DE2742175A1 - Phenoxy-pyridinyl and pyrimidinyl alkanol(s) - useful as antimycotic agents for human or veterinary use - Google Patents

Abstract

Antimycotic agents are claimed contg. >=1 azolyether deriv. of formula (I) in which R is alkyl, opt. substd. aryl or aralkyl; X is N or CH; Y is halogen, (cyclo)alkyl, alkoxy, haloalkyl, alkylthio, opt. substd. phenyl, phenoxy, phenoxy alkyl or phenylalkyl; and n = 0-5. Physiologically acceptable acid addn. salts and metal complexes of the (I) are also claimed. (I) are esp. useful in the treatment of dermatomycosis and system mycosis in human and veterinary medicine. They can be applied or dispensed in the form of tablets, capsules, suppositories, solns., emulsions, pastes, gels, creams, lotions, powders, etc. to combat fungi such as Candida albicans, Epidermophyton floccosum, Aspergillus niger and A. fumigatus, Trichophyton mentagrophytes, Penicillium commune, etc. Normal doese is e.g. 10-300 mg esp. 50-200 mg/kg body wt. per 24 hrs.

Description

Antimicrobial agents

The present invention relates to the use of new phenoxypyridinyl (pyrimidinyl) alkanols as antimicrobial agents, particularly as antifungal agents.

It is already known that certain azole derivatives, such as in particular 3,3-dimethyl-l-phenoxy-l- (1,2,4-triazol-l-yl) or. -imidazol-l-yl-butan-2-ols, have good antifungal effects (compare DT-OS 2 324 424 [Le A 15 011] and DT-OS 2 333 355 [Le A 15 145]). However, their effect is, especially against Dermatophytes, not always entirely satisfactory.

It has been found that the new phenoxypyridinyl (pyrimidinyl) alkanols of the formula in which R represents alkyl, optionally substituted aryl or aralkyl, X represents a nitrogen atom or the CH group, Y represents halogen, alkyl, cycloalkyl, alkoxy, haloalkyl, alkylthio, optionally substituted phenyl, phenoxy, phenoxyalkyl or phenylalkyl and n stands for whole numbers from 0 to 5, and their physiologically compatible acid addition salts and metal complexes have good antimicrobial, in particular antimycotic, properties.

The compounds of formula (I) have an asymmetric carbon atom; they can therefore exist in the two optical isomers or as a racemate. All isomers are claimed according to the invention, surprisingly show the phenoxypyridinyl (pyrimidinyl) alkanols of the formula which can be used according to the invention (I) better antifungal, therapeutically useful efficacy than that from 3,3-dimethyl-1-phenoxyl- (1,2,4-triazol-1-yl) or known in the art. -imidazol-l-yl-butan-2-ols, which chemically and physically close compounds are. The substances that can be used according to the invention are thus an enrichment of the Pharmacy.

The active ingredients which can be used according to the invention are represented by the formula (I) generally defined. In this formula, R preferably stands for straight-chain or branched alkyl having 1 to 4 carbon atoms and optionally substituted Aryl or aralkyl with 6 to 10 carbon atoms in the aryl part and up to 4 carbon atoms in the alkyl part, such as, in particular, phenyl and benzyl, with preferred substituents the radicals which are mentioned as preferred for Y come into consideration. Y is preferably for halogen, in particular fluorine, chlorine or bromine, straight-chain or branched Alkyl having 1 to 4 carbon atoms, cycloalkyl having 5 to 7 carbon atoms, such as in particular cyclohexyl, haloalkyl with up to 2 carbon atoms and up to 5 identical ones or various halogen atoms, such as, in particular, fluorine or chlorine atoms; Farther Y preferably represents alkoxy and alkylthio with up to 2 carbon atoms and for optionally substituted phenyl, phenoxy, phenoxyalkyl or phenylalkyl each having 1 or 2 carbon atoms in the alkyl part, with as substituents in Phenyl part are preferably: halogen, in particular fluorine, chlorine or Bromine and alkyl with up to 4 carbon atoms. The index n is preferably for the integers from 0 to 3 and X has the one specified in the definition of the invention Meaning.

The active ingredients to be used according to the invention, their acid addition salts and metal complexes are not yet known. However, they can be prepared according to your own suggestion by using phenoxyketones of the formula in which R, Y and n have the meaning given above, with a pyridinyl or pyrimidinyl halide of the formula in which Z stands for halogen, in particular chlorine or bromine, and X has the meaning given above, in the presence of an inert organic solvent or solvent mixture, such as diethyl ether and tetrahydrofuran, and in the presence of an organic alkali metal compound such as n-butyllithium, as a base at temperatures between -1500C and -500C under an inert gas such as nitrogen. To isolate the end products, the reaction mixture is worked up and purified in the customary manner; the salt or the metal complex is optionally prepared.

The phenoxy ketones of the formula (II) are known (cf. DT-OS 2 105 490 and DT-OS 2 201 063) or can easily be done using the methods described there produce. They are obtained, for example, by combining corresponding phenols with corresponding Reacts halogen ketones in the presence of an acid binder and a diluent.

The halides of the formula (III) are generally known compounds of organic chemistry.

ur preparation of acid addition salts of the compounds of formula (I) all physiologically compatible acids are possible. These preferably include the hydrohalic acids, such as z.3. hydrochloric acid and hydrobromic acid, in particular hydrochloric acid, furthermore phosphoric acid, nitric acid, sulfuric acid, mono- and bifunctional carboxylic acids and hydrocarboxylic acids, e.g.

Acetic acid, maleic 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 according to customary salt formation methods, e.g. B. by dissolving a compound of the formula (I) in a suitable inert solvent and adding the acid, e.g. hydrochloric acid, are obtained and in a known manner, for example by filtering off, isolated and optionally can be purified by washing with an inert organic solvent.

For the preparation of metal salt complexes of the compounds of the formula (I) preferably cork salts of metals from II. To IV. Main and I. and II. And IV. To VIII. Subgroup in question, whereby copper, zinc, manganese, magnesium, Tin, iron and nickel may be mentioned as examples. Such anions can be used as anions of the salts into consideration, which are derived from physiologically acceptable acids. These include preferably the hydrogen halide 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, e.g. by dissolving the metal salt in alcohol, e.g. ethanol, and adding to the compound of formula (I). One can Metal salt complexes in a known manner, e.g. by filtering off, isolating and optionally Purify by recrystallization.

The compounds of the formula (I), and which can be used according to the invention their acid addition salts and metal complexes have antimicrobial properties, in particular strong antifungal effects.

They have a very broad spectrum of antifungal activity, in particular 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, like Penicillium commune. The list of these microorganisms is by no means a restriction of the germs that can be combated, 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.

The following can be listed as indicator areas in veterinary medicine, for example be: All dermatomycoses and systemic mycoses, especially those caused by the the above-mentioned pathogens.

The present invention includes pharmaceutical preparations, the one 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 as well as 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. tablets, coated tablets, capsules, pills, suppositories and ampoules are present, whose active ingredient content corresponds to a fraction or a multiple of a single dose. The dosage units can 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 in a Application is administered and usually a full, half or corresponds to 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, Called pastes, 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. quaternary Ammonium compounds, (g) wetting agents, e.g. cetyl alcohol, glycerol monostearate, (h) Adsorbents, e.g. kaolin and bentonite and (i) lubricants, z.

B. talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) to (i).

The tablets, coated tablets, capsules, pills and granules can be used with the customary coatings and envelopes, 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 release, whereby as embedding compounds e.g.

Polvmersubstanzen and waxes can be used.

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. C * 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 Usual carriers such as solvents, solubilizers and emulsifiers, z.3. 'gZasser, 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, glycerin, 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 or ingredients, 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 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, 2.3. Contain 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 percent by weight of the total mixture be.

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 wiping the Active ingredients with the daily ingredient (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 healing of 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 of about 10.

to about 300, preferably .50 to.? °° mg / kg of body weight per 24 Hours, if necessary in the form of several individual doses to achieve the desired Deliver results.

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 Amount of active ingredient to 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 19 germs / ml substrate carried out. The nutrient medium used was a) for dermatophytes and molds: Sabouraud's milieu d'epreuve b) for yeasts: meat extract-glucose broth.

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

Table A: Antifungal in vitro activity MIC values in y / ml nutrient medium for Tricho- Penicil- Asper- Micro- phyton lium gillus sporon Active ingredients mentagr. commune species species r OH O-CH-C (CH,) 3 N (r 32>64> 64 N ~ ml (known) N OH (CH3) (NN 4>64> 64 64 (known) OH CH3'0-CH-C'HC (CH3) 3 CH3 Ki 4>64> 64 64 N 1l N (known) OH F -% - O-CH-C'HC (CH3) 3 64 64> 64 - It N (known) OH (CH3) 3C- <C) -O-CH-CH-C (CHs) 3 (known) 32>64> 64 OH C1-5 O-CH-CH-C (CH3) 3 1 N; (named) 1>64> 4 32 (($ 4 (known) II 909813/0297 Table A: (continued) Antifungal in vitro activity MIC values in γ / ml nutrient medium for active ingredients Tricho- Penicil- Asper- Mikrophyton lium gillus sporen mentagr. commune species species compounds from example no.

(1) 4 - 32 4 (3) <1 8 4 4 (4) # 1 (5) '1 4' 1 1 (6) '1 4 # 1 (7) # 1 4 # 1 (9) # 1 - # 1 (10) <1 8 8 8 (11) 4 - # 1 # 1 (12) 4 - '4 - (15) 8 - # 1 - (18) # - 8 4 (23) 4 - 64 8 (27) # 1 - 4 4 (28) # 1 - 16 4 (29) # 1 - # 1 1 (37) # 1 - 4 1 Production Examples Example 1 Under a dry nitrogen atmosphere, 50 ml of a 15% solution of n-butyllithium in n- are added to a solution, cooled to -1100C, of 12.6 g (0.1 mol) of bromopyridine in 150 ml of a 2: 1 mixture of absolute tetrahydrofuran and absolute ether Hexane was slowly added dropwise. After the addition is complete, the reaction mixture is allowed to warm to -800C, stirred at this temperature for 10 minutes and then the mixture is cooled down to -110 to -1200C. At this temperature, a solution of 19.2 g (0.1 mol) of 3 , 3-Dimethyl-1-phenoxy-butan-2-one in 80 ml of absolute tetrahydrofuran was added dropwise. The mixture is then left to stir at -780C overnight. Then allowed to warm to room temperature and add 200 ml of ether.

The reaction mixture is extracted three times with 1N hydrochloric acid.

The combined hydrochloric acid extracts are washed with ether Poured solid sodium bicarbonate and extracted several times with Esigester. The E3sigesterldsung is washed with water, dried over sodium sulfate and concentrated. The residue is recrystallized from cyclohexane. 15 g (55% of theory) of 3,3-dimethyl-1-phenoxy-2-pyridin-3-yl-butan-2-ol are obtained of melting point 89-90.50C.

Example 2 A solution of 19.2 g (0.1 mol) of 3,3-dimethyl-1-phenoxy-butan-2-one in 110 ml of absolute tetrahydrofuran and 70 ml of absolute ether is cooled to -1200 ° C. under a dry nitrogen atmosphere. A solution of 15.7 g (0.1 mol) of 5-bromopyrimidine in 50 ml of absolute tetrahydrofuran is added dropwise to this. Then 60 ml of a 15% n-butyllithium solution in n-hexane are slowly added dropwise at -1200C. The mixture is initially allowed to stir for 2 hours at about -1100 ° C., then overnight at -780 ° C. The reaction mixture is warmed to room temperature, 100 ml of 10% ammonium chloride solution are added and the mixture is concentrated in vacuo. The aqueous suspension is then extracted with ethyl acetate. The ethyl acetate extract is washed in succession twice with 1N hydrochloric acid, twice with water and once with saturated sodium chloride solution, dried over sodium sulfate and concentrated. The residue is recrystallized from cyclohexane. 10.5 g (39% of theory) of 3,3-dimethyl-1-phenoxy-2-pyrimidin-5-ylbutan-2-ol with a melting point of 127-1290 ° C. are obtained.

The examples in Table 1 below are obtained analogously: Table-1 Ex. Y No. nx R melting point (0c) 3 2CH3 CH C (CH)), 66-68 4 2,4-C12 CH C (CH3) 3 113.5-115 5 4-Br CH C (CH 3) 3 171-173 6 4-OCH3 CH C (CH3), 178-180 7 4-C1 CH C (CH3) 3 162-164 8 4-CH, CH C (CH 3) 3 131-133 9 2-CH3,4-C1 CH C (CH5) 3 127-128 10 4-F CH C (CH 3) 3 120-121 11 3,4-C12 CH C (CH3) 3 125-126.5 12 3-CF3 CH C (CH3) 3 132-133.5 13 4-O-CH2 4 CH C (CH3) 3 125-126 14 2-OCH3, 4-Cl CH c (CH3) 3 128-129 15 4 o CH C (CH 3) 120-121 16 2,4-C12 CH 17 - CH ~ O 194-197 (x2LMDS) 18 4-C1 CH ~ O 182-185 (x2LtXDS) Cl 19 4-C1 CH b> 250 (xiNDS) 20 2-CH3,4-Cl CH t 187-l90 (xiNDS) Ex. Yn XR melting point No. n (0c) 21 3-CF3 CH 4 238-240 (xi1VDS) 22 4-OCH3 OH 4 175-177 (xiNDS) 23 2,4-C12 CH CH3 98.5-100 24 - CH CH3 204-208 (x2NDS) 25 4-CH3 CH CH3 184-186 (x2 NDS) 26 4-OCH3 CH CH3 200-203 (xiNDS) 27 4-C1 NC (CH3) 3 172-174 28 4-FNC (CH3) 3 163.5-164.5 29 3,4-C12 NC (CH3) 3 155-157 30 4-CH3 NC (CH3) 3 152-153.5 31 4-0-CH, to NC (CH3) 3 122-124 32 2,4-C12 NC (CH3) 3 96-99 33 - N <) viscous oil 34 4-0- CH C (CH3) 3 103-104 ° C 35 4-F CH t 222-225 ° C (xiNDS) 36 4-CH30 N -C (CH3) 3 136-137 37 2,4-C12 CH ~ viscous. Oil NDS = 1,5-naphthalenedisulfonic acid

Claims (3)

Claims 1. Antifungal agent, characterized by a content of at least one azolyl ether derivative of the formula in which R represents alkyl, optionally substituted aryl or aralkyl, X represents a nitrogen atom or the CH group, Y represents halogen, alkyl, cycloalkyl, alkoxy, haloalkyl, alkylthio, optionally substituted phenyl, phenoxy, phenoxyalkyl or phenylalkyl and n stands for whole numbers from 0 to 5, and / or their physiologically acceptable acid addition salts and metal complexes. 2. A method of making an antifungal agent, thereby characterized in that azolyl ether derivatives according to the formula in claim 1 with inert, non-toxic, pharmaceutically suitable carriers mixed. 3. A method for the treatment of mycoses, characterized in that azolyl ether derivatives according to the formula in claim 1 are administered to humans or animals, who suffer from mycoses.