A derivative of benzimidazole, pharmaceutical composition and method of modulation of gabaand-receptor complex

 

(57) Abstract:

A derivative of benzimidazole of the formula 1

< / BR>
where R3- the residue of formula (a)

< / BR>
in which each of a, b and D are CH or one or two of a, b and D are N and the others are CH; R11- monocyclic heteroaryl selected from pyrimidine, imidazole, pyrrole, thiazole, oxadiazole, pyrazole, pyridine, furan, possibly substituted lower alkyl, amino, pyridium, oxadiazolyl; one of R6and R7is hydrogen and the other furanyl or isoxazolyl, or its pharmaceutically acceptable salt or oxide or pharmaceutical composition based on it provides modulation of GABAA-receptor complex of the Central nervous system of a living organism. 3 s and 5 C. p. F.-ly, 2 tab.

This invention relates to novel benzimidazole compounds, pharmaceutical compositions containing these compounds, methods of their application in medical practice and process for the preparation of such compounds of benzimidazole. The new compounds are useful for treating diseases and disorders of the Central nervous system is sensitive to modulation of GABAAND-receptor complex, such as the alarm condition is namakani acid (GABA), GABAANDreceptors are the most common receptor inhibition in the mammalian brain. Structural GABAANDthe receptor is a macromolecular heteropentameric complex (combination , and / protein subunits). Through the use of modern molecular biological approaches described several subtypes such GABAAND-receptors. Any GABAAND-receptor complex contains a channel for chloride ion, which controls the flow of chloride ions through the membrane of nerve cells, and numerous sites of recognition for small molecule modulators of the type benzodiazepines, barbiturates, picrotoxin and some steroids. When GABA interacts with its receptor, the ion channel is open, the influx of chloride ions reinforced membrane hyperpolarization and the cell becomes less sensitive to vozbujdayuschego the stimulus. This induced GABA ion flow can be regulated by a variety of agents, including agents that interact with the receptor or site of recognition of benzdiazepine.

Agents that bind or interact with modulatory sites GABAAND-receptor complex, such as for example benzodiazepinovyj is receptor (agonists, partial agonists), or a dampening effect on the action of GABA, to realize the negative modulation of receptor inverse agonists, partial inverse agonists), or they can competitively block the effect of both agonists and inverse agonists (antagonists or ligands without internal activity).

Agonists generally have miorelaksantnoe, hypnotic, sedative, anxiolytic and/or anticonvulsant effect, while inverse agonists have proconvulsive, protivoallergennoy entries and impact. Partial agonists are characterized as compounds, providing a tranquilizing effect, but do not possess or have minor miorelaksantnoe, hypnotic and sedative effect, while the use of partial inverse agonist is useful for enhancing cognitive abilities.

In the last three decades have synthesized a large number of compounds belonging to different groups of compounds with affinity to benzodiazepinovym receptors. However, despite the fact that the sites of receptor benzdiazepine are still considered very attractive biological Sanae connection acting on these receptor sites, failed clinical trials due rendered them unacceptable side effects.

The present invention offers new benzimidazole compounds that interact with benzodiazepinovym receptor GABAAND-receptor complex. Compounds of the present invention are useful modulators GABAAND-receptor complex.

The present invention is the creation of new benzimidazole compounds and their pharmaceutically acceptable salts, obtained by joining acids, which are useful in the treatment of disorders, diseases or ailments of the Central nervous system is sensitive to modulation of GABAAND-receptor complex and, in particular, to a positive modulation of GABAAND-receptor complex.

The present invention also includes the creation of pharmaceutical compositions containing the new compounds of benzimidazole, useful for the above applications. Another object of the present invention is to provide a new method of treatment with novel compounds of benzimidazole.

The present invention also solves the problem POPs is from the following further description, and the rest will be clear to experts in this field.

Thus, according to this invention, inter alia, proposed that one or in combination:

the connection formulas

< / BR>
or its pharmaceutically acceptable salt or oxide, where R3represents a

< / BR>
where each of A, b and D represents CH, or one or two of a, b and D are N and the others are CH; R11represents phenyl, benzimidazolyl or monocyclic heteroaryl, which can be substituted one or more times with substituents selected from alkyl, alkoxyl, halogen, CF3, amino-, nitro-, ceanography, alluminare, acyl, phenyl and monocyclic heteroaryl; one of R6and R7represents hydrogen and the other represents furanyl or isoxazolyl, each of which can be substituted one or more times with substituents selected from halogen, alkyl, alkoxyl and phenyl; the above compound, which is a 1-(3-(1-imidazolyl)phenyl)-5-(3-furanyl)benzimidazole, 1-(3- (2-methyl-1-imidazolyl)phenyl)-5-(3-furanyl)benzimidazole, or 1-(3-(5-pyrimidinyl) phenyl)-5-(3-furanyl) benzimidazole or its pharmaceutically acceptable salt or its pharmaceutically acceptable salt or oxide together with at least one pharmaceutically acceptable carrier or diluent; the use of any of the above compounds for the manufacture of a medicinal product for the treatment of a disorder or disease of a living animal body, including a human, with a disorder or disease responsive to modulation of GABAAND-receptor complex of the Central nervous system; use of any of the above compounds for the manufacture of a medicinal product for the treatment of a disorder or disease of a living animal body, including a human, with a disorder or disease responsive to positive modulation of GABAAND-receptor complex of the Central nervous system; use of any of the above compounds for the manufacture of a medicinal product for the treatment of disorders or diseases selected from anxiety, sleep disorders, memory disorders, epilepsy or any other convulsive syndrome; a method of treatment of a disorder or disease of a living animal body, including a human, with a disorder or disease responsive to modulation of GABAAND-receptor complex of the Central nervous system, in which specified a living animal body, including human, act, think is where the treatment of disorders or diseases, sensitive to positive modulation of GABAAND-receptor complex; the above-mentioned method in which the treatment of anxiety, sleep disorders, memory disorders, epilepsy or any other convulsive syndrome; and the above-mentioned method, in which the active ingredient is administered in the form of a pharmaceutical composition in which it is present together with a pharmaceutically acceptable carrier or diluent.

Halogen represents fluorine, chlorine, bromine or iodine.

Alkyl means a straight chain or branched chain of carbon atoms in the amount of from one to eight, or cyclic alkyl, consisting of atoms of carbon in the amount of from three to seven, including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; preferred groups are methyl, ethyl, propyl, isopropyl and tert-butyl.

Alkoxyl means O-alkyl, in which alkyl such as defined above.

Acyl means -(C= O)-H or -(C=O)-alkyl, in which alkyl such as defined above.

Alluminare represents an acyl-NH-, where the acyl such as defined by who, as specified above.

Monocyclic heteroaryl represents a 5 - or 6-membered monocyclic heterocyclic group. Such monocyclic heteroaryl group includes, for example, oxazol-2-yl, oxazol-4 - yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazole-3-yl, 1,2,4-thiadiazole-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,5-thiadiazole-3-yl, 1,2,5-thiadiazole-4-yl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2 pirimidil, 4 pirimidil, 5 pirimidil, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl and 4-pyrazolyl.

Examples of pharmaceutically acceptable salts obtained by the joining of the acid include salts obtained by the accession of inorganic and organic acids, such as hydrochloride, hydrobromide, phosphate, nitrate, perchlorate, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate, benzoate, ascorbate, cinnamate, bansilalpet, methanesulfonate, stearate, succinate, glutamate, glycolate, toluene-p-sulfonate, formate, m is though and are not among the pharmaceutically acceptable, can be used in the preparation of salts useful as an intermediate derivatives upon receipt of the compounds according to the invention and their pharmaceutically acceptable salts formed by the addition of acid. Such salts are formed according to methods well-known to specialists.

In addition, the compounds of this invention may exist in resolutional, as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. To solve problems of the present invention solvated and nonsolvated forms are seen mainly as equivalent.

Some of the compounds of the present invention exist in (+) and (-)-forms, as well as in racemic forms. The racemic forms can be divided into optical isomers known methods, for example by separation of the diastereomeric salts obtained by processing the optically active acid, and the release of the optically active amine compound in the processing base. Another method of separation of racemates on the optical isomers based on chromatography on optically active matrix. Thus, Raney crystallization of d - or 1-salts (for example, the tartratami, mandelate or camphorsulfonate). Compounds according to this invention may also be separated by formation of diastereoisomeric amides from the reaction of the compounds of the present invention with an optically active activated carboxylic acid type acid derived from (+) or ( - ) phenylalanine, (+) or (- ) phenylglycine, (+) or (-)-campanulas acid, or through the formation of diastereomeric carbamates in the reaction of compounds of the present invention with an optically active chloroformiate or similar connection.

Can be used for more well-known methods of separation of optical isomers, obvious to a person skilled in the art (J. Jaques, A. Collet, and S. Wilen "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, New York (1981)).

Compounds according to the invention can be obtained in a variety of ways.

Thus, the compounds according to the invention and their pharmaceutically acceptable derivatives may be obtained by any known prior art method of obtaining compounds of similar structure and thus, as illustrated by the following examples.

Fig.1-6 show the methods for producing compounds according to the invention, in which R6is sobienie according to the invention, in which R7is furanyl or isoxazolyl, and R6is hydrogen.

Starting materials for the processes described in this application for the invention are known or can be obtained by known methods from commercially available chemicals.

The products described herein reactions produce by conventional means, such as extraction, crystallization, distillation, chromatography and the like.

Biology.

4-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter, and its effect, as previously established, implemented through the Central and through the peripheral nervous system. Currently, there are two types of GABA receptors, GABAAand GABAB-receptors. Modern molecular-biological methods demonstrated that GABAAreceptors can be subdivided into numerous lubricator in accordance with the selective and/or pharmacological private effects observed for certain ligands benzodiazepinovogo receptor, in contrast to non-selective effects observed for classical ligands benzodiazepinovogo receptor, which is the tion). GABAAreceptors associated with the flow of chloride ions through situating them chloride channel, while activation of GABABreceptors indirectly affects the change in the permeability of channels for potassium ions and calcium, and also modifies the production of secondary vectors. The recognition sites of the GABAAcan be activated GABA, muscimol and, for example, isoguvacine, but not GABABagonists, such as baclofen. Modulatory site of recognition GABAAin benzodiazepine receptor sites can be selectively labeled with radioactive isotope3H-flunitrazepam. This gives the opportunity to assess the affinity of different possible ligands for the benzodiazepine sites of the receptor, determining the ability of test compounds to displace3H-flunitrazepam.

Way

The product fabric: Drugs are prepared at a temperature of 0-4oC except as noted. The cerebral cortex of individuals of male Wistar rats (150-200 g) homogenized for 5-10 s in 20 ml of Tris-HCl (30 mm; pH of 7.4) using a homogenizer (Ultra-Turrax. The suspension is centrifuged at 27000 x g for 15 min and the precipitate washed three times with buffer solution (centrifuger every time at 27000 x g for 10 min). min to remove endogenous GABA, then centrifuged for 10 min at 27000 x g. Then the sediment homogenized in buffer and centrifuged 10 minutes at 27000 x g. The final precipitate resuspended in 30 ml of buffer solution, frozen and stored at -20oC.

Analysis: Membrane preparation is thawed and centrifuged at 2oC, 27000 x g for 10 min. the Precipitate washed twice with 20 ml of 50 mm Tris-citrate, pH of 7.1, using a homogenizer (Ultra-Turrax and centrifuger for 10 min at 27000 x g. After the precipitate resuspended in 50 mm Tris-citrate, pH 7,1 (500 ml buffer solution of 1 g of original tissue) and then used for analysis of binding. Aliquots of cloth material with a volume of 0.5 ml is added to 25 μl of a solution of test compound and 25 μl of3H-FNM (final concentration 1 nm), mixed and incubated for 2oC for 40 minutes, the Degree of non-specific binding determine using clonazepam (final concentration 1 μm). After incubation the sample is added to 5 ml of chilled in ice buffer solution, poured directly onto Whatman GF/C glass fiber filters, filtered using suction and immediately washed with 5 ml chilled in ice buffer solution. The quantity of radioactive material on the filters op is e minus nonspecific binding.

The measured value is calculated as IR50(concentration (nm) of the tested compounds inhibiting specific binding3H-FNM 50%).

The test results of individual compounds of the present invention is shown below.

Test compound: - IC50(nm)

1-(3-(1-Imidazolyl)-phenyl)-5-(3-furanyl)benzimidazole - 0,4

1-(3-(2-Methyl-1-imidazolyl)-phenyl)-5-(3-furanyl) benzimidazole - 0,4

Pharmaceutical compositions

As for use in therapy, it is possible the introduction of compounds according to the invention in the form of the raw chemical, it is preferable to present the active ingredient as a pharmaceutical drug.

Thus, according to this invention proposed a pharmaceutical preparation containing the compound of the invention or its pharmaceutically acceptable salt or its derivative together with one or more pharmaceutically acceptable carrier, and possibly other ingredients for the treatment and/or prevention. The carrier (s) must be "acceptable" in the sense of compatibility with other ingredients of the drug and safety for the recipient.

Pharmaceutical preparations included is whether sublingual), vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration, or a form suitable for administration by inhalation or insufflation.

Compounds according to the invention together with a conventional adjuvant, carrier or diluent can, therefore, be represented in the form of pharmaceutical compositions and in their standard doses, and in this form can be used in the form of solid dosage forms such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or filled with the specified liquid capsules (all the above for oral administration), in the form of suppositories for rectal administration, or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and their form in the form of standard doses may contain conventional ingredients in conventional proportions, with an additional active compounds or components, or without them, and such forms of standard doses may contain any suitable effective amount of the active ingredient commensurate with the assigned daily dose that you want to use. Drugs, containing one (1) mi is most appropriate WMD standard dose.

Compounds of the present invention can be applied in the form of a large variety of dosage forms for oral and parenteral administration. Specialists will be clear that the following dosage forms may contain as the active component as the connection according to the invention, or its pharmaceutically acceptable salt.

Upon receipt of the pharmaceutical compositions of the compounds according to the present invention, pharmaceutically acceptable carriers can be either in solid and in liquid form. Drugs in solid form are powders, tablets, coated tablets, capsules, starch wafers, suppositories and dispersed granules. A solid carrier can be one or more substances which may also act as diluents, corrigentov, soljubilizatory, lubricants, suspendresume tools, binders, preservatives, leavening tablets or encapsulating material.

In powders, the carrier is a finely ground solid substance, which is present in a mixture with finely ground active ingredient.

In tablets, the active ingredient in acceptable proportions is mixed with carrier having the necessary with the oshki and tablets contain from one to about seventy percent of the active compounds. Acceptable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragakant, methylcellulose, sodium carboxymethyl cellulose, a wax with a low melting temperature, cocoa butter and the like. The term "drug" refers to a composition containing the active ingredient with encapsulating material used as a carrier providing a capsule in which the active ingredient with the carriers, or without them, is surrounded by carrier, which thus turns out to be associated with him. Similarly this applies to the starch wafers and cakes. Tablets, powders, capsules, pills, starch wafers and cakes can be used as solid forms suitable for oral administration.

To obtain suppositories first melt having a low melting point wax type of a mixture of glycerides of fatty acids or cocoa butter and homogeneous dispersed active component, for example by stirring. The molten homogeneous mixture is then poured into forms convenient size, she is allowed to cool and thereby to harden.

Drugs suitable for vaginal put, containing in addition to the active ingredient known from the prior art associated media.

The liquid forms are solutions, suspensions and emulsions, for example aqueous solutions or solutions in aqueous solutions of propylene glycol. For example injecting liquid preparations for parenteral administration can be prepared as solutions in aqueous solution of polyethylene glycol.

Compounds of the present invention can thus be prepared in the form of preparations for parenteral administration (for example for injection, such as injection of a test dose of the substance or continuous infusion) and may be presented in the form of a standard dose in ampoules, pre-filled syringes, containers for infusion of small volumes or vessels with multiple dose with the addition of preservative. These compositions can take the form of suspensions, solutions or emulsions in oil or aqueous solvents and may contain agents of type suspendida, stabilizing and/or dispersing. On the other hand, the active ingredient may be in powder form obtained by aseptic selection of sterile solid content or lyophilization of the solution is military water.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding, if desired, a suitable dye, corrigentov, stabilizing and thickening agents.

Aqueous suspensions suitable for oral use can be obtained by dispersing finely ground active component in water with viscous material such as natural or synthetic resins, polymers, methylcellulose, sodium salt of carboxymethylcellulose, and other well-known suspendresume agents.

The invention also covers drugs in solid form, which are intended for transfer, immediately before use, in preparations in liquid form for oral administration. Such liquid forms are solutions, suspensions and emulsions. These drugs, in addition to the active ingredient, may contain dyes, corrigentov, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickening and solubilizing agents and the like excipients.

For topical application to the epidermis of the compounds according to the invention can be a suburb North-East, to be prepared in an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions can be prepared in water or oil based and usually also contain one or more emulsifiers, stabilizers, dispersing agents, suspendida agents, thickeners or dyes.

Drugs suitable for the local introduction of the oral cavity, which represent the pellet containing the active agent enclosed in corrigent, which usually sucrose and the Arabian gum or tragakant; tablets containing the active ingredient enclosed in an inert basis of the type of gelatin and glycerin or sucrose and Arabian gum; and liquid mouth rinse containing the active ingredient in an appropriate liquid medium.

Solutions or suspensions applied directly to the nasal cavity by conventional methods, for example using a dropper, pipette or spray. May be offered drugs in the form of single or multiple doses. In the latter case, when using a dropper or pipette, this can be achieved by the introduction of the patient is appropriate, predetermined volume of solution or suspen is the open air.

Introduction to the respiratory tract may also be achieved through the use of the drug in aerosol form, the active ingredient of which is presented in a sealed package with an acceptable propellants type of chlorofluorocarbon (CFC), such as DICHLORODIFLUOROMETHANE, trichloromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gas. The aerosol may also contain a surfactant such as lecithin. The dose of the drug can be controlled by setting the metering valve.

On the other hand, the active ingredients can be represented in the form of a dry powder, for example a powder mixture of this compound in a suitable powder base type lactose, starch, derivatives of starch, such as hypromellose and polyvinylpyrrolidine (PVP). Well, if powdered media will form in the nasal cavity gel. The composition in powder form can be represented in the form of a standard dose of, for example, capsules or cartridges, in particular, gelatin, or blister packs, powder of which can be entered using the inhaler.

The particle size of the compounds in preparations intended for Vvedenie 5 microns or less. Such particle size can be obtained by means known in the art methods, for example by using a micron mill.

If desired, can be used preparations adapted for long-term release of the active ingredient.

The pharmaceutical preparations are preferably presented in the form of a standard dose. In such form the preparation is subdivided into standard doses containing appropriate quantities of the active component. The standard dose can be a packaged preparation, the package contains the separated quantity of the drug, such as packaged tablets, capsules, and powders in vials or ampoules. In addition, the form of standard-dose itself may be presented as capsules, tablets, starch wafer or pellet, or it can be the appropriate number of any of these in packaged form.

The preferred compositions are tablets and capsules for oral administration and liquids for intravenous administration.

Method of application

Compounds of the present invention is extremely useful in the treatment of disorders and disease of a living animal body in light of the present invention is extremely useful in the treatment of convulsions, anxiety, sleep disorders, memory disorders, as well as other diseases that are sensitive to modulation of GABAA-receptor. Compounds according to this invention can therefore be administered to a subject, including humans, in need of the treatment, alleviation or elimination of disorders or diseases associated with GABAA-receptors. In particular, this applies to convulsions, anxiety, sleep disorders and memory disorders.

Acceptable dose lies in the range from 0.01 to 100 milligrams per day, 0.1 to 50 milligrams daily, and especially 0.1 to 30 milligrams a day, usually depending on the method of administration, the input form of the medicinal product, directions for use, subject and weight of the subject, for the treatment which is applied drug, as well as the opinions and experience of the attending physician or veterinarian.

The following examples are given to further illustrate the invention, but they should not be construed as limiting the scope of the invention. Compounds according to the invention is obtained in the following examples in tables 1-2 in the end of the description.

Example 1. 4-Fluoro-1-iodine-3-nitrobenzene (1B): a Suspension of 4-fluoro-3-nitro - aniline (100 g, 0.64 mol) in conc the Oia (48.6 g; 0.7 mol) in 100 ml of water, maintaining the temperature below -15oC. Upon completion of addition the mixture is stirred for 45 minutes at a temperature of from -20oC to -15oC. To the resulting solution was added a solution of potassium iodide (132,8 g; 0.8 mol) in 260 ml of water with such speed that the temperature of the mixture was maintained below 0oC. the Mixture is stirred until then, until there is no further evolution of nitrogen. Add aqueous sodium sulfite (200 ml; 1 M) and the mixture extracted with diethyl ether. The ether extract is washed twice with cooled in ice 1 M aqueous sodium hydroxide and twice with saline. In conclusion, the extract was dried over magnesium sulfate, concentrated and purified column chromatography on silica gel, using as eluent a mixture of ethyl acetate and petroleum ether (1:9). Compound 1B is isolated in the form of oil, which crystallized in the refrigerator. Output: to 132.6 g (78%).

Example 2. 3-(5-Pyrimidyl)aniline (2B): a Suspension containing 5-bromo-pyrimidine (15 g; 94,3 mmol), hemisulfate 3-aminophenylarsonic acid (19.3 g; 104 mmol), sodium bicarbonate (39,6 g, 472 mmol) and tetrakis(triphenylphosphine) palladium (O) (1 g) in a mixture of water (75 ml) and dimethoxyethane (150 ml) is heated overnight at 80oC with a nitrogen purge. On Obedinenie 2B (15 g; 93%). So pl. 164 - 165oC.

3-(2-Thiazolyl)aniline (2U) was obtained similarly from 2 - bromothiazole. The product was purified column chromatography, using as eluent a mixture of ethyl acetate and petroleum ether (1:1). Yield: 25%. So pl. 43-49oC.

Example 3. 3-(1-Imidazolyl)aniline (2G): a Mixture of 1-iodine-3-nitrobenzene (90 g; 0.36 mol), imidazole (54 g; 0,79 mol), potassium carbonate (54 g; to 0.39 mol) and powdered copper powder (1 g) is heated to 200oC. the Melt is stirred under nitrogen atmosphere for 2 hours. Water vapor released during the reaction, catch using molecular sieves, placed between the reaction vessel and a refrigerator. Upon completion of the reaction the mixture is cooled to 100oC and to it was added water. The mixture is allowed to cool to room temperature and the crude product is filtered and dried. Recrystallization from toluene (200 - 250 ml) allows to obtain pure 3-(1-imidazolyl)nitrobenzene (54,2 g; 79%). So pl. 101-102oC.

To 3-(1-imidazolyl) nitrobenzene (51,6 g; 0.27 mol) in acetic acid (500 ml) is added palladium catalyst (5 g 5% Pd on activated carbon) and the mixture hydronaut under pressure (Pstart: 4 bar) as long as you do not stop the absorption of vodila-brown color. Output: 40,4 g (93%).

N-Acetyl-3-(1-imidazolyl) aniline(2D): Compound 2G (5,88 g; 37 mmol) is stirred without a temperature in acetic anhydride (30 ml) for 1 hour. The mixture was poured into ice-cold water and alkalinized by adding aqueous sodium hydroxide (12 M). The product is filtered, washed with water and dried, obtaining the compound 2D (6,34 g; 85%). So pl. 181-183oC.

Example 4. 3-(2-Pyridyl)aniline (2A): To a solution of 2-(3-nitrophenyl) pyridine (obtained as described (J. Chem.Soc. 1958 R. 1759)) (12,7 g, 63.5 mmol) in absolute ethanol added palladium catalyst (1.3 g 5% Pd on activated carbon) and the mixture hydronaut under atmospheric pressure until, until there is no further absorption of hydrogen. The mixture is filtered through brownmillerite and the filtrate concentrated under reduced pressure. The residue is purified column chromatography on silica gel, using as eluent a mixture of ethyl acetate and petroleum ether (9:1) to give compound 2E (9.5 g; 88 %) as a oil light brown color.

5-(3-furanyl)-2-(3-carboxyphenyl)aminoaniline (13C) was obtained in a similar manner from compound 12C (Example 21). As eluent for chromatographic stage of the cleaning process used ethyl acetate. Yield: 91%. So pl. 211-212oC.

5-Bromo-2 -(dimethylamino)pyrimidine. The above product (5,07 g; 41,22 mmol) was dissolved in glacial acetic acid (25 ml) and to it add bromine (2,15 ml; 41,95 mmol). The mixture is stirred for 30 min without temperature control, after which it was poured into ice-cold water. The mixture is alkalinized by adding 10 M sodium hydroxide. The product is filtered, washed with water and dried, obtaining 4,72 g (57 %). So pl. 162-164oC.

3-(2-(Dimethylamino)-5-pyrimidyl) aniline (2H) : a Mixture containing 5-bromo-2-(dimethylamino)pyrimidine (6,76 g; 33,17 mmol), hemisulfate 3-aminophenylarsonic acid (7.4 g; 39,78 mmol), potassium carbonate (13,73 g; 99,49 mmol), 1,3-propandiol (12 ml, 166 mmol) and tetrakis(triphenylphosphine) palladium (O) (0.2 g) in a mixture of water (30 ml) and dimethoxyethane (60 ml), heated over night at 80oC in nitrogen atmosphere. After cooling, the mixture is diluted with water and ethyl acetate and filtered through skladka the United organic phases are dried over sodium sulfate and evaporated to dryness. The residue is triturated with a mixture of ethyl acetate and petroleum ether (1: 1) to give compound 2H in crystalline form (5,26 g; 74%). So pl. of 115.5-117oC.

N-Acetyl-3-(2-Mei-1-yl) aniline (2K): acetic anhydride (100 ml) portions without temperature control type 3-(2 - Mei-1-yl)aniline (11 g; of 63.6 mmol). After stirring for 1 hour the mixture was poured into water (300 ml). The resulting solution was cooled in an ice bath and alkalinized with aqueous sodium hydroxide (12 M). The product is filtered, thoroughly washed with water and dried, obtaining the compound 2K (12.3 g; 97%). So pl. 238-240oC.

Example 6. 1-(3-Nitrophenyl) pyrrole: a Mixture of 3-nitroaniline (15 g, 0.11 mol), 2,5-dimethoxytetrahydrofuran (42 ml; 0.33 mmol) and catalytic amounts of pTSA in dry toluene (150 ml) is refluxed for 2 hours. After cooling, the mixture is concentrated under reduced pressure and the residue purified column chromatography on silica gel, using as eluent a mixture of ethyl acetate and petroleum ether (1:1). Yield: 16 g (78%). So pl. 65-70oC.

3-(1-Pyrrolyl) aniline: To a suspension of the above product (16 g; 85,1 mmol) in glacial acetic acid (100 ml) is added palladium of katalizatora, the absorption of hydrogen. The mixture is filtered through celite and the solvent is removed by evaporation. The crude product is used without purification in the next stage.

N-Acetyl-3-(1-pyrrolyl) aniline (2l): received the above product is added acetic anhydride (40 ml) and the mixture is stirred without temperature control throughout the night. The mixture is then poured into water. The crude product is filtered, washed with water and dried. Recrystallization from a mixture of water and ethanol (3:2) to obtain a pure compound l Output: to 9.93 g (58 %). So pl. 134-136oC.

Example 7. 3-(2-Aminopyridin-5-yl) aniline (2m): a Mixture containing 2-(atsetamino)-5-bromopyrimidine (5,4 g; 25 mmol), hemisulfate 3-aminophenylarsonic acid (5,58 g; 30 mmol), potassium carbonate (10.4 g; 75 mmol), 1,3-propandiol (9 ml; 0.13 mol) and tetrakis(triphenylphosphine) palladium (0) (0.5 g) in a mixture of water (25 ml) and dimethoxyethane (50 ml), stirred by blowing nitrogen over night at 80oC. After cooling, the mixture was poured into ice-cold water. Product (deacetylating during the reaction) is filtered off, washed with water and dried, obtaining the connection 2m (4,19 g; 90%). So pl. 171-172oC.

Example 8. N-Acetyl-N-(3-(1-imidazolyl) phenyl)-2-nitro-4 - stanlin (6V): the joint Solution is make sodium hydride (7.2 g 60% dispersion in mineral oil). After the evolution of hydrogen to the mixture add a solution of compound 1B of Example 1 (52 g; to 0.19 mol) in 50 ml of DMF. The mixture was stirred at 120oC for 5 hours and left overnight without temperature control. The reaction mixture is poured into a fourfold volume of water, after which the crude product is filtered off. Purification on silica gel using as eluent a mixture of ethyl acetate and petroleum ether (3: 17) allows to obtain a pure compound 6b in the form of oil (17 g; 25%).

Example 9. N-(3-(2-Methyl-1-imidazolyl)phenyl)-2-nitro-4-stanlin (6K): To a solution of compound 2K from Example 5 (2 g, 9.3 mmol) in dry N-methyl-2-pyrrolidone (20 ml) at 0oC in nitrogen atmosphere are added in several portions sodium hydride (0,37 g 60% dispersion in mineral oil). The mixture is stirred for 1 hours, the last 30 min at room temperature. To the mixture add the connection 1B of Example 1 (2.67 g; 10 mmol), the temperature was raised to 40-50oC and the mixture was kept at this temperature during the night. After cooling, the mixture was poured into water (100 ml) and produce extraction with dichloromethane. The organic phase is extracted with 4 M hydrochloric acid. The acid extract is cooled in ice, alkalinized by adding sodium hydroxide (12 M) and extracted with what MESU dichloromethane and diethyl ether (1:1). This extract was concentrated under reduced pressure and the residue is dissolved in dimethoxyethane (60 ml). Add aqueous sodium hydroxide (28 ml; 1 M) and the mixture is stirred over night without temperature control. The mixture is then poured into water (200 ml) and thereto was added with stirring a small amount of ethanol. The product is filtered, washed with water and dried, obtaining the connection 6K (2 g, 51%). So pl. 135-136oC.

N-(3-(1-Pyrrolyl)phenyl)-2-nitro-4-nitroaniline (6L) was obtained in a similar manner from compounds 1B (Example 1) and 2l (Example 6). Yield: 30%. So pl. 116-118oC.

Example 10. Hydrofloric N-(3-(2-(dimethylamino)pyrimid-5-yl) phenyl-2-nitro-4-joanina (s): a Mixture of compounds 1B of Example 1 (3 g; and 11.2 mmol) and 2H from Example 5 (2.4 g; and 11.2 mmol) in dry N-2-pyrrolidone (10 ml) is stirred under nitrogen atmosphere for 6 hours at a temperature of 120-135oC. the Mixture is allowed to cool to room temperature and stirring is continued over night. To the resulting suspension add water. The product is filtered, dried and washed with ethyl acetate, which allows to obtain a connection s (of 3.46 g; 64%). So pl. 202-203oC.

Hydrofloric N-(3-(2-aminopyridin-5-yl) phenyl)-2-nitro - 4-joanina (6m) received similar Ob-2-nitroaniline (6N) was obtained in a similar manner from compounds 1B (Example 1) and 2n (Example 16). The base was isolated by treatment with aqueous sodium carbonate. Yield: 23%. So pl. 165-166oC.

N-(3-(2-Methylthiazole-4-yl)phenyl)-4-iodine-2 - nitroaniline (6o) was obtained in a similar manner from compounds 1B (Example 1) and 20 (Example 17). Yield: 32%. So pl. 137-138oC.

N-(3-(5-Pyrimidyl) phenyl)-4-iodine-2-nitroaniline (6b) was obtained in a similar manner from compounds 1B (Example 1) and 2B (Example 2). Yield: 79%. So pl. 214-217oC.

N-(3-(2-Pyridyl)phenyl)-4-iodine-2-nitroaniline (6E) was obtained in a similar manner from compounds 1B (Example 1) and 2E (Example 4). Yield: 40%. So pl. 195-196oC.

Example 11. N-(3-(1-Imidazolyl)phenyl)-4-(3-furanyl)-2-nitroaniline (7b) : a Mixture of compound 6 of Example 8 (17 g, 38 mmol), 3-fornevermore acid (5.6 g; 50 mmol), 1,3-propandiol (14 ml; to 0.17 mol), potassium carbonate (15.7 g; 0.11 mol) and tetrakis(triphenylphosphine) palladium (O) (0.5 g) in a mixture of water (60 ml) and dimethoxyethane (120 ml), refluxed in nitrogen atmosphere for 4 hours. After cooling, the mixture was poured into water (800 ml) and stirred at 0oC as long, until the loss oily crystals. The crude product (mixture of acetylated and deacetylating product) is filtered and dissolved in dimethoxyethane (200 is followed by a session poured into water (500 ml) and the product is filtered, washed with water and dried. Yield: 13.1 g (100 %). So pl. 129-131oC.

N-(3-(1-Imidazolyl)phenyl)-4-(2-furanyl)-2-nitroaniline (7s) was obtained in a similar manner from compound 6b (Example 8) and 2-furylmethanol acid. Yield: 77%. So pl. 147-149oC.

Example 12. N-(3-(2-Mei-1-yl)phenyl)-4-(3-furanyl)-2 - nitroaniline (7K): a Mixture containing the compound 6K from Example 9 (1 g; of 2.38 mmol), 3-fornevermore acid (0.4 g; 3,57 mmol), potassium carbonate (1 g; of 7.25 mmol), 1,3-propandiol (0.9 ml; and 11.2 mmol) and tetrakis(triphenylphosphine) palladium (O) (50 mg) in a mixture of dimethoxyethane (7 ml) and water (3.5 ml), refluxed in nitrogen atmosphere for 4 hours. After cooling, the mixture was poured into water (30 ml) and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrate under reduced pressure. The residue is purified column chromatography on silica gel, using as eluent a mixture of ethanol and ethyl acetate (1:4). Yield: 0.8 g (93%). The product was isolated in the form of butter.

N-(3-(2-(dimethylamino)pyrimid-5-yl)phenyl)-4-(3 - furanyl)-2-nitroaniline (s) was obtained similarly from the connection s (Example 10) with 87% yield. So pl. 181-182oC.

N-(3-(2-(dimethylamino)pyrimid-5-yl)phenyl)-4-(2-furanyl) -2-neath the house. So pl. 160-161oC.

N-(3-(1-Pyrrolyl)phenyl)-4-(3-furanyl)-2-nitroaniline (7 l) was obtained in a similar manner from compound 6 (Example 9) and 3-furylmethanol acid. Yield: 86%. So pl. 129-131oC.

N-(3-(1-Pyrrolyl)phenyl)-4-(2-furanyl)-2-nitroaniline (o) was obtained in a similar manner from compound 6 (Example 9) and 2-furylmethanol acid. Yield: 83%. Allocated in the form of oil is a brownish-red colour.

N-(3-(2-Aminopyridin-5-yl)phenyl)-4-(3-furanyl)-2 - nitroaniline (7m) was obtained similarly from the connection 6m (Example 10) and 3-furylmethanol acid with a quantitative yield. So pl. 185-186oC.

N-(3-(2-Aminopyridin-5-yl) phenyl)-4-(2-furanyl)-2 - nitroaniline (7đ) was obtained similarly from the connection 6m (Example 10) and 2-furylmethanol acid with a quantitative yield. So pl. 178-180oC.

1-(3-(5-Pyrimidyl) phenyl)-5-(3-furanyl)benzimidazole (9b) was obtained in a similar manner from compound 116 (Example 15) and 3-furylmethanol acid. On stage chromatographic purification as eluent used a mixture of dichloromethane and methanol (19:1). Yield: 48%. So pl. 216-218oC.

1-(3-(2-Methylthiazole-4-yl)-5-(3-furanyl)benzimidazole (o) was obtained similarly from the connection a (Example 15) and 3-Furat and petroleum ether (1:1). Yield: 73%. So pl. 136-138oC.

1-(3-(1-Pyrazolyl)phenyl)-5-(3-furanyl)benzimidazole (n) was obtained similarly from the connection 11n (Example 15) and 3-furylmethanol acid. Yield: 64%. So pl. 170-173oC.

1-(3-(2-Pyridyl)phenyl)-5-(2-furanyl)benzimidazole (9F) was obtained in a similar manner from compounds 11th (Example 15) and 2-furylmethanol acid. The crude product was purified by treatment of an ethanol solution of activated carbon. Yield: 42%. So pl. 135-136oC.

1-(3-(3-Furanyl)phenyl)-5-(3-furanyl) benzimidazole (9c) was obtained similarly from the compound 14C (Example 15). Output: approximately 15%. So pl. 149-150oC.

N-(2-(1-Imidazolyl) pyridine-6-yl)-4-(3-furanyl)-2 - nitroaniline (16B) was obtained similarly from the compound 16A (Example 25). The chromatographic purification was not performed. The product crystallizes with quantitative yield by adding water. So pl. 173-174oC.

Example 13. N-(3-(1-Imidazolyl)phenyl)-2-amino-4-(3-furanyl)aniline (8b) To a solution of compound 7b from Example 11 (13 g; of 37.6 mmol) in ethanol (25 ml) is added ammonium chloride (6,03 r; 113 mmol) and sodium sulfide nonahydrate (27.05 per g, 113 mmol). The mixture is refluxed for 1 hour. After cooling, the mixture is(8.7 g; 73%). So pl. 188-189oC.

N-(3-(2-Mei-1-yl)phenyl)-2-amino-4-(3-furanyl)- aniline (8K) was obtained similarly from the connection 7K (Example 12) with a quantitative yield. So pl. 98-99oC.

N-(3-(1-Pyrrolyl)phenyl)-2-amino-4-(3-furanyl)aniline (8L) was obtained similarly from the connection 7L (Example 12). Yield: 80%. So pl. 194-195oC.

N-(3-(1-Imidazolyl)phenyl)-2-amino-4-(2-furanyl)aniline (8s) was obtained similarly from the connection 7s (Example 11). Yield: 94%. So pl. 191-194oC.

N-(3-(1-Pyrrolyl)phenyl)-2-amino-4-(2-furanyl)aniline (a) was obtained similarly from the connection a (Example 12). Yield: 77%. So pl. 163-164oC.

N-(3-(2-(dimethylamino)pyrimid-5-yl)phenyl)-2-amino-4-(3 - furanyl)aniline (z) was obtained similarly from the connection s (Example 12). The connection is allocated in the form of butter.

N-(3-(2-(dimethylamino)pyrimid-5-yl)phenyl)-2-amino-4-(2 - furanyl)aniline (8h) was obtained similarly from the compound 7h (Example 12). The connection is allocated in the form of butter.

N-(3-(1-Pyrazolyl)phenyl)-2-amino-4-stanlin (10h) was obtained similarly from the compound 6N (Example 10). Yield: 75%. So pl. 134-135oC.

N-(3-(5-Pyrimidyl)phenyl)-2-amino-4-stanlin (10B) was obtained in a similar manner of connection is a logical way of compound 6E (Example 10). The product is directly used in the next stage. Cm. Example 15.

N-(3-(2-Methylthiazole-4-yl)phenyl)-2-amino-4-stanlin (10) was obtained in a similar way, from the compound 6o (Example 10). Yield: 73%. So pl. 151-152oC.

N-(3-Bromophenyl)-2-amino-4-(3-furanyl) aniline in a mixture with N - (3-itfinal)-2-amino-4-(3-furanyl)aniline (13C) was obtained in a similar manner from compound 12C (Example 20). The mixture of products was separated in the form of oil. Output: approximately 76%.

N-(3-(2-Thiazolyl)phenyl)-2-amino-4-nitroaniline (20F) was obtained similarly from the connection f (Example 27). Yield: 96%. So pl. 146-159oC.

Example 14. N-(3-(2-Aminopyridin-5-yl)phenyl)-2-amino-4-(2-furanyl) -aniline (8m).

To a suspension of compound 7đ from Example 12 (0.87 g; 2,33 mmol) in ethanol (10 ml) is added 0.1 g of palladium catalyst (5% Pd on activated carbon) and the mixture hydronaut at atmospheric pressure until the cessation of hydrogen absorption. The mixture is filtered through brownmillerite, which successively washed with ethanol and DMF. The filtrate is evaporated under reduced pressure and the residue triturated with water. The product is filtered, washed with water and subjected to air drying, receiving the connection 8m (0.5 g; 63 %). So pl. 211-212oC.

N-(3-(2-neck, receiving a connection 8P (43 %). So pl. 208-209oC.

Example 15. 1-(3-(1-Imidazolyl)phenyl)-5-(3-furanyl)benzimidazole (9b) : a Solution of compound 8b from Example 13 (8.7 g; 27.5 mmol) in formic acid (100 ml) is refluxed for 30 minutes After cooling the mixture was poured into water (500 ml) and alkalinized by adding aqueous sodium hydroxide (12 M). The crude product is filtered, washed with water and subjected to air drying. The solution of this crude product in a mixture of ethanol (200 ml) and dichloromethane (400 ml) is treated with activated carbon while boiling under reflux for 15 minutes the Mixture is filtered through brownmillerite and the filtrate concentrated under reduced pressure until the beginning of sedimentation. The deposition is complete, cooling the mixture in an ice bath. The product is filtered and dried. Yield: 7.5 g (84%). So pl. 203-204oC.

1-(3-(2-(dimethylamino)pyrimid-5-yl)phenyl)-5-(3 - furanyl)-benzimidazole (s) was obtained similarly from the connection s (Example 13). Purification was performed by column chromatography on silica gel, using as eluent a mixture of dichloromethane and acetone (9:1). Yield: 32 % (from s). So pl. 183-184oC.

1-(3-(2-Mei-1-yl)phenyl)-5-(3-furanyl) benzimidazole on silica gel, using as eluent a mixture of ethyl acetate and methanol (9:1). Yield: 71%. So pl. 105-107oC.

1-(3-(1-Pyrrolyl)phenyl)-5-(3-furanyl)benzimidazole (9L) was obtained similarly from the compound 8L (Example 13). Purification was performed by column chromatography on silica gel, using as eluent a mixture of ethyl acetate and petroleum ether (1:1). Yield: 42%. So pl. 144-145oC.

1-(3-(2-Aminopyridin-5-yl)phenyl)-5-(2 - furanyl)benzimidazole (9) was obtained in a similar manner from compound 8 (Example 14). Purification was performed by column chromatography on silica gel, using as eluent a mixture of ethyl acetate and methanol (9:1). Yield: 11%. So pl. 220-222oC.

1-(3-(2-(dimethylamino)pyrimid-5-yl)phenyl)-5-(2-furanyl) -benzimidazole (n) was obtained in a similar manner from compounds of 8h (Example 13). Purification was performed by column chromatography on silica gel, using as eluent a mixture of ethyl acetate and petroleum ether (1:1). Yield: 42% (from compound 7h). So pl. 170-172oC.

1-(3-(1-Pyrrolyl)phenyl)-5-(2-furanyl) benzimidazole (o) was obtained similarly from the connection a (Example 13) and was purified as described for compound n. Yield: 53%. So pl. 137-139oC.

1-(3-(1-Imidazolyl)phenyl)-5-is but to connect 9V. Yield: 46%. So pl. 175-177oC.

1-(3-(2-Aminopyridin-5-yl)phenyl)-5-(3-furanyl) benzimidazole (9R) was obtained similarly from the connection 8P (Example 14) and was purified as described for compound m Output: 5%. So pl. 222-223oC.

1-(3 -(5-Pyrimidyl) phenyl)-5-identitytotal (11b) was obtained in a similar manner from compound 10B (Example 13). The crude product was used without further purification. Yield: 91%. So pl. 197-199oC.

1-(3-(2-Methylthiazole-4-yl)phenyl)-5-identitytotal (o) was obtained in a similar manner from compound 10 (Example 13). Yield: 98%. So pl. 163-164oC.

1-(3-(1-Pyrazolyl)phenyl)-5-identitytotal (11n) was obtained similarly from the compound 10h (Example 13). Yield: 86%. So pl. 209-211oC.

1-(3-(2-Pyridyl)phenyl)-5-identitytotal (11e) was obtained similarly from the compound 10E (Example 13). Yield: 53% (from compound 6f). So pl. 157-158oC.

1-(3-Bromophenyl)-5-(3-furanyl)benzimidazole in a mixture with 1-(3 - itfinal)-5-(3-furanyl)benzimidazole (14C) was obtained in a similar manner from compound 13C (Example 13). The crude product was used without further purification (Example 12). Yield: 47%.

1-(4-(1-Imidazolyl)pyrimid-6-yl)-5-(3-furanyl) benzimidazole (18b) received analogichnym)-5-(3-furanyl)benzimidazole (18V) was obtained in a similar manner from compound 17B (Example 26). The product was isolated by extraction and crystallization from ethyl acetate. Yield: 29%. So pl. 170-173oC.

1-(3-(2-Thiazolyl)phenyl)-5-nitrobenzimidazole (21F) were obtained similarly from the compound 20F (Example 13) with a quantitative yield. So pl. 251-260oC.

Example 16. 1-(3-Nitrophenyl)pyrazole. A mixture of 1-iodine-3-nitrobenzene (18.7 g; 75 mmol), pyrazole (7,66 g, 113 mmol), potassium carbonate (11.2 g; 81 mmol) and catalytic amounts of copper iodide and copper bronze in dry N-methyl-2-pyrrolidone (50 ml) is heated to 180oC for 4.5 hours. After cooling, the mixture is filtered through brownmillerite. The filtrate is poured into ice water (700 ml) and the product is filtered, washed with water and dried, obtaining 13,57, Yield: 96%. So pl. 85-87oC.

3-(1-Pyrazolyl)aniline (2n): a Suspension of 3-(1-pyrazolyl)-1 - nitrobenzene (5.5 g; 34.6 mmol) in concentrated hydrochloric acid (50 ml) is heated to the temperature of reflux distilled. To the suspension are added in several portions chloride divalent tin dehydrate (24.2 g; 0.11 mol) and boiling under reflux continued for half an hour. After cooling, the precipitate is filtered and dissolved in 200 ml of water. The resulting solution was cooled in an ice bath, alkalinized by adding 12 M aqueous sodium hydroxide and E. the product in the form of a brownish oil painting. Yield: 3.9 g (71%).

1-(3-(2-Thiazolyl)phenyl)-5-aminobenzimidazole (f) was obtained similarly from the compound 21F (Example 15). The compound was isolated in the form of oil. Yield: 65%.

Example 17. 3-(2-Methylthiazole-4-yl) aniline (2): a Mixture of 2-bromo-3'- nitroacetophenone (5 g; 20,5 mmol) and thioacetamide (1.4 g; of 18.6 mmol) in glacial acetic acid (50 ml) is refluxed overnight. After cooling, the precipitate is filtered off, washed with water and dried, obtaining 2-methyl-4- (3-nitrophenyl)thiazole (3,47 g; 85%). So pl. 87-88oC. This product hydronaut as described in Example 4, when receiving the connection 2O with a quantitative yield. So pl. 80-81oC.

Example 18. N-Acetyl-4-ROM-2-nitroaniline (1 g): a Solution of 4-bromoacetanilide (20 g; for 93.4 mmol) in methanesulfonic acid is cooled to 10oC. To the solution was added concentrated nitric acid (12,6 ml) and the mixture was stirred at 40oC for 2 hours. The mixture was poured into ice-cold water. The product is filtered, washed with water and dried. Output: 23,59 g (97%). So pl. 99-100oC.

4-Bromo-2-nitroaniline (1e): a Mixture of compound 1G (3.5 g; 13.5 mmol), dimethoxyethane (100 ml) and aqueous sodium hydroxide (50 ml; 1 M) was heated to 80oC for 1 hour. After klaeden-110oC.

Example 19. N-Acetyl-4-(3-furanyl)-2-nitroaniline (1D): a Mixture of compound 1G of Example 18 (8.5 g; 32,8 mmol), 3 - furylmethanol acid (3,67 g; 32,8 mmol), sodium bicarbonate (13.8 g; 0.16 mol) and tetrakis(triphenylphosphine) palladium (O) (0.5 g) in a mixture of water (40 ml) and dimethoxyethane (80 ml) is heated overnight to 80oC with a nitrogen purge. After cooling, the mixture was poured into water and extracted with ethyl acetate. The organic phase is washed with saline, dried over sodium sulfate and concentrate under reduced pressure. (*). The residue is dissolved in 40 ml of dimethoxyethane. Add aqueous sodium hydroxide (78 ml, 1 M) and the mixture is stirred without temperature control throughout the night. The mixture was poured into water and acidified with diluted hydrochloric acid. The precipitate is filtered off, washed with water and dried, obtaining the compound 1D (5,09 g; 76%). So pl. 152-154oC.

1-(3-(2-Thiazolyl)phenyl)-5-(3-furanyl)benzimidazole (9F) was obtained similarly from the compound 23f (Example 28) to the stage (*). The residue was suirable through silica gel using a mixture of ethyl acetate and petroleum ether (1:1). Yield: 9%. So pl. 102-105oC.

Example 20. N-(3-Bromophenyl)-4-(3-furanyl)-2-nitroaniline in a mixture with N - (3-itfinal)-4-(3-furanyl)-2-nitrone,93 g; of 21.2 mmol) and catalytic amounts of copper bronze in dry N-methyl-2 - pyrrolidone is heated to 180oC during the night. After cooling, the mixture was poured into water. Add ethyl acetate and the mixture filtered through brownmillerite. Share phase and the aqueous phase is extracted twice with ethyl acetate. The combined organic extracts dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified column chromatography on silica gel, using as eluent a mixture of ethyl acetate and petroleum ether (1:9). The mixture of products (12C) is isolated in the form of oil red (1.44 g), which are used directly in the next step (see Example 13).

Example 21. N-(3-Carboxyphenyl)-4-(3-furanyl)-2-nitroaniline (12T): a Mixture of compound 1D of Example 19 (5 g, 24.5 mmol), 3-identies acid (6,69 g; 27 mmol), potassium carbonate (3,79 g; 27.5 mmol) and catalytic amounts of copper bronze in 30 ml of N-methyl-2 - pyrrolidone is heated to a temperature of 180oC during the night. After cooling, water is added and the mixture is washed twice with ethyl acetate. The aqueous phase is acidified with diluted hydrochloric acid and filtered oily residue. The precipitate is extracted with ethyl acetate and the extract is cleaned kolonen the od: 2,56 g (32 %). So pl. 203 - 205oC.

Example 22. 1-(3-Carboxyphenyl)-5-(3-furanyl)benzimidazole (14T): connection C from Example 4 (2.4 g; 8.16 mmol) is added formic acid (25 ml) and the mixture was stirred at 80oC for 1.5 hours. After cooling, the mixture was poured into ice-cold water. The precipitate is filtered off, washed with methanol and dried, obtaining the connection 14T (0,89 g; 40 %). So pl. 272-274oC.

1-(3-(3-(2-Pyridyl)oxadiazol-5-yl)phenyl)-5-(3-furanyl) -benzimidazole (9): a Solution of compound 14T (0,43 g; of 1.41 mmol) in dry THF (10 ml) is heated under nitrogen atmosphere to reflux distilled. Add carbonyldiimidazole (0.4 g; 2.48 mmol) and boiling under reflux continued for 3 hours. Add 2-(oxyimino)pyridine (0,48 g, 3.54 mmol) and the resulting mixture refluxed overnight. After cooling, the solvent is removed by evaporation and the residue partitioned between water and ethyl acetate. The organic phase is dried over sodium sulfate and evaporated to dryness. The residue is dissolved in toluene (15 ml), add a catalytic amount of pTSA and the mixture is refluxed over night. The solvent is evaporated under reduced pressure and the residue purified column chromatography on silica gel, using LASS="ptx2">

1-(3-(3-Cyclopropylamino-5-yl)phenyl)-5-(3-furanyl) -benzimidazole (9D) was obtained similarly from the connection 14T and cyclopropylacetylene. Yield: 19%. So pl. 144-146oC.

Example 23. 2-Chloro-6-(1-imidazolyl) pyridine (15A): a Mixture of 2,6-dichloropyridine (5 g; 33,78 mmol), imidazole (2.3 g; 33,78 mmol) and potassium carbonate (4,66 g; 33,78 mmol) in DMF (50 ml) is heated to 85oC during the night. The cooled mixture was poured into ice-ox and unreacted starting material is filtered off. The filtrate is acidified with diluted hydrochloric acid and once extracted with ethyl acetate. The aqueous phase is alkalinized by adding aqueous sodium hydroxide (10 M) and extracted with ethyl acetate. The organic extract was dried over sodium sulfate, concentrated under reduced pressure and elute over silica gel using a mixture of ethyl acetate and methanol (9:1). Evaporation of the solvent gives compound 15A. Output: 2,37 g (39%). So pl. 71-73oC.

Example 24. 4-Chloro-6-(1-imidazolyl)pyrimidine (15B): a Mixture of 4,6-dichloropyrimidine (5 g; 33,56 mmol), imidazole (2.28 g; 33,56 mmol) and potassium carbonate (4,63 g; 33,56 mmol) in DMF (50 ml) was stirred at room temperature overnight. The mixture is diluted with four volumes of water and extracted with dichloromethane. Organizes methanol (9: 1). Evaporation of the solvent and rubbing the residue in a mixture of diethyl ether and petroleum ether (1:1) gives compound 15B (4,07 g; 67%). So pl. 198-200oC.

Example 25. N-(2-(1-Imidazolyl)pyridine-6-yl)-4-bromo-2-nitroaniline (16A): To a solution of compound 1E of Example 18 (2.7 g; 12.5 mmol) in dry DMF (25 ml) is added sodium hydride (0.5 g of 60% dispersion in mineral oil) and the mixture is stirred for 30 minutes Add the connection 15A (Example 23) (2.25 g; 12.5 mmol) and the mixture is heated at 100oC during the night. After cooling, the mixture was poured into ice-cold water. The precipitate is filtered off, dried and pererastayut in ethyl acetate. The filtrate is extracted with ethyl acetate. The combined solution of the product concentrate and purified column chromatography on silica gel, using as eluent a mixture of ethyl acetate and methanol (9: 1). Evaporation of the solvent and rubbing the residue in a mixture of petroleum ether and diethyl ether (1:1) gives compound 16A (0,93 g; 21%). So pl. 194-195oC.

N-(4-(1-Imidazolyl)pyrimid-6-yl)-4-(3-furanyl)-2-nitroaniline (16B) was obtained in a similar manner from compound 15B (Example 24) and compound 1D (Example 19). As eluent for chromatographic stage of the cleaning process used ethyl acetate. Yield: 23%. So the organisations 16B (Example 25) (0,38 g; 1.1 mmol) in a mixture of ethanol and dichloromethane hydronaut without temperature control, using as catalyst Raney Nickel (50% slurry in water). After absorption of hydrogen, the mixture is filtered through brownmillerite and the filtrate is evaporated, receiving the connection 17B in the form of oil, which is used without further purification.

N-(2-(1-Imidazolyl)pyrid-6-yl)-2-amino-4-(3-furanyl) aniline (17B): To a suspension of compound 16B from Example 12 (0.9 g; 2.6 mmol) in 50 ml of a mixture of ethanol and dichloromethane (4:1) add the Pd catalyst (0.15 g of 5% on charcoal) and hydronaut without temperature control to the cessation of hydrogen absorption. The mixture is filtered through brownmillerite and the filtrate is evaporated, receiving the connection 17B in the form of oil, which is used without further purification.

Example 27. N-(3-(2-Thiazolyl)phenyl)-2,4-dinitroaniline (f): a Mixture of 2,4-dinitrofluorobenzene (1,14 ml, 9.1 mmol), compound 2F from Example 2 (1.6 g; 9.1 mmol) and sodium carbonate (1.51 g; 10.9 mmol) in dry N-methyl-2-pyrrolidone (10 ml) is heated to 80oC for 2 hours. The cooled mixture was poured into ice-cold water. The precipitate is filtered off, washed with water and dried, obtaining 3,05 g (98%). So pl. 197-203oC.

Example 28. 1-(3-(2-Thiazolyl)phenyl)-5-identitytotal (23f): Suspen the Ute solution of sodium nitrite (0,22 g; 3.2 mmol) in 3 ml of water, keeping the temperature below 0oC. Upon completion of addition the mixture is stirred at a temperature of from -5oC and 0oC for 20 minutes. Add a solution of potassium iodide (0.6 g; of 3.64 mmol) in 3 ml of water and the mixture is stirred without temperature control throughout the night. To the reaction mixture are added water and sodium sulfite until then, until there is no longer the iodine color. The resulting mixture was extracted with ethyl acetate. The organic phase is washed with aqueous sodium carbonate, dried over sodium sulfate and filtered through silica gel. The filtrate is evaporated to dryness, obtaining the compound 23f. Yield: 23%. Melts with decomposition starting from 175oC.

Example 29. N-(3-Itfinal)-4-cyano-2-nitroaniline (29): To a solution of 4-chloro-3-nitrobenzonitrile (1,82 g; 10 mmol) in dry DMF (25 ml), add triethylamine (1,54 ml; 11 mmol) and 3-stanlin (1.2 ml; 10 mmol) and the mixture is heated to 80-100oC during the night. After cooling, the mixture was poured in four-fold volume of ice-cold water. The precipitate is filtered off, washed with water and dried. This crude product is washed with warm ethanol, obtaining 2.1 g (58%) named in the connection header. So pl. 211-212oC.

Example 30. 2-Amino-(N-(3-itfinal))-4-cyanoaniline (30): To suspendered (4,14 g; to 17.25 mmol) and the mixture is heated to the temperature of reflux distilled for 1.5 hours. After cooling, the mixture was poured into ice water (200 ml) and the product is filtered, washed with water and dried, obtaining 1.8 g (93%) named in the connection header. So pl. 170-172oC.

Example 31. 5-Cyano-1-(3-itfinal)benzimidazole (31): a Suspension of compound (30) (1.8 g; are 5.36 mmol) in formic acid (20 ml) is heated to 80-100oC for 1.5 hours. The reaction mixture was hot filtered through a cotton substrate into ice-cold water (100 ml). The precipitate is filtered off, washed with water and dried. The crude product is dissolved in dichloromethane and adding petroleum ether, achieve drop it into the sediment. The product is filtered and dried. Exit named in the header connection: 1,38 g (75%). So pl. 177-179oC.

Example 32. 5-Cyano-1-(3-(3-pyridyl)phenyl)benzimidazole (32A): a Mixture containing the compound (31) (4 g; 11.6 mmol), diethyl-3 - pyridylboron (2,04 g; a 13.9 mmol), potassium carbonate (4.8 g; 34.8 mmol) and tetrakis(triphenylphosphine) palladium (O) (0.2 g) in a mixture of water (20 ml) and dimethoxyethane, stirred at a temperature of 80oC in nitrogen atmosphere overnight. After cooling, the resulting suspension was poured into water and the crude product is barely, using as eluent a mixture of ethyl acetate and methanol (9: 1). Exit named in the header connection: 2,46 g (72%). So pl. 191-193oC.

5-Cyano-1-(3-(1-imidazolyl)phenyl) benzimidazole (32b) was obtained in the same way.

Example 33. 2 Tributylstannyl(thiazole) (33): To a solution of thiazole (0,71 ml; 10 mmol) in dry THF (20 ml) dropwise in an argon atmosphere at a temperature of -78oC was added 1.6 M BuLi in hexane (6.9 ml; 11 mmol). The reaction mixture was stirred at -78oC for 0.5 hours, and then thereto was added dropwise Bu3SnCl (3.1 ml; 11 mmol). After stirring for 1 h at -78oC and 1 h at room temperature the mixture was concentrated, triturated with water (50 ml) and was extracted with diethyl ether (100 ml x 3). The extract was washed with brine, dried and concentrated under reduced pressure, obtaining the compound (33) as a colorless oil. (3.7 g; Quant.).

Example 34. 5-Acetyl-1-(3-(2-thiazolyl)phenyl)benzimidazole (34): To a solution of compound (33) (3.6 g; 9.7 mmol) in dry THF (20 ml) in an argon atmosphere was added 5-acetyl-1-(3-bromophenyl)benzimidazole (1.5 g, 4.8 mmol) and (PPh3)2PdCl2(340 mg; 0.48 mmol). The reaction mixture in a sealed vessel with a capacity of 50 ml was stirred at a temperature of 80B>Cl2(200 ml x 3). The extract was washed with brine, dried and concentrated under reduced pressure. The residue was washed with ether, which allowed to obtain the compound (34) in crystalline form (1.5 g, 89%).

5-Acetyl-1-(3-bromophenyl)benzimidazole was prepared as follows:

4-Acetyl-2-nitroaniline: To a mixture of water and concentrated sulfuric acid, 150 ml (1: 2), was added N-(4-acetyl-2-nitrophenyl) ndimethylacetamide (26,5 g; 11,94 mmol). After 15 minutes, the mixture was poured into water. The product was filtered, washed with water and dried.

N-(3-bromophenyl)-4-acetyl-2-nitroaniline: a Mixture of 4-acetyl-2 - nitroaniline (3,41 g; 18,94 mmol), 1,3-dibromobenzene with (4.6 ml; 38,06 mmol), potassium carbonate (2,62 g; 19 mmol) and catalytic amounts of copper bronze is heated to 180oC by purging with nitrogen with stirring for 2 days. After cooling, the solid reaction residue is extracted with a mixture of dichloromethane and methanol (9: 1). The extract was concentrated under reduced pressure. The residue is extracted with ethyl acetate. This extract was concentrated under reduced pressure and the residue elute over silica gel using a mixture of petroleum ether and ethyl acetate (4: 1), which allows to obtain pure product. Output: 0,67 g (10,6%). So pl. 142-144oC.

ethanol (100 ml). Added Raney Nickel and the mixture was first made at atmospheric pressure for 20 hours. Added chloroform, and the mixture was filtered through brownmillerite and was evaporated in vacuum, obtaining 8,03 g of oil. To the obtained oil was added 80 ml of formic acid and the mixture was heated at 80oC for 1.5 hours. The excess formic acid was removed in vacuum. The residue was stirred in water and podslushivaet aqueous sodium hydroxide. The product was filtered, washed with water and dried.

Example 35. 5-Cyano-1-(3-(2-thiazolyl)phenyl)benzimidazole (35): 5-cyano-1-(3-(2-thiazolyl)phenyl)benzimidazole was synthesized as described in Example 34 using the compound (31) (2.0 g; 5.9 mmol) instead of 5-acetyl-1-(3-bromophenyl)benzimidazole, (PPh3)2PdCl2(100 mg; 0.14 mmol) and 2-(tributylstannyl)thiazole (3.6 g; 9.7 mmol). In the reaction was obtained 5-cyano-1-(3-(2 - thiazolyl)phenyl)benzimidazole (1.5 g, 86%).

Example 36. 4-(3-Nitrophenyl) pyrimidine (36): a Mixture of 4-phenylpyrimidine (10 g, 64 mmol) and conc. H2SO4(33 ml) was added at a temperature of 0oC to a mixture of conc. H2SO4(22 ml) and conc. HNO3(16 ml). The resulting mixture was stirred at 0oC for 2 h, poured into crushed ice and was extracted with CH2Cl2Extraline. The residue is triturated with isopropanol, the precipitate was filtered and dried under reduced pressure, obtaining the compound (36) (6.4 g; 50 %).

Example 37. 4-(3-AMINOPHENYL)pyrimidine (37): To a suspension of compound (36) (6.3 g; 31 mmol) in a mixture of MeOH (60 ml) and THF (30 ml) was added 5% palladium on charcoal (300 mg) and the mixture was first made at atmospheric pressure for 1 h the Mixture was filtered and concentrated under reduced pressure. The residue was purified column chromatography on silica gel, using as eluent a mixture of hexane and ethyl acetate (3:1), and obtained the compound (37) (5,1 g; 96%).

Example 38. N-(3-(4-Pyrimidyl)phenyl)-4-cyano-2-nitroaniline (38): To a mixture of compound (37) (5.5 g; 30 mmol) and 4-chloro-3 - nitrobenzonitrile (5,1 g; 30 mmol) in THF (120 ml) was added sodium hydride (2.3 g; 50% suspension in mineral oil). After stirring at room temperature for 2 days, the mixture was poured into water and was extracted with CH2Cl2. The extract was concentrated under reduced pressure and the residue triturated with diethyl ether, obtaining the compound (38) in the crystalline state (9,2 g; 96%).

Example 39. N-(3-(4-Pyrimidyl)phenyl)-4-cyano-2-aminoaniline (39): synthesized exactly as described in Example 37, using the connection (38) ( (8,3 g; the Quant.).

Example 40. 5-Cyano-1-(3-(4-pyrimidinyl)phenyl)benzimidazole (40): a Mixture of compound (39) (3.0 g; 10 mmol) and HCO2H (20 ml) was stirred at a temperature of 110oC for 1 h the Mixture was concentrated in vacuum. The residue was distributed between 5% aqueous NaHCO3CH2Cl2. The organic phase was dried over MgSO4and the solvent was removed by evaporation. The residue is triturated with ethyl acetate, obtaining the compound (40) in the crystalline state (2.6 g; 85%).

Example 41. 5-Formyl-1-(3-(4-pyrimidinyl)phenyl)benzimidazole (41A): To a solution of compound (40) (3,9 g) in a mixture of HCO2H (48 ml) and water (18 ml) was added Raney Nickel (2.2 g). The mixture was stirred in argon atmosphere at 100oC for 0.5 hours. After cooling, the mixture was filtered. The filtrate was concentrated and distributed between 1 m solution of NaHCO3and ethyl acetate. An ethyl acetate extract was washed with saline, dried and concentrated under reduced pressure, obtaining the compound (41A) (2.7 g; 69%).

5-Formyl-1-(3-(2-thiazolyl)phenyl)benzimidazole (41B) was obtained similarly from the compound (35);

5-Formyl-1-(3-(1-imidazolyl)phenyl)benzimidazole (41C) was obtained in a similar manner from compound (32b);

5-Formyl-1-(3-(3-pyridyl)phenyl)Bandini)phenyl)benzimidazole (42): To a mixture of ethanol (100 ml), NH2OHHCl (1,9 g; 3 EQ.) triethylamine (1.3 ml; 1 EQ. ) was added compound 41A (2.7 g) and the mixture was stirred at 60oC for one hour. The mixture was cooled to 0oC, the precipitate was filtered, washed with water and dried under reduced pressure, obtaining the compound (42A) (2.2 g; 77 %).

The reaction of 5-formyl-1-(3-(2-thiazolyl)phenyl) benzimidazole (42B) was obtained in a similar manner from compound (41B);

The reaction of 5-formyl-1-(3-(1-imidazolyl)phenyl)benzimidazole (42V) was obtained in a similar manner from compound (41C) ;

The reaction of 5-formyl-1-(3-(3-pyridyl)phenyl)benzimidazole (42 g) was obtained in a similar manner from compound (41G).

Example 43. 5-(3-Isoxazolyl)-1-(3-(4- pyrimidinyl)phenyl)benzimidazole (43A): a Mixture of compound 42A (2.1 g) and N-chlorosuccinimide (1.1 g; 1.2 EQ.) in DMF (100 ml) was stirred in argon atmosphere at a temperature of 60oC for 0.5 hours. To the reaction mixture, cooled in ice, was added vinylboronic (25 ml) followed by adding dropwise within one hour of triethylamine (4.8 ml; 5 EQ.) in 15 ml of DMF. The mixture was stirred at 0oC for 3 hours and at room temperature over night. The mixture was poured into water and was extracted with ethyl acetate. The organic phase was washed with brine, dried and conc eluent a mixture of CH2Cl2methanol (30:1), and received 5-(3-isoxazolyl)-1 -(3-(4 - pyrimidinyl)phenyl)benzimidazole (1.5 g, 64%). So pl. 214-215oC.

5-(3-Isoxazolyl)-1-(3-(2-thiazolyl)phenyl)benzimidazole (43B) So pl. 157-158oC was obtained in a similar manner from compound (42B).

5-(3-Isoxazolyl)-1-(3-(1-imidazolyl)phenyl) benzimidazole (V) was obtained similarly from the compound (42). So pl. 230-234oC.

5-(3-Isoxazolyl)-1-(3-(3-pyridyl)phenyl)benzimidazole (43g) was obtained in a similar manner from compound (42G). So pl. 208-210oC.

Example 44. 5-Acetyl-1-(3-(3-pyridyl)phenyl)benzimidazole (44a): 4-Fluoro-3-nitroacetophenone: Concentrated sulfuric acid (200 ml) is cooled to 5oC. Add 4-peracetate (20 ml; 164,76 mmol) in such a way that the temperature of the mixture did not exceed 10oC. the Mixture is cooled to 0-5oC and the portions within 2 hours add the potassium nitrate (25 g; 247,14 mmol), keeping the temperature at 0-5oC. Upon completion of addition the mixture is stirred at this temperature for 2 hours. The mixture was poured onto ice (600 g) and the crude product is filtered off. Purification of column chromatography on silica gel using as eluent a mixture of ethyl acetate and petroleum ether (1: ridine (8.53 g; 54 mmol) in dimethyl ether of ethylene glycol (180 ml) is added 3-nitrophenylarsonic acid (10 g; 59,95 mmol), aqueous potassium carbonate (90 ml; 2 M) and tetrakis(triphenylphosphine) palladium (0.5 g, 0.43 mmol). The mixture gently refluxed under nitrogen atmosphere overnight. The cooled reaction mixture is filtered and to the filtrate add water (600 ml). The precipitate is filtered off and washed with water. The crude product is dissolved in hot water (400 ml) with addition of hydrochloric acid (25 ml, 4 M). The mixture is filtered while hot. The filtrate is cooled in an ice bath and clean 3-(3-pyridyl) nitrobenzene precipitated by adding 12 M NaOH. Output 9,14 g (85%).

3-(3-Pyridyl)aniline: 3-(3-pyridyl) nitrobenzene (9,1 g, with 45.5 mmol) in ethanol (125 ml) hydronaut at atmospheric pressure for about 1.75 hours, using as the catalyst of the Raney Nickel. Filtering the resulting solution through brownmillerite with subsequent evaporation of the solvent gives 3-(3-pyridyl)aniline with a quantitative yield.

4-Acetyl-2-nitro-N-(3-(3-pyridyl)phenyl)aniline: a Mixture of 4-fluoro-3-nitroacetophenone (5 g; 27,3 mmol) and 3-(3-pyridyl) aniline (4,62 g; for 27.2 mmol) in dry 1-methyl-2-pyrrolidone (10 ml) is stirred at a temperature of 40-50oC during the night. Received teletrabajo, washed with water and dried, obtaining of 7.68 g of 4-acetyl-2-nitro-N- (3-(3-pyridyl)phenyl)aniline (85%).

5-Acetyl-2-(3-(3-pyridyl)phenylamino)aniline: 4-acetyl-2-nitro-N-(3-(3-pyridyl)phenyl)aniline (2 g, 6 mmol) is suspended in ethanol (50 ml) and dichloromethane (10 ml) and hydronaut at atmospheric pressure, using as catalyst a palladium (5% on charcoal). Filtering the resulting solution through brownmillerite with subsequent evaporation of the solvent gives an oil, rubbing which with a mixture of diethyl ether and petroleum ether (1: 1) to receive a 1.46 g of pure 5-acetyl-2-(3-(3-pyridyl)phenylamino)aniline (80%).

5-Acetyl-1-(3-(3-pyridyl)phenyl) benzimidazole: 5-acetyl-2-(3-(3-pyridyl)phenylamino)aniline (5 g, 16.5 mmol) in formic acid (50 ml) was stirred at 90oC for 1.5 hours. The cooled reaction mixture is alkalinized by adding 12 M NaOH. 5-Acetyl-1-(3-(3-pyridyl)phenyl) benzimidazole is filtered off, washed with water and dried. The quantitative output. So pl. 195-197oC.

The following compound was obtained in a similar way: 5 -

Acetyl-1-(3-(4-pyrimidinyl)phenyl) benzimidazole (b).

Example 45. 5-(5-Isoxazolyl)-1-(3-(4-pyrimidinyl)phenyl) benzimidazole (45A) made a club the reaction of the compound (b) (314 mg) with DMF-dimethylacetal (1.5 ml) in an argon atmosphere in DMF (3 ml) at 120oC for 5 hours. After cooling the mixture was poured into water and was extracted with ethyl acetate. The organic phase was washed with brine, dried and concentrated under reduced pressure. The residue was purified column chromatography on silica gel, using as eluent a mixture of CH2Cl2and methanol (30:1), and received 5-(3-dimethylamino-1-oxo-2-propen-1-yl)-1-(3-(4- pyrimidinyl)phenyl)benzimidazole (320 mg; 87%).

5-(5-Isoxazolyl)-1-(3-(4-pyrimidinyl)phenyl)benzimidazole: a Mixture of 5-(3-dimethylamino-1-oxo-2-propen-1-yl)-1-(3-(4-pyrimidinyl) phenyl) benzimidazole (307 mg) and NH2OHHCl (135 mg; 2.5 EQ.) in methanol (14 ml) was stirred at 80oC for 2 hours. After cooling the mixture was poured into water and was extracted with ethyl acetate. The organic phase was washed with brine, dried and concentrated under reduced pressure. The residue was purified by chromatography (CH2Cl2-methanol 40: 1 (on/o)) to give 5-(5-isoxazolyl)-1-(3-(4- pyrimidinyl)phenyl)benzimidazole (226 mg; 80%).

The following compounds were obtained in a similar way:

5-(5-Isoxazolyl)-1-(3-(2- thiazolyl)phenyl)benzimidazole (45) was obtained in a similar manner from compound (34). So pl. 186-188oC.

5-(5-Isoxazolyl)-1-(3-(3-pyridyl)phenyl)benzamides above examples, listed in the following tables 1 and 2.

1. A derivative of benzimidazole of the formula I

< / BR>
and its pharmaceutically acceptable salt or oxide, where R3represents a

< / BR>
in which each of A, B, and D represents CH, or one or two of A, B and D are N and the others are CH;

R11represents a monocyclic heteroaryl selected from pyrimidine, imidazole, pyrrole, thiazole, oxadiazole, pyrazole, pyridine, furan, possibly substituted lower alkyl, amino, pyridium, oxadiazolyl;

one of R6and R7represents hydrogen and the other represents furanyl or isoxazolyl.

2. Derived under item 1, which is 1-(3-(1-imidazolyl)phenyl)-5-(3-furanyl)benzimidazole; 1-(3-(2-methyl-1-imidazolyl)phenyl)-5-(3-furanyl)benzimidazole; or 1-(3-(5-pyrimidyl)phenyl)-5-(3-furanyl)benzimidazole; or its pharmaceutically acceptable salt or oxide.

3. Connection on p. 1, which is 1-(3-(2-(dimethylamino)pyrimid-5-yl)phenyl)-5-(3-furanyl)-benzimidazole; 1-(3-(1-pyrrolyl)phenyl)-5(3-furanyl)benzimidazole; 1-(3-(2-aminopyridin-5-yl)phenyl)-5-(2-furanyl)benzimidazole; 1-(3-(2-(dimethylamino)pyrimid-5-yl)phenyl)-5-(2-furanyl)-Benzema arimid-5-yl)phenyl)-5-(3-furanyl)benzimidazole; 1-(4-(1-imidazolyl)pyrimidine-6-yl)-5-(3-furanyl)benzimidazole; 1-(2-(1-imidazolyl)pyridine-6-yl)-5-(3-furanyl)benzimidazole; 1-(3-(2-thiazolyl)phenyl)-5-(3-furanyl)benzimidazole; 1-(3-(2-methylthiazole-4-yl)-5-(3-furanyl)benzimidazole; 1-(3-(1-pyrazolyl)phenyl)-5-(3-furanyl)benzimidazole; 1-(3-(2-pyridyl)phenyl)-5-(2-furanyl)benzimidazole; 1-(3-(3-furanyl)phenyl)-5-(3-furanyl)benzimidazole; 1-(3-(3-(2-pyridyl)oxadiazol-5-yl)phenyl)-5-(3-furanyl)-benzimidazole; 1-(3-(3-cyclopropylamino-5-yl)phenyl)-5-(3-furanyl)-benzimidazole; 5-(3-isoxazolyl)-1-(3-(4-pyrimidinyl)phenyl)benzimidazole; 5-(3-isoxazolyl)-1-(3-(2-thiazolyl)phenyl)benzimidazole; 5-(3-isoxazolyl)-1-(3-(1-imidazolyl)phenyl)benzimidazole; 5-(3-isoxazolyl)-1-(3-pyridyl)phenyl)benzimidazole; 5-(5-isoxazolyl)-1-(3-(4-pyrimidinyl)phenyl)benzimidazole; 5-(5-isoxazolyl)-1-(3-(2-thiazolyl)phenyl)benzimidazole; or 5-(5-isoxazolyl)-1-(3-(3-pyridyl)phenyl)benzimidazole; or its pharmaceutically acceptable salt or oxide.

4. The pharmaceutical composition that provides modulation of GABAAND- receptor complex of the Central nervous system of a living organism, containing an effective amount of a compound according to any one of paragraphs.1 to 3, or its pharmaceutically acceptable salt or oxide together with at least one pharmaceutically acceptable nosing systems of the body, includes introduction to the specified living organism a therapeutically effective amount of a compound according to any one of paragraphs.1 - 3.

6. The method according to p. 5, characterized in that the modulation of GABAAND- receptor complex of the Central nervous system of a living organism is a positive modulation.

7. The method according to p. 5 or 6, characterized in that the modulation of GABAAND- receptor complex of the Central nervous system of a living organism conduct in the treatment of anxiety, sleep disorders, memory disorders, epilepsy or any other convulsive syndrome.

8. The method according to p. 5, characterized in that the active ingredient is administered in the form of a pharmaceutical composition in which it is present together with a pharmaceutically acceptable carrier or diluent.

 

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