JP2887522B2 - Novel triazole derivatives and their salts - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel triazole derivative having antifungal activity and exhibiting an excellent therapeutic effect on human and animal diseases, and a salt thereof.

Accordingly, it is an object of the present invention to provide a compound which exhibits excellent antifungal activity and exhibits an excellent therapeutic effect on human and animal diseases.

[Prior Art] Amphotericin B (US Pat. No. 2,908,611) and flucytosine (US Pat. No. 2802005) are currently mainly used as therapeutic agents for deep mycosis, and further, azole antifungal agents For example, ketoconazole (JP-A-53-95973) and fluconazole (JP-A-5-95973)
8-32868) on the market and reported to be useful as a therapeutic agent for mycosis.

[Problems to be Solved by the Invention] However, the above therapeutic agents cannot be said to be sufficient in terms of pharmacokinetics, toxicity, antibacterial spectrum, and the like, and the development of more excellent compounds has been desired.

[Means for Solving the Problems] Under such circumstances, the present inventors have made intensive studies and found that the following general formula [I] Wherein R ¹ is an optionally substituted aryl or a heterocyclic group linked via a carbon atom in the ring; R ² and R ³ are the same or different and each represents a hydrogen atom, And a cycloalkyl ring formed together with an optionally substituted alkyl, cycloalkyl, alkenyl, aryl or heterocyclic group bonded through a carbon atom in the ring or a carbon atom to which R ² and R ³ are bonded. It has been found that the novel triazole derivative represented by the formula (I) and salts thereof have excellent antifungal activity, are excellent in absorbability, and further exhibit excellent pharmacokinetics, and have completed the present invention. Was.

 Hereinafter, the compound of the present invention will be described in detail.

In this specification, unless otherwise specified, a halogen atom means, for example, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; an alkyl group means, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, sec- butyl, tert- butyl, pentyl, hexyl, a C ₁ ~ ₁₀ alkyl groups, such as heptyl, and octyl; and the alkenyl group, for example, vinyl, C ₂ ~ ₁₀ alkenyl groups such as propenyl and butenyl;
An alkoxy group is, for example, methoxy, ethoxy, n
- propoxy, isopropoxy, n- butoxy, isobutoxy, sec- butoxy, tert- butoxy, pentyloxy, hexyloxy, a C ₁ ~ ₁₀ alkoxy groups such as heptyloxy, and octyloxy; and alkoxycarbonyl groups are, for example, methoxy carbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, a C ₁ ~ ₄ alkoxy -CO- group such as iso-butoxycarbonyl and tert- butoxycarbonyl; and alkylthio groups such as methylthio, ethylthio, n- propylthio , isopropylthio, n- butylthio, isobutylthio, sec- butylthio, tert- butylthio, pentylthio, hexylthio, a C ₁ ~ ₁₀ alkylthio groups, such as heptylthio and octylthio; and an aryl group , For example, groups such as phenyl and naphthyl; the cycloalkyl group, for example, cyclopropyl, cyclobutyl, C ₃ ~ ₈ cycloalkyl groups such as cyclopentyl and cycloheptyl; as halo-lower alkyl group is, for example, fluoro Methyl, chloromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl and 1,1,2,2,3,3,3- C ₁ ~ ₄ alkyl group substituted with a halogen atom such as heptafluoropropyl; and heterocyclic group, for example, thienyl, furyl, imidazolyl, triazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyridyl, At least one of pyridazyl, pyrimidyl, pyrazyl, and triazyl Oxygen, 5-membered or 6-membered heterocyclic group containing sulfur or nitrogen atom; and, the term "lower" represents a group of C ₁ ~ ₄ respectively.

The heterocyclic group bonded via a carbon atom in the ring of R ¹ , R ² and R ³ includes a 5- or 6-membered heterocyclic group containing at least one oxygen, sulfur or nitrogen atom, for example, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2H-
Pyran-3-yl, pyrrol-3-yl, imidazol-2-yl, thiazol-2-yl, thiazol-4-
Yl, isothiazol-3-yl, isoxazole-
3-yl, pyridin-2-yl, pyridin-3-yl,
Pyrazin-2-yl, pyrimidin-2-yl, pyrrolidin-2-yl, 2-pyrrolin-3-yl, imidazolidine-2-yl, 2-imidazolin-4-yl, piperidin-2-yl and morpholine-3 -Yl and the like.

Examples of the cycloalkyl ring formed together with the carbon atom to which R ² and R ³ are bonded include cyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like.

Each group in R ¹ , R ² and R ³ is, for example, one selected from a halogen atom, lower alkyl, lower alkoxy, lower alkylthio, hydroxyl, cyano, amino, carbamoyl, alkoxycarbonyl, halo-lower alkyl and heterocyclic group. It may be substituted with one or more substituents.

Salts of the compound of the general formula [I] include pharmaceutically acceptable salts, for example, salts with mineral acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid; acetic acid, fumaric acid, maleic acid, malic acid, tartaric acid, Salts with carboxylic acids such as citric acid, acid and aspartic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid.

The compound of the present invention further includes all isomers (geometric isomers, optical isomers), hydrates and all crystal forms.

The novel triazole derivative of the general formula [I] or a salt thereof is generally produced by a combination of methods known per se, and for example, can be produced by the following method.

Manufacturing method 1 Wherein X is a halogen atom; R ¹ , R ² and R ³ are
It has the same meaning as described above. The compound of the general formula [II] or a salt thereof can be obtained by reacting the compound of the general formula [II] with the compound of the general formula [III] or a salt thereof.

Salts of the compound of the general formula [III] include, for example, salts with alkali metals such as potassium and sodium; and triethylamine, tributylamine and 1,8-
And salts with organic bases such as diazabicyclo [5.4.0] undec-7-ene (DBU). Further, these salts can be formed in a reaction system.

This reaction can be carried out in the presence or absence of a solvent, the solvent used is not particularly limited as long as it does not adversely affect the reaction, for example, N,
Amides such as N-dimethylformamide and N, N-dimethylacetamide; alcohols such as methanol and ethanol; ethers such as diethyl ether and tetrahydrofuran; aromatic hydrocarbons such as benzene and toluene; nitriles such as acetonitrile; Dimethyl sulfoxide; sulfolane; water; and the like, and these solvents may be used as a mixture of two or more kinds.

The compound of the general formula [III] or a salt thereof has the general formula [I
It may be used 1 to 10 times the molar amount of the compound of I].

This reaction may be usually carried out at 20 to 100 ° C. for 1 to 24 hours.

Manufacturing method 2 In "wherein, R ^2a and R ^3a are the same or different, alkyl optionally substituted, cycloalkyl, alkenyl, heterocyclic group and bonded via a carbon atom of an aryl or a ring; R ⁴ is , A carboxyl protecting group; Y ¹ and Y ²
Represents a halogen atom; R ¹ has the same meaning as described above. Examples of the salt of the compound of the general formula [Ia], [Ib] or [V] include the same salts as the salt of the compound of the general formula [I].

Each group in R ^2a and R ^3a may be substituted with the same substituent as the substituent in R ¹ , R ² and R ³ .

Examples of the carboxyl protecting group for R ⁴ include a usual carboxyl protecting group, for example, a lower alkyl group.

() By reacting a compound of the general formula [VIa] or [VIb] with a compound of the general formula [IV], a compound of the general formula [Ia] or a salt thereof or a compound of the general formula [V] or a salt thereof is obtained. Obtainable.

This reaction can be performed in the presence of a solvent, the solvent used is not particularly limited as long as it does not adversely affect the reaction, for example, diethyl ether,
Examples include ethers such as tetrahydrofuran and 1,2-dimethoxyethane, and these solvents may be used in combination of two or more.

The compound of the general formula [VIa] or [VIb] has the general formula [I
The compound [V] may be used 1 to 10 times by mole.

This reaction is usually carried out under an inert gas at −80 to 100 ° C.
It may be carried out for 1 to 24 hours.

The compound of general formula [V] or a salt thereof and the compound of general formula [Ia] or a salt thereof can be separated by ordinary isolation and purification operations such as column chromatography and recrystallization.

(Iii) A compound of the general formula [Ib] or a salt thereof can be obtained by reacting a compound of the general formula [VIc] or [VId] with a compound of the general formula [V] or a salt thereof.

This reaction can be performed according to the method described in the above (i).

Manufacturing method 3 “Wherein R ¹ , R ^2a and R ⁴ have the same meanings as described above.” As the salt of the compound of the general formula [Ic] or [Id], a salt of the compound of the general formula [I] may be used. Similar salts are mentioned.

The compound of general formula [Ic] or [Id] or a salt thereof can be obtained by reacting the compound of general formula [IV] or [V] with a reducing agent.

Examples of the reducing agent include metal hydrides such as lithium aluminum hydride, lithium tri (t-butoxy) aluminum hydride, sodium borohydride and diisobutylaluminum hydride.

The solvent used is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include ethers such as diethyl ether and tetrahydrofuran;
Aromatic hydrocarbons such as benzene and triene; alcohols such as methanol and ethanol; and water. These solvents may be used as a mixture of two or more kinds.

The reducing agent may be used in a molar amount of 0.2 to 5 times the compound of the general formula [IV] or [V].

This reaction may be usually performed at −80 to 100 ° C. for 0.1 to 20 hours.

Manufacturing method 4 "Wherein A represents an optionally substituted alkoxy, alkylthio, amino or nitrogen-containing heterocyclic group; R ¹ and R ^2a have the same meanings as described above." Examples of the salt of the compound of [If] include the same salts as the salts of the compound of the general formula [I].

Salts of the compound of the general formula [VIII] include compounds of the general formula [II]
Salts similar to the salt of the compound of I] can be mentioned.

As the nitrogen-containing heterocyclic group for A, a 5- or 6-membered nitrogen-containing heterocyclic group bonded via a nitrogen atom in the ring, for example, 1H-imidazol-1-yl, 1H-1,2, 4-triazol-1-yl, piperazin-1-yl and morpholin-4-yl and the like.

Each group in A may be substituted with the same substituent as the substituent in R ¹ , R ² and R ³ .

Compounds of general formula [VII] or [IX]
By reacting a compound of the formula [I] or [III] or a salt thereof, a compound of the general formula [Ie] or [If] is obtained, respectively.
Or a salt thereof.

This reaction can be carried out according to the method described in Production Method 1.

Next, a method for producing compounds of the general formulas [II], [IV], [VII] and [IX], which are raw materials for producing the compound of the present invention, will be described.

The compound of the general formula [VII] can be obtained by reacting a compound of the general formula [V] with a methylene agent.

Examples of the methylenating agent include dimethyloxosulfonium methylide, dimethylsulfonium methylide, diazomethane and the like.

This method is described in Journal of American Chemical Society (J. Am. Chem. Soc.), Vol. 87, p. 1353 (1965), Organic Reactions (Org. Reac).
t.) The method can be carried out according to the method described in Vol. 8, pp. 364-429 (1954).

The compounds of the general formulas [II], [IV] and [IX] can be produced, for example, according to the following production method.

Wherein Y ³ is a halogen atom; R ¹ , R ^2a , R ^3a , R ⁴ ,
X, Y ¹ and Y ² denote the same as above. The compounds of the general formulas [X] and [XI] can be produced by a known method or a method analogous thereto.

 Next, each step will be described.

(I) Production of a compound of the general formula [XIII] or [IV].

By reacting the compound of the general formula [X] or [XI] with the compound of the general formula [XII] in the presence of a solvent and zinc, the compound of the general formula [XIII] or [IV] can be obtained, respectively. it can.

Examples of the compound of the general formula [XII] include ethyl bromodifluoroacetate.

This method is based on the Tetrahedron letter
Lett.), Vol. 25, p. 2301 (1984).

(Ii) Preparation of the compound of the general formula [XIV] or [IIa].

The compound of the general formula [XIII] is prepared by converting the compound of the general formula [VIa] or [V
By reacting the compound of formula [Ib]
V] and further a compound of general formula [VIc] or [VId]
The compound of the general formula [IIa] can be obtained by reacting the compound of the general formula [IIa].

 This reaction can be performed according to Production method 2.

(Iii) Preparation of the compound of the general formula [IIb] or [IIc].

By reacting a compound of the general formula [XII] or [XIV] with a reducing agent, a compound of the general formula [IIb] or [IIc] can be obtained, respectively.

 This reaction can be performed according to Production method 3.

(Iv) Preparation of the compound of the general formula [XV] or [IX].

The compound of the general formula [XV] can be obtained by reacting the compound of the general formula [XIV] with a base.

Bases include, for example, inorganic bases such as sodium hydroxide and potassium hydroxide; and organic bases such as triethylamine, tributylamine and DBU.

The solvent used is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include ethers such as diethyl ether and tetrahydrofuran;
Aromatic hydrocarbons such as benzene and toluene; alcohols such as methanol and ethanol; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; and water. These may be used in combination.

The base may be used in 0.5 to 5 times the molar amount of the compound of the formula [XIV].

This reaction may be usually carried out at −20 to 100 ° C. for 0.1 to 24 hours.

Further, a compound of the general formula [IX] can be obtained by a method similar to the method of reacting a compound of the general formula [XV] with a compound of the general formula [V] described above with a methylene reagent.

The compound of the general formula [I] or a salt thereof thus obtained can be isolated and purified by a usual method such as extraction, crystallization, distillation and column chromatography.

The compound of the general formula [I] or a salt thereof is reacted with a compound represented by the general formula [I] by appropriately combining known methods such as an oxidation reaction, a reduction reaction, an addition reaction, a substitution reaction, a deprotection and a hydrolysis reaction. Compound (I) or a salt thereof can be derived.

When the compound of the present invention is used as a medicament, pharmaceutically acceptable excipients, carriers and additives such as a diluent may be appropriately mixed.
It can be orally or parenterally administered in the form of granules, fine granules, powders or injections. In the case of oral administration, the dose is usually about 0.05 to 200 mg / kg of adult body weight 1 kg.
It is administered once or several times a day, depending on the age, weight and symptoms.

[Effect of the Invention] Next, the pharmacological action of the representative compound of the present invention will be described.

The test compound No. used in the following pharmacological tests was
Reference was made to the example number, and in each test fluconazole and ketoconazole were used as control compounds.

1. Minimum Inhibitory Concentration (MIC) The method of Marriott (MSMarriott) [25th Interscie
nce Conference on Antimicrobial Agents and Chemoth
erapy, page 243 (1985)].

Candida albicans ON-28
Is a Sabouraud degar
xtrose agar) medium (neopeptone 10g, glucose 20g,
(Agar 15 g / l) at 30 ° C. for 1-2 days, and suspended in sterile distilled water. Asperg
illus fumigatus) IAM-3006 is a potato dextrose agar medium (Nissui Pharmaceutical)
The conidia were cultured at 30 ° C. until conidia were abundantly formed, and the conidia formed were suspended in sterile physiological saline containing 0.6% Tween 80. TC broth medium containing a drug such that Candida albicans or Aspergillus fumigatus has a final bacterial volume of 10 ⁴ spores / ml (east carbon base 1.17 g, ammonium sulfate 0.25 g, L-glutamic acid-containing MEM amino acid 50-fold concentrated solution) 2.0ml, 0.5M phosphate buffer (pH7.5) 20ml, 7.5% sodium bicarbonate 1.33ml / 100
ml) and cultured at 37 ° C. for 3 days. Observe the presence or absence of bacterial growth, and determine the minimum concentration at which bacterial growth was inhibited by MIC (μg / m
l)

 Table 1 shows the results.

2. Infection treatment experiment Using a mouse experimentally infected with Candida albicans ON-28, the oral therapeutic effect of the compound of the present invention was measured.

Candida albicans ON-28 3.9 × 10 ⁶ cells / mouse were administered to 5 ICR male mice (weight 19 to 21 g) per group by tail vein administration to induce infection. Two hours after the infection, 0.1 ml of the test compound was orally administered once per mouse, and the mice were observed for survival for 10 days, and the relative therapeutic index was determined from the average survival days.

 Table 2 shows the results.

Table 2 shows the relative therapeutic index of the test compound when the average survival time of ketoconazole was 100.

Using a mouse experimentally infected with Aspergillus fumigatus IAM-3006, the oral therapeutic effect of the compound of the present invention was measured.

Cyclophosphamide 200 mg / kg was intraperitoneally administered to 10 ICR male mice (body weight 17 to 20 g) per group, and 4 days later, Aspergillus fumigatus IAM-3006 7.6 × 10 ⁶ cells / mouse were administered to the tail vein. , Caused the infection. Two hours after infection, 0.5 mg of test compound was orally administered once per mouse, and
The daily survival was observed, and the relative treatment index was determined from the average survival days.

 Table 3 shows the results.

Table 3 shows the relative therapeutic index of the test compound when the average survival time of fluconazole was 100.

2. Acute toxicity A test compound was intravenously administered to three ICR male mice (body weight 19 to 20 g) per group, and the acute toxicity was examined.

The test compound was prepared by dissolving in propylene glycol.

As a result, no mortality was observed for the test compounds No. 1 and 9 at 200 mg / kg.

[Effects of the Invention] As is clear from the above, it can be understood that the compound of the present invention exerts an extremely excellent pharmacological effect and is a highly safe compound.

[Examples] Reference examples and examples will be given in order to explain the present invention in more detail, but the present invention is not limited to these.

The carrier in the column chromatography was silica gel manufactured by Merck [Kieselgel 60, art, 7774].
(Kieselgel 60, Art.7734)].

 The mixing ratio in the elution solvent depends on the volume ratio.

In addition, in the text and tables, [] indicates a recrystallization solvent, and the following abbreviations have the following meanings.

Me: methyl, Et; ethyl, DEE; diethyl ether, IPE;
Diisopropyl ether, AcOEt; ethyl acetate Reference Example 1 After suspending 8.1 g of zinc in 200 ml of dry tetrahydrofuran, 25.1 g of ethyl bromodifluoroacetate is added dropwise under reflux. Then, dry tetrahydrofuran 100ml
2-chloro-2 ', 4'-difluoroacetophenone 1
A solution having 9.6 g dissolved therein is added dropwise under reflux. Then, after reacting under reflux for 10 minutes, the insoluble matter is removed, and the solvent is distilled off under reduced pressure. 200 ml of ethyl acetate and 200 ml of water are added to the obtained residue, and the pH is adjusted to 1.0 with 6N hydrochloric acid. The organic layer is separated, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography (eluent: n-hexane: toluene = 1: 2) to give oily ethyl = 4.
19.7 g of chloro-3- (2,4-difluorophenyl) -2,2-difluoro-3-hydroxybutyrate (yield 61
%).

IR (neat) cm ^-1 ; 3500,2970,1755,1610,1590 The compounds in Table 4 were obtained in the same manner.

REFERENCE EXAMPLE 2 Ethyl 4-chloro-3 was added to 160 ml of a dry diethyl ether solution containing methyl magnesium iodide prepared from 4.85 g of magnesium and 28.3 g of methyl iodide at 5 to 10 ° C.
-(2,4-difluorophenyl) -2,2-difluoro-3
80 ml of a dry diethyl ether solution containing 15.7 g of hydroxybutyrate are added dropwise. Then, after reacting at 20 to 25 ° C. for 2 hours, the reaction solution is introduced into a mixed solvent of 160 ml of ethyl acetate and 160 ml of water, and adjusted to pH 1.0 with 6N hydrochloric acid. The organic layer is separated, washed sequentially with a 1% aqueous solution of sodium thiosulfate and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is purified by column chromatography (elution solvent: toluene: ethyl acetate = 50: 1) to give 1-chloro-2- (2,4 difluorophenyl) -3,3-difluoro-4-methyl −2,4−
12.3 g (82% yield) of pentanediol are obtained.

Melting point: 55.5-57.0 ° C [n-hexane] IR (KBr) cm ^-1 ; 3480, 3350, 1610, 1590, 1490 Similarly, the compounds in Table 5 were obtained.

Reference Example 3 To 160 ml of a dry diethyl ether solution containing methyl magnesium iodide prepared from 3.64 g of magnesium and 21.2 g of methyl iodide, 160 ml of dry tetrahydrofuran was added dropwise at -10 to 0 ° C. Then, at −70 to −60 ° C., ethyl =
4-chloro-3- (2,4-difluorophenyl) -2,2-
After 80 ml of a dry diethyl ether solution containing 15.7 g of difluoro-3-hydroxybutyrate is added dropwise, the temperature is raised to 5 to 10 ° C over 1 hour. After completion of the reaction, the reaction solution is introduced into a mixed solvent of 160 ml of ethyl acetate and 160 ml of water, and adjusted to pH 1.0 with 6N hydrochloric acid. The organic layer is separated, washed sequentially with a 1% aqueous solution of sodium thiosulfate and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is purified by column chromatography (elution solvent: toluene: n-hexane = 2: 1) to give an oily 5-chloro-4- (2,4-difluorophenyl)-.
3,3-difluoro-4-hydroxy-2-pentanone 12.
5 g (88% yield) are obtained.

IR (neat) cm ^-1 ; 3480,1735,1605,1585,1490 In the same manner, the following compound is obtained.

○ 5-chloro-3,3-difluoro-4- (4-fluorophenyl) -4-hydroxy-2-pentanone oily IR (neat) cm ^-1 ; 3500,1735,1590,1500,1350 ○ 4-chloro- 1,3-bis (2,4-difluorophenyl)
-2,2-difluoro-3-hydroxy-1-butanone oily IR (neat) cm ^-1 ; 3530,1705,1605,1590,1495 Reference Example 4 0.35 g of thiazole and phenyllithium (2N-cyclohexane / diethyl ether solution) To a 10 ml dry tetrahydrofuran solution containing 2-lithiothiazole prepared from 2.07 ml was added ethyl 4-chloro-3- at -75 to -60 ° C.
(2,4-difluorophenyl) -2,2-difluoro-3-
5 ml of a dry tetrahydrofuran solution containing 0.85 g of hydroxybutyrate is added dropwise. React at the same temperature for 1.5 hours.
After completion of the reaction, the reaction solution is introduced into a mixed solvent of 10 ml of ethyl acetate and 10 ml of water, and adjusted to pH 2.0 with 2N hydrochloric acid. The organic layer is separated, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is purified by column chromatography (elution solvent; n-hexane: ethyl acetate = 10: 1) to give oily 4-chloro-3- (2,4-difluorophenyl) -2,2-. 0.53 g (55% yield) of difluoro-3-hydroxy-1- (2-thiazolyl) -1-butanone is obtained.

IR (KBr) cm ^-1 ; 3125, 1710, 1615, 1500, 1420 In the same manner, the following compound was obtained.

○ 4-chloro-1- (1-cyanocyclopropyl) -3
-(2,4-difluorophenyl) -2,2-difluoro-3
-Hydroxy-1-butanone Melting point: 71.5 to 74.5 ° C IR (KBr) cm ^-1 ; 3350, 2265, 1730, 1620, 1600 Reference Example 5 Contains ethyl magnesium bromide prepared from 0.60 g of magnesium and 2.7 g of ethyl bromide. Dry diethyl ether solution containing 2.8 g of 5-chloro-4- (2,4-difluorophenyl) -3,3-difluoro-4-hydroxy-2-pentanone at 5 to 10 ° C. in 30 ml of dry diethyl ether solution
15 ml are added dropwise. Then, after reacting at the same temperature for 2 hours, the reaction solution is introduced into a mixed solvent of 30 ml of ethyl acetate and 30 ml of water, and adjusted to pH 1.0 with 6N hydrochloric acid. Separate the organic layer,
After successively washing with a 1% aqueous sodium thiosulfate solution and a saturated saline solution, the extract is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is subjected to column chromatography (elution solvent; toluene: ethyl acetate = 100: 1).
1.9 g (61% yield) of 1-chloro-2- (2,4-difluorophenyl) -3,3-difluoro-4-methyl-2,4-hexanediol is obtained.

Melting point: 103.5-104.0 ° C [n-hexane • IPE] IR (KBr) cm ^-1 ; 3380, 1610, 1595, 1500 The compounds in Table 6 were obtained in the same manner.

Reference Example 6 5-chloro-4- (2,4-difluorophenyl) -3,3
After dissolving 2.8 g of difluoro-4-hydroxy-2-pentanone in 28 ml of methanol, 0.19 g of sodium borohydride is added in portions at 5 to 10 ° C. Then at the same temperature 1
After reacting for 0 minutes, the reaction mixture was diluted with 100 ml of ethyl acetate
The mixture is introduced into 100 ml of a mixed solvent, and adjusted to pH 1.0 with 6N hydrochloric acid.
The organic layer is separated, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was recrystallized from a mixed solvent of diisopropyl ether and n-hexane to give 1-chloro-2- (2,
1.9 g (67% yield) of 4-difluorophenyl) -3,3-difluoro-2,4-pentanediol are obtained.

Melting point: 101.5-102.5 ° C [n-hexane • IPE] IR (KBr) cm ^-1 ; 3440, 1610, 1590, 1495, 1410 The following compounds were obtained in the same manner.

○ 4-chloro-1- (1-cyanocyclopropyl) -3
-(2,4-difluorophenyl) -2,2-difluoro-1,
3-butanediol foam IR (KBr) cm ^-1 ; 3400,2240,1605,1590,1490 Reference Example 7 4-chloro-1,3-bis (2,4-difluorophenyl)
-2,2-difluoro-3-hydroxy-1-butanone 1.9
g in 190 ml of benzene and triethylamine 15
g and reflux for 20 hours. After the reaction is completed, the reaction solution is
and adjust to pH 1.0 with 6N hydrochloric acid. The organic layer is separated, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography (eluent: n-hexane: toluene = 3: 1) to give oily 1,3-bis (2,4-
0.7 g of difluorophenyl) -3,4-epoxy-2,2-difluoro-1-butanone (41% yield) is obtained.

IR (neat) cm ^-1 ; 1705, 1610, 1505, 1425, 1270 The following compounds were obtained in the same manner.

○ 4- (2,4-difluorophenyl) -4,5-epoxy-
3,3-difluoro-2-pentanone oily IR (neat) cm ^-1 ; 1750,1610,1595,1505,1425 Reference Example 8 To 3.5 ml of dry dimethyl sulfoxide was added 52 mg of sodium hydride (purity 60%), and At 25 ° C., 0.29 g of trimethyloxosulfonium iodide is added in portions, and the reaction is allowed to continue until hydrogen evolution stops. Then, at the same temperature 1,3-bis (2,4-
0.35 g of (difluorophenyl) -3,4-epoxy-2,2-difluoro-1-butanone is added and reacted for 1 hour. After the completion of the reaction, the reaction solution is introduced into a mixed solvent of 20 ml of water and 20 ml of ethyl acetate, and adjusted to pH 2.0 with 2N hydrochloric acid. The organic layer is separated, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is subjected to column chromatography (elution solvent; n-hexane:
Purification with toluene = 3: 1 yields oily 2,4-bis (2,4
-Difluorophenyl)-(1,2), (4,5) -diepoxy-3,3-difluoropentane 0.22 g (60% yield) is obtained.

IR (neat) cm ^-1 ; 1610,1590,1500,1420,1265 The following compounds were obtained in the same manner.

○ 2- (2,4-difluorophenyl)-(1,2), (4,
5) One of the diastereomers of -diepoxy-3,3-difluoro-4-methyl-pentane Oily IR (neat) cm ^-1 ; 1610,1590,1500,1420,1265 Reference Example 9 Zinc, ethyl bromodifluoroacetate And 1-
Using (2,4-difluorophenyl) -2- (1H-1,2,4-triazol-1-yl) ethanone, in the same manner as in Reference Example 1, ethyl = 3- (2,4-difluorophenyl) −
2,2-difluoro-3-hydroxy-4- (1H-1,2,4-
(Triazol-1-yl) butyrate is obtained.

Melting point: 106.5-108.0 ° C [n-hexane / benzene] IR (KBr) cm ^-1 ; 3445, 3110, 1765, 1615, 1505 Reference Example 10 Methylmagnesium iodide and ethyl = 3- (2,4
-Difluorophenyl) -2,2-difluoro-3-hydroxy-4- (1H-1,2,4-triazol-1-yl)
Using butyrate, 4- (2,4
-Difluorophenyl) -3,3-difluoro-4-hydroxy-5- (1H-1,2,4-triazol-1-yl)
-2-pentanone is obtained.

Melting point: 121.0-122.0 ° C [n-hexane / benzene] IR (KBr) cm ^-1 ; 3105,1745,1615,1505,1420 Example 1 1-Chloro-2- (2,4-difluorophenyl) -3, 3−
Difluoro-4-methyl-2,4-pentanediol 12.0 g
Was dissolved in 120 ml of N, N-dimethylformamide, 11.0 g of anhydrous potassium carbonate and 5.5 g of 1,2,4-triazole were added, the mixture was reacted at 80 to 90 ° C. for 5 hours, and the solvent was distilled off under reduced pressure. Leave. 120 ml of ethyl acetate and 1 part of water were added to the obtained residue.
Add 20 ml and adjust to pH 1.0 with 6N hydrochloric acid. The organic layer is separated, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is subjected to column chromatography (elution solvent: chloroform:
Purification with methanol = 100: 1) yields 2- (2,4-difluorophenyl) -3,3-difluoro-4-methyl-1-methyl.
8.9 g (67% yield) of (1H-1,2,4-triazol-1-yl) -2,4-pentanediol are obtained.

Melting point: 113.0-114.0 ° C [IPE] IR (KBr) cm ^-1 ; 3250, 3120, 1610, 1595, 1510 Examples 2 to 36 In the same manner as in Example 1, the compounds in Table 7 were obtained.

Example 37 2,4-bis (2,4-difluorophenyl)-(1,2),
0.15 g of (4,5) -diepoxy-3,3-difluoropentane
Was dissolved in 15 ml of N, N-dimethylformamide, and 0.17 g of anhydrous potassium carbonate and 0.09 g of 1,2,4-triazole were dissolved.
After reacting at 80 to 90 ° C. for 2 hours, the solvent is distilled off under reduced pressure. 15 ml of ethyl acetate and water were added to the obtained residue.
Add 15 ml and adjust to pH 1.0 with 6N hydrochloric acid. The organic layer is separated, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is subjected to column chromatography (elution solvent: chloroform:
Purification with methanol = 50: 1) gives 2,4-bis (2,4-difluorophenyl) -3,3-difluoro-1,5-bis (1H
0.09 g (43% yield) of 1,2,4-triazol-1-yl) -2,4-pentanediol is obtained.

Melting point: 83.0-86.0 ° C [IPE] IR (KBr) cm ^-1 ; 3380,1615,1600 Example 38 2- (2,4-difluorophenyl)-(1,2), (4,
5) Using 2-diepoxy-3,3-difluoro-4-methylpentane in the same manner as in Example 37, 2- (2,4-difluorophenyl) -3,3-difluoro-4-methyl-1,5 −
One of the diastereomers of bis (1H-1,2,4-triazol-1-yl) -2,4-pentanediol is obtained.

Melting point: 157.0-158.0 ° C IR (KBr) cm ^-1 ; 3100,1610,1590 Example 39 Ethyl = 3- (2,4-difluorophenyl) -2,2-difluoro-3-hydroxy-4- (1H- Using 1,2,4-triazol-1-yl) butyrate and sodium borohydride, 3- (2,4-difluorophenyl) -2,2-difluoro-4- (1H −1,
(2,4-Triazol-1-yl) -1,3-butanediol is obtained.

Melting point: 105.0-107.0 ° C IR (KBr) cm ^-1 ; 3330,1620, 1505, 1275, 1110 Example 40 Lithium diisopropylamide prepared from 960 mg of diisopropylamine and 5.70 ml of n-butyllithium (1.66 N n-hexane solution) 1.10 g of ethyl isobutyrate is added dropwise to 10 ml of a dry diethyl ether solution containing at -75 to -65 ° C, and the mixture is reacted at the same temperature for 15 minutes. Then, -75 to -65
Dry tetrahydrofuran containing 1.0 g of 4- (2,4-difluorophenyl) -3,3-difluoro-4-hydroxy-5- (1H-1,2,4-triazol-1-yl) -2-pentanone at ° C. After dropping 10 ml of the solution, the temperature is raised to 20 ° C. over 3 hours. After completion of the reaction, the reaction mixture is introduced into a mixed solvent of 50 ml of ethyl acetate and 50 ml of water. The organic layer is separated, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography (eluent; toluene: ethyl acetate = 2: 1) to give oily ethyl = 5- (2,4-difluorophenyl) -4,4-difluoro-3, 530 mg (39% yield) of 5-dihydroxy-2,2,3-trimethyl-6- (1H-1,2,4-triazol-1-yl) hexanoate are obtained.

IR (neat) cm ^-1 ; 3345,2975,1745,1615 Example 41 Using ethyl acetate instead of ethyl isobutyrate
Oily ethyl = 5- (2,4-difluorophenyl) -4,4-difluoro-3,5-dihydroxy-
3-methyl-6- (1H-1,2,4-triazol-1-yl) hexanoate is obtained.

IR (neat) cm ^-1 ; 3390,1730,1615,1505,1425 Example 42 Ethyl = 5- (2,4-difluorophenyl) -4,4-difluoro-3,5-dihydroxy-2,2,3 -Trimethyl-6
Reference Example 5 using-(1H-1,2,4-triazol-1-yl) hexanoate and methylmagnesium iodide
In the same manner as described above, 2- (2,4-difluorophenyl) -3,3
-Difluoro-4,5,5,6-tetramethyl-1- (1H-1,
(2,4-Triazol-1-yl) -2,4,6-heptanetriol is obtained.

Melting point: 134.0-136.0 ° C IR (KBr) cm ^-1 ; 3265,2985,1615,1505,1420 Example 43 In the same manner as in Example 42, 2- (2,4-difluorophenyl) -3,3-difluoro -4,6-dimethyl-1- (1H-
After obtaining 1,2,4-triazol-1-yl) -2,4,6-heptanetriol, this compound is treated with 2N hydrogen chloride-dioxane to obtain a foamy hydrochloride.

IR (KBr) cm ^-1 ; 3450, 1615, 1505, 1420

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI // A61K 31/41 ADZ A61K 31/41 ADZ 31/425 31/425 (72) Inventor Hiroshi Sakai 1575 Shimomakino, Takaoka City, Toyama Prefecture (72) Inventor Hirokazu Narita 6-40 Okuda Honcho, Toyama City, Toyama Prefecture Examiner Shunichi Yokoo (56) References JP-A-3-232883 (JP, A) JP-A-2-286668 (JP, A) JP-A 2-191262 (JP, A) JP-A-1-249755 (JP, A) JP-A-1-301665 (JP, A) JP-A-63-60975 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 249/08 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] (1) General formula Wherein R ¹ is an optionally substituted aryl or a heterocyclic group attached through a carbon atom in the ring; R ² and
R ³ is the same or different and is a hydrogen atom, an optionally substituted alkyl, cycloalkyl, alkenyl, aryl or a heterocyclic group bonded via a carbon atom in the ring, or R ² and R ³ are bonded Indicate a cycloalkyl ring formed together with carbon atoms. ] The triazole derivative represented by these, and its salt.