CS235346B2 - A fungicidal agent for the treatment of plants or seeds and a method of producing the active ingredients - Google Patents

Abstract

A fungicidal composition for treating plants or seeds, characterized in that it contains as an active ingredient a triazole derivative of the general formula I OH N^N—CH2-C—(CF2)n-CF3 {I) \=N I n in which R represents a phenyl group, optionally substituted with one to three substituents independently selected from the group comprising fluorine, chlorine, bromine and iodine atoms and a trifluoromethyl group and n has the value 0, 1 or 2, or an agriculturally usable salt thereof, together with an agriculturally usable diluent or carrier.

Description

The invention relates to novel triazole derivatives exhibiting antifungal activity and useful for the treatment of fungal infections in animals, including humans, and as agricultural fungicides, as well as a process for the production of these substances.

Accordingly, the invention describes a process for the preparation of compounds of general formula 1

(I) in which

R represents a phenyl group optionally substituted with one to three substituents independently selected from the group consisting of fluorine, chlorine, bromine and iodine atoms and a trifluoromethyl group, and n has a value of 0, 1 or 2, and pharmaceutically and agriculturally usable salts thereof.

The invention also includes a fungicidal composition for protecting plants and seeds, comprising a compound of general formula I or an agriculturally acceptable salt thereof, together with an agriculturally acceptable diluent or carrier.

If R represents the above-mentioned optionally substituted phenyl group, this group is preferably a phenyl group substituted by one to three, even more preferably one to three, even more preferably one or two substituents, independently selected from the group comprising fluorine, chlorine and iodine atoms, and a trifluoromethyl group. The residue R thus in particular represents a 4-fluorophenyl group, a 4-chlorophenyl group, a 4-trifluoromethylphenyl group, a 2-fluorophenyl group, a 2,4-dichlorophenyl group, a 2,4-difluorophenyl group, a 2-fluoro-4-chlorophenyl group, a 2,5-difluorophenyl group,

2,4,6-trifluorophenyl group or 4-bromo-2,5-difluorophenyl group.

Most preferably, R represents a 2,4-dichlorophenyl or 2,4-difluorophenyl group.

The symbol fl most preferably has the value 0 or 1.

These compounds of general formula I, in which a has the value 0, can be prepared according to the invention by a process according to the following reaction scheme:

CF ₃ COCH ₂ .Hal + (IV)

R.Li

OH

1,2,4-triazole, base (e.g. ^K 2 ^CO 3^ temperature up to 130 °C, reaction time db 24 hours

OH

The symbol Hal in the above reaction scheme represents chlorine or bromine.

Instead of 1,2,4-triazole and potassium carbonate, an alkali metal salt of 1,2,4-triazole can also be used, which can be prepared, for example, from sodium hydride and triazole.

In accordance with a typical embodiment of this reaction, the haloketone of formula IV and the lithium derivative or Grignard reagent are stirred for about 1 hour at -78 °C, for example in diethyl ether. The intermediate haloalkanol of formula V can optionally be isolated in conventional manner. This haloalkanol is then heated together with the 1,2,4-triazole, for example in dimethylformamide, to a temperature of about 50 to 130 °C, in the presence of a base, such as potassium carbonate, for a period of up to about 24 hours. The product of formula IA can then be isolated in conventional manner.

Compounds of the above general formula I, in which n has the value 1 or 2, can be prepared by a procedure analogous to that described above for the preparation of compounds of the general formula IA, i.e. by a procedure according to the following reaction scheme:

1,2,4-triazole

Hal.CH ₂ -C-(CF ₂ ) _n -C® ₃ ^K 2 ^C °3 50-130 °C

-CH

OH _l2 _c-(cF ₂ ) _n -CF ₃ R (IB)

In the formulas shown in this scheme, Hal represents chlorine or bromine and has a value of 1 or 2.

This reaction is carried out under similar conditions to the reaction described above, for example by heating in dimethylformamide to a temperature of up to about 130 °C for a period of up to about 24 hours. In this case too, the product can be isolated in a conventional manner. The starting materials can be prepared in a conventional manner, for example by procedures according to the following schemes:

(and)

BrCE ₃ (CH ₂ ) _n COCH ₃ concentrated

-> CF ₃ (CF ₂ ) _n C0CH ₂ Br

H ₂ S°4 fsee J. Am. Chem. Soc., 22, 2268-2270 (1956)]

R.Li, R.MgBr or R.Ngl -:->

OH

AND

_CH3 ( _CF2 ) _n -C- _CH2Br

R or (b)

Cgt^MgBr ^Cř 3 ^(CP 2 ^} n ¹ -* ^Cř 3 ^(CF 2> n ^MgBr

-78°C

OH

C1CH ₂ COR, -20 °C -----ClCH ₂ -C-(CF ₂ ) _n CF ₃

In this scheme, a has the value 1 or 2.

Pharmaceutically acceptable addition salts of the compound of formula I are those prepared with strong acids forming non-toxic addition salts with 3 acids, such as hydrobromic acid, hydrochloric acid, sulfuric acid, oxalic acid and methanesulfonic acid.

These salts can be prepared in conventional manner, for example by mixing solutions containing equimolar amounts of the free base and the desired acid. The desired salt, if insoluble, is isolated by filtration or may be isolated by evaporation of the solvent.

The invention also includes alkali metal salts which can be prepared in a conventional manner.

The compounds of formula I and their pharmaceutically acceptable salts are antifungal agents which can be used to combat fungal infections in animals, including humans. For example, these substances can be used to treat local fungal infections in humans, caused, among others, by Candida, Trichophyton, Microsporum or Epidermophyton species, or infections of the mucous membranes caused by Candida albicans (for example, oral and vaginal candidiasis). The described compounds can also be used to treat systemic fungal infections caused, for example, by Candida albicans, Cryptococcus neoformans, Aapergillus fumigatus, Coccidioides, Paracoccidioides, Histoplasma or Blastomyces.

The antifungal activity of the described compounds in vitro can be assessed by determining the minimum inhibitory concentration (MIC), which is the concentration of the test compound in a suitable medium at which the growth of the relevant microorganism does not occur. In practice, a series of agar plates, each containing the test compound at the appropriate concentration, are inoculated with a standard culture of, for example, Candida albicans, the plates are incubated for 48 hours at 37 °C, after which the growth of the fungus (rep. absence of the fungus) is evaluated on them and the MIC value is determined. Other microorganisms that can be used in these tests include, for example, Cryptococcus neoformans, Aspergillus fumigatus, Trichophyton spec., Microsporum spec., Epidermophyton floccosum, Coccidioides immitis and Torulopsis glabrata.

The in vivo efficacy of the compounds described can be assessed by administering these compounds by intraperitoneal or intravenous injection, or orally, in a series of appropriately graded doses to mice inoculated with a strain of Candida albicans. Efficacy is demonstrated by the survival of the treated group of mice after the death of the untreated group of mice when assessed after 48 hours. The dose of the test compound that provides 50% protection against lethality (PB^θ) is determined.

In the above-described test, the following PD^q values were found (oral administration to mice against Candida albicans):

Test substance PDj _Q ⁽ · ^ιη 8/ ^ΐ£ β> orally)

Product from example TI 0.1

0.1

1.5

1.5

0.1

1.1

0.1

0.15

0.2

Test substance

PDj0 (mg/kg, oral)

Product from Example 10 0.2 11 0.1 12 0.2 13 0.4 14 0.1 15 0.2

Preferred compounds are the products of Examples 1 and 8.

When used in human medicine, the antifungal compounds of formula I may be administered alone, but are generally administered in admixture with a pharmaceutical carrier selected with due regard to the intended route of administration and standard pharmaceutical practice. For example, these compounds may be administered orally in the form of tablets containing, for example, starch or lactose as a carrier, or in the form of capsules or globules, where they are contained either alone or in admixture with carriers or excipients, or in the form of elixirs or suspensions containing flavorings or colorings. The compounds may also be administered parenterally! by injection, for example intravenously, intramuscularly or subcutaneously. For parenteral administration, the compounds of the invention are best used in the form of a sterile aqueous solution, which may contain other substances, for example, an appropriate amount of salts or glucose to make the solution isotonic.

For oral and parenteral administration in human medicine, the daily doses (both oral and parenteral) of antifungally active compounds of the general formula 1 range from 0.1 to 10 mg/kg (possibly administered in divided doses). Tablets or capsules containing the active ingredient according to the invention will therefore contain from 5 mg to 0.5 g of the active ingredient for single, double or multiple administrations per day, as appropriate in each case. The specific dose that will be most suitable for the patient in question and will vary depending on the age, weight and response of the patient to the preparation will be determined in each case by the attending physician.

The above dosage is only an example of an average case and individual cases may of course arise in which higher or lower doses will have to be administered. All such cases fall within the scope of the invention.

Alternatively, the antifungal compounds of the general formula I can be applied in the form of a suppository or pessary, or they can be applied topically in the form of a lotion, solution, cream, ointment or powder. For example, these active ingredients can be incorporated into a cream consisting of a scientific emulsion of polyethylene glycols or liquid paraffin, or they can be incorporated in a concentration of between 1 and 10% into a butter base consisting of white wax or white soft paraffin, optionally together with suitable stabilizers and preservatives.

The compounds of general formula I and their salts also show activity against a wide variety of phytopathogenic fungi, including, for example, various rusts, powdery mildews and molds, and can therefore be used to treat plants and seeds to prevent or treat these diseases.

The efficacy of the described compounds against phytopathogenic fungi in vitro can be determined by measuring their minimum inhibitory concentrations in the same manner as described above, with the only difference being that the plates are incubated for 48 hours or longer at 30 °C before evaluating the growth (or absence) of the fungus.

Microorganisms useful in these tests include Cochliobolus carbonum,

Pyricularia oryzae, Glomerella cingulata, Penicillium digitatum, Botrytis cinerea and Rhizoctonia solani.

and

The following section presents the results of efficacy tests against phytopathogenic fungi, carried out as described above. These results are given in minimum inhibitory concentrations (MIC) values in µM/ml.

Experimental mushrooms are indicated with capital letters and the following meanings:

A = Glomerella cingulata

B = Helminthosporium carbonum

C = Penicillium digitatum

D = Botrytis cinerea

E = Pyricularia oryzae

The sign indicates that the test was not performed in that case.

Test Substance (Product from Example No.) MIC (^ug/ml) against A B C D E 1 0.8 3 0.8 0.8 6 2 50 100 0.8 1.6 3 4 50 25 3 - 6 6 50 0.8 3 - 0.8 . 8 50 1.6 0.8 0.8 0.8 10 50 100 0.8 0.8 1.6 12 25 1.6 0.8 - 1.6 13 100 6 3 - 6 14 - 1.6 0.8 - 3

In agricultural and horticultural applications, the compounds of the invention and their agriculturally usable salts are preferably used in the form of compositions prepared for the respective use and the desired purpose. These compounds can be applied in the form of dusts or granules, seed dressings, aqueous solutions, dispersions or emulsions, drench compositions, sprays, aerosols or fumigants. These compositions can also be supplied in the form of dispersible powders, granules or grains, or concentrates intended for dilution before use. Such compositions may contain conventional carriers, diluents or auxiliaries, as is known and commonly used in agriculture and horticulture, and are manufactured in a conventional manner. The compositions described may also contain other active ingredients, for example compounds having herbicidal or insecticidal activity, or other fungicides. The compounds and compositions of the invention can be applied in a variety of ways, for example directly to plant leaves, stems, branches, seeds or roots of plants, or to the soil or other growing medium, and can be used not only to treat disease, but also prophylactically to protect plants or their seeds from disease attack.

The invention is illustrated by the following examples, which do not limit the scope of the invention in any way.

Example

Preparation of 2-(2,4-difluorophenyl)-1-(1Η-1,2,4-triazol-1-yl)-3,3,3-trifluoropropan-2-ol

1,2,4- ^triazole

K2CO2

£ 6 ml of diethyl ether are added 9.6 ml of a 1.55 M hexane solution of n-butyllithium (14.9 mmol), the resulting solution is cooled to -78 ° C, a solution of 3.03 g (15.7 mmol) of 2,4-difluorobromobenzene in 100 ml of diethyl ether is added dropwise over 15 minutes and the mixture is stirred for another 15 minutes at a temperature of -78 ° C, after which a solution of 2.4 g (12.6 mmol) of 1-bromo-3,3,3-trifluoropropan-2-one in 100 ml of diethyl ether is added dropwise over 15 minutes. The resulting mixture is stirred for another 30 minutes at a temperature of -78 ° C, then a solution of 2 ml of glacial acetic acid in 5 ml of diethyl ether is added first and then 15 ml of water. The mixture is allowed to warm to 0 ° C, the aqueous layer is separated and washed twice with 30 ml of diethyl ether. The combined diethyl ether extracts are dried over magnesium sulphate, evaporated and the oily residue is dissolved in 40 ml of dimethylformamide. To this solution are added 2.5 g (36.2 mmol) of 1,2,4-triazole and 10 g (72.5 mmol) of anhydrous potassium carbonate, the mixture is heated to 70 °C with stirring for 18 hours, then cooled, poured into 150 ml of water and extracted three times with 100 ml of ethyl acetate. The combined ethyl acetate extracts are washed with .00 ml of water and, after drying over magnesium sulphate, evaporated. The residue is chromatographed on silica gel (230 to 400 mesh) using a mixture of ethyl acetate and hexane (60:40 by volume) as eluent. After a subsequent recrystallization from a mixture of ethyl acetate and hexane, 1.7 g (47%) of the title compound, melting point 1.0-1.11 °C.

Analysis: for C2H8F2N3O calculated 45.05% C, 2.75% H, 14.33% N;

found 45.16% C, 2.73% H, 14.56% N.

Examples 2 to 7

The compounds of the following Examples 2 to 7 are prepared by methods analogous to those of the preceding Examples using the respective aryllithium (Examples 2, 3, 5 and 6) or Orignaid reagent (Examples 4 and 7). In Examples 4 and 6, tetrahydrofuran is used in the final reaction step instead of dimethylformamide.

OH f/^N—CH.—c—CF, \ / ² I ³ ' ^Z== NI

R

Example R Profit Temperature Analysis (%) - found (calculated) number <*> melting point (°C) C H N

148-150

35.90 1.93 11.42 (35.51 1.90 11.29)

Br

Cl

94-96

134-136

89-91

144-147

44.36 2.76 13.13 (44.32 2.79 12.92) 47.78 3.20 15.49 (48.00 3.30 15.27) 42.77 2.27 13.88 (42.46 2.27 13.50) 37.19 3.04 10.67 (37.02 3.11 10.79) 43.4 2.7 13.0 (42.7 2.6 13.6)

Legend:

^χ ) as methanesulfone

Example 8 (A) Preparation of 1-bromo-3,3,4,4,4-pentafluorobutanone

Br.

ct ₃ cf ₂ coch ₃ > CøjCFgCOCHgBr

3.9 g (0.02407 mol) of methyl pentafluoroethyl ketone [j. Am. Chem. Soc. 78, 2 268 - 2 270 (1956)] are stirred at room temperature under reflux with solid carbon dioxide in 10 ml of concentrated sulfuric acid, after which 1.92 g (0.012035 mol) of bromine are slowly added with vigorous stirring over 2 hours. The mixture is stirred for 1 hour at 50 °C and the resulting amber-colored solution is subjected to distillation at atmospheric pressure. One main fraction weighing 4.41 g (76%), boiling at 94-97 °C, is obtained. The mass spectrum confirms the stated structure, since it shows the presence of two molecular ions at 240 and 242, corresponding to C^BrF^O (two Br isotopes).

(B) Preparation of 2-(2,4-difluorophenyl)-3,3,4,4,4-pentafluoro-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

N—NH

_{K2CO3 ​}

3.32 ml of a 1.5 M hexane solution of n-butyllithium (0.00498 mol) in 5 ml of diethyl ether is cooled to -78 °C with stirring and a solution of 1.0 g (0.00519 mol) is slowly added over 15 minutes.

2,4-difluorobromobenzene in 8 ml of ether. The reaction mixture was cooled to -78 °C for 15 minutes, then 1.0 g (0.00415 mol) of 1-bromo-3,3,4,4,4-pentafluorobutanone in 6 ml of ether was added at -78 °C over 15 minutes. The mixture was stirred at -78 °C for 30 minutes, then 0.7 g of acetic acid in 5 ml of ether and then 8 ml of water were added. The resulting mixture was allowed to warm to room temperature, the ether layer was separated and the aqueous layer was washed twice with 15 ml of ether each time. The combined ethereal layers were dried over magnesium sulfate and evaporated to an oily residue, to which were added 0.86 g (0.01245 mol) of 1,2,4-triazole, 5.73 g (0.0415 mol) of anhydrous potassium carbonate and 15 ml of anhydrous dimethylformamide. The reaction mixture was heated with stirring at 80°C for 3 1/2 hours, then cooled to room temperature and poured into 150 ml of water. The aqueous mixture was extracted three times with 60 ml of methylene chloride each time, the combined organic extracts were dried over magnesium sulfate and evaporated to a brown oily residue, which was flash chromatographed on silica gel (230-400 mesh). Elution with ethyl acetate:hexane (60:40 by volume) gave 400 mg (28%) of the title compound as a white solid melting at 95-96°C after crystallization from cyclohexane.

Analysis:

calculated found for C ₁₂ H _q F ₇ N ₃ O

42.0% C, 2.3% H, 12.2% Nj 41.8% C, 2.3% H, 12.0% N.

Examples up to 13

In a manner analogous to the previous example, the following compounds are prepared from the appropriate starting materials:

\=N

OH

AND

-ch ₂ —C—CF ₂ CF ₃ R

Example number

Yield Melting point (%) (°C)

Analysis (%) - found (calculated) C H R

38.39

109-110 (38.32

34.32

168-170 (34.14

41.98

108-110 (41.61

44.3

95-97 (44.3

44.6

5.9 95-97 (44.3

2.12 11.12 2.14 11.17) 1.67 9.58 1.67 9.95) 2.42 11.16 2.42 11.20) 2.7 12.7 2.8 12.9) 2.8 13.3 2.8 12.9)

Example 1

Preparation of 2d 14 ,4-difluorophenyl)-3,3,4,4,5,5,5-heptafluoro-1-(1H-1,2,4-triazol-1-yl)pentan-2-ol cich ₂ c (cf ₂ ; ₂ cf ₃ ' F

OH

OH

1,2,4-triazole

_{K2CO3 ​}

F

To a solution of 5 g (0.017 mol) of heptafluoropropyl iodide in 20 ml of ether, cooled to -78 °C, 5.6 ml of a 3 M ethereal solution of phenylmagnesium bromide (0.017 mol) are added dropwise at such a rate that the temperature of the reaction mixture does not exceed -50 ^° C. After adding all the phenylmagnesium bromide, the mixture is stirred at -50 °C for 0.5 hour and then cooled again to -78 °C and a solution of 3.6 g (0.019 mol) ^of 2chloro-2,4-difluoroacetephenene in 20 ml of ether is added dropwise at such a rate that the temperature of the mixture does not exceed -50 °C. After the addition was complete, the reaction mixture was allowed to warm to -20°C, stirred at this temperature for 2 hours, then a solution of 3 ml of glacial acetic acid in 5 ml of ether was added first, followed by 15 ml of water, and the resulting mixture was allowed to warm to approximately 5°C. The aqueous phase was separated, extracted twice with 50 ml of ether, the combined ether extracts were dried over magnesium sulfate and evaporated. 6.7 g of a light yellow oily material was obtained, which was added to a mixture of 5.87 g (0.085 mol) of 1,2,4-triazole and 17.5 g (0.127 mol) of anhydrous potassium carbonate in 60 ml of dimethylformamide. The reaction mixture was stirred at 80°C for 3 hours, then cooled, the dimethylformamide was evaporated and the residue was partitioned between 200 ml of water and 150 ml of ethyl acetate. The aqueous layer was separated and extracted three times with 150 ml of ethyl acetate. The combined ethyl acetate extracts were washed successively with aqueous sodium bisulfite and water, dried over magnesium sulfate, evaporated and the residue was flash chromatographed on silica gel (230-400 mesh) using a mixture of hexane, isopropyl alcohol and ammonium hydroxide (density 0.88) in a volume ratio of 80:20:1.5 as the eluent.

After a single subsequent recrystallization from a mixture of hexane and dichloromethane, 1.51 g of the title compound are obtained, melting point 128° C. The yield is 23%.

Analysis: calculated for 39.7% C, 2.1% H, 10.7% N; found 39.8% C, 2.0% H, 10.6% N.

Example 15

By a procedure analogous to the previous example, 2-(4-fluorophenyl)-3,3,4,4,5,5,5-heptafluoro-1-(1H-1,2,4-triazel-1-yl)pentan-2-yl was prepared from the corresponding starting material in a yield of 7%, with a melting point of 126 to 127 ^° C.

Analysis: calculated for C12H18F18N12O: 41.6% C, 2.4% H, 11.2% N;

found 41.9 « C, 2.4% H, 11.3% N.

Claims (6)

OBJECT OF THE INVENTION A fungicidal composition for the treatment of plants or seeds, characterized in that it contains, as an active ingredient, a triazole derivative of the general formula 1 OH I (i) N N-CH ₂ -C- (CF ₂ ) _n -CF ₃ I 'in which R is a phenyl group optionally substituted with one to three substituents independently selected from the group consisting of fluorine, chlorine, bromine and iodine and trifluoromethyl aq is 0, 1 or 2, or an agriculturally acceptable salt thereof, together with an agriculturally useful diluent, or carrier. 23S346 2. A process for the preparation of triazole derivatives of the general formula I according to claim 1 and their salts, characterized in that 1,2,4-triazole or its alkali metal salt is reacted with a compound of the general formula VI OH Hal-CH ₂ -C- (CF ₂ ) _n -CF ₃ (VI) wherein Ran has the meaning given above and Hal represents chlorine or bromine, whereupon optionally the resulting product of formula (I) is converted into its salt in a conventional manner. 3. The process of claim 2 wherein the reaction is carried out either using 1,2,4-triazole in the presence of a base or using 1,2,4-triazole sodium. 4. A process according to claim 3, wherein the base is potassium carbonate. 5. A process according to any one of Claims 2 to 4, wherein the corresponding starting materials are used to form compounds of the general formula: ## STR4 ## wherein R is 4-fluorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 2- fluoro-phenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2-fluoro-4-chlorophenyl, 2,5-difluorophenyl, 2,4,6-trifluorophenyl or 4-bromo-2,5- a difluorophenyl group of β and having a value of 0,1 or 2. 6. A process according to claim 2, wherein the corresponding starting materials are used to form compounds of formula (I) in which a is 0 and R is as in 1.