Derivatives of aminoquinoline and aminopyridine and their using as adenosine ligands a3

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of aminoquinoline and aminopyridine. Invention describes compounds of the general formula (I): wherein R1 means hydrogen atom or direct or branched (C1-C4)-alkyl group; R2 means hydrogen atom or direct or branched (C1-C4)-alkyl group; R3 means hydrogen atom or direct or branched (C1-C4)-alkyl group or phenyl group, thienyl group or furyl group optionally substituted with one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group or halogen atom; R4 and R5 form in common 1,3-butadienyl group optionally substituted with methylenedioxy-group or one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group, hydroxy-group or halogen atom; R6 means hydrogen atom or cyano-group; R7 means hydrogen atom or direct or branched (C1-C4)-alkyl group, phenyl group, benzyl group, thienyl group, or furyl group optionally substituted with methylenedioxy-group or one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group, hydroxy-group, trifluoromethyl group, cyano-group or halogen atom; X means -NH-group, -NR8-group or sulfur atom, or oxygen atom, or sulfo-group, or sulfoxy-group wherein R8 means direct or branched (C1-C4)-alkyl group or (C3-C6)-cycloalkyl group; n = 0, 1 or 2, and their salts. Also, invention describes a method for preparing compounds of the formula (I). a pharmaceutical composition based on thereof, using compounds of the formula (I) as antagonists of A3 receptors for preparing a pharmaceutical composition used in treatment of different diseases (variants), compounds of the formula (IA), (II), (III) and (IV) given in the invention description. Invention provides preparing new compounds possessing the useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

15 cl, 6 tbl, 6 dwg, 172 ex

 

This invention relates to ligands of the receptor adenosine A3General formula (I), preferably antagonists, and their salts, solvate, and isomers and containing pharmaceutical compositions, to the use of compounds of General formula (I)and their salts, solvate and isomers, to obtain compounds of General formula (I) and their salts, solvate or isomer, as well as to new intermediate compounds of General formula (II), (III) and (IV) and to receive them.

Adenosine is a well-known component of several endogenous molecules (ATP, NAD+, nucleic acids). In addition, it plays an important regulatory role in many physiological processes. The effect of adenosine on the heart function was detected as early as 1929 (Drury and Szentgyörgyi, J. Physiol 68:213, 1929). Identification of an increasing number of physiological functions, mediasound of adenosine, and the opening of new subtypes of adenosine receptor has provided the opportunity for therapeutic application of specific ligands (Poulse, S.A. and Quinn, R. J. Bioorganic and Medicinal Chemistry 6:619, 1998).

To date adenosine receptors have been classified into three main classes: (A1And2and a3. Subtype And1partially responsible for the inhibition of adenylate cyclase in combination with protein Gimembrane, partially affects other systems secondary messing the EPA. Subtype receptor And2can be divided into two further subtypes - A2Aand a2bthat stimulate adenylate cyclase activity. The sequence of the receptors of adenosine A3was recently identified from a cDNA library of the testes of rats. It was later proven that it complies with the new functional adenosine receptor. Activation of receptors And3also associated with multiple second messenger systems: inhibition of adenylate cyclase, stimulation of phospholipase C and D.

Adenosine receptors are found in several organs and regulate their functions. Both receptor And1and a3play an important role in the Central nervous system and cardiovascular system. In the CNS, adenosine inhibits the release of synaptic transmitters, this action madirovalo receptors And1. In the heart of the receptors And1mediashout negative inotropic, chronotropic and dromotropic effects of adenosine. Adenosine receptors And2Alocated in relatively large quantities in the striatum, demonstrate a functional interaction with dopamine receptors in the regulation of synaptic transmission. Adenosine receptors And2Aon the endothelial cells and smooth muscle responsible for induced adenosine vasodilation.

On the basis of the ID manually is their mRNA adenosine receptors And 2bwidely distributed in various tissues. They were found in almost every cell type, but their greatest expression observed in the intestine and bladder. This subtype will probably also has an important regulatory function in the regulation of vascular tone and plays a role in the functioning of mastocytes.

Unlike receptors And1and a2Atheir distribution in tissues is determined at the protein level, the presence of receptors And2band a3is determined on the basis of their level of mRNA. Expression levels of receptors for adenosine A3relatively slow compared with other subtypes, and to a large extent depends on the species. Adenosine receptors And3expressed primarily in the Central nervous system, testes, immune system and are likely involved in modulating the selection of a mediator from mastocytes in direct reaction of hypersensitivity.

Antagonists And3described in the literature at present, belong to the group of flavonoids and derivatives of 1,4-dihydropyridines, triazolopyridazines, thiazoleethanol and triazolopyrimidines. This invention relates to a new type of effective antagonists And3that have aminoquinolinic structure.

For therapeutic applications, it is important to be sure that the mole is ula is not attached or is attached only in the case of very high concentrations of a 1And2Aand a2bsubtypes of adenosine receptor. This invention relates to compounds of General formula (I)and their salts, solvate and isomers, which have greater selectivity to the subtype And3the adenosine receptor.

The purpose of this invention to provide ligands And3which first of all have a quinoline structure, preferably antagonists, which have a strong antagonistic effect and show a high selectivity to the receptor And3i.e. they inhibit the receptor And3in much lower concentrations than they inhibit the receptors And1And2Aand a2b. Another goal is to obtain such stability, bioavailability, therapeutic index and toxicity, which allow you to apply new compounds in medicinal substances, which due to their good absorption in the small intestine can be administered orally.

Found that compounds of General formula (I), where

R1is a hydrogen atom or a straight or branched C1-4alkyl group;

R2is a hydrogen atom or a straight or branched C1-4alkyl group;

R3is a hydrogen atom or a straight or branched C1-4alkyl group, or phenyl group, thienyl group or fu is strong group, optionally substituted by one or more straight or branched C1-4alkyl group, straight or branched C1-4alkoxygroup or halogen atom, or is a 5 - or 6-membered heteroaromatic ring containing one, two or three nitrogen atom, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulphur atom, optionally substituted by one or more straight or branched C1-4alkyl group, straight or branched

With1-4alkoxygroup or a halogen atom;

R4and R5is a hydrogen atom, or together they form a 1,3-butadienyl group, optionally substituted by methylendioxyphenyl or one or more straight or branched C1-4alkyl group, straight or branched

With1-4alkoxygroup, hydroxy-group or a halogen atom;

R6is a hydrogen atom or a cyano, aminocarbonyl group1-4alkoxycarbonyl group or carboxypropyl;

R7is a hydrogen atom or a straight or branched C1-4alkyl group or phenyl group, benzyl group, thienyl group or shriley group, optionally substituted by methylendioxyphenyl or one or more straight or branched C1-4alkyl group, straight or razwell is authorized

With1-4alkoxygroup, hydroxy-group, triptorelin group, cyano or halogen atom, or is a 5 - or 6-membered heteroaromatic ring containing one, two or three nitrogen atom or one nitrogen atom and one oxygen atom or one nitrogen atom and one sulphur atom, optionally substituted by one or more straight or branched C1-4alkyl group, straight or branched C1-4alkoxygroup or a halogen atom,

X is-CH2group, a-NH - group, -NR8group or sulfur atom or an oxygen atom or sulfopropyl, or sulfoxylate, where R8is a straight or branched C1-4alkyl group or a C3-6cycloalkyl group;

n is zero, 1 or 2,

and their salts, solvate and isomers, and salts, solvate last meet this criterion.

The exact values of the above substituents are as follows.

Under straight or branched C1-4alkyl group understand methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-, sec-butyl, tert-butyl, preferably ethyl or methyl group.

Under straight or branched C1-4alkoxygroup understand methoxy-, ethoxy-, propoxy-, isopropoxy, butoxy, isobutoxy-, second -, butoxy-, tert-butoxy, preferably ethoxy or a methoxy group.

Under the C3-6 cycloalkyl group understand cyclopropyl-, cyclobutyl, cyclopentyl or tsiklogeksilnogo group.

Under 1,3-butadienyl group understand (-CH=CH-CH=CH-) group, for example a pyridine ring, a substituted R4and R5Vice is benzopyrylium ring or, if we call it the trivial name, quinoline ring.

Heteroaromatic ring containing one, or two, or three nitrogen atom, include pyrrole, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, pyridine, pyrimidine, pyridazine, pyrazin and 1,3,4-triazine ring. Ring optionally substituted C1-4the alkyl or alkoxygroup or a halogen atom.

Heteroaromatic ring containing one nitrogen atom and one oxygen atom or sulfur, includes oxazol, isoxazol, thiazole, isothiazol. Ring optionally substituted C1-4the alkyl or alkoxygroup, or a halogen atom.

Salts of compounds of General formula (I) include salts derived from inorganic and organic acids and bases. The preferred salts are the salts derived from pharmaceutically acceptable acids, for example hydrochloric acid, sulfuric acid, econsultation, tartaric acid, succinic acid, fumaric acid, malic acid, citric acid, and bases such as, for example, sodium hydroxide, potassium hydroxide, ethanolamine.

The solvate Osnach who have a solvate, obtained with different solvents such as water or ethanol.

Compounds of General formula (I) have geometrical and optical isomerism, therefore, this invention also relates to mixtures of geometric isomers, racemic or optically active geometric isomers, and their salts and solvate.

A preferred group of compounds of General formula (I) are compounds of General formula (IA) in which

R1is a hydrogen atom or a straight or branched C1-4alkyl group;

R2is a hydrogen atom or a straight or branched C1-4alkyl group;

R3is a hydrogen atom or a straight or branched C1-4alkyl group, or phenyl group, thienyl group or shriley group, optionally substituted by one or more straight or branched C1-4alkyl group, straight or branched C1-4alkoxygroup or halogen atom, or is a 5 - or 6-membered heteroaromatic ring containing one, two or three nitrogen atom or one nitrogen atom and one oxygen atom or one nitrogen atom and one sulphur atom, optionally substituted by one or more straight or branched C1-4alkyl group, straight or branched

With1-4alkoxygroup or a halogen atom;

R9, R10, R11and R12independently are a hydrogen atom or a straight or branched C1-4alkyl group, straight or branched C1-4alkoxygroup, hydroxy-group or halogen atom, or

R9and R12are a hydrogen atom and R10and R11together form methylenedioxy;

R6is a hydrogen atom or a cyano, aminocarbonyl group1-4alkoxycarbonyl group or carboxypropyl;

R7is a hydrogen atom or a straight or branched C1-4alkyl group or phenyl group, benzyl group, thienyl group, shriley group, optionally substituted by methylendioxyphenyl or one or more straight or branched C1-4alkyl group, straight or branched

With1-4alkoxygroup, hydroxy-group, triptorelin group, cyano or halogen atom, or is a 5 - or 6-membered heteroaromatic ring containing one, two or three nitrogen atom or one nitrogen atom and one oxygen atom or one nitrogen atom and one sulphur atom, optionally substituted by one or more straight or branched C1-4alkyl group, straight or branched C1-4alkoxygroup or a halogen atom,

X is-CH2group, -NH - gr is POI, -NR8group or sulfur atom or an oxygen atom or sulfopropyl or sulfoxylate, where R8is a straight or branched C1-4alkyl group or a C3-6cycloalkyl group;

n is zero, 1 or 2,

and their salts, solvate and isomers, and salts, solvate of the latter.

A preferred group of compounds of General formula (IA) are compounds in which

R1is a hydrogen atom or methyl group;

R2is a hydrogen atom or methyl group;

R3is phenyl, thienyl or shriley group;

R9, R10, R11and R12independently are a hydrogen atom or a straight or branched C1-4alkyl group, straight or branched C1-4alkoxygroup, hydroxy-group or halogen atom, or

R9and R12are a hydrogen atom and R10and R11together form methylenedioxy;

R6is a hydrogen atom or cyano;

R7is a 4-metoksifenilny, 3-methylphenylene, 3-metoksifenilny, 3-thienyl or 3-shriley group,

X is-NH - group or an oxygen atom, and

n is 1,

and their salts, solvate and isomers, and salts, solvate of the latter.

Especially preferred are the following compounds responsible presents is use criteria:

3-methyl-N-(4-benzylamino-3-cyanohydrin-2-yl)benzamide;

4-methoxy-N-(4-benzylamino-3-cyanohydrin-2-yl)benzamide;

3-methoxy-N-(4-benzylamino-3-cyanohydrin-2-yl)benzamide;

3,4-methylendioxy-N-(4-benzylamino-3-cyanohydrin-2-yl)benzamide;

N-(4-benzylamino-3-cyanohydrin-2-yl)thiophene-2-carboxamide;

N-(4-[2-titelmelodie]-3-cyanohydrin-2-yl)thiophene-3-carboxamide;

4-methoxy-N-(4-[2-titelmelodie]-3-cyanohydrin-2-yl)benzamide;

3,4-methylendioxy-N-(4-[2-titelmelodie]-3-cyanohydrin-2-yl)benzamide;

N-(4-[2-pyrimethamine]-3-cyanohydrin-2-yl)furan-2-carboxamide;

N-(4-[2-pyrimethamine]-3-cyanohydrin-2-yl)thiophene-3-carboxamide,

and their salts, solvate and isomers, and their salts, solvate.

According to another aspect, the invention also relates to pharmaceutical compositions containing as active ingredient compounds of General formula (I) or their isomers, salts and solvate, which are preferably compositions for oral use, but the object of the present invention are also inhalation, parenteral and transdermal composition. The above pharmaceutical compositions may be solid or liquid, such as tablets, pills, capsules, plasters, solutions, suspensions or emulsions. Solid compositions, particularly tablets and capsules are preferred headlamp is aceticism forms.

The above pharmaceutical composition is produced by adding the usual pharmaceutical excipients using standard methods.

Compounds of General formula (I) can be used in the treatment of pathologies in the development of which plays the role of the receptor And3.

Compounds in accordance with this invention have selective activity against receptor And3can be used for therapeutic and/or prophylactic treatment of dysfunctions of the heart, kidneys, respiratory system, Central nervous system. They inhibit the protective effect of adenosine in growing tumor cells, prevent the degranulation of mastocytes, inhibit the production of cytokines, reduce intraocular pressure, inhibit the secretion of TNFα, inhibit the migration of eosinophils, neutrophils and other immune cells, inhibit bronchostenosis and transudate plasma.

Whereas the above-described action, the receptor antagonists of the adenosine A3in accordance with this invention can be used therapeutically as anti-inflammatory agents, anti-asthma agents, anti-ischemic agents, antidepressants, anti-arrhythmic agents, renal protective agents, antitumor agents, antiparkinsonian agents, and agents that improve cognitive ability, the institutional capacity. They can also be used in the treatment or prevention of myocardial reperfusion injury, chronic obstructive pulmonary disease (COPD) and respiratory distress syndrome in adults (rdsw), including chronic bronchitis, pulmonary emphysema or dyspnea, allergic reactions (e.g., rhinitis, reactions to poison ivy, hives, scleroderma, arthritis, and other autoimmune diseases, inflammation of the intestine, Addison's disease, Crohn's disease, psoriasis, rheumatism, hypertension, disorders of neurological function, glaucoma and diabetes (K.N. Klotz, Naunyn-Schmiedberg''s Arch. Pharmacol. 362:382, 2000; P.G. Baraldi and P.A. Borea, TiPS 21:456, 2000).

Compounds in accordance with this invention preferably can be used to treat diseases such as asthma, COPD and rdsw, glaucoma, tumors, allergic and inflammatory diseases, ischemia, hypoxia, arrhythmias and kidney diseases.

According to another aspect of this invention relates to the use of compounds of General formula (I) for the treatment of the above disorders. We offer a daily dose of from 1 to 100 mg of active ingredient, depending on the nature and severity of the disease and sex, weight, etc. of the patient.

Another object of this invention to provide compounds of General formula (I) and intermediates of General formula (II), (III) and (IV).

About eroticne compounds of General formula (II), (III) and (IV), which are used in the retrieval process in accordance with this invention, are partly new. The substituents in the General formula (II), (III) and (IV) have the above values.

In the method in accordance with this invention bis-carboxamide General formula (II) selectively hydrolyzing and the compound obtained of General formula (I), if desired, converted into its salt, solvate or separated from its salts, MES and divided into geometric or optical isomers.

The substituents of the compounds of General formula (I) can be converted into each other known methods.

The selective hydrolysis is carried out with the use of alcohol solution, preferably a solution of alkali metal hydroxide in methanol, preferably solutions of potassium hydroxide and/or sodium, but can also apply to other agents that promote the hydrolysis of amides.

Selective hydrolysis can be conducted in a wide range of temperatures, preferably at from 20 to 100°C.

Compounds of General formula (II)in which R1, R2, R3, R4, R5, R6, R7, R8, X and n are such as defined above, can be obtained by several known methods, one of which is shown in scheme 1 (6), by acylation of compounds of formula (III) using the method of acylation, known in the field of organic is their share capital. As Alliluyeva agent may be used acylchlorides, as the acid binding agent is triethylamine and/or pyridine, can also be used other agents that bind acid.

Compounds of General formula (III)in which R1, R2, R3, R4, R5, R6, R8, X and n are such as defined above, can be obtained from compounds of formula (IV) by methods known in the art (Nan Zhang, Bioorg. and Med. Chem. Lett., 10, 2825, 2000).

Compounds of General formula (IV)in which R4, R5and R6such as defined above, can be obtained from compounds of formula (V) by methods known in the art (D.L. Leysen, J. Heterocyclic Chem., 24, 1611, 1987).

Compounds of General formula (V)in which R4, R5and R6such as defined above, can be obtained from compounds of formula (VI) by methods known in the art (Pfizer Inc) USP 4175193).

Compounds in accordance with this invention of the General formula (I), (II), (III) and (IV)receive and biological activity demonstrated by the following examples without limiting the scope of formulas of the present invention.

Figure 1 shows the General formula (I), figure 2 shows the General formula (IA), figure 3 shows the General formula (II), figure 4 shows the General formula (III) and figure 5 shows the General formula (IV), the and 6 shows scheme 1, the course of the reaction to obtain compounds of General formula (I).

EXAMPLES

Example 1

3-Methyl-N-(4-benzylamino-3-cyanohydrin-2-yl)benzamide:

In the General formula (I) R1and R2are hydrogen atoms, R3is a phenyl group, R4and R5together form 1,3-butadienyl group, R6is cyano, R7the 3-methylphenylene group, X is-NH group, n is 1.

a) 2-Amino-3-cyano-4-chlorhydrin:

A mixture of 10 g of 2-amino-3-cyano-4-hydroxyquinoline solution and 15 ml of phosphorylchloride heated under stirring at a temperature of 110°C. the Reaction mixture is cooled, poured into 100 ml of a mixture of ice-water and neutralized with 60 ml of 10% sodium hydroxide solution. The obtained yellow precipitate is filtered off, washed with 50 ml of water. After drying receive 7.5 g specified in the connection header, so pl. 210°C.

NMR, δn(400 MHz, DMSO-d6): 7,21 ppm, (s, 2H, NH2), 7,35-7,40 ppm, (DD, 1H, 6-H), 7,53-EUR 7.57 ppm (d, 1H, 5-H), 7,70 to 7.75 ppm, (DD, 1H, 7-H), to 7.93-7,98 ppm, (d, 1H, 8-H)

b) 2-Amino-3-cyano-4-benzylaminopurine:

5 g of 2-Amino-3-cyano-4-chlorhydrin and 11 ml of benzylamine heated under stirring at a temperature of 130°C. the Reaction mixture was poured into 50 ml water, the precipitate is filtered off, washed with 50 ml of water. A pale yellow precipitate is recrystallized from dimethylformamide to obtain 5.2 g specified in the head of the connection.

So pl. 206°C.

NMR, δn(400 MHz, DMSO-d6): 5,02-to 5.03 ppm, (d, 2H, N-CH2), to 6.22 ppm, (s, 2H, NH2), 7,14-7,16 ppm, (DD, 1H, 6-H), 7.24 to 7,26 ppm, (DD, 1H, 5-H), 7,30 ppm, (s, 5H, Ph), 7,50-7,52 ppm, (DD, 1H, 7-H), 8,16-8,19 ppm, (d, 1H, 8-H), 8.30 to-8,33 ppm, (t, 1H, NH).

Applying instead of benzylamine 2-aminomethylpyridine or 3-aminomethylpyridine or 4-aminomethylpyridine can be obtained the corresponding compounds of formula III.

C) 3-Methyl-N-(3-methylbenzoyl)-N-(4-benzylamino-3-cyanohydrin-2-yl)benzamide:

To a solution of 5 g of 2-amino-3-cyano-4-benzylaminopurine in 30 ml of pyridine are added dropwise 6 ml of 3-methylbenzylamine under stirring at a temperature of 0°C. the Reaction mixture is stirred at a temperature of 80°C for 8 hours, then poured into 150 ml of a mixture of ice-water. The precipitate is filtered off, washed twice with 40 ml of water. The obtained white crystalline substance is recrystallized from 200 ml of ethanol to obtain 9.2 grams specified in the connection header, so pl. 234°C.

Using pyridine-3-carbonylchloride as Alliluyeva agent, it is possible to obtain the corresponding compound of General formula II.

d) 3-Methyl-N-(4-benzylamino-3-cyanohydrin-2-yl)benzamid

To a solution of 5 g of 3-methyl-N-(3-methylbenzoyl)-N-(4-benzylamino-3-cyanohydrin-2-yl)benzamide in 80 ml of acetonitrile, add 20 ml of a 1N solution of potassium hydroxide in methanol. The reaction mixture boil the t under reflux for 3 minutes, then add 3 ml of glacial acetic acid, the mixture is then neutralized with 50 ml of 1M sodium hydrogen carbonate solution and the resulting crystals filtered off. The white crystalline substance is recrystallized from 130 ml of acetonitrile to obtain 3.1 g specified in the header of the compounds of General formula (I). So pl. 230°C.

Example 2

4-Methoxy-N-(4-benzylamino-3-cyanohydrin-2-yl)benzamid

In the General formula (I) R1and R2are hydrogen atoms, R3is a phenyl group, R4and R5together form 1,3-butadienyl group, R6is cyano, R7is a 4-metoksifenilny group, X is-NH-group, n is 1.

2-Amino-3-cyano-4-benzylaminopurine, obtained as described in example 1, turn, using 4-methoxybenzylamine by analogy with example 1, 4-methoxy-N-(4-methoxybenzoyl)-N-(4-benzylamino-3-cyanohydrin-2-yl)benzamide, which after selective hydrolysis by the method described in example 1 gives specified in the header of the compound of General formula (I). The melting temperature specified in the connection header 188°C.

Sodium salt specified in the connection header receive the following method:

4-Methoxy-N-(4-benzylamino-3-cyanohydrin-2-yl)benzamide dissolved in methanol and to it add an equivalent amount of sodium hydroxide in meta is OLE. The precipitated white crystalline substance is filtered off. So pl. 255°C.

Econsultant specified in the connection header receive the following method:

4-Methoxy-N-(4-benzylamino-3-cyanohydrin-2-yl)benzamide dissolved in methanol and to it add the equivalent amount of econsultancy. The precipitated white crystalline substance is filtered off. So pl. 223°C.

Example 3

3-Methoxy-N-(4-benzylamino-3-cyanohydrin-2-yl)benzamid

In the General formula (I) R1and R2are hydrogen atoms, R3is a phenyl group, R4and R5together form 1,3-butadienyl group, R6is cyano, R7the 3-metoksifenilny group, X is-NH group, n is 1.

2-Amino-3-cyano-4-benzylaminopurine, obtained as described in example 1, turn, using 3-methoxybenzylamine by analogy with example 1, 3-methoxy-N-(3-methoxybenzoyl)-N-(4-benzylamino-3-cyanohydrin-2-yl)benzamide, which after selective hydrolysis by the method described in example 1 gives specified in the header of the compound of General formula (I). The melting temperature specified in the connection header 186°C.

Example 4

3,4-Methylendioxy-N-(4-benzylamino-3-cyanohydrin-2-yl)benzamid

In the General formula (I) R1and R2are hydrogen atoms, R3is what I'm phenyl group, R4and R5together form 1,3-butadienyl group, R6is cyano, R7is 3,4-methylenedioxyphenyl group, X is-NH group, n is 1.

2-Amino-3-cyano-4-benzylaminopurine, obtained as described in example 1, turn, using 4-methoxybenzylamine by analogy with example 1, 3,4-methylendioxy-N-(3,4-methylenedioxybenzyl)-N-(4-benzylamino-3-cyanohydrin-2-yl)benzamide, which after selective hydrolysis by the method described in example 1 gives specified in the header of the compound of General formula (I). The melting temperature specified in the connection header 231°C.

Example 5

N-(4-benzylamino-3-cyanohydrin-2-yl)thiophene-2-carboxamide

In the General formula (I) R1and R2are hydrogen atoms, R3is a phenyl group, R4and R5together form 1,3-butadienyl group, R6is cyano, R7is a 2-thienyl group, X is-NH group, n is 1.

2-Amino-3-cyano-4-benzylaminopurine, obtained as described in example 1, turn, using thiophene-2-carbonylchloride by analogy with example 1, N-(2-thiophencarboxylic)-N-(4-benzylamino-3-cyanohydrin-2-yl)thiophene-2-carboxamide, which after selective hydrolysis by the method described in example 1 gives specified in the header of the compound of General formula (I). T is mperature melting specified in the connection header 197° C.

Example 6

N-(4-[2-titelmelodie]-3-cyanohydrin-2-yl)thiophene-3-carboxamide

In the General formula (I) R1and R2are hydrogen atoms, R3is a 2-thienyl group, R4and R5together form 1,3-butadienyl group, R6is cyano, R7is a 3-thienyl group, X is-NH group, n is 1.

a) 2-Amino-3-cyano-4-(2-titelmelodie)quinoline

5 g of 2-amino-3-cyano-4-chlorhydrin, obtained as described in example 1, mixed with 11 ml of 2-titelmelodie at a temperature of 130°C for 3 hours. The reaction mixture is poured into 50 ml water, the precipitate is filtered off, washed with 50 ml of water. Pale yellow substance is recrystallized from 25 ml of ethanol with the receipt of 5.2 g specified in the connection header, so pl. 208°C.

2-Amino-3-cyano-4-(2-titelmelodie)quinoline, obtained as described above, transform, using thiophene-3-carbonylchloride by analogy with example 1, N-(3-thiophencarboxylic)-N-(4-[2-titelmelodie]-3-cyanohydrin-2-yl)thiophene-3-carboxamide, which after selective hydrolysis by the method described in example 1 gives specified in the header of the compound of General formula (I). The melting temperature specified in the connection header 223°C.

Example 7

4-methoxy-N-(4-[2-titelmelodie]-3-cyanohydrin-2-yl)benzamid

In General f is rule (I) R 1and R2are hydrogen atoms, R3is a 2-thienyl group, R4and R5together form 1,3-butadienyl group, R6is cyano, R7is a 4-metoksifenilny group, X is-NH group, n is 1.

2-Amino-3-cyano-4-(2-titelmelodie)quinoline, obtained as described in example 6, turn, using 4-methoxybenzylamine the method described in example 1, 4-methoxy-N-(4-methoxybenzoyl)-N-(4-[2-titelmelodie]-3-cyanohydrin-2-yl)benzamide, which after selective hydrolysis by the method described in example 1 gives specified in the header of the compound of General formula (I). The melting temperature specified in the connection header 173°C.

Example 8

3,4-methylendioxy-N-(4-[2-titelmelodie]-3-cyanohydrin-2-yl)benzamid

In the General formula (I) R1and R2are hydrogen atoms, R3is a 2-thienyl group, R4and R5together form 1,3-butadienyl group, R6is cyano, R7is 3,4-methylenedioxyphenyl group, X is-NH group, n is 1.

2-Amino-3-cyano-4-(2-titelmelodie)quinoline, obtained as described in example 6, turn, using 3,4-methylenedioxyphenethylamine the method described in example 1, 3,4-methylendioxy-N-(3,4-methylenedioxybenzyl)-N-(4-[2-titelmelodie]-3-qi is nominaly-2-yl)benzamid, after selective hydrolysis by the method described in example 1 gives specified in the header of the compound of General formula (I). The melting temperature specified in the connection header 241°C.

Example 9

N-(4-[2-pyrimethamine]-3-cyanohydrin-2-yl)furan-2-carboxamide

In the General formula (I) R1and R2are hydrogen atoms, R3the 2-shriley group, R4and R5together form 1,3-butadienyl group, R6is cyano, R7the 2-shriley group, X is-NH group, n is 1.

a) 2-Amino-3-cyano-4-(2-pyrimethamine)quinoline

5 g of 2-amino-3-cyano-4-chlorhydrin, obtained as described in example 1 is stirred with 1 ml of 2-pyrimethamine (furfurylamine) at a temperature of 130°C for 3 hours. The reaction mixture is poured into 50 ml water, the precipitate is filtered off, washed with 50 ml of water. Pale yellow substance is recrystallized from 20 ml of ethanol to obtain 4.8 g specified in the connection header, so pl. 208°C.

2-Amino-3-cyano-4-(2-pyrimethamine)quinoline, obtained as described above, transform, when applied furan-2-carbonylchloride by analogy with example 1, N-(2-furancarboxylic)-N-(4-[2-pyrimethamine]-3-cyanohydrin-2-yl)furan-2-carboxamide, which after selective hydrolysis by the method described in example 1 gives specified in the header is a compound of General formula (I). The melting temperature specified in the connection header 196°C.

Example 10

N-(4-[2-pyrimethamine]-3-cyanohydrin-2-yl)thiophene-3-carboxamide

In the General formula (I) R1and R2are hydrogen atoms, R3the 2-shriley group, R4and R5together form 1,3-butadienyl group, R6is cyano, R7is a 3-thienyl group, X is-NH group, n is 1.

2-Amino-3-cyano-4-(2-pyrimethamine)quinoline, obtained as described in example 6, turn, using thiophene-3-carbonylchloride by analogy with example 1, N-(3-thiophencarboxylic)-N-(4-[2-pyrimethamine]-3-cyanohydrin-2-yl)thiophene-3-carboxamide, which after selective hydrolysis by the method described in example 1 gives specified in the header of the compound of General formula (I). The melting temperature specified in the connection header 118°C.

Structure and physical characteristics of other compounds of General formula (I)obtained by the method described in example 1 shown in tabl and II.

Structure and physical characteristics of the intermediate compounds of General formula (II)obtained by the method described in example 1 shown in table III.

Structure and physical characteristics of the intermediate compounds of General formulas (III) and (IIIa)obtained by the method described in example 1 shown in .IV.

Structure and physical characteristics of the intermediate compounds of General formula (V)obtained by the method described in example 1 shown in .V.

Example 172

Tablets having the following composition, get known methods used in the pharmaceutical industry.

The active ingredient25 mg
Lactose50 mg
Avicel21 mg
Crosspovidone3 mg
The MAG stearate is s 1 mg

Biological tests

Methods

Linking human adenosine receptor And3

Getting the suspension membrane: collect cells Chinese hamster ovary (Cho)expressing the receptors hA3triple rinse the ice saline solution with phosphate buffer (RFB), centrifuged at CD for 10 min, homogenized for 15 seconds in buffer (50 mm Tris, 10 mm MgCl2, 1 mm add, pH 8.0), centrifuged at CD within 10 minutes (Sigma 3K30), suspended the preparation of the membrane in the buffer mentioned above, store aliquots at a temperature of -80°C.

Protocol binding: incubate the preparation of membranes SNO-hA3(the protein content of 2 μg) in incubation buffer (50 mm Tris, 10 mm MgCl2, 1 mm etc, 3 U/ml adelaideans, pH 8.0) in the presence of 0.5 nm [125I]AB-MECA (p-aminobenzenesulfonamide) (100,000 pulses/min) and 100 μm R-PIA (N6-[L-2-phenylisopropyl]adenosine) to determine nonspecific binding or test compounds in a total volume of 50 μl for 1 hour at room temperature. Filtered through filters made of glass fiber Whatman GF/B (pre-soaked in 0.5% polyethylenimine within 3 hours), washed four times with 1 ml ice-cold 50 mm Tris, 10 mm MgCl2, 1 mm etc, (pH 8.0) in a 96-cell Brandel Cell Harvester. Definition is the activity: the count of gamma radiation (1470 Wizard, Wallac). Inhibition [%]=100-((activity in the presence of the test compound is a non-specific

activity)/(total activity - non-specific activity))*100.

Linking human adenosine receptor And1

Getting the suspension membrane: collect cells SNO expressing receptors hA1three-time washing with ice RFB, centrifuged at CD for 10 min, homogenized for 15 seconds in buffer (50 mm Tris, pH 7.4), centrifuged at CD within 10 minutes (Sigma 3K30), suspended the preparation of the membrane in the buffer mentioned above, store aliquots at a temperature of -80°C.

Protocol binding: incubate the preparation of membranes of CHO-hA1(50 µg protein) in incubation buffer (50 mm Tris, 3 U/ml adelaideans, pH 7.4), 10 nm of [3N]SSRA (2-chloro-N6-cyclopentylacetyl) (80000 u./min) and 10 μm R-PIA (N6-[L-2-phenylisopropyl]adenosine) to determine nonspecific binding or test compounds in a total volume of 100 μl for 3 hours at room temperature. Filtered through filters made of glass fiber Whatman GF/B (pre-soaked in 0.5% polyethylenimine within 3 hours), washed four times with 1 ml ice-cold 50 mm Tris, (pH 7.4) in 96-cell Brandel Cell Harvester. Definition of activity: in 96-cell tablet in the presence of HiSafe 3 cocktail at the counter beta of the teachings (1450 Microbeta, Wallac). Inhibition [%]=100 - ((activity in the presence of test compounds - non-specific activity)/(total activity - non-specific activity))*100.

Linking human adenosine receptor And2A

Protocol binding:incubated 7 μg of membranes (human receptors adenosine A2A, transfection in cells SOME of 293 source: Receptor Biology, Inc.), buffer (50 mm Tris-HCl, 10 mm MgCl2, 1 mm etc, 2 U/ml adelaideans, pH 7.4), 20 nm of [3H]CGS-21680 (2-[p-(2-carbonylethyl)phenylethylamine]-5'-N-ethylcarbodiimide-adenosine) (200,000 u./min) and 50 μm NECA (5'-N-ethylcarbodiimide-adenosine) to determine nonspecific binding or test compounds in a total volume of 100 μl for 90 minutes at room temperature. Filtered through filters made of glass fiber Whatman GF/B (pre-soaked in 0.5% polyethylenimine), washed four times with 1 ml ice-cold 50 mm Tris, 10 mm MgCl2, 1 mm etc, 0.9% NaCl (pH 7.4) in 96-cell Brandel Cell Harvester. Definition of activity: in 96-cell tablet in the presence of HiSafe 3 cocktail at the counter beta radiation (1450 Microbeta, Wallac). Inhibition [%]=100 - ((activity in the presence of test compounds - non-specific activity)/(total activity - non-specific activity))*100.

Linking human adenosine receptor And2b

Protocol binding:incubated 20,8 μg of membranes (human receptors adenosine A 2b, transfection in cells SOME of 293 source: Receptor Biology, Inc.), buffer (50 mm Tris-HCl, 10 mm MgCl2, 1 mm etc, 0.1 mm of benzamidine, 2 U/ml adelaideans, pH 6.5), 32,4 nm [3H]DPCPX (8-cyclopentyl-1,3-dipropylacetic) (800000 u./min) and 100 μm NECA (5'-N-ethylcarbodiimide) to determine nonspecific binding or test compounds in a total volume of 100 μl for 30 minutes at room temperature. Filtered through filters made of glass fiber Whatman GF/B (pre-soaked in 0.5% polyethylenimine), washed four times with 1 ml ice-cold 50 mm Tris-HCl (pH 6.5) in a 96-cell Brandel Cell Harvester. Definition of activity: in 96-cell tablet in the presence of HiSafe 3 cocktail at the counter beta radiation (1450 Microbeta, Wallac). Inhibition [%]=100 - ((activity in the presence of test compounds - non-specific activity)/(total activity - non-specific activity))*100.

Results

Compounds are considered active if they inhibit the binding of radioligand with human receptors adenosine A3with an activity of over 80% at 1 μm in experimental conditions.

The dissociation constant (Kd) [125I]AB-MECA on the preparation of the membranes of CHO-hA3is determined by examining the isotopic saturation analysis of Scatchard (G. Scatchard, Ann. N. Y. Acad. Sci. 51:660, 1949). IC50turn in design is the ant affinity (K i) using the equation of Cheng-Prusoff (Y. J. Cheng and W. H. Prusoff, Biochem. Pharmacol. 22:3099, 1973).

Some compounds of General formula (I), (II), (III) and (IV) display remarkable biological effects. Compounds of General formula (IA), as defined in paragraph 2 as a subgroup of compounds of General formula (I), as defined in paragraph 1, have the most important effect. Except for the 5 compounds their values of Kinot higher than 20 nm. Connection data as examples, are particularly preferred. Their values of Kiobtained in the study of binding to the human receptor adenosine A3is from 0.19 to 0.69 nm. Values of Kithe most preferred compounds are from 0.14 to 0.15 nm.

The compounds possess appropriate bioavailability and at least 10000-fold selectivity for subtypes of the human receptor adenosine A2And2Aand a2b.

Further, the duration of their action in intravenous and oral administration is large enough, their values ED50low, their Toxicological profile and the profile of side effects are predominant.

Data values IC50in the study of binding to the human receptor adenosine A3for a number of compounds of the formula (I) are presented in .VI.

Table VI

Compound of Example No.IC50nm
10,57
20,47
30,84
40,63
50,48
60,23
70,44
80,38
90,71
100,18
380,14

The above data make compounds of General formula (I) suitable for therapeutic applications.

1. Compounds of General formula (I)

where R1is a hydrogen atom or a straight or branched C1-4alkyl group;

R2is a hydrogen atom or a straight or branched C1-4alkyl group;

R3is a hydrogen atom or a straight or branched C1-4alkyl group, or phenyl group, thienyl group or shriley group, optionally substituted by one or more straight or branched C1-4alkyl group, straight or branched C1-4alkoxygroup or a halogen atom;

R4and R5together form 1,3-butadienyl group, not necessarily replacing the military methylendioxyphenyl or one or more straight or branched C 1-4alkyl group, straight or branched C1-4alkoxygroup, hydroxy-group or a halogen atom;

R6is a hydrogen atom or cyano;

R7is a hydrogen atom or a straight or branched C1-4alkyl group, phenyl group, benzyl group, thienyl group or shriley group, optionally substituted by methylendioxyphenyl or one or more straight or branched C1-4alkyl group, straight or branched C1-4alkoxygroup, hydroxy-group, triptorelin group, a cyano or a halogen atom;

X is-NH-group, -NR8group or sulfur atom or an oxygen atom or sulfopropyl or sulfoxylate, where R8is a straight or branched C1-4alkyl group or a C3-6cycloalkyl group;

n is zero, 1 or 2,

and their salts.

2. Compounds of General formula (IA) according to claim 1

in which R1is a hydrogen atom or a straight or branched C1-4alkyl group;

R2is a hydrogen atom or a straight or branched C1-4alkyl group;

R3is a hydrogen atom or a straight or branched C1-4alkyl group, Il is phenyl group, thienyl group or shriley group, optionally substituted by one or more straight or branched C1-4alkyl group, straight or branched C1-4alkoxygroup or a halogen atom;

R9, R10, R11and R12independently are a hydrogen atom or a straight or branched C1-4alkyl group, straight or branched C1-4alkoxygroup, hydroxy-group or halogen atom, or

R9and R12are a hydrogen atom, and R10and R11together form methylenedioxy;

R6is a hydrogen atom or cyano;

R7is a hydrogen atom or a straight or branched C1-4alkyl group, phenyl group, benzyl group, thienyl group or shriley group, optionally substituted by methylendioxyphenyl or one or more straight or branched C1-4alkyl group, straight or branched C1-4alkoxygroup, hydroxy-group, triptorelin group, a cyano or a halogen atom;

X is-NH-group, -NR8group, or a sulfur atom or an oxygen atom or sulfopropyl or sulfoxylate, where R8is a straight or branched C1-4alkyl group or a C3-6cycloalkyl group

n is zero, 1 or 2,

and their salts.

3. The compounds of formula (IA) according to claim 2,

where R1is a hydrogen atom or methyl group;

R2is a hydrogen atom or methyl group;

R3is phenyl, thienyl or shriley group;

R9, R10, R11and R12independently are a hydrogen atom or a straight or branched C1-4alkyl group, straight or branched C1-4alkoxygroup, hydroxy-group or halogen atom, or

R9and R12are a hydrogen atom, and R10and R11together form methylenedioxy;

R6is a hydrogen atom or cyano;

R7is a 4-metoksifenilny, 3-methylphenylene, 3-thienyl or 3-shriley group,

X is-NH-group or an oxygen atom;

n is 1,

and their salts.

4. Compounds according to any one of claims 1 to 3, representing

3-methyl-N-(4-benzylamino-3-cyanohydrin-2-yl)benzamide;

4-methoxy-N-(4-benzylamino-3-cyanohydrin-2-yl)benzamide;

3-methoxy-N-(4-benzylamino-3-cyanohydrin-2-yl)benzamide;

3,4-methylendioxy-N-(4-benzylamino-3-cyanohydrin-2-yl)benzamide;

N-(4-benzylamino-3-cyanohydrin-2-yl)thiophene-3-carboxamide;

N-(4-[2-thienylmethyl is but]-3-cyanohydrin-2-yl)thiophene-3-carboxamide;

4-methoxy-N-(4-[2-titelmelodie]-3-cyanohydrin-2-yl)benzamide;

3,4-methylendioxy-N-(4-[2-titelmelodie]-3-cyanohydrin-2-yl)benzamide;

N-(4-[2-pyrimethamine]-3-cyanohydrin-2-yl)furan-2-carboxamide;

N-(4-[2-pyrimethamine]-3-cyanohydrin-2-yl)thiophene-2-carboxamid,

and their salts.

5. The method of obtaining compounds of General formula (I)

and its salts, where R1, R2, R3, R4, R5, R6, R7, R8, X and n have the meanings defined in claim 1, including selective hydrolysis of amide bis acid of General formula (II)

where R1, R2, R3, R4, R5, R6, R7, R8, X and n have the meanings given in claim 1 and, optionally, the conversion of the substituents thus obtained compounds of General formula (I) into each other, and/or the transformation of the thus obtained compounds of formula (I) and their salts, or release them from their salts.

6. The method according to claim 5, comprising the selective hydrolysis in alcoholic medium in the presence of alkali metal hydroxide, preferably potassium hydroxide or sodium.

7. The pharmaceutical composition used in treating diseases whose development plays the role of the receptor And3containing as the active ingredient one or more compounds of General formula (I), where R1, R2, R3, R4, R5, R6, R7, R8, X and n have the meanings defined in claim 1, or salt, in a mixture with one or more excipients used in the pharmaceutical industry.

8. The pharmaceutical composition according to claim 7, containing as active ingredient one or more compounds of General formula (IA)where R1, R2, R3, R6, R7, R8, R9, R10, R11, R12, X and n have the meanings defined in claim 2, or their salts, in a mixture with one or more excipients used in the pharmaceutical industry.

9. The pharmaceutical composition of claim 8 containing as active ingredient one or more compounds according to claim 4.

10. The use of compounds of General formula (I), where R1, R2, R3, R4, R5, R6, R7, R8, X and n have the meanings given in claim 1 as a receptor antagonist And3for the manufacture of pharmaceutical compositions for the treatment of diseases, such as asthma, chronic obstructive pulmonary disease (COPD), respiratory distress syndrome in adults (rdsw), glaucoma, tumor, allergic and inflammatory diseases, ischemia, hypoxia, arrhythmia, and kidney disease.

11. The use of compounds of General formula (IA)where R1, R2, R3, R6, R7, R , R9, R10, R11, R12, X and n have the meanings defined in claim 2, as an antagonist of the receptor And3for the manufacture of pharmaceutical compositions for the treatment of diseases, such as asthma, chronic obstructive pulmonary disease (COPD), respiratory distress syndrome in adults (rdsw), glaucoma, tumor, allergic and inflammatory diseases, ischemia, hypoxia, arrhythmia, and kidney disease.

12. Compounds of General formula (IA) and their salts, representing

3-Methyl-N-(4-benzylamino-3-cyanohydrin-2-yl)benzamid,

4-Methoxy-N-(4-benzylamino-3-cyanohydrin-2-yl)benzamid,

3-Methoxy-N-(4-benzylamino-3-cyanohydrin-2-yl)benzamid,

3,4-Methylendioxy-N-(4-benzylamino-3-cyanohydrin-2-yl)benzamid,

N-(4-benzylamino-3-cyanohydrin-2-yl)thiophene-2-carboxamid,

N-(4-[2-titelmelodie]-3-cyanohydrin-2-yl)thiophene-3-carboxamide,

4-methoxy-N-(4-[2-titelmelodie]-3-cyanohydrin-2-yl)benzamid,

3,4-methylendioxy-N-(4-[2-titelmelodie]-3-cyanohydrin-2-yl)benzamid,

N-(4-[2-pyrimethamine]-3-cyanohydrin-2-yl)furan-2-carboxamide,

N-(4-[2-pyrimethamine]-3-cyanohydrin-2-yl)thiophene-3-carboxamide,

or the compounds of formula

where

or the compounds of formula

where

or the compounds of formula

13. Compounds of General formula (II)

where R1, R2, R3, R4, R5, R6, R7, R8, X and n have the meanings given in claim 1.

14. Compounds of General formula (III)

where R1, R2, R3, R4, R5, R6, R8, X and n have the meanings defined in claim 1, provided that R3cannot be phenyl group, if R1and R2are a hydrogen atom, n=1, X is-NH - group, R4and R5together form 1,3-butadienyl group, and R6is cyano, another condition that R3may not be straight or branched C1-4alkyl group or a phenyl group, a substituted straight or branched C1-4alkoxygroup, if n=0, X is-NH - or-NR8group, R8matter, Azania in claim 1, R4and R5together form 1,3-butadienyl group, and R6is cyano.

15. Compounds of General formula (IV)

where R4, R5and R6have the meanings defined in claim 1, provided that R6cannot be a hydrogen atom when R4and R5are a hydrogen atom.



 

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25 cl, 6 tbl

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12 cl

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (I) in racemic form, enantiomer form or in any combinations of these forms possessing affinity to somatostatin receptors. In the general formula (I): R1 means phenyl; R2 means hydrogen atom (H) or -(CH2)p-Z3 or one of the following radicals: and Z3 means (C3-C8)-cycloalkyl, possibly substituted carbocyclic or heterocyclic aryl wherein carbocyclic aryl is chosen from phenyl, naphthyl and fluorenyl being it can be substituted, and heterocyclic aryl is chosen from indolyl, thienyl, thiazolyl, carbazolyl, or radicals of the formulae and and it can be substituted with one or some substitutes, or also radical of the formula: R4 means -(CH2)p-Z4 or wherein Z4 means amino-group, (C1-C12)-alkyl, (C3-C8)-cycloalkyl substituted with -CH2-NH-C(O)O-(C1-C6)-alkyl, radical (C1-C6)-alkylamino-, N,N-di-(C1-C12)-alkylamino-, amino-(C3-C6)-cycloalkyl, amino-(C1-C6)-alkyl-(C3-C6)-cycloalkyl-(C1-C6)-alkyl, (C1-C12)-alkoxy-, (C1-C12)-alkenyl, -NH-C(O)O-(C1-C6)-alkyl, possibly substituted carbocyclic or heterocyclic aryl; p = 0 or a whole number from 1 to 6 if it presents; q = a whole number from 1 to 5 if it presents; X means oxygen (O) or sulfur (S) atom n = 0 or 1. Also, invention relates to methods for preparing compounds of the general formula (I), intermediate compounds and a pharmaceutical composition. Proposed compounds can be used in treatment of pathological states or diseases, for example, acromegaly, hypophysis adenomas, Cushing's syndrome and others.

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

11 cl, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes new derivatives of triazole of the general formula (I): wherein X represents group of the general formula (II): wherein R' means halogen atom; R4 means (C1-C6)-alkyl; L means group of the formula: -La-Lb wherein La means a simple bond, oxygen atom, phenyl group that can be optionally substituted with halogen atom, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group or (C1-C6)-alkyl substituted with a single group -O-P(=O)(OH)2, naphthyl group, 5-membered heteroaryl group comprising as a heteroatom oxygen (O) or sulfur (S) atom, or (C3-C7)-cycloalkyl group that is substituted with carboxyl group; and Lb means (C1-C5)-alkylene group that can be optionally substituted with (C1-C6)-alkyl, carboxyl group or di-[(C1-C6)-alkyl]-amino-(C1-C6)-alkyl group; R means hydrogen atom, (C1-C6)-alkanoyl that can be optionally substituted with group: -Q-NR2'R3' wherein Q means a simple bond or carbonyl group, and R2' and R3' in common with nitrogen atom with that they are bound form piperazinyl ring substituted with (C1-C6)-alkyl and/or carboxyl group, or group: -O-P(=O)(OH)2; or their pharmacologically acceptable salts, pharmaceutical composition based on thereof, and a method for treatment of fungal infections.

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

24 cl, 14 tbl, 1 dwg, 45 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to quinazoline derivatives of the formula (I) or their pharmaceutically acceptable salts wherein m = 0 or 1; each group R1 can be similar or different and represents halogen atom, hydroxy- and (C1-C6)-alkoxy-group, or group of the formula Q3-X1 wherein X1 represents oxygen atom (O); Q3 represents phenyl-(C1-C6)-alkyl, heteroaryl-(C1-C6)-alkyl, heterocyclyl or heterocyclyl-(C1-C6)-alkyl, and wherein heteroaryl group represents aromatic 5- or 6-membered monocyclic rings with one or two nitrogen heteroatoms, and any heterocyclyl group defined as the group R1 represents non-aromatic saturated or partially saturated 3-6-membered monocyclic ring with one or two heteroatoms chosen from oxygen and nitrogen atoms, and wherein adjacent carbon atoms in any (C2-C6)-alkylene chain in the substitute R1 are separated optionally by incorporation of oxygen atom (O) in the chain, and wherein any group CH2 or CH3 in the substitute R1 comprises optionally in each of indicated groups CH2 or CH3 one or some halogen substitutes or a substitute chosen from hydroxy-, (C1-C6)-alkoxy-group, (C1-C6)-alkylsulfonyl or pyridyloxy-group, and wherein any heteroaryl or heterocyclyl group in the substitute R1 comprises optionally 1, 2 or 3 substitutes that can be similar or different and chosen from hydroxy-group, carbamoyl, (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl, N-(C1-C6)-alkylcarbamoyl, N,N-di-[(C1-C6)-alkyl]-carbamoyl, (C1-C6)-alkoxy-(C1-C6)-alkyl and cyano-(C1-C6)-alkyl, or among group of the formula -X5-Q6 wherein X5 represents a direct bond or -CO, and Q6 represents heterocyclyl or heterocyclyl-(C1-C6)-alkyl that comprises optionally (C1-C6)-alkyl as a substitute wherein heterocyclyl group represents non-aromatic, fully or partially saturated 5- or 6-membered monocyclic ring with one or two heteroatoms chosen from nitrogen and oxygen atom; R2 represents hydrogen atom; R3 represents hydrogen atom; Z represents a direct bond or oxygen atom; Q1 represents phenyl, (C3-C7)-cycloalkyl, heteroaryl-(C1-C6)-alkyl, heterocyclyl or heterocyclyl-(C1-C6)-alkyl wherein heteroaryl group represents 5- or 6-membered aromatic monocyclic ring with I, 2 or 3 heteroatoms of nitrogen, and any heterocyclyl group represents non-aromatic fully or partially saturated 5- or 6-membered monocyclic ring with one or two heteroatoms chosen from oxygen, nitrogen or sulfur atom, or when Z represents oxygen atom (O) then Q1 can represent (C1-C6)-alkyl or (C1-C6)-alkoxy-(C1-C6)-alkyl and wherein any heterocyclyl group in the group -Q1-Z- comprises substitutes chosen from (C1-C6)-alkyl, (C1-C)-alkoxycarbonyl and pyridylmethyl, and wherein any heterocyclyl group in the group -Q1-Z- comprises optionally 1 or 2 oxo-substitutes; Q2 represents aryl group of the formula (Ia): wherein G1 represents halogen atom, trifluoromethyl, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C2-C6)-alkanoyl, pyrrolyl, pyrrolidinyl, piperidinyl and morpholinomethyl, and each G2, G3, G4 and G5 that can be similar or different represents hydrogen, halogen atom, cyano-group, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl and (C1-C6)-alkoxy-group, or G1 and G2 form in common group of formulae -CH=CH-CH=CH-, -CH=CH-O- or -O-CH=CH- being each group carries optionally halogen atom as a substitute, or G1 and G2 form in common group of formulae -O-CH2-O- or -O-CH2-CH2-O-, or -O-CH2-CH2-O-, and each among G3 and G4 represents hydrogen atom, and G5 is chosen from hydrogen and halogen atom. Proposed compounds possess anti-tumor activity and designated for preparing a medicine preparation for its using as an anti-tumor agent for suppression and/or treatment of solid tumors. Also, invention relates to a pharmaceutical composition based on abovementioned compounds.

EFFECT: valuable medicinal properties of compounds.

20 cl, 7 tbl, 57 ex

FIELD: organic chemistry, antibacterial agents.

SUBSTANCE: invention relates to a novel heterocyclic compound, in particular, 3-(5-nitrofuryl)-7-(5-nitrofurfurylidene-3,3a,4,5,6,7-hexahydro-2H-indazole of the formula (1): that elicits an antibacterial activity with respect to bacterium of genus Staphylococcus and can be used in medicine. The compound of the formula 91) is prepared by reaction of 2,6-di-(5-nitrofurfurylidene)-cyclohexanone with hydrazine hydrate in propanol-2 medium. The yield is 80%, m. p. at 193-195°C, empirical formula is C16H14N4O6, LD50 value at intraperitoneal administration is 500 mg/kg. This compound exceeds activity of furacilinum and furazolidone by 16 and 2-31 times, respectively. Invention provides preparing compound possessing the higher and selective antibacterial activity and low toxicity.

EFFECT: valuable properties of compound.

1 cl, 3 tbl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds that act as agonists of arginine-vasopressin V2-receptors. Invention describes a derivative of 4,4-difluoro-1,2,3,4-tetrahydro-5H-benzazepine represented by the general formula (I): or its pharmaceutically acceptable salt wherein symbols have the following values: R1 represents -OH, -O-lower alkyl or optionally substituted amino-group; R2 represents lower alkyl that can be substituted with one or more halogen atoms, or halogen atom; among R3 and R4 one of them represents -H, lower alkyl or halogen atom, and another represents optionally substituted nonaromatic cyclic amino-group, or optionally substituted aromatic cyclic amino-group; R5 represents -H, lower alkyl or halogen atom. Also, invention describes a pharmaceutical composition representing agonist of arginine-vasopressin V2-receptors. Invention provides preparing new compounds possessing with useful biological properties.

EFFECT: valuable medicinal properties of compound and composition.

9 cl, 18 tbl, 13 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

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

wherein m = 0, 1, 2 or 3; each group R1 that can be similar or different is taken among halogen atom, trifluoromethyl, hydroxy-, amino-group, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkoxy-, (C2-C6)-alkenyloxy-, (C2-C6)-alkynyloxy-, (C1-C6)-alkylamino-, di-[(C1-C6)-alkyl]amino- and (C2-C6)-alkanoylamino-group, or among the group of the formula: Q1-X1- wherein X1 represents oxygen atom (O); Q1 represents aryl-(C1-C6)-alkyl, heteroaryl, heteroaryl-(C1-C6)-alkyl, heterocyclyl or heterocyclyl-(C1-C6)-alkyl and wherein neighboring carbon atoms in any (C2-C6)-alkylene chain in substitute at R1 are separated optionally by insertion to the chain the group taken among oxygen atom (O) and N(R5) wherein R5 represents hydrogen atom or (C1-C6)-alkyl, or when the inserted group represents N(R5); R5 can represent also (C2-C6)-alkanoyl and wherein any group -CH2 or -CH3 in substitute R1 carries one or more substitutes in each indicated group -CH2 or -CH3 and wherein these substitutes are taken among halogen atom or (C1-C6)-alkyl, or substitute taken among hydroxy-, amino-group, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C1-C6)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylamino-, di-[(C1-C6)-alkyl]amino-, (C2-C6)-alkanoyloxy, (C2-C6)-alkanoylamino- and N-(C1-C6)-alktyl-(C2-C6)-alkanoylamino-group, or among the group of the formula: -X3-Q3wherein X3 represents oxygen atom (O) and Q3 represents heteroaryl, and wherein any aryl, heteroaryl or heterocyclyl group in substitute at R1 carries optionally 1, 2 or 3 substitutes that can be similar or different and taken among halogen atom, trifluoromethyl, cyano-, hydroxy-, amino-group, carbamoyl, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkoxy-, (C2-C6)-alkenyloxy, (C2-C6)-alkynyloxy,(C1-C6)-alkylthio-group, (C1-C)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylamino-, di-[(C1-C6)-alkyl]amino-group, (C1-C6)-alkoxycarbonyl, N-(C1-C6)-alkylcarbamoyl, N,N-di-[(C1-C6)-alkyl]carbamoyl, (C2-C6)-alkanoyl, (C2-C6)-alkanoyloxy-, (C2-C)-alkanoylamino- and N-(C1-C6)-alkyl-(C2-C6)-alkanoylamino-group, or among the group of the formula: -X4-R8 wherein X4 represents a simple bond and R8 represents hydroxy-(C1-C6)-alkyl, (C1-C6)-alkoxy-(C1-C6)-alkyl, cyano-(C1-C6)-alkyl, amino-(C1-C6)-alkyl, (C1-C6)-alkylamino-(C1-C6)-alkyl or di-[(C1-C6)-alkyl]amino-(C1-C6)-alkyl, or among the group of the formula: -X5-Q4 wherein X5 represents a simple bond or -CO, and Q4 represents heterocyclyl or heterocyclyl-(C1-C6)-alkyl that carries optionally 1 or 2 substitutes that can be similar or different and taken among halogen atom, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl and (C1-C6)-alkoxy-group and wherein any heterocyclyl group in substitute at R1 carries optionally 1 or 2 oxo-substitutes, and wherein any aryl group in the group R1 represents phenyl; any heteroaryl group in the group R1 is taken among pyrrolyl, imidazolyl, triazolyl and pyridyl, and any heterocyclyl group in the group R1 is taken among oxyranyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, 1,1-dioxotetrahydro-1,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl and homopiperazinyl; R2 represents hydrogen atom; n = 0, 1, 2 or 3; R3 represents halogen atom, trifluoromethyl, cyano-, hydroxy-group, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl or (C1-C6)-alkoxy-group, or its pharmaceutically acceptable salt. Also, invention relates to methods for preparing compounds of the formula (1) and to pharmaceutical composition based on thereof for using as an anti-tumor agent. Invention provides preparing new derivatives of quinazoline possessing an anti-tumor activity.

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

17 cl, 7 tbl, 7 ex

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

SUBSTANCE: invention relates to new derivatives of 4-aminopiptidine of the general formula (I): wherein R1 means (C1-C6)-alkyl, -(CH2)m-Y-Z11 or -(CH2)m-Z12 wherein Z11 means (C1-C6)-alkyl; Z12 means bis-phenyl, (C3-C7)-cycloalkyl, (C3-C7)-heterocycloalkyl with 1 or 2 heteroatoms taken among nitrogen (N) or oxygen (O) atoms, possibly substituted phenyl, naphthyl, possibly substituted (C5-C9)-heteroaryl wherein heteroatoms are taken among N; or Z12 means ; Y means O; or R1 means ; R2 means -C(Y)-NHX1, -C(O)X2 or -SO2X3; R3 means hydrogen atom (H), (C1-C4)-alkyl, (C2-C4)-alkenyl, possibly substituted heteroarylalkyl or -C(Y)-NHX1, -(CH2)n-C(O)X2 or -SO2X3 wherein X1-X3 have different values. Also, invention describes methods for preparing indicated substances by synthesis in liquid and solid phase. These compounds possessing good affinity to definite subtypes of somatostatin receptors can be used in treatment of pathological states or diseases caused by one or some somatostatin receptors.

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

14 cl, 4 tbl, 778 ex

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

SUBSTANCE: invention relates to new derivatives of 1-aziridino-1-hydroxyiminomethyl of the general formula (I):

wherein R means a single bond or organic radical that can bind aziridinoxime groups by a covalent bond and taken among the group including saturated or unsaturated alkanes with normal or branched chain and comprising up to 6 carbon atoms, substituted azino-group -(R')C=N-N=C(R'') wherein R' and R'' represent independently of one another hydrogen atom or lower alkyl, heterocyclic compounds comprising from 3 to 6 atoms in ring and up to 4 heteroatoms taken among -N- and -O-, and aromatic compounds comprising up to 8 atoms in ring; R1 and R2 mean independently of one another -H, -COOH, -COOCH3, -COOC2H5 or -CONH2; n means a whole number 2 or 3; with exception the compound wherein R represents a single bond and R1 and R2 are both hydrogen atom, and also with exception the compound wherein R represents a single bond and one of substitutes is hydrogen atom among the group R1 and R2. Also, invention describes a method for their preparing and medicinal preparations comprising these compounds that possess an antitumor effect.

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

7 cl, 3 tbl, 19 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, medicine, pharmacy.

SUBSTANCE: invention describes new derivatives of triazole of the general formula (I): wherein X represents group of the general formula (II): wherein R' means halogen atom; R4 means (C1-C6)-alkyl; L means group of the formula: -La-Lb wherein La means a simple bond, oxygen atom, phenyl group that can be optionally substituted with halogen atom, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group or (C1-C6)-alkyl substituted with a single group -O-P(=O)(OH)2, naphthyl group, 5-membered heteroaryl group comprising as a heteroatom oxygen (O) or sulfur (S) atom, or (C3-C7)-cycloalkyl group that is substituted with carboxyl group; and Lb means (C1-C5)-alkylene group that can be optionally substituted with (C1-C6)-alkyl, carboxyl group or di-[(C1-C6)-alkyl]-amino-(C1-C6)-alkyl group; R means hydrogen atom, (C1-C6)-alkanoyl that can be optionally substituted with group: -Q-NR2'R3' wherein Q means a simple bond or carbonyl group, and R2' and R3' in common with nitrogen atom with that they are bound form piperazinyl ring substituted with (C1-C6)-alkyl and/or carboxyl group, or group: -O-P(=O)(OH)2; or their pharmacologically acceptable salts, pharmaceutical composition based on thereof, and a method for treatment of fungal infections.

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

24 cl, 14 tbl, 1 dwg, 45 ex

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