MXPA97006283A - New polyen antibiotics, 3874 hi to h6, procedures for preparation and emp - Google Patents

Abstract

The present invention relates to compounds of the formulas, 3874 H1, empirical formula: C58H86N2O18, MW 1099.3 3874 H2, empirical formula; C59H88N2O18, MW 1113.3 3874 H3, empirical formula: C57H87NO18, PM 1074, 3 3874 H4, empirical formula: C58H84N2O18, PM 1097, 3 3874 H5, empirical formula: C59H86N2O18, PM 1111, 3 3874 H6, empirical formula: C57H85NO18, PM 1072, 3, are suitable for the treatment of fungal diseases and for the treatment of diseases that they are accompanied by an increased concentration of steroid

Description

New polyene antibiotics, 3874 Hl to H6, procedures for its preparation and use The present invention relates to new heptaeno antibiotics, to processes for their preparation and to their use. A large number of heptane antibiotics have already been described. Heptaene antibiotics are macrocyclic lactones which, as a characteristic feature, contain 7 cgated double bonds. They are microbially obtained natural substances that, as antimycotics, find application as agents against Tricho onas or as agents for the fixation of steroids (cholesterol). However, in part they are very toxic compounds that, therefore, are not (injected) systemically, with the exception of the commercial product Amphotericin B (The Merck Index, eleventh edition, 1989, page 93), the archetype of antibiotics in polyene Due to the increasing number of fungal diseases, there is also a great demand for new antifungal antibiotics that are more effective or better compatible than the known polyene antibiotics. It has now been found, surprisingly, that Strep-tomyces spec. HAG 3874, DSM 11007 is capable of forming very active new heptaeno antibiotics, which are not only very effective, but, in part, also well compatible. Accordingly, the compounds of the invention are compounds 3874 H1-H6, as well as their physiologically compatible salts, as well as their notorious chemical equivalents. 3874 H2, empirical formula: CJ9H8gN20lfl, PM 1113.3 3874 H3, empirical formula: CJ7Hg7NOI8, PM 1074.3 3874 H4, empirical formula: C58H84N.018, PM 1097.3 3874 H5, empirical formula: CjgHggNjOjj, PM 1111.3 3874 H6, empirical formula: C5-H8JNO | 8, PM 1072.3.

By the indicated structural or empirical formulas and the two cis double bonds in the position? 28/29 as well? 30/31, which are the same in all the compounds according to the invention, the antibiotics 3874 Hl to H6 differ from substances known from the literature. The compounds according to the invention have characteristic ultraviolet spectra. Furthermore, the methods for the preparation of the mentioned compounds belong to the object of the present invention. A process for the preparation of the mentioned compounds is characterized in that the microorganism Streptomyces species HAG 3874 (DSM 11007) is cultured in an aqueous nutrient medium and then the target compounds are isolated and purified. The mentioned microorganism was deposited on June 21, 1996 under the conditions of the Budapest Treaty in the German Collection of Microorganisms and Cultures, Cellular, Mascheroder Weg Ib, D-38124 Braunschweig, under the number DSM 11007. Streptomyces spec. DSM 11007 has a white aerial mycelium and gray spore chains. It forms the spore chains characteristic of Est reptomycetes. In a nutrient solution containing a carbon source and a nitrogen source, as well as the usual inorganic salts, Strep-tomyces spec. DSM 11007 produces compound 3874 Hl to H6. Instead of strain DSM 11007, its mutants and variants can also be used, provided that they synthesize the compounds according to the invention. Such mutants can be created in a manner known per se by physical means, for example irradiation, such as with ultraviolet or X-rays, or by chemical mutagens, such as, for example, ethylmethyl- sulfonate (EMS); 2-hydroxy-4-methoxy-benzophenone (MOB) or N-me-t i 1-N '-ni tro-N-ni trosoguanidine (MNNG). The screening of mutants and variants that produce the antibiotics according to the invention can be carried out by determining the biological activity of the active substances accumulated in the culture broth, for example by testing the antimycotics activity, according to the procedure described below. Carbon hydrates and sugar-assimilable alcohols are suitable as the preferred carbon source for aerobic fermentation, such as glucose, lactose or D-mannitol, as well as natural products with carbohydrate content, such as for example malt extract. Suitable nutritional substances with nitrogen content are: amino acids, peptides and proteins, as well as their degradation products, such as peptones or tryptons, as well as meat extracts, ground seeds, for example maize, wheat, beans, soybeans or the cotton plant, residues from the distillation of the preparation of alcohols, meat meals or yeast extracts, but also salts of ammonium and nitrates. In inorganic salts, the nutrient solution may contain, for example, chlorides, carbonates, sulfates or phosphates of the alkaline metals or inothermal lime, iron, zinc, cobalt and manganese. The formation of heptanes 3874 Hl to H6 runs particularly well, for example, in a nutrient solution containing approximately 0.5 to 5% glucose, preferably 1 to 2%, 0.5 to 5% soybean meal , preferably 1 to 2%, corn laceration liquid, preferably 0.2 to 1%, 0.05 to 1.0% CaCOj, preferably 0.1 to 0.5% and 0.1 to 2 % NaCl, preferably 0.2 to 1%, in each case based on the weight of the total nutrient solution. The culture is carried out under aerobic conditions, that is to say, for example, immersed under shaking or stirring in shaker flasks or fermentors, possibly under the introduction of air or oxygen. Fermentation can carried out, for example, in inclined body bottles or round flasks of different volumes, in glass fermenters or VjA steel tanks. It can be carried out in a temperature range of about 20 to 35OC, preferably at about 25 to 30QC. The pH value should be between 4 and 10, advantageously between 5.5 and 8.5. The microorganism is grown under these conditions, generally over a period of time of 20 to 300 hours, preferably 24 to 140 hours. Advantageously, the cultivation is carried out in several stages, that is, first one or several previous cultures are prepared in a liquid nutrient medium which is then superinoculated in the production medium itself, the main culture, for example in a volume ratio. : 10 The prior cultivation is obtained, for example, by superimposing an expected mycelium in a nutrient solution and allowing it to develop for approximately 20 to 120 hours, preferably 24 to 72 hours. The spore mycelium can be obtained, for example, by developing the strain for about 1 to 40 days, preferably 3 to 10 days, in a solid or liquid nutrient medium, for example yeast-bad agar or potato-dext pink agar. The course of the fermentation and the formation of the antibiotics 3874 Hl to H6 can be monitored by methods known to a person skilled in the art, such as, for example, by assaying the biological activity in bioassays or by chromatographic methods, such as thin layer chromatography (CCD) or high resolution liquid chromatography (HPLC). It is a peculiarity of the strain HAG 3874 (DSM 11007) that along with the heptaenes is able to form, in addition, the antibiotics Carbazo icina B and Pimprinina known by the bibliography. Antibiotics 3874 Hl to H6 can occur both in the mycelium and in the culture filtrate, usually the main amount is found in the cell mass (mycelium). Therefore, it is convenient to separate This is filtered by filtration or centrifugation. The filtrate is extracted with a water immiscible solvent, such as for example 1-butanol, ethyl acetate, chloroform or the like. The mycelium is conveniently extracted with methanol or acetone, but the aforementioned water immiscible solvents can also be used. The extractions can be carried out over a wide range of pH's, but it is convenient to work in a neutral medium, preferably between pH 5 and pH 9. The organic extracts can be concentrated, for example, under vacuum, and dried. A method of isolating heptanes 3874 Hl to H6 is the distribution of the solution in a manner known per se.

Another purification method is chromatography on adsorption resins, such as for example in Diaion® HP-20 (Mitsubishi Casei Corp., Tokyo), in Amberlite® XAD 7 (Rohm and Haas, USA), in Amberchrom® CG (Toso Haas, Philadelphia, USA) or similar. The separations can be carried out over a wide range of pH's. The range of pH 1 to pH 13 is preferred; especially preferred is the pH 2 to pH 12 range. In addition, numerous reverse phase supports, for example RP | 8, as generally disclosed in the liquid chromatography at high pressure (HPLC) are suitable. ). Another possibility of purification for the antibiotics according to the invention is the use, in a manner known per se, of so-called normal phase chromatography supports, such as for example silica gel or Al, O, or others. For this, many solutions and their mixtures are suitable, such as, for example, mixtures of chloroform / methane 1, to which basic solvents have been added, such as, for example, pyridine. An alternative isolation method is the use, in a manner known per se, of molecular sieves, such as, for example, Fractogel® TSK HW-40, Sephadex® LH-20 and others. In addition to this, it is also possible to obtain heptaenes by crystallization from enriched material. For this purpose, for example, organic solvents and their mixtures, anhydrous or with the addition of water, are suitable. A further process for the isolation and purification of the antibiotics according to the invention consists in the use of anion exchangers, preferably in the pH range of 7 to 10, and of cation exchangers, preferably in the pH range of 3 to 7. The use of buffer solutions to which portions of organic solvents have been added is particularly suitable for this purpose. Antibiotics 3874 Hl to H6 or derivatized chemical derivatives can be converted into the corresponding pharmacologically compatible salts according to methods known to those skilled in the art. Obvious chemical equivalents of the compounds according to the invention are compounds which have a slight chemical difference, ie they have the same activity or are transformed, under mild conditions, into the compounds according to the invention. To said equivalents belong, for example, esters, amino derivatives, complexes or adducts of or with the compounds according to the invention. The pharmacologically compatible salts of the compounds according to the invention are understood to mean both inorganic and organic salts, as described in Remington's Pharmaceutical Sciences (17th edition, page 1418 (1985)). Suitable salts include, in particular, alkali metal, ammonium, alkaline earth metal salts, salts with physiologically acceptable amines and salts with inorganic or organic acids, such as, for example, HCl, HBr, H SO, maleic acid, fumaric The physicochemical as well as spectroscopic properties of the antibiotics according to the invention can be summarized as follows: 3874 Hl Appearance: green-yellow substance, soluble in methanol, acetonitrile and chloroform. Stable in neutral and soft alkaline medium, but unstable in acid and strongly alkaline solution, as well as under the action of light, heat and oxygen.

Empirical formula: C58 * 86N2 ° 18 Molecular weight: 1099.3? -RMN: see Table 1 UV maximums (log €): 232 nm (4.49), 286 nm (4.32), 338 nm (4 , 64), 357 nm (4.86), 377 nm (5.00), 398 nm (4.98). 3874 H2 Appearance: green-yellow substance, soluble in methanol, acetonitrile and chloroform. Stable in neutral and soft alkaline medium, but unstable in acid and strongly alkaline solution, as well as under the action of light, heat and oxygen.

Empirical formula: C5H88N2 ° 18 Molecular weight: 1113.3 UV maxima (lag e): 232 nm (4.49), 286 nm (4.32), 338 nm (4.64), 357 nm (4.86), 377 nm (5.00), 398 nm (4.98). 3874 H3 Appearance: green-yellow substance, soluble in methanol and other lower alcohols, acetonitrile and chloroform. Stable in neutral and soft alkaline medium, but unstable in acid and strongly alkaline solution, as well as under the action of light, heat and oxygen.

Empirical formula: Cj7H8-NO [. Molecular weight: 1074.3 ? -RMN: see Table 1 UV Maxima (log e): 233 nm (4.39), 241 nm (4.39), 249 nm (4.28), 275 nm (4.41), 341 nm (4.54), 358 nm (4.82), 378 nm (5.00), 399 nm (4.94). 3874 H4 Appearance: green-yellow substance, soluble in methanol, acetonitrile and chloroform. Stable in neutral and soft alkaline medium, but unstable in acid and strongly alkaline solution, as well as under the action of light, heat and oxygen.

Empirical formula: C58H84N2 ° 18 Molecular weight: 1097.3 UV maximums (log e): 232 nm (4.49), 286 nm (4.32), 338 nm (4.64), 357 nm (4.86) ), 377 nm (5.00), 398 nm (4.98). 3874 H5 Appearance: green-yellow substance, soluble in methanol, acetonitrile and chloroform. Stable in neutral and soft alkaline medium, but unstable in acid and strongly alkaline solution, as well as under the action of light, heat and oxygen.

Empirical formula: C59H86N2 ° 18 Molecular weight: 1111.3 UV maximums (log e): 232 nm (4.49), 286 nm (4.32), 338 nm (4.64), 357 nm (4.86) ), 377 nm (5.00), 398 nm (4.98). 3874 H6 Appearance: green-yellow substance, soluble in methanol and other lower alcohols, acetonitrile and chloroform. Stable in the middle Neutral and mildly alkaline, but unstable in acid and strongly alkaline solution, as well as under the action of light, heat and oxygen.

Empirical formula: C57H85NOn Molecular weight: 1072, 3? -RMN: see Table 1 UV maxima (log e): 233 nm (4.39), 241 nm (4.39), 249 nm (4.28), 275 nm (4.41), 233 nm (4.39), 341 nm (4.54), 358 nm (4.82), 378 nm (5.00), 399 nm (4.94).

Due to the good solubility, the antibiotics according to the invention advantageously differ from Amphotericin B, which is only difficult to dissolve in the aforementioned solvents, as well as in others, and with this, offers great problems in the application.

Table 1: The chemical shifts in the H-NMR spectra of 3874 H3 and 3874 Hl, collected in deuteromethanol at 17QC ' Position in the Atoe »of C Position in 3874 H3 3874 H1 < »» Atoßo de c 3874 H3 3874 H1 Furthermore, it was found that the compounds according to the invention have extraordinarily strong fungicidal effects, that is to say exterminators of fungi, and, furthermore, the activity extends to a broad spectrum of fungal and yeast genera. Table 2 summarizes by way of example the minimum inhibitory concentrations of 3874 Hl and 3874 H3.

Table 2: In vitro activity against dermatophytes, yeasts and molds (Microdi fi cation test in RPMI 1640 medium) Minimum inhibitor concentration, CHM Uig nl) CEPA 3874 H1 3874 H3 Of i-mato fi cs T. mentagrophytes 100/25 4 8 T. rubrum 101/58 16 16 E. floccosum 190/143 16 16 Yeasts C. albicans ATCC 90028 2 4 C. albicans ATCC 90029 2 4 C. glabrata ATCC 90030 4 4 C. glabrata Berlin 12 2 4 C. kruseí 203/230 4 4 C. kruseí Berlin 1 2 2 C. tropicalis 201/201 2 4 C. tropicalis 201/202 2 4 C. pseudotropicalis 202218 2 4 C. parapsilosis ATCC 90018 4 4 C. neoformans ATCC90112 2 2 Molds A. mger ATCC 16404 2 8 A. fumigatus ATCC 9197 4 4 A. flavus ATCC 9643 8 16 Incubation: 48 h 35 QC (yeasts) 6 days at 30 ° C (dermatophytes and molds) The superiority of the antibiotics according to the invention manifests itself in particular in the so-called diffusion tests, in which the compounds are diffused into an agar layer containing the test germs. The diameter of the inhibitory zones is then a measure of the activity of the antibiotics (Table 3).

Table 3 Inhibitory zones dependent on the concentration in mm, which are caused by the 3874 Hl and H3 antibiotics in comparison with Amphotericin B Concentration in mg / ml 3874 Hl 3874 H3 Amphotericin B 0. 2 26 22 14 0. 1 25 20 12 0. 05 24 18 10 0. 025 21 14 8 0. 0125 19 13 0 0. 0063 17 12 0 The effects of the compounds according to the invention surpass those of the commercial product Amphotericin B, in part considerably, and, therefore, represent very valuable agents. The effect is apparently based on the ability of the new heptaenes to establish ergosterin in the form of a heptaeno / ergosterin complex. Ergosterin is an essential component of fungal plasma membranes. Through the formation of the complex, the ergosterin is modified in the membranes in such a way that the structure is destroyed of the plasma membrane and the fungus cell dies. The ergosterin as a component of the membrane corresponds, in the cells of animals homeotermos, cholesterol. Many heptanes known from the literature fix cholesterol as well as ergosterin and, therefore, are toxic compounds. Due to the stronger fixation, in particular of the antibiotics 3874 H3 and 3874 H6 to ergosterin in comparison with cholesterol, these compounds are especially suitable for combating fungal infections in man and animals. In addition to the antimicotic effect, the antibiotics according to the invention possess extraordinary inhibitory effects against protozoa., such as, for example, Trichohous species. However, by virtue of the cholesterol and sterol binding capacity, compounds 3874 Hl to H6 can also be used in medicine where too high concentrations of steroids are undesirable. Examples of this are the decrease in the level of cholesterol in general or, in particular, the treatment of benign prostatic hypertrophies. The present invention therefore also relates to the application of the compounds according to the invention as medicaments, as well as to the use of the corresponding compounds for the preparation of medicaments for the treatment and / or prophylaxis of fungal infections. , or for the treatment of diseases that are accompanied by an increased concentration of steroids. In addition, the present invention relates to medicaments with a content in at least one compound according to the invention. The medicaments according to the invention can be applied enterally (orally), parenterally (intravenously), rectally or locally (topically). They can be administered in the form of solutions, powders, tablets, capsules (including microcapsules), ointments (creams or gel), liposome preparations, Lipids, colloidal dispersions or suppositories. Suitable adjuvants for formulations of this type include liquid filler materials, or pharmaceutically customary solids and extender agents, solvents, emulsifiers, glidants, flavor correctors, dyes and / or buffer substances. As a convenient dosage, 0.1-10, preferably 0.2-8 mg / kg body weight are administered. These amounts are conveniently administered in dosage units containing at least the effective daily amount of the compounds according to the invention, for example 30-3000, preferably 50-1000 mg. The present invention will be explained in more detail by means of the following embodiment examples as well as by the content of the claims.

Example 1: Preparation of a suspension of spores of the producing strain. 100 ml of nutrient solution (20 g of malt extract, 2 g of yeast extract, 10 g of glucose, 0.5 g of (NH4) jHP04 in 1 1 of tap water, pH value before sterilization: 6.0) in a 500 ml sterile Erlenmeyer flask are inoculated with the strain and incubated for 72 hours at 25 ° C and 140 rpm on a rotary shaker. Next, 120 ml of culture liquid in a 500 ml sterile Erlenmeyer flask with the nutrient medium infused oatmeal, 2.0 g / 1, to which 15 g of agar / 1 was added for consolidation, they were evenly distributed and they opted for it. The cultures are incubated for 10 to 14 days at 25 ° C. The spores of a flask that result after this time are suspended with 500 ml of deionized water containing a drop of a commercially available nonionic surfactant (eg ®Triton X 100 , Firma Serva), immediately continue to be used or stored at -22QC in 50% glycerol or 10% dimethylsulphoxide.

Example 2: Preparation of a culture or a previous culture of the producing strain in Erlenmeyer flasks.

A sterile Erlenmeyer flask of 500 ml with 100 ml of the nutrient solution described in Example 1 is inoculated with a culture grown in an inclined tube or with 0.2 ml of spore suspension and incubated in a shaker in the dark. 140 rpm and 25 C. The maximum production of the compounds according to the invention has been reached after about 72 hours. For the inoculation of fermenters of 10 and 100 1 a submerged culture is sufficient for 72 hours (amount of inoculation, approximately 5%) based on the same nutrient solution.

Example 3: Preparation of antibiotics 3874 Hl-H6.

A 10 1 fermenter is operated under the following conditions: Nourishing medium: Glucose 15 g / 1 Soy flour 15 g / 1 Maceration liquid 5 g / 1 corn CaCOi 2 g / 1 NaCl 5 g / 1 pH 7.0 (before sterilization) Incubation time: 24 or 48 hours Incubation temperature: 25 C Stirring speed: 200 rpm, excluding light Aeration: 5 1 air / min.

By the repeated addition of a few drops of ethanolic polyol solution, foam formation can be suppressed. The maximum production is reached after 48 hours.

Example 4: Isolation of the antibiotics 3874 Hl to H6. 9 1 of the culture solution obtained according to Example 3 are separated by centrifugation and the cell mass (~ 1.1 1) is extracted twice with stirring, in each case with 2.2 1 of methanol. The combined extracts are concentrated in vacuo, dried and the dry mass is digested with diethyl ether. The degreased residue (41 g), thus washed, is dissolved in 25% iso-propanol / 75% water and incorporated in a 3 l capacity column, filled with the MCI Gel® CHP20P adsorption resin. Measures of the column: width x height: 11.3 cm x 30 cm. It is eluted with a solvent gradient of 25% isopropanol in water to 100% isopropanol, and the effluents from the column are collected in fractions of 2 1 each. The fractions containing heptanes, which were verified by HPLC analysis, collected and concentrated in vacuo as well as lyophilized (3.2 g).

Example 5: High pressure liquid chromatography (HPLC) of heptanes 3874 Hl to H6.

Column: Nucleosil® 100 - 5 C, 8AB, 250/4 Mobile phase: 37.5% acetonitrile in 10 mM potassium phosphate buffer, pH 7.0 Flow rate: 1 ml per minute Detection by UV absorption at 320 nm.

For the different components, the following retention times were found. Next to them are indicated the corresponding molecular weights (M + H) calculated by mass spectrometry by HPLC. For HPLC-MS, instead of phosphate buffer, 10.mM ammonium acetate is used.

Retention time Compound (M + H) 7.05 Min 3874 H1 1099.6 8.64 Min 3874 H4 10977 13.93 Min 3874 H2 1113f7 17.90 Min 3874 H5 1111 # 8 19.23 Min 3874 H3 10745 24.28 Min 3874 H6 1072.5 Example 6: Enrichment of the components of 3874 H. 2 g of the product obtained according to Example 4 are incorporated in a column of 3 liters capacity, filled with Fractogel® TSK MW-40 s (width x height = 10 cm x 50 cm). The eluent: methanol is pumped through the column at a flow rate of 50 ml per minute, and the eluent in the column is collected fractionally (65 ml). In fractions 28 to 35 is mainly the antibiotic 3874 H3 (after drying: 210 mg), in fractions 39 - 43: H6 (9 mg), in the fractions 50 - 60: 3874 Hl, as well as H2 (280 mg) and, finally, in fractions 71 to 78: compounds 3874 H4 and H5 (17 mg).

Example 7: Final purification of 3874 Hl, H2 and H3.

The enriched 3874 Hl and H2 (280 mg) and 3874 H3 (210 mg) antibiotics, obtained according to Example 6, are separated in each case on a Nucleosil® HPLC column 12C.oAB (width x height = 3.2 cm x 25 cm) in a gradient procedure with 25% to 50% acetonitrile in water. The fractions investigated by analytical HPLC (see Example 5) are combined in a corresponding manner, concentrated in vacuo and lyophilized. They provide 29 mg of 3874 Hl with a purity of 95%, 11 mg of 3874 H2 with a purity of 94%, 65 mg of 3874 H3 with a purity of 97%.

Example 8: Final purification by preparative HPLC in a phosphate / isopropanol buffer system.

Procedure as in Example 7, but 10 mM potassium phosphate buffer, pH 7, as well as isopropanol are used as the eluent. Desalination of the components mentioned as in Example 7. 38 mg of 3874 Hl with a purity of 97%, 21 mg of 3874 H2 with a purity of 96%, 83 mg of 3874 H3 with a purity of 98%.

Claims (10)

1. - Compounds 3874 Hl to H6 with the following empirical formulas 3874 Hl, empirical formula:, PM 1099.3 3874 H2, empirical formula: C59H8g 20lg, PM m3,3 3874 H3, empirical formula: C | 7H8-NO | 84 PM 1074.3 3874 H4, empirical formula: CjgH ^ NjOjj, PM 1097,3 3874 H5, empirical formula: C ^ HggNjOjg, P 1111.3 3874 H6, empirical formula: C ^ HgjNO ^, PM 1072.3, its physiologically compatible salts, as well as its notorious chemical equivalents.

2. Compounds according to claim 1, preparable by fermenting the microorganism DSM 11007 or one of its variants or tantes under suitable conditions, isolating one or more of the compounds H1 to H6 and, eventually, transforming them into their salts or chemical equivalents.

3. Process for the preparation of compounds according to claim 1, characterized in that the microorganism DSM 11007 or one of its variants or mutants is fermented under suitable conditions, one or more of the compounds H1 to H6 are isolated and, if necessary, transformed in its salts or chemical equivalents.

4. Process according to claim 3, character- because the fermentation is carried out under aerobic conditions at a temperature between 20 and 35 OC and at a pH between 4 and 10.

5. Compounds according to claims 1 or 2, for use as medicaments.

6. Use of compounds according to claims 1 or 2, for the preparation of drugs for the treatment of fungal diseases or diseases by Trichomonas.

7. Use of compounds according to claims 1 or 2, for the preparation of medicaments for the treatment of diseases that are accompanied by an increased concentration of steroids.

8. Medicaments with a content in at least one compound according to claims 1 or 2.

9. - Process for the preparation of medicaments according to claim 8, characterized in that at least one compound according to claims 1 or 2 is brought to a suitable administration form with suitable adjuvants and / or support substances. 10.- Streptomyces species DSM 11007. Summary of the Invention Compounds of the formulas 3874 Hl, empirical formula: CjgHgjNjOjg, PM 1099,3 3874 H2, empirical formula: CjjHggNjOjg, PM 1113.3 3 3874 H4, empirical formula: CjgHg ^ Ojg, PM 1097,3 3874 H5, empirical formula: CjjHggN-Ojg, PM 1111.3 3874 H6, empirical formula: Cj-HgjNOjg, PM 1072.3, they are suitable for the treatment of fungal diseases and for the treatment of conditions that are accompanied by an increased concentration of steroids.