IE52852B1 - Antimicrobial imidazole derivatives - Google Patents

Description

This invention relates to antimicrobial imidazole derivatives, processes for their preparation and compositions containing them.

Ketal derivatives of 1-(2-aryl-2-oxoethyl)-lH-imidazoles are disclosed, inter alia, in the following references: U.S.Pat. No. 3,575,999; and U.S.Pat. No. 4.079.062.

D.O.S. No. 2,604,487, in the broadest meaning of its scope, theoretically embraces dithioketals of 1 -(2-aryl-2 -oxoethyl)-1££10 imidazoles or possible starting materials for the preparation of metal salt complexes with antifungal activity. Nowhere in said reference is there any description or any other indication of particular dithioketals.

The compounds of the present invention are nowhere disclosed in the prior art and are deemed to be novel.

The present invention provides a series of dithiaketal derivatives of 1-(2-oxo-2-phenylethyl)-lH.-imidazoles and the corresponding sulfones and sulfoxides thereof, being represented by the formula (I). the possible stereoehemically isomeric forms, 52S5S - 3 the acid addition salts and the metal salt complexes thereof, wherein; Rj and R^ are each independently selected from hydrogen, halo and methyl; Rj and R^ are each independently selected from C^-C^-alkyl and C3~C^- alkenyl, or R3 and R4 form, together with the sulfur atoms to which they are attached and the bridging carbon atom, a 5-,6-or 7-membered ring which is optionally substituted with 1 to 4 C^-C^alkyl groups; R3 is selected from hydrogen, C^-Cj-alkyl, 2-propenyl and 2-propynyl; and n is Ο, 1 or 2.

As used in the foregoing and in the following definitions, halo is generic to fluoro, chloro, bromo and iodo; alkyl is meant to include straight and branched hydrocarbon radicals having a number of carbon atoms within the indicated limits, such as, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, I-methylpropyl, 2-methylpropyl and 1, l-dimethylethyl for C^-G^-alkyl and, for C^-Calkyl the foregoing plus the different isomers of pentyl and hexyl.

Preferred compounds within the scope of formula (I) are those wherein R^ is hydrogen or chloro and Rj is chloro. .

Particularly preferred are compounds of formula (I) wherein Rj is hydrogen or chloro, R^ is chloro and Rj and Κ·4 together with the sulfur atoms to which they are attached and the bridging carbon atom form a 5-or 6-membered ring which is optionally substituted with a C^Cj- alkyl radical.

Especially preferred are compounds of formula (I) wherein Rj is hydrogen or chloro, R^ is chloro, Rj and R^ together with the sulfur atoms to which they are attached and the bridging carbon atom form a 5* or 6-membered ring which is optionally substituted with a C^Cj- alkyl radical and Rg is hydrogen or Cj-C^-alkyl. 52853 - 4 More especially preferred are compounds of formula (I) wherein Rj is hydrogen or chloro, Rj is chloro, R^ and R^ together with the sulfur atoms to which they are attached and the bridging carbon atom form a 5- or 6-membered ring which is optionally substituted with a -C^- alkyl radical and R^ is hydrogen.

Most especially preferred are compounds of formula (I) wherein R^ and are both chloro, Rj and R^ together with the sulfur atoms to which they are attached and the bridging carbon atom form a 5-membered ring which is optionally substituted with a methyl, ethyl or propyl group and R„ is hydrogen.

Preferred species within the scope of formula (1) are the following: -(2,4-iichlorophenyl)-l, 3-dithiolan-2 -yl/methy^-lH.15 imidazole; -//2-(2, 4-dichloropheayl) -4 -methyl-1,3 -dithiolan-2 -yl/methyl/-lH-imidazole; -££. -(2,4-dichlorophenyl) -4-ethyl-l, 3 -dithiolan-2 -yl7methyl/ Iff-imidazole; 1 -2Z2-{2,4-dichlorophenyl)-4-propyl-l, 3 -dithiolan-2-yl/methyl/-ΙΙϊ-imidazole; and 1-/1-/2-(2,4-dichlorophenyl)-1,3-dithiolan-2-yl/ethyl/-lH imidazole.

The compounds of formula (I) wherein n is 0, said compounds being represented by the formula (I-a) may be prepared by subjecting an appropriate ketone of the formula 5 (Π) wherein R^, R2 and Rg are as defined in formula (I), or an appropriate ketal derivative thereof to a thioketalization reaction with appropriate thiols of the formulae R -SH, and R„-SH 4 (HI) (XV) or a dithiol of the formula HS-R,-R.-SH 3 4 (V) wherein R, and R . are as defined in formula (I). 4 '52853 - 6 The said thioketalization reaction, is advantageously carried out in the presence of an appropriate Lewis acid, and, unless the acid itself has suitable solvent properties, preferably in an appropriate reaction-inert organic solvent.

Suitable Lewis acids which may be used in the above procedure include strong protonic acids, e.g. sulfonic acids such as me thane sulfonic, benzene sulfonic and. 4-methylbenzenesulfonic acid, and non-protonic Lewis acids such as, for example, aluminum chloride, zinc chloride and tin chloride.

IQ Appropriate solvents include, for example, aliphatic and aromatic hydrocarbons, e.g. hexane, cyclohexane, heptane, benzene, methylbenzene and dimethylbenzene; chlorinated hydrocarbons such as, for example,di-, tri-and tetrachloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, and tetrachloroethene; and ethers such as tetrahydrofuran and 1,4-dioxane. hi order to enhance the reaction rate, particularly when a protonic acid is used, there may be added to the reaction mixture an appropriate tri(lower alkyloxy)methane, preferably 1,1l-^methylidynetris(oxy]7trls(eNiane).

Elevated temperatures are advantageous and,preferably, the reaction go is carried out at the reflux temperature of the reaction mixture.

Ketal derivatives of the ketones (Π) which may be used as starting materials include di-lower alkylketals, such as the dimethyl-, diethyl-, dipropyl- and dibutyl ketals and cyclic ketals such as the dioxolane ketals derived from ethanediol.

The compounds of formula (i) wherein n is 1 or 2, said compounds being represented by the formulae (I-b) and (I-c) , respectively, can be derived from the corresponding (Γ-a) by oxidizing the latter with an appropriate oxidizing agent. By appropriately selecting the oxidizing agent and the reaction circumstances either sulfones or sulfoxides can 5Q be obtained substantially free from the other. - 7 Appropriate oxidizing agents include, for example, periodates, e.g., sodium periodate and potassium periodate; peroxides, e.g., hydrogen peroxide; and peracids, e.g. perbenzoic acid and preferably 3-chloroperbenzoic acid. These oxidation reactions may be carried out by methodologies which are well-known in the art.

The ketones of formula (Π) and the corresponding ketals which are used-as starting materials are well-known. Such compounds are described for example in: Patent Specification No. Yifti.yY'.

Patent Specification No, '·.·* +\'r .

IQ Patent Specification Mo. 44283.

The thiols of formulae (HI), (IV) and (V) are generally known and may all be prepared by the application of art-known methodologies.

It is obvious from formula (I) that the compounds of the present invention may possibly exist under different stereochemically isomeric forms.

Whenever n is the integer 1 or 2 and/or R^ and R^ are not identical or form an alkylene radical which is unsymmetrically substituted, the carbon atom bearing the two sulfur atoms is an asymmetrically substituted carbon atom. Additional chiral centres may exist in R^ and R^ and when Rg is other than hydrogen. Each of these chiral centres may exist inanR- and S-configuration, this R- and S-notation being in correspondence with the rules described by R.S. Cahn, C. Ingold and V.

Prelog in Angew, Chem., Int. Ed. Engl., 385-511 (1966).

Pure stereochemically isomeric forms of the compounds of formula (I) may be obtained by the application of art-known procedures. Diastereoisomers may be separated by physical separation methods such as selective crystallization and chromatography techniques, e.g., counter current distribution, and enantiomers may be separated from each other by the selective crystallization of their diastereoisomeric salts with optically active acids.

Pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Stereochemically isomeric forms of the compounds of formula (I) are naturally intended to be embraced within the scope of the invention. - 8 In view of their basic properties, the compounds of formula (I) may be converted into their acid addition salt forms by reacting them with appropriate acids such as, for example, inorganic acids, e.g., hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric,5 phosphonic,or nitric acid, or organic acids, e.g., acetic, propanoic, hydroxyacetie, 2-hydroxypropanoic, 2-oxopr opanoic, ethanedioic, propanedioic, butanedioic, (Z)-2-hutenedioic, (£)-2butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2hydroxy-1,2,3-propanetricarboxylic, benzoic, 3 -phenyl-2-propenoic, a -hydroxybenzeneacetic, methanesulfonic, ethane sulfonic,' hydroxyethane sulfonic, 4-methylbenzene sulfonic, 2-hydroxybenzoic, 4-amino 2-hydroxybenzoic, 2-phenoxybenzoic, 2-acetyloxybenzoic, 2,4-hexadienoic or 1,5-naphthalenedicarboxylic acid.

Metal salt complexes of formula (I) may be obtained by the complexation-r eaction of an Imidazole of formula (I) with an organic or inorganic metal salt such as, for example, hydrohalides, nitrates, sulfates, phosphates, and 2,3-dihydxo^butanedioates of, for example, copper, manganese, zinc, and.- iron, which may be present in each of their possible valencies.

Stoichiometrically defined metal salt complexes may be prepared by dissolving a compound of formula (I) in a water-miscible solvent (e.g. warm ethanol, methanol, 1,4-dioxane or N,N_-dimethylformamide) and adding thereto an aqueous solution of the desired metal salts such as, for example, CuSO^. 5H^O, or FeClg. 6H2O.

The foregoing enumerations are intended to illustrate and not to limit the scope of the present invention. - 9 The compounds of formula (I) and the acid addition salts and metal salt complexes have potent antimicrobial, in particular antifungal, properties and as such they can be used for combating the growth of microorganisms in and/or on living and non-living materials of any nature.

Particularly, the compounds of formula (I) possess a very advantageous antimicrobial spectrum, rendering them useful for the protection of crops without causing undesired side-reactions.

Examples of crops within the scope of this invention are the following: cereals, maize, rice, vegetables, sugar-beet, soybeans, ground-nuts, fruit-trees, ornamentals, grapevines, hops, cucurbitaceae (gherkins, cucumbers, melons), solanaceae such as potatoes, tobacco and tomatoes, as well as bananas, cocoa and rubber.

The compounds of formula (I) can be used to reduce or des1 □ troy fungal growth on plants of these or related crops or on parts of such plants (e.g., fruits, blossoms, foliage, stems, tubers, roots), whereby the newly outgrowing parts of such plants are also protected against fungal attack. The compounds of this invention are active against phytopathogenic fungi, belonging to the following classes: Ascomycetes (e.g. Erysiphaceae, Fusarium, Helminthosporium); Basidiomycetes such as particularly rust-fungi ( e.g., Puccinia); Fungi imperfecti (e.g., Moniliales, Cercospora and Botrytis) and Oomycetes belonging to the class of the Phycomycetes such as, for example, Phytophthora and Plasmopara. They can further be used as seed-dressings for the treatment of seed (e.g. fruits, tubers, grains) and cuttings to protect them from fungal infection, and against fungi occurring in the soil.

The compounds of formula (1) can be used alone or in admixture with appropriate carriers and/or additives. Appropriate carriers and additives can be solid or fluid and are generally known in the art of formulating, such as, for example, natural and regenerated mineral substances, solvents, dispersants, wetting agents, adhesives, thickeners, binders or fertilizers. - 10 The concentration of the active ingredient in commercial preparations can vary from about 0.1 to 90%.

For their application the compounds of formula (I) can be formulated in the following composition-forms (whereby suitable concentrations of the active ingredient are indicated within brackets): solid compositions : dusts (up to 10%), granulates, coated granulates, impregnated granulates and homogeneous granulates, pellets (from 1 to 80% ); liquid compositions: a) water-dispersible concentrates: wettable powders and pastes (25-90% in commercial form, 0.01-15% in the IS ready for use solution): emulsion- and solution-concentrates (10-50%; 0.0115% in ready for use solution); h) solutions (0.1-20%); aerosols.

If desired, in order to extend their spectrum of activity the compounds of formula (I) may he combined with other appropriate pesticides such as, for example, fungicides, bactericides, insecticides, acaricides, herbicides and plant-growth regulators.

Such compositions are intended to he within the scope of the present invention.

The content of active substance in the above agents is from 0.1 to 95%, preferably from 1 to 80%. The forms may be diluted from this concentration down to 0.001% . The employed doses are ia general from 0.01 to 10 kg of active substance per ha, preferably from 0. 025 to 5 kg/ha. - 11 Due to their broad antifungal spectrum the compounds of formula (I) are especially useful as seed-dressings, in the preservation of human and animal feeding stuffs, in particular animal fodder, and, generally, in the protection of non-living materials such as, for example, coatings, e.g., oil paints, dispersion paints, lacquers, whitewash; wood, e.g., timber,lumber, railway sleepers, telephonepoles, fences, wood coverings, wicker-work, plywood, particle board, clipboard, joinery, bridges or wood products which are generally used in housebuilding, or pulp wood used in paper manufacture; textiles, e.g., carpets, canvas, awnings, fishing nets, ropes and packing materials; and other materials of diverse nature such as, for example joint fillings of tile walls, tiles in polymeric materials, paper-hangings, hides, leather, artificial leather, bath carpets, shower curtains, technical devices in plastic, glues, mortar as well as walls which are penetrated or fouled by organic materials, cutting oils and fuel oils.

The materials which are treated with agents according to the invention are protected from moulding, rotting, loss of their useful mechanical properties such as breaking strength, resistance to shock and shearing strenght; or decay of their optical or other useful properties such as the occurrence of odour,staining, spot formation and dote caused by the following microorganisms; Aspergillus species, Penicillium species, Verticillium species, Alternaria species, Rhizopus species, Mucor species, Paecelomyces species, Saccharomyces species, Trichoderma viride, Chaetomiura globosum, Stachybotrys atra, Myrothecium verrucaria, Oospora lactis and other woodrot and wood decay fungi.

Special emphasis should be led on the good activity against moulds such as Aspergillus niger, Penicillium funiculosum, Trichoderma viride, Alternaria alternata, fungi such as Chaetomium globosum, Trychophyton mentagrophytes, Coriolus versicolor, Coniophora cerebella, Poria monticola, Merulius (Serpula) lacrymans and Lenzites trabea, and yeasts such as Candida albicans and Saccharomyces species. - 12 The compounds of formula (I) may be used in agents according to the present invention on their own or in combination with appropriate carriers and/or other additives. Appropriate carriers and additives can be solid or liquid and correspond to the substances usually used 5 in formulation techniques such as natural or regenerated inorganic substances, solvents, dispersants, emulsifiers, wetting agents, adhesion agents, thickeners or binding agents.

The compounds of formula (1) show good solubility in organic solvents and in driving gases for aerosols. The lack of colour and odour of the compounds of formula (I) is in this connection of great practical value.

The following Examples are intended to illustrate and not to limit the scope of the present invention. Unless otherwise indicated all parts therein are by weight. - 13 A. Examples of chemical preparation: Example I A mixture of 1 part of 4-methylbenzene sulfonic acid and 90 parts of dimethylbenzene was distilled azeotropically to dry.

Then there were added 5 parts of 1-//-(2,4-dichlorophenyl)-2,2-dimethoxyethyl7-lH-£midazole 4-methylbenzenesulfonate, 4.7 parts of 1,2-ethanedithiol and 1.5 parts of 1,11,1 -/methylidynetrisfoxyj/trisethane and the whole was stirred and refluxed for 8 days with water-separator. The reaction mixture was cooled and stirred with a sodium hydroxide solution 20%. The whole was poured onto water and the product was extracted with 2,2'-oxybispropane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluant.

IS The pure fractions were collected and the eluent was evaporated.

The residue was converted into the nitrate salt in 4-methyl-2pentanone and 2,2'-oxybispropane. The salt was filtered off and crystallized from 2-propanol, yielding 1.7 parts (43%) of 1 -//2-(2,4-dichlorophenyl)-1,3-dithiolan-2-yl/methyj/-lH-imidazole nitrate; mp. 184.7’C.

The compounds prepared according to Example I or prepared in an analogous manner are listed in the following table I. - 14 Table I : Compounds of formula I No.R1R2 R,, R, 3 4 a Salt form phys, data 1 Cl Cl -CH^CI^- 0 hno3 mp. 184.7*C 2 Cl Cl -CI^-CHj- 0 .HC1 'mp. 236.7‘C 3 H Cl -C^-CH^ 0 - - 4 CH, Br -CHj-CHj- 0 - - 5 H ch3 -CHj-CHj- 0 - - 6 Br Br -CH2-CH2- 0 - - _ 7 Cl Cl -CHj-CHiCHjj- 0 HNOj mp. 167.0‘C 8 Cl Cl CH, -CH(C7H-)- 0 cis+trans.HCl mp. 220.0‘C 9 Cl Cl -CH2-CH(C3H7)- 0 cis+trans. HC3 mp. 204.8’C 10 Cl Cl -CH2-CH(C4H9)- 0 - - 11 Cl Cl -chccHjJ-chccHj)- 0 - - 12 Cl Cl -CH(CH3)-CH<^- 0 - * 13 Cl Cl -CH2-CH2-CH2- 0 - - 14 Cl Cl -CHj-CHj-CHCCHj)- 0 - - 15 Cl Cl 0 - • Ιό Cl Cl -CH2-C(CH3^-CH2- 0 - - 17 Cl Cl -(ch2)4. 0 - 18 Cl Cl -CHj, -CH3 0 - - 19 Cl Cl -C?HV -C2H5 0 - - 20 Cl Cl -c3H7, -c3h7 0 - - 21 Cl Cl -C4Hg, -C4Hg 0 - - 22 Cl Cl -CH2-CH=CH2, -CH2-CH=CH2 0 23 Cl Cl -CH2-CH2- 1 - - 24 Cl Cl -CH2-CH2- 2 - - 25 Cl Cl -CH2-CH(CH3)- - 1 - 26 Cl Cl -CH2-CH(C2H5)- 1 - 27 Cl Cl -CH2-CH(C3H7)- 1 - 28 Cl Cl -3 1 52853 - 15 Example II A mixture of 6 parts of 1 -(2,4-dichlorophenyl)-2-(l£L-imidazol-1 -yl)-l -propanone and 30 parts ai me thane sulfonic acid was stirred till all solid entered solution. After cooling, 5. 5 parts of 1,2-ethanedithiol were added while nitrogen gas was introduced.

The whole was stirred overnight at room temperature. The reaction mixture was diluted with trichloromethane till a volume of 150 parts. This solution was added dropwise to a vigorously stirred solution of potassium carbonate in water. The organic phase was separated, washed with water, dried, filtered and evaporated. The oily residue was converted into the nitrate salt in 2-propanol. 2,2'Oxybispropane was added till turbid and the formed salt was allowed to crystallize. It was filtered off and dried, yielding 6 parts of 1-/Ϊ-/2-(2,4-dichlorophenyl)-1,3-dithiolan-2-yl/ethyl/-lH15 imidazole? mp. 141.9°C. (compound 29).

S2852 - 16 B. Pharmacological Examples.

Example ΠΙ Activity against Erysiphe cichoracearum on gherkins upon foliar treatment.

Young gherkin plants, about 10 days old, were sprayed with an aqueous solution containing 100, 10 or 1 ppm of the compound to be tested while controls were kept untreated. After drying of the plants, artificial infection with spores of Erysiphe cichoracearum was carried out by slightly rubbing the plants with a heavily infected leaf. At the 15th day after artificial infection the degree of fungal attack was evaluated by counting the number of spots per plant.

The results given in column 1 of table H were the percentages of fungal attack in comparison with the untreated plant·.

Example IV Activity against Erysiphe graminis on barley upon foliar treatment.

Barley plants, about 8 cm in height, were sprayed with an aqueous solution containing 100, 10 or 1 ppm of the compound to be tested while controls were kept untreated. After 3-4 hours the plants were dusted with conidia of the fungus. The infected barley plants were then placed in a glass-house at about 22 °C and fungal attack was evaluated 10 days after the day of infection.

The results given in column 2 of table II were the percentages of fungal attack in comparison with the untreated plants.

Example V Activity against Uromyces appendiculatus on phaseolum beans upon foliar treatment.

Bean plants, having the primary leaves fully developed, were sprayed with an aqueous solution containing 250, 100 or 10 ppm of the compound to be tested while controls were kept untreated. After 3-4 hours the plants were infected with a suspension of spores of the fungus. After the plants were placed in an incubation room at 20°C at 100% relative humidity for 24 hours they were placed in a glass-house at about 22 °C and fungal attack was evaluated 14 days after the day of infection.

The results given in column 3 of table Π were the percentages of fungal attack in comparison with the untreated plants. - 17 Example VI Activity against Botrytis cinerea on broad beans.

Broad bean plants, about 10 cm in height, were sprayed with an aqueous solution containing 250,-100 or 10 ppm of the compound to 5 be tested while controls were kept untreated. After 48 hours the plants were infected with a suspension of spores of the fungus. After incubating the infected plants for 2-3 days at 95-100% relative humidity and at 21 *C the fungal infection was evaluated.

The results given in column 4 of table Ilwere the percentages offungal 10 attack in comparison with the untreated plants.

Table II 'v Test E. cichoracearum E. graminis U. appendiculatus B. cinerea Compound 100 10 1 100 10 1 250 100 1C 250 100 10 1 0 68 83 27 100 100 28 100 100 5 10 63 7 2 100 100 50 100 100 0 1 100 4 10 20 8 4 - - - - - 0 0 63 0 25 62 9 100 98 38 100 42 10 100 100 95 99 90 85 29 J2 -7 LQ LQ LL 75 Q 0 12£L 2l 2 Example VII la-vitro antifungal screening.

The compounds of the invention were tested against the following fungi; Coriolus versicolor (white rot) (C.V.) Coniophora cerebella (brown rot) (C.c.) Poria monticola (brown rot) (P.m.) Chaetonium globosum (e.g.) Pullularia pullulans (blue stain) (?.p.) Aspergillus candidus (A. c.) Penicillium islandicum (P.i.) Cladosporium resinae (C.r.) Aspergillus niger (A. n.) Aspergillus flavus (A.f.) 52853 - 18 - 11. Trichoderma viride (T.v.) 12. Mucor sp. (Muc.) 13. Rhizopus sp. (RH.) 14. Absidia ramosa (A.r.) The fungi were grown onmaltagar at 25’C and 7 days old cultures were used in the tests. -10 mg of each test substance was dissolved first in 5 ml of ethanol/water l/l and the thus obtained stock solutions were diluted with water in such a way that the final concentration in the Petri-dish after mixing with the warm agar was 10, 1 or 0.1 ppm.

The agarwas inoculated with + 1 mm mycelium in the centre of the Petri-dish and incubated at 25*C. The results were evaluated after 14 days by measuring die diameter of fungal growth in mm. and expressed according to the following score system. score 1 2 3 4 growth in % of control none <25% -50% 50-75% >75% The results were given in the following tables El-a and IH-b.

Table Hl-a : Scores in In-vitro antifungal screening.

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The active substances were mixed with the carriers and ground and in this form can be processed to dusts for application.

Example DC Granulate: The following substances were used to prepare a 5% granulate: parts of active substance 0.25 parts of epichlorohydrin 0.25 parts of cetyl polyglycol ether 3.25 parts of polyethylene glycol parts, of kaolin (particle size 0.3 - 0.8 mm.).

The active substance was mixed with epichlorohydrin and the mixture was dis solved in 6 parts of 2-propanone. Then polyethylene glycol and cetyl polyglycol ether were added. The resultant solution was sprayed on kaolin and the 2-propanone was evaporated in vacuo. Such a micro-granulate was advantageously used for combating soil fungi. - 21 52853 Example X Wettable powders: The following constituents were used to prepare a) a 70%, b) a 40%, c) and d) a 25% and e) a 10% wettable powder: a) 70 parts of active substance parts of sodium dibutylnaphthyl sulfonate 3 parts of naphthalene sulfonic acid/phenolsulfonic acid/ formaldehyde condensate (3:2:1). parts of kaolin parts of Champagne chalk. b) 40 parts of active substance parts of sodium ligninsulfonate 1 part of sodium dibutylnaphthalene sulfonic acid 54 parts of silicic acid. c) 25 parts of active substance 4. 5 parts of calcium ligninsulfonate 1.9 parts of Champagne chalk/hydroxyethyl cellulose mixture (1:1) 1.5 parts of sodium dibutylnaphthalene sulfonate 19. 5 parts of silicic acid 19. 5 parts of Champagne chalk 28.1 parts of kaolin d) 2S parts of active substance 2.5 parts of isooctylphenoxy-polyethylene-ethanol 1.7 parts of a Champagne chalk/hydroxyethyl cellulose mixture (1:1) 8.3 parts of sodium aluminium silicate 16.5 parts of kieselguhr 46 parts of kaolin - 22 5 28 5 2 e) 10 parts of active substance parts of a mixture of the sodium salts of saturated fatty alcohol sulfates parts of naphthalene sulfonic acid/formaldehyde coa5 densate parts of kaolin.

The active substances were intimately mixed in suitable mixers with the additives and ground in appropriate mills and rollers.

Wettable powders of excellent wettability and suspension powder were obtained. These wettable powders can. be diluted with water to give suspensions of the desired concentration and can be used in particular for leaf application.

Example ΧΓ Emulsifiable concentrates: the following substances were used to prepare a 25% emulsifiable concentrate: parts of active substance 2.5 parts of epoxidised vegetable oil parts of an alkylarylsulfonatqffatty alcohol polyglycol ether mixture parts of dimethyl formamide 57. 5 parts of dimethylbenzene.

By diluting such a concentrate with water it was possible to prepare emulsions of the desired concentration, which were especially suitable for leaf application.

Claims (10)

CLAIMS:

1. An imidazole derivative having the formula: or a possible stereoehemically isomeric form, acid addition salt or metal salt complex thereof, wherein: Rj and are, each independently , selected from hydrogen, halo and methyl; Rj and R^ are, each independently, selected from C^-Cg-alkyl and Cj-C^ -alkenyl, or R^ and R^ form, together with the sulfur atoms to which they are attached and the bridging carbon atom, a 57 6-or 7-membered ring which is optionally substituted with 1 to 4 Cj-C^-alkyl groups; R g is selected from hydrogen, C^-C^-alkyl, 2-propenyl and 2-propynyl; and n is 0, 1 or 2.

2. A compound according to claim 1,wherein R^ is hydrogen or chloro and R^ is chloro.

3. A compound according to claim I,wherein R^ is hydrogen or chloro, R^ is chloro and Rg and R^ together with the sulfur atoms to which they are attached and the bridging carbon atom form a 5or 6-membered ring which is optionally substituted with a Cj-Chalky 1 radical.

4. A compound according to claim 1,wherein Rg is hydrogen or chloro, R 2 is chloro, Rg and R^ together with the sulfur atoms to which they are attached and the bridging carbon atom form a 5or 6-membered ring which is optionally substituted with a Cj-Cgalkyl radical and Rg is hydrogen or C^-C^- alkyl. 5. Ing Examples. 30. A method according to Claim 13 of combating microorganisms, substantially as hereinbefore described with particular reference to pharmacological Examples III to VII of the accompanying Examples. 5 and, if desired, preparing an acid addition salt or metal salt complex of a product of the above steps, and also,if desired, preparing a stereochemically isomeric form of a compound of the formula (I). 20. A process according to Claim 19, wherein the thio10 ketalization reaction is carried out in the presence of a Lewis acid and a reaction-inert organic solvent, at an elevated temperature. 21. A process for preparing 1-//2-(2,4-dichloropheny1)1,3-dithiolan-2-yl7methyl/-lH-imidazole or a stereochemically 15 isomeric form, acid addition salt or metal salt complex thereof, which comprises thioketalization of 1-(2,4-dichlorophenyl) -2-( lH-imidazol-l-yl)ethanone or a ketal derivative thereof with 1,2-ethanedithiol. 22. A process for preparing 1-//2-(2,4-dichlorophenyl)20 4-methyl-l,3-dithiolan-2-yl/methyl-lH-imidazole or a stereochemically isomeric form, acid addition salt or metal salt - 27 complex thereof, which comprises thioketalization of 1-(2,4dichlorophenyl)-2-(IH-imidazol-l-yl)ethanone or a ketal Ίιτ Ivative thereof with 1,2-propanedithiol. 23. A process for preparing 1-//2-(2,4-dichlorophenyl)5 4-ethyl-l,3-dithiolan-2-yl/methyl7-lH-imidazole or a stereochemically isomeric form, acid addition salt or metal salt complex thereof, which comprises thioketalization of 1-(2,4dichlorophenyl)-2-(IH-imidazol-l-yl)ethanone or a ketal derivative thereof with 1,2-butanedithiol. 10 24. A process for preparing l-//2-(2,4-dichlorophenyl)4-propyl-l,3-dithiolan-2-yl7methyl7~lH-imidazole or a stereochemically isomeric form, acid addition salt or metal salt complex thereof, which comprises thioketalization of 1-(2,4dichlorophenyl)-2-(IH-imidazol-l-yl)ethanone or a ketal 15 derivative thereof with 1,2-pentanedithiol. 25. A process for preparing l-/l-/2-(2,4-dichlorophenyl)1,3-dithiolan-2-yl7ethyl7 - lH-imidazole or a stereochemically isomeric form, acid addition salt or metal salt complex thereof, which comprises thioketalization of 1-(2,4-dichloro20 phenyl)-2-(IH-imidazol-l-yl)-1-propanone or a ketal derivative thereof with 1,2-ethanedithiol. 26. An imidazole derivative of the formula (I) given and defined in Claim 1 or a possible stereochemically isomeric form, acid addition salt or metal salt complex thereof, sub25 stantially as hereinbefore described with particular reference to preparation Examples I and II of the accompanying Examples. 27. A process for preparing an imidazole derivative of the formula (I) given and defined in Claim 1 or a possible stereochemically isomeric form, acid addition salt or metal 30 salt complex thereof, substantially as hereinbefore described with particular reference to preparation Examples I and II of the accompanying Examples. 28. An imidazole derivative of the formula (I) given and defined in Claim 1 or a possible stereochemically isomeric 35 form, acid addition salt or metal salt complex thereof, - 28 whenever prepared by a process claimed in a preceding claim. 29. An antimicrobial composition according to Claim 12 substantially as hereinbefore described with particular reference to formulation Examples VIII to XI of the accompany

5. A compound according to claim 1,wherein Rg is hydrogen or chloro, Rj is chloro, Rg and R^ together with the sulfur atoms - 24 to which they are attached and the bridging carbon atom form a 5- or 6-membered ring which is optionally substituted with a Cjj-Cj-alkyl radical and Rg is hydrogen.

6. A compound according to claim 1, wherein R^ and Rg 5 are both chloro, Rg and R^ together with the sulfur atoms to which they are attached and the bridging carbon atom form a 5-membered ring which is optionally substituted with a methyl, ethyl or propyl group and Rg is hydrogen.

7. 1-//2-(2,4-Dichlorophenyl)-1,3-dithiolan-2-yl/ methyl? 10 iH-imidazole or a stereochemically isomeric form, acid addition salt or metal salt complex thereof.

8. 1-//2-(2,4-Dichlorophenyl)-4-methyl-l,3-dithiolan2-yl/methyl/-lH-imidazole or a stereochemically isomeric form acid addition salt or metal salt complex thereof. 15

9. 1-//2-(2,4-Dichlorophenyl)-4-ethyl-l,3-dithiolan-2yl/methyl/-lH-imidazole or a stereochemically isomeric form, acid addition salt or metal salt complex thereof. 10. 1-//2-(2,4-Dichlorophenyl)-4-propyl-l,3-dithiolan2-yl/methyl/-lH-imidazole or a stereochemically isomeric form, 20 acid addition salt or metal salt complex thereof. 11. 1-/Ϊ-/2-(2,4-Dichlorophenyl)-1,3-dithiolan-2-yl/ethy1/-1H-imidazole, or a stereochemically isomeric form, acid addition salt or metal salt complex thereof. 12. An antimicrobial composition, comprising an inert 25 carrier material and as an active ingredient an antimicrobially effective amount of a compound according to any one of claims 1 to 11. 13. A method of combating microorganisms which comprises contacting said microorganisms with an effective 30 antimicrobial amount of a compound according to any one of Claims 1 to 11. 14. A method of protecting non-living materials from microbial attack which comprises treating said materials with - 25 an effective antimicrobial amount of a compound according to any one of Claims 1 to 11. 15. A method according to claim 14, wherein said nonliving materials are wood or coatings. 5 16. A method according to claim 14, wherein said nonliving materials are textiles. 17. A method according to claim 14, wherein said nonliving materials are feedstuffs. 18. A compound according to any one of Claims 1 to 11 10 or a composition according to Claim 12, for use as an antimicrobial agent. 19. A process for preparing a compound according to any one of Claims 1 to 11, which comprises subjecting a ketone of the formula (II) (ID wherein R^, R 2 and Rg are as defined in Claim 1, or a ketal derivative thereof, to a thioketalization reaction with thiols of the formulae R 3 -SH and R 4 -SH (III) (IV) 20 or a dithiol of the formula hs-r 3 -r 4 -sh (V) wherein Rj and R 4 are as defined in Claim 1, in order to obtain a compound of the formula and, if desired, oxidizing the thus obtained compound (I-a) in order to obtain a compound of the formula

10. 31. A method according to Claim 14 of protecting nonliving materials from microbial attack, substantially as hereinbefore described with particular reference to pharmacological Examples III to VII of the accompanying Examples.