DE2847050A1 - 1-Ethylene azole derivs. as antimycotics - with broad spectrum activity, effective against dermatomycoses and system-mycoses - Google Patents

Abstract

An antimycotic agent contains a 1-ethyl-ene azole deriv. of formula (I) or its acid addn salts or metals complex. (where R1 is alkyl, alkoxy, alhylthio, alkylsulphonyl, alkylcarbonyl, Ph, PhO, PhS, PhSO2 or PhCO, the last 5 gps all opt. substd R2 is alkyl, cycloalkyl or opt substd Ph; Y is N or CH). (I) have a very broad antimycotic spectrum and are esp effective against dermatophytes and gemmiparous fungi as well as biphasic fungi eg against candida, Epidermophyten, Aspergillus. Trichophyton, Microsporon and Pennicillium. (I) can be used against dermatomycoses and systemmycoses. Suitable doses of (I) are 10-300 (pref 50-200)mg/kg body weight per 24 hrs.

Description

Antimicrobial agents

The present invention relates to the use of new 1-ethylene-azole derivatives as antimicrobial agents, particularly as antifungal agents.

It has already become known that 1-ethyl-imidazole and triazole derivatives, such as in particular 1- (imidazol-1-yl) or. - (1,2,4-Triazol-1-yl) -1-phenoxy-4,4-dimethyl-pentan-3-ones have a good antifungal effect (compare DE - () S 22 42 454 (Le A 14 581) and DE-OS 23 47 057 (Le A 15 248). Their effect is, however, especially against Dermatophytes, not always entirely satisfactory.

It was found that the new 1-ethylene-azole derivatives of the general formula in W (1 cher represents alkyl, alkoxy, alkylthio, alkylsulfonyl, alkylcarbonyl, optionally substituted phenyl, optionally substituted phenoxy, optionally substituted phenylthio, optionally substituted phenylsulfonyl or optionally substituted phenylcarbonyl, R2 represents alkyl, cycloalkyl or optionally substituted phenyl, and Y stands for a nitrogen atom or the CEI group, and their physiologically compatible acid addition salts and metal salt complexes have good antimicrobial, in particular antimycotic, properties.

The compounds of the formula (I) can exist in two geometric isomeric forms are present, depending on the arrangement of the groups which are bonded to the carbon atoms linked by the double bond. Both the isomers and the Mixtures of the two are claimed according to the invention.

Surprisingly, the 1-ethylene-azole derivatives which can be used according to the invention show of formula (I) a better antifungal activity than that from the prior 1- (Imidazol-1-yl) - or - (1,2,4-Triazol-1-yl) -1-phenoxy-4,4-dimethyl-pentan-3-ones known in the art, Which chemically and in terms of effect are obvious compounds. The substances that can be used according to the invention are thus an enrichment for pharmacy represent.

The 1-ethylene-azole derivatives according to the invention are represented by the formula (I) generally defined. In this formula, R1 preferably stands for straight-chain or branched alkyl, alkoxy, alkylthio, alkylsulfonyl and alkylcarbonyl with each 1 to 4 carbon atoms in the alkyl part. R1 also preferably represents in each case optionally substituted phenyl, phenoxy, phenylthio, phenylsulfonyl and phenylcarbonyl, where preferred substituents are: halogen, straight-chain or branched alkyl with 1 to 4 carbon atoms, haloalkyl with 1 to 2 carbon atoms and 1 to 5 identical or different halogen atoms, such as in particular fluorine and Chlorine atoms, and optionally halogen-substituted phenyl.

R2 preferably represents straight-chain or branched alkyl with 1-4 carbon atoms, cycloalkyl with 5-7 carbon atoms as well as for optionally substituted phenyl, where the phenyl substituents are preferably those already in R1 mentioned come into question. Y preferably represents a nitrogen atom or the CH group.

Very particularly preferred are those compounds of the formula (I) in which R1 represents flour, methoxy, methylthio, methylsulfonyl, acetyl, ethyl, isopropyl, tert-butyl, and each optionally single or multiple, identically or differently through fluorine, chlorine , Bromine, methyl, ethyl or phenyl-substituted phenyl7 phenoxy, phenylthio, phenylsulfonyl or phenylcarbonyl; R2 stands for methyl, isopropyl, tert-butyl, cyclohexyl, and also for phenyl which is optionally substituted one or more times, identically or differently by fluorine, chlorine, bromine, methyl, ethyl or phenyl; and Y stands for a nitrogen atom or the CH group.In addition to the compounds mentioned in the preparation examples, the following compounds of the general formula (I) may be mentioned: nl 1L2 Y C113 Oo N (CH) c, Ik N (CH) i-c3n1% to N (CH) t-C4Ii öo N (cn> Cn3 9 Cl N (CH) CIi3 oyCOi N (CH) C. R1 R2 Rl R2 6 N (ca) CH3S- N (ei ') cIf3so Oo r, (o> N (CR) ena Co- Oo N (efL) N (CE) 3> 61 N cl 0 + 1 N (CIf) Cl? Ji 0 N (eIf) C1 Claot eC1 N (Cit) ci u Cl t + l N (CII) 1 el 0 N (CH) Cl + ~ <+ N (CA) egg ei4M l J3r e (en3 ON Cl el0 0 (CI) 3 N cl FO C (CII3) 3 N Co ° ~ to N (CH) R- R2 y Cl + N (CH> ior el;) 0 O to N (CH) F0- O- to N (CH) CI! 30 N (eII) U \ ON (cn) e O- @ N (CH) 7 \ ol Oo N (eH) eo- Oo N (cH) Clf + CO ~ - N (eH) Cl Cl 4 CO to N (cn) F + CO- CO- @ N (CH) N (eH) CH3CO- Co N (CH) ella Co N (Cll) Cl o & ooeo- CN (ei ') 0-s- e (en3) 3 N (CH) C1 S- e (eir3) N (eIi) R1 R2 Y CII3 e (e113 p F + S- S to ce (e%) 3) 3 N (CH) C-OSOa e (e113) 3 N (CH) eiSo2- c (cEl3) 3 N (Cl3) Cfl3SO2- C (CHa) 3 sc N (cH) F + SO- C (CH3) 3 N (CH) The active ingredients to be used according to the invention, their acid addition salts and metal salt complexes are not yet known. However, they can be prepared according to our own proposal by using 1-halo-ethylene derivatives of the formula in which R1 and R2 have the meaning given above and Hal stands for halogen, with alkali metal salts of azoles of the formula in which Y has the meaning given above and M stands for an alkali metal, in the presence of an inert organic solvent1 such as, for example, acetanitrile1 at temperatures between 20 and 1200C. To isolate the end products, the reaction mixture is freed from the solvent and the residue is taken up with an organic solvent, washed several times with water, dried and further worked up in the usual way; if necessary, the salt or a metal complex is produced. In some cases it proves to be advantageous to obtain the compounds of the formula (1) in pure form via their salts. In general, when carrying out the stated process, one isomer is obtained in a larger amount than the other. If necessary, the isomers can be separated by generally known methods, such as, for example, by gas / liquid chromatography. However, it can also be more expedient to use the isomer mixture as the active ingredient.

Some of the l-halo-ethylene derivatives of the formula (II) are known; they can be obtained in a generally known manner by using corresponding ethylene derivatives of the formula in which R1 and R2 have the meaning given above, with a halogenating agent such as phosphorus and sulfur halides, for example thionyl chloride, sulfuryl chloride, phosphorus trichloride or bromide and phosphorus oxychloride, optionally in the presence of a diluent such as toluene or xylene, at temperatures between 20 and 1000C converts (compare also the preparation examples).

Ilie 1-hydride) xy-ethylene derivatives of the formula (IV) are known in some cases.

(Compare, inter alia, Liebigs Ann.Chem. 379, 230 (1911) or they can be obtained in a generally known manner by using known hetones of the formula in which R1 and R2 have the meaning given above, with formic acid esters of the formula H-CO-OR3 (VI) in which R3 is methyl or ethyl, in the presence of sodium methylate or ethylate in methanol or ethanol at temperatures between 0 and 400C converts (compare also the preparation examples).

For the preparation of acid addition salts of the compounds of the formula (I) all physiologically compatible acids come into consideration. These preferably include the hydrohalic acids, such as hydrochloric acid and hydrobromic acid, in particular hydrochloric acid, furthermore phosphoric acid, nitric acid, sulfuric acid, mono- and bifunctional carboxylic acids and hydroxycarboxylic acids, such as acetic acid, Malein- acid, succinic acid, fumaric acid, tartaric acid, citric acid, Salicylic acid, sorbic acid, lactic acid, and sulfonic acids such as p-toluenesulfonic acid and 1,5-naphthalenedisulfonic acid.

The salts of the compounds of the formula (I) can be used in a simple manner by customary salt formation methods, e.g.

by dissolving a compound of formula (I) in a suitable inert one Solvent and adding the acid such as hydrochloric acid and in a known manner, for example by filtering off, isolated and optionally by Wash with an inert organic solvent.

For the preparation of metal salt complexes of the compounds of the formula (I) are preferably salts of metals from II. To IV.-main and from I. and II and IV. To VIII. Subgroup in question, whereby copper, zinc, manganese, magnesium, Tin, iron and nickel may be mentioned as examples. Come as anions of the salts those that are derived from physiological acids are taken into account. These include preferably the hydrohalic acids such as hydrochloric acid and hydrobromic acid, furthermore phosphoric acid, nitric acid and sulfuric acid.

The metal salt complexes of the compounds of the formula (I) can be used in a simple manner Manner can be obtained by conventional methods, for example by dissolving the metal salt in alcohol, e.g., ethanol, and adding to the compound of formula (I). One can Metal salt complexes in known Way, e.g. by filtering, isolate and, if necessary, purify by recrystallization.

The compounds of the formula (I) which can be used according to the invention, their Acid addition salts and metal salt complexes have antimicrobial, in particular strong antifungal effects. They own a very broad antifungal Spectrum of activity, especially against dermatophytes and fungi as well as bisphasic 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, such as Trichophyton species, such as Trichophyton mentagrophytes, Microsporon species, such as Microsporon felineum and Penicillium species such as Penicillium commune. The list these microorganisms do not in any way limit the number of germs that can be controlled but is only of an explanatory nature.

Indication areas in human medicine can be named, for example be: dermatomycoses and systemic mycoses caused by Trichophyton mentagrophytes and others Trichophyton species, microsporon species, Epidermophyton floccosum, sprouts and biphasic Caused by fungi as well as molds.

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. tables, dragges, Capsules, pills, suppositories and ampoules are available whose active ingredient content is a A fraction or a multiple of a single dose. The dosage units e.g. 1, 2, 3 or 4 single doses or 1/2, 1/3 or 1/4 of a single dose contain.

A single dose preferably contains the amount of active ingredient required for an application is administered and usually a whole, half an 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, Pastes, Called 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) binding agents, 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., quartenary 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 those under (a) to (i) listed substances.

The tablets, coated tablets, capsules, pills and granules can be used with the customary coatings and casings, optionally containing opacifying agents be and also be composed so that they only or the active ingredient or preferably in a certain part of the intestinal tract, possibly delayed using e.g. polymer substances and waxes as embedding compounds can be.

The active ingredient (s) can optionally be combined with one or more of the above-mentioned carriers are also in microencapsulated form.

In addition to the active ingredient (s), suppositories can contain the usual water-soluble ones 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 Fabrics.

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 the usual propellants e.g.

Contain 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, Benzylene benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular Cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesa oil, glycerine, 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 metahydroxide, 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 saccharine.

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% 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 or the active ingredients with the carrier or carriers.

The present invention also includes the use of the invention Active ingredients and pharmaceutical preparations which contain one or more according to 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 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 mentioned amount of active ingredient, while in other cases the above The amount of active ingredient must be exceeded. The determination of the required optimal dosage and type of application of the active ingredients can through easily done by any skilled person based on his or her specialist knowledge.

Example A Antifungal in vitro activity Description of the experiment: The in vitro tests were in the serial dilution test with germ inocula of average 5 x 10 germs / ml substrate carried out. The nutrient medium used was a) for dermatophytes and molds: Sabourand's milieu d'epresive b) for yeasts: Isotonic Sensitest-Broth of oxide.

° The incubation temperature was 28 C; Incubation time was 24 hours for yeasts and 96 hours for dermatophytes and molds.

The agents according to the invention show in Trichophyton ment. and partially also with Candida alb. lower MIC values than the known means.

Example B In Vivo Antimicrobial Effectiveness (Oral) in Murine Candidiasis Trial description

Mice of the SPF-CF type were injected intravenously with 1–2 x logarithmic growth Candida cells suspended in physiological saline were infected One hour before and seven hours after infection, the animals are each with 50 - 100 mg / kg body weight of the preparations treated orally.

Experience: 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%.

On the other hand, Example 1 according to the invention, for example, showed a good effect (t 80% survivors on the 6th day p.i.).

Example 1 256.7 g <1 mol) of 1-chloro-2- {4-fluorophenoxy) -4.4 are added to a suspension of 90 g (1 mol) of sodium imidazole, prepared from sodium methylate and imidazole in methanol, in 2500 ml of acetonitrile -dimethyl-pentene-3-o: added dropwise to 150 ml of acetonitrile with stirring. The reaction mixture is then heated to boiling for 6 hours. The mixture is allowed to cool to room temperature and concentrated by distilling off the solvent in vacuo. The residue is taken up in 1000 ml of ethyl acetate, washed three times with 200 ml of water each time, the organic phase is dried over sodium sulfate and concentrated by distilling off the solvent in vacuo. 272.4 g (94.5% of theory) of crude 1- (imidazol-1-yl) -2- (4-fluorophenoxy) -4,4-dimethyl-penten-3-one are obtained as a brown oil.

To a solution of 252 g (0.874 mol) of this oil in 315 ml of chloroform a solution of 52.5 ml of 96% strength is obtained while stirring and cooling with ice at ° 10-20 C Nitric acid in 105 ml of chloroform. Then the clear solution becomes slow 860 ml of diethyl ether are added. 194.5 g (63.3% of theory) 1-imidazol-1-yl) -2- (4-fluorophenoxy) -4,4-dimethyl-penten-3-one nitrate are obtained of melting point 132-1330C (dec.).

Manufacture of the preliminary stages 297.5 g (2.5 mol) of thionyl chloride are slowly poured into a solution of 404.6 g (1.7 mol) of 1-hydroxy-2- (4-fluorophenoxy) -4,4-dimethyl-pentene, heated to 600C -3-one stirred into 3000 ml of anhydrous toluene. It is kept at this temperature for 12 hours and then the solvent and excess thionyl chloride are distilled off. The remaining oil is distilled in vacuo. 353.3 g (81% of theory) of 1-chloro-2- (4-fluorophenoxy) -4,4-dimethyl-penten-3-one with a boiling point of 95-1030 ° C./0.3 mm are obtained.

163 g (2.2 mol) of ethyl formate are added dropwise at OOC to a solution of 136 g of sodium ethylate in 1500 ml of ethanol. Then 420 g (2 mol) of 2,2-dimethyl-4- (4-fluorophenoxy) -butan-3-one are slowly stirred in at OOC. After a reaction time of 24 hours at OOC, the mixture is allowed to warm to room temperature and stirred at this temperature for a further 96 hours. The reaction mixture is poured into 5000 ml of ice water and the organic phase is separated off by extraction with chloroform. Unreacted starting material can be isolated from this chloroform solution and used again. The aqueous phase is acidified with 10% hydrochloric acid while cooling and the oil which separates out is taken up in chloroform. the chloroform phase is dried over sodium sulfate and concentrated by distilling off the solvent in vacuo. The remaining oil is distilled in vacuo. 170 g (83% of theory, based on the converted product) of 1-hydroxy-2- (4-fluorophenoxy) -4,4-dimethyl-penten-3-one with a boiling point of 101-1020C / 0.6 mm (nD20 = 1.5132).

418.3 g (3.11 mol) of 2,2-dimethyl-4-chloro-butan-3-one are in a boiling suspension of 315 g (2.8 mol) of 4-fluorophenol and 386.4 g (2.8 Mol) of potassium carbonate in 1500 ml of acetone was added dropwise. The mixture is refluxed for 4 hours stir. After cooling to room temperature, the precipitated salt is filtered off and the filtrate was concentrated in vacuo. The remaining oil is distilled in vacuo. 101.5 g (86.2% of theory) of 2,2-dimethyl-4- (4-fluorophenoxy) butan-3-one are obtained from 20 boiling point 83-84 ° C 0.05 mm (n D = 1.4919).

Example 2 20 g (0.057 mol) 1- (imidazol-1-yl) -2- (4-fluorophenoxy) -4,4-dimethyl-penten-3-one nitrate (Example 1) are suspended in water. The suspension is made alkaline with 10% sodium carbonate solution. Extraction of the aqueous alkaline phase with chloroform gives 16.4 g (100% of theory) of 1- (imidazol-1-yl) -2- (4-fluorophenoxy) -4,4-dimethyl-pentene using the customary work-up methods -3-on of refractive index 20 n = 1.5590.

D20 The following compounds of Table 1 are obtained in a corresponding manner: Table 1 Ex. R1 R2 Y melting point OC No. 3 -0- o-Coc1 -Cl C (CH3) 3 CH 93-4 40cLCl e "98-9 5 o-oo to 1 II 117-18 6 -0- o-Co-cH3 II Ii 104-05 7 - ° - zuII zu II 164 (decomp.) (X HN03) 8 -0- o-CocH3 II 145 (decomp.) (X HN03) 9 -0- k "II 132 (decomp.) (X HN03) 10 0-Cocl II 144 (decomp.) (X HN03) 11 -0- II "128-29 12 c; f3 1I 153 (decomp.) (X HN03) ßsp. R1 R2 Y melting point OC No. 13 "250-52 (x 1/2 NDS) 14 -0- g 115-16 15 -0- to 110-11 16 -0- 4 145 (decomp.) (X HN03) 17-0- g 202-05 (x HCl) 18 -0- to 140 (decomp.) (X HN03) 19 -0- to 123 (dec.) (X HNO3) (L 20 -0 q 152 (decomp.) (X HN03) 21 "115-17 22 0 ~ g Cl 84-5 23 Co Co 116-17 24 zuCo cl-Co - 157 (decomp.) (XHN03) 25 Q Co N 157-58 26- ° - to -Cl C (CH3) 3 N 87-8 27 o {% o-ci "117-18 28 O-Co-CH3 74-5 29 -0- to -0-Co-Co 166-67 30 0-Co-F 113 (decomp.) (X HN03) 2o 31 0 -O-Co- - F CtCH3) 3 N nD = 1.5460 CL 32-0) 104-07 (x HN03) CH3 33 1; 95-8 34 -0-% 94-5 35 -O-Co 103 (decomp.) (X HN03) ½ocl 36 126-28 E.g. R1 R2 <0'J No. YY Melting Point C 37 0yy2Cl II 103 (decomp.) (X HNO3) 38 0-Co lt lt 120-22 38 -0- @ 39 0 fl "52-3 40 -o-to-F "CH 127 (decomp.) (X HN03) 41 0 - \> Ii CH 124 (decomp.) (X HN03) The starting products of the formula (II) listed in Table 2 below are obtained by a known process and in accordance with precursor (II-l) in Preparation Example 1: Table 2 Ex. R1 R2 Hal boiling point (° C) / mm Hg column E.g. R Melting point ° C No. Melting point .OC I1-2 -0-Cl C (CH3) 3 Cl 115-17 / 0.1 I1-3 -0- lt "135-37 / 0.07 II-4 o to ö1 Ul II-50-Co-CH3 lt "114-16 / 0.4 II-6 -0- X "121-23 / 0.4 II-7 CL II b 107-10 / 0.15 II-8 -0- to lt "98-100 / 0.25 II-9 -0- Q Ii 132 / 0.3 11-10 -0- l1 II 126-30 / 0.2 ce Co II-11 To "mp 60-61 (pure isomer) II-12 to C1 e - "Mp. 79-80 ( II-13 Co (o>"142-45 / 0.2

Claims (2)

Claims 1 mycotic agent, characterized by a content of at least one 1-et1iylenazlderivat of the general. en formula in which R1 represents alkyl, mkoxy, alkylthio, alkylsulfonyl, alkylcarbonyl, optionally substituted phenyl, optionally substituted phenoxy, optionally substituted phenylthio, optionally substituted phenylsulfonyl or optionally substituted phenylcarbonyl, R2 represents alkyl, cycloalkyl or optionally substituted phenyl, and Y represents a Nitrogen atom or the CH group, and their physiologically acceptable acid addition salts and metal salt complexes. 2. A method of making an antifungal agent, thereby characterized in that 1-Ethylenazoleivate according to the formula in claim 1 with inert, non-toxic, pharmaceutically suitable carriers mixed.