AP435A - Substituted azolone derivatives. - Google Patents

Abstract

The use of the manufacture of a madicament for treating

Description

SUB^TITUTED AZOLONE DERIVATIVES

The present invention is concerned with substituted azolone derivatives which are potent anti-Helicobacter agents and which may be used in a monotherapy in the eradication of Helicobacter pylori and related species.

US-4,791,111 discloses 4-(4-phenyl-l-piperazinyl)phenols which are intermediates in the preparation of [[4-[4-(4-phenyl-l-piperazinyl)phenoxymethyl]-l,3-dioxolan-2yl]methyl]-lH-imidazoles and lH-l,2,4-triazoles.

( In US-4,931,444 there are described 4-(4-phenyl-l-piperazinyl)phenols having

5-lipoxygenase inhibiting activity. The present compounds are distinguished therefrom ^k 15 by their useful and-Helicobacter activity.

Afflictions of the gastro-enteric tract are widespread. Modem medicine still fails to cure a lot of them, in particular those related to the presence in the gastric mucosa of the bacterium Helicobacter, e.g. chronic gastritis, duodenal ulcer and duodenal ulcer relapse.

Dual therapies in the eradication of Helicobacter, comprising the separate administration of two antibiotic drugs, have not been satisfactory up till now, because of one or more of the following reasons: a low eradication rate, numerous side effects and development of resistance by Helicobacter.

Triple therapies comprising the administration of two antibiotics and a bismuth compound have been shown to be effective, but are very demanding for the patients and C are also complicated by side effects.

The present invention is concerned with the use for the manufacture of a medicament for treating Helicobacter-related diseases of a compound of formula

O

Ar—X

I

N-C—Z t ι.

(I), the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein

X and Y each independently are CH or N;

R¹, R² and R³ each independently are hydrogen or Chalky!

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-2R⁴ and R⁵ each independently are hydrogen, halo, Ci-4alkyl, Cj^alkyloxy, hydroxy, trifluoromethyl, trifluoromethyloxy or difluoromethyloxy;

Z is C=O or CHOH; and

Ar is phenyl optionally substituted with up to three substituents selected from hydroxy, 5 C_Malkyl, C^alkyloxy, halo, trifluoromethyl, triCiujalkylsilyloxy, nitro, amino and cyano or pyridinyl substituted with hydroxy or Chalky loxy; and

The present invention is also concerned with a method of treating subjects suffering from //e/zcohacier-related diseases said method comprising administering to said subjects an effective anti-Helicobacter amount of a compound of formula (I).

Further, the present invention relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and as active ingredient an effective amount of a compound having the formula (I), a pharmaceutically acceptable acid addition salt thereof or a stereochemically isomeric form thereof, wherein X, Y, R¹ to R⁵, Z, Ar and (ΓαΛ>— are as defined in hereinabove, provided that Ar is other than

4-hydroxyphenyl, 3-Cj galkyl-4-hydroxyphenyl or 3,5-diCi^alkyl-4-hydroxyphenyl, when X = N and

is a radical of formula (a-1).

The present invention is also concerned with a compound having the formula (I), a pharmaceutically acceptable acid addition salt thereof or a stereochemically isomeric form thereof, wherein X, Y, R^ to R², Z, Ar and

are as defined hereinabove, provided that

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-3Ar is other than 4-hydroxyphenyl, 3-Ci-4alkyl-4-hydroxyphenyl, 3,5-diCi_4alkyl-4hydroxyphenyl or 4-methoxyphenyl when X = N and

is a radical of formula (a-1).

r

C (

f ²⁵

As used in the foregoing definitions halo defines fluoro, chloro, bromo and iodo; Cl-4alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl.

The term pharmaceutically acceptable acid addition salt as used hereinbefore defines the non-toxic, therapeutically active acid addition salt forms which the compounds of formula (I) may form. The compounds of formula (I) having basic properties may be converted into the corresponding therapeutically active, non-toxic acid addition salt forms by treating the free base form with a suitable amount of an appropriate acid following conventional procedures. Examples of appropriate acids are inorganic acids such as hydrohalic acid, i.e. hydrochloric, hydrobromic and the like acids, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids, such as, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic,

2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic,

2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids.

The term pharmaceutically acceptable acid addition salts also comprises the solvates which the compounds of formula (I) may form, e.g. the hydrates, alcoholates and the like.

The term stereochemically isomeric forms as used hereinbefore defines the different isomeric as well as conformational forms which the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically and conformationally isomeric forms, said mixtures containing all diastereomers, enantiomers and/or conformers of the basic molecular structure. AU stereochemically isomeric forms of the compounds of formula (I) both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention.

The absolute configuration of each chiral center may be indicated by the stereochemical descriptors R and S.

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-4Some compounds of the present invention may exist in different tautomeric forms and all such tautomeric forms are intended to be included within the scope of the present invention.

Particular compounds are those compounds of formula (I) wherein R⁴ and R⁵ each independently are hydrogen or halo, and Ar is phenyl substituted with up to three substituents selected from hydroxy, Ci-4alkyl and Cj^alkyloxy, or pyridinyl substituted with hydroxy or Ci^jalkyloxy.

A first group of interesting compounds are those compounds of formula (I) wherein Ar is a radical of formula

wherein

R⁶, R⁷, R¹®, R¹¹, Rl2 _an(j r13 _each independently are hydroxy or Cj^alkyloxy; and R⁸ and R⁹ are Chalky!.

A second group of interesting compounds are those compounds of formula (I) wherein Xis N.

A third group of interesting compounds are those compounds of formula (I) wherein

is a radical of formula (a-1), (a-2) or (a-3).

A fourth group of interesting compounds are those compounds of formula (I) wherein Y is N and R¹ is hydrogen.

A fifth group of interesting compounds are those compounds of formula (I) wherein R² is ethyl and is hydrogen.

A sixth group of interesting compounds are those compounds of formula (I) wherein R⁴ 30 is halo substituted at the para position and R^ is hydrogen.

Preferred compounds are those compounds of formula (I) wherein

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-5R? is Cj^alkyl;

R⁴ is halo substituted at the para position; and Rl, and R^ are hydrogen.

More preferred compounds are those preferred compounds wherein

Ar is hydroxyphenyl, methoxyphenyl, dimethoxyphenyl, Ci_4alkylphenyl, diCi_4alkylphenyl or methoxypyridinyl;

is a radical of formula (a-1), (a-2) or (a-3).

The most preferred compounds are [l-(4-chlorobenzoyl)propyl]-2,4-dihydro-4-[6-[4-(4-methoxyphenyl)-l-piperazinyl]-3pyridinyl]-3H-1,2,4-triazol-3-one;

2- [l-(4-chlorobenzoyl)propyl]-2,4-dihydro-4-[6-[4-(3-hydroxyphenyl)-l-piperazinyl]3- pyridinyl]-3H-1,2,4-triazol-3-one;

2-[l-[(4-chlorophenyl)hydroxymethyI]propyl]-2,4-dihydro-4-[6-[4-(3-hydroxyphenyl)1- piperazinyl]-3-pyridinyl]-3H-l,2,4-triazol-3-one;

2- [l-[(4-chlorophenyl)hydroxymethyl]propyl]-2,4-dihydro-4-[4-[4-(6-methoxy3- pyridinyl)-l-piperazinyl]phenyl]-3H-l,2,4-triazol-3-one;

2-[l-(4-chlorobenzoyl)propyl]-4-[6-[4-(3-methoxyphenyl)-l-piperazinyl]-3-pyridinyl]2,4-dihydro-3H-1,2,4-triazol-3-one;

2-[l-[(4-chlorophenyl)hydroxymethyl]propyl]-2,4-dihydro-4-[6-[4-(3-methoxyphenyl)1- piperazinyl]-3-pyridinyl]-3H-l,2,4-triazol-3-one;

2- [l-(4-chlorobenzoyl)propyl]-4-[6-[4-(3,4-dimethoxyphenyl)-l-piperidinyl]3- pyridinyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;

2-[l-[(4-chlorophenyl)hydroxymethyl]propyl]-2,4-dihydro-4-[4-[4-(6-methoxy2-pyridinyl)-1 -piperazinyl]phenyl]-3H-1,2,4-triazol-3-one; 2-[l-[(4-chlorophenyl)hydroxymethyl]propyl]-4-[6-[4-(3,4-dimethoxyphenyl)1- piperazinyl]-3-pyridinyl]-2,4-dihydro-3H-l,2,4-triazol-3-one; and

2- [l-(4-chlorobenzoyl)propyl]-4-[6-[4-(3,4-dimethoxyphenyl)-l-piperazinyl]3- pyridinyl]-2,4-dihydro-3H-1,2,4-triazol-3-one, the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof.

Procedures for the preparation of compounds such as the present compounds of formula (I) have been described in US-4,791,111 and US-4,931,444.

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AP ο Ο Ο 4 3 5 •6In particular, the compounds of formula (I) can be prepared by N-alkylating an intermediate of formula (II) with a reagent of formula (III).

(Π)

The N-alkylation reaction of (II) with (III) can conveniently be conducted by stirring and heating a mixture of the reagents in an appropriate solvent in the presence of a suitable base. Appropriate solvents are, for example dipolar aprotic solvents, e.g. N,N-dimethylC - formamide, Ν,Ν-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone; aromatic solvents,

e.g. benzene, methylbenzene; an ether, e.g 1,1 ’-oxybisethane, tetrahydrofuran; a halogenated hydrocarbon, e.g. dichloromethane, trichloromethane; or a mixture of such solvents.

Suitable bases are, for example, sodium bis(trimethylsilyl)amide, alkali metal and earth alkaline metal carbonates or hydrogen carbonates, e.g. sodium or potassium carbonate; or organic bases, e.g. triethylamine and the like bases.

The compounds of formula (I) can also be converted into each other following artknown procedures of functional group transformation.

For example, the compounds of formula (I) wherein Z represents C=O can be converted into the compounds of formula (I) wherein Z represents CHOH following art-known reductions. For example, said reduction can conveniently be conducted by reaction with a metal hydride or complex metal hydride, e.g. sodium borohydride, sodium cyanoboro25 hydride and the like in water, 1-methyl-pyrrolidinone, an alcoholic medium, e.g.

methanol, ethanol, or an ether, e.g. tetrahydrofuran, 1,4-dioxane; or in a mixture of such solvents.

Alternatively, said reduction can be conducted by reaction with tris(l-methylethoxy)30 potassium hydroborate in a reaction-inert solvent, e.g. tetrahydrofuran.

Further, the compounds of formula (I) wherein Ar is substituted with at least one hydroxy can be prepared from the corresponding Cj^alkyloxy derivatives by an appropriate dealkylation reaction, for example using trifluoroacetic acid, or in particular a

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Γ· c

( 25 c

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-7mineral acid such as concentrated hydrohalic acid, e.g. hydrobromic acid, hydroiodic acid, optionally in admixture with a saturated solution of hydrobromic acid in glacial acetic acid; a Lewis acid, e.g. boron tribromide in a reaction-inert solvent, e.g. dichloromethane. In the instance where hydrobromic acid is used it may be advantageous to conduct said dealkylation reaction in the presence of a bromine scavenger such as, for example sodium sulfite or hydrogen sulfite.

Conversely, the compounds of formula (I), wherein Ar is substituted with at least one Cj^alkyloxy can be prepared by alkylating the corresponding hydroxy derivatives with an appropriate alkylating reagent, e.g. dimethylsulfate and the like. Optionally, said alkylation may be carried out by applying art-known conditions of phase transfer catalysis reactions. Said conditions comprise stirring the reactants with an appropriate base, e.g. sodium hydroxide in a reaction-inert solvent, e.g. dichloromethane, in the presence of a suitable phase transfer catalyst, e.g. benzyltriethylammonium chloride and the like.

The compounds of formula (I) wherein Ar is substituted with a hydroxy group may be converted in the corresponding triCj_4alkylsilyloxy compound upon reaction with triCi-4alkyl-Si-L⁷, L⁷ being a reactive leaving group, e.g. halo, in a reaction-inert solvent, e.g. pyridine, dichloromethane.

Conversely, the compounds of formula (I) wherein Ar is substituted with a triCi_4alkylsilyloxy group may be converted in the corresponding hydroxy compound upon reaction with a fluoride such as (n-GtH^N+F' in a reaction-inert solvent, e.g. tetrahydrofuran, dichloromethane.

Finally, pure isomeric forms of the compounds of formula (I) can be separated from the mixture by conventional separation methods. In particular, the enantiomers may be separated by column chromatography using a chiral stationary phase such as a suitably derivatized cellulose, for example, tri(dimethylcarbamoyl)cellulose (Chiralcel OD®) and similar chiral stationary phases.

In all foregoing and in the following preparations, the reaction products may be isolated from the reaction mixture and, if necesarry, further purified according to methodologies generally known in the art.

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-8Some intermediates and starting materials in the foregoing preparations are known compounds which may be prepared according to art-known methodologies of preparing said or similar compounds

The intermediates of formula (II) can be prepared by cyclizing an intermediate of formula (IV) with a reagent of formula (V) or a derivative thereof.

NH

II

R¹ — C-NH₂ (Π) (V)

An appropriate reaction-inert solvent for the above cyclization reaction is, for example, a dipolar aprotic solvent, e.g. Ν,Ν-dimethylformamide, dimethyl sulfoxide and the like, or an alcohol, e.g. ethanol, 1-butanol and the like.

The intermediates of formula (IV) can be prepared by reacting an intermediate of formula 15 (VI) with hydrazine or a derivative thereof in a reaction-inert solvent, e.g. 1,4-dioxane and the like.

The intermediates of formula (VI) can be prepared by reacting an intermediate of formula (VII) with phenyl chloroform ate in a reaction-inert solvent, such as, for example, a dipolar aprotic solvent, e.g. N,N-dimethylformamide, Ν,Ν-dimethylacetamide, an aromatic solvent, e.g. pyridine, or a halogenated hydrocarbon, e.g. dichloromethane and the like, or a mixture of such solvents.

The intermediates of formula (VII) can be prepared by reducing the corresponding nitro compound of formula (VIII) following art-known procedures.

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(VII)

Suitable art-known reduction procedures are, for example, catalytic hydrogenation in a suitable solvent, e.g. methanol, tetrahydrofuran, Ν,Ν-dimethylformamide, in the presence of hydrogen and an appropriate catalyst, e.g. palladium-on-charcoal, Raney nickel and the like, optionally in the presence of thiophene.

Alternatively, the intermediates of formula (VII) can be prepared by reacting the compounds of formula (VIII) with hydrazine or a derivative thereof in a reaction-inert solvent, e.g. methanol, in the presence of a catalyst, e.g. Raney nickel.

Further, the intermediates of formula (VII) wherein

is a radical of formula (a-4) can be prepared by reacting the intermediates of formula (IX) or a derivative thereof according to the following reaction procedure.

Ar-X

(CH₃)₂N—CH=C-CHZZN(CH₃)2 N=CH-N(CH₃)₂

C1O₄‘

N=CH-N(CH₃)₂

Ar-X (VH-a) ,^N<

λ

N-

NH₂

The preparation of the intermediates of formula (X) as described above is conveniently conducted in a reaction-inert solvent, e.g. 1-propanol, methanol or a mixture thereof, preferably in the presence of a base, e.g. sodium methoxide. The preparation of the intermediates (Vll-a) from the intermediates (X) may be conducted in the presence of a base, e.g. sodium hydroxide and the like.

The intermediates of formula (VIII) can be prepared by reacting the intermediates of formula (XI) with a reagent of formula (XII) wherein L is a reactive leaving group, e.g.

halo, in a reaction-inert solvent, e.g. Ν,Ν-dimethylacetamide, dimethyl sulfoxide,

Ν,Ν-dimethylformamide, bis(2-methoxyethyl)ether, 3-methoxy-l-propanol and the like, preferably in the presence of a base, e.g. potassium carbonate and the like.

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Ar-X

N-H (XI)

(XII) (vni)

The intermediates of formula (XI) wherein X is N, said intermediates being represented by the formula (ΧΙ-a), can be prepared by reacting the intermediates of formula (XIII) with a reagent of formula (XIV) wherein L¹ and L² are reactive leaving groups, e.g. halo, in a reaction-inert solvent, e.g. 1-butanol, hexanol and the like, preferably in the presence of a base, e.g. potassium carbonate and optionally in the presence of a small amount of potassium iodide.

Ar—NH₂ +

H

L¹— CH₂—ch₂—n—ch₂—ch₂-l² (xni) (XIV)

Ar-N N-H (XI-a)

Optionally, the above reaction may be conducted using an N-protected intermediate (XIV), e.g. the tosyl derivative thereof. After reaction with intermediate (XIII), the protective group may be removed upon treatment with a diluted acid, e.g. sulfuric acid.

Alternatively, the intermediates of formula (XI-a) wherein Ar is substituted with methoxy can be prepared by the following reaction procedure.

Ar*

(X'h

X¹ —Ar

acid (' c

-N^N-CH₂^~^ (XVIII)

CH₃O—Ar

N-H (XI-a-1)

Ar¹ as used hereinabove represents phenyl of pyridinyl, P¹ represents a protective group, e.g. Ci-4alkyloxycarbonyl, X¹ represents halo, in particular bromo or iodo, and

L³ represents a reactive leaving group, e.g. halo. The preparation of the intermediates of formula (XVI) is preferably conducted in a reaction-inert solvent, e.g. carbon disulfide.

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-11The protective group in the intermediates of formula (XVI) may be removed upon treatment with an acid, e.g. hydrobromic acid. The preparation of the intermediates of formula (XVIII) preferably is conducted in a reaction-inert solvent, e.g. dimethylbenzene, optionally in the presence of a base, e.g. sodium hydrogen carbonate. Further, the preparation of the intermediates of formula (XIX) as described above may optionally be conducted in the presence of a catalyst, e.g. copper(I)iodide and the like, optionally under nitrogen atmosphere. Finally, the benzyl moiety in the intermediates of formula (XIX) may be removed upon catalytic hydrogenation following art-known procedures. Alternatively, the intermediate of formula (XVI) may be prepared from the corresponding aniline compound following art-known procedures.

In order to prepare the intermediates of formula (II), an intermediate of formula (VI) can be reacted with a reagent of formula (XX) wherein L⁴ and L⁵ are reactive leaving groups, e.g. CMalkyloxy, in a reaction-inert solvent, e.g. 1,4-dioxane and the like, yielding an intermediate of formula (XXI). The latter intermediate may then be cyclized upon treatment with an acid, e.g. hydrochloric acid.

In a further alternative, the intermediates of formula (II) can be prepared by first reacting an intermediate of formula (VI) with a reagent of formula (XXII) or a derivative thereof in a reaction-inert solvent, e.g. 1,4-dioxane, optionally in the presence of a base, e.g.

N,N-dimethyl-4-pyridinamine to yield an intermediate of formula (ΧΧΙΠ). The latter intermediate may then be cyclized upon treatment with an acid, e.g. formic acid.

/^-\ °x x° h₂n-ch₂—c— (XXII)

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C (' 20 (

(XXIII) acid (II)

The intermediates of formula (II) can also be prepared by reacting an intermediate of formula (VII) with a reagent of formula (XXIV) wherein R⁶ is Cj^alkyl, e.g.methyl or ethyl, and L⁶ represents a reactive leaving group, e.g. Ci^alkyloxy or di(Ci_6alkyl)amino, e.g. methoxy, ethoxy or dimethylamino, in a reaction-inert solvent, e.g. tetrahydrothiophene 1,1-dioxide and the like.

R⁶OOC-NH ^κγΝ

L⁶ (XXIV) (Π)

The compounds of formula (I), the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof display useful pharmacological activity against Helicobacter species; e.g. Helicobacter pylori, Helicobacter mustelae, Helicobacter felis and the like, in particular Helicobacter pylori.

Particularly important in this context is the finding that the subject compounds show inhibitory activity against the growth of Helicobacter as well as bactericidal activity against said bacteria. The bactericidal effect on Helicobacter was determined with suspension cultures by means of a procedure described in Antimicrob. Agents Chemother., 1991, vol. 35, pp. 869-872.

An interesting feature of the present compounds relates to their highly specific activity against Helicobacter. The compounds of formula (I) were found to show no inhibitory activity against any of the following species: Campylobactor jejuni, Campylobacter coli, Campylobacter fetus, Campylobacter sputorum, Vibrio spp., Staphylococcus aureus and Escherichia coli, tested at concentrations up to 10'³ M.

An important asset of the present compounds is their sustained activity against H. pylori at pH below the normal neutral pH. Activity at a low pH in vitro may indicate that a compound is not adversely affected by the acidic environment of the stomach in vivo.

Consequently, the subject compounds are considered to be valuable therapeutical drugs for treating warm-blooded animals, particularly humans, suffering from Helicobacter

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-13related diseases or afflictions. Examples of said diseases or afflictions are gastritis, stomach ulcers, duodenal ulcers and gastric cancer.

In view of their useful anti-Helicobacter properties, the subject compounds may be formulated into various pharmaceutical forms for administration purposes. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, in base or acid addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, rectally, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions: or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.

When the pharmaceutical composition takes the form of an aqueous solution, those compounds of formula (I) which display low solubility may be formulated as a salt form, or a co-solvent may be added which is water-miscible and physiologically acceptable, e.g. dimethylsulfoxide and the like, or the compounds of formula (I) may be solubilized with a suitable carrier, e.g. a cyclodextrin (CD) or in particular a cyclodextrin derivative such as the cyclodextrin derivates described in US-3,459,731, EP-A-149,197 (July 24, 1985), EP-A-197,571 (October 15, 1986), US-4,535,152 or WO 90/12035 (October 18, 1990). Typically such derivatives comprise α-, β- or γ-CD wherein one or more hydroxylgroups are substituted with Cj.^alkyl, particularly methyl, ethyl or isopropyl; hydroxyCi.^alkyl, particularly hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxyCi_6alkyl, particularly carboxymethyl or carboxyethyl; Ci.^alkylcarbonyl, particularly acetyl; Ci.^alkyloxycarbonylCi.^alkyl; carboxyChalkyloxyCi.galkyl, particularly carboxymethoxypropyl or carboxyethoxypropyl or Cj.galkyl35

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I 25

C

-14carbonyloxyCi-galkyl, particularly 2-acetyloxypropyl. Especially noteworthy as complexants and/or solubilizers are β-CD, 2,6-dimethyl-p-CD and in particular

2-hydroxypropyl-p-CD, 2-hydroxyethyl*p-CD, 2-hydroxyethyl-y-CD, 2-hydroxypropyl-y-CD and (2-carboxymethoxy)propyl-p-CD. In the aforementioned cyclodextrin derivatives, the DS (degree of substitution, i.e. the average number of substituted hydroxy functions per glucose unit) is preferably in the range of 0.125 to 3, in particular

0.2 to 2, or 0.2 to 1.5. More preferably the DS ranges from about 0.2 to about 0.7, in particular from about 0.35 to about 0.5 and most particularly is about 0.4. The MS (molar degree of substitution, i.e. the average number of moles of the substituting agent per glucose unit) is in the range of 0.125 to 10, in particular of 0.3 to 3, or 0.3 to 1.5. More preferably the MS ranges from about 0.3 to about 0.8, in particular from about 0.35 to about 0.5 and most particularly is about 0.4. The most preferred cyclodextrin derivative for use in the compositions of the present invention is hydroxypropyl-βcyclodextrin having a M.S. in the range of from 0.35 to 0.50 and containing less than 1.5% unsubstituted β-cyclodextrin. The amount of the cyclodextrin or ether derivative thereof in the final composition generally ranges from about 1% to about 40%, particularly from 2.5% to 25% and more particularly from 5 % to 20%.

It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions and the like, and segregated multiples thereof.

In view of the usefulness of the subject compounds in the treatment of Helicobacter related diseases it is evident that the present invention provides a method of treating warm-blooded animals, in particular humans, suffering from Helicobacter related diseases, said method comprising the systemic administration of a pharmaceutically effective amount of a compound of formula (I), a pharmaceutically acceptable acid addition salt thereof or a stereochemically isomeric form thereof, in admixture with a pharmaceutical carrier. In general it is contemplated that an effective daily amount would be from 0.05 mg/kg to 20 mg/kg body weight, preferably from 0.1 mg/kg to 10 mg/kg body weight and more preferably form 0.5 mg/kg to 5 mg/kg body weight.

It is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician

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-15prescribing the compounds of the instant invention. The effective daily amount ranges mentioned hereinabove are therefore guidelines only and are not intended to limit the scope or use of the invention to any extent.

Optionally, other active compounds used for the eradication of Helicobacter can be administered in combination with the compounds of the present invention. The administration may occur separately (i.e. simultaneously, concurrently or consecutively) or the different drugs may be combined in one dosage form. The preferred compounds for a combination therapy are bismuth compounds, e.g. bismuth subcitrate, bismuth subsalicylate, and the like, and proton pump inhibitors, e.g. omeprazole, lansoprazole, and the like.

r

Experimental Part A, Preparation of the intermediates

Example 1

a) A mixture of l-(4-methoxyphenyl)piperazine dihydrochloride (0.050 mol), 1-chloro4-nitrobenzene (0.050 mol) and potassium carbonate (lO.Og) in N,N-dimethylformamide (100ml) was stirred and refluxed overnight. The reaction mixture was diluted with water and extracted twice with trichloromethane. The organic layers were combined, dried (MgSO4), filtered and evaporated in vacuum. The residue was successively triturated in 4-methyl-2-pentanone and recrystallized from 1,4-dioxane. The product was filtered off and dried, yielding 10.5g (67%) of l-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine; mp. 195.1°C (interm. 1).

b) A mixture of intermediate (1) (0.038 mol) in methanol (250ml) and tetrahydrofuran (250ml) was hydrogenated at normal pressure and room temperature with palladium on activated carbon 10% (2g) as a catalyst. After uptake of hydrogen (3 equiv), the catalyst ( was filtered off and rinsed with Ν,Ν-dimethylacetamide. The combined filtrates were poured into water. The precipitate was filtered off and recrystallized from 1-butanol.

The product was filtered off and dried, yielding 8g (74%) 4-[4-(4-methoxyphenyl)30 l-piperazinyl]benzenamine; mp. 191.8°C (interm. 2).

c) A mixture of intermediate (2) (0.021 mol) and phenyl chloroformate (0.023 mol) in pyridine (75 ml) and dichloromethane (75ml) was stirred and heated until complete dissolution. Stirring was continued for 30 minutes at room temperature. The reaction mixture was poured into a mixture of 500ml of water and 300ml of 2,2'-oxybispropane.

After stirring, the precipitate was filtered off, dried and recrystallized from 1-butanol.

The product was filtered off and dried, yielding 5.2g (61%) of phenyl [4-[4-(4-methoxyphenyl)-l-piperazinyl]phenyl]carbamate; mp. 204.5°C (interm. 3).

d) A mixture of intermediate (3) (0.008 mol) in hydrazine monohydrate (50 ml) and

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-161,4-dioxane (100 ml) was stirred and refluxed for 3 hours. After cooling, the reaction mixture was poured into water. The precipitate was filtered off and recrystallized from Ν,Ν-dimethylformamide. The product was filtered off and dried, yielding 1.7g (62%) of N-[4-[4-(4-methoxyphenyl)-1 -piperazinyl]phenyl]hydrazinecarboxamide; mp.

>300°C (interm. 4).

e) A mixture of intermediate (4) (0.001 mol) and methanimidamide acetate (0.029 mol) in dimethyl sulfoxide (10ml) was heated for 2 hours at 160°C. After cooling, the reaction mixture was poured into a mixture of 4-methyl-2-pentanone and 2,2’-oxybispropane. The precipitate was filtered off and treated with activated charcoal in N,N-di10 methylformamide. After filtration, the product was allowed to crystallize. The product was filtered off and dried, yielding lg (28%) of 2,4-dihydro-4-[4-[4-(4-methoxy^< phenyl)-l-piperazinyl]phenyl]-3H-l,2,4-triazol-3-one; mp > 300°C (interm. 5).

( Example 2

A mixture of intermediate (4) (0.15mol) and ethanimidamide hydrochloride (0.56mol) in Ν,Ν-dimethylformamide (150ml) was stirred for 3 hours at 130°C. After cooling, the reaction mixture was poured into water. The precipitate was filtered off, washed with water and CH3OH and crystallized from Ν,Ν-dimethylformamide. The product was filtered off and recrystallized from 1,4-dioxane, yielding 19.5g (33.3%) of 2,4-dihydro20 4-[4-[4-(4-methoxyphenyl)-1 -piperazinyl]phenyl]-5-methyl-3H-1,2,4-triazol-4-one;

mp. 298.4°C (interm. 6).

Example 3

a) A mixture of 10 g of intermediate (3), 3 g of 2,2-dimethoxyethanamine and 100 ml of ( 25 1,4-dioxane was stirred and refluxed for 6 hours. The reaction mixture was cooled.

The precipitated product was filtered off, washed with 1,4-dioxane and purified by ( column-chromatography over silica gel using a mixture of trichloromethane and methanol (99:1) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 1,4-dioxane, yielding 3.9 g of N-(2,230 dimethoxyethyl)-N’-[4-[4-(4-methoxyphenyl)-l-piperazinyl]phenyl]urea; mp. 225°C (interm. 7).

b) A mixture of 70 g of intermediate (7), 84 g of concentrated hydrochloric acid, 300 ml of water and 350 ml of methanol was stirred and heated for 30 minutes at 80°C. The reaction mixture was allowed to cool to room temperature while the product was allowed to crystallize. It was filtered off, washed with water and dried, yielding 24.5 g (37%) of l,3-dihydro-l-[4-[4-(4-methoxyphenyl)-l-piperazinyl]phenyl]-2H-imidazol-2-one monohydrochloride monohydrate; mp. 256.2°C (interm. 8).

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AP Ο 00 43 5

-1710 f^Λ c

( 25 c

Example 4

a) A mixture of 4.4 g of intermediate (3), 1.6 g of 2-aminomethyl-2-methyl-l,3dioxolane monohydrate, 100 ml of 1,4 dioxane, 1 g of N,N-dimethyl-4-pyridinamine and 4 g of Ν,Ν-diethylethanamine were stirred and refluxed for 3 hours. Water was added and the mixture was cooled and allowed to crystallize. The product was filtered off, washed with water and 2-propanol and dried, yielding 3.8 g (89.1%) of N-[4-[4-(4methoxyphenyl)-l-piperazinyl]phenyl]-N’-[(2-methyl-l,3-dioxolane-2-yl)methyl]urea (interm. 9)

b) A mixture of 3.3 g of intermediate (9) and 100 ml of formic acid was stirred for 1 hour at 70°C. The reaction mixture w’as evaporated and the residue was neutralized with a sodium hydrogen carbonate solution. 4-Methyl-2-pentanone was added. The whole was stirred and the product was filtered off. The residue was washed with water and

4-methyl-2-pentanone. The product was recrystallized from Ν,Ν-dimethylformamide, yielding 2.0 g (71.3%) of l,3-dihydro-l-[4-[4-(4-methoxyphenyl)-l-piperazinyl]phenyl]-5-methyl-2H-imidazol-2-one; mp. > 300°C (interm. 10).

Example 5

a) To a stirred and cooled (<10°C) mixture of 150 g of ethyl 4-(2-pyridinyl)-l-piperazinecarboxylate and 1535 ml of carbon sulfide were added dropwise 32.8 ml of bromine. Upon completion, stirring was continued for 18 hours, while meantime the mixture was allowed to reach room temperature. At a temperature below 20°C, there was added a solution of 70 g of sodium hydroxide solution 10N in 300 ml of water.

After stirring for 3 hours at room temperature, the layers were separated. The aqueous phase was extracted twice with trichloromethane. The combined organic phases were washed with water, dried, filtered and evaporated. 46 ml of benzene were added to the residue and the whole was evaporated again. Upon standing for 48 hours, the product was solidified. The oily phase was decanted and the solid product was crystallized twice from 2,2’-oxybispropane at 10°C. It was filtered off and dried, yielding 100 g of ethyl

4-(5-bromo-2-pyridinyl)-l-piperazinecarboxylate; mp. 68°C (interm. 11).

b) A mixture of 18 g of intermediate (11) and 50 ml of an aqueous hydrobromic acid solution 48% was stirred and refluxed for 2 hours. The reaction mixture was cooled and evaporated. The solid residue was dissolved in water and the solution was alkalized with a sodium hydroxide solution 10N at a temperature below 20°C. The product was extracted twice with trichloromethane. The combined extracts were washed with water, dried, filtered and evaporated. The solid residue was dried at room temperature at the air, yielding 12.3 g of l-(5-bromo-2-pyridinyl)piperazine; mp. 70.6°C (interm. 12).

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AP Ο Ο Ο 4 3 5

-18c) A mixture of 9.7 g of intermediate (12), 3.7 g of sodium hydrogen carbonate and 40 ml of dimethylbenzene was stirred and heated to reflux. Then there was added dropwise a solution 4.8 ml (bromomethyl)benzene in 10 ml dimethylbenzene at reflux. Upon completion, stirring at reflux was continued for 4 hours. The reaction mixture was cooled to room temperature, 75 ml of water were added and the layers were separated. The aqueous phase was extracted with trichloromethane. The combined organic phases were dried, filtered and evaporated in vacuo. The residue was crystallized from 2,2’-oxybispropane at 4°C. The product was sucked off and dried, yielding 6.5 g of l-(5-bromo-2-pyridinyl)-4-(phenylmethyl)piperazine; mp. 100°C (interm. 13).

d) Sodium (0.6 mol) was added portionwise to methanol (500ml) upon stirring and the mixture was stirred till all the product reacted. Intermediate (13) (0.15 mol), cuprous iodide (0.15 mol) and Ν,Ν-dimethylformamide (500ml) were added and the mixture was stirred and refluxed for 48 hours. The mixture was filtered off and evaporated. The residue was purified by column chromatography over silica gel (eluent: EtOAc/hexane/

CH2CI2 1/1/2). The pure fractions were collected and evaporated, yielding 33.5g (79%) of l-(5-methoxy-2-pyridinyl)-4-(phenylmethyl)piperazine (interm 14).

e) Intermediate (14) (0.11 mol) in methanol (250ml) was hydrogenated with palladiumon-activated charcoal (10%) (7g) as a catalyst at 50°C. After uptake of hydrogen (2eq), the catalyst was filtered off and the filtrate was evaporated, yielding 19.3g (88%) of l-(5-methoxy-2-pyridinyl)piperazine (interm. 15).

f) A mixture of intermediate (15) (0.094 mol) and Ν,Ν-dimethylacetamide (0.15 mol) in potassium carbonate (100ml) was stirred at room temperature. l-Fluoro-4-nitrobenzene (0.12 mol) was added dropwise and the mixture was stirred at room temperature overnight. The mixture was poured into water, the precipitate was filtered off and dried, yielding 20.6g (70%) of product. A sample (lg) was crystallized from 2-propanol and purified by column chromatography over silica gel (eluent: CH2CI2/CH3CN/CH3OH 97/2/0.25). The pure fractions were collected and evaporated. The residue (0.8g) was triturated with 2,2'-oxybispropane, yielding 0.8g of l-(5-methoxy-2-pyridinyl)4-(4-nitrophenyl)piperazine; mp. 160.2°C (interm. 16).

g) Intermediate (16) (0.062 mol) in Ν,Ν-dimethylformamide (500ml) was hydrogenated with Raney nickel (6g) as a catalyst at 50°C overnight. After uptake of hydrogen (3eq), the catalyst was filtered off and the filtrate was evaporated. The residue was used without further purification, yielding 17.6g (100%) of 4-[4-(5-methoxy-2-pyridinyl)l-piperazinyl]benzenamine (interm. 17).

h) Phenyl chloroformate (0.11 mol) was added dropwise to a stirring mixture of intermediate (17) (0.062 mol) in Ν,Ν-dimethylformamide (100ml) on a waterbath and the mixture was stirred overnight. Water was added, the precipitate was filtered off and

BAD ORIGINAL A

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C ί 25

Γ

-19dried, yielding 25g (99%) of phenyl [4-[4-(5-methoxy-2-pyridinyl)-l-piperazinyl]phenyl]carbamate (interm. 18).

i) A mixture of intermediate (18) (0.062 mol) and hydrazine monohydrate (0.62 mol) in

1,4-dioxane (500ml) was stirred at 50°C for 48 hours. The mixture was poured into water, the precipitate was filtered off and dried, yielding 15g (71%) of N-[4-[4-(5methoxy-2-pyridinyl)-l-piperazinyl]phenyl]hydrazinecarboxamide (interm. 19).

j) A mixture of intermediate (19) (0.044 mol) and methanimidamide acetate (0.22 mol) in 1-butanol (300ml) was stirred and refluxed overnight. The mixture was poured into water and extracted with CH2CI2. The organic layer was dried, filtered off and evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2CI2/CH3OH 95/5). The pure fractions were collected and evaporated, yielding 3.2g of 2,4-dihydro-4-[4-[4-(5-methoxy-2-pyridinyl)-l-piperazinyl]phenyl]-3H-l,2,4-triazol3-one (interm. 20).

Example 6

a) A mixture of 36 g of l-(4-methoxyphenyl)piperazine dihydrochloride, 22 g of

2-chloro-5-nitropyridine, 58 g of potassium carbonate and 227 ml of dimethyl sulfoxide was stirred overnight at 140°C. The reaction mixture was cooled and poured onto water. The precipitated product was filtered off, washed with water and dissolved in dichloromethane. The solution was treated with activated charcoal. The latter is filtered off and the filtrate was evaporated. The residue was triturated in 2-propanol. The product was filtered off and crystallized from 1-butanol, yielding 24.5 g of l-(4-methoxyphenyl)-4(5-nitro-2-pyridinyl)piperazine; mp. 170°C (interm. 21).

b) To a mixture of 36 ml of hydrazine monohydrate, 4.0 g of Raney nickel and 1000 ml of methanol in reflux, were added portionwise over 25 minutes 35.0 g of intermediate (21). After stirring for 35 minutes at reflux temperature, an additional 11 ml of hydrazine monohydrate was added. The reflux was continued for 10 minutes. An additional 0.5 g of Raney nickel was added and the mixture was refluxed for 15 minutes. The reaction mixture was cooled, the catalyst was filtered off and the filtrate was evaporated, yielding 33.57 g of 6-[4-(4-methoxyphenyl)-l-piperazinyl]-3-pyridinamine as crude product; mp. 144-147°C (interm. 22).

c) A mixture of 31.21 g intermediate (22), 38.40 g of (1-ethoxyethylidene) hydrazinecarboxylic acid ethyl ester and 10 ml of tetrahydrothiophene 1,1 -dioxide was heated in an oil bath of 154-158°C for 17 hours. After cooling, 150 ml of 2-propanol was added and the mixture was filtered. The residue was recrystallized from a mixture of acetonitrile and Ν,Ν-dimethylformamide (90/10). The residue was purified by flash chromatography (eluent; CH2CI2 / CH3OH(NH4OH 10%) 98:2 -> 96:4). The eluent of

BAD ORIGINAL

AP 0 0 0 4 3 5

-20the desired fraction was evaporated and the residue was recrystallized from a mixture of Ν,Ν-dimethylformamide and acetonitrile, yielding 2,4-dihydro-4-[6-[4-(4-methoxyphenyl)-1 -piperazinyl]-3-pyridinyl]-5-methyl-3H-1,2,4-triazol-3-one; mp. 251-252°C (interm. 23).

Example 7

a) To a mixture of 20 g of 4-(4-methoxyphenyl)-l-piperazinecarboximidamide and 21 g of N-[3-(dimethylamino)methylene]amino]-2-propenylidene]-N-methylmethanaminium perchlorate in 200 ml of 1-propanol were added dropwise 70 ml of a solution of sodium methoxide in methanol (1M). After stirring for 2 hours there were added dropwise again 70 ml of a solution of sodium methoxide in methanol (1M). Then the mixture was stirred and refluxed for 2 hours. After cooling, the reaction mixture was evaporated and the residue was purified by column chromatography (eluent: CH2CI2/CH3OH 97:3).

The eluent of the desired fraction was evaporated, yielding 15 g (62.5%) of N-[(dimethylamino)methylene]-2-[4-(4-methoxyphenyl)-l-piperazinyl]-5-pyrimidinamine (interm. 24);

b) A mixture of 10 g of intermediate (24) and 150 ml of sulfuric acid (0.2M) was stirred and refluxed for 4 hours. After cooling, the mixture was neutralized with a solution of potassium carbonate in water. The product was extracted with dichloromethane and the extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography (eluent: CH2CI2/CH3OH 98:2). The eluent of the desired fraction was evaporated and the residue was crystallized from ethyl acetate. The product was filtered off and dried in vacuo at 50°C, yielding 3.5 g (40.9%) of 2-[4-(4-methoxyphenyl)-l-piperazinyl]-5-pyrimidinamine; mp. 157.1°C (interm. 25).

c) To a stirred mixture of 10 g of intermediate (25) in 100 ml of Ν,Ν-dimethylacetamide on an ice-bath was added dropwise 4.8 ml of phenyl chloroformate. After stirring for hours at room temperature, the reaction mixture was poured into ice-water. The precipitate was filtered off and dried in vacuo at 50°C, yielding 7.7 g (54.3%) of phenyl [2-[4-(4-methoxyphenyl)-1 -piperazinyl]-5-pyrimidinyl]carbamate (interm. 26).

d) A mixture of 7.7 g of intermediate (26), 10 ml hydrazine monohydrate and 60 ml of

1,4-dioxane was stirred overnight at room temperature. The reaction mixture was poured into water and the precipitate was filtered off and washed with methanol. The product was purified by column chromatography (eluent: CH2CI2/CH3OH 96:4). The eluent of the desired fraction was evaporated and the residue was stirred in methanol, filtered off and dried in vacuo at 75°C, yielding 1.5 g (23.0%) of N-[2-[4-(4-methoxyphenyl)-l-piperazinyl]-5-pyridinyl]hydrazinecarboxamide; mp. > 300°C (decomp.) (interm. 27).

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AP Ο Ο Ο 4 3 5 <· [

C { 25

C

-21e) A mixture of 3 g of intermediate (27), 3.7 g of methanimidamide acetate and 35 ml of

1-butanol was stirred and refluxed overnight. The reaction mixture was cooled and the precipitate was filtered off, washed with 2,2'-oxybispropane and dried in vacuo at 70°C, yielding 2.0 g (62.9%) of 2,4-dihydro-4-[2-[4-(4-methoxyphenyl)-l-piperazinyl]-5pyrimidinyl]-3H-l,2,4-triazol-3-one; mp. 272.5°C (interm. 28).

Example 8

a) A mixture of 6-methoxy-3-pyridinamine (0.2 mol) and 2-chloro-N-(2-chloroethyl)ethanamine hydrochloride (0.3 mol) in 2-butanol (500ml) was stirred and refluxed. Potassium carbonate (0.7 mol) was added portionwise (20g/h), the mixture was refluxed for 48 hours, an additional amount of potassium carbonate (30g) was added and the mixture was stirred for 48 hours. The mixture was poured into water, extracted with CH2CI2 and separated. The organic layer was dried, filtered and evaporated, yielding 38g (98%) of l-(6-methoxy-3-pyridinyl)piperazine (interm. 29).

b) A mixture of intermediate (29) (0.2 mol) and potassium carbonate (0.5 mol) in Ν,Ν-dimethylacetamide (500ml) was stirred at room temperature. l-Fluoro-4-nitrobenzene (0.24 mol) was added dropwise and the mixture was stirred overnight. The mixture was poured into water and the precipitate was filtered off, yielding 16.3g (30%) of l-(6-methoxy-3-pyridinyl)-4-(4-nitrophenyl)piperazine (interm. 30).

In a similar way but using bis(2-methoxyethyl)ether as a solvent there were prepared:

1- (3-methoxyphenyl)-4-(5-nitro-2-pyridinyl)piperazine (interm. 31);

2- [4-(3-methoxyphenyl)-l-piperidinyl]-5-nitropyridine; mp. 147.3°C (interm. 32); and l-(2-methoxyphenyl)-4-(5-nitro-2-pyridinyl)piperazine; mp. 130.8°C (interm. 33).

c) Intermediate (30) (0.042 mol) in Ν,Ν-dimethylformamide (500ml) was hydrogenated with Raney nickel (6g) as a catalyst at 50°C overnight. After uptake of hydrogen (3 eq.), the catalyst was filtered off and the filtrate was evaporated. The residue was triturated with 2,2'-oxybispropane, yielding 11.5g (96%) of product. A sample (0.5g) was recrystallized from 2,2'-oxybispropane, yielding 0.3g of 4-[4-(6-methoxy-3-pyridinyl)l-piperazinyl]benzenamine mp. 150.0°C (interm. 34).

In a similar way there were prepared :

6-[4-(3-methoxyphenyl)-l-piperazinyl]-3-pyridinamine; mp. 110.6°C (interm. 35); 6-[4-(3-methoxyphenyl)-l-piperidinyl]-3-pyridinamine; mp. 124.9°C (interm. 36); and 6-[4-(2-methoxyphenyl)-l-piperjzinyl]-3-pyridinamine (interm. 37).

d) A mixture of intermediate (34) (0.025 mol) and ethyl 2-[(dimethylamino)methylene]hydrazinecarboxylate (0.075 mol) in tetrahydrothiophene 1,1-dioxide (10ml) was stirred at 150°C for 5 hours. A mixture of 2-propanol/2,2'-oxybispropane 50/50 was added.

The precipitate was filtered off, washed and dried, yielding 6.5g (74%) of 2,4-dihydro35

BAD ORIGINAL &

AP Ο Ο Ο 4 3 5

-2210 s~Ο ( 25 (

4-[4-[4-(6-methoxy-3-pyridinyl)-1 -pi pe razin y I ]phe ny 1 ] - 3Η-1,2,4-triazol-3-one (interm. 38).

In a similar way there were prepared :

2.4- dihydro-4-[6-[4-(3-methoxyphenyl)-l-piperazinyl]-3-pyridinyl]-3H-l,2,4-triazol-3one; mp. 242.6°C (interm. 39);

2.4- dihydro-4-[6-[4-(3-methoxyphenyl)-l-piperidinyI]-3-pyridinyl]-3H-l,2,4-triazol-3one (interm. 40); and

2.4- dihydro-4-[6-[4-(2-methoxyphenyl)-l-piperazinyl]-3-pyridinyl]-3H-l,2,4-triazol-3one (interm. 41).

Example 9

a) A mixture of 10 g of 4-methoxy-3,5-dimethylbenzenamine hydrochloride, 19.9 g of N,N.-bis(2-chloroethyl)-4-methylbenzenesulfonamide, 16.8 g of sodium carbonate, 0.5 g of potassium iodide and 100 ml of cyclohexanol was stirred overnight at 150-160°C. After cooling, the reaction mixture was 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 over silica gel using trichloromethane as eluent. The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 1-butanol, yielding 10 g (50.4%) of 4-(4-methoxy-3,5-dimethylphenyl)-l-[(4-methylphenyl)sulfonyl]piperazine;

mp. 174.2°C (interm. 42).

b) A mixture of 77.6 g of intermediate (42), 121.2 ml of concentrated sulfuric acid and 140 ml of water was stirred and refluxed overnight. Another portion of 30.4 g of concentrated sulfuric acid was added and stirring at reflux was continued overnight. The reaction mixture was cooled and treated with sodium hydroxide. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was converted into the hydrochloric salt in 2-propanol and 2,2’-oxybispropane. The salt was filtered off and crystallized from 2-propanol, yielding 18.5 g of l-(4-methoxy-3,5-dimethylphenyl)piperazine dihydrochloride (interm. 43).

c) A mixture of 14.1 g of l-fluoro-4-nitrobenzene, 26 g of intermediate (43), 15gof sodium carbonate and 272.7 ml of dimethyl sulfoxide was stirred for 4 hours at 60°C. The reaction mixture was cooled and poured into water. The product was extracted with methylbenzene. The extract was washed with water, dried, filtered and evaporated. The residue was triturated in 2,2-oxybispropane. The product was filtered off and crystallized from 2-propanol, yielding 17.5 g (64.1%) of l-(4-methoxy-3,5-dimethylphenyl)4-(4-nitrophenyl)piperazine; mp. 135.3°C (interm. 44).

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AP Ο Ο Ο 4 3 5

Ο

C 25

C

-23d) A mixture of 15 g of intermediate (44), 1 ml of a solution of thiophene in methanol (4%) and 202.5 ml of methanol was hydrogenated at normal pressure and at 50°C with 2 g of palladium-on-charcoal catalyst (10%). After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was converted into the hydrochloride salt in 2-propanol. The salt was filtered off and dried, yielding 15.7 g (92.8%) of 4-[4-(4-methoxy-3,5-dimethylphenyl)-l-piperazinyl]benzenamine dihydrochloride; mp. 289.5°C (interm. 45).

e) A mixture of 65 g of intermediate (45), 39.3g of (l-ethoxyethylidene)hydrazinecarboxylic acid ethyl ester and 100 ml of tetrahydrothiophene 1,1-dioxide was stirred for 3 hours at 120°C under a nitrogen atmosphere. The mixture was cooled and

2- propanol was added. The obtained precipitate was filtered off and dried. The residue was purified by column chromatography (eluent: CHCI3/CH3OH 99:1). The eluent of the desired fraction was evaporated and the residue was crystallized from 1,4-dioxane, yielding 36.75 g (44.9%) of 2,4-dihydro-4-[4-[4-[4-methoxy-3,5-dimethylphenyl)l-piperazinyl]phenyl]-5-methyl-3H-l,2,4-triazol-3-one; mp. 280.1°C (interm. 46).

B. Preparation of the final compounds

Example 10

A mixture of 2,4-dihydro-4-[6-[4-(4-methoxyphenyl)-l-piperazinyl]-3-pyridinyl]-3Hl,2,4-triazol-3-one (0.014 mol) and sodium carbonate (0.06 mol) in methylbenzene (30ml) and Ν,Ν-dimethylformamide (70ml) was stirred and refluxed. 2-Bromo-l-(4chlorophenyl)-l-butanone (0.015 mol) in trichloromethane (20ml) was added dropwise and the mixture was stirred and refluxed with a water separator for lhour. The mixture was filtered warm and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2CI2/CH3OH 98/2). The pure fractions were collected and evaporated. The residue was crystallized from 2-propanol, yielding 6g (80%) of (±)-2-[l-(4-chlorobenzoyl)propyl]-2,4-dihydro-4-[6-[4-(4-methoxyphenyl)l-piperazinyl]-3-pyridinyl]-3H-l,2,4-triazol-3-one; mp. 142.4°C (comp. 1).

In a similar way there were prepared :

(±)-2-[l-(4-chlorobenzoyl)propyl]-2,4-dihydro-4-[5-[4-(4-methoxyphenyl)l-piperazinyl]-2-pyridinyl]-3H-l,2,4-triazol-3-one; mp. 127.2°C (comp. 2); (±)-2-[l-(4-chlorobenzoyl)propyl]-2,4-dihydro-4-[4-[4-(5-methoxy-2-pyridinyl)l-piperazinyl]phenyl]-3H-l,2,4-triazol-3-one; mp. 165.1°C (comp. 3); (±)-2-[l-(4-chlorobenzoyl)propyl]-4-[6-[4-(3-methoxyphenyl)-l-piperazinyl]3- pyridinyl]-2,4-dihydro-3H-l,2,4-triazol-3-one; mp. 128.3°C (comp. 4);

(±)-2-[l-(4-chlorobenzoyl)propyl]-2,4-dihydro-4-[6-[4-(2-methoxyphenyl)l-piperazinyl]-3-pyridinyl]-3H-l,2,4-triazol-3-one; mp. 195.6°C (comp. 5);

BAD ORIGINAL

A

R 96.273

R 96.9S9

Γ ( 25

C

-24(±)-2-[l-(4-chlorobenzoyl)propyl]-2,4-dihydro-4-[4-[4-(6-methoxy-3-pyridinyl)l-piperazinyl]phenyl]-3H-l,2,4-triazol-3-one; mp. 188.4°C (comp. 6); (±)-2-[l-(4-chlorobenzoyl)propyl]-2,4-dihydro-4-[6-[4-(3-methoxyphenyl)l-piperidinyl]-3-pyridinyl]-3H-l,2,4-triazol-3-one; mp. 125.7°C(comp. 7);

(+)-2-( l-(4-chlorobenzoyl)propyl]-2,4-dihydro-4-[6-[4-(5-methoxy-2-pyridinyl)l-piperazinyl]-3-pyridinyl]-3H-l,2,4-triazol-3-one; mp. 145.9°C (comp. 37);

(±)-2-[ 1 -(4-chlorobenzoyl)propyl]-2,4-dihydro-4-[4-(4-phenyl- l-piperazinyl)phenyl]3H-l,2,4-triazol-3-one; mp. 18O.7°C (comp. 39);

(±)-2-[l-(4-chlorobenzoyl)propyl]-4-[6-[4-(2-chlorophenyl)-l-piperazinyl]-3-pyridinyl]2,4-dihydro-3H-l,2,4-triazol-3-one (comp. 41);

(±)-2-[l-(4-chlorobenzoyl)propyl]-2,4-dihydro-4-[6-[4-[3-(trifluoromethyl)phenyl]l-piperazinyl]-3-pyridinyl]-3H-l,2,4-triazol-3-one; mp. 126.7°C (comp. 42); (±)-2-[l-(4-chlorobenzoyl)propyl]-4-[6-[4-(3,5-dimethylphenyl)-l-piperazinyl]3-pyridinyl]-2,4-dihydro-3H-l,2,4-triazol-3-one dihydrochloride (comp. 43); (±)-2-[l-(4-chlorobenzoyl)propyl]-4-[6-[4-(3-ethylphenyl)-l-piperazinyl]-3-pyridinyl]2.4- dihydro-3H-l,2,4-triazol-3-one dihydrochloride (comp. 44);

(±)-2-[l-(4-chlorobenzoyl)propyl]-4-[6-[4-(3,4-dimethoxyphenyl)-l-piperidinyl]3-pyridinyl]-2,4-dihydro-3H-l,2,4-triazol-3-one; mp. 107.7°C (comp. 45); and (±)-2-[l-(4-chlorobenzoyl)propyl]-4-[6-[4-(3,4-dimethoxyphenyl)-l-piperazinyl]3-pyridinyl]-2,4-dihydro-3H-l,2,4-triazol-3-one dihydrochloride; mp. 197.3°C (comp. 48).

Example 11

2.4- Dihydro-4-[2-[4-(4-methoxyphenyl)-l-piperazinyl]-5-pyrimidinyl]-3H-l,2,4triazol-3-one (0.019 mol) and Ν,Ν-dimethylformamide (200ml) were stirred. A solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (1M) (21ml) was added dropwise under N2 and the mixture was stirred for 30 minutes at room temperature. 2-Bromo1-(4-chlorophenyl)-1-butanone (0.021 mol) dissolved in a little Ν,Ν-dimethylformamide was added dropwise and the mixture was stirred for 3 hours at room temperature. The mixture was poured into water and extracted with dichloromethane. The organic layer was washed with water, dried and evaporated. The residue was crystallized from 1-propanol. The precipitate was filtered off and dried in vacuo at 75°C, yielding 6g (60%) of (±)-2-[l-(4-chlorobenzoyl)propyl|-2,4-dihydro-4-[2-[4-(4-methoxyphenyl)l-piperazinyl]-5-pyrimidinyl]-3H-l,2,4-triazol-3-one; mp. 184.6°C(comp. 8).

Example 12

To a cooled solution (temp -5 °C) of 5.4 g of l-[l-(4-bromobenzoyl)ethyl]-l,3-dihydro-3-[4-[4-(4-hydroxyphenyl)-l-piperazinyl]phenyl]-2H-imidazol-2-one in 500 ml

BAD ORIGINAL ft

Ο

C

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-25of tetrahydrofuran were added dropwise 20 ml of a solution of tris(l-methylethoxy)potassium hydroborate in tetrahydrofuran 1M. After stirring for 2 hours at room temperature, the reaction mixture was diluted with 1500 ml of water and stirring was continued for 2 hours. The precipitate was filtered off, washed with water and dried. The product was recrystallized from 1,4-dioxane. The product was filtered off and dried in vacuo, yielding 3.4 parts (64.5%) of [A]+[B]-l-[2-(4-bromophenyl)-2-hydroxyl-methylethyl]-l,3-dihydro-3-[4-[4-(4-hydroxyphenyl)-l-piperazinyl]phenyl]-2Himidazol-2-one ; mp. 253.8 °C (comp. 9);

In a similar way there were prepared :

(+)-(R*,R*)-2-[2-(3,4-dichlorophenyl)-2-hydroxy-l-methylethyl]-2,4-dihydro-4-[4-[4(4-hydroxy-3,5-dimethylphenyl)-1 -piperazinyl]phenyl]-5-methyl-3H-1,2,4-triazol3-one hemihydrate; mp. 184.9°C (comp. 10);

l-[2-(4-chlorophenyI)-2-hydroxy-l-methyIethyl]-l,3-dihydro-3-[4-[4-(4-hydroxyphenyl)-l-piperazinyl]phenyl]-4-methyl-2H-imidazol-2-one; mp. 245.7°C (comp. 11); l-[2-(4-chlorophenyl)-2-hydroxy-1-methylethyl]-1,3-dihydro-3-[4-[4-(4-hydroxyphenyl)-l-piperazinyl]phenyl]-2H-imidazol-2-one; mp. 252.8°C (comp. 12); (±)-2-[l-[(4-bromophenyl)hydroxymethyl]-l-methylpropyl]-2,4-dihydro-4-[4-[4-(4hydroxyphenyl)-l-piperazinyl]phenyl]-5-methyl-3H-l,2,4-triazol-3-one; mp. 215.1°C (comp. 13);

(±)-2-[l-[(4-chlorophenyl)hydroxymethyl]propyl]-2,4-dihydro-4-[6-[4-(4-hydroxyphenyl)-l-piperazinyl]-3-pyridinyl]-3H-l,2,4-triazol-3-one; mp. 231.7°C (comp. 14); (±)-(RR,SS)-2-[l-[(4-chlorophenyl)hydroxymethyl]propyl]-2,4-dihydro-4-[4-[4-(5methoxy-2-pyridinyl)-l-piperazinyl]phenyl]-3H-l,2,4-triazol-3-one; mp. 208.5°C (comp. 15);

(±)-(R*,R*)-2-[l-[(4-chlorophenyl)hydroxymethyl]propyl]-2,4-dihydro-4-[6-[4-(3methoxyphenyl)-l-piperazinyl]-3-pyridinyl]-3H-l,2,4-triazol-3-one; mp. 203.8°C (comp. 16);

(±)-(R*,R*)-2-[l-[(4-chlorophenyl)hydroxymethyl]propyl]-2,4-dihydro-4-[6-[4-(2methoxyphenyl)-l-piperazinyl]-3-pyridinyl]-3H-l,2,4-triazol-3-one; mp. 199.3°C (comp. 17);

(±)-(R*,R*)-2-[l-[(4-chlorophenyl)hydroxymethyl]propyl]-2,4-dihydro-4-[6-[4-(3hydroxyphenyl)-l-piperazinyl]-3-pyridinyl]-3H-l,2,4-triazol-3-one; mp. 240.8°C (comp. 18);

(±)-(R*,R*)-2-[l-[(4-chlorophenyl)hydroxymethyl]propyl]-2,4-dihydro-4-[6-[4-(2hydroxyphenyl)-l-piperazinyl]-3-pyridinyl]-3H-l,2,4-triazoI-3-one; mp. 221.6°C (comp. 19);

BAD ORIGINAL 4

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C 25 c

-26(±)-(R*,R*)-2-[l-[(4-chlorophenyl)hydroxymethyl]propyl]-2,4-dihydro-4-[4-[4-(6methoxy-3-pyridinyl)- l-piperazinyl]phenyl]-3H-l,2,4-triazol-3-one; mp. 209.5°C (comp. 20);

(±)-(R*,R*)-1 -[ 1 -[(4-chlorophenyl)hydroxymethyl]propyl] -1,3-dihydro-3-[6-[4-(4methoxyphenyl)-l-piperazinyl]-3-pyridinyl]-2H-imidazol-2-one; mp. 192.0°C (comp. 38); and (±)-(R*,R*)-2-[l-[(4-chlorophenyl)hydroxymethyl]propyl]-2,4-dihydro-4-[4-[4-(6methoxy-2-pyridinyl)-l-piperazinyl]phenyl]-3H-l,2,4-triazol-3-one; mp. 18O.8°C (comp. 46).

Example 13

A mixture of 2-[2-(4-bromophenyl)-1,1 -dimethyl-2-oxoethyl]-2,4-dihydro-4-[4-[4-(4hydroxyphenyl)-l-piperazinyl]phenyl]-3H-l,2,4-triazol-3-one (0.009mol) and sodium tetrahydroborate (0.025mol) in 1,4-dioxane (100ml), methanol (30ml) and water (50ml) was stirred overnight. Acetic acid (5ml) was added, followed by addition of water (500ml). Crystallization resulted. The reaction mixture was stirred for 4 hours at room temperature. The precipitate was filtered off by suction (Buchner) and the solid was crystallized from 1-butanol. The precipitate was filtered off and dried, yielding 4.4 g (87%) of (±)-2-[2-(4-bromophenyl)-2-hydroxy-l,l-dimethylethyl]-2,4-dihydro-4-[4-[4(4-hydroxyphenyl)-l-piperazinyl]phenyl]-3H-l,2,4-triazol-3-one; mp. 224.5°C (comp. 21).

In a similar way there was prepared :

(±)-2-[2-(4-bromophenyl)-2-hydroxy-l,l-dimethylethyl]-2,4-dihydro-4-[4-[4-(4hydroxyphenyl)-l-piperazinyl]phenyl]-5-methyl-3H-l,2,4-triazol-3-one; mp. >300°C (comp. 22);

2,4-dihydro-2-[2-hydroxy-l-methyl-2-(4-methylphenyl)ethyl]-4-[4-[4-(4-hydroxyphenyl)-l-piperazinyl]phenyl]-3H-l,2,4-triazol-3-one; 259.8°C (comp. 33); (±)-(R*,R*)-2-[2-(4-bromophenyl)-2-hydroxy-l-methylethyl]-4-[4-[4-[4-[[(l, 1-dimethylethyl )dimethylsilyl]oxy]phenyl]-l-piperazinyl]phenyl]-2,4-dihydro-3H-1,2,4triazol-3-one; mp. 241.3°C (comp. 34);

(±)-(R*,R*)-2-[l-[(4-chlorophenyl)hydroxymethyl]butyl]-2,4-dihydro-4-[6-[4-(3methoxyphenyl)-l-piperazinyl]-3-pyridinyl]-3H-l,2,4-triazol-3-one; mp. 202.4°C (comp. 40); and (±)-(R*,R*)-2-[l-[(4-chlorophenyl)hydroxymethyl]propyl]-4-[6-[4-(3,4-dimethoxyphenyl)-l-piperazinyl]-3-pyridinyl]-2,4-dihydro-3H-l,2,4-triazol-3-one (comp. 49).

In a similar way but in the presence of l-methyl-2-pyrrolidinone instead of 1,4-dioxane was prepared :

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-272-[2-(4-bromophenyl)-2-hydroxy-l-methyIethyl]-2,4-dihydro-4-[6-[4-(4-hydroxyphenyl)-1 -piperazinyl]-3-pyridinyl]-5-methyl-3H-1,2,4-triazol-3-one; mp. 195.1°C (comp. 23).

Example 14

Sodium sulfite (few crystals) was added to an aqueous hydrobromic acid solution 48% (100ml) till colourless. (±)-2-[l-(4-chlorobenzoyl)propyl]-2,4-dihydro-4-[5-[4-(4methoxyphenyl)-l-piperazinyl]-2-pyridinyl]-3H-l,2,4-triazol-3-one (0.0047 mol) was added and the mixture was stirred and refluxed for 2 hours. The mixture was poured into water and neutralized with NH4OH. The precipitate was filtered off and dried. The residue was purified by column chromatography over silica gel (eluent: CH2CI2/ CH3OH 98/2). The pure fractions were collected and evaporated, yielding 2.2g (90%) of product. A sample (lg) was crystallized from C4H9OH, yielding 0.7 g of (±)-2-[ 1(4-chlorobenzoyl)propyl]-2,4-dihydro-4-[5-[4-(4-hydroxyphenyl)-l-piperazinyl]-215 pyridinyl]-3H-l,2,4-triazol-3-one; mp. 185.6°C (comp. 24).

In a similar way there were prepared :

(±)-2-[l-(4-chlorobenzoyl)propyl]-2,4-dihydro-4-[6-[4-(4-hydroxyphenyl)-l-piperazinyl]-3-pyridinyl]-3H-l,2,4-triazol-3-one; mp. 185.2°C (comp. 25); (±)-2-[l-(4-chlorobenzoyl)propyl]-2,4-dihydro-4-[2-[4-(4-hydroxyphenyl)-l-pipera20 zinyl]-5-pyrimidinyl]-3H-l,2,4-triazol-3-one; mp. 195.3°C (comp. 26);

(±)-2-[l-(4-chlorobenzoyl)propyl]-2,4-dihydro-4-[4-[4-(5-hydroxy-2-pyridinyl)-lpiperazinyl]phenyl]-3H-l,2,4-triazol-3-one; mp. 193.3°C (comp. 27); (±)-2-[l-(4-chlorobenzoyl)propyl]-2,4-dihydro-4-[6-[4-(3-hydroxyphenyl)-l-piperazinyl]-3-pyridinyl]-3H-l,2,4-triazol-3-one; mp. 103.1 °C (comp. 28); and (±)-2-[l-(4-chlorobenzoyl)propyl]-2,4-dihydro-4-[6-[4-(2-hydroxyphenyl)-l-piperazinyl]-3-pyridinyl]-3H-l,2,4-triazol-3-one (comp. 29).

Example 15

To a mixture of 25 g of boron tribromide and 100 ml of dichloromethane was added dropwise a solution of 6.1 g of l-[l-(4-chlorobenzoyl)ethyl]-l,3-dihydro-3-[4-[4-(4methoxyphenyl)-l-piperazinyl]phenyl]-4-methyl-2H-imidazol-2-one in 200 ml of dichloromethane (temp < 10 °C). After stirring for 2 hours, the reaction mixture was poured into a mixture of NH4OH and ice. Then there were added 300 ml of dichloromethane and the whole was stirred for 1 hour. The organic layer was separated, dried, filtered and evaporated. The residue was purified by column chromatography (silica gel;

CH2CI2 / CH3OH 99.T). The eluent of the desired fraction was evaporated and the residue was triturated in methanol. The product was filtered off and dried, yielding 4.3 g (72.3%) of l-[l-(4-chlorobenzoyl)ethyl]-l,3-dihydro-3-[4-[4-(4-hydroxyphenyl)-lBAD ORIGINAL A

AP Ο Ο Ο 4 3 5

-28piperazinyl]phenyl]-4-methyl-2H-imidazol-2-one; mp. 229.7 °C (comp. 30).

In a similar way there was prepared :

2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-l-piperazinyl]phenyl]-2-[l-(4-methoxybenzoyl)ethyl]-3H-l,2,4-triazol-3-one; mp. 204.5°C (comp. 35).

Example 16

A mixture of 2-[ 1 -(4-chlorobenzoyl)propyl]-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)l-piperazinyl]phenylJ-3H-l,2,4-triazol-3-one (0.009 mol) and benzyltriethylammonium chloride (0.25g) in dichloromethane (150ml) was stirred. Sodium hydroxide 25% (50ml) was added and the mixture was stirred for 10 minutes. Dimethyl sulfate (0.015 mol) was added and the mixture was stirred at room temperature for lhour. The mixture was diluted with water (100ml) and separated. The organic layer was washed with water and dried. The residue was purified by column chromatography over silica gel (eluent: CH2CI2/CH3OH 98/2). The pure fractions were collected and evaporated, yielding 4.3g of product. This fraction was purified by column chromatography CHIRACELOD® (1kg) (eluent: C2H5OH). The pure fractions were collected and evaporated, yielding 0.9g (+)-(A)-2-[l-(4-chlorobenzoyl)propyl]-2,4-dihydro-4-[4-[4-

Example 17 (±)-(R*,R*)-2-[2-(2,4-dichlorophenyl)-2-hydroxy-l-methylethyl]-2,4-dihydro-4-[4-[4(4-hydroxy-3,5-dimethylphenyl)-l-piperazinyl]phenyl]-5-methyl-3H-l,2,4-triazol-3one monohydrate (1.5g) was purified by column chromatography CHIRACEL OD® (1kg) ζ 25 (eluent: n.hexane / 2-propanol 80:20). The pure fractions were collected and evaporated. The residue was crystallized from 2-propanol, yielding 0.5 g of (+)-(R*,R*)-2C [2-(2,4-dichlorophenyl)-2-hydroxy-l-methylethyl]-2,4-dihydro-4-[4-[4-(4-hydroxy3,5-dimethylphenyl)-l-piperazinyl]phenyl]-5-methyl-3H-l,2,4-triazol-3-one dihydrate; mp. 123.5°C; [α]θ° = +28.2° (comp. 32).

Example 18

A mixture of (±)-4-[4-[4-[4-[[(l,l-dimethylethyI)dimethylsilyl]oxy]phenyl]-lpiperazinyl]phenyl]-2,4-dihydro-2-[2-hydroxy-2-[4-(trifluoromethoxy)phenyl]ethyl]-5methyl-3H-l,2,4-triazol-3-one (0.0043 mol) was dissolved in dichloromethane (100ml) upon stirring. A solution of tetrabutylammonium fluoride in tetrahydrofuran (0.0045 mol) was added and the mixture was stirred at room temperature for 15 minutes. Water was added and the mixture was stirred for 30 minutes. The precipitate was filtered off,

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-29dried and crystallized from n-butanol, yielding l.lg (58.2%) of (±)-2,4-dihydro-4-[4[4-(4-hydroxyphenyl)-l-piperazinyl]phenyl]-2-[2-hydroxy-2-[4-(trifluoromethoxy)phenyl]ethyl]-5-methyl-3H-l,2,4-triazol-3-one; mp. 230.6°C (comp. 36).

Example 19

A solution of 2-(chlorodimethylsilyl)-2-methyIpropane (0.011 mol) in dichloromethane (20ml) was added to a stirred solution of 2-[l-(4-bromobenzoyl)ethyl]-2,4-dihydro-4[4-[4-(4-hydroxyphenyl)-l-piperazinyl]phenyl]-3H-l,2,4-triazol-3-one (0.009 mol) in pyridine (20ml) under a nitrogen atmosphere. Stirring was continued for 1 week at room temperature. The reaction mixture was evaporated and the residue was dissolved in dichloromethane. This solution was purified over silica gel on a glass filter (eluent: dichloromethane). The pure fractions were collected and the solvent was evaporated. The residue (3.5g) was recrystallized from ethyl acetate. The product was filtered off and dried, yielding 2.7g (45%) of 2-[l-(4-bromobenzoyl)ethyl]-4-[4-[4-[4-[[(l,l-dimethylethyl)dimethylsilyl]oxy]phenyl]-l-piperazinyl]phenyl]-2,4-dihydro-3H-l,2,4triazol-3-one; mp. 177.8°C (comp. 47).

C. Pharmacological example

The anti-Helicobacter activity of the subject compounds was assessed by the following in-vitro test procedure.

Activity of test compounds versus Helicobacter

The activity of test compounds against Helicobacter pylori was determined against a standard set of 5 H. pylori strains obtained from clinical material. Minimal inhibitory concentrations (MICs) were determined by measuring the activity of H. pylori urease after treatment of growing cultures of the bacteria with the antimicrobial agents.

The test compounds were dissolved in DMSO at a concentration of 10'³M. A dilution to 10'⁴M in DMSO was also prepared. 10 μΐ volumes of these solutions were pipetted in the wells of Repli-Dishes (®Sterilin). Wells containing DMSO alone were included as controls in each Repli-Dish. Ampicillin ((+)-6-[(2-amino-2-phenylacetyl)amino]3,3-dimethyl-7-oxo-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxylic acid, trihydrate) and metronidazole (2-methyl-5-nitro-lH-imidazol-l-ethanol) were included as reference compounds in each batch of tests. (These compounds were tested at final concentrations of 10-5, IO*⁶, IO*⁷ and 10’⁸M). Test plates were stored at 4°C until used.

The five isolates of H. pylori were maintained by subculture on 10% blood agar every 2 or 3 days. The bacteria were grown at 37°C under an atmosphere containing 5% oxygen, 10% CO2 and 85% nitrogen. Suspensions of Helicobacter pylori for inoculum

BAD ORIGINAL ft

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-30were prepared in Brain-heart infusion broth and adjusted to an absorbance of 1.5±0.3 at 530 nM.

Freshly prepared 10% blood agar held at 45°C was added in 1 ml volumes to the wells of the test plates, thus diluting the test compounds to 10'^ and 10‘^M. The medium was allowed to cool, then 10 μΐ volumes of bacterial suspension were pipetted on the agar surface. The plates were incubated for 48 h at 37°C under the microaerophilic atmosphere described above. To facilitate reading of the plates and to ensure that any growth on the media was truly H. pylori, advantage was taken of the highly potent urease activity unique to this species. After the 48 h of incubation, 1 ml volumes of urease broth were gently added to each Repli-Dish well and the plates were incubated at 37°C for 2 h. 100 μΐ samples of fluid from each well were then pipetted into the wells of 96place microdilution plates. A purple colour was interpreted as growth, yellow-orange as no growth of H. pylori. By this means a clear end-point was obtained, from which the inhibitory effects could be determined. All compounds that showed activity at either of the two concentrations tested was retested with further dilutions included to establish the MIC and with a broader spectrum of bacterial species as target organisms.

Table 1 summarizes the MIC values determined by the above procedure for a subset of the subject compounds.

Table 1

Comp. No.	MIC (μΜ)
1	0.1
2	10
3	0.1
4	0.01
5	0.1
6	0.1
7	0.1
8	0.1
9	1
10	1
11	1
12	0.1
13	0.1
14	0.1
15	0.1

Comp. No.	MIC (μΜ)
25	0.1
26	0.1
27	0.1
28	0.01
29	0.1
30	1
31	1
32	1
33	1
34	1/0.1
35	10
36	10
37	0.1
38	0.1
39	1/0.1

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Comp. No.	MIC (μΜ)
16	0.1/0.01
17	0.1
18	0.1/0.01
19	0.1/1
20	0.1/0.01
21	0.1
22	1
23	1
24	1/0.1

Comp. No.	MIC(pM)
40	0.1
41	1/0.1
42	1/0.01
43	1/0.1
44	1/0.1
45	0.01
46	1/0.1
47	1
48	<0.001
49	0.01

,· D, Composition examples “Active ingredient” (A.I.) as used throughout these examples relates to a compound of formula (I), a pharmaceutically acceptable acid addition salt or a stereochemically isomeric form thereof.

Example 20: ORAL DROPS

500 Grams of the A.I. was dissolved in 0.5 1 of 2-hydroxypropanoic acid and 1.5 1 of the polyethylene glycol at 60~80°C. After cooling to 30~40°C there were added 35 1 of polyethylene glycol and the mixture was stirred well. Then there was added a solution of

1750 grams of sodium saccharin in 2.5 1 of purified water and while stirring there were added 2.5 1 of cocoa flavor and polyethylene glycol q.s. to a volume of 501, providing an oral drop solution comprising 10 mg/ml of A.I.. The resulting solution was filled into ( suitable containers.

ζ Example 21 : CAPSULES

20 Grams of the A.I., 6 grams sodium lauryl sulfate, 56 grams starch, 56 grams lactose,

0.8 grams colloidal silicon dioxide, and 1.2 grams magnesium stearate were vigorously stirred together. The resulting mixture was subsequently filled into 1000 suitable hardened gelatin capsules, comprising each 20 mg of the active ingredient

Example 22: FILM-COATED TABLETS

Preparation of tablet core

A mixture of 100 grams of the A.I., 570 grams lactose and 200 grams starch was mixed well and thereafter humidified with a solution of 5 grams sodium dodecyl sulfate and 10 grams polyvinylpyrrolidone in about 200 ml of water. The wet powder mixture was sieved, dried and sieved again. Then there was added 100 grams microcrystalline cellulose and 15 grams hydrogenated vegetable oil. The whole was mixed well and

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-32compressed into tablets, giving 10.000 tablets, each containing 10 mg of the active ingredient.

Coating

To a solution of 10 grams methyl cellulose in 75 ml of denaturated ethanol there was added a solution of 5 grams of ethyl cellulose in 150 ml of dichloromethane. Then there were added 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 Grams of polyethylene glycol was molten and dissolved in 75 ml of dichloromethane. The latter solution was added to the former and then there were added 2.5 grams of magnesium octadecanoate, 5 grams of polyvinylpyrrolidone and 30 ml of concentrated colour suspension and the whole was homogenated. The tablet cores were coated with the thus obtained mixture in a coating apparatus.

Example 23 : INJECTABLE SOLUTION

1.8 Grams methyl 4-hydroxybenzoate and 0.2 grams propyl 4-hydroxybenzoate were dissolved in about 0.5 1 of boiling water for injection. After cooling to about 50°C there were added while stirring 4 grams lactic acid, 0.05 grams propylene glycol and 4 grams of the A.I.. The solution was cooled to room temperature and supplemented with water for injection q.s. ad 11, giving a solution comprising 4 mg/ml of A.I.. The solution was sterilized by filtration and filled in sterile containers.

Example 24 : SUPPOSITORIES

Grams A.I. was dissolved in a solution of 3 grams 2,3-dihydroxybutanedioic acid in 25 ml polyethylene glycol 400. 12 Grams surfactant and triglycerides q.s. ad 300 grams were molten together. The latter mixture was mixed well with the former solution. The thus obtained mixture was poured into moulds at a temperature of 37-38°C to form 100 suppositories each containing 30 mg/ml of the A.I.

Example 25 : CYCLODEXTRIN CONTAINING FORMULATION

100 ml of propylene glycol is treated with 3.76 ml concentrated HCl, stirred and slightly heated. 10 g A.I. is added and stirring is continued until homogeneous.

In a separate vessel, 400 g hydroxypropyl-p-cyclodextrin is dissolved in 400 ml distilled water. The solution of the active ingredient is added slowly to the cyclodextrin solution while stirring. The sorbitol solution (190 ml) is added and stirred till homogeneous.

The sodium saccharin (0.6 g) is dissolved in 50 ml distilled water and added to the mixture. The flavours are added and the pH of the mixture (about 1.7) is adjusted with a 10 N NaOH solution to pH 2.0 + 0.1. The resulting solution is diluted with distilled water to an end volume of 1 litre. A pharmaceutical dosage form is obtained by filtering the previous solution and filling it into suitable containers, e.g. in 100 ml glass bottles with a screw cap.

Claims (9)

1. Qaims

   1. The use for the manufacture of a medicament for treating Helicobacter-related 5 diseases of a compound of formula a pharmaceutically acceptable acid addition salt or a stereochemically isomeric form 10 thereof, wherein

   C X and Y each independently are CH or N;

   R¹, R² and R³ each independently are hydrogen or Cj^alkyl;

   R⁴ and R⁵ each independently are hydrogen, halo, Ci4alkyl, Cj^alkyloxy, hydroxy, trifluoromethyl, trifluoromethyloxy or difluoromethyloxy;

   15 Z is C=O or CHOH; and

   Ar is phenyl optionally substituted with up to three substituents selected from hydroxy, Cj^alkyl, Cj^alkyloxy, halo, trifluoromethyl, triCi4alkylsilyloxy, nitro, amino and cyano or pyridinyl substituted with hydroxy or Cj.4alkyloxy; and
2. 2. A use according to claim 1 of a compound of formula (I) wherein Ar is a radical of formula

   BAD ORIGINAL

   AP 0 D 0 4 3 5 (b-3).

   wherein

   R⁶, R⁷, R¹⁰, R¹¹, R¹² and R¹³ each independently are hydroxy or Cj^alkyloxy; and R8 and R⁹ are Cj^alkyl.
3. 3. A use according to claim 1 of a compound of formula (Γ) wherein radical of formula (a-1), (a-2) or (a-3).

   is a
4. 4. A use according to claim 1 of a compound of formula (I) wherein R² is Ciutalkyl;

   R⁴ is halo substituted at the para position; and R¹, R³ and R⁵ are hydrogen.
5. 5. A use according to claim 4 of a compound of formula (I) wherein Ar is hydroxyphenyl, methoxyphenyl, dimethoxyphenyl, Ci^alkylphenyl, diCi^alkylphenyl or methoxypyridinyl.
6. 6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of a compound having the formula a pharmaceutically acceptable acid addition salt thereof or a stereochemically isomeric form thereof, wherein X, Y, R^ to R⁵, Z, Ar and —— are as defined in claim 1, provided that Ar is other than 4-hydroxyphenyl, 3-Ci^alkyl-4-hydroxyphenyl, or 3,5-diCi_4alkyl-4-hydroxyphenyl, when X = N and formula (a-1).

   is a radical of

   BAD ORIGINAL ft

   AP 0 0 0 4 3 5

   -357. A process for preparing a pharmaceutical composition as claimed in claim 6, characterized in that a therapeutically effective amount of a compound as defined in claim 6 is intimately mixed with a pharmaceutical carrier.
7. 8. A compound having the formula

   Ar-X a pharmaceutically acceptable acid addition salt thereof or a stercochemically isomeric form thereof, wherein X, Y, to R⁵, Z, Ar and are as defined in claim 1, provided that

   Ar is other than 4-hydroxyphenyl, 3-Ci-4alkyl-4-hydroxyphenyl, 3,5-diCj.4alkyl4-hydroxyphenyl or 4-methoxyphenyl when X = N and is a radical of formula (a-1).
8. 9. A compound according to claim 8 wherein said compound is [l-(4-chlorobenzoyl)propyl]-2,4-dihydro-4-[6-[4-(4-methoxyphenyl)-l-piperazinyl]3-pyridinyl]-3H-1,2,4-triazol-3-one;

   2- [l-(4-chlorobenzoyl)propyl]-2,4-dihydro-4-[6-[4-(3-hydroxyphenyl)-l-piperazinyl]3- pyridinyl]-3H* 1,2,4-triazol-3-one;

   2-[l-[(4-chlorophenyl)hydroxymethyl]propyl]-2,4-dihydro-4-[6-[4-(3-hydroxyphenyl)1- piperazinyl]-3-pyridinyl]-3H-l,2,4-triazol-3-one;

   2- [l-[(4-chlorophenyl)hydroxymethyI]propyl]-2,4-dihydro-4-[4-[4-(6-methoxy3- pyridi nyl)-1 -piperazinyl]phenyl]-3H-1,2,4-triazol-3-one;

   2-[l-(4-chlorobenzoyl)propyl]-4-[6-[4-(3-methoxyphenyl)-l-piperazinyl]-3-pyridinyl]2,4-dihydro-3H-1,2,4-triazol-3-one; and

   2-[l-[(4-chlorophenyl)hydroxymethyl]propyl]-2,4-dihydro-4-[6-[4-(3-methoxyphenyl)1- piperazinyl]-3-pyridinyl]-3H-l,2,4-triazol-3-one;

   2- [l-(4-chlorobenzoyl)propyl]-4-[6-[4-(3,4-dimethoxyphenyl)-1-piperidinyl]3- pyridinyl]-2,4-dihydro-3ii-1,2,4-triazol-3-one;

   2-[l-[(4-chlorophenyl)hydroxymethyl]propyl]-2,4-dihydro-4-[4-[4-(6-methoxy2-pyridinyl)-l-piperazinyl]phenyl]-3H-l,2,4-triazol-3-one;

   BAD ORIGINAL ft

   AP Ο Ο Ο 4 3 5

   -362-[l-[(4-chlorophenyl)hydroxymethyl]propyl]-4-[6-[4-(3,4-dimethoxyphenyl)1 -piperazinyl]-3-pyridinyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;

   2- [l-(4-chlorobenzoyl)propyl]-4-(6-[4-(3,4-dimethoxyphenyl)-l-piperazinyl]3- pyridinyl]-2,4-dihydro-3H-l,2,4-triazol-3-one, a pharmaceutically acceptable acid 5 addition salt or a stereochemically isomeric form thereof.
9. 10. A process for preparing a compound of formula (I).

   are as defined in claim 1, characterized bv

   N-alkylating an intermediate of formula (II) with a reagent of formula (ΙΠ) (ΙΠ) (Π) in a reaction-inert solvent in the presence of a base;

   and further if desired, converting the compounds of formula (I) into each other following art-known functional group transformation procedures; converting the compounds of formula (I) into an acid addition salt form by treatment with a pharmaceutically

   20 acceptable acid; or conversely, converting the salt form into the free base by treatment with alkali; and/or preparing stereochemically isomeric forms thereof.