DK160428B - Analogy process for preparing (4-phenylpiperazin-1- ylaryloxymethyl-1,3-dioxolan-2-yl)methyl-1H-imidazole or 1H-1,2,4-triazole derivatives, pharmaceutically acceptable acid addition salts and/or stereochemically isomeric forms thereof - Google Patents

Description

DK 160428 B

in U.S. Patent No. 3,936,470 and Belgian Pat.

No. 837,831 discloses a number of 1- (4-aryloxymethyl-1,3-dioxolan-2-ylmethyl) -1H-imidazoles and 1H-1,2,4-triazoles with antifungal and anti-bacterial properties. The compounds of the invention differ substantially from the foregoing in the substitution of the aryloxy group with a 4-phenylpiperazinyl group, wherein the phenyl group is further substituted by a heterocyclic radical attached to the phenyl group by a carbon-nitrogen bond and distinguished by having better antifungal properties than the compounds thus known by virtue of their increased activity against Candida albicans.

The present invention relates to an analogue and process for the preparation of novel (4-phenylpiperazin-1-yl-aryloxymethyl-1,3-dioxolan-2-yl) -methyl-1H-imidazole or 1H-1,2, 4-triazole derivatives of the form

15 - N

or pharmaceutically acceptable acid addition salts and / or stereochemically isomeric forms thereof, wherein Q represents CH or N, Ar represents phenyl, thienyl, monohalogen thienyl or phenyl substituted with from 1 to 3 substituents, which are individually selected from halogen, C1-C8 alkyl,

Cj-Cg alkyloxy and trifluoromethyl, and radical Y is a 1H-pyrrol-1-yl radical of the formula 30 R 1 R 3 -nH (*) RR 35 wherein R 1, R 2, R 3 and R 4 each represent hydrogen, C alkyl, Ar 1 or Ar 1 C 1 -C 6 alkyl, wherein Ar 1 represents phenyl or phenyl substituted with from 1 to 3 substituents, each of which is selected from

2 DK 160428 B

halogen, C1-C8 alkyl, C1-C8 alkoxy and trifluoromethyl, a 1H-pyrazol-1-yl radical of the formula 5 / N2 · 5, b)

-N (W.

7B® B7 wherein R5, R6 and R7 each represent hydrogen, C 1 -C 6 alkyl, Ar 1 or 10 Ter Ar 1 -C 2 -C 8 alkyl, Ar * having the previously defined meaning, 1 H-imidazole -l-yl radical of formula B.8 Q - 4 ^ 10 · B / B.

Wherein R represents hydrogen, C 1 -C 6 alkyl, C 1 -C 8 alkylthio or Ar-C 2 -C 8 alkyl thio, and R 1 and R 2 are each independently selected from hydrogen, C 1 -C 11. 20 alkyl, Ar and Ar-C 2 -C 6 alkyl, Ar having the previously defined meaning, a 1H-1,2,4-triazol-1-yl radical of the formula y1, -N (i)

25> = N

Wherein one of the groups R and R represents hydrogen, C 1 -C 6 alkylthio or Ar * -C 2 -C 8 alkylthio, and the other group represents hydrogen, C 1 -C 6 alkyl or Ar * -C 2 -C 6 alkyl, where Ar * has the previously defined meaning, a 4H-1,2,4-triazol-4-yl radical of the formula

S = N

B.14

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Wherein R represents hydrogen, mercapto, hydroxy, -Cg allkyl thio or Ar * -Cj-Cg allkyl thio, and R * represents hydrogen, Cj-Cg alkyl, Ar * or Ar * -Cj-Cg alkyl wherein Ar * has the meaning previously defined, a 2,3-dihydro-4H-1,2,4-triazol-4-yl radical of formula 5 O. 15 - R 16 wherein R * 5 represents Cj-Cg alkyl or Ar *-Cj-Cg alkyl, and R * 6 represents hydrogen, Cj-Cg alkyl or Ar *-Cj-Cg alkyl, Ar Ar having the previously defined meaning, a 1H-1,2. 3,4-tetrazol-1-yl radical of formula * 5 -NI (g)

\ =. N

R1 represents 17, wherein R represents hydrogen, -Cg all-alkyl, Ar or Ar -Cj-Cg-all-alkyl, with Ar * having the meaning previously defined.

The method is peculiar to the characterizing part of claim 1.

13

It is understood that radicals of formula (e) wherein R stands for mercapto or hydroxy may also exist in their tautomers or thioxo and oxoforms, respectively. Of course, such thioxo and oxoforms are believed to be included in formula (I), although not explicitly stated in the above structures.

The preferred compounds of the invention are compounds wherein the 4-phenylpiperazinyl function is linked to the phenoxymethyl group at the para position.

As the term "halogen" is used in the foregoing and in the following definitions, it is generic for fluorine, chlorine, bromine, and iodine, and by "C carbon atoms such as e.g. methyl, ethyl, 1-methyl ethyl, 1,1-dimethyl ethyl, propyl, 1-methyl propyl, 2-methyl propyl, butyl, pentyl, hexyl and the like.

In order to simplify the structural illustration of the compounds (I) and of certain starting materials and intermediates used in

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In the preparation thereof, the 2-Ar-2- (1H-imidazol-1-ylmethyl or 1H-1,2,4-triazol-1-yl-methyl) -1,3-dioxolan-4-yl group wherein Ar has the previously defined meaning, then illustrated by the symbol D: 5

CH Ar = D

L_U

Q = CH or N

The compounds of formula (I) wherein Y has the previously defined meaning but are different from a radical of formula (e) wherein 13 R represents mercapto or hydroxy, which Y is illustrated by Y *, and 15 which are illustrated by formula ( Γ) can be prepared by O-alkylation of a suitable phenol of formula (III) with a reactive ester of formula (II).

D-CH 2 -W + - O-alkylation (II) (ΠΙ) 25.-v ___ Y, d-ch 2 -O- ^ Λ W \ 1 / (1 ') In the formula (II), W means reactive ester residues such as e.g. halogen, preferably chlorine, bromine or iodine, or a sulfonyloxy group such as e.g. methyl sulfonyloxy or 4-methyl phenyl sulfonyloxy and the like.

The reaction of (II) with (III) is carried out under conditions known to those skilled in the art for carrying out O-alkylations with reactive esters. The reaction is usually carried out in a suitable reaction-inert organic solvent, such as, for example. Ν, Ν-dimethylformamide, N, N-dimethylacetate

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5 amide, hexamethylphosphoric triamide, dimethyl sulfoxide, 4-methyl-2-pentanone and the like, optionally in admixture with other reaction-inert solvents such as e.g. aromatic hydrocarbons, e.g. benzene, methylbenzene, dimethyl benzene and the like. In addition, it is advantageous for the reaction mixture to set an appropriate base such as e.g. an alkali metal hydride or carbonate, to increase the reaction rate. Alternatively, it may be advantageous to first convert the substituted phenol (III) to a metal salt thereof, preferably the sodium salt, in the usual manner, e.g. by reacting (III) with metal bases such as sodium hydride, sodium hydroxide and the like, and then using the metal salt in the reaction with (II). Slightly elevated temperatures are appropriate to increase the reaction rate, and the reaction is particularly preferably carried out at from ca. 80 ° C to approx. 130 ° C.

Yet another method for preparing compounds of formula (I) is by cyclizing an appropriate intermediate of formula (VIII), wherein A represents an amino group or derivative thereof, with a suitable cyclization agent by following methods known to those skilled in the art or by introduce substituents into the resulting heterocyclic compounds.

Ρ, Η2, θθϋ cyclization ^ (introduction of substituents) (VIII) Both the nature of A in the formula (VIII) and the nature of the cyclization agent used in the cyclization step depend on the significance of Y in the desired compounds (I) as will be explained in more detail later.

The compounds of formula (I) wherein Y represents radical (a), wherein R 1, R 2, R 3 and R 4 have the previously defined meaning, which compounds are illustrated by formula (I a), can be obtained from a suitable amine of formula (I). VIII-a) by cyclizing the latter with a tetrahydro-2,5-di (lower al kyloxy) furan of formula (IX-b).

35

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6 p.cH2-o ^ y (Ήζ (VIII-a) 5R-Ο-Alkyl r3 ^ <4V -> R Js O-alkyl

10 K

(iX-b) R1 R3 is d-ch2-ooo; k4 (i-a) The reaction of (VIII-a) with (IX-b) is preferably carried out in a polar solvent, e.g. acetic acid and the like.

The compounds of formula (VIII-a) used as intermediates herein exhibit strong antifungal and antibacterial properties.

The compounds of formula (I) wherein Y represents a radical of formula (e) wherein R 14 has the previously defined meaning and wherein 19 13 R stands for mercapto or hydroxy, which R is illustrated by XH wherein X represents 0 or S, and which compounds are illustrated by formula (Ie-1), can be obtained from an intermediate of formula (VIII-e) by cyclizing the latter with a suitable imidamide of formula (XVI) or an acid addition salt thereof.

X

D-ch2-o- ^ j ^ \ _ + R14-c-nh2 -> (VIII-e) (XVI) DK 160428 3 7

XH

) = N

5 \ = n d.cVo.ØW \ J7 (I-e-I) 10

The ring closure may be carried out in accordance with methods well known to those skilled in the art, e.g. by mixing and reacting the reactants, if desired, in the presence of a suitable reaction-inert organic solvent with a relatively high boiling point, such as e.g. 1,1'-oxybis- (2- methoxyethane).

The compounds of formula (I) wherein Y represents a radical 16 (f) wherein R and R have the previously defined meaning, which compounds are illustrated by formula (If), can be obtained from a suitable compound of formula (Ie-1) ), wherein R13 represents OH, (IIb), by 20 N-alkylation of the latter with a suitable reactive ester of formula (XVIII), wherein W and R15 have the meanings previously defined.

25 / "\ / '♦ * 15-W _,

> N

p 16 (XVIII) (I-e-l-b) Ά 30

ISLAND

f. Λ J \ JT \ Vn-R15

d-ch2-o- ^ \ _JI

(I-f) 35 ^ DK 160428 B: i 8 5

This N-alkylation may be carried out in the usual manner, e.g. by stirring the reactants together and heating in a suitable organic solvent such as e.g. dimethyl sulfoxide and the like, in the presence of | a suitable base, "such as e.g. an alkali metal hydride or carbonate. The compounds of formula (I) wherein Y represents radical (g) may be obtained generally from an intermediate of formula (VIII-a) by cyclizing the latter with an azide, preferably an alkali metal azide, e.g. sodium azide, and a suitable Ι, Γ, Γ 'tri (lower all kyloxy) -al may be of formula (XIX) in a suitable acidic medium, e.g. acetic acid, preferably under heating.

(VIII-a) + N '+ R17 -C / p- (c, -Cg alkyljTj _ ^ J (XIX)

20 ._, / N «N

K17a 25 (I-g-1)

The imidazole and triazole derivatives of formula (I) obtained in base form in the foregoing preparations may be converted to their therapeutically useful acid addition salts by reaction with a suitable acid such as an inorganic acid such as hydrohalic and acetic acid, i.e. hydrochloric, hydrobromic or iodobaric, sulfuric, nitric or thiocyanic, a phosphoric acid, an organic acid such as acetic acid, propanoic acid, hydroxyacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, ethaneic carboxylic acid, 1,4-carboxylic acid, propane carboxylic acid acid, (Z) -2-butenedicarboxylic acid, (E) -2-butenedicarboxylic acid, 2-hydroxy-1,4-butanedicarboxylic acid, 2,3-dihydroxy-1,4-butane carboxylic acid, 2-hydroxy -1,2,3-propanetricarboxylic acid, benzoic acid, 3-phenyl-2-propenoic acid, α-hydroxybenzeneacetic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, 4-methyl

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9 benzenesulfonic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid, 2-phenoxybenzoic acid or 2-acetyloxybenzoic acid. The salts can again be converted to the corresponding free bases in the usual manner, e.g. by reaction with alkali, such as sodium or potassium hydroxide.

Some of the intermediates and starting materials used in the foregoing preparations are known compounds, others may be prepared in accordance with methods known in the art for preparing similar compounds, and some of them are novel and their preparation is described hereinafter.

The intermediates of formula (III), wherein Y 'has the previously defined meaning, can generally be prepared from the corresponding methoxy-substituted compounds of formula (XX) by converting the methoxy group of the latter into a hydroxy group by acid hydrolysis using a strong non-oxidizing mineral acid such as e.g.

15 hydrobromic acid in glacial acetic acid.

__, __ Y '

JT-Sf N

CH3-0- ^ J N - f (HI) 20 (XX)

The intermediates of formula (XX) used as starting materials herein can be obtained by cyclizing an N, N-bis (2-haloethyl) -4-methoxybenzenamine of formula (XXI) with a suitable benzenamine of formula (XXII) wherein Y 'has the meaning previously defined.

CH3-o / ^ rCIVCIVhal0 ♦ νη2 / ^ Τ (XX) 3 \ - / vCH, -CH, -halo 2 X = J ► 30 2 2 (XXII) (XXI)

The reaction is carried out by stirring the reactants together in the presence of a suitable polar solvent, e.g. water, in admixture with a suitable water-miscible organic solvent, such as e.g. 2-propanol, 2-propanone and the like, preferably at elevated temperature, to increase the reaction rate, and especially preferably in the presence of a suitable alkali metal or alkaline earth metal iodide such as

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10 e.g. kalium'odid.

The preparation of the compounds of formula (XXI) is described in J.

Chem. Soc., 1949, 183-191.

The intermediates of formula (XX) may alternatively be prepared by cyclizing an appropriate intermediate of formula (XXIII), wherein A represents an amine group or a derivative thereof, with an appropriate cyclization agent and, if desired, introducing appropriate substituents into the heterocyclic compounds thus obtained. by following the previously described methods of preparing the compounds (I) from 10 (VIII).

GH3-0 ^ NN - / {^ Cycle _ (χχ) (introduction of substituents) 15 (ΧΧΙΠ)

The intermediates of formula (XXIII) wherein A represents an amino group (XXIII-a) can be prepared by N-alkylation of a compound of formula (XXIV) with a suitable chloro-nitrobenzene (XXV) by follow 20 standard procedures for N-alkylation followed by reduction of the thus obtained nitro compounds (XXVI), e.g. by catalytic hydrogenation in a relatively polar solvent such as e.g. methanol, in the presence of a suitable catalyst, e.g. palladium-on-charcoal.

N02 NH + Cl2 X .N-alkylation 30 ch3-O ^^ W \ LJ -> (xxrv) (xxv) 35

11 DK 160428 B

NO / 2 5 / \ rt cvo ^ w "<2> -—► (XXVI) 10 nh2 15 ch3-o - / ^ T ^ —f \ == / (XXIII-a) 20

The intermediates of formula (XXIII) wherein A represents an isothiocyanate group (XXIII-b) can be obtained from a suitable compound of formula (XXIII-a) by treating the latter with carbon disulfide in the presence of dicyclohexylcarbodiimide, preferably in the presence of an appropriate organic solvent such as, for example, pyridine.

(XXIII-a) + CS2 f ^ 30 εΗ3 · ° βΌ0Μ53 35 (XXIII-b)

The intermediates of formula (XXIII) wherein A represents a hydrazine carbothiamide group (XXIII-c-1) can be obtained from a compound of

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12 the formula (XXIII-b) by stirring and heating the latter with hydrazine hydrate in the presence of a suitable solvent such as e.g.

1,4-dioxane and the like.

S

| In

nh-c-nh-nk2 (xxm-b) + NH2-NH2 -; - η3ο ^ Λ.ν_ (xxm-c-i)

The intermediates of formula (XXIII) wherein A represents a hydrazinecarbonamide group (XIII-c-2) can be obtained from a compound of formula (XXIII-a) by stirring and heating the latter with phenylcarbon halide in a suitable solvent , eg. dichloromethane, in the presence of a suitable base such as e.g. pyridine and the like, followed by reaction of the thus obtained (XXIII-d) with hydrazine hydrate in the presence of a suitable solvent, e.g. 1,4-dioxane and the like.

ISLAND

(ΧΧΙΠ - a) f halo- C

ISLAND

(xxm - d) -.- O- <X2r (ΧΧΙΠ - c - 2)

The starting materials of formula (XXII) can generally be prepared by reducing a corresponding nitro compound of formula 35 (XXVIII-a), e.g. by catalytic hydrogenation in a relatively polar solvent such as e.g. an alkanol in the presence of a suitable catalyst, e.g. platinum-on-charcoal.

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13 NOaØ? ' - '5 (XXV m-a) (ΧΧΠ)

The starting materials of formula (XXVIII-a) may be prepared by starting from suitable precursors by following the methods known to those skilled in the art as previously described herein for the preparation of compounds of formula (I) from (VIII) and a suitable cyclization agent.

Starting materials of formula (II) wherein Q stands for CH and processes for their preparation are described in Belgian Patent Specification No. 837,831. In general, the reactive esters of formula (II) can be prepared according to the following reaction sequence.

A suitable 1-Ar-2-bromethanone of formula (XXX) is subjected to ket-1 in serous reaction with 1,2,3-propanetriol following methodologies analogous to those described in Synthesis, 1974, (I), 23.

In a preferred way of carrying out the reaction, both reactants are refluxed for several hours with azeotropic water removal in a suitable organic solvent, preferably in the presence of a simple alcohol such as e.g. ethanol, propanol, butanol, pentanol and the like, and in the presence of a suitably strong acid such as 4-methylbenzenesulfonic acid. Suitable organic solvents are e.g. aromatic hydrocarbons such as benzene, methylbenzene, dimethyl benzene and the like, and 25 saturated hydrocarbons such as cyclohexane.

The dioxalane (XXXI) thus obtained is then reacted with benzoyl chloride to give a benzoate of formula (XXXII), and the latter is then reacted with 1H-imidazole or 1H-1,2,4-triazole. This reaction is preferably carried out by stirring the reactants together and heating in a suitable organic solvent, e.g. N, N-dimethyl formamide, in the presence of a suitably strong metal base, e.g., sodium methanolate, to give an intermediate of formula (XXXIII). The desired reactive esters of formula (II) are then conveniently prepared by first hydrolyzing in alkaline medium and then converting the hydroxy group of the thus obtained (XXXIV) to a reactive ester thereof in accordance with generally known methodologies in the art. Eg. methanesulfonates and 4-methylbenzenesulfonates are conveniently prepared by reacting the alcohol with methanesulfonyl chloride or 4-methylbenzenesulfonyl chloride,

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14 and halides can be prepared by reacting the alcohol with a suitable halogenating agent such as e.g. thionyl chloride, phosphorus pentachloride, phosphorus pentabromide, phosphoryl chloride and the like. When the reactive ester is an iodide, it is preferably prepared from the corresponding chloride or bromide by replacing the halogen in question with iodine.

The preceding turnovers can be illustrated as follows:

O OH

Br-CH2-C-Ar + HO-CH2-CH-CH2-OH -> (XXX)

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15

Br-CH Ar Br-CH_ Ar oK VS ™ I_L --i_i

CH_ OH

CH-ό 2 (XXXI) (ΧΧΧΠ) 1E-imidazole or 1H-1,2,4-triazole

- in D

NaOCH / DMF |

C> T

M? CH-O-C-C.H ^ 2 0 3 (xxxm) oh * Γ ^ ► CH2 Ar

CO

I_I

SCH-, -OH

(XXXIV) Formation of Reactive Ester 's (Π)

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16

From the formula (I), it is clear that the compounds of the invention have at least two asymmetric carbon atoms in their structures, namely those located at the 2- and 4-position of the dioxolane nucleus and, consequently, they may exist in different stereochemically iso-5 more forms. The preparation of the stereochemically isomeric forms of (I) and the pharmaceutically acceptable acid addition salts thereof are also within the scope of the invention.

The diastereomeric racemates of (I), designated as cis and trans forms, respectively, according to the rules described in C.A., 76, Index Guide, Section 10 IV, p. 85 (1972), can be obtained separately by conventional methods. Suitable methods which can advantageously be used therefore include e.g. selective crystallization and chromatographic separation, e.g. column chromatography.

Since the stereochemical configuration is already established in some of the 15 intermediate compounds, e.g. in intermediates of formulas (II) and (VIII), it is also possible to separate cis and trans forms on this or even an earlier step, after which the corresponding forms of (I) can be obtained therefrom in the manner previously stated. The separation of cis and trans forms of such intermediates can be accomplished by 20 conventional methods as described above for separating cis and trans forms of the compounds (I).

It is to be understood that the cis- and trans-diastereomeric racemates can be further resolved into their optical isomers, cis (+), cis (-), trans (+) and trans (-), using methods known to those skilled in the art. .

The compounds of formula (I) and the pharmaceutically acceptable acid addition salts thereof are useful agents in the control of fungi and bacteria. Eg. For example, the compounds and acid addition salts thereof have been found to be highly active against many different fungi such as e.g. Microsporum canis, Ctenomyces mentagrophytes, Trichophyton rubrum, Phia-30 1 ophora verrucosa, Cryptococcus neoformans, Candida tropical ice, Candida albicans, Mucor species, Aspergillus fumigatus, Sporotricum schenckii, and Saprolegnia species, and for example bacteria . Erysipelotrix intrusiosa, Staphylococci such as Staphylococcus hemolyticus and Streptococci such as Streptococcus pyogenes. By virtue of their strong local as well as systemic, antimicrobial activity, the compounds of this invention provide useful tools for destroying or preventing the growth of fungi and bacteria, and they may be more particularly used effectively in the treatment of articles suffering from such disorders.

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17 microorganisms.

The strong antimicrobial activity of the compounds (I) is evident from the data obtained in subsequent experiments.

Experiment A:

Activity of compounds (I) against vaginal candidosis in rats.

Female Wistar rats with ± 100 g body weight are used. They are subjected to ovariotomy and hysterectomy, and after three weeks of recovery, 100 µg oestradiol undecylate in sesame oil is administered subcutaneously once every 10 weeks for three consecutive weeks. The pseudo-oestrus thus induced is checked by microscopic examination of vaginal smear preparations. Free access to feed and water is provided. Rats are infected intravaginally with 8 x 10 6 cells of Candida albicans, grown on Sa bouraud substrate for 48 hours at 37 ° C and diluted with saline. The day of infection varies from day +25 to day +32 after surgical intervention, depending on the appearance of signs of induced pseudo-oestrus.

The drugs under study are administered orally once a day for two days starting from the day of infection. At each trial, there are placebo-treated control animals. The results are illustrated by the fact that some days 20 after the infection, vaginal smears with sterile tampons are taken. The tampons are placed in Sabouraud substrate in Petri dishes and incubated for 48 hours at 37 ° C. If no growth of Candida albicans occurs, ie. when the animals are negative at the end of the experiment, this is due to drug administration because it never occurs in placebo-treated animals.

The following table gives the lowest oral dose of the drug studied, which is found to be active by the 14th day after infection.

Experiment B:

Activity of Compounds (I) against Kroc Candidosis in Turkeys.

C

14-day-old turkeys are infected in the inn with 4 x 10 Candida al bi-cans cells grown on Sabouraud substrate for 48 hours at 37 ° C and diluted with saline. The inoculum volume is 1 ml. The drugs under investigation are premixed in 500 mg of 1 acton and then mixed in 1000 g of meal without any additives. The concentration of the investigated drug in the meal is expressed in mg / kg.

The animals are given the medicated feed for 13 consecutive months

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18 days, starting on the day of infection. At the end of the experiment, all the animals are slaughtered. The animals' inn is removed by autopsy, emptied and ground in an ultra-turrax mixer in 15 ml of sterile saline. Colony counting is done on Sabouraud agar and the results reported in the table represent the EDgQ value, ie. the dose of the drug at which the inn in 50% of the animals is completely negative with regard to Candida albicans.

cT ~ J ci CH_ -fVci O'O \ - / ci3 Y Q Vaginal candidosis in Kro- candidosis in cal-.

rats: lowest effective cows: EDgg in mg / kg in j dose in mg / kg oral feed; ^ ____________ _ - - -______ i / * »-N. CH 2.5 N 2.5 -N I CH 1.25 f; -NJ N 1.25 16 £ CH 0.63 16

\ = N

-N ^ l N 0.63 - - / VSCH3 -N. I 'CH 2.5 jt * SCH3 -N I N 1.25 31' nli '1 / ^ CH3 -N I CH 2.5> .N CS3

^ sch3 I

-N I N 4 = 0.63

La_L _-___

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Vaginal candidosis in Kro-candidosis in turkey Y rats: lowest effective levels: ED ^ q in mg / kg in dose in mg / kg oral feed 19 SCH, i

> = N

. »Μ æ, -Ni N 2.5!

V = N

sch3 i -N I N 0.63

^ == N

ch3 sch3.

-N j CH - 31

\ R = N

/ CH3 ch3

FCN

-N I CH 0.63 16 '/ 1 nch3 CH.

\ -j / = N.

-N i N ^ 0.63 16 0WnCH3

/ N = N

-N I N 2.5 j

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20

Vaginal candidosis in Kro-candidosis in cal-Y Q rats: lowest effective kin: ED5Q in mg / kg in dose in mg / kg feed

N-CH

-N | N> 0.63

\ = - N

Οχ

N-CH

-N I 3 CH 1.0 16

\ = N

q

7-N-C H

-N I 2 5 CH 1.25 31

\ = N

V-N-aC, H7 -N I 37 CH 0.63 -> = »CH3 o

/ -N-C H

-N I 2 5 N <0.63 y = -n CH 3

ISLAND

UN-nC.H7 <N I 3 1 N 0.5 kr

Vn-c.h, v -N | N> 0.16

\ = N

q / -N-C H- -N I 2 5 CH 1.25

> = N

CH3

21 DK 160428 B

By virtue of the anti-fungal and antibacterial properties, the compounds may be formulated into compositions comprising as the active component the compounds of formula (I) or acid addition salts thereof in a solvent or solid / semi-solid or liquid diluent. or carrier. Anti fungal and antibacterial compositions comprising an effective amount of an active compound (I), either alone or in combination with other active therapeutic ingredients, in admixture with suitable carriers can be readily prepared according to conventional pharmaceutical techniques for the usual adjuvants. ministers ring roads.

Preferred compositions are in unit dosage form, since the unit dose comprises an effective amount of the active ingredient in admixture with suitable carriers. Although the amount of the active ingredient per unit dose may vary within fairly wide range, unit doses comprising from 50 to approx. 500 mg, and especially from ca. 100 to approx. 250 mg of the active ingredient.

The following Examples 1-20 illustrate the preparation of the starting materials, while Examples 21-27 illustrate the process of the invention.

Unless otherwise indicated, all parts therein are by weight.

A) Manufacture of intermediates:

Example 1

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

A mixture 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-charcoal catalysis. tor 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and washed with N, N-dimethylacetamide. The filtrate is poured into water. The precipitated product is filtered off and crystallized from 1-buta- I

nol to give 8 parts (74%) of 4- [4- (4-methoxyphenyl) -1-piperazinyl] -1H

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22 benzenamine; snip. 191.8 ° C.

Example 2

To a stirred and cooled (ice-bath) mixture of 5 parts of Ν, Ν'-methanetetra-5-ylbis [cyclohexanamine], 25.2 parts of carbon disulfide and 40 parts of pyridine are added 6 parts of 4- [4- (4-methoxyphenyl) -1- piperazinyl] benzenamine, and the combined mixture is first stirred for 1 hour in an ice bath and further for 2 hours at room temperature. 35 parts of 2,2'-oxybispropane are added and the combined mixture is stirred for 30 minutes. The precipitated product is filtered off and crystallized from 4-methyl-2-pentanone. The product is filtered off again 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-methoxy-phenyl] piperazine, 100 parts of hydrazine hydrate and 400 parts of 1,4-dioxane is stirred and refluxed for 1 hour. The reaction mixture is cooled and poured into water.

The precipitated product is filtered off, washed with water and with methanol and dried to give 46 parts (89%) of N- {4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl} hydrazinecarboth in oil .

Example 3

A mixture of 23 parts of N- {4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl} hydrazine carbothioamide, 23 parts of methanimidamide acetate and 80 parts of 1-butanol is stirred and refluxed for 1 hour. The reaction mixture is cooled and poured into water. 2,2'-oxybispropane is added. The precipitated product is filtered off, washed with water and methanol and crystallized from 1-butanol to give 17.7 parts of 4- {4 - [- (4-methoxyphenyl) -1-piperazinyl] phenyl} -4H-l, 2,4-triazole-3-thiol; mp. 231.9 ° C.

Following the same procedure using an equivalent amount of ethanimidamide, hydrochloride instead of the methanimidamide acetate 30, 4 - {- 4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl} -5-methyl-4H-1 is obtained. 2,4-triazole-3-thiol; mp. 260.3 ° C.

Example 4

A mixture of 9 parts of 4- {4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl} -4H-1,2,4-triazole-3-thiol, 2 parts of sodium hydroxide and 160 parts of methanol stirring and heating until all the solid dissolves. Then 3.3 parts of dimethyl sulphate are added and stirring is continued for 3 hours at room temperature. The reaction mixture is poured into water. The precipitated product from

DK 160428 B

23 is filtered and crystallized from 1-butanol to give 5.3 parts of 1- (4-methoxyphenyl) -4- {4- [3- (methylthio) -4H-1,2,4-triazole-4- yl] phenyl} pi perazin; mp. 180 ° C.

Similarly prepared: 1- (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 of 50 parts of 2- (4-nitrophenyl) hydrazine carbothioamide and 10 270 parts of methyl benzene is azeotropically distilled to dryness. Then 26 parts of acetic anhydride are added and the mixture is stirred and refluxed for 3 hours. The reaction mixture is cooled. The precipitated product is filtered off, washed with 2-propanol and crystallized from ethanol. It is again filtered off and dried at 100 ° C to give 31.5 parts of acetic acid, 2- (amino-thioxomethyl) -1- (4-nitrophenyl) hydrazide; mp. 241.5 ° C.

In addition, following the same acylation process and using equivalent amounts of the appropriate starting materials, the following are prepared: butanoic acid, 2- (aminothioxomethyl) -1- (4-nitrophenyl) hydrazide, monohydrate; mp. 197.2 ° C and propanoic acid, 2- (aminothioxomethyl) -1- (4-nitrophenyl) hydrazide; mp.

216.1 ° C.

Example 6 40 parts of acetic acid, 2- (aminothioxomethyl) -1- (4-nitrophenyl) hydrazide 25 are dissolved in a mixture of 10 parts of sodium hydroxide and 400 parts of water and the solution is stirred for 30 minutes at room temperature. The reaction mixture is acidified with concentrated hydrochloric acid. The precipitated product is filtered off, washed with water and with 2-propanol and crystallized from 1,4-dioxane to give 22.4 parts of 5-methyl-1- (4-nitrophenyl) -1H-1,2,4-triazole. 3-30 thiol; mp. 202.1 ° C.

Similarly, 1- (4-nitrophenyl) -5-propyl-1H-1,2,4-triazole-3-thiol is also prepared; mp. 190.7 ° C, and 5-ethyl-1- (4-nitrophenyl) -1H-1,2,4-triazole-3-thiol; mp. 206.1 ° C.

35

Example 7

To 80 parts of methanol, 4.7 parts of 5-methyl-1- (4-nitrophenyl) -1H-1,2,4-triazole-3-thiol and 1.2 parts of sodium hydroxide are added and stirred.

DK 160428 B

24 to all solids dissolve. Then 2.66 parts of dimethyl sulfate are added and stirring is continued for 1 hour at room temperature. 100 parts of water are added. The precipitated product is filtered off, washed with water, dried and crystallized from 2,2'-oxybispropane to give 3.3 parts (66%) of 5-5 methyl-3- (methylthio) -1- (4-nitrophenyl) -1H -l, 2,4-triazole; mp. 121-125 ° C.

Further, following the same procedure for S-methylation and using equivalent amounts of the appropriate starting materials: 5-ethyl-3- (methylthio) -1- (4-nitrophenyl) -1H-1,2,4-triazole; mp.

77.8 ° C, and 3- (methyl thio) -1- (4-nitrophenyl) -1H-1,2,4-tri azole; mp. 140 ° C.

Example 8

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

Also following the same hydrogenation process are prepared: 4- [3- (methylthio) -1H-1,2,4-triazol-1-yl] benzenamine as a residue.

25

Example 9

A mixture of 41 parts of 5-ethyl-3- (methylthio) -1- (4-nitrophenyl) -1H-1,2,4-triazole and 80 parts of methanol is hydrogenated at normal pressure and at room temperature with 1 part of palladium on top. charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is crystallized from Ι, Γ-oxybisbutane.

The product is filtered off and dried to give 33 parts (91%) of 4- [5-ethyl-3- (methylthio) -1H-1,2,4-triazol-1-yl] benzenamine; mp. 131.7 ° C.

Similarly, 4- (2-methyl-1H-imidazol-1-yl) benzenamine is also prepared; mp. 105 ° C.

Example 10

A mixture of 20 parts of 4- [5-methyl-3- (methylthio) -1H-1,2,4-triazole

DK 160428 B

25 l-yl] benzenamine, 15 parts Raney nickel catalyst and 400 parts methanol are stirred and refluxed for 2 hours. The Raney nickel is filtered off and 15 other parts of the catalyst are added. Stirring at reflux is continued for 4 hours. The reaction mixture is filtered, washed on filter 5 with methanol and the filtrate is evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone, 2,2'-oxybispropane and petroleum ether. The product is filtered off and dried to give 7.6 parts (47%) of 4- (5-methyl-1H-1,2,4-triazol-1-yl) benzenamine; mp. 145 ° C.

Example 11

A mixture of 35 parts of 1- (4-nitrophenyl) -5-propyl-1H-1,2,4-triazole-3-thiol, 83 parts of concentrated nitric acid solution and 150 parts of water is stirred and heated to 60 ° C. With stirring, the mixture is allowed to cool to room temperature and stirred overnight at room temperature. The precipitated product is filtered off, washed with water and added to a hot solution of 20 parts potassium carbonate in 200 parts water at 100 ° C. The reaction mixture is allowed to cool to room temperature with stirring. The precipitated product is filtered, dried and crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The product 20 is filtered off 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.

20 parts of 3,3'-di thi obi s [1- (4-nitrophenyl) -5-propyl-1H-1,2,4-tri azole] are dissolved in 100 parts of acetic acid with stirring and heating. 55 parts of hydrogen peroxide solution are then added dropwise 30%; reflux temperature is reached. After completion, stirring is continued under reflux for 1 hour. The reaction mixture is cooled and poured into a mixture of crushed ice and a 50% sodium hydroxide solution. The precipitated product is filtered off and dissolved in dichloromethane. The solution is washed with a sodium sulfite solution, dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using trichloromethane as eluant. The pure fractions are collected and the eluent is evaporated. The residue is converted to the hydrochloride salt in 2-propanol. The salt is filtered off and crystallized from ethanol to give 3.9 parts (19%) of 1- (4-nitrophenyl) -5-propyl-1H-1,2,4-tri azole, monohydrochloride; mp.

178.7 ° C.

A mixture of 38.3 parts of 1- (4-nitrophenyl) -5-propyl-1H-1,2,4-triazole monohydrochloride and 400 parts of methanol is hydrogenated under normal pressure.

DK 160428 B

26 and at room temperature with 3 parts of pal 1 adium-on-charcoal catalyst 10%.

After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is dissolved in water and neutralized with sodium bicarbonate. The product is extracted with dichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is converted to the hydrochloride salt in 2-propanol. The salt is filtered off and dried to give 35 parts (91%) of 4- (5-propyl-1H-1,2,4-triazol-1-yl) benzenamine dihydrochloride.

Example 12

A mixture of 4 parts of N- (4-nitrophenyl) hydrazine carboxamide, 5 parts of ethanimidamide, hydrochloride and 5 parts of sodium acetate is stirred and heated for 4 hours at 140 ° C. The reaction mixture is cooled, water is added and stirred until the product crystallizes. It is filtered off and recrystallized from 2-propanol to give 1.5 parts (34%) of 2,4-dihydro-5-methyl-4- (4-nitrophenyl) -3H-1,2,4-triazole. 3-one; mp. 226, l ° C.

To a stirred mixture of 13.5 parts of 2,4-dihydro-5-methyl-4- (4-nitrophenyl) -3H-1,2,4-triazol-3-one in 100 parts of dimethyl sulfoxide is added 2 share sodium hydride dispersion 78% and stir until foaming has ceased. Then 8.1 parts of dimethyl sul fat are added dropwise. After completion, stirring is continued for 3 hours at room temperature. The reaction mixture is poured into water and the product is extracted 3 times with trichloromethane. The combined extracts are washed with water, dried, filtered and evaporated. The residue is crystallized from a mixture of 2-propanol and 2,2'-oxybispropane. The product is filtered off 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- triazol-3-one; mp. 153.2 ° C.

A mixture of 9 parts of 2,4-dihydro-2,5-dimethyl-4- (4-nitrophenyl) -3H-1,2,4-triazol-3-one and 200 parts of methanol is hydrogenated at normal pressure and at room temperature. with 3 parts Raney nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is decomposed into 2,2'-oxybispropane. The product is filtered off and dried to give 7.5 parts (95%) of 4- (4-aminophenyl) -2,4-dihydro-2,5-dimethyl-3H-1,2,4-triazol-3-one ; mp. 160 ° C.

35

Example 13

A mixture of 53 parts of N- {4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl) hydrazinecarboxamide, 53 parts of ethanimidamide, hydrochloride and 135 parts

DK 160428 B

27 N, N-dimethyl formamide is stirred and heated for 3 hours at 130 ° C. The reaction mixture is cooled and poured into water. The precipitated product is filtered off, washed with water and with methanol and crystallized from Ν, Ν-dimethylformamide. The product is filtered off and recrystallized from 1,4-dioxane to give 19.5 parts of 2,4-dihydro-4- {4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl} -5-methyl -3H-l, 2,4-triazol-3-one; mp. 298.4 ° C.

Example 14 19.2 parts of 2,4-dihydro-4- {4-74-methoxyphenyl) -1-piperazinyl] phenyl} -3H-1,2,4-triazol-3-one are dissolved in 450 parts dimethyl sul foxide at ca.

100 ° C. Then 3.1 parts of sodium hydride dispersion is added 50% and stirred to a temperature of approx. 50 ° C is reached. 8.2 parts of dimethyl sulphate are added and stirring is continued overnight at room temperature. The reaction mixture is poured into water and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98: 2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 1-butanol to give 5.8 parts of 2,4-dihydro-4- {4- [4-20 (4-methoxyphenyl) -1-piperazinyl] phenyl} -2-methyl-3H-1,2 , 4-triazol-3-one; mp. 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 are dissolved in 300 parts of dimethyl sul foxide at 100 ° C. Then 1.6 parts sodium hydride dispersion is added 50% and stirring is continued while the mixture is allowed to cool to ca. 50 ° C.

3.9 parts of 1-bromopropane are added and the whole is stirred overnight at room temperature. The reaction mixture is poured into water and the product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98: 2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is decomposed into 2-propanol. The product is filtered off and dried to give 7.5 parts (65%) of 2,4-dihydro-4- {4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl} -2-propyl-3 1,2,4-triazol-3-one.

By following the N-al cooling process together and using equiv.

DK 160428 B

28 valent amounts of suitable starting materials are prepared: 2-ethyl-2,4-dihydro-4- {4 - [- (4-methoxyphenyl) -1-piperazinyl] phenyl} -5-methyl-3H-1,2,4- triazol-3-one; mp. 179.8 ° C.

2,4-dihydro-4- {4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl} -5-methyl-2-propyl-3H-1,2,4-triazole-3 one; mp. 144.5 ° C, and 2-ethyl-2,4-dihydro-4- {4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl} -3H-1,2,4-triazole 3-one; mp. 210.2 ° C.

Example 16 A mixture of 12.5 parts of N, N-bis (2-chloroethyl) 4-methoxybenzenamine, 8 parts of 4- (1H-pyrazol-1-yl) benzenamine, 2 parts of potassium iodide, 80 parts of 2-propanone and 100 parts of water are stirred and refluxed for 24 hours. The reaction mixture is cooled. The precipitated product is filtered off (the filtrate is set aside), washed with water and with 2-propanone to give a first crude fraction of 6 parts.

The filtrate (see above) is neutralized with a sodium hydrogen carbonate solution and extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is decomposed into 2-propanol. The product is filtered off and washed with methanol to give another crude fraction of 20 parts. The combined crude products (6 and 2 parts, respectively) are crystallized from 1-butanol to give 7.1 parts of 1- (4-methoxyphenyl) -4- [4- (1H-pyrazol-1-yl) phenyl] piperazine; mp. 207.7 ° C.

Following the same procedure and using equivalent amounts of suitable starting materials are also prepared: 1- [4- (1H-i-dazol-1-yl) phenyl] -4- (4-methoxyphenyl) piperazine; mp.

255-256 ° C, 1- (4-methoxyphenyl) -4- [4- (1H-1,2,4-triazol-1-yl) phenyl] piperazine; mp. 230.3 ° C, 1- (4-methoxyphenyl) -4- {4- [3- (methylthio) -1H-1,2,4-triazol-1-yl] phenyl} piperazine; mp. 186.5 ° C, 1- (4-methoxyphenyl) -4- {4- [5-methyl-3- (methylthio) -1H-1,2,4-triazol-1-yl] phenyl} piperazine; mp. 153.3 ° C, 1- (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-1,2,4- triazol-3-one; mp. 196.7 ° C, 1- (4-methoxyphenyl) -4- [4- (5-propyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine; mp. 196.3 ° C.

DK 160428 B

1- {4- [5-ethyl-3- (methylthio) -1H-1,2,4-triazol-1-yl] phenyl} -4- (4-methoxyphenyl) piperazine; mp. 142.3 ° C and 1- (4-methoxyphenyl) -4- [4- (2-methyl-1H-imidazol-1-yl) phenyl] piperazine; mp. 178.5 ° C.

5

Example 17

A mixture of 6 parts of 4- [4- (4-methoxyphenyl) -1-piperazinyl] benzenamine, 3.6 parts of phenylcarbon chloride, 75 parts of pyridine and 98 parts of dichloromethane is stirred and heated until all the solid dissolves. . Stirring is continued for 30 minutes at room temperature. The reaction mixture is poured into 500 parts of water and 210 parts of 2,2'-oxybispropane are added. It's all stirred for a while.

The precipitated product is 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 of phenyl {4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl] carbamate, 50 parts of hydrazine hydrate and 100 parts of 1,4-dioxane is stirred and refluxed for 3 hours. The reaction mixture is cooled and poured into water. The precipitated product is filtered off and crystallized from 20 N, N-dimethyl formamide to give 1.7 parts (63%) of N- {4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl} hydrazine carboxamide; mp. -300 ° C.

A mixture of 3.4 parts of N- {4- [4- (4-methoxyphenyl) -1-piperazinyl] -phenyl} hydrazinecarboxamide, 3 parts of methanimidamide acetate and 10 parts of dimethyl sulfoxide is stirred and heated for 2 hours at 100 ° C. The reaction mixture is cooled and poured into a mixture of 4-methyl-2-pentanone and 2,2'-oxy-bispropane. The precipitated product is filtered off and crystallized from N, N-dimethyl formamide (activated charcoal) to give 1 part (28%) of 2,4-dihydro-4- {4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl) -3H-l, 2,4-tria-zol-3-one; mp. -300 ° C.

30

Example 18

A mixture of 4- [4- (4-methoxyphenyl) -1-piperazinyl] benzenamine and 300 parts of a hydrobromic acid solution 48% in water is stirred and refluxed for 10 days. The reaction mixture is evaporated and the residue is made alkaline with sodium hydroxide. The mixture is filtered and the filtrate is acidified with acetic acid. The precipitated product is filtered off and crystallized from 1,4-dioxane to give 12 parts (44%) of 4- [4- (4-aminophenyl) -1-piperazinyl] phenyl.

DK 160428 B

30

Following the same procedure and using equivalent amounts of suitable starting materials, the following are also prepared: 4- {4- [4- (1H-pyrazol-1-yl] phenyl] -1-piperazinyl} phenol, 4- {4- [4- (1H- imidazol-1-yl) phenyl] -1-piperazinyl} phenol;

5> 260 ° C.

4- {4- [4- (lH-l, 2,4-triazol-1-y1) phenyl] -1-piperazinyl} phenol; mp.

276.6 ° C, 4. [4- {4- [3- (3_ (methylthio) -1H-1,2,4-triazol-1-yl] phenyl} -1-piperazinyl] phenol; 225.5 ° C, 4- [4- {4- [5-methyl-3- (methyl thio) -1H-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-ylphenyl} -1-piperazinyl] phenol, 2,4-dihydro-4- {4- [4- ( 4-hydroxyphenyl) -1-piperazinyl] phenyl} -2,5-dimethyl-3H-1,2,4-triazol-3-one: mp -260 ° C, 2,4-dihydro-4- {4- [4- (4-hydroxyphenyl) -1-piperazinyl] phenyl} -2-propyl-3H-1,2,4-triazol-3-one, 4- {4- [4- (2) -methyl-1H-imidazol-1-yl) phenyl] -1-piperazinyl} phenol, mp -300 ° C, 4- [4- {4- [5-ethyl-3- (methylthio) -1H-1], 2,4-triazol-1-yl] phenyl} -1-piperazinyl] phenol, mp 232.6 ° 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-di hydro-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-triazole 3-one, 2-ethyl-2,4-dihydro-4- {4- [4- (4-hydroxyphenyl) -1-piperazinyl] phenyl} -3H-1,2,4-triazol-3-one ; mp. 217 ° C, and 4- {4- [4- (5-propyl-1H-1,2,4-triazol-1-yl) phenyl] -1-piperazinyl} phenol; mp. 225.6 ° C.

Example 19

To a stirred solution of 3 parts of 4- [4- (4-aminophenyl) -1-piperazine]

DK 160428 B

31 nyl] phenol in 50 parts of dimethyl sul foxide, 0.5 parts of a sodium hydride dispersion is added 50%. It is all stirred at 50 ° C until foaming has ceased.

Then, 4.1 parts of cis- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-2-yl-methyl) -1,3-dioxolan-4-ylmethyl] methanesulfonate are added and stirring is continued. for 2 hours at 70 ° C. The reaction mixture is cooled and poured into water. The product is extracted with dichloromethane. The extract is washed with a dilute sodium hydroxide solution, dried, filtered and evaporated. The residue is purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (98: 2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2-propanol. The product is filtered off and dried to give 1.3 parts (22%) of cis-4- [4- {4- [2- (2,4-dichlorophenyl) -2- (1H-i] dazol-1-ylmethyl) - 1,3-dioxolan-4-ylmethoxy] -phenyl} -1-piperazinyl] -benzenamine; mp. 174.4 ° C.

15

Example 20

To a stirred solution of 8 parts of 4- [4- (4-aminophenyl) -1-piperazinyl] phenol in 100 parts of dimethyl sulfoxide add 1.5 parts of sodium hydride dispersion 50% and stirring is continued until foaming has ceased. . Then 12.3 parts of cis- [2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4 are added thereto -ylmethyl] methanesulfonate and the whole is stirred and heated for 4 hours at 50 ° C. The reaction mixture is cooled and poured into water. The product is extracted three times with dichloromethane. The combined extracts are washed with a dilute sodium hydroxide solution and treated with activated charcoal. The latter is filtered off and the filtrate is evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98: 2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 1-butanol to give 5.1 parts of cis-4 - [- {4- [2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) ) -1,3-di oxolan-4-ylmethoxy] phenyl} -1-piperazinyl] benzenamine; mp. 186.8 ° C.

B) Preparation of End Products Example 21 To a solution of 3.2 parts of 4- {4- [4- (1H-pyrazol-1-yl) phenyl] -1-piperazinyl} phenol in 100 parts of dimethyl sulphoxide is added. 0.32 parts of a sodium hydride dispersion 78% and it is all stirred at 50 ° C until foaming has ceased. Then 4.1 parts of cis-2- (2,4-dichlorophenyl) -2- (1H-imidazole-321-ylmethyl) -1,3-dioxolane-4-ylmethyl methanesulfonate are added and stirring is continued. for 3 hours at 100 ° C. The reaction mixture is cooled, poured into water and the product is extracted with dichloromethane. The extract is washed with dilute sodium hydroxide solution, dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98: 2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated.

The residue is again purified by column chromatography over silica gel using a mixture of methyl benzene and ethanol (95: 5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from methyl benzene to give 2.2 parts (34%) of cis-1- {4- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1, 3-dioxolan-4-ylmethoxy] -phenyl} -4- [4- (1H-pyrazol-1-yl) phenyl] piperazine; mp. 195.1 ° C.

Following the same procedure and using equivalent amounts of the appropriate starting materials are also prepared: cis-1- {4- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3- di- oxolan-4-ylmethoxy] -phenyl-4- [4- (lH-imidazol-1-yl) phenyl] piperazine; mp.

166.7 ° C, cis-1- {4- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] - phenyl} -4- [4- (1H-1,2,4-triazol-1-yl) phenyl] piperazine-zin; mp. 175.3 ° C, cis-1- {4- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] - phenyl} -4- {4- [3- (methylthio) -LH-l, 2,4-triazol-l-yl] phenyl} piperazine; mp. 178.3 ° C, cis-1- {4- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl} -4- {4- [3-methyl-5- (methylthio) -4H-1,2,4-triazol-4-yl] phenyl} piperazine; mp. 127.8 ° C, cis-1- {4- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] - 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-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl} -4- {4- [3- (methylthio) -4H-1,2,4-triazol-4-yl] -phenyl} piperazine; mp. 176,4, cis-4- {4- [4- {4 - [- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl } -1-piperazinyl] phenyl} -2,4-dihydro-2,5- 'dimethyl-3H-1,2,4-triazol-3-one; mp. 149.3 ° C,

DK 160423 B

33 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-2-propyl-3H-l, 2,4-triazol-3-one; mp. 185.7 ° C, cis-1- {4- [2- (2,4-dichlorophenyl) -2- (ΙΗ-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] - phenyl} -4- [4- (5-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine; mp. 154.1 ° C, cis-1- {4- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl} -4- [4- (2-methyl-lH-imidazol-1-yl) phenyl] piperazine-pipe; mp. 180.1 ° C, 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-3H-1,2,4-triazol-3-one; mp. 212.8 ° C, cis-4- {4- [4- {4- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] 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-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl} -l-piperazinyl] phenyl} -2,4-dihydro-5-me-thyl-2-propyl-3H-1,2,4-triazol-3-one monohydrate; mp. 153.9 ° C, cisl - {- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl} - 4- {4- [5-ethyl-3- (methylthio) -LH-l, 2,4-tria-zol-1-yl] phenyl} piperazine; mp. 136.3 ° C, cis-1- {4- [2- (2,4-dichlorophenyl) -2- (ΙΗ-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl} -4- [4- (5-propyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine; mp. 150.4 ° C, and 25 cis-4- {4- [4- {4- [2- (2,4-dichlorophenyl) -2- (ΙΗ-imidazol-1-ylmethyl) -1,3-dioxolane-4 ylmethoxy] phenyl} -l-piperazinyl] phenyl} -2-ethyl-2,4-dihydro-5-methyl-3H-l, 2,4-triazol-3-one monohydrate; mp. 135.5 ° C.

Example 22 A mixture of 2 parts sodium azide, 5.8 parts cis-4- [4- {4- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl) -1 3-Dioxolan-4-ylmethoxy] phenyl} -1-piperazinyl] benzenamine, 4 parts 1, Γ, Γ '- [methylidyntris (oxy)] trisethane and 50 parts acetic acid are stirred and heated overnight at 70 ° C. The reaction mixture is cooled and neutralized with a potassium carbonate solution. The product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using trichloromethane and methanol (98: 2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated.

34 DK 160428 B

The residue is crystallized from 1-butanol. The product is filtered off and dried to give 3.8 parts (60%) of cis-1- {4- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolane -4-ylmethoxy] phenyl} -4- [4- (1H-tetrazol-1-yl) phenyl] piperazine; mp. 201.3 ° C.

5

Example 23

To a stirred solution of 3 parts of 4- {4- [4- (1H-1,2,4-triazol-1-yl} -phenyl] -1-piperazinyl) phenol in 100 parts of dimethyl sulfoxide is added 0.3 parts sodium hydride dispersion 78% and it is all stirred at 50 ° C until foaming 10 is stopped. Then 3.7 parts of cis- [2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-ylmethyl] methanesulfonate are added, and stirring is continued for 3 hours at 100 ° C. The reaction mixture is cooled and poured into water. The product is extracted three times with dichloromethane. The combined extracts are washed with a dilute sodium hydroxide solution, dried, filtered and evaporated. The residue is crystallized from 1-butanol. The product is filtered off and dried to give 4.3 parts (75%) 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-1,2,4-triazol-1-yl] phenyl] piperazine;

219.6 ° C.

Following the same procedure and using equivalent amounts of suitable starting materials, cis-1- {4- [2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) ) - 1,3-dioxolan-4-ylmethoxy] phenyl} -4- [4- (1H-pyrazol-1-yl) phenyl] piperazine; mp. 188.3 ° C, 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; mp. 194.3 ° C, cis-1- {4- [2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-di oxolan-4-ylmethoxy ] -phenyl} -4- [4- (5-methyl-1H-1,2,4-triazol-1-yl) -phenyl] piperazine; mp. 166.5 ° C, cisl- {4- [2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl} -4- {4- [3- (methylthio) -1H-1,2,4-triazol-1-yl] phenyl) piperazine; mp. 153.9 ° C, cis-1- {4- [2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4 -ylmethoxy] phenyl} -4- (4- [5-methyl-3- (methylthio) -1H-1,2,4-triazol-1-yl] phenyl} piperazine; mp 164.1 ° C, cis -4- {4- [4- {4- [2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-yl methoxy] phenyl} -l-piperazinyl] phenyl} -3- (methyl

DK 160428 B

Thio) -4H-1,2,4-triazole; mp. 147-152.6 ° C, cis-1- {4- [2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolane-4 ylmethoxy] pheny1} -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-ylmethyl) -l, 3-dioxolan-4-ylmethoxy] phenyl} -l-piperazinyl] phenyl} -2,4-dihy-dro-2,5-dimethyl-3H-1,2,4-triazol-3-one "monohydrate ; mp. 161.9 ° C, cis-4- {4- [4- {4- [2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) - 1,3-di oxolan-4-ylmethoxy] phenyl} -1-piperazinyl] phenyl} -2,4-dihydro-2-propyl-3H-1,2,4-triazol-3-one; mp. 167.3 ° C, cis-1- {4- [2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] pheny1} -4- [4- (2-methyl-lH-imidazol-l-yl) phenyl carbonyl] piperazine; mp. 175.6 ° C, cis-4- {4-74- {4- [2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-yl-methyl) - 1,3-dioxolan-4-ylmethoxy] phenyl} -l-piperazinyl] phenyl} -2,4-di-hydro-2-methyl-3H-l, 2,4-triazol-3-one; mp. 193.8 ° C, cis-4 - {- [4- {4- [2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1 3-di oxolan-4-ylmethoxy] phenyl} -1-piperazinyl] phenyl} -2-ethyl-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one; mp. 178.3 ° C, cis-4- {4- [4- {4- [2- (2,4-Dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -2- thyl) -1,3-dioxolan-4-ylmethoxy] phenyl} -1-piperazinyl] phenyl} -2,4-dihydro-5-methyl-2-propyl-3H-1,2,4-triazole 3-one monohydrate; mp. 165.5 ° C, cis-4- {4- [4- {4- [2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl} -1-piperazinyl] phenyl} -2-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one; mp. 186 ° C, and cis-1- {4- [2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolane-4 ylmethoxy] phenyl} -4- [4- (5-propyl-lH-l, 2,4-triazol-l-yl) phenyl] piperazine; mp. 140.9 ° C.

Example 24

A mixture of 4 parts of cis-4- [4- {4- [2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4 -ylmethoxy] phenyl} -1-piperazinyl] benzenamine, 0.5 parts sodium azide, 1.08 parts 1, 1 ', 1 "- [methylidyntris (oxy)] trisethane and 50 parts acetic acid are stirred for 5 hours at 70 ° C.

An additional 0.5 parts sodium azazide and 1.08 parts Ι, Γ, Γ'-methylidyntris- (oxy)] trisethane are added and stirring at 70 ° C is continued for 15 hours. The reaction mixture is cooled and poured into a mixture of potassium carbonate and water. The product is extracted with dichloromethane. The extract is dried,

DK 160428 B

36 is filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98: 2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 1-butanol to give 2.1 parts (48%) of cis-1- {4- [2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazole) 1-ylmethyl) -1,3-di oxolan-4-ylmethoxy] phenyl} -4- [4- (1H-tetrazol-1-yl) phenyl] piperazine; mp. 192.5 ° C.

Example 25 To a stirred mixture of 5.7 parts of cis-4- [4- {4- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3 -dioxolan-4-ylmethoxy] phenyl} -1-piperazinyl] benzenamine and 100 parts acetic acid are added 1.5 parts tetrahydro-2,5-dimethoxyyfuran at 50 ° C. It is all stirred and refluxed for 5 minutes. The reaction mixture is poured into crushed ice and the whole is neutralized with 50% sodium hydroxide solution. The product is extracted with dichloromethane. The extract is treated with activated charcoal. The latter is filtered off and the filtrate is evaporated. The residue is crystallized from 1-butanol to give 3.3 parts (52%) of cis-1- {4- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1 3-dioxolan-4-ylmethoxy] phenyl} -4- [4- (1H-pyrrol-1-yl) phenyl] piperazine; mp. 188.9 ° C.

Similarly, cis-1- {4- [2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolane-4 is also prepared ylmethoxy] phenyl} -4- [4- (lH-pyrrol-l-yl) phenyl] piperazine; mp. 184.9 ° C.

25

Example 26

A mixture of 40 parts of ethanimidamide, hydrochloride, 20 parts of cis-N- {4- [4- {4- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3 -dioxolan-4-ylmethoxy] phenyl} -1-piperazinyl] phenyl} hydrazine carboxamide, 40 parts sodium acetate and 90 parts N, N-dimethyl formamide are stirred and heated for 4 hours at 130 ° C. The reaction mixture is cooled and 100 parts of water are added.

The precipitated product is filtered off, washed with water and with 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-ylmethyl) -1,3-dioxolan-4-yl-methoxy] phenyl} -1-piperazinyl] phenyl} -2,4-dihydro-5-methyl-3H-1 , 2,4-triazol-3-one-2-propanolate (2: 1); mp. 295.7 ° C.

Similarly, cis-4- {4- [4- {4- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -

DK 160428 B

37 1,3-dioxolan-4-ylmethoxy] phenyl} -1-piperazinyl] phenyl} -5-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one; mp. 275.6 ° C, and cis-4- {4- [4- {4- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-di oxolan-4 ylmethoxy] phenyl} -1-piperazinyl] phenyl} -2,4-dihydro-3H-5,2,4-triazol-3-one; mp. 255 ° C.

Example 27

A mixture 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 3,3-dioxolan-4-ylmethoxy-phenyl} -1-piperazinyl] phenyl} -2,4-dihydro-3H-, 1,2,4-triazol-3-one and 100 parts of dimethyl sul foxide is stirred at 50 ° C and 0.4 parts sodium hydride dispersion 50% is added. After stirring for 1 hour at 50 ° C, an additional 1.31 parts of 2-bromopropane and 0.4 parts of sodium hydride dispersion are added 50% and stirring is continued for 1 hour at 50 ° C. The reaction mixture is cooled and poured into water. The product is extracted with dichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99: 1 by volume) as the eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone to give 2 parts (37%) of cis-4- {4- [4- (4- [2- (2,4-dichlorophenyl) -2- (1H) -imidazol-1-ylmethyl) -l, 3-di- oxolan-4-ylmethoxy] phenyl} -l-piperazinyl] phenyl} -2,4-dihydro-2- (l-Me-methylethyl) -3 H 2,4-triazol-3-one, mp 222.1 ° C.

Similarly, cis-2-butyl-4- {4- [4- {4- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl-methyl) 1,3-dioxolan-4-ylmethoxy] phenyl} -l-piperazinyl] phenyl} -2,4-dihy-dro-3H-l, 2,4-triazol-3-one; mp. 199.2 ° C, and cis-4- {4- [4- {4- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy ] phenyl} -1-piperazinyl] phenyl} -5-ethyl-2,4-dihydro-2-propyl-3H-1,2,4-triazol-3-one; mp. 170.4 ° C.

Claims (6)

1. Analogous process for the preparation of (4-phenylpiperazin-1-yl-aryloxymethyl-1,3-dioxolan-2-yl) -methyl-1H-imidazole or 1H-1,2,4-5 triazole derivatives of the formula rN0 1.1 or pharmaceutically acceptable acid addition salts and / or stereochemically isomeric forms thereof, wherein Q represents CH or N, Ar represents phenyl, thienyl, monohalogen thienyl or phenyl substituted with from 1 to 3 substituents each selected from halogen, C -C8 alkyl, C1-C8 alkyloxy and trifluoromethyl, and the radical Y is a 1H-pyrrol-1-yl radical of the formula 20 T? ^ \ J · 'Q w B · 4 1 2 3 4 1 wherein R, R, R and R are each independently hydrogen, O, -O substituted with from 1 to 3 substituents each selected from 30 halogen, C1-C8 alkyl, C1-C8 alkoxy and trifluoromethyl, a 1H-pyrazol-1-yl radical of the formula "5 / N = fR - N {b) 35 7 R ° R7 5 β 7 1 wherein R, R and R are each independently hydrogen, C 1 -C 6 alkyl, Ar or 39 UK Ί bU 4 ^ Bb or Ar 1 C 1 -C 6 alkyl, Ar 1 having the previously defined meaning, a 1H-imidazol-1-yl radical of the formula R8) = rN5 <J (c) R4 R10 wherein R8 represents hydrogen, C1-C8 alkyl, C1-C8 alkylthio or Ar C 10 alkylthio, and R 9 and R 10 are each selected from hydrogen, C 1 -C 1- 11 alkyl, Ar and Ar-C 2 -C 8 alkyl, Ar having the previously defined meaning, 1H-1, 2.4 -triazol-1-yl radical of the formula RU 15 ./'I w \ = NR ^ wherein one of the groups R11 and R12 represents hydrogen, C1-C8 alkylthio or Ar1 C1-C8 alkyl thio, and the second group represents hydrogen, C 1 -C 6 alkyl or Ar * -C 2 -C 8 alkyl, with Ar 1 having the previously defined meaning, a 4 H-1,2,4-triazol-4-yl radical of the formula R -NIW R14 13 30 wherein R represents hydrogen, mercapto, hydroxy, C 1 -C 1 alkylthio or 11A 1 OJ Ar-C 2 -C 8 alkylthio, and R represents hydrogen, C 1 -C 8 alkyl, Ar or Ar 1 -C 2 -C 8 al. cool, with Ar1 having the meaning previously defined, a 2,3-dihydro-4H-1,2,4-triazol-4-yl radical of the formula Wherein R15 represents C1-C8 alkyl or Ar * -C1-C6 alkyl, and R16 represents hydrogen, C1-C8 alkyl or Ar1-C2-C8 alkyl, wherein Ar1 has the previously defined meaning , an IH-1,2,3,4-tetrazol-1-yl radical of the formula 5 / N = N -NI i,> = N. (S) R 1 7 10 wherein R 17 represents hydrogen, C 1 -C 6 alkyl, Ar 1 or Ar 1 C 1 -C 6 alkyl, Ar * having the previously defined meaning, CHARACTERISTICS characterized by a) reacting a compound of formula Or a metal salt thereof, in which compound Y has the same meaning as previously defined for Y, but is different from a radical of formula (e) wherein R represents mercapto or hydroxy, with a compound of the formula Dt ^ -W (II) wherein D represents π-N 25 -W 'I-L. wherein Q and Ar have the previously defined meanings and W is a reactive ester residue to prepare a compound of formula 30 d-ch 2 -O- / Ά \ _ / \ = / 35 (I ·) wherein D and Y 'have the previously defined meaning, the reaction being carried out in a reaction-inert organic solvent at elevated temperature and preferably in the presence of a base or b) preparing a compound of formula R 1 R 3 s H 2 10 (Ia) wherein D, R1, R2, R3 and R4 have the previously defined meanings by reacting an amine of formula (VIII-a) 20 wherein D has the previously defined meaning with a compound of formula R1 O-Alkyl 25. o R 1 O-alkyl (IX-b) wherein R, R, R and R are as defined previously, the reaction being preferably carried out in a polar solvent, or c) preparing a compound of formula (I) wherein Y is for a radical of formula (e) wherein R * 4 has the previously defined meaning, and R stands for mercapto or hydroxy, by cyclizing a compound of formula DK 160428 B 42 X ΝΗ-ϋ-ΝΗ-ΝΗ Pc 2 -O 2 -Of 5 (Vin-e) wherein D has the previously defined meaning, and X represents O or $, with a compound of the formula 10 NH 14 11 R -C-NH 2 15 (XVI) or an acid addition salt thereof, having the previously defined meaning, the cyclization being preferably carried out by mixing and reacting the reactants if desired in the presence of a reaction-inert organic solvent having a relatively high boiling point, or d) preparing a compound of formula (I) wherein Y illustrates a radical (f) wherein R and R have the previously defined meaning , from a compound of formula 25 / - / T ~ \ OH> N (1-elb) rU 30 16 wherein D and R have the previously defined meanings, by N-alkylation of the latter with a reactive ester of formula R15W ( XVIII), wherein W and R15 have the meanings previously defined, wherein Preferably, the N-alkylation is carried out by stirring the reactants and heating in an organic solvent in the presence of a base, or e) preparing a compound of formula (I) wherein Y represents the radical (g) wherein R has the previously defined meaning by cyclizing a compound of formula (VIII-a) wherein (D) has the previously defined meaning, with an azide, preferably an all potassium metal azide, and a compound of the formula R17-C [O-C1-C6 alkyl] 3 (XIX) in a suitable acidic medium, the reaction being preferably carried out under heating and, if desired, producing pharmaceutically acceptable acid addition salts or stereochemically isomeric forms of the compounds thus prepared. An analogue method according to claim 1 for the preparation of a chemical compound selected from cis-1- (4- [2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazole) 1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl} -4- [4- (1H-imidazol-1-yl) phenyl] -piperazine and the pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof, by reacting 4- {4- [4- (1H-imidazol-1-yl) phenyl] -1-piperazinyl} phenol with cis-25 [2- (2,4-dichlorophenyl) -2- (1H- l, 2,4-triazol-l-ylmethyl) -l, 3-dioxolan-4-ylmethylJmethansulfonat. The anal and method of claim 1 for the preparation of a chemical compound selected from cis-1- {4- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3 -dioxolan-4-ylmethoxy] phenyl} -4- [4- (1H-1,2,4-triazol-1-yl) phenyl] piperazine and the pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof, Reacts 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-4-ylmethyl] methanesulfonate. An analogue method according to claim 1 for the preparation of a chemical compound selected from cis-4- {4- [4- {4- [2- (2,4-dichlorophenyl) -2- 44 GB 16 0 4 2 8 B (IH-imidazol-l-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl} -l-piperazinyl-carbonyl] phenyl} -2,4-dihydro-2,5-dimethyl-3H-l, 2, 4-Triazol-3-One and the Pharmaceutically Acceptable Acid Addition Salts and Stereochemically Isomeric Forms thereof, CHARACTERIZED BY Reacting 2,4-dihydro-4- {4- [4- (4-hydroxy-5-phenyl) -1-piperazinyl ] phenyl} -2,5-dimethyl-3H-1,2,4-triazol-3-one with cis- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1 , 3-dioxolan-4-yl-methyl] methanesulfonate. An analogue method according to claim 1 for the preparation of a chemical compound selected from cis-4- {4- [4- {4- [2- (2,4-dichlorophenyl) -2- (1H-1, 2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl} -1-piperazanyl] phenyl} -2,4-dihydro-2,5-di methyl-3 1,2,4-triazol-3-one, monohydrate and the pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof, CHARACTERIZED BY reacting 2,4-dihydro-4- {4- [4- (4-15 hydroxyphenyl) ) -1-piperazinyl] phenyl} -2,5-dimethyl-3H-1,2,4-triazol-3-one with cis- [2- (2,4-dichlorophenyl) -2- (1H-1,2) , 4-triazol-l-ylmethyl) -l, 3-dioxolan-4-ylmethyl] methanesulfonate. An analogue method according to claim 1 for preparing a compound of formula cis-1- {4- [2- (2,4-dichlorophenyl) -2- (1H-1,2,4triazole-1 ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl} -4- [4- (5-methyl-1H-1,2,4-triazol-1-yl) phenyl] piperazine, FEATURED BY 4- {4- [4- (5-methyl-1H-1,2,4-triazol-1-yl) phenyl] -1-piperazinyl} phenol with cis- [2- (2,4-dichlorophenyl) - 2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-ylmethyl] methanesulfonate. 30 35