Substituted derivatives of isolona, the method of production thereof, pharmaceutical composition and method of reception

 

(57) Abstract:

To obtain drugs intended for treatment associated with Helicobacter diseases using compounds of formula (I), their pharmaceutically acceptable salts with acids or their stereochemical isomers, where X and Y each independently represents CH or N; R1; R2and R3each independently represents hydrogen or C1-C4-alkyl; R4and R5each independently represents hydrogen, halogen, C1-C4-alkyl, C1-C4-alkyloxy, the hydroxy-group, trifluoromethyl, cryptometrics or deformations; Z is C=O or SNON and Ar represents phenyl, possibly substituted up to three substituents selected from a hydroxy-group, WITH1-C4-alkyl, C1-C4-alkyloxy, halogen, trifloromethyl, three(C1-C4-alkyl)silyloxy, or pyridinyl, substituted by a hydroxy-group and C1-C4-alkyloxy, and (A) represents a radical of formula (a-1), (a-2), (a-3), (a-4), (a-5). Describes the method of production thereof, and pharmaceutical preparation containing as an active ingredient a substituted derivatives atlona formula (I) and the way e is loam, which is an effective anti-Helicobacter tools that can be used as monotherapy for eradication of Helicobacter pylori and related species.

Known (U.S. patent 4,791,111) 4-(4-phenyl-1-piperazinil)phenols, which are intermediate compounds in the synthesis of[[4-[4-(4-phenyl-1-piperazinil)phenoxymethyl] -1,3-dioxolan-2 - yl]methyl]-1H-imidazoles and 1H-1,2,4-triazoles.

Also described 4-(4-phenyl-1-piperazinil)phenols having inhibiting 5-lipoxygenase activity (U.S. patent 4.931.444). Compounds of the present invention differ from those of its compounds are useful anti-Helicobacter activity.

Diseases of the gastrointestinal tract are widely distributed. Modern medicine is still powerless in the study of a number of diseases, particularly diseases associated with the presence in the mucosa of the stomach bacterium Helicobacter, such as chronic gastritis, duodenal ulcers and acute ulcer of the duodenum. Dual therapy for eradication of Helicobacter composed before the introduction of separately two drugs-antibiotics, to date has not given satisfactory results for one or more of the following reasons: low level liquid is Pius, consisting in the introduction of two antibiotics and bismuth compounds, as shown, is effective, but the need for these patients is very high and their application is also complicated side effects.

The objective of the present invention are compounds having anti-Helicobacter activity, suitable for the production of medicines for the treatment of diseases caused by bacteria Helicobacter, as well as a method of treatment for these diseases using new medicines on the basis of data connections.

This object is achieved by the use of substituted derivatives of isolona formula:

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its pharmaceutically acceptable salts with acids and its stereochemical isomers:

where X and Y independently represent CH or N;

R1, R2and R3each independently represents hydrogen or C1-C4-alkyl;

R4and R5each independently represents hydrogen, halogen, C1-C4-alkyl, C1-C4-alkyloxy, the hydroxy-group, trifluoromethyl, cryptometrics or deformations;

Z is C=O or CHOH;

Ar represents phenyl, possibly substituted up to three substituents, chosen, three(C1-C4-alkyl)silyloxy, nitro, amino and ceanography or pyridinyl, substituted hydroxy-group or C1-C4-alkyloxy; group

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represents a radical of the formula:

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The present invention relates also to a method of treating patients suffering from associated with Helicobacter diseases, including introduction to the subject an effective anti-Helicobacter amount of the compounds of formula (I).

In addition, the present invention relates to pharmaceutical preparations containing pharmaceutically acceptable carrier and as active ingredient a compound of the formula (I), its pharmaceutically acceptable salt with acid or its stereochemical isomer, where X, Y, R1-R5, Z, Ar and group

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Take the above values, provided that Ar is different from 4-hydroxyphenyl, 3-(C1-C4-alkyl)-4-hydroxyphenyl or 3,5-di(C1-C4-alkyl)-4-hydroxyphenyl, when X = N and group

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represents a radical of the formula (a-I).

The present invention relates also to the compound of formula (I), its pharmaceutically acceptable salt with an acid or the stereochemical isomer, where X, Y, R1-R5, Z, Ar is UB>-C4-alkyl)-4-hydroxyphenyl, 3,5-di(C1-C4-alkyl)-4-hydroxyphenyl or 4-methoxyphenyl, when X = N and group

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represents a radical of the formula (a-I).

The above definitions as used here, the mean value: halogen includes chlorine, fluorine, bromine and iodine; C1-C4-alkyl defines a saturated hydrocarbon radical with a straight or branched chain and 1-4 carbon atoms, for example: methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl.

The term "pharmaceutically acceptable salt with the acid used in the value determines therapeutically active non-toxic salts which the compounds of formula (I) can form when adding acids. The compounds of formula (I) have basic properties can be converted into the corresponding therapeutically active salts with acids by treatment of the free base in the usual manner acceptable amount of the appropriate acid. Examples of acceptable acids include inorganic acids such as hydrohalogenation, for example: hydrochloric, Hydrobromic and the like acids, sulfuric acid, nitric acid, phosphoric acid, etc. or organic acid is undecylate, perpendiculat, butanedioate, Z-2-butandikislota, (E)-butandikislota, 2-hydroxymandelate, 2,3-dihydroxybutanedioate, 2-hydroxy-1,2,3-propanetricarboxylate, methansulfonate, econsultancy, benzosulfimide, 4-methylbenzenesulfonate, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. The term "pharmaceutically acceptable salts with acids" also includes sulfate, which is able to form compounds of formula (I), for example hydrates, alcoholate etc.

The term "stereochemical isomers" as used here, the value specifies the different isomeric as well as conformational forms inherent in the compounds of formula (I). If there are no other references or indications, the chemical designation of compounds denotes the mixture of all possible stereochemical and conformational isomeric forms, and such mixtures containing all diastereomers, enantiomers and/or conformers of the basic molecular structure.

The absolute configuration of each chiral center may be indicated stereochemical designations R and s

Individual compounds of the present invention may exist in different tautomeric forms, and such tautomeric what are those compounds of formula (I), in which R4and R5each independently represents a hydrogen or halogen and Ar is phenyl, substituted with up to three substituents selected from a hydroxy-group, C1-C4-alkyl and C1-C4-alkyloxy, or pyridinyl, substituted by a hydroxy-group or C1-C4-alkyloxyaryl.

The first group representing the interest of compounds is formed by those compounds of formula (I) in which Ar is a radical of the formula:

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where R6, R7, R10, R11and R12each independently represents a hydroxy-group or C1-C4-alkyloxy; R8and R9- C1-C4-alkyl.

The second group of interesting compounds consists of those compounds of formula (I) in which X = n

The third group of interesting compounds are those compounds of formula (I), in which the group

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

A fourth group of interesting compounds comprise those compounds of formula (I) in which Y = N and R1- hydrogen.

The fifth group of interesting compounds consists of those compounds of formula (I) in which R2- the ethyl ormula (I), in which R4- halogen, substituted in the para-position and R5- hydrogen.

Preferred compounds of formula (I) in which R2- C1-C4-alkyl,

R4- halogen, substituted in the para-position and R1, R3and R5- hydrogen.

More preferred are those of the featured compounds of formula (I) in which Ar represents hydroxyphenyl, methoxyphenyl, acid, C1-C4-alkylphenyl, di(C1-C4-alkyl)phenyl or methoxypyridine; group

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

The most preferred are the following compounds:

[1-(4-chlorobenzoyl)propyl] -2,4-dihydro-4-[6-[4-(4- methoxyphenyl)-1-piperazinil]-3-pyridinyl]-3H-1,2,4-triazole-3-one;

2-[1-(4-chlorobenzoyl)propyl] -2,4-dihydro-4-[6-[4-(3- hydroxyphenyl)-1-piperazinil]-3-pyridinyl]-3H-1,2,4-triazole-3-one;

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

2-[1-[(4-chlorophenyl)hydroxymethyl] propyl] -2,4-dihydro-4- [4-[4-(6-methoxy-3-pyridinyl)-1-piperazinil]phenyl]- 3H-1,2,4-triazole-3-one;

2-[1-(4-chlorobenzoyl)propyl] -4-[6-[4-(3-methoxyphenyl)-1 - piperazinil]-3-pyridinyl]-2,4-dihydro - 3H-1,2,4-triazole-3-one;

2-he;

2-[1-(4-chlorobenzoyl)propyl]-4-[6-[4-(3,4-acid)-1 - piperidinyl] -3-pyridinyl]-2,4-dihydro-3H-1,2,4-triazole-3-one;

2-[1-[(4-chlorophenyl)hydroxymethyl] propyl] -2,4-dihydro-4- [4-[4-(6-methoxy-2-pyridinyl)-1-piperazinil]phenyl]- 3H-1,2,4-triazole-3-one;

2-[1-[(4-chlorophenyl)hydroxymethyl] propyl] -4-[6-[4-(3,4- acid)-1-piperazinil]-3-pyridinyl]-2,4-dihydro - 3H-1,2,4-triazole-3-one and

2-[1-[(4-chlorobenzoyl)propyl] -4-[6-[4-(3,4-acid)-1 - piperazinil] -3-pyridinyl] -2,4-dihydro-3H-1,2,4-triazole-3-one, their pharmaceutically acceptable salts with acids and their stereochemical isomers.

Methods of producing compounds of the present invention of formula (I) are described, for example, in U.S. patent 4,791,111 and U.S. patent 4,931,444.

In particular, the compounds of formula (I) can be obtained by N-alkylation of the intermediate compounds of formula (II) with a reagent of formula (III):

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The reaction of N-alkylation of compounds of formula (II) with the compound of the formula (III) is conveniently carried out with stirring and heating a mixture of the reagents in the appropriate solvent in the presence of an appropriate base. Acceptable solvents include, for example, dipolar aprotic solvents such as N, N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazoli rehydrator; halogenated hydrocarbons, for example: dichloromethane, tetrahydrofuran or mixtures of these solvents.

Acceptable bases include, for example: bis(trimethylsilyl) amide, sodium, carbonates and bicarbonates of alkali and alkaline earth metals such as sodium carbonate or potassium hydroxide, or organic bases, such as triethylamine, and a similar reason.

The compounds of formula (I) can be converted into each other by known methods of transformation of functional groups.

For example the compounds of formula (I) where Z represents C=O, can be converted into compounds of formula (I), where Z is CHOH, known in the art recovery techniques. For example, the recovery is carried out with a metal hydride or a complex metal hydride, e.g. sodium borohydride, cyanoborohydride sodium, etc. in water, 1-organic, in alcoholic medium, for example, methanol, ethanol or simply ether, such as tetrahydrofuran, 1,4-dioxane or mixtures of these solvents.

Or restoration can be carried out by reaction with hydroboration Tris(1-methylethoxy)potassium inert under the reaction conditions, the solvent, such as tetrahydrofuran.

In addition to the corresponding C1-C4-alkyloxybenzoic acceptable in the dealkylation reaction, for example, the use of triperoxonane acid or, in particular, mineral acids such as concentrated hydrohalogen acid, for example: Hydrobromic acid, uudistoodetena acid, possibly in a mixture with a saturated solution itestosterone acid in glacial acetic acid; a Lewis acid such as: trichromate boron in inert under the reaction conditions, the solvent, for example: dichloromethane. When using Hydrobromic acid it is recommended that the dealkylation reaction carried out in the presence of a binding promiseth, such as, for example: sulfite or hydrosulfite sodium.

On the contrary, the compounds of formula (I) in which Ar is substituted by at least C1-C4-alkyloxyaryl can be obtained by alkylation of the corresponding hydroxy acceptable alkylating agent, for example: dimethylsulfate, etc. May be conducted alkylation reaction known to experts in the conditions of the catalytic reaction with the transfer phases. These conditions include mixing of the reagents with the appropriate base, e.g. sodium hydroxide in an inert under the conditions of reaction is eltletomonchier.com etc.

The compounds of formula (I) in which Ar is substituted by a hydroxy-group, can be converted into the corresponding three(C1-C4-alkyl)similarverizon reaction with three (C1-C4-alkyl)-Si-L7where L7is reactive waste group, for example halogen in an inert reaction conditions solvent, for example, pyridine, dichloromethane.

Conversely, the compounds of formula (I) in which Ar is substituted by three (C1-C4-alkyl)silyloxy, can be converted into the corresponding hydroxy by reaction with fluoride, for example, (n-C4H9)4N+F-in an inert under the reaction conditions solvent, such as tetrahydrofuran, dichloromethane.

And finally, pure isomeric forms of the compounds of formula (I) can be isolated from the mixture by conventional methods of separation. In particular, the enantiomers can be separated by column chromatography using chiral stationary phase, for example, derivatizing cellulose, such as three(dimethylcarbamoyl)cellulose (Chiralcel, ODand similar chiral stationary phases.

In all previous and subsequent methods to obtain the reaction products can be isolated is adikam.

Some intermediate and source of compounds used in the above methods of preparation, are known compounds which can be synthesized by well-known specialists in the techniques for obtaining these or similar compounds.

Intermediate compounds of formula (II) can be synthesized by cyclization of an intermediate compound of formula (IV) with a reagent of formula (V) or its derivatives.

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Acceptable for the specified reaction solvent is, for example, inert under the reaction conditions dipolar aprotic solvent, for example N, N-dimethylformamide, dimethylsulfoxide, etc., or an alcohol, such as ethanol, 1-butanol, etc.

The intermediate compound of formula (IV) can be synthesized by reaction of the intermediate of formula (VI) with hydrazine or its derivative in an inert under the reaction conditions solvent, for example: 1,4-dioxane, etc., (formula (IV) below).

The intermediate compound of formula (VI) can be synthesized by reaction of the intermediate of formula (VII) with phenylcarbamates in an inert under the reaction conditions solvent, such as, for example: N,N-dimethylformamide, N, N-dimethylacetamide, aromatic solvent, e.g. the oil.

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Intermediate compounds of formula (VII) can be obtained by reduction by known experts methods corresponding nitro-derivatives of the formula (VIII).

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Acceptable known recovery methods include, for example: catalytic hydrogenation in a suitable solvent, such as methanol, tetrahydrofuran, N, N-dimethylformamide in the presence of an appropriate catalyst, such as: palladium on charcoal, Raney Nickel, etc., under hydrogen pressure, possibly in the presence of thiophene.

Or the intermediate compound of formula (VII) can be obtained by reaction of compounds of formula (VIII) with hydrazine or its derivative in an inert under the reaction conditions solvent, such as methanol in the presence of a catalyst, such as Raney Nickel.

In addition, the intermediate compounds of formula (VII), in which the group is a radical of formula (a-4) can be obtained by the reaction of intermediate compounds of formula (IX) or its derivative according to the following reaction scheme:

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The intermediate compounds of the above formula (X) is usually conducted in an inert reaction conditions solvent, for example, 1-propanol, methanol or their mixtures, site) from intermediates of formula (X) may be carried out in the presence of a base, for example: sodium hydroxide, etc.

Intermediate compounds of formula (VIII) can be obtained by the reaction of intermediates of formula (XI) with a reagent of formula (XII), where L is a reactive waste group, for example: halogen in an inert under the reaction conditions solvent, for example N,N-dimethylacetamide, dimethylsulfoxide, N, N-dimethylformamide, bis(2-methoxyethoxy) ether, 3-methoxy-1-propanol, etc., preferably in the presence of a base such as potassium carbonate, etc.

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Intermediate compounds of formula (XI) in which X = N, that is, the intermediate compounds represented by formula (XI-a), can be obtained by the reaction of intermediates of formula (XIII) with a reagent of formula (XIV), where L1and L2are reactive waste group, for example: halogen, in an inert under the reaction conditions solvent, for example, 1-butanol, hexanol, etc., preferably in the presence of a base such as potassium carbonate and possibly in the presence of a small amount of potassium iodide.

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It is possible to conduct these reactions the use of N-protected intermediate compound of formula (XIV), for example, toiling derived. After the reaction intermediate with whom iSlate.

Or intermediate compounds of formula (XI-a), in which Ar is substituted by a methoxy group can be obtained according to the following reaction scheme.

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Ar1as used here, the value represents phenyl or pyridinyl, R1represents a protective group, for example, C1-C4-allyloxycarbonyl, X1represents halogen, in particular bromine or iodine and L3is reactive waste group, for example halogen. Synthesis of intermediate compounds of formula (XVI) recommended in an inert under the reaction conditions solvent, for example, carbon disulfide.

The protective group in the intermediate compounds of formula (XVI) may be removed by the action of acid, e.g. Hydrobromic acid. The intermediate compounds of formula (XVIII) recommended in an inert under the reaction conditions solvent, for example xylene, possibly in the presence of a base, such as sodium bicarbonate. In addition, obtaining the above intermediate compounds of formula (XIX) is possible in the presence of a catalyst, for example, copper iodide (I), etc. may in nitrogen atmosphere. Finally, the benzyl group in the intermediate compounds of formula (XIX) may be delete the set obtained from the corresponding anilinopyrimidines the application of known methods.

To obtain the intermediate compounds of formula (II) an intermediate compound of formula (VI) may be introduced into the reaction with the reagent of formula (XX), where L4and L5are reactive waste group, for example, C1-C4-alkyloxy in an inert under the reaction conditions solvent, for example, 1,4-dioxane, etc., to obtain the intermediate compounds of formula (XXI). The last intermediate connection then cyclist acid, for example hydrochloric acid.

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In another embodiment, the intermediate compounds of formula (II) can be synthesized by reaction of the intermediate of formula (VI) with a reagent of formula (XXII) or its derivative in an inert under the reaction conditions solvent, for example, 1,4-dioxane, possibly in the presence of a base, for example N, N-dimethyl-4-pyridylamine with the formation of intermediate compounds of formula (XXIII). The obtained intermediate compound can be cyklinowanie acid, for example formic acid.

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Intermediate compounds of formula (II) can be also obtained by the reaction of intermediate compounds of formula (VII) with a reagent of formula (XXIV), where R6-C1-C6-alkyl, for example: methyl, or the PU or di(C1-C6-alkyl)amino group, for example: methoxy, ethoxy or dimethylaminopropyl in an inert under the reaction conditions solvent, for example, tetrahydrothiophene-1,1-dioxide, etc.

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The compounds of formula (I), their pharmaceutically acceptable salts with acids and their stereochemical isomers exhibit useful pharmacological activity against bacteria Helicobacter species, for example: Helicobacter pylori, Helicobacter mustelae, Helicobacter felis, etc., in particular Helicobacter pylori.

In this regard, of particular importance is the discovery that these compounds exhibit inhibitory activity against the growth of Helicobacter, and bactericidal activity against specified bacteria. A bactericidal effect on Helicobacter determine in suspended cultures using the method described in the publication "antimicrobial Chemotherapy means", 1991, T. 35, pp. 869-872.

An interesting feature of the compounds of the present invention is their high specific activity against Helicobacter. The compounds of formula (I) exhibit inhibitory activity against any of the following species: Campylobacter jejuni, Campylobacter coli, Campylobacter fetus, Campolybacter sputorum, Vibrio spp., Staphylococcus aureus and Escherichial coli when tested at concentrations up to 10-5M. of H. Ativ pylori at pH below the normal neutral pH. Activity at low pH in vitro can serve as an indication that the connection will not adversely impact the acidic environment of the stomach in vivo.

Therefore these compounds can be considered as valuable therapeutic agents for warm-blooded animals, in particular humans, suffering from diseases and lesions, the causative agent of which is Helicobacter. Examples of such diseases or conditions include gastritis, gastric ulcer, duodenal ulcer and gastric cancer.

Having useful anti - Helicobacter properties of these compounds may be included in the various pharmaceutical forms for administration for therapeutic purposes. To obtain pharmaceutical preparations according to the present invention, an effective amount of a particular compound (in the form of a base or as a salt with the acid) as an active ingredient are mixed in a uniform with a pharmaceutically acceptable carrier, which may be of various forms depending on the target shape intended for injection. Such pharmaceutical preparations are recommended in single dozirovanno is the iMER, upon receipt of drugs in oral dosage form may be used any conventional pharmaceutical environment, such as, for example, water, glycols, oils, alcohols, etc., in the case of oral liquid preparations such as suspensions, syrups, elixirs or solutions, or solid carriers such as starches, sugars, kaolin, lubricants, binders, strukturator, etc. in the case of powders, pills and tablets. Due to ease their introduction of tablets and capsules represent the most recommended oral dosage forms, and in this case, obviously, use solid pharmaceutical carriers. For parenteral preparations as a carrier usually used sterile water, component, at least a large part of the drug, although the drug may include other components, for example, contributing to the solubility of the substance. Can be prepared, for example, injectione solutions in which the carrier is a saline solution, glucose solution or a mixture of saline and glucose solution. Can also be prepared injectisome suspension, and in this case, use the appropriate liquid carriers, suspendresume tools, etc.

If phoremost, can be entered into the product in the form of a salt or may be added miscible with water and physiologically acceptable co-solvent, for example: dimethylsulfoxide, etc. or a compound of formula (I) can be solubilisation acceptable carrier, for example, cyclodextrin (CD) or, in particular, derivatives of cyclodextrin, for example, cyclodextrin derivatives, disclosed in U.S. patent 3,459,731, European patent EP-A-149,197 (July 24, 1985), the European patent EP-A-197,571 (October 15, 1986), U.S. patent 4,535,152 or WO 90/12035 (October 18, 1990). Typically, these derivatives consist of, or CD, in which one or more hydroxyl groups substituted C1-C6-alkyl, in particular, stands, ethyl or isopropyl; hydroxy-C1-C6-alkyl, particularly hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxy-C1-C6-alkyl, in particular, carboxymethyl or carboxyethyl; C1-C6-alkylcarboxylic, in particular, acetyl; C1-C6-allyloxycarbonyl-C1-C6-alkyl; carboxy-C1-C6-alkyloxy-C1-C6-alkyl, in particular, carboxyphenoxypropane or carboxitherapy, or C1-C6-alkylcarboxylic-C1-C6-alkyl,TV deserve-CD, 2,6-dimethyl--CD, and especially 2-hydroxypropyl --CD,2-hydroxyethyl--CD, 2-hydroxyethyl--CD, 2-hydroxypropyl --CD and (2-carboxymethoxy)propyl--CSD. For the above-mentioned derivatives of cyclodextrin C3 (degree of substitution, i.e. the average number of substituted hydroxybenzyl on the link glucose) is in the range 0,125-3, in particular, 0.2 to 2 0.2 to 1.5. More preferred values of C3 are in the range of 0.2 to 0.7, in particular from 0.35 to 5 and especially about 0.4. MS (molar degree of substitution, i.e. the average number of moles of the substituting substance on the link glucose) is in the range 0,125-10, in particular from 0.3 to 3 0.3 to 1.5. More preferred values S are in the range of 0.3 to 0.8, in particular from 0.35 to 0.5, and particularly about 0.4. Most recommended for use in the preparations of the present invention derivatives of cyclodextrin is hydroxypropyl --cyclodextrin with MS in the range of 0.35-0.5 and containing less than 1.5% unsubstituted-cyclodextrin. The amount of cyclodextrin or its derivative in the final product, typically is in the range of 1-40%, in particular 2.5 to 25% and especially 5 to 20%.

The above-mentioned pharmaceutical preparations especially recommended manufacturing in dosage unit forms, facilitating the introduction and ensure which belongs to a physically discrete unit, applied as a single dose, with each unit contains a specified quantity of active ingredient calculated to create the desired therapeutic effect, in a mixture with the required pharmaceutical carrier. Examples of such dosage unit forms include tablets (including corrugated and having a shell tablets), capsules, pills, powders in sachets, waffles, injectisome solutions or suspensions, etc., and such individual forms can be combined in one package.

In view of the applicability of the compounds for the treatment associated with Helicobacter diseases it is evident that the present invention provides a method of treating warm-blooded animals, including man, suffering associated with Helicobacter infection. How is the systemic administration of pharmaceutically effective amounts of compounds of formula (I), its pharmaceutically acceptable salt with an acid or its stereochemical isomer in a mixture with a pharmaceutical carrier. As a rule, believe that daily, the effective amount is in the range of 0.05-20 mg/kg body weight, preferably 0.1 to 10 μg/kg body weight and more preferably 0.5 to 5 mg/kg of body weight. It is obvious that the effective daily dose can observations of the attending physician, prescribing the compounds of the present invention. The above-mentioned intervals effective daily amounts, therefore, are only indicative and are not intended in any way to limit the scope of the invention. Mainly suitable pharmaceutical composition comprises the compound of formula 1 in the amount of 3,5-1400 mg, in particular 7-700 mg, more preferably 35-350 mg

In combination with the compounds of the present invention it is also possible introduction and other active compounds used to inhibit Helicobacter. The introduction can be carried out separately (for example: at the same time, together or sequentially) or various drugs can be combined in a single dosage form. Recommended for combined treatment of compounds are compounds of bismuth such as bismuth subcitrate, bismuth subsalicylate, etc. and inhibitors pumping of protons, for example: omeprazol, lansoprazol etc.

Experimental part

The intermediate compounds

Example 1.

a) a mixture of 2-(4-methoxyphenyl)piperazine dihydrochloride (0.05 m), 1-chloro-4-nitrobenzene (0.05 m) and potassium carbonate (10 g) in N,N-dimethylformamide (100 ml) is boiled zanichellia layers combine, dried (MgSO4), filtered and evaporated in vacuum. The residue is successively rinsed 4-methyl-2-pentanone and recrystallized from 1,4-dioxane. Filtration and drying of the product receive a 10.5 g (67%) of 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine, so pl. 195,1oC (InterMedia. Conn. I).

b) a mixture of intermediate (1) (0,038 mol) in methanol (250 ml) and tetrahydrofuran (250 ml) hydronaut under normal pressure and at room temperature using as catalyst 10% palladium on charcoal (2 g). After uptake of hydrogen (3 EQ.) the catalyst is filtered off and rinsed with N,N-dimethylacetamide. The combined filtrates are transferred into the water. The precipitate is filtered off and recrystallized from 1-butanol. By filtering and drying the product to obtain 8 g(74%) 4-[4-(4-methoxyphenyl)-1-piperazinil]benzoylamino, so pl. 191,8oC (InterMedia. Conn. 2).

c) a Mixture of intermediate compound (2) (0,021 mol) and phenylcarbamate (is 0.023 mole) in pyridine (75 ml) and dichloromethane (75 ml) is stirred and heated until complete dissolution of the reagents. Stirring is continued for 30 minutes at room temperature. The reaction mixture is transferred into a mixture of 500 ml of water and 300 ml of 2,2'-oxybisethane. The precipitate after mixing from the 2 g (61%) of phenyl [4-[4-(4-methoxyphenyl)-1-piperazinil]phenyl] carbamate, so pl. 204,5oC (InterMedia. Conn. 3).

d) a Mixture of intermediate compound (3) (0,008 mole) of hydrazine monohydrate (50 ml) in 1,4-dioxane (100 ml) is boiled with stirring for 3 hours. After cooling, the reaction mixture is transferred into the water. The precipitate is filtered off and recrystallized from N,N-dimethylformamide. Filtration and drying of the product is obtained 1.7 g (62%) of N-[4-[4-methoxyphenyl)-1-piperazinil]phenyl]hydrazinecarboxamide, so pl. > 300oC (InterMedia. Conn. 4).

e) a Mixture of intermediate compound (4) (0,001 mol) and acetate methanimidamide (0,029 mole) in dimethyl sulfoxide (10 ml) is heated for 2 hours at 160oC. After cooling, the reaction mixture was transferred to a mixture of 4-methyl-2-pentanone and 2,2'-oxybisethane. The precipitate is filtered off and treated with activated carbon in N,N-dimethylformamide. After filtration the product is left for crystallization. Filtration and drying of the product is obtained 1 g (28%) of 2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinil]phenyl]- 3H-1,2,4-triazole-3-one, so pl. > 300oC (InterMedia. Conn. 5).

Example 2.

A mixture of intermediate compound (4) (0,015 mol) and hydrochloride ethanimine high (0.56 mol) in N,N-dimethylformamide (150 ml) is stirred for 3 hours at 130oC. After cooling the reaction, see the IDA. Filtration of the product and recrystallization from 1,4-dioxane obtain 19.5 g (33.3%) of 2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinil]phenyl]-5-methyl - 3H-1,2,4-triazole-4-it, so pl. 298.4oC (InterMedia. Conn. 6).

Example 3.

a) a Mixture of 10 g of the intermediate compound (3), 3 g of 2,2-dimethoxyethane and 100 ml of 1,4-dioxane is boiled with stirring for 6 hours, after which the reaction mixture is cooled. Usageprice the product is filtered, washed with 1,4-dioxane and purified column chromatography on silica gel using as eluent a mixture of trichloromethane with methanol (99:1). Collect the pure fractions and the eluent is evaporated. Crystallization of the residue from 1,4-dioxane gain of 3.9 g of N-(2,2-dimethoxymethyl)-N'-[4-[4-methoxyphenyl)-1-piperazinil] phenyl]-urea, so pl. 225oC (InterMedia. Conn. 7).

b) a Mixture of 70 g of the intermediate compound (7), 84 g of concentrated hydrochloric acid, 300 ml of water and 350 ml of methanol is heated with stirring for 30 minutes at 80oC. the Reaction mixture was left to warm to room temperature with simultaneous crystallization of the product. The product is filtered, washed with water and after drying obtain 24.5 g (37%) monohydrate monohydrochloride 1,3-dihydro-1-[4-[4-(4-methoxyphenyl)-1-piperazinil]phenyl]-2H-imidazol-2-he is 6 g 2-aminomethyl-2-methyl-1,3-dioxolane monohydrate, 100 ml of 1,4-dioxane, 1 g N,N-dimethyl-4-pyridylamine and 4 g of N,N-diethylethanamine is boiled with stirring for 3 hours. Water is added and the mixture is cooled to crystallize the product. The product is filtered, washed with water and 2-propanol and after drying obtain 3.8 g (89,1%) N-[4-[4-(4-methoxyphenyl)-1-piperazinil] phenyl]-N'-[(2-methyl-1,3 - dioxolan-2-yl)methyl]urea (InterMedia. Conn. 9).

b) a Mixture of 3.3 g of intermediate compound (9) and 100 ml of formic acid is stirred for 1 hour at 70oC. the Reaction mixture is evaporated and the residue is neutralized with sodium hydrogen carbonate solution. Add 4-methyl-2-pentanon, the mixture is stirred and the product is filtered. The precipitate is washed with water and 4-methyl-2-pentanone. By recrystallization of the product from N,N-dimethylformamide get 2 g (71.3 per cent) of 1,3-dihydro-1-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-5-methyl-2H-imidazol-2-it, so pl. > 300oC (InterMedia. Conn. 10).

Example 5.

a) To a stirred and cooled mixture of ( < 10o(C) 150 g of ethyl ester of 4-(2-pyridinyl)-1-piperazinecarboxamide acid and 1535 ml of carbon disulfide are added dropwise to 32.8 ml of bromine. Upon completion of the addition, stirring is continued for 18 hours with increasing temperature to room. At temperatures below 20oC add a solution of 70 the second phase is extracted with twice trichlormethane. The combined organic phases are washed with water, dried, filtered and evaporated. To the residue add 46 ml of benzene and the mixture is again evaporated. After standing 48 hours product hardens. Oily phase is decanted and the solid product is crystallized twice from 2,2'-oxybisethane at 10oC. Filtration and drying obtain 100 g of ethyl ester of 4-(5-bromo-2-pyridinyl)-1-piperazinecarboxamide acid, so pl. 68oC (InterMedia. Conn. 11).

b) a Mixture of 18 g of the intermediate compound (11) and 50 ml of 48% aqueous Hydrobromic acid is boiled with stirring for 2 hours. The reaction mixture is cooled and evaporated. The solid residue is dissolved in water and at a temperature below 20oC the solution is alkalinized 10 N. solution of sodium hydroxide. The product is extracted twice with trichloromethane. The combined extracts washed with water, dried, filtered and evaporated. Drying of the solid product in air at room temperature to obtain 12.3 g of 1-(5-bromo-2-pyridinyl)piperazine, so pl. 70,6oC (InterMedia. Conn. 12).

c) a Mixture of 9.7 g of the intermediate (12) 3.7 g of sodium bicarbonate and 40 ml of xylene is boiled with stirring. Then boiling the mixture was added dropwise a solution of 4.8 ml (methyl bromide) benzene in 10 ml of xylene. The eye is mperature, add 75 ml of water and the layers separated. The aqueous phase is extracted with trichloromethane. The combined organic phases are dried, filtered and evaporated in vacuum. The residue is crystallized at 4oC of 2,2'-oxybisethane. The product is sucked off and after drying obtain 6.5 g of 1-(5-bromo-2-pyridinyl)-4-(phenylmethyl)-piperazine, so pl. 100oC (InterMedia. Conn. 13).

d) To 500 ml of methanol was added with stirring in portions sodium (0,6 mol) and the mixture is stirred until the full implementation of the reaction of sodium. Then add the intermediate compound (13) (0,15 mol), copper iodide (1) (0,15 mol) and N, N-dimethylformamide (500 ml) and the mixture is boiled with stirring for 48 hours. The mixture is then filtered and evaporated. The residue is purified column chromatography on silica gel (eluent: EtOAc-hexane-CH2Cl2, 1 : 1 : 2). Pure fractions are collected and evaporated, receiving of 33.5 g (79%) of 1-(5-methoxy-2-pyridinyl)-4-(phenylmethyl)-piperazine (InterMedia. Conn. 14).

e) an Intermediate compound (14) (of 0.11 mol) in methanol hydronaut at 50oC in the presence as catalyst 10% palladium on charcoal (7 g). After absorbing 2 EQ. hydrogen the catalyst is filtered off and evaporation of the filtrate obtain 19.3 g (88%) of 1-(5-methoxy-2-pyridinyl)piperazine (InterMedia. Conn. 15).

l) was stirred at room temperature. Added dropwise 1-fluoro-4-nitrobenzene (0.12 moles) and the mixture is stirred for about a day at room temperature. The mixture is transferred into water, the precipitate is filtered off and after drying obtain 20.6 g (70%) of product. The product sample (1 g) crystallized from 2-propanol and purified column chromatography on silica gel (eluent: CH2Cl2-CH3CN-CH3OH, 97 : 2 : 0,25). Pure fractions are collected and evaporated. Washing the residue (0.8 g) 2,2'-oxybisethanol obtain 0.8 g of 1-(5-methoxy-2-pyridinyl)-4-(4-nitrophenyl)piperazine, so pl. 160,2oC (InterMedia. Conn. 16).

g) of the Intermediate compound (16) (0,061 mol) in N,N-dimethylformamide (500 ml) hydronaut about the day when 50oC using as a catalyst of Raney Nickel. After absorption 3 EQ. hydrogen the catalyst is filtered off and the filtrate evaporated. The residue is used without further purification. Get 17,6 g(100 %) 4-[4-(5-methoxy-2-pyridinyl)-1-piperazinil] benzenamine (InterMedia. Conn. 17).

h) To mix in a water bath a mixture of intermediate (17) (0,062 mol) and N,N-dimethylformamide (100 ml) was added dropwise phenylcarbamate (of 0.11 mol) and the mixture is stirred for about a day. Then add water, the precipitate is filtered off and after drying receive a 25 g full-time connection (18) (0,062 mol) and hydrazine monohydrate (of 0.62 mol) in 1,4-dioxane (500 ml) is stirred for 48 hours PR 50oC. the Mixture is transferred into water, the precipitate is filtered off and after drying receive 15 g (71%) N-[4-[4-(5-methoxy-2-pyridinyl)-1-piperazinil] phenyl] hydrazinecarboxamide (InterMedia. Conn. 19).

j) a Mixture of intermediate (19) (0,044 mol) and acetate methanimidamide (to 0.22 mol) in 1-butanol (300 ml) is boiled with stirring for about a day. The mixture is transferred into water and extracted with CH2Cl2. The organic layer is dried, filtered and evaporated. The residue is purified column chromatography on silica gel (eluent: CH2Cl2-CH3OH, 95 : 5). Pure fractions are collected and after evaporation obtain 3.2 g of 2,4-dihydro-4-[4-[4-(5-methoxy-2-pyridinyl)-1-piperazinil]phenyl]-3H-1,2,4-triazole-3-one (InterMedia. Conn. 20).

Example 6.

a) a Mixture of 36 g of the dihydrochloride of 1-(4-methoxyphenyl)piperazine, 22 g of 2-chloro-5-nitropyridine, 58 g of potassium carbonate and 227 ml of dimethylsulfoxide is stirred for about days at 140oC. the Reaction mixture is cooled and transferred into the water. Usageprice the product is filtered, washed with water and dissolved in dichloromethane. The solution is treated with activated carbon. The charcoal is filtered off and the filtrate evaporated. The residue is rinsed with 2-propanol. Filtration of the product and its crystallization from 1-butanol get 24,5 art 36 ml of hydrazine monohydrate, 4 g of Raney Nickel and 1000 ml of methanol is added in portions over 25 minutes, 35 g of the intermediate (21). After boiling for 35 minutes with stirring, add 11 ml of hydrazine monohydrate and continue boiling for 10 minutes. Add an additional 0.5 g of Raney Nickel and the mixture is boiled for 15 minutes. The reaction mixture is cooled, the catalyst is filtered off and evaporation of the filtrate get 33,57 g of 6-[4-(4-methoxyphenyl)-1-piperazinil] -3-pyridylamine in the form of a crude product, so pl. 144 - 147oC (InterMedia. Conn. 22).

c) a Mixture of 31,21 g of the intermediate compound (22), of 38.4 g of ethyl ester (1-amoxicillin)hydrazinecarboxamide acid and 10 ml of tetrahydrothiophene-1,1-dioxide is heated for 17 hours at an oil bath at 154 - 158oC. After cooling, add 150 ml of 2-propanol and the mixture is filtered. The residue is recrystallized from a mixture of acetonitrile with N,N-dimethylformamide (90 : 10). The residue is purified pressure chromatography (eluent: CH2Cl2-CH3OH(NH4OH 10%), 98 : 2 ---> 96 : 4). Evaporation of the eluent in the target fractions and recrystallization of the residue from a mixture of N,N-dimethylformamide with acetonitrile receive 2,4-dihydro-4-[6-[4-(4-methoxyphenyl)-1-piperazinil] -3-pyridinyl] -5-methyl-3H-1,2,4-triazole-3-one, so pl. 251 - 252oC (InterMedia. Conn. 23).

2Cl2-CH3OH, 97 : 3). Evaporation of the eluent in the target fractions receive 15 g (62.5%) and N-[(dimethylamino)methylene] -2-[4-(4-methoxyphenyl)-1-piperazinil]- 5-pyrimidinamine (InterMedia. Conn. 24).

b) a Mixture of 10 g of the intermediate compound (24) and 150 ml of sulfuric acid (0.2 M) is boiled with stirring for 4 hours. After cooling, the mixture is neutralized with an aqueous solution of potassium carbonate. The product is extracted with dichloromethane, the extract washed with water, dried, filtered and evaporated. The residue is purified column chromatography (eluent: CH2Cl2-CH3OH, 98 : 2). Eluent in the target fractions evaporated and the residue crystallized from ethyl acetate. The product is filtered and after drying in vacuum at 50oC get 3.5 g(40,9%) 2-[4-(4-methoxyphenyl)-1-piperazinil]-5-pyrimidinamine, so pl. 157,1oC (InterMedia. Conn. 25).

c) To stir in the bath with ice mixture of 10 g of intermediate compound (25) and 100 ml of n, N-dimethylacetamide are added dropwise 4.8 ml of phenylcarbamate. After stirring 2 hours vacuum at 50oC gain of 7.7 g (54,3%) phenyl[2-[4-(4-methoxyphenyl)-1-piperazinil]-5-pyrimidinyl]carbamate (InterMedia. Conn. 26).

d) a Mixture of 7.7 g of the intermediate compound (26), 10 ml of hydrazine monohydrate and 60 ml of 1,4-dioxane was stirred at room temperature for about a day. The reaction mixture is transferred into water, the precipitate is filtered and washed with methanol. The product was then purified column chromatography (eluent: CH2Cl2-CH3OH, 96 : 4). Eluent in the target fractions are evaporated, the residue is stirred in methanol, filtered and after drying in vacuum at 75oC obtain 1.5 g (23%) N-[2-[4-(4-methoxyphenyl)- 1-piperazinil]-5-pyridinyl]hydrazine-carboxamide, so pl. > 300oC (decomp.) (InterMedia. Conn. 27).

e) a Mixture of 3 g of the intermediate compound (27), 3.7 g of acetate methanimidamide and 35 ml of 1-butanol is boiled with stirring for about a day. The reaction mixture is cooled, the precipitate filtered off, washed with 2,2'-oxybisethanol and after drying in vacuum at 70oC get 2 g (62,9%) of 2,4-dihydro-4-[2-[4-(4-methoxyphenyl)-1-piperazinil] -5 - pyrimidinyl]-3H-1,2,4-triazole-3-one, so pl. 272,5oC (InterMedia. Conn. 28).

Example 8.

a) a Mixture of 6-methoxy-3-pyrimidinamine (0,2 mol) and 2-chloro-N-(2-chloroethyl)ethanamine hydrochloride (0,3 mol) in 2-butanol (500 add a further quantity of potassium carbonate (30 g) and the mixture is stirred for 48 hours. The mixture is transferred into water, extracted with CH2Cl2and share. The organic layer is dried, filtered and after evaporation obtain 38 g (98%) of 1-(6-methoxy-3-pyridinyl)piperazine (InterMedia. Conn. 29).

b) a Mixture of intermediate (29) (0,2 mol) and potassium carbonate (0,5 mol) in N,N-dimethylacetamide (500 ml) was stirred at room temperature. Added dropwise 1-fluoro-4-nitrobenzene (0,24 mol) and the mixture is stirred for about a day. The mixture is transferred into water and filtering the precipitate obtain 16.3 g (30 %) 1-(6-methoxy-3-pyridinyl)-4-(4-nitrophenyl)piperazine (InterMedia. Conn. 30).

In a similar way, but using as solvent bis(2-methoxyethoxy) ether synthesized:

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

2-[4-(3-methoxyphenyl)-1-piperidinyl] -5-nitropyridine, so pl. 147,3oC (InterMedia. Conn. 32) and

1-(2-methoxyphenyl)-4-(5-nitro-2-pyridinyl)piperazine (InterMedia. Conn. 33).

c) an Intermediate compound (30) (0,042 mol) in N,N-dimethylformamide (500 ml) hydronaut about days at 60oC using as a catalyst of Raney Nickel (6 g). After absorption 3 EQ. hydrogen the catalyst is filtered off and the filtrate evaporated. Rinse residue 2,2'-oxybisethanol polki-3-pyridinyl)-1 - piperazinil]benzoylamino, so pl. 150oC (InterMedia. Conn. 34).

Similarly synthesized:

6-[4-(3-methoxyphenyl)-1-piperazinil] -3-pyridylamine, so pl. 110,6oC (InterMedia. Conn. 35);

6-[4-(3-methoxyphenyl)-1-piperidinyl] -3-pyridylamine, so pl. 124,9oC (InterMedia. Conn. 36) and

6-[4-(2-methoxyphenyl)-1-piperazinil]-3-pyridylamine (InterMedia. Conn. 37).

d) a Mixture of intermediate compound (34) (0,025 mol) and ethyl-2-[(dimethylamino)methylene] hydrazinecarboxamide (0,075 mol) tetrahydrothiophene-1,1-dioxide (10 ml) is stirred for 5 hours at 150oC. Add a mixture of 2-propanol with 2,2'-oxybisethanol (50 : 50), the precipitate is filtered off, washed and after drying obtain 6.5 g (74%) of 2,4-dihydro-4-[4-[4-(6-methoxy-3-pyridinyl)-1-piperazinil]phenyl]-3H-1,2,4-triazole-3-one (InterMedia. Conn. 38).

Similarly synthesized:

2,4-dihydro-4-[6-[4-(3-methoxyphenyl)-1-piperazinil] -3-pyridinyl] -3H-1,2,4-triazole-3-one, so pl. 242,6oC (InterMedia. Conn. 39);

2,4-dihydro-4-[6-[4-(3-methoxyphenyl)-1-piperidinyl] -3 - pyridinyl]-3H-1,2,4-triazole-3-one (InterMedia. Conn. 40) and

2,4-dihydro-4-[6-[4-(2-methoxyphenyl)-1-piperazinil] -3 - pyridinyl]-3H-1,2,4-triazole-3-one (InterMedia. Conn. 41).

Example 9.

a) a Mixture of 10 g of the hydrochloride of 4-methoxy-3,5-dimethylbenzenamine, 19.9 g of N, N-bis(2-chloroethyl)-4-methyl and at 150 - 160oC. After cooling, the reaction mixture is transferred into water and the product extracted with dichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is purified column chromatography on silica gel using as eluent trichlormethane. Pure fractions are collected and the solvent evaporated. Crystallization of the residue from 1-butanol get 10 g (50.4 percent) of 4-(4-methoxy-3, 5dimethylphenyl)-1-[(4-were) sulfonyl] piperazine, so pl. 174,2oC (InterMedia. Conn. 42).

b) a Mixture of 77.6 per g of the intermediate compound (42), 121,2 ml of concentrated sulfuric acid and 140 ml of water is boiled with stirring for about a day. Another portion of 30.4 g of concentrated sulfuric acid is added and boiling with stirring is continued for approximately another day. The reaction mixture is cooled and treated with sodium hydroxide. The product is extracted with dichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is converted into the salt with hydrochloric acid in 2-propanol and 2,2'-oxybisethane. Salt is filtered and crystallization from 2-propanol gain of 18.5 g of 1-(4-methoxy-3, 5dimethylphenyl)piperazine dihydrochloride (InterMedia. Conn. 43).

c) a Mixture of 14.1 g of 1-fluoro-4-nitrobenzene, 26 g of the intermediate compound (43), the t and transferred into the water. The products are extracted with methylbenzol. The extract is washed with water, dried, filtered and evaporated. The residue is rinsed 2,2-oxybisethanol. The product is filtered and crystallization from 2-propanol get 17,5 g (64.1%) of 1-(4-methoxy-3, 5dimethylphenyl)-4-(4-nitrophenyl)piperazine, so pl. 135,3oC (InterMedia. Conn. 44).

d) a Mixture of 15 g of the intermediate compound (44), 1 ml of 4% solution of thiophene in methanol and 202,5 ml of methanol hydronaut under normal pressure and at 50oC in the presence as catalyst 10% palladium on coal (2 g). After absorption of the calculated amount of hydrogen the catalyst was filtered and the filtrate evaporated. The remainder of the turn in 2-propanol hydrochloride in. Salt is filtered and after drying obtain 15.7 g (92,8%) of the dihydrochloride of 4-[4-(4-methoxy-3, 5dimethylphenyl)-1-piperazinil]benzoylamino, so pl. 289,5oC (InterMedia. Conn. 45).

e) a Mixture of 65 g of the intermediate compound (45), to 39.3 g (1-ataxiatelangiectasia acid ethyl ester and 100 ml of tetrahydrothiophene-1,1-dioxide is stirred for 3 hours at 120oC in nitrogen atmosphere. The mixture is cooled and add 2-propanol. The formed precipitate is filtered off and dried. The residue is purified column chromatography (eluent: CHCl3-CH3OH, 99 : 1). Eluent in the target Freccia)-1-piperazinil] phenyl] -5-methyl-3H-1,2,4-triazole-3-one, so pl. 280,1oC (InterMedia. Conn. 46).

B. Obtain the target compounds

Example 10.

A mixture of 2,4-dihydro-4-[6-[4-(4-methoxyphenyl)-1-piperazinil]-3 - pyridinyl] -3H-1,2,4-triazole-3-one (of 0.014 mol) and sodium carbonate (0,06 mol) in methylbenzene (30 ml) and N,N-dimethylformamide (70 ml) is boiled with stirring. Added dropwise to 2-bromo-1-(4-chlorophenyl)-1-butanone (0,015 mol) in trichloromethane (20 ml) and the mixture is boiled with stirring for 1 hour with a trap for water. The mixture is filtered warm and the filtrate evaporated. The residue is purified column chromatography on silica gel (eluent: CH2Cl2-CH3OH, 98 : 2). Pure fractions are collected and evaporated. Crystallization of the residue from 2-propanol receive 6 g(80%) ()-2-[1-(4-chlorobenzoyl)propyl]-2,4-dihydro-4-[6-[4-(4-methoxyphenyl)-1-piperazinil] -3-pyridinyl] -3H-1,2,4-triazole-3-one, so pl. 142,4oC (Conn. 1).

Similarly synthesized:

()-2-[1-(4-chlorobenzoyl)propyl] -2,4-dihydro-4-[5-[4-(4- methoxyphenyl)-1-piperazinil]-2-pyridinyl]-3H-1,2,4-triazole-3-one, so pl. 127,2oC (connection 2);

()-2-[1-(4-chlorobenzoyl)propyl] -2,4-dihydro-4-[4-[4- (5-methoxy-2-pyridinyl)-1-piperazinil] phenyl-3H-1,2,4-triazole-3-one, so pl. 165,1oC (Conn. 3);

()-2-[1-(4-chlorobenzoyl)propyl]-4-[6-[4-(3-methoxyphenyl)-1 - piperazinil] -3-pyridinylmethyl)-1-piperazinil]-3-pyridinyl]-3H-1,2,4-triazole-3-one, so pl. 195,6oC (Conn. 5);

()-2-[1-(4-chlorobenzoyl)propyl]-2,4-dihydro-4-[4-[4-(6- methoxy-3-pyridinyl)-1-piperazinil]phenyl]-3H-1,2,4-triazole-3-one, so pl. EUR 188.4oC (Conn. 6);

()-2-[1-(4-chlorobenzoyl)propyl] -2,4-dihydro-4[6-[4-(3- methoxyphenyl)-1-piperidinyl]-3-pyridinyl]-3H-1,2,4-triazole-3-one, so pl. 125,7oC (Conn. 7);

()-2-[1-(4-chlorobenzoyl)propyl] -4-[6-[4-(5-methoxy-2 - pyridinyl)-1-piperazinil] -3-pyridinyl] -2,4-dihydro-3H-1,2,4-triazole-3-one, so pl. 145,9oC (Conn. 37);

()-2-[1-(4-chlorobenzoyl)propyl] -2,4-dihydro-4-[4-(4 - phenyl-1-piperazinil)phenyl]-3H-1,2,4-triazole-3-one, so pl. 180,7oC (Conn. 39);

()-2-[1-(4-chlorobenzoyl)propyl] -4-[6-[4-(2-chlorophenyl)-1 - piperazinil]-3-pyridinyl]-2,4-dihydro-3H-1,2,4-triazole-3-one, (Conn. 41);

-2-[1-(4-chlorobenzoyl)propyl]-2,4-dihydro-4-[6-[4-[3- (trifluoromethyl)phenyl] -1-piperazinil]-3-pyridinyl]-3H-1,2,4 - triazole-3-one, so pl. a 126.7oC (Conn. 42);

()-2-[1-(4-chlorobenzoyl)propyl-4-[6-[4-(3,5-dimetilfenil)- 1-piperazinil] -3-pyridinyl] -2,4-dihydro-3H-1,2,4-triazole-3-she dihydrochloride (Conn. 43);

()-2-[1-(4-chlorobenzoyl)propyl-4-[6-[4-(3-ethylphenyl)-1 - piperazinil] -3-pyridinyl]-2,4-dihydro-3H-1,2,4-triazole-3-she dihydrochloride (Conn. 44);

()-2-[1-(4-chlorobenzoyl)propyl-4-[6-[4-(3,4- acid)-1-piperidinyl] -3-pyridinyl] -2,4-dihydro - 3H-1,2,4-triazole-3-one, so pl. to 107.7oC (Conn. 45) and
oC (Conn. 48).

Example 11.

Mix 2,4-dihydro-4-[2-[4-(4-methoxyphenyl)-1-piperazinil] -5-pyrimidinyl] -3H-1,2,4-triazole-3-he is 0.019 mol) and N,N-dimethylformamide (200 ml). Added dropwise under N2a solution of bis(trimethylsilyl)amide sodium in tetrahydrofuran (1 M, 21 ml) and the mixture is stirred for 30 minutes at room temperature. Added dropwise to 2-bromo-1-(4-chlorophenyl)-1-butanone (0,021 mole), dissolved in a small amount of N,N-dimethylformamide, and the mixture is stirred for 3 hours at room temperature. The mixture is transferred into water and extracted with dichloromethane. The organic layer is washed with water, dried and evaporated. The residue is crystallized from 1-propanol. The precipitate is filtered off and after drying in vacuum at 75oC get 6 g(60%) ()-2-[1-(4-chlorobenzoyl)propyl]-2,4-dihydro-4-[2-[4-(4- methoxyphenyl)-1-piperazinil] -5-pyrimidinyl] -3H-1,2,4-triazole-3-one, so pl. 184,6oC (Conn. 8).

Example 12.

To a cooled solution (t = -5oC) of 5.4 g of 1-[1-(4-nitrobenzoyl)ethyl]-1,3-dihydro-3-[4-[4-(4-hydroxyphenyl)-1 - piperazinil]phenyl]-2H-imidazol-2-it in 500 ml of tetrahydrofuran are added dropwise 20 ml of 1 M Tris solution(1 methylethoxy)kalogeropoulou in tetrahydrofuran. After stirring 2 hours at room temparraymajor with water and dried. The product is recrystallized from 1,4-dioxane. The product is filtered off and after drying in a vacuum gain of 3.4 parts (64,5%) [A] + [B]-1-[2-(4-bromophenyl)-2-hydroxy-1-methylethyl] -1,3-dihydro-3- [4-[4-(4-hydroxyphenyl)-1-piperazinil]phenyl-2H-imidazol-2-it, so pl. 253,8oC (Conn. 9).

Similarly synthesized:

-(R*, R*)-2-[2-(3,4-dichlorophenyl)-2-hydroxy-1 - methylethyl]-2,4-dihydro-4-[4-[4-(4-hydroxy-3, 5dimethylphenyl)-1 - piperazinil] phenyl] -5-methyl-3H-1,2,4-triazole-3-one hemihydrate, so pl. 184,9oC (Conn. 10);

1-[2-(4-chlorophenyl)-2-hydroxy-1-methylethyl] -1,3-dihydro-3- [4-[4-(4-hydroxyphenyl)-1-piperazinil]phenyl]-4-methyl-2H-imidazol-2-it, so pl. 245,7oC (Conn. 11);

1-[2-(4-chlorophenyl)-2-hydroxy-1-methylethyl] -2,3-dihydro-3-[4-[4- (4-hydroxyphenyl)-1-piperazinil] phenyl]-2H-imidazol-2-it, so pl. 252,8oC (Conn. 12);

()-2-[1-[(4-bromophenyl)hydroxymethyl] -1-methylpropyl] - 2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinil]phenyl]-5 - methyl-3H-1,2,4-triazole-3-one, so pl. 215,1oC (Conn. 13);

()-2-[1-[(4-chlorophenyl)hydroxymethyl] propyl] -2,4-dihydro- 4-[6-[4-(4-hydroxyphenyl)-1-piperazinil] -3-pyridinyl] - 3H-1,2,4-triazole-3-one, so pl. 231,7oC (Conn. 14);

()-(RR, SS)-2-[1-[(4-chlorophenyl)hydroxymethyl] propyl] - 2,4-dihydro-4-[4-[4-(5-methoxy-2-pyridinyl)-1-piperazinil] phenyl] - 3H-1,2,4-Tr is about-4-[6-[4-(3-methoxyphenyl)-1-piperazinil] -3 - pyridinyl]-3H-1,2,4-triazole-3-one, so pl. 203,8oC (Conn. 16);

()-(R*, R*)-2-[1-[(4-chlorophenyl)hydroxymethyl] propyl-2,4-dihydro-4-[6-[4-(2-methoxyphenyl)-1-piperazinil] -3 - pyridinyl]-3H-1,2,4-triazole-3-one, so pl. 199,3oC (Conn. 17);

()-(R*, R*)-2-[1-[(4-chlorophenyl)hydroxymethyl] propyl]-2,4-dihydro-4-[6-[4-(3-hydroxyphenyl)-1-piperazinil] -3 - pyridinyl]-3H-1,2,4-triazole-3-one, so pl. 240,8oC (Conn. 18);

()-(R*, R*)-2-[1-[(4-chlorophenyl)hydroxymethyl] propyl-2,4-dihydro-4-[6-[4-(2-hydroxyphenyl)-1-piperazinil] -3 - pyridinyl]-3H-1,2,4-triazole-3-one, so pl. 221,6oC (Conn. 19);

()-(R*, R*)-2-[1-[(4-chlorophenyl)hydroxymethyl] propyl]-2,4-dihydro-4-[4-[4-(6-methoxy-3-pyridinyl)-1-piperazinil] phenyl]-3H-1,2,4-triazole-3-one, so pl. of 209.5oC (Conn. 20);

()-(R*, R*)-2-[1-[(4-chlorophenyl)hydroxymethyl] propyl]-1,3-dihydro-3-[6-[4-(4-methoxyphenyl)-1-piperazinil]-3 - pyridinyl]-2H-imidazol-2-it, so pl. 192oC (Conn. 38) and

()-(R*, R*)-2-[1-[(4-chlorophenyl) hydroxymethyl]propyl]-2,4-dihydro-4-[4-[4-(6-methoxy-2 - pyridinyl)-1-piperazinil]phenyl-3H-1,2,4-triazole-3-one, so pl. 180,8oC (Conn. 46).

Example 13.

A mixture of 2-[2-(4-bromophenyl)-1,1-dimethyl-2-oxoethyl]-2,4 - dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinil] phenyl]-3H - 1,2,4-triazole-3-one (0,009 mole) of tetrahydroborate sodium (position 0, currently acid (5 ml) and then water (500 ml) is crystallization. The reaction mixture is stirred 4 hours at room temperature, the precipitate is filtered off with suction on a Buchner funnel and the solid is crystallized from 1-butanol. The precipitate is filtered off and after drying obtain 4.4 g(87%) ()-2-[2-(4-bromophenyl-2-hydroxy-1,1-dimethylethyl] -2,4 - dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinil] phenyl] -3H-1,2,4 - triazole-3-one, so pl. of 224.5oC (Conn. 21).

Similarly synthesized:

()-2-[2-(4-bromophenyl)-2-hydroxy-1,1-dimethylethyl] -2,4-dihydro-4- [4-[4-(4-hydroxyphenyl)-1-piperazinil]phenyl]-5-methyl-3H-1,2,4 - triazole-3-one, so pl. > 300oC (Conn. 22);

2,4-dihydro-2-[2-hydroxy-1-methyl-2-(4-were)ethyl] -4-[4-[4- (4-hydroxyphenyl)-1-piperazinil] phenyl] -3H-1,2,4-triazole-3-one, so pl. 259,8oC (Conn. 33);

()-(R*, R*)-2-[2-(4-bromophenyl)-2-hydroxy-1-methylethyl] -4-[4-[4- [4-[[(1,1-dimethylethyl)dimethylsilane] oxy] phenyl] -1-piperazinil] phenyl]-2,4-dihydro-3H-1,2,4-triazole-3-one, so pl. 241,3oC (Conn. 34);

()-(R*, R*)-2-[1-[(4-chlorophenyl)hydroxymethyl] butyl]-2,4-dihydro- 4-[6-[4-(3-methoxyphenyl)-1-piperazinil] -3-pyridinyl] -3H-1,2,4 - triazole-3-one, so pl. 202,4oC (Conn. 40) and

()-(R*, R*)-2-[1-[(4-chlorophenyl)hydroxymethyl]propyl]-4-[6-[4- (3,4-acid)-1-piperazinil]-3-pyridinyl]-2,4-dihydro-3H - 1,2,4-triazole-the Rowan:

2-[2-(4-bromophenyl)-2-hydroxy-1-methylethyl] -2,4-dihydro-4-[6-[4- (4-hydroxyphenyl)-1-piperazinil] -3-pyridinyl] -5-methyl-3H-1,2,4 - triazole-3-one, so pl. 195,1oC (Conn. 23).

Example 14.

To 48% aqueous Hydrobromic acid (100 ml) add a few crystals of sodium sulfate with the objective of discoloration acid. Then add()-2-[1-(4-chlorobenzoyl)propyl] -2,4-dihydro-4-[5-[4-(4-methoxyphenyl)-1-piperazinil] -2-pyridinyl]-3H-1,2,4-triazole-3-one (0,0047 mol) and the mixture is boiled with stirring for 2 hours. The mixture is transferred into water and neutralized NH4OH. The precipitate is filtered off and dried. The residue is purified column chromatography on silica gel (eluent: CH2-Cl2-CH3OH, 98:2). Pure fractions are collected and after evaporation obtain 2.2 g (0%) of product. Crystallization of the product sample (1 g) from C4H9OH get 0.7 g()-2-[1-(4-chlorobenzoyl)propyl]-2,4-dihydro-4- [5-[4-(4-hydroxyphenyl)-1-piperazinil] -2-pyridinyl]-3H-1,2,4-triazole-3-one, so pl. 185,6oC (Conn. 24).

Similarly synthesized:

()-2-[1-(4-chlorobenzoyl)propyl] -2,4-dihydro-4-[6-[4-(4-hydroxyphenyl) -1-piperazinil] -3-pyridinyl] -3H-1,2,4-triazole-3-one, so pl. 185,2oC (Conn. 25);

()-2-[1-(4-chlorobenzoyl)propyl] -2,4-dihydro-4-[2-[4-(4-hydroxyphenyl) -1-piperazinil] -5-pyrim)-2-pyridinyl)-1-piperazinil] phenyl]-3H-1,2,4-triazole-3-one, so pl. 193.3 M.oC (Conn. 27);

()-2-[1-(4-chlorobenzoyl)propyl] -2,4-dihydro-4-[6-[4-(3- hydroxyphenyl)-1-piperazinil]-3-pyridinyl]-3H-1,2,4-triazole-3-one, so pl. 103,1oC (Conn. 28) and

()-2-[1-(4-chlorobenzoyl)propyl] -2,4-dihydro-4-[6-[4-(2- hydroxyphenyl)-1-piperazinil]-3-pyridinyl]-3H-1,2,4-triazole-3-one (Conn. 29).

Example 15.

To a mixture of 25 g trichromate boron and 100 ml of dichloromethane is added dropwise a solution of 6.1 g of 1-[1-(4-chlorobenzoyl)ethyl]- 1,3-dihydro-3-[4-[4-(4-methoxyphenyl)-1-piperazinil]phenyl]-4-methyl - 2H-imidazol-2-it in 200 ml dichloromethane (t < 10oC). After stirring 2 hours, the reaction mixture was transferred into a mixture of NH4OH with ice. Then add 300 ml of dichloromethane and everything is stirred for 1 hour. The organic layer is separated, dried, filtered and evaporated. The residue is purified column chromatography (silica gel; CH2Cl2-CH3OH, 99:1). Eluent in the target fractions are evaporated, the residue is rinsed with methanol, then filtered and after drying obtain 4.3 g(72,3%) 1-[1-(4-chlorobenzoyl)ethyl]-1,3-dihydro- 3-[4-[4-(4-hydroxyphenyl)-1-piperazinil]phenyl]-4-methyl-2H-imidazol-2-it, so pl. 229,7oC (Conn. 30).

Similarly synthesized:

2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinil]phenyl]-2-[1- (4-methoxybenzoyl)ethyl]-3H-1,2,4-triazole-3-he shall PROXIFIER)-1-piperazinil] phenyl] -3H-1,2,4-triazole-3-one (0,009) and benzyltriethylammonium (0,25) is stirred in dichloromethane (150 ml). Add 25% sodium hydroxide solution (50 ml) and the mixture is stirred for 10 minutes. After adding dimethylsulfate (0,015 mol) the mixture is stirred for 1 hour at room temperature. The mixture was diluted with water (100 ml) and the layers separated. The organic layer is washed with water and dried. The residue is purified by chromatography on silica gel (eluent: CH2Cl2-CH3OH, 98: 2). Pure fractions are collected and after evaporation obtain 4.3 g of product. The product is optionally purified on a column filled with 1 kg of HERZELIA OD(eluent: C2H5OH). Pure fractions are collected and after evaporation obtain 0.9 g of (+)-(A)-2-[1-(4-chlorobenzoyl)propyl]-2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinil] phenyl]-3H-1,2,4-triazole-3-one, so pl. 199,6oC []2D0163,01o(Conn. 31).

Example 17.

Monohydrate ()-(R*, R*)-2-[2-(2,4-dichlorophenyl)-2-hydroxy-1-methylethyl] -2,4-dihydro- 4-[4-[4-(4-hydroxy-3, 5dimethylphenyl)-1-piperazinil] phenyl]-5-methyl-3H-1,2,4-triazole-3-one (1.5 g) purified column chromatography on CHIRACEL OD(1 kg) with elution with a mixture of n-hexane and 2-propanol (80:20). Pure fractions are collected and evaporated. Crystallization of the residue from 2-propanol obtain 0.5 g of (+)-(R*, R*)-2-[2-(2,4-dichlorophenyl)-2-hydrox the ATA, so pl. 123,5oC []2D0= + 28,2o(Conn. 32).

Example 18.

In 100 ml of dichloromethane under stirring to dissolve(+)-4-[4-[4- [4-[[(1,1-dimethylethyl)dimethylsilane] oxy] phenyl] -1-piperazinil] phenyl]-2,4-dihydro-2-[2-hydroxy-2-[4-(triptoreline)phenyl] ethyl] -5-methyl-3H-1,2,4-triazole-3-one (0,0043 mol). Add a solution of tetrabutylammonium (0,0045 mol) in tetrahydrofuran and the mixture is stirred for 15 minutes. Then water is added and the mixture is stirred for 30 minutes the Precipitate is filtered off, dried, and after crystallization from n-butanol obtain 1.1 g (58.2 per cent) (a)-2,4-dihydro-4-[4-[4-(4- hydroxyphenyl)-1-piperazinil] phenyl] -2-[2-hydroxy-2-[4-(triptoreline) phenyl]ethyl]-5-methyl-3H-1,2,4-triazole-3-one, so pl. 230,6oC (Conn. 36).

Example 19.

To a stirred solution of 2-[1-(4-bromobenzoyl)ethyl]-2,4 - dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinil] phenyl]-3H-1,2,4 - triazole-3-one (0,009 mol) in pyridine (20 ml) under nitrogen atmosphere add a solution of 2-(chlorodimethylsilyl)-2-methylpropane (to 0.011 mol) in dichloromethane (20 ml). The stirring is continued for 1 week at room temperature. The reaction mixture is evaporated and the residue is dissolved in dichloromethane. The resulting solution was purified on silica gel with a glass filter. Pure fractions are collected and rycaut 2.7 g(45%) 2-[1-(4-bromophenyl)ethyl]-4-[4-[4-[4- [[(1,1-dimethylethyl)dimethylsilane] oxy] phenyl] -1-piperazinil]phenyl]- 2,4-dihydro-3H-1,2,4-triazole-3-one, so pl. of 177.8oC (Conn. 47).

C. Pharmacological example

The activity of compounds of the invention against Helicobacter identified by applying the following test methods in vitro.

The activity of test compounds relative to Helicobacter

The activity of the tested compounds against Helicobacter pylori was determined by applying the standard choice of 5 strains of H. pylori obtained on the basis of clinical material. Minimum inhibitory concentration (MIC) is determined by measuring the activity of the urease of H. pylori after treatment growing cultures of bacteria to antimicrobial agents.

The subjects of the compounds dissolved in a concentration of 10-3M in DMSO. In addition, prepare a dilution of up to 10-4M in DMSO. The obtained solution with a pipette transfer in the amount of 10 μl in the wells of bulk packing: spindle-DISHA ( Sterilin). Each tablet as a control provided by wells containing only DMSO. In each series of experiments as reference compounds used ampicilin (Trihydrate(+)-6-[(2-amino-2-phenylacetyl)amino[-3,3-dimethyl-7 - oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid) and metronidazole (2-methyl-5-nitro-1H-imidazole-1-ethanol). These compounds are used in final concentrations of 10-5oC in an atmosphere containing 5% oxygen, 10% CO2and 85% nitrogen. Suspension of Helicobacter pylori for inoculum prepared cardio-cerebral infusion broth, and the suspension is brought to absorb 1,50,3 at 530 nm.

Freshly prepared 10% blood agar, heated to 45oC add in the volume of 1 ml in the wells of tablets for testing with a dilution thereby compound up to 10-5and 10-6M. Environment is allowed to cool, after which the surface of the agar with a pipette put 10 ál of bacterial suspension. Tablets incubated 48 hours at 37oC in the above microaerophilic atmosphere. To facilitate reading of the tablets and to ensure that growth on the environment associated with H. pylori, using characteristic for the type of bacteria is extremely high urease activity. After 48 hours incubation in each well of the tablet bulk packing: spindle-DISHA carefully make 1 ml of urease broth and tablets incubated for 2 hours. Then from each of the wells with the pipette select 100 µl of liquid sample and placed in wells for microrasbora 96 seats. Purple color is considered to be evidence of ROS is to obtain a clear end point, on the basis of which can be determined the inhibitory activity of the compounds. All connections for which it was shown activity in any of the two concentrations, subjected to additional testing in greater dilution determination of MIC and with a wider spectrum of bacteria in as the target microorganisms.

Table 1 summarizes the data for values MICK defined by the above technique for a number of compounds of the invention.

D. Examples of drugs

The term "active component" (AK) value used in all subsequent examples, refers to compounds of the formula (I), their pharmaceutically acceptable salts with acids or their stereochemical isomers.

Example 20. Oral drops

In 0.5 l of 2-hydroxypropanoic acid and 1.5 l of the polyethylene glycol is dissolved at 60 - 80oC 500 g A. K. After cooling to 30 - 40oC added 35 l of polyethylene glycol and the mixture was thoroughly stirred. Then add a solution of 1750 g of saccharin sodium 2.5 l of purified water and while stirring add 2.5 liters taste of corrigenda cocoa and polyethylene in an amount necessary to bring the total volume to 50 l, to obtain the solution of peror/P> Example 21. Capsules

Intense mixing to form a mixture of 20 g A. K., 6 g of lauryl sodium, 56 g of starch, 56 g of lactose, 0.8 g of colloidal silicon dioxide, and 1.2 g of magnesium stearate. The mixture populate the corresponding hard gelatin capsules (1000 pieces), each of which contains 20 mg of the active component.

Example 22. The tablets are film-coated.

Getting the Central part tablets

A mixture of 100 g A. K., 570 g lactose and 200 g starch is thoroughly mixed, then moistened with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone in about 200 ml of water.

The wetted powder mixture is sieved, dried, and sift again. Then add 100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil. All are thoroughly mixed and pressed into tablets to obtain 10,000 tablets each containing 10 mg of the active component.

Shell

To a solution of 10 g of medienallee in 75 ml of denatured ethanol is added a solution of 5 g of ethyl cellulose in 150 ml of dichloromethane. Then add 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. Polyethylene glycol (10 g) was transferred in the molten state and dissolved in 75 ml dichloro what I 5 g of polyvinylpyrrolidone and 30 ml of concentrated dye solution and all is brought to a homogeneous state. In the apparatus for coating the Central parts of the tablets create the shell of the resulting mixture.

Example 23. Injectively solution

About 0.5 to about the boiling of water for injection is dissolved 1.8 g of methyl ester of 4-hydroxybenzoic acid and 0.2 g propyl ester of the same acid. After cooling to approximately the 50oC with stirring 4 g lactic acid, 0.05 grams propylene glycol and 4 g A. K. the Solution is cooled to room temperature and added water for injection in an amount necessary to bring the total volume to 1 l with obtaining a solution containing 4 mg/ml A. K. the Solution is sterilized by filtration and filled in sterile containers.

Example 24. Suppository

In the solution of 3 g of 2,3-dihydroxybutanedioate acid in 25 ml of polyethylene glycol 400 dissolve 3 g A. K. melted Together 12 g of surface-active substances and triglyceride in an amount necessary to obtain a total of 300 G. of the resulting mixture is poured into molds at a temperature of 37 - 38oC preparation of 100 suppositories, each of which contain a 3,76 concentrated HCl, stirred and slightly heated. Add 10 g A. K., and stirring is continued until a homogeneous state. In a separate vessel in 400 ml of distilled water dissolve 400 g of hydroxypropyl -- cyclodextrin. To a stirred solution of the active component is slowly added a solution of cyclodextrin. Add the sorbitol solution (190 ml) and stirred until a homogeneous state. In 50 ml of distilled water dissolve saccharin sodium (0.6 g) and the resulting solution is added to the previously prepared mixture. Add corrigent and the pH of the mixture (about 1.7) added 10 N. NaOH is set to 2,00,1. The resulting solution was diluted with distilled water to a final volume of 1 liter. Pharmaceutical dosage forms obtained by filtering the resulting solution and filling them with acceptable containers, e.g. glass bottles of 100 ml with screw caps.

1. Substituted derivatives of isolona General formula (I)

< / BR>
their pharmaceutically acceptable salts with an acid or stereochemical isomers,

where X and Y each independently represents CH or N;

R1, R2and R3each independently represents hydrogen or C1-C4-alkyl;

R4and R5each is a group, trifluoromethyl, cryptometrics or deformations;

Z is C=O or CHOH;

Ar represents phenyl, possibly substituted up to three substituents selected from a hydroxy-group, C1-C4-alkyl, C1-C4-alkyloxy, halogen, trifloromethyl, three(C1-C4-alkyl) silyloxy, or pyridinyl, substituted by a hydroxy-group or C1-C4-alkyloxy,

group

< / BR>
represents a radical of the formula

< / BR>
< / BR>
provided that Ar is different from 4-hydroxyphenyl, three(C1-C4-alkyl)-4-hydroxyphenyl, 3,5-di(C1-C4-alkyl)-4-hydroxyphenyl or 4-methoxyphenyl, when X = N and group

< / BR>
represents a radical of the formula (a-1).

2. Connection on p. 1, characterized in that it is:

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

2-[1-(4-chlorobenzoyl)propyl]-2,4-dihydro-4-[6-[4-(3-hydroxyphenyl)-1-piperazinil]-3-pyridinyl]-3H-1,2,4-triazole-3-one;

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

2-[1-(4-chlorophenyl)hydroxymethyl] propyl] -2,4-dihydro-4-[4-[4-(6-methoxy-3-pyridine the yl]-3-pyridyl]-2,4-dihydro-3H-1,2,4-triazole-3-one;

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

2-[1-(4-chlorobenzoyl)propyl] -4-[6-[4-(3,4-acid)-1-piperidinyl] -3-pyridinyl]-2,4-dihydro-3H-1,2,4-triazole-3-one;

2-[1-(4-chlorophenyl)hydroxymethyl] propyl] -2,4-dihydro-4-[4-[4-(6-methoxy-2-pyridinyl)-1 - piperazinil]-phenyl]-3H-1,2,4-triazole-3-one;

2-[1-(4-chlorophenyl)hydroxymethyl] propyl] -4-[6-[4-(3,4-acid)-1-piperazinil]-3-pyridinyl]-2,4-dihydro-3H-1,2,4-triazole-3-one;

2-[1-(4-chlorobenzoyl)propyl] -4-[6-[4-(3,4-acid)-1-piperazinil] -3-pyridinyl]-2,4-dihydro-3H-1,2,4-triazole-3-one,

their pharmaceutically acceptable salts with acids or their stereochemical isomers.

3. The method of obtaining substituted atlona formula (I)

< / BR>
where Ar, X, R1, R2, R3, R4, R5Z and group

< / BR>
take the values under item 1, characterized in that an intermediate compound of formula (II) N-alkylate the reagent of formula (III)

< / BR>
< / BR>
in an inert under the reaction conditions solvent and in the presence of a base, followed, if desired, converting compounds of formula (I) into each other by transformation of functional groups, the conversion of compounds of formula (I) and their salts with acids obrabotaet and/or receiving stereochemical isomers.

4. Pharmaceutical composition having antibacterial against Helicobacter pylori activity containing a pharmaceutically acceptable carrier and an active component, characterized in that the active ingredient it contains a compound according to any one of paragraphs. 1 - 3 in the amount of 3,5 - 1400 mg.

5. A method of obtaining a pharmaceutical composition according to p. 4, wherein therapeutically effective amount of the compounds on p. 1 uniformly mixed with a pharmaceutically acceptable carrier.

 

Same patents:

The invention relates to crystals containing water of crystallization (hereinafter referred to as hydrated form or simply hydrate), and the crystals without water of crystallization (hereinafter referred to as the anhydrous form or simply anhydrous), to a method for selective receipt of these crystals and, in addition, to pharmaceutical preparations containing such crystalline form

The invention relates to new chemical substances possessing valuable properties, in particular nitrogen-containing cyclic derivative of General formula

< / BR>
where X is carbinieri, unsubstituted or substituted at the nitrogen atom by alkyl, aryl, heteroaryl or cyano, carbonyl, thiocarbonyl, sulfonyl, 1-nitroethene-2,2-diyl or 1,1-dicyano-Eten-2,2-diyl,

Y is unsubstituted or substituted Rcor Rdor Rcand Rdnonbranched alkylen or albaniles with 2 to 4 carbon atoms, which may optionally be substituted by one or two alkyl groups and in which one or two methylene groups can be replaced by a carbonyl, 1,2-cycloalkyl with 5 to 7 carbon atoms, unsubstituted or substituted Rcor Rdor Rcand Rd, 1,2 - cycloalkenyl with 5 to 7 carbon atoms, unsubstituted or substituted Rcor Rdor Rcand Rd, 1,2-Allen, 1,2-phenylene, in which one or two methine groups are replaced by nitrogen atom or one or two groups-CH=CH - replaced by a group-CO-NH - or a methine group substituted by nitrogen atom and one group-CH= CH - replaced by a group-CO-NH-, and above heterocycles or substituted Rcor Rd,

the first of the residues Ra- Rdmeans A group-B-, in which A group of the formula

< / BR>
< / BR>
or

< / BR>
where pentostatin can be monogamist the remainder R25mono - or Disaese the remainder R26or monogamist the remainder R25and additionally monogamist the remainder R26and the substituents R25and R26that may be the same or different and have the meanings stated below, in one bancoestado 1 - 3 methine group may be replaced by a nitrogen atom or a group-CH= CH - may be replaced by a group-CO-NR1or one methine group may be replaced by nitrogen atom and one group-CH=CH - may be replaced by a group-CO-NR1-, where R1means a hydrogen atom or alkyl,

G1and G4- bond or methylene which may be mono - or Disaese the alkyl, aryl or heteroaryl, and the substituents may be the same or different,

G2- bond or methylene, substituted residues R7and R8,

G3communication, methyl nitrogen atom or Metin, unsubstituted or substituted by alkyl, aryl or heteroaryl,

R2is a hydrogen atom, alkyl, aryl or heteroaryl or hydroxyl or alkoxyl if at least one of the groups G2and G3doesn't mean the relationship,

R3is a hydrogen atom, alkyl, aryl or heteroaryl or R3together with R2form an oxygen atom, if at least one of the groups G2and G3doesn't mean the relationship,

R4and R14is a hydrogen atom, cycloalkyl with 3 to 7 carbon atoms, cycloalkyl with 3 to 7 carbon atoms in cycloalkyl parts, alkyl with 1 to 8 carbon atoms, alkenyl with 3 to 8 carbon atoms, which may not be linked to the nitrogen atom through the vinyl group, hydroxyalkyl, alkoxyalkyl, aminoalkyl, acylaminoalkyl, dialkylaminoalkyl, cianelli, carboxyethyl, alkoxycarbonylmethyl, aminocarbonylmethyl, N-alkylaminocarbonyl, N,N-dialkylaminoalkyl, arylalkyl, heteroallyl, alkoxycarbonyl, allmediascotland, formyl, acetyl, TRIFLUOROACETYL, allyloxycarbonyl, amidino or R11CO-0-(R12CR13)-O-CO-, where R11is alkyl with 1 to 8 carbon atoms, cycloalkyl with 5 to 7 carbon atoms, aryl or arylalkyl, R12is a hydrogen atom, alkyl, cycloalkyl with sweetlenny alkylen 2 - 4 carbon atoms or methylene, if G2doesn't mean the relationship,

R5is a hydrogen atom, alkyl, aryl or heteroaryl or hydroxyl or alkoxyl, if G1no means of communication, or R4together with R5mean an additional bond, if G1means of communication,

R6is a hydrogen atom, alkyl, aryl or heteroaryl or a chlorine atom, a hydroxyl, methoxyl, amino, alkylamino or dialkylamino, if G1means linking and R4together with R5mean an additional bond, or R6together with R5mean oxygen atom, if G1doesn't mean the relationship,

R7is a hydrogen atom, alkyl, aryl or heteroaryl,

R8is a hydrogen atom, alkyl, aryl or heteroaryl or R8together with R4mean the unbranched alkylene with 2 to 5 carbon atoms,

R9is a hydrogen atom, alkyl, aryl or heteroaryl or hydroxyl or alkoxyl, if G2doesn't mean the relationship,

R10is a hydrogen atom, alkyl, aryl or heteroaryl or R10together with R4mean the unbranched alkylene with 2 to 4 carbon atoms,

R15is a hydrogen atom or chlorine, alkyl, aryl, heteroaryl, hydroxyl, methoxyl, amino, alkylamino or dialkylamino,

R16- foelkel 1 8 carbon atoms, alkenyl with 3 to 8 carbon atoms, which may not be linked to the nitrogen atom through the vinyl group, hydroxyalkyl, alkoxyalkyl, aminoalkyl, acylaminoalkyl, dialkylaminoalkyl, cianelli, carboxyethyl, alkoxycarbonylmethyl, aminocarbonylmethyl, N-alkylaminocarbonyl, N,N-dialkylaminoalkyl or arylalkyl,

R17is a hydrogen atom or alkyl, or R16together with R17mean an additional bond, if G4means of communication,

R18is a hydrogen atom, alkyl or fluorine atom, chlorine or bromine, hydroxyl, methoxyl, amino, alkylamino or dialkylamino, if G4means linking and R16and R17together denote an additional bond,

n is the number 1 or 2,

In - line, alkylen, albaniles, Allen, peridinin, pyrimidinyl, personalen or pyridazinyl, in which one or two groups-CH=N - can be replaced by a group-CO-NH - and one of the nitrogen atoms may be associated with the remainder of A connection instead of a hydrogen atom, and these heterocyclic groups may be optionally substituted by one or two alkyl groups, cycloalkyl with 4 to 7 carbon atoms, unsubstituted or substituted by one or two alkyl groups, unsubstituted or RC="http://www.fips.ru/fullimg2/rupat3/19993/003.dwl/2126002-6t.gif" ALIGN="ABSMIDDLE">replaced by a nitrogen atom, and, in addition, in the above mentioned 5 - to 7-membered rings, one adjacent to the nitrogen atom of the methylene group may be replaced by carbonyl, the second of the residues Ra- Rdmeans a group of the formula

F - E - D-,

where D is alkylene with 1 to 6 carbon atoms in which one methylene group may be replaced by oxygen atom or sulfur, sulfinil, sulfonium or the group-NR19-, where R19means a hydrogen atom, alkyl, alkylaryl, alkylsulfonyl, arylcarbamoyl or arylsulfonyl, or in which one ethylene group may be replaced by a group-CO-NR20- or-NR20-CO-, where R20means a hydrogen atom or alkyl, albaniles with 2 to 6 carbon atoms, Allen, peridinin, pyrimidinyl, personalen or pyridazinyl, in which one or two groups-CH=N - can be replaced by a group-CO-NH - and one of the nitrogen atoms, together with the hydrogen atom may also be linked with the rest of E, if the latter does not mean the connection or not connected via a heteroatom or a carbonyl with the rest of D, and these heterocyclic groups may be optionally substituted by one or two alkyl groups, indaniel, naftilan, 1,2,3,4-tetrahydronaphthalen or benzoguanamine, in which one of the be substituted by one or two alkyl groups, and the aromatic ring may be substituted by fluorine atom, chlorine, bromine or iodine, alkyl, trifluoromethyl, hydroxyl, alkoxyl, alkylsulfanyl, alkylsulfonyl, alkylsulfonyl or cyano, cycloalkyl with 4 to 7 carbon atoms, unsubstituted or substituted by one or two alkyl groups, unsubstituted or substituted by one or two alkyl groups cycloalkyl with 5 to 7 carbon atoms, in which one groupreplaced by a nitrogen atom, and, in addition, in the above mentioned 5 - to 7-membered rings, one adjacent to the nitrogen atom of the methylene group may be replaced by carbonyl, unsubstituted or substituted by one or two alkyl groups piperazinyl in which one adjacent to the nitrogen atom of the methylene group may be replaced by a carbonyl, or alkilenkarbonatov with the total number of carbon atoms 2-6, if E is a cyclic aminogroup, and a carbonyl linked to a nitrogen atom of a cyclic aminogroup group E, or a link, if E does not mean the relationship,

E - communication, alkylene with 1 to 6 carbon atoms which may be substituted by one or two alkyl groups with 1 to 8 carbon atoms, alkenyl or quinil with 2 to 4 carbon atoms, hydroxyl, is POI with the total number of carbon atoms of 2 10, the group HNR21- or N-alkyl-NR21-, where R21means alkylsulphonyl or alkylsulfonyl with 1 to 8 carbon atoms in the alkyl part, allyloxycarbonyl with the total number of carbon atoms 2 and 5 cycloalkylcarbonyl or cycloalkylcarbonyl with 5 to 7 carbon atoms in cycloalkyl part, arylalkylamines, arylalkylamines, arylethoxysilanes, arylcarbamoyl or arylsulfonyl, albaniles with 2 to 6 carbon atoms, Allen, peridinin, pyrimidinyl, personalen or pyridazinyl, unsubstituted or substituted by one or two alkyl groups, unsubstituted or substituted by one or two alkyl groups cycloalkyl with 5 to 7 carbon atoms, in which one groupreplaced by a nitrogen atom linked to the carbon atom of the residue D, cycloalkyl with 4 to 7 carbon atoms in cycloalkanones part, unsubstituted or substituted by one or two alkyl groups with 1 to 8 carbon atoms, alkenyl or quinil with 2 to 4 carbon atoms, hydroxyl, amino, aryl, heteroaryl, alkoxyl or alkylamino with 1 to 8 carbon atoms, dialkylamino with the total number of carbon atoms of 2 to 10, a group HNR21- or N-alkyl-NR21-, where R2119-, -NR20-CO - or-CO-NR20-, where R19and R20have the above meanings, with alkylene may be optionally substituted by one or two alkyl groups with 1 to 8 carbon atoms, alkenyl or quinil with 2 to 4 carbon atoms, hydroxyl, amino, aryl, heteroaryl, alkoxyl or alkylamino with 1 to 8 carbon atoms, dialkylamino with the total number of carbon atoms of 2 to 10, group-HNR21- or N-alkyl-NR21where R21have the above significance, with an additional heteroatom substituent heteroatom is separated from the remainder of W by at least two carbon atoms, if D does not mean the relationship,

F - carbonyl, substituted by hydroxyl, alkoxyl with 1 to 8 carbon atoms, arialcategory or group R22O-, where R22means cycloalkyl with 4 to 8 carbon atoms and cycloalkyl with 3 to 8 carbon atoms in cycloalkyl part, in which cycloalkyl part may be substituted by alkyl, alkoxyl or dialkylamino, or alkyl and 1 to 3 methyl groups, with one methylene group in the 4 - to 8-membered cycloalkyl part may be replaced by oxygen atom or alkylaminocarbonyl, benzocyclobutene the PA R23CO-O-CHR24-O-CO-, where R23means alkyl or alkoxy with 1 to 8 carbon atoms, cycloalkyl with 5 to 7 carbon atoms, cycloalkyl with 5 to 7 carbon atoms in cycloalkyl parts, aryl, aryloxy, arylalkyl or Allakaket and R24is a hydrogen atom or alkyl,

the shortest distance between the residue of F and located at a maximum distance from the rest F the nitrogen atom of the group A-B - is at least 11 links,

the third of the residues Ra- Rdmeans a hydrogen atom, alkyl, perfluoroalkyl, alkoxy, alkylsulfanyl, alkylsulfonyl, alkylsulfonyl, amino, alkylamino, dialkylamino, aryl, heteroaryl or arylalkyl,

the fourth of the residue Ra- Rdmeans a hydrogen atom, alkyl or aryl, and if nothing else is mentioned,

under the above term "aryl" is to be understood phenyl, which can be monogamist the remainder R25mono-, di - or triamese the remainder R26or monogamist the remainder R25and additionally mono - or Disaese the remainder R26and the substituents may be the same or different, R25means cyano, carboxyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, alkoxycarbonyl, alkylboron, the Mino, alkylamino, dialkylamino, alkylcarboxylic, phenylalkylamine, phenylcarbonylamino, alkylsulfonyl, phenylalkylamine, phenylcarbonylamino, N-alkyl-alkylcarboxylic, N-alkyl-phenylalaninamide, N-alkyl-phenylcarbonylamino, N-alkyl-alkylsulfonyl, N-alkyl-phenylalaninamide, N-alkyl-phenylcarbonylamino, aminosulfonyl, alkylaminocarbonyl or dialkylaminoalkyl, R26- alkyl, hydroxyl or alkoxy, fluorine atom, chlorine, bromine or iodine, and two residue R26if they are linked to adjacent carbon atoms, may also be alkylene with 3 to 6 carbon atoms, 1,3-butadiene-1,4-deelen or methylendioxy group

under the above term "Allen" should be understood phenylene, which can be monogamist the remainder R25mono - or Disaese the remainder R26or monogamist the remainder R25and additionally monogamist the remainder R26and the substituents may be the same or different and have the above values,

under the above term "heteroaryl" should read 5-membered heteroaromatic ring containing one atom of oxygen, sulfur or nitrogen, one atom of nitrogen and one atom of oxygen, sulfur is certain heteroaromatic ring, in which one or two of the groups-CH= N - can be replaced by a group-CO-NR20where R20has the above value, the heteroaromatic ring can be substituted by one or two alkyl groups or by a fluorine atom, chlorine, bromine or iodine, hydroxyl or alkoxyl in the carbon skeleton,

and, if nothing else is mentioned, the above alkyl, alkylene or CNS groups can contain 1 to 4 carbon atoms and each of the carbon atoms in the above alkilinity and cycloalkenes groups associated at least one heteroatom,

mixtures of their isomers, or individual isomers or salts

The invention relates to piperazine derivatives or its salts, which are used as therapeutic agents for diseases of the circulatory organs and areas of the brain

The invention relates to the derivatives of pyrazine formula I, where R1- H or C1-8-alkyl, R2- C1-8-alkyl, unsubstituted or substituted C1-4-alkoxyl, hydroxyl, fenoxaprop, which in turn is one - or multi-substituted C1-4-alkyl, C1-4-alkoxyl, alkoxyalkyl or cyano, aminowhere R3- H or C1-4-alkyl, R4-phenyl, repeatedly substituted C1-4-alkyl, a substituted amino group dichlorobenzenesulfonyl, C1-4-alkyl, unsubstituted or substituted residues selected from the group of hydroxyl, fenoxaprop, in turn multiply substituted by halogen or alkoxyalkyl, carbonylation formula II, where X is oxygen or-NH-, piperidinyl, N-substituted C1-8-alkyl, and phenyl unsubstituted or substituted C1-4-alkoxyl, amidinopropane formulawhere R5is phenyl, substituted by halogen or C1-4-alkyl, and a group of the formula III, where R1- H, or R1and R2together with the nitrogen atom to which they are bound, form a pieperazinove ring, unsubstituted or substituted in position 4 by a group IV, V,-alkyl, or alkoxyalkyl, and-naftussya, and if R1- H, R2does not mean alkyl, benzyl, fluorine - or chlorbenzyl, phenethyl, hydroxyethyl or HOCH2- (CHOH)4- CH2or if R1- C1-3-alkyl, R2does not mean C1-4-alkyl, and an acid additive salt

The invention relates to new N-substituted derivatives of 3-azabicyclo[3.2.0] -heptane and its salts with physiologically tolerated acids, possessing neuroleptic activity

The invention relates to 2-/2-imidazolin-2-yl/benzoheterocycles compounds, which have the following structure:

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in which: R1is hydrogen, CI/C1-C4/ alkylamino,

C1-C12the alkyl may be substituted by one to three substituents: C1-C4alkoxy, C1-C4alkylthio, halogen, hydroxy, C1-C4cycloalkyl, benzoyloxy, fullam, phenyl, possibly substituted by nitro, one to three halogen, C1-C4alkyl groups or C1-C4alkoxy groups, carboxy, C1-C4alkoxycarbonyl, cyano or three/C1-C4/ alkylammonium a halide;

C3-C12alkenyl may be substituted by one to three substituents: C1-C4alkoxy, phenyl, halogen or C1-C4alkoxycarbonyl;

C3-C6cycloalkyl, can be substituted one to three C1-C4alkyl groups;

C3-C16the quinil may be substituted by one to three halogen or a cation;

R2is C1-C4by alkyl;

R3is C1-C4the alkyl or C3-C6cyclo is the best C1-C4cycloalkyl possibly replaced by stands;

B is hydrogen, COR4or SO2R5with the proviso that when B is COR4or SO2R5, R1is other than hydrogen or a cation, and R9different from hydrogen;

R4is C1-C11the alkyl, chlorochilon or phenyl, possibly substituted with halogen, nitro or C1-C4by alkyl;

R5is C1-C4the alkyl or phenyl, possibly substituted C1-C4by alkyl;

X, Y and Z each independently is CR6, CR7R8, N or NR9with the proviso that at least one of X, Y and Z must be N or NR9;

configuration is either a simple bond or double bond with the proviso that when any of X, Y or Z is CR7R8or NR9then === configuration, attached to it, is a simple connection, with one proviso that at least one of the === configuration represents a simple bond;

R6, R7and R8are independently hydrogen, halogen, C1-C4alkoxy or C1-C4the alkyl may be substituted one is;

R9is hydrogen or C1-C4the alkyl possibly substituted by hydroxy or one to three halogen, C1-C4alkoxy groups, or C1-C4alkylthio groups;

Q is hydrogen, halogen, C1-C4alkoxy or C1-C4the alkyl, possibly substituted by one to three of the following substituents: halogen, C1-C4alkoxy, C1-C4alkylthio or C2-C4alkenyl;

their optical isomers, when R2and R3not the same or when R7and R8unequal;

their tautomers and geometric isomers, and their attached salts of acids, except when R1is salabrasion cation

The invention relates to new substituted pyrazolylborate, and to their use as herbicide compositions

The invention relates to cyclic Amida substituted in-the position of different aryl groups, agricultural suitable salts and their mixtures, and their use as fungicides systemic or selective action

The invention relates to new chemical compounds having valuable properties, in particular to new derivatives of sulfonamidophenylhydrazine

The invention relates to the production of 1-arestriction formula I, where R is lower alkyl; X is halogen, lower alkyl, nitro, hydroxy, -NHSO2R', -Ni(SO2R')2, -N(R')SO2R'; R' is lower alkyl; n is an integer from 0 to 3, processing of arestriction formula II halogenoacetyl acid or its salt in the environment tert-butanol - water at a weight ratio of (95-70):(5-30), respectively

The invention relates to the field of synthesis of heterocyclic compounds

The invention relates to organic chemistry, specifically to diacrylate derived triazolone formula I

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which can be used as a modifier acrylic photopolymerizable compositions and creation on their basis of protective and strengthening coatings of optical fibers
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