KR20070020335A - Aminoquinoline derivatives and their use as adenosine a3 ligands - Google Patents

Abstract

The present invention relates to compounds of formula (I) which are potent adenosine A ₃ receptor ligands, preferably antagonists:

Wherein R, R ⁴ and R ⁵ are methylene-dioxide group or one or more linear or branched C _{1 -4} alkyl group, a linear or branched C _{1 -4} alkoxy group, hydroxyl that is substituted or not substituted by the lock time, or a halogen atom with A 1,3-butadienyl group is formed.

Adenosine A3 Receptor Ligands, Antagonists

Description

Aminoquinoline derivatives and their use as adenosine A3 ligands {AMINOQUINOLINE DERIVATIVES AND THEIR USE AS ADENOSINE A3 LIGANDS}

1 shows formula (I),

2 shows formula (IA),

3 shows formula (II),

4 shows formula (III),

5 shows formula (IV).

6 shows Scheme 1, which is a reaction pathway for preparing compounds of formula (I).

The present invention relates to adenosine A ₃ receptor ligands of formula (I), preferably antagonists and salts, solvates and isomers thereof, and pharmaceutical compositions containing them, compounds of formula (I) and salts, solvates and isomers thereof It relates to the use, preparation of compounds of formula (I) and salts, solvates and isomers thereof, and further to novel intermediates of formula (II), (III) and (IV) and the preparation thereof.

Adenosine is a well known component of several endogenous molecules (ATP, NAD ⁺ , nucleic acids). It also plays an important regulatory role in many physiological processes. The effect of adenosine on cardiac function was already revealed in 1929 (Drury and Szentgyorgyi, J Physiol 68: 213, 1929). The identification of physiological functions mediated by an increasing number of adenosines and the discovery of new adenosine receptor subtypes offer the potential for therapeutic applications of specific ligands (Poulse, SA and Quinn, RJ Bioorganic and Medicinal Chemistry 6: 619). , 1998).

To date, receptors for adenosine have been classified into three main classes (A ₁ , A ₂ and A ₃ ). The A ₁ subtype is partly involved in inhibiting adenylate cyclase by coupling with a G _i membrane protein and partly affects other secondary messenger systems. A ₂ receptor subtypes can be subdivided into two further subtypes A _2a and A _2b , which receptors stimulate adenylate cyclase activity. The sequence of a series of A ₃ receptors was recently identified from the rat testicular cDNA library. This sequence was then proved to correspond to a novel functional adenosine receptor. Activation of the A ₃ receptor is also associated with a number of secondary messenger systems responsible for the inhibition of adenylate cyclase, the stimulation of phospholipase C and D.

Adenosine receptors are found in many organs and regulate their function. Both A ₁ and A _2a receptors play important roles in the central nervous system and the cardiovascular system. In the CNS, adenosine inhibits the release of synaptic transporters mediated by A ₁ receptors. In the heart, the A ₁ receptor also mediates the contractile force reducing effect, a heart rate fluctuation effect, and substation effect of adenosine. Adenosine A _2a receptors present in relatively high amounts in the striatum exhibit functional interaction with dopamine receptors in regulating synaptic transmission. A _2a adenosine receptors on endothelial cells and smooth muscle cells are responsible for adenosine induced vasodilation.

Based on mRNA identification, A _2b adenosine receptors are widely distributed in different tissues. They have been identified in almost all cell types but their expression is highest in the intestine and bladder. These subtypes also have important regulatory functions in the regulation of vascular tension and will play a role in the function of mast cells.

In contrast to the A ₁ and A _2a receptors whose tissue distribution is detected at the protein level, the presence of A _2b and A ₃ receptors is detected based on their mRNA levels. The expression level of the A ₃ adenosine receptor is low and highly species dependent compared to other subtypes. A ₃ adenosine receptors are mainly expressed in the central nervous system, testes, and immune system and are believed to be involved in regulating mediator release from mast cells in immediate type hypersensitivity reactions.

The A ₃ antagonists disclosed so far belong to the group of flavonoids, 1,4-dihydropyridine derivatives, triazoloquinazolines, thiazolonaphthyridines and thiazolopyrimidines. The present invention relates to novel types of effective A ₃ antagonists with aminoquinoline structures.

For therapeutic use, it is essential to confirm that the molecule does not bind to adenosine receptors of the A ₁ , A _2a and A _2b subtypes, or only in very high concentrations. The present invention relates to compounds of formula (I), salts, solvates and isomers thereof having high selectivity for adenosine receptors of the A ₃ subtype.

What is the purpose of the invention all have strong antagonistic effect on the A ₃ receptor with high selectivity, that is, a quinoline structure, for suppressing the A ₃ receptor in much lower concentration than that inhibit A _1, A _2a and A _2b receptor And to prepare an A ₃ ligand, preferably an antagonist. A further object is to provide stability, bioavailability, therapeutic index and toxicity data for the development of new compounds as medicinal substances, and because of their good intestinal absorption, these compounds can be applied orally.

The inventor,

R ¹ is a hydrogen atom or a linear or branched C _{1 -4} alkyl group,

R ² is a hydrogen atom or a linear or branched C _{1 -4} alkyl group,

R ³ is a hydrogen atom or a linear or branched C _{1 -4} alkyl group, or one or more linear or branched C _{1 -4} alkyl group, a linear or branched C ₁ -C ₄ alkoxy group, or a non-substituted or not substituted by a halogen atom a phenyl group, thienyl group or furyl group, or, one or more linear or branched C ₁ -C ₄ alkyl group, a linear or branched C _{1 -4} alkoxy group or a halogen atom, a substituted or unsubstituted 1 to 3 nitrogen atoms or by 1 A 5 or 6 membered heteroaromatic ring containing 1 nitrogen atom and 1 oxygen atom or 1 nitrogen atom and 1 sulfur atom,

R ⁴ and R ⁵ is not 1,3-dioxide with a methylene group or one or more linear or branched C _{1 -4} alkyl group be a linear or branched C _{1 -4} alkoxy group, hydroxyl group or halogen atom or substituted by a substituted Forming a butadienyl group,

R ⁶ is a hydrogen atom or a cyano group, aminocarbonyl group, C _{1 -4} alkoxycarbonyl group, or carboxy group,

R ⁷ is a hydrogen atom or a linear or branched C _{1 -4} alkyl group, or a methylene group-dioxide or one or more linear or branched C _{1 -4} alkyl group, a linear or branched C _{1 -4} alkoxy group, hydroxyl group, trifluoromethyl a methyl group, a cyano group, or are substituted or not substituted by a halogen atom, phenyl group, benzyl group, thienyl group or furyl group, or, one or more linear or branched C _{1 -4} alkyl group, straight or branched C _{1 -4} alkoxy group, or A 5- or 6-membered heteroaromatic ring containing 1 to 3 nitrogen atoms or 1 nitrogen atom and 1 oxygen atom or 1 nitrogen atom and 1 sulfur atom unsubstituted or substituted by a halogen atom,

Group X is -CH _2, -NH- group, -NR ⁸ - group (wherein, R ⁸ is a linear or branched C _{1 -4} alkyl or C _{3 -6} cycloalkyl alkyl group) or a sulfur atom or an oxygen atom or a sulfo group Or snowfall,

It has been found that the compounds of formula (I) and their salts, solvates and isomers and salts, solvates of the isomers, wherein n is 0, 1 or 2, meet the above criteria.

The detailed meanings of the substituents listed above are as follows:

It is a linear or branched C _{1 -4} alkyl group means a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, secondary butyl group, tertiary butyl group, preferably an ethyl or methyl group.

Linear or branched C _{1 -4} alkoxy group is a methoxy group, an ethoxy group, a propoxy group, isopropoxy group, butoxy group, isobutoxy Messenger group, secondary butoxy group, tertiary butoxy group, preferably ethoxy or methoxy group in Means.

C to _3-6 cycloalkyl group means a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.

A 1,3-butadienyl group means a benzopyridine ring or a quinoline ring, commonly referred to as a (-CH = CH-CH = CH-) group, ie a pyridine ring unsubstituted or substituted by a R ⁴ and R ⁵ substituent. do.

Heteroaromatic rings containing 1-3 nitrogen atoms include pyrrole, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, pyridine, pyrimidine, pyridazine, pyrazine and 1 , 3,4-triazine ring. This ring is not substituted by C _{1 -4} alkyl group or an alkoxy group or a halogen atom or a substituted.

A heteroaromatic ring containing one nitrogen atom and one oxygen or sulfur atom means an oxazole, isoxazole, thiazole, isothiazole ring. Such rings are unsubstituted or substituted by C _1-4 alkyl groups or mono- or halogen atoms.

Salts of compounds of formula (I) mean salts with inorganic and organic acids and bases. Preferred salts are salts with pharmaceutically acceptable acids such as hydrochloric acid, sulfuric acid, ethanesulfonic acid, tartaric acid, succinic acid, fumaric acid, malic acid, citric acid, and bases such as sodium hydroxide, potassium hydroxide and ethanolamine And salts.

Solvate means a solvate of various solvents such as water or ethanol.

Since the compounds of formula (I) exhibit geometric and optical isomerism, the invention also relates to mixtures of geometric isomers, racemic or optically active geometric isomers, and salts and solvates thereof.

Preferred groups of compounds of formula (I) are

R ¹ is a hydrogen atom or a linear or branched C _{1 -4} alkyl group,

R ² is a hydrogen atom or a linear or branched C _{1 -4} alkyl group,

R ³ is a hydrogen atom or a linear or branched C _{1 -4} alkyl group, or one or more linear or branched C _{1 -4} alkyl group, a linear or branched C _{1 -4} alkoxy groups or halogen atoms or substituted by an unsubstituted phenyl group , a thienyl group or a furyl group, or one or more linear or branched C ₁ -C ₄ alkyl group, a linear or branched C _{1 -4} alkoxy group, or a non-substituted or not substituted by a halogen atom, one to three nitrogen atoms or one nitrogen A 5 or 6 membered heteroaromatic ring containing an atom and 1 oxygen atom or 1 nitrogen atom and 1 sulfur atom,

R ^9, R ^10, R ¹¹ and R ¹² are independently a hydrogen atom or a linear or branched C _{1 -4} alkyl group, or a linear or branched C _{1 -4} alkoxy group or a hydroxyl group or a halogen atom,

R ⁹ and R ¹² are hydrogen atoms and R ¹⁰ and R ¹¹ together form a methylenedioxy group,

R ⁶ is a hydrogen atom or a cyano group, aminocarbonyl group, C _{1 -4} alkoxycarbonyl group, or carboxy group,

R ⁷ is a hydrogen atom or a linear or branched C _{1 -4} alkyl group, or a methylene group-dioxide or one or more linear or branched C _{1 -4} alkyl group, a linear or branched C _{1 -4} alkoxy group, hydroxyl group, trifluoromethyl a methyl group, a cyano group or a non-substituted or not substituted by a halogen atom, phenyl group, benzyl group, thienyl group or furyl group, or, one or more linear or branched C _{1 -4} alkyl group, a linear or branched C _{1 -4} alkoxy group, or A 5- or 6-membered heteroaromatic ring containing 1 to 3 nitrogen atoms or 1 nitrogen atom and 1 oxygen atom or 1 nitrogen atom and 1 sulfur atom unsubstituted or substituted by a halogen atom,

Group X is -CH _2, -NH- group, -NR ⁸ - group (wherein, R ⁸ is a linear or branched C _{1 -4} alkyl or C _{3 -6} cycloalkyl alkyl group) or a sulfur atom or an oxygen atom or a sulfo group Or snowfall,

formed by compounds of formula (IA) wherein n is 0, 1 or 2 and salts, solvates, isomers and salts of isomers, solvates thereof.

Preferred groups of compounds of formula (IA) are

R ¹ is a hydrogen atom or a methyl group,

R ² is a hydrogen atom or a methyl group,

R ³ is a phenyl group or thienyl group or a furyl group,

R ^9, R ^10, R ¹¹ and R ¹² are independently a hydrogen atom or a linear or branched C _1-4 alkyl group or a linear or branched C _{1 -4} alkoxy group or a hydroxyl group or a halogen atom,

R ⁹ and R ¹² are hydrogen atoms and R ¹⁰ and R ¹¹ together form a methylenedioxy group,

R ⁶ is a hydrogen atom or a cyano group,

R ⁷ is 4-methoxyphenyl group, 3-methylphenyl group, 3-methoxyphenyl group, 3-thiethyl group or 3-furyl group,

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

It is formed by a compound of which n is 1 and salts, solvates, isomers and salts of isomers, solvates thereof.

Particularly preferred compounds are the following compounds and salts, solvates, isomers and salts of isomers, solvates thereof, which comply with the above criteria:

3-methyl-N- (4-benzylamino-3-cyanoquinolin-2-yl) benzamide,

4-methoxy-N- (4-benzylamino-3-cyanoquinolin-2-yl) benzamide,

3-methoxy-N- (4-benzylamino-3-cyanoquinolin-2-yl) benzamide,

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

N- (4-benzylamino-3-cyanoquinolin-2-yl) thiophene-2-carboxamide,

N- (4- [2-thiethylmethylamino] -3-cyanoquinolin-2-yl) thiophene-3-carboxamide,

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

3,4-methylenedioxy-N- (4- [2-thienylmethylamino] -3-cyanoquinolin-2-yl) -benzamide,

N- (4- [2-furylmethylamino] -3-cyanoquinolin-2-yl) furan-2-carboxamide,

N- (4- [2-furylmethylamino] -3-cyanoquinolin-2-yl) thiophene-3-carboxamide.

According to another aspect, the present invention also relates to a pharmaceutical composition comprising as an active ingredient a compound of formula (I) or an isomer, salt and solvate thereof, which is preferably an oral composition but inhalation, parenteral and Transdermal formulations are also subject of the present invention. Such pharmaceutical compositions may be solid or liquid, such as tablets, pellets, capsules, patches, solutions, suspensions or emulsions. Solid compositions, and above all tablets and capsules, are preferred pharmaceutical forms.

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

Compounds of formula (I) may be used to treat pathological conditions in which A ₃ receptors play a role in its progression.

Compounds of the invention having selective activity on the A ₃ receptor can be used for therapeutic and / or prophylactic treatment of dysfunction of the heart, kidneys, respiratory system, central nervous system. They inhibit the protective effect of adenosine in proliferating tumor cells, prevent mast cell degranulation, inhibit cytokine production, reduce intraocular pressure, inhibit TNFα release, inhibit eosinophils, neutrophils and other immune cells. Inhibit migration, inhibit bronchial contraction and plasma outflow.

Based on these effects, the adenosine A ₃ receptor antagonist of the present invention is an anti-inflammatory, anti-asthmatic, anti-ischemic, anti-depressive, anti-arrhythmic, renal protective, anti-tumor, anti-Pakison and cognitive enhancement agent. It may be therapeutically useful. They may also include adult respiratory distress syndrome (ARDS), including myocardial reperfusion injury, chronic obstructive pulmonary disease (COPD) and chronic bronchitis, pulmonary pneumoconiosis or dyspnea, allergic reactions (eg, rhinitis, ivy-induced reactions, urticaria, Scleroderma, arthritis) May be useful for the treatment or prevention of other autoimmune diseases, inflammatory bowel disease, Addison's disease, Crohn's disease, psoriasis, rheumatism, high blood pressure, neurological dysfunction, 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 the present invention can be preferably used for the treatment of diseases such as asthma, COPD and ARDS, glaucoma, tumors, allergic and inflammatory diseases, ischemia, hypoxia, arrhythmia and kidney disease.

According to another aspect thereof, the present invention relates to the use of a compound of formula (I) in the treatment of said pathological condition. The proposed daily dose is from 1 to 100 mg of active ingredient, depending on the nature and severity of the disease and sex, weight, etc. of the patient.

A further subject of the invention is the preparation of compounds of formula (I) and intermediates of formula (II), (III) and (IV).

The intermediates of the formulas (II), (III) and (IV) used in the preparation process according to the invention are partially novel. Substituents of formula (II), (III) and (IV) have the meaning as defined above.

In the process according to the invention, the bis-carboxamides of formula (II) are optionally hydrolyzed and the resulting compounds of formula (I) are optionally converted into salts or solvates thereof, or salts thereof Liberated from solvates and separated into their geometric or optical isomers.

Substituents of compounds of formula (I) may be interchanged by known methods.

Selective hydrolysis can be carried out using an alcoholic solution, preferably a methanolic alkali hydroxide solution, preferably potassium hydroxide and / or sodium hydroxide solution, but other agents that aid in the hydrolysis of the amide can also be used. .

Selective hydrolysis can be carried out over a wide range of temperatures, advantageously from 20 ° C to 100 ° C.

Compounds of formula (II) in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , X and n are as defined above may be used in a number of known methods, in particular in Scheme 1 By the depicted method (FIG. 6), by acylating the compound of formula (III), it can be obtained using an acylation method known in organic chemistry. The acylating agent is preferably acyl chloride applied and triethylamine and / or pyridine may be applied as the acid binder, but other acid binders may be used.

Compounds of formula (III) wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , X and n are as defined above are prepared from compounds of formula (IV) using known methods. (Nan Zhang, Bioorg and Med., Chem. Lett., 10, 2825, 2000).

Compounds of formula (IV) wherein R ⁴ , R ⁵ and R ⁶ are as defined above can be prepared from compounds of formula (V) using known methods (DL Leysen, J. Heterocyclic Chem., 24, 1611, 1987).

Compounds of formula (V) wherein R ⁴ , R ⁵ and R ⁶ are as defined above may be prepared from compounds of formula (VI) using known methods (Pfizer (Inc) USP 4,175,193).

The compounds of formula (I), (II), (III) and (IV) of the present invention, their preparation and biological activity are illustrated in the following examples, but the claims are not limited to these examples. .

Example

Example 1

3- methyl -N- (4- Benzylamino -3- Cyanoquinoline -2 days) Benzamide :

In formula (I), R ¹ and R ² are hydrogen atoms, R ³ is a phenyl group, R ⁴ and R ⁵ together form a 1,3-butadienyl group, R ⁶ is a cyano group, and R ⁷ is 3-methylphenyl group, X is -NH group, n is 1.

a) 2-amino-3- cyano- 4 -chloroquinoline :

A mixture of 10 g 2-amino-3-cyano-4-hydroxyquinoline and 15 ml phosphoryl chloride was heated at 110 ° C. under stirring. The reaction mixture was cooled, poured into 100 ml of ice water and neutralized with 60 ml of 10% sodium hydroxide solution. The resulting yellow precipitate was filtered off and washed with 50 ml of water. After drying, 7.5 g of the title compound were obtained. Melting point: 210 ° C.

NMR, δ _H (400 MHz, DMSO-d ₆ ): 7.21 ppm, (s, 2H, NH ₂ ), 7.35-7.40 ppm, (dd, 1H, 6-H), 7.53-7.57 ppm, (d, 1H , 5-H), 7.70-7.75 ppm, (dd, 1H, 7-H), 7.93-7.98 ppm, (d, 1H, 8-H)

b) 2-amino-3- cyano- 4- benzylaminoquinoline

5 g of 2-amino-3-cyano-4-chloroquinoline and 11 ml of benzylamine were heated at 130 ° C. under stirring. The reaction mixture was poured into 50 ml of water and the resulting precipitate was filtered off and washed with 50 ml of water. The pale yellow precipitate was recrystallized from dimethylformamide to give 5.2 g of the title compound. Melting point: 206 캜.

NMR, δ _H (400 MHz, DMSO-d ₆ ): 5.02-5.03 ppm, (d, 2H, N-CH ₂ ), 6.22ppm (s, 2H, NH ₂ ), 7.14-7.16ppm, (dd, 1H , 6-H), 7.24-7.26 ppm, (dd, 1H, 5-H), 7.30 ppm, (s, 5H, Ph), 7.50-7.52 ppm (dd, 1H, 7-H), 8.16-8.19 ppm , (d, 1H, 8-H), 8.30-8.33 ppm (t, 1H, NH).

2-aminomethylpyridine or 3-aminomethylpyridine or 4-aminomethylpyridine can be used in place of benzylamine to obtain a suitable compound of formula (III).

c) 3- methyl- N- (3- methylbenzoyl ) -N- (4- benzylamino- 3 -cyanoquinolin -2-yl) benzamide :

To 5 g solution of 2-amino-3-cyano-4-benzylaminoquinoline in 30 ml of pyridine, 6 ml of 3-methylbenzoyl chloride was added dropwise at 0 ° C under stirring. The reaction mixture was stirred at 80 ° C. for 8 hours and then poured into 150 ml of ice water. The precipitate was filtered off and washed twice with 40 ml of water. The resulting white crystalline material was recrystallized from 200 ml of ethanol to give 9.2 g of the title compound. Melting point: 234 ° C.

Pyridine-3-carbonyl chloride as the acylating agent can be used to obtain a suitable compound of formula (II).

d) 3- methyl- N- (4- benzylamino- 3 -cyanoquinolin -2-yl) benzamide

20 ml of 1N methanolic potassium hydroxide solution was added to a solution of 5 g of 3-methyl-N- (3-methylbenzoyl) -N- (4-benzylamino-3-cyanoquinolin-2-yl) benzamide in 80 ml of acetonitrile. Added. After the reaction mixture was refluxed for 3 minutes, 3 ml of glacial acetic acid was added, followed by neutralization with 50 ml of 1 M sodium hydrogen carbonate solution, and the resulting crystals were filtered. The white crystalline material was recrystallized from 130 ml of acetonitrile to give 3.1 g of the title compound of formula (I). Melting point: 230 ° C.

Example 2

4- Methoxy -N- (4- Benzylamino -3- Cyanoquinoline -2 days) Benzamide

In formula (I), R ¹ and R ² are hydrogen atoms, R ³ is a phenyl group, R ⁴ and R ⁵ together are a 1,3-butadienyl group, R ⁶ is a cyano group, and R ⁷ is 4- Is a methoxyphenyl group, X is a -NH- group, and n is 1.

2-amino-3-cyano-4-benzylaminoquinoline prepared as described in Example 1 was prepared using 4-methoxybenzoyl chloride similar to that described in Example 1 using 4-methoxy-N- (4 -Methoxybenzoyl) -N- (4-benzylamino-3-cyanoquinolin-2-yl) benzamide and optionally hydrolyzed by the method described in Example 1, followed by formula (I) The compound was obtained. Melting point of title compound: 188 ° C.

The sodium salt of the title compound was prepared by the following method:

4-methoxy-N- (4-benzylamino-3-cyanoquinolin-2-yl) benzamide was dissolved in methanol and the same amount of sodium hydroxide in methanol was added thereto. The precipitated white crystalline material was filtered off. Melting point 255 ° C.

The ethanesulfonate salt of the title compound was prepared by the following method:

4-methoxy-N- (4-benzylamino-3-cyanoquinolin-2-yl) benzamide was dissolved in methanol and the same amount of ethanesulfonic acid was added thereto. The precipitated white crystalline material was filtered off. Melting point 223 ° C.

Example 3

3- Methoxy -N- (4- Benzylamino -3- Cyanoquinoline -2 days) Benzamide

In formula (I), R ¹ and R ² are hydrogen atoms, R ³ is a phenyl group, R ⁴ and R ⁵ together are a 1,3-butadienyl group, R ⁶ is a cyano group, and R ⁷ is 3- Is a methoxyphenyl group, X is a -NH- group, and n is 1.

2-amino-3-cyano-4-benzylaminoquinoline prepared as described in Example 1 was prepared using 3-methoxybenzoyl chloride similarly as described in Example 1 using 3-methoxy-N- (3 -Methoxybenzoyl) -N- (4-benzylamino-3-cyanoquinolin-2-yl) benzamide and optionally hydrolyzed by the method described in Example 1, followed by the title of formula (I) The compound was obtained. Melting point of the title compound: 186 ° C.

Example 4

3,4- Methylenedioxy -N- (4- Benzylamino -3- Cyanoquinoline -2 days) Benzamide

In formula (I), R ¹ and R ² are hydrogen atoms, R ³ is a phenyl group, R ⁴ and R ⁵ together are a 1,3-butadienyl group, R ⁶ is a cyano group, R ⁷ is 3, It is a 4-methylenedioxyphenyl group, X is a -NH- group, n is 1.

2-amino-3-cyano-4-benzylaminoquinoline prepared as described in Example 1 was treated with 3,4-methylenedioxy-N using 4-methoxybenzoyl chloride similarly as described in Example 1. -(3,4-methylenedioxybenzoyl) -N- (4-benzylamino-3-cyanoquinolin-2-yl) benzamide and optionally hydrolyzed by the method described in Example 1 The title compound of formula (I) was obtained. Melting point of the title compound: 231 ° C.

Example 5

N- (4- Benzylamino -3- Cyanoquinoline -2-yl) thiophene-2- Carboxamide

In formula (I), R ¹ and R ² are hydrogen atoms, R ³ is a phenyl group, R ⁴ and R ⁵ together are a 1,3-butadienyl group, R ⁶ is a cyano group, and R ⁷ is 2- Thienyl group, X is -NH- group, n is 1.

2-amino-3-cyano-4-benzylaminoquinoline prepared as described in Example 1 was treated with N- (2-thiophene using thiophene-2-carbonyl chloride similarly as described in Example 1. After converting to carbonyl) -N- (4-benzylamino-3-cyanoquinolin-2-yl) thiophene-2-carboxamide and optionally hydrolyzing by the method described in Example 1 ) Gave the title compound. Melting point of title compound: 197 ° C.

Example 6

N- (4- [2- Thienylmethylamino ] -3- Cyanoquinoline -2-yl) thiophene-3- Carboxamide

In formula (I), R ¹ and R ² are hydrogen atoms, R ³ is 2-thienyl group, R ⁴ and R ⁵ together are 1,3-butadienyl group, R ⁶ is cyano group, R ⁷ Is a 3-thienyl group, X is a -NH- group, and n is 1.

a) 2-amino-3- cyano- 4- (2- thienylmethylamino ) quinoline

5 g of 2-amino-3-cyano-4-chloroquinoline prepared as described in Example 1 were stirred with 11 ml of 2-thienylmethylamine for 3 hours at 130 ° C. The reaction mixture was poured into 50 ml of water and the precipitate obtained was filtered off and washed with 50 ml of water. The pale yellow material was recrystallized from 25 ml of ethanol to give 5.2 g of the title compound. Melting point: 208 캜.

2-amino-3-cyano-4- (2-thienylmethylamino) quinoline prepared as described above was prepared using N- (3 using thiophene-3-carbonyl chloride similarly as described in Example 1. -Thiophencarbonyl) -N- (4- [2-thienylmethylamino] -3-cyanoquinolin-2-yl) -thiophene-3-carboxamide and the method described in Example 1 After selective hydrolysis by, the title compound of formula (I) was obtained. Melting point of the title compound: 223 ° C.

Example 7

4- Methoxy -N- (4- [2- Thienylmethylamino ] -3- Cyanoquinoline -2 days) Benzamide

In formula (I), R ¹ and R ² are hydrogen atoms, R ³ is 2-thienyl group, R ⁴ and R ⁵ together are 1,3-butadienyl group, R ⁶ is cyano group, R ⁷ Is a 4-methoxyphenyl group, X is a -NH- group, and n is 1.

2-amino-3-cyano-4- (2-thienylmethylamino) quinoline prepared as described in Example 6 was prepared using 4-methoxybenzoyl chloride by the method described in Example 1 Methoxy-N- (4-methoxybenzoyl) -N- (4- [2-thienylmethylamino] -3-cyanoquinolin-2-yl) benzamide, optionally hydrolyzed and then converted into The title compound of I) was obtained. Melting point of title compound: 173 ° C.

Example 8

3,4- methylenedioxy- N- (4- [2- thienylmethylamino ] -3 -cyanoquinolin -2-yl) benzamide

In formula (I), R ¹ and R ² are hydrogen atoms, R ³ is 2-thienyl group, R ⁴ and R ⁵ together are 1,3-butadienyl group, R ⁶ is cyano group, R ⁷ Is a 3,4-methylenedioxyphenyl group, X is a -NH- group, and n is 1.

2-amino-3-cyano-4- (2-thienylmethylamino) quinoline prepared as described in Example 6 was prepared using 3,4-methylenedioxybenzoyl chloride by the method described in Example 1. 3,4-methylenedioxy-N- (3,4-methylenedioxybenzoyl) -N- (4- [2-thienylmethylamino] -3-cyanoquinolin-2-yl) benzamide And optionally hydrolyzed to afford the title compound of formula (I). Melting point of the title compound: 241 ° C.

Example 9

N- (4- [2- Furylmethylamino ] -3- Cyanoquinoline -2-yl) furan-2- Carboxamide

In formula (I), R ¹ and R ² are hydrogen atoms, R ³ is 2-furyl group, R ⁴ and R ⁵ together are 1,3-butadienyl group, R ⁶ is cyano group, R ⁷ Is a 2-furyl group, X is a -NH- group, and n is 1.

a) 2-amino-3- cyano- 4- (2- furylmethylamino ) quinoline

5 g of 2-amino-3-cyano-4-chloroquinoline prepared as described in Example 1 were stirred with 1 ml of 2-furylmethylamine (furfurylamine) at 130 ° C. for 3 hours. The reaction mixture was poured into 50 ml of water and the resulting precipitate was filtered off and washed with 50 ml of water. The pale yellow material was recrystallized from 20 ml of ethanol to give 4.8 g of the title compound. Melting point: 208 캜.

2-Amino-3-cyano-4- (2-furylmethylamino) quinoline prepared as described above was treated with N- (2-furan using furan-2-carbonyl chloride by the method described in Example 1. Carbonyl) -N- (4- [2-furylmethylamino] -3-cyanoquinolin-2-yl) furan-2-carboxamide, optionally hydrolyzed and then titled Formula (I) The compound was obtained. Melting point of title compound: 196 ° C.

Example 10

N- (4- [2- Furylmethylamino ] -3- Cyanoquinoline -2-yl) thiophene-3- Carboxamide

In formula (I), R ¹ and R ² are hydrogen atoms, R ³ is 2-furyl group, R ⁴ and R ^{5 together} are 1,3-butadienyl group, R ⁶ is cyano group, R ⁷ is a 3-thienyl group, X is a -NH- group, and n is 1.

2-Amino-3-cyano-4- (2-furylmethylamino) quinoline prepared as described in Example 6 was treated with N- using thiophene-3-carbonyl chloride by the method described in Example 1. (3-thiophene carbonyl) -N- (4- [2-furylmethylamino] -3-cyanoquinolin-2-yl) thiophene-3-carboxamide, and as described in Example 1 Similarly, after selective hydrolysis, the title compound of formula (I) is obtained. Melting point of title compound: 118 ° C.

The structural and physical characteristics of additional compounds of formula (I) prepared by the process described in Example 1 are shown in Tables I and II.

Table I.

Table II.

The structural and physical properties of the intermediates of formula (II) prepared by the method described in Example 1 are shown in Table III.

Table III.

The structural and physical characteristics of the intermediates of formulas (III) and (IIIa) prepared by the method described in Example 1 are shown in Table IV.

Table IV.

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

Table V.

Example 167

Tablets having the following composition are prepared by known methods used in the pharmaceutical industry.

25 mg active ingredient

Lactose 50mg

Avicel 21mg

Crospovidone 3mg

Magnesium Stearate 1mg

biology

Way

Human Adenosine A ₃  Receptor binding

Preparation of Membrane Suspension: CHO cells expressing hA ₃ receptors were harvested three times with ice cold PBS, centrifuged at 1000 xg for 10 minutes, and in buffer (50 mM Tris, 10 mM MgCl ₂ , 1 mM EDTA, pH 8.0). Homogenize for 15 seconds, centrifuge at 43,000 xg for 10 minutes (Sigma 3K30) and suspend the membrane preparation in the above-mentioned buffer and store the aliquots at -80 ° C.

Binding protocol: CHO-hA ₃ membrane preparation (2 μg protein content) was added with 0.5 nM [ ¹²⁵ I] AB-MECA (p-amino-benzyl-methylcarboxamido-adenosine) (100.000 cpm) and 100 μM R-PIA ( Incubate in the presence of N ^6- [L-2-phenylisopropyl] adenosine) (50 mM Tris, 10 mM MgCl ₂ , 1 mM EDTA, 3 U / ml adenosine deaminase, pH 8.0) for a total of 1 hour at room temperature Define nonspecific binding or test compounds in 50 μL of volume. Filter on a Whatman GF / B glass fiber filter (pre-soaked in 0.5% polyethyleneimine for 3 hours) and 4 on a 96-well Brandel cell collector with 1 mL ice-cold 50 mM Tris, 10 mM MgCl ₂ , 1 mM EDTA, pH 8.0. Wash twice. Activity is detected in a gamma-counter (1470 Wizard, Wallac). % Inhibition = 100-((activity in the presence of test compound-nonspecific activity) / (total activity-nonspecific activity)) * 100

Human Adenosine A _One  Receptor binding

Preparation of Membrane Suspension: CHO cells expressing hA ₁ receptors were harvested three times with ice cold PBS, centrifuged at 1000 xg for 10 minutes, homogenized in buffer (50 mM Tris, pH 7.4) for 15 seconds, and 10 Centrifuge at 43,000 xg for minutes (Sigma 3K30) and suspend the membrane preparation in the above-mentioned buffer and store the aliquot at -80 ° C.

Binding protocol: incubation buffer (50 mM Tris, 3 U / ml adenosine deaminase, pH 7.4), 10 nM [ ³ H] CCPA (2-chloro-N ⁶ -cyclopentyl) in a CHO-hA ₁ membrane preparation (50 μg protein content) Incubate in adenosine) (80.000dpm) and 10 μM R-PIA (N ^6- [L-2-phenylisopropyl] adenosine) to define nonspecific binding or test compounds in 100 μL total volume for 3 hours at room temperature. Filter on a Whatman GF / B glass fiber filter (presoaked in 0.5% polyethyleneimine for 3 hours) and wash 4 times on a 96 well Brandel cell harvester with 1 mL ice cold 50 mM Tris (pH 7.4). Activity is detected in 96-well plates in the beta-counter (1450 Microbeta, Wallac) in the presence of a HiSafe-3 cocktail. % Inhibition = 100-((activity in the presence of test compound-nonspecific activity) / (total activity-nonspecific activity)) * 100

Human Adenosine A _2a  Receptor binding

Binding protocol: 7 μg of membrane (human A _2a adenosine receptor transfected with HEK-293 cells, Receptor Biology, Inc.), 7 μg, buffer (50 mM Tris-HCl, 10 mM MgCl ₂ , 1 mM EDTA, 2U / ml adenosine des) Aminase, pH 7.4), 20 nM [ ³ H] CGS-21680 (2- [p- (2-carbonylethyl) phenylethylamino] -5'-N-ethylcarboxamido-adenosine) (200.000dpm) And 50 μM NECA (5′-N-ethylcarboxamido-adenosine) to incubate non-specific binding or test compounds in 100 μL total volume for 90 minutes at room temperature. Filter on a Whatman GF / B glass fiber filter (presoaked in 0.5% polyethyleneimine) and filter on a 96 well Brandel cell collector with 1 mL ice cold 50 mM Tris, 10 mM MgCl ₂ , 1 mM EDTA, 0.9% NaCl pH 7.4. Wash 4 times. Activity is detected in 96-well plates in the beta-counter (1450 Microbeta, Wallac) in the presence of a HiSafe-3 cocktail. % Inhibition = 100-((activity in the presence of test compound-nonspecific activity) / (total activity-nonspecific activity)) * 100

Human Adenosine A _2b  Receptor binding

Binding protocol: 20.8 μg of membrane (human A _2b adenosine receptor transfected with HEK-293 cells, Receptor Biology, Inc.), buffer (50 mM Tris-HCl, 10 mM MgCl ₂ , 1 mM EDTA, 0.1 mM benzamidine , 2U / ml adenosine deaminase, pH 6.5), 32.4 nM [ ³ H] DPCPX (8-cyclopentyl-1,3-dipropylxanthine) (800.000dpm) and 100 μM NECA (5′-N-ethylca Incubation in voxamido-adenosine to define nonspecific binding or test compounds in a total volume of 100 μL for 30 minutes at room temperature. Filter on a Whatman GF / C glass fiber filter (presoaked in 0.5% polyethyleneimine) and wash four times on a 96 well Brandel cell collector with 1 mL ice cold 50 mM Tris-HCl, pH 6.5. Activity is detected in 96-well plates in the beta-counter (1450 Microbeta, Wallac) in the presence of a HiSafe-3 cocktail. % Inhibition = 100-((activity in the presence of test compound-nonspecific activity) / (total activity-nonspecific activity)) * 100.

result

The inventors deem that the compounds of the present invention are biologically active when they inhibit the binding of the radioligand to the human A ₃ receptor with greater than 80% activity at 1 μM under the present experimental conditions.

The dissociation constant (K _d ) of [ ¹²⁵ I] AB-MECA on CHO-hA ₃ membrane formulation is determined by isotope saturation studies with reference to Scatchard analysis (G. Scatchard, Ann. NY Acad. Sci. 51 : 660, 1949). IC ₅₀ is converted to an affinity constant (K _i ) by applying the Blue-Fruthor equation (YJ Cheng and WH Prusoff, Biochem. Pharmacol. 22: 3099, 1973).

Many of the compounds of formula (I), (II), (III) and (IV) show significant biological effects. Compounds of formula (IA) as defined in claim 2 as subgroups of formula (I) as defined in claim 1 exhibit the most important activities. Except for five compounds, its K _i value is 20 nM or less. Particularly advantageous are the compounds given as examples. In human adenosine A ₃ receptor binding studies, their K _i values are between 0.19 and 0.69 nM. K _i values of the most advantageous compounds are from 0.14 to 0.15 nM.

The compounds of the present invention have a suitable bioavailability and exerted more than 10,000 fold selectivity compared to human adenosine A ₁ , A _2a and A _2b receptor subtypes.

In addition, its duration of action is long enough for intravenous and oral administration, its ED ₅₀ value is low, and its toxicological and side effects profile is advantageous.

The data make promising therapeutic applications of the compounds of formula (I).

The present invention, among other things, has a strong antagonistic effect on the A ₃ receptor and a high selectivity, i.e., a quinoline structure that inhibits the A ₃ receptor at a much lower concentration than inhibiting the A ₁ , A _2a and A _2b receptors. _It produces the effect of preparing _three ligands, preferably antagonists.

Claims (4)

A pharmaceutical composition for anti-inflammatory, anti-asthma, anti-ischemic, anti-depressive, antiarrhythmic, renal protection, anti-tumor, anti-Pakison and cognitive enhancement, comprising a compound of formula (I) Adult respiratory distress syndrome (ARDS), including injury, chronic obstructive pulmonary disease (COPD) and chronic bronchitis, pulmonary pneumoconiosis or dyspnea ) Pharmaceutical compositions used to treat other autoimmune diseases, inflammatory bowel disease, Addison's disease, Crohn's disease, psoriasis, rheumatism, hypertension, neurological dysfunction, glaucoma and diabetes:

Where R ¹ is a hydrogen atom or a linear or branched C _{1 -4} alkyl group, R ² is a hydrogen atom or a linear or branched C _{1 -4} alkyl group, R ³ is a hydrogen atom or a linear or branched C _{1 -4} alkyl group, or one or more linear or branched C _{1 -4} alkyl group, a linear or branched C ₁ -C ₄ alkoxy group, or a non-substituted or not substituted by a halogen atom a phenyl group, thienyl group or furyl group, or, one or more linear or branched C ₁ -C ₄ alkyl group, a linear or branched C _{1 -4} alkoxy group or a halogen atom, a substituted or unsubstituted 1 to 3 nitrogen atoms or by 1 A 5 or 6 membered heteroaromatic ring containing 1 nitrogen atom and 1 oxygen atom or 1 nitrogen atom and 1 sulfur atom, R ⁴ and R ⁵ together are 1,3-dioxide are methylene group or one or more linear or branched C _{1 -4} alkyl group, a linear or branched C _{1 -4} alkoxy group, hydroxyl group or optionally substituted by a halogen atom Forming a butadienyl group, R ⁶ is a hydrogen atom or a cyano group, aminocarbonyl group, C _{1 -4} alkoxycarbonyl group, or carboxy group, R ⁷ is a hydrogen atom or a linear or branched C _{1 -4} alkyl group, or a methylene group-dioxide or one or more linear or branched C _{1 -4} alkyl group, a linear or branched C _{1 -4} alkoxy group, hydroxyl group, trifluoromethyl a methyl group, a cyano group or a non-substituted or not substituted by a halogen atom, phenyl group, benzyl group, thienyl group or furyl group, or, one or more linear or branched C _{1 -4} alkyl group, a linear or branched C _{1 -4} alkoxy group, or A 5- or 6-membered heteroaromatic ring containing 1 to 3 nitrogen atoms or 1 nitrogen atom and 1 oxygen atom or 1 nitrogen atom and 1 sulfur atom not substituted or substituted by a halogen atom, X is a -CH ₂ group, -NH- group, -NR ⁸ - group giving (wherein, R ⁸ is a linear or branched C _{1 -4} alkyl or C _{3 -6} cycloalkyl alkyl group) or a sulfur atom or an oxygen atom or a sulfonic Or snowfall, n is 0, 1 or 2. A compound of formula (I) according to claim ¹ , wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , X and n have the same meaning as defined in claim 1 A pharmaceutical composition for use in the treatment of asthma, COPD and ARDS, glaucoma, tumors, allergic and inflammatory diseases, ischemia, hypoxia, arrhythmia and kidney disease, comprising. A pharmaceutical composition for anti-inflammatory, anti-asthma, anti-ischemic, anti-depressive, antiarrhythmic, renal protection, anti-tumor, anti-Pakison and cognitive enhancement, comprising a compound of formula (IA) Adult respiratory distress syndrome (ARDS), including injury, chronic obstructive pulmonary disease (COPD) and chronic bronchitis, pulmonary pneumoconiosis or dyspnea ) Pharmaceutical compositions used to treat other autoimmune diseases, inflammatory bowel disease, Addison's disease, Crohn's disease, psoriasis, rheumatism, hypertension, neurological dysfunction, glaucoma and diabetes:

Where R ¹ is a hydrogen atom or a linear or branched C _{1 -4} alkyl group, R ² is a hydrogen atom or a linear or branched C _{1 -4} alkyl group, R ³ is a hydrogen atom or a linear or branched C _{1 -4} alkyl group, or one or more linear or branched C _{1 -4} alkyl group, a linear or branched C _{1 -4} alkoxy groups or halogen atoms or substituted by an unsubstituted phenyl group , a thienyl group or a furyl group, or, one or more linear or branched C ₁ -C ₄ alkyl group, a linear or branched C _{1 -4} alkoxy group, or a non-substituted or not substituted by a halogen atom, one to three nitrogen atoms or one A 5 or 6 membered heteroaromatic ring containing a nitrogen atom and 1 oxygen atom or 1 nitrogen atom and 1 sulfur atom, R ^9, R ^10, R ¹¹ and R ¹² are each independently a hydrogen atom, or a linear or branched C _1-4 alkyl group, a linear or branched C _{1 -4} alkoxy group, or a hydroxyl group or a halogen atom, R ⁹ and R ¹² are hydrogen atoms and R ¹⁰ and R ¹¹ together form a methylenedioxy group, R ⁶ is a hydrogen atom or a cyano group, aminocarbonyl group, C _{1 -4} alkoxycarbonyl group, or carboxy group, R ⁷ is a hydrogen atom or a linear or branched C _{1 -4} alkyl group, or methylene-dioxide group, or one or more linear or branched C _{1 -4} alkyl group, a linear or branched C _{1 -4} alkoxy group, hydroxyl group, tri It substituted by a methyl group, a cyano group or a halogen atom, a fluoroalkyl or unsubstituted phenyl group, benzyl group, thienyl group or furyl group, or, one or more linear or branched C _{1 -4} alkyl group, a linear or branched C _{1 -4} alkoxy group Or a 5- or 6-membered heteroaromatic ring containing 1 to 3 nitrogen atoms or 1 nitrogen atom and 1 oxygen atom or 1 nitrogen atom and 1 sulfur atom unsubstituted or substituted by a halogen atom, X is -CH ₂ - group, -NH- group, -NR ⁸ - group (wherein, R ⁸ is a linear or branched C _{1 -4} alkyl or C _{3 -6} cycloalkyl alkyl group) or a sulfur atom or an oxygen atom or a sulfonic Give up or snowfall, n is 0, 1 or 2. 4. A compound according to claim 3 wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , X and n A pharmaceutical composition for use in the treatment of asthma, COPD and ARDS, glaucoma, tumors, allergies and inflammatory diseases, ischemia, hypoxia, arrhythmia and kidney disease, comprising a compound of formula (IA) having the same meaning as defined.

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