IE51146B1 - 1,1-diphenyl-2-.(1,2,4-triazol-1-yl)-ethan-1-ols,their preparation and therapeutic agents containing these compounds - Google Patents

1,1-diphenyl-2-.(1,2,4-triazol-1-yl)-ethan-1-ols,their preparation and therapeutic agents containing these compounds

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IE51146B1
IE51146B1 IE533/81A IE53381A IE51146B1 IE 51146 B1 IE51146 B1 IE 51146B1 IE 533/81 A IE533/81 A IE 533/81A IE 53381 A IE53381 A IE 53381A IE 51146 B1 IE51146 B1 IE 51146B1
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ethan
triazol
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chlorophenyl
dichlorophenyl
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Basf Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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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 present invention relates to lfl-diphenyl-2(l,2,4-triazol-l-yl)-ethan-l-ols and their pharmaceutically tolerated addition salts with acids, processes for their preparation , and therapeutic agents which contain these compounds and may he used as chemotherapeutic compositions, especially as antimycotics for internal and external use.
A large number of antimycotic agents, for example miconazole or clotrimazole, are known, but their action is not always satisfactory. It is an object of the present invention to provide novel and more effective antimycotics.
We have found that good results are achieved by providing compounds of the general formula I where one of the radicals R , R , and R is chlorine and the others, which are identical or different, are hydrogen or chlorine, and their pharmacologically tolerated addition salts with acids; these compounds exhibit valuable pharmacological properties.
Amongst the novel compounds of the formula I, those where R^ is in the para-position to the ethyl chain, and which accordingly correspond to the general-formula II p=rN N^N-CH.
(II) and' their pharmacologically tolerated addition salts with acids, are particularly preferred.
Conventional acids for forming pharmacologically tolerated salts include in particular nitric acid, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, lactic acid, succinic acid, tartaric acid, citric acid, benzoic acid, salicylic acid and nicotinic acid; others may be found, for example, in Fortschritte der Arzneimittelforschung, Birkhfluser Verlag, Basel and Stuttgart, 10 (1966)» 224-225.
Preferred acids are the inorganic acids mentioned, especially nitric acid and hydrochloric acid, whose salts with the compounds according to the Invention crystallize particularly well.
The compounds according to the invention, in which the phenyl radicals are different from one another, exhibit a center of asymmetry at the carbon atom which carries the hydroxyl. The separation, isolation or preparation of a particular optical isomer can be carried out in a con20 ventional manner. The present invention includes the optical isomers and their preparation.
The compounds of the general formula I and their addition salts with acids may be prepared by reacting a (III) compound of the general formula III 0H Z-^ R1 x-ch2-k2 3 where R, R and Ru have the meanings given for formula I and X is halogen, preferably chlorine or bromine, with 1,2,4-triazole IV I— ι N<. Ji-H (IV) in a conventional manner and, if desired, converting the resulting compound to a pharmacologically tolerated addition salt with an acid.
This reaction is advantageously carried out with stoichiometric amounts in the presence of an acid acceptor, or with excess 1,2,4—triazole, either in the presence or in the absence of a solvent or diluent.
The diluents used are, in the main, organic solvents, for example dimethylformamide, hexamethylphosphorotriamide, acetonitrile or benzene.
Preferred acid acceptors are an excess of 1,2,4triazole, or one of the conventional acid acceptors, for example a hydroxide, carbonate or alcoholate of an alkali metal or alkaline earth metal, especially of sodium, potassium, magnesium or calcium, as well as organic bases for example pyridine, or tertiary amines, such as triethylamine .
The reaction temperatures can be varied over a substantial range. In general, the reaction is carried out at from 0 to 150°C, preferably from 30 to 120°C.
The preparation of the starting compounds of the formula III may be carried out in a conventional manner, using methods for the preparation of tertiary alcohols from ketones or carboxylic acid derivatives and Grignard compounds, for example as described in Houben-Weyl, Methoden der organischen Chemie, 13/2a (1973), 46-527.
If, for example, 1-(2,4-dichlorophenyl)-1-(4chlorophenyl)-2-chloro-ethan-l-ol, prepared from 2,2’,4’trichloroacetophenone and 4-chlorophenyl-magnesium bromide, and 1,2,4-triazole are used as starting materials, the course of the reaction can be represented by the following equation: Cl Cl Cl Cl The compounds of the formula I and their salts possess excellent chemotherapeutic, especially antimycotic, properties.
Accordingly, the present invention also provides an antimycotic agent, which contains a compound of the general formula I, or a pharmacologically tolerated addition salt thereof with an acid, as the active compound, together with an acceptable (e.g. conventional) carrier or diluent.
The surprising antimicrobial activity was shown by the following test in vitro, using Candida albicans: Pseudomycelium and mycelium phase test with Candida albicans: This test takes account of the fact that C. albicans in vivo can form not only budding cells, hut also a pseudomycelium and a true mycelium (dimorphism). In vitro, the development of all growth phases of this fungus, and the influence of antimycotically active substances is tested as follows: Candida albicans (Robin) Berkhout No.2O/M (a strain from Mykothek, Nordmark-Werke GmbH) is transferred, with an inoculating loop, onto the surface A of the nutrient medium (Brain Heart Infusion, Difco) and also, as a stab, at B (cf. the Figure).
Additionally, a cover slip C is placed over the zone of the stab culture (to create microaerophilic con20 ditions). The nutrient medium in the petri dish D contains a geometrically graded dilution series of the particular test substance. After incubation of these test plates for 2 days at 37°C, a control plate not containing the antimycotic agent exhibits growth of exclusively budding cells (yeast phase) in the aerobic zone A and exclusively pseudohyphae and true hyphae in the microaerophilic zone B.
The minimum inhibitory concentration is the con51146 . centration step of the test formulation at which 100% inhibition of the particular fungal growth is observed.
This test method makes it possible to differentiate between the minimum inhibitory concentration of the yeast phase (MlCy^^ phaseof phase or mycelium phase (MICmycellum phage) for Candida albicans.
Whilst the MIC values for the yeast phase are greater than 128 gg/ml, the MIC values for the mycelium phase are extremely low, as may be seen from Table 1.
TABLE 1 Example No. R1 R2 R3 Salt "^myc.ph LD5° (mouse) (/Ug/m’i)' p.o. (mg/kg) 1 H 4-C1 4-Cl - < 0,125 > 1000 2 H 4-C1 4-C1 HCl < 0.125 > 1000 3 2-C1 4-Cl 4-C1 - <0.125 > 4000 4 2-C1 4-Cl 4-C1 •HCl <0.125 > 1000 5 2-C1 4-Cl 4-C1 hno3 <0.125 > 1000 6 2-C1 H H HCl <0.125 >1000 7 H 4-C1 H HCl <0.125 > 1000 8 H 4-C1 H hno3 <0.125 >1000 9 2-C1 4-Cl H - <0.125 >1000 10 2-C1 4-C1 H HCl <0.125 >1000 11 2-C1 4-Cl H hno3 <0.125 >1000 12 2-C1 H 4-C1 HCl 1 >1000 13 2-C1 4-Cl 2-C1 - 1 >1000 14 2-C1 4-Cl 2-C1 HCl 1 >1000 15 2-C1 4-Cl 3-C1 - <0.125 >1000 16 2-C1 4-Cl 3-C1 HCl 1 > 1000 5114 6 The antimicrobial activity in vitro against dermatophytes was determined by the agar dilution test (cf. P. Klein, Bakteriologische Grundlagen der chemotherapeutischen Laboratoriumspraxis). The result of these investigations, taking compound No.3 as an example, is shown in Table 2.
TABLE 2 MIC (pg/ml) Microsporon species: M. audouinii No. 4 0.25 M. ferruglneum No. 5 0,5 M. canis No. 167 4 M. canis No. 168 2 M. canis No. 169 8 Trichophyton species: - T. schoenleinli No. ' 9 0.25 T. violaceum No. 10 2 T. mentagroph. No. 159 0,125 T. mentagroph. No. 172 0,25 T. mentagroph. No. 173 0.25 Epidermophyton species: E. floccosum No. 157 16 Experimental candidosis in mice, caused by Candida albicans 2o To ascertain the oral effectiveness, groups of 10 mice weighing about 20 g were pretreated for 2 days with 50 mg/kg per mouse per day of hydrocortisone administered intramuscularly, in order to achieve rapid development of the infection. The mice were then each Infected intravenously with 500,000 Candida albicans germs, after which they were given 100 mg/kg of the test substance orally twice daily for 4 days.
In addition to the infected group and the untreated control group, one group each was treated with the reference substances miconazole and clotrimazole, for comparison.
Table 3 shows that on the 10th day after infection up to 100% of the animals treated with the compounds io according to the invention survived, whilst in the control group and in the case of the animals treated with the reference substances the survival rate was only up to 30%.
TABLE 3 (Dosage: 100 mg/kg twice daily) Example Number of surviving animals on the ... day No. after infection • 1. 2. 3. 4. 5- 6. 7. 8. 9. 10, 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 10 10 10 10 10 10 10 1» 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 10 10 10 10 10 10 9 9 8 8 Miconazole 10 10 8 8 6 4 2 2 1 1 Clotrimazole 10 10 10 9 8 6 5 5 4 3 Control 10 10 8 7 4 3 2 1 1 1 To test the intensity of the effect in vivo, groups of 10 mice were infected with Candida albicans germs as described above and then treated twice daily, for 4 days, with 46.4 mg/kg (Table 4) or 21,5 mg/kg (Table 5) of a selection of test substances.
TABLE 4 (Dosage: 46.4 mg/kg twice daily) Example Number of surviving animals on the ... day No. after infection 1. 2. 3. 4. 5. 6. 7. ' 8. 9. 10. 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 1010 10 10 9 9 5 10 10 10 10 - 10 Ϊ0 . 10 9 9 9 11 10 10 10 10' 10 10 10 10 9 9 Clotrimazole 10 10 9 8 8 7 6 6 4 3 Control 10 10 8 7 4 3 1 1 1 1 TABLE 5 (Dosage: 21.5 mg/kg twice daily) Example No. Number of surviving animals on the ... day after infection 7- 1. 2. 3. 4. 5. 6. 8. 9- 10. 2 10 10 10 • 10 10 9 9 8 8 8 3 10 10 10 10 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 11 10 10 10 10 10 10 10 9 9 9 Clotrimazole 10 10 9 5 5 3 2 2 0 0 Control 10 10 8 5 3 1 1 1 0 0 Notes on Tables 3, 4 and 5: The Example numbers stand for the following compounds : = l,l-bis-(4-chlorophenyl)-2-(l,2,4-triazol-l-yl)ethan-l-ol = 1,1-bis-(4-chlorophenyl)-2-(1,2,4-triazol-l-yl)ethan-l-ol hydrochloride = l-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-2-(l,2,4triazol-l-yl)-ethan-l-ol = l-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-2-(l,2,4triazol-l-yl)-ethan-l-ol hydrochloride = l-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-2-(l,2,410 triazol-l-yl)-ethan-l-ol nitrate = 1-phenyl-l-(2-chlorophenyl)-2-(1,2,4-triazol-l-yl)ethan-l-ol hydrochloride = l-phenyl-l-(4-chlorophenyl)-2-(l,2,4-triazol-l-yl)~ ethan-l-ol hydrochloride = l-phenyl-l-(4-chlorophenyl)-2-(l,2,4-triazol-l-yl)ethan-l-ol nitrate = 1-phenyl-l-(2,4-dichlorophenyl)-2-(1,2,4-triazol-lyl )-ethan-l-ol = l-phenyl-l-(2,4-dichlorophenyl)-2-(l,2,’4-triazol-l20 yl)-ethan-l-ol hydrochloride = 1-phenyl-l-(2,4-dichlorophenyl)-2-(1,2,4-triazol-lyl )-ethan-l-ol nitrate = l-(3-chlorophenyl)-l-(2,4-dichlorophenyl)-2-(l,2,4triazol-l-yl)-ethan-l-ol The results show that the compounds accordingto the invention, of the general formula I, are distinctly superior,in vivo, to the medically used antimycotics mic cnazdLe (l-[2,4dichloro-β- (2,4-dichlorobenzyloxy)-phenethyl]-imidazole nitrate) and clotrimazoie [l-(o-chloro-a, Since the medicaments hitherto available for treating systemic mycoses are not . fully satisfactory and a further increase in such diseases is expected (literature: Infection 2 (1974), 95; Chemotherapy 22 (1976), 1; Dtsch. Apoth. Ztg. 118 (1978), 1269), the novel compounds constitute a genuine enrichment of the medicinal armory.
The novel compounds are particularly suitable for oral and external treatment of fungal infections in man and animals.
Examples of fields of indication in man and animals are: dermatomycoses, dermatophytoses and systemic mycoses, especially caused by dermatophytes, such as species of the genera Epidermophyton, Microsporum or Trichophyton, yeasts, such as species of the genus Candida, and molds, such as species of the genus Aspergillus, Mucor or Absidia.
The compounds may be used alone or together with 20 other conventional active compounds, especially antibiotics.
The chemotherapeutic agents or formulations, containing conventional solids, semi-solid or liquid carriers or diluents and conventional pharmaceutical auxiliaries appropriate to the desired route of administration, plus a dosage of active compound appropriate for internal administratiai or external application, are prepared in a conventional manner, especially by mixing the ingredients (cf. L.G. Goodman and A. Gilman, The Pharmacological Basis of Therapeutics).
Examples of formulations suitable for internal administration and external application include tablets, dragees, capsules, pills, aqueous solutions, suspensions and emulsions, sterile injectable solutions, non-aqueous emulsions, suspensions and solutions, ointments, creams, pastes, lotions, powders, gels, sprays and the like.
In general, it has proved advantageous, both in human medicine and in veterinary medicine, to administer the active compound in amounts of from about 10 to about 250 mg/kg of body weight per 24 hours, preferabXy in the form of several individual doses, if the desired results are to be achieved. It may however be necessary to deviate from the dosages mentioned, in particular depending on the nature and severity of the disease, the type of formulation and maimer of administration of the drug, and the period or interval in which it is administered.
Thus it may in some cases suffice to use less than the above amount of active compound, whilst in other cases the above amount must be exceeded. The requisite optimum dose and route of administration of the active compound can readily be established, for the particular case, by a skilled worker, making use of his expert knowledge.
For external, local application, the formulation contains from 0.5 to 5, preferably from 1 to 2, % by weight of active compound. For oral administration, suitable individual doses are from 50 to 250 mg. As a rule, the active compound is administered from 1 to 4 times daily.
The conventional pharmaceutical forms, suoh as tablets, can, for example, be prepared by mixing the active compound with conventional auxiliaries, for example inert diluents, such as dextrose, sucrose, sorbitol, mannitol, polyvinylpyrrolidone, calcium carbonate, calcium phosphate or lactose, disintegrating agents, such as corn starch or alginic acid, binders, such as starch.or gelatin^ lubricants, such as magnesium stearate or talc, and/or agents for achieving a depot effect, such as carboxypolymethylene, carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets can also consist of a plurality of layers.
Correspondingly, dragees can be prepared by coating cores, prepared similarly to the tablets, with agents conventionally used in dragee coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
The dragee coating can also consist of a plurality of layers, and the auxiliaries mentioned above in connection with tablets may be used therein.
Solutions or suspensions containing the active compounds to he used according to the invention may additionally contain sweeteners, such as saccharin, cyclamate or sugar, and also, for example, flavorings, such as vanillin or orange extract. They may also contain suspending agents, such as sodium carboxymethylcellulose, or preservatives, such as phydroxybenzoates. Capsules containing the active compounds may he prepared, for example, hy mixing the active compound with an inert carrier, such as lactose or sorbitol, and encapsulating it in gelatin capsules.
Ointments, pastes, creams and gels for external use may contain the conventional carriers In addition to the active compound or compounds, for example animal and vegetable fats, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc or zinc oxide or mixtures of these materials. 1° Powders and sprays may contain the conventional carriers in addition to the active compound, for example lactose, talc, silica, aluminum hydroxide, calcium silicate and nylon powder or mixtures of these substances. Sprays may additionally contain conventional propellants, eg. chlorofluorohydrocarbons.
Solutions and emulsions may contain the conventional carriers in addition to the active compound or compounds, such as solvents, solubilizers and emulsifiers, for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame oil, glycerol, glycerol formal, tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters of sorbitan, or mixtures of these materials.
EXAMPLE 1 58.6 g of l-bromo-4-chlorobenzene are reacted with 8 g of magnesium filings in 250 ml of diethyl ether at the boil, and 12.4 g of ethyl chloroacetate are then added dropwise at 0-10°C. The reaction mixture is stirred for one hour at room temperature and is then treated with ice and aqueous ammonium chloride solution. The organic phase is dried over sodium sulfate and concentrated under reduced pressure. The oily reaction product is then stirred with 20.8 g of 1,2,4-triazole and 8.4 g of sodium bicarbonate for 2 hours as a melt, at 130°C bath temperature, and after cooling the mixture is extracted by shaking with water and chloroform. The organic phase is dried over sodium sulfate and concentrated, and the residue is triturated with diethyl ether. Recrystallization from 1,2-dichloroethane gives 17.3 g of crystalline 1,1-bis(4-chlorophenyl)-2-(1,2,4-triazol-l-yl)-ethan-l-ol of melting point 144°C.C16H13C12N3° (334.22) Calculated %: C 57.50 H 3.92 Cl 21.22 N 12.57 Found %: 57.4 3.9 21.4 12.7 EXAMPLE 2 The base obtained in Example 1 is treated with a solution of hydrogen chloride in diisopropyl ether. 1,1-Bis-(4-chlorophenyl)-2-(1,2,4-triazol-l-yl)-ethan-lol hydrochloride, of melting point 117°C, is obtained.
EXAMPLE 3 29.3 g of l-bromo-4-chlorobenzene are reacted with 4 g of magnesium filings in 250 ml of diethyl ether at the boil, and 22.4 g of 2,2',4'-trichloroacetophenone are then added dropwise.
After an hour, the mixture is decom51146 posed with aqueous ammonium chloride solution and the organic phase is washed neutral, dried over sodium sulfate and concentrated under reduced pressure. The oily reaction product is stirred with 20.8 g of 1,2,4-triazole and 3.4 g of sodium bicarbonate for 2 hours as a melt at 130°C bath temperature, and, when it has cooled, the mixture is extracted by shaking with ice water and chloroform. The organic phase is dried over sodium sulfate and concentrated, and the residue is triturated with diethyl ether. 22.8 g of crystalline l-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-2-(l,2,4-triazol-l-yl)-ethan-l-ol of melting point 187°C are obtained.
C16H12C13N3° (368·67) Calculated %: C 52.13 H 3.28 Cl 28.85 N 11.40 Found %: 52.06 3.45 29.4 11.27 EXAMPLE 4 The base obtained in Example 3 is treated with a solution of hydrogen chloride in diisopropyl ether. 1-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazoll-yl)-ethan-l-ol hydrochloride, of melting point 130°C, is obtained.
EXAMPLE 5 The base obtained in Example 3 is treated with a solution of 100% strength nitric acid in diisopropyl ether. 1-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-2(l,2,4-triazol-l-yl)-ethan-l-ol nitrate, of melting point 176°C, is obtained.
EXAMPLE 6 ΤΘ 16 The following compounds were synthesized by methods similar to those of Examples 3, 4 and 5: 6. 1-Phenyl-1-(2-chlorophenyl)-2-(1,2,4-triazol-l-yl)ethan-l-ol hydrochloride, melting point 134°C. 7. 1-Phenyl-l-(4-chlorophenyl)-2-(1,2,4-triazol-l-yl)ethan-l-ol hydrochloride, melting point 208°C. 8. 1-Phenyl-l-(4-chlorophenyl)-2-(1,2,4-triazol-l-yl)ethan-l-ol nitrate, melting point 201°C„ 9. 1-Phenyl-l-(2,4-dichlorophenyl)-2-(l,2,4-triazol-lyl )-ethan-l-ol, melting point 203°C. io 10. l-Phenyl-l-(2,4-dichlorophenyl)-2-(l,2,4-triazol-lyl )-ethan-l-ol hydrochloride, melting point 183°C. 11. 1-Phenyl-l-(2,4-dichlorophenyl)-2-(1,2,4-triazol-lyl )-etban-Irol nitrate, melting point 2l4°C. 12. 1-(2-Chlorophenyl)-1-(4-chlorophenyl)-2-(1,2,4triazol-l-yl)-ethan-l-ol hydrochloride, melting point 228°C. 13. 1-(2-Chlorophenyl)-1-(2,4-dichlorophenyl)-2-(1,2,4triazol-l-yl)-ethan-l-ol, melting point l6l°C. 14. 1-(2-Chlorophenyl)-1-(2,4-dichlorophenyl)-2-(1,2,42o triazol-l-yl)-ethan-l-ol hydrochloride, melting point 195°C. . 1-(3-Chlorophenyl)-1-(2,4-dichlorophenyl)-2-(1,2,4triazol-l-yl)-ethan-l-ol, melting point 149°C. 16. 1-(3-Chlorophenyl)-1-(2,4-dichlorophenyl)-2-(1,2,4triazol-l-yl)-ethan-l-ol hydrochloride, melting point 135°C.
EXAMPLE 17 Tablet containing 250 mg of active compound Active compound from Example No.3 [l_ (4-chlorophenyl)-1-(2,4-dichlorophenyl)2-(1,2,4-triazol-l-yl)-ethan-l-ol] 250 g Potato starch 100 g Lactose 50 g 4% strength gelatin solution about 45 g Talc 10 g 1,000 tablets = about 410 g Preparation: The finely powdered active compound, potato starch 10 and lactose are mixed. The mixture is moistened with about 45 g of 4% strength gelatin solution, finely granulated and dried. The dry granules are sieved, mixed with 10 g of talc and tableted on a rotary tableting machine. The tablets are packed in tightly closed polypropylene containers.
EXAMPLE 18 Cream containing 2% of active compound Active compound from Example No.3 [l- (4-chlorophenyl)-1-(2,4-dichlorophenyl)2-(l,2,4-triazol-l-yl)-ethan-l-ol] 2.0 g Glycerol monostearate 10.0 g Cetyl alcohol g Polyethylene glycol 400-stearate 10.0 g Polyethylene glycol sorbitan monostearate 10.0 g Propylene glycol 6.0 g Methyl p-hydroxybenzoate 0.2 g Demineralized water ad 100.0 g Preparation: The very finely powdered active compound is sus· pended in propylene glycol and the suspension is stirred into a melt, heated to 65°C, of glycerol monostearate, cetyl alcohol, polyethylene glycol 400-stearate and polyethylene glycol sorbitan monostearate. The methyl p-hydroxybenzoate is dissolved in water and the solution, at 70°C, is emulsified in the above mixture. When the cream has cooled, it is homogenized in a colloid mill and packed in tubes.
EXAMPLE 19 Powder containing 2% of active compound 10 Active compound from Example No.3 [1-(4-chlorophenyl)-1-(2,4-dichlorophenyl)2-(l,2,4-triazol-l-yl)-ethan-l-ol] 2.0 g Zinc oxide 10.0 g Magnesium oxide 10.0 g Highly disperse silica 2.5 g Magnesium stearate 1.0 g Talc 74.5 g Preparation: The active compound is micronized in an air jet 20 mill and mixed homogeneously with the other constituents.
The mixture is beaten through a No.7 sieve and is packed in polyethylene containers having a sprinkler insert.

Claims (12)

1. A 1,ί-dipheny1-2-(1,2,4-triazol-l-yl)-ethanol of the general formula I 12 · . where one of the radicals R , R and R is chlorine and the others, which are identical or different, are hydrogen or chlorine, and its pharmacologically tolerated salts.
2. A compound as claimed in claim 1, wherein R 1 in formula I is chlorine in the para-position to the ethyl chain.
3. A compound according to claim 1 which has been identified in any of Examples Nos. 1 to 16.
4. 1,l-Bis-(4-chlorophenyl)-2-(1,2,4-triazol-l-yl)ethan-l-ol and its pharmacologically tolerated salts.
5. 1-Pheny1-1-(2,4-dichlorophenyl)-2-(1,2,4-triazoll-yl)-ethan-l-ol and its pharmacologically tolerated salts.
6. 1-(4-Chiorophenyl)-1-(2,4-dichloropheny1)-2(1,2,4-triazol-l-yl)-ethan-l-ol and its pharmacologically tolerated salts.
7. A process for the preparation of a compound as claimed in claim 1, wherein a compound of the general formula III 12 5 where R , R and R have the meanings given in claim 1 and X is halogen, is reacted with 1,2,4-triazole, and, if desired, the resulting compound is converted to a pharmacologically tolerated addition salt with an acid.
8. A process as claimed in claim 7, wherein 1,l-bis-(4-chlorophenyl)-2-ehloro-ethan-l-ol is reacted.
9. A process as claimed in claim 7, wherein 1-pheny1-1-(2,4-dichlorophenyl)-2-chloro-ethan-l-ol is reacted.
10. A process as claimed in claim 7, wherein 1-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-2-chloro-ethanl-ol is reacted.
11. A therapeutic agent which contains a compound as claimed in any of claims 1 to 6 as the active compound, in addition to a pharmaceutically acceptable auxiliary or carrier.
12. Use of a compound as claimed in any of claims 1 to 6 as a drug in combating mycoses excluding the use thereof on or in humans.
IE533/81A 1980-03-15 1981-03-11 1,1-diphenyl-2-.(1,2,4-triazol-1-yl)-ethan-1-ols,their preparation and therapeutic agents containing these compounds IE51146B1 (en)

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US4654332A (en) 1979-03-07 1987-03-31 Imperial Chemical Industries Plc Heterocyclic compounds
US4927839A (en) * 1979-03-07 1990-05-22 Imperial Chemical Industries Plc Method of preventing fungal attack on wood, hides, leather or paint films using a triazole
EP0131684B1 (en) * 1980-08-18 1992-03-11 Imperial Chemical Industries Plc Use of triazolylethanol derivatives and their compositions as non-agricultural fungicides
ZA815700B (en) * 1980-08-28 1982-08-25 Ici Ltd Pharmaceutical compositions
EP0122452A1 (en) * 1983-03-18 1984-10-24 Schering Corporation Triazolyl- and imidazolyl-substituted fluoroalkane derivatives, process for their preparation and pharmaceutical compositions containing them
US4482564A (en) * 1983-06-03 1984-11-13 Schering Corporation Triazolyl-substituted propane derivatives
GB8319984D0 (en) * 1983-07-25 1983-08-24 Ici Plc Optically active fungicidal compound
PH20855A (en) * 1984-01-24 1987-05-19 Pfizer Antifungal agents
DE3511409A1 (en) * 1985-03-29 1986-10-02 Basf Ag, 6700 Ludwigshafen PRODUCTION OF MEDICINES AGAINST VIRUS DISEASES
US4729986A (en) * 1986-04-24 1988-03-08 E. I. Du Pont De Nemours And Company Fungicidal triazoles and imidazoles
WO2010149758A1 (en) * 2009-06-25 2010-12-29 Basf Se Antifungal 1, 2, 4-triazolyl derivatives
CN107879991A (en) * 2017-11-24 2018-04-06 沈阳感光化工研究院有限公司 A kind of synthetic method of fluorine-containing triazolinones

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DE2324010C3 (en) * 1973-05-12 1981-10-08 Bayer Ag, 5090 Leverkusen 1-Substituted 2-triazolyl-2-phenoxyethanol compounds, process for their preparation and their use for combating fungi
DE2431407C2 (en) * 1974-06-29 1982-12-02 Bayer Ag, 5090 Leverkusen 1,2,4-Triazol-1-yl-alkanones and alkanols, processes for their preparation and their use as fungicides
DE2547954A1 (en) * 1975-10-27 1977-04-28 Bayer Ag 1- (2-HALOGEN-2-PHENYL-AETHYL) -TRIAZOLE, METHOD FOR THEIR MANUFACTURING AND THEIR USE AS FUNGICIDES
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