23 In the same manner as in Reference Example 22, 1- (4-nitrophenyl)
-3- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -2 (1H, 3H) -imidazolone to 1- (4-aminophenyl) -3- [4- (1,1,
2,2-Tetrafluoroethoxy) phenyl] -2 (1
H, 3H) -imidazolone was obtained. Melting point: 150 to 151 ° C. Elemental analysis value: Calculated value as C ₁₇ H ₁₃ F ₄ N ₃ O ₂ (%): C, 55.59; H, 3.57; N, 11.44 Actual value (%): C, 55.74; H, 3.40; N, 11.49

Reference Example 24 2- (4-aminophenyl) -4- [4- (2,2,
3,3-Tetrafluoropropoxy) phenyl] -3
(2H, 4H) -1,2,4-triazolone (4.6
g) and pyridine (1.43 g) with ethyl acetate (200 m
l) dissolved. A solution of phenyl chlorocarbonate (2.83 g) in ethyl acetate (20 ml) was added dropwise to this solution at room temperature. After the addition was completed, the reaction solution was stirred at room temperature for 2 hours. Water (200 ml), ethyl acetate (600 ml) and tetrahydrofuran (300 ml) were added to the reaction liquid to separate it. 5 organic layers
After washing with% phosphoric acid water (200 ml × 2) and water (200 ml), it was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to a liquid volume of about 50 ml, and the precipitated crystals were collected by filtration. The crystals obtained are washed with diethyl ether and then dried,
4- [5-oxo-4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -1H, 4H-1,
Phenyl 2,4-triazol-1-yl] phenylcarbamate (5.6 g, 93%) was obtained as colorless flaky crystals. Melting point: 204 to 206 ° C. Elemental analysis value: Calculated as C ₂₄ H ₁₈ F ₄ N ₄ O ₄ (%): C, 57.37; H, 3.61; N, 11.15 Actual value (%): C, 57.50; H, 3.67; N, 11.13

Reference Examples 25 to 31 In the same manner as in Reference Example 24, the compounds shown in Table 3 were obtained.

[0128]

[Table 3]

Reference Example 32 4- [5-oxo-4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -1H, 4H-1,
Phenyl 2,4-triazol-1-yl] phenylcarbamate (5.6 g) was added to a mixture of ethanol (100 ml) and tetrahydrofuran (100 ml). Add hydrazine hydrate (3 g) to this mixture while stirring,
The mixture was stirred at 80 ° C for 2 hours. The reaction solution was concentrated under reduced pressure until the liquid volume became about 20 ml, and water (100 ml) was added. The precipitated crystals were collected by filtration, washed with ethanol, and dried under reduced pressure to give 4-
[4- [5-oxo-4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -1H, 4H-
1,2,4-Triazol-1-yl] phenyl] semicarbazide (4.8 g, 98%) was obtained as colorless prism crystals. Melting point:> 350 ° C. Elemental analysis value: Calculated as C ₁₈ H ₁₆ F ₄ N ₆ O ₃ (%): C, 49.10; H, 3.66; N, 19.08 Measured value (%): C, 48.95; H, 3.72 ; N, 19.20

Reference Examples 33 to 39 In the same manner as in Reference Example 32, the compounds shown in Table 4 were obtained.

[0131]

[Table 4]

Reference Example 40 4- [4- [5-oxo-4- [4- (2,2,3,3
-Tetrafluoropropoxy) phenyl] -1H, 4H
-1,2,4-Triazol-1-yl] phenyl] semicarbazide (4.75g) was added to N, N-dimethylformamide (60ml). Acetic acid (4 g) and formamidine acetate (6 g) were added to this mixed solution, and the mixture was stirred at room temperature for 3 hours and subsequently at 80 ° C. for 1.5 hours. After cooling, water (300 ml) was added to the reaction solution, and the precipitated crystals were collected by filtration and washed with water (100 ml). The crystals were air-dried and then dissolved in a mixed solution of tetrahydrofuran (300 ml) and ethyl acetate (600 ml) while being heated. The resulting solution was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Ethyl acetate (50 ml) was added to the residue, and the precipitated crystals were collected by filtration and recrystallized from tetrahydrofuran to give 4- [4- [5-oxo-4- [4- (2,2,3,3- Tetrafluoropropoxy) phenyl] -1H, 4H-1,2,4-triazol-1-yl] phenyl] -3 (2H, 4H)-
1,2,4-Triazolone (2.4 g, 49%) was obtained as white powder crystals. Melting point: 297 to 298 ° C Elemental analysis value: Calculated value as C ₁₉ H ₁₄ F ₄ N ₆ O ₃ (%): C, 50.67; H, 3.13; N, 18.66 Actual value (%): C, 50.49; H, 3.20; N, 18.50

Reference Examples 41 to 47 In the same manner as in Reference Example 40, the compounds shown in Table 5 were obtained.

[0134]

[Table 5]

Reference Example 48 Phenyl 4- (1H-1,2,4-triazol-1-yl) phenylcarbamate (13 g), 2,2-diethoxyethylamine (7.4 g), pyridine (3.67)
The mixture of g) was heated at 50 ° C. for 3 hours. The reaction solution was cooled, and the precipitated crystals were washed with a mixed solution of diisopropyl ether and petroleum ether (1: 1, 100 ml × 2) to give 1
-(2,2-diethoxyethyl) -3- [4- (1H-
1,2,4-triazol-1-yl) phenyl] urea (14.5 g) was obtained as colorless powder crystals. Melting point: 139 to 140 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.25 (6H, t, J = 7.2Hz), 3.43 (2H,
t, J = 5Hz), 3.52-3.85 (4H, m), 4.57 (1H, t, J = 5H
z), 5.08-5.18 (1H, m), 7.16 (1H, br), 7.49 (2H, d,
J = 9.4Hz), 7.57 (2H, d, J = 9.4Hz), 8.08 (1H, s), 8.
48 (1H, s)

Reference Examples 49 to 50 In the same manner as in Reference Example 48, the compounds shown in Table 6 were obtained.

[0137]

[Table 6]

Reference Example 51 1- (2,2-diethoxyethyl) -3- [4- (1H
-1,2,4-Triazol-1-yl) phenyl] urea (14.5 g) was added to methanol (214 ml) and water (8
Dissolve in a mixed solution of 5 ml) and dilute hydrochloric acid (0.48 M, 104 m
l) was added dropwise. The reaction mixture was stirred at room temperature for 14 hours, and the precipitated crystals were collected by filtration to give 1- [4- (1H-1,
2,4-triazol-1-yl) phenyl] -2-
(1H, 3H) -imidazolone (8.0 g) was obtained as colorless powdery crystals. The filtrate was concentrated under reduced pressure to about 200 ml, and the precipitated crystals were collected by filtration to obtain the second crystal (1.08 g). Melting point: 294-296 ° C

Reference Examples 52 to 53 In the same manner as in Reference Example 51, the compounds shown in Table 7 were obtained.

[0140]

[Table 7]

Reference Example 54 (1S) -1-[(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethanol (1.0
g) in dichloromethane (14 ml) at −78 ° C. under nitrogen atmosphere and diisopropylethylamine (0.96 ml).
Was added and then trifluoromethanesulfonic anhydride (0.93 ml) was added dropwise over 5 minutes. 2 at -78 ° C
After stirring for 0 minutes and then at -25 ° C for 25 minutes, -10
The reaction solution was concentrated to about 10 ml at ℃. The concentrate was subjected to flash column chromatography using silica gel and eluted with dichloromethane-hexane (1: 1). The desired fraction was concentrated to about 10 ml, and the residue was treated with 4- [4- [5-oxo-4- [4- (2,2,2
3,3-Tetrafluoropropoxy) phenyl] -1
H, 4H-1,2,4-triazol-1-yl] phenyl] -3 (2H, 4H) -1,2,4-triazolone (2.1 g), dimethylformamide (40 ml), dimethyl sulfoxide (50 ml) To a solution prepared from and 60% oily sodium hydride (180 mg) was added at -14 ° C, and the mixture was stirred for 20 minutes. The reaction solution was further stirred at −5 ° C. for 20 minutes. Water (500 ml) was poured into the reaction solution, and the mixture was extracted twice with dichloromethane (300 ml). The dichloromethane layer was washed twice with water (200 ml) and once with saturated brine,
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a colorless powder. This product was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 1/1 → 1/2) and then crystallized from ethyl acetate-hexane to give 2-[(1R, 2S) -2- ( 2,4-Difluorophenyl) -2,3-epoxy-1-methylpropyl]
-4- [4- [5-oxo-4- [4- (2,2,3
3-Tetrafluoropropoxy) phenyl] -1H-
1,2,4-triazol-1-yl] phenyl] -3
(2H, 4H) -1,2,4-triazolone (0.29
g) was obtained as colorless powder crystals. Melting point: 181 to 183 ° C Elemental analysis value: Calculated as C ₂₉ H ₂₂ F ₆ N ₆ O ₄ (%): C, 55.07; H, 3.51; N, 13.29 Measured value (%): C, 55.12; H, 3.34; N, 13.24

Reference Examples 55 to 63 In the same manner as in Reference Example 40, the compounds shown in Table 8 were obtained.

[Table 8]

Reference Examples 64-72 The compounds shown in Table 9 were obtained in the same manner as in Reference Example 51.

[Table 9]

Reference Example 73 1- [4- (1H-1-tetrazolyl) phenyl] -2
(1H, 3H) -Imidazolone (5.0 g) was added to acetic acid (5
It was dissolved in 100 ml of water, 10% palladium-carbon (50% water content, 5.0 g) was added, and the mixture was stirred under a hydrogen atmosphere at 40 ° C. for 4 hours. The catalyst was filtered off, the catalyst portion was washed with acetic acid, and the filtrate and washings were combined and evaporated under reduced pressure. Crystallization of the residue from ethanol gave 1- [4- (1H-1-tetrazolyl) phenyl] -2-imidazolidinone (4.1 g) as colorless crystals.

Melting point: 237-240 ° C. (dec.) ¹ H-NMR (db-DMSO) δ: 3.45 (2H, t, J = 7Hz), 3.93 (2H,
t, J = 7Hz), 7.20 (1H, s), 7.82 (4H, s), 10.02 (1H,
s) Elemental analysis value: Calculated as C ₁₀ H ₁₀ N ₆ O: C, 52.17; H, 4.38; N, 36.50 Actual value: C, 51.99; H, 4.33; N, 36.41

Reference Example 74 (1S) -1-[(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethanol (1.20)
g) in dichloromethane (26 ml) at −78 ° C. under a nitrogen atmosphere and diisopropylethylamine (1.15 ml).
Was added, then trifluoromethanesulfonic anhydride (1.10 ml) was added dropwise over 5 minutes. 2 at -78 ° C
After stirring for 0 min and then at -30 ° C for 15 min, hexane (26 ml) was added and subjected to flash column chromatography on silica gel eluting with dichloromethane-hexane (1: 1). The desired fraction was concentrated to about 20 ml, and the residue was mixed with 1- [4- (1H-1-tetrazolyl) phenyl] -2 (1H, 3H) -imidazolone (940 mg), dimethylformamide (20 ml) and dimethyl. Sulfoxide (10 ml), tetrahydrofuran (1
0 ml) and 72% oily sodium hydride (126 mg) were added to the solution at -30 ° C, and the mixture was stirred for 20 minutes.
The reaction solution was further stirred under ice cooling for 40 minutes. Water (100 ml) was poured into the reaction solution, and the mixture was extracted with ethyl acetate (150 ml). The ethyl acetate layer was washed twice with water (100 ml) and once with saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give a colorless powder. This product was chromatographed on silica gel (eluent: hexane / ethyl acetate = 1 /
3) and 1-[(1R, 2S) -2- (2,4-
Difluorophenyl) -2,3-epoxy-1-methylpropyl] -3- [4- (1H-1-tetrazolyl) phenyl] -2 (1H, 3H) -imidazolone (0.13
g) and (2R) -2- (2,4-difluorophenyl)
2-[(1R) -1- [1- [4- (1H-1-tetrazolyl) phenyl] -2-imidazolyloxy] ethyl] oxirane (0.05 g) was obtained.

1-[(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] -3- [4- (1H-1-tetrazolyl) phenyl]- 2 (1H, 3H) -imidazolone: colorless powder crystal

Melting point: 205-207 ° C. ¹ H-NMR (CDCL ₃ ) δ: 1.39 (3H, d, J = 7Hz), 2.73 (1H,
d, J = 5Hz), 2.83 (1H, d, J = 5Hz), 5.09 (1H, q, J = 7H
z), 6.52 (1H, d, J = 3Hz), 6.66 (1H, d, J = 3Hz), 6.81-
6.96 (2H, m), 7.36-7.48 (1H, m), 7.78 (2H, d, J = 9H
z), 7.94 (2H, d, J = 9Hz), 9.02 (1H, s) SIMS (MH ⁺ ): 411

Reference Example 75 A solution of (1S) -1-[(2R) -2- (2-fluorophenyl) -2-oxiranyl] ethanol (1.21 g) in dichloromethane (25 ml) was added under a nitrogen atmosphere at -78.
Diisopropylethylamine (1.27 ml) was added at ℃, followed by trifluoromethanesulfonic anhydride (1.
22 ml) was added dropwise over 5 minutes. After stirring at −78 ° C. for 15 minutes and then at −30 ° C. for 15 minutes, hexane (25 ml) was added to the reaction solution, which was subjected to flash column chromatography using silica gel and dichloromethane-hexane (1: 1). It eluted. About 2 target fractions
It was concentrated to 0 ml and the residue was 1- [4- (1H-
1-Tetrazolyl) phenyl] -2 (1H, 3H) -imidazolone (1.14 g), 1-methyl-2-pyrrolidone (30 ml) and 72% oily sodium hydride (150 m
g) was added to the solution prepared from and at −30 ° C., and the mixture was stirred for 15 minutes. The reaction solution was further stirred at −10 ° C. for 15 minutes.
Water (100 ml) was poured into the reaction solution, and ethyl acetate (150
ml). The ethyl acetate layer was diluted with water (100 ml) to 1
The extract was washed once with saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give a colorless powder. This product was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 1/3) to give 1-[(1R, 2S) -2.
-(2-Fluorophenyl) -2,3-epoxy-1-
Methylpropyl] -3- [4- (1H-1-tetrazolyl) phenyl] -2 (1H, 3H) -imidazolone (0.39g) and (2R) -2- (2-fluorophenyl) -2-[( 1R) -1- [1- [4- (1H-1-
Tetrazolyl) phenyl] -2-imidazolyloxy]
Ethyl] oxirane (0.18 g) was obtained. 1-[(1R, 2S) -2- (2-fluorophenyl)
-2,3-Epoxy-1-methylpropyl] -3- [4
-(1H-1-tetrazolyl) phenyl] -2 (1H,
3H) -Imidazolone: colorless powder crystal

¹ H-NMR (CDCL ₃ ) δ: 1.39 (3H, d, J = 7Hz),
2.76 (1H, d, J = 5Hz), 2.84 (1H, d, J = 5Hz), 5.15 (1
H, q, J = 7Hz), 6.55 (1H, d, J = 3Hz), 6.67 (1H, d, J = 3
Hz), 7.06-7.49 (4H, m), 7.79 (2H, d, J = 9Hz), 7.96
(2H, d, J = 9Hz), 9.04 (1H, s)

Reference Example 76 (S) -Ethyl lactate (75 g) and morpholine (164)
The mixture of g) was heated at 80 ° C. for 64 hours. The reaction mixture was concentrated and the residue was subjected to silica gel chromatography (eluent: hexane-ethyl acetate (4: 1) → ethyl acetate) to give 4-[(S) -2-hydroxypropionyl].
Morpholine (69.4 g) was obtained as a pale yellow oil.

4-[(S) -2-hydroxypropionyl] morpholine (69.4 g) in dichloromethane (30
(0 ml), p-toluenesulfonic acid monohydrate (0.82 g) was added, and the mixture was cooled with ice to give 3,4-dihydro-2.
H-pyran (40.3 g) was added dropwise. The reaction mixture was stirred at 0 ° C. for 30 minutes and then washed with 5% aqueous sodium hydrogen carbonate. The organic layer was dried over magnesium sulfate and concentrated, and the residue was subjected to silica gel chromatography (eluent: hexane-ethyl acetate (8: 1) → ethyl acetate) to give 4-[(2S)
-2- (3,4,5,6-tetrahydro-2H-pyran-2-yloxy) propionyl] morpholine (89.
1 g) was obtained as a pale yellow oil.

1-Bromo-2-fluorobenzene (15
g) and 4-[(2S) -2- (3,4,5,6-tetrahydro-2H-pyran-2-yloxy) propionyl] morpholine (40 g) in tetrahydrofuran (20 g).
It was dissolved in 0 ml), magnesium (shavings, 4.4 g) was added, and the mixture was vigorously stirred. When the internal temperature of the reaction solution reached 35 ° C, the reaction vessel was cooled, and 1-bromo-2-fluorobenzene (16.7) was added while keeping the internal temperature at 35 to 37 ° C.
g) was added dropwise over 10 minutes. 30-35 ℃ reaction liquid
After stirring at room temperature for 2 hours, the mixture was cooled with ice, saturated aqueous ammonium chloride solution (100 ml) and water (100 ml) were added, and the mixture was extracted with ethyl acetate (200 ml × 2,100 ml). The extract was washed with water and brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography (eluent: hexane-ethyl acetate = 10: 1 → 5:
When attached to 1), (2S) -2′-fluoro-2- (3,3
4,5,6-Tetrahydro-2H-pyran-2-yloxy) propiophenone (22.4 g) was obtained as a pale yellow oil.

(2S) -2'-fluoro-2- (3,
4,5,6-Tetrahydro-2H-pyran-2-yloxy) propiophenone (25 g) was added to ethanol (20
0 ml), pyridinium p-toluenesulfonate (1.28 g) was added, and the mixture was stirred at 55 ° C for 2.5 hr. The reaction solution was concentrated, and the residue was subjected to silica gel chromatography (eluent: hexane-ethyl acetate = 9: 1 → 5:
When subjected to 1), (2S) -2′-fluoro-2-hydroxypropiophenone (16.4 g) was obtained as a colorless oil.

[0155] IR (neat): 1690 (C = 0) cm -1 1 H-NMR (CDCL 3) δ: 1.41 (3H, dd, J = 7Hz, J = 1.4Hz),
3.78 (1H, d, J = 6Hz), 4.98-5.15 (1H, m), 7.12-7.36
(2H, m), 7.54-7.68 (1H, m), 7.90-8.00 (1H, m)

Reference Example 77 (2S) -2 ', 4'-difluoro-2-hydroxypropiophenone (synthesized by the method described in JP-A-5-230038: 26.01 g) was added to dichloromethane (300 m).
l), diisopropylethylamine (19.90 g) was added at -60 ° C under a nitrogen atmosphere, and then trifluoromethanesulfonic anhydride (25.90 ml) was added to 20%.
It was added dropwise over a period of minutes. The reaction temperature was gradually raised to -30 ° C, and the mixture was further stirred for 30 minutes. The reaction solution was purified by subjecting it to silica gel chromatography [silica gel 400 g, eluent (dichloromethane: hexane = 1: 1)].
Pale yellow oily (2S) -2 ', 4'-difluoro-2-
Trifluoromethanesulfonyloxypropiophenone (39.21 g) was obtained.

¹ H-NMR (CDCL ₃ ) δ: 1.73 (3H, dd, J = 7.0H
z, 1.6Hz), 5.93 (1H, q, J = 7.0Hz), 6.90-7.12 (2H,
m), 8.03 (1H, dt, J = 6.4Hz, 8.6Hz) [α] _D ²³ + 29.2 ° (c = 1.12, in methanol)

Reference Example 78 (2S) -2'-Fluoro-2-hydroxypropiophenone (synthesized by the method described in Reference Example 76: 3.36)
g) was dissolved in dichloromethane (30 ml), and diisopropylethylamine (4.18) was prepared at -60 ° C under a nitrogen atmosphere.
ml) and then trifluoromethanesulfonic anhydride (4.03 ml) was added dropwise over 2 minutes. The reaction temperature was gradually raised to -25 ° C, and the mixture was further stirred for 30 minutes. The reaction solution is subjected to silica gel chromatography [silica gel 60
g, eluate (dichloromethane: hexane = 1: 1)] and purified to obtain (2S) -2′-fluoro-2-trifluoromethanesulfonyloxypropiophenone (5.30 g) as a pale yellow oil. Was given.

¹ H-NMR (CDCL ₃ ) δ: 1.73 (3H, dd, J = 7Hz,
J = 1.6Hz), 6.49 (1H, q, J = 7Hz), 7.15-7.38 (2H, m),
7.58-7.72 (1H, m), 7.97 (1H, dt, J = 1.8Hz, J = 7.6Hz)

Reference Example 79 1- [4- (1H-1,2,4-triazol-1-yl) phenyl] -2 (1H, 3H) -imidazolone (3.39 g) was added to 1-methyl-2-pyrrolidone. (220
72% oily sodium hydride (528 m
g) was added and stirred at room temperature for 1 hour. The reaction solution was ice-cooled and cooled to -20 ° C under a nitrogen atmosphere (2S) -2 '.
A solution of -fluoro-2-trifluoromethanesulfonyloxypropiophenone (4.7g) in tetrahydrofuran (100ml) was added dropwise over 15 minutes. After completion of dropping, the reaction temperature was raised to 10 ° C. over 30 minutes, and the mixture was further stirred for 12 hours. The reaction solution was diluted with acetic acid (10 ml) and ethyl acetate (500 ml), water (250 ml × 2),
0.5N hydrochloric acid (250 ml x 2) and saturated saline solution (25
The extract was washed with 0 ml), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel [silica gel, eluent (hexane: ethyl acetate:
After purification with acetic acid = 1: 4: 0.06] and recrystallization from diisopropyl ether (25 ml), 1-[(1
R) -2-Fluorophenyl) -2-oxo-1-methylethyl] -3- [4- (1H-1,2,4-triazol-1-yl) phenyl] -2 (1H, 3H) -imidazolone Was obtained as colorless powder crystals.

¹ H-NMR (CDCL ₃ ) δ: 1.65 (3H, d, J = 7.2H
z), 5.82 (1H, q, J = 7.2Hz), 6.64 (1H, d, J = 3.2Hz),
6.70 (1H, d, J = 3.2Hz), 7.14-7.31 (2H, m), 7.53-7.9
4 (6H, m), 8.11 (1H, s), 8.56 (1H, s)

Reference Example 80 1- [4- (1H-1-tetrazolyl) phenyl] -2
(1H, 3H) -Imidazolone (0.94 g) was dissolved in 1-methyl-2-pyrrolidone (25 ml), 72% oily sodium hydride (0.126 g) was added, and the mixture was stirred at room temperature for 30 minutes.
Stirred for minutes. This reaction solution was ice-cooled, and under nitrogen atmosphere, -1
(2S) -2'-Fluoro-2-trifluoromethanesulfonyloxypropiophenone (1.
57 g) in tetrahydrofuran (25 ml) was added dropwise over 10 minutes. After completion of the dropping, the reaction temperature was raised to 0 ° C. over 15 minutes, and the mixture was further stirred for 30 minutes. Dilute the reaction with acetic acid (3 ml) and ethyl acetate (100 ml),
The extract was washed with water (50 ml × 2), 0.5N hydrochloric acid (50 ml × 2) and saturated saline (50 ml), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography [eluent, hexane: ethyl acetate: acetic acid = 1: 3: 0.05] and then recrystallized from diisopropyl ether (20 ml) to give 1-
[(1R) -2-fluorophenyl) -2-oxo-1
-Methylethyl] -3- [4- (1H-1-tetrazolyl) phenyl] -2 (1H, 3H) -imidazolone (0.22g) was obtained as colorless powder crystals.

Melting point: 162-164 ° C. ¹ H-NMR (CDCL ₃ ) δ: 1.66 (3H, d, J = 7.2Hz), 5.83 (1H,
q, J = 7.2Hz), 6.67 (1H, d, J = 3.2Hz), 6.74 (1H, d,
J = 3.2Hz), 7.16-7.33 (2H, m), 7.54-7.98 (2H, m), 7.
77 (2H, d, J = 9Hz), 7.91 (2H, d, J = 9Hz), 9.03 (1H,
s)

Reference Example 81 Chloromethylisopropoxydimethylsilane (2.14)
g) and magnesium (for Grignard reaction, 313 mg)
Was added to tetrahydrofuran (15 ml) and heated to 60 ° C. Magnesium pieces activated with methyl iodide were added to this mixed solution, and the mixture was stirred at a bath temperature of 60 ° C for 3 hours.

The solution of the obtained Grignard reagent was cooled to 1-[(1R) -2- (2-fluorophenyl) -2 under ice cooling.
-Oxo-1-methylethyl] -3- [4- (1H-1
-Tetrazolyl) phenyl] -2 (1H, 3H) -imidazolone (1 g) was added dropwise to a tetrahydrofuran (150 ml) solution over 10 minutes, and then the mixture was stirred under ice cooling for 30 minutes. The reaction mixture was ice-cooled, cold saturated ammonium chloride solution (30 ml) and cold water (100 ml) were added, and the mixture was extracted with ethyl acetate (200 ml). The extract was washed with brine, dried over magnesium sulfate, concentrated under reduced pressure, and the residue was recrystallized from a mixed solution of diisopropyl ether and ethyl acetate to give 1-[(1R, 2S) -2- (2fluorophenyl). ) -2-Hydroxy-3- (isopropoxydimethylsilyl) -1-methylpropyl] -3- [4- (1H-
1-Tetrazolyl) phenyl] -2 (1H, 3H) -imidazolone (637 mg) was obtained as colorless powder crystals.

¹ H-NMR (d ₆ -DMSO) δ: -0.30 (3H, s), -0.
28 (3H, s), 0.99-1.64 (11H, m), 3.83 (1H, quintet,
J = 6Hz), 4.81 (1H, q, J = 7Hz), 5.21 (1H, br), 6.93-
7.77 (6H, m), 8.05 (2H, d, J = 9Hz), 8.17 (2H, d, J =
9Hz), 10.17 (1H, s)

Reference Example 82 1-[(1R, 2S) -2- (2-fluorophenyl)
2-Hydroxy-3- (isopropoxydimethylsilyl) -1-methylpropyl] -3- [4- (1H-1-
Tetrazolyl) phenyl] -2 (1H, 3H) -imidazolone (1 g) was dissolved in a mixture of methanol and tetrahydrofuran (1: 1, 20 ml), and 30% aqueous hydrogen peroxide solution (2 ml) and sodium hydrogen carbonate (157 mg) were added. In addition, it heated at 50 degreeC for 4 hours. The reaction solution was cooled and extracted with ethyl acetate (100 ml). The extract is water (30 ml),
The extract was washed with Na ₂ S ₂ O ₃ aqueous solution (30 ml × 2) and brine (30 ml), dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography [eluent (hexane: ethyl acetate = 1: 4)] and recrystallized from diethyl ether (20 ml) to give 1-[(1
R, 2S) -2- (2-fluorophenyl) -2,3-
Dihydroxy-1-methylpropyl] -3- [4- (1
H-1-tetrazolyl) phenyl] -2 (1H, 3H)
-Imidazolone (440 mg) was obtained as colorless powder crystals.

¹ H-NMR (CDCl ₃ ) δ: 1.17 (3H, d, J = 7Hz),
3.52-3.62 (1H, m), 4.05-4.18 (2H, m), 5.01 (1H,
q, J = 7Hz), 6.72 (1H, d, J = 3.2Hz), 6.82 (1H, d, J =
3.2Hz), 7.01-7.33 (3H, m), 7.70-7.78 (1H, m), 7.90
(2H, d, J = 9Hz), 7.99 (2H, d, J = 9Hz), 9.55 (1H, s)

Reference Example 83 1-[(1R, 2S) -2- (2-fluorophenyl)
-2,3-Dihydroxy-1-methylpropyl] -3-
(4- (1H-1-tetrazolyl) phenyl] -2 (1
(H, 3H) -Imidazolone (440 mg) was dissolved in a mixed solution of ethyl acetate and tetrahydrofuran (1: 2, 30 ml), and methanesulfonyl chloride (0.18 g) and triethylamine (0.16 g) were added dropwise under ice cooling. The reaction solution was stirred at 0 ° C. for 30 minutes and then washed with water (15 ml × 2) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography [eluent (hexane: ethyl acetate = 1: 4)] to give 1-[(1R, 2S) -2-.
(2-Fluorophenyl) -2-hydroxy-3-methanesulfonyloxy-1-methylpropyl] -3- [4
-(1H-1-tetrazolyl) phenyl] -2 (1H,
3H) -Imidazolone (330 mg) was obtained as colorless powder crystals.

¹ H-NMR (CDCl ₃ ) δ: 1.27 (3H, d, J = 7Hz),
2.87 (3H, s), 4.54 (1H, d, J = 12Hz), 4.73-4.88 (2
H, m), 6.63 (1H, d, J = 3.2Hz), 6.72 (1H, d, J = 3.2H
z), 7.09-7.39 (3H, m), 7.75-7.94 (1H, m), 7.81 (2H,
d, J = 9Hz), 7.93 (2H, d, J = 9Hz), 9.04 (1H, s)

Reference Example 84 1-[(1R, 2S) -2- (2-fluorophenyl)
-2-Hydroxy-3-methanesulfonyloxy-1-
Methylpropyl] -3- [4- (1H-1-tetrazolyl) phenyl] -2 (1H, 3H) -imidazolone (1
00 mg) was dissolved in dimethylformamide (4 ml), potassium carbonate (42 mg) was added, and the mixture was heated at 40 ° C for 1 hr. After diluting with ethyl acetate (20 ml), it was washed with water (10 ml) and brine (10 ml). The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent (hexane: ethyl acetate = 1: 4)]. The desired fraction is concentrated and recrystallized from diisopropyl ether to give 1-
[(1R, 2S) -2- (2-fluorophenyl)-
2,3-Epoxy-1-methylpropyl] -3- [4-
(1H-1-tetrazolyl) phenyl] -2 (1H, 3
H) -imidazolone (58 mg) was obtained as colorless powder crystals.

¹ H-NMR (CDCl ₃ ) δ: 1.40 (3H, d, J = 7Hz),
2.76 (1H, d, J = 5Hz), 2.84 (1H, d, J = 5Hz), 5.15 (1
H, q, J = 7Hz), 6.55 (1H, d, J = 3.2Hz), 6.67 (1H, d,
J = 3.2Hz), 7.07-7.48 (4H, m), 7.79 (2H, d, J = 9Hz),
7.95 (2H, d, J = 9Hz), 9.05 (1H, s)

Example 1 60% oily sodium hydride (108 mg) was dispersed in dimethylformamide (4 ml), and 1,2,2.
4-Triazole (207 mg) was added and the mixture was stirred at room temperature for 10 minutes. Then, 2-[(1R, 2S) -2- (2,
4-difluorophenyl) -2,3-epoxy-1-methylpropyl] -4- [4- [5-oxo-4- [4-
(2,2,3,3-Tetrafluoropropoxy) phenyl] -1H-1,2,4-triazol-1-yl] phenyl] -3 (2H, 4H) -1,2,4-triazolone (560 mg) Dimethylformamide solution (2 ml) was added and the mixture was heated at 60 ° C. for 11 hours. After cooling, cold water (40 ml) and ethyl acetate (40 ml) were added to the reaction mixture to separate it,
The aqueous layer was extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed sequentially with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was chromatographed on silica gel (eluent: ethyl acetate / hexane = 19 /
1-> ethyl acetate) and then purified by reverse phase chromatography (eluent: methanol / water = 4/1) to give 2-[(1R, 2R) -2- (2,4-difluoro). Phenyl) -2-hydroxy-1-methyl-3- (1
H-1,2,4-triazol-1-yl) propyl]
-4- [4- [5-oxo-4- [4- (2,2,3
3-Tetrafluoropropoxy) phenyl] -1H-
1,2,4-triazol-1-yl] phenyl] -3
(2H, 4H) -1,2,4-triazolone (compound
1 ; 0.21 g) was obtained as a colorless powder. [Α] ²⁰ _D -16.9 ° (c = 1.0% in MeOH) Elemental analysis value: Calculated value as C ₃₁ H ₂₅ F ₆ N ₉ O ₄ .0.5H ₂ O (%): C, 52.40; H, 3.69; N, 17.74 Found (%): C, 52.59; H, 3.67; N, 17.69

Example 2 (2R, 3S) -2- (2,4-difluorophenyl)
-3-Methyl-2- (1H-1,2,4-triazol-1-yl) methyloxirane (1.2 g), 4- [4
-[2-oxo-3- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -1H, 3H-imidazol-1-yl] phenyl] -3 (2H, 4H)-
1,2,4-Triazolone (2.2 g) and potassium carbonate (powder: 3.5 g) were added to N, N-dimethylformamide (50 ml), and the mixture was heated at 90 ° C. for 42 hours while stirring. After cooling the reaction mixture, ethyl acetate (150 m
l), diluted with tetrahydrofuran (50 ml), added to ice water (150 ml) and the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate (100 ml). The ethyl acetate layers were combined, 0.5N-aqueous sodium hydroxide (100 ml), 1
N-hydrochloric acid (100 ml), followed by saturated saline solution (100 ml)
And washed. After drying the ethyl acetate layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / acetone = 10/1) and then crystallized from tetrahydrofuran-diisopropyl ether to give 2-
[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-triazol-1-yl) propyl] -4-
[4- [2-oxo-3- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -1H, 3H-imidazol-1-yl] phenyl] -3 (2H, 4H)
-1,2,4-triazolone (Compound 2 ; 0.26 g)
Was obtained as colorless powder crystals.

Melting point: 181 to 183 ° C. Elemental analysis value: Calculated value as C ₃₂ H ₂₆ F ₆ N ₈ O ₄ (%): C, 54.86; H, 3.74; N, 15.99 Actual value (%): C, 54.58 H, 3.75; N, 15.71 [α] ²⁰ _D -18.9 ° (c = 1.0% in MeOH)

Example 3 In the same manner as in Example 2, 2-[(1R, 2R) -2-
(2,4-difluorophenyl) -2-hydroxy-1
-Methyl-3- (1H-1,2,4-triazole-1
-Yl) propyl] -4- [4- [2-oxo-3-
[4- (1,1,2,2-Tetrafluoroethoxy) phenyl] -1H, 3H-imidazol-1-yl] phenyl] -3 (2H, 4H) -1,2,4-triazolone (Compound 3 ) was gotten.

Colorless powder crystal Melting point: 214 to 215 ° C. Elemental analysis value: Calculated as C ₃₁ H ₂₄ F ₆ N ₈ O ₄ (%): C, 54.23; H, 3.52; N, 16.32 Measured value (%): C, 54.05; H, 3.37; N, 16.32 [α] ²⁰ _D -19.0 ° (c = 1.0% in MeOH)

Example 4 A mixture of 60% oily sodium hydride (0.24 g) and dimethyl sulfoxide (60 ml) was stirred at 80 ° C. for 30 minutes. To this mixture was added 4- [4- [5-oxo-4
-(2,2,2-trifluoroethyl) -1H, 4H-
1,2,4-triazol-1-yl] phenyl] -3
(2H, 4H) -1,2,4-triazolone (1.94
g) and after stirring for 5 minutes, (2R, 3S) -2
-(2,4-Difluorophenyl) -3-methyl-2-
(1H-1,2,4-triazol-1-yl) methyloxirane (1.0 g) was added, and the mixture was stirred under an argon atmosphere for 8 hours.
Stir at 0 ° C. for 24 hours. After cooling the reaction solution, it was diluted with ethyl acetate (300 ml) and washed with water (50 ml × 2) and brine (50 ml). The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Silica gel chromatography of the residue (eluent: hexane / ethyl acetate = 1/2 →
When purified by subjecting to 2-((1R, 2
R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- [4- [5- Oxo-4- (2,2,2-trifluoroethyl) -1H,
4H-1,2,4-triazol-1-yl] phenyl] -3- (2H, 4H) -1,2,4-triazolone (Compound 4 ; 0.46 g) was obtained as a pale yellow powder.

¹ H-NMR (CDCl ₃ ) δ: 1.31 (3H, d, J = 7Hz),
4.36 (2H, q, J = 8.4Hz), 4.37 (1H, d, J = 14Hz), 5.03
(1H, d, J = 14Hz), 5.10 (1H, q, J = 7Hz), 5.44 (1H,
s), 6.75-6.88 (2H, m), 7.48-7.65 (1H, m), 7.67 (2H,
d, J = 9Hz), 7.68 (1H, s), 7.69 (1H, s), 7.83 (1H,
s), 7.94 (1H, s), 8.16 (2H, d, J = 9Hz)

Example 5 (2R, 3S) -2- (2,4-difluorophenyl)
-3-Methyl-2- (1H-1,2,4-triazol-1-yl) methyloxirane (1.0 g) and 4- [4
-(1H-1,2,4-triazol-1-yl) phenyl] -3 (2H, 4H) -1,2,4-triazolone (0.91 g) was reacted in the same manner as in Example 4 to give 2-
[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-triazol-1-yl) propyl] -4-
[4- (1H-1,2,4-triazol-1-yl)
Phenyl] -3 (2H, 4H) -1,2,4-triazolone (Compound 5 ; 0.54 g) was obtained.

Colorless powdery crystal Melting point: 182 to 184 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.32 (3H, d, J = 7Hz), 4.40 (1H,
d, J = 14.4Hz), 5.03 (1H, d, J = 14.4Hz), 5.11 (1H, q,
J = 7Hz), 5.41 (1H, s), 6.75-6.90 (2H, m), 7.50-7.65
(1H, m), 7.69 (1H, s), 7.79 (2H, d, J = 9Hz), 7.88
(2H, d, J = 9Hz), 7.92 (1H, s) 7.96 (1H, s), 8.14 (1
H, s), 8.65 (1H, s) Elemental analysis value: Calculated as C ₂₂ H ₁₉ F ₂ N ₉ O ₂ (%): C, 55.11; H, 3.99; N, 26.29 Measured value (%): C , 55.05; H, 4.01; N, 26.14 IR (KBr): 1714, 1618, 1556, 1527, 1394cm ^-1

Example 6 (2R, 3S) -2- (2,4-difluorophenyl)
-3-Methyl-2- (1H-1,2,4-triazol-1-yl) methyloxirane (1.0 g) and 4- [4
-(1H-1,2,3-triazol-1-yl) phenyl] -3 (2H, 4H) -1,2,4-triazolone (1.09 g) was reacted in the same manner as in Example 4 to give 2-
[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-triazol-1-yl) propyl] -4-
[4- (1H-1,2,3-triazol-1-yl)
Phenyl] -3 (2H, 4H) -1,2,4-triazolone (Compound 6 ; 0.27 g) was obtained.

Colorless powdery crystal Melting point: 219 to 220 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.32 (3H, d, J = 7Hz), 4.40 (1H,
d, J = 14.2Hz), 5.03 (1H, d, J = 14.2Hz), 5.10 (1H, q,
J = 7Hz), 5.38 (1H, s), 6.75-6.90 (2H, m), 7.50-7.65
(1H, m), 7.70 (1H, s), 7.82 (2H, d, J = 9Hz), 7.88
(1H, s), 7.90 (1H, s), 7.94 (2H, d, J = 9Hz), 7.94
(1H, s), 8.05 (1H, s) Elemental analysis value: Calculated value as C ₂₂ H ₁₉ F ₂ N ₉ O ₂ (%): C, 55.11; H, 3.99; N, 26.29 Measured value (%): C, 54.91; H, 3.97; N, 26.26 IR (KBr): 1700, 1675, 1618, 1556, 1527, 1502
cm ^-1

Example 7 (2R, 3S) -2- (2,4-difluorophenyl)
-3-Methyl-2- (1H-1,2,4-triazol-1-yl) methyloxirane (1,0 g) and 4- [4
-(2H-1,2,3-triazol-2-yl) phenyl] -3 (2H, 4H) -1,2,4-triazolone (1.09 g) was reacted in the same manner as in Example 4 to give 2-
[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-triazol-1-yl) propyl] -4-
[4- (2H-1,2,3-triazol-2-yl)
Phenyl] -3 (2H, 4H) -1,2,4-triazolone (Compound 7 ; 0.65 g) was obtained.

Light yellow plate crystal Melting point: 213-215 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.32 (3H, d, J = 7Hz), 4.38 (1H,
d, J = 14.2Hz), 5.04 (1H, d, J = 14.2Hz), 5.11 (1H, q,
J = 7Hz), 5.42 (1H, s), 6.75-6.90 (2H, m), 7.50-7.64
(1H, m), 7.69 (1H, s), 7.74 (2H, d, J = 9Hz), 7.85
(2H, s), 7.86 (1H, s), 7.95 (1H, s), 8.25 (2H, d,
J = 9Hz) Elemental analysis value: Calculated value as C ₂₂ H ₁₉ F ₂ N ₉ O ₂ (%): C, 55.11; H, 3.99; N, 26.29 Actual value (%): C, 54.97; H, 3.96; N, 26.29 IR (KBr): 1697, 1623, 1602, 1564, 1519, 1510
cm ^-1

Example 8 In the same manner as in Example 4, 2-[(1R, 2R) -2-
(2,4-difluorophenyl) -2-hydroxy-1
-Methyl-3- (1H-1,2,4-triazole-1
-Yl) propyl] -4- [4- [5-oxo-4-
(2,2,3,3-tetrafluoropropyl) -1H,
4H-1,2,4-triazol-1-yl] phenyl] -3 (2H, 4H) -1,2,4-triazolone (Compound 8 ) was obtained.

Light yellow powder ¹ H-NMR (CDCl ₃ ) δ: 1.31 (3H, d, J = 7Hz), 4.34 (2H,
t, J = 14Hz), 4.37 (1H, d, J = 14Hz), 5.04 (1H, d, J = 14)
Hz), 5.10 (1H, q, J = 7Hz), 5.46 (1H, s), 5.98 (1H,
tt, J = 53Hz, J = 2.4Hz), 6.75-6.90 (2H, m), 7.50-7.65
(1H, m), 7.67 (2H, d, J = 9Hz), 7.68 (1H, s), 7.72
(1H, s), 7.86 (1H, s), 7.96 (1H, s), 8.16 (2H, d,
(J = 9Hz)

Example 9 (2R, 3S) -2- (2,4-difluorophenyl)
-3-Methyl-2- (1H-1,2,4-triazol-1-yl) methyloxirane (2.5 g), 1- [4
-(1H-1,2,4-triazol-1-yl) phenyl] -2 (1H, 3H) -imidazolone (2.72
g) and cesium carbonate (powder form: 9.7 g) with N, N
-Add to dimethylformamide (150 ml) and heat with stirring at 80 ° C for 9.5 hours. After cooling the reaction solution,
It was diluted with ethyl acetate (400 ml), added to ice water (150 ml) and the ethyl acetate layer was separated. The aqueous layer was washed with ethyl acetate (1
00 ml). Combine the ethyl acetate layers to 0.5N
-Aqueous sodium hydroxide (100 ml), 1N-hydrochloric acid (10
It was washed with 0 ml × 2) and then saturated saline solution (50 ml).
After drying the ethyl acetate layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. Silica gel column chromatography of the residue (eluent: ethyl acetate / acetone = 2/1)
When purified by adding 1-[(1R, 2R) -2-
(2,4-difluorophenyl) -2-hydroxy-1
-Methyl-3- (1H-1,2,4-triazole-1
-Yl) propyl] -3- [4- (1H-1,2,4-
Triazol-1-yl) phenyl] -2 (1H, 3
H) -Imidazolone (Compound 9 ; 1.03 g) was obtained as a pale yellow powder.

¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, d, J = 7Hz),
4.22 (1H, d, J = 14.2Hz), 5.01 (1H, q, J = 7Hz), 5.12
(1H, d, J = 14.2Hz), 5.50 (1H, br), 6.72 (1H, d, J =
3.2Hz), 6.73-6.90 (2H, m), 6.83 (1H, d, J = 3.2Hz),
7.40-7.55 (1H, m), 7.75 (1H, s), 7.78 (2H, d, J = 9.
4Hz), 7.86 (1H, s), 7.86 (2H, d, J = 9.4Hz), 8.13 (1
H, s), 8.59 (1H, s) IR (KBr): 3400, 3118, 1683, 1616, 1527, 1500
cm ^-1

Example 10 1-[(1R, 2R) -2- (2 obtained in Example 9
4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (1H-1,2,4-triazole- 1-yl) phenyl] -2 (1H, 3H)-
Imidazolone (0.50 g) was dissolved in acetic acid (25 ml), 10% palladium-carbon (200 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours and further at 50 ° C for 3 hours. After the catalyst was filtered off, the filtrate was concentrated and the residue was subjected to silica gel chromatography (eluent: ethyl acetate / acetone =
After purification by 5/1 → 2/1) and recrystallization from ethyl acetate-diisopropyl ether, 1-[(1
R, 2R) -2- (2,4-difluorophenyl) -2
-Hydroxy-1-methyl-3- (1H-1,2,4-
Triazol-1-yl) propyl] -3- [4- (1
H-1,2,4-triazol-1-yl) phenyl]
-2-Imidazolidinone (compound 10 ; 0.37 g) was obtained as colorless powder crystals.

¹ H-NMR (CDCl ₃ ) δ: 1.08 (3H, d, J = 7.2H
z), 3.68-4.18 (4H, m), 4.52 (1H, d, J = 14Hz), 4.58-
4.80 (1H, m), 5.12 (1H, d, J = 14Hz), 5.38 (1H, br),
6.70-6.86 (2H, m), 7.35-7.50 (1H, m), 7.66 (2H, dt,
J = 9.4Hz, J = 2.4Hz), 7.75 (2H, dt, J = 9.4Hz, J = 2.4H
z), 7.77 (1H, s), 7.87 (1H, s), 8.11 (1H, s), 8.53
(1H, s) Elemental _{analysis: C 23 H 22 F 2 N} 8 O 2 Calculated (%): C, 57.50; H, 4.62; N, 23.32 Found (%): C, 57.46; H, 4.47 N, 23.19 IR (KBr): 3390, 3106, 1677, 1614, 1523, 1484
cm ^-1

Example 11 1- [4- (1H-1,2,3-triazol-1-yl) phenyl] -2 (1H, 3H) -imidazolone (2.72 g) and 1-methyl-2-pyrrolidone (100
a mixture of sodium hydride (70% oily, 0.
40 g) and stirred at room temperature for 1 hour, and then (2R,
3S) -2- (2,4-Difluorophenyl) -3-methyl-2- (1H-1,2,4-triazol-1-yl) methyloxirane (2.51 g) was added and 100 ° C. in an argon atmosphere. The mixture was heated and stirred for 8 hours. After cooling, ethyl acetate (400 ml) was added to the reaction mixture, water (100 ml), 1
It was washed with N-hydrochloric acid (100 ml × 2) and brine (50 ml). The ethyl acetate layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was chromatographed on silica gel (eluent: ethyl acetate → ethyl acetate / acetone = 5 /
After purification by 1) and recrystallization from ethyl acetate-diisopropyl ether, 1-[(1R, 2R)-
2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (1H-1,2 ，
3-triazol-1-yl) phenyl] -2 (1H,
3H) -Imidazolone (Compound 11 ; 1.82 g) was obtained as pale yellow powdery crystals.

Melting point: 178-181 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.22 (3H, d, J = 7Hz), 4.22 (1H,
d, J = 14.4Hz), 5.01 (1H, q, J = 7Hz), 5.12 (1H, d, J =
14.4Hz), 5.38 (1H, br), 6.70-6.88 (4H, m), 7.40-7.5
5 (1H, m), 7.76 (1H, s), 7.80-7.93 (6H, m), 8.03 (1
H, s) Elemental _{analysis: C 23 H 20 F 2 N} 8 O 2 Calculated (%): C, 57.74; H, 4.21; N, 23.42 Found (%): C, 57.46; H, 4.25; N, 23.30 IR (KBr): 1691, 1656, 1619, 1527, 1502, 1430
cm ^-1

Example 12 1-[(1R, 2R) -2-obtained in Example 11
(2,4-difluorophenyl) -2-hydroxy-1
-Methyl-3- (1H-1,2,4-triazole-1
-Yl) propyl] -3- [4- (1H-1,2,3-
Triazol-1-yl) phenyl] -2 (1H, 3
H) -Imidazolone (0.80 g) was subjected to catalytic reduction reaction in the same manner as in Example 10 to give 1-[(1R, 2R)-
2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (1H-1,2 ，
3-Triazol-1-yl) phenyl] -2-imidazolidinone (Compound 12 ; 0.69 g) was obtained.

Colorless powdery crystal ¹ H-NMR (CDCl ₃ ) δ: 1.08 (3H, d, J = 7Hz), 3.70-4.14
(4H, m), 4.52 (1H, d, J = 14.2Hz), 4.60-4.78 (1H, m),
5.12 (1H, d, J = 14.2Hz), 5.38 (1H, br), 6.70-6.86
(2H, m), 7.35-7.50 (1H, m), 7.68-7.82 (4H, m), 7.7
7 (1H, s), 7.86 (2H, s), 7.97 (1H, s) Elemental analysis value: Calculated as C ₂₃ H ₂₂ F ₂ N ₈ O ₂ (%): C, 57.50; H, 4.62; N , 23.32 Measured value (%): C, 57.38; H, 4.59; N, 23.41 IR (KBr): 1697, 1664, 1618, 1527, 1502, 1427
cm ^-1

Example 13 (2R, 3S) -2- (2,4-difluorophenyl)
-3-methyl-2- (1H-1,2,4-triazol-1-yl) methyloxirane (2.51 g), 1-
[4- (2H-1,2,3-triazol-2-yl)
Phenyl] -2 (1H, 3H) -imidazolone (2.7
2 g) was reacted in the same manner as in Example 11 to give 1-
[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-triazol-1-yl) propyl] -3-
[4- (2H-1,2,3-triazol-2-yl)
Phenyl] -2 (1H, 3H) -imidazolone (compound
13 ; 1.41 g) was obtained.

Light yellow needle crystals Melting point: 182 to 185 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.22 (3H, d, J = 7Hz), 4.22 (1H,
d, J = 14.4Hz), 4.99 (1H, q, J = 7Hz), 5.01 (1H, d, J =
14.4Hz), 5.13 (1H, br), 6.70-6.88 (4H, m), 7.40-7.5
6 (1H, m), 7.75 (1H, s), 7.81 (2H, d, J = 9.2Hz), 7.8
4 (2H, s), 7.86 (1H, s), 8.18 (2H, d, J = 9.2Hz) Elemental analysis value: Calculated value as C ₂₃ H ₂₀ F ₂ N ₈ O ₂ (%): C, 57.74; H, 4.21; N, 23.42 actual value (%): C, 57.67; H, 4.20; N, 23.59 IR (KBr): 3328, 1664, 1614, 1519, 1430, 1384
cm ^-1

Example 14 1-[(1R, 2R) -2-obtained in Example 13
(2,4-difluorophenyl) -2-hydroxy-1
-Methyl-3- (1H-1,2,4-triazole-1
-Yl) propyl] -3- [4- (2H-1,2,3-
Triazol-2-yl) phenyl] -2 (1H, 3
H) -Imidazolone (0.80 g) was subjected to catalytic reduction reaction in the same manner as in Example 10 to give 1-[(1R, 2R)-
2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (2H-1,2 ，
3-Triazol-2-yl) phenyl] -2-imidazolidinone (Compound 14 ; 0.70 g) was obtained.

Colorless powdery crystal Melting point: 196-197 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.08 (3H, d, J = 7.4Hz), 3.68-4.12
(4H, m), 4.53 (1H, d, J = 14Hz), 4.58-4.76 (1H, m),
5.13 (1H, d, J = 14Hz), 5.42 (1H, br), 6.70-6.85 (2H,
m), 7.36-7.50 (1H, m), 7.71 (2H, d, J = 9Hz), 7.76
(1H, s), 7.81 (2H, s), 7.87 (1H, s), 8.07 (2H, d,
J = 9Hz) IR (KBr): 3426, 1687, 1658, 1616, 1517, 1484
cm ^-1

Example 15 (2R, 3S) -2- (2,4-difluorophenyl)
-3-Methyl-2- (1H-1,2,4-triazol-1-yl) methyloxirane and 1- [4- (1H-1
When -pyrazolyl) phenyl] -2 (1H, 3H) -imidazolone was reacted in the same manner as in Example 11, 1-
[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-triazol-1-yl) propyl] -3-
[4- (1H-1-pyrazolyl) phenyl] -2 (1
H, 3H) -Imidazolone (Compound 15 ) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, d, J = 7Hz),
4.22 (1H, d, J = 14.4Hz), 4.98 (1H, q, J = 7Hz), 5.12
(1H, d, J = 14.4Hz), 5.56 (1H, br), 6.47-6.54 (1H,
m), 6.68-6.88 (4H, m), 7.40-7.56 (1H, m), 7.70-7.8
5 (6H, m), 7.85 (1H, s), 7.94 (1H, d, J = 2.4Hz) Elemental analysis value: Calculated as C ₂₄ H ₂₁ F ₂ N ₇ O ₂ (%): C, 60.37; H, 4.43; N, 20.53 actual value (%): C, 60.29; H, 4.42; N, 20.50

Example 16 1-[(1R, 2R) -2-obtained in Example 15
(2,4-difluorophenyl) -2-hydroxy-1
-Methyl-3- (1H-1,2,4-triazole-1
-Yl) propyl] -3- [4- (1H-1-pyrazolyl) phenyl] -2 (1H, 3H) -imidazolone (compound 15 ) was subjected to catalytic reduction reaction in the same manner as in Example 10. And 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1
H-1,2,4-triazol-1-yl) propyl]
-3- [4- (1H-1-pyrazolyl) phenyl] -2
-Imidazolidinone (compound 16 ) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.08 (3H, d, J = 7Hz),
3.65-4.10 (4H, m), 4.53 (1H, d, J = 14.2Hz), 4.55-4.
75 (1H, m), 5.12 (1H, d, J = 14.2Hz), 5.45 (1H, br),
6.46-6.48 (1H, m), 6.70-6.85 (2H, m), 7.35-7.50 (1
H, m), 7.60-7.75 (5H, m), 7.76 (1H, s), 7.88 (1H,
s), 7.90 (1H, d, J = 2.6Hz) Elemental analysis value: Calculated as C ₂₄ H ₂₃ F ₂ N ₇ O ₂ (%): C, 60.12; H, 4.83; N, 20.45 Measured value (%) ): C, 60.02; H, 4.95; N, 20.34

Example 17 (2R, 3S) -2- (2,4-difluorophenyl)
-3-Methyl-2- (1H-1,2,4-triazol-1-yl) methyloxirane and 1- [4- (1H-
When 1,2,4-triazol-1-ylmethyl) phenyl] -2 (1H, 3H) -imidazolone was reacted in the same manner as in Example 11, 1-[(1R, 2R) -2-
(2,4-difluorophenyl) -2-hydroxy-1
-Methyl-3- (1H-1,2,4-triazole-1
-Yl) propyl] -3- [4- (1H-1,2,4-
Triazol-1-ylmethyl) phenyl] -2 (1
H, 3H) -Imidazolone (Compound 17 ) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, d, J = 7Hz),
4.19 (1H, d, J = 14.4Hz), 4.97 (1H, q, J = 7Hz), 5.10
(1H, d, J = 14.4Hz), 5.37 (2H, s), 5.55 (1H, br), 6.
65 (1H, d, J = 3.2Hz), 6.70-6.90 (3H, m), 7.37 (2H,
d, J = 8.6Hz), 7.35-7.55 (1H, m), 7.69 (2H, d, J = 8.6H
z), 7.74 (1H, s), 7.85 (1H, s), 7.99 (1H, s), 8.10
(1H, s)

Example 18 (2R, 3S) -2- (2,4-difluorophenyl)
-3-Methyl-2- (1H-1,2,4-triazol-1-yl) methyloxirane and 4- [4- (1H-
When 1,2,4-triazol-1-ylmethyl) phenyl] -3 (2H, 4H) -1,2,4-triazolone was reacted in the same manner as in Example 11, 2-[(1R,
2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- [4- (1H-
1,2,4-triazol-1-ylmethyl) phenyl] -3 (2H, 4H) -1,2,4-triazolone (Compound 18 ) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, d, J = 7.2H
z), 4.36 (1H, d, J = 14.2Hz), 5.02 (1H, d, J = 14.2Hz),
5.09 (1H, q, J = 7.2Hz), 5.42 (2H, s), 5.43 (1H, s),
6.75-6.90 (2H, m), 7.43 (2H, d, J = 8.6Hz), 7.50-7.
67 (1H, m), 7.63 (2H, d, J = 8.6Hz), 7.69 (1H, s),
7.82 (1H, s), 7.94 (1H, s), 8.01 (1H, s), 8.15 (1
H, s)

Example 19 (2R, 3S) -2- (2,4-difluorophenyl)
-3-methyl-2- (1H-1,2,4-triazol-1-yl) methyloxirane and 4- [4- (1H-1
-Pyrazolyl) phenyl] -3 (2H, 4H) -1,
When 2,4-triazolone was reacted in the same manner as in Example 11, 2-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3-
(1H-1,2,4-triazol-1-yl) propyl] -4- [4- (1H-1-pyrazolyl) phenyl]
-3 (2H, 4H) -1,2,4-triazolone (Compound 19 ) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.32 (3H, d, J = 7Hz),
4.38 (1H, d, J = 14.4Hz), 5.05 (1H, d, J = 14.4Hz),
5.11 (1H, q, J = 7Hz), 5.45 (1H, s), 6.52-6.54 (1H,
m), 6.76-6.90 (2H, m), 7.50-7.65 (1H, m), 7.65-7.93
(7H, m), 7.96 (1H, s), 7.98 (1H, d, J = 2.6Hz)

Example 20 (2R, 3S) -2- (2,4-difluorophenyl)
-3-Methyl-2- (1H-1,2,4-triazol-1-yl) methyloxirane and 1- [4- (2H-
When 1,2,3-triazol-2-ylmethyl) phenyl] -2 (1H, 3H) -imidazolone was reacted in the same manner as in Example 11, 1-[(1R, 2R) -2-
(2,4-difluorophenyl) -2-hydroxy-1
-Methyl-3- (1H-1,2,4-triazole-1
-Yl) propyl] -3- [4- (2H-1,2,3-
Triazol-2-ylmethyl) phenyl] -2 (1
H, 3H) -Imidazolone (Compound 20 ) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.19 (3H, d, J = 7Hz),
4.17 (1H, d, J = 14.4Hz), 4.95 (1H, q, J = 7Hz), 5.09
(1H, d, J = 14.4Hz), 5.55 (1H, br), 5.63 (2H, s), 6.
63 (1H, d, J = 3.2Hz), 6.70-6.86 (3H, m), 7.40-7.55
(1H, m), 7.42 (2H, d, J = 8.6Hz), 7.64 (2H, s), 7.64
(2H, d, J = 8.6Hz), 7.73 (1H, s), 7.85 (1H, s)

Example 21 (2R, 3S) -2- (2,4-difluorophenyl)
-3-Methyl-2- (1H-1,2,4-triazol-1-yl) methyloxirane and 4- [4- (2H-
When 1,2,3-triazol-2-ylmethyl) phenyl] -3 (2H, 4H) -1,2,4-triazolone was reacted in the same manner as in Example 11, 2-[(1R,
2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- [4- (2H-
1,2,3-triazol-2-ylmethyl) phenyl] -3 (2H, 4H) -1,2,4-triazolone (Compound 21 ) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.29 (3H, d, J = 7Hz),
4.34 (1H, d, J = 14.4Hz), 5.02 (1H, d, J = 14.4Hz),
5.08 (1H, q, J = 7Hz), 5.44 (1H, s), 5.66 (2H, s), 6.
73-6.87 (2H, m), 7.46 (2H, d, J = 8.6Hz), 7.50-7.62
(1H, m), 7.58 (2H, d, J = 8.6Hz), 7.66 (2H, s), 7.68
(1H, s), 7.78 (1H, s), 7.94 (1H, s) Elemental analysis value: Calculated as C ₂₃ H ₂₁ F ₂ N ₉ O ₂ (%): C, 55.98; H, 4.29; N, 25.55 observed (%): C, 55.87; H, 4.18; N, 25.42

Example 22 (2R, 3S) -2- (2,4-difluorophenyl)
-3-methyl-2- (1H-1,2,4-triazol-1-yl) methyloxirane and 4- [4- (1H-1
-Imidazolyl) phenyl] -3 (2H, 4H) -1,
When 2,4-triazolone was reacted in the same manner as in Example 11, 2-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3-
(1H-1,2,4-triazol-1-yl) propyl] -4- [4- (1H-1-imidazolyl) phenyl] -3 (2H, 4H) -1,2,4-triazolone (Compound 22 )was gotten.

¹ H-NMR (CDCl ₃ ) δ: 1.32 (3H, d, J = 7Hz),
4.40 (1H, d, J = 14Hz), 5.03 (1H, d, J = 14Hz), 5.11
(1H, q, J = 7Hz), 5.42 (1H, s), 6.73-6.88 (2H, m),
7.26 (1H, s), 7.33 (1H, s), 7.51-7.65 (1H, m), 7.57
(2H, d, J = 9Hz), 7.71 (1H, s), 7.76 (2H, d, J = 9H)
z), 7.86 (1H, s), 7.91 (1H, s), 7.95 (1H, s)

Example 23 (2R, 3S) -2- (2,4-difluorophenyl)
-3-Methyl-2- (1H-1,2,4-triazol-1-yl) methyloxirane and 1- [4- (1H-1
-Imidazolyl) phenyl] -2 (1H, 3H) -imidazolone was reacted in the same manner as in Example 11 to give 1-
[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-triazol-1-yl) propyl] -3-
[4- (1H-1-imidazolyl) phenyl] -2 (1
H, 3H) -Imidazolone (Compound 23 ) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, d, J = 7Hz),
4.22 (1H, d, J = 14Hz), 5.00 (1H, q, J = 7Hz), 5.12 (1
H, d, J = 14Hz), 5.56 (1H, br), 6.70 (1H, d, J = 3Hz),
6.76-6.86 (3H, m), 7.23 (1H, s), 7.30 (1H, s), 7.
42-7.54 (1H, m), 7.49 (2H, d, J = 8Hz), 7.75 (1H, s),
7.78 (1H, s), 7.84 (2H, d, J = 8Hz), 7.86 (1H, s)

Example 24 1-[(1R, 2R) -2-obtained in Example 23
(2,4-difluorophenyl) -2-hydroxy-1
-Methyl-3- (1H-1,2,4-triazole-1
-Yl) propyl] -3- [4- (1H-1-imidazolyl) phenyl] -2 (1H, 3H) -imidazolone (Compound 23 ) was subjected to catalytic reduction reaction in the same manner as in Example 10 to give 1- [. (1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3-
(1H-1,2,4-triazol-1-yl) propyl] -3- [4- (1H-1-imidazolyl) phenyl] -2-imidazolidinone (Compound 24 ) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.08 (3H, d, J = 7Hz),
3.70-4.08 (4H, m), 4.52 (1H, d, J = 14Hz), 4.55-4.76
(1H, m), 5.11 (1H, d, J = 14Hz), 5.40 (1H, br), 6.7
3-6.84 (2H, m), 7.20 (1H, s), 7.26 (1H, s), 7.36-7.
50 (1H, m), 7.39 (2H, d, J = 9Hz), 7.69 (2H, d, J = 9H
z), 7.76 (1H, s), 7.82 (1H, s), 7.87 (1H, s)

Example 25 (2R, 3S) -2- (2,4-difluorophenyl)
-3-Methyl-2- (1H-1,2,4-triazol-1-yl) methyloxirane and 4- [4- (2H-2
-Tetrazolyl) phenyl] -3 (2H, 4H) -1,
When 2,4-triazolone was reacted in the same manner as in Example 11, 2-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3-
(1H-1,2,4-triazol-1-yl) propyl] -4- [4- (2H-2-tetrazolyl) phenyl] -3 (2H, 4H) -1,2,4-triazolone (Compound 25 )was gotten.

¹ H-NMR (CDCl ₃ ) δ: 1.33 (3H, d, J = 7Hz),
4.40 (1H, d, J = 14Hz), 5.04 (1H, d, J = 14Hz), 5.11
(1H, q, J = 7Hz), 5.37 (1H, s), 6.77-6.88 (2H, m),
7.52-7.64 (1H, m), 7.71 (1H, s), 7.87 (2H, d, J = 9H
z), 7.92 (1H, s), 7.95 (1H, s), 8.34 (2H, d, J = 9H
z), 8.71 (1H, s) Elemental analysis value: Calculated as C ₂₁ H ₁₈ F ₂ N ₁₀ O ₂ (%): C, 52.50; H, 3.78; N, 29.15 Measured value (%): C, 52.36 H, 3.85; N, 29.02

Example 26 (2R, 3S) -2- (2,4-difluorophenyl)
-3-Methyl-2- (1H-1,2,4-triazol-1-yl) methyloxirane and 1- [4- (2H-2
-Tetrazolyl) phenyl] -2 (1H, 3H) -imidazolone was reacted in the same manner as in Example 11 to give 1-
[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-triazol-1-yl) propyl] -3-
[4- (2H-2-tetrazolyl) phenyl] -2 (1
H, 3H) -Imidazolone (compound 26 ) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, d, J = 7Hz),
4.22 (1H, d, J = 14Hz), 5.02 (1H, q, J = 7Hz), 5.12 (1
H, d, J = 14Hz), 5.49 (1H, br), 6.75 (1H, d, J = 3Hz),
6.75-6.85 (2H, m), 6.85 (1H, d, J = 3Hz), 7.42-7.54
(1H, m), 7.76 (1H, s), 7.85 (1H, s), 7.93 (2H, d,
J = 9Hz), 8.25 (2H, d, J = 9Hz), 8.68 (1H, s)

Example 27 1-[(1R, 2R) -2-obtained in Example 26
(2,4-difluorophenyl) -2-hydroxy-1
-Methyl-3- (1H-1,2,4-triazole-1
-Yl) propyl] -3- [4- (2H-2-tetrazolyl) phenyl] -2 (1H, 3H) -imidazolone (Compound 26 ) was subjected to catalytic reduction reaction in the same manner as in Example 10 to give 1- [. (1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3-
(1H-1,2,4-triazol-1-yl) propyl] -3- [4- (2H-2-tetrazolyl) phenyl] -2-imidazolidinone (Compound 27 ) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.08 (3H, d, J = 7Hz),
3.69-3.81 (1H, m), 3.94-4.10 (3H, m), 4.52 (1H, m
d, J = 14Hz), 4.62-4.80 (1H, m), 5.13 (1H, d, J = 14H
z), 5.25-5.50 (1H, br), 6.72-6.84 (2H, m), 7.36-7.4
9 (1H, m), 7.77 (1H, s), 7.80 (2H, d, J = 9Hz), 7.86
(1H, s), 8.13 (2H, d, J = 9Hz), 8.64 (1H, s)

Example 28 (2R, 3S) -2- (2,4-difluorophenyl)
-3-Methyl-2- (1H-1,2,4-triazol-1-yl) methyloxirane and 1- [4- (1H-
When 1,2,3-triazol-1-ylmethyl) phenyl] -2 (1H, 3H) -imidazolone was reacted in the same manner as in Example 11, 1-[(1R, 2R) -2-
(2,4-difluorophenyl) -2-hydroxy-1
-Methyl-3- (1H-1,2,4-triazole-1
-Yl) propyl] -3- [4- (1H-1,2,3-
Triazol-1-ylmethyl) phenyl] -2 (1
H, 3H) -Imidazolone (Compound 28 ) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, d, J = 7Hz),
4.19 (1H, d, J = 14Hz), 4.97 (1H, q, J = 7Hz), 5.09 (1
H, d, J = 14Hz), 5.55 (1H, br), 5.59 (2H, s), 6.65
(1H, d, J = 3.2Hz), 6.75-6.90 (3H, m), 7.35-7.55 (4H,
m), 7.66-7.75 (4H, m), 7.84 (1H, s)

Example 29 (2R, 3S) -2- (2,4-difluorophenyl)
-3-Methyl-2- (1H-1,2,4-triazol-1-yl) methyloxirane and 4- [4- (1H-
When 1,2,3-triazol-1-ylmethyl) phenyl] -3 (2H, 4H) -1,2,4-triazolone was reacted in the same manner as in Example 2, 2-[(1R, 2
R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- [4- (1H-
1,2,3-triazol-1-ylmethyl) phenyl] -3 (2H, 4H) -1,2,4-triazolone (Compound 29 ) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, d, J = 7Hz),
4.36 (1H, d, J = 14Hz), 5.00 (1H, d, J = 14Hz), 5.08
(1H, q, J = 7Hz), 5.41 (1H, s), 5.63 (2H, s), 6.75-6.
90 (2H, m), 7.40-7.64 (6H, m), 7.69 (1H, s), 7.76
(1H, s), 7.80 (1H, s), 7.94 (1H, s)

Example 30 (2R, 3S) -2- (2,4-difluorophenyl)
-3-Methyl-2- (1H-1,2,4-triazol-1-yl) methyloxirane and 1- [4- (2-methyl-4-thiazolyl) phenyl] -2 (1H, 3H)-
When imidazolone is reacted in the same manner as in Example 11,
1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-triazol-1-yl) propyl] -3
-[4- (2-Methyl-4-thiazolyl) phenyl]-
2 (1H, 3H) -imidazolone (Compound 30 ) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, d, J = 7Hz),
2.78 (3H, s), 4.22 (1H, d, J = 14Hz), 4.98 (1H, q,
J = 7Hz), 5.12 (1H, d, J = 14Hz), 5.60 (1H, br), 6.70-
6.85 (4H, m), 7.33 (1H, s), 7.40-7.55 (1H, m), 7.6
9-8.00 (6H, m)

Example 31 (2R, 3S) -2- (2,4-difluorophenyl)
-3-Methyl-2- (1H-1,2,4-triazol-1-yl) methyloxirane and 4- [4- (2-methyl-4-thiazolyl) phenyl] -3 (2H, 4H)-
When 1,2,4-triazolone was reacted in the same manner as in Example 2, 2-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3-
(1H-1,2,4-triazol-1-yl) propyl] -4- [4- (2-methyl-4-thiazolyl) phenyl] -3 (2H, 4H) -1,2,4-triazolone ( Compound 31 ) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.31 (3H, d, J = 7Hz),
2.79 (3H, s), 4.37 (1H, d, J = 14Hz), 5.04 (1H, d,
J = 14Hz), 5.11 (1H, q, J = 7Hz), 5.47 (1H, s), 6.77-6.
90 (2H, m), 7.39 (1H, s), 7.50-7.70 (4H, m), 7.85-
8.05 (4H, m)

Example 32 (2R, 3S) -2- (2-fluorophenyl) -3-
Methyl-2- (1H-1,2,4-triazole-1-
Yl) methyloxirane and 1- [4- (1H-1,2,2
3-triazol-1-yl) phenyl] -2 (1H,
When 3H) -imidazolone was reacted in the same manner as in Example 11, 1-[(1R, 2R) -2- (2-fluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-triazol-1-yl) propyl] -3
-[4- (1H-1,2,3-triazol-1-yl) phenyl)]-2 (1H, 3H) -imidazolone (Compound 32 ) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, d, J = 7Hz),
4.23 (1H, d, J = 14.2Hz), 5.08 (1H, q, J = 7Hz), 5.17
(1H, d, J = 14.2Hz), 5.36 (1H, br), 6.73 (1H, d, J =
3.2Hz), 6.86 (1H, d, J = 3.2Hz), 6.99-7.09 (2H, m),
7.19-7.52 (2H, m), 7.51-7.92 (6H, m), 7.80 (1H, s),
8.03 (1H, s) Elemental analysis value: Calculated as C ₂₃ H ₂₁ FN ₈ O ₂ (%): C, 59.99; H, 4.60; N, 24.23 Measured value (%): C, 59.62; H, 4.61; N, 24.13

Example 33 (2R, 3S) -2- (2-fluorophenyl) -3-
Methyl-2- (1H-1,2,4-triazole-1-
And yl) methyloxirane and 1- [4- (2H-1,2,2
3-triazol-2-yl) phenyl] -2 (1H,
When 3H) -imidazolone was reacted in the same manner as in Example 11, 1-[(1R, 2R) -2- (2-fluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-triazol-1-yl) propyl] -3
-[4- (2H-1,2,3-Triazol-2-yl) phenyl] -2 (1H, 3H) -imidazolone (compound 33 ) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, d, J = 7Hz),
4.23 (1H, d, J = 14Hz), 5.07 (1H, q, J = 7Hz), 5.18 (1
H, d, J = 14Hz), 5.37 (1H, br), 6.70 (1H, d, J = 3.2H
z), 6.83 (1H, d, J = 3.2Hz), 6.98-7.08 (2H, m), 7.19-
7.51 (2H, m), 7.73 (1H, s), 7.75 (2H, d, J = 9.2Hz),
7.83 (2H, s), 7.85 (1H, s), 8.17 (2H, d, J = 9.2Hz) Elemental _{analysis: C 23 H 21 FN 8 O} 2 Calculated (%): C, 59.99; H, 4.60; N, 24.33 Found (%): C, 59.80; H, 4.58; N, 23.87

Example 34 1-[(1R, 2R) -2- (2 obtained in Example 32
-Fluorophenyl) -2-hydroxy-1-methyl-
3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (1H-1,2,3-triazol-1-yl) phenyl] -2 (1H, 3H)- Imidazolone (Compound 32 ) was subjected to catalytic reduction reaction in the same manner as in Example 10 to give 1-[(1R, 2R) -2- (2-fluorophenyl) -2-hydroxy-1-methyl-3-
(1H-1,2,4-triazol-1-yl) propyl] -3- [4- (1H-1,2,3-triazole-
1-yl) phenyl] -2-imidazolidinone (compound
34 ) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.08 (3H, d, J = 7Hz),
3.72-4.14 (4H, m), 4.54 (1H, d, J = 14.2Hz), 4.70-4.
84 (1H, m), 5.17 (1H, d, J = 14.2Hz), 5.30 (1H, br),
6.96-7.08 (2H, m), 7.18-7.50 (2H, m), 7.68-7.78 (4
H, m), 7.75 (1H, s), 7.84 (2H, s), 7.98 (1H, s) Elemental analysis value: C ₂₃ H ₂₃ FN ₈ O ₂ Calculated value (%): C, 59.73; H, 5.01; N, 24.23 Found (%): C, 59.32; H, 4.99; N, 24.00

Example 35 1-[(1R, 2R) -2- (2 obtained in Example 33
-Fluorophenyl) -2-hydroxy-1-methyl-
3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (2H-1,2,3-triazol-2-yl) phenyl] -2 (1H, 3H)- Imidazolone (Compound 33 ) was subjected to catalytic reduction reaction in the same manner as in Example 10 to give 1-[(1R, 2R) -2- (2-fluorophenyl) -2-hydroxy-1-methyl-3-.
(1H-1,2,4-triazol-1-yl) propyl] -3- [4- (2H-1,2,3-triazole-
2-yl) phenyl] -2-imidazolidinone (compound
35 ) was obtained. Melting point: 178-179 ° C

¹ H-NMR (CDCl ₃ ) δ: 1.08 (3H, d, J = 7Hz),
3.71-4.07 (4H, m), 4.54 (1H, d, J = 14Hz), 4.74-4.77
(1H, m), 5.18 (1H, d, J = 14Hz), 5.38 (1H, br), 6.9
6-7.06 (2H, m), 7.16-7.51 (2H, m), 7.71 (2H, d, J = 9
Hz), 7.74 (1H, s), 7.80 (2H, s), 7.83 (1H, s), 8.0
7 (2H, d, J = 9Hz) Elemental _{analysis: C 23 H 23 FN 8 O} 2 Calculated (%): C, 59.73; H, 5.01; N, 24.23 Found (%): C, 59.49; H, 5.23; N, 24.01

Example 36 (2R, 3S) -2- (2,4-difluorophenyl)
-3-Methyl-2- (1H-1,2,4-triazol-1-yl) methyloxirane (0.50 g), 4-
[4- (2-Methyl-4-oxazolyl) phenyl]-
3 (2H, 4H) -1,2,4-triazolone (0.5
6 g) and potassium carbonate (powder form: 1.38 g) 1
-Methyl-2-pyrrolidone (5 ml) and N, N-dimethylformamide (4 ml) were added to the mixture, and while stirring,
Heat at 0 ° C. for 20 hours. The reaction mixture was cooled, diluted with ethyl acetate (40 ml), added to ice water (40 ml) and the ethyl acetate layer was separated. The ethyl acetate layer was washed with 0.5N-aqueous sodium hydroxide (40 ml), 1N-hydrochloric acid (40 ml) and then with saturated saline (40 ml). After drying the ethyl acetate layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent:
After purification by subjecting to ethyl acetate → ethyl acetate: methanol = 9: 1) and crystallizing from ethyl acetate-diisopropyl ether, 2-[(1R, 2R) -2- (2,2
4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- [4- (2-methyl-4-oxazolyl) phenyl] -3 (2H, 4H) -1,2,4-
Triazolone (Compound 36 , 0.33 g) was obtained

¹ H-NMR (CDCl ₃ ) δ: 1.31 (3H, d, J = 7Hz),
2.54 (3H, s), 4.36 (1H, d, J = 14Hz), 5.04 (1H, d,
J = 14Hz), 5.10 (1H, q, J = 7Hz), 5.47 (1H, s), 6.77-6.
88 (2H, m), 7.51-7.69 (4H, m), 7.85 (1H, s), 7.86
(2H, d, J = 8Hz), 7.88 (1H, s), 7.96 (1H, s)

Example 37 (2R, 3S) -2- (2,4-difluorophenyl)
-3-Methyl-2- (1H-1,2,4-triazol-1-yl) methyloxirane and 1- [4- (2-methyl-4-oxazolyl) phenyl] -2 (1H, 3H)
When imidazolone was reacted in the same manner as in Example 11, 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H
-1,2,4-triazol-1-yl) propyl]-
3- [4- (2-Methyl-4-oxazolyl) phenyl] -2 (1H, 3H) -imidazolone (Compound 37 )
was gotten.

¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, d, J = 7Hz),
2.53 (3H, s), 4.21 (1H, d, J = 14Hz), 4.97 (1H, q,
J = 7Hz), 5.12 (1H, d, J = 14Hz), 5.60 (1H, br), 6.69-
6.86 (4H, m), 7.42-7.55 (1H, m), 7.69 (2H, d, J = 9H
z), 7.73 (1H, s), 7.80 (2H, d, J = 9Hz), 7.84 (1H,
s), 7.86 (1H, s)

Example 38 (2R, 3S) -2- (2-fluorophenyl) -3-
Methyl-2- (1H-1,2,4-triazole-1-
Il) methyloxirane (2.24 g), 1- [4-
(1H-1,2,4-triazol-1-yl) phenyl] -2 (1H, 3H) -imidazolone (2.17g)
And cesium carbonate (powder form: 7.76 g) were added to dimethylsulfoxide (100 ml) and stirred for 10
Heated at 0 ° C. for 17 hours. After cooling the reaction solution, it was diluted with ethyl acetate (200 ml) and added to ice water (200 ml) to separate the ethyl acetate layer. The aqueous layer was extracted with ethyl acetate (100 ml). The ethyl acetate layers were combined and 0.5N-aqueous sodium hydroxide (100 ml), 1N-hydrochloric acid (100 ml x
2), followed by washing with saturated saline (100 ml). After drying the ethyl acetate layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate: acetone = 4: 1) to give 1-[(1R, 2R) -2- (2-fluorophenyl) -2-hydroxy-1. -Methyl-3
(1H-1,2,4-triazol-1-yl) propyl] -3- [4- (1H-1,2,4-triazol-
1-yl) phenyl] -2 (1H, 3H) -imidazolone (Compound 38 , 0.45 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, d, J = 7Hz),
4.23 (1H, d, J = 14Hz), 5.02 (1H, q, J = 7Hz), 5.17 (1
H, d, J = 14Hz), 5.37 (1H, br), 6.71 (1H, d, J = 3.2H
z), 6.86 (1H, d, J = 3.2Hz), 6.99-7.10 (2H, m), 7.20-
7.52 (2H, m), 7.70-7.89 (6H, m), 8.13 (1H, s), 8.58
(1H, s)

Example 39 1-[(1R, 2R) -2- (2 obtained in Example 38
-Fluorophenyl) -2-hydroxy-1-methyl-
3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (1H-1,2,4-triazol-1-yl) phenyl] -2 (1H, 3H)- Imidazolone (Compound 38 ) was subjected to catalytic reduction reaction in the same manner as in Example 10 to give 1-[(1R, 2R) -2- (2-fluorophenyl) -2-hydroxy-1-methyl-3-.
(1H-1,2,4-triazol-1-yl) propyl] -3- [4- (1H-1,2,4-triazol-
1-yl) phenyl] -2-imidazolidinone (compound
39 ) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.08 (3H, d, J = 7Hz),
3.72-4.10 (4H, m), 4.53 (1H, d, J = 14.2Hz), 4.76-4.
79 (1H, m), 5.17 (1H, d, J = 14.2Hz), 5.19 (1H, br),
6.97-7.09 (2H, m), 7.17-7.46 (2H, m), 7.63-7.77 (5
H, m), 7.82 (1H, s), 8.10 (1H, s), 8.52 (1H, s) Elemental analysis value: Calculated value as C ₂₃ H ₂₃ FN ₈ O ₂ (%): C, 59.73; H, 5.01; N, 24.23 Found (%): C, 59.33; H, 5.03; N, 23.98

Example 40 (2R, 3S) -2- (2-Fluorophenyl) -3-
Methyl-2- (1H-1,2,4-triazole-1-
Il) methyloxirane (2.34 g), 1- [4-
(2H-2-tetrazolyl) phenyl] -2 (1H, 3
H) -Imidazolone (2.28 g) and cesium carbonate (powder: 6.52 g) were added to 1-methyl-2-pyrrolidone (100 ml) and heated at 80 ° C. for 18 hours with stirring. After cooling the reaction solution, it was diluted with ethyl acetate (200 ml) and added to ice water (200 ml) to separate the ethyl acetate layer. The aqueous layer was extracted with ethyl acetate (100 ml). The ethyl acetate layers were combined and washed with 1N-hydrochloric acid (100 ml × 2) and then saturated brine (100 ml). After drying the ethyl acetate layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel (eluent:
When purified by subjecting to hexane: acetone = 1: 1), 1
-[(1R, 2R) -2- (2-fluorophenyl)-
2-hydroxy-1-methyl-3- (1H-1,2,4
-Triazol-1-yl) propyl] -3- [4-
(2H-2-tetrazolyl) phenyl] -2 (1H, 3
H) -Imidazolone (Compound 40 , 0.494 g) was obtained as colorless powder crystals.

¹ H-NMR (CDCL ₃ ) δ: 1.21 (3H, d, J = 7Hz),
4.23 (1H, d, J = 14Hz), 5.10 (1H, q, J = 7Hz), 5.19 (1
H, d, J = 14Hz), 5.34 (1H, br), 6.75 (1H, d, J = 3.2H
z), 6.88 (1H, d, J = 3.2Hz), 6.99-7.09 (2H, m), 7.20-
7.51 (2H, m), 7.75 (1H, s), 7.81 (1H, s), 7.94 (2H,
d, J = 9Hz), 8.25 (2H, d, J = 9Hz), 8.68 (1H, s) Elemental _{analysis: C 22 H 20 FN 9 O} 2 Calculated: C, 57.26; H, 4.37 ; N, 27.32 Found: C, 57.19; H, 4.29; N, 27.07.

Example 41 1-[(1R, 2R) -2- (2 obtained in Example 40
-Fluorophenyl) -2-hydroxy-1-methyl-
3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (2H-2-tetrazolyl) phenyl] -2 (1H, 3H) -imidazolone (Compound 4
0 ) was subjected to catalytic reduction reaction in the same manner as in Example 10 to give 1
-[(1R, 2R) -2- (2-fluorophenyl)-
2-hydroxy-1-methyl-3- (1H-1,2,4
-Triazol-1-yl) propyl] -3- [4-
(2H-2-tetrazolyl) phenyl] -2-imidazolidinone (Compound 41 ) was obtained as colorless powder crystals.

¹ H-NMR (CDCL ₃ ) δ: 1.08 (3H, d, J = 7Hz),
3.74-3.81 (1H, m), 3.94-4.13 (3H, m), 4.53 (1H,
d, J = 14Hz), 4.63-4.81 (1H, m), 5.13 (1H, d, J = 14H
z), 5.15-5.30 (1H, br), 6.97-7.07 (2H, m), 7.17-7.4
5 (2H, m), 7.78 (1H, s), 7.79 (2H, d, J = 9Hz), 7.83
(1H, s), 8.13 ( 2H, d, J = 9Hz), 8.65 (1H, s) Elemental _{analysis: C 22 H 22 FN 9 O} 2 Calculated: C, 57.01; H, 4.78 ; N, 27.20 Found: C, 56.96; H, 4.86; N, 26.84.

Example 42 72% oily sodium hydride (17 mg) was dispersed in dimethylformamide (3 ml), and 1,2,4 was cooled with ice.
-Triazole (42 mg) was added and stirred at room temperature for 40 minutes. Then, 1-[(1R, 2S) -2- (2,4-
Difluorophenyl) -2,3-epoxy-1-methylpropyl] -3- [4- (1H-1-tetrazolyl) phenyl] -2 (1H, 3H) -imidazolone (0.20
5 g) of dimethylformamide solution (2 ml) was added to give 5
Heated at 0 ° C. for 6 hours. After cooling, cold water (30 m
l) and ethyl acetate (30 ml) were added for liquid separation, and the aqueous layer was extracted twice with ethyl acetate. Combine the ethyl acetate layers with water,
The extract was washed successively with saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate) to give 1-
[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-triazol-1-yl) propyl] -3-
[4- (1H-1-tetrazolyl) phenyl] -2 (1
H, 3H) -Imidazolone (Compound 42 , 0.15 g)
Was obtained as colorless powder crystals.

¹ H-NMR (CDCL ₃ ) δ: 1.21 (3H, d, J = 7Hz),
4.22 (1H, d, J = 14Hz), 5.03 (1H, q, J = 7Hz), 5.13 (1
H, d, J = 14Hz), 5.45 (1H, br), 6.74-6.88 (4H, m),
7.42-7.55 (1H, m), 7.77 (1H, s), 7.82 (2H, d, J = 9H
z), 7.86 (1H, s), 7.96 (2H, d, J = 9Hz), 9.06 (1H, s) Reaction was carried out under the same conditions using potassium carbonate instead of sodium hydride in the above reaction. The identical product (compound 42 ) was obtained in each case.

Example 43 1-[(1R, 2R) -2-obtained in Example 42
(2,4-difluorophenyl) -2-hydroxy-1
-Methyl-3- (1H-1,2,4-triazole-1
-Yl) propyl] -3- [4- (1H-1-tetrazolyl) phenyl] -2 (1H, 3H) -imidazolone (Compound 42 ) was subjected to catalytic reduction reaction in the same manner as in Example 10 to give 1- [. (1R, 2R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3-
(1H-1,2,4-triazol-1-yl) propyl] -3- [4- (1H-1-tetrazolyl) phenyl] -2-imidazolidinone (Compound 43 ) was obtained as colorless powder crystals. It was

¹ H-NMR (CDCL ₃ ) δ: 1.08 (3H, d, J = 7Hz),
3.69-4.14 (4H, m), 4.52 (1H, d, J = 14Hz), 4.65-4.80
(1H, m), 5.12 (1H, d, J = 14Hz), 5.35 (1H, br), 6.7
4-6.84 (2H, m), 7.36-7.49 (1H, m), 7.68 (2H, d, J = 9
Hz), 7.77 (1H, s), 7.82 (2H, d, J = 9Hz), 7.87 (1H,
s), 8.98 (1H, s)

Example 44 72% oily sodium hydride (120 mg) was dispersed in dimethylformamide (10 ml) and cooled with ice to give 1,2,2.
4-Triazole (290 mg) was added and the mixture was stirred at room temperature for 30 minutes. Then, 1-[(1R, 2S) -2- (2-
Fluorophenyl) -2,3-epoxy-1-methylpropyl] -3- [4- (1H-1-tetrazolyl) phenyl] -2 (1H, 3H) -imidazolone (0.82
g) dimethylformamide solution (5 ml) was added to 50
Heated at ° C. for 5 hours. After cooling, cold water (30 m
l) and ethyl acetate (40 ml) were added for liquid separation, and the aqueous layer was extracted twice with ethyl acetate. Combine the ethyl acetate layers with water,
The extract was washed successively with saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate) to give 1-
[(1R, 2R) -2- (2-Fluorophenyl) -2
-Hydroxy-1-methyl-3- (1H-1,2,4-
Triazol-1-yl) propyl] -3- [4- (1
H-1-tetrazolyl) phenyl] -2 (1H, 3H)
-Imidazolone (Compound 44 , 0.30 g) was obtained as colorless powder crystals.

¹ H-NMR (CDCL ₃ ) δ: 1.21 (3H, d, J = 7Hz),
4.22 (1H, d, J = 14Hz), 5.10 (1H, q, J = 7Hz), 5.18 (1
H, d, J = 14Hz), 5.31 (1H, br), 6.75 (1H, d, J = 3Hz),
6.90 (1H, d, J = 3Hz), 6.99-7.32 (3H, m), 7.43-7.51
(1H, m), 7.75 (1H, s), 7.80-7.85 (3H, m), 7.97 (2
H, d, J = 9Hz), 9.07 (1H, s)

Example 45 1-[(1R, 2R) -2- (2 obtained in Example 44
-Fluorophenyl) -2-hydroxy-1-methyl-
3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (1H-1-tetrazolyl) phenyl] -2 (1H, 3H) -imidazolone (Compound 4
4 ) was subjected to catalytic reduction reaction in the same manner as in Example 10 to give 1
-[(1R, 2R) -2- (2-fluorophenyl)-
2-hydroxy-1-methyl-3- (1H-1,2,4
-Triazol-1-yl) propyl] -3- [4-
(1H-1-tetrazolyl) phenyl] -2-imidazolidinone (Compound 45 ) was obtained.

¹ H-NMR (CDCL ₃ ) δ: 1.08 (3H, d, J = 7Hz),
3.70-4.19 (4H, m), 4.53 (1H, d, J = 14Hz), 4.72-4.88
(1H, m), 5.10-5.26 (2H, m), 6.97-7.45 (4H, m), 7.
68 (2H, d, J = 9Hz), 7.76 (1H, s), 7.82 (1H, s), 7.8
3 (2H, d, J = 9Hz), 8.97 (1H, s)

Example 46 1-[(1R, 2S) -2- (2-fluorophenyl)
-2-Hydroxy-3-methanesulfonyloxy-1-
Methylpropyl] -3- [4- (1H-1-terazolyl) phenyl] -2 (1H, 3H) -imidazolone (2
00 mg) in dimethylformamide (10 ml),
1H-1,2,4-triazole (83 mg) and potassium carbonate (168 mg) were added, and the mixture was heated at 50 ° C. for 20 hours.
The reaction mixture was diluted with ethyl acetate (30 ml) and then diluted with water (15 m
l) 1N-hydrochloric acid (15 ml × 2) and saline (15 m)
Washed in l). After drying the organic layer over magnesium sulfate,
The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography [eluent, ethyl acetate]. The desired fraction was concentrated and recrystallized from a mixed solution of ethyl acetate and diisopropyl ether to give 1-[(1R, 2R) -2-
(2-Fluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (1H-1-tetrazolyl) phenyl]- 2 (1H, 3H) - imidazolone (reduction <br/> compound 44: 65 mg) as a colorless crystalline powder.

¹ H-NMR (CDCL ₃ ) δ: 1.21 (3H, d, J = 7Hz),
4.22 (1H, d, J = 14Hz), 5.11 (1H, q, J = 7Hz), 5.18 (1
H, d, J = 14Hz), 5.32 (1H, br), 6.75 (1H, d, J = 3Hz),
6.90 (1H, d, J = 3Hz), 7.00-7.27 (3H, m), 7.43-7.51
(1H, m), 7.75 (1H, s), 7.80-7.84 (3H, m), 7.97 (2
H, d, J = 9Hz), 9.06 (1H, s)

A preferable group of compounds belonging to the compound (I) of the present invention is shown in Tables 10 to 14, but the present invention is not limited to these compounds.

[0265]

[Table 10]

[0266]

[Table 11]

[0267]

[Table 12]

[0268]

[Table 13]

[0269]

[Table 14]

[0270] Using the compound 7 obtained by Formulation Example 1 Example 7 above, mixed with all the components of the formulation shown below was filled into gelatin capsules, per capsule, the capsule containing the compound 7 of 50mg The agent was manufactured. Compound of Example 7 7 50 mg Lactose 100mg Cornstarch 40mg Magnesium stearate 10mg Total 200mg

Formulation Example 2 Compound 10 obtained according to Example 10 above and magnesium stearate are granulated with an aqueous solution of soluble starch,
After drying, it was mixed with lactose and corn starch. The mixture was compression-molded to produce tablets having the following formulation.

[0272] The compound of Example 10 10 50 mg Lactose 65mg Cornstarch 30mg Soluble starch 35mg Magnesium stearate 20mg Total 200mg

Experimental Example 1 Method: Five-week-old Crj: CDF ₁ mice were intravenously inoculated with the minimum lethal dose of Candida albicans TA. The test compound was treated with 30% HPCD (hydroxypropyl-β-
Cyclodextrin) solution was orally administered once immediately after infection. The efficacy was shown by the ED ₅₀ value calculated by the Reed and Muench method from the survival rate of the mice 7 days after infection. Results: Tables 15 and 16 show the protective effects of the compounds of the present invention on experimental mouse infections.

[0274]

[Table 15]

[0275]

[Table 16]

[0276]

The compound of the present invention or a salt thereof has low toxicity and excellent antifungal activity. Therefore, the compound of the present invention or a salt thereof can be used as an antifungal agent for the prevention and treatment of fungal infections in mammals. Further, the compound of the present invention or a salt thereof can also be used as an agricultural antifungal agent.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical indication location A61K 31/42 A61K 31/42 31/425 31/425 C07D 403/10 231 C07D 403/10 231 233 233 403/14 231 403 403/14 231 233 233 413/10 249 413/10 249 413/14 233 413/14 233 417/10 249 417/10 249 417/14 233 417/14 233

Claims (22)

[Claims] 1. A compound of the general formula (I) [In the formula, Ar represents an optionally substituted phenyl group, R
¹ and R ² are the same or different and each is a hydrogen atom or a lower alkyl group, or R ¹ and R ² are combined to form a lower alkylene group; R ³ is a hydrogen atom or an acyl group;
Is a nitrogen atom or a methine group, A is Y = Z (Y and Z
Are the same or different and each represents a methine group which may be substituted with a nitrogen atom or a lower alkyl group) or an ethylene group which may be substituted with a lower alkyl group, and n is 0.
Az represents an optionally substituted azolyl group, or an integer of 2] or a salt thereof. 2. Ar is a halogen atom or halogenated C
_1-4 alkyl group, halogenated C _1-4 alkoxy group, C _1-4
A phenyl group which may be substituted with 1 to 3 substituents selected from the group consisting of an alkylsulfonyl group and a halogenated C _1-4 alkylsulfonyl group is used as R ¹ and R ²
Are the same or different and each is a hydrogen atom or a C _1-4 alkyl group, or R ¹ and R ² are combined to form a C _2-4 alkylene group, and R ³ is a hydrogen atom, a C _1-7 alkanoyl group, C
_7-15 arylcarbonyl group, C _2-7 alkoxycarbonyl group, C _7-15 aryloxycarbonyl group or C _8-20
An aralkylcarbonyl group, A is Y = Z (Y and Z are the same or different and each represents a nitrogen atom or a methine group which may be substituted with a C _1-4 alkyl group) or C _1-4
The ethylene group which may be substituted with an alkyl group is represented by Az
Is an oxo group, a hydroxyl group, a carboxyl group, an optionally esterified carboxyl group, a nitro group, an amino group, C
_1-10 alkanoylamino group, mono-C _1-10 alkylamino group, di-C _1-10 alkylamino group, C _1-6 alkyl group, C _1-6 alkoxy group, halogen atom, halogenated C
_1-6 alkyl group, halogenated C _1-6 alkoxy group, thioxo group, mercapto group, C _1-6 alkylthio group, C _1-6 alkylsulfonyl group, C _1-10 alkanoyl group, phenyl group, C _1-6 1 or 2 substituents selected from the group consisting of an alkylphenyl group, a C _1-6 alkoxyphenyl group, a halogenated phenyl group, a halogenated C _1-6 alkylphenyl group and a halogenated C _1-6 alkoxyphenyl group. The compound according to claim 1, which represents an azolyl group which may be substituted with. 3. A 5-membered aromatic heterocyclic group in which the azolyl group of Az contains 1 to 4 nitrogen atoms as ring-constituting atoms and may further contain a sulfur or oxygen atom as a ring-constituting atom. The compound according to claim 1. 4. The compound according to claim 1, wherein ^one of R ¹ and R ² is a hydrogen atom and the other is a C _1-4 alkyl group. 5. The compound according to claim 4, wherein the carbon atom to which Ar is bonded is (R) -coordinated and the carbon atom to which R ² is bonded is (R) -coordinated. 6. The compound according to claim 1, wherein R ³ is a hydrogen atom. 7. The compound according to claim 1, wherein X is a nitrogen atom. 8. The compound according to claim 1, wherein Ar is a phenyl group substituted with a halogen atom. 9. The compound according to claim 8, wherein Ar is a phenyl group substituted with 1 or 2 fluorine atoms. 10. The compound according to claim 9, wherein Ar is a 2-fluorophenyl group or a 2,4-difluorophenyl group. 11. The method according to claim 1, wherein A is —CH ₂ —CH ₂ —.
A compound as described. 12. The compound according to claim 1, wherein A is -N = CH-, -CH = N- or -CH = CH-. 13. The compound according to claim 1, wherein n is 0. 14. The azolyl group represented by Az is 1 selected from the group consisting of an oxo group, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group and a halogenated C _1-6 alkyloxyphenyl group. The compound according to claim 1, which is a diazolyl, triazolyl, tetrazolyl, thiazolyl or oxazolyl group which may be substituted with two substituents. 15. The compound according to claim 1, wherein the azolyl group represented by Az is a triazolyl group or a tetrazolyl group. 16. A compound of formula (I ′): [Wherein Ar ′ is a monofluorophenyl or difluorophenyl group, and A ′ is —N═CH—, —CH═CH
- or -CH ₂ -CH ₂ - and is, Az 'is an oxo group,
A diazolyl, a triazolyl optionally substituted with one or two substituents selected from the group consisting of a C _1-6 alkyl group, a halogenated C _1-6 alkyl group and a halogenated C _1-6 alkoxyphenyl group, A compound represented by the formula: tetrazolyl, thiazolyl or oxazolyl group] or a salt thereof. 17. The compound according to claim 16, wherein A ′ is —CH ₂ —CH ₂ — and Az ′ is triazolyl or tetrazolyl. 18. 1-[(1R, 2R) -2- (2,4)
-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl)
The compound according to claim 1, which is propyl] -3- [4- (1H-1,2,4-triazol-1-yl) phenyl] -2-imidazolidinone or a salt thereof. 19. 1-[(1R, 2R) -2- (2,4)
-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl)
The compound according to claim 1, which is propyl] -3- [4- (1H-1,2,3-triazol-1-yl) phenyl] -2-imidazolidinone or a salt thereof. 20. 1-[(1R, 2R) -2- (2,4)
-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl)
The compound according to claim 1, which is propyl] -3- [4- (2H-2-tetrazolyl) phenyl] -2-imidazolidinone or a salt thereof. 21. The formula (II): [In the formula, Ar represents an optionally substituted phenyl group, R
¹ and R ² are the same or different and each is a hydrogen atom or a lower alkyl group, or R ¹ and R ² are combined to form a lower alkylene group, and A is Y = Z (Y and Z are the same or different and each is a nitrogen atom). Atom or a methine group optionally substituted with a lower alkyl group) or an ethylene group optionally substituted with a lower alkyl group, n is an integer of 0 to 2, and Az is an optionally substituted azolyl group. A group represented by the formula] or a salt thereof, and a compound of the formula (III): [Wherein, X represents a nitrogen atom or a methine group] or a salt thereof is reacted with and optionally acylated, or (2) Formula (IV) [In the formula, Ar represents an optionally substituted phenyl group, R
¹ and R ² are the same or different and each is a hydrogen atom or a lower alkyl group, or R ¹ and R ² are combined to form a lower alkylene group, and X is a nitrogen atom or a methine group. A salt and a compound of formula (V ′) [In formula, A '' is -N = CH-, -CH = N- or -C
H═CH—, n is an integer of 0 to 2, and Az represents an optionally substituted azolyl group] or a salt thereof, and is optionally acylated,
(3) Formula (I ″) [In the formula, Ar represents an optionally substituted phenyl group, R
¹ and R ² are the same or different and each is a hydrogen atom or a lower alkyl group, or R ¹ and R ² are combined to form a lower alkylene group, R ³ is a hydrogen atom or an acyl group, and X is a nitrogen atom or a methine group. Is an integer from 0 to 2 Az
Represents an optionally substituted azolyl group] or a salt thereof and, if necessary, acylates the compound. 22. A pharmaceutical composition containing the compound of claim 1.