JPS6345391B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is structurally represented by the formula where Q is a member selected from the group consisting of CH and N; Ar is 2,4-dihalophenyl; and the group Y is of the formula a group of , where R ¹ is selected from the group consisting of hydrogen and lower alkylthio; a group of , with each R ⁴ and R ⁵ independently selected from the group consisting of hydrogen and lower alkyl; where n is an integer of 0 or 1, E is a member selected from the group consisting of N and CR ⁹ ,
R ⁶ , R ⁷ and R ⁸ are each independently hydrogen, lower alkyl,
selected from the group consisting of lower alkyloxy, nitro and aminocarbonyl, or R ⁷ and R ⁸
taken together represent a group of the formula -CH=CH-CH=CH-; and R ⁹ represents hydrogen or lower alkyl. where M is a member selected from the group consisting of N and CH, and R ¹⁰ and R ¹¹ are each independently selected from the group consisting of hydrogen and amino; a group of, where R ¹⁴ is selected from the group consisting of hydrogen and lower alkyloxy, and R ¹³ is selected from the group consisting of lower alkylthio and lower alkoxy; , where L is a member selected from the group consisting of S and N-R ¹⁸ , R ¹⁸ is lower alkyl, and R ¹⁶ and R ¹⁷ are each independently selected from the group consisting of hydrogen and nitro. or R ¹⁶ and R ¹⁷
taken together represent a group of the formula -CH=CH-CH=CH-; and the formula with the proviso that R ¹⁹ and R ²⁰ are each independently selected from the group consisting of hydrogen and lower alkyl; an optionally substituted mononuclear or dinuclear nitrogen heteroaromatic group selected from the group consisting of; Novel 1H-imidazole and
This invention relates to 1H-1,2,4-triazole derivatives and their pharmaceutically acceptable acid addition salts and stereochemically isomeric forms. Preferred compounds of the invention are those in which the 1-piperazinyl group is attached to the phenoxymethyl moiety at the 4-position of the phenyl group. The term "halo" as used in the definitions above and below is generic to fluoro, chloro, bromo and iodo; "lower alkyl" refers to straight and branched chain hydrocarbons having from 1 to 6 carbon atoms; groups such as methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, 1-methylpropyl, 2
- Means to include methylpropyl, butyl, pentyl, hexyl, etc. To simplify the structural formula representation of compound () and certain starting materials and intermediates used in its preparation,
2-(2,4-dihalophenyl)-2-(1H-
imidazol-1-ylmethyl or 1H-1,2,
The group 4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl, where Ar is as defined above, is designated below by the symbol D: Compounds of formula () can generally be prepared by reaction of a suitable reactive ester of formula () with a suitably substituted phenol of formula () by standard O-alkylation methods. . In formula (), W has the meaning of a reactive ester residue such as halo, methylsulfonyloxy, 4-methylphenylsulfonyloxy, etc. The reaction of compounds of formula () with () is carried out with reactive esters under conditions known in the art for carrying out O-alkylation. This reaction is generally carried out in an inert organic solvent suitable for the reaction, such as N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, dimethylsulfoxide, 4-methyl-2-pentanone, etc. In other reactions, inert solvents such as aromatic hydrocarbons such as benzene,
It is carried out in a mixture with methylbenzene, dimethylbenzene, etc. Furthermore, in order to increase the reaction rate,
It is advantageous to add a suitable base to the reaction mixture, such as an alkali metal hydride or carbonate. Alternatively, the substituted phenol () is first converted into its metal salt, preferably the sodium salt, in a conventional manner, for example by reaction of formula () with a metal base such as sodium hydride, sodium hydroxide, etc., and then It may be advantageous to use the metal salt in the reaction with formula (). Somewhat elevated temperature is appropriate to increase the rate of reaction, and most preferably the reaction is conducted at about 80°C to about 130°C. A compound of formula (), where Y is as defined above, but other than a group (a) or (b), and wherein Y is represented by Ya, the compound is represented by formula (-a).
, represents a suitable substituted piperazine of formula ( ), according to standard N-alkylation methods,
However, W has the meaning as defined above and can be prepared by N-alkylation with a suitable reactive ester. The reaction between formulas () and () is preferably carried out in a suitable reaction inert organic solvent such as an alcohol such as butanol; an amide such as N,N-dimethylformamide, N,N-dimethylacetamide,
Hexamethylphosphoric acid triamide, etc.; dimethyl sulfoxide; 4-methyl-2-pentanone, etc., optionally in an inert organic solvent for the second reaction, such as an aromatic hydrocarbon, such as benzene, methylbenzene, dimethyl It is carried out in a mixture with benzene etc. Furthermore, in order to increase the reaction rate, it is advantageous to add suitable bases, such as alkali metal hydrides or carbonates, to the reaction mixture. Slightly elevated temperature is appropriate, most preferably this reaction is carried out at about 80°C.
It is carried out at a temperature of 130°C to about 130°C. In addition, a compound of formula (), where Y represents a group of formula (a), R ¹ is something other than hydrogen, and the compound is represented by formula (-b-1) is as follows: Can be prepared by: A suitable isothiocyanate () in which R ²¹ is lower alkyl or aryl lower alkyl is suitably substituted by a suitable reaction in the presence of an inert organic solvent such as a halogenated hydrocarbon such as dichloromethane. Stir and heat with piperazine amine (); then the thiourea () thus obtained
The reactants are stirred together in the presence of a suitable reaction-inert organic solvent such as ethyl acetate, most preferably in the presence of an organic acid such as acetic acid to prevent quaternization of the tertiary amino group. Optionally, a halide ( ), where R ¹ ' is lower alkyl, aryl or aryl lower alkyl, and halo is preferably chloro, bromo or iodo, is converted to the corresponding carbamimidothioate ( ) The carbamimidothioate () thus obtained is cyclized by stirring and heating in an aqueous acid medium, for example aqueous hydrochloric acid. The above reaction is represented by the following reaction equation: A compound of formula (), where Y represents a group (a) in which R ¹ is hydrogen, and the compound is represented by formula (-b-1), can be prepared in a conventional manner by, for example, formula (-b
By treating the compound of formula (-1) with Raney nickel or dilute nitric acid, the compound of formula (-b-1) can be easily obtained by desulfurization. A compound of formula (), where Y represents a group (b), where R ⁴ is hydrogen and R ⁵ is as defined above, the compound is represented by formula (-c-1), can be prepared as follows: A suitably substituted piperazine amine () is subjected to a suitable reaction in an inert solvent such as a halogenated hydrocarbon such as trichloromethane, preferably liberated during the reaction. To neutralize hydrochloric acid, in the presence of pyridine, N,N-diethylethanamine, etc., a suitable carbon chloridate (XI), with R ²² being lower alkyl, aryl or aryl lower alkyl; Stir; then the carbamate (XII) thus obtained
is reacted with hydrazine by stirring and heating the reactants together in the presence of a suitable reaction inert solvent such as a cyclic ether such as 1,4-dioxane, tetrahydrofuran; and the hydrazine carboxamide thus obtained. () is appropriately substituted with imidamide (
), or if necessary in the presence of a suitable solvent such as water, acetic acid, etc., the reactants are heated and melted to cyclize. The above reaction is shown by the following reaction equation: A compound of formula () in which Y represents a group (b), provided that R ⁴
is lower alkyl, aryl or aryl lower alkyl, R ⁴ is represented by R ⁴ a and R ⁵ is as defined above, and the compound has the formula (-c
-2) represents a compound of formula (-c-1) according to the standard N-alkylation method described above.
)), where R ⁴ and W are as defined above.
By N-substitution with a reactant of the formula (-c
-1) can be derived from the compound. A compound of formula () in which Y represents a group (f), provided that R ¹⁶
and R ¹⁷ are hydrogen, lower alkyl or aryl lower alkyl, and L is S, the compound of formula (-d) can be prepared as follows: Suitably substituted piperazine () in the presence of a suitable reaction-inert solvent, such as an alkanol such as methanol, preferably in the presence of a suitable base, such as an alkali metal or alkaline earth metal hydroxide, such as sodium hydroxide, and a suitable isothiocyanate. (
), where R ¹⁶ , R ¹⁷ and R ²¹ are as defined above, with stirring and heating; the thus obtained carbothioamide (X) is then cyclized in an aqueous acidic medium such as hydrochloric acid; and The R ²¹ O- group of the thus obtained 4,5-dihydrothiazole () was treated with a strong non-oxidizing acid,
For example, it is removed using hydrobromic acid in glacial acetic acid. The above reaction is shown by the following reaction equation: The formula () obtained in the basic form in the above production method
The imidazole derivatives of can be converted into therapeutically useful acid addition salts by reaction with a suitable acid such as an inorganic acid such as hydrohalic acid, i.e. hydrochloric acid, hydrobromic acid or iodine. Hydrohydric acid; sulfuric acid, nitric acid or thiocyanic acid; phosphoric acid; organic acids such as acetic acid, propanoic acid, hydroxyacetic acid, 2-hydroxypropanonic acid, 2-oxopropanonic acid, ethanedioic acid, propanedioic acid, 1,4 -Butanedioic acid, (Z)-
2-butenedioic acid, (E)-2-butenedioic acid, 2-hydroxy-1,4-butanedioic acid, 2,3-dihydroxy-1,4-butanedioic acid, 2-hydroxy-1,2,3-propane tricarboxylic acid acid, benzoic acid, 3-phenyl-2
-Propenoic acid, α-hydroxybenzeneacetic acid,
Methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, 4-methylbenzenesulfonic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid, 2-phenoxybenzoic acid or 2-acetyloxybenzoic acid . The salt can also be converted into the corresponding free acid in conventional manner, for example by reaction with an alkali such as sodium hydroxide or potassium hydroxide. Many of the intermediates and starting materials used in the above production methods are known compounds, and others can be produced according to methods known in the art for producing similar compounds; Part 2 is a new compound, and the method for producing it will therefore be described below. an intermediate of formula (), where Y is as defined above, but other than a group (a) or (b), and wherein Y is represented by Ya, said intermediate is of formula (-a)
is a suitably substituted piperazine () according to the same method already described in preparing compounds of formula (-a) starting from formulas () and (), where R ²² is hydrogen or lower alkyl. can be prepared by N-alkylation with a suitable reactive ester (), and when R ²² is lower alkyl, the lower alkyloxy group of formula () thus obtained can then be prepared by Conversion to hydroxyl groups is carried out by acid hydrolysis using a strong non-oxidizing acid such as hydrobromic acid in eg glacial acetic acid. An intermediate of formula (), where Y represents a group (a), and the intermediate is represented by formula (-b), starts from formula () and () and is converted to formula (-b-1) and formula (
-b-2) can be derived from a suitably substituted piperazine amine ( ), with R ²² as defined above, according to one of the methods already mentioned in preparing the compound of -b-2); And when R ²² is lower alkyl, then the lower alkyloxy group of the formula () thus obtained is
For example, it is converted into a hydroxyl group by hydrolysis with hydrobromic acid in glacial acetic acid. An intermediate of formula (), where Y represents a group (b), and the intermediate is represented by formula (-c), starts from formulas () and () and is converted to formulas (-c-1) and (
-c-2) can be prepared starting from a suitably substituted piperazine amine () according to one of the methods already mentioned in the preparation of the compound of c-2), and when R ²² is lower alkyl. teeth,
The lower alkyloxy group of formula () thus obtained is then converted into a hydroxyl group by acid hydrolysis, for example with hydrobromic acid in glacial acetic acid. The above reaction is represented by the following reaction equation: An intermediate of formula () in which Y represents a group (f), provided that R ¹⁶
and R ¹⁷ is hydrogen, lower alkyl or aryl lower alkyl, and L is S, and the intermediate is represented by formula (-d). Starting from formula (), a compound of formula (-d) is prepared. Following the same method described in the preparation, the appropriate piperazine (), with R ²² as defined above, can be derived and when R ²² is lower alkyl, the thus obtained The lower alkyloxy group of formula () is hydrolyzed using, for example, hydrobromic acid in glacial acetic acid. Intermediates of formula () can be prepared from formulas () and () by following standard O-alkylation procedures as previously described in preparing compounds of formula () starting from formula () and (). represents a suitable protecting group, such as phenylmethyl group, 2-methylethyl group, etc., with a suitable reactive ester of formula (), and the thus obtained protecting group of formula () is then treated in a conventional manner. , depending on the nature of P, e.g. by catalytic hydrogenation or in an acidic aqueous medium.
-Remove methylethenyl derivatives by hydrolysis. Following the same procedure described for the preparation of compounds of formula () starting from formula (), replacing the reactive ester () used then with the appropriate formula (
) using the reactive ester of the corresponding formula (
) was advantageously obtained. Intermediates of formula () can be easily prepared as follows: In the presence of a suitable relatively polar solvent such as water, optionally a water-miscible solvent such as 1,
reacting piperazine () in an acidic medium such as acetic acid, most preferably at low temperature, with nitrous acid or a salt thereof such as sodium nitrite in a mixture with 4-dioxane; and then the nitropiperazine thus obtained () in the presence of a suitable reaction inert organic solvent such as tetrahydrofuran, preferably a mixture with a second reaction inert organic solvent such as an aromatic hydrocarbon such as benzene, etc.
Reduction is carried out with a suitable reducing agent, for example a suitable complex metal hydride such as lithium aluminum hydride. Starting from formula (), starting materials of formula () can be prepared according to the same methods described in preparing compounds of formula () starting from formula (). Starting materials of the formula where Q is CH and methods for their preparation are described in US Pat. No. 4,144,346. Generally, reactive esters of formula () can be prepared according to the following reaction sequence. The appropriate 1-Ar-2-bromoethanone of formula () is acetalized by reaction with 1,2,3-propanetriol according to the same method described in Synthesis, 1974 , (), 23. A preferred method of carrying out the above reaction is to combine both reactants, preferably in the presence of a simple alcohol such as ethanol, propanol, butanol, pentanol and in the presence of a suitable strong acid such as 4-methylbenzenesulfonic acid. is refluxed for several hours in a suitable organic solvent with azeotropic removal of water. Suitable organic solvents are, for example, aromatic hydrocarbons, such as benzene, methylbenzene, dimethylbenzene, etc., and saturated hydrocarbons, such as cyclohexane. Then the dioxolane thus obtained ()
is reacted with benzoyl chloride to obtain a benzoate of formula (), which is then reacted with 1H-imidazole or 1H-1,2,4-triazole. The above reaction is preferably carried out in the presence of a suitable strong metal base such as sodium methanolate and in a suitable organic solvent such as N,
This is done by stirring and heating the reactants together in N-dimethylformamide to give an intermediate of formula (). The reactive ester of a given formula () is then prepared by first hydrolyzing the formula () in an alkaline medium and then following methods generally known in the art to obtain the thus obtained formula (
) is advantageously prepared by converting the hydroxy group of ) into its reactive ester. For example, methanesulfonate and 4-methylbenzenesulfonate are advantageously prepared by reaction of an alcohol with methanesulfonyl chloride or 4-methylbenzenesulfonyl chloride; It can be produced by reaction with chloride, phosphorus pentachloride, phosphorus pentabromide, phosphoryl chloride, etc. When the reactive ester is an iodide, it is preferably derived from the corresponding chloride or bromide by replacing the halogen with iodine. The above reaction can be represented by the following reaction equation: It is clear from formula () that the compound of the invention has at least two asymmetric carbon atoms in its structural formula, i.e. these are in the 2- and 4-positions of the dioxolane nucleus, and therefore the compound of the invention may exist in different stereochemically isomeric forms. Stereochemically isomeric forms of formula () and pharmaceutically acceptable acid addition salts thereof are intended to be included within the scope of this invention. CA., 76 , Index Guide, Section, page 85 (1972), the diastereomeric racemates of formula (), shown as cis and trans forms, respectively, are obtained separately in the usual manner. be able to. Suitable methods that may be advantageously used therefore include, for example, fractional crystallization and chromatographic separation;
Examples include column chromatographs. Because the stereochemical configuration is already fixed in the intermediates () and (), the cis and trans forms can be separated at this point and also at an early stage, with the corresponding forms of formula () can be derived from this using the method already described. Separation of the cis and trans forms of such intermediates can be carried out by conventional methods such as those described above for the separation of the cis and trans forms of compound (). The cis and trans diastereomeric racemates can be further separated into their optical isomers, cis(+), cis(-), trans(+) and trans, using methods known to those skilled in the art. It is clear that it can be divided into (-). Compounds of formula () and their pharmaceutically acceptable acid addition salts are useful agents in controlling fungi. For example, the present compounds and their acid addition salts can be used in a wide variety of fungi, such as Microsporum canis.
canis), Ctenomyces mentagrophytes, Trichophyton rubrum, Phialophora verrucosa, Cryptococcus neoformans, Candida tropicalis ) Candida albicans, Mucor
Aspergillus species), Aspergillus species
fumigatus), Sporotrichosis pathogens (Sporotrichum schenckii) and Saprolegnia species. In view of their potency, the local as well as systemic fungicidal activity of the compounds of the present invention makes them useful agents for eradicating or preventing fungal growth, making them particularly useful for the treatment of infections with such bacteria. can. The strong bactericidal activity of compound () is evident from the data obtained in the experiments described below, and this data is merely to illustrate the useful bactericidal properties of all compounds (), and the range of susceptible bacteria. Nor is it intended to limit the scope of the invention to any of the compounds of formula (). Example A Activity of compound () against vaginal candidiasis in rats Female Wistar rats weighing ±100 g were used. Rats were ovariectomized and hysterectomized, and 3 weeks after recovery they were administered subcutaneously 100 μg of estradiol undecilate in sesame oil once a week for 3 consecutive weeks. The pseudoestrus thus induced was controlled by microscopic examination of vaginal contents application. Feed and water were given ad libitum. 8x cells of Candida acnes grown in rat Sabouraud broth for 48 hours at 37°C and diluted in saline.
10 ⁵ were infected vaginally. Infection data varied from +25 days to +32 days after surgical intervention, depending on the appearance of induced pseudoestrus microhous. Test drugs were administered orally once daily for 2 days starting from the day of infection. A mock-treated control was created for each experiment. A few days after infection, vaginal contents were applied using a sterile cotton swab for evaluation. This cotton swab was placed in Sabouraud broth in a Petri dish and incubated at 37°C for 48 hours. If Candida albicans does not grow, ie the animals are negative at the end of the experiment, this is also due to the drug administration, as it never occurs in the sham-treated controls. The table below shows the lowest oral dosage of test drug found to be active at 14 days post-infection. Experimental example B Activity of compound () against candidiasis in turkeys 14-day-old turkeys were treated with Sabouraud gravy for 48 hours.
4×10 ⁶ cells of Candida acnes grown at 37° C. and diluted in saline were so infected.
The volume of the inoculum was 1 ml. The test drug was premixed with 500 mg of lactone and then compounded with 1000 g of ground without all additives. The concentration of the test drug in the minced meat was expressed in mg/Kg. Animals were fed drug feed for 13 consecutive days starting from the day of infection. All animals were sacrificed at the end of the experiment. At the time of double inspection, remove the bag, dry it, and place it in 15 ml of sterile salt water.
turrax) ground in a mixer. The number of colonies on Sabouraud agar was counted and the tabulated results were expressed as ED ₅₀ , ie the drug dosage at which 50% of the animals were completely negative for Candida acnes. The compounds shown in the table are for illustrative purposes only and are not intended to limit the scope of the invention.

【table】

【table】

[Table] The compounds shown in the table above were administered intraperitoneally to rats for 40 minutes.
As a result of toxicity tests conducted at doses of mg/Kg, there were no fatal cases for any of the compounds (therefore, the LD ₅₀ value is much higher than 40 mg/Kg). In view of its antifungal properties, the present invention provides valuable preparations comprising as active ingredient a compound of formula () or an acid addition salt thereof in a solvent or solid, semi-solid or liquid diluent or carrier. death,
In addition, by using an antifungal effective amount of such a compound () or a salt thereof, an effective method for controlling fungal growth is provided. Antifungal preparations comprising an effective amount of the active compound () alone or in combination with other therapeutically active ingredients in a formulation with a suitable carrier can be prepared according to conventional pharmaceutical practice for the usual routes of administration. It can be easily manufactured. A preferred preparation is as a formulation with a suitable carrier,
The dosage unit form comprises an effective amount of active ingredient per dosage unit. The amount of active ingredient per dosage unit can vary within a wide range, but from approximately 50 to
Dosage units of about 500 mg, especially about 100 to about 250 mg, are preferred. The following examples illustrate the invention:
All parts are by weight unless otherwise stated, which is not intended to limit the scope of the invention. Example 1 A solution of 20.8 parts of sodium nitrite in 100 parts of water is added to a stirred mixture of 52.6 parts of 1-(4-methoxyphenyl)piperazine dihydrochloride, 100 parts of acetic acid and 100 parts of water over a period of 1.50 hours. It was added dropwise at a temperature between ~5°C. After the addition was complete, stirring was continued for 30 minutes. The reaction mixture was diluted with water. The precipitated product was separated and crystallized from 2-propanol to yield 1-(4-methoxyphenyl)-4-nitrosopiperazine 22.5
%; melting point 94.5°C. To a stirred suspension of 10 parts of lithium aluminum hydride in 900 parts of tetrahydrofuran was added 1-(4-methoxyphenyl)-4 in 720 parts of benzene.
- A solution of 40 parts of nitrosopiperazine was added dropwise over 20 hours. After the addition was complete, stirring was continued for 20 hours at room temperature. The reaction mixture was decomposed by successively adding dropwise 100 parts of water, 7.5 parts of 50% sodium hydroxide solution and 30 parts of water. The whole was filtered and the liquid was evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (98:2 parts by volume) as eluent.
The pure fraction was collected and the eluent was evaporated.
The residue was crystallized from 1,1'-oxybisbutane. The product was separated and dried to yield 18.56 parts of 4-(4-methoxyphenyl)-1-piperazineamine; melting point 107°C. Example 2 A mixture of 8.3 parts of 4-(4-methoxyphenyl)-1-piperazineamine, 5.9 parts of 1-isocyanato-2,2-dimethoxyethane and 130 parts of dichloromethane was stirred and refluxed for 1 hour. The reaction mixture was evaporated and the residue was crystallized from 4-methyl-2-pentanone. The product is separated, dried and N-
(2,2-dimethoxyethyl)-N'-[4-(4
8.9 parts (63%) of -methoxyphenyl)-1-piperazinyl]thiourea were obtained; melting point 156.6°C. N-(2,2-dimethoxyethyl)-N'[4-
(4-methoxyphenyl)-1-piperazinyl]
A mixture of 17.3 parts of thiourea, 17 parts of iodoethane, 180 parts of ethyl acetate and 20 parts of acetic acid was stirred for 3 hours.
The product precipitated when the 2,2'-oxybispropane was added. Apart from this, 4-methyl-2-
Disintegrated in pentanone. Separate the product, 2-
Crystallized from propanol, ethyl N-(2,2
9 parts of -dimethoxyethyl)-N'-[4-(4-methoxyphenyl)-1-piperazinyl] carbamimidothioate monohydriodide were obtained. Ethyl N-(2,2-dimethoxyethyl)-
A mixture of 9 parts of N'-[4-(4-methoxyphenyl)-1-piperazinyl]carbamimidothioate monohydriodide and 100 parts of 6N hydrochloric acid solution was stirred and refluxed for 1 hour. Cool the reaction mixture and incubate for 50 min.
The pH value was adjusted to 10 with % sodium hydroxide solution. The product was extracted with dichloromethane. The extract was dried and evaporated. The residue was crystallized from 1,1′-oxybisbutane (activated carbon) to give 1-[2-
(Ethylthio)-1H-imidazol-1-yl]-
6 parts (100%) of 4-(4-methoxyphenyl)piperazine were obtained; melting point 111.8°C. Example 3 N-(2,2-dimethoxyethyl)-N'-
A mixture of 5.3 parts of [4-(4-methoxyphenyl)-1-piperazinyl]thiourea, 6 parts of iodomethane, 5 parts of acetic acid and 90 parts of ethyl acetate was stirred at room temperature for 2 days. The product crystallized out when the 2,2'-oxybispropane was added. This was separated, dried, and methyl N-(2,2-dimethoxyethyl)-
6 parts (80%) of N'-[4-(4-methoxyphenyl)-1-piperazinyl]carbamimidothioate monohydriodide were obtained. Methyl N-(2,2-dimethoxyethyl)-
A mixture of 6 parts of N'-[4-(4-methoxyphenyl)-1-piperazinyl]carbamimidothioate monohydriodide and 30 parts of 6N hydrochloric acid solution was stirred and refluxed for 1 hour. The reaction mixture was cooled and the PH value was adjusted to 10 with sodium hydroxide solution. The precipitated product was separated and crystallized from 4-methyl-2-pentanone to yield 1-(4-methoxyphenyl).
3.7 parts (100%) of -4-[2-(methylthio)-1H-imidazol-1-yl]piperazine were obtained;
Melting point: 140.1℃. Example 4 1-(4-methoxyphenyl)-4-[2-
A mixture of 5.5 parts of (methylthio)-1H-imidazol-1-yl]piperazinyl, 8 parts of Raney nickel catalyst, and 80 parts of methanol was stirred and refluxed overnight. The Raney nickel was separated and another 8 parts of Raney nickel catalyst was added. The whole was further stirred and refluxed overnight. The reaction mixture was filtered and the liquid was evaporated. The residue was crystallized from 1,1'-oxybisbutane. The product was separated and dried to yield 3.6 parts (77%) of 1-(1H-imidazol-1-yl)-4-(4-methoxyphenyl)piperazine; melting point
158.6℃. Example 5 A mixture of 10.8 parts of 4-(1-piperazinyl)phenol hydrobromide, 2.6 parts of 2-isothiocyanato-1,1-dimethoxyethane and 54 parts of methanol was stirred and refluxed for 30 minutes. Then 4.7 parts of sodium hydroxide were added and the whole was stirred at room temperature overnight. The precipitated product was separated and crystallized from 4-methyl-2-pentanone and N-(2,2-dimethoxyethyl)-4-( 4-hydroxyphenyl)-1
-4.9 parts of piperazine carbothioamide were obtained; melting point 161.4°C. N-(2,2-dimethoxyethyl)-4-(4
A mixture of 6 parts of -hydroxyphenyl)-1-piperazinecarbothioamide and 25 parts of dilute hydrochloric acid solution was stirred at room temperature overnight. The product crystallized out upon addition of sodium bicarbonate. This was separated and recrystallized from ethanol to obtain 4.3 parts (73%) of 4-[4-(4,5-dihydro-5-methoxy-2-thiazolyl)-1-piperazinyl]-phenol; melting point 165.6. ℃. A mixture of 4 parts of 4-[4-(4,5-dihydro-5-methoxy-2-thiazolyl)-1-piperazinyl]phenol and 150 parts of 48% hydrogen bromide solution was added.
Stir and reflux for 12 hours. The reaction mixture was evaporated and crystallized from 4-methyl-2-pentanone. The product was separated, dried and 4-[4-(2-
thiazolyl)-1-piperazinyl]phenol
2.5 parts (68%) were obtained; melting point 169.9°C. Example 6 A mixture of 10.6 parts of 1-(4-methoxyphenyl)piperazine hydrobromide, 7.9 parts of 2-bromopyridine, 8.4 parts of potassium carbonate, and 90 parts of N,N-dimethylformamide was stirred and refluxed overnight. . The reaction mixture was diluted with water and the product was extracted twice with benzene. The combined extracts were dried, filtered and evaporated. The residue was crystallized from 1,1'-oxybisbutane. Separate the product, dry it,
8 parts (74%) of -(4-methoxyphenyl)-4-(2-pyridinyl)piperazine were obtained; melting point
125.6℃. Example 7 A mixture of 10.2 parts of 4-(1-piperazinyl)phenol dihydrobromide, 5.7 parts of 2-chloroquinoline, 6.3 parts of potassium carbonate and 80 parts of 1-butanol was stirred and refluxed overnight. The reaction mixture was diluted with water and 2,2'-oxybispropane was added; the product crystallized out. Apart from this, 4-methyl-2
- Recrystallization from pentane yielded 6.4 parts (70%) of 4-[4-(2-quinolinyl)-1-piperazinyl]phenol; melting point 198.1°C. Example 8 4 in 5 parts of pyridine and 45 parts of trichloromethane
To a stirred solution of 8 parts of -(4-methoxyphenyl)-1-piperazine amine was added dropwise 7.8 parts of phenyl carbon chloridate over 30 minutes.
After the addition was complete, stirring was continued for 30 minutes at room temperature. Water was added to the reaction mixture and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was triturated in 4-methyl-2-pentanone. The product was separated and crystallized from 1,4-dioxane to yield 9 parts (70%) of phenyl [4-(4-methoxyphenyl)-1-piperazinyl] carbamate. Phenyl [4-(4-methoxyphenyl)-1
Piperazinyl] 8 parts carbamate, 15 parts hydrazine
1,4-dioxane and 50 parts of 1,4-dioxane were stirred and refluxed for 4 hours. The reaction mixture was evaporated.
The residue was triturated in 2-propanol. The product was separated, crystallized from 1-butanol, and N-[4
-(4-Methoxyphenyl)-1-piperazinyl]hydrazinecarboxamide 6.5 parts (84%)
I got it. Example 9 6.5 parts of N-[4-(4-methoxyphenyl)-1-piperazinyl]hydrazinecarboxamide and 6.5 parts of methanimidamide acetate (1:1)
Both parts were melted at 140°C for 1 hour. Water was added to the melt. The solid product was separated and crystallized from 1-butanol to give 2,4-dihydro-4-[4-
(4-methoxyphenyl)-1-piperazinyl]
4.5 parts (68%) of -3H-1,2,4-triazol-3-one was obtained. Example 10 N-[4-(4-methoxyphenyl)-1-piperazinyl]hydrazinecarboxamide 13 parts ethanimidamide hydrochloride 14.2 parts, sodium acetate
A mixture of 12.3 parts and 95 parts of 1,1'-oxybis[2-methoxyethane] was stirred at 130°C for 3 hours.
The reaction mixture was poured into water and the product was extracted twice with dichloromethane. The combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (98:2 parts by volume) as eluent. The pure fraction was collected and the eluent was evaporated. The residue was converted into 4-methyl-2
-Crystallized from pentanone, 2,4-dihydro-
Obtained 5.1 parts (35%) of 4-[4-(4-methoxyphenyl)-1-piperazinyl]-5-methyl-3H-1,2,4-triazol-3-one; melting point
264.3℃. Example 11 2,4-dihydro-4-[4-(4-methoxyphenyl)-1-piperazinyl]-3H-1,2,
A mixture of 4.5 parts of 4-triazol-3-one, 0.8 parts of 78% sodium hydride dispersion, and 27 parts of N,N-dimethylformamide was stirred at room temperature for 1 hour.
Then 2.5 parts of dimethyl sulfate were added and stirring continued for an additional hour at room temperature. Water was added to the reaction mixture and the product was extracted twice with dichloromethane. The extract was dried, filtered and evaporated. The residue was eluted with trichloromethane and methanol (98:2).
The mixture (parts by volume) was purified by column chromatography on silica gel. The pure fraction was collected, the eluent was evaporated, and the 2,4-dihydro-4-[4-(4-methoxyphenyl)-1-
piperazinyl]-2-methyl-3H-1,2,4
-3.3 parts (71%) of triazol-3-one were obtained;
Melting point: 178.2℃. The following was also produced in the same manner as above: 2,4-dihydro-4-[4-(4-methoxyphenyl)-1piperazinyl]-2,5-dimethyl-3H-1,2,4- triazol-3-one;
Melting point: 179.2℃. Example 12 1-(1H-imidazol-1-yl)-4-
A mixture of 3.1 parts of (4-methoxyphenyl)piperazine and 150 parts of a 48% solution of hydrobromic acid in glacial acetic acid was stirred and refluxed overnight. evaporate the reaction mixture;
The residue was dissolved in water. The product crystallized when excess sodium bicarbonate was added. This was separated, recrystallized from a mixture of N,N-dimethylformamide and water, and 4-[4-(1H-imidazol-1-yl)-1-piperazinyl]phenol
2.8% (95%) was obtained; melting point 282.4°C. Also following a similar method and using equivalent amounts of the appropriate starting materials, the following was prepared: 4-{4-[2-(methylthio)-1H-imidazol-1-yl]-1-piperazinyl}phenol; Melting point 237℃; 4-{4-[2-(ethylthio)-1H-imidazol-1-yl]-piperazinyl}phenol; Melting point 178.2℃; 4-[4-[2-(pyridinyl)-1-piperazinyl]phenol ; Melting point: 165.5°C; 2,4-dihydro-4-[4-(4-hydroxyphenyl)-1-piperazinyl]-2-methyl-3H-1,2,4-triazol-3-one;
Melting point: 210.3°C; and 2,4-dihydro-4-[4-(4-hydroxyphenyl)-1-piperazinyl]-2,5-dimethyl-3H-1,2,4-triazol-3-one; Melting point 262℃. Example 13 A mixture of 2.9 parts of 4-[4-(2-pyridinyl)-1-piperazinyl]phenol, 0.4 parts of 78% sodium hydride dispersion, and 100 parts of dimethyl sulfoxide was stirred at 50°C for 1 hour. Next, Sis-2-
4.2 parts of (2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl methanesulfonate was added, and the whole was stirred at 100°C for 3 hours. The reaction mixture was cooled, water was added and the product was extracted three times with benzene. The combined extracts were dried, filtered and evaporated. The residue was crystallized from 1,1'-oxybisbutane (activated carbon). Separate the product
Dry, cis-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4-(2 -pyridinyl)piperazine 3.9 parts (68%) were obtained; melting point 155.6°C. The following was also prepared following the same method as above and using equivalent amounts of the appropriate starting materials: cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazole) -1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4-(1H-imidazole-1-
yl) piperazine; melting point 189.5-190°C; cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolane-4- ylmethoxy]phenyl}-4-[2-(methylthio)-
1H-imidazol-1-yl]piperazine; melting point
149.1℃; Cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4- 2-(ethylthio)-1H
-imidazol-1-yl]piperazine; melting point 124
°C; cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4-( 2-thiazolyl)piperazine; melting point 152.5℃; cis-2-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazole-1-)
ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]quinoline; melting point 155.2℃; cis-4-[4-{4-[2-(2,4-dichlorophenyl)-2 -(1H-imidazole-1-
ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]-
2,4-dihydro-2-methyl-3H-1,2,
4-triazol-3-one ethanedioate (1:1) monohydrate; melting point 162.6°C; and cis-4-[4-{4-[2-(2,4-dihydrophenyl)-2-] (1H-imidazole-1-
ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]-
2,4-dihydro-2,5-dimethyl-3H-1,
2,4-triazol-3-one ethanedioate (1:1) monohydrate; melting point 163.7°C. Example 14 4-[4-(1H-imidazol-1-yl)-
To a stirred mixture of 2.9 parts of 1-piperazinyl]phenol and 75 parts of dimethyl sulfoxide was added 0.6 parts of 50% sodium hydride dispersion. 1 at room temperature
After stirring for an hour, cis-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl]methanesulfonate 4.1 parts were added and the whole was stirred and heated at 100°C for 6 hours.
The reaction mixture was cooled and poured into water. The product was extracted twice with dichloromethane. The combined extracts were washed with water, dilute sodium hydroxide solution and water again, dried, filtered and evaporated. The residue was crystallized from 4-methyl-2-pentanone to give cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1
3.8 parts of phenyl}-4-(1H-imidazol)-1-yl)piperazine hemihydrate were obtained; melting point 171.5°C. The following was also prepared following the same method as above and using equivalent amounts of the appropriate starting materials: cis-1-{4-[2-(2,4-dichlorophenyl-2-(1H-1, 2,4-triazole-
1-ylmethyl)-1,3-dioxolane-4-
ylmethoxy]phenyl}-4-[2-(methylthio)-1H-imidazol-1-yl]piperazine; melting point 152.2℃; cis-1-{4-[2-(2,4-dichlorophenyl)-2- (1H-1,2,4-triazol-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4-[2-(ethylthio)-1H-imidazol-1-yl]piperazine; melting point 114.8°C and Cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4
-ylmethoxy]phenyl}-4-(2-thiazolyl)piperazine; melting point 171.9°C. Example 15 1.9 parts of 2-chloro-3-nitropyridine, cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)
A mixture of 4.9 parts of -1,3-dioxolan-4-ylmethoxy]phenylpiperazine, 2 parts of potassium carbonate, and 80 parts of 1-butanol was stirred and refluxed overnight. The reaction mixture was diluted with water and 90 parts of methylbenzene was added. Separate the organic phase, dry and
filtered and evaporated. The residue was converted into 4-methyl-2
-Crystalized from pentanone. Separate the product
Dry, cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazole-1-
ylmethyl)-1,3-dioxolane-4-ylmethoxy]phenyl}-4-(3-nitro-2-
5.4 parts (88%) of piperazine (pyridinyl) were obtained;
Melting point: 145.5℃. The following was also prepared following the same method as above and using equivalent amounts of the appropriate starting materials: cis-2[4-{4-[2-(2,4-dichlorophenyl)-2-(1H -imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]piperidine, N-oxide; melting point 186.7°C; cis-2[4-{4-[2-(2, 4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]benzothiazole; melting point 157.7℃; cis-2[4-{ 4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]pyrimidine; melting point 178.5°C; cis-2[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl ] Pyrazine; melting point 171.1℃ and cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane -4
-ylmethoxy]phenyl}-4-(5-nitro-2-pyridinyl)piperazine; melting point 144.8°C. Example 16 8-chloro-7-ethyl-3,7-dihydro-
2.9 parts of 1,3-dimethyl-1H-purine-2,6-dione, cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazole-1
A mixture of 4.9 parts of phenyl-ylmethyl)-1,3-dioxolan-4-ylmethoxy]piperazine, 3 parts of potassium carbonate, and 50 parts of dimethyl sulfoxide was stirred at 130°C overnight. The reaction mixture was diluted with water and the product was extracted twice with dichloromethane. The combined extracts were washed twice with water, dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (98:2 parts by volume) as eluent. The pure fraction was collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentason. The product was separated, dried under vacuum at 150°C, and cis-8-
[4-{4-[2-(2,4-dichlorophenyl)
-2-(1H-imidazol-1-ylmethyl)-
1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]-7-ethyl-3,
Obtained 5.6 parts (80%) of 7-dihydro-1,3-dimethyl-1H-purine-2,6-dione; melting point
205.4℃. Also, following the same method as above and using equivalent amounts of the appropriate starting materials, the following was produced; cis-6-[4-{4-[2-(2,4-dichlorophenyl)-2-( 1H-imidazole-1-
ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]-3
-Pyridinecarboxamide; melting point 215.1℃; cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy ] phenyl}-4-(5-nitro-2-pyridinyl)piperazine; melting point 181.2℃; cis-2-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazole) -1-
ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]-4
-Methylquinoline; melting point 153.1℃; cis-2-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazole-1-
ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]-3
-Methylquinoxaline; melting point 182.2-187.2℃; cis-4-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazole-1-)
ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]-
2,6-dimethoxypyrimidine; melting point 131.1℃; cis-4-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazole-1-)
ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]-2
-(Methylthio)pyrimidine monohydrate; melting point
103.1℃; cis-6-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazole-1-
ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1piperazinyl]-1,
3,5-triazine-2,4-diamine ethanedioate (1:2); melting point 228.2°C; cis-2-[4-{4-[2-(2,4-dichlorophenyl)-2-( 1H-imidazole-1-
ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]-1
-Methyl-1H-benzimidazole; Melting point 149.7
°C; Cis-2-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazole-1-
ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]-1
-Ethyl-1H-benzimidazole ethanedioate (1:2) monohydrate; melting point 158.1℃ and cis-8-[4-{4-[2-(2,4-dichlorophenyl)-2-( 1H-imidazole-1-
ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]-
3,7-dihydro-1,3,7-trimethyl-
1H-Brine-2,6-dione; melting point 198.6°C. Example 17 1.3 parts of 2-bromo-5-nitrothiazole, cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)
A mixture of 3 parts of -1,3-dioxolan-4-ylmethoxyphenylpiperazine, 2 parts of potassium carbonate, and 90 parts of N,N-dimethylformamide was added to 60 parts of N,N-dimethylformamide.
Stirred at ℃ for 3 hours. Dilute the reaction mixture with water,
The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. 1 residue
Crystallized from butanol. The product was separated, dried and cis-2-[4-{4-[2-(2,4-
dichlorophenyl)-2-(1H-imidazole-
1-ylmethyl)-1,3-dioxolane-4-
ylmethoxy[phenyl}-1-piperazinyl]
-2.4 parts (63%) of 5-nitrothiazole were obtained;
Melting point: 219.2℃. Example 18 3.2 parts of 2-chloro-6-ethoxypyridine, cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)
A mixture of 4.9 parts of -1,3-dioxolan-4-ylmethoxy]phenylpiperazine and 2 parts of potassium carbonate was stirred and heated to 140°C for 48 hours.
The reaction mixture was cooled and purified twice by column chromatography on silica gel, first with trichloromethane and then with a mixture of methylbenzene and ethanol (95:5 parts by volume) as eluent. The pure fraction was collected and the eluent was evaporated. The residue was triturated in 2,2'-oxybispropane. The product was separated, dried, and cis-1-{4
-[2-(2,4-dichlorophenyl)-2-
(1H-imidazol-1-ylmethyl)-1,3-
Dioxolan-4-ylmethoxy]phenyl}-
1.2 parts (20%) of 4-(6-ethoxy-2-pyridinyl)piperazine were obtained; melting point 132.7°C.

Claims (1)

[Claims] 1 formula where Q is a member selected from the group consisting of CH and N; Ar is 2,4-dihalophenyl; and the group Y is of the formula (a) a group of [where R ¹ is selected from the group consisting of hydrogen and lower alkylthio]; (b) of the formula a group of [where R ⁴ and R ⁵ are each independently selected from the group consisting of hydrogen and lower alkyl]; (c) of the formula group [where n is an integer of 0 or 1,
E is a member selected from the group consisting of N and C- ^R9 , and ^R6 , ^R7 and ^R8 each independently represent hydrogen,
selected from the group consisting of lower alkyl, lower alkyloxy, nitro and aminocarbonyl, or R ⁷ and R ⁸ together represent a group of the formula -CH=CH-CH=CH-, and R ⁹ is hydrogen or represents lower alkyl]; (d) formula a group of [where M is a member selected from the group consisting of N and CH, and R ¹⁰ and R ¹¹ are each independently selected from the group consisting of hydrogen and amino]; (e) formula a group of [where R ¹⁴ is selected from the group consisting of hydrogen and lower alkyloxy, and R ¹³ is selected from the group consisting of lower alkylthio and lower alkoxy]; (f) formula [wherein L is a member selected from the group consisting of S and N-R ¹⁸ , R ¹⁸ is lower alkyl, and R ¹⁶ and R ¹⁷ are each independently a group consisting of hydrogen and nitro] or R ¹⁶ and R ¹⁷ together form the formula - CH=CH - CH=CH
- represents a group]; and (g) formula [wherein R ¹⁹ and R ²⁰ are each independently selected from the group consisting of hydrogen and lower alkyl]; an optionally substituted mononuclear or dinuclear nitrogen-containing heteroaromatic group selected from the group consisting of; A compound selected from the group consisting of azole derivatives, and their pharmaceutically acceptable acid addition salts and stereochemically isomeric forms. 2 cis-8-[4-{4-[2-(2,4-dichlorophenyl)-3-(1H-imidazole-1
-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]-
A compound selected from the group consisting of 7-ethyl-3,7-dihydro-1,3-dimethyl-1-purine-2,6-dione and a pharmaceutically acceptable acid addition salt thereof Compound according to item 1. 3 Cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-
The compound according to claim 1, which is a compound selected from the group consisting of 4-ylmethoxy]phenyl}-4-(2-thiazolyl)piperazine and a pharmaceutically acceptable acid addition salt thereof. 4 Cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-
Claim 1, which is a compound selected from the group consisting of 4-ylmethoxy]phenyl}-4-(1H-imidazol-1-yl)piperazine hemihydrate and a pharmaceutically acceptable acid addition salt thereof. Compounds described. 5 formula where Q is a member selected from the group consisting of CH and N; Ar is 2,4-dihalophenyl; and the group Y is of the formula (a) a group of [where R ¹ is selected from the group consisting of hydrogen and lower alkylthio]; (b) of the formula a group of [where R ⁴ and R ⁵ are each independently selected from the group consisting of hydrogen and lower alkyl]; (c) of the formula group [where E is CH, R ⁶ , R ⁷ and R ⁸
each represents hydrogen]; (f) Equation a group [wherein L is a member selected from the group consisting of S and N-R ¹⁸ , R ¹⁸ is lower alkyl, R ¹⁶ and R ¹⁷ are each independently hydrogen, or R ¹⁶ and R ¹⁷ together represent a group of the formula -CH=CH-CH=CH-; and (g) the formula [wherein R ¹⁹ and R ²⁰ are each independently selected from the group consisting of hydrogen and lower alkyl]; an optionally substituted mononuclear or dinuclear nitrogen-containing heteroaromatic group selected from the group consisting of; An antifungal agent characterized in that it contains as an active ingredient a compound selected from the group consisting of azole derivatives having the following, as well as pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof.