JPH05202005A - Triazole derivative and antifungal agent containing the same as active ingredient - Google Patents

Abstract

(57) [Summary] [Object] To provide a triazole derivative having antifungal activity. [Structure] General formula (I) (In the formula, Ar represents a phenyl group substituted with a halogen atom or a trifluoromethyl group, n represents 1 to 2, and R represents a lower alkyl group.) And a physiologically acceptable triazole derivative. And salts thereof and antifungal agents containing these as active ingredients. They have a very strong antifungal action and are effective for the treatment of superficial or deep mycoses in animals and humans.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a triazole derivative having antifungal activity.

[0002]

2. Description of the Related Art Conventionally, commercially available ketoconazole and the like have been known as antifungal agents.

[0003]

DISCLOSURE OF THE INVENTION The present inventors have conducted diligent research to find compounds having more effective antifungal activity, and as a result, newly synthesized triazole derivatives and physiologically acceptable salts thereof. However, the bacteria of the genus Candida and Aspergillus (Aspergillus) that cause candidiasis and aspergillosis, which are extremely clinically important,
The present invention has been found to have an extremely strong antifungal action against a bacterium of the genus Gillus).

An object of the present invention is to provide a triazole derivative useful as an antifungal agent.

[0005]

According to the present invention, the following general formula (I)

[0006]

[Chemical 2]

(Wherein Ar represents a phenyl group substituted with a halogen atom or a trifluoromethyl group, and n is 1
To 2 and R represents a lower alkyl group. ) And a physiologically acceptable salt thereof.

The compound (I) of the present invention has at least one asymmetric center and has a plurality of optical isomers and diastereomers. The compound (I) of the present invention includes all these optical isomers and diastereomers, and mixtures thereof.

The salt of the compound (I) of the present invention is not particularly limited as long as it is a physiologically acceptable salt.
For example, hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid,
Salts with inorganic acids such as phosphoric acid, acetic acid, tartaric acid, fumaric acid, maleic acid, malic acid, methanesulfonic acid, ethanesulfonic acid, camphorsulfonic acid, benzenesulfonic acid, salts with organic acids such as toluenesulfonic acid, Examples thereof include salts with alkali metals such as sodium and potassium. The present invention also includes hydrates of the compound (I) of the present invention and physiologically acceptable salts thereof.

The compound (I) of the present invention is prepared by the following step-1,
It can be produced according to 2, 3, 4 ', 5 or steps-1, 2, 3, 4.

[Step-1] Halogeno-substituted benzene (II)
And the α-halogeno-substituted acid halide (III) are subjected to Friedel-Crafts reaction in the absence or presence of a solvent to produce an acyl derivative (IV). Dichloromethane, chloroform, carbon disulfide, nitrobenzene and the like are used as the reaction solvent, and the reaction temperature is -10 to 120 ° C, preferably 0 to 70 ° C.

[0012]

[Chemical 3]

However, in the acyl compound (IV), when Ar is a trifluoromethylphenyl group, it can be produced by the following reaction step. That is, the alcohol compound (VI) is produced by a general Grignard reaction in which (V) is reacted with isopropylmagnesium halide, and then oxidized with a suitable oxidizing agent such as pyridinium chlorochromate (PCC) to obtain (VII). The acyl compound (IV) is produced by halogenating this with an appropriate halogenating agent such as bromine.

[0014]

[Chemical 4]

[Step-2] The acyl derivative (IV) is reacted with the alkali metal salt (VIII) of the phenol derivative, or the acyl derivative (IV) and the phenol derivative (VIII) are reacted with potassium carbonate, sodium carbonate, or hydroxide. The ketone body (IX) is produced by reacting in a solvent usually used in the presence of a base such as potassium or sodium hydroxide or an alkali alkoxide such as potassium t-butoxide. Reaction temperature is -20
C. to the boiling point of the solvent, preferably 0 to 70.degree. The solvent is N, N-dimethylformamide,
Acetone or the like is used, but it is not particularly limited.

[0016]

[Chemical 5]

[Step-3] The oxirane compound (X) is obtained by reacting the ketone compound (IX) with dimethylsulfonium methylide or dimethyloxosulfonium methylide.
To manufacture. Dimethyl sulfoxide or the like is used as the reaction solvent, but it is not particularly limited. The reaction temperature is from -20 ° C to the boiling point of the solvent, preferably 0.
It is preferable to carry out at 120 ° C.

[0018]

[Chemical 6]

[Step-4 '] (m of oxirane compound (X)
Is 0) The oxirane compound (X) is reacted with 1 to 5 equivalents of an alkali metal salt of 1,2,4-triazole, or the oxirane compound (X) is reacted with 1 to 5 equivalents of 1,2,4-. Intermediate (I ′) is produced by reacting triazole with a base such as potassium carbonate, sodium carbonate, potassium hydroxide or sodium hydroxide or an alkali alkoxide such as potassium t-butoxide in a suitable solvent. .. As the reaction solvent, N, N-dimethylformamide, dimethyl sulfoxide and the like are used, but the reaction solvent is not particularly limited. The reaction temperature is from -10 ° C to the boiling point of the solvent, preferably room temperature to 130 ° C.

[0020]

[Chemical 7]

[Step-5] The intermediate (I ') is oxidized with an appropriate oxidizing agent such as metachloroperbenzoic acid (m-CPBA) and hydrogen peroxide to produce the compound (I) of the present invention. Chloroform, dichloromethane, acetic acid and the like are used as the reaction solvent, but the reaction solvent is not particularly limited. The reaction temperature is from -40 ° C to the boiling point of the solvent, preferably 0.
It is better to carry out at ℃ ~ room temperature.

The sulfinyl compound represented by n = 1 of the compound (I) of the present invention uses about 1 equivalent of an oxidizing agent with respect to the intermediate (I '), and the sulfonyl compound represented by n = 2 is It can be produced by using about 2 equivalents. Also,
These can be converted into physiologically acceptable salts by adding an appropriate acid or base.

[0023]

[Chemical 8]

[Step-4] (when m of oxirane compound (X) is 1 or 2) Is oxirane compound (X) reacted with 1 to 5 equivalents of an alkali metal salt of 1,2,4-triazole? , Oxirane compound (X) and 1 to 5 equivalents of 1,2,4-triazole in the presence of a base such as potassium carbonate, sodium carbonate, potassium hydroxide or sodium hydroxide or an alkali alkoxide such as potassium t-butoxide, The compound (I) of the present invention is produced by reacting in a suitable solvent. As the reaction solvent, N, N-dimethylformamide, dimethyl sulfoxide and the like are used, but the reaction solvent is not particularly limited. The reaction temperature is from -10 ° C to the boiling point of the solvent, preferably room temperature to 130 ° C.

[0025]

[Chemical 9]

The optically active substance can be produced by the following reaction step.

First, the oxirane compound (X) is reacted with an alkali metal acetate in the presence of a cyclic ether such as 18-crown-6 to directly react the diol compound (XII) without isolation of the acetate compound (XI). To get This diol (XII) is an optically active N- (t-butoxycarbonyl) proline, N- (trifluoroacetyl) proline, N-tosylproline, N-acetylphenylalanine, 10-camphorsulfonic acid, 2-chloropropionic acid. Dehydration condensation with a suitable organic acid-based resolving agent and a suitable dehydrating condensing agent (for example, 2-chloro-1,3-dimethylimidazolinium chloride), or acid halides of these optically active resolving agents. (For example (S)-
(−)-N- (trifluoroacetyl) prolyl chloride) to give the diastereomer (XI
II) is manufactured. The diastereomers (XIII) can be separated by an appropriate resolution method such as column chromatography.

[0028]

[Chemical 10]

The diastereomer A (XIII ') thus separated is converted into an optically active diol (XII') by ordinary hydrolysis, and then mesylated with methanesulfonyl chloride in a suitable solvent such as pyridine to form a mesyl (XIV '). ) Is manufactured.

[0030]

[Chemical 11]

The mesyl derivative (XIV) is ring-closed in an appropriate solvent such as N, N-dimethylformamide in the presence of a suitable base such as sodium hydride to give an oxirane derivative (X '). Next, 1 to 5 with oxirane compound (X ')
An equivalent amount of an alkali metal salt of 1,2,4-triazole is reacted, or an oxirane compound (X ′) and 1 to 5 equivalents of 1,2,4-triazole are potassium carbonate, sodium carbonate, potassium hydroxide, Intermediate (I ′) can be obtained by reacting in a suitable solvent in the presence of a base such as sodium hydroxide or an alkali alkoxide such as potassium t-butoxide.

[0032]

[Chemical formula 12]

The mesyl derivative (XIV) is reacted with 1 to 5 equivalents of an alkali metal salt of 1,2,4-triazole or 1 to 5 equivalents of 1,2,4-triazole with potassium carbonate. , Sodium carbonate, potassium hydroxide, sodium hydroxide or the like base or potassium t-butoxide or the like alkali alkoxide in the presence of a suitable solvent to give an intermediate without isolation of the oxirane compound (X ′). The body (I ′) can be produced.

[0034]

[Chemical 13]

When the intermediate (I ') is oxidized with 1 equivalent of metachloroperbenzoic acid (m-CPBA) or a suitable oxidizing agent such as hydrogen peroxide, n becomes 1 to form a diastereomer. The optically active substance (I) can be separated by an appropriate method such as liquid column chromatography. Further, when the oxidizing agent is used in an amount of 2 equivalents or more, the optically active substance (I) in which n is 2 can be produced. Chloroform, dichloromethane, acetic acid and the like are used as the reaction solvent, but the reaction solvent is not particularly limited.

[0036]

[Chemical 14]

The enantiomer of the optically active substance (I) can be produced from the diastereomer B (XIII ') by the same procedure.

[0038]

EXAMPLES The compound of the present invention and the method for producing the same will be described below with reference to examples.

Reference Example 1 2-Bromo-2 ', 4'-difluoro-2-methylpro
200 g (1.75 mol) of piophenone m-difluorobenzene,
201 g of 2-bromo-2-methylpropionyl bromide
(0.87 mol) under ice cooling, anhydrous aluminum chloride 1
16 g (0.87 mol) was added in 1 hour. After stirring overnight at room temperature, pour into 1.5 l of ice water and add 600 ml of dichloromethane.
Extracted with ml × 2. After washing the organic layer with 400 ml of water,
It was dried and concentrated. The obtained residue was purified by distillation under reduced pressure to obtain 113 g (49.1%) of 2-bromo-2 ', 4'-difluoro-2-methylpropiophenone.

Reference Example 2 2 ', 4'-difluoro-2-methyl-2- [4- (me
Tylsulfinyl) phenoxy] propiophenone 4- (methylsulfinyl) phenol 1.87 g (1
2 mmol) 25 ml of N, N-dimethylformamide
And potassium t-butoxide (1.34 g)
(12 mmol) was added. After stirring for 5 minutes, 2.63 g (10 mmol) of 2-bromo-2 ′, 4′-difluoro-2-methylpropiophenone obtained in Reference Example 1 was added to 5
Dropped in minutes. After stirring for 1 hour, 60 ml of water was added and the mixture was extracted with 60 ml of ethyl acetate. After washing with 30 ml of 5% aqueous sodium hydrogen carbonate solution and 30 ml of water, the mixture was dried and the solvent was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (ethyl acetate: hexane = 5: 1).
Attached to 2 ', 4'-difluoro-2-methyl-2-
3.00 g (88.8%) of [4- (methylsulfinyl) phenoxy] propiophenone was obtained.

Reference Example 3 2- (2,4-difluorophenyl) -2- [1-methyi]
L-1- [4- (methylsulfinyl) phenoxy] e
Cyl] oxirane 2 ′, 4′-difluoro-2-methyl-obtained in Reference Example 2
2- [4- (methylsulfinyl) phenoxy] propiophenone 3.00 g (8.9 mmol), trimethylsulfoxonium iodide 2.93 g (13.3 mm)
was dissolved in 15 ml of dimethyl sulfoxide, and 1.39 g (12.4 mmol) of potassium t-butoxide was added while maintaining the reaction temperature at 30 ° C. or lower. After stirring for 15 minutes, the mixture was stirred at 60 ° C. for 2 hours. Cool the reaction,
80 ml of water was added and extracted with 100 ml of ethyl acetate.
The organic layer was washed with 40 ml of water × 2, dried, and concentrated.
(2,4-Difluorophenyl) -2- [1-methyl-
3.00 g (95.6%) of 1- [4- (methylsulfinyl) phenoxy] ethyl] oxirane was obtained.

(Example 1) 2- (2,4-difluorophenyl) -3-methyl-3
-[4- (Methylsulfinyl) phenoxy] -1-
(1H-1,2,4-triazol-1-yl) butane
2-ol (Compound No. 1) 2- (2,4-difluorophenyl) -obtained in Reference Example 3
2- [1-methyl-1- [4- (methylsulfinyl)
Phenoxy] ethyl] oxirane 3.00 g (8.5 m
mol) was dissolved in 20 ml of N, N-dimethylformamide, and 0.88 g (1
2.8 mmol) and Na of 1,2,4-triazole
1.29 g (14.2 mmol) of salt was added, and 80-10
Stirred at 0 ° C. for 3 hours. The reaction solution was cooled, 80 ml of water was added, and then extracted with 80 ml of ethyl acetate × 2. The organic layers were combined, washed with 40 ml of water × 2, dried and concentrated.
The obtained residue was separated and purified by silica gel column chromatography (chloroform: methanol = 98: 2) to give 2- (2,4-difluorophenyl) -3-methyl-3- [4- (methylsulfinyl) phenoxy]-. 1
2.43 g (6 of 6- (1H-1,2,4-triazol-1-yl) butan-2-ol as white crystalline powder)
7.9%).

(Example 2) 2- (2,4-difluorophenyl) -3-methyl-3
-[4- (Methylsulfinyl) phenoxy] -1-
(1H-1,2,4-triazol-1-yl) butane
2-ol (Compound No. 1) 2- (2,4-difluorophenyl) -2- [1-methyl-1- [4- (methylsulfinyl) phenoxy] ethyl] oxirane instead of 2- (2,4 -Difluorophenyl) -2- [1-methyl-1- [4- (methylthio) phenoxy] ethyl] oxirane was used, but 2- (2,4-difluorophenyl) was obtained by the same procedure as in Example 1. -3-Methyl-3- [4- (methylthio)
Phenoxy] -1- (1H-1,2,4-triazol-1-yl) butan-2-ol 0.50 g (1.23
mmol) in 30 ml of chloroform, and under ice cooling,
0.24 g (1.22) of m-chloroperbenzoic acid (88%)
mmol) was added. After stirring for 10 minutes, 0.06 g of sodium hydroxide dissolved in 5 ml of water was added and stirred. The chloroform layer was separated and washed with 10 ml of water. The chloroform layer was dried, concentrated, and subjected to silica gel column chromatography (chloroform: methanol = 10: 1) to give 2- (2,4-difluorophenyl) -3-methyl-3- [4- (methylsulfinyl) phenoxy. ] -1
0.45 g (8) of-(1H-1,2,4-triazol-1-yl) butan-2-ol as white crystalline powder.
6.6%).

(Example 3) 2- (2,4-difluorophenyl) -3-methyl-3
-[4- (methylsulfonyl) phenoxy] -1- (1
H-1,2,4-triazol-1-yl) butane-2
-Ol (Compound No. 2) 2- (2,4-difluorophenyl) -2- [1-methyl-1- [4- (methylsulfinyl) phenoxy] ethyl] oxirane instead of 2- (2,4-difluoro) Phenyl-2- [1-methyl-1- [4- (methylsulfonyl) phenoxy] ethyl] oxirane 3.14 g
According to Example 1 except that (8.53 mmol) was used,
2- (2,4-difluorophenyl) -3-methyl-3
-[4- (methylsulfonyl) phenoxy] -1- (1
H-1,2,4-triazol-1-yl) butane-2
-Ool was obtained as white crystals, 3.10 g (83.1%).

Example 4 2- (4-fluorophenyl) -3-methyl-3- [4
-(Methylsulfinyl) phenoxy] -1- (1H-
1,2,4-triazol-1-yl) butan-2-o
(Compound No. 3) 2- (2,4-difluorophenyl) -2- [1-methyl-1- [4- (methylsulfinyl) phenoxy] ethyl] oxirane instead of 2- (4-fluorophenyl) 2.85 g of 2- [1-methyl-1- [4- (methylsulfinyl) phenoxy] ethyl] oxirane
According to Example 1 except that (8.56 mmol) was used,
2- (4-fluorophenyl) -3-methyl-3- [4
-(Methylsulfinyl) phenoxy] -1- (1H-
2.58 g (75.0%) of 1,2,4-triazol-1-yl) butan-2-ol was obtained as a white crystalline powder.

Example 5 2- (4-Fluorophenyl) -3-methyl-3- [4
-(Methylsulfonyl) phenoxy] -1- (1H-
1,2,4-triazol-1-yl) butan-2-o
(Compound No. 4) 2- (2,4-difluorophenyl) -2- [1-methyl-1- [4- (methylsulfinyl) phenoxy] ethyl] oxirane instead of 2- (4-fluorophenyl) 2.98 g (8.-2- [1-methyl-1- [4- (methylsulfonyl) phenoxy] ethyl] oxirane
28 mmol) was used, and according to Example 1,
(4-Fluorophenyl) -3-methyl-3- [4-
(Methylsulfonyl) phenoxy] -1- (1H-1,
2.80 g (78.5%) of 2,4-triazol-1-yl) butan-2-ol was obtained as white crystals.

(Example 6) 2- (2,4-difluorophenyl) -3-methyl-3
-[4- (methylsulfonyl) phenoxy] -1- (1
H-1,2,4-triazol-1-yl) butane-2
-Ol (Compound No. 2) 2- (2,4-difluorophenyl) -obtained in Example 1-
3-Methyl-3- [4- (methylsulfinyl) phenoxy] -1- (1H-1,2,4-triazole-1-
Il) Butan-2-ol 1.00 g (2.38 mmo
l) was dissolved in 100 ml of chloroform, and 0.46 g (2.35 mmo) of m-chloroperbenzoic acid (88%) under ice cooling.
l) was added. After stirring for 30 minutes, the mixture was washed with 50 ml of dilute aqueous sodium hydroxide solution. The chloroform layer was dried, concentrated, and subjected to silica gel column chromatography (ethyl acetate) to give 2- (2,4-difluorophenyl) -3.
0.89 g of -methyl-3- [4- (methylsulfonyl) phenoxy] -1- (1H-1,2,4-triazol-1-yl) butan-2-ol as white crystals.
(85.7%) was obtained.

(Example 7) 2- (2,4-difluorophenyl) -3-methyl-3
-[4- (methylsulfonyl) phenoxy] -1- (1
H-1,2,4-triazol-1-yl) butane-2
-Ol (Compound No. 2) 2- (2,4-difluorophenyl) -2- [1-methyl-1- [4- (methylsulfinyl) phenoxy] ethyl] oxirane instead of 2- (2,4-difluoro) 2- (2,4-Difluorophenyl) -3-obtained by the same procedure as in Example 1 except that phenyl-2- [1-methyl-1- [4- (methylthio) phenoxy] ethyl] oxirane was used. Methyl-3- [4- (methylthio)
Phenoxy] -1- (1H-1,2,4-triazol-1-yl) butan-2-ol 1.00 g (2.47)
mmol) in 100 ml of chloroform, and under ice-cooling 1.15 g (5.87) of m-chloroperbenzoic acid (88%).
mmol) was added. After stirring for 40 minutes, the mixture was washed with 50 ml of dilute aqueous sodium hydroxide solution. The chloroform layer was dried, concentrated, and subjected to silica gel column chromatography (ethyl acetate) to give 2- (2,4-difluorophenyl).
-3-Methyl-3- [4- (methylsulfonyl) phenoxy] -1- (1H-1,2,4-triazole-1-
0.89 g of (yl) butan-2-ol as white crystals
(82.5%) was obtained.

(Examples 8 to 17) Examples 1, 2, 3 and
Compound Nos. 5 to 14 shown in Table II were synthesized according to 6 and 7.

Reference Example 4 2-Methyl-1-[(4-trifluoromethyl) phenyl
Lu] propan-1-ol metal magnesium (cutting) 5.44 g (224 mmo
Tetrahydrofuran (50 ml) was added to l), and a small amount of iodine was added thereto. Isopropyl bromide 25.0 g
(203 mmol) of tetrahydrofuran (25 ml)
About 2 ml of the solution was added to the reaction solution and heated. After the heat generation, the heating was stopped, and the remaining solution was gradually added so that the reaction temperature became about 65 ° C. After the reaction is completed, the reaction solution is cooled with ice,
4- (trifluoromethyl) benzaldehyde 13.9
g (102 mmol) of tetrahydrofuran (20 m
l) The solution was added dropwise. After 30 minutes, the reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted with ether. The ether layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was applied to a silica gel column (hexane:
Chloroform = 3: 1-> 1: 1) refine | purified and it obtained 2-methyl-1-[(4-trifluoromethyl) phenyl] propan-1-ol 8.52g (38.4%).

Reference Example 5 2-Methyl-4 '-(trifluoromethyl) propioff
Enon Reference Example 4 to give 2-methyl-1 - [(4-trifluoromethyl) phenyl] propan-1-ol 8.52g
Pyridinium chlorochromate (P) was added to a solution of (39.0 mmol) in methylene chloride (100 ml) with stirring under ice cooling.
CC) 16.8 g (77.9 mmol) was added. After stirring at room temperature for 3 hours, ether and methanol were added to the reaction solution, and the insoluble material was filtered off. The filtrate was concentrated and purified with a silica gel column (chloroform), 2-methyl-4'-
(Trifluoromethyl) propiophenone 7.80 g
(92.4%) was obtained.

Reference Example 6 2-Bromo-2-methyl-4 '-(trifluoromethyi)
Le) propiophenone in Reference Example 5 to give 2-methyl-4 '- (trifluoromethyl) propiophenone 7.80 g (36.1 mmol)
Solution of acetic acid (20 ml) at 40 ° C.
ml (39.8 mmol) was added dropwise. After stirring for 3 hours, the reaction solution was poured into ice water. It was extracted with ether. The ether layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column (hexane: chloroform = 5: 1) to obtain 2-bromo-2-methyl-4 ′-(trifluoromethyl) propiophenone 8.75 g (82.2%).

Reference Example 7 2-Methyl-2- [4- (methylthio) phenoxy]-
4 '-(trifluoromethyl) propiophenone potassium t-butoxide 1.89 g (16.9 mmo)
1) N, N-dimethylformamide (50 ml) solution under ice cooling with stirring, 4- (methylthio) phenol 2.60
g (18.6 mmol) was added. After 30 minutes, 2-bromo-2-methyl-4 '-(trifluoromethyl) propiophenone (5.00 g, 16.9 mmol) of N, N-.
A dimethylformamide (5 ml) solution was added dropwise. After completion of dropping, stirring was continued overnight at room temperature. Add water to the reaction mixture,
It was extracted with ether. The organic layer was washed with 1N aqueous sodium hydroxide solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 2-methyl-2- [4- (methylthio) phenoxy] -4 '-(trifluoromethyl).
6.00 g (100%) of propiophenone was obtained.

Reference Example 8 2- [1-methyl-1- [4- (methylthio) phenoxy
Ci] ethyl] -2- [4- (trifluoromethyl) phene
Nyl] oxirane sodium hydride (55%) 1.33 g (30.5 mm
ol) in a dimethylsulfoxide (50 ml) suspension under stirring with cooling with water, and trimethylsulfoxonium iodide 6.
73 g (30.5 mmol) was added slowly. After 30 minutes, 2-methyl-2- [4- (methylthio) phenoxy] -4 ′-(trifluoromethyl) synthesized in Reference Example 7.
A solution of 6.00 g of propiophenone in dimethyl sulfoxide (10 ml) was added dropwise. After completion of dropping, the reaction solution was stirred at room temperature for 1 hour. Water was added to the reaction solution, which was extracted with ether. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 2- [1-methyl-
1- [4- (methylthio) phenoxy] ethyl] -2-
5.38 g (86.3%) of [4- (trifluoromethyl) phenyl] oxirane was obtained.

Reference Example 9 3-Methyl-3- [4- (methylthio) phenoxy]-
1- (1H-1,2,4-triazol-1-yl)-
2- [4- (trifluoromethyl) phenyl] butane-
2-ol 2- [1-Methyl-1- [4- (methylthio) phenoxy] ethyl] -2- [4- (trifluoromethyl) phenyl] oxirane obtained in Reference Example 5.38 g (14.6)
mmol) and 1,2,4-triazole 3.03 g (4
3.9 mmol) and a solution of 2.00 g (22.0 mmol) of sodium salt of 1,2,4-triazole in N, N-dimethylformamide (50 ml) was heated for 3 hours (90
(° C), water was added to the reaction solution, and it was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by a silica gel column (chloroform: methanol = 100: 1 → 25: 1) and 3-methyl-3- [4- (methylthio) phenoxy] -1- (1H-1,2,4-triazole-1. -Yl) -2- [4- (trifluoromethyl) phenyl] butan-2-ol 4.29 g (67.1%) was obtained.

Example 18 3-Methyl-3- [4- (methylsulfinyl) pheno
Xy] -1- (1H-1,2,4-triazole-1-
Yl) -2- [4- (trifluoromethyl) phenyl]
Butan-2-ol (Compound No. 15) 3-Methyl-3- [4- (methylthio) phenoxy]-
1- (1H-1,2,4-triazol-1-yl)-
2- [4- (trifluoromethyl) phenyl] butane-
To a solution of 2-ol 874 mg (2.00 mmol) in methylene chloride (70 ml) was gradually added 410 mg (1.90 mmol) of m-chloroperbenzoic acid (80%) under ice-cooling stirring. After 30 minutes, water was added to the reaction solution. The organic layer was washed with aqueous sodium hydroxide solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue is a silica gel column (chloroform → chloroform: methanol = 2).
0: 1) and colorless oily substance 3-methyl-3- [4-
(Methylsulfinyl) phenoxy] -1- (1H-
1,2,4-triazol-1-yl) -2- [4-
700 mg (77.2%) of (trifluoromethyl) phenyl] butan-2-ol was obtained.

(Example 19) 3-methyl-3- [4- (methylsulfonyl) phenoxy
Si] -1- (1H-1,2,4-triazol-1-i
) -2- [4- (trifluoromethyl) phenyl] bu
Tan-2-ol (Compound No. 16) 3-Methyl-3- [4- (methylthio) phenoxy]-
1- (1H-1,2,4-triazol-1-yl)-
2- [4- (trifluoromethyl) phenyl] butane-
1.29 g (5.98 mmol) of m-chloroperbenzoic acid (80%) was gradually added to a methylene chloride (70 ml) solution of 2-ol 874 mg (2.00 mmol) under ice-cooling. After 30 minutes from setting the reaction temperature to room temperature, water was added to the reaction solution. The organic layer is an aqueous sodium hydroxide solution, water,
The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give crystals. Wash the crystals with hexane-ether,
White crystals of 3-methyl-3- [4- (methylsulfonyl) phenoxy] -1- (1H-1,2,4-triazol-1-yl) -2- [4- (trifluoromethyl)
Phenyl] butan-2-ol 815 mg (86.9
%) Was obtained.

Example 20 2- (2,4-difluorophenyl) -3-methyl-3
-[4- (Methylsulfinyl) phenoxy] -1-
(1H-1,2,4-triazol-1-yl) butane
2-ol hydrochloride (Compound No. 17) 2- (2,4-difluorophenyl) -obtained in Example 1
3-Methyl-3- [4- (methylsulfinyl) phenoxy] -1- (1H-1,2,4-triazole-1-
Ile) butan-2-ol 0.45 g (1.07 mmo
l) was dissolved in 20 ml of ethyl acetate, an equivalent amount of 4N-hydrogen chloride in ethyl acetate was added, and 2- (2,4-difluorophenyl) -3-methyl-3- [4- (methylsulfinyl) phenoxy] -1 was added. -(1H-1,2,4-triazol-1-yl) butan-2-ol hydrochloride was quantitatively obtained.

(Examples 21 to 27) Compound Nos. 18 to 24 shown in Table III were synthesized according to Example-20.

Reference Example 10 2- (2,4-difluorophenyl) -3-methyl-3
-[4- (Methylthio) phenoxy] -1,2-butane
20.6 g (61.3 mmol) of diol 2- (2,4-difluorophenyl) -2- [1-methyl-1- [4- (methylthio) phenoxy] ethyl] oxirane was added to N, N-dimethylformamide (100 ml). Dissolved in 30.1 g (207 mmol) of potassium acetate and 18-crown-
6 16.2 g (61.3 mmol) was added to give 100
The mixture was stirred at 0 ° C for 20 hours. After cooling, ice water (200 ml) was added, and the mixture was extracted with ethyl acetate (2 x 300 ml). The organic layer was washed with water, dehydrated with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained brown oil was purified by silica gel column chromatography (solvent: hexane-ethyl acetate = 5: 1, v / v), and 2
-(2,4-Difluorophenyl) -3-methyl-3-
16.2 g (75%) of [4- (methylthio) phenoxy] -1,2-butanediol was obtained.

Reference Example 11 1-[(S) -N- (t-butoxycarbonyl) prolyl
Luoxy] -2- (2,4-difluorophenyl) -3
-Methyl-3- [4- (methylthio) phenoxy] but
N-2-ol and its diastereomer 2- (2,4-difluorophenyl) -3-methyl-3
-[4- (Methylthio) phenoxy] -1,2-butanediol 13.0 g (36.7 mmol), (S) -N
11.9 g of (-t-butoxycarbonylproline) (55.
1 mmol) and 9.31 g (55.1) of 2-chloro-1,3-dimethylimidazolinium chloride (DMC).
methylene chloride (50 ml) was dissolved, and a solution of pyridine 8.89 ml (110 mmol) in methylene chloride (10 ml) was added dropwise over 15 minutes while stirring with ice cooling. Then, after stirring at room temperature for 3 hours, water (100 ml) was added and the organic layer was separated. Chloroform (200m)
l), the organic layers were combined and 0.5N hydrochloric acid (100 m
It was washed with l). The extract was washed with a 5% aqueous sodium hydrogen carbonate solution and water, dried over saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 1-[(S)-
N- (t-butoxycarbonyl) prolyloxy] -2
-(2,4-Difluorophenyl) -3-methyl-3-
A diastereomeric mixture of [4- (methylthio) phenoxy] butan-2-ol was obtained as a pale yellow oil. These diastereomers were subjected to silica gel column chromatography (solvent: hexane-ethyl acetate = 5:
1, v / v), and the fraction that elutes first [T
Rf value of 0.35 on LC (chloroform: ethyl acetate =
10: 1, v / v)] and 9.36 g (47%) of the fraction to be eluted later. [Rf value on TLC: 0.31 (chloroform: ethyl acetate = 10: 1, v / v)] 20 g
(46%) was obtained.

Reference Example 12 (+)-2- (2,4-difluorophenyl) -3-me
Cyl-3- [4- (methylthio) phenoxy] -1,2
- on TLC was obtained by butanediol Reference Example 11, Rf value 0.35 (chloroform: ethyl acetate = 10: 1, v / v ) corresponding to the fraction 6.78 g (12.3 mmol) in methanol (37m
l) and dissolved in 2N aqueous sodium hydroxide solution (18.5
ml) was added and the mixture was stirred at 60 ° C. for 1 hour and 40 minutes. After allowing to cool, the methanol was distilled off under reduced pressure, and water (50 ml) was added to the residue.
Was added and extracted with chloroform (2 × 150 ml).
The chloroform layer was washed with water and then dehydrated with saturated saline. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, the residue was recrystallized (ethyl acetate-hexane), and (+)-2-
(2,4-Difluorophenyl) -3-methyl-3-
4.33 g (99.5%) of [4- (methylthio) phenoxy] -1,2-butanediol was obtained.

Reference Example 13 (-)-2- (2,4-difluorophenyl) -3-me
Cyl-3- [4- (methylthiophenoxy] -1,2-
Butanediol TLC obtained in Reference Example 11 in the same manner as in Reference Example 12
Upper Rf value 0.31 (chloroform: ethyl acetate = 1
(-) From 3.96 g of a fraction corresponding to 0: 1, v / v)
-2- (2,4-difluorophenyl) -3-methyl-
2.47 g (97%) of 3- [4- (methylthio) phenoxy] -1,2-butanediol was obtained.

Reference Example 14 (+)-2- (2,4-difluorophenyl) -3-me
Cyl-1-methylsulfonyloxy-3- [4- (meth
Luthio) phenoxy] butane-2 -ol (+)-2- (2,4-difluorophenyl) -3-methyl-3- [4- (methylthio) phenoxy] -1,2
-Butanediol (3.57 g, 10.1 mmol) was dissolved in pyridine (36 ml), and methanesulfonyl chloride (1.25 ml, 16.1 mmol) was added dropwise over 15 minutes under ice-cooling stirring, followed by stirring at room temperature for 4 hours. After completion of the reaction, pyridine was distilled off under reduced pressure, 5% aqueous sodium hydrogen carbonate solution (100 ml) was added to the obtained residue, and the mixture was extracted with ethyl acetate (2 × 150 ml). The ethyl acetate layer was dried over saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give crude (+)-2- (2,4-difluorophenyl) -3-methyl-1-methyl. 4.36 g (100%) of sulfonyloxy-3- [4- (methylthio) phenoxy] butan-2-ol was obtained.

Reference Example 15 (+)-2- (2,4-difluorophenyl) -3-me
Cyl-3- [4- (methylthio) phenoxy] -1-
(1H-1,2,4-triazol-1-yl) butane
-2-ol (+)-2- (2,4-difluorophenyl) -3-methyl-1-methylsulfonyloxy-obtained in Reference Example 14
4.36 g of 3- [4- (methylthio) phenoxy] butan-2-ol was added to N, N-dimethylformamide (35
ml) and added with 4.09 g (40.4 mmol) of Na salt of 1,2,4-triazole (90%),
It was stirred at 70 ° C. for 19 hours. After cooling, ice water (100m
l) was added and extracted with chloroform (2 × 150 ml). The chloroform layer was dehydrated with saturated saline and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained oil was subjected to silica gel column chromatography (solvent: chloroform → chloroform-ethyl acetate = 99: 1, v
/ V) and recrystallize from hexane to give (+)-2- (2,4-difluorophenyl) -3.
-Methyl-3- [4- (methylthio) phenoxy] -1
3.70 g (91%) of-(1H-1,2,4-triazol-1-yl) butan-2-ol was obtained.

Reference Example 16 (-)-2- (2,4-difluorophenyl) -3-me
Cyl-1-methylsulfonyloxy-3- [4- (meth
(Luthio) phenoxy] butan-2-ol By the same method as in Reference Example 14, (−)-2- (2,4-
Difluorophenyl) -3-methyl-3- [4- (methylthio) phenoxy] -1,2-butanediol 3.4
From 4 g (10.1 mmol), (-)-2- (2,4-
4.20 g (100%) of difluorophenyl) -3-methyl-1-methylsulfonyloxy-3- [4- (methylthio) phenoxy] butan-2-ol was obtained.

Reference Example 17 (-)-2- (2,4-difluorophenyl) -3-me
Cyl-3- [4- (methylthio) phenoxy] -1-
(1H-1,2,4-triazol-1-yl) butane
-2-ol By the same method as in Reference Example 15, (-)-2- (2,4-
(-)-2- (2,4) from 4.20 g of difluorophenyl) -3-methyl-1-methylsulfonyloxy-3- [4- (methylthio) phenoxy] butan-2-ol.
-Difluorophenyl) -3-methyl-3- [4- (methylthio) phenoxy] -1- (1H-1,2,4-triazol-1-yl) butan-2-ol at 3.50
g (89%) was obtained.

Example 28 (+)-2- (2,4-difluorophenyl) -3-me
Cyl-3- [4- (methylsulfonyl) phenoxy]-
1- (1H-1,2,4-triazol-1-yl) bu
Tan-2-ol (Compound No. 25) (+)-2- (2,4-difluorophenyl) -3-methyl-3- [4- (methylthio) phenoxy] -1- (1H obtained in Reference Example 15. -1,2,4-triazole-1
-Yl) butan-2-ol 3.78 g (9.33 mm)
ol) was dissolved in chloroform (50 ml), and m-chloroperbenzoic acid (82%) 4.32 g (2
0.5 mmol) was added over 20 minutes and then stirred at room temperature for 1 hour. After completion of the reaction, chloroform was added to the reaction solution and the solution was washed with a dilute aqueous sodium hydroxide solution. The extract was washed with a 5% aqueous sodium thiosulfate solution, washed with water, dehydrated with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained oily substance was subjected to silica gel column chromatography (solvent: chloroform: ethyl acetate = 5:
1, (v / v) and recrystallized with 5 volumes of isopropyl alcohol (IPA) to give (+)-2-
(2,4-Difluorophenyl) -3-methyl-3-
[4- (methylsulfonyl) phenoxy] -1- (1H
-1,2,4-triazol-1-yl) butane-2-
3.78 g (93%) of oar was obtained as white crystals.

(Example 29) (-)-2- (2,4-difluorophenyl) -3-me
Cyl-3- [4- (methylsulfonyl) phenoxy]-
1- (1H-1,2,4-triazol-1-yl) bu
Tan-2-ol (Compound No. 26) In the same manner as in Example 28, (−)-2- (2,4-difluorophenyl) -3-methyl-3- [4- (methylthio) phenoxy] -1- (1H-1,2,4-triazol-1-yl) butan-2-ol 3.32 g to (-)-2- (2,4-difluorophenyl) -3-methyl-3- [4- (methyl Sulfonyl) phenoxy]-
3.40 g (95%) of 1- (1H-1,2,4-triazol-1-yl) butan-2-ol as white crystals.
%)Obtained.

Example 30 (+)-2- (2,4-difluorophenyl) -3-me
Cyl-3- [4- (methylsulfonyl) phenoxy]-
1- (1H-1,2,4-triazol-1-yl) bu
Tan-2-ol (Compound No. 25) and (−)-2-
(2,4-Difluorophenyl) -3-methyl-3-
[4- (methylsulfonyl) phenoxy] -1- (1H
-1,2,4-triazol-1-yl) butane-2-
All (Compound No. 26) (±) -2- (2,4-difluorophenyl) -3-methyl-3- [4- (methylsulfonyl) phenoxy] -1- (1H-1 obtained in Example 3 , 2,4-Triazol-1-yl) butan-2-ol (5 mg) was dissolved in 5 ml of hexane-isopropanol (1: 1), and 100 μl of the solution was added to a column for separation of optical isomers [CHIRA
LCEL OD (4.6 × 250 mm)] was used for injection to perform separation of optical isomers. Separation conditions are column temperature: room temperature, eluent: hexane-isopropanol (4: 1), flow rate: 1.0 ml.
/ Min. , Detection: performed with an ultraviolet absorptiometer (245 nm). 2m each by repeating the above method
g of (+)-2- (2,4-difluorophenyl) -3
-Methyl-3- [4- (methylsulfonyl) phenoxy] -1- (1H-1,2,4-triazol-1-yl) butan-2-ol and (-)-2- (2,4-difluoro) Phenyl) -3-methyl-3- [4- (methylsulfonyl) phenoxy] -1- (1H-1,2,4-triazol-1-yl) butan-2-ol was obtained.

[0071]

[Table 1]

[0072]

[Table 2]

[0073]

[Table 3]

[0074]

[Table 4]

[0075]

[Table 5]

[0076]

[Table 6]

[0077]

[Table 7]

[0078]

[Table 8]

[0079]

[Table 9]

[0080]

[Table 10]

[0081]

[Table 11]

[0082]

[Table 12]

[0083]

[Table 13]

[0084]

[Table 14]

[0085]

[Table 15]

[0086]

[Table 16]

[0087]

[Table 17]

[0088]

[Table 18]

[0089]

[Table 19]

[0090]

[Table 20]

[0091]

[Table 21]

[0092]

INDUSTRIAL APPLICABILITY The compound of the present invention and physiologically acceptable salts thereof are effective for the treatment of superficial or deep-seated mycosis in animals and humans, such as Trichophyton rubrum and microsporum.・ Ringworm, dermatophytosis caused by canis (Microsporum canis),
Candida albicans and other candidiasis, Aspergillu fumigatus
s fumigatus) and other aspergillosis, Cryptococcus neoformans
), Etc., and Coccidioides immitis (important mycosis)
It can be used for the treatment of coccidioidosis caused by itis, histoplasmosis caused by Histoplasma capsulatum, and paracoccidioidosis caused by Paracoccidioides brasiliensis.

The antifungal activity of the compounds of the present invention was tested in vitro.
And an in vivo infection experiment using mice.

Candida albicans
cans) Evaluation of in vitro antifungal activity against TTB 273. The in vitro antifungal activity of the compound of the present invention was evaluated by literature (Yo Mikami, Katsuyoshi Yazawa, Jun Uno, Akihiro Matsumae: Chemotherap).
y, 38 (10), 1039-1047 (1990)). That is, a 96-well microplate in which a 2-fold dilution series of drug solution was dispensed was inoculated with a Candida albicans bacterial solution at a final concentration of 5 × 10 ⁴ cells / ml, and then 48 hours,
Cultured at 37 ° C. Test liquid was measured turbidity at a wavelength of over time 650 nm, the minimum medicament concentration of drug addition group which does not exceed 1/2 of turbidity when no drug addition group reaches the stationary phase as an IC ₅₀ value Calculated. The results are shown in Table V.

[0095]

[Table 22]

Candida albicans
cans) Evaluation of in vivo antifungal activity against TTB 273 ICR male mice (body weight 22 to 26 g) were injected with Candida albicans TTB 273 from the tail vein to infect them. 1
After 10 hours, 10 mg / kg of the test compound was orally administered, and 1, 2, 3, and 4 days after infection, the same was also orally administered once daily. The average number of days to live was measured 14 days after infection. The results are shown in Table VI.

[0097]

[Table 23]

Aspergil Fumigatus
Evaluation of in vivo antifungal activity against lus fumigatus) TTB 1776 ICR male mice (body weight 22 to 26 g) were infected with Aspergillus fumigatus TTB 1776 by injecting from the tail vein. Test compound 4 after 1 hour
Oral administration of 0 mg / kg and infection 1, 2, 3, 4
After the day, it was also orally administered once a day. The average number of days to live was measured 14 days after infection. The results are shown in Table VII.

[0099]

[Table 24]

As described above, the compound of the present invention is
It is concluded that the compound is extremely effective against both experimental infections of Albicans and Aspergillus fumigatus and is an excellent compound as an antifungal agent.

For the toxicity evaluation of the compounds of the present invention, see IC
The test compound was continuously administered to male R mice at 200 mg / kg for 5 days using an oral probe for mice, but no death was observed.

The compound (I) of the present invention and a physiologically acceptable salt thereof are mixed with themselves or generally used additives for pharmaceutical preparations to give tablets, capsules, powders, granules, injections, syrups, It can be administered orally or parenterally in the form of suspension, emulsion, suppository, and the like. Although the dose varies depending on the symptoms, age, weight, and administration method, it is usually
The dose can be appropriately adjusted within the range of 0.1 to 150 mg / kg per day.

Further, the compound (I) of the present invention and physiologically acceptable salts thereof include ointments, creams, sprays,
It can also be used as an external preparation such as a jelly or a solution, and in this case, for example, it is usually 0.1 to 1 per 1 g of the additive.
A content in the range of 50 mg is preferred.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Osamu Sakuma 2-33-3 Akabanekita, Kita-ku, Tokyo Inside Tanabe Pharma Co., Ltd. R & D Headquarters (72) Inventor Hiroyuki Ohne Akabanekita 2-33-3 Tokyo Tanabe Pharma Co., Ltd. R & D Headquarters (72) Inventor Yoko Iwase 2-33-3 Akabanekita, Kita-ku, Tokyo Tokyo Tanabe Pharma Co., Ltd. R & D Headquarters

Claims (3)

[Claims] 1. A compound represented by the general formula (I): (In the formula, Ar represents a phenyl group substituted with a halogen atom or a trifluoromethyl group, n represents 1 to 2, and R represents a lower alkyl group.) And a physiologically acceptable triazole derivative. That salt that will be. 2. 2- (2,4-difluorophenyl)-
3-Methyl-3- [4- (methylsulfinyl) phenoxy] -1- (1H-1,2,4-triazole-1-
Iyl) butan-2-ol, 2- (2,4-difluorophenyl) -3-methyl-3- [4- (methylsulfonyl) phenoxy] -1- (1H-1,2,4-triazole-1- Yl) butan-2-ol, 2- (4-fluorophenyl) -3-methyl-3- [4- (methylsulfinyl) phenoxy] -1- (1H-1,2,4-triazol-1-yl) Butan-2-ol, 2- (4
-Fluorophenyl) -3-methyl-3- [4- (methylsulfonyl) phenoxy] -1- (1H-1,2,4
-Triazol-1-yl) butan-2-ol, 2-
(4-chlorophenyl) -3-methyl-3- [4- (methylsulfinyl) phenoxy] -1- (1H-1,
2,4-triazol-1-yl) butan-2-ol, 2- (4-chlorophenyl) -3-methyl-3-
[4- (methylsulfonyl) phenoxy] -1- (1H
-1,2,4-triazol-1-yl) butane-2-
All, 2- (4-trifluoromethylphenyl) -3
-Methyl-3- [4- (methylsulfinyl) phenoxy] -1- (1H-1,2,4-triazol-1-yl) butan-2-ol, 2- (4-trifluoromethylphenyl) -3 -Methyl-3- [4- (methylsulfonyl) phenoxy] -1- (1H-1,2,4-triazol-1-yl) butan-2-ol, 2- (2,4
-Dichlorophenyl) -3-methyl-3- [4- (methylsulfinyl) phenoxy] -1- (1H-1,2,
4-triazol-1-yl) butan-2-ol, 2
-(2,4-Dichlorophenyl) -3-methyl-3-
[4- (methylsulfonyl) phenoxy] -1- (1H
-1,2,4-triazol-1-yl) butane-2-
All, 2- (2,4-difluorophenyl) -3-
[4- (Ethylsulfinyl) phenoxy] -3-methyl-1- (1H-1,2,4-triazol-1-yl) butan-2-ol, 2- (2,4-difluorophenyl) -3- [4- (Ethylsulfonyl) phenoxy] -3-methyl-1- (1H-1,2,4-triazol-1-yl) butan-2-ol, (−)-2-
(2,4-Difluorophenyl) -3-methyl-3-
[4- (Methylsulfinyl) phenoxy] -1- (1
H-1,2,4-triazol-1-yl) butane-2
-Ol, (+)-2- (2,4-difluorophenyl) -3-methyl-3- [4- (methylsulfinyl)
Phenoxy] -1- (1H-1,2,4-triazol-1-yl) butan-2-ol, (−)-2- (2,
4-difluorophenyl) -3-methyl-3- [4-
(Methylsulfonyl) phenoxy] -1- (1H-1,
2,4-triazol-1-yl) butan-2-ol or (+)-2- (2,4-difluorophenyl) -3
-Methyl-3- [4- (methylsulfonyl) phenoxy] -1- (1H-1,2,4-triazol-1-yl) butan-2-ol and the triazole derivative according to claim 1 and physiologically. That salt that is acceptable. 3. An antifungal agent comprising the triazole derivative according to claim 1 or 2 and a physiologically acceptable salt thereof as an active ingredient.