Bicyclic derivatives of imidazo-3-ylamine, method for their preparing and medicinal agent based on thereof

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention describes derivatives of imidazo-3-ylamine of the general formula (I):

wherein X and Y mean CH or nitrogen atom (N) under condition that X and Y don't mean nitrogen atom (N) simultaneously; R1 means tert.-butyl, (CH2)nCN wherein n means 4, 5 or 6, phenyl substituted optionally with (C1-C4)-alkyl, (C1-C4)-alkoxy-group, (C4-C8)-cycloalkyl, 1,1,3,3-tetramethylbutyl or CH2Ra wherein Ra represents hydrogen atom, branched or linear (C1-C8)-alkyl, phenyl substituted optionally with halogen atom, (C1-C4)-alkoxy-group, CO(OR') wherein R' means linear (C1-C4)-alkyl or branched (C3-C5)-alkyl, PO(OR')2 wherein R' means linear (C1-C4)-alkyl or branched (C3-C5)-alkyl; R2 means hydrogen atom, CORb wherein Rb represents branched or linear (C1-C4)-alkyl; R3 means methyl, ethyl, tert.-butyl, (C3-C8)-cycloalkyl, phenyl monosubstituted optionally at position 3, 5 or 6 or optionally multisubstituted at position 4 and additionally at position 2 and/or 3, and/or 5, and/or 6 with halogen atom, hydroxyl group (OH), (C1-C4)-alkyl or (C1-C4)-alkoxy-group, naphthyl, optionally substituted (C1-C4)-alkoxy-group, di-(C1-C4)-alkylamino-group, pyrrole substituted optionally with (C1-C4)-alkyl, benzylsulfonyl, COOCH3, pyridyl substituted optionally with (C1-C4)-alkyl, OH, hydroxy-(C1-C4)-alkyl, furan substituted optionally with (C1-C4)-alkyl, nitro-group (-NO2), halogen-substituted phenyl, CH2COOCH3, COOH, thiophene substituted optionally with halogen atom, (C1-C4)-alkyl, (C1-C4)alkylsulfanyl, -NO2, phenoxy-group, thiophene, alkynylphenyl, unsubstituted anthracene or quinoline substituted optionally with halogen atom under condition that R3 doesn't means cyclohexyl-unsubstituted phenyl or phenyl monosubstituted with carboxylic acid amide at position 3 if R1 means tert.-butyl, n-propyl, n-butyl, 1,1,3,3-tetramethylbutyl, cyclohexyl, monosubstituted phenyl, 2,6-dimethylphenyl or benzyl, and R2 means simultaneously hydrogen atom or -CO-(methyl) and under condition that R2 doesn't mean hydrogen atom if R1 means benzyl simultaneously and R3 means methyl or R1 means simultaneously CH2C(O)-tert.-butyl and R3 means unsubstituted phenyl, in forms of bases or pharmaceutically acceptable salts, and a method for their preparing and a medicinal agent based on thereof. Described compounds possess analgesic activity and can be used in medicine.

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

7 cl, 2 tbl, 33 ex

 

The present invention relates to substituted bicyclic, imidazo-3-aluminum and containing these compounds medicines.

It is known that some compounds from the class of imidazo-3-ylamino have interesting in regard to pharmacological properties. For example, in a number of publications describe certain imidazo[1,2-a]pyridine as active substances that lower blood pressure (GB-1135893), as an antihelminthic funds and antifungal agents (Journ. Med. Chem. 15, str-985 (1972) and as antisecretory active substances for the treatment of inflammatory diseases (EP-A 0068378). The effectiveness of some imidazopyridines in their application against inflammatory diseases, particularly diseases of the stomach, also described in the application EP-A 0266890 and in Journ. Med. Chem. 30, str-2046 (1987).

Among other pharmacological properties possessed by individual members of the class of imidazo-3-ylamino described their antibacterial properties (Chem. Pharm. Bull. 40, str (1992)), antiviral properties (Journ. Med. Chem. 41, str-5112 (1998)), and their action as an antagonist of the benzodiazepine receptor (Journ. Heterocyclic Chem. 35, str-1217 (1998)).

Taking into account the relevance of the above properties in the past few years have been synthesized by various representatives from the class of substituted imidazo-3-ylamino. In the firstpart attempts were made to increase the practical availability replaced imidazo-3-ylamino using combined methods of synthesis. Thus, in particular, S. Blackburn, and others described in Tetrahedron Lett. 39, str-5472 (1998) three-component solid phase synthesis with the aim of obtaining imidazo-3-ylamino, and in Tetrahedron Lett. 39, str-3638 (1998) three - component condensation carried out in parallel with the synthesis of imidazo-3-ylamino. Similar to the last reaction and synthesis described K. Groebke and others in Synlett, str-663 (1998). Multicomponent reaction, which is carried in Raman synthesis of imidazo-3-ylamino and which also receive a separate imidazo-5-amines described also Navipane and .Bouzid in Angew. Chem. 110 (16), str-2352 (1998).

However, according to the prior art the ability to vary the choice of substituents at the amine nitrogen in position 2 of the imidazole ring remained in all cases limited.

Based on the foregoing, the present invention was based on the task to get other bicyclic, imidazo-3-ylamine and develop the containing medicines.

The object of the invention in accordance with this are the bicyclic imidazo-3-ylamine General formula I

in which

X and Y represent CH or N, provided that X and Y do not simultaneously denote N

R1represents tert-butyl, (CH2)nCN, where n represents 4, 5 or 6, optionally substituted phenyl,4-C8cycloalkyl, CH2CH2R(R denotes 4-morpholine), 1,1,3,3-TETRAMETHYLBUTYL or CH2Rawhere Rarepresents hydrogen, HE, WITH1-C8alkyl (branched or unbranched), optionally substituted phenyl, CO(OR') (where R' denotes unbranched1-C4alkyl or branched C1-C5alkyl), PO(OR')2(where R' denotes unbranched1-C4alkyl or branched C1-C5alkyl) or Si(RXRYRZ) (where RX, RYand RZeach independently from each other represents C1-C4alkyl (branched or unbranched), C4-C8cycloalkyl or phenyl),

R2denotes hydrogen, CORbwhere Rbrepresents a C1-C4alkyl (branched or unbranched) or (C3-C8cycloalkyl, CH2CH2CO(ORC), where RCrepresents a C1-C4alkyl (branched or unbranched, substituted, optionally substituted phenyl, optionally substituted 1-naphthyl or 2-naphthyl or optionally substituted 2-pyridyl, 3-pyridyl, 4-pyridyl, thiazolyl or furoyl, CH2phenyl, CH2CH2Rdwhere Rdrepresents optionally substituted phenyl, or CONHRewhere Rerepresents a C1-C8alkyl (branched or Neretva is undertaken), With3-C8cycloalkyl or optionally substituted phenyl,

R3denotes methyl, ethyl, tert-butyl,3-C8cycloalkyl, phenyl, optional one-deputizing at position 3, 5 or 6 or optional mnogozalny in position 4 and optionally in position 2 and/or 3 and/or 5 and/or 6, fenoxaprop, optionally substituted naphthyl, optionally substituted pyrrole, optionally substituted pyridyl, optionally substituted furan, optionally substituted thiophene, optionally substituted anthracene, optionally substituted phenanthrene or optionally substituted quinoline, provided that R3not denotes n-propyl, cyclohexyl, unsubstituted phenyl or one-deputizing in position 3 group amide carboxylic acid phenyl when R1denotes tert-botep, n-propyl, n-butyl, 1,1,3,3-TETRAMETHYLBUTYL, cyclohexyl, CH2CH2R (where R is 4-morpholine), one-deputizing phenyl, 2,6-dimetilfenil or benzyl and, simultaneously, R2denotes hydrogen or- (methyl), and R2does not denote hydrogen if R1denotes benzyl, and R3denotes methyl, or together R1denotes CH2C(O)-mpem-butyl, and R3denotes unsubstituted phenyl, in the form of bases or pharmaceutically acceptable salts.

According to the invention preferred the ri are such compounds, in which R2denotes hydrogen, R1selected from the group comprising (CH2)nCN, where n represents 4, 5 or 6, cyclohexyl, CH2WITH(methyl), 2,6-dimetilfenil, 1,1,3,3-TETRAMETHYLBUTYL, tert-butyl or n-butyl, and R3selected from the group comprising 2-pyridyl, 3-pyridyl, 2-furanyl, 2-pyrrol, methyl, tert-butyl, 3-hydroxyphenyl, 3,4-acid, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2-methoxyphenyl, 2,3-acid, 3-bromophenyl, 4-bromo-2-forfinal, 5-bromo-2-forfinal, 3-bromo-4-forfinal, 3-chlorophenyl, 3,4-dichlorophenyl, 3-forfinal, 3-were 3-phenoxyphenyl, 3-(4-chlorophenoxy)phenyl, 2-chloro-4-forfinal, 2-chloro-6-forfinal, 2,4-dimetilfenil, 2,5-dimetilfenil, 2-bromophenyl, 2-forfinal or 2-(trifluoromethyl)phenyl.

It is particularly preferred according to the invention are bicyclic, imidazo-3-ylamine from the group including

(6-sociological)-(2-pyridin-2-elimidate[1,2-a]pyridine-3-yl)amine,

(2-furan-2-elimidate[1,2-a]pyridine-3-yl)-(6-sociological)amine,

(2 cycloheximide[1,2-a]pyrazin-3-yl)-(6-sociological)amine,

(2,6-dimetilfenil)-(2-furan-2-elimidate[1,2-a]pyridine-3-yl)amine,

methyl ether (2-furan-2-elimidate[1,2-a]pyrazin-3-ylamino)acetic acid,

methyl ether (2-cyclohexylamino[1,2-a]pyrimidine-3-ylamino)acetic acid,

methyl ether (2-methylimidazo[1,2-a]pyrazin-3-ylamino)acetic acid,

(2-pyridin-elimidate[1,2-a]pyrazin-3-yl)-(1,1,3,3-TETRAMETHYLBUTYL)amine,

(2 methylimidazo[1,2-a]pyrazin-3-yl)-(1,1,3,3-TETRAMETHYLBUTYL)amine,

3-(3-tert-butylaminoethyl[1,2-a]pyridine-2-yl)phenol,

butyl[2-(2,3-dichlorophenyl)imidazo[1,2-a]pyrazin-3-yl]amine,

diethyl ester of [(2-phenylimidazo[1,2-a]pyridine-3-ylamino)methyl]phosphonic acid,

tert-butyl(2-tert-butylimido[1,2-a]pyridine-3-yl)amine, butyl(2-o-tolylimidazo[1,2-a]pyrimidine-3-yl)amine,

(2,6-dimetilfenil)-[2-(2-methoxyphenyl)imidazo[1,2-a]pyrazin-3-yl]amine,

butyl(2-o-tolylimidazo[1,2-a]pyrimidine-3-yl)amine,

tert-butyl(2-pyridin-3-elimidate[1,2-a]pyrimidine-3-yl)amine,

tert-butyl(2-methylimidazo[1,2-a]pyridine-3-yl)amine,

[2-(1H-pyrrol-2-yl)imidazo[1,2-a]pyrimidine-3-yl)]-(1,1,3,3-TETRAMETHYLBUTYL)amine,

cyclohexyl(2-furan-2-elimidate[1,2-a]pyridine-3-yl)amine,

tert-butyl(2-pyridin-3-elimidate[1,2-a]pyridine-3-yl)amine,

tert-butyl(2-pyridin-2-elimidate[1,2-a]pyridine-3-yl)amine,

tert-butyl(2-thiophene-2-elimidate[1,2-a]pyridine-3-yl)amine,

cyclohexyl(2-methylimidazo[1,2-a]pyridine-3-yl)amine,

N-cyclohexyl-N-[2-(5-methylfuran-2-yl)imidazo[l,2-a]pyridine-3-yl]acetamide", she

tert-butyl[2-(5-methylsulfonylmethane-2-yl)-imidazo[1,2-a]pyrimidine-3-yl]amine,

[2-(3-bromothiophene-2-yl)imidazo[1,2-a]pyridine-3-yl]cyclohexylamine,

2-methoxy-4-[3-(1,1,3,3-tetramethylbutylamine)imidazo[1,2-a]pyrimidine-2-yl]phenyl ester of acetic acid,

[2-(2-chloro-4-forfinal)imidazo[1,2-a]pyrimidine-3-yl]-(1,1,33-TETRAMETHYLBUTYL)amine,

(2-anthracene-9-elimidate[1,2-a]pyrazin-3-yl)tert-butylamine,

tert-butyl(2-naphthalene-1-elimidate[1,2-a]pyridine-3-yl)amine,

N-cyclohexyl-N-[2-(4,5-dimethylfuran-2-yl)imidazo[1,2-a]pyrimidine-3-yl]ndimethylacetamide and

(1,1,3,3-TETRAMETHYLBUTYL)-[2-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]pyridine-3-yl]amine.

Because the proposed bicyclic, imidazo-3-ylamine contain optically active carbon atoms, the enantiomers of these compounds and mixtures thereof are also an object of the present invention.

The object of the invention is, moreover, drugs, containing as active substance at least one bicyclic, imidazo-3-ylamine General formula I, in which R1-R3, X and Y have the above meanings, in the form of a base or pharmaceutically acceptable salts, preferably Hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, almond acid, fumaric acid, lactic acid, citric acid, glutamic acid and/or aspartic acid or primarily of hydrochloric acid.

Unexpectedly it was found that the compounds according to the invention not only are potential active substances suitable for use in the above mentioned level in the equipment testimony, but also possess analgesic effect.

Particularly preferably proposed in the invention medicines contain as active substance at least one bicyclic, imidazo-3-ylamine selected from the group including

(6-sociological)-(2-pyridin-2-elimidate[1,2-a]pyridine-3-yl)amine,

(2-furan-2-elimidate[1,2-a]pyridine-3-yl)-(6-sociological)amine,

(2 cycloheximide[1,2-a]pyrazin-3-yl)-(6-sociological)amine,

(2,6-dimetilfenil)-(2-furan-2-elimidate[1,2-a]pyridine-3-yl)amine,

methyl ether (2-furan-2-elimidate[1,2-a]pyrazin-3-ylamino)acetic acid,

methyl ether (2-cyclohexylamino[1,2-a]pyrimidine-3-ylamino)acetic acid,

methyl ether (2-methylimidazo[1,2-a]pyrazin-3-ylamino)acetic acid,

(2-pyridine-4-elimidate[1,2-a]pyrazin-3-yl)-(1,1,3,3-TETRAMETHYLBUTYL)amine,

(2 methylimidazo[1,2-a]pyrazin-3-yl)-(1,1,3,3-TETRAMETHYLBUTYL)amine,

3-(3-tert-butylaminoethyl[1,2-a]pyridine-2-yl)phenol,

butyl[2-(2,3-dichlorophenyl)imidazo[1,2-a]pyrazin-3-yl]amine, diethyl ether

[(2-phenylimidazo[1,2-a]pyridine-3-ylamino)methyl]phosphonic acid,

tert-butyl(2-tert-butylimido[1,2-a]pyridine-3-yl)amine,

butyl(2-o-tolylimidazo[1,2-a]pyrimidine-3-yl)amine,

(2,6-dimetilfenil)-[2-(2-methoxyphenyl)imidazo[1,2-a]pyrazin-3-yl]amine,

butyl(2-o-tolylimidazo[1,2-a]pyrimidine-3-yl)amine,

tert-butyl-pyridine-3-elimidate[1,2-a]pyrimidine-3-yl)amine,

tert-butyl(2-methylimidazo[1,2-a]pyridine-3-yl)amine,

[2-(1H-pyrrol-2-yl)imidazo[1,2-a]pyrimidine-3-yl)]-(1,1,3,3-TETRAMETHYLBUTYL)amine,

cyclohexyl(2-furan-2-elimidate[1,2-a]pyridine-3-yl)amine,

tert-butyl(2-pyridin-3-elimidate[1,2-a]pyridine-3-yl)amine,

tert-butyl(2-pyridin-2-elimidate[1,2-a]pyridine-3-yl)amine,

tert-butyl(2-thiophene-2-elimidate[1,2-a]pyridine-3-yl)amine,

cyclohexyl(2-methylimidazo[1,2-a]pyridine-3-yl)amine,

N-cyclohexyl-N-[2-(5-methylfuran-2-yl)imidazo[l,2-a]pyridine-3-yl]acetamide", she

tert-butyl[2-(5-methylsulfonylmethane-2-yl)-imidazo[1,2-a]pyrimidine-3-yl]amine,

[2-(3-bromothiophene-2-yl)imidazo[1,2-a]pyridine-3-yl]cyclohexylamine,

2-methoxy-4-[3-(1,1,3,3-tetramethylbutylamine)imidazo[1,2-a]pyrimidine-2-yl]phenyl ester of acetic acid,

[2-(2-chloro-4-forfinal)imidazo[1,2-a]pyrimidine-3-yl]-(1,1,3,3-TETRAMETHYLBUTYL)amine,

(2-anthracene-9-elimidate[1,2-a]pyrazin-3-yl)tert-butylamine,

tert-butyl(2-naphthalene-1-elimidate[1,2-a]pyridine-3-yl)amine,

N-cyclohexyl-N-[2-(4,5-dimethylfuran-2-yl)imidazo[1,2-a]pyrimidine-3-yl]ndimethylacetamide and

(1,1,3,3-TETRAMETHYLBUTYL)-[2-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]pyridine-3-yl]amine,

or one of the pharmaceutically acceptable salts of these compounds.

Particularly preferable to apply the bicyclic imidazo-3-ylamine together with one or more excipients to obtain with the existing drugs, designed for treatment of pain.

To obtain the appropriate medicines along with at least one active substance according to the invention use one or more auxiliary substances, preferably carriers, fillers, solvents, diluents, dyes and/or binders. The choice of auxiliary substances, as well as the quantities used depend on whether the drug for oral, intravenous, intraperitoneal, percutaneous, intramuscular, nasal, buccal or topical application. For oral administration suitable compositions in the form of tablets, pills, capsules, granules, drops, medicines and syrups, and for parenteral, local, and inhalation use can be solutions, suspensions, easily reconstructed dry compositions, as well as aerosols. Designed for percutaneous introduction of the composition may contain active substances according to the invention in a depot (i.e. for prolonged action), in dissolved form or embedded in a plaster, optionally with the addition of tools to facilitate penetration. Intended for oral or dermal application forms may release the active substances according to the invention gradually slowed down, in other words, to have a prolonged action.

Assigned to a particular patient, the amount of active ingredients varies depending on the weight of the patient, method of administration, indications for use and the severity of the disease.

The proposed synthesis of the invention compounds is as follows: amidine General formula II, primarily 2-aminopyridine, 2-aminopyrazine and derivatives of 2-aminopyridine, which is commercially available products of such companies as Acros, Avocado, Aldrich, Fluka, Lancaster, Maybridge, Merck, Sigma and TCI-Jp, is subjected to interaction with a variety of ketones or preferably with aldehydes of the formula III and isonitrile formula IV in the presence of 20%perchloric acid in a three-component reaction. Thus R1- R3, X and Y have the values specified above for compounds of formula I.

In order to ensure a trouble-free course of the reaction is an important condition is the addition of the parent compounds in the following sequence: first, amidin II, then the aldehyde III and at the end of isonitrile IV. It is preferable to conduct the reaction in dichloromethane (DHM) at a temperature preferably in the range from 0 to 40°primarily in the range from 10 to 20°C.

To obtain the compounds according to the invention, in which R2does not denote hydrogen, formed by conducting the above reaction with the unity of formula Ia, preferably after their dissolution in THF, subject depending on the desired end-product interaction with connection R2Hal, where Hal represents bromine, iodine or preferably chlorine, for example, optionally substituted alkyl-, arylhalides or acid chloride acid or optionally substituted isocyanate ReNCO in the presence of morpholinos resin (for example politicalmoneyline company Argonaut) in dichloromethane, carrying out the reaction for 2-24 h at temperatures in the range from 10 to 40°according to the following scheme:

Excess reagents are removed then from the reaction mixture by filtration through a layer immobilized on the polymer of Tris(2-amino-ethyl) - amine (manufacturer firm Novabiochem) and the filtrate is concentrated preferably in a vacuum centrifuge. The method in General can be carried out in an automated installation for synthesis.

The compounds of formula I can be translated in a known manner into their salts, using the physiologically acceptable acid, preferably Hydrobromic acid, sulfuric acid, methanesulfonate acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, almond acid, fumaric acid, lactic acid, citric acid, glutaminase the acid and/or aspartic acid and especially hydrochloric acid. The formation of salt should be carried out in an appropriate solvent, preferably in diethyl ether, diisopropyl ether, Akilova ether acetic acid, acetone or 2-butanone or in mixtures of these solvents. To obtain hydrochloride suitable also trimethylsilane in aqueous solution.

Examples

Below the invention is explained in more detail by examples, which do not limit its scope.

General recommendations 1 (automated synthesis)

This synthesis was performed on an automated installation company Zymark according to the following General recommendations.

Glass round bottom tube (diameter 16 mm, length 125 mm) with thread manually equipped with a stirrer and a capping position was closed with a screw cap with a membranous lining. With the help of a robot 1 tube was installed in the reactor block, which was kept at a temperature of 15°C. With the help of a robot 2 pipette consistently added the following reagents:

1) 1 ml of 0.1-molar solution of amidine and 20%HClO4in dichloromethane,

2) 0.5 ml of 0.3 molar solution of aldehyde in dichloromethane,

3) 0,575 ml 0.2-molar solution of isonitrile in dichloromethane.

The reaction mixture was stirred at 15°in a mixing unit for 660 minutes Then the reaction solution was filtered to position the filter. When this tube two the water was washed with dichloromethane and water in portions of 1 ml and 200 μl, respectively.

Then the tripod with tubes manually set the position of the processing, where the reaction mixture using a cyclone mixer was mixed with 3 ml of 10%NaCl solution and 1.5 ml of dichloromethane. During the next 10 minutes were thoroughly mixed in a centrifugal reactor, and the slow decrease of the speed of rotation formed a clear phase boundary. This boundary was determined by optical and the organic phase was removed by pipette. At the next stage, the reaction mixture is again mixed with 1.5 ml of dichloromethane, after which the solution was shaken, centrifuged and the organic phase was removed by pipette. The combined organic phases were dried over 2.4 g MgSO4(granulated) and the solvent was removed in a vacuum centrifuge.

General recommendation 2 (manual synthesis)

(Equivalent mean mol. equivalents in terms of used isonitrile)

In the corresponding reaction vessel suspended, respectively, was dissolved first 1.15 equivalent heterocyclic amine in dichloromethane (2 ml per mmol of used isonitrile). Then, to the suspension, respectively, to the solution was sequentially added 1.5 equivalent of aldehyde, one equivalent of isonitrile and then an aqueous solution of perchloric acid (20 wt.%; 0,098 ml per mmol of used isonitrile), after which the mixture for 20 h and was stirred at room the Oh temperature. For further processing was added a saturated solution of sodium chloride (approximately 5 ml per mmol of used isonitrile) and dichloromethane (approximately 4 ml per mmol of used isonitrile), the phases were separated and the organic phase was extracted twice more with dichloromethane (each approximately 2 ml per mmol of used isonitrile). The combined organic phases are then washed with buffer solution (pH 10; approximately 2 ml per mmol of used isonitrile) and saturated sodium chloride solution (about 2 ml per mmol of used isonitrile), dried over sodium sulfate, filtered, concentrated in vacuo using a rotary evaporator and the remaining solvent was removed in vacuum, generated by an oil pump.

All used chemicals and solvents are commercially available products. Each substance was analyzed by the method of mass spectroscopy with ionization by electron beam (MS (ESI)) and/or NMR.

General recommendation 3 (interaction with acetylchloride)

Obtained according to the General recommendations 1. the product was dissolved in dichloromethane, mixed with 4 mol. equivalents of acetylchloride and within 4 h was mixed with 18°C. Excess acetylchloride and the solvent was removed in vacuum at 40-60°C. Each substance, analisia the Ali method of mass spectroscopy with ionization by electron beam (MS (ESI)).

Example 1

6-(sociological)-(2-pyridin-2-elimidate[1,2-a]pyridine-3-yl)amine (compound 1)

Compound 1 was obtained according to General recommendation 1 from 1.0 ml of a solution of 2-aminopyridine (0,1M, DHM), 0,575 ml solution of 1,6-diisocyanate (0.2 M, DJM), 0,500 ml pyridine-2-carbaldehyde (0.3 M, DHM) and 10 μl perchloric acid (20 wt.%-Noah).

Estimated weight 321,43; found mass M-N=320,4 (MS (ESI)).

Example 2

(2-furan-2-elimidate[1,2-a]pyridine-3-yl)-(6-sociological)amine (compound 2)

Compound 2 was obtained according to General recommendation 1 from 1.0 ml of a solution of 2-aminopyridine (0.1 M, DJM), 0,575 ml solution of 1,6-diisocyanate (0.2 M, DJM), 0,500 ml of furfural (0.3 M, DHM) and 10 μl perchloric acid (20 wt.%-Noah).

Estimated weight 310,40; found mass M-N=309,4 (MS (ESI)).

Example 3

(2 cycloheximide[1,2-a]pyrazin-3-yl)-(6-sociological)amine (compound 3)

Compound 3 was obtained according to General recommendation 1 from 1.0 ml of a solution of aminopyrazine (0.1 M, DJM), 0,575 ml solution of 1,6-diisocyanate (0.2 M, DJM), 0,500 ml of cyclohexanecarboxaldehyde (0.3 M, DHM) and 10 μl perchloric acid (20 wt.%-Noah).

Estimated weight 327,48; found mass M-N=326,5 (MS (ESI)).

Example 4

(2,6-dimetilfenil)-(2-furan-2-elimidate[1,2-a]pyridine-3-yl)amine (compound 4)

Compound 4 was obtained according to General recommendation 1 from 1.0 ml of a solution of 2-aminopyridine (0,1M, DH is), 0,575 ml 2,6-dimethylbenzonitrile (0,2M, DHM), 0,500 ml of furfural (0,3M, DHM) and 10 μl perchloric acid (20 wt.%-Noah).

Estimated weight 303,37; found mass 304,4 (MS (ESI)).

Example 5

Methyl ether (2-furan-2-elimidate[1,2-a]pyrazin-3-ylamino)acetic acid (compound 5)

Compound 5 was obtained according to General recommendation 1 from 1.0 ml of a solution of aminopyrazine (0,1M, DHM), 0,575 ml methyl ester isocyanurates acid (0.2m, DHM), 0,500 ml of furfural (0,3M, DHM) and 10 μl perchloric acid (20 wt.%-Noah).

Estimated weight 272,27; found mass 273,4 (MS (ESI)).

Example 6

Methyl ether (2-cyclohexylamino[1,2-a]pyrimidine-3-ylamino)acetic acid (compound 6)

Compound 6 was obtained according to General recommendation 1 from 1.0 ml of a solution of 2-aminopyrimidine (0,1M, DHM), 0,575 ml methyl ester isocyanurates acid (0.2m, DHM), 0,500 ml of cyclohexylcarbodiimide (0,3M, DHM) and 10 μl perchloric acid (20 wt.%-Noah).

Estimated weight 288,35; found mass 289,4 (MS (ESI)).

Example 7

Methyl ether (2-methylimidazo[1,2-a]pyrazin-3-ylamino)acetic acid (compound 7)

Compound 7 was obtained according to General recommendation 1 from 1.0 ml of a solution of aminopyrazine (0,1M, DHM), 0,575 ml methyl ester isocyanurates acid (0.2m, DHM), 0,500 ml of a solution of acetaldehyde (0,3M, DHM) and 10 MK is perchloric acid (20 wt.%-Noah).

Estimated weight 220,23; found mass 221,3 (MS (ESI)).

Example 8

(2-pyridine-4-elimidate[1,2-a]pyrazin-3-yl)-(1,1,3,3-TETRAMETHYLBUTYL)amine (compound 8)

Compound 8 was obtained according to General recommendation 1 from 1.0 ml of a solution of aminopyrazine (0,1M, DHM), 0,575 ml 1,1,3,3-tetramethylbutylamine (0,2M, DHM), 0,500 ml of a solution of pyridine-4-carbaldehyde (0,3M, DHM) and 10 μl perchloric acid (20 wt.%-Noah).

Estimated weight 323,44; found mass 324,4 (MS (ESI)).

Example 9

(2 methylimidazo[1,2-a]pyrazin-3-yl)-(1,1,3,3-TETRAMETHYLBUTYL)amine (compound 9)

Compound 9 was obtained according to General recommendation 1 from 1.0 ml of a solution of aminopyrazine (0,1M, DHM), 0,575 ml 1,1,3,3-tetramethylbutylamine (0,2M, DHM), 0,500 ml of a solution of acetaldehyde (0,3M, DHM) and 10 μl perchloric acid (20 wt.%-Noah).

Estimated weight 260,39; found mass 261,4 (MS (ESI)).

Example 10

3-(3-tert-butylaminoethyl[1,2-a]pyridine-2-yl)phenol (compound 10)

Compound 10 was obtained according to General recommendation 1 from 1.0 ml of a solution of 2-aminopyridine (0,1M, DHM), 0,575 ml solution of tert-utilityfree (0,2M, DHM), 0,500 ml of hydroxybenzaldehyde (0,3M, DHM) and 10 μl perchloric acid (20 wt.%-Noah).

Estimated weight 281,36; detected by mass of 282.3 (MS (ESI)).

Example 11

Butyl[2-(2,3-dichlorophenyl)imidazo[1,2-a]pyrazin-3-yl]amine (compound 11)

Compound 11 was obtained according about what her recommendation 1 from 1.0 ml of a solution of aminopyrazine (0,1M, DHM), 0,575 ml n-utilityfree (0,2M, DHM), 0,500 ml solution of 2,3-dichlorobenzaldehyde (0,3M, DHM) and 10 μl perchloric acid (20 wt.%-Noah).

Estimated weight 335,24; found mass 335,4 (MS (ESI)).

Example 12

Diethyl ester of [(2-phenylimidazo[1,2-a]pyridine-3-ylamino)methyl]phosphonic acid (compound 12)

Compound 12 was obtained according to General recommendation 2 of 2-aminopyridine, diethylenetriaminepentaacetate, benzaldehyde and perchloric acid (20 wt.%-Noah).

The structure was analyzed by NMR spectroscopy.

Example 13

tert-Butyl(2-tert-butylimido[1,2-a]pyridine-3-yl)amine (compound 13)

Compound 13 was obtained according to General recommendation 2 of 2-aminopyridine, tert-utilitaria, piveleged and perchloric acid (20 wt.%-Noah).

The structure was analyzed by NMR spectroscopy.

Example 14

Butyl(2-o-tolylimidazo[1,2-a]pyrimidine-3-yl)amine (compound 14)

Compound 14 was obtained according to General recommendation 1 from 1.0 ml of a solution of 2-aminopyrimidine (0.1 M, DJM), 0,575 ml n-utilityfree (0,2M, DHM), 0,500 ml solution of 2-methylbenzaldehyde (0,4M, DHM) and 10 μl perchloric acid (20 wt.%-Noah).

Estimated weight 280,38; found mass 281,3 (MS (ESI)).

Example 15

(2,6-dimetilfenil)-[2-(2-methoxyphenyl)imidazo[1,2-a]pyrazin-3-yl)amine (compound 15)

Compound 15 was obtained according to the General advice is then 1 from 1.0 ml of a solution of aminopyrazine (0,1M, DHM), 0,575 ml 2,6-dimethylphenylsilane (0,2M, DHM), 0,500 ml solution of 2-methoxybenzaldehyde (0,3M, DHM) and 10 μl perchloric acid (20 wt.%-Noah).

Estimated weight 344,42; found mass 345,4 (MS (ESI)).

Example 16

Butyl(2-o-tolylimidazo[1,2-a]pyrimidine-3-yl)amine (compound 16)

Compound 16 was obtained according to General recommendation 1 from 1.0 ml of a solution of 2-aminopyrimidine (0,1M, DHM), 0,575 ml n-utilityfree (0,2M, DHM), 0,500 ml solution of 2-methylbenzaldehyde (0,4M, DHM) and 10 μl perchloric acid (20 wt.%-Noah).

Estimated weight 280,38; found mass 281,3 (MS (ESI)).

Example 17

tert-Butyl(2-pyridin-3-elimidate[1,2-a]pyrimidine-3-yl)amine (compound 17)

Compound 17 was obtained according to General recommendation 1 from 1.0 ml of a solution of 2-aminopyrimidine (0,1M, DHM), 0,575 ml solution of tert-utilityfree (0,2M, DHM), 0,500 ml pyridine-3-carbaldehyde (0,4M, DHM) and 10 μl perchloric acid (20 wt.%-Noah).

Estimated weight 267,34; found mass 268,3 (MS (ESI)).

Example 18

tert-Butyl(2-methylimidazo[1,2-a]pyridine-3-yl)amine (compound 18)

Compound 18 was obtained according to General recommendation 1 from 1.0 ml of a solution of 2-aminopyridine (0,1M, DHM), 0,575 ml solution of tert-utilityfree (0,2M, DHM), 0,500 ml of a solution of acetaldehyde (0,4M, DHM) and 10 μl perchloric acid (20 wt.%-Noah).

Estimated weight 203,29; found mass 204,3 (MS (ESI)).

Example 19

[2(1H-pyrrol-2-yl)imidazo[1,2-a]pyrimidine-3-yl]-(1,1,3,3-TETRAMETHYLBUTYL)amine (compound 19)

Compound 19 was obtained according to General recommendation 1 from 1.0 ml of a solution of 2-aminopyrimidine (0,1M, DHM), 0,575 ml 1,1,3,3-tetramethylbutylamine (0,2M, DHM), 0,500 ml pyrrole-3-carbaldehyde (0,3M, DHM) and 10 μl perchloric acid (20 wt.%-Noah).

Estimated weight 311,43; found mass=312,4 (MS (ESI)).

Example 20

Cyclohexyl(2-furan-2-elimidate[1,2-a]pyridine-3-yl)amine (compound 20)

Compound 20 was obtained according to General recommendation 2 of 2-aminopyridine, cyclohexylaniline, furfural and perchloric acid.

The structure was analyzed by NMR spectroscopy.

Example 21

tert-Butyl(2-pyridin-3-elimidate[1,2-a]pyridine-3-yl)amine (compound 21)

Compound 21 was obtained according to General recommendation 2 of 2-aminopyridine, tert-utilitaria, nicotinanilide and perchloric acid.

The structure was analyzed by NMR spectroscopy.

Example 22

tert-Butyl(2-pyridin-2-elimidate[1,2-a]pyridine-3-yl)amine (compound 22)

Compound 22 was obtained according to General recommendation 2 of 2-aminopyridine, tert-utilitaria, 2-pyridylcarbonyl and perchloric acid.

The structure was analyzed by NMR spectroscopy.

Example 23

tert-Butyl(2-thiophene-2-elimidate[1,2-a]pyridine-3-yl)amine (compound 23)

Compound 23 was obtained according to General recommendation 2 of 2-aminopyridine, tert-is utilitaria, thiophene-2-carbaldehyde and perchloric acid.

The structure was analyzed by NMR spectroscopy.

Example 24

Cyclohexyl(2-methylimidazo[1,2-a]pyridine-3-yl)amine (compound 24)

Compound 24 was obtained according to General recommendation 2 of 2-aminopyridine, cyclohexylaniline, acetaldehyde and perchloric acid.

The structure was analyzed by NMR spectroscopy.

Example 25

N-cyclohexyl-N-[2-(5-methylfuran-2-yl)imidazo[1,2-a]pyridine-3-yl]ndimethylacetamide (compound 25)

Compound 25 was obtained by interaction of the product obtained according to the General recommendations 1 from 1.0 ml of a solution of 2-aminopyridine (0,1M, DHM), 0,575 ml of cyclohexyldiamine (0,2M, DHM), 0,500 ml solution of 5-methylpyrrole (0,3M, DHM) and 10 μl perchloric acid (20 wt.%-Noah, acetylchloride according to the General recommendations 3.

Estimated weight 337,4; found mass 338,5; M-acetyl 296,5 (MS (ESI)).

Example 26

tert-Butyl[2-(5-methylsulfonylmethane-2-yl)imidazo[1,2-a]pyrimidine-3-yl]amine (compound 26)

Compound 26 was obtained according to General recommendation 1 from 1.0 ml of a solution of 2-aminopyrimidine (0,1M, DHM), 0,575 ml solution of tert-butylidenephthalide (0,2M, DHM), 0,500 ml solution of 5-methylsulfonylmethane-2-carbaldehyde (0,3M, DHM) and 10 μl perchloric acid (20 wt.%-Noah).

Estimated weight 318,5; found mass spreads for about 319.2 (MS (ESI)).

Example 27

[2-(3-brantii the h-2-yl)imidazo[1,2-a]pyridine-3-yl]cyclohexylamine (compound 27)

Compound 27 was obtained according to General recommendation 1 from 1.0 ml of a solution of 2-aminopyridine (0,1M, DHM), 0,575 ml of cyclohexyldiamine (0,2M, DHM), 0,500 ml solution of 3-bromothiophene-2-carbaldehyde (0,3M, DHM) and 10 μl perchloric acid (20 wt.%-Noah).

Estimated weight 376.3 on; found mass 376,4/378,3 (MS (ESI)).

Example 28

2-methoxy-4-[3-(1,1,3,3-tetramethylbutylamine)imidazo[1,2-a]pyrimidine-2-yl]phenyl ester of acetic acid (compound 28)

Compound 28 was obtained according to General recommendation 1 from 1.0 ml of a solution of 2-aminopyrimidine (0,1M, DHM), 0,575 ml 1,1,3,3-tetramethylbutylamine (0,2M, DHM), 0,500 ml solution of 4-formyl-2-methoxyphenyl ether acetic acid (0.3 m, DHM) and 10 μl perchloric acid (20 wt.%-Noah).

Estimated weight 410,5; found mass 411,3 (MS (ESI)).

Example 29

[2-(2-chloro-4-forfinal)imidazo[1,2-a]pyrimidine-3-yl]-(1,1,3,3-TETRAMETHYLBUTYL)amine (compound 29)

Compound 29 was obtained according to General recommendation 1 from 1.0 ml of a solution of 2-aminopyrimidine (0,1M, DHM), 0,575 ml 1,1,3,3-tetramethylbutylamine (0,2M, DHM), 0,500 ml solution of 2-chloro-4-forventelige (0,3M, DHM) and 10 μl perchloric acid (20 wt.%-Noah).

Estimated weight 374,9; found mass 375,3 (MS (ESI)).

Example 30

(2-anthracene-9-elimidate[1,2-a]pyrazin-3-yl)-tert-butylamine (compound 30)

Compound 30 was obtained according to General recommendation 1 from 1.0 ml R is the target 2-aminopyrazine (0,1M, DHM), 0,575 ml of tertbutylbenzene (0,2M, DHM), 0,500 ml antrain-9-carbaldehyde (0,3M, DHM) and 10 μl perchloric acid (20 wt.%-Noah).

Estimated weight 366,5; found mass 367,3 (MS (ESI)).

Example 31

tert-Butyl(2-naphthalene-1-elimidate[1,2-a]pyridine-3-yl)amine (compound 31)

Compound 31 was obtained according to General recommendation 1 from 1.0 ml of a solution of 2-aminopyridine (0,1M, DHM), 0,575 ml solution of tert-utilizationa (0,2M, DHM), 0,500 ml naphthalene-1-carbaldehyde (0,3M, DHM) and 10 μl perchloric acid (20 wt.%-Noah).

Estimated weight 315,4; found mass 316,3 (MS (ESI)).

Example 32

N-cyclohexyl-N-[2-(4,5-dimethylfuran-2-yl)imidazo[1,2-a]pyrimidine-3-yl]ndimethylacetamide (compound 32)

Compound 32 was obtained by interaction of the product obtained according to the General recommendations 1 from 1.0 ml of a solution of 2-aminopyrimidine (0,1M, DHM), 0,575 ml of cyclohexyldiamine (0,2M, DHM), 0,500 ml of a solution of 4,5-dimethylpyrrole (0,3M, DHM) and 10 μl perchloric acid (20 wt.%-Noah, acetylchloride according to the General recommendations 3.

Estimated weight 352,4; found mass 353,4 (MS (ESI)).

Example 33

(1,1,3,3-TETRAMETHYLBUTYL)-[2-(3,4,5-trimethoxyphenyl)imidazo[ 1,2-a]pyridine-3-yl]amine (compound 33).

Compound 33 was obtained according to General recommendation 1 from 1.0 ml of a solution of 2-aminopyridine (0,1M, DHM), 0,575 ml 1,1,3,3-tetramethylbutylamine (0,2M, DHM), 0,500 ml of a solution of 3,4,5-trimethoxybenzaldehyde (0,3M, DHM) and 10 μl perchloric acid (20 wt.%-Noah).

Estimated weight 411,5; found mass 412,3 (MS (ESI)).

Research analgesia in mice in the test for pain

Analgesic efficacy was investigated in mice by studying their behavioural response in the test on pain induced by familienaam (modified method according to I.C. Hendershot and J. Forsaith, described in Journ. Pharmacol. Exp. Ther., volume 125, str-240 (1959)). For these purposes, as experimental animals used male NMRI mice weighing 25-30 g Groups of 10 animals each, were selected for testing one dose of the test substance, 10 minutes after intravenous or subcutaneous injection of this substance was administered intraperitoneally at a dosage of 0.3 ml/mouse of a 0.02%aqueous solution of finishinga (phenylbenzophenone, the company Sigma, Deisenhofen; preparation of the solution with the addition of 5% ethanol and the extract in a water bath at 45°). Animals were placed singly in a special cell to monitor and using a push-button counter in intervals from 5 to 20 minutes after administration of finishinga counted the number of induced pain extensor movements (so-called behavioral response to pain, i.e. in this case, the bowing of the body with stretching of the hind limbs). As control served as the animals, which were introduced only physiologically the solution. All substances were tested in a standard dose of 10 mg/kg intravenously or 21,5 mg/kg subcutaneously. The percentage degree of suppression (% suppression) reaction to pain as a result of introduction of the respective substance was calculated by the following formula:

All past pilot-tested compounds showed a pronounced analgesic effect. The results are presented in the following table 1

Table:1

Research analgesia in mice in the test for pain
Example% reduction reactions pain at 21 mg/kg subcutaneously% reduction reactions pain at 10 mg/kg intravenous
1290
1386 when to 2.15 mg/kg
2043
2180
2253
2362
2456

The toxicity study

To determine the Toxicological data of the claimed compounds was carried out spymania in accordance with the method described in the company's catalog Roche No. 1465007. The results are presented in the following table 2.

Table:2

Toxicological data
structurenameestimated weightdetected mass (M+1)cytotoxicity test on cells
(3-methoxyphenyl)-[2-(5-nitrofuran-2-yl)-imidazo[1,2-a]pyridine-3-yl]amine350,1351,4100
C
(3-methoxyphenyl)-[2-(5-methylfuran-2-yl)-imidazo[1,2-a]pyridine-3-yl]amine319,1320,4100
C
(3-methoxyphenyl)-[2-(5-nitrothiophen-2-yl)-imidazo[1,2-a]pyridine-3-yl]amine366,1367,3100
C
{2-[5-(4-chlorophenyl)-furan-2-yl]-imidazo[1,2-a]pyridine-3-yl}-(3-methoxyphenyl)-amine415,1416,4100
C
{2-[5-(3-chlorophenyl)-furan-2-yl]-imidazo[1,2-a]pyridine-3-yl{-(3-methoxyphenyl)-amine415,1416,4100
C
[2-(1-benzylmethyl-1H-pyrrol-2-yl)-imidazo[1,2-a]pyridine-3-yl]-(3-methoxyphenyl)-amine444,1445,3100
C
methyl ester of 4-[3-(3-methoxyphenyl)-imidazo[1,2-a]pyridine-2-yl]-2,5-dimethyl-1H-pyrrole-3-carboxylic acid390,2391,291
K0022134
(3-methoxyphenyl)-(2-quinoline-4-yl-imidazo[1,2-a]pyridine-3-yl)-amine366,1367,580
C
[2-(2-chlorhydrin-3-yl)-imidazo[1,2-a]pyridine-3-yl]-(4-methoxybenzyl)-Amin414,1of 415.387
C
methyl ester of 4-[3-(2-chlorobenzylamino)-imidazo[1,2-a]pyridine-2-yl]-2,5-dimethyl-1H-pyrrol-3-arbonboy acid 408,1409,287
C
(4-methoxybenzyl)-[2-(3-phenoxathiin-2-yl)-imidazo[1,2-a]pyridine-3-yl]-amine427,1428,388
C
methyl ester 5-[3-(2-methoxybenzyl-amino)-imidazo[1,2-a]-pyridine-2-yl]-furan-2-yl-acetic acid391,2392,388
K0023101
(2 Chlorobenzyl)-[2-(4-methoxynaphthalene-1-yl)-imidazo[1,2-a]pyridine-3-yl]-amine413,1414,389
K0023403
(2 Chlorobenzyl)-[2-(4-dimethylaminonaphthalene-1-yl)-imidazo[1,2-a]-pyridine-3-yl]-amineto 426.2427,389
K0023411
2-hydroxy-5[3-(2-methoxybenzylamine)-imidazo[1,2-a]pyridine-2-yl]-benzoic acid389,1RUR 390.490
K0021653

Table 2
(2-methoxybenzyl)-[2-(1-methyl-1H-pyrrol-2-yl)-imidazo[1,2-a]-pyridine-3-yl]-amine332,2333,490
K0026141
(3-methoxybenzyl)-[2-(5-methyl-furan-2-yl)-imidazo[1,2-a]-pyridine-3-yl]-amine333,1334,391
C
(4-methoxybenzyl)-(2-quinoline-4-yl)-imidazo[1,2-a]pyridine-3-yl]-amine380,2381,491
C
5-hydroxymethyl-4-[3-(2-methoxybenzyl-amino)-imidazo[1,2-a]-pyridine-2-yl]-2-methyl-pyridine-3-ol390,2391,391
C
(2-[2,2']bithiophene-5-yl-imidazo[1,2-a]-pyridine-3-yl)-(4-methoxybenzyl)-Amin417,1418,392
C
(2 Chlorobenzyl)-[2-(5-phenylethynyl-thiophene-2-yl)-imidazo-[1,2-and-pyridin-3-yl]-amine 439,1440,593
C
5-[3-(2-Chlorobenzyl-amino)-imidazo-[1,2-a]-pyridine-2-yl]-furan-2-carboxylic acid367,1368,598
C
(2-methoxybenzyl)-[2-[5-phenylethynyl-thiophene-2-yl)-imidazo-[1,2-a]pyridine-3-yl]-amine435,1436,498
C

1. Bicyclic, imidazo-3-ylamine General formula I

in which X and Y represent CH or N, provided that X and Y do not simultaneously denote N, R1represents tert-butyl, (CH2)nCN, where n represents 4, 5 or 6, phenyl, optionally substituted C1-C4the alkyl, C1-C4alkoxy, C4-C8cycloalkyl, 1,1,3,3-TETRAMETHYLBUTYL or CH2Rawhere Rarepresents hydrogen, a branched or unbranched1-C8alkyl, phenyl, optionally substituted with halogen, C1-C4alkoxy, CO(OR')where R' denotes unbranched1-C4alkyl or branched C3-C5alkyl; PO(OR')2where R' denotes h is branched C 1-C4alkyl or branched C3-C5alkyl,

R2denotes hydrogen, CORbwhere Rbrepresents a branched or unbranched1-C4alkyl,

R3denotes methyl, ethyl, tert-butyl,3-C8cycloalkyl, phenyl, optional one-deputizing at position 3, 5 or 6 or optional mnogozalny in position 4 and optionally in position 2 and/or 3 and/or 5 and/or 6 halogen, HE1-C4the alkyl or C1-C4alkoxy, naphthyl, optionally substituted C1-C4alkoxy, dis1-C4alkylaminocarbonyl, pyrrole, optionally substituted C1-C4the alkyl, benzylalkonium, SOON3, pyridyl, optionally substituted C1-C4the alkyl, HE, hydroxys1-C4the alkyl, furan, optionally substituted C1-C4the alkyl, NO2substituted by a halogen phenyl, CH2SOON3, COOH, thiophene, optionally substituted with halogen, C1-C4the alkyl, C1-C4alkylsulfanyl, NO2phenoxy, thiophene, alkenylphenol, unsubstituted anthracene or quinoline, optionally substituted with halogen, provided that R3doesn't mean cyclohexyl, unsubstituted phenyl or one-deputizing in position 3 group amide carboxylic acid phenyl, e is if R 1represents tert-butyl, n-propyl, n-butyl, 1,1,3,3-TETRAMETHYLBUTYL, cyclohexyl, one-deputizing phenyl, 2,6-dimetilfenil or benzyl and, simultaneously, R2denotes hydrogen or- (methyl), and provided that R2does not denote hydrogen if R1denotes benzyl, and R3denotes methyl, or together R1denotes CH2C(O)-tert-butyl, and R3denotes unsubstituted phenyl, in the form of bases or pharmaceutically acceptable salts.

2. Bicyclic, imidazo-3-ylamine according to claim 1, characterized in that

R2denotes hydrogen,

R1selected from the group comprising (CH2)nCN, where n represents 4, 5 or 6, cyclohexyl, CH2WITH(Said;"), 2,6-dimetilfenil, 1,1,3,3-TETRAMETHYLBUTYL, tert-butyl or n-butyl,

R3selected from the group comprising 2-pyridyl, 3-pyridyl, 2-furanyl, 2-pyrrol, methyl, tert-butyl, 3-hydroxyphenyl, 3,4-acid, 2,4-dichlorophenyl, 3-bromophenyl, 4-bromo-2-forfinal, 3-bromo-4-forfinal, 3-chlorophenyl, 3,4-dichlorophenyl, 3-forfinal, 3-were 3-phenoxyphenyl, 3-(4-chlorophenoxy)phenyl, 2-chloro-4-forfinal, 2,4-dimetilfenil.

3. Bicyclic, imidazo-3-ylamine according to claim 1 or 2, characterized in that they represent the following compounds:

(6-sociological)-(2-pyridin-2-elimidate[1,2-a]pyridine-3-yl)amine,

(2-furan-2-elimidate[1,2-a]p is ridin-3-yl)-(6-sociological)amine,

(2 cycloheximide[1,2-a]pyrazin-3-yl)-(6-sociological)amine,

(2,6-dimetilfenil)-(2-furan-2-elimidate[1,2-a]pyridine-3-yl)amine, methyl ether

(2-furan-2-elimidate[1,2-a]pyrazin-3-ylamino)acetic acid,

methyl ether (2-cyclohexylamino[1,2-a]pyrimidine-3-ylamino)acetic acid,

methyl ether (2-methylimidazo[1,2-a]pyrazin-3-ylamino)acetic acid,

(2-pyridine-4-elimidate[1,2-a]pyrazin-3-yl)-(1,1,3,3-TETRAMETHYLBUTYL)amine,

(2 methylimidazo[1,2-a]pyrazin-3-yl)-(1,1,3,3-TETRAMETHYLBUTYL)amine,

3-(3-tert-butylaminoethyl[1,2-a]pyridine-2-yl)phenol, diethyl ether

[(2-phenylimidazo[1,2-a]pyridine-3-ylamino)methyl]-phosphonic acid,

tert-butyl(2-tert-butylimido[1,2-a]pyridine-3-yl)amine,

tert-butyl(2-pyridin-3-elimidate[1,2-a]pyrimidine-3-yl)amine,

tert-butyl(2-methylimidazo[1,2-a]pyridine-3-yl)amine,

[2-(1H-pyrrol-2-yl)imidazo[1,2-a]pyrimidine-3-yl)]-(1,1,3,3-TETRAMETHYLBUTYL)amine,

cyclohexyl-(2-furan-2-elimidate[1,2-a]pyridine-3-yl)amine,

tert-butyl(2-pyridin-3-elimidate[1,2-a]pyridine-3-yl)amine,

tert-butyl(2-pyridin-2-elimidate[1,2-a]pyridine-3-yl)amine,

tert-butyl(2-thiophene-2-elimidate[1,2-a]pyridine-3-yl)amine,

cyclohexyl-(2-methylimidazo[1,2-a]pyridine-3-yl)amine,

N-cyclohexyl-N-[2-(5-methylfuran-2-yl)imidazo[1,2-who]pyridine-3-yl]acetamide", she

tert-butyl[2-(5-methylsulfonylmethane-2-yl)imidazo[1,2-a]pyrimidine-3-yl]amine,

[2-(3-bromothiophene-2-yl)imidazo[1,2-a]pyridine-3-yl]cyclohexylamine,

2-methoxy-4-[3-(1,1,3,3-tetramethylbutylamine)imidazo[1,2-a]pyrimidine-2-yl]phenyl ester of acetic acid,

[2-(2-chloro-4-forfinal)imidazo[1,2-a]pyrimidine-3-yl]-(1,1,3,3-TETRAMETHYLBUTYL)amine,

(2-anthracene-9-elimidate[1,2-a]pyrazin-3-yl)tert-butylamine,

tert-butyl(2-naphthalene-1-elimidate[1,2-a]pyridine-3-yl)amine,

N-cyclohexyl-N-[2-(4,5-dimethylfuran-2-yl)imidazo[1,2-a]pyrimidine-3-yl]ndimethylacetamide and

(1,1,3,3-TETRAMETHYLBUTYL)-[2-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]pyridine-3-yl]amine.

4. Drug having analgesic activity, containing as active substance at least one bicyclic, imidazo-3-ylamine General formula I according to claim 1, in which R1,R2, R3X and Y have the meanings indicated in claim 1, in the form of a base or pharmaceutically acceptable salt.

5. The drug according to claim 4, characterized in that it contains as active substance at least one bicyclic, imidazo-3-ylamine selected from the group including

(6-sociological)-(2-pyridin-2-elimidate[1,2-a]pyridine-3-yl)amine,

(2-furan-2-elimidate[1,2-a]pyridine-3-yl)-(6-sociological)amine,

(2 cycloheximide[1,2-a]pyrazin-3-yl)-(6-sociological)amine,

(2,6-dimetilfenil)-(2-furan-2-elimidate[1,2-a]pyridine-3-yl)amine,

methyl ether (2-furan-2-elimidate[1,2-a]pyrazin-3-ylamino)acetic acid,

methyl ether (2-cyclohexylamino[1,2-a]pyrimidine-3-ylamino)acetic acid,

methyl ether (2-methylimidazo[1,2-a]pyrazin-3-ylamino)acetic acid,

(2-pyridine-4-elimidate[1,2-a]pyrazin-3-yl)-(1,1,3,3-TETRAMETHYLBUTYL)amine,

(2 methylimidazo[1,2-a]pyrazin-3-yl)-(1,1,3,3-TETRAMETHYLBUTYL)amine,

3-(3-tert-butylaminoethyl[1,2-a]pyridine-2-yl)phenol,

butyl[2-(2,3-dichlorophenyl)imidazo[1,2-a]pyrazin-3-yl]amine, diethyl ether

[(2-phenylimidazo[1,2-a]pyridine-3-ylamino)methyl]phosphonic acid,

tert-butyl(2-tert-butylimido[1,2-a]pyridine-3-yl)amine, butyl(2-o-tolylimidazo[1,2-a]pyrimidine-3-yl)amine,

(2,6-dimetilfenil)-[2-(2-methoxyphenyl)imidazo[1,2-a]pyrazin-3-yl]amine,

butyl(2-o-tolylimidazo[1,2-a]pyrimidine-3-yl)amine,

tert-butyl(2-pyridin-3-elimidate[1,2-a]pyrimidine-3-yl)amine,

tert-butyl(2-methylimidazo[1,2-a]pyridine-3-yl)amine,

[2-(1H-pyrrol-2-yl)imidazo[1,2-a]pyrimidine-3-yl)]-(1,1,3,3-TETRAMETHYLBUTYL)amine,

cyclohexyl(2-furan-2-elimidate[1,2-a]pyridine-3-yl)amine,

tert-butyl(2-pyridin-3-elimidate[1,2-a]pyridine-3-yl)amine,

tre the-butyl(2-pyridin-2-elimidate[1,2-a]pyridine-3-yl)amine,

tert-butyl(2-thiophene-2-elimidate[1,2-a]pyridine-3-yl)amine,

cyclohexyl(2-methylimidazo[1,2-a]pyridine-3-yl)amine,

N-cyclohexyl-N-[2-(5-methylfuran-2-yl)imidazo[1,2-a]pyridine-3-yl]acetamide", she

tert-butyl[2-(5-methylsulfonylmethane-2-yl)-imidazo[1,2-a]pyrimidine-3-yl]amine,

[2-(3-bromothiophene-2-yl)imidazo[1,2-a]pyridine-3-yl]cyclohexylamine,

2-methoxy-4-[3-(1,1,3,3-tetramethylbutylamine)imidazo[1,2-a]pyrimidine-2-yl]phenyl ester of acetic acid,

[2-(2-chloro-4-forfinal)imidazo[1,2-a]pyrimidine-3-yl]-(1,1,3,3-TETRAMETHYLBUTYL)amine,

(2-anthracene-9-elimidate[1,2-a]pyrazin-3-yl)tert-butylamine,

tert-butyl(2-naphthalene-1-elimidate[1,2-a]pyridine-3-yl)amine,

N-cyclohexyl-N-[2-(4,5-dimethylfuran-2-yl)imidazo[1,2-a]pyrimidine-3-yl]ndimethylacetamide and

(1,1,3,3-TETRAMETHYLBUTYL)-[2-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]pyridine-3-yl]amine,

or one of the pharmaceutically acceptable salts of these compounds.

6. Bicyclic, imidazo-3-ylamine General formula I according to claim 1 for obtaining a medicinal product intended for dealing with pain.

7. The way to obtain the bicyclic imidazo-3-ylamino General formula I according to claims 1 to 3, characterized in that amidino General formula II

where X and Y are specified in claim 1 values in dichloromethane as solvent placentas is positive add the aldehyde of General formula III

where R3has specified in claim 1 values, and isonitrile General formula IV

where R1has specified in claim 1 values

in the presence of perchloric acid, and the obtained target product, where R2means hydrogen, if necessary, is subjected to the interaction with the compound of General formula R2Hal, where R2has specified in claim 1 is, with the exception of hydrogen.



 

Same patents:

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to new derivatives of pyrrolopyrimidine of the formula (1) and their pharmaceutically acceptable salts possessing properties of selective inhibitor of specific cyclic guanosine 3',5'-monophosphate phosphodiesterase (specific cGMP PDE) (PDE V). In the formula (1) R1 represents hydrogen atom (H), (C1-C3)-alkyl substituted optionally with one or some fluorine atoms; R2 represents H, halogen atom, (C1-C6)-alkyl substituted optionally with hydroxyl group (-OH), (C1-C3)-alkoxy-group, (C3-C6)-cycloalkyl or one or some fluorine atoms, (C3-C6)-cycloalkyl; R3 represents (C1-C6)-alkyl substituted optionally with (C3-C6)-cycloalkyl or one or some fluorine atoms; R4 represents (C1-C6)-alkyl substituted optionally with one or some fluorine atoms; R5 represents -SO2NR6R, -NHSO2R8 or heterocyclyl such as tetrazolyl; each R6 and R7 represents independently H or (C1-C6)-alkyl substituted optionally with -CO2H or one or some fluorine atoms; or in common with nitrogen atom to which they are bound form monocylic ring, such as imidazole, pyrrolidine, piperidine, morpholine, piperazine and homopiperazine wherein indicated group is replaced optionally with R9 wherein R9 represents (C1-C6)-alkyl substituted optionally with one or some halogen atoms, hydroxyl group (OH), (C1-C3)-alkoxy-group that is replaced optionally with one or some fluorine atoms, -NR11R12, -C=NR13(NR14R15) or tetrazolyl group, 6-membered nitrogen-containing heteroaryl group; each R11 and R12 represents independently H or (C1-C4)-alkyl; R13represents H; each R14 and R15 represents independently H. Also, invention relates to intermediate compounds, methods for preparing compounds and pharmaceutical compositions. Proposed compounds can be used in treatment of impotency, sexual dysfunction in females, stable, nonstable and variant (Prinzmental) stenocardia and other diseases also.

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

15 cl, 1 tbl, 250 ex

FIELD: organic chemistry, medicine, hormones.

SUBSTANCE: invention describes imidazole derivatives of the formula (I) , racemic-diastereomeric mixtures and optical isomers, pharmaceutical salts wherein ---- represents an optional bond; R1 represents hydrogen atom (H), -(CH2)m-C(O)-(CH2)m-Z1, -(CH2)m-Z1; R2 represents hydrogen atom (H), or R1 and R2 are joined with nitrogen atoms to which they are bound forming compounds represented by formulae (Ia), (Ib) or (Ic) wherein R3 represents -(CH2)m-E-(CH2)m-Z2; R4 represents hydrogen atom (H) or -(CH2)m-A1; R5 represents (C1-C12)-alkyl, (C0-C6)-alkyl-C(O)-NH-(CH2)m-Z3 and optionally substituted phenyl; R6 represents hydrogen atom (H); R7 represents (C1-C12)-alkyl or -(CH2)m-Z4; m = 0 or a whole number from 1 to 6; n is a whole number from 1 to 5. Proposed compounds bind with subtypes of somatostatin receptors selectively.

EFFECT: valuable properties of compounds.

20 cl, 13776 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes 2-phenyl-substituted imidazotriazinones of the general formula (I): wherein R1 and R2 mean independently linear (C1-C4)-alkyl; R3 and R4 are similar or distinct and represent hydrogen atom or linear or branched (C1-C4)-alkenyl or (C1-C4)-alkoxy-group, linear or branched (C1-C6)-alkyl chain that can be broken by oxygen atom, and/or it can comprise from to some similar or different the following substitutes: methoxy-, hydroxy-, carboxyl, linear or branched (C1-C4)-alkoxycarbonyl, and/or residues of formulae -SO3H, -(A)a-NR7R8, -O-CO-NR7'R8', and/or wherein A means a number 0 or 1; A means residue -CO or -SO2; R7 and R8 mean hydrogen atom (H), cyclopentyl, cyclohexyl, cycloheptyl, phenyl, piperidinyl or pyridyl that can be substituted with different substitutes, methoxy-, (C1-C6)-alkyl and others; R7' and R8' mean (C1-C6)-alkyl. Also, other values of radicals R3 and R4 are given, a method for their preparing and a pharmaceutical composition. Described compounds are inhibitors of phosphodiesterases and can be used in manufacturing agents showing an anti-thrombosis, anti-proliferative, anti-vasospastic and vasodilating effect.

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

10 cl, 6 tbl, 337 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to substituted pyridines and pyridazines with angiogenesis inhibition activity of general formula I

(I)1, wherein ring containing A, B, D, E, and L represents phenyl or nitrogen-containing heterocycle; X and Y are various linkage groups; R1 and R2 are identical or different and represent specific substituents or together form linkage ring; ring J represents aryl, pyridyl or cycloalkyl; and G's represent various specific substituents. Also disclosed are pharmaceutical composition containing claimed compounds, as well as method for treating of mammalian with abnormal angiogenesis or treating of increased penetrability using the same.

EFFECT: new pyridine and pyridazine derivatives with angiogenesis inhibition activity.

26 cl, 6 tbl, 114 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, medicine, pharmacy.

SUBSTANCE: invention relates to new azaheterocycles comprising fragment of piperidin-2-yl- of the general formula (1):

as separate enantiomers or mixture of enantiomers, or their pharmaceutically acceptable salts, oxides or hydrates. In compounds of the formula (1) R1 represents hydrogen atom, inert substitute or NH-protecting substitute; W represents optionally substituted azaheterocycle, such as: pyridin-3-yl, pyrazolo[1,5-a]pyridin-6-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-7-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-9-yl, imidazo[1,2-a]pyrimidin-6-yl, imidazo[1,2-a]pyrimidin-8-yl or [1,8]naphthyridin-3-yl. Compounds elicit activity with respect to nicotine receptors and can be used in pharmaceutical industry. Also, invention relates to the focused library for search of physiologically active compound-leaders, and to pharmaceutical compositions based on new compounds of the formula (1).

EFFECT: valuable medicinal and pharmacological properties of compounds.

9 cl, 1 tbl, 15 sch, 22 ex

FIELD: organic chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention describes bicyclical nitrogen-containing heterocycles of the general formula (I): , wherein R1 means hydrogen atom, (C1-C7)-alkyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl, pyridyl, naphthyl, furyl-(C1-C4)-alkyl, phenyl optionally substituted with di-(C1-C7)-alkylamino-(C1-C7)-group, halogen atom, (C1-C7)-alkoxy-group or hydroxy-(C1-C7)-alkyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxy-group, amino-(C1-C7)-alkyl, amino-group or di-(C1-C7)-alkylamino-(C1-C7)-alkoxy-group; R2 means (C1-C7)-alkyl, (C3-C7)-cycloalkyl, furyl-(C1-C4)-alkyl, pyridyl or its N-oxide; phenyl optionally substituted with halogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-group, hydroxy-group or trifluoromethyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxy-group; R3 means hydrogen atom, (C1-C7)-alkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl, (C3-C7)-cycloalkenyl, pyridyl-(C1-C4)-alkyl, naphthyl, phenyl optionally substituted with phthalimido-(C1-C4)-alkyl, amino-(C1-C7)-alkyl, hydroxy-(C1-C7)-alkyl, (C1-C7)-alkylamino-(C1-C7)-alkyl, di-(C1-C7)-alkylamino-(C1-C7)-alkyl, morpholino-(C1-C4)-alkyl or piperazinyl-(C1-C4)-alkyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxycarbonyl or carboxy-group. Also, invention relates to pharmaceutically acceptable salts of compounds of the formula (I) as a base with acids or pharmaceutically acceptable salts of compounds of the formula (I) as acid with bases, and pharmaceutical composition based on thereof. Compounds described above show inhibitory activity with respect to tyrosine kinase and can be used in treatment or prophylaxis of inflammatory, immunological, oncological, bronchopulmonary, dermatological and cardiovascular diseases, for treatment of asthma, disorders in the central nervous system or complications associated with diabetes mellitus, or for prophylaxis against transplant rejection after surgery transplantation.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 1 tbl, 92 ex

FIELD: organic chemistry, medicine, gastroenterology, pharmacy.

SUBSTANCE: invention relates to a pyrrolopyridazine derivative of the following formula: wherein R1 represents (C3-C7)-cycloalkyl-(C1-C6)-alkyl group that can be substituted optionally with (C1-C6)-alkyl group; R2 represents (C1-C6)-alkyl group; R3 represents hydroxymethyl group, (C2-C6)-aliphatic acyloxymethyl group, (C6-C10)-arylcarbonyloxymethyl group, (C1-C6)-alkoxycarbonyloxymethyl group, formyl group, carboxyl group, (C1-C6)-alkoxycarbonyl group or (C6-C10)-aryloxycarbonyl group; R4 represents (C6-C10)-aryl group that can be substituted optionally with substitutes taken among the group consisting of (C1-C6)-alkyl groups, halogen-(C1-C6)-alkyl groups, (C1-C6)-alkoxy-groups, halogen-(C1-C6)-alkoxy-groups and halogen atoms; A represents imino-group, oxygen or sulfur atom, or its pharmaceutically acceptable salt. Pyrrolopyridazine derivatives elicit inhibitory activity with respect to gastric juice secretion and protective activity with respect to stomach mucosa and can be useful as a curative agent for prophylaxis or treatment of ulcer disease. Except for, invention relates to a pharmaceutical composition based on compounds of the invention and to a method for prophylaxis and treatment of ulcer disease.

EFFECT: valuable medicinal properties of compound.

25 cl, 1 tbl, 11 ex

FIELD: organic chemistry, pharmaceutical composition.

SUBSTANCE: compounds satisfying the formula I 1 are disclosed, wherein each R1 and R2 independently to one another are H, OH, OA or Hal; or R1 and R2 together are -O-CH2-O- or -O-CH2-CH2-O-; R3 and R4 are A-group; X - group monosubstituted with R8, R5 or R7; R5 is linear or branched C1-C10-alkylene, wherein one or two CH2-groups may be substituted with oxygen atom; R7 is phenyl or phenylmethyl; R8 is COOH, COOA, CONH2, CONHA, CON(A)2 or CN; F is C1-C6-alkyl; and Hal is F, Cl, Br, or I, as well as physiologically acceptable salts or solvates thereof. Methods for production of claimed compounds (I) and pharmaceutical composition containing the same also are disclosed. Said compounds and pharmaceutical composition have activity as phosphodiesterase V inhibitors and are useful in treatment of cardiovascular diseases and potency disorders.

EFFECT: pharmaceutically applicable compounds and compositions.

7 cl, 16 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to novel pyrasolbenzodiazepines of formula I 1 (in formula R1 is hydrogen, -NO2, -CN, halogen, -OR5, -COOR7, -CONR8R9, -NR10R11, NHCOR12, NHSO2R13; each R2 and R4 independently of one another are hydrogen, halogen, -NO2, -CF3; R3 is hydpegen, C3-C8-cycloalkyl, aryl, in particular C6-C10-aromatic group having 1 or 2 rings, 5-10-membered heteroaryl, having 1 or 2 rings and1-3 heteroatoms, selected from N, O, and S, -COOR7, CN, C2-C6-alkenyl, -CONR8R9 or C1-C6-alkyl optionally substituted with OR9-group, F or aryl as mentioned above; R5 is C1-C6-alkyl; R7 is hydrogen or C1-C6-alkyl; each independently of one another are hydrogen or C1-C6-alkyl optionally substituted with hydroxyl or NH2, or alternatively R8 and R9 together form morpholino group; each R10,R11 and R12 independently of one another are hydrogen or C1-C6-alkyl; R13 is C1-C6-alkyl optionally substituted with halogen or -NR14R15; each R14 and R15 independently of one another are hydrogen or C1-C6-alkyl optionally substituted with halogen; or alternatively -NR14R15 is morpholino group) or pharmaceutically acceptable salts thereof, as well as to certain pyrasolbenzodiazepine derivatives, thiolactam intermediates for production of compound (I) and pharmaceutical compositions containing the same. Compound and pharmaceutical composition of present invention are cycline-dependent kinase (CDK2) inhibitors and antiproliferation agents used in treatment or controlling disorders associated with cell proliferation, in particular breast, colon, lung and/or prostate tumors.

EFFECT: new antiproliferation agents.

20 cl, 12 tbl, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:

; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.

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

40 cl, 51 tbl, 741 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds. Invention describes compounds or their salts of the general formula (I): A-B-N(O)s (I) wherein s = 2; A means R-T1- wherein R represents radical of a medicinal substance under condition that a medicinal substance by the formula R-T1-Z or R-T1-OZ wherein Z represents hydrogen atom (H) or (C1-C5)-alkyl is taken among paracetamol, salbutamol, ambroxol, alendronic acid,, cetirizine, ampicillin, aciclovir, doxorubicin, simvastatin, diphylline, tacrine, clopidogrel, dimethylomeprazol, diclofenac, ferulic acid, enalapril, propranolol, benfurodil hemisuccinate, tolrestate or sulindac; T1 means (CO), oxygen atom (O) or NH; B means TB-X2-O- wherein TB means bivalent radical R1B-X-R2B wherein R1B and R2B are similar or different and represent linear or branched (C1-C6)-alkylenes and X represents a bond, oxygen (O), sulfur (S) atom or NR1C wherein NR1C represents hydrogen atom (H) or linear or branched (C1-C6)-alkyl; corresponding precursor B is represented by the formula -TB-X2-OH wherein TB means (CO) and free valence in TB represents -OZ wherein Z is determined above, or TB means oxygen atom (O), and free valence in TB represents hydrogen atom (H) under condition that in the formula (I) when X2 in precursor B represents linear or branched (C2-C20)-alkylene then a medicinal substance by the formula R-T1-Z or R-T1-OZ used in the formula (I) doesn't belong to the following substances: enalapril (ACE inhibitors) and diclofenac (NSAID). Also, invention describes pharmaceutical compositions for using in cases of oxidative stress and 4-nitroxybutanoic acid 4'-acetylaminophenyl ester. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of medicinal substances and compositions.

7 cl, 8 tbl, 32 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of carboxylic acids of the formula: wherein Y is taken independently in each case among the group comprising C(O), N, CR1, C(R2)(R3), NR5, CH; q means a whole number from 3 to 10; A is taken among the group comprising NR6; E is taken among the group comprising NR7; J is taken among the group comprising O; T is taken among the group comprising (CH2)b wherein b = 0; M is taken among the group comprising C(R9)(R10), (CH2)u wherein u means a whole number from 0 to 3; L is taken among the group comprising NR11 and (CH2)n wherein n means 0; X is taken among the group comprising CO2H, tetrazolyl; W is taken among the group comprising C, CR15 and N; R1, R2, R3 and R15 are taken independently among th group comprising hydrogen atom, halogen atom, hydroxyl, alkyl, alkoxy-group, -CF3, amino-group, -NHC(O)N(C1-C3-alkyl)-C(O)NH-(C1-C3-alkyl), -NHC(O)NH-(C1-C6-alkyl), alkylamino-, alkoxyalkoxy-group, aryl, aryloxy-, arylamino-group, heterocyclyl, heterocyclylalkyl, heterocyclylamino-group wherein heteroatom is taken among N atom or O atom, -NHSO2-(C1-C3-alkyl), aryloxyalkyl; R4 is taken among the group comprising hydrogen atom, aryl, aralkyl, benzofuranyl, dihydrobenzofuranyl, dihydroindenyl, alkyl, benzodioxolyl, dihydrobenzodioxynyl, furyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, indolyl, thienyl, biphenyl, 2-oxo-2,3-dihydro-1H-benzimidazolyl, pyrimidinyl and carbazolyl. Other values of radicals are given in the claimed invention. Also, invention relates to pharmaceutical composition used for inhibition binding α4β1-integrin in mammal based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof in aims for treatment or prophylaxis of diseases associated with α4β1-integrin.

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

33 cl, 7 tbl, 42 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, medicinal biochemistry, pharmacy.

SUBSTANCE: invention relates to substituted benzimidazoles of the formula (I): and/or their stereoisomeric forms, and/or their physiologically acceptable salts wherein one of substitutes R1, R2, R3 and R4 means a residue of the formula (II): wherein D means -C(O)-; R8 means hydrogen atom or (C1-C4)-alkyl; R9 means: 1. (C1-C6)-alkyl wherein alkyl is linear or branched and can be free of substituted by one-, bi- or tri-fold; Z means: 1. a residue of 5-14-membered aromatic system that comprises from 1 to 4 heteroatoms as members of the cycle that represent nitrogen and oxygen atoms wherein aromatic system is free or substituted; 1.1 a heterocycle taken among the group of oxadiazole or oxadiazolone that can be unsubstituted or substituted; 2. (C1-C6)-alkyl wherein alkyl is a linear or branched and monosubstituted with phenyl or group -OH; or 3. -C(O)-R10 wherein R10 means -O-R11, -N(R11)2 or morpholinyl; or R8 and R9 in common with nitrogen atom and carbon atom with that they are bound, respectively, form heterocycle of the formula (IIa): wherein D, Z and R10 have values given in the formula (II); A means a residue -CH2-; B means a residue -CH-; Y is absent or means a residue -CH2-; or X and Y in common form phenyl. The cyclic system formed by N, A, X, Y, B and carbon atom is unsubstituted or monosubstituted with (C1-C8)-alkyl wherein alkyl is monosubstituted with phenyl, and other substitutes R1, R2, R3 and R4 mean independently of one another hydrogen atom, respectively; R5 means hydrogen atom; R6 means the heteroaromatic cyclic system with 5-14 members in cycle that comprises 1 or 2 nitrogen atoms and can be unsubstituted or substituted. Also, invention relates to a medicinal agent for inhibition of activity of IkB kinase based on these compounds and to a method for preparing the indicated agent. Invention provides preparing new compounds and medicinal agents based on thereof for aims for prophylaxis and treatment of diseases associated with the enhanced activity of NFkB.

EFFECT: valuable medicinal properties of compounds and composition.

4 cl, 7 tbl, 224 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives if azaindole of the formula (I)

or its pharmaceutically acceptable salts wherein the formula is taken among the group consisting of , , and and wherein each among R1, R2, R3 and R4 is taken independently among the group consisting of hydrogen atom (H), (C1-C6)-alkyl, (C2-C6)-alkenyl, halogen atom, cyano-group (CN), phenyl, nitro-group, -OC(O)R15, -C(O)R15, -C(O)OR16, -OR19, -SR20 and NR21R22 wherein R15 is taken independently among the group including hydrogen atom (H),(C1-C6)-alkyl and (C2-C6)-alkenyl; each among R16, R19 and R0 is taken independently among the group including hydrogen atom (H), (C1-C6)-alkyl or (C1-C6)-alkyl substituted with from 1 to 3 halogen atoms; each among R21 and R22 is taken among the group including hydrogen atom(H), hydroxy-group (OH), (C1-C6)-alkyl; R5 represents the group (O)m wherein m = 0 or 1; n = 1 or 2; R6 is taken among the group including hydrogen atom (H), (C1-C6)-alkyl, -C(O)R24 and -C(O)OR5 under condition that carbon atoms comprising carbon-carbon double bond of indicated (C3-C6)-alkenyl are not the addition point to nitrogen atom to which R6 is joined; R24 is taken among the group consisting of hydrogen atom (H), and (C1-C6)-alkyl; R25 represents (C1-C6)-alkyl; each among R7, R8, R9, R10, R11, R12, R13 and R14 is taken independently among the group including hydrogen atom (H) and (C1-C6)-alkyl; Ar is taken among the group including:

, and . Compounds of the formula (I) inhibit HIV-1 that allows proposing their applying in medicine.

EFFECT: valuable medicinal and antiviral properties of compounds.

22 cl, 13 sch, 2 tbl

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, medicine, pharmacy.

SUBSTANCE: invention relates to new azaheterocycles comprising fragment of piperidin-2-yl- of the general formula (1):

as separate enantiomers or mixture of enantiomers, or their pharmaceutically acceptable salts, oxides or hydrates. In compounds of the formula (1) R1 represents hydrogen atom, inert substitute or NH-protecting substitute; W represents optionally substituted azaheterocycle, such as: pyridin-3-yl, pyrazolo[1,5-a]pyridin-6-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-7-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-9-yl, imidazo[1,2-a]pyrimidin-6-yl, imidazo[1,2-a]pyrimidin-8-yl or [1,8]naphthyridin-3-yl. Compounds elicit activity with respect to nicotine receptors and can be used in pharmaceutical industry. Also, invention relates to the focused library for search of physiologically active compound-leaders, and to pharmaceutical compositions based on new compounds of the formula (1).

EFFECT: valuable medicinal and pharmacological properties of compounds.

9 cl, 1 tbl, 15 sch, 22 ex

FIELD: organic chemistry, medicine, psychiatry, pharmacy.

SUBSTANCE: invention relates to medicinal agents used for prophylaxis and treatment of schizophrenia by inhibition or suppression of neurodegenerative disease caused by hypofunction of glutamic acid receptors. As an active component agents comprise derivative of 5-substituted 3-oxadiazolyl-1,6-naphthiridine-2(1H)-one of the formula (I):

wherein Het represents oxadiazolyl group; R1 represents hydrogen atom, lower alkyl group, lower cycloalkyl group, trifluoromethyl group, lower alkenyl group, lower alkynyl group, lower alkoxyl group, lower alkoxy-(lower)-alkyl group, lower hydroxyalkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group; R2 represents hydrogen atom, lower alkyl group, lower cycloalkyl group, lower cycloalkylmethyl group, lower alkenyl group, lower cycloalkenyl group, lower alkynyl group, substituted or unsubstituted aryl group and substituted or unsubstituted heteroaryl group wherein indicated groups represent phenyl or naphthyl and indicated heteroaryl groups represents furyl, thienyl or pyridyl, or their physiologically acceptable acid-additive salts.

EFFECT: valuable medicinal properties of agents.

10 cl, 1 tbl

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines of the general formula (1)

that are effective inhibitors if caspase-3 that can be used for preparing medicinal agents and for experimental (in vitro, in vivo) investigation of apoptosis processes as "pharmacological tools". Also, invention proposes pharmaceutical composition and a method for their preparing and applying. In the general formula (1) radicals R1, R2, R3 and R8 represent independently of one another hydrogen atom, halogen atom, CF3, CN, inert substitute, optionally substituted hydroxyl group, optionally substituted carboxy-(C1-C6)-alkyl group, optionally substituted carbamoyl group; R4 represents hydrogen atom, halogen atom, inert substitute, optionally substituted amino-group, substituted hydroxyl group; R5 represents hydrogen atom, inert substitute, optionally substituted hydroxy-(C1-C5)-alkyl, optionally substituted amino-(C1-C7)-alkyl, optionally substituted amino-group, optionally substituted hydroxyl group; R6 and R7 represent independently of one another hydrogen atom, inert substitute, optionally substituted amino-(C1-C7)-alkyl, optionally substituted amino-group, optionally substituted hydroxyl group; or R6 and R7 in common with nitrogen atom to which they are bound represent optionally substituted and optionally additionally including heteroatom taken among group: oxygen, nitrogen or sulfur, 3-10-membered cycle; or R6 and R7 in common with nitrogen atom to which they are bound represent condensed heterocycle being optionally substituted and optionally additionally including heteroatom taken among group: oxygen, nitrogen or sulfur.

EFFECT: improved preparing method and treatment.

9 cl, 19 sch, 7 tbl, 25 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:

; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.

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

40 cl, 51 tbl, 741 ex

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