JPH11279160A - Triazole derivative or salt thereof, method for producing the same, and medicament containing the compound as an active ingredient - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce the subject new compound having excellent antimicrobial actions on fungi including those of the genera Aspergillus and Candida, high safety and further a cyclopropylthio group or a cyclopropylsulfonyl group. SOLUTION: This compound is represented by formula I [R<1> is H, a lower alkyl or an aralkyl; X<1> and X<2> are each H, a halogen or a halogenoalkyl; (n) is 0-2], e.g. 1-(cyclopropylthio)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4- triazol-1-yl)-2-propanol. The compound represented by formula I is obtained by converting a 2-halo-acetophenone derivative represented by formula II into a cyclopropylthio compound, then difluorinating the resultant cyclopropylthio compound, thereby providing a compound represented by formula III and directly triazolemethylating the prepared compound represented by formula III or once epoxymethylenating the compound represented by formula III, affording a compound represented by formula IV and subsequently converting the resultant compound into a triazole.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a triazole derivative or a salt thereof having excellent antifungal activity and high safety, a production intermediate thereof, and a medicament containing the same as an active ingredient.

[0002]

2. Description of the Related Art Mycosis includes superficial mycosis typified by various ringworm, tinea, psoriasis, cutaneous candidiasis and the like, fungal meningitis, fungal respiratory infections, mycemia, and urinary tract. There is deep mycosis typified by mycosis and the like. Of these, candidiasis,
Deep mycosis such as aspergillosis has been increasing especially in recent years due to the frequent use of cancer chemotherapeutic agents and immunosuppressants, and a decrease in in vivo immunity due to HIV infection and the like. Is desired.

However, as a drug effective against Aspergillus and Candida, amphotericin B and azole compounds such as fluconazole and itraconazole have been known, but they are still scarce. In addition, all of these drugs have problems in terms of safety or antifungal activity, and antifungal agents effective against Aspergillus and Candida have been desired. Currently, more effective azole compounds are being developed. For example, compounds having a difluoromethylene group are disclosed in JP-A-59-163374, JP-A-5-163269, and JP-A-9-227.
No. 531 is known. Further, as the compound in which the tertiary hydroxyl group is substituted, a cyclic compound is disclosed in
The compounds described in JP-A-8-104676 and JP-A-9-183768 are known as acyl compounds such as JP-A-217778 and JP-A-8-33367. Absent.

[0004]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a compound which is highly safe and has an effective antifungal activity against Aspergillus and Candida.

[0005]

Under such circumstances, the present inventors have synthesized a large number of triazole derivatives and their salts, and studied the antifungal activity effective against Aspergillus and Candida. The triazole derivatives having a cyclopropylthio group or a cyclopropylsulfonyl group represented by the following general formula (1) and salts thereof are superior to fungicides including Aspergillus and Candida compared to conventionally known similar compounds. It has been found that it has an antibacterial action and high safety, and has completed the present invention.

That is, the present invention provides the following general formula (1)

[0007]

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Wherein R ¹ represents a hydrogen atom, a lower alkyl group or an aralkyl group; X ¹ and X ² are the same or different and each represent a hydrogen atom, a halogen atom or a halogenoalkyl group; Or a salt thereof, an intermediate for producing the compound, and a method for producing these compounds.

Further, the present invention provides a medicament comprising the triazole derivative represented by the above general formula (1) or a salt thereof as an active ingredient.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION In the triazole derivative of the present invention, the lower alkyl group represented by R ¹ in the general formula (1) includes a linear or branched one having 1 to 6 carbon atoms. Specifically, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,
sec-butyl group, t-butyl group, n-pentyl group, i
-Pentyl group, n-hexyl group and the like. The aralkyl group represented by R ¹ is preferably one having 7 to 10 carbon atoms, more preferably a phenyl-C _1-4 alkyl group, and specific examples include a benzyl group, a phenethyl group and a phenylpropyl group. . R ¹ is preferably a methyl group or a benzyl group. Further, as the halogen atom among the groups represented by X ¹ and X ² , a fluorine atom, a chlorine atom,
Although a bromine atom and an iodine atom are mentioned, a fluorine atom or a chlorine atom is particularly preferable. Examples of the halogenoalkyl group include those in which the halogen atom is substituted for the alkyl group having 1 to 6 carbon atoms. Among them, a perfluoro C ₁ -C ₆ alkyl group is preferable, and a trifluoromethyl group, a pentafluoro group An ethyl group is preferred, and a trifluoromethyl group is more preferred. The number n of oxygen atoms is an integer of 0 to 2, preferably 0 or 2.

The salt of the triazole derivative (1) of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt, but acid addition salts such as hydrochloride, nitrate, hydrobromide, p-toluene Sulfonate, methanesulfonate,
Fumarate, succinate, lactate and the like.

The triazole derivative (1) of the present invention and its salt have stereoisomers based on an asymmetric carbon atom and a sulfoxide. In the present invention, any of these isomers and racemic isomers Also included are isomer mixtures of
In addition, the triazole derivative (1) or a salt thereof may exist in the form of a solvate represented by a hydrate,
These are also included in the present invention.

The triazole derivative (1) of the present invention can be produced, for example, according to the following reaction formula.

[0014]

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Wherein R ¹ , X ¹ and X ² are the same as above, and X ³ is a halogen atom.

That is, the known compound 2-halo-a
Cyclopropylthioation of the cetophenone derivative (5),
Difluorination of the obtained cyclopropylthio compound (4)
To obtain compound (2), and the obtained compound
(2) by direct triazole methylation, or
The compound (3) is obtained after being subjected to simmenation to give the compound (3).
Is converted into a triazole to give the above-mentioned general formula (1)
In this case, the compound (1a) wherein n = 0 can be produced.
Wear. Further, if necessary, R of this compound (1a) ¹To
It can be alkylated or aralkylated. Ma
The compound (1a) is oxidized to give a compound of the general formula (1)
In the compound (1b) wherein n = 1 and n = 2
Compound (1c) can be produced. Also, compounds
(1c) can also be obtained by oxidizing compound (1b).
Can be manufactured. In this process, the general formula
2,2-difluoro-2-cycloprop represented by (2)
Ripylthioacetophenone derivative and represented by general formula (3)
The oxirane derivatives referred to have been synthesized by the inventor.
A novel compound, which is a compound of the triazole derivative (1).
It is useful as an intermediate.

Hereinafter, the present invention will be described in accordance with the above steps.

Step (5-4): Compound (4) can be produced by subjecting compound (5) to cyclopropylthioation.

In the compound (5) as a raw material, the compound represented by the general formula
X in (5)^ThreeAs fluorine, chlorine, bromine
Atoms, among which chlorine or bromine
Is preferred. X of the compound (5)^ThreeIs a fluorine atom,
Chlorine atom, bromine atom, etc. ¹And X^TwoAre both fluorine sources
The parent compound is commercially available, for example, from Aldrich.
I have.

Compound (4) can be produced by reacting compound (5) with a cyclopropylthioating agent in the presence of a base. As the cyclopropyl thiolating agent, cyclopropyl mercaptan (J. Am. Chem. Soc., 11
4,3492, (1992.)). As a reaction solvent, methanol, ethanol, diethyl ether, methanol-
A mixed solvent of diethyl ether, N, N-dimethylformamide, 1,4-dioxane, tetrahydrofuran and the like can be used, and methanol and a mixed solvent of methanol and diethyl ether are particularly preferable. As the base, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide,
Pyridine, triethylamine and the like can be used, but potassium carbonate is preferred.

Step (4-2): Compound (2) can be produced by reacting compound (4) with a fluorinating reagent in a solvent.

Examples of the fluorinating reagent include fluorine gas, perchloryl fluoride, potassium fluoride, spray-dried potassium fluoride, freeze-dried potassium fluoride, tetraalkylammonium fluoride, tris (dimethylamino) sulfa (trimethylsilyl) difluoride, N 2 -Fluoropyridone, N-fluoro-N-alkyl-arene sulfonamide, N-fluoroquinuclidinium salt,
N-fluoroperfluoroalkylsulfonimide, N
-Fluorosultam, xenon fluoride, N-fluoropyridinium salt, N-fluoropyridinium sulfonate, etc., are commercially available as Onoda Florinate FP
-T300, FP-T500, FP-T700, FP-B300, FP-B500, FP-B70
0, FP-B800 (all made by Chichibu Onoda Co., Ltd.),
MEC-01, MEC-02, MEC-03, MEC-
04, MEC-05 (all manufactured by Daikin Industries, Ltd.) and the like. The amount of the fluorinated reagent used is the same as the compound (4)
The amount is preferably 2 to 20 equivalents per 1 mol. As a reaction solvent, 1,2-dichloroethane, 1,1,2-trichloroethane, chloroform, methylene chloride, diethyl ether, ethyl acetate, tetrahydrofuran and the like can be used, and 1,1,2-trichloroethane is particularly preferable.
The reaction temperature is preferably in the range of -78 ° C to the boiling point of the solvent, particularly preferably 80 to 100 ° C.

A Lewis acid or a base can be used to improve the yield. As Lewis acids,
Aluminum chloride, zinc chloride, tin chloride and the like,
Examples of the base include sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, potassium tert-butoxy, lithium diisopropylamide, potassium hexamethyldisilazane, and the like.

Step (2-1a): The direct synthesis of compound (1a) from compound (2) is based on 1 mole of compound (2)
1 to 5 moles of an epoxymethylene reagent and 1 to 4 moles in a solvent
Using 1,2,4-triazole or an alkali metal salt thereof in a molar amount of from -100 ° C to room temperature
The reaction is performed for 30 hours. Examples of the epoxymethylene agent include trimethylsulfoxonium iodide and trimethylsulfonium iodide. Examples of the base include sodium hydroxide, potassium hydroxide, barium hydroxide, sodium methoxide, sodium carbonate, potassium carbonate, sodium hydride and the like, with potassium hydroxide being particularly preferred. As the solvent, methanol, ethanol, isopropanol, n-butanol, sec-butanol, tert-butanol and the like are preferable.

Step (2-3): Compound (1a) can be produced via compound (3). Compound (3)
Is obtained by reacting compound (2) with 1-2 equivalents of an epoxymethylene reagent such as trimethylsulfoxonium iodide or trimethylsulfonium iodide in the presence of 1 to 5 equivalents of an alkali in a solvent. Can be. As the solvent, dimethyl sulfoxide, tetrahydrofuran and the like can be suitably used. As the base, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, sodium hydride and the like can be used, and sodium hydride is particularly preferable. The reaction temperature is -100
C. to the boiling point range of the solvent is preferred, especially -40 to 50 C.
It is preferable to be within the range.

Step (3-1a): Compound (1a) can be obtained by reacting compound (3) with 1,2,4-triazole or an alkali metal salt thereof in a solvent in the presence of a base. . As the solvent, N, N-dimethylformamide, acetonitrile, N, N-dimethylacetamide, dimethylsulfoxide and the like can be suitably used. As the base, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate,
Tert-butoxy potassium and the like can be used. The reaction temperature is preferably in the range of 0 ° C. to the boiling point of the solvent, particularly preferably 20 to 6 ° C.
The temperature is preferably in the range of 0 ° C.

In the case of (1a), a tertiary hydroxyl group can be alkylated in the presence of a base, if necessary. Examples of the alkyl halide used for the alkylation include methyl iodide, ethyl iodide, propyl iodide, benzyl chloride and the like. As the base, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate,
Sodium hydride and the like. Examples of the solvent include alcohol solvents such as methanol and ethanol, non-aqueous polar solvents such as N, N-dimethylformamide, and ether solvents such as 1,4-dioxane and tetrahydrofuran. In particular, N, N-dimethylformamide Is preferred. The reaction temperature is preferably in the range of −40 ° C. to the boiling point of the solvent, and particularly preferably 0 to 20 ° C.

Step (1a-1c): Compound (1c) is
2 equivalents or more, preferably 2.2 equivalents to compound (1a)
It can be produced by using .about.2.3 equivalents of oxidizing agent. As the oxidizing agent, m-chloroperbenzoic acid,
Aqueous hydrogen peroxide, peracetic acid, tetrapropylammonium pearl tenate, osmium tetroxide, potassium permanganate, oxone and the like can be used. As the solvent,
Chloroform, dichloromethane, acetic acid, methanol,
Examples thereof include water, acetonitrile, carbon tetrachloride, and a mixed solvent thereof. The reaction temperature is preferably in the range of −40 ° C. to the boiling point of the solvent, and particularly preferably 0 to 50 ° C. Further, in order to improve the yield, ruthenium trichloride, selenium dioxide, sodium tungstate, sodium molybdate, vanadium oxide or the like may be used as a catalyst.

Step (1a-1b) and Step (1b-1)
c): Compound (1b) is 1 to 1 relative to compound (1a)
It can be prepared by using 2 equivalents, preferably 1.2 equivalents of oxidizing agent. As the oxidizing agent, m-chloroperbenzoic acid, hydrogen peroxide solution, peracetic acid, tetrapropylammonium pearl tenate, osmium tetroxide, potassium permanganate, oxone and the like can be used. Examples of the solvent include chloroform, dichloromethane, acetic acid, methanol, water, acetonitrile, carbon tetrachloride, and a mixed solvent thereof. The reaction temperature is -4
The range of 0 ° C to the boiling point of the solvent is preferable, and particularly preferably 0 to 50 ° C. Further, in order to improve the yield, ruthenium trichloride, selenium dioxide, sodium tungstate, sodium molybdate, vanadium oxide or the like may be used as a catalyst. Step (1b-1c) can be performed in the same manner.

Compounds (1a), (1b) and (1c) each have an enantiomer based on an asymmetric carbon atom, and the optically active substance is separated using an optical isomer separation column. Can be manufactured. Optically active stationary phases include synthetic optically active polymers, natural polymers,
Examples include amino acid metal complexes and the like, and silica gel coated with a cellulose derivative is preferred. As the column filled with the silica gel coated with the cellulose derivative, commercially available products such as Chiral Cell OD and Chiral Pack AS (all manufactured by Daicel Chemical Industries, Ltd.) can be used, and Chiral Cell OD is particularly preferable. Also,
As the format of the chromatography, liquid chromatography is preferable. In this case, hexane-ethanol, hexane-isopropyl alcohol, or the like can be used as the eluent as the mobile phase. The optically active substance can also be produced by an optical resolution method. As the optical resolving agent, for example, an optically active camphorsulfonic acid or a salt thereof which may be substituted by a halogen atom, specifically, (+)-camphor-10-sulfonic acid, (−)-
Camphor-10-sulfonic acid, (+)-3-bromocamphor-8-sulfonic acid, (−)-3-bromocamphor-8-sulfonic acid, (+)-3-bromocamphor-10-sulfonic acid, ( -)-3-Bromocamphor-
10-sulfonic acid, (+)-3-bromocamphor-8
-Sulfonic acid ammonium salt, (-)-3-bromocamphor-8-sulfonic acid ammonium salt, and the like;
In particular, (+)-3-bromocamphor-8-sulfonic acid,
(-)-3-bromocamphor-8-sulfonic acid,
(+)-3-Bromocamphor-8-sulfonic acid ammonium salt and (-)-3-bromocamphor-8-sulfonic acid ammonium salt are preferred.

The means for isolating the target substance from the reaction mixture in the above reaction is not particularly limited, and can be carried out by, for example, recrystallization, various types of chromatography, or the like. The conversion of the target compound into a desired salt can also be carried out according to a conventional method.

The compound (1) of the present invention or a salt thereof is in v
It has excellent antifungal activity against fungi including Aspergillus and Candida in in vitro and in vivo , and has high safety, so that it is useful as a medicament for preventing and treating various fungal infectious diseases.

The compound (1) of the present invention can be prepared by various methods such as tablets, granules, powders, capsules, suspensions, injections, suppositories, and external preparations, especially antifungals. It can be. These pharmaceutical compositions can be produced by compounding compound (1) with a pharmaceutically acceptable carrier. Specifically, in the case of a solid preparation, the compound (1) of the present invention is added to an excipient and, if necessary, a binder, a disintegrant, a bulking agent, a coating agent, a sugar coating, and the like, and produced by a conventional method. be able to. In the case of an injection, the compound (1) of the present invention is dissolved in an aqueous carrier such as distilled water for injection, dispersed or emulsified beforehand to give a liquid for injection, or a powder for injection, or dissolved in a powder for injection. I just need. Injection administration methods include intravenous administration, intraarterial administration, subcutaneous administration, and intravenous infusion.

The dose of the compound (1) of the present invention or a salt thereof as a medicament varies depending on various factors such as disease, symptom, body weight, age, sex, administration route and the like.
When used as an antifungal agent, the compound of the present invention (1) or a salt thereof is usually 0.1 to 1000 for adults.
mg / day, preferably 1-300 mg / day is used. This amount may be administered once a day or divided into 2 to 4 times.

[0035]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Reference Examples and Examples, but the present invention is not limited thereto.

Reference Example 1 2 ', 4'-difluoro-2-
(Cyclopropylthio) acetophenone [compound (4-
1)] Synthesis of 2-chloro-2 ', 4'-difluoroacetophenone (2.8 g, 0.015 mmol) in a methanol (100 ml) solution (J. Am. Chem. So
c., 114, 3492 (1992).), an ether solution of cyclopropyl mercaptan obtained from cyclopropyl bromide (4.8 g, 0.039 mol) was added, and potassium carbonate (2.5 g, 0.018 mol) was added under ice cooling. ) Was added and stirred at room temperature for 1.5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, water was added to the reaction solution, and the mixture was extracted with ether. The extract was washed sequentially with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained oil was distilled under reduced pressure (120 ° C., 2 mmHg) to give 2 ′, 4′-difluoro-2- (cyclopropylthio) as a colorless oil.
Acetophenone (2.3 g, 67% yield) was obtained.

¹ H-NMR (CDCl ₃ , δ): 0.41-0.96 (4H, m),
1.72-1.98 (1H, m), 3.85 (2H, d, J = 2Hz), 6.76-7.10 (2H, m),
7.87-8.14 (1H, m).

Reference Example 2 2- (cyclopropylthio)-
Synthesis of 4'-fluoroacetophenone [compound (4-2)]: In the same manner as in Reference Example 1, except that 2-chloro-4'-fluoroacetophenone was used instead of 2-chloro-2 ', 4'-difluoroacetophenone. Thus, 2- (cyclopropylthio) -4'-fluoroacetophenone was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ , δ): 0.48-1.05 (4H, m),
1.86-2.03 (1H, m), 3.86 (2H, s), 7.04-7.26 (2H, m), 7.94-
8.10 (2H, m).

Reference Example 3 2- (cyclopropylthio)-
Synthesis of 4 '-(trifluoromethyl) acetophenone [compound (4-3)]: Using 2-bromo-4'-(trifluoromethyl) acetophenone instead of 2-chloro-2 ', 4'-difluoroacetophenone And Reference Example 1
In the same manner as in the above, 2- (cyclopropylthio) -4 '-(trifluoromethyl) acetophenone was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ , δ): 0.45-0.99 (4H, m),
1.77-2.03 (1H, m), 3.89 (2H, s), 7.73 (2H, d, J = 8Hz), 8.09
(2H, d, J = 8Hz).

Example 1 2-cyclopropylthio-2,
Synthesis of 2,2 ', 4'-tetrafluoroacetophenone [compound (2-1)]: 2', 4'-difluoro-2-
(Cyclopropylthio) acetophenone (13.6 g,
0.059 mol) of 1,1,2-trichloroethane (3
N-fluoro-4-methylpyridinium-2-sulfonate (MEC-02, manufactured by Daikin Industries, Ltd.) (29.6 g, 0.155 mol) at an internal temperature of 90 ° C.
l) was added little by little, and the mixture was stirred at an internal temperature of 90 to 93 ° C for 2 hours. After completion of the reaction, the internal temperature was cooled to 50 ° C. or lower, water was added to the reaction solution, and the mixture was extracted with 1,1,2-trichloroethane. The extract was washed sequentially with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained oil was subjected to silica gel column chromatography,
From the chloroform eluate, 2-cyclopropylthio-2,2,2 ', 4'-tetrafluoroacetophenone (5.6 g, yield 36%) was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ , δ): 0.70-1.05 (4H, m),
1.94-2.29 (1H, m), 6.81-7.07 (2H, m), 7.85-8.11 (1H, m).

Example 2 2-Cyclopropylthio-2,
2,4'-trifluoroacetophenone [compound (2-
2)]: The procedure of Example 1 was repeated, except that 2- (cyclopropylthio) -4'-fluoroacetophenone was used in place of 2 ', 4'-difluoro-2- (cyclopropylthio) acetophenone. As a colorless oil
Cyclopropylthio-2,2,4'-trifluoroacetophenone was obtained.

¹ H-NMR (CDCl ₃ , δ): 0.60-1.05 (4H, m),
1.98-2.24 (1H, m), 7.07-7.26 (2H, m), 8.10-8.26 (2H, m).

Example 3 2-Cyclopropylthio-2,
Synthesis of 2-difluoro-4 '-(trifluoromethyl) acetophenone [compound (2-3)]: 2- (cyclopropylthio) instead of 2', 4'-difluoro-2- (cyclopropylthio) acetophenone Except that -4 '-(trifluoromethyl) acetophenone was used, 2-cyclopropylthio-2,2-difluoro-4'-(trifluoromethyl) acetophenone was used as a colorless oil in the same manner as in Example 1. Obtained.

¹ H-NMR (CDCl ₃ , δ): 0.61-1.13 (4H, m),
1.92-2.12 (1H, m), 7.76 (2H, d, J = 8Hz), 8.24 (2H, d, J = 8H
z).

Example 4 2-[(cyclopropylthio)
Synthesis of (difluoro) methyl] -2- (2,4-difluorophenyl) -oxirane [compound (3-1)]: 6
A suspension of 0% sodium hydride (1.0 g, 0.025 mol) in tetrahydrofuran (50 ml) -dimethyl sulfoxide (70 ml) was heated to an external temperature of 50 ° C., and trimethylsulfoxonium iodide (5.6 g, 0.0
25 mol) was added little by little, and stirred at the same temperature for 1 hour.
After cooling to −20 ° C., 2-cyclopropylthio-2,2,
2 ', 4'-tetrafluoroacetophenone (5.6
g, 0.021 mol) of tetrahydrofuran (20 ml)
The solution was added dropwise. After stirring at room temperature for 2 hours, the reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed sequentially with water and saturated saline, dried over magnesium sulfate,
The solvent was distilled off under reduced pressure to give 2-[(cyclopropylthio) (difluoro) methyl] -2- (2,2 as a pale yellow oil.
4-Difluorophenyl) -oxirane (5.0 g, yield 86%) was obtained.

¹ H-NMR (CDCl ₃ , δ): 0.66-0.98 (4H, m),
1.93-2.25 (1H, m), 2.95-2.98 (1H, m), 3.48 (1H, d, J = 5Hz),
6.71-6.99 (2H, m), 7.40-7.65 (1H, m).

Example 5 2-[(cyclopropylthio)
Synthesis of (difluoro) methyl] -2- (4-fluorophenyl) oxirane [compound (3-2)]: 2-cyclopropylthio-2,2,2 ′, 4′-tetrafluoroacetophenone Cyclopropylthio-
Except that 2,2,4'-trifluoroacetophenone was used, the same procedure as in Example 4 was repeated to give 2-yellow oil as a pale yellow oil.
[(Cyclopropylthio) (difluoro) methyl] -2
-(4-Fluorophenyl) oxirane was obtained.

¹ H-NMR (CDCl ₃ , δ): 0.57-1.03 (4H, m),
1.94-2.21 (1H, m), 2.81-2.90 (1H, m), 3.46 (1H, d, J = 5Hz),
6.91-7.15 (2H, m), 7.44-7.60 (2H, m).

Example 6 2-[(cyclopropylthio)
Synthesis of (difluoro) methyl] -2- (4-trifluoromethyl) phenyloxirane [compound (3-3)]:
Other than using 2-cyclopropylthio-2,2-difluoro-4 '-(trifluoromethyl) acetophenone in place of 2-cyclopropylthio-2,2,2', 4'-tetrafluoroacetophenone, In the same manner as in Example 4, 2-[(cyclopropylthio) (difluoro) methyl] -2- (4-trifluoromethylphenyl) oxirane was obtained as a pale yellow oil.

¹ H-NMR (CDCl ₃ , δ): 0.59-1.04 (4H, m),
2.00-2.12 (1H, m), 2.80-2.89 (1H, m), 3.50 (1H, d, J = 6Hz),
7.65 (4H, br.s).

Example 7 1- (Cyclopropylthio)-
Synthesis of 2- (2,4-difluorophenyl) -1,1-difluoro-3- ( 1H -1,2,4-triazol-1-yl) -2-propanol [compound (1a-1)]: 2-[(cyclopropylthio) (difluoro) methyl] -2- (2,4-difluorophenyl) -oxirane (5.0 g, 0.017 mol) in DMSO (70 ml)
1,2,4-Triazole (3.48 g, 0.0
5mol) and potassium carbonate (6.95g, 0.05mol)
Was added and stirred at 55 ° C. for 1.5 hours. After the reaction,
Water was added and extracted with ethyl acetate. The extract was washed successively with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from isopropyl ether-ethyl acetate to give 1- (cyclohexane) as colorless crystals. Propylthio) -2- (2,4-difluorophenyl) -1,1-difluoro-3- ( 1H -1,2,4-
Triazol-1-yl) -2-propanol (2.3
5 g, yield 32%).

Melting point: 99 to 102 ° C. IR (KBr) ν _max cm ⁻¹ : 3111, 1685, 1508, 1148. MS (FAB): 348 (M + H) ¹ H-NMR (CDCl ₃ , δ): 0.58 -1.06 (4H, m), 1.89-2.14 (1H,
m), 4.79 (1H, d, J = 14Hz), 1.28 (1H, d, J = 14Hz), 5.65 (1H, d, J = 14Hz)
s), 6.60-6.95 (2H, m), 7.58-7.85 (1H, m), 7.81 (1H, s),
8.08 (1H, s).

Example 8 1- (cyclopropylthio)-
1,1-difluoro-2- (4-fluorophenyl)-
3- ( 1H -1,2,4-triazol-1-yl)-
Synthesis of 2-propanol [compound (1a-2)]:
[(Cyclopropylthio) (difluoro) methyl] -2
Using 2-[(cyclopropylthio) (difluoro) methyl] -2- (4-fluorophenyl) oxirane in place of-(2,4-difluorophenyl) -oxirane, colorless as in Example 7. 1- (Cyclopropylthio) -1,1-difluoro-2- (4-fluorophenyl) -3- ( 1H -1,2,4-triazol-1-yl) -2-propanol was obtained as crystals. .

Melting point: 101 to 102 ° C. IR (KBr) ν _max cm ⁻¹ : 3143, 1607, 1511, 1141. MS (FAB): 330 (M + H) ¹ H-NMR (CDCl ₃ , δ): 0.60 -0.94 (4H, m), 1.88-2.10 (1H,
m), 4.68 (1H, d, J = 15Hz), 1.90 (1H, d, J = 15Hz), 5.26 (1H, d, J = 15Hz)
s), 6.92-7.11 (2H, m), 7.44-7.60 (2H, m), 7.85 (1H, s),
7.91 (1H, s).

Example 9 1- (cyclopropylthio)-
1,1-difluoro-2- (4-trifluoromethylphenyl) -3- ( 1H -1,2,4-triazole-1
Synthesis of-[yl] -2-propanol [compound (1a-3)]: 2-[(cyclopropylthio) (difluoro) methyl] -2- (2,4-difluorophenyl) -oxirane Using (cyclopropylthio) (difluoro) methyl] -2- (4-trifluoromethylphenyl) oxirane as 1- (cyclopropylthio) -1,1-difluoro as colorless crystals in the same manner as in Example 7. -2- (4-trifluoromethylphenyl) -3
-( 1H -1,2,4-triazol-1-yl) -2
-Propanol was obtained.

Melting point: 114 to 115 ° C. IR (KBr) ν _max cm ^-1 : 3140, 1621, 1514, 1139. MS (FAB): 380 (M + H) ¹ H-NMR (CDCl ₃ , δ): 0.55 -1.03 (4H, m), 1.85-2.18 (1H,
m), 4.68 (1H, d, J = 14Hz), 1.90 (1H, d, J = 14Hz), 5.70 (1H,
s), 7.46-7.76 (4H, m), 7.81 (1H, s), 7.94 (1H, s).

Example 10 1- [3- (Cyclopropylthio) -2- (2,4-difluorophenyl) -3,3
- difluoro-2-methoxypropyl] -1 H -1,
Synthesis of 2,4-triazole [compound (1a-4)]:
1- (cyclopropylthio) -2- (2,4-difluorophenyl) -1,1-difluoro-3- ( 1H- 1,
2,4-Triazol-1-yl) -2-propanol (0.50 g, 1.44 mmol) was added with 60% sodium hydride (75 mg, 1.87 mmol) in N, N-dimethylformamide (50 ml) under ice cooling. The solution was dropped into the solution at room temperature for 30 minutes.
Minutes. Then, under ice cooling, methyl iodide (270 mg,
(1.87 mmol) was added dropwise and stirred at room temperature for 1 hour. Water was added to the reaction solution, which was extracted with ether. The ether solution was washed with water, dried over sodium sulfate, and evaporated under reduced pressure. The obtained residue was applied to a silica gel column, and 1- [3- (cyclopropylthio) -2- (2,4-difluorophenyl) was obtained as a colorless oil from a chloroform eluate.
3,3-difluoro-2-methoxypropyl] -1 H
-1,2,4-triazole (0.31 g, yield 60
%).

MS (FAB): 362 (M + H) ¹ H-NMR (CDCl ₃ , δ): 0.54-0.98 (4H, m), 1.85-2.10 (1H,
m), 3.70 (3H, fine t, J = 2Hz), 1.09 (2H, t, J = 15Hz), 6.65-
6.94 (2H, m), 7.46-7.66 (1H, m), 7.78 (1H, s), 7.98 (1H,
s).

Example 11 1- [2- (benzyloxy) -3- (cyclopropylthio) -2- (2,4-difluorophenyl) -3,3-difluoropropyl]-
1H -1,2,4-triazole [compound (1a-
5) Synthesis of 1- [2- (benzyloxy) -3- (cyclopropylthio) -2-in the same manner as in Example 10 except that benzyl chloride was used instead of methyl iodide.
(2,4-difluorophenyl) -3,3-difluoro-propyl] The -1 H-1,2,4-triazole was obtained as a colorless oil.

MS (FAB): 438 (M + H) ¹ H-NMR (CDCl ₃ , δ): 0.56-0.99 (4H, m), 1.93-2.18 (1H,
m), 4.85 (1H, d, J = 14Hz), 5.13 (1H, d, J = 14Hz), 5.21 (1H, b
rs), 6.69-6.90 (2H, m), 7.38 (5H, s), 7.46-7.64 (1H, m),
7.77 (1H, s), 7.93 (1H, s).

Example 12 1- (Cyclopropylsulfonyl) -2- (2,4-difluorophenyl) -1,1
-Difluoro-3- ( 1H -1,2,4-triazol-1-yl) -2-propanol [compound (1c-
1)] Synthesis of 1- (cyclopropylthio) -2-
(2,4-difluorophenyl) -1,1-difluoro-3- ( 1H -1,2,4-triazol-1-yl)
To a solution of -2-propanol (2.3 g, 6.63 mmol) in dichloromethane (200 ml) was added 85% m-chloroperbenzoic acid (3.6 g, 14.58 mmol) at room temperature, and the mixture was stirred at room temperature for 12 hours. . After completion of the reaction, a saturated aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium bicarbonate were added to the reaction solution, and the mixture was stirred. The dichloromethane solution was separated, washed with water, dried over magnesium sulfate, and evaporated under reduced pressure. The obtained residue was crystallized from isopropyl ether-ethyl acetate to give 1- (cyclopropylsulfonyl) -2- (2,2) as colorless crystals.
4-difluorophenyl) -1,1-difluoro-3-
( 1H -1,2,4-triazol-1-yl) -2-
Propanol (1.9 g, yield 76%) was obtained.

Melting point: 155 to 156 ° C. IR (KBr) ν _max cm ^-1 : 3111, 1613, 1504, 1346. MS (FAB): 380 (M + H) ¹ H-NMR (CDCl ₃ , δ): 1.12 -1.45 (4H, m), 2.67-2.73 (1H,
m), 5.19 (1H, d, J = 14Hz), 5.33 (1H, d, J = 14Hz), 5.92 (1H, d, J = 14Hz)
s), 6.65-6.93 (2H, m), 7.67-7.73 (1H, m), 7.79 (1H, s),
8.07 (1H, s).

Example 13 1- (Cyclopropylsulfonyl) -2- (4-fluorophenyl) -1,1-difluoro-3- ( 1H -1,2,4-triazole-1-
Synthesis of yl) -2-propanol [compound (1c-2)]: 1- (cyclopropylthio) -2- (2,4-difluorophenyl) -1,1-difluoro-3- (1 H −
1- (cyclopropylthio) -2- (4) instead of 1,2,4-triazol-1-yl) -2-propanol
-Fluorophenyl) -1,1-difluoro-3- (1
Except for using H -1,2,4-triazol-1-yl) -2-propanol, as in Example 12, 1- (cyclopropylsulfonyl) -2- as colorless crystals.
(4-fluorophenyl) -1,1-difluoro-3-
( 1H -1,2,4-triazol-1-yl) -2-
Propanol was obtained.

Melting point: 197 to 199 ° C. IR (KBr) ν _max cm ^-1 : 3088, 1604, 1508, 1333. MS (FAB): 362 (M + H) ¹ H-NMR (CDCl ₃ , δ): 1.10 -1.18 (4H, m), 2.77-2.81 (1H,
m), 4.99 (1H, d, J = 15Hz), 5.14 (1H, d, J = 15Hz), 7.09-7.14
(2H, m), 7.54-7.58 (2H, m), 7.72 (1H, s), 8.21 (1H, s).

Example 14 1- (Cyclopropylsulfonyl) -1,1-difluoro-2- (4-trifluoromethylphenyl) -3- ( 1H -1,2,4-triazol-1-yl)- 2-propanol [compound (1c-
3)] Synthesis of 1- (cyclopropylthio) -2-
(2,4-difluorophenyl) -1,1-difluoro-3- ( 1H -1,2,4-triazol-1-yl)
1- (cyclopropylthio) -1,1-difluoro-2- (4-trifluoromethylphenyl) -3- ( 1H -1,2,4-triazol-1-yl) in place of -2-propanol Except for using 2-propanol, as in Example 12, 1- (cyclopropylsulfonyl) -1,1-difluoro-2- (4-trifluoromethylphenyl) -3- (1 H-1, 2, 4
-Triazol-1-yl) -2-propanol was obtained.

Melting point: 194 ° -195 ° C. IR (KBr) ν _max cm ⁻¹ : 3080, 1620, 1514, 1324. MS (FAB): 412 (M + H) ¹ H-NMR (CDCl ₃ , δ): 1.12 -1.21 (4H, m), 5.03 (1H, d, J = 1
5Hz), 5.20 (1H, d, J = 15Hz), 5.56 (1H, s), 7.66 (2H, d, J = 8H
z), 7.70 (1H, s), 7.75 (2H, d, J = 8Hz), 8.26 (1H, s).

Example 15 1- [3- (Cyclopropylsulfonyl) -2- (2,4-difluorophenyl)-
3,3-difluoro-2-methoxypropyl] -1 H -
Synthesis of 1,2,4-triazole [Compound (1c-4)]: 1- (cyclopropylthio) -2- (2,4-difluorophenyl) -1,1-difluoro-3-(1 H -
1- [3- (cyclopropylthio) -2 instead of 1,2,4-triazol-1-yl) -2-propanol
- (2,4-difluorophenyl) -3,3-difluoro-2-methoxy-propyl] except for using -1 H-1,2,4-triazole, in the same manner as in Example 12, as a colorless oil 1- [3- (cyclopropylsulfonyl)
2- (2,4-difluorophenyl) -3,3-difluoro-2-methoxypropyl] -1 H-1,2,4-
The triazole was obtained.

MS (FAB): 394 (M + H) ¹ H-NMR (CDCl ₃ , δ): 1.11-1.47 (4H, m), 2.46-2.62 (1H,
m), 3.75 (3H, s), 5.11 (1H, d, J = 15Hz), 5.36 (1H, d, J = 15H
z), 6.68-6.98 (2H, m), 7.45-7.72 (1H, m), 7.79 (1H, s),
8.08 (1H, s).

Example 16 1- [2- (benzyloxy) -3- (cyclopropylsulfonyl) -2- (2,2
4-difluorophenyl) -3,3-difluoro-propyl] -1 H-1,2,4-triazole [Compound (1c
-5)]: 1- (cyclopropylthio) -2-
(2,4-difluorophenyl) -1,1-difluoro-3- ( 1H -1,2,4-triazol-1-yl)
Instead of 2-propanol, 1- [2- (benzyloxy) -3- (cyclopropylthio) -2- (2,4-
Difluorophenyl) -3,3-difluoropropyl]
Except for using the -1 H-1,2,4-triazole, in the same manner as in Example 12, as colorless crystals 11- [2- (benzyloxy) -3- (cyclopropylsulfonyl) -
To give 2- (2,4-difluorophenyl) -3,3-difluoro-propyl] The -1 H-1,2,4-triazole.

Melting point: 124 to 125 ° C. IR (KBr) ν _max cm ^-1 : 1616, 1499, 1347. MS (FAB): 470 (M + H) ¹ H-NMR (CDCl ₃ , δ): 1.10-1.15 (2H, m), 1.33-1.37 (2H,
m), 2.50-2.54 (1H, m), 5.02 (1H, d, J = 10Hz), 5.11 (1H, d, J
= 10Hz), 5.31 (1H, d, J = 15Hz), 5.45 (1H, d, J = 15Hz), 6.80-
6.87 (2H, m), 7.31-7.46 (5H, m), 7.58-7.64 (1H, m), 7.79
(1H, s), 8.02 (1H, s).

Example 17 1- (Cyclopropylsulfonyl) -2- (2,4-difluorophenyl) -1,1
Optical resolution of -difluoro-3- ( 1H -1,2,4-triazol-1-yl) -2-propanol: (±)-
1- (cyclopropylsulfonyl) -2- (2,4-difluorophenyl) -1,1-difluoro-3- ( 1H
30 mg of -1,2,4-triazol-1-yl) -2-propanol was applied to a chiral cell OD optically active substance separation column (manufactured by Daicel Chemical Industries, Ltd.), and hexane: isopropyl alcohol = 4: 1 eluted. From the fractions, 14 mg of a colorless crystal (+) form (100% ee optical purity) and 13 mg of a colorless crystal (−) form (100% ee optical purity) were obtained in the order of elution.

(1) (+)-1- (cyclopropylsulfonyl) -2- (2,4-difluorophenyl) -1,
1-difluoro-3- ( 1H -1,2,4-triazol-1-yl) -2-propanol: [α] _D ^21.7 + 22.5 ° (C = 0.1, aceton
e) Melting point: 130-132 ° C IR (KBr) ν _max cm ^-1 : 3111, 1613, 1504, 1346. MS (FAB): 380 (M + H) ¹ H-NMR (CDCl ₃ , δ): 1.12 1.45 (4H, m), 2.67-2.73 (1H,
m), 5.19 (1H, d, J = 14Hz), 5.33 (1H, d, J = 14Hz), 5.92 (1H, d, J = 14Hz)
s), 6.65-6.93 (2H, m), 7.67-7.73 (1H, m), 7.79 (1H, s),
8.07 (1H, s).

(2) (-)-1- (cyclopropylsulfonyl) -2- (2,4-difluorophenyl) -1,
1-difluoro-3- ( 1H -1,2,4-triazol-1-yl) -2-propanol: [α] _D ^21.7 −24.5 ° (C = 0.1, aceton
e) Melting point: 130-132 ° C IR (KBr) ν _max cm ^-1 : 3111, 1613, 1504, 1346. MS (FAB): 380 (M + H) ¹ H-NMR (CDCl ₃ , δ): 1.12 1.45 (4H, m), 2.67-2.73 (1H,
m), 5.19 (1H, d, J = 14Hz), 5.33 (1H, d, J = 14Hz), 5.92 (1H, d, J = 14Hz)
s), 6.65-6.93 (2H, m), 7.67-7.73 (1H, m), 7.79 (1H, s),
8.07 (1H, s).

Example 18 1- (Cyclopropylsulfonyl) -2- (4-fluorophenyl) -1,1-difluoro-3- ( 1H -1,2,4-triazole-1-
Il) Optical resolution of 2-propanol: (±) -1-
(Cyclopropylsulfonyl) -2- (4-difluorophenyl) -1,1-difluoro-3- ( 1H- 1,
30 mg of 2,4-triazol-1-yl) -2-propanol was applied to a column for separation of chiral cell OD optically active substance (manufactured by Daicel Chemical Industries, Ltd.). In the order of elution, 10 mg of the (+) form of colorless crystals (100% ee in optical purity) and 10 mg of the (-) form of colorless crystals (100% in ee) were obtained.

(1) (+)-1- (cyclopropylsulfonyl) -2- (4-fluorophenyl) -1,1-difluoro-3- (1H-1,2,4-triazole-1
-Yl) -2-propanol: [α] _D ^21.7 + 22.5 ° (C = 0.1, aceton
e) Melting point: 144-145 ° C IR (KBr) ν _max cm ^-1 : 3122, 1605, 1514, 1332. MS (FAB): 362 (M + H) ¹ H-NMR (CDCl ₃ , δ): 1.10- 1.18 (4H, m), 2.77-2.81 (1H,
m), 4.99 (1H, d, J = 15Hz), 5.14 (1H, d, J = 15Hz), 7.09-7.14
(2H, m), 7.54-7.58 (2H, m), 7.72 (1H, s), 8.21 (1H, s).

(2) (-)-1- (cyclopropylsulfonyl) -2- (4-fluorophenyl) -1,1-difluoro-3- ( 1H -1,2,4-triazole-1
-Yl) -2-propanol: [α] _D ^21.7 −23.5 ° (C = 0.1, aceton
e) Melting point: 145-146 ° C IR (KBr) ν _max cm ^-1 : 3122, 1605, 1514, 1332. MS (FAB): 362 (M + H) ¹ H-NMR (CDCl ₃ , δ): 1.10- 1.18 (4H, m), 2.77-2.81 (1H,
m), 4.99 (1H, d, J = 15Hz), 5.14 (1H, d, J = 15Hz), 7.09-7.14
(2H, m), 7.54-7.58 (2H, m), 7.72 (1H, s), 8.21 (1H, s).

Test Example 1 Candida albicans ( Cand
to each well of action (in vitro) 96-well microplate for ida albicans), 10% fetal bovine serum pressurized MEM medium (glutamine, drug dilutions were prepared in carbonate-containing) dispensed 75μl fraction, further the same medium 4.0 × 10 ⁴ cells / ml of suspended C. albicans ATCC 44859
Was added at 37 ° C. in a carbon dioxide gas incubator.
For 24 hours. After culturing, the morphological changes of C. albicans were observed under an inverted microscope, and the minimum drug concentration that clearly inhibited mycelial growth compared to the control without drug was determined as the endpoint (ng
/ Ml). In addition, fluconazole and known compound A ((-)-compound (1c-1) of JP-A-9-227331) were used as comparative drugs. Table 1 shows the results.

Test Example 2 Effect on Aspergillus fumigatus ( in vitro ) In each well of a 96-well microplate, 0.165M MOPS-containing RPMI1640 medium (glutamine, phenol red-containing, carbonate-free; pH 7) was added. 100 μl of the prepared drug diluent was dispensed, and 20% alamar Blu
6.0 × 10 ⁴ conidia / ml suspended in the same medium containing
Add 100 μl of A. fumigatus IFM 40808 spore solution and add
The cells were cultured at 5 ° C for 48 hours. Judgment was made by visual observation, and the minimum drug concentration at which the medium did not turn red (keeped blue) was defined as the MIC value (μg / ml). In addition, fluconazole and a known compound A ((-) of Japanese Patent Application Laid-Open No.
-Compound (1c-1)) was used. Table 1 shows the results.

[0082]

[Table 1]

Test Example 3 Candida albicans ( Cand
Action on Ida albicans ( in vivo ) ICR strain (CRJ: CD-1) 4-week-old male mice were fasted for 6 hours, and then C. albicans IFM 40009 was treated with 3.
The mice were inoculated into the tail vein at a concentration of 0 × 10 ⁶ cells / mouse to establish infection. Control group is 11 per group
Each group consisted of 5 animals, each group consisting of 5 animals. The drug dissolved in 20% polyethylene glycol was administered once at 1 hour after inoculation of the bacteria, and once a day after 24 hours, once a day for a total of 4 times at a dose of 1.25 mg / kg each. Was administered. The survival status up to 14 days after infection was compared. In addition, the survival days of the control group and each drug administration group were
The test was performed by the Kaplan-Meier method (Cox mantel test). In addition, fluconazole was used as a comparative drug. Table 2 shows the results
Shown in

[0084]

[Table 2]

Example 19 Tablet

[0086]

[Table 3] Compound of Example 17 (2) 50 mg Microcrystalline cellulose 50 mg Lactose 50 mg Hydroxypropyl cellulose 18 mg Magnesium stearate 2 mg Total 170 mg

A tablet having the above composition was produced by a conventional method.
These tablets can be made into sugar-coated tablets and film-coated tablets, if necessary.

Example 20 Capsule

[0089]

Table 4 Compound of Example 17 (2) 50 mg Light anhydrous silicic acid 25 mg Lactose 100 mg Starch 50 mg Talc 25 mg Total 250 mg

The above components were filled in No. 1 capsule to obtain a capsule.

Example 21 Granules

[0092]

Table 5 Compound of Example 17 (2) 50 mg Lactose 600 mg Corn starch 200 mg Sodium carboxymethyl cellulose 20 mg Hydroxypropyl cellulose 130 mg Total 1000 mg

A granule having the above composition was produced by a conventional method.

Example 22 Powder

[0095]

Table 6 Compound of Example 17 (2) 50 mg Light anhydrous silicic acid 20 mg Precipitable calcium carbonate 10 mg Lactose 250 mg Starch 70 mg Total 400 mg

A powder having the above composition was produced by a conventional method.

Example 23 Injection

[0098]

Table 7 Compound of Example 17 (2) 5 mg Hardened castor oil 85 mg Propylene glycol 60 mg Glucose 50 mg Distilled water for injection qs 1 ml in total

An injection having the above composition was produced by a conventional method.

Example 24 Intravenous Infusion

[0101]

Table 8 Compound of Example 17 (2) 50 mg Hardened castor oil 5 g Propylene glycol 10 mg Glucose 14.5 mg Distilled water for injection qs 100 ml

An intravenous infusion having the above composition was produced by a conventional method.

[0103]

Industrial Applicability The triazole derivative of the present invention or a salt thereof has high antifungal activity, and an antifungal agent containing the triazole derivative as an active ingredient is useful for preventing and treating fungal infections in mammals including humans.

 ────────────────────────────────────────────────── ─── Continuing on the front page (72) Inventor Kazuya Ishida 2-38-1 Kotsu no Mori, Narita City, Chiba Prefecture Berheim B-203 (72) Inventor Kazuki Maebashi 5-9-13-502 Motokubo, Narashino City, Chiba Prefecture (72) Inventor Masaru Matsumoto 6-12-18 Hiyoshidai, Tomisato-cho, Inba-gun, Chiba Prefecture (72) Inventor Takemitsu Asaoka 1-17-1-306, Karabe, Narita City, Chiba Prefecture (72) Inventor Susumu Sato, Narita Chiba Prefecture 6-15-5 Ichitamazo

Claims (6)

[Claims] 1. The following general formula (1): [Wherein, R ¹ represents a hydrogen atom, a lower alkyl group or an aralkyl group, X ¹ and X ² are the same or different and represent a hydrogen atom, a halogen atom or a halogenoalkyl group, and n is an integer of 0 to 2. Or a salt thereof. 2. The following general formula (2): [Wherein X ¹ and X ² are the same or different and each represent a hydrogen atom, a halogen atom or a halogenoalkyl group], and a 2,2-difluoro-2-cyclopropylthioacetophenone derivative represented by the following formula: 3. The following general formula (3): [Wherein X ¹ and X ² are the same or different and each represent a hydrogen atom, a halogen atom or a halogenoalkyl group]. 4. The following general formula (2): Wherein X ¹ and X ² are the same or different and each represent a hydrogen atom, a halogen atom, or a halogenoalkyl group; a 2,2-difluoro-2-cyclopropylthioacetophenone derivative represented by the following formula: Reacting 1,2,4-triazole or a salt thereof,
The method for producing a triazole derivative or a salt thereof according to claim 1, wherein the tertiary hydroxyl group is alkylated as necessary, and further oxidized as needed. 5. A medicament comprising the triazole derivative according to claim 1 or a salt thereof as an active ingredient. 6. The medicament according to claim 5, which is an antifungal agent.