WO1995026343A1 - Novel triazole derivative and antimycotic agent containing the same as active ingredient - Google Patents

Abstract

An antimycotic triazole derivative represented by general formula (I), a physiologically acceptable salt thereof, and an antimycotic agent containing the same as the active ingredient: wherein R?1 and R2¿ represent each independently hydrogen, lower alkyl or cycloalkyl, or R?1 and R2¿ are combined together to represent alkylene; R3 represents lower alkyl, cycloalkyl, alkyl having a double bond(s), optionally substituted heterocycle or -NR5R6; R5 represents hydrogen or lower alkyl and R6 represents optionally substituted heterocycle, or R?5 and R6¿ are combined together to represent sulfur-containing alkylene; R4 represents hydrogen or lower alkyl; X1 represents hydrogen, halogen or trifluoromethyl; X2 represents hydrogen or halogen; and n represents 0 to 2. These substances have a remarkably potent antimycotic activity and are useful for curing animal and human superficial and deep-seated mycoses.

Description

 Description Novel triazole derivative and antifungal agent containing the same as active ingredient

 The compound of the present invention relates to a triazole derivative having antifungal activity. Background art

 Conventionally, various compounds have been known as antifungal agents. For example,

—230038, JP-A-5-49775, JP-A-4-3656471 and JP-A-5-3457768 describe compounds similar to the compounds of the present invention. is there. The present inventors have made intensive studies to find a compound having more effective antifungal activity. As a result, newly synthesized triazole derivatives and physiologically acceptable salts thereof are particularly clinically useful. It is an extremely important antifungal agent against Aspergillus (A spergi 11 us), a bacterium of the genus Caspida which is a very important cause of candidiasis (C andida). The present invention has been found to be a compound that is more excellent in safety than known compounds and has arrived at the present invention. An object of the present invention is to provide a triazole derivative useful as an antifungal agent. Disclosure of the invention

The present invention provides a compound represented by the following general formula (I): One R ³

(Wherein, R ¹ and R ² each represent a hydrogen atom, a lower alkyl group or a cycloalkyl group, or R ¹ and R together represent an alkylene group, and R ³ represents a lower alkyl group or a cycloalkyl group. Represents an alkyl group, an alkyl group having a double bond, a heterocyclic ring which may have a substituent or one NR ⁵ R ⁶ , wherein R ⁵ is a hydrogen atom or a lower alkyl group, and R ⁶ has a substituent. And R "and R ^Q together represent an alkylene group having a sulfur atom; R ⁴ represents a hydrogen atom or a lower alkyl group; X ¹ represents a hydrogen atom, a halogen atom or X ² represents a hydrogen atom or a halogen atom, and n represents 0 to 2.) A triazole derivative represented by the formula (I), a physiologically acceptable salt thereof, and an antibody containing these as an active ingredient. It is a fungicide.

In the triazole derivative (I) of the present invention, the lower alkyl group may be a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert.-butyl group, a pentyl group, a hexyl group. Cycloalkyl groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group; and alkylene groups such as methylene group, ethylene group, trimethylene group, tetramethylene group, pentamethylene group, etc. Examples of the alkyl group having a double bond include a prenyl group, a geranyl group, and a phenyl group. Examples of the optionally substituted heterocyclic ring such as a nesyl group include 4-methyl-4H—1,2,4-triazolyl-3-yl group and 4H—1,2,4— Rear zone 3-inole group, imidazo group 2-inole group, imidazo group 41-yl group, tetrazole-5-yl group, 2-furyl group, 3-furyl group, 2 —Chenyl group, .3 —Cenyl group, thiazol-2-yl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2 — (methylsulfonyl) pyridin-5-yl Group, 2 — (methylsulfinyl) pyridin — 5 —yl group, 2 — (methylthio) pyridin-1-yl group, 5 — (methylsulfonyl) pyridin-1-yl group, 5 — (methyl Sulfinyl) pyridin-2-yl group, 5— (methylthio) pyridin-2-yl group, 2—fluoro Resin-1 5 —yl group, 5 —Fluoropyridin— 2 —yl group, 2 —Black mouth pyridin-5-yl group, 5 —Chloropyridin-1 2 —yl group, 2 — Tri group Fluoromethylpyridin-1-yl, 5—Trifluoromethylpyridine—2—yl, 2—Methoxypyridin-5-yl, 5-Methoxypyridin-12-yl, 2—ethoxypyridin-5-yl group, 5—ethoxypyridin-12-yl group or N-oxide, pyrazine-12-yl group, pyrazol-3-yl group, pyrazole of these pyridine rings — 4-yl group, pyrrole— 2-yl group, 1-methylvirazole—3-yl group, 1—methylpyrazole-4-yl group, 1—methylvirazole—5—yl group, 1-methylpyrrole 1 2 —yl group, 1 —methylpyrroyl 3-yl group, 1-vinyl alcohol Amino having substituents such as 3-yl group, 1-vinylpyrazole-4-yl group, 1-phenylpyrazole-5-yl group, 1-phenylpyrrolyl-2-yl group, etc. Examples of the group (—NR “R ⁶ ) include (3,5 dichloro-m-pyridin-2-yl) amino, (1-ethylfurazol-3-yl) amino, and (5— Methyl-1,3,4-thiadiazol-2-yl) amino group, (2-methoxypyridine-1-yl) amino group, (3 1-methylisothiazol-5-yl) amino group, (5-methylisoxazol-3-yl) amino group, (4-methylthiazol-2-yl) amino group, (thiazole-2— Amino group, (1,2,4—triazine--3-yl) amino group, (5-trifluoromethyl-1,3,4-thiadiazol-2-yl) amino And the like.

 The triazole derivative (I) of the present invention has at least one asymmetric center, and has a plurality of optical isomers and diastereomers, each of which or a mixture thereof is included in the present invention.

 The physiologically acceptable salts of the triazole derivative (I) of the present invention include salts with inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, hydrogen bromide, hydrogen iodide, phosphoric acid, acetic acid, tartaric acid, fumaric acid and the like. Examples thereof include salts with organic acids such as acid, maleic acid, lingic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid, and salts with alkali metals such as sodium and potassium. Hydrates of the triazole derivative (I) and physiologically acceptable salts thereof are also included in the present invention.

The triazole derivative (I) of the present invention can be produced according to the following reaction steps (in each formula, RRR′RRRRXX ² and n are as defined above.)

 [Production method 1]

(II) (R ⁴ : hydrogen atom)

Hydrogen peroxide) -R ³

特開平 4 - 7 4 1 6 8号公報に記載のエポキシ体 （II) を溶媒に溶解 し、 炭酸力リゥム、 炭酸ナ ト リウム、 水酸化力リゥム、 水酸化ナ 卜 リ ゥ ム、 カリウム t e r t . —ブトキシ ド、 金属ナ ト リゥム等の塩基の存 在下、 チォ一ルケ ト ン体 （III ) と反応させることによって ト リァゾ一 ル誘導体 （ I ) (n = 0 ) を製造することができる。 溶媒としてはメ タ ノール、 エタノール、 プロパノール、 ブタノール、 ジメチルスルホキシ ド （ D M S O ) 、 ジメチルホルムアミ ド （ D M F ) 、 ベンゼン、 トルェ ン等が使用される。 反応温度は一 2 0°Cから溶媒の沸点までであり、 好 ま しくは室温から 1 2 0 °Cで行う。

The epoxy compound (II) described in Japanese Patent Application Laid-Open No. 4-74168 is dissolved in a solvent, and carbonic acid lime, sodium carbonate, hydroxylic lime, sodium hydroxide, and potassium tert. — Presence of bases such as butoxide and metallic sodium In the presence, a triazole derivative (I) (n = 0) can be produced by reacting with a diol ketone (III). As the solvent, methanol, ethanol, propanol, butanol, dimethylsulfoxide (DMSO), dimethylformamide (DMF), benzene, toluene, or the like is used. The reaction temperature is from 120 ° C to the boiling point of the solvent, preferably from room temperature to 120 ° C.

 Optically active epoxy (II) and optically active thiol ketone (III)

(R ¹ and R ² are different) under the same conditions, an optically active triazole derivative (I) can be produced.

Further, the optically active epoxy material (II) and Chio one Luque tons member (III) after the (R ¹ and R ² are different) was reacted under the same conditions, resulting Jiasutereo mer (Epima) the Karamukuroma bets chromatography The optically active triazole derivative (I) (n = 0) can be produced by separation by a commonly used separation method such as a fractional recrystallization method.

(2 R *, 3 S *) or (2 R-, 3 R *) —Epoxy (II) and optically active thiol ketone (III) (R ¹ and R ² are different) under similar conditions After the reaction in step (a), the optically active triazole derivative (I) (n = 0) can also be obtained by resolving the diastereomer formed by a commonly used resolving method such as column chromatography or fractional recrystallization. Can be manufactured.

[Production method 2] SH

 (IV)

R ³

特開平 4 - 7 4 1 6 8号公報に記載の方法により製造されるチオール 体 （IV) を溶媒に溶解し、 炭酸カリウム、 炭酸ナ ト リウム、 水酸化力 リ ゥム、 水酸化ナ ト リウム、 カリウム t e r t . —ブトキシ ド、 金属ナ ト リウム等の塩基で処理した後、 ハロゲノケ トン体 （V) と反応させる ごとによって ト リァゾ一ル誘導体 （ I ) (n = 0) を合成することがで きる。 溶媒としてはメタノール、 エタノール、 プロパノール、 ブタノー ル、 ジメチルスルホキシ ド （DM SO) 、 ジメチルホルムアミ ド （DMF) 、 ベンゼン、 トルエン等が使用される。 反応温度は— 3 0 °Cから溶媒の沸 点までであり、 好ましくは一 1 0〜 7 0°Cで行う。 Oxidizing agent (eg, m-CPBA, hydrogen peroxide)

The thiol compound (IV) produced by the method described in Japanese Patent Application Laid-Open No. 4-74168 is dissolved in a solvent, and potassium carbonate, sodium carbonate, hydrating water, sodium hydroxide are dissolved. After treatment with a base such as potassium tert.-butoxide or sodium metal, the triazole derivative (I) (n = 0) can be synthesized by reacting with the halogenoketone (V). Wear. As the solvent, methanol, ethanol, propanol, butanol, dimethylsulfoxide (DMSO), dimethylformamide (DMF), benzene, toluene and the like are used. The reaction temperature is from −30 ° C. to the boiling point of the solvent, and preferably from 110 to 70 ° C.

In addition, the optically active thiol (IV) and the optically active halogenoketone (V) (R ¹ and R ² are different) are reacted under the same conditions to obtain the optically active triazole derivative (I) (n = 0) can be manufactured.

After the optically active thiol body (IV) and Harogenoke tons bodies (V) (R ¹ are different) was reacted under the same conditions, resulting Jiasutereoma (E Pima) the Karamukuroma bets chromatography, fractional recrystallization, etc. The optically active triazole derivative (I) (n = 0) can be produced by resolving by a commonly used resolving method.

Incidentally, optically active thiol body (IV) is, (2 R-, 3 R * ) or ^{(2 R *, 3 S τ} ) Chioru body and (IV) Nyu- Toshirupuro suitable optically active, such as Li down After reacting an organic acid or its acid chloride with an appropriate dehydrating condensing agent such as hexylcarbodiimide, the obtained diastereomer is usually used in column chromatography, fractional recrystallization and the like. After splitting by a splitting method, it can be produced by hydrolysis. In addition, (2R *, 3R *) or (2, 3S *) — thiol form (IV) and optically active halogenoketone form (V) (R ¹ and R ² are different) under the same conditions After the reaction, the resulting diastereomer is subjected to column chromatography, The optically active triazole derivative (I) (n = 0) can also be produced by dividing by a commonly used dividing method such as a fractional recrystallization method.

 [Production method 3]

,Hydrogen oxide)

,

-R ³

The sulfonate (VI) is dissolved in a solvent, and the presence of a base such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium tert.-butoxide, metal sodium, etc. The triazole derivative (I) (n = 0) can be produced by reacting with the thiol ketone (III). As the solvent, methanol, ethanol, propanol, butanol, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), benzene, toluene and the like are used. The reaction temperature is from 120 ° C to the boiling point of the solvent, preferably from 0 to 120 ° C. When the optically active sulfonate (VI) and the optically active thiol ketone (III) (R ¹ and R ² are different) are reacted under the same conditions, the optically active triazole derivative (I) ( n = 0) can be produced.

After the optically active Suruhone preparative member (VI) and Chioruke tons body (III) (R ¹ and R ² are different) are reacted under the same conditions, resulting Jiasutereo mer (Epima) the Karamukuroma bets chromatography, fractional The optically active triazole derivative (I) (n = 0) can be produced by dividing by a commonly used dividing method such as a crystallization method. Further, (2 R *, 3 R *) or (2 R *, 3 S * ) - Suruhone Bokutai (VI) with an optically active Chioruke tons member (III) (R ¹ and R ² are different) similar After reacting under the conditions, the resulting diastereomer is separated by a commonly used separation method such as column chromatography, fractional recrystallization, etc., to produce the optically active triazole derivative (I) (n = 0). Can be built.

 [Production method 4]

 (IX)

Dimethyl sulfoxonium methylide or dimethyl sulfoxonium methylide

(X)

(X)

Alkaline gold urine salt of 1,2,4-triazole or 1,2,4-triazole and base

 Contact

酸化剤 （例； m-CPBA， 過酸化水素）

Oxidizing agent (eg, m-CPBA, hydrogen peroxide)

An appropriate protecting group for a carbonyl group, such as a thiol ketone compound (VIII) protected by acetal, is dissolved in a solvent, and potassium carbonate, sodium carbonate, hydroxylated sodium hydroxide, sodium hydroxide, and potassium hydroxide are dissolved in a solvent. After treatment with a base such as tert. butoxide, metal sodium, etc., it is reacted with a healogenop-opened piofunone compound (VII) to produce an intermediate (IX). By reacting this with dimethylsulfonium methylide or dimethyloxosulfonium methylide, an epoxy compound (X) is produced, and then an alkali metal salt of 1,2,4-triazole or 1,2, Suitable solvents in the presence of 4 -triazole and bases such as carbon dioxide, sodium carbonate, hydroxide, sodium hydroxide, potassium tert.-butoxide, and sodium metal To produce the intermediate (XI). The intermediate (XI) is heated in the presence of an appropriate deprotecting agent such as an acid to remove the protecting group, whereby a triazole derivative (I) (n = 0) can be produced.

When an optically active protected thiol ketone (VIII) is used, the diastereomer intermediate (IX) formed is separated by column chromatography and fractionation. An epoxy compound (X) which is a diastereomer (epimer) is produced by a separation by a commonly used separation method such as a recrystallization method, and a reaction of this with dimethylsulfonium methylide or dimethyloxosulfonium methylide. . This epoxy compound (X) is separated by a commonly used separation method such as column chromatography, fractional recrystallization, and the like, and then an alkali metal salt of 1,2,4-triazole or 1,2,4-triazole is added to Optical reaction by reacting in a suitable solvent in the presence of a base such as sodium carbonate, sodium carbonate, sodium hydroxide, sodium hydroxide, potassium tert.-butoxide, metal sodium, etc. Produce the active intermediate (XI). The intermediate (XI) is heated in the presence of an appropriate deprotecting agent such as an acid to remove the protecting group to produce an optically active triazole derivative (I) (n = 0). Can be.

In the case of using an optically active phenyllogenopropionone derivative (VII) and a protected thiol ketone derivative (VIII), an optically active triazole derivative (VIII) can be obtained in the same manner as described above. I) (n = 0). If using optically active α- halogeno-prop-off We Roh emissions body and (VII) optically active protected been Chioruke tons body (VIII) (R ¹ and R ² are different) is a Jiasutereoma (Epima) An epoxy compound (X) can be separated by a conventional method, and then reacted and treated in the same manner to produce an optically active triazole derivative (I) (η = 0).

 [Production method 5]

(IX)

製造法 4で得られる中間体 （IX) と （ 1 H— 1 , 2 , 4— ト リアゾ一 ノレ一 1 一ィル） メチルハライ ドとマグネシウムから製造される （ I H.— 1 , 2， 4一 ト リァゾールー 1 一ィル） メチルマグネシウムハライ ドを 反応させて中間体 （XI) を製造することができる。 光学活性な中間体 （Π) を使用した場合、 生成するジァステレオマー （ェピマー） の中間体 （XI) をカラムクロマ トグラフィー、 分別再結晶法等の通常用いられる分割法 により分割し、 酸等の適当な脱保護剤の存在下加熱することによって保 護基を除去して、 光学活性な ト リァゾ一ル誘導体 （ I ) (_n = 0 ) を製 造することができる。

Intermediate (IX) obtained by Production Method 4, (1H-1,2,4-triazo-1-yl) methyl halide and magnesium (IH.-1,2,4) Intermediate (XI) can be produced by reacting 1-triazole-1-methyl) methyl magnesium halide. When an optically active intermediate (Π) is used, the diastereomer (epimer) intermediate (XI) to be formed is separated by a commonly used separation method such as column chromatography, fractional recrystallization, etc. The protective group can be removed by heating in the presence of a deprotecting agent to produce an optically active triazole derivative (I) ( _n = 0).

 [Production method 6]

(When R ¹ is a thigh alkyl group and R ² is a hydrogen atom)

-R ³

Lukir Khalid

(n=0〜1の場合）

(when n = 0 to 1)

 Oxidizing agent (eg, m-CPBA, hydrogen peroxide)

(When R ¹ and R ² represent a lower alkyl group at the same time, or R ¹ and R ^{2 form} an alkylene group together)

Killha ride

化水素）

Hydrogen)

When R ¹ and R ² in the triazole derivative (I) are a hydrogen atom, such as sodium metal, sodium hydride and potassium tert.-butoxide in an equivalent mole to the triazole derivative (I). By reacting with an appropriate base and then reacting with an equimolar amount of a lower alkyl halide, a triazole derivative (I) in which ^one of R ^{1 and} R ² is a lower alkyl group can be produced. ·

In the optically active triazole derivative (I), when R ¹ and R ² are hydrogen atoms, metal sodium, sodium hydride, and potassium tert. Equivalent to the triazole derivative (I) in an equimolar amount. Deactivates bases such as butoxide And then reacting with an equimolar amount of a lower alkyl halide to produce a triazole derivative (I) (a diastereomer (epimer)) in which either R ¹ or R ² is a lower alkyl group. Can be done. This is resolved by a commonly used resolution method such as column chromatography, fractional recrystallization, etc., to obtain an optically active triazole derivative (I) in which either R ¹ or R ² is a lower alkyl group. (n = 0) can be manufactured.

In addition, after reacting the triazole derivative (I) with a base such as sodium metal, sodium hydride, potassium tert.-butoxide of about 2 moles, about 2 moles of lower alkylhalide is reacted. Or an equimolar amount of a dihalogenoalkylene to form a triazole derivative (I) in which R ¹ and R ² are lower alkyl groups, or R ¹ and R ² together form an alkylene group The triazole derivative (I) can be produced. As the solvent, methanol, ethanol, propanol, butanol, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), benzene, toluene and the like are used. The reaction temperature is from 120 ° C to the boiling point of the solvent, preferably from 0 to 120 ° C.

 The triazole derivative (I) (II = 1 or 2) can be prepared by adding the triazol derivative (I) (n = 0) in an appropriate solvent to a peroxide such as m-chloroperbenzoic acid (m-CPBA) or hydrogen peroxide. It can be synthesized by reacting with an oxide. As the reaction solvent, chloroform, dichloromethane, carbon tetrachloride, methanol, acetic acid, ethyl acetate and the like are used. The reaction temperature ranges from 140 ° C to the boiling point of the solvent, and is preferably from 0 ° C to room temperature.

 The triazole derivative (I) of the present invention can be converted into a physiologically acceptable salt by adding an appropriate acid or base.

The compounds of the present invention can be used as such or in combination with commonly used pharmaceutical additives. It can be administered orally or parenterally in the form of tablets, capsules, powders, granules, injections, syrups, suspensions, emulsions, suppositories, etc. Although it depends on the body weight and the route of administration, it can usually be adjusted appropriately within the range of 0.1 llS OmgZkg per day. They can also be used as external preparations such as ointments, creams, sprays, jellies, solutions, etc., and the amount added is, for example, 0.1 to 1 g per 1 g of additives. A range of 50 mg is preferred. BEST MODE FOR CARRYING OUT THE INVENTION

 [Reference Example 1]

 2—Propionylfuran:

 A mixture of 6.80 g of furan and 14.97 g of propionic anhydride was cooled on ice, and 1.23 ml of boron trifluoride getyl ether complex was added dropwise over 5 minutes. Thereafter, the reaction temperature was raised to 110 ° C., and the mixture was allowed to cool at room temperature. The reaction solution was poured into ice water (10 Om 1) and extracted twice with getyl ether (100 ml). The ether layers were combined, washed with water, dehydrated with a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained oily product was purified by silica gel chromatography (n-hexane: ethyl acetate = 97: 3) to obtain 5.10 g of 2-propionylfuran.

 ½-Mardal R (CDC 1.) 5 p pm: 1.21 (3 H, t, J = 7Η ζ), 2.86 (2Η, q, J = 7Η ζ), 6.53 (1Η, dd, J = 2, 3 2 ζ), 7.18 (1Η, d, J = 3Η ζ), 7.57 (1Η, d, J = 2Η ζ)) ο

 [Reference Example 2]

 2- (2-bromopropionyl) furan:

1.25 g of 2-propionylfuran obtained in Reference Example 1 was No. (50 ml), and 3.36 g of pyridinamide was added under stirring at room temperature, followed by stirring for 4 hours. After completion of the reaction, the mixture was poured into ice water (100 ml) and extracted twice with getyl ether (500 ml). The organic layers were combined, washed with water, dehydrated with a saturated saline solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.80 g of 2- (2-bromoprozeonyl) furan.

½-Marauder R (CDC 1 ₃ ) δ p pm: 1.87 (3 H, d, J = 7 H z), 5.16 (1 H, q, J = 7 H z), 6.60 (1H, dd, J = 2, 3Hz), 7.35 (1H, d, J = 3Hz), 7.65 (1H, d, J = 2Hz).

 [Reference Example 3]

 3-Propionyl-1-4-methyl-4H-1,2,4-triazonole: 4-methyl-4H-1,2,4-triazonole 1.65 g is added to tetrahydrofuran (80 ml). After dissolving, 25.9 ml of lithium bis (trimethylsilyl) amide (1 M tetrahydrofuran solution) was added dropwise at 125 ° C. under a stream of argon over 5 minutes. Thereafter, the mixture was stirred at −20 to −25 ° C. for 15 minutes, cooled to 130 ° C., and N, N-dimethylpropionamide 2.84 ml was added dropwise over 1 minute. After stirring at room temperature for 2 hours, a saturated aqueous ammonium chloride solution (50 ml) was added, and the mixture was separated to separate a tetrahydrofuran layer. The aqueous layer was extracted with tetrahydrofuran (50 ml), and the organic layers were combined and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained oil was purified by silica gel chromatography (chloroform: methanol = 98: 2) to give 3-propionyl 4-methyl-4H-1, 2.32 g of 2,4-triazole was obtained.

½-NMR (CDC) δ p pm: 1.24 (3H, t, J = 7Hz), 3.27 (2H, q, J = 7Hz), 3.98 (3H, s), 8.20 (1H, s).

 [Reference Example 4]

 3 — (2 —Bromopropionyl) 1-4 monomethyl — 4 H— 1, 2, 4-triazole hydrobromide:

 2.0 g of 3-propionyl-4-monomethyl-4H-1,2,4-triazole obtained in Reference Example 3 was dissolved in acetic acid (10 ml), and bromine 0.7 was stirred at room temperature. 4 ml was added and the mixture was stirred at 60 to 70 ° C for 9 hours. After completion of the reaction, the reaction solution was allowed to cool, ethyl acetate (50 ml) was added, and the mixture was stirred for 30 minutes. The precipitated crystals are collected by filtration, washed with ethyl acetate and dried, and 3.17 g of 3- (2-bromopropionyl) -4-methyl-4H-1,2,4-triazole hydrobromide is added. Obtained.

^ - NMR (DM SO - d 6) <5 ppm:. 1 8 1 (3 H, d, J = 7 H z), 3. 9 0 (3 H, s), 5. 7 6 (1 H, q, J = 7Hz), 8.87 (1H, s).

 [Reference Example 5]

 4- (2-bromopropionyl) thiomorpholine:

 To a solution of 2.30 g of thiomorpholine in benzene (30 ml) was added dropwise 2.0 g of 2-bromopropionyl bromide with stirring under ice cooling. After completion of the dropwise addition, the reaction solution was stirred under water cooling for 20 minutes, and then stirred at room temperature for 3 hours. Water (100 ml) was added to the reaction solution, and extracted with ethyl acetate (100 ml). The organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 2.23 g of oily 4- (2-bromopropionyl) thiomorpholine.

¹ H-NMR (CDC 1) δ ppm: l 82-1.85 (3 H, m), 2.55-2.73 (3 H, m), 28 3-2.91 (1H, m), 3.67 to 3.75 (2H, m), 3886 to 3.93 (1H, m), 4.11 to 4.17 (lH, m), 4.53 (1H, q, J = 7Hz) ₀ [Example 1]

 (2 R *, 3 R *)-3-(1-acetylethyl) thio-2-(2,4-difluoro-phenyl)-1-1 (1 H-1, 2, 4-1-tri-1-) Le) Butane-1-ol (Compound No. 1):

 (2 R *, 3 R *) 1-2-(2,4-difluorophenyl)-1-3-mercapto 1-1 (1 H-1, 2, 4-triazole-1-1 yl) butane 0.47 g was dissolved in ethanol (14 ml) under a stream of argon gas, and 0.19 g of potassium t-butoxide was added. Next, 0.26 g of 3-chloro-2-butanone was added at 5 to 10 ° C, and the mixture was stirred for 3 hours. After the reaction, the mixture was concentrated under reduced pressure, and water (10 ml) and ethyl acetate (50 ml) were added to the obtained residue, followed by thorough stirring. The ethyl acetate layer was separated and washed with saturated saline (10 ml). After drying, the residue was concentrated under reduced pressure, and the obtained residue was subjected to gel chromatography on silica gel (form: chloroform: methanol = 3: 1) to give (2, 3R *) — 3— (1-acetylethyl) 0.36 g of thio-2— (2,4-difluorophenyl) —1— (1H—1,2,4-triazolu-1-yl) butan-1-ol was obtained as a white powder.

½-NMR (CDC) 5 ppm: 1.11 (1.5 H, d, J = 7 Hz), 1.12 (1.5 H, d, J = 7 Hz), 1.4 7 (1.5 H, d, J = 7 Hz), 1.50 (1.5 H, d, J = 7 Hz), 2.33 (1.5 H, s), 2.35 ( 1.5 H, s), 3.29 (0.5 H, q, J = 7 Hz), 3.34 (0.5 H, q, J = 7 Hz), 3.48 ( 0.5 H, q, J = 7 H z), 3.60 (0.5 H, q, J-7 H z), 4.74 (0.5 H, d, J = 14 H z) , 4.80 (0.5 H, d, J = 14 Hz), 4.9 to 5.1 (2 H, m), 6.7 to 6.8 (2 H, m), 7 3 to 7.4 (1H, m), 7.77 (1H, s), 7.78 (1H, s).

 [Example 2]

 (2 R *, 3 R *) 1 2— (2,4-difluorophenyl) — 3— “1-” (4-Methyl-4Η—1,2,4—triazole—3-yl) carbonyl [Ethyl] Thio 1- (1Η-1,2,4-triazole-11-yl) butan-2-ol (Diastereomer Α) (Compound No. 2) and (Diastereomer Β):

(2 R *, 3 R-)-2-(2,4-difluorophenyl)-1-Menolecapto 1-1 (1 Η-1, 2, 4-triazole-1-1-yl) Dissolve 1.0 g of butan-2-ol in ethanol (20 ml), and stir the mixture under ice-cooling, and obtain the 3- (2-bromopropionyl) —4-methyl-4H—1,2 obtained in Reference Example 4. Then, 1.26 g of 1,4-triazole hydrobromide and 0.94 g of potassium t-butoxide were added and stirred for 2 hours. After stirring at room temperature for 2 hours, the ethanol was distilled off under reduced pressure, ice water was added, and the mixture was extracted twice with ethyl acetate (50 ml). The ethyl acetate layers were combined, washed with water, dehydrated with a saturated saline solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 3R *)-2-(2,4-difluorophenyl) 13-[1-(4-methyl-14H-1, 2, 4, 4-triazole-3-) L) Carbonyl] ethyl] thio 1- (1H- 1,2,4-triazole- 1-yl) butane-2-ol diastereomeric mixture was obtained as a crystalline residue. This was recrystallized from ethyl acetate-hexane, and the compound (diastereomer A) having a 1¾ value of 0.48 (ethyl acetate: methanol = 10: 1) was obtained as a white powder on TLC (760 mg). Obtained. The recrystallized mother liquor was purified by gel chromatography on silica gel (ethyl acetate: methanol = 98: 2), and the R f value 0.38 (ethyl acetate: 7 Omg of the compound (diastereomer B) of methanol = 10: 1) as a pale yellow oil Obtained.

 (Gysteromer A)

 ½-NMR (CDC 13) δ p pm: 1.27 (3H, d, J = 7 Hz)

1.63 (3 H, d, J = 7 Hz), 3.73 (1 H, q, J = 7 Hz) 4.06 (3 H, s), 4.8 1 (2 H, AB q, J = 15Hz), 5

1 8 (1 H, q, J = 7 H z), 6.65 to 6.75 (2 H, m), 680 (1 H, s), 7.30 to 7.40 (1 H, m), 7.61 (1 Hs), 8.27 (1H, s), 8.46 (1H, s).

 (Gysteromer B)

 ! H-N R (CDC 13) δ p pm: 1.20 (3 H, d, J = 7H z),

1.64 (3H, d, J = 7Hz), 3.87 (1H, q, J = 7Hz), 4.03 (3H, s), 4.60 (1H, q, J = 14 Hz), 4.70 to 4.85 (2 H, m), 5.03 (1 H, brs), 6.65 to 6.80 (2 H, m), 7.25 to 7.35 (1H, m), 7.73 (1H, s), 7.76 (lH, s), 8.30 (lH, s).

 [Example 3]

(2 R *, 3 R *) — 2— (2,4-difluorophenyl) 1-3 — “1— (4-methyl-4 H—1, 2, 4, 4-triazol-3-yl) carbonylylethyl 1 Thio 1- (1H-1,2,4-triazole-1-yl) butan-2-ol (diastereomer A) (Compound No. 2): obtained in Example 2 (2R *, 3R- ) — 2— (2,4-difluorophenyl) 1 3— [1.-[(4-Methyl-4H—1,2,4-triazole-1-3-yl) carbonyl] ethyl] thiol 70 mg of 1- (1H-1,2,4-triazole-1yl) butan-2-ol (diastereomer B) was dissolved in chloroform (5 ml) and allowed to stand at room temperature. By evaporating the solvent under reduced pressure, the isomer 3 R *)-2-(2, 4-difluorophenyl) 1-3-[1-[(4-methyl-4 H-1, 2, 4 -triazo-1-3-yl) carbonyl] ethyl] Thio 1-(1 H-1, 2, 4 — 70 mg of triazo-l-l-yl) butane-l- 2-nore (Diastereomer A) was obtained as a white powder (structure confirmed by NMR). ·

 [Example 4]

 (2 R *, 3 R-) 1 2— (2,4-difluorophenyl) 1 3— [1-(thiomorpholinocarbonyl) ethyl] Thio— 1 — (1 H— 1,2,4 Triazo 1-ruil 1-yl) butane 2- 2-all (diastereomers A) and (diastereomers B):

(2 R *, 3 R *)-2-(2,4-difluorophenyl) 1-3-menolecapto 1-(1 H-1, 2, 4-triazo 1-1-yl) butane — 2 —To a solution of 0.40 g of dimethylformamide (5 ml) was gradually added 0.175 g of argon air-flowing lithium-t-butoxide, and the mixture was stirred at room temperature for 30 minutes. A solution of 0.36 g of 4- (2-bromopropionyl) thiomorpholine obtained in Reference Example 5 in dimethylformamide (3 ml) was added thereto, followed by stirring at room temperature for 2 hours. Water (50 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 ml). After the organic layer was washed with saturated saline, magnesium sulfate was added thereto and dried. This was concentrated under reduced pressure, and the obtained oily product was purified by silica gel column chromatography (ethyl acetate: n-hexane = 2 _: 1). Fraction eluted earlier, (2R *, 3R *) — 21- (2,4-difluorophenyl) 13- [1— (thiomorpholine rubonyl) ethyl] thio—1-1 (1H — 1, 2, 4 -triazolyl 1-yl) butane-2-ol (diastereomeric A) as an oil 0.21 g, later eluted fraction, (2R *, 3R * )-2-(2,4-Difluorophenyl)-3-"1- (thiomorpholinocarbonyl) ethyl] 0.14 g of thiol (1H-1,2,4-triazole-11yl) butan-2-ol (diastereomer B) was obtained as an oil.

 (Gia Stereo A)

_{^ -NMR (CDC 1 3) δ} p pm: 1. 18 (3 H, d, J = 7 H z), 1. .5 7 (3 H, d, J = 7 H z), 2. 64~ 2.82 (4H.m),

3.6 1 (1 H, q, J = 7 H z), 3.87 to 3.97 (5 H, m),

4.77 (1 H, d, J = 14 Hz), 5.00 (1 H, d, J = 14 Hz),

5.02 (1H, s), 6.70 to 6.78 (2H, m), 7.29 to 7.38 (1H, m), 7.77 (1H, s), 7.82 (1H, s). (Gysteromer B)

 ½-NMR (CDC 13) δ p pm: 1.10 (3H, d, J = 7 Hz), 1.60 (3H, d, J = 7 Hz), 2.62 to 2.84 ( 4 H, m),

3.44 (1 H, q, J = 7 H z), 3.73 to 4.13 (5 H, m),

4.80 (1 H, d, J = 14 Hz), 5.05 (1 H, s), 5.12 (1 H, d, J = 14 Hz), 6.70 To 6.78 (2H, m), 7.

3 1 to 7.40 (1H, m), 7.79 (1H, s), 7.82 (1H, s) o

 [Example 5]

 (2 R *, 3 R *) 1-3-(1-acetylethyl) Thio 2-(2, 4-difluorophenyl)-1-(1 H-1, 2, 4, triazole-1-yl) butane 2- All (Compound No. 1):

Under an argon gas atmosphere, 0.90 g of 3-mercapto-12-butanone was dissolved in N, N-dimethylformamide (70 ml), and the mixture was dissolved under ice-cooling. 97 g were added. After thorough stirring, 3S *) — 2- (2,4-difluorophenyl) -1-methyl-2-[(1H—1,2,4-triazol-1-yl) methyl] oxylan 2.17 g And heated at 85 ° C. for 10 hours. After the reaction, the mixture was poured into water (30 ml) and extracted with ethyl acetate (50 ml). After washing twice with water (30 ml), it was dried and concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography (chloroform: methanol = 3: 1) to give (2 R *, 3 R *)-3-

(1-acetylethyl) Thio 2- (2,4-difluorophenyl) '-1- (1H-1,2,4-triazo-1-yl) butane-2-ol 1.63 g Obtained (structure confirmed by ¹ H-NMR).

 [Examples 6 to 12]

According to Example 1, 2 or 4, the compounds described in Examples 6 to 12 in Tables 1 to 6 were synthesized.

αι ο n Table 1

οε

οε

.6S00 / S6df / XDd [£ P £ 9Z / S6 OAV ts3 C

 O n o cn Table 3

to CO

 o o Table 4

αι ο

Table 5 Physical properties

 Example number X R R R

(Compound number) 丄 Η— NMR (solvent) dppm Colorless foam

(CDC 1 ₀₎

 2, 4-F-H16 (1.5H.J = 7Hz)

 20 (1.5H. J = 7Hz)

d d d

-,,

t ο Table 6

[Example 13]

 (2 R *, 3 R *) 1 2 — (2, 4 —difluorophenyl) -3 — “1-(thiomorpholinocarbonyl) ethyl 1 thio — 1 1 (1 Η— 1, 2, 4 — triazole- 1-yl) butane 2- 2-ol hydrochloride (Diastereomer II) (Compound No. 8):

 3R *) 1 2 — (2, 4 — difluorophenyl) -3 — [1-(thiomorpholine carbonyl) ethyl] obtained in Example 4 Thio 1 — 1 (1 Η 1, 2, 4) 1 triazo 1 roux 1 1) butane 1 2 —all

(Diastereomer) 0.20 g was dissolved in ethyl acetate (5 ml), and under ice cooling, 1.1 equivalents of 4N-hydrogen chloride / ethyl acetate was added thereto, followed by stirring. Then, the mixture was concentrated under reduced pressure, and (2Κ *, 3Κ *) — 2— (2,4—difluorophenyl) 13— [1— (thiomorpholinocarbonyl) ethyl] thio (1 1—1, There was obtained 0.21 g of 2,4-triazolu-1-yl) butane-2-monohydrochloride (diastereomer Α).

_{^ -NMR (CDC 1 3 - DMS} O- d 6) δ ρ pm: 1. 1 7 (3 Η, d, J = 7 Η ζ), 1. 5 7 (3 Η, d, J = 7 Η ζ ), 2.64 to 2.78 (4Η, m), 3.66 to 3.89 (6Η, m), 4.86 (1Η, d, J = 1 44ζ) ), 5.23 (1Η, d, J-14 4 Η), 6.70 to 6.8.2 (2Η, m), 7.24 to 7.32 (1Η, m ), 8.04

(1Η, s), 9.25 (1Η, b rs).

 [Examples 14 to 15]

According to Example 13, the compounds described in Examples 14 to 15 in Tables 7 to 8 were synthesized. t

 n ο

Table 7 Physical properties

 Example number X R 'R R

(Compound number) ½-N R (5 ppm colorless foam

(DMSO-d _e )

 ο

 14 2.4-F -CH 0.94 (1.5H, d, J = 7Hz) (9) 04 (1.5H, d, J = 7Hz)

 56 (1, 5H, d, J = 7Hz) 57 (1.5H, d, J = 7Hz)

3.72 co5H, q.J = 7Hz) 3.87 co.5H, q, J = 7Hz) 4.25 (0.5H, d, J = 14Hz) 4, 59 (0.5H, d, J = (14Hz) 4.70 to 4.80 (1.5H, m) 4.93 (0.5H.q, J = 7Hz) 6.85 -6.90 (1H, m) 7.05 -7.20 ( 2H, m) 7.75 (0.5H, s)

 7.78 (0.5H.s)

 8.19 (0.5H, d, J = 3Hz) 8.21 (0.5H, d, J = 3Hz) 8.27 (0.5H.d.J = 3Hz) 8.31 (0.5H. d. J = 3Hz) 8.47 (0.5H, s)

8.49 (0.5H, s)

t

 cn ϋι ο Table 8

[Example 16]

 (2 R, 3 R) 1 2 — (2,4-difluorophenyl) 1 3 — “1 —“ (pyridine 1-4yl) carbonyl] ethyl 1 thiol 1 (1 H-1,

2,4-triazo-1-yl) butane-2-ol (Compound No. 10): (2R, 3R) -12- (2,4-difluorophenyl) -13- under an argon gas stream Dissolve 0.40 g of mercapto-11- (1H-1,2,4-triazo-1-yl) tan-2-ol in ethanol (20 ml) and add potassium t under ice-cooling. — 0.58 g of toxide was added. Then, 0.66 g of 4- (2-lomopropionyl) pyridine hydrobromide was added, and the mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate (100 ml) and water (40 ml) were added, and the mixture was stirred well. The organic layer was washed with saturated saline (40m), dried, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (form: methanol = 20: 1) to give (2R, 3R) -12- (2,4-difluorophenyl) 13- [ 1-[(Pyridine-1-41-yl) carbonyl] ethyl] Thio 1— (1H—1,2,4-triazol-1-yl) 2--2-ol (Compound No. 10) 0.35 g was obtained.

 ! H-NMR (CDC 13) 5 ppm: 0.95 (1.5 H, d, J = 7 Hz), 1.19 (1.5 H, d, J = 7 Hz), 1 64 (1.5 H, d, J = 7 Hz), 1.69 (1.5 H, d, J = 7 Hz), 3.3 ~

3.5 (1 H, m), 4.3 to 4.7 (2 H, m), 4.9 to 5.1 (2 H, m), 6.6 to 6.8 (2 H, m ), 7.2-7.3 (1H, m), 7.6 to 7.9 (4H, m), 8.8 to 8.9 (2H, m).

 [Example 17]

2- (2,4-difluorophenyl) 1-3-methyl-3 -— (Pyridine-13-yl) power rubonyluethyl thiol — 1 (1H—1,2, 4-triazole-1-yl) butane-2-ol (diastereomer A) and 2- (2,4-difluorophenyl) —3-methyl-3-([1- (pyridin-3-yl) carbonyl 1 Ethyl 1 Thio 1 — (1 H— 1, 2, 4 -triazole 1 -yl) Butane 1-2 -ol (Diastereoma B):

 Under an argon gas stream, 2- (2,4-difluorophenyl) -1-methyl-3--3-mercapto-1— (1H—1,2,4-triazole-1—yl) tan—2— Dissolve 0.33 g of all in ethanol (15 ml), add 0.4 g of potassium t-oxide under ice-cooling and stir, stir, then add 3- (2-bromopropionyl) pyri. 0.52 g of gin hydrobromide was added and stirred for 1 hour. Then, after stirring at room temperature for 2 hours, the suspended matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 3: 1), and 2- (2,4-difluorophenyl) -13-methyl-3 — [1 [(Pyridin-3-yl) capillonyl] ethyl] Thio 1 (1 H— 1, 2,4,1 Triazole-1 1) 1 2 1—2—1 (northone diastereomer A) 0.18 g, and the fraction eluted later is 2- (2,4-difluorophenyl) -13-methyl-3- [1-[(pyridine-13-yl) carbonyl] ethyl] thio- (1H—1,2,4—triazo-1-yl) Butane-1-2-ol (diasteromer B) 0.05 g

 (Gysteromer A)

^ -NMR (CDC 13) p pm: l. 30 (3 H, d, J = 4 Hz), 1.42 (3 H, s), 1.57 (3 H, d, J = 7 Hz), 4.9-5.2 (3H, m), 5.33 (1H, s), 6.5 to 6.8 (2H, m), 7.4 to 7.6 (2H, m), 7.59 (1H, s), 7.96 (1 H, d, J = 3 Hz), 8.3 to 8.4 (1 H, m), 8.79 (1 H, dd, J = 2, 5 Hz), 9.29 ( 1 H, d, J = 3 H z) ₀

 (Gysteromer B)

^! H-NMR (CDC 13) 5 ppm: 1.22 (3 H, s), 1.34 (3 H, d, J = 3 H z), 1.63 (3 H, d, J = 7 Hz), 5.0 to 5.3 (3 H, m), 5.63 (1 H, s), 6.5 to 6.8 (2 H, m), 7.4 to 7. 6 (2H, m), 7.74 (1H, s), 8.07 (1H, d, J = 3Hz), 8.3 to 8.4 (1H, m), 6.82 (1H, dd, J = 2, 5Hz), 9.30 (1H, d, J = 3Hz).

 The compounds of the present invention and physiologically acceptable salts thereof are effective in treating superficial or deep mycosis in animals and humans, and include, for example, Trichophyton * Noref "Norem (T richophytonrubrum), microspornolem., tinea due to force varnish (Microsporum canis), dermatophytosis, candidiasis due to Candida a bicans (C andidaa 1 bicans), etc., Aspergillus fumigatus. (A spergi 11 usfumigatus), etc., Cryptococcus neoformans (Cryptococcusneoformans), etc., and Coccidioidesi mititis (Cocciidioidesi mmitis, called imported mycosis) Coccidioidomycosis, Histoplasma and Rivus ratum (Histop 1 asmacap su 1 atum) for the treatment of histoplasmosis and paracoccidioides caused by Paracoccidioides brasiliensis (Paracoccidioidesbrasi 1iens ιs). Can be used.

The antifungal effect of the compound of the present invention will be explained by an in vivo infection experiment using mice. [Pharmacological test 1]

 Evaluation of the antifungal activity of invivo against Candida albicans (Candidad aa1biccans) TTB273:

ICR male mice (weighing 22 to 26 g) were infected with Candida albicans TTB273 from the tail vein. One hour later, 1 mg of the test compound was orally administered, and 1 day, 2, 3, and 4 days after the infection, the compound was orally administered once a day. The average number of surviving days was measured after 14 days of infection. Table 9 shows the results.

Table 9

 Compound number Average surviving days

 1〉 12.50

 2> 13.50

 3〉 14.00

 4> 14.00

 5〉 14.00

 6> 1.00

 7> 13.25

 8〉 13.75

 9> 14.00

 10> 14.00

 Ketoconazole 6.2

 Drug-free 2.0 [Pharmacological test 2]

A spergi 1_us f um igatus) Evaluation of the antifungal activity of invivo against TTB 1776:

 ICR male mice (weighing 22 to 26 g) were infected with Aspergillus fumigas (Aspergii11usfmuigatus) TTB1776 injected from the tail vein. One hour later, 40 mg / kg of the test compound was orally administered, and further, once a day, once, two, three, and four days after the infection. The average number of surviving days was measured 14 days after infection. Table 10 shows the results. Table 10

 Compound number Average surviving days

1> 13.75

 5> 14.00

 6〉 14.00

 7> 11. 75

 8> 11.25

10> 14.00 Ketoconazole 5.0 No agent 2.0 5/26343

 44

[Toxicity test]

 In the toxicity test of the compound of the present invention, the test compound (compounds 1 to 9) was administered to ICR male mice (body weight 24,426 g) at 400 mg / kg for 5 consecutive days using an oral probe for mice. No cases were found. Industrial applicability

 As described above, the compound of the present invention has extremely high efficacy against experimental infections of Candida albicans and experimental infections of Aspergillus fumigatus, and is useful as an antifungal agent.

Claims

The scope of the claims 1. —general formula

(Wherein, R ¹ and R ² each represent a hydrogen atom, a lower alkyl group or a cycloalkyl group, or R ¹ and R ² together represent an alkylene group, R ³ is a lower alkyl group, Represents a cycloalkyl group, an alkyl group having a double bond, a heterocyclic ring which may have a substituent or one NR ⁵ R ⁶ , wherein R ³ is a hydrogen atom or a lower alkyl group, and R ⁶ has a substituent R ⁵ and R ^D together represent an alkylene group having a sulfur atom; R ⁴ represents a hydrogen atom or a lower alkyl group; X ¹ represents a hydrogen atom, a halogen atom or trifluoromethyl X ² represents a hydrogen atom or a halogen atom, and n represents 0 to 2.) and a physiologically acceptable salt thereof. 2. The triazole derivative and a physiologically acceptable salt thereof according to claim 1, wherein R ¹ is a lower alkyl group, is a hydrogen atom, and R ³ is an optionally substituted heterocyclic ring. 3. The triazole derivative according to claim 1, wherein R ¹ and R are each a lower alkyl group, and R ″ is a hydrogen atom, and a physiologically acceptable triazole derivative thereof. 4. R ¹ is a lower alkyl group, R ² is a hydrogen atom, R ^{3 is} --NR ⁵ R ⁶ (where R ⁵ is a hydrogen atom or a lower alkyl group and R ⁶ is an optionally substituted complex And R ⁴ and R ⁵ together represent an alkylene group containing a sulfur atom.) The triazole derivative according to claim 1, and a physiologically acceptable salt thereof.  5. An antifungal agent comprising the triazole derivative according to claim 1, 2, 3 or 4 and a physiologically acceptable salt thereof as an active ingredient.