DE2822326A1 - ANTIMYCOTIC AGENTS - Google Patents

Description

Antifungal agents

The invention relates to a new antifungal agent which contains a compound of the formula (1) in which R1 and R2 are a hydrogen atom, a methyl or ethyl group and X is an oxygen or sulfur atom, a carbonyl group, the methylene radical -CH2-, in which a hydrogen atom is optionally substituted by methyl or ethyl, or the radical mean, or one of their physiologically acceptable acid addition salts, in addition to conventional carriers and diluents as active ingredient, the preparation of this agent and the use of the compounds of formula (1) for combating fungal infections in humans and animals.

The compounds of the formula (1) and to be used according to the invention their salts have a high chemotherapeutic, especially antifungal, activity on. These properties make it possible to use them as new valuable drugs. It should be noted that the compounds of formula (1) in the patent applications P 26 56 747.5, P 27 27 482.4 and P 27 53 278.1 already as fungicides for control of plant diseases have been suggested. Your beneficial and opposite commercially available agents sometimes have a superior effect on fungi which are pathogenic to humans However, it is surprising and was by no means foreseeable.

The compounds of the formula (1) are prepared in a conventional manner, for example by reacting 3-p-tert-butyl-phenyl-2-methyl-propanal in the presence of a reducing agent, for example formic acid, at temperatures from 50 ° C. to 110 ° C. with a Amine of formula (2) in which R1, R2 and X have the meanings given above.

For salt formation with a physiologically compatible one that is customary per se Acids come organic or inorganic acids, such as nitric acid, hydrochloric acid, Sulfuric acid, phosphoric acid, acetic acid, propionic acid, lactic acid, succinic acid, Tartaric acid, citric acid, benzene acid, salicylic acid or nicotinic acid can be considered. However, the inorganic acids mentioned, in particular hydrochloric acid, are preferred.

The preparation of N-substituted 3,5-dimethylpiperidin-4-ones, compounds of the formula 1, in which X is a carbonyl group, to be used according to the invention is expediently carried out by reacting the primary amine (3) with 2,4-dimethylpenta-1, 4-diene-4-one (4): The primary amine required can be prepared from the corresponding aldehyde by reductive amination (Houben-Weyl "Methods of Organic Chemistry", Volume 11/1, pages 602 ff). The 2-methyl-3- (p-tert-butylphenyl) propylamine can be prepared, for example, according to the following procedure.

800 parts (parts by weight) of 2-methyl-3- (p-tert-butylphenyl) propanal are dissolved in 800 parts of methanol and together with 150 parts of Raney nickel in filled a 3 l hydrogenation autoclave. 540 parts of ammonia are injected, then the reaction mixture is heated to 90 ° C .; At 900C it becomes hydrogen for as long pressed on until an overall pressure of 100 bar is reached. With this constant Pressure is hydrogenated for 30 hours.

The reaction product is then filtered and the filtrate is distilled worked up. This gives 750 parts (5 93% of theory) of 2-methyl-3- (p-tert-butylphenyl) propylamine, Bp 0.01: 97 C.

The synthesis of 2,4-dimethylpenta-1,4-dien-3-one can be from diisopropyl ketone by bromination and elimination of hydrogen bromide (0. Sorokin, I zv. Akad, Nauk SSSR 1961, 460 --466) or according to Houben-Weyl "Methods of Organic Chemistry Volume 7/2 a, page 743 and S. F. Reed, J. Org. Chem. 27, page 4 114 (1962).

The compounds of the formula (1) can, insofar as they are dimethyl or diethyl derivatives, for example such as the 2,6-dimethylpiperidine compound, exist as cis-trans isomers and according to the production with a uniform Amine of formula (2) or by physical methods such as fractional distillation or fractional crystallization, from the cis-trans mixture formed during manufacture produced as pure cis and trans isomers or at least in enriched form werden4 It is also pointed out that the connections the Formula (1) have a center of chirality and therefore with the help of the usual racemate separation agents can be split into the optically active antipodes.

The compounds of the formula (1) and to be used according to the invention their salts have strong antifungal effects. You own a broad one Antifungal spectrum of activity, especially against dermatophytes, e.g. Epidermophyton species, such as Epidermophyton floccosum, Trichophyton species, such as Trichophyton mentagrophytes, Microsporon species, such as Microsporon ferrugineum.

The listing of these microorganisms is not intended to be a limitation of the represent microorganisms to be controlled, but serve only for explanation.

The effect against microorganisms can be based on methods like them for example in P. Klein, Bacteriological Basics of chemotherapeutis chen Laboratoriumspraxis, Springer-Verlag Berlin, 1957, are shown will.

For example, it was checked what minimum inhibitory concentrations (MIC values) can be achieved in the agar dilution test against pathogenic fungi.

The results are summarized in Tables 1 and 2 below: Table 1 Minimum inhibitory concentration (MIC) in μg / ml nutrient medium (Brain Heart Infusion Agar), agar dilution test Compound dermatophytes according to the example Epidermophyton Microsporum Microsporum Trichophyton Trichophyton No. floccosum audouinii ferrrugineum mentagrophytes schoenleinii 3 1.6 1.6 0.8 0.8 1.6 7 1.6 1.6 1.6 6.4 0.8 8 3.2 <0.1 0.8 3.2 0.8 9 0.8 0.4 0.2 0.8 0.8 10 0.4 0.2 0.4 0.8 0.4 12 3.2 0.4 0.4 1.6 0.4 13 0.2 <0.1 <0.1 0.2 <0.1 14 0.8 0.4 0.4 0.4 0.4 15 0.4 0.2 0.4 3.2 0.4 17 0.4 0.4 0.4 0.8 0.4 19 3.2 0.2 0.2 3.2 0.8 20 1.6 <0.1 0.64 1.6 0.8 21 3.2 <0.1 0.8 1.6 0.8 22 1.6 0.2 0.4 0.8 0.4 Comparative substances A 0.32 0.02 0.16 0.32 0.04 B 0.32-0.16 1.28 0.64 C> 1.28 ->1.28>1.28> 1.28 Table 2 Acute toxicity values after oral administration to the mouse Connection according to LD50 (mouse) Example No. (mg / kg) 3> 2150 7? 464 <1000 8> 1000 <2150 10) 464 α2150 13> 1000 <2150 15> 2150 17> 2150 19> 2150 20> 2150 21> 2150 22> 1000 <2150 The following known compounds were used as comparison substances: A = tolnaftate (2-naphthyl-N-methyl-N- (3-tolyl) thiocarbamate) B = clotrimazole (bisphenyl- (2-chlorophenyl-1-imidazolyl) methane) C = Miconazole (1-C214-DichloFB- (2,4-dichloroboxyloxy) -phenylethyl2-imidazole nitrate).

Table 1 shows the very good effectiveness of various compounds against dermatophytes in vitro. Particularly noteworthy is the connection according to the example 13, which is characterized by outstanding effectiveness. It is essential because of it smaller MIC values are more effective than the known imidazole derivatives clotrimazole (B) and miconazole (C). Even tolnaftate (A), one of the most effective compounds of the Prior art, in comparison, the compound of Example 13 only cuts about equally well, and in the case of two dermatophytes, the compound Example 13 is even more effective than tolnaftate, namely Epidermophyton floccosum and Trichophyton mentagrophytes.

The LD50 values given in Table 2 do not leave any disadvantages either recognize the compounds to be used according to the invention.

Accordingly, the areas of indication for humans and animals are in Consideration: dermatomycoses, dermatophytoses and systemic mycoses, especially caused by species of the genera Epidermophyton, Microsporum and Trichophyton.

The compounds can be known alone or together with others Active ingredients, especially antibiotics, are used.

The present invention also includes the manufacture of chemotherapeutic ones Agents or preparations made with conventional carriers or diluents and those commonly used pharmaceutical-technical excipients according to the desired type of application with a suitable one for the application Dosing takes place in the usual way, in particular by mixing.

These agents according to the invention are used in particular internally and external use. They are preferably oral or topical, but can can also be administered perenterally or in the form of suppositories.

Usually it has been used in both human and veterinary medicine Proven to be advantageous, the active ingredient (s) in amounts of about 30 to about 200, preferably 50 to 200 mg / kg of body weight per 24 hours, optionally in To be administered in the form of several single doses to achieve the desired results. However, it is also possible to deviate from the stated dosages, namely in Dependence on the type and severity of the disease, the type of preparation and the application of the drug. The determination of the required optimal dosage and type of application of the active ingredient can be determined by the person skilled in the art Easily done because of his expertise.

As a rule, the single doses are administered 1 to 2 times a day. When used externally, locally, the preparations contain 0.5 to 5, preferably 1 to 2 Ges. » Active ingredient.

Preparations for oral administration are, for example, tablets, Film-coated tablets, coated tablets, capsules, pills, powders or suspensions.

Corresponding tablets can, for example, by mixing the active ingredient with known auxiliaries, for example inert diluents such as dextrose, Sugar sorbitol, mannitol, polyvinylpyrrolidone, Calcium carbonate, calcium phosphate or lactose, disintegrants such as corn, starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and / or Means to achieve the depot effect, such as carboxypolymethylene, carboxymethyl cellulose, Cellulose acetate phthalate or polyvinyl acetate can be obtained. The tablets can also consist of several layers.

Correspondingly, coated tablets can be coated analogously to the tablets manufactured cores with agents commonly used in dragee coatings, for example Kollidon or shellac, gum arabic, talc, titanium dioxide or sugar will. The coated tablet shell can also consist of several layers, with the Auxiliary substances mentioned above for the tables can be used.

Suspensions with the active ingredients to be used according to the invention can in addition, taste-enhancing agents such as saccharin, cyclamate or sugar as well e.g. contain flavorings such as vanillin or orange extract. You can also Suspending aids, such as sodium carboxymethyl cellulose, or protective substances, such as p-hydroxybenzoates. Capsules containing active ingredients can, for example can be made by mixing the active ingredient with an inert carrier, such as lactose or sorbitol, mixed and encapsulated in gelatin capsules.

For external use, pastes, ointments, gels, Creams, lotions, powders, solutions or emulsions and sprays into consideration.

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, starches, 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, ble, in particular Cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil1, 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), 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.

Preparation of compounds of formula (1) Example 1 Synthesis of N (3-p-tert-butyl-phenyl-2-methyl-1-propyl) -cis-2> 6 - dimethylmorpholine 2,6-dimethylmorpholine, obtained by the cyclization of di-isopropanolamine catalyzed with sulfuric acid is made by fractional distillation over a stainless steel wire mesh spiral filled distillation column in the cis and trans form separated. About 75% (by weight) of the 2,6-dimethylmorpholine are in the cis form, the rest in trans form. The isomers can be separated by fractional distillation on a column with about 40 separation stages. The cis form is a 99% product at 800C to 810C under a pressure of 100 torr above.

The trans form of 2,6-dimethylmorpholine may be among the same Conditions in the transition temperature range at 88 to 890/100 Torr than above 95 S iges Product can be obtained.

In a stirred apparatus equipped with a reflux condenser> thermometer and Is equipped dropping funnel, 575 g of 98% formic acid are presented. Under 345 g of 99% 2,6-cis-dimethylmorpholine are then added dropwise, stirring and cooling. The mixture is then slowly heated to 70 ° C in a water bath. In the course of 4 hours are added to the reaction mixture when a temperature of about 1000 ° C. is maintained 612 g of 3-p-tert-butyl-phenyl-2-methyl-propanal were added dropwise. Under strong CO 2 development condensation takes place. After the reaction has ended, the mixture will still be Maintained at 1000C for 2 hours with stirring.

The excess formic acid is then removed under reduced pressure distilled off. The formic acid is largely separated off in a vacuum Water jet pump at 1000C.

The base is released from the formate by adding dropwise 500 g of 40% strength aqueous sodium hydroxide solution. The addition of the sodium hydroxide solution is expedient at 800C to 1000C to allow the amine phase to be mixed with the lye phase to favor. To lower the viscosity, 200 g of toluene are added. After the lye phase has been separated off, the organic phase is washed twice with 250 g of water each time washed.

For further purification, the amine is passed through a distillation column at 0.2 torr fractionally distilled with 5 floors. In addition to a small advance (up to 1430C / 0.2 Torr; 50 g) becomes 865 g N (3-tert -Butylphenyl-2-methyl-1-propyl) -2,6-cis -dimethylmorpholine obtain. These go over at 0.2 Torr between 1430 and 1460.

According to gas chromatographic analysis, the amine has a content of more than 98 g of pure substance. Based on the aldehyde, a yield of 84.5% received.

Example 2 For conversion into the hydrochloride, 30 g of N (3-tert-butylphenyl-2-methyl-1-propyl) -2, 6-cis-dimethylmorpholine in 50 g of ethanol, which at room temperature with hydrogen chloride was saturated, dissolved. After cooling, 23 g of the melting at 220 ° C are N (3-tert-butylphenyl-2-methyl-1-propyl) -2,6-cis -dimethylmorpholine hydrochloride received in very pure form.

Example 3 Synthesis of N (3-p-tert-butylphenyl-2-methyl-1-propyl) -2,6-trans -dimethylmorpholine 29 g of 2,6-trans-dimethylmorpholine are added to 70 g of 98% formic acid with cooling entered with ice. 41 g of 3-p-tert-butylphenyl-2-methylpropanal are then added with stirring admitted. The reaction mixture is heated to 100 ° C. for 6 hours. At the beginning of Implementation shows a very strong CO 2 development, which is noticeable after about 1 hour subsides. The further work-up takes place as explained in more detail under Example 1 became.

At 5 torr the N (3-p-tert-butylphenyl-2-methyl-1-propyl) -2,6-trans-dimethylmorpholine goes at 1680 to 1690 about. Yield 52 g = 86 Z based on the aldehyde. 11 g of the amine are dissolved in 20 g of ethyl acetate which has been saturated with dry hydrogen chloride. On cooling, the hydrochloride criticizes out.

M.p. 1650C.

The following compounds are obtained in a corresponding manner: Bp: 1700C / 5.0 torr. Mp: 2060C Heated at reflux for 12 hours. The excess formic acid is then distilled off under reduced pressure. The base is released by adding 100 g of 25% strength potassium hydroxide solution and separated from the aqueous phase by adding 50 g of toluene.

The amine is purified by distilling the toluene solution at 0.2 torr. In addition to a pre-run of 9 g, which is up to a transition temperature of 1380 passes at 0.2 torr, the bulk of the amine distills between 138 and 1400 at 0.2 torr. 41 g are obtained. A lag of 4 g goes up to a temperature of 1470C / 0.2 torr above. According to gas chromatographic analysis consists the main amount of pure (98%) N- [3 '- (- p-tert-butylphenyl) -2'-methyl-propyl-1'] - 4-ethylpiperidine.

C21H35N C H N calc. 83.7% 11.7% 4.6% found 87.8% 11.5% 4.8% example 8 20 g of N- [3 '- (p-tert-butylphenyl) -2'-methy-propyl-i'] - 4-ethylpiperidine are with 20 g of ethyl acetate mixed together. By adding 40 g in the cold with hydrogen chloride The hydrochloride of the amine is formed with saturated ethyl acetate. After rubbing with The salt crystallizes out from a glass of dust. It is made by suction through a glass frit and washing obtained pure with a small amount of ice-cold ethyl acetate. To Allow 12 hours of drying at room temperature under a pressure of about 20 torr 20 g of salt (hydrochloride) were obtained. Mp = 224 ° C.

C21H36NCl CHN Cl calc. 74.6% 10.7% 4.1% 10.5% found. 74.8% 10.8% 4.4% 10.1% The following compounds are prepared analogously to Example 7 or 8: Mp: 1980C bp: 170-172 ° / 3.0 torr. Mp: 1760C bp: 124-130 ° / 0.3 torr bp: 130135O / 0.3 torr Mp: 2100C bp: 150-153 ° / 0.3 torr. Mp. 2080C, mp: 1850C, bp: 1400 / 0.1 torr bp: 187 ° C / 0.3 torr Mp: 210 ° Bp. 200 ° C / 5.0 Torr Mp: 1400C Examples of pharmaceutical preparations: 1. Example for tablets 1. Active ingredient 200 mg 2. Polyvinylpyrrolidone (avg. Average MW 4,000) 14 mg 4. Hydroxypropylmethylcellulose 40 mg 5. Talc 4 mg 6. Magnesium stearate 2 mg 280 mg The active ingredient is moistened with polyvinylpyrrolidone in 10% aqueous solution and driven through a sieve with a mesh size of 1.0 mm and dried at 500C. These granules are mixed with polyethylene glycol (average MW 4,000), hydroxypropylmethylcellulose, talc and magnesium stearate and compressed into tablets of 280 mg each.

2. Example of coated tablets 1. Active ingredient 150 mg 2. Lactose 60 mg 3. Corn starch 30 mg 4. Polyvinylpyrrolidone 4 mg 5. Magnesium stearate 1 mg 245 mg The mixture of Active substance with lactose and corn starch is mixed with an 8% aqueous solution of the polyvinylpyrrolidone granulated through a 1.5 mm sieve, dried at 50 ° C. and again rubbed through sieve 1.0 mm. The granules obtained in this way are made with magnesium stearate mixed and pressed into tablet cores. The tablet cores obtained are in usual Covered with a shell, which essentially consists of sugar and talc.

3. Example of a cream with 2% active ingredient 1. Active ingredient 2.0 g 2. Glycerol monostearate 10.0 g 3. Cetyl alcohol 5.0 g 4. Polyethylene glycol 400 stearate 10.0 g 5. Polyethylene glycol sorbitan monostearate 10.0 g 6. Propylene glycol 6.0 g 7. methyl p-hydroxybenzoate 0.2 g 8. Demineralized Water ad 100.0 g The finely powdered active ingredient is suspended in propylglycol and the suspension in the melt of glycerol monostearate, cetyl alcohol, heated to 65 ° C, Polyethylene glycol - 400 stearate and polyethylene glycol sorbitan monostearate stirred. The hot solution of p-hydroxybenzoic acid methyl ester is poured into this mixture emulsified in water. After cooling, the cream is homogenized using a colloid mill and filled into tubes.

4. Example of powder with 2 S active ingredient 1. Active ingredient 2.0 g 2. Zinc oxide 10.0 g 3. Magnesium oxide 10.0 g 4. Fumed silica 2.5 g 5. Magnesium stearate 1.0 g 6. Talc 75.5 g The active ingredient is micronized on an air jet mill and mixed homogeneously with the other ingredients.

The mixture is passed through a No. 7 sieve and placed in a polyethylene container filled with litter insert.

Claims (1)

Patent claim Antifungal agent, characterized by a content of a compound of the formula (1) in which R¹ and R2 are a hydrogen atom, a methyl or ethyl group and X is an oxygen or sulfur atom, a carbonyl group, the methylene radical -CH2-, in which a hydrogen atom is optionally substituted by methyl or ethyl, or the radical mean, or its physiologically acceptable acid addition salt as an active ingredient in addition to customary carriers and diluents.