JP3108997B2 - Azole compounds, their production and use - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel azole compound having an antifungal action, a method for producing the same, and a use thereof.

[0002]

2. Description of the Related Art Various azole compounds having an antifungal effect have been known. For example, JP-A-6-2
No. 93740 discloses a formula:

Embedded image (Wherein, Ar represents a substituted phenyl, R ¹ and R ² may be the same or different and represent a hydrogen atom or a lower alkyl group, or may be linked to form a lower alkylene group, and R ³ is a carbon atom R ⁴ represents a hydrogen atom or an acyl group, X represents a nitrogen atom or a methine group, and Y and Z may be the same or different and are substituted with a nitrogen atom or a lower alkyl group. An azole compound represented by the following formula:

Embedded image (In the formula, Ar represents an optionally substituted phenyl group, R ¹
And R ² are the same or different and are 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, Y is a nitrogen atom or a methine group, And A each represent a saturated cyclic amide group which may have a substituent and is bonded by a nitrogen atom), or a salt thereof according to WO96
25410A ₁ (corresponding to Japanese Patent Application Laid-Open No. 9-183768)
Has the formula:

Embedded image [Wherein, Ar represents a phenyl group which may be substituted;
¹ and R ² are the same or different and each represents a hydrogen atom or a lower alkyl group, or R ¹ and R ² are combined to form a lower alkylene group, R ³ is a hydrogen atom or an acyl group,
Represents a nitrogen atom or a methine group, and A represents Y = Z (Y and Z
Represents the same or different and represents a methine group which may be substituted with a nitrogen atom or a lower alkyl group) or an ethylene group which may be substituted with a lower alkyl group;
And Az represents an azolyl group which may be substituted] or a salt thereof.

On the other hand, as a quaternary ammonium salt type derivative of an azole (imidazole, triazole) compound which is hydrolyzed enzymatically and / or non-enzymatically, a group of compounds called soft drugs has been known. For example, a quaternary salt derivative of 1-methylimidazole has been described in Journal of Medicinal Chemistry 2
3, 469, 1980 (antibacterial action), 23, 566, 1980 (antitumor action), 23, 4
Page 74 1980 (Anticholinergic action) and 32, 4
Page 93, 1989 (Acetylcholinesterase reactivating action). These are quaternary salts themselves having biological activity, and it is considered that one of the features is that hydrolysis occurs immediately. ing. On the other hand, quaternary ammonium salt-type derivatives of azole compounds as a kind of prodrug include Pharmaceutical Research, Vol. 9, pp. 372 (1992) (anti-glaucoma drugs) and Entmolologica Experimentalis et Aprica, Vol. 44, p. Insecticides) have only been reported. Further, an example of the use of a quaternary ammonium derivative of imidazole as a synthetic intermediate utilizing the fact that it is easily hydrolyzed is described in Journal of Chemical Society, Parkin I, p. 1341.
997 and New Journal of Chemistry
16, 107, 1992. U.S. Pat. No. 4,061,722,4,160,099 discloses a series of 4
A quaternary ammonium salt type derivative is described. However, enzymatically and / or non-enzymatically hydrolyzed quaternary salt derivatives of azole compounds having antifungal activity are not known.

[0004]

The above-mentioned azole compounds having an antifungal effect are not always sufficiently soluble in water for use as an injection, for example, and are not sufficiently absorbable in the body to exhibit a high therapeutic effect. However, it is difficult to say that they are sufficiently satisfactory in terms of water solubility and improvement in water solubility and in vivo absorption is desired.

[0005]

Means for Solving the Problems The present inventors have conducted various studies in view of these points and found that 1H-
A derivative obtained by quaternizing a nitrogen atom contained in an imidazol-1-yl group or a 1H-1,2,4-triazol-1-yl group has improved solubility in water, and is enzymatically and / or in vivo. This finding was found to be non-enzymatically hydrolyzed to produce a compound having a 1H-imidazol-1-yl group or a 1H-1,2,4-triazol-1-yl group and having antifungal activity. Based on this, the present invention has been completed. That is, in the present invention, one of the nitrogen atoms constituting the azole ring is quaternized with a substituent which is eliminated in vivo, and the substituent is eliminated in vivo and converted into an antifungal azole compound. The present invention relates to a quaternized nitrogen-containing imidazol-1-yl or 1,2,4-triazol-1-yl compound, a method for producing the compound, and a pharmaceutical composition containing the compound. The above-mentioned "One of the nitrogen atoms constituting the azole ring is quaternized with a substituent capable of leaving in vivo, and the substituent can be removed in vivo and converted to an antifungal azole compound. Graded nitrogen imidazol-1-yl or 1,2,4
-Triazol-1-yl compound [hereinafter may be referred to as compound (I)] has imidazole-1-in its molecule.
Having an yl group or a 1,2,4-triazol-1-yl group, a nitrogen atom at the 3-position of the imidazol-1-yl group and a 2- or 4-position of the 1,2,4-triazol-1-yl group Having a substituent on the nitrogen atom of
The substituent is hydrolyzed in the living body to be eliminated, and has an imidazol-1-yl group or a 1,2,4-triazol-1-yl group having no quaternized nitrogen atom. Is a compound that converts into a compound having an antifungal action.

[0006] Such compounds include those of the formula:

Embedded image (Wherein Q is imidazole-1 quaternized with a substituent in which one of the nitrogen atoms constituting the azole ring is eliminated in vivo.
-Yl or 1,2,4-triazol-1-yl group,
Ar represents an optionally substituted phenyl group, A represents an optionally substituted hydrocarbon group or a heterocyclic group,
X ¹ represents an oxygen atom or a methylene group, X ² represents an optionally oxidized sulfur atom, and m and p each represent 0 or 1
The, Y ^- represents an anion, R ^3, R ⁴ and R ⁵ are the same or different, and represent a hydrogen atom or a lower alkyl group, R ³ represents a hydrogen atom or a lower alkyl group, and R ⁴ and R ⁵ together show a lower alkylene group,
R ⁵ represents a hydrogen atom or a lower alkyl group, and R ³
And R ⁴ together represent a lower alkylene group. ) Or a salt thereof [hereinafter may also be referred to as compound (Ia)]. The imidazol-1-yl or 1,2,1 quaternized by a substituent in which one of the nitrogen atoms constituting the azole ring is eliminated in vivo represented by Q
The “substituent that leaves in vivo” in the “4-triazol-1-yl group” may be any group that is hydrolyzed in vivo, and the group represented by Q is represented by the formula:

Embedded image (Wherein, R ¹ represents an optionally substituted hydrocarbon group or a heterocyclic group, R ² represents a hydrogen atom or a lower alkyl group, X represents a nitrogen atom or a methine group, and n represents 0 or 1. )).

The "hydrocarbon group" of the "optionally substituted hydrocarbon group" for R ¹ includes an aliphatic hydrocarbon group, an aromatic hydrocarbon group and an araliphatic hydrocarbon group. Examples of the aliphatic hydrocarbon group include an alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an alkenyl group, and an alkynyl group. Examples of the alkyl group include, for example, methyl, ethyl, n-propyl, isopropyl, n -Butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl,
Examples thereof include linear or branched alkyl groups having 1 to 20 carbon atoms such as octyl, nonyl, decyl, and dodecyl, and particularly lower alkyl groups having 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl) are preferred. Examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl and the like.
And a cycloalkyl group having 3 to 6 carbon atoms (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) is preferred. Examples of the cycloalkylalkyl group include those having 4 to 12 carbon atoms such as cyclopropylmethyl, cyclopentylmethyl, and cyclohexylmethyl, and particularly cycloalkylalkyl groups having 6 to 8 carbon atoms (eg,
Cyclopentylmethyl, cyclohexylmethyl) are preferred. Examples of the alkenyl group include those having 2 to 4 carbon atoms such as vinyl, propenyl, and butenyl.
Particularly, alkenyl having 2 to 3 carbon atoms (eg, vinyl, propenyl) is preferable. Examples of the alkynyl group include those having 2 to 4 carbon atoms such as ethynyl, propynyl, and butynyl, and alkynyl having 2 to 3 carbon atoms (eg, ethynyl, propynyl) is particularly preferable.

The aromatic hydrocarbon group includes phenyl,
Those having 6 to 14 carbon atoms, such as naphthyl, biphenyl, anthryl and indenyl, are particularly preferred.
An aryl group of 0 (eg, phenyl, naphthyl) is preferred. The araliphatic hydrocarbon group may have 7 to 15 carbon atoms.
Aralkyl groups such as benzyl, phenethyl, phenylpropyl, naphthylmethyl, indanyl, indanylmethyl, 1,2,3,4-tetrahydronaphthyl, 1,2,
3,4-tetrahydronaphthylmethyl and the like, and particularly, an aralkyl group having 7 to 11 carbon atoms (eg, benzyl,
Phenethyl, naphthylmethyl, etc.) are preferred.

The "heterocyclic group" of the "optionally substituted heterocyclic group" for R ¹ represents a group formed by removing one hydrogen atom bonded to the heterocyclic ring. The ring is, for example, a 5- to 8-membered ring containing 1 to several, preferably 1 to 4, hetero atoms such as a nitrogen atom (which may be oxidized), an oxygen atom and a sulfur atom, or a fused ring thereof. Specific examples of such a heterocyclic group include pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, 1,2,
3-oxadiazolyl, 1,2,4-oxadiazolyl,
1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4- Thiadiazolyl, pyrrolidinyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl, indolyl, pyranyl, thiopyranyl, dioxinyl, dioxolyl, quinolyl, pyrido [2,3-d] pyrimidyl, 1,5-, 1,
6-, 1,7-, 1,8-, 2,6- or 2,7-naphthyridinyl, thieno [2,3-d] pyridyl, benzopyranyl, tetrahydrofuryl, tetrahydropyranyl, dioxolanyl, dioxanyl, etc. .

The substituent in the “optionally substituted hydrocarbon group” and the “optionally substituted heterocyclic group” for R ¹ includes, for example, a heterocyclic group, an oxo group, a hydroxyl group, a C _{1 -6} alkoxy group, C _3-10 cycloalkyloxy group, C _6-10 aryloxy group, C _7-19 aralkyloxy group, heterocyclic oxy group, mercapto group, C _1-6 alkylthio group (where the sulfur atom is an oxide C _3-10 cycloalkylthio group (the sulfur atom may be oxidized), C _6-10 arylthio group (the sulfur atom may be oxidized), C _{3-10 7-19} aralkylthio group (the sulfur atom may be oxidized), heterocyclic thio group, heterocyclic sulfinyl group, heterocyclic sulfonyl group, amino group, mono C _1-6 alkylamino group,
Di-C _1-6 alkylamino group, tri-C _1-6 alkylammonio group, C _3-10 cycloalkylamino group, C _6-10 arylamino group, C _7-19 aralkylamino group, heterocyclic amino group, cyclic Amino group, nitro group, halogen atom, cyano group, carboxyl group, _C1-10 alkoxy-carbonyl group, _C6-10 aryloxy-carbonyl group, _C7-19 aralkyloxy-carbonyl group, _C6-10 aryl- Carbonyl group, C _1-6 alkanoyl group, C _3-5 alkenoyl group,
A C _6-10 aryl-carbonyloxy group, a C _2-6 alkanoyloxy group, a C _3-5 alkenoyloxy group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, A carbamoyloxy group, a C _1-6 alkanoylamino group, a C _6-10 aryl-carbonylamino group, a C _1-10 alkoxy-carboxamide group, a C _6-10 aryloxy-carboxamide group,
_C7-19 aralkyloxy-carboxamide group, _C1-10 alkoxy-carbonyloxy group, _C6-10 aryloxy-carbonyloxy group, _C7-19 aralkyloxy-carbonyloxy group, _C3-10 cycloalkyloxy- Examples thereof include a carbonyloxy group and an optionally substituted ureido group, and 1 to 4 identical or different groups may be present. As the “C _1-6 alkoxy group”, for example,
Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy and the like are examples of the “C _3-10 cycloalkyloxy group” such as cyclopropyloxy, cyclohexyl Oxy and the like as “C _6-10 aryloxy group”, for example, phenoxy and naphthyloxy; and as “C _7-19 aralkyloxy group”, for example, benzyloxy, 1-phenylethyloxy,
-Phenylethyloxy, benzhydryloxy and the like are examples of "C _1-6 alkylthio group (the sulfur atom may be oxidized)" such as methylthio,
Ethylthio, n-propylthio, n-butylthio, methylsulfinyl, methylsulfonyl and the like are examples of “C _3-10 cycloalkylthio group (the sulfur atom may be oxidized)” such as cyclopropylthio,
Examples of cyclohexylthio, cyclopentylsulfinyl, cyclohexylsulfonyl and the like as “C _6-10 arylthio group (the sulfur atom may be oxidized)” include, for example, phenylthio, naphthylthio, phenylsulfinyl, phenylsulfonyl and the like. _{As the 7-19} aralkylthio group (the sulfur atom may be oxidized), for example, benzylthio, phenylethylthio, benzhydrylthio, benzylsulfinyl, benzylsulfonyl and the like include “mono C _1-6 alkylamino Examples of the "group" include methylamino, ethylamino, n-propylamino, n-butylamino and the like.
For example, the "di-C _1-6 alkylamino group", dimethylamino, diethylamino, methylethylamino, di - (n-propyl) amino, di - (n-butyl) and amino is, "tri C _1-6 alkyl Examples of the “ammonio group” include trimethylammonio and the like, and examples of the “C _3-10 cycloalkylamino group” include cyclopropylamino, cyclopentylamino and cyclohexylamino, and the like as the “C _6-10 arylamino group”. Are, for example, anilino, N-methylanilino, etc., and the "C _7-19 aralkylamino group" are, for example, benzylamino, 1-phenylethylamino, 2-phenylethylamino, benzhydrylamino, etc .; "
For example, 1-pyrrolidinyl, piperidino, 1
-Piperazinyl, morpholino, thiomorpholino and the like,
"Halogen atom" includes, for example, fluorine, chlorine, bromine, iodine, etc., and " _C1-10 alkoxy-carbonyl group" includes, for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxy. Carbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, norbornyloxycarbonyl and the like, and the “C _6-10 aryloxy-carbonyl group” include, for example, phenoxycarbonyl, naphthyloxycarbonyl and the like. ,
Examples of the “C _7-19 aralkyloxy-carbonyl group” include benzyloxycarbonyl and benzhydryloxycarbonyl, and examples of the “C _6-10 aryl-carbonyl group” include benzoyl, naphthoyl, phenylacetyl and the like. For example, the "C _1-6 alkanoyl group" include formyl, acetyl, propionyl, butyryl, valeryl, pivaloyl is, as "C _3-5 alkenoyl group" for example, acryloyl, crotonoyl and the like, "C _6-10 aryl - For example, as a carbonyloxy group ", benzoyloxy, naphthoyloxy, etc. phenylacetoxy is, as" C _2-6 alkanoyloxy group "for example, acetoxy, propionyloxy, butyryloxy, valeryloxy, pivaloyloxy and the like," C _{3 -5} As Rukenoiruokishi group "for example, acryloyloxy, etc. crotonoyloxy oxy," optionally substituted carbamoyl group ", for example, C _1-4 alkyl group (e.g., methyl, ethyl, etc.), a phenyl group, C _{1 -7} acyl group (eg, acetyl,
A carbamoyl group which may be substituted with one or two substituents selected from a propionyl, a benzoyl, etc.), a C _1-4 alkoxy-phenyl group (eg, methoxyphenyl, etc.), and a cyclic aminocarbonyl group. For example, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N-
Phenylcarbamoyl, N-acetylcarbamoyl, N
-Benzoylcarbamoyl, N- (p-methoxyphenyl) carbamoyl, 1-pyrrolidinylcarbonyl, piperidinocarbonyl, 1-piperazinylcarbonyl, morpholinocarbonyl and the like are referred to as "optionally substituted thiocarbamoyl groups". Is, for example, a thiocarbamoyl group which may be substituted with one or two substituents selected from a C _1-4 alkyl group (eg, methyl, ethyl, etc.), a phenyl group and the like. , N-methylthiocarbamoyl, N-phenylthiocarbamoyl and the like, and the “optionally substituted carbamoyloxy group” are selected from, for example, a C _1-4 alkyl group (eg, methyl, ethyl and the like), a phenyl group and the like. A carbamoyloxy group optionally substituted with one or two substituents is used. The example, carbamoyloxy, N- methylcarbamoyloxy, N, N- dimethylcarbamoyloxy, N- ethylcarbamoyloxy, etc. N- phenylcarbamoyloxy is, "C _1-6
Examples of the "alkanoylamino group" include, for example, acetamido, propionamido, butyroamido, valeroamide,
Pibaroamido etc., - it is the "C _6-10 aryl-carbonyl group" for example, benzamide, naphthamide, phthalimide and the like, - as "C _1-10 alkoxy-carboxamide group" for example, methoxy carboxamide (CH ₃ OCONH-), Ethoxycarboxamide, t
ert-butoxycarboxamide and the like, and “C _6-10 aryloxy-carboxamide group” include, for example, phenoxycarboxamide (C ₆ H ₅ OCONH-) and the like.
Examples of the “C _7-10 aralkyloxy-carboxamide group” include, for example, benzyloxycarboxamide (C ₆ H ₅ C
H ₂ OCONH-), etc. benzhydryloxy carboxamides found - as "C _1-10 alkoxy-carbonyloxy group" for example, methoxycarbonyloxy, ethoxycarbonyloxy, n- propoxycarbonyloxy, isopropoxycarbonyloxy, n- Butoxycarbonyloxy, tert-butoxycarbonyloxy,
Examples of “C _6-10 aryloxy-carbonyloxy group” include n-pentyloxycarbonyloxy, n-hexyloxycarbonyloxy and the like, for example, phenoxycarbonyloxy, naphthyloxycarbonyloxy and the like, and “C _7-19 aralkyloxy”. -Carbonyloxy group "includes, for example, benzyloxycarbonyloxy, 1-phenylethyloxycarbonyloxy,
Phenylethyloxycarbonyloxy, benzhydryloxycarbonyloxy and the like are examples of the "C _3-10 cycloalkyloxy-carbonyloxy group".
Examples of the "ureido group which may be substituted" include cyclopropyloxycarbonyloxy, cyclohexyloxycarbonyloxy, etc., for example, a group selected from C _1-4 alkyl groups (eg, methyl, ethyl, etc.), and phenyl groups. And a ureido group optionally substituted with 3 substituents, for example, ureide, 1-methylureide, 3-methylureide, 3,3-dimethylureide,
1,3-dimethylureide, 3-phenylureide and the like.

Examples of the substituent of the "optionally substituted heterocyclic group" for R ¹ include, in addition to those described above, a C _1-6 alkyl group, a C _3-6 cycloalkyl group, a C _{4- 7}
Cycloalkylalkyl group, C _2-3 alkenyl group, C _2-3
An alkynyl group, a C _6-10 aryl group, a C _7-11 aralkyl group and the like are used. As the “C _1-6 alkyl group”, for example, methyl, ethyl, n-propyl, isopropyl, n
-Butyl, isobutyl, sec-butyl, tert-butyl and the like, as the “C _3-6 cycloalkyl group”, for example,
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like; "C _4-7 cycloalkylalkyl group" such as cyclopropylmethyl and cyclopentylmethyl; and "C _2-3 alkenyl group" such as vinyl and propenyl However, the "C _2-3 alkynyl group" includes, for example, ethynyl, propynyl and the like, the "C _6-10 aryl group" includes phenyl and naphthyl, and the "C _7-11 aralkyl group" includes, for example, benzyl and phenethyl. , Naphthylmethyl and the like. The number of these substituents in the “optionally substituted hydrocarbon group” and the “optionally substituted heterocyclic group” represented by R ¹ is not limited to one, and may be the same or different and a plurality (2 to 4).

A heterocyclic group, a heterocyclic oxy group, a heterocyclic thio group in the substituents of the “hydrocarbon group” and the “heterocyclic group”,
The heterocyclic group in the heterocyclic sulfinyl group, the heterocyclic sulfonyl group, and the heterocyclic amino group represents a group formed by removing one hydrogen atom bonded to the heterocyclic ring. Such a heterocyclic ring is, for example, a nitrogen atom ( A 5- to 8-membered ring containing 1 to several, preferably 1 to 4 heteroatoms such as an oxygen atom, an oxygen atom and a sulfur atom, or a condensed ring thereof. Such heterocyclic groups include, for example, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, 1,2,
3-oxadiazolyl, 1,2,4-oxadiazolyl,
1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4- Thiadiazolyl, pyrrolidinyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl, indolyl, pyranyl, thiopyranyl, dioxinyl, dioxolyl, quinolyl, pyrido [2,3-d] pyrimidyl, 1,5-, 1,
6-, 1,7-, 1,8-, 2,6- or 2,7-naphthyridinyl, thieno [2,3-d] pyridyl, benzopyranyl, tetrahydrofuryl, tetrahydropyranyl, dioxolanyl, dioxanyl and the like. And these heterocyclic groups are one to three selected from C _1-4 alkyl groups (eg, methyl, ethyl, etc.), hydroxyl groups, oxo groups, C _1-4 alkoxy groups (eg, methoxy, ethoxy, etc.). It may be substituted by a substituent.

In the optionally substituted hydrocarbon group or heterocyclic group represented by R ¹ , the “optionally substituted hydrocarbon group” includes a hydroxyl group, a C _1-6 alkoxy group, a C _{7- 19} aralkyloxy, C _1-6 alkylthio, C _1-6 alkylsulfonyl, C _1-6 alkanoylamino, C _1-10 alkoxy-carbonyl, C _7-19 aralkyloxy-carbonyl, substituted A carbamoyl group, a C _1-10 alkoxy-carboxamide,
1-3 selected from C _7-10 aralkyloxy-carboxamide, a heterocyclic group (optionally substituted) and the like.
(As the C _1-6 alkyl groups such as methyl, ethyl, n- propyl, isopropyl, n- butyl, isobutyl, etc. tert- butyl) pieces of which may be substituted with a substituent C _1-6 alkyl group Preferably, specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxymethyl, ethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 1-ethoxyethyl, -Ethoxyethyl, 2-benzyloxyethyl, 3-benzyloxypropyl, 1,3-dibenzyloxy-2-propyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3- Dihydroxypropyl, 1,3-dihydroxy-2-propyl,
Methylthiomethyl, methylsulfonylethyl, acetamidomethyl, 1-acetamidoethyl, 2-acetamidoethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, tert-butoxycarbonylmethyl, 1-ethoxycarbonylethyl, 2-ethoxycarbonylethyl, 1-methoxycarbonyl -1-methylethyl, 1-
Ethoxycarbonyl-1-methylethyl, 1-tert-butoxycarbonyl-1-methylethyl, 1-benzyloxycarbonylethyl, 1-benzyloxycarbonyl-1-methylethyl, carbamoylmethyl, N, N-dimethylcarbamoylmethyl, methoxy Carboxamidomethyl, ethoxycarboxamidomethyl, tert-butoxycarboxamidomethyl, benzyloxycarboxamidomethyl, 2-ethoxycarboxamidoethyl, 2-furylmethyl, 2-tetrahydrofurylmethyl, 1,3-dioxolan-2-ylmethyl, 1,3-dioxolane −
4-ylmethyl, 2-oxo-1,3-dioxolane-
4-ylmethyl, 2,2-dimethyl-1,3-dioxolan-4-ylmethyl, 1,3-dioxan-5-ylmethyl, 1-ethoxycarbonyl-1- (2,3,4-trihydroxyphenyl) methyl, 1-acetamide-2-
Ethoxycarbonyl, 1-acetamido-3-ethoxycarbonylpropyl, 2-acetamido-2-ethoxycarbonylethyl, 3-acetamido-3-ethoxycarbonylpropyl, 1-acetamido-2-carbamoylethyl, 1-acetamido-3-carbamoylpropyl And the like. The most preferred C _1-6 alkyl group _optionally substituted with 1 to 3 substituents is methyl, ethyl, n-propyl, isopropyl,
Linear and branched C _1-4 alkyl groups such as n-butyl, isobutyl, tert-butyl and the like and 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 1,3-dihydroxy-2 -Propyl, 2-methoxyethyl, 2-ethoxyethyl, 3-benzyloxypropyl, ethoxycarbonylmethyl, 1-ethoxycarbonylethyl, 1-benzyloxycarbonylethyl, 2-furylmethyl, 2-tetrahydrofurylmethyl, 1,3 Hydroxyl groups such as -dioxolan-4-ylmethyl, 2-oxo-1,3-dioxolan-4-ylmethyl, 2,2-dimethyl-1,3-dioxolan-4-ylmethyl, C _1-6 alkoxy group, C _{1- A} linear or branched C _1-4 alkyl substituted with a ₁₀ alkoxy-carbonyl group or a heterocyclic group (optionally substituted); It is a kill group.

In the optionally substituted hydrocarbon group or heterocyclic group represented by R ¹ , the “optionally substituted heterocyclic group” includes oxo group, hydroxyl group,
1 selected from _1-6 alkyl group, C _1-6 alkoxy group, etc.
Heterocyclic groups substituted with up to 3 substituents are preferred, with specific examples being furyl, thienyl, pyranyl, thiopyranyl, dioxinyl, dioxolyl, benzopyranyl,
Tetrahydrofuryl, tetrahydropyranyl, dioxolanyl, dioxanyl, methylfuryl, hydroxyfuryl, methylthienyl, methoxyfuryl, 2-oxo-
1,3-dioxolyl, 2,2-dimethyl-1,3-dioxolyl, 2-oxo-1,3-dioxolanyl, 2,2
-Dimethyl-1,3-dioxolanyl, 2-oxo-1,
Examples thereof include 3-dioxanyl, 2,2-dimethyl-1,3-dioxanyl, and among them, furyl, thienyl, dioxanyl, 2-oxo-1,3-dioxanyl, and 2,2-dimethyl-1,3-dioxanyl are particularly preferable. preferable.

The lower alkyl group represented by R ² includes:
For example, a lower alkyl group having 1 to 4 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, etc.), and methyl is particularly preferred. R ² is particularly preferably a hydrogen atom or methyl. X represents a nitrogen atom or a methine group, preferably a nitrogen atom. Examples of the optionally oxidized sulfur atom represented by X ² include thio, sulfinyl,
Sulfonyl. m and p each represent 0 or 1, and preferably both are 0. 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 (eg, fluoro Methyl, trifluoromethyl, chloromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, etc., halogenated lower (C _1-4 ) alkoxy groups (eg, fluoro Methoxy, trifluoromethoxy, chloromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 1,1-difluoroethoxy, 1,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,
2,2-trifluoroethoxy, 2,2,3,3-tetrafluoropropoxy, 2,2,3,3,3-pentafluoropropoxy, etc.). The substituent is preferably halogen (eg, fluorine, chlorine, bromine, iodine, etc.), and particularly preferably fluorine. The number of substituents is preferably 1 to 3, more preferably 1 or 2.

Preferred examples of Ar include a halogenophenyl group, a halogenated lower (C _1-4 ) alkylphenyl group, and a halogenated lower (C _1-4 ) alkoxyphenyl group. Examples of the halogenophenyl group include 2,4-difluorophenyl, 2,4-dichlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 2-
Chlorophenyl, 2-fluorophenyl, 2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, 2,4,6-trifluorophenyl, 4-bromophenyl and the like can be mentioned. Examples of the halogenated lower (C _1-4 ) alkylphenyl group include 4-trifluoromethylphenyl. The halogenated lower (C
_1-4 ) Examples of the alkoxyphenyl group include 4-trifluoromethoxyphenyl, 4- (1,1,2,2-tetrafluoroethoxy) phenyl, 4- (2,2,2-trifluoroethoxy) phenyl, 4- (2,2,3,3-tetrafluoropropoxy) phenyl, 4- (2,2,3,
3,3-pentafluoropropoxy) phenyl and the like. Specifically, Ar is preferably 1 to 2
Phenyl groups substituted with two halogens, for example 2,4-
Difluorophenyl, 2,4-dichlorophenyl, 4-
Chlorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-fluorophenyl, 2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, 4
And phenyl substituted with one or two fluorine atoms, such as 4-fluorophenyl, 2-fluorophenyl, and 2,4-difluorophenyl, and more preferably 2-fluorophenyl. Phenyl, 2,4-difluorophenyl and the like.

[0017] Y ^- anion represented by are those obtained by removing one proton from an organic or inorganic acid, examples of the organic acids such as acetic acid, propionic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic Sulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid and the like can be mentioned, and examples of inorganic acids include hydrochloric acid, sulfuric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, water and the like. . As Y ⁻ , an anion obtained by removing one proton from an inorganic acid is preferable. Among them, a proton from a hydrohalic acid such as hydrochloric acid, hydrofluoric acid, hydrobromic acid and hydroiodic acid is preferably used.
The anion obtained by removing one proton is preferable, and particularly the anion obtained by removing one proton from hydrochloric acid, hydrobromic acid, and hydroiodic acid is preferable. Y ⁻ can also be defined as a group having a negative charge, and preferred examples thereof include, for example, Cl ⁻ , F ⁻ ,
Examples thereof include Br ⁻ , I ⁻ , HSO ₃ ⁻ , HSO ₄ ⁻ , H ₂ PO ₄ ⁻ , and OH ⁻ , among which Cl ⁻ , F ⁻ , Br ⁻ , and I ⁻ are preferable, and Cl ⁻ , Br ⁻ , and I are particularly preferable. ^- is preferable. As the lower alkyl group represented by R ³ , R ⁴ and R ⁵ , for example, straight or branched C 1 -C 1 such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl And an alkyl group of 4, and among them, methyl is preferable.

When R ³ and R ⁴ or R ⁴ and R ⁵ are combined to represent a lower alkylene group, examples of the lower alkylene include those having 1 to 4 carbon atoms such as methylene, ethylene, propylene and butylene. Among them, methylene and ethylene are preferred when R ³ and R ⁴ combine to represent lower alkylene, and ethylene is preferred when R ⁴ and R ⁵ combine to represent lower alkylene. R ³ is preferably a hydrogen atom. R ⁴ and R ⁵ are both hydrogen atoms,
Both are preferably methyl groups or one is a hydrogen atom and the other is a methyl group. It is particularly preferred that one of R ⁴ and R ⁵ is a hydrogen atom and the other is methyl. Examples of the “optionally substituted hydrocarbon group” or “optionally substituted heterocyclic group” represented by A include the same as those described for R ¹ above.

Embedded image (Wherein, R ⁶ represents an optionally substituted hydrocarbon group or an aromatic heterocyclic group, and Z represents an optionally substituted lower alkylene group or a compound represented by the formula: -D = E- (D And E are the same or different and represent a nitrogen atom or a methine group which may be substituted with lower alkyl.)
Represents a group represented by Are preferred. R ⁶
Examples of the hydrocarbon group in the “optionally substituted hydrocarbon group” for include an aliphatic hydrocarbon group, an aromatic hydrocarbon group and an araliphatic hydrocarbon group.

Examples of the aliphatic hydrocarbon group include an alkyl, cycloalkyl, alkenyl, alkynyl group and the like. Examples of the alkyl group include a linear or branched alkyl group having 1 to 12 carbon atoms. Specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, ter
t-butyl, heptyl, octyl, nonyl, decyl, dodecyl and the like, and especially a lower alkyl group having 1 to 4 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl) , Tert-
Butyl, etc.) are preferred. Examples of the cycloalkyl group include a cycloalkyl group having 3 to 8 carbon atoms. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like, and particularly a cycloalkyl group having 3 to 6 carbon atoms (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like) is preferable. Examples of the alkenyl group include, for example, an alkenyl group having 2 to 4 carbon atoms. Specifically, vinyl, propenyl, butenyl and the like can be mentioned, and an alkenyl group having 2 to 3 carbon atoms (eg, vinyl, propenyl and the like) is particularly preferable. Examples of the alkynyl group include an alkynyl group having 2 to 4 carbon atoms. Specific examples include ethynyl, propynyl, butynyl and the like, and particularly preferably an alkynyl group having 2 to 3 carbon atoms (eg, ethynyl, propynyl and the like).

The aromatic hydrocarbon group includes, for example, 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, and an aryl group having 6 to 10 carbon atoms (eg, phenyl, naphthyl and the like) is particularly preferable. Examples of the araliphatic hydrocarbon group include an arylalkyl group having 7 to 15 carbon atoms. Specifically, benzyl, phenethyl, phenylpropyl, naphthylmethyl, indanyl, indanylmethyl,
1,2,3,4-tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthylmethyl, biphenylmethyl, benzhydryl and the like, among which aralkyl groups having 7 to 11 carbon atoms (eg, benzyl, phenethyl, naphthylmethyl) Etc.) are preferred.

Examples of the aromatic heterocyclic group in the "aromatic heterocyclic group optionally having substituent (s)" for R ⁶ include at least one selected from a nitrogen atom, a sulfur atom and an oxygen atom. And an aromatic heterocyclic group containing a hetero atom. 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, pyrazinyl, pyrimidinyl, oxazolyl,
Aromatic heterocyclic groups such as isoxazolyl and condensed aromatic heterocyclic groups such as benzimidazolyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridinyl, benzothiazolyl, quinolyl, isoquinolyl, quinazolinyl and indolyl; Can be
Examples of the aromatic heterocyclic group include 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 and the like) are preferred.

Substituents in the "optionally substituted aliphatic, aromatic or araliphatic hydrocarbon group or the optionally substituted aromatic heterocyclic group" for R ⁶ Examples thereof include a hydroxyl group, a carboxyl group which may be esterified (eg, an alkoxycarbonyl having 1 to 6 carbon atoms such as carboxy, methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, etc.), a nitro group, an amino group, an acylamino group (Eg, acetylamino,
1 to 1 carbon atoms such as propionylamino and butyrylamino
0 alkanoylamino, etc.), an amino group mono- or di-substituted with an alkyl group having 1 to 10 carbon atoms (eg, methylamino, dimethylamino, diethylamino, dibutylamino, etc.), optionally substituted 5- or 6-membered Cyclic amino group (e.g., 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)- 4-piperazinyl and the like),
An alkoxy group having 1 to 6 carbon atoms (eg, methoxy, ethoxy, propoxy, butoxy, etc.), a halogen atom (eg, fluorine, chlorine, bromine, etc.), an alkyl group having 1 to 6 carbon atoms (eg, methyl, propyl, butyl) Etc.), cycloalkyl groups having 3 to 6 carbon atoms (eg, cyclopropyl, cyclopentyl, etc.), halogeno-alkyl groups having 1 to 6 carbon atoms (eg, trifluoromethyl, dichloromethyl, trifluoroethyl, etc.), halogeno- An alkoxy group having 1 to 6 carbon atoms (eg,
Trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2,2,
3,3-tetrafluoropropoxy, 2,2,3,3,3-
Pentafluoropropoxy 2,2,3,3,4,4,5,5
-Octafluoropentoxy, 2-fluoroethoxy, etc.), oxo group, thioxo group, mercapto group, carbon number 1
To 6 alkylthio groups (eg, methylthio, ethylthio,
Butylthio, etc.), an alkylsulfonyl group having 1 to 6 carbon atoms (eg, methanesulfonyl, ethanesulfonyl, butanesulfonyl, etc.), an alkanoyl group having 1 to 10 carbon atoms (eg,
Acetyl, formyl, propionyl, butyryl, etc.), 5
Alternatively, a 6-membered aromatic heterocyclic group (eg, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,
4-triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, flazanil, 1,3,4-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,4-thiadiazolyl, thienyl, Frill, pyridyl, pyrimidinyl,
Pyridazinyl, etc.), condensed aromatic heterocyclic groups (eg, benzimidazolyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, benzothiazolyl, quinolyl, isoquinolyl, quinazolyl,
And the like. In particular, halogeno-an alkoxy group having 1 to 6 carbon atoms and a 5-membered aromatic heterocyclic group are preferable, and among them, 1,1,2,2-tetrafluoroethoxy, 2,2,3, 3-tetrafluoropropoxy, pyrazolyl (eg, 1H-pyrazol-1-yl), imidazolyl (eg, 1H-imidazol-1-yl), 1,2,3-
Triazolyl (eg, 1H-1,2,3-triazole-1
-Yl, 2H-1,2,3-triazol-2-yl),
1,2,4-Triazolyl (eg, 1H-1,2,4-triazol-1-yl) and tetrazolyl (eg, 1H-tetrazol-1-yl, 2H-tetrazol-2-yl) are particularly preferred.

The number of the above substituents is preferably 1 to 3, more preferably 1 or 2. The optionally substituted aliphatic, aromatic or araliphatic hydrocarbon group or the optionally substituted aromatic heterocyclic group represented by R ⁶ has a substituent. An aromatic hydrocarbon group which may be substituted is preferable, and a fer group having a substituent is particularly preferable.
A phenyl group substituted by an alkoxy group [e.g., 4-
(1,1,2,2-tetrafluoroethoxy) phenyl,
4- (2,2,3,3-tetrafluoropropoxy) phenyl] and a phenyl group substituted with a 5-membered aromatic heterocyclic group [eg, 4- (1H-pyrazol-1-yl) phenyl, 4- (1H-imidazol-1-yl) phenyl,
4- (1H-1,2,3-triazol-1-yl) phenyl, 4- (2H-1,2,3-triazol-2-yl) phenyl, 4- (1H-1,2,4-triazole −
1-yl) phenyl, 4- (1H-tetrazole-1-
Yl) phenyl, 4- (2H-tetrazol-2-yl) phenyl] is preferred.

The lower alkylene group in the "optionally substituted lower alkylene group" for Z is, for example, one having 1 to carbon atoms such as methylene, ethylene and propylene.
3, among which ethylene is preferred.
Examples of the substituent in the “optionally substituted lower alkylene group” include methyl, ethyl, n-propyl,
Isopropyl, n-butyl, isobutyl, sec-butyl,
Linear or branched C1-C4 such as tert-butyl
Is preferred, and methyl and ethyl are more preferred, and methyl is particularly preferred. Preferred examples of the ethylene group which may be substituted with a lower alkyl group represented by Z include ethylene, 1-methylethylene, 1,1
-Dimethylethylene, 1,2-dimethylethylene, 1-
Ethyl ethylene, 1,2-diethyl ethylene and the like are mentioned, and ethylene is particularly preferable.

When Z is D = E, a “methine group optionally substituted by a lower alkyl group” represented by D or E
Examples of the lower alkyl group in the above include linear or branched alkyl groups having 1 to 4 carbon atoms (methyl, ethyl, n
-Propyl, isopropyl, n-butyl, isobutyl,
sec-butyl, tert-butyl), of which methyl is preferred. Preferred examples of the lower alkyl methine group optionally substituted with a group represented by D or E, methine, ethylidyne _{(-C (CH 3) =)} , pro pyridine _{(-C (CH 2 CH 3)} = ), Butyridine (-C
(CH ₂ CH ₂ CH ₃ ) =) and the like, particularly preferably methine, ethylidine and the like, and particularly preferably methine and the like. D and E are one in which one is a nitrogen atom and the other is methine; both D and E are methine; both D and E are nitrogen atoms; one of D and E is nitrogen It is particularly preferable that one of D and E is a nitrogen atom and the other is methine; or that both of D and E are methine.

Specifically, as Z, -N = CH-,-
CH = N-, -CH = CH-, -N = N-, -N = C
_{(CH 3) -, - C} (CH 3) = N -, - CH 2 -CH 2 - and the like are preferred, -N = CH -, - CH = N -, - C
_{H = CH -, - CH 2} -CH 2 - are more preferable, -N
_{= CH -, - CH 2 -CH} 2 - is most preferred.

Embedded image Examples of the group represented by

Embedded image Are preferred, and especially

Embedded image Are preferred.

When a reactive atom such as a nitrogen atom is present in the optionally substituted hydrocarbon group or the optionally substituted heterocyclic group represented by A, the atom is represented by the formula:

Embedded image (Wherein each symbol is as defined above), may be bonded. When the compound (I) has one or more asymmetric carbon atoms in the molecule, there are two or more stereoisomers, and both the stereoisomers and a mixture thereof are included in the present invention. Is what is done. In the compound represented by the general formula (Ia), Q is a group represented by the formula (II), and A is

Embedded image M and p are both 0, R ⁴ is a hydrogen atom, R ⁵
Is a methyl group, an optically active substance in which both the carbon bonded to the optionally substituted phenyl group represented by Ar and the carbon bonded to R ⁵ have the (R) configuration is particularly preferable. In the formula (Ia), when Q is a group represented by the formula (II), the formula (Ia) is represented by the formula:

Embedded image (Wherein each symbol is as defined above). The compounds of the present invention may be either hydrates or non-hydrates. The compound of the present invention has the formula:

Embedded image (Wherein each symbol has the same meaning as described above).

Table 1 shows specific examples of the compound of the present invention.
It is not limited to the exemplified compounds.

[Table 1]

[0029]

[Table 2]

[0030]

[Table 3]

[0031]

[Table 4]

The compound (I) of the present invention is an imidazole-
It can be produced by introducing a group capable of leaving in vivo to an antifungal compound having a 1-yl group or a 1,2,4-triazol-1-yl group. Examples of the antifungal compound having an imidazol-1-yl group or a 1,2,4-triazol-1-yl group include miconazole, ketoconazole, fluconazole, itraconazole, saperconazole, clotrimazole, D087.
0, voriconazole, econazole, isoconazole,
Sulconazole, butconazole, thioconazole, bifonazole, croconazole, oxyconazole, terconazole, SSY-726, KP-103, Sch-
56592, Sch-51048, UR-9746, MF
B-1041, UR-9751, UR-9728, UR
-9825, ER-30346, T-8581, BAY
-W-9279, fenticonazole, omoconazole, flutrimazole, everconazole, lanconazole, neticonazole, sataconazole, known azole antifungal compounds such as genaconazole and the like, but these known antifungals also include It is not limited.

Compound (Ia-1) is, for example, compound (II)
I) and the formula:

Embedded image (Wherein, Y ¹ represents a halogen atom, and other symbols are as defined above) [hereinafter, compound (IV)
And, if necessary, anion exchange. The halogen atom represented by Y ^1, preferably chlorine, bromine, or iodine. The reaction between compound (III) and compound (IV) is usually performed without a solvent or in a solvent that does not inhibit the reaction. Examples of the solvent that does not inhibit the reaction include ketones (eg, acetone, 2-butanone, 2-pentanone, etc.), sulfoxides (eg, dimethyl sulfoxide, etc.), ethers (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), Nitriles (eg, acetonitrile, etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, 1,2-dichloroethane, etc.), esters (eg, Ethyl acetate, etc.), amides (eg, dimethylformamide, acetamide, dimethylacetamide, 1-methyl-2-pyrrolidinone, etc.), ureylene (eg, 1,
3-dimethyl-2-imidazolidinone) and the like. These may be used alone or as a mixture of two or more at an appropriate ratio.

Compound (IV) is used in an amount of about 1 to 100 equivalents, preferably about 1 to 50 equivalents, relative to compound (III). The reaction temperature is not particularly limited, but is usually about 0
To 150 ° C, preferably about 20 to 120 ° C. The reaction time is about several minutes to several hundred hours (eg, 5 minutes to 100 hours). The compound thus obtained can be led to a compound (Ia) having a desired anion (Y ⁻ ) by anion exchange, if necessary.
The anion exchange is carried out in the presence of water or a mixed solvent of water and an organic solvent (eg, acetone, acetonitrile, tetrahydrofuran, methanol, ethanol, etc.) or an organic solvent in the presence of an anion-type ion-exchange resin or the organic solvent described above for Y ^−. Alkali metals of acids or inorganic acids (eg,
(Sodium, potassium, etc.) salt. The compound (I) of the present invention thus obtained can be obtained from the reaction mixture by a means known per se, such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography, thin-layer chromatography, or the like. , Isolation and purification.

When the compound (I) of the present invention has one or more asymmetric carbon atoms in the molecule, two or more stereoisomers exist, and if desired, these isomers are individually produced. You can also. For example, starting compounds (III) and (I
When V) has an asymmetric carbon in the molecule, a single isomer of the compound (Ia) of the present invention can be obtained by performing the above reaction using the single isomer . Further, the above reaction is carried out using a single isomer of the starting compound (III), whereby a single isomer of the present reaction compound (Ia) can be obtained. When the product is a mixture of two or more isomers, the product can be separated into the respective isomers by a usual separation method, for example, separation means such as various types of chromatography and fractional recrystallization. When the raw material compound (III) of the present invention is a per se known antifungal agent exemplified above, its production method is known, and a method for producing a group of compounds useful as an antifungal agent is known per se, For example, JP-A-6-293740, JP-A-8-104
676, WO-9625410A. Still another production method of the starting compound (IV) is also known, for example, Synthesis pp. 588, 1971 and Synthetic Communications, Vol. 25, 273.
It can be produced by the method described on page 9, 1995, or a method analogous thereto.

The compound (I) of the present invention has low toxicity and is a fungus, for example, Candida spp. [Examples: Aspergillus niger, Aspergillus fumigatus, etc.], Cryptococcus genus [eg: Cryptococcus neoformans, etc.], Trichophyton genus [eg: Trichophyton lupulum, Trichophyton mentagrophytes etc.], Microsporum genus [eg: Microsporum] Gypseum etc.], Malassezia spp. [Examples: Malassezia furfa etc.], etc., so that fungal infections in mammals (humans, livestock, poultry etc.) [eg mucosa caused by Candida spp.] Candidiasis (thrush, stomatitis) Vulva vaginal candidiasis, penile candidiasis), skin candidiasis (candida albicans, candidal intertrigo, candidiasis anal, eczema dermatophytosis, Candida nail disease, Candida nail disease, Candida External otitis, skin lesions of candida sepsis, generalized superficial candidiasis, Candida granuloma, congenital cutaneous candidiasis, candidide, chronic mucocutaneous candidiasis and visceral candidiasis (respiratory candidiasis, gastrointestinal tract) Candida, Candida sepsis, Candida endocarditis, urinary candidiasis, ocular candidiasis, central nervous system candidiasis, joint and bone candidiasis, Candida peritonitis, hepatic candidiasis, intrauterine candidiasis), etc .; Pulmonary histoplasmosis, chronic pulmonary histoplasmosis and disseminated histoplasmosis due to aspergillus; Aspergillosis (allergic aspergillosis, bronchial aspergillosis, aspergillosis, pulmonary aspergillosis (acute invasive aspergillosis, chronic necrotizing pulmonary aspergillosis), aspergillosis empyema), disseminated aspergillosis, central nervous aspergillosis, aspergillosis Endocarditis, Aspergillus myocarditis, Aspergillus pericarditis, Aspergillus mycosis, External auditory canal aspergillosis, Aspergillus onyxitis, Aspergillus nail dissection, Aspergillus keratitis, Aspergillus endophthalmitis, Cutaneous aspergillosis and sinus orbital aspergillosis Etc .; Pulmonary cryptococcosis due to cryptococcus, CNS cryptococcosis, skin and mucosal cryptococcosis, bone and joint cryptococcosis, lymph node cryptococcosis, systemic Cryptococcosis and hematopoietic cryptococcosis, etc .; Trichophyton spp., Microsporum spp., Tinea capitis, tinea, celsius acne, tinea pea, tinea pedis, tinea pedis, ecchymosis Tinea pedis, tinea unguium, tinea unguium, tinea rash and tinea granuloma; Malassezia spp. Versicolor, etc.); it can. Furthermore, the compound (I) of the present invention can also be used as an agricultural antifungal agent.

When the compound (I) of the present invention is administered to humans, the compound (I) itself or a mixture thereof with an appropriate pharmacologically acceptable carrier, excipient, diluent or the like is used for oral administration (eg, powder, Granules, tablets, capsules, etc.), parenteral administration [eg:
Orally or parenterally safely as a pharmaceutical composition such as injections, external preparations (eg, transnasal preparations, transdermal preparations, etc.), suppositories (eg, rectal suppositories, vaginal suppositories, etc.) Can be administered. These preparations can be produced by a method known per se which is generally used in the production process. The compounding ratio of the compound (I) of the present invention in the preparation may vary depending on the form, but may be a ratio generally used for an antifungal agent. For example, in the above-mentioned oral administration agent, it is about 10 to 95% by weight. In the parenteral preparation, about 0.1 was obtained.
001 to 95% by weight. For example, an injection can be prepared by dispersing the compound (I) of the present invention into a dispersant [eg, Tween 80].
(Manufactured by Atlas Powder, USA), HCO60 (manufactured by Nikko Chemicals), carboxymethylcellulose, sodium alginate, etc.), preservatives (eg, methylparaben, propylparaben, benzyl alcohol, chlorobutanol, etc.), isotonic agents (eg, chloride) Oily injection by dissolving, suspending or emulsifying in aqueous injection with sodium, glycerin, sorbitol, glucose, etc.) or in vegetable oil (eg, olive oil, sesame oil, peanut oil, cottonseed oil, corn oil, etc.), propylene glycol, etc. It is manufactured by molding.

The preparation for oral administration contains the compound (I) of the present invention,
For example, excipients (eg, lactose, sucrose, starch, etc.), disintegrants (eg, starch, calcium carbonate), binders (eg, starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, etc.) or lubricants Additives (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.) and compression-molded, then coat with a known method for taste masking, enteric or long-lasting purposes as required. It can be manufactured by the following. Examples of the coating agent include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, and Eudragg (manufactured by Rohm). ,
West Germany, methacrylic acid, acrylic acid copolymerization) and pigments such as titanium oxide and red iron oxide are used.

The compound (I) of the present invention can be used as a solid, semi-solid or liquid external preparation. For example, as a solid external preparation, the compound (I) of the present invention may be used as it is or as an excipient (eg, glycol, mannitol, starch,
Microcrystalline cellulose, etc.), thickeners (eg, natural gums, cellulose derivatives, acrylic acid polymers, etc.) 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 ointment. Liquid external preparations
It is almost the same as an injection, and is prepared by making it into an oily or aqueous suspension. In addition to the above-mentioned solid, semi-solid or liquid external preparations, pH adjusters (eg, carbonic acid, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, etc.), preservatives (eg, paraoxybenzoic acid esters, chlorobutanol) , Benzalkonium chloride, etc.). Specifically, for example, using petrolatum, lanolin or the like as a base,
An ointment containing about 0.1 to 100 mg of the compound (I) of the present invention per gram can be used for sterilization and disinfection of skin or mucous membranes. The compound (I) of the present invention can also be used as an oily or aqueous solid, semi-solid or liquid suppository. Examples of the oily base for producing suppositories include glycerides of higher fatty acids (eg, cocoa butter, witepsol (manufactured by Dynamite Nobel), etc.), and intermediate fatty acids [eg: miglyolic acid (manufactured by Dynamite Nobel)] Etc.] or vegetable oils [eg, sesame oil, soybean oil, cottonseed oil, etc.]. Examples of the aqueous base include polyethylene glycols and propylene glycol, and examples of the aqueous gel base include natural gums and the like.
Examples include cellulose derivatives, vinyl polymers, and acrylic acid polymers.

The dose of the compound (I) of the present invention varies depending on the state of infection and the route of administration. .01 to 100mg / kg
/ Day, preferably about 0.1 to 50 mg / kg / day. More preferably, it is about 0.5 to 10 mg / kg / day. In the preparation of the present invention, compound (I) contains 2
More than one species may be used in combination. Moreover, you may use together with antifungal compounds other than compound (I). When the compound (I) of the present invention is used as an antifungal agent for agriculture, the compound (I) of the present invention is used.
Is dissolved or dispersed in a suitable liquid carrier (eg, a solvent) or mixed with or adsorbed on a suitable solid carrier (eg, a diluent, extender), and if necessary, further added with an emulsifier, Suspending agents, spreading agents, penetrants, wetting agents, mucilage agents, stabilizers and the like may be added and used as dosage forms such as emulsions, wettable powders, powders, and granules. These preparations can be prepared by a method known per se. The use amount of the compound (I) of the present invention is, for example, about 25 to 150 g, more preferably about 40 to 80 g, per are of a paddy field in controlling rice blast. The compound (I) of the present invention may be used in combination of two or more kinds, and may be used in combination with other agricultural antifungal compounds.

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, 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.), and these can be used alone or as a mixture of two or more at an appropriate ratio. As the solid carrier, vegetable powders (eg, soybean powder, tobacco powder, flour, etc.), mineral powders (eg, kaolin, bentonite, etc.), alumina, sulfur powder, activated carbon, etc. are used. Two or more kinds can be used by mixing at an appropriate ratio.

[0042]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference to Reference Examples, Examples, Formulation Examples and Experimental Examples, but the present invention is not limited thereto. ^{The 1} H-NMR spectrum was measured with a Varian Gemini 200 (200 MHz) type spectrometer using tetramethylsilane as an internal standard, and all δ values were shown in ppm. The numerical values shown in parentheses in the mixed solvents are volume mixing ratios of the respective solvents.
% Means percent by weight unless otherwise specified. Further, the ratio of the solvent in the silica gel chromatography indicates the volume ratio of the solvent to be mixed. The symbols in the examples have the following meanings. s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, t
t: triple triplet, m: multiplet, b
r: Wide, J: Coupling constant

Reference Example 1 Tetrahydrofurfuryl alcohol (19.4 g) was dissolved in anhydrous ether (500 ml), pyridine (15 g) was added under ice cooling, and chloromethyl chloroformate (25 g) was added dropwise.
After stirring the reaction solution at room temperature for 17 hours, the precipitated pyridine hydrochloride was removed by filtration and washed with ether (50 ml × 2).
The filtrate and the washing solution were combined, washed with water (300 ml × 2), and dried over magnesium sulfate. The solvent is distilled off under reduced pressure to give chloromethyl (2,3,4,5-tetrahydrofurfuryl) carbonate
(33.9 g) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.59-1.73 (1 H, m), 1.83-2.11 (3 H, m),
3.75-3.97 (2H, m), 4.11-4.34 (3H, m), 5.74 (2H, s) chloromethyl (2,3,4,5-tetrahydrofurfuryl) carbonate (3.4 g) and sodium iodide (10.46 g) was added to acetonitrile (70 ml) and heated at 60 ° C. for 90 minutes with stirring. After cooling the reaction solution, the solvent was distilled off under reduced pressure, and the residue was partitioned between ether (70 ml) and saturated saline (50 ml). 5 organic layers
The extract was washed with a 50% aqueous solution of sodium thiosulfate (50 ml), water (50 ml), and saturated saline (50 ml), and dried over magnesium sulfate.
The solvent was distilled off under reduced pressure to obtain iodomethyl (2,3,4,5-tetrahydrofurfuryl) carbonate (4.8 g) as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.54-1.73 (1 H, m), 1.84-2.11 (3 H, m),
3.73-3.96 (2H, m), 4.10-4.32 (3H, m), 5.96 (2H, s)

Reference Example 2 Glycerol formal (14 g) was added to anhydrous ether (400 ml).
After adding pyridine (15 g) at -10 ° C, chloroformic acid chloromethyl ester (25 g) in anhydrous ether (50 ml)
The solution was added dropwise over 10 minutes. After the reaction solution was stirred at room temperature for 20 hours, the precipitated pyridine hydrochloride was removed by filtration.
The filtrate was washed with a saturated saline solution (400 ml × 2) and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography (eluent: ethyl acetate / hexane = 1/5 → ethyl acetate / hexane = 1/3), and purified using chloromethyl (1,3- Dioxan-5-yl) carbonate (1.7 g) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 4.05 (4H, d, J = 3.2 Hz), 4.67 (1H, q
uintet, J = 3.2Hz), 4.82 (1H, d, J = 6.2Hz), 4.95 (1H, d,
J = 6.2 Hz), 5.75 (2H, s). The compound (1.7 g) obtained above and sodium iodide (5.1 g) were added to acetonitrile (40 ml), and the mixture was heated with stirring at 60 ° C. for 2 hours. The solvent obtained by evaporating the solvent of the reaction solution under reduced pressure was treated with ether (1.
00%), 5% aqueous sodium thiosulfate (50 ml),
After sequentially washing with water (50 ml) and saturated saline (50 ml), the mixture was dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure (1,3
-Dioxan-5-yl) iodomethyl carbonate (3.
2g) was obtained as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) d: 4.04 (4H, d, J = 3.0 Hz), 4.66 (1H, qu
intet, J = 3.0 Hz), 4.81 (1H, d, J = 6.2 Hz), 4.95
(1H, d, J = 6.2Hz), 5.97 (2H, s).

Reference Example 3 (R) -glycerol acetonide (10 g) was added to anhydrous ether
(200 ml), pyridine (6.6 g) was added at -10 ° C, and chloroformic acid chloromethyl ester (10.7 g) was added.
Was added dropwise over 10 minutes. After stirring the reaction solution at room temperature for 20 hours, the precipitated pyridine hydrochloride was removed by filtration. The filtrate was washed with saturated saline (200
After washing with ml × 2), it was dried over anhydrous magnesium sulfate.
The residue obtained by distilling off the solvent under reduced pressure was subjected to silica gel chromatography (eluent: hexane → ethyl acetate / hexane =
Purification by 1/5 → ethyl acetate / hexane = 3/5) gives chloromethyl [(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methyl carbonate (17 g) as colorless Obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.37 (3 H, s), 1.44 (3 H, s), 3.
80 (1H, dd, J = 8.8, 5.8 Hz), 4.07-4.42 (4 H, m),
5.74 (2 H, s). The compound obtained above (2 g) and sodium iodide (5.3 g)
Was added to acetonitrile (40 ml), and the mixture was heated with stirring at 60 ° C. for 2 hours. The residue obtained by evaporating the solvent of the reaction solution under reduced pressure was dissolved in ether (50 ml), and a 5% aqueous sodium thiosulfate solution (5%) was added.
0 ml), water (50 ml) and saturated saline (50 ml) in that order, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain [(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methyliodomethyl carbonate (2.1 g) as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.37 (3 H, s), 1.44 (3 H, s), 3.
79 (1H, dd, J = 8.0, 5.0 Hz), 4.06-4.41 (4 H, m),
5.96 (2 H, s).

Reference Example 4 Benzyl 4-hydroxybutanoate (Weber et a
pyridine (2.3 ml) was added to a solution of 5.0 g) in diethyl ether (100 ml) under a nitrogen atmosphere, followed by addition of −10, as described in l., J. Med. Chem.
Chloroformic acid chloromethyl ester (3.7 g) was added dropwise at ℃. The reaction was stirred at room temperature for 20 hours. The reaction solution was filtered with a glass filter and washed sequentially with water and saturated saline. After the organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure. Benzyloxycarbonylpropyl) carbonate (7.25 g) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) d: 2.02-2.12 (2H, m), 2.49 (2H, t, J
= 7 Hz), 4.28 (2H, t, J = 6Hz), 5.13 (2H, s), 5.71 (2
H, s), 7.36 (5H, s). Compound (2.5 g) obtained above in acetonitrile (67 ml)
Sodium iodide (5.2 g) was added to the solution under a nitrogen stream, and the mixture was stirred at 60 ° C for 8.5 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in diethyl ether (100 ml).
The mixture was sequentially washed with sodium thiosulfate, water and saturated saline. The organic layer was dried over sodium sulfate and concentrated under reduced pressure.
(3-Benzyloxycarbonylpropyl) iodomethyl carbonate (2.98 g) was obtained as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) d: 2.01-2.08 (2H, m), 2.49 (2H, t,
J = 7 Hz), 4.28 (2H, t, J = 6Hz), 5.14 (2H, s), 5.9
4 (2H, s), 7.36 (5H, s).

REFERENCE EXAMPLE 5 A mixture of (S) -ethyl lactate (23.6 g), pyridine (15.8 g) and diethyl ether (400 ml) was added to a mixture of chloroformic acid chloromethyl ester (25.6 g) and diethyl ether under ice cooling. (100ml)
The solution was added dropwise over 40 minutes. After stirring at room temperature for 14 hours, the resulting solid was filtered off. The filtrate was concentrated under reduced pressure, the residue was dissolved in ethyl acetate (250 ml), and washed with water (150 ml × 2) and saturated saline (150 ml). After drying over anhydrous magnesium sulfate and distilling off the solvent under reduced pressure, chloromethyl [(1S)
-1- (Ethoxycarbonyl) ethyl] carbonate (38.5g)
Was obtained as a colorless liquid. ¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.2 Hz), 1.57 (3H, d, J =
7.0Hz), 4.25 (2H, q, J = 7.2Hz), 5.07 (1H, q, J = 7.0Hz), 5.
71 (1H, d, J = 6.4Hz), 5.80 (1H, d, J = 6.4Hz).

Reference Example 6 To a mixture of (S) -benzyl lactate (30.6 g), pyridine (13.4 g) and diethyl ether (300 ml) was added chloroform under ice cooling.
Chloromethyl ester (21.9 g) in diethyl ether (100 m
l) The solution was added dropwise over 30 minutes. After stirring at room temperature for 5 hours, the resulting solid was filtered off. The filtrate was concentrated under reduced pressure, the residue was dissolved in ethyl acetate (200 ml), and washed with water (100 ml × 2) and saturated saline (100 ml). After drying over anhydrous magnesium sulfate and evaporating the solvent under reduced pressure, [(1S) -1- (benzyloxycarbonyl) ethyl] chloromethyl carbonate
(45.0 g) was obtained as a colorless liquid. ¹ H-NMR (CDCl ₃ ) δ: 1.57 (3H, d, J = 7 Hz), 5.07-5.28 (3H,
m), 5.69 (1H, d, J = 6 Hz), 5.78 (1H, d, J = 6 Hz), 7.36 (5H,
s). [(1S) -1- (benzyloxycarbonyl) ethyl] Chloromethyl carbonate (2.7 g) was dissolved in acetonitrile (4 ml), sodium iodide (6.0 g) was added, and the mixture was stirred at 60 ° C. for 2 hours under an argon atmosphere. did. After concentrating the reaction solution under reduced pressure,
Diethyl ether (100 ml) and water (100 ml) were added to the residue, and the layers were separated. The diethyl ether layer was washed with a 5% aqueous solution of sodium thiosulfate (80 ml), water (80 ml), and saturated saline (80 ml). After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain [(1S) -1- (benzyloxycarbonyl) ethyl] iodomethyl carbonate (3.3 g) as a colorless liquid. ¹ H-NMR (CDCl ₃ ) δ: 1.56 (3H, d, J = 7 Hz), 5.07-5.29 (3H,
m), 5.93 (1H, d, J = 5Hz), 5.98 (1H, d, J = 5Hz), 7.37 (5H,
s).

Reference Example 7 3- (benzyloxy) propanol (Wei et al., J. Org. Che
m., 54, 5768-5774 (1989), synthesized: 15.1 g), pyridine (7.18 g) and diethyl ether (15 g).
0 ml), a solution of chloromethyl chloroformate (11.7 g) in diethyl ether (50 ml) was added dropwise over 20 minutes under ice-cooling. After stirring at room temperature for 15 hours, the resulting solid was filtered off and washed with ethyl acetate (100ml). The filtrate and the washing were combined, washed with water (100 ml × 2) and saturated saline (50 ml), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (silica gel 200 g, eluent: ethyl acetate-hexane = 1: 4) to give [3- (benzyloxy) propyl] chloromethyl carbonate (21.0 g) as a colorless liquid. Obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.01 (2H, quintet, J = 6.2 Hz), 3.57 (2
H, t, J = 6.0Hz), 4.36 (2H, t, J = 6.4Hz), 4.51 (2H, s), 5.7
1 (2H, s), 7.33 (5H, s). [3- (Benzyloxy) propyl] chloromethyl carbonate (2.0 g) was dissolved in acetonitrile (3 ml), sodium iodide (4.6 g) was added, and the mixture was stirred at 60 ° C. for 2 hours under an argon atmosphere. The reaction solution was poured into water (100 ml) and ethyl acetate (10
0 ml). The ethyl acetate layer was washed with a 5% aqueous solution of sodium thiosulfate (50 ml × 2), water (50 ml × 2), and saturated saline (50 ml). After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain [3- (benzyloxy) propyl] iodomethyl carbonate (2.5 g) as a pale yellow liquid. ¹ H-NMR (CDCl ₃ ) δ: 2.00 (2H, quintet, J = 6.2 Hz), 3.57 (2
H, t, J = 6.0Hz), 4.36 (2H, t, J = 6.4Hz), 4.51 (2H, s), 5.9
4 (2H, s), 7.34 (5H, s).

Reference Example 8 2-acetylaminoethanol (20.0 g), pyridine (15.3
g) and tetrahydrofuran (100 ml) were added dropwise over 30 minutes to a solution of chloromethyl chloroformate (25.2 g) in tetrahydrofuran (50 ml) under ice-cooling. After stirring at room temperature for 16 hours, the resulting solid was filtered off and washed with tetrahydrofuran (30 ml). The filtrate and the washing were combined and concentrated under reduced pressure. Ethyl acetate (300 ml) and water (100 ml) were added to the residue.
Was added, and the mixture was separated. The aqueous layer was extracted twice with a mixture of ethyl acetate (150 ml) and tetrahydrofuran (50 ml). The organic layers were combined, washed with saturated saline (100 ml), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (240 g of silica gel, eluent:
Purification by subjecting to ethyl acetate-hexane = 1: 1 → ethyl acetate) provided [2- (acetylamino) ethyl] chloromethyl carbonate (32.4 g) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 2.01 (3H, s), 3.58 (2H, q, J = 6 Hz), 4.3
2 (2H, t, J = 6Hz), 5.75 (2H, s), 5.87 (1H, br). [2- (Acetylamino) ethyl] chloromethyl carbonate (5.0 g) was dissolved in acetonitrile (15 ml), sodium iodide (15.0 g) was added, and the mixture was stirred at 60 ° C. for 2 hours under an argon atmosphere. The reaction solution was poured into ice water (200 ml), and ethyl acetate (20 ml) was added.
0 ml). Ethyl acetate layer is 5% sodium thiosulfate aqueous solution (100 ml × 2), water (100 ml × 2) and saturated saline (50 ml)
And washed. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain [2- (acetylamino) ethyl] iodomethyl carbonate (3.5 g) as a yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 2.00 (3H, s), 3.54 (2H, q, J = 6 Hz), 4.2
8 (2H, t, J = 6Hz), 5.93 (2H, s), 6.12 (1H, br).

Reference Example 9 To a mixture of 3- (methoxy) propanol (6.0 g), pyridine (5.3 g) and diethyl ether (50 ml) was added, under ice-cooling, chloroformic acid chloromethyl ester (8.6 g) in diethyl ether. (1
0 ml) solution was added dropwise over 15 minutes. After stirring at room temperature for 16 hours, water (100 ml) and ethyl acetate (100 ml) were added to the reaction solution, and the mixture was separated. The organic layer was washed with water (100 ml) and saturated saline (50 m
After washing with l) and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (silica gel 70 g, eluent: ethyl acetate-hexane =
1: 2) to give chloromethyl [3- (methoxy)
Propyl] carbonate (11.0 g) was obtained as a colorless liquid. ¹ H-NMR (CDCl ₃ ) δ: 1.97 (2H, quintet, J = 6.2 Hz), 3.34 (3
H, s), 3.47 (2H, t, J = 6.2Hz), 4.33 (2H, t, J = 6.2Hz), 5.7
4 (2H, s). Chloromethyl [3- (methoxy) propyl] carbonate
(3.7 g) was dissolved in acetonitrile (12 ml), sodium iodide (12.0 g) was added, and the mixture was stirred at 55 ° C. for 4 hours under an argon atmosphere. The reaction solution was poured into water (100 ml) and ethyl acetate (100 ml).
Extracted. The ethyl acetate layer was washed with a 5% aqueous solution of sodium thiosulfate (50 ml × 2), water (50 ml), and saturated saline (50 ml). After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain iodomethyl [3- (methoxy) propyl] carbonate (5.0 g) as a pale yellow liquid. ¹ H-NMR (CDCl ₃ ) δ: 1.96 (2H, quintet, J = 6.2 Hz), 3.35 (3
H, s), 3.47 (2H, t, J = 6.2Hz), 4.33 (2H, t, J = 6.2Hz), 5.96
(2H, s).

[0052]

EXAMPLES Example 1 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-Triazol-1-yl) propyl] -3-
A mixture of [4- (1H-1,2,3-triazol-1-yl) phenyl] -2-imidazolidinone (0.25 g) and chloromethyl pivalate (3.0 g) was treated at 100 ° C.
For 24 hours. After cooling, diethyl ether (5 ml) was added to the reaction solution, and the resulting powder was collected by filtration. The obtained powder was purified by octadecyl silica (ODS) column chromatography (eluent: methanol / water = 3/2) to give 1-[(2R, 3R) -2- (2,4-difluorophenyl). ) -2-Hydroxy-3- [2-oxo-3- [4- (1H-1,2,3-triazol-1-yl) phenyl] -1-imidazolidinyl] butyl] -4
-[(2,2-dimethylpropanoyloxy) methyl]
-1H-1,2,4-triazolium chloride (compound
1 , 0.10 g) was obtained as a white powder. ¹ H-NM
R (d ₆ -DMSO) δ: 0.97 (3H, d, J = 7 Hz), 1.13 (9H,
s), 3.61-4.10 (4H, m), 4.65-4.75 (1H, m), 4.89 (1H, d,
J = 14Hz), 5.13 (1H, d, J = 14Hz), 6.17 (2H, s), 6.74 (1H,
s), 6.91 ~ 7.01 (1H, m), 7.21 ~ 7.36 (2H, m), 7.82 ~ 7.93
(4H, m), 7.95 (1H, d, J = 1.2Hz), 8.79 (1H, d, J = 1.2Hz), 9.
11 (1H, s), 10.53 (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-
A mixture of [4- (1H-1,2,3-triazol-1-yl) phenyl] -2-imidazolidinone (0.5 g) and chloromethyl pivalate (3.1 g) was heated and stirred at 100 ° C. for 2 hours. did. After cooling, diisopropyl ether (10 ml) was added to the reaction solution, and the resulting powder was collected by filtration. The obtained powder was purified by silica gel flash chromatography (eluent: ethyl acetate → acetone → acetone / ethanol = 10/1 → acetone / ethanol = 5/1) to give 1-[(2R, 3R)-. 2- (2,4-difluorophenyl) -2-hydroxy-3- [2-oxo-3- [4- (1H-1,2,3-triazole-1-
Yl) phenyl] -1-imidazolidinyl] butyl]-
4-[(2,2-Dimethylpropanoyloxy) methyl] -1H-1,2,4-triazolium chloride (0.34 g of compound 1 ) was obtained as a white powder.

Example 3 1-[(1R, 2R) -2- (2,4-difluorophenyl)
Ru) -2-hydroxy-1-methyl-3- (1H-1,
2,4-Triazol-1-yl) propyl] -3-
[4- (1H-1,2,3-triazol-1-yl) phenyl
Enyl] -2-imidazolidinone (0.5 g) and chloro
A mixture of methyl pivalate (4.7 g) at 100 ° C.
The mixture was heated and stirred for 6 hours. After cooling, add diisopropyl
Then, the resulting powder was collected by filtration. Get
Powder obtained by CHP-20P column chromatography
(Eluent: water → 5% acetonitrile aqueous solution → 30% acetotrile
Tonitrile aqueous solution → 5% tetrahydrofuran aqueous solution → 1
0% tetrahydrofuran aqueous solution → 20% tetrahydrofuran
(Aqueous orchid solution) to give 1-[(2R, 3
R) -2- (2,4-Difluorophenyl) -2-hydrido
Roxy-3- [2-oxo-3- [4- [3- (2,2
-Dimethylpropanoyloxy) methyl-1 (1H)-
1,2,3-triazolio] phenyl] -1-imidazoli
Dinyl] butyl] -4-[(2,2-dimethylpropano
Yloxy) methyl] -1H-1,2,4-triazolyu
Mu dichloride (compound8, 134mg) and compound1
(141 mg) were obtained as white powders. Compound8:¹H-NMR (d₆-DMSO) δ: 0.97 (3H,
d, J = 6.8Hz), 1.13 (9H, s), 1.21 (9H, s), 3.63-3.66 (1H,
m), 3.98-4.15 (3H, m), 4.62-4.78 (1H, m), 4.88 (1H, d, J
= 14Hz), 5.23 (1H, d, J = 14Hz), 6.17 (2H, s), 6.64 (2H, s),
 6.88 (1H, s), 6.90-7.00 (1H, m), 7.21-7.36 (2H, m), 7.9
8 (2H, d, J = 9.8Hz), 8.05 (2H, d, J = 9.8Hz), 9.10 (1H, s),
9.34 (1H, d, J = 2.0Hz), 9.68 (1H, d, J = 2.0Hz), 10.64 (1H, d
s).

Example 4 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-Triazol-1-yl) propyl] -3-
[4- (1H-tetrazol-1-yl) phenyl]-
2-imidazolidinone (0.48 g) and acetone (10 m
To the mixture of l), add chloromethyl pivalate (2.9 ml)
Was added, and the mixture was refluxed and stirred. Chloromethyl after 88 hours
Pivalate (1.45 ml) was added, and the mixture was further refluxed and stirred for 14 hours. The reaction solution was concentrated under reduced pressure, diethyl ether (8 ml) was added to the residue, and the resulting powder was collected by filtration. The obtained powder is subjected to ODS column chromatography (eluent:
Purification by subjecting to methanol / water = 3/2) gave 1-
[(2R, 3R) -2- (2,4-difluorophenyl)
-2-Hydroxy-3- [2-oxo-3- [4- (1
H- tetrazol-1-yl) phenyl] -1-imidazolidinyl] butyl] -4 - [(2,2-dimethylpropanoyloxy) methyl]-1H-1,2,4-triazolium chloride (Compound 2, 0. 25g) was obtained as a white powder. ¹ H-NMR (d ₆ -DMSO) δ: 0.97 (3H, d, J = 7 Hz),
1.13 (9H, s), 3.61 ~ 4.09 (4H, m), 4.65 ~ 4.75 (1H, m), 4.
88 (1H, d, J = 14Hz), 5.14 (1H, d, J = 14Hz), 6.16 (2H, s), 6.
75 (1H, s), 6.91 ~ 7.01 (1H, m), 7.21 ~ 7.37 (2H, m), 7.90
(4H, s), 9.10 (1H, s), 10.07 (1H, s), 10.53 (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-
[4- (1H-tetrazol-1-yl) phenyl]-
2-imidazolidinone (0.5 g), chloromethyl pivalate (15.7 g) and acetonitrile (2.4 g)
Was stirred at 100 ° C. for 6.5 hours. After cooling, diisopropyl ether (10 ml) was added to the reaction solution, and the resulting powder was collected by filtration. The obtained powder is subjected to silica gel column chromatography (eluent: ethyl acetate → acetone →
Purification by acetone / ethanol = 10/1 → acetone / ethanol = 5/1) gave 1-[(2R, 3
R) -2- (2,4-Difluorophenyl) -2-hydroxy-3- [2-oxo-3- [4- (1H-tetrazol-1-yl) phenyl] -1-imidazolidinyl] butyl] -4 -[(2,2-dimethylpropanoyloxy) methyl] -1H-1,2,4-triazolium
Chloride (Compound 2 , 0.32 g) was obtained as a white powder. Compound 2 (0.4 g) was added to ethyl acetate (20 m
Crystallization from l) gave white crystals of compound 2 (0.3 g). Mp 196-197 ° C. (decomposition) Elemental analysis C ₂₈ H ₃₂ ClF Calculated _{2 N 9 O 4 (%)} : C, 53.21; H, 5.10; N, 19.94 Found (%): C, 53.17; H , 5.15; N, 19.76

Example 6 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-Triazol-1-yl) propyl] -3-
A mixture of [4- (1H-1,2,3-triazol-1-yl) phenyl] -2-imidazolidinone (0.30 g) and chloromethyl acetate (1.35 g) was added to 100 parts.
The mixture was heated and stirred at 24 ° C. for 24 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by ODS column chromatography (eluent: methanol / water = 3/2) to give 4-acetoxymethyl-1-[(2R, 3R) -2- ( 2,4-difluorophenyl) -2-hydroxy-3- [2-oxo-
3- [4- (1H-1,2,3-triazol-1-yl) phenyl] -1-imidazolidinyl] butyl] -1
H-1,2,4-triazolium chloride (compound 3 ,
45 mg) as a white powder. ¹ H-NMR (d ₆
−DMSO) δ: 0.97 (3H, d, J = 7 Hz), 2.08 (3H, s), 3.61
~ 4.08 (4H, m), 4.65 ~ 4.75 (1H, m), 4.86 (1H, d, J = 14Hz),
5.11 (1H, d, J = 14Hz), 6.07 ~ 6.20 (2H, m), 6.69 (1H, s),
6.96 ~ 7.05 (1H, m), 7.25 ~ 7.36 (2H, m), 7.82 ~ 7.95 (5H, m
m), 8.78 (1H, s), 9.06 (1H, s), 10.46 (1H, s).

Example 7 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-Triazol-1-yl) propyl] -3-
To a mixture of [4- (1H-1,2,3-triazol-1-yl) phenyl] -2-imidazolidinone (0.63 g) and acetonitrile (20 ml) was added chloromethyl isobutyrate (1.71 g). The mixture was stirred under reflux for 130 hours. The reaction solution was concentrated under reduced pressure, diisopropyl ether (10 ml) was added to the residue, and the resulting powder was collected by filtration. The obtained powder is subjected to ODS column chromatography (eluent:
(Methanol / water = 3/2) for purification. After the effluent was concentrated under reduced pressure, the residue was dissolved in water (20 ml) and lyophilized to give 1-[(2R, 3R) -2- (2,4-difluorophenyl) -2-hydroxy-3- [ 2-oxo-3- [4- (1H-1,2,3-triazol-1-yl) phenyl] -1-imidazolidinyl] butyl] -4
-[(2-methylpropanoyloxy) methyl] -1H
-1,2,4-triazolium chloride (compound 4 ,
0.335 g) was obtained as a white powder. ¹ H-NMR (d ₆ -DMSO) δ: 0.97 (3H, d, J = 7 Hz),
1.07 (6H, d, J = 7Hz), 2.59 (1H, quintet, J = 7Hz), 3.60
~ 4.09 (4H, m), 4.65 ~ 4.75 (1H, m), 4.87 (1H, d, J = 14Hz),
5.10 (1H, d, J = 14Hz), 6.10 ~ 6.22 (2H, m), 6.69 (1H, s),
6.93 to 7.02 (1H, m), 7.23 to 7.35 (2H, m), 7.82 to 7.93 (4H,
m), 7.95 (1H, s), 8.78 (1H, s), 9.08 (1H, s), 10.48 (1H,
s).

Example 8 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-Triazol-1-yl) propyl] -3-
[4- (1H-tetrazol-1-yl) phenyl]-
2-imidazolidinone (0.50 g) and acetone (20 m
l) to the mixture of chloromethyl isobutyrate (1.3
7 g) was added and the mixture was stirred under reflux for 50 hours. The reaction solution was concentrated under reduced pressure, diisopropyl ether (10 ml) was added to the residue, and the resulting powder was collected by filtration. The obtained powder was subjected to ODS column chromatography (eluent: methanol / water = 3 /
Purified by 2). After the effluent was concentrated under reduced pressure, the residue was dissolved in water (20 ml) and lyophilized to give 1-
[(2R, 3R) -2- (2,4-difluorophenyl)
-2-Hydroxy-3- [2-oxo-3- [4- (1
H-tetrazol-1-yl) phenyl] -1-imidazolidinyl] butyl] -4-[(2-methylpropanoyloxy) methyl] -1H-1,2,4-triazolium chloride (Compound 5 , 0.15 g) Was obtained as a white powder. ¹ H-NMR (d ₆ -DMSO) δ: 0.97 (3H,
d, J = 7Hz), 1.07 (6H, d, J = 7Hz), 2.59 (1H, quintet, J = 7H
z), 3.61 ~ 4.08 (4H, m), 4.65 ~ 4.75 (1H, m), 4.87 (1H, d,
J = 14Hz), 5.11 (1H, d, J = 14Hz), 6.14 ~ 6.22 (2H, m), 6.69
(1H, s), 6.92 ~ 7.03 (1H, m), 7.22 ~ 7.37 (2H, m), 7.90 (4
H, s), 9.09 (1H, s), 10.08 (1H, s), 10.48 (1H, s). The product (50 mg) was crystallized from physiological saline (1 ml) to give Compound 5 To obtain 41 mg of white powdery crystals. Melting point 217-219
° C. (decomposition) Elemental analysis _{C 27 H 30 ClF 2 N 9} O 4 · 0.5H 2 O Calculated (%): C, 51.72; H, 4.98; N, 20.10 Found (%): C, 51.79 H, 4.83; N, 20.04

Example 9 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-Triazol-1-yl) propyl] -3-
Acetonitrile (0.5 ml) was added to a mixture of [4- (1H-1,2,3-triazol-1-yl) phenyl] -2-imidazolidinone (100 mg) and 1-chloroethyl ethyl carbonate (1.0 g). In addition, 60 at 85 ° C
Stirred for hours. After cooling, diisopropyl ether (4 ml) was added to the reaction solution, and the resulting powder was collected by filtration. The obtained powder was purified by ODS column chromatography (eluent: methanol / water = 3/2). After concentrating the effluent under reduced pressure, the residue was dissolved in water (10 ml) and lyophilized to give 1-[(2R, 3R) -2- (2,4-difluorophenyl) -2-hydroxy-3- [ 2-oxo-3-
[4- (1H-1,2,3-triazol-1-yl) phenyl] -1-imidazolidinyl] butyl] -4- [1
-(Ethoxycarbonyloxy) ethyl] -1H-1,
2,4-triazolium chloride (compound 6 , 36 mg)
Was obtained as a white powder. ¹ H-NMR (d ₆ -DMS
O) δ: 0.97 (3H, d, J = 7 Hz), 1.21, 1.22 (3H, t, J = 7 Hz),
1.80 (3H, d, J = 6Hz), 3.61 ~ 4.25 (6H, m), 4.63 ~ 5.09 (3H,
m), 6.67-6.83 (2H, m), 6.94-7.03 (1H, m), 7.21-7.37
(2H, m), 7.82 to 8.05 (5H, m), 8.79 (1
H, s), 9.22 (0.5H, s), 9.27
(0.5H, s), 10.70 (0.5H, s),
10.80 (0.5H, s).

Example 10 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-Triazol-1-yl) propyl] -3-
[4- (1H-tetrazol-1-yl) phenyl]-
Acetonitrile (1 ml) was added to a mixture of 2-imidazolidinone (0.61 g) and 1-chloroethyl ethyl carbonate (3.7 g), and the mixture was stirred at 95 ° C for 38 hours. The reaction solution was concentrated under reduced pressure, diisopropyl ether (10 ml) was added to the residue, and the resulting powder was collected by filtration. The obtained powder was purified by ODS column chromatography (eluent: methanol / water = 3/2). After the effluent was concentrated under reduced pressure, the residue was dissolved in water (10 ml) and lyophilized to give 1-[(2R, 3R) -2- (2,4-difluorophenyl) -2-hydroxy-3- [ 2-oxo-
3- [4- (1H-tetrazol-1-yl) phenyl] -1-imidazolidinyl] butyl] -4- [1-
(Ethoxycarbonyloxy) ethyl] -1H-1,2,
4-Triazolium chloride (Compound 7 , 90 mg) was obtained as a white powder. ¹ H-NMR (d ₆ -DMS
O) δ: 0.97 (3H, d, J = 7 Hz), 1.21, 1.22 (3H, t, J = 7 Hz),
1.79,1.80 (3H, d, J = 6Hz), 3.62-4.23 (6H, m), 4.65-5.1
0 (3H, m), 6.69 ~ 6.82 (2H, m), 6.94 ~ 7.04 (1H, m), 7.26
~ 7.38 (2H, m), 7.90 (4H, s), 9.23 (0.5H, s), 9.27 (0.5H,
s), 10.08 (1H, s), 10.72 (0.5H, s), 10.82 (0.5H, s).

Example 11 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-Triazol-1-yl) propyl] -3-
A mixture of [4- (1H-1,2,3-triazol-1-yl) phenyl] -2-imidazolidinone (0.5 g), chloromethyl isopropyl carbonate (3.2 g) and acetonitrile (1 ml) was prepared. The mixture was heated and stirred at 100 ° C. for 25 hours. After cooling, diisopropyl ether (10 ml) was added to the reaction solution, and the resulting powder was collected by filtration and subjected to silica gel column chromatography (eluent: ethyl acetate → acetone → acetone / ethanol = 10/1 → acetone / ethanol = 5/1). Attached. The residue obtained by evaporating the solvent under reduced pressure was recrystallized from ethyl acetate, dissolved in water (10 ml), and the aqueous solution was lyophilized to give 1-[(2R, 3R)-
2- (2,4-difluorophenyl) -2-hydroxy-3- [2-oxo-3- [4- (1H-1,2,3-triazol-1-yl) phenyl] -1-imidazolidinyl] butyl ] -4-[(Isopropoxycarbonyloxy) methyl] -1H-1,2,4-triazolium chloride (Compound 9 , 0.18 g) was obtained as a white powder. ¹ H-NMR (d ₆ -DMSO) δ: 0.98 (3H, d, J = 7
Hz), 1.24 (6H, d, J = 6.4Hz), 3.52-3.67 (1H, m), 3.93-4.0
0 (3H, m), 4.69 (1H, q, J = 7Hz), 4.80 (1H, quintet, J = 6.4H
z), 4.88 (1H, d, J = 13.8Hz), 5.05 (1H, d, J = 13.8Hz), 6.12
(1H, d, J = 10.8Hz), 6.20 (1H, d, J = 10.8Hz), 6.98-7.03 (1
H, m), 7.23-7.36 (2H, m), 7.84 (2H, d, J = 8Hz), 7.91 (2H,
d, J = 8Hz), 7.94 (1H, d, J = 1Hz), 8.77 (1H, d, J = 1Hz), 9.10
(1H, s), 10.38 (1H, s). A freeze-dried product of the above compound 9 (0.05 g) was crystallized from acetonitrile (3 ml) to give a white crystal of compound 9 (0.1 g).
01g). Elemental analysis _{C 28 H 31 ClF 2 N 8} O 5 · H 2 O Calculated (%): C, 51.65; H, 5.11; N, 17.21 Found (%): C, 51.64; H, 4.68; N , 17.06

Example 12 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-Triazol-1-yl) propyl] -3
To a mixture of-[4- (1H-1,2,3-triazol-1-yl) phenyl] -2-imidazolidinone (0.5 g) and acetonitrile (10 ml) was added bromomethyl acetate.
(0.1 ml), and the mixture was heated and stirred at 50 ° C. for 24 hours. The reaction solution was subjected to silica gel flash chromatography (silica gel:
25 g, eluent: ethyl acetate → acetone → acetone / ethanol = 10/1), and the residue was crystallized from ethanol to give 4-acetoxymethyl-1-[(2
R, 3R) -2- (2,4-difluorophenyl) -2
-Hydroxy-3- [2-oxo-3- [4- (1H-
1,2,3-triazol-1-yl) phenyl] -1
-Imidazolidinyl] butyl] -1H-1,2,4-triazolium bromide (Compound 10 , 0.135 g) was obtained as colorless crystals. ¹ H-NMR (d ₆ -DMSO) δ: 0.98 (3H, d, J = 7Hz), 2.08 (3H, s),
3.62-4.08 (4H, m), 4.66-4.75 (1H, m), 4.87 (1H, d, J = 14
Hz), 4.99 (1H, d, J = 14Hz), 6.07-6.21 (2H, m), 6.34 (1H,
s), 6.96- 7.07 (1H, m), 7.24-7.35 (2H, m), 7.83-7.94
(5H, m), 8.80 (1H, s), 9.09 (1H, s), 10.24 (1H, s)

Example 13 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-Triazol-1-yl) propyl] -3
-[4- (1H-tetrazol-1-yl) phenyl]
-2-Imidazolidinone (0.5g) and acetonitrile (10ml)
Bromomethyl acetate (0.2 ml) was added to the mixture of
The mixture was heated and stirred at 50 ° C. for 16 hours. The reaction mixture was purified by silica gel flash chromatography (silica gel: 25 g, eluent: ethyl acetate → acetone → acetone / ethanol = 10/1), and the residue was crystallized from ethanol.
4-acetoxymethyl-1-[(2R, 3R) -2-
(2,4-difluorophenyl) -2-hydroxy-3
-[2-oxo-3- [4- (1H-tetrazole-
1-yl) phenyl] -1-imidazolidinyl] butyl] -1H-1,2,4-triazolium bromide (compound 11 , 0.39 g) was obtained as colorless crystals. ¹ H-NMR (d ₆ -DMSO) δ: 0.99 (3H, d, J = 7Hz), 2.09 (3H, s),
3.64-4.08 (4H, m), 4.68-4.72 (1H, m), 4.86 (1H, d, J =
14Hz), 5.01 (1H, d, J = 14Hz), 6.07-6.21 (2H, m), 6.35 (1
H, s), 7.00- 7.09 (1H, m), 7.28-7.38 (2H, m), 7.91 (4H,
s), 9.10 (1H, s), 10.08 (1H, s), 10.28 (1H, s)

Example 14 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-Triazol-1-yl) propyl] -3
-[4- (1H-tetrazol-1-yl) phenyl]
-2-imidazolidinone (0.5 g) and acetonitrile (10 m
To the mixture obtained in l), iodomethyl (2,3,4,5-tetrahydrofurfuryl) carbonate (0.594 g) was added, and the mixture was heated with stirring at 50 ° C. for 15 hours. The reaction solution was purified by silica gel flash chromatography (eluent: ethyl acetate → acetone → acetone / ethanol = 10/1), and the target fraction was concentrated under reduced pressure. ODS column chromatography of the residue
(Eluent: methanol / water = 3/2), purified under reduced pressure, and lyophilized to give 1-[(2R, 3R) -2-
(2,4-difluorophenyl) -2-hydroxy-3
-[2-oxo-3- [4- (1H-tetrazole-1)
-Yl) phenyl] -1-imidazolidinyl] butyl]
-4-[(2,3,4,5-tetrahydrofurfuryl) oxycarbonyloxymethyl] -1H-1,2,4-triazolium iodide (Compound 30 , 0.4 g) was obtained as a colorless powder. Dissolve this product in water (15 ml) and add Dowex 1 × 8 (Cl ^- type)
And then concentrate the target fraction under reduced pressure.
When freeze-dried, 1-[(2R, 3R) -2- (2,4
-Difluorophenyl) -2-hydroxy-3- [2-
Oxo-3- [4- (1H-tetrazol-1-yl)
Phenyl] -1-imidazolidinyl] butyl] -4-
[(2,3,4,5-Tetrahydrofurfuryl) oxycarbonyloxymethyl] -1H-1,2,4-triazolium chloride (Compound 21 , 0.24 g) was obtained as a colorless powder. ¹ H-NMR (d ₆ -DMSO) δ: 0.97 (3H, d, J = 7 Hz), 1.52-1.99 (4
H, m), 3.61-4.17 (9H, m), 4.67-4.82 (1H, m), 4.86 (1H, d,
J = 14Hz), 5.10 (1H, d, J = 14Hz), 6.11-6.25 (2H, m), 6.65
(1H, s), 6.69-7.06 (1H, m), 7.28-7.39 (2H, m), 7.90 (4H,
s), 9.10 (1H, s), 10.08 (1H, s), 10.47 (1H, s)

Example 15 4-acetoxymethyl-1-[(2R, 3R) -2-
(2,4-difluorophenyl) -2-hydroxy-3
-[2-oxo-3- [4- (1H-tetrazole-1)
-Yl) phenyl] -1-imidazolidinyl] butyl]
-1H-1,2,4-triazolium bromide (compound 11 , 0.81 g) was applied to Dowex 1x8 (Cl ^- form) (eluent: water) and lyophilized to give 4-acetoxymethyl- 1-
[(2R, 3R) -2- (2,4-difluorophenyl) -2-hydroxy-3- [2-oxo-3- [4-
(1H-tetrazol-1-yl) phenyl] -1-imidazolidinyl] butyl] -1H-1,2,4-triazolium chloride (Compound 12 , 0.61 g) was obtained as a white powder. ¹ H-NMR (d ₆ -DMSO) δ: 0.97 (3 H, d, J = 7.4 Hz), 2.08
(3 H, s), 3.62-3.66 (1H, m), 3.90-4.07 (3 H, m), 4.69
(1H, q, J = 7.4 Hz), 4.85 (1H, d, J = 14.6 Hz), 5.04 (1
H, d, J = 14.6Hz), 6.09 (1H, d, J = 11 Hz), 6.16 (1H, d, J
= 11 Hz), 6.55 (1H, s), 6.98-7.06 (1H, m), 7.23-7.38
(2 H, m), 7.90 (4 H, s), 9.06 (1H, s), 10.06 (1H, s),
10.34 (1H, s). The freeze-dried product of compound 12 obtained above (1.1 g) was recrystallized from ethanol (20 ml) to give white crystals of compound 12 (1
g) was obtained. Elemental analysis: C ₂₅ H ₂₆ ClF ₂ N ₉ O ₄ Calculated (%): C; 50.89, H; 4.44, N; 21.37, Cl; 6.01, Found (%): C; 50.61, H; 4.38, N; 21.24, Cl; 5.80. Dissolve the crystal of compound 12 (0.63 g) in water (10 ml), and add 0 ° C.
And left overnight to obtain a hydrate of compound 12 (0.61 g) as white crystals. Elemental analysis: calculated as C ₂₅ H ₂₆ ClF ₂ N ₉ O ₄ H ₂ O (%): C; 49.39, H; 4.64, N; 20.73, found (%): C; 49.56, H; 4.64, N ; 20.85.

Example 16 4-acetoxymethyl-1-[(2R, 3R) -2-
(2,4-difluorophenyl) -2-hydroxy-3
-[2-oxo-3- [4- (1H-tetrazole-1)
-Yl) phenyl] -1-imidazolidinyl] butyl]
1H-1,2,4-triazolium bromide (compound 11 , 0.5 g) was dissolved in tetrahydrofuran (100 ml), and the mixture was shaken with saturated saline (100 ml) and separated.
Repeated times. After the organic layer was dried over magnesium sulfate, the residue obtained by evaporation under reduced pressure was recrystallized from ethanol (5 ml) to give 4-acetoxymethyl-1-[(2R, 3R)
-2- (2,4-difluorophenyl) -2-hydroxy-3- [2-oxo-3- [4- (1H-tetrazol-1-yl) phenyl] -1-imidazolidinyl] butyl] -1H-1 , 2,4-triazolium chloride
(Compound 12 , 0.28 g) was obtained as white crystals. This product had the same physicochemical properties as the crystals of Compound 12 crystallized from ethanol in Example 15.

Example 17 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-Triazol-1-yl) propyl] -3
-[4- (1H-tetrazol-1-yl) phenyl]
-2- A mixture of imidazolidinone (1 g) and iodomethyl acetate (0.8 g) was treated with acetonitrile (15 ml).
The mixture was heated and stirred at 50-55 ° C for 15 hours. The residue obtained by evaporating the solvent under reduced pressure was treated with tetrahydrofuran (100 ml)
Saline solution containing a small amount of sodium thiosulfate
(100 ml) and then washed with saturated saline (100 ml).
Washed twice. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure.
(Eluent: ethyl acetate → acetone → acetone / ethanol = 10/1 → acetone / ethanol = 5/1). The residue obtained by evaporating the solvent under reduced pressure is ethanol
(10 ml) was crystallized from 4-acetoxymethyl-
1-[(2R, 3R) -2- (2,4-difluorophenyl) -2-hydroxy-3- [2-oxo-3- [4
-(1H-tetrazol-1-yl) phenyl] -1-
[Imidazolidinyl] butyl] -1H-1,2,4-triazolium chloride (Compound 12 , 0.44 g) was obtained as white crystals. This product had the same physicochemical properties as the crystals of Compound 12 crystallized from ethanol in Example 15.

Example 18 4-acetoxymethyl-1-[(2R, 3R) -2-
(2,4-difluorophenyl) -2-hydroxy-3
-[2-oxo-3- [4- (1H-1,2,3-triazol-1-yl) phenyl] -1-imidazolidinyl] butyl] -1H-1,2,4-triazolium bromide (compound 10 , 0.03 g) was applied to Dowex 1 × 8 (Cl ⁻ form) (eluent: water) and lyophilized to give 4-acetoxymethyl-1-[(2R, 3R) -2- (2,4-difluorophenyl). ) -2-Hydroxy-3- [2-oxo-
3- [4- (1H-1,2,3-triazol-1-yl) phenyl] -1-imidazolidinyl] butyl] -1
H-1,2,4-triazolium chloride (compound
3 , 0.02 g) as a white powder. Elemental analysis: C ₂₆ H ₂₇ ClF ₂ N ₈ O ₄ 2H ₂ O Calculated: C; 49.96, H; 5.00, N; 17.93, Cl; 5.67, Found: C; 49.98, H; 4.57, N; 17.95 , Cl; 6.04.

Example 19 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-Triazol-1-yl) propyl] -3
-[4- (1H-tetrazol-1-yl) phenyl]
-2-Imidazolidinone (0.5 g), chloromethyl propyl carbonate (3.2 g) and acetonitrile (1 m
The mixture of l) was heated and stirred at 100 ° C. for 12 hours. After cooling, diisopropyl ether (10 ml) was added to the reaction mixture, and the resulting powder was collected by filtration. ). The residue obtained by evaporating the solvent under reduced pressure is further subjected to ODS column chromatography (eluent: methanol / water = 3
/ 2) to give 1-[(2R, 3R) -2- (2,
4-difluorophenyl) -2-hydroxy-3- [2
-Oxo-3- [4- (1H-tetrazol-1-yl) phenyl] -1-imidazolidinyl] butyl] -4
-Propoxycarbonyloxymethyl-1H-1,2,2
4-triazolium chloride (Compound 19 , 0.02 g)
Was obtained as a white powder. ¹ H-NMR (d ₆ -DMSO) δ: 0.88 (3 H, t, J = 7.8 Hz), 0.97
(3 H, d, J = 7.0 Hz), 1.62 (2 H, tq, J = 7.8 Hz), 3.63-3.
67 (1H, m), 3.80-4.05 (3 H, m), 4.09 (2 H, t, J = 7.8 H
z), 4.69 (1H, q, J = 7.0 Hz), 4.88 (1H, d, J = 14.4 Hz),
5.05 (1H, d, J = 14.4 Hz), 6.13 (1H, d, J = 10.6 Hz),
6.21 (1H, d, J = 10.6 Hz), 6.52 (1H, s), 6.94-7.02
(1H, m), 7.24-7.33 (2 H, m), 7.90 (4 H, s), 9.10 (1
H, s), 10.05 (1H, s), 10.39 (1H, s).

Example 20 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-Triazol-1-yl) propyl] -3
-[4- (1H-tetrazol-1-yl) phenyl]
A mixture of -2-imidazolidinone (1 g) and iodomethyl propyl carbonate (0.9 g) was heated and stirred at 50-55 ° C for 12 hours in acetonitrile (15 ml).
Silica gel chromatography (eluent: ethyl acetate / hexane = 5/1 → ethyl acetate → acetone → acetone / ethanol = 10/1 → acetone / ethanol = 5/1) and ODS column chromatography (eluent: methanol / Water = 3/2) and purified by 1-[(2R, 3R) -2- (2,4-difluorophenyl) -2-hydroxy-3- [2-oxo-3- [4
-(1H-tetrazol-1-yl) phenyl] -1-
Imidazolidinyl] butyl] -4-propoxycarbonyloxymethyl-1H-1,2,4-triazolium
Iodide (Compound 20 , 1 g) was obtained as a pale yellow powder. ¹ H-NMR (d ₆ -DMSO) δ: 0.88 (3 H, t, J = 7.2 Hz), 0.98
(3 H, d, J = 7.2 Hz), 1.61 (2 H, tq, J = 7.2 Hz), 3.50-3.
70 (1H, m), 3.84-4.13 (3 H, m), 4.09 (2 H, t, J = 7.2
Hz), 4.68 (1H, q, J = 7.2 Hz), 4.86 (1H, d, J = 13.8 H
z), 4.96 (1H, d, J = 13.8 Hz), 6.12 (1H, d, J = 11 Hz),
6.20 (1H, d, J = 11 Hz), 6.33 (1H, s), 6.97-7.07 (1H,
m), 7.21-7.38 (2 H, m), 7.90 (4 H, s), 9.11 (1H, s),
10.05 (1H, s), 10.21 (1H, s).

Example 21 1-[(2R, 3R) -2- (2,4-difluorophenyl) -2-hydroxy-3- [2-oxo-3- [4
-(1H-tetrazol-1-yl) phenyl] -1-
Imidazolidinyl] butyl] -4-propoxycarbonyloxymethyl-1H-1,2,4-triazolium
Iodide (compound 20 , 0.3 g) was added to tetrahydrofuran /
The residue was dissolved in a mixture of ethyl acetate (3/1) (100 ml) and washed four times with a saturated saline solution (50 ml). The organic layer was dried over magnesium sulfate and evaporated under reduced pressure.
Crystallization from acetone gives 1-[(2R, 3R) -2-
(2,4-difluorophenyl) -2-hydroxy-3
-[2-oxo-3- [4- (1H-tetrazole-1)
-Yl) phenyl] -1-imidazolidinyl] butyl]
-4-propoxycarbonyloxymethyl-1H-1,
2,4-triazolium chloride (compound 19 , 0.09
g) was obtained as a white powder. Elemental analysis _{C 27 H 30 ClF 2 N 9} O 5 0.5H 2 O Calculated: C; 50.43, H; 4.86 , N; 19.60, Cl; 5.51, Found: C; 50.25, H; 4.71 , N; 19.31, Cl; 5.42.

Example 22 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-Triazol-1-yl) propyl] -3
-[4- (1H-1,2,3-triazol-1-yl) phenyl] -2-imidazolidinone (0.80 g)
Acetonitrile (1.6 ml) was added to a mixture of and chloromethyl propanate (4.07 g), followed by stirring at 100 ° C. for 12 hours under an argon atmosphere. The reaction solution was concentrated under reduced pressure,
Diisopropyl ether (8 ml) was added to the residue, and the resulting powder was collected by filtration. The resulting powder was subjected to silica gel flash chromatography (eluent: ethyl acetate → acetone → acetone / ethanol = 9/1 → 4/1), and the target fraction was concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: methanol / water = 3/2). The effluent was concentrated under reduced pressure, dissolved in water (10 ml), and lyophilized to give 1-[(2R, 3R) -2-.
(2,4-difluorophenyl) -2-hydroxy-3
-[2-oxo-3- [4- (1H-1,2,3-triazol-1-yl) phenyl] -1-imidazolidinyl] butyl] -4-propanoyloxymethyl-1H-
1,2,4-triazolium chloride (compound 13 ,
0.11 g) was obtained as a white powder. ¹ H-NMR (d ₆ -DMSO) δ: 0.92-1.12 (6H, m),
2.25-2.55 (2H, m), 3.60-4.10 (4H, m), 4.64-4.75 (1H,
m), 4.86 (1H, d, J = 14Hz), 5.08 (1H, d, J = 14Hz), 6.09-6.
21 (2H, m), 6.64 (1H, s), 6.96 ~ 7.06 (1H, m), 7.22 ~ 7.42
(2H, m), 7.80 ~ 8.02 (5H, m), 8.80 (1H, brs), 9.07 (1H,
s), 10.42 (1H, s).

Example 23 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-Triazol-1-yl) propyl] -3
-[4- (1H-tetrazol-1-yl) phenyl]
-2-Imidazolidinone (0.80 g) and chloromethyl
Acetonitrile (1.6 ml) was added to a mixture of propanate (4.07 g), and the mixture was heated at 100 ° C. under an argon atmosphere.
Stirred for 0 hours. The reaction solution was concentrated under reduced pressure, diisopropyl ether (8 ml) was added to the residue, and the resulting powder was collected by filtration. The resulting powder was subjected to silica gel flash chromatography (eluent: ethyl acetate → acetone → acetone / ethanol = 9/1 → 5/1), and the target fraction was concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: methanol / water = 3/2). After the effluent was concentrated under reduced pressure, the residue was dissolved in water (10 ml) and lyophilized to give 1-[(2R, 3R) -2- (2,2).
4-difluorophenyl) -2-hydroxy-3- [2
-Oxo-3- [4- (1H-tetrazol-1-yl) phenyl] -1-imidazolidinyl] butyl] -4
-Propanoyloxymethyl-1H-1,2,4-triazolium chloride (Compound 14 , 0.04 g) was obtained as a white powder. ¹ H-NMR (d ₆ -DMSO) δ: 0.97 (3H, d, J = 7 Hz),
1.01 (3H, t, J = 7.4Hz), 2.38 (2H, q, J = 7.4Hz), 3.61 ~ 4.09
(4H, m), 4.65-4.75 (1H, m), 4.86 (1H, d, J = 14Hz), 5.08 (1
H, d, J = 14Hz), 6.11 (1H, d, J = 11Hz), 6.19 (1H, d, J = 11Hz),
6.61 (1H, s), 6.96 ~ 7.06 (1H, m), 7.25 ~ 7.49 (2H, m),
7.90 (4H, s), 9.07 (1H, s), 10.07 (1H, s), 10.40 (1H, s).

Example 24 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-Triazol-1-yl) propyl] -3
-[4- (1H-1,2,3-triazol-1-yl) phenyl] -2-imidazolidinone (0.50 g)
Acetonitrile (0.5 ml) was added to a mixture of chloromethyl ethyl carbonate (2.9 g) and chloromethyl ethyl carbonate (2.9 g).
For 22 hours. The reaction solution was concentrated under reduced pressure, diisopropyl ether (10 ml) was added to the residue, and the resulting powder was collected by filtration. The obtained powder is subjected to silica gel flash chromatography (eluent: ethyl acetate / acetone = 1/1).
→ acetone → acetone / ethanol = 9/1 → 4/1)
And the target fraction was concentrated under reduced pressure. The residue was subjected to ODS column chromatography (eluent: methanol / water = 3 /
After purification by 2), the residue was dissolved in water (15 ml) and lyophilized to give 1-[(2R, 3R) -2- (2,4-difluorophenyl) -2-hydroxy-3- [2- Oxo-3- [4- (1H-1,2,3-triazole-1-
Yl) phenyl] -1-imidazolidinyl] butyl]-
4-ethoxycarbonyloxymethyl-1H-1,2,2
4-triazolium chloride (compound 15 , 0.14
g) was obtained as a white powder. ¹ H-NMR (d ₆ -DMSO) δ: 0.97 (3H, d, J = 7 Hz),
1.22 (3H, t, J = 7Hz), 3.60 ~ 4.08 (4H, m), 4.18 (2H, q, J = 7H
z), 4.63 ~ 4.73 (1H, m), 4.87 (1H, d, J = 14Hz), 5.10 (1H, m
d, J = 14Hz), 6.13 (1H, d, J = 11Hz), 6.21 (1H, d, J = 11Hz),
6.65 (1H, s), 6.96 ~ 7.04 (1H, m), 7.24 ~ 7.37 (2H, m), 7.
82 ~ 7.95 (5H, m), 8.78 (1H, d, J = 1Hz), 9.09 (1H, s), 10.4
8 (1H, s).

Example 25 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-Triazol-1-yl) propyl] -3
-[4- (1H-tetrazol-1-yl) phenyl]
Acetonitrile (20 ml) was added to a mixture of -2-imidazolidinone (1.31 g) and ethyl iodomethyl carbonate (1.25 g), and the mixture was added under an argon atmosphere.
Stirred at C for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel flash chromatography (eluent: ethyl acetate → acetone → acetone / ethanol = 4/1).
And the target fraction was concentrated under reduced pressure. The residue was subjected to ODS column chromatography (eluent: methanol / water = 3 /
Purification by 2) gives 1-[(2R, 3R) -2-
(2,4-difluorophenyl) -2-hydroxy-3
-[2-oxo-3- [4- (1H-tetrazole-1)
-Yl) phenyl] -1-imidazolidinyl] butyl]
-4-ethoxycarbonyloxymethyl-1H-1,
2,4-triazolium iodide (compound 17 , 1.1
g) was obtained as a pale yellow powder. ¹ H-NMR (d ₆ -DMSO) δ: 0.99 (3H, d, J = 7 Hz),
1.23 (3H, t, J = 7Hz), 3.64-4.05 (4H, m), 4.19 (2H, q, J = 7H
z), 4.64-4.74 (1H, m), 4.87 (1H, d, J = 14Hz), 4.97 (1H, m
d, J = 14Hz), 6.13 (1H, d, J = 11Hz), 6.21 (1H, d, J = 11Hz),
6.33 (1H, br), 6.99-7.07 (1H, m), 7.22-7.39 (2H, m), 7.9
1 (4H, s), 9.12 (1H, s), 10.06 (1H, s), 10.23 (1H, s).

Example 26 1-[(2R, 3R) -2- (2,4-difluorophenyl) -2-hydroxy-3- [2-oxo-3- [4
-(1H-tetrazol-1-yl) phenyl] -1-
Imidazolidinyl] butyl] -4-ethoxycarbonyloxymethyl-1H-1,2,4-triazolium iodide (Compound 17 , 1.10 g) was subjected to ion exchange chromatography (DOWEX 1 × 8, Cl ^- type, 300 m).
l), the target fraction was concentrated under reduced pressure, and recrystallized from ethanol to give 1-[(2R, 3R) -2- (2,4-
Difluorophenyl) -2-hydroxy-3- [2-oxo-3- [4- (1H-tetrazol-1-yl) phenyl] -1-imidazolidinyl] butyl] -4-ethoxycarbonyloxymethyl-1H-1, 2,4-Triazolium chloride (Compound 16 , 0.70 g) was obtained as colorless powdery crystals. ¹ H-NMR (d ₆ -DMSO) δ: 0.97 (3H, d, J = 7 Hz),
1.22 (3H, t, J = 7Hz), 3.60-4.08 (4H, m), 4.18 (2H, q, J = 7H
z), 4.63-4.73 (1H, m), 4.87 (1H, d, J = 14Hz), 5.10 (1H, d,
J = 14Hz), 6.13 (1H, d, J = 11Hz), 6.21 (1H, d, J = 11Hz), 6.6
6 (1H, s), 6.96-7.04 (1H, m), 7.24-7.36 (2H, m), 7.90
(4H, s), 9.09 (1H, s), 10.07 (1H, s), 10.48 (1H, s).

Example 27 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy
-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (1H-tetrazol-1-yl) phenyl] -2-imidazolidinone (0.5 g ), Chloromethyl isopropyl
A mixture of carbonate (3.17 g) and acetonitrile (1 ml) was heated and stirred at 100 ° C. for 6 hours. After cooling, add diisopropyl ether (10 ml) to the reaction solution, filter the resulting powder, and chromatograph on silica gel (eluent: ethyl acetate → acetone → acetone / ethanol = 10/1 → acetone / ethanol = 5/1). Attached. The residue obtained by evaporating the solvent under reduced pressure was crystallized from ethanol-acetone,
[(2R, 3R) -2- (2,4-difluorophenyl) -2-hydroxy-3
-[2-oxo-3- [4- (1H-tetrazol-1-yl) phenyl]-
1-Imidazolidinyl] butyl] -4- (isopropoxycarbonyloxy) methyl-1H-1,2,4-triazolium chloride (Compound 18 , 110 mg) was obtained as white powdery crystals. ¹ H-NMR (d ₆ -DMSO) δ: 0.98 (3 H, d, J = 7.4 Hz), 1.24
(6 H, d, J = 6.2 Hz), 3.62-3.66 (1H, m), 3.98-4.0 (3
H, m), 4.69 (1H, q, J = 7.4 Hz), 4.80 (1H, quintet, J =
6.2 Hz), 4.87 (1H, d, J = 14.4 Hz), 5.04 (1H, d, J = 1
4.4 Hz), 6.11 (1H, d, J = 11 Hz), 6.19 (1H, d, J = 11 H
z), 6.51 (1H, s), 6.96-7.03 (1H, m), 7.22-7.38 (2 H,
m), 7.90 (4 H, s), 9.10 (1H, s), 10.06 (1H, s), 10.36
(1H, s).

Example 28 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy
-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (1H-tetrazol-1-yl) phenyl] -2-imidazolidinone (2.5 g ) And (1,3-dioxan-5-yl)
A mixture of iodomethyl carbonate (3 g) was stirred with heating in acetonitrile (40 ml) at 50-55 ° C. for 12 hours. Silica gel chromatography of the reaction solution (eluent: ethyl acetate / hexane = 1/1 → ethyl acetate / hexane
= 10/1 → ethyl acetate → acetone → acetone / ethanol
= 5/1) to give 1-[(2R, 3R) -2- (2,4-difluorophenyl) -2-hydroxy-3- [2-oxo-3- [4- (1H -
Tetrazol-1-yl) phenyl] -1-imidazolidinyl]
Butyl] -4-[(1,3-dioxan-5-yl) oxycarbonyloxymethyl] -1H-1,2,4-triazolium iodide
(Compound 31 , 4.22 g) was obtained as a yellow powder. ¹ H-NMR (d ₆ -DMSO) δ: 0.98 (3 H, d, J =
7 Hz), 3.55-3.75 (1H, m),
3.87-4.02 (7H, m), 4.50-
4.58 (1H, m), 4.67-4.93 (5
H, m), 6.16 (1H, d, J = 11H
z), 6.24 (1H, d, J = 11 Hz),
6.33 (1H, s), 6.97-7.07
(1H, m), 7.21-7.39 (2H,
m), 7.90 (4 H, s), 9.12 (1
H, s), 10.05 (1H, s), 10.23
(1H, s).

Example 29 1-[(2R, 3R) -2- (2,4-difluorophenyl) -2-hydroxy-3- [2-oxo-3- [4- (1H-tetrazol-1-yl) ) Phenyl] -1-imidazolidinyl] butyl] -4-
[(1,3-dioxan-5-yl) oxycarbonyloxymethyl] -1H-1,2,4-triazolium iodide (compounds 31 and 1
g) was applied to Dowex 1 × 8 (Cl ⁻ form) (eluent: water) and lyophilized to give 1-[(2R, 3R) -2- (2,4-difluorophenyl) -2-hydroxy- 3- [2-oxo-3- [4- (1H-tetrazole
-1-yl) phenyl] -1-imidazolidinyl] butyl] -4-
[(1,3-Dioxan-5-yl) oxycarbonyloxymethyl] -1H-1,2,4-triazolium chloride (compound 22 , 0.
23 g) was obtained as a white powder. ¹ H-NMR (d ₆ -DMSO) δ: 0.97 (3 H, d, J = 6.6 Hz), 3.63-
3.66 (1H, m), 3.87-4.02 (7 H, m), 4.52-4.59 (1H, m),
4.60-5.11 (5 H, m), 6.17 (1H, d, J = 11 Hz), 6.25 (1H, m
d, J = 11 Hz), 6.59 (1H, s), 6.97-7.04 (1H, m), 7.23-
7.40 (2 H, m), 7.90 (4H, s), 9.11 (1H, s), 10.06 (1H,
s), 10.44 (1H, s). A freeze-dried product of the above compound 22 (0.15 g) was crystallized from ethanol (20 ml) to give white crystals of compound 22 (0.14 g). Elemental _{analysis: C 28 H 30 ClF 2 N} 9 O 7 Calculated (%): C, 49.60; H, 4.46; N, 18.59 Found (%): C, 49.60; H, 4.46; N, 18.40

Example 30 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy
-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (1H-tetrazol-1-yl) phenyl] -2-imidazolidinone (0.50 g ) And chloromethyl [(1S) -1- (ethoxycarbonyl) ethyl] carbonate (1.09 g) were added with acetonitrile (5 ml), and the mixture was stirred at 95 ° C for 68 hours.
The reaction solution was concentrated under reduced pressure, and diisopropyl ether was added to the residue.
(6 ml) was added and the resulting powder was collected by filtration. The resulting powder was subjected to silica gel flash chromatography (eluent: ethyl acetate → ethyl acetate / acetone = 1/1 → acetone → acetone / ethanol = 5/1), and the target fraction was concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: methanol / water = 3/2). After concentrating the effluent, dissolving in water (50 ml) and freeze-drying, 1-[(2R, 3R)
-2- (2,4-difluorophenyl) -2-hydroxy-3- [2-oxo-3- [4- (1H-tetrazol-1-yl) phenyl] -1-imidazolidinyl] butyl] -4- [ [(1S) -1-Ethoxycarbonylethoxy] carbonyloxymethyl] -1H-1,2,4-triazolium chloride (Compound 23 , 0.22 g) was obtained as a white powder. ¹ H-NMR (d ₆ -DMSO) δ: 0.98 (3H, d, J = 7 Hz), 1.17 (3H, t, J = 7H
z), 1.43 (3H, d, J = 7Hz), 3.60-4.08 (4H, m), 4.14 (2H, q, J =
7Hz), 4.65-4.75 (1H, m), 4.86 (1H, d, J = 14Hz), 5.02 (1H, m
q, J = 7Hz), 5.11 (1H, d, J = 14Hz), 6.24 (2H, s), 6.65 (1H,
s), 6.95-7.05 (1H, m), 7.25-7.39 (2H, m), 7.90 (4H, s),
9.11 (1H, s), 10.07 (1H, s), 10.52 (1H, s)

Example 31 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy
-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (1H-tetrazol-1-yl) phenyl] -2-imidazolidinone (1.0 g ) And [(1S) -1- (benzyloxycarbonyl) ethyl] iodomethyl carbonate (1.53 g) was added with acetonitrile (15 ml), and the mixture was stirred at 60 ° C for 12 hours under an argon atmosphere. After concentrating the reaction solution under reduced pressure,
The residue was subjected to silica gel flash chromatography (eluent: ethyl acetate → acetone → acetone / ethanol = 4/1), and the target fraction was concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: methanol / water = 3/2), followed by ion exchange chromatography (DOWEX 1 ×
8, Cl ^- form) and the target fraction was concentrated under reduced pressure to give 1-[(2R, 3
R) -2- (2,4-Difluorophenyl) -2-hydroxy-3- [2-oxo-3- [4- (1H-tetrazol-1-yl) phenyl] -1-imidazolidinyl] butyl] -4 -[[(1S) -1- (benzyloxycarbonylethoxy] carbonyloxymethyl] -1H-1,2,4-
Triazolium chloride (Compound 24 , 0.25 g) was obtained as a white powder. ¹ H-NMR (d ₆ -DMSO) δ: 0.97 (3H, d, J = 7.0)
Hz), 1.45 (3H, d, J = 6.6 Hz),
3.60-4.08 (4H, m), 4.65-4.7
8 (1H, m), 4.85 (1H, d, J = 14H
z), 5.07-5.18 (4H, m), 6.23
(2H, s), 6.67 (1H, s), 6.95-
7.04 (1H, m), 7.24-7.37 (7H,
m), 7.9 (4H, s), 9.09 (1H,
s), 10.07 (1H, s), 10.53 (1
H, s)

Example 32 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl ) Propyl] -3- [4- (1H-tetrazol-1-yl)
Acetonitrile (20 ml) was added to a mixture of [phenyl] -2-imidazolidinone (2.0 g) and (3-benzyloxypropyl) iodomethyl carbonate (2.9 g), and the mixture was stirred at 50 to 55 ° C for 20 hours under an argon atmosphere. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in a mixture of ethyl acetate (100 ml) and tetrahydrofuran (50 ml), and shaken with a mixture of saturated saline (50 ml) and a 5% aqueous solution of sodium thiosulfate (0.1 ml). did. The organic layer was further washed with saturated saline (50 ml) four times, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel flash chromatography (eluent: ethyl acetate → acetone → acetone / ethanol = 4 /
In 1), the target fraction was concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: methanol / water = 3/2), followed by ion exchange chromatography (DOW
EX 1 × 8, Cl ^- type), and the target fraction was concentrated under reduced pressure to give 1-
[(2R, 3R) -2- (2,4-difluorophenyl) -2-hydroxy-3
-[2-oxo-3- [4- (1H-tetrazol-1-yl) phenyl]-
1-Imidazolidinyl] butyl] -4-[(3-benzyloxypropoxy) carbonyloxymethyl] -1H-1,2,4-triazolium chloride (Compound 25 , 0.79 g) was obtained as a white powder. ¹ H-NMR (d ₆ -DMSO) δ: 0.97 (3H, d, J = 7.2 Hz), 1.89 (2H, quin
tet, J = 6.4Hz), 3.47 (2H, t, J = 6.2Hz), 3.60-4.09 (4H, m),
4.22 (2H, t, J = 6.6Hz), 4.44 (2H, s), 4.65-4.75 (1H, m),
4.86 (1H, d, J = 14Hz), 5.09 (1H, d, 14Hz), 6.12 (1H, d, J = 11
Hz), 6.20 (1H, d, J = 11Hz), 6.62 (1H, s), 6.94-7.04 (1H,
m), 7.24-7.36 (7H, m), 7.9 (4H, s), 9.09 (1H, s), 10.07
(1H, s), 10.45 (1H, s)

Example 33 1-[(2R, 3R) -2- (2,4-difluorophenyl) -2-hydroxy-3- [2-oxo-3- [4-
(1H-tetrazol-1-yl) phenyl] -1-imidazolidinyl] butyl] -4-[(3-benzyloxypropoxy) carbonyloxymethyl] -1H-1,
2,4-triazolium chloride (compound 25 , 0.6
6 g) was dissolved in methanol (25 ml), 1N hydrochloric acid (0.89 ml) and 10% palladium-carbon (50% water content, 0.33 g) were added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 1.5 hours. After filtering off the catalyst, the filtrate was concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: methanol / water = 3/2) and recrystallized from ethanol to give 1-[(2R, 3R) -2- (2,4
-Difluorophenyl) -2-hydroxy-3- [2-
Oxo-3- [4- (1H-tetrazol-1-yl)
Phenyl] -1-imidazolidinyl] butyl] -4-
[(3-Hydroxypropoxy) carbonyloxymethyl] -1H-1,2,4-triazolium chloride (Compound 26 , 0.19 g) was obtained as colorless powdery crystals. ¹ H-NMR (d ₆ -DMSO) δ: 0.98 (3H, d, J = 7 Hz),
1.74 (2H, quintet, J = 6Hz), 3.44 (2H, dt, J = 6Hz, 5Hz), 3.6
0-4.10 (4H, m), 4.20 (2H, t, J = 6Hz), 4.59 (1H, t, J = 5Hz),
4.65-4.75 (1H, m), 4.87 (1H, d, J = 14Hz), 5.10 (1H, d, J = 14
Hz), 6.13 (1H, d, J = 11Hz), 6.21 (1H, d, J = 11Hz), 6.63 (1
H, s), 6.95-7.05 (1H, m), 7.25-7.37 (2H, m), 7.89 (4H, s),
9.09 (1H, s), 10.06 (1H, s), 10.48 (1H, s).

Example 34 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy
-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (1H-tetrazol-1-yl) phenyl] -2-imidazolidinone (1.6 g ) And iodomethyl [(4S) -2,2-
Dimethyl-1,3-dioxolan-4-yl] methyl carbonate (2.1 g) in acetonitrile (20 ml).
The mixture was heated and stirred at 5 ° C for 15 hours. The reaction mixture was purified by silica gel chromatography after subjecting the (eluent ethyl acetate → acetone → acetone / ethanol = 5/1), further ion exchange chromatography (Dowex 1x8, Cl ^-) (eluent: water)
Attached. The residue obtained by evaporating the effluent under reduced pressure is purified by ODS column chromatography (eluent: methanol / water = 3/2), and the residue obtained by evaporating the solvent under reduced pressure is crystallized from ethanol. Then 1-[(2R, 3R) -2- (2,4-difluorophenyl) -2-hydroxy-3- [2-oxo-3- [4- (1H-tetrazole
-1-yl) phenyl] -1-imidazolidinyl] butyl] -4-
[[(4S) -2,2-Dimethyl-1,3-dioxolan-4-yl] methyloxycarbonyloxymethyl] -1H-1,2,4-triazolium chloride (Compound 27 , 0.4 g) as white crystals Obtained. ¹ H-NMR (d ₆ -DMSO) δ: 0.98 (3H, d, J = 7.0 Hz), 1.26 (3H, s),
1.30 (3H, s), 3.62-3.72 (2H, m), 3.97-4.34 (7H, m), 4.70
(1H, q, J = 7.0Hz), 4.88 (1H, d, J = 14.2Hz), 5.12 (1H, d, 14.
2Hz), 6.16 (1H, d, J = 11.0Hz), 6.24 (1H, d, J = 11.0Hz), 6.
66 (1H, s), 6.94-7.03 (1H, m), 7.21-7.38 (2H, m), 7.89 (4
H, s), 9.10 (1H, s), 10.05 (1H, s), 10.51 (1H, s)

Example 35 1-[(2R, 3R) -2- (2,4-difluorophenyl) -2-hydroxy
-3- [2-oxo-3- [4- (1H-tetrazol-1-yl) phenyl] -1-imidazolidinyl] butyl] -4-[[(4S) -2,2-dimethyl-1,3- Dioxolan-4-yl] methyloxycarbonyloxymethyl] -1H-1,2,4-triazolium chloride
(Compound 27 , 0.1 g) was dissolved in tetrahydrofuran (1.5 ml), 1N hydrochloric acid aqueous solution (1.5 ml) was added under ice cooling, and the mixture was stirred at room temperature for 4 hours. The reaction solution was purified by ODS column chromatography (eluent: methanol / water = 3/2) to give 1-[(2R, 3R) -2- (2,4-difluorophenyl) -2-
Hydroxy-3- [2-oxo-3- [4- (1H-tetrazol-1-yl) phenyl] -1-imidazolidinyl] butyl] -4-[[(2S)-
2,3-dihydroxypropoxy] carbonyloxymethyl]
-1H-1,2,4-triazolium chloride (compound 28 , 0.05
g) was obtained as a white powder. ¹ H-NMR (d ₆ -DMSO) δ: 0.98 (3 H, d, J = 7.0 Hz), 3.26-
4.24 (9 H, m), 4.70 (1H, q, J = 7.0 Hz), 4.86 (1H, d, J
= 14.6 Hz), 5.09 (1H, d, J = 14.6Hz), 6.15 (1H, d, J = 1
1.0 Hz), 6.22 (1H, d, J = 11.0 Hz), 6.63 (1H, s), 6.96
-7.06 (1H, m), 7.23-7.36 (2 H, m), 7.90 (4 H, s), 9.1
0 (1H, s), 10.06 (1H, s), 10.46 (1H, s).

Example 36 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy
-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (1H-tetrazol-1-yl) phenyl] -2-
Imidazolidinone (1.0 g) in acetonitrile (15 ml)
To the solution was added (3-benzyloxycarbonylpropyl) iodomethyl carbonate (1.0 g) under a nitrogen stream, and the mixture was stirred at 45 to 50 ° C for 20 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (
Eluate: ethyl acetate → acetone), and the target fraction was concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: methanol / water = 3/2) to give 4-[(3-benzyloxycarbonylpropoxy) carbonyloxymethyl]-1-[(2R, 3R) -2-
(2,4-Difluorophenyl) -2-hydroxy-3
-[2-oxo-3-[4- (1H-tetrazol-1-yl) phenyl]-1-imidazolidinyl] butyl]-1H -1, 2,
4-triazolium iodide (Compound 32 , 1.47 g)
Was obtained as a yellow powder. ¹ H-NMR (d ₆ -DMSO) δ: 1.04 (3H, d, J = 7 Hz), 1.83-1.97
(2H, m), 2.45 (2H, t, J = 7 Hz), 3.57-3.69 (2H, m),
3.90-4.09 (2H, m), 4.18 (2H, t, J = 7 Hz), 4.69 (1H, q,
J = 7 Hz), 4.87 (1H, d, J = 14 Hz), 4.98 (1H, d, J = 14
Hz), 5.08 (2H, s), 6.14 (1H, d, J = 11 Hz), 6.22 (1H,
d, J = 11 Hz), 6.33 (1H, s), 6.99-7.08 (1H, m), 7.23-
7.32 (2H, m), 7.35 (5H, s), 7.91 (4H, s), 9.12 (1H,
s), 10.07 (1H, s), 10.24 (1H, s).

Example 37 4-[(3-benzyloxycarbonylpropoxy) carbonyloxymethyl] -1-[(2R, 3R) -2- (2,4-
Difluorophenyl)-2-hydroxy-3- [2--
Oxo-3-[4- (1H-tetrazol-1-yl) phenyl]-1-imidazolidinyl] butyl]-1H-1, 2, 4
-Triazolium iodide (Compound 32 , 1.47 g) was subjected to ion exchange chromatography (Dowex 1x8, Cl ^- form, 5
00 ml) and concentrate the target fraction under reduced pressure to give 4
-[(3-benzyloxycarbonylpropoxy) carbonyloxymethyl]-1-[(2R, 3R)-2-(2, 4
-Difluorophenyl)-2-hydroxy-3-[2-
Oxo-3-[4- (1H-tetrazol-1-yl) phenyl]-1-imidazolidinyl] butyl]-1H-1,2,4-
Triazolium chloride (Compound 29 , 893 mg) was obtained as a white powder. ¹ H-NMR (d ₆ -DMSO) d: 1.04 (3H, d, J = 7 Hz), 1.82-1.9
9 (2H, m), 2.44 (2H, t, J = 7 Hz), 3.53-3.67 (2H, m),
3.95-4.03 (2H, m), 4.17 (2H, t, J = 7 Hz), 4.68 (1H, q,
J = 7 Hz), 4.87 (1H, d, J = 14 Hz), 5.06 (1H, d, J = 14
Hz), 5.07 (2H, s), 6.13 (1H, d, J = 11 Hz), 6.21 (1H,
d, J = 11 Hz), 6.56 (1H, s), 6.95-7.05 (1H, m), 7.23-
7.33 (2H, m), 7.34 (5H, s), 7.90 (4H, s), 9.09 (1H,
s), 10.07 (1H, s), 10.41 (1H, s).

Example 38 4-[(3-benzyloxycarbonylpropoxy) carbonyloxymethyl] -1-[(2R, 3R) -2- (2,4-
Difluorophenyl)-2-hydroxy-3- [2--
Oxo-3-[4- (1H-tetrazol-1-yl) phenyl]-1-imidazolidinyl] butyl]-1H-1, 2, 4
-Triazolium chloride (Compound 29 , 155 mg)
Was dissolved in methanol (6 ml), 1N hydrochloric acid (0.2 ml) and 10% palladium-carbon (50% water-containing, 77 mg) were added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 0.5 hour. After filtering off the catalyst, add distilled water to the filtrate, concentrate under reduced pressure, and freeze-dry.
-2-hydroxy-3-[2-oxo-3-[4-(1H-
Tetrazol-1-yl) phenyl]-1-imidazolidinyl] butyl]-4-[(3-carboxypropoxy)
Carbonyloxymethyl] -1H-1,2,4-triazolium chloride (Compound 33 , 122 mg) was obtained as a white powder. ¹ H-NMR (d ₆ -DMSO) d: 0.98 (3H, d, J = 7 Hz), 1.78-1.9
0 (2H, m), 2.29 (2H, t, J = 7 Hz), 3.54-3.69 (2H, m),
3.94-4.04 (2H, m), 4.16 (2H, t, J = 7 Hz), 4.69 (1H, q,
J = 7 Hz), 4.87 (1H, d, J = 14 Hz), 5.06 (1H, d, J = 14
Hz), 6.13 (1H, d, J = 11 Hz), 6.21 (1H, d, J = 11 Hz),
6.54 (1H, s), 6.95-7.10 (1H, m), 7.24-7.37 (2H, m),
7.90 (4H, s), 8.31 (1H, s), 9.09 (1H, s), 10.06 (1H,
s), 10.34 (1H, s).

Example 39 Bromomethyl acetate (2.4 g) and sodium iodide (2.3 g) were heated and stirred at 80 ° C. for 2 hours in acetonitrile (75 ml). After the reaction solution was cooled to room temperature, the precipitated crystals were removed by filtration. 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-
Triazol-1-yl) propyl] -3- [4- (1H-tetrazol-1-yl) phenyl] -2-imidazolidinone (5 g) was added, and the mixture was heated with stirring at 45 ° C. for 16 hours. The precipitate in the reaction solution was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was dissolved in tetrahydrofuran (150 ml) and saturated saline (150 ml)
And a 5% aqueous solution of sodium thiosulfate (10 ml), and then washed twice with a saturated saline solution (150 ml). After the tetrahydrofuran layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. Add ethanol (50 ml) to the resulting residue
And acetone (3 ml) and ethanol (1.3 ml) were added, and the mixture was allowed to stand at 0 ° C. for 2 hours. Ethanol (3 ml) was added to the precipitated white solid, which was collected by filtration and dried under reduced pressure. The obtained white powder is tetrahydrofuran
(400 ml) and methanol (70 ml), and the mixture was washed seven times with saturated saline (250 ml). After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in a mixture of ethanol (150 ml) and acetone (50 ml), and distilled under reduced pressure. Then, ethanol (100 ml) was added, and the solvent was again distilled under reduced pressure. Add ethanol to the obtained residue.
(150 ml) and acetone (50 ml) were added and dissolved, and the solvent was distilled off under reduced pressure until the solution became about 20 ml, and then left at room temperature for 2 hours. The resulting solid was collected by filtration to give 4-acetoxymethyl-1-[(2R, 3R) -2- (2,4-difluorophenyl) -2.
-Hydroxy-3- [2-oxo-3- [4- (1H-tetrazol-1-yl) phenyl] -1-imidazolidinyl] butyl] -1H-1,2,4-
Triazolium chloride (Compound 12 , 3.6 g) was obtained as white crystals. This product had the same physicochemical properties as the crystals of Compound 12 crystallized from ethanol in Example 15.

Example 40 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy
-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (1H-tetrazol-1-yl) phenyl] -2-imidazolidinone (2.0 g ) And [2- (acetylamino) ethyl] iodomethyl carbonate (2.9 g) were added with acetonitrile (20 ml), and the mixture was added at 50-55 ° C under an argon atmosphere.
Stirred for 0 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in a mixture of ethyl acetate (100 ml) and tetrahydrofuran (50 ml), and shaken with a mixture of saturated saline (50 ml) and a 5% aqueous solution of sodium thiosulfate (0.1 ml). did. The organic layer was further washed with saturated saline (50 ml) four times, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel flash chromatography (eluent: ethyl acetate → acetone → acetone / ethanol = 4/1), and the target fraction was concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: methanol / water = 3/2), and then ion exchange chromatography (Dowex 1 × 8, Cl ⁻ type)
The target fraction was concentrated under reduced pressure to give 1-[(2R, 3R) -2- (2,
4-difluorophenyl) -2-hydroxy-3- [2-oxo-3-
[4- (1H-tetrazol-1-yl) phenyl] -1-imidazolidinyl] butyl] -4-[(2-acetylaminoethoxy) carbonyloxymethyl] -1H-1,2,4-triazolium chloride
(Compound 34 , 0.50 g) was obtained as a white powder. ¹ H-NMR (d ₆ -DMSO) δ: 0.97 (3H, d, J = 7 Hz), 1.77 (3H, s),
3.30 (2H, q, J = 6Hz), 3.60-3.72 (1H, m), 3.92-4.08 (3H,
m), 4.12 (2H, t, J = 6Hz), 4.65-4.75 (1H, m), 4.87 (1H, d, J
= 14Hz), 5.10 (1H, d, J = 14Hz), 6.14 (1H, d, J = 11Hz), 6.23
(1H, d, J = 11Hz), 6.63 (1H, s), 6.95-7.05 (1H, m), 7.26-
7.37 (2H, m), 7.90 (4H, s), 8.09 (1H, t, J = 6Hz), 9.10 (1H,
s), 10.07 (1H, s), 10.49 (1H, s).

Example 41 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy
-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (1H-tetrazol-1-yl) phenyl] -2-imidazolidinone (1.0 g ) And iodomethyl [3- (methoxy) propyl] carbonate (1.1 g) in a mixture of acetonitrile
(10 ml), and the mixture was stirred at 40 to 50 ° C for 15 hours under an argon atmosphere. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in acetonitrile (5 ml) and ethyl acetate (100 ml), and saturated saline was added.
(50 ml) and a mixture of 5% aqueous sodium thiosulfate (0.1 ml). The organic layer was further saturated with brine (50 ml)
And dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel flash chromatography (eluent: ethyl acetate → acetone → acetone / ethanol = 4/1), and the target fraction was concentrated under reduced pressure. The residue was subjected to ion exchange chromatography (Dowex 1 ×
8, Cl ^- form) and then purified by ODS column chromatography (eluent: methanol / water = 3/2), yielding 1-[(2
(R, 3R) -2- (2,4-difluorophenyl) -2-hydroxy-3- [2
-Oxo-3- [4- (1H-tetrazol-1-yl) phenyl] -1-
Imidazolidinyl] butyl] -4-[(3-methoxypropoxy)
Carbonyloxymethyl] -1H-1,2,4-triazolium chloride (compound 35 , 0.80 g) was obtained as a white powder. ¹ H-NMR (d ₆ -DMSO) δ: 0.97 (3H, d, J = 7 Hz), 1.83 (2H, quint
et, J = 6Hz), 3.20 (3H, s), 3.35 (2H, t, J = 6Hz), 3.55-3.70
(1H, m), 3.90-4.10 (3H, m), 4.18 (2H, t, J = 6Hz), 4.64-4.
75 (1H, m), 4.87 (1H, d, J = 14Hz), 5.11 (1H, d, J = 14Hz), 6.
14 (1H, d, J = 11Hz), 6.22 (1H, d, J = 11Hz), 6.66 (1H, s), 6.
95-7.05 (1H, m), 7.25-7.39 (2H, m), 7.90 (4H, s), 9.10 (1
H, s), 10.07 (1H, s), 10.48 (1H, s). Example 42 Bromomethyl acetate (424 mg) and sodium iodide (415 mg) were dissolved in acetonitrile (15 ml) at 80 ° C.
The mixture was heated and stirred for an hour. After cooling the reaction solution to room temperature, precipitated sodium bromide was removed by filtration. Add 2-[(1R, 2R) to the filtrate
-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] -3- (2H, 4H)
-1,2,4-Triazolone (1 g) was added, and the mixture was heated with stirring at 45 ° C for 16 hours. The precipitate in the reaction solution was removed by filtration, and the solvent was distilled off under reduced pressure. Residue in tetrahydrofuran (30 ml)
And washed with a mixture of saturated saline (30 ml) and a 5% aqueous sodium thiosulfate solution (2 ml), and then saturated saline (30 ml).
ml) twice. After the tetrahydrofuran layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel chromatography (eluent:
Ethyl acetate → ethyl acetate / ethanol = 10/1 → 4 /
After 1), further add Dowex 1x8 (Cl ^- form) (eluent:
Water) and lyophilized to give 4-acetoxymethyl-
1-[(2R, 3R) -2- (2,4-difluorophenyl) -2-hydroxy
-3- [4,5-dihydro-5-oxo-4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -1H-1,2,4-triazole-1-
[Ill] butyl-1H-1,2,4-triazolium chloride (Compound 36 , 294 mg) was obtained as a white powder. ¹ H-NMR (d ₆ -DMSO) δ: 1.22 (3H, d, J = 7Hz), 2.08 (3H,
s), 4.66 (2H, t, J = 14Hz), 4.85 (1H, d, J = 14Hz), 4.
89 (1H, q, J = 7Hz), 4.98 (1H, d, J = 14Hz), 6.09 (1H,
d, J = 11Hz), 6.19 (1H, d, J = 11Hz), 6.26 (1H, s),
6.69 (1H, tt, J = 52, 5Hz), 6.97-7.06 (1H, m), 7.23
(2H, d, J = 9Hz), 7.25-7.41 (2H, m), 7.69 (2H, d, J = 9
Hz), 8.58 (1H, s), 9.09 (1H, s), 10.25 (1H, s).

Example 43 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy
-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (1H-tetrazol-1-yl) phenyl] -2-imidazolidinone (200 mg ) And bromomethyl acetate (77.
1 mg) in acetonitrile (2 ml) under argon atmosphere
The mixture was heated and stirred at 0 ° C for 7 hours. Add acetonitrile (11
ml) was added, and the precipitated crystals were dissolved by heating to 80 ° C.
After cooling to room temperature, silica gel (400 mg) was added.
Stirred for 10 minutes. The silica gel was filtered off and washed with a mixed solution of acetonitrile and tetrahydrofuran (1/1, 2 ml × 3). A saturated saline solution (10 ml) was added to the solution obtained by combining the mother liquor and the washing solution.
Was added and stirred at room temperature for 30 minutes, and then the organic layer was separated. The same operation [saturated saline (10 ml) addition, stirring at room temperature for 30 minutes, and separation of the organic layer] was further repeated three times. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
Dissolve the residue in tetrahydrofuran (3 ml) and add
Left for hours. The precipitated white solid (179 mg) was collected by filtration and dissolved in a mixture of methanol and tetrahydrofuran (1/1, 4 ml). After concentration under reduced pressure, tetrahydrofuran (2
ml) was added and dissolved, and left at room temperature for 5 hours. The precipitated white powder (167 mg) was collected by filtration, and dissolved by adding a mixed solution of ethanol (6 ml) and acetone (0.5 ml). The solution was concentrated under reduced pressure to about 2 ml and left at room temperature for 3 hours. The precipitated solid was collected by filtration to give 4-acetoxymethyl-1-[(2R, 3R) -2- (2,4
-Difluorophenyl) -2-hydroxy-3- [2-oxo-3- [4
-(1H-Tetrazol-1-yl) phenyl] -1-imidazolidinyl] butyl] -1H-1,2,4-triazolium chloride (Compound 12 , 126 mg) was obtained as white crystals. This product was compound 12 crystallized from ethanol in Example 15.
The crystal and physicochemical properties were consistent. Formulation Example 1 Injection having the following composition was produced using Compound 2 obtained in Example 4 above. Compound 2 of Example 4 100 mg 5% aqueous glucose solution for injection 100 ml Formulation Example 2 Using Compound 1 obtained in Example 1 above, mix all the ingredients of the following formulation, fill a gelatin capsule, and fill Capsules containing 50 mg of compound 1 per unit were prepared. 2 and magnesium stearate compound obtained by the compound 1 50 mg Lactose 100mg Cornstarch 40mg Magnesium stearate 10mg Total 200mg Formulation Example 3 Example 4 above in Example 1 was granulated with an aqueous solution of soluble starch, dried, and lactose and corn starch Mixed. The mixture was compression-molded to produce tablets having the following formulation. Compound 2 of Example 4 50 mg Lactose 65 mg Corn starch 30 mg Soluble starch 35 mg Magnesium stearate 20 mg Total 200 mg

[0094] Experimental Example 1 Method: Five-week-old Crj: were Candida albicans TA minimum lethal dose to CDF ₁ mice were inoculated intravenously. The test compound was intravenously administered once immediately after infection as a 5% aqueous glucose solution. The efficacy was shown by the ED ₅₀ value calculated by the Reed and Muench method from the survival rate of mice 7 days after infection. Results: [Table 5] shows the protective effect of the compound of the present invention on experimental mouse infections by intravenous administration.

[Table 5] Compound No. ED ₅₀ (μmol / kg) iv 1 2.3 2 1.5

[0095] Experiment 2 Method: Five-week-old Crj: were Candida albicans TA minimum lethal dose to CDF ₁ mice were inoculated intravenously. The test compound was orally administered once immediately after infection as a 5% aqueous glucose solution. The efficacy was shown by the ED ₅₀ value calculated by the Reed and Muench method from the survival rate of mice 7 days after infection. Results: Table 6 shows the protective effect of the compound of the present invention on oral administration of the compound in experimental mouse infections.

[Table 6] Compound No. _{ED 50 (μmol / kg) po} 1 2.9 2 1.8

[0096] Experimental Example 3 Methods: Five-week-old Crj: were Candida albicans TA minimum lethal dose to CDF ₁ mice were inoculated intravenously. The compound of the present invention is dissolved in a 5% aqueous glucose solution, and
1.04 μmol / kg was administered intravenously (iv) or orally (po). The protective effect against infection was indicated by the number of surviving mice 7 days after infection (5 mice per group) and the average number of surviving days for mice that died before 7 days. Results: [Table 7] shows the protective effect of the compound of the present invention on experimental mouse infections by intravenous administration and oral administration. Table 7 also shows the protective effect of the compound of formula (V), which is a control compound, on the oral administration (1.04 μmol / kg as a 0.5% sodium carboxymethylcellulose suspension). .

[0097]

[Table 7]

[0098]

The compound of the present invention has a high solubility in water, is suitable for use as an injection, and has excellent absorbability in the body, so that a high therapeutic effect can be expected.

[0099]

[Brief description of the drawings]

FIG. 1 shows a powder X-ray diffraction spectrum (Cu, 40 kV, 50 mA) of Form I crystal (non-hydrate) crystallized from ethanol of Compound 12 obtained in Example 15. The horizontal axis indicates the diffraction angle (2θ), and the vertical axis indicates the peak intensity.

FIG. 2 shows a powder X-ray diffraction spectrum (Cu, 40 kV, 50 mA) of a type II crystal (hydrate) crystallized from water of compound 12 obtained in Example 15. The horizontal axis indicates the diffraction angle (2θ), and the vertical axis indicates the peak intensity.

Continuation of the front page (56) References JP-A-10-114758 (JP, A) JP-A-51-100073 (JP, A) JP-A-55-36478 (JP, A) JP-A-56-46880 (JP) , A) European Patent Application Publication 195116 (EP, A2) WO 96/25410 (WO, A1) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 403/14 C07D 405/06 CA ( STN)

Claims (3)

(57) [Claims] (1) 4-acetoxymethyl-1-[(2R, 3
R) -2- (2,4-Difluorophenyl) -2-hydroxy-3- [2-oxo-3- [4- (1H-tetrazol-1-yl) phenyl] -1-imidazolidinyl] butyl] -1H -1,2,4-triazolium chloride. 2. A pharmaceutical composition comprising the compound according to claim 1. 3. The pharmaceutical composition according to claim 2 , which is an antifungal agent.