KR830002277B1 - Method for preparing hydroxyethyl-azole compound - Google Patents

Abstract

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Description

Method for preparing hydroxyethyl-azole compound

The present invention relates to a process for preparing hydroxy ethyl-azole and the salts of the following general formula (I).

In the above general formula

Az represents an imidazole or triazole group and R represents any substituted phenyl, naphthyl or tetrahydro naphthyl group

R ¹ represents an optionally substituted phenyl or cycloalkyl group

R ² represents a hydrogen atom or R ¹ and R ² in the ortho position represent a methylene bridge having several CH ₂ optionally substituted together or naphthyl together with a phenyl ring.

R ³ represents a halogen atom or an alkyl, alkoxy or halogeno alkyl group

n is 0, 1, 2 or 3.

The present invention relates to novel hydroxypropyl-triazole compounds and their preparation and use as antifungal agents.

In particular, 1- (β-aryl) -ethyl imidazole derivatives such as 1- [2,4-dichloro-β- (2,4-dichlorobenzyloxy) -phenyl] -imidazole nitrate have excellent antifungal action. Is already revealed. (Reference: DE-AS 1940388) However, their in vivo action, especially on candida, is not always completely satisfactory.

The compounds of the present invention have potent antifungal action.

According to the present invention there is provided a process for preparing a compound of the invention as a) or b).

a) reacting azolylmethyl phenyl ketone of the following general formula (II) with a Grignard compound of the following general formula (III)

b) 1-halogeno-ethyl-2-ol of the following general formula (IV) is reacted with an azole of the following general formula (V), preferably in the presence of an acid-binding agent and in the presence of a diluent.

In the above general formula

Az, R ¹ , R ² , R ³ R and n are as described above

X represents a halogen atom (preferably chlorine or bromine)

Y represents a halogen atom (preferably chlorine or bromine),

Z represents a hydrogen atom or an alkali metal.

The product according to preparation (a) or (b) can be converted into salts by reaction with an acid, if necessary.

The hydroxyethyl-azoles of formula (I) obtainable according to the invention can be converted into salts by reaction with an acid. Pharmaceutically acceptable salts of the novel hydroxyethyl-ethylazole salts of the present invention are particularly important and preferred. Surprisingly, the hydroxyethylazoles according to the invention not only have good in vitro antifungal activity but also known 1- [2,4-dichloro-β- (2,4-dichlorobenzyloxy) -phenethyl] -imidazole nitrate. Better therapeutic activity than canlate, especially for Candida. Thus, the active compounds according to the invention represent a more valuable advance in pharmacy.

Preferred hydroxyethylazoles of the present invention are the following compounds. That is, phenyl, naphthyl or tetrahydronaphthyl where Az represents an imidazol-1-yl 1,2 4-triazol-1-yl or 1,3,4-triazol-1-yl group and R is optionally substituted Group, preferably fluorine, chlorine and bromine, in each case 1 to 4 straight chain and branched chain alkyl and alkoxy, halogenoalkyl having 1 to 4 carbon atoms and 5 halogen atoms (preferably having 1 or 2 carbon atoms). And up to the same or different halogen atom 3, halogen is fluorine and chlorine and trifluoromethyl is preferred), R ¹ is optionally substituted phenyl or a cycloalkyl group of C ₃ to C ₇ [preferable substituent is halogen (fluorine , Chlorine or bromine are preferred) and alkyl having 1 to 4 (preferably 1 to 2) carbon atoms; and R ² represents a hydrogen atom or R ¹ and R ² together form 3 in an ortho-position to one another. Has a methylene group of 5 to 5 Righteousness mono- or multi-substituted methylene bridge [The preferred substituents are (preferably a chlorine, fluorine or bromine), a halogen and having 1 to 4 carbon atoms, preferably 1 to alkyl having 2 or represent, R ¹ and R ² And together with the phenyl ring form a naphthyl group, R ³ is a halogen atom (preferably fluorine, chlorine, bromine), in each case a straight or branched chain alkyl or alkoxy group having 1 to 4 carbon atoms or 1 to 4 carbon atoms and 5 Halogenoalkyl groups having halogen atoms up to [preferably halogenoalkyl groups having 1 or 2 carbon atoms and 3 same or different halogen atoms (fluorine and chlorine) (e.g. trifluoromethyl)]. , n is 0,1 or 2

Very particularly preferred compounds of the invention are the following compounds:

Az represents an imidazol-1-yl or 1,2,4-triazol-1-yl group

R optionally represents a phenyl group mono- or di-substituted by chlorine, fluorine or methyl or represents a naphthyl or tetrahydronaphthyl group R ¹ represents phenyl, cyclopentyl or mono- or di-substituted optionally with chlorine, bromine, fluorine or methyl A cytylhexyl group and R ² represents a hydrogen atom or R ¹ and R ² together represent a trimethylene, tetramethylene or pentamethylene bond optionally substituted with chlorine or methyl in the ortho-position to each other or together with a phenyl ring Form a tilt group,

R ³ represents a chlorine or fluorine atom or a methyl group and n represents 0 or 1.

The following compounds having general formula (I) may be specifically mentioned in addition to the compounds mentioned in the preparation examples.

For example, when 4-biphenyl imidazol-1-yl methyl ketone and 4-chlorophenyl-magnesium chloride are used as starting materials, the reaction route can be represented by the following scheme (strain (a)).

When 1- (4-biphenyl) -1- (2,4-dichlorophenyl) -2-chloro-ethanol and sodium imidazole are used as starting materials, the reaction route can be represented by the following scheme (variation (b )).

Preferred compounds having the general formula (II) used as starting materials for variant (a) are mentioned in the preferred hydroxyethylazoles and very particularly preferred hydroxyethylazoles in which Az, R ¹ , R ² , R ³ and n are preferred. Compound as shown.

Azolyl ethyl phenyl ketones of the general formula (II) are novel. However, these compounds can be prepared by known methods. That is, the corresponding penacyl halide of the following formula (VI) is prepared by reacting at a temperature of 20 to 80 ° C. in the presence of a diluent such as azole and dimethylformamide, in particular in the presence of an excess of an acid binder such as azole (US Patent Specification) 3,658,813).

In the above general formula

R ¹ , R ² , R ³ and n are as described above and Hal represents a chlorine or bromine atom.

Examples of starting materials of the general formula (II) are as follows: 4-biphenyl imidazol-1-yl-methylketone, 4- (4'-chlorophenylyl) imidazol-1-yl-methylketone, 2-biphenyl imidazol-1-yl-methyl ketone, 4- (2 ', 4'-dichlorobiphenylyl) imidazol-1-yl-methyl ketone, 2-chloro-4-biphenyl imidazole-1 -Yl-methylketone, 2-chloro-4- (4'-chlorobiphenyl) imidazol-1-yl-methylketone, 4-cyclohexylphenyl imidazol-1-yl-methyl ketone, 4-cyclopentyl- Phenyl imidazol-1-yl-methylketone, 4-chloro-3-cyclohexyl-phenyl imidazol-1-yl-methylketone, 4- (3-bromocyclohexyl) -phenyl imidazol-1-yl- Methyl ketone, 4-cyclopentyl-2-chlorophenylidazol-1-yl-methyl ketone, 4-cyclopentyl-2- pullophenyl imidazol-1-yl-methyl ketone, 4-cyclopentyl-2 -Methyl-phenyl imidazol-1-yl-methylketone, 4- (1-methylcyclohexyl) -phenyl imidazol-1-yl-methylketone, 4-cyclohep Phenyl imidazol-1-yl-methylketone, 4-cycloheptyl-2-chlorophenyl imidazol-1-yl-methylketone, naphth-1-yl imidazol-1-yl-methylketone, naphth-2 -Yl imidazol-1-yl-methyl ketone, 1,2,3,4-tetrahydro-naphth-5-yl imidazol-1-yl-methyl ketone, 1,2,3,4-tetrahydro- Naphth-6-yl imidazol-1-yl-methyl ketone, and indan-4-yl imidazole-1-methyl ketone, and the corresponding 1,2,4-triazol-1-yl ketone and 1,3 , 4-triazol-1-yl ketone.

Preferred Grignard compounds having the general formula (III) used as starting materials for variant (a) are those in which R has the meanings mentioned above.

Grignard compounds of general formula (III) are generally compounds known in organic chemistry. Examples are: phenyl-magnesium chloride, 4-chlorophenyl-magnesium chloride, 2,4-dichlorophenyl-magnesium chloride, 2,6-dichlorophenyl-magnesium chloride, 2-chloro-6-fluorophenyl-magnesium Chloride, 2-chlorophenyl-magnesium chloride, 3-chlorophenyl-magnesium chloride, 3,4-dichlorophenyl-magnesium chloride, naphth-2-yl-magnesium chloride and 1,2,3,4-tetrahydronaft -6-yl-magnesium chloride, and the corresponding bromide.

Preferred 1-halogenoethan-2-ols used as starting materials in variant (b) refer to R, R ¹ , R ² , R ³ and n above preferred hydroxyethylazoles and particularly preferred these compounds. As compounds.

1-halogeno-2-ol of formula (IV) is novel. However, they can be prepared by a known method of reacting a ketone of general formula (VI) with a Grignard compound of general formula (III) according to variant (a) (DE-OS) 2623129 Arc and preparation examples).

Preferred azoles Az of general formula (V) used as starting material for variant (b) have the meanings mentioned in the above preferred hydroxyethylazoles and in particular those preferred compounds and Z is preferably a hydrogen atom or sodium or potassium It is a compound which represents.

The azoles of formula (V) are generally compounds known in organic chemistry.

In variant (a) according to the invention all solvents customarily used in the Grignard reaction can be used. Preferred solvents include ethers such as diethyl ether or tetrahydrofuran and mixtures with other organic solvents such as benzene.

In variant (a) the reaction temperature can be varied within a substantial range. The reaction is preferably carried out between 20 and 120 ° C, more preferably 30 to 80 ° C.

When performing variant (a) it is preferred to use an excess of Grignard compound having 3 to 5 moles of general formula (III) per mole of compound of general formula (II). Separation of the compound of general formula (I) is carried out by a known method.

Preferred diluents used in variant (b) of the present invention are inert organic solvents. Preferred solvents include ketones such as diethyl ketone, in particular acetone and methyl, ethyl, ketone and propionitrile and nitriles such as acetonitrile, alcohols such as ethanol or isopropyl, ethers such as tetrahydrofuran or dioxane, Aromatic hydrocarbons such as benzene, toluene and dichlorobenzene, formamides such as dimethylformamide, halogenated hydrocarbons such as methylene chloride tetrachloride or chloroform and the like.

When the variant (b) according to the invention is carried out in the presence of an acid binder, any of the inorganic or organic acid linkages which can be used in common can be added. Examples of inorganic or organic acid binders are alkali metal carbonates (sodium carbonate, potassium carbonate and sodium bicarbonate) or lower tertiary alkylamines, cycloalkylamines or aralkylamines, for example triethylamine, N, N-dimethylcyclohexylamine , Dicyclohexylmethylamine N, N-dimethylbenzylamine and pyridine and diazabicyclooctane. Excess azoles are preferably used.

The reaction temperature of variant (b) can be varied within a substantial range. The reaction is preferably carried out at 30 to 200 ° C. and the boiling point of the solvent is more preferable.

In the performance of variant (b) according to the present invention, 1 to 2.5 moles of azole and 1 to 2.5 moles of acid binder are preferably used per mole of the compound of formula (IV). When using an alkali metal salt, it is preferable to use 1-1.5 mol of alkali metal salts per mol of general formula (IV) compounds. To separate the compound of general formula (I), the solvent is distilled off and the residue is dissolved directly with water or dissolved in an organic solvent and washed, in which case the organic layer is dried over sodium sulfate and the solvent is removed under vacuum. The residue is purified by distillation or recrystallization or chromatography. Any acid that forms a physiologically acceptable salt can be used to prepare such salts. Hydrochloric acids such as hydrochloric acid and hydrobromic acid are preferred for these acids, and in particular hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid, monofunctional and difunctional carboxylic acid and acetic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, Hydroxycarboxylic acids such as sorbic acid and lactic acid and sulfonic acids such as P-toluenesulfonic acid and 1,5-naphthalene disulfonic acid.

Salts of compounds of formula (I) can be obtained by conventional salt forming methods, for example, by dissolving the compounds of formula (I) in a suitable inert solvent and adding an acid such as hydrochloric acid, which are known methods, for example It can be separated by filtration and, if necessary, can be washed and purified with an inert organic solvent.

The compounds according to the invention exhibit antimicrobial action, in particular antifungal action. These include not only dermatophytes and yeasts but also biphasic fungi such as Candida Albicans, Epidermophyton, and Aspergillus niger. genus Aspergillus, such as Aspergillus fumigatus, genus Trichophyton, such as Trichophyton mentagrophytes, and microsporon felineum, such as It has a particularly broad antifungal activity against the genus Penicillum such as penicillum commune. Meaning of the microorganisms that can affect the printing of the bacterium is never meant to be merely for illustration. Examples that may be mentioned in the field of application to anthropology include peony and other ringworm fungi, vesicle fungi, hairy fungi, yeasts and filaments, as well as dermatophytes and systemic filaments caused by biphasic fungi.

Areas of application in veterinary medicine include dermatophytosis and mycorrhizal fungi caused by the above-mentioned pathogens.

As mentioned above, the present invention also relates to the use of the compounds of the present invention in anthropology and veterinary medicine.

The present invention is a compound of the present invention as an active ingredient with a solid or liquefied gas phase diluent or exemplified in the presence of a surfactant, and mixed with a liquid diluent other than a solvent having a molecular weight of 200 or less (preferably 350 or less). It provides a pharmaceutical composition containing.

The present invention also provides a pharmaceutical composition containing the compound of the present invention as an active ingredient in the form of sterile and / or physiological isotonic solution.

The invention also provides a drug in dosage unit form containing a compound of the invention. Drugs in dosage form include tablets (including dragees and granules), dragees, capsules, pills, ampoules or suppositories.

As used herein, "drug" means a physically discrete, tacky form suitable for medicinal administration.

As used herein, a "dose unit form of drug" means a daily dose or several doses (up to four times) or a daily dose of water (1) in admixture with a carrier and or contained in an envelope. Physically separable cohesive form suitable for medical administration containing a dose). Depending on how many times a drug is administered per day, for example, once, twice, three or four times a day, the daily dose or 1/2, 1/3 of the daily dose Or 1/4.

The pharmaceutical compositions of the present invention may be in the form of ointments, gels, pastas, creams, sprays (including aerosols), lotions, suspensions, solutions and emulsions in aqueous or non-aqueous diluents, syrups, granules or powders. have.

Diluents used in pharmaceutical compositions (eg granules) to be prepared as tablets, dragees, capsules, pills, are as follows:

(a) Fillers and extenders such as starch, sucrose, mannitol and silicic acid, etc.

(b) Binders such as carboxymethylcellulose and other cellulose derivatives, alginates, gelatin and polyvinyl pyrrolidone ::

(c) humectants, such as glycerol:

(d) disintegrants such as agar-agar, calcium carbonate and sodium bicarbonate:

(e) dissolution retardants such as paraffin:

(f) resorption accelerators, such as quaternary ammonium compounds:

(g) Surfactants such as Cetyl Alcohol, Glycerul Monostearate:

(h) Adsorption carriers such as kaolin and bentonite:

(i) lubricants such as talc, calcium and magnesium stearate and solid polyethylene glycols.

Tablets, dragees, capsules and pills may have conventional coatings, shells and protective matrices (including milk whites). Such formulations release the active ingredient in some of the intestinal tract over a period of time. Coatings, envelopes and protective matrices consist of polymeric materials or waxes.

The active ingredient may be made into microcapsules together with one or several diluents described above.

Diluents used in suppositories are conventional water-soluble or water-insoluble diluents (e.g. polyethylene glycol and fats such as cocoa oil and esters [e.g. C ₁₄ -alcohols and C ₁₆ fatty acids]) or mixtures of such diluents. do. Ointments, pasteases, creams and gel diluents of animal and vegetable fats, waxes, paraffins, starches, tragacanths, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or of such substances Mixtures are used. Diluents used in powders and sprays may be lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these materials. Aerosol sprays include sprays such as conventional chlorofluorohydrocarbons.

Diluents used in liquids and emulsifiers are common diluents such as solvents, solubilizers, emulsifiers, examples of which include water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, Fatty acid esters of 2-butylene glycol, dimethylformamide, oils (such as peanut oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitol, or mixtures thereof.

Solutions or emulsifiers for parenteral administration should be sterile and isotonic. Suspending agents include water, ethyl alcohol, propylene glycol, surfactants (e.g., ethoxylated isotearyl alcohol, polyoxyethylene sorbitan and sorbitan esters), microcrystalline cellulose, aluminum metahydroxide, And common diluents such as bentonite, agar-agar and tragacanth or mixtures thereof.

The pharmaceutical compositions according to the invention may contain colorants and preservatives, fragrances, flavoring agents (eg peppermint oil and eucharitus oil) and sweetening agents (eg saccharin) and the like.

The pharmaceutical composition according to the invention may contain 0.1 to 99.5% by weight of active ingredient, preferably 0.5 to 95%.

In addition to the compounds of the present invention, the pharmaceutical compositions and drugs of the present invention may also contain other pharmaceutically active compounds. They may also contain a number of compounds according to the invention.

The diluent in the drug according to the present invention may be any of the above-mentioned diluents associated with the pharmaceutical composition of the present invention. Such drugs may contain solvents up to 200 molecular weight in a single diluent.

The discrete sticky forms of the drug according to the invention may be administered medicament by their appearance or packaging, for example in the form of tablets, pills, dragees, capsules, suppositories, ampoules, etc. This type can be made slow release. Some (encapsulated) include a protective sheath that confers a physically discrete, tacky drug form.

Preferred daily doses for the administration of the drugs of the invention are 2.5 to 10 g of active ingredient. The production of the pharmaceutical compositions and drugs mentioned above is carried out by known methods, for example, by mixing the active ingredient with a diluent to form a pharmaceutical composition (eg granules) and then making the composition a medicament (eg tablets).

The invention also provides a method for the prevention, alleviation and treatment of diseases of humans and animals by administering to the animal a compound of the invention alone, in admixture with a diluent or in the form of a medicament according to the invention. These active compounds are parenterally (eg intramuscular, intraperitoneal, subcutaneous and intravenous), rectal or topical, with parenteral administration being preferred, particularly intravenous administration. Preferred pharmaceutical compositions and medicaments are suited for dosage forms such as parenteral administration.

Parenteral administration of the administration method of the present invention is preferred. In general, 10 mg to 300 mg / kg of body weight kg is administered daily to obtain efficacy, and preferably 50 mg to 200 mg / kg is proved to be advantageous. However, the dosage ratio and in particular the function of the body and the weight of the human and animal being treated, the individual response of the therapeutic agent, the form and method of administration of the active ingredient are administered, the stage of disease or the interval between administrations. Therefore, sometimes it is sufficient to use less than the dose mentioned above, while sometimes it is necessary to exceed the above mentioned upper limit. If the dosage is large, it is better to divide it several times a day.

The following Examples A, B and C illustrate the in vitro and in vivo activity of the compounds of the present invention.

Example A

In vitro antifungal activity

Description of the experiment: In vitro testing is performed by a series of dilutions inoculated with an average of 5 × 10 ⁴ bacteria per ml of substrate. Nutrient medium is used a) sabouraud's milieu depreuve for skin fungi and fungi and b) broth / glucose buoyant media for yeast.

The culture temperature is 27 ℃ and the incubation period is 24 to 96 hours. In this test the compounds according to the invention showed very good minimum inhibitory concentration values.

Example B

In vivo antifungal activity (oral) test method in candidiasis of mouse

SPF-CF type ₁ mice are infected by intravenous administration of physiological saline suspended in 1-2 × 10 ⁶ logarithmic Candida cells. The animals are treated orally one hour before and seven hours after infection and in each case 50-100 mg / kg body weight.

result

Untreated animals died 3-6 days after infection. The survival rate at day 6 post infection was about 5% for untreated control animals. The compounds according to the invention in this test showed very good action in some cases (60-90% retention at 6 days post infection), while "myconazole" did not show any action at these doses.

It is particularly noteworthy that some of the compounds according to the invention are effective for oral treatment of Aspergillus disease in mice.

Example C

In Vivo (Local) Antifungal Activity Using Molecular Ringworm As Experimental Example

The fine conidia and macroconidia suspensions of S. aureus are infected with hairs shaved alive with Pyrbright-White species white malt. Typical patterns of dermatosis include redness, crusting and hair loss, to overall cortical defects. In untreated animals, this happens within 12 hours after infection. Infected animals start on the third day of infection and are administered topically once a day with a 1% concentration solution in polyethylene glycol of the formulation according to the invention.

At 14 days post-infection, the untreated control animals showed a typical pattern in Pabucha, whereas the formulations of Examples 1,2,4,8 and 10 partially partially inhibited the infection pathway.

The following examples illustrate the preparation of the compounds of the invention.

Example 1

(Manufacturing b)

20.0 g (0.297 moles) of imidazole is added to a solution containing 9.5 g (0.175 moles) of sodium methylate in 49 ml of methyl alcohol. A solution containing 44.3 g (0.135 moles) of 1- (4-bivinyl) -2-chloro-1- (4-fluorofannyl) ethanol in 0.3 mole of dimentylformamide was added dropwise and the reaction mixture was allowed to react at 60 deg. Heat up to 90 minutes. The solvent is concentrated by evaporation in vacuo and the residue is stirred with water. The remaining crystals are washed with acetonitrile and recrystallized from ethyl alcohol. 13.5 g (28% of theory) of 1- (4-bivinyl-1- (4-fluorophenyl) -2- (imidazol-1-yl) -ethanol having a melting point of 220 ° C. are obtained.

Preparation of Starting Material

34.5 g (0.15 mole) of 4-pentylphenacyl chloride in 4-fluoro- pentyl-magnesium bromide solution [7.3 g (0.33 mole) of magnesium and 52.5 g (0.3 mole) of 4-fluorobromobenzene in diethyl ether Obtained by dissolving in 100 ml]. The reaction mixture is heated at reflux for 2 hours and then added to an aqueous ammonium chloride solution. The ether layer is separated, washed with water and evaporated to dryness with sodium sulfate. 44.3 g of 1- (4-biphenylyl) -2-chloro-1- (4-fluorophenyl) ethanol are obtained.

Example 2

Similar to Example 1, 7.02 g (0.13 mole) sodium mentilate, 14.96 g (0.22 mole) triazole, 40 g (0.1 mole) 1- (2'-chloro-4-biphenylyl) -2- Chloro-1- (4-chlorophenyl) -ethanol, 36 ml of methyl alcohol and 75 ml of di

The menthylformamide mixture was heated to 70 ° C. for 3 hours and then 16.2 g (40% of theory) of 1- (2'-chloro-4-biphenylyl) -1- (4-chlorophenyl)-having a melting point of 190 ° C. 2- (1,2,4-triazol-1-yl) ethanol is obtained.

Preparation of Starting Material

Similar to Example 1, 75 g from 10.69 g (0.44 mole) magnesium 76.6 g (0.4 mole) 4-bromochlorobenzene and 53 g (0.2 mole) 4- (2-chlorophenyl) -phenacyl chloride 1- (2'-Chloro-4-biphenylyl) -2-chloro-1- (4-chlorophenyl) -ethanol is obtained.

293.7 g (2.2 moles) of aluminum chloride is partially introduced into a solution containing 377 g (2 moles) of 2-chloro biphenyl in 160 ml (2 moles) of chloro acetyl chloride and 100 ml of menthylene chloride. After 18 hours the reaction mixture is poured onto ice and hydrochloric acid.

The organic layer is dried over separated washed sodium sulfate and the solvent is concentrated by evaporation in vacuo. The remaining oil is distilled off. 478.7 g (90% of theory) of 4- (2-chlorophenyl) -phenacyl chloride having a melting point of 47 ° C are obtained.

Example 3

(Manufacturing a)

13.1 g (0.05 mole) of 4-biphenylyl imidazol-1-yl-mentyl carton was charged with 21.6 g (0.1 mole) of 3-chlorophenyl-magnesium bromide [2.4 g (0.1 mole) of magnesium and 19.1 in 70 ml of ether. g (0.1 mole) from 3-bromochlorobenzene] in small portions. After adding 500 ml of anhydrous toluene, the ether is distilled off and the suspension formed is treated with aqueous ammonium chloride solution. The toluene layer is separated and filtered to dry the filtrate with sodium sulfate. Toluene was evaporated in vacuo and the crystalline residue was stirred with acetonitrile. Recrystallization of the residue from ethanol gave 9.4 g of 1- (4-biphenylyl) -1- (3-chlorophenyl) -2- (imidazol-1-yl) -ethanol having a melting point of 202 DEG C (50% of theory). Is obtained. The compounds of Table 1 below are obtained according to one of the preparations (a) or (b).

TABLE 1

The invention also encompasses pharmaceutically toxic bioprecursors of the active compounds of the invention.

The term "pharmaceutically toxic bioprecursor" refers to a compound which differs from the active compound in its structural formula but which is converted into the active compound in the patient upon administration to an animal or human.

Claims (1)

A process for preparing hydroxyethyl-azole of the general formula (I) or a salt thereof, wherein 1-halogeno-ethane-2ol of the general formula (IV) is reacted with an azole of the general formula (V).

Wherein Az represents an imidazole or triazole group, R represents an optionally substituted phenyl, naphthyl or tetrahydro naphthyl group, R ¹ represents an optionally substituted phenyl or cycloalkyl group and R ² represents a hydrogen atom, or R ¹ and R ² together represent a menthylene bridge having several CH ₂ optionally substituted at the ortho-position, or naphthyl together with a phenyl ring and R ³ represents halogen, alkyl, alkoxy or halogenoalkyl n represents 0,1,2 or 3, Y represents a halogen atom and Z represents a hydrogen atom or an alkali metal.