RU2317290C2 - Derivatives of aminoquinoline and their using as adenosine a3 ligands - Google Patents

Abstract

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to novel compounds of the general formula (I):

wherein R¹ represents hydrogen atom or linear or branched (C₁-C₄)-alkyl group; R² represents hydrogen atom or linear or branched (C₁-C₄)-alkyl group; R³ represents phenyl, thienyl or furyl group that are substituted optionally with one or more linear or branched (C₁-C₄)-alkyl group, linear or branched (C₁-C₄)-alkoxy-group or halogen atom; R⁴ and R⁵ represent independently of one another hydrogen atom, (C₃-C₆)-cycloalkyl group, linear or branched (C₁-C₄)-alkyl group comprising optionally amino-group or amino-group substituted with one or two linear or branched (C₁-C₄)-alkyl groups, hydroxy-group, carboxy-group or alkoxy-group substituted with linear or branched (C₁-C₄)-alkyl group; or R⁴ represents hydrogen atom or linear or branched (C₁-C₄)-alkyl group or benzyl group; R⁵ represents hydrogen atom, group -SO₂OH or formyl group, or R⁴ and R⁵ in common with nitrogen atom form group of the general formula (a):

wherein R⁷ and R⁸ represent independently one another hydrogen atom, linear or branched (C₁-C₄)-alkyl group; R⁶ represents phenyl, benzyl, thienyl or furyl group that are substituted optionally with methylenedioxy-group or one or more linear or branched (C₁-C₄)-alkyl group, linear or branched (C₁-C₄)-alkoxy-group or halogen atom; X represents group -NH or oxygen atom; Z represents oxygen atom, sulfur atom, group -CH₂, group -NH or group -NR¹¹ wherein R¹¹ represents hydrogen atom, linear or branched (C₁-C₄)-alkyl group, group -SO₂OH, linear or branched (C₁-C₄)-acyl group; n = 0, 1 or 2; m = 1, 2 or 3; o = 1, 2 or 3; p = 0 or 1; r = 0 or 1, and their salts and solvates. Also, invention relates to a method for synthesis of compounds of the general formula (I), to a pharmaceutical composition, its using and to compounds of the general formulas (I''), (II''), (III''), (IV''), (V''), (VI''), (VII''), (VIII'') and (XIII'') given in the invention description. Invention provides synthesis of novel biologically active compounds that are ligands of adenosine A₃ receptors but as antagonists preferably.

EFFECT: valuable biological properties of compounds.

20 cl, 1 tbl, 40 ex

Description

The invention relates to ligands of adenosine A ₃ receptors _{of the} general formula (I), preferably antagonists, as well as their salts, solvates and isomers (tautomers, desmotropic forms, optically active isomers), pharmaceutical compositions containing them, and the use of compounds of the general formula ( I) and their salts, solvates and isomers, to obtain compounds of the general formula (I) and their salts, solvates and isomers, to partially new intermediate products of the general formulas (II "), (III"), (IV "), (V "), (VI"), (VII "), (VIII") and (XIII ") and to their receipt.

Adenosine is a well-known component of certain endogenous molecules (ATP, NAD ⁺ , nucleic acids). It plays an important regulatory role in many physiological processes. The effect of adenosine on cardiac activity was already described in 1929 (Drury and Szentgyorgyi, Physiol. 68: 213, 1929). Identification of the increasing number of physiological functions mediated by adenosine and the discovery of new subtypes of adenosine receptors open up the optionalities for the therapeutic use of specific ligands (Poulse, SA and Quinn, RJ Bioorganic and Medicinal Chemistry 6: 619, 1998).

To date, adenosine receptors are classified into three main classes: A ₁ , A ₂ and A ₃ . Subtype A _{1 is} partially responsible for the inhibition of adenosine cyclase by attaching a membrane to the G ₁ protein and partially affects other secondary signaling systems. The A ₂ receptor subtype can be subdivided into two additional subtypes A _2a and A _2b , which stimulate adenylate cyclase activity. The adenosine A ₃ receptor sequence was first identified from a rat testis cDNA library. It was later found that it corresponds to a new functional adenosine receptor. Activation of A ₃ receptors is also associated with some secondary signaling systems: inhibition of adenylate cyclase, stimulation of phospholipase C and D.

Adenosine receptors are found in various organs and (they) regulate their functions. Both receptors A ₁ and A _2a play an important role in the central nervous system and cardiovascular system. In the central nervous system, adenosine inhibits the release of synaptic mediators, the effect of which is mediated by A ₁ receptors. In the heart, A ₁ receptors also mediate the negative inotropic, chronotropic and dromotropic effects of adenosine. Adenosine A _2a receptors, which are localized in a relatively large amount in the striatum, exhibit functional interaction with dopamine receptors in the regulation of synaptic transmission. Adenosine A _2a receptors of endothelial and smooth muscle cells are responsible for adenosine-induced vasodilation.

According to RNA identification, adenosine A _2b receptors are widely distributed in various tissues. They are identified in almost all types of cells, but their expression is highest in the intestines and bladder. The indicated subtype probably also performs an important regulatory function in the regulation of vascular tone and plays a role in the activity of mast cells.

In contrast to receptors A ₁ and A _2a , where tissue distribution was determined by protein level, the presence of A _2b and A ₃ receptors was determined based on their level in mRNA. The expression levels of A ₃ adenosine receptors are quite low compared to other subtypes and are highly dependent on the type of tissue. A ₃ Adenosine receptors are expressed primarily in the central nervous system, in the testis, and in the immune system and are apparently involved in modulating the release of mediator from mast cells in a direct allergic reaction.

For use in therapy, it is sufficient to ensure that the molecule does not bind or binds only in the case of a very high concentration with subtypes of A ₁ , A _2a and A _2b adenosine receptors.

Our present invention relates to compounds of the general formula (I), as well as their salts, solvates and isomers, which are highly selective for the A ₃ subtype of adenosine receptors.

A ₃ antagonists, so far published in the literature, belong to the groups of flavonoids, derivatives of 1,4-dihydropyridine, triazoloquinazolines, thiazolonaphthyridines and thiazolopyrimidines. The most effective and selective for the subtypes of adenosine antagonists exhibit strong lipophilic properties and therefore they are moderately soluble in water. This property makes it difficult to apply the compounds in vivo. In the literature, more and more studies are aimed at finding optionally water-soluble adenosine A3 receptor antagonists (Ch. E. Mueller et al., J. Med. Chem. 45: 3440, 2002; A. Maconi et al., J. Med. Chem 45: 3579, 2002).

In patent application WO 02/096879, derivatives of 2-amino-3-cyanoquinoline are proposed as a structurally new type of effective A ₃ antagonists. The compounds of formula (I) described in patent application WO 02/096879 are antagonists of A ₃ with high selectivity.

In the general formula (I)

R ^{1 '} represents a hydrogen atom or a linear or branched C _1-4 alkyl group;

R ^{2 '} represents a hydrogen atom or a linear or branched C _1-4 alkyl group;

R ^{3 ′} represents a hydrogen atom or a linear or branched C _1-4 alkyl group, a phenyl, thienyl or furyl group optionally substituted with one or more linear or branched C _1-4 alkyl group, a linear or branched C _1-4 alkoxy group or atom halogen; a six- or five-membered heteroaromatic ring containing one, two or three nitrogen atoms, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, optionally substituted with one or more linear or branched C _1-4 alkyl groups, linear or a branched C _1-4 alkoxy group or a halogen atom;

R ^{9 '} , R ^10' , R ^{11 '} and R ^12' independently represent a hydrogen atom, a linear or branched C _1-4 alkyl group, a linear or branched C _1-4 alkoxy group, a hydroxy group or a halogen atom, or R ^{9 '} and R ^12' represent a hydrogen atom, and R ^{10 '} and R ^11' together form a methylenedioxy group;

R ^{6 ′} represents a hydrogen atom or a cyano group, an aminocarbonyl group, a C _1-4 alkoxycarbonyl group or a carboxy group;

R ^{7 ′} represents a hydrogen atom or a linear or branched C _1-4 alkyl group, a phenyl, benzyl, thienyl or furyl group optionally substituted with a methylenedioxy group or one or more linear or branched C _1-4 alkyl group, a linear or branched C _{1- 4} alkoxy group, hydroxy group, trifluoromethyl group, cyano group or a halogen atom; or a six- or five-membered heteroaromatic ring containing one, two or three nitrogen atoms, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, optionally substituted with one or more linear or branched C _1-4 alkyl a group, a linear or branched C _1-4 alkoxy group or a halogen atom;

X represents a —CH ₂ group, —NH group, —NR ^{8 ′} group or a sulfur atom, an oxygen atom, a sulfo group or a sulfoxy group, where R ^{8 ′} represents a linear or branched C _1-4 alkyl group or a C _3-6 cycloalkyl group ;

n 'is zero, 1 or 2.

These compounds also have a characteristic disadvantage, since they are only sparingly soluble, which interferes with their processing into drugs.

The aim of the authors was to obtain A ₃ ligands, preferably antagonists, of the quinoline structure, which have a strong antagonistic effect and high selectivity for A ₃ receptors, that is, inhibit A ₃ receptors at a lower concentration than they inhibit A ₁ , A _2a and A _2b receptors . An additional goal was to ensure stability, bioavailability, therapeutic index, toxicity and solubility, which make it unnecessary to process these new compounds into drugs, and that the new compounds have favorable absorption in the intestine for oral administration.

It was found that the compounds of General formula (I),

wherein

R ¹ represents a hydrogen atom or a linear or branched C _1-4 alkyl group;

R ² represents a hydrogen atom or a linear or branched C _1-4 alkyl group;

R ³ represents a hydrogen atom or a linear or branched C _1-4 alkyl group, a C _3-6 cycloalkyl group, a phenyl, thienyl or furyl group optionally substituted with one or more linear or branched C _1-4 alkyl group, a linear or branched C _1-4 alkoxygroup or halogen atom; a six- or five-membered heteroaromatic ring containing one, two or three nitrogen atoms, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, optionally substituted with one or more linear or branched C _1-4 alkyl groups a linear or branched C _1-4 alkoxy group or a halogen atom;

R ⁴ and R ⁵ independently represent a hydrogen atom, a C _3-6 cycloalkyl group, a linear or branched C _1-4 alkyl group, optionally containing an amino group or an amino group substituted by one or more linear or branched C _1-4 alkyl groups a hydroxy group, a carboxy group or an alkoxy group substituted with a linear or branched C _1-4 alkyl group; or

R ⁴ represents a hydrogen atom or a linear or branched C _1-4 alkyl group or benzyl group, and

R ⁵ represents a hydrogen atom, a —SO ₂ OH group, or a linear or branched C _1-4 acyl group, or

R ⁴ and R ⁵ together with a nitrogen atom form a group of the general formula a.), Where R ⁷ and R ⁸ independently represent a hydrogen atom, a linear or branched C _1-4 alkyl group or a C _3-6 cycloalkyl group;

R ⁶ represents a hydrogen atom or a linear or branched C _1-4 alkyl group, a phenyl, benzyl, thienyl or furyl group, optionally substituted with a methylenedioxy group or one or more linear or branched C _1-4 alkyl group, a linear or branched C _1-4 alkoxy group, hydroxy group, trifluoromethyl group, cyano group or a halogen atom; or a six- or five-membered heteroaromatic ring containing one, two or three nitrogen atoms, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, optionally substituted with one or more linear or branched C _1-4 alkyl groups, a linear or branched C _1-4 alkoxy group or a halogen atom;

X represents a —CH ₂ group, —NH group, —NR ⁹ group or a sulfur atom, an oxygen atom, a sulfo group or a sulfoxy group, where R ⁹ represents a linear or branched C _1-4 alkyl group or a C _3-6 cycloalkyl group;

Z represents an oxygen atom, a sulfur atom, a group —CHR ¹⁰ or a group —NR ¹¹ , where R ¹⁰ represents a hydrogen atom, a linear or branched C _1-4 alkyl group or a C _3-6 cycloalkyl group, and R ¹¹ represents an atom hydrogen, a linear or branched C _1-4 alkyl group, a C _3-6 cycloalkyl group, a —SO ₂ OH group or a linear or branched C _1-4 acyl group;

n is zero, 1 or 2;

m is 1, 2 or 3;

o is 1, 2 or 3;

p is zero or 1;

r is zero or 1,

and their salts, solvates, isomers (tautomers, desmotropic forms, optically active isomers), as well as their salts and solvates, satisfy the above criteria, their solubility is much better than the known 2-amino-3-cyanoquinolines, and in addition they highly active.

As shown by a liquid-phase NMR study, an equilibrium mixture of tautomeric forms (IA) and (IB) exists in a solution of compounds of general formula (I). In the solid phase, tautomers (IA) and (IB) can be isolated separately as desmotropic forms (IA) and (IB).

According to the above results, the invention also relates to desmotropic isomers (IA) and (IB). The meanings of the substituents in the general formulas (IA) and (IB) are as defined for the general formula (I).

The compounds of general formula (I) may have a chiral center depending, for example, on the position of the substituents R ¹ , R ² and R ³ . Thus, the invention also relates to racemic and optically active forms of the compounds of general formula (I) and their salts, tautomers and desmotropic forms.

The detailed meanings of these substituents are as follows.

By a linear or branched C _1-4 alkyl group is meant a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl group, preferably an ethyl or methyl group.

By a straight or branched C _1-4 alkoxy group is meant a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, preferably an ethoxy group or a methoxy group.

By a C _3-6 cycloalkyl group is meant a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.

By a linear or branched C _1-4 acyl group is meant a formyl, acetyl, propionyl, 2-methylpropionyl or butyryl group.

A heteroaromatic ring containing one, two or three nitrogen atoms means pyrrole, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, pyridine, pyrimidine, pyridazine, pyrazine or 1,2,4- triazine ring. The ring may be substituted with a C _1-4 alkyl group, a C _1-4 alkoxy group or a halogen atom.

A heteroaromatic ring containing one nitrogen atom and one oxygen or sulfur atom is understood to mean an oxazole, isoxazole, thiazole or isothiazole ring. The ring may be substituted with a C _1-4 alkyl group, a C _1-4 alkoxy group or a halogen atom.

Group a.) Is preferably pyrrolidino, piperidino, piperazino, 4-methylpiperazino, 4-formylpiperazino, 4-sulfonylpiperazino or a morpholino group.

By salts of the compounds of general formula (I) we mean salts formed with inorganic or organic acids and bases. Preferred salts are formed with pharmaceutically acceptable acids, such as, for example, hydrochloric acid, sulfuric acid, ethanesulfonic acid, tartaric acid, malic acid, citric acid, fumaric acid, and with pharmaceutically acceptable bases, such as sodium hydroxide, potassium hydroxide and ethanolamine. Salts used for purification or isolation, such as methanesulfonates or tetrafluoroborates, are also an object of the invention.

Solvates are understood to mean solvates formed with various solvents, such as, for example, water or ethanol.

A preferred group of compounds of general formula (I) are those wherein

R ¹ represents a hydrogen atom or a linear or branched C _1-4 alkyl group;

R ² represents a hydrogen atom or a linear or branched C _1-4 alkyl group;

R ³ represents a hydrogen atom or a linear or branched C _1-4 alkyl group, a C _3-6 cycloalkyl group, a phenyl, thienyl or furyl group optionally substituted with one or more linear or branched C _1-4 alkyl group, a linear or branched C _1-4 alkoxygroup or halogen atom;

R ⁴ and R ⁵ independently represent a hydrogen atom, a C _3-6 cycloalkyl group, a linear or branched C _1-4 alkyl group, optionally containing an amino group or an amino group substituted by one or more linear or branched C _1-4 alkyl groups a hydroxy group, a carboxy group or an alkoxy group substituted with a linear or branched C _1-4 alkyl group; or

R ⁴ represents a hydrogen atom or a linear or branched C _1-4 alkyl group or benzyl group, and

R ⁵ represents a hydrogen atom, a —SO ₂ OH group, or a linear or branched C _1-4 alkyl group, or

R ⁴ and R ⁵ together with a nitrogen atom form a group of the general formula a.), Where R ⁷ and R ⁸ independently represent a hydrogen atom, a linear or branched C _1-4 alkyl group or a C _3-6 cycloalkyl group;

R ⁶ represents a hydrogen atom or a linear or branched C _1-4 alkyl group, a phenyl, benzyl, thienyl or furyl group, optionally substituted with a methylenedioxy group or one or more linear or branched C _1-4 alkyl group, a linear or branched C _1-4 alkoxy group, hydroxy group, trifluoromethyl group, cyano group or a halogen atom; or a six- or five-membered heteroaromatic ring containing one, two or three nitrogen atoms, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, optionally substituted with one or more linear or branched C _1-4 alkyl groups, a linear or branched C _1-4 alkoxy group or a halogen atom;

X represents a —CH ₂ group, —NH group, —NR ⁹ group or a sulfur atom, an oxygen atom, a sulfo group or a sulfoxy group, where R ⁹ represents a linear or branched C _1-4 alkyl group or a C _3-6 cycloalkyl group;

Z represents an oxygen atom, a sulfur atom, a group —CHR ¹⁰ or a group —NR ¹¹ , where R ¹⁰ represents a hydrogen atom, a linear or branched C _1-4 alkyl group or a C _3-6 cycloalkyl group, and R ¹¹ represents an atom hydrogen, a linear or branched C _1-4 alkyl group, a C _3-6 cycloalkyl group, an —SO ₂ OH group or a formyl group;

n is zero, 1 or 2;

m is 1, 2 or 3;

o is 1, 2 or 3;

p is zero or 1;

r is zero or 1,

and their salts, solvates, isomers (tautomers, desmotropic forms, optically active isomers), as well as their salts and solvates.

A particularly preferred group of compounds of general formula (I) are those wherein

R ¹ represents a hydrogen atom or a methyl group;

R ² represents a hydrogen atom or a methyl group;

R ³ represents a phenyl, thienyl or furyl group;

R ⁴ and R ⁵ independently represent a hydrogen atom, a C _3-6 cycloalkyl group, a linear or branched C _1-4 alkyl group, optionally containing an amino group or an amino group substituted by one or two linear or branched C _1-4 alkyl groups a hydroxy group, a carboxy group or an alkoxy group substituted with a linear or branched C _1-4 alkyl group; or

R ⁴ represents a hydrogen atom or a linear or branched C _1-4 alkyl group or benzyl group, and

R ⁵ represents a hydrogen atom, a —SO ₂ OH group, or a linear or branched C _1-4 acyl group, or

R ⁴ and R ⁵ together with a nitrogen atom form a group of the general formula a.), Where R ⁷ and R ⁸ independently represent a hydrogen atom, a linear or branched C _1-4 alkyl group or a C _3-6 cycloalkyl group;

R ⁶ represents a 4-methoxyphenyl, 3-methylphenyl, 3-methoxyphenyl, 3,4-methylenedioxyphenyl group, 4-fluorophenyl, 2-thienyl or 2-furyl group;

X represents an —NH group or an oxygen atom;

Z represents an oxygen atom, a sulfur atom, a —CH ₂ group, an —NH group or an —NR ¹¹ group, where R ¹¹ represents a linear or branched C _1-4 alkyl group, a C _3-6 cycloalkyl group, an —SO ₂ OH group or formyl group; and

n is 1;

m is 2;

o is 2;

p is zero;

r is zero

and their salts, solvates, isomers (tautomers, desmotropic forms, optically active isomers), as well as their salts and solvates.

Particularly favorable are the following compounds that satisfy the above criteria:

4-methoxy-N- [6- (morpholin-4-yl) -4-benzylamino-3-cyanoquinolin-2-yl] benzamide;

4-methoxy-N- [6- (4-methylpiperazin-1-yl) -4-benzylamino-3-cyanoquinolin-2-yl] benzamide;

4-methoxy-N- (6-dimethylamino-4-benzylamino-3-cyanoquinolin-2-yl) benzamide;

3,4-methylenedioxy-N- (6-dimethylamino-4-benzylamino-3-cyanoquinolin-2-yl) benzamide;

4-fluoro-N- (6-dimethylamino-4-benzylamino-3-cyanoquinolin-2-yl) benzamide;

4-methoxy-N- (6-piperazin-1-yl) -4-benzylamino-3-cyanoquinolin-2-yl) benzamide;

4-methoxy-N- (6-amino-4-benzylamino-3-cyanoquinolin-2-yl) benzamide;

N - [4- (benzylamino) -3-cyano-6- (4-formylpiperazin-1-yl) quinolin-2-yl] -4-methoxybenzamide;

4- {4- (benzylamino) -3-cyano-2 - [(4-methoxybenzoyl) amino] quinolin-6-yl} piperazine-1-sulfonic acid;

N- {3-cyano-6- (formylamino) -4 - [(2-thienylmethyl) amino] quinolin-2-yl} -4-methoxybenzamide;

N {-3-cyano-6- (formylamino) -4 - [(2-thienylmethyl) amino] quinolin-2-yl} -1,3-benzodioxol-5-carboxamide;

N- [4- (benzylamino) -3-cyano-6- (formylamino) quinolin-2-yl] -1,3-benzodioxol-5-carboxamide;

N- [4- (benzylamino) -3-cyano-6- (formylamino) quinolin-2-yl] -4-methoxybenzamide;

N- {4- (benzylamino) -3-cyano-6- [formyl (methyl) amino] quinolin-2-yl} -4-methoxybenzamide;

N- {3-cyano-6- [formyl (methyl) amino] -4 - [(2-thienylmethyl) amino] quinolin-2-yl} -4-methoxybenzamide;

{3-cyano-2 - [(4-methoxybenzoyl) amino] -4 - [(2-thienylmethyl) amino] quinolin-6-yl} methylsulfamic acid;

{4- (benzylamino) -3-cyano-2 - [(4-methoxybenzoyl) amino] quinolin-6-yl} methylsulfamic acid;

{4- (benzylamino) -3-cyano-2 - [(4-methoxybenzoyl) amino] quinolin-6-yl} sulfamic acid;

[2 - [(1,3-benzodioxol-5-ylcarbonyl) amino] 4- (benzylamino) -3-cyanoquinolin-6-yl] sulfamic acid;

{2 - [(1,3-benzodioxo-5-ylcarbonyl) amino] -3-cyano-4 - [(2-thienylmethyl) amino] quinolin-6-yl} sulfamic acid;

{3-cyano-2 - [(4-methoxybenzoyl) amino] 4 - [(2-thienylmethyl) amino] quinolin-6-yl} sulfamic acid

and their salts, solvates, isomers (tautomers, desmotropic forms), as well as their salts and solvates.

The compounds of general formula (I) according to this invention, as well as their salts, solvates and isomers (tautomers, desmotropic forms, optically active isomers) and their salts, solvates, exhibit suitable solubility and are therefore suitable for use as active substances in pharmaceutical compositions.

The solubility values in water and in aqueous buffer solutions (pH = 6.5 and 7.5) for compounds of formula (I) of patent application WO 02/096879 are less than 1 mg / l, while for compounds of general formula (I) of this invention they are 1-200 mg / l.

This invention also relates to pharmaceutical compositions containing, as active components, compounds of the general formula (I) or their isomers (tautomers, desmotropic forms, optically active isomers), salts or solvates, which are preferably oral compositions, however, formulations for inhalation, parenteral and transdermal forms are also an object of the invention. The above pharmaceutical compositions may be solid or liquid, such as tablets, pellets, capsules, plates, solutions, suspensions or emulsions. Solid compositions, especially tablets and capsules, are preferred.

The above pharmaceutical compositions are prepared using conventional pharmaceutical excipients and using standard methods.

The compounds of general formula (I) can be used to treat pathologies in which A ₃ receptors play a role in the development of the disease.

The compounds of this invention, having a selective effect on A ₃ receptors, can be used in the therapeutic and / or prophylactic treatment of dysfunctions of the heart, kidneys, respiratory system, central nervous system. They inhibit the protective effect of adenosine upon the growth of tumor cells, prevent mast cell degranulation, inhibit cytokine production, reduce intraocular pressure, inhibit the release of TNFα, inhibit the migration of eosinophils, neutrophils and other immune cells, inhibit bronchostenosis and plasma extravasation.

Based on these effects, the adenosine A ₃ receptor antagonists _{of the} present invention may be useful in therapy as anti-inflammatory, anti-asthma, anti-ischemic agents, antidepressants, antiarrhythmic, renal-protective, anti-tumor agents, anti-Parkinson drugs and cognitive enhancers. They can also be useful in treating or preventing reperfusion injuries of the myocardium, chronic obstructive pulmonary disease (COPD) and adult respiratory distress syndrome (ARDS), including chronic bronchitis, pulmonary emphysema or shortness of breath, allergic reactions (e.g., rhinitis, reactions induced by poison ivy, urticaria, scleroderma, arthritis), other autoimmune diseases, inflammatory bowel diseases, Addison’s disease, Crohn’s disease, psoriasis, rheumatism, hypertension, functional neurol ogic disorders, glaucoma, and diabetes (KN Klotz, Naunyn-Schmiedberg's Arch. Pharmacol. 362: 382, 2000; PG Baraldi es PA Borea, TiPS 21: 456, 2000).

The compounds of this invention can preferably be used to make a pharmaceutical composition for the treatment of diseases such as asthma, COPD and ARDS, glaucoma, tumor, allergic and inflammatory diseases, ischemia, hypoxia, arrhythmia and renal diseases.

In addition, this invention relates to the use of compounds of the general formula (I) in the treatment of the above pathologies. The proposed daily dose is 0.1-1000 mg of the active ingredient, depending on the nature and severity of the disease and on gender, weight, etc. the patient.

An additional object of the invention is the preparation of compounds of general formula (I).

Substituents in the formulas of intermediates and reagents of the general formulas (I "), (II"), (III "), (IV"), (V "), (VI"), (VII "), (VIII"), ( IX "), (X"), (XI "), (XII"), (XIII ") and (XIV") have the following meanings.

R ^{1 "} represents a hydrogen atom or a linear or branched C _1-4 alkyl group;

R ^{2 "} represents a hydrogen atom or a linear or branched C _1-4 alkyl group;

R ^{3 "} represents a hydrogen atom or a linear or branched C _1-4 alkyl group, a C _3-6 cycloalkyl group, a phenyl, thienyl or furyl group optionally substituted with one or more linear or branched C _1-4 alkyl group, linear or branched With a _1-4 alkoxy group or a halogen atom; a six- or five-membered heteroaromatic ring containing one, two or three nitrogen atoms, or a five-membered heteroaromatic ring containing one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom optionally substituted with one or more linear or branched C _1-4 alkyl groups, a linear or branched C _1-4 alkoxy group or a halogen atom;

R ^{4 "} and R ^5" independently represent a hydrogen atom, a C _3-6 cycloalkyl group, a linear or branched C _1-4 alkyl group, optionally containing an amino group or an amino group substituted by one or two linear or branched C _1-4 alkyl groups, a carboxy group or an alkoxy group substituted with a linear or branched C _1-4 alkyl group, or a protective group; or

R ^{4 "} represents a hydrogen atom or a linear or branched C _1-4 alkyl group or benzyl group, and

R ^{5 "} represents a hydrogen atom, a —SO ₂ OH group or a linear or branched C _1-4 acyl group or a protecting group, or

R ^{4 "} and R ^5" together with a nitrogen atom form a nitro group or a group of the general formula a.), In which R ^{7 "} and R ^8" independently represent a hydrogen atom, a linear or branched C _1-4 alkyl group or C _3-6 cycloalkyl group;

R ^{6 "} represents a hydrogen atom or a linear or branched C _1-4 alkyl group, a phenyl, benzyl, thienyl or furyl group optionally substituted with a methylenedioxy group or one or more linear or branched C _1-4 alkyl group, a linear or branched C _{1- 4} alkoxy group, hydroxy group, trifluoromethyl group, cyano group or halogen atom, or six- or five-membered heteroaromatic ring containing one, two or three nitrogen atoms, or one nitrogen atom and one oxygen atom, or one atom and ota and one sulfur atom, optionally substituted by one or more linear or branched C _1-4 alkyl group, a linear or branched C _1-4 alkoxy group or a halogen atom;

X ^″ represents a —CH ₂ group, —NH group, —NR ^{9 ″} group or a sulfur atom, an oxygen atom, a sulfo group or a sulfoxy group, where R ^{9 ″} represents a linear or branched C _1-4 alkyl group or a C _3-6 cycloalkyl a group;

Z ^" represents an oxygen atom, a sulfur atom, a group -CHR ^10" or a group -NR ^{11 "} , where R ^10" represents a hydrogen atom, a linear or branched C _1-4 alkyl group or a C _3-6 cycloalkyl group and R ^{11 "} represents a hydrogen atom, a linear or branched C _1-4 alkyl group, a C _3-6 cycloalkyl group, a -SO ₂ OH group, a linear or branched C _1-4 alkyl group or a protecting group;

R ^{12 "} represents a linear or branched C _1-3 alkyl group;

Y ^" represents a leaving group;

n ^" is 0, 1 or 2;

m ^" is 1, 2 or 3;

o ^" is 1, 2 or 3;

p ^" is zero or 1;

r ^" is zero or 1.

An additional object of the invention is the preparation of compounds of general formula (I) and partially new intermediate products of general formulas (I "), (II"), (III "), (IV"), (V "), (VI"), (VII "), (VIII") and (XIII ").

In the method according to the invention

v.) a bis-carboxamide of the general formula (II ") is selectively hydrolyzed and, if desired, the protective group is removed, or

v / i.) to obtain a compound of general formula (I) in which R ⁴ represents a hydrogen atom, a linear or branched C _1-4 alkyl group or a benzyl group, and R ⁵ represents a linear or branched C _1-4 acyl group or R ⁴ and R ⁵ together with the nitrogen atom form a group of the general formula a.), where Z represents a group —NR ¹¹ , in which R ¹¹ represents a linear or branched C _1-4 acyl group, and R ¹ , R ² , R ³ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , X, n, m, o, p and r are as defined above,

a compound of general formula (I) in which R ⁴ represents a hydrogen atom, a linear or branched C _1-4 alkyl group or benzyl group, and R ⁵ represents a hydrogen atom or R ⁴ and R ⁵ together with a nitrogen atom form a group of general formula a .), where Z represents a group —NH, and R ¹ , R ² , R ³ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , X, n, m, o, p and r are as defined above,

acylated with a compound of the general formula R ^{12 "} COY ^" , where R ^{12 "} and Y ^" are as defined above, or

v / ii.) to obtain a compound of general formula (I) in which R ⁴ represents a hydrogen atom, a linear or branched C _1-4 alkyl group or a benzyl group and R ⁵ represents a —SO ₂ OH or R ⁴ group and R ⁵ together with the nitrogen atom form a group of the general formula a.), Where Z represents the group —NR ¹¹ , R ¹¹ represents the group —SO ₂ OH, and R ¹ , R ² , R ³ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , X, n, m, o, p and r are as defined above,

a compound of general formula (I) in which R ⁴ represents a hydrogen atom, a linear or branched C _1-4 alkyl group or benzyl group, and R ⁵ represents a hydrogen atom or R ⁴ and R ⁵ together with a nitrogen atom form a group of general formula a .), where Z represents a group —NH, and R ¹ , R ² , R ³ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , X, n, m, o, p and r are as defined above,

reacting with the pyridine-SO ₃ complex or with ClCO ₃ H, or

v / iii.) to obtain a compound of general formula (I) in which R ⁴ represents a hydrogen atom, a linear or branched C _1-4 alkyl group or a benzyl group and R ⁵ represents a —SO ₂ OH group, and R ¹ , R ² , R ³ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , X, Z, n, m, o, p and r are as defined above,

a compound of general formula (XIII ") in which R ¹ , R ² , R ³ , R ⁶ , R ⁹ , X, and n are as defined above,

subjected to interaction with Na ₂ S ₂ O ₄ or NaHSO ₃ ,

or

recover and the resulting compound of General formula (XIV "), in which R ^4" represents a hydrogen atom, and R ^{1 "} , R ^2" , R ^{3 "} , R ^6" , R ^{9 "} , X ^" and n "have the values defined above are sulfated with the pyridine-SO ₃ or ClSO ₃ H complex,

if desired, then R ^{4 "} representing a hydrogen atom is converted into a linear or branched C _1-4 alkyl group or benzyl group, or

v / iv.) to obtain a compound of general formula (I) in which R ⁴ represents a hydrogen atom, a C _3-6 cycloalkyl group, a benzyl group, a linear or branched C _1-4 alkyl group, optionally containing an amino group or an amino group substituted one or more linear or branched C _1-4 alkyl groups, a hydroxy group, a carboxy group or an alkoxy group substituted by a linear or branched C _1-4 alkyl group, and R ⁵ represents a hydrogen atom, or

R ⁴ and R ⁵ together with the nitrogen atom form a group of the general formula a.), In which R ⁷ and R ⁸ independently represent a hydrogen atom, a linear or branched C _1-4 alkyl group or a C _3-6 cycloalkyl group, and Z represents a group —NR ¹¹ in which R ¹¹ represents a hydrogen atom,

remove the protective group of the compounds of General formula (I "), in which

R ^{4 "} represents a hydrogen atom, a C _3-6 cycloalkyl group, a linear or branched C _1-4 linear group, optionally containing an amino group or an amino group substituted by one or two linear or branched C _1-4 alkyl groups, a hydroxy group, a carboxy group, or an alkoxy group substituted with a linear or branched C _1-4 alkyl group, and R ^{5 "} represents a protective group, or

R ^{4 "} and R ^5" together with the nitrogen atom form a group of the general formula a ".), In which R ^7" and R ^{8 "} independently represent a hydrogen atom, a linear or branched C _1-4 alkyl group or C _{3 -6 a} cycloalkyl group, and Z represents a group —NR ^{11 ″} , where R ^{11 ″} represents a protective group,

And, if desired, the substituents of the obtained compound of general formula (I) are converted into each other by known methods and / or the obtained compound of general formula (I) is converted to its salt or solvate, or released from its salt or solvate, and, if desired, cleaved on its optically active isomers, and, if desired, this desmotropic (form) is converted into another desmotropic form.

As selective hydrolysis agents, alkali metal hydroxides, preferably potassium hydroxide and / or sodium hydroxide, dissolved in alcohol, preferably methanol, can be used, but other agents known in organic chemistry that promote the hydrolysis of amides can also be used.

Selective hydrolysis can be carried out in a wide temperature range, preferably in the range from 20 ° C to 100 ° C.

Reaction v / i.) Can be carried out using an ester derivative of the corresponding acid at elevated temperature or using an activated derivative of an acid (e.g. acid halide) at room temperature or elevated temperature using a suitable base (e.g. triethylamine).

Reaction v / ii.) Can be carried out using the pyridine-SO ₃ complex in a suitable solvent (preferably pyridine) or using ClSO ₃ H in a suitable solvent (preferably pyridine or chloroform) using a strong organic base (like DBU) or inorganic base (similar to K ₂ CO ₃ ) at room temperature or at elevated temperature.

Reaction v / iii.) Can be carried out in an appropriate aqueous alkaline nitro compound solution using an excess of Na ₂ S ₂ O ₄ or NaHSO ₃ as a reagent at room temperature or at elevated temperature (100 ° C).

According to reaction variant v / iii.), The nitro derivative is reduced by any known method, and the obtained amino derivative is first alkylated or benzylated under known reductive alkylation or benzylation conditions, and the resulting alkyl or benzyl amino derivatives can be sulfated as described in ii.).

The protecting group may be any known protecting group. Examples of protective groups, as well as methods for protecting and removing various protective functional groups, are given in "Protective Groups in Organic Synthesis", Green et al., 2nd edition * John Wiley & Sons, Inc, New York., 1991. Preferred protective the groups are Boc, ethoxycarbonyl, benzyloxycarbonyl, etc., the most preferred benzyl group.

Substituents of the compounds of general formula (I) can be transformed by any of the known methods (Comprehensive Organic Transformation, R. C. Larock, VCH Publisher, New York, 1989).

Salts can be prepared by adding one equivalent of acid to an alcohol, preferably ethanol, base solution and diluting the solution with diethyl ether, and finally filtering and drying the resulting crystals.

Compounds of general formula (II ') in which R ^{1 "} , R ^2" , R ^{3 "} , R ^4" , R ^{5 "} , R ^6" , R ^{7 "} , R ^8" , X ", Z", n " , o ", p", r "and m" have the meanings defined above, can be obtained by various known methods, among them the method shown in reaction scheme 1, by acylating the compounds of formula (III ") by the acylation method known in organic chemistry. Preferably, an acid chloride can be used as an acylating agent, an acid, triethylamine and / or pyridine binding agent, but other compounds known as acid binders can also be used.

Compounds of general formula (III ") in which R ^1" , R ^{2 "} , R ^3" , R ^{4 "} , R ^5" , R ^{6 "} , R ^7" , R ^{8 "} , X", Z ", n" , o ", p", r "and m" have the meanings defined above, can be obtained directly from the compounds of formula (IV ") by known methods per se (Nan Zhang, Bioorg. And Med. Chem. Lett., 10, 2825, 2000).

The compounds of general formula (IV ") in which R ^4" , R ^{5 "} , R ^6" , R ^{7 "} , R ^8" , X ", Z", r ", o", p "and m" have the meanings as defined above, can be obtained by known methods, as such, directly from the compounds of formula (V ") (DL Leysen, J. Heterocyclic Chem., 24, 1611, 1987).

Compounds of general formula (V ") in which R ^4" , R ^{5 "} , R ^7" , R ^{8 "} , Z", r ", o", p "and m" have the meanings given above, can be prepared by known by methods, as such, directly from the compounds of formula (VI ") (Pfizer (Inc) USP 4, 175, 193).

Compounds of the general formula (VI ″) in which R ^{4 ″} , R ^{5 ″} , R ^{7 ″} , R ^{8 ″} , Z ″, r ″, o ″, p ″ and m ″ are as defined above can be prepared as known by methods, as such, directly from the compounds of formula (VII ") (DL Leusen, J. Heterocyclic Chem., 24, 1611, 1987).

Compounds of the general formula (VII ″) in which R ⁴ ″, R ⁵ ″, R ⁷ ″, R ⁸ ″, Z ″, r ″, o ″, p ″ and m ″ have the meanings defined above, can be prepared by known by methods, as such, directly from compounds of formula (VIII ″) (DHKlaubert and JHSellstedt, J. Med. Chem., 24, 742, 1981) or are commercially available products, such as a compound where R ⁴ ″ and R ⁵ ″ together with a nitrogen atom form a nitro group.

The compounds of general formula (VIII ″) in which R ⁴ ″, R ⁵ ″, R ⁷ ″, R ⁸ ″, Z ″, r ″, o ″, p ″ and m ″ have the meanings defined above, can be obtained known by methods, as such, directly from compounds of formula (IX ″) (JHutchinson and JJCook, J. Med. Chem. 39, 4583, 1996).

Compounds of general formulas (I), (I ′), (II ″), (III ″), (IV ″), (V ″), (VI ″), (VII ″), (VIII ″), (XIII ″ ) and (XIV ″) according to the invention, as well as their preparation and biological activity, are demonstrated by the examples below, without limiting the claims to the examples.

Example 1

4-Methoxy-N- [6- (morpholin-4-yl) -4-benzylamino-3-cyanoquinolin-2-yl] benzamide

In the general formula (I), R ¹ and R ² are hydrogen atoms, R ³ is a phenyl group, and.) Is a morpholino group, R ⁶ is a 4-methoxy group, X is —NH— and n is 1.

a.) 2-Nitro-5- (morpholin-4-yl) benzoic acid.

A mixture of 5 g of 2-nitro-5-chlorobenzoic acid and 15 ml of morpholine is stirred at 120 ° C for 6 hours. 150 ml of ethyl acetate are added to the reaction mixture. The precipitated yellow crystalline substance is filtered off and dissolved in 15 ml of water. The pH of the mixture was adjusted to 6 with acetic acid. The precipitated material was filtered off, washed with water and dried, yielding 4.2 g of the title compound. Mp: 172 ° C.

¹ H-NMR (DMSO-d ₆ ) 7.85 ppm (m, 1H), 7.0-6.9 (m, 2H), 3.67 (m, 4H), 2.85 (m, 4H).

b.) 2-amino-5- (morpholin-4-yl) benzoic acid.

A mixture of 6 g of 2-nitro-5- (morpholin-4-yl) benzoic acid, 15 ml of cyclohexene and 3 g of Pd / C (10%) is heated under reflux in 120 ml of ethanol for 6 hours. The hot reaction mixture is filtered through a celite filter. The filtrate was evaporated, yielding 4.8 g of the title compound. Mp: 242 ° C.

¹ H-NMR (DMSO-d ₆ ) 7.25 ppm (m, 1H), 6.96 (m, 1H), 6.62 (m, 1H), 3.69 (m, 4H), 2.85 (m, 4H).

C.) 5- (Morpholin-4-yl) isatoic anhydride.

To a mixture of 8.9 g of 2-amino-5- (morpholin-4-yl) benzoic acid in 60 ml of dioxane, 10 ml of diphosgene are added dropwise with stirring and external cooling with cold water. The mixture was heated under reflux for 4 hours. From the cooled reaction mixture, the solid is filtered off and washed with 50 ml of ether. The product is stirred for 5 minutes in a mixture of 50 ml of methanol and 5 ml of triethylamine, filtered and washed with 30 ml of methanol. After drying, 7 g of the title product are obtained, mp: 235 ° C.

¹ H-NMR (DMSO-d ₆ ) 7.8 ppm (m, 1H), 6.78 (m, 1H), 6.66 (m, 1H), 3.73 (m, 4H), 2.92 (m, 4H).

d.) 2-amino-3-cyano-4-hydroxy-6- (morpholin-4-yl) quinoline.

4 g of Malononitrile is dissolved in 50 ml of dimethylformamide. To the solution, 2.4 g of a 60% sodium hydride oil dispersion are added in several portions. To a clear solution was added 8 g of 5- (morpholin-4-yl) isatoic anhydride and the mixture was stirred at room temperature for 10 hours. The reaction mixture was diluted with 70 ml of water and extracted with 2 × 30 ml of ethyl acetate. The aqueous phase is evaporated in vacuo, the solid residue is dissolved in 20 ml of water, and the pH is adjusted to 6 with acetic acid. The precipitated substance is filtered off and washed with water. After drying, 6.5 g of the title compound are obtained, mp: 291 ° C.

¹ H-NMR (DMSO-d ₆ ) 7.27 ppm (m, 1H), 7.14 (m, 1H), 7.03 (m, 1H), 3.74 (m, 4H), 3.12 (m, 4H).

e.) 2-amino-3-cyano-4-chloro-6- (morpholin-4-yl) quinoline.

A mixture of 1.7 g of 2-amino-3-cyano-4-hydroxy-6- (morpholin-4-yl) quinoline and 3.4 ml of phosphoryl chloride was stirred at 120 ° C. for 4 hours. The cooled reaction mixture was poured onto 30 g of ice, the mixture was adjusted to pH 8 with a 10% sodium hydroxide solution, and the precipitated substance was filtered off. After drying, 1.5 g of the title compound are obtained, mp: 206 ° C.

¹ H-NMR (DMSO-d ₆ ) 7.69 ppm (m, 1H), 7.49 (m, 1H), 7.08 (m, 1H), 6.83 (s, 2H), 3.74 (m, 4H), 3.08 (m, 4H) .

f.) 2-amino-3-cyano-4-benzylamino-6- (morpholin-4-yl) quinoline.

3 g of 2-amino-3-cyano-4-chloro-6- (morpholin-4-yl) quinoline and 6 ml of benzylamine are stirred at 125 ° C. for 3 hours. The reaction mixture was poured into 30 ml of water. The precipitated substance is filtered off and washed with 20 ml of water. After drying, 2.3 g of the title compound are obtained, mp: 202 ° C.

¹ H-NMR (DMSO-d ₆ ) 8.14 ppm (m, 1H), 7.5-7.2 (m, 8H), 5.85 (s, 2H), 5.04 (d, 2H), 3.65 (m, 4H), 3.1 ( m, 4H).

g.) 4-Methoxy-N- (4-methoxybenzoyl) -N- (6- (morpholin-4-yl) -4-benzylamino-3-cyanoquinolin-2-yl) benzamide.

To a solution of 0.4 g of 2-amino-3-cyano-4-benzylamino-6- (morpholin-4-yl) quinoline in 2 ml of pyridine, 0.4 ml of 4-methoxybenzoyl chloride was added with stirring and cooling. The reaction mixture was stirred at 80 ° C for 8 hours and then poured into 5 ml of ice water. The precipitated substance is filtered off and washed twice with 3 ml of water. After drying, 0.53 g of the title compound is obtained, mp: 157 ° C.

¹ H-NMR (DMSO-d ₆ ) 8.92 ppm (t, 1H), 8.32 (m, 4H), 7.61 (m, 3H), 7.38 (m, 5H), 7.12 (m, 4H), 5.1 (d, 2H) 3.82 (m, 8H).

h.) 4-Methoxy-N - [(b-morpholin-4-yl) -4-benzylamino-3-cyanoquinolin-2-yl] benzamide.

To a solution of 2.3 g of 4-methoxy-N- (4-methoxybenzoyl) -N- (6-morpholin-4-yl) -4-benzylamino-3-cyanoquinolin-2-yl) benzylamide in 20 ml of acetonitrile, 5 ml 1 n potassium hydroxide methanol solution. The reaction mixture is heated under reflux for 10 minutes, 1.5 ml of glacial acetic acid are added and then 15 ml of a 1 M sodium hydrogen carbonate solution are neutralized. The precipitate was filtered off and the yellow crystalline solid was recrystallized from a mixture of 5 ml of dimethylformamide and 40 ml of ethanol. After drying, 1.3 g of the title compound are obtained, mp: 260 ° C.

¹ H-NMR (DMSO-d ₆ ) 10.5 ppm (s, 1H), 8.92 (t, 1H), 8.4 (m, 2H), 7.66 (m, 3H), 7.35 (m, 5H), 7.05 (, 2H), 5.1 (d, 2H); 3.82 (m, 8H).

Example 2

4-Methoxy-N- [6- (4-methylpiperazin-1-yl) -4-benzylamino-3-cyanoquinolin-2-yl] benzamide

In the general formula (I), R ¹ and R ² are hydrogen atoms, R ³ is a phenyl group, and.) Is a 4-methylpiperazine -! - group, R ⁶ is a methoxyphenyl group, X is —NH— and n is 1.

a.) 2-Nitro-5- (4-methylpiperazin-1-yl) benzoic acid.

A mixture of 10 g of 2-nitro-5-chlorobenzoic acid and 30 ml of N-methylpiperazine was stirred at 120 ° C for 6 hours. 150 ml of ethyl acetate are added to the reaction mixture. The precipitated yellow crystalline substance is filtered off and dissolved in 15 ml of water. The mixture was adjusted to pH 6 with acetic acid. The precipitated material was filtered off, washed with water and dried, yielding 11.2 g of the title compound. Mp: 212 ° C.

¹ H-NMR (DMSO-d ₆ ) 7.89 ppm (d, 1H), 7.03-6.93 (m, 2H), 3.7-3.45 (m, 8H), 2.25 (s, 3H).

b.) 2-amino-5- (4-methylpiperazin-1-yl) benzoic acid.

A mixture of 9 g of 2-nitro-5- (4-methylpiperazino) benzoic acid, 20 ml of cyclohexene and 3.5 g of Pd / C (10%) is heated at reflux in 120 ml of ethanol for 6 hours. The hot reaction mixture is filtered through a celite filter. The filtrate was evaporated, yielding 3.5 g of the title compound. Mp: 212 ° C.

¹ H-NMR (DMSO-d ₆ ) 7.19 ppm (d, 1H), 7.06 (m, 1H), 6.69 (d, 1H), 2.9 (m, 4H), 2.43 (m, 4H), 2.22 (s, 3H) .

C.) 5- (4-Methylpiperazin-1-yl) isatoic anhydride.

To a mixture of 5.3 g of 2-amino-5- (4-methylpiperazino) benzoic acid in 30 ml of dioxane, 6 ml of diphosgene are added dropwise with stirring and external cooling with cold water. The mixture was heated under reflux for 4 hours. A solid is filtered off from the cold reaction mixture and washed with 50 ml of ether. The product is stirred for 5 minutes in a mixture of 50 ml of methanol and 5 ml of triethylamine, filtered and washed with 30 ml of methanol. After drying, 5.4 g of the title compound are obtained, mp: 285 ° C.

¹ H-NMR (DMSO-d ₆ ) 7.81 ppm (m, 1H), 6.73 (m, 1H), 6.62 (m, 1H), 3.73-2.92 (m, 8H), 2.23 (s, 3H).

d.) 2-amino-3-cyano-4-hydroxy-6- (4-methylpiperazin-1-yl) quinoline.

2 g of Malononitrile is dissolved in 30 ml of dimethylformamide. To the solution, 1.3 g of a 60% sodium hydride oil dispersion was added in several portions. 6.5 g of 5- (4-methylpiperazino) isatoic acid anhydride was added to the clear solution, and the mixture was stirred at room temperature for 10 hours. The reaction mixture was diluted with 70 ml of water and extracted with 2 × 30 ml of ethyl acetate. The aqueous phase is evaporated in vacuo, the solid residue is dissolved in 20 ml of water and the pH is adjusted to 6 with acetic acid. The precipitated substance is filtered off and washed with water. After drying, 5.2 g of the title compound are obtained, mp: 156 ° C.

¹ H-NMR (DMSO-d ₆ ) 7.23 ppm (m, 1H), 7.12 (m, 1H), 7.03 (m, 1H), 3.65-2.83 (m, 8H), 2.1 (s, 3H).

e.) 2-amino-3-cyano-4-chloro-6- (4-methylpiperazin-1-yl) quinoline.

A mixture of 2 g of 2-amino-3-cyano-4-hydroxy-6- (4-methylpiperazino) quinoline and 4 ml of phosphoryl chloride was stirred at 120 ° C. for 4 hours. The cooled reaction mixture was poured onto 40 g of ice, the pH of the mixture was adjusted to 8 with 10% sodium hydroxide solution and the precipitated substance was filtered off. After drying, 1.5 g of the title compound are obtained, mp: 189 ° C.

¹ H-NMR (DMSO-d ₆ ) 7.69 ppm (m, 1H), 7.49 (m, 1H), 7.08 (m, 1H), 6.83 (s, 2H), 3.25-2.57 (m, 8H), 2.29 ( s, 3H).

f.) 2-amino-3-cyano-4-benzylamino-6- (4-methylpiperazin-1-yl) quinoline.

3 g of 2-amino-3-cyano-4-chloro-6- (4-methylpiperazino) quinoline and 6 ml of benzylamine are stirred at 125 ° C. for 3 hours. The reaction mixture was poured into 30 ml of water. The precipitated substance is filtered off and washed with 20 ml of water. After drying, 2.3 g of the title compound are obtained, mp: 176 ° C.

¹ H-NMR (DMSO-d ₆ ) 8.5 ppm (t, 1H), 7.5-7.15 (m, 8H), 5.85 (s, 2H), 5.04 (d, 2H), 3.65-3.12 (m, 8H), 2.23 (s, 3H).

g.) 4-Methoxy-N- (4-methoxybenzoyl) -N- [6- (4-methylpiperazin-1-yl) -4-benzylamino-3-cyanoquinolin-2-yl] benzamide.

To a solution of 0.6 g of 2-amino-3-cyano-4-benzylamino-6- (4-methylpiperazino) quinoline in 2 ml of pyridine, 0.6 ml of 4-methoxybenzoyl chloride was added with stirring and cooling. The reaction mixture was stirred at 80 ° C for 8 hours and then poured into 5 ml of ice water. The precipitated substance is filtered off and washed twice with 3 ml of water. After drying, 0.63 g of the title compound is obtained, mp: 176 ° C.

¹ H-NMR (DMSO-d ₆ ) 8.39 ppm (m, 1H), 7.95 (m, 2H), 7.47 (m, 5H), 7.32 (m, 5H), 7.14 (m, 4H), 5.1 (m, 2H) 3.82 (s, 3H); 3.52-2.98 (m, 8H); 2.25 (s, 3H).

h.) 4-Methoxy-N- [6- (4-methylpiperazin-1-yl) -4-benzylamino-3-cyanoquinolin-2-yl] benzamide.

To a solution of 2.3 g of 4-methoxy-N- (4-methoxybenzoyl) -N- (6- (4-methylpiperazino) -4-benzylamino-3-cyanoquinolin-2-yl) benzamide in 15 ml of acetonitrile was added 4 ml of 1N . potassium hydroxide methanol solution. The reaction mixture is heated under reflux for 10 minutes, 1 ml of glacial acetic acid is added, and then 12 ml of a 1M sodium hydrogen carbonate solution are neutralized. The precipitate was filtered off, the yellow crystalline solid was recrystallized from a mixture of 15 ml of methanol and 35 ml of water. After drying, 1.1 g of the title compound are obtained, mp. 173 ° C.

¹ H-NMR (DMSO-d ₆ ) 10.53 ppm (m, 1H), 8.39 (m, 1H), 7.95 (m, 2H), 7.57 (m, 3H), 7.34 (m, 5H), 7.04 (m, 2H) 5.1 (m, 2H); 3.82 (s, 3H); 3.52-2.98 (m, 8H); 2.25 (s, 3H).

Example 3

4-Methoxy-N- (6-dimethylamino-4-benzylamino-3-cyanoquinolin-2-yl) benzamide

In the general formula (I), R ¹ and R ² are hydrogen atoms, R ³ is a phenyl group, R ⁴ and R ⁵ are methyl groups, R ⁶ is a 4-methoxyphenyl group, X is —NH— and n is 1.

A.) 2-Nitro-5-dimethylaminobenzoic acid.

A mixture of 5 g of 2-nitro-5-chlorobenzoic acid and 15 ml of a 60% aqueous solution of dimethylamine is stirred at 100 ° C. for 6 hours. The reaction mixture was evaporated and the residue was dissolved in 15 ml of water. The pH of the mixture was adjusted to 6 with acetic acid. The precipitated yellow crystalline solid was filtered off, washed with water and dried, yielding 3.4 g of the title compound. Mp: 189 ° C.

¹ H-NMR (DMSO-d ₆ ) 7.78 ppm (d, 1H), 6.59 (m, 1H), 6.48 (m, 1H), 3.0 (s, 6H).

b.) 2-amino-5-dimethylaminobenzoic acid.

A mixture of 2.1 g of 2-nitro-5-dimethylaminobenzoic acid, 7 ml of cyclohexene and 1.5 g of Pd / C (10%) is heated under reflux in 60 ml of ethanol for 6 hours. The hot reaction mixture is filtered through a celite filter. The filtrate was evaporated to give 1.1 g of the title compound. Mp: 232 ° C.

¹ H-NMR (DMSO-d ₆ ) 7.01 ppm (m, 1H), 6.84 (m, 1H), 6.78 (m, 1H), 2.88 (s, 6H).

c.) 5-Dimethylaminoisoyl anhydride.

To a mixture of 8.9 g of 2-amino-5-dimethylaminobenzoic acid in 60 ml of dioxane, 10 ml of diphosgene are added dropwise with stirring and external cooling with cold water. The mixture was heated under reflux for 4 hours. From the cold reaction mixture, the solid is filtered off and washed with 50 ml of ether. The product is stirred for 5 minutes in a mixture of 50 ml of methanol and 5 ml of triethylamine, filtered and washed with 30 ml of methanol. After drying, 7 g of the title product are obtained. Mp: 258 ° C.

¹ H-NMR (DMSO-d ₆ ) 7.56 ppm (m, 1H), 7.42 (m, 1H), 7.13 (m, 1H), 2.97 (s, 6H).

d.) 2-amino-3-cyano-4-hydroxy-6-dimethylaminoquinoline.

To a solution of 4 g of malononitrile in 50 ml of dimethylformamide, 2.4 g of a 60% sodium hydride oil dispersion are added in several portions. 8 g of 5-dimethylaminoisatoic acid anhydride was added to the clear solution, and the mixture was stirred at room temperature for 10 hours. The mixture was diluted with 70 ml of water and extracted with 2 × 30 ml of ethyl acetate. The aqueous phase is evaporated in vacuo, the solid residue is dissolved in 20 ml of water and the pH is adjusted to 6 with acetic acid. The precipitated substance is filtered off and washed with water. After drying, 6.5 g of the title compound are obtained, mp: 360 ° C.

¹ H-NMR (DMSO-d ₆ ) 7.43 ppm (m, 1H), 7.23 (m, 1H), 7.11 (m, 1H), 2.95 (s, 6H).

e.) 2-amino-3-cyano-4-chloro-6-dimethylaminoquinoline.

A mixture of 1.7 g of 2-amino-3-cyano-4-hydroxy-6-dimethylaminoquinoline and 3.4 ml of phosphoryl chloride was stirred at 120 ° C. for 4 hours. The cooled reaction mixture was poured onto 30 g of ice, the mixture was adjusted to pH 8 with 10% sodium hydroxide solution and the precipitated substance was filtered off. After drying, 1.5 g of the title compound was obtained, mp: 285 ° C.

¹ H-NMR (DMSO-d ₆ ) 7.43 ppm (mm, 1H), 7.21 (m, 1H), 7.05 (m, 1H), 6.75 (s, 2H), 2.99 (s, 6H).

f.) 2-amino-3-cyano-4-benzylamino-6-dimethylaminoquinoline.

3 g of 2-amino-3-cyano-4-chloro-6-dimethylaminoquinoline and 6 ml of benzylamine are stirred at 125 ° C. for 3 hours. The reaction mixture was poured into 30 ml of water. The precipitated substance is filtered off and washed with 20 ml of water. After drying, 2.3 g of the title compound are obtained, mp: 265 ° C.

¹ H-NMR (DMSO-d ₆ ) 8.55-8.45 ppm (m, 2H), 7.8 (m, 1H), 7.5-7.23 (m, 7H), 6.25 (s, 2H), 5.08 (d, 2H), 2.99 ( s, 6H).

g.) 4-Methoxy-N- (4-methoxybenzoyl) -N- (6-dimethylamino-4-benzylamino-3-cyanoquinolin-2-yl) benzamide.

To a solution of 0.4 g of 2-amino-3-cyano-4-benzylamino-6-dimethylaminoquinoline in 2 ml of pyridine, 0.4 ml of 4-methoxybenzoyl chloride was added with stirring and cooling. The reaction mixture was stirred at 80 ° C for 8 hours and then poured into 5 ml of ice water. The precipitated substance is filtered off and washed twice with 3 ml of water. After drying, 0.53 g of the title compound is obtained, mp: 156 ° C.

¹ H-NMR (DMSO-d ₆ ) 8.35 ppm (m, 1H), 7.9 (m, 2H), 7.47 (m, 5H), 7.3 (m, 5H), 7.1 (m, 4H), 5.12 (m, 2H) 3.82 (s, 3H); 3.0 (s, 6H).

h.) 4-Methoxy-N- (6-dimethylamino-4-benzylamino-3-cyanoquinolin-2-yl) benzylamide.

To a solution of 2.3 g of 4-methoxy-N- (4-methoxybenzoyl) -N- (6-dimethylamino-4-benzylamino-3-cyanoquinolin-2-yl) benzamide in 20 ml of acetonitrile was added 5 ml of 1N. potassium hydroxide methanol solution. The reaction mixture was heated under reflux for 10 minutes, 1.5 ml of glacial acetic acid was added, and then 15 ml of a 1M sodium hydrogen carbonate solution was neutralized. The precipitate was filtered off, the yellow crystalline solid was recrystallized from a mixture of 5 ml of dimethylformamide and 40 ml of ethanol. After drying, 1.3 g of the title compound are obtained, mp: 185 ° C.

¹ H-NMR (DMSO-d ₆ ) 10.5 ppm (m, 1H), 8.35 (m, 1H), 7.91 (m, 2H), 7.53 (m, 3H), 7.3 (m, 5H), 7.02 (m, 2H) 5.1 (m, 2H); 3.85 (s, 3H); 3.0 (s, 6H).

Example 4

4-Methoxy-N- (6-dimethylamino-4- [2-furylmethylamino] -3-cyanoquinolin-2-yl) benzamide

In the general formula (I), R ¹ and R ² are hydrogen atoms, R ³ is a 2-furylamino group, R ⁴ and R ⁵ are methyl groups, R ⁶ is a 4-methoxyphenyl group, X is —NH— and n is 1.

a.) 2-amino-3-cyano-4- [2-furylmethylamino] -6-dimethylaminoquinoline.

3 g of 2-amino-3-cyano-4-chloro-6-dimethylaminoquinoline and 6 ml of furylamine are stirred at 125 ° C. for 3 hours. The reaction mixture was poured into 30 ml of water. The precipitated substance is filtered off and washed with 20 ml of water. After drying, 2.05 g of the title compound is obtained, mp: 235 ° C.

¹ H-NMR (DMSO-d ₆ ) 8.7 ppm (m, 1H), 7.6 (m, 1H), 7.35-7.23 (m, 3H), 6.8 (s, 2H), 6.4 (m, 2H), 5.06 ( d, 2H), 2.96 (s, 6H).

b.) 4-Methoxy-N- (4-methoxybenzoyl) -N- (6-dimethylamino-4- [2-furylmethylamino] -3-cyanoquinolin-2-yl) benzamide.

To a solution of 0.4 g of 2-amino-3-cyano-4- [2-furylmethylamino] -6-dimethylaminoquinoline in 2 ml of pyridine, 0.4 ml of 4-methoxybenzoyl chloride was added with stirring and cooling. The reaction mixture was stirred at 80 ° C for 8 hours and then poured into 5 ml of ice water. The precipitated substance is filtered off and washed twice with 3 ml of water. After drying, 0.5 g of the title compound is obtained, mp: 143 ° C.

¹ H-NMR (DMSO-d ₆ ) 8.35 ppm (m, 1H), 7.9-7.1 (m, 14H), 5.12 (m, 2H), 3.82 (s, 6H), 3.0 (s, 6H).

c.) 4-Methoxy-N- (6-dimethylamino-4- [2-furylmethylamino] -3-cyanoquinolin-2-yl) benzylamide.

To a solution of 2.3 g of 4-methoxy-N- (4-methoxybenzoyl) -N- (6-dimethylamino-4- [2-furylmethylamino] -3-cyanoquinolin-2-yl) benzamide in 20 ml of acetonitrile was added 5 ml of 1N . potassium hydroxide methanol solution. The reaction mixture was heated under reflux for 10 minutes, 1.5 ml of glacial acetic acid was added, and then 15 ml of a 1M sodium hydrogen carbonate solution was neutralized. The precipitate was filtered off, the yellow crystalline solid was recrystallized from a mixture of 5 ml of dimethylformamide and 40 ml of ethanol. After drying, 1.1 g of the title compound are obtained, mp: 195 ° C.

¹ H-NMR (DMSO-d ₆ ) 10.5 ppm (m, 1H), 8.25 (t, 1H), 7.98 (m, 2H), 7.63-7.03 (m, 7H), 6.42 (d, 1H), 5.04 ( d, 2H), 3.85 (s, 3H), 3.05 (s, 6H).

Example 5

4-Methoxy-N- (6-dimethylamino-4- [2-thienylmethylamino] -3-cyanoquinolin-2-yl) benzamide

In the general formula (I), R ¹ and R ² are hydrogen atoms, R ³ is a 2-thienyl group, R ⁴ and R ⁵ are methyl groups, R ⁶ is a 4-methoxyphenyl group, X is —NH— and n is 1.

a.) 2-amino-3-cyano-4- [2-thienylmethylamino] -6-dimethylaminoquinoline.

3 g of 2-amino-3-cyano-4-chloro-6-dimethylaminoquinoline and 6 ml of 2-thienylmethylamine are stirred at 125 ° C. for 3 hours. The reaction mixture was poured into 30 ml of water. The precipitated substance is filtered off and washed with 20 ml of water. After drying, 1.9 g of the title compound are obtained, mp: 211 ° C.

¹ H-NMR (DMSO-d ₆ ) 8.2 ppm (m, 1H), 7.46-6.95 (m, 6H), 6.08 (s, 2H), 5.18 (d, 2H), 2.94 (s, 6H).

b.) 4-Methoxy-N- (4-methoxybenzoyl) -N- (6-dimethylamino-4- [2-thienylmethylamino] -3-cyanoquinolin-2-yl) benzamide.

To a solution of 0.4 g of 2-amino-3-cyano-4- [2-thienylmethylamino] -6-dimethylaminoquinoline in 2 ml of pyridine, 0.4 ml of 4-methoxybenzoyl chloride was added with stirring and cooling. The reaction mixture was stirred at 80 ° C for 8 hours and then poured into 5 ml of ice water. The precipitated substance is filtered off and washed twice with 3 ml of water. After drying, 0.43 g of the title compound is obtained, mp: 171 ° C.

¹ H-NMR (DMSO-d ₆ ) 8.35 ppm (m, 1H), 7.9-7.05 (m, 14H), 5.12 (m, 2H), 3.82 (s, 6H), 3.0 (s, 6H).

c.) 4-Methoxy-N- (6-dimethylamino-4- [2-thienylmethylamino] -3-cyanoquinolin-2-yl) benzylamide.

To a solution of 2.3 g of 4-methoxy-N- (4-methoxybenzoyl) -N- (6-dimethylamino-4- [2-thienylmethylamino] -3-cyanoquinolin-2-yl) benzamide in 20 ml of acetonitrile was added 5 ml of 1N . potassium hydroxide methanol solution. The reaction mixture was heated under reflux for 10 minutes, 1.5 ml of glacial acetic acid was added, and then 15 ml of a 1M sodium hydrogen carbonate solution was neutralized. The precipitate was filtered off, the yellow crystalline solid was recrystallized from a mixture of 5 ml of dimethylformamide and 40 ml of ethanol. After drying, 1.15 g of the title compound is obtained, mp: 163 ° C.

¹ H-NMR (DMSO-d ₆ ) 10.5 ppm (m, 1H), 8.3 (t, 1H), 7.98 (m, 2H), 7.63-6.96 (m, 8H), 5.2 (d, 2H), 3.85 ( s, 3H), 3.05 (s, 6H).

Example 6

4-Methoxy-N- [6- (piperazin-1-yl) -4-benzylamino-3-cyanoquinolin-2-yl] benzamide

In the general formula (I), R ¹ and R ² are hydrogen atoms, R ³ is a phenyl group, group a.) Is a piperazino group, R ⁶ is a 4-methoxyphenyl group, X is —NH— and n is 1.

a.) 2-Nitro-5- (4-benzylpiperazin-1-yl) benzoic acid.

A mixture of 20 g of 2-nitro-5-chlorobenzoic acid and 50 ml of N-benzylpiperazine is stirred at 120 ° C. for 6 hours. 250 ml of ethyl acetate are added to the reaction mixture. The precipitated yellow crystalline substance is filtered off and dissolved in 200 ml of water. The pH of the mixture was adjusted to 6 with acetic acid. The precipitated material was filtered off and washed with water to obtain 30 g of the title compound. Mp: 172 ° C.

¹ H-NMR (DMSO-d ₆ ) 7.8-6.7 ppm (m, 8H), 3.5 (s, 2H), 3.5-2.8 (m, 8H).

b.) 2-amino-5- (4-benzylpiperazin-1-yl) benzoic acid.

A mixture of 6 g of 2-nitro-5- (4-benzylpiperazin-1-yl) benzoic acid, 15 ml of cyclohexene and 3 g of Pd / C (10%) is heated at reflux in 120 ml of ethanol for 6 hours . The hot reaction mixture is filtered through a celite filter. The filtrate was evaporated in vacuo to give 4.8 g of the title compound. Mp: 242 ° C.

¹ H-NMR (DMSO-d ₆ ) 7.5-6.8 ppm (m, 8H), 3.68 (s, 3H), 3.5-2.95 (m, 8H).

C.) 5- (4-Benzylpiperazin-1-yl) isatoic anhydride.

To a mixture of 15 g of 2-amino-5- (4-benzylpiperazin-1-yl) benzoic acid in 90 ml of dioxane, 12.7 ml of diphosgene are added dropwise with stirring and external cooling with cold water. The mixture was heated under reflux for 4 hours. From the cold reaction mixture, the solid is filtered off and washed with 120 ml of ether. The product is stirred for 5 minutes in a mixture of 100 ml of methanol and 10 ml of triethylamine, filtered and washed with 50 ml of methanol. After drying, 17 g of the title compound are obtained, mp: 235 ° C.

¹ H NMR (DMSO-d ₆₎ ppm: 7,68-7,1 (m, 8H), 3.6 (s, 2H), 3.5-2.5 (m, 8H).

d.) 2-amino-3-cyano-4-hydroxy-6- (4-benzylpiperazin-1-yl) quinoline.

6.1 g of Malononitrile is dissolved in 100 ml of dimethylformamide. 3.6 g of a 60% sodium hydride oil dispersion is added in portions to the solution in several portions. To the clear solution was added 18 g of 5- (4-benzylpiperazin-1-yl) isatoic acid anhydride and the mixture was stirred at room temperature for 10 hours. The reaction mixture was diluted with 100 ml of water and extracted with 2 × 50 ml of ethyl acetate. The aqueous phase is evaporated in vacuo, the solid residue is dissolved in 50 ml of water, the pH is adjusted to 6 with acetic acid and refluxed for 5 hours. After cooling, the precipitated substance is filtered off and washed with water. After drying, 14.3 g of the title compound are obtained, mp: 291 ° C.

¹ H-NMR (DMSO-d ₆ ) 7.7-6.5 ppm (m, 10H), 4.2 (s, 2H), 3.5-2.5 (m, 8H).

e.) 2-amino-3-cyano-4-chloro-6- (4-benzylpiperazin-1-yl) quinoline.

A mixture of 14 g of 2-amino-3-cyano-4-hydroxy-6- (4-benzylpiperazin-1-yl) quinoline and 28 ml of phosphoryl chloride was stirred at 120 ° C. for 6 hours. The cooled reaction mixture was poured onto 500 g of ice, the pH of the mixture was adjusted to 8 with 10% sodium hydroxide solution and the precipitated substance was filtered off. After drying, 14.5 g of the title compound are obtained, mp: 206 ° C.

¹ H-NMR (DMSO-d ₆₎ ppm: 7,7-7,14 (m, 8H), 6.9 (s, 2H), 3.7 (s, 2H), 3.5-2.5 (m, 8H).

f.) 2-amino-3-cyano-4-benzylamino-6- (4-benzylpiperazin-1-yl) quinoline.

14 g of 2-amino-3-cyano-4-chloro-6- (4-benzylpiperazin-1-yl) quinoline and 28 ml of benzylamine are stirred at 125 ° C. for 4 hours. The reaction mixture was poured into 100 ml of water. The precipitated substance is filtered off and washed with 2 × 50 ml of water. After drying, 8 g of the title compound are obtained, mp: 202 ° C.

¹ H-NMR (DMSO-d ₆ ) 8.1 ppm (m, 1H), 7.5-7.2 (m, 13H), 5.8 (s, 2H), 5.0 (d, 2H), 3.54 (s, 2H), 5.5- 2.5 (m, 8H).

g.) 4-Methoxy-N- (4-methoxybenzoyl) -N- (6- (4-benzylpiperazin-1-yl) -4-benzylamino-3-cyanoquinolin-2-yl) benzamide.

To a solution of 0.9 g of 2-amino-3-cyano-4-benzylamino-6- (4-benzylpiperazin-1-yl) quinoline in 5 ml of ethyl acetate containing 0.3 ml of triethylamine, 0.5 was added with stirring and cooling. ml of 4-methoxybenzoyl chloride. The reaction mixture was stirred at 80 ° C for 8 hours and then poured into 10 ml of ice water. The precipitated substance is filtered off and washed twice with 3 ml of water. After drying, 0.53 g of the title compound is obtained, mp: 157 ° C.

¹ H-NMR (DMSO-d ₆ ) 8.92 ppm (t, 1H), 8.32 (m, 4H), 7.61 (m, 3H), 7.38 (m, 5H), 7.12 (m, 4H), 5.1 (d, 2H) 3.82 (s, 6H); 3.56 (s, 2H); 3.25-2.5 (m, 8H).

h.) 4-Methoxy-N - [(6- (4-benzylpiperazin-1-yl) -4-benzylamino-3-cyanoquinolin-2-yl] benzylamide.

To a solution of 2.0 g of 4-methoxy-N- (4-methoxybenzoyl) -N- (6- (4-benzylpiperazin-1-yl) -4-benzylamino-3-cyanoquinolin-2-yl) benzamide in 20 ml of acetonitrile add 4 ml of 1N. potassium hydroxide methanol solution. The reaction mixture was heated under reflux for 10 minutes, 1.5 ml of glacial acetic acid was added, and then 15 ml of a 1M sodium hydrogen carbonate solution was neutralized. The precipitate was filtered off, the yellow crystalline solid was recrystallized from a mixture of 5 ml of dimethylformamide and 40 ml of ethanol. After drying, 1.3 g of the title compound are obtained, mp: 260 ° C.

¹ H-NMR (DMSO-d ₆ ) 10.5 ppm (s, 1H), 8.92 (t, 1H), 7.97-7.01 (m, 17H), 5.1 (d, 2H), 3.82 (s, 3H), 3.56 ( s, 2H), 3.5-2.5 (m, 8H).

i.) 4-Methoxy-N - [(6- (piperazin-1-yl) -4-benzylamino-3-cyanoquinolin-2-yl] benzamide.

1 g of 4-Methoxy-N - [(6- (4-benzylpiperazin-1-yl) -4-benzylamino-3-cyanoquinolin-2-yl] benzamide is dissolved in dimethylformamide and water containing 0.5 ml of acetic acid, and hydrogenated in the presence of 50 mg Pd / C (10%) for 4 hours at 45 ° C. After filtering off the catalyst and evaporating the solvent, the crude product was purified by chromatography to give 0.65 g of the title compound, mp: 145 ° C.

¹ H-NMR (DMSO-d ₆ ) 10.5 ppm (s, 1H), 8.48 (m, 1H), 7.94 (m, 2H), 7.6-7.35 (m, 2H), 7.33 (s, 5H), 7.24 ( m, 1H), 7.02 (m, 2H), 5.08 (d, 2H), 3.83 (s, 3H), 3.22 (m, 4H), 2.86 (m, 4H).

Example 7

N- [6-amino-4- (benzylamino) -3-cyanoquinolin-2-yl] -4-methoxybenzamide

In the general formula (I), R ¹ and R ² are hydrogen atoms, R ³ is a phenyl group, NR ⁴ R ⁵ is NH ₂ , R ⁶ is a 4-methoxyphenyl group, X is —NH— and n is 1.

a.) 5-Nitroisoyl anhydride.

To a mixture of 37 g of 2-amino-5-nitrobenzoic acid in 500 ml of dioxane, 24.5 ml of diphosgene are added dropwise with stirring. The mixture is heated at the boil under reflux for 6 hours and then evaporated to dryness. The residue was suspended in 100 ml of ether and filtered off, yielding 41.4 g of the title compound as an HCl salt, mp: 256-259 ° C. LC-MS: MH ⁺ 209; retention time: 5.00 min.

¹ H-NMR (DMSO-d ₆ ) 8.54 (d, 1H), 8.46 (dd, 1H), 7.37 (d, 1H) ppm.

b.) 2-amino-3-cyano-4-hydroxy-6-nitroquinoline.

To a solution of 47.25 g of 5-nitroisoic anhydride in 230 ml of DMF was added 15 g of malononitrile and 63.3 ml of triethylamine, and the reaction mixture was stirred at 60 ° C for 2 hours. The solvent was evaporated under reduced pressure, the residue was mixed with 570 ml of acetonitrile and 114 ml of conc. HCl and the solution was stirred at room temperature overnight. The precipitate was then filtered off, washed with water and ethanol to obtain 49.7 g of product, mp:> 360 ° C. LC-MS: MH ⁺ 231; retention time: 4.78 min.

¹ H-NMR (DMSO-d ₆ ) 8.64 (d, 1H), 8.36 (dd, 1H), 7.6 (s, 2H), 7.55 (d, 1H) ppm.

C.) 2-amino-3-cyano-4-chloro-6-nitroquinoline.

A stirred mixture of 48.5 g of 2-amino-3-cyano-4-hydroxy-6-nitroquinoline and 550 ml of phosphoryl chloride is refluxed for 4 hours. The reaction mixture was concentrated to half its volume and the residue was poured onto 1500 g of ice. The yellow precipitate was filtered off, washed with water and 60.5 g of a solid were obtained. 25 g of the indicated solid are stirred at room temperature in 500 ml of 0.5N. HCl for 6 hours, then the precipitate is filtered off and washed with water to obtain 18.5 g of the product, mp:> 360 ° C. LC-MS: MH ⁺ 249; retention time: 5.94 min.

¹ H-NMR (DMSO-d ₆ ) 8.73 (d, 1H), 8.48 (dd, 1H), 7.92 (d, 1H) ppm.

d.) 2-amino-3-cyano-4-benzylamino-6-nitroquinoline.

A mixture of 7 g of 2-amino-3-cyano-4-chloro-6-nitroquinoline and 30 ml of benzylamine is stirred at 55 ° C. for 1.5 hours. The reaction mixture was poured into 30 ml of water. The precipitated substance is filtered off and washed with water to obtain 7 g of the title compound, mp: 280-283 ° C. LC-MS: MH ⁺ 2320; retention time: 5.19 minutes

¹ H-NMR (DMSO-d ₆ ): 9.28 (d, 1H), 8.90 (t, 1H), 8.24 (dd, 1H), 7.3 (m, 5H), 6.98 (s, 2H); 5.04 (d, 2H) ppm.

e.) 4-Methoxy-N- (4-methoxybenzoyl) -N- (4-benzylamino-3-cyano-6-nitroquinolin-2-yl) benzamide.

A suspension of 3.5 g of 2-amino-3-cyano-4-benzylamino-6-nitroquinoline in 50 ml of dry pyridine is refluxed with 5.6 g of 4-methoxybenzoyl chloride for 3.5 hours. The solvent was evaporated under reduced pressure, and the residue was suspended in 30 ml of a saturated solution of Na ₂ CO ₃ in water. The suspension is extracted with 3 × 25 ml of CH ₂ Cl ₂ . The combined organic extract was evaporated to dryness, the residue was dissolved in diethyl ether and the solution was kept in the refrigerator overnight. The precipitate was filtered off, washed with diethyl ether to give 6.25 g of the title compound, mp: 145-148 ° C. LC-MS: MH ⁺ 588; retention time: 7.00 min.

f.) N - [(4-benzylamino-3-cyano-6-nitroquinolin-2-yl] -4-methoxybenzylamide.

A suspension of 6.2 g of N- (4-methoxybenzoyl) -N- (4-benzylamino-3-cyano-6-nitroquinolin-2-yl) -4-methoxybenzamide in 75 ml of acetonitrile is refluxed with 25.2 ml of 1N . potassium hydroxide solution for 6 minutes 4.4 ml of glacial acetic acid was added dropwise to the hot solution, 56.3 ml of a 1M aqueous solution of NaHCO _{3 was} cooled and neutralized. The precipitate was filtered off and washed with water to obtain 4.1 g of the title compound, mp: 264-266 ° C.

¹ H-NMR (DMSO-d ₆ ) 10.9 (s, 1H), 9.55 (d, 1H), 9.28 (t, 1H), 8.77 (d, 1H), 8.48 ( dd, 1H), 8.00 (d, 2H), 7.90 (d, 1H), 7.4 (m, 4H), 7.29 (m, 1H), 7.05 (d, 2H), 5.12 (d, 2H); 3.84 (s, 3H) ppm.

g.) N- [6-amino-4- (benzylamino) -3-cyanoquinolin-2-yl] -4-methoxybenzamide.

A mixture of 320 ml of ethanol, 80 ml of water, 200 ml of THF, 7.6 g of Fe-powder and 1 ml of conc. HCl is refluxed for 10 minutes. Then 9 g of N - [(4-benzylamino-3-cyano-6-nitroquinolin-2-yl] -4-methoxybenzamide are added, the reaction mixture is refluxed vigorously for 2 hours and cooled to 35 ° C. The precipitate is filtered off and washed with a 1: 1 mixture of CH ₂ Cl ₂ and ethanol. The combined organic solution was filtered through activated carbon and evaporated to dryness. The residue was suspended in a mixture of 50 ml of water and 10 ml of ethanol, the solid was filtered and washed with water to obtain 6.65 g of the title compounds, mp: 228-230 ° C. LC-MS: MH ⁺ 424; retention time: 5.33 min.

¹ H-NMR (DMSO-d ₆ ) 10.44 (s, 1H), 8.0 (s + d, 3H), 7.50 (d, 1H), 7.3-7.1 (m, 7H ), 7.03 (d, 2H), 5.55 (s, 2H), 5.04 (d, 2H), 3.38 (d, 3H) ppm.

Example 8

N- {6-amino-4 - [(2-thienylmethyl) amino)] - 3-cyanoquinolin-2-yl} -4-methoxybenzamide

In the general formula (I), R ¹ and R ² are hydrogen atoms, R ^{3 is a} 2-thienyl group, NR ⁴ R ⁵ is NH ₂ , R ⁶ is a 4-methoxyphenyl group, X is —NH— and n is 1.

a) 2-amino-3-cyano-4- (2-thienylmethyl) amino-6-nitroquinoline.

Using a procedure similar to that described in example 7d with the change that instead of benzylamine, (2-thienylmethyl) amine is used, getting 7.1 g of the title compound, mp: 277-280 ° C. LC-MS: MH ⁺ 326; retention time: 5.25 minutes

b.) N- (4-Methoxybenzoyl) -N- [3-cyano-6-nitro-4- (2-thienylmethyl) aminoquinolin-2-yl] -4-methoxybenzamide.

Starting from 2-amino-3-cyano-4- (2-thienylmethyl) amino-6-nitroquinoline (3.6 g) and using a procedure similar to that described in Example 7e, 6.3 g of the title compound are obtained, i.e. pl .: 174-177 ° C. LC-MS: MH ⁺ 595; retention time: 7.16 minutes

c.) N- [3-Cyano-6-nitro-4- (2-thienylmethyl) aminoquinolin-2-yl] -4-methoxybenzamide.

Starting from N- (4-methoxybenzoyl) -N- [3-cyano-6-nitro-4- (2-thienylmethyl) amino] quinolin-2-yl) -4-methoxybenzamide (6.2 g) and using the procedure, Cited for Example 7f, 4.3 g of the title compound are obtained, mp: 217-220 ° C. LC-MS: MH ⁺ 460; retention time: 6.57 min.

¹ H NMR (DMSO-d _6): 11.0 (s, 1H), 9.50 (s, 1H), 9.29 (s, 1H), 8.48 (dd, 1H), 8.02 (d, 2H), 7.90 (d, 1H), 7.48 (dd, 1H), 7.21 (d, 1H), 7.0 (m, 3H), 5.27 (s, 2H) 3.85 (s, 3H) ppm.

d.) N- {6-amino-4 - [(2-thienylmethyl) amino] -3-cyanoquinolin-2-yl} -4-methoxybenzamide.

Starting from N- [4- (2-thienylmethyl) amino-3-cyano-6-nitroquinolin-2-yl] -4-methoxybenzamide (10 g) and using the procedure described for example 7g, 9.3 g of the title compound, mp: 200-203 ° C. LC-MS: MH ⁺ 430; retention time: 5.52 min.

¹ H-NMR (DMSO-d ₆ ) 10.48 (s, 1H), 7.98 (s + d, 3H), 7.50 (d, 1H), 7.41 (dd, 1H), 7, 21 (s, 1H), 7.16 (dd, 1H), 7.11 (d, 1H), 7.04 (d, 2H), 6.98 (dd, 1H), 5.45 (s, 2H) ), 5.18 (d, 2H), 3.84 (s, 3H) ppm.

Example 9

N- {4- (Benzylamino) -3-cyano-6- (methylamino) quinolin-2-yl} -4-methoxybenzamide

In the general formula (I), R ¹ and R ² are hydrogen atoms, R ³ is a phenyl group, R ⁴ is Me, R ⁵ is H and R ⁶ is a 4-methoxyphenyl group, X is —NH— and n is 1 .

A suspension of 1 g of N- {4- (benzylamino) -3-cyano-6-aminoquinolin-2-yl} -4-methoxybenzamide and 0.65 g of paraformaldehyde in a mixture of 48 ml of ethanol and 48 ml of CH ₂ Cl _{2 is} refluxed with 0.5 ml of a 54% solution of HBF ₄ in diethyl ether for 1.5 hours. After adding 0.3 g of NaBH _4, boiling under reflux was continued for another 1.5 hours, followed by the addition of an additional amount of 0.3 g of NaBH ₄ and boiling under reflux for 2 hours. After the addition of 0.25 ml of a 54% solution of HBF ₄ in diethyl ether and 0.3 g of NaBH _4, refluxing was continued for an additional 1.5 hours. The reaction mixture was filtered hot and the solid was washed with a 1: 1 mixture of CH ₂ Cl ₂ and ethanol. The combined organic solution was concentrated and the residue was chromatographed on silica gel with a 50: 1 mixture of CHCl ₃ and ethyl acetate to give a crude product. It was recrystallized from a 2: 1 mixture of ethanol and DMF to give 0.6 g of the title compound, mp: 237-240 ° C. LC-MS: MH ⁺ 438; retention time: 5.76 minutes

¹ H-NMR (DMSO-d ₆ ) 10.43 (s, 1H), 8.18 (t, 1H), 7.94 (d, 2H), 7.50 (d, 1H), 7.3- 7.0 (m, 9H), 6.24 (m, 1H), 5.08 (d, 2H), 3.83 (s, 3H), 2.83 (d, 3H) ppm.

Example 10

N- {3-Cyano-6- (formylamino) -4 - [(2-thienylmethyl) amino] quinolin-2-yl] -4-methoxybenzamide

In the general formula (I), R ¹ and R ² are hydrogen atoms, R ³ is a 2-thienyl group, R ⁴ is a hydrogen atom, R ⁵ is CHO and R ⁶ is a 4-methoxyphenyl group, X is —NH— and n is 1.

A suspension of 0.32 g of N- {6-amino-4 - [(2-thienylmethyl) amino] -3-cyanoquinolin-2-yl} -4-methoxybenzamide was maintained in 60 ml of methyl formate at 100 ° C in a closed apparatus (internal pressure : 10 bar) for 7 hours. After cooling, the solvent was evaporated and the residue was recrystallized from CH ₂ Cl ₂ / MeOH, to give 0.22 g of the title compound, mp: 223-226 ° C. LCMS: MH ⁺ 458; retention time: 5.71 minutes

Example 11

{4- (Benzylamino) -3-cyano-2 - [(4-methoxybenzoyl) amino] quinolin-6-yl} sulfamic acid

In the general formula (I), R ¹ and R ² are hydrogen atoms, R ³ is a phenyl group, R ⁴ is H, R ⁵ is SO ₂ OH and R ⁶ is a 4-methoxyphenyl group, X is —NH— and n equal to 1.

To a solution of 5.2 g of Na ₂ S ₂ CO ₄ (purity: 85%) in 160 ml of water and 200 ml of ethanol was added 20 ml of aqueous 1N. NaOH solution. The solution is heated to boiling, then 2.27 g of N - [(4-benzylamino-3-cyano-6-nitroquinolin-2-yl] -4-methoxybenzamide are added and refluxing is continued for 2 hours. The reaction mixture is left to stand at room temperature overnight and then concentrated to half its volume.The residue was alkalinized (pH = 8) by the addition of 1N NaOH and extracted with CH ₂ Cl _{2. The} aqueous solution was acidified to pH = 5 by the addition of conc. HCl solution and the precipitate was filtered off. the substance is chromatographed on silica gel, eluting first with a mixture of ethyl acetate / methanol / 25% ammonia = 220/30/2, and then 200/80/2, obtaining the title compound as an ammonium salt, mp: 220-222 ° C. LC-MS: MH ⁺ 504; retention time: 5.56 min.

¹ H-NMR (DMSO-d ₆ ) 10.48 (s, 1H), 8.21 (s, 1H), 8.09 (t, 1H), 7.95 (d, 2H), 7.70 ( s, 1H), 7.62 (d, 1H), 7.56 (d, 1H), 7.3 (m, 4H), 7.25 (m, 1H), 7.03 (d, 2H), 5.05 (d, 2H); 3.83 (s, 3H) ppm.

Example 12

{4- (Benzylamino) -3-cyano-2 - [(4-methoxybenzoyl) amino] quinolin-6-yl} methylsulfamic acid

In the general formula (I) R ¹ and R ² are hydrogen atoms, R ³ is a phenyl group, R ⁴ represents Me, R ⁵ represents a SO ₂ OH and R ⁶ is a 4-methoxyphenyl group, X is -NH- and n equal to 1.

A solution of 110 mg of N- {4- (benzylamino) -3-cyano-6- (methylamino) quinolin-2-yl} -4-methoxybenzamide in 10 ml of pyridine is stirred at room temperature with 0.2 ml of DBU and 150 mg of the pyridinium complex -SO ₃ for 2 hours. The reaction mixture was concentrated to dryness, the residue was chromatographed on silica gel using ethyl acetate / methanol / 25% ammonia = 200/80/2 as eluent to give 10 mg of the title compound as an ammonium salt. LC-MS: MH ⁺ 518; retention time: 6.22 min.

Example 13

N- {4- (Benzylamino) -3-cyano-6- [formyl (methyl) amino] quinolin-2-yl} -4-methoxybenzamide

In the general formula (I), R ¹ and R ² are hydrogen atoms, R ³ is a phenyl group, R ⁴ is Me, R ⁵ is CHO and R ⁶ is a 4-methoxyphenyl group, X is —NH— and n is 1 .

A suspension of 110 mg of N- {4- (benzylamino) -3-cyano-6- (methylamine) quinolin-2-yl} -4-methoxybenzamide in 10 ml of ethyl formate is refluxed for 24 hours. After cooling, the precipitated crystals are filtered off, washed with ethyl formate and alcohol to obtain 30 mg of the title compound, mp: 237-240 ° C. LC-MS: MH ⁺ 465; retention time: 6.11 minutes

Example 14

4-Methoxy-N- [6- (4-formylpiperazin-1-yl) -4-benzylamino-3-cyanoquinolin-2-yl] benzamide

In the general formula (I), R ¹ and R ² are hydrogen atoms, R ³ is a phenyl group, group a.) Is a 4-formylpiperazino group, R ⁶ is a 4-methoxyphenyl group, X is —NH— and n is 1.

A solution of 120 mg of 4-methoxy-N- [6- (piperazin-1-yl) -4-benzylamino-3-cyanoquinolin-2-yl] benzamide in 5 ml of ethyl formate is refluxed for 2 hours. After cooling, the solvent was evaporated and the residue was recrystallized from methanol to obtain 65 mg of the title compound, mp: 243 ° C.

¹ H-NMR (DMSO-d ₆ ) 10.6 ppm (s, 1H), 8.48 (m, 1H), 8.1 (s, 1H), 7.94 (m, 2H), 7.6-7.1 (m, 8H), 7.05 ( m, 2H), 5.1 (d, 2H), 3.83 (s, 3H), 3.7-3.2 (m, 8H).

Example 15

4- [2- (Benzoylamino) -4-benzylamino) -3-cyanoquinolin-6-yl] piperazine-1-sulfonic acid

In the general formula (I), R ¹ and R ² are hydrogen atoms, R ³ is a phenyl group, and.) Is a 4-sulfonylpiperazino group, R ⁶ is a 4-methoxyphenyl group, X is —NH— and n is 1.

A solution of 50 mg of 4-methoxy-N- [6- (piperazin-1-yl) -4-benzylamino-3-cyanoquinolin-2-yl] benzamide in 0.5 ml of pyridine and the pyridinium-SO ₃ complex are refluxed for 2 hours and processed in accordance with the methodology published in the literature (GFSmith and DATaylor, Tetrahedron, 29, 669, 1973).

LC-MS: MH ⁺ 572; retention time: 5.9 minutes

The structure and physical characteristics of the additional compounds of the general formula (I) in which R ¹ and R ² are hydrogen atoms, X represents a —NH group and n is 1 are shown in Table I

Table I No R ³ R ⁴ R ⁵ R ⁶ Mp (° C) LC-MS MH ⁺ / retention time (min) Example Method 16

Me Me

211 four 17

Me Me

208 four

eighteen

Me Me

198 four 19

Me Me

176 four twenty

Me Me

152 four 21

Me Me

163 four 22

Me Me

172 four 23

Me Me

158 four 24

Me Me

170 four 25

Me Me

171 four 26

Me Me

165 four 27

Me Me

148 four 28

H H

235 424 / 5.65 7 29th

H H

234 470 / 6.12 7 thirty

H H

222 444 / 5.54 7 31

H Me

160 444 / 5.74 9 32

H

217 517 / 5.86 eleven 33

H

257 509 / 5.70 eleven 34

H

208 523 / 5.97 eleven 35

H Cho

465 / 7.53 10 36

H Cho

452 / 5.69 10 37

H Cho

247 471 / 5.75 10 38

Me

523 / 6.14 12 39

Me Cho

248 471 / 5.86 13

Example 40

Known methods receive tablets of the following composition:

Active ingredient: 25 mg Lactose 50 mg Avicel 21 mg Crospovidone 3 mg Magnesium stearate 1 mg

Biology

Methods

Human Adenosine A Receptor Binding ₃

Preparation of membrane suspension: Chinese hamster ovary cells expressing the cloned human A ₃ receptors (further: CHO-hA _3), respectively, were cultured and maintained. After reaching the formed cell layer, the medium is separated from the cells by washing them with 37 ° C PBS, then the cells are suspended in ice-cold PBS, centrifuged (1000 × g 10 min) (Sigma 3K30) and homogenized using a teflon homogenizer (B. Braun Potter S) at rotational speeds of 1500 / min for 15 s in the following buffer solution: 50 mM Tris, 10 mM MgCl ₂ , 1 mM EDTA, pH 8.0. The suspension is centrifuged (43000 g, 10 min). Cell residues are suspended in the above buffer solution, protein concentration 0.1 mg / ml (Bradford method). Aliquots of the membrane preparation are stored at -80 ° C.

Binding protocol: incubate CHO-hA ₃ , a membrane preparation (protein content 2 μg) in an incubation buffer solution (50 mM Tris, 10 mM MgCl ₂ , 1 mM EDTA, 3 U / ml adenosine deaminase, pH 8.0) in the presence of 0, 5 nM [ ¹²⁵ I] AB-MECA (para-amino-3-iodobenzyl-5'-N-methylcarboxamidoadenosine) (100,000 cpm) and 100 μM R-PIA (N ⁶ - [L-2-phenylisopropyl] adenosine to determine non-specific binding of the test compound in a total volume of 50 μl for 1 h at room temperature, Filter through a Whatman GF / B glass fiber filter (previously soaked in 0.5% polyethyleneimine for 3 hours), p 4 x 1 ml of ice-cold 50 mM Tris, 10 mM MgCl ₂ , 1 mM EDTA (pH 8.0) are poured onto a 96-well Brandel cell harvester. Activity determination: gamma counter (1470 Wizard, Wallac.). Inhibition [%] = 100 - ((activity in the presence of the test compound is nonspecific activity) / (total activity is nonspecific activity) × 100

Binding of adenosine receptors Human A ₁

Preparation of a membrane suspension: Chinese hamster ovary cells expressing human cloned A ₁ receptors (hereinafter: CHO-hA ₁ ), respectively, are cultured and maintained. After reaching the formed cell layer, the medium is removed from the cells by washing them with 37 ° C PBS, then the cells are suspended in ice-cold PBS, centrifuged (1000 × g, 10 min) (Sigma 3K30) and homogenized using a Teflon homogenizer (B. Braun Potter S) at a rotation speed of 1500 / min for 15 s in the following buffer solution: 50 mM Tris, 10 mM HCl ₂ , pH 7.4. The suspension is centrifuged (43000 g, 10 min). Cell residues are suspended in the above buffer solution, protein concentration 5 mg / ml (Bradford method). Aliquots of the membrane preparation are stored at -80 ° C.

Binding protocol: incubate CHO-hA ₁ , a membrane preparation (protein content 50 μg) in an incubation buffer solution (50 mM Tris, 3 U / ml adenosine deaminase, pH 7.4) (in the presence of) 10 nM [ ³ N] SSRA (2 -chloro-N ⁶ cyclopentyladenodenosine) (80,000 dpm) and 100 μM R-PIA (N ⁶ - [L-2-phenylisopropyl] adenosine) to determine non-specific binding of the test compound in a total volume of 100 μl for 3 hours at room temperature. Filter through a Whatman GF / B glass fiber filter (pre-soaked in 0.5% polyethyleneimine for 3 hours), wash 4 × 1 ml of ice-cold 50 mM Tris (pH 7.4) in a 96-well Brandel cell harvester. Determination of activity: in the presence of 200 μl HiSafe-3 cocktail in a beta counter (1450 Microbeta, Wallac.). Inhibition [%] = 100 - ((activity in the presence of the test compound is nonspecific activity) / (total activity is nonspecific activity) × 100

Human Adenosine A _2a Receptor Binding

Binding protocol: 7 μg of membranes are incubated (human adenosine A _2a receptors transfected into HEK-293 cells, source: Receptor Biology, Inc.) in a buffer solution (50 mM Tris-HCl, 10 mM MgCl ₂ , 1 mM EDTA, 2 U / ml adenosine deaminase, pH 7.4) (in the presence of) 20 nM [ ³ H] CGS-21680 (2- [pair (2-carbonylethyl) phenylethylamino] -5'-N-ethylcarboxamidoadenosine) (200000 dpm) and 50 mM NECA (5'-N-ethylcarboxamidoadenosine) to determine the non-specific binding of the test compound in a total volume of 100 μl in 90 minutes at room temperature. Filtered in vacuo through a Whatman GF / B glass fiber filter (pre-soaked in 0.5% polyethyleneimine for 3 hours), washed with 4 × 1 ml of ice-cold 50 mM Tris, 10 mM MgCl ₂ , 1 mM EDTA, 0.9% NaCl (pH 7.4) on a 96-well Brandel cell harvester. Determination of activity: in a beta counter (1450 Microbeta, Wallac.) In the presence of 200 μl HiSafe-3 cocktail. Inhibition [%] = 100 - ((activity in the presence of the test compound is nonspecific activity) / (total activity is nonspecific activity) × 100

Human Adenosine A _2b Receptor Binding

Binding Protocol: 20.8 μg of membranes are incubated (human adenosine A _2b receptors transfected into HEK-293 cells, source: Receptor Biology, Inc.) in buffer solution (50 mM Tris-HCl, 10 mM MgCl ₂ , 1 mM EDTA, 1 mM benzamidine, 3 U / ml adenosine deaminase, pH 6.5) (in the presence of) 32.4 nM [ ³ N] DPCPX (8 cyclopentyl-1,3-dipropylxanthine) (800,000 dpm) and 100 mM NECA (5'-N- ethylcarboxamidoadenosine) to determine the non-specific binding of the test compound in a total volume of 100 μl for 30 minutes at room temperature. Filter in vacuo 25 mm Hg through a Whatman GF / B glass fiber filter (pre-soaked in 0.5% polyethyleneimine for 3 hours), washed with 4 × 1 ml ice-cold 50 mM Tris-HCl (pH 6.5) in a 96-well harvester for Brandel cells. Determination of activity: in the presence of 200 μl HiSafe-3 cocktail in a beta counter (1450 Microbeta, Wallac.). Inhibition [%] = 100 - ((activity in the presence of the test compound is nonspecific activity) / (total activity is nonspecific activity) × 100

results

Compounds in accordance with the present invention are considered biologically active if they inhibit the binding of human adenosine A ₃ receptor radioligands with activity above 80% at (concentration) 1 mM under the conditions of the authors' experiments.

The dissociation constant (K _d ) [ ¹²⁵ I] AB-MECA on the CHO-hA ₃ membrane is determined by studying isotope saturation using a Scatchard analysis (G. Scatchard, Ann. NY Acad. Sci. 51: 660, 1949). (Value) IC _{50 is} converted to an affinity constant (K _i ) using the Cheng-Prusoff equation (YJ Cheng and WH Prusoff, Biochem. Pharmacol. 22: 3099, 1973).

A number of compounds of the general formula (I) exhibit a noticeable biological effect. The most active compounds of general formula (I) are those defined in claims 2-4. Particularly preferred are the compounds given in the examples, the values of K _i which are in the range from 0.5 nm to 900 nm, preferably from 0.5 nm to 700 nm. The K _i values of the most preferred compounds are in the range from 0.5 nM to 18 nM, most preferably from 0.5 to 15 nM.

The compounds have good bioavailability and selectivity of at least 3 orders of magnitude with respect to subtypes of human adenosine A ₁ , A _2a and A _2b receptors.

Additionally, the duration of their action with intravenous and oral administration is large, their ED ₅₀ values are small and their toxicity and side effects are favorable.

The above data are favorable for the therapeutic use of the compounds of general formula (I).

Claims (23)

1. Compounds of General Formula (I)

, in which R ¹ represents a hydrogen atom or a linear or branched C _1-4 alkyl group; R ² represents a hydrogen atom or a linear or branched C _1-4 alkyl group; R ³ represents a phenyl, thienyl or furyl group optionally substituted with one or more linear or branched C _1-4 alkyl groups, a linear or branched C _1-4 alkoxy group or a halogen atom; R ⁴ and R ⁵ independently represent a hydrogen atom, a C _3-6 cycloalkyl group, a linear or branched C _1-4 alkyl group, optionally containing an amino group or an amino group substituted by one or two linear or branched C _1-4 alkyl groups a hydroxy group, a carboxy group or an alkoxy group substituted with a linear or branched C _1-4 alkyl group; or R ⁴ represents a hydrogen atom or a linear or branched C _1-4 alkyl group or benzyl group and R ⁵ represents a hydrogen atom, a —SO ₂ OH group or a formyl group, or R ⁴ and R ⁵ together with the nitrogen atom form a group of the general formula a)

in which R ⁷ and R ⁸ independently from each other represent a hydrogen atom, a linear or branched C _1-4 alkyl group; R ⁶ represents a phenyl, benzyl, thienyl or furyl group optionally substituted with a methylenedioxy group or one or more linear or branched C _1-4 alkyl groups, a linear or branched C _1-4 alkoxy group or a halogen atom; X represents an —NH group or an oxygen atom; Z represents an oxygen atom, a sulfur atom, an —CH ₂ group, an —NH group or an —NR ¹¹ group in which R ¹¹ represents a hydrogen atom, a linear or branched C _1-4 alkyl group, an —SO ₂ OH group, linear or branched C _1-4 acyl group; n is zero, 1 or 2; m is 1, 2 or 3; o is 1, 2 or 3; p is zero or 1; r is zero or 1, and their salts and solvates. 2. The compounds of General formula (I) according to claim 1, in which R ¹ represents a hydrogen atom or a methyl group; R ² represents a hydrogen atom or a methyl group; R ³ represents a phenyl, thienyl or furyl group; R ⁴ and R ⁵ independently represent a hydrogen atom, a C _3-6 cycloalkyl group, a linear or branched C _1-4 alkyl group, optionally containing an amino group or an amino group substituted by one or two linear or branched C _1-4 alkyl groups a hydroxy group, a carboxy group or an alkoxy group substituted with a linear or branched C _1-4 alkyl group; or R ⁴ represents a hydrogen atom or a linear or branched C _1-4 alkyl group or benzyl group and R ⁵ represents a hydrogen atom, a —SO ₂ OH group or a formyl group, or R ⁴ and R ⁵ together with the nitrogen atom form a group of the general formula a) in which R ⁷ and R ⁸ independently represent a hydrogen atom, a linear or branched C _1-4 alkyl group or a C _3-6 cycloalkyl group; R ⁶ represents a 4-methoxyphenyl, 3-methylphenyl, 3-methoxyphenyl, 3,4-methylenedioxyphenyl, 4-fluorophenyl, 2-thienyl or 2-furyl group; X represents an —NH group or an oxygen atom; Z represents an oxygen atom, a sulfur atom, a —CH ₂ group, an —NH group or an —NR ¹¹ group in which R ¹¹ represents a linear or branched C _1-4 alkyl group, an —SO ₂ OH group or a formyl group, and n is 1; m is 2; o is 2; p is zero; r is zero and their salts and solvates. 3. The compounds according to claim 2, which are: 4-methoxy-N- [6- (morpholin-4-yl) -4-benzylamino-3-cyanoquinolin-2-yl] benzamide; 4-methoxy-N- [6- (4-methylpiperazin-1-yl) -4-benzylamino-3-cyanoquinolin-2-yl] benzamide; 4-methoxy-N- (6-dimethylamino-4-benzylamino-3-cyanoquinolin-2-yl) benzamide; 3,4-methylenedioxy-N- (6-dimethylamino-4-benzylamino-3-cyanoquinolin-2-yl) benzamide; 4-fluoro-N- (6-dimethylamino-4-benzylamino-3-cyanoquinolin-2-yl) benzamide; 4-methoxy-N- (6- (piperazin-1-yl) -4-benzylamino-3-cyanoquinolin-2-yl) benzamide; 4-methoxy-N- (6-amino-4-benzylamino-3-cyanoquinolin-2-yl) benzamide; N- [4- (benzylamino) -3-cyano-6- (4-formylpiperazin-1-yl) quinolin-2-yl] -4-methoxybenzamide; 4- {4- (benzylamino) -3-cyano-2 - [(4-methoxybenzoyl) amino] quinolin-6-yl} piperazine-1-sulfonic acid; N- {3-cyano-6- (formylamino) -4 - [(2-thienylmethyl) amino] quinolin-2-yl} -4-methoxybenzamide; N- {3-cyano-6- (formylamino) -4 - [(2-thienylmethyl) amino] quinolin-2-yl) -1,3-benzodioxol-5-carboxamide; N- [4- (benzylamino) -3-cyano-6- (formylamino) quinolin-2-yl] -1,3-benzodioxol-5-carboxamide; N- [4- (benzylamino) -3-cyano-6- (formylamino) quinolin-2-yl] -4-methoxybenzamide; N- {4- (benzylamino) -3-cyano-6- [formyl (methyl) amino] quinolin-2-yl} -4-methoxybenzamide; N- {3-cyano-6- [formyl (methyl) amino] -4 - [(2-thienylmethyl) amino] quinolin-2-yl} -4-methoxybenzamide; {3-cyano-2 - [(4-methoxybenzoyl) amino] -4 - [(2-thienylmethyl) amino] quinolin-6-yl} methylsulfamic acid; {4- (benzylamino) -3-cyano-2 - [(4-methoxybenzoyl) amino] quinolin-6-yl} methylsulfamic acid; {4- (benzylamino) -3-cyano-2 - [(4-methoxybenzoyl) amino] quinolin-6-yl} sulfamic acid; [2 - [(1,3-benzodioxol-5-ylcarbonyl) amino] -4- (benzylamino) -3-cyanoquinolin-6-yl] sulfamic acid; {2 - [(1,3-benzodioxol-5-ylcarbonyl) amino] -3-cyano-4 - [(2-thienylmethyl) amino] quinolin-6-yl} sulfamic acid; {3-cyano-2 - [(4-methoxybenzoyl) amino] -4 - [(2-thienylmethyl) amino] quinolin-6-yl} sulfamic acid, and their salts and solvates. 4. A method of obtaining compounds of General formula (I)

and their salts, solvates, where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , X, Z, n, o, p, r and m have the meanings defined in claim 1, characterized in that v) a bis-carboxamide of general formula (II ″) in which R ¹ ″ represents a hydrogen atom or a linear or branched C _1-4 alkyl group; R ² ″ represents a hydrogen atom or a linear or branched C _1-4 alkyl group; R ³ ″ represents a phenyl, thienyl or furyl group optionally substituted with one or more linear or branched C _1-4 alkyl groups, a linear or branched C _1-4 alkoxy group or a halogen atom; R ^{4 ″} and R ^{5 ″} independently of each other represent a hydrogen atom, a C _3-6 cycloalkyl group, a linear or branched C _1-4 alkyl group, optionally containing an amino group or an amino group substituted with one or two linear or branched C _1-4 alkyl groups, a hydroxy group, a carboxy group or an alkoxy group substituted with a linear or branched C _1-4 alkyl group, or a protecting group; or R ⁴ ″ represents a hydrogen atom or a linear or branched C _1-4 alkyl group or benzyl group and R ⁵ ″ represents a hydrogen atom, a —SO ₂ OH group, a formyl group or a protective group, or R ⁴ ″ and R ⁵ ″ together with the nitrogen atom form a nitro group or a group of the general formula a) in which R ⁷ ″ and R ⁸ ″ independently of each other represent a hydrogen atom, a linear or branched C _1-4 alkyl group; R ⁶ ″ represents a phenyl, benzyl, thienyl or furyl group optionally substituted with a methylenedioxy group or one or more linear or branched C _1-4 alkyl groups, a linear or branched C _1-4 alkoxy group or a halogen atom; X ″ represents a group —NH, an oxygen atom, Z ″ represents an oxygen atom, a sulfur atom, an —CH ₂ group, an —NH group or an —NR ¹¹ group in which R ¹¹ represents a hydrogen atom, a linear or branched C _1-4 alkyl group, an —SO ₂ OH group, linear or a branched C _1-4 acyl group. n ″ is zero, 1 or 2; m ″ is 1, 2 or 3; o ″ is 1, 2 or 3; p ″ is zero or 1; r ″ is zero or 1, selectively hydrolyze and optionally remove the protective groups, or v / i) to obtain compounds of the general formula (I) in which R ⁴ represents a hydrogen atom or a linear or branched C _1-4 alkyl group or benzyl group and R ⁵ represents formyl a group or R ⁴ and R ⁵ together with a nitrogen atom form a group of the general formula a) in which Z represents a —NR ¹¹ group, where R ¹¹ represents a linear or branched C _1-4 acyl group, and R ¹ R ² , R ³ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , X, n, m, o, p and r are as defined above, a compound of general formula (I) in which R ⁴ represents a hydrogen atom, a linear or branched C _1-4 alkyl group or benzyl group, and R ⁵ represents a hydrogen atom or R ⁴ and R ⁵ together with a nitrogen atom form a group of general formula a ), in which Z represents a group —NH, and R ¹ , R ² , R ³ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , X, n, m, o, p, and r are as defined above , acylated with a compound of the general formula R ¹² ″ COY ″ in which R ¹² ″ is a linear or branched C _1-3 alkyl group and Y ^″ represents a leaving group; v / ii) to obtain a compound of general formula (I) in which R ⁴ represents a hydrogen atom, a linear or branched C _1-4 alkyl group or a benzyl group and R ⁵ represents a —SO ₂ OH or R ⁴ and R ⁵ group together with a nitrogen atom form a group of the general formula a), in which Z represents a group —NR ¹¹ , where R ¹¹ represents a group —SO ₂ OH and R ¹ , R ² , R ³ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , X, n, m, o, p and r are as defined above, a compound of general formula (I) in which R ⁴ represents a hydrogen atom, a linear or branched C _1-4 alkyl group or benzyl group, and R ⁵ represents a hydrogen atom or R ⁴ and R ⁵ together with a nitrogen atom form a group of general formula a ), in which Z represents a group —NH, and R ¹ , R ² , R ³ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , X, n, m, o, p and r are as defined above, is reacted with a complex of pyridine -SO ₃ or with ClSO ₃ H, or v / iii) to obtain a compound of general formula (I) in which R ⁴ represents a hydrogen atom, a linear or branched C _1-4 alkyl group or a benzyl group and R ⁵ represents a —SO ₂ OH group, and R ¹ , R ² , R ³ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , X, Z, n, m, o, p and r have the meanings defined above, a compound of the general formula (XIII ″) in which R ¹ R ² , R ³ , R ⁶ , R ⁹ , X and n are as defined above, subjected to interaction with Na ₂ S ₂ O ₄ or NaHSO ₃ , or restore and the resulting compound of General formula (XIV ″), in which R ⁴ ″ represents a hydrogen atom, and R ^{1 ″} , R ^{2 ″} , R ^{3 ″} , R ^{6 ″} , R ^{9 ″} , X ″ and n ″ have as defined above, sulfonated pyridine complex ClSO ₃ or -SO ₃ H, and, if desired, then converting the hydrogen atom R ^{4 ″} into a linear or branched C _1-4 alkyl group or benzyl group; or v / iv) for the preparation of compounds of general formula (I) in which R ⁴ represents a hydrogen atom, a C _3-6 cycloalkyl group, a benzyl group, a linear or branched C _1-4 alkyl group, optionally containing an amino group or an amino group substituted with one or two linear or branched C _1-4 alkyl groups, a hydroxy group, a carboxy group or an alkoxy group substituted with a linear or branched C _1-4 alkyl group, and R ⁵ represents a hydrogen atom or R ⁴ and R ⁵ together with a nitrogen atom form a group of the general formula a) in which R ⁷ and R ⁸ independently from each other represent a hydrogen atom, a linear or branched C _1-4 alkyl group, and Z represents a group —NR ¹¹ in which R ¹¹ represents a hydrogen atom, remove the protective group of the compounds of General formula (I ^″ ), in which R ^{4 ″} represents a hydrogen atom, a C _3-6 cycloalkyl group, a benzyl group, a linear or branched C _1-4 alkyl group, optionally containing an amino group or an amino group substituted by one or two linear or branched C _1-4 alkyl groups, a hydroxy group, a carboxy group or an alkoxy group substituted with a linear or branched C _1-4 alkyl group, and R ⁵ represents a protective group or R ⁴ ″ and R ⁵ ″ together with the nitrogen atom form a group of the general formula a ^″ ), in which R ⁷ ″ and R ⁸ ″ Independently from each other dstavlyayut a hydrogen atom, a linear or branched C _1-4 alkyl group and Z represents a group -NR ¹¹ ", wherein R ¹¹ 'represents a protecting group, and, if desired, substituents in the resulting compound of general formula (I) and / or the compounds of general formula (I) thus obtained are converted to their salts or solvates or released from salts or solvates thereof. 5. The method according to claim 4, characterized in that the selective hydrolysis is carried out with an alkali metal hydroxide dissolved in an alcoholic medium, preferably a methanolic solution of potassium or sodium hydroxide. 6. A pharmaceutical composition having action as adenosine A3 ligands, characterized in that it contains one or more compounds of the general formula (I) in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R, R ⁷ , R ⁸ , X, Z, n, m, o, p and r have the meanings defined in claim 1, and / or their salts and solvates and one or more excipients commonly used in the pharmaceutical industry. 7. The pharmaceutical composition according to claim 6, characterized in that it contains as an active substance one or more of the compounds defined in claim 3. 8. The use of compounds of general formula (I), their salts, solvates, where R ¹ R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , X, Z, n, m, o, p and r have the meanings defined in claim 1, for the manufacture of a pharmaceutical composition for the treatment of diseases in the development of which the A ₃ receptor plays a role. 9. The use of compounds of general formula (I), their salts, solvates of claim 8, where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , X, Z, n, m, o, p and r have the meanings defined in claim 1, as A ₃ ligands for the manufacture of a pharmaceutical composition for the treatment of heart, kidney, respiratory and central nervous system diseases and for inhibiting the protection of adenosine in growing tumor cells, preventing degranulation mast cells, inhibition of cytokine production, reduction of intraocular pressure, inhibition of TNFα release, inhibition of migration eosinophils, neutrophils and other immune cells, inhibition of bronchoconstriction and plasma extravasation. 10. The use of compounds of General formula (I), their salts, solvates, according to claim 9, where R ¹ , R ² , R ³ , R4, R ⁵ , R ⁶ , R ⁷ , R ⁸ , X, Z, n, m, o, p and r have the meanings defined in claim 1, as antagonists of A ₃ receptors for the manufacture of anti-inflammatory, anti-asthma, anti-ischemic drugs, antidepressants, antiarrhythmic drugs, kidney protectants, anti-tumor drugs, anti-Parkinson drugs and pharmaceutical compositions cognitive enhancers and compositions for treating or preventing reperfusion injury myocardium, chronic obstructive pulmonary disease (COPD) and adult respiratory distress syndrome (ARDS), including chronic bronchitis, pulmonary emphysema or shortness of breath, allergic reactions (e.g., rhinitis, toxic ivy-induced reactions, urticaria, scleroderma, arthritis), other autoimmune diseases, inflammatory bowel diseases, Addison’s disease, Crohn’s disease, psoriasis, rheumatism, hypertension, functional neurological disorders, glaucoma and diabetes. 11. The use of compounds of General formula (I), their salts, solvates according to claim 9 and 10, where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , X, Z, n, m, o, p and r have the meanings defined in claim 1 as antagonists of A ₃ receptors for the manufacture of pharmaceutical compositions for the treatment of diseases such as asthma, COPD and ARDS, glaucoma, tumors, allergic reactions, inflammatory diseases, ischemia, hypoxia, arrhythmia and renal disease. 12. Compounds of General Formula (I ″)

in which R ^{1 ″} , R ^{2 ″} , R ^{3 ″} , R ^{6 ″} , R ^{7 ″} , R ^{8 ″} , X ^″ , n ″, m ″, o ″, p ″ and r ″ have the meanings defined in 4, and R ^{4 ″} represents a hydrogen atom, a C _3-6 cycloalkyl group, a benzyl group, a linear or branched C _1-4 alkyl group, optionally containing an amino group or an amino group substituted by one or two linear or branched C _1-4 alkyl groups, a hydroxy group, a carboxy group or an alkoxy group substituted with a linear or branched C _1-4 alkyl group, and R ^{5 ″} represents a protective group, or R ^{4 ″} and R ^{5 ″} together with the nitrogen atom form a group of the general formula a ”), in which R ^{7 ″} and R ^{8 ″} independently of each other represent a hydrogen atom, a linear or branched C _1-4 alkyl group or a C _{3- 6 is a} cycloalkyl group and Z is a group —NR ^{11 ″} , where R ^{11 ″} is a protecting group. 13. Compounds of General formula (II ^″ )

in which R ^{1 ″} , R ^{2 ″} , R ^{3 ″} , R ^{4 ″} , R ^{5 ″} , R ^{6 ″} , R ^{7 ″} , R ^{8 ″} , X ″, Z ″, n ″, m ″, about ″, p ″ And r ″ have the meanings defined in clause 4. 14. Compounds of General formula (III ″)

in which R ^{1 ″} , R ^{2 ″} , R ^{3 ″} , R ^{4 ″} , R ^{5 ″} , R ^{7 ″} , R ^{8 ″} , X ″, Z ″, n ″, m ″, o ″, p ″ and r ″ have the meanings defined in clause 4. 15. Compounds of General Formula (IV ″)

in which R ^{4 ″} , R ^{5 ″} , R ^{7 ″} , R ^{8 ″} , Z ″, m ″, o ″, p ″ and r ″ have the meanings defined in clause 4. 16. The compounds of General formula (V ″)

in which R ^{4 ″} , R ^{5 ″} , R ^{7 ″} , R ^{8 ″} , Z ″, m ″, o ″, p ″ and r ″ have the meanings defined in clause 4. 17. Compounds of General formula (VI ″)

in which R ^{4 ″} , R ^{5 ″} , R ^{7 ″} , R ^{8 ″} , Z ^″ , m ″, o ″, p ″ and r ″ are as defined in claim 4, provided that R ^{4 ″} and R ^{5 ″} together with the nitrogen atom have values different from the dimethylamino group, amino group and nitro group. 18. Compounds of General formula (VII ″)

in which R ^{4 ″} , R ^{5 ″} , R ^{7 ″} , R ^{8 ″} , Z ″, m ″, o ″, p ″ and r ″ are as defined in claim 4, provided that R ^{4 ″} and R ^{5 ″} together with the nitrogen atom have values different from the dimethylamino, diethylamino and amino groups, with the exception of a compound in which R ^{4 ″} represents a hydrogen atom, R ^{5 ″} represents a linear or branched C _1-4 acyl group. 19. Compounds of General Formula (VIII ″)

wherein R ^{4 ″} and R ^{5 ″} together with the nitrogen atom are a morpholino, N-methylpiperazino, piperazino or 4-benzylpiperazino group. 20. Compounds of General Formula (XIII ^″ )

in which the substituents R ^{1 ″} , R ^{2 ″} , R ^{3 ″} , R ^{6 ″} and n ″ have the meanings defined in clause 4. Priority on points and signs: 07/31/2003 according to claims 1-12 and 14-20 (for radicals not included in later priorities). 07/21/2004: compounds of the general formula (I), (II ^″ ), (III ^″ ), (IV ^″ ), (V ^″ ), (VI ^″ ), (VII ^″ ), (VIII ^″ ), where R ⁴ and R ^{4 ″} respectively represent a hydrogen atom or a linear or branched C _1-4 alkyl or benzyl group and R ⁵ and R ⁵ ″ respectively represent a hydrogen atom, a —SO ₂ OH group or a C _1-4 acyl group, or where R ¹¹ and R ^{11 ″} respectively represents a —SO ₂ OH or C _1-4 acyl group; claim 4, in particular, compounds 4-methoxy-N- (6-dimethylamino-4-benzylamino-3-cyanoquinolin-2-yl) benzamide; N- [4- (benzylamino) -3-cyano-6- (4-formylpiperazin-1-yl) quinolin-2-yl] -4-methoxybenzamide; 4- {4- (benzylamino) -3-cyano-2 - [(4-methoxybenzoyl) amino] quinolin-6-yl} piperazine-1-sulfonic acid; N- {3-cyano-6- (formylamino) -4 - [(2-thienylmethyl) amino] quinolin-2-yl} -4-methoxybenzamide; N- {3-cyano-6- (formylamino) -4 - [(2-thienylmethyl) amino] quinolin-2-yl} -1,3-benzodioxol-5-carboxamide; N- [4- (benzylamino) -3-cyano-6- (formylamino) quinolin-2-yl] -1,3-benzodioxol-5-carboxamide; N- [4- (benzylamino) -3-cyano-6- (formylamino) quinolin-2-yl] -4-methoxybenzamide; N- {4- (benzylamino) -3-cyano-6- [formyl (methyl) amino] quinolin-2-yl} -4-methoxybenzamide; N- {3-cyano-6- [formyl (methyl) amino] -4 - [(2-thienylmethyl) amino] quinolin-2-yl} -4-methoxybenzamide; {3-cyano-2 - [(4-methoxybenzoyl) amino] -4 - [(2-thienylmethyl) amino] quinolin-6-yl} methylsulfamic acid; {4- (benzylamino) -3-cyano-2 - [(4-methoxybenzoyl) amino] quinolin-6-yl} methylsulfamic acid; {4- (benzylamino) -3-cyano-2 - [(4-methoxybenzoyl) amino] quinolin-6-yl} sulfamic acid; [2 - [(1,3-benzodioxol-5-ylcarbonyl) amino] -4- (benzylamino) -3-cyanoquinolin-6-yl] sulfamic acid; {2 - [(1,3-benzodioxol-5-ylcarbonyl) amino] -3-cyano-4 - [(2-thienylmethyl) amino] quinolin-6-yl} sulfamic acid; {3-cyano-2 - [(4-methoxybenzoyl) amino] -4 - [(2-thienylmethyl) amino] quinolin-6-yl} sulfamic acid; methods v / I), v / ii), v / iii) and viv); item 21; the compounds of General formula (I ^″ ) according to item 13, where R ^{4 ″} represents a hydrogen atom and R ⁵ ″ represents a protective group or R ^{4 ″} and R ^{5 ″} together with a nitrogen atom form a protective group; compounds of general formulas (II ^″ ), (III ^″ ), (IV ^″ ), (V ^″ ), (VI ^″ ), (VII ^″ ), where R ^{4 ″} represents a hydrogen atom and R ^{5 ″} represents a protective group or R ^{4 ″} and R ^{5 ″} together with the nitrogen atom form a nitro group or a group of the formula a ″), in which Z ″ represents a group —NR ¹¹ , where R ¹¹ represents a protective group; the compounds of General formula (VIII ^″ ) according to claim 20, where R ^{4 ″} and R ^{5 ″} together with the nitrogen atom represent a 4-benzylpiperazino group. 07/23/2004: Compounds of general formula (I ^″ ) according to claim 13, wherein R ⁴ ″ represents a benzyl group, a C _3-6 cycloalkyl group, a branched or linear C _1-4 alkyl group, optionally containing an amino group or an amino group substituted with one or two linear or branched C _1-4 alkyl groups, a hydroxy group, a carboxy group or an alkoxy group substituted with a linear or branched C _1-4 alkyl group, and R ⁵ ″ represents a protecting group; compounds of general formulas (II ^″ ), (III ^″ ), (IV ^″ ), (V ^″ ), (VI ^″ ), (VII ″), where R ^{5 ″} represents a protecting group and R ^{4 ″ is} not hydrogen; Process v / iv) for preparing compounds of formula (I), wherein R ⁵ is hydrogen and R ^{4 is} not hydrogen.

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