JPS60174773A - Triazole antifungal - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is a novel antifungal agent that has antifungal activity and is effective in treating fungal infections in animals including humans, and is used as an agricultural (including horticultural) antifungal agent. The present invention relates to a triazole derivative.

The present invention provides compounds of the following general formula 1, O-esters, O-ethers and pharmaceutically and agriculturally acceptable salts thereof: wherein R and R are each independently unsubstituted or F'
, Ci, Br, I, CF3. C□-
represents a phenyl group substituted with 1 to 3 substituents each independently selected from the group consisting of C4 alkyl and C□-04 alkoxyl groups, R2 is H, CH3 or F3, R is H or Represents CH3; however, R and R3
Either one of these represents a group other than H.

Furthermore, the present invention provides a compound of general formula (I) -1: Bamboo shoots 0-ester, 0-ether or pharmaceutically acceptable salt for use in medicine, particularly in the treatment of fungal infections in humans.

Furthermore, the present invention provides a compound of the general formula Or include it in antifungal compositions for agricultural use.

The present invention also provides a method of treating a patient with a fungal infection, comprising administering an effective amount of a compound of general formula (I) or an 0-ester, 0-ether or pharmaceutically acceptable salt thereof. do.

Furthermore, the present invention provides seeds or plants or their growing sites with compounds of the general formula (Il or 0-esters thereof,
Also included is a method of treating or preventing fungal infection of seeds or plants comprising contacting them with an antifungal effective amount of an O-ether or a Convention-acceptable salt.

R and R are preferably F, C7l,
Br.

(2) A phenyl group substituted with 1 to 3, preferably 1 or 2 substituents selected from the group consisting of CF3 and CF3. Specifically in this regard, R and R1 are respectively 4-fluorophenyl, 4-chlorophenyl, 4-)
! jFluoromethylphenyl, 2-fluorophenyl*
z4-y chlorophenyl + 2+4-difluorophenyl, 4-10 rho 2-fluorophenyl, 2-10 rho 4-fluorophenyl, z5-difluorophenyl,
246-) IJ can be fluorophenyl or 4-furomo-25-difluorophenyl. Most preferably, R and R are -ttL4-10lophenyl, 4-fluoro7enyl, z4-ychlorophenylti is 24-difluorophenyl.

In one aspect of the invention R is F%R is H, in another aspect of the invention R is H, CH3 or F;
is CH3.

The alcohol 〇-ether of general formula (I) includes, for example, C□-06 alkyl, C2-C4 alkenyl-2C2-
C4 alkynyl- and aralkyl (e.g. halogen,
There are indyl-ethers optionally substituted on the cy ring with one or two substituents, each selected from the group consisting of C1-04 alkyl and C□-04 alkoxyl.

o-ester of the general formula (T) or 2
(banzoyl optionally substituted with one or more substituents)
-There are esters.

A preferred 0-ester is an acetyl ester. "Halogen" means F, C7l, B+- or .

Compounds of general formula (1) can be prepared according to the following reaction scheme: (■B) (IIIB) In a typical reaction, an organometallic compound (IIA or B) in a solution of the ketone (Ill A or B), for example in anhydrous diethyl ether, at low temperature, preferably at about -
Add dropwise at 70° C. under nitrogen atmosphere. Tetrahydrofuran can also be used as a solvent. The reaction mixture is then allowed to reach room temperature. If necessary, the reaction mixture can be heated to 70° C. under reflux, for example for several hours, until the reaction is complete. Next, the product +
Il is collected and laminated as usual. If the product (i) has one or two chiral centers, the pairs of optical isomers or diastereomers can be separated in a conventional manner.

The ketone starting materials (I[[A) and (RIB) can be prepared by conventional methods, as described in the Preparation section below.

For example, ketones in which R is CH3 and R is H or CH3 can be methylated under normal conditions (e.g., European Patent Publication Nos. 0122056 and 01
20276); (using 2 equivalents of NaH/CHa) starting material C
■') is a known compound (for example, European Patent Publication No. 0044605 or British Patent Specification No. 2
No. 099818A, No. 1464224, No. 15337
05 and 1533706).

The fluorine-substituted ketone (IIIA and B, R-F') can be converted to ketone (IV)'! using sodium hydride followed by perchloryl fluoride. : can be prepared by (HI C)k fluorination. This alternative route (see Preparation Example 6) involves combining the appropriate 2-chloro-2-fluoroacetophenone with L24 in the presence of potassium carbonate.
-) There is a lyazole reaction.

When R and R are the same and R and R are CH3, the following method can be used to prepare the desired product: (or an alkali metal salt thereof) HaAI-C7l-straddling Bt (IA ) Typically, LZ is dissolved in sodium hydride in a suitable solvent such as anhydrous dimethylformamide (DMI').
A solution of 4-1 azole in the same solvent is added at about 0°C.

The ester (■), preferably ethyl 2-bromoisobutyrate iDMF, is then added and the reaction mixture is stirred until the initial exothermic reaction has subsided and the conversion to the intermediate (Vl) is sufficiently complete. Heat to 50°-80°C. After purification, the intermediate (Vl) is treated with Grignard or lithium reagents RMgBr, RMg or RLt (of course requiring the presence of at least 2 equivalents of these reagents).
, the reaction is carried out in the same manner as described above. Next, the product (IA
) is isolated and purified using the method described above.

The ether is an alkali metal salt, such as the lithium or sodium salt, of an alcohol of the general formula (II) with a suitable halide, such as an alkyl 10-genide.

Alkenyl halide, alkynyl halide.

Aryl halide or fc can be produced by treatment with aralkyl halide.

Esters can be prepared by treating an alkali metal salt of compound (I) with a suitable acid chloride, acid bromide or acid anhydride.

When the compounds of the invention contain one or more chiral centers, the invention includes both resolved and unresolved forms. Example 7 shows that the product of general formula (II)
Example 12
We now describe the conversion of the product into two optically active forms.

Pharmaceutically and Conventionally acceptable acid addition salts of compounds of general formula (1) form non-toxic acid addition salts such as hydrochloric acid, hydrobromic acid, sulfuric acid, oxalic acid and methanesulfonic acid. It is a salt that can be formed from strong acids.

Such medium can be obtained by conventional methods, for example by mixing solutions containing equimolar amounts of the free base and the preferred acid, respectively, by filtration if the desired salt is insoluble, or by adding a solvent to the solution. can be recovered by evaporation.

Also included are alkali metal salts which can be prepared in conventional manner.

Compounds of general formula (I) are 0-esters thereof.

O-ethers, including 0-ethers and their pharmaceutically acceptable salts, are anti-fungal agents and have been shown to be effective in animals, including humans.
4 Useful in overcoming K< staining. For example, these are if! in humans. jK Candida
), ')Trichnphyt
on).

/L, Mophytoy PA (F:pidermophy
It is useful in the treatment of localized fungal infections caused by C. albicans species, or mucosal infections caused by C. albicans (eg, oral and vaginal candidiasis). For example, Candida albicans, Cryptococcus neo7
Cryptocoacue nθotor
n+ans), Asvedioides (Paracocc
idioidee), Histoplasma (Hlst
oplaema) or Plastomyces (Blast
It can also be used to treat systemic fungal infections caused by bacteria such as P. omyces.

In vitro evaluation of the antibacterial activity of the compound is determined by determining the minimum inhibitory concentration (m, i, c,) of the test compound that inhibits the growth of a specific microorganism in an appropriate medium. : Can be done by measuring. In practice, a series of agar plates containing a specified concentration of the test compound are inoculated with, for example, a standard culture of Candida albicans, and each plate is then incubated for 48 hours at 37°C. Next, the plate is examined for the presence or absence of growth of the fungi, and appropriate m, i, c values are recorded. Other microorganisms used in this type of test include Cryptococcus floccoeum), Coccidioides immitis (C.

imynitis) *- and Torulopsis glabrata.

In vivo evaluation of the compound was performed by administering a series of doses intraperitoneally to mice inoculated with a strain of Candida jlbicans.
c can be administered by intravenous injection or orally. Activity is based on survival of mice in the treated group after death of mice in the untreated group after a 48 hour observation period. The compound provides 50% protection against the lethal effects of infection.
D5o) is recorded.

For human use, the antifungal compounds of formula (I) can be administered alone, but will generally be administered in a mixture with a pharmaceutical carrier chosen with respect to the intended route of administration and standard means of formulation. There will be. For example, they may be in the form of tablets containing excipients such as starch or lactose, or in capsules or ovals, alone or mixed with excipients, or containing flavorings or colorants. It can be administered orally in the form of an elixir or suspension. They can also be injected parenterally, eg intravenously, intramuscularly or subcutaneously. 'For parenteral administration, other substances a
It is best used in the form of a sterile aqueous solution containing, for example, sufficient salt or glucose to make the solution isotonic with blood.

For oral and parenteral administration to patients (humans), the daily dose level of the antifungal compound of formula (I) is 01-5 mg/kl/(
(in divided doses). A tablet or capsule of the present compound will therefore contain from 5m7 to 0.511' of active compound for one or more administrations at one time, as appropriate. In any event, the physician will determine the actual amount that is likely to be optimal for an individual patient. This will vary depending on the age, weight and response of the patient. The above dosages are examples of the average case; there may, of course, be individual cases where higher or lower dosages may be beneficial. This is also within the scope of the present invention.

The antifungal compounds of formula fI) can be administered in the form of suppositories or pessaries, or they can be administered topically in the form of lotions, solutions, creams, ointments or powders. . For example, they may be contained in a cream, such as an aqueous emulsion of polyethylene glycol or fluid rough-in, or they may be contained in a cream, such as an aqueous emulsion of polyethylene glycol or fluid rough-in, or a white wax or white wax base and any necessary stabilizers and preservatives. It may also be included in the ointment at a concentration of 1 to 10%.

Compounds of formula (Il), including their 0-esters, 0-ethers and salts thereof, are useful in various rusts,
They are also useful against a variety of plant pathogens, including powdery mildew and mold, and thus the compounds are useful in treating plants to control or prevent these diseases.

In vitro evaluation of the activity of the compounds against fungi in plants can be carried out by determining their minimum inhibitory concentrations in the same manner as described above. However, the flat plate is 3
After culturing at 0°C for 48 hours or more, it is necessary to check for growth.

The microorganisms used in testing this yuzu include Cochliobolus
Carbonum (Cocihliobolus carbo)
num).

Pyricularia e oryzae (Pyricularia o
ryzae).

Glomerella singulata (Gl・t+narsll)
a cinci u1ata) + ' Penicill-1um digi
tatum), Potrytes 6 cinerea (Botry-t
is cinerea) and Rhizoctoria solani (
Rhizoctonia aolani) is included.

For agricultural and horticultural purposes, it is preferred to use the compounds and their agriculturally acceptable salts in the form of compositions tailored to the use and desired purpose. For example, this compound may be used as a powder, granule, or seed treatment agent (
It can be applied in the form of seeds, reesings, aqueous solutions, dispersions or emulsions, dips, sprays, aerosols or fumigants. The compositions can also be supplied in the form of dispersible powders, granules or particles, or as concentrates for dilution before use. Compositions of this type may contain conventional carriers, diluents or adjuvants which are known and accepted in the agricultural and horticultural arts and which are prepared in a conventional manner. These compositions may also contain other active ingredients, such as compounds with herbicidal or insecticidal activity, or other fungicides. These compounds and compositions can be applied in a sterile manner.

For example, they can be applied directly to the leaves, trunks, branches, seeds or roots of plants, or to the soil or culture medium in which they are grown, and they can be used not only to control diseases, but also preventatively. It can also be used to protect seeds from attacks.

The composition typically contains o, oi to 95% by weight of active ingredient, more preferably 0.01 to 1% by weight.

The appropriate ratio of active ingredients for baking is 5 to 500.9/i
It is o.

The following examples illustrate the invention.

All temperatures are in °C.

Example 1 Magnesium shavings (024y, to
While stirring under nitrogen atmosphere, p-bromochlorobanzene (1,17,9,6 mM) was added dropwise to the solution (1,17,9,6 mM). A violent reaction occurred resulting in a clear light brown solution containing excess magnesium shavings. This solution was mixed under nitrogen atmosphere with -
2/,4/-difluoro-2-fluoro-2-(IH-124-triazole-
1-yl) propiophenone (0.51M, '2mM
) was added dropwise over a period of 10 minutes to a solution of 20 ml of anhydrous ether C1').

The resulting mixture was allowed to warm up to room temperature for 3 hours, then stirred at room temperature overnight.

The reaction mixture was then mixed with a saturated aqueous solution of ammonium chloride (2
0 mg), separate the ether layer and add brine (2
Washed with (1 m), dried with MgL)04 and evaporated to an oil.

Silica (Merck, trade name [Kie-
Flash chromatography was performed on selgel 60 J) 40.9 with ether and hexane (4:
Elution was carried out with a mixture with a volume to volume ratio of 1). Fraction containing the target product (t, 11.cK, l: evaluation)
were combined and evaporated until 018 g of a white solid was obtained. This solid was recrystallized from ethyl acetate to obtain colorless crystals of the title compound (melting point 176-179°C) o, xtg (yield 15%).

The product N, M-R·S showed that the two diastereomers were present in approximately equal amounts.

These separations were not performed.

Analysis %: Experimental value: C55,4; H3,7; N 11.50
□7H□3N30F3C/Calculated value for closing: C55,5
; H3,6; N 11.4 Examples 2 to 5 From the ketone of the following formula: For 23 and 4, the chromatographic eluents were ether, ether/hexane (9:1) and ether, respectively. In Example 5, there was no need to perform chromatography. The recrystallization solvent used in Examples 2-5 was ethyl acetate containing 50, 30, 30 and 40 parts (by volume) of hexane, respectively. The isolated product 1r of Example 2 was a single diastereomer.

Example 6 From ethyl 2-(IH-L-4-triazol-1-yl)inbutyrate and 2 equivalents of Grignard reagent prepared from the reaction of magnesium shavings with p-bromofluorocarbons, Example Using reaction conditions similar to 1,
Ll-bis(4-fluorophenyl)-2-methyl-2
-(IH-124-)riazol-1-yl)zoronoξ
-1-ol (melting point 167-9°C) was prepared. The eluent used for chromatography was ethyl acetate/hexane (
4:6) The recrystallization solvent was ethyl acetate containing 20 qb of hexane.

Analysis experimental value: C66,7; H5,2; N 12.8C
Subtraction value as 18H□7N30F2: C65,7;
H5,2; N12.8 Example 7 To magnesium turnings (x29 mr) in anhydrous diethyl ether (5011 L/) was added p-chlorobromobenzene (660 μ>1) and the mixture was heated under reflux for b hours. The obtained Grignard reagent was converted into 2-(IH-124-
) Riazol-1-yl)-2 #2'14'-Trifluoroacetophenone (300 μg) was added to a solution dissolved in total anhydrous diethyl ether (20 mg) under a nitrogen atmosphere.
The solution was added dropwise with stirring at 10°C. The reaction mixture was then allowed to warm to room temperature for 11/2 hours and heated under reflux for 2 hours. Saturated aqueous solution of ammonium chloride (
20 mg) and the mixture was diluted with diethyl ether (axx
ooml). The organic extracts were combined, dried over magnesium sulfate, evaporated and evaporated to give a yellow oil which was then chromatographed on silica and extracted with diethyl ether and n-hexane (4: After elution with the mixture of 1), collecting and evaporating the appropriate fractions, diastereomer ① (melting point 199-201°C)
7■ and diastereomer 1■ (melting point 146-148℃)
45 rng were obtained.

Analysis: Experimental values: C54, 3; H3, 2; N 11
．． 8 and C54,25; fl 3.3; N 12.
Division value as IC□6H□1C/F'3N30: C5
4,3; H3,1; N 11.9R'・MgHa/
The following compound t- was prepared from the Grignard reagent in the same manner as in Example 7. In the case of Example 10, only one diastereomer was isolated.

Example 12 Resolution of the product of Example 8 The product of Example 8 was converted to R-(-1-1-(1-naphthyl)
Two diastereomeric carbamate esters were prepared by reaction with ethyl incyanate and separated by chromatography. Each carbamate ester was then cleaved by treatment with lithium aluminum hydride to yield the optically active form of the product of Example 8.

1. Preparation and separation of diastereomeric carbamate esters 2-fluoro-cx-:)-<4-fluorophenyl)
-2-(L24-triazol-1-yl)ethanol 1.9F, R-H-1-(1-naphthyl)ethyl incyanate 2.69F and bis(tri-n-butyltin)
Oxide "120" under nitrogen atmosphere.

Heated at reflux in anhydrous tetrahydrofuran (8me) for 48 hours. The reaction mixture was allowed to cool and poured with ice (so,
9) and extracted with ethyl acetate (2X50rug), the organic layer was dried (MgSO4) and evaporated to give a gum (S, 2g).

This gum was subjected to repeated flash chromatography on silica (300,!7) using ethyl acetate:hexane::)ethylamine (50:50:1.5).
Extracted with a mixture of After one chromatography run, most of the fast running diastereomers and about half of the slow running diastereomers were obtained in pure form.

The diastereomeric residue, which ran slowly, was still contaminated with starting material. Using a silica column inactivated by standing overnight in a mixed eluent (ethyl acetate:hexane:diethylamine-50:50:1.5),
It has been discovered that this diastereomer can be well separated from the starting material. The majority of each diastereomer thus obtained after using two columns was completely free of the other diastereomer, although it still contained small amounts of other impurities. Each diastereomer was further flash chromatographed using the same eluent as before to obtain (a) 1.2 g of the fast eluting diastereomer and 1.2 g of the hl slower eluting diastereomer.
．． 119'li-, obtained as a glass. These diastereomers are reduced to the starting alcohol by lithium aluminum hydride (see below) and the NMR spectra show the presence of a triazole proton at 8.58 and a methyl doublet at 1.6δ, J7Hz. By clearly indicating the characteristics of

The 7-component cleavage diastereomer (a) (990■) was dissolved in ether (25
Lithium aluminum hydride (45 liters) was added in small portions over 40 minutes while stirring at 0°C. After stirring for a further 30 minutes, water was added carefully, initially dropwise (20 ml). The reaction mixture was then extracted with ethyl acetate (3 x 30 ml), the organic extracts were dried (Mg5o4) and evaporated to a semi-solid (990r
ng) Got money.

Flash chromatography on sil, M; Traces of impurities were removed by chromatography on sJ, 'luated methylene:methanol::)ethylamine (94:4:1). Recrystallization from ethyl acetate/cyclohexane gives colorless crystals (melting point 154° to 1
55°; [αzo5'-141,8° (methanol))89 4807rlj was obtained.

Analysis: Experimental value: C60,2; H3,8; N 13.2C
Calculated value as 16H12F3N30: C60,2;
H3,8; N13.2 diastereomer (bl is cleaved in a similar manner to give colorless crystals (melting point 151°-154°)
°; [αzo5°+141.5°89 (methanol)] was obtained.

Analysis: Experimental value: C59,9; H3,7; N 12.9C
Calculated value as □6H□2F3N30: C60,2;
H3,8; N 13.2 Next production example (all temperatures are °C
) describes the production of the starting materials.

Production example 1 2't4L in tetrahydrone run (70mA'):)
Fluoro-2-(1)? -L2.4- Triazole-
1-yl)acetophenone (3.7g, 16.6mM
) was added and stirred, the solution was cooled to 5°C, and a suspension of 50 m of sodium hydride in oil (33.2 m
It was added as a suspension containing M 1.58.9). After 30 minutes, methyl iodide (5,2'gt 36.5mM) was added to
Added yc+ for a minute. Stirring was continued for 20 hours at room temperature.

The mixture was then poured into ice water (150ml) and extracted with ethyl acetate (3X50ml'). The organic extracts were combined, washed with water 3×20+++e) and dried over anhydrous magnesium sulfate. Evaporation gave a solid crude product (weight 46I).

Purification was carried out using Merck's "Kie day e1ge160 J"
Flash column chromatography under mild pressure (2p, s, i) using a 230-400 mesh silica column recrystallized from cyclohexane/n-pentane to give the pure title compound (melting point 45°-47°). 1.5.9 (yield: 36.3%) was obtained.

Calculated value as analysis ChiC□2H□□F'2N30: C57,4;
H4,4; N 16.7 Experimental value: C57,6;
H4,1; N 16.4 product N, M, R,, ■,
The R and mass spectrum data were consistent with the structure described above.

Production example 2 4'-chloro-2-(IH-124-)riazole-1
Using lycetophenone, sodium hydride and methyl iodide as starting materials, 4'-chloro-2-methyl-2-(IH-L24-)lyazol-1-yl)propiophenone (melting point 118° to 119°) Production Example 1
Manufactured in the same way.

Analytical experimental values: C57.8; H4.9; N 16.9C
Calculated value as □2H1□ClN30: C57,7; H
4,8; N 16.8 Production Example 3 2/, 41-difluoro-2-(IH-LZ4-) lyazole-t-(l)propiophenone hydrochloride tetrahydrofuran 90 furan (75 m/) to 2', 4/- Difluoro-2-(IH-LZ4-to-1-noazol-1-yl)7-c/y (4#, 17.9 mM) was added to the stirred solution. Medium 50% dispersion (17.9mM sodium hydride)
It was added as a dispersion containing 0.861 k. After 20 minutes, methyl iodide (2,8,9,19,7mM)'t
Added over 5 minutes 1 [Xl. Stirring was continued for 19 hours at room temperature.

The mixture was then poured into ice water (100d) and extracted with methylene chloride (3X30d). The combined organic extracts were washed 3×40 mA with water and dried over anhydrous magnesium sulfate. Evaporate and oily substance (ju-uta 4.7.
9) t" was obtained. Purification was carried out using Merck's jKieaθI
Flash column chromatography was carried out using a ge'160J 230-400 mesh 71 column under 1 weak pressure (2p 8.1).
Elution was performed with The appropriate fractions were combined, reduced in volume by evaporation (soft) and treated with gaseous f4 (arsenic). Compound (melting point 1
47-1500) 1.66 g were obtained as fine crystals (yield: 33.9 cm).

Analysis Ch: C□, H, F'2N30・) Calculated value as IcJ: C4
8,3; H3,7; N 15.4 Experimental value: C48
,1; H3,5; N 15.7 Product N, M, R
, , R0 and mass vector data were consistent with the structure described above.

Production Example 4 Sodium hydride (60% suspension in oil 12I) was added to anhydrous dimethylformamyl, stirred at 0°C,
A solution of L24- ) lyazole (21 g) in anhydrous dimethylformamide was added. Stirring was continued for 15 min at 0°C, then ethyl 2-bromoisobutyrate (ss, s
A solution of 9) in anhydrous dimethylformamide (50 aff) was added. After the exothermic reaction subsides, the reaction mixture t″60
Heated at ~65° for 16 hours. The cooled solution was then filtered, the filtrate was evaporated under reduced pressure and the remaining dimethylformamyt was removed by azeotropic distillation with xylene under reduced pressure. Residue tA: A colorless oil (boiling point,
98° at 0.4mxHg) 41.8,9 t-
Obtained. This material was then subjected to flash chromatography on silica, eluting with ethyl acetate to give the title compound as a colorless oil, 299.

This material was used without purification.

N, M, R, (CDCA!,) δx1.2. t, J
s=7Hz, 3H; 1.85°s, 6H; 4.17
j qt J=7H2,2H;7.95. s, IH
;8.27. e, 18 Production Example 5 2',4'-difluoro-2-(1)1-124-)
lyazol-1-yl)propiophenone (free base,
While stirring at room temperature, sodium hydride (6 (044 g, 1.3 eq. as a dispersion in 1 oil) was added. Gas evaporation. At the end of the reaction, the resulting clear liquid was exposed to an atmosphere of velchloryl fluoride until no absorption occurred. The solvent was removed under reduced pressure and the residue was dissolved in ether ('50 m
The ether was saturated with water to destroy any residual sodium hydride present in the residue. The ether solution was then carefully decanted to separate the inorganic solids. The remaining inorganic solids were washed with anhydrous ether (20 m/) and the ether was decanted and added to the first ether extract.

The ether was then evaporated to give the title compound as a pale yellow clear product (2,01), which was used without purification.

N, M, R, (CDC/J3): δ-8,54, IH,
e;8.0. IH,s;7.8. IH, m; 6.9
．． 2H,m; 2.27.3H,d, J-19Hz Production Example 6 L3-:) Fluorobenzey (2,021!; 1
7.7mM) and anhydrous aluminum chloride (2,60,f;
19.47mM) in a dry nitrogen atmosphere.
Stir at room temperature. Fluoroacetyl chloride (1,7
1#; 17.7mM) of anhydrous methylene chloride C2ml)
The solution was added over 30 minutes. This mixture was then heated at approximately 50° for 3 hours. Upon cooling, methylene chloride (4(bzl)i) was added and the mixture was poured onto ice.

The methylene chloride layer was separated, dried over magnesium sulphate and evaporated to give the white homologue. This material was chromatographed on a silica column and eluted with a mixture of hexane/methylene chloride (65:35 by volume).
Fractions containing the product, ft. were collected. These horns were evaporated to crystallize out the title compound, which was dried in a vacuum desiccator to form a colorless crystalline solid (melting point 5
7~58°) 1, 121! (yield: 36 cm).

Analysis test value: C55,0; H2,8 Calculated value as 08H5F30: C55,2; )1
2.91) 2.2', 4'-) Refluoro-2-
Chloroacetophenone 2-6 2.2',4'-trifluoroacetophenone (1,6
A solution of 0I; 9.2mM) in sulfuryl chloride (41!1g) was heated at 75° for 18 hours. The mixture was then cooled and ice-cold water (40ml) was added. The product was extracted into ether (80d) and the ether extract was washed with water and aqueous sodium bicarbonate and dried over magnesium sulfate. Evaporation gave the desired product as a strongly lachrymatory colorless liquid (2,0,9; 100 g).

N, M, R and 1. of this liquid. The R and S overlaps matched the target structure. This material was used directly in the next step.

(N, M, R, (CDC/3): δ-8,542H)
;6.87 (d, IH, J=51), 1. R, (KBr
), 17101 CWL to -C-) 1 A mixture of LZ4-triazole (1,25,9; 18mM) and anhydrous potassium carbonate (2,0,9; 14.5mM) in 80 mL of anhydrous tetrahydrofuran (20ml!) , stirred at reflux temperature. Then 2.2',4'-trifluoro-2=chloroacetophenone (1,5,9;
A solution of 7.19 mM) in tetrahydrofuran (10al) was added over a period of 1 minute. The mixture was refluxed for 2 hours and then left at room temperature overnight. Water (50ml
)e and the mixture was diluted with methylene chloride (2X100fi/)
Extracted with. The combined organic extracts were dried over magnesium sulfate and evaporated to give a gum. Chromatography was carried out on a silica column, eluting with ethyl acetate/hexane/diethylamine (70:30:3 by volume), and after evaporation of the appropriate fractions, the desired product was found in the form of a gum (130 cm, 7. 5%). The N, M, and R of this matched the target structure.

The compound is characterized as a methanesulfonate salt (melting point 158-160°) prepared by mixing an ether/acetone solution of the free base and an ether/acetone solution of the acid and recovering the precipitated salt. did.

Analysis tlb: Experimental value: C39,1; H3,0; N 12.4C
Calculated value as 1oH6F'3N30- CH403S: C39,2; H3,0; N 12.5 Sodium hydride (285~ as dispersion in 50% oil; Sodium hydride 5.94mM) k Washed with ether, Dry under nitrogen atmosphere. Anhydrous tetrahydrofuran (15M)
Gold addition followed by 2',4'-difluoro-2-(IH-
L24-) lyazol-1-yl) acetophenone (1
, 115,9; 5mM) (UK Patent Application Publication No. 209
9818A) was added in small portions over 5 minutes. The resulting brown liquid was stirred under a fluorinated perchloryl atmosphere until the theoretical amount was absorbed. The pale yellow suspension was evaporated and partitioned between water (25-) and ethyl acetate (50 mJ). The ethyl acetate layer was separated, washed with water, dried over magnesium sulphate and evaporated to give an oil which crystallized (1.21g).

The product was confirmed to be the same as the product of Preparation Example 6 (++1) (free base form, approximately 80% purity) by N, M, R and t, Il, c-.

In an alternative method, after evaporation of the suspension, the residue was chromatographed on silica, eluting with K ether and hexane (9:1) to give the title compound.

Preparation Examples 8 and 9 The second starting material, acetophenone, was prepared similarly to the process of Preparation Example 7 from secondary noketone intermediate gold, the appropriate acetophenone, sodium hydride and fluoride, and chloryl as described in British Patent Application Publication No. 2099818A. 27.4/
-difluoro-2-(IH-124-triazole-1
-yl) acetophenone.

Using the test method described above, the following PD5o values were obtained for Candig albicans in mice: Compound P
D5o (πli!/kg) Product of Example 1 0.95 Product of Example 2 <1.0 Product of Example 3 <1.0 Product of Example 4 23 Product of Example 5 22 Product of Example 6 1.6 Product of Example 7 (Diastereomer I) 1.6 Product of Example 7 (Diastereomer ■) 03 Product of Example 8 0.3 Product of Example 9 Product (Diastereomer I) 0.3 Product of Example 9 (Diastereomer II) 0.5 Product of Example 10 3.2 Product of Example 11 <1, Compound of Example 12 ( -1-10,75 Compound of Example 12 ←) 0.2 Continued from page 1 Priority claim 01% disease April 14th 0 United Kingdom (GB) [
20(3)0 Inventor Geoffrey Edward 1 St Geimer Road, Kent, United Kingdom
9 Ivy Berry, Wingham, Parma

Claims (1)

[Claims] (1) The following general formula: (In the formula, R, !: R are each independently unsubstituted or F
, C1, Br, I, CH3, C1-04 alkyl and cl-C4 alkoxyl each independently selected from the group consisting of 1 to 3 substituents directly substituted phenyl group; R2 represents H, CH3 or F; R represents H or CH3; one of R and R represents a group other than H), or its 0-ester, 0-ether, or its pharmaceuticals Salt that is technically or technically acceptable. (21R, !: R each independently, F', C1, B
2. The compound according to claim 1, which is a phenyl group substituted with 1 to 3 substituents each independently selected from the group consisting of r, ■, and CF3. 431 R and R each independently represent 4-fluorophenyl, 4-10rophenyl, 4-t+)fluoromethylphenyl, 2-fluorophenyl. 24-:) chlorophenyl, z4-:) fluorophenyl, 4-chloro-2-fluorophenyl, 2+chloro-
4-fluorophenyl, 25-:)fluorophenyl,
246-17 Fluorophenyl 4-7' Romo 25-) Fluorophenyl Claim 2
Compounds described in Section. (4) Claim 3 in which R and R each independently represent 4-chlorophenyl, 4-fluorophenyl, 24-dichlorophenylt or 24-difluorophenylte.
Compounds described in Section. (5) The compound according to claim 1, wherein R is F and R is H. +61 The compound according to claim 1, wherein R3 is CH3 and R2 is H, CH3 or F. (α) The 〇-ester is a C2-C4 alkanoyl or +dbenzoyl ester, and the benzoyl group is unsubstituted or halogen, C, -C4 alkyl and
-04 alkoxyl group, each independently selected from the group consisting of one or two substituents, and the tbl nucleus 〇-ether is C, -C6 alkyl, C2-
C4 alkenyl, C2-C4 fluorynyl'! fc
halogenyl ether, wherein the benzyl l and t are unsubstituted or one or two (6 A compound according to any one of paragraphs 1 to 6 of claim 4i0. of claim !11, which is substituted in the ring by a substituent. (8) Pharmaceutically acceptable. Together with a diluent or carrier, a compound of general formula (11), or its 〇-
A pharmaceutical composition comprising an ester, O-ether or a pharmaceutically acceptable salt thereof. (9) patents, 1. with an agriculturally acceptable diluent or gearia; From claim 1? An antifungal composition for agriculture and cultivation, comprising a compound of general formula +1) according to any one of item A7, ' or an 0-ester, 0-ether or an agriculturally acceptable salt thereof. +101 1+': Scope of claims for seed breaking or treatment of fungal infection of plants (W or a method of prevention. R and R are as defined in claim 1) and this reaction is optionally followed by the following steps: 1) the 〇-ester of the product l or Patent M11, characterized in that one or both of 〇-conversion into an ether and ++) conversion of the product into a pharmaceutically and agriculturally acceptable salt are carried out.
A method for producing a compound of the general formula (11) described in the first section of the first prophecy of K. (12) Compound of the following formula: and after this reaction optionally carrying out step (1) and/or (ll'e) as defined in claim 11. A method for producing a compound of general formula (1) according to claim 1, characterized in that R and R are the same and both R and R are CH3. , a compound of the general formula (1) according to any one of claims 1 to 7, or a 〇-ester, 〇-ether moji, or a pharmaceutically acceptable salt thereof.