NL8201572A - Phenyl-propenyl-imidazole derivs. - useful as antimicrobial agents and fungicides - Google Patents

Abstract

Phenylpropenylimidazoles of formula (I) and their acid-addn. salts are new: (where n is 0-2; R1 is halogen, CF3 or 1-6C alkyl or alkoxy; R3 is 1-6C alkyl, 2-4C alkenyl or 3-6C cycloalkyl; R3 is H, 1-6C alkyl or 2-4C alkenyl; R4 is H, 1-6C alkyl or NO2). (I) are antimicrobial agents active against fungi (esp. Candida and Trichophyton app.) and Gram-positive bacteria. They may also be used as fungicides for protection of plants and foodstuffs. The cpd. 1-(2-(4-chlorobenzyl) -3,3-dimethyl-1-butenyl) -1H-imidazole is specifically claimed.

Description

c * J * "* \

Gist-Brocades N.V.

Fropenyllldazolder vessels with fungicidal activity, methods of their preparation and preparations containing these compounds.

Applicants cite Piet Johannes Akkerboom and Cornells van der Stelt as inventors.

The invention relates to new propenylimidazole derivatives of the formula "v" Ox 10 \

f * I

Hf -

15 VA

where n is 0, 1 or 2,

R1 represents a halogen atom, a trifluoromethyl group or an alkyl-20 or alkoxy group with at most 6 carbon atoms, R2 represents an alkyl group with at most 6 carbon atoms, an alkenyl group with 2 to 4 carbon atoms or a cycloalkyl group with 3 to 6 carbon atoms, R3 a hydrogen atom, an alkyl group with at most 6 carbon atoms or an alkenyl group with 2 to 4 carbon atoms and R4 represents a hydrogen atom, an alkyl group with at most 6 carbon atoms or a nitro group, and their acid addition salts.

The terms "alkyl and" alkenyl "in this specification include both straight and branched groups.

The new propenylimidazole derivatives of formula I and their acid addition salts are active against fungi, a 8201572 w. * - 2 - group of microorganisms including fungi, yeasts and dermatophytes. In particular, they are active against species of the genera Candida and Trychophyton.

In the form of free bases or pharmaceutically acceptable acid addition salts, the compounds can be used to control local and systemic conditions in humans and animals caused by these organisms. The compounds of formula I and their acid addition salts can also be used to control fungal infections in agricultural and horticultural products such as fruits, seeds, bulbs and tubers and in foods such as cheese and sausages.

The propenylimidazoles of formula I and their acid addition salts also exhibit antibacterial activity, especially against gram-positive bacteria, such as Bacillus subtilis and 15 different species of the genera Staphylococcus and Streptococcus

Preferred compounds of formula I for their activity are those in which R 1 is chloro, η 1 or 2 and R 2 alkyl of 2 to 4 carbon atoms and R 3 and R 3. 20 are both hydrogen. Especially preferred are the compounds in which (R1) n is 4-chloro or 2,4-dichloro and / or R2 is n-propyl, sec-butyl, tert-butyl or cyclohexyl.

Especially preferred is the compound 1- 2- (4-chlorophenyl) methyl -3,3-dimethyl-1-butenyl-1H-25 imidazole and its acid addition salts.

Several compounds similar in structure to the compounds of formula I are already known. French patent application 7833416 is directed to the preparation of compounds having amoebicidal and antitrichomonas activity of the formula

-N

35 ° 2Ν ~ ΝνΧ · "Κι

R

8201572 s-3 - wherein R can represent an unsaturated, straight or branched chain hydrocarbon group substituted with a phenyl group and wherein R 1 can represent an alkyl group of 1 to 8 carbon atoms or a nitro group. In the compounds actually described, R is a lower alkyl group.

German patent application 2845406 relates to compounds of the formula N-i

O

15 Λ 4 - (R) 20 wherein A represents a straight or branched alkylene group of 1 to 3 carbon atoms or a straight or branched alkenylene or alkinylene group of 2 or 3 carbon atoms, n is an integer (at least 1) and R is a represents a saturated alkyl group of 1 to 4 carbon atoms or an unsaturated alkyl group of 2 to 4 carbon atoms. The definitions of the symbols are further subject to some limitations as to the possible combinations.

The compounds inhibit the synthesis of thromboxane A2 and are therefore effective against thromboembolic disorders. In the compounds actually described, the imidazol core is substituted in 1 position with a benzyl or cinnamyl group.

35 French Patent No. 1,486,817 relates to compounds of the formula 8201572 - 4 -

\ / N - Bi IV

5 · i.

R1 may represent, inter alia, a saturated or unsaturated, straight or branched chain alkyl group of 1 to 13 carbon atoms, which may be substituted with a phenyl, a nitrophenyl or an alkyl phenyl group.

R2 represents a hydrogen atom or an alkyl group of 1 to 3 carbon atoms optionally substituted with a hydroxyl group and R3 represents a hydrogen atom or an ethyl group, optionally substituted with hydroxyl or chlorine.

The compounds show synergistic activity with insecticides of the pyrethrin, carbamate and phosphate type. The compounds actually described do not include phenylpropenylimidazoles.

German patent application 2750030 describes analogous compounds having an insecticidal effect.

Finally, reference can be made to the Netherlands patent application 8005204 filed on September 17, 1980 and the European patent application 81201040.3 based on September 16, 1981 based thereon, which relates to antimycotics of the formula U.L R,

2 V.

30 ^ H

C - R.

5 3

N

/ X 35 in which the different symbols have the same meanings as in formula I.

According to the invention, the propenylimidazole derivatives of * 5201572 - 5-5% * * derivatives of formula I can be prepared by an imidazole propanol of the formula

"• 'XX

CH-1 R | X0H

10 ° H "R3

N

To dehydrate, for example by treatment with a water-extracting agent, preferably thionyl chloride. Preferably, the reaction with thionyl chloride is carried out at low temperature (t R4 P »15 in which the R symbols and n have the meanings mentioned above. for example, between -10 and + 10 ° C) in pyridine.

The starting compounds of the formula VI can be obtained by a benzylmagnesium bromide of the formula 25

X

-CHg MgBr VII

Wherein R] and n have the meanings mentioned above to react with a ketone of the formula 35 8201572 i \ - 6 -, \ K \ - CH - C - R »\ / i I1 2 * 3 ° 5 R4 wherein R2, R3 and R4 have the aforementioned meanings and to hydrolyze the product obtained. For example, the reaction can be carried out by heating the compounds in an anhydrous organic solvent such as diethyl ether or tetrahydrofuran and hydrolyzing the resulting compound with a dilute ammonium chloride solution.

The preparation of the compounds of the application is illustrated by the following Examples. In the NMR spectra, tetramethylsilane served as an internal (in CDCI3) or external (in DMSO-dg) standard. The chemical shifts are given in ppm.

Example 1 a. 2,4-Dichlorobenzyl bromide

4.5 ml (63 mmol) of phosphorus tribromide were added dropwise to a solution of 21.6 g (0.12 mol) of 2.4 dichlorobenzyl alcohol in 165 ml of diethyl ether. After stirring at 5 ° C for 30 minutes and at room temperature for 30 minutes, the reaction mixture was refluxed for 1 hour. After cooling, the organic layer was separated, washed with water and a sodium bicarbonate solution, dried and evaporated. Yield 97% oil, which slowly solidifies. Melting point 31-32 ° C. The substance was used without further purification.

30 b. 1- (1-lmidazolyl) -3,3-dimethylbutanone-2

52 ml of bromine (1 mol) was added dropwise at 6-10 ° C to a mixture of 100 g (1 mol) of pinakolone, 2 g of aluminum chloride and 250 ml of dry diethyl ether. After stirring for 1 hour, 250 ml of water was added with cooling. The reaction mixture was extracted with diethyl ether. The extract was washed successively with water, 1M sodium bicarbonate solution and brine, dried and evaporated. The resulting oil was taken up in 150 ml of chloroform and on a refluxing mixture of 100 g of 8201572

---: "I.

t #, - 7 - (1.47 mol) imidazole, added 153 ml (1.1 mol) of thylamine and 300 ml of chloroform. After refluxing for 2 hours, the reaction mixture was cooled and extracted with water. The collected water layers were extracted 1x with chloroform. The collected chloroform layers were filtered, dried and evaporated. The residue was purified by silica gel chromatography (9x16 cm) with 10% methanol in ethyl acetate as eluent. Rf (ethyl acetate / methanol 4: 1) = 0.5 Melting point 37-39 ° C.

10 c. 2- (2,4-dichlorobenzyl) -3,3-dimethyl-1- (1-imidazolyl) -butanol-2

To 1 g (0.042 at) of magnesium in 10 ml of dry diethyl ether, a solution of 8.64 g (0.036 mol) of 2.4-15 dichlorobenzyl bromide in 20 ml of diethyl ether was dripped so that the ether refluxed gently. After refluxing for an additional 45 minutes, 23 g (18 mmol) of 1- (1-imidazolyl) -3,3-dimethylbutanone-2 was added under ice cooling. After refluxing for 1 hour, the reaction mixture was poured into a saturated ammonium chloride solution and extracted with methylene chloride. The extract was dried and evaporated. The residue was purified by silica gel chromatography (2.5x55cm) with ethyl acetate / methanol / 25% ammonia 95: 4: 1 as eluent. Rf (ethyl acetate / methanol 9: 1) -0.6.

25 d. 2- (2'-dl-chlorobenzyl) ^, 3-dimethyl-1- (1-1midazolyl) -butene-1 hydrochloride.

To a solution of 2.2 g (6.7 mmol) of 2- (2,4-dichlorobenzyl) -3,3-dimethyl-1- (1-imidazolyl) butanol-2 in 13, 30 ml of pyridine were added at -5 ° C drop a solution of 2.1 ml (29 mmol) of thionyl chloride in 5.5 ml of pyridine. After stirring at room temperature for 2 hours, the reaction mixture was poured into 100 ml of 10% sodium carbonate solution and extracted with ethyl acetate. The extract was dried and evaporated. The residue 35 was chromatographed on silica gel (2.5x47 cm) using ethyl acetate / methanol / 25 ammonia 195: 4: 1 as the eluent. The fractions with the component having Rf (ethyl acetate / methanol 9: 1) = 0.7 were collected and evaporated. The residue was dissolved in 5 8201572-8 * * * ml of toluene, after which 0.9 ml of 3.5δΜ HCl in diethyl ether was added. After standing at 5 ° C for some time, the crystals were filtered off, washed with toluene and dried. Melting point 236-239 ° C. NMR (in DMS0-d6): 1.18 (singlet, 9H), 3.58 (singlet, 2H), 6.94-7.45 (multiplet, 6H), 9.11 (singlet, 1H).

Example 2 a. N, N-diethylcyclohexylcarboxamide

To a solution of 80 ml (0.77 mol) of diethylamine in 320 ml of toluene, a solution of 50 g (0.34 mol) of cyclohexylcarboxylic chloride in 170 ml of toluene was added dropwise at 30-40 ° C. After stirring for 1 hour, the precipitate formed was filtered off and washed with toluene. The filtrate was evaporated and the residue was stirred with 100 ml of hexane. After storing overnight at 5 ° C, the precipitate was filtered off and the filtrate evaporated. n ^ 3 = 1.4735 · The substance was used without further purification.

20 b. Acetylcyclohexane

A mixture of 21.2 g (0.11 mol) of N, N-diethyl-cyclohexylcarboxamide, 8 ml of N, N, N ', N'-tetramethyl ethylene diamine and 230 ml of dry diethyl ether was used at -40 ° C. # 25 solution of methyl lithium in ether is dripped. After stirring at -40 ° C for 45 minutes, 7 ml of methanol, 35 ml of concentrated HCl and water were successively added. The reaction mixture was extracted with diethyl ether. The extract was washed successively with dilute HCl and with sodium bicarbonate solution, dried and evaporated. The residue was distilled in vacuo. Boiling point 70-71 ° C / l8 mm, n ^ 5 = 1Λ4497 (litt. 69 ° C / 12 mm, n16 = 1.4565) c. (2- (1-imidazolyl) acetyl) cyclohexane 35 To a solution of 12.6 g (0.1 mol) acetylcyclohexane in 60 ml of methanol, 5.5 ml of bromine was added at 0-5 ° C. After stirring for 1 hour at 5-10 ° C, 30 ml of water was added. After stirring for an additional 1 hour at room temperature, the 8201572 * i - 9 reaction mixture was neutralized with a 20 g solution. sodium bicarbonate in 300 ml of water and extracted with diethyl ether. The extract was evaporated and the residue taken up in methylene chloride, dried and evaporated again. The residue was taken up in 20 ml of chloroform and added dropwise to a refluxing mixture of 9.9 g (0.146 mol) imidazole, 15.3 ml triethylamine and 30 ml chloroform. After refluxing for 1 hour, the reaction mixture was cooled, washed 2x with water and evaporated. The residue was purified by silica gel chromatography (9x15.5 cm) with ethyl acetate / methanol / 25% ammonia 95: 4: 1 as eluent.

d. 1- (4-chlorophenyl) -2-cyclohexyl-3- (1-imidazolyl) propanol-2

To a solution of 4-chlorobenzylmagnesium-15 bromide (from 0.02 at Mg and 0.019 mol of 4-chlorobenzyl bromide) in 20 ml of diethyl ether, a solution of 2.4 g (12.7 mmol) (2- (1-imidazolyl)) drop of acetylcyclohexane in 10 ml of tetrahydrofuran After refluxing for 30 minutes, the reaction mixture was poured into 50 ml of 20% ammonium chloride solution and extracted with methylene chloride The extract was washed with ammonium chloride solution, dried and evaporated, the residue was taken up in 20 ml of ethyl acetate and evaporated to slightly smaller volume After some scratching the substance started to crystallize After overnight in the refrigerator the solid was filtered off and dried Rf (ethyl acetate / methanol 4: 1) = 0.7.

e. 3- (4-chlorophenyl) -2-cyclohexyl-1- (imidazolyl) propene-1 hydrochloride.

In a suspension of 1.97 g (6.2 mmol) 1— (4-30 chlorophenyl) -2-cyclohexyl-3- (1-inidazolyl) propanol-2 in 11 ml of dry pyridine, at -3 a -8 ° 0 drop a solution of 1.7 ml thionyl chloride in 4 ml pyridine. After stirring at room temperature for 2 hours, the reaction mixture was poured into 100 ml of 10% sodium carbonate solution and extracted with ethyl acetate. The extract was evaporated. Evaporation with toluene 2x removed water and the residue was chromatographed on silica gel (2.5x48 cm) with ethyl acetate / methanol / 25% ammonia 195: 4: 1 as eluent. The fractions with the component having Rf 1 * 8201572 - 10 - (ethyl acetate / methanol / 25 # ammonia 97: 2: 1) = 0.53 were collected and evaporated. The residue was taken up in toluene and converted into the hydrochloride with 0.8 ml of 3.5δ HCl in diethyl ether. A mixture of the E and Z isomers was formed.

5 Melting point 171-173 ° C. NMR (in DMSO-dg): 0.8-2.2 (multiplet, 11H), 3.43 + 3.49 (2 x singlet, 2H), 6.4 + 6.8 (2 x singlet, 1H) , 7.29-7.63 (multiplet, 6H), 9.24 (broad singlet, 1H).

Example 3 10 a. 2- (3,4-dlchlorobenzyl) -3,3-dlmethyl-1- (1-1midazolyl) -butanol-2

To a solution of 3,4-dichlorobenzylmagnesium bromide (from 0.062 at Mg and 0.054 mol 3,4-dichlorobenzyl-15 bromide) in 45 ml diethyl ether, a solution of 4.5 g (0.027 mol) 1- (1) was added at room temperature. imidazolyl) -3,3-dimethyl-butanone-2 (see Example 1) dropwise into 35 ml of tetrahydrofuran. After refluxing for 75 minutes, the reaction mixture was poured into 20/5 ammonium chloride solution and extracted with methylene chloride. The extract was evaporated, taken up in chloroform, dried and evaporated again. The residue was recrystallized from 10 ml of ethyl acetate. Rf (ethyl acetate / methanol 9: 1) = 0.5.

25 b. 2- (3, ^ - dichlorobenzyl) -3,3-dimethyl-1- (1-imldazolyl) -butene-1 hydrochloride

In a suspension of 1.9 g (5.8 mmol) of 2- (3,4-dichlorobenzyl) -3,3-dimethyl-1- (1-imidazolyl) butanol-2 in 11 ml of dry pyridine, at -6 a Drop a solution of 1.8 ml of thionyl chloride in 5 ml of pyridine at -8 ° C. After stirring at room temperature for 90 minutes, the reaction mixture was poured into 100 ml of 10 # sodium carbonate solution and extracted with ethyl acetate. The extract was dried and evaporated. The residue was chromatographed on silica gel (2.5x52 cm) with 35 ethyl acetate / methanol / 25 # ammonia 195: 4: 1 as eluent. The fractions with the component having Rf (ethyl acetate / methanol 9: 1) = 0.74 were collected and evaporated. The residue was taken up in toluene and converted into hydrochloric acid with 0.7 ml of 3.58M HCl and diethyl ether. A mixture of the E and Z isomers was formed. Melting point 168-170 ° C. NMR (in DMSO-dg): 0.92 + 1.20 (2 x singlet, 9H), 3.63 + 3.68 (2 x singlet, 2H), 6.47 (singlet, 0.6H), 6 .9-7.9 (multiplet, 5.4H), 9.26 + 9.46 (2 x 5 singlet, 1H).

Example 4 a. 2-Cyclohexyl-3- (3,4-chlorchlorphenyl) -1- (1-lmldazolyl) -10 propanol-2

To a solution of 3,4-dichlorobenzylmagnesium bromide (from 0.0625 at Mg and 0.054 mol 3,4-dichlorobenzyl bromide) in 40 ml diethyl ether, a solution of 5.2 g (0.027 mol) (2- (1-imldazolyl) acetyl) cyclo-15 hexane (see Example 2) dropwise into 35 ml of tetrahydrofuran. After stirring at reflux temperature for 105 minutes, the reaction mixture was poured into 100 m 20% ammonium chloride solution and extracted with methylene chloride, the extract was washed with ammonium chloride solution, dried and evaporated. The residue was recrystallized from 10 ml of ethyl acetate. Rf (ethyl acetate / methanol 9: 1) = 0.6.

b. 2-Cyclohexyl-3- (3,4-dlchlorophenyl) -1- (1-imidazolyl) propene 1 hydrochloride 25 At a suspension of 3.1 g (8.8 mmol) 2-cyclohexyl-3- (3, 4-dichlorophenyl) -1- (1-imidazolyl) propanol-2 in 17 ml of dry pyridine was added dropwise at -4 a -10 ° C, a solution of 2.7 ml of thionyl chloride in 7 ml of pyridine. After stirring at room temperature for 105 minutes, the reaction mixture was poured into 160 ml of 10% sodium carbonate solution and extracted with ethyl acetate. The extract was dried and evaporated. The residue was chromatographed on silica gel (2.5x52 cm) with ethyl acetate / methanol / 25 / ammonia 195: 4: 1 as eluent. The fractions with the component having Rf (ethyl acetate / methanol 9: 1) = 0.67 were collected and evaporated. The residue was not yet completely pure, since an oil formed during the preparation of the hydrochloride. The free base was therefore purified on a Lobar Lichroprep Si60 column C from Merck with ethyl acetate / meth-8201572 1 * 12 anole / 25 # ammonia 198: 1: 1 as eluent. The resulting substance was converted into the hydrochloride with 3.58M HCl in diethyl ether. Melting point 159-161 ° C. NMR (in DMS0-6ö): 0.8-2.3 (multiplet, 11H), 3.52 (singlet, 2H), 6.43 (singlet, 1H), 7.1-7.8 (multiplet, 5H), 9.15 (singlet, 1H).

i

Example 5 a. 2-Cyclohexyl-1- (2,4-dichlorophenyl) -3- (1-imidazolyl) propanol-2

To a solution of 2,4-dichlorobenzylmagnesium bromide (from 0.083 at Mg and 0.079 mol of 2,4-dichlorobenzyl bromide) in 65 ml of diethyl ether, a solution of 6.3 g (0.033 mol) (2- (l imidazolyl) acetyl) cyclo-15 hexane (see Example 2) dropwise into 35 ml of tetrahydrofuran. After stirring at room temperature for 2 hours, the reaction mixture was poured into 20 # ammonium chloride solution and extracted with methylene chloride. The extract was washed with ammonium chloride solution, dried and evaporated. The residue 20 was chromatographed on silica gel (9x14 cm) using ethyl acetate / methanol / 25 # ammonia 95: 4: 1 as the eluent. The oil obtained crystallized partly on dissolution in acetone. Hf (ethyl acetate / methanol 9: 1) = 0.525 b. 2-Cyclohexyl-3- (2,4-dichlorophenyl) -1-imidazolyl) propene-1 hydrochloride

To a suspension of 3.9 g (11 mmol) of 2-cyclohexyl-1- (2,4-dichlorophenyl) -3- (1-imidazolyl) propanol-2 in 20 ml of pyridine at -10 ° C, a solution of 3 Drop 4 ml of thionyl-30 chloride into 8 ml of pyridine. After stirring at 0 ° C for 1 hour, the reaction mixture was poured into 100 ml of 20 # sodium carbonate solution and extracted with ethyl acetate. The extract was washed with brine, dried and evaporated. The residue was chromatographed on silica gel (2.5x66 cm) using ethyl-35 acetate / methanol / 25 # ammonia 195: 4: 1 as the eluent. The fractions - with the component having Rf (ethyl acetate / methanol 9: 1) = 0.69 were collected and evaporated. The product was taken up in toluene and converted into the hydrochloride 8201572 ρ, 13-13 with 3.58M HCl in diethyl ether. A mixture of the E and Z isomers was formed. Melting point 126-129 ° C. NMR (in DMSO-dg): 1.0-2.3 (multiplet, 11H), 3.54 (broad singlet, 2H), 6.06 + 6.84 (2 x singlet, 1H), 7.2- 7.7 (multiplet, 5H), 9.15 + 9.26 (2 x singlet, 1H).

5

Example 6 a. 1- (1-Imidazolyl) -3-methylbutanone-2

In a cooled solution of 86 g (1 mole) of 3-10 methylbutanone-2 in 600 ml of methanol, 55 ral bromine was dropped at a fairly high rate, causing the temperature to rise from -10 ° C to 3 ° C. After stirring at 10 ° C for 2 hours and at room temperature for 16 hours, the reaction mixture was poured into a solution of 75 g of sodium carbonate in 900 ml of water and extracted with 15 d-ethyl ether. The extract was washed with 200 ml of 10% potassium carbonate, dried and evaporated. The residue was taken up in 100 ml chloroform and added dropwise to a refluxing mixture of 100 g (1.47 mol) imidazole, 155 ml triethylamine and 290 ml chloroform. After refluxing for 2 hours, the reaction mixture was cooled, washed 2x with 250 ml of water, dried and evaporated. The residue was chromatographed on silica gel (9x16 cm) using ethyl acetate / methanol / 25 # ammonia 95: 4: 1 as the eluent. Rf (ethyl acetate / methanol / 25 # ammonia 8: 1: 1) = 0.6.

25 b. 2- (4-Chlorobenzyl) -1- (1-imidazolyl) -3-meth, ylbutanol-2

To a solution of 4-chlorobenzylmagnesium bromide (from 0.063 at Mg and 0.06 mol of 4-chlorobenzyl bromide) in 55 ml of diethyl ether, a solution of 5 g (0.033 mol) of 1- (1-imidazolyl) -3 was added at 5 ° C. -methylbutanone-2 added in 25 ml of tetrahydrofuran. After stirring at room temperature for 2 hours, the reaction mixture was poured into 200 ml of a 20% ammonium chloride solution and extracted with methylene chloride. The extract was washed with ammonium chloride solution, dried and evaporated. The residue was chromatographed on silica gel (7.5x16 cm) with ethyl acetate / methanol / 25 # ammonia 95: 4: 1 as eluent. Rf (ethyl acetate / methanol / 25 # ammonia 8: 1: 1) = 0.7c. 2- (4-Chlorobenzyl) -1- (1-lmidazole, yl) -3-methylbutene-1-hydrochloride 8201572-14-.

A solution of 5.5 g (20 mmol) of 2- (4-chlorobenzyl) -1- (1-imidazolyl) -3-methylbutanol-2 in 36 ml of pyridine was dissolved at -2 a -5 ° C of 6.2 ml of thionyl chloride in 10 ml of pyridine. After stirring at 0 ° C for 105 minutes, the reaction mixture was poured into 100 ml of 10% sodium carbonate solution and extracted with ethyl acetate. The extract was dried and evaporated. The residue was chromatographed on silica gel (2.5x73 cm) with ethyl acetate / methanol / 25% ammonia 195: 4: 1 as the eluent. The fractions with the component containing Rf 10 (ethyl acetate / methanol / 25y5 ammonia 16: 1: 1) = 0.7 were collected and evaporated. The product was taken up in toluene and converted to the hydrochloride with 3.58M HCl in diethyl ether. A mixture of the E and Z isomers was formed. Melting point 103-105 ° C. NMR (in DMSO-dö): 0.96 + 1.11 (2 x doublet, 6H), 2.0-15 2.8 (multiplet, 1H), 3.50 (broad singlet, 2H), 7.08 -7.30 (multiplet, 5H), 7.75 (multiplet, 2H), 9.38 (broad singlet, 1H).

Example 7 20 a. Cx - [(4-Chlorophenyl) methyl 3 -a- (1,1-dimethyl-ethyl) -1H-1mldazole-1-ethanol

To 4 g (0.17 at) of magnesium in 150 ml of dry diethyl ether, 24 g (0.15 mol) of 4-chlorobenzyl chloride were added dropwise under reflux under nitrogen. After refluxing for another 30 minutes, 14 g (0.09 mol) of 1-1H-imidazol-1-yl-3,3-dimethyl-2-butanone were added dropwise into 100 ml of dry tetrahydrofuran, after which the mixture was refluxed for an additional 2 hours. Then it was cooled and decomposed with an ammonium chloride solution. The organic layer was separated, dried and evaporated. The desired substance crystallized from the solution of the residue in diethyl ether. Melting point 151 ° C.

b. 1- [2- [(4-Chlorophenyl) methyl] -3,3-dimethyl-1-butenyl ^ -1H-imidazole hydrochloride 35 To a solution of 8.5 g of no - ((4-chlorophenyl) methyl] - α- (1,1-dimethylethyl) -1H-imidazole-1-ethanol in 90 ml of pyridine was added dropwise with 9 ml of thionyl chloride while stirring at 0 ° C. After stirring for two hours at room temperature, the solution was poured into ice and the mixture extracted with ethyl acetate After drying and evaporation, the oil was purified on a diesel gel column with ethyl acetate / chloroform / 25 ammonia 50: 50: 1 as eluent. Two substances were isolated, the first of which was the first desired base was This was converted into the hydrochloride The substance was found to be a mixture of the E and Z isomers Melting point 146 ° C.

NMR: 0.89 + 1.17 (2 x singlet, tert-butyl); 3.60 + 3.65 (2 x 10 broad singlet, CH2); 6.40-7.90 (multiplet); 8.89 + 9.09 (2 x broad singlet, CH in 2 position of imidazole ring).

Example 8 a. 2— (2,4-dichlorobenzyl) -1-Cl-imidazole, yl) -3-methylbutanol-2 In a solution of 2,4-dichlorobenzylmagnesium bromide (from 0.096 at Mg and 91 mmol 2, 4-dichlorobenzyl bromide) in 85 ml diethyl ether was added dropwise with ice cooling to a solution of 7.6 g (50 mmol) of 1- (1-imidazolyl) -3-methylbutanone-2 (see Example 6) in 30 ml of tetrahydrofuran. This was followed by a precipitate which dissolved when 50 ml of tetrahydrofuran was added. After refluxing for 30 minutes, the reaction mixture was poured into 300 ml of 20% ammonium chloride solution and extracted with ethyl acetate. The extract was washed with ammonium chloride solution, dried and evaporated. The residue 25 was chromatographed on silica gel (7.5 x 15 cm) with ethyl acetate / methanol / 25 ammonia 195: 4: 1 as eluent. Rf (ethyl acetate / methanol / 25% ammonia 18: 1: 1) = 0.6.

b. 2- (2,4-dichlorobenzyl) -1- (1-imidazolyl) -3-methyl-butene-1 hydrochloride.

In a suspension of 4.2 g (13.4 mmol) of 2- (2,4-dichlorobenzyl) -1- (1-imidazolyl) -3-methylbutanol-2 in 25 ml of pyridine at -5 a -10 ° C a solution of 4.2 ml of thionyl chloride in 6.8 ml of pyridine was dropped. After stirring at 0 ° C for 105 minutes, the reaction mixture was poured into 100 ml of 10% sodium carbonate solution and extracted with ethyl acetate.

The extract was dried and evaporated. The residue was chromatographed on silica gel (2.5 x 70 cm) with ethyl acetate / methanol / 25 ammonia 195: 4: 1 as eluent. The 8201572 t-16 fractions with the component containing Rf (ethyl acetate / methanol / 25 / ammonia 18: 1: 1 = 0.7 were collected and evaporated. The residue was converted into the hydrochloride with 3.5 M HCl in diethyl ether. A mixture of the E and Z isomers was formed.

5 Melting point 138-142 ° C. NMR (in DMSO-dé): 1.06 + 1.10 (2 x doublet, 6H), 1.9-2.7 (multiplet, 1H), 3.57 (broad singlet, 2H), 6.11 + 6.97 (2 x singlet, 1H), 7.2-7.8 (multiplet, 6H), 9.23 + 9.37 (2 x singlet, 1H).

Example 9 a. 2- (4-Bromobenzyl) -1- (1-imldazolyl) -3,3-dimethylbutanol-2

To a solution of 4-bromobenzylmagnesium bromide (from 25 mat Mg and 20 mmol 4-bromobenzyl bromide) in 40 ml diethyl ether, a solution of 3 g (18 mmol) 1- (1-imidazolyl) -3,3- was added at 10 ° C. dimethylbutanone-2 (see Example 1) in 15 ml of diethyl ether. After stirring at room temperature for 30 minutes, 25 ml of 20¾ ammonium chloride solution was added and the reaction mixture was extracted with ethyl acetate. The extract was dried and evaporated. The residue was dissolved in a warm mixture of 15 ml of methylene chloride and 25 ml of ethyl acetate. The solution was partially evaporated and set aside. The crystallized substance was filtered off and dried. A second amount was obtained by chromatography of the mother liquor on silica gel (3 x 50 cm) with ethyl acetate / methanol / 25 ammonia 198: 1: 1, later 95: 4: 1 as eluent. Rf (ethyl acetate / methanol / 25 / ammonia 18: 1: 1) = 0.7b. 2- (4-Bromobenzyl) -1- (1-imldazolyl) -3,3-dimethylbutene-1 30 At a suspension of 2.5 g (7.5 mmol) 2- (4-bromobenzyl) -1- (1-Imidazolyl) -3,3-dimethylbutanol-2 in 14 ml pyridine was dropped at -5 to -10 ° C, a solution of 2.4 ml thionyl chloride in 7 ml pyridine. After stirring at 0 ° C for 1 hour, the reaction mixture was poured into 100 ml of 10¾ sodium carbonate solution and extracted with ethyl acetate. The extract was dried and evaporated. The residue was chromatographed on silica gel (3 x 50 cm) with ethyl acetate / methanol / 25 ammonia 195: 4: 1, later 100: 4: 1 as eluent. The groups with the 8201572 Λ Γ. 17 component with Hf (ethyl acetate / methanol / 255S ammonia 38: 1: 1) = 0.7 were collected and evaporated. The residue was taken up in 7 ml diethyl ether and treated with 1.2 ml 3.58 DJ HCl in diethyl ether. A waxy substance precipitated, which was stirred with ethyl acetate after decantation, leading to crystallization. A mixture of the E eri de Z isomer was formed. Melting point 160-170 ° C. NMR (in CDCI3): 1 * 03 + 1.27 (2 x singlet, 9H), 3.52 + 3.62 (2 x singlet, 2H), 6.15 (wide singlet, 0.55 H), 6 .7-7.6 (multiplet, 6.45H), 9.29 + 9.45 (2 x 10 singlet, 1H).

The compounds of the invention were tested in vitro using the conventional agar dilution test. The results after two days (in tests with Candida albicans also after five days) were expressed as the minimum concentrations that gave complete inhibition of the tested strains (MIC). A number of results are shown in the following tables. The letters A through E have the following meanings.

A: 1 - [2 - [(4-chlorophenyl) methyl] -3,3-dimethyl-1-butenyl] -1H-imidazole hydrochloride; B: 3- (4-chlorophenyl) -2-cyclohexyl-1- (1-imidazolyl) -propylene-1 hydrochloride; C: 2- (2,4-dichlorobenzyl) -3,3-dimethyl-1- (1-25 imidazolyl) butene-1 hydrochloride; D: 2- (3,4-dichlorobenzyl) -3,3-dimethyl-1- (1-imidazolyl) butene-1 hydrochloride; E: 2-cyclohexyl-3- (3,4-dichlorophenyl) -1- (1-imidazycyl) propylene-1 hydrochloride.

O

8201572, -5 «

- 18 - Table I

MIC50 in μg / ml A B C D E! mico-nazol

Gram-positive bacteria Staphylococcus aureus A321 3 12.5 6 6 3 1.5 A2000 3 12.5 6 6 1.5 0.8 A355 3 12.5 6 6 1.5 0.8

Streptococcus pyogenes ATCC 12344 25 25 12.5, 12.5. 1.5 3 faecalis 180 6 25 12.5 25 3 3 faeclum A1078 3 3 1.5 3 1.5 0.8 ATCC 8043 6 25 12.5 25 12.5 6

Bacillus subtilis ATCC 6633 3 6 6 6 0.8 0.8

Trichophyton - species T. mentagrophytes R 177 0.2 25 1.5 6> 100 25 R 178 0.2 12.5 1.5 1.5> 100 0.8

Bayer A2352 0.2 25 12.5 6> 100 100

Rotta RRL305 0.2 66 6> 100 6 367-68 0.2 1.5 3), 05 0.8 1.5 <0.05 asteroids 421-67 0.2 3 0.4 1.5 3 0, 1 T. rubrum A8l0 0.2 1.5 $ 0.05 0.4 3 0.1 494-62 0.2 12.5 3 0.8> 100 3 218-65 0.05 12.5 0.2 0 .8> 100 3 A2038 0.05 - - 1.5 0.4 T. verrucosum 134-66 0.013 3 $ 0.05 0.2 12.5 1.5 A2922, 0.013 3 <0.05 0.2 12 .5 0.8 T. equinum 182-76 0.05 12.5 6 1.5> 100 50 444-51 0.013 0.4 <0.05 <0.05 - <0.05 T. quinckeanum A2040 0, 1 25 12.5 6> 100 25 T. Schoenleinli 435-63 0.025 6 0.4 <0.05> 100 12.5 T. Violaceum 442-62 0.003 1.5 30.05 <0.05 1.5 0 .4 T. soudanense 440-63 0.003 0.2 <0.05 <0.05 0.8 <0.05 T. tonsurans 561-50 0.05 6 0.4 0.8 1.5 0.8 • i * 8201572 * ί, - 19 -

Table II

MIC in µg / ml bU

t A B C D E miconazole 2 days 5 days 2 days 5 days 2 days 5 days 2 days 5 days 2 days 5 days 2 days 5 days

Candida albicans A7 36 12.5 12.5 12.5 12.5 663333 A3140 3 3 12.5 12.5 6 12.5 3 6 3 3 3 3 A3141 3 6 12.5 12.5 6 12.5 3 6 12.5 12.5 3 6 A3142 3 6 12.5 12.5 12.5 12.5 6 6 12.5 12.5 6 6 A3143 3 3 12.5 12.5 6 12.5 3 3 3 6 3 3 A3144 3 6 12.5 12.5 12.5 12.5 336633 A3145 3 3 12.5 12.5 12.5 12.5 366 12.5 3 3 A3165 3 3 12.5 12.5 12 .5 12.5 666 12.5 3 3 A3166 3 6 12.5 25 6 6 6 6 12.5 12.5 6 6 A3167 336666666666 A3168 366666 12.5 12.5 12.5 25 .12.5 12, 5 A3169 6 6 12.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5 6 6 A3171 6 6 12.5 25 12.5 12.5 12.5 12.5 12 .5 25 6 12.5 A3184 6 6 12.5 12.5 12.5 12.5 6 6 6 12.5 6 6 A3190 6 6 12.5 25 12.5 12.5 12.5 12.5 3 12.5 6 25 A3191 3 6 12.5 12.5 12.5 12.5 366633 A3192 3 3 12.5 12.5 12.5 12.5 666636 A3194 3 6 12.5 12.5 12.5 12.5 12.5 12.5 12.5 25 6 6 A3196 3 3 12.5 12.5 12.5 12.5 6 12.5 3.3 1.5 3 8201 572 - 20 -

The invention includes pharmaceutical compositions containing at least one propenylimidazole derivative of the formula I or a pharmaceutically acceptable acid addition salt thereof as the active ingredient. These preparations can be prepared using conventional methods in pharmacy.

The substances can be administered by oral, local, intraperitoneal, parenteral, or rectal route. The oral application is of particular importance because the substances according to the invention are absorbed relatively well. For oral administration, for example, tablets or capsules can be chosen, formulated according to the pharmaceutical methods customary for this type of preparation. Locally applicable dosage forms can be in the form of powders, ointments, creams or sprays, but the compounds found can also be used in other dosage forms. The said pharmaceutical preparations may contain, in addition to the active substance, a suitable carrier, for example a dermatological ointment base such as polyethylene glycol 400 or plastibase and further one or more pharmaceutical excipients. The content of active substance in, for example, an ointment is preferably between 0.5 and 10%, a percentage of 2% is preferred.

The invention also includes compositions for combating fungal infections in agricultural and horticultural products and in foodstuffs containing one or more compounds of the formula I or their acid addition salts.

Liquid formulations are preferably used, such as solutions, suspensions and emulsions of the active substance in water or an organic solvent. The free bases of the formula I can be dissolved in organic solvents, for example in hydrocarbon mixtures such as petrol, aromatics such as benzene, hydrochlorides such as chlorobenzenes, chloromethanes and chloroethanes, alcohols such as butanol and glycol or highly polar solvents such as dimethylformamide and dimethyl sulfoxide. .

Preferably, the compounds are used in the form of their acid addition salts, which can be dissolved in water to which a surfactant has optionally been added.

8201572 f - 21 - ** · .- p *

As examples of other formulations, there may be mentioned dusts, in which the active substance is mixed with an aerosol propellant such as dichlorodifluoromethane or trichlorofluoromethane, and powders consisting of a mixture of the active substance with a solid carrier, such as kaolin, talc or diatomaceous earth .

The products to be protected can be treated, for example, by mixing or dipping them in a liquid containing a compound of the formula I or by spraying or brushing them with such a liquid. It will be clear that the amount of active substance to be used will depend on the nature of the product to be treated, especially on the total surface area.

Examples of preferred amounts to be used, in relation to the amount of product to be treated, are - in the case of seeds and grains (diameter 0.5-10 mm): 1-10,000 ppm (weight), in particular 10-2000 ppm; - for bulbs, tubers and potatoes (diameter 0.5-6 cm): 0.2-1500 ppm (weight), in particular 2-300 ppm; With cheese: 0.5-500 mcg / cm2, in particular 2-20 mcg / cm2.

\ 8201572

Claims (13)

Propenylimidazole derivatives according to claim 1, wherein R 1, chlorine, 1 or 2 and R 2 are alkyl of 2 to 4 carbon atoms and R 3 and R 4 are both hydrogen. Propenylimidazole derivatives according to claim 2, wherein (R 1) n is 4-chloro or 2,4-dichloro and / or R 2 is n-propyl, sec-butyl, tert-butyl or cyclohexyl. 4. 1- [2- [(4-chlorophenyl) methyl] -3,3-dimethyl-1-butenyl] -1H-imidazole and its acid addition salts. 5. Process for the preparation of propenylimidic attic derivatives according to claim 1, characterized in that an imidazole propanol of the formula 8201572 V ^ - 23 - - jk (*,.) "- f! CH- I ^ OH CH - 'R 3 I N, 4- 1 10 κ4 V TSt dehydrates. 6. Process according to claim 5, characterized in that the dehydration is carried out by treatment with thionyl chloride. Process according to claim 6, characterized in that the reaction is carried out at low temperature in pyridine. Preparations effective against fungi, characterized in that they contain, as active ingredient, a propenylimidazole derivative according to any one of claims 1 to 4 or an acid addition salt thereof. Pharmaceutical preparations, characterized in that they contain, as active ingredient, a propenylimidazole derivative according to any one of claims 1 to 4 or a pharmaceutically acceptable acid addition salt thereof. 10. A method for combating fungal infections, characterized in that agricultural or horticultural products or foodstuffs are treated with a propenylimidazole derivative according to any one of claims 1 to 4. Process according to claim 10 for the treatment of seeds and grains, characterized in that from 100 to 1000 ppm of active substance is used, based on the amount by weight of the product to be treated. Process according to claim 11, characterized in that from 10 to 2000 ppm of active substance is used, based on the weight amount of the product to be treated. 8201572 v »¢. =. - 24 - Method according to claim 10 for the treatment of bulbs, potatoes and tubers, characterized in that from 0.2 to 1500 ppm active substance is used, based on the amount by weight of the product to be treated. Method according to claim 13, characterized in that from 2 to 300 ppm of active substance is used, based on the amount by weight of the product to be treated. 15. Process according to claim 10 for the treatment of cheese, characterized in that 0.5 to 500 mcg of active substance are used per cm of product. Process according to claim 15, characterized in that 2-20 mcg of active substance per cm2 is used. 17. Agricultural and horticultural products and foodstuffs treated according to any one of claims 10 to 16. 8201572