DE2848221A1 - Antimycotic 1, 2, 3-di:thiazole derivs. - prepd. by reacting 4, 5-di:chloro-1, 2, 3-dithiazolidinium chloride derivs. with proton active substances - Google Patents

Abstract

derivs. of formula (I) (where X is O, S or = NR; R is 1-4C alkyl or Ph, opt. substd. by NO2 halogen lower alkoxy or CF3). are new. (I) are pharmaceuticals, esp. antimycotics. (I) and their HCl adducts have strong antimycotic properties with simultaneous sporicidal effects not found in commercially available prods. such as griseofulvin and mystalin. (I) are pharmaceuticals, esp. antimycotics. (I) and their HCl adducts have strong antimycotic properties with simultaneous sporicidal effects not found in commercially available prods. such as griseofulvin and nystalin. (I) have a very broad antimycotic spectrum and are esp. effective against dermatophytes gemmiparous fungi and biphasic fungi e.g. against Candida, Epidermophyton, Aspergillus, Trichophyton, Microsporon and Penicillium.

Description

1,2,3-Dithiazole derivatives, process for their preparation

as well as their use as medicaments The present invention relates to new 1,2,3-dithiazole derivatives, a process for their preparation and their use as drugs, especially antifungal drugs.

It is already known that iniC-position by five-membered Hetrocyclene-substituted N-Ber.zylimidazole have a good antifungal effect (compare DT-OS 1 911 646). Their effect is, however, especially at low levels Use concentrations, not always entirely satisfactory.

It has now been found that the new 1,2,3-dithiazole derivatives of the formula in which X stands for oxygen, sulfur or the group = NR, where R is alkyl with 1-4 carbon atoms or phenyl, which can be substituted by nitro, halogen, lower alkoxy or CF3, and their hydrogen halide adducts have strong antifungal properties with simultaneous sporocidal properties Effectiveness aw iron.

It has also been found that 1,2,3-dithiazoide derivatives of the formula (I) are obtained when 4,5-dichloro-1,2,3-dithiazolidinium chloride of the formula with proton-active substances.

First of all, water is mentioned as a proton-active substance, i.e. the compound (II) is easily hydrolyzed to the compound (I, X = O). Better, however this reaction is carried out with molar amounts of formic acid, with CO and develop IICl. Another suitable proton-active substance is hydrogen sulfide, by which the compound (II) is converted into the compound (I, X = S). aside from that Aliphatic and aromatic amines can be used as proton-active substances, the may also be used in the form of their silyl derivatives.

The substituted 1,2,3-dithiazoe according to the invention and their non-toxic , Physiologically compatible salts have strong antifungal effects with simultaneous sporicidal effectiveness.

Surprisingly, the substituted 1,2,3-dithiazoles according to the invention show a better, therapeutically useful antifungal efficacy, especially against Dermatophytes, as the substituted heterocycles known from the prior art. In particular, the active compounds according to the invention show an additional sporocidal effect Effect that does not exist even with commercial products such as griseofulvin and nystatin is. The active ingredients according to the invention are therefore a valuable asset in pharmacy.

The course of the reaction can be represented by the following reaction scheme: The 4,5-dichloro-1,2,3-dithiazolidinium chloride of the formula (II) used as the starting material is not yet known. However, it can be prepared in good yield by reacting monochloroacetonitrile in CH2Cl2 with 4 mol of S2Cl2. The reaction of dichloroacetonitrile with a slight excess of S2Cl2 also gives II in good yield. When acetonitrile is reacted with 4 Alol S2Cl2, II is only in moderate yield, which, however, can be increased if 2 mol of chlorine are introduced into the reaction mixture at the beginning.

As a solvent or diluent for carrying out the inventive Halogenated hydrocarbons, e.g. dichloromethane, chloroform are particularly suitable for the reaction and carbon tetrachloride, also acetonitrile, tetrahydrofuran, toluene and Ether, the reaction time depending on the lubricant.

So it is at room temperature or when using ice cooling of acetonitrile and tetrahydrofuran 30 - 60 minutes, of dichloromethane 4 - 6 hours, from chloroform and toluene 8 hours and from ether 36 hours, with increasing polarity of the solvent, the reaction proceeds more quickly. The inventive reaction is used at temperatures between 00 and the boiling point of the solvent used, preferably carried out at room temperature. When implemented with amines if necessary cooled with ice.

The compounds according to the invention have antimicrobial, in particular strong antifungal effects af. They own a very broad antifungal Spectrum of effects, especially against dermatophytes and fungi as well as biphasic Fungi, e.g. against Candida species such as Candida albicans, Epidermophyton species such as Epidermophyton floccosum, Aspergillus species such as Aspergillus niger and Aspergillus fumigatus, Trichophyton species, such as Trichophyton mentagrophytes, Microsporon species, such as Microsporon felineum and Penicillium species such as Penicillium commune. The list These microorganisms do not in any way limit the number of germs that can be combated but is only of an explanatory nature.

As areas of indication in human medicine, for example are mentioned: Dermatomycoses and systemic mycoses caused by Trichophyton mentagrophytes and other Trichophyton species, microsporon species, Epidermophyton floccosum, sprouts and biphasic molds and molds are caused.

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

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.

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

Solutions and suspensions are preferred pharmaceutical preparations and emulsions, pastes, ointments called gels, creams, lotions, powders and sprays.

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

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 use the usual propellants, e.g. chlorofluorocarbons contain.

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 acetate, benzyl alcohol, 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.

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 of these Contain substances.

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 according to known Methods, e.g. by mixing of the active ingredient (s) with the carrier (s).

The present invention also includes the use of the invention Active ingredients and 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.

In general it has been used in both human and veterinary medicine as advantageously enviesenr the or the active ingredients 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 medicinal product and the period or interval within which the administration he follows. So in some cases it may be sufficient with less than the above named amount of active ingredient get along, while in other cases the above specified amount of active ingredient must be exceeded. The determination of the required optimal dosage and type of application of the active ingredients can be made by any specialist easily done due to his expertise.

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 10t germs / nl substrate carried out. The nutrient medium used was a) for dermatophytes and molds: Sabourand's milieu d'epreuve b) for yeasts: meat extract-dextrose-boullon.

The incubation temperature was 280C, the incubation time was 24 to 96 hours.

The compounds according to the invention showed significant results in these experiments smaller minimum inhibitory concentrations than the already known compounds.

Example B Antifungal in vivo activity (local) on the model of experimental guinea pig trichophytosis Experiment description: White guinea pigs of the Pirbright-white breed have a shaved, non-scarified back with of a microconidial and macroconidial suspension of Trichophyton mentagrophytes. Untreated animals develop within 12 days p.i. the typical picture a dermatophytosis with reddening, scaling and hair loss up to a total integument defect at the site of infection. The infected animals were - starting on the 3rd day pi. - Once a day with 1 own polyethylene glycol solutions of the invention Preparations treated locally.

On the 14th day p.i. the untreated control animals show the typical Picture of a dermatophytosis, while e.g.

4-chloro-5- (3'-trifluoromethylphenylimino) -1,2,3-dithiazole and 4-chloro-5-thiooxo-1,2,3-dithiazole had inhibited the infection from progressing.

Example C Sporocidal effect Experimental arrangement: There are spore suspensions produced in physiological saline solution containing approx. 106 microconidia per ml contained by Trichophyton mentagrophytes. After adding 10, 50 and 100JrXml of active ingredient these spore suspensions are incubated at 280C; after 24, 48, 96, 120 and 240 Hours samples are taken, diluted 1: 1C00 and then on malt extract agar plates spatulated homogeneously. After 3 days of incubation at 280C, the fungal colonies open These agar plates are counted as a measure of the number of germinable spores. The evaluation takes place in comparison to germ controls without active ingredient.

4-chloro-5- (2'-chlorophenylimino) -1,2,3-dithiazole and 4-chloro-5- (3'-trifluoromethylphenylimino) -1,2,3-dithiazole show a very good, sporocidal effect in concentrations of 10 (/ ml: after All spores used were killed for 24 hours of exposure.

Example 1 4,5-dichloro-1,2,3-dithiazolidinium chloride (II) monochloroacetonitrile (4Mol) and S2Cl2 (20Mol) are stirred in 1.51 CH2Cl2. Starts after approx. 45 minutes II to precipitate with evolution of HCl in yellow then greenish colored crystals The reaction has ended after about 16 hours. II is fritted with CH2Cl2 and CS2 washed and dried.

Yield: 704 g (85%) FP: above 13600 (with decomposition) Example 2 4-chloro-5-oxo-1,2,3-dithiazole (I, X = 0) 1.5 moles of II are mixed with 1.5 moles of formic acid stirred in 800 ml of CH2Cl2 at room temperature. Gas evolution ceases after about 24 hours completed. The solution is fritted from a sparingly soluble fraction, concentrated and distilled in an oil pump vacuum. The initially pure yellow solid substance begins to turn brown after a few hours. It is dissolved in CH2Cl2 over activated charcoal filtered and recrystallized from CH2Cl2 / petroleum ether. The product cleaned in this way is not subject to further decomposition.

Yield: 166 g (72%) FP: 390C Example 3 4-Chloro-5-thiooxo-1,2,3-dithiazole (I, X = S) One passes into a mixture of 59.1 g (0.25 mol) II and 600 ml CH2C12 while stirring at room temperature H2S.

After completion of the reaction, the solution of poorly soluble impurities fritted. The compound can be removed from CH2Cl2 / Recrystallize petroleum ether. Another cleaning is achieved by sublimation in an oil pump vacuum at room temperature. Yield: 25.4 g (62%) FP .: 78-79UC Dark red Crystals Example 4 General procedure for the preparation of 4-chloro-5-arylimino-1,2,3-dithiazole To a mixture of 0.5 mol (II) and 1.5 1 CH2Cl2 is added while stirring within one hour 1.5 moles of the aniline derivative. The mixture is then stirred for a further 8 hours and filtered off from the hydrochloride. The solution is diluted with HCl, then several times washed with water and dried over CaCl2. After concentration of the solvent the compounds can be recrystallized from dichloromethane / petroleum ether.

Dry hydrogen chloride is passed in to isolate the hydrochloride into the methylene chloride solution, wherein the hydrochloride precipitate. The precipitation can be completed by adding a little petroleum ether.

To recover the free bases from the hydrochlorides one can proceed as follows: R = p-bromophenyl or p-thoxyphenyl: The hydrochlorides are dissolved in aqueous acetone.

When more water is added, the HCl-free bases fall out of the Solution. They are filtered off and washed with water.

R = phenyl or m-trichlorophenylmethyl: the hydrochlorides are in Stirring dichloromethane and water. Here the free bases go into the organic, Hydrogen chloride into the aqueous phase.

This is almost neutralized with NaHCO3 solution.

Then it is washed with several portions of water, the organic Phase dried with CaCl2 and the methylene chloride is distilled off in vacuo.

This method gives: 4-chloro-5-phenylimino-1, 2, 3-dithiazole hydrochloride, yellow crystals, m.p. 1680C (add.) Yield: 74% 4-chloro-5- (2'-chlorophenylimino) -1,2,3-dithiazole, FP: 78-790C, yellow crystals Yield: 71%.

Hydrobromide: FP: N1480C (decomposition) 4-chloro-5- (3'-nitrophenylimino) -1,2,3-dithiazole, FP: 1220C Yield: 78%.

Hydrobromide: FP: 175 ° C.

4-chloro-5- (4'-nitrophenylimino) -1,2,3-dithiazole, ° FP: 160 - 161 C. Yield 76%.

4-chloro-5- (4i-methoxyphenylimino) -1,2,3-dithiazole, m.p .: 890C. yield 85% 4-chloro-5- (3'-trifluoromethylphenylimino) -1,2,3-dithiazole, dark brown liquid. Yield 96 ° s.

Hydrochloride, yellow crystals, m.p. 1480C. Yield 85%.

° Hydrobromide, yellow crystals, m.p. 176 C (dec.), Yield 86%.

4-chloro-5- (4'-bromophenylimino) -1,2,3-dithiazole, yellow crystals, F. 123 ° C. Yield 76 t.

Hydrochloride, yellow crystals, M.p. 1600C (dec.), Yield 82%.

4-chloro-5- (4'-ethoxyphenylimino) -1,2,3-dithiazole, yellow crystals, 111 ° C. Yield 79%.

Hydrochloride, yellow crystals, m.p. 1590C (dec.), Yield 84%.

Example 5 4-Chloro-5-methylimino-1,2,3-dithiazole (I, X = = N-CH3) To a mixture of 20.85 g (0.1 mol) (II) and 100 ml CH2C12 are added with stirring at room temperature 17.5 g (0.1 mol) of heptamethyldisilazane, dissolved in 50 ml of CH2Cl2, dripped. After the reaction, the mixture is stirred for two hours and then solvent is drawn off and trimethylchlorosilane formed in vacuo. The initially dark product becomes by repeated recrystallization from methylene chloride / petroleum ether cleaned.

Yield: 8 g (48%) ° FP. : 112 C light yellow crystals.

Example 6 To a suspension of 0.05 mol (II) in 200 ml CH2Cl2 0.05 mol of n-butyltrimethylsilylamine are added with stirring for 6 hours at room temperature, dissolved in 100 ml of dichloromethane, added dropwise. Then impurities are filtered off and the solvent concentrated. When petroleum ether is added, 4-chloro-5- (n-butylimino ) -1,2,3-dithiazole.

Colorless crystals, FP. 1600C (to)

Claims (3)

Claims 1,2,3-dithiazole derivatives of the formula in which X stands for oxygen, sulfur or the group = N - R, where R is alkyl with 1-4 carbon atoms or phenyl, which can be substituted by nitro, halogen, lower alkoxy or CF3. 2.) Process for the preparation of 1,2,3-dithiazole derivatives of the formula in which X stands for oxygen, sulfur or the group = NR, where R is alkyl with 1 - 4 carbon atoms or phenyl, which can be substituted by nitro, halogen, lower alkoxy or CF3, characterized in that 4,5- Dichloro-1, 2, 3-dithiazolidinium chloride of the formula with proton-active substances. 3.) Medicines, characterized by a content of at least one 1,2,3-dithiazole derivative according to Claim 1.