JPH08104676A - Azole compound, its production and use - Google Patents

Abstract

PURPOSE: To obtain a low-toxic new compound having potent antifungal power on Mycota and broad antimycotic spectrum, thus useful as an antimycotic agent. CONSTITUTION: This compound (salt) is expressed by formula I (Ar is phenyl; R<1> and R<2> are each H, a lower alkyl, etc.; R<3> is H or an acyl; Y is N or methyne; A is a saturated cyclic amide linking itself through N-atom), e.g. 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3(1H-1,2,4-triazo l-1-yl) propyl]-3-(4-trifluoromethoxyphenyl)-2-imidazolidinone. This compound is obtained by reaction between a compound of formula II and a compound of formula III normally in an inert solvent such as THF pref. in the presence of a base such as an alkali metal hydroxide followed by, if needed, treating the reaction product, one of the objective compound (where, R<3> is H), with an acylating agent.

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 and EP0122693A1 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. As a therapeutic agent for mycosis, a compound having higher safety, good absorbability in the body, and stronger antifungal activity is desired.

[0004]

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

[Chemical 7] [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 Y is a nitrogen atom or a methine group. , And A each represent a saturated cyclic amide group which may be substituted and which is bonded by a nitrogen atom] or a salt thereof, (2) R
The compound according to (1) above, wherein one of ¹ and R ² is a hydrogen atom and the other is a lower alkyl group, (3) the compound according to (1) above wherein Y is a nitrogen atom, and (4) Ar is a halogen atom. The compound according to (1) above, which is a substituted phenyl group, and (5) the compound according to (4) above, wherein Ar is a phenyl group substituted with one or two fluorine atoms. (6)
The compound according to (1) above, wherein the saturated cyclic amide group in A is a 5- or 6-membered ring group, (7) above (1) in which the saturated cyclic amide group in A further contains one nitrogen atom in its ring. The compound according to (7), wherein the saturated cyclic amide group further containing one nitrogen atom in the ring in (8) A has a substituent at the nitrogen atom.
(9) The saturated cyclic amide group in A has the formula

Embedded image [In the formula, R ⁴ represents a substituted phenyl group] 3-
The compound according to (1) above, which is a substituted phenyl-2-oxo-1-imidazolidinyl group, and the saturated cyclic amide group in (10) A has the formula:

[Chemical 9] [Wherein R ⁵ is the same meaning as R ⁴ ] is a 4-substituted phenyl-2,5-dioxo-1-piperazinyl group represented by the above (1), saturated in (11) A a substituent of a cyclic amide group is a substituted phenyl group, substituted phenyl group is a halogen atom, a halogenated C _1-6 alkyl group, one substituent selected from the group consisting of halogenated C _1-6 Arukishi group or The compound according to (1) above, which is a phenyl group having two, (12) the compound according to (11) above, wherein the substituent of the substituted phenyl group is a fluorine atom, a fluorinated lower alkyl group or a fluorinated lower alkoxy group, (13) General formula (II)

[Chemical 10] [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 may have a substituent,
Saturated cyclic amide groups bonded by a nitrogen atom are respectively shown]
And a compound represented by the general formula (III)

[Chemical 11] [Wherein Y represents a nitrogen atom or a methine group] or a salt thereof is reacted to obtain R of the compound (I).
A compound (I) or a salt thereof according to the above (1), characterized in that a compound in which ³ is a hydrogen atom is obtained, and optionally treated with an acylating agent to obtain a compound in which the corresponding R ³ is an acyl group. (14) General formula (I ′)

[Chemical 12] [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 Y is a nitrogen atom or a methine group. , And A ″ each represent a 3-substituted phenyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl group] or a salt thereof is subjected to a reduction reaction. (9) above
A method for producing the described compound or a salt thereof, and (15)
It relates to an antifungal agent comprising the compound (I) described in (1) above or a pharmaceutically acceptable salt thereof and an excipient and / or a carrier.

In the general formulas (I), (II) and (I '), 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 and halogenated (C _{1- 4} ) An alkylsulfonyl group and the like can be mentioned. The substituent is preferably halogen (eg, fluorine, chlorine, bromine, iodine, etc.) and the like, and particularly preferably fluorine. The number of substituents is preferably 1 to 3, and more preferably 1 to 2.

Examples of Ar include a halogenophenyl group, a halogenated lower (C _1-4 ) alkylphenyl group, a halogenated lower (C _1-4 ) alkoxyphenyl group, a lower (C _1-4 ) alkylsulfonylphenyl group, Examples include halogenated lower (C _1-4 ) alkylsulfonylphenyl groups. Here, as the halogenophenyl group, for example, 2,4-difluorophenyl, 2,4-dichlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 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 and 4- (2,2,2 2-trifluoroethoxy) phenyl, 4- (2,2,3,3-tetrafluoropropoxy) phenyl, 4- (2,2,3,3,3-pentafluoropropoxy)
Examples include phenyl and the like. Examples of the lower (C _1-4 ) alkylsulfonylphenyl group include 4-methanesulfonylphenyl and the like. Low halogenated (C _1-4 )
Examples of the alkylsulfonylphenyl group include 4-
(2,2,2-trifluoroethanesulfonyl) phenyl,
4- (2,2,3,3-tetrafluoropropanesulfonyl)
Examples thereof include phenyl and 4- (2,2,3,3,3-pentafluoropropanesulfonyl) phenyl.

As Ar, among others, a phenyl group substituted by 1 or 2 halogens, such as 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 and 2,4-difluorophenyl are particularly preferable. .

In the general formulas (I), (II) and (I '), the lower alkyl group represented by R ¹ or R ² is
Examples thereof include linear or branched alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, and among them, methyl is preferable. R ¹ and R ² are both preferably a hydrogen atom, a hydrogen atom and methyl, and a combination of methyl and methyl. 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, and among them, ethylene is preferable. As R ¹ and R ^2, it is particularly preferable that one is a hydrogen atom and the other is methyl.

With respect to the general formulas (I) and (I '), R ³
Examples of the acyl group represented by 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 (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 aryl having 7 to 11 carbon atoms. Carbonyl group; alkoxycarbonyl group, preferably alkoxycarbonyl group having 2 to 7 carbon atoms (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
Isobutoxycarbonyl, sec-butoxycarbonyl, t
ert-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 Aryloxycarbonyl group having 7 to 11 carbon atoms; aralkylcarbonyl group, preferably 8 carbon atoms
To 20 aralkylcarbonyl groups (eg, benzylcarbonyl, phenethylcarbonyl, phenylpropylcarbonyl, naphthylethylcarbonyl, etc.), particularly preferably aralkylcarbonyl groups having 8 to 14 carbon atoms. These may be substituted with 1 to 3 appropriate substituents. Examples of suitable substituents include optionally halogenated lower alkyl groups, aryl groups, halogens and the like. The acyl group is preferably one that can be hydrolyzed in vivo. Specific examples thereof include formyl, acetyl, benzoyl, benzylcarbonyl and the like.

With respect to the general formulas (I) and (II), the saturated cyclic amide group represented by A, which may have a substituent and which is bonded to a nitrogen atom, is preferably a saturated cyclic amide group.

[Chemical 13] Is a saturated heterocyclic group represented by, which has 1 to 3 nitrogen atoms in the ring and may further have 1 oxygen or sulfur atom in the ring. The saturated cyclic amide group is a 4- to 8-membered ring group, preferably a 5- or 6-membered ring group, and examples of such a saturated cyclic amide group include 2-oxo-1-imidazolidinyl and 5-oxo-1- Imidazolidinyl, 2-oxo-1-pyrrolidinyl, 3-oxo-
2-pyrazolidinyl, 2-oxo-1-piperazinyl,
2-oxo-1-piperidinyl, 3-oxomorpholino, 2-oxo-1-perhydropyrimidinyl and the like can be mentioned. The saturated cyclic amide group particularly preferably contains two nitrogen atoms in the ring, and examples of such a saturated cyclic amide group include 2-oxo-1-imidazolidinyl and 2-oxo-1-piperazinyl. , 2-oxo-
1-perhydropyrimidinyl and the like can be mentioned.

Examples of the substituent in the saturated cyclic amide group represented by A include an oxo group, a halogen (eg, fluorine, chlorine, bromine, iodine, etc.), and an aliphatic hydrocarbon group which may have a substituent. , An aromatic hydrocarbon group which may have a substituent, and an aromatic heterocyclic group which may have a substituent. The number of substituents on the saturated cyclic amide is 1.
Or 3 or preferably 1 or 2.

The substituent in the saturated cyclic amide group represented by A is an "aliphatic hydrocarbon group which may have a substituent".
Examples of the aliphatic hydrocarbon group in the case of are alkyl, cycloalkyl, alkenyl, alkynyl groups and the like. Examples of the alkyl group include linear or branched alkyl groups having 1 to 12 carbon atoms. Specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, heptyl, octyl, nonyl, decyl, dodecyl and the like are mentioned, and particularly those having 1 to 4 carbon atoms. Lower alkyl group (eg, methyl, ethyl, n-propyl,
Isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl etc.) are preferred.

Examples of the cycloalkyl group include cycloalkyl groups having 3 to 8 carbon atoms. Specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like, and a cycloalkyl group having 3 to 6 carbon atoms (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) is particularly preferable. Examples of the alkenyl group include alkenyl groups having 2 to 4 carbon atoms. Specific examples thereof include vinyl, propenyl, butenyl, and the like, and an alkenyl group having 2 to 3 carbon atoms (eg, vinyl, propenyl, etc.) is particularly preferable. Examples of the alkynyl group include an alkynyl group having 2 to 4 carbon atoms. Specific examples thereof include ethynyl, propynyl, butynyl and the like, with an alkynyl group having 2 to 3 carbon atoms (eg, ethynyl, propynyl etc.) being particularly preferable.

The substituent in the saturated cyclic amide group represented by A is an "aromatic hydrocarbon group which may have a substituent".
Examples of the aromatic hydrocarbon group in the case of are an aryl group having 6 to 14 carbon atoms. Examples of the aryl group include, for example, phenyl, naphthyl, biphenylyl, anthryl, indenyl and the like, with an aryl group having 6 to 10 carbon atoms (eg, phenyl, naphthyl, etc.) being particularly preferable.

When the substituent in the saturated cyclic amide group represented by A is "an aromatic heterocyclic group which may have a substituent", examples of the aromatic heterocyclic group include a nitrogen atom and sulfur. At least one selected from atoms and oxygen atoms
And aromatic heterocyclic groups containing 4 heteroatoms. The aromatic heterocyclic group may be condensed with a benzene ring or a 5- or 6-membered heterocyclic ring. Examples of such aromatic heterocyclic groups include, for example, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, thiazolyl, thiadiazolyl, thienyl, furyl, pyrrolyl,
Aromatic heterocyclic groups such as pyrazinyl, pyrimidinyl, oxazolyl, isoxazolyl and benzimidazolyl,
Examples thereof include condensed aromatic heterocyclic groups such as imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, benzothiazolyl, quinolyl, isoquinolyl, quinazolinyl, and indolyl. As the aromatic heterocyclic group, especially a 5- or 6-membered aromatic heterocyclic group containing 1 to 3 heteroatoms arbitrarily selected from a nitrogen atom, a sulfur atom and an oxygen atom (eg, imidazolyl,
Triazolyl, thiazolyl, thiadiazolyl, thienyl, furyl, pyridyl, pyrimidinyl, etc.) are preferred.

Examples of the substituent in the above-mentioned "aliphatic or aromatic hydrocarbon group optionally having substituent (s) or aromatic heterocyclic group optionally having substituent (s)" are:
For example, a hydroxyl group, an optionally esterified carboxyl group (eg, carboxyl, methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, etc., having 1 to 6 carbon atoms), a nitro group, an amino group, an acylamino group (eg, acetyl). Amino groups such as amino, propionylamino, butyrylamino, etc., alkanoylamino, etc.), amino groups mono- or di-substituted with alkyl groups having 1-10 carbon atoms (eg, methylamino, dimethylamino, diethylamino, dibutylamino, etc.) ), An optionally substituted 5- or 6-membered heterocyclic group (eg, pyrrolidinyl, morpholino, piperidino, pyrazolidinyl, perhydroazepinyl, piperazinyl, 4-benzylpiperazinyl, 4-acetylpiperazinyl, 4 -(4-trifluoromethoxyphenyl ) -1-Piperazinyl, 4- [4
-(1,1,2,2-Tetrafluoroethoxy) phenyl]-
1-piperazinyl, 4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -1-piperazinyl, 4-
[4- (2,2,2-trifluoroethoxy) phenyl]-
1-piperazinyl, 4- [4- (2,2,3,3,3-pentafluoropropoxy) phenyl] -1-piperazinyl, 4
-(4-trifluoromethylphenyl) -1-piperazinyl etc.), an alkoxy group having 1 to 6 carbon atoms (eg methoxy, ethoxy, butoxy etc.), a halogen atom (eg fluorine, chlorine, bromine etc.), halogeno- Alkyl groups having 1 to 6 carbon atoms (eg trifluoromethyl, dichloromethyl, trifluoroethyl etc.), halogeno-alkoxy groups having 1 to 6 carbon atoms (eg trifluoromethoxy, 1,1,2,2-tetra Fluoroethoxy, 2,2,2-trifluoroethoxy, 2,
2,3,3-Tetrafluoropropoxy, 2,2,3,3,3-pentafluoropropoxy, 2,2,3,3,4,4,5,5-octafluoropentoxy, 2-fluoroethoxy, etc. ), An oxo group,
Thioxo group, mercapto group, alkylthio group having 1 to 6 carbon atoms (eg, methylthio, ethylthio, butylthio, etc.),
Examples thereof include an alkylsulfonyl group having 1 to 6 carbon atoms (eg, methanesulfonyl, ethanesulfonyl, butanesulfonyl, etc.) and an alkanoyl group having 1 to 10 carbon atoms (eg, acetyl, formyl, propionyl, butyryl, etc.).

Among the substituents on the saturated cyclic amide group represented by A above, an aliphatic hydrocarbon which may have a substituent, an aromatic hydrocarbon group which may have a substituent, and a substituent The aromatic heterocyclic group which may have a group is preferably bonded to the nitrogen atom constituting the broken line portion in the ring of the saturated cyclic amide group described above.

Preferred examples of A include unsubstituted saturated cyclic amide group, saturated cyclic amide group substituted with oxo group, saturated cyclic amide group substituted with halogenophenyl group, halogenophenyl group and oxo group. Saturated cyclic amide group, saturated cyclic amide group substituted with halogenated (C _1-6 ) alkylphenyl, saturated cyclic amide group substituted with halogenated (C _1-6 ) alkylphenyl and oxo group, halogenated (C _{1- 6)} alkoxyphenyl in substituted saturated cyclic amide group, halogenated lower (C _1-6) alkoxyphenyl and a saturated cyclic amide group substituted by an oxo group, and the like.

Here, examples of the unsubstituted saturated cyclic amide group include 2-oxo-1-imidazolidinyl and 5
-Oxo-1-imidazolidinyl, 2-oxo-1-pyrrolidinyl, 3-oxo-2-pyrazolidinyl, 2-oxo-1-piperazinyl, 2-oxo-1-piperidinyl, 3-oxomorpholino, 2-oxo-1- Perhydropyrimidinyl and the like can be mentioned.

Examples of the saturated cyclic amide group substituted with an oxo group include 2,4-dioxo-1-imidazolidinyl, 2,5-dioxo-1-imidazolidinyl, 2,4-dioxo-1-pyrrolidinyl and 3,5 -Dioxo-2-pyrazolidinyl, 2,3-dioxo-1-piperazinyl, 2,5-dioxo-1-piperazinyl, 2,3-dioxo-1-piperidinyl and the like can be mentioned. The above-mentioned unsubstituted saturated cyclic amide group and saturated cyclic amide group substituted with an oxo group are R
^In addition to the nitrogen atom bonded to the carbon to which ¹ and R ² are bonded, it is preferable to further contain one nitrogen atom in the ring. This further nitrogen atom, halogenophenyl group as described below, halogeno C _1-6 alkyl phenyl group, that are bonded with a substituent such as a halogeno C _1-6 alkoxyphenyl group.

Examples of the saturated cyclic amide group substituted with a halogenophenyl group include 3-halogenophenyl-2-
Oxo-1-imidazolidinyl, 3-halogenophenyl-2-oxo-1-pyrrolidinyl, 4-halogenophenyl-2-oxo-1-piperazinyl, 4-halogenophenyl-2-oxo-1-piperidinyl and the like, particularly, Preferably 3-halogenophenyl-2-oxo-1-
It is imidazolidinyl. Examples of the saturated cyclic amide group substituted with a halogenophenyl group and an oxo group include 3-halogenophenyl-2,4-dioxo-1-imidazolidinyl and 3-halogenophenyl-2,4-dioxo-1.
-Pyrrolidinyl, 4-halogenophenyl-2,5-dioxo-1-piperazinyl, 4-halogenophenyl-2,3-
Dioxo-1-piperazinyl, 4-halogenophenyl-
2,3-dioxo-1-piperidinyl and the like, particularly 3-halogenophenyl-2,4-dioxo-1-imidazolidinyl, 4-halogenophenyl-2,5-dioxo-1.
-Piperazinyl and 4-halogenophenyl-2,3-dioxo-1-piperazinyl are preferred.

Examples of the saturated cyclic amide group substituted with halogenated (C _1-6 ) alkylphenyl include 3-halogenated (C _1-6 ) alkylphenyl-2-oxo-1-
Imidazolidinyl, 3-halogenated (C _1-6 ) alkylphenyl-2-oxo-1-pyrrolidinyl, 4-halogenated (C _1-6 ) alkylphenyl-2-oxo-1-piperazinyl, 4-halogenated (C _1-6 ) alkylphenyl-2-oxo-1-piperidinyl and the like can be mentioned, and 3-halogenated (C _1-6 ) alkylphenyl-2-oxo-1-imidazolidinyl is particularly preferable.

The saturated cyclic amide group substituted with a halogenated (C _1-6 ) alkylphenyl and oxo group includes
For example, 3-halogenated (C _1-6 ) alkylphenyl-2,4
-Dioxo-1-imidazolidinyl, 3-halogenated (C _1-6 ) alkylphenyl-2,4-dioxo-1-pyrrolidinyl, 4-halogenated (C _1-6 ) alkylphenyl-2,5-dioxo-1 -Piperazinyl, 4-halogenated (C _1-6 ) alkylphenyl-2,3-dioxo-1-piperazinyl, 4-halogenated (C _1-6 ) alkylphenyl-2,3-dioxo-1-piperidinyl, etc. Particularly, 3-halogenated (C _1-6 ) alkylphenyl-2,4-dioxo-1-imidazolidinyl, 4-halogenated (C _1-6 )
_1-6) alkylphenyl-2,5-dioxo-1-piperazinyl, 4-halogenated (C _1-6) alkylphenyl-2,3
-Dioxo-1-piperazinyl is preferred.

Examples of the saturated cyclic amide group substituted with halogenated (C _1-6 ) alkoxyphenyl include 3-halogenated (C _1-6 ) alkoxyphenyl-2-oxo-
1-imidazolidinyl, 3-halogenated (C _1-6 ) alkoxyphenyl-2-oxo-1-pyrrolidinyl, 4-
Examples thereof include halogenated (C _1-6 ) alkoxyphenyl-2-oxo-1-piperazinyl, 4-halogenated (C _1-6 ) alkoxyphenyl-2-oxo-1-piperidinyl, and the like, particularly 3-halogenated ( C _1-6 ) alkoxyphenyl-2-oxo-1-imidazolidinyl is preferred.

Examples of the saturated cyclic amide group substituted with a halogenated (C _1-6 ) alkoxyphenyl and an oxo group include 3-halogenated (C _1-6 ) alkoxyphenyl-2,4-dioxo-1-imidazolidinyl. , 3-halogenated (C _1-6 ) alkoxyphenyl-2,4-dioxo-
1-pyrrolidinyl, 4-halogenated (C _1-6 ) alkoxyphenyl-2,5-dioxo-1-piperazinyl, 4-
Halogenated (C _1-6 ) alkoxyphenyl-2,3-dioxo-1-piperazinyl, 4-halogenated (C _1-6 ) alkoxyphenyl-2,3-dioxo-1-piperidinyl and the like, and the like, In particular, 3-halogenated (C _1-6 ) alkoxyphenyl-2,4-dioxo-1-imidazolidinyl, 4-halogenated (C _1-6 ) alkoxyphenyl-2,5
-Dioxo-1-piperazinyl, 4-halogenated (C
_1-6 ) Alkoxyphenyl-2,3-dioxo-1-piperazinyl is preferred.

A is more preferably substituted with a saturated cyclic amide group substituted with a halogenophenyl group, a saturated cyclic amide group substituted with a halogenophenyl group and an oxo group, and a halogenated (C _1-6 ) alkylphenyl group. Saturated cyclic amide group, saturated cyclic amide group substituted with halogenated (C _1-6 ) alkylphenyl and oxo group, saturated cyclic amide group substituted with halogenated (C _1-6 ) alkoxyphenyl, halogenated (C _{1 -6)} is alkoxyphenyl and a saturated cyclic amide group substituted with an oxo group.

A is particularly preferably 3-halogenophenyl-2-oxo-1-imidazolidinyl [eg: 3- (2,
4-difluorophenyl) -2-oxo-1-imidazolidinyl, 3- (4-fluorophenyl) -2-oxo-1-imidazolidinyl, etc.], 3-halogenated lower (C
_1-4 ) Alkylphenyl-2-oxo-1-imidazolidinyl [Example: 3- (4-trifluoromethylphenyl)
2-oxo-1-imidazolidinyl, etc.], 3-halogenated lower (C _1-4 ) alkoxyphenyl-2-oxo-
1-imidazolidinyl [Example: 3- (4-trifluoromethoxyphenyl) -2-oxo-1-imidazolidinyl, 3- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -2-oxo- 1-imidazolidinyl,
3- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -2-oxo-1-imidazolidinyl, 3- [4
-(2,2,3,3,3-Pentafluoropropoxy) phenyl] -2-oxo-1-imidazolidinyl, 3- [4-
(2,2,2-trifluoroethoxy) phenyl] -2-oxo-1-imidazolidinyl and the like] and the like.

Particularly preferable examples of the above-mentioned "optionally substituted saturated cyclic amide group bonded by a nitrogen atom" are represented by the formula:

Embedded image [In the formula, R ⁴ represents a substituted phenyl group] 3-
A substituted phenyl-2-oxo-1-imidazolidinyl group,
Or expression

[Chemical 15] It can be represented by a 4-substituted phenyl-2,5-dioxo-1-piperazinyl group represented by the formula: wherein R ⁵ has the same meaning as R ⁴ . The above examples of the substituted phenyl group represented by R ⁴ or R ⁵ are halogenophenyl group described as a substituent of the saturated cyclic amide, halogeno (C _1-6) alkylphenyl group, a halogeno (C _1-6) Examples thereof include an alkoxyphenyl group.

The compound (I) is also used as a salt. As such a salt, a pharmacologically acceptable salt, for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid. ,
Examples thereof include salts with organic acids such as acetic acid, tartaric acid, citric acid, fumaric acid, maleic acid, toluenesulfonic acid and methanesulfonic acid. The compound represented by the general formula (I) or a salt thereof (hereinafter, abbreviated as the compound of the present invention) has at least one asymmetric atom in the molecule and therefore has two or more stereoisomers. However, any of its stereoisomers and their mixtures are included in the present invention. In particular, when R 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 and the carbon to which R ² is bound have the (R) configuration. Optically active forms are preferred.

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

Embedded image [Wherein the symbols have the same meanings as defined above] and a compound of the general formula (III)

[Chemical 17] It can be produced by reacting a compound represented by the formula [wherein the symbols have the same meaning as defined above] or a salt thereof, and treating with an acylating agent if necessary.

This reaction is usually carried out in a solvent that does not interfere with the reaction. As the solvent that does not inhibit the reaction, for example, water,
Ketones (eg: acetone), 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 etc.), ureylenes (eg 1,3-dimethyl-2) −
Imidazolidinone etc.) and the like are used. These may be used alone or as a mixture of two or more kinds 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-butylate, etc.), tetrabutylammonium fluoride, bis (tri-n-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 O.001 to 100 equivalents, preferably about 0.01 to 50 equivalents, relative to compound (II). Compound (III) or a salt thereof is used in about 1 to 100 equivalents, preferably about 1 to 50 equivalents, relative to compound (II). 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 hours (for example, 5 minutes to 50 hours).

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

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

[Chemical 19] 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 of the general formula (I) in which R ³ is a hydrogen atom is obtained.

This reaction is usually carried out in a solvent that does not interfere with the reaction. As the solvent that does not inhibit the reaction, for example, water,
Ketones (eg acetone), 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.), ureylenes (eg 1,3-dimethyl-2) −
Imidazolidinone etc.) and the like are used. These may be used alone or as a mixture of two or more kinds 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, etc.), tetrabutylammonium fluoride, bis (trinormal butylstannyl) oxode, etc. are preferably present, and tetrabutylammonium fluoride is particularly preferred.

The desired compound can also be produced by carrying out the reaction in the above-mentioned solvent using a metal salt (eg, an alkali metal such as sodium or potassium) instead of the compound (V). The amount of base used is usually about 0.001 to 100 equivalents, preferably about 0.01 to 50 equivalents, relative to compound (V). Compound (V) or a salt thereof is used in an amount of about 0.1 to 100 equivalents, preferably about 0.1 to 50 equivalents, relative to compound (IV). 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 hours (for example, 5 minutes to 50 hours).

In the general formula (I), for example, a compound in which A is 2-oxo-1-imidazolidinyl optionally having a substituent or a salt thereof is, for example, the general formula (VI).

Embedded image [In the formula, A'is optionally substituted 2-oxo-
2,3-dihydro-1H-imidazol-1-yl group,
Other symbols have the same meanings as described above] and can be produced by subjecting a compound represented by the formula or a salt thereof to a catalytic reduction reaction.

The above 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 ( (Example: ethyl acetate etc.), hydrocarbons (eg benzene, toluene, hexane, xylene etc.), organic carboxylic acids (eg acetic acid, propionic acid etc.)
Etc. alone or in the presence of 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 (III), (IV) and (VI)
The same salt as the salt of compound (I) is used.
In the above reaction, when a compound of the general formula (I) in which R ³ is a hydrogen atom is obtained, this compound or a salt thereof can be converted into a suitable acylating agent R ³ X by a conventional method.
[R ³ is an aliphatic or aromatic carboxylic acid residue (eg, acetyl, propionyl, butyryl, ethoxycarbonyl, benzoyl, substituted benzoyl, etc.), and X is a group to be removed (eg, halogen such as chlorine or bromine). Atom; active ester group etc.)] in the general formula (I)
It can lead to compounds in which ³ is an acyl group.

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, benzene, toluene, aromatic hydrocarbons such as xylene, dichloromethane, Chloroform, halogenated hydrocarbons such as 1,2-dichloroethane, esters such as ethyl acetate, amides such as dimethylformamide, acetamide, dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, etc. Urerilenes and the like. In order to accelerate the reaction, a base (eg, dimethylaminopyridine, pyridine,
Pyroline, triethylamine) can be added to the reaction system. The compound of the present invention thus obtained is obtained from the reaction mixture by a means known per se, for example, extraction, concentration, neutralization,
It can be isolated and purified by using means such as filtration, recrystallization, column chromatography, thin layer chromatography and the like.

The compounds of the present invention may have at least two stereoisomers. Both these individual isomers and mixtures thereof are included in the present invention, but if desired, these isomers can also be prepared individually. For example,
A single isomer of the compound of the present invention can be obtained by carrying out the above reaction using a single isomer of each of the starting compounds (II), (IV) and (VI), When the product is a mixture of two or more 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.), various chromatography, fractionation. Each isomer can also be separated by a separation means such as recrystallization. The salt of the compound (I) of the present invention can be produced according to a method known per se, for example, by adding the above-mentioned inorganic acid or organic acid to the compound (I).

In the starting compound (II) of the present invention, R ¹ is a hydrogen atom, R ² is a methyl group, the carbon to which Ar is bound is the (S) configuration, and the carbon to which R ² is bound is the (R) configuration. (VII) can be produced by the method represented by the following reaction formula.

[Chemical 21] [In the formula, Me is a methyl group, Et is an ethyl group, Pr is a propyl group, Ph is a phenyl group, DMF is dimethylformamide, and other symbols have the same meanings as above]

The starting compound (VIII) in this reaction scheme is
For example, it can be produced by the method represented by the following reaction formula.

[Chemical formula 22] [In the formula, THP represents a tetrahydropyranyl group, and DM
SO means dimethylsulfoxide, and other symbols have the same meanings as above]

In the starting compound (VI) of the present invention
R¹Is a hydrogen atom, R²Is a methyl group, R ³Is a hydrogen atom, Ar is
Bonded carbon and R²Both of the bonded carbons are (R)
The compound (XVII) having the configuration is represented by, for example, the following reaction formula.
It can be manufactured by the method described above.

[Chemical formula 23] [Wherein the symbols have the same meanings as defined above] The starting compound (XX) in this reaction formula is, for example, EP054855.
It can be synthesized by the method described in 3A or EP0421210A.

In the starting compound (XVIII) of the present invention, 2-oxo-2,3-, in which A'has a substituent at the 3-position
Compound (XXI) which is dihydro-1H-imidazol-1-yl can be produced, for example, by the method shown in the following reaction scheme.

[Chemical formula 24] [In the formula, R ⁴ 'represents the substituent in the above A, and other symbols have the same meanings as above]

The compound (XXIV) in which A is 2-oxo-1-imidazolidinyl in which A has a substituent at the 3-position in compound (V) can be produced, for example, by the method shown in the following reaction scheme. it can.

[Chemical 25] [In the formula, symbols have the same meanings as above]

Further, the compound (XXV) in which A is a 2,5-dioxo-1-piperazinyl having a substituent at the 4-position in the compound (V) is produced, for example, by the method shown in the following reaction scheme. be able to.

[Chemical formula 26] [In the formula, R ⁵ 'represents a substituent in the above A, and other symbols have the same meanings as described above]

Furthermore, in the compound (V), the compound (XXVIII) in which A is a 2,3-dioxo-1-piperazinyl having a substituent at the 4-position can be produced by the method shown in the following reaction scheme. You can

[Chemical 27] [In the formula, symbols have the same meanings as above]

Further, the synthetic intermediate (IX) in the present invention
Can also be produced, for example, by the method shown by the following reaction formula.

[Chemical 28] [Wherein the symbols have the same meanings as described above] The above-mentioned raw material compounds can be prepared by a method known per se from the reaction mixture, such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography, thin layer chromatography, etc. It can be isolated and purified by using a means.

The compounds of the present invention have low toxicity and are fungi, for example, Candida spp. [Candida albicans, Candida utilis, Candida glabrata, etc.], Aspergillus spp. (Eg, Aspergillus niger, Aspergillus fumigatus, etc.), Cryptococcus spp. : Cryptococcus neoformans, etc.], Trichophyton genus [eg: Trichophyton ruplum, Tricophyton mentaglophytes, etc.], Microsporum genus [eg: Microsporum gypseum, etc.] with strong antibacterial activity and broad antifungal spectrum Because I have
Fungal infections of mammals (humans, livestock, poultry, etc.) (eg:
Candidiasis, histoplasmosis, aspergillosis,
It can be used for the prevention and treatment of cryptococcosis, trichophytonism, microsporum disease, etc.). Furthermore, the compound (I) of the present invention can be used as an antifungal agent for agriculture. Further, in the starting compound (VI) for producing the compound (I) of the present invention, the compound in which R ³ is a hydrogen atom also has antibacterial activity against the above fungi.

When the compound of the present invention is administered to humans,
Orally or by mixing with an appropriate pharmacologically acceptable carrier, excipient, diluent, etc., orally administered drug (eg powder, granules, tablets, capsules, etc.), parenteral drug [eg injection Orally or parenterally safely as a pharmaceutical composition such as an agent, an external preparation (eg, nasal preparation, transdermal preparation, etc.), suppository (eg, rectal suppository, vaginal suppository etc.), etc. can do.
These preparations can be produced by a method known per se which is generally used in the preparation process.

For example, injectable preparations are prepared by dispersing the compound of the present invention (eg, Tween 80 (manufactured by Atlas Powder Co., USA), HCO60 (manufactured by Nikko Chemicals), carboxymethyl cellulose, sodium alginate, etc.), preservative (eg : Methylparaben, propylparaben, benzyl alcohol, chlorobutanol, etc.), tonicity agent (eg:
Aqueous injection with sodium chloride, glycerin, sorbitol, glucose, etc., or oily injection by dissolving, suspending or emulsifying in vegetable oil (eg olive oil, sesame oil, peanut oil, cottonseed oil, corn oil, etc.), propylene glycol, etc. It is manufactured by molding into a drug.

The preparation for oral administration contains the compound of the present invention, 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 may be used as it is, or an excipient (eg, glycol, mannitol, starch, microcrystalline cellulose, etc.), a thickener (eg, natural gums, cellulose derivative, acrylic acid polymer). Etc.) and the like are added 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 an ointment. Liquid external preparations are almost the same as injectable preparations, and are produced by making them oily or aqueous suspensions. In addition to the above-mentioned solid, semi-solid or liquid external preparations, pH adjusting agents (eg carbonic acid, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, etc.), preservatives (eg paraoxybenzoic acid esters, chlorobutanol) , Benzalkonium chloride, etc.) and the like. Specifically, it can be used for sterilization and disinfection of skin or mucous membranes as an ointment containing, for example, petrolatum or lanolin as a base and usually containing about 0.1 to 100 mg of the compound of the present invention per gram.

The compounds of the present invention are oily or aqueous solids,
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 / min. kg / day, preferably about 0.1 to 50 mg / kg / day. More preferably about
0.1 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. Agent) or adsorbed to it, and if necessary, further add an emulsifier, suspending agent, spreading agent, penetrating agent, wetting agent, thickener, stabilizer, etc., emulsion, hydration It may be used as a dosage form such as a drug, a powder, and a granule. 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. Examples of the solid carrier include vegetable powder (eg, soybean powder, tobacco powder, wheat flour, etc.), mineral powder (eg, kaolin, bentonite, etc.), alumina, sulfur powder, activated carbon, etc. Two or more kinds can be mixed and used at an appropriate ratio.

[0061]

[Examples] Reference examples, examples and formulation examples are described below,
The present invention will be specifically described, but the present invention is not limited thereto. ¹ H-NMR spectrum was measured using Varian Gemini 200 (20
Measured with a 0 MHz type spectrometer, and all δ values are in ppm
Indicated by. In the mixed solvent, the value shown in parentheses is the volume mixing ratio of each solvent. % Means percent by weight unless otherwise stated. Further, the solvent ratio in silica gel chromatography indicates the volume ratio of the mixed solvent. 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, quintet:
Quintet, septet: septet, br: wide, 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: 104-107 ° 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 solution 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),
2.05 (1H, br), 2.80 (1H, d, J = 5.2Hz), 3.30 (1H, 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 brine, 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 dissolved in methanol (800 ml) and cooled under ice. A 28% sodium methylate-methanol solution (12.9 ml) was added, and the reaction solution was stirred at room temperature for 6 hours. 1N Hydrochloric acid (63.2 ml) was added to the reaction solution, and the solvent was evaporated under reduced pressure. Silica gel chromatography of the residue (eluent: hexane / ethyl acetate = 6/1 → 2
/ 1) for purification, (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, 2.2Hz),
2.24 (1H, d, J = 1HZ), 2.92 (1H, d, J = 5Hz), 3.28 (1H,
d, J = 5Hz), 4.12 (1H, q, J = 6.4Hz), 6.77-6.95 (2H,
m), 7.34 (1H, m) IR ν _max ^neat _cm ^-1 : 3420, 2980, 1615, 1600, 1500, 1
425

Reference Example 5 2,4-difluoroaniline (25 g) and pyridine (2
5.2 g) was dissolved in dichloromethane (200 ml), and phenyl chloroformate (33.3 g) was added dropwise under ice cooling.
After stirring for 30 minutes under ice-cooling, the reaction solution was washed with water, dried and the solvent was distilled off to obtain a mixture of phenyl 2,4-difluorophenylcarbamate and pyridine. 2- (diethoxy) ethylamine (30.7
g) was added and the mixture was stirred at room temperature, and the precipitated crystals were collected by filtration and washed with petroleum ether to give N- (2,2-diethoxyethyl) -N '-(2,4-difluorophenyl) urea (37 0.8 g) was obtained as colorless crystals. This urea compound (37.5 g) was added with methanol (560 ml) and water (28
0 ml), 0.48 M hydrochloric acid (300 ml) was added, and the mixture was stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure, and the precipitated crystals were washed with a water-methanol (5: 1) mixed solution to give 1- (2,4-difluorophenyl) -2- (1
H, 3H) -Imidazolone (22.8 g) was obtained as a colorless powder. Melting point: 192-194 ° C. Elemental analysis value: Calculated as C ₉ H ₆ F ₂ N ₂ O (%): C 55.11 H 3.08 N 14.28 Actual value (%): C 55.14 H 3.29 N 14.18

Reference Examples 6 to 13 In the same manner as in Reference Example 5, the imidazolone derivatives shown in Table 1 were obtained.

[0068]

[Table 1]

Reference Example 14 Phenyl 2,4-difluorophenylcarbamate (5.0 g), glycine ethyl ester hydrochloride (4.2
g) was dissolved in pyridine (30 ml) and heated at 80 ° C. for 14 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (80 ml) and water (20 ml) were added to the residue. The ethyl acetate layer was washed with brine (10 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Hexane (50 ml) was added to the residue and the precipitated solid was collected by filtration to give N- (2,4-difluorophenyl) -N'-ethoxycarbonylmethylurea (4.58 g) as a colorless powder. ¹ H-NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7Hz), 4.07 (2H,
d, J = 5.4Hz), 4.24 (2H, q, J = 7Hz), 5.57 (1H, br),
6.75-6.90 (3H, m), 7.84-7.98 (1H, m) Dissolve this product (4.1g) in methanol (80ml) and
8% sodium methoxide methanol solution (3.0 g)
Was added and stirred at room temperature for 2.5 hours. To the reaction mixture was added 1N-hydrochloric acid (15 ml) and the mixture was concentrated under reduced pressure, and the residue was mixed with water (20 m).
l) was added and the mixture was extracted with ethyl acetate (80 ml). The extract was washed with water (20 ml) and saturated brine (20 ml), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Crystallization of the residue from diethyl ether yielded 3- (2,
4-Difluorophenyl) -2,4-imidazolidinedione (1.0 g) was obtained as a colorless powder. Melting point: 161-170 ° C ¹ H-NMR (CDCl ₃ ) δ: 4.20 (2H, s), 5.90 (1H, br), 6.9
5-7.10 (2H, m), 7.25-7.40 (1H, m)

Reference Example 15 1- [4- (2,2,3,3-tetrafluoropropoxy
Si) phenyl] -2 (1H, 3H) -imidazolone
Dissolve (2.0 g) in acetic acid (10 ml) and add 10%
Um-carbon (0.5 g) was added, and under a hydrogen atmosphere, 7.5
Stirred for hours. The catalyst is filtered off and the catalyst part is washed with acetic acid.
Then, the filtrate and the washing solution were combined and evaporated under reduced pressure. Water and vinegar on the residue
Ethyl acid (40 ml each) was added for liquid separation, and the ethyl acetate layer was separated.
Dry (MgSO4 _FourAfter that, the solvent was distilled off under reduced pressure. Colorless obtained
The crystals are washed with diisopropyl ether to give 1- [4-
(2,2,3,3-tetrafluoropropoxy) pheny
]]-2-Imidazolidinone (1.86 g) as colorless crystals
Got as. Melting point: 180-181 ° C¹ H-NMR (CDCl₃) δ: 3.53-3.61 (2H, m), 3.87-3.95 (2
H, m), 4.32 (2H, tt, J = 11.8Hz, 1.6Hz), 4.97 (1H, br
s), 6.06 (1H, tt, J = 53Hz, 5.0Hz), 6.91 (2H, d, J =
9.2Hz), 7.47 (2H, d, J = 9.2Hz) IR (KBr) νmax: 3250, 1705, 1680, 1515, 1485 (c
m^-1) Elemental analysis value: C₁₂H₁₂F_FourN₂O₂Calculated value (%): C 49.32 H 4.14 N 9.59 Actual value (%): C 49.24 H 3.96 N 9.59

Reference Examples 16 to 19 The imidazolidinone shown in Table 2 was obtained in the same manner as in Reference Example 15.

[0072]

[Table 2]

Reference Example 20 (1S) -1-[(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethanol (535 m
g) in dichloromethane (15 ml) at −78 ° C. under a nitrogen atmosphere and diisopropylethylamine (0.51 ml).
Was added, and then trifluoromethanesulfonic anhydride (0.49 ml) was added dropwise over 3 minutes. After stirring at −78 ° C. for 20 minutes and then at −20 ° C. for 20 minutes, the reaction solution was concentrated at −10 ° C. to about 9 ml. The concentrate was subjected to flash column chromatography using silica gel (3.2 × 4 cm) and eluted with dichloromethane-hexane (1: 1). The desired fraction was concentrated to about 3 ml, and the residue was treated with 1- (4-trifluoromethylphenyl) -2 (1H, 3H) -imidazolone (606 mg),
Add to a sodium salt solution of 1- (4-trifluoromethylphenyl) -2 (1H, 3H) -imidazolone prepared from dimethylformamide (3 ml) and 60% oily sodium hydride (85 mg) at -10 ° C and add 10 Stir for minutes. The reaction solution was further stirred at 0 ° C. for 20 minutes. Water (30 ml) was poured into the reaction mixture, and the mixture was extracted 4 times with ethyl acetate (30 ml). The ethyl acetate layer was washed twice with water (20 ml) and once with saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give a colorless oil. This product was subjected to silica gel chromatography (eluent: hexane / ethyl acetate = 3
1/1 → 2/1 → 1/1) and purified by 1-[(1R, 2
S) -2- (2,4-difluorophenyl) -2,3-
Epoxy-1-methylpropyl] -3- (4-trifluoromethylphenyl) -2 (1H, 3H) -imidazolone (362 mg) and (2R) -2- (2,4-difluorophenyl) -2-[( 1R) -1- [1- (4-trifluoromethylphenyl) -2-imidazolyloxy] ethyl] oxirane (209 mg) was obtained. 1-[(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] -3
-(4-trifluoromethylphenyl) -2 (1H, 3
H) -imidazolone: colorless prism crystal Melting point: 135-136 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.37 (3H, d, J = 7.2Hz), 2.72 (1H,
d, J = 4.4Hz), 2.82 (1H, d, J = 4.4Hz), 5.09 (1H, q,
J = 7.2Hz), 6.50 (1H, d, J = 3.2Hz), 6.64 (1H, d, J =
3.2Hz), 6.80-6.97 (2H, m), 7.35-7.50 (1H, m), 7.69
(2H, d, J = 8.4Hz), 7.82 (2H, d, J = 8.4Hz)

60% oily sodium hydride (65 mg) was dispersed in dimethylformamide (4 ml), 1,2,4-triazole (118 mg) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour.
Stir for 0 minutes. 1-[(1R, 2S) -2 obtained above
-(2,4-Difluorophenyl) -2,3-epoxy-1-methylpropyl] -3- (4-trifluoromethylphenyl) -2 (1H, 3H) -imidazolone (36
2 mg) of dimethylformamide solution (2 ml) was added to give 5
Heated at 0 ° C. for 5 hours. After cooling, cool water (8 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 chromatographed on silica gel (eluent: ethyl acetate / hexane = 1/1 → 2/1
→ When purified with ethyl acetate, 1-[(1R, 2
R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- (4-trifluoromethyl Phenyl) -2 (1H, 3H) -imidazolone (350 mg) was obtained as a white powder. ¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, d, J = 7.2Hz), 4.19 (1H,
d, J = 14.2Hz), 5.00 (1H, q, J = 7.2Hz), 5.11 (1H, d,
J = 14.2Hz), 5.46 (1H, s), 6.71 (1H, d, J = 3.2Hz), 6.8
3 (1H, d, J = 3.2Hz), 6.72-6.90 (2H, m), 7.40-7.56
(1H, m), 7.72 (2H, d, J = 8.4Hz), 7.75 (1H, s), 7.83
(2H, d, J = 8.4Hz), 7.84 (1H, s) IRν _max ^neat _cm ^-1 : 3404, 3383, 3000, 1693, 1618, 1
599, 1524, 1500, 1429, 1327 Elemental analysis value: Calculated as C ₂₂ H ₁₈ F ₅ N ₅ O ₂ (%): C 55.12 H 3.78 N 14.61 Actual value (%): C 54.81 H 3.97 N 14.39

Reference Examples 21 to 23 In the same manner as in Reference Example 20, the following compounds were obtained. Reference Example 21 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-triazol-1-yl) propyl] -3
-(2,4-difluorophenyl) -2 (1H, 3H)
-Imidazolone colorless powdery crystal Yield: 416 mg Yield: 66% Melting point: 134-136 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, d, J = 7Hz), 4.19 (1H,
d, J = 14.4Hz), 4.95 (1H, q, J = 7Hz), 5.11 (1H, d, J =
14.4Hz), 5.52 (1H, br), 6.52 (1H, t, J = 2.6Hz), 6.70
-6.86 (3H, m), 6.92-7.06 (2H, m), 7.40-7.68 (2H,
m), 7.74 (1H, s), 7.85 (1H, s)

Reference Example 22 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-triazol-1-yl) propyl] -3
-(4-trifluoromethoxyphenyl) -2 (1H,
3H) -Imidazolone white powder Yield: 500 mg Yield: 71% 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), 5.51 (1H, br), 6.39 (1H, d, J = 3.2Hz), 6.64
(1H, d, J = 3.2Hz), 6.70-6.86 (2H, m), 7.31 (2H, d,
J = 9Hz), 7.38-7.54 (1H, m), 7.69 (2H, d, J = 9Hz), 7.
74 (1H, s), 7.84 (1H, s)

Reference Example 23 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-triazol-1-yl) propyl] -3
-(4-Fluorophenyl) -2 (1H, 3H) -imidazolone colorless powder Yield: 971 mg Yield: 74% ¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, d, J = 7Hz), 4.20 (1H ,
d, J = 14.2Hz), 4.95 (1H, q, J = 7Hz), 5.10 (1H, d, J =
14.2Hz), 5.58 (1H, br), 6.60 (1H, d, J = 3.2Hz), 6.74
(1H, d, J = 3.2Hz), 6.70-6.88 (2H, m), 7.05-7.20 (2
H, m), 7.40-7.65 (3H, m), 7.73 (1H, s), 7.85 (1H,
s)

Reference Example 24 (1S) -1-[(2R) -2- (2,4-difluorophenyl) -2-oxiranyl] ethanol (1.36
g) in dichloromethane (30 ml) at 60 ° C. under a nitrogen atmosphere and diisopropylethylamine (1.31 ml).
Was added, and then trifluoromethanesulfonic anhydride (1.26 ml) was added dropwise over 3 minutes. After stirring at −60 ° C. for 20 minutes and then at −20 ° C. for 20 minutes, the reaction was subjected to flash chromatography using silica gel (27 g), dichloromethane-hexane (1: 1,22).
0 ml). The desired fraction was concentrated to about 9 ml and the residue was treated with 3- (2,4-difluorophenyl)-
To a mixed solution of 2,4-imidazolidinedione (1.15 g), dimethylformamide (18 ml) and 60% oily sodium hydride (0.20 g) was added at -10 ° C, and the mixture was stirred for 20 minutes. The reaction mixture was further stirred at 0 ° C. for 20 minutes, water (20 ml) was added, and the mixture was extracted with ethyl acetate (100 ml). The ethyl acetate layer was washed with saturated brine (20 ml), dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1) to give 1-[(1
R, 2S) -2- (2,4-difluorophenyl)-
2,3-Epoxy-1-methylpropyl] -3- (2,
4-Difluorophenyl) -2,4-imidazolidinedione (1.25 g) was obtained as a white solid. Melting point: 124-125 ° C (recrystallized from ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, d, J = 7.2Hz), 2.81 (1H,
d, J = 4.6Hz), 3.08 (1H, d, J = 4.6Hz), 4.06 (1H, d,
J = 17.8Hz), 4.22 (1H, d, J = 17.8Hz), 4.97 (1H, q, J =
7.2Hz), 6.78-7.04 (4H, m), 7.20-7.45 (2H, m)

Reference Examples 25-29 In the same manner as in Reference Example 24, the following compounds were obtained. Reference Example 25 1-[(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] -3
-[4- (2,2,3,3-tetrafluoropropoxy)
Phenyl] -2-imidazolidinone colorless powder ¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, d, J = 7.2Hz), 2.75 (1H,
d, J = 7.0Hz), 3.15 (1H, d, J = 7.0Hz), 3.42-3.64 (2
H, m), 3.71-3.81 (2H, m), 4.32 (2H, tt, J = 12Hz, 1.
4Hz), 4.80 (1H, q, J = 7.2Hz), 6.06 (1H, tt, J = 53Hz,
5Hz), 6.76-6.9 (2H, m), 6.91 (2H, d, J = 9.2Hz), 7.
35-7.5 (1H, m), 7.48 (2H, d, J = 9.2Hz)

Reference Example 26 1-[(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] -3
-[4- (1,1,2,2-tetrafluoroethoxy)
Phenyl] -2-imidazolidinone colorless powder ¹ H-NMR (CDCl ₃ ) δ: 1.22 (3H, d, J = 7.4Hz), 2.75 (1H,
d, J = 5Hz), 3.14 (1H, d, J = 5Hz), 3.44-3.65 (2H, m),
3.73-3.84 (2H, m), 4.80 (1H, q, J = 7.4Hz), 5.89 (1
H, tt, J = 53Hz, 2.8Hz), 6.77-6.93 (2H, m), 7.17 (2
H, d, J = 9Hz), 7.34-7.46 (1H, m), 7.55 (2H, d, J = 9H)
z) IR (KBr) νmax: 1680, 1615, 1510, 1485, 1425 (cm
^-1 )

Reference Example 27 1-[(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] -3
-[4- (2,2,3,3,3-pentafluoropropoxy) phenyl] -2-imidazolidinone colorless prism crystal Melting point: 142-144 ° C (ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ). δ: 1.22 (3H, d, J = 7Hz), 2.75 (1H,
d, J = 5.0Hz), 3.15 (1H, d, J = 5.0Hz), 3.42-3.64 (2H,
m), 3.73-3.82 (2H, m), 4.39 (2H, dt, J = 12.4Hz, 1.2
Hz), 4.80 (1H, q, J = 7Hz), 6.77-6.90 (2H, m), 6.92
(2H, d, J = 9.2Hz), 7.34-7.42 (1H, m), 7.48 (2H, d, J
= 9.2Hz) Elemental analysis value: Calculated value as C ₂₂ H ₁₉ F ₇ N ₂ O ₃ (%): C 53.66 H 3.89 N 5.69 Measured value (%): C 53.37 H 3.74 N 5.62 IR (KBr) νmax: 1700 , 1520, 1485, 1430, 1265 (cm
^-1 )

Reference Example 28 1-[(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] -3
-[4- (2,2,2-Trifluoroethoxy) phenyl] -2-imidazolidinone colorless needle crystal Melting point: 131-132 ° C (diethyl ether) ¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H , d, J = 7.2Hz), 2.75 (1H,
d, J = 5Hz), 3.15 (1H, d, J = 5Hz), 3.42-3.64 (2H,
m), 3.73-3.82 (2H, m), 4.32 (2H, q, J = 8.2Hz), 4.80
(1H, q, J = 7.2Hz), 6.77-6.88 (2H, m), 6.92 (2H, d,
J = 9Hz), 7.34-7.44 (1H, m), 7.48 (2H, d, J = 9Hz) Elemental analysis value: Calculated as C ₂₁ H ₁₉ F ₅ N ₂ O ₃ (%): C 57.02 H 4.33 N 6.33 Measured value (%): C 57.33 H 4.06 N 6.39 IR (KBr) νmax: 1695, 1515, 1485, 1425, 1265, 12
40 (cm ^-1 )

Reference Example 29 1- (4-chlorophenyl) -3-[(1R, 2S)-
2- (2,4-Difluorophenyl) -2,3-epoxy-1-methylpropyl] -2-imidazolidinone colorless needle crystal Melting point: 130-131 ° C (ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.22 (3H, d, J = 7Hz), 2.75 (1H,
d, J = 5Hz), 3.14 (1H, d, J = 5Hz), 3.43-3.65 (2H, m),
3.73-3.82 (2H, m), 4.80 (1H, q, J = 7Hz), 6.77-6.93
(2H, m), 7.28 (2H, d, J = 9Hz), 7.34-7.54 (1H, m),
7.49 (2H, d, J = 9Hz) Elemental analysis value: Calculated as C ₁₉ H ₁₇ ClF ₂ N ₂ O ₂ (%): C 60.24 H 4.52 N 7.40 Measured value (%): C 60.45 H 4.38 N 7.45 IR (KBr) νmax: 1700, 1615, 1600, 1500, 1425, 12
70 (cm ^-1 )

Reference Example 30 4- (2,2,3,3-tetrafluoropropoxy) aniline (8.6 g), ethyl chloroacetate (4.8 g),
A mixture of sodium hydrogen carbonate (4.8 g), sodium iodide (3.0 g) and acetone (300 ml) was added to 2 parts.
Refluxed for 1 hour. The solvent was evaporated under reduced pressure, ice water (200 ml) and dichloromethane (200 ml) were added to the residue, and the layers were separated. The dichloromethane layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate: hexane =
Purification with 1: 3 v / v) gave N-ethoxycarbonylmethyl-4- (2,2,3,3-tetrafluoropropoxy) aniline (9.4 g) as pale yellow crystals.

The obtained N-ethoxycarbonylmethyl-
A mixture of 4- (2,2,3,3-tetrafluoropropoxy) aniline (2.1 g), triethylamine (1.1 ml) and dichloromethane (50 ml) was mixed with chloroacetyl chloride (0.6 ml) in dichloromethane under ice cooling. (6m
l) was added dropwise, and the mixture was stirred at room temperature for 5 hours. Dichloromethane (50 ml) and ice water (100 ml) were added to the reaction mixture to separate the layers. The dichloromethane layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 2 v / v) to give N-chloroacetyl-N-ethoxycarbonylmethyl-4- (2,2 ，
3,3-tetrafluoropropoxy) aniline (2.4
g) was obtained as a yellow oil.

10.5% of the obtained N-chloroacetyl-N-ethoxycarbonylmethyl-4- (2,2,3,3-tetrafluoropropoxy) aniline (1.9 g) was added.
It was dissolved in ammonia-ethanol (20 ml) and stirred at 60 ° C. for 4 hours. After cooling, the precipitated crystals were collected by filtration and washed with cold ethanol to give 1- [4- (2,2,3,3
-Tetrafluoropropoxy) phenyl] -2,5-piperazinedione (1.5 g) was obtained as colorless crystals. ¹ H-NMR (d6-DMSO) δ: 3.95 (2H, s), 4.20 (2H, s), 4.
60 (2H, t, J = 14Hz), 6.67 (1H, tt, J = 52Hz, 5.4Hz),
7.08 (2H, d, J = 9Hz), 7.30 (2H, d, J = 9Hz), 8.27 (1H,
brs) Elemental analysis value: Calculated value as C ₁₃ H ₁₂ F ₄ N ₂ O ₃ (%): C 48.76 H 3.78 N 8.75 Actual value (%): C 48.99 H 3.65 N 8.88 SIMS (MH ⁺ ): 321 IR ( KBr) νmax: 3440, 3250, 1670, 1650, 1510, 13
30 (cm ^-1 )

Reference Example 31 In the same manner as in Reference Example 24, 1-[(1R, 2S) -2-
(2,4-Difluorophenyl) -2,3-epoxy-
1-methylpropyl] -4- [4- (2,2,3,3-
Tetrafluoropropoxy) phenyl] -2,5-piperazinedione was obtained. Colorless powder crystal ¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, d, J = 7.2Hz), 2.85 (1H,
d, J = 5Hz), 3.10 (1H, d, J = 5Hz), 4.07 (1H, d, J = 17
Hz), 4.21 (1H, d, J = 17Hz), 4.23 (1H, d, J = 16Hz),
4.34 (1H, d, J = 16Hz), 4.36 (2H, t, J = 12Hz), 5.37
(1H, q, J = 7.2Hz), 6.06 (1H, tt, J = 53Hz, 4.8Hz), 6.7
8-6.95 (2H, m), 6.98 (2H, d, J = 9Hz), 7.23 (2H, d, J
= 9Hz), 7.35-7.47 (1H, m) mp: 155-156 ° C. (ethyl acetate - hexane) Elemental analysis: Calculated _{C 23 H 20 F 6 N 2} O 4 (%): C 54.99 H 4.01 N 5.58 Measured value (%): C 54.77 H 4.03 N 5.36

Reference Example 32 1- (4-trifluoromethylphenyl) -2 (1H,
3H) -Imidazolone (1.15 g) in acetic acid (20 ml)
In 10% palladium-carbon (0.3 g) was added, and the mixture was stirred in a hydrogen stream for 6 hours. After the catalyst was filtered off, the solvent was evaporated and the residue was recrystallized from ethyl acetate-diisopropyl ether to give 1- (4-trifluoromethylphenyl) -2-imidazolidinone (0.95 g) as colorless prism crystals. Was obtained as. Melting point: 169-171 ° C (ethyl acetate-diisopropyl ether) ¹ H-NMR (CDCl ₃ ) δ: 3.63 (2H, t, J = 8Hz), 3.99 (2H,
t, J = 8Hz), 4.95 (1H, br), 7.59 (2H, d, J = 9Hz), 7.68
(2H, d, J = 9Hz) Elemental analysis value: Calculated value as C ₁₀ H ₉ F ₃ N ₂ O (%): C 52.18 H 3.94 N 12.17 Actual value (%): C 51.94 H 3.89 N 12.23

Reference Example 33 In the same manner as in Reference Example 24, 1-[(1R, 2S) -2-
(2,4-Difluorophenyl) -2,3-epoxy-
1-Methylpropyl] -3- (4-trifluoromethylphenyl) -2-imidazolidinone was obtained as a colorless powder. ¹ H-NMR (CDCl ₃ ) δ: 1.24 (3H, d, J = 7.2Hz), 2.76 (1H,
d, J = 4.8Hz), 3.14 (1H, d, J = 4.8Hz), 3.48-3.70 (2
H, m), 3.78-3.90 (2H, m), 4.83 (1H, q, J = 7.2Hz),
6.78-6.95 (2H, m), 7.35-7.48 (1H, m), 7.57 (2H, d,
J = 8.8Hz), 7.67 (2H, d, J = 8.8Hz)

Reference Example 34 4- (1,1,2,2-tetrafluoroethoxy) aniline was used as a starting material and a reaction was carried out in the same manner as in Reference Example 30. 1- [4- (1,1,2 , 2-Tetrafluoroethoxy) phenyl] -2,5-piperazinedione was obtained as colorless crystals. ¹ H-NMR (DMSO-d ₆ ) δ: 3.97 (2H, s), 4.27 (2H, s), 6.
81 (1H, tt, J = 52Hz, 3Hz), 7.32 (2H, d, J = 9Hz), 7.46
(2H, d, J = 9Hz), 8.31 (1H, br) Elemental analysis value: Calculated value as C ₁₂ H ₁₀ F ₄ N ₂ O ₃ (%): C 47.07 H 3.29 N 9.15 Measured value (%): C 46.89 H 3.26 N 9.08 Melting point:> 250 ° C

Reference Example 35 In the same manner as in Reference Example 24, 1-[(1R, 2S) -2-
(2,4-Difluorophenyl) -2,3-epoxy-
1-methylpropyl] -4- [4- (1,1,2,2-
Tetrafluoroethoxy) phenyl] -2,5-piperazinedione was obtained. Colorless powder crystal ¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, d, J = 7Hz), 2.85 (1H,
d, J = 5Hz), 3.09 (1H, d, J = 5Hz), 4.08 (1H, d, J = 17H
z), 4.22 (1H, d, J = 17Hz), 4.26 (1H, d, J = 16Hz), 4.
37 (1H, d, J = 16Hz), 5.36 (1H, q, J = 7Hz), 5.92 (1H,
tt, J = 53Hz, 3Hz), 6.78-6.95 (2H, m), 7.29 (4H, s),
7.30-7.47 (1H, m) Melting point: 168-170 ° C Elemental analysis value: Calculated as C ₂₂ H ₁₈ F ₆ N ₂ O ₄ (%): C 54.11 H 3.71 N 5.74 Measured value (%): C 54.08 H 3.75 N 5.64

Reference Example 36 4- (2,2,3,3-tetrafluoropropoxy) aniline (7.4 g), N- (2-bromoethyl) phthalimide (9.0 g), potassium carbonate (6.9 g), A mixture of potassium iodide (5.5 g) and N, N-dimethylformamide (80 ml) was refluxed for 22 hours. The solvent was evaporated under reduced pressure, ice water (200 ml) and ethyl acetate (200 ml) were added to the residue, and the layers were separated. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure.
The residue was purified by silica gel column chromatography (eluted with ethyl acetate: hexane = 1: 2 v / v),
Recrystallization from ethyl acetate-diisopropyl ether gave N- (2-phthalimido) ethyl-4- (2,2,2
3,3-Tetrafluoropropoxy) aniline (5.4
g) was obtained as white crystals. To the obtained mixture of N- (2-phthalimido) ethyl-4- (2,2,3,3-tetrafluoropropoxy) aniline (3.2 g), triethylamine (1.2 ml) and dichloromethane (60 ml), A dichloromethane solution (10 ml) of ethyl chloroglyoxylate (0.9 ml) was added dropwise at 65 ° C, and the mixture was stirred at -40 ° C for 1 hr. Ice water (50
ml) was added and the layers were separated, and the dichloromethane layer was washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure,
The residue was recrystallized from ethyl acetate-hexane to give N-
Etoxaryl-N- (2-phthalimido) ethyl-4-
(2,2,3,3-Tetrafluoropropoxy) aniline (3.1 g) was obtained as colorless powder crystals.

The obtained N-ethoxalyl-N- (2-phthalimido) ethyl-4- (2,2,3,3-tetrafluoropropoxy) aniline (3.4 g) and hydrazine monohydrate (0.7 ml). ) And ethanol (80 ml) at reflux for 9 hours. After the precipitated crystals were filtered off with heat, the solvent of the filtered solution was distilled off under reduced pressure. Water on the residue (150m
l) and ethyl acetate (300 ml) were added for liquid separation, and the ethyl acetate layer was washed with 5% aqueous sodium hydrogen carbonate and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with ethyl acetate: dichloromethane: methanol = 7: 7: 1 v / v) to give 1- [4- (2,2,3,3 -Tetrafluoropropoxy) phenyl] -2,3-piperazinedione (0.8g) was obtained as a colorless powder. ¹ H-NMR (DMSO-d ₆ ) δ: 3.44-3.55 (2H, m), 3.83-3.89
(2H, m), 4.61 (2H, t, J = 13Hz), 6.68 (2H, tt, J = 52
Hz, 6Hz), 7.09 (2H, d, J = 9Hz), 7.34 (2H, d, J = 9H)
z), 8.73 (1H, br) Elemental analysis value: Calculated value as C ₁₃ H ₁₂ F ₄ N ₂ O ₃ (%): C 48.76 H 3.78 N 8.75 Actual value (%): C 48.44 H 3.62 N 8.73 SIMS ( MH ⁺ ): 321

Reference Example 37 In the same manner as in Reference Example 24, 1-[(1R, 2S) -2-
(2,4-Difluorophenyl) -2,3-epoxy-
1-methylpropyl] -4- [4- (2,2,3,3-
Tetrafluoropropoxy) phenyl] -2,3-piperazinedione was obtained. Colorless powder crystal ¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, d, J = 7Hz), 2.81 (1H,
d, J = 5Hz), 3.13 (1H, d, J = 5Hz), 3.61-3.81 (3H, m),
3.90-4.04 (1H, m), 4.36 (2H, t, J = 12Hz), 5.40 (1H,
q, J = 7Hz), 6.06 (1H, tt, J = 53Hz, 5Hz), 6.80-6.95
(2H, m), 6.97 (2H, d, J = 9Hz), 7.32 (2H, d, J = 9Hz),
7.35-7.47 (1H, m) Elemental analysis value: Calculated as C ₂₃ H ₂₀ F ₆ N ₂ O ₄ (%): C 54.99 H 4.01 N 5.58 Actual value (%): C 54.61 H 4.01 N 5.65 Melting point: 197 ~ 201 ℃

Reference Example 38 In the same manner as in Reference Example 36, 4- (1,1,2,2-tetrafluoroethoxy) aniline was converted into 1- [4- (1,
1,2,2-Tetrafluoroethoxy) phenyl]-
2,3-piperazinedione was obtained. Colorless powder crystal ¹ H-NMR (DMSO-d ₆ ) δ: 3.46-3.53 (2H, m), 3.90-3.96
(2H, m), 6.81 (1H, tt, J = 52Hz, 3Hz), 7.33 (2H, d,
J = 9Hz), 7.50 (2H, d, J = 9Hz), 8.78 (1H, br) Elemental analysis value: Calculated as C ₁₂ H ₁₀ F ₄ N ₂ O ₃ (%): C 47.07 H 3.29 N 9.15 Actual measurement Value (%): C 46.86 H 3.24 N 9.11 Melting point: 240 to 242 ° C

Reference Example 39 In the same manner as in Reference Example 24, 1-[(1R, 2S) -2-
(2,4-Difluorophenyl) -2,3-epoxy-
1-methylpropyl] -4- [4- (1,1,2,2-
Tetrafluoroethoxy) phenyl] -2,3-piperazinedione was obtained. Colorless powder crystal ¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, d, J = 7Hz), 2.80 (1H,
d, J = 5Hz), 3.13 (1H, d, J = 5Hz), 3.60-3.85 (3H, m),
3.95-4.08 (1H, m), 5.37 (1H, q, J = 7Hz), 5.92 (1H,
tt, J = 53Hz, 3Hz), 6.81-6.93 (2H, m), 7.25 (2H, d,
J = 8Hz), 7.34-7.45 (3H, m) Melting point: 214-215 ° C Elemental analysis value: Calculated as C ₂₂ H ₁₈ F ₆ N ₂ O ₄ (%): C 54.11 H 3.71 N 5.74 Measured value (%) ): C 53.88 H 3.68 N 5.72

Reference Example 40 2- (2-Fluorophenyl) -2-[(1R) -1-
(3,4,5,6-tetrahydro-2H-pyran-2-
[(1R) -1-[(2R) -2- (2-fluorophenyl) -2-oxiranyl]] by the method shown in Reference Example 1 with (yl) oxyethyl] oxirane (synthesized by the method described in EP0548553A). Ethyl] led to 3,5-dinitrobenzoate. Colorless prism crystal (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, t,
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 ₁₂ FN ₂ O ₇ ( %): C 54.41 H 3.22 N 7.46 Actual value (%): C 54.23 H 3.25 N 7.41

Reference Example 41 [(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), 4.15 (1H, m), 6.99-7.47 (4H, m)

Reference Example 42 (1R) -1-[(2R) -2- (2-fluorophenyl) -2-oxiranyl] ethanol was added to (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, dd, J = 7Hz, 2Hz), 7.03-7.44 (4H, m)

Reference Example 43 In the same manner as in Reference Example 24, 1-[(1R, 2S) -2,
3-Epoxy-2- (2-fluorophenyl-1-methylpropyl) -3- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -2-imidazolidinone was obtained as a colorless powder. Crystal (crystallized from diisopropyl ether) Melting point: 148 to 149 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.24 (3H, d, J = 7.2 Hz), 2.78 (1H,
d, J = 5.0Hz), 3.15 (1H, d, J = 5.0Hz), 3.45-3.84 (4
H, m), 4.85 (1H, q, J = 7.2Hz), 5.90 (1H, tt, J = 53.2
Hz, 2.8Hz), 7.02-7.60 (8H, m) Elemental analysis value: Calculated as C ₂₁ H ₁₉ F ₅ N ₂ O ₃ (%): C 57.02 H 4.33 N 6.33 Measured value (%): C 56.90 H 4.36 N 6.31

Reference Example 44 In the same manner as in Reference Example 24, 1-[(1R, 2S) -2,
3-Epoxy-2- (2-fluorophenyl) -1-methylpropyl] -3- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -2-imidazolidinone was obtained. Colorless powder crystal (crystallized from diisopropyl ether) Melting point: 144 to 145 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.22 (3H, d, J = 7.4Hz), 2.77 (1H,
d, J = 5.0Hz), 3.16 (1H, d, J = 5.0Hz), 3.47-3.77 (4
H, m), 4.32 (2H, tt, J = 12Hz, 1.6Hz), 4.85 (1H, q,
J = 7.4Hz), 6.07 (1H, tt, J = 53Hz, 5Hz), 6.89-7.52 (8
H, m) Elemental analysis value: C ₂₂ H ₂₁ F ₅ N ₂ O ₃ calculated value (%): C 57.90 H 4.64 N 6.14 Measured value (%): C 57.94 H 4.60 N 6.19

Reference Example 45 (2R, 3S) -2- (4-fluorophenyl) -3-
Methyl-2- (1H-1,2,4-triazole-1-
Il) methyloxirane (1.5 g), 1- [4-
(1,1,2,2-Tetrafluoroethoxy) phenyl] -2 (1H, 3H) -imidazolone (2.66 g)
Cesium carbonate (6.3 g) were added to N, N-dimethylformamide (25 ml), and the mixture was stirred at 80 ° C for 5 hr. After cooling the reaction mixture, it was diluted with ethyl acetate (100 ml) and washed with water (100 ml × 2) and saturated brine (100 ml). The ethyl acetate layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/3) to give 1- [(1R, 2R)
-2- (4-fluorophenyl) -2-hydroxy-1
-Methyl-3- (1H-1,2,4-triazole-1
-Yl) propyl] -3- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -2 (1H, 3H)
-Imidazolone (1.21 g) was obtained as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, d, J = 7.2Hz), 4.19 (1H,
d, J = 14Hz), 4.70 (1H, d, J = 14Hz), 4.79 (1H, q, J =
7.2Hz), 5.34-5.39 (1H, bs), 5.92 (1H, tt, J = 2.8Hz,
53Hz), 6.63 (1H, d, J = 3Hz), 6.78 (1H, d, J = 3Hz),
6.94-7.03 (2H, m), 7.28-7.39 (4H, m), 7.66 (2H, d,
J = 9Hz), 7.69 (1H, s), 7.78 (1H, s)

Reference Example 46 In the same manner as in Reference Example 45, 1-[(1R, 2R) -2-
(4-Fluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (2,2,3,3-tetra Fluoropropoxy) phenyl] -2 (1H, 3H)-
I got imidazolone. ¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, d, J = 7Hz), 4.20 (1H,
d, J = 14Hz), 4.41 (2H, t, J = 12Hz), 4.68-4.80 (2H,
m), 5.42-5.48 (1H, bs), 6.07 (1H, tt, J = 5Hz, 53Hz),
6.59 (1H, d, J = 3Hz), 6.76 (1H, d, J = 3Hz), 6.92-7.0
4 (2H, m), 7.30-7.39 (4H, m), 7.58 (2H, d, J = 9Hz),
7.66 (1H, s), 7.78 (1H, s)

Reference Example 47 In the same manner as in Reference Example 45, 1-[(1R, 2R) -2-
(2,4-difluorophenyl) -2-hydroxy-1
-Methyl-3- (1H-1,2,4-triazole-1
-Yl) propyl] -3- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -2 (1H, 3H)
-I got imidazolone. ¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, d, J = 7Hz), 4.19 (1H,
d, J = 14Hz), 4.97 (1H, q, J = 7Hz), 5.10 (1H, d, J = 14H
z), 5.41-5.59 (1H, br), 5.93 (1H, tt, J = 53Hz, 2.8H
z), 6.64 (1H, d, J = 3Hz), 6.77 (1H, d, J = 3Hz), 6.74
-6.87 (2H, m), 7.30 (2H, d, J = 9Hz), 7.40-7.56 (1H,
m), 7.66 (2H, d, 9Hz), 7.74 (1H, s), 7.85 (1H, s)

Reference Example 48 In the same manner as in Reference Example 45, 1-[(1R, 2R) -2-
(2,4-difluorophenyl) -2-hydroxy-1
-Methyl-3- (1H-1,2,4-triazole-1
-Yl) propyl] -3- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -2 (1H, 3
H) -imidazolone was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, d, J = 7Hz), 4.20 (1H,
d, J = 14Hz), 4.37 (2H, t, J = 12Hz), 4.94 (1H, q, J = 7H
z), 5.09 (1H, d, J = 14Hz), 5.54-5.75 (1H, br), 6.06
(1H, tt, J = 53Hz, 5Hz), 6.59 (1H, d, J = 3Hz), 6.72
(1H, d, J = 3Hz), 6.74-6.86 (2H, m), 7.00 (2H, d, J =
9Hz), 7.42-7.55 (1H, m), 7.57 (2H, d, 9Hz), 7.72 (1
H, s), 7.85 (1H, s)

Reference Example 49 (2R, 3S) -2- (2-fluorophenyl) -3-
Methyl-2- (1H-1,2,4-triazole-1-
Il) methyloxirane (1.5 g), 1- [4-
(1,1,2,2-tetrafluoroethoxy) phenyl
] -2 (1H, 3H) -Imidazolone (2.66 g)
And 60% oily sodium hydride (0.386 g)
Add to N, N-dimethylformamide (25 ml), add 80
The mixture was stirred at 0 ° C for 20 hours. After cooling the reaction solution, water (100 m
l) and extracted with ethyl acetate (50 ml × 2). Extraction
After washing the liquid with water and drying over anhydrous magnesium sulfate,
It was distilled off. Silica gel column chromatograph of the residue
(Eluent: hexane / ethyl acetate = 3/2)
And purified, 1-[(1R, 2R) -2- (2-full
Orophenyl) -2-hydroxy-1-methyl-3-
(1H-1,2,4-triazol-1-yl) propy
]]-3- [4- (1,1,2,2-tetrafluoroe
Toxy) phenyl] -2 (1H, 3H) -imidazolone
(0.27g) was obtained as a colorless powder. Elemental analysis value: C_{twenty three}H₂₀F_FiveN_FiveO₃Calculated value (%): C 54.23 H 3.96 N 13.75 Actual value (%): C 53.83 H 3.99 N 13.56¹ H-NMR (CDCl₃) δ: 1.20 (3H, d, J = 7Hz), 4.20 (1H,
d, J = 14Hz), 5.05 (1H, q, J = 7Hz), 5.16 (1H, d, J = 14H
z), 5.30-5.41 (1H, br), 5.93 (1H, tt, J = 53Hz, 2.8H
z), 6.65 (1H, d, J = 3Hz), 6.81 (1H, d, J = 3Hz), 6.98-
7.08 (2H, m), 7.18-7.51 (2H, m), 7.30 (2H, d, J = 9Hz),
 7.70 (2H, d, J = 9Hz), 7.73 (1H, s), 7.81 (1H, s)

Reference Example 50 In the same manner as in Reference Example 20, (1S) -1-[(2R)-
The following compounds were obtained from 2- (2-fluorophenyl) -2-oxiranyl] ethanol. 1-[(1R,
2S) -2- (2-Fluorophenyl) -2,3-epoxy-1-methylpropyl] -3- [4- (2,2,
3,3-Tetrafluoropropoxy) phenyl] -2
(1H, 3H) -Imidazolone: colorless powder crystal (crystallized from diisopropyl ether) Melting point: 118 to 119 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.37 (3H, d, J = 7Hz), 2.72 (1H,
d, J = 5Hz), 2.81 (1H, d, J = 5Hz), 4.36 (2H, tt, J = 12H)
z, 2Hz), 5.12 (1H, q, J = 7Hz), 6.07 (1H, tt, J = 53Hz,
5Hz), 6.45 (1H, d, J = 3Hz), 6.51 (1H, d, J = 3Hz),
6.98 (2H, d, J = 9Hz), 7.04-7.19 (2H, m), 7.28-7.47
(2H, m), 7.57 (2H, d, J = 9Hz) 1-[(1R, 2R) -2- (2-fluorophenyl)
-2-Hydroxy-1-methyl-3- (1H-1,2,
4-triazol-1-yl) propyl] -3- [4-
(2,2,3,3-Tetrafluoropropoxy) phenyl] -2 (1H, 3H) -imidazolone: colorless powder crystal elemental analysis value: calculated as C ₂₄ H ₂₂ F ₅ N ₅ O ₃ (%): C 55.07 H 4.24 N 13.38 Found (%): C 54.98 H 4.18 N 13.35 ¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, d, J = 7Hz), 4.21 (1H,
d, J = 14Hz), 4.37 (2H, t, J = 12Hz), 4.95-5.11 (1H,
m), 5.15 (1H, d, J = 14Hz), 5.34-5.56 (1H, br), 6.07
(1H, tt, J = 53Hz, 5Hz), 6.59 (1H, d, J = 3Hz), 6.76
(1H, d, J = 3Hz), 6.97-7.07 (2H, m), 7.01 (2H, d, J = 9
Hz), 7.17-7.29 (1H, m), 7.44-7.52 (1H, m), 7.59 (2
H, d, J = 9Hz), 7.72 (1H, s), 7.82 (1H, s)

Reference Example 51 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 (22.91g) was dissolved in methanol (700ml), and 1N aqueous sodium hydroxide solution (146.5) was added under ice cooling.
ml) was added and the reaction was stirred at room temperature for 1 hour. 1N Hydrochloric acid (85.5 ml) was added to the reaction solution, the solvent was evaporated under reduced pressure, and ethyl acetate (500 ml) and water (50
0 ml) was added and the layers were separated. The organic layer was 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 = 3/1) to give (1S) -1-[(2R) -2- (2-fluorophenyl) -2-oxiranyl. ] Ethanol (10.76
g) was obtained as a colorless oil. This product is Reference Example 42
It was identical to the compound obtained in.

Reference Example 52 1- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -2 (1H, 3H) -imidazolone (1
To a solution of 6.6 g) in dimethylformamide (180 ml), 60% oily sodium hydride (2.4 g) was added little by little with stirring, and the mixture was stirred at room temperature for 30 minutes. In this mixture, (2R, 3S) -2- (2.4-difluorophenyl)
-3-Methyl-2- (1H-1,2,4-triazol-1-yl) methyloxirane (10 g) was added and 80
The mixture was stirred at 0 ° C for 20 hours. After cooling the reaction solution, it was concentrated under reduced pressure to a volume of about 50 ml, and ice water (400 ml) and ethyl acetate (5
00 ml) was added. The ethyl acetate layer was separated, washed with 10% aqueous phosphoric acid solution (400 ml) and brine (400 ml x 2), and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate 1/1 → 2/1) to give 1-[(1R, 2R) -2- (2 ，
4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (1,1,2,2-tetrafluoro Ethoxy) phenyl] -2 (1H, 3H) -imidazolone (7.56 g) was obtained as an oil. This product was identical to the compound obtained in Reference Example 47.

Example 1 1-[(1R, 2R) -2-obtained in Reference Example 22
(2,4-difluorophenyl) -2-hydroxy-1
-Methyl-3- (1H-1,2,4-triazole-1
-Yl) propyl] -3- (4-trifluoromethoxyphenyl) -2 (1H, 3H) -imidazolone (100
mg) was dissolved in acetic acid (10 ml), 10% palladium carbon (50 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 8 hours. After the catalyst was filtered off, the filtrate was concentrated and the residue was subjected to silica gel chromatography (eluent: hexane / ethyl acetate =
When purified by 1/5), 1-[(1R, 2R)-
2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- (4-trifluoromethoxyphenyl)- 2-Imidazolidinone (66 mg: compound 1 ) was obtained as a colorless powder. ¹ H-NMR (CDCl ₃ ) δ: 1.08 (3H, d, J = 7Hz), 3.65-4.05
(4H, m), 4.53 (1H, d, J = 14.2Hz), 4.60-4.80 (1H, m),
5.10 (1H, d, J = 14.2Hz), 5.40 (1H, br), 6.68-6.85
(2H, m), 7.31 (2H, d, J = 9Hz), 7.32-7.48 (1H, m),
7.69 (2H, d, J = 9Hz), 7.76 (1H, s), 7.88 (1H, s)

Example 2 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-triazol-1-yl) propyl] -3
-(2,4-difluorophenyl) -2 (1H, 3H)
From imidazolone as in Example 1, 1-[(1
R, 2R) -2- (2,4-difluorophenyl) -2
-Hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- (2,4-difluorophenyl) -2-imidazolidinone (compound
2 ) was obtained. Colorless powder ¹ H-NMR (CDCl ₃ ) δ: 1.07 (3H, d, J = 7Hz), 3.65-4.05
(4H, m), 4.55 (1H, d, J = 14.2Hz), 4.45-4.65 (1H, m),
5.10 (1H, d, J = 14.2Hz), 5.60 (1H, br), 6.68-7.02
(4H, m), 7.36-7.68 (2H, m), 7.76 (1H, s), 7.93 (1
H, s)

Example 3 1H-1,2,4-triazole (0.41 g), 60
% Oily sodium hydride (0.19 g) and dimethylformamide (12 ml) were stirred at room temperature for 20 minutes, and then obtained in Reference Example 24 1-[(1R, 2S) -2.
-(2,4-Difluorophenyl) -2,3-epoxy-1-methylpropyl] -3- (2,4-difluorophenyl) -2,4-imidazolidinedione (0.85
g) was added and the mixture was heated at 60 ° C. for 4 hours. After cooling, water (20 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (80 ml). The extract was washed with saturated brine (20 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by subjecting it to silica gel chromatography (eluent: hexane / ethyl acetate = 1/2 → 1/5) to give 1-
[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-triazol-1-yl) propyl] -3-
(2,4-Difluorophenyl) -2,4-imidazolidinedione (Compound 3 : 0.12 g) was obtained as a colorless powder. ¹ H-NMR (CDCl ₃ ) δ: 1.10 (3H, d, J = 7Hz), 4.25 (1H,
d, J = 18Hz), 4.41 (1H, d, J = 14.2Hz), 4.67 (1H, d, J =
18Hz), 4.94 (1H, dq, J = 1.6Hz, J = 7Hz), 5.15 (1H, d,
J = 14.2Hz), 5.35 (1H, d, J = 1.6Hz), 6.70-6.84 (2H,
m), 6.94-7.06 (2H, m), 7.27-7.44 (2H, m), 7.80 (1
H, s), 7.82 (1H, s)

Example 4 (Method A) 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3-
(1H-1,2,4-triazol-1-yl) propyl-3- (4-trifluoromethylphenyl) -2 (1
H, 3H) -imidazolone in the same manner as in Example 1,
1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-triazol-1-yl) propyl] -3
-(4-Trifluoromethylphenyl) -2-imidazolidinone (Compound 4 ) was obtained. (Method B) 1-[(1R, 2S) -obtained in Reference Example 33
The same reaction as in Example 3 was performed using 2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] -3- (4-trifluoromethylphenyl) -2-imidazolidinone. Do 1-[(1R, 2R) -2-
(2,4-difluorophenyl) -2-hydroxy-1
-Methyl-3- (1H-1,2,4-triazole-1
-Yl) propyl] -3- (4-trifluoromethylphenyl) -2-imidazolidinone (Compound 4 ) was obtained as a colorless powder. Elemental analysis value: Calculated value as C ₂₂ H ₂₀ F ₅ N ₅ O ₂ (%): C 54.89 H 4.19 N 14.55 Actual value (%): C 54.72 H 4.19 N 14.29 ¹ H-NMR (CDCl ₃ ) δ: 1.07 (3H, d, J = 7Hz), 3.60-4.12
(4H, m), 4.49 (1H, d, J = 14.2Hz), 4.60-4.80 (1H, m),
5.11 (1H, d, J = 14.2Hz), 5.36 (1H, br), 6.70-6.85
(2H, m), 7.32-7.48 (1H, m), 7.60 (2H, d, J = 8.8Hz),
7.70 (1H, d, J = 8.8Hz), 7.76 (1H, s), 7.85 (1H, s)

Example 5 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-triazol-1-yl) propyl] -3
In the same manner as in Example 1, 1-[(1R, 2 was prepared from-(4-fluorophenyl) -2 (1H, 3H) -imidazolone.
R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- (4-fluorophenyl) 2-Imidazolidinone (Compound 5 ) was obtained. Colorless powder crystal Melting point: 74-78 ° C (ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.06 (3H, d, J = 7.0Hz), 3.65-3.73
(1H, m), 3.79-4.00 (3H, m), 4.51 (1H, d, J = 14Hz),
4.60 (1H, m), 5.07 (1H, d, J = 14Hz), 5.3-5.7 (1H, b
r), 6.71-6.82 (2H, m), 6.99-7.11 (2H, m), 7.36-7.56
(3H, m), 7.74 (1H, s), 7.87 (1H, s) IR (KBr) νmax: 3420, 1690, 1615, 1510, 1480, 14
20 (cm ^-1 )

Example 6 (Method A) 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3-
Example 1 from (1H-1,2,4-triazol-1-yl) propyl-3- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -2 (1H, 3H) -imidazolone And 1-[(1R, 2R) -2
-(2,4-Difluorophenyl) -2-hydroxy-
1-methyl-3- (1H-1,2,4-triazole-
1-yl) propyl] -3- [4- (2,2,3,3-
Tetrafluoropropoxy) phenyl] -2-imidazolidinone (Compound 6 ) was obtained. (Method B) 1-[(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] -3- [4- (2,2,3,3- From tetrafluoropropoxy) phenyl] -2-imidazolidinone, in the same manner as in Example 3, 1-[(1R, 2R) -2- (2,2
4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (2,2,3,3-tetrafluoro Propoxy) phenyl] -2-imidazolidinone (Compound 6 ) was obtained. Colorless powder crystal ¹ H-NMR (CDCl ₃ ) δ: 1.06 (3H, d, J = 7.0Hz), 3.66-3.73
(1H, m), 3.80-3.95 (3H, m), 4.33 (2H, tt, J = 12Hz,
1.6Hz), 4.52 (1H, d, J = 14.4Hz), 4.5-4.65 (1H, m),
5.08 (1H, d, J = 14.4Hz), 5.45-5.65 (1H, br), 6.06 (1
H, tt, J = 53Hz, 4.8Hz), 6.70-6.83 (2H, m), 6.94 (2
H, d, J = 9.2Hz), 7.39-7.54 (1H, m), 7.50 (2H, d, J =
9.2Hz), 7.74 (1H, s), 7.88 (1H, s) Elemental analysis value: Calculated value as C ₂₄ H ₂₃ F ₆ N ₅ O ₃ (%): C 53.04 H 4.27 N 12.89 Measured value (%): C 53.04 H 4.50 N 12.82 IR (KBr) νmax: 3380, 1690, 1665, 1510, 1485, 14
40 (cm ^-1 )

Example 7 (Method A) 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3-
From (1H-1,2,4-triazol-1-yl) propyl-3- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -2 (1H, 3H) -imidazolone to Example 1 Similarly to 1-[(1R, 2R) -2-
(2,4-difluorophenyl) -2-hydroxy-1
-Methyl-3- (1H-1,2,4-triazole-1
-Yl) propyl] -3- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -2-imidazolidinone (Compound 7 ) was obtained. (Method B) 1-[(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] -3- [4- (1,1,2,2- From tetrafluoroethoxy) phenyl] -2-imidazolidinone, in the same manner as in Example 3, 1-[(1R, 2R) -2- (2,4
-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl)
Propyl] -3-4- (1,1,2,2-tetrafluoroethoxy) phenyl] -2-imidazolidinone (Compound 7 ) was obtained. Colorless powder crystal ¹ H-NMR (CDCl ₃ ) δ: 1.07 (3H, d, J = 7Hz), 3.67-3.75
(1H, m), 3.82-4.01 (3H, m), 4.50 (1H, d, J = 15Hz),
4.65 (1H, m), 5.10 (1H, d, J = 15Hz), 5.3-5.6 (1H, b
r), 5.91 (1H, tt, J = 53Hz, 3.0Hz), 6.72-6.83 (2H,
m), 7.21 (2H, d, J = 9.2Hz), 7.36-7.49 (1H, m), 7.58
(2H, d, J = 9.2Hz), 7.75 (1H, s), 7.86 (1H, s) Elemental analysis value: Calculated as C ₂₃ H ₂₁ F ₆ N ₅ O ₃ (%): C 52.18 H 4.00 N 13.23 Measured value (%): C 52.30 H 3.95 N 13.28 IR (KBr) νmax: 3380, 1680, 1615, 1510, 1480, 14
25 (cm ^-1 )

Examples 8 to 14 The following compounds were obtained in the same manner as in Example 3. Example 8 1-[(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] -3
-[4- (2,2,3,3,3-pentafluoropropoxy) phenyl] -2-imidazolidinone, 1-
[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-triazol-1-yl) propyl] -3-
[4- (2,2,3,3,3-pentafluoropropoxy) phenyl] -2-imidazolidinone (Compound 8 ) was obtained. Colorless powder ¹ H-NMR (CDCl ₃ ) δ: 1.06 (3H, d, J = 7.2Hz), 3.66-3.73
(1H, m), 3.79-4.01 (3H, m), 4.41 (2H, t, J = 12.4H
z), 4.52 (1H, d, J = 14Hz), 4.51-4.68 (1H, m), 5.08
(1H, d, J = 14Hz), 5.3-5.8 (1H, br), 6.71-6.82 (2H,
m), 6.96 (2H, d, J = 9.2Hz), 7.37-7.5 (1H, m), 7.51
(2H, d, J = 9.2Hz), 7.74 (1H, s), 7.88 (1H, s) Elemental analysis value: Calculated as C ₂₄ H ₂₂ F ₇ N ₅ O ₃ (%): C 51.34 H 3.95 N 12.47 Measured value (%): C 51.14 H 3.95 N 12.32 IR (KBr) νmax: 3420, 1690, 1610, 1510, 1480, 14
25 (cm ^-1 )

Example 9 1-[(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] -3
From [[4- (2,2,2-trifluoroethoxy) phenyl] -2-imidazolidinone, 1-[(1R, 2
R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (2, Two
2-Trifluoroethoxy) phenyl] -2-imidazolidinone (Compound 9 ) was obtained. Colorless powder crystal Melting point: 80-83 ° C (diethyl ether) ¹ H-NMR (CDCl ₃ ) δ: 1.06 (3H, d, J = 7.2Hz), 3.65-3.74
(1H, m), 3.79-3.95 (3H, m), 4.34 (2H, q, J = 8Hz),
4.52 (1H, d, J = 14Hz), 4.5-4.65 (1H, m), 5.08 (1H,
d, J = 14Hz), 5.4-5.7 (1H, br), 6.71-6.81 (2H, m), 6.
96 (2H, d, J = 9.2Hz), 7.387.5 (1H, m), 7.50 (2H, d,
J = 9.2Hz), 7.74 (1H, s), 7.88 (1H, s) Elemental analysis value: Calculated as C ₂₃ H ₂₂ F ₅ N ₅ O ₃ (%): C 54.01 H 4.34 N 13.69 Measured value (%) ): C 53.67 H 4.27 N 13.79 IR (KBr) νmax: 3410, 1690, 1610, 1510, 1480, 14
20 (cm ^-1 )

Example 10 1- (4-chlorophenyl) -3-[(1R, 2S)-
From 2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] -2-imidazolidinone, 1- (4-chlorophenyl) -3-[(1R, 2
R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -2-imidazolidinone (Compound 10 ) Got. Colorless powder crystal Melting point: 138-139 ° C (diethyl ether-hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.06 (3H, d, J = 7.0Hz), 3.64-3.75
(1H, m), 3.80-4.03 (3H, m), 4.50 (1H, d, J = 15Hz),
4.54-4.72 (1H, m), 5.09 (1H, d, J = 15Hz), 5.3-5.6
(1H, br), 6.73-6.83 (2H, m), 7.31 (2H, d, J = 9Hz),
7.35-7.45 (1H, m), 7.52 (2H, d, J = 9Hz), 7.75 (1H,
s), 7.86 (1H, s) Elemental analysis value: Calculated value as C ₂₁ H ₂₀ ClF ₂ N ₅ O ₂ (%): C 56.32 H 4.50 N 15.64 Measured value (%): C 56.35 H 4.36 N 15.93 IR ( KBr) νmax: 3400, 1695, 1660, 1618, 1500, 14
20, 1270 (cm ^-1 )

Example 11 1-[(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] -4
-[4- (2,2,3,3-tetrafluoropropoxy) phenyl] -2,5-piperazinedione to 1-
[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-triazol-1-yl) propyl] -4-
[4- (2,2,3,3-tetrafluoropropoxy)
Phenyl] -2,5-piperazinedione (Compound 11 )
I got Colorless powder ¹ H-NMR (CDCl ₃ ) δ: 1.07 (3H, d, J = 7Hz), 4.24-4.52
(6H, m), 4.74 (1H, d, J = 18Hz), 5.16 (1H, d, J = 14H
z), 5.29 (1H, s), 5.36 (1H, q, J = 7Hz), 6.06 (1H, t
t, J = 53Hz, 5Hz), 6.74-6.83 (2H, m), 7.00 (2H, d, J
= 9Hz), 7.29 (2H, d, J = 9Hz), 7.31-7.47 (1H, m), 7.8
0 (1H, s), 7.82 (1H, s) IR (KBr) νmax: 3410, 1660, 1610, 1505, 1450, 13
15 (cm ^-1 )

Example 12 1-[(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] -4
-[4- (1,1,2,2-tetrafluoroethoxy)
Phenyl] -2,5-piperazinedione to 1-
[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-triazol-1-yl) propyl] -4-
[4- (1,1,2,2-Tetrafluoroethoxy) phenyl] -2,5-piperazinedione (Compound 12 ) was obtained. White powder ¹ H-NMR (CDCl ₃ ) δ: 1.07 (3H, d, J = 7Hz), 4.25-4.38
(2H, m), 4.45 (2H, s), 4.74 (1H, d, J = 17Hz), 5.15
(1H, d, J = 14Hz), 5.30-5.41 (2H, m), 5.92 (1H, tt,
J = 53Hz, 3Hz), 6.73-6.82 (2H, m), 7.28 (2H, d, J = 9H
z), 7.30-7.45 (3H, m), 7.79 (1H, s), 7.82 (1H, s) Elemental analysis value: Calculated value as C ₂₄ H ₂₁ F ₆ N ₅ O ₄ (%): C 51.71 H 3.80 N 12.56 measured value (%): C 51.54 H 3.79 N 12.56

Example 13 1-[(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] -4
-[4- (2,2,3,3-tetrafluoropropoxy) phenyl] -2,3-piperazinedione to 1-
[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-triazol-1-yl) propyl] -4-
[4- (2,2,3,3-tetrafluoropropoxy)
Phenyl] -2,3-piperazinedione (Compound 14 )
I got White powder ¹ H-NMR (CDCl ₃ ) δ: 1.07 (3H, d, J = 7Hz), 3.79-3.90
(2H, m), 4.04-4.27 (2H, m), 4.36 (2H, t, J = 12Hz),
4.39 (1H, d, J = 13Hz), 5.24 (1H, d, J = 13Hz), 5.27-
5.40 (2H, m), 6.06 (1H, tt, J = 53Hz, 5Hz), 6.72-6.8
3 (2H, m), 6.98 (2H, d, J = 9Hz), 7.31-7.44 (3H, m),
7.78 (1H, s), 7.82 (1H, s) Elemental analysis value: Calculated as C ₂₅ H ₂₃ F ₆ N ₅ O ₄ (%): C 52.54 H 4.06 N 12.25 Measured value (%): C 52.34 H 4.12 N 12.10

Example 14 1-[(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] -4
-[4- (1,1,2,2-tetrafluoroethoxy)
Phenyl] -2,3-piperazinedione to 1-
[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-triazol-1-yl) propyl] -4-
[4- (1,1,2,2-Tetrafluoroethoxy) phenyl] -2,3-piperazinedione (Compound 15 ) was obtained. Colorless powder crystal ¹ H-NMR (CDCl ₃ ) δ: 1.07 (3H, d, J = 7Hz), 3.78-3.98
(2H, m), 4.10-4.29 (2H, m), 4.40 (2H, d, J = 15Hz),
5.25 (1H, d, J = 15Hz), 5.25-5.40 (2H, m), 5.93 (1H,
tt, J = 53Hz, 3Hz), 6.73-6.84 (2H, m), 7.28 (2H, d,
J = 9Hz), 7.30-7.42 (1H, m), 7.44 (2H, d, J = 9Hz), 7.
79 (1H, s), 7.82 (1H, s) Elemental analysis value: Calculated as C ₂₄ H ₂₁ F ₆ N ₅ O ₄ .0.5 H ₂ O (%): C 50.89 H 3.91 N 12.36 Measured value (%) : C 51.13 H 4.07 N 12.45 Melting point: 174-175 ° C

Example 15 (Method A) In the same manner as in Example 1, 1-[(1R, 2R)
-2- (2-fluorophenyl) -2-hydroxy-1
-Methyl-3- (1H-1,2,4-triazole-1
-Yl) propyl] -3- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -2 (1H, 3H)
-From imidazolone, 1-[(1R, 2R) -2- (2
-Fluorophenyl) -2-hydroxy-1-methyl-
3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -2-imidazolidinone (compound 16 ) was obtained. (Method B) In the same manner as in Example 3, 1-[(1R, 2S)
-2,3-epoxy-2- (2-fluorophenyl)-
1-methylpropyl] -3- [4- (1,1,2,2-
From tetrafluoroethoxy) phenyl] -2-imidazolidinone, 1-[(1R, 2R) -2- (2-fluorophenyl) -2-hydroxy-1-methyl-3- (1
H-1,2,4-triazol-1-yl) propyl]
-3- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -2-imidazolidinone (Compound 16 )
I got Colorless needle crystals ¹ H-NMR (CDCl ₃ ) δ: 1.06 (3H, d, J = 7.0Hz), 3.68-4.05
(4H, m), 4.51 (1H, d, J = 14.4Hz), 4.65-4.80 (1H,
m), 5.15 (1H, d, J = 14.4Hz), 5.25 (1H, br), 5.91 (1
H, tt, J = 53.2Hz, 3Hz), 6.95-7.63 (8H, m), 7.74 (1
H, s), 7.82 (1H, s) Elemental analysis value: Calculated as C ₂₃ H ₂₂ F ₅ N ₅ O ₃ (%): C 54.01 H 4.34 N 13.69 Measured value (%): C 53.96 H 4.48 N 13.69

Example 16 (Method A) In the same manner as in Example 1, 1-[(1R, 2R)
-2- (2-fluorophenyl) -2-hydroxy-1
-Methyl-3- (1H-1,2,4-triazole-1
-Yl) propyl] -3- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -2 (1H, 3
H) -imidazolone to 1-[(1R, 2R) -2-
(2-Fluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (2,2,3,3-tetra Fluoropropoxy) phenyl] -2-imidazolidinone (Compound 17 ) was obtained. (Method B) In the same manner as in Example 3, 1-[(1R, 2S)
-2,3-epoxy-2- (2-fluorophenyl)-
1-methylpropyl] -3- [4- (2,2,3,3-
From tetrafluoropropoxy) phenyl] -2-imidazolidinone to 1-[(1R, 2R) -2- (2-fluorophenyl) -2-hydroxy-1-methyl-3-
(1H-1,2,4-triazol-1-yl) propyl] -3- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -2-imidazolidinone (compound
17 ) was obtained. Colorless powder crystal ¹ H-NMR (CDCl ₃ ) δ: 1.06 (3H, d, J = 7.0Hz), 3.66-4.05
(4H, m), 4.33 (2H, tt, J = 12Hz, 1.6Hz), 4.52 (1H,
d, J = 14Hz), 4.60-4.77 (1H, m), 5.13 (1H, d, J = 14H
z), 5.35 (1H, br), 6.07 (1H, tt, J = 53Hz, 5Hz), 6.9
1-7.53 (8H, m), 7.73 (1H, s), 7.83 (1H, s) Elemental analysis value: Calculated as C ₂₄ H ₂₄ F ₅ N ₅ O ₃ (%): C 54.86 H 4.60 N 13.33 Actual measurement Value (%): C 54.66 H 4.57 N 13.26

Example 17 1-[(1R, 2R) -2- (4-fluorophenyl)
-2-Hydroxy-1-methyl-3- (1H-1,2,
4-triazol-1-yl) propyl] -3- [4-
Example 1 from (1,1,2,2-tetrafluoroethoxy) phenyl] -2 (1H, 3H) -imidazolone
In the same manner as in 1-[(1R, 2R) -2- (4-fluorophenyl) -2-hydroxy-1-methyl-3-
(1H-1,2,4-triazol-1-yl) propyl] -3- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -2-imidazolidinone (Compound 1
8 ) was obtained. Colorless powder crystal ¹ H-NMR (CDCl ₃ ) δ: 1.06 (3H, d, J = 7.2Hz), 3.69-4.02
(4H, m), 4.42 (1H, q, J = 7.2Hz), 4.48 (1H, d, J = 14H
z), 4.72 (1H, d, J = 14Hz), 5.22-5.39 (1H, bs), 5.91
(1H, tt, J = 2.4Hz, 53Hz), 6.93-7.01 (2H, m), 7.20-
7.34 (4H, m), 7.58 (2H, d, J = 9Hz), 7.65 (1H, s),
7.80 (1H, s) Elemental analysis value: Calculated value as C ₂₃ H ₂₂ F ₅ N ₅ O ₃ (%): C 54.01 H 4.34 N 13.69 Actual value (%): C 53.82 H 4.32 N 13.66

Example 18 1-[(1R, 2R) -2- (4-fluorophenyl)
-2-Hydroxy-1-methyl-3- (1H-1,2,
4-triazol-1-yl) propyl] -3- [4-
From (2,2,3,3-tetrafluoropropoxy) phenyl] -2 (1H, 3H) -imidazolone, in the same manner as in Example 1, 1-[(1R, 2R) -2- (4-fluorophenyl) 2-hydroxy-1-methyl-3- (1
H-1,2,4-triazol-1-yl) propyl]
-3- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -2-imidazolidinone (Compound 1
9 ) was obtained. Colorless powder crystal ¹ H-NMR (CDCl ₃ ) δ: 1.06 (3H, d, J = 7.2Hz), 3.70-3.93
(4H, m), 4.28-4.45 (3H, m), 4.49 (1H, d, J = 14Hz),
4.72 (1H, d, J = 14Hz), 5.32-5.48 (1H, bs), 6.07 (1H,
tt, J = 5Hz, 53Hz), 6.93-7.00 (4H, m), 7.30-7.34 (2
H, m), 7.50 (2H, d, J = 9Hz), 7.66 (1H, s), 7.80 (1
H, s) Elemental analysis value: C ₂₄ H ₂₄ F ₅ N ₅ O ₃ Calculated value (%): C 54.86 H 4.60 N 13.33 Actual value (%): C 54.86 H 4.68 N 12.94 Compound (I) of the present invention A preferred group of compounds belonging to Table 3 and Table 4 are exemplified, but the present invention is not limited to these compounds.

[0128]

[Table 3]

[0129]

[Table 4]

[0130] 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

[0131] Formulation Example 2 Compound 4 and magnesium stearate obtained by the above Example 4 were granulated with an aqueous solution of soluble starch, dried and mixed with lactose and corn starch. The mixture was compression-molded to produce tablets having the formulations shown below. Compound of Example 4 4 50 mg Lactose 65mg Cornstarch 30mg Soluble starch 35mg Magnesium stearate 20mg Total 200mg

The antifungal activity of the compound of the present invention was evaluated by the following method. That is, 1000 µg / ml of the compound of the present invention
A filter paper disk (Toyo Seisakusho, diameter 8 mm) immersed in a methanol solution is attached to an agar plate containing various fungi, and the temperature is 28 ° C.
After culturing for 2 days, the diameter of the growth-inhibiting circle formed around the filter paper disk was measured. The medium used is as follows. A: Yeast nitrogen base agar medium (pH
7.0) B: Peptone-yeast extract-glucose agar medium (pH 7.0) The antifungal spectrum of the compound of the present invention is shown in Table 5.

[0133]

[Table 5]

The antibacterial activity of the compound of the present invention against Candida albicans is shown in Table 6.

[0135]

[Table 6]

The protective effects of the compounds of the present invention on experimental mouse infections are shown in Tables 7 and 8. Experimental method: Crj: CDF ₁ mice of 5 weeks of age were inoculated intravenously with the minimum lethal dose of Candida albicans TA. The test compound was orally administered as a 0.2% or 0.5% sodium carboxymethylcellulose (CMC) suspension once immediately after infection. The drug efficacy was indicated by the ED ₅₀ value calculated by the Reed and Muench method from the survival rate of mice 7 days after infection.

[0137]

[Table 7]

[0138]

[Table 8]

Table 9 shows the protective effect of the compound represented by the general formula (VI), which is the starting compound of the compound (I) of the present invention, on the experimental mouse infection. Experimental method: Crj: CDF ₁ mice of 5 weeks old were inoculated intravenously with the minimum lethal dose of Candida albicans TA. The test compound was orally administered once as a suspension of 0.5% sodium carboxymethyl cellulose (CMC) immediately after infection. The drug efficacy was indicated by the ED ₅₀ value calculated by the Reed and muench method from the survival rate of mice 7 days after infection.

[0140]

[Table 9]

[0141]

The compound of the present invention or a salt thereof has excellent antifungal activity. The compound of the present invention or a salt thereof is
As an antifungal agent, it can be used for the prevention and treatment of fungal infections in mammals. The compound of the present invention or a salt thereof can also be used as an antifungal agent for agriculture.

─────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] November 29, 1994

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0006

[Correction method] Change

[Correction content]

Examples of Ar include a halogenophenyl group, a halogenated lower (C _1-4 ) alkylphenyl group, a halogenated lower (C _1-4 ) alkoxyphenyl group, a lower (C _1-4 ) alkylsulfonylphenyl group , Examples include halogenated lower (C _1-4 ) alkylsulfonylphenyl groups. Here, as the halogenophenyl group,
For example, 2,4-difluorophenyl, 2,4-dichlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 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.

[Procedure Amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0097

[Correction method] Change

[Correction content]

Reference Example 40 2- (2-Fluorophenyl) -2-[(1R) -1-
(3,4,5,6-tetrahydro-2H-pyran-2-
[(1R) -1-[(2R) -2- (2-fluorophenyl) -2-oxiranyl]] by the method shown in Reference Example 1 with (yl) oxyethyl] oxirane (synthesized by the method described in EP0548553A). Ethyl] led to 3,5-dinitrobenzoate. Colorless prism crystal (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, t,
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

[Procedure 3]

[Document name to be amended] Statement

[Correction target item name] 0100

[Correction method] Change

[Correction content]

Reference Example 43 In the same manner as in Reference Example 24, 1-[(1R, 2S) -2,
3-Epoxy-2- (2-fluorophenyl ) -1-methylpropyl] -3- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -2-imidazolidinone was obtained. Colorless powder crystal (crystallized from diisopropyl ether) Melting point: 148 to 149 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.24 (3H, d, J = 7.2Hz), 2.78 (1H,
d, J = 5.0Hz), 3.15 (1H, d, J = 5.0Hz), 3.45-3.84 (4
H, m), 4.85 (1H, q, J = 7.2Hz), 5.90 (1H, tt, J = 53.2
Hz, 2.8Hz), 7.02-7.60 (8H, m) Elemental analysis value: Calculated as C ₂₁ H ₁₉ F ₅ N ₂ O ₃ (%): C 57.02 H 4.33 N 6.33 Measured value (%): C 56.90 H 4.36 N 6.31

[Procedure amendment 4]

[Document name to be amended] Statement

[Name of item to be corrected] 0113

[Correction method] Change

[Correction content]

Example 4 (Method A) 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3-
(1H-1,2,4-triazol-1-yl) propyl ] -3- (4-trifluoromethylphenyl) -2
1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H) from (1H, 3H) -imidazolone as in Example 1.
-1,2,4-triazol-1-yl) propyl]-
3- (4-Trifluoromethylphenyl) -2-imidazolidinone (Compound 4) was obtained. (Method B) 1-[(1R, 2S) -obtained in Reference Example 33
The same reaction as in Example 3 was performed using 2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] -3- (4-trifluoromethylphenyl) -2-imidazolidinone. Do 1-[(1R, 2R) -2-
(2,4-difluorophenyl) -2-hydroxy-1
-Methyl-3- (1H-1,2,4-triazole-1
-Yl) propyl] -3- (4-trifluoromethylphenyl) -2-imidazolidinone (Compound 4) was obtained as a colorless powder. Elemental analysis value: Calculated value as C ₂₂ H ₂₀ F ₅ N ₅ O ₂ (%): C 54.89 H 4.19 N 14.55 Actual value (%): C 54.72 H 4.19 N 14.29 ¹ H-NMR (CDCl ₃ ) δ: 1.07 (3H, d, J = 7Hz), 3.60-4.12
(4H, m), 4.49 (1H, d, J = 14.2Hz), 4.60-4.80 (1H, m),
5.11 (1H, d, J = 14.2Hz), 5.36 (1H, br), 6.70-6.85
(2H, m), 7.32-7.48 (1H, m), 7.60 (2H, d, J = 8.8Hz),
7.70 (1H, d, J = 8.8Hz), 7.76 (1H, s), 7.85 (1H, s)

[Procedure Amendment 5]

[Document name to be amended] Statement

[Correction target item name] 0115

[Correction method] Change

[Correction content]

Example 6 (Method A) 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3-
(IH-1,2,4-triazol-1-yl) prop <br/> le] -3- [4- (2,2,3,3-tetrafluoro) phenyl] -2 (IH, 3H) -From imidazolone, as in Example 1, 1-[(1R, 2R)-
2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (2,2,3 , 3
-Tetrafluoropropoxy) phenyl] -2-imidazolidinone (Compound 6) was obtained. (Method B) 1-[(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] -3- [4- (2,2,3,3- From tetrafluoropropoxy) phenyl] -2-imidazolidinone, in the same manner as in Example 3, 1-[(1R, 2R) -2- (2,2
4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (2,2,3,3-tetrafluoro Propoxy) phenyl] -2-imidazolidinone (Compound 6) was obtained. Colorless powder crystal ¹ H-NMR (CDCl ₃ ) δ: 1.06 (3H, d, J = 7.0Hz), 3.66-3.73
(1H, m), 3.80-3.95 (3H, m), 4.33 (2H, tt, J = 12Hz,
1.6Hz), 4.52 (1H, d, J = 14.4Hz), 4.5-4.65 (1H, m),
5.08 (1H, d, J = 14.4Hz), 5.45-5.65 (1H, br), 6.06 (1
H, tt, J = 53Hz, 4.8Hz), 6.70-6.83 (2H, m), 6.94 (2
H, d, J = 9.2Hz), 7.39-7.54 (1H, m), 7.50 (2H, d, J =
9.2Hz), 7.74 (1H, s), 7.88 (1H, s) Elemental analysis value: Calculated as C ₂₄ H ₂₃ F ₆ N ₅ O ₃ (%): C 53.04 H 4.27 N 12.89 Measured value (%): C 53.04 H 4.50 N 12.82 IR (KBr) νmax: 3380, 1690, 1665, 1510, 1485, 14
40 (cm ^-1 )

[Procedure correction 6]

[Document name to be amended] Statement

[Correction target item name] 0116

[Correction method] Change

[Correction content]

Example 7 (Method A) 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3-
(IH-1,2,4-triazol-1-yl) prop <br/> le] -3- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -2 (IH, 3H) -From imidazolone as in Example 1, 1-[(1R, 2R) -2
-(2,4-Difluorophenyl) -2-hydroxy-
1-methyl-3- (1H-1,2,4-triazole-
1-yl) propyl] -3- [4- (1,1,2,2-
Tetrafluoroethoxy) phenyl] -2-imidazolidinone (Compound 7) was obtained. (Method B) 1-[(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] -3- [4- (1,1,2,2- From tetrafluoroethoxy) phenyl] -2-imidazolidinone, in the same manner as in Example 3, 1-[(1R, 2R) -2- (2,4
-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl)
Propyl] -3- [ 4- (1,1,2,2-tetrafluoroethoxy) phenyl] -2-imidazolidinone (Compound 7) was obtained. Colorless powder crystal ¹ H-NMR (CDCl ₃ ) δ: 1.07 (3H, d, J = 7Hz), 3.67-3.75
(1H, m), 3.82-4.01 (3H, m), 4.50 (1H, d, J = 15Hz),
4.65 (1H, m), 5.10 (1H, d, J = 15Hz), 5.3-5.6 (1H, b
r), 5.91 (1H, tt, J = 53Hz, 3.0Hz), 6.72-6.83 (2H,
m), 7.21 (2H, d, J = 9.2Hz), 7.36-7.49 (1H, m), 7.58
(2H, d, J = 9.2Hz), 7.75 (1H, s), 7.86 (1H, s) Elemental analysis value: Calculated as C ₂₃ H ₂₁ F ₆ N ₅ O ₃ (%): C 52.18 H 4.00 N 13.23 Measured value (%): C 52.30 H 3.95 N 13.28 IR (KBr) νmax: 3380, 1680, 1615, 1510, 1480, 14
25 (cm ^-1 )

[Procedure Amendment 7]

[Document name to be amended] Statement

[Name of item to be corrected] 0123

[Correction method] Change

[Correction content]

Example 14 1-[(1R, 2S) -2- (2,4-difluorophenyl) -2,3-epoxy-1-methylpropyl] -4
-[4- (1,1,2,2-tetrafluoroethoxy)
Phenyl] -2,3-piperazinedione to 1-
[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-triazol-1-yl) propyl] -4-
[4- (1,1,2,2-Tetrafluoroethoxy) phenyl] -2,3-piperazinedione (Compound 15) was obtained. Colorless powder crystal ¹ H-NMR (CDCl ₃ ) δ: 1.07 (3H, d, J = 7Hz), 3.78-3.98
(2H, m), 4.10-4.29 (2H, m), 4.40 (1H, d, J = 15Hz),
5.25 (1H, d, J = 15Hz), 5.5.25-5.40 (2H, m), 5.93 (1
H, tt, J = 53Hz, 3Hz), 6.73-6.84 (2H, m), 7.28 (2H,
d, J = 9Hz), 7.30-7.42 (1H, m), 7.44 (2H, d, J = 9Hz),
7.79 (1H, s), 7.82 (1H, s) Elemental analysis value: Calculated as C ₂₄ H ₂₁ F ₆ N ₅ O ₄ .0.5 H ₂ O (%): C 50.89 H 3.91 N 12.36 Measured value (%) : C 51.13 H 4.07 N 12.45 Melting point: 174-175 ° C

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication C07D 403/06 233 249 413/06

Claims (15)

[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, and Y is a nitrogen atom or a methine group. , And A each represent a saturated cyclic amide group which may be substituted and which is bonded by a nitrogen atom] or a salt thereof. 2. The compound according to claim 1, wherein ^one of R ¹ and R ² is a hydrogen atom and the other is a lower alkyl group. 3. The compound according to claim 1, wherein Y is a nitrogen atom. 4. The compound according to claim 1, wherein Ar is a phenyl group substituted with a halogen atom. 5. The compound according to claim 4, wherein Ar is a phenyl group substituted with one or two fluorine atoms. 6. The compound according to claim 1, wherein the saturated cyclic amide group in A is a 5- or 6-membered ring group. 7. The compound according to claim 1, wherein the saturated cyclic amide group in A further contains one nitrogen atom in the ring. 8. The compound according to claim 7, wherein the saturated cyclic amide group containing one nitrogen atom in the ring of A has a substituent at the nitrogen atom. 9. The saturated cyclic amide group in A has the formula: [In the formula, R ⁴ represents a substituted phenyl group] 3-
The compound according to claim 1, which is a substituted 2-oxo-1-imidazolidinyl group. 10. The saturated cyclic amide group in A has the formula: [In the formula, R ⁵ has the same meaning as R ⁴ ] 4-substituted-2,
The compound according to claim 1, which is a 5-dioxo-1-piperazinyl group. 11. The substituent of the saturated cyclic amide group in A is a substituted phenyl group, and the substituted phenyl group is selected from the group consisting of a halogen atom, a halogenated C _1-6 alkyl group and a halogenated C _1-6 alkoxy group. The compound according to claim 1, which is a phenyl group having one or two substituents. 12. The compound according to claim 11, wherein the substituent of the substituted phenyl group is a fluorine atom, a fluorinated lower alkyl group or a fluorinated lower alkoxy group. 13. A compound represented by the general 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 may have a substituent,
Saturated cyclic amide groups bonded by a nitrogen atom are respectively shown]
And a compound represented by the general formula (III): [Wherein Y represents a nitrogen atom or a methine group] or a salt thereof is reacted to obtain R of the compound (I).
^3. A compound (I) or a salt thereof according to claim 1, wherein a compound in which ³ is a hydrogen atom is obtained, and optionally treated with an acylating agent to obtain a corresponding compound in which R ³ is an acyl group. Production method. 14. A compound represented by 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, and Y is a nitrogen atom or a methine group. , And A ″ each represent a 3-substituted phenyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl group] or a salt thereof is subjected to a reduction reaction. A method for producing the compound or salt thereof according to claim 9. 15. An antifungal agent comprising the compound according to claim 1, or a pharmaceutically acceptable salt thereof, and an excipient and / or a carrier.