WO1999033826A1

WO1999033826A1 - Triazole derivatives, antimycotic agents, and uses thereof

Info

Publication number: WO1999033826A1
Application number: PCT/JP1998/005872
Authority: WO
Inventors: Takashi Kagawa; Hiroki Kodama; Yuri Goto; Yoshimi Niwano; Masanori Yoshida
Original assignee: Nihon Nohyaku Co., Ltd.
Priority date: 1997-12-27
Filing date: 1998-12-24
Publication date: 1999-07-08
Also published as: JPH11199411A; AU1688699A

Abstract

Triazole derivatives of R-configuration represented by general formula (I) or pharmacologically acceptable salts thereof, wherein X represents 0 to 5 substituents which are each independently selected from among halogeno, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, nitro and cyano; drug compositions characterized by containing the derivatives or salts as the active ingredient; use of the derivatives or salts in the treatment or prevention of mycosis; and methods for the treatment or prevention of mycosis, characterized by administering or applying an pharmacologically effective dose of the derivative or salt to homo sapiens or animals.

Description

Description Triazole derivatives, antifungal agents and methods of using the same

TECHNICAL FIELD The present invention relates to an optically active triazole derivative and salts thereof, an antifungal agent containing the optically active substance, its racemate or salts thereof as an active ingredient, and a method of using them. For example, they Trichophyton (Trichophyton), Candida Candida), Asuperugi Angeles genus, As _Perg ill _u like due to local fungal infection, mucosal infection, can be used for systemic fungal infections such as the therapy. Background art

Conventionally, various azole compounds having antifungal activity have been known. JP-A-60-218387 describes that an imidazole derivative having a ketene dithioacetal structure is useful as an agricultural fungicide, and JP-A-62-93227 discloses that the midazole derivative is useful as an antifungal agent JP-A-62-275877 and JP-A-9-100797 describe optically active isomers, but do not describe or suggest triazole derivatives. Japanese Patent Application Laid-Open No. 61-57565 discloses a triazole derivative as an agricultural fungicide, but does not disclose or suggest a use as a medical antifungal agent or an optically active substance. Disclosure of the invention

An object of the present invention is to provide a triazole derivative which exhibits excellent antifungal activity and has less side effects, and a method for using the same.

The present invention provides a compound represented by the general formula (I):

(Wherein X may be the same or different, halogen atom, alkyl group having 1 to 6 carbon atoms, haloalkyl group having 1 to 6 carbon atoms, alkoxy group having 1 to 6 carbon atoms, 1 carbon atom And 0 to 5 substituents selected from a haloalkoxy group, a nitro group or a cyano group, and a triazole derivative having an absolute configuration of R or a pharmacologically acceptable derivative thereof. Regarding salts.

Further, the present invention relates to a pharmaceutical composition comprising a triazole derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.

Furthermore, the present invention relates to the use of the triliazol derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof for the treatment or prevention of mycosis.

Further, the present invention is characterized in that a pharmacologically effective amount of a triazole derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof is administered or applied to a human or animal. The present invention relates to a method for treating or preventing mycosis. BEST MODE FOR CARRYING OUT THE INVENTION

In the present invention, the halogen atom represented by X is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

An alkyl group having 1 to 6 carbon atoms means a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, and an n-butyl group. , Isobutyl, sec-butyl, ieri-butyl, n-pentyl, isopentyl, neopentyl, iari-pentyl, n-hexyl, 1-ethylpropyl, 1,2-dimethyl It represents a propyl group, an isohexyl group, a 1-methylpentyl group, a 1,2-dimethylbutyl group, a 2-ethylbutyl group, or the like.

A haloalkyl group having 1 to 6 carbon atoms means a linear or branched alkyl group having 1 to 6 carbon atoms in which one or more halogen atoms which may be the same or different are substituted, for example, trifluoromethyl Group, difluoromethyl group, bromodifluoromethyl group, 2,2,2-trifluoroethyl group, 2,2,2-trichloroethyl group, 2,2,2-tribromoethyl group, 2-bromoethyl group, 11-fluoroethyl group 1, 1-chloroethyl, 1-bromoethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-odoethyl, 1,1,2,2-tetrafluoroethyl Group, 1,1,2,2,2-pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, 1-fluoropropyl, 2-chloropropyl, 3-bromopropyl , 3-eord Ropyl, 2,3-dibromopropyl, 2,2,3,3-tetrafluoropropyl, 1,1,2,2,3,3,3-heptafluoropropyl, 4-fluorobutyl Group, 4-chlorobutynole group, 4-bromobutyl group, 4-bromobutyl group, 5-fluoropentyl group, 5-chloropentyl group, 5-bromopentyl group, 5-bromopentyl group, 6-fluoropentyl group, 6-fluorohexyl group, 6- A hexyl group, 6-bromohexyl group, 6-hexyl hexyl group, etc.

The haloalkoxy group having 1 to 6 carbon atoms means a linear or branched alkoxy group having 1 to 6 carbon atoms in which one or more halogen atoms which may be the same or different are substituted.

The triazole derivative represented by the general formula (I) can be produced, for example, by the production method described in JP-A-61-57565. The (R) -enantiomer of the triazole derivative represented by the general formula (I) can be produced by the following production method.

(II) (I)

(In the formula, X ¹ and X ² may be the same or different and represent a methanesulfonyloxy group, a p-toluenesulfonyloxy group or a halogen atom, and M represents an alkali metal atom.)

That is, similarly to the production method described in JP-A-9-1100279, an optically active daricol derivative having the absolute configuration of S represented by the general formula (一般) or an equivalent thereof and a general formula (m) The desired compound can be produced by reacting the compound with a dithiolate salt. Examples of the halogen atom of X ′ or X ² in the optically active daricol derivative represented by the general formula (Π) include, for example, a chlorine atom, a bromine atom and an iodine atom. Examples of the alkali metal atom in the dithiolate salt represented by the general formula (m) include, for example, alkali metal atoms such as lithium, sodium and potassium.

The dithiolate salt represented by the general formula (m) can be produced by reacting the following 11-cyanomethyltriazole with carbon disulfide in the presence of a base and an inert solvent.

(III)

(Where M is the same as above)

The inert solvent that can be used in this reaction may be any solvent that does not hinder the progress of this reaction. For example, alcohols such as methanol, ethanol, and isopropanol, dimethyl sulfoxide (hereinafter, referred to as DMS0), dimethylformamide (hereinafter, DMF) ), Polar solvents such as acetonitrile, water, and mixed solvents thereof. Examples of the base include sodium carbonate, carbonic acid lime, sodium hydroxide, and hydroxylic lime. These can be used as a solid or dissolved in an inert solvent. The amount of the base used may be selected from the range of 2 to 8 moles, preferably 4 to 6 moles relative to 1-cyanomethyltriazole. It is.

The compound of the general formula (Π) can be used in an equimolar amount or in excess with respect to 1-cyanomethyltriazole, and the reaction temperature may be selected from the range of 0 ° C to 100 ° C, preferably room temperature. It is nearby. The reaction time can be selected from the range of 0.5 to 24 hours. The obtained compound is a mixture of geometric isomers of E and Z. The desired E-isomer of the triazole derivative represented by the general formula (I) can be obtained by a method such as silica gel column chromatography or fractional crystallization. Can be isolated and purified. As a solvent for purification by fractionation and recrystallization, ethanol, ethyl acetate, ether, hexane, acetone and the like and a mixed solvent thereof can be used, but it is not particularly limited. The optically active raw material compound represented by the general formula (H) can be produced by the same method as in JP-A-9-1100279. In the present invention, an antifungal agent comprising an optically active triazole derivative represented by the general formula (I), its racemate and a pharmacologically acceptable salt as an active ingredient is useful for treating fungal infections in humans and animals. They are useful, for example, they can be used for the treatment of local fungal infections, mucosal infections, systemic fungal infections and the like caused by Trichophyton (Trichophyton). The optically active triazole derivative represented by the general formula (I) of the present invention, its racemic form and the pharmaceutically acceptable salts are compositions comprising an inert carrier or diluent alone or pharmaceutically acceptable. Dosage forms suitable for oral or parenteral administration, such as solutions, tablets (including sugar-coated tablets and film-coated tablets), powders, granules, capsules (including soft capsules), injections, and suspensions It is used as a liquid, suppository, emulsifier, ointment, cream, lotion, poultice, etc. The dosage varies depending on the age, body weight and mode of administration.In the case of systemic treatment, usually 0.05 mg or more per kg of body weight per adult per day, preferably 0.5 to 5.0 mg once or several times Can be divided and administered. Topical treatment, for example, in the case of the coating agent, the effective concentration of the component is 0.001% or more on, preferably optimally 2% 0.1, by coating the fabric in a range of l OOmg coating amount from 1 cm ² per 30nig Good. This drug may be used in admixture with other antifungals and antibacterials, such as amphotericin B, tricomycin, valitoin, and clotrimazole. Example

Next, Examples, Reference Examples, Formulation Examples and Test Examples are shown as embodiments of the present invention, but the present invention is not limited to these. In Examples and Reference Examples, "Me" represents a methyl group, and parts in Formulation Examples represent parts by weight.

Table 1 shows typical examples of the triazole derivative represented by the general formula (I) of the present invention.

Table l

Compound No. Substituent X Melting point (° C)

1 2—Black mouth (racemic) 88-91

2 2—Black mouth (R body) 76-78

3 4— Trifluoromethyl (racemic) 96-97

4 4-Trifluoromethyl (R-form) 156-158

5 4—Difluorometinole (racemic) 105-107

6 4-Difluoromethyl (R-form) 103-105

7 2,4 difluoro (racemic) 161-163

8 2,4 GF (R type) 1 14 to 1 15

9 2, 4-Dichro mouth (racemic) 158-160

10 2, 4-Dichloro (R form) 15 to 152

Example 1

(R) ― (E) of [4- (2,4-difluorophenyl) -1, 3-dithiolan-1-ylidene] 1-triazolylacetonitrinole (Compound No. 8) Manufacture

2.55 g of lithium hydroxide was added to 25 ml of DMSO, and a solution of 1.9 g of 1-cyanomethyltriazole and 1.38 g of carbon disulfide in 15 ml of DMSO was added dropwise while cooling in a water bath. Thereafter, the mixture was stirred at room temperature for 1 hour to prepare a dithiolate solution. Next, a dithiolate solution prepared above was added dropwise to a solution of 5.0 g of (S) -11- (2,4-difluorophenyl) -1-ethane-1,2-bismethanesulfonate in 25 ml of DMSO while cooling in a water bath. After stirring at room temperature for 2 hours, the reaction solution was poured into ice water, and the desired product was extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography (ethyl acetate n-hexane = 2-1 (v / v)). did. The obtained crystals were recrystallized from an ethanol solvent to give 1.9 g of the desired product with an optical purity of 99% ee and a melting point of 124 to 125 ° C.

(Note): Optical purity was calculated from the HPLC area percentage measured using an optically active HPLC column [CHIRALCEL 0D, manufactured by Daicel Chemical Industries, Ltd.].

Example 2

Preparation of (R)-(E)-[4- (2,4-dichlorophenyl) 1-1,3-dithiolan-1-ylidene] -1-triazolylacecetonitrile (Compound No. 10)

2. Ig of lithium hydroxide was added to 20 tnl of DMSO, and a solution of 3.2 g of 1-cyanomethyltriazole and 2.0 g of carbon disulfide in 7 ml of DMSO was added dropwise while cooling in a water bath. Thereafter, the mixture was stirred at room temperature for 2 hours to prepare a dithiolate solution. (S) -1- (2,4-Dichlorophenyl) -12-chloro-11-To a solution of 6 g of methanesulfonate in 30 ml of DMSO, the previously prepared dithiolate solution was added dropwise while cooling in a water bath. After stirring at room temperature for 2 hours, the reaction mixture was poured into ice water, and the target substance was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate _n- hexane = 2Zl (v / v)). The obtained crystals were recrystallized from a mixed solvent of ethyl ethyl acetate-hexane to give 1.5 g of the desired product with an optical purity of 99% ee and a melting point of 151 to 152 ° C.

Example 3

(E) Production of 1- (4- (4-trifluoromethylphenyl) -11,3-dithiolan-12-ylidene) -11-triazolylacetonitrile (Compound No. 3)

4.6 g of potassium hydroxide was added to 20 ml of DMSO, and a solution of 3.9 g of 11-cyanomethyltriazole and 2.7 g of carbon disulfide in 20 ml of DMSO was added dropwise while cooling in a water bath. Thereafter, the mixture was stirred at room temperature for 2 hours to prepare a dithiolate solution. Next, to a solution of 8.3 g of 2- (4-trifluoromethyl-phenyl) -12-chloroethyl-11-methanesulfonate in 30 ml of DMSO, the dithiole solution prepared above was added dropwise while cooling in a water bath. . After stirring at room temperature for 2 hours, the reaction solution was poured into ice water, and the desired product was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / π-hexane = 1 (ν / ν)). The obtained crystals were recrystallized from a mixed solvent of ethyl acetate / η-hexane to give 1.5 g of the desired product at a melting point of 96 to 97 ° C.

Reference example 1

(S) 1- (2,4-difluorophenyl) -ethane 1,2-bismethanesulfonate

(S) —1- (2,4-difluorophenyl) -1,2-ethanediol 6.42 g and triethylamine (16.4 g) produced by a known method [Org. Chem., 57: 2768 (1992)]. Was dissolved in methylene chloride (200 ml), and 7.7 g of methanesulfuryluricide was added dropwise under ice cooling. Then, after stirring at room temperature for 2 hours, the reaction solution was washed with water, and the organic layer was dried over anhydrous magnesium sulfate. After drying, the solvent was distilled off under reduced pressure to obtain 14.0 g of the desired product. Next, formulation examples are shown below, but the present invention is not limited to these.

Prescription example 1

Compounds listed in Table 1 10 parts

Magnesium stearate 10 parts

Lactose 80 parts

The above is uniformly mixed and powdered as powder or fine granules. Prescription example 2

Compounds listed in Table 1 20 parts

Starch 10 parts

Lactose 15 parts Ethyl cellulose 20 parts Polyvinyl alcohol 5 parts Water 30 parts After uniformly mixing and mixing, crushed and granulated, and sieved to obtain granules. Prescription example 3

Compounds listed in Table 1 0.5 parts Nonionic surfactants 2.5 parts Physiological saline 97 parts After mixing by heating, sterilize to make injections _c Formulation Example 4

Compounds listed in Table 1 0.01 parts

0.5% carboxymethinoresenolerose 99. 99 parts or more were suspended to prepare a suspension. Prescription example 5

Compounds listed in Table 1 1 part Polyethylene dalicol 400 99 parts or more were mixed and dissolved to prepare a coating solution. Prescription example 6

Compounds listed in Table 1 2 parts Polyethylene glycol 400 49 parts Polyethylene glycol 4000 49 parts After mixing and dissolving with heating, the mixture was cooled to obtain an ointment. Prescription example 7

Compounds listed in Table 1 3 parts

1,2-propanediol 5 parts

Glycerol stearate 5 parts

Whale wax 5

Isopropyl myrestate 10 parts

Polysorbet 4 parts

After heating and mixing the above, 68 parts of water was added while cooling and stirring to obtain a cream.

Prescription example 8

One part of the compound shown in Table 1, 5 parts of benzyl alcohol, 30 parts of ethanol and 47 parts of propylene glycol were mixed and dissolved, and then 1 part of Hibisco® 104 (manufactured by Wako Pure Chemical Industries, Ltd.) was purified in this solution. An aqueous solution consisting of 15 parts of water was added to obtain a uniform solution. Further, disopropanolamine was added with stirring to obtain a gel.

Prescription example 9

1 part of the compound shown in Table 1 was dissolved in 5 parts of benzyl alcohol and 5 parts of getyl sebacate, and 5 parts of ethyl alcohol, 5 parts of stearyl alcohol, 1 part of sorbitan monostearate and 1 part of polyoxyethylene monostearate Eight parts were added and dissolved by heating to 70 ° C. While maintaining the obtained homogeneous solution at 70 ° C., 69 parts of purified water heated to 70 ° C. was added, and the mixture was cooled while stirring to obtain a cream composition. Test Example 1 //? W iro antiaspergillus activity

^ 5 ^ ¾¾ Aspergillus fumigatus TIMM1728

35. Potato dextrose agar (Potato dextrose agar) on a gradient medium. C. Sterile physiological saline containing 0.1% (w / v) TweenSO (Kanto Chemical Co., Ltd.) was added to the test bacteria cultured for 2 days to release conidia. After filtering the conidia suspension with sterile gauze 2 ply, and counting the number of conidia a hemocytometer abacus, inoculated with which conidia concentration in the same solution were adjusted to be 1 chi 10 ^beta pieces Zml A bacterial solution was used. Each compound was dissolved in dimethyl sulfoxide (DMS0), and a kashiaton agar (Casitone agar) plate medium containing the compound DMS0 solution was prepared so that the final concentration was 1% (v / v). About S gZml of the inoculum was used to inoculate a compound-containing plate medium using a microplanter (Sakuma Seisakusho). After culturing at 35 ° C for 2 days, the minimum concentration of the compound in which no bacterial growth was visually observed was defined as the minimum inhibitory concentration (MIC).

The results are shown in Table 2. Table 2

(Compound No.MIC value Zml)

1 0.06

2 0. 016

3 1.000

4 1.000

5 0. 500

6 0. 250

7 0. 063

8 0. 063

9 0. 031

10 0.008 Test Example 2 Life extension effect on mouse systemic aspergillosis

0.5% (w / v) carboxymethylcellulose to each compound

(Carboxymethyl cellulose) was suspended in an aqueous solution to prepare an administration solution. The control drug itraconazole is hydroxypropyl-β-cyclodextrin.

It was dissolved in an aqueous solution of (hydroxypropyl β-cyclodextrin) to a predetermined concentration to prepare a solution for administration. The inoculum was used to adjust the concentration of conidia to 6.25 x 10 'conidia / ml in the same manner as in the case of the inoculum in / ί / Ό anti-Aspergillus activity. The animals used were ddy male mice (6 to 7 weeks old), and cyclophosphamide dissolved in physiological saline was added at 150 mg / kg and 100 mg / kg, respectively, 2 days before and 4 days after inoculation. Cortisone acetate suspended in saline one day before subcutaneous administration and one day before bacterial inoculation

(cortisone acetate) was administered subcutaneously at a rate of 150 mg / kg to make it immunosuppressed. Bacterial inoculation was inoculated into the tail vein of mice at a rate of 4 ml Zkg (0.25xl0 ^fi conidia / kg). Each compound suspension or solution was orally administered at a rate of 5 mlZkg 1 hour after inoculation of the bacteria and once a day from the next day for 3 days. The number of surviving animals was examined for 14 days after bacterial inoculation, and the average number of surviving days was calculated.

Table 3 shows the results. Table 3

(Note) i-Traconazole (generic name): (Sat) 1 11 sec-ptyl-41 [p- [4-1 [p- [[(2R *, 4S *) —2— (2,4-dichloroph Enyl) 1 2— (1H—1, 2, 4‐1 Triazole-1 1,3-dioxolan-1-yl) methoxy] phenyl] 1-1-piperazinyl) phenyl) 1 Δ ^ΰ — 1,2,4-triazoline-1-5-one Industrial applicability

According to the present invention, an antifungal agent exhibiting excellent antifungal activity and having less side effects is provided. The antifungal agent of the present invention can be used for the treatment of local fungal infection, mucosal infection, systemic fungal infection and the like caused by Trichophyton, Candida, Aspergillus and the like.

Claims

The scope of the claims

1. General formula (I)

(In the formula, X may be the same or different; a halogen atom, an alkyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, 1 carbon atom And 0 to 5 substituents selected from a haloalkoxy group, a nitro group or a cyano group, and a triazole derivative having an absolute configuration of R or a pharmacologically acceptable derivative thereof. No, no.

2. The substituent X may be the same or different, and is 0 to 5 substituents selected from a halogen atom, a haloalkyl group having 1 to 6 carbon atoms, or a haloalkoxy group having 1 to 6 carbon atoms. The optically active triazole derivative described above and pharmacologically acceptable salts thereof.

3. The optical activity according to claim 2, wherein the substituents X may be the same or different and are 0 to 2 substituents selected from a fluoro group, a chloro group, a bromo group, a trifluoromethyl group and a difluoromethoxy group. Triazole derivatives and pharmacologically acceptable salts.

4. General formula (I)

(In the formula, X may be the same or different; a halogen atom, an alkyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, 1 carbon atom And 0 to 5 substituents selected from haloalkoxy, nitro and cyano groups of the formula (1) to (6), or a pharmacologically acceptable salt thereof as an active ingredient. A pharmaceutical composition comprising:

5. The substituent X may be the same or different, and is 0 to 5 substituents selected from a halogen atom, a haloalkyl group having 1 to 6 carbon atoms, or a haloalkoxy group having 1 to 6 carbon atoms. The described pharmaceutical composition.

6. The pharmaceutical composition according to claim 5, wherein the substituents X may be the same or different and are 0 to 2 substituents selected from a fluoro group, a chloro group, a bromo group, a trifluoromethyl group and a difluoromethoxy group. object.

7. The pharmaceutical composition according to claim 4, wherein the absolute configuration of the general formula (I) is R.

8. Use of the triazole derivative according to claim 4 or a pharmaceutically acceptable salt thereof for the treatment or prevention of mycosis.

9. Use according to claim 8, characterized in that a pharmacologically effective amount of a triazole derivative or a pharmacologically acceptable salt thereof is administered or applied to a local or systemic fungal infection.

10. A method for treating mycoses, which comprises administering or applying a pharmacologically effective amount of the triazole derivative according to claim 4 or a pharmacologically acceptable salt thereof to a human or animal. Or how to prevent.