JPH0977750A - New optically active triazole derivative or its salt, its production, antimycotic drug and its use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To prepare the subject compound useful for treating local fungus infection, mucous infection and systemic fungus infection caused by genus trichophton, genus candida and genus Aspergillus. SOLUTION: The compound is a derivative (salt) of formula I [R1 and R2 are each H, a halogen, a halo-1-6C alkyl (R1 and R2 are not H in the same time); R3 is a (substituted)phenyl; a 1-6C alkyl and a (substituted) ailyl; n is 1 or 2], for example (2R, 3S)-2-(2,4-difluorophenyl)-4-(4-fluorophenyl)-3-methyl-1-(1 H-1,2,4-triazol-1-yl)butan-2-ol. This compound is produced by carrying out the reaction of a compound of formula II with a Grignard reagent of the formula R3 -(CH2 )n -MgX (X is a halogen).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel optically active triazole derivative or a salt thereof, a method for producing the same, an antifungal agent containing the compound or a pharmacologically acceptable salt thereof as an active ingredient, and a method for using the same. .

[0002]

2. Description of the Related Art In recent years, infection with fungal diseases due to weakened immunity has become a problem due to immunodeficiency or the use of anticancer agents, and various antifungal agents are known.

[0003]

[Problems to be Solved by the Invention] General formula (I):

Embedded image [In the formula, R ₁ and R ₂ are the same or different and represent a hydrogen atom, a halogen atom or a halo C ₁ -C ₆ alkyl group, and R ₃
Is a phenyl group, the same or different, a halogen atom, a halo C
₁ -C ₆ alkyl group, halo C ₁ -C ₆ alkoxy group or a phenyl group having one or more substituents selected from cyano group, or the same or different C ₁ -C ₆ alkyl group, a phenyl group or a halogen atom Represents a silyl group having one or more substituents selected from a phenyl group substituted by, and n represents an integer of 1 or 2. However, R ₁ and R
₂ excludes the case where it represents a hydrogen atom at the same time. ] The optically active triazole derivative represented by the following formula and a structurally similar triazole compound have agricultural bactericidal activity is disclosed in JP-A-1-27.
Although described in Japanese Patent No. 5566, it was not known that it has antifungal activity for medical purposes.

[0004]

The present inventors have previously found that the racemic form of the optically active triazole derivative represented by the above-mentioned general formula (I) has antifungal activity.
The patent application was filed as 80889. Japanese Patent Application 6-8
The compound represented by the general formula (I) described in JP-A-0889 (JP-A-7-316140) has two asymmetric centers in its molecule, and it is considered that four kinds of isomers exist. Therefore, the present inventors have found a method for selectively producing an optically active triazole derivative having the most potent antifungal activity among these four isomers or a salt thereof and an optically active triazole derivative, and the present invention Has been completed.

In the definition of the substituent represented by the general formula (I) of the present invention, the halogen atom is, for example, a chlorine atom,
Represents a fluorine atom, a bromine atom or an iodine atom, and is C ₁ -C
₆ alkyl groups include, for example, straight-chain or branched-chain such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like. 1 carbon atom
To 6 alkyl groups, and examples of the halo C _{1 to} C ₆ alkyl group include chloromethyl, fluoromethyl, bromomethyl, iodomethyl, dichloromethyl, difluoromethyl, trifluoromethyl, chloroethyl, fluoroethyl, bromoethyl, iodoethyl, dichloro. ethyl,
A haloalkyl group having 1 to 6 carbon atoms, which is substituted with one or more halogen atoms which may be the same or different and may be difluoroethyl, trifluoroethyl, chloropropyl, fluoropropyl, fluorobutyl or the like, and is halo C ₁ -C
Examples of the _6- alkoxy group include linear or branched haloalkoxy groups having 1 to 6 carbon atoms such as chloromethoxy, fluoromethoxy, trifluoromethoxy, and trifluoroethoxy.

Preferably, R ₁ and R ₂ represent a chlorine atom or a fluorine atom which may be the same or different, and R ₃ represents a phenyl group substituted by a chlorine atom, a fluorine atom or a cyano group. The optically active triazole derivative represented by the general formula (I) of the present invention can be used as it is or in the form of an acid addition salt as an antifungal agent. Examples of the acid used include hydrochloric acid, sulfuric acid and nitric acid. And the like, and organic acids such as oxalic acid and methanesulfonic acid.

The optically active triazole derivative represented by the general formula (I) can be produced, for example, by the method shown below.

[Chemical 6] [In the formula, R ₁ , R ₂ , R ₃ and n are the same as defined above, and X
Represents a halogen atom. ]

The optically active triazole derivative represented by the general formula (I) can be prepared by a known method, for example, Chem. Pharm. Bull., 3
9, 2241 (1991), Chem. Pharm. Bull., 41, 1035 (199
3) can be produced by reacting the compound represented by the general formula (II) and the Grignard reagent represented by the general formula (III) with a reagent prepared from a copper salt. it can. The compound represented by the general formula (II) is EP
-A-0421210-A2 and EP-A-0473387-A2. In addition, the reaction of Grignard reagent with an epoxide compound in the presence of copper salt is described by Org. Synth., 69, 1 (1990), Tetr.
ahedron, 37, 3879 (1981), j. Org. Chem., 48, 4131 (19
83) etc. The amount of the copper salt to be used is generally a catalytic amount, but it can also be appropriately selected and used from the range of an equivalent amount to an excess amount, if necessary, as the copper salt, for example, copper iodide, copper bromide, Copper cyanide, copper bromide / dimethylsulfoxide complex or the like can be used, and a Lewis acid such as boron trifluoride or aluminum chloride can be added if necessary. Any inert solvent can be used in this reaction as long as it does not significantly inhibit the progress of this reaction, and for example, ether, tetrahydrofuran, n-hexane, toluene and a mixed solvent obtained by combining these inert solvents are used. be able to. In addition, the general formula (I)
The optically active triazole derivative represented by, and its racemate are optically active HPLC (high performance liquid chromatography),
It can also be produced by a usual optical resolution method such as preferential crystallization.

The optically active triazole derivatives represented by the general formula (I) of the present invention are antifungal agents useful for treating fungal infections of humans and animals, for example, they are Trichophyton (T.
It can be used for the treatment of local fungal infections, mucosal infections and systemic fungal infections caused by richophyton, Candida, Aspergills and the like. When the compound of the present invention is used as an antifungal agent,
A dosage form suitable for oral or parenteral administration of a composition comprising an inert carrier or diluent which is singly or pharmaceutically acceptable, such as a solution, a tablet, a suppository, an emulsifier, an ointment, a cream, a lotion and a poultice It is prepared and used. The dose varies depending on symptoms, age, body weight, administration form, etc., but in the case of systemic treatment, it is usually 1k / day for an adult.
0.05-100 mg per g, preferably 0.5-5
0 mg can be administered once or in several divided doses.
The concentration of the active ingredient in local treatment is 0.001% to 5
%, Preferably 0.1% to 2% is optimum. In the application of this agent, it can be used by mixing with other antifungal agents and antibacterial agents such as amphotesin B, tricomycin, valitoin, clotrimazole and the like.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION Next, examples of the present invention, prescription examples, test examples and the like will be shown as embodiments of the present invention, but the present invention is not limited to these. Example 1 (2R, 3S) -2- (2,4-difluorophenyl)
-4- (4-fluorophenyl) -3-methyl-1-
Production of (1H-1,2,4-triazol-1-yl) butan-2-ol (Compound 1). To a suspension of 200 mg of copper iodide in 8 ml of anhydrous ether was added a solution of 145 mg of magnesium and 870 mg of 4-fluorobenzyl chloride in 10 ml of anhydrous ether of Grignard reagent at -30 ° C. 3 at -20 ° C
After stirring for 0 minutes, at the same temperature (2R, 3S) -2- (2,2
4-difluorophenyl) -3-methyl-2-[(1H
A solution of 500 mg of -1,2,4-triazol-1-yl) methyl] oxirane in 12 ml of anhydrous ether was added. After stirring at −20 ° C. for 2 hours, a saturated aqueous solution of ammonium chloride was added, the desired product was extracted with ethyl acetate, the organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by silica gel column chromatography (ethyl acetate: n-hexane = 2: 1) to give the desired product 466 m.
g was obtained as a colorless oil.

Example 2 (2R, 3S) -2,4-bis (2,4-difluorophenyl) -3-methyl-1- (1H-1,2,4-triazol-1-yl) butane-2 -All (compound 2)
Manufacturing of. To a suspension of 200 mg of copper iodide in 8 ml of anhydrous ether was added a solution of 145 mg of magnesium and 1.24 g of 2,4-difluorobenzyl bromide in 10 ml of anhydrous ether of Grignard reagent at -30 ° C. -20
After stirring at ℃ for 30 minutes, at the same temperature (2R, 3S) -2-
(2,4-difluorophenyl) -3-methyl-2-
A solution of 500 mg of [(1H-1,2,4-triazol-1-yl) methyl] oxirane in 12 ml of anhydrous ether was added. After stirring at −20 ° C. for 2 hours, a saturated aqueous solution of ammonium chloride was added, the desired product was extracted with ethyl acetate, the organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:
By purifying with n-hexane = 2: 1), 603 mg of the desired product was obtained as a colorless oil.

Example 3 (2R, 3R) -2- (2,4-difluorophenyl)
-3-Methyl-4-trimethylsilyl-1- (1H-
Production of 1,2,4-triazol-1-yl) butan-2-ol (Compound 5). To a suspension of 200 mg of copper iodide in 8 ml of anhydrous ether, 4.2 ml of a 12 ml solution of the Grignard reagent in anhydrous ether prepared from 290 mg of magnesium and 1.46 g of chloromethyltrimethylsilane was added at -30 ° C. After stirring at 10 ° C for 1 hour, at -20 ° C (2R, 3
S) -2- (2,4-Difluorophenyl) -3-methyl-2-[(1H-1,2,4-triazol-1-yl) methyl] oxirane 300 mg anhydrous ether 10
ml solution was added. After stirring at the same temperature for 2 hours, a saturated aqueous solution of ammonium chloride was added, the desired product was extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 2: 1) to obtain 245 mg of the desired product as a colorless oil.

Example 4 (2R, 3S) -4- (4-cyanophenyl) -2-
(2,4-Dimelorophenyl) -3-methyl-1-
Production of (1H-1,2,4-triazol-1-yl) butan-2-ol (Compound 7). (1). 19 g of 2,4-difluoropropiophenone was dissolved in 150 ml of tetrahydrofuran, and 112 ml of a 1N-tetrahydrofuran solution of lithium hexamethyldisilazide in 20 ml was cooled with a dry ice-acetone bath.
It dripped over minutes. After completion of the dropwise addition, the mixture was stirred at the same temperature for 1 hour, then a solution of 4-cyanobenzyl bromide (14 g) in tetrahydrofuran (50 ml) was added dropwise over 20 minutes, and the mixture was stirred overnight at room temperature. After adding a saturated ammonium chloride aqueous solution to the reaction solution, the mixture was poured into water, the desired product was extracted with ethyl acetate, the organic layer was washed with saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 9) to give 2 ′, 4′-difluoro-2-methyl-3-.
13 g of (4-cyanophenyl) -2-propiophenone
I got Yield 41%

(2). 60% sodium hydride 1.0
g was dissolved in 50 ml of dimethyl sulfoxide, and the mixture was stirred at 60 ° C. for 1 hour. The reaction solution was cooled to 15 ° C. or lower, 5.6 g of trimethylsulfoxonium iodide was added, and the mixture was stirred at room temperature for 1 hour, cooled to 15 ° C. or lower again, and 2,4-
Difluoro-2-methyl-3- (4-cyanophenyl)
-Propiophenone 2.4 g of dimethyl sulfoxide 1
0 ml solution was added. Then, stir at 60 ° C for 1 hour,
After cooling to room temperature, the reaction solution was poured into ice water, the target product was extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. By distilling off the solvent under reduced pressure, 2- (2,4-difluorophenyl) -3-methyl-3- (4-cyanophenyl) -1,
2.3 g of 2-butane oxide was obtained. 95% yield

(3). 2- (2,4-difluorophenyl) -3-methyl-3- (4-cyanophenyl) -1,
2.3 g of 2-butane oxide was dissolved in 50 ml of N, N-dimethylformamide, 2.1 g of 1,2,4-triazole and 2.0 g of potassium tert-butoxide were added, and the mixture was stirred at 100 ° C. for 2 hours. Then, the mixture was cooled to room temperature, the reaction mixture was poured into ice water, the target product was extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 2: 1) to give 4- (4-cyanophenyl) -2- (2,2). 4-difluorophenyl) -5-methyl-1- (1H-1,2,4-
1.5 g of triazol-1-yl) butan-2-ol
I got 52% yield

(4). 4- (4-cyanophenyl) -2
-(2,4-Difluorophenyl) -5-methyl-1-
1.2 g of (1H-1,2,4-triazol-1-yl) butan-2-ol is dissolved in a solvent, and a preparative column (μ-bonder sphere 19 mm × 15 cm) is used for high performance liquid chromatography. And collected. Retention time [fast] (erythro form) 0.5 g and retention time [slow] (threo form) 0.4 g were obtained. The obtained erythro body is (2R ^* , 3S ^* )-4- (4-cyanophenyl) -2- (2,4-difluorophenyl).
-3-methyl-1- (1H-1,2,4-triazol-1-yl) butan-2-ol was optically resolved by high performance liquid chromatography using a preparative column,
An optically active substance with [α] _D −47.3 ° (c = 0.11, methanol) was obtained.

Hereinafter, the general formula (I) produced according to the examples
Representative examples of the optically active triazole compound represented by Table 1
Shown in General formula (I):

[Chemical 7]

[0018]

[Table 1]

[0019]

[Table 2]

[0020]

[Table 3] HPLC: [chiralcel (trademark) OD (Daicel Chemical Industries, Ltd., ethanol: n-hexane = 3:
7, 0.9 ml / min, column temperature 30 ° C.)]

Formulation Example 1 Compound of the present invention 0.01 part 0.5% Carboxymethyl cellulose 99.99 parts The above was suspended to give a suspension. Formulation Example 2 Compound of the present invention 1.00 part Polyethylene glycol 400 99.00 part The above was uniformly dissolved to obtain a coating liquid agent. Formulation Example 3 Compound of the present invention 2.00 parts Polyethylene glycol 400 49.00 parts Polyethylene glycol 4000 49.00 parts The above components were mixed and dissolved under heating and then cooled to obtain an ointment.

Formulation Example 4 Compound of the present invention 3.00 parts 1,2-propanediol 5.00 parts glycerol stearate 5.00 parts spermaceti wax 5.00 parts isopropyl myristate 10.00 parts polysorbate 4.00 parts The mixture was warmed, allowed to cool, and then stirred to add 68.00 parts of water to make it cream. Formulation Example 5 Compound of the present invention 0.10 parts Stearyl alcohol 5.00 parts Cetanol 5.00 parts Medium chain fatty acid triglyceride 10.00 parts Isopropyl myristate 5.00 parts Polysorbate 60 4.00 parts Sorbitan monostearate 1.00 parts Methyl paraoxybenzoate 0.14 parts Propyl paraoxybenzoate 0.06 parts Dibutylhydroxytoluene 0.02 parts Purified water Remainder The above mixture was prepared according to a conventional method to give a cream.

Test Example 1 Candida albi was added to 9.8 ml of Sabouraud's glucose broth.
cans IFO 1270 (1.0 × 10 ⁶ cells / ml) 0.1 ml
Dimethylsulfoxide solution of test compound 0.1
ml to 10 μg / ml and 0.1 μg / ml, respectively
Was added so that the concentration became. Then, the growth inhibition rate of the bacterium after shaking culture at 37 ° C. for 2 days was measured. Table 2 shows the results.

[0024]

[Table 4] A is cis-1-acetyl-4- [4-[[2- (2,4-dichlorophenyl) -2- (imidazol-1-ylmethyl) -1,3-oxolan-4-yl] methoxy as a control drug. ] Phenyl] piperazine (generic name: ketoconazole) was used.

Test Example 2 Six-week-old ddY mice were tested with 10 mice as a control group and 5 mice as a drug administration group. Sabouraud's glucos
Candida albica cultured at 37 ° C for 24 hours on e agar
ns IFO 1270 (2.5 × 10 ⁷ cells / ml) 4ml / k
g of the test compound and 0.02% of the test compound.
5% CMC aqueous solution (10% polyethylene glycol 40
0 and 0.1% Tween 80) were orally administered in a volume of 5 ml / kg once a day for 4 days. The survival number was investigated for 10 days from the date of inoculation, and the survival rate on the final day was calculated. The results are shown in Table 3.

[0026]

[Table 5] Control drug A is the same as in Test Example 1.

[0027]

INDUSTRIAL APPLICABILITY The optically active triazole derivative of the present invention is an antifungal agent useful for treating fungal infections of humans and animals.

Continuation of front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display location // C07M 7:00

Claims (5)

[Claims] [Claim 1] General formula (I): [In the formula, R ₁ and R ₂ are the same or different and represent a hydrogen atom, a halogen atom or a halo C ₁ -C ₆ alkyl group, and R ₃
Is a phenyl group, the same or different, a halogen atom, a halo C
₁ -C ₆ alkyl group, halo C ₁ -C ₆ alkoxy group or a phenyl group having one or more substituents selected from cyano group, or the same or different C ₁ -C ₆ alkyl group, a phenyl group or a halogen atom Represents a silyl group having one or more substituents selected from a phenyl group substituted by, and n represents an integer of 1 or 2. However, R ₁ and R
₂ excludes the case where it represents a hydrogen atom at the same time. ] The optically active triazole derivative represented by these, and its pharmacologically acceptable salt. 2. R ₁ and R ₂ are the same or different and represent a halogen atom, R ₃ are the same or different and represent a phenyl group having one or more substituents selected from a halogen atom or a cyano group, and n is The optically active triazole derivative according to claim 1, which represents one integer, or a pharmaceutically acceptable salt thereof. 3. General formula (II): [In the formula, R ₁ and R ₂ are the same or different and each represents a hydrogen atom, a halogen atom or a halo C ₁ -C ₆ alkyl group. A compound represented by the general formula (III): embedded image R ₃ — (CH ₂ ) n MgX (III) [wherein R ₃ is a phenyl group, the same or different, a halogen atom, halo C _1- A phenyl group having one or more substituents selected from a C ₆ alkyl group, a halo C ₁ -C ₆ alkoxy group or a cyano group, or the same or different C ₁ -C
₆ represents a silyl group having one or more substituents selected from an alkyl group, a phenyl group or a phenyl group substituted with a halogen atom, n represents an integer of 1 or 2, and X represents a halogen atom. ] The general formula (I) characterized by reacting with a Grignard reagent represented by: [In formula, R < ₁ >, R < ₂ >, R < ₃ > and n are the same as the above. ] The manufacturing method of the optically active triazole derivative represented by these. 4. An antifungal agent containing the optically active triazole derivative according to claim 1 or 2 or a pharmacologically acceptable salt as an active ingredient. 5. Use of an effective amount of an antifungal agent containing the optically active triazole derivative according to claim 1 or 2 or a pharmacologically acceptable salt as an active ingredient for the treatment of mycosis in humans or animals. how to.