Acyl derivatives of solonov, the method of production thereof, pharmaceutical composition and method of reception

 

(57) Abstract:

Describes the new acyl derivatives of solonov General formula (1), where the values of R1-R6, A, Y, Z are specified in paragraph 1 of the claims, their pharmaceutically acceptable salts accession acids and stereochemical isomeric forms, which are powerful agents against microorganism Helicobacter. Also describes the method of production thereof, compositions comprising these compounds, methods for their preparation and the use of these compounds as a medicine. 4 C. and 4 h.p. f-crystals, 1 PL.

The present invention relates to substituted derivatives of solonov, which are powerful agents against Helicobacter. US - 4791111 describes asolani, which have a structure similar to the structure of the compounds of the present invention, and which are intermediate compounds in obtaining[[4-[4-(4-phenyl-1 - piperazinil)phenoxymethyl] -1,3-dioxolane-2-yl]methyl]-1H - imidazoles and 1H-1,2,4-triazoles.

In US - 4931444 describe substituted derivatives Aslanov with inhibiting 5 - lipoxygenase activity. Compounds of the present invention differ from them useful activity against Helicobacter.

For destruction Helicobacter is th effect of one or more of the following reasons: low speed destruction, numerous side effects and development of resistance in Helicobacter. It is shown that triple therapy, including the introduction of two antibiotics and bismuth compounds is effective, but requires the patient increased requirements and also compromised by side effects. These compounds have the advantage that they can be used in monotherapy for the destruction of Helicobact pylori and related species.

The present invention relates to compounds of the formula

< / BR>
their pharmaceutically acceptable salts accession acids and stereochemical isomeric forms,

where: Y represents CH or N;

R1, R2and R3each independently represents hydrogen or C1-4alkyl;

R4and R5each independently represents hydrogen, halogen, C1-4alkyl, C1-4alkyloxy, hydroxy, trifluoromethyl, cryptometrics or deformations;

R6represents hydrogen or

R6represents phenyl, optionally substituted with halogen; pyridinyl; furanyl; thienyl; 3 chlorobenzo[b]Tien-2-yl; trifluoromethyl; C1-4allyloxycarbonyl; dihalogenoalkane; C3-6cycloalkyl; substituted C2-6alkenyl, optionally substituted galom, phenyloxy, piperidinium, pyrrolidinium, piperazinil, C1-4alkylpiperazine, C1-4alquilervillapeniscola, C1-4allyloxycarbonyl, phthalimido, amino, mono - or di(C1-20)alkylamino or C3-6cyclooctylamino; Z is C=O or CHOH; and

< / BR>
is a radical of the formula

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
Used in this document to determine the halogen denotes fluorine, chlorine, bromine and iodine; C1-4alkyl refers to saturated hydrocarbon radicals, straight and branched chain, containing from 1 to 4 carbon atoms, such as, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl; C1-6alkyl represents C1-4alkyl radicals, as defined above in this document, and their higher homologs containing from 5 to 6 carbon atoms, such as, for example, pentyl or hexyl; C1-20alkyl represents C1-4alkyl radicals, as defined above in this document, and their higher homologs containing from 5 to 20 carbon atoms; C3-6cycloalkyl is the common name for cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; C1-6alkenyl denotes uglev the 6 carbon atoms.

As used herein, the term pharmaceutically acceptable salt accession acid refers to non-toxic, therapeutically active forms of salt accession acids, which may be formed by the compounds of formula (I). The compounds of formula (I) have basic properties can be transformed into the corresponding therapeutically active, non-toxic salt accession acids by the action of the free base with a suitable amount of the corresponding acid according to conventional methods. Suitable acids include, for example, inorganic acids such as halogenation acid, for example hydrochloric or Hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids, such as, for example, acetic, propanoic, oxiana, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methansulfonate, econsultancy, benzolsulfonat, p-toluensulfonate, cyclemania, salicylic, p-aminosalicylic, amoeba and similar acids. The term salt of accession, as used herein, also includes a solvate, which the compounds of formula (I), and the min stereochemical isomeric forms, as used herein, refers to different isomeric as well as conformational forms which may be the compounds of formula (I). If not specified or not mentioned otherwise indicated, the chemical designation of compounds denotes the mixture of all possible stereochemical or conformationally isomeric forms; and the mixture contains all diastereoisomers, enantiomers and/or conformers of the main molecular structure. All stereochemical izmerenie form compounds of formula (I), both in pure form and in the form of a mixture with each other, should be considered within the scope of the present invention.

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

For compounds with two chiral center, respectively, are stereochemical designations R*and S*in accordance with the rules of chemical designations (Chemical Substance Name Selection Manual (CA), 1982 edition, volume III, Chapter 20).

Some compounds according to the present invention may exist in different tautomeric forms, and all such tautomeric forms should be considered as being within the scope of the present invention.

The first group is SUP>5is hydrogen.

The second group of compounds of interest are compounds of formula (I), in which

< / BR>
is a radical of formula (a-1) or (a-2).

The third group of compounds of interest are compounds of formula (I) in which Y is N, and R1is hydrogen.

The fourth group of compounds of interest are compounds of formula (I) in which R2is C1-4the alkyl, a R3is hydrogen.

The fifth group of compounds of interest are compounds of formula (I) in which R6is pyridinyl, phenyl, halogenfree, benzyl, C3-6cycloalkyl, C1-4allyloxycarbonyl, stands or trifluoromethyl.

The preferred compounds are the compounds of formula (I), in which

R1, R3and R5are hydrogen;

R2is C1-4by alkyl;

R4is halogen and

Y is n

More preferred compounds are the compounds of formula (I), in which

R1, R3and R5are hydrogen;

R2is ethyl;

R4it is the UB> cycloalkyl, C1-4allyloxycarbonyl, stands or trifluoromethyl; and

< / BR>
is a radical of formula (a-1) or (a-2).

The most preferred compounds are 1-[4-[2-[1-(4- chlorobenzoyl)propyl]-2,3-dihydro-3-oxo-4H-1,2,4-triazole-4 - yl]phenyl]-4-(cyclopropanecarbonyl)piperazine; 1-(4-chlorobenzoyl) - 4-[5-[2-[1-(4-chlorobenzoyl) propyl] -2,3-dihydro-3-oxo-4H-1, 2, 4-triazole-4-yl]-2-pyridinyl]piperazine;

1-benzoyl-4-[4-[2-[1- [4-chlorophenyl)hydroxymethyl] propyl]-2,3-dihydro-3-oxo - 4H-1,2,4-triazole-4-yl]phenyl]piperazine; 1-(4-chlorobenzoyl)-4- [4-[2-[1-[(4-chlorophenyl)hydroxymethyl] propyl] -2,3-dihydro - 3-oxo-4H-1,2,4-triazole-4-yl] phenyl] piperazine; their pharmaceutically acceptable salts accession acids and stereochemical isomeric form.

Similar methods of producing compounds, such as compounds of formula (I) according to the present invention, described in US-4791111 and US-4931444.

The compounds of formula (I) can be obtained by N-alkylation of the intermediate compounds of formula (II) with a reagent of formula (III), where L is the reaction removable group, such as, for example, halogen, di(C1-4alkyl)amino, etc.

< / BR>
The above-mentioned N-alkylation can be performed in the usual way in a suitable solvent and in priately, for example N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone; aromatic solvents such as benzene, methylbenzol; an ether, e.g. 1,1'-oxybisethane, tetrahydrofuran, 1-methoxy-2-propanol; halogenated hydrocarbons such as dichloromethane, trichloromethane or a mixture of such solvents.

Suitable bases are, for example, bis(trimethylsilyl)amide, sodium, sodium hydroxide, carbonates or bicarbonates of alkali and alkaline earth metals, for example sodium carbonate or potassium; or organic bases such as triethylamine and the like of the base.

The compounds of formula (I) in which R6represents methyl or trifluoromethyl; and specified R6presents R6-aand these compounds by formula (I-a), can be obtained by reacting the intermediate compounds of formula (II) and acetic anhydride (III-a) or triperoxonane anhydride (III-b) in a reaction inert solvent, for example dichloromethane, toluene, etc., optionally in the presence of bases, such as carbonates or bicarbonates of alkali and alkaline earth metals, for example sodium carbonate or potassium.

< / BR>
The compounds of formula (I) can also be obtained by which the presence of a suitable base.

< / BR>
The compounds of formula (I) can also be transformed into each other by using the following well-known specialists of techniques for the transformation of functional groups.

For example, the compounds of formula (I) in which R6represents C1-4alkyl, substituted piperidinium, pyrrolidinium, piperazinil, C1-4alkylpiperazine, C1-4alquilervillapeniscola, C1-4allyloxycarbonyl, amino, mono - or di(C1-20)alkylamino or C3-6cyclooctylamino; moreover, these substituents represented by R7and these compounds by formula (I-b) can be obtained by reaction of compounds of formula (I-C) and the reagent of formula (IV) in a reaction inert solvent, for example N,N-dimethylformamide.

< / BR>
Further, the compounds of formula (I) in which Z represents C=O, may be transformed into compounds of formula (I) in which Z is CHOH, using the following well-known specialists of recovery techniques. For example, this recovery can be conveniently carried out with the help of interaction with the metal hydride or a complex metal hydride such as sodium borohydride, lamborghini.com sodium, etc. in water, 1-methylpyrrolidinone, acetonitrile,such solvents. Alternatively, the specified recovery can be done through interaction with hydroboration Tris(1-methylethoxy) potassium, hydroboration Tris(1-methylpropyl) sodium or hydroboration Tris(1-methylpropyl) potassium in a reaction inert solvent, for example tetrahydrofuran or N,N-dimethylformamide.

Optionally, the reaction of the compound of formula (I-C) with a reagent of formula (IV) and recovery described above can be performed in a single reaction vessel.

And finally, pure isomeric forms of the compounds of formula (I) can be divided into the mixture using standard methods of separation. In particular, the enantiomers can be separated by column chromatography using chiral stationary phases, such as suitable derivatives of cellulose, for example three (dimethylcarbamoyl) cellulose (Chiralcel ODand such chiral stationary phases.

In all previously described and the subsequent reactions, the reaction products can be isolated from the reaction medium and, if necessary, be subjected to further purification according to conventional techniques well known to specialists.

Intermediate compounds of formula (II) can be obtained by reacting the compounds of formula (V) and which should be obtained according to the method described above to obtain compounds of formula (I) from intermediates of formula (II).

The compounds of formula (I) and their pharmaceutically acceptable salts accession acids and stereochemical isomeric forms possess useful pharmacological activity against Helicobacter species, such as Helicobacter pylori, Helicobacter mustelae, Helicobacter fellis, etc., especially Helicobacter pylori.

Especially important in this context is the discovery that these compounds show inhibitory activity against the growth of Helicobacter, and bactericidal activity against specified bacteria. Bactericidal effect on Helicobacter defined in suspension cultures using the techniques described in Antimicrob. Agents Chemother., 1991, volume 35, pages 869 - 872.

Interesting distinguishing feature of these compounds is related to their highly specific activity against Hlicobacter. The compounds of formula (I), as it appeared to have no inhibitory activity against any of the following species: Campylobacter jejuni, Campylobacter coli, Campylobacter fetus, Campylobacter sputorum, Vibrio spp., Staphylococcus aureus and Escherichia coli at concentrations up to 10-5M

Important valuable as these compounds is their prolonged activity against H. pylori pivet adverse effect of acidic environment of the stomach in vivo.

Thus, these compounds are considered as a valuable therapeutic drugs for the treatment of warm-blooded animals, in particular humans, suffering from a disease or condition associated with Helicobacter. Examples of these diseases or conditions are gastritis, gastric ulcers and duodenal ulcers and stomach cancer.

From the point of view of their anti-Helicobacter properties of these compounds can be placed in various pharmaceutical forms for different routes of administration. For the manufacture of pharmaceutical compositions of the present invention an effective amount of a particular compound, in the form of a base or salt of accession, as the active ingredient is combined in a homogeneous mixture with a pharmaceutically acceptable carrier, which may take very different views depending on desirable for the injection form of the drug. Preferably, these pharmaceutical compositions were in the form of standard doses, convenient, preferably, for oral, rectal or parenteral administration. For example, in the manufacture of compositions in the form for oral administration, you can use any of the usual pharmaceutical substances, such as suspension, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricating agents, binding agents, disintegrating agents, etc., in the case of powders, pills, capsules and tablets. For parenteral compositions, the carrier typically includes sterile water, at least in the most part, though you can also include other ingredients, for example, to enhance solubility. For example, it is possible to make solutions for injection, in which the carrier comprises saline solution, glucose solution or a mixture of saline solution and glucose. It is possible to make a suspension for injection in this case, use the appropriate liquid carriers, suspendresume agents, etc.

If the pharmaceutical composition is made in the form of an aqueous solution, the compounds of formula (I), which have low solubility, can be converted to the salt form and add a co-solvent that is miscible with water and is physiologically acceptable, such as dimethylsulfoxide, etc., or compounds of formula (I) can be solubilisate a suitable carrier, such as a cyclodextrin (CD) or, in particular, derivatives of cyclodextrin, such as cyclodextrin derivatives described in US-3459731, EP-A-149197 (July 24, 1985), CODEXTER or ethers and mixed ethers, in which one or more hydroxyl groups in the glucose residues in the cyclodextrin substituted by the following groups: C1-6alkyl, especially methyl, ethyl or isopropyl; hydraxis1-6alkyl, particularly hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxyl1-6alkyl, particularly carboxymethyl or carboxyethyl; C1-6alkyl-carbonyl, especially acetyl; C1-6allyloxycarbonyl1-6alkyl or carboxy1-6alkalosis1-6alkyl, especially carboxyphenoxypropane or carboxitherapy; C1-6alkylcarboxylic1-6alkyl, especially 2-acetyloxybenzoic. Especially noteworthy as complexing agents and/or solubilizing agents are - CD, 2,6-dimethyl --CD, 2-hydroxyethyl --CD 2-hidroxietil --CD, and 2-hydroxypropyl --CD and (2-carboxymethoxy)- propyl --CD, and especially, 2-hydroxypropyl -- CSD.

The term mixed ether means derivative of cyclodextrin in which at least two hydroxyl groups of the cyclodextrin tarifitsirovana different groups, such as, for example, hydroxypropyl or hydroxyethyl.

The average molar substitution (MOH) was used as a measure of the average number of moles of alkoxy units in the odik, such as nuclear magnetic resonance (NMR), mass spectrometry (MS) and infrared spectroscopy (IR). Depending on the used method of analysis for each specific cyclodextrin derivative can be obtained slightly different from each other in size. The hydroxyalkyl derivatives of cyclodextrin used for the compositions of the present invention, the value of the MOH on the results of the mass spectrometry is in the range from 0.125 to 10, in particular from 0.3 to 3, or from 0.3 to 1.5. Preferably the amount of MOH varies from approximately 0.3 to 0.8, in particular from about 0.35 to 0.5 and particularly preferably about 0.4. The magnitude of the MOH identified by NMR or IR, preferably ranging from 0.3 to 1, in particular from 0.55 to 0.75.

The average degree of substitution (Sz) refers to the average number of substituted hydroxyl groups per mole glucose residues. The value of Sz can be identified using various analytical techniques such as nuclear magnetic resonance (NMR), mass spectrometry (MS) and infrared spectroscopy (IR). Depending on the used method of analysis for each specific cyclodextrin derivative can be obtained slightly different kolicina NW on the results of the MS is in the range from 0.125 to 3, in particular from 0.2 to 2, or from 0.2 to 1.5. Preferably the value of Sz varies approximately from 0.2 to 0.7, in particular from about 0.35 to 0.5 and particularly preferably about 0.4. Size Sz defined by NMR or IR, preferably ranging from 0.3 to 1, in particular from 0.55 to 0.75.

More specifically, hydroxyalkyl derivatives - and - cyclodextrin for use in the compositions of the present invention are partially substituted derivatives of cyclodextrin, in which the average degree of alkylation with hydroxyl groups at different positions glucose residues ranged from approximately 0% to 20% for 3 positions, from 2% to 70% for 2 positions and from about 5% to 90% for 6 positions. Preferably the number of unsubstituted and - cyclodextrin is less than 5% of the total content of the cyclodextrin and, in particular, is less than 1.5%. Another particularly interesting derivative of cyclodextrin is randomly methylated - cyclodextrin.

The most preferred cyclodextrin derivatives for use in the compositions of the present invention are partially substituted esters or mixed esters - cyclodextrin, with the l).

The most preferred cyclodextrin derivative for use in the compositions of the present invention is hydroxypropyl -- cyclodextrin with the MOH in the range from 0.35 to 0.50 and containing less than 1.5% unsubstituted - cyclodextrin. The magnitude of the MOH identified by NMR or IR, preferably ranging from 0.55 to 0.75.

For ease of use and standard dosages particularly advantageous to create the above pharmaceutical composition in the form of a standard dosage units. Standard dosage unit referred to in the present description and the claims refers to physically discrete units suitable as standard dosages, each unit contains a certain quantity of active ingredient calculated to provide the desired therapeutic effect, in combination with the required pharmaceutical carrier. Examples of such dosage units are tablets (including tablets serif and coated tablet), capsules, pills, sachets of powder, pills, solutions or suspensions for injection, etc. and packaging of many of these isolated units.

From the point of view presessional a method of treating warm-blooded animals, in particular, people suffering from diseases associated with Helicobacter, which includes a systemic introduction of pharmaceutically effective amounts of compounds of formula (I), its pharmaceutically acceptable salt or accession or stereochemical isomeric form, in a mixture with a pharmaceutical carrier. In another aspect of the present invention the considered compounds are used as medicines.

In General, it is assumed that the effective daily amount would be from 0.05 mg/kg to 50 mg/kg body weight, preferably from 0.1 mg/kg to 30 mg/kg body weight and most preferably from 0.5 mg/kg to 10 mg/kg body weight.

It is obvious that the effective daily amount may be reduced or increased, depending on the reaction of the patient being treated, and/or depending on the evaluation of the physician prescribing the compounds of the present invention. Thus, the above effective limits are a guide only and are not intended to limit in whatever degree, amount or application of the present invention.

Not necessarily, in combination with the compounds of the present invention can be administered with other active is whether consistently or different drugs can be combined in one dosage form. Suitable compounds for combination therapy are compounds of bismuth such as bismuth subcitrate, bismuth subsalicylate, etc., antibiotics, such as ampicillin, amoxicillin, clarithromycin, etc., antagonists H2receptors, such as cimetidine, ranitidine, etc., and, in particular, proton pump inhibitors such as omeprazole, lanzoprazol, pantoprazole, etc., For these compounds, which can be useful for combination therapy with compounds of the formula (I), an effective daily amount would be from 0.05 mg/kg to 50 mg/kg body weight.

Experimental part

In this document, "DMF" means N,N-dimethylformamide, "DMSO" means dimethyl sulfoxide and "THF" means tetrahydrofuran.

Example 1

a) a Mixture of (a)-ethyl 4-[4-[2-[1-(4- chlorobenzoyl)propyl]-2,3-dihydro-3-oxo-4H-1,2,4-triazole-4 - yl]phenyl]-1-piperidinecarboxylate (15 g) in 48% aqueous solution of Hydrobromic acid (150 ml) was stirred and heated under reflux for 6 hours and then stirred overnight. The mixture is evaporated, the residue was dissolved in CH2Cl2and washed with NaHCO3/H2O. the Organic layer was dried, filtered and the solvent wipe. The precipitate was filtered and recrystallized from CH3CN, getting 7.9g(2,2%) ()-2-[1-(4-chlorobenzoyl)propyl]-2,4-dihydro-4-[4- (1-piperazinil)phenyl]-3H-1,2,4-triazole-3-one.dihydrochloride. monohydrate; so pl. 175,9oC (intermediate compound 1).

b) sodium Hydroxide (4 g) dissolved in water (20 ml) was added to a mixture of intermediate (1) (6 g) in CH2Cl2(180 ml) and the mixture was stirred for 30 minutes. Was added dropwise benzalacetophenone (2.3 g) in CH2Cl2(20 ml) and the mixture was stirred at 20oC for 2 hours. Added water and the layers were separated. The organic layer was dried, filtered and the solvent evaporated. The residue was led from 2-propanol. The precipitate was filtered and dried, obtaining 4.7g(59%) ()-1-[4-[2-[1-(4-chlorobenzoyl)propyl]-2,3-dihydro-3 - oxo-4H-1,2,4-triazole-4-yl]phenyl]-4-(phenylacetyl) piperazine; so pl. 172oC (compound 1).

Example 2

A mixture of acetic anhydride (10.2 g), intermediate (1) (10 g) and sodium carbonate (10.6 g) in toluene (200 ml) was stirred and heated under reflux overnight. The mixture was cooled, added water and layers were separated. The organic layer was dried, filtered and the solvent evaporated. The residue was led from 2 - phenyl]piperazine; so pl. 125oC (compound 2).

Example 3

A mixture of compound (27) (2 g) in DMF (100 ml) was stirred at 40oC. was added dropwise 1 M K[OCH(CH3)2]3BH in THF (11 ml) and the mixture was stirred over night. The mixture was poured into water and was stirred for 2 hours. The precipitate was filtered and purified by column chromatography on silica gel (eluent: CH2Cl2/CH3OH 98/2). Pure fractions were collected and evaporated. The residue was washed with ethyl acetate/diisopropyl ether, receiving 1 g (51%) ()-(R*, R*)-1-[5-[2-[1-[(4-chlorophenyl) hydroxymethyl]propyl]-2,3-dihydro-3-oxo-4H-1,2,4 - triazole-4-yl] -2-pyridinyl] -4-triazole-4-yl] - 2-pyridinyl]-4-(2-pyridylcarbonyl)piperazine; so pl. 210oC (compound 3).

Example 4

A mixture of compound (16) (0.35 g) in 1-propanamine (0.5 ml) and DMF (2 ml) was stirred at room temperature overnight. The mixture was purified by GHWR on silica gel (eluent: CH2Cl2100 to CH2Cl2/CH3OH 90/10 for 20 minutes and at 120 ml/min and up to CH3OH 100 after 20 minutes). The desired fraction was collected and evaporated getting the solution 0,22 g()-4-[5-[2-[1-(4-chlorobenzoyl) propyl]-2,3-dihydro-3-oxo-4H-1,2,4-triazole-4-yl]-2 - pyridinyl] -1-[(propylamino)acetyl]piperazine in DM is l) was stirred for 1 hour. Added 1 M K[OCH(CH3)2]3BH in THF (1.5 ml) and the mixture was stirred for 1 hour. Solution was added NH4Cl (0.25 ml), the mixture was stirred for 1 hour, and then was purified by GHWR on silica gel (eluent: CH2Cl2/CH3OH 90/10 to CH2Cl2/CH3OH 70/30 for 20 minutes and at 120 ml/min). The desired fraction was collected and evaporated, obtaining a solution of 0.09 g ()-(R*,R*)-4-[5- [2-[1-[(4-chlorophenyl)hydroxymethyl]propyl] -2,3-dihydro-3 - oxo-4H-1,2,4-triazole-4-yl]-2-pyridinyl]-1- (propylamino)acetyl]piperazine in DMSO (8.5 ml) (32,2%) (compound 5).

The compounds listed in the table were obtained according to one of the procedures described above.

Pharmacological example

The activity of the tested compounds against Helicobacter evaluated using the following test procedures in vitro.

Example 10

The activity of the tested compounds against Helicobacter

The activity of the tested compounds against Helicobacter pylori was determined against a standard set of 5 strains of H. pylori obtained from clinical material. The minimum inhibiting concentration (MIC) was determined by measuring the activity of the urease of H. pylori after treatment growing cultures of bacteria antimicrobial agent is the introduction of 10-4in DMSO. 10 μl volumes of these solutions using pipettes were placed in the wells of tablets Repli (Sterilin). Wells containing only DMSO was included in each plate Repli as controls. In each series of tests as standards for comparison included ampicillin((+)-6-[(1-amino-2-phenylacetyl) amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3,2,0] heptane-2 - carboxylic acid trihydrate) and metronidazole (2-methyl-5-nitro - 1H-imidazole-1-ethanol). (These compounds were tested at final concentrations of 10-5, 10-6, 10-7and 10-8M). Test tablets were stored until use at 4oC. Five strains of H. pylori were supported by peresecheniem 10% blood agar every 2-3 days.

Bacteria were grown at 37oC in atmosphere containing 5% oxygen, 10% CO2and 85% nitrogen. Suspension of Helicobacter pylori to inoculum was produced in the broth made from the infusion of heart and brain tissue and conveyed to the absorption 1,5 0,3 at 530 nm.

Freshly prepared 10% blood agar with temperature 45oC in a volume of 1 ml was added to the wells of the test tablets, breeding, thus, compound 10-5and 10-6. The medium was allowed to cool, and then the pipette was placed 10 ál volumes of bacterial suspension on a surface is E. To facilitate reading of the tablets and to ensure that any growth in the medium really is H. pylori, the preferred high activity against urea unique to these species. After 48 hours incubation, 1 ml volumes of broth containing urease, was carefully added to each well of tablets Repli and the plates were incubated at 37oC for 2 hours. Then 110 μl samples of fluid from each of the wells with a pipette transferred to the wells of 96-well microtiter plates. Purple interpreted as growth, yellow-orange as the lack of growth of H. pylori. In this way achieved the point from which the inhibiting effects cannot be determined. All compounds showed activity at either of the two concentrations were tested with further dilutions to determine the MIC with a wider range of bacterial species as organisms targets. In this way it was found that the MIC of the compounds of the 1, 3,7-9, 11, 12, 14, 17-20, 27, 28, 30, 33, 35-37, 40, 102, 105 and 106 is equal to or less than 1 μm.

Examples of compositions

Active ingredient (AI) in the examples relates to a compound of formula (I), its pharmaceutically acceptable salt accession acid or structural in 0.5 l of 2-oxopropanoic acid and 1.5 l of the polyethylene glycol at 60~ 80oC. After cooling to 30~40oC was added 35 l of polyethylene glycol and the mixture was thoroughly stirred. Then was added a solution of 1750 grams of saccharin-sodium 2.5 l of purified water. Under stirring was added 2.5 l of corrigenda chocolatey and q glycol.S. up to a volume of 50 l, resulting in a solution for oral drops containing 10 mg/ml AI. The resulting solution was filling appropriate containers.

Example 12

Capsules

20 grams AI, 6 grams of lauryl sodium, 56 grams of starch, 56 grams of lactose, 0.8 grams of colloidal silicon dioxide, and 1.2 grams of magnesium stearate was intensively mixed with one another. The mixture was then filled with 1000 suitable hard gelatin capsules, which contained 20 mg of the active ingredient.

Example 13

Tablets, film-coated

Manufacturing core tablets

A mixture of 100 grams AI, 570 grams of lactose and 200 grams of starch were thoroughly stirred, and then moistened with a solution of 5 grams of sodium dodecyl sulfate and 100 grams of polyvinylpyrrolidone in 200 ml of water. Wet powder mixture was sieved, dried and re-sieved. Added 100 g microcrystalline cellulose and 15 grams hydrogenized the active ingredient each.

Floor

To a solution of 10 grams methyl cellulose in 75 ml of denatured ethanol was added a solution of 5 grams of ethyl cellulose in 150 ml of dichloromethane. Then added 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 grams of polyethylene glycol was melted and dissolved in 75 ml of dichloromethane. The latter solution was added to the previous, and then added 2.5 grams of octadecanoate magnesium, 5 grams of polyvinylpyrrolidone and 30 ml of concentrated suspensions of the dye together and homogenized. Core tablets were coated thus obtained mixture in a machine for coating.

Example 14

Suppositories

3 grams AI was dissolved in a solution of 3 grams of 2,3-dihydroxybutanedioate in 25 ml of polyethylene glycol 400. Together melted 12 grams of surfactants and triglycerides q.S. to 300 grams. The latter mixture was well mixed with the previous solution. Thus obtained mixture was poured into moulds at a temperature of 37 - 38oC, receiving 100 suppositories containing each 30 mg/ml AI.

1. Acyl derivatives of solonov General formula I

< / BR>
their pharmaceutically acceptable salts accession acids and stereochemical isomeric forms,

where Y PR is 4 is hydrogen;

R5- halogen,

R6is hydrogen, phenyl, optionally substituted with halogen; pyridinyl; or (C1-4-alkyl, optionally substituted with halogen, phenyl, halogenfree, piperidinium,1-4-alquilervillapeniscola,1-4-allyloxycarbonyl, or di(C1-20)-alkylamino;

Z is C=O or SNAN; and

< / BR>
is a radical of the formula

< / BR>
< / BR>
2. Connection on p. 1, wherein R6represents phenyl, optionally substituted with halogen; pyridinyl or1-4-alkyl, optionally substituted with halogen, phenyl, halogenfree, piperidinium,1-4-alquilervillapeniscola,1-4-allyloxycarbonyl, or di(C1-20)-alkylamino.

3. Connection on p. 1, wherein R2represents ethyl; R6is pyridinyl, phenyl, halogenfree, benzyl, or methyl and

< / BR>
is a radical of formula (a-1) or (a-2).

4. Connection on p. 1, characterized in that the specified connection is

1-(4-chlorobenzoyl)-4-[5-[2-[1-(4-chlorobenzoyl)propyl] -2,3-dihydro-3-oxo-4H-1,2,4-triazole-4-yl]-2-pyridinyl]piperazine;

1-benzoyl-4-[4-[1-[(4-chlorophenyl)hydroxymethyl] PTR]propyl]-2,3-dihydro-3-oxo-4H-1,2,4-triazole-4-yl]phenyl]piperazine;

their pharmaceutically acceptable salts accession acids and stereochemical isomeric form.

5. Pharmaceutical composition having activity against Helicobacter comprising an effective amount of a compound according to any one of paragraphs.1 to 4 and a pharmaceutically acceptable carrier.

6. A method of obtaining a pharmaceutical composition for p. 5, characterized in that an effective amount of a compound according to any one of paragraphs.1 - 4 homogeneous mixed with a pharmaceutically acceptable carrier.

7. The compound according to any one of paragraphs.1 to 5 as an active ingredient for a pharmaceutical composition according to p. 6.

8. The method of obtaining acyl derivatives of solonov formula I

< / BR>
where R1, R2, R3, R4, R5, R6, Y, Z, and

< / BR>
defined in paragraph 1,

their pharmaceutically acceptable salts accession acids and stereochemical isomeric forms, characterized in that the compound of General formula II

< / BR>
the values of the radicals R1, R2, R3, R4, R5, Y, Z, and

< / BR>
defined above, is subjected to N-acylation reagent of General formula III

< / BR>
R6has the above meaning;

L denotes the reaction of the deleted group,

the treatment of compounds of formula I in salt accession acid through the impact of the pharmaceutically acceptable acid.

 

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< / BR>
where R is hydrogen, hydroxyl;

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The invention relates to new derivatives of benzimidazole with valuable properties, in particular a derivative of benzimidazole of General formula (I)

< / BR>
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