DE3824939A1 - Antimycotic compositions containing 2,2-dihalocyclopropylhydroxyethyltriazoles - Google Patents

Abstract

The substituted 2,2-dihalocyclopropylhydroxyethyltriazoles of the formula <IMAGE> in which Ar, Y, R, X<1> and X<2> have the meaning indicated in the description, can be used as active ingredients of antimycotic compositions.

Description

The present invention relates to novel 2,2-dihalocyclopropylhydroxyethyltriazoles and their pharmacologically acceptable acid addition salts for the treatment of diseases, in particular mycoses.

It is already known that certain azolylmethylcyclopropyl-carbinol derivatives, such as 1-(4-chlorophenyl)-1-(1-fluoro-cycloprop-1-yl)-2-(1,2,4-triazol-1-yl)-ethan-1-ol and 1-(4-chlorophenyl)-1-[1-(2,4-dichlorophenoxy)-cycloprop-1-yl]-2-(1,2,4-triazol-1-yl)-ethan-1-ol, have antimycotic properties (see EP-OS 1 80 850). However, the effect of these substances is not always completely satisfactory in all indication areas.

It was found that the new 2,2-dihalocyclopropyl-hydroxyethyltriazoles of the formula

in which
Ar represents optionally substituted aryl;
R is alkyl, optionally substituted aryl or optionally substituted aralkyl;
X¹ stands for halogen;
X² stands for halogen and
Y represents the groups -OCH₂-, -SCH₂-, -CH₂CH₂- or -CH=CH-, where the heteroatom is connected to the aryl radical when Y represents -OCH₂- or -SCH₂-,
and their acid addition salts have good antimicrobial, especially antimycotic properties.

The substances according to the invention contain an asymmetrically substituted carbon atom. They can therefore be obtained in optical isomer forms. In addition, those substances of formula (I) in which Y is a -CH=CH group can also be present in the form of E or Z isomers. The invention relates to both the individual isomers and their mixtures.

The 2,2-dihalocyclopropyl-hydroxyethyltriazoles to be used according to the invention are generally defined by the formula (I). In this formula, preferably
Ar represents phenyl which is optionally mono- to trisubstituted by identical or different substituents, the following being preferred as substituents: halogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, haloalkyl having 1 or 2 carbon atoms and 1 to 5 identical or different halogen atoms, haloalkoxy having 1 or 2 carbon atoms and 1 to 5 identical or different halogen atoms, haloalkylthio having 1 or 2 carbon atoms and up to 5 identical or different halogen atoms, alkoximinoalkyl having 1 to 4 carbon atoms in each alkyl moiety, phenoximinoalkyl having 1 to 4 carbon atoms in the alkyl moiety which is optionally substituted by alkyl having 1 or 2 carbon atoms and/or halogen, phenyl which is optionally substituted by alkyl having 1 or 2 carbon atoms and/or halogen, or which is optionally substituted by alkyl having 1 or 2 carbon atoms. and/or halogen substituted phenoxy;
R represents alkyl having 1 to 4 carbon atoms and represents phenyl or benzyl, each optionally mono- to tri-substituted by identical or different substituents, the preferred substituents being those already mentioned as preferred for Ar;
X¹ represents fluorine, chlorine or bromine;
X² stands for fluorine, chlorine or bromine and
Y represents the moieties -OCH₂-, -SCH₂-, -CH₂CH₂- or -CH=CH-, wherein the heteroatom is connected to the aryl radical when Y represents -OCH₂- or -SCH₂.

Particularly preferred are those compounds of formula (I) in which
Ar represents phenyl which is optionally mono- to tri-substituted by identical or different substituents, where the following may be mentioned as substituents: fluorine, chlorine, bromine, methyl, ethyl, isopropyl, tert-butyl, methoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, methoximinomethyl, 1-methoximino-1-ethyl, ethoximinomethyl, phenyl which is optionally substituted by fluorine, chlorine and/or methyl, or phenoxy which is optionally substituted by fluorine, chlorine and/or methyl;
R represents methyl, ethyl, isopropyl, tert-butyl and phenyl or phenoxy which are each optionally mono- to disubstituted by identical or different substituents from the group consisting of fluorine, chlorine or methyl;
X¹ stands for fluorine or chlorine;
X² stands for fluorine or chlorine and
Y represents the groups -OCH₂-, -SCH₂-, -CH₂CH₂- or -CH=CH-, where the heteroatom is bonded to the aryl residue when Y is -OCH₂- or -SCH₂-.

Very particularly preferred are those compounds of formula (I) in which
Ar represents phenyl which is optionally mono- to tri-substituted by identical or different substituents, where the following may be mentioned as substituents: fluorine, chlorine, bromine, methyl, ethyl, isopropyl, tert-butyl, methoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, methoximinomethyl, 1-methoximino-1-ethyl, ethoximinomethyl, phenyl which is optionally substituted by fluorine, chlorine and/or methyl, or phenoxy which is optionally substituted by fluorine, chlorine and/or methyl;
R is methyl;
X¹ stands for fluorine;
X² stands for fluorine and
Y represents the groups -OCH₂-, -SCH₂-, -CH₂CH₂- or -CH=CH-, where the heteroatom is bonded to the aryl radical when Y represents -OCH₂- or -SCH₂-.

Preferred compounds according to the invention are also addition products of acids and those 2,2-dihalocyclopropyl-hydroxy-ethyltriazoles of the formula (I) in which Ar, R, X¹, X² and Y have the meanings which have already been mentioned as preferred for these radicals.

The acids that can be added preferably include hydrohalic acids, such as hydrochloric acid and hydrobromic acid, in particular hydrochloric acid, and also phosphoric acid, nitric acid, sulfuric acid, mono- and bifunctional carboxylic acids and hydroxycarboxylic acids, such as acetic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acid and lactic acid, and sulfonic acids, such as p-toluenesulfonic acid, 1,5-naphthalenedisulfonic acid or camphorsulfonic acid.

Examples of 2,2-dihalocyclopropyl-hydroxyethyltriazoles of formula (I) are the substances listed in the following table: Table 1

The 2,2-dihalocyclopropylhydroxyethyltriazoles of the formula (I) to be used according to the invention and their acid addition salts are not yet known. However, they are the subject of a separate, parallel patent application. They can be obtained by the process described therein by reacting oxiranes of the formula

in which
Ar, R, X¹, X² and Y have the meanings given above,
with 1,2,4-triazole of the formula

in the presence of an acid binder, such as potassium carbonate or potassium tert-butoxide, and in the presence of a diluent, such as acetonitrile or dimethylformamide, at temperatures between 50°C and 150°C and, if appropriate, subsequently adding an acid to the compounds of formula (I) thus obtained in the usual manner.

• a) Cyclopropylketone der Formel
  
  in welcher
  Ar, R, X¹, X² und Y die oben angegebene Bedeutung haben,
  entweder
  • &alpha;) mit Dimethyloxosulfonium-methylid der Formel
    
    oder
  • &beta;) mit Dimethylsulfonium-methylid der Formel
    
    in Gegenwart eines Verdünnungsmittels umsetzt.

The oxiranes of formula (II) are not yet known. They can be prepared by

• a) Cyclopropyl ketones of the formula
  
  in which
  Ar, R, X¹, X² and Y have the meaning given above,
  either
  • &alpha; ) with dimethyloxosulfonium methylide of the formula
    
    or
  • β ) with dimethylsulfonium methylide of the formula
    
    in the presence of a diluent.

• b) Halogenketone der Formel
  
  in welcher
  Hal für Chlor oder Brom steht und
  R, X¹ und X² die oben angegebenen Bedeutungen haben,
  mit Verbindungen der Formel
  AR-Z-H (VIII)
  in welcher
  Ar die oben angegebene Bedeutung hat und
  Z für Sauerstoff oder Schwefel steht,
  in Gegenwart eines Säurebindemittels und gegebenenfalls in Gegenwart eines Verdünnungsmittels umsetzt;
  oder
• c) Aldehyde der Formel
  Ar-CHO (IX)
  in welcher
  Ar die oben angegebene Bedeutung hat,
  mit Methyl-cyclopropyl-ketonen der Formel
  
  in welcher
  R, X¹ und X² die oben angegebenen Bedeutungen haben,
  in Gegenwart eines Katalysators und in Gegenwart eines Verdünnungsmittels umsetzt und gegebenenfalls die dabei entstehenden Cyclopropylketone der Formel
  
  in welcher
  Ar, R, X¹ und X² die oben angegebenen Bedeutungen haben,
  in Gegenwart eines Katalysators und in Gegenwart eines Verdünnungsmittels hydriert.

The cyclopropyl ketones of formula (IV) required as starting materials for carrying out process (a) are not yet known. They can be prepared by

• b) Halogen ketones of the formula
  
  in which
  Hal stands for chlorine or bromine and
  R, X¹ and X² have the meanings given above,
  with compounds of the formula
  AR-ZH (VIII)
  in which
  Ar has the meaning given above and
  Z stands for oxygen or sulfur,
  in the presence of an acid binder and optionally in the presence of a diluent;
  or
• c) Aldehydes of the formula
  Ar-CHO (IX)
  in which
  Ar has the meaning given above,
  with methyl cyclopropyl ketones of the formula
  
  in which
  R, X¹ and X² have the meanings given above,
  in the presence of a catalyst and in the presence of a diluent and optionally the resulting cyclopropyl ketones of the formula
  
  in which
  Ar, R, X¹ and X² have the meanings given above,
  hydrogenated in the presence of a catalyst and in the presence of a diluent.

• d) Methyl-cyclopropyl-ketone der Formel
  
  in welcher
  R, X¹ und X² die oben angegebenen Bedeutungen haben,
  mit Chlorierungsmitteln oder Bromierungsmitteln in Gegenwart eines Verdünnungsmittels umsetzt.

The halogen ketones of formula (VII) required as starting materials in process (b) are not yet known. They can be prepared by

• d) Methyl cyclopropyl ketones of the formula
  
  in which
  R, X¹ and X² have the meanings given above,
  with chlorinating agents or brominating agents in the presence of a diluent.

The ketones of formula (X) required as starting materials in processes (c) and (d) are also not yet known. They can be prepared by reacting vinylcyclopropane derivatives of formula

in which
R, X¹ and X² have the meanings given above,
in a generally known manner with strong oxidizing agents, such as potassium permanganate in the presence of a diluent, such as water, at temperatures between 0°C and 30°C, oxidized and the resulting cyclopropanecarboxylic acids of the formula

in which
R, X¹ and X² have the meanings given above,
also converted into the corresponding methyl ketones in a generally known manner, such as by reaction with methyllithium in the presence of a diluent, for example diethyl ether, at temperatures between -80 and +20°C.

The vinylcyclopropane derivatives of the formula (XII) are partly known (cf. Chem. Ber. 109, 2351 (1976)); or they can be prepared in a generally known manner, such as, for example, by addition of dihalocarbenes to corresponding dienes.

Suitable chlorinating and brominating agents in process (d) are all chlorinating and bromination reagents customary for such reactions. Sulfuryl chloride, sulfuryl bromide and bromine are preferably used.

Suitable diluents for process (d) are all inert organic solvents customary for such reactions. Halogenated aliphatic hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride are preferably used.

The reaction temperatures in process (d) can be varied within a certain range. In general, the reaction is carried out at temperatures between -10°C and +60°C, preferably between 0°C and +40°C. When carrying out process (d), as in the other processes described in this application, the reaction is generally carried out under normal pressure. However, it is also possible to work under increased or reduced pressure.

When carrying out process (d), a stoichiometric amount or a slight excess of chlorinating or brominating agent is generally used per 1 mole of ketone of formula (XII). The mixture is worked up by conventional methods. In general, the reaction mixture is washed successively with dilute aqueous sodium hydrogen carbonate solution and water, then dried and concentrated.

The aldehydes of the formula (IX) which are also required as starting materials in process (c) are generally known compounds of organic chemistry.

All reaction accelerators customary for such condensations can be used as catalysts for carrying out the first step of process (c). Basic substances, e.g. alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, are preferably used.

Suitable diluents for carrying out the first step of process (c) are all inert organic solvents customary for such reactions. Alcohols such as methanol, ethanol, isopropanol, n-butanol and tert-butanol are preferably used.

The reaction temperatures can be varied within a wide range when carrying out the first step of process (c). In general, temperatures between 0°C and 100°C, preferably between 10°C and 80°C, are used.

The first step of process (c) is generally carried out under normal pressure. However, it is also possible to work under increased or reduced pressure.

When carrying out the first step of process (c), 1 mole of aldehyde of formula (IX) and a catalytic amount of reaction accelerator are used for 1 mole of methyl cyclopropyl ketone of formula (X). However, it is also possible to use one or the other component in excess. The work-up is carried out using conventional methods. In general, the reaction products obtained in the solid state are filtered off with suction and, after prior purification if necessary, used for further reactions.

In the second stage of process (c), the cyclopropyl ketones of the formula (XI) are hydrogenated with hydrogen in the presence of a catalyst and a diluent. The process is carried out in the liquid phase using a suspended, powdered hydrogenation catalyst (heterogeneous) or using a catalyst complex soluble in the diluent (homogeneous). The hydrogenation can be carried out discontinuously (batchwise) or continuously as a bottom phase or trickle phase hydrogenation in known hydrogenation reactors, such as autoclaves, autoclave cascades, tubular reactors or circulation reactors. The preferred method of operation is the discontinuous bottom phase hydrogenation in the autoclave at elevated pressure.

Inert organic solvents are suitable as diluents for carrying out the second step of process (c). These preferably include alcohols such as methanol, ethanol, isopropanol or ethylene glycol; ethers such as diethyl ether, diisopropyl ether, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, dioxane or tetrahydrofuran; saturated hydrocarbons such as n-heptane or cyclohexane; aromatic hydrocarbons such as toluene; and esters such as ethyl acetate.

Hydrogenation catalysts suitable for the second stage of process (c) are, for example, those which consist of or contain metals and/or compounds of elements of the eighth subgroup of the Periodic Table of the Elements according to Mendeleev. The metals ruthenium, rhodium, palladium, platinum, cobalt and nickel and their compounds are preferred. The metal compounds can be for example, chlorides, oxides, hydroxides and/or oxyhydrates. In addition, the metals copper, vanadium, molybdenum, chromium and/or manganese, as well as compounds of these metals, may be present.

The hydrogenation catalysts can consist exclusively or predominantly of hydrogen-transferring substances, but these can also be applied to support materials.

Examples of possible carrier materials for the hydrogen-transferring substances are: inorganic materials such as diatomaceous earth, silica, aluminum oxide, alkali and alkaline earth silicates, aluminum silicates, montmorillonite, zeolites, spinels, dolomite, kaolin, magnesium silicates, zirconium oxide, zinc oxide, calcium carbonate, silicon carbide, aluminum phosphate, boron phosphate, asbestos, activated carbon or barium sulfate, but also organic materials, for example naturally occurring or synthetic compounds with high molecular weights such as silk, polyamides, polystyrenes, cellulose or polyurethanes. Inorganic carrier materials in powder form are preferred.

Such supported catalysts can generally contain 0.5 to 50% by weight, preferably 1 to 10% by weight, of the hydrogen-transferring substance, based on the total mass of the supported catalyst. The hydrogen-transferring substance can be distributed homogeneously in the support material, but catalysts in whose outer layer or on whose surface the hydrogen-transferring substance is deposited are preferred. The production and shaping of the catalysts which can be used in process (c) can be carried out in a known manner (see, for example, Houben-Weyl, Methods of Organic Chemistry, Volume IV, Ic, Part I, pp. 16 to 26, Georg Thieme Verlag, Stuttgart, 1980).

Preferred supported catalysts are ruthenium on carbon, ruthenium on alumina, rhodium on carbon, rhodium on alumina, palladium on carbon, palladium on alumina, palladium on calcium carbonate, palladium on barium sulfate, palladium on silica, platinum on carbon and platinum on alumina, nickel on diatomaceous earth, nickel on alumina and nickel and palladium on alumina.

Preferred hydrogenation catalysts for hydrogenation in heterogeneous systems, which consist exclusively or predominantly of hydrogen-transferring substances, are, for example, oxidic catalysts such as palladium oxide, platinum oxide, ruthenium oxide and/or rhodium oxide/platinum oxide according to Nishimura, and also black catalysts which can be prepared by reducing corresponding metal salts or metal salt mixtures with alkali hydrides, alkali boranates, metal alkyls, hydrazine, formaldehyde, hydrogen or electropositive metals, such as palladium/black, platinum/black and rhodium/black; and skeletal catalysts of the Raney type, such as Raney nickel, Raney cobalt, Raney nickel-cobalt, Raney nickel-iron, Raney nickel-copper, Raney nickel-iron-chromium, Raney nickel-palladium and Raney nickel-iron-vanadium.

In the case of hydrogenation in a heterogeneous system, the hydrogenation catalysts are used in the second stage of process (c) in an amount such that 0.05 to 2.5, preferably 0.1 to 1, % by weight of hydrogen-transferring substance is present, based on the total mixture of the reaction mixture.

To carry out the second step of process (c), mixtures of two or more of the hydrogenation catalysts mentioned can also be used.

The catalytic activity of the hydrogenation catalysts is generally largely retained when the second step of process (c) is carried out, so that they can be used repeatedly in batch operations and can remain in use for a longer period in continuous operations.

The reaction temperatures in the second step of process (c) can be varied within a wide range. In general, the reaction is carried out in the range between 0°C and 150°C, preferably between 20°C and 120°C.

The heterogeneous catalyzed hydrogenations in the second stage of process (c) are preferably carried out at elevated pressure. In general, the pressure used is between 1 and 150 bar, preferably between 10 and 60 bar.

In addition to the above-mentioned hydrogenation catalysts of a heterogeneous nature, homogeneously dissolved hydrogenation catalysts can also be used when carrying out the second stage of process (c). The often higher selectivity of homogeneous hydrogenation catalysts compared to heterogeneous catalysts allows the selective hydrogenation of cyclopropyl ketones of formula (XI) which contain additional hydrogenatable or hydrolysis-sensitive substituents, such as halogen on the phenyl radical. Such homogeneous hydrogenation catalysts are, for example, complexes which contain metals from the eighth subgroup of the Mendeleev Periodic Table of the Elements as the central atom. The metals ruthenium, rhodium, palladium, iridium, cobalt and nickel are preferred. Ruthenium, rhodium and indium are particularly preferred. Examples of such metal complexes are tris-(triphenylphosphine)-rhodium(I) chloride, tris-(triphenylphosphine)-ruthenium(II) chloride and bis-(triphenylphosphine)-carbonyl-iridium(I) chloride.

When using homogeneously dissolved hydrogenation catalysts, inert organic solvents can be used as diluents when carrying out the second stage of process (c). Alcohols such as methanol, ethanol, isopropanol or ethylene glycol, hydrocarbons such as toluene, ketones such as acetone and butanone, and also esters such as ethyl acetate are preferably used.

In the hydrogenation in a homogeneous system, the hydrogenation catalysts used in carrying out the second step of process (c) are generally used in an amount such that 0.01 to 0.2 mol%, preferably 0.05 to 1.0 mol% of hydrogenation catalyst complex are present, based on the cyclopropyl ketone of the formula (XI) used.

The reaction temperatures can also be varied within a wide range during hydrogenation in a homogeneous system when carrying out the second step of process (c). In general, temperatures between 0°C and 150°C, preferably between 20°C and 120°C, are used.

The hydrogenations carried out in the homogeneous system in the second stage of process (c) are preferably carried out under elevated pressure. In general, pressures between 1 and 150 bar, preferably between 10 and 100 bar, are used.

In a variant, the hydrogenation in the homogeneous system in the second stage of process (c) can also be carried out in such a way that the hydrogenation is not carried out with molecular hydrogen, but that reducing agents are used which are capable of transferring one or more hydrogen atoms to the cyclopropyl ketone of the formula (XI) in the presence of a suitable catalyst in the sense of a transfer hydrogenation and therefore act as hydrogen donors. In principle, the complexes of metals from the eighth subgroup of the Mendeleev Periodic Table of the Elements already described for the homogeneously catalyzed hydrogenation with molecular hydrogen in the second stage of process (d) can be used as catalysts for such a transfer hydrogenation.

Primary and secondary, mono- or polyhydric alcohols can be considered as hydrogen donors. Preferably used are methanol, ethanol, n-propanol, i-propanol, n-butanol, 2-butanol, benzyl alcohol, ethylene glycol, 1,3-propanediol, 1,4-butanediol and 1,5-pentanediol. These alcohols can serve both as hydrogen donors and as solvents.

Other hydrogen donors that can be used in the second stage of process (c) are alkali metal and alkaline earth metal salts of formic acid, such as sodium formate and potassium formate, and also formic acid itself. - When using a salt of formic acid, the second stage of process (c) can be carried out in the form of a phase-transfer catalysis, in which the cyclopropyl ketone of the formula (XI) and the hydrogenation catalyst are dissolved in a suitable inert solvent and the formate is present as an aqueous solution in a second phase. Suitable solvents in this context are therefore those solvents which on the one hand dissolve the cyclopropyl ketone of the formula (XI) and the hydrogenation catalyst, but on the other hand are not miscible with water. Such solvents are, for example, benzene, toluene, chlorobenzene, dichlorobenzenes and methylene chloride. - All reaction accelerators which can be used for this purpose in organic chemistry can be considered as phase-transfer catalysts. Tetrabutylammonium bromide and methyltridecylammonium chloride (Aliquat®336) are preferably used.

The reaction time required for the second stage of process (c) depends on the reaction temperature, the hydrogen partial pressure, the intensity of the mixing of the reaction mixture and the activity and concentration of the hydrogenation catalyst. In general, the reaction time required is in the range from 15 minutes to several hours. - The work-up is carried out using conventional methods.

The compounds of formula (VIII) also required as starting materials in process (b) are generally known compounds of organic chemistry.

All customary acid acceptors can be used as acid binders when carrying out process (b). Alkali metal carbonates and hydrogen carbonates, such as sodium carbonate, potassium carbonate or sodium hydrogen carbonate, and alkali metal hydroxides and alcohols, such as sodium hydroxide, potassium hydroxide, sodium methylate or potassium tert-butoxide, and tertiary aliphatic or aromatic amines, such as triethylamine, N,N-dimethylcyclohexylamine, N,N-dimethylbenzylamine and pyridine, and also cyclic amines, such as 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,4-diazabicyclo[2.2.2]octane (DABCO) are preferably used.

All inert organic solvents can be used as diluents when carrying out process (b). Preferably used are aliphatic and aromatic, optionally halogenated hydrocarbons such as pentane, hexane, heptane, cyclohexane, petroleum ether, gasoline, ligroin, benzene, toluene, xylene, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, chlorobenzene and o-dichlorobenzene, ethers such as dimethyl and dibutyl ether, glycol dimethyl ether and diglycol dimethyl ether, tetrahydrofuran and dioxane, ketones such as acetone, methyl ethyl, methyl isopropyl and methyl isobutyl ketone, esters such as methyl acetate and ethyl acetate, nitriles such as acetonitrile and propionitrile and pyridine, and also strongly polar solvents such as dimethylformamide and dimethyl sulfoxide.

The reaction temperatures in process (b) can be varied within a wide range. In general, temperatures between 0°C and 150°C are used, preferably between 20°C and 130°C.

When carrying out process (b), 1 to 1.5 moles of compounds of formula (VIII) and 1 to 2 moles of acid binder are generally used for 1 mole of halogen ketone of formula (VII). The work-up is carried out by conventional methods. In general, the reaction mixture is concentrated after filtering off any salts that have separated out, the residue is taken up in an organic residue that is sparingly miscible with water, the resulting solution is washed, dried and then concentrated.

The dimethyl oxosulfonium methylide of formula (V) required as a reaction component in process (a) is known (cf. J. Am. Chem. Soc. 87, 1363-1364 (1965)). It is processed in the above reaction in a freshly prepared state by producing it in situ by reacting trimethyloxosulfonium iodide with sodium hydride or sodium amide, in particular with potassium tert-butoxide or sodium methylate, in the presence of a diluent.

Dimethylsulfonium methylide of the formula (VI), which can also be used as a reaction component in process (a), is also known (cf. Heterocycles 8, 397 (1977)). It is also used in the above reaction in a freshly prepared state by producing it in situ, for example from trimethylsulfonium halide or trimethylsulfonium methylsulfate, in the presence of a strong base, such as sodium hydride, sodium amide, sodium methylate, potassium tert-butoxide or potassium hydroxide, in the presence of a diluent, such as tert-butanol or dimethyl sulfoxide.

Inert organic solvents are suitable as diluents for carrying out process (a). Alcohols such as tert-butanol, ethers such as tetrahydrofuran or dioxane, and also aliphatic and aromatic hydrocarbons such as benzene, toluene or xylene, and strongly polar solvents such as dimethyl sulfoxide are preferably used.

When carrying out process (a), the reaction temperatures can be varied within a wider range In general, temperatures are between 0°C and 100°C, preferably between 10°C and 60°C.

When carrying out process (a), 1 to 3 moles of dimethyloxosulfonium methylide of the formula (V) or of dimethylsulfonium methylide of the formula (VI) are generally employed per mole of cyclopropyl ketone of the formula (IV). The oxiranes of the formula (II) are isolated by conventional methods.

The 1,2,4-triazole of the formula (III), which is also required as a reaction component in carrying out the process according to the invention, is a generally known compound of organic chemistry.

The acid addition salts of the compounds of formula (I) can be obtained in a simple manner by conventional salt formation methods, for example by dissolving a compound of formula (I) in a suitable inert solvent and adding the acid, for example hydrochloric acid, and can be isolated in a known manner, for example by filtration, and optionally purified by washing with an inert organic solvent.

The compounds of formula (I) according to the invention and their acid addition salts have antimicrobial, in particular strong antimycotic effects. They have a very broad antimycotic spectrum of activity, in particular against dermatophytes and yeast fungi and biphasic fungi, e.g. against Candida species such as Candida albicans, Epidermophyton species such as Epidermophyton floccosum, Aspergillus species such as Aspergillus niger and Aspergillus fumigatus, Trichophyton species such as Trichophyton mentagrophytes, Microsporon species such as Microsporon felineum and Torulopsis species such as Torulopsis glabrata. The list of these microorganisms in no way represents a restriction of the germs that can be combated, but is merely illustrative.

Examples of indications in human medicine include:

Dermatomycoses and systemic mycoses caused by Trichophyton mentagrophytes and other Trichophyton species, Microsporon species and Epidermophyton floccosum, yeast and biphasic fungi as well as molds.

Examples of indications in veterinary medicine include:

All dermatomycoses and systemic mycoses, especially those caused by the pathogens mentioned above.

The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable carriers, contain one or more active ingredients according to the invention or which consist of one or more active ingredients according to the invention.

The present invention also includes pharmaceutical preparations in dosage units. This means that the preparations are in the form of individual parts, e.g. tablets, dragees, capsules, pills, suppositories and ampoules, whose active ingredient content corresponds to a fraction or a multiple of a single dose. The dosage units can contain, for example, 1, 2, 3 or 4 single doses or ½, ¹/₃ or ¼ of a single dose. A single dose preferably contains the amount of active ingredient that is administered in one application and which usually corresponds to a whole, half, third or quarter of a daily dose.

Non-toxic, inert pharmaceutically acceptable carriers include solid, semi-solid or liquid diluents, fillers or formulation aids of any kind.

Preferred pharmaceutical preparations include tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders or sprays.

Tablets, dragees, capsules, pills and granules may contain the active ingredient(s) in addition to the usual carriers such as (a) fillers or extenders, e.g. starches, lactose, cane sugar, glucose, mannitol and silica, (b) binders, e.g. carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, (c) humectants, e.g. glycerol, (d) disintegrants, e.g. agar-agar, calcium carbonate and sodium bicarbonate, (e) dissolution retarders, e.g. paraffin and (f) absorption accelerators, e.g. quaternary ammonium compounds, (g) wetting agents, e.g. cetyl alcohol, glycerol monostearate, (h) adsorbents, e.g. kaolin and bentonite and (i) lubricants, e.g. B. Talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) to (i).

The tablets, dragees, capsules, pills and granules can be provided with the usual coatings and shells, optionally containing opacifying agents, and can be composed in such a way that they release the active ingredient(s) only or preferentially in a certain part of the intestinal tract, optionally with a delay, whereby polymer substances and waxes, for example, can be used as embedding materials.

The active ingredient(s) may also be in microencapsulated form, if appropriate, with one or more of the excipients indicated above.

In addition to the active ingredient(s), suppositories may contain the usual water-soluble or water-insoluble carriers, e.g. polyethylene glycols, fats, e.g. cocoa fat and higher esters (e.g. C₁₄ alcohol with C₁₆ fatty acid) or mixtures of these substances.

In addition to the active ingredient(s), ointments, pastes, creams and gels may contain the usual carrier substances, e.g. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silocones, bentonites, silica, talc and zinc oxide or mixtures of these substances.

In addition to the active ingredient(s), powders and sprays may contain the usual carrier substances, e.g. lactose, talc, silica, aluminium hydroxide, calcium silicate and polyamide powder or mixtures of these substances; sprays may additionally contain the usual propellants, e.g. chlorofluorocarbons.

Solutions and emulsions may contain, in addition to the active ingredient(s), the usual carriers such as solvents, dissolution retarders and emulsifiers, e.g. water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerin, glycerin formal, tetrahydrofurfuryl alcohol, Contain polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.

For parenteral administration, the solutions and emulsions can also be available in sterile and blood-isotonic form.

In addition to the active ingredient(s), suspensions may contain the usual carriers, such as liquid diluents, e.g. water, ethyl alcohol, propyl alcohol, suspending agents, e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances.

The above-mentioned formulations may also contain colorants, preservatives, odor and flavor enhancers, such as peppermint oil and eucalyptus oil, and sweeteners, such as saccharin.

The therapeutically active compounds should preferably be present in the above-mentioned pharmaceutical preparations in a concentration of about 0.1 to 99.5, preferably 0.5 to 95% by weight of the total mixture.

The pharmaceutical preparations listed above may contain other pharmaceutical active ingredients in addition to the active ingredients according to the invention.

The pharmaceutical preparations listed above are manufactured in the usual way using known methods, e.g. by mixing the active ingredient(s) with the carrier(s).

The present invention also includes the use of the active ingredients according to the invention, as well as of pharmaceutical preparations containing one or more active ingredients according to the invention, in human and veterinary medicine for preventing, improving and/or curing the diseases listed above.

The active substances or the pharmaceutical preparations can be administered locally, orally, parenterally, intraperitoneally and/or rectally, preferably parenterally, in particular intravenously.

In general, it has proven advantageous in both human and veterinary medicine to administer the active ingredient(s) according to the invention in total amounts of about 2.5 to about 200, preferably 5 to 150 mg/kg body weight per 24 hours, optionally in the form of several individual doses to achieve the desired results.

In the case of oral administration, the active ingredients according to the invention are administered in total amounts of about 2.5 to about 200, preferably 5 to 150 mg/kg body weight per 24 hours and in the case of parenteral administration in total amounts of about 2.5 to about 50, preferably 1 to 25 mg/kg body weight per 24 hours.

However, it may be necessary to deviate from the dosages mentioned, depending on the type and body weight of the object to be treated, the type and severity of the illness, the method of preparation and application of the drug, and the period or interval within which the drug is administered. In some cases, it may be sufficient to use less than the amount of active ingredient mentioned above, while in other cases the amount of active ingredient listed above must be exceeded. The optimal dosage and method of application of the active ingredients required in each case can easily be determined by any specialist based on his or her specialist knowledge.

Manufacturing examples example 1

4.2 g (0.015 mol) of 2-(4-chlorophenoxymethyl)-2-(2,2-difluoro-1-methylcyclopropyl)-oxirane, 2.1 g (0.03 mol) of 1,2,4-triazole and 4.2 g (0.03 mol) of potassium carbonate are stirred in 30 ml of dimethylformamide overnight at 90°C. After removing the solvent using the oil pump, the residue is stirred with water/methylene chloride, the organic phase is separated and concentrated. The residue is purified by column chromatography (chloroform/ethyl acetate = 4:1) on silica gel.

2.3 g (44.6% of theory) of 1-(4-chlorophenoxy)-2-(2,2-difluoro-1-methylcyclopropyl)-2-hydroxy-3-(1,2,4-triazol-1-yl)-propane are obtained with a melting point of 110°C. Production of starting materials

2.4 g (0.044 mol) of sodium methylate are added to a solution of 30 ml (0.04 mol) of a 1.36 molar solution of trimethylsulfonium methylsulfate in acetonitrile and the mixture is stirred for 30 minutes. Then 5.8 g (0.022 mol) of 1-(4-chlorophenoxyacetyl)-1-methyl-2,2-difluorocyclopropane are added and the mixture is stirred overnight at 20°C. The mixture is poured into 200 ml of water, the oxirane is extracted with methylene chloride, the organic phase is washed with water and the organic phase is concentrated.

4.3 g (GC content of 73%; 71.6% of theory) of 2-(4-chlorophenoxymethyl)-2-(2, 2-difluoro-1-methylcyclopropyl)-oxirane are obtained as a viscous resin, which is directly further reacted.

6 g (0.028 mol) of 1-bromoacetyl-1-methyl-2,2-difluorocyclopropane are refluxed overnight with stirring in 30 ml of acetone with the addition of 4.4 g (0.032 mol) of potassium carbonate and 4.1 g (0.032 mol) of 4-chlorophenol. The mixture is diluted with water, the product is extracted with methylene chloride, the organic phase is washed once with dilute sodium hydroxide solution, then with water and concentrated.

6 g of 1-(4-chlorophenoxyacetyl)-1-methyl-2,2-difluorocyclopropane are obtained as crude product with a purity (GC) of 66% (54.4% of theory).

4.7 ml (0.09 mol) of bromine dissolved in 30 ml of methylene chloride are added dropwise to a solution of 12.5 g (0.09 mol) of 1-acetyl-1-methyl-2,2-difluoro-cyclopropane in 50 ml of methanol at 20°C while stirring. After complete decolorization, pour into 200 ml of water and extract the bromoketone with methylene chloride. After concentration, 20 g (GC content 47%; 47% of theory) of crude 1-bromoacetyl-1-methyl-2,2-difluorocyclopropane are obtained, which is used directly without further purification.

333 ml of a 1.5 molar methyllithium solution (0.5 mol) are added dropwise to 34 g (0.25 mol) of 2,2-difluoro-1-methylcyclopropanecarboxylic acid in 250 ml of dry diethyl ether at -78°C under nitrogen. The mixture is stirred for a further hour at -78°C, warmed to 0°C and the reaction solution is poured onto 500 g of ice and 50 ml of concentrated hydrochloric acid. The organic phase is separated and the aqueous phase is extracted with ether. The combined organic phases are dried over sodium sulfate, the solvent is distilled off and the product is distilled under a slight vacuum.

21 g (63% of theory) of 2,2-difluoro-1-methylcyclopropylmethyl ketone with a boiling point of 58-60°C/60 mbar are obtained.

840g 2.3 kg (14.47 mol) of potassium permanganate are added in portions to (7.12 mol) of 2,2-difluoro-1-methyl-1-vinyl-cyclopropane in 10 l of water. The mixture is stirred for 36 hours, filtered off to remove manganese dioxide and washed well with water. The filtrate is acidified with concentrated hydrochloric acid and extracted with dichloromethane. After drying, the solvent is removed in vacuo and the residue is distilled.

This gives 750 g (77% of theory) of 2,2-difluoro-1-methylcyclopropanecarboxylic acid (77% of theory) with a melting point of 59-61°C.

The addition of difluorocarbene to isoprene to form 2,2-difluoro-1-methyl-1-vinyl-cyclopropane is already known and described by M. Kamel, W. Kimpenhaus, J. Buddrus, Chem. Ber. 109, 2351 (1976). Example 2

To a solution of 3.3 g (0.048 mol) of 1,2,4-triazole in 30 ml of dimethylformamide, 1.4 g (0.048 mol) of 80% sodium hydride are added in portions and the mixture is stirred for 30 minutes at 20-30°C. Then 6.6 g (0.024 mol) of 2-(2,2-difluoro-1-methyl-cyclopropyl)-2-[2-(4-chlorophenyl)-ethen-1-yl]-oxirane are added and the mixture is stirred overnight at 90°C. The mixture is then poured into water, the product is extracted with methylene chloride, the organic phase is concentrated and the residue is purified by chromatography on silica gel (chloroform/ethyl acetate = 4:1).

This gives 2.4 g (29.6% of theory) of 1-(4-chlorophenyl)-3-(2,2-difluoro-1-methylcyclopropyl)-3-hydroxy-4-(1,2,4-triazol-1-yl)-but-1-ene with a melting point of 131°C. Preparation of starting materials

41 ml (0.06 mol) of a 1.46 molar solution of trimethylsulfonium methylsulfate in acetonitrile are mixed with 3.6 g (0.066 mol) of sodium methylate and stirred for 30 minutes. Then 10 g (0.039 mol) of (2,2-difluoro-1-methyl-cyclopropyl)-[(2-(4-chlorophenyl)-ethen-1-yl]-ketone, dissolved in 100 ml of acetonitrile, are added and stirred overnight. The mixture is then poured into water, the product is extracted with methylene chloride, the organic Phase twice with water and concentrate the organic phase in vacuo.

This gives 6.8 g (GC content 38%; 24% of theory) of 2-(2,2-difluoro-1-methylcyclopropyl-2-[2-(4-chlorophenyl)-ethen-1-yl]-oxirane, which is reacted directly without further purification.

15 g (0.11 mol) of 1-acetyl-2,2-difluoro-1-methylcyclopropane in 20 ml of 10% methanolic sodium hydroxide solution are mixed with 15.5 g (0.11 mol) of p-chlorobenzaldehyde, dissolved in 20 ml of methanol, at 20°C while stirring. After 15 minutes, a further 40 ml of 10% methanolic sodium hydroxide solution are added and stirring is continued overnight. The mixture is poured into water, the product is extracted with methylene chloride, the organic phase is washed with water and concentrated in vacuo.

25 g (88% of theory) of crude (2,2-difluoro-1-methylcyclopropyl)-[2-(4-chlorophenyl)-ethen-1-yl]-ketone are obtained as an oil, which is directly further reacted.

According to Examples 1 and 2 and according to the process conditions indicated, the substances listed in Table 2 below are obtained: Table 2

Examples of use

In the following examples, the compounds listed below are used as reference substances:

(known from EP-OS 1 80 850).

Example A Antifungal in vitro efficacy Experiment description

• a) für Dermatophyten und Schimmelpilze:
  Sabouraud's milieu d'epreuve
• b) für Hefen:
  Fleischextrakt-Traubenzucker-Bouillon.

The in vitro tests were carried out in a serial dilution test with germ inocula of an average of 5 × 10³ to 10⁴ germs/ml substrate. The culture medium used was

• a) for dermatophytes and moulds:
  Sabouraud's environment
• b) for yeasts:
  Meat extract-dextrose broth.

The incubation temperature was 28°C to 37°C, the incubation time was 24 to 96 hours for yeasts and 96 hours for dermatophytes and molds.

In this test, for example, the compounds I-1, I-2, I-3, I-4 and I-5 according to the invention show a better antimycotic activity than the compounds (A) and (B) known from the prior art. Table A Antimycotic in vitro activity
&udf53;TA5,6:14,6:33,6:5,6:14,6:18,6:22,6:26,6:30,6:33,6&udf54;&udf53;TW,4&udf54;&udf53;TZ5&udf54;&udf53;SG8&udf54;\Active ingredient\ MIC values in Óg/ml culture medium\ \ Tricho-&udf50;phyton&udf50;mentagr.\ Micro-&udf50;sporum&udf50;canis\ Candida&udf50;albi-&udf50;cans\ Toru-&f50;popsis&udf50;gla-&udf 50;brata\ Asper-&f51;gillus&udf50;fumi-&f50;gatus&udf53;TZ5,10&udf54;&udf53;TW,4&udf54;&udf53;SG9&udf54;&udf53;TA5,6:14,6:18,6:22,6:26,6:30,6:33,6&udf54;\(A) (known)\ >¤64\ ^\ >¤64\ ^\ >64&udf53;TZ&udf54; \(B) (known)\ ¤64\ ^\ 16\ 64\ >64&udf53;TZ5&udf54; \Compounds according to preparation example&udf53;TZ&udf54; \I-1\ 2\ ^\ 8\ 64\ 16&udf53;TZ&udf54; \I-2\ <¤1\ 2\ 4\ 8\ <¤1&udf53;TZ&udf54; \I-3\ <¤1\ 16\ 16\ 64\ 8&udf53;TZ&udf54; \I-4\ <¤1\ 16\ 8\ 64\ 16&udf53;TZ&udf54; \I-5\ <¤1\ 2\ 4\ 8\ 2&udf53;TZ&udf54;&udf53;TE&udf54;&udf53;SB37,6&udf54;&udf53;EL1,6&udf54;

Example B Antifungal in vivo activity (oral) in murine candidiasis Experiment description

SPF-CF1 mice were infected intravenously with 1-2 × 106 logarithmically growing Candida cells suspended in physiological saline. One hour before and seven hours after infection, the animals were treated orally with 10-100 mg/kg body weight of the preparations.

Result

Untreated animals died 3 to 6 days post-infection. The survival rate on day 6 post-infection in untreated control animals was about 5%.

In this test, for example, the compounds (I-1) and (I-2) according to the invention show a better effect than the compounds (A) and (B) known from the prior art. Table B Antimycotic in vitro efficacy (oral) in mouse candidiasis
&udf53;TA5,6:25,6:33,6&udf54;&udf53;TW,4&udf54;&udf53;TZ5&udf54;&udf53;SG8&udf54;\Active ingredient\ Effect&udf53;TZ5,10&udf54;&udf53;TW,4&udf54;&udf53;SG9&udf54;\(A) (known)\ n/a&udf53;TZ&udf54; \(B) (known)\ n/a&udf53;TZ5&udf54; \Compound according to preparation example&udf53;TZ&udf54; \(I-1)\ +++++&udf53;TZ&udf54; \(I-2)\ +++&udf53;TZ5&udf54;&udf53;TE&udf54;&udf53;SG8&udf54;\Key:&udf50;&udf53;TA5,6:9,6:17,6:33,6&udf54;\+++++\ =¤very good effect\ =¤90% survivors on day 6 p.¤i.&udf53;TZ&udf54; \¸++++\ =¤good effect\ =¤80% survivors on day 6 p.¤i.&udf53;TZ&udf54; \¸¸+++\ =¤effect\ =¤60% survivors on day 6 p.¤i.&udf53;TZ&udf54; \¸¸¸++\ =¤weak effect\ =¤40% survivors on day 6 p.¤i.&udf53;TZ&udf54; \¸¸¸¸+\ =¤trace effect\ =¤less than 40% survivors on day 6 p.¤i.&udf53;TZ&udf54; \n.¤W.\ \ =¤no difference from untreated infection control&udf53;TZ&udf54;&udf53;TE&udf54;&udf53;SB37.6&udf54;&udf53;EL1.6&udf54;&udf53;SG9&udf54; Example C formulations
&udf53;TA5,6,,12:31:33,6&udf54;&udf53;TZ&udf54; \1. Solution:&udf53;TZ&udf54;&udf53;TK1&udf54;&udf53;FE&udf54;&udf53;TK&udf54;\¸Active ingredient according to formula (I)\ ¸10¤g&udf53;TZ&udf54; \¸Alcohol, pure (96%)\ Æ300¤g&udf53;TZ&udf54; \¸Isopropyl myristate\ °=UÆ526¤g°=u&udf53;TZ&udf54; \\ Æ836äg&udf53;TZ10&udf54; \2. Cream: &udf53;TZ&udf54; \¸Active ingredient according to¿Å formula (I)\ ÆÆ10¤g&udf53;TZ&udf54; \¸Aralcel 60 (sorbitan monostearate)\ ÆÆ20¤g&udf53;TZ&udf54; \¸Tween 60 (polyoxyethylene (2)-sorbitan monostearate)\ ÆÆ15¤g&udf53;TZ&udf54; \¸Spermace, artificial (mixture of esters of saturated fatty acids CÉÈ^CÉÌ and fatty alcohols CÉÈ^CÉÌ)\ ¸30¤g&udf53;TZ&udf54; \¸Lanette O\ Æ100¤g&udf53;TZ&udf54; \¸Eutanol G (2-octyl-dodecanol)\ Æ135¤g&udf53;TZ&udf54; \¸Benzyl alcohol\ ÆÆ10¤g&udf53;TZ&udf54; \¸Water, demineralized\ °=UÆ680¤g°=u&udf53;TZ&udf54; \\ 1000¤g&udf53;TZ&udf54;&udf53;TE&udf54;&udf53;SB37,6&udf54;&udf53;EL1,6&udf54;

Claims (10)

1. 2,2-Dihalocyclopropyl-hydroxy-ethyltriazole of the formula

in which
Ar represents optionally substituted aryl;
R is alkyl, optionally substituted aryl or optionally substituted aralkyl;
X¹ stands for halogen;
X² stands for halogen and
Y represents the groups -OCH₂-, -SCH₂-, -CH₂CH₂- or -CH=CH-, where the heteroatom is connected to the aryl radical when Y represents -OCH₂- or -SCH₂- ,
and their acid addition salts to combat diseases. 2. 2,2-Dihalocyclopropyl-hydroxyethyltriazoles according to claim 1, in which
Ar represents phenyl which is optionally mono- to trisubstituted by identical or different substituents, where the following may be mentioned as substituents: halogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, haloalkyl having 1 or 2 carbon atoms and 1 to 5 identical or different halogen atoms, haloalkoxy having 1 or 2 carbon atoms and 1 to 5 identical or different halogen atoms, haloalkylthio having 1 or 2 carbon atoms and 1 to 5 identical or different halogen atoms, alkoximinoalkyl having 1 to 4 carbon atoms in each alkyl moiety, phenoximinoalkyl having 1 to 4 carbon atoms in the alkyl moiety which is optionally substituted by alkyl having 1 or 2 carbon atoms and/or halogen, phenoxy which is optionally substituted by alkyl having 1 or 2 carbon atoms and/or halogen;
R represents alkyl having 1 to 4 carbon atoms and represents phenyl or benzyl, each optionally mono- to tri-substituted by identical or different substituents, where the substituents already mentioned for Ar are possible substituents;
X¹ represents fluorine, chlorine or bromine;
X² stands for fluorine, chlorine or bromine and
Y represents the groups -OCH₂-, -SCH₂-, -CH₂CH₂- or -CH=CH-, where the heteroatom is connected to the aryl radical when Y represents -OCH₂- or -SCH₂
and their acid addition salts to combat diseases. 3. 2,2-Dihalocyclopropyl-hydroxyethyl-triazoles according to claim 1, in which
Ar represents phenyl which is optionally mono- to tri-substituted by identical or different substituents, where the following may be mentioned as substituents: fluorine, chlorine, bromine, methyl, ethyl, isopropyl, tert-butyl, methoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, methoximinomethyl, 1-methoximino-1-ethyl, ethoximinomethyl, phenyl which is optionally substituted by fluorine, chlorine and/or methyl, or phenoxy which is optionally substituted by fluorine, chlorine and/or methyl;
R represents methyl, ethyl, isopropyl, tert-butyl and phenyl or phenoxy which are each optionally mono- to disubstituted by identical or different substituents from the group consisting of fluorine, chlorine or methyl;
X¹ stands for fluorine or chlorine;
X² stands for fluorine or chlorine and
Y represents the groups -OCH₂-, -SCH₂-, -CH₂CH₂- or -CH=CH-, where the heteroatom is bonded to the aryl radical when Y represents -OCH₂- or -SCH₂-,
and their acid addition salts to combat diseases. 4. 2,2-Dihalocyclopropyl-hydroxyalkylthiazoles according to claims 1 to 3 for combating mycoses. 5. Medicaments containing 2,2-dihalocyclopropyl-hydroxyethyltriazoles according to claims 1 to 3. 6. Antimycotic agents containing 2,2-dihalocyclopropyl-hydroxyethyltriazoles according to claims 1 to 3. 7. Use of 2,2-dihalocyclopropyl-hydroxyethyltriazoles according to claims 1 to 3 in the control of diseases. 8. Use of 2,2-dihalocyclopropylhydroxyethyltriazoles according to claims 1 to 3 in the preparation of medicaments. 9. Use of 2,2-dihalocyclopropylhydroxyethyltriazoles according to claims 1 to 3 in the control of diseases. 10. Use of 2,2-dihalocyclopropylhydroxyethyltriazoles according to claims 1 to 3 for combating mycoses.