Adenosine is a well-known component of several endogenous molecules (ATP, NAD+, nucleic acids). Besides, it plays an important regulatory role in many physiological processes. The effect of adenosine on heart function was discovered already in 1929.

(Drury and Szentgyörgyi, J Physiol 68: 213,1929). The identification of an increasing number of physiological functions mediated by adenosine and the discovery of new adenosine receptor subtypes give possibilities for therapeutic application of specific ligands (Poulse, S. A. and Quinn, R. J. Bioorganic and Medicinal Chemistry 6: 619, 1998).

To date, the receptors for adenosine have been classified into three main classes: Al, A2 and A3. The Al subtype is partly responsible for inhibiting the adenylate cyclase by coupling to Gi membrane protein, partly influences other second messenger systems. The A2 receptor subtype can be subdivided into two further subtypes-A2a and A2b-, which receptors stimulate the adenylate cyclase activity. The sequence of adenosine A3 receptors have been recently identified from rat testis cDNA library. Later it was proved that it r, : corresponds to a novel, functional adenosine receptor. The activation of the A3 receptors is connected also with several second-messenger systems: inhibiting of adenylate cyclase, stimulating of phospholipase C and D.

The adenosine receptors are found in several organs and regulate their functions.

Both Al and A2a receptors play important roles in the central nervous system and cardiovascular system. In the CNS, the adenosine inhibits the release of synaptic transmitters which effect is mediated by Al receptors. In the heart, also the A1 receptors mediate the negative inotropic, chronotropic and dromotropic effects of adenosine. The A,,. recentors located relativelv in a higher amount in the striatum, display a

functional interaction with dopamine receptors in regulating the synaptic transmission. The A2a adenosine receptors on endothelial and smooth muscle cells are responsible for adenosine-induced vasodilation.

On the basis of mRNA identification, the A2b adenosine receptors are widely distributed in different tissues. They have been identified almost in every cell type, but its expression is the highest in the intestine and the bladder. This subtype probably also has important regulatory function in the regulation of the vascular tone and plays a role in the function of mast cells.

Contrary to Al and A2a receptors, where the tissue distribution was detected on the protein level, the presence of A2b and A3 receptors was detected on the basis of their mRNA level. Expression levels for A3 adenosine receptors are rather low comparing to other subtypes and highly species dependent. A3 adenosine receptors are expressed primarily in the central nervous system, testis, immune system and appear to be involved in the modulation of mediator release from mast cells in immediate hypersensitivity reaction.

The A3 antagonists published so far in the literature belong to the groups of flavonoides, 1,4-dihydropyridine derivatives, triazoloquinazolines, thiazolonaphthyridines and thiazolopyrimidines. The present invention relates to a novel type of effective A3 antagonists, which have the aminoquinoline structure.

For therapeutic use it is essential to ensure that the molecule does not bind, or bind only in the case of very high concentration to the Al, A2a and A2b sub-types of the adenosine receptor. Our present invention relates to the compounds of the general formula (I) as well as their salts, solvates and isomers which have great selectivity for the A3 sub- type of the adenosine receptor.

Our aim was to prepare A3 ligands first of all with quinoline structure, and within those preferably antagonists, which have strong antagonistic effect and show high selectivity for the A3 receptor, ie. they inhibit the A3 receptor in much lower concentration than they inhibit the Al, Aaa and A2b receptors. Further aims were to have stability, bioavailability, therapeutic index and toxicity data which make possible to develope the new compounds into drug substances and that due to their favourable enteral absorbtion the compounds can be applied orally.

We have found that the compounds of the general formula (n-wherein Rl stands for hydrogen atom or a straight or branched Cl 4 alkyl group; R2 stands for hydrogen atom or a straight or branched Cl 4 alkyl group; stands for hydrogen atom or a straight or branched Cl-4 alkyl group, or a phenyl group, thienyl group, or furyl group, optionally substituted by one or more straight or branched C1-4 alkyl group, straight or branched C1-4 alkoxy group, or halogen atom, or for a 5-or 6 membered heteroaromatic ring-containing one, two or three nitrogen atoms or one nitrogen atom and one oxygen atom or one nitrogen atom and one sulphur atom- optionally substituted by one or more straight or branched Cl 4 alkyl group, straight or branched Cl-4 alkoxy group, or halogen atom; R4 and Rs stand for hydrogen atom or form together an 1,3-butadienyl group, optionally substituted by a methylenedioxy group or one or more straight or branched Cl 4 alkyl group, straight or branched Ci. 4 alkoxy group, hydroxy group or halogen atom; R6 stands for hydrogen atom or a cyano group, aminocarbonyl group, C1-4 alkoxycarbonyl group, or carboxy group; stands for hydrogen atom or a straight or branched Cl 4 alkyl group, or a phenyl group, benzyl group, thienyl group or furyl group, optionally substituted by a methylenedioxy group, or one or more straight or branched Cl4 alkyl group, straight or branched 1-4 alkoxy group, hydroxy group, trifluoromethyl group, cyano group or halogen atom, or for a 5 or 6 membered heteroaromatic ring-containing one, two or three nitrogen atoms or one nitrogen atom and one oxygen atom or one nitrogen atom and one sulphur atom-optionally substituted by one or more straight or branched Cl 4 alkyl group, straight or branched 1-4 alkoxy group, or halogen atom, X stands for a-CH2-group,-NH-group,-NR8-group, or a sulphur atom or an oxygen atom or a sulpho group or a sulphoxy group-wherein R8 stands for a straight or branched Cl 4 alkyl group or C3-6 cycloalkyl group- ; n stands for zero, 1 or 2-and their salts, solvates, and isomers and the salts, solvates of the latter, fulfill the above criteria.

Detailed meanings of the above listed substituents are as follows: By a straight or branched C1 4 alkyl group we mean methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-, secondary-butyl-, terciary-butyl-, preferably ethyl-or methyl group.

By a straight or branched Cul-4 alkoxy group we mean methoxy-, ethoxy-, propoxy-, isopropoxy-, butoxy-, isobutoxy-, secondary-butoxy-, terciary-butoxy-, preferably ethoxy- or methoxy group.

By a C3-6 cycloalkyl group we mean cyclopropyl-, cyclobutyl-, cyclopentyl-or cyclohexyl group.

By 1,3-butadienyl-group we mean (-CH=CH-CH=CH-) -group, ie. the pyridine ring substituted by R4 and Rs substituents means a benzopyridine ring or by its trivial name a quinoline ring.

The heteroaromatic ring containing one or two or three nitrogen atoms means pyrrol, imidazole, pyrazole, 1,2, 3-triazole, 1,2, 4-triazole, pyridine, pyrimidine, pyridazine, pyrazine and 1,3, 4-triazine ring. The ring is optionally substituted by a C1 4 alkyl, or alkoxy group or by a halogen atom.

The heteroaromatic ring containing one nitrogen atom and one oxygen or sulphur atom means oxazole, isoxazole, thiazole, isothiazole ring. The ring is optionally substituted by a C1 4 alkyl, or alkoxy group or by a halogen atom.

Salts of the compounds of the general formula (I) mean salts given with inorganic and organic acids and bases. Preferred salts are those given with pharmaceutically accepted acids as for instance hydrochloric acid, sulphuric acid, ethanesulphonic acid, tartaric acid, succinic acid, fumaric acid, malic acid, citric acid, and bases, as for instance sodium hydroxide, potassium hydroxide, ethanolamine.

Solvates mean solvates given with various solvents, as for instance with water or ethanol.

The compounds of the general formula (I) show geometric and optical isomerism, therefore the invention also relates to mixtures of the geometric isomers, to racemic or optically active geometric isomers, as well as to their salts and solvates.

A favourable group of the compounds of the general formula (I) is formed by the compounds of the general formula (IA), wherein Ru stands for hydrogen atom or a straight or branched 1-4 alkyl group ; R2 stands for hydrogen atom or a straight or branched Cl 4 alkyl group, stands for hydrogen atom or a straight or branched C1 4 alkyl group, or a phenyl group, thienyl group, or furyl group, optionally substituted by one or more straight or branched C1 4 alkyl group, straight or branched 1-4 alkoxy group, or halogen atom, or for a 5-or 6 membered heteroaromatic ring-containing one, two or three nitrogen atoms or one nitrogen atom and one oxygen atom or one nitrogen atom and one sulphur atom-optionally substituted by one or more straight or branched 1-4 alkyl group, straight or branched 1-4 alkoxy group, or halogen atom; R9, R10, R", and 12 independently mean hydrogen atom or straight or branched C1-4 alkyl group, or straight or branched C1 4 alkoxy group, or hydroxy group or halogen atom, or R9 and R12 stand for hydrogen atom and Rlo and Rll form together a methylenedioxy group; R stands for hydrogen atom or a cyano group, aminocarbonyl group, C1-4 alkoxycarbonyl group, or carboxy group ; R7 stands for hydrogen atom or a straight or branched C1 4 alkyl group, or a phenyl group, benzyl group, thienyl group or furyl group, optionally substituted by a methylenedioxy group, or one or more straight or branched C1 4 alkyl group, straight or branched Cri-4 alkoxy group, hydroxy group, trifluoromethyl group, cyano group or halogen atom, or for a 5 or 6 membered heteroaromatic ring-containing one, two or three nitrogen atoms or one nitrogen atom and one oxygen atom or one nitrogen atom and one sulphur atom-optionally substituted by one or more straight or branched C1 4 alkyl group, straight or branched 1-4 alkoxy group, or halogen atom, stands for a-CH2-group,-NH-group,-NRg-group, or a sulphur atom or an oxygen atom or a sulpho group or a sulphoxy group-wherein R8 stands for a straight or branched C1 4 alkyl group or C3-6 cycloalkyl group- ; n stands for zero, 1 or 2- and their salts, solvates, optically active isomers and the salts, solvates thereof.

A favourable group of the compounds of the general formula (IA) is formed by the compounds wherein Rl stands for hydrogen atom, or methyl group; R2 stands for hydrogen atom, or methyl group; stands for phenyl-or thienyl-or furyl group; R9, R10, R", and Ria mean independently hydrogen atom or straight or branched C1 4 alkyl group, or straight or branched Cl alkoxy group, or hydroxy group or halogen atom, or R9 and R12 stand for hydrogen atom and Rl° and Rll form together a methylenedioxy group ; R6 stands for hydrogen atom, or cyano group; R stands for 4-methoxyphenyl-, 3-methylphenyl-, 3-methoxyphenyl-, 3-thienyl-, or 3- furyl-group, X stands for-NH-group or for oxygen atom and n stands for 1- and their salts, solvates, optically active isomers and the salts, solvates thereof.

Especially favourable are the following compounds complying with the above criteria: 3-methyl-N- (4-benzylamino-3-cyanoquinolin-2-yl) benzamide; 4-methoxy-N- (4-benzylamino-3-cyanoquinolin-2-yl) benzamide ; 3-methoxy-N- (4-benzylamino-3-cyanoquinolin-2-yl) benzamide ; 3, 4-methylenedioxy-N- (4-benzylamino-3-cyanoquinolin-2-yl) benzamide; N- (4-benzylamino-3-cyanoquinolin-2-yl) thiophene-2-carboxamide; N-(4- [2-thienylmethylamino]-3-cyanoquinolin-2-yl) thiophene-3-carboxamide ; 4-methoxy-N- (4- [2-thienylmethylamino]-3-cyanoquinolin-2-yl) benzamide; 3, 4-methylenedioxy-N- (4- [2-thienylmethylamino]-3-cyanoquinolin-2-yl)-benzamide ; N- (4- [2-furylmethylamino]-3-cyanoquinolin-2-yl) furan-2-carboxamide; N- (4- [2-furylmethylamino]-3-cyanoquinolin-2-yl) thiophene-3-carboxamide, and their salts, solvates, optically active isomers and the salts, solvates thereof.

According to another of its aspects, the present invention also relates to pharmaceutical compositions containing as active principles the compounds of the general formula (I) or their isomers, salts and solvates, which are preferably oral compositions, but

inhalable, parenteral and transdermal formulations are also subjects of the invention. The above pharmaceutical compositions may be solids or liquides, such as tablets, pellets, capsules, patches, solutions, suspensions or emulsions. The solid compositions, first of all tablets and capsules are the preferred pharmaceutical forms.

The above pharmaceutical compositions are prepared by applying usual pharmaceutical excipients and by using standard methods.

The compounds of the general formula (I) can be used in treating pathologies, in the development of which A3 receptor plays a role.

The compounds of the present invention having selective activity on the A3 receptor can be used in the therapeutic and/or preventive treatment of disfunctions of the heart, kidney, respiratory system, central nervous system. They inhibit the protective effect of adenosine in growing tumor cells, prevent mast cell degranulation, inhibit the cytoldne production, reduce the inraocular pressure, inhibit the TNFoc release, inhibit the migration of eosinophils, neutrophils and other immune cells, inhibit the bronchoconstriction and plasma extravasation.

Based on these effects, adenosine A3 receptor antagonists of the present invention may be therapeutically useful as antiinflammatory, antiasthmatic, antiischemic, antidepressant, antiarrhytmic, renal protective, antitumor, antiparkinson and cognitive enhancing drugs. They also may be useful in the treatment or prevention of miocardial reperfusion injury, chronic obstructive pulmonary disease (COPD) and adult respiratory distress syndrome (ARDS) including chronic bronchitis, pulmonary emphysema or dyspnea, allergic reactions (e. g. rhinitis, poison ivy induced responses, urticaria, scleroderma, arthritis) other autoimmune diseases, inflammatory bowel disease, Addisons disease, Crohn's disease, psoriasis, rheumatism, hypertension, neurogical function disorders, glaucoma and diabetes (K. N. Klotz, Naunyn-Schmiedberg's Arch. Pharmacol.

362: 382,2000 ; P. G. Baraldi es P. A. Borea, TIPS 21: 456,2000).

The compounds of the present invention may be preferable used for the treatment of diseases such as asthma, COPD and ARDS, glaucoma, tumor, allergic and inflammatory diseases, ischemia, hypoxia, arrythmia and renal diseases.

According to another of its aspects, the present invention relates to the use of the compounds of the general formula (I) in the treatment of the above pathologies. Suggested

daily dose is 1-100 mg active ingredient depending on the nature and severeness of the disease and on sex, weight etc. of the patient.

Further subject of the invention is the preparation of the compounds of the general formula (1) and of the intermediates of the general formulae (II) (III) and (IV).

The intermediates of the general formulae (II) (III) and (IV) which are used in the preparation process according to the invention, are novel. Substituents of the general formulae (II), (III) and (IV) have the meanings as defined above. hi the process according to our invention the bis-carboxamide of the general formula (II) is selectively hydrolysed and the resulting compound of the general formula (I) is, if desired, transformed into its salts, solvates or, liberated from its salt, solvate and separated into its geometric or optical isomers.

Substituents of the compounds of the general formula (I) may be transformed into each other by known methods.

Selective hydrolysis is performed by using alcoholic, preferably methanolic alkali hydroxide solution, preferably potassium and/or sodium hydroxide solutions, but other agents helping the hydrolysis of amides can also be used.

The selective hydrolysis can be carried out in a wide temperature range, favourably between 20 °C-100 °C.

The compounds of the general formula (II) -wherein the meanings of R, R2, R3, R4, R5, R6, R7, R8, X and n are as defined above-can be obtained by several known methods, among them the one demonstrated in Scheme 1 (Figure 6), by acylation of the compounds of the formula (III), by using an acylation method known in the organic chemistry. For acylating agent preferably acyl chloride, for acid binding agent triethylamine and/or pyiridine can be applied, but other acid binding agents can also be used.

The compounds of the general formula (III) -wherein the meanings of R1, R2, R3, R4, R5, R6, R8, X and n are as defined above-can be prepared from the compounds of the formula (IV) -by using methods known per se (Nan Zhang, Bioorg. and Med. Chem. Lett., 10,2825, 2000).

The compounds of the general formula (IV) -wherein the meanings of R4, Rus rand R6 are as defined above-can be prepared from the compounds of the formula (V), by using methods known per se (D. L. Leysen, J. Heterocyclic Chem. , 24,1611, 1987).

The compounds of the general formula (V) -wherein the meanings of R4, Rs and R6 are as defined above-can be prepared from the compounds of the formula (VI), by using methods known per se (Pfizer (Inc) USP 4,175, 193).

The compounds of the invention, of the general formulae (1), (II), (III) and (IV), their preparation and biological activity are demonstrated in the following Examples, without limiting the scope of claims to the Examples.

Figure 1 shows general formula (I), Figure 2 shows general formula (IA), Figure 3 shows general formula (II), Figure 4 shows general formula (III) and Figure 5 shows general formula (IV). Figure 6 shows Scheme 1 the reaction route for the preparation of compounds of the general formula (I).

Examples Example 1 3-Methyl-N- (4-benzylamino-3-cyanoquinolin-2-yl) benzamide : In general formula (I) R1 and R2 stand for hydrogen atoms, R3 for phenyl group, R4 and Rs form together a 1,3-butadienyl group, R6 stands for cyano group, R7 for 3-methylphenyl group, the meaning of X is-NH group, n is 1. a. ) 2-Amino-3-cyano-4-chloroquinoline : The mixture of 10 g of 2-amino-3-cyano-4-hydroxyquinoline and 15 ml of phosphoryl chloride is heated under stirring at 110 °C. The reaction mixture is cooled down, poured onto 100 ml of ice-water and neutralized with 60 ml of 10 % sodium hydroxide solution.

The resulting yellow precipitate is filtered off, washed with 50 ml of water. After drying 7.5 g of the title compound is obtained, mp.: 210 °C.

NMR, ah (400 MHz, DMSO-d6): 7.21 ppm, (s, 2H, NH2), 7.35-7. 40 ppm, (dd, 1H, 6-H), 7.53-7. 57 ppm, (d, 1H, 5-H), 7.70-7. 75 ppm, (dd, 1H, 7-H), 7.93-7. 98 ppm, (d, 1H, 8-H) b. ) 2-Amino-3-cyano-4-benzylaminoquinoline 5 g of 2-amino-3-cyano-4-chloroquinoline and 11 ml of benzylamine are heated under stirring at 130 °C. The reaction mixture is poured onto 50 ml of water, the resulting precipitate is filtered off, washed with 50 ml of water. The pale-yellow precipitate is recrystallized from dimethylformamide to obtain 5.2 g of the title compound.

Mp.: 206 °C.

NMR, bH (400 MHz, DMSO-d6) : 5.02-5. 03 ppm, (d, 2H, N-CH2), 6.22 ppm, (s, 2H, NH2), 7.14-7. 16 ppm, (dd, 1H, 6-H), 7.24-7. 26 ppm, (dd, lH, 5-H), 7.30 ppm, (s, 5H, Ph), 7.50- 7.52 ppm, (dd, 1H, 7-H), 8.16-8. 19 ppm, (d, 1H, 8-H), 8.30-8. 33 ppm, (t, 1H, NH) Using 2-aminomethylpyridine or 3-aminomethylpyridine or 4-aminomethylpyridine instead of benzylamine, the appropriate compounds of general formula III can be obtained.

c. ) 3-Methyl-3-methylbenzoyl)-N- (4-benzylamino-3-cyanoquinoline-2-yl) benzamide: To the solution of 5 g of 2-amino-3-cyano-4-benzylaminoquinoline in 30 ml of pyridine 6 ml of 3-methylbenzoyl chloride are dropped, under stirring at 0°C. The reaction mixture is stirred at 80 °C for 8 hour, then it is poured onto 150 ml of ice-water. The precipitate is filtered off, washed twice with 40 ml of water. The resulting white crystalline material is recrystallized from 200 ml of ethanol to give 9.2 g of the title compound, mp.: 234 °C By using pyridine-3-carbonyl chloride as acylating agent, the appropriate compound of general formula II can be obtained. d.) 3-Methyl-N- (4-benzylamino-3-cyanoquinolin-2-yl) benzamide To the solution of 5 g of 3-methyl-N- (3-methylbenzoyl)-N- (4-benzylamino-3- cyanoquinolin-2-yl) benzamide in 80 ml of acetonitrile 20 ml of 1N methanolic potassium hydroxide solution are added. The reaction mixture is refluxed for 3 minutes, then 3 ml of glacial acetic acid is added to it, then it is neutralized with 50 ml of 1M sodium hydrogen carbonate solution and the resulting crystals are filtered off. The white crystalline material is recrystallized from 130 ml of acetonitrile to give 3.1 g of the title compound of general formula (1). Mp.: 230 °C.

Example 2 4-Methoxy-N-(4-benzylamino-3-cyanoquinolin-2-yl ! benzamide In the general formula (1) the meaning of Rl and R2 is hydrogen atom, R3 is phenyl group, R4 and Rs mean together a 1,3-butadienyl group, R6 means cyano group, R7 means 4- methoxyphenyl group, X means-NH-group, n is 1.

2-amino-3-cyano-4-benzylaminoquinoline, prepared as described in Example 1., is transformed with 4-methoxybenzoyl chloride, analogously as described in Example 1., into 4-methoxy-N- (4-methoxybenzoyl)-N- (4-benzylamino-3-cyanoquinolin-2-yl) benzamide, which after selective hydrolysis, by the method described in Example 1., results the title compound of general formula (I). Melting point of the title compound: 188 °C.

Sodium salt of the title compound is prepared by the following method:

4-methoxy-N- (4-benzylamino-3-cyanoquinolin-2-yl) benzamide is dissolved in methanol and equivalent amount of sodium hydroxide in methanol is added to it. The precipitated white crystalline material is filtered off. Mp.: 255 °C.

Ethanesulfonate salt of the title compound is prepared by the following method: 4-methoxy-N- (4-benzylamino-3-cyanoquinolin-2-yl) benzamide is dissolved in methanol and equivalent amount of ethanesulfonic acid is added to it. The precipitated white crystalline material is filtered off. Mp.: 223 °C.

Example 3 3-Methoxy-N-(4-benzvlamino-3-cyanoquinolin-2-vl ! benzamide In the general formula (I) the meaning of R'and R is hydrogen atom, R3 is phenyl group, R4 and Rs mean together a 1,3-butadienyl group, R6 means cyano group, R7 means 3- methoxyphenyl group, X means-NH-group, n is 1.

2-amino-3-cyano-4-benzylaminoquinoline, prepared as described in Example 1., is transformed with 3-methoxybenzoyl chloride, analogously as described in Example 1., into 3-methoxy-N- (3-methoxybenzoyl)-N- (4-benzylamino-3-cyanoquinolin-2-yl) benzamide, which after selective hydrolysis by the method described in Example 1., results the title compound of general formula (1). Melting point of the title compound: 186 °C.

Example 4 3, 4-Methylenedioxv-N- (4-benzvlamino-3-cyanoquinolin-2-y) benzamide In the general formula (I) the meaning of Rl and R2 is hydrogen atom, is phenyl group, R4 and Rs mean together a 1,3-butadienyl group, R6 means cyano group, R7 means 3,4- methylenedioxyphenyl group, X means-NH-group, n is 1.

2-amino-3-cyano-4-benzylaminoquinoline prepared as described in Example 1., is transformed with 4-methoxybenzoyl chloride analogously as described in Example 1., into 3, 4-methylenedioxy-N- (3, 4-methylenedioxybenzoyl)-N- (4-benzylamino-3-cyanoquinolin- 2-yl) benzamide which after selective hydrolysis by the method described in Example 1.,

results the title compound of general formula (I).

Melting point of the title compound: 231 °C.

Example 5 N- (4-benzylamino-3-cyanoquinolin-2-yl) thiophene-2-carboxamide In the general formula (I) the meaning of Rl and R2 is hydrogen atom, R3 is phenyl group, R4 and R 5 mean together a 1,3-butadienyl group, R6 means cyano group, R7 means 2- thienyl group, X means-NH-group, n is 1.

2-amino-3-cyano-4-benzylaminoquinoline prepared as described in Example 1. is transfomed with thiophene-2-carbonyl chloride, analogously as described in Example 1., into N- (2-thiophenecarbonyl)-N- (4-benzylamino-3-cyanoquinolin-2-yl) thiophene-2- carboxamide, which after selective hydrolysis, by the method described in Example 1., results the title compound of general formula (I).

Melting point of the title compound: 197°C.

Example 6 N- 4- [2-thienylmethvlamino]-3-cyanoquinolin-2-yl) thiophene-3-carboxamide hi the general formula (1) the meaning of Rl and R2 is hydrogen atom, R3 is 2-thienyl group, R4 and R 5 mean together a 1,3-butadienyl group, R6 means cyano group, R7 means 3-thienyl group, X means-NH-group, n is 1. a. ) 2-amino-3-cyano-4-(2-thienylmethylamino) quinoline 5 g of 2-amino-3-cyano-4-chloroquinoline, prepared as described in Example 1, is stirred with 11 ml of 2-thienylmethylamine at 130 °C for 3 hours. The reaction mixture is poured onto 50 ml of water, the resulting precipitate is filtered off, washed with 50 ml of water.

The pale yellow material is recrystallized from 25 ml of ethanol to obtain 5.2 g of title compound, mp.: 208 °C.

The 2-amino-3-cyano-4-(2-thienylmethylamino) quinoline prepared as described above is transformed with thiophene-3-carbonyl chloride, analogously as described in Example 1, into N-(3-thiophenecarbonyl)-N-(4-[2-thienylmethylamino]-3-cyanoq uinolin-2-yl)-

thiophene-3-carboxamide which after selective hydrolysis, by the method described in Example 1, gives the title compound of general formula (I). Melting point of the title compound: 223 °C.

Example 7 4-methoxv4- [2-thien lylamino]-3-cyanoquinolin-2-yl) benzamide In the general formula (1) the meaning of R1 and R2 is hydrogen atom, R3 is 2-thienyl group, R4 and Rs mean together a 1,3-butadienyl group, R6 means cyano group, R7 means 4-methoxyphenyl group, X means-NH-group, n is 1.

The 2-amino-3-cyano-4- (2-thienylmethylamino) quinoline prepared as described in Example 6. is transformed with 4-methoxybenzoyl chloride into 4-methoxy-N- (4- methoxybenzoyl)-N- (4- [2-thienylmethylamino]-3-cyanoquinolin-2-yl) benzamide by the method described in Example 1, which after selective hydrolysis gives the title compound of general formula (I). Melting point of the title compound: 173 °C.

Example 8 3, 4-methylenedioxy-N- (4- [2-thienylmethvlamino]-3-cyanoquinolin-2-yl)-benzamide In the general formula (1) the meaning of R'and W is hydrogen atom, R3 is 2-thienyl group, R4 and Rs mean together a 1,3-butadienyl group, R6 means cyano group, R7 means 3,4-methylenedioxyphenyl group, X means-NH-group, n is 1.

2-amino-3-cyano-4- (2-thienylmethylamino) quinoline prepared as described in Example 6. is transformed with 3, 4-methylenedioxybenzoyl chloride into 3, 4-methylenedioxy-N- (3, 4- methylenedioxybenzoyl)-N- (4- [2-thienylmethylamino]-3-cyanoquinolin-2-yl) benzamide by the method described in Example 1, which after selective hydrolysis gives the title compound of general formula (I). Melting point of the title compound: 241°C.

Example 9 N-(4-[2-furylmethylamino]-3-cyanoquinolin-2-yl)furan-2-carbo xamide

In the general formula (I) the meaning of R'and R is hydrogen atom, R3 is 2-furyl group, R4 and Rus mean together a 1,3-butadienyl group, R6 means cyano group, R7 means 2-fuuyl group, X means-NH-group, n is 1. a. ) 2-Amino-3-cyano-4-(2-furylmethylamino ! quinoline 5 g of 2-amino-3-cyano-4-chloroquinoline, prepared as described in Example 1 are stirred with 1 ml of 2-furylmethylamine (furfurylamine) at 130 °C for 3 hours. The reaction mixture is poured onto 50 ml of water, the resulting precipitate is filtered off, washed with 50 ml of water. The pale yellow material is recrystallized from 20 ml of ethanol to obtain 4.8 g of the title compound, mp.: 208 °C.

The 2-amino-3-cyano-4-(2-furylmethylamino) quinoline prepared as described above is transformed with furan-2-carbonyl chloride by the method described in Example 1. into N- (2-furancarbonyl)-N- (4- [2-furylmethylamino] -3-cyanoquinolin-2-yl) furan-2-carboxamide which after selective hydrolysis gives the title compound of general formula (I). Melting point of the title compound: 196 °C.

Example 10 N- (4- [2-furylmethvlamino]-3-cvanoquinolin-2yl) thiophene-3-carboxamide In the general formula (I) the meaning of R1 and R2 is hydrogen atom, R3 is 2-furyl group, Ri and Rs mean together a 1,3-butadienyl group, R6 means cyano group, R7 means 3- thienyl group, X means-NH-group, n is 1.

1.

The 2-amino-3-cyano-4-(2-furylmethylamino) quinoline prepared analogously as described in Example 6. is transformed with thiophene-3-carbonyl chloride by the method described in Example 1. into N- (3-thiophene carbonyl)-N- (4- [2-furylmethylamino]-3-cyanoquinolin- 2-yl) thiophene-3-carboxamide which after selective hydrolysis, performed analogously as described in Example 1. gives the title compound of general formula (I). Melting point of the title compound: 118 °C.

Structure and physical characteristics of further compounds of general formula (I) prepared by the method described in Example 1. are shown in Tables I. and II.

TABLEL I.

No. : X R3 R6 R7 n Mp ruz 11. NH CN 1 237 , orme 12. NH CN 1 128 OMe 13. NH CN OMe 1 116 oye OMe 14. NH 'CN \ I 1 100, 5 OMe OMe 15. NH CN ome 1 223 TOME OMe 16. NH CN ci 1 193, 5 C) Cl 17. NH CN) 1 193 \ \ CI F 18. NH CN 1 208 CF3 19. NH CN 1 215 20. NH CN 1 250 'CL 21. NH CN Me 1 205 Me mye 22. NH CN Me 1 238 me /O 23. NH CN 1 212 0 24. NH CN 1 215 S 25. NH \ I CN 1 234 26. NH CN 1 160, 5 27. NH CN-Me 1 184 28. NH \t3 CN ~Me 1 141, 5 Me mye Me 29. NH/I CN Me 1 194 0 O 30. NH CN 1 203 O 31. NH CN 1 152 OMe 0 OMe 32. NH CN 1 190 \ O/O 33. NH CN I > 1 202 O O Me 0 . . Me 34. NH CN 1 207 \ O O 35. NH \0/CN 1 159 O S 36. NH CN _ 200 S OMe 37. NH CN/I 1 206 con S Me 38. NH \ /CN/I 1 221 s 0 S O 39. NH \\ CN \\//1 198 s 0 40 NH < CN ß 1 158 s s 41. NH \\//CN \\//1 178 ci 42. NH CN 1 198, 5 \ orme ci 43. NH CN 1 197, 5 OMe OMe 44. NH/CN/I 1 191 \ orme 45. NH \OMe CN \OMe 1 168, 5 OMe OMe oye zoé 47. NH \ I H \ I 1 172 TOME OMe 48. NH H 1 250 0 49. NH H > 1 264 po 50. NH I H 1 265 \ /S 51. NH \O H X 1 163 52. O \43 CN \OMe 1 157 zoé 53. S \ I CN \ I 1 196 zoé 54. S=O CN 1 205 OMe zu 55. NH CN OMe 0 266 "-""OMe 56. NH j1 CN ! 1 1 154 OH spi 57 NH CN <\OI I _ 145 ou TABLE II. Rl R2 R R RS R Mp c 58. Me H 165 OMe 59. H Me)) 145 4Me cl 60. H H OMe 119 OMe O CI 61. H H //t ! 119 OMe

ho 62. H H \ I \ ! 243 cri 63. H H ome 176 OMe S cri 64. H H 171 OMe s S 65. H H \\//j 199 _ S,, 66. H H \ I 203 orme Cet Ct r 67. H H 180 ci Cl r 68. H H I (117 N \ \ OMe g CI 70. H H C Cl nOMe 153 OMe w 71. H H it f) j) 215 CI OMe 72. H H 237 Oye S 73. H H 275 \ orme OMe s MeO 74. H H 245 OMe /w/ 75. H H \ I \ \ I 247 OMe OMe mye0/ 76. H H ! L, ! 222 \ \ OMe //w/ " r Ti 77. H H 218 s Me S Mye,/ 78. H H \0/OMe 214 \ OMe S / 79. H H 252 SO 11 11 oye 80. H H 178 OMe I //w/ 81. H H)) 173 J LJ Me s 82. H H 212 \ I 83. H H 3 v 184 J kJ OMe l 84. H H 150 N OMe mye m 85. H H \ I/\ I 195 s Me S Mye/ 86. H H 171 OMe \ 87. H H 217 orme S I// 88. H H oye 149 \ OMe me 89. H H \ I \ I 135 Me S i,/ 90. H H ) J 127 Me s 90 _] 37 91. H H 257 ~ S- S fizz S 92. H H X \t t1 260 _ 93. H H \43 t ß 153 ~S w 94. H H X \t 9 145 s mes 95. H H 214 OMe mou 96. H H 183 OMe , OMe 97. H H H H 167 OMe 98. H H \43 H H OMe 162 99. H H H H ome 183 OMe 0 100 H H \t H H 6 216 \ 1 1 101 H H/I H H 206 \

Structure and physical characteristics of intermediates of general formula (II) prepared by the method described in Example 1. are shown in Table III.

TABLE III.

No. : X R3 R6 R7 Mp [°C] 102 NH \43 CN \t3 213 /OMe 103. NH CN 208 \ I OMe 104 NH CN 178s 105 NH CN OMe 158 TOME OMe 106 NH CN OMe 210 zoé 107 NH CN Me 223 Me mye 108 NH CN Me 224 me 109 NH CN XCN 212 \ CN 110 NH \O CN 198 OMe 111 NH \t CN \OMe 208 \ OMe 112 NH \ CN \ 168 OMe OMe CI 113 NH CN 168 oye ORME 0 1 14 NH CN 225 \ 115 NH CN Me 152 116 NH \O CN Et 192 \ O 117 NH CN"'aOMe 177 "OMe OMe 118 NH \ CN r ! 169 0 119 NH 6 CN \O 151 -0 po O Me 120 NH CN, Me 218 0 0 O O 121 NH X CN < 194 S 122 NH CN 188 \ orme CN 179 123 NH ~¢9 CN nO 179 \ O S mye 124 NH CN 239 125 NH H 162 TOME 0 126 NH 3 H t>1 O) 262 O 127 s CN 170 TOME O"S"o CN OMe 228 zoé Structure and physical characteristics of intermediates of general formula (III) and (IIIa) prepared by the method described in Example 1. are shown in Table IV.

TABLE IV. No. : Ri R2 R3 R4 R5 X n Mp [OCI OMe 129 H H NH 1 192 u 130 H H OMe NH 1 202 ci 0 131 H H \03 t NH 1 250 cri u \ CI 132 H H < t NH 1 167 - 133 H,,, Me NH 1 183 \ \ 134 H Me NH 1 182 _ 135 H H NH 2 172 oye . OMe 136 H H \O N 2 143 "OMe 137 H \Me \ \ 138 H oMe \43 C NH 2 136 _ t 3 g C N-Me | 1 212 \ \ 140 H H s 1 168 \ \ 141 H H \ t O 1 213 _. cl 142 H H NH 1 234 \ W O CI 143 H R NH 1 221 Me 144 H H NH 1 198 \ \ Me0 145 H H/I/\ NH 1 201 \ \ S CI 146 H H ! r"NH 1 201 s C ) 147 LI H NH 1 198 C) I 147 H H NH 1 201 s mye S mye 148 H H NH 1 167 mye \ Me 149 H H NH 1 156 /w S 150 H H NH 1 187 mye OMe 151 H H NH 1 178 Me OMe S f ! <, NH 6 1 207 Cri \ 153 H H \ C|JS NH 1 217 \ cri \ S 154 H H NH 1 204 ci 0 155 H H NH 1 216 s cri Cl S cri 156 H H NH 1 205 ci \ CI 158 H H t NH 1 213 HO \ HO 159 H H/I/ NH 1 200 160 NH 0 214 \ \

Structure and physical characteristics of intermediates of general formula (V) prepared by the method described in Example 1. are shown in Table V.

TABLE V.

No : R4 Rs Mp [OCI Ho 161. HO 360 1 cl 62. Cl 250 . 163. 278 Cl mye 164 met 283 1 Met 165. MeO 360 166. 234 oye OMe Me 167 246 L 168 267 Me I 169 l\ß\ 293 ci 170 289 Z", 171 1v\ 307 ci

Example 172.

Tablets of the following composition are made by known methods used in the pharmaceutical industry Active ingredient 25 mg Lactose 50 mg Avicel 21 mg Crospovidone 3 mg Magnesium stearate 1 mg Biology Methods Human adenosine A3 receptor binding Preparing membrane suspension: collect CHO cells expressing hA3 receptors by washing three times with ice cold PBS, centrifugate at 1000 x g 10 min, homogenize for 15 sec in buffer (50 mM Tris, 10 mM MgCl2, 1 mM EDTA, pH 8.0), centrifugate at 43.000 x g for 10 min (Sigma 3K30), suspense the membrane preparation in the buffer mentioned above, store the aliquots at-80 C.

Binding protocol: incubate CHO-hA3 membrane preparation (2 ig protein content) in incubation buffer (50 mM Tris, 10 mM MgCl2, 1 mM EDTA, 3 U/mL adenosine deaminase, pH 8.0), in the presence of 0.5 nM [121,] AB-MECA (p-amino-benzyl- methylcarboxamido-adenosine) (100.000 cpm) and 100 uM R-PIA (N6-[L-2- phenylisopropyl] adenosine) to define non-specific binding or test compound in a total volume of 50 uL for 1 hr at room temperature. Filter over Whatman GF/B glass fibre filters (presoaked in 0.5% polyethylenimine for 3 hours), wash 4x with 1 mL ice-cold 50 mM Tris, 10 mM MgCl2, 1 mM EDTA (pH 8.0) on 96-well Brandel Cell Harvester. Detection of activity: in gamma-counter (1470 Wizard, Wallac). Inhibition [%] = 100-((activity in the presence of test compound-non-specific activity)/ (total activity-non-specific activity) ) * 100

Human adecosine A1 receptor binding Preparing membrane suspension: collect CHO cells expressing hAl receptors by washing three times with ice cold PBS, centrifugate at 1000 x g 10 min, homogenize for 15 sec in buffer (50 mM Tris, pH 7.4), centrifugate at 43.000 x g for 10 min (Sigma 3K30), suspense the membrane preparation in the buffer mentioned above, store the aliquots at - 80 °C.

Binding protocol: incubate CHO-hAl membrane preparation (50 u. g protein content) in incubation buffer (50 mM Tris, 3 U/mL adenosine deaminase, pH 7.4), 10 nM [3H] CCPA (2-chloro-N6-cyclopenthyl-adenosine) (80.000 dpm) and 10 pM RPIA (N6-[L-2- phenylisopropyl] adenosine) to define the non-specific binding or test compound in a total volume of 100 ttL for 3 hr at room temperature. Filter over Whatman GF/B glass fibre filters (presoaked in 0.5% polyethylenimine for 3 hours), wash 4x with 1 mL ice-cold 50 mM Tris (pH 7.4) on 96-well Brandel Cell Harvester. Detection of activity: in 96-well plate in the presence of HiSafe-3 coctail in beta-counter (1450 Microbeta, Wallac).

Inhibition [%] = 100-((activity in the presence of test compound-non-specific activity)/ (total activity-non-specific activity) ) * 100 Human adenosine A2a receptor binding Binding protocol: incubate 7 llg of membranes (human A2a adenosine receptors transfected into HEK-293 cells, source: Receptor Biology, Inc. ), buffer (50 mM Tris-HCI, 10 mM MgCl2, 1 mM EDTA, 2 U/mL adenosine deaminase, pH 7.4), 20 nM [3H] CGS- 21680 (2- [p- (2-carbonylethyl) phenylethylamino]-5'-N-ethylcarboxamido-adenosine) (200.000 dpm) and 50, uM NECA (5'-N-ethylcarboxamido-adenosine) to define the non- specific binding or test compound in a total volume of 100 p1 for 90 min at room temperature. Filter over Whatman GF/B glass fibre filters (presoaked in 0.5% polyethylenimine), wash 4x with 1 mL ice-cold 50 mM Tris, 10 mM MgCl2, 1 mM EDTA, 0.9 % NaCl, pH 7.4) on 96-well Brandel Cell Harvester. Detection of activity: in 96-well plate in the presence of HiSafe-3 coctail in beta-counter (1450 Microbeta, Wallac).

Inhibition [%] = 100-((activity in the presence of test compound-non-specific activity)/ (total activity-non-specific activity)) * 100

Human adenosine A2b receptor binding Binding protocol: incubate 20. 8, ug of membranes (human A2b adenosine receptors transfected into HEK-293 cells, source: Receptor Biology, Inc.), buffer (50 mM Tris-HCI, 10 mM MgCl2, 1 mM EDTA, 0.1 mM benzamidine, 2 U/mL adenosine deaminase, pH 6.5), 32.4 nM [3H] DPCPX (8-cyclopenthyl-1, 3-dipropylxanthine) (800.000 dpm) and 100 uM NECA (5'-N-ethylcarboxamido-adenosine) to define non-specific binding or test compound in a total volume of 100 uL for 30 min at room temperature. Filter over Whatman GF/C glass fibre filters (presoaked in 0. 5% polyethylenimine), wash 4x with 1 mL ice-50 mM Tris-HCl (pH 6.5) on 96-well Brandel Cell Harvester. Detection of activity: in 96-well plate in the presence of HiSafe-3 coctail in beta-counter (1450 Microbeta, Wallac). Inhibition [%] = 100- ( (activity in the presence of test compound-non-specific activity)/ (total activity-non-specific activity)) * 100 Results We consider the compounds as biologically active ones if they inhibit the binding of the radioligand on human adenosine A3 receptors with an activity above 80 % at 1 uM in our experimental conditions.

The dissociation constant (Kd) of [125I] AB-MECA on CHO-hA3 membrane preparation is determined by isotope saturation studies with the help of Scatchard analysis (G. Scatchard, Ann. N. Y. Acad. Sci. 51: 660,1949). The ICso is converted to an affinity constant (Ki) by application of the Cheng-Prusoff equation (Y. J. Cheng and W. H. Prusoff, Biochem. Pharmacol. 22: 3099, 1973).

Several compounds of the general formula (I), (II), (III) and (IV) display remarkable biological effects. The compounds of the general formula (IA), defined in claim 2, as a subgroup of the general formula (I), defined in claim 1, exert the most important activities.

Except of 5 compounds, their Ki values are not higher than 20 nM. The compounds given as examples are especially advantageous. Their Ki values in human adenosine A3 receptor binding studies are between 0.19 and 0.69 nM. The Ki values of the most advantageous compounds are 0.14 and 0.15 nM.

The compounds possess proper bioviabilities and exert at least 10, 000-fold selectivity in respect of human adenosine Ai, A2a and A2b receptor subtypes.

Further, the duration of their action at intravenous and oral administration is long enough, their ED50 values are low, their toxicological and side-effect profiles are advantageous.

Data above make the compounds of the general formula (I) probable for therapeutic applications.