DE3242249A1 - Antimycotic agents - Google Patents

Abstract

The novel hydroxyalkynylazolyl derivatives of the general formula <IMAGE> in which R, X and Az have the meanings given in the description, have good action against human pathogenic fungi and can be used as antimycotics.

Description

Antifungal agents

The present invention relates to antifungal agents which are novel Hydroxyalkynyl-azolyl derivatives contain as active ingredients.

It is already known that certain hydroxyalkenyl-azolyl derivatives, such as 1- (4-chlorophenyl) -4,4-dimethyl-3- (imidazol-1-ylmethyl) -1-penten-3-ol, have good antifungal properties (cf.

DE-OS 3 018 865 (Le A 20 351)). The effect of these compounds is however, not always fully satisfactory.

It has been found that the new hydroxyalkynyl-azolyl derivatives of the general formula in which Az is 1,2,4-triazolyl or imidazolyl, X is optionally substituted phenyl or alkyl and R is the groupings where R1 is hydrogen or halogen, R2 is halogen, R3 is alkylthio, haloalkoxy, haloalkylthio, alkenyl, alkoxycarbonyl, cyano, and each optionally substituted phenyl, phenoxy, phenylthio, phenylalkoxy and phenylalkylthio, n is the number 0 , 1 or 2, m stands for the numbers 0 or 1 and Het stands for optionally substituted dioxolanyl or dioxanyl, and acid addition salts thereof have good antimicrobial, in particular antimycotic, properties.

The compounds of the formula (I) have an asymmetric carbon atom and can therefore occur in the two optical isomer forms.

The hydroxyalkynyl-azolyl derivatives according to the invention are generally defined by the formula (I). In this formula, Az is preferably 1,2,4-triazol-1-yl or imidazol-1-yl; X stands for straight-chain or branched alkyl having 1 to 4 carbon atoms and for phenyl which is optionally mono- or polysubstituted, identically or differently substituted, the following substituents being: halogen, alkyl having 1 to 4 carbon atoms, alkoxy and alkylthio each having 1 to 2 carbon atoms, haloalkyl , Haloalkoxy and haloalkylthio each with 1 to 2 carbon atoms and 1 to 5 identical or different halogen atoms, such as fluorine and chlorine atoms, the aldoxime or ketoxime radical and their ether derivatives, as well as phenyl optionally substituted by halogen and alkyl with 1 to 2 carbon atoms, Phenoxy, benzyl and benzyloxy; and R for the groupings where R1 is hydrogen, fluorine, chlorine or bromine; R2 represents fluorine, chlorine or bromine; R3 for alkylthio with 1 to 4 carbon atoms, for haloalkoxy and haloalkylthio with 1 to 2 carbon atoms and 1 to 5 identical or different halogen atoms, such as fluorine and chlorine atoms, also for alkenyl with 2 to 6 carbon atoms, for alkoxycarbonyl with 1 to 4 Carbon atoms in the alkyl part, for cyano and each optionally mono- or polysubstituted, identically or differently substituted phenyl, phenoxy, phenylthio, phenylalkoxy with 1 to 4 carbon atoms in the alkyl part and phenylalkylthio with 1 to 4 carbon atoms in the alkyl part, phenyl substituents which may be mentioned as preferred : Halogen, alkyl of 1 to 4 carbon atoms; Alkoxy and alkylthio each having 1 to 2 carbon atoms; Haloalkyl, Hdlogenalkoxy and haloalkylthio each with 1 to 2 carbon and 1 to 5 identical or different halogen atoms, such as in particular fluorine and chlorine atoms, cyclohexyl, dialkylamino with 1 to 4 carbon atoms in each alkyl part, nitro, cyano, alkoxycarbonyl with 1 to 4 carbon atoms in the alkyl part, as well as phenyl optionally substituted by halogen; n stands for the numbers 0, 1 or 2; Het is each optionally mono- or polysubstituted, identically or differently substituted dioxolan-2-yl or 1,3-dioxanyl, where the following substituents may be mentioned: alkyl having 1 to 4 carbon atoms and in each case optionally mono- or polysubstituted, identically or differently substituted phenyl and Phenoxyalkyl with 1 to 4 carbon atoms in the alkyl part, the following phenyl substituents being mentioned: halogen, alkyl with 1 to 4 carbon atoms, alkoxy and alkylthio with 1 to 2 carbon atoms and haloalkyl, haloalkoxy and haloalkylthio with 1 to 2 carbon atoms and 1 to 5 identical or different halogen atoms, such as preferably fluorine and chlorine atoms; and m stands for the numbers 0 or 1.

Those compounds of the formula (I) in which Az is 1,2,4-triazol-1-yl or imidazol-1-yl are particularly preferred; X represents methyl, ethyl, tert-butyl and optionally mono- to triple, identically or differently substituted phenyl, the following substituents being: fluorine, chlorine, bromine, methyl, tert-butyl, methoxy, methylthio, trifluoromethyl, trifluoromethoxy , Trifluoromethylthio, hydroximinomethyl, 1-hydroximinoethyl, methoximinomethyl, 1-methoximinoethyl and phenyl, phenoxy, benzyl or benzyloxy which are optionally substituted by fluorine, chlorine and / or methyl; and R for the groupings stands; where R1 is hydrogen, fluorine or chlorine; R2 represents fluorine or chlorine; R3 stands for methylthio, ethylthio, trifluoromethoxy, trifluoromethylthio, vinyl, methoxycarbonyl, ethoxycarbonyl, cyano and also for phenyl, phenoxy, phenylthio, phenylmethoxy or phenylmethylthio, each of which may be mentioned as phenyl substituents: fluorine, chlorine , Methyl, ethyl, methoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, dimethylamino, methoxycarbonyl and ethoxycarbonyl; n stands for the numbers 0, 1 or 2; Het stands for dioxolan-2-yl, 1,3-dioxan-5-yl or 1,3-dioxan-2-yl, which may be mono- to trisubstituted, identically or differently substituted, where the following may be mentioned as substituents: methyl, ethyl, n Propyl, isopropyl and, in each case, optionally mono- to three-fold, identically or differently, phenyl and phenoxymethyl substituted by fluorine, chlorine, methyl, trifluoromethyl or trifluoromethoxy; and m stands for the numbers 0 or 1.

Preferred compounds according to the invention are also addition products from acids and those hydroxyalkinylazolyl derivatives of the formula (I) in which the substituents Az, R and X have the meanings which are already preferred for these substituents were named.

The acids that can be added preferably include hydrohalic acids, such as hydrochloric acid and hydrobromic acid, especially the Hydrochloric acid, also phosphoric acid, nitric 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, as well as sulfonic acids such as p-toluenesulfonic acid and 1,5-naphthalenedisulfonic acid.

The active ingredients to be used according to the invention and their acid addition salts are not yet known. However, they can be obtained in a known manner, by using azolyl ketones of the formula Az-CH2-CO-R (11) in which Az and R are the above have given meaning, with acetylene derivatives of the formula X-C - C-H (III) in which X has the meaning given above, in the presence of a strong base, such as for example butyllithium, and in the presence of a diluent such as Tetrahydrofuran, and optionally in the presence of a phase transfer catalyst at temperatures between -10 and + 1200C.

Optionally, in a two-phase system, such as aqueous sodium or potassium hydroxide solution / toluene or methylene chloride are used.

The end products are isolated in the generally customary manner.

The compounds of the formula (I) thus obtained can optionally then an acid can be added.

The acid addition salts of the compounds of the formula (I) can be used in simple way by common salt formation methods, by dissolving a compound of formula (I) in a suitable solvent and adding the acid, e.g. Hydrochloric acid, and in a known manner, for example by filtration isolated and optionally by washing with an inert organic solvent getting cleaned.

The azolyl ketones of the formula (II) are known (cf., for example DE-OS 2 820 361, DE-OS 3 048 266 and EP-OS 0 043 923) or are the subject of their own older patent applications that have not yet been published (cf.

the German patent applications P 32 22 220 from June 12, 1982 and P 32 24 129 dated June 29, 1982 or they can be produced according to processes that are known in principle.

The acetylene derivatives of the formula (III) are generally known compounds of organic chemistry.

The present invention includes pharmaceutical preparations, the substances in addition to non-toxic, inert pharmaceutically suitable carriers or more Active ingredients according to the invention contain or from consist of one or more active ingredients according to the invention, as well as processes for 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 are present, whose active ingredient content corresponds to a fraction or a multiple of a single dose. The dosage units can be, for example, 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 amount 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 the 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 the active ingredients in addition to the usual carrier contain substances, such as (a) fillers and extenders, e.g.

Starches, milk sugar, cane sugar, glucose, mannitol and silica, (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 below (a) to (i) listed substances.

The tablets, coated tablets, capsules, pills and granules can be used with the usual coatings and casings, optionally containing opacifying agents be provided and also be composed in such a way that they contain the active ingredient (s) only or preferably in a certain part of the intestinal tract, if appropriate Delayed release, e.g. polymer substances and waxes as embedding compounds 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, bentonites, 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 contain the usual propellants, e.g. chlorofluorocarbons.

Solutions and emulsions can, in addition to the active ingredient or ingredients, the customary carriers such as solvents, solubilizers 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 oil, olive oil, castor oil and sesame oil, glycerin, Glycerin formal, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of 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 contain the usual carriers such as liquid diluents, e.g. water, ethyl alcohol, propylene glycol, suspending agents, e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline Cellulose, aluminum methahydroxide, bentonite, agar-agar and tragacanth or mixtures contain these substances.

The formulation forms mentioned can also contain colorants and 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 about 0.5 to 95 percent by weight of the total mixture be.

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 and pharmaceutical preparations that contain one or more invented proper use 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 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 10 to about 300, preferably 50 to 200 mg / kg of body weight per 24 hours, possibly in the form of several individual doses to achieve the desired results to administer.

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 and the period or interval within which the administration he follows. So in some cases it may be sufficient with less than the above Amount of active ingredient get along, while in other cases the amount of active ingredient listed above must be exceeded. Determining the optimal dosage required in each case and type of application of the active ingredients can be carried out by any person skilled in the art on the basis of his specialist knowledge easily done.

Preparation examples Example 1 62 ml of butyllithium (15% in hexane, 0.1 mol) are added dropwise to 13.65 g (0.1 mol) of 4-chlorophenyl acetylene in 50 ml of absolute tetrahydrofuran at OOC under nitrogen. The mixture is allowed to stir at OOC for 15 minutes and then 18.5 g (0.1 mol) of 3,3-dimethyl-4-fluoro-1- (1,2,4-triazol-1-yl) -2- are added dropwise. butanone in 30 ml of absolute tetrahydrofuran. The reaction mixture is then allowed to warm to room temperature and stirred for a further 14 hours. The mixture is concentrated by partially distilling off the solvent, the residue is taken up in ether, washed neutral with water, dried over sodium sulfate and concentrated. The residue is recrystallized from diisopropyl ether. 19.9 g (61.9% of theory) 1- (4-chlorophenyl) -4,4-dimethyl-5-fluoro-3- (1,2,4-triazol-1-yl-methyl) - are obtained 1-pentyn-3-ol of m.p.

1200C.

In an analogous manner and in accordance with the specified process conditions, the following compounds of the general formula obtain: Ex 1, melting No.RX Az point (oC) 2 -C (CH) Z-CHZCL CL 2 -C <CH3) 2-CH2Ct 129 3 -C (CH2F) 2-CH3 C -N1 128 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 of an average of 5 × 10 4 germs / ml substrate. The nutrient medium used was a) for dermatophytes and molds: Sabourand's milieu d'èpreuve b) for yeasts: meat extract-glucose broth.

The incubation temperature was 20 ° C, the incubation time was 24 to 96 hours for yeasts and 96 hours for dermatophytes and molds.

In this test, for example, compounds 1 and 2 show a better antifungal activity than the compound known from the prior art 1- (4-chlorophenyl) -4,4-dimethyl-3- (imidazol-1-yl-methyl) -1-penten-3-ol.

Table A Antifungal activity in vitro MIC values in y / ml nutrient medium Micro toru Tricho- Candida Aspergillus sporum lopsis phyton albicans fumig canis gLa- Active ingredient mentagr. brata OH CL g CH = CH-β-C (CH3) 3 4 8 16 16 4 CH2 (known) i N Connections according to Manufact. Ex.

1 <1 C1 2 4 4 2 <1 (1 2 4 4 Example B Antifungal in vivo efficacy (oral) in candidiasis mice Description of the experiment: Type mice SPF-CF1 were administered intravenously with 1 to 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 50 to 100 mg / kg body weight of the preparations.

Result: Untreated animals died 3 to 6 days after infection.

The survival rate on the 6th day post infection was in the untreated Control animals about 5%.

In this test, for example, the compounds according to the invention 1 and 2 effect to very good effect.

Explanation of symbols: +++++ = very good effect = 90% survivors on 6th day p.i.

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

+++ = effect = 60% survivors on the 6th day p.i.

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

+ = Trace effect = no information = no effect Tabel B Antifungal in vivo efficacy (oral) in the case of candidate mice W i r k s t 0 f f Effectiveness according to Herst.Bsp.

2

Claims (8)

Claims 1. Hydroxyalkinylazolyl derivatives of the general formula in which Az is 1,2,4-triazolyl or imidazolyl, X is optionally substituted phenyl or alkyl and R is the groupings where R1 is hydrogen or halogen, R2 is halogen, R3 is alkylthio, haloalkoxy, haloalkylthio, alkenyl, alkoxycarbonyl, cyano, and optionally substituted phenyl, phenoxy, phenylthio, phenylalkoxy and phenylalkylthio, and n is the number 0 , 1 or 2, m stands for the numbers 0 or 1 and Het stands for optionally substituted dioxolanyl or dioxanyl, as well as their acid addition salts for combating mycoses. 2. Hydroxyalkynyl-azolyl derivatives of the general formula (I) in claim 1, in which Az is 1,2,4-triazol-1-yl or imidazol-1-yl, X is straight-chain or branched alkyl having 1 to 4 carbon atoms and for phenyl which is optionally mono- or polysubstituted, identically or differently substituted, the following substituents being: halogen, alkyl with 1 to 4 carbon atoms, alkoxy and alkylthio with in each case 1 to 2 carbon atoms, haloalkyl, haloalkoxy and haloalkylthio with in each case 1 to 2 carbon atoms and 1 to 5 identical or different halogen atoms, such as fluorine and chlorine atoms, the aldoxime or ketoxime radical and their ether derivatives, and phenyl, phenoxy, benzyl and benzyloxy, each optionally substituted by halogen and alkyl with 1 to 2 carbon atoms, R for the Groupings where R1 represents hydrogen, fluorine, chlorine or bromine, R2 represents fluorine, chlorine or bromine, R3 represents alkylthio with 1 to 4 carbon atoms, for haloalkoxy and haloalkylthio each with 1 to 2 carbon atoms and 1 to 5 identical or different halogen atoms, such as Fluorine and chlorine atoms, also for alkenyl with 2 to 6 carbon atoms, for alkoxycarbonyl with 1 to 4 carbon atoms in the alkyl part, for cyano and for each optionally mono- or multiply, identically or differently substituted phenyl, phenoxy, phenylthio, phenylalkoxy with 1 to 4 carbon atoms in the alkyl part and phenylalkylthio with 1 to 4 carbon atoms in the alkyl part, the following preferably being mentioned as phenyl substituents: halogen, alkyl with 1 to 4 carbon atoms; Alkoxy and alkylthio each having 1 to 2 carbon atoms; Haloalkyl, haloalkoxy and haloalkylthio each with 1 to 2 carbon and 1 to 5 identical or different halogen atoms, such as in particular fluorine and chlorine atoms, cyclohexyl, dialkylamino with 1 to 4 carbon atoms in each alkyl part, nitro, cyano, alkoxycarbonyl with 1 to 4 carbon atoms , in the alkyl moiety, as well as phenyl which is optionally substituted by halogen, n is the numbers 0, 1 or 2, m is the numbers 0 or 1 and Het is each optionally mono- or polysubstituted, identically or differently substituted dioxolan-2-yl or 1 , 3-Dioxanyl, where the following substituents may be mentioned: alkyl with 1 to 4 carbon atoms and in each case optionally mono- or multiply, identically or differently substituted phenyl and phenoxyalkyl with 1 to 4 carbon atoms in the alkyl part, where the following phenyl substituents may be mentioned: halogen, alkyl with 1 to 4 carbon atoms, alkoxy and alkylthio each with 1 to 2 carbon atoms, and haloalkyl, halogens nalkoxy and haloalkylthio each having 1 to 2 carbon atoms and 1 to 5 identical or different halogen atoms, such as preferably fluorine and chlorine atoms, are used to combat mycoses. 3. Hydroxyalkynyl-azolyl derivatives of the general formula (I) in claim 1, in which Az is 1,2,4-triazol-1-yl or imidazol-1-yl, X is methyl, ethyl, tert. -Butyl and optionally mono- to three-fold, identically or differently substituted phenyl, the following substituents being: fluorine, chlorine, bromine, methyl, tert-butyl, methoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, hydroximinomethyl, 1-hydroximinoethyl , Methoximinomethyl, 1-methoximinoethyl and any phenyl, phenoxy, benzyl or benzyloxy optionally substituted by fluorine, chlorine and / or methyl; and R for the groupings stands; where R1 stands for hydrogen, fluorine or chlorine, R2 stands for fluorine or chlorine, R3 for methylthio, ethylthio, trifluoromethoxy, trifluoromethylthio, vinyl, methoxycarbonyl, ethoxycarbonyl, cyano and each optionally mono- to disubstituted, identically or differently substituted phenyl, phenoxy, Phenylthio, phenylmethoxy or phenylmethylthio, where the following phenyl substituents may be mentioned: fluorine, chlorine, methyl, ethyl, methoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, dimethylamino, methoxycarbonyl and ethoxycarbonyl; n stands for the numbers 0, 1 or 2, m stands for the numbers 0 or 1 and Het for each optionally mono- to triple, identically or differently substituted dioxolan-2-yl, 1,3-dioxan-5-yl or 1, 3-Dioxan-2-yl, where the following may be mentioned as substituents: methyl, ethyl, n-propyl, isopropyl and, in each case, phenyl and phenoxymethyl optionally substituted one to three times, identically or differently by fluorine, chlorine, methyl, trifluoromethyl or trifluoromethoxy to combat mycoses. 4. Antifungal agent, characterized by a content of at least one Hydroxyalkinylazolylderivate of the general formula in which Az is 1,2,4-triazolyl or imidazolyl, X is optionally substituted phenyl or alkyl and R is the groupings where R1 is hydrogen or halogen, R2 is halogen, R3 is alkylthio, haloalkoxy, haloalkylthio, alkenyl, alkoxycarbonyl, cyano, and each optionally substituted phenyl, phenoxy, phenylthio, phenylalkoxy and phenylalkylthio, n is the number 0 , 1 or 2, m stands for the numbers 0 or 1 and Het stands for optionally substituted dioxolanyl or dioxanyl, as well as their acid addition salts. 5. Antifungal agent, characterized by a content of at least one hydroxyalkynyl-azolyl derivative of the general formula (I) in claim 1, in which Az is 1,2,4-triazol-1-yl or imidazol-1-yl, X is straight-chain or branched alkyl with 1 to 4 carbon atoms and optionally mono- or polysubstituted or identical or differently substituted phenyl, the following substituents being: halogen, alkyl with 1 to 4 carbon atoms, alkoxy and alkylthio each with 1 to 2 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, the aldoxime or ketoxime radical and their ether derivatives, and phenyl, phenoxy, each optionally substituted by halogen and alkyl having 1 to 2 carbon atoms , Benzyl and benzyloxy, R for the groupings where R1 represents hydrogen, fluorine, chlorine or bromine, R2 represents fluorine, chlorine or bromine, R3 represents alkylthio with 1 to 4 carbon atoms, for haloalkoxy and haloalkylthio each with 1 to 2 carbon atoms and 1 to 5 identical or different halogen atoms, such as Fluorine and chlorine atoms, also for alkenyl with 2 to 6 carbon atoms, for alkoxycarbonyl with 1 to 4 carbon atoms in the alkyl part, for cyano and for each optionally mono- or multiply, identically or differently substituted phenyl, phenoxy, phenylthio, phenylalkoxy with 1 to 4 carbon atoms in the alkyl part and phenylalkylthio with 1 to 4 carbon atoms in the alkyl part, the following preferably being mentioned as phenyl substituents: halogen, alkyl with 1 to 4 carbon atoms; Alkoxy and alkylthio each having 1 to 2 carbon atoms; Haloalkyl, haloalkoxy and haloalkylthio each with 1 to 2 carbon and 1 to 5 identical or different halogen atoms, such as in particular fluorine and chlorine atoms, cyclohexyl, dialkylamino with 1 to 4 carbon atoms in each alkyl part, nitro, cyano, alkoxycarbonyl with 1 to 4 carbon atoms , in the alkyl moiety, as well as phenyl which is optionally substituted by halogen, n is the numbers 0, 1 or 2, m is the numbers 0 or 1 and Het is each optionally mono- or polysubstituted, identically or differently substituted dioxolan-2-yl or 1 , 3-Dioxanyl, where the following substituents may be mentioned: alkyl with 1 to 4 carbon atoms and in each case optionally mono- or multiply, identically or differently substituted phenyl and phenoxyalkyl with 1 to 4 carbon atoms in the alkyl part, where the following phenyl substituents may be mentioned: halogen, alkyl with 1 to 4 carbon atoms, alkoxy and alkylthio each with 1 to 2 carbon atoms, and haloalkyl, halogens nalkoxy and haloalkylthio each having 1 to 2 carbon atoms and 1 to 5 identical or different halogen atoms, such as preferably fluorine and chlorine atoms. 6. Antifungal agent, characterized by a content of at least one hydroxyalkynyl-azolyl derivative of the general formula (I) in claim 1, in which Az is 1,2,4-triazol-1-yl or imidazol-1-yl, X is methyl , Ethyl, tert. -Butyl and optionally mono- to three-fold, identically or differently substituted phenyl, the following substituents being: fluorine, chlorine, bromine, methyl, tert-butyl, methoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, hydroximinomethyl, 1-hydroximinoethyl , Methoximinomethyl, 1-methoximinoethyl and any phenyl, phenoxy, benzyl or benzyloxy optionally substituted by fluorine, chlorine and / or methyl; and R for the groupings stands; where R1 stands for hydrogen, fluorine or chlorine, R2 stands for fluorine or chlorine, R3 for methylthio, ethylthio, trifluoromethoxy, trifluoromethylthio, vinyl, methoxycarbonyl, ethoxycarbonyl, cyano and each optionally mono- to disubstituted, identically or differently substituted phenyl, phenoxy, Phenylthio, phenylmethoxy or phenylmethylthio, where the following phenyl substituents may be mentioned: fluorine, chlorine, methyl, ethyl, methoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, dimethylamino, methoxycarbonyl and ethoxycarbonyl; n stands for the numbers 0, 1 or 2, m stands for the numbers 0 or 1 and Het for each optionally mono- to triple, identically or differently substituted dioxolan-2-yl, 1,3-dioxan-5-yl or 1, 3-Dioxan-2-yl, where the following may be mentioned as substituents: methyl, ethyl, n-propyl, isopropyl and, in each case, phenyl and phenoxymethyl optionally substituted one to three times, identically or differently by fluorine, chlorine, methyl, trifluoromethyl or trifluoromethoxy . 7. A method of making an antifungal agent, thereby characterized in that one hydroxyalkynyl-azolyl derivatives according to the formula in claim 1 mixed with inert, non-toxic, pharmaceutically suitable carriers. 8. Use of hydroxyalkynyl azolyl derivatives of the formula in claim 1 to combat mycoses.