CS241468B2 - Method of 1h-imidazole and 1h-1,2,4-triazole new derivatives production - Google Patents

Abstract

The reaction of piprazinophenols with 1,3-dioxolan-4-ylmethylmesylates gave title compds. I(Q = CH or N ; Ar = Ph, thienyl, halothienyl, haloalkyl-, alkoxy-, or (trifluoromethyl)phenyl; Y = III; R1,R2,R3,,R4 = H, lower alkyl, aryl lower alkyl), which exhibited bactericidal activity.

Description

in which

Q is CH or N,

Ar represents a halothienyl or phenyl group optionally substituted by one to three of the same or different substituents selected from the group consisting of halogen atoms, methyl, methoxy and ethoxy, and

Y is an amino group or a radical selected from the group consisting of 1H-pyrrol-1-yl of formula a

(and)

1H-pyrazol-1-yl radical of formula b

The 1H-imidazol-1-yl radical of formula (c)

R 14 represents a hydrogen atom, a methyl group or an ethyl group,

A 2,3-dihydro-4H-1,2,4-triazol-4-yl radical of formula f

(П where

R 15 represents an alkyl group having 1 to 6 carbon atoms or an aralkyl group having 1 to 2 carbon atoms in the alkyl moiety, wherein the aryl moiety is a phenyl group optionally substituted by one or two identical or different halogen atoms, and

R ¹⁶ represents a hydrogen atom, a methyl group or an ethyl group, and a 1H-1,2,3,4-tetrazol-1-yl radical of formula g

c) where

R ⁸ represents a hydrogen atom, a methyl group or a methylthio group, a 1H-1,2,4-triazol-1-yl radical of formula d

wherein one of R ¹¹ and R 12 is selected from the group. including a hydrogen atom and a methylthio group, the other of which is selected from the group consisting of hydrogen and alkyl having 1 to 3 carbon atoms, a 4H-1,2,4-triazol-4-yl radical of formula e, and pharmaceutically acceptable addition salts thereof with acids and stereochemically isomeric forms.

It is understood that the radical of the general 'formula e wherein R ⁿ is merkaptoskuplnu, may also exist in tautomeric' thioxo form. This thioxo form, although not expressly represented by the above structural formula, is obviously within the scope of the compounds of formula I.

As used hereinbefore and hereinafter, the term "halogen" refers to fluorine, chlorine, bromine and iodine, and the term "C 1 -C 6 alkyl" refers to straight and branched hydrocarbon radicals containing 1 to 6 carbon atoms, such as methyl, ethyl , 1-methylethyl, 1,1-dimethylethyl, propyl, 1-methylpropyl,

2-methylpropyl, butyl, pentyl, hexyl and the like.

The compounds of the above general formula (I) according to the invention are prepared by the addition of phenol. of formula III

Vn

(III) wherein

Y is as defined above, or a metal salt thereof, with a compound of formula II wherein

R13 represents a hydrogen atom, a mercapto group or a methylthio group;

241409

in which l

Ar is as defined above and

W represents a reactive ester residue, such as a halogen atom, preferably chlorine, bromine or iodine, or a sulfonyloxy group, such as a methylsulfoxy group or a 4-methylphenylsulfonyl group.

The reaction of a compound of formula II with a compound of formula III is carried out under conditions known in the art for carrying out O-alkylation using reactive esters. The reaction is generally carried out in an appropriate inert organic solvent such as N, N-dimethylforminamide, Ν, Ν-dimethylacetamide, hexamethylphosphoric triamide, dimethylsulfoxide, 4-methyl-2-pentanone and the like, optionally in admixture with other inert solvents such as aromatic hydrocarbons , for example benzene, methylbenzene, dimethylbenzone and the like. To accelerate the reaction, a suitable base, such as an alkali metal hydride or carbonate, is further preferably added to the reaction mixture. Alternatively, it is advantageous to convert the phenol of the formula III into its metal salt, preferably the sodium salt, in a customary manner, for example by reaction with a basic metal compound such as sodium hydride, sodium hydroxide and the like, and the metal salt is converted into a metal salt. then react with a compound of formula

II. To accelerate the reaction, it is expedient to operate at an elevated temperature, most preferably at a temperature of about 80 to 130 ° C

The imidazole and triazole derivatives of the formula (I) obtained in the above reaction in basic form can be converted into therapeutically useful acid addition salts by reaction with an appropriate acid such as an inorganic acid such as hydrohalic acid, e.g. hydrochloric, hydrobromic or hydroiodic acid, sulfuric, nitric or thiocyanic acid, or phosphoric acid, or with an organic acid such as acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, 1,4-butanedioic acid (Z) -2-butenedioic acid, (EJ-2-butenedioic acid, 2-hydroxy-1,4-butanedioic acid, 2,3-dihydroxy-1,4-butanedioic acid, 2-hydroxy-1,2,3-propanetricarboxylic acid, benzoic, 3-phenylb2-propene, α-hydroxybenzeneacetic, methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, 4-methylbenzenesulfonic, 2'-hydroxybenzoic, 4-amino-2-hydroxybenzoic, 2-phenoxybenzoic, or α-acetyloxyb Conversely, salts can be converted in the conventional manner into the corresponding free bases, for example by reaction with a base such as sodium or potassium hydroxide.

Generally, the starting materials of formula III, wherein Y is as defined above, can be prepared from the corresponding methoxy substituted compounds of formula IV by converting the methoxy group in the latter compounds to a hydroxyl group by acid hydrolysis using a strong non-oxidizing mineral acid such as hydrobromic acid in glacial acetic acid.

The above reaction scheme is illustrated by the following reaction scheme:

(III (IV))

The compounds of formula IV used in this case as starting materials can be obtained by cyclization of Ν, Ν-bis (2-haloethyl) -4-methoxybenzenamine of formula V with the corresponding benzenamide of formula VI, in which Y is as defined above.

This reaction can be described by the following reaction scheme wherein hal is a halogen atom:

This reaction is carried out by mixing the reactants in the presence of a suitable polar solvent, for example water, in a mixture with a suitable water-miscible organic solvent, for example 2-propanol, 2-propanone and the like, preferably at elevated temperature to accelerate reaction and most preferably in the presence of an iodide of a suitable alkali metal or alkaline earth metal such as potassium iodide.

The preparation of compounds of formula V is described in J. Chem. Soc., 1949, 183-191.

Alternatively, intermediates of formula IV may be prepared by cyclizing the corresponding intermediate of formula VII wherein A is amino or a derivative thereof, for example, isothiocyanato, hydrazinecarbothioamido, hydrazinecarboxamido, and the like, with a suitable cyclizing agent and optionally introducing appropriate substituents into the heterocyclic compounds so obtained. This process can be illustrated by the following reaction scheme:

(VII) cyclization introduces 7 ν ') substitution ntu ·

The nature of the symbol A in formula VII as well as the nature of the cyclizing agent used in the cyclization reaction depend on the importance of the symbol Y in the desired compounds of formula IV. The cyclization reactions as well as the optional further introduction of the substituents into the heterocyclic radicals are generally carried out in a manner known per se. Many of these reactions are described in the Examples section of the application describing the preparation of starting materials. It is understood that in the compounds of formula (IV) prepared by these processes, Y is not an amino group.

Intermediates of formula VII in which A is an amino group, which is designated VII-α, can be prepared by N-alkylating a compound of formula VIII with the appropriate chloronitrobenzene of formula IX using standard procedures known for carrying out N-alkylations, followed by reduction nitro compounds of formula X, for example by catalytic hydrogenation in a relatively polar solvent such as methanol, in the presence of a suitable catalyst, for example palladium on carbon.

The above process can be described by the following reaction scheme:

CH 2 O

(vin)

Intermediates of formula VII wherein A is an isothiocyanato group, which are designated VII-Ь, can be prepared from the corresponding compound of formula VII-a by reaction with carbon disulfide in the presence of dicyclohexylcarbodiimide and preferably in the presence of a suitable organic solvent such as pyridine.

The following reaction scheme illustrates this reaction:

í Vll-b)

Intermediates of formula (VII) wherein A is a hydrazinecarbothioamino group, which compounds are represented by formula (VII-c-1), may be prepared from a compound of formula (VII-b) by heating with hydrazine hydrate in the presence of a suitable solvent. such as 1,4-dioxane and the like.

The following reaction scheme illustrates this reaction:

1 H-b) NH ₃ -NH 2 -> CH ₃ O

with

NH-C-NH-NH 2 (VH-c-11

Intermediates of formula VII wherein A is a hydrazinecarboxamido group, which are designated VII-c-2, may be prepared from a compound of formula VII-a by heating the compound with stirring with a phenoxycarbonyl halide in a suitable solvent, for example to dichloromethane, in the presence of a suitable base such as pyridine and the like, and the thus obtained compound of formula VII-d is reacted with hydrazine hydrate in the presence of a suitable solvent, for example 1,4-dioxane and the like.

This procedure is illustrated by the following reaction scheme wherein hal is as defined above

^(VII ' ^d} _d :

NH2NH2 H ₂ 0 \ я '.

- ^w * CM ^ O ~~ у - \ y— ~ C ~ NH-NH ·: (VII-c-2)

Starting materials of formula II, v. wherein Q is CH, and methods for making these are described in Belgian Patent 837,831. In general, the active esters of Formula II can be prepared by the following sequence of reactions.

A suitable 1-Ar-2-bromoethanone of formula XI is subjected to a ketallization reaction with 1,2,3-propanetriol using an analogous procedure to that described in Synthesis, 1974 (Ij, 23).

According to a preferred embodiment of this reaction, the two reactants are refluxed for several hours under azeotropic removal of water, in the presence of a suitable organic solvent, preferably a simple alcohol such as ethanol, propanol, butanol, pentanol and the like. presence of a suitable strong acid such as 4-methylbenzenesulfonic acid. Suitable organic solvents are, for example, aromatic hydrocarbons such as benzene, methylbenzene, dimethylbenzene and the like, and saturated hydrocarbons such as cyclohexane.

The dioxolane of formula XII thus obtained is reacted with benzoyl chloride to give benzoates of formula XIII, which is then reacted with 1H-imidazole or 1H-1,2,4-triazole. This reaction is preferably carried out by heating the reactants with stirring in a suitable organic solvent, for example in Ν, dimethyl-dimethylformamide, in the presence of a suitable strong basic metal compound, for example sodium methoxide, to form the intermediate of formula XIV. The desired reactive esters of formula (II) are then conveniently prepared by first hydrolyzing the compound of formula (XIV) in an alkaline medium and then converting the hydroxyl group into this. obtained from the compound of formula XV to the rest of the reactive esters, using methods generally known in the art. For example, methanesulfonates and 4-methylbenzenesulfonates are conveniently prepared by reacting the alcohol with methanesulfonyl chloride or 4-methylbenzenesulfonyl chloride, and the halides may be prepared by reacting the alcohol with a suitable halogenating agent such as thionyl chloride, phosphorus pentachloride, phosphorus tribromide, phosphoryl chloride and the like. If the reactive ester is iodide, it is preferably prepared from the corresponding 241468. chloride or bromide by replacing these halogens with iodine.

'Β

The reaction scheme described above is illustrated by the following reaction scheme:

Q joct ^C _t ^H (XI)

C-0

4? 5 1H-imidazole or 1H-1,2,4-triazole, NaOCH 3 / dimethylformamide

formation of reactive ester

-----------> _(Π )

It is apparent from formula I that the compounds of the invention contain at least 2 asymmetric carbon atoms, namely, the carbon atoms at positions -2 and 4 of the dioxolane nucleus, and can therefore exist in different stereochemically isomeric forms. Stereochemically isomeric forms of the compounds of Formula I and their pharmaceutically acceptable acid addition salts are also within the scope of the invention.

The diastereomeric racemates of the compounds of formula I, referred to in C.A., 76, Index Gulde, Section IV, p. 85 (1972) as cis and trans forms, can be separated by conventional methods. Methods which may be used in the present case are, for example, selective crystallization and chromatographic separation, for example column chromatography.

Since the chemical configuration is already fixed in a number of starting materials and intermediates, for example in the case of the compounds of the formula II, it is also possible to separate the cis and trans forms in this or. even at an earlier stage, the corresponding forms of the compounds of formula (I) can be derived from these separated forms as described above. Separation of the cis and tris forms of these starting materials and intermediates can be accomplished by conventional methods as described above for separation of cis and trans forms of the compounds of formula I.

It is understood that cis- and trans-diastereomeric racemates can be further resolved into the respective optical isomers, i.e., the cis (+), cis (-), trans (-, -) and trans (-) isomers, and By methods known in the art.

The compounds of formula I and their pharmaceutically acceptable acid addition salts are useful agents for controlling fungi and bacteria. For example, it has been found that these compounds and their addition

The acid salts are highly effective against a wide variety of fungi such as, for example, Micrcsporum canis, Ctenomyces mentagrophytes, Trichophyton rubrum, Phialophora verrucosa, Cryptococcus neoformans, Candida tropicalis, Mucor spec., Aspergillus fumigegatus, Sporotricumnia, Sporotricumnia. against bacteria such as Erysipelotrix insidiosa, staphylococci such as Staphylococcus hemoly ticus, and streptococci such as Streptococcus pyogenes. Because of their potent local and systemic antimicrobial activity, the compounds of the present invention are useful agents for controlling or preventing the growth of fungi and bacteria, and are particularly useful for treating patients infected with these microorganisms.

The strong antimicrobial activity of the compounds of formula I is clearly demonstrated by the results obtained in the experiments described below. These results merely illustrate the useful antimicrobial properties of all compounds of formula (I), but do not limit the invention in any way to the extent of microorganisms susceptible to the disclosed compounds or to the range of compounds of formula (I).

Attempt A

Activity of compounds of formula I against vaginal candidiasis in rats

The rats (Wistar) weighing about 100 g are used for the test. The ovaries and the uterus are removed from these rats, and after three weeks of convalescence they are given 100 µg of estradiol undecylate in sesame oil once a week for 3 consecutive weeks. The pseudo-estrus thus induced is monitored by microscopic examination of vaginal swabs. Animals do not limit their intake of food and water. The rats are then intravaginally infected with 8 ΙΟ ³ Candida albicans cells grown for 48 hours at 37 ° C on Sabouraud broth. and diluted with brine. The infection is carried out from day 25 to day 32 after surgery, depending on when signs of induced pseudo-oestrus appear.

Test substances are administered orally once daily for two days starting from the day of infection. In each experiment, a control experiment was performed concurrently in which the animals received placebo only. The results are obtained by collecting vaginal swabs with sterile swabs for several days after infection. The swabs are placed in Sabouraud medium in Petri dishes and incubated at 37 ° C for 48 hours. If no growth of Candida albicans occurs, i. if the animals are negative at the end of the experiment, this condition is due to the administration of the active substance, since it will never occur in the above control trials.

The table below shows the lowest orally administered doses of test compounds that were shown to be effective 14 days after infection.

Pokus В

The anti-candidiasis activity of the compounds of formula (I) in turkeys days old turkeys are infested with 4.10 ^G Candida albicans cells grown in Sabouraud medium at 37 ° C and diluted with saline for 48 hours. The inoculum volume is 1 ml. The test compounds are premixed with 500 mg of lactone and then mixed with 1000 grams of flour without further additives. The concentration of test substances in flour is expressed in mg / kg.

The animals receive food with the active ingredient for 13 consecutive days, starting on the day of infection. At the end of the experiment, all animals were sacrificed, their oxen removed, emptied and ground in a mixer in 15 ml of sterile saline. After cultivation on Sabouraud medium, the growth of the microorganism is evaluated. The results obtained are shown in the following table as ED 50 values, i.e., the dose of the compound after which 50% of the animals are totally negative for the incidence of Candida albicans.

The compounds and results shown in the following table are illustrative only and in no way limit the scope of the invention.

Q Vaginal candidiasis in rats; lowest effective dose in mg / k [oral administration]

2.5

2.5

1,25

1,25

0.63

0.63

2.5

1,25

2.5

Й 0.63

2.5

2.5

0.63 candidate for turkey;

ED ₅ ov mg / kg feed

Y Q Vaginal candidiasis in rats; candidate for the lowest effective dose in mg / kg in turkeys;

(oral administration) ED50 in mg / kg feed

SCHj

CH 31 -N Ή % N = N-1 0.63 16 0 ^X CH ₃ H-1C CH 1 0 N á 0.63 16 ^N M - ^N - CH. - <Vn-.ck N <2.5 N 0,63 CH 1.0 16 0 CH 1,25 31 ₃ CH 0.83 - ^< S ^- NC _to H _S -я CH ₃ N <0.63 - θ -N 1 N 0.5 -

ch ₃

241488

Y Q Vaginal candidiasis in rats; candidate choose the lowest effective dose in mg / kg in turkeys;

(oral administration) ED ₅₀ in mg / kg feed.

\ -Ν-0 ₂ Η ₅ -N O N > 0.16 -N CH . 1,25 r _f ; ₃ NH2 CH 1,25 NH2 N 0.63

Because of their antifungal and antibacterial activity, the compounds of the formula I or their acid addition salts can be formulated into valuable formulations containing the compounds as active substances and a solid, semi-solid or liquid diluent or carrier. The invention also includes an effective method for controlling the growth of fungi and bacteria using an antifungal or antibacterially effective amount of a compound of formula I or a salt thereof. As mentioned above in part, the antifungal and antibacterial compositions of the invention comprise an effective amount of a compound of Formula I or a salt thereof, either alone or in combination with other therapeutically active agents, in admixture with suitable carriers. These compositions can be readily prepared by conventional pharmaceutical techniques used to prepare dosage forms for conventional modes of administration.

Preferred compositions are unit dosage forms comprising, in unit dosage, an effective amount of a compound of the invention in admixture with suitable carriers. Although the amount of active ingredient per unit dose may vary within wide limits, unit doses containing from about 50 to 500 mg of active ingredient, in particular from about 100 to 250 mg, are generally preferred.

The following Examples illustrate embodiments _{of L} which however the invention is not limited by the examples. Unless otherwise indicated, all parts are by weight.

A) Preparation of starting materials

Example 1

Зшйз 13.4 dik; 14 parts (Methylphenyl) piperazine dihydrochloride, 7.9 parts of 1-chloro-4-nitro-dehydrogen, 10 parts of potassium carbonate and parts of Ν, Ν-dimethylformamide are stirred and refluxed overnight. The reaction mixture was diluted with water and the product was extracted twice with trichloroethane. The combined extracts were dried and evaporated. The residue was triturated in 4-methyl-2-pentanone, the product was filtered off and crystallized from 1,4-dioxane. 10.5 parts (67%) of 1- (4-methoxyphenyl) -4- (4-nitrophenyl) piperazine of melting point 195.1 ^DEG C. are obtained.

A mixture of 12 parts of 1- (4-methoxyphenyl) -4- (4-nitrophenyl) piperazine, 200 parts of methanol and 225 parts of tetrahydrofuran is hydrogenated under normal pressure at room temperature in the presence of 2 parts of 10% palladium on carbon catalyst. After the calculated amount of hydrogen had been consumed, the catalyst was filtered off and washed with N, N-dimethylacetamide. The filtrate is poured into water, the precipitated product is filtered off and crystallized from 1-butanol. 8 parts (74%) of 4- [4- (4-methoxyphenyl) -1-piperazinyl] benzenamine are obtained, m.p. 191.8 ° C.

Example 1 a d 2

To a mixture of 5 parts of N, N'-methantetraylbis [cyclohexanamine], 25.2 parts of carbon disulphide and 40 parts of pyridine, 6 parts of 4- [4- (4-methoxyphenyl) -1-piperazinyl] benzenamine are added under stirring and cooling in ice. The mixture was stirred for 1 hour under ice-cooling and then for 2 hours at room temperature. After adding 35 parts of 2,2'-oxybispropane, the reaction mixture is stirred for 30 minutes, then the precipitated product is filtered off and crystallized from 4-methyl-2-pentanone. The precipitated product is filtered off and recrystallized from 1,4-dioxane. 2.45 parts of 1- (4-isothiocyanatophenyl) -4- (4-methoxyphenyl) piperazine of melting point 180.6 DEG are obtained.

A mixture of 47.8 parts of 1- (4-isothiocyanatophenyl) -4- (4-methoxyphenyl) piperazine, 100 parts of hydrazine hydrate and 400 parts of 1,4-diovan is added with

Cooking is heated at reflux for 1 hour. The reaction mixture is cooled, poured into water, the precipitated product is filtered off and washed after washing with water and methanol. 46 parts (89%) of N- (4- (4 · -)

(4-Methoxyphenyl) -1-piperazinyl] phenyl] hydrazinecarbothioamide.

Example. 3

A mixture of 23 parts of N- {4- (4- (4-methoxyphenyl) -1-piperazinyl] phenyl} hydrazinecarbothioamide, 23 parts of methanimidamide acetate and 80 parts of 1-butanol is stirred and refluxed for 1 hour. The mixture was cooled, poured into water, 2,2'-oxybispropane was added, the precipitated product was filtered off and, after washing with water and methanol, crystallized from 1-butanol to give 17.7 parts of 4- {4-

- (4- (4-methoxyphenyl) -1-piperazinyl] phenyl) -4H-1,2,4-triazole-3-thiol, m.p. 231.9 ac.

In an analogous manner, using an equivalent amount of ethanimidamide hydrochloride instead of methanimidamide acetate, 4- (4- (4- (4-methoxyphenyl) -1-piperazinyl) phenyl) -5-methyl-4H-1,2,4- is obtained. ri azole-3-thiol, mp 260.3 C. ^q

Example 4

A mixture of 9 parts of 4- (-4-4-methoxyphenyl) -1-piperazin-5-yl] -1H-4H-: 1,2,4-triazole-3-thiol, 2 parts of sodium hydroxide and 160 parts of methanol are heated with stirring until all solids have dissolved. 3.3 parts of dimethyl sulfate were added to the resulting mixture, and stirring was continued at room temperature for 3 hours. The reaction mixture was poured into water, the precipitated product was filtered off and crystallized from 1-butanol. 5.3 parts of 1- (4-methoxyphenyl) -4- (4- (3- (methylthio) -4H-1,2,4-triazol-4-yl) phenyl) piperazine are obtained, m.p. .

1- (4-Methoxyphenyl) -4- (4- (3-methyl-5- (methylthio) -4H-1,2,4-triazol-4-yl) phenyl) piperazine dihydric chloride was prepared analogously. Deň: 32 ° C.

Example 5

A mixture of 50 parts of 2- (4-nitrophenyl) hydrazinecarbothioamide and 270 parts of methylbenzene is distilled azeotropically to dryness, then 26 parts of acetic anhydride are added, and the reaction mixture is heated under reflux for 3 hours and then cooled. The precipitated product is filtered off and washed with 2-propanol, crystallized from ethanol, filtered and dried at 100 DEG C. to give 31.5 parts of acetic acid 2- (aminothioxomethyl) -1- (4-mtrophthyl) hydrazide. mp 241.5 C ^O.

Using the same acylation procedure, the following compounds are also obtained using always equivalent amounts of the respective starting materials:

Butanoic acid 2- (aminocyclohexyl) -1- (4-nitrophenyl) hydrazide monohydrate at a melting point of 197.2%: a

Propanoic acid 2- (aminothioxymethyl) -1- (4-nitrophenyl) hydrazide, m.p. 216.1%.

Example 6 parts of 2- (aminothioxo) -4- (4-nitro) phenyl] acetic acid hydrazide were dissolved in a mixture of 10 parts of sodium hydroxide and 400 parts of water, and the resulting solution was stirred at room temperature for 30 minutes. The reaction mixture was acidified with concentrated hydrochloric acid, the precipitated product was filtered off, washed with water and 2-propanol, and crystallized from 1,4-dioxane to give 22.4 parts of 5-methyl-1- (4-). nitrophenyl) -lH-l, 2,4-triazole-3-thiol, mp 202.1 C. ^Q

The following compounds are also prepared in an analogous manner:

1- (4-Mirophenyl) -5-propyl-1H-1,2,4-triazole-

3-thiol, mp 190.7 ^C, and C

5-ethyl-1- (4-nitrophenyl) -1H-1,2,4-triazole-3-thiol, m.p. 206.1 ° C.

Example 7

To 80 parts of methanol was added. 4.7 parts of 5-methyl-1- (4-nitrophenyl) -1H-1,2,4-triazole-3-thiol and 1.2 parts of sodium hydroxide are added and the mixture is stirred until all solids have dissolved, then 2.66 parts of dimethyl sulfate are added and stirring is continued for 1 hour at room temperature. After adding 100 parts of water, the precipitated product is filtered off, washed with water. and drying is crystallized from 2,2'-oxybutane. 3.3 parts (66%) of 5-methyl-1H-methylthio) -1- (4-nitrophenyl) -1H-1,2,4-triazole of melting point 121-125% are obtained.

The following compounds are also obtained by analogous methylation using in each case equivalent amounts of the respective starting materials:

5-ethyl-3- (methylthio) -1- (4-nitrophenyl) -1H-1,2,4-triazole, m.p. 77.8 ° C; and

3- (methylthio) -1- (4-nitrophenyl) -1H-1,2,4-

-triazole, m.p. 140 ° C.

Example 8

A mixture of 2.5 parts of 5-methyl-1- (4-nitrophenyl) -1H-1,2,4-triazole and 120 parts of methanol in the presence of 2 parts 10% of platinum on carbon catalyst is hydrogenated at normal pressure at room temperature. After the calculated amount of hydrogen has been consumed, the catalyst is filtered off, the filtrate is evaporated, the residue is crystallized from a mixture of 4-methyl-2-pentanone and petroleum ether, the product is filtered off and dried. 1.5 parts (68%) are obtained

4- (5-methyl-3- (methylthio) -1H-1,2,4-triazol-1-yl) benzenamine, m.p. 130-136%.

ia

2Ί

-4- [3- (Methylthio) -1H-1,2,4-triazol-1-yl] benzenamine was also prepared by the same hydrogenation procedure.

Example 9

A mixture of 41 parts of 5-ethyl-3- (methylthio) -1- (4-nitrophenyl) -1H-1,2,4-triazole and 80 parts of methanol is hydrogenated under normal pressure in the presence of 1 part of 10% palladium on carbon catalyst. room temperature. After the calculated amount of hydrogen has been consumed, the catalyst is filtered off, the filtrate is evaporated, the residue is crystallized from 1,1'-oxybisbutane, the product is filtered off and dried. 33 parts (91-%) of 4- [5-ethyl-3- (methylthio) -1H-1,2,4-triazol-1-yl] benzenamine are obtained, m.p. 131.7 ° C.

In a similar way also. Preparation of 4- (2 - [ ₍ 1-methyl-1-yl) -1H-1 H -methyl] - _{(4 (} azo) -1-yl) benzenamine melting at 105 ^° C.

Example 10

A mixture of 20 parts of 4- [5-methyl-3- (methylthio) -1H-1,2,4-triazol-1-yl] -benzerLamine, 15 parts of Raney-nickel-like. of catalyst and 400 parts of methanol are refluxed for 2 hours with stirring. The nickel-nickel is filtered off, an additional 15 parts of catalyst are added and stirring is continued at reflux for 4 hours. - The reaction mixture was filtered, the filter residue washed with _methyl% of ethanol and the filtrate evaporated. The residue was crystallized from a mixture of 4-methyl-2-pentanone, 2,2'-oxybispropane and petroleum ether, the product was filtered off and dried. 7.6 parts (47%) of 4- (5-methyl-1H-1,2,4,4-thiazol-1-yl) benzenamine, m.p. 145 DEG C., are obtained.

Example 11

A mixture of 35 parts of ly (4-methophthyl) -5-pro-2-l-1,2-triazole-3-thiol, 83 parts of concentrated nitric acid and 150 parts of water is heated to 60 ° C with stirring, then the mixture is heated. The precipitated product is filtered off, washed with water and added to a hot solution of 20 parts of potassium carbonate in 200 parts of water at 100 ° C. The reaction mixture is allowed to cool to room temperature with stirring, the precipitated product is filtered off, dried, crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, filtered again and recrystallized from -4-methyl 2-pentanone to give 19.8 parts of 3,3'-dithiobis [1- (4-nitrophenyl) -5-propyl-1H-1,2,4-riazole], m.p. 171.5 ° C. C.

parts of 3,3 ^&apos; -dithiobis [1- (4-nitrophenyl) -5-propyl-1H-1,2,4-triazole] are dissolved in 1.0 parts of acetic acid by stirring and heating and 55 parts are added dropwise. 30% hydrogen peroxide solution, the reaction mixture being heated to reflux. After the addition was complete, the resulting mixture was boiled under stirring at reflux for 1 hour, then cooled and poured into a mixture of crushed ice and 50% sodium hydroxide solution. The precipitated product is filtered off, dissolved in dichloromethane, the solution is washed with sodium sulphite solution, dried and the filtrate is evaporated. The residue was purified by silica gel column chromatography using trichloromethane. n as eluent. The pure fractions were combined, the solvent was evaporated and the residue was converted to the hydrochloride in 2-propanol. The salt was filtered off and crystallized from ethanol to give 3.9 parts (19%) of 1- (4-nitrophenyl) -5-propyl-1H-1,2,4-triazole monohydrochloride, m.p. 178.7 °. C.

A mixture of 38.3 parts of 1- (4-nitrophenyl) -5-propyl-1H-1,2,4-triazole monohydrochloride and 400 parts of methanol is hydrogenated under normal pressure in the presence of 3 parts of 10% palladium on carbon catalyst. at room temperature. After the calculated amount of hydrogen had been consumed, the catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in water and the solution was neutralized with sodium bicarbonate. The product was extracted with dichloromethane, the extract was washed with water and then filtered and evaporated. The residue is in

2-Propanol is converted to the hydrochloride salt, the salt is filtered off and dried. 35 parts (91%) of 4- (4-methyl-1H-1,2,4-riazol-1-yl) benzenamine dihydrochloride are obtained.

Example 1 a d 12

A mixture of 4 parts of N- (4-nitrophenyl) hydrazlnkarboxamidu, 5 parts of ethanimidamide hydrochloride and 5 parts of sodium acetate SE- heated for 4 hours with stirring at 140 C. The reaction mixture ^q SE- cooled, treated with water and the resulting mixture was stirred until the product crystallized out, which was filtered off and recrystallized from 2-propanol. 1.5 parts (34%) of 2,4-dihydro-5-methyl-4- (4-nitrophenyl) -3H-1,2,4-triazol-3-one of melting point -226.1 are obtained. Deň: 32 ° C.

To a solution of 13.5 parts of 2,4-dihydro-5-methyl-4- (4-nitrophenyl) -3H-1,2,4-triazol-3-one. in 100 parts of dimethylsulfoxide, 2 parts of a 78% sodium hydride dispersion are added with stirring, and - the resulting mixture is stirred until the foaming has subsided and 8.1 parts of dimethyl sulfate are added dropwise thereto. After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours, then poured into water and the product was extracted three times with trichloromethane. The combined extracts were washed with water, dried and, after filtration, evaporated. The residue - crystallized from a mixture of 2-propanol and 2,2'-oxybispropane. The product was filtered off and recrystallized from 4-methyl-2-pentanone to give 6.3 parts

2,4-dihydro-d, 5-methyl-4- (4-nitrophenyl) -3H-1,2,4-triazol-3-one, m.p. 153.2 ° C.

A mixture of 9 parts 2,4-dihydro-2,5-dimethyl-4- (h-nitrophenyl) -3H-1,2,4-triazol-3-one and 200 parts methanol in the presence of 3 parts Raney241468

The catalyst is hydrogenated. as normal. pressure at room temperature. After the calculated amount of hydrogen had been consumed, the catalyst was filtered off and the filtrate was evaporated. The residue was triturated with 2,2'-oxybispropane, the product was filtered off and dried. 7.5 parts [95%] of 4- (4-aminophenyl) -2,4-dihydro-2 H -imidazol-1-yl are obtained. _; 23 - ¹ i ^ thiazol-3-one, mp 160 · C ^Q

Example 13

Mixture of 53 parts

The piperazinylphenylhydrazinecarboxamide, 53 parts of ethanimidamide hydrochloride and 135 parts of Ν, Ν-dimethylformamide were heated to 130 ° C with stirring for 3 hours. The reaction mixture was cooled, poured into water, the precipitated product was filtered off, washed with water and methanol, and crystallized from Ν, Ν-dimethylformamide. The product is filtered off and recrystallized from 1,4-dioxane to give 19.5 parts of 2-nitro-4 '- 4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl-5-methyl-3H-1. 2,4,4-triazol-3-one, m.p. 293.4 ° C.

Example 14

19.2 parts of 2,4-dihydro-4- [4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl] -3H-1,2,4-triazol-3-one at a temperature of about 100 ° Dissolve C in 450 parts dimethylsulfoxide, · add 3.1 parts · 50% sodium hydride dispersion and stir until about 50 ° C, then add 8.2 parts of dimethyl sulphate and continue stirring overnight · . at room temperature. The reaction mixture was poured into water and the product was extracted with trichloromethane. The extract was dried and evaporated after filtration. The residue was purified by silica gel column chromatography using a 98: 2 by volume mixture of trichloromethane and methanol as eluent. The pure fractions were combined, the solvent was evaporated and the residue was crystallized from 1-butanol. There were obtained 5.8 parts of 2,4-dihydro-4-4- [4- (4-methoxyphenyl) -1-piperazinyl] -1H-pentyl] -2,2-methyl-3H4: 1,2, 245.7 ° C.

and the residue was triturated with 2-propanol. Filtration and drying of the product gave

7.5 dl (65%) -2,4-dihydrl-1- (444- (--- methoxyphenyl) -1-piperazinyl] phenyl-2-propyl-3H-1,2,4- triazol-3-one.

The following compounds are obtained by analogous N-alkylation using always equivalent amounts of the respective starting materials:

Ethyl-2,4-dihydro-4-: 4- [4- (4-methoxyphenyl) -1-piperazinyl] ethylene-5-methyl-3H-1 ₅ 2 ₅ 4-triazole-3 - melting point 179,8 ° C,

2-> 4- [4- (4-methoxyphenyl) -1-. 144,5 ° C and eldenyl-4,4'-dihydric-4- [4- (4-piperazinyl) phenyl] methyl-2-propyl-3H-1,2,4-triazol-3-one; (methoxyphenyl) -1-piperazinylphenyl) -3H-1,2,4r

-triazo + 3-one, m.p. 210.2 ° C.

Example 16

Mixture 12.5. part N _; N-dimethylamino-4-methoxybenzenamine, 8 parts of 4- (1H-pyrazol-1-yl) benzenamine, 2 parts of potassium iodide, 80 parts of 2-propanone and 100 parts of water are boiled under stirring for 24 hours under reflux. The reaction mixture was cooled, the precipitated product was filtered off (the filtrate was discarded), washed with water and 2-propanone to give 6 parts of the first crude fraction.

The filtrate obtained above is neutralized with sodium bicarbonate solution and extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was triturated with 2-propanol, the product was filtered off and washed with methanol to give 2 parts of a second crude fraction. The combined crude fractions (6 + 2 parts) were crystallized from 1-butanol. 7.1 parts of 1- (4-methoxyphenyl) -4-1H-piperazol-1-yl) phenyl] piperazine are obtained, m.p. 207.7 ° C. _д

The following compounds are also prepared in an analogous manner using always equivalent amounts of the respective starting materials:

EXAMPLE 15 parts of 2,4-4 -idydro-4- [4- [4- (4-methoxyphenyl) -1-piperazinyl]] thenyl-3H-1,2,4-triazol-3-one dissolve in 300 parts of dimethyl sulfoxide at 100 ^DEG C., 1.6 parts of a 50% sodium hydride dispersion are added to the solution, and the mixture is allowed to cool to about 50 DEG C. with stirring, followed by the addition of 3.9 parts of 1-bromopropane. . The reaction mixture was stirred at room temperature overnight, then poured into water and the product was extracted with trichloromethane. The extract was washed with water, dried. and evaporated after filtration. . The residue was purified by silica gel column chromatography using a mixture of trichloromethane and methanol (98: 2 by volume) as eluent. The pure tractions were combined, the solvent was evaporated

1- [4- (Н ^^ЬОООССС--ЦЦЦЦЦЦЦЦ tyЦЦЦЦЦЦЦЦЦЦЦЦЦЦЦЦЦ), m.p. 255-256 ° C,

1- ((4-tiη thiyl-4- [4- (11Hl, 2,4-triazole) ·

-1-yl Ifenviloiperazine of melting point

230.3 ^° C,

1- (4-Methoxyphenyl) -4- (4- (3- (methylthio) -1H-1,2,4-triazol-1-ylphenyl) piperazine, mp 186.5 ° C) edy-4- (4- [5-methyl-3- (methylthio) -1H-1,2,4-triazol-1-yl) phenyl] piperazine, m.p. 153.3 ° C,

1- (4-Methoxyphenyl) -4- (4- (5-methyl-1H241468)

-1,2,4-triazol-l-yl) phenyl Jpiperazin O · m.p. 191.1 ^C -C

2,4-dihydro-4-; 4- [4- [4-methoxyphenyl] -1-piperazinyl] phenyl; -2,5-dimethyl-3H-1,2,4-trolol-3-one, m.p. 196 7 ^Q C

1- (4-Methoxyphenyl) -4-; 4- (5-propyl-1H-

-1,2,4-triazol-yl) phenyl lpiperazine, m.p. 196.3 ° C; 1- {4- [5-ethyl-3- (methylthio) -111-1,2,4-triazole-1- yl] phenylgl '(4-methoxyphenyl) piperazine, m.p. 142.3 ° C;

1- (4-methoxyphenyl) -4- [4- (2-methyl-1H-imidazol-1-yl) phenyl] piperazine, m.p. 178.5 ° d

Example 17

A mixture of 6 parts of 4- [4- (4-methylphenyl) -1-piperazinyl] benzenamine, 3.6 parts of phenoxycarbonyl chloride, 75 parts of pyridine and 98 parts of dichloromethane is heated with stirring until all solids have dissolved. The reaction mixture was stirred for another 30 minutes at room temperature, then poured into 500 parts of water and 219 cells of 2,2'-oxybispropane were added. The resulting mixture was stirred for a while, then the precipitated product was filtered off and crystallized from 1-butanol. 5.2 parts (61%) of phenyl-4- [4- (4-methylphenyl) -1-piperazio-yl] phenyl} carbamate are obtained, m.p. 204.5 ° C.

A mixture of 3.2 parts of phonyl- {4- [4- (4-methoxyphenyl) -1-piperazinyl Ifenylcarbemate, 50 parts of hydrazine hydrate and 100 parts of 1,4-dioxanium was heated under reflux for 3 hours. The reaction mixture was cooled, poured into water, the precipitated product was filtered off and crystallized from N-dimethylformamide. Yielding 1.7 parts [63%) of N- [4- (4- (4-methoxyphenyl) piperazinyl jfenyllhydrazinkarboxamidu mp 300 C ^Q

A mixture of 3.4 parts of N- [4- [4- (4-methoxyphenyl) -1-piperazinyl] phenylihydrazinecarboxamide, 3 parts of methanimidamide acetate and 10 parts of dimethylsulfoxide was heated to 100 ^° C with stirring for 2 hours. The reaction mixture was cooled and poured into a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The precipitated product was filtered off and crystallized from N, N-dimethylformamide using activated carbon to give 1 part (23%) of 2,4-dihydro-4- [4- [4- (4-methoxyphenyl) -1-piporazinyl if enyl]; -3H-1,2,4-triazol-3-one of melting point 300 ^C. G.

Example 18

A mixture of ZP parts of 4- [4- (4-methoxyphenyl) -1-piperazinylbenzamide] and 300 parts of a 48% solution of hydrobromic acid in water was stirred and refluxed for 10 days. The reaction mixture was evaporated, the residue basified with sodium hydride, filtered and the filtrate acidified with acetic acid. The precipitated product was filtered off and after crystallization from 1,4-dioxane gave 12 parts (44%) of 4- [4- (4-aminophenyl) -1-piperazinyl] phenol.

The following compounds are also prepared in an analogous manner using always equivalent amounts of the respective starting materials:

4- (4- [4- (1H-pyrazol-1-yl) phenyl] -1-piperazinyl) phenol,

444- [4- (1H-imidazol-1-yl) phenyl] -1-piperazinybphenol, melting above 260 ^and C,

4- {4 [4- (111-1,2,4-triazol-1-yl) phenyl] -1-piperazinylphenol, m.p.

276.6 ^Q C,

4- (4- (4- [3- (methylthio) -1H-1,2,4-triazol-1-yl) phenyl; -1-piperazinyl) phenol, m.p. 225.5 ° C,

4- (4- (4- [5-methyl-3- (methylthio) -1H-1,2,4-triazol-11-yl) phenyl | -1-piperazinyl) phenol, m.p. 255.8 ° C ,

4- (4--4 [3-methyl-5- (methylthio) -4H-1,2,4-triazol-4-yl] phenyl} -1-piperazinyl) phenol, <4- [4- (5 methyl-1H-1,2,4-triazol-1-yl) phenyl] -1-piperazinyl, phenol, m.p.

4- (4- (4- [3- (methylthio) -4H-1,2,4-triazol-4-yl] phenyl-1-piperazinyl) phenol,

2,4-dihydro-4- [4- [4- (4-hydroxyphenyl) -1-piperazinyl] phenyl (-2,5-dimethyl-3H-1,2,4-triazol-3-one) at a temperature of 260 ° G,

2,4-dihydro-4- [4- [4- (4-hydroxyphenyl) -1-piperazinyl] phenyl} -2-propyl-3H-1,2,4-triazol-3-one;

4- (4- [4- (2-methyl-1H-imidazol-1-yl) phenyl] -1-piperazinylphenol, m.p. 300 ° C,

4- (4- (4- [5-ethyl-3- (methylthio) -1H-1,2,4-triazol-1-yl) phenyl] -1-piperazinyl) phenol, m.p. 232.6 ° C,

2-ethyl-2,4 dihydro-4- (4- [4- (4-hydroxyphenyl) -1-piperazinyl] phenyl} -5-methyl-3 H -1,2,4-triazol-3-one, m.p.

237,8 T,

2,4-dihydro-4- [4- [4- (4-hydroxyphenyl) -1-piperazinyl] phenyl] -5-methyl-2-propyl-3H-1,2,4-triazol-3-one, m.p.

258.2%

2,4-dihydro-4-; 4- [4- (4-hydroxyphenyl) -1-piperazinyl] phenyl] -2-methyl-3H-1,2,4-triazol-3-one;

2414В а

2-ethyl-2,4,4-dihydro-4- (4- [4- (4-hydroxyphenyl) -1-piperazinyl] phenyl) -1H-1,2,4-triazol-3-one at a temperature of mp 217 ° C a

4- {4- [4- (5-Propyl-1H-1,2,4-triazol-1-yl) phenyl] -1-piperazinyl] phenol, m.p. 225.6 ° C.

B. Preparation of final products

Example 19

К solution of 3 parts of 4- ^r 4- (4-aminophenyl) -l-piperazinyl) phenol in 50 parts diinethylsulfoxidu added with stirring 0.5 parts of 5O ° / o sodium hydride dispersion. The mixture was stirred at 50 ° C until foaming ceased and 4.1 parts of cis- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-2-ylmethyl) -1] added. 3-dioxolan-4-ylmethyl] methanesulfonate and stirring is continued for 2 hours at 70 ^Q C. the reaction mixture was cooled, poured into water and the product extracted with dichloromethane. The extract was washed with dilute sodium hydroxide solution, dried and evaporated after filtration. The residue was purified by silica gel column chromatography using a 98: 2 by volume mixture of trichloromethane and methanol as eluent. The pure fractions were combined, the solvent was evaporated and the residue was crystallized from 2-propanol. Filtration and drying of the product yielded 1.3 parts (22%) of cis-4- (4- (4- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3) 174.4 ° C; -dioxolan-4-ylmethoxy] phenyl-1-piperazinyl) benzenamine.

Example 20

To a solution of 3.2 parts of 4- (4- (4- (1H-pyrazol-1-yl) phenyl) -1-piperazinyl-phenol) in 100 parts of dimethylsulfoxide was added 0.32 parts of 78% sodium hydride dispersion, the mixture was stirred at 50 ° C. ^C. until foaming ceased, 4.1 parts of cis- (2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethyl) were added. The reaction mixture was cooled, poured into water and the product was extracted with dichloromethane, the extract was washed with dilute sodium hydroxide solution, dried and evaporated after filtration. Silica gel column chromatography using a mixture of trichloromethane and methanol (98: 2 by volume) as eluent The pure fractions were collected, the solvent was evaporated and the residue purified again by silica gel column chromatography using a mixture of methylbenzene and ethanol (95: 5 by volume) as The pure fractions were combined, e The solvent was evaporated and the residue was crystallized from methylbenzene to give 2.2 parts (34%) of cis-1,4- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,15]. 2-dioxolan-4-ylmethoxy] phenyl-4- [4- (1H-pyrazol-1-yl) phenyl] piperazine, m.p. 195.1 ° C.

The following compounds are also prepared in an analogous manner using always equivalent amounts of the respective starting materials:

cis-1- (4- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl) -4- [4- 166.7 ° C, mp-1- (4- [2- (2,4-dichlorophenyl) 2- (1H-imidazol-1-ylmethyl) -1,3] (1H-imidazol-1-yl) phenyl] piperazine; -4- [4- (1H-1,2,4-triazol-1-yl) phenyl] piperazine, m.p. 175.3 ° C; 2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl] -4- [4- (3- (methylthio) -1H-1,2,4)] - triazol-1-yl] phenyl] piperazine, m.p. 178.3 ° C; cis-1- (4- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1), 3-dioxolan-4-ylmethoxy] phenyl, -4- (4- [3-methyl-5- (methylthio) -4H-1,2,4-triazol-4-yl] phenyl) piperazine, m.p. 127.8 ° C C, cis-1- [4- (2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxyphenyl) -4- [4- (5-methyl-3- (methylthio) -1H-1,2,4-triazol-1-yl) phenyl] piperazine, m.p. 183.9 ° C; 4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dio xolan-4-ylmethoxy] phenyl | -4- {4- [3- (methylthio) -4H-1,2,4-triazol-4-yl] phenyl] piperazine, mp 176.4 ^° C, cis-4- / 4- (4- (4- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxyphenyl} -1-piperazinyl) f 149,4 ° C, cis-4- / 4- (4- (4- (4-methyl-2-methyl-3H-1,2,4-triazol-3-one)); [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl-1-piperazinyl) phenyl] -2,4-dihydro-2 propyl-3H-1,2,4-triazol-3-one, m.p. 185.7 ° C; cis-1- (4- [2- (2,4-dichlorophenyl) -2- (1H-imidazole- 1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl-4- [4- (5-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine, m.p. 154, 1% cis-1- {4- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl] -4- [4] - (2-methyl-1H-imidazol-1-yl) phenyl] piperazine, m.p. 180.1 ° C, cis-4- / 4- (4- (4- [2- (2,4-dichlorophenyl) - 2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-yl-ethoxy] phenyl-1-pipera zinc / phenyl / -2,4-dihydro-3H-1,2,4-triazol-3-one, m.p. 212.8 ° C, cis-4- / 4- (4- 14- [2- ( 2,4-Difluorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-diol-4-ylmethoxy-phenyl-1-piperazinyl) phenyl] -2-ethyl-2,4-dihydro-3H 1,2,7-triazol-3-one, m.p. 204.7 ° C, cis-4- / 4- (4- | 4- [2- (2,4-dichlorophenyl) -2- (1H) -imidazole) (1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl] -1-piperazinyl) phenyl] -2,4-dihydrot-5-dimethyl-2-propyl-3Ht-1,2,4-triazole- 3-on-monohydrate, m.p. 153.9 cc, cis-1- [4- [2- (2,4-di-chlorophenyl) -2- (1H-imidazol-2-ylmethyl) -1,3-dihydro-4-ylmethoxy] Phenyl] -4- {4- [5-ethyl-3- (methylthio) -1H-1,2,4-triazol-1-yl] phenyl] piperazine, m.p. 4-Diohlorophenyl] -2- (1H-imidazol-1-ylmethyl) -1,3-dilan-4-ylmethoxy] phenyl] -4- [4- (5-propyl-1 H, 1,2)] 1,4-triazol-1-yl] phenyl 1 piperazine, m.p. 150.4 · a (: 18-4- / 4- (4-4-γ ₂ - (2,4-dichlorophenyl) -2 · · (1H) (imidazol-1-ylmethyl) -1,3-dicxolan-4-ylmethoxy-1-phenyl - ^. 1.tpipeгaz1nyl) phenyl] / t -2-ethyl] -2,4-d.hydro methyWH-S-l ^^ - trlazolt3 monohvdrát-one melting at 135.5 ° C. '

Example 21

To a solution of 8 parts of 4- [4- (4-amino-phenyl) -1-piperazinyl] phenol in 100 parts of dimethylsulfoxide is added 1.5 parts of a 50% sodium hydride dispersion with stirring, stirring is continued until foaming ceases. then 12.3 parts of cis- [2- (2,4-di-chlorophenyl) -2- (1H-1,2,4-triazol-4-ylmethyl) -1,3- of dioxolane-4-ylinethylthio] methanil-3-oxoate, and the resulting mixture was heated to 50 ° C with stirring for 4 hours, cooled, poured into water and extracted three times with dichloromethane. The residue was purified by silica gel column chromatography using a mixture of trichloromethane and methanol (98: 2 by volume) as eluent. The pure fractions were combined, the solvent was evaporated and the residue crystallized from silica gel. 1-butanol was obtained, yielding 5.1 parts of cis -4- [4- [2,4- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) - 1,3-di (M: -) N-4-ylmethoxythienylphenyl-piperazinyl) benzanaline at a melting point of 186.8 ° C.

Example 1 and d. 22nd

To a solution of 3 parts of 4- {4- [4--114-1,2,4-trlazcl-1-yl] phenyl] -1-piperazinyl-phenoxy in 100 parts of dimethylsulfoxide is added 0.3 part

78% sodium hydride dispersion, stirred at 50 [deg.] C. until foaming subsided, then 3.7 parts of [alpha] - [2- (2,4-dichlorophenyl) -2- (1Htl, 2,4-trlazolite) were added: The mixture was stirred for 3 hours at 100 DEG C. The reaction mixture was cooled and poured into water, and the product was extracted three times with dichloromethane, and the combined extracts were washed with dilute hydroxide solution. The residue was crystallized from 1-butanol, the product was filtered off and dried.

4.3 parts (75% cis-4 - [[2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] Phenyl 4 - [4- (1H, 1,2,4-triazol-1-yl) phenyl] plperazine, mp 219.6 ° C.

In an analogous manner, the following compounds are obtained using equivalent amounts of the respective starting materials:

cis-1- {4- [2- (2,4-η 5 -phenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] -1 enyl} -4-

- [4- (1H-pyrazol-1-yl) phenyl] piperazine, m.p. 188.3 ° C, cis [4t [2- (2,4-dichlorophenyl) -2- (1H-1,2,4)] (Triazolylmethyl) -1,3-dioxolanthyltylmethoxy] phenyl-4-

- [4- (1H imidazoltl-yl] phenyl] piperazine, m.p. 194.3 · ^Q C · cis l- {4- [2- (2,4-dichlorophenyl] -2- _(1HtУ) 2.4 -triazolylmethyl] -1,3-ditoxolan-4-ylmethoxy] phenyl} -4-

1 ', 4'(5'-Methyl-1H-11,4-triazolyl- ₁ -yl) -phenyl] piperazine, m.p. 166.5 ° C, cis-1- [4- (2- (2,4-dichlorophenyl) -2-) - (1Ht1,2,4-Triazolyltylmethyl) -1,3-ditoxolan-4-ylmethoxy] phenyl] -4- {4- [3- (methylthio) -1H-1,2,4-triazolithyl] phenyl; 9 ° C, of cis-l- {4- [2- (2,4-а1сЫ ^ епу1) -2- _(1H-У> 2,4-triazoltУtylmethyl] -1,3-di-oxolant4tylmethoxy] -phenyl ^ - {4- [5-Methyl-3- (methylthio) -1H-1,2,1 -14 [eta] &lt; 2 &gt; -1-1-yl] phenyl] piperazine, m.p. 164.1 [deg.] C., cis-4- / 4-4- [4- (2- (2,4-dichlorophenyl) -2t (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxo-tert-4-ylmethoxy) phenyl] -1-piperazinyl) phenyl] -3t (methylthio) -4H -1,2,4-triazole, m.p. 147-152.6 ° C; cis-1- {4- [2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazolyltylmethyl) tl, 3-Dit-4-enyl-4-ylmethoxy] -phenyl-4- {4- [5-methyl-4- (methylthio) -4H-1,2,4-trlazol-4-yl] -phenyl] -piperazine, m.p. 118.3 ° C, cis-4- / 4- (4- (4- [2- (2,4-dichlorophenyl) -2- (1H-1,2,1-tazolyl) yl) yl) -1,3dioxo241468

Lan-4-ylmethoxy] phenyl (1-piperazinyl) phenyl] -2,4-dihydro-2,5-dimethyl-3H-1,2,4-triazol-3-one monohydrate, m.p. 161.9 ,3, cis-4- / 4- (4- {4- [2- (2,4- <RTIgt; chlorophenyl) -2- (1H-1,2,4-thiazol-1-ylinethyl) </RTI> ] -l, 3-dioxolan-4-ylmethoxylfenylj-piperazinyl) phenyl / -2,4-dihydro-2-propyl-3G-l, 2,4-triazol-3-one of melting point 167.3 ^C. C cis-1- {4- [2- (2H-dichlorophenyl) -2- (1H-1,2 H -triazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy} phenyl) -4-

- [4- (2-methyl-1H-imidazol-1-yl) phenyl] piperazine, m.p. 175.6 ° C, cis-4- / 4- (4,7- [2- (2,4-dichlorophenyl) - 2- (1H-1,2'-triazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy'-phenyl | -1-piperazinyl) phenyl] -2,4-dihydro-2-methyl-4-yl -3H-1.2! _J 4-triazol-3-one; mp 193.8 ° C, cis-4- / 4- (4- (4- [2- (2,4-d ichlorf) -2- (lH-l, (N-triazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxyphenyl (1-piperazinyl) phenyl] -2-ethyl-2,4-dihydro-5-methyl-3H-1,2,4 mp 178.3 ° C, cis-4- / 4- (4- {4- [2- (2,4-dichlorophenyl) -2-) -triazol-3-one;

- (1H-1,2,2-Triazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl} -1-piperazinyl) phenyl] -2,4-dihydro-5-methyl-2-propyl -3H-1,2,4-Triazol-3-one monohydrate, m.p. 165.5 ° C, cis-4- / 4- (4 {4i [2- (2,4-dichlorophenyl) -2] - (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolane-1-ylmethoxy-phenyl-1-piperazinyl) phenyl] -2-ethyl-2,4-dihydro-3H-1,2, 186 DEG C. and cis-1- {4- [2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) </RTI> 4-triazol-3-one. ) -1,3-dioxolan-4-ylmethoxy-1-phenyl-4-

- [4- (5-propyl-1H-1,2,4-riazol-1-yl) phenyl] piperazine, m.p. 140.9 ° C.

Example 23

By analogy to Example 20, except that the reaction is carried out in Ν, Ν-dimethylformamide while boiling the reaction mixture (about 155-165 ° C), the following compounds are also prepared:

cis-1- [4- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl] -4- [4] - (1H-tetrazol-1-yl) phenyl] piperazine, m.p. 202.1 ° C, cis-1- [4- [2- -2,4-dichlorophenyl) -2- (1H-1,2, 4-Thiazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl-4- [4- (1H-tetrazol-1-yl) phenyl] piperazine, mp 192.9 ^C , cis -1- {4- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolane-1-ylmethoxyphenyl] -4- [4- (1H- 187.8 ° C, cis-1- {4- [2- (2,4-dichlorophenyl) -2- (1H-1,2,4- pyrrolidin-1-yl) phenyl] piperazine; triazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy-phenyl-N- [4- (1H-pyrrol-1-yl) -phenyl] -piperazine, mp 184.1 ° C, cis-4- - 1- [2- (2,4-Dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolane-1-ylmethoxy] phenyl] -1-piperazinyl) fep , y'í ./- e ^ -e ^ Tinly 4 ¹ 4-dihydro-3H- 2,4-triazol-3-one; mp 276.3 ° C

- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl-1-piperazinyl) phenyl] -

12.4- dihydroc3H1,2'-triazol-3-one ethanolate (1: 1), m.p. 256.2 ° C, ciSi4- / 4--4 {4- [2- -2,4-dicone] fe 1) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl] -1-piperazinyl) phenyl] -

12.4-Dihydro-2- -1- (4H, 4H, 4H, 3H) -311-1,2,4-triazol-3-one, m.p. 221.5 ° C, cis -2-butyl-4- / 4- (4- {4i [2- (2H-dichlorophenyl) -2- (1H-imidazoo-1-ylmethyl) -1,3-dioxolane-1-ylmethoxy) ] -phenyl-1-piperazinyl)) phenyl --- 2 _and 4-dihydro-3H-1,2,4-triazol-3-one; mp 198.4 ° C, and cis-4- / 4- / 4- | 4i [2- (2-1H-Midazol-1-ylmethyl) -1,3-dioxolanc-1-ylmethoxy] phenyl-1-piperazinyl) phenyl] -5-ethyl-2,4-dihydrocyclopropyl-3H- 1,2,4-triazol-3-one, m.p.

171.2 ° G.

Example 1 a d 24

By analogy to Example 20, except that the reaction was carried out in Ν, Ν-dimethylformamide - at 30 ° C, the following compounds were also prepared:

cis-1- {4- [2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl] -4- 4- [2- (methylthio) -1H-imidazol-1-yl] phenyllpiperazine, mp 132.1 ° C, cis-144i [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1)] ylmethyl) -l, 3-dioxolan - / - ylmethoxy] phenyl 4- {4- [2 - (methylthio) -lH-imidazol-l-yl] fenyljpiperazin mp 140.6 ° ^C,

241483 cis-2-butyl-4-14- / 4- (4 - ([2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolane-4-) yl] methoxy (phenyl) -1-piperazinyl-1H-phenyl-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one, mp 160 ° C, cis-4-14- / 4- (4 - ((2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy) phenyl) -1-piperazinyl / phenyl -2,4-dihydro-5-methyl-2- (1-methyl-ethyl) -3H-1,2,4-triazol-3-one, m.p. 146.1 ^° C, cis-2-butyl-4 - / 4- (4- (4- [2- (2,4-dichlorophenyl) -2- (β-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy) phenyl] piperazinyl) phenyl / -2,4-dihydro-3H-l, 2,4-triazol-3-one; mp 180.5 C ^R, cis-4- / 4- (4 (4- [2- - (2,4-dichlorophenyl) -2- (111 1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl-1-piperazinyl) phenyl / -2, 4-dihydro-3H-1,2,4-triazol-3-one, m.p. 254.4 ^° C, cis-4- / 4- (4- (4- [2- (2,4-dichlorophenyl)) - 2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl-1-piperazinyl) phenyl] -2,4-dihydro-2- (2-methylpropyl) - Mp 155.8 ° C, cis-4- / 4- (4 (4- [2- (2,4-dichlorophenyl) -2- (1H- 1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl-1-piperazinyl) phenyl] -2,4-dihydro-2- (1-methylethyl) -3H-1, 2,4-triazol-3-one, m.p. 200.4 ^° C, cis-4- / 4- (4- {4- [2- (2,4-dichlorophenyl) -2-

- (1H-1,2,4 triazol-1-ylmethyl) -1,3-dloxolan-4-ylmethoxy] phenyl-1-piperazinyl) phenyl] -2,4-dihydro-5-methyl-2- (2 -methylpropyl) -3H-1,2,4-triazol-3-one, m.p. 140 ° C, cis-2-butyl-4- / 4- (4 (4- [2- (2,4-dichloro) enyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-ylmethylphenyl-1-piperazinyl) phenyl] -2,4-dihydro-5- methyl-3H-1,2,4-triazol-3-one, mp 113.2 ° C, cis-4- / 4- (4 (4- [2- (2,4-dichlorophenyl) -2-)

- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dloxolan-4-ylmethoxy] phenyl-1-piperazinyl) phenyl] -2,4-dihydro-5-methyl-2- (1 158,6 ° C, cis-4-14- / 4- (4 - ([2- (2,4-dichlorophenyl) -methylethyl) -3H-1,2,4-triazol-3-one monohydrate) ) -2- (ΙΗ-imidazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy] phenyl) -1-piperazinyl / phenyl | -2,4 dihydro-5-methyl-2- (2- methylpropyl) -3H-l, 2,4-triazol-3-one; mp 150.3 C ^Q cis-4-14- / 4- (4- ([2- (2,4-dichlorophenyl) -2 - (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy] phenyl) -1-piperazinyl / phenyl | -2,4-dihydro-5-methyl- 3H-1,2,4-Triazol-3-one ethanolate (2: 1), mp 212.4 ° C, cis-4- / 4- (4- (4- [2- ( 2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1S-dioxolan-4-ylmethoxy] phenyl | -1-piperazinyl) phenyl] -2,4-dihydro-2- (2-methylpropyl) -3H-1,2,4-trlazol-3-one, mp 195 ^C , cis-4-14 / 4- (4 - ([2- (2,4-dichlorophenyl) -2- (1H-imidazole)) -1-ylmethyl) -1,3-dioxolan-4-yl] methoxy (phenyl) -1-piperazinyl / phenyl) -2,4-dihydro-2- (1-methyl) 170,7 ° C, cis-2 - [(4-chlorophenyl) methyl] -4-14- / 4- (4 - ( 2- (2,4-dichlorophenyl) -2- [1H-imidazol-1-ylmethyl) -1,3-dloxolan-4-yl-1-methoxyphenyl) -1-piperazinyl / phenyl | -2,4-dihydro-3H -1,4,4-triazol-3-one, m.p. 175.5 ° C, cis-4-14 74- (4 - ((2- (2,4-dichlorophenyl) -2- (III-imidazole- 1-ylmethyl) -1,3-dioxolan-4-yl] methoxy (phenyl) -1-piperazinyl / phenyl | -2,4-dihydro-5-methyl-2- (1-methylpropyl) -3H-1,2,4-triazol-3-one, m.p. 133.8 ° C, cis-4-14- 4- (4 - ([2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy) phenyl] -1-piperazinyl / phenyl | -2 170.4 ° C, 4-dihydro-5-methyl-2- (2-phenylethyl) -3H-1,2,4-triazol-3-one, cis-4-14 / 4- (4- ((2- (2,4-Dichlorophenyl) -2- (1,1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy) phenyl) -1-piperazinyl / phenyl | 4-Dihydro-5-methyl-2- (3-methylbutyl) -3H-1,2,4-triazol-3-one, m.p. 185.5 ° C, cis-4-14- / 4- (4 - ((2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxyphenyl) -1-piperazinyl / phenyl | -2, 4-Dihydro-5-methyl-2- (phenylmethyl) -3H-1,2,4-triazol-3-one, m.p. 164.3 ° C, cis-4-14- / 4- (4- ( (2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolane

-4-yl] methoxy (phenyl) -1-piperazinyl / phenyl |

-2 - [(2,4-dichlorophenyl) methyl] -2,4241468

-dihydro-5-methyl-3H-1,2,4-triazol-3-one, m.p. 171.8 ° C, cis-2 - [[4-chlorophenyl) methyl] -4-14- / 4- ( 4- | [2- (2,4-dichlorophenyl) -2-

- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxyphenyl) -1-piperazinyl / phenyl | -2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one, m.p. 171 ° C, cls-4-14- / 4- (4 - ([2- (2, 4-Dichlorophenyl) -2- (ΙΗ-imidazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy] phenyl) -1-piperazinyl / phenyl | -2,4-dihydr 0-2- (methylbutyl) -311-1,2,4-triazol-3-one, m.p. 202.7 ° C, cis-4-14- / 4- (4 - ([2- (2,4-dichlorophenyl)) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy] phenyl) -1-piperazinyl / phenyl | -2 - [(2,4-dichlorophenyl) methyl] -2 184.4 ° C, 4-dihydro-3H-1,2,4-triazol-3-one, cis-4-14- / 4- (4 - ([2- (2,4-dichlorophenyl)) - 2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy-phenyl) -1-piperazinyl-1H-phenyl--2,4-dihydro-2- (2-phenylethyl) -3H- 1,2,4 Triazol-3-one, cis-2 - [(2-chlorophenyl) methyl] -4-14- / 4- (4 - ([2- (2,4-dichlorophenyl) -2-

- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy-phenyl) -1-piperazinyl / phenyl [-2,4-dihydro-3H-1,2,4-triazole- 3-one, m.p. 178.7 ° C, cis-4-14- / 4- (4 - ([2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazole- 1-ylmethyl) -1,3-dioxolan-4-yl] methoxy] phenyl) -1-plperazinyl / phenyl-2,4-dihydro-5-methyl-2- (1-methylpropyl) -3H-1,2,4 146,1 ° C, cis-4-14- / 4- (4 - ([2- (2,4-dichlorophenyl) -2- (1H -1,2,4)) -triazol-3-one; -triazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy-phenyl) -1-piperazinyl / phenyl | -2,4-dihydro-2- (phenylmethyl) -3H-1,2,4-triazole -3-one, mp 143.3 ° C, cis-4-14- / 4- (4 - ([2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazole) -1-ylmethyl) -1,3-dioxolan-4-yl] methoxy-phenyl) -1-piperazinyl / phenyl | -2,4-dihydro-5-methyl-2- (3-methylbutyl) -3H-1,2 4-triazol-3-one, m.p. 122.5 ° C, cis-4-14- / 4- (4 - ([2- (2,4-dichlorophenyl)) -2- (1H-1,2) (4-triazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy (phenyl) -1-piperazinyl / phenyl | -2,4-dihydro-5-methyl-2- (2-phenylethyl) - 174.9 ° C, cis-4-1474- (4 - ([2- (2,4-dichlorophenyl) -2- (1H-1,2,4)) -triazol-1-ylmethyl) -1,3-dioxolan-4-yl] methyl-xy (phenyl) -1-piperazinyl / phenyl | -2,4-dihydro-2- (3-methylbutyl) - 183H ^and C, cis-4-14- / 4- (4 - ([2- (2,4-dichlorophenyl) -2- (1H)]); -1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy (phenyl) -1-piperazinyl / phenyl | 166.4 ° C, -2,4-dihydro-2- (1-methylpropyl) -3H-1,2,4-triazol-3-one, cis-4-14- / 4- (4- ( (2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy) phenyl) -1-piperazinyl / phenyl | -2,4-dihydro-2- (2-phenylethyl) -3H-l, 2,4-triazol-3-one -monohydrát mp 181.4 ^<! C, cis-2- [(2-chlorophenyl methyl] -4-14- / 4- (4 - ((2- (2,4-dichlorophenyl) -2- (1H-1,2,4 triazol-1-ylmethyl) -1,3-dioxolane) 4-yl] methoxy (phenyl) -1-piperazinyl / phenyl | -2,4-dihydro-3H-1,2,4-triazol-3-one, m.p. 4- (4 - ((2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy) phenyl) - 161-C, cis-2 - [(4 chlorophenyl) 1-piperazinyl / phenyl] -2,4-dihydro-2- (phenylmethyl) -3H-1,2,4-triazol-3-one methyl] -4-14- / 4- (4 - ([2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolane- 4-yl) methoxy-phenyl) -1-piperazinyl / phenyl | -2,4-dihydro-3H-1,2,4-triazol-3-one, m.p. 4-dic chlorophenyl) methyl) -4- [4- (4 - ([2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolane)] - 4-yl] methoxy (phenyl) -1-piperazinyl / phenyl | -2,4-dihydro-3H-1,2,4-triazol-3-one, m.p. 168 DEG C., cis-2- [2- (4-chlorophenyl) ethyl] -4- [4-] - 4- (4 - ((2- (2,4-Dichlorophenyl) · 2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-yl) methoxy) phenyl) -1-piperazinyl (phenyl) -2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one, m.p. 188.0 ^° C, cis-2- [2- (4-chlorophenyl) ethyl] -4-147 4- (4 - ([2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy) enyl) -1-piperazinyl / phenyl | -2,4-dihydro-3H-1,2,4-triazol-3-one, m.p. 199.0 ° C, cis-2- [2- (4-chlorophenyl) ethyl] -4-147 4- (4 - ([2- (2,4-dichlorophenyl) -2- (1H-1 _: 2,4-triazolyl) methyl) -1,3-diolola) ·

4-yl] methoxy] phenyl) -1-piperazinyl / 35 phenyl -2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one, m.p. 183.8 ^° C, cis-2- [2- (4-chlorophenyl) ethyl] -4- 14- / 4- (4) [2- (2,4-dichloro-phenyl) -2- (1H-1,2,4-triazol-ylmethyl) -1,3-dioxolan-4-ylmethoxy] -phenyl) -1-piperazinyl / phenyl | 2,4-dihydro-3 H -1,2,4-triazol-3-one, m.p. 206.1 ° C, cis-4-14- / 4- (4 - ((2- (4-chlorophenyl) - 2- (1H-imidazol-1-ylmethyl) -1,3-dioxolaz-4-yl] methoxy-phenyl) -1-piperazinyl-1H-phenyl | -2,4-dihydro-2-

- (1-ethylethyl) -3H-1,2,4-triazol-3-one, m.p. 229.3 ° C, cis-4-14 / 4- (4 - ((2- (2-chloro-4-)) Fluorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy-phenyl) -1-piperazinyl-1H-phenyl | -2,4-dihydro-2- (1-methylethyl) ) -3H-1,2,4-triazol-3-one, m.p. 195.5 ^and C, cis-4-147 4- (4 - ([2- (2-chloro-4-methylphenyl) -2) - (1 H -imidazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy] phenyl) -1-piperazinyl / phenyl | -2,4-dihydro-2-

- (1-methylethyl) -3 H l, 2,4-triazol-3-one; mp 200.9 C ^q, trans-4-14- / 4- (4- ([2- (4-chlorophenyl) - 2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxyphenyl) -1-piperazinyl / phenyl | -2,4-dihydro-2- (1-methylethyl) -3H-1,2,4 -triazol-3-one, m.p. 186.6 ° C; cis-4-14- / 4- (4- (2- (2-chloro-4-methoxyphenyl)) -2- (1H- imidazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy] phenyl} -1-piperazinyl / phenyl | -2,4-dihydro-2-

- (1-methylethyl) -3H-l, 2,4-triazol-3-one, m.p. 2'06,5 ^C C, cis-4-14- / 4 - (4- (Г 2- (2, 4-Dibromophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy-phenyl) -1-piperazinyl / phenyl | -2,4-dihydro-2H-(1-methylethyl) ) -3H-l, 2,4-triazol-3-one; mp 230.1 C ^Q cis-4-1474- (4- ([2- (2- chlorophenyl) -2- (1H-imidazol 1-ylmethyl) -1,3-dioxolan-4-yl] methoxy] phenyl) -1-piperazinyl / phenyl | -2,4-dihydro-2-

- (1-methylethyl) -3H-1,2,4-triazol-3-one, m.p. 188.3 ° C, cis-4-14- / 4- (4 - ((2- (4-bromophenyl)) -2- (1H-imidazol-1-ylmethyl) -1,3-dloxolan-4-yl] methoxyphenyl) -1-piperazinyl / phenyl | -2,4dihydro-2-

- (1 methylethyl) -3H-1,2,4-triazol-3-one, m.p. 230.0 ° C, trans-4-14- / 4- (4 - ([2- (2-chloro241488 phenyl)) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy] phenyl) -1-piperazinyl / phenyl | -2,4-dihydro-2-

- (1-methylethyl) -3H-1,2,4-triazol-3-one, mp 192.5 ° C, trans-4 · 1474- (4 ([2- (4-bromophenyl) 1-2) - (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy-phenyl) -1-piperazinyl / phenyl | -2,4-dihydro-2- (1-methylethyl) -3H-1,2, 4-triazol-3-one, m.p. 188.7 ° C, cis-2,4-dihydro-4-14- / 4- (4 - ([2- (1H-imidazol-1-ylmethyl) -2-) - (4-Methoxyphenyl) -1,3-dioxolan-4-yl] methoxy} phenyl) -1-piperazinyl / phenyl | -2- (1-methylethyl) -3H-1,2,4-triazole-3- he, as a residue, cis-4-14- / 4- (4 - ([2- (4-bromo-2-chlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolane-4-one) -yl] methoxy (phenyl) -1-piperazinyl / phenyl | -2,4-dihydro-2- (1-methylethyl) -3H-1,2,4-triazol-3-one, m.p. 234.2 ° C cis-4-14- / 4- (4 - ([2- (4-chlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-yl) (methoxy) phenyl) -1-piperazinyl / phenyl | -2,4-dihydro-2- (1-methylethyl) -3H-1,2,4-triazol-3-one, m.p. 219.8 ° C; trans-4-14- / 4- (4 - ([2- (4-chlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolane)

-4-yl] methoxy] phenyl) -1-piperazinyl / phenyl | -2,4-dihydro-2- (1-methylethyl) -3H-1,2,4-triazol-3-one, m.p. 190.3 ° C, cis-2,4-dihydro-4-14- / 4- (4 - ((3- (1H-imidazol-1-ylmethyl) -2- (4-methoxyphenyl) -1,3-dioxolan-4-yl) methoxy) phenyl) -1-piperazinyl / phenyl | -2- (1-methylethyl) -3H-1,2,4-triazol-3-one, m.p. 193.5-195.2 ^and C, cis-4 14- / 4- (4- ([2- (4-Chlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxyphenyl) -1-piperazinyl / phenyl-2,4-dihydro-2- (2- methylpropyl) -3H-1,2,4-triazol-3-one, m.p. 192.1 ° C, cis-2,4-dihydro-4- [4- / 4- (4 - ([2- (1H) -imidazol-1-ylmethyl) -2- (2,3,4-trichlorophenyl) -1,3-dioxollan-4-yl] methoxy] phenyl) -1H-1-piperazinyl-1-phenyl | -2 | - (1-methylethyl) -3H-1,2,4-triazol-3-one; mp 259.2 C ^Q cis-4-14- / 4- (4- ([2- (4-chlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy] phenyl) -1-piperazinyl / phenyl

-2,4-dihydro-2- (1-methylpropyl) 241468

-3H-1,2,4-triazol-3-one, m.p. 185.2 ° C, cis-4-1 4- / 4- (4 - ([2- (4-fluorophenyl) -2- (1H)]) -imidazol-1-ylmethyl) -1,3-dloxolan-4-yl] methoxy] phenyl-1-piperazinyl / phenyl | -2,4-dihydro-2- (1-methylpropyl) -3H-1,2,4- triazol-3-one, m.p. 201.1 ° C, cis-4-1 4- / 4- (4 - ([2- (2-bromo-4-chlorophenyl) -2- [ΙΗ -imidazol-1-one]) ylmethyl) -1,3-dioxolan-4-yl) methoxy (phenyl) -1-piperazinyl / phenyl | -2,4-dihydro-2- (1-methylethyl) -3H-1,2,4-triazol-3 -one, mp 217.1 'C ^q, (±) -trans-4- | 4- / 4- (4 - ([2- (2,4-dlchlorf) -2- (lH-2 (4-1-triazol-4-yl-4-yl) -1,3-dihydro-4-yl-methoxy-phenyl) -1-piperazinyl-phenyl-2,4-dihydro-2-

- (1-methyl thylpr propylpyrid) -3H-l, 2,4-triazol-3-one; mp 131.7 ^Q C, cis-4- (4- / 4- (4- ((2- [2- -bromo-4-methoxyphenyl) -2- (ΙΗ-imidazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxyphenyl) -1-piperazinyl / phenyl | -2,4-dihydro- 2- (1-methylethyl) -3H-1,2,4-triazol-3-one, m.p. 202.1 DEG C., (+) - (2R, cis) -4-14- / 4- (4). - ([2- (2,4-dichlorophenyl) -2- ((-imidazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy] phenyl) -1-piperazinyl / phenyl | -2,4 -dihydro-2- (1-methylethyl) -3H-1,2,4-triazol-3-one, m.p. 227.4 ^° C, (-) - (2S, cis) -4-14- / 4- (4 - ([2- (2,4-Dichlorophenyl) -2- (id-imidazol-1-ylmethyl) -1,3-diaminophenol-4-yl) ™ 6-hydroxy-phenyl-4 '-.

-1-piperazinyl) phenyl] -2,4-dihydro-2-

- (1-methylethyl) | -3H-1,2,4-triazol-3-one, m.p. 218.5 ° C, cis-2,4-dihydro-2- (1-methylethyl) -4-14- / 4- (4- { [2- (1H-1,2,4-triazol-1-ylmethyl) -2-

- [2,3,4-trichlorophenyl) -1,3-dioxolan-4-yl] methoxyphenyl) -1-piperazinyl / phenyl} -3H, 1,2,4-triazol-3-one at temperature mp 229.1 ° C, cis-4- (4- / 4- (4 - ((2- {4-chloro-2-methoxyphenyl) -2- (ΙΗ-imidazol-1-ylmethyl) -1,3-) dioxolan-4-yl] methoxy; phenyl) -1-piperazinyl / phenyl | -2,4-dihydro-2- (1-methylethyl) -3H-1,2,4-triazol-3-one, m.p. 191.7 ° C, cis-4-14- / 4- (4 - ([2- (4-fluorophenyl) -2- (1H, -1,2,4-thiazol-1-ylmethyl)) - (13- (4- (4-oxolan-4-yl) methoxyphenyl) -1-piperazinyl / phenyl) -

204-dihydro-2- (1-methylethyl) -3H-1,2,4-triazol-3-one, m.p. 204.9 ° C, cis-d, 4-dihydro-4- | 4- / 4- (4 - ((2- (1H-imidazol-1-ylmethyl) -2- (2,4,5-trichlorophenyl) -1,3-)

-dioxolan-4-yl] methoxyphenyl) -1-piperazinyl / phenyl | 2- (1-methylethyl) -3H-1,4-riazol-3-one ethaneduate (1: 1), m.p. 168.7 ^and C, cis-4-14- / 4- (4 - ([2- (4-Fluorophenyl) -2- (1H-imidazolil-ylmethyl) -1,3-dioxolan-4-yl] methoxy) piperazine; 2,4-2,4- <2'-2H-2'-2- (1-methyl: h / 11-eh) -3H - 1,2,4-triazol-3-one ethanedioate (1: 1) o mp 206.4 ° C, cis-4-1474- (4 - ((2- (2-bromo-4-chlorophenyl) -2- (ΙΗ-imidazol-1-ylmethyl) -1,3-dioxolanane) -4-yl] methoxyphenyl) -1-piperazinyl / phenyl | -2,4-2-oxo-2- (1-methylethyl) -3H-1,2,4-triazol-3-one, m.p. 205, 6 ° C, trans -4-14- / 4- (4 - ([2- (2,4-tert-1-yl) phenyl) -2- (1H-1, d, 4-triazol-1-ylmethyl) - 1,3-dioxolan-4-yl] methoxy (phenyl) -1-piperazinyl / phenyl | -2,4-01-oxo-2- (1-methylethyl) -3H-1, d, 4- triazol-3-one, m.p. 150.4 ° C, cis-4-14- / 4- (4 - ((2- (2-3110-enyl) -2- (1H-4-ylmethoxy) phenyl) -1,1-Piperazinyl-phenyl / -D, 4-dihydro-2- (1-chloro-1-ene) | -311-1,2,4-t, 9701-3o · mp 177.9 ° C, cis-4-14- / 4- (4 - ((2 - (4-bromophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxoian-4-yl] methoxy] phenyl) -1-piperazinyl / phenyl | 2,4-31,1у2го-2- (1-methyl-methyl) -3, H-1,2,4-triazol-3-one, m.p. 223,8 ° C, cis-4 - 4- (4 - ([2- (4-chlorophenyl) -2- (1H-1,2,4-, -triazol-1-ylmethyl) -1,3-dloxolan-4-yl) methoxy! phenyl) -1-piperazinyl / benzenamine, cis-4-14- / 4- (4 - ((2- (4-chloro-2-fluorophenyl)) -2- (1'-imidazol-1-ylmethyl) -1 1,3-dioxoian-4-yl] methoxy (phenyl) -1-piperazinyl / phenyl | -2,4-fluoro-2- [1-methylethyl) -3H-1,4-triazol-3-one, m.p. 225.1 ° C, cis-4-] 4- / 4- (4- ([2- (d-chloro-4-ethoxyphenyl) -2- (ΙΗ-imidazol-1-ylmethyl) -1,3-dioxolane-4-ylmethoxy | phenyl-1-piperazinyl / phthyl) | -2,4-ethoxyphenyl -2- (1-methylethyl-triazol-3- ^one ), m.p. 208.4 ° C, cis-4-14- / 4- (4 - ((2- [2,4-cyclohexyl)) -2- (1H-1, d, 4-thiazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxyphenyl) -1-piperazinyl / phenyl | m-methylethyl) -3H-1,2,4-triazol-3-one, m.p. 207.7 ° C, cis-4-14- / 4- (4 - ((2- (5-Γι10Γ-2)) (1-piperidinyl) -1- (4-imidazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy] phenyl / 1-piperazinyl / phenyl | -2,4-dihydro-2- (1- methyl ethyl) -3H-1,4-triazol-3-one, m.p. 201.3 ° C, cis-4- | 4- / 4- (4} [2,4-dimethylphenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy-phenyl) -1-piperazinyl / phenyl | -2,4-dihydro-2- (1-methyl) lethyl) -3H-1,2,4-riazol-3-one ethanedioate (1: 1), m.p. C, cis-4-14- / 4- (4 - ([2- (2-fluorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy) phenyl ) -1-piperazinyl / phenyl | -2,4-dihydro-2- (1-methylthyl) -3H-1,2,4-triazol-3-one, m.p. 214.5 ° C, cis-4-14- / 4- (4 - ([2- (5-chloro-2,4-dimethoxyphenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-yl 1 methoxy] phenyl) -1 -piperazinyl / phenyl | -2,4-dihydro-2- (1-methylethyl) -3H-1,2,4-triazol-3-one, m.p. 185.0 ° C, cis-4- 14- / 4- (4 - ((2- (4-chlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy) phenyl) - 1-piperazinyl / phenyl | -2,4-dihydro-2- (1-methylphenyl) -3H-1,2,4-triazol-3-one, m.p. 180.3 ° C, cis-2, 4-Dihydro-4-14- / 4- (4 - ((2- (1H-imidazol-1-yl) -1-2H) -2- (3,4,5-trimethoxyphenyl) -1,3-dioxolane-4) -yl] methoxy (phenyl) -1-plperazinyl / phenyl | -2- (1-methylethyl) -3H-1,2,4-triazol-3-one, m.p. 167.8 ^and C, cis-4-14 - / 4- (4 - ([2- (2,4-difluorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-yl) methoxy) phenyl)> -1,1-piperazinyl (phenyl) -2,4-dihydro-2- (1-methylethyl) -3H-1,2,4-triazol-3-one, m.p. 211.1 ° C, cis-4-) 4} 4} [2- (4-Chlorophenyl) -2- (1H-imidazol-4-ylmethyl) -1,3-dioxolan-4-yl] methoxy] phenyl) -1-piperazinyl / beuzenamine, m.p. 202, 3 ° C, cis-4-14- / 4- (4 - ([2- (2,4-dichlorophenyl) -2- (1H-1,2,4-thiazol-1-yl) β) 1) -1,3-dioxolan-4-yl] methoxy (phenyl) -1-piperazinyl / phenyl | -2,4-dihydro-2- (1-methylpropyl) -3H-1,2,4-triazol-3-one sulfate (1: 2), mp 220.3 ° C, cis-4- 14- / 4- (4} [2- (2,4-dlchlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy (phenyl) -1-piperazinyl / phenyl | -2,4-dihydro-2- (1-methylpropyl) -3H-1,2,4-triazol-3-one methanesulfonate (1: 3), m.p. 131.5 ° C, cis-4 / 4- (4 {[2- (4-fluorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy] phenyl) -1-piperazinyl / benzenamine and trans- 2,4-dihydro-4-1 4- / 4- (4 - ((2- (1H-imidazol-1-ylmethyl) -2- (2-thienyl) -1,3-dioxolan-4-yl) 1-Methoxy-phenyl) -1-piperazinyl / phenyl-2- (1-methylethyl) -33.H1,2,4-triazol-3-one, m.p. 201.3 ° C.

Claims (2)

SUBJECT OF THE INVENTION A process for the preparation of the novel 1H-imidazole and 1H-1,2,4-triazole derivatives of the general formula I in which: Q is -CH or -. . nitrogen atom, Ar represents a halothienyl or phenyl group optionally substituted by one to three of the same or different substituents selected from the group consisting of halogen atoms, methyl, methoxy and ethoxy, and Y is an amino group or a radical selected from the group consisting of 1H-pyrrol-1-yl radical of formula 'and 1H-pyrazol-1-yl radical of formula b R ⁸ is hydrogen, methyl or methylthio, lH-l, 2,4-triazol-l-yl radical 'of formula ¹ D T R ¹ⁱ (dl where one of R ^and R12 is selected from the group consisting of hydrogen and methylthio and the second of these "symbols is selected from the group consisting of hydrogen and alkyl of 1 to 3 carbon atoms, lH-2 a 1-triazol-4-yl radical of formula e (e) wherein. R13 represents a hydrogen atom, a mercapto group or a methylthio group; R 14 represents a hydrogen atom, a methyl group or; ethyl, A 2,3-dihodro-4H-1,2,4-triazocoyl radical of formula f R 15 represents an alkyl group having 1 to 6 carbon atoms or an aralkyl group having 1 to 2 carbon atoms in the alkyl moiety, the aryl moiety being a phenyl moiety optionally substituted by one or two identical or different halogen atoms, and R 16 represents a hydrogen atom, a methyl group or an ethyl group, and a 1H-1,2,3,1-tetrazol-1-yl radical of formula -UJ and their pharmaceutically acceptable acid addition salts and stereochemically isomeric forms, characterized in that the phenol of formula III (wherein: Y is as hereinbefore defined, or as a metal salt, reacted with a compound of formula II wherein: Ar is as defined above and W represents a reactive ester residue such as halogen, preferably chlorine, bromine or iodine, or a sulfonyloxy group such methylsulfonyioxyskupinu or L-Methylphenylsulphonyl sulfonyloxy, in an inert organic solvent at a temperature from 30 ° C * 100 ^Q C, and the resulting product optionally converting it to a pharmaceutically acceptable acid addition salt thereof and / or preparing stereochemically isomeric forms of the compound of formula (I).