JPS6233228B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to certain new hydroxypropyl-imidazole compounds, their preparation and their use as antifungal agents. Conventionally, especially 1-[2,4-dichloro-β-
It has already been disclosed that 1-(β-aryl)-ethyl-imidazole derivatives such as (2,4-dichlorobenzyloxy)-phenethyl]-imidazole nitrate (“Miconazol” (trademark)) exhibit good antifungal activity. (West German public announcement details)
(see 1940388). However, their action in vivo is not fully satisfactory, especially against Candida. According to the present invention, the following general formula In the formula, R is phenyl which may be substituted with halogen or alkyl having 1 to 4 carbon atoms, or is a naphthyl or tetrahydronaphthyl group, and R ¹ is halogen or a phenyl group having 1 to 4 carbon atoms.
is phenyl optionally substituted with alkyl, or is a cycloalkyl group having 5, 6 or 7 carbon atoms, and R ² is a hydrogen atom, or R ¹ and R ² are in the ortho position to each other. Taken together, there are provided compounds which are hydroxypropyl-imidazoles or pharmaceutically acceptable acid addition salts thereof representing trimethylene, tetramethylene or pentamethylene bridges. These compounds of the invention exhibit strong antifungal properties. These compounds of the invention are: In the formula, R ¹ _and R ² have the above-mentioned meanings. and X is a halogen atom, preferably a chlorine or bromine atom, in the presence of a diluent, or (b) the general formula ¹ - ^halogen-
Propan-2-ol can be prepared by reacting it with imidazole, preferably in the presence of an acid binder and preferably in the presence of a diluent. In certain cases it has proven advantageous to replace imidazole with an alkali metal salt of imidazole, such as the sodium or potassium salt. Hydroxypropyl obtained according to the invention -
Imidazoles can be converted into salts by reaction with acids. Surprisingly, in addition to good in vivo antifungal activity, the hydroxypropyl-imidazoles according to the invention are known from the state of the art and are recognized as good drugs with homologous action. 1-[2,4-dichloro-β
-(2,4-dichlorobenzyloxy)-phenethyl]-imidazole nitrate exhibits better therapeutically useful in vivo activity against Candida. The active compounds according to the invention thus make a valuable contribution to the enrichment of pharmaceuticals. Preferred compounds of formula () according to the invention are:
It is as follows. That is, in the formula, R is phenyl, which may be substituted with halogen or alkyl having 1 to 4 carbon atoms, or naphthyl or tetrahydronaphthyl, and the halogen is especially fluorine, chlorine, bromine, and the carbon Alkyl of numbers 1 to 4 may be linear or branched; R ¹ is halogen or carbon number 1
phenyl optionally substituted with alkyl of 1 to 4 carbon atoms, or cycloalkyl of 5, 6 or 7 carbon atoms, and the halogen is particularly fluorine, chlorine or bromine, and the alkyl of 1 to 4 carbon atoms is particularly preferably alkyl having 1 to 3 carbon atoms; R ² is hydrogen, or R ¹ and R ² are ortho to each other and are trimethylene, tetramethylene or pentamethylene. be. Very preferred compounds of formula () are those in which R represents a phenyl group, optionally mono- or di-substituted by chlorine, fluorine or methyl, or naphthyl or tetrahydronaphthyl;
R ¹ represents phenyl, cyclopentyl or cyclohexyl, optionally mono- or di-substituted by chlorine, bromine, fluorine, methyl, ethyl or isopropyl, respectively; and
R ² represents hydrogen or R ¹ and R ² taken together in the mutually ortho position represent trimethylene, tetramethylene or pentamethylene bridges, each optionally substituted by chlorine or methyl; represents. For example, when 4-biphenylylimidazol-1-yl-methylketone and 4-chlorobenzyl-magnesium chloride are used as starting materials, the reaction steps can be represented by the following reaction formula (step ( a)). Also, for example, 2-(4-biphenylyl)-3-
When chloro-1-(2,4-dichlorophenyl)-propan-2-ol and sodium imidazole are used as starting materials, the reaction steps can be represented by the following reaction formula (step
(b)). Formula () gives a general definition of the imidazolylmethyl phenyl ketones used as starting materials in step (a). In this formula, R ¹ and R ² preferably represent the groups already mentioned as preferred in the case of compounds of formula (). Imidazolyl methyl phenyl ketones of formula () are hitherto unknown. However, these ketones have the following formula: In the formula, R ¹ and R ² have the meanings given above and Hal represents chlorine or bromine. The agent can be prepared in a conventional and known manner by reacting the agent, especially in the presence of an excess of imidazole, at a temperature of 20 to 80°C (this content is described in US Pat. No. 3,658,813). and manufacturing examples). Examples of starting materials of formula () include, for example, 4-biphenylylimidazole-1
-yl-methylketone, 4-(4'-chlorobiphenylyl)imidazol-1-yl-methylketone, 2-biphenylylimidazol-1-yl-
Methyl ketone, 4-(2',4'-dichlorobiphnylyl)imidazol-1-yl-methylketone, 2
-Chloro-4-biphenylyl-imidazole-1
-yl-methylketone, 2-chloro-4-(4'-
Chlorobiphenyl)imidazol-1-yl-
Methyl ketone, 4-chlorohexyl-phenylimidazol-1-yl-methyl ketone, 4-cyclopentylphenylimidazol-1-yl-methyl ketone, 4-chloro-3-cyclohexylphenylimidazol-1-yl-methyl ketone,
4-(3-bromocyclohexyl)-phenylimidazol-1-yl-methylketone, 4-cyclopentyl-2-chlorophenylimidazole-
1-yl-methylketone, 4-cyclopentyl-
2-Fluorophenylimidazol-1-yl-
Methyl ketone, 4-cyclopentyl-2-methylphenylimidazol-1-yl-methylketone, 4-(1-methylcyclohexyl)-phenylimidazol-1-yl-methylketone, 4-
Cycloheptylphenylimidazol-1-yl-methylketone, 4-cycloheptyl-2-chlorophenylimidazol-1-yl-methylketone, naphth-1-ylimidazol-1-yl-
Methyl ketone, naphtho-2-ylimidazole
1-yl-methylketone, 1,2,3,4-tetrahydronaphtho-5-ylimidazol-1-yl-methylketone, 1,2,3,4-tetrahydronaphtho-6-ylimidazol-1-yl-methylketone and Indan-4-ylimidazol-1-yl-methylketone. Formula () also gives a general definition of the Grignard compounds used as starting materials for step (a). In this formula, R preferably represents the radicals already mentioned as preferred in the case of formula (). Grignard compounds of formula () are commonly known compounds in organic chemistry. Examples include, for example, benzyl-magnesium chloride, 4-chlorobenzyl-magnesium chloride, 2,4-dichlorobenzyl-magnesium chloride, 2,6-dichlorobenzyl-magnesium chloride, 2-chloro-6-fluorobenzyl - Magnesium chloride, 2-chlorobenzyl-magnesium chloride, 3-chlorobenzyl-magnesium chloride, 3,4-dichlorobenzyl-magnesium chloride, naphth-2-yl-methyl-magnesium chloride,
1,2,3,4-tetrahydronaphth-6-yl-methyl-magnesium chloride and their corresponding bromides. Formula () gives a general definition of the 1-halogeno-propan-2-ols used as starting materials for step (b). In this formula, R, R ¹ and
R ² preferably represents the radicals already mentioned as preferred in the case of compounds of formula (). The 1-halogeno-propan-2-ols of formula () have not yet been known. However, these compounds can be produced by generally customary and known methods by reacting ketones of formula () with Grignard compounds of formula () in a manner corresponding to the method of step (a). (For this content, please refer to the description and production examples of West German Publication No. 2623129). According to the invention, all solvents customary for Grignard reactions can be used as diluents for the reaction of step (a). For example, preferred are ethers such as diethyl ether or tetrahydrofuran and mixed solvents thereof with organic solvents such as benzene. The reaction temperature can be varied within a substantial range of step (a). Generally, the reaction is carried out between about 20°C and about 120°C, preferably between about 30°C and about 80°C. In carrying out step (a), an excess of 3 to 5 mol of the Grignard compound of formula () is preferably used per 1 mol of the compound of formula (). Isolation of compounds of formula () is carried out by conventional methods. According to the invention, inert organic solvents can be used as preferred diluents for the reaction of step (b).
These are, for example, preferably ketones such as diethyl ketone, especially acetone or methyl ethyl ketone; nitrites such as propionitrile, especially acetonitrile; alcohols such as ethanol or isopropanol; ethers such as tetrahydrofuran or dioxane; aromatic hydrocarbons such as benzene, toluene or dioxane. Chlorobenzene, etc.; Formamide, especially dimethylformamide, etc.;
and halogenated hydrocarbons such as methylene chloride, carbon tetrachloride or chloroform. If step (b) is carried out according to the method of the invention in the presence of an acid binder, it is possible to add any commonly used inorganic or organic acid binder. These acid binders include, for example, alkali metal carbonates such as soda carbonate, potassium carbonate, sodium hydrogen carbonate, etc.; or lower tertiary alkyl amines, cycloalkylamines or aralkylamines such as triethylamine, N,N-dimethylcyclohexylamine, etc. , dicyclohexylmethylamine, N,N-dimethylbenzylamine and also pyridine and diazabicyclooctane. Excess imidazole is preferably used. The reaction temperature can be varied within a substantial range in step (b). Generally, the reaction is carried out between about 30<0>C and about 200<0>C, preferably at the boiling point of the solvent. When carrying out step (b) according to the present invention,
1 to 2.5 moles of imidazole and 1 to 2.5 moles of acid binder are preferably used per mole of compound of formula (). When using an alkali metal salt, 1 to 1.5 moles of the alkali metal salt are preferably used per mole of the compound of formula (). In order to isolate the compound of formula (), the solvent is distilled off and the residue is washed directly with water or, after being taken up in an organic solvent, if appropriate the organic phase is dried with sodium sulfate and the solvent is removed in vacuo. remove. The residue is
Preferably, it is purified as appropriate by distillation, recrystallization or chromatography. Any physiologically acceptable acid can be used in the preparation of acid addition salts of compounds of formula (). These acids are preferably, for example, hydrohalic acids, such as hydrochloric acid, hydrobromic acid and especially hydrochloric acid, but also phosphoric acid, nitric acid, sulfuric acid, monofunctional or difunctional carboxylic acids and hydroxycarboxylic acids, For example, acetic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, oxalic acid, salicylic acid, sorbic acid, butyric acid, etc., and sulfonic acids such as p-
These include toluenesulfonic acid and 1,5-naphthalenedisulfonic acid. Salts of compounds of formula () can be easily obtained by conventional salt formation methods, for example by dissolving the compound of formula () in a suitable inert solvent and adding an acid such as acetic acid. These salts can be isolated, for example, by any number of known methods and, if appropriate, purified by washing with an inert organic solvent. Examples describing particularly active representatives of the active compounds according to the invention are, in addition to the preparation examples according to the invention and the examples in Table 1, furthermore:

【table】

【table】

[Table] The compounds of formula () and their acid addition salts according to the invention exhibit antimicrobial activity, particularly antifungal activity. They exhibit a very broad spectrum of antifungal action, in particular against biphase fungi, as well as dermatophytes and blastomyces. Such bacteria include, for example, Candida varieties such as Candida albicans;
Epidermophyton floccosum
Variants of epidermophytes such as Asper-gillus niger and Aspergillus fumigatu; Spore bacteria (Micros)
varieties of microsporum such as poron felineum and penicillum comm.
It exhibits antibacterial activity against varieties of Penicillium genus bacteria such as P. une). This list of microorganisms is in no way limiting to the types of bacteria that may be combated, but is merely illustrative. Examples that can be mentioned in the field of human drug application include, for example, dermatomycoses and molds, as well as gypsum-like group B. aeruginosa, other varieties of M. feline, feline microsporum varieties, hairy epidermophyte. These include systemic mycoses caused by fungi, blastomycetes, and biphasic fungi. Examples that can be mentioned in the field of application of veterinary medicine are:
Examples include dermatophytosis and systemic mycoses caused in particular by the microorganisms mentioned above. As mentioned above, the present invention also relates to veterinary medicine of the compounds of the present invention as well as to the use in humans. The present invention uses the compound of the present invention as an active ingredient,
200 unless contained as a mixture with solid or liquefied gas diluents or in the presence of surfactants.
There is provided a pharmaceutical composition containing in admixture with a liquid diluent other than a solvent having a molecular weight below (preferably below 350). The invention further provides pharmaceutical compositions containing the compounds of the invention as active ingredients in the form of sterile and/or physiologically isotonic aqueous solutions. The invention also provides a medicament in dosage unit form comprising a compound of the invention. The invention also provides medicaments in the form of tablets (including lozenges and granules), dragees, capsules, pills, ampoules or suppositories, comprising a compound of the invention. As used herein, "drug" refers to a physically discrete, intimate area suitable for drug administration. As used herein, "medicament in dosage unit form" refers to a drug in combination with a carrier and/or
or a physical package suitable for drug administration containing the compound of the invention in a daily dose or in a multiple (up to 4 times) or in a fraction (up to 1/40) of the daily dose in an outer package. It means a unit that is discontinuous and close to each other. Whether a drug contains a daily dose or, for example, one-half, one-third or one-fourth of a daily dose, means that the drug is administered once a day, respectively. It depends on whether it is administered in one dose or, for example, in two, three or four doses. Pharmaceutical compositions according to the invention can be used, for example, as ointments,
They may take the form of gels, pastes, creams, sprays (including aerosols), lotions, suspensions or solutions of the active compound in aqueous or non-aqueous diluents, syrups, granules or powders. Diluents used in pharmaceutical compositions (eg granules) suitable for tablet, dragee, capsule and pill form include, for example: (a) Fillers and extenders such as starch, sugar, mannitol and silicic acid; (b) Binders such as carboxy-methyl cellulose and other cellulose derivatives, alginates and polyvinylpyrrolidone; (c) Moisturizing agents. ) for example glycerol; (d) disintegrants such as agar, calcium carbonate and sodium bicarbonate; (e) dissolution retardants such as paraffin; (f) absorption enhancers such as quaternary ammonium compounds; (e) surfactants such as cetyl alcohol, Glycerin monostearate;
(h) adsorption carriers such as kaolin and bentonite;
(i) Lubricants such as talc, calcium stearate, magnesium stearate and solid polyethylene glycols. Tablets, dragees, capsules and pills formed from the pharmaceutical compositions of the present invention can have conventional coatings, envelopes and protective matrices which may include opacifying agents. These agents are designed to release the active ingredient only at or preferably over a certain period of time at a specific location in the intestinal tract. Coatings, envelopes and protective matrices can be made of polymeric substances or waxes, for example. The active ingredient can also be in microencapsulated form together with one or more of the diluents mentioned above. Diluents used in pharmaceutical compositions suitable for suppository form can be, for example, conventional water-soluble diluents. For example, polyethylene glycols, fats such as cocoa butter and higher esters (eg esters of C ₁₄ -alcohols and C ₁₆ -fatty acids) or mixtures of these diluents. Pharmaceutical compositions that are ointments, pastes, creams and gels, for example, may contain conventional diluents, e.g.
animal and vegetable fats, waxes, paraffin, starch, tragacanth, cellulose derivatives,
It can contain polyethylene glycol, silicon, bentonite, silicic acid, talc and zinc oxide or mixtures of these substances, and the like. Pharmaceutical compositions, which are powders and sprays, can contain, for example, the usual diluents such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder or mixtures of these substances. Aerosol sprays can contain conventional propellants, such as chlorofluorohydrocarbons. Pharmaceutical compositions that are solutions or emulsions include:
For example, conventional diluents (excluding, of course, solvents with a molecular weight of less than 200, as described above, unless a surfactant is present), such as solvents, solubilizers and emulsifiers, can be included. Specific examples of such diluents are, for example, water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-
Fatty acid esters of butylene glycol, dimethylformamide, oils (for example ground raw oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitol, or mixtures thereof. For parenteral administration, solutions and emulsions should be sterile and, where appropriate, isotonic with blood. Pharmaceutical compositions that are suspensions may contain conventional diluents such as water, ethyl alcohol, propylene glycol, surfactants such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, Conventional diluents such as aluminum metahydroxide, bentonite, agar and tragacanth or mixtures thereof may be included. Pharmaceutical compositions according to the invention may all contain flavoring agents, flavoring agents (eg peppermint oil and eucalyptus oil) and sweetening agents (eg saccharin) as well as coloring agents and preservatives. The pharmaceutical compositions of the invention generally contain from 0.1 to 99.5%, usually from 0.5 to 95%, of active ingredient by weight of the total composition. In addition to the compounds of the invention, the pharmaceutical compositions and medicaments of the invention may also contain other pharmaceutically active compounds. Similarly, a plurality of compounds of the present invention can be contained. The diluent in the medicament of the invention may be any of those described above with respect to the pharmaceutical composition of the invention. Such agents can include a solvent with a molecular weight of 200 or less as the sole diluent. The discrete, intimate parts constituting the medicament of the invention are generally adapted by their form or drug administration packaging and can be, for example, any of the following: Tablets (including lozenges and granules), pills, dragees, capsules, suppositories and ampoules. Some of these forms are
Made to delay the release of active ingredients. Some, such as capsules, contain the drug part,
Includes a protective envelope that is intended to be physically discontinuous and cohesive. The preferred daily dosage for administering the medicament of the invention is between 2.5g and 10g of active ingredient. The manufacture of the pharmaceutical compositions and medicaments described above may involve, for example, mixing the active ingredient(s) with the diluent(s) to form a pharmaceutical composition (e.g. granules) and then combining this composition with the medicament (e.g. , tablets) by methods known in the art. The present invention further provides a method for treating diseases such as those mentioned above in human or non-human animals, which comprises administering a compound of the present invention, alone or in a mixture with a diluent or in the form of a drug according to the invention, to a human or non-human animal. Provide methods for combating (including prevention, mitigation and treatment). These active compounds may be administered orally, parenterally (e.g. intramuscularly, intraperitoneally, subcutaneously and intravenously), rectally or topically, preferably parenterally, especially intravenously. That is possible.
Therefore, preferred pharmaceutical compositions and agents are those suitable for administration, such as parenteral administration.
Administration in the method of the invention is preferably parenteral. In general, it has been found advantageous to administer amounts of from 10 mg to 300 mg, preferably from 50 mg to 200 mg per kg of body weight per day, in order to achieve effective results. However, it may often be necessary to deviate from these dosage rates. In particular, the physical strength and weight of the human or non-human animal to be treated, the subject's individual response to such treatment,
It will be necessary to do so as a function of the form of preparation in which the active ingredient is administered and the manner in which the administration is carried out, as well as the critical points in the progression of the disease or the intervals at which it is to be administered. For example, in some cases,
In some cases it may be sufficient to use less than the above-mentioned minimum dosage rate, while in other cases it may be necessary to exceed the above-mentioned upper limit to achieve the desired results. When administering a relatively large amount, several times a day.
It is recommended that these be administered in several doses. Examples A and B below illustrate the antimicrobial activity of the compounds used in the invention. Example A Description of in vitro antifungal activity experiments: In vitro studies were carried out using a bacterial inoculum with an average of 5 x 10 ⁴ bacteria/ml substrate and a series of dilutions. The nutrient medium is a) Sabouraud's millien d''epreuve for dermatophytes and molds, and b) meat extract/glucose for yeasts. The incubation temperature was 20°C and the incubation period was 24-96 hours. In these experiments, the compounds according to the present invention exhibited good minimum inhibitory concentrations against the above-mentioned molds. The results are shown in Table B.

[Table] Example B: In vivo antimicrobial activity against Candida mycosis in mice (oral) SPF-CF ₁ type mice were suspended in physiological saline and 1 to 2 x 10 ⁶ Candida cells were grown in contrast. The cells were infected intravenously. The animals were treated orally with 50-100 mg/kg body weight of the formulation at 1 hour before infection and 7 hours after infection. Results: Untreated animals died from the infection 3-6 days after infection. The survival rate on the 6th day after infection is
It was approximately 5% in untreated animals. Known 1-[2,4-dichloro-β-(2,4
-dichlorobenzyloxy)-phenyl-ethyl]-imidazole nitrate (MICONAZOL)
showed no effect at this dose. In contrast, for example, the compounds of Examples 1 and 4 according to the invention have a good effect (survival rate on day 6 post-infection ≧80%) to a very good effect (survival rate on day 6 post-infection ≧80%). 90%). The following examples illustrate the preparation of compounds of the invention. Example 1 Embodiment of step a 13.1 g (0.05 mol) of 4- in 500 ml of benzene
A solution of bifnylylimidazol-yl-methylketone, 6.1 g (0.25 mol) in 150 ml of ether.
of magnesium and 40.2 g (0.25 mol) of 4-chlorobenzyl chloride was added dropwise to a 4-chlorobenzyl-magnesium chloride solution obtained from 40.2 g (0.25 mol) of 4-chlorobenzyl chloride. Thereafter, the ether was distilled off and the reaction mixture was heated to 80° C. for about 8 hours. The cooled solution was poured into ammonium chloride solution and the organic phase was separated, washed with water and dried over sodium sulfate.
After distilling off the benzene, the remaining crystal sludge was stirred with ether and the crystals were separated off and recrystallized from acetonitrile. 3.5g (theoretical value)
18%) of 2-biphenylyl)-1-(4-chlorophenyl)-3-(imidazol-1-yl)-
Propan-2-ol, melting point 182°C, was obtained. Production of starting materials 39 g (0.14 mol) of 4-phenyl phenacyl bromide were introduced in portions with cooling into a solution of 48.2 g (0.7 mol) of imidazole in 140 ml of dimethylformamide. The mixture was then reacted for 15 hours and the solution was poured into water. The separated crystalline solid was recrystallized from ethanol. 4-biphenylylimidazole-1- with melting point 198℃
24 g (65% of theory) of yl-methylketone were obtained. Example 2 Embodiment of step b A solution of 39.15 g (0.1 mol) of 2-(4-biphenylyl)-3-chloro-1-(2,4-dichlorophenyl)-propan-2-ol in 300 ml of acetonitrile is dissolved in 200 ml of acetonitrile. 3.6g of
(0.12 mol) of sodium hydride and 8.2 g
(0.12 mol) of imidazole dropwise. After heating at 80° C. for 3 hours, the cooled reaction mixture was filtered and the crystalline solids were washed with water and setonitrile. Touch point 168℃ 2-
(4-biphenylyl)-1-(2,4-dichlorophenyl)-3-(imidazol-1-yl)-
32.5 g (77% of theory) of propan-2-ol were obtained. Production of starting materials 4-phenyl phenacyl chloride 69.3g
(0.3 mol) in 300 ml of ether, 15.9 g (0.65
2,4-dichlorobenzyl-magnesium chloride obtained from 117.3 g (0.6 mol) of 2,4-dichlorobenzyl chloride.
The reaction mixture was then poured into an aqueous solution of ammonium chloride and the ether layer was separated, washed with water, dried over sodium sulfate and evaporated. The remaining oil was extracted with petroleum ether and the petroleum ether solution was evaporated. The crystals were separated and dried. 2-(4-biphenylyl)-3- with melting point 84℃
62 g (53% of theory) of chloro-1-(2,4-dichlorophenyl)-propan-2-ol were obtained. Example 3 Embodiment of step b 39.8 g (0.1 mol) in 200 ml acetonitrile
2-(4-cyclohexyl-phenyl)-3-
A solution of chloro-1-(2,4-dichlorophenyl)-propan-2-ol was suspended in 3.6 g (0.12 mol) of sodium hydride and 8.2 g (0.12 mol) of imidazole in 200 ml of acetonitrile. Add it dropwise. After the mixture was heated to a temperature of 80° C. for 3 hours, it was filtered, the crystalline solid was washed with water and recrystallized from acetonitrile. 2-(4cyclohexylphenyl)-1-(2,4-dichlorophenyl)-3- with melting point 142℃
24.9 g (imidazol-1-yl)-propan-2-ol (58% of theory) were obtained. Production of starting materials 47.3 g (0.2 mol) of 4- in 200 ml of ether
A solution of cyclohexylphenysyl chloride,
dropwise into a solution of 0.4 mol of 2,4-dichlorobenzylmagnesium chloride obtained from 10.6 g (0.44 mol) of magnesium and 78 g (0.4 mol) of 2,4-dichlorobenzyl chloride in 150 ml of ether. added. The reaction mixture was poured into aqueous ammonium chloride solution and the ether layer was separated, washed with water, dried over sodium sulfate and evaporated. 79.5 g of 2-(4-cyclohexyl)-3-chloro-1-(2,4-dichlorophenyl)-propan-2-ol with refractive index n ²⁰ _D = 1.5780 (theoretical value
99%) was obtained. Examples 4 to 35 The compounds in Table 1 below were obtained in the same manner as described above, either by the embodiment of step a or the embodiment of step b.

【table】

【table】

【table】

TABLE OF THE INVENTION Among the novel hydroxypropyl-imidazole salts of the present invention, pharmaceutically acceptable salts are particularly important and preferred. The novel free hydroxypropyl-imidazole of general formula () and its salts can be converted into each other by known appropriate methods. Such interconversion methods are well known in the art. The invention likewise includes pharmaceutically acceptable in vivo precursors of the active compounds of the invention. For the purposes of this specification, the term "pharmaceutically acceptable in vivo precursor" of an active compound of the invention is a compound that differs in its structural formula from the active compound, but that nevertheless It refers to a compound that, upon administration to humans, is converted into an active compound within the patient's body.

Claims (1)

[Claims] 1. General formula In the formula, R is phenyl optionally substituted with halogen or alkyl having 1 to 4 carbon atoms, or naphthyl or tetrahydronaphthyl; R ¹ is substituted with halogen or alkyl having 1 to 4 carbon atoms; or cycloalkyl having 5, 6 or 7 carbon atoms; R ² is hydrogen, or R ¹ and R ² are ortho to each other and together form trimethylene. , a tetramethylene or pentamethylene bridge, which are hydroxypropyl-imidazoles or physiologically acceptable acid addition salts thereof. 2 General formula In the formula, R is phenyl optionally substituted with halogen or alkyl having 1 to 4 carbon atoms, or naphthyl or tetrahydronaphthyl; R ¹ is substituted with halogen or alkyl having 1 to 4 carbon atoms; or cycloalkyl having 5, 6 or 7 carbon atoms; R ² is hydrogen, or R ¹ and R ² are ortho to each other and together form trimethylene. , representing a tetramethylene or pentamethylene bridge, are hydroxypropyl-imidazoles or physiologically acceptable acid addition salts thereof, comprising: (a) the general formula; In the formula, the definitions of R ¹ and R ² are the same as above, and the imidazolyl-methyl phenyl ketone of the general formula, R-CH ₂ -Mg-X () where R is the same as above, and X is a halogen atom, is reacted with a Guniya compound of in the presence of a diluent, or (b) general formula In the formula, the definitions of R, R ¹ and R ² are the same as above, and Y is a halogen atom. How to characterize it. 3. The method according to (a) or (b) of claim 2, wherein X or Y is a chlorine or bromine atom, respectively. 4. A process according to claim 2(b) or 3, wherein the reaction is carried out in the presence of an acid binder. 5. A method according to any one of claims 2(b), 3, or 4, wherein the reaction is carried out in the presence of a diluent. 6 General formula In the formula, R is phenyl optionally substituted with halogen or alkyl having 1 to 4 carbon atoms, or naphthyl or tetrahydronaphthyl; R ¹ is substituted with halogen or alkyl having 1 to 4 carbon atoms; or cycloalkyl having 5, 6 or 7 carbon atoms; R ² is hydrogen, or R ¹ and R ² are ortho to each other and together form trimethylene. , representing a tetramethylene or pentamethylene bridge, are hydroxypropyl-imidazoles or physiologically acceptable acid addition salts thereof; 1. An anti-mycotic composition, characterized in that it is contained as a mixture with an agent or a liquid diluent other than a solvent having a molecular weight of 200 or less, except when a surfactant is present. 7. A composition according to claim 6 in the form of a sterile or physiologically isotonic aqueous solution. 8. Compositions according to claim 6 or 7 containing from 0.5 to 95% by weight of active ingredient. 9. A composition according to claim 6 in dosage unit form. 10. A composition according to any of claims 6 to 9 in the form of a tablet, pill, dragee, capsule, ampoule or suppository.