DE3535456A1 - Antimycotic compositions - Google Patents

Abstract

The novel substituted azolylmethylcyclopropylcarbinol derivatives of the formula <IMAGE> in which Ar, R<1>, R<2>, R<3>, X and Y have the meaning indicated in the description, can be used as active compounds of antimycotic compositions.

Description

Antifungal agents

The present invention relates to the use of new substituted Azolylmethyl-cyclopropyl-carbinol derivatives as antimicrobial agents, in particular as antifungal drugs.

It is already well known that certain diazolyl derivatives, such as, for example, 1,3-di- (1,2,4-triazol-1-yl) -2- (3-chlorophenyl) - or - (4-chlorophenyl) - or. -phenyl-2-propanol, have antifungal properties (see EP-OS 0 044 605). However, the effect of these substances is not always in all areas of indication fully satisfactory.

It has been found that the new substituted azolylmethyl-cyclopropyl-carbinol derivatives of the formula (I) in which Ar represents optionally substituted aryl or optionally substituted fetaryl, R¹ represents hydrogen, alkyl, alkenyl, alkynyl, trialkylsilyl, optionally substituted phenylalkyl or the acyl radical, represents halogen, cyano, thiocyanato, alkylcarbonyloxy, alkylcarbonylthio or the groups - X-R3 and -NR4R5 are, in which R³ is alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkylthioalkyl, carboxyalkyl, alkoxycarbonylalkyl, optionally substituted aryl, optionally substituted aralkyl or the remainder of the formula stands, (4-chlorophenyl) - or -phenyl-2-propanol, which constitutionally and in terms of action are obvious compounds.

The substituted azolylmethyl-cyclopropyl-carbinol derivatives according to the invention are generally defined by the formula (I). In this formula, Ar preferably stands for phenyl which is optionally mono- or polysubstituted, identically or differently substituted, the following preferably being mentioned as substituents: analogs, alkyl, alkoxy and alkylthio each having 1 to 4 carbon atoms; Haloalkyl, haloalkoxy and haloalkylthio each having 1 to 2 carbon atoms and 1 to 5 identical or different halogen atoms, such as fluorine and chlorine atoms; and in each case phenyl or phenoxy which is optionally substituted by alkyl having 1 or 2 carbon atoms and / or halogen; furthermore for naphthyl as well as for an optionally singly or multiply, identically or differently substituted 5- to 6-membered heteroaromatic with nitrogen, oxygen and / or sulfur as heteroatoms, the above-mentioned phenyl substituents preferably being possible as substituents; R1 stands for hydrogen, straight-chain or branched alkyl with 1 to 4 carbon atoms, straight-chain or branched alkenyl and alkynyl with 2 to 4 carbon atoms each, trialkylsilyl with 1 to 4 carbon atoms in each alkyl part, alkylcarbonyl with 1 to 4 carbon atoms in the alkyl part, as well as for optionally simple phenylalkyl with 1 to 2 carbon atoms in the alkyl moiety, substituted one or more times, identically or differently, with the phenyl substituents already mentioned for Ar preferably being possible as substituents; for fluorine, chlorine, bromine, cyano, thiocyanato, alkylcarbonyloxy with 1 to 4 carbon atoms in the alkyl part, alkylcarbonylthio with 1 to 4 carbon atoms in the alkyl part, or for the groupings -X-R3 and -R4R5, where 3 R is preferably straight-chain or branched alkyl with 1 to 18 carbon atoms, cycloalkyl with 3 to 8 carbon atoms, straight-chain or branched alkenyl with 2 to 18 carbon atoms, straight-chain or intermediate alkynyl with 2 to 18 carbon atoms, t.:y droxyalkvl with 1 to 18 carbon atoms, alkylthioalkyl with 1 to 6 carbon atoms in the alkylthio group and 1 to 6 carbon atoms in the alkyl group, carboxyalkyl with up to 18 carbon atoms in the alkyl part, alkoxycarbonylalkyl with 1 to 6 carbon atoms in the alkoxy part and 1 to 6 carbon atoms in the alkyl part, and for each optionally single or multiple, identical or different substituted phenyl or phenylalkyl with 1 or 2 carbon atoms in the alkyl part, where as substituents in each case the phenyl substituents mentioned as preferred for Ar come into question, or for the remainder of the formula R4 and R5, independently of one another, preferably represent hydrogen or straight-chain or branched alkyl having 1 to 4 carbon atoms, or R4 and R5 together with the nitrogen atom to which they are attached, preferably represent an optionally substituted by alkyl having 1 to 4 carbon atoms or alkylcarbonyl with 1 to 1 lenstoffatomen in the alkyl part are substituted 5- or 6-membered ring, the Saurstoff1 can contain sulfur and / or nitrogen as further heteroatoms, and X stands for oxygen, sulfur, an SO or an SO2 group, and also for Hydrogen is when Ar stands for an optionally substituted 5- or 6-membered hetero atom, and Y stands for nitrogen or a CH group.

Particularly preferred compounds of the formula (I) are those in which Ar is optionally mono- to triple, in particular mono- or disubstituted, identically or differently substituted phenyl, the following substituents being mentioned: fluorine, chlorine, methyl, isopropyl, tert-butyl , Methoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, and in each case phenyl or phenoxy optionally substituted by fluorine, chlorine and / or methyl; furthermore represents naphthyl as well as furyl, thienyl, pyridinyl or pyrimidinyl which is optionally mono- or disubstituted, identically or differently substituted, the abovementioned phenyl substituents being possible as substituents; R2 for hydrogen, methyl, methyl, n-propyl, isopropyl, n-3utyl, isobutyl, allyl, propargyl, trimethylsilyl, methyl carbonyl, ethyl carbonyl, n-propyl carbonyl, zsopropyl carbonyl, n-butyl carbonyl, isobutyl carbonyl, and for optionally single to triple, in particular singly or doubly, identically, the differently substituted benzyl, the phenyl substituents already mentioned as preferred for Ar being possible, R2 for fluorine, chlorine, 3rom, cyano, thiocyanato, methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isobutylcarbonyloxy, methylcarbonylthio , Ethylcarbonylthio, n-Propylcarbonylthio, Isopropylcarbonylthio, n-Butylcarbonylthio or represents the groupings -X-R3 or -NR4R5, wherein R3 represents straight-chain or branched alkyl with 1 to 12 carbon atoms, cycloalkyl with 5 to 7 carbon atoms, straight-chain or branched alkenyl with 2 to 12 carbon atoms, straight-chain or branched alkynyl with 2 to 12 Ko carbon atoms, hydroxyalkyl with 1 to 12 carbon atoms, alkylthioalkyl with 1 to 4 carbon atoms in the alkylthio group and 1 to 4 carbon atoms in the alkyl group, carboxyalkyl with 1 to 12 carbon atoms in the alkyl part, alkoxycarbonylalkyl with 1 to 4 carbon atoms in the alkoxy part and 1 to 4 carbon atoms in the Alkyl part, as well as each optionally single to triple, in particular single or double, identically or differently substituted phenyl or benzyl, where the particularly preferred phenyl substituents already mentioned above for Ar are possible, or R3 is the remainder of the formula R4 and R5 independently of one another represent hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl, or R4 and R5 together with the nitrogen atom to which they are attached represent each optionally represented by methyl, ethyl, methylcarbonyl or ethylcarbonyl-substituted piperidinyl, piperazinyl or morpholinyl, and X stands for oxygen, sulfur, an SO or an SO2 group, and in addition R2 also stands for hydrogen if Ar stands for one of the abovementioned optionally substituted heteroaromatic compounds, and Y for Nitrogen or a CH group.

Preferred compounds according to the invention are also addition products from acids and those substituted azolylmethyl-cyclopropyl-carbinol derivatives of the formula (I), in which Ar, R1, R2 and Y have the meanings which are already preferred for these remnants were named.

The acids that can be added preferably include hydrohalic acids, such as hydrochloric acid and hydrobromic acid, in particular hydrochloric acid, 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 also sulfonic acids such as p-toluenesulfonic acid, 1,5-naphthalenedisulfonic acid or camphorsulfonic acid. The substituted azolylmethyl-cyclopropyl-carbinol derivatives to be used according to the invention and their acid addition salts have not yet been described. They can be obtained in a generally known manner by a) in a first stage aryl-cyclopropyl-ketones of the formula (II) in which Ar and R² have the meaning given above, with dimethyloxosulfonium methylide of the formula (III) #### (CH3) 2SOCH2 (III) in the presence of a diluent, such as dimethyl sulfoxide, reacted at temperatures between 200C and 800C ( see J. Am. Chem. Soc. 87, 1363-1364 (1965)); and the resulting aryl-cyclopropyl-oxiranes of the formula (IV) in which Ar and R2 have the meaning given above, in a second stage with azoles of the formula (V) in which Y has the meaning given above, in the presence of an inert organic solvent, such as acetonitrile or dimethylformamide, and in the presence of a base, such as potassium carbonate or potassium hydroxide, at temperatures between 60 and 150 ° C., or b) azolyl-keto compounds of formula (VI) in which R2, Ar and Y have the meaning given above, with dimethyloxosulfonium methylide of the formula (III) (CH3) 2 SO CH2 (III) in the presence of a diluent such as dimethyl sulfoxide, at temperatures between 200 ° C. and 80 ° C. (cf. J. Amer. Chem.

Soc. 87: 1363-1365 (1965)); and optionally c) the azolylmethylthiocyclopropyl-carbinol derivatives of the formula (Ia) in which Ar, R3 and Y have the meaning given above, obtained by process (a) or (b), oxidized by known methods in the customary manner, with the Use of 1 mole of oxidizing agent, such as m-chloroperbenzoic acid in methylene chloride or hydrogen peroxide in acetic acid or acetic anhydride at temperatures between -300C to + 300C, preferably the compounds of the formula (I) according to the invention with the -SO group are formed; and in the case of an excess of oxidizing agent and higher temperatures (10 to 80 ° C.), the compounds of the formula (I) according to the invention with the 502 group are preferably formed; and optionally d) the hydroxy compounds of the formula (Ib) obtained by process (a), (b) or (c) in which Ar, R2 and Y have the meaning given above, in the presence of a diluent, converted into the alcoholate and this with a halide of the formula (VII) R-Hal (VII) in which R represents alkyl, alkenyl, alkynyl, trialkylsilyl, if appropriate substituted phenylalkyl or the acyl radical and Hal stands for halogen, in the presence of an inert organic solvent, such as ether or chlorinated hydrocarbons, at temperatures between 20 and 1000C.

In a preferred embodiment of process (d) is expediently proceed in such a way that one starts from a hydroxy compound of the formula (Ib), the latter in a suitable organic solvent using alkali metal hydride or alkali metal amide converted into the alkali metal alcoholate and the latter immediately without isolation converts a halide of the formula (VI), with the escape of alkali halide the compounds of the formula (1) according to the invention are obtained in one operation will.

According to a further preferred embodiment of process (d) are expediently the production of the Alcoholates as well as the Alkylation in a two-phase system, such as, for example, aqueous sodium or potassium hydroxide solution / toluene or methylene chloride, with the addition of 0.01 to 1 mol of a phase transfer catalyst, such as ammonium or phosphonium compounds, carried out, where in the organic phase or at the interface the alcoholates and with those in the organic phase contained halides are implemented.

The acid addition salts of the compounds of the formula (I) can be used in simply by using common salt formation methods, e.g. by dissolving a compound of formula (I) in a suitable inert solvent and adding the acid, e.g. hydrochloric acid, and in a known manner, e.g. by filtering off, isolated and optionally by washing with an inert organic solvent getting cleaned.

The aryl-cyclopropyl-ketones of the formula (II) are not yet known. They are obtained by using arylhalopropyl ketones of formula (VIII) in which Ar has the meaning given above, Hal 'stands for fluorine, chlorine or bromine and stands for bromine or chlorine, with compounds of the formula HR6 (IX) in which R6 represents cyano, thiocyanato, alkylcarbonyloxy, alkylcarbonylthio or the groups -XR3 and -NR4R5, wherein R³ represents alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkylthiaalkyl, carboxyalkyl, alkoxycarbonylalkyl, optionally substituted Aryl, optionally substituted aralkyl or the radical dz formula R4 and R5 independently represent hydrogen or alkyl or R4 and R5 together with the nitrogen atom to which they are bonded represent an optionally substituted cycloaliphatic ring which may contain further heteroatoms, and X represents oxygen, sulfur, an SO - or an SO2 group is reacted in the presence of a diluent and in the presence of a base, or B) heated directly in the presence of a diluent and in the presence of a base (ketones of the formula (II) with R6 = halogen being obtained.

As a diluent come for the preparation of the ketones of the formula (II) according to variants (a) and (B) organic inert under the reaction conditions Solvent in question. These preferably include alcohols such as methanol, ethanol, Methoxyethanol, propanol, or t-butanol; Ketones such as acetone and 2-butanone; Nitriles, such as acetonitrile; Esters such as ethyl acetate; Ethers such as dioxane; aromatic hydrocarbons, such as benzene and toluene; or amides such as dimethylformamide.

All bases are suitable for the reaction according to variants (C) and (B) Inorganic and organic bases which can usually be used are suitable. For this preferably include alkali carbonates such as sodium and potassium carbonate; Alkali hydroxides, such as sodium and potassium hydroxide; Alkali alcoholates, such as sodium and potassium methylate, ethylate and tert-butylate; Alkali hydrides such as sodium hydride; as well as lower tertiary Alkylamines, Cycloalkylamines and aralkylamines, such as in particular Triethylamine.

The reaction temperatures can be used when carrying out the variants (a) and (B) can be varied within a larger range. Generally one works at temperatures between 0 and 2000C, preferably between 20 and 1500C.

When carrying out the implementation according to variant (α) sets one preferably to 1 mole of ketone of the formula (VIII) 1 to 2 moles of the compound Formula (IX) and 1 to 2 moles of base. These intermediates are isolated in a generally accepted manner.

The aryl halopropyl ketones of the formula (VIII) are known (cf. e.g. DE-OS 25 21 104, DE-OS 23 20 355 and DE-OS 23 51 948); or they can in general can be obtained in the usual way.

The aryl halopropyl ketones of the formula (VIII) with Hal '= fluorine can, for example, by reacting the corresponding ketones with Hal' = bromine with alkali fluorides in the presence of an inert organic solvent, such as benzene, and in the presence of a macrocyclic ether, such as 18-crown-6 (1,4,7,10,13,16-hexaoxacyclooctadecane of the formula can be obtained at the boiling point of the solvent used in each case (cf. also the preparation examples).

The aryl-cyclopropyl-ketones of the formula (II) are generally interesting Intermediates.

The compounds of the formula (IX) are generally known compounds of organic chemistry.

This also applies to the first stage of the process according to the invention (a) as well as dimethyloxosulfonium methylide required as starting material for process (b) according to the invention the formula (III) is known (cf.

J. Am. Chem. Soc. 87: 1363-1364 (1965)). It will do the above implementation Processed in a freshly prepared state by putting it in situ through implementation of trimethyloxosulfonium iodide with sodium hydride or sodium amide, in particular with potassium tert-butoxide or sodium methylate, in the presence of a diluent generated.

Also for the second stage of the process according to the invention (A) Azoles of the formula (V) required as starting materials are well known Compounds of organic chemistry.

Those occurring as intermediates in process (a) according to the invention Aryl-cyclopropyl-oxiranes of the formula (IV) are not yet known. They pose in general interesting intermediates.

Those to be used as starting materials for process (b) according to the invention Azolyl-keto compounds are generally defined by the formula (VI). In this Formula (VI) R2, Ar and X preferably represent those radicals which are already im Connection with the description of the substances of the formula (1) according to the invention as preferred for these substituents.

The azolyl-keto compounds of the formula (VI) are not yet known. It is obtained by using ketones of the formula (X) in which Ar and R have the meaning given above, with hydroxymethylazoles of the formula (XI) in which Y has the meaning given above, is reacted in the presence of a diluent and in the presence of a catalyst.

The diluents used in this process are used for production of the azolyl-keto derivatives of the formula (VI), preferably inert organic solvents in question.

These preferably include alcohols such as methanol and ethanol; Ether, such as tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene and toluene; as well as halogenated aliphatic and aromatic hydrocarbons, such as methylene chloride, Chloroform, chlorobenzene and dichlorobenzene.

This process is carried out in the presence of a catalyst. All acidic and, in particular, basic catalysts which can usually be used can be used as well as their buffer mixtures. These preferably include Lewis acids, such as boron trifluoride, boron trichloride, tin tetrachloride or titanium tetrachloride; organic bases such as pyridine and piperidine; and in particular piperidine acetate.

The reaction temperatures can be used when carrying out this process can be varied in a larger area. Generally one works between 20 and 1600C, preferably at the boiling point of the respective solvent.

When carrying out this process, 1 mole of ketone is used Formula (X) 1 to 1.5 moles of hydroxymethylazole of the formula (XI) and catalytic bis 0.2 molar amounts of catalyst.

The ketones of the formula (X) are generally known compounds of organic chemistry or can be in analogous to methods known in principle Manufacture way.

The hydroxymethylazoles of the formula (XI) are also known (EP 000 6102 and Chem. Heterocycl. Comp.

1980, 189).

The azolyl-keto derivatives of the formula (VI) are interesting intermediates and also show antimycotic, fungicidal and plant growth regulating properties.

Those to be used as starting materials for process (b) according to the invention Azolylmethyl-thiocyclopropyl-carbinol derivatives of the formula (Ia) are according to the invention Links.

Those to be used as starting materials for process (c) according to the invention Hydroxy compounds of the formula (Ib) are also compounds according to the invention. Their conversion into the corresponding alcoholates is generally known Way by using suitable strong bases, such as alkali metal amides or -hydrides, quaternary ammonium hydroxides or phosphonium hydroxides in an indifferent Solvent, such as dioxane, reacted at room temperature.

The also for process (d) according to the invention as starting materials Halides to be used are generally defined by the formula (VII). In this Formula R preferably has the meanings that are already in connection with the description of the substances of the formula (I) according to the invention for the substituent R1 were mentioned, with the exception of the meaning of hydrogen.

The halides of the formula (VII) are generally known compounds of organic chemistry.

The compounds of the formula (I) which can be used according to the invention and their Acid addition salts have antimicrobial, in particular, strong antifungal effects on. They have a very broad spectrum of antifungal effects, in particular against dermatophytes and SproB fungi as well as bi-phasic 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, Trichphyton species such as Trichophyton mentagrophytes, Microsporon species such as Microsporon felineum and Torulospsis species, like Torulospsis glabrata. The list of these microorganisms is by no means a restriction of the germs that can be combated, but is only of an explanatory nature.

As examples of indications in human medicine, for example to be named: Dermatomycoses and systemic mycoses caused by Trichophyton mentagrophytes and other Trichophyton species, Microsporon species, Epidermophyton floccosum, Sprout and biphasic fungi as well as molds caused.

As an indication area in veterinary medicine, for example, can be listed be: All dermatomycoses and systemic mycoses, especially those caused by the above-mentioned pathogens are caused.

The present invention includes pharmaceutical preparations, which in addition to non-toxic, inert pharmaceutically suitable carrier substances or contain more than one active ingredient according to the invention, or one or more There are active ingredients according to the invention and processes for the production of these preparations.

The present invention also includes pharmaceutical preparations in dosage units. This means that the preparations in the form of individual parts, e.g. tablets, coated tablets, capsules, pills, suppositories and ampoules, their Active ingredient content corresponds to a fraction or a multiple of a single dose. The dosage units can e.g. 1, 2, 3 or 4 single doses or 1/2, 1/3 or Contain 1/4 of a single dose. A single dose preferably contains the amounts Active substance that is administered in one application and that usually corresponds to a whole, corresponds to half a day or a third or a quarter of a daily dose.

Among non-toxic, inert pharmaceutically acceptable carriers are solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of any kind to understand.

Preferred pharmaceutical preparations are tablets, coated tablets, Capsules, pills, granules, suppositories, solutions, suspensions and emulsions, Called pastes, ointments, gels, creams, lotions, powders and sprays.

Tablets, coated tablets, capsules, pills and granules can be the or contain the active ingredients in addition to the usual carriers, such as (a) fillers and extenders, e.g. starches, milk sugar, cane sugar, glucose, mannitol and silicic acid, (b) binders, e.g. carboxymethyl cellulose, alginates, gelatine, polyvinylpyrrolidone, (c) humectants, e.g. glycerine, (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., talc, calcium and magnesium stearate, and solid polyethylene glycols or mixtures of the substances listed under (a) to (i) The tablets, coated tablets, capsules, pills and granules can be used with the usual if necessary Opaque coatings and sheaths contained therein be provided and so composed be that they have the active ingredient or ingredients only or preferably in one certain part of the intestinal tract, possibly with a delay, whereby as Embedding compounds e.g. polymer substances and waxes can be used.

The active ingredient (s) can optionally be combined with one or more the above carrier substances are also available in microencapsulated form.

In addition to the active ingredient or ingredients, suppositories can contain the usual water-soluble ones or contain 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.

Ointments, pastes, creams and gels can be used in addition to the active ingredient or ingredients contain the usual carriers, e.g. animal and vegetable fats, waxes, Paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentione, Silicic acid, talc and zinc oxide or mixtures of these substances.

Powders and sprays can be the usual ones in addition to the active ingredient or ingredients Contain carrier substances, e.g. lactose, talc, silica, aluminum hydroxide, Calcium silicate and polyamide powder or mixtures of these substances. Sprays can also be used the usual propellants e.g. contain chlorofluorocarbons.

Solutions and emulsions can, in addition to the active ingredient or ingredients, the common carriers such as solvents, solvents solution delay 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, especially cottonseed oil, peanut oil, olive oil, castor oil and sesame oil, glycerine, Glycerin formal, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters des sorbitan or mixtures of these substances.

The solutions and emulsions can also be used for parenteral administration are in sterile and blood isotonic form.

In addition to the active ingredient (s), suspensions can include 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, aluminum metahydroxide, bentonite, agar-agar and tragacanth or mixtures contain these substances.

The formulation forms mentioned can also-colorants, preservatives as well as additives that improve smell and taste, e.g. peppermint oil and eucalyptus oil and sweeteners such as saccharin.

The therapeutically active compounds are intended to be in those listed above pharmaceutical preparations preferably in a concentration of about 0.1 to 99.5, preferably from 0.5 to 95% by weight of the total mixture.

The pharmaceutical preparations listed above can except the active ingredients according to the invention also contain further pharmaceutical active ingredients.

The manufacture of the pharmaceutical preparations listed above takes place in the usual way by known methods, e.g. by mixing the Active ingredients with the carrier (s).

The present invention also includes the use of the invention Active ingredients, as well as pharmaceutical preparations that contain one or more of the invention Contains active ingredients in human and veterinary medicine for prevention and improvement and / or cure the diseases listed above.

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

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

When administered orally, the active compounds according to the invention are in Total amounts of about 2.5 to about 200, preferably 5 to 150 mg / kg of body weight every 24 hours and with parenteral administration in total amounts of about 2.5 to administered about 50, preferably 1 to 25 mg / kg body weight per 24 hours.

However, it may be necessary to deviate from the stated dosages, depending on the type and body weight of the object to be treated, the type and severity of the disease, the type of preparation and application of the drug as well as the period or interval, within which the administration takes place. Thus, in some cases it may be sufficient to make do with less than the above-mentioned amount of active ingredient, while in other cases the above-mentioned amount of active ingredient must be exceeded. Any person skilled in the art can easily determine the required optimal dosage and type of application of the active ingredients on the basis of his specialist knowledge. Preparation examples Example 1 (Procedure a) 1st stage 170 ml of dry dimethyl sulfoxide are added dropwise at 100 ° C. to a mixture of 6.4 g of sodium hydride (80%) and 44.2 g of trimethylsulfoxonium iodide, and the mixture is stirred for one hour at room temperature. 40 g (0.167 mol) of 1- (4-chlorobenzoyl) -1-ethylthio-cyclopropane in 50 ml of dimethyl sulfoxide are then added dropwise. The reaction mixture is stirred for two days at room temperature. Then it is poured onto 500 g of ice, extracted several times with ethyl acetate, the combined organic phases are washed with water, dried over sodium sulfate and concentrated. 40.5 g (95.5% of theory) of crude l-Lf- (4-chlorophenyl) oxiranyl7-lethylthio-cyclopropane are obtained as b1, which is further reacted directly.

2nd stage A solution of 40.5 g (0.16 mol) of crude 1-L7- (4-chlorophenyl) - is added dropwise to a boiling mixture of 33.5 g of 1,2,4-triazole and 22 g of potassium carbonate in 150 ml of acetonitrile. oxiranyl] -1-ethylthio-cyclopropane (Example IV-1) in 50 ml of acetonitrile and the reaction mixture is refluxed for 8 hours. It is allowed to cool, 400 ml of water are added and the crystalline product is filtered off with suction. After recrystallization from ethanol / water, 26.5 g (51% of theory) 1- (4-chlorophenyl) -1-z1- (ethylthio) -1-cyclopropyl7-2- (1,2,4-triazole- 1-yI) -1-ethanol of melting point 1650C.

Manufacture of the starting product A solution of 38 g of potassium hydroxide in 250 ml of methanol is added dropwise at 0OC to 100 ° C. to a solution of 100 g (0.338 mol) of 4-chlorophenyl (1-bromo-3-chloropropyl) ketone and 21 g of ethyl thiol in 200 ml of dimethylformamide.

The mixture is left at room temperature for one hour and under reflux for one hour stir. It is then concentrated in vacuo and the residue in a mixture taken up by water and methylene chloride. The organic phase is separated washed with water, dried over sodium sulfate and concentrated in vacuo. Of the The residue is distilled in a high vacuum. 70.1 g (86% of theory) of 1- (4-chlorobenzoyl) -1-ethylthio-cyclopropane are obtained melting point bp 0.15 = 1270 ° C.

Example 2 (Method b) 19.7 g (0.06 mol) 1- (4-chlorophenoxy) -2- (1,2,4-triazol-1-yl) propiophenone are added in portions to a solution of dimethylsulfoxonium methylide in 70 ml Dimethyl sulfoxide (prepared from 27.6 g (0.125 mol) trimethylsulfoxonium iodide and 14.03 g (0.125 mol) potassium tert-butoxide). The mixture is stirred for 6 hours at 60 ° C., then diluted with 1000 ml of water, the precipitated oil is taken up in chloroform, dried over sodium sulfate, concentrated and purified by chromatography (silica gel F60 Merck / mobile phase: chloroform).

The remaining oil crystallizes on stirring with acetonitrile. 1.7 g (8% of theory) of 1- (4-chlorophenoxy) -1- / 1-hydroxy-1-phenyl-2- (1,2,4-triazol-1-ylL7-cyclopropane are obtained of melting point 1700C.

Manufacture of the preliminary product 29.4 g (0.12 mol) - (4-chlorophenoxy) acetophenone and 11.9 g (0.12 mol) 1,2,4-triazol-1-yl-methyl alcohol in 200 ml toluene are successively mixed with 10 , 8 g (0.18 mol) of acetic acid and 1.8 ml (0.018 mol) of piperidine were added.

and cooked on the water separator until the amount of water separated remains constant. The toluene solution is then washed with water, dried over sodium sulfate and concentrated, and the oily residue is purified by chromatography (silica gel F60 Merck / mobile phase chloroform). 20.8 g (53% of theory) of 1- (4-chlorophenoxy) -2- (1,2,4-triazol-1-yl) propiophenone with a melting point of 1260 ° C. are obtained.

A solution of 154.6 g (1 mol) of (/ -chloroacetophenone in 250 ml of butanone is in a boiling solution of 129 g (1 mol) of 4-chlorophenol, 140 g (1 mol) of potassium carbonate and 2 g of potassium iodide in 800 ml of butanone and the mixture is after the end Addition kept boiling for a further 12 hours. The reaction mixture obtained is filtered and evaporated. 179 g (73% of theory) of - (4-chlorophenoxy) acetophenone are obtained of melting point 970C.

Example 3 (Method c) 5 g (0.0155 mol) 1- (4-chlorophenyl) -1- / 1- (ethylthio) -1-cyclopropyl7-2- (1,2,4-triazol-1-yl) -1 -ethanol (Example 1) are stirred with 3.3 g of m-chlorobenzoic acid (80 to 90 Fig.) in 40 ml of methylene chloride at room temperature overnight and then under reflux for one hour.

Then twice with 20 ml of 5% sodium hydroxide solution and twice washed with water. The organic phase is dried over sodium sulfate and concentrated in vacuo. The residue is recrystallized from glycol monomethyl ether acetate. 3 g (57% of theory) 1- (4-chlorophenyl) -1- [1- (ethylsulfinyl) -1-cyclopropyl7-2- (1,2,4-triazol-1-yl) -1-ethanol are obtained from melting point 1850C.

Example 4 (Method c) 3.2 g (0.01 mol) 1- (4-chlorophenyl) -1- [1- (ethylthio) -1-cyclopropy17-2- (1, 2,4-triazol-1-yl) -1-ethanol (Example 1) are dissolved in 20 ml of glacial acetic acid and stirred with 4 ml of 30% strength hydrogen peroxide for six hours at 70.degree. 100 ml of ice water are then added, the mixture is neutralized with concentrated sodium hydroxide solution and the crystalline solid is filtered off with suction. 3.4 g (96% of theory) 1- (4-chloropheynl) -1- [1- (ethylsulfonyl) -1-cyclopropyl] -2- (1,2,4-triazol-1-yl) - are obtained 1-ethanol with a melting point of 215 ° C.

In an analogous manner and in accordance with the process according to the invention, the compounds of the formula (I) listed in Table 1 below can be used can be obtained: Table 1 E.g. Ar R1 y R2 melting No. point (OC) 1-5 Cl o HN -OO 139 I-6 u HN -S- (CH2) 3CH3 129 1-7 "HN -502- (CH2) 3CN3 136 1-8 n HNF 128 I-9 n HN -O- -C1 167 I-10 "H CH -O- O Cl 211 1-11 "HN -S -Cl)) - C1 137 I-12 OHN -S- q 161 21 1-13 Cl o HN -S-CH, -C1 183 I-74 C1 HN -S 1-14 Cl-HN -S-CH2-Cl I-15 XHN -O t 121 Table 1 (continued) Ex. Ar R1 Y R2 melting No. point (OC) 1-16 Cl-C) - HN -SCH3 124 1-17 n H CH -SCH3 159 I-18 HBN -SO2-CH3 193 I-19 9 HN -SO2-C2H5 185 I-20 n H CH -S-C2H5 158 I-21 n HN -S- (CH2) 2-CH3 131 1-22 n H CH -S- (CH2) 2-CH3 133 I-23 n HN -S-CH2-CH = CH2 134 I-24 n HN -S 141-143 I-25 n H CH ~ S 145 1-26 n HN -S - C1 94 I-27 n H CH ~ O 208 1-28 n HN -O-Cl 165 Table 1 (continued) Ex. Ar R1 Y R2 melting No. point (° C) Cl I-29 Cl- HN ~ Ot 119 C1 1-30 n HN Ot-Cl 181 ci I-31 CH -Ot-Cl 213 I-32 n HN -N-CH3 122 1-33 F <) - HNF 148 I-34 .1 HN -SCH3 113 I-35 r H CH -SCH3 156 1-36 u HN -SC2H5 126 1-37 n H CH -SC2H5 161 1-38 n HN -S- (CH2) 3CH3 130 1-39 "H CH -S- (CH2) 3CH3 140 1-40 HHN -O - Cl Table 1 (continued) Ex. Ar R1 Y R2 melting No. point (OC) 1-41 F t - HN -OO 171 I-42 n HN -O - C1 144 1-43 "H CH -O - CI 184 I-44 n HN - Ob-Cl 141 1-45 n H CH -O- (0) -C1 227 1-46 HRN-O 122 1-47 b HN -SC2H5 137 f-48 HH CH -5C2H5 179 I-49 n HN -SO-Cl 144 1-50 n H CH -SO-Cl 168 1-51 H CH -O-Cl 177 Cl 1-52 1 H CH -O-Cl 245 Table 1 (continued) Ex. Ar R1 Y R2 melting point No. (eC) I-53 »HNF 123 1-54 r HN -SCH3 163 I-55 n H CH -SCH3 160 I-56 n HN -SC2H5 155 I-57 n H CH -SC2H5 I-58 n HN -S- (CH2) 3-CH3 136 Cl I-59 Cl + HN -SC2H5 1.5420 I-60br 1 I-60 di HN -SC3H7 1.5102 - C1 1-61 Cl to HN -SC3H7 1.5610 J 1-62 Cl e HN -SC4H9 86 ~ Cl I-63 9 HN -SC4H9 1.5790 4th 1-64 Cl to HN -S-CH2CH = C (CH3) 2 1.5698 C1 I-65 Cll HN -S-C3H7-i 128 Table 1 (continued) Example no. Ar R1 Y R2 melting point ("c) F. 1-66 F 4 HN SC2H5 110 I-67 g of HN -S-CH2CH = C (CH3) 2 1.5598 I-68 C1 4 HN -SC3H7 112 I-69 ß 1 HN -SC2H5 1.5560 1-70 $ HN -S-CH2C3H7-i 1.5700 1-71 H 1 N -S- (CH2) 5CH3 1.5450 1-72 C1 4 HH CH F 176 I-73 Cl- to - HN -SO2 e -Cl 166 CH3 1-74 CI- N 104 I-75 C1 4 HHN (CH3) 2 137 CH3 I-76 C1 e - '3 N 147 I-77 Cl t HNN (CHZ) 5CH3 730 1 I-78 Cl t - HN -CH2-CH2-CH-CH3 Table 1 (continued) Ar au R1 Y R2 melting point / õc? No. or refractive -20- I-79 Cl-- HN -SO-C4Hg-n 1-80 Cl- HN -SO-C3H7-n 146 CH, I-81 Cl- 4 - H ' 1-82 Cl-HN -F 147 I-83 C1 e - HN 130 1-84 C1 4 - HN -C1 149 I-85 C1- O-HNS (C 2) 11 C 3 111 I-86 C1-- HNS ° (CH2) 3 CH3 153 I-87 C1 H CH -S e 191 1-88 Cl 4 - HN - -SQ 142 I-89 C1 4 - HN SC- (CH2} 11 3 oil I-90 1) - HNHN -S ° 2- (cH2) 11-cH3 91 I-91 Cl 4 - HN -S-CH2-C; H2 t 75 Table 1 (continued) Ar R1 Y R2 lower point Z ° c7 or refractive index 7 I-92 Cl- to - HN -93 {H3 189 (1 diastereo- res) 1-93 Cl- OHNN -SO-CH3 172 (diastereo- neresB. ) 1-94 C1- HN S02-C3H7 n 128 CH I-95 Cl-OHNN -SO2-CH-C2H5 117 I-96 C1-- HN SO2-CH (CH3) 2 159 1-97 Cl-O-HN -SO2-CH2-CH (CH3) 2 I-98 C1 4 - HN -so, - (CH,) egg "CH? 140 I-99 C1 4-HN -SO, -CH, -QI -CH (CH3) 2 165 I-100 C1- HN -SO2 e 176 I-101 C1-- HN -CH -S-CH, -M, -S-C2H5 95 I-102 C1 HN -S-CH2iXXtH3 118 I-103 C1 HN -S-CH2-CH2 to 138 Table 1 (continued) Ex. Ar R1 Y R2 SSmelnxikt Loc7 No. or refractive in3ex 07 . I-104 FHNHN -SO- (CH2) 3-CH3 oil I-105 PH CH -S-CH (CH3) 2 191 I-106 P g-HN -SiE (CH3) 2 155 I-) 07 F e - HN -Cl 121 1-108 O - ONHS ° 2C 3 162 1-109 O-HN -S-CH (CH3) 2 136 1-110 O-H CH -F 162 1-111 O - HN -F 105 I-112 NHN -SM, 108 1-113 O-H CN -SCH3 167 I-114 O-H CH -S-C4Hg-n 134 1-115 O - HN S4H9-n 125 I-116 Br-O-HN -F 123 1-117 Br 4 - HN -SC2H5 168 Table 1 (continued) 1 2 Ar RY R2 SiwElqnkt LOC / No. or refractive index -20- I-118 Br-HN -C1 127 I-119 Br-O-HN "SCH3 127 I-120 CH3 to - HN -F 111 I-121 CH3 4-HN -SC2H5 119 3 I-122 J- e - HN <139 C1 I-123 Cl 4 - HN -S-CqHg-n 170 C1 1-124 Cl to - HN -SO ~ C4Hg-n resin C1 1-125 C1 HN -SO2-C4Hg-n 159 Cl \ I-126 Cl-- HN -SCH3 142 C1 1-127 C1 HN -992CH3 Table 1 (continued) Bcn. Ar R1 Y R2 temperature point t ° C No. or index Cls 1-128 ClO- HN -S22 <3 CI I-129 Cj 4 - HN -S-C2H5 I-130 Cl t - HN -S-CH (CH3) 2 F. I-131 F4 FHN -S-CH3 83 1-132 Fç F FM £ cH, - 13 N CH I-133 F4 FHN-Cl I-134 F 13 N 1-135 CH3- O-HN -F 127 I-135 CH3 e - NN -SC2H5 125 I-137 3Ii ()) - 13 HN <1) 146 I-138 CH3 13 - HN 1-139% 4-HN 1-140 CH3- HN -S22 QI H3 1-141 CH3 HN I-142 CH3 4-NN -S- (CH2) 3-CH3 Table 1 (continued) Bsn SCm5t> 1t5- F0cj E.g. . i = Ss- rx I- 143 N -SO2CH3 189 I- 144 F. g -S02-CH (CH3) 2 177 1-145 FH -SO-CH (CH3) 2 141 1- 146 C1 HN -F 176 I- 14i C1 E fiH -SO-CH3 189 I- 148 Fe Ht N -C1 109 I- 149 Ft HN-0- 133 cl I-150 Cl N 2 -S02- (CH2) 2-CH3 104 cl I-151 Cl ¼ N -SO- (0H2) 2-CH3 140 C1 1-152 C1-5. L 'N -S02-CH2-CH3 135 cl 1-153 Cl N -S0-CH2-CH3 112 C1 I- 15 C1-5 H -S02 - tH (CH3) 2 137 1-155 C to s -S0-CH (CH3) 2 131 Cl I-; 56 C1- / O ~ ½ ç -S02-CH3 160 I- 157 CH FN -F 127 3ff Table 1 (continued) Ex. 5 - Sci3lcr, tt / oC7 No. Hrw B w or indexLn / 1-158 CH3 e HN -S-CH-CH3 125 1-159 CH3 to 5 N -S-CH3 116 I-160 CH3 to HN -S02-CH (CH3) 2 149 1-161 CH 4 HN -SO-CH (CH3) 2 127 1-162 CH3 F. HN -S (CH2) 2-CH3 115 1-163 CH-9 z N -S-CH2-CH (CH3) 2 123 1-164 CH3 u -S- (CH2) 3 CH3 107 1-165 CH30 to .0 N -F 111 1-166 CH30 3 N -S-CH2-CH3 119 1-167 .9 N -S- to 1.5630 t \ Cl I-168 t N -SC3H7 75 F. -169 H-N -SC4H9 75 1-170 4 It -S-CH (CH3) 2 1.5630 C1 I-171; t XN -SC (CH3) 3 1.5660 CH3 1-172 HFN -S-CH-C2H5 1.5582 Cl Table 1 (continued) Melting point [° C] or refractive index (nD20] 1-173 FHHN -S-CH (CH3) 2 106 I-174 N -S-C3H7 110 I-175 HN -S-C3H7 1.5420 I. -176 FHN -S-CH (CH3) 2 118 I-177 EN -S-CH (CH3) 2 80 Further production examples for the starting materials (II) Example (II-2) 14 g of potassium carbonate are added to a solution of 29.6 g (0.1 mol) of 4-chlorophenyl (1-bromo-3-chloropropyl) ketone and 9.4 g of phenol in 60 ml of dimethylformamide and the mixture is heated to 50 ° C. for three hours . 8.4 g of potassium hydroxide in 40 ml of methanol are then added dropwise at room temperature and the mixture is heated to 60 ° C. for three hours. It is concentrated in vacuo and taken up in a water / methylene chloride mixture. The organic phase is separated off, washed with water, dried over sodium sulfate and concentrated in vacuo. The residue is distilled in a high vacuum. 20.7 g (76.1% of theory) of 1- (4-chlorobenzoyl) -1-phenoxy-cyclopropane with a boiling point of bp 0.15 = 170-800 ° C. are obtained.

Example (II-3) A solution of 29.6 g (0.1 mol) of 4-chlorophenyl (1-bromo-3-chloropropyl) ketone in 30 ml of dimethylformamide at room temperature. The mixture is left to stir for three hours and then a solution of 9 g of potassium hydroxide in 30 ml of methanol is added dropwise. The reaction mixture is stirred for one hour at 50 ° C. and concentrated in vacuo. The residue is taken up in ethyl acetate / water, the organic phase is separated off, washed with water, dried over sodium sulfate and concentrated in vacuo. The residue is chromatographed over silica gel with chloroform / ethanol (97: 3). 14 g (50.3% of theory) 1- (4-chlorobenzoyl) -1- (4-methyl-piperazin-1-yl) -cyclopropane are obtained as a reddish oil which can be used further directly.

Example (II-4) 20 g (0.085 mol) of 4-chlorophenyl (1-fluoro-3-chloropropyl) ketone are dissolved in 150 ml of tert-butanol, and 15 g of potassium tert-butoxide are added in portions.

The mixture is then stirred for 2 hours at 40 ° C. and concentrated in vacuo. Of the The residue is taken up in methylene chloride and water. Separate the organic Phase off, dries over sodium sulfate and concentrated in vacuo. Of the The residue is distilled in a high vacuum. 14.4 g (85% of theory) are obtained (4-chlorobenzoyl) -1-fluorocyclopropane with a boiling point of Kpgrl = 750C.

Production of the outdoor product and 200 ml of dry benzene is refluxed for 8 hours. 200 ml of water are then added, the organic phase is separated off, washed several times with water, dried over sodium sulfate and concentrated in vacuo. The residue is stirred with light gasoline with the addition of a little toluene. After filtering off with suction and drying, 28.5 g (53% of theory) of 4-chlorophenyl (1-fluoro-3-chloropropyl) ketone with a melting point of 530 ° C. are obtained.

A mixture of 68 g of 4-chlorophenyl (1-bromo-3-chloropropyl) ketone, 27.5 g of dried potassium fluoride, 11 g of 18-crown-6 (1,4,7,10,13,16-hexaoxacyclooctadecane der Formula.

A solution of 483 g (2.23 mol) of 4-chlorophenyl-3-chloropropyl ketone in 1200 ml of methylene chloride is added dropwise at 20 ° C. to a solution of 358 g Bromine in 350 ml of methylene chloride was added. The mixture is left to stir for an hour and then concentrated dam in a vacuum. The residue is mixed with 300 ml of petroleum ether and up to Completeness of crystallization stirred. One cools down to 100C and sucks the Precipitation from. 582 g (88.3% of theory) of 4-chlorophenyl- (1-bromo-3-chloropropyl) are obtained -ketone with a melting point of 730C.

According to Examples (II-1) to (II-4) and according to the specified process conditions, the precursors of the formula (II) listed in Table 2 below can be used will be obtained: Ex. No. Ar R2 Physical. constant 11-5 cl- -S- (CH2) 3CH3 apo, 1-1330C 11-6 cl-- -S-CH3 Kg, 01 = 1200C 11-7 Cl- -C (CH3) 3 visc. bl lI-8 Cl-cO1Cl Xp0.1 = 1600C KPOI1 t 1600C 11-9 Cl e - -O- O -Cl Apo 1 t 1730C 11-10 -O - Cl Apo, 01 = 143au 11-11 b C bp 0.01 1460C 11-12 -S-Cl m.p. t 860C 11-13 -SCH3 m.p. n 980C 11-14 Fc O -SCH3 Kr0.1 = 1020C 11-15 F t - -O Kp 0.1 e 125-1309C II-16 F- O -O t Kp0.1 = 145-1500C 11-17 Fe - -O b Xp0.1 = 165-1730C Ex. No. Ar R2 Physical. constant 11-18 F to -S-C2H5 apo, 07 r 95 "C -11-19 F- o (CH2) 3CH3 bp 0.1 = 113-1160C 11-20 »-S-C2H5 m.p. = 860C II-21 X -O t m.p. = 77 "C C1 11-22 F- -O t Kpo 1 = 147-155 ° C C1 II-23 Cl- o -O <2 Kp0.07 = 1540C 11-24 Cl- O -S- Bp 0.1 = 163-1700C 11-25 Cl- -S- Cl m.p. = 1040C 11-26 cl- -S-CH2-CH = CH2 KP0.06 = 1220C II-27 Cl- O -C3H7-n Kpo 15 = 118 ° C 11-28 kg, 15 F- F bp 0.07 = 55 ° C 11-29 w Pro, 15 = 1380C / Fp. 730C 11-30 CH3 F KP0.1 n 690C Ex. No. Ar R2 Physlkal. Ronstante 11-31 CH3O- F apo, 1 n 980C 11-32 Br t - F Apo 1 ~ 880C According to Example 1 and according to the specified process conditions, the intermediates of the formula (IV) listed in Table 3 below can be used will be obtained: Ex. No. Ar R2 Physical. constant IV-2 Cl --- O, o, viscous. bl IV-3 S (CH2) 3CH3 count. bl IV-4 u F Kp0.2 = 830C IV-5 "-SCH3 IV-6 n SC2B5 bl IV-7 "-S- (CH2) 3-CH3 t'l IV-8 "-S-CH2-CH = CH2 t'l IV-9 "-S- (CR212-CH3 Ol IV-10 "-SO tsl IV-11 "-S t -Cl b IV-12 IV-13 1 -0- -C1 o1 Cl IV-14 "-O t -Cl m.p. 810C IV-15 O-O- m.p. 970C Ex. No. Ar R2 Physical. constant IV-16 Cl t - F Kr0.2 r 830C IV-17 1 IV-17 "-N N-CH3 IV-18 F- -SCH3 IV-19 n -SC2H5 IV-20 1 -S- (CH2) 3-CH3 oil IV-21 "-O oil IV-22 n -O - Cl oil Cl IV-23 1 -O-Cl m.p. 720C Cl IV-24 1 -O oil IV-25 1 F oil IV-26 »-SCH3 oil IV-27 1 -SC2Hs oil IV-28 1 -S- (CH2) 3-CH3 oil Ex. No. Ar R2 Physical. constant IV-29 X ~ OO m.p. 940C IV-30 -O-Cl m.p. 910C IV-31 n F oil IV-32 -SC2H5- oil IV-33 -S t -C1 oil IV-34 (I -OO-Cl oil C1 IV-35 -O- t -C1 m.p. 620C According to Example 2 and according to the specified process conditions, the intermediates of the formula (VI) listed in Table 4 below can be used will be obtained: Example no. Ar X R2 physical constant VI-2 Cl-N -S-CH2-Cl m.p. 102-C VI-2 C1- VI-3 Cli-N m.p. 690C VI-4 Cl-N -S t -Cl m.p. 1020C 1 CI VI-6 Cl- - N "m.p. 1480C VI-7 Cl-CH -O-Cl m.p. 1530C CH VI-8 N -O-Cl m.p. 1390C C1 VI-9 NO-) 1 m.p. 1560C VI-10 Cl-N -O-Cl m.p. 128 ° C E.g. melting point No. Ar Y R2 ("C) VI-11> N -S 4 102 VI-12 C1 <N -S-C2H5 50 C1 VI-13 Cl t \ - N -S-C3H7 1.5632 1 VI-14> N -S-C2H5 62 I. VI-15 k N -S-C3H7 58 '. Ccl N -SC, H- / 58 VI-16 C1 to N -S-C4H9 1.5742 VI-17 C1-l \ VI-17 Clc1 N -S-CH (CH3) 2 1.5762 C1 Examples of use In the in vitro test, the compounds given below and known from EP-OS 0 044 605 are used as comparison substances: Example A Antimycotic in vitro activity Description of the experiment: The in vitro tests were carried out in the serial dilution test with germ inocula averaging 5 × 10 3 to 10 4 germs / ml substrate. The nutrient medium used was a) for dermatophytes and molds: Sabourand's milieu d'épreuve b) for yeasts: meat extract-glucose broth.

The incubation temperature was 28 to 370C, the incubation time was 24 to 96 hours for yeasts and 96 hours for dermatophytes and molds.

In this test, for example, the compounds according to the invention 1, 2, 3, 4, 5, 6, 7, 11 and 12 have better antifungal effects than those from the Prior art known compounds (A), (B) and (C).

Table A Antifungal activity in vitro MIC values in mg / ml nutrient medium Tricho- Micro- Candida Toru- Asperphyton sporum albilopsis gillus active ingredient mentagr. canis cans glabrata fumigatus (A) (known) 32 -> 64> 64? 64 (B) (known) 16-2 64> 64 (C) (known) 64-64> 64 764 compounds according to the preparation example I-1 <1 4 <1 <1 4 I-2 <1 32 <1 4 4 I-3 2 64 <1 64 32 I-4 <1 2 <1 4 2 I-5 <1> 64 <1 <1 64 I-6 2> 64 <1 16 64 I-7 <1 2 4 <1 <1 I-11 2 16 <1 32> 64 I-12 4 64 <1 8> 64 example B Antimycotic in vivo efficacy (oral) in candidiasis mice. Mice of the type SPF-CF1 were injected intravenously with 1-2 x 106 logarithmically growing Candida cells, which are suspended in physiological saline, infected.

One hour before and seven hours after infection, the animals are treated orally with in each case 10 to 100 mg / kg body weight of the preparations.

Result Untreated animals died on the 3rd to 6th day after infection. The survival rate on the 6th day post infection was in untreated control animals about 5%.

In this test, for example, compounds 1, 2, 3, 4, 5, 6, 7 and 13 good to very good effect, i.e. 60% survivors on the 6th day pi.

Table B In vivo antifungal activity (oral) in candidosis of mice Active ingredient Effect I-1 I-2 +++++ I-3 +++++ I-4 +++ I-5 +++++ I-6 ++++ I-7 I-13 ++ +++ Explanation of symbols +++++ = very good effect = 90% survivors on the 6th day p.i.

++++ = good effect = 80% survivors on the 6th day p.i.

= Effect = 60% survivors on day 6 p.i.

++ = weak effect = 40% survivors on day 6 p.i.

+ = Trace effect = under 40% survivors on the 6th day p.i.

k.W. = no difference to the untreated infection control.

Claims (8)

Claims 1. Azolylmethyl-cyclopropyl-carbinol derivatives of the general formula (1) in which Ar represents optionally substituted aryl or optionally substituted fetaryl, represents hydrogen, alkyl alkenyl, alkynyl trialkylsilyl, optionally substituted phenylalkyl or the acyl radical, R² represents halogen, cyano, thiocyanates, alkylcarbonyloxy, alkylcarbonylthio or the groupings -X-R³ and -NR4R5, and also represents hydrogen when Ar represents optionally substituted hetaryl, R³ represents alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkylthioalkyl, carboxylalkyl, alkoxycarbonylalkyl, optionally substituted aryl, optionally substituted aralkyl or the remainder of the formula stands, R4 and R5 are identical or different and stand for hydrogen or alkyl, and together with the nitrogen atom to which they are attached, stand for an optionally substituted cycloaliphatic ring which optionally contains further heteroatoms, X for oxygen, sulfur, the SO - Or 502 group and Y stands for a nitrogen atom or the CH group, as well as their acid addition salts for use in the therapeutic treatment of the human or animal body. 2. Compounds of the general formula (I) according to claim 1, in which Ar represents phenyl which is optionally mono- or polysubstituted, identically or differently substituted, where the following may be mentioned as substituents: halogen; Alkyl, alkoxy and alkylthio each having 1 to 4 carbon atoms; Haloalkyl, haloalkoxy and haloalkylthio each having 1 to 2 carbon atoms and 1 to 5 identical or different halogen atoms, such as fluorine and chlorine atoms, and phenyl or phenoxy optionally substituted by alkyl having 1 or 2 carbon atoms and / or halogen, furthermore naphthyl and represents an optionally mono- or polysubstituted, identically or differently substituted 5- or 6-membered heteroaromatic with nitrogen, oxygen and / or sulfur as heteroatoms, the abovementioned phenyl substituents being possible as substituents; R1 for hydrogen, straight-chain or branched alkyl with 1 to 4 carbon atoms, straight-chain or branched alkenyl and alkynyl with 2 to 4 carbon atoms each, for trialkylsilyl with 1 to 4 carbon atoms in each alkyl part, alkylcarbonyl with 1 to 4 carbon atoms in the alkyl part, and optionally phenylalkyl with 1 to 2 carbon atoms which is mono- or polysubstituted, identically or differently substituted in the alkyl moiety, possible substituents being the phenyl substituents already mentioned for Ar; R² stands for fluorine, chlorine, bromine, cyano, thiocyanato, alkylcarbonyloxy or alkylcarbonylthio each with 1 to 4 carbon atoms in the alkyl part or for the groupings -X-R3 and -NR4R5, and also stands for hydrogen if Ar is an optionally substituted heteroaromatic, R3 for straight-chain or branched alkyl with 1 to 12 carbon atoms, cycloalkyl with 5 to 7 carbon atoms, straight-chain or branched alkenyl with 2 to 12 carbon atoms, straight-chain or branched alkynyl with 2 to 12 carbon atoms, hydroxyalkyl with 1 to 12 carbon atoms, alkylthioalkyl with 1 to 4 carbon atoms in the alkylthio group and 1 to 4 carbon atoms in the alkyl group, carboxyalkyl with 1 to 12 raw material atoms in the alkyl part, alkoxycarbonylalkyl with 1 to 4 carbon atoms in the alkoxy part and 1 to 4 carbon atoms in the alkyl part, and for each optionally single to triple, in particular single or twofold, similar or different substituted phenyl or benzyl, the particularly preferred phenyl substituents already mentioned above for Ar being possible as substituents, or R3 for the remainder of the formula R4 and R5, which may be the same or different, represent hydrogen, straight-chain or branched alkyl having 1 to 4 carbon atoms and, together with the nitrogen, alkyl to which they are attached, an optionally substituted by alkyl having 1 to 4 carbon atoms 5- or 6-membered ring with optionally oxygen, sulfur or nitrogen as further heteroatoms, X for oxygen, sulfur, the SO or SO 2 group and Y for a nitrogen atom or the CH group is for use in the therapeutic treatment of the human or animal body. 3. Compounds of the general formula (I) according to claim 1, in which Ar is optionally mono- to triple, in particular singly or doubly, identically or differently substituted phenyl, where the following may be mentioned as substituents: fluorine, chlorine, methyl, isopropyl, tert. -Butyl, methoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, as well as phenyl or phenoxy optionally substituted in each case by fluorine, chlorine and / or methyl; furthermore represents naphthyl as well as furyl, thienyl, pyridinyl or pyrimidinyl which is optionally mono- or disubstituted, identically or differently substituted, the abovementioned phenyl substituents being possible as substituents; R1 for hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, allyl, propargyl, trimethylsilyl, methylcarbonyl, ethyl carbonyl, n-propyl carbonyl, isopropyl carbonyl, n-butyl carbonyl, isobutyl carbonyl, and optionally single to triple , in particular singly or twice, identically or differently substituted benzyl, the phenyl substituents already mentioned for Ar being possible and R2 being fluorine, chlorine, bromine, cyano, thiocyanato, methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, n- Butylcarbonyloxy, isobutylcarbonyloxy, methylcarbonylthio, ethylcarbonylthio, n- or i-propylcarbonylthio, n- or i-butylcarbonylthio or represents the groupings -X-R³ and -NR4R5, and also represents hydrogen if Ar represents an optionally substituted heteroaromatic; R3 for straight-chain or branched alkyl with 1 to 12 carbon atoms, cycloalkyl with 5 to 7 carbon atoms, straight-chain or branched alkenyl with 2 to 12 carbon atoms, straight-chain or branched alkynyl with 2 to 12 carbon atoms, hydroxyalkyl with 1 to 12 carbon atoms, alkynylthioalkyl with 1 to 4 carbon atoms in the alkylthio group and 1 to 4 carbon atoms in the alkyl group, carboxyalkyl with 1 to 12 carbon atoms in the alkyl part, alkoxycarbonylalkyl with 1 to 4 carbon atoms in the alkoxy part and 1 to 4 carbon atoms in the alkyl part, and for each optionally one to three times, in particular Phenyl or benzyl which is mono- or disubstituted, identically or differently substituted, possible substituents being the particularly preferred phenyl substituents already mentioned above for Ar, or R3 for the remainder of the formula R4 and R5, which can, however, be identical or different, stand for hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl, and also for piperidine, piperazine, each optionally substituted by methyl, ethyl, methylcarbonyl or ethylcarbonyl or morpholine; X stands for oxygen, sulfur, the SO or SO 2 group and Y stands for a nitrogen atom or the CH group for use in the therapeutic treatment of the human or animal body. 4. 1- (4-Chlorophenyl) -1- / 1- (n-butylsulfinyl) -1-cyclopropyl7-2- (1,2,4-triazol-1-yl) -1-ethanol for use in the therapeutic treatment of the human or animal Body. 5. 1- (4-Chlorophenyl) -1- / 1- (n-butylsulfinyl) -1-cyclopropyl / -2- (1,2,4-triazol-1-yl) -1-ethanol for use in the therapeutic treatment of the human or animal Body. 6. Use of the compounds of general formula (I) according to Claims 1 to 3 for use in the antifungal treatment of the human or animal body. 7. Medicaments containing at least one compound of the general Formula (I) according to Claims 1 to 3. 8. A method for the production of medicaments according to claim 7, characterized in that characterized in that the active ingredient or ingredients are optionally used converted from customary auxiliaries and / or carriers into a suitable application form.