NZ199983A - Antimicrobial imidazole derivatives - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number 1 99983 1999 8 3 Fr80Tyn>*' -^v m ■ Com;;k«c3ficatiGn Filed: ./ B 1 JAN 1985 P.O. Jc-'.-.-nd, No: .... e 0 ■ • pip Patents Form No. 5 Number PATENTS ACT 1953 Dated COMPLETE SPECIFICATION NOVEL ANTIMICROBIAL IMIDAZOLE DERIVATIVES $We JANSSEN PHARMACEUTICA N.V. of Turnhoutsebaan 30, B-2340 Beerse, Belgium, a Belgian Corporation do hereby declare the invention for which X/we pray that a Patent may be granted to bok/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - 1 - (followed by page la) , OCOOT I///uJ -la- Background of the Invention: Ketal derivatives of 1-(2-aryl-2-oxoethyl)-lH-imidazoles are disclosed, inter alia, in the following references: U.S. Patent No. 4,085,209, in the broadest meaning of its scope, theoretically embraces dithioketals of 1- (2-aryl-2-oxoethyl) -1H-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 canpounds of the present invention are nowhere disclosed in the prior art and are deemed to be novel.

Description of the preferred embodiments: The subject invention relates to a series of novel dithioketal derivatives of 1- (2-oxo-2-phenylethyl) -1H-imidazoles and the corresponding sulfones and sulfoxides thereof, being represented by the formula U.S. Pat. No. 3,575,999; and New Zealand Patent No. 179,111.

(I), the possible stereochemical^ isomeric forms, 1 P: O " ^ ^ U J the acid addition salts and the metal salt complexes thereof, wherein: Rj and R^ are each independently selected from the group consisting of hydrogen, halo and methyl; R^ and R^ are each independently selected from the group consisting of Cj-C^-lower alkyl and C^-C^-lower alkenyl, or R^ and R^ 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^-lower alkyl groups; R^ is a member selected from the group consisting of hydrogen, Cj- C^-lower alkyl, 2-propenyl and 2-propynyl; and n is 0, 1 or 2.

As used in the foregoing and in the following definitions, "halo" is generic to fluoro, chloro, bromo and iodo; "lower 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, 1 -methyl-propyl, 2-methylpropyl and 1,1-dimethylethyl for C^-C^-lower alkyl and, for C^-C^-lower alkyl 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 R^ is chloro. .

Particularly preferred are compounds of formula (I) wherein R^ is hydrogen or chloro, R^ is chloro and 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^-C^-lower alkyl radical.

Especially preferred are compounds of formula (I) wherein R^ is hydrogen or chloro, R^ 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^-lower alkyl radical and Rj. is hydrogen or Cj-C^-lower alkyl. 19 ^ C) .n 3 More especially preferred are compounds of formula (I) wherein is hydrogen or chloro, R^ is chloro, R^ and Ra 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. -C, lower alkyl radical and R_ is 1 o 5 hydrogen.

Most especially preferred are compounds of formula (I) wherein R^ and R£ are both chloro, R^ and R^ together with the sulfur atoms to which they are attached and the bridging carbon atom 10 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 (I) are the following: 1 -(2,4-dichlorophenyl)-l, 3 -dithiolan-2 -yl"Jmethyj/-1H-15 imidazole; 1 -/^2 -(2, 4-dichlorophenyl)-4-methyl-l, 3 -dithiolan-2 -ylj-methyl/ -lH-imidazole; 1 ~£/2~(2 , 4-dichlorophenylj-4-ethyl-l , 3 -dithiolan-2 -yl/ me thyl7-1H- imidazole; 1 , 4-dichlorophenyl)-4-propyl-l , 3 -dithiolan-2 -yl/- methyl^-lH-imidazole; and 2 -(2 , 4-dichlorophenyl)-2 ~[l -(lH-imidazol-1 -yl)ethy_17 -1,3-dithiolane.

V -j 00007 I ✓ ; / u J The compounds of formula (I) wherein n is 0, said compounds being represented by the formula (1-a) (I-a) may be prepared by subjecting an appropriate ketone of the formula (H) rr—N O ^ (n) or an appropriate ketal derivative thereof to a thioketalization reaction with an appropriate thiol of the formula R,-SH, QX R,-SH 3 ' , \ 4 (III) (IV) or a dithiol of the formula HS-R, -R. -SH 3 4 (V) wherein R„ and R . are as defined in formula (I). 3 4 , ' ; /3""Ei5T OFFICE 2 5 MAY 1984 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 benzene sulfonic and 4-me thylbenzene sulfonic acid, and non-protonic Lewis acids such as, for example, aluminum chloride, zinc chloride, tin chloride and the like. 2 0 Appropriate solvents include, for example, aliphatic and aromatic hydrocarbons, e.g. hexane, cyclohexane, heptane, benzene, methyl-benzene, dimethylbenzene and the like; chlorinated hydrocarbons such as, for example,di-, tri- and tetrachloromethane, 1, 2-dichloroethane, 1,1 , 2, 2-tetrachloroethane, tetrachloroethene and the like; and ethers ^5 such as tetrahydrofuran and 1,4-dioxane. In 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 1,11,111 -^methylidynetris(oxy}7tr*s(etkane). Elevated temperatures are advantageous and,preferably, the reaction is carried out at the reflux temperature of the reaction mixture.

Ketal derivatives of the ketones (II) 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 formula (I-b), respectively (1-c), can be derived from the corresponding (1-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 3 0 be obtained substantially free from the other. strong protonic acids, e.g. sulfonic acids such as me thane sulfonic, (I-b) (I-c) ?'.2. PATEiJT OrF'.CE MAY 1984 'i ccq RECEIVED I Appropriate oxidizing agents include, for example, periodates, e.g., sodium periodate, potassium periodate and the like; peroxides, e.g. , hydrogen peroxide and the like; and peracids, e.g. perbenzoic acid and preferably 3-chloroperbenzoic acid. These oxidation reactions may 5 be carried out by methodologies which are well-known in the art.

The ketones of formula (II) and the corresponding ketals which are used-as starting materials are well-known. Such compounds are described for example in: New Zealand Patent. No., 19J-,.pl4 ; : New Zealand Pat. No,. 191,015 jq Brit. Pat. No. 1,533,706..

The thiols of formulas (III), (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 1 5 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 centers may exist in R„ and R„ 3 4 and when Rj. is other than hydrogen. Each of these chiral centers may exist in a R- and S-configuration, this R- and S-notation being in corres-pondance with the rules described by R.S. Cahn, C. Ingold and V.

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

Pure stereochemically isomeric forms of the compounds of 2 5 formula (l) 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 3 0 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 stereospeci-fically. Stereochemically isomeric forms of the compounds of formula 3 5 (I) are naturally intended to be embraced within the scope of the invention. <1 9 9 3 3 7 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, nitric and the like acids, or organic acid, e.g. , acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2, 3-dihydroxybutanedioic, 2-hydroxy-1,2,3 -propanetricarboxylic, benzoic, 3 -phenyl-2 -propenoic, 10 a -hydroxybenzeneacetic , methane sulfonic, ethane sulfonic," hydroxy-e thane sulfonic, 4-me thylbenzene sulfonic, 2-hydroxybenzoic, 4-amino -2-hydroxybenzoic, 2-phenoxybenzoic, 2-acetyloxybenzoic, 2,4-hexa-dienoic or 1, 5-naphthalenedicarboxylic acid.

Metal salt complexes of formula (I) may be obtained by the 15 complexation-reaction of an imidazole of formula (I) with an organic or inorganic metal salt such as, for example, hydrohalides, nitrates, sulfates, phosphates, 2, 3-dihydroxybutanedioates and the like of copper, manganese, zinc, iron and the like transition metals, which may be present in each of their possible valencies. 20 Stoechiometrically 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-dim ethyl -formamide) and adding thereto an aqueous solution of the desired metal salts such as, for example, CuSO^. SH^O, M^NO^)^. 4H^O, 2 5 FeCl^ . and the like.

The foregoing enumerations are intended to illustrate and not to limit the scope of the present invention. 199 9- - ' - ^ w ^ 8 • 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 5 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 followings: 10 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 des-15 troy fungal growth on plants of these or related crops or on parts of such plants (e.g., fruits, blossoms, foliage, stams, 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: 20 Ascomycetes (e.g. Erysiphaceae, Fusarium, Helminthosporium); Basidiomycetes such as particularly rust-fungi ( e.g., Puccinia); Fungi imperfecti (e.g., Moniliales etc., Cercospora and Botrytis) and Oomycetes belonging to the class of the Phycomycetes such as, for example, Phytophthora and Plasmopara. They can further be 25 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 occuring in the soil.

The compounds of formula (I) can be used alone or in admixture with appropriate carriers and/or additives. Appropriate 30 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.

Li w ^ ' >> ^ V v J The concentration of the active ingredient in commercial preparations can vary from about 0.1 to about 90%.

For their application the compounds of formula (I) can be -formulated in the following composition-forms (whereby suitable 5 concentrations of the active ingredient are indicated within brackets): solid compositions : dusts (up to 10%), granulates, coated granulates, impregnated granulates and homogeneous granulates, pellets 10 (from 1 to 80% ); liquid compositions: a) water-dispersible concentrates: wettable powders and pastes (25-90% in commercial form, 0.01-15% in the 15 ready for use solution); emulsion- and solution-concentrates (10-50%; 0.01-1 5% in ready for use solution); b) solutions (0.1-20%); aerosols.

If desired, in order to extend their spectrum of activity 20 the compounds of formula (I) may be combined with other appropriate pesticides such as, for example, fungicides, bactericides, insecticides, acaricides, herbicides, plant-growth regulators and the like. Such compositions are intended to be 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 in general from 0.01 to 1 0 kg of active substance pro ha, preferably from 0. 025 to 5 kg/ha.

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 5 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 10 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, 15 glues, mortar as well as walls which are penetrated or fouled by organic materials, cutting oils, fuel oils and the like.

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 strenght, resistance 20 to shock and shearing strenght; or decay of their optical or other useful properties such as the occurence of odor, 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, Chaetomium 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 3 0 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. 1 6 ^ Q n ^ i y j ^ <3 i a 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 (I) show good solubility in organic solvents and in driving gases for aerosols. The lack of color and odor 10 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.

A. Examples of chemical preparation; Example I A mixture of 1 part of 4-methylbenzenesulfonic acid and 90 parts of dimethylbenzene was distilled azeotropically to dry. 5 Then there were added 5 parts of 1-/2-(2, 4-dichlorophenyl)-2,2-di-methoxyethyl7-lH-imidazole 4-methylbenzenesulfonate, 4.7 parts of 1,2 -ethanedithiol and 1 . 5 parts of 1,11,1" -/methylidynetris(oxyj7-trisethane and the whole was stirred and refluxed for 8 days with water-separator. The reaction mixture was cooled and stirred with 10 a sodium hydroxide solution 20%. The whole was poured onto water and the product was extracted with 2, 2'-oxy bis propane. 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 eluent. 15 The pure fractions were collected and the eluent was evaporated. The residue was converted into the nitrate salt in 4-methyl-2-pentanone and 2,2'-oxybispropane. The salt was filtered off and crystallized from 2-propanol, yielding 1.7 parts (43%) of 1 2, 4-dichlorophenyl)-l, 3 -dithiolan-2 -yljm ethyl/-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. 13 Table I : Compounds of formula I 19 9 9 8 3 No.

Ri R2 VR4 n Salt form phys. data 1 CI CI -CH^CH^ 0 hno3 mp. 184. 7°C 2 CI CI -CH^CH^ 0 HCl mp. 236. 7°C 3 H CI -CVCV 0 - - 4 CH3 Br -CH^CH^ 0 - - H CH3 -CH^CH^ 0 - - 6 Br Br -CH2-CH2- 0 - - 7 CI CI -CH2-CH(CH3)- 0 hno3 mp. 167 . 0°C 8 CI CI -CH2-CH(C2H5)- 0 cis+trans .HCl mp. 220. 0°C 9 CI CI -ch2-ch(c3h7)- 0 cis+trans. HC] mp. 2 04. 8 0 C CI CI -CJ^-CH^Hg)- 0 - - 11 CI CI -CH(CH3)-CH(CH3)- 0 - - 12 CI CI -CH(CH3)-CHC2H5)- 0 - - 13 CI CI ~GH2 ~CH2 "CH2 " 0 - - 14 CI CI -CH2 "CH^ -CH(CHj)- 0 - - CI CI -CH(C^)-CI^ -CKpy- 0 - - 16 CI cr "ch2-c(ch3^-ch2- 0 - - 17 CI CI -(ch2)4- 0 - - 18 CI CI -ch3, -ch3 0 - - 19 CI CI -C2H5' -C2H5 0 - - CI CI -c3h7, -c3h7 0 - - 21 CI CI -c4h9, -c4h9 0 - - 22 CI CI -CH2-CH=CHz> 0 - - -CH -CH=CH 23 CI CI 1 0 ►P 1 0 1 1 1 - - 24 CI CI -ch2-ch2. 2 - - CI CI -CH2-CH(CH3)- 1 - - 26 CI CI -CH_-CH(C,H_)- u CD 1 - 27 CI CI -CH^-CH(C,H^)- 1 - - 28 CI CI -(ch2)3 1 • 14 Example II A mixture of 6 parts of 1-(2, 4-dichlorophenyl)-2-(lJi-imi-dazol-l-yl)-l-propanone and 30 parts of 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 2 -(2, 4-dichlorophenyl)-2 -^7-(1 H-imidazol-1 -yljethyl/-1,3- dithio-lane; mp. 141. 9°C. (compound 29). 19 B. Pharmacoloeical Examples.

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

Young gherkin plants, about 10 days old, were sprayed with 5 an aqueous solution containing 100, 1 0 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 10 attack was evaluated by counting the number of spots per plant. The results given in column 1 of table II were the percentages of fungal attack in comparison with the untreated plants.

Example IV Activity against Erysiphe graminis on barley upon foliar treatment. 15 Barley plants, about 8 cm in height, were sprayed with an aqueous solution containing 100, 1 0 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 20 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 2 5 foliar treatment.

Bean plants, having the primary leaves fully developed, were sprayed with an aqueous solution containing 2 50, 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 3 0 the fungus. After the plants were placed in an incubation room at °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 II were the percentages of fungal 35 attack in comparison with the untreated plants.

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 II we re the percentages of fungal 10 attack in comparison with the untreated plants.

Table II Test CompourrK E. cichoracearum E. graminis U. appendiculatus B. cinerea 100 1 100 1 250 100 1C 250 100 1 0 68 83 27 100 100 28 100 100 63 7 2 100 100 50 100 100 0 1 100 4 8 4 - - - - - 0 0 63 0 62 9 100 98 38 100 42 100 100 95 99 90 85 29 0 7 1 0 16 7"? 0 0 100 0 2 ■?, Example VII In-vitro antifungal screening.

The subject compounds were tested against the following fungi: 1.

Coriolus versicolor (white rot) (C.v.) 2.

Coniophora cerebella (brown rot) (C.c.) 3.

Poria monticola (brown rot) (P.m.) 4.

Chaetonium globosum (e.g.) .

Pullularia pullulans (blue stain) (P.p.) 6.

Aspergillus candidus (A. c.) 7.

Penicillium islandicum (P.i.) 8.

Cladosporium resinae (C. r.) 9.

Aspergillus niger (A.n.) .

Aspergillus flavus (A. f.) 11. Trichoderma viride (T.v.) 12. Mucor sp. (Muc.) 13. Rhizopus sp. (Rh.) 14. Absidia ramosa (A.r.) The fungi we re grown on malt agar at 258 C and 7 days old cultures were used in the tests. 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 agar was 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 the diameter of fungal growth in mm. and expressed according to the following score system. score growth in % of control 0 none 1 < 25% 2 25-50% 3 50-75% 4 > 75% The results were given in the following tables Ill-a and Ill-b.

Table IH-a : Scores in in-vitro antifungal screening. \ doae \n ppm C, v.

C. c • P;m. e.g. p.p.

A.c.

P.i. com\ sound \. l(f 1 0.1 1 0. 1 1 0. 1 1 0.1 1 0.1 1 0.1 1 0.1 1 0 0 - 2 4 - •- T - 0 0 - i. 1 - 0 3 - 0 4 - 7 0 1 4 0 3 4 0 0 4 0 0 - 0 2 4 0 0 1 0 3 - 8 0 0 - 0 0 - - - - 0 0 - 1 1 - 0 0 - 0 2 - 9 0 - - 0 3 - 0 0 1 0 - - 1 1 - 0 0 0 0 2 - 29 0 - - 0 • - - 0 2 - 1 3 - 0 0 2 1 - - Table IH-b : Scores in in-vitro antifungal screening.

S. . dose \jn ppm C. r • A. n.

A. f.

T.v.

Muc • Rh.

A. r. com\ pound \ 1 0. 1 1 0. 1 1 0. 1 1 0.1 1 0.1 1 0,1 1 0.1 1 0 0 - 0 3 • 1 3 - a 4 - 0 4 - o. 4 • - 0 4 - 7 0 0 0 0 4 0 2 4 I 4 4 4 4 - 0 4 - 0 0 - 8 0 0 - 0 0 - 0 1 - •i 4 - 0 4 - P 3 - 0 1 - ' 9 0 1 - 0 0 3 0 1 2 - - - 0 0 - 0 0 - 1 29 1 1 3 0 0 3 0 2 3 3 - ~ * 19998 19 C. Formulation Examples.

Example VIII Dusts: The following substances were used to prepare a) 5% and b) a 2% dust: a) 5 parts of active substance 95 parts of talc; b) 2 parts of active substance 1 part of highly dispersed silicic acid 97 parts of talc.

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: 5 parts of active substance 0.2 5 parts of epichlorohydrin 0.2 5 parts of cetyl polyglycol ether 3.25 parts of polyethylene glycol 91 parts of kaolin (particle size 0.3 - 0.8 mm.).

The active substance was mixed with epichlorohydrin and the mixture was dissolved 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. 19998 W Example X Wettable powders: The following constituents were used to prepare a) a 70%, b) a 40%, c) and d) a 2 5% and e) a 10% wettable powder: a) 70 parts of active substance 5 parts of sodium dibutylnaphthylsulfonate 3 parts of naphthalene sulfonic acid/phenol sulfonic acid/ formaldehyde condensate (3:2:1). parts of kaolin 12 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 20 19. 5 parts of Champagne chalk 28.1 parts of kaolin d) 2 5 parts of active substance 2.5 parts of isooctylphenoxy-polyethylene-ethanol 1 . 7 parts of a Champagne chalk/hydroxyethyl cellulose 25 mixture (1:1) 8.3 parts of sodium aluminium silicate 16.5 parts of kieselguhr 46 parts of kaolin 1. 199 9 3 3 21 e) 10 parts of active substance 3 parts of a mixture of the sodium salts of saturated fatty-ale ohol sulfates parts of naphthalene sulfonic acid/formaldehyde con-5 densate 82 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 10 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 XI Emulsifiable concentrates: the following substances were used to 15 prepare a 25% emulsifiable concentrate: 2 5 parts of active substance 2. 5 parts of epoxidised vegetable oil 10 parts of an alkylarylsulfonat^fatty alcohol polyglycol ether mixture 20 5 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. 19998 3 22

Claims (1)

1.WHAT WE CLAIM IS: 1 1. A compound selected from the group consisting of an 2 imidazole derivative having the formula n N U fc_ s si~ R3 (°»n 3 the possible stereochemically isomeric forms, the acid addition 4 salts and the metal salt complexes thereof, wherein: 5 R^ and R^ are, each independently , selected from the group 6 consisting of hydrogen, halo and methyl; 7 R^ and R^ are, each independently, selected from the group con- 8 sisting of C^-C^-lower alkyl and C^-C^-lower alkenyl, 9 or R, and R . form, together with the sulfur atoms to 3 4 10 which they are attached and the bridging carbon atom, a 5" 11 6-or 7-membered ring which is optionally substituted with 12 1 to 4 Cj-C^-lower alkyl groups; 13 Rg is a member selected from the group consisting of hydrogen, 14 C^-C^-lower alkyl, 2-propenyl and 2-propynyl; and 15 n is 0, 1 or 2. 1 2. A compound according to claim 1 wherein R^ is hydrogen 2 or chloro and R^ is chloro. 1 3. A compound according to claim 1 wherein R^ is hydrogen 2 or chloro, R^ is chloro and R^ and R^ together with the sulfur atoms 3 to which they are attached and the bridging carbon atom form a 5- 4 or 6-membered ring which is optionally substituted with a C^-C^- 5 lower alkyl radical. 1 4. A compound according to claim 1 wherein Rj is hydrogen 2 or chloro, R^ is chloro, R^ and R^ together with the sulfur atoms 3 to which they are attached and the bridging carbon atom form a 5- 4 or 6-membered ring which is optionally substituted with a C^-C^- 5 lower alkyl radical and R^ is hydrogen or C^-C^-lower alkyl. 1 5. A compound according to claim 1 wherein Rj is hydrogen 2 or chloro, R^ is chloro, R^ and R^ together with the sulfur atoms 3 4 5 1 2 3 4 5 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 23 to which they are attached and the bridging carbon atom form a 5-or 6-membered ring which is optionally substituted with a Cj-C^-lower alkyl radical and R^ is hydrogen. 6. A compound according to claim 1 wherein R^ and R^ are both chloro, R^ 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. 7. A compound selected from the group consisting of 1-/^2-(2 , 4-dichlorophenyl)-l, 3 -dithiolan-2methyl-1H.-imidazole, the possible stereochemically isomeric forms, the acid addition salts and the metal salt complexes thereof. 8. A compound selected from the group consisting of 1 -(Jj--(2 ,4 -dichlorophenyl)-4-methyl-l, 3 -dithiolan-2 -yl/methyl/-1H-imidazole, the possible stereochemically isomeric forms, the acid addition salts and the metal salt complexes thereof. 9. A compound selected from the group consisting of 1-/2?" (2 ,4 -dichlorophenyl)-4 -ethyl-1, 3 -dithiolan-2 - yl~fmethyl-1H-imidazole, the possible stereochemically isomeric forms, the acid addition salts and the metal salt complexes thereof. 10. A compound selected from the group consisting of 1-/^2-(2 , 4 -dichlorophenyl)-4-propyl-l, 3 -dithiolan-2 -yl/methyl/-1 H_~ imidazole, the possible stereochemically isomeric forms, the acid addition salts and the metal salt complexes thereof. 11 . A compound selected from the group consisting of 2 -(2 , 4-dichlorophenyl)-2-£T-(1 H-imidazol-1 -yl)ethy]7-1, 3 -dithio-lane, the possible stereochemically isomeric forms, the acid addition salts and the metal salt complexes thereof. 12. An antimicrobial composition, comprising inert carrier materials and as an active ingredient an antimicrobially effective amount of a compound selected from the group consisting of an imidazole derivative having the formula 5 6 7 8 Q 10 11 12 13 14 15 16 17 1 2 3 1 2 3 4 5 6 1 2 3 4 5 6 ,'99933 ' 24 the possible stereochemically isomeric forms, the acid addition salts and the metal salt complexes thereof, wherein: Rj and R£ are, each independently, selected from the group consisting of hydrogen, halo and methyl; Rj and R^ are, each independently, selected from the group consisting of C^-C^-lower alkyl and C^-C^-lower alkenyl, or R^ and R^ 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 Cj -C^-lower alkyl groups; Rg is a member selected from the group consisting of hydrogen, Cj-C^-lower alkyl, 2-propenyl and 2-propynyl; and n is 0, 1 or 2. 13. An antimicrobial composition according to claim 12 wherein said active ingredient is a compound according to claim 1 wherein R^ is hydrogen or chloro and R^ is chloro. 14. An antimicrobial composition according to claim 12 wherein said active ingredient is a compound according to claim 1 wherein R^ is hydrogen or chloro, R^ is chloro and 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^-C^-lower alkyl radical. 15. An antimicrobial composition according to claim 12 wherein said active ingredient is a compound according to claim 1 wherein Rj is hydrogen or chloro, R^ 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 Cj-C^-lower alkyl radical and R,_ is hydrogen or C^-C^-lower alkyl. 1 2 3 4 5 6 1 2 3 4 5 6 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 199983 25 16. An antimicrobial composition according to claim 12 wherein said active ingredient is a compound according to claim 1 wherein Rj is hydrogen or chloro, is chloro, R^ and R4 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 Cj-C^-lower alkyl radical and R^ is hydrogen. 17. An antimicrobial composition according to claim 12 wherein said active ingredient is a compound according to claim 1 wherein Rj and R^ are both chloro, R^ 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. 18. An antimicrobial composition according to claim 12 wherein said active ingredient is a compound selected from the group consisting of 1-/22 -(2,4-dichlorophenyl) -1, 3 -dithiolan-2 -yl/methyl/-1H-imidazole, the possible stereochemically isomeric forms, the acid addition salts and the metal salt complexes thereof. 19- An antimicrobial composition according to claim 12 wherein said active ingredient is a compound selected from the group consisting of 1 -/T?-(2, 4-dichlorophenyl)-4-methyl-1 , 3 -dithiolan-2-yl/-methy]^-1 H-imidazole. the possible stereochemically isomeric forms, the acid addition salts and the metal salt complexes thereof. 20. An antimicrobial composition according to claim 12' wherein said active ingredient is a compound selected from the group consisting of 1 -/22-(2, 4-dichlorophenyl)-4-ethyl-1, 3 -dithiolan-2 -yl/-methyl7-1 H-imidazole, the possible stereochemically isomeric forms, the acid addition salts and the metal salt complexes thereof. 21. An antimicrobial composition according to claim 12 wherein said active ingredient is a compound selected from the group consisting of l-/2?"(2» 4-dichlorophenyl)-4-propyl-l ,3-dithiolan-2 -yl/-methyl^-lH-imidazole, the possible stereochemically isomeric forms, the acid addition salts and the metal salt complexes thereof. t 99^33 26 1 22. An antimicrobial composition according to claim 12 where - 2 in said active ingredient is a compound selected from the group con- 3 sisting of 2-(2,4-dichlorophenyl)-2-/I-(1 H-irnidazol-1 -yl)ethyj7- 4 1, 3-dithiolane, the possible stereochemically isomeric forms, the 5 acid addition salts and the metal salt complexes thereof. 1 23 A method of combating microorganisms which comprises 2 contacting said microorganisms with an effective antimicrobial amount 3 of a compound selected from the group consisting of an imidazole 4 derivative having the formula o N R, N" I } N R -CH —U y-R_ (I)» 5 s" "sW 2 R3 R^<°>n 5 the possible stereochemically isomeric forms, the acid addition 6 salts and the metal salt complexes thereof, wherein: 7 R^ and R^ are, each independently, selected from the group 8 consisting of hydrogen, halo and methyl; 9 R^ and R^ are, each independently, selected from the group con- 10 sisting of C^-C^-lower alkyl and C^-C^-lower alkenyl, 11 or R_ and R, form, together with the sulfur atoms to which 3 4 12 they are attached and the bridging carbon atom, a 5", 6-or 13 7-membered ring which is optionally substituted with 1 14 to 4 C j -C^-lower alkyl groups; 15 Rg is a member selected from the group consisting of hydrogen, 16 Cj -C^-lower alkyl, 2-propenyl and 2-propynyl; and 17 n is 0, 1 or Z, with the proviso that the method does not canprise combating microorganisms in or on humans. 2 5 MAY 1984 1 2 3 1 2 3 4 5 6 1 2 3 4 5 6 1 2 3 4 5 6 1 2 3 4 5 6 1 2 3 4 5 1 2 3 • * o £>, 9 a 3;y & & * w 27 24. A method according to claim 23 wherein said compound is a compound according to claim 1 wherein R^ is hydrogen or chloro and R-2 is chloro. 25. A method according to claim 23 wherein said compound is a compound according to claim 1 wherein Rj is hydrogen or chloro, R„ is chloro and R„ and R . together with the sulfur atoms to which 2 3 4 ° they are attached and the bridging carbon atom form a 5- or 6-membered ring which is optionally substituted with a C^-C^-lower alkyl radical. 26. A method according to claim 23 wherein said compound is a compound according to claim 1 wherein R^ is hydrogen or chloro, R is chloro, R and R together with the sulfur atoms to which they u J 4 are attached and the bridging carbon atom form a 5- or 6-membered ring which is optionally substituted with a C^-C^-lower alkyl radical and R^ is hydrogen or -C^-lower alkyl. 27. A method according to claim 23 wherein said compound is a compound according to claim 1 wherein R^ is hydrogen or chloro, R^ 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^-C^ -lower alkyl radical and R^ is hydrogen. 28. A method according to claim 23 wherein said compound is a compound according to claim 1 wherein R^ and R^ are both chloro, R^ 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 Rj. is hydrogen. 29. A method according to claim 23 wherein said compound is a compound selected from the group consisting of 1 -(2 ,4-dichlorophenyl) -1, 3 -dithiolan-2-yl^methyl7-lH-imidazole, the possible stereochemically isomeric forms, the acid addition salts and the metal salt complexes thereof. 30. A method according to claim 23 wherein said compound is a compound selected from the group consisting of 1-/^2-(2, 4-dichlorophenyl)-4-methyl-l, 3 -dithiolan-2-yl/methy^-1 H-imidazole, 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 6 7 8 9 1 1 1 28 the possible stereochemically isomeric forms, the acid addition salts and the metal salt complexes thereof. 31. A method according to claim 23 wherein said compound is a compound selected from the group consisting of 1 -/2Z-(Z ,4-dichlorophenyl)-4-ethyl-l, 3-dithiolan-2-y]7methy^-1IJ,-imidazole, the possible stereochemically isomeric forms, the acid addition salts and the metal salt complexes thereof. 32. A method according to claim 23 wherein said compound is a compound selected from the group consisting of 1-/^2-(2,4-dichlorophenyl)-4-propyl-1, 3-dithiolan-2 -y^methyl^-lH-imidazole » the possible stereochemically isomeric forms, the acid addition salts and the metal salt complexes thereof. 33. A method according to claim 23 wherein said compound is a compound selected from the group consisting of 2-(2,4-dichlorophenyl)^ -^1-(1 H-imidazol-1 -yl)ethyl7"l, 3 -dithiolane, the possible stereochemically isomeric forms, the acid addition salts and the metal salt complexes thereof. 34. A method of protecting non-living materials from microbial attack which comprises treating said materials with an effective antimicrobial amount of a compound selected from the group consisting of an imidazole derivative having the formula the possible stereochemically isomeric forms, the acid addition salts and the metal salt complexes thereof, wherein: and are each independently selected from the group consisting of hydrogen, halo and methyl; R^ and are each independently selected from the group consisting of C, -C,-lower alkyl and C_-C -lower alkenyl, or R„ and R, 1 6 3 4 3 4 form, together with the sulfur atoms to which they are attached and the bridging carbon atom, a 5-, 6- or 7-membered ring 29 13 which is optionally substituted with 1 to 4 C^-C^ -lower 14 alkyl groups; 15 Rg is a member selected from the group consisting of hydrogen, 16 Cj-C^-lower alkyl, 2-propenyl and 2-propynyl; and 17 n is 0, 1 or 2. 1 3 5. A method according to claim 34 wherein said non- 2 living materials are wood or coatings. 1 36. A method according to claim 34 wherein said non- 2 living materials are textiles. 1 37. A method according to claim 34 wherein said non- 2 living materials are feedstuffs. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 -30- 38. A process for preparing a compound selected from the group consisting of an imidazole derivative having the formula the possible stereochemically isomeric forms, the acid addition salts and the metal salt complexes thereof, where in: R1 and R2 are, each independently, selected from the group consisting of hydrogen, halo and methyl; and R^ are. the same and are selected from the group consisting of C^-Cg-lower alkyl and C^-C^-lower alkenyl, or R^ and R^ 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^-lower alkyl groups; R^ is a memeber selected from the group consisting of n is 0, 1 or 2, characterized by subjecting an appropriate ketone of the formula (II) (I) hydrogen, C^-C^-lower alkyl, 2-propenyl and 2-propynyl; and -31- or an appropriate ketal derivative thereof to a thioketaliza-tion reaction with an appropriate thiol of the formula R3-SH, or R4-SH (III) (IV) or a dithol of the formula hs-r3-r4-sh (V) wherein R3 and R4 are as defined in formula (I), in order to prepare a compound of the formula (I-a) and, if desired, oxidizing said compound (I-a) with an appropriate oxidizing agent in order to prepare a compound of the formula N ' , N U ^ Q ri. i, C .. i, (I-b) (I-c) said oxidizing agent and reaction circumstances being appropriately selected in order to prepare either sulfones or sulfoxides, and, if desired, preparing possible stereochemical isomeric forms, acid addition salts or metal salt complexes of the products thereof. 39. A process according to claim 38 wherein the thioketaliza-tion is carried out in the presence of an appropriate Lewis acid, and, unless the acid itself has suitable solvent properties, in an appropriate reaction-inert organic solvent, at temperatures up to reflux temperature. 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 n.z. patent OFF ICE i O O 0 7 I y x / O -J 25 MAY 1984 -32- cei vno 40. A process for preparing a compound selected from the group consisting of 1-[[2-(2,4-dichlorophenyl)-1,3-dithiolan-2-yl]methyl]-1H-imidazole, the possible stereochemically isomeric forms, the acid addition salts and the metal salt complexes thereof, according to Claim 39, characterized by reacting 1,2-ethanedithiol with 1—{2—(2,4— dichlorophenyl)-2,2-dimethoxyethyl]-IH-imidazole, and, if desired, preparing possible stereochemical isomeric forms, acid addition salts or metal salt complexes of the products thereof. 41. A process for preparing a compound selected from the group consisting of 1-[[2-(2,4-dichlorophenyl)-4-methyl-1,3-dithiolan-2-yl]methyl]-1H-imidazole, the possible stereochemically isomeric forms, the acid addition salts and the metal salt complexes thereof, according to Claim 39, characterized by reacting 1,2-propanedithiol with l-[2-(2,4-dichlorophenyl)-2,2-dimethoxyethyl]-1H-imidazole, and, if desired, preparing possible stereochemical isomeric forms, acid addition salts or metal salt complexes of the products thereof. from the group consisting of 1-[[2-(2,4-dichlorophenyl)-4-ethyl-1,3-dithiolan-2-yl]methyl]-1H-imidazole, the possible stereochemically isomeric forms, the acid addition salts and the metal salt complexes thereof, according to Claim 39, characterized by reacting 1,2-butanedithiol with l-[2-(2,4-dichlorophenyl)-2,2-dimethoxyethyl]-1H-imidazole, and, if desired, preparing possible stereochemical isomeric forms, acid addition salts or metal salt complexes of the products thereof. from the group consisting of 1-[[2-(2,4-dichlorophenyl)-4-propyl-1,3-dithiolan-2-yl]methyl]-1H-imidazole, the possible stereochemically isomeric forms, the acid addition salts and the metal salt complexes thereof, according to Claim 39, characterized by reacting 1,2-pentanedithiol with l-[2-(2,4-dichlorophenyl)-2,2-dimethoxyethyl]-IH-imidazole, and, if 42. A process for preparing a compound selected 4$. ■ A process for preparing a compound selected -33- desired, preparing possible stereochemical isomeric forms, acid addition salts or metal salt complexes of the products thereof. 44. A process for preparing a compound selected from the group consisting of 2-(2,4-dichlorophenyl)-2-(1H-imidazol-l-yl)ethyl]-1,3-dithiolane, the possible stereochemically isomeric forms, the acid addition salts and the metal salt complexes thereof, according to Claim 39, characterized by reacting 1,2-ethanedithiol with l-(2,4-dichlorophenyl)-2-(lH-imidazol-l-yl)-1-propanone, and, if desired, preparing possible stereochemical isomerical forms, acid addition salts or metal salt complexes of the products thereof. 45. The use, excluding the use on or in humans, as an antimicrobial agent, of a compound of the formula (I) herein. WEST-WALKER,^ McCACE