DE2922883A1 - N-PHENAETHYLIMIDAZOLE DERIVATIVES, THE PROCESS FOR THEIR MANUFACTURING AND THE PHARMACEUTICAL OR VETERINARY MEDICINAL PRODUCTS CONTAINING THEM - Google Patents

Description

The invention relates to new N-phenethylimidazole derivatives, processes for their preparation and pharmaceutical and veterinary agents containing them.

The novel compounds forming an object of the invention have the general formula

I.

where mean:

A -O- or -S-;

R a) C [deep] 1-C [deep] 8-alkyl, C [deep] 2-C [deep] 8-alkenyl or C [deep] 2-C [deep] 8-alkynyl,

b) a cycloaliphatic radical with 3 to 7 carbon atoms,

c) an aryl or aryl-C [deep] 1-C [deep] 6-alkyl group, in which the aryl groups can be unsubstituted or substituted by one or more substituents from the group halogen, -NO [deep] 2, cyano, C [deep] 1-C [deep] 6-alkyl, C [deep] 1-C [deep] 6-alkoxy, C [deep] 1-C [deep] 6-alkylthio, trihalomethyl, -SO [deep] 2CH [deep] 3;

Z is a branched or straight-chain (unbranched) C [deep] 1-C [deep] 15-alkylene radical;

each of the Y groups, which can be the same or different from one another, in each case one representative from the group hydrogen, halogen, -NO [deep] 2, cyano, C [deep] 1-C [deep] 2-alkyl, C [deep] ] 1-C [deep] 2-alkoxy, C [deep] 1-C [deep] 2-alkylthio, trihalomethyl, -SO [deep] 2CH [deep] 3 and phenyl that may be unsubstituted or substituted by one or more halogen atoms can; and

n is the number 0 or an integer from 1 to 5.

The present invention also encompasses the salts of the compounds of the formula (I), in particular the pharmaceutically and veterinarily acceptable salts and all possible isomers, for example the stereoisomers of the compounds of the formula (I) and their mixtures, the metabolites which have a pharmacologically valuable activity, for example an antifungal activity, as well as the metabolic precursors of the compounds of formula (I).

Examples of salts of the compounds according to the invention, in particular those which are pharmaceutically and veterinary-medically acceptable, are the salts with inorganic acids such as nitric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid and phosphoric acid and those with organic acids such as acetic acid, propionic acid, glycolic acid, Lactic acid, oxalic acid, malonic acid, fumaric acid, malic acid, maleic acid,

Tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid and methanesulfonic acid. Preferred salts of the compounds according to the invention are the salts of the compounds of the formula (I) with inorganic acids, such as nitric acid, hydrochloric acid, hydrobromic acid and sulfuric acid, and in particular the salts with nitric acid.

The alkyl, alkenyl, alkynyl and alkoxy groups can be straight-chain (unbranched) or branched-chain.

Preferred examples of a C [deep] 1 -C [deep] 8 -alkyl group are n-hexyl and n-octyl.

Preferred examples of a C [deep] 2-C [deep] 8-alkenyl group are vinyl and allyl.

Preferred examples of a C [deep] 2-C [deep] 8-alkynyl group are ethynyl and propargyl.

If R is a cycloaliphatic C [deep] 3-C [deep] 7 radical, it is preferably cyclopentyl or cyclohexyl.

When R represents an aryl group, it is preferably phenyl; if R represents an aryl-C [deep] 1-C [deep] 6-alkyl group, this is preferably an aryl-C [deep] 2-C [deep] 6-alkyl.

A preferred halogen atom is fluorine, chlorine or bromine; a trihalomethyl group is preferably trifluoromethyl.

Preferred examples of a C [deep] 1-C [deep] 6-alkoxy group are methoxy, ethoxy and propoxy.

Preferred examples of a C [deep] 1-C [deep] 6-alkylthio group are methylthio, ethylthio and propylthio.

Preferred compounds according to the invention are the compounds of the formula (I) in which A is -O- or -S-, R is phenyl, which is unsubstituted or is substituted by one or more substituents from the group halogen, C [deep] 1-C [deep] 6-alkyl and trihalomethyl, ZC [deep] 1-C [deep] 4-alkylene, Y halogen or unsubstituted phenyl, where then when Y is halogen, n is the number 2, or when Y is unsubstituted phenyl, n is the number 1, and the salts, in particular the pharmaceutically or veterinarily acceptable salts thereof.

Particularly preferred compounds according to the invention are compounds of the formula (I) in which A -O- or -S-, R is phenyl which is unsubstituted or substituted by one or more substituents from the group consisting of halogen and C [deep] 1-C [deep] 4-Alkyl, Z denotes methylene or ethylene, Y denotes chlorine and n denotes the number 2, and the salts, in particular the pharmaceutically and veterinarily acceptable salts thereof.

Examples of preferred compounds according to the invention are as follows:

1) 1- [2,4-dichloro-small beta (2 ', 4'-dichloro-phenoxymethylene-oxy) -phenethyl] -imidazole;

2) 1- [2,4-dichloro-small beta (4'-chlorophenoxymethylene-oxy) phenethyl] imidazole;

3) 1- [2,4-dichloro-small beta (2 ', 4', 5'-trichloro-phenoxymethylene-oxy) -phenethyl] -imidazole;

4) 1- [2,4-dichloro-small beta (3 ', 5'-dichloro-phenoxymethylene-oxy) -phenethyl] -imidazole;

5) 1- [2,4-dichloro-small beta (2 ', 6'-dichloro-phenoxymethylene-oxy) -phenethyl] -imidazole;

6) 1- [2,4-dichloro-small beta (4'-methyl-phenoxymethylene-oxy) -phenethyl] -imidazole;

7) 1- [2,4-dichloro-small beta (2'-chloro-4'-methyl-phenoxymethylene-oxy) -phenethyl] -imidazole;

8) 1- [2,4-dichloro-small beta (2'-chloro-4'-propyl-phenoxymethylene-oxy) -phenethyl] -imidazole;

9) 1- [2,4-dichloro-small beta (4'-tert-butyl-phenoxymethylene-oxy) -phenethyl] -imidazole;

10) 1- [2,4-dichloro-small beta (4'-fluoro-phenoxymethylene-oxy) phenethyl] imidazole;

11) 1- [2,4-dichloro-small beta (4'-trifluoromethyl-phenoxymethylene-oxy) -phenethyl] -imidazole;

12) 1- [2,4-dichloro-small beta (3'-trifluoromethyl-phenoxymethylene-oxy) -phenethyl] -imidazole;

13) 1- [2,4-dichloro-small beta (2'-chloro-4'-ethyl-phenoxymethylene-oxy) -phenethyl] -imidazole;

14) 1- [2,4-dichloro-small beta (2 ', 4', 6'-trichloro-phenoxymethylene-oxy) -phenethyl] -imidazole;

15) 1- [2,4-dichloro-small beta (2'-methyl-4'-chloro-phenoxymethylene-oxy) -phenethyl] -imidazole;

16) 1- [2,4-dichloro-small beta (2 ', 4'-dibromophenoxymethylene-oxy) phenethyl] imidazole;

17) 1- [2,4-dichloro-small beta (2'-chloro-4'-tert-butyl-phenoxymethylene-oxy) -phenethyl] -imidazole;

18) 1- [4-phenyl-small beta (4'-chloro-phenoxymethylene-oxy) -phenethyl] -imidazole;

19) 1- [4-phenyl-small beta (2 ', 4'-dichloro-phenoxymethylene-oxy) -phenethyl] -imidazole;

20) 1- [2,4-dichloro-small beta (4'-chloro-phenoxy-ethylene-oxy) -phenethyl] -imidazole;

21) 1- [2,4-dichloro-small beta (2 ', 4'-dichloro-phenoxyethylene-oxy) -phenethyl] -imidazole;

22) 1- [2,4-dichloro-small beta (2 ', 6'-dichloro-phenoxyethylene-oxy) -phenethyl] -imidazole;

23) 1- [2,4-dichloro-small beta (4'-bromophenoxyethylene-oxy) phenethyl] imidazole;

24) 1- [2,4-dichloro-small beta (4'-methyl-phenoxyethylene-oxy) -phenethyl] -imidazole;

25) 1- [2,4-dichloro-small beta (2'-chloro-4'-methyl-phenoxyethylene-oxy) -phenethyl] -imidazole;

26) 1- [2,4-dichloro-small beta (2'-chloro-4'-ethyl-phenoxyethylene-oxy) -phenethyl] -imidazole;

27) 1- [2,4-dichloro-small beta (2'-chloro-4'-propyl-phenoxyethylene-oxy) -phenethyl] -imidazole;

28) 1- [2,4-dichloro-small beta (2 ', 4', 6'-trichloro-phenoxyethylene-oxy) -phenethyl] -imidazole;

29) 1- [4-phenyl-small beta (2'-chloro-4'-ethyl-phenoxyethylene-oxy) -phenethyl] -imidazole;

30) 1- [2,4-dichloro-small beta (4'-chlorophenoxypropylene-oxy) phenethyl] imidazole;

31) 1- [2,4-dichloro-small beta (2 ', 4'-dichloro-phenoxypropylene-oxy) -phenethyl] -imidazole;

32) 1- [2,4-dichloro-small beta (4'-fluoro-phenoxypropylene-oxy) -phenethyl] -imidazole;

33) 1- [2,4-dichloro-small beta (2'-chloro-4'-ethyl-phenoxypropylene-oxy) -phenethyl] -imidazole;

34) 1- [4-phenyl-small beta (4'-chloro-phenoxypropylene-oxy) -phenethyl] -imidazole;

35) 1- [2,4-dichloro-small beta (4'-chlorophenoxybutylene-oxy) phenethyl] imidazole;

36) 1- [2,4-dichloro-small beta (phenoxybutylene-oxy) phenethyl] imidazole;

37) 1- [2,4-dichloro-small beta (4'-chloro-phenylthio-methylen-oxy) -phenethyl] -imidazole;

38) 1- [2,4-dichloro-small beta (2 ', 4'-dichloro-phenylthio-methylen-oxy) -phenethyl] -imidazole;

39) 1- [2,4-dichloro-small beta (2'-chloro-4'-methyl-phenylthio-methylen-oxy) -phenethyl] -imidazole;

40) 1- [2,4-dichloro-small beta (3 ', 4'-dichloro-phenylthio-methylen-oxy) -phenethyl] -imidazole;

41) 1- [2,4-dichloro-small beta (4'-methyl-phenylthio-methylen-oxy) -phenethyl] -imidazole;

42) 1- [2,4-dichloro-small beta (4'-trifluoromethyl-phenylthio-methylen-oxy) -phenethyl] -imidazole;

43) 1- [2,4-dichloro-small beta (2'-chloro-4'-propyl-phenylthio-methylen-oxy) -phenethyl] -imidazole;

44) 1- [2,4-dichloro-small beta (4'-chlorophenylthio-ethylene-oxy) -phenethyl] -imidazole;

45) 1- [2,4-dichloro-small beta (2 ', 4'-dichloro-phenylthio-ethylene-oxy) -phenethyl] -imidazole;

46) 1- [2,4-dichloro-small beta (2'-chloro-4'-methylphenylthio-ethylene-oxy) -phenethyl] -imidazole;

47) 1- [2,4-dichloro-small beta (2'-chloro-4'-ethylphenylthio-ethylene-oxy) phenethyl] imidazole;

48) 1- [4-phenyl-small beta (4'-chlorophenylthio-ethylene-oxy) -phenethyl] -imidazole;

49) 1- [4-phenyl-small beta (2 ', 4'-dichlorophenylthio-ethylene-oxy) -phenethyl] -imidazole;

50) 1- [2,4-dichloro-small beta (4'-chlorophenylthio-propylene-oxy) phenethyl] imidazole;

51) 1- [2,4-dichloro-small beta (2 ', 4'-dichlorophenylthio-propylene-oxy) phenethyl] imidazole;

52) 1- [2,4-dichloro-small beta (4'-fluorophenylthio-propylene-oxy) -phenethyl] -imidazole, and their salts, in particular their pharmaceutically or veterinarily acceptable salts, especially the salts with nitric acid.

The structural formulas of the abovementioned compounds are given in the table below according to their increasing number.

Tabel

The compounds according to the invention are prepared by a process which is a further subject of the invention by reacting a compound of the general formula

II

wherein Y and n have the meanings given above,

with a compound of the general formula

B'-Z-A-R (III)

wherein Z, A and R have the meanings given above,

where in the above formulas (II) and (III) one of the groups B and B 'is halogen or the residue of a reactive ester of an alcohol and the other is an -OM group, in which M is hydrogen or a cation,

and, if desired, converting a compound of the formula (I) into another compound of the formula (I) and / or, if desired, converting a compound of the formula (I) into a salt and / or, if desired, separating an isomer mixture into the individual isomers.

If B in the compound of the formula (II) or B 'in the compound of the formula (III) is halogen, it is preferably chlorine or bromine. If B or B 'is the residue of a reactive ester of an alcohol, it is preferably -O-mesyl or -O-tosyl.

If B or B 'represents the group -OM, M is preferably a cation, in particular an alkaline cation, such as sodium or potassium.

It can be seen from the above that when B represents halogen or the radical of a reactive ester of an alcohol, the compound of the formula (II) is reacted with a compound of the formula (III) in which B 'represents a group -OM, while when B represents a group -OM, the compound of the formula (II) is reacted with a compound of the formula (III) in which B 'represents halogen or the residue of a reactive ester of an alcohol.

When it is desired to prepare a compound of the formula (I) in which Z represents an unsubstituted or alkyl-substituted methylene group, the reaction between the compound of the formula (II) and the compound of the formula (III) is carried out using a compound of the formula ( II), wherein B represents a group -OM, and a compound of the formula (III), wherein B 'represents halogen.

The reaction between a compound of the formula (II) and a compound of the formula (III) can, for example, be carried out using equimolar amounts of the reagents in a solvent such as an aromatic hydrocarbon, preferably benzene, toluene, xylene, or else in dimethylformamide , Dimethylacetamide, hexamethylphosphoric triamide, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, at temperatures ranging from about 20 ° C to

The reflux temperature of the solvent used will vary, with reaction times varying from about 1 hour to about 12 hours.

The compounds of the formula (III) are known from the literature or they can be prepared from known products by known processes.

The compounds of the formula (II) in which B is -OM in which M is hydrogen can be prepared by reducing compounds of the formula

IV

wherein Y and n have the meanings given above.

The above reduction can be carried out, for example:

a) With sodium borohydride in a solvent such as methyl or ethyl alcohol, or in a mixture of water and ethyl alcohol in equal parts or with lithium aluminum hydride in an anhydrous solvent such as ethyl ether or in tetrahydrofuran at temperatures that in both cases from 0 ° C to vary to reflux temperature for reaction times varying from 1 to 6 hours;

b) by catalytic hydrogenation in the presence of a suitable catalyst, such as palladium, platinum, PtO [deep] 2, ruthenium, Raney nickel, in a solvent, preferably one selected from the group consisting of methyl alcohol, ethyl alcohol, acetic acid and cyclohexane , n-hexane, ethyl acetate, benzene, toluene, whereby one at a pressure varying from atmospheric to about 50 atmospheres and at temperatures varying from about 20 to about 100 ° C.

The compounds of formula (II) in which B is -OM, in which M is a cation, for example an alkaline cation, can be prepared from the corresponding compounds of formula (II) in which B is -OH by treatment with a strong suitable one Base, for example sodium amide or potassium amide, or by treatment with the hydride of an alkali metal, preferably sodium hydride, under conditions such as are generally used in organic chemistry for this type of conversion into a salt.

The compounds of the formula (II) in which B is halogen can be prepared from the corresponding compounds of the formula (II) in which B is -OH by known processes, for example by treatment with a phosphorus trihalide, for example with PCl [deep] 3 or POCl [deep] 3, in a suitable solvent selected, for example, from the group of benzene, toluene and xylene, at the reflux temperature or using an excess of the phosphorus halide at temperatures within the range of about 40 to about 100 ° C, wherein the reaction times vary from 2 to 8 hours in both cases, or by treatment with PCl [deep] 3 or SOCl [deep] 2 in dimethylformamide at about 70 to about 100 ° C. to form a Vilsmeier reagent or by treatment with SOCl [deep ] 2 in a known manner, optionally in the presence of ZnCl [deep] 2 as a catalyst.

The compounds of formula (II) in which B is the residue of a reactive Capable ester of an alcohol, for example an -O-mesyl- or -O-tosyl group, can be prepared from the corresponding compounds of the formula (II), in which B is -OH, by known processes, for example by treatment with the appropriate one Acyl halide, preferably acyl chloride, for example with p-toluenesulphonyl chloride or methanesulphonyl chloride, working, for example, at room temperature in anhydrous pyridine.

The conversion can be carried out in an analogous manner for the compounds of the formula (III). Compounds of formula (IV) can be prepared from the corresponding small alpha-halo-acetophenones of the general formula

V

wherein Y and n have the meanings given above and X is a halogen atom, preferably chlorine or bromine, by reaction with imidazole or a salt thereof with an alkali metal, preferably sodium or potassium, or a silver salt thereof.

The compounds of the formula (V) are known or they can be prepared from known compounds by known processes.

The reaction of a compound of the formula (V) with imidazole or one of its salts can either be carried out in the absence of a solvent at temperatures which vary from about 40 to about 180 ° C., with reaction times which can vary from a few minutes to about 24 hours, using an excess of imidazole or a salt thereof, if necessary, or in the presence a suitable solvent, preferably in dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide, benzene, toluene, ethyl alcohol, dioxane, acetone, at temperatures that vary from 0 ° C to the reflux temperature of the solvent, for reaction times that vary from a few minutes to about 12 hours If necessary, if free imidazole is used, an excess of the latter or a stoichiometric amount of a tertiary base, preferably triethylamine, is used.

The compounds according to the invention have a broad spectrum of antifungal activity and they are therefore suitable in human and veterinary medicine for the treatment of surface and internal mycosis caused by fungi, for example of the genus Trichophyton, Epidermophyton, Microsporum and Candida. Aspergillus niger, Trichophyton asteroides, Trichophyton rubrum, Trichophyton mentagrophytes, Microsporum canis, Candida albicans and Saccharomyces cerevisiae were used as test mycetes.

For example, in the tests carried out in a Sabouraud medium by the serial dilution method, activity values within the range from 0.05 to 12.5 μg / ml, expressed as minimum inhibitory concentrations, were found in 7 strains of the mycetes belonging to the three different genera Candida, Aspergillus and Saccharomyces are found.

In addition, the compounds according to the invention have also proven to be very active against dermatophytes. The activity values, expressed as the minimum inhibitory concentration, lie between 0.1 and 6.2 µg / ml. The compounds according to the invention also have an antibacterial activity and they are therefore also suitable in the frequent case of bacterial superinfection of mycotic injuries, in particular against gram-positive bacteria. Bacillus subtilis, Staphylococcus aureus, Streptococcus pyogenes, Streptococcus faecalis, Clostridium bifermentans, and Clostridium sporogenes were used as test microorganisms. Antibacterial activity was determined using the serial dilution method in a brain-heart infusion agar or in a thioglycolate fluid medium and values, expressed as the minimum inhibitory concentration, were obtained within the range of 0.4 to 3.1 µg / ml.

In view of their high therapeutic index (LD [low] 50 / ED [low] 50), the compounds according to the invention can be used safely both in human medicine and in veterinary medicine. For example, the acute toxicity (LD [low] 50) of the compound was 1- [2,4-dichloro-small beta (2 ', 4'-dichloro-phenoxymethyleneoxy) -phenethyl] -imidazole, determined in individual mice Administration in increasing doses and measured on the 7th day of treatment orally> 800 mg / kg. Analogous toxicity data were found for the other compounds according to the invention.

The pharmaceutical or veterinary agents which are another object of the invention and which contain the compounds according to the invention are prepared in a conventional manner and they can, for example, in the form of tablets, capsules, sugar-coated tablets for oral administration or in the form of lotions, creams , Ointments or powders for topical use and even in the form of bougies for vaginal use are present.

Together with the active substance (the active ingredient), the pharmaceutical compositions or veterinary compositions for oral use optionally contain diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose; Lubricants such as silicon dioxide, talc, stearic acid, magnesium or calcium stearate and / or polyethylene glycols; or they can also contain binders such as starches, gelatin, methyl cellulose, carboxymethyl cellulose, gum arabic, polyvinylpyrrolidone; Disintegrants such as starches, alginic acid, alginates; Effervescent mixes; Colorants (dyes); Sweeteners; Humectants such as lecithin, polysorbate, lauryl sulfate. The vaginal bougies can also be produced in a conventional manner.

The lotions can be produced, for example, by adding hydroxytoluene butylate and polyethylene glycol to the active principle (active ingredient); The creams can be made by adding chlorocresol, spermacet, stearyl alcohol, ethyl alcohol, glycerin, petrolatum, sodium lauryl sulfate and distilled water to the active principle (active ingredient).

In addition, the powders can be produced, for example, by adding talc and silicon dioxide to the active principle (active ingredient).

The concentration of the lotions can vary, for example, from 0.005 to 0.01 g of active ingredient per ml of lotion. The concentration of the creams can vary, for example, from 0.005 to 0.01 g per g of cream, while the concentration of the powder can be, for example, from about 2.5 to about 5 mg per g of powder.

Twice a day application is preferred for topical use, while tablets containing 0.2 to 0.5 g of active ingredient can be used for oral administration, the average dose for adults preferably 10 to 15 mg / kg body weight 2 to 3 times a day. Finally, the vaginal bougies can contain, for example, 0.05 to 0.1 g of active ingredient and they are only introduced once a day, preferably in the evening, for about 5 to about 6 consecutive days.

The IR spectrum of the compounds according to the invention was determined in the solid phase (KBr) or in solutions in Nujol or in a suitable solvent, such as CHCl [deep] 3, using a Perkin Elmer 125 spectrophotometer.

The NMR spectrum was preferably determined in a dimethyl sulfoxide-d [deep] 6 or CDCl [deep] 3 solution using a Bruker HFX 90 MHz device.

The R [deep] f values were determined by thin layer chromatography using ready-to-use silica gel plates at a layer thickness of 0.25 mm.

The invention is illustrated in more detail by the following examples, without, however, being restricted thereto.

example 1

A solution of 3.86 g of 1- [2,4-dichloro (small beta-hydroxy) phenethyl] imidazole in 15 ml of anhydrous dimethylformamide was with a suspension of

Treated 0.8 g of sodium hydride in 10 ml of anhydrous dimethylformamide. The reaction mixture was slowly heated to 50 ° C. and then cooled to room temperature, 3.5 g of phenyl (2,4-dichloro) chloromethyl ether being added in small portions. This mixture was stirred for about 1 hour at room temperature and then for an additional hour at 50 ° C, then it was evaporated to dryness under reduced pressure and the residue, which was taken up in 100 ml of water, was repeatedly extracted with chloroform. The organic solution was evaporated to dryness after washing with water and after drying. The residue dissolved in 20 ml of ethanol was treated with 70% HNO [deep] 3. The solution treated with ethyl ether gave a precipitate which, after crystallization in aqueous methanol, was 6.5 g of 1- [2,4-dichloro-small beta (2 ', 4'-dichloro-phenoxymethyleneoxy) -phenethyl] -imidazole nitrate, F 149-152 ° C.

Elemental analysis for C [deep] 18H [deep] 15Cl [deep] 4N [deep] 3O [deep] 5:

Calculated: C 43.66; H 3.05; N 8.49; Cl 28.65

Found: C 43.65; H 2.98; N 8.38; Cl 28.66%

TLC eluent CHCl [deep] 3: MeOH: NH [deep] 4OH (32%) = 190: 10: 0.5

R [deep] f = 0.5

N.M.R. (DMSO) p.p.m.

4.62 2H d

5.28 1H d

5.52 2H m

(-CH [with underscore] -CH [deep] 2-)

9.15 1H s (H-CH [with underscore] = N)

Using the same procedure, the following compounds were made:

1- [2,4-dichloro-small beta (2 ', 4', 5'-trichloro-phenoxymethyleneoxy) -phenethyl] -imidazole nitrate, mp 164-166 ° C.

(Ethyl acetate / petroleum ether).

Elemental analysis for C [deep] 18H [deep] 14ClN [deep] 3O [deep] 5:

Calcd .: C 40.76; H 2.62; N 7.95; Cl 33.3

Found: C 40.3; H 2.66; N 7.87; Cl 33.2%

TLC eluent CHCl [deep] 3: MeOH: NH [deep] 4OH (32%) = 190: 10: 1

R [deep] f = 0.6

N.M.R. (DMSO) p.p.m.

4.63 1H d

5.37 1H d

5.54 1H t (-CH [with underscore] -CH [deep] 2)

5.59 1H d

9.18 1H s (N-CH [with underscore] = N)

1- [2,4-dichloro-small beta (4'-chlorophenoxymethyleneoxy) phenethyl] imidazole nitrate, mp 115 to 117 ° C (ethyl acetate / benzene)

Elemental analysis for C [deep] 18H [deep] 16Cl [deep] 3N [deep] 3O [deep] 5:

Calcd .: C 46.9; H 3.50; N 9.2; Cl 23.1

Found: C 46.6; H 3.53; N 9.6; Cl 23.07%

TLC eluent CHCl [deep] 3: MeOH: NH [deep] 4OH (32%) = 190: 10: 1

R [deep] f = 0.58

1- [2,4-dichloro-small beta (n-hexyloxy-methylen-oxy) -phenethyl] -imidazole nitrate, mp 89-91 ° C. (H [low] 2O)

Elemental analysis for C [deep] 18H [deep] 25Cl [deep] 2N [deep] 3O [deep] 5:

calc .: C 49.7; H 5.80; N 9.6; Cl 16.3

Found: C 49.9; H 5.85; N 9.49; Cl 16.31%

TLC eluent CHCl [deep] 3: MeOH: NH [deep] 4OH (32%) = 190: 10: 0.5

R [deep] f = 0.60

1- [2,4-dichloro-small beta (4'-chloro-phenylthio-methylen-oxy) -phenethyl] -imidazole nitrate, mp 134-137 ° C. (H [low] 2O)

Elemental analysis for C [deep] 18H [deep] 16Cl [deep] 3N [deep] 3O [deep] 4S:

Calcd .: C 45.37; H 3.37; N 8.8; Cl 22.3; S 6.71

Found: C 45.56; H 3.37; N 8.61; Cl 22.39; S 6.72%

TLC eluent CHCl [deep] 3: MeOH: NH [deep] 4OH (32%) = 190: 10: 0.5

R [deep] f = 0.58

N.M.R. (DMSO) p.p.m.

4.53 2H d (CH-CH [with underscore] [deep] 2-N)

4.82 1H d

5.20 1H d

5.46 1H t (-CH [with underscore] -CH [deep] 2-)

8.88 1H s (N-CH [with underscore] = N)

1- [2,4-dichloro-small beta (3 ', 5'-dichloro-phenoxymethylene-oxy) -phenethyl] -imidazole, mp 115-117 ° C;

Elemental analysis for C [deep] 18H [deep] 14Cl [deep] 4N [deep] 2O [deep] 2:

calc .: C 50.04; H 3.29; Cl 32.7; N 6.46

Found: C 50.09; H 3.34; Cl 32.07; N 6.31%

TLC eluent CHCl [deep] 3: MeOH = 180:20

R [deep] f = 0.58

I.R. (KBr) small Ny (C-O-C-O-C) 1100-1000 cm [high] -1

1- [2,4-dichloro-small beta (2 ', 6'-dichloro-phenoxymethylene-oxy) -phenethyl] -imidazole-nitrate, mp 139-141 ° C (isopropanol)

Elemental analysis for C [deep] 18H [deep] 15Cl [deep] 4N [deep] 3O [deep] 5:

Calculated: C 43.66; H 3.05; N 8.48; Cl 28.64

Found: C, 43.46; H 3.09; N 8.47; Cl 28.31%

TLC eluent CHCl [deep] 3: MeOH: NH [deep] 4OH (32%) = 180: 20: 1

R [deep] f = 0.7

I.R. (KBr): small Ny (N-H [high] (+)) imidazole: 3150-2420 cm [high] -1

small Ny (N = O) NO [deep] 3 [high] (-) group: 1375 cm [high] -1

small Ny (C-O-C-O-C): 950 cm [high] -1

1- [2,4-dichloro-small beta (4'-methyl-phenoxymethylene-oxy) -phenethyl] -imidazole-nitrate, mp 151-154 ° C;

Elemental analysis for C [deep] 19H [deep] 18Cl [deep] 2N [deep] 2O [deep] 2. ENT [deep] 3:

Calculated: C 51.83; H 4.35; Cl 16.12; N 9.54

Found: C, 51.82; H 4.40; Cl 16.29; N 9.59%

I.R. (CHCl [deep] 3) small Ny (C = N) imidazole 1540 cm [high] -1

small Ny (N = O) NO [deep] 3 [high] (-) group 1400 cm [high] -1

small Ny (C-O-C-O-C) 1010 cm [high] -1

N.M.R. (CDCl [deep] 3) small delta 2.23 (s; 3H; -CH [deep] 2 [with underscore])

small delta 4.55 (d; 2H; CH-CH [deep] 2 [with underscore] -N)

small delta 5.07 (d; 1H; small delta 5.34 (d; 1H; small delta 5.47 (t; 1H; small delta 6.60-7.80 (m; 9H; aromatics + imidazole)

small delta 9.09 (s; 1H; = N-CH [with underscore] = N-)

TLC eluent CHCl [deep] 3: MeOH: NH [deep] 4OH (32%) = 190: 10: 1

R [deep] f = 62%

1- [2,4-dichloro-small beta (2'-chloro-4'-methyl-phenoxymethyleneoxy) -phenethyl] -imidazole;

1- [2,4-dichloro-small beta (2'-chloro-4'-propyl-phenoxymethyleneoxy) -phenethyl] -imidazole nitrate, mp 151-152 ° C.

Elemental analysis for C [deep] 21H [deep] 21Cl [deep] 3N [deep] 2O [deep] 2. ENT [deep] 3:

Calcd .: C 50.16; H 4.41; Cl 21.16; N 8.35

Found: C, 50.33; H 4.44; Cl 21.11; N 8.32%

TLC eluent CHCl [deep] 3: MeOH: NH [deep] 4OH (32%) = 190: 10: 0.5

R [deep] f = 0.63

I.R. (KBr): small Ny (C = N) imidazole 1535 cm [high] -1

small Ny (N = O) NO [deep] 3 [high] (-) group 1380 cm [high] -1

small Ny (C-O-C-O-C) 990 cm [high] -1

N.M.R. (DMSO) small delta 0.84 (t, 3H; CH [deep] 2-CH [deep] 2-CH [deep] 3 [with underscore]);

small delta 1.57 (m, 2H; CH [deep] 2-CH [deep] 2 [with underscore] -CH [deep] 3);

small delta 2.51 (t, 2H; CH [deep] 2-CH [deep] 2 [with underscore] -CH [deep] 3);

small delta 4.60 (d, 2H; CH-CH [low] 3 [with underscore] -N);

small delta 5.22 (d, 1H; small delta 5.47 (d, 1H; small delta 5.53 (t, 1H; small delta 7.00-7.80 (m, 8H; aromatics + imidazole);

small delta 9.14 (s, 1H; N-CH [with underscore] = N-);

1- [2,4-dichloro-small beta (4'-tert-butyl-phenoxymethylene-oxy) -phenethyl] -imidazole-nitrate, mp 130-131 ° C;

Elemental analysis for C [deep] 22H [deep] 24Cl [deep] 2N [deep] 2O [deep] 2. ENT [deep] 3:

Calculated: C 54.77; H 5.22; Cl 14.7; N 8.71

Found: C, 55.01; H 5.27; Cl 14.74; N 8.75%

TLC eluent CHCl [deep] 3: MeOH: NH [deep] 4OH (32%) = 195: 5: 0.5,

R [low] f = 48%.

I.R. (CHCl [deep] 3) small Ny (C = N) imidazole 1540-1530 cm [high] -1

small Ny (N = O) NO [deep] 3 [high] (-) group 1400 cm [high] -1

small Ny (C-O-C-O-C) 1010 cm [high] -1

N.M.R. (CDCl [deep] 3) small delta 1.24 (s, 9H; -C- (CH [deep] 3 [with underscore]) [deep] 3)

small delta 4.51 (m, 2H; = CH-CH [deep] 3 [with underscore] -N)

small delta 5.00 (d, 1H; small delta 5.33 (d, 1H; small delta 5.51 (dd, 1H; O-CH [with underscore] -CH [deep] 2)

small delta 6.66-7.53 (m, 9H; aromatics + imidazole);

small delta 9.25 (s, 1H; N-CH [with underscore] = N)

1- [2,4-dichloro-small beta (4'-fluorophenoxymethyleneoxy) phenethyl] imidazole;

1- [2,4-dichloro-small beta (4'-nitro-phenoxymethyleneoxy) -phenethyl] -imidazole;

1- [2,4-dichloro-small beta (2'-chloro-4'-nitro-phenoxymethyleneoxy) -phenethyl] -imidazole;

1- [2,4-dichloro-small beta (4'-trifluoromethyl-phenoxymethyleneoxy) -phenethyl] -imidazole;

1- [2,4-dichloro-small beta (3'-trifluoromethyl-phenoxymethyleneoxy) -phenethyl] -imidazole-nitrate, mp 115-117 ° C.

Elemental analysis for C [deep] 18H [deep] 15Cl [deep] 2F [deep] 3N [deep] 2O [deep] 2. ENT [deep] 3:

Calculated: C 46.17; H 3.26; Cl 14.35; N 8.50

Found: C 46.21; H 3.30; Cl 14.34; N 8.47%

I.R. (KBr): small Ny (C = N) imidazole 1545 cm [high] -1

small Ny (N = O) NO [deep] 3 [high] (-) group 1390 cm [high] -1

small Ny (C-O-C-O-C) 1010 cm [high] -1

N.M.R. (CHCl [deep] 3) small delta 4.58 (m, 2H; CH-CH [deep] 2 [with underscore] -N)

small delta 5.07 (d, 1H; small delta 5.40 (d, 1H; small delta 5.54 (dd, 1H; small delta 7.00-7.60 (m, 8H; aromatics + imidazole)

small delta 9.38 (s, 1H; -N-CH [with underscore] = N-)

TLC eluent CHCl [deep] 3: MeOH: NH [deep] 4OH (32%) = 195: 5: 1,

R [low] f = 0.53%.

1- [2,4-dichloro-small beta (4'-methylsulfonyl-phenoxymethyleneoxy) -phenethyl] -imidazole;

1- [2,4-dichloro-small beta (n-octyloxymethyleneoxy) phenethyl] imidazole;

1- [2,4-dichloro-small beta (4'-chloro-phenyl-propyloxymethyleneoxy) -phenethyl] -imidazole;

1- [4-chloro-small beta (2 ', 4'-dichloro-phenoxymethyleneoxy) -phenethyl] -imidazole;

1- [4-chloro-small beta (2'-chloro-4'-propyl-phenoxymethyleneoxy) -phenethyl] -imidazole;

1- [4-chloro-small beta (n-octyloxymethylene-oxy) phenethyl] imidazole;

1- [4-methoxy-small beta (2 ', 4', 5'-trichlorophenoxymethyleneoxy) phenethyl] imidazole;

1- [2,4,6-trichloro-small beta (4'-chloro-phenoxymethylene-oxy) -phenethyl] -imidazole, mp 154-159 ° C;

Elemental analysis for C [deep] 18H [deep] 14N [deep] 2O [deep] 2Cl [deep] 4. ENT [deep] 3:

Calculated: C 43.66; H 3.05; N 8.48; Cl 28.69

Found: C, 44.15; H 3.10; N 8.24; Cl 28.46%

TLC eluent CHCl [deep] 3: MeOH: formic acid (99%) = 160: 20: 20,

R [deep] f = 0.43

I.R. (KBr): small Ny (N-H [high] (+)) imidazole 3150-2550 cm [high] -1

small Ny (N = O) NO [deep] 3 [high] (-) group 1380 cm [high] -1

1- [2,4,6-trichloro-small beta (4'-fluorophenoxymethyleneoxy) phenethyl] imidazole;

1- [2,4,6-trichloro-small beta (2'-chloro-4'-methyl-phenoxymethyleneoxy) -phenethyl] -imidazole;

1- [2,4,6-trichloro-small beta (4'-methoxyphenoxymethyleneoxy) phenethyl] imidazole;

1- [2,4-dichloro-small beta (2 ', 4'-dichlorophenylthiomethyleneoxy) phenethyl] imidazole nitrate, mp 144-145 ° C;

Elemental analysis for C [deep] 18H [deep] 19N [deep] 2Cl [deep] 4OS.HNO [deep] 3:

Calculated: C 42.29; H 2.95; N 8.21; Cl 27.74; S 6.27

Found: C 42.25; H 2.98; N 8.09; Cl 27.30; S 6.33%

TLC eluent CHCl [deep] 3: MeOH: NH [deep] 4OH (32%) = 190: 10: 0.5

R [deep] f = 0.58

I.R. (KBr): small Ny (N-H [high] (+)) imidazole 3140-2420 cm [high] -1

small Ny (N = O) NO [deep] 3 [high] (-) group 1380 cm [high] -1

1- [2,4-dichloro-small beta (2'-chloro-4'-methyl-phenylthiomethyleneoxy) phenethyl] imidazole;

1- [2,4-dichloro-small beta (3 ', 4'-dichlorophenylthiomethylene-oxy) phenethyl] imidazole nitrate, mp 185 ° C (dec.);

Elemental analysis for C [deep] 18H [deep] 14Cl [deep] 4N [deep] 2OS.HNO [deep] 3:

Calculated: C 42.20; H 2.95; Cl 27.70; N 8.19; S 6.26

Found: C 42.17; H 2.93; Cl 27.73; N 8.10; S 6.16%

TLC eluent CHCl [deep] 3: MeOH: NH [deep] 4OH (32%) = 190: 10: 1,

R [deep] f = 0.63

I.R. (KBr): small Ny (N-H [high] (+)) 3150-2400 cm [high] -1;

small Ny (N = O) NO [deep] 3 [high] (-) group 1380 cm [high] -1

1- [2,4-dichloro-small beta (4'-methyl-phenylthio-methylen-oxy) -phenethyl] -imidazole;

1- [2,4-dichloro-small beta (4'-trifluoromethyl-phenylthiomethylene-oxy) phenethyl] imidazole;

1- [2,4-dichloro-small beta (2'-chloro-4'-propyl-phenylthio-methylen-oxy) -phenethyl] -imidazole;

1- [2,4-dichloro-small beta (2'-chloro-4'-nitro-phenylthio-methylen-oxy) -phenethyl] -imidazole;

1- [2,4-dichloro-small beta (n-octyl-thiomethylene-oxy) -phenethyl] -imidazole;

1- [2,4,6-trichloro-small beta (4'-methyl-sulfonyl-phenylthiomethylene-oxy) -phenethyl] -imidazole.

Example 2

A solution of 2 g of 1- [2,4-dichloro (small beta-hydroxy) phenethyl] imidazole in 15 ml of anhydrous dimethylformamide was added to a suspension of 0.2 g of sodium hydride in 10 ml of anhydrous dimethylformamide. The reaction mixture was slowly warmed to 50 ° C., then, after cooling to room temperature, 1.6 g of phenyl (2-chloro-4-ethyl) chloromethyl ether were added in portions. Stirring was continued for 1 hour at room temperature and an additional hour at 50 ° C, then the reaction mixture was evaporated to dryness in vacuo and the residue was taken up in 100 ml of water. The aqueous solution obtained was extracted several times with chloroform, the organic phase was washed with water, dried over Na [deep] 2SO [deep] 4 and evaporated to dryness. The residue was dissolved in 20 ml of ethanol and treated with a small excess of 70% HNO [deep] 3, then ethyl ether was added. The solid obtained was filtered off and crystallized in aqueous methanol, 1.5 g of 1- [2,4-dichloro-small beta (2'-chloro-4'-ethyl-phenoxymethyleneoxy) -phenethyl] imidazole nitrate, F. Received 164-166 ° C.

Elemental analysis for C [deep] 20H [deep] 20N [deep] 3O [deep] 5Cl:

Calculated: C 49.15; H 4.12; N 8.59; Cl 21.76

Found: C 48.93; H 4.13; N 8.68; Cl 21.34%

TLC eluent CHCl [deep] 3: MeOH: NH [deep] 4OH (32%) = 190: 10: 0.5

R [deep] f = 0.6

I.R. (Nujol) small Ny (C-O-C-O-C) 1005 cm [high] -1

small Ny (C = N) imidazole 1550 cm [high] -1

The following compounds were prepared in an analogous manner:

1- [2,4-dichloro-small beta (2 ', 4', 6'-trichlorophenoxymethyleneoxy) phenethyl] imidazole nitrate, mp 113-115 ° C;

Elemental analysis for C [deep] 18H [deep] 13N [deep] 2O [deep] 2Cl [deep] 5:

Calcd .: C 46.34; H 2.80; N 6.00; Cl 37.99

Found: C 45.77; H 2.90; N 5.72; Cl 35.76%

TLC eluent CHCl [deep] 3: MeOH: NH [deep] 4OH (32%) = 190: 10: 0.5

R [deep] f = 0.56

I.R. (KBr): small Ny (C-O-C-O-C) 1015 cm [high] -1;

1- [2,4-dichloro-small beta (2'-methyl-4'-chlorophenoxymethyleneoxy) phenethyl] imidazole nitrate, mp 145-148 ° C;

Elemental analysis for C [deep] 19H [deep] 18N [deep] 3O [deep] 5Cl [deep] 3:

Calculated: C 48.07; H 3.82; N 8.85; Cl 22.40

Found: C 47.87; H 3.87; N 8.85; Cl 22.37%

TLC eluent CHCl [deep] 3: MeOH: HCOOH (99%) = 180: 20: 10

R [deep] f = 0.34

I.R. (KBr): small Ny (C-N) imidazole 1540 cm [high] -1

small Ny (C-O-C-O-C) 1010 cm [high] -1

1- [2,4-dichloro-small beta (2 ', 4'-dibromophenoxymethyleneoxy) phenethyl] imidazole nitrate, mp 138-142 ° C;

Elemental analysis for C [deep] 18H [deep] 14Br [deep] 2Cl [deep] 2N [deep] 2O [deep] 4:

Calculated: C 37.03; H 2.59; Br 27.3; Cl 12.14; N 7.21

Found: C 36.63; H 2.71; Br 26.98; Cl 12.31; N 7.25%

TLC eluent CHCl [deep] 3: MeOH: NH [deep] 4OH (32%) = 190: 10: 1

R [deep] f = 0.55

I.R. (KBr): small Ny (N-H [high] (+)) imidazole 3180-2300 cm [high] -1

small Ny (N = O) NO [deep] 3 [high] (-) group 1380 cm [high] -1

small Ny (C-O-C-O-C) 1035 cm [high] -1

1- [2,4-dichloro-small beta (2'-chloro-4'-tert-butyl-phenoxymethyleneoxy) -phenethyl] -imidazole nitrate, mp 163-167 ° C

Elemental analysis for C [deep] 22H [deep] 23Cl [deep] 3N [deep] 2O [deep] 2. ENT [deep] 3:

Calcd .: C 51.1; H 4.68; Cl 20.6; N 8.13

Found: C, 50.26; H 4.59; Cl 20.89; N 8.22%

TLC eluent CHCl [deep] 3: MeOH: NH [deep] 4OH (32%) = 190: 10: 0.5

R [deep] f = 0.59

I.R. (KBr): small Ny (N = O) NO [deep] 3 [high] (-) group 1390 cm [high] -1

small Ny (C-O-C-O-C) 1005 cm [high] -1

Example 3

A solution of 1.28 g of 1- [2,4-dichloro (small beta-hydroxy) phenethyl] imidazole in 10 ml of anhydrous dimethylformamide was added to a suspension of 0.13 g of sodium hydride in 5 ml of anhydrous dimethylformamide. The reaction mixture was stirred at room temperature until the evolution of hydrogen ceased, then a solution of 1.86 g of 2- (2,4-dichlorophenoxy) -1-ethyl-p-toluenesulfonate in 10 ml of anhydrous dimethylformamide was added in portions. After stirring for 4 hours at room temperature, the mixture was evaporated to dryness in vacuo and the residue was taken up in 50 ml of water and extracted repeatedly with chloroform. The organic phase was washed with water, dried over Na [deep] 2SO [deep] 4 and evaporated to dryness. The residue was taken up in ethyl ether and treated with 70% HNO [deep] 3, 2 g of 1- [2,4-dichloro-small beta (2 ', 4'-dichloro-phenoxyethyleneoxy) phenethyl] imidazole nitrate , M.p. 165-170 ° C.

Elemental analysis for C [deep] 19H [deep] 17N [deep] 3O [deep] 5Cl [deep] 4:

Calculated: C 44.82; H 3.36; N 8.25; Cl 27.85

Found: C, 44.71; H 3.37; N 8.15; Cl 27.45%

TLC eluent CHCl [deep] 3: MeOH: HCOOH (99%) = 160: 20: 20

R [deep] f = 0.48

I.R. (KBr): small Ny (N = O) NO [deep] 3 [high] (-) group 1400-1350 cm [high] -1

NMR (DMSO) small delta ppm: 3.80 m, 2H

4.24 m, 2H

4.60 m, 2H

5.32 dd, 1H

9.18 wide, s,

The following compounds were prepared in an analogous manner:

1- [2,4-dichloro-small beta (4'-chlorophenoxyethyleneoxy) phenethyl] imidazole nitrate, mp 125-128 ° C.

Elemental analysis for C [deep] 19H [deep] 18N [deep] 3O [deep] 5Cl [deep] 3:

Calculated: C 48.07; H 3.82; N 8.85; Cl 22.40

Found: C 47.79; H 3.86; N 8.77; Cl 22.04%

TLC eluent CHCl [deep] 3: MeOH: NH [deep] 4OH (32%) = 190: 10: 0.5

R [deep] f = 0.55

I.R. (KBr): small Ny (N-H [high] (+)) imidazole 3140-2300 cm [high] -1

small Ny (N = O) NO [deep] 3 [high] (-) group 1380 cm [high] -1;

1- [2,4-dichloro-small beta (2 ', 6'-dichloro-phenoxyethylene-oxy) phenethyl] imidazole;

1- [2,4-dichloro-small beta (4'-bromophenoxyethylene-oxy) phenethyl] imidazole;

1- [2,4-dichloro-small beta (4'-methyl-phenoxyethylene-oxy) -phenethyl] -imidazole;

1- [2,4-dichloro-small beta (2'-chloro-4'-methyl-phenoxyethylene-oxy) -phenethyl] -imidazole;

1- [2,4-dichloro-small beta (2'-chloro-4'-ethyl-phenoxyethylene-oxy) -phenethyl] -imidazole;

1- [2,4-dichloro-small beta (2'-chloro-4'-propyl-phenoxy-ethylene-oxy) -phenethyl] -imidazole;

1- [2,4-dichloro-small beta (2 ', 4', 6'-trichloro-phenoxyethylene-oxy) -phenethyl] -imidazole;

1- [2,4-dichloro-small beta (n-pentyloxy-ethylene-oxy) -phenethyl] -imidazole;

1- [2,4-dichloro-small beta (n-heptyloxy-ethylene-oxy) -phenethyl] -imidazole;

1- [4-chloro-small beta (2 ', 4'-dichloro-phenoxyethylene-oxy) phenethyl] imidazole;

1- [4-chloro-small beta (2'-chloro-4'-propyl-phenoxyethylene-oxy) -phenethyl] -imidazole;

1- [4-chloro-small beta (2 ', 4', 6'-trichloro-phenoxyethylene-oxy) -phenethyl] -imidazole.

The 2- (2,4-dichlorophenoxy) -1-ethyl-p-toluenesulfonate was prepared by treating (2,4-dichlorophenoxy) -1-ethanol with p-toluenesulfonyl chloride in pyridine; the resulting low-melting solid was used as such in the subsequent reaction.

Example 4

A solution of 4 g of 1- [2,4-dichloro (small beta-hydroxy) phenethyl] imidazole in 10 ml of anhydrous dimethylformamide was added to a suspension of 0.4 g of sodium hydride in 10 ml of anhydrous dimethylformamide. The reaction mixture was stirred at room temperature until the evolution of hydrogen ceased, then a solution of 2.64 g of 3- (4'-chlorophenoxy) -1-bromopropane in 15 ml of anhydrous dimethylformamide was added in portions. After stirring for 12 hours at room temperature, the reaction mixture was evaporated to dryness in vacuo and the residue was taken up with 50 ml of water and extracted repeatedly with chloroform. The organic phase was washed with water, dried and evaporated to dryness. The residue was taken up in ethyl ether and treated with 70% HNO [deep] 3, a solid being obtained. After filtering off, one obtained

5 g of 1- [2,4-dichloro-small beta (4'-chlorophenoxypropyleneoxy) phenethyl] imidazole nitrate, mp 114-115 ° C.

Elemental analysis for C [deep] 20H [deep] 20N [deep] 3O [deep] 5Cl [deep] 3:

Calculated: C 49.14; H 4.12; N 8.59; Cl 21.90

Found: C, 49.05; H 4.14; N 8.50; Cl 21.72%

TLC eluent CHCl [deep] 3: MeOH = 180:20

R [deep] f = 0.53

NMR (DMSO) small delta ppm: 1.94 m, 2H

3.51 t, 2H

4.01 t, 2H

4.60 m, 2H

5.15 dd, 1H

9.18 wide s, 1H

The following compounds were prepared in an analogous manner:

1- [2,4-dichloro-small beta (2 ', 4'-dichloro-phenoxypropylene-oxy) -phenethyl] -imidazole nitrate, mp 130-132 ° C;

Elemental analysis for C [deep] 20H [deep] 18N [deep] 2O [deep] 2Cl [deep] 4. ENT [deep] 3:

Calculated: C 45.91; H 3.66; N 8.03; Cl 27.10

Found: C, 45.85; H 3.60; N 8.10; Cl 27.35%

TLC eluent CHCl [deep] 3: MeOH = 180:20

R [low] f = 0.61;

1- [2,4-dichloro-small beta (phenoxybutylene-oxy) phenethyl] imidazole nitrate, mp 113-115 ° C;

Elemental analysis for C [deep] 21H [deep] 22N [deep] 2O [deep] 2Cl [deep] 2. ENT [deep] 3:

Calculated: C, 53.85; H 4.95; N 8.97; Cl 15.13

Found: C, 53.45; H 4.84; N 8.84; Cl 15.31%

TLC eluent CHCl [deep] 3: MeOH: NH [deep] 4OH (32%) = 170: 30: 2

R [deep] f = 0.77

1- [2,4-dichloro-small beta (4'-fluoro-phenoxypropylene-oxy) -phenethyl] -imidazole;

1- [2,4-dichloro-small beta (2'-chloro-4'-ethyl-phenoxypropylene-oxy) -phenethyl] -imidazole;

1- [4-chloro-small beta (4'-chloro-phenoxypropylene-oxy) -phenethyl] -imidazole;

1- [4-chloro-small beta (2 ', 4'-dichloro-phenoxypropylene-oxy) -phenethyl] -imidazole;

1- [4-chloro-small beta (2'-chloro-4'-ethyl-phenoxypropylene-oxy) -phenethyl] -imidazole;

1- [2,4-dichloro-small beta (4'-chlorophenoxybutylene-oxy) phenethyl] imidazole;

1- [4-chloro-small beta (2 ', 4'-dichloro-phenoxybutylene-oxy) -phenethyl] -imidazole;

1- [2,4-dichloro-small beta (4'-chlorophenylthio-ethylene-oxy) phenethyl] imidazole;

1- [2,4-dichloro-small beta (2 ', 4'-dichlorophenylthio-ethylene-oxy) -phenethyl] -imidazole;

1- [2,4-dichloro-small beta (2'-chloro-4'-methylphenylthio-ethylene-oxy) -phenethyl] -imidazole;

1- [2,4-dichloro-small beta (2'-chloro-4'-ethylphenylthio-ethylene-oxy) phenethyl] imidazole;

1- [2,4-dichloro-small beta (n-penthylthio-ethylene-oxy) -phenethyl] -imidazole;

1- [4-chloro-small beta (4'-chlorophenylthio-ethylene-oxy) phenethyl] imidazole;

1- [4-chloro-small beta (2 ', 4'-dichlorophenylthio-ethylene-oxy) phenethyl] imidazole;

1- [4-chloro-small beta (2'-chloro-4'-ethylphenylthio-ethylene-oxy) -phenethyl] -imidazole;

1- [2,4-dichloro-small beta (4'-chlorophenylthio-propylene-oxy) phenethyl] imidazole;

1- [2,4-dichloro-small beta (2 ', 4'-dichlorophenylthio-propylene-oxy) phenethyl] imidazole;

1- [2,4-dichloro-small beta (4'-fluorophenylthio-propylene-oxy) phenethyl] imidazole;

1- [4-chloro-small beta (4'-chlorophenylthio-propylene-oxy) phenethyl] imidazole;

1- [4-chloro-small beta (4'-fluoro-phenylthio-propylene-oxy) -phenethyl] -imidazole;

1- [4-chloro-small beta (4'-chlorophenylthio-butylene-oxy) phenethyl] imidazole.

The 1- [2,4-dichloro (small beta-hydroxy) phenethyl] imidazole used as starting material was obtained by reducing 2,4-dichloro-small alpha (1-imidazolyl) acetophenone nitrate with sodium borohydride in methanol Reflux, mp 134-135 ° C.

Elemental analysis for C [deep] 11H [deep] 10Cl [deep] 2N [deep] 2O [deep] 2:

Calcd .: C 51.38; H 3.92; N 10.9; Cl 27.58

Found: C 51.2; H 3.96; N 10.84; Cl 27.4%

The above 2,4-dichloro-small alpha (1-imidazolyl) acetophenone nitrate was made as follows:

17.7 ml of bromine were added dropwise to a solution of 65 g of 2,4-dichloroacetophenone in 250 ml of ethyl ether. The reaction solution was washed with water, dried and evaporated to dryness. The remaining oil was added in portions to a solution of 120 g of imidazole in 85 ml of dimethylformamide, which was kept cool, and stirred. After the addition was complete and the reaction mixture was kept at room temperature for 1 hour, this mixture was poured into water and extracted with CHCl [deep] 3. The orga- Niche solution was washed with an ice-cold, dilute Na [deep] 2CO [deep] 3 solution, then with water, dried and evaporated. The residue was dissolved in ethanol and treated with 70% HNO [deep] 3, 49 g of a solid having a melting point of 168-170 ° C. (ethanol) being obtained.

Elemental analysis for C [deep] 11H [deep] 9Cl [deep] 2N [deep] 3O [deep] 4:

Calculated: C 41.53; H 2.82; N 13.2; Cl 22.3

Found: C 41.5; H 2.88; N 13.25; Cl 22.29%

Example 5

A solution of 2 g of 1- [4-phenyl- (small beta-hydroxy) phenethyl] imidazole in 15 ml of anhydrous dimethylformamide was added to a suspension of 0.2 g of sodium hydride in 15 ml of anhydrous dimethylformamide. The reaction mixture was slowly heated to 50 ° C., then, after cooling to room temperature, 1.4 g of phenyl (4-chloro) chloromethyl ether were added in portions. The mixture was stirred for 1 hour at room temperature, then heated to 50 ° C. and stirred for a further hour at this temperature and finally evaporated to dryness in vacuo. The residue was taken up in 100 ml of water and extracted several times with chloroform. The organic phase was washed with water, dried and evaporated to dryness to give a residue which was dissolved in 20 ml of ethanol and treated with 70% HNO [deep] 3. The addition of ethyl ether gave a solid which, after filtering and crystallizing in isopropanol, 1.5 g of 1- [4-phenyl-small beta (4'-chlorophenoxymethyleneoxy) phenethyl] imidazole nitrate, mp 155-157 ° C.

Elemental analysis for C [deep] 24H [deep] 21N [deep] 2O [deep] 2Cl.HNO [deep] 3:

Calculated: C 61.60; H 4.73; N 8.98; Cl 7.57

Found: C, 61.24; H 4.68; N 8.81; Cl 7.40%

TLC eluent CHCl [deep] 3: MeOH (32%) = 180:20

R [deep] f = 0.6

I.R. (KBr): small Ny (NO [deep] 3 [high] (-)) 1390 cm [high] -1

small Ny (C-O-C) 1235-1090 cm [high] -1

small Ny (1-4 substituted) 830 cm [high] -1

small Ny (monosubstituted) 700 cm [high] -1.

The following compounds were prepared in an analogous manner:

1- [4-phenyl-small beta (2'-chloro-4'-ethyl-phenoxyethylene-oxy) -phenethyl] -imidazole;

1- [4-phenyl-small beta (4'-chloro-phenoxyethylene-oxy) -phenethyl] -imidazole;

1- [4-phenyl-small beta (2 ', 4'-dichloro-phenoxymethylene-oxy) -phenethyl] -imidazole;

1- [4-phenyl-small beta (4'-chlorophenylthio-ethylene-oxy) -phenethyl] -imidazole;

1- [4-phenyl-small beta (2 ', 4'-dichlorophenylthio-ethyleneoxy) -phenethyl] -imidazole.

The starting material 1- [4-phenyl- (small beta-hydroxy) -phenethyl] -imidazole was prepared by reducing 4-phenyl-small alpha (1-imidazolyl) -acetophenone with sodium borohydride in methanol at room temperature, m.p. 175- 177 ° C.

Elemental analysis for C [deep] 17H [deep] 16N [deep] 2O:

Calculated: C 77.25; H 6.09; N 10.59

Found: C 77.15; H 6.15; N 10.7%

The above 4-phenyl-small alpha (1-imidazolyl) acetophenone was made by the following procedure:

11 g of small alpha-bromo-p-phenyl-acetophenone were added in portions to a solution of 13 g of imidazole in 25 ml of dimethylformamide with cooling and

Stirring added. The reaction mixture was stirred at room temperature for 1 hour, then poured into water and extracted with chloroform. The organic phase was washed with water, then extracted with an aqueous dilute hydrochloric acid solution, the acidic aqueous layer was treated with NaHCO [deep] 3 until neutral to give a white solid which was filtered off and dried (8 g, m.p. 201 to 203 ° C).

NMR (CDCl3 [deep] 3) ppm: 5.4 s, 2H

Example 6

Below are some examples of pharmaceutical agents that have been used to control mycosis. The parts specified therein relate to parts by weight.

Powder for spraying

10 parts of 1- [2,4-dichloro-small beta (2 ', 4'-dichloro-phenoxymethyleneoxy) -phenethyl] -imidazole nitrate, mixed with 490 parts of talc F.U. (according to Pharm.).

lotion

10 parts of 1- [2,4-dichloro-small beta (2 ', 4'-dichloro-phenoxyethyleneoxy) -phenethyl] -imidazole nitrate, dissolved in 490 parts of polyethylene glycol 400.

ointment

10 parts of 1- [2,4-dichloro-small beta (2'-chloro-4'-ethylphenoxymethyleneoxy) phenylethyl] imidazole nitrate, dissolved under heating in a mixture of 300 parts of polyethylene glycol 400, 120 parts of polyethylene glycol 1500 and 70 parts Polyethylene glycol 4000.

Vaginal bougies

Each bougie contained 100 mg of 1- [2,4-dichloro-small beta (2'-chloro-4'-n-propyl-phenoxymethyleneoxy) -phenethyl] -imidazole nitrate, dissolved under heating in a previously melted mixture of 900 mg of polyethylene glycol 6000, 1580 mg polyethylene glycol 1500 and 420 mg polyethylene glycol 4000 monostearate.

Claims (21)

1. N-phenethylimidazole derivative, characterized by the general formula (I) where mean: A -O- or -S-; R a) C [deep] 1-C [deep] 8-alkyl, C [deep] 2-C [deep] 8-alkenyl or C [deep] 2-C [deep] 8-alkynyl, b) a cycloaliphatic radical with 3 to 7 carbon atoms, c) an aryl or aryl-C [deep] 1-C [deep] 6-alkyl group, in which the alkyl groups can be unsubstituted or substituted by one or more substituents from the group consisting of halogen, -NO [deep] 2, cyano, C [deep] 1-C [deep] 6-alkyl, C [deep] 1-C [deep] 6-alkoxy, C [deep] 1-C [deep] 6-alkylthio, trihalomethyl, -SO [deep] 2CH [ deep] 3; Z is a branched or straight-chain (unbranched) C [deep] 1-C [deep] 15-alkylene radical; each of the Y groups, which can be the same or different from one another, a representative from the group consisting of hydrogen, halogen, -NO [deep] 2, cyano, C [deep] 1-C [deep] 2-alkyl, C [deep] 1-C [deep] 2-alkoxy, C [deep] 1-C [deep] 2-alkylthio, trihalomethyl, -SO [deep] 2CH [deep] 3 and phenyl, which can be unsubstituted or substituted by one or more halogen atoms ; and n is the number 0 or an integer from 1 to 5, and the salts, in particular the pharmaceutically or veterinarily acceptable salts thereof. 2. A compound according to claim 1, characterized in that in the general formula (I) A -O- or -S-; R is phenyl which is unsubstituted or substituted by one or more substituents from the group consisting of halogen, C [deep] 1-C [deep] 6-alkyl and trihalomethyl; ZC [deep] 1-C [deep] 4-alkylene, Y halogen or unsubstituted phenyl, where when Y is halogen, n is the number 2, or when Y is unsubstituted phenyl, n is the number 1 , and the salts, in particular the pharmaceutically or veterinarily acceptable salts thereof. 3. A compound according to claim 1, characterized in that in the general formula (I) A -O- or -S-; R is phenyl that is unsubstituted or substituted by one or more substituents from the group consisting of halogen and C [deep] 1-C [deep] 4-alkyl, Z is methylene or ethylene, Y is chlorine and n is the number 2, as well as the salts, in particular the pharmaceutically or veterinarily acceptable salts thereof. 4. A compound according to any one of claims 1 to 3, characterized in that it is selected from the group: 1- [2,4-dichloro-small beta (2 ', 4'-dichloro-phenoxymethylene-oxy) phenethyl] imidazole; 1- [2,4-dichloro-small beta (4'-chloro-phenoxymethylene-oxy) -phenethyl] -imidazole; 1- [2,4-dichloro-small beta (2 ', 4', 5'-trichloro-phenoxymethylene-oxy) -phenethyl] -imidazole; 1- [2,4-dichloro-small beta (3 ', 5'-dichloro-phenoxymethylene-oxy) phenethyl] imidazole; 1- [2,4-dichloro-small beta (2 ', 6'-dichloro-phenoxymethylene-oxy) -phenethyl] -imidazole; 1- [2,4-dichloro-small beta (4'-methyl-phenoxymethylene-oxy) -phenethyl] -imidazole; 1- [2,4-dichloro-small beta (2'-chloro-4'-methyl-phenoxymethylene-oxy) -phenethyl] -imidazole; 1- [2,4-dichloro-small beta (2'-chloro-4'-propyl-phenoxymethylene-oxy) -phenethyl] -imidazole; 1- [2,4-dichloro-small beta (4'-tert-butyl-phenoxymethylene-oxy) phenethyl] imidazole; 1- [2,4-dichloro-small beta (4'-fluoro-phenoxymethylene-oxy) -phenethyl] -imidazole; 1- [2,4-dichloro-small beta (4'-trifluoromethyl-phenoxymethylene-oxy) -phenethyl] -imidazole; 1- [2,4-dichloro-small beta (3'-trifluoromethyl-phenoxymethylene-oxy) -phenethyl] -imidazole; 1- [2,4-dichloro-small beta (2'-chloro-4'-ethyl-phenoxymethylene-oxy) -phenethyl] -imidazole; 1- [2,4-dichloro-small beta (2 ', 4', 6'-trichloro-phenoxymethylene-oxy) -phenethyl] -imidazole; 1- [2,4-dichloro-small beta (2'-methyl-4'-chloro-phenoxymethylene-oxy) phenethyl] imidazole; 1- [2,4-dichloro-small beta (2 ', 4'-dibromophenoxymethylene-oxy) phenethyl] imidazole; 1- [2,4-dichloro-small beta (2'-chloro-4'-tert-butyl-phenoxymethylene-oxy) -phenethyl] -imidazole; 1- [4-phenyl-small beta (4'-chloro-phenoxymethylene-oxy) -phenethyl] -imidazole; 1- [4-phenyl-small beta (2 ', 4'-dichloro-phenoxymethylene-oxy) -phenethyl] -imidazole; and the salts, in particular the pharmaceutically or veterinarily acceptable salts thereof. 5. A compound according to any one of claims 1 to 3, characterized in that it is selected from the group: 1- [2,4-dichloro-small beta (4'-chloro-phenoxy-ethylene-oxy) -phenethyl] -imidazole; 1- [2,4-dichloro-small beta (2 ', 4'-dichloro-phenoxyethylene-oxy) phenethyl] imidazole; 1- [2,4-dichloro-small beta (2 ', 6'-dichloro-phenoxyethylene-oxy) phenethyl] imidazole; 1- [2,4-dichloro-small beta (4'-bromophenoxyethylene-oxy) phenethyl] imidazole; 1- [2,4-dichloro-small beta (4'-methyl-phenoxyethylene-oxy) -phenethyl] -imidazole; 1- [2,4-dichloro-small beta (2'-chloro-4'-methyl-phenoxyethylene-oxy) -phenethyl] -imidazole; 1- [2,4-dichloro-small beta (2'-chloro-4'-ethyl-phenoxyethylene-oxy) -phenethyl] -imidazole; 1- [2,4-dichloro-small beta (2'-chloro-4'-propyl-phenoxyethylene-oxy) -phenethyl] -imidazole; 1- [2,4-dichloro-small beta (2 ', 4', 6'-trichloro-phenoxyethylene-oxy) -phenethyl] -imidazole; 1- [4-phenyl-small beta (2'-chloro-4'-ethyl-phenoxyethylene-oxy) -phenethyl] -imidazole; and the salts, in particular the pharmaceutically or veterinarily acceptable salts thereof. 6. A compound according to any one of claims 1 to 3, characterized in that it is selected from the group: 1- [2,4-dichloro-small beta (4'-chloro-phenoxypropylene-oxy) -phenethyl] -imidazole; 1- [2,4-dichloro-small beta (2 ', 4'-dichloro-phenoxypropylene-oxy) -phenethyl] -imidazole; 1- [2,4-dichloro-small beta (4'-fluoro-phenoxypropylene-oxy) -phenethyl] -imidazole; 1- [2,4-dichloro-small beta (2'-chloro-4'-ethyl-phenoxypropylene-oxy) -phenethyl] -imidazole; 1- [4-phenyl-small beta (4'-chloro-phenoxypropylene-oxy) -phenethyl] -imidazole; and the salts, in particular the pharmaceutically or veterinarily acceptable salts thereof. 7. A compound according to any one of claims 1 to 3, characterized in that it is selected from the group: 1- [2,4-dichloro-small beta (4'-chlorophenoxybutylene-oxy) phenethyl] imidazole; 1- [2,4-dichloro-small beta (phenoxybutylene-oxy) phenethyl] imidazole; and the salts, in particular the pharmaceutically or veterinarily acceptable salts thereof. 8. A compound according to any one of claims 1 to 3, characterized in that it is selected from the group: 1- [2,4-dichloro-small beta (4'-chloro-phenylthio-methylen-oxy) -phenethyl] -imidazole; 1- [2,4-dichloro-small beta (2 ', 4'-dichloro-phenylthio-methylen-oxy) -phenethyl] -imidazole; 1- [2,4-dichloro-small beta (2'-chloro-4'-methyl-phenylthio-methylen-oxy) -phenethyl] -imidazole; 1- [2,4-dichloro-small beta (3 ', 4'-dichloro-phenylthio-methylen-oxy) -phenethyl] -imidazole; 1- [2,4-dichloro-small beta (4'-methyl-phenylthio-methylen-oxy) -phenethyl] -imidazole; 1- [2,4-dichloro-small beta (4'-trifluoromethyl-phenylthio-methylen-oxy) -phenethyl] -imidazole; 1- [2,4-dichloro-small beta (2'-chloro-4'-propyl-phenylthio-methylen-oxy) -phenethyl] -imidazole; and the salts, in particular the pharmaceutically or veterinarily acceptable salts thereof. 9. A compound according to any one of claims 1 to 3, characterized in that it is selected from the group: 1- [2,4-dichloro-small beta (4'-chlorophenylthio-ethylene-oxy) -phenethyl] -imidazole; 1- [2,4-dichloro-small beta (2 ', 4'-dichloro-phenylthio-ethylene-oxy) -phenethyl] -imidazole; 1- [2,4-dichloro-small beta (2'-chloro-4'-methylphenylthio-ethylene-oxy) -phenethyl] -imidazole; 1- [2,4-dichloro-small beta (2'-chloro-4'-ethylphenylthio-ethylene-oxy) phenethyl] imidazole; 1- [4-phenyl-small beta (4'-chlorophenylthio-ethylene-oxy) -phenethyl] -imidazole; 1- [4-phenyl-small beta (2 ', 4'-dichlorophenylthio-ethylene-oxy) -phenethyl] -imidazole; and the salts, in particular the pharmaceutically or veterinarily acceptable salts thereof. 10. A compound according to any one of claims 1 to 3, characterized in that it is selected from the group: 1- [2,4-dichloro-small beta (4'-chlorophenylthio-propylene-oxy) phenethyl] imidazole; 1- [2,4-dichloro-small beta (2 ', 4'-dichlorophenylthio-propylene-oxy) phenethyl] imidazole; 1- [2,4-dichloro-small beta (4'-fluorophenylthio-propylene-oxy) phenethyl] imidazole; and the salts, in particular the pharmaceutically or veterinarily acceptable salts thereof. 11. 1- [2,4-dichloro-small beta (2'-chloro-4'-propyl-phenoxymethyleneoxy) -phenethyl] -imidazole and the salts, in particular the pharmaceutically or veterinarily acceptable salts thereof. 12. Salt of the compound according to claim 11 with an inorganic acid. 13. Salt according to claim 12, characterized in that the inorganic acid is nitric acid. 14. 1- [2,4-dichloro-small beta (2'-chloro-4'-ethyl-phenoxymethyleneoxy) -phenethyl] -imidazole and its salts, in particular its pharmaceutically or veterinarily acceptable salts. 15. Salt of the compound according to claim 14 with an inorganic acid. 16. Salt according to claim 15, characterized in that the inorganic acid is nitric acid. 17. 1- [2,4-dichloro-small beta (2 ', 4'-dichloro-phenoxyethyleneoxy) -phenethyl] -imidazole and its salts, in particular its pharmaceutically or veterinarily acceptable salts. 18. Salt of the compound according to claim 17 with an inorganic acid. 19. Salt according to claim 18, characterized in that the inorganic acid is nitric acid. 20. Process for the preparation of an N-phenethylimidazole derivative according to one of claims 1 to 19, characterized in that a compound of the general formula is used (II) wherein Y and n have the meanings given in claim 1, with a compound of the general formula B'-Z-A-R (III) wherein Z, A and R have the meanings given in claim 1 and in formulas (II) and (III) one of the groups B and B 'is halogen or the residue of a reactive ester of an alcohol and the other is an -OM group, in which M represents hydrogen or a cation, mean, and if desired, a compound of the formula (I) is converted into another compound of the formula (I) and / or, if desired, a compound of the formula (I) is converted into a salt and / or, if desired, an isomer mixture is separated into the individual isomers. 21. Pharmaceutical agent or veterinary agent, characterized in that it contains at least one N-phenethylimidazole derivative according to one of claims 1 to 19, optionally in combination with at least one pharmaceutically or veterinarily acceptable carrier and / or diluent.