BG60430B2 - Heterocyclic derivatives of (4-phenylpiperazine-1-il-aryloxymethyl-1,3-dioxolan-2-il)-methyl-1 h-imidasoles and 1h-1,2,4-triasoles, methods for their preparation and compositions containing them - Google Patents

Abstract

The compounds have antifungicidal and antimicrobial activity and are used in medicine. They are selected among a group of azole derivatives having the general formula (formula) where their substitute have the respective meanings. The invention is also related to pharmaceutically acceptable acid-adjoint salts and stereochemical isomer forms of the compounds.

Description

BACKGROUND OF THE INVENTION

US Patent Nos. 3,936,470 and BE 837,831 describe a large number of derivatives of ΙΟ, 3-dioxolan-2-ylmethyl) -1H-imidazole and 1H-

1,2,4-triazole which have antifungal and antibacterial properties. The compounds of the invention differ substantially from those mentioned above in that the aryloxy group in them is substituted by a 4-phenylpiperazinyl group, and the phenyl moiety is further replaced by a heterocyclic radical which binds to the phenyl via a carbon-nitrogen bond. Similar compounds in which the heterocyclic radical binds directly to the aryloxy group via a carbon-nitrogen bond are described in DE 28 03870 A.

DESCRIPTION OF THE PREFERRED EXAMPLES

The invention relates to novel derivatives of 1H-imidazole and 1H-1,2,4-triazole having the following structural formula

I

CH, Ar (I)

О ^ХХ О Υ

as well as their pharmaceutically acceptable acid addition salts and their stereochemically isomeric forms, in which

Q represents a group selected from CH and Ν; Ar represents a group selected from phenyl, thienyl, halogenethyl and substituted phenyl, phenyl having from 1 to 3 substituents selected from halogen, lower alkyl, lower alkyloxy and trifluoromethyl; and Υ means a radical selected from the group consisting of the following 1H-pyrrol-1-yl radicals of formula

wherein RpRj.Rj and R _g each independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-lower alkyl;

1H-pyrazol-1-yl of the formula:

wherein R ₁ , R ₆ and R _{7 are} independently and independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-lower alkyl;

N-imidazol-1-yl of the formula:

in which R _g is selected from the group consisting of hydrogen, lower alkyl, mercapto, lower alkylthio and aryl-lower alkylthio, and R _g and R ₁₀ are independently and independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-lower alkyl;

1H-1,2,4-triazol-1-yl of the formula:

in either group, hydrogen, hydroxy, mercapto, lower alkylthio and aryl-lower alkylthio are selected, and the other is selected from hydrogen, lower alkyl and aryl-lower alkyl;

4H-1,2,4-triazol-4-yl of the formula:

wherein R ₁₃ is selected from the group consisting of hydrogen, mercapto, hydroxy, lower alkylthio and aryl-lower alkylthio, a R _lg is selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-lower alkyl;

2,3-dihydro-4H-1,2,4-triazol-4-yl of the formula:

wherein R ₁₃ is selected from the group consisting of lower alkyl and aryl-lower alkyl and R ₁₆ is selected from the group consisting of hydrogen, lower alkyl and aryl-lower alkyl;

1H-1,2,3,4-tetrazol-1-yl of the formula

-N \ = N (g),

R in which R ₁₇ is selected from the group consisting of hydrogen, mercapto, lower alkyl, aryl and aryl-lower alkyl;

wherein said aryl as used herein is selected from the group consisting of phenyl and substituted phenyl, said substituted phenyl having from 1 to 3 substituents, each of which is independently selected and independently from group _d consisting of halogen , lower alkyl, lower alkyloxy and trifluoromethyl.

It is known that the radicals of formulas (c) and (g) in which R 1 and R ₁₇ denote mercapto, respectively, and the radicals of formulas (d) and (e), in which R _n and R ₁₂ , respectively R ₁₃ mean mercapto or hydroxy, these radicals may also exist in their tautomeric thioxo, respectively oxoforms. Such thioxo and oxoforms, although not explicitly mentioned in the above structures, are naturally included within the scope of formula (I).

Preferred compounds of the invention are those in which the 4-phenylpiperazinyl functional group is attached to the phenoxymethyl portion of the vapor site.

As used herein, the term "halogen" refers to fluorine, chlorine, bromine and iodine; and the term "lower alkyl" means a straight or branched chain hydrocarbon radical and contains from 1 to 6 carbon atoms, for example methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, 1-methylpropyl, 2-methylpropyl, butyl, pentyl, hexyl and the like.

To facilitate the structural representation of the compounds of formula (I), of certain starting materials and intermediates used to prepare them, the groups 2A2-2- (1H-imidazol-1-ylmethyl or 1H-1,2,4triazole- 1-ylmethyl) -1,3-dioxolan-4-yl, in which Ar has the meanings defined above, these groups will hereinafter be represented by the symbol D

I CH, Ar - D

X

I — L

Q is CH or N

The compounds of formula (I), in which Y is as defined above but does not represent a radical of formula (c) or (g), wherein R ,, respectively, R ₁₇ represents mercapto, but not a radical of formula (d ) or (e), where R _n or R _(i , respectively R _{) 3} denotes mercapto or hydroxy, said radical Y being represented by the symbol Y 'and said compounds represented by formula (D), these compounds may be obtained by O-alkylation of a suitable phenol of formula (III) with a reactive ester of formula (II).

D ~~ \ .J} µG O-alkylation.

o-c ^ -w ♦ U (11> <'>

In formula (II), W means a reactive ester residue, for example halogen, preferably chlorine, bromine or iodine or a sulfonyloxy group, for example methylsulfonyloxy or 4-methylphenylsulfonyloxy and the like.

The reaction of (II) with (III) is carried out according to known conditions for carrying out 0-alkylation with reactive esters. Typically, the reaction is carried out in an environment of a suitable inert to the reaction medium, an organic solvent, for example Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetamide, hexamethylphosphorotriamide, dimethylsulfoxide, 4-methyl-2-pentanone and the like, unbound solvents inert to the reaction medium, for example aromatic hydrocarbons such as benzene, methylbenzene, dimethylbenzene and the like. It is preferable to add to the reaction mixture a suitable base, for example alkali metal or carbonate hydride, to add a suitable base, for example alkali metal or carbonate hydride, to increase the reaction rate. In other words, it may be advantageous to first transform the substituted phenol (III) into its metal salt, preferably into its sodium salt by conventional methods, for example, by reacting (III) with metal bases such as sodium hydride, sodium hydroxide and the like, after which said metal salt is used to react with (II). The elevated to some extent 10 temperatures are suitable for increasing the rate of reaction, most preferably carried out at a temperature in the range of 80 ° C to 130 ° C.

Typically, the compounds of formula (I), 15 in which Y has the above meanings, can be prepared by cyclizing an intermediate of formula (IV) with a suitably substituted aminobenzene of formula (V).

oh sleep _mr

., dream _g -sn ₂ -l »1o (IV)

cyclization

The reaction is carried out by stirring the reagents in a suitable polar solvent, for example water, or in a mixture of a suitable miscible organic solvent, for example 2-propanol, 2-propanone and the like, preferably at elevated temperature, in order to accelerate the reaction. and most preferably in the presence of a suitable alkali metal or alkaline earth metal iodide, for example $$ potassium iodide.

The compounds of formula (1) are prepared alternatively by N-alkylation of compounds of formula (VI) with suitably substituted halogen-benzene of formula (VII) according to the known N-alkylation procedure.

(VII | I1)

N-alkylation can be carried out according to known methods, for example by co-stirring the reagents, preferably at slightly elevated temperatures, in an environment of a suitable organic solvent, for example dimethylsulfoxide, dimethylformamide and the like, and in the presence of a suitable base, for example alkyd hydride

linen or carbonate.

Another method of preparing the compounds of formula (I) is to cyclize a suitable intermediate of formula (VIII), in which A represents an amino group of a suitable derivative thereof, with a suitable cyclizing agent, following the methods known in the art and optionally substituted substituents are introduced into the resulting heterocyclic compounds.

cyclization ---------------------------------- »<1) / introduction of substitutes / (VIII»

The nature of A in formula (VIII), as well as the nature of the cyclizing substance used in the cyclization step, depends on the significance of Υ in the desired compounds (I). This is explained in more detail below.

The compounds of formula (I) in which Υ represents the radical (a), wherein R ₁ , R ₂ , R ₂ and R ₄ have the above meanings, said compounds being represented by formula (Ι-a), can be obtained from a suitable amine of formula (VIII-a) by cyclization with a suitable diketone of formula (IX-a) or tetrahydro-2,5-di- (lower alkyloxy) furan of formula (1X-b).

The reaction of (VIII-a) with (1x-a) is best accomplished by stirring the reagents and refluxing them in a suitable solvent medium, for example lower alkanol, e.g. ethanol and the like, preferably but not necessarily , in the presence of a suitable base such as an alkali metal carbonate, for example potassium carbonate and the like.

The reaction of (VIII-a) with (ΙΧ-b) is preferably carried out in a polar solvent, for example acetic acid and the like.

The compounds of formula (VIII-a) used herein as intermediates exhibit potent fungicidal and bactericidal properties and are within the scope of the invention both as intermediates and as fungicidal and bactericidal agents.

Compounds of formula (I) in which Y 15 means the radical (b), wherein R ₅ , R ₆ and R have the meanings given above, these compounds being represented by formula (Ι-b), can be prepared of the appropriate hydrazine of formula (VIII-b), which is commonly used in the form of its acid addition salt, by cyclization of said hydrazine with the appropriate diketone of formula (X).

The reaction of (VIII-b) with (X) is carried out as in (1-a) using starting materials (VIII-a) and (XI-a). When _R} represents hydrogen in formula (X), it is preferred that the adjacent carbonyl group is acetylated before (X) to react with (VIII-b) in order to obtain a pyrazole derivative wherein R _t occupies exactly the fifth position. Mixtures of positional isomers, which may otherwise be obtained using non-acetylated aldehydes or ketones of formula (X), may be subjected to standard isolation and purification to separate the pure constituents from one another.

Compounds of formula (I) in which Y is the radical (c), where R, and R ₁₀ are as defined above, and R 1 is mercapto, said compounds are represented by formula (Ic-1), is obtained by cyclizing a suitable isothiocyanate of formula (VIII-c) with a suitable aminoethanone or aminoacetaldehyde of formula (XI).

(Vlll-i) (XI)

The reaction of (VIII-c) with (XI) is preferably carried out by stirring the reagents and co-heating them in an environment of a suitable organic solvent, for example a lower alcohol, for example 2-propanol, in the presence of a suitable base such as an alkali metal and alkaline earth metal carbonate or alkaline and alkaline earth metal bicarbonate.

Compounds of formula (I) in which Y is the radical (c), where R, and R ₁₀ are as defined above, and R _g is hydrogen, said compounds are represented by formula (IC-2), are obtained by desulfurization of compounds of formula (Ic-1) by conventional methods, for example by treating the latter with pre-nickel or dilute nitric acid.

The compounds of formula (I), in which Y represents the radical (c) wherein R, and R _lo have the above mentioned meanings, a R, is lower alkylthio or aryl-lower alkylthio, said compounds being represented by formula (1 -c-3) may be prepared by subjecting the corresponding compounds of formula (Ic-1) to standard S-alkylation with a suitable reactive ester of formula (XII), wherein R1 * represents lower alkyl or aryl-lower alkyl and where W has the meanings given above.

The compounds of formula (I-c-3) can be desulfurized to give the compounds of formula (I-c-2).

The above reactions can be schematically illustrated as follows

desulfurization desulfurization & -sm ₂ -o (I-c-21

Compounds of formula (I) in which Y is the radical (d), wherein R _u is X, X is oxygen or sulfur, and R ₁₂ is hydrogen, lower alkyl or aryl-lower alkyl, with said substituent R ₁₂ being - 5 joined by R ₁₂ 'and said compounds represented by formula (I-dl) can be prepared by cyclization of hydrazincarbothioamide or hydrazincarboxamide of formula (XIII-d-1) with a suitable carboxylic acid of the formula

II

R '', -C-OH (XIII) or a functional derivative thereof such as an acyl halide, ester or preferably imidamide of the formula

NH

II

R ”, - C — NH, (HS-a)

The reaction is preferably carried out by co-stirring and heating the reagents in an environment of a suitable organic solvent, for example lower alkanol, such as 2-propanol, butanol and the like.

Alternatively, the compounds of formula 25 (Ι-dl) may be prepared by initially acylating with (a) (VIII-d-1) with a suitable anhydride (ΧΙΠ-b) or with an alkanoyl halide (XIIIc) which is derived from a carboxylic acid (XIII), to obtain the intermediate of formula (XIV), after which this intermediate is cyclized by stirring and heating it in an alcohol-alkaline medium.

And!

J

CLI (R ^{, 2} CO »jO (XIII- ·) / cyclization x

And H-W-C-NHj

The intermediates of formula (VIII-d-1) used herein as starting materials can be prepared by reacting an alkali metal isothiocyanate, for example potassium isothiocyanate, with the corresponding hydrazine derivative of formula (VIIIb).

Another method of preparing the compounds of formula (dl-dl) involves reacting a hydrazine hydrochloride of formula (VIIIb) with a compound of formula (ΧΙΠ-d) in which X is oxygen or sulfur, in a medium of Ν, ети diethylethanamine, followed by the reaction the mixture was washed with water, the solvent was evaporated and the residue was stirred and heated in a mixture of dichloromethane and ethanol in the presence of an alkaline substance.

° || N. N - dimethylethanemia (Vlll-b) + X = C-N-C-R ".------ (Xlll-d) dichloromethane ethanol

The compounds of formula (I), in which Y represents the radical (d), wherein _{R] 2} is R ₁₂ *, a R _H is hydrogen, said compounds being represented by formula (Id-2) may readily be prepared by desulfurization of the corresponding compound of formula (Ι-dl) in which XH is SH, said compounds are represented by the formula (Id-1-a), the same procedure as for desulfurization of ((-cl) is obtained to obtain (Ic -2).

The compounds of formula (I) in which Y is the radical (d), wherein R ₁₂ is R ₁₂ 'and R _n is lower alkylthio or aryl-lower alkylthio, said compounds are represented by formula (Id-3). They can be prepared by S-alkylation of a compound of formula (Id-1-a) with a reactive ester of formula (XV-a) wherein W has the above meanings and R _n * denotes lower alkyl or aryl- lower alkyl, following the same procedure as for the preparation of (1-c-3) with starting materials (Ι-cl) and (XII).

By repeating the same desulfurization procedure as described above, the compounds of formula (I-d-3) can be converted to the compounds of formula (I-d-2).

The above reactions can be schematically illustrated as follows

And the XV's

desulfurization desulfurization

Compounds of formula (I) in which R _n is X, X being oxygen or sulfur, and R _n is hydrogen, lower alkyl or aryl-lower alkyl, said substituent R _H being represented by the symbol R _n ^b and mentioned compounds are represented by the formula (Id-4), can be prepared by cyclizing the appropriate (aminocarbonyl) - or (aminothiocarbonyl) hydrazine of formula (VIII-d-2) with a suitable carboxylic acid ((-d) or a functional derivative thereof a compound, for example, an acyl halide, an ester, or preferably imidamide.

Preferably said reaction is carried out in the presence of a suitable organic solvent, for example lower alkanol, for example 2-propanol, butanol and the like.

(Vtll-4-2) or a derivative thereof

(«-4-4)

Compounds of formula (I) in which Y is the radical (d), where R _{| 2} is hydrogen and R _n has the same meanings as R _{1 (} ^b , said compounds being represented by formula (Id-5), can be are obtained by desulfurizing a compound of formula (Id-4) in which X is S, (Id-4-a), for example, by treating the latter with pre-nickel or dilute nitric acid.

The compounds of formula (I), in which Y represents the radical (d), where R _|} is lower alkylthio or aryl-lower alkylthio, a R _H 5 has the same meaning as R _H ^b, said compounds being represented by formula (Id -b), these compounds can be prepared by S-alkylating a compound of formula (Id-4-a) with a reactive ester of 10 formula (XV-b) in which W has the above meanings, and R ₁₂ ^b represents lower alkyl or aryl-lower alkyl, then repeating the steps described above to obtain (1-c-3) at starting compounds ((-cl) and (XII). The compounds of formula (Id-b) can in turn be converted into the compounds of formula (Id-5) by the desulfurization method described above in detail.

The reactions described above can be schematically expressed as follows:

The compounds of formula (I) in which Y is a radical of formula (e), wherein R _1X has the meanings given above and R ₁₃ denotes mercapto or hydroxy, which is mentioned for the _L- displacement R 1, is represented by formula XH 45 ¹³ wherein X is oxygen or sulfur, and said compounds being represented by formula (IF-1), and the same may be prepared from an intermediate of formula (VIII-a) through 50 cyclizing the latter with an appropriate intermediate formula (XVI) or an acid addition salt thereof.

X NH-C-NK-NH, / I ►

(VIII- ·) (XVI) xn5

Π— · —I)

The cyclization can be carried out 10 by known methods, for example by co-mixing and melting the reagents, if necessary, in the presence of a suitable, inert, organic solvent with a relatively high boiling point, 15 such as 1,1'-oxybis (2 methoxyethane).

Compounds of formula (I), in which Υ means radical (e), where R _t4 has the meanings indicated above, and R ₁₃ denotes lower alkylthio or aryl-lower alkylthio, said substituent R ₁₃ is represented by the formula SR ₁₃ *. in which R ₁₃ * represents lower alkyl or aryl-lower alkyl, said compounds are represented by the formula (I-e-3) and can be prepared by S-alkylation of 25 compounds of formula (Ι-el) in which R ₁₃ represents -SH, (Ie-1-a), with a reactive ester of formula (XVII), in which W has the above meaning, according to methods known in the art. 30

Compounds of formula (I) in which Y is the radical (e), where R _u has the above meanings and R ₁₃ is hydrogen, said compounds are represented by the formula (1-e-2) and can be obtained by 35 desulfurization of the corresponding compound of formula (Ie-1-a) or compounds of formula (I-e-3) according to the known desulfurization reactions described above.

The above reactions are schematically illustrated as follows:

Compounds of formula (I), in which Y is a radical (f), wherein R ₃ and R ₁₆ have the meanings given above, said compounds are represented by the formula (ΙΟ) and can be obtained from the corresponding compound of formula (Ι -el), in which XH is OH, (Ie-1-b), by N-alkylation of the latter with a suitable reactive ester of formula (XVIII), in which W and R ₁₃ have the above meanings.

The above N-alkylation can be carried out according to known methods, for example by co-stirring and heating the reagents in an environment of a suitable organic solvent such as dimethyl sulfoxide and the like in the presence of a suitable base such as an alkali metal hydride or carbonate.

The compounds of formula (I) in which Y is the radical (g), where R ₁₇ has the meanings given above, except for mercapto, said compounds are represented by the formula (gl-gl) and said substituent R _n is represented with the symbol R _n *, these compounds are generally obtained from an intermediate of formula (VIII-a) by cyclization with azide, preferably alkali methyl azide, for example sodium azide, and with the appropriate Ι, Ι ′, Ι ”-tri (lower alkyloxy) -alkane of formula (XIX) in a suitable acidic medium, for example acetic acid and preferably heated ack.

desulfurization desulfurization (VIII- ·)

R ^{, 7} _a -C (O- (lower alkyl) Ig (X 1 X>,

(1-I-1)

The compounds of formula (I) in which Y is the radical (g), wherein R _n is mercapto, said compounds being represented by formula (Ig-2) and may be obtained by cyclization of isothiocyanate of formula (VIII-c) with a suitable azide, preferably sodium azide, in a medium of a suitable organic solvent, for example in a lower alkanol such as methanol, ethanol, 2-propanol and the like, and in the presence of an alkaline substance.

(VIII-c) · N

N - N

(1-9-2)

Said cyclization reaction may also be carried out by stirring (VIII-c) with azide in the presence of a suitable quaternary ammonium salt, preferably N, N, N-triethyl benzene methanammonium chloride, in a suitable solvent such as water, preferably in admixture with a suitable organic solvent, for example 1,4-dioxane, which facilitates the solubility of the reagents.

Compounds of formula (Ig) in which R _n is hydrogen, (Ig-3) can be prepared by desulfurizing a compound of formula (Ig-2) according to known methods.

butanedicarbonic, 2-hydroxy-1,2,3-propantricarboxylic, benzoic, 3-phenyl-2-acrylic, -hydroxy-benzoacetic, methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, 5 4-methylbenzenesulfonic, 2-hydroxybenzoic, 2-hydroxybenzoic, 2-phenoxybenzoic or 2-acetyloxybenzoic acid. In turn, the salts can be converted to the corresponding free bases by conventional methods, 10 for example by reacting them with alkaline substances such as sodium or potassium hydroxide.

Many of the intermediates and starting materials used in the methods described above are known compounds, others may be prepared according to known methods of preparing such compounds, and some of them are novel and are prepared here below.

The intermediates of formula (III) in which Y 'has the meanings described above are prepared from the corresponding compounds of formula (XX) substituted with a methoxy group by converting their methoxy group to their hydroxy group by acid hydrolysis, using a strong non-oxidizing mineral acid such as hydrobromic acid in glacial acetic acid.

desulfurization

The imidazole and triazole derivatives of formula (I), obtained in the form of a base according to the methods described above, can be converted into their therapeutically useful acid addition salts by reaction with a suitable acid such as an inorganic acid, for example hydrochloric acid, for example hydrochloric acid, hydrobromic or hydroiodic acid; sulfuric, nitric or thiocyanic acid; phosphoric acid; organic acid, for example, acetic, propionic, hydroxyacetic, 2hydroxypropionic, 2-oxopropionic, ethanedicarboxylic, propandicarboxylic, 1,4butanedicarboxylic, (Z) -2-butenedicarboxylic, (E) -2-butenedicarboxylic, 2-hydroxy-1,4butanedicarboxylic -dihydroxy-1,4-

(XX »

The intermediates of formula (XX) used herein as starting compounds 35 can be prepared by cyclization of Ν, Νbis (2-halogenethyl) -4-methoxybenzolamine of formula (XXI) with a suitable benzolamine of formula (XXII) in which '' Has the meanings given above, using the same method 40 described above for the preparation of (I) for starting compounds (IV) and (V).

CMj-0

(XXI)

(XXII)

The preparation of the compounds of formula (XXI) is described in J. Chem. Soc., 1949, 183-191.

Alternatively, the intermediates of formula (XX) may be prepared by cyclizing a suitable intermediate of formula (XXIII) in which A represents an amine group or a derivative thereof, with a suitable cyclizing agent, and, if necessary, suitable substituents are introduced into the heterocyclic compounds thus obtained. , followed by the methods described above for the preparation of compounds (I) with starting compound (VIII).

A stirring and heating with hydrazine hydrate in the presence of a suitable solvent, for example, 1,4-dioxane and similar solvents.

s

(XXIII -C-11

(XX) cyclization

-------------> Introducing Substitutes (XX) ₁₀

The intermediates of formula (XXIII) in which A is an amino group (XXIII-a) can be prepared by alkylation of a compound of formula (XXIV) 15 with appropriate chloro-nitrobenzene (XXV) according to standard N-alkylation methods, whereupon the resulting nitro compound (XXVI) is reduced, for example, by catalytic hydrogenation in a relatively polar solvent such as 20 methanol in the presence of a suitable catalyst,

The intermediates of formula (XXIII), in which A is a hydrazincarbonamide group (XXIII-c-2), can be prepared from a compound of formula (XXIII-a) by stirring and heating the latter with phenylcarbonyl halide in a suitable solvent medium. , for example in dichloromethane and in the presence of a suitable base, for example pyridine and the like, then the resulting compound (XXIII-d) is reacted with hydrazine hydrate in the presence of a suitable solvent such as 1,4-dioxane and the like.

(XXIII- ·) for example palladium on charcoal.

N-alkylation (XXIV reduction

The intermediates of formula (XXIII), in which A is an isothiocyanate group (XXIII-b), can be prepared from a suitable compound of formula (XXIII-a) by treating the latter with sulfur carbon in the presence of dicyclohexylcarbodiimide, preferably in the presence of a suitable organic solvent, for example pyridine.

(XXIII- ·) »cs ₂

N-C-S (XXIII-C-d)

The intermediates of formula (IV) are prepared by 0-alkylation of 4-aminophenol of formula (XXVI) with a reactive ester of formula (II) according to the same method described above for the preparation of (D), and thus the compounds of formula (XXVII) obtained are reacted with appropriate dihalogenethane following the procedure described in J.Chem. Soc., 1949, 183-191.

HO ^ y ^NH '(XXVI) o-CHj-w (Η)

(XXVII) halo-CH ^ -CH ^ -haio

---------------------> (IV) o-alkylation --------------->

(XXIII-b)

The intermediates of formula (XXIII) in which A is a hydrazincarbothioamide group (XXIII-c-1) can be prepared from a compound of formula (XXIII-b) by

The intermediates of formula (V) as well as the starting compounds of formula (XXII) are generally obtained by reduction of the corresponding nitro compound of formula (XXVIII), respectively (XXVIII-a), for example by catalytic hydrogenation in a relatively polar solvent such as alkanol in the presence of a suitable catalyst, for example platinum on carbon.

”° 2

(XXVIII) γ ·

NO

(XXVIII-a) (V)>

<XXII)

The starting compounds of formula (XXVIII), respectively (XXVIII-a), are prepared from suitable starting materials according to the above and known methods for preparing the compounds of formula (I) from starting compound (VIII) and a suitable cyclizing agent.

The intermediates of formula (VI) are prepared by 0-alkylation of a suitable compound of formula (XXIX) with a reactive ester of formula (II) following the usual 0-alkylation method.

D-CHj-W * NO (II) / o-oxidation

VT * (XXIX) (VI)

The starting compounds of formula (II), in which Q is CH and methods for preparing them, are described in Belgian Patent No. 837,831. In general, the reactive esters of formula (II) can be prepared according to the following reaction sequence.

Suitable I-Ar-2-bromethanone of formula (XXX) is acetalized with 1,2,3 propanetriol according to procedures similar to those described in Synthesis, 1974, (I), 23.

A preferred way of carrying out the reaction is to reflux both reagents together under reflux for several hours by azeotropically separating the water in an environment of a suitable organic solvent, preferably in the presence of a simple alcohol, for example ethanol, propanol, butanol, pentanol and the like in the 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 other similar and saturated hydrocarbons, for example cyclohexane.

The dioxolane (XXXI) thus obtained is reacted with benzoyl chloride to give the benzoate of formula (XXXII), and then the latter is reacted with 1H-imidazole or 1H-1,2,4-triazole. Said reaction is accomplished by co-stirring and heating the reagents in a suitable organic solvent, for example Ν, мети dimethylformamide, in the presence of a suitable strong metal base, for example sodium methanolate, to give an intermediate of formula (XXXIII). The required reactive esters of formula (II) are readily obtained first by hydrolysis of (XXXIV) into an alkaline medium and then converting the hydroxy group of the compound thus obtained (XXXV) into its reactive ester according to conventional methods known in the art. For example, for example methanesulfonates and 4-methylbenzenesulfonates are easily obtained by the interaction of alcohol with methanesulfonyl chloride or 4-methylbenzenesulfonyl chloride, and the halides may be obtained by the interaction of alcohols with, for example, such as, for example, When the reactive ester is iodide, it is preferable to obtain it from the corresponding chloride or bromide by replacing that halogen with iodine.

The above reactions can be illustrated as follows:

oh he

II I

Br-CH, -C-At + NO-CH, -CH-CH, -O ------------ (XXX)

C «HjCOCI (XXXI) & -CH, Αί <Ho ¹ —I r * o (XXXII) I c * o I

NaOCH ^ / DMF

H-imidazole or 1H-1,2,4-trnazole

(XXXIII)

O II CHjO-c-CgHj

CH Ar oXo

I — k

CHj-OH (XXXIV) formation of a reactive ester

HD

It is apparent from formula (I) that the compounds of the invention have at least two asymmetric carbon atoms in their structure, namely those which are located at the 2nd and 4th positions in the dioxolane molecule and therefore may exist under different stereochemical isomeric forms. The stereochemical isomeric forms of (I) and their pharmaceutically acceptable acid addition salts are within the scope of the invention.

The diastereoisomeric racemates of (I), respectively referred to as cis and lasting forms according to the rules described in CA, 76, Index Guide, Section IV, p 85 (1972), can be obtained separately by conventional methods. Suitable methods that can be used are selective crystallization and chromatographic separation, for example column chromatography.

Since the stereochemical configuration is already known in many of the intermediates, for example in the intermediates of formulas (II), (IV), (VI) and (VIII), it is also possible to separate the cis and transforms of this or even at an early stage in which step the corresponding forms of (I) can be obtained therefrom in the manner indicated above. Separation of cis- and transforms of such intermediates is carried out by the usual methods described above for the separation of cis- and transforms of compounds (I).

It is obvious that the cis- and trans-diastereoisomeric racemates can be further dissolved in their optical isomers, cis (+), cis (-), trans (+) and last (-) according to known methods in the art.

The compounds of formula (I) and their pharmaceutically acceptable acid addition salts are useful anti-fungal and bacterial agents. For example, said compounds and their acid addition salts are highly active compounds against a variety of fungi such as Microsporum canis, Ctenomyces mertagoephytes, Trichophyton rubrum, Phialophora verrucosa, Cryptococcus neoformans, Candida tropicalis, Candida albicans, Mucor species, Asperguscicus spumumigum spumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumumum and fumarum sprays bacteria such as Erysipelotrix insidiosa, Staphylococci such as Staphylococcus hemolyticus and Streptococci as Streptococcus pyogenes. In view of their potency, local and systemic antimicrobial activity, the compounds of the invention are useful agents for the destruction or prevention of the development of fungi and bacteria, and in particular they can be effectively used to treat subjects suffering from these microorganisms.

The strong antimicrobial activity of the compounds (I) is clearly evident from the data obtained in the following experiments, which data are given only to illustrate the beneficial antimicrobial properties of all the compounds (I) and not to limit the invention as regards the scope of the microorganisms subject to the effects of these compounds, and to the extent of the compounds represented by formula (I).

Experiment A

Activity of Compound (I) against vaginal candidiasis in rats.

Female Wistar rats weighing about 100 grams were used, underwent ovariectomy and hysterectomy, and after subcutaneous recovery, 100 μg of oestradiol undecylate were administered subcutaneously once a week for three consecutive weeks. The pseudo-estrus condition thus induced is controlled by microscopic examination of vaginal fluid. Animals are left with food and water as they absorb. Rats were infected intravaginally with 8.10 ⁵ Candida albicans cells grown on Sabouraud and left in this medium for 48 h at 37 ° C and then diluted with saline. Infection data vary from day 25 to day 32 after surgery, depending on the appearance of scars on induced pseudo-oestrus.

The medicines to be tested are given orally once a day for two days from the day of infection. Placebo-treated control animals were isolated for each experiment. The results were analyzed by taking the vaginal fluid with sterile swabs for several days after infection. The tampons were placed in Sabouraud medium in petri dishes and incubated for 48 hours at 37 ° C. If Candida albicans does not develop, i. when the animal samples were negative at the end of the experiment, this was clearly due to the administration of the drug, as such results were not obtained in placebo-treated control animals.

The table below shows the lowest oral doses of the drug under study that were found to be active 14 days after infection.

Experiment C

Activity of compounds (I) against candidiasis in turkeys.

Turkeys at 14 days of age were infected with cereals containing 4.10 ⁶ Candida albicans cells grown on Sabouraud medium for 48 h at 37 ° C and diluted with brine. The volume of the seed medium is 1 ml. The drug to be tested is stirred with 500 mg lactone and then mixed with 1000 g of food without other additives. The concentration in the food of the investigational medicinal product is expressed in mg / kg.

Animals were administered medicated foods for 13 consecutive days, starting counting from the day of infection. At the end of the experiment, all animals were killed. At necropsy, the cereals are removed, dried and milled in an ultra-turrax mixer in sterile 15 ml saline. Is performed counting the colonies on Sabouraudagar, and the results given in the table represent the E ^e ₅₀ t.e.dozata medicament, wherein the grains in 50% of the animals show a completely negative for the presence of Candida albicans.

The compounds given in the table merely illustrate but do not limit the scope of the invention.

cis

Vaginal Can-

rat didodosis: lowest oral eff. dose, mg / kg 2.5

2.5

1.25

1.25

0.63

0.63

2.5

1.25

2.5 cereals: ED ₅₀ in mg / kg

Vaginal candidiasis according to the pl

Y Q hove: lowest oral efficacy, mg / kg cereal turkeys: ED (.0 in g / kg SCH_ / ^J N = / / “ ^{N dream of} N <0.63 SCH-, -N | } = ^{N CH} 3 N 2.5 - -Z ~ | SCH ₃ N 2.5 - N - ^N 'J Z' ^{N CH} 3 N 0.63 - SCH,> = N -N | > = ^N % CH - 31 CH-> Ln -N | ₀ > ~ \ ^{0 CH} 3 CH 0.63 16 CH_> u -N | ₀ > ~ \ ^{0 CH} 3 N <0.63 16 N - N V = TNJ N <2.5 -

Vaginal Can-

Y Q -didose by rat: lowest oral efficacy, mg / kg cereals: ED ₅ g in mg / kg 0 ^ N-CHg ~ ^N \ _n N 50.63 - O ^ N-CH3 ~ ^N \ _n CH 1.0 16 0 ^ = nc ₂ h ₅ ~ ^N V_n CH 1.25 31 0 _y S = N-nC ₃ H ₇ -Ν I> = ^N CH ₃ CH 0.63 - 0 / = N- ^C 2 ^H s -N | > = N% N <0.63 1 0 / = N-nC ₃ H ₇ -N | > ^{N sleep with} N 0.5 - 0 ^ = nc ₂ h ₅ ~ ^N k — N N 50.16 - 0> = ^N - ^C 2 ^H 5 -N | \ x = N% CH 1.25 -

In view of the fungicidal and bactericidal properties of the compounds according to the invention, the same provides valuable compositions containing these compounds of formula (1) or their acid addition salts as active substance in a solvent medium or together with a solid, semi-solid or liquid diluent or carrier, and in addition the invention provides an effective method of combating fungi or bacteria by using an effective fungicidal or bactericidal amount of the compounds (I) or their salts. Fungicidal and bactericidal compositions containing an effective amount of active compound (I), alone or in combination with other active therapeutic ingredients, in admixture with suitable carriers, can be readily prepared according to conventional pharmaceutical methods that are used for treatment in known ways.

Preferred formulations are in unit dosage form, which in one dosage unit contains an effective amount of the active substance in admixture with suitable carriers. Although the amount of active substance in a single unit dose may vary within a very wide range, those dosage units containing from 50 to 500 mg, in particular from 100 to 250 mg, of the active substance are preferred.

The following examples are intended to illustrate but not limit the scope of the invention.

Unless otherwise stated, all parts are by weight.

A) Preparation of intermediates

Example 1. A mixture of 13.4 parts 1- (4-methoxyphenyl) piperazine dihydrochloride, 7.9 parts 1-chloro-4-nitrobenzene, 10 parts potassium carbonate and 90 parts Ν, dimethylformamide, was stirred and boiled under reflux overnight. The reaction mixture was diluted with water and the product extracted twice with trichloromethane. The combined extracts were dried, filtered and evaporated. The residue was triturated with 4-methyl-2pentanone. The product was filtered and crystallized from 1,4-dioxane to give 10.5 parts (67%) of 1- (4-methoxyphenyl) -4- (4-nitrophenyl) piperazine; mp Mp 195.1 ° C.

A mixture consisting of 12 parts of 1- (4-methoxyphenyl) -4- (4-nitrophenyl) piperazine, 200 parts of methanol and 225 parts of tetrahydrofuran is hydrogenated at normal pressure and at room temperature with 2 parts of palladium on carbon catalyst ( 19%). After the calculated amount of hydrogen is captured, the catalyst is filtered off and washed with N, N-dimethylacetamide. The filtrate is poured into water. The precipitated product was filtered and crystallized from 1-butanol, yielding 8 parts (74%) of 4- [4- (4-methoxyphenyl) -1-piperazinyl] -benzolamine; mp 191.8 ° C.

EXAMPLE 2 To a cooled mixture (in an ice bath) consisting of 5 parts N, N'-methane tetraylbis (cyclohexanamine), 25.2 parts sulfur carbon and 40 parts pyridine, 6 parts 4- / 4- ( 4-methoxyphenyl) -

1-piperazinyl / benzolamine and the whole mixture was stirred first for 1 hour in an ice bath and then for 2 hours at room temperature. 35 parts of 2,2'-oxybispropane were added and the whole mixture was stirred for 30 minutes. The precipitated product was filtered off and crystallized from 4-methyl-2-pentanone, the product was again filtered off and recrystallized from 1,4-dioxane to give 2.45 parts of 1- (4-isothiocyanatophenyl) -4- (4-methoxyphenyl) piperazine; mp 180.6 ° C.

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-dioxane was stirred and refluxed for 1 hour. The reaction mixture was cooled and poured into water. The precipitated product was filtered off, washed with water and methanol and dried, yielding 46 parts (89%) of N- [4- (4- (4-methoxyphenyl) 1-piperazinyl) phenyl] hydrazinecarbothioamide.

Example 3. A mixture consisting of 23 parts of N- [4- / 4- (4-methoxyphenyl) -1-piperazinyl / phenyl / hydrazincarbothioamide, 23 parts of methanimidamide acetate and 80 parts of 1-butanol was stirred and refluxed. for 1 hour. The reaction mixture was cooled and poured into water. 2,2'Oxybispropane is added. The precipitated product was filtered off, washed with water and methanol and crystallized from 1-butanol to give 17.7 parts of 4- [4- (4- (4-methoxyphenyl) -1-piperazinyl) -4H-

1,2,4-triazole-3-thiol; mp 231.9 ° C.

Using the same procedure and an equivalent amount of ethanimidamide hydrochloride instead of metanimidamide acetate, 4- (4- (4- (4-methoxyphenyl) -1-piperazinyl) phenyl) -5-methyl-4H-1,2,4- triazole-3-thiol; mp 260.3 ° C.

Example 4. A mixture consisting of 9 parts 4- [4- (4- (4-methoxyphenyl) -1-piperazinyl) phenyl] -4H-1,2,4-triazole-3-thiol, 2 parts sodium hydroxide and 160 parts of methanol, stirred and warmed until all solids were dissolved. Then, 3, 3 parts of dimethyl sulfate are added and stirring is continued for 3 hours at room temperature. The reaction mixture was poured into water. The precipitated product was filtered off and crystallized from 1-butanol to give 5.3 parts of 1- (4-methoxyphenyl) -4- (4-).

3- (methylthio) -4H-1,2,4-triazol-4-yl / phenyl / piperazine; mp 180 ° C.

The compound is similarly prepared

- (4-methoxyphenyl) -4- (4- (3-methyl-5 (methylthio) -4H-1,2,4-triazol-4-yl) phenyl) piperazine dihydrochloride; mp 210 ° C.

Example 5 A mixture consisting of 50 parts of 2- (4-nitrophenyl) hydrazincarbothioamide and 270 parts of methylbenzene was distilled azeotropically to dryness. Then 26 parts of acetic anhydride were added and the whole mixture was stirred and refluxed for 3 hours. The reaction mixture was cooled. The precipitated product was filtered off, washed with 2-propanol and crystallized from ethanol. The product was filtered again and dried at 100 ° C to give 31.5 parts of 2- (aminothioxomethyl) -1- (4-nitrophenyl) acetic acid hydrazide; mp 214.5 ° C.

By the same method of acetylation and using equivalent amounts of the appropriate starting materials, the compounds 2- (aminothioxomethyl) -1 (4-nitrophenyl) hydrazide butyric acid monohydrate are also obtained; mp 197.2 ° C; and 2- (aminothioxomethyl) -1- (4-nitrophenyl) propionic acid hydrazide; mp 216.1 ° C.

Example 6. 40 parts of 2- (aminothioxomethyl) -1- (4-nitrophenyl) acetic acid hydrazide were dissolved in a mixture consisting of 10 parts of sodium hydroxide and 40 parts of water, and the solution was stirred for 30 minutes at room temperature. temperature. The solution was acidified with concentrated hydrochloric acid. The precipitated product was filtered, washed with water and 2-propanol and crystallized from 1,4 dioxane to give 22.4 parts of 5-methyl-1 (4-nitrophenyl) -1 Η-1,2,4-triazole-3 -thiol; mp 202.1 ° C.

Similarly, the compounds 1- (4-nitrophenyl) -5-propyl-1H-

1.2.4- triazole-3-thiol; mp 190.7 ° C; and 5-ethyl-1- (4-nitrophenyl) -1H -1,2,4-triazole-

3-thiol; mp 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 and the mixture was stirred until dissolved of all solids. 2.66 parts of dimethyl sulfate are then added and stirring is continued for 1 hour at room temperature. 100 parts of water are added. The precipitated product was filtered, washed with water, dried and crystallized from 2,2'-oxybispropane. 3.3 parts (66%) of 5-methyl-3- (methylthio) -1- (4-nitrophenyl) -1 N-1,2,4 triazole are obtained; mp 121-125 ° C.

Repeating the same S-methylation procedure and using equivalent amounts of the appropriate starting materials also yields 5-ethyl-3- (methylthio) -1- (4-nitrophenyl) 1H-1,2,4 -triazole; mp 77.8 ° C; and

3- (methylthio) -1- (4-nitrophenyl) -1Η-1,2,4triazole; mp 140 ° C.

Example 8. A mixture consisting of 2.5 parts 5-methyl-3- (methylthio) -1- (4-nitrophenyl) 1H-1,2,4-triazole and 120 parts methanol was hydrogenated at normal pressure and at room temperature with 2 parts platinum catalyst on carbon (10%). After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue was crystallized from a mixture of 4-methyl-2-pentanone and petroleum ether. The product was filtered off and dried, yielding 1.5 parts (68%) of 4- [5-methyl-3- (methylthio) -1H-1,2,4-triazol-1-yl / benzolamine; mp 130-136 ° C.

By the same hydrogenation process, the compound 4- [3- (methylthio) -1H- is obtained

1.2.4- Triazol-1-yl / benzolamine as a residue.

Example 9. A mixture consisting of 41 parts of 5-ethyl-3- (methylthio) -1- (4-nitrophenyl) 1H-1,2,4-triazole and 80 parts of methanol was hydrogenated at normal pressure and at room temperature with 1 part palladium catalyst on carbon (10%). After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from 1,1'-oxybisbutane. The product was filtered off and dried, yielding 33 parts (91%) of 4- [5-ethyl-3- (methylthio) -1H-

1,2,4-triazol-1-yl / benzamine; mp 131.7 ° C.

The compound is similarly prepared

4- (2-methyl-1H-imidazol-1-yl) benzolamine; mp 105 ° C.

Example 10 A mixture consisting of 20 parts of 4- [5-methyl-3- (methylthio) -1 N-1,2,4-triazole-

1-yl / benzamine, 15 parts of nickel catalyst previously and 400 parts of methanol, was stirred and refluxed for 2 hours. The catalyst was filtered and an additional 15 parts of the same catalyst were added. Stirring and refluxing continue for another 4 hours. The reaction mixture was filtered, the filtrate was washed with methanol and the filtrate was 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, yielding 7.6 parts (47%) of 4- (5-methyl-1H-1,2,4-triazol-1-yl) benzalamine; mp 145 ° C.

Example 11. A mixture consisting of 35 parts 1- (4-nitrophenyl) -5-propyl-1 N-1,2,4-triazole-3-thiol, 83 parts concentrated nitric acid solution and 150 parts water was stirred and warms to 60 ° C. While stirring, the mixture was allowed to cool to room temperature, followed by stirring overnight at room temperature. The precipitated product was filtered, washed with water and poured into a hot solution consisting of 20 parts of potassium carbonate dissolved in 20 parts of water at 100 ° C. The reaction mixture was allowed to cool to room temperature and stirring was continued continuously. The precipitated product was filtered, dried and crystallized from a mixture of 4-methyl-2-pentanone and 2,2'oxybispropane. The product was filtered 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-triazole); mp 171.5 ° C.

With continuous stirring and heating, 20 parts of 3,3'-dithiobis (1- (4-nitrophenyl) 5-propyl-1H-1,2,4-triazole) were dissolved in 100 parts of acetic acid. Then, 55 parts of a 30% solution of hydrogen peroxide are added dropwise, the reflux temperature is reached. After completion of the reaction, stirring and refluxing continued for another 1 hour. The reaction mixture was cooled and poured into a mixture of crushed ice and 50% sodium hydroxide solution. The precipitated product was filtered off and dissolved in dichloromethane. The solution was washed with sodium sulfite solution, filtered and evaporated. The residue was purified by silica gel column chromatography using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in 2-propanol. The salt was filtered and crystallized from ethanol to give 3.9 parts (19%)

1- (4-nitrophenyl) -5-propyl-1 N-1,2,4-triazole monohydrochloride; mp 178.7 ° C.

A mixture of 38.3 parts 1- (4nitrophenyl) -5-propyl-1H-1,2,4-triazole monohydrochloride and 400 parts methanol is hydrogenated at normal pressure and at room temperature with 3 parts palladium on carbon charcoal 10 %. After absorbing the calculated amount of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in water and neutralized with sodium bicarbonate. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was converted into the hydrochloride salt in 2-propanol. The salt was filtered off and dried, yielding 35 parts of 91% 4- (5-propyl-1H-1,2,4-triazol-1-yl) benzenamine dihydrochloride.

Example 12 A mixture consisting of 4 parts N- (4-nitrophenyl) hydrazincarboxamide, 5 parts ethanimidamide hydrochloride and 5 parts sodium acetate was stirred and heated for 4 hours at 140 ° C. The reaction mixture was cooled, water was added and stirred until the product crystallized. It was filtered and recrystallized from 2-propanol to give 1.5 parts (34%)

2.4-Dihydro-5-methyl-4- (4-nitrophenyl) -3H-

1.2.4- triazol-3-one; mp Mp 226.1 ° C.

To a solution consisting of 13.5 parts

2.4-Dihydro-5-methyl-4- (4-nitrophenyl) -3H-

1.2.4-Triazol-3-one in 100 parts dimethyl sulfoxide, stirring 2 parts 78% sodium hydride dispersion was added and the whole mixture was stirred until foam ceased. 8.1 parts of dimethyl sulfate are then added dropwise. After completion of the reaction, stirring was continued for another 3 h at room temperature. The reaction mixture was poured into water and the product extracted three times with trichloromethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was crystallized from a mixture of 2-propanol and 2,2'-oxybispropane. The product was filtered and recrystallized from 4-methyl-2-pentanone to give 6.3 parts of 2,4-dihydro-2,5-dimethyl-4- (4-nitrophenyl) -3H-1,2,4-triazole-

3- he; mp 153.2 ° C.

A mixture of 9 parts of 2,4-dihydro-2,5-dimethyl-4- (4-nitrophenyl-3H-1,2,4triazol-3-one and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 3 parts catalyst formerly nickel After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated The residue is triturated with 2,2'oxybispropane The product is filtered off and dried to give 7.5 parts 95% 4- (4-aminophenyl) -

2,4-dihydro-2,5-dimethyl-3H-1,2,4-triazol-3one; mp. 160 ° C.

Example 13. A mixture consisting of 53 parts of N- [4- (4- (4-methoxyphenyl) -1-piperazinyl) phenyl] hydrazincarboxamide, 53 parts of ethanimidamide hydrochloride and 135 parts of N, N-dimethylformamide was stirred and heated in for 3 h at 130 ° C. The reaction mixture was cooled and poured into water. The precipitated product was filtered, washed with water and methanol and crystallized from Ν, мети dimethylformamide. The product was filtered and recrystallized from 1,4-dioxane to give 19.5 parts of 2,4-dihydro-4- (4- / 4- (4methoxyphenyl) -1-piperazinyl) phenyl) -5-methyl-3H -1,2,4-triazol-3-one; mp 298.4 ° C.

Example 14. 19.2 parts of 2,4-dihydro-4- /

4- [(4-Methoxyphenyl) -1-piperazinyl] phenyl] 3H-1,2,4-triazol-3-one was dissolved in 450 parts of dimethyl sulfoxide at about 100 ° C. 3.1 parts of 50% sodium hydride dispersion are then added and the whole mixture is stirred until a temperature of approximately 50 ° C is reached. 8.2 parts of dimethyl sulfate were added and stirring was continued overnight at room temperature. The reaction mixture was poured into water and the product extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue was purified by column chromatography on silica gel, using a mixture of trichloromethane and methanol 98: 2 v / v. as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 1-butanol to give 5.8 parts of 2,4-dihydro-4 / 4- [4- (4methoxyphenyl) -piperazinyl] phenyl] -2-methyl-3H-1,2,4-triazole- 3-it; 245.7 ° C.

Example 15. 10 parts of 2,4-dihydro-4- [4 / 4- (4-methoxyphenyl) -1-piperazinyl] phenyl] -3H-1,2,4-triazol-3-one were dissolved in 300 parts of dimethyl sulfoxide at a temperature of 100 ° C. 1.6 parts of 50% sodium hydride dispersion are then added and stirring is continued while allowing the mixture to cool to about 50 ° C. They are added

3.9 parts of 1-bromopropane and the whole mixture was stirred overnight at room temperature. The reaction mixture was poured into water and the product extracted with trichloromethane. The extract was washed 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 by volume as eluent. The pure fractions were combined and the eluent was evaporated. The residue was triturated with 2-propanol. The product was filtered off and dried, yielding 7.5 parts (65%) of 2,4-dihydro-4 / 4- / 4- (4-methoxyphenyl) 1-piperazinyl / phenyl / -2-propyl-3H-1,2 , 4triazol-3-one.

Following the same alkylation procedure and using equivalent amounts of suitable starting materials, the following compounds are also obtained:

2-ethyl-2,4-dihydro-4- [4- (4- (4-methoxyphenyl) -1-piperazinyl) phenyl] -5-methyl-3H-

1.2.4- triazol-3-one; mp 179.80 ° C.

2,4-dihydro-4- [4- [4- (4-methoxyphenyl) 1-piperazinyl] phenyl] -5-methyl-2-propyl-3H-1,2,4-triazol-3-one; mp 144.5 C; and 2-ethyl-

2.4-dihydro-4- [4- (4- (4-methoxyphenyl) -1-piperazinyl) phenyl) -3H-1,2,4-triazol-3-one; mp 210.2 ° C.

Example 16. A mixture consisting of 12.5 parts of N, N-bis (2-chloroethyl) -4-methoxybenzolamine, 8 parts of 4- (1H-pyrazol-1-yl) benzolamine, 2 parts of potassium iodide, 80 parts of 2-propanone and 100 parts water, stirred and refluxed for 24 hours. The reaction mixture was cooled. The precipitated product was filtered off (the filtrate was removed sideways), washed with water and 2 propanone to give 6 parts of the first crude fraction. The filtrate was neutralized with sodium bicarbonate solution and extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue was triturated with 2 propanol. The product was filtered and washed with methanol to give 2 parts of the second crude fraction. The two crude fractions, respectively 6 and 2 parts, were combined and crystallized from 1-butanol to give 7.1 parts 1- (4-methoxyphenyl) -4- / 4- (1H-pyrazol-1-yl) -phenyl / piperazine;

mp 207.7 ° C.

Repeating the same procedure and using equivalent amounts of appropriate starting materials also yields the following compounds:

1- / 4- (1H-imidazol-1-yl) phenyl] -4- (4methoxyphenyl) piperazine; mp. 255-256 ° C.

- (4-methoxyphenyl) -4- / 4- (l-1,2,4triazol-1-yl) phenyl / piperazine; mp 230.3 ° C.

- (4-methoxyphenyl) -4- [4- (3- (methylthio) -1H-1,2,4-triazol-1-yl] phenyl] piperazine; mp 186.5 ° C.

- (4-methoxyphenyl) -4- [4- (5-methyl-3 (methylthio) -1] -1,2,4-triazol-1-yl) phenyl / piperazine; mp 153.3 ° C.

- (4-methoxyphenyl) -4- / 4- (5-methyl-1H-

1,2,4-triazol-1-yl) phenyl] -piperazine; mp 191.1 ° C.

2,4-Dihydro-4- [4- / 4- (4-methoxyphenyl) -

1-piperazinyl (phenyl) -2,5-dimethyl-3H-1,2,4triazol-3-one; mp 196.7 ° C.

1- (4-methoxyphenyl) -4- [4- (5-propyl-N-1,2,4-triazol-1-yl) phenyl] -piperazine; mp 196.3 ° C.

- (4- (5-ethyl-3- (methylthio) -1 -1-1,2,4triazol-1-yl) phenyl) -4- (4-methoxyphenyl) piperazine; so on. 142.3 ° C; and

- (4-methoxyphenyl) -4- / 4- (2-methyl-1H-imidazol-1-yl) phenyl / piperazine; mp 178.5 ° C.

EXAMPLE 17 A mixture of 6 parts of 4- [4- (4-methoxyphenyl) -1-piperazinyl / benzolamine, 3.6 parts of phenylcarbonyl chloride, 75 parts of pyridine and 98 parts of dichloromethane was stirred and heated to dissolve the solids. . Stirring was continued for 30 min at room temperature. The reaction mixture was poured into 500 parts water and 210 parts 2,2'-oxybispropane were added. The mixture was stirred for a short time.

The precipitated product was filtered off and crystallized from 1-butanol to give 5.2 parts (61%) of phenyl / 4- / 4- (4-methoxyphenyl) -1-piperazinyl / phenyl / carbamate; mp 204.5 ° C.

A mixture of 3.2 parts phenyl / 4- / 4- (4-methoxyphenyl) -1-piperazinyl / phenyl / carbamate, 50 parts hydrazine hydrate and 100 parts 1,4-dioxane was stirred and refluxed. for 3 hours. The reaction mixture was cooled and poured into water. The precipitated product was filtered off and crystallized from N, N-dimethylformamide to give 1.7 parts (63%) of N- [4- / 4- (4-methoxyphenyl) 1-piperazinyl / phenyl] hydrazinecarboxamide; mp + 300 ° C.

A mixture of 3.4 parts N- [4- (4- (4-methoxyphenyl) -1-piperazinyl) phenyl] hydrazincarboxamide, 3 parts methanimidamide acetate and 10 parts dimethyl sulfoxide was stirred and heated for 2 hours at a temperature of 100 ° C. 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 (activated carbon) to give 1 part 28% 2,4-dihydro-4- / 4- / 4- (4-methoxyphenyl) -1-piperazinyl / phenyl N-3H-1,2,4triazol-3-one; mp + 300 ° C.

EXAMPLE 18 A mixture of 30 parts of 4- [4- (4-methoxyphenyl) -1-piperazinyl] benzolamine and 300 parts of hydrobromic acid (48%) was stirred and refluxed for 10 days. . The reaction mixture was evaporated and the residue basified with sodium hydroxide. The mixture was filtered and the filtrate was acidified with acetic acid. The precipitated product was filtered off and crystallized from 1,4-dioxane. 12 parts (44%) of 4- [4- (4-aminophenyl) -1-piperazinyl / phenol are obtained.

Repeating the same procedure and using equivalent amounts of the appropriate starting materials yields the following compounds:

4- (4-) 4- (1H-pyrazol-1-yl) phenyl) -1-piperazinyl / phenol;

4- (4-) 4- (1H-imidazol-1-yl) phenyl] -1-piperazinyl / phenol; mp> 260 ° C;

4- [4- / 4- (1-1,2,4-triazol-1-yl) phenyl] -1-piperazinyl] phenol; mp 276.6 ° C;

4- (4- (4- (3- (methylthio) -1H-1,2,4-triazol-1-yl) phenyl) -1-piperazinyl) phenol; mp 225.5 ° C;

4 / 4- / 4- (5-methyl-3- (methylthio) -1H21

1.2.4-triazol-1-yl / phenyl / -1-piperazinyl / phenol; mp 255.8 ° C;

4- (4-) 4- (3-methyl-5- (methylthio) -4H-

1.2.4-triazol-4-yl (phenyl) -1-piperazinyl / phenol;

4- (4- / 4- (5-methyl-1H-1,2,4-triazol-1-yl) phenyl) -1-piperazinyl) phenol; mp 281.1 ° C;

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

2,4-dihydro-4- [4- [4- (4-hydroxyphenyl) 1-piperazinyl] phenyl] -2,5-dimethyl-3H-1,2,4triazol-3-one; mp + 260 ° C;

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

4- (4- (4- (2-methyl-1H-imidazol-1-yl) phenyl) -1-piperazinyl) phenol; mp + 300 ° C;

4- (4- / 4- (5-ethyl-3- (methylthio) -1 Η-1,2,4triazol-1-yl) phenyl) -1-piperazinyl / phenol; mp 222.6 ° C;

2-ethyl-2,4-dihydro-4- [4- (4- (4-hydroxyphenyl) -1-piperazinyl) phenyl] -5-methyl-3H-

1.2.4- triazol-3-one; mp 287.8 ° C;

2.4-Dihydro-4- [4- / 4- (4-hydroxyphenyl) 1-piperazinyl] phenyl] -5-methyl-2-propyl-3H-

1,2,4-triazol-3-one; mp 258.2 ° C;

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

2-ethyl-2,4-dihydro-4- [4- (4- (4-hydroxyphenyl) -1-piperazinyl) phenyl) -3H-1,2,4triazol-3-one; mp 217 ° C; and

4- [4- (4- (5-propyl-1 N-1,2,4-triazol-1 yl) phenyl) -1-piperazinyl] phenol; 225.6 ° C.

B) Preparation of the final compounds

Example 19. To a solution consisting of 3 parts of 4- [4- (4-aminophenyl) -1-piperazinyl / phenol dissolved in 50 parts of dimethyl sulfoxide was added, with stirring, 0.5 parts of a 50% sodium dispersion. hydride. The mixture was stirred at 50 ° C until foam ceased to form. Then, 4.1 parts of cis / -2- (2,4-dichlorophenyl) - are added.

2- (1H-imidazol-2-yl-methyl) -1,3-dioxolan-4-ylmethyl) -methanesulfonate and stirring was continued for 2 h at 70 ° C. The reaction mixture was cooled and poured into water. The product was extracted with dichloromethane. The extract was washed with dilute sodium hydroxide solution, dried, filtered and evaporated. The residue was purified by silica gel column chromatography using a mixture of trichloromethane and methanol 98: 2 v / v as eluent. The pure fractions were collected together and the eluent evaporated. The residue was crystallized from 2-propanol. The product is filtered and dried. 1.3 parts (22%) of cis 4- (4- (4-) 2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolane- 4-yl-methoxy (phenyl) -1-piperazinyl / benzolamine; mp 174.4 ° C.

EXAMPLE 20 To a solution consisting of

3.2 parts of 4- (4- (4-1H-pyrazol-1-yl) phenyl) -

1- piperazinyl / phenol in 100 parts of dimethyl sulfoxide, 0.32 parts of 78% sodium hydride dispersion were added and the whole mixture was stirred at 50 ° C until foam ceased. Then they are added

4.1 parts of cis-2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl-methyl) -1,3-dioxolan-4-yl-methyl-methanesulfonate and stirring was continued for 3 h at 100 ° 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, filtered and evaporated. The residue was purified by column chromatography on silica gel, using a mixture of trichloromethane and methanol 98: 2 - vol. The pure fractions were combined and the eluent was evaporated.

The residue was purified again by silica gel column chromatography, using a mixture of methyl benzene and ethanol 95: 5 - vol. The pure fractions were collected together and the eluent evaporated. The residue was crystallized from ethylbenzene to give 2.2 parts (34%) of cis-1- / 4- / 2- (2,4-dichlorophenyl) -

2- (1H-imidazol-1-yl-methyl) -1,3-dioxolan4-yl-methoxy] -phenyl] -4- [4- (1H-pyrazol-1-yl) phenyl] piperazine; mp Mp 195.1 ° C.

Repeating the same procedure and using equivalent amounts of the appropriate starting materials yields the following compounds:

cis-1- / 4- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy] phenyl-4- / 4- ( 1H-imidazol-1-yl) phenyl / piperazine; mp 166.7 ° C.

cis-1- / 4- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy] phenyl] -4- / 4- (1H-1,2,4-triazol-1-yl) phenyl / piperazine; mp 175.3 ° C.

cis-1- / 4- [2- (2,4-dichlorophenyl) -2- (1H22 imidazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy] -phenyl] -4- / -4- / 3- (methylthio) -1H-1,2,4triazol-1-yl / phenyl / piperazine; mp 178.3 ° C.

cis-1- / 4- / 2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl-methyl) -1,3-dioxolan-4-ylmethoxy / phenyl / -4- / 4- / 3 -methyl-5- (methylthio) 4H-1,2,4-triazol-4-yl / phenyl / piperazine; mp 127.8 ° C.

cis-1- / 4- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy] -phenyl] -4- / 4 - (5-methyl-3- (methylthio) 1H-1,2,4-triazol-1-yl) phenyl / piperazine; mp 188.9 ° C.

cis-1- / 4- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy] 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-yl-methyl) -1,3-dioxolan-4-yl-methoxy (phenyl) -1-piperazinyl (phenyl) -

2,4-dihydro-2,5-dimethyl-3H-1,2,4-triazole-Zone; mp 149.3 ° C.

cis-4- [4- (4-) 4- (2- (2,4-dichlorophenyl) -

2- (1H-imidazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy / phenyl) -1-piperazinyl (phenyl) -

2.4-dihydro-2-propyl-3H-1,2,4-triazol-3-one; mp 185.7 ° C.

cis-1- (4-) 2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy) -phenyl] -4- / 4 - (5-methyl-1 N-1,2,4-triazol-1-yl) -phenyl / piperazine; mp 154.1 ° C.

cis-1- / 4- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy] phenyl] -4- / 4- (2-methyl-1H-imidazol-1 yl) phenyl] -piperazine; mp 180.1 ° C.

cis-4- [4- (4-) 4- (2- (2,4-dichlorophenyl) -

2- (1H-imidazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy (phenyl) -1-piperazinyl (phenyl) -

2,4-dihydro-3H -1,2,4-triazol-3-one; mp 212.8 ° C.

cis-4- / 4- (4-) 4- (2- (2,4-dihydrophenyl) -

2- (1H-imidazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy / phenyl / -1-piperazinyl / phenyl / -2-ethyl-2,4-dihydro-3H-1,2,4 -triazol-3-one; mp 204.7 ° C.

cis-4- [4- (4-) 4- (2- (2,4-dichlorophenyl) -

2- (1H-imidazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy (phenyl) -1-piperazinyl (phenyl) -

2,4-dihydro-5-methyl-2-propyl-3H-1,2,4-triazol-3-one monohydrate; mp 153.9 ° C.

cis-1- (4-) 2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy / phenyl / 4- (4) - / 5-ethyl-3- (methylthio) -1H-

1,2,4-triazol-1-yl / phenyl / piperazine; mp 136.3 ° C.

cis-1- [4- (2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy) phenyl] -4- [4- (5-propyl-1H-1,2,4-triazol-1-yl) -phenyl / piperazine; mp 150.4 ° C; and cis-4- / 4- / 4- / 4- / 2 - (2,4-dichlorophenyl) -

2- (1H-imidazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy (phenyl) -1-piperazinyl) phenyl-2-ethyl-2,4-dihydro-5-methyl-3H-1, 2,4-triazol-3one monohydrate; mp 135.5 ° C.

Example 21 A mixture consisting of 2 parts of sodium azide, 5.8 parts of cis-4- (4- / 4- / 2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl) -1 , 3-dioxolan-4-yl-methoxy / phenyl / -1-piperazinyl / benzolamine, 4 parts 1, 1, 1 "- / methyldinoxy) trisetane and 50 parts acetic acid, stirred and heated overnight at 70 ° C. . The reaction mixture was cooled and neutralized with potassium carbonate solution. The product was extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue was purified by column chromatography on silica gel, using a mixture of trichloromethane and methanol 98: 2vol. The pure fractions were combined and the eluent evaporated. The residue was crystallized from 1-butanol. The product was filtered to give 3.8 parts of 60% cis-1- (4) 2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmutel) -1,3-dioxolane after drying. 4-yl-methoxy (phenyl) -4- (4- (1H-tetrazol-1-yl) -phenyl) piperazine; mp 201.3 ° C.

Example 22 To a solution consisting of 8 parts of 4- [4- (4-aminophenyl) -1-piperazinyl / phenol in 100 parts of dimethyl sulfoxide, 1.5 parts of a 50% dispersion of sodium hydride were added with stirring. stirring is continued until foam ceases to form. 12.3 parts of cis- / are then added

2- (2,4-Dichlorophenyl) -2- (1-1,2,4-triazol-1-yl-methyl) -1,3-dioxolan-4-yl-methyl / methanesulfonate and the whole mixture was stirred and heated for 4 h at 50 ° C. The reaction mixture was cooled and poured into water. The product is extracted three times with dichloromethane. The combined extracts were washed with dilute sodium hydroxide solution and treated with activated carbon. The latter was filtered and the filtrate evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol 98: 2 vol. The pure fractions were collected together and the eluent evaporated. The residue was crystallized from 1-butanol to give 5.1 parts of cis-4- (4- / 4- / 2- (2,4-dichlorophenyl) -2- (1H-

1,2,4-triazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy (phenyl) -1-piperazinyl) -benzolamine; mp 186.8 °.

Example 23. To a solution consisting of 3 parts 4- (4-) 4- (1H-1,2,4-triazol-1-yl) phenyl) -1-piperazinyl / phenol in 100 parts dimethyl sulfoxide was added at stirring 0.3 parts 78% sodium hydride dispersion and the mixture was stirred at 50 ° C until foam formation ceased. Then, 3.7 parts of cis- [2- (2,4-dichlorophenyl) -2- (1-1,2,4-triazol-1-yl-methyl) -1,3-dioxolan-4-yl are added -methyl / methanesulfonate and stirring was continued for 3 h at 100 ° C. The reaction mixture was cooled and poured into water. The product is extracted three times with dichloromethane. The combined extracts were washed with dilute sodium hydroxide solution, dried, filtered and evaporated. The residue was crystallized from 1-butanol. The product is filtered and dried. They are obtained

4.3 parts (75%) of cis-1- / 4- / 2- (2,4-dichlorophenyl) -2- (1-1,2,4-triazol-1-yl-methyl) -1,3 -dioxolan-4-yl-methoxy (phenyl) -4- (4- (1-1,2,4-triazol-1-yl) phenyl) -piperazine; mp 219.6 ° C.

Repeating the same procedure and using equivalent amounts of the appropriate starting materials gave the following compounds: cis-1- / 4- / 2- (2,4-dichlorophenyl) -2- (1 Η-1,2,4 -Triazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy (phenyl) -4- (1H-pyrazole-

1-yl) phenyl / piperazine; mp 183.3 ° C.

cis-1- / 4- / 2- (2,4-dichlorophenyl) -2- (1H-

1.2.4-triazol-1-yl-methyl) -1,3-dioxolan-4-ylmethoxy (phenyl) -4- [4- (1H-imidazol-1-yl) phenyl] piperazine; mp 194.3 ° C.

cis-1- / 4- / 2- (2,4-dichlorophenyl) -2- (1H-

1.2.4-triazol-1-yl-methyl) -1,3-dioxolan-4-ylmethoxy (phenyl) -4- / 4- (5-methyl-1H-1,2,4-triazol-1-yl) phenyl / piperazine; 166.5 ° C.

cis-1- / 4- / 2- (2,4-dichlorophenyl) -2- (1H-

1.2.4-triazol-1-yl-methyl) -1,3-dioxolan-4-ylmethoxy (phenyl) -4- [4- (3- (methylthio) -1] -1,2,4-triazol-1-yl (phenyl) piperazine; mp 153.9 ° C.

cis-1-1- [4- (2- (2,4-dichlorophenyl) -2 (1-1,2,4-triazol-1-yl-methyl) -1,3-dioxolan4-yl-methoxy) phenyl) -4- (4- (5-methyl-3-) (methylthio-1 -1,1,4-triazol-1-yl) phenyl] piperazine; mp 164.1 ° C.

cis-4- [4- (4-) 4- (2- (2,4-dichlorophenyl) -

2- (1-1,2,4-triazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy / phenyl / -1-piperazinyl / phenyl / -3- (methylthio) -4H -1,2,4-triazole; mp 147-152.6 °.

cis-1- / 4- / 2- (2,4-dichlorophenyl) -2- (1H-

1,2,4-triazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy (phenyl) -4- [4- (3-methyl-5- (methylthio) -4H-1,2, 4-triazol-4-yl / phenyl / piperazine; mp 118.3 ° C.

cis-4- [4- (4-) 4- (2- (2,4-dichlorophenyl) -

2- (1H-1,2,4-triazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy (phenyl) -1-piperazinyl (phenyl) -2,4-dihydro-2, 5-dimethyl-3H-1,2,4triazol-3-one monohydrate; mp 161.9 ° C.

cis-4- [4- (4-) 4- (2- (2,4-dichlorophenyl) -

2- (1H-1,2,4-triazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy / phenyl / -1-piperazinyl / phenyl / -2,4-dihydro-2 -propyl-3H-1,2,4-triazole-

3- he; mp 167.3 ° C.

cis-1- / 4- / 2- (2,4-dichlorophenyl) -2- (1H-

1.2.4-triazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy (phenyl) -4- [4- (2-methyl-1H-imidazol-1-yl) phenyl] piperazine; mp 175.6 ° C.

cis-4- [4- (4-) 4- (2- (2,4-dichlorophenyl) -

2- (1-1,2,4-triazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy / phenyl / -1-piperazinyl / phenyl / -2,4-dihydro-2 -methyl-3H-1,2,4-triazol-3-one; mp 193.8 ° C.

cis-4- [4- (4-) 4- (2- (2,4-dichlorophenyl) -

2- (1H-1,2,4-triazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy / phenyl / -1-piperazinyl / phenyl / -2-ethyl-2,4- dihydro-5-methyl-3H-1,2,4triazol-3-one; mp 178.8 ° C.

cis-4- [4- (4-) 4- (2- (2,4-dichlorophenyl) -

2- (1-1,2,4-triazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy / phenyl / -1-piperazinyl / phenyl / -2,4-dihydro-5 -methyl-2-propyl-3H-

1.2.4-triazol-3-one monohydrate; mp Mp 165.5 ° C.

cis-4- [4- (4-) 4- (2- (2,4-dichlorophenyl) -

2- (1-1,2,4-triazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy (phenyl) -1-piperazinyl / phenyl) -2-ethyl-2,4 -dihydro-3H-1,2,4-triazole-Zone; mp 186 C; and cis-1- / 4- / 2- (2,4-dichlorophenyl) -2- (1H-

1.2.4-triazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy (phenyl) -4- [4- (5-propyl-1-1,2,4,4-triazol-1-yl) phenyl / piperazine; mp 140.9 ° C.

EXAMPLE 24 A mixture of 4 parts CIS-4- (4-) 4- (2- (2,4-dichlorophenyl) -2- (1H24)

1,2,4-triazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy / phenyl) -1-piperazinyl / benzolamine, 0.5 parts sodium azide, 1.08 parts 1, 1, 1 '- / methylidinis (oxy) / - trisetane and 50 parts acetic acid, stirred for 5 h at 70 ° C. Another 0.5 parts of sodium azide and 1.08 parts of 1, 1, 1 '- / methylidintris (oxy) / trisetane were added and stirring was continued for another 15 hours at 70 ° C. The reaction mixture was cooled and poured into a mixture of potassium carbonate and water. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography on silica gel, using a mixture of trichloromethane and methanol 98: 2 as eluent. The pure fractions were collected together and the eluent evaporated. The euc residue was crystallized from 1-butanol to give 2.1 parts (48%) of cis-1- / 4- / 2- (2,4dichlorophenyl) -2- (1H-1,2,4-triazol-1 -ylmethyl) -1,3-dioxolan-4-yl-methoxy (phenyl) -4- [4- (1H-tetrazol-1-yl) phenyl] piperazine; mp 192.5 ° C.

Example 25 To a mixture consisting of

5.7 parts of cis-4 / 4- / 4- / 2- (2,4-dichlorophenyl) -

2- (1H-imidazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy / -phenyl / -1-piperazinyl / benzolamine and 100 parts acetic acid are added with stirring 1.5 parts tetrahydro- 2,5-dimethoxyfuran at 50 ° C. The mixture was stirred and refluxed for 5 minutes. The reaction mixture was poured onto crushed ice and the whole mixture was neutralized with 50% sodium hydroxide solution. The product was extracted with dichloromethane. The extract is treated with activated charcoal. The latter was filtered off and the filtrate was evaporated. The residue was crystallized from 1-butanol to give 3.3 parts (52%) of cis-1/4 / -2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl-methyl) -1,3 -dioxolan-4-yl-methoxy (phenyl) -4- [4- (1H-pyrrol-1-yl) -phenyl] -piperazine; mp 188.9'C.

The following compound was similarly prepared: cis-1- / 4- / 2- (2,4dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3- dioxolan-4-yl-methoxy (phenyl) -4- [4- (1H-pyrrol-1-yl) phenyl] piperazine; mp 184,9'C.

Example 26. A mixture consisting of 40 parts of ethanimidamide hydrochloride, 20 parts of cis

N- [4- (4-) 4- [2- (2,4-Dichlorophenyl) -2- (1H-imidazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy] phenyl (-1-piperazinyl / phenyl) -hydrazinecarboxamide, 40 parts of sodium acetate and 90 parts of N, N-dimethylformamide were stirred and heated for 4 hours at 130 ° C. The reaction mixture was cooled and 100 parts of water were added thereto. The precipitated product was filtered off, washed with water and 2 propanol and crystallized from 1-butanol to give 9 parts (44%) of cis- (4- / 4 / 4- / 4- / 2- (2,4- dichlorophenyl) -2- (1H-imidazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy / phenyl / -1-piperazinyl / phenyl / -2,4-dihydro-5methyl-3H-1 2,4-triazol-3-one 2-propanolate 2: 1; mp 295.7 ° C.

Similarly, the compounds cis-4- [4- (4- (4-) 4- (2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl-methyl) -1,3- dioxolan-4-yl-methoxy // phenyl (-1-piperazinyl) phenyl) -5-ethyl-2,4-dihydro-3H-1,2,4-triazole-

3-it; mp 275.6 ° C; and cis-4 / 4- (4- (4-) 4- (2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl-methyl) -

1,3-dioxolan-4-yl-methoxy (phenyl) -1-piperazinyl] -phenyl) -2,4-dihydro-3H-1,2,4-triazol-3-one; mp 255 ° C.

EXAMPLE 27 A mixture consisting of 1.31 parts of 2-bromopropane, 5 parts of cis-4- (4- / 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-triazol-3-one and 100 parts of dimethyl sulfoxide, stirred at 50 ° C, after which 0.4 parts of 50% sodium hydride dispersion were added. The mixture was stirred for 1 h at 50 ° C, then a further 1.31 parts of 2-bromopropane and another 0.4 parts of 50% sodium hydride dispersion were added and stirring continued for another 1 h at 50 ° C. . The reaction mixture was cooled and poured into water. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography on silica gel, using a mixture of trichloromethane and methanol 99: 1 - v / v as eluent. The pure fractions were combined and the eluent evaporated. The residue was crystallized from 4-methyl-2pentanone to give 2 parts (37%) of cis-4- / 4- / 4- / 4- / 2- (2,4-dichlorophenyl) -

2- (1H-imidazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy (phenyl) -1-piperazinyl (phenyl)

2,4-dihydro-2- (1-methylethyl) -3H-1,2,4-triazol-3-one; mp 222.1 ° C.

The following compounds were similarly prepared: cis-2-butyl-4- [4- (4-) 4- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy (phenyl) -1-piperazinyl (phenyl) -2,4-dihydro-3H-1,2,4-triazol-3-one; mp 199.2 ° C; and cis-4- [4- (4-) 4- [2- (2,4-dichlorophenyl) -2 (1H-imidazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy] phenyl (-1-piperazinyl) -phenyl] -5ethyl-2,4-dihydro-2-propyl-3H-1,2,4-triazole-

3-it; mp 170.4 ° C.

Example 28. Repeating the procedure described in Example 19, the following compounds were obtained: trans-3- (4-) 4- (2- (5-bromo-2-thienyl) -2- (1H-imidazole- 1-yl-methyl) -1,3-dioxolon-4-yl-methoxy / phenyl-1-piperazinyl / benzolamine; 4- [4- / 4- / 2- (2-chloro-6-methylphenyl) -2- (1-1,2,4-triazol-1-yl-methyl) -1,3-dioxolan-4- yl-methoxy / phenyl / -1-piperazinyl / benzolamine;

4- (4-) 4- (2- (1H-imidazol-1-yl-methyl) -

2- (4-methoxyphenyl) -1,3-dioxolan-4-yl-methoxy] -phenyl] -1-piperazinyl / benzolamine;

3- (4-) 4- (2- (5-chloro-2-thienyl) -2- (1H-

1.2.4-triazol-1-yl-methyl) -1,3-dioxolan-4-ylmethoxy-phenyl (-1-piperazinyl) benzolamine.

Repeating the procedure described in Example 20, the following compounds were obtained:

cis-1- / 4- [2- (3-ethoxyphenyl) -2- (1H-imidazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy] -phenyl] -4- / 4- ( 3-methyl-1H-pyrrol-1-yl) phenyl] -piperazine;

1- [3- / 2- (1H-imidazol-1-yl-methyl) -2 (2-thienyl) -1,3-dioxolan-4-yl-methoxy] -phenyl] -4- / 3- ( 4-phenyl-1H-pyrrol-1-yl) phenyl / piperazine;

trans-1- / 4- / 2- (4-bromophenyl) -2- (1H-

1,2,4-triazol-1-yl-methyl) -1,3-dioxolan-4-ylmethoxy] -phenyl-4- [4- (1H-pyrrol-1-yl) phenyl] piperazine;

cis-1- / 3- / 2- (4-bromo-2-thienyl) -2- (1H-

1,2,4-triazol-1-yl-methyl) -1,3-dioxolan-4-ylmethoxy] -phenyl] 4- (4- (2,5-diethyl-1H-pyrrol-1-yl) phenyl) piperazine;

4- [3- (4-methyl-1H-pyrazol-1-yl) phenyl] -1 -4- [2- (2-thienyl) -2- (1 H -1,2,4-triazol-1 -ylmethyl) -1,3-dioxolan-4-yl-methoxy / phenyl / piperazine;

trans-1- (4- (2- (5-bromo-2-thienyl) -2- (1H-imidazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy) phenyl) -4- / 4- (2-ethylthio-4-phenyl-1H-imidazol-1-yl-) phenyl / piperazine;

cis-4- / 4- (5-ethyl-2-mercapto-1H-imidazol-1-yl) phenyl) -1- [3- (2-phenyl-2- (1H-

1.2.4-triazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy (phenyl) -piperazine;

- [4- / 2- (4-Bromo-2-ethoxyphenyl) -2 (1H-imidazol-1-yl-methyl) -1,3-dioxolan-4-yl methoxy / phenyl] -4- / 3- (5 -phenyl-1 N-1,2,4 triazol-1-yl) phenyl / piperazine;

trans-1- / 3- / 2- (5-chloro-2-thienyl) -2 (1H-1,2,4-triazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy (phenyl) -4- (2- (3-methylthio5-pentyl-4H-1,2,4-triazol-4-yl) phenyl) piperazine;

4- (4- (4-) 4- (2- (2,6-Diethoxyphenyl) -2 (1H-imidazol-1-yl-methyl) 1,3-dioxolan-4-yl-methoxy) phenyl] -1- piperazinyl / phenyl / -

2.4-dihydro-2-phenylmethyl-3H-1,2,4-triazole-

3-it;

cis-4- [4- (4-) 4- [2- (2-thienyl) -2- (1H-

1.2.4-triazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy (phenyl) -1-piperazinyl (phenyl) -

2,4-Dihydro-2-methyl-5-phenylmethyl-3H-1,2,4triazol-3-one.

Example 30. Repeating the method described in Example 21, the following compounds were obtained:

1- / 4- / 2- (4-fluorophenyl) -2- (1H-imidazol-1-yl-methyl) -1,3-dioxolan-4-yl-methoxy / phenyl) -4- / 4- ( 5-methylthio-1H-tetrazol-1-yl) phenyl / piperazine;

trans-1- / 4- / 2- (5-chloro-2-thienyl) -2 (1-1,2,4-triazol-1-yl-methyl) -1,3-dioxolan-4-yl- methoxy (phenyl) -4- [4- (5-phenylethyl) N-tetrazol-1-yl) phenyl] piperazine.

Claims (22)

Claims A compound selected from azole derivatives of the general formula and pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof, wherein Q - means a representative of a group covering CH and N, Ar - means a representative of a group consisting of phenyl, thienyl, halogenethyl and substituted phenyl, said substituted phenyl residue having from 1 to 3 substituents, which are always independently selected from the group consisting of halogen, C ₁ - C ₄ -alkyl, C ₁ -C ₄ -alkoxy and trifluoromethyl; and the rest Y is a member of the group consisting of 1H-pyrrol-1-yl residue of the general formula in which R'.R ^ R ³ and R ⁴ are selected in each case independently of one another from the group consisting of hydrogen, C ₁ -C ₄ alkyl, aryl and aryl-C 1 -C ₆ alkyl; 1 H-pyrazol-1-yl radical of the formula in which R ^5, R 'and R ⁷ in each case independently of one another are selected from the group consisting of hydrogen, Cj-C ^ alkyl, aryl and aryl-C -C ₄ alkyl; 1 H-imidazol-1-yl radical having general formula wherein R * is selected from the group .sastoyashta of hydrogen, Cj-Cj-alkyl, mercapto, C, C ₆ alkylthio and aryl-C _{(-C 4} - alkylthio and R 'and R ^{10 are} independently selected from the group consisting of hydrogen, C ₁ -C ₄ -alkyl aryl and aryl-C ₁ -C ₄ -alkyl; of 1H-1,2,4-triazol-1-yl residue of the general formula wherein either R ' ¹ or R' ² is selected from the group consisting of hydrogen, hydroxy, mercapto, C 1 -C ₄ -alkylthio and aryl-C 1 -C 6 alkylthio, while the other residue is selected from the group consisting of hydrogen, C ₁ -C ₆ -alkyl and aryl-C ₁ -C ₄ -alkyl; of 4H-1,2,4-triazol-4-yl residue of the general formula in which R 'is selected from the group consisting of hydrogen, mercapto, hydroxy, C 1 -C ₄ alkylthio and aryl-C ₁ -C ₄ - alkylthio and R ¹⁴ is selected from the group consisting of hydrogen, C ₍ -C ₄ alkyl, aryl and aryl-C ₍ -C ₄ -alkyl; 2-dihydro-4H-1,2,4-triazol-4 -or a residue of the general formula wherein R ¹⁵ is selected from the group consisting of C 1 -C ₄ -alkyl and aryl-C ₁ -C ₄ -alkyl and R ¹⁶ is selected from the group consisting of hydrogen, Cj-Cj-alkyl and aryl-C ₁ -C ₄ -alkyl; of 1H-1,2,3,4-tetrazol-1-yl residue of the general formula wherein R ¹⁷ is selected from the group consisting of hydrogen, mercapto, C ₍ -C ₄ -alkyl, aryl and aryl-C ₁ -C ₄ -alkyl, wherein said aryl can be used as in the above definitions, selected from the group consisting of phenyl and substituted phenyl, wherein said substituted phenyl has from 1 to 3 substituents always selected independently of one another from the group consisting of halogen, C _t C ₄ -alkyl, C ₁ -C ₆ -alkoxy and trifluoromethyl. 2. A compound selected from the group consisting of cis-1- (4- (2- (2,4-dichlorophenyl) -2- (1-1,2,4-triazol-1-ylmethyl) -1, 3-dioxolan-4-ylmethoxy-phenyl (-4-) -4H-imidazol-1-yl) -phenyl] piperazine and its pharmaceutically acceptable acid addition salts and stereochemically isomeric forms. 3. A compound selected from the group consisting of cis-1- (4- (2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolane). 4-ylmethoxy-phenyl] -4- [4- (1H-1,2,4triazol-1-yl) -phenyl] -piperazine and its pharmaceutically acceptable acid addition salts and stereochemically isomeric forms. 4. A compound selected from the group consisting of cis-4- (4- (4-) 4- (2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) - 1,3dioxolan-4-ylmethoxy (phenyl) -1-piperazinyl (phenyl) -2,4-dihydro-2,5-dimethyl-3H- 1.2.4- Triazol-3-one and its pharmaceutically acceptable acid addition salts and stereoisomeric isomeric forms. 5. A compound selected from the group consisting of cis-4- / 4- (4-) 4- (2- (2,4-dichlorophenyl) -2- (1) -1,2,4-triazole -1-ylmethyl / - 1.3-dioxolan-4-ylmethoxy (phenyl) -1-piperazinyl-phenyl) -2,4-dihydro-2,5-dimethyl-3H- 1.2.4- Triazol-3-one monohydrate and its pharmaceutically acceptable acid addition salts and stereochemically isomeric forms. 6. A compound selected from the group consisting of cis-1- (4- (2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1 , 3-dioxolan-4-ylmethoxy) -phenyl-4- (4- (1H-tetrazol-1-yl) phenyl) -piperazine and its pharmaceutically acceptable acid addition salts and stereochemically isomeric forms. 7. A compound selected from the group consisting of cis-1- (4- (2- (2,4-dichlorophenyl) -2- (1-1,2,4-triazol-1-ylmethyl) - 1,3dioxolan-4-yl methoxy (phenyl) -4- [4- (3-methylthio) -1,1,2,4-triazol-1-yl] phenyl] piperazine and its pharmaceutically acceptable addition agents acid salts and stereochemical isomeric forms. 8. A compound selected from the group consisting of cis-4- (4-) 4- (4-) 2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazole) -1-ylmethyl / - 1,3-dioxolan-4-ylmethoxy (phenyl) -1-piperazinyl] phenyl] -2-ethyl-2,4-dihydro-5-methyl3H-1,2,4-triazol-3-one and its pharmaceutically acceptable addition agents with acid salts and stereochemical isomeric forms. 9. A compound selected from the group consisting of cis-4 - [- 4- (4-) 4- (2,4-dichlorophenyl) -2- [1] -1,2,4-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 and its acid addition salts and stereochemically isomeric forms. A compound selected from the group consisting of 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-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one and its acids salts and stereochemical isomeric forms. A composition for combating the growth and development of microorganisms selected from the group of fungi and bacteria, comprising an inert carrier material and as an active ingredient an antifungal and antibacterially effective amount of a compound according to any one of claims 1 to 10. A compound of general formula and its pharmaceutically acceptable acid addition salts and stereochemically isomeric forms, in which: Q means a representative of a group consisting of CH and N, Ar represents a group consisting of phenyl, thienyl, halogenethyl and substituted phenyl, wherein said substituted phenyl has from 1 to 3 substituents always independently of one another from the group consisting of halogen, lower alkyl, lower alkyloxy and trifluoromethyl. A composition for combating the growth and development of microorganisms selected from the group of fungi and bacteria, comprising an inert carrier material and as an active ingredient an antifungal and antibacterially effective amount of a compound according to claim 12. A process for the preparation of a compound according to claim 1, characterized in that a / is a compound of formula wherein the reaction is carried out by co-stirring the reaction components in a suitable polar solvent, in admixture with a suitable water-miscible organic mixture solvent; or c) a compound of general formula (III) is reacted with a compound of general formula D - CH ₂ --W in which D is Ah, I-L and W represent a reactive ester residue; in which Y 'is defined as Y above, however, has a meaning other than a residue of the general formulas / c / or / g /, where R' respectively R 'stands for mercapto, and they have a meaning other than a residue of the general formula (d), wherein R ¹¹ or R ¹² or R ¹³ respectively are mercapto or hydroxy; for the preparation of a compound of the general formula (17), the reaction is carried out in a suitable reaction-inert solvent at elevated temperature and, if desired, the substituted phenol (III) is first converted to a metal salt and then this metal salt is reacted with / II /; or b) a compound of the general formula CH ₂ -CH ₂ -halO CH2-CH8-halo (IV) is cyclized with a compound of the general formula N-alkylated with a compound of the general formula (VII), wherein the N-alkylation is accomplished by co-stirring the reaction substances in the presence of 20 suitable bases; or d) a compound of the general formula (VIII) in which A represents an amino group or 3θ a suitable derivative thereof is cyclized with a corresponding cyclizing agent, and optionally introducing substituents into the heterocyclic compound thus obtained, wherein the species of A in formula / VIII), how and the type of cyclization agent used in the cyclization step depends on the importance of Y in the desired compound (I), wherein r-1 (compounds of formula (14) ⁱⁿ which Y denotes the residue (a), where R ', R ² , R ³ 4θ and R ⁴ have the meaning indicated above, are c are separated from the corresponding amine of general formula (VIII-a) by cyclizing the latter with a compound of the general forum 50 about 0 m.p.-CH-CH-C-R _{/ 1x} . _{a /} I | R 'R * or with a compound of general formula to form a compound of general formula (I-a) wherein the reaction of (VIII-a) with (IX-a) is effected by co-stirring and refluxing the components in the corresponding a solvent in the presence of a suitable base; r-N (compounds of formula (I) in which Y represents the residue (b) where R ⁵ , R ⁶ and R ⁷ have the above meanings are obtained from the corresponding hydrazine of the general formula ___ __ NH-NH ₂ (VIII-b) by cyclizing the latter with the corresponding dione of the general formula IIII R * -C-CH-C-R * / X / R 'to form a compound of the general formula (1-b) wherein the reaction of (VIII-b) with (X) is carried out in the same manner as the preparation of (I-a) from (VIII-a) and (IX) -a), and in case R ⁵ represents hydrogen, the adjacent carbonyl group, preferably before reacting with said compound (X), is acetalized with a compound of formula (VIII-b) to form a pyrazole derivative, at which R ⁶ is unambiguously in the 5th position; d-III (compounds of formula (I) in which Y represents the residue (c), where R 'and R ¹⁰ have the above meanings and R' represents a mercapto group, are obtained by cyclization of the corresponding isothiocyanate of general formula (VIIFc) / with a compound of the general formula R 10 is obtained to provide a compound of the general formula (1-c-1) wherein the reaction of (VIIIc) with (XI) is effected by co-stirring the reaction components in a suitable organic solvent in the presence of a corresponding base, such as the compounds of general formula (I) in which Y represents the residue (c) in which R 'and R ¹⁰ have the above meanings and R * represents hydrogen, are obtained by desulfurizing the compound of general formula (1-C-1) (to form a compound of general formula (I-c-2) wherein the compounds of general formula (I) , in which Y represents a residue (c), wherein R 'and R ¹⁰ are as defined above and R 3 represents C 1 -C 6 alkylthio or aryl-C 1 -C 6 alkylthio, are obtained by the usual S-alkylation of the corresponding compounds with a common formula (1-c-1) with a suitable reactive ester of the general formula 5 e-1 (the compounds of the general formula (1-d1) are prepared alternatively by first (VIII-d-1) acylating with the corresponding general formula anhydride R 1 -W (XII), (R _{1 I} ² CO / _J 0 (XIII-b) or with an alkanoyl halide having R 4 denotes C ₁ -C 6 -alkyl or a 1 S aryl-C ₁ -C, - alkyl and in which W is as defined above 10 in the formation of a compound of the general formula mule / XIII-c / formula in the formation of a compound of the general x II N-NH-C-NH, (1-c-3), and optionally the compounds of formula 20 (1-c-3) are desulfurized to form the compounds of general formula (1-c-2), or e (compounds of formula (I) in which Y represents the residue (d), wherein R ¹¹ is X, wherein X is oxygen or sulfur, and 25 where R ¹² is hydrogen, C 1 -C 6 -alkyl or aryl-C 1-4 -C 1-6 alkyl, the residue of which R ¹² is derived from Ra ¹² , is prepared by cyclizing a compound of the general formula (VIII-d-1) with a compound of the general formula II R ', - C-ΌΗ (XIII), or with a functional derivative thereof, wherein the product obtained is a compound having the general formula mulla (Id-1), which reaction is conveniently effected by co-stirring and heating. of the reaction components in a suitable organic solvent; or (XIV) and thereafter cyclized by stirring and heating in an alcoholic alkaline medium; or e-N (compounds of formula (N-d-1)) are prepared by reacting hydrazine hydrochloride with the general formula (VIII-b) with a compound of the general formula II X = C = N-C13 / XIII-d / in Ν, Ν-diethylethanamine medium, washing the reaction mixture with water, removing the solvent by evaporation and subsequent stirring and heating the residue in a mixture of dichloromethane and ethanol in the presence of an alkaline agent; or e-III (compounds of formula (I) in which Y represents the residue (d), where R ¹² is in the form of R _a ¹² and where R ¹¹ means hydrogen, are obtained by desulfurizing a corresponding compound of formula (Ι) -dl /, in which XH stands for SH, which compounds can be represented by the following general form- (ld-1-a), in the same manner as for desulfurization of (1-c-1) for the preparation of (1-c-2), wherein the product is a compound of formula (Id-2) or e-1U (compounds of formula (I), wherein Y represents the residue (d) in which R ¹² is in the form of R _a ¹² and R ¹¹ in which KIC ates C, -C ₆ alkylthio or aryl-C ^ C ^ alkylthio, are obtained by S-alkylation of a compound of formula / Id-1-a / a reactive ester of the general formula R _t ^{H is} -W (XV-a) in which W has the above meaning and in which R ¹¹ is C ₁ -C ₆ -alkyl or aryl-C ₁ -C ₆ -alkyl, following the same procedure as in the preparation (I-c-3) of (1-c-1) and (XII), wherein the product is a compound of the general formula (1d-3), and if desired after carrying out the same desulfurization process as described above. above, the compounds of the formula (Id-3) are converted to the compounds of the formula (Id-2 / J or e-V) of the compounds of the formula (I), in which Y represents the residue (d) in which R ¹² denotes X, wherein X is oxygen or sulfur and in which R ¹¹ is Ava hydrogen, C, -C ₆ -alkyl or aryl-C ₁ -C ₆ -alkyl, in which the R moiety is illustrated by the symbol R ^ ¹ can be prepared by cyclising a compound of formula ^x chs / ^H 2 I N-NH2 (VIII-d-2) with a compound of general formula or a functional derivative thereof to form a compound of general formula (Id-4), or e-VI (compounds of general formula (I), in which Y represents the residue / d wherein R ¹² is hydrogen and in which R has the meaning of R ¹ , are obtained by desulfurizing a compound of general formula (Id-4-a) to form a compound of general formula (1d-5), or e -VII / eat of formula (I) wherein Y represents the residue (d) in which R ¹² is C 1 -C 1 -alkylthio or aryl-C 1 -C 4 -alkylthio and in which R has the meaning of R ¹ , are obtained by S-alkylation of a compound of general formula (Id-4-a) with a reactive ester of general formula K _b ^{, d is} - W / XV-b / in which W has the above meanings, and in which I ¹² is C 1 -C ₆ -alkyl or aryl-C ₍ -C ₆ -alkyl), the method previously described for the preparation of (I-c-3) from (1-C-1) and (XII), wherein the product has the general formula for the acidification of a compound of the general formula (Id-6) and wherein as described in The above method of desulfonation of the compounds of formula (Id-b) on their part can be converted to the compounds of formula (I-d5); or is (compounds of formula) (I) in which Y represents a residue of the formula (e) , wherein R ¹⁴ is as defined above and where R ¹³ is mercapto or hydroxy, which residue R ¹³ is represented by XH, where X is oxygen or sulfur, are obtained by cyclizing a compound of the general formula x II ___ NH-C-NH-NHj (XIII), with a compound of the general formula NH rJ-nh, (XW) or an acid addition salt thereof, wherein the product is a compound of the general formula xn (1-e-1), or e-1 (compounds of formula (I), wherein Y represents the residue) is /, in which R ¹⁴ has the above meanings, and where R ¹³ denotes C 1 -C 6 alkylthio or aryl-C 1-6 alkylthio, which residue R ¹³ is represented by the symbol SRJ ³ , where R ¹³ represents C C ₁ -C ₄ alkyl or aryl-C ₁ -C ₄ -alkyl are prepared by S-al- (Ie-1-a) with a compound of the general formula R, ³ W (XVII) wherein the product is of the general formula (1-is-3), and optionally, compounds of the formula (I) in which Y represents the residue (e) in which R ¹⁴ is defined as above, and R ¹³ represents hydrogen, may be obtained by desulfurization of a corresponding compound of general formula (Ie-1-a) or of a compound of general formula (I-e-3), using standard desulfonation reactions , as described above, the product obtained is a compound of general formula (1-e-2), or g (compounds of general formula (I), in which Y represents the residue (f) in which R ¹⁵ and R ¹⁶ possess the above-d D values are obtained by N-alkylation of the corresponding compound of formula one / Ie-1-b / a corresponding ester of general formula R ^{, 5} W (XVIII), wherein W and R ¹⁵ have the meanings described above, wherein the product is a compound of the general formula _R 16 (If), or 3 (compounds of the formula (I), in which Y is a residue (g) in which R ¹ 'has the meanings described above, has no meaning other than mercapto, and in which R' is represented by the symbol RJ ⁷ , are obtained by cyclizing a compound of formula (VIII-a) with azide and a compound of the general formula RJ ⁷ -C (O-) lower alkyl // ₃ (XIX) in a corresponding acidic medium, wherein the product obtained is a compound of general formula (Ig-1), or 3-I (compounds of formula (I), in which Y means the residue (g) in which R ¹⁷ represents mercapto is obtained by cyclization of an isothiocyanate of formula (VIII-c) with the corresponding azide in a suitable organic solvent in the presence of an alkaline agent, wherein the product is a compound of the general formula N - N (Ig-2), wherein the cyclization reaction can also be accomplished by stirring a compound of formula (VIII-c) with azide in the presence of the corresponding quaternary ammonium salt; or 3-II (compounds of formula (Ig) wherein R ¹⁷ is hydrogen are prepared by desulfurizing a compound of general formula (Ig-2), wherein the product is a compound of general formula (Ig-3), and at optionally, pharmaceutically acceptable acid addition salts of the products of the preceding steps are obtained and stoichiometric isomeric forms of the compound of general formula (I) are also obtained if desired. 15. A process for the preparation of a compound selected from the group consisting of cis-1- (4-) 2- (2,4-dichlorophenyl) -2- (1H-). 1,2,4-triazol-1-ylmethyl (-1,3-dioxolan-4-ylmethoxy) -phenyl] -4- (4- (1H-imidazol-1-yl) phenyl) -piperazine and its pharmaceutically acceptable acid addition salts and stereochemically isomeric forms, characterized in that they interact 4- (4-) 4- (1H-imidazol-1-yl) -phenyl (-1-piperazinyl) -phenol with cis- (2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazole- 1-ylmethyl / -1,3-dioxolane- 4-ylmethyl-methanesulfonate. 16. A process for the preparation of a compound selected from the group consisting of cis-1- (4- (2-) 2,4-dichlorophenyl) -2- (1H-imidazol-1- (ylmethyl) -1,3-dioxolane -4-ylmethoxy (phenyl) -4- (4- (1) -1,2,4-triazol-1-yl) phenyl] piperazine and its pharmaceutically acceptable acid addition salts and stereochemically isomeric forms, characterized by by interacting 4- / 4- / 4- (1H-1,2,4-triazol-1-yl) -phenyl] -1-piperazinyl] phenol with cis- (2-) 2,4-dichlorophenyl) -2 / 1H-imidazol-1 - ylmethyl (-1,3-dioxolan-4ylmethyl) -methanesulfonate. 17. A process for the preparation of a compound selected from the group consisting of cis-4- (4- (4-) 4- (2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) - 1,3-dioxolan-4-ylmethoxy (phenyl) -1-piperazinyl] phenyl] -2,4-dihydro-1,5-dimethyl-3H-1,2,4-triazol-3-one and its pharmaceutically acceptable addition agents with acid salts and stereochemical isomeric forms, characterized by reacting 2,4-dihydro-4- (4- (4- (4-hydroxyphenyl) -1-piperazinyl) -phenyl) -2,5-dimethyl-3H -1,2,4-triazol-3-one with cis- (2- (2,4dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) 34 1,3-dioxolan-4-ylmethyl] -methanesulfonate. 18. A process for the preparation of a compound selected from the group consisting of cis-4- (4- (4) -4- (2- (2,4-dichlorophenyl) -2- (1H-) 1,2,4-triazol-1-ylmethyl] -1,3-dioxolan-4-yl-5 methoxy (phenyl) -1-piperazinyl] phenyl] -2,4-dihydro-2,5-dimethyl-3H- 1,2,4-tyrazol-3-one and its pharmaceutically acceptable acid addition salts and stereochemically isomeric forms, characterized in that 10 is reacted with 2,4-dihydro-4- / 4- / 4- / 4-hydroxyphenyl (-1-piperazinyl) -phenyl] -2,5-dimethyl-3H-1,2,4-triazol-3-one with cis / 2- (2,4dichlorophenyl) -2- (1H-1,2,4) -Triazol-1-ylmethyl (-1,3-dioxolan-4-ylmethyl) -methane-15 sulfonate. 19. A process for the preparation of a compound of formula cis- [4- (2- (2,4-dichlorophenyl) -2- [1,1-1,2,4-triazol-1-ylmethyl] -1,3-dioxolane- 4ylmethoxy) -phenyl] -4- (4- (5-methyl-1H-1,2,4-20 triazol-1-yl) -phenyl) -piperazine, characterized in that they react 4- (4-) 4- (5-methyl-1 N-1,2,4-triazol-1-yl) -phenyl (-1-piperazinyl) -phenol- with cis- (2- (2,4-dichlorophenyl) -2-) 1-1,2,4-triazol-1-ylmethyl) -1,3-di-25 oxolan-4-ylmethyl) methanesulfonate. 20. A process for the preparation of a compound according to claim 12, wherein the compound of formula (II) is reacted with CH (II) in which D represents and W represents a reactive ester residue with a compound of the general formula in a corresponding reaction-inert solvent at elevated temperatures or, if desired, by the preliminary conversion of the substituted phenol to a metal salt thereof and subsequent application of this metal salt for interaction with (II). A compound according to any one of claims 1 to 10 or 12, or a composition according to claim 11 or 13 for use in combating the growth and development of a fungus or bacterium. A method for preparing a pharmaceutical composition comprising mixing an effective amount of a compound according to any one of claims 1 to 10 or 12 with an inert carrier.