CS221824B2 - Method of making the 1,1-diphenyl-2-/1,2,4-triazole-1-yl/-1-ethanole - Google Patents

Abstract

1. A 1,1-diphenyl-2-(1,2,4-triazol-1-1-yl)-ethanol of the general formula I see diagramm : EP0036153,P8,F1 where one of the radicals R**1, R**2 and R**3 is chlorine and the others, which may be identical or different, are hydrogen or chlorine, and its pharmacologically tolerated salts as antimycotics.

Description

The invention relates to a process for the preparation of 1,1-diphenyl-2-1) 2,4-triazol-1-yl-11-ethanol and their pharmaceutically acceptable acid addition salts. These compounds are valuable as cheneoeeappetic agents, especially as antiaycotics for both internal and external administration.

It is known to treat a variety of anti ^ce Koti ^y h ^{c c} cal substances, for example miconazole not ^b the cloned trimazol. the effect of these substances is not always completely satisfactory. SUMMARY OF THE INVENTION It is an object of the present invention to provide a process for the preparation of novel active artimycotic agents.

Accordingly, the present invention provides a process for the preparation of 1,1-diphenyl-2- (1,2,4-triazol-1-yl) -1,4-di-3 of the formula I, ---- N.

I i

N, N-CH

(I) wherein one of the radicals r 1 to i x represents a chlorine atom and the other of the same or different denotes hydrogen or chlorine, as well as the acid addition salts of these compounds with pharmaceutically acceptable acids. · - · · U. :

Particularly preferred compounds of formula I are those in which the S is in the para position with respect to the style chain and which can be derived from formula II

(И) where

F ¹ to F ¹ are as defined above, as well as pharmacologically acceptable acid addition salts of these compounds.

Suitable salts for forming salts are, in particular, nitric, hydrochloric, sulfuric, phosphoric, acetic, propionic, lactic, succinic, tartaric, citric, benzoic, salicylic and nicotinic acids, or other acids can be used as described in Arzneimittelforschung, Vol. 10, pp. 224-225, Birkhauser Verlag, Basel und Stuttgart, 1966.

Preference is given to the above-mentioned inorganic salts, in particular salts with nitric or hydrochloric acid, which crystallize well.

Compounds in which the radicals to R ^ differ from one another or in which the phenyl radical carries the same substituents at different positions contain an asymmetric center on the carbon atom which carries the hydroxyl group. The separation, isolation or production of the optical isomer is carried out in a conventional manner. Optical isomers are within the scope of the invention.

The compounds of formula I and their acid addition salts can be obtained by reacting a compound of formula III wherein:

(III) pi to _{m has the} meaning given in formula Ia

X represents a halogen atom, preferably a chlorine or bromine atom, with the 1,2,4-trlazole of formula IV

Γ = ι *

N / N-H (IV) in a conventional manner and the compound obtained is optionally converted to its pharmacologically acceptable acid addition salt.

The reaction is preferably carried out in stoichiometric amounts, in the presence of an acid binding agent or an excess of 1,2,4-triazole, or in the presence or absence of a solvent or diluent.

Particularly suitable solvents are organic solvents, for example dimethylformamide, hexamethylphosphoric triamide, acetonitrile or benzyl.

Of the acid binding agents, it is preferably an excess of 1,2,4-trlazole or other conventional reagent such as alkali or alkaline earth metal hydroxides, carbonates and alcoholates, especially sodium, potassium, magnesium or calcium or an organic base , for example pyridine or tertiary amines such as triethylamine.

The reaction temperature may vary within a wide range. In general, the process can be carried out at a temperature of 0 to 150 ° C. preferably 30 to 120 ° C.

The starting compounds of the formula III can be obtained in a known manner for the preparation of tertiary alcohols from ketones or carboxylic acid derivatives and Orignard compounds, as described, for example, in Houben-Weyl, Methoden der organischen Chemie, vol. 13/2 &. 46-527 (1973).

In the case where, for example, 1- (2,4-dichlorophenyl) -1- (4-chlorophenyl) -2-chloro-1-ethanol obtained from 2,2 *, 4 * trichloroacetophenone and 4- chlorophenyl magnesium bromide and 1,2,4-triezole, the reaction can be illustrated by the following reaction scheme:

The compounds of the formula I and their salts have a chemotherapeutic, in particular antifungal, action.

Accordingly, the present invention provides a process for the preparation of compounds which can be used in antifungal compositions comprising a compound of formula (I) or its acid addition salt as an active ingredient and, in addition, a carrier or diluent. *

Surprising in vitro antimicrobial efficacy was demonstrated in a subsequent experiment on Candida albicans.

A test for the formation of Pseudomycelia and mycelial phase was performed with Candida albicans.

In this test, it is taken into account that Candida albicans not only produces normal cell types in wolf, but also pseudomycelium and true mycelium, so that it is dimorphic. In vitro, the formation of all growth phases and the effect of antifungal agents can be demonstrated by transferring Candida albicans (Robin) Berkhout No. 20 / M (strain of the Nordmark-Werke GtabH collection) to the surface A of the medium, which is the infusion from brain and heart (Difco) and, moreover, it is vaccinated somewhat in depth on area B, as shown in the attached illustration.

A coverslip C is deposited in the region in which the culture has been inoculated in depth so that microaerophilic conditions arise. The Petri dish D contains a dilution series of the test substance in the nutrient medium. These plates were incubated for 2 days at 37 ° C, while observing the control plates, only budding yeast cells could be found in aerobic region A, whereas only pseudohyphae and true hyphae could be observed in the microaerophilic region V.

The minimum effective concentration is the concentration of the active ingredient, thereby inhibiting 100% growth.

In this experimental design, the minimum phase to prevent the growth of the yeast form can be distinguished from the minimum effective concentration to prevent the mycelial phase.

The minimum effective concentration to inhibit the growth of the yeast phase is usually greater than 128 µg / ml, while the minimum effective doses to prevent the growth of the mycelial phase are very low, as shown in Table 1 below.

Table 1

Example number R ¹ R ² R ³ Salt MHK ((ULg / ml) “50 p. (mice) (mg / kg) 1 H 4-C1 4-C1 <0.125 > 1 000 2 H 4-C1 4-C1 HCl <0.125 > 1 000 3 2-C1 4-C1 4-C1 - <0.125 > 4 000 4 2-C1 4-C1 4-C1 HCl <0.125 > 1 000 5 2-C1 4-C1 4-C1 HNO ₃ <0.125 > 1 000 6. 2-C1 H H HCl <0.135 > 1 000 7 H 4-C1 H HCl <0.125 > 1 000 8 H 4-C1 H HNO3 <0.125 > 1 000 9 3-C1 4-C1 H - <0.125 > 1 000 10 2-C1 4-C1 H HCl <0.125 > 1 000 11 2-C1 4-C1 H HNO ₃ <0.125 > 1 000 12 2-C1 H 4-C1 HCl 1 > 1 000 13 2-C1 4-C1 2-C1 - 1 > 1 000 14 2-C1 4-C1 2-C1 HCl 1 > 1 000 15 Dec 2-C1 4-C1 3-C1 - <0.125 > 1 000 16 2-C1 4-C1 3-C1 HCl 1 > 1 000

The anti-microbial efficacy in vitro against disintegrating agents has been demonstrated by a more recent agar experiment (pckHe P. Klein IBKterrologisch Grmdlagen dar chemotherapuUischen LabMraioriumspruds). the results of these experiments with compound ort. 3 are shown in Table 2.

Table 2

MLorosporon Minimum Inhibitory Concentration (µg ^ m.) M. audttMLnnl No. 4 0.25 M ferrroglneuu No 5 0.5 M. csnLs No. 167 4 X. csnis No. 168 2 X. cs ^ Ls No. 169 8 TrLehofyton T. echomleinni No. 9 0.25 T. vLolsceu · No. 10 2 T. aentsgroph. No. 159 0.125 T. aentsgroph. No. 172 0.25 T. aentsgroph. No 173 0.25 SpL deruophyte X. flcccosus 8. 157 16

221624

Experimental candidiasis in mice induced by Candida albicane

To determine the oral efficacy, mice weighing 10 to 20 g were treated with hydrocortisone intremuscularly for 2 days at a dose of 50 mg / kg in order to observe the infection well. Mice were then injected intravenously with 500,000 Candida albicane cells, and then 100 mg / kg twice daily for 4 days.

In addition to the infected group and the untreated control group, groups treated with the comparator compounds miconazole and clotrimazole were also used.

Table 3 shows that up to 100% of the animals treated with the compounds according to the invention still survived 10 days after infection, whereas only 30% of the test animals survived in the control and reference active groups. .

Table 3

Dose twice daily 100 mg / kg

Example number 1. Number of surviving animals on that day after infection 10 2. 3. 4. 5. 6. 7. 8. 9. 1 10 10 10 10 10 10 10 10 10 9 2 10 10 10 10 10 10 9 9 9 9 3 10 10 10 io; 10 10 10 10 10 10 4 10 10 10 10 10 10 10 10 10 10 5 10 10 10 10 10 10 10 10 10 10 6 10 10 ¹⁰ 10 10 10 10 10 9 9 7 10 10 10 10 10 10 10 10 10 10 8 10 10 10 10 10 10 10 10 10 10 9 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 11 10 10 10 10 10 10 10 9 9 9 15 Dec 10 10 10 10 10 10 9 9 8 8 Miconazole 10 10 8 8 6 4 2 2 1 1 Clotrimasol 10 10 10 9 8 6 5 5 4 3 Control 10 10 8 7 4 3 2 1 1 1

After demonstrating the intensity of the effect in vivo, groups of 10 Candida albicans mice were infected and treated for 4 days twice daily with 46.4 mg / kg (Table 4) or 21.5 mg / kg (Table 5) of the active substance.

Table 4

Dose twice daily 46.4 mg / kg

Example number 1. Number of surviving animals on that day after infection 10 2. 3. 4. 5. 6. 7. 8. 9. 2 10 10 10 10 10 10 10 10 9 9 3 10 10 10 10 10 10 10 10 10 10 4 10 10 10 10 10 10 10 10 9 9 5 10 10 10 10 10 10 10 .9 9 9 11 10 10 10 10 10 10 10 10 9 9 Clotrimazal. 10 10 9 8 8 7 6 6 4 3 Koonrola 10 10 8 7 4 3 1 1 1 .1

Table 5

Dose twice daily 21.5 mg / kg

Example number 1. 2. Number of survivors animals that day after infection 3. 4. 5. 6. 7. 8. 9. 10 2 10 10 10 10 10 9 9 8 8 8 3 10 10 10 10 10 10 10 10 10 1C 4 10 10 10 10 10 10 10 10 10 10 5 10 10 10 10 10 10 10 10 10 10 11 10 10 10 10 10 10 10 9 9 9 Clltrimazll 10 10 9 5 5 3 2 2 0 C Ko ^ nla 10 10 8 5 3 1 1 1 0 E

Explanatory notes to tabultata 3, 4 and 5:

Example number = 1,1-biv- (4-chlorophenyl) -2- (1,2,4-triazol-1-yl) -1-ethanol = in 1,1-) biv- (4-chlorophenyl) - 2- (1,2,4-triazole) Ц-1 -eaanol hydrochloride = 11-chloro-η 5 -1-Z 2 -dichloro-na-4-K 1 -

1- (4-chlorophenyl-1- (2,4-dichlorophenyl) -2- (1,2'-triazol-1-yl) -) ethanol-4-chloro-1-chloro-1 - (-. chloroperin) -) - (2,4-Lichhorfb-α) -2- (112,4-lriazol-1-allyl-ethanol) narate

- 1-feaal-1- (2-chloro-aal) -2- (1,2,4-trizol-) saline-1-eaalolium chloride = 1-f-lS-1 - (- chloro-rnS) - 2- (1,2'-araazo-1) syl) -1eeaanolhadrochlorad = 1 phenSH- (4-chloifeine-S) -2- (1,2,4-trlazole-1 - (S) 11-thanoO) nar = Ь---η 6 - (2,4-dlchlorophenyl) -2- (1,2,4-trlazol-1-yl) -1-ethaol = 1-phenoxy-1- (2,4 -dachloro-aaS) -2- (1,2, -tetraazol-1-allyl) -a-ethanohadrochloride = 1-phenylene-M2,4-dl-naphthyl) -2- (1,2,4-traazol-1-) sl) -1-ethanol-naphtha = 1- (3-chloro-phosphine) -1- (2,4-dachlorophine) -2- (1,2,4-ariazol-11Sl) -1-et-aol

The results show that the compounds of formula I are ia vivo comparison btžnt Uzi ^Van YML antirnakoaity ^{miklnazllem-,} i.e. ¹ - ^[2, 4- ^d 1c ^{L1 b} eaa- or- (2,4-dichtertenzyloxy jfenettrll · imidazzorntréa and clotrimazole 1- (1-chloro-alpha, alpha-dilanylLZs1) imidazole for Candida albieans infection in mice substantially outweighs the efficacy of these shade shadows.

Since the aforementioned compounds are not yet suitable for the systemic treatment of mycoses and these diseases occur in increasing numbers, as. . See, for example, Infection 2, 95 (1974), Chernmoherapy 22, 1 (1976), Dtsch. Apoth. Ztg. 118, 1269 (1978).

The compounds produced by the process of the invention are particularly suitable for the oral and external treatment of fungal infections in humans and animals.

For example, in humans and animals, it can be used against deraatomycoses, dermatophytoses and systemic mycoses, especially those caused by iermototytes, such as epidermoophyton, microspouum or trichophyton, yeasts such as candida and fungi, e.g. Aappegillus, Mucor or Ate ^ Tla.

The compounds according to the invention can be used as such or together with other known active loves, in particular lithiotics.

The preparation of the chhero-therapeutic compositions or preparations which contain as excipients, solid, semi-solid or liquid carriers or diluents and, in addition, conventional excipients is carried out in the conventional manner according to the intended route of administration and the intended dose, in particular by mixing as described in FIG. i LG Good ^ can, A. Gilmm, The Pentathetical Basis of Therapeuuics.

Formulations for internal and external administration include, for example, tablets, dragees, capsules, pills, aqueous solutions, suspensions and emulsions, and sterile injectable solutions, non-aqueous emulsions, suspensions and solutions, lotions, creams, pastes, lotions. , powders, jellies, sprays and the like.

In general, it is preferred in human veterinary medicine to administer the active ingredient (s) at a dose of 10 to 250 mg / kg per 24 hours, preferably in the form of a number of individual doses to achieve the desired effect. However, it may be desirable to deviate from the above dosage, depending on the nature and severity of the oner afternoon, the way the patient is attained, or the time interval at which the effective dose is administered. served. In some cases, the dose of the active ingredient may be more rotating than the above, while in some cases the dose may need to be exceeded. Determination of the optimum dose and route of administration can be readily accomplished by any person skilled in the art.

When administered topically, the pharmaceutical compositions contain 0.5 to 5, preferably 1 to 2,% by weight of active ingredient. For oral inflammation - a single-dose dose contains 50 to 250 mg of the active substance. The active ingredients are usually administered 1 to 4 times a day.

In conventional galenic formulations, tablets contain the active compound with known excipients, for example, diluents such as dextrose, sodium, soobite, copper, polyvinylpropylidone, lime carbonate, calcium phosphate, milk drk, and the like. such as maize starch or alginic acid, binders such as starch or gelatin, glidants such as magnesium tertiary or magnesium stearate and / or depot-acting agents such as ketylpolytoryl, cellulose cellulose, and cellulose acetate or polyvinyl acetate. The tablets may be composed of several layers.

It is also possible to coat the dragees whose cores have the same composition as ttrt, it is exemplified by koldoonim or shellac, acacia, talc, thioan oxide or sugar. Dragee may also contain an incoliktvrttevil coating as well as other excipients.

The solutions or suspensions may additionally contain flavor enhancers, for example carbohydrate cyclamate or sugar, aro-alcohols such as bath or orange extract. They may also contain suspending agents, for example sodium carboxylate cellulose, or preservatives, for example p-hexyloxybenzot. The active ingredient capsules are prepared by mixing the active ingredient with an inert carrier, for example, milk sugar or a salt, and filling the resulting mixture into a gelatinous capsule.

Ointments, pastes, creams and gels for topical administration contain tavern active substances more conventional carriers, such as fats of animal or rostliímého origin, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene ^to ols, silicone, benionit oxide, křerniiitý, talc oxide zinc or mixtures thereof.

In addition to the active ingredients, powders and sprays also contain conventional carriers such as, for example, milk powder, magnesium stearate, quartz oxide, aluminum hydroxide, calcium silicate and powdered polyamide or a mixture thereof. Sprays may additionally contain a propellant, for example chlorinated and fluorinated hydrocarbons.

The solutions and emulsions may contain, in addition to the active ingredients, conventional carriers such as solvents, co-solvents, and emulsifiers, for example, water, ethyl alcohol, isopropanol, ethylcarborate, ethyl acetate, bennylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide. in particular cottonseed oil, corn oil, corn-germ oil, waxy oil, castor oil or sesame oil, glycerin, glycerine oimal, tetra (alfluoroalkyl), polyethylene glycides and aliphatic esters of sorbitol or mixtures thereof.

The following examples illustrate the invention.

Example 1

58.6 g of 1-toom-4-chlorobenzide are reacted in 2150 mil. G of magnesium chips at boiling point, and then 12.4 g of ethyl ester are added dropwise at 0-10 ° C. ehllrilcilic acid. After stirring at room temperature for 1 hour, the reaction mixture was stirred for 1 h. ice and aqueous ammonium chloride solution were added. The organic phase is dried over sodium sulphate and evaporated in vacuo. The oily oil reaction product was stirred with 20.8 g of 1,2,4-triazole and 8.4 g of sodium bicarbonate for 2 hours at a bath temperature of 130 ° C and then, after cooling, shaken with water and chlorofom. The organ phase was washed with diethyl ether and allowed to stand overlaid from 1,2-di-trifluoride to give 17.3 g of crystalline 1,1-bis- (4-fluorophenil) -2- (1,2,4-triazole-1). 144-C-γ-D-1-ethide.

Analysis for MCW (334,22) calculated: 57.50% C, 3.92% H, 21.22% Cl, 12.57 % N; found: 57.4% .C, 3.9% H, 21.4% Cl, 12.7 % N. He said a. d 2

Free. The base obtained by the method of Example 1 is reacted with hydrogen chloride in solution. Dii soipe · OIpléteru to give 1,1-bl8- (2-chUllfeгil) - 2 ((12.4-triazo0-1-yl) -1-гiandUydrochUorid mp 117 C. ^U

Example 3

29.3 g of 1-bromo-4-chlorobenzol are reacted in 250 ml of diethyl ether with 4 g of magnesium chips at boiling point, and then 22.4 g of 2,2 ', 4 &apos; -cycloterrorium oxide are added dropwise.

After 1 hour, the reaction mixture is quenched with ammonium chloride solution, the organic phase is washed neutral, dried with sodium sulphate and dried in vacuo. The oily reaction was stirred with 20.8 g of 12,4-trisol and 3.4 mg of sodium bicarbonate at a bath temperature of 130 ° C for 2 hours and, after cooling, shaken with water, crushed ice and chloroform. The organic phase is dried over sodium sulphate, evaporated and triturated with .delta. This yielded 22.8 g of crystalline 1- (4-ihlolfeIilL-1- (2,4-dlihUorfeeil) -2- (12.4 iriazol-1-ll-one-et-mo ^l uo, This toni ¹⁸ 7 ° C.

221624

Analysis for (366.67) calculated: 52.13% 0, 3.28% H, 28.85% 01, 11.40% N;

found: 52.06% 0, 3.45% H, 29.4% 01, 11.27% N.

Hříkl ^ i ^ d 4

When the free base of Example 3 is reacted with a solution of hydrogen chloride in diisopropyl ether, 1- (4-chlorotrenyl) -1- (2,4-diclorophene -) - 2- (1,2,4,4-triazole-) is obtained. 1-yl) -1-ethanol hydrochloride, m.p.

Example 5

If the free base of Example 3 is reacted with 100% nitric acid dissolved in dCC (2-propanol) to give 1- (4-chloro-2-carboxylic acid) () V ((^ 2,4tdCcllo ieeinlO 2- (1,2,4ttriazrO- ¹ - ^LO) - ¹ -etanrlnitгát mp ¹⁷⁶ ° C.

Example 6

Pootupeetell described in Examples 3-5, is obtained at poožití appropriate starting materials 1-teernlo11-1 (2t ^c kL0R ^г eelnl) T2T (1,2,4-traarot11-yt1t1-ataюllidrocllrrCi mp 134 ° 0th

Example 7

When used as in Examples 3 to 15, 1-enen-11 (4-chlorophenol) -1,2,4-traarotyl allyl-1-atanol aldro-hydrochloride was obtained with a melting point of 208 ° C.

EXAMPLE 8 was prepared according to the method of Examples 3-5, starting from the polarized starting materials 1teen (4-chloromethyl) -2- (1,2,4-tetrahydro-10) -1-ethanol nitrate, m.p. 201 DEG.

Example 9

The compound was prepared by the method of Examples 3 to 5 to give 1- (2,4-dichlorophenyl) -1- (1,2,4-triazolyl) -1-ethanole at the appropriate starting materials. mp 203 ° 0.

Example 10

Portululeell was obtained by the method of Examples 3-5. 1-enen-1 (2,4-dichlorophenol) -t (1,2,4-tetrahydro-1-yl) -atrolollyl-pyrrolidine, m.p. 183 DEG C., is obtained using the appropriate starting materials.

Example 11

When the pellet is prepared according to the method of Examples 3 to 5, 1te · wl- (2,4-di-chloro-2-yl) -2- (1,2,4-a1-azrl (-1-10)) is obtained with the corresponding starting materials. -1-ethanol nitrate, m.p. 214 DEG.

Example 12

Following the procedure of Examples 3-5, 1- (2-chlorophenyl) -1- (4-chlorophenyl) -2- (1,2,4-traazol-1-yl) was obtained using the appropriate starting materials. -1-Ethanol hydrochloride, m.p. 228 ° C.

Example 13.

Following the procedure of Examples 3 to 15, 1- (2-chloro-phenyl) -1-12,4-dichloro-butyl (2-112,4-thiazolyl) was obtained using the appropriate starting materials. -1-ethanol at temperature. mp 161 ° C.

Example ^^ d 14

If the procedure described in Examples 3 Al 5 obtained when after-ižití appropriate starting materials 1-12-1chloufernl) -1- (2,4-diclloгf-phenyl) -2-1) _J-2,4-1 tгiazol m.p. 195 [deg.] C.

Example 15

After being prepared according to the methods of Examples 3 and 5, 1-13-chloro-1- (2,4-dichlorophenyl) -1, 2,41-triazul-1-I-11-ethylenediamine is obtained using appropriate starting materials. mp 149 ° C.

Example 16

Following the procedure of Examples 3 to 15, 1- (3-chloophenyl) -1- (2,4-dichlorophenyl) -2-11,2,4-triazul-1-11 is obtained by ingestion of the appropriate starting materials. -) 1- ^, tenull — fertilizer with a melting point of 135 ° C.

Example 17

A tablet containing 250 mg of active ingredient can be obtained from the following mixture:

The active substance of Example 3, i.e.) - (4-chlorophenyl) - (2,41 Ullllorphene)

-2-11,2,4-thiazol-1-l-11-ethanol 250 _g potato starch 100 g milk sugar 50 g 4% ielatin solution - 45 g talc 10 g 1000 tablets = 410 g

Production:

The finely powdered active ingredient, potato starch and milk sugar are mixed. The mixture is moistened with 45 g of a 4% strength solution, granulated to a fine granule and dried. The dried granulate is passed through a sieve, mixed with 10 g of talc and compressed into a tablet machine. The tablets are then filled into a tightly sealed poly-polypropylene package.

Example 18

A cream with an active ingredient content of ^2% may be prepared from n i ^ l% f f v U zí

The active ingredient of Example 3, i.e. 1- (4-chloro-4-yl) -1,14,4-tetrahydro-phenyl-1,2 -,2,2,4-thiazol-11-yl 2.0 g

11 221824 glyc eri nm onos teará t 10,0 g cetylalkohol 4.0 g polyethylene glycol 400 stearate 10,0 g polyethylene glycol sorbitan monostearate 10,0 g propylene glycol 6> o g methyl p-hydroxybenzoate 0.2 g demineralized water to 100.0 g

Production:

The finely powdered active ingredient is suspended in ethylene glycol and mixed in the melt of glycerol monostearate, cetyl alcohol, polyethylene glycol 400 stearate and polyethylene glycol sorbitan monostearate heated to 65 ° C. A solution of methyl p-hydroxybenzoate in water heated to 70 ° C is emulsified in the resulting mixture. After cooling, the cream is homogenized in a collagen mill and filled into tubes.

Example 19

A powder with an active ingredient content of 2% can be made from the following mixture:

The active ingredient of Example 3, i.e. 1- (4-chlorophenyl) -1- (2,4-dlchlorophenyl)

-2- (1,2,4-triazol-1-yl) -1-ethanol 2.0 g zinc oxide 10.0 g magnesium oxide 10.0 g highly dispersed silica 2.5 g magnesium stearate 1.0 g talc 74.5 g

Production:

The active ingredient is micronized in an air mill and mixed homogeneously with the other ingredients. The mixture ее is passed through a No. 7 sieve and filled into a polyethylene spreader.

Claims (1)

A process for the preparation of 1,1-diphenyl-2- (1,2,4-triazol-1-yl) -1-ethanol of the general formula I (I) wherein one of the residues R ¹ iP is a chlorine atom and the other radicals are identical or different, represent a hydrogen or chlorine atom, and addition salts thereof with acids acceptable farmekologického aspect, characterized in that reacting a compound of formula III ( ΙΠ) 221824 12 where В ¹ to have the meaning given in formula I and X represents a halogen atom, and 1,2,4-triazole, and the compound obtained is optionally converted into its organic acid-acceptable acid addition salt.