CS246089B2 - Fungicide for use in agriculture and method of efficient substances production - Google Patents

Description

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

Accordingly, the invention provides a process for the preparation of compounds of formula I comprising fluorine, chlorine, bromine and iodine atoms, and a trifluoromethyl group, and

R ^{1 * * * V} represents a radical of formula O OH

II I -C (CF2) _nCF3 or -CH (CF _{2) n} CF ₃

in which

R is a phenyl group optionally substituted with one to three substituents independently selected from the group consisting of n or 1, and pharmaceutically and agriculturally acceptable salts thereof.

The invention further provides a fungicidal composition for use in agriculture comprising, as an active ingredient, a compound of formula (I) or an agriculturally acceptable salt thereof, together with an agriculturally useful diluent or carrier.

Further described is a method of treating a fungus infested seed or plant, which comprises contacting the seed or plant, or a locus thereof, with an antifungal effective amount of a compound of formula I or an agriculturally useful salt thereof.

R is preferably a phenyl group bearing 1 to 3 substituents, more preferably 1 or 2 substituents independently selected from the group consisting of fluoro, chloro, bromo, iodo and trifluoromethyl SKU ^J pin. Thus, the symbol R represents in particular:

4-fluorophenyl,

4-chlorophenyl,

4-trifluoromethylphenyl, 2-fluorophenyl,

2,4-dichlorophenyl,

2,4-difluorophenyl,

2-fluoro-4-chlorophenyl,

2.5- difluo: a phenyl group,

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

Most preferably, R is:

2,4-difluorophenyl,

2,4-dichlorophenyl,

A 4-chlorophenyl group; or

4-fluorophenyl.

The hydroxyketones of formula I can be prepared by the general procedure of the following reaction scheme:

OH < ₂ &gt; -C-COQ

(lA)

In the formulas shown in this scheme, Ran is as defined in formula (I) and Q is (C 1 -C 4) alkoxy.

The anion CF3 (CF2), r is preferably obtained using the Grignard reagent CF3 (CF2) _n MgI or CF3 (CF2) _n MgBr, usually in the form of a mixture of both reagents prepared from compound CF3 (CF2j _n I and methylmagnesium bromide).

In accordance with a typical embodiment of this reaction, the iodide of formula CF3 (CF2 _n in a suitable solvent, for example, dry ether) is reacted with methylmagnesium bromide at a temperature between about -05 to -70 ° C. The compound of formula (II) is slowly added thereto while maintaining the temperature at -65 ° C or even lower, for example in dry ether.

The mixture was stirred at the above temperature for about 1 hour, then allowed to slowly warm to about -25 ° C, an aqueous ammonium chloride solution was added, the ether layer was separated and washed with water. The aqueous layer was extracted with ether, the combined ether extracts were dried over magnesium sulphate, evaporated and the residue chromatographed on silica gel in conventional manner to give the desired product.

The starting materials of the formula II can be prepared in a conventional manner, for example according to the following reaction scheme:

RMBr or

RLi

Br-CH 3 CCOOatk

OH er-CK-c-cootk-2,4-triazole Potassium carbonate, dimethylformamide up to 60 ° C

In the above formulas, alk is C 1 -C 4 alkyl.

Most preferably the ethyl ester is used in the reaction described above.

The diols of formula (I) may be prepared by reducing the ketones of formula (IA) by a conventional method. Sodium borohydride is preferably used as the reducing agent.

The compounds of the invention contain either one or two optical centers. In the case of compounds containing a single optical center, the invention includes both cleaved and uncleaved forms of the products.

In the case of compounds containing two optical centers, the invention includes both the resolved and non-resolved forms of the individual diastereomers.

Pharmaceutically useful addition salts of the compounds of formula (I) are those with strong acids forming non-toxic addition salts, such as hydrochlorides, hydrobromides, sulfates, oxalates and methaosulfonates.

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

The invention also includes alkali metal salts which are also prepared in conventional manner.

The compounds of formula I and their pharmaceutically acceptable salts are antifungal agents useful for combating fungal infections in animals, including humans. For example, the compounds may be used in human medicine to treat local fungal infections caused, inter alia, by Candida, Trichophyton, Microsporum or Epidermophyton, or to treat mucosal infections caused by Candida albicans (e.g. oral candidiasis and vaginal candidiasis).

The compounds may also be used to treat systemic fungal infections caused, for example, by Candida albicans, Cryptoicoccus neoformans, Aspergillus fumigatus, Coccidioides, Paracoccidioides, Histoplasma or Elastomyces.

The in vitro evaluation of the in vitro efficacy of the disclosed compounds can be carried out by determining the minimum inhibitory concentrations of the test compounds in a suitable environment without growth of the respective microorganism.

In practice, a series of agar plates, each containing the test compound at the appropriate concentration, are inoculated with a standard culture, such as Candida albicans, and all plates are then incubated at 37 ° C for 48 hours. On all boards, the lever is detected to grow, respectively. in the absence of fungal growth and the appropriate value of the minimum inhibitory concentration is calculated.

Other microorganisms useful for these assays include Cryptoicoccus neoformans, Aspergillus fumigatus, Trichophyton spp., Microsporum spp., Epidermophyton floccosum, Coccidioides immitis and Torulopsis glabrata.

The in vivo efficacy of the disclosed compounds can be evaluated by administering a series of different doses of the test compound to mice inoculated with Candida albicans by intraperitoneal or intravenous injection.

Efficacy is then calculated based on the number of surviving specimens of the test animals in the treated group after the death of the untreated mice. The observation period is 48 hours. The dose at which the test compound provides 50% protection against the total effect of infection (PDsoj.

For use 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 regard to the intended route of administration and standard pharmaceutical practice. For example, they can be administered orally in the form of tablets containing carriers, starch or lactose, or in the form of capsules or ovules in which they are contained alone or in admixture with carriers, or in the form of elixirs or suspensions containing flavoring agents. or dyes.

The disclosed compounds may be administered by parenteral injection, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, the disclosed compounds are best used in the form of a sterile aqueous solution which may contain other substances, such as salts or glucose, to render the solution isotonic.

For oral or parenteral administration in human medicine, the daily doses of the anti-fungal active compounds of formula I will range from 0.1 to 5 mg / kg, the total dose being administered in several divided doses.

Thus, tablets or capsules will contain from 5 mg to 0.5 g of the active ingredient and will be administered once, twice or more daily as appropriate. The appropriate dose, which will be most suitable for the patient and will vary depending on the patient's age, weight and response, will be determined by the attending physician.

The above dosage range is merely an example of an average case, and of course there will be individual cases where higher or lower doses are required. These cases are also within the scope of the invention.

Alternatively, the antifungal compounds of the invention may be administered in the form of suppositories or pessaries, or administered topically in the form of a lotion, solution, cream, ointment or powder. For example, the compounds may be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin, or may be incorporated at a concentration of between 1 and 10% into an ointment consisting of white wax or white soft paraffin, optionally together with stabilizers and preservatives.

The compounds of formula I and their salts are also active against a number of phytopathogenic fungi, including, for example, various rusts, mildews and molds, and the compounds described herein can therefore be used to treat plants and seeds for the treatment or prevention of such diseases.

Evaluation of the activity of the compounds of the invention against phytopathogenic fungi in yitro is performed by detecting their minimum inhibitory concentrations using the same procedure as above except that plates are incubated at 30 ° C for 48 hours or longer before assessing fungal growth. .

Microorganisms used in these tests include Cochliobolus carbonum, Pyrioularia oryzae, Glomerella clngulata,

AND

Active Substance Example No. H Pen

Penicillium digitatum, Botrytis cinerea and Rhizoctonia solani.

The following is the results of tests for the efficacy of the compounds of the invention against phytopathogenic fungi. The results are reported as the minimum inhibitory concentration (MIC) values for the following phytopathogenic organisms:

H = Helminthosporium

Pen = Penicillium

B = Botrytis

Py = Pyricularia

MIC (iug / ml)

B Py

0,4 3,1

25.0 50.0

3.1 12.5

12.5 50.0

For agricultural and horticultural applications, the compounds of the invention and their agriculturally useful salts are preferably used in the form of a composition adapted to the mode of application and the intended use. Thus, these compounds can be applied in the form of dusts, granules, seed dressings, aqueous solutions, dispersions or emulsions, sprays, aerosols or fumes.

The disclosed compounds can also be supplied in the form of dispersible powders, granules or grains, or concentrates to be diluted prior to application. Such compositions may also contain conventional carriers, diluents or excipients as known and used in agriculture and horticulture, and may be prepared by conventional techniques.

The disclosed compositions may also contain other active ingredients, for example compounds exhibiting herbicidal or insecticidal activity, or other fungicides.

The compounds of the invention and compositions containing them can be applied directly to the leaves, stems, branches, seeds or roots of plants, or to soil or other growth media, and can be used not only to treat disease but also prophylactically to protect plants or seeds from fungal infestation. .

The invention is illustrated by the following non-limiting examples.

ÍŘW

Example 1 (A) Preparation of 1- (ethoxycarbonyl) -1- (4-fluorophenyl) -2- (1H-1,2,4-triazol-1-yl) ethanol

OH 11 N-CH 2 C-COO C ₉ H _s

LU ^{2 2} g (0.29 mol) of p-fluorobromobenzene are reacted with 10 g (0.42 mol) of magnesium shavings in 200 ml of dry ether to form the Grignard reagent. The resulting Grignard reagent solution was added to a solution of 46.4 grams (0.24 mol) of ethyl bromopyruvate in 300 mL of dry ether and the resulting solution was cooled to -70 to -65 ° C for about 2 hours.

The reaction mixture was stirred at -70 ° C for 0.5 h, allowed to warm to -30 ° C over a further 0.5 h, while maintaining the temperature below 0 ° C, a solution of 100 g of ammonium chloride in 300 mL of water was added and the resulting mixture was allowed to warm to room temperature (20 ° C).

The ether layer was separated and the aqueous layer was extracted twice with 500 ml of ether each time. The combined ether phases were dried over magnesium sulfate and evaporated. The obtained crude intermediate (A) is reacted for about 4 hours with 50 g (0.72 mol) of 1,2,4-triazole and 100 g (0.72 mol) of anhydrous potassium carbonate in 300 ml of dry dimethylformamide at 50-60 ° C. Noc: 2 ° C.

The reaction mixture was allowed to cool to room temperature (20 ° C) and then 500 mL of ether was added. The ether layer was washed with 500 mL of water and the aqueous layer was extracted twice with 500 mL of ether each time. The combined ether fractions were washed three times with 200 ml of water each time, dried over magnesium sulphate and evaporated. The crude product, after chromatography on silica gel (230-400 mesh) using ethyl acetate as eluent, followed by trituration with petro ether (60-80 ° C), gave 20 g (yield 30%) of the title compound.

A small sample of the product was converted for characterization by reaction with methanesulfonic acid in dry ether followed by recrystallization from ethyl acetate to methanesulfonate, m.p. 142-144 ° C. Analysis: for C 13 H 14 FN 3 O 3. CH3SO3H calculated:

44.8% C, 4.8% H, 11.2 θ / ο N;

45.1% C, 4.9% H, 11.1% N.

(B) Preparation of 2-hydroxy-2- (4-fluorophenyl) -4,4,5,5,5-pentafluoro-1- (1H-1,2,4-triazol-1-yl) pentane-3- onu, / ·. *, iT '

OH

14

A flask containing 40 ml of dry ether cooled to -70 ° C, equipped with a solid carbon dioxide-cooled condenser, was charged with 5 g (0.02 mol) of pentafluoroethyl iodide gas and then added over 5 minutes maintaining the temperature between -70 and -65 In step C, 5.8 mL of a 3 M solution of methylmagnesium bromide (0.017 mol) was added.

The resulting mixture was stirred at -70 ° C for 0.5 h and then 1.3 g (0.0047 mol) of 1-ethoxycarbonyl-1- was added over 10 minutes while maintaining the temperature at -65 ° C or below. (4-Fluorophenyl) -2- (1H-1,2,4-triazol-1-yl) ethanol in 10 mL dry ether. The reaction mixture was stirred at -70 ° C for 1 hour, then allowed to warm to -25 ° C over 1.5 hours. A solution of 5 g of ammonium chloride in 30 ml of water was added.

The ether layer was separated and the aqueous phase was extracted twice more with 40 ml of ether each time. The ether layers were combined, dried (MgSO 4) and evaporated. The crude title compound was obtained as an oil which was purified by silica gel chromatography (230-400 mesh) eluting with ethyl acetate / petroleum ether (b.p. 60-80 ° C) 4: 1 (v / v) as eluent. . The product melts after recrystallization from cyclohexane at 128-132 ° C. For C13H9F6N3O2 calculated:

44.2% C, 2.6% H, 11.9% N;

found:

44.3% C, 2.6% H, 11.7% N. Examples 2-5

The following compounds were prepared from the appropriate starting materials in an analogous manner to that described in Parts (A) and (B) of Example 1:

OH

Example R R ¹ Temperature Analysis (%) number thaw found (° C) (calculated) C H

O

II-C (CF 2) 2 CF 3

41,6 2,2

130-133 (41.7 2.25

10.4

10.4)

O — CCF2CF3

O

II — CCF2CF3 cl o

II — CCF2CF3

Cl

42,0 2,2

147-150 (42.1 2.2

38,9 2,1

151-153 (38.6 2.0

42.0

100—101 (42.2

11.1

11.3)

10.5

10.4)

2,4 11,4

2,45 11,4)

246039

The ester starting materials prepared in the first step (Part A) were characterized in the following forms.

Ol-I

C HH ^C-COOCgHg

L = -4 A | R Melting point (° C) C Analysis (%) found (calculated) H

F

42.45

117-119 (42.75

4.3

4.4

10.6

10.7) characterized as the methanesulfonic acid salt

126 to 128

47.1 (47.3

4,0 12,8

4.0 12.7)

Whose

53.8 to 52 (52.8

5,2 14,0

4,8 14,2]

Legend:

*) Product prepared using 2,4-dichloroiodobenzene.

Example 6

Preparation of 2- (4-fluorophenyl) 4,4,5,5,5-pentafluoro-l- (lH-l, 2,4-triazol-l-yl) pentane-2,3-diol class; · ¹ ' ”- -

OH OH

0.2 g (0.00057 mol) of 2-hydroxy-2- (4-fluorophenyl) -4,4,5,5,5-pentafluoro-1- (1H-1,2,4-triazole-1) The solution is cooled in ice, 0.2 g (0.005 mol) of sodium borohydride is added and the mixture is stirred under ice-cooling for 1 hour. After addition of 10 ml of 2 N hydrochloric acid, the isopropylalcohol is evaporated off, the remaining solution is neutralized with dilute aqueous sodium hydrogen carbonate solution and extracted three times with 10 ml of methylene chloride each time.

The combined methylene chloride extracts were dried over magnesium sulphate and evaporated. The residue was chromatographed on silica gel (230-400 mesh) using ethyl acetate as eluent. 0.09 g of pure title compound is obtained, which after recrystallization from a mixture of ethyl acetate and petroilether (b.p. 60-80 ° C) melts at 165-168 ° C.

For C13H11F6N3O2 calculated:

% C, 43.95;% H, 11.8%; found:

44.2% C, 3.1% H, 11.9% N. Examples 7 to 9

In analogy to Example 6, the following compounds were prepared by reduction of the corresponding ketones with sodium borohydride:

L

-N

OH

Example R R ¹ Temperature Analysis (%) number thaw found (° C) (calculated)

C Η N

OH —CHCF2CF3

41.9

197—199 (41.8

2,5 11,2

2.7 11.3)

OH - CH (CF 2) 2 CF 3

41.4

145—148 (41.5

2,7 10,3

2.7 10.4)

38.4

200-203 (38.4

2,5 10,2

2.5 10.35)

In the above test, the PD 50 values (oral administration, 48 hours) were determined for the individual compounds of the Examples in Candida albicans infected mice.

The product PD 50 (mg / kg, oral) of example no

1 (B)

9

0.7

1.4 <1.0 <1.0 <1.0 <1.0 <1.0

3.1 <1.0

Claims (8)

SUBJECT Fungicidal composition for use in agriculture, characterized in that it contains, as an active ingredient, a compound of the formula I in which: R is phenyl optionally substituted with one to three substituents independently selected from fluoro, chloro, bromo and iodo, and trifluoromethyl; and R ¹ represents a radical of formula O OH II - —C— (CF2) _n CF3 or —CH (CF2) _n CF3 wherein n is a number of 1 or 2, or a salt thereof, and an agriculturally acceptable diluent or carrier. 2. A process for the preparation of the compounds of the formula I according to claim 1, and salts thereof, characterized in that the compound of the formula II ON - C Ηη € ~~ CO · 0 U i (h) in which R is as defined above and Q is C 1 -C 4 alkoxy, reacted with an anion of formula CF 3 (CF 2) n wherein n is as defined above to give a compound of formula I wherein R ¹ is a residue OF THE INVENTION O - C - (CF 2) _n CF 3, optionally followed by a compound of formula I wherein R ¹ is a residue O -C (CF 2) _n CF 3 is reduced to give a compound of formula I wherein R ¹ is -CH (OH) (CF 2) _n CF 3, or / and the resulting product of formula I is converted to its salt. 3. The process of claim 2, wherein the required anion of Formula 1 is obtained using CF3 (CF2) _n MgBr, CF3 (CF2) _n MgI, or a mixture thereof. 4. Method according to claim 3, characterized in that the application of the corresponding starting material, to give a compound of formula I wherein R ¹ denotes a group of formula -CO (CF2) _n CF3, and R and n are as defined above. 5. Method according to claim 3, characterized in that corresponding starting ilátky used as the reducing agent sodium borohydride, to give a compound of formula I wherein R ¹ denotes a group of formula -CH (OH) (CF3 CF2j _n wherein R and n are as defined above. 6. A process according to any one of claims 2 to 5, wherein the corresponding starting materials are used to form a compound of formula I wherein R is phenyl substituted by one or two substituents independently selected from fluoro, chloro , bromo, iodo and trifluoromethyl and R ¹ is as defined above. 7. A process according to claim 6, wherein the corresponding starting materials are used to form a compound of formula (I) wherein R is: 4-fluorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 2-fluorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2-fluoro-4-chlorophenyl, 2,5-difluorophenyl, 2,4,6-trifluorophenyl or 4-bromo-2,5-difluorophenyl and R ¹ is as defined above. 8. A process according to claim 7, wherein the corresponding starting materials are used to form a compound of formula (I) wherein R is: 4-chlorophenyl, 4-fluorophenyl, 2,4-dichlorophenyl; or 2,4-difluorophenyl and R ¹ is as defined above.