DE3126818A1 - N-[3-(4'-tert-butylcyclohexen-3'-yl)-2-methyl-1-propyl]cycloalkyla mines, processes for their preparation and antimycotic agents containing these compounds - Google Patents

Abstract

The invention relates to novel, useful N-[3-(4'-tert-butylcyclohexen-3-yl)-2-methyl-1-propyl]cycloalkylamines and their physiologically tolerated acid addition salts, to processes for their preparation and to antimycotic agents containing these compounds.

Description

N- [3- (4'-tert-butyl-cycohexen-3'-yl) methylpropyl-11-

-cycloalkylamines, process for their preparation and containing them Antifungal Agents The invention relates to. new valuable N- [3- (4'-tert-butyl-cycl6hexen-3-yl ) -2-methyl-propyl-l) -cycloalkylamines and their physiologically acceptable acid addition salts, Process for their preparation and antifungal agents containing them.

From DE-OS 27 52 135 it is known that 3- (4'-ter.-ButylK -cyclohexyl-1 ') -2-methyl-1- (3'-methyl-1'-piperidino) propane, 3- (4'-tert-butyl-cyclohexyl-1 ') -2-methyl-1- (3', 5'-dimethyl-11-piperidino) propane and 3- (4'-tert * -butyl-cycohexyl-1) -2-methyl-1- (21 6 '2', 6 ') - cis-dimethyl-morpholino) -pro pan and its salts for combating phytopathogenic fungi and also human pathogens Fungi and yeasts such as Candida albicans, Trichophyton mentagrophy tes and Histoplasma capsulatumJ can be used.

The compounds mentioned lie with regard to the two substituents on the cyclohexane ring in the 1,4-position as cis-trans isomer mixtures. In the DE-OS 29 21 221 it is described that in each case the pure trans compound compared to the cis compound has a much stronger effect.

It has now been found that compounds of the formula 1 in which N and X are members of a five-, six- or seven-membered heterocyclic ring, where X is an alkylene chain with four, five or six members, which optionally contains a heteroatom, such as oxygen, as a chain link, and the alkylene radicals thereof optionally one or are substituted several times by alkyl radicals with 1 to 4 carbon atoms and their physiologically acceptable acid addition salts have a valuable antifungal effect.

Alkylene radicals are, for example, tetramethylene, pentamethylene, hexamethylene, Alkyl radicals with -1 to 4 carbon atoms are, for example, methyl, ethyl, propyl, iso-butyl, sec-butyl, n-butyl, of which methyl and ethyl are preferred.

An alkylene radical containing a hetero atom is, for example, oxatetramethylene.

The compounds according to the invention are obtained in very good yields and in a simple manner by using the aldehyde of the formula II, in which R1 and R2 are different and represent hydrogen or a tert-butyl group, in the form of the mixture with regard to the position of the tert-butyl group in the presence of an amine of the formula III, in which N and X have the meanings given for formula I, are reacted with hydrogen in the presence of a hydrogenation catalyst, the amine mixture obtained is converted into a physiologically acceptable salt with regard to the position of the tert-butyl radical and the pure 4-tert-butyl compound isolated by crystallization of the salt.

The preparation of the compounds of the formula 1 can of course also start from the pure aldehyde of the compound of the formula IVβ and these react with an amine of the formula III, as indicated above, in the presence of a hydrogenation catalyst with hydrogen.

Compounds of the formula IV are obtained, for example, by separating a mixture of the compound of the formula II by distillation. The compounds of the formula II can be obtained, for example, in the following way: Surprisingly, in the further reaction with amines of the formula III in the presence of a hydrogenation catalyst with hydrogen to give the compounds of claim 1, the double bond in the cyclohexene ring remains completely intact at the point indicated, while the double bond in the side chain is hydrogenated.

Suitable amines of the formula III are e.g. pyrrolidine, morpholine, thiomorpholine, 2,6-dimethylmorpholine (cis / trans mixture), cis-2,6-dimethylmorpholine, 2,5-dimethylmorpholine, 3,5-dimethylpiperidine, 3-methylpiperidine, 3,4-dimethylpiperidine, 3-ethyl-4-methylpiperidine, 3-methyl-4-ethyl-piperidine, 2,6-dimethylpiperidine, hexamethyleneimine, 2-methyl-hexamethyleneimine, 3-methylhexamethyleneimine.

Palladium is particularly suitable as catalysts for the reaction and rhodium, but preferably palladium, on an inert support such as Al 2 O 3> TiO2, coal etc. Also natural or artificial silicates such as aluminum silicates or magnesium silicate, are suitable as carriers.

The reaction temperature is from 25 to 1800C, preferably from 30 to 1100C. The hydrogen pressure is 2 to 100 bar.

The present invention also provides an antifungal Means for topical and systemic use, characterized by a content on a compound according to claim 1 or its physiologically compatible Acid addition salt as an active ingredient in addition to customary carriers and diluents as well the use of the compounds in the control of mycoses.

For salt formation with a physiologically compatible one that is customary per se Acid come organic carboxylic acids 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, benzoic acid, salicylic acid or nicotinic acid can be considered. However, the inorganic acids mentioned, in particular hydrochloric acid, are preferred.

The compounds to be used according to the invention and their salts have strong antifungal effects. They have a broad spectrum of antifungal activity, especially against dermatophytes, such as species of the genera Epidermophyton, Mlerosporum and Trichophyton and yeasts such as Species of the genus Candida. the List of these microorganisms is intended to limit the microorganisms to be controlled represent, but only serve for explanation.

The effect against dermatophytes can be according to methods such as, for example in P. Klein, Bacteriological Basics of Chemotherapeutic Laboratory Practice, Springer-Verlag Berlin, 1957, are shown. The surprising one Effect against yeast was shown in the pseudomycelium and mycelium phase test with Candida albicans proven (see German patent application P 30 10 093.7 from 03/15/1980).

For example, it was tested, soft minimal inhibitory concentrations (MIC values) can be achieved in the agar dilution test against pathogenic fungi In the following table 1 summarizes the results: Tabel 1 Comparative MIC values (μg / ml) of the compound according to Example 4b with clotrimazole (2), miconazole (3) and tolnaftate (4).

Species Verb. Na 2 3 4 Ex. 4b Epidermophyton floccosum <0.125 0.32> 1.28- 0.32 No. 157 / M + Microsporum ferrugineum <0.125 # 0.16) 1.28 0.16 No. 5 / M Trichophyton mentagrophytes 40.125 1.28> 1.28 0.32 M = strain of mykothek, Nordmark-Werke GmbH An MIC became against Candida albicans (No. 20 / M) mycelium phase found to be 0.125 / µg / ml.

In the model of guinea pig trichophytia (Trichophyton mentagrophytes) see Heffter-Heubner: Handbuch d. exp.

Pharmacology, Vol. XVI / IIA, is the compound Example 4b for external Use of 1% and 2% suspensions (tragacanth) 1 x 1 nc / day x 7 days more effective than a 1% clotrimazole suspension (Tab. 2).

Since the infected skin area, each treated with 1 ml, is ~ 24 cm2 is coarse, it is found that the compound is present in an amount of 0.08 mg / cm 2 skin surface area is fully effective when used externally.

Table 2 Cultural pathogen detection x / n animals 6 d 8 d 10 d 13 d p.inf. p.inf. p.in £. p p.inf.

= 2xtherapy = 4xtherapy = 7xtherapy connection Example 4b 1% 5/5 0/5 0/5 O / 5 Compound Example 4b 0.2% 5/5 0/5 O / 5 O / 5 Clotrimazole 1% 5/5 5/5 3/5 3/5 From Table 1 it can be seen that, for example, the compound according to Example 4b compared to the well-known antifungal agents clotrimazole, miconazole and especially against Tolnaftate, currently one of the most widely used agents for dermatomycoses, has lower MIC values. Accordingly, humans are indicated as areas of indication and animal dermatomycoses, dermatophytoses and systemic mycoses, in particular by species of the genera Epidermophyton, Microsporum and Trichophyton and yeasts, such as species of the genus Candida.

The present invention also includes the production of the agents or preparations made with conventional solid, semi-solid or liquid carriers or diluents and the commonly used pharmaceutical-technical ones Excipients with a dosage suitable for systemic and external use in the usual way, in particular by mixing (cf. L.G. Godman, A. Gilman, The Pharmacological Basis of Therapeutics).

As a rule, it has been used in both human and veterinary medicine Prove to be advantageous, the active ingredient (s) in amounts of about 0.07 to 0.1 g / cm2 body surface area every 24 hours, if necessary in the form of several single doses, to be applied externally.

However, it is also possible to deviate from the stated dosages, depending on the type and severity of the disease. The definition the optimal dosage required in each case and its frequency can be determined by the attending physician may be varied based on their knowledge.

As a rule, the individual doses are applied 1 to 2 times a day. When used externally, locally, the preparations contain 0.5 to 5, preferably 1 to 2% by weight of active ingredient.

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.

In addition to the active ingredient, powders and sprays can contain the usual carriers contain, e.g. lactose, talc, silica, calcium silicate and polyamide powder or mixtures these substances. Sprays can also be the usual Propellants such as 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 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, glycerine, Glycerin formal, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.

Examples of dosage forms for systemic use are Tablets, coated tablets, capsules, pills, aqueous solutions, suspensions and emulsions, optionally sterile injectable solutions, non-aqueous emulsions, suspensions and solutions under consideration. In the case of oral administration, the individual doses are in amounts of 50 to 250 mg are possible. As a rule, the active ingredient is administered 1 to 4 times a day.

In general it has been used in both human and veterinary medicine Proven to be advantageous, the active ingredient (s) in amounts of about 10 to about 50 mg / kg body weight per 24 hours, preferably in the form of several single doses to be administered to achieve the desired results. It may, however, also be required be able to deviate from the stated dosages.

1. Manufacture mg of starting compounds Example 1 tert-butylbutadiene To 1 mole of methyl vinyl tert-butyl carbinol, prepared in a known manner from a Vinyl magnesium chloride solution in tetrahydrofuran and methyl tert-butyl ketone 30 g of oxalic acid, 50 ml of water and 2 g of hydroquinone. It is heated under for 30 minutes Reflux and then distilled the resulting tert-butylbutadiene together with water slowly from.

Yield is 92 g.

Example 2 tert-butyl-cyclohexenecarboxaldehyde Tert-butylbutadiene and acrolein are refluxed in molar amounts for 6 to 8 hours. You get a mixture of 4-tert. Butyl-cyclohexene-3-carboxaldehyde-1 ~ 70% and 3-tert. Butyl-cyclohexene-3-carboxaldehyde-1 , 30 30 - in about 80% yield. Kp. L120C / 28 mbar.

Example 3 A mixture prepared according to Example 2 of 3-4 tert -butyl and h 3-3-tert-butyl-tetrahydrobenzaldehyde is treated with propionaldehyde in a known manner condensed. 2-Methyl- (4-tert-butyl-cyclohexen-3-yl) -propen-2-al-1 is obtained in 80% yield and 2-methyl- (3-tert-butyl-cyclohexen-3-yl) -propen-2-al-1 approx. 70:30, bp 1530C, 30 mbar.

2. Preparation of Compounds According to the Invention Example 4 a) 73 g of a mixture prepared according to Example 3 are dissolved in 500 g of methanol, mixed with 40 g of cis-2,6-dimethylmorpholine and in the presence of 7.8 g of 0.5% Pd converted to # -Al2O3 in a stirred autoclave at 400C and an H2 pressure of 50 bar, until the hydrogen uptake drops below 1 bar / h. Then it is still at 1000C and rehydrated at 50 bar / h for 1 hour. The discharge is worked up by distillation and receives n- (3-r4'-tert-butyl-cyclohexen-3t-yl] -2-methyl-propyl-1) -CiS-2,6-dimethylmorpholine in about 75% yield and the corresponding 3'-tert-butyl compound in a ratio of 70:30, bp 142 up to 144 ° C / 1 mbar.

b) The amine mixture from Example 4a is used in methanol as the inert solvent converted into the hydrochloride by gassing in dry HCl gas, this from methanol recrystallized (melting point 1900C) and the salt decomposed again into the base. You get pure N- (3-r4'-tert-butyl- [yclohexen-3'-yl] -2-methyl-propy 1-1) -cis-2,6-dimethylmorpholine. The 3'-tert-butyl isomer can no longer be detected by spectroscopy.

Examples 5 to 9 The procedure described in Example 4 is followed, the amines obtained are purified by recrystallization of their hydrochlorides and, after distillation of the bases released, the following amines with antifungal activity are obtained: Bp. 1870C / 15 mbar Bp. 2090C / 15 mbar Bp. 215 ° C / 15 mbar Bp. 1200C / 0.1 mbar Bp. 1470G / 0.4 mbar 3. Examples of pharmaceutical preparations: 1. Example for cream with 2nd % Active ingredient a) active ingredient 2.0 gb) glycerol monostearate 10.0 gc) cetyl alcohol 5.0 gd) polyethylene glycol 400 stearate 10.0 ge) polyethylene glycol sorbitan monostearate 10.0 gf) propylene glycol 6, ogg) p-hydroxybenzoic acid methyl ester 0.2 gh) demineralized water ad. 100.0 g of the finely powdered active ingredient is suspended in propylene glycol and the suspension is stirred into the melt of glycerol monostearate, cetyl alcohol, polyethylene glycol 40Q stearate and polyethylene glycol sorbitan monostearate, which is heated to 650C. The 70 ° C. solution of the methyl p-hydroxybenzoate is emulsified in water into this mixture. After cooling, the cream is homogenized using a colloid mill and filled into tubes.

2. Example of powder with 2% active ingredient a) Active ingredient 2.0 g b) zinc oxide 10.0 g c) Magnesium oxide 10.0 g d) Highly dispersed silicon oxide 2.5 g e) Magnesium stearate 1.0 g f) 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 No. 7 sieve and placed in polyethylene containers filled with litter insert.

3. Example of tablets with 250 mg of active ingredient Active ingredient 3 250 g of potato starch 100 g milk sugar 50 g gelatin solution 4% approx. 45 g talc 10 g 1000 tablets = 41P g Production: The finely powdered active ingredient, potato starch and lactose are made mixed. The mixture is moistened with about 45 g of 4% gelatin solution, fine-grained granulated and dried. The dry granules are sieved and mixed with 10 g of talc and compressed into tablets on a rotary tablet machine.

The tablets are placed in tightly fitting polypropylene containers filled.

Claims (4)

Patent claims 1. -Composition of the formula I, in. The N and X are members of a five-, six- or seven-membered heterocyclic ring, where X is an alkylene chain with four, five or six members, which optionally contains a heteroatom as a chain link, and the alkylene radicals thereof optionally one or more times through alkyl radicals are substituted by 1 to 4 carbon atoms and their physiologically acceptable acid addition salts. 2. Process for the preparation of compounds according to claim 1, characterized in that the aldehyde of the formula II, in which R1 and R2 are different and represent hydrogen or a tert-butyl group, in the form of the mixture with regard to the position of the tert-butyl group in the presence of an amine of the formula III, in which N and X have the meanings given in claim 1, are reacted with hydrogen in the presence of a hydrogenation catalyst, the amine mixture obtained is converted into a physiologically acceptable salt and the pure 4-tert.-butyl compound is isolated by crystallization of the salt. 3. Process for the preparation of compounds according to claim 1, characterized in that the aldehyde of the formula IV is reacted with an amine of the formula III in the presence of a hydrogenation catalyst with hydrogen and the compound obtained is optionally converted into a physiologically acceptable acid addition salt. 4. Antifungal agent, characterized by a content of one Compound according to Claim 1 or its physiologically acceptable acid addition salt as an active ingredient in addition to the usual carriers and diluents.