ZA200308865B - Aminoquinoline derivatives and their use as adenosine A3 ligands. - Google Patents

Description

PCT/HU02/00048

AMINOQUINOLINE DERIVATIVES AND THEIR USE AS ADENOSINE A3 LIGANDS

The present invention relates to adenosine Aj; receptor ligands of the general formula (I), within those preferably antagonists, as well as their salts, solvates and isomers, and the pharmaceutical compositions containing them, to the use of the compounds of the general formula (I), as well as their salts, solvates and isomers, to the preparation of the compounds of the general formula (I) and their salts, solvates and isomers, furthermore to the new intermediates of the general formulae (II) (III) and (IV) and to the preparation thereof. .

Co 10

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 Szentgydrgyi, J Physiol 68:213, 1929). The identification of an increasing npumber of physiological functions mediated by adenosine and the discovery of mew 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:

Ay, Az and Az. The A; subtype is partly responsible for inhibiting the adenylate cyclase by coupling to G; membrane protein, partly influences other second messenger systems. The

A; receptor subtype can be subdivided into two further subtypes — Az and Ap -, which a receptors stimulate the adenylate cyclase activity. "The sequence of adenosine Aj; receptors have been recently identified from rat testis cDNA library. Later it was proved that it : corresponds to a novel, functional adenosine receptor. The activation of the Aj 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 A; and As, 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 A; receptors. In the heart, also the A; receptors mediate the negative inotropic, chronotropic and dromotropic effects of adenosine. The adenosine Az, receptors located relatively in a higher amount in the striatum, display a

AMENDED SHEET

, functional interaction with dopamine receptors in regulating the synaptic transmission. The

Az, adenosine receptors on endothelial and smooth muscle cells are responsible for adenosine-induced vasodilation.

On the basis of mRNA identification, the A, 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 A; and Aj, receptors, where the tissue distribution was detected on the protein level, the presence of Ay, and Aj receptors was detected on the basis of their mRNA level. Expression levels for A; adenosine receptors are rather low comparing to : other subtypes and highly species dependent. A; adenosine recepiors 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 A; 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 Aj 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 A;, Az, and Az 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 Az sub- type of the adenosine receptor.

Our aim was to prepare Aj ligands first of all with quinoline structure, and within those preferably antagonists, which have strong antagonistic effect and show high selectivity for the A; receptor, ie. they inhibit the Az receptor in much lower concentration than they inhibit the A), Az. and Ag, 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. N

SUBSTITUTE SHEET (RULE 26)

_ o :

RE - PCT/HU02/00048 ’

We have found that the compounds of the general formula (I) - wherein

R! stands for hydrogen atom or a straight or branched C;.4 alkyl group; i : R? stands for hydrogen atom or a straight or branched C4 alkyl group; } rR? stands for hydrogen atom or a straight or branched Ci4 alkyl group, or a phenyl : group, thienyl group, or furyl group, optionally substituted by one or more straight or branched C4 alkyl group, straight or branched Cj.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- Co oo Ce optionally substituted by one or more straight or branched Cy.4 alkyl group, straight

Co or branched C4 alkoxy group, or halogen atom; oo

R* and R’ form together an 1,3-butadienyl group, optionally substituted by a methylenedioxy group or one or more straight or branched C, 4 alkyl group, straight or branched C4 alkoxy group, hydroxy group or halogen atom;

RS stands for hydrogen I or a cyano group, aminocarbonyl group, Ci4 alkoxycarbonyl group, or carboxy group;

Rr’ stands for hydrogen atom or a straight or branched Ci. 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 Cj. alkyl group, straight or branched C,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 C;4 alkyl group, straight or branched Ci4 alkoxy group, or halogen atom, | :

X stands for a —CHa- group, —NH- group, -NR®- group, or a sulphur atom or an oxygen atom or a sulpho group or a sulphoxy group -wherein R® stands for a straight or branched C; 4 alkyl group or Cs. cycloalkyl group-; i. n stands for zero, 1 or 2 — and their salts, solvates, and isomers and the salts, solvates of the latter, fulfill the above criteria.

AMENDED SHEET

‘

Detailed meanings of the above listed substituents are as follows: : By a straight or branched C;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 C;4 alkoxy group we mean methoxy-, ethoxy-, propoxy-, isopropoxy-, butoxy-, isobutoxy-, secondary-butoxy-, terciary-butoxy-, preferably ethoxy- or methoxy group.

By a Ci 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 R* and R® 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 C4 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 Cy. 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.

SURSTITUTE SHEET (RULE 26)

SUBSTITUTE SHEET (RULE 26)

Co PCT/HU02/00048 : : A favourable group of the compounds of the general formula (I) is formed by the compounds of the general formula (IA), wherein

R! stands for hydrogen atom or a straight or branched Ci alkyl group; © R? stands for hydrogen atom or a straight or branched C4 alkyl group;

R stands for hydrogen atom or a straight or branched C14 alkyl group, or a phenyl group, thienyl | group, or fury! group, optionally substituted by one or more straight : or branched C4 alkyl group, straight or branched C4 alkoxy group, or halogen atom, or for a 5- or 6 membered heteroaromatic ring -containing one, two or three nitrogen atoms or one nitro gen atom and one oxygen atom or one nitrogen atom and . one sulphur atom- optionally substituted by one or more straight or branched Cy4 alkyl group, straight or branched C;4 alkoxy group, or halogen atom; - | R’, R' R!, and R'? independently mean hydrogen atom or straight or branched Ci4 alkyl group, or straight or branched C;4 alkoxy group, or hydroxy group or halogen atom, or

Rr and R" stand for hydrogen atom and R'® and R'! form together a methylenedioxy group;

RS stands for hydrogen atom or a cyano group, aminocarbonyl group, Cy alkoxycarbonyl group, or carboxy group; rR’ stands for hydrogen atom or a straight or branched C14 alkyl group, or a phenyl group, benzyl group, thienyl group or furyl group, optionally substituted by a oo methylenedioxy group, or one or more straight or branched Ci4 alkyl group, straight or branched C4 alkoxy group, hydroxy group, trifluoromethyl group, cyano a 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 C4 alkyl group, straight or branched C,4 alkoxy group, or halogen atom, oo

X stands for a —~CH,- group, —NH- group, “NRE: group, or a sulphur atom or an oxygen atom or a sulpho group or a sulphoxy group -wherein R® stands for a = straight or branched C,4 alkyl group or Cos cycloalkyl group-; ) n stands for zero, 1 or 2 — and their salts, solvates, isomers and the salts, solvates thereof. oo

AMENDED SHEET

® : : . | PCT/HU02/00048 :

A favourable group of the compounds of the general formula (IA) is formed by the compounds wherein : : N - R! stands for hydrogen atom, or methyl group; : : R? stands for hydrogen atom, or methyl group;

R3 stands for phenyl- or thienyl- or furyl group;

R%, R'®, RY, and R!? mean independently hydrogen atom or straight or branched C;4 alkyl group, or straight or branched C4 alkoxy group, or hydroxy group or halogen atom, : or :

R® and R' stand for hydrogen atom and R'® and R'' form together a methylenedioxy group; IE :

RS stands for hydrogen atom, or cyano group;

Co 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 — : | en : ’ and their salts, solvates, 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, oo and their salts, solvates, 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

AMENDED SHEET 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 ’ 5 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 A; receptor plays a role.

The compounds of the present invention having selective activity on the Aj 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 cytokine production, reduce the inraocular pressure, inhibit the TNFa release, inhibit the migration of eosinophils, neutrophils and other immune cells, inhibit the bronchoconstriction and plasma extravasation.

Based on these effects, adenosine Aj 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, Addison's 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 és 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 sresment of the above pathologies. Suggested

QURQTITIHITE QUERT (RII E 2A)

SUBSTITUTE SHEET (RULE 26)

1 Os 16-06-2003 | | &ered 2 HUO200048 : 8 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 (I) and of the intermediates of the general formulae (I) (II) and AV ).

The intermediates of the general formulae (II) (IIT) and (AV) which are used in the preparation process according to the invention, are partly novel. Substituents of the general formulae (II), (IM) and (IV) have the meanings as defined above.

In 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 (IT) ~wherein the meanings of R!, RZ R3 ,

RY R% RR’, R’ 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 (II), 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 (II) — wherein the meanings of R', R?, R?,

R* Rr’, R® R® 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). oo - 30 The compounds of the general formula (IV) - wherein the meanings of R*, R> and

R® are as defined above — can be prepared from the compounds of the forrmula (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 R®,

R® and R® 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 (I), (II), (III) and (IV), ’ 5 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 (II) 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).

SUBSTITUTE SHEET (RULE 26)

Examples

Example 1 . 3-Methyl-N-(4-benzylamino-3-cyanoquinolin-2-yl)benzamide:

In general formula (I) R! and R? stand for hydrogen atoms, R> for phenyl group, R*and R® ° form together a 1,3-butadienyl group, R® stands for cyano group, R’ for 3-methylphenyl group, the meaning of X is —-NH group, nis 1. a.) 2-Amino-3-cyano-4-chloroguinoline:

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 gof the title compound is obtained, mp.: 210 °C.

NMR, 4 (400 MHz, DMSO-dg): 7.21 ppm, (s, 2H, NHy), 7.35-7.40 ppm, (dd, 1H, 6-H), 7.53-1.57 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, 64 (400 MHz, DMSO-dg): 5.02-5.03 ppm, (d, 2H, N-CH>), 6.22 ppm, (s, 2H, NH), 7.14-7.16 ppm, (dd, 1H, 6-H), 7.24-7.26 ppm,(dd,1H, 5-H), 7.30 ppm, (s, 5H, Ph), 7.50- ’ 7.52 ppm, (dd, 1H, 7-H), 8.16-8.19 ppm, (d, 1H, 8-H), 8.30-8.33 ppm, (t, 1H, NH)

Using 2-aminomethylpyridine or 3-aminomethylpyridine or 4-aminomethylpyridine instead of benzylamine, the appropriate compounds of general formula ITI can be obtained.

SUBSTITUTE SHEET (RULE 26)

c.) 3-Methyl-N-(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 : 5 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 10 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 15 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 (I). Mp.: 230 °C. 20

Example 2 4-Methoxy-N-(4-benzylamino-3-cyanoquinolin-2-yl)benzamide

In the general formula (I) the meaning of R! and R? is hydrogen atom, R> is phenyl group,

R* and R® mean together a 1,3-butadienyl group, R® means cyano group, R” means 4- 25 methoxyphenyl group, X means -NH-group, nis 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:

SUBSTITUTE SHEET (RULE 26)

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. 5 .

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-benzylamino-3-cyanoquinolin-2-yl)benzamide

In the general formula (I) the meaning of R' and R? is hydrogen atom, R® is phenyl group,

R* and R® mean together a 1,3-butadienyl group, R® means cyano group, R’ means 3- methoxyphenyl group, X means -NH-group, nis 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 (I). Melting point of the title compound: 186 °C.

Example 4 3.4-Methylenedioxy-N-(4-benzylamino-3-cyanoquinolin-2-yl)benzamide

In the general formula (I) the meaning of R' and R? is hydrogen atom, R? is phenyl group,

R* and R® mean together a 1,3-butadienyl group, RS means cyano group, R’ means 3,4- . methylenedioxyphenyl group, X means -NH-group, nis 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.,

SUBSTITUTE SHEET (RULE 26)

results the title compound of general formula (I). ) Melting point of the title compound: 231 °C. ’ 5 Example 5

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

In the general formula (I) the meaning of R' and R? is hydrogen atom, R? is phenyl group,

R* and R® mean together a 1,3-butadienyl group, R® means cyano group, R’ means 2- thienyl group, X means -NH-group, nis 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-thienylmethylamino]-3-cyanoquinolin-2-yl)thiophene-3-carboxamide

In the general formula (I) the meaning of R' and R? is hydrogen atom, R? is 2-thienyl group, R* and R® mean together a 1,3-butadienyl group, R® means cyano group, R’ 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-cyanoquinolin-2-yl)-

SUBSTITUTE SHEET (RULE 26)

thiophene-3-carboxamide which after selective hydrolysis, by the method described in

Example 1, gives the title compound of general formula (D. Melting point of the title - compound: 223 °C. 5 .

Example 7 4-methoxy-N-(4-[2-thienylmethylamino]-3-cyanoquinolin-2-yl)benzamide

In the general formula (I) the meaning of R! and R? is hydrogen atom, R? is 2-thieny! group, R* and R® mean together a 1,3-butadienyl group, R® means cyano group, R” 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-thienylmethylamino]-3-cyanoquinolin-2-yl)-benzamide

In the general formula (I) the meaning of R! and R? is hydrogen atom, R® is 2-thienyl group, R* and R® mean together a 1,3-butadienyl group, R® means cyano group, R’ 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-yDfuran-2-carboxamide

SUBSTITUTE SHEET (RULE 26)

In the general formula (I) the meaning of R' and R? is hydrogen atom, R? is 2-furyl group, : R* and R® mean together a 1,3-butadienyl group, R® means cyano group, R” means 2-furyl group, X means -NH-group, n is 1. ) 5 a.) 2-Amino-3-cyano-4-(2-furylmethylamino)quinoline 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-furylmethylamino]-3-cyanoquinolin-2yDthiophene-3-carboxamide

In the general formula (I) the meaning of R' and R? is hydrogen atom, R? is 2-furyl group,

R* and R® mean together a 1,3-butadienyl group, R® means cyano group, R7 means 3- thienyl group, X means -NH-group, nis 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-

X 2-ylthiophene-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.

SUBSTITUTE SHEET (RULE 26)

TABLE L

R3 / x (CH,),

RS

S90 1

Nn

N” °N R’

H

No.: X R® R® R’ n | Mp [°C]

OMe 12. NH hg CN R 1 128

OMe 13. | NH hg CN Xr 1 | 116

OMe

Olle 14. | NH 0 CN or 1 | 1005

Ole ,

Olle 15. NH hg CN 1 223

OMe

ONle

SUBSTITUTE SHEET (RULE 26)

16. | NH hg CN Tu 1 | 1935 cl } cl 17. | NH hg CN {I 1 | 193 cl

F

18. | NH hg CN Tr 1 | 208

CF, [1 AGEING] 1] ais 20. | nm hg) CN TL 1 | 250

CN

21. | NH hg CN Tu 1 | 205

Me

Me 2. | NH hg CN x 1 | 238

Me o 23. | NH hg CN IY, 1 212 o 24. | nH hg! CN { /] 1] 215 . Ss 25. | NH hg CN \ /) 1] 234

SUBSTITUTE SHEET (RULE 26)

EERE IEEE

Me

Me 0 30. NH In CN hg 1 203 o_. 31. | NH IY, CN TL 1 | 1s2

ONe 0 OMe 32. NH J CN Tr 1 190 0 0 33. | NH IY, CN Tr S11] 20 o 0] Me 34, NH 7 CN Xr 1 | 207 0 o 35. | NH {J CN ) /] 1 | 159 0 Ss 36. NH IY, CN ny 1 | 200

SUBSTITUTE SHEET (RULE 26)

s OMe 37. | NH ~~ CN Tr 1 | 206 . S Me 38. NH J CN Tr 1 | 221 s lo) 39, NH ~~ CN J 1 | 198

Ss lo} 40 | NH J CN \ /] 1 | 158 s Ss 41. NH ny CN ~~) 1 | 178 cl 42. NH CN Tu 1 | 1985

OMe _ cl 43. NH Or CN TL 1] 1975

OMe

OMe 44, NH CN Tu 1 191

OMe , 45. NH TL CN Tu 1 168.5

OMe OMe 46. N-Me hg CN Tu 1 155

OMe

SUBSTITUTE SHEET (RULE 26)

47. NH hg H Tu 1 172

OMe

OMe - 48. | Nu hg H Tr 1] 250 o 49. NH H > 1 264 o 0 50. | NH hg H ~~ 1 | 265

Ss si. | NH hg H 7 1 | 163

OMe 53. S hg CN TL 1 196

OMe soso | 0) Je | CU fr] ms

OMe

H

55. NH CN TL 266

OMe , 56. NH hg CN | TL 1 154

OH

SUBSTITUTE SHEET (RULE 26)

s 57 | NH IY CN TL 1 | 14s

OH

TABLE IL

R3

Co PAS Co So

NH “R2 4

RN vr

H

R' | R? R3 R* | R’ R’ Mp [°C] 2 ewe YC | CL 165 x OMe = 50. | H | Me hg $ Tu 145 x Olle . cl a

BhslRe hee xX OMe x

OMe

SUBSTITUTE SHEET (RULE 26)

62. | H | H 243

NS .

Olle cl : 63. | H | H hg TL 176 =

Olle

NS

S Cl 64. | H | H J

J | hg mn

OMe

J.

S| % 65. | H | H {J J @ TL 199

NS cl OMe ~| C

H | J \ J « 203

OMe cl z= 67. | H | H hg TL 180

NN

ONle cl = ~d

JU RGINGE RG WE

~ NS

N OMe 70. | H | BH \ / -

OMe ‘ 2 ,

SEEING INGIRGERE

Ny

Cl OMe

SUBSTITUTE SHEET (RULE 26)

= = 72. | H | H C 237 : Na EES

OMe 73. | H | H ~() ~ : \ / « 275

OMe

OMe :

S MeO =

OMe y 75. H H hg TL 247 x

OMe

OMe

MeO yz : 76. | H H : ~ h@\ 222 i OMe = 77. H H hg @ TL 218

NN i . S Me = ww | CO)

H \ / “ 214

OMe 79.| H | H \ / « 252

I

I =

H H ~ 178 . OMe

I

SUBSTITUTE SHEET (RULE 26) ’

= 81. | H | H 173

NS .

Me

CL s 82. |u| 1 « J 212

I a 83. | H | B 184

NS

OMe a ~~ 84. | H H “ 150 x OMe

Me : 8s. | H | H hg yp TL 195

I OMe

S Me

H | H ~~) p Xu 171 - OMe

I

= 87. | H | u hg TT TL 217

NN

OMe s I~ 8s. | H | BH IY T TL 149 :

OMe 7

H| H hg T Q 135

NS

SUBSTITUTE SHEET (RULE 26)

® ) oo

PCT/HU02/00048 -

S 1

H| H ~~) TT ol 127 | : oo Ne l S

S I _S i i s 93. | H | H RG TCT \ /] 153.

Ss NG §

Ss MeO os. mH | LJ T RQ | 214

OMe :

MeO Z

H| H hg T TL 183

OMe

AMENDED SHEET

: PCT/HU02/00048 ’

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

TABLE IIL

JH

X* 'H

RS

- | § ¥ J 0) R’

No: X R® RS R’ Mp : [°C] s =] 0 00 : OMe oo

NH hg CN ~ : 208.

AMENDED SHEET

. PCT/HU02/00048 .

OMe :

NH hg RES XT 178s oo 1 100] NH : RG CN XL 158 © "OMe | .

Co : OMe 1 101| NH hg CN TI | 210

OMe 102 | NH hg | on TL das \ Me

Me 103 NH hg CN XX 1 224 : Me 104 | NH hg CN TL | 212 g “CN

OMe SE 106 | NH CN TL . | 208 ’ OMe 107 | NH TL CN TL 168

OMe OMe cl Fn 108 | Nu CN h@ 168

OMe

AMENDED SHEET

PCT/HU02/00048 : 0 109 | NH hg ol {J |= (0) . 112 | NH J CN TL 177

OMe o OMe 113 | wu ~ J CN xr | 169 114 NH ~~ J CN TI 151 o 0) Me 115 NH ~ J CN hg 218 lo) lo) : 116 NH ~~ CN IY, 194 a. s 117 NH RY, CN 188

OMe . 118 NH {7 CN RS 179 0

AMENDED SHEET

PCT/HU02/00048

S Me 119 | NH ~~ CN Tr 239 120 NH hg H h@ 162

OMe 0) 121 NH Hq Xr 5 | 262 o . 122 | s hg CN hg 170

OMe 123 | Osg20 hg CN TL 228

OMe

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. : 5

AMENDED SHEET

PCT/HU02/00048 : : 30 IE

TABLE IV. -

R®

CRRA] 4 el oo

R™ ON” NH,

No: |R'| BR | RF R* | RB | X Mp [°Cl

Co OMe 124 | H H = NH [1 | 192 :

Sg 125|H| H hg ® NH | 1 | 202

OMe xX 126 | H H Z NH | 1 | 250 “ - — oo 127 | gm H = NH | 1] 167

J

128 | H | Me = NH | 1 | 183

AN

129 | H _Me = NH 1 182 -

AN

AMENDED SHEET

PCT/HU02/00048 . oo 31 [130 | m H | z NH | 2 | 172 ] NS

OMe : 131 | H H XI $ NH | 2 | 143

OMe A 132 | H Z| Nm | 2 | 129

Co 133 | H| _Me Z NH | 2 | 136

NE

134 |H| H Id N-Me | 1] 212

NS

135 | H| H Zz s | 1] 168

NN

136 | H H ~ 1] 213

NS

: » 137 | H H = NH | 1 | 234 “ lo) cl {138 | H H In, =~ NH | 1 | 221 : NS

Me : 139 | H| H RG = NH | 1 | 198

NN

AMENDED SHEET

PCT/HU02/00048

MeO } 140! 0 H =~ NH | 1 {201 2

Ss cl 141 | H H ~~ = NH | 1 | 213

NN

Ss NG 142 | g H ~~ NH | 1 | 198 . : Jn

NG oo 143 | H H NH | 1 | 201

AN

S Me 144 | H H In gy NH | 1 | 167 “ 145 | H H NH 1 156 . zz . NS

S Z

146 | H H ~~ $ NH | 1] 187

OMe 147 | #1 H = NH | 1 | 178

NS

OMe E

S = 148 | H H ~~ J je NH | 1 | 207

SE

AMENDED SHEET

’ PCT/HU02/00048 33 CL 19H | H hg = NH | 1217 cr x

S PZ : 150| H H {J | NH | 1 | 204 ~ cr 151| H H | = NH | 1216

SN

BE Cl

S cl 152 H H {J NH | 1 | 205 =

Cl 1531 H H NH 1 213 =

SQ

HO

154| H Z| Ng | 1 | 200 x 155 = NH - 214

RN

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

S

AMENDED SHEET

PCT/HU02/00048

TABLE V.

Cl .

RY CN

Pp gl

R™ N” "NH,

HO

156 = 360 - SN cl 157 = 250

NN

158 Z | 278 or : Me 159 - = 283

NS } }

MeO 160 = : 360 161 = 234 xn : | OMe

Me : 162 246 = ) A

AMENDED SHEET

. } PCT/HU02/00048 | . oo 35 163 ~ 267 - x

Me : 164 : 293

EN cl 165 289 . B gE XX 166 Z 307

NN

Cl

AMENDED SHEET

PCT/HU02/00048 -

Example 167 :

Tablets of the following composition are made by known methods used in the pharmaceutical industry . Active ingredient 25mg

Lactose 50 mg

Avicel 21 mg

Crospovidone 3mg

Magnesium stearate ~~ 1 mg :

Methods

Human adenosine A; 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, bomogenize for 15 sec in buffer (50 mM Tris, 10 mM MgCl, 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-hA; membrane preparation (2 pg protein content) in incubation buffer (50 mM Tris, 10 mM MgCl, 1 mM EDTA, 3 U/mL adenosine deaminase, pH 8.0), in the presence of 0.5 nM [‘“IJAB-MECA (p-amino-benzyl- methylcarboxamido-adenosine) (100.000 cpm) and 100 pM R-PIA (NE-[L-2- phenylisopropyl]adenosine) to define non-specific binding or test compound in a total volume of 50 pL 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 MgCl,, | mM EDTA (pH 8.0) on 96-well Brandel Cell Harvester. Detection of activity: in gamma-counter (1470 Wizard, Wallac). Inhibition [%6] = 100-((activity in the presence of test compound - non-specific activity)/(total activity - non-specific activity))*100

AMENDED SHEET

Human adenosine A; receptor binding - Preparing membrane suspension: collect CHO cells expressing hA; 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), : 5 suspense the membrane preparation in the buffer mentioned above, store the aliquots at -80 °C.

Binding protocol: incubate CHO-hA; membrane preparation (50 pg protein content) in incubation buffer (50 mM Tris, 3 U/mL adenosine deaminase, pH 7.4), 10 nM [PH]JCCPA (2-chloro-N®-cyclopenthyl-adenosine) (80.000 dpm) and 10 uM R-PIA (N®-[L-2- phenylisopropyl]adenosine) to define the non-specific binding or test compound in a total volume of 100 pL 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 Az, receptor binding

Binding protocol: incubate 7 pg of membranes (human A;, adenosine receptors transfected into HEK-293 cells, source: Receptor Biology, Inc.), buffer (50 mM Tris-HCI, 10 mM MgCly, 1 mM EDTA, 2 U/mL adenosine deaminase, pH 7.4), 20 nM ["H]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 pul 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 MgCl,, 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

SUBSTITUTE SHEET (RULE 26)

Human adenosine Ay, receptor binding

Binding protocol: incubate 20.8 pg of membranes (human Aj, adenosine receptors transfected into HEK-293 cells, source: Receptor Biology, Inc.), buffer (50 mM Tris-HCI, : 10 mM MgCl, 1 mM EDTA, 0.1 mM benzamidine, 2 U/ml adenosine deaminase, pH 6.5), 32.4 nM [PH]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 pL 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-HCI (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 A; receptors with an activity above 80 % at 1 uM in our experimental conditions.

The dissociation constant (Kq) of [*IJAB-MECA on CHO-hA; 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 ICs is converted to an affinity constant (K;) 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 (D, (I), (II) and (IV) display remarkable biological effects. The compounds of the general formula (IA), defined in claim 2, as a subgroup of the general formula (D, defined in claim 1, exert the most important activities.

Except of 5 compounds, their K; values are not higher than 20 nM. The compounds given as examples are especially advantageous. Their K; values in human adenosine Aj 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 Aj, Az, and Ay, receptor subtypes.

SUBSTITUTE SHEET (RULE 26)

Further, the duration of their action at intravenous and oral administration is long enough, their EDsy 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.

SUBSTITUTE SHEET (RULE 26)

Claims (1)

16-06-2003 | | weld Huo20004

Claims 1) Compounds of the general formula (I) - wherein R' stands for hydrogen atom or a straight or branched C, 4 alkyl group; R? stands for h ydrogen atom or a straight or branched C; 4 alkyl group;

’ 5 R? stands for hydrogen atom or a straight or branched C,4 alkyl group, or a phenyl group, thienyl group, or furyl group, optionally substituted by one or more straight or branched C;.4 alkyl group, straight or branched C4 alkoxy group, or halogen atom, or for one , two or three nitrogen atoms or one nitrogen atom and one oxygen atom Or one nitrogen atom and one sulphur atom containing 5- or 6 membered heteroaromatic ring,

optionally substituted by one or more straight or branched C4 alkyl group, straight or branched C,4 alkoxy group, or halogen atom; R* and R® 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 C4 alkyl group, straight or branched C, 4 alkoxy group, hydroxy group or halogen atom;

"15 RS stands for hydrogen atom or a cyano group, aminocarbonyl group, C;4 alkoxycarbonyl group, or carboxy group; R’ stands for hydrogen atom or a straight or branched C, 4 alkyl group, a phenyl group, benzyl group, thienyl group or furyl group, optionally substituted by a methylenedioxy group, or one or more straight or branched C4 alkyl group, straight or branched C, 4 alkoxy group, hydroxy group, trifluoromethyl group, cyano group or halogen atom , orfor one , two or three nitrogen atoms or one nitrogen atom and one oxygen atom or one nitrogen atom and one sulphur atom containing 5 or 6 membered heteroaromatic ring, optionally substituted by one or more straight or branched C4 alkyl group, straight or. branched C,4 alkoxy group, or halogen atom;

X stands for a —CH,- group, -NH- group, -NR®- group, or a sulphur atom or an oxygen atom or a sulpho group or a sulphoxy group -wherein R® stands for a straight or branched C,4 alkyl group or Cs.6 cycloalkyl] group-;

n stands for zero, 1 or 2 —

+ and their salts and solvates, optically active isomers and their salts and solvates.

AMENDED SHEET

16-06-2003 HU020004¢

2) Compounds of the general formula (IA) according to claim | - wherein R' stands for hydrogen atom or a straight or branched Ci alkyl group; R? stands for hydrogen atom or a straight or branched C, 4 alkyl group;

R? stands for hydrogen atom or a straight or branched Ci4 alkyl group, or a phenyl group, thienyl group, or furyl group, optionally substituted by one or more straight or branched C4 alkyl group, straight or branched Ci4 alkoxy group, or halogen atom, or for one , two or three nitrogen atoms or one nitrogen atom and one oxygen atom or one nitrogen atom and one sulphur atom containing 5- or 6 membered heteroaromatic ring,

optionally substituted by one or more straight or branched Ci alkyl group, straight or branched C;.4 alkoxy group, or halogen atom: R’, R'%, RY or R'? stand independently from each other for hydrogen atom, or straight ] or branched C,4 alkyl group, straight or branched C; alkoxy group, hydroxy group or halogen atom; or R® and R'2 stand for hydrogen atom and R'® and R"' form together a methylendioxy group; . E R® stands for hydrogen atom or a cyano group, aminocarbonyl group, Cia alkoxycarbonyl group, or carboxy group; R’ stands for hydrogen atom or a straight or branched C, alkyl group, a phenyl group, benzyl group, thienyl group or furyl group, optionally substituted with a methylenedioxy group, Or one or more straight or branched C, 4 alkyl group, strai ght or branched C, 4 alkoxy group, hydroxy group, trifluoromethyl group, cyano group or halogen atom , or for one , two or three nitrogen atoms or one nitrogen atom and one OXygen atom or one nitrogen atom and one sulphur atom containing 5 or 6 membered heteroaromatic ring, optionally substituted with one or more straight or branched C4 alkyl group, straight or branched Ci. alkoxy group, or halogen atom; X stands for a -CH>- group, -NH- group, -NR2- group, or a sulphur atom or an oxygen atom or a sulpho group or a sulphoxy group -wherein R® stands for a strai ght or branched C4 alkyl group or Cj ¢ cycloalkyl group-; ) n stands for zero, 1 or 2 — and their salts and solvates, optically active isomers and their salts and solvates.

AMENDED SHEET r . 16-06-2003 HU020004¢

3) Compounds of the formula (IA) according to claim 2, -wherein ' R' stands for hydrogen atom or a methyl group; y R? stands for hydrogen atom or a methyl group; R? stands for phenyl group, thienyl group or furyl group; R® R'®, R'"' or R'? stand independently from each other for hydrogen atom, or straight or branched C, 4 alkyl group, straight or branched C,_4 alkoxy group, hydroxy group or halogen atom; or R® and R"? stand for hydrogen atom and R'? and R" form together a methylendioxy group, R® stands for hydrogen atom or cyano group; R’ stands for 4-methoxyphenyl group, 3-methylphenyl group, 3-thienyl group or 3-furyl group; X stands for -NH- group or oxygen atom and n stands for 1- : : and their salts, solvates and optically active isomers and their salts and solvates. 4) Compounds according to claims 1-3 as follows: 3-Methyl-N-(4-benzylamino-3-cyano-quinolin-2-yl)benzamide; 4-Methoxy-N-(4-benzylamino-3-cyano-quinolin-2-yl)benzamide; 3-Methoxy- N-(4-benzylamino-3-cyano-quinolin-2-yl)benzamide; 3,4-Methylenedioxy-N-(4-benzylamino-3-cyano-quinolin-2-yl)benzamide; N-(4-benzylamino-3-cyano-quinolin-2-yl)thiophene-3-carboxamide; N-(4-[2-thienylmethylamino]-3-cyano-quinolin-2-yl)thiophene-3-carboxamide; 4-Methoxy-N-(4-[2-thienylmethylamino]-3-cyano-quinolin-2-yl)benzamide; 3,4-Methylenedioxy-N-(4-[2-thienylmethylamino}-3-cyano-quinolin-2-yl)benzamide; N-(4-[2-furylmethylamino]-3-cyano-quinolin-2-yl)furan-2-carboxamide; N-(4-[2-furylmethylamino}-3-cyano-quinolin-2-yl)thiophene-2-carboxamide ’ and their salts, solvates, optically active isomers and their salts and solvates.

5) Process for the preparation of a compound of the general formula (I), its salts, solvates, optically active isomers and their salts and solvates-wherein in the formula R', R?, R3, R% R’ RS, R’, R®, X and n have the same meaning as defined in claim 1, characterized AMENDED SHEET

—#2003 HU0200048 by selective hydrolysis of a bis acid amide of the general formula (II) -wherein R', R?, R3, RY, R?, RS, R7, R%, X and n have the same meaning as defined in claim I- and if ] desired transforming the substituens of the compound of the general formula (I) thus obtained in each other by methods known per se and/or transforming the compound of ’ the general formula (I) thus obtained into its salts, or solvates, or liberating it from its salts or solvates and/or separating it into its optically active isomeric forms or transforming the optically active forms into the racemic form 6) Process according to claim 5, characterized by carrying out the selective hydrolysis in an alcoholic medium in the presence of an alkali hydroxide, preferable potassium or sodium hydroxide 7) Pharmaceutical compositions containing as active ingredient one or more compounds of the general formula (I) — wherein R', R%, R>, RY, R>, R%, R’, R®, X and n have the same meaning as defined in claim 1 — or their salts, solvates, or optically active isomers and the salts, solvates thereof, in admixture with one or more excipients used in the pharmaceutical industry. 8) Pharmaceutical compositions according to claim 7 containing as active ingredient one or more compounds of the general formula (IA) — wherein R', R% R%, RS, R, RS, R7, RY, Rr! R'2, X and n have the same meaning as defined in claim 2 — or their salts, solvates, or optically active isomers and the salts, solvates thereof, in admixture with one or more excipients used in the pharmaceutical industry

9) Pharmaceutical composition according to claim 8 containing as active ingredient one or more compound of claim 4. 10)Use of the compounds of the general formula (I) - wherein R!, R?, R3, RY, R% RS R, . R83, X and n have the same meaning as defined in claim 1 - in the treatment of diseases in development of which the receptor As plays a role.

AMENDED SHEET

. 16-06-2003 HU020004¢

11)Use of the compounds of the general formula (I) — wherein R!, R2, R3,R% R®, RS, R’, R%, X and n have the same meaning as defined in claim 1 - according to claim 10 as Aj; ligand in the case of diseases of the heart, kidney, respiratory organs and central nervous system. for the inhibition of the protection of adenosine in growing tumor * 5 cells, prevention of mast cell degranulation, inhibition of the cytokine production, reduction of intraocular pressure. inhibition of the TNFq release, inhibition of eosinophil. neutrophil and other immune cell migration., inhibition of bronchoconstriction and plasma extravasation. 12) Use of the compounds of the general formula (I) — wherein R’, R% R?, R* R°, RS, R’, R®, X and n have the same meaning as defined in claim 1 - according to claims 10 and 11 as A; receptor antagonist in antiinflamatory, antiasthmatic, antiischemic, antidepressant, antiarrhytmic, renal protective, antitumor, antiparkinson and cognitive enhancing pharmaceutical compositions and in compositions for 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, Addison's disease, Crohn's disease, psoriasis, rheumatism, hypertension, neurogical function disorders, glaucoma and diabetes as active ingredient. 13) Use of the compounds of the general formula (I) — wherein R', R? R®. RY BR, RS, R’, R%, X and n have the same meaning as defined in claim 1 — according to claims 10, 11 and 12 as A; receptor antagonist for the treatment of diseases such as asthma, COPD and ARDS, glaucoma, tumor, allergic and inflammatory diseases, ischemia, hypoxia, arrhytmia and renal diseases as active ingredient. . 14) Use of the compounds of the general formula (IA) — wherein R!,R% BR, RS, R7, R® R? R'% R" RY, X and n have the same meaning as defined in claim 2 - in the treatment of diseases in development of which the receptor As plays a role.

AMENDED SHEET SS

6-06-2003 HU0200048

15) Use of the compounds of the general formula (IA) — wherein R', R?, R3, RS, R’, RE, R®, R', R'".R' X and n have the same meaning as defined in claim 2 - according “to claim 13 as Az ligand in the case of diseases of the heart, kidney, respiratory organs and central nervous system, for the inhibition or protection of adenosine in growing tumor cells, prevention of mast cell degranulation, inhibition of the cytokine ' production, reduction of the inraocular pressure, inhibition of the TNFa release, - inhibition of eosinophil, neutrophil and other immune cell migration., inhibition of bronchoconstriction and plasma extravasation. 16) Use of the compounds of the general formula (IA) — wherein R', R2, R3, R® R’, R®, R®, R'®, RY, R'2, X and n have the same meaning as defined in claim 2 - according to claims 13 and 14 as A; receptor antagonist in antiinflamatory, antiasthmatic, antiischemic, antidepressant, antiarthytmic, renal protective, antitumor, antiparkinson and cognitive enhancing pharmaceutical compositions and in compositions for 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, Addison's disease, Crohn's disease, psoriasis, rheumatism, hypertension, neurogical function disorders, glaucoma and diabetes as active ingredient. 17) Use of the compounds of the general formula (I) — wherein R’, R?, R?, R* R? RS, rR, RS, X and n have the same meaning as defined in claim 1 — according to claims 14, 15 and 16 as A; receptor antagonist for the treatment of diseases such as asthma, COPD and ARDS, glaucoma, tumor, allergic reactions, inflammatory diseases, ischemia, hypoxia, arrhytmia and renal diseases. : 18) Compounds of the general formula (I)- wherein R!, R2, R?, R*, R>, R®, R7, R®, X and n ’ have the same meaning as defined in claim 1. AMENDED SHEET Co]

16-06:2008 | HU0200048

19) Compounds of the general formula (I)-wherein R', R? R3, RY, RS, RS, R®, X and n have the same meaning as defined in claim 1, with the proviso that R? cannot : stand for pheny! group, if R' and R? stand for hydrogenatom, n=1, X stands for a ~NH— . group, R* and R’ form together an 1,3-butadienyl group and RS stands for a cyano group, with the further proviso that .R* cannot stand for hydrogenatom , methyl, ethyl, 4-methoxyphenyl or cyclohexyl group , if n=0, X stands for a ~NR® - group, R® stands for hydrogenatom or methyl group R* and R® form together an 1,3-butadienyl group and RS stands for a cyano group, and with the further proviso that R* cannot stand for hydrogenatom, if , n=0, X stands for a ~CH,- group, R*and R’ form together an 1,3-butadienyl group and R® stands for a cyano or amino-carbonyl group.

20) Compounds of the general formula (IV)- wherein R?, R3, and R® have the same meaning as defined in claim 1, with the proviso that R® cannot stand for hydrogenatom, if R*stands for hydrogwnatom and R® stands for a 4-halogenatom.

, : AMENDED SHEET