DD272405A5 - FUNGICIDAL AGENTS - Google Patents

Abstract

The invention relates to fungicidal compositions containing as active ingredient a 1-hydroxy-1-azolylmethyl-benzocycloalkene derivative of general formula II in which the substituents have the meaning given in the description. Formula II

Description

Field of application of the invention

The invention relates to fungicidal compositions containing i-hydroxy-i-azolylmethyl-benzocycloalkene derivatives as active ingredients.

Characteristic of the known state of the art

In GB-PS 2143523 A i-aryl-i-azolylmethyl-i ^ -dihydroisobenzofurane be described as fungicides in crop protection, jeodch not the compounds of the invention.

Object of the invention

The aim of the invention is to provide novel compounds with a broad spectrum of activity, in particular with antimycotic activity, which can be used in agriculture and for the treatment of fungal infections in the human and veterinary field.

-2- 272 405 Presentation of the Essence of the Invention

It has now been found that the compounds used according to the invention, which differ substantially from the abovementioned compounds by the nature of the ring system, have very good antimicrobial, in particular fungicidal and antifungal properties. They are therefore suitable for controlling fungi in humans, animals and plants. According to the invention, compounds of the general formula II are used

(II)

wherein

A is CH or N

к 1 or 2 means

η is 1,2 or 3

W is the atom necessary to complete a benzene, naphthalene or thiophene ring system, X is a radical> C (R ³ ) ₂ , and in the event that W necessitates the completion of a benzene or naphthalene ring system

Atoms also means oxygen or sulfur, R ¹ and R ^{2 are the} same or different and each is hydrogen, fluorine, chlorine, bromine, iodine, (C ₁ -Cg) -AlkVl, unbranched or

branched, unsubstituted or substituted by 1-9 fluorine or chlorine atoms, (Сз-С _в ) -СусІоаІкуІ, (C ₁ -Cg) -Aikoxy, o, cyano or nitro mean.

and in the event that at the same time W is the atom necessary to complete a benzene ring, R ^{1 is} also phenyl, phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, benzyl, benzyloxy or hydroxy, where the phenyl groups are unsubstituted or substituted by one or two substituents in these substituents may be substituted and these substituents are identical or different and in each case fluorine, chlorine, bromine, iodine, (C ₁ -C ₄ I-AIkYl branched or unbranched, unsubstituted or substituted by 1-9 fluorine or chlorine atoms, (Сз-С ₈ ) -СусІоаІкуІ, (C ₁ -C ₄ -alkoxy, (C ₁ -C ₄ -H-cyano), cyano or nitro, or R ¹ , R ² , if they are ortho-oriented, together form one (Сз-С5) -Alkylene chain and R ³ as a substituent of the chain - (CH ₂ K, or of X independently of one another is H or (C ₁ -Cg) -alkyl or two radicals R ³ , when they are bonded to the same carbon atom, a ( Qj-Cel alkylene chain as well as theirw stereoi and the salts thereof, with the proviso that the formula II does not denote the compounds 1-hydroxy-1- (azol-1-ylmethyl) -1,2,3,4-tetrahydronaphthalene, whereby under "azole" 1H- imidazole or 1,2,4-triazole.

The (C ₁ -C ₈ ) - or (C ₁ -C ₄ ) -alkyl groups which occur as substituents or in conjunction with other substituents may be unbranched or branched and, for example, the methyl, ethyl, propyl, 1-methyl ethyl, butyl, 2-methylpropyl, 1,1-dimethyl-ethyl, pentyl, hexyl, heptyl or octyl; the fluorine- or chlorine-substituted alkyl groups may be, for example, the trifluoromethyl, trichloromethyl, thiyl, tetrafluoroethyl or nonafluorobutyl group; the (Cj-Cgi-cycloalkyl groups may mean the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group.

The compounds of the formula II have at least one asymmetric C atom and can therefore occur as enantiomers and diastereomers. The invention includes both the use of the pure isomers and their mixtures. The mixtures of diastereomers can be separated into the components by conventional methods, for example by selective crystallization from suitable solvents or by chromatography on silica gel or alumina. Racemates can be separated into the enantiomers by customary methods, for example by salt formation with an optically active acid, separation of the diastereomeric salts and liberation of the pure enantiomers by means of a base.

The compounds of the formula II exhibit antimicrobial, in particular antifungal properties. They are therefore suitable for controlling fungi in humans and animals. By fungicidal and growth-regulating properties, they are also suitable as pesticides.

The present invention relates to the use of the compounds of formula II in the form of the free base or an acid addition salt or a physiologically hydrolyzable and acceptable derivative.

Examples of pharmaceutically acceptable salt-forming acids are inorganic acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, phosphoric acid or nitric acid or organic acids such as malonic acid, oxalic acid, gluconic acid, camphorsulfonic acid, benzenesulfonic acid, acetic acid, propionic acid or p-toluenesulfonic acid.

Suitable physiologically hydrolyzable and acceptable derivatives are, for example, derivatives derivatized on the hydroxy group which are hydrolyzable under physiological conditions to the free acids, which in turn are physiologically acceptable, ie. H. are not toxic at the necessary doses.

The compounds of the formula II can be prepared by reacting a compound of the formula (VI)

'Il / nit \

(Vl)

in which W, X, k, n, R ¹ , R ² and R ^{3 have} the abovementioned meanings, with a sulfur ylide of the formula (VII)

> s

• tt (O) ₁

ЦЬ S ·> * η

wherein ζ is 0 or 1,

to a compound of formula (VIII)

0th

R

and then the compound of the formula (VIII) with a compound of the formula (IX)

(IX)

wherein A has the meanings given above and Μ hydrogen, which means trimethylsilyl group or a metal equivalent, to give a compound of formula (II). For this purpose, in a first reaction step for preparing the compounds of the formula (VIII), a ketone of the formula (VI) in which R ¹ , R ² , R ³ , W, X, к and η have the meanings given above, with a sulfurylide of the formula (VII) in an inert solvent, preferably dimethyl sulfoxide, or in mixtures of dimethyl sulfoxide with other inert solvents, e.g. B. tetrahydrofuran reacted. When using a sulfur ylide of formula (VII), for which ζ = 0, a temperature range between -10 ° and 50 ° C, preferably between 0 ° and 30 ⁰ C is appropriate. When using a sulfur ylide of formula (VII), for which ζ = 1, a temperature range between 0 ° and 80 °, preferably between 20 ° and 50 °.

The ketones of the formula (VI) or the sulfur ylides (VII) are prepared by methods described in the literature. Thus, for example, the compounds (VI) are synthesized as described in Org. Synth. Coll. Vol. IV p. 898 or loc. cit. Vol. IIS. 569 produced. The conversion of the intermediates of the formula (VIII) into the end products of the formula (II) is carried out in a second reaction step by reaction with a compound of the formula (IX) in which A and M have the meanings given above, in an inert solvent, for , B. N, N-dimethylformamide, Ν, Ν-dimethylacetamide, dimethyl sulfoxide, acetonitrile, benzonitrile, sulfolane, N-methylpyrrolidone, dioxane or tetrahydrofuran, in a temperature range between 20 ° C and 150 ⁰ C. The compound (IX) can be in Form of an alkali or alkaline earth metal salt, preferably as the sodium salt, or in the form of the free base in the presence of a strong base, are reacted. Suitable bases are, for. As alkali or alkaline earth metal hydrides, amides or alkoxides.

The second reaction step can also be carried out by reacting the compound of formula (VIII) with imidazole or triazole in equivalent amounts, or with imidazole or triazole in excess, without solvents in a temperature range of 90-160 ° C.

The process described above can be conveniently carried out as a one-pot process by reacting a compound of formula (Vl) with a sulfurylide of formula (VII) as described above to give a compound of formula (VIII) and then without working up the reaction mixture and without Isolation of the compound of formula (VIII) by adding a compound of formula (IX) to the reaction mixture to give a compound of formula (II) and isolating them in the form of the free base or an acid addition salt or a physiologically hydrolyzable and acceptable derivative.

The compounds of the formula II according to the invention are distinguished by an outstanding fungicidal action

phytopathogenic fungi. Even fungal pathogens already infiltrated into the plant tissue can be successfully controlled successfully. This is particularly important and advantageous in those fungal diseases that can no longer be effectively controlled after infection with the usual fungicides. The spectrum of action of the new

Compounds detected a variety of different phytopathogenic fungi, such. B. Piricularia oryzae, Pellicularia sasakii,

various types of rust, but especially Venturia inaequalis, Cercospora species and powdery mildew fungi in fruit, vegetable,

Cereal and ornamental plants. The novel compounds can be used as wettable powders, emulsifiable concentrates, sprayable solutions, dusts, mordants, Dispersions, granules or microgranules are used in the usual preparations. Injection powders are understood in water to be uniformly dispersible preparations, in addition to the active ingredient except

optionally a diluent or inert or wetting agent, for. As polyoxethylated alkylphenols, polyoxethylated

Fatty alcohols, alkyl or alkyl phenyl sulfonates and dispersants e.g. Sodium lignosulfonate, 2,2'-dinaphthylmethane

β, β'-disulfonic acid sodium, dibutylnaphthalene-sulfonic acid sodium or oleoylmethyltaurine acid.

Their preparation is carried out in the usual manner, for. B. by grinding and mixing of the components. Emulsifiable concentrates may, for. B. by dissolving the active ingredient in an inert organic solvent, for. B. butanol, Cyclohexanone, dimethylformamide, xylene or higher-boiling aromatics or hydrocarbons with the addition of

one or more emulsifiers are produced. In the case of liquid active substances, the proportion of solvent can also be omitted completely or partially. Examples of emulsifiers which can be used are: alkylarylsulfonic acid calcium salts, such as cadodecylbenzenesulfonate, or nonionic emulsifiers, such as fatty acid polyglycol esters, alkylaryl polyglycol ethers,

Fatty alcohol polyglylene ethers, propylene oxide-ethylene oxide condensation products, fatty alcohol-propylene oxide-ethylene oxide Condensation products, alkylpolyglycol ethers, sorbitan fatty acid esters, polyoxethylenesorbitan fatty acid esters or Polyoxethylensorbitester. Dusts are obtained by grinding the active substance with finely divided, solid substances, eg. As talc, natural clays like Kaolin, bentonite, pyrophillite or diatomaceous earth obtained. Granules can be prepared either by spraying the active ingredient onto adsorptive, granulated inert material

or by applying active ingredient concentrates by means of binders, for. As polyvinyl alcohol, polyacrylic acid sodium or mineral oils on the surface of carriers such as sand, kaolinite or granulated inert material. Also, suitable active ingredients may be used in the manner customary for the production of fertilizer granules, if desired

Mixture with fertilizers, be granulated. In wettable powders, the active ingredient concentration is ζ. B. about 10-90 wt .-%, the remainder to 100 wt .-% consists of conventional Formulation components. For emulsifiable concentrates, the active ingredient concentration may be about 10-80% by weight of active ingredient,

for sprayable solutions about 1-20Gew .-% amount. In the case of granules, the active ingredient content depends, in part, on whether the active compound is liquid or solid and which granulating aids, fillers, etc. are used.

In addition, the active substance formulations mentioned optionally contain the customary adhesive, wetting, dispersing, Emulsifiers, penetrants, solvents, fillers or carriers. For use, the present in commercial form concentrates are optionally diluted in a conventional manner, for. B.

for wettable powders, emulsifiable concentrates, dispersions and sometimes also for microgranules by means of water.

Dusty and granulated preparations and sprayable solutions are usually not before use

more diluted with other inert substances.

Depending on the indication, the required application rates can vary within wide limits and also vary within Dependence on external factors such as soil conditions, climatic conditions. In general, the dose levels are

between 0.01 and 10 kg of active ingredient per ha, in particular between 0.15 and 1.0 kg per ha.

Also, mixtures or blends with other agents, e.g. Insecticides, acaricides, herbicides, Fertilizers, growth regulators or other fungicides may be possible, with u. U. also synergistic Increases in impact can be achieved. In the following, some formulation examples are given: A dusting agent is obtained by mixing 10 parts by weight of active compound and 90 parts by weight of talc as inert material and mixing in

crushed a hammer mill.

A wettable powder readily dispersible in water is obtained by adding 25 parts by weight of active compound, 65 parts by weight

quaternary quartz as an inert material, 10 parts by weight of lignosulfonic acid potassium and 1 part by weight of oleoylmethyltaurine acid

Mix sodium as wetting and dispersing agent and grind in a pin mill. A dispersion concentrate readily dispersible in water is prepared by adding 20 parts by weight of active compound

6 parts by weight of alkylphenol polyglycol ether (Triton X 207), 3 parts by weight of isotridecanol polyglycol ether (8 AeO) and 71 parts by weight of paraffinic mineral oil (boiling range eg about 255 to over 377 ° C) and ground to a fineness below 5 microns in a ball mill.

An emulsifiable concentrate can be prepared from 15 parts by weight of active compound, 75 parts by weight of cyclohexanone as Solvent and 10 parts by weight of ethoxylated nonylphenyl (10AeO) as an emulsifier. embodiment The following examples serve to illustrate the invention without limiting it. Example A

4-methyl-1- (1H-imidazol-1-ylmethyl) indan-1-OI

To a similar to Example 22 of 6.4 g (0.21 mol) of sodium hydride (80% in oil) and 50.9 (0.23 mol) Trimethylsuifoxoniumjodid prepared in 250ml of dry dimethyl sulfoxide solution of Dimethylsulfoxoniommethylid gave a solution of 26.0g (0.18 mole) of 4-methyl-indan-1-one (example AD in 170ml of dry tetrahydrofuran. the mixture was stirred 1 h at room temperature and 1 h at 5O ⁰ C. 16.2 (0.18 mol were at this temperature, ) of imidazole sodium salt and 12.2 g (0.18 mol) of imidazole was added. the mixture was stirred an additional hour at 50 ⁰ C and 3 h at 80 ⁰ C. the procedure was analogous to example 33. This gave 17.8 g of colorless crystals (43, 8% of theory). F .: 155-157 ° C

Example A1 4-methyl-indan-1-one

a) 2-methylcinnamic acid was hydrogenated on palladium / carbon and the resulting 3- (2-methylphenyl) propionic acid (mp 97-98 ⁰ C) with thionyl chloride into the acid chloride (bp: 125 ° C / 20mm).

b) To a suspension of 40.0 g (0.3 mol) of aluminum trichloride in a mixture of 200 ml of carbon disulfide and 100 ml of 1,2-dichloroethane was added dropwise with vigorous stirring at a temperature of 20 ⁰ C 50.6 g (0.28 mol ) 3- (2-methylphenyl) -propionic acid chloride. The mixture was stirred for 6 h at room temperature, poured onto ice and concentrated with conc. Hydrochloric acid strongly acidic. The organic phase was dried and concentrated. The crude product was recrystallized from ethanol. 26.8 g (66.2% of theory) of yellow crystals were obtained.

Mp .: 103-104 ⁰ C

Example B

1- (1H-imidazol-1-ylmethyl) -3,3-dimethyl-indan-1-ol

To a solution of dimethylsulfoxonium methylide prepared from 6.5 g of sodium hydride (80% in oil) and 50.0 g (0.23 mol) of trimethylsulfoxonium iodide in 300 ml of dry dimethylsulfoxide was added a solution of 32.0 g (0.20 mol) of 3 , 3-Dimethylindan-1-one prepared from S-methyl-S-phenylbutyric acid (J. Amer. Chem. Soc., 76, 1911 [1954] by conversion to the acid chloride and cyclization with aluminum chloride in 100 ml of dry dimethylsulfoxide h at room temperature and 2 h at 50 ° C. After addition of 14.0 g (0.2 mol) of imidazole and 18.0 g (0.2 mol) of imidazole sodium salt, a further 2 h at 50 ° C and 2 h at 70 ⁰ C. After cooling, stirred (41% of theory..) was poured onto ice, neutralized with dry ice and filtered off with suction the precipitated product. for purification, the crude product was heated with Essigester. this gave 20.0 g of colorless crystals.

table

Verb.-Nr.

R ¹

Fp ⁰ C

1 2 3 4 5 6 7 8 9 10

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH ₂ 1 S 2 CH ₂ 3 CHZ 3 CH ₂ 1 CH ₂ 1 CH ₂ 1 CH ₂ 1 CH ₂ 1 CH ₂ 1

3-CI

3-F

2-F

4-F

3-CH ₃

4-CH ₃

4-CI

129-130 162-163 164-165 108-109 164-165 148-149 144-146 175-176 149-151 152-154

CH

CH ₂

136-138

CH

CH ₂

172 (hydrochloride)

13 CH 14 CH 15 CH 16 CH 17 CH 18 CH 19 CH 20 CH 21 CH 22 CH 23 CH 24 CH 25 CH 26 CH 27 CH 28 N 29 CH 30 N 31 CH 32 N 33 CH 34 N 35 CH 36 N 37 CH 38 N * see example A

CH ₂ 1 CH ₂ 1 CH ₂ 2 CH ₂ 2 CH ₂ 2 CH ₂ 2 CH ₂ 1 CH ₂ 2 CH ₂ 2 CH ₂ 2 CH ₂ 2 CH ₂ 2 CH ₂ 2 CH ₂ 2 O 3 O 3 O 3 O 3 O 3 O 3 O 3 0 3 S 3 S 3 S 3 S 3

2-CH ₃

5-CH ₃

2-CH ₃

2-CI

3-CI

2-F

2-0-C ₆ H ₅

4-0-C ₆ H ₅

3-0-C ₆ H ₆

4-SC ₆ H ₅

3-F

3-OCH ₃

4-OCH ₃

1-0CH ₃

4-CI

4-CI

3-CI

3-CI

4-F

4-F

4-CI

4-CI

4-CH ₃

4-CI

4-CI

155-157 *

149-150

190-191

163-165

159-160

resin

119-121

138-139

131-133

162-165

158-159

161-162

143-145

Compounds of the formula II in which W denotes the C atoms required to complete a naphthalene, tetrahydronaphthalene or thiophene ring system.

No. 39 fp. 177-178 ⁰ C

HO

HIGH,

Mp 184-186 ° C mp 153-155 ° C

но

Mp 205-210 ⁰ C

Mp 142-144 ⁰ C

45 HO

CH-mp. 140-142 ⁰ C

Mp 163-165 ⁰ C

НО

Cl

Biological examples

Plant protection experiment I

Wheat plants are heavily inoculated in the 3-Batt stage with conidia of wheat powdery mildew (Erysiphe graminis) and placed in a greenhouse at 20 ° C and a relative humidity of 90-95%. 3 days after inoculation, the plants are evenly wetted with the compounds listed in Table 6 in the indicated drug concentrations. After an incubation period of 10 days, the plants are examined for infestation with wheat powdery mildew. The level of infestation is expressed in% of infected leaf area, based on untreated, infected control plants (= 100% infestation). The result is summarized in Table 2.

Table 2 Connection no. leaf area affected by wheat powdery mildew in% at mg active substance / liter spray mixture 500 250 125 60 0-3 0 3 0-3 42 (Table 1) 10 (Table 1) 0 0 0 0 100 untreated, infected plants

Try Il

Cucumber plants (variety Delikateß) are strongly inoculated in the 2-leaf stage with a conidia suspension of cucumber powdery mildew (Erysiphe cichoracearum). After a drying time of the spore suspension of 30 minutes, the plants are placed in a greenhouse at 22 ⁰ C and 90% relative humidity.

3 days after infection, the plants with the compound mentioned in Table 3 and drug concentration are wetted dripping wet evenly. After 10 days, the rating is done. The level of infestation is expressed in% of infected leaf area, based on untreated, infected control plants (= 100% infestation). The result is summarized in Table 3.

Table 3

Com. with cucumber powdery mildew affected leaf area in%

mg active ingredient / liter spray mixture 500 250 125 60

10 (Tab.1) 0 0 0 0

untreated,

infected

Plants 100

Trial III

Apple pads (BM IX) were uniformly wetted at the 4-leaf stage with the claimed compound at the concentration of use given in Table 4. After the active ingredient coating had dried on, the plants were strongly infected with conidia of the apple scab (Venturia inaequalis) and placed in a drip-wet climate chamber whose temperature was 22 ° C. and whose relative humidity was 100%. After an infection time of 48 hours, the plants came into a greenhouse with 18 ° C and a relative humidity of 95-100%.

After an incubation period of 14 days, the plants were examined for infestation with apple scab (Venturia inaequalis). The assessment of the infestation was done as usual by inspection. The degree of infestation of the plants with apple scab was expressed in% of infected leaf area relative to untreated, infected plants and is shown in Table 4.

Table 4

Com. % Scab infestation at mg active substance / l spray mixture 500 250 125 60

42 (Table 1) 0 0 0 0-3

untreated,

infected

Plants 100

Trial IV

Biomalzagar was added to the claimed compounds in the concentrations indicated in Table 5. After solidification of the agar, inoculation was carried out with Pseudocercosporella cultures. Each 20 μl of a spore suspension was applied to the center of the agar plate. The experiments were evaluated 6 days after inoculation. The efficiency of the active ingredients is expressed in% compared to the control (agar medium without active substance).

Table 5

Connection efficiency over pseudo-

cercosporella herpotrichoides in% at ppm active ingredient

No. 500 250 125 10 (Tab.1) 11 (Tab.1) 100 100 100 100 100 100 control 100

Claims (2)

1. Fungicidal agent, characterized by a content of a 1-hydroxy-i-azolylmethylbenzocycloalkene derivative of the general formula II он R ¹ (ID wherein A is CH or N к 1 or 2 means η is 1,2 or 3 W necessary to complete a benzene, naphthalene or thiophene ring system Atoms means
X is a radical> C (R ³ ) ₂ , as well as in the event that W to complete a benzene or Naphthalene ring system necessary atoms, also oxygen or sulfur, R ¹ and R ^{2 are} gjeich or different and in each case hydrogen, fluorine, chlorine, bromine, iodine, (Ci-C ₈ ) alkyl, unbranched or branched, unsubstituted or with 1-9 fluorine or chlorine atoms substituted (Сз _{С-8) 1} -C ₈ J -alkoxy, (C mean -СусІоаІкуІ, (C ₁ -Ce) -alkylthio, cyano or nitro, as well as in the event that W at the same time means the necessary to complete a benzene ring atoms, R ^{1 is} also phenyl, phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, benzyl, benzyloxy or hydroxy, where the phenyl groups in these substituents may be unsubstituted or substituted by one or two substituents and these substituents are the same or different and each is fluoro, chloro, bromo , Iodine, (C ₁ -C ₄ ) -alkyl, branched or unbranched, unsubstituted or substituted by 1-9 fluorine or chlorine atoms, (Сз-С ₈ ) -СусІоаІкуІ, (C ₁ -C ₄ ) -alkoxy, (G , -C ₄ ) -Alkylthio, cyano or nitro, or R ¹ , R ² , if they are ortho-oriented, together represent a (C ₃ -Cs) alkylene chain and R ³ as a substituent of the chain (CH ₂ ) n or X independently of one another is H or (C ₁ -C 6) -alkyl or two R ³ radicals, when bonded to the same carbon atom, denote a (C 2 -C ₆ ) -alkylene chain, and their stereoisomers and their salts, with the restriction that the general formula II is not the compounds 1-hydroxy-1 - (azol-1-ylmethyl) -1,2,3,4-tetrahydronaphthalene, wherein "azole" 1H-imidazole or 1,2,4-triazole is to be understood, in addition to customary extenders and / or formulation auxiliaries. 2. Use of a compound of general formula II according to claim 1, characterized in that it is used as a fungicide.