Amide derivatives of carboxylic acid, method for their preparing and pharmaceutical compositions based on thereof

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new amide derivatives of carboxylic acid that are antagonists of NMDA receptors of the formula (I): , wherein one radical among R1, R2, R3 and R4 represents -OH or NH2-group and others are hydrogen atoms; or two adjacent groups R1, R2, R3 and R4 in this case in common with one or more similar or different additional heteroatoms and -CH= and/or -CH2-groups form 5-6-membvered homo- or heterocyclic ring but preferably pyrrole, pyrazole, imidazole, oxazole, oxooxazolidine or 3-oxo-1,4-oxazine ring; two other groups among R1, R2, R3 and R4 radicals represent hydrogen atoms; R5 and R6 in common with nitrogen atom between them form saturated or unsaturated 4-6-membered heterocyclic ring that is substituted with phenoxy-, phenyl-[(C1-C4)-alkoxy]-, phenoxy-[(C1-C4)-alkyl]-, benzoyl-group optionally substituted in aromatic ring with one or more halogen atoms, (C1-C4)-alkyl or (C1-C4)-alkoxy-group; X and Y mean independently oxygen, nitrogen atom or group -CH=, and to their salts formed with acids and bases. Also, invention relates to a method for preparing compounds of the formula (I) and pharmaceutical compositions showing activity as selective antagonists of NR2B receptor based on these compounds. Invention provides preparing new compounds and pharmaceutical compositions based on thereof for aims in treatment of the following diseases: chronic neurodegenerative diseases, chronic painful states, bacterial and viral infections.

EFFECT: improved preparing method, valuable medicinal properties of compounds and compositions.

11 cl, 2 tbl, 27 ex

 

The invention relates to novel antagonists of the NMDA receptor, which represents an amide derivatives of carboxylic acids of the formula (I)

where

one of R1R2, R3and R4is a HE or NH2group, and the others are hydrogen atoms or

two adjacent R1, R2, R3and R4group together with one or more identical or different additional heteroatoms and-CH= and/or-CH2groups form a 5-6-membered Homo - or heterocyclic ring, preferably pyrrole, pyrazole nucleus, imidazole, oxazole, oxo-oxazolidinone or 3-oxo-1,4-oxazine ring, and the other two R1, R2, R3and R4groups are hydrogen atoms, R5and R6together with the nitrogen atom between them form a saturated or unsaturated 4-6 membered heterocyclic ring which is substituted with hydroxyl group, and/or in this case, phenyl or groups of phenoxy, phenyl-(C1-C4-alkyl), phenyl-(C1-C4-alkoxy), phenoxy-(C1-C4-alkyl), aniline, phenyl-(C1-C4-alkylamino), [phenyl-(C1-C4-alkyl)]-amino, benzoyl, hydroxydiphenylmethyl, C1-C4-alkoxycarbonylmethyl or benzhydrylidene group, optionally substituted arene, the political ring by one or more halogen atoms, cyano or hydroxyl group, C1-C4-alkyl or C1-C4-alkoxygroup,

X and Y independently represent an oxygen atom or a nitrogen atom or-CH= group, and their salts formed with acids and bases.

Since the present invention relates also to the salts of compounds of formula (I)formed with acids or bases, in particular the salts formed with pharmaceutically acceptable acids or bases, the values given for the compounds of formula (I) belong either to the free compound or salt, if not specified.

A particularly significant group of compounds of the present invention are the compounds of formula (Ia),

where the values of R1, R2, R3, R4, R5and R6the same as described for compounds of formula (I).

Especially important amide derivatives of carboxylic acids of the formula (I) are the following:

6-(4-benzylpiperidine-1-carbonyl)]-1,5-dihydrooxazolo[4,5-1]indole-2-it,

6-[4-(4-formanilide-1-carbonyl)]-1,5-dihydrooxazolo[4,5-f]indol-2-it,

(4-benzylpiperidine-1-yl)-(3,6-dihydropyrrolo[3,2-e]indazol-7-yl)methanon,

[4-(4-formanilide-1-yl)]-(3,6-dihydropyrrolo[3,2-e]indazol-7-yl)methanon,

(4-p-tolylacetate-1-yl)]-(3,6-dihydropyrrolo[3,2-e]indazol-7-yl)methanon,

(4-Ben is reprein-1-yl)-(3,6-dihydro-imidazo[4,5-f]indol-7-yl)methanon.

The invention also relates to pharmaceutical compositions containing as active ingredient the compounds of formula (I).

In addition, objects of the present invention is a method of obtaining compounds of formula (I) and chemical and pharmaceutical production, medicaments containing these compounds, and a method of treatment using these compounds, which consists in the introduction of the mammal to be treated, including man, an effective amount/amounts of compounds of formula (I) of the present invention as such or in the form of medicines.

The term "halogen" as a substituent is as previously defined means fluorine, chlorine, bromine or iodine, preferably fluorine and chlorine. The term C1-C4is an alkyl group used in the present description, means a metal, ethyl, linear and ISO-propyl and various butylene group. These C1-C4is an alkyl group can be part of C1-C4-alkoxygroup. The term C1-C4-alkanoyloxy means a monovalent alloctype containing a hydrogen atom, and C1-C6alkyl group and carbonyloxy (-CO-O-), attached to it, preferably formyloxy, acetoxy, propionyloxy, butyryloxy, valerolactam and ciprolex the group.

The invention relates also to the salts of compounds of formula (I)formed with acids or bases.

Both organic and inorganic acids may be used to form the acid additive salts. Suitable inorganic acids can be, for example, hydrochloric acid, sulfuric acid and phosphoric acid. Representatives of monovalent organic acids can be, for example, formic acid, acetic acid, propionic acid and various butyric acid, valeric acid and capric acid. Representatives of bivalent organic acid can be, for example, oxalic acid, malonic acid, maleic acid, fumaric acid and succinic acid. Other organic acids can also be used, such as hydroxy acids, for example citric acid, tartaric acid or aromatic carboxylic acid, for example, benzoic acid or salicylic acid, as well as aliphatic and aromatic sulfonic acids, for example, methanesulfonate acid and p-toluensulfonate acid. An especially valuable group of acid additive salts is that in which itself is acidic component has no therapeutic effect in the applied dose, or it does not adversely affect the efficiency of the active components is NTA. These acid additive salts are pharmaceutically acceptable acid additive salts. The reason why the acid additive salts that are pharmaceutically acceptable acid additive salts, but relate to the present invention, is that if necessary, they can be useful in the purification and selection of the desired connection.

Among the salts formed with bases, especially important are the salts formed with alkali metals such as sodium, potassium, alkaline earth metals, e.g. calcium and magnesium, as well as with ammonia or organic amines. The last reason may have additional substituents, for example, hydroxy - or amino groups, which can affect, for example, solubility and handling product.

In accordance with the invention the compounds of formula (I) are obtained by the formation of amide bond between the carboxylic acid of formula (II)

where the values of R1, R2, R3, R4X and Y are as described above for the compounds of formula (I) and an amine of formula (III)

where the values of R5and R6are as described above for the compounds of formula (I), and then the obtained amide carboxylic acid derivative of the formula (I) where mn is ing R 1, R2, R3, R4, R5, R6X and Y are as described above for the compounds of formula (I) is optionally transferred to another compound of formula (I) by introducing new substituents and/or modifying or removing the existing deputies, and/or salt formation and/or release of compounds from salts, and/or the resulting racemates liquor isomers using optically active acids or bases by known methods.

The amide bond formation is preferably carried out by obtaining the active carboxylic acid derivative of the formula (II), with its subsequent interaction with the amine of formula (III), preferably in the presence of a base.

In a solution of carboxylic acid is transferred to active derivative in situ during the formation of amide linkages in a suitable solvent (e.g. dimethylformamide, acetonitrile, chlorinated hydrocarbons or hydrocarbons). Active derivatives may be an acid anhydrides (for example, derived from a carboxylic acid with thionyl chloride), mixed anhydrides (e.g., derived from carboxylic acids with isobutylacetate in the presence of a base, e.g. triethylamine), active esters (such as those derived from carboxylic acids with hydroxybenzotriazole and dicyclohexylcarbodiimide or O-benzotriazol-1-yl-N,N',N'-tetramethylethylenediamine (HBTU) in the presence of a base, for example, triethylamine). Active derivatives get at a temperature between room temperature and 0°C. To the resulting solution or suspension is added the appropriate amine of formula (III) in the form of a base or as a salt formed with an inorganic acid, so that the base, such as triethylamine, necessary to highlight the amine is added to the reaction mixture separately. The condensation reaction monitor thin-layer chromatography. The necessary reaction time is between 6 and 20 hours Processing the reaction mixture is carried out in various ways.

When the reaction mixture is a suspension, the precipitate is filtered off and recrystallized from a suitable solvent to obtain pure product. If crystallization does not clean the product, then cleaning it, you can then apply column chromatography. Column chromatography is carried out either in normal phase using kieselgel 60 as adsorbent and in different solvent system, for example, toluene/methanol, chloroform/methanol or toluene/acetone as eluents, or reversed phase, using fillers of type Prep-Pak-500/C18 (manufactured by Waters Associates) and a mixture of acetonitrile/water/triperoxonane acid as eluent. If the reaction mixture at the end of the acylation reaction is a solution, its focus and stop the current crystallized or purified by chromatography on a column as explained above. The product structure was determined by IR, NMR and mass spectrometry.

Alternatively, the reaction mixture can be purified using column chromatography without concentration at the end of the reaction. The fractions containing the desired compound is concentrated and the residues dissolved in dimethyl sulfoxide and structure, purity, as well as the concentration of the product was determined by HPLC/MS (column chromatography, high pressure, with subsequent mass spectrometry).

The obtained amide derivatives of carboxylic acids of the formula (I) regardless of the method of receipt - if necessary, can be converted into another compound of formula (I) introduction of other substituents and/or modifying and/or removing existing substituents and/or by formation of salts with acids and/or allocation amide carboxylic acid derivative of the formula (I) from the obtained acid additive salts by treatment with a base, and/or free amide carboxylic acid derivative of the formula (I) can be converted into a salt by treatment with a base.

Carboxylic acids of formula (II) and primary or secondary amines of the formula (III) are either commercially available or can be obtained by known methods. Synthesis of some commercially available carboxylic acids of the formula (II) described in the examples Following these ways, can also be obtained with other commercially available carboxylic acids of the formula (II).

Compounds according to the invention, as well as their pharmaceutically acceptable salts can be used alone or in the form of pharmaceutical compositions. These compositions (drug) can be in solid, liquid or semi-liquid form and can be added pharmaceutical adjuvant and excipients, which are widely known in practice, such as carriers, fillers, diluents, stabilizers, moisturizers or emulsifying agents, substances affecting the pH value and osmotic pressure, fragrances or flavorings and additives, such as leavening agents or fillers.

The dose required for therapeutic action, may vary within wide limits and corresponds to the individual requirements in each particular case, depending on the stage of the disease, condition and body weight in treatment of the patient, and the patient's sensitivity to the active ingredient, route of administration and number of treatments per day. Accurate used dose of the active ingredient can be safely determined by the attending physician on the basis of knowledge of the prior art, and in treatment of the patient.

Pharmaceutical compositions containing Akti is hydrated ingredient in accordance with the present invention, usually contain from 0.01 to 100 mg of active ingredient in the same dosage unit. Of course, it is possible that the amount of the active ingredient in some tracks is more or less the boundaries defined above.

Solid forms of pharmaceutical compositions can be, for example, tablets, coated tablets, capsules, pills or liofilizovannye powders in capsules, suitable for injection. Liquid compositions are injectable and infusion of the composition, liquid medicines, sealed and liquid drops. Semi-liquid compositions can be ointments, balms, creams, shake medicines and suppositories.

For a simple introduction, it is desirable that the pharmaceutical compositions included a dosage unit containing a quantity of the active ingredient, which should be entered only once or a few times or a half, a third or fourth part of them. Such dosage units are, for example, tablets that can be separated by grooves, separating half or a quarter of a tablet for the exact introduction of the necessary amount of the active ingredient.

Tablets can be coated, soluble in acid, to ensure the release of the content of the active ingredient after passing through the stomach. Such tablets are coated in enteroscope Inoi shell. This may also be achieved by encapsulation of the active ingredient.

Pharmaceutical compositions for oral administration can contain, for example, lactose or starch as fillers, carboxymethylcellulose sodium, methylcellulose, polyvinylpyrrolidine or starch paste as binders or granulating agents. Add potato starch or microcrystalline cellulose as a loosening agent, and can also be used ultramylonite or formaldehyde casein. As anti-adhesive means and lubricants can be used talc, colloidal silicic acid, stearin, calcium stearate or magnesium.

The tablet can be obtained, for example, wet granulation followed by compression. Mixed active ingredients and excipients, and optionally part of the loosening agents granularit in aqueous, alcoholic or aqueous-alcoholic solution of a binder with suitable equipment, then the granulate is dried. To the dry granulate add other loosening agents, lubricants and release agents, and the mixture is pressed into a tablet. In this case, the tablets are manufactured with grooves dividing the tablet in half, for each injection.

Tablets can be manufactured presso what W directly from a mixture of the active ingredient and the desired excipients. If necessary, the tablets can be coated with a layer of additives, is widely known in the pharmaceutical practice, such as stabilizers, fragrances, dyes, such as sugar, cellulose derivatives (methyl - or ethylcellulose, carboxymethylcellulose sodium, etc.), polyvinylpyrrolidone, calcium phosphate, calcium carbonate, dyes, food, tinctures, flavors, pigments based on iron oxide, etc. In the case of capsules, the mixture of active ingredient and excipients are placed in capsules.

Liquid oral compositions, such as suspensions, syrups, elixirs, can be made with water, glycols, oils, alcohols, dyes and perfumes.

For rectal administration of composition is in suppositories or enemas. Suppositories in addition to the active ingredient may contain a carrier, the so-called presupposition on the basis of pork fat. Carriers can be vegetable oils, such as hydrogenated vegetable oils, triglycerides of C12-C18fatty acids (preferably the media, with the brand name Witepsol). The active ingredient is homogeneous mixed with molten presupposition on the basis of pork fat and form suppositories.

For parenteral administration, the composition is in the form of injection solution. To receive injections rest who R active ingredients are dissolved in distilled water and/or various organic solvents, such as glycol ethers, in this case, in the presence of solvents, for example, polyoxyethylenesorbitan-monolaurate-monooleate or monostearate (Tween 20, Tween 60, Tween 80). The injection solution may also contain various excipients, such as preservatives, for example, tetraacetylethylenediamine, as well as agents that support the value of pH, and buffers, and in this case local anaesthetic agent, such as lidocaine. Injecting a solution containing the active ingredient according to the invention, is filtered prior to its insertion into ampoules and sterilized after application.

If the active ingredient is hygroscopic, it can then be stabilized by lyophilization.

Close structural analogues amide derivatives of carboxylic acids of the formula (I) are known from the prior art.

Substituted derivatives of indole-2-incorporeality similar to the compounds according to the invention described in WO 9618628 and two publications [J. Med. Chem.,39, 3769 (1996)and J. Med. Chem.,42, 4140 (1999)]. These compounds with inhibitory activity of reverse transcriptase can be used to treat patients with AIDS.

Amides indole-2-carboxylic acid are also known [Bioorg. Med. Chem. Letters,10, 483. (2000)], inhibit RRc-srctyrosinekinase, and therefore they can be used to treat patients suffering from the PMC is logical diseases. These publications do not describe the antagonistic action at the NMDA receptor.

Derivative benzofuran-2-yl-piperidine described in WO 2000012074. These compounds possess inhibitory effect on R-kinase and, therefore, can be used for the treatment of infectious diseases caused by gram-negative bacteria, as well as patients with respiratory painful syndrome.

Derived methanone described in Protein Sci,6 (7), 1412 (1997), an inhibitor of thrombin. These publications do not describe the antagonistic action at the NMDA receptor.

Unexpectedly, it was found that in contrast to the known compounds structurally similar compounds which are known to possess only any abscopal action on the enzyme - new amide derivatives of carboxylic acids of the formula (I) of the present invention are highly effective and selective antagonists of NMDA (N-methyl-D-aspartate) receptors, and moreover, most of the compounds are selective antagonists of the NR2B subtype of NMDA receptor. This selectivity is particularly important for reducing the undesirable side effects of the compounds.

Antagonists of the NMDA receptor can be used in many diseases, which are accompanied by excess release of glutamate, the main excitatory, neoperene the Chica in the Central nervous system. Overactivate NMDA receptors by glutamate may lead to accumulation of calcium in the cells. This may start a cascade of intracellular processes that can modify cellular function and even lead to neuronal death [TINS, 10, 299-302 (1987)].

Recognition of patterns of NMDA-receptor function and pharmacology cause recent advances in molecular biology. NMDA receptors are heteromera complexes, built at least one NR1 subunit and at least one of the four NR2-subunits (NR2A-D). As the spatial structure of CNS, and pharmacological sensitivity of NMDA receptors built from different NR2-subunits are different. Of particular interest is the NR2B-subunit is restricted designs (the highest density is observed in prednaskova and mostly gelatinases matter of the spinal ligaments). Compounds selective for this subtype, known [Curr. Pharm. Des.5, 381-404 (1999)] and, as proven, are effective in animal models of paralysis [Stroke28, 2244-2251 (1997)], traumatic brain injury [Brain Res.792, 291-298 (1998)], Parkinson's [Exp. Neurol.163, 239-243 (2000)], neuropathic and inflammatory pain [Neuropharmacology38, 611-623 (1999)]. Subtype selective antagonists of NMDA receptors, as expected, shows little or unfavorable for the full effects, caused by the action of non-selective antagonists of the NMDA receptor at the binding site of glutamate or in the aisle of the tunnel.

Diseases that are known to be associated with NMDA antagonists [Drug News Perspect 11, 523-569 (1998) and WO 00/00197], are cerebral ischaemia of any origin (e.g., shock, thermal effects), chronic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, human immunodeficiency virus (HIV)associated with neuron damage, traumatic brain injury or spinal ligaments, pain (such as post-traumatic or post-operative and chronic pain, such as neuropathic pain or pain associated with cancer. Antagonists of the NMDA receptor can also be used to treat epilepsy, anxiety, depression, migraine, psychosis, muscle spasm, multi-infarct dementia and dementia of other origin, hypoglycemia, degenerative diseases of the retina (e.g., CMV retinitis), asthma, tinnitus, hearing loss, caused by aminoglycoside antibiotic. NMDA-antagonist can be used to reduce the tolerance and/or dependence to opioid treatment of pain and for the treatment of dependence syndrome, for example, from alcohol, opioids and cocaine.

Because of the claimed compounds have videocase the major biological activity, objects of the present invention are a method for the treatment of amide derivatives of carboxylic acids of the formula (I) or their salts, which involves the administration to a mammal being treated, including man, an effective amount/amounts of compounds of formula (I) of the present invention alone or in the form of medicines.

It is known that during postnatal development of the subunit composition of neuronal NMDA receptor changes. Such changes are detected in cell cultures of neurons [Eur. J. Neurosci.10, 1704-1715 (1998)]. In accordance with literature data and own immuno-cytochemical studies of neural cells, culturename for 4-7 days in vitro, the authors of the present invention, is expressed predominantly NR2B-subunit together with NR1-subunit. Such a functional test on NMDA antagonism in these cells mainly reflects the effect of NR2B subunit containing receptors. Since NMDA receptors are known to be permeable to calcium ions in the excitation process, the authors have described the activation of the NMDA receptor by measuring the increase in concentration of calcium inside the cells after addition to the cells of the agonist (NMDA).

The determination of the activity of the NMDA antagonist in vitro by measuring the concentration of calcium inside the cells fluorimetric cell count

Measurement of calcium inside the cells spend in the primary neocortical cultures of cells derived from embryos Charles River rats at the age of 17 days (for a more detailed description of obtaining neocortical cell culture see Johnson, M.I.; Bunge, R.P. (1992): Primary cell cultures of peripheral and central neurons and glia. In: Protocols for Neural Cell Culture, eds: Fedoroff, S.; Richardson, A., The Humana Press Inc., 13-38.) After isolation, the cells are placed in a standard 96-cell microplate and culture support in an atmosphere of 95% air-5% CO2at 37°With prior measurements of calcium.

Culture is used for measurement of calcium inside the cells in 4 to 7 days in vitro. Before measurement in cells injected with fluorescent CA2+- sensitive dye, Fluo-4/AM (2-2 .5 μm). To stop the introduction cells are washed twice with a solution used for measurement (140 mm NaCl, 5 mm KCl, 2 mm CaCl2, 5 mm HEPES, 5 mm HEPES-Na, 20 mm glucose, 10 μm glycine, pH 7.4). After washing, cells are added test compound in the above solution (90 μl/cell). Measurement of calcium inside the cells spend fluorimetric cell counter: increase in Fluo-4 fluorescence and, therefore, calcium inside the cell causes the introduction of 40 μm NMDA. Inhibiting activity of the test compounds is evaluated by measuring the decrease in calcium levels in the presence of various concentrations of compounds. After you edit the rhenium use the standard calibration procedure with minor changes to convert the fluorescence data in the concentrations of calcium [Meth. Cell. Biol.40, 155-181 (1994)].

Curves dose - response and IC50-values are estimated using data obtained from at least three independent experiments. Inhibitory activity of compounds at the point of unit concentration is expressed as the inhibition percentage of the NMDA response. Sigmoidal curves the concentration - inhibition correspond to and define the IC50of magnitude as the concentration that takes half the maximum inhibition caused by the connection.

Table 1 presents the IC50values for most effective compounds of this invention, as measured in this test (columns 1-2), together with the most effective of the investigated compounds from the prior art (column 3-4).

The compounds of the prior art are the following:

With 101244: 1-[2-(4-hydroxyphenoxy)ethyl]-4-hydroxy-4-(4-methylbenzyl) piperidine

EMD 95885: 6-[3-(4-terbisil)piperidine-1-yl]propionyl]-2,3-dihydroisoxazole-2-he

CP-101,606: (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidine-1-yl)-1-propanol

Co-111103: 1-[2-(4-hydroxyphenoxy)ethyl]-4-(4-terbisil)piperidine

Ro 25.6981: R-(R*,S*)-1-(4-hydroxyphenyl)-2-methyl-3-[4-(phenylmethyl)piperidine-1-yl]-1-propanol.

As table 1 shows, most of the compounds of the present invention, subjected to the study, preview.tpo activity of compounds known from the prior art.

Test subunit selectivity for cells expressing recombinant NMDA receptors in rats

To confirm the selectivity of NR2B-subunit compounds using cells, transfetsirovannyh with DNA of the rat NR1a and NR2A or NR2B-subunit. Genes cloned in accordance with known sequences [gi508809 (NRIa rats), gi205738 (rat NR2B), gi2905805 (rat NR2A)]is inserted into the induced expression vectors mammal carrying different resistance genes (hygromycin if NRIa or neomycin in the case of NO2-subunits). Construction of vectors injected into NC cells using cationic lipid method of transfection. The expression of a protein called with 3 μm of Murieron A. Cell support in the presence of a 365 µm ketamine within 48-72 hours in an atmosphere of 95% air-5% CO2at 37°With experiment.

Evaluation of NMDA-antagonistic activity in cells transfected NR1a/NR2B-subunit fluorimetric method

For the introduction of cell clones stably expressing NR1a/NR2B receptors, transfetsirovannyh cells treated with selected antibiotics for 4 weeks, then grow resistant clones. The expression of NR2B protein-subunit is carried out using a flow immunocytochemical method based cytometry. A further positive clones t is strout on functional activity in experiments with fixed division. The best clone, producing the largest ion flow caused by NMDA, used for testing NMDA antagonism by measuring NMDA receptors, causing increased concentrations of calcium in the cytosol. Induction of protein expression and cultivation of the cells were the same as described above.

Cells placed in a standard 96-cell microplate. To measure NMDA antagonism using fluorometric tests using a counter on the substrate. Essentially the method is the same as the method described above for testing of primary cultures of cortical neurons of rats.

Evaluation of NMDA-antagonistic activity in cells transfected NR1a/NR2A-subunit, the method with a fixed division

In experiments with a fixed spot using cells, quickly expressing NR1a/NR2A receptors and grown under the cover glass. Whole cell recording device with a fixed division shall be made in accordance with standard methods. Cell culture is constantly washed with extracellular solution (140 mm NaCl, 5 mm KCl, 5 mm Hepes, 5 mm Na-Hepes, 2 mm CaCl2, 20 mm glucose, 10 μm glycine, pH 7.35) at room temperature. Separating the pipette resistance between 3 and 6 M Ω fill extracellular solution (140 mm CsCl, 11 mm EGTA and 10 mm Hepes, pH 7.3). Write internal flow caused by 100 μm NMDA, from tile is to at a fixed voltage of -70 mV. The connection is passed through multibarreled eject the device, which is controlled by the solenoid valves. First of NMDA re-enter to stabilize the response, then injected test the connection. The degree of inhibition is expressed as a percentage is calculated from the peak flows caused by NMDA in the presence and absence of test compounds. The ratio of selectivity (NR2B/NR2A) calculated as the ratio of the tested doses of NR1/2A transfetsirovannyh cells and IR50the magnitude of NMDA antagonism on NR1/NR2B expressed cells. The results are presented in Table 2.

Table 2

Evaluation of selectivity for NR2B from NR2A subunit containing receptors
ConnectionNR1/NR2B*NR1/NR2A** % inhibition of NMDA CA+- responseSelectivity
X50
[µm]15-mm
45700014610.01514.9>1000
45700022600.0303.3>500
CP-101,6060.033-8.8>1200

*: Data NEC cells, stably expressing NR1a/NR2B subunit, measurement of intracellular calcium concentration schetchikova fluorimeter on the substrate. Presents the values of 3 experiments.

**: The results of the experiments with a fixed division of NR1a/NR2A quickly transfairusa SOME cells. Presents the tested concentration. The values 3, 6, 2 experiments for 4570001461, 45070002260 and CP-101,606, respectively.

Selectivity: the selectivity ratio (NR2B/NR2A), calculated as the ratio of the tested concentrations of NR1/2A transfetsirovannyh cells and IR50the magnitude of NR1/NR2B expressing cells.

In accordance with the results presented in Table 2, the compounds 4570001461 and 4570002260, as well as CP-101,606, are highly selective in respect of NR2B subunit containing NMDA receptors. The synthesis of compounds and pharmaceutical compositions in accordance with the invention presents the following non-limiting examples. Code numbers connections that are listed in the biological tests listed after the names of the compounds obtained in the Examples.

Example 1

6-(4-Benzylpiperidine-1-carbonyl-3H-furo[3',2':4,5]benzo[1,2-d]oxazol-2-he (4514255)

a) Ethyl 3H-furo[2,3-f]benzoxazol-2-one-6-carboxylate

A mixture of 0.9 g (4.2 mmol) of ethyl 5-hydroxy-6-aminobenzophenone-2-carboxylate Helv. Chim. Acta77, 100 (1994)], 60 ml of tetrahydrofuran (THF, 3.1 ml of 20% aqueous solution of phosgene in toluene and 2.0 ml of triethylamine was stirred at room temperature for one hour. The tetrahydrofuran is distilled off in vacuo, to the residue water is added and the product extracted with ethyl acetate. The combined organic layers washed with 5% aqueous sodium hydrogen carbonate solution, water, 1 N hydrochloric acid and again with water, dried over sodium sulfate and concentrated, giving 1.0 g (96%) of the titled compound as oil.

b) 3H-Furo[2,3-f]benzoxazol-2-one-6-carboxylic acid

Stir a mixture of 1.0 g (4 mmol) of ethyl 3H-furo[2,3-f]benzoxazol-2-one-6-carboxylate, 100 ml of ethanol and 0.5 g of potassium hydroxide are heated at the boil under reflux for one hour. The mixture is concentrated and the residue is dissolved in water and acidified with 20% aqueous solution of sulfuric acid. The precipitated crystals are filtered and washed with water, which gives 0.84 g (95%) of the named compound. TPL:190-192°With (water).

c) 6-(4-Benzylpiperidine-1-carbonyl)-3H-furo[3',2':4,5]benzo[1,2-d]oxazol-2-he

A mixture of 0.42 g (1.9 mmol) of 3H-furo[2,3-f]benzoxazol-2-one-6-carboxylic acid, 0.3 ml (2.1 mmol) of triethylamine and 0.35 ml (2.0 mmol) of 4-benzylpiperidine, 0.76 g (2.0 mmol) of HBTU (Advanced Chem. Tech.) and 10 ml of dimethylformamide is stirred at room temperature for 6 hours. The reaction mixture was concentrated and the residue purified is by using a chromatographic column, using kieselgel 60 as adsorbent (Merck) and a mixture of toluene: acetone = 2:1 as eluent, the product is then crystallized from diethyl ether, giving 0.39 g (54%) of the named compound. TPL:205-210° (diethyl ether).

Example 2

6-(4-Benzyloxypyridine-1-carbonyl)-3H-furo[3',2':4,5]benzo[1,2-d]oxazol-2-he (4514254)

The named compound is obtained from 3H-furo[2,3-f]benzoxazol-2-one-6-carboxylic acid and 4-benzyloxypyridine in accordance with the method described in example 1/s TPL: 217-219° (diethyl ether).

Example 3

1-(4-Benzylpiperidine-1-yl)-1-(1,6-dihydro-1,6-diaza-AZ-indocin-2-yl)methanon (4514305)

a) Methyl (2)-2-azido-3-(1H-indol-5-yl)acrylate

In a nitrogen atmosphere to a solution of sodium methoxide (obtained from 15 ml of methanol and 0.66 g (29 mmol) of sodium) is added dropwise at a temperature of 0°With a mixture of 1.02 g (7 mmol) of indole-5-carbaldehyde [Helv. Chim. Acta, 1616 (1968)], 3.34 g (29 mmol) of the methyl azido-acetate and 7 ml of methanol and the thus obtained mixture was stirred at the same temperature for 5 hours. Then the reaction mixture is diluted with 50 ml of water and extracted with three times 50 ml of chloroform. The combined organic layers washed with 20 ml of water, filtered through a separating phase porous paper and concentrate, which gives 1.3 g (77%) of the named compound. TPL: 130-133°With (chloroform).

b) Methyl ester 1.6-dihydro-1,6-diaza-AZ-and is dozen-2-carboxylic acid

To the boiling solution of 36 ml of xylene add small doses of 1.09 g (4.5 mmol) of methyl ether (2)-2-azido-3-(1H-indol-5-yl)acrylic acid. The reaction mixture is heated at boiling under reflux until the evolution of nitrogen, then concentrated and the residue is crystallized with hexane, the product is filtered and washed with hexane, giving 0.6 g (62%) of the named compound. TPL: 183-184°C (hexane).

(C) 1,6-Dihydro-1,6-diaza-AZ-indocin-2-carboxylic acid

A mixture of 0.53 g (2.5 mmol) of methyl ether of 1,6-dihydro-1,6-diaza-AZ-indocin-2-carboxylic acid, 0.36 g (2.5 mmol) of trimethylsilanol potassium (Aldrich) and 6.0 ml of tetrahydrofuran is heated at the boil under reflux for one hour, then add another 0.18 g (1.25 mmol) of trimethylsilanol potassium and after 5 hours of heating at boiling under reflux, the reaction mixture was concentrated. The residue is stirred with 20 ml of water, the undissolved residue is filtered off, the filtrate is added 0.32 ml of hydrochloric acid, the precipitated crude product is filtered and purified by chromatographic column using kizilyalli 60 (Merck) as adsorbent and a mixture of chloroform: methanol = 9:1 as eluent. The product is crystallized from diethyl ether, giving 0.22 g (44%) of the named compound. TPL: 248-250° (diethyl ether).

d) 1-(4-Benzylpiperidine-1-yl)-1-(1,dihydro-1,6-diaza-AZ-indocin-2-yl)methanon

The named compound is obtained from 1,6-dihydro-1,6-diaza-AZ-indocin-2-carboxylic acid and 4-benzylpiperidine in accordance with the method described in example 1/s TPL:186-188° (diethyl ether).

Example 4

(4-Benzylpiperidine-1-yl)-(2-propyl-8H-oxazol[5,4-g]indol-7-yl)methanon (4570001079)

a) 1-(4-Benzylpiperidine-1-yl)-1-(6-hydroxy-1H-indol-2-yl)methanon

A mixture of 5.0 g (28.2 mmol) of 6-hydroxyindole-2-carboxylic acid [J. Chem. Soc. 1605-1608 (1948)], 4.4 ml (of 31.6 mmol) of triethylamine, 5.0 g (28.5 mmol) of 4-benzylpiperidine, 12.0 g (of 31.6 mmol) HBTU (Advanced Chem. Tech.) and 50 ml of dimethylformamide is stirred at room temperature for 6 hours. Precipitated precipitated product is filtered off and recrystallized from ethanol, giving 6.75 g (71%) of the named compound. TPL: 214-215°C (ethanol).

b) (4-Benzylpiperidine-1-yl)-(2-propyl-8H-oxazol[5,4-g]indol-7-yl)methanon

In an argon atmosphere to a solution of 0.5 g (1.49 mmol) of 1-(4-benzylpiperidine-1-yl)-1-(6-hydroxy-1H-indol-2-yl)methanone and 0.14 g (0.2 mmol) of n-butylamine in 100 ml of dimethyl ether of ethylene glycol added portions dropwise at a temperature of 0°With 10 g (115 mmol) of manganese dioxide. After stirring for one hour the reaction mixture is filtered, the filtrate concentrated and the residue purified by chromatographic column using kieselgel 60 as adsorbent (Merck) and a mixture of hexane: ethyl acetate = 2:1 - as the eluent, that gives 0.1 g (17.3%) of the named compound. TPL: 195-196°With (hexane - ethyl acetate).

Example 5

6-(4-Benzylpiperidine-1-carbonyl)-1,5-dihydro-oxazol[4,5-f]indol-2-he (4570001461)

a) Methyl ether (2)-2-azido-3-(4-benzyloxy-3-nitrophenyl)acrylic acid

In an argon atmosphere to a solution of sodium methoxide (obtained from 2.5 g (108.7 mmol) of sodium and 70 ml of methanol) is added at a temperature of 0°With a mixture of 6.1 g (23.7 mmol) of 4-benzyloxy-3-nitrobenzaldehyde and 11.2 g (97.3 mmol) of methylacetoacetate in 100 ml of methanol. The mixture was stirred at 0°C for 5 hours, then diluted with 350 ml of water, the precipitated crystals are filtered, washed with water and dried, giving 4.93 g (59%) of the named compound. TPL: 95-96°With (water).

b) Methyl ester of 6-benzyloxy-5-nitro-indole-2-carboxylic acid

To a mixed solution of 200 ml of boiling xylene 4.93 g(13.9 mmol) is added in small doses methyl ether (2)-2-azido-3-(4-benzyloxy-3-nitrophenyl)acrylic acid. After complete addition, the reaction mixture is heated at boiling under reflux until the formation of gas (about 0.5 hours), then cooled to room temperature, precipitated precipitated product is filtered off and washed with n-hexane, giving 0.67 g (15%) of the named compound. TPL: 184-187° (xylene).

c) Methyl ester of 5-amino-6-hydroxyindole-2-carboxylic what sloty

A mixture of 0.67 g (2.0 mmol) of methyl ester of 6-benzyloxy-5-nitro-indole-2-carboxylic acid, 60 ml of tetrahydrofuran hydronaut for 5 hours using 0.1 g of 10% Pd/C. the Catalyst is filtered off and the filtrate containing the named compound is used directly in the next step.

d) Methyl ester of 2-oxo-1,5-dihydro-2H-oxazol[4,5-f]indole-6-carboxylic acid

The named compound is obtained from the methyl ester of 5-amino-6-hydroxyindole-2-carboxylic acid in accordance with the method described in example I/a. TPL: 267-277°With (water).

e) 2-Oxo-1,5-dihydro-2H-oxazol[4,5-f]indole-6-carboxylic acid

The named compound is obtained from the methyl ester of 2-oxo-1,5-dihydro-2H-oxazol[4,5-f]indole-6-carboxylic acid in accordance with the method described in example 1/b. TPL: 288-290°With (water).

g) 6-(4-Benzylpiperidine-1-carbonyl)-1,5-dihydrooxazolo[4,5-f]indol-2-he

The named compound is obtained from 2-oxo-1,5-dihydro-2H-oxazol[4,5-f]indole-6-carboxylic acid and 4-benzylpiperidine in accordance with the method described in example 1/s TPL: 270-271° (diethyl ether).

Example 6

6-(4-Benzyloxypyridine-1-carbonyl)-1,5-dihydrooxazolo[4,5-f]indol-2-he (4570001462)

The named compound is obtained from 2-oxo-1,5-dihydro-2H-oxazol[4,5-f]indole-6-carboxylic acid and 4-benzyloxypyridine [hedron 54, 13981, (1998)] in accordance with the method described in the example 1/C. TPL: 258-261° (diethyl ether).

Example 7

6-[4-(4-Formanilide-1-carbonyl-1,5-dihydrooxazolo[4,5-a]indol-2-he (4570001484)

The named compound is obtained from 2-oxo-1,5-dihydro-2H-oxazol[4,5-f]indole-6-carboxylic acid and 4-(4-terbisil)piperidine [J. Med. Chem., 35, 4903, (1992)] in accordance with the method described in example 1/s TPL: 244-247° (diethyl ether).

Example 8

[4-(4-Terbisil)piperidine-1-yl]-(1,6-dihydropyrrolo[2,3-g]indazol-7-yl)-methanon (the other tautomeric form of the compound is [4-(4-terbisil)piperidine-1-yl]-(36-dihydropyrrolo[2,3-g]indazol-7-yl)methanon) (4570001661)

a) Ethyl ester of 2-[(1H-indazol-6-yl)-hydrazono]-propionic acid (the other tautomeric form of the compound - ethyl ester 2-[(3H-indazol-6-yl)-hydrazono]-propionic acid)

To a stirred mixture of 6.66 g (50 mmol) of 6-aminoindazole, 40 ml of water and 25 ml of concentrated hydrochloric acid is added dropwise at a temperature of 0°With 3.5 g of sodium nitrite in 10 ml of water and stirring is continued at the same temperature for 0.5 hours. Then the thus obtained solution is added to the next mix mixture: 86 ml of water, 15 g of potassium hydroxide, 15 g of sodium acetate, 60 ml of ethanol and 8 ml of ethyl ether 2-methylacetoacetate acid (purity 90%). After the addition the reaction mixture is stirred at a temperature of 0°within an hour, fell in OS the iPod, the product is filtered, washed with water and dried, giving 8.16 g (66%) of the named compound. TPL: 210-211°C (ethanol).

b) Ethyl ester of 1,6-dihydro-pyrrol[2.3-g]indazol-7-carboxylic acid (the other tautomeric form of the compound ethyl ester 3.6-dihydropyrrolo[2,3-g]indazol-7-carboxylic acid)

A mixture of 4.0 g (16.2 mmol) of the ethyl ester of 2-[(1H-indazol-6-yl)-hydrazono]-propionic acid and 20 g of polyphosphoric acid are slowly heated to 120°C and maintained at this temperature for 0.5 hours. Then the reaction mixture is cooled to room temperature, add 30 ml of water and 15 ml of concentrated hydrochloric acid. Thus the resulting mixture was extracted with ethyl acetate, dried over sodium sulfate and concentrated, giving 1.6 g (43%) of the named compound. TPL: 120-121°With (ethyl acetate).

(C) 1,6-Dihydropyrrolo[2,3-g]indazol-7-carboxylic acid (the other tautomeric form of the compound is 3,6-dihydropyrrolo[2,3-g]indazol-7-carboxylic acid)

The named compound is obtained from ethyl ether 1,6-dihydropyrrolo[2,3-g]indazol-7-carboxylic acid in accordance with the method described in example 1/b. TPL: 270-275°With (water).

d) [4-(4-Terbisil)piperidine-1-yl)-(1,6-dihydropyrrolo[2,3-g]indazol-7-yl)-methanon (the other tautomeric form of the compound is [4-(4-terbisil)piperidine-1-yl)-(3,6-dihydropyrrolo[2,3-g]indazol-7-yl)-methanon)

The named compound is obtained from 1,6-di is incropera[2,3-g]indazol-7-carboxylic acid and 4-(4-terbisil)piperidine according to method described in example 1/s TPL: 162 to 165° (diethyl ether).

Example 9

(4-Benzylpiperidine-1-yl)-(1,6-dihydropyrrolo[2.3-g]indazol-7-yl)-methanon (the other tautomeric form of the compound - (4-benzylpiperidine-1-yl)-(3,6-dihydropyrrolo[2.3-g]indazol-7-yl)-methanon) (4570001662)

The named compound is obtained from 1,6-dihydropyrrolo[2,3-g]indazol-7-carboxylic acid and 4-benzylpiperidine in accordance with the method described in example 1/s TPL: 209-210° (diethyl ether).

Example 10

[4-(4-Terbisil)piperidine-1-yl]-(3.6-dihydroimidazo[4,5-f]indol-7-yl)methanon (the other tautomeric form of the compound is [4-(4-terbisil)piperidine-1-yl]-(1,6-dihydroimidazo[4,5-f]indol-7-yl)methanon) (4570001688)

a) Ethyl ester of 2-[(1H-benzimidazole-5-yl)-hydrazono]-propionic acid (the other tautomeric form of the compound - ethyl ester 2-[(3H-benzimidazole-5-yl)-hydrazono]-propionic acid)

The named compound is obtained from 5-amino-benzimidazole [Helv. China. Acta, 32, 135 (1949)] in accordance with the method described in Example 8/A. TPL: 121-1276C. (water).

b) Ethyl ester of 3,6-dihydro-imidazo[4,5-e]indole-7-carboxylic acid (the other tautomeric form of the compound is ethyl ester of 1,6-dihydroimidazo[4,5-e]indole-7-carboxylic acid)

The named compound is obtained from the ethyl ester of 2-[(1H-benzimidazole-5-yl)-hydrazono]-propionic acid in accordance with the method described in note the re 8/b. TPL: foam

C) 3,6-Dihydroimidazo[4,5-e]indole-7-carboxylic acid (the other tautomeric form of the compound is 1,6-dihydroimidazo[4,5-e]indole-7-carboxylic acid)

The named compound is obtained from the ethyl ester of 3,6-dihydroimidazo[4,5-e]indole-7-carboxylic acid in accordance with the method described in example 1/b. TPL: 185-190°With (water).

d) [4-(4-Terbisil)piperidine-1-yl]-(3,6-dihydroimidazo[4,5-f]indol-7-yl)methanon (the other tautomeric form of the compound is [4-(4-terbisil)piperidine-1-yl-(1,6-dihydro-imidazo[4,5-f]indol-7-yl)methanon]

The named compound is obtained from 3,6-dihydro-imidazo[4,5-e]indole-7-carboxylic acid and 4-(4-terbisil)piperidine according to the method described in example 1/s TPL: 283-287° (diethyl ether).

Example 11

(4-Benzylpiperidine-1-yl)-(3,6-dihydropyrrolo[3,2-e]indazol-7-yl)methanon (the other tautomeric form of the compound - (4-benzylpiperidine-1-yl)-(1,6-dihydropyrrolo[3,2-e]indazol-7-yl)methanon) (4570001689)

a) Ethyl ester of 2-[(1H-indazol-5-yl)-hydrazono]-propionic acid (the other tautomeric form of the compound - ethyl ester 2-[(3H-indazol-5-yl)-hydrazono-1-propionic acid)

The named compound is obtained from 5-aminoindazole in accordance with the method described in example 8/A. TPL: 111-113°With (water).

b) Ethyl ester of 3,6-dihydropyrrolo[3,2-e]indazol-7-carboxylic acid (the other tautomeric form of the compounds is con - ethyl ester of 1,6-dihydropyrrolo[3,2-e]indazol-7-carboxylic acid)

The named compound is obtained from the ethyl ester of 2-[(1H-indazol-5-yl)-hydrazono]-propionic acid in accordance with the method described in example 8/b. TPL: 220-221°C (methanol).

(C) 3.6-Dihydropyrrolo[3,2-e]indazol-7-carboxylic acid (the other tautomeric form of the compound is 1,6-dihydropyrrolo[3,2-e]indazol-7-carboxylic acid)

The named compound is obtained from the ethyl ester of 3,6-dihydropyrrolo[3,2-e]indazol-7-carboxylic acid in accordance with the method described in example 1/b. TPL: 183-189°With (water).

d) (4-Benzylpiperidine-1-yl)-(3,6-dihydro-pyrrol[3,2-e]indazol-7-yl)methanon (the other tautomeric form of the compound - (4-benzylpiperidine-1-yl)-(1,6-dihydropyrrolo[3,2-e]indazol-7-yl)methanon)

The named compound is obtained from 3,6-dihydropyrrolo[3,2-e]indazol-7-carboxylic acid and 4-benzylpiperidine in accordance with the method described in example 1/s TPL: 205-207° (diethyl ether).

Example 12

[4-(4-Terbisil)piperidine-1-yl]-(3,6-dihydropyrrolo[3,2-e]indazol-7-yl)methanon (the other tautomeric form of the compound is [4-(4-terbisil)piperidine-1-yl]-(1,6-dihydropyrrolo [3,2-e]indazol-7-yl)methanon) (4570001690)

The named compound is obtained from 3,6-dihydro-pyrrol[3,2-e]indazol-7-carboxylic acid and 4-(4-terbisil)piperidine according to the method described in example 1/S. So what HP: 169-173° C (diethyl ether).

Example 13

(4-Benzylpiperidine-1-yl)-(3,6-dihydroimidazo[4,5-f]indol-7-yl)methanon (the other tautomeric form of the compound - (4-benzylpiperidine-1-yl)-(1,6-dihydroimidazo[4,5-f]indol-7-yl)methanon) (4570001779)

The named compound is obtained from 3,6-dihydro-imidazo[4,5-e]indole-7-carboxylic acid and 4-benzylpiperidine in accordance with the method described in example 1/s TPL: 256-257° (diethyl ether).

Example 14

7-(4-Benzylpiperidine-1-carbonyl)-1,6-dihydro-3-oxa-1,6,8-triaza-AZ-indocin-2-he other tautomeric form of the compound is 7-(4-benzylpiperidine-1-carbonyl)-1,8-dihydro-3-oxa-1,6,8-triaza-AZ-indocin-2-one) (4570001971)

a) N-Butyl-N'-(4-methoxy-2-nitrophenyl)-oxalate

To a suspension of 44.0 g (164 mmol) of ethyl ester of N-(4-methoxy-2-nitrophenyl)-assalamou acid [J. Med. Chem., 18, 926 (1975)] in 330 ml of toluene is added dropwise, keeping the temperature below 20°S, 16.8 ml (170 mmol) of n-butylamine, and the mixture is then stirred at room temperature overnight. The reaction mixture was concentrated and added dropwise to the residue 200 ml of diethyl ether. Thus the resulting suspension is filtered, washed with diethyl ether and dried, giving 45.3 g (93%) of the named compound. TPL: 127-128° (diethyl ether).

b) N-(2-Amino-4-methoxyphenyl)-N'-butyl-oxalate

A mixture of 27.0 g (91 mmol) of N-butyl-N'-(4-methoxy-2-nitrophenyl)-oxalated, 1200 ml metanoia 7.3 g of 10% Pd/C catalyst hydronaut for 3 hours. The catalyst is filtered off, washed with acetone, the filtrate is concentrated and the residue is treated with 100 ml of diethyl ether. The resulting product is filtered, washed with diethyl ether and dried, giving 21.8 g (90%) of the named compound. TPL: 180-181° (diethyl ether).

(C) Butylamide 6-methoxy-1H-benzimidazole-2-carboxylic acid (the other tautomeric form of the compound - butylamide 5-methoxy-1H-benzimidazole-2-carboxylic acid)

In nitrogen atmosphere 41.0 g (154 mmol) of N-(2-amino-4-methoxyphenyl)-N'-butylacrylamide heated to 240 C for 10 minutes. After cooling, the residue is treated with 300 ml of acetone, filtered and the filtrate concentrated. The thus obtained residue is crystallized from 150 ml of hexane, filtered and dried, giving 26.5 g (69.5%) of these compounds. TPL: 125-126°C (hexane).

d) 6-Hydroxy-1H-benzimidazole-2-carboxylic acid (the other tautomeric form of the compound is 5-hydroxy-1H-benzimidazole-2-carboxylic acid)

A solution of 26.0 g (105 mmol) of butylamine 6-methoxy-1H-benzimidazole-2-carboxylic acid in 780 ml of 48% HBR was stirred at 90°C for 12 hours, and then at 125°C for 12 hours. The reaction mixture is cooled, precipitated precipitated product is filtered off, washed with water and dried, which gives 14.4 g (76%) of the named compound. TPL: 206-207°With (water).

e) 6-Hydroxy-7-nitro-1-the-benzimidazole-2-carboxylic acid (the other tautomeric form of the compound - 5-hydroxy-4-nitro-1H-benzimidazole-2-carboxylic acid)

To a solution of 2.0 g (11.2 mmol) of 6-hydroxy-1-H-benzimidazole-2-carboxylic acid in 25 ml triperoxonane the acid is added at a temperature below 20°With 1.0 g (11.7 mmol) of sodium nitrate and the mixture is stirred at 20°C for 2 hours. The reaction mixture was poured into ice water, the precipitated precipitated product is filtered off, washed with water and dried, giving 1.7 g (68%) of the named compound. TPL: 218°With (water).

f) (4-Benzylpiperidine-1-yl)-(6-hydroxy-7-nitro-1H-benzimidazole-2-yl)methanon (the other tautomeric form of the compound - (4-benzylpiperidine-1-yl)-(5-hydroxy-4-nitro-1H-benzimidazole-2-yl)methanon)

The named compound is obtained from 6-hydroxy-7-nitro-1H-benzimidazole-2-carboxylic acid and 4-benzylpiperidine in accordance with the method described in example 1/s TPL: 102° (diethyl ether).

g) (7-Amino-6-hydroxy-1H-benzimidazole-2-yl)-(4-benzylpiperidine-1-yl)methanon (the other tautomeric form of the compound - (4-amino-5-hydroxy-1H-benzimidazole-2-yl)-(4-benzylpiperidine-1-yl)methanon

A mixture of 1.0 g of (4-benzylpiperidine-1-yl)-(6-hydroxy-7-nitro-1H-benzimidazole-2-yl)methanone, 30 ml of methanol hydronaut for 2 hours with 0.4 g 10% Pd/C catalyst. The catalyst is filtered off and the filtrate concentrated. The residue is treated with diethyl ether, the crystalline product is filtered off, raybaut diethyl ether and dried, that gives 0.5 g (54%) of the named compound. TPL: 108° (diethyl ether).

h) 7-(4-Benzylpiperidine-1-carbonyl)-1,6-dihydro-3-oxa-1,6,8-triaza-AZ-indocin-2-he (the other tautomeric form of the compound is 7-(4-benzylpiperidine-1-carbonyl)-1,8-dihydro-3-oxa-1,6,8-triaza-AZ-indocin-2-one)

To a solution of 0.45 g (1.28 mmol) of (7-amino-6-hydroxy-1H-benzimidazole-2-yl)-(4-benzylpiperidine-1-yl)methanone in 5 ml of tetrahydrofuran was added when the temperature of 20°With 0.2 g (1.37 mmol) of 1,1'-carbonyldiimidazole. The reaction mixture was stirred at room temperature for 2 hours, then concentrated. The residue is purified by chromatographic column using kieselgel 60 as adsorbent (Merck) and a mixture of toluene: methanol = 4:1 as eluent. The thus obtained product is crystallized from isopropanol, filtered and dried, giving 0.45 g (93.5%) of these compounds. TPL: >270°C (isopropanol).

Example 15

6-(4-Benzylpiperidine-1-carbonyl)for 3,5-dihydroimidazo[4',5';4,5]benzo[1,2-d]oxazol-2-he (the other tautomeric form of the compound is 6-(4-benzylpiperidine-1-carbonyl)was 3.7-dihydro-imidazo [4',5';4,5]benzo[1,2-d]oxazol-2-one) (4570001972)

a)6-Amino-5-nitro-3H-benzoxazol-2-he

To a solution of 2.0 g (13.3 mmol) 6-amino-3H-benzoxazol-2-[J. Chem. Soc., 321 (1938)] in 20 ml of triperoxonane acids are added at a temperature below 20°With 1.2 g (14.1 mmol) of sodium nitrate. The reaction mixture is stirred at room temperature overnight, then concentrate. The residue is purified by chromatographic column using kieselgel 60 as adsorbent (Merck) and a mixture of toluene: methanol = 4:1 as eluent, giving 2.50 g (96%) of the named compound. TPL: 198° (toluene - methanol).

b) Ethyl ester of (4-benzylpiperidine-1-yl)octoxynol acid

To a solution of 10 g (57 mmol) of 4-benzylpiperidine and 10 ml (57.4 mmol) of N-ethyl ester Diisopropylamine in 100 ml of dichloromethane is added dropwise at a temperature of 0°7.05 ml (63.1 mmol) of ETHYLACETYLENE, then the mixture is stirred at the same temperature for 30 minutes. The reaction mixture is diluted with water, separated, the organic layer is dried and concentrated, giving 15.5 g (99%) of the titled compound as oil.

c) (4-Benzylpiperidine-1-yl)Okrokana acid

A mixture of 15.5 g (56 mmol) of ethyl ether (4-benzylpiperidine-1-yl)octoxynol acid, 5 g (79.4 mmol) of potassium hydroxide and 250 ml of methanol was stirred at room temperature for 6 hours. Then the reaction mixture was concentrated, the residue is transferred into water, acidified with 1N hydrochloric acid, precipitated precipitated product is filtered off, washed with water and dried, giving 11.95 g (85%) of the named compound. TPL: 115°With (water).

d) (4-Benzylpiperidine-1-yl)oxoacetate

A mixture of 26.2 g (106 mmol) (4-benzylpiperidine-1-yl)octoxynol acid and 50 ml tinerilor is Yes heated at the boil under reflux for 2 hours, then cooled and concentrated, giving 28.0 g (99.5%) of the titled compound as oil.

e) 2-(4-Benzylpiperidine-1-yl)-N-(5-nitro-2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-oxo-ndimethylacetamide

To a solution of 3.23 g (16.56 mmol) 6-amino-5-nitro-3H-benzoxazol-2-it (stage a), 2.58 ml (18.5 mmol) of triethylamine and 100 ml of chloroform is added dropwise at a temperature of 20°5.25 g (19.75 mmol) (4-benzylpiperidine-1-yl)oxoacetate in 20 ml of chloroform, the mixture is then stirred at room temperature for 2 hours. The mixture is washed with water, the organic layer is dried and concentrated. The residue is purified by chromatographic column using kieselgel 60 as adsorbent (Merck) and a mixture of toluene: methanol = 4:1 as eluent, giving 3.3 g (47%) of the named compound. TPL: foam.

f) N-(5-Amino-2-oxo-2,3-dihydroisoxazole-6-yl)-2-(4-benzylpiperidine-1-yl-2-oxo-ndimethylacetamide

A mixture of 3.3 g (7.7 mmol) of 2-(4-benzylpiperidine-1-yl)-N-(5-nitro-2-oxo-2,3-dihydroisoxazole-6-yl)-2-oxo-ndimethylacetamide, 100 ml of methanol hydronaut for 8 hours with 0.3 g of 10% Pd/C catalyst. The catalyst is filtered off and the filtrate concentrated. The residue is purified by chromatographic column using kieselgel 60 as adsorbent (Merck) and a mixture of toluene: acetone = 2:1 as eluent, giving 1.06 g (34.5%) of the named compound. TPL: 296° (toluene - acetone).

g) 6-Benzile Eridan-1-carbonyl)for 3,5-dihydroimidazo[4',5'; 4,5]benzo[1,2-d]oxazol-2-he (the other tautomeric form of the compound is 6-(4-benzylpiperidine-1-carbonyl)was 3.7-dihydroimidazo[4',5':4,5]benzo[1,2-d]oxazol-2-one)

1.0 g (2.5 mmol) of N-(5-amino-2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-(4-benzylpiperidine-1-yl)-2-oxo-ndimethylacetamide heated to 240°C for 10 minutes, then cooled. The resulting mixture was purified by chromatographic column using kieselgel 60 as adsorbent (Merck) and a mixture of toluene: acetone = 1:1 as eluent, giving 0.16 g (17%) of the named compound. TPL: >290° (toluene - acetone).

Example 16

6-(4-Benzylpiperidine-1-carbonyl)for 3,5-dihydro-1H-imidazo[4,5-f]indol-2-he (4570002045)

a) Ethyl ester-[(2-oxo-2,3-dihydro-1H-benzimidazole-5-yl)hydrazono]-propionic acid

The named compound is obtained from 5-amino-1,3-dihydro-benzimidazole-2-[J. Am. Chem. Soc.,80, 1657 (1958)] in accordance with the method described in example 8/A. TPL: 220°With (water).

b) Ethyl ester of 2-oxo-1,2.3,5-tetrahydroimidazo[4,5-f]indole-6-carboxylic acid

The named compound is obtained from the ethyl ester of 2-[(2-oxo-2,3-dihydro-1H-benzimidazole-5-yl)-hydrazono]-propionic acid in accordance with the method described in example 8/b. TPL: 196-197°With (ethyl acetate).

c) 2-Oxo-1,2,3,5-tetrahydro-imidazo[4,5-1]indole-6-carboxylic acid

The named compound is obtained from the ethyl ester of 2-oxo-1,2,3,5-tetrahydro-imides the[4,5-f]indole-6-carboxylic acid in accordance with the method, described in example 1/b. TPL: >270°With (water).

e) 6-(4-Benzylpiperidine-1-carbonyl)for 3,5-dihydro-1H-imidazo[4,5-g]indole-2-he

The named compound is obtained from 2-oxo-1,2,3,5-tetrahydroimidazo[4,5-f]indole-6-carboxylic acid and 4-benzylpiperidine in accordance with the method described in example 1/s TPL: >270°C (acetonitrile).

Example 17

2-(4-Benzylpiperidine-1-carbonyl)-1,5-dihydro-8-oxa-1,5-diaza-cyclopent[b]naphthalene-6-he (4570002185)

a) Methyl ester of 6-oxo-1,5,6,7-tetrahydro-8-oxa-1,5-diaza-cyclopent[b]naphthalene-2-carboxylic acid

To a solution of 2.0 g (9.7 mmol) of the methyl ester of 5-amino-6-hydroxyindole-2-carboxylic acid (Example 5/s) in 300 ml of tetrahydrofuran added 2.45 g (29.2 mmol) of sodium bicarbonate and 1.3 ml (16.3 mmol) of chloroacetanilide and the mixture is stirred at room temperature overnight. The reaction mixture was concentrated and to the residue was added 100 ml of water. The precipitated crystals are filtered, washed with water and suspended in 120 ml of acetonitrile. To the suspension is added 4.05 g (29.3 mmol) of potassium carbonate and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated and to the residue was added 100 ml of water. The product is filtered, washed with water and dried, giving 1.7 g (71%) of the named compound. TPL: 188-196°With (water).

b) 6-Oxo-1,5,6,7-tetrahydro-8-oxa-1,5-diaza-cyclopent[b-2-carboxylic acid

The named compound is obtained from the methyl ester of 6-oxo-1,5,6,7-tetrahydro-8-oxa-1,5-diaza-cyclopent[b]naphthalene-2-carboxylic acid in accordance with the method described in example 8/b. TPL:231-237°With (water).

C) 2-(4-Benzylpiperidine-1-carbonyl)-1,5-dihydro-8-oxa-1,5-diaza-cyclopent[b]naphthalene-6-he

The named compound is obtained from 6-oxo-1,5,6,7-tetrahydro-8-oxa-1,5-diaza-cyclopent[b]naphthalene-2-carboxylic acid and 4-benzylpiperidine in accordance with the method described in example 1/s TPL: 225-231° (diethyl ether).

Example 18

2-[4-(4-Terbisil)piperidine-1-carbonyl]-1,5-dihydro-8-oxa-1,5-disallowment[b]naphthalene-6-he (4570002193)

The named compound is obtained from 6-oxo-1,5,6,7-tetrahydro-8-oxa-1,5-diaza-cyclopent[b]naphthalene-2-carboxylic acid and 4-(4-terbisil)piperidine according to the method described in example 1/s TPL: 219-226° (diethyl ether).

Example 19

(3,6-Dihydro-pyrrol[3,2-e]indazol-7-yl)-(4-p-tolylacetate-1-yl)methanon (the other tautomeric form of the compound - (1,6-dihydropyrrolo[3,2-e]indazol-7-yl)-(4-p-tolylacetate-1-yl)methanon (4570002260)

The named compound is obtained from 3,6-dihydropyrrolo[3,2-e]imidazol-7-carboxylic acid (Example 11/C) and 4-p-tolylacetylene [J. Med. Chem.,21, 309 (1978)] in accordance with the method described in example 1/s TPL: 218-222° (diethyl ether).

Example 20

(36-Dihydro-pyrrol[3,2-e]indazol-7-yl)-[4-(4-methylbenzyl)piperidine-1-yl]metano (the other tautomeric form of the compound - (1,6-dihydro-pyrrol[3,2-e]indazol-7-yl)-[4-(4-methylbenzyl)piperidine-1-yl]metano (4570002340)

The named compound is obtained from 3,6-dihydropyrrolo[3,2-e]indazol-7-carboxylic acid (Example 11/C) and 4-(4-methylbenzyl)piperidine [J. Org. Chem.,64, 3763 (1999)] in accordance with the method described in example 1/s TPL: 253-255° (diethyl ether).

Example 21

1-(4-Benzylpiperidine-1-yl)-1-(6-hydroxy-1H-indol-2-yl)methanon (4513579)

A mixture of 5.0 g (28.2 mmol) of 6-hydroxyindole-2-carboxylic acid [J. Chem. Soc. 1605-1608 (1948)], 4.4 ml (31.6 mmol) of triethylamine, 5.0 g (28.5 mmol) of 4-benzylpiperidine, 12.0 g (31.6 mmol) of HBTU (Advanced Chem. Tech.) and 50 ml of dimethylformamide is stirred at room temperature for 6 hours. The resulting product is filtered and recrystallized from ethanol to obtain 6.75 g (71%) of the named compound. TPL: 214-215°C (ethanol).

Example 22

1-[4-(4-Terbisil)piperidine-1-yl]-1-(6-hydroxy-1H-indol-2-yl)methanon (4513848)

The named compound is obtained from 4-(4-terbisil)piperidine [J. Med. Chem., 35, 4903 (1992)] and 6-hydroxy-1H-indole-2-carboxylic acid in acetonitrile at room temperature. The reaction mixture was concentrated and the residue purified via chromatography on a column using Kieselgel 60 as adsorbent (Merck) and a mixture of toluene: methanol = 4:1 as eluent. TPL: 180-182°C (toluene).

Example 23

1-(4-Benzylpiperidine-1-yl)-1-(5-nitro-1H-indol-yl)methanon (4514205)

The named compound is obtained from 5-nitroindole-2-carboxylic acid (J. Am. Chem. Soc., 4621 (1958)] and 4-benzylpiperidine in accordance with the method described in example 1/s TPL 220-224° (diethyl ether).

Example 24

1-(5-Amino-1H-indol-2-yl)-1-(4-benzylpiperidine-1-yl)methanon (4514244)

A mixture of 0.5 g (1.38 mmol) of 1-(4-benzylpiperidine-1-yl)-1-(5-nitro-1H-indol-2-yl)methanone, 20 ml of methanol and 0.1 g of 10% Pd/C catalyst hydronaut for 5 hours.

The catalyst is filtered off, washed with methanol and the filtrate concentrated. The residue is treated with diethyl ether and precipitated precipitated crystals are filtered off to obtain 0.27 g (59%) of the named compound. TPL: 175-180° (diethyl ether).

Example 25

(4-Benzylpiperidine-1-yl)-(6-hydroxy-1H-benzoimidazol-2-yl)-methanon (4570001103)

a) N-Butyl-N'-(4-methoxy-2-nitrophenyl)oxalate

To a suspension of 44.0 g (164 mmol) of ethyl ester of N-(4-methoxy-2-nitrophenyl)assalamou acid [J. Med. Chem., 18, 926 (1975)] and 330 ml of toluene added 16.8 ml (170 mmol) of n-butylamine at a temperature of about 20°C. the Reaction mixture was stirred at room temperature for 10 hours, then concentrated and the residue is crystallized from diethyl ether, precipitated precipitated product is filtered off, washed with diethyl ether and dried to obtain 45.3 g (93.3%) of the named compound. TPL: 127-128° (diethyl ether).

b) N-(2-Amino-methoxyphenyl)-N'-butyl-oxalate

A mixture of 27.0 g (91 mmol) of N-Butyl-N'-(4-methoxy-2-nitrophenyl)oxolamine, 1200 ml of methanol and 7.3 g of 5% Pd/C catalyst hydronaut for 3 hours. To the reaction mixture add 600 ml of acetone. The catalyst is filtered off, washed with acetone, the filtrate is concentrated and the residue is crystallized from diethyl ether to obtain 21.8 g (90.1%) of these compounds. TPL: 180-181° (diethyl ether).

c) Butylamide 6-methoxy-1H-benzoimidazol-2-carboxylic acid

In nitrogen atmosphere at a temperature of 240 C for 10 minutes mix 41.0 g (154 mmol) of N-(2-amino-4-methoxyphenyl)-N'-butylacetamide. The mixture is cooled to room temperature, then add 300 ml of acetone and stirred for one hour. The resulting product is filtered off. The filtrate is concentrated and the residue is mixed with 150 ml n-hexane. The resulting product is filtered, washed with hexane and dried to obtain 26.5 g (69.5%) of these compounds. TPL: 125-126°C (n-hexane).

d) 6-Hydroxy-1H-benzoimidazol-2-carboxylic acid

A mixture of 26.0 g (105 mmol) of 6-methoxy-1H-benzoimidazol-2-carboxylic acid butylamide and 780 ml of 48% aqueous Hydrobromic acid is stirred at a temperature of 110°C for 8 hours, then heated at the boil under reflux for 12 hours. The mixture is cooled to room temperature, precipitated in the sludge product ochiltree is up, washed with water up until the pH is not neutral, and dried to obtain 14.3 g (76.2%) of these compounds. TPL: 206-207°With (water).

e) (4-Benzylpiperidine-1-yl)-(6-hydroxy-1H-benzoimidazol-2-yl)-methanon (4570001103)

A mixture of 3.0 g (16.75 mmol) 6-hydroxy-1H-benzoimidazol-2 carboxylic acid, 2.4 ml (17.2 mmol) of triethylamine, 3.0 g (17.1 mmol) of 4-benzylpiperidine, 7.0 g (18.5 mmol) of HBTU and 100 ml of dimethylformamide is stirred at room temperature for 16 hours. The reaction mixture was concentrated and the residue purified by chromatographic column using Kieselgel 60 as adsorbent (Merck) and a mixture of toluene: methanol = 4:1 as eluent, the product is then recrystallized from toluene to obtain 3.58 g (63.5%) of the named compound. TPL: 186°C (toluene).

Example 26

(6-Hydroxy-1H-benzoimidazol-2-yl'[4-(4-methylbenzyl)-piperidine-1-yl]-methanon (4570001378)

The named compound is obtained from 6-hydroxy-1H-benzoimidazol-2-carboxylic acid [example 25 (d] and 4-(4-methylbenzyl)piperidine [J.Org. Chem., 64, 3763 (1999)] in accordance with the method described in example 25. TPL: 93° (diisopropyl ether).

Example 27

Obtaining pharmaceutical compositions:

a) Tablets:

0.01-50% of the active ingredient, 15-50% lactose, 15-50% of potato starch, 5-15% polyvinylpyrrolidone, 1-5% talc, 0.01-3% of magnesium stearate, 1% to 3% colloidal di is xida silicon and 2-7% of ultramicrobacteria mix, then granularit using wet granulation and pressed into tablets.

b) pills, tablets, film-coated:

Tablets made in accordance with the method described above, the cover layer consisting of entero - or gastroentology film or sugar and talc. The coated tablets are polished with a mixture of beeswax and Carnauba wax.

c) Capsules:

0.01-50% of the active ingredient, 1-5% lauryl sodium, 15-50% starch, 15-50% lactose, 1% to 3% colloidal silicon dioxide and 0.01-3% of magnesium stearate are thoroughly mixed, the mixture is passed through a sieve and fill it hard gelatin capsules.

d) Suspension;

Ingredients: 0.01-15% of the active ingredient, 0.1-2% sodium hydroxide, 0.1-3% citric acid, 0.05-0.2% nipagina (methyl 4-hydroxybenzoate sodium), 0.005-0.02% nipazola, 0.01-0.5% carbopol (polyacrylic acid), 0.1-5% ethyl alcohol 96%, 0.1-1% odorants, 20-70% sorbitol (70% aqueous solution) and 30-50% distilled water.

To a solution of nipagin and citric acid in 20 ml of distilled water add small doses of carbopol with vigorous stirring and the solution allowed to stand for 10-12 hours. Then added with stirring sodium hydroxide in 1 ml of distilled water, an aqueous solution of sorbitol, and then extract with raspberry flavor. The active ingredient is added to the received media in small doses and spenderat with immersion homogenizer. In the end, the suspension is diluted to the desired final volume with distilled water and the suspension is in the form of syrup is passed through a colloidal mill equipment.

e) Candle:

For each candle 0.01-15% of the active component and 1 to 20% lactose are thoroughly mixed, then melt 50-95% of the Agency on a candle (e.g., Witepsol 4), cooled to 35°and the mixture of active ingredient and the lactose are mixed using a homogenizer. The mixture obtained is formed in the cooled forms.

f) Liofilizovannye powdered in capsules:

Prepare a 5% solution of mannitol or lactose with bidistilled water for injection use, after which the solution is filtered so as to make it sterile. Prepare 0.01-5% solution of the active component with bidistilled water for use in injections and the resulting solution is filtered to make it sterile. Obtained two solutions are mixed under aseptic conditions, filled into ampoules dose of 1 ml, the contents of the ampoules lyophilized and the ampoules sealed under nitrogen atmosphere. The content of the ampoule is dissolved in sterile water or 0.9% (physiological), sterile aqueous solution of sodium chloride before the introduction.

1. New amide derivatives of carboxylic acids, which are antagonists of the NMDA receptor, of the formula (I)

where one of R1, R2, R3and R4is a HE or NH2group, and the others are hydrogen atoms, or two adjacent R1, R2, R3and R4group, in this case, together with one or more identical or different additional heteroatoms and-CH= and/or-CH2groups form a 5-6 membered Homo - or heterocyclic ring, preferably pyrrole, pyrazole nucleus, imidazole, oxazole, oxoacridine or 3-oxo-1,4-oxazine ring, and the other two R1, R2, R3and R4groups are hydrogen atoms,

R5and R6together with the nitrogen atom between them form a saturated or unsaturated, 4-6 - membered heterocyclic ring which is substituted groups phenoxy, phenyl-(C1-C4-alkoxy), phenoxy-(C1-C4-alkyl), benzoyl group, optionally substituted on the aromatic ring by one or more halogen atoms, C1-C4-alkyl or C1-C4-alkoxygroup,

X and Y independently are an oxygen atom, nitrogen or-CH= group

and their salts formed with acids and bases.

2. Amide derivatives of carboxylic acid according to item 1, which represent a limited group of amide derivatives of carboxylic KIS is the notes of the formula (Ia):

where the values of R1, R2, R3, R4, R5and R6the same as defined in claim 1, and their salts formed with acids and bases.

3. Amide derivatives of carboxylic acid according to claim 1, selected from the following groups:

6-(4-benzylpiperidine-1-carbonyl)-1,5-dihydro-oxazol[4,5-f]indol-2-it,

6-[4-(4-formanilide-1-carbonyl)]-1,5-dihydro-oxazol[4,5-f]indol-2-it,

(4-benzylpiperidine-1-yl)-(3,b-dihydropyrrolo[3,2-e]indazol-7-yl)methanon,

[4-(4-formanilide-1-yl)]-(3,6-dihydropyrrolo[3,2-e]indazol-7-yl)methanon,

(4-p-tolylacetate-1-yl)-(3,6-dihydropyrrolo[3,2-e]indazol-7-yl)methanon,

(4-benzylpiperidine-1-yl)-(3,6-dihydroimidazo[4,5-f]indol-7-yl)methanon.

4. Pharmaceutical composition having activity as selective antagonists of the NR2B receptor containing biologically effective dose amide

carboxylic acid derivative of the formula (I):

where the values of R1, R2, R3, R4, R5, R6X and Y are the same as defined in claim 1, and/or their pharmaceutically acceptable salts formed with acids or bases, as the active ingredient, carriers, fillers and the like additives commonly used in the pharmaceutical industry.

. The method of obtaining the amide derivatives of carboxylic acids of the formula (I):

where the values of R1, R2, R3, R4, R5, R6X and Y are the same as defined in claim 1,

and their salts formed with acids and bases, consisting in education

amide bond between the carboxylic acid of formula (II)

where the values of R1, R2, R3, R4X and Y are the same as described in claim 1, and an amine of formula (III)

where the values of R5and R6the same as given in claim 1, after which the thus obtained amide carboxylic acid derivative of the formula (I), where the values of R1, R2, R3, R4, R5, R6X and Y are the same as defined in claim 1, if necessary, converted into other compounds of formula (I) by introducing new substituents and/or modifying or removing the existing ones, and/or forming a salt, and/or releasing the connection from the salts by known methods.

6. The method according to claim 5, characterized by the participation of the acid of formula (II), where the values of R1, R2, R3, R4X and Y are the same as defined in claim 1, as active derivative in the amidation reaction.

7. The method according to claim 5, characterized by participation is islote formula (II), where the values of R1, R2, R3, R4X and Y are the same as defined in claim 1, in the form of an active ester formed with O-benzotriazol-1-yl-tetramethylpropylenediamine, in the amidation reaction.

8. The method according to claim 5, characterized by the participation of the acid of formula (II), where the values of R1, R2, R3, R4X and Y are the same as defined in claim 1, in the form of gelegenheid acid in the amidation reaction.

9. The method according to claim 8, characterized by the participation of the acid of formula (II), where the values of R1, R2, R3, R4X and Y are the same as defined in claim 1, in the form of a carboxylic acid in the amidation reaction.

10. The method of preparation of pharmaceutical compositions having activity as selective antagonists of the NR2B receptor, which consists in mixing the amide carboxylic acid derivative of the formula (I),

where the values of R1, R2, R3, R4, R5, R6X and Y are the same as defined in claim 1, and/or its pharmaceutically acceptable salts formed with acids or bases, carriers, fillers and the like additives commonly used in the pharmaceutical industry.

11. Method for the treatment and relief of symptoms of the following diseases of mammals, including humans: chronic neurodegenerative disease is, such as stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease, spinal cord injury, epilepsy, anxiety, depression, brain ischemia, of any origin, muscle spasms, multi-infarct dementia, brain injury, pain (such as post-traumatic or post-operative and chronic pain conditions such as neuropathic pain or pain associated with cancer, migraine, neuronal damage associated with human immunodeficiency virus (HIV), hypoglycemia, amyotrophic lateral sclerosis (ALS), bacterial scleroses, maculardegeneration, degenerative diseases of the retina (for example, caused by CMV retinitis), asthma, tinnitus, hearing loss, caused by aminoglycoside antibiotic, bacterial and viral infection; to reduce addiction and/or dependency to drugs and alcohol and treatment of abstinence syndrome associated with drug and alcohol abuse, psychosis, weakness of the bladder, including the introduction of an effective amount/amounts of amide carboxylic acid derivative of the formula (I):

where the values of R1, R2, R3, R4, R5, R6X and Y are the same as defined in claim 1, and/or its pharmaceutically acceptable salts formed with acids or bases mammals, including humans, n is eduwise treatment in the form of compounds as such or in the form of pharmaceutical compositions obtained in known accessories commonly used in the pharmaceutical industry.



 

Same patents:

FIELD: biochemistry, medicine, in particular new bioactive compounds having peptide hormone vasopressin agonistic activity.

SUBSTANCE: disclosed are compounds of general formula 1 or 2 or tautomers, or pharmaceutically acceptable salts thereof, wherein W represents N or C-R4; R1-R4 are independently H, F, Cl, Br, alkyl, O-alkyl, NH2, NH-alkyl, N(alkyl)2, NO2 or R2 and R3 together may form -CH=CH-CH=CH-; G1 represents bicyclic or tricyclic condensed azepine derivatives selected from general formulae 3-8 wherein A1, A4, A7, and A10 are independently CH3, O, and NR5; A2, A3, A9, A11, A12, A14, and A15 are independently CH and N; or A5 represents covalent bond and A6 represents S; or A5 represents N=CN and A6 represents covalent bond; A8 and A12 are independently NH, N-CH3 and S; A16 and A17 both represent CH2 or one of A16 and A17 represents CH2 and the other represents CH(OH), CF2, O, SOa, and NR5; R5 represents H, alkyl, CO-alkyl, and (CH2)bR6; R6 represents phenyl, pyridyl, OH, CO2H; a = 0-2; b = 1-4; Y represents CH or N; Z represents CH=CH or S; and G2 represents group selected from groups of formulae 9-11 wherein Ar represents phenyl, pyridyl, naphthyl, and mono- or polysubstituted phenyl, pyridyl, wherein substituents are selected from F, Cl, Br, alkyl, NO2; D represents covalent bond or NH; E1 and E2 both are H, OMe, F, or one of E1 and E2 represents OH, O-alkyl, OBn, OPh, OAc, F, Cl, Br, N2, NH2, NHBn or NHAc and the other represents H; or E1 and E2 together form =O, -O(CH2)gO- or -S(CN2)gS-; F1 and F2 both represent H or together form =O or =R; L represents OH, O-alkyl, NH2, NH-alkyl, and NR9R10; R7 represents COR8; R8 represents OH, O-alkyl, NH2, NH-alkyl, N(alkyl)2, pyrolidinyl, and piperidinyl; R9 and R10 both are alkyl or together form -(CH2)h-; V represents O, N-CN or S; c = 0 or 1; d = 0 or 1, e = 0 or 1; f = 0-4; g = 2 or 3; h = 3-5, with the proviso, that both d and e are not 0. Also disclosed are pharmaceutical composition having agonistic activity in relate to V2 receptor, method for treatment one or more diseases (e.g., enuresis, nycturia, diabetes insipidus, hemorrhage disorders, urinary incontinence.

EFFECT: new compounds with value biological characteristics.

41 cl, 19 tbl, 193 ex

FIELD: organic chemistry, medicine, hematology.

SUBSTANCE: invention elates to new compounds that inhibit activated blood coagulating factor X (Fxa factor) eliciting the strong anti-coagulating effect. Invention proposes compound of the formula (1): Q1-Q2-C(=C)-N-(R1)-Q3-N(R2)-T1-Q4(1) wherein R1, R2, Q1, Q2, Q4 and T1 have corresponding values, and Q2 represents the group of the formula: wherein R9, R10 and Q5 have corresponding values also, or its salt, solvate or N-oxide. Invention provides the development of a novel compound possessing strong Fxa-inhibiting effect and showing the rapid, significant and stable anti-thrombosis effectin oral administration.

EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacology.

SUBSTANCE: invention relates to gyrase inhibitors that reduce amount of microorganisms in biological sample by contacting the indicated sample with compound of the formula (I): , to a method for treatment of bacterial infection by using compounds of the formula (I), compounds of the formula (I) and a pharmaceutical composition comprising compounds of the formula (I). Invention provides the enhanced effectiveness of treatment.

EFFECT: valuable medicinal properties of gyrase.

54 cl, 5 tbl, 13 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (1)

wherein A represents bicyclic or tricyclic azepine derivative; V1 and V2 both represent hydrogen atom (H) or one among V1 and V2 represents hydrogen atom (H), OMe, OBn, OPh, O-acyl, Br, Cl, F, N3, NH2, NHBn and another represents hydrogen atom (H); or V1 and V2 represent in common =O or -O(CH2)pO-; W1 represents oxygen (O) or sulfur (S) atom; X1 and X2 both represent hydrogen atom (H) or in common represent =O or =S; Y represents OR5 or NR6R7; R1 means hydrogen atom (H), lower alkyl, F, Cl and Br; R2 means lower alkoxy-group or values given for R1; R3 and R5 are taken independently among hydrogen atom (H) and lower alkyl; R4 means hydrogen atom (H); R6 and R7 are taken independently among hydrogen atom (H) and lower alkyl, or they in common mean -(CH2)n-; n = 3, 4, 5 or 6; p = 2 or 3. These compounds are agonists of vasopressin V2 receptors and useful as antidiuretic and procoagulants, and also to pharmaceutical compositions comprising these vasopressin agonists. These compositions are useful especially in treatment of diabetes insipidus of the central origin and night enuresis.

EFFECT: valuable medicinal properties of compounds, improved method for treatment.

26 cl, 1 tbl, 119 ex

FIELD: organic chemistry, madicine.

SUBSTANCE: tricyclic benzodiazepines of formula I as well as their pharmaceutical acceptable salts, pharmaceutical composition containing the same and methods for hypertension treatment are disclosed. In formula A is -C(O)-; Y is CH2 or CH as olefinic site; X is CH2 or CH as olefinic site S, O or NR3 (R3 is C1-C8-alkyl) with the proviso that when Y is CH, X also is CH; Z is N or CH; R1 is hydrogen, C1-C8-alkyl, C1-C8-alkoxy or halogen; R2 is NR4COAr (R4 is hydrogen; Ar is phenyl optionally substituted with 1-3 substitutes independently selected from C1-C8-alkyl, halogen, hydroxyl, fluorinated C1-C8-alkylthio and another phenyl optionally substituted with substitute selected from C1-C4-alkyl, halogen, and hydroxyl); R5 is hydrogen, C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine, hydroxyl or di-(C1-C4)-alkylamino.

EFFECT: improved pharmaceutical composition for hypertension treatment.

12 cl, 5 tbl, 52 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to oxazolo- and thiazolo-[4,5-c]-quinoline-4-amines of the general formula (I)

wherein R1 is taken among group consisting of oxygen and sulfur atoms; R2 is taken among hydrogen atom, alkyl, alkyl-OH (hydroxyalkyl), alkyl-X-alkyl, alkyl-O-C(O)-N(R5)2, morpholinyl, pyrrolidinyl, alkyl-X-aryl radical, alkenyl-X-aryl radical; each substitute R3 and R4 represents hydrogen atom or substitutes R3 and R4 taken in common form the condensed aromatic or [1,5]-naphthiridine system; X represents -O- or a single bond; R5 represents hydrogen atom. Also, invention describes intermediate compounds, pharmaceutical composition and a method for stimulating biosynthesis of cytokinins (cytokines) based on these compounds. Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable properties of compounds.

21 cl, 2 tbl, 64 ex

FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention describes a method for preparing compounds of the formula (I):

wherein each R1, R2, R3 means independently of one another (C-C6)-alkyl; R can represent also pyridyl; R4 and R5 in common with nitrogen atoms to which they are joined form unsaturated 5-8-membered heterocyclic ring that can be broken by oxygen atom; G means hydrogen atom. Method involves interaction of compound of the formula (II):

wherein R1, R2 and R3 have above given values; R6 is a group RR9N-; R7 is a group R10R11N-; each among R8, R, R10 and R11 means independently of one another hydrogen atom or (C1-C6)-alkyl in inert organic solvent being optionally with the presence of a base with compound of the formula (IV) ,

(IVa)

or (IVb) ,

wherein R4 and R have above given values; H x Hal means hydrogen halide. The prepared compound of the formula (I) wherein G represents ammonium cation is converted to the corresponding compound of the formula (I) by treatment with Brensted's acid wherein G represents hydrogen atom. Also, invention describes compound of the formula (II) wherein R1, R2, R3, R6 and R7 have above indicated values.

EFFECT: improved preparing method.

9 cl, 12 ex

The invention relates to the field of organic chemistry, namely to new individual compounds of class benzoxazines that exhibit fluorescent properties and can be used as starting products for the synthesis of new heterocyclic systems, as well as substances for sample labeling and additives for reflective paints

The invention relates to new nitrogen-containing aromatic 6-membered cyclic compounds of the formula (I) or their pharmaceutically acceptable salts, demonstrating excellent selective PDE V inhibitory activity

The invention relates to new physiologically active substituted oxazolo[4,5-d]pyridazine General formula (1), (2) or (3) and combinatorial library designed to search among them physiologically active substances, compounds leaders and candidates (drug-candidates) on the basis of screening

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to 5-aminoalkylpyrazolo[4,3-d]pyrimidines of the general formula (I): wherein R1 and R2 are similar or different and represent independently of one another (C1-C8)-alkyl group; R3 and R4 are similar or different and represent independently of one another (C1-C8)-alkoxy-group or halogen atom; R5 and R6 can be similar or different and represent independently of one another hydrogen atom, linear or branched (C1-C8)-alkyl group that can be substituted with one or more hydroxyl groups, (C1-C8)-alkoxy-, amino-, mono-(C1-C8)-alkyl-amino-, di-[(C1-C8)-alkyl]-amino-, N-morpholino- or pyridyl groups or in common with nitrogen atom to which they are bound form unsaturated heterocyclic ring that comprises optionally one or more additional atoms of nitrogen and/or oxygen and substituted with one or more hydroxyl, (C1-C8)-alkylol, (C1-C6)-oligohydroxyalkyl, amino-, mono-[(C1-C8)-alkyl]-amino- or di-[(C1-C8)-alkyl]-amino-groups. Proposed compounds inhibit activity of cGMP-phosphodiesterase and can be used in treatment of states of cardiovascular system and for treatment in potency disturbances. Also, invention relates to a medicinal preparation used for inhibition of activity of cGMP-phosphodiesterase based on indicated compounds, a method for preparing compounds of the formula (I) and a method for preparing the medicinal preparation.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and composition.

7 cl, 15 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of β-carboline of the general formula (I)

showing properties of phosphodiesterase V inhibitor (PDE V). In the general formula (I) R1 means hydrogen atom; n = 0; X is taken among the group consisting of oxygen (O), sulfur (S) atoms and NRD; R2 is taken among the following group: phenyl (that can be optionally substituted with 1-3 RB), 6-membered nitrogen-containing heteroaryl and 5-6-membered heterocycloalkyl comprising 1-2 oxygen atoms and condensed with benzene ring (optionally substituted with 1-3 RB); R4 is taken among the group consisting of hydrogen atom, carboxy-group. (C1-C6)-alkylcarbonyl, di-[C1-C8)-alkyl]-aminoalkoxycarbonyl, di-[(C1-C8)-alkyl]-amino-(C1-C8)-alkylaminocarbonyl; a = a whole number from 0 to 1; Y is taken among the group consisting of -CH2, -C(O); Z is taken among the group consisting of -CH2, -CHOH, and -C(O) under condition that when Z represents -CHOH or -C(O) then X represents -NH; is taken among the group consisting of naphthyl, 5-6-membered heteroaryl comprising 1-3 heteroatoms taken among nitrogen, oxygen and/or sulfur atoms possibly condensed with benzene ring; m = a whole number from 0 to 2; R3 is taken independently among the group consisting of halogen atom, nitro-group, (C1-C8)-alkyl, (C1-C8)-alkoxy-group, trifluorophenyl, phenyl (optionally substituted with 1-3 RB), phenylsulfonyl, naphthyl, (C1-C8)-aralkyl, 5-6-membered heteroaryl comprising 1-3 nitrogen atoms in the ring (optionally substituted with 1-3 RB). Also, invention relates to a pharmaceutical composition, a method for its preparing and methods for inhibition of phosphodiesterase V activity (PDE V), and for increase of the cGMP concentration.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and composition.

14 cl, 11 sch, 7 tbl, 13 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention describes phenyl-substituted heterocyclic 1,3-ketoenols of the formula (I): wherein R1 and R3 mean independently of one another ethyl or (C1-C2)-alkoxy-group; Q means the group of the formula (Q1): or (Q2): wherein R4 and R5 in common with atoms to which they are joined form 5-7-membered cycle that can comprise additionally anellated alkylene chain consisting of 2-6 carbon atoms that, in turn, can comprise two heteroatoms taken among oxygen atom, and indicated cycle can be substituted with halogen atom, hydroxy-group, (C1-C6)-alkoxy-group, (C1-C6)-alkoxy-(C1-C6)-alkoxy-group, (C1-C4)-alkylcarbonyloxy-group, hydroxy-(C1-C4)-alkoxy-group, hydroxycarbonyl-(C1-C2)-alkoxy-group, methoxycarbonyl-(C1-C2)-alkoxy-group, methoxyimino-, methoxyethoxyethoxy-group; R6 and R7 means (C1-C10)-alkyl; R8 means hydrogen atom; X means oxygen atom; R20 means (C1-C10)-alkyl, and also agronomically acceptable salts and isomers of these compounds. Also, invention describes a method for preparing compounds of the formula (I), herbicide agent and a method for control of weed growth based on compounds of the formula (I). Invention provides preparing compounds possessing the herbicide activity.

EFFECT: improved preparing method, valuable properties of compounds and agents.

5 cl, 28 tbl, 5 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of pyridopyrimidines of the formula (I): or (II): wherein Z means nitrogen atom (N) or -CH; W means -NR2; X1 means oxygen atom (O), -NR4 (wherein R4 means hydrogen atom or alkyl), sulfur atom (S) or -CR5R6 (wherein R5 and R6 mean hydrogen atom); X2 means oxygen atom (O); Ar1 means unsubstituted or substituted phenyl; R2 means hydrogen atom, alkyl or acyl; R1 means hydrogen atom, alkyl, halide alkyl and others; R3 means alkyl; cycloalkyl and others; R8 and R9 mean hydrogen atom, alkylsulfonyl and others, and to their pharmaceutically acceptable salts, and to intermediate compounds that are used for preparing compounds of the formula (I) and (II). Indicated compounds show inhibitory activity with respect to activity of p38 kinase and can be used in preparing a medicine agent for treatment of p38-mediated disturbances.

EFFECT: improved preparing methods, valuable medicinal properties of compounds and composition.

38 cl, 3 tbl, 116 ex

FIELD: biochemistry, medicine, in particular new bioactive compounds having peptide hormone vasopressin agonistic activity.

SUBSTANCE: disclosed are compounds of general formula 1 or 2 or tautomers, or pharmaceutically acceptable salts thereof, wherein W represents N or C-R4; R1-R4 are independently H, F, Cl, Br, alkyl, O-alkyl, NH2, NH-alkyl, N(alkyl)2, NO2 or R2 and R3 together may form -CH=CH-CH=CH-; G1 represents bicyclic or tricyclic condensed azepine derivatives selected from general formulae 3-8 wherein A1, A4, A7, and A10 are independently CH3, O, and NR5; A2, A3, A9, A11, A12, A14, and A15 are independently CH and N; or A5 represents covalent bond and A6 represents S; or A5 represents N=CN and A6 represents covalent bond; A8 and A12 are independently NH, N-CH3 and S; A16 and A17 both represent CH2 or one of A16 and A17 represents CH2 and the other represents CH(OH), CF2, O, SOa, and NR5; R5 represents H, alkyl, CO-alkyl, and (CH2)bR6; R6 represents phenyl, pyridyl, OH, CO2H; a = 0-2; b = 1-4; Y represents CH or N; Z represents CH=CH or S; and G2 represents group selected from groups of formulae 9-11 wherein Ar represents phenyl, pyridyl, naphthyl, and mono- or polysubstituted phenyl, pyridyl, wherein substituents are selected from F, Cl, Br, alkyl, NO2; D represents covalent bond or NH; E1 and E2 both are H, OMe, F, or one of E1 and E2 represents OH, O-alkyl, OBn, OPh, OAc, F, Cl, Br, N2, NH2, NHBn or NHAc and the other represents H; or E1 and E2 together form =O, -O(CH2)gO- or -S(CN2)gS-; F1 and F2 both represent H or together form =O or =R; L represents OH, O-alkyl, NH2, NH-alkyl, and NR9R10; R7 represents COR8; R8 represents OH, O-alkyl, NH2, NH-alkyl, N(alkyl)2, pyrolidinyl, and piperidinyl; R9 and R10 both are alkyl or together form -(CH2)h-; V represents O, N-CN or S; c = 0 or 1; d = 0 or 1, e = 0 or 1; f = 0-4; g = 2 or 3; h = 3-5, with the proviso, that both d and e are not 0. Also disclosed are pharmaceutical composition having agonistic activity in relate to V2 receptor, method for treatment one or more diseases (e.g., enuresis, nycturia, diabetes insipidus, hemorrhage disorders, urinary incontinence.

EFFECT: new compounds with value biological characteristics.

41 cl, 19 tbl, 193 ex

FIELD: organic chemistry, amino acids, medicine, pharmacy.

SUBSTANCE: invention relates to using derivatives of cysteine for preparing a medicinal agent. The proposed agent is designated for treatment of diseases arising as a result of formation of heterotrimeric protein G, and to new derivatives of cysteine, and pharmaceutical composition based on thereof. Derivatives of cysteine, in particular, involve the following compounds: bis-1,1'-[7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo-[2,2a]-pyrazine]-disulfide and bis-1,1'-[7-(2-amino-1-oxo-3-thiopropyl)-2-91-naphthyl)-8-(2-methylpropyl)-5,6,7,8-tetrahydroimidazo-[1,2a]-pyrazine-7-yl]-disulfide. Invention provides high effectiveness of treatment.

EFFECT: valuable medicinal properties of compounds.

6 cl, 7 dwg, 2 tbl, 7 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes bicyclic N-acylated imidazo-3-amines or imidazo-5-amines salts of the general formula (I): wherein R1 means tert.-butyl, 1,1,3,3-tetramethylbutyl, (C4-C8)-cycloalkyl, phenyl disubstituted with (C1-C4)-alkyl, -CH2Ra wherein Ra means the group -CO(OR') wherein R' means (C1-C8)-alkyl; R2 means hydrogen atom, the group -CORb wherein Rb means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R3 means (C1-C8)-alkyl, (C3-C8)-cycloalkyl, phenyl, pyridyl, furfuryl or thiophenyl; A means tri-linked fragment of ring of the formula: wherein R6 and R7 mean hydrogen atom or tetra-linked fragment of ring of the following formulae: wherein R4' means hydrogen atom or benzyloxy-group; R5' means hydrogen atom; R6' means hydrogen atom, (C1-C8)-alkyl or nitro- (NO2)-group; R7' means hydrogen atom, (C1-C8)-alkyl, or R6' and R7' mean in common the following fragment of ring: -CRi=CRj-CH=CH- wherein Ri and Rj mean hydrogen atom; R5'' means hydrogen, chlorine atom or (C1-C8)-alkyl; R6'' means hydrogen atom; R7''n means hydrogen atom, amino- (NH2)-group or (C1-C8)-alkyl; R4''', R6''' and R7''' mean hydrogen atom; R8 means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; X means anion of inorganic or organic acid, or their acid-additive compounds. Also, invention relates to a method for their preparing and a pharmaceutical composition based on thereof. These new compounds show affinity to opiate μ-receptor and can be used, in particular, as analgesic agents.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical compositions.

12 cl, 2 dwg, 32 ex

FIELD: organic chemistry, medicine, hematology.

SUBSTANCE: invention elates to new compounds that inhibit activated blood coagulating factor X (Fxa factor) eliciting the strong anti-coagulating effect. Invention proposes compound of the formula (1): Q1-Q2-C(=C)-N-(R1)-Q3-N(R2)-T1-Q4(1) wherein R1, R2, Q1, Q2, Q4 and T1 have corresponding values, and Q2 represents the group of the formula: wherein R9, R10 and Q5 have corresponding values also, or its salt, solvate or N-oxide. Invention provides the development of a novel compound possessing strong Fxa-inhibiting effect and showing the rapid, significant and stable anti-thrombosis effectin oral administration.

EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new anellated carbamoyl azaheterocycles of the general formula (1)

or (2) possessing the inhibitory effect on protein kinase activity, a focused library comprising these compounds, and pharmaceutical composition based on thereof. In the general formula (1) or (2) R1 represents hydrogen atom or optionally substituted (C1-C6)-alkyl; R2 and R3 represent independently of one another hydrogen atom, inert substitute, optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl; R4 represents optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl; A and B in common with carbon and nitrogen atoms joined to the form an optionally substituted and optionally condensed azaheterocycle; D and F in common with carbon atoms joined form an optionally substituted and optionally condensed phenyl or aryl, optionally substituted and optionally condensed azaheterocycle. K and L in common with carbon and nitrogen atoms joined to them form an optionally substituted azaheterocycle. Also, invention related to methods for preparing compounds of the general formulae (1) or (2).

EFFECT: improved preparing methods.

10 cl, 2 sch, 25 tbl, 7 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to a heteroarylamino-substituted derivative of dihydropyrimido[4,5-d]pyrimidinone taken among of compounds order corresponding to the formula (I): wherein a subscript symbol n mans a whole number 1; R1 means (C1-C6)-alkyl (substituted with one or two substitutes taken among group involving hydroxy group, (C1-C6)-alkoxy group and others), piperidinyl-(C0-C4)-alkyl [wherein piperidinyl fragment is monosubstituted optionally with benzyl, carbamoyl, (C1-C4)-alkane sulfonyl, (C1-C6)-alkyl and so on], morpholinyl-(C0-C4)-alkyl, tetrahydropyranyl-(C0-C4)-alkyl, 2-oxoimidazolidinyl-(C0-C4)-alkyl, 2-oxopyrrolidinyl-(C0-C4)-alkyl or 1,1-dioxotetrahydrothienyl-(C0-C4)-alkyl, (C3-C6)-cycloalkyl (monosubstituted with monohydroxy group, (C1-C6)-alkoxy group and so on), 1,4-dioxaspiro[4,5]decane-8-yl, 2,4-dione-1,3-diazaspiro[4,5]decane-8-yl or (3-hydroxymethyl-3-methyl)-1,5-dioxaspiro[5,5]undecane-9-yl; R2 means (C1-C4)-alkyl, halogen atom; R3 means hydrogen atom, (C1-C6)-alkyl (optionally substituted with one or two substitutes taken among group involving (C1-C4)-alkoxy group, pyrrolidinyl, di-(C1-C4-alkyl)-amino-group and so on), phenyl, benzyl or piperidinyl (N-substituted optionally with (C1-C4)-alkyl); R4 means hydrogen atom, and also its individual isomers, racemic and nonracemic mixtures of isomers, prodrugs and its pharmaceutically acceptable salts. Also, invention proposes a pharmaceutical composition possessing inhibitory activity with respect to activity of p38 MAP kinase. The composition comprises a heteroalkylamino-derivative of dihydropyrimido[4,5-d]pyrimidinone of the formula (I), isomer, racemic or nonracemic mixture of isomers or its pharmaceutically acceptable salt in mixture with at least one pharmaceutically acceptable vehicle. Invention provides representing a heteroalkylamino-substituted derivative of dihydropyrimido[4,5-d]pyrimidinone possessing inhibitory activity with respect to activity of p38 MAP kinase.

EFFECT: valuable biochemical properties of compounds and composition.

14 cl, 4 tbl, 90 ex

FIELD: organic chemistry, medicinal virology, biochemistry, pharmacy.

SUBSTANCE: invention relates to derivatives of pyrazole of the formula (I-A):

wherein R1 means (C1-C12)-alkyl that can be optionally substituted with 1-3 substitutes taken among fluorine, chlorine and bromine atoms, (C3-C8)-cycloalkyl, phenyl, pyridyl or (C1-C4)-alkyl substituted with phenyl; R2' means optionally substituted phenyl wherein phenyl can be substituted with 1-2 substitutes taken among (C1-C4)-alkyl, (C1-C4)-alkoxyl, hydroxyl, fluorine, chlorine and bromine atoms, cyano- and nitro-group; R3 means (C1-C12)-alkyl or (C1-C4)-alkoxy-(C1-C4)-alkyl; A' means (C1-C4)-alkyl optionally substituted with phenyl or optionally substituted with 4-pyridyl wherein phenyl or 4-pyridyl can be substituted with 1-2 substitutes taken among (C1-C4)-alkyl, (C1-C4)-alkoxyl, hydroxyl, fluorine, chlorine and bromine atoms, cyano-group and NRR' wherein R and R' mean independently of one another hydrogen atom or (C1-C4)-alkyl; or A' means group of the formula CH2-U-heterocyclyl wherein U represents O, S or NR'' wherein R'' means hydrogen atom or (C1-C4)-alkyl and wherein heterocyclyl means pyridyl or pyrimidinyl that is optionally substituted with 1-2 substitutes taken among (C1-C4)-alkyl, fluorine, chlorine and bromine atoms, cyano-, nitro-group and NRR' wherein R and R' mean independently of one another hydrogen atom or (C1-C4)-alkyl; or A' means group of the formula CH(OH)-phenyl; or A' means the group CH=CHW wherein W means phenyl; X means S or O, and their pharmaceutically acceptable salts. These compounds are inhibitors of human immunodeficiency virus (HIV) reverse transcriptase and, therefore, can be used in treatment of HIV-mediated diseases. Also, invention relates to a pharmaceutical composition used in treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and composition.

11 cl, 5 tbl, 32 ex

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