JPH05163269A - New triazole derivative and its salt - Google Patents

Abstract

(57) [Summary] (Modified) [Structure] Triazole derivatives represented by the general formula (1) and salts thereof. [In the formula, A represents O or NR ⁶ , R ¹ is a (substituted) aryl group, R ² and R ³ are H, F, an alkyl group, or a cycloalkyl group formed with a carbon atom to which both are bonded, R ⁴ and R ⁵ are H, a (substituted) alkyl group or a cycloalkyl group formed together with the carbon atom to which they are bound, and R ⁶ is H, a (substituted) alkyl group, an aryl group,
The compound of the present invention has an excellent antifungal action,
It is also highly absorbable, exhibits excellent pharmacokinetics, and is useful as an antifungal agent.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel triazole derivative and a salt thereof which have antifungal activity and exhibit an excellent therapeutic effect against human and animal diseases. Therefore, an object of the present invention is to provide a compound that exhibits excellent antifungal activity and exhibits excellent therapeutic effect against human and animal diseases.

[0002]

BACKGROUND OF THE INVENTION Currently, amphotericin B (US Pat. No. 2,908,611) and flucytosine (US Pat. No. 2802005) are mainly used as therapeutic agents for deep-seated mycosis, and further, azole antifungal agents. As such, for example, ketoconazole (JP-A-53-95973) and fluconazole (JP-A-58-32868) have been put on the market and reported to be useful as therapeutic agents for fungal diseases.

[0003]

However, the above-mentioned therapeutic agents cannot be said to be sufficient in terms of pharmacokinetics, toxicity, antibacterial spectrum, etc., and further excellent compounds have been desired to be developed.

[0004]

Under the circumstances, the inventors of the present invention have conducted diligent research, and as a result, the following general formula [1] is obtained.

[Chemical 3] [In the formula, R ¹ represents an optionally substituted aryl group;
R ² and R ³ are the same or different and each is a hydrogen atom, a fluorine atom, an alkyl group or a cycloalkyl ring formed together with the carbon atom to which R ² and R ³ are bonded; R ⁴ and R ⁵ are The same or different, a hydrogen atom, an optionally substituted alkyl group or a cycloalkyl ring formed together with the carbon atom to which R ⁴ and R ⁵ are bonded; A is
Oxygen atom or formula

[Chemical 4] (In the formula, R ⁶ represents a hydrogen atom, an optionally substituted alkyl, aryl or acyl group.). The present inventors have found that the novel triazole derivative represented by the formula and a salt thereof exhibit excellent antifungal activity, excellent absorbability, and excellent pharmacokinetics, and have completed the present invention.

The compound of the present invention will be described in detail below. Unless otherwise specified in this specification, the halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; the alkyl group means, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl. , sec- butyl, tert- butyl, pentyl, hexyl, C ₁ ~ ₁₀ linear or branched, such as heptyl, and octyl
An alkyl group; 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, e.g., methoxycarbonyl, ethoxycarbonyl, n- propoxycarbonyl, isopropoxycarbonyl, n- butoxycarbonyl, iso Butoxycarbonyl, sec-butoxycarbonyl and te
rt- a C ₁ ~ ₄ alkoxycarbonyl group such as 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; the aryl group, for example, phenyl and naphthyl groups; and halo-lower alkyl group, for example, fluoromethyl, chloromethyl, trifluoromethyl Methyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,1,2,
2,2-pentafluoroethyl and 1,1,2,2,3,
3,3 heptafluoropropyl C ₁ ~ ₄ alkyl group substituted with a halogen atom such as; the acyl group, e.g., formyl group, C ₂ ~ ₁₀ alkanoyl group and benzoyl and naphthyl carbonyl such as acetyl and ethylcarbonyl Aroyl groups such as; also "lower"
And represents a group of C ₁ ~ ₄ respectively. R ² and R ³ and R
The cycloalkyl ^{ring 4} and R ⁵ form together with the carbon atom bonded, for example, cyclopropane, cyclobutane, include C ₃ ~ ₈ cycloalkyl ring, such as cyclopentane and cycloheptane. The aryl group for R ^1, the alkyl group for R ⁴ and R ^5, the cycloalkyl group formed together with the carbon atom to which R ⁴ and R ⁵ are bonded, and the alkyl, aryl or acyl group for R ⁶ are, for example, halogen. It may be substituted with one or more substituents selected from atoms, lower alkyl, lower alkoxy, lower alkylthio, hydroxyl, cyano, carbamoyl, alkoxycarbonyl and halo lower alkyl groups. The salt of the compound of the general formula [1] is a pharmaceutically acceptable salt, for example,
Salts with mineral acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid; salts with carboxylic acids such as acetic acid, fumaric acid, maleic acid, malic acid, tartaric acid, citric acid, oxalic acid and aspartic acid; and methanesulfonic acid, benzene Examples thereof include salts with sulfonic acids such as sulfonic acid and toluenesulfonic acid.

The compounds of the present invention further include all geometric and optical isomers, hydrates, solvates and all crystalline forms. The novel triazole derivative of the general formula [1] or a salt thereof is generally produced by combining methods known per se, and can be produced, for example, by the following production methods 1 and 2.

[0007]

[Chemical 5] Production Method 1 [wherein R ^6a represents a hydrogen atom, an optionally substituted alkyl or aryl group; R ⁷ represents a carboxyl-protecting group; R ¹ , R ² , R ³ , R ⁴ and R ⁵ represent ,Each,
It has the same meaning as described above. As the substituent of the alkyl or aryl group for R ^6a, the same groups as the substituents for R ⁶ can be mentioned. Examples of the carboxyl-protecting group for R ⁷ include usual carboxyl-protecting groups such as a lower alkyl group.
A compound of the general formula [1a] or a salt thereof can be obtained by reacting a compound of the general formula [2] or a salt thereof with a compound of the general formula [3] or a salt thereof or a hydrate thereof. This reaction can be carried out in the presence or absence of a solvent, and the solvent used is
It is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include amides such as N, 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; sulfoxides such as dimethyl sulfoxide; sulfolane; and water, and these solvents are used alone or in combination of two or more. You may. The amount of the compound of the general formula [3] or a salt thereof or a hydrate thereof to be used is 1 to 10 times mol of the compound of the general formula [2] or a salt thereof. This reaction may be carried out usually at 20 to 150 ° C. for 0.1 to 24 hours.

[0008]

[Chemical 6] Process 2 “In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁷ each have the same meaning as described above.” The compound of the general formula [2] or a salt thereof is converted into hydroxyl group. The compound of the general formula [1b] or a salt thereof can be obtained by reacting with an amine or a salt thereof. This reaction may be carried out in the same manner as the method described in Production method 1.

Examples of the salts of the compounds of the general formulas [1a], [1b] and [2] include the same salts as the salts of the compound of the general formula [1]. The compound of the general formula [3] and the salt of hydroxylamine include salts with mineral acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid. Is mentioned.

Next, a method for producing the compound of the general formula [2] or a salt thereof, which is a raw material for producing the compound of the present invention and is useful as an intermediate, will be explained. The compound of the general formula [2] or a salt thereof can be produced, for example, by the production method shown below.

[0011]

[Chemical 7] Process A "In the formula, X and Y ¹ are halogen atoms; R ⁸ is a carboxyl-protecting group; R ¹ , R ⁴ , R ⁵ and R ⁷ each have the same meaning as described above. Examples of the carboxyl-protecting group for R ⁸ include a usual protecting group for a carboxyl group, such as a lower alkyl group. The compound of general formula [4] can be produced by a known method or a method analogous thereto. Next, each step will be described.

(1) Production of compound of general formula [6] The compound of general formula [4] is added to the compound of general formula [5] in the presence of a solvent.
The compound of the general formula [6] can be obtained by reacting with the compound of (4) and zinc. This method is described, for example, in the Tetrahedron Lett.
It can be carried out according to the method described in Volume 5, page 2301 (1984).

(2) Production of Compound of General Formula [7] The compound of general formula [7] can be obtained by reacting the compound of general formula [6] with a base. Examples of the base used in this reaction include inorganic bases such as sodium hydroxide and potassium hydroxide; triethylamine, tributylamine and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU). The organic bases of The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include halogenated hydrocarbons such as methylene chloride and chloroform; ethers such as diethyl ether and tetrahydrofuran; benzene and Aromatic hydrocarbons such as toluene; alcohols such as methanol and ethanol; amides such as N, N-dimethylacetamide; and water. These solvents may be used alone or in combination of two or more. May be. The amount of the base used is 1 to 5 times mols of the compound of the general formula [6]. This reaction is usually -20 to 100 ℃
Then, it may be carried out for 0.1 to 24 hours.

(3) Production of compound of general formula [9] or [10] By reacting the compound of general formula [6] or [7] with the compound of general formula [8], respectively, 9] or [10] can be obtained. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, for example,
Diethyl ether, tetrahydrofuran and 1,2-
Examples thereof include ethers such as dimethoxyethane, and these solvents may be used alone or in combination of two or more.
The amount of the compound of the general formula [8] used is 1 to 5 times mol of the compound of the general formula [6] or [7], respectively. This reaction is usually carried out in the presence of an inert gas at -80 to 50
It may be carried out at 0.1 ° C. for 0.1 to 10 hours.

(4) Preparation of the compound of the general formula [2a] or a salt thereof The compound of the general formula [9] or [10] is reacted with 1,2,4-triazole or a salt thereof. 2a] or a salt thereof can be obtained. Examples of the salt of 1,2,4-triazole include, for example,
Salts with alkali metals such as potassium and sodium;
And triethylamine, tributylamine and DB
Examples thereof include salts with organic bases such as U. This reaction can be carried out in the presence or absence of a solvent, and the solvent used is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include N, N-dimethylformamide and Amides such as N, N-dimethylacetamide; alcohols such as methanol and ethanol; nitriles such as acetonitrile; sulfoxides such as dimethylsulfoxide; sulfolane; and water. You may use it in mixture of 2 or more types. The amount of 1,2,4-triazole or a salt thereof to be used is 1 to 10-fold the molar amount of the compound of the general formula [9] or [10]. This reaction may be carried out usually at 20 to 100 ° C for 1 to 24 hours.

[0016]

[Chemical 8] Production Method B "In the formula, Y ² represents a halogen atom; R ⁹ represents an optionally substituted alkyl group; R ¹ and R ⁷ each have the same meaning as described above." R ⁹ Examples of the substituent of the alkyl group in R are R ¹ , R ⁴ ,
The same substituents as each group for R ⁵ and R ⁶ can be mentioned. The compound of the general formula [2b] or a salt thereof is reacted with the compound of the general formula [11] in the presence of a base to give a compound of the general formula [2c] or a salt thereof and / or a compound of the general formula [2d]. Alternatively, its salt can be obtained. Examples of the base used in this reaction include:
Inorganic bases such as sodium carbonate and potassium carbonate; and triethylamine, tributylamine and DBU
Organic bases such as. The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction, and for example, amides such as N, N-dimethylformamide and N, N-dimethylacetamide; methanol and ethanol and the like. Examples thereof include alcohols; nitriles such as acetonitrile; and sulfoxides such as dimethyl sulfoxide; sulfolane, and these solvents may be used alone or in combination of two or more. The amount of the compound of the general formula [11] and the base to be used is 1 to 10-fold the molar amount of the compound of the general formula [2b] or a salt thereof. This reaction is usually 0-100 ℃
Then, it may be carried out for 0.5 to 24 hours. The general formula [2
The compound of c] or a salt thereof and the compound of the general formula [2d] or a salt thereof can be separated by a usual isolation and purification operation such as column chromatography and recrystallization.

Manufacturing method C

[Chemical 9] "In the formula, R ¹⁰ and R ¹¹ are the same or different and each represents a hydrogen atom, an alkyl group or a cycloalkyl ring formed together with a carbon atom to which R ¹⁰ and R ¹¹ are bonded;
R ¹ , R ⁷ , R ⁹ and Y ² each have the same meaning as described above. "

(1) Production of compound of general formula [14] The compound of general formula [12] is prepared by a conventional method according to general formula [12]
Reactive derivatives of compounds (eg active esters, active acid amides, acid halides and mixed acid anhydrides)
Induce to. Then, the compound of the general formula [14] can be obtained by reacting the reactive derivative of the compound of the general formula [12] with the compound of the general formula [13] in the presence of a base. Bases include, for example, metal hydrides such as sodium and potassium hydride; and metal alcoholates such as sodium ethoxide and potassium tert-butoxide. The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction, and for example, amides such as N, N-dimethylformamide and N, N-dimethylacetamide; methanol and ethanol and the like. Examples thereof include alcohols; and ethers such as diethyl ether and tetrahydrofuran, and these solvents may be used alone or in combination of two or more. General formula [1
The amounts of the compound [3] and the base used are 1 to 5 times mols of the compound of the general formula [12], respectively. This reaction may be carried out usually at -20 to 100 ° C for 0.1 to 10 hours. The compound of the general formula [12] is disclosed in JP-A-59-82376.
And the methods described in JP-A-1-249755 or methods similar thereto.

(2) Production of compound of general formula [2e] or salt thereof The compound of general formula [2e] or salt thereof can be obtained by reacting the compound of general formula [14] with an acid. Acids include, for example, carboxylic acids such as formic acid and trifluoroacetic acid; and sulfonic acids such as p-toluenesulfonic acid. This reaction can be carried out in the presence or absence of a solvent, and the solvent to be used is not particularly limited as long as it does not adversely influence the reaction, and examples thereof include halogenated compounds such as methylene chloride and chloroform. Examples thereof include hydrocarbons; aromatic hydrocarbons such as benzene and toluene; and ethers such as diethyl ether and tetrahydrofuran. These solvents may be used alone or in combination of two or more. The amount of the acid used is 0.01 to 20 times mol of the compound of the general formula [14]. This reaction is usually 0-1
It may be carried out at 20 ° C for 0.5 to 24 hours.

(3) Production of compound of general formula [2f] or salt thereof and compound of general formula [2g] or salt thereof: compound of general formula [2e] or salt thereof in the presence of a base, ] The compound of the general formula [2f] or a salt thereof and / or the compound of the general formula [2g] or a salt thereof can be obtained by reacting with the compound of the formula [2]. This reaction may be carried out in the same manner as the method described in the production method B. The compound of the general formula [2f] or a salt thereof and the compound of the general formula [2g] or a salt thereof can be separated by a usual isolation and purification operation such as column chromatography and recrystallization.

The general formulas [2a], [2b] and [2]
Examples of the salt of the compound of c], [2d], [2e], [2f] and [2g] include the same salts as the salt of the compound of the general formula [1]. The compound of the general formula [1] or a salt thereof thus obtained can be isolated and purified by a usual method such as extraction, crystallization, distillation and column chromatography. In addition, by appropriately combining the compound of the general formula [1] or a salt thereof with a known method such as an oxidation reaction, a reduction reaction, an addition reaction, a substitution reaction, a deprotection, an acylation reaction and a hydrolysis reaction, The compound of the general formula [1] or a salt thereof can be derived. When the compound of the present invention is used as a medicine, additives such as pharmaceutically acceptable excipients, carriers and diluents may be appropriately mixed. It can be administered orally or parenterally in the form of a drug, powder or injection. In the case of oral administration, the dose is usually about 0.05 to 200 mg / kg body weight of an adult, which may be administered once or in several divided doses. It may be adjusted according to age, weight and symptoms. You can choose.

Next, the pharmacological action of the representative compounds of the present invention will be described. The test compound Nos. Used in the following pharmacological tests were quoted from Example No., and ketoconazole was used as a control compound in each test. 1. Minimum inhibitory concentration (MIC) MS Marriott method [No. 25
25th Interscience Conference on
Antimicrobial Agents and Chemotherapy) p. 243 (198
5 years)]]. Candida albicans
da albicans) ON28, Sabouraud dextrose agar (Sabouraud dextrose agar) medium (neopeptone 10 g,
Glucose 20 g and agar 15 g / l) are cultured at 30 ° C. for 1 to 2 days and suspended in sterile distilled water. On the other hand, Aspergillus
Fumigatus (Aspergillus fumigatus) IF08868, potato dextrose agar (Potato dextrose agar) medium (manufactured by Nissui Pharmaceutical Co., Ltd.) was cultivated at 30 ° C. until conidia are abundantly formed, 0.1% tween conidia formed ( Suspend in sterile saline containing Tween) 80. Candida albicans or Aspergillus fumigatus has a final bacterial count of 1
0 ⁴ TC broth medium containing an agent such that spores / ml (East Carbon-based 1.17 g, ammonium sulfate 0.2
5 g, MEM amino acid 50 times concentrated solution containing L-glutamic acid 2.
0 ml, 20 ml of 0.5 M phosphate buffer (pH 7.5) and 7.5% sodium hydrogen carbonate 1.33 ml / 100 ml) are inoculated and cultured at 37 ° C. for 3 days. The presence or absence of bacterial growth was observed, and the minimum concentration at which bacterial growth was inhibited was defined as MIC (μg / ml). The results are shown in Table 1.

[0023]

[Table 1]

2. Infection treatment experiment The therapeutic effect of oral administration of the compound of the present invention was measured using mice experimentally infected with Candida albicans ON-28. Candida albicans ON-28 3.5 × 10 ⁶ cells / mouse was intravenously administered to 5 ICR male mice (body weight: 19 to 21 g) per group by tail vein injection to induce infection. 2 hours after infection, mouse 1
0.1 mg of the test compound was orally administered once to each animal, and life and death were observed for 10 days, and the relative therapeutic index was calculated from the average number of days alive. The results are shown in Table 2a. Note that Table 2a shows the relative therapeutic index of the test compound when the average survival time of ketoconazole is 100.

[0025]

[Table 2a]

Experimentally Aspergillus fumigatus
The therapeutic effect of oral administration of the compound of the present invention was measured using mice infected with IFO8868. Aspergillus fumigatus I was added to 5 male ICR mice (weight 19 to 21 g) per group.
FO8868 8.6X10 ⁶ cells / mouse was administered to the tail vein to induce infection. Two hours after infection, test compound 0 per mouse.
8 mg was orally administered once, and life and death were observed for 10 days, and the relative therapeutic index was calculated from the average survival time. The results are shown in Table 2b. In addition, in Table 2b, the relative therapeutic index of the test compound when the average survival time of ketoconazole is 100 is shown.

[0027]

[Table 2b]

3. Acute toxicity The compound of Example 1 was intravenously administered to 3 male ICR mice (body weight: 29 to 31 g) per group by tail vein to examine the acute toxicity. The test compound was prepared by dissolving it in 50% polyethylene glycol 300. As a result, no death was observed when the test compound was administered at 100 mg / kg.

[0029]

EFFECTS OF THE INVENTION As is clear from the above, it can be understood that the compounds of the present invention exhibit extremely excellent pharmacological effects and are highly safe.

[0030]

EXAMPLES Next, the present invention will be explained with reference to reference examples and examples, but the present invention is not limited thereto. Silica gel 60 (manufactured by Merck) was used as a carrier in column chromatography. All the mixing ratios in the eluent are volume ratios. In addition, No. in the table is
The numbers of Reference Example and Example are shown.

Reference Example 1 8.1 g of zinc was suspended in 200 ml of dry tetrahydrofuran,
25.1 g of ethyl bromodifluoroacetate are added dropwise under reflux. Then 2 to 100 ml of dry tetrahydrofuran
A solution in which 19.6 g of -chloro-2 ', 4'-difluoroacetophenone was dissolved was added dropwise under reflux. Then, after refluxing for 10 minutes, the insoluble matter is filtered off, 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 brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue was subjected to column chromatography (eluent; n-hexane: toluene = 1: 1).
After purification by 2), oily ethyl = 4-chloro-3- (2,
19.7 g of 4-difluorophenyl) -2,2-difluoro-3-hydroxybutyrate are obtained. IR (neat) cm ^-1 ; 3500,2970,1755,1610,1590

Reference Examples 2 to 5 In the same manner as in Reference Example 1, the compounds in Table 3 are obtained. In addition, R ¹ and X in Table 3 are respectively expressed by the following equations.

[0033]

[Chemical 10] The substituents of the compound represented by are shown below.

[0034]

[Table 3]

Reference Example 6 Ethyl = 4-chloro-3- (2,4-difluorophenyl) -2,2-difluoro-3-hydroxybutyrate 1
Dissolve 5.7 g in 150 ml of methylene chloride, and at 5-10 ℃,
8-diazabicyclo [5.4.0] undec-7-ene 8.4 g
Is dripped. Then, after stirring at the same temperature for 2 hours, the reaction mixture is introduced into 150 ml of water, and the pH is adjusted to 1.0 with 6N hydrochloric acid.
The organic layer is separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue was purified by column chromatography (eluent: n-hexane: toluene = 2: 1) to give oily ethyl =
3- (2,4-difluorophenyl) -3,4-epoxy-
11.1 g of 2,2-difluorobutyrate are obtained. IR (neat) cm ^-1 ; 1770,1620,1510,1145

Reference Examples 7 to 9 In the same manner as in Reference Example 6, the compounds in Table 4 are obtained. Note that R ¹ in Table 4 is the following formula, respectively.

[0037]

[Chemical 11] The substituents of the compound represented by are shown below.

[0038]

[Table 4]

Reference Example 10 4.8 g of diisopropylamine was dried in 50% tetrahydrofuran.
30 ml of n-butyllithium (1.61N n-hexane solution) is added dropwise at −70 to −65 ° C. under a nitrogen atmosphere, and the mixture is stirred at the same temperature for 10 minutes. Then, at the same temperature, ethyl isobutyrate
Add 5.6 g dropwise and stir for 5 minutes at the same temperature. Then, at the same temperature, 20 ml of dry tetrahydrofuran was added with ethyl = 3- (2,4
A solution containing 11.1 g of -difluorophenyl) -3,4-epoxy-2,2-difluorobutyrate dissolved therein is added dropwise. After stirring for 10 minutes at the same temperature, the reaction mixture was introduced into a mixed solvent of 200 ml of ethyl acetate and 200 ml of water, and the pH was adjusted with 6N hydrochloric acid.
Adjust to 1.0. The organic layer is separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue was purified by column chromatography (eluent; n-hexane: toluene = 2: 1),
Oily ethyl = 5- (2,4-difluorophenyl) -5,
6-epoxy-4,4-difluoro-2,2-dimethyl-
13.6 g of 3-oxohexanoate are obtained. IR (neat) cm ^-1 ; 1760,1730,1620,1510

Reference Examples 11 to 15 In the same manner as in Reference Example 10, the compounds in Table 5 are obtained. In addition,
R ¹ in Table 5, R ⁴ and R ⁵ each, of the following formula

[0041]

[Chemical 12] The substituents of the compound represented by are shown below.

[0042]

[Table 5]

Reference Example 16 Ethyl = 5- (2,4-difluorophenyl) -5,6-epoxy-4,4-difluoro-2,2-dimethyl-3-oxohexanoate 10.4 g of N, N- Dissolve in 50 ml of dimethylformamide to give 7.4 g of anhydrous potassium carbonate and 1,2,
After adding 3.7 g of 4-triazole and stirring at 20 to 25 ° C for 12 hours, the solvent is distilled off under reduced pressure. 100 ml of ethyl acetate and 100 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 brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue was purified by column chromatography (eluent: chloroform) to give ethyl = 5- (2,4
-Difluorophenyl) -4,4-difluoro-5-hydroxy-2,2-dimethyl-3-oxo-6- (1H-
1,2,4-triazol-1-yl) hexanoate 5.9
get g. Melting point; 112.0-113.5 ° C IR (KBr) cm ^-1 ; 3140,1755,1725,1615

Reference Examples 17 to 21 In the same manner as in Reference Example 16, the compounds in Table 6 are obtained. In addition,
R ¹ , R ⁴ and R ⁵ in Table 6 are respectively represented by the following formulas.

[0045]

[Chemical 13] The substituents of the compound represented by are shown below.

[0046]

[Table 6]

Reference Example 22 3.0 g of diisopropylamine was added to 30 ml of dry tetrahydrofuran.
It is dissolved in ml, and 18.4 ml of n-butyllithium (1.61N n-hexane solution) is added dropwise at -70 to -65 ° C under nitrogen atmosphere, and the mixture is stirred at the same temperature for 10 minutes. Then, 3.4 g of ethyl isobutyrate is added dropwise at the same temperature, and the mixture is stirred at the same temperature for 5 minutes. Then, at the same temperature, a solution prepared by dissolving 3.1 g of ethyl 4-chloro-3- (2,4-difluorophenyl) -2,2-difluoro-3-hydroxybutyrate in 15 ml of dry tetrahydrofuran was added dropwise. After stirring for 10 minutes at the same temperature, the reaction mixture was introduced into a mixed solvent of 150 ml of ethyl acetate and 150 ml of water, and 6N
Adjust to pH 1.0 with hydrochloric acid. The organic layer is separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue was purified by column chromatography (eluent: n-hexane: ethyl acetate = 30: 1) to give oily ethyl = 6-chloro-5- (2,4-
Difluorophenyl) -4,4-difluoro-5-hydroxy-2,2-dimethyl-3-oxohexanoate 2.8
get g. IR (neat) cm ^-1 ; 3465,1755,1730,1505

Reference Example 23 In the same manner as in Reference Example 22, oily ethyl = 6-chloro-
4,4-difluoro-5- (2-fluorophenyl) -5
-Hydroxy-2,2-dimethyl-3-oxohexanoate is obtained. IR (neat) cm ^-1 ; 3475,1750,1730,1490

Reference Example 24 Ethyl = 6-chloro-5- (2,4-difluorophenyl) -4,4-difluoro-5-hydroxy-2,2-dimethyl-3-oxohexanoate Dissolve in 14 ml of N-dimethylformamide and dry with anhydrous potassium carbonate 2.
Add 5g and 1.3g 1,2,4-triazole, 20-25 ℃
After stirring for 12 hours, the solvent is distilled off under reduced pressure. 50 ml of ethyl acetate and 50 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 brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue was purified by column chromatography (eluent: chloroform) to give ethyl =
5- (2,4-difluorophenyl) -4,4-difluoro-5-hydroxy-2,2-dimethyl-3-oxo-6
1.3 g of-(1H-1,2,4-triazol-1-yl) hexanoate are obtained. The melting point and IR spectrum of this compound coincided with the melting point and IR of the compound of Reference Example 16.

Reference Example 25 In the same manner as in Reference Example 24, ethyl = 4,4-difluoro-5- (2-fluorophenyl) -5-hydroxy-2,
2-Dimethyl-3-oxo-6- (1H-1,2,4-triazol-1-yl) hexanoate is obtained. Melting point; 107.5-109.5 ° C IR (KBr) cm ^-1 ; 3460,1755,1725,1615

Reference Example 26 Ethyl = 5- (2,4-difluorophenyl) -4,4-difluoro-5-hydroxy-3-oxo-6- (1H-
1,2,4-triazol-1-yl) hexanoate 1.9
g was dissolved in 19 ml of N, N-dimethylformamide, 2.0 g of anhydrous potassium carbonate and 2.3 g of ethyl iodide were added, and
After stirring at 30 ° C for 15 hours, the reaction mixture was mixed with 50 ml of ethyl acetate.
It is introduced into a mixed solvent of 50 ml of water and water and adjusted to pH 1.0 with 6N hydrochloric acid. The organic layer is separated, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue was purified by column chromatography (eluent; toluene: ethyl acetate = 15: 1) to give ethyl = 5- (2,4-difluorophenyl) -2,
2-diethyl-4,4-difluoro-5-hydroxy-
3-oxo-6- (1H-1,2,4-triazole-1
-Yl) 0.26 g of hexanoate is obtained. Melting point: 123.5-126.0 ° C IR (KBr) cm ^-1 ; 3445,1745,1725,1620

Reference Example 27 (1) 1- (1-Carboxycyclopropyl) -1- (2,4
6.2 g of -difluorophenyl) -2- (1H-1,2,4-triazol-1-yl) ethanol and 2.3 g of N-hydroxysuccinimide were dissolved in 120 ml of anhydrous dioxane to give 4.1 g of N, N'-dicyclohexylcarbodiimide. After adding and stirring at room temperature for 1 hour, the insoluble matter is filtered off, and the solvent is distilled off under reduced pressure. The residue obtained is dissolved in 60 ml of N, N-dimethylformamide. (2) To 40 ml of N, N-dimethylformamide, 0.80 g of sodium hydride (purity 60%) was added, 3.8 g of tert-butyl ethyl malonate was added dropwise at 5 to 10 ° C, and then hydrogenated at 15 to 20 ° C. Stir until development stops. Then, the N, N-dimethylformamide solution obtained in (1) was added dropwise at 5 to 10 ° C.,
After stirring at -20 ° C for 1 hour, the solvent was distilled off under reduced pressure, 100 ml of ethyl acetate and 100 ml of water were added to the obtained residue,
Adjust to pH 1.0 with 6N hydrochloric acid. The organic layer is separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue was purified by column chromatography (eluent: toluene: ethyl acetate = 2: 1) to give powdery tert-butyl = 3- {1- [1-
(2,4-difluorophenyl) -1-hydroxy-2-
6.0 g of (1H-1,2,4-triazol-1-yl) ethyl] cyclopropyl} -2-ethoxycarbonyl-3-oxopropionate are obtained. IR (KBr) cm ^-1 ; 3420,1750,1735,1700

Reference Example 28 In the same manner as in Reference Example 27, powdery tert-butyl = 5-
(2,4-Difluorophenyl) -2-ethoxycarbonyl-5-hydroxy-4-methyl-3-oxo-6-
(1H-1,2,4-triazol-1-yl) hexanoate is obtained. IR (KBr) cm ^-1 ; 3445,1750,1715,1645

Reference Example 29 tert-butyl = 3- {1- [1- (2,4-difluorophenyl) -1-hydroxy-2- (1H-1,2,4-triazol-1-yl) ethyl] Cyclopropyl} -2-
4.8 g of ethoxycarbonyl-3-oxopropionate are dissolved in 70 ml of methylene chloride and at 5-10 ° C. 25 ml of trifluoroacetic acid are added. Then, after stirring at 20 to 25 ° C for 10 hours, the solvent was distilled off under reduced pressure, 50 ml of ethyl acetate and 50 ml of water were added to the obtained residue, and the pH was adjusted with sodium hydrogen carbonate.
Adjust to 6.5. The organic layer is separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue was recrystallized from diethyl ether to give ethyl = 3- {1- [1- (2,4-difluorophenyl) -1-hydroxy-2- (1H-1,2,4-
Triazol-1-yl)] ethylcyclopropyl}-
3.1 g of 3-oxopropionate are obtained. Melting point; 87.0-88.5 ° C IR (KBr) cm ^-1 ; 3225,1740,1685,1500

Reference Example 30 In the same manner as in Reference Example 29, ethyl foam powder = 5- (2,4)
-Difluorophenyl) -5-hydroxy-4-methyl-3-oxo-6- (1H-1,2,4-triazole-
1-yl) hexanoate IR (KBr) cm ^-1 ; 3445,1740,1705,1500

Reference Example 31 Ethyl = 3- {1- [1- (2,4-difluorophenyl) -1-hydroxy-2- (1H-1,2,4-triazol-1-yl) ethyl] cyclopropyl } -3-Oxopropionate 3.0 g was added to N, N-dimethylformamide 6
Dissolve in 0 ml, methyl iodide 3.4 g and potassium carbonate
After adding 3.3 g and stirring at 20 to 25 ° C for 1 hour, the solvent was distilled off under reduced pressure, and 50 ml of ethyl acetate and water were added to the obtained residue.
Add 50 ml and adjust to pH 1.0 with 6N hydrochloric acid. The organic layer is separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue was purified by column chromatography (eluent: n-hexane: ethyl acetate = 2: 1) to obtain ethyl = 3- {1- [1-
(2,4-difluorophenyl) -1-hydroxy-2-
0.90 g of (1H-1,2,4-triazol-1-yl) ethyl] cyclopropyl} -2,2-dimethyl-3-oxopropionate is obtained. Melting point: 75.5-77.0 ° C IR (KBr) cm ^-1 ; 3420,1735,1690,1615

Reference Example 32 In the column chromatography of Reference Example 31, further eluting with n-hexane: ethyl acetate = 1: 1,
Ethyl = 3- {1- [1- (2,4-difluorophenyl) -1-hydroxy-2- (1H-1,2,4-triazol-1-yl) ethyl] cyclopropyl} -2-methyl- 0.80 g of 3-oxopropionate is obtained. Melting point; 118.0-121.5 ° C IR (KBr) cm ^-1 ; 3445,1740,1685,1615

Reference Example 33 In the same manner as in Reference Example 31, ethyl = 5- (2,4-difluorophenyl) -5-hydroxy-4-methyl-2,2-
Dimethyl-3-oxo-6- (1H-1,2,4-triazol-1-yl) hexanoate is obtained. Melting point; 79.0-79.5 ° C IR (KBr) cm ^-1 ; 3445,1740,1680,1620

Example 1 Ethyl = 5- (2,4-difluorophenyl) -4,4-difluoro-5-hydroxy-2,2-dimethyl-3-oxo-6- (1H-1,2,4- (Triazol-1-yl)
Hexanoate (2.1 g) was suspended in ethanol (21 ml), hydrazine monohydrate (0.38 g) was added, the mixture was refluxed for 0.5 hours, and then the solvent was distilled off under reduced pressure.
l and 100 ml of water are added, and the pH is adjusted to 1.0 with 6N hydrochloric acid. The organic layer is separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give 2- (2,4-difluorophenyl) -1- (4,4-dimethyl-5-oxo-2-pyrazolin-3-yl) -1,1. -Difluoro-
3- (1H-1,2,4-triazol-1-yl) -2-
1.7 g of propanol are obtained. Melting point; 181.0-182.0 ° C IR (KBr) cm ^-1 ; 3205,1715,1615,1505

Examples 2 to 10 In the same manner as in Example 1, the compounds in Tables 7 and 8 are obtained.
In Tables 7 and 8, R ¹ , R ² , R ³ , R ⁴ , and R ⁵
And A are, respectively,

[0061]

[Chemical 14] The substituents of the compound represented by are shown below.

[0062]

[Table 7]

[0063]

[Table 8]

Example 12 Ethyl = 5- (2,4-difluorophenyl) -4,4-
Difluoro-5-hydroxy-2,2-dimethyl-3-
After 0.83 g of oxo-6- (1H-1,2,4-triazol-1-yl) hexanoate was suspended in 8 ml of ethanol, 0.27 g of methylhydrazine was added, and the mixture was refluxed for 5 hours, then, under reduced pressure. The solvent is evaporated, 30 ml of ethyl acetate and 30 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 brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure.
The obtained residue was subjected to column chromatography (eluent;
If purified with chloroform: methanol = 100: 1), 2-
(2,4-difluorophenyl) -1,1-difluoro-3
-(1H-1,2,4-triazol-1-yl) -1-
0.36 g of (1,4,4-trimethyl-5-oxo-2-pyrazolin-3-yl) -2-propanol is obtained. Melting point; 118.0-122.5 ° C IR (KBr) cm ^-1 ; 3430,1710,1615,1500

Examples 13 to 14 In the same manner as in Example 12, the compounds in Table 9 are obtained. In addition,
R ¹ , R ² , R ³ , R ⁴ , R ⁵ and A in Table 9 are respectively represented by the following formulas.

[0066]

[Chemical 15]

The substituents of the compound represented by are shown below.

[Table 9]

Example 15 Ethyl = 5- (2,4-difluorophenyl) -4,4-difluoro-5-hydroxy-2,2-dimethyl-3-oxo-6- (1H-1,2,4- (Triazol-1-yl)
Hexanoate 0.42 g is suspended in ethanol 4 ml, hydroxylamine hydrochloride 0.35 g and sodium hydrogen carbonate 0.4
After adding 2 g and refluxing for 2 hours, the solvent was distilled off under reduced pressure,
20 ml of ethyl acetate and 20 ml of water were added to the obtained residue,
Adjust to pH 1.0 with 6N hydrochloric acid. The organic layer is separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue was subjected to column chromatography (eluent; chloroform: methanol = 100:
If purified in 1), 2- (2,4-difluorophenyl)-
1- (4,4-dimethyl-5-oxo-2-isoxazolin-3-yl) -1,1-difluoro-3- (1H-1,
2,4-triazol-1-yl) -2-propanol 0.
Get 31g. Melting point: 135.0-136.5 ° C IR (KBr) cm ^-1 ; 3110,1815,1615,1505

Examples 16 to 18 In the same manner as in Example 15, the compounds in Table 10 are obtained. In Table 10, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and A
Are respectively the following expressions

[0070]

[Chemical 16] The substituents of the compound represented by are shown below.

[0071]

[Table 10]

Example 19 2- (2,4-Difluorophenyl) -1- (4,4-dimethyl-5-oxo-2-pyrazolin-3-yl) -1,1
-Difluoro-3- (1H-1,2,4-triazole-
1-yl) -2-propanol 0.77 g chloroform 15 ml
Suspended in water, added 0.20 g of acetyl chloride, and 5-10 ℃
Then, 3 ml of a chloroform solution containing 0.26 g of triethylamine
Is dripped. After stirring for 1 hour at the same temperature, the reaction mixture is introduced into 15 ml of water and adjusted to pH 1.0 with 6N hydrochloric acid. The organic layer is separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue was recrystallized from a mixed solvent of ethyl acetate and diisopropyl ether to give 1- (1-acetyl-4,4-dimethyl-5-oxo-2-pyrazolin-3-yl) -2-
(2,4-difluorophenyl) -1,1-difluoro-3
0.61 g of-(1H-1,2,4-triazol-1-yl) -2-propanol is obtained. Melting point; 119.0 to 12.0 ° C IR (KBr) cm ^-1 ; 3145,1795,1755,1615

Continuation of front page (51) Int.Cl. ⁵ Identification code Office reference number FI Technical display location C07D 231: 00 6701-4C 249: 00) 7180-4C (C07D 413/06 249: 00 7180-4C 261: 00 ) 9283-4C (72) Inventor Akira Yotsuji 30 Ueno, Kosugi-cho, Imizu-gun, Toyama Prefecture (72) Inventor Junichi Mitsuyama 1-6-30 Shimookui, Toyama City, Toyama Prefecture (72) Inventor Katsumi Shimizu Nakatomi, Daiji, Toyama City, Toyama Prefecture Warrior 106-8 (72) Inventor Hiroshi Sakai 1575 Shimomakino, Takaoka City, Toyama Prefecture (72) Inventor Hirokazu Narita 6-40 Okudahonmachi, Toyama City, Toyama Prefecture

Claims (1)

[Claims] 1. A general formula: [In the formula, R ¹ represents an optionally substituted aryl group;
R ² and R ³ are the same or different and each is a hydrogen atom, a fluorine atom, an alkyl group or a cycloalkyl ring formed together with the carbon atom to which R ² and R ³ are bonded; R ⁴ and R ⁵ are The same or different, a hydrogen atom, an optionally substituted alkyl group or a cycloalkyl ring formed together with the carbon atom to which R ⁴ and R ⁵ are bonded; A is
Oxygen atom or formula (In the formula, R ⁶ represents a hydrogen atom, an optionally substituted alkyl, aryl or acyl group.). And a salt thereof.