MXPA96004610A - Ester derivatives and anti-helicobac azolone carbamate - Google Patents

Abstract

The present invention relates to a compound characterized in that it has the formula: a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof, wherein Y is CH or N; R1, R2 and R3 are each independently hydrogen or C1 alkyl - R4 and R5 are each independently hydrogen, halogen, C1-4alkyl, C1-4alkyloxy, hydroxyl, trifluoromethyl, trifluoromethyloxy or difluoromethyloxy, R6 is C1-6alkyl, hydroxyC1-6alkyl, alkyloxy C 1-4-C 1-6 alkyl, phenyl or phenyl-C 1-4 alkyl; Z is CO or CH

Description

ESTER DERIVATIVES AND THE RZOLONHS RNTI-HELICOBFYCTER CflllPO OF THE INVENTION The present invention relates to substituted azolone derivatives which are potent anti-Helicobacter agents.

BACKGROUND OF THE INVENTION US Pat. No. 791,111 describes azolones having a structure similar to that of the compounds present and which are intermediates in the preparation of CC4-E4 - (4-phenyl-1-piperazinyl) phenoxy ethyl] -1,3-ioxolan -2-yl] methyl] -lH-imidazoles and -lH-1,2,4-triazoles. US-4,931,444 discloses substituted azolone derivatives having inhibition activity of 5-lipoxygenase. The present compounds are distinguished from them by their useful anti-Helicobacter activity. In the eradication of Helicobacter, dual therapies comprising the separate administration of two antibiotics due to one or more of the following reasons: a low eradication regimen, numerous side effects and development of Helicobacter resistance have not been satisfactory. Triple therapies involving the administration of two antibiotics and a bismuth compound have been shown to be effective, but they are very demanding for patients and are also compromised by side effects. The present compounds show the advantage that they can be used in a monotherapy in the eradication of Helicobacter pylori and related species.

DESCRIPTION OF THE INVENTION The present invention relates to compounds having the formula pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein X and Y are each independently CH or N; Ri, 2 and Ra. are each independently hydrogen or Ci-C alkyl; R * and Rs are each independently hydrogen, halogen, Ci-C4-alkyl, Ci-C4-alkyloxy, hydroxyl, trifluoromethyl, trifluoromethyloxy or difluoror-dinoyloxy; Rβ is Ci-Cß alkyl, Ci-Cβ hydroxyalkyl, C ?C «-C de-Cß alkyl alkyl, phenyl or phenylalkyl of Ci-CA; Z is C = 0 or CHOH; and the As used in the foregoing definitions, halogen defines fluorine, chlorine, bromine and iodine; C 1 -C 4 alkyl defines straight or branched chain saturated hydrocarbon radicals having from one to four carbon atoms, that is, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methyl-ropy, 2-methylpropyl and 1, 1, -di ethylethyl; C 1 -C 3 alkyl defines C 1 -C 4 alkyl radicals as defined above and higher homologs thereof having 5 to 6 carbon atoms, such as, for example, pentyl and hexyl.

The term pharmaceutically acceptable acid addition salt, as used above, defines the non-toxic therapeutically active addition acidic salt that the compounds of formula (I) can form. The compounds of formula (I) having basic properties can be converted into their corresponding therapeutically active non-toxic acid addition salt forms by treating the free base with a suitable amount of an appropriate acid, following conventional procedures. Examples of suitable acids are inorganic acids such as hydrohalic acid, ie, 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 - dihydro-butanediic acid, 2-hydroxy-l, 2,3-propanetricarboxylic acid, rnetanosulonic, ethanesulphonic, benzenesulonic, 4-rnethylbenzenesulfonic, cyclohexanesulfaic, 2-hydroxybenzoic, 4-arnino-2-hydroxybenzoic acid and the like acids. The term "pharmaceutically acceptable acid addition salts" also comprises solvates which can form the compounds of formula (I) and salts thereof, for example, hydrates, alcoholates and the like. The term stereochemically isomeric forms, 'as used before, it defines the different isomeric forms that the compounds of formula (I) may have. Unless otherwise indicated or mentioned, the chemical designation of the compounds denotes the mixture of all stereochemically isomeric and conformationally possible forms, said mixtures containing all the diastereoisomers, enantiomers and / or co-formants of the basic molecular structure. It is intended that all isomeric forms of the compounds of formula (I), both in pure form and in mixtures thereof, be embraced within the scope of the present invention. The absolute configuration of each chiral center is indicated by the stereochemical descriptors R and S. For the compounds that have two chiral centers, the relative stereo descriptors R * and S * are used, in accordance with the rules of the Chemical fibstracts (Manual de Selección de Name of Chemical Substances (CO) Edition 1982, Vol. III, chapter 20). Some compounds of the present invention may exist in different tautomeric forms and it is intended that all these tautomeric forms be included within the scope of the present invention. A first group of compounds of interest are the compounds of formula (I) wherein Re is C 1 -C 2 alkyl- A second group of compounds of interest are the compounds of formula (I) wherein X is N. A third group of compounds of interest are the -compounds of formula (I) wherein is a radical of formula (a-1) or (a-2) A fourth group of compounds of interest are the compounds of formula (I) wherein Y is N and Ri is hydrogen. A fifth group of compounds of interest are the compounds of formula (I) wherein R 2 is C 1 -C 6 alkyl and R a is hydrogen. A sixth group of compounds of interest are the compounds of formula (I) wherein R * is halogen and Rs is hydrogen or halogen. Preferred compounds are the compounds of formula (I) wherein: Ri and Ra_ are hydrogen; R2 and e are Ci-C "alkyl; R * is halogen; and Rs is halogen or hydrogen. Very preferred compounds are the compounds of formula (I) wherein Ri and R3. they are hydrogen; R2 and e are ethyl; R * is halogen; Rs is halogen or hydrogen; X and Y are N; Z is CHOH; Y is a radical of formula (a-1) or (a-2) The most preferred compounds are 4C5-C2-Cl-C (4-chlorophenyl) hydroxymethyl] propyl] -2,3-dihydro-3-oxo-4H-1, 2,4-triazol-4-yl] -2-pyridinyl ] -l-? iperazincarbo ethyl ilate; 4C4-C2-Cl-C (4-chlorophenyl) hydroxymethyl] propyl] -2,3-dihydro-3-oxo-4H-l, 2, 4-triazol-4-ethyl-3-phenyl-3-l-piperazinecarboxylate; 4C4-C2-C1-C (4-fluorophenyl) hydroxymethyl-3-propyl] -2,3-dihydro-3-oxo-4H-1, 2,4-thiazol-4-yl] -phenyl] -l-piperazinecarboxylic acid ethyl ester; the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof. In US-4,791,111 and US-4,931,444 analogous processes have been described for the preparation of such compounds or the present compounds of formula (I). In particular, the compounds of formula (I) can be prepared by N-alkylation of an intermediate of formula (II) with a reagent of formula (III).

(II) The reaction of N-alkylation of (II) with (III) can be conveniently carried out by stirring and heating a mixture of the reactants in an appropriate solvent in the presence of a suitable base. Suitable solvents are, for example, dipolar aprotic solvents, e.g. eg, N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone; aromatic solvents, p. eg, benzene, ethylbenzene; an ether, p. eg, 1,1 '-oxibisetane, tetrahydrofuran, l-methoxy-2-propanol; a halogenated hydrocarbon, p. eg, dichloromethane, trichloromethane; or a mixture of such solvents. Suitable bases are, for example, sodium bis (trimethylsilyl) arnide, carbonates or acid carbonates of alkali metals or alkaline earth metals, for example, sodium or potassium carbonate; or organic bases, p. eg, triethanolamine and similar bases. The compounds of formula (I) wherein X is N, said compounds represented by formula (Ia) can be prepared by N-acylation of an intermediate of formula (IV) with a reagent of formula (V) wherein L * is a salient reactive group, such as halogen and others of the same type.

(IV) O The above N-acylation can be conveniently carried out in a suitable solvent, e.g. eg, dichloromethane, in the presence of a base, p. g., sodium carbonate, triethylamine and the like. The compounds of formula (I) can also be interconverted by following procedures known in the art of functional group transformation. For example, the compounds of formula (I) wherein Z represents C = 0, can be converted into the compounds of formula (I) wherein Z represents CHOH, following reductions known in the art. For example, said reduction can be carried out conveniently p > or reaction with a metal hydride or complex metal hydride, e.g. g., sodium borohydride, zinc borohydride, sodium cyanoborohydride and the like in water, N, N-dimethylformamide, 1-rnethylpyrrolidinone, an alcoholic medium, e.g. eg, ethanol, ethanol, or an ether, p. g., tetrahydrofuran, 1,4-dioxane; or a mixture of such solvents. Alternatively, said reduction can be carried out by reaction with potassium tris (l-rnetyletoxy) -hydroborate, sodium tris (l-rnethylpropyl) -hydroborate or potassium tris (1-rnethylpropyl) -hydroborate, in an inert reaction solvent , p. eg, tetrahydrofuran or N, N-dimethylforrnarnide. Zinc borohydride and potassium tris (l-methyletoxy) -hydroborate are suitably used for the stereospecific reduction of the carbonyl entity. In addition, compounds of formula (I) wherein R * or Rs are hydroxyl can be prepared from the corresponding Ci-C "alkyloxy derivatives by an appropriate dealkylation reaction, for example using trifluoroacetic acid, or in particular a mineral acid such as concentrated halogenhydric acid, e.g. eg hydrochloric acid, hydroiodic acid, optionally mixed with a saturated solution of hydrobromic acid in glacial acetic acid; an acid of Le is, p. eg, boron tribromide in an inert reaction solvent, e.g. eg, dichloroethane or N / N-dimethylaceta ida. In the case where hydrobromic acid is used, said dealkylation reaction can advantageously be carried out in the presence of a bromine scavenger such as, for example, sodium sulphite or sodium acid. The compounds of formula (I) wherein R2 and / or Rg_ are C1-C4 alkyl can be prepared by the alkylation of the corresponding compound wherein R2 and / or Rg_ are hydrogen, with a suitable alkylating reagent, e.g. eg, Ci-C "haloalkane, in an inert reaction solvent, e.g. eg, N, N-dirnethylformamide, in the presence of a base, e.g. eg, potassium hydroxide. Optionally, the alkylation reaction can be carried out in a compound of formula (I) wherein R600C-is replaced by a suitable protecting group, e.g. eg, a benzyl group. This benzyl derivative can then be converted to the corresponding compound of formula (I) by reaction with a reagent of formula (V), in inert reaction solvent, e.g. eg, dichloromethane, in the presence of a base p. eg, calcium oxide. Finally, the pure isomeric forms of the compounds of formula (I) can be separated from the mixture by conventional separation methods. In particular, the enantiomers can be separated by column chromatography using a chiral stationary phase such as a suitably derived cellulose, for example, tri (dimethylcarbarnoyl) cellulose (Chiralcel OD) and similar chiral stationary phases. In all the above and the following preparations, the reaction products can be isolated from the reaction mixture, and, if necessary, further purified according to the methodologies generally known in the art. Some intermediates and starting materials in the above preparations are known compounds that can be prepared according to methodologies known in the art of preparing said compounds or similar compounds. Other intermediaries are novel, such as the intermediaries of formula (II). The intermediates of formula (II), wherein X is N, said intermediates represented by the formula (Il-a), can be prepared by cyclization of an intermediate of formula (VI) with a reagent of formula (VID or a derivative thereof .

An inert reaction solvent suitable for the above cyclization reaction is, for example, a dipolar aprotic solvent, e.g. eg, N, N-dirnethylformamide, dimethylsulfoxide and the like, or an alcohol, e.g. eg, ethanol, 1-butanol and the like. The intermediates of formula (II-a) can be further prepared by cyclization of an intermediate of formula (VIII) with a reagent of formula (IX) where R? is Ci-Ce alkyl, p. eg, ethyl and L1 is a leaving reactive group, e.g. eg, ethoxy, dirnethylamino, and the like, optionally in an inert reaction solvent, e.g. eg, tetrahydrothiophene 1,1-dioxide.

(VIII) The intermediates of formula (II) wherein Y is CH, said intermediates represented by the formula (Il-b), can be prepared by reaction of an intermediate of formula (X) with a reagent of formula (XI) wherein L2 and L3 are aldehyde protection groups, p. eg, rnetoxy, in an inert reaction solvent, e.g. eg, 1,4-dioxane, yielding an intermediate of formula (XII). The last termediary can be cyclized by treatment with an acid, e.g. For example, formic acid.

(Xii) The intermediates of formula (IV) can be prepared by the reaction of a compound of formula (I-a) with an acid, e.g. ex. hydrobromic acid and the like.

The compounds of formula (I), the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof exhibit useful pharmacological activity against Helicobacter species, for example Helicobacter pylori, Helicobacter ustelae, Helicobacter felis and the like, in particular Helicobacter pylori. Particularly important in this context is the finding that the compounds of the invention 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 a procedure described in "Antirnicrob Agents Chemother.", 1991, vol. 35, pp. 869-872. An interesting feature of the present compounds refers to their highly specific activity against Helicobacter. It was found that the compounds of formula (I) show no inhibitory activity against any of the following species: Campylobacter jejuni, Campylobacter coli, Campylobacter fetus, Campylobacter sputorum, Vibrio spp, Staphylococcus aureus and Escherichia coli, tested at concentrations up to 10-5M. . An important advantage of the present compounds is their sustained activity against H. pilory at pH below the neutral pH. The activity at pH below the neutral in vitro may indicate that a compound is not adversely affected by the acid medium of the stomach in vivo. In view of their useful anti-Helicobacter properties, the compounds of the invention can 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 the form of acid or basic addition salt, is combined as the active ingredient in intimate admixture with a pharmaceutically acceptable carrier which can take a variety of forms, depending on of the desired preparation form for administration. These pharmaceutical compositions are conveniently in a suitable dosage form, preferably for administration orally, rectally or by parenteral injection. For example, in the preparation of the compositions in oral dosage form any of the usual pharmaceutical media, such as by example water, glycols, oil, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, can be employed. 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. For parenteral compositions, the vehicle will usually comprise sterile water, at least in large part, although other ingredients may be included, for example, to aid solubility. For example, injectable solutions may be prepared in which the vehicle comprises saline solution, glucose solution or a mixture of saline and glucose. Injectable suspensions may also be prepared in which case suitable liquid carriers, suspending agents and the like may be employed. When the pharmaceutical compositions take the form of an aqueous solution, the compounds of formula (I) which exhibit low solubility can be formulated as a salt form, or a cosolvent which is water miscible and physiologically acceptable, for example dimethylsulfoxide and the like, can be added. , or the compounds of formula (I) can be solubilized with a suitable vehicle, for example a cyclodextrin (CD) or in particular a cyclodextrin derivative such as the cyclodextrin derivatives described in US-3,459,731, EP-A-149 197 (24 of July 3, 1995), EP-A-197,571 (October 15, 1996), US-4,535,152 or UO 90/12035 (October 18, 1990).

Suitable cyclodextrin derivatives are α-, β-, 3-cyclodextrins or mixed ethers and ethers thereof wherein one or more of the hydroxyl groups of the anhydroglucose units of the cyclodextrin are substituted with Ci-β alkyl, particularly methyl , ethyl or isopropyl; hydroxyalkyl of Ci-β, particularly hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxyalkyl of Ci-β, particularly carboxymethyl or carboxyethyl; Ci-β alkylcarbonyl, particularly acetyl; Ci-β-alkyloxycarbonyl-Ci-β alkyl or carboxy-Ci-β-alkyloxy-Ci-β alkyl, particularly carboxymethoxypropyl or carboxyethoxypropyl; Ci-β-alkylcarbonyloxy-Ci-β alkyl, particularly 2-acetyloxypropyl. Especially notable as complexers and / or solubilizers are β-CD, 2,6-dimethyl-βCD, 2-hydroxyethyl-β-CD, 2-hydroxyethyl-t-CD, 2-hydroxypropyl-t-CD and (2-carboxylic acid). rnetoxy) propyl- (3-CD, and in particular 2-hydroxypropyl-β-CD) The term mixed ether denotes cyclodextrin derivatives wherein at least two hydroxyl groups of cyclodextrin are etherified with different groups such as for example hydroxypropyl and hydroxyethyl The average molar substitution (MS) is used as a measure of the average number of moles of alkoxy units per mole of anhydroglucose The MS value can be determined by different analytical techniques such as nuclear magnetic resonance (NMR), mass spectroscopy (MS) and infrared (IR) spectroscopy Depending on the technique used, slightly different values may be obtained for a given cyclodextrin derivative In the hydroxyalkyl derivatives of cyclodextrin for use in the compositions according to the present invention The value of M.S., determined by mass spectroscopy, is on the scale of 0.125 to 10, in particular 0.3 to 3, or 0.3 to 1.5. Preferably, the value of M.S. it varies from 0.3 to 0.8 approximately, in particular from 0.35 to 0.5, approximately, and more particularly it is approximately 0.4. Values of M.S. determined by NMR or IR preferably vary from 0.3 to 1, in particular from 0.55 to 0.75. The average degree of substitution (D.S.) refers to the average number of substituted hydroxyls per anhydroglucose unit. The D.S. value can be determined by different analytical techniques such as nuclear magnetic resonance (NMR), mass spectroscopy (MS) and infrared spectroscopy (IR). Depending on the technique used, slightly different values may be obtained for a given cyclodextrin derivative. In the cyclodextrin derivatives to be used in the compositions according to the present invention, the D.S. which was determined by MS is on the scale of 0.125 to 3, in particular, 0.2 to 2 or 0.2 to 1.5. Preferably, the D.S. it varies from 0.2 to 0.7, approximately, in particular from 0.35 to 0.5 approximately, and more particularly it is approximately 0.4. D.S. determined by NMR or IR preferably vary from 0.3 to 1, in particular from 0.55 to 0.75. More particularly, the hydroxyalkyl derivatives of β- and t-cyclodextrin for use in the compositions according to the present invention are partially substituted cyclodextrin derivatives wherein the average degree of alkylation at the hydroxyl groups of different positions of the anhydroglucose units is about 0 to 20% for the 3-position, 2 to 70% for the 2-position and about 5 to 90% for the 6-position. Preferably, the amount of unsubstituted β- or t-cyclodextrin is less than 5% of the total content of cyclodextrin and in particular less than 1.5%. Another particularly interesting cyclodextrin derivative is the randomly-denatured β-cyclodextrin. Most preferred cyclodextrin derivatives for use in the present invention are the partially substituted β-cyclodextrin ethers or mixed ethers having hydroxypropyl, hydroxyethyl substituents, and in particular, 2-hydroxy-ropy and / or 2- (1-) hydroxypropyl) . The most preferred cyclodextrin derivative for use in the compositions of the present invention is hydroxypropyl-β-cyclodextrin having a value of M.S. on the scale from 0.35 to 0.50 and contains less than 1.5% unsubstituted β-cyclodextrin. Values of M.S. determined by NMR or IR preferably vary from 0.55 to 0.75. It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. The unit dose form, as used in the specification and the present claims, refers to physically discrete units suitable as unit doses, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage forms are tablets (including nucleated or coated tablets), capsules, pills, compact powders, wafers, injectable solutions or suspensions and the like, and segregated derivations thereof. In view of the utility of the compounds in question in the treatment of Helicobacter-related diseases, it is evident that the present invention provides a method of treatment for warm-blooded animals, in particular humans, suffering from disorders or diseases related to Helicobacter, said method comprises the systemic administration of a pharmaceutically effective amount of a compound of formula (I), a pharmaceutically acceptable acid addition salt or a stereochemically isomeric form thereof, mixed with a pharmaceutical carrier. Examples of such diseases or disorders are gastritis, stomach ulcers, duodenal ulcers and gastric cancer. In a further aspect of the invention, the compounds of the invention are administered for use as a medicine.

In general, it is contemplated that an effective daily amount would be from 0.05 rng / kg to 50 rng / kg in body weight, preferably from 0.1 mg / kg to 30 rng / kg, in body weight and most preferably 0.5 rng / kg. at 10 rng / kg, in body weight. It is evident that said effective daily amount can be decreased or increased "depending" on the response of the treated subject and / or depending on the evaluation of the physician prescribing the compounds of the present invention. The effective scales mentioned above are therefore only a guide and are not intended to limit the scope or use of the invention to any degree. Optionally, other active compounds used for the eradication of Helicobacter in combination with the compounds of the present invention can be administered. The administration can occur separately (that is, simultaneously, concurrently or consecutively) or the different drugs can be combined in a dosage form. Suitable compounds for a combination therapy are bismuth compounds, for example, bismuth subcitrate, bismuth subsalicylate, and the like, antibiotics p. ampicillin, amoxicillin, clarithromycin and the like, H2 receptor antagonists, for example cirnetidine, ranitidine and the like, and in particular proton pump inhibitors, for example omeprazole, lansoprazole, pantoprazole and the like. For the compounds mentioned to be useful for combination therapy with the compounds of formula (I), an effective daily amount would be from 0.05 mg / kg to 50 mg / kg body weight.

EXPERIMENTAL PART The compounds of formula (I) and some intermediates have a stereogenic center. In those cases where the racemate was separated in its enantiomers, the stereochemically isomeric form that was first isolated was designated as "A" and the second as "B", without further reference to the actual stereochemical configuration.

Example 1 a) A mixture of ethyl 4-C5-C (fenexicarbonyl) amino3-2-pyridinyl] -l-piperazinecarboxylate (0.3 mole "of crude residue) and hydrazine hydrate (1.5 mole) in 1,4-dioxane was stirred ( 1100 ml) for 6 hours at room temperature. The reaction mixture was poured into water (400 mL) and the resulting precipitate was filtered. The filtrate was extracted three times with CH2Cl2 (700 ml each time). The separated organic layer was washed with water, dried, filtered and the solvent was evaporated. The residue was stirred in DIPE. The precipitate was filtered and dried (25 ° C, 20 hours), yielding 62 g (67%) of ethyl 4-C5- [hydrazinocarbonyl] arnino] -2-pyridyl-yl] -l-piperazinecarboxylate (interm 9).

In a similar manner, N-C 4- C 4- (phenylethyl) -1-piperazinyl) phenylhydrazincarboxarnide (interm. 10) was prepared. bl) A mixture of intermediate (9) (0.178 mol) and methanirnidamide acetate (0.62 mol) in 1-butanol (800 ml) was stirred and refluxed for 24 hours. The reaction mixture was allowed to cool, then it was poured into water (500 mL). This mixture was extracted with dichloromethane (200 ml). The separated organic layer was washed with water, dried (MgSO 4), filtered and the solvent was evaporated. The residue was stirred in 2-propanol, filtered and dried (vacuum, 40 ° C, 12 hours); yielding 24 g of ethyl 4-C5- (2,3-dihydro-3-oxo-4H-l, 2,4-triazol-4-yl) -2-pyridinyl] -l-piperazinecarboxylate (42%) (interm.) . 1). In a similar manner, it was prepared: 4-C5- (1, 5-dihydro-3-rnetyl-5-oxo-4H-1, 2,4-triazol-4-yl) -2-pyridinyl] -l-piperazinecarboxylate « of ethyl; p.f. 206.9 ° C (interm 3); and 2,4-dihydro-4-C4-C4- (phenylmethyl) -l-piperazinyl] phenylH-3H-1, 2,4-triazol-3-one (interm. 11). b2) A mixture of ethyl 4- (5-amino-2-pyridinyl) -l-piperazinecarboxylate (0.18 mol) and ethyl 2- C (di-diallylamino) methylene] hydrazinecarboxylate (0.54 mol) in 1,1-dioxide was stirred. of tetrahydrothiophene, (50ml) at 150 ° C for 3 hours. The mixture was cooled to 100 ° C; 2-propanol was added until recrystallization. The precipitate was filtered and recrystallized from methanol, yielding 30.5 g of 4-C5- (2,3-dihydro-3-oxo-4H-l, 2,4-triazole-4-? L) -2-pi idinylD- l-pip > ethyl ethylcarboxylate (53.3%); p.f 220.8 ° C (interm. In a similar manner there were prepared: ethyl l-C4- (2,3-dihydro-3-oxo-4H-l, 2,4-triazol-4-yl) -phenyl] -4-piperidinecarboxylate; p.f. 225.4ßC (interm. 4); 4-C4- (2,3-dihydro-3-oxo-4H-l, 2,4-triazol-4-yl) -phenyl] -l-pi? Ezinecarboxylic acid ethyl ester; p.f. 195.9 ° C (interm 5); and ethyl 4-C4- (1, 5-dihydro-3-methyl-5-oxo-4H-l, 2,4-triazol-4-yl) -phenyl-3-yl-piperazinecarboxylate; p.f. 204.7 ° C (interm 6). c) A mixture of ethyl 4-C4- (enoxycarbonyl) amino] phenyl] -l-piperazinecarboxylate (0.1 mol) and 2,2-dirnetoxyethamine (0.2 mol) in 1,4-dioxane was stirred. (500rnl) and refluxed for 3 hours. The mixture was evaporated, the residue was taken up in formic acid (300 ml) and the mixture was stirred at 60 ° C for 2 hours. The mixture was evaporated, the residue was taken up in CH 2 Cl 2, neutralized with NaHCO 3 solution and the precipitate was filtered, yielding 28.5 g (90%) of the product. A sample (2 g) was crystallized from EtOAc, yielding 1.3 g of ethyl 4-C4- (2,3-dihydro-2-oxo-lH-imidazol-1-yl) phenylH-1-piperazinecarboxylate p.f. 196.1 ° C (interm 7); In a similar manner, there was prepared: ethyl 4-C5- (2,3-dihydro-2-oxo-lH-irnidazol-l-yl) -2-pyridinyl] -l-piperazinecarboxylate m.p. 196.2 ° C (i terrn 8) d) A mixture of intermediate (1) (0.087 mol), 2-bromo-l- (4-chlorophenyl) -l-butanone (0.097 mol) and sodium carbonate (0.1) was stirred. moles) in N, N-dimethylformamide (300 rnl) for 6 hours at 80 ° C. The mixture was cooled, poured into water, extracted with dichloroethane and washed with water. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH 99/1). The pure fractions were collected and evaporated. The residue was crystallized from netanol, yielding 33.7 g of (±) 4-C5-C2-Cl- (4-chlorobenzoyl)? Ropil] -2,3-dihydro-3-oxo-4H-l, 2,4 ~ triazole -4-yl) -2-pyridinyl.l-piperazinecarboxylic acid ethyl ester (78%). A sample (4 g) was crystallized from n-butanol, yielding 3.5 g "of (±) 4-C5-C2- [1- (4-chlorobenzoyl) propyl H ~ 2,3- dihydro-3-oxo Ethyl 4H-1,2,4-triazol-4-yl) -2-pyridinyl-H-l-piperazinecarboxylate; p.f. 139.1 ° C (cornp.1).

Example 2 a) A mixture of compound (1) (0.048 mol) in hydrobromic acid in 48% aqueous solution (250 ml) was stirred and refluxed overnight. The mixture was evaporated, the residue was dissolved in dichloromethane, neutralized with NH 4 OH / H 2 O and extracted with dichloromethane. The organic layer was washed with water, dried, filtered and evaporated. A sample "(3.5 g) of the residue (total 18 g) was purified by column chromatography on silica gel (eluent: CH2Cl2 / (CHaOHNH3) 99/1). The pure fractions were collected and evaporated. The residue was dissolved in 2-propanol and converted to the hydrochloric acid salt (1: 1) in 2-proanol. The precipitate was filtered, washed with 2-propnaol and dried at 150 ° C to yield 1.7 g of (±) 2-Cl- (4-chlorobenzoyl) propyl] -2,4-dihydro-4-C6 monohydrochloride. - (1-piperazinyl) -3-pyridinyl] -3H-1, 2,4-triazol-3-one (39.4%); p.f. 209.8ßC (interm. 2). b) A mixture of butyl carbonchloridate was stirred (0.015 moles), the free base of intermediate 2 (0.013 moles) and sodium carbonate (0.03 moles) in dichloromethane (100 rnl) at room temperature overnight. Water was added and the layers separated. The organic layer was dried, filtered and evaporated. The residue was crystallized from ethanol. The precipitate was filtered and dried yielding 3.3 g of (±) 4-C5-C2-Cl- (4-chlorobenzoyl) propyl-2,3-dihydro-3-oxo-4H-1, 2,4-triazole- 4- butyl) -2-pyridinyl] -l-piperazinecarboxylate (48%). The filtrate was evaporated, yielding 3.6 g of (±) 4-C5-C2-Cl- (4-chlorobenzoyl)? Ropil] -2,3-dihydro-3-oxo-4H-1, 2,4-triazole-4 -yl) -butyl-2-pyridinyl.ll-piperazinecarboxylate (52%).

Producing a total: 6.9 g of (±) 4- [5- [2-Cl- (4-chlorobenzoyl)? Ropil] -2,3-dihydro-3-oxo-4H-l, 2,4-triazole-4 -yl) -butyl-2-pyridinyl-l-piperazinecarboxylate (± 100%) (Compound 41).

Example 3 Compound 1 (0.01 rnol) was cooled in N, N-dimethylformamide (100 ml) to -30 ° C. A 1M solution of potassium tris (1-methylethoxy) hydroborate in tetrahydrofuran (0.02 mol) was added dropwise at -30 ° C and the mixture was allowed to slowly come to room temperature. The mixture was poured into water and filtered. The precipitate was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH 99/1). The pure fractions were collected and evaporated. The residue was crystallized from 2-propanol yielding 3.2 g of (±) (R *, R *) - 4-C5-C2-Cl - (4-chlorophenyl) hydroxymethyl] propyl3-2.3-dihydro-3-oxo -4H-1, 2,4-triazol-4-yl) -2-? Iridinyl] -l-? Iperazinecarboxylic acid ethyl ester (63.9%); p.f. 196.1 ° C (cornp.3).

Example 4 A mixture of compound (35) (0.02 mol) in hydrobromic acid in 48% aqueous solution (50 rnl) was stirred and refluxed overnight. The solvent was evaporated. The residue was dissolved in dichloromethane. The organic solution was washed with an aqueous Na 2 C 3 solution, dried, filtered and the solvent was evaporated. The residue was dissolved in N, N-dimethylacetamide (50 ml). Carbonylhydrochloric acid ethyl ester (3 g) was added and the reaction mixture was stirred for 2 hours. The reaction mixture was poured into water and stirred for 30 minutes. The supernatant was decanted and the oily residue was dissolved in dichloromethane. The organic solution was washed, dried, filtered and the solvent was evaporated. The residue was purified twice by column chromatography on silica gel (eluent CH2Cl2 / CH3? H / Hexane / ethyl acetate 48/2/20/30). The pure fractions were collected and the solvent was evaporated (for 2 hours at 20 ° C). The residue was cooled in a C 2/2-propanol bath. The solid was dried (vacuum, room temperature); yielding 2.3 grams of (4- [5- [2-Cl ~ (4-hydroxybenzoyl) propyl.l-2,3-dihydro-3-oxo-4H-1, 2,4-triazol-4-yl] - 2-? Iridinyl-ll-piperazinecarboxylate, ethyl (24%), mp 94.3 ° C (co p.4).

Example 5 Separated (+) (R *, R *) - 4-C4-C2-Cl [(4-f) lorofenhydrohydropropyl 13-2, 3-dihydro-3-oxo-4H-l, 2,4-triazole-4 ethyl] -phenyl] -l-piperazinecarboxylate (Compound 63) (0.001 mole) by chiral resolution on CHIRALCEL OD 20μrn " (eluent: hexane / C2HeOH 70/30). The pure fractions were collected and evaporated; producing 0.18 grams of CA- (R *, R- *) -l-4- [4- [2- [l-p4-fluoro-enyl) -hydroxymethyl] -propyl-l-2,3-dihydro-3-oxo Ethyl 4H-l,, -triazol-4-yl] phenylD-1-piperazinecarboxylate (37.2%), mp 161.2 ° C (Compound 5). and 0.18 g of CB- (R *, R *)] - 4-C4 ~ C2-ül-C (4-fluorophenyl) hydroxymethyl] propyl] -2,3-dihydro-3-oxo-4H-1, 2, Ethyl 4-triazol-4-ill phenyl] -l-piperazinecarboxylate (37.2%); p.f. 151.2 ° C (cornp.6). Example 6 a) A mixture of intermediate (11) (0.01 mol) in N, N-dimethylformamide (50 ml) was stirred under nitrogen. A solution of sodium bis (trimethylsilyl) amine in tetrahydrofuran (2M) (0.01 mole) was added dropwise and the mixture was stirred at room temperature for 10 minutes. L- (4-chlorophenyl) -2-bromopropanone (0.0015 mol) dissolved in N, N-dirnethylformamide was added in the form of drops and the mixture was stirred at room temperature for 1 hour. The mixture was poured into water and stirred. The precipitate was filtered, dissolved in CH2Cl2, dried, filtered and evaporated to a small volume. The oily residue was purified by column chromatography on silica gel (eluent: CH2Cl2 / hexane / EtOAc 1/2/1). The pure fractions were collected and evaporated. The residue (2.3 g) was crystallized from EtOAc, yielding 1.7 g (34%) of (+) 2-C2- (4-chlorophenyl) -l-methyl-2-oxoethyl] -2,4-dihydro-4-C4 - C - (phenylmethyl) -l-piperazinyl-3-phenyl] -3H-1, 2,4-triazol-3-one; p.f. 164.3 ° C (interm.12). b) A mixture of intermediate (12) (0.022 moles) in N, N-dimethylformamide (60 ml) was stirred under nitrogen at room temperature until most of the intermediate 12 was dissolved. Potassium hydroxide (0.025 mole) was added thereto and the mixture was stirred for 5 minutes. Iodonetane (0.025 mol) dissolved in N, N-dirnethylformamide was added in the form of drops and the mixture was stirred at room temperature for 1 hour. The mixture was poured into ice water (500 ml) while stirring, and filtered. The precipitate was washed with water on a filter and dissolved in CH2Cl2. The organic layer was dried (MgSO.sub.0), filtered and evaporated. The residue was purified by column chromatography on silica gel (eluent: EtOAc / hexane / CH2Cl2 / CH3? H 20/30/49/1). Fraction 1 was collected and evaporated. The residue was crystallized from EtOAc, producing 3. 3 g (29%) of the product. The product was crystallized again, yielding 2.58 grams (23%) of 2-C2-Í-chlorophenyl) -l, l-dimethyl-2-oxoethyl-3-2,4-dihydro-4- [4-C4- (phenylmethyl) - l-piperazinyl-3-phenyl-3H-1, 2,4-triazol-3-one; p.f. 150.3 ° C (interm. 13). c) A mixture of intermediate (13) (0.145 moles), ethyl chloroformate (0.02 moles) and calcium oxide (5 grams) in dichloromethane (150 ml) was stirred overnight at room temperature. The mixture was filtered and the filtrate was evaporated. The precipitate was filtered and crystallized from EtOAc / hexane. The precipitate was filtered and dried yielding 4.85 g (67.2%) of 4-C4-C1-C2- (4-chlorophenyl) -l, l-dimethyl-2-oxoeti 11-1, 5- ihydro-5-oxo- 4H-1,2, 4-triazol-4-yl] phenyl] -l-piperazinecarboxylate "ethyl, mp 137.0 ° C, (comp.78).

Example 7 Compound (78) (0.0057 mol) was dissolved in, N-dimethylforamide (50 ml) by stirring. Sodium borohydride (0.017 mol) was added and the mixture was stirred at room temperature for 3 hours. The mixture was poured into ice water and stirred for 30 minutes. The precipitate was filtered and recrystallized from EtOAc and DIPE. The precipitate was filtered and dried, yielding 1.8 g (63.2%) of (+) 4-C4-Cl-C2- (4-chlorophenyl) -2-hydroxy-l, 1-direthylethyl-1-dihydro-S-oxo ^ Hl ^^ - triazole ^ -illyphenyl-l-piperazinecarboxylate of ethyl; p.f. 108.4 ° C (Comp.79).

Example 8 A mixture of compound (1) (0.0044) in tetrahydrofuran (150 ml) was stirred under nitrogen at 0 ° C in an ice bath. Zinc borohydride (0.0051 mol) was added as drops at 0 ° C and the mixture was stirred at 0 ° C for 1 hour. The mixture was allowed to warm to room temperature and was stirred at this temperature for 1 hour. The mixture was evaporated in vacuo and water and 10% CH3COOH were added to the residue. CHCl3 was added and the layers separated. The organic layer was dried (MgSOu), filtered and evap > gold. The residue (3 g) was purified by column chromatography on silica gel (eluent: hexane / EtOAc 20/80). The appropriate fractions were collected and evaporated. The oily residue was triturated in water. The precipitate was filtered, washed with water and dried at 80 ° C overnight, yielding l.l &g (52.6%) of (+) (R *, S *) - 4-C5-C1-C1- C (4-chloro-phenyl) hydro-imethyl-propyl-3-1,5-dihydro-5-oxo-4H-l, 2,4-triazol-4-yl-3-pyridinyl-3-l-pi? Ezinecarboxylic acid ethyl ester hern i hydrated; p.f. 118.4 ° C (cornp.82). Tables 1, 2 and 3 below summarize the compounds prepared in accordance with one of the or. no F no R6 R4 R5 Physical data 28 CH3-CH2- N N 3-Cl 4-Cl p.f. l22.0'C 29 CH3-CH2- N CH4-CH3 H Pf-160.1 ° C / HCl 30 CH3-CH2- NN 4-Br H pf.l50.1 ° C 31 CH3-CH2- N CH 4 -Br H Pf -121.9 ° C 32 CH3-CH2- N CH 4 -O-CH3 H P f.l54.9 ° C / HCl 33 CH3-CH2- NN 4 -CH3 H jf. 110.6 ° C 34 CH3-CH2- NN 2-a 4-Cl Pf -175.1 ° C 35 CH3-CH2- NN 4-0-CH3 H Pf- 109.2 ° C 36 CH3-CH2- N CH 2-a 4-Cl pf 109.3 ° C 37 CH3-CH2- N CH4-Cl H p.f. 110.9 ° C 2 2 CH 3 - (CH 2) 3- N CH 4 -Cl H p.f. 146.4 ° C / HC1 39 2 CH 3 - (CH 2) 2- N CH 4 -Cl H HC 1 40 2 CH 3 - N CH 4 -Cl H p.f. l85.2 ° C / HCl 41 2 CH3- (CH2) 3- NN 4-Cl H 74 2 C6H5-CH2- N CH4-Cl H pfl60.1 ° C / HCl 75 2 C6H5-CH2- NN 4- Cl H 76 2 C6H5- NN 4-Cl H 77 2 C6H5- N CH4-Cl H HC1 83 2 (CH3) 2-CH- NN 4-Cl H pf 150.3 ° C 84 2 CH3 NN 4-Cl H p.f. 107.8 ° C 85 2 (CH3) 3-C- N N 4-Cl H P-f- 160.1 ° C TABLE 2 ) no II no R6 R4 R5 Physical data 8 5 CH3-CH2 N CH 4-Cl H pf .206.3 ° C / [B- (R *, R *) J 9 3 CH3-CH2 N CH 2 -Br 4- Br pf132.6 ° C (R *, R *) .H20 0 3 CH3-CH2 NN 2 -F 4-F Pf-179.5 ° C / (R *, R *) 1 3 CH3-CH2 NN 2-Br 4- Br Pf-182.5 ° C / (R *, R *) 2 3 CH3.CH2 N CH3-CF3 H pfl35.1 ° C / (R *, R *) 3 3 CH3-CH2 NN 3-CF3 H Pf -187.9 ° C / (R *, R *) 4 3 CH3-CH2 NN 2-Ci H pfll0.2 ° C / (R *, R *).? / 2H2O 5 3 CH3-CH2 N CH 3 -Br H Pf-154.8 ° C / (R *, R *) 6 3 CH3-CH2 NN 3-Br H Pf-173.6 ° C / (R *, R *) 3 CH3-CH2 N CH2-C1 H p.f, 93.4 ° C / (R *, R *) 3 CH3-CH2 N N 4-F H p.f.185.4 ° C / (R *, R *) 3 CH3-CH2 N N 3-Cl H p.f.160.0 ° C / (R *, R *) 3 CH3-CH2 N CH 3-Cl H P, f- 157.1 ° C / (R *, R *) 3 CH3-CH2 N CH H H p, f • 160.0 ° C / (R *, R *) 3 CH3-CH2 N CH 3-Cl 4-Cl P-f-191.5 ° C / (R *, R *) 3 CH3-CH2 N CH 4 -F H p.f.l80.0 ° C / (R *, R *) 3 CH3-CH2 N CH 4-Br H p.f.202.0 ° C / (R *, R *) 3 CH3-CH2 N N 3-Cl 4-Cl P-f-201.8 ° C / (R *, R *) 3 CH3-CH2 N N 4-Br H P-f-213.3 ° C / (R *, R *) 3 CH3-CH2 N CH 4 -CH3 H p-f * 185.8 ° C / (R *, R *) 3 CH3-CH2 NN 2-C1 4-Cl p * f-184.5 ° C / (R *, R *) 3 CH3-CH2 N CH 4 -OCH3 H | Pf- 174.9 ° C / (R *, R *) 3 CH3-CH2 NN 4 -CH3 H p, f * 162.2 ° a (R *, R *) 3 CH3- CH2 NN 4-OCH3 H pf • 154.2 ° C / (R *, R *) 5 CH3-CH2 N CH 4 -FH Pf- 161.2 ° C / [A- (R *, R *)] CH3-CH2 N CH 4 -F H P-f- 151.2 ° C / [B- (R *, R *) j 3 CH3-CH2 NN 3-Cl 3-Cl p * f '173.7 ° C / (R *, R *) 3 C6H5-CH2 NN 4-Cl H pf180.2 ° C / (R *, R *) 3 (CH3 ) 3C NN 4-Cl H Pf- 199.7 ° C / (R *, R *) 3 (CH3) 2CH NN 4-Cl H Pf • 197.4 ° (R *, R *) 3 CH3 NN 4-Cl H Pf- 212.5 ° C / (R *, R *) 3 CH3 N CH 4-Cl HP * f- 187.4 ° C / (R *, R *) 3 CH3- (CH2) 2 N CH 4-Cl H p * f ' 175.9 ° C / (R *, R *) 3 C6H5-CH2 N, CH4-Cl H Pf 155.8 ° C (R *, R *) 3 CH3- (CH2) 3 N CH4-Cl H Pf 150.3 ° C / (R *, R *) 3 N CH 4 -F 2-FI Pf-154.4 ° g (R * .R ») OUREKD 3 Example 9: Pharmacological Example The anti-Helicobacter activity of the compounds of the invention was determined by the following in vitro test procedure.

Activity of the test compounds against Helicobacter The activity of the test compounds against Helicobacter pylori was determined against a group of 5 normal strains of H. ylori obtained from clinical material. Minimum inhibitory concentrations (MICs) were determined by determining the activity of H. ylori urease after treatment with the antimicrobial agents of the bacteria grown cultures. The test compounds were dissolved in DMSO at a concentration of 10_3M. A dilution of 10-M in DMSO was also prepared. Volumes of 10 ul of these solutions were pipetted into the cavities of Repli-Dishes (R Sterilin). Cavities containing only DMSO were included as controls in each Repli-Dish. Ampicillin ((+) - 6-C (2-amino-2-phenylacetyl) amino-3-3,3-dimethyl-7-oxo-4-thia-1-azabicycloC3 acid was included in each test batch as reference compounds. 2.03hentane-2-carboxylic acid trihydrate) and etronidazole (2-methyl-5-nitro-lH-imidazole-l-ethanol) (These compounds were tested at final concentrations of 10-s, 10-6 t 10"" 7 and 10-8 M). The test plates were stored at 4 ° C until they were used. The 5 isolates of H. pylori were maintained by subculture on 10% blood agar every 2 or 3 days. The bacteria developed at 37 ° C under an atmosphere containing 5% "oxygen, 10% CO2 and 85%" nitrogen. Helicobacter pylori suspensions were prepared for inoculum in brain-heart infusion broth and adjusted to an absorption < from 1.5 + 0.3 to 530 nm. Freshly prepared 10% blood agar was added, maintained at 45 ° C, in 1 ml volumes, in the cavities of the test plates, thus diluting the test compounds at 10-s and 10_6M. The medium was allowed to cool, then volumes of 10 ul of bacterial suspension were pipetted onto the surface of the agar. Plates were incubated for 48 hours at 37 ° C under the microaerophilic atmosphere described above. To facilitate the reading of the plates and to ensure that any growth on the medium was truly H. pylori, the highly potent unique urease activity of this species was exploited. After 48 hours of incubation, volumes of 1 ml of urea broth were gently added to each Repli-Dieh cavity, and the plates were incubated at 37 ° C for 2 hours. Then samples of 100 ul of fluid were pipetted from each well into the wells of the 96-microdilution plates. A purple color was interpreted as growth and yellow-orange without growth of H. pylori. By this means a clear endpoint was obtained from which the effects of inhibition could be detrimental. All compounds that demonstrated activity at either of the two tested concentrations were tested again, with additional dilutions included, to establish the MIC and with a broader spectrum of bacterial species or target organisms. It was found that the MIC values for the compounds NO. 1-3, 5-6, 8-11, 13-28, 30-37, 39-43, 45-72, 74-77, 81-82, 88, 91-93, 96-98 and 102-107 were equal or below 1 uM.

Examples of composition "Active ingredient" (A.I) as used in all these examples, refers to a compound "of formula (I), a pharmaceutically acceptable acid addition salt or a stereochemically isomeric form thereof.

Example 10: ORAL DROPS 500 grams of A. I were dissolved in 0.5 1 of 2-hydroxypropanoic acid and 1.5 liters of polyethylene glycol at 60 ~ 80 ° C. After cooling to 30 ~ 40 ° C, 35 1 of polyethylene glycol was added and the mixture was stirred well. Then a solution of 1750 grams of sodium saccharin in 2.5 1 of purified water was added., and at the same time, 2.5 liters of cocoa and polyethylene glycol flavor were added in sufficient quantity for a volume of 50 liters, producing a solution in oral drops constituted by 10 mg / ml of A. I.

The resulting solution was filled in suitable containers.

Example 11: CAPSULES grams of A.I., 6 grams of sodium lauryl sulfate, 56 grams of starch, 56 grams of lactose, 0.8 grams of colloidal silicon dioxide, and 1.2 grams of magnesium stearate were vigorously stirred. Subsequently the resulting mixture was filled into 1000 hard gelatin capsules, each containing 20 rng of the active ingredient.

Example 12: FILM COATED TABLETS Preparation of the tablet core A mixture of 100 grams of AI, 570 grams of lactose and 200 grams of "ally" was mixed well and then moistened with a solution of 5 grams of sodium dodecylsulfate and 10 grams of polyvinylpyrrolidone in 200 grams. my water The wet powder mixture was sieved, dried and sieved again. They added 100 grams of microcrystalline cellulose and 15 grams of hydrogenated vegetable oil. Everything was mixed thoroughly and compressed into tablets, giving 10,000 tablets each containing 10 mg of the active ingredient. Covering. To a solution of 10 grams of methylcellulose 75 nr of denatured methanol was added a solution of 5 grams of ethylcellulose and .150 ml of dichloromethane. Then 75 ml of dichloromethane and 2.5 rnl of 1,2,3-propanetriol were added. 10 grams of polyethylene glycol were melted and dissolved in 75 ml of dichloromethane. The last solution was added to the first one and then 2.5 grams of magnesium octadecanoate, 5 grams of polyvinylpyrrolidone and 30 rnl of concentrated color suspension were added and everything was homogenized. The tablet cores were coated with the mixture thus obtained in a coating apparatus.

Example 13: SUPPOSITORIES 3 grams of A.I was dissolved in a solution of 3 grams of 2,3-dihydroxybutanedione acid in 25 ml of polyethylene glycol 400. 12 grams of surfactant and triglycerides were melted together in an amount sufficient to reach 300 grams. This mixture was mixed well with the first solution. The mixture thus obtained was molten at a temperature of 37-38 ° C to form 100 suppositories each containing 30 mg / l of A. I.

Claims (10)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound that has the formula a pharmaceutically acceptable acid addition salt or a stereoquinhanically isomeric form thereof, wherein X and Y are each independently CH or N; Ri, R2 and Rg_ are each independently hydrogen or Ci-alkyl; R * and Rs are each independently hydrogen, halogen, C1-C4 alkyl, Ci-C4 alkyloxy, hydroxyl, trifluoromethyl, trifluoromethyloxy or difluoromethyloxy; Re is Ci-Cß alkyl, Ci-Cß hydroxy, C 1 -C 4 alkyl-Ci-Cß alkyl alkyloxy, phenyl or phenylalkyl of C-C "; Z is C = 0 or CHOH; Y is a radical of formula

2. - A compound according to claim 1 wherein R6 is C? -c-alkyl "-

3. A compound according to claim 2 further characterized in that R2 is C? -c" alkyl; R1 and R3 are hydrogen; R * is halogen and R5 is hydrogen or halogen.

4.- The compound according to the claim 3, further characterized in that said compound is 4-C5-32-C1-C (4-chlorophenyl) hydroxy-phenyl-propyl-2,3-dihydro-3-oxo-4H-1, 2,4-triazol-4-yl-3 ethyl-pyridinyl-3-l-piperazinecarboxylate; 4-C4-C2-C1C (4-chlorophenyl) hydroxy-phenyl-3-o-pyrrol3-2,3-dihydro-3-oxo-4H-l, 2,4-triazol-4-yl-3-phenyl-3-l-? -perazinecarboxylate, ethyl; 4-C4-C2-Cl-C (4-fluorophenyl) hydroxyrnenyl propyl3-2.3-dihydro-3-oxo-4H-l, 2,4-triazol-4-yl phenyl-3-l-? -perazinecarboxylic acid ethyl ester; a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof.

5. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1, and a pharmaceutically acceptable carrier.

6. - A process for the preparation of a composition, according to claim 5, characterized in that a therapeutically effective amount of a compound, according to claim 1, is intimately mixed with a vehicle.

7. A compound "in accordance with claim 1 for use as a medicine. 8.- A procedure for the preparation of a compound "of formula in «don < of X, Ri, R2, 3, 4, R

S, R6, Z and are as defined in claim 1. characterized by a) N-alkylation of an intermediate of formula (II) with a reagent of formula (III). (II) in an inert reaction solvent in the presence of a base; b) N-acylation of an intermediate of formula (IV) with a reagent of formula (V). (IV) a-a) in an inert reaction solvent in the presence of a base: and further, if desired, converting the compounds of formula (I) to one another following transformation procedures of functional groups known in the art; converting the compounds of formula (I) into a form of acid addition salt by treatment with a pharmaceutically acceptable acid; or conversely, converting the salt form into the free base by treatment with alkali; and / or preparing isomeric forms stereochemically thereof.

9. A compound that has the formula an acceptable acid addition salt or stereochemically isomeric form thereof, wherein R6, X, Ri and Y are as defined in claim 1.

10. A therapeutic combination comprising a compound, in accordance with any of the claims 1 to 4, and a proton pump inhibitor.