Triazolo[1,5-a]quinolines as ligands of adenosine a3 receptor

FIELD: biotechnologies.

SUBSTANCE: new derivatives of triazolo[1,5-a]quinoline of general formula (I)

, where X means -NH-; R13-cyano; R1 and R2 mean H or methyl; R5-phenyl, possibly substituted, or 5- or 6-member heterocyclyl; R3 means phenyl or one atom of nitrogen containing 6-member heterocyclyl; R4 - one atom of nitrogen containing 6-member heterocyclyl or a group of the formula (a), , where R6 and R7 - independently mean C3-6cycloalkyl or C1-4alkyl; or a group of the formula (b) , where R8 and R9 mean C1-4alkyl; Z - oxygen or a group -NR12-, where R12 - hydrogen, C1-4alkyl, C3-6 cycloalkyl, benzyl, -CH2-acetyl, -CH2-CH2-O-CH2-CH3 or acetyl; W means nitrogen atom or a group -CH-; m and o mean 2; p and r mean zero or 1; t means zero; methods of their production, new intermediate compounds of described methods of production, a pharmaceutical composition containing these compounds, and application of compounds of common formula (I) and their pharmaceutical acceptable salts as ligands of adenosine A3 receptor in treatment of different diseases.

EFFECT: improved properties of compounds.

 

The present invention relates to ligands of the receptor adenosine aA3General formula (I), preferably to the antagonists, to their salts, solvate, N-oxides and isomers, to pharmaceutical compositions containing compounds of General formula (I), their salts, solvate, N-oxides and isomers, to the use of compounds of General formula (I), their salts, solvate, N-oxides and isomers, to obtain compounds of General formula (I), their salts, solvate, N-oxides and isomers, as well as to new intermediate compounds of General formula (II), (VI), (XI), (XII) and (XV), and to receive them.

Adenosine is a known component of several biologically active endogenous molecules (ATP, NAD+, nucleic acids). In addition, it plays an important regulatory role in many physiological processes. The effect of adenosine on cardiac function was discovered already in 1929 (Drury and Szentgyörgyi, J Physiol 68:213, 1929). Identification of an increasing number of physiological functions mediated by adenosine, and the opening of new adenosine receptor subtypes provides opportunities for therapeutic application of certain ligands (Poulse S.A. and R.J. Quinn Bioorganic and Medicinal Chemistry 6:619, 1998).

To date adenosine receptors have been classified into three main classes: (A1, A2and A3. Subtype And1partly responsible for the inhibition of adenylate cyclase way the binding membrane protein G ipartially affects other systems of second messengers. The subtype of receptor-A2can be subdivided into two subtypes - A2aand A2b- which stimulate adenylate cyclase activity. The sequence of the receptors of adenosine A3was recently identified from a cDNA library of rat testis. Later it was proved that it complies with the new functional adenosine receptor. Activation of receptors A3is also associated with multiple systems of second messengers, for example, inhibition of adenylate cyclase and stimulation of phospholipase C, and D.

Adenosine receptors were found in several organs and regulate their functions. As a1and A2areceptors play an important role in the Central nervous system and cardiovascular system. In the CNS, adenosine inhibits synaptic release of neurotransmitters, and this effect is mediated by receptors And1. In the heart of the receptors And1mediate negative inotropic, chronotropic and dromotropic effects of adenosine. Receptors of adenosine A2athat are localized in a relatively higher number in the striatum, show functional interaction with dopamine receptors in the regulation of synaptic conduction. Adenosine receptorsA2aon endothelial and gladkomyshechne the x cells responsible for induced by the adenosine vasodilation (P.G. Baraldi et al. Chem. Rev. 2008, 108, 238-263).

Based on the identification of mRNA receptors adenosine A2bwidely distributed in various tissues. They were identified in almost every cell type, but their expression is highest in the intestine and bladder. This subtype probably also has an important regulatory function in the regulation of the tonus of the smooth muscle cells of blood vessels and plays a role in the function of fat cells (R. Volpini et al. Curr. Topics in Med. Chem. 2003, 3, 427-443).

The levels of expression of receptors of adenosine A3are relatively low compared with other subtypes, and depend greatly on the species. Receptors of adenosine A3expressed primarily in the Central nervous system, testis and the immune system and, apparently, involved in the modulation of release of mediators of mast cells in allergic reactions of immediate type and migration of neutrophilic granulocytes (Y.Chen et al., Science 2006,314:1792-1795).

For therapeutic use, it is important to ensure that the molecules are selective to other adenosine receptor, so do not contact, or be contacted only in case of very high concentrations, with subtypes And1, A2aand A2badenosine receptor.

Antagonists of A3described in the literature to date, belong to the group of flavonoids and derivatives of 1,4-dihydropyridines, tiato is naftiridinov, triazolopyrimidines and aminoquinolines. However, many of the most effective and selective for subtypes of adenosine antagonists have strongly oleophilic character, therefore, they have insufficient solubility. This property prevents their use in vivo. As you can see from the literature, a growing number of studies aimed at obtaining water-soluble antagonists of receptor-A3adenosine (Ch. E. Mϋller et al., J. Med. Chem. 45:3440, 2002; A. Maconi et al., J. Med. Chem. 45:3579, 2002).

In the patent application WO 03/053968 described derivatives triazolo-quinoline, new structural group effective antagonists of the adenosine A3. Compounds of General formulas (1) and (1a) of the patent application WO 03/053968 are antagonists of the adenosine A3with high selectivity.

In the patent application WO 03/053968 the stated compounds of the General formulas (1) and (1a), in which

R1'means a hydrogen atom or a straight or branched C1-4alkyl;

R2'means a hydrogen atom or a straight or branched C1-4alkyl;

R3'means a hydrogen atom or a straight or branched C1-4alkyl, or phenyl, thienyl or furyl, if necessary substituted by one or more straight or branched C1-4alkyl groups, straight or branched C1-4alkoxy groups, or halogen atom, is whether 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 sulfur atom, if necessary substituted by one or more straight or branched C1-4alkyl groups, straight or branched C1-4alkoxy groups or halogen atoms;

R6'denotes a hydrogen atom or cyano group, aminocarbonyl, C1-4alkoxycarbonyl or carboxyl group;

R7'means a hydrogen atom or a straight or branched C1-4alkyl, or phenyl, benzyl, thienyl, furyl, if necessary, replaced methylenedioxy group, or one or more straight or branched C1-4alkyl groups, straight or branched C1-4alkoxy groups, hydroxyl groups, triptoreline groups, cyano groups or halogen atoms, or 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 sulfur atom, if necessary substituted by one or more straight or branched C1-4alkyl groups, straight or branched C1-4alkoxy groups or halogen atoms,

R8', R9', R10'and R11'independently represent a hydrogen atom, straight or branched C1-4alkyl, p is the hole or branched C 1-4alkoxy, hydroxyl group or halogen atom; or

R8'and R11'represent a hydrogen atom, and R9'and R10'together form methylenedioxy-group;

X denotes the group-CH2-, a group-NH-, group-NR8'or sulfur atom or an oxygen atom or alphagroup or sulfoxy group, and R8'denotes a straight or branched C1-4alkyl or C3-6cycloalkyl;

n has a value of zero, 1 or 2

and their salts, solvate and optically active isomers and their salts, solvate.

These compounds also have the characteristic disadvantage that they are very poorly soluble in water, sometimes not dissolve completely, which complicates their use as pharmaceuticals.

The inventors aimed to obtain new ligands of the adenosine A3with quinoline quinoline skeleton, of which preferably antagonists, which would be a strong antagonistic effect and be selective in relation to receptor A3i.e. inhibited receptor-A3at a much lower concentration compared with receptors And1, A2aand A2b. The intent of the authors of the invention was also to ensure the stability, bioavailability, metabolism, therapeutic index, toxicity and solubility of new connections that would allow the development of Lekarstvo the th tools based on them. The next goal was to connect, due to their favorable absorption in the small intestine, could be administered orally.

The inventors have discovered that compounds of General formula (I),

in which

R1denotes a hydrogen atom or a straight or branched C1-4alkyl;

R2denotes a hydrogen atom or a straight or branched C1-4alkyl;

R3denotes a hydrogen atom or a straight or branched C1-4alkyl or C3-6cycloalkyl, or

phenyl, or thienyl, or furyl, if necessary substituted by one or more, identical or different, straight or branched C1-4alkyl groups, straight or branched C1-4alkoxy groups, hydroxyl groups or halogen atoms, or

5 - or 6-membered heterocyclic ring containing one, two, or three nitrogen atom, or a 5-membered heterocyclic ring containing one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, if necessary substituted by one or more, identical or different, straight or branched C1-4alkyl groups, straight or branched C1-4alkoxy groups, hydroxyl groups or halogen atoms;

R4denotes phenyl, benzyl, thienyl is whether furyl, if necessary, replaced methylenedioxy group, or one or more, identical or different, straight or branched C1-4alkyl groups, straight or branched C1-4alkoxy groups, hydroxyl groups, triptoreline groups, cyano groups or halogen atoms, or

5 - or 6-membered heterocyclic ring containing one or two or three or four nitrogen atom, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, if necessary substituted by one or more, identical or different, straight or branched C1-4alkyl groups, straight or branched C1-4alkoxy groups, or halogen atoms, or

a group of the General formula (a),

in which

R6and R7independently represent a hydrogen atom, a C3-6cycloalkylor benzyl, or

straight or branched C1-4alkyl, if necessary substituted amino group, amino group, substituted by one or two identical or different straight or branched C1-4alkyl groups, hydroxyl group, carboxyl group, or a straight or branched C1-4alkoxy group, or

a group of the General formula (b),

in which

R8and R9 independently represent a straight or branched C1-4alkyl, C3-6cycloalkyl or hydroxyl group;

Z represents an oxygen atom, a sulfur atom, a group-CHR11- or the group-NR12-where R11and R12independently represent a hydrogen atom, straight or branched C1-4alkyl, C3-6cycloalkyl, benzyl or-CH2-(straight or branched C1-5acyl)-, -CH2-CH2-O-(straight or branched C1-4alkyl) -, or straight or branched C1-5acyl;

W represents a nitrogen atom or a group-CH-;

m is 1, 2 or 3;

o is 1, 2 or 3;

p has a value of zero or 1;

r has a value of zero or 1;

t has a value of zero or 1;

R5denotes a hydrogen atom, straight or branched C1-4alkyl, or

phenyl, benzyl, thienyl or furyl, if necessary, replaced methylendioxy-group or one or more, identical or different, straight or branched C1-4alkyl groups, straight or branched C1-4alkoxy groups, hydroxyl groups, triptoreline groups, cyano groups or halogen atoms, or

5 - or 6-membered heterocyclic ring containing one or two or three or four nitrogen atom, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, sluceainosti substituted by one or more identical or different straight or branched C 1-4alkyl groups, straight or branched C1-4alkoxy groups, hydroxyl groups or halogen atoms;

R13denotes a cyano group, aminocarbonyl group, -CO-O-(straight or branched C1-4alkyl or carboxyl group;

X denotes the group-CH2-, a group-NH-, group-NR10or sulfur atom, or oxygen atom or the group,- SO - or-SO2-where R10denotes a straight or branched C1-4alkyl or C3-6cycloalkyl;

n has a value of zero, 1 or 2;

and their salts, solvate, N-oxides and isomers, and their salts and solvate meet defined above criteria, they have better solubility than the well-known derivative triazole-3-cyanohydrin, and at the same time, they have a strong adenosine A3antagonistic effect and selectivity.

In addition, the inventors have found that compounds of General formula (I) according to the invention exhibit an outstanding anti-inflammatory effect.

Another advantage of the compounds of General formula (I) is that they have very favourable properties of metabolism. The triazole ring is stable, in the course of its metabolism undesirable aromatic amines were not formed.

Another advantage of the compounds of General formula (I) according to the present invention is that is, they have favorable pharmacokinetic properties.

Detailed values of the above substituents are as follows:

Under the halogen atom mean an atom of chlorine, fluorine, iodine or bromine.

Straight or branched C1-4the mean alkyl methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, preferably ethyl or methyl.

Straight or branched C1-4alkoxy mean methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, Deut.-butoxy, tert.-butoxy, preferably ethoxy or methoxy.

Under C3-6cycloalkyl mean cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

Under C1-5the acyl mean formyl, acetyl, propionyl, 2-methylpropionyl, butyryl or valeryl.

Under the 5 - or 6-membered heterocyclic ring containing one, two, three or four nitrogen atom mean aromatic ring or unsaturated, partially saturated or fully saturated heterocyclic ring such as pyrrole, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazin, 1,2,4-triazine, 1,3,5-triazine, 1,2,4,5-tetrazine, pyrrolin, imidazolin, pyrazolin. This ring can be substituted C1-4alkyl or alkoxy group or a hydroxyl group or a halogen atom.

Hetaeras the cycle, containing one nitrogen atom and one oxygen atom or one nitrogen atom and one sulfur atom, may be an aromatic ring, unsaturated, partially saturated or saturated heterocycle, such as, for example, oxazol, isoxazol, thiazole, isothiazol, 1,2-oxazin, 1,3-oxazin, 1,4-oxazin, 1,2-thiazin, 1,3-thiazin, 1,4-thiazin. This ring can be substituted C1-4alkyl or alkoxy group or a hydroxyl group or a halogen atom.

Group (b) preferably represents pyrrolidine, piperidine, piperazine derivatives, 4-methylpiperazine, 4-acetylpiperidine, 4-acetylethylenediamine, 4-ethoxymethyleneamino, 4-benzylpiperazine, morpholine or 2,6-dimethylmorpholine group.

Under the salts of the compounds of General formula (I) include salts derived from inorganic and organic acids. Preferred salts are obtained with pharmaceutically acceptable acids, such as, for example, hydrochloric acid, sulfuric acid, econsultancy acid, tartaric acid, malic acid, citric acid, fumaric acid. Salts, which are formed during purification or separation, for example methanesulfonate and tetrafluoroborate, are also included in the scope of the invention.

Under the solvate mean a solvate obtained with different solvents, such as, for example, water, methyl ethyl ketone or ethanol.

The nitrogen atoms in lice triazolo-quinoline or perhaps, in the substituents R3, R4or R5can be oxidized to N-oxides.

Under the isomers involve structural or stereoisomers. Structural isomers may be tautomers in equilibrium, or they can be selected demotape, which are also objects of the invention. Compounds of General formula (I) can contain one or more asymmetric carbon atoms (for example, depending on the values of R1, R2and R3and, therefore, they can exist in the form of optical isomers, enantiomers or diastereoisomers. These enantiomers and diastereoisomers, as well as mixtures thereof, including racemates, are also objects of the invention.

A narrower group of the compounds of General formula (I) is formed by compounds

in which

R1denotes a hydrogen atom or a straight or branched C1-4alkyl;

R2denotes a hydrogen atom or a straight or branched C1-4alkyl;

R3denotes a hydrogen atom or a straight or branched C1-4alkyl or C3-6cycloalkyl, or

phenyl or thienyl, or furyl, if necessary substituted by one or more, identical or different, straight or branched C1-4alkyl groups, straight or branched C1-4alkoxy groups, or atoms of Galaga is a, or

5 - or 6-membered heterocyclic ring containing one, two, or three nitrogen atom, or a 5-membered heterocyclic ring containing one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, if necessary substituted by one or more, identical or different, straight or branched C1-4alkyl groups, straight or branched C1-4alkoxy groups, or halogen atoms;

R4denotes phenyl, benzyl, thienyl or furyl, if necessary, replaced methylendioxy-group or one or more, identical or different, straight or branched C1-4alkyl groups, straight or branched C1-4alkoxy groups, hydroxyl groups, triptoreline groups, cyano groups or halogen atoms, or

5 - or 6-membered heterocyclic ring containing one or two or three or four nitrogen atom, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, if necessary substituted by one or more, identical or different, straight or branched C1-4alkyl groups, straight or branched C1-4alkoxy groups or halogen atoms, or a group of the General formula (a), in which

R6and R7independently represent a hydrogen atom, a C3-6the cycle is alkyl, benzyl or straight or branched C1-4alkyl, if necessary substituted amino group, amino group, substituted by one or two identical or different, straight or branchedC1-4alkyl groups, hydroxyl groups, carboxyl groups, or a straight or branched C1-4alkoxy groups, or

a group of the General formula (b), in which

R8and R9independently represent a straight or branched C1-4alkyl or C3-6cycloalkyl;

Z represents an oxygen atom, a sulfur atom, a group-CHR11or-NR12where R11and R12independently represent a hydrogen atom, straight or branched C1-4alkyl, C3-6cycloalkyl, benzyl or-CH2-(straight or branched C1-5acyl)-, -CH2-CH2-O-(straight or branched C1-4alkyl) -, or straight or branched C1-5acyl;

W represents a nitrogen atom or a group-CH-;

m is 1, 2 or 3;

o is 1, 2 or 3;

p has a value of zero or 1;

r has a value of zero or 1;

t has a value of zero or 1;

R5denotes a hydrogen atom, straight or branched C1-4alkyl, or phenyl, benzyl, thienyl or furyl, if necessary, replaced methylenedioxy group, or one or more, identical or different, straight or branched who passed C 1-4alkyl groups, straight or branched C1-4alkoxy groups, hydroxyl groups, triptoreline groups, cyano groups or halogen atoms,

or 5 - or 6-membered heterocyclic ring containing one or two or three or four nitrogen atom, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, if necessary substituted by one or more, identical or different, straight or branched C1-4alkyl groups, straight or branched C1-4alkoxy groups or halogen atoms;

R13denotes a cyano group, aminocarbonyl, group-CO-O-(straight or branched C1-4alkyl or carboxyl group;

X denotes the group-CH2-, a group-NH-, group-NR10or sulfur atom, or oxygen atom or the group,- SO - or-SO2-where R10denotes a straight or branched C1-4alkyl or C3-6cycloalkyl;

n has a value of zero, 1 or 2;

and their salts, solvate, N-oxides and isomers, and their salts and solvate.

Another narrower group of the compounds of General formula (I) is formed by compounds

in which

R1denotes a hydrogen atom or a straight or branched C1-4alkyl;

R2denotes a hydrogen atom or a straight or branched C1-4alkyl;

R3the convoy is achet phenyl or thienyl, or furyl, if necessary substituted by one or more, identical or different, straight or branched C1-4alkyl groups, straight or branched C1-4alkoxy groups or halogen atoms, or

5 - or 6-membered heterocyclic ring containing three nitrogen atom, or a 5-membered heterocyclic ring containing one nitrogen atom and one oxygen atom or one nitrogen atom and one sulfur atom, if necessary substituted straight or branched C1-4alkyl group, straight or branched C1-4alkoxy group or a halogen atom;

R4denotes phenyl, benzyl, thienyl or furyl, if necessary, replaced methylenedioxy group, or one or more, identical or different, straight or branched C1-4alkyl groups, straight or branched C1-4alkoxy groups, hydroxyl groups, triptoreline groups, cyano groups or halogen atoms, or

5 - or 6-membered heterocyclic ring containing one or two or three or four nitrogen atom, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, if necessary substituted by one or more, identical or different, straight or branched C1-4alkyl groups, straight or branched C1-4

a group of the General formula (a), in which

R6and R7independently represent a hydrogen atom, a C3-6cycloalkyl or benzyl or straight or branched C1-4alkyl, if necessary substituted amino group, amino group, substituted by one or two identical or different, straight or branched C1-4alkyl groups, hydroxyl groups, carboxyl groups, or a straight or branched C1-4alkoxy groups, or

a group of the General formula (b), in which

R8and R9independently represent a straight or branched C1-4alkyl or C3-6cycloalkyl;

Z represents an oxygen atom, a sulfur atom, a group-CHR11or-NR12where R11and R12independently represent a hydrogen atom, straight or branched C1-4alkyl, C3-6cycloalkyl, benzyl or-CH2-(straight or branched C1-5acyl)-, -CH2-CH2-O-(straight or branched C1-4alkyl) -, or straight or branched C1-5acyl;

W represents a nitrogen atom or a group-CH-;

m is 1, 2 or 3;

o is 1, 2 or 3;

p has a value of zero or 1;

r has a value of zero or 1;

t has a value of zero or 1;

R5denotes phenyl, benzyl, thienyl or furyl, if necessary, replaced methylenedioxy group, or about the Noi or more, the same or different, straight or branched C1-4alkyl groups, straight or branched C1-4alkoxy groups, hydroxyl groups, triptoreline groups, cyano groups or halogen atoms, or

5 - or 6-membered heterocyclic ring containing one or two or three or four nitrogen atom, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, if necessary substituted by one or more, identical or different, straight or branched C1-4alkyl groups, straight or branched C1-4alkoxy groups or halogen atoms;

R13denotes a cyano group;

X denotes the group-NH-;

n has a value of zero, 1 or 2;

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

Another narrower group of the compounds of General formula (I) is formed by compounds

in which

R1denotes a hydrogen atom or methyl;

R2denotes a hydrogen atom or methyl;

R3denotes phenyl or thienyl, or furyl, if necessary substituted by one or more, identical or different, straight or branched C1-4alkyl groups, straight or branched C1-4alkoxy groups, or halogen atoms, or

5 - or 6-membered heterocyclic ring containing one who does two or three, nitrogen atom, or a 5-membered heterocyclic ring containing one nitrogen atom and one oxygen atom or one nitrogen atom and one sulfur atom, if necessary substituted by one or more, identical or different, straight or branched C1-4alkyl groups, straight or branched C1-4alkoxy groups or halogen atoms;

R4denotes a 6-membered heterocyclic ring containing one nitrogen atom, or

a group of the General formula (a), in which

R6and R7independently represent a straight or branched C1-4alkyl, or

a group of the General formula (b), in which

R8and R9independently represent a straight or branched C1-4alkyl;

Z represents an oxygen atom or the group-NR12-where R12denotes a hydrogen atom, straight or branched C1-4alkyl, benzyl or acetyl;

W represents a nitrogen atom;

m has a value of 2;

o has a value of 2;

p has a value of zero or 1;

r has a value of zero or 1;

t has a value of zero;

R5denotes phenyl, benzyl, thienyl or furyl, if necessary, replaced methylendioxy-group or one or more, identical or different, straight or branched C1-4alkyl groups, straight or branched C1-4alkoxy groups, hydroxyl what governmental groups, triptoreline groups, cyano groups or halogen atoms, or

5 - or 6-membered heterocyclic ring containing one or two or three or four nitrogen atom, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, if necessary substituted by one or more, identical or different, straight or branched C1-4alkyl groups, straight or branched C1-4alkoxy groups or halogen atoms;

R13denotes a cyano group;

X denotes the group-NH-;

n has a value of zero, 1 or 2;

and their salts, solvate, N-oxides and isomers and their salts and solvate.

Another narrower group of the compounds of General formula (I) is formed by compounds

in which

R1denotes a hydrogen atom or methyl;

R2denotes a hydrogen atom or methyl;

R3denotes phenyl or 6-membered heterocyclic ring containing one nitrogen atom;

R4denotes phenyl, benzyl, thienyl or furyl, if necessary, replaced methylendioxy-group or one or more, identical or different, straight or branched C1-4alkyl groups, straight or branched C1-4alkoxy groups, hydroxyl groups, triptoreline groups, cyano groups or halogen atoms, or

5 - or 6-membered heterocyclics ring, containing one, two, or three, or four nitrogen atom, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, if necessary substituted by one or more, identical or different, straight or branched C1-4alkyl groups, straight or branched C1-4alkoxy groups or halogen atoms, or

a group of the General formula (a), in which

R6and R7independently represent a hydrogen atom, a C3-6cycloalkyl, benzyl or straight or branched C1-4alkyl, if necessary substituted amino group, amino group, substituted by one or two identical or different, straight or branched C1-4alkyl groups, hydroxyl groups, carboxyl groups, or a straight or branched C1-4alkoxy groups, or

a group of the General formula (b), in which

R8and R9independently represent a straight or branched C1-4alkyl or C3-6cycloalkyl;

Z represents an oxygen atom, a sulfur atom, a group-CHR11- or the group-NR12-where R11and R12independently represent a hydrogen atom, straight or branched C1-4alkyl, C3-6cycloalkyl, benzyl or-CH2-(straight or branched C1-5acyl)-, -CH2-CH2-O-(straight or branched C1-4alkyl)- or direct the Oh or branched C 1-5acyl;

W represents a nitrogen atom or a group-CH-;

m is 1, 2 or 3;

o is 1, 2 or 3;

p has a value of zero or 1;

r has a value of zero or 1;

t has a value of zero or 1;

R5denotes phenyl, benzyl, thienyl or furyl, if necessary, replaced methylendioxy-group or one or more, identical or different, straight or branched C1-4alkyl groups, straight or branched C1-4alkoxy groups, hydroxyl groups, triptoreline groups, cyano groups or halogen atoms, or

5 - or 6-membered heterocyclic ring containing one or two or three or four nitrogen atom, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, if necessary substituted by one or more, identical or different, straight or branched C1-4alkyl groups, straight or branched C1-4alkoxy groups or halogen atoms;

R13denotes a cyano group;

X denotes the group-NH-;

n has a value of zero, 1 or 2;

and their salts, solvate, N-oxides and isomers and their salts and solvate.

Another narrower group of the compounds of General formula (I) is formed by compounds

in which

R1denotes a hydrogen atom or methyl;

R2denotes the atom in which Orada or methyl;

R3denotes phenyl or thienyl, or furyl group, if appropriate substituted by one or more, identical or different, straight or branched C1-4alkyl groups, straight or branched C1-4alkoxy groups or halogen atoms, or

5 - or 6-membered heterocyclic ring containing one, two, or three nitrogen atom, or a 5-membered heterocyclic ring containing one nitrogen atom and one oxygen atom or one nitrogen atom and one sulfur atom, if necessary substituted by one or more, identical or different, straight or branched C1-4alkyl groups, straight or branched C1-4alkoxy groups or halogen atoms;

R4denotes phenyl, benzyl, thienyl or furyl, if necessary, replaced methylendioxy-group or one or more, identical or different, straight or branched C1-4alkyl groups, straight or branched C1-4alkoxy groups, hydroxyl groups, triptoreline groups, cyano groups or halogen atoms, or

5 - or 6-membered heterocyclic ring containing one or two or three or four nitrogen atom, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, if necessary substituted by one or more, one is the same or different, straight or branched C1-4alkyl groups, straight or branched C1-4alkoxy groups or halogen atoms, or

a group of the General formula (a), in which

R6and R7independently represent a hydrogen atom, a C3-6cycloalkyl, benzyl or straight or branched C1-4alkyl, if necessary substituted amino group, amino group, substituted by one or two identical or different, straight or branched C1-4alkyl groups, hydroxyl groups, carboxyl groups, or a straight or branched C1-4alkoxy groups, or

a group of the General formula (b), in which

R8and R9independently represent a straight or branched C1-4alkyl or C3-6cycloalkyl;

Z represents an oxygen atom, a sulfur atom, a group-CHR11- or the group-NR12-where R11and R12independently represent a hydrogen atom, straight or branched C1-4alkyl, C3-6cycloalkyl, benzyl or-CH2-(straight or branched C1-5acyl)-, -CH2-CH2-O-(straight or branched C1-4alkyl) -, or straight or branched C1-5acyl;

W represents a nitrogen atom or a group-CH-;

m is 1, 2 or 3;

o is 1, 2 or 3;

p has a value of zero or 1;

r has a value of zero or 1;

t has the value zero or 1;

R5denotes phenyl, if necessary substituted methoxy group, hydroxyl group or halogen atom, or

5 - or 6-membered heterocyclic ring containing one nitrogen atom or one nitrogen atom and one sulfur atom;

R13denotes a cyano group;

X denotes the group-NH-;

n has a value of zero, 1 or 2;

and their salts, solvate, N-oxides and isomers and their salts and solvate.

Another narrow group of compounds of General formula (I) is formed by compounds

in which

R1denotes a hydrogen atom or methyl;

R2denotes a hydrogen atom or methyl;

R3denotes phenyl or thienyl, or furyl, or

5 - or 6-membered heterocyclic ring containing one, two, or three nitrogen atom, or a 5-membered heterocyclic ring containing one nitrogen atom and one oxygen atom or one nitrogen atom and one sulfur atom;

R4denotes a 5 - or 6-membered heterocyclic ring containing one or two or three or four nitrogen atom, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, or

a group of the General formula (a), in which

R6and R7independently represent a hydrogen atom, a C3-6cycloalkyl, benzyl or straight or branched C1-4alkyl, or

a group of the General formula (b), in which

R8and R9 independently represent a straight or branched C1-4alkyl;

Z represents an oxygen atom or the group-NR12-where R12denotes a hydrogen atom, straight or branched C1-4alkyl, C3-6cycloalkyl, benzyl or-CH2-acetyl, -CH2-CH2-O-CH2-CH3or acetyl;

W represents a nitrogen atom or a group-CH-;

m has a value of 2;

o has a value of 2;

p has a value of zero or 1;

r has a value of zero or 1;

t has a value of zero;

R5denotes phenyl, thienyl or furyl, if necessary, replaced methylendioxy-group or one or more, identical or different, straight or branched C1-4alkyl groups, straight or branched C1-4alkoxy groups, hydroxyl groups, triptoreline groups, cyano groups or halogen atoms, or

5 - or 6-membered heterocyclic ring containing one or two or three or four nitrogen atom, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom;

R13denotes a cyano group;

X denotes the group-NH-;

n has a value of 1;

and their salts, solvate, N-oxides and isomers and their salts and solvate.

Even narrower group of the compounds of General formula (I) is formed by compounds

in which

R1denotes a hydrogen atom;

R2denotes a hydrogen atom;

R3denotes phenyl, or

6-membered heterocyclic ring containing one nitrogen atom;

R4denotes a 6-membered heterocyclic ring containing one nitrogen atom, or

a group of the General formula (b), in which

R8and R9denote methyl;

Z represents an oxygen atom or the group-NR12-where R12denotes a hydrogen atom, methyl or acetyl;

W represents a nitrogen atom;

m has a value of 2;

o has a value of 2;

p has a value of zero or 1;

r has a value of zero or 1;

t has a value of zero;

R5denotes phenyl, if necessary substituted methoxy group, hydroxyl group or halogen atom, or

5 - or 6-membered heterocyclic ring containing one nitrogen atom or one nitrogen atom and one sulfur atom;

R13denotes a cyano group;

X denotes the group-NH-;

n has a value of 1;

and their salts, solvate, N-oxides and isomers and their salts and solvate.

Representative compounds of General formula (I) are, for example, the following connections:

2-(3-methoxyphenyl)-7-(morpholine-4-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline,

2-(4-methoxyphenyl)-7-(morpholine-4-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline,

2-(4-methoxyphenyl)-7-(2,6-TRANS-dimethylmorpholine-4-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline,

2-(pyridin-4-yl)-7-(4-methylpiperazin-1-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline,

2-(4-methoxyphenyl)-7-(4-methylpiperazin-1-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline,

2-(3-methoxyphenyl)-7-(4-methylpiperazin-1-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline,

2-(3-hydroxyphenyl)-7-(4-ethylpiperazin-1-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline,

2-(3-methoxyphenyl)-7-(4-acetylpiperidine-1-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline,

2-(3-methoxyphenyl)-7-(piperazine-1-yl)-9-butylamino-10-cyano-s-triazolo[1,5-a]quinoline,

2-phenyl-7-(pyridin-3-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline,

2-phenyl-7-(4-methylpiperazin-1-yl)-9-(2-pyridylmethylamine)-10-cyano-s-triazolo[1,5-a]quinoline,

2-(3-methoxyphenyl)-7-(pyridin-3-yl)-9-(4-pyridylmethylamine)-10-cyano-s-triazolo[1,5-a]quinoline,

and their salts, solvate, N-oxides and isomers and their salts and solvate.

Representative salts of the compounds of General formula (I) are, for example, the following connections:

2-(3-methoxyphenyl)-7-(morpholine-4-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline hydrochloride

2-(4-methoxyphenyl)-7-(morpholine-4-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline hydrochloride

2-(4-methoxyphenyl)-7-(2,6-dimethylmorpholine-4-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline the hydrosulfate,

2-(pyridin-4-yl)-7-(4-methylpiperazin-1-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline maleate,

2-(3-methoxyphenyl)-7-(4-methylpiperazin-1-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline-hemifumarate hemihydrate,

2-(3-hydroxyphenyl)-7-(4-methylpiperazin-1-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline hydrochloride

2-(3-methoxyphenyl)-7-(4-acetylpiperidine-1-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline the hydrosulfate,

2-(3-methoxyphenyl)-7-(piperazine-1-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline maleate,

2-Phenyl-7-(pyridin-3-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline the hydrosulfate,

2-phenyl-7-(4-methylpiperazin-1-yl)-9-(2-pyridylmethylamine)-10-cyano-s-triazolo[1,5-a]quinoline hydrochloride

2-(3-Methoxyphenyl)-7-(pyridin-3-yl)-9-(4-pyridylmethylamine)-10-cyano-s-triazolo[1,5-a]quinoline the hydrosulfate.

According to another of its aspects, the present invention also relates to pharmaceutical compositions containing as active principles of compounds of General formula (I) or their isomers, salts and solvate, which are the preferred oral compositions, but the formulations for inhalation, parenteral and percutaneous injection are also objects of the invention. The above pharmaceutical compositions may be solid or liquid, such as tablets, granules, capsules, plasters, solutions, suspensions or emulsions. Solid compositions, particularly tablets and capsules represent prefer the performance communications pharmaceutical forms.

The above pharmaceutical compositions have, using pharmaceutical excipients commonly used in pharmaceutical industry and conventional manufacturing operations.

Compounds of General formula (I) according to the present invention can be used for the treatment of pathologies where the receptor is A3plays a role in the development of the disease.

Compounds that have a selective effect on receptor-a3can be used in the treatment and/or prophylaxis of dysfunctions of the heart (Y. Guo et al., J Mol. Cell Cardiol. 2001,33:825-30, R.G. Black et al. Circ Res. 2002, 91:165-72), eyes, kidneys (H.T. Lee et al. Am J Physiol Regul Integr Comp Physiol. 2006, 291:R959-69), the respiratory system, joints (L. Madi J Rheumatol. 2007,34:20-6) gastrointestinal tract (L. Antonioli et al. Infiamm Bowel Dis. 2007 Nov 16, L. Rybaczyk et al. Gastroenterology 2007;132(Suppl 2):(A-246) and the Central nervous system (GJ Chen et al. J Neurosci Res. 2006, 84:1848-55). They inhibit the degranulation of mast cells, inhibit the production of cytokines, reduce intraocular pressure, reduce the release of TNFα, prevent the migration and activation of eosinophil and neutrophils and other inflammatory cells, inhibit the contraction of smooth muscles of the Airways and prevent infiltration of blood plasma through the blood vessel. By inhibiting receptor adenosine A3can be cured diseases, which are associated with increased productsample (for example, asthma and COPD).

Mast cells play a key role in the pathological mechanism not only allergies, asthma, and irritable bowel syndrome (IBS). Fat cells transmit signals of stress transmitted along the axis of the brain-gut resulting in the release of proinflammatory mediators that can cause an irritation of the nerve endings, which can affect the afferent nerve endings and change their perception, affect the mobility of the intestine, increase the permeability of the intestine and, in sensitive individuals, to modulate inflammation (World J. Gastroenterol. 2007, 22:3027-30). A subpopulation of patients suffering from IBS, has increased the number of mast cells in the mucosa of the colon and large intestine (Gut 2008, 57:468-473). In addition, activated mast cells near the nerves of the colon and colon correlate with abdominal pain and visceral hypersensitivity in the patients suffering from diarrhoea within IBS (Gastroenterology 2004, 126:693-702, J Gastroenterol Hepatol 2006, 21(1 Pt l):71-8). Fat cells are under as paracrine and autocrine regulation of adenosine, partly through adenosine receptor-a3fat cells.

On the basis of the above effects, antagonists of receptor-A3adenosine can be therapeutically suitable for use as anti-asthmatic, anti-ischemic, medium is in, antidepressants, anti-arrhythmic, anti-rheumatic tools, anti-glaucoma, anti-inflammatory drugs for inflammatory and irritable bowel disease, COPD, means for protecting renal function, means for preventing tumors, antiparkinsonian tools and medicines to stimulate cognitive function. They can also be used in the treatment or prophylaxis of the following diseases: damage to the heart muscle during reperfusion, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), including chronic bronchitis, pulmonary emphysema or shortness of breath, allergic reactions (e.g. reactions, induced by poisonous spitting, urticaria, scleroderma, arthritis, other autoimmune diseases, inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, irritable bowel syndrome (IBS), Addison disease, psoriasis, joint diseases, hypertension, abnormal neurological function, glaucoma, and diabetes (Naunyn-Schmiedberg''s Arch. Pharmacol. 362:382, 2000; 21 TiPS:456, 2000, Am. J. Resp.Cell Mol. Biol. 35: 549, 2006).

Compounds according to the present invention can preferably be used in the treatment of such disorders as asthma (Clin. Exp. Allergy 32:824, 2002; J. Allergy. Clin. Measurement., 114:737, 2004), COPD (Am. J. Respir. Crit. CareMed., 173:398, 2006), rdsw, glaucoma (Investigative Ophthalmology & Visual Science, Vol. 46, 2005), tumor, IBD, IBS (World J. Gastroenterol. 2007, 22:3027-30), allergic and inflammatory pain (Pain 121:105, 2006), rheumatoid arthritis (J. Rheumatol. 34:20-6, 2007), ischemia, hypoxia, cardiac arrhythmia, renal diseases and diseases associated with mood (JPET Fast Forward. Published on April 25, 2007 as DOI:10.1124/jpet.107.121665).

According to another of its aspects, the present invention relates to the use of compounds of General formula (I) in the treatment of the above disorders. The suggested daily dose of 1-100 mg of the active ingredient depending on the nature and severity of the disease and on gender, body weight, etc. of the patient.

The next object of the invention to provide compounds of General formula (I) and intermediates of General formula (II), (III), (V), (VI), (IX), (X), (XI), (XII), (XIV) and (XV).

Part of the intermediate compounds of General formula (II), (III), (V), (VI), (IX), (X), (XI), (XII), (XIV) and (XV)used in the method according to the invention, are new.

Method (A) according to the invention is shown in reaction scheme 1 (figure 1).

According to Method (A) according to the invention for preparing compounds of General formula (I)in which R1, R2, R3, R4, R5, R13, X and n have the meanings mentioned above, salt 1,2-diamino-azine General formula (II)

in which R1, R2, R3, R4, R13 , X and n have the meanings mentioned above, and TsO-denotes the anion p-toluensulfonate, enter into reaction with the compound of General formula (IV)

in which

- the value of R5so, as above, and Y denotes a hydrogen atom, halogen atom or C1-4alkoxy, preferably with a suitable acid anhydrides or esters (D.W. Robertson, J. Med. Chem., 28, 717, 1985), and if desired, the substituents of the compounds of General formula (I) transform into each other by way of the famousper seand/or the compound obtained of General formula (I) is converted into its salt, MES, N-oxide or release of its salts of MES, and/or separated into its optically active isomers, or optically active isomer is converted into the racemic compound and if desired, separate structural isomers.

Aldehydes can also be used for ring closure. As ciclismo agent may preferably be used triethylamine in dimethylformamide, but other agents of this type are known in organic chemistry, can also be used. The cyclization can be carried out at various temperatures, preferably at temperatures from 20°C to 150°C.

Method (B) according to the invention is shown in reaction scheme 2 (figure 2).

According to the invention for preparing compounds of General Faure the uly (I), where

R4denotes phenyl, benzyl, thienyl or furyl, substituted methylenedioxy-group or one or more, identical or different, straight or branched C1-4alkyl groups, straight or branched C1-4alkoxy groups, hydroxyl groups, triptoreline groups, cyano groups or halogen atoms,

or 5 - or 6-membered heterocyclic ring bound through a carbon atom, containing one, two, or three, or four nitrogen atom, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, if necessary substituted by one or more, identical or different, straight or branched C1-4alkyl groups, straight or branched C1-4alkoxy groups or halogen atoms, or

a group of the General formula (b), where, if the value t=1, then W represents a nitrogen atom or a group-CH-, or, if the value t=0, then W represents a group-CH-, and Z-values, m, o, p, r, R8and R9are as defined above,

and the values of R1, R2, R3, R5, R13, X and n are as defined above,

in method B/1) triazole derivative of General formula (V)

where E denotes a halogen atom or trifloromethyl, and the values of R1, R2, R3, R5, R13X and pavlata such as defined above, and the compound of General formula (VII)

R4-B(OH)2

(VII)

- where the value of R4is the same as defined above for method B), is introduced into the reaction conditions of the Suzuki reaction (A. Kotschy, G. Timari,: Heterocycles from Transition Metal Catalysis. Springer, 2005), or

in method B/2) derived triamcinolone-triazole of the General formula (VI)

where R14denotes a straight or branched C1-4alkyl, and R1, R2, R3R5R13, X and n are as defined above, and the compound of General formula (VIII)

R4-E (VIII)

where E denotes a halogen atom or trifloromethyl and the value of R4is the same as defined above for method B), is introduced into the reaction under the reaction conditions Stille (A. Kotschy, G. Timari,: Heterocycles from Transition Metal Catalysis. Springer, 2005); and if desired, the substituents of the compounds of General formula (I) transform into each other by way of the famousper seand/or the compound obtained of General formula (I) is converted into its salt, MES, N-oxide or release of its salts of MES, and/or separated into its optically active isomers, or optically active isomer is converted into the racemic compound and if desired a separate structural isomers.

Method (C) according to the invention is shown in reaction scheme 3 (figure 3).

According to the SPO is training C) according to the invention, to obtain the compounds of General formula (I), where the values of R1, R2, R3, R4, R5, R13, X and n are as defined above, triazole derivative of General formula (XII)

where the values of R4, R5and R13are as defined above, and the compound of General formula (XIII)

where the values of X, R1, R2and R3and n are as defined above, is introduced into the reaction by way of the famousper se(Nan Zhang, Bioorg. and Med. Chem. Lett., 10, 2825, 2000), and if desired, the substituents of the compounds of General formula (I) transform into each other by way of the famousper seand/or the compound obtained of General formula (I) is converted into its salt, MES, N-oxide or release of its salts of MES, and/or separated into its optically active isomers, or optically active isomer is converted into the racemic compound and if desired a separate structural isomers.

Method (D) according to the invention is shown in reaction scheme 4 (figure 4). According to method (D) according to the invention, to obtain the compounds of General formula (I), where the values of R1, R2, R3, R4, R5, R13, X and n are as defined above, can also be used a compound of General formula (XV),

where sub> X, R1, R2, R3, R4, R5, R13and n are as defined above, and TsO-denotes p-toluensulfonate anion, which cyclist in the presence of organic or inorganic bases, preferably triethylamine or pyridine, and if desired, the substituents of the compounds of General formula (I) transform into each other by way of the famousper seand/or the compound obtained of General formula (I) is converted into its salt, MES, N-oxide or release of its salts of MES, and/or separated into its optically active isomers, or optically active isomer is converted into the racemic compound and if desired a separate structural isomers.

The source materials used in the above methods, and receipt of them are shown as follows.

Compounds of General formula (II)

where the values of R1, R2, R3, R4, R13and n are as defined above, and TsO-denotes p-toluensulfonate anion, are new materials, and they can be obtained by several known methods, among others, for example, as shown in reaction scheme 1 (figure 1), from compounds of General formula (III)

where the values of X, R1, R2, R3, R4, R13and n I is comprised of such as defined above, by reaction of N-amination, known in organic chemistry (E.E. Glover, R.T. Rowbotton, J. Chem. Soc. Perkin Trans L, 376, 1976; G. Timari, Gy. Hajόs, S. Batori and A. Messmer, Chem. Ber., 125, 929, 1992). As for the N-amineralo agent, preferably using O-dailydressupgames (TSH), but other known compounds may also be used as N-mineralsa agents.

Compounds of General formula (III) partially known from patent application WO 2005/009969, or they can be obtained by analogy with the method described therein.

Compounds of General formula (III), in which

R4denotes phenyl, benzyl, thienyl or furyl, substituted methylenedioxy-group or one or more, identical or different, straight or branched C1-4alkyl groups, straight or branched C1-4alkoxy groups, hydroxyl groups, triptoreline groups, cyano groups or halogen atoms, or

5 - or 6-membered heterocyclic ring bound through a carbon atom, containing one, two, or three, or four nitrogen atom, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, if necessary substituted by one or more, identical or different, straight or branched C1-4alkyl groups, straight or branched C1-4alkoxy groups or halogen atoms, or

if the value t=1, then W represents a nitrogen atom or a group-CH-, or if the value t=0, W represents a group-CH-, and Z-values, m, o, p, r, R8and R9are as defined above,

and the values of R1, R2, R3, R5, R13, X and n are as defined above,

can be obtained similarly to the version of method B/1) according to the invention when using the 6-halogen-aminoquinolinic derivatives known from patent application WO 02/096879, or their analogues as source material.

Compounds of General formula (V)

where E denotes a halogen atom and R1, R2, R3, R5, R13, X and n are as defined above, partially known from international patent application WO 03/053968 or can be obtained by analogy with the method described therein.

Compounds of General formula (V), where E denotes trifloromethyl and the values of R1, R2, R3, R5, R13, X and n are as defined above, can be obtained from the corresponding compounds described in the international patent application WO 03/053968 or their analogues containing a hydroxyl group to group E, in a way known in organic chemistry (G. Timari, T. Soόs, Gy. Hajόs, A. Messmer, J. Nacsa and J. Molnar, Bioorg. Med. Chem. Lett, 2831, 1996).

Compounds of General formula (VI)

where R14denotes a straight or branched C1-4alkyl, and R1, R2, R3, R5, R13, X and n are as defined above, are new compounds. Intermediate compounds of General formula (VI) can be obtained by several known methods, for example, according to scheme 2 reaction (figure 2), from compounds of General formula (V) by methods known in organic chemistry (A. Kotschy, G. Timari: Heterocycles from Transition Metal Catalysis. Springer, 2005, WO 2006/051341). To obtain trialkylamines group preferably use hexamethyldisilane.

Compounds of General formula (XII)

where the values of R4, R5and R13are as defined above, are new compounds. Compounds of General formula (XII), where the values of R4, R3and R13are as defined above, can be obtained from compounds of General formula (XI)

where the values of R4, R5and R13are as defined above, by methods knownper se(D.L. Leysen, J. Heterocyclic Chem., 24, 1611, 1987), according to scheme 3 reaction (figure 3).

Compounds of General formula (XI) where the values of R4, R5and R13are as defined above are new compounds. To obtain a salt of 1,2-diamino-azine total is ormula (X)

where the values of R4and R13are as defined above, and TsO-denotes p-toluensulfonate anion is introduced into the reaction with the compound of General formula (IV)

where the values of R5are as defined above, and Y denotes a hydrogen atom, halogen atom or C1-4alkoxy group, preferably with suitable acid anhydrides or esters (D.W. Robertson, J. Med. Chem., 28, 717, 1985). Aldehydes can also be used for ring closure.

As ciclismo agent preferably using triethylamine in dimethylformamide, but other agents of this type are known in organic chemistry, can also be used. The cyclization can be carried out at various temperatures, preferably at 20°C-150°C.

Compounds of General formula (X) where the values of R4and R13are as defined above are novel compounds, they can be obtained by several known methods, for example, according to scheme 3 reaction (figure 3), from compounds of General formula (IX),

where the values of R4and R13are as defined above, by reaction of N-amination, known in organic chemistry (E.E. Glover, R.T. Rowbotton, J. Chem. Soc. Perkin Trans L, 376, 1976, G. Timari, Gy. Hajόs, S. Batori ad A. Messmer, Chem. Ber., 125, 929, 1992). As for the N-amineralo agent preferably used O-tosyl-hydroxylamine (TSH), but other known compounds may also be used as N-mineralsa agents.

Compounds of General formula (IX) partially known from international patent application WO 2005/009969 or can be obtained by analogy with the method described in international patent application WO 2005/009969, based on 2-nitrobenzoic acid containing the corresponding substituent R4in position 5.

Compounds of General formula (XV)

where X, R1, R2, R3, R4, R5, R13and n have the meanings as defined above, and TsO-denotes p-toluensulfonate anion are new compounds. Intermediate compounds of General formula (XV) can be obtained by several known methods, for example, according to scheme 4 reaction (figure 4), from compounds of General formula (XIV),

where the values of X, R1, R2, R3, R4, R5, R13and n are as defined above, by reaction of N-amination, known in organic chemistry (E.E. Glover, R.T. Rowbotton, J. Chem. Soc. Perkin Trans L, 376, 1976, G. Timari, Gy. Hajόs, S. Batori and A. Messmer, Chem. Ber., 125, 929, 1992). As N-amineralo agent preferably used O-tosyl-hydroxylamine (TSH), but others from the local connection can also be used as N-mineralsa agents.

Compounds of General formula (XIV) are partially known from international patent application WO 2005/009969 or can be obtained by analogy with the method described in the patent application WO 2005/009969, from compounds of General formula (III).

The General procedure to obtain the N-oxides:

The corresponding amine was dissolved in chloroform and the excess mCPBA was added parts. After stirring at ambient temperature for 5 hours, the reaction mixture was extracted with 10% sodium carbonate solution, and the organic layer was evaporated. The solid residue was purified by chromatography, obtaining the desired N-oxides.

The General procedure for obtaining salts:

To a solution of a suitable base, dissolved in tetrahydrofuran, the solution was added 1.2 equivalents of acid (hydrochloric acid, sulfuric acid, fumaric acid, maleic acid in ethanol and stirred at ambient temperature. The precipitate was filtered and washed with cold ethanol, getting the desired salt.

Compounds according to the invention of General formula (I) (II), (III), (V), (VI), (IX), (X), (XI), (XII), (XIV) and (XV), receipt and biological activity of the compounds of General formula (I) are demonstrated in the following examples, which do not limit the invention.

EXAMPLES

EXAMPLE 1

2-(3-methoxyphenyl)-7-(morpholine-4-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline

In General form the Le (I) R 1and R2represent a hydrogen atom, R3denotes phenyl, R5denotes 3-methoxyphenyl, R4refers to a group (b), where W denotes the nitrogen atom, Z represents an oxygen atom, the values of m and o is 2, the values of r, p and t is 0, R13denotes a cyano group, X represents a group NH, and n=1.

a) 1,2-diamino-3-cyano-4-benzylamino-6-(morpholine-4-yl)chinoline toilet:

To a solution of 3 g of 2-amino-3-cyano-4-benzylamino-6-morpholino-quinoline in 20 ml of dimethylformamide, 2.2 g of O-dailytorsemide dissolved in 25 ml of dichloromethane, was added dropwise at 20°C for 15 minutes. After 5 hours of stirring the precipitated crystalline material was filtered. After drying was obtained 3.8 g of target compound (MN+:376).

b) 2-(3-methoxyphenyl)-7-(morpholine-4-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline:

3.5 g of 1,2-diamino-3-cyano-4-benzylamino-6-(morpholine-4-yl)chinoline tosilata was dissolved in 50 ml of ethanol and to the solution was added 12 ml of ateleta sodium concentration of 1 mol/l in ethanol solution and 2 g of 3-methoxybenzaldehyde. The reaction mixture was heated at the boiling temperature of the solvent for 4 hours. The precipitated crystalline material was filtered and recrystallize from dimethylformamide. After drying were obtained 1.8 g of target compound (MN+:491).

1H-NMR (DMSO-d6), δ, ppm: 8,68 (user., 1H); 8,23(d, 1H); 7,79-to 7.64 (m, 4H); 7,43-7,05 (m, 7H); 5,15 (d, 2H); of 3.84 (s, 3H); 3,80-of 3.78 (m, 4H); 3,32-3,30 (m, 4H).

EXAMPLE 1.2

2-(3-methoxyphenyl)-7-(morpholine-4-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline hydrochloride

To a solution of 0.4 g of 2-(3-methoxyphenyl)-7-(morpholine-4-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline in 30 ml of ethyl acetate was added 5 ml of hydrogen chloride concentration of 4 mol/liter in solution in a simple ether. The precipitated crystalline material was filtered. After drying was received at 0.42 g of target compound (MN+:491).

1H-NMR (DMSO-d6), δ, ppm: 8,68 (user., 1H); 8,23 (d, 1H); 7,82-to 7.64 (m, 4H); 7,43-7,05 (m, 7H); 5,15 (d, 2H); of 3.84 (s, 3H); 3,82-of 3.78 (m, 4H); 3.43 points-3,30 (m, 4H)

EXAMPLE 2

2-(4-methoxyphenyl)-7-(morpholine-4-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline

In the General formula (I) R1and R2represent a hydrogen atom, R3denotes phenyl, R5represents 4-methoxyphenyl, R4refers to a group (b), where W denotes the nitrogen atom, Z represents an oxygen atom, the values of m and o is 2, the values of r, p and t is 0, R13denotes a cyano group, X represents a group NH, and n=1.

a) 2-(4-methoxyphenyl)-7-(morpholine-4-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline:

To a solution of 3.5 g of 1,2-diamino-3-cyano-4-benzylamino-6-(morpholine-4-yl)chinoline tosilata described in Example 1, in 50 ml of ethanol was added 12 ml of ateleta sodium in a concentration of 1 mol/l in ethanol, restoree 2 g of 4-methoxybenzaldehyde. The reaction mixture was heated at the boiling temperature of the solvent for 4 hours. The precipitated crystalline material was filtered and recrystallize from dimethylformamide. After drying were received of 1.65 g of target compound (MN+:491).

1H-NMR(DMSO-d6), δ, ppm: 8,72 (user., 1H); 8,23 (d, 1H); 7,79-to 7.64 (m, 4H); 7,43-7,05 (m, 7H); 5,13 (d, 2H); of 3.94 (s, 3H); 3,80-of 3.78 (m, 4H); 3,32-3,30 (m, 4H).

EXAMPLE 2.2

2-(4-methoxyphenyl)-7-(morpholine-4-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline hydrochloride

The target compound was obtained by the General method disclosed above, adding hydrochloric acid to the compound obtained according to Example 2.

1H-NMR (DMSO-d6), δ, ppm: 8,81 (user., 1H); with 8.33 (d, 1H); 7,82-to 7.64 (m, 4H); 7,43-7,05 (m, 7H); 5,15 (d, 2H); of 3.96 (s, 3H); 3,80-of 3.78 (m, 4H); 3,36-of 3.32 (m, 4H).

EXAMPLE 3

2-(4-methoxyphenyl)-7-(2,6-dimethylmorpholine-4-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline

In the General formula (I) R1and R2represent a hydrogen atom, R3denotes phenyl, R5represents 4-methoxyphenyl, R4refers to a group (b), where W denotes the nitrogen atom, Z represents an oxygen atom, the values of m and o is 2, the values of r and p is 1, R8and R9denote methyl, the value t=0, R13denotes a cyano group, X represents a group NH, and n=1.

a) 2-nitro-5-(2,6-dimethylmorpholine-4-yl)benzoic acid

A mixture of 5 g of 2-nitro-5-chlorobenzo the Noah acid and 15 ml of 2,6-dimethylmorpholine was stirred at 120°C for 6 hours. To the reaction mixture was added 150 ml of ethyl acetate. The precipitated yellow crystalline material was filtered, dissolved in 15 ml of water. Established pH of the mixture is equal to 6, using acetic acid. Precipitated material was filtered, washed with water and dried, obtaining of 4.2 g of target compound (MN+:281).

b) 2-Amino-5-(2,6-dimethylmorpholine-4-yl)benzoic acid:

A mixture of 6 g of 2-nitro-5-(2,6-dimethylmorpholine-4-yl)benzoic acid, 15 ml of cyclohexene and 3 g of Pd/C (10%) was heated under reflux for 6 hours. The hot reaction mixture was filtered through a layer of celite. After evaporation of the filtrate was obtained 4.8 g of the target product (MN+:251).

c) an anhydride of 5-(2,6-dimethylmorpholine-4-yl)eSATAII acid:

To a mixture of 8.9 g of 2-amino-5-(2,6-dimethylmorpholine-4-yl)benzoic acid in 60 ml of dioxane, under stirring and external cooling with cold water was added dropwise 10 ml of diphosgene. The mixture was heated under reflux for 4 hours. To the cold reaction mixture was filtered, the solid material was washed with 50 ml of a simple ester. The product was stirred for 5 minutes in a mixture of 50 ml of methanol and 5 ml of triethylamine, then was filtered and washed with 30 ml of methanol. After drying was obtained 7 g of the target product (MN+:277).

d) 2-amino-3-cyano-4-hydroxy-6-(2,6-dimethylmorpholine-4-yl)quinoline:

4 g of malonitrile was dissolved 50 ml of dimethylformamide. To the solution, in several parts, was added 2.4 g of 60%dispersion of sodium hydride in oil. To the clear solution was added 8 g of the anhydride of 5-(2,6-dimethylmorpholine-4-yl)eSATAII acid and the mixture was stirred at ambient temperature for 10 hours. The reaction mixture was diluted with 70 ml water and was extracted with 2×30 ml of ethyl acetate. The aqueous phase was evaporated in vacuo, the solid residue was dissolved in 20 ml of water and set pH 6. Precipitated material was filtered, washed with water. After drying were obtained 6.5 g of target compound (MN+: 299).

e) 2-Amino-3-cyano-4-chloro-6-(2,6-dimethylmorpholine-4-yl)quinoline:

A mixture of 1.7 g of 2-amino-3-cyano-4-hydroxy-6-(2,6-dimethylmorpholine-4-yl)quinoline and 3.4 ml of phosphorylchloride was stirred at 120°C for 4 hours. The cooled reaction mixture is poured onto 30 g of ice, the pH of the mixture was set equal to 8, with 10%sodium hydroxide solution, and the precipitated material was filtered. After drying was obtained 1.5 g of target compound (MN+: 317).

f) 2-Amino-3-cyano-4-benzylamino-6-(2,6-dimethylmorpholine-4-yl)quinoline:

3 g of 2-amino-3-cyano-4-chloro-6-(2,6-dimethylmorpholine-4-yl)quinoline and 6 ml of benzylamine was stirred at 125°C for 3 hours. The reaction mixture was poured on 30 ml of water. Precipitated material was filtered off, washed with 20 ml of water. After drying was obtained 2.3 g of target compound (MN+: 388).

g) 1,2-d is amino-3-cyano-4-benzylamino-6-(2,6-dimethylmorpholine-4-yl)chinoline toilet:

To a solution of 3.2 g of 2-amino-3-cyano-4-benzylamino-6-(2,6-dimethylmorpholine-4-yl)quinoline in 20 ml of dimethylformamide was added dropwise 2.2 g of O-dailytorsemide in 25 ml of dichloromethane at 20°C for 15 minutes. After 5 hours of stirring the precipitated crystalline material was filtered. After drying was obtained 3.4 g of target compound (MN+:403).

h) 2-(4-methoxyphenyl)-7-(2,6-dimethylmorpholine-4-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline:

3.5 g of 1,2-diamino-3-cyano-4-benzylamino-6-(2,6-dimethylmorpholine-4-yl)chinoline tosilata was dissolved in 50 ml of ethanol and to this solution was added 12 ml of ateleta sodium concentration of 1 mol/l in ethanol solution and 2 g of 4-methoxybenzaldehyde. The reaction mixture was heated at the boiling temperature of the solvent for 4 hours. The precipitated crystalline material was filtered and recrystallize from dimethylformamide. After drying was obtained 1.85 g of target compound (MH+:518).

1H-NMR(DMSO-d6), δ, ppm: 8,70 (user., 1H); compared to 8.26 (d, 1H); 7,89-to 7.64 (m, 4H); 7,43-to 7.15 (m, 7H); 5,16 (d, 2H); 3,90 (s, 3H); of 3.77-3,74 (m, 4H); 2,41-of 2.38 (m, 2H); 1,2 (d, 6H).

EXAMPLE 3.2

2-(4-methoxyphenyl)-7-(2,6-dimethylmorpholine-4-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline the hydrosulfate:

The target compound was obtained by the General method disclosed above, adding sulfuric acid to the compound obtained according to Example 3.

1H-NMR (DMSO-d6), δ, ppm: 8,70 (user., 1H); 8,42 (d, 1H); to $ 7.91-to 7.64 (m, 4H); 7,53-7,25 (m, 7H); 5,26 (d, 2H); to 3.92 (s, 3H); 3,97 is 3.76 (m, 4H); of 2.51-2,48 (m, 2H); of 1.25 (d, 6H).

EXAMPLE 4

2-(Pyridin-4-yl)-7-(4-methylpiperazin-1-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline

In the General formula (I) R1and R2represent a hydrogen atom, R3denotes phenyl, R5denotes pyridine-4-yl, R4refers to a group (b), where W denotes the nitrogen atom, Z denotes the group-NR12-where R12denotes methyl, the values of m and o is 2, the values of r, p and t is 0, R13denotes a cyano group, X represents a group NH and n=1.

a) 1,2-diamino-3-cyano-4-benzylamino-6-(4-amino-4-methylpiperazin-4-s-1-yl)chinoline ditosylate.

To a solution of 3.7 g of 2-amino-3-cyano-4-benzylamino-6-(4-methylpiperazin-1-yl)quinoline in 20 ml of dimethylformamide was added dropwise at 20°C for 15 minutes 4.4 g O-dailytorsemide in 50 ml of dichloromethane. After 5 hours of stirring the precipitated crystalline material was filtered. After drying was obtained 3,3 g of target compound (MN+: 404).

b) 2-(pyridine-4-yl)-7-(4-methylpiperazin-1-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline:

3.2 g of 1,2-diamino-3-cyano-4-benzylamino-6-(4-amino-4-methylpiperazin-4-s-1-yl)chinoline of ditosylate was dissolved in 50 ml of ethanol and to this solution was added 20 ml of ateleta sodium concentration of 1 mol/l in ethanol solution and 2.1 g the feast of the DIN-4-carbaldehyde. The reaction mixture was heated at the boiling temperature of the solvent for 4 hours. The precipitated crystalline material was filtered and recrystallize from dimethylformamide. After drying were received of 1.15 g of target compound (MN+: 474).

1H-NMR(DMSO-d6), δ, ppm: 8,77 (user., 1H); 8,23 (d, 1H); 8,12-to 7.64 (m, 6H); 7,43-7,05 (m, 5H); 5,13 (d, 2H); 3,86 (s, 3H); 3.46 in-to 3.34 (m, 4H); 2,53 is 2.46 (m, 4H); of 2.28 (s, 3H).

EXAMPLE 4.2

2-(pyridin-4-yl)-7-(4-methylpiperazin-1-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline maleate:

The target compound was obtained by the General method disclosed above, adding a solution of maleic acid to the compound obtained according to Example 4.

1H-NMR(DMSO-d6), δ, ppm: 8,78 (user., 1H); 8,24 (d, 1H); 8,12-to 7.64 (m, 6H); 7,43-7,05 (m, 5H); and 6.3 (s, 2H); 5,15 (d, 2H); 3,86 (s, 3H); 3.46 in-to 3.34 (m, 4H); of 2.51 is 2.46 (m, 4H); 2,31 (s, 3H).

EXAMPLE 5

2-(4-methoxyphenyl)-7-(4-methylpiperazin-1-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline

In the General formula (I) R1and R2represent a hydrogen atom, R3denotes phenyl, R5represents 4-methoxyphenyl, R4refers to a group (b), where W denotes the nitrogen atom, Z denotes the group-NR12-where R12denotes methyl, the values of m and o is 2, the values of r, p and t is 0, R13denotes a cyano group, X represents a group NH, and n=1.

a) 2-(4-methoxyphenyl)-7-(4-methylpiperazin-1-yl)-9-benzylamino-10-cyano-s-t is Iesolo[1,5-a]quinoline:

3.2 g of 1,2-diamino-3-cyano-4-benzylamino-6-(4-amino-4-methylpiperazin-4-s-1-yl)chinoline of ditosylate, obtained according to Example 4, was dissolved in 50 ml of ethanol and to this solution was added 20 ml of ateleta sodium concentration of 1 mol/l in ethanol solution and 2 g of 4-methoxybenzaldehyde. The reaction mixture was heated at the boiling temperature of the solvent for 4 hours. The precipitated crystalline material was filtered and recrystallize from dimethylformamide. After drying was obtained 1.1 g of target compound (MN+:504).

1H-NMR (DMSO-d6), δ, ppm: 8,65 (user., 1H); 8,21 (d, 1H); to 7.77-to 7.64 (m, 4H); 7,43-7,05 (m, 7H); 5,12 (d, 2H); 3,81 (s, 3H); 3,36-to 3.34 (m, 4H); 2,53-2,49 (m, 4H); and 2.26 (s, 3H).

EXAMPLE 5.2

2-(4-methoxyphenyl)-7-(4-methylpiperazin-1-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline-hemifumarate monohydrate:

The target compound was obtained by the General method disclosed above, adding a solution of fumaric acid to the compound obtained according to Example 5.

1H-NMR (DMSO-d6), δ, ppm: 8,68 (user., 1H); 8,23 (d, 1H); 7,81-to 7.64 (m, 4H); 7,53-7,05 (m, 7H); to 6.75 (s, 1H); 5,14 (d, 2H); of 3.84 (s, 3H); 3,36-to 3.34 (m, 4H); 2,53-2,49 (m, 4H); of 2.33 (s, 3H).

EXAMPLE 6

2-(3-methoxyphenyl)-7-(4-methylpiperazin-1-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline

In the General formula (I) R1and R2represent a hydrogen atom, R3denotes phenyl, R5denotes 3-methoxyphenyl, R4indicates what the RUPE (b), where W denotes a nitrogen atom, Z denotes the group-NR12-where R12denotes methyl, the values of m and o is 2, the values of r, p and t is 0, R13denotes a cyano group, X represents a group NH, and n=1.

a.) 2-(3-methoxyphenyl)-7-(4-methylpiperazin-1-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline:

3,3 g of 1,2-diamino-3-cyano-4-benzylamino-6-(4-amino-4-methylpiperazin-4-s-1-yl)chinoline of ditosylate, obtained according to Example 4, was dissolved in 50 ml of ethanol and to this solution was added 20 ml of ateleta sodium concentration of 1 mol/l in ethanol solution and 2.1 g of 3-methoxybenzaldehyde. The reaction mixture was heated at the boiling temperature of the solvent for 4 hours. The precipitated crystalline material was filtered and recrystallize from dimethylformamide. After drying were received of 1.15 g of target compound (MN+: 504).

1H-NMR(DMSO-d6), δ, ppm: 8,68 (user., 1H); 8,23 (d, 1H); 7,79-to 7.64 (m, 4H); 7,43-7,05 (m, 7H); 5,12 (d, 2H); of 3.84 (s, 3H); 3,36-to 3.34 (m, 4H); 2,53-2,49 (m, 4H); and 2.26 (s, 3H).

EXAMPLE 6.2

2-(3-methoxyphenyl)-7-(4-methylpiperazin-1-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline-hemifumarate hemihydrate:

The target compound was obtained by the General method disclosed above, adding a solution of fumaric acid to the compound obtained according to Example 6.

1H-NMR(DMSO-d6), δ, ppm: 8,68 (user., 1H); 8,23 (d, 1H); 7,79-to 7.64 (m, 4H); 7,43-7,05 (m, 7H); to 6.75 (s, 1H); 5,12 (d, 2H); of 3.84 (s, 3H); 3,36-to 3.34 (m, 4H); 2,53-2,49 (m, 4H); 2,31 (s, 3H).

EXAMPLE 7

2-(3-hydroxyphenyl)-7-(4-methylpiperazin-1-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline

In the General formula (I) R1and R2represent a hydrogen atom, R3denotes phenyl, R5denotes 3-hydroxyphenyl, R4refers to a group (b), where W denotes the nitrogen atom, Z denotes the group-NR12-where R12denotes methyl, the values of m and o is 2, the values of r, p and t is 0, R13denotes a cyano group, X represents a group NH, and n=1.

a.) 2-(3-hydroxyphenyl)-7-(4-methylpiperazin-1-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline:

3.1 g of 1,2-diamino-3-cyano-4-benzylamino-6-(4-amino-4-methylpiperazin-4-s-1-yl)chinoline ditosylate, obtained according to Example 4, was dissolved in 50 ml of ethanol and to this solution was added 20 ml of ateleta sodium concentration of 1 mol/l in ethanol solution and 2 g of 3-hydroxybenzaldehyde. The reaction mixture was heated at the boiling temperature of the solvent for 4 hours. The precipitated crystalline material was filtered and recrystallize from dimethylformamide. After drying were received of 1.05 g of target compound (MN+: 490).

1H-NMR (DMSO-d6), δ, ppm: being 9.61 (s, 1H); 8,68 (user., 1H); 8,23 (d, 1H); 7,79-to 7.64 (m, 4H); 7,43-7,05 (m, 7H); 5,12 (d, 2H); 3,36-to 3.34 (m, 4H); 2,53-2,49 (m, 4H); and 2.26 (s, 3H).

EXAMPLE 7.2

2-(3-hydroxyphenyl)-7-(4-methyl who piperazin-1-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline hydrochloride

The target compound is obtained by the General method disclosed above, adding hydrochloric acid to the compound obtained according to Example 7.

1H-NMR(DMSO-d6), δ, ppm: being 9.61 (s, 1H); 8,78 (user., 1H); compared to 8.26 (d, 1H); 7,81-to 7.64 (m, 4H); of 7.48-7,05 (m, 7H); 5,16 (d, 2H); 3.46 in-to 3.34 (m, 4H); to 2.55-2.49 USD (m, 4H); a 2.36 (s, 3H).

EXAMPLE 8

2-(3-Methoxyphenyl)-7-(4-acetylpiperidine-1-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline

In the General formula (I) R1and R2represent a hydrogen atom, R3denotes phenyl, R5denotes 3-methoxyphenyl, R4refers to a group (b), where W denotes the nitrogen atom, Z denotes the group-NR12-where R12denotes acetyl group, the values of m and o is 2, the values of r, p and t is 0, R13denotes a cyano group, X represents a group NH, and n=1.

a) 2-nitro-5-(piperazine-1-yl)benzoic acid:

To a suspension of 50 g of 2-nitro-5-chlorbenzoyl acid in 750 ml of water was added 86 g of piperazine and the reaction mixture was heated at the boiling temperature of the solvent for 20 hours. The mixture was then neutralized with concentrated hydrochloric acid and the precipitated crystalline material was filtered and dried, obtaining 62 g of target compound (MN+:252).

b) 2-nitro-5-(4-acetylpiperidine-1-yl)benzoic acid:

30 g of 2-nitro-5-(piperazine-1-yl)benzoic acid was added to 250 ml of acetic anhydride and the mixture is displaced is ivali at 100°C for 1 hour. The reaction mixture was diluted with 350 ml of ice water, the precipitated crystalline material was filtered and dried, obtaining 29 g of target compound (MN+: 294).

c) 2-amino-5-(4-acetylpiperidine-1-yl)benzoic acid:

A mixture of 7 g of 2-nitro-5-(4-acetylpiperidine-1-yl)benzoic acid, 15 ml of cyclohexene and 3 g of Pd/C (10%) was heated in 120 ml of ethanol at the boiling temperature of the solvent for 6 hours. The reaction mixture was filtered hot filtration through a layer of celite, the filtrate was evaporated, getting to 46.4 g of target compound (MN+: 264).

d) the anhydride of 5-(4-acetylpiperidine-1-yl)eSATAII acid:

To a mixture of 18 g of 2-amino-5-(4-acetylpiperidine-1-yl)benzoic acid and 60 ml of dioxane, was added dropwise under stirring and cooling with cold water 10 ml diphosgene. The mixture then was heated at the boiling temperature of the solvent for 2 hours. After cooling, the solid material was filtered off, washed with 50 ml of simple ether, and dried. Received 24 g of target compound (MN+: 290).

e) 2-Amino-3-cyano-4-hydroxy-6-(4-acetylpiperidine-1-yl)quinoline:

4 g of malonitrile was dissolved in 50 ml of dimethylformamide and a few parts were added 2.4 g of 60% dispersion of sodium hydride. To the clear solution was added 8 g of the anhydride of 5-(4-acetylpiperidine-1-yl)eSATAII acid and the mixture was stirred at ambient temperature for 10 hours. P is a promotional mixture was diluted with 70 ml water and was extracted with 2×30 ml of ethyl acetate. The aqueous phase was evaporated to dryness under reduced pressure, the solid residue was dissolved in 20 ml of water and pH 6 was installed acetic acid. Precipitated material was filtered and washed with water. After drying were obtained 6.5 g of target compound (MN+: 312).

f) 2-Amino-3-cyano-4-chloro-6-(4-acetylpiperidine-1-yl)quinoline:

A mixture of 1.7 g of 2-amino-3-cyano-4-hydroxy-6-(4-acetylpiperidine-1-yl)quinoline, 50 ml of acetonitrile and 3.4 ml of phosphorylchloride was heated at the boiling temperature of the solvent for 4 hours. The cooled reaction mixture is poured onto 30 g of ice, was established pH of the mixture equal to 8, with 10%sodium hydroxide solution, and the precipitate was filtered. After drying was obtained 1.5 g of target compound (MN+: 330).

g) 2-Amino-3-cyano-4-benzylamino-6-(4-acetylpiperidine-1-yl)quinoline:

5g 2-amino-3-cyano-4-chloro-6-(4-acetylpiperidine-1-yl)quinoline and 15 ml of benzylamine was stirred at 125°C for 1 hour. The reaction mixture is then poured on 30 ml of water, the precipitate was filtered, washed with 20 ml water and dried, receiving 4 g of target compound (MH+:401).

h) 3-Methoxy-N-[6-(4-acetylpiperidine-1-yl)-4-benzylamino-3-cyanohydrin-2-yl]benzamide:

To a solution of 1.2 g of 2-amino-3-cyano-4-benzylamino-6-(4-acetylpiperidine-1-yl)quinoline in 20 ml of pyridine was added 1.5 g of 3-methoxybenzoyl chloride and the mixture was heated at the boiling point p is storytale for 5 hours. The reaction mixture is poured onto 30 g of ice water and the precipitated solid material was filtered. After drying was obtained 0.45 g of target compound (MN+: 535).

i) 1-Amino-2-(3-methoxybenzylamine)-3-cyano-4-benzylamino-6-(4-acetylpiperidine-1-yl)chinoline toilet:

The solution to 0.72 g of 3-methoxy-N-[6-(4-acetylpiperidine-1-yl)-4-benzylamino-3-cyanohydrin-2-yl]benzamide in 20 ml of dimethylformamide was added dropwise at 20°C for 15 minutes, 0.6 g of O-dailytorsemide in 25 ml of dichloromethane. After 5 hours of stirring the precipitated crystalline material was filtered. After drying was obtained 0.65 g of target compound (MN+: 551).

j) 2-(3-Methoxyphenyl)-7-(4-acetylpiperidine-1-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline:

A solution of 0.7 g of 1-amino-2-(3-methoxybenzylamine)-3-cyano-4-benzylamino-6-(4-acetylpiperidine-1-yl)chinoline tosilata, 5 ml of pyridine and 0.3 ml of DBU was heated at the boiling temperature of the solvent for 8 hours. The reaction mixture is poured into 15 ml of water and the precipitated solid material was filtered. After drying was obtained 0.15 g of target compound (MN+: 532).

1H-NMR(DMSO-d6), δ, ppm: 8,68 (user., 1H); with 8.33 (d, 1H); 7,89-to 7.64 (m, 4H); 7,53-7,05 (m, 7H); 5,15 (d,2H); is 3.82 (s, 3H); 3,38-to 3.35 (m, 4H); 2.63 in at 2.59 (m, 4H); of 2.45 (s, 3H).

EXAMPLE 8.2

2-(3-Methoxyphenyl)-7-(4-acetylpiperidine-1-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline the hydrosulfate:

The target with the unity received a General way, disclosed above, adding sulfuric acid to the compound obtained according to Example 8.

1H-NMR(DMSO-d6), δ, ppm: 8,78 (user.,1H); scored 8.38 (d, 1H); to $ 7.91-to 7.64 (m, 4H); 7,63-7,05 (m, 7H); to 5.17 (d,2H); 3,88 (s, 3H); 3,68 is-3.45 (m, 4H); 2.63 in at 2.59 (m, 4H); 2,48 (s, 3H).

EXAMPLE 9

2-(3-methoxyphenyl)-7-(piperazine-1-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline

In the General formula (I) R1and R2represent a hydrogen atom, R3denotes phenyl, R5denotes 3-methoxyphenyl, R4refers to a group (b), where W denotes the nitrogen atom, Z denotes the group-NR12-where R12denotes a hydrogen atom, the values of m and o is 2, the values of r, p and t is 0, R13denotes a cyano group, X represents a group NH, and n=1.

a) 2-(3-methoxyphenyl)-7-(piperazine-1-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline:

0.24 g of 2-(3-methoxyphenyl)-7-(4-acetylpiperidine-1-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline in 8 ml of 3 n hydrochloric acid was heated at the boiling temperature of the solvent for 6 hours. The reaction mixture was neutralized 10%sodium hydroxide solution, and the precipitated solid material was filtered. After drying was obtained 0.1 g of target compound (MN+: 490).

1H-NMR (DMSO-d6), δ, ppm: 8,68 (user., 1H); with 8.33 (d, 1H); 8,11 (user., 1H); 7,89-to 7.64 (m, 4H); 7,53-7,05 (m, 7H); 5,15 (d, 2H); is 3.82 (s, 3H); 3,38-to 3.35 (m, 4H); 2.63 in at 2.59 (m, 4H).

EXAMPLE 9.2

2-(3-label fenil)-7-(piperazine-1-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline maleate:

The target compound was obtained by the General method disclosed above, adding a solution of maleic acid to the compound obtained according to Example 9.

1H-NMR(DMSO-d6), δ, ppm: 8,68 (user., 1H); with 8.33 (d, 1H); 8,02 (user.,1H); 7,89-to 7.64 (m, 4H); 7,53-7,05 (m, 7H); 6,32 (s, 2H); 5,13 (d, 2H); is 3.82 (s, 3H); 3,38-to 3.35 (m, 4H); 2.63 in at 2.59 (m, 4H).

EXAMPLE 10

2-Phenyl-7-(pyridin-3-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline

In the General formula (I) R1and R2represent a hydrogen atom, R3denotes phenyl, R4denotes pyridine-3-yl, R5denotes phenyl, R13denotes a cyano group, X represents a group NH, and n=1.

a) 1,2-Diamino-3-cyano-4-hydroxy-6-athinaiki toilet:

of 0.62 g of 2-amino-3-cyano-4-hydroxy-6-athineon was stirred for 40 minutes in 10 ml of dimethylformamide in the presence of 1 g of solid potassium carbonate was then added dropwise a solution of 0.6 g of O-tosyl-hydroxylamine in 14 ml of dichloromethane. After stirring the reaction mixture at ambient temperature for 4 hours, the precipitated solid material was filtered and dried, obtaining of 0.57 g of target compound (MN+: 327).

b) 2-Phenyl-7-iodine-9-hydroxy-10-cyano-s-triazolo[1,5-a]quinoline:

0.32 g of 1,2-diamino-3-cyano-4-hydroxy-6-athinaiki tosilata was dissolved in 15 ml of ethanol and to this solution was added 2 ml of ateleta sodium concentration of 1 mol/l in ethanol RA the creation and 0.16 g of benzaldehyde. The reaction mixture was heated at the boiling temperature of the solvent for 1 hour. The precipitated crystalline material was filtered and washed with ethanol and water. After drying was obtained 0.34 g of target compound (MN+: 413).

c) 2-Phenyl-7-iodine-9-chloro-10-cyano-s-triazolo[1,5-a]quinoline:

To a solution of 5 g of 2-phenyl-7-iodine-9-hydroxy-10-cyano-s-triazolo[1,5-a]quinoline in 50 ml of acetonitrile was added 9 g of phosphorylchloride and the mixture was heated at the boiling temperature of the solvent for 5 hours. The reaction mixture is poured onto 500 ml of ice water, the solid material was filtered and dried, obtaining 5 g of target compound (MN+: 431).

d) 2-phenyl-7-iodine-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline:

2.5 g of 2-phenyl-7-iodine-9-chloro-10-cyano-s-triazolo[1,5-a]quinoline and 10 g of benzylamine were mixed and stirred at ambient temperature for 15 minutes. The reaction mixture was diluted with a mixture of simple diethyl ether-hexane and the precipitated solid material was filtered. After drying received 1.88 g of target compound (MN+: 562).

e) 2-phenyl-7-(pyridin-3-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline:

To a suspension of 0.6 g of 2-phenyl-7-iodine-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline in 10 ml of dimethoxyethane was added 0.1 g of tetrakis(triphenylphosphine)palladium (0), 0.25 g of pyridine-3-Bronevoy acid and 10 ml of sodium bicarbonate solution in the concentration is 1 mol/liter. The reaction mixture was stirred under argon atmosphere at the boiling temperature of the solvent for 5 hours, then it was evaporated and the residue was treated with ethyl acetate. The precipitated solid material was filtered. After drying was obtained 0.3 g of target compound (MN+: 453).

The above compound can also be obtained in the following way:

f) 2-Phenyl-7-tributylstannyl-9 benzylamino-10-cyano-s-triazolo[1,5-a]quinoline:

A solution of 0.25 g of 2-phenyl-7-iodine-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline, 0.6 g of hexamethyldisilazane and 0.1 g of tetrakis(triphenylphosphine)palladium (0) in 3 ml of dioxane was heated at the boiling temperature of the solvent under nitrogen atmosphere for 5 hours. The solvent was then removed and the residue was treated with simple diethyl ether. The precipitated solid material was filtered. After drying was obtained 0.24 g of target compound (M+:539).

g) 2-Phenyl-7-(pyridin-3-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline:

To a solution of 0.2 g of 2-phenyl-7-tributylstannyl-9 benzylamino-10-cyano-s-triazolo[1,5-a]quinoline in 10 ml of dimethylformamide was added 0.05 g tetranitroaniline (O) and 0.1 g of 3-bromopyridine. The solution was stirred at 100°C under nitrogen atmosphere. The solvent was then removed under reduced pressure and the residue was treated with ethyl acetate. The precipitated solid material was filtered. After drying in which Uchali 0.1 g of target compound (MN +:453).

1H-NMR(DMSO-d6), δ, ppm: 8,68 (user., 1H); with 8.33 (d, 1H); 8,12-to $ 7.91 (m, 4H); 7,89-to 7.64 (m, 5H); 7,53-7,05 (m, 7H); 5,15 (d, 2H).

EXAMPLE 10.2

2-Phenyl-7-(pyridin-3-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline the hydrosulfate:

The target compound was obtained by the General method disclosed above, adding sulfuric acid to the compound obtained according to Example 10.

1H-NMR(DMSO-d6), δ, ppm: 8,78 (user., 1H); 8,43 (d, 1H); 8,32-of 7.96 (m, 4H); 7,89-7,74 (m, 5H); 7,53-7,05 (m, 7H); to 5.17 (d, 2H).

EXAMPLE 11

2-Phenyl-7-(4-methylpiperazin-1-yl)-9-(2-pyridylmethylamine)-10-cyano-s-triazolo[1,5-a]quinoline

In the General formula (I) R1and R2represent a hydrogen atom, R3denotes pyridine-2-yl, R4refers to a group (b), where W denotes the nitrogen atom, Z denotes the group-NR12-where R12denotes methyl, the values of m and o is 2, the values of r, p and t is 0, R5denotes phenyl, R13denotes a cyano group, X represents a group NH, and n=1.

a) 1,2-Diamino-3-cyano-4-hydroxy-6-(4-amino-4-methylpiperazin-4-s-1-yl)chinoline ditosylate:

To a solution of 3.7 g of 2-amino-3-cyano-4-hydroxy-6-(4-methylpiperazin-1-yl)quinoline in 20 ml of dimethylformamide was added dropwise at 20°C for 15 minutes 4.4 g of O-dailytorsemide in 50 ml of dichloromethane. After 5 hours of stirring the precipitated crystalline material was filtered and dried, obtaining 3.1 g of the target is soedineniya (MN +:315).

b) 2-Phenyl-7-(4-methylpiperazin-1-yl)-9-hydroxy-10-cyano-s-triazolo[1,5-a]quinoline:

3.1 g of 1,2-diamino-3-cyano-4-hydroxy-6-(4-amino-4-methylpiperazin-4-s-1-yl)chinoline of ditosylate was dissolved in 50 ml of ethanol and to this solution was added 20 ml of ateleta sodium in a concentration of 1 mol/l in ethanol and 2 g of benzaldehyde. The reaction mixture was heated at the boiling temperature of the solvent for 4 hours. The precipitated crystalline material was filtered and recrystallize from dimethylformamide. After drying were received of 1.15 g of target compound (MN+:385).

c) 2-Phenyl-7-(4-methylpiperazin-1-yl)-9-chloro-10-cyano-s-triazolo[1,5-a]quinoline:

A mixture of 1.5 g of 2-phenyl-7-(4-methylpiperazin-1-yl)-9-hydroxy-10-cyano-s-triazolo[1,5-a]quinoline and 3.4 ml of phosphorylchloride was heated at 120°C for 4 hours. The cooled reaction mixture is poured onto 30 g of ice, was established pH of the mixture equal to 8, 10%sodium hydroxide solution and the precipitate was filtered. After drying was obtained 1.3 g of target compound (MN+:403).

d) 2-phenyl-7-(4-methylpiperazin-1-yl)-9-(2-pyridylmethylamine)-10-cyano-s-triazolo[1,5-a]quinoline:

1 g of 2-phenyl-7-(4-methylpiperazin-1-yl)-9-chloro-10-cyano-s-triazolo[1,5-a]quinoline in 5 ml of 2-(aminomethyl)of pyridine was stirred at ambient temperature for 2 hours, then the reaction mixture was diluted with 20 ml water and the precipitated solid mA is erial was filtered. After drying was obtained 1.1 g of target compound (MN+:475).

1H-NMR(DMSO-d6), δ, ppm: 8,68 (user., 1H); with 8.33 (d, 1H); 8,19-to 7.64 (m, 4H); 7,53-7,05 (m, 7H); 5,15 (d,2H); 3,38-to 3.35 (m, 4H); 2.63 in at 2.59 (m, 4H); and 2.26 (s, 3H).

EXAMPLE 11.2

2-phenyl-7-(4-methylpiperazin-1-yl)-9-(2-pyridylmethylamine)-10-cyano-s-triazolo[1,5-a]quinoline hydrochloride:

The target compound was obtained by the General method disclosed above, adding hydrochloric acid to the compound obtained according to Example 11.

1H-NMR(DMSO-d6), δ, ppm: 8,78 (user., 1H); 8,43 (d, 1H); 8,29-to 7.64 (m, 4H); 7,53-7,05 (m, 7H); 5,15 (d, 2H); 3,38-to 3.35 (m, 4H); 2,73 at 2.59 (m, 4H); a 2.36 (s, 3H).

EXAMPLE 12

2-(3-methoxyphenyl)-7-(pyridin-3-yl)-9-(4-pyridylmethylamine)-10-cyano-s-triazolo[1,5-a]quinoline

In the General formula (I) R1and R2represent a hydrogen atom, R3denotes pyridine-4-yl, R4denotes pyridine-3-yl, R5denotes 3-methoxyphenyl, R13denotes a cyano group, X represents a group NH, and n=1.

a) 1,2-Diamino-3-cyano-4-hydroxy-6-iodine-chinoline toilet:

of 0.62 g of 2-amino-3-cyano-4-hydroxy-6-athineon in 10 ml of dimethylformamide was stirred with 1 g of solid potassium carbonate in 40 minutes. Then to the reaction mixture was added dropwise 0.6 g of O-dailytorsemide in 14 ml of dichloromethane. The stirring at ambient temperature was continued for 4 hours. The precipitated crystalline Mat the Rial was filtered and dried, getting 0,57 g of target compound (MN+:327).

b) 2-(3-Methoxyphenyl)-7-iodine-9-hydroxy-10-cyano-s-triazolo[1,5-a]quinoline:

0.32 g of 1,2-diamino-3-cyano-4-hydroxy-6-athinaiki tosilata obtained in Example 10, was dissolved in 15 ml of ethanol and to this solution was added 2 ml of ateleta sodium in a concentration of 1 mol/l in ethanol solution and 0.16 g of 3-methoxybenzaldehyde. The reaction mixture was heated at the boiling temperature of the solvent for 1 hour. The precipitated solid material was filtered and washed with ethanol and water. After drying was obtained 0.33 g of target compound (MN+:442).

c) 2-(3-methoxyphenyl)-7-iodine-9-chloro-10-cyano-s-triazolo[1,5-a]quinoline:

To a solution of 5 g of 2-(3-methoxyphenyl)-7-iodine-9-hydroxy-10-cyano-s-triazolo[1,5-a]quinoline in 50 ml of acetonitrile was added 9 g of phosphorylchloride and the mixture was heated at the boiling temperature of the solvent for 5 hours. The reaction mixture is poured onto 500 ml of ice water, the precipitate was filtered and dried, obtaining 5 g of target compound (MN+:461).

d) 2-(3-Methoxyphenyl)-7-iodine-9-(4-pyridylmethylamine)-10-cyano-s-triazolo[1,5-a]quinoline:

2.5 g of 2-(3-methoxyphenyl)-7-iodine-9-chloro-10-cyano-s-triazolo[1,5-a]quinoline and 10 g of (4-pyridyl)methylamine were mixed and stirred at ambient temperature for 15 minutes. The reaction mixture was diluted with a mixture of simple diethyl ether/hexane and the precipitated solid is a material was filtered. After drying received 1.88 g of target compound (MN+:533).

e.) 2-(3-methoxyphenyl)-7-(pyridin-3-yl)-9-(4-pyridylmethylamine)-10-cyano-s-triazolo[1,5-a]quinoline:

To a suspension of 0.6 g of 2-(3-methoxyphenyl)-7-iodine-9-(4-pyridylmethylamine)-10-cyano-s-triazolo[1,5-a]quinoline in 10 ml of dimethoxyethane was added 0.1 g tetranitroaniline (0), 0.25 g of pyridine-3-Bronevoy acid and 10 ml of sodium bicarbonate solution in a concentration of 1 mol/liter. The reaction mixture was stirred under argon atmosphere at the boiling temperature of the solvent for 5 hours, then it was evaporated and the residue was treated with ethyl acetate. The precipitated solid material was filtered. After drying was obtained 0.35 g of target compound (MN+:484).

1H-NMR(DMSO-d6), δ, ppm: 8,68 (user., 1H); with 8.33 (d, 1H); 8,29-to 7.84 (m, 4H); 7,79-to 7.64 (m, 3H); 7,53-7,05 (m, 7H); 5,18 (d, 2H); of 3.84 (s, 3H).

EXAMPLE 12.2

2-(3-Methoxyphenyl)-7-(pyridin-3-yl)-9-(4-pyridylmethylamine)-10-cyano-s-triazolo[1,5-a]quinoline the hydrosulfate:

The target compound was obtained by the General method disclosed above, adding sulfuric acid to the compound obtained according to Example 12.

1H-NMR(DMSO-d6), δ, ppm: 8,78 (user., 1H); scored 8.38 (d, 1H); at 8.36-7,89 (m, 4H); 7,79-of 7.69 (m, 3H); 7,63-7,05 (m, 7H); 5,18 (d, 2H); 3,91 (s, 3H).

In accordance with the procedures outlined above, using appropriate starting materials, were obtained the following compounds of General is ormula (I), shown in Table 1:

EXAMPLE 39

Known methods received the tablets of the following composition:

The active ingredient25 mg
Lactose50 mg
Avicel21 mg
Crosspovidone3 mg
Magnesium stearate1 mg

BIOLOGY

WAYS

Binding to the human receptor adenosine A3

Obtaining membrane suspension: cells of the ovary cloned Golden hamster expressing the human receptor And3(hereinafter referred to as CHO-hA3), were cultured in an appropriate way. Upon reaching the merge cell layer liquid for cultivation was removed from the cells by washing them with PBS temperature of 37°C. the cells are then suspended in ice-cold PBS, washed 3 times with PBS, centrifuged (1000×g, 10 minutes) (Sigma 3K30) and homogenized using a Teflon homogenizer (B.Braun Potter S) when the speed of rotation of 1500 rpm for 15 s in the following buffer: 50 mm Tris,10 mm MgCl 2, 1 mm EDTA, pH 8.0. The homogenate was centrifuged (43,000 g, 10 minutes). Sediment suspended in the above buffer, the protein concentration of 0.1 mg/ml (Bradford method). Aliquots of membrane preparations were kept at -80°C. an Alternative used in membrane preparation hA3-CHO from Perkin Elmer.

Protocol binding: incubate membrane drugCHO-hA3(2 µg protein) in the presence of the test material and 0.5 nm [125I]AB-MECA (4-amino-3-iodine-benzyl-5'-N-methylcarbamyl-adenosine) (100,000 cpm) in incubation buffer (50 mm Tris, 10 mm MgCl2, 1 mm EDTA, 3 Ed./ml adelaideans, pH 8.0). Determine the nonspecific binding of labeled ligand in the presence of 100 μm R-PIA (N6-[L-2-phenylisopropyl]adenosine). Full reaction volume of 50 μl for 60 minutes at ambient temperature. Filtered the reaction mixture through a filter made of glass fiber Whatman GF/B (pre-soaked in 0.5% polyethylenimine for 3 hours under a vacuum of 25 Ndmm, washed with 4×1 ml ice-cold wash buffer (50 mm Tris, 10 mm MgCl2, 1 mm EDTA, pH 8.0)at a cellular Brandel harvester with 96 wells. Detects radioactivity in a gamma counter (1470 Wizard, Wallac). Inhibition [%]=100-((activity in the presence of test compounds-non-specific activity)/(total activity-non-specific activity))*100

Linking human receptormediated A 1

Protocol binding: incubate membrane preparation expressing the human adenosine receptor A1 cells CHO (protein content: 10 μg), (source: Perkin-Elmer) in the presence of the test material and 10 nm [3H]DPCPX (8-cyclopentyl-1,3-dipropylacetic) (200,000 dpm) in incubation buffer (50 mm Tris HCl, pH 7,4, 3 Ed./ml adelaideans). Determine the nonspecific binding of labeled ligand in the presence of 10 μm R-PIA (N6-[L-2-phenylisopropyl]adenosine). Full reaction volume: 100 µl, for 3 hours at ambient temperature. Filtered the reaction mixture through a filter made of glass fiber Whatman GF/B (pre-soaked in 0.5% polyethylenimine for 3 hours under a vacuum of 25 Ndmm, washed with 4×1 ml ice-cold wash buffer (50 mm Tris HCl, pH 7,4) at the cellular Brandel harvester with 96 wells. Detects radioactivity in the counter beta-particles (1450 Microbeta, Wallac), in the presence of 200 μl of the cocktail HiSafe-3. Inhibition [%]=100-((activity in the presence of test compounds - non-specific activity)/(total activity - non-specific activity))*100.

Binding to the human receptor adenosine A2a

Protocol binding: Incubate membrane preparation cells HEK-293 expressing the human receptor adenosine A2A(10 µg protein), (source: Perkin-Elmer, in the presence of the tested m the material and 20 nm [ 3H]CGS-21680 (2-[p-(2-carbonylethyl)phenylethylamine]-5'-N-ethylcarbodiimide-adenosine) (200,000 dpm) in incubation buffer (50 mm Tris-HCl, 10 mm MgCl2, 1 mm EDTA, 2 Ed./ml adenosine deaminase, pH 7,4). Determine the nonspecific binding in the presence of 50 μm NECA (5'-N-ethylcarbodiimide-adenosine). Full reaction volume: 100 μl for 90 minutes at ambient temperature. Filter the reaction mixture under vacuum of 25 mm Hg through the filters glass fiber Whatman GF/B (pre-soaked in 0.5% polyethylenimine within 3 hours), washed with 4×1 ml ice-cold wash buffer (50 mm Tris HCl, 10 mm MgCl2, 1 mm EDTA, 0.9% NaCl, pH 7,4) at the cellular Brandel harvester with 96 wells. Detects radioactivity in the counter beta-particles (1450 Microbeta, Wallac) in the presence of 200 μl of the cocktail HiSafe-3. Inhibition [%]=100-((activity in the presence of test compounds - non-specific activity)/(total activity - non-specific activity))*100.

Binding to the human receptor adenosine A2b

Protocol binding: Incubate membrane preparation cells HEK-293 expressing the human receptor adenosine A2b(10 µg protein), (source: Perkin-Elmer, in the presence of the test material and 32.4 nm [3H]DPCPX (8-cyclopentyl-1,3-dipropylacetic) (800,000 dpm) in incubation buffer (50 mm Tris-HCl, 10 mm MgCl2, 1 mm EDTA, 0.1 mm of benzamidine, 2 U/ml adenusi deaminase, a pH of 6.5). Determine the nonspecific binding of labeled ligand in the presence of 100 μm NECA (5'-N-ethylcarbodiimide-adenosine). Total volume of the reaction mixture: 100 μl for 30 minutes at ambient temperature. Filter the reaction mixture under vacuum 25 NDM through filters glass fiber Whatman GF/B (pre-soaked in 0.5% polyethylenimine within 3 hours), washed with 4×1 ml ice-cold wash buffer (50 mm Tris-HCl, pH 6.5) at the cellular Brandel harvester with 96 wells. Detects radioactivity in the counter beta-particles (1450 Microbeta, Wallac) in the presence of 200 μl of the cocktail HiSafe-3. Inhibition [%]=100-((activity in the presence of test compounds-non-specific activity)/(total activity-non-specific activity))*100.

Allergic to model mouse

For experiments used male BalbC mice weighing 20-25 g In animals first caused the Allergy egg albumin, and then, three weeks after the first injection of egg albumin was included in the experiment. On the day of experiment, mice were treated (by ingestion) experimental material (or media that contains no active ingredient), then, after a suitable waiting period, they were subjected to anesthesia. After surgical opening of the trachea, the trachea was introduced 10 microlitres 1%-aqueous solution of egg albumin.

The control group is Ocala medium (physiological saline solution) into the trachea. After surgical closure of the trachea and treatment of wounds of the animals were separated and kept under control in their normal conditions of life within 24 hours.

After 24 hours the animals were killed by overdose of anesthesia, the trachea was again opened and light was rinsed with buffer solution. Buffer solution was centrifuged, the precipitate cells re-suspended and then counted the number of cells. Determined the total number of cells and various leukocytes were sorted on the basis of morphology. To determine the efficacy of experimental data to calculate the % inhibition compared with the control group. To determine the value of the effect is performed statistical evaluation.

BIOLOGICAL RESULTS:

A connection is considered active if at a concentration of 1 μm, in the above described experimental conditions, it inhibits the binding of labeled ligand to human receptors adenosine A3with an activity of over 80%.

On the basis of radioisotope saturation curves using Scatchard analysis (G. Scatchard, Ann. N. Y. Acad. Sci. 51:660, 1949) determined the dissociation constant (Kd) labeled ligand [125I]AB-MECA on the membrane drugCHO-hA3. The value of Kdusing the equation of Cheng-Prusoff (Y. J. Cheng and W. H. Prusoff, Biochem. Pharmacol. 22:3099, 1973) affinity constants (Ki) of the test compounds was calculated from the values of the deposits IC 50.

Compounds of General formula (I) show in General the value of the IC50less than 500 nm. Preferred compounds illustrated in the examples that show the value of the IC50less than 100 nm. The most active compounds of General formula (I) show the value of the IC50in the range from 1 nm to 20 nm.

Compounds of General formula (I) have good bioavailability and are selective in comparison with the subtype of human receptors for adenosine A1And2Aand A2b.

In vivo studies of compounds of General formula (I) according to the invention have shown that they are highly active inhibitors of inflammation observed in asthma.

In addition, the duration of action of compounds of General formula (I) after intravenous and oral administration is great, their values ID50are low and their Toxicological profiles and the profiles of the side effects are good.

For example, the receptor binding of adenosine A3, solubility and anti-inflammatory activity of the compounds of General formula (I)described in examples 1, 17 and 18, are shown in table 2 as follows.

Table 2.
ExampleIC50[nm] Solubility [mg/l] pH:1; 6,5; 7,5Inhibition of cell migration [%]*
138500; 0,2; 281
177,73000; 0,5; 588
18112500; 0,5; 1357
* Induced by egg albumin migration of cells % inhibition (full), orally in mice within 24 hours, 10 mg/kg CMC.

The above data show that the compounds of General formula (I) according to the invention are potentially outstanding therapeutic means.

1. Compounds of General formula (I)

in which R1denotes a hydrogen atom or methyl;
R2denotes a hydrogen atom or methyl;
R3denotes phenyl or
6-membered heterocyclic ring containing one nitrogen atom;
R4denotes a 6-membered heterocyclic ring containing one nitrogen atom, or
a group of the General formula (a),

in which R6and R7independently denote With3-6cycloalkyl, direct and and branched C 1-4alkyl or
a group of the General formula (b)

in which R8and R9independently represent a straight or branched C1-4alkyl;
Z represents an oxygen atom or the group-NR12-where R12denotes a hydrogen atom, straight or branched C1-4alkyl, C3-6cycloalkyl, benzyl, -CH2-acetyl, -CH2-CH2-O-CH2-CH3or acetyl;
W represents a nitrogen atom or a group-CH-;
m has a value of 2;
o has a value of 2;
p has a value of zero or 1;
r has a value of zero or 1;
t has a value of zero;
R5denotes phenyl, if appropriate substituted by one or more identical or different, straight or branched C1-4alkyl groups, straight or branched C1-4alkoxygroup, hydroxyl groups or halogen atoms, or a 5 - or 6-membered heterocyclic ring containing one nitrogen atom or one nitrogen atom and one sulfur atom;
R13denotes cyano;
X denotes the group-NH-;
n has a value of 1;
and their pharmaceutically acceptable salt and solvate.

2. Compounds of General formula (I) according to claim 1, in which
R1denotes a hydrogen atom;
R2denotes a hydrogen atom;
R3denotes phenyl or
6-membered heterocyclic ring containing one nitrogen atom;
Rsup> 4denotes a 6-membered heterocyclic ring containing one nitrogen atom, or a group of the General formula (b), in which
R8and R9denote methyl;
Z represents an oxygen atom or the group-NR12-where R12denotes a hydrogen atom, methyl, benzyl or acetyl;
W represents a nitrogen atom;
m has a value of 2;
o has a value of 2;
p has a value of zero or 1;
r has a value of zero or 1;
t has a value of zero;
R5denotes phenyl, if appropriate substituted by a methoxy group, hydroxyl group or halogen atom, or a 5 - or 6-membered heterocyclic ring containing one nitrogen atom or one nitrogen atom and one sulfur atom;
R13denotes cyano;
X denotes the group-NH-;
n has a value of 1;
and their pharmaceutically acceptable salt and solvate.

3. The following compounds according to claim 1:
2-(3-methoxyphenyl)-7-(morpholine-4-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline,
2-(4-methoxyphenyl)-7-(morpholine-4-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline,
2-(4-methoxyphenyl)-7-(2,6-TRANS-dimethylmorpholine-4-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline,
2-(pyridin-4-yl)-7-(4-methylpiperazin-1-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline,
2-(4-methoxyphenyl)-7-(4-methylpiperazin-1-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline,
2-(3-methoxyphenyl)-7-(4-methylpiperazin-1-yl)-9-benzilate is about-10-cyano-s-triazolo[1,5-a]quinoline,
2-(3-hydroxyphenyl)-7-(4-methylpiperazin-1-yl)-9-benzylamino-10-cyano-3-triazolo[1,5-a]quinoline,
2-(3-methoxyphenyl)-7-(4-acetylpiperidine-1-yl)-9-benzylamino-10-cyano-3-triazolo[1,5-a]quinoline,
2-(3-methoxyphenyl)-7-(piperazine-1-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline,
2-phenyl-7-(pyridin-3-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline,
2-phenyl-7-(4-methylpiperazin-1-yl)-9-(2-pyridylmethylamine)-10-cyano-s-triazolo[1,5-a]quinoline,
2-(3-methoxyphenyl)-7-(pyridin-3-yl)-9-(4-pyridylmethylamine)-10-cyano-3-triazolo[1,5-a]quinoline,
and their pharmaceutically acceptable salt and solvate.

4. The following compounds according to claim 1:
2-(3-methoxyphenyl)-7-(morpholine-4-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline hydrochloride,
2-(4-methoxyphenyl)-7-(morpholine-4-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline hydrochloride,
2-(4-methoxyphenyl)-7-(2,6-dimethylmorpholine-4-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline the hydrosulfate,
2-(pyridin-4-yl)-7-(4-methylpiperazin-1-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline maleate,
2-(4-methoxyphenyl)-7-(4-methylpiperazin-1-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline-hemifumarate monohydrate,
2-(3-methoxyphenyl)-7-(4-methylpiperazin-1-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline-hemifumarate hemihydrate,
2-(3-hydroxyphenyl)-7-(4-methylpiperazin-1-yl)-9-benzylamino-10-cyano-3-triazolo[1,5-a]quinoline hydrochloride,
2-(3-methoxyphenyl)-7-(4-acetyl perazin-1-yl)-9-benzylamino-10-cyano-3-triazolo[1,5-a]quinoline the hydrosulfate,
2-(3-methoxyphenyl)-7-(piperazine-1-yl)-9-benzylamino-10-cyano-s-triazolo[1,5-a]quinoline maleate,
2-phenyl-7-(pyridin-3-yl)-9-benzylamino-10-cyano-5-triazolo[1,5-a]quinoline the hydrosulfate,
2-phenyl-7-(4-methylpiperazin-1-yl)-9-(2-pyridylmethylamine)-10-cyano-s-triazolo[1,5-a]quinoline hydrochloride,
2-(3-methoxyphenyl)-7-(pyridin-3-yl)-9-(4-pyridylmethylamine)-10-cyano-s-triazolo[1,5-a]quinoline the hydrosulfate.

5. The method of obtaining compounds of General formula (I) according to claim 1 and their pharmaceutically acceptable salts and solvate, characterized in that to obtain the compounds of General formula (I)in which R1, R2, R3, R4, R5, R13, X and n have the meanings defined in claim 1, salt 1,2-diaminoethane General formula (II)

in which R1, R2, R3, R4, R13, X and n have the meanings defined in claim 1, and TsO-denotes p-toluensulfonate anion,
enter into reaction with the compound of General formula (IV)

in which the value of R5defined in claim 1 and Y represents a hydrogen atom, a halogen atom or With1-4alkoxygroup; and,
if desired, the compound obtained of General formula (I) is converted into its pharmaceutically acceptable salt or MES.

6. The method of obtaining compounds of General formula (I) according to claim 1 and their pharmaceutically acceptable salts and solvate, characterized t is m, to obtain compounds of General formula (I)in which R4denotes a 6-membered heterocyclic ring bound through a carbon atom, containing one nitrogen atom, or a group of the General formula (b), in which W represents a group-CH - and Z-values, m, o, p, r, R8and R9are as defined in claim 1, and R1R2, R3, R5, R13, X and n are as defined in claim 1,
injected into the reaction triazole derivative of General formula (V)

in which E represents a halogen atom or trifloromethyl, and the values of R1, R2, R3, R5, R13, X and n are as defined in claim 1,
and the compound of General formula (VII)

in which the value of R4is as defined above;
and, if it is desired, the compound obtained of General formula (I) is converted into its pharmaceutically acceptable salt or MES.

7. The method of obtaining compounds of General formula (I) according to claim 1, and their pharmaceutically acceptable salts and solvate, characterized in that to obtain the compounds of General formula (I)in which R4denotes a 6-membered heterocyclic ring bound through a carbon atom, containing one nitrogen atom, or a group of the General formula (b), in which W represents a group-CH - and Z-values, m, o, p, r, R8and R9 are as defined in claim 1, and R1, R2, R3, R5, R13, X and n are as defined in claim 1,
injected into the reaction derived trialkylborane General formula (VI)

in which R14denotes a straight or branched C1-4alkyl, and R1, R2, R3R5R13, X and n are as defined in claim 1,
and the compound of General formula (VIII)

in which E represents a halogen atom or trifloromethyl and the value of R4is as defined above;
and, if it is desired, the compound obtained of General formula (I) is converted into its pharmaceutically acceptable salt or MES.

8. The method of obtaining compounds of General formula (I) according to claim 1 and their pharmaceutically acceptable salts and solvate, characterized in that to obtain the compounds of General formula (I), where the values of R1, R2, R3, R4, R5, R13, X and n are as defined in claim 1, is introduced into the reaction of triazole derivative of General formula (XII)

in which R4, R5and R13are as defined in claim 1,
and the compound of General formula (XIII)

in which X, R1, R2and R3and n are the SJ such as defined in claim 1;
and, if it is desired, the compound obtained of General formula (I) is converted into its pharmaceutically acceptable salt or MES.

9. The method of obtaining compounds of General formula (I) according to claim 1 and their pharmaceutically acceptable salts and solvate, characterized in that to obtain the compounds of General formula (I), where the values of R1, R2, R3, R4, R5, R13, X and n are as defined in claim 1, the compound of General formula (XV)

where the values of X, R1, R2, R3, R4, R5, R13and n are as defined in claim 1, TsO-denotes p-toluensulfonate anion, cyclist in the presence of organic or inorganic bases and, if desired, the compound obtained of General formula (I) is converted into its pharmaceutically acceptable salt or MES.

10. Pharmaceutical composition for the treatment of diseases whose development plays the role of the receptor for adenosine A3, characterized in that it contains one or more compounds of General formula (I), where R1, R2, R3, R4, R5, R13, X and n have the meanings defined in claim 1, and/or its pharmaceutically acceptable salt or MES and one or more excipients used in the pharmaceutical industry.

11. The pharmaceutical composition is I of claim 10, characterized in that it contains one or more compounds according to claim 3 or 4.

12. Compounds of General formula (I), where R1, R2, R3, R4, R5, R13, X and n have the meanings defined in claim 1, and their pharmaceutically acceptable salt and solvate for use in the treatment of diseases whose development plays the role of the receptor for adenosine A3.

13. Compounds of General formula (I), where R1, R2, R3, R4, R5, R13, X and n have the meanings defined in claim 1, and their pharmaceutically acceptable salt and solvate for use in para.12 as receptor ligands of the adenosine A3for the treatment of dysfunctions of the heart, eyes, kidneys, the respiratory system, gastrointestinal tract, joints and Central nervous system, for inhibition of degranulation of mast cells, for inhibiting the production of cytokines, for lowering intraocular pressure, inhibiting the release of TNFα, to prevent migration and activation of eosinophil and neutrophils and other inflammatory cells, for inhibiting the reduction of smooth muscles of the respiratory tract and to prevent infiltration of blood plasma through the blood vessel and the inhibition increased production of mucin.

14. Compounds of General formula (I), where R1, R2, R3, R4, R5, R13, X and n have the values defined in claim 1, and their pharmaceutically acceptable salt and solvate for use according to any one of p, 13, as receptor antagonists of the adenosine A3as the active pharmaceutical ingredient in anti-asthmatic, anti-ischemic tool, antidepressant, anti-arrhythmic, anti-rheumatic vehicle, anti-glaucoma, anti-inflammatory agent in inflammatory and irritable bowel disease, D, tool for protection of renal function, the means for the prevention of tumors, antiparkinsonian tool or medicine to stimulate cognitive function and in the treatment or prophylaxis of the following diseases: damage to the heart muscle during reperfusion, acute respiratory distress syndrome, chronic obstructive pulmonary disease, including chronic bronchitis, pulmonary emphysema or shortness of breath, allergic reactions, including rhinitis, reactions, induced toxic plusem, urticaria, scleroderma, arthritis, other autoimmune diseases, inflammatory bowel disease, including Crohn's disease and ulcerative colitis, irritable bowel syndrome, Addison disease, psoriasis, joint diseases, hypertension, abnormal neurological function, glaucoma and diabetes.

15. Connections about the soup of the formula (I), where R1, R2, R3, R4, R5, R13, X and n have the meanings given in paragraph 1, and their pharmaceutically acceptable salt and solvate for use according to any one of p-14 in the treatment of diseases such as asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome, glaucoma, tumor, inflammatory bowel disease, irritable bowel syndrome, allergic and inflammatory pain, rheumatoid arthritis, ischemia, hypoxia, cardiac arrhythmia, renal diseases and diseases associated with mood.

16. The use of compounds of General formula (I), where R1, R2, R3, R4, R5, R13, X and n have the meanings defined in claim 1, and/or their pharmaceutically acceptable salts and solvate to obtain drugs suitable for use in the treatment of diseases whose development plays the role of the receptor And3.

17. The use of compounds of General formula (I), where R1, R2, R3, R4, R5, R13, X and n have the meanings defined in claim 1, and/or their pharmaceutically acceptable salts and solvate according to article 16, to obtain drugs for the treatment of diseases, such as asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome, glaucoma, tumor, inflammatory ill the of the intestines, irritable bowel syndrome, allergic and inflammatory pain, rheumatoid arthritis, ischemia, hypoxia, cardiac arrhythmia, renal diseases and diseases associated with mood.

18. The method of treatment or prophylaxis of a patient develops the disease, which plays the role of the receptor And3involving the introduction of a specified patient pharmaceutically effective amount of one or more compounds of General formula (I), where R1, R2, R3, R4, R5, R13, X and n have the meanings defined in claim 1, or its pharmaceutically acceptable salt or MES.

19. The method according to p, in which the disease is asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome, glaucoma, tumor, inflammatory bowel disease, irritable bowel syndrome, allergic and inflammatory pain, rheumatoid arthritis, ischemia, hypoxia, cardiac arrhythmia, renal diseases and diseases associated with mood.

20. Compounds of General formula (II)

in which R1, R2, R13, X and n are as defined in claim 1, R3denotes phenyl, R4denotes a 6-membered heterocyclyl containing one nitrogen atom and one oxygen atom as heteroatoms and may substituted With two1-4skillname groups, and TsO-denotes p-toluensulfonate anion.

21. Compounds of General formula (VI)

in which R14denotes a straight or branched C1-4alkyl, R1, R2, R13, X and n are as defined in claim 1, and R3and R5denote phenyl.

22. Compounds of General formula (XI)

in which R13are as defined in claim 1, R4denotes a 6-membered heterocyclyl containing two nitrogen atom as heteroatoms and substituted C1-4the alkyl, and R5denotes phenyl.

23. Compounds of General formula (XII)

where the values of R13are as defined in claim 1, R4denotes a 6-membered heterocyclyl containing two nitrogen atom as heteroatoms and substituted C1-4the alkyl, and R5denotes phenyl.

24. Compounds of General formula (XV)

in which X, R1, R2, R13and n are as defined in claim 1, R3denotes phenyl, R4denotes a 6-membered heterocyclyl containing two nitrogen atom as heteroatoms and substituted C1-4the acyl, R5denotes phenyl, substituted C1-4alkoxy, and TsO-denotes p-toluensulfonate anion.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: method of producing organotin tris(N,N-dialkylcarbamate) involves reaction of a tin halide with a secondary amine and carbon dioxide gas, filtering the dialkylammonium halide residue, evaporating the filtrate, where at the beginning, the mixture of secondary amine and aromatic solvent are saturated with carbon dioxide gas until the end of the reaction, and an organotin trihalide solution, which is taken as a starting compound, is added and further saturation with carbon dioxide gas is carried out for 1 hour. The method of producing modified tin (IV) oxide thin films from organotin tris(N,N-dialkylcarbamate) solution, obtained using the method described above, involves depositing the solution onto a substrate, drying in air at room temperature, followed by heat treatment at 200-300°C.

EFFECT: simple method of producing starting components and tin oxide thin films based on said components.

7 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an actinic radiation cured coating composition containing a compound which contains at least two isocyanate groups, a compound which contains at least two hydroxyl groups, a sensitising agent and a photolatent catalyst for an isocyanate-hydroxl coupling reaction, where the photolatent catalyst is an organometallic compound, containing tin as a catalytically active metal, and where the atom of the catalytically active metal in the organometallic compound is not bonded to atoms of other metals. The invention also describes a method of coating a substrate, involving a step for applying said composition onto the substrate, as well as a set of parts for preparing said actinic radiation cured coating composition.

EFFECT: obtaining an actinic radiation cured coating composition having a good balance of long life and fast curing after application and irradiation, and leads to formation of cured coatings, the colour of which is not affected by coloured residues or photolatent catalyst fragments.

13 cl, 6 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: disclosed is a rubber mixture containing a rubber component, silicon dioxide and an activated silane compound obtained from a reaction between a hydrocarbyl oxysilane compound and an organic compound of tin, titanium or aluminium in an organic solvent. Disclosed also is a casing made using said rubber mixture for part of its components.

EFFECT: improved fracture and wear resistance and low heating capacity of articles made from the disclosed rubber mixture.

6 cl, 2 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula used as herbicides, in which Q1 is H or F; Q2 is a halogen provided that when Q1 is H, Q2 is Cl or Br; R1 and R2 independently denote H, C1-C6-acyl; and Ar is a polysubstituted aryl group selected from a group consisting of

a) , b) , c) in which W1 is a halogen; X1 is C1-C4-alkyl, C1-C4-alkoxy, C1-C4-halogenalkyl, -NR3R4; Y1 is C1-C4-alkyl, C1-C4-halogenalkyl, halogen or -CN, or when X1 and Y1 are taken together denotes -O(CH2)nO-, in which n=1; and R3 and R4 independently denote H or C1-C4-alkyl; W2 is F or Cl; X2 is F, CI, -CN, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylthio, C1-C4-alkylthionyl, C1-C4-alkylsulphonyl, C1-C4-halogenalkyl, C1-C4-halogenalkoxy, C1-C4-alkoxy-substituted C1-C4-alkyl, C1-C4-alkoxy-substituted C1-C4-alkoxy, -NR3R4 or fluorinated acetyl; Y2 is a halogen, C1-C4-alkyl, C1-C4-halogenalkyl or -CN, or when W2 is F, Xz and Y2, taken together, denote -O(CH2)nO-, in which n=1; and R3 and R4 independently denote H or C1-C6-alkyl; Y3 is a halogen or -CN; Z3 is F, CI, -NO2, C1-C4-alkoxy, -NR3R4; and R3 and R4 independently denote H; derivatives on the carboxyl group which are suitable for use in agriculture.

EFFECT: compounds are excellent herbicides with a wide range action against weeds and excellent selectivity towards agricultural crops.

19 cl, 7 tbl, 69 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a dialkyltin compound, involving: a reaction for redistribution of alkyl groups and/or a reaction for dealkylation of a composition of a deactivated form of a catalyst based on dialkyltin, which is formed during synthesis of an ester derivative using a dialkyltin-based catalyst. The dialkyltin-based catalyst is a compound of at least one type selected from a group comprising a dialkyltin compound of formula (1) and tetraalkyldistanoxane of formula (2): (1) (where each of R1 and R2 independently denote a straight or branched alkyl group containing 1-12 carbon atoms, each of X1 and X2 independently denotes a substitute of at least one type selected from a group comprising an alkoxy group, an acyloxy group and a halogen atom, a and b independently denote an integer from 0 to 2 and a+b=2, and c and d independently denote an integer from 0 to 2 and c+d=2; (2), (where each of R3, R4, R5 and R6 independently denote a straight or branched alkyl group containing 1-12 carbon atoms, each of X3 and X4 independently denote a substitute of at least one type selected from a group comprising an alkoxy group, an acyloxy group and a halogen atom, and e, f, g and h independently denote an integer from 0 to 2, e+f=2 and g+h=2). The ester derivative is a compound of at least one type selected from a group comprising a carboxylic ester, a carbamate and isocyanate.

EFFECT: method enables production of versions of dialkyltin alkoxide compounds in active form in form of dialkyltin alkoxide compounds.

37 cl, 34 ex, 7 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to separation and extraction of tialkyl tin dialkoxide from a catalyst composition of alkyl tin alkoxide used as a catalyst during synthesis of ether or carbonate. The invention describes a method of separating and extracting dialkyl tin dialkoxide from an alkyl tin alkoxide catalyst composition which cannot be separated through distillation for use in production a carbonate which contains a high-boiling deactivated component having boiling point higher than 250°C at normal pressure, and an active component having two tin-carbon bonds on each tin atom in the alkyl tin alkoxide, involving the following steps: (1) reaction of the alkyl tin alkoxide catalyst composition with an alcohol and/or carbonate to obtain a reaction solution which contains a product formed from the active component; and (2) distillation of the reaction solution obtained at step (1) so as to separate and extract dialkyl tin dialkoxide from the product formed from the active compound.

EFFECT: efficient separation and extraction from an alkyl tin alkoxide catalyst composition which cannot be separated through distillation, where said composition contains a high-boiling deactivated component and a dialkyl tin dialkoxide active component.

17 cl, 24 ex, 2 tbl, 3 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to compounds with general formula (I) and its isomers, where R1 is a hydrogen atom of an alkyl C1-4 group with a straight or branched chain, or a phenyl group, thienyl group or furyl group, optionally substituted with one or more alkyl C1-4 groups with a straight or branched chain, C1-4 alkoxy groups with a straight or branched chain, or halogen atoms; R2 is a hydrogen atom or an alkyl C1-4 group with a straight or branched chain, or a phenyl, benzyl, thienyl or furyl group, optionally substituted with a methylenedioxy group, or one or more alkyl C1-4 groups with a straight or branched chain, or C1-4 alkoxy-, hydroxyl-, trifluoromethyl- or cyano-group with a straight or branched chain, or halogen atoms, as well as to a method of producing said compound. The invention also relates to new intermediates with general formula (II) and their production.

EFFECT: radioligands A3 with antagonistic action are obtained and described, labeled with iodine isotopes with mass number 125, which have high specific activity.

16 cl, 3 ex, 2 tbl, 1 dwg

FIELD: chemistry.

SUBSTANCE: description is given of a method of obtaining alkoxides of alkyl tin, which involves dehydration reaction of at least one alkyl tin compound, used as the initial compound and chosen from organo-tin compounds, with tin-oxygen-tin bonds, and hydroxy compounds, used as a reagent, with obtaining of alkoxide of alkyl tin, corresponding the given initial material and reagent, where the given initial compound and the given reagent are continuously put into a reactor. Low boiling components, containing water are taken out of the above mentioned reactor with continuous removal of the reaction liquid, containing alkoxide of alkyl tin from the lower part of the reactor.

EFFECT: obtaining alkoxides of alkyl tin.

1 cl, 24 ex, 14 dwg

FIELD: chemistry of metalloorganic compounds, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of acetylene organotin compounds of the general formula: R4-nSn(C≡CR1)n wherein R means lower alkyl; R1 means phenyl, hexinyl, trimethylsilylethynyl and others; n = 3 or 4. In aims for simplifying and safety of the method invention proposes carrying out synthesis of these compounds by interaction of alkyltrihalides tin or tetrahalides tin with 1-alkynes in the presence of secondary-tertiary aliphatic amine and zinc chloride in hydrocarbon solvent medium at temperature 20-70°Cand in the mole ratio tetrahalide tin : 1-alkyne : zinc chloride : amine = 1:4:4.2:8.4, respectively, or in the mole ratio alkyltrichlorotin : 1-alkyne : zinc chloride : amine = 1:3:3.1:6.2, respectively, in yields 48-82%.

EFFECT: improved method of synthesis.

2 cl, 8 ex

FIELD: chemistry of metalloorganic compounds, catalysts.

SUBSTANCE: invention relates to a metalloorganic compound and catalytic composition comprising indicated metalloorganic compound of the general formula (I): [HC(CRR'R'')(CRR'R'')]+[M2X9]- wherein R means hydrogen atom (H) or M1R1R2R3; R' means M1R4R5R6; R'' means H, (C1-C12)-alkyl; M means Zr or Hf; M' means Si or Sn; X means halogen atom; R1-R6 mean (C1-C12)-alkyl. Also, invention relates to a method for homo- and co-polymerization of isoolefins or olefins in the presence of indicated metalloorganic compound. Described catalytic system based on compound of the formula (I) shows high activity in the co-polymerization reaction of isobutylene.

EFFECT: valuable chemical and catalytic properties of compound.

10 cl, 2 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to cyclic azaindole-3-carboxamides of formula (I) in any of its stereoisomeric forms or in the form of a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof or a physiologically acceptable solvate of any of them: wherein A is specified in O, S and C(Ra)2; Ra is specified in hydrogen and (C1-C4)-alkyl wherein the two groups Ra are independent from each other and may be identical or different; R is specified from hydrogen, (C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl-, (C1-C4)-alkyl-O-(C1-C4)-alkyl-, phenyl-(C1-C4)-alkyl-, (C1-C4)-alkyl-O-CO-CuH2u- and R1-NH-CO-CuH2u-, wherein all the groups R are independent from each other and may be identical or different; R1 is specified from hydrogen, (C1-C4)-alkyl and H2N-CO-(C1-C4)-alkyl-; R10 is specified from hydrogen, (C1-C6)-alkyl-O-CO-; R20 is specified from phenyl which is optionally substituted by one or more identical or different substitutes specified in halogen, (C1-C4)-alkyl and (C1-C4)-alkyl-O-; R30 is specified from (C3-C7)-cycloalkyl and phenyl, wherein phenyl is optionaly substituted by one or more identical or different substitutes specified in halogen and (C1-C6)-alkyl; R40 is specified in halogen, (C1-C4)-alkyl, phenyl-(C1-C4)-alkyl-, hydroxy, (C1-C4)-alkyl-O-, HO-CO-(C1-C4)-alkyl-O- and (C1-C4)-alkyl-O-CO-(C1-C4)-alkyl-O-, wherein all the substitutes R40 are independent from each other and may be identical or different; one of the groups Y1, Y2, Y3 and Y4 represents N, while the others are identical or different groups CH or CR40; n is specified in 0, 1, 2 and 3; p and q which are independent from each other and may be identical or different being specified in 2 and 3; n is specified in 0, 1 and 2, wherein all the values are independent from each other and may be identical or different; wherein all the alkyl groups are independently from each other optionally substituted by one or more fluorine atoms; wherein all the phenyl groups found in R and R40 are independently from each other optionally substituted by one or more identical or different substitutes specified in halogen and (C1-C4)-alkyl. Besides, the invention describes a method for preparing a compound of formula I, a pharmaceutical compositions having renin inhibitory activity and containing the compound of formula I and to using the compound of formula I for making a therapeutic preparation.

EFFECT: described and prepared are the new compounds that inhibit the enzyme renin, and modulate activity of the renin-angiotensin system, and are effective for treating the diseases such as, eg hypertension.

7 cl, 141 ex, 8 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I) or pharmaceutically acceptable salts thereof wherein A, R1, R2, R3 and m are specified in the patent claim. The present invention also refers to the number of specific compounds, and to a pharmaceutical composition containing the above compounds effective for inhibition of kinases, such as glycogen synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus kinase (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2.

EFFECT: preparing the specific compounds and pharmaceutical composition containing the above compounds effective for kinase inhibition.

18 cl, 393 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to pharmacy and medicine, and concerns using the pyridopyrazine derivatives for preparing a drug for treating or preventing the physiological and/or pathophysiological conditions associated withPI3K kinase inhibition in mammals.

EFFECT: invention provides high clinical effectiveness.

7 cl, 4 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: disclosed is a compound having chemical formula or a salt thereof, where: Ar is an optionally substituted heteroaryl; R1 in each case is independently selected from a group which includes halogen, lower alkyl, optionally substituted with one or more substitutes selected from fluorine, lower alkoxy, fluorine-substituted lower alkoxy, monoalkylamino, dialkylamino, -O-R5, -N(R5)-R6 and -N(R5)-C(X)-R7; m equals 0 or 1; n equals 0, 1 or 2; R2 is hydrogen or a halogen; L2 is -S(O)2-; R3 is a lower alkyl, optionally substituted with fluorine, C3-6 cycloalkyl, optionally substituted with a lower alkyl, a 5- or 6-member nitrogen-containing heterocycloalkyl, optionally substituted with one or more substitutes selected from fluorine, lower alkyl, fluorine-substituted lower alkyl, lower alkoxy, fluorine-substituted lower alkoxy, lower alkylthio or fluorine-substituted lower alkylthio, aryl, optionally substituted with a halogen, lower alkyl, optionally substituted with a halogen or lower alkoxy, optionally substituted with a halogen, or a heteroaryl, optionally substituted with a halogen or a lower alkyl; L1 is selected from a group which includes -O-, -C(R12R13)-X-, -X-C(R12R13)-, -C(R12R13)-N(R11)-, -(R11)-C(R12R13)-, -C(X)-N(R11)-, -N(R11)-C(X)-; X is O; R11 is hydrogen; R4 is hydrogen or a lower alkyl; R5 and R6 in each case are independently selected from a group which includes hydrogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, where each is optionally substituted with one or more substitutes selected from fluorine, lower alkoxy, fluorine-substituted lower alkoxy, lower alkylthio, fluorine-substituted lower alkylthio, monoalkylamino, dialkylamino; R7 in each case is independently selected from a group which includes lower alkyl; where the terms "lower alkyl", "lower alkoxy", "lower alkylthio", "monoalkylamino", "dialkylamino", "cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", are as described in the claim. The invention also discloses a pharmaceutical composition for treating Raf kinase mediated diseases which is based on a compound of formula I; use of the compound of formula I to produce a medicinal agent is also disclosed.

EFFECT: novel compound which can be useful in treating diseases and conditions associated with aberrant activity of protein kinases is obtained and described.

9 cl, 13 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new polycyclic compounds, pharmaceutically acceptable salts thereof of general formula wherein R1 -phenyl, pyridyl, optionally substituted, or C3-7-cycloalkyl; R2 -H, -CH2R3, -C(=O)R3, -C(=O)N(R4)R3, and -SO2-pyridyl, wherein R3-H, C1-6 alkyl, C2-6 alkenyl, C3-7-cycloalkyl, -(CH2)m-phenyl -(CH2)m-(5-, 6- or 9-member heterocyclyl with 1-3 heteroatoms N, O or S); m is equal to 0-6; R4 -H; X represents O or S; the alkyl, alkenyl, cycloalkyl, phenyl and heterocyclyl groups may be substituted by one or more substitutes. A together with atoms whereto attached forms phenyl or heteroaryl with 1 or 2 nitrogen atoms, optionally substituted; B-C means -CH2-(CH2)z-, wherein z is equal to 1 or 2; D represents -CRIIIRIV-, wherein RIII and RIV are identical, and mean CH3 or H; or RIII and RIV together with the atom C whereto attached form a 3-member cycloalkyl ring, a pharmaceutical composition containing them, and the use of the above compounds for treating viral RSV infections.

EFFECT: new polycyclic compounds are described.

24 cl, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to azaindole-indole derivatives and pharmaceutically acceptable salts thereof of general formula: Y=Z (G), wherein Y means a group of azaindole of formula (Yl) Z means a group of indole of formula (Z1) or (Z2) wherein the values "=", R, R1, R1', R2, R3, R4, R2', R3, R4', R5' are presented in cl. 1 of the patent claim.

EFFECT: compounds inhibit cycline-dependent kinase that enables using them in a pharmaceutical composition.

6 cl, 3 dwg, 9 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely to new 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivatives of formula I or pharmaceutically acceptable salts thereof, wherein R1 represents H; R2 represents (C1-3)alkyl; R3 represents (C1-4)alkyl optionally substituted by three halogen atoms; R4 represents H; X represents O; n is equal to 1 or 2 or 3; Y is specified in OH, NR5R6 and Z, wherein Z represents a saturated 5- or 6-member heterocyclic ring containing 1 heteroatom specified in NR7, wherein the ring can be substituted by oxo(C1-3)alkyl, hydroxy(C1-3)alkyl; or wherein Z represents an aromatic 5- or 6-member heterocyclic ring containing 1-2 heretoatoms specified in N wherein the ring can be substituted by (C1-3)alkyl; R5 and R6 optionally represent H, (C3-8)cycloalkyl or (C1-6)alkyl optionally substituted 1-2 times by halogen, OH, (C1-6)alkyloxy, CONR14R15, NR14R15 or a 6-member saturated heterocyclic group containing a heteroatom specified in NR8; or R5 and R6 together with a nitrogen atom whereto attached form a 5-10-member saturated heterocyclic ring optionally additionally containing 1, 3 heteroatoms specified in NR9, with the ring optionally substituted by OH, oxo, (C1-4)alkyl, hydroxy(C1-3)alkyl, CONR10R11 or NR10R11; R7 represents H; R8 represents (C1-3)alkyl; R9 represents H, (C1-3)alkyl, hydroxy(C1-3)alkyl, (C1-3)alkoxy(C1-3)alykl, (C1-6)alkylcarbonyl, (C1-6)alkyloxycarbonyl, CONR12R13 or a 6-member heteroaryl group containing 1-2 heteroatoms specified in N; R10 and R11 optionally represent H or (C1-3)alkyl; R12 and R13 optionally represent (C1-3)alkyl; or R14 and R15 optionally represent (C1-3)alkyl. Also, the invention refers to the use of 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivative of formula I and a pharmaceutical composition thereof.

EFFECT: there are prepared new 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivatives effective for treating osteoporosis, atherosclerosis, inflammation and immune disorders, such as rheumatoid arthritis, psoriasis and chronic pain, such as neuropathic pain .

9 cl, 31 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel quinoline compounds of formula (I) and physiologically acceptable acid addition salts and N oxides thereof, wherein R denotes a polycyclic group of formula (R) wherein * indicates the quinolinyl radical binding site; A denotes (CH2)a, where a equals 0, 1, 2 or 3; B denotes (CH2)b, where b equals 0, 1, 2 or 3; X' denotes (CH2)x where x equals 0, 1, 2 or 3; Y denotes (CH2)y where y equals 0, 1, 2 or 3; provided that a+b=1, 2, 3 or 4, x+y=1, 2, 3 or 4, and a+b+x+y=3, 4, 5, 6 or 7; Q denotes N; R1 denotes hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl-C1-C4-alkyl, phenyl-C1-C4-alkyl, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, phenoxycarbonyl or benzyloxycarbonyl, where phenyl rings in last two said groups are unsubstituted or carry 1, 2 or 3 substitutes selected from halogen, C1-C4-alkyl or C1-C4-halogenalkyl; R2 denotes hydrogen; R3 denotes hydrogen; p=0, 1 or 2; R4, if present, denotes C1-C4-alkyl and is bonded with X and/or Y, if p=2, two radicals R4, which are bonded with adjacent carbon atoms of X or Y, together can also denote a straight C2-C5-alkylene; q=0; n=0; m=0; X denotes S(O)2; which is located in position 3 of quinoline; Ar denotes a radical Ar1, wherein Ar1 is a phenyl, wherein the phenyl can be unsubstituted or can carry 1 substitute Rx wherein Rx denotes halogen, CN, C1-C6-alkyl, C1-C6-halogenalkyl, C1-C6-alkoxy, C1-C6-halogenalkoxy, C1-C6-alkylthio, C1-C6-halogenalkylthio, NRx1 Rx2, wherein Rx1 and Rx2 independently denote hydrogen, C1-C6-alkyl, or Rx1 and Rx2 together with a nitrogen atom form an N-bonded 5-, 6- or 7-member saturated heteromonocyclic ring or an N-boned 7-, 8-, 9- or 10-member saturated heterobicyclic ring, which are unsubstituted or carry 1, 2, 3 or 4 radicals selected from C1-C4-alkyl. The invention also relates to a pharmaceutical composition based on the compound of formula (I), a method of treatment using the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel quinoline derivatives are obtained, which respond to modulation of the serotonin 5-HT6 receptor.

23 cl, 2 tbl, 44 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel N-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-3-(5-isopropoxy-1H-pyarazol-3-yl)-3H-imidazo[4,5-b]pyridine-5-amine or pharmaceutically acceptable salt thereof, having inhibiting activity with respect to Trk (tropomyosin-related kinase). The compounds can be used as a medicinal agent for treating cancer. The invention also relates to use of said compound of pharmaceutically acceptable salt thereof to produce a medicinal agent for treating cancer in a warm-blooded animal and a pharmaceutical composition containing said compound or pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, a solvent or an inert filler.

EFFECT: high efficiency of using the compound.

4 cl, 26 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: given invention refers to a compound of formula I, wherein W and Z represent CH; Y represents CH2; wherein R1 and R2 independently represent H, halogen, CH2F, CHF2, CF3, CF2CF3, or C1-C6alkyl; R' represents H; R3 and R4 independently represent H, or C1-C3alkyl, all mentioned C1-C3alkyl groups and mentioned C1-C6alkyl groups are independently substituted by one or two groups independently substituted by one or two groups independently specified in OH, halogen, C1-C3alkyl, OC1-C3alkyl or trifluoromethyl; q=1 or 0; R5 represents C1-C6alkyl; and to pharmaceutically acceptable salts thereof. Furthermore, the invention refers to a composition, a tablet and pharmaceutical syrup having potassium channel modulation activity and containing the compound of formula I, to a method of preventing and treating diseases that are affected by the activation of potentially opened potassium channels.

EFFECT: there are prepared and described the new biologically active compounds which may be effective in the prevention or treatment of diseases or disorders that are affected by potassium channel activity.

21 cl, 2 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention refers to a compound of formula I where A represents an optionally substituted aryl or heteroaryl, B - a benzene or thiophene cycle, C - a benzene or aliphatic hydrocarbon cycle, while values of other radicals are disclosed in the description. The compound according to the present invention, and the based pharmaceutical compositions exhibit a strong antagonistic effect in relation to GnRH receptor that makes them applicable for treatment of GnRH-related diseases, particularly prostate cancer, benign prostatic hyperplasia, breast cancer, endometriosis and/or uterine fibroid tumour.

EFFECT: improved clinical effectiveness.

11 cl, 70 tbl, 765 ex

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