Benzoxazole derivatives and pharmaceutical composition having properties of adenosine receptor ligands

FIELD: chemistry.

SUBSTANCE: invention refers to benzothiazole derivatives of general formula I and to their pharmaceutically acceptable acid-additive salts as adenosine receptor ligands and based medicinal product. Compounds can be applied for treatment and prevention of diseases mediated by adenosine receptors, e.g., epilepsy, depressions, narcomania, Parkinson's disease. In general formula I R denotes phenyl unsubstituted or substituted with halogen or -SN2N(CH3) (CH2)nOCH3, or denotes benzyl, lower alkyl, lower alkoxy-group, - (CH2)nOCH3, or denotes pyridine-3- or -4-yl unsubstituted or substituted with lower alkyl, halogen, morpholinyl, - (CH2)n-halogen, - (CH2)nOCH3, - (CH2)n-diethylene-imide oxide-4-yl, or (CH2)n-tetrahydropyrrole-1-yl; R1 denotes phenyl unsubstituted or substituted with halogen tetrahydropyran-4-yl, 3,6-2H-2n-pyran-4-yl or morpholine-4-yl; n denotes mutually independent 1 or 2.

EFFECT: production of benzothiazole derivatives which can be applied for treatment and prevention of diseases mediated by adenosine receptors.

9 cl, 4 dwg, 27 ex

 

The present invention relates to compounds of General formula

where

R denotes phenyl, unsubstituted or substituted with halogen or-CH2N(CH3)(CH3)nOch3or denotes benzyl, lower alkyl, lower alkoxy group, -(CH2)nOch3or denotes pyridine-3 - or-4-yl, unsubstituted or substituted lower alkyl, halogen, morpholinyl, -(CH2)n-halogen, -(CH2)nOch3, -(CH2)n-morpholine-4-yl, or -(CH2)n-pyrrolidin-1-yl;

R1denotes phenyl, unsubstituted or substituted with halogen tetrahydropyran-4-yl, 3,6-dihydro-2H-Piran-4-yl or morpholine-4-yl;

n denotes independently from each other 1 or 2;

and their pharmaceutically acceptable acid additive salts.

It has been unexpectedly found that compounds of General formula I are ligands of the adenosine receptor. In particular, the compounds according to the present invention have a good affinity And2A-receptor and a high selectivity to A1and And3-receptors.

Adenosine simulates a wide area of physiological functions by interacting with specific surface receptors of the cells. Review potential adenosine receptor as a drug who's target was first published in 1982 Adenosine as structural and metabolic relates to bioactive nucleotides: adenosine triphosphate (ATP), adenosine diphosphate (ADP), the monophosphate (AMP) and cyclic monophosphate (C-AMP); biochemical meteorous agent of S-adenosyl-L-methionine (SAM); and structurally to the coenzyme NAD, FAD, and coenzyme A; and RNA. Together adenosine and these related compounds play an important role in regulating many aspects of cellular metabolism and modulation of different activity of the Central nervous system.

In addition, it is known that the binding of agonist adenosine receptor with fat cells, expressing And3receptor rats, leads to an increase inositoltrifosfata and intracellular calcium concentrations, which patentiert induced by antigen secretion of inflammatory mediators. Therefore, A3receptor plays a mediating role when asthma attacks and other allergic reactions.

Adenosine is a neuromodulator that is able to modulate many aspects of the physiological functions of the brain. Endogenous adenosine, the Central link between energy metabolism and neuronal activity, changes in accordance with behavioral state and (Pato)physiological conditions. In conditions of increased demand and reduced availability of energy (such as the ISU is Xia, hypoglycemia and/or excessive neuronal activity) adenosine provides a powerful protective feedback mechanism. Interaction with the adenosine receptor is a promising target for therapeutic intervention in a number of neurological and psychiatric diseases, such as epilepsy, sleep disorders, movement disorders (Parkinson's disease or Huntington), depression, schizophrenia or drug addiction. Increased release of the neurotransmitter follows the injury, such as hypoxia, ischemia and seizures. These neurotransmitters, in the end, responsible for neural degeneration and neural death, causing brain damage or death of the individual. Agonists of the adenosine A1that mimic the Central inhibitory effects of adenosine, can therefore be used as neuroprotective agents. Adenosine has been proposed as an endogenous anticonvulsive agent that inhibits the release of glutamate from the excited neurons and inhibitory neuronal inflammation. Agonists of adenosine can be used therefore as anti-epileptic agents. Antagonists of adenosine stimulate the activity of the Central nervous system and, as it turns out, are effective as agents improving cognitively. Selective And2Aantagonists have terapeutiche is a great potential in the treatment of various forms of dementia, for example, Alzheimer's disease, and neurodegenerative disorders such as stroke. The antagonist of the adenosine A2Areceptor models the activity veins GABA-eliteskin neurons and regulates smooth and well-coordinated movement, giving thus the opportunity for therapy parkinsonism syndromes. Adenosine is also involved in a number of physiological processes included in sedation, hypnosis, schizophrenia, fear, pain, lack of breath, depression, drug addiction (amphetamine, cocaine, opioids, ethanol, nicotine, organic substances derived from cannabis). Therefore, drugs acting on adenosine receptors have therapeutic potential as sedatives, muscle relaxants, antipsychotics, the anti-anxiety agents, analgesics, respiratory stimulants, antidepressants, and in the treatment of drug abuse. They can also be used in the treatment of ADHD (attention deficit-induced hyperactivity).

An important role for the cardiovascular system adenosine performs as a cardioprotective agent. The levels of endogenous adenosine are increased in response to ischemia and hypoxia and protect the tissue of the heart muscle during and after injury (preconditioning). Effect on A 1receptor agonists And1adenosine is able to protect from damage caused by myocardial ischemia and reperfusion. Simulating the effect of A2Areceptors on adrenergic function may be important for various diseases, such as coronary arterial disease and heart failure. And2Aantagonists may provide a fruitful therapeutic effect in situations in which the desired enhanced antiadrainergicakimi reaction, such as during acute myocardial ischemia. Selective antagonists And2Areceptors can also enhance the effectiveness of adenosine in the final stage of supraventricular arrhythmia.

Adenosine simulates many aspects of renal function, including the secretion of renin, the rate of glomerular filtration and renal flow of blood. Compounds that counteract the renal effects of adenosine have potential as a renal protective agent. In addition, the adenosine A3and/or And2Aantagonists can be used in the treatment of asthma and other allergic reactions and in the treatment of diabetes and obesity.

Numerous documents describe current research on adenosine receptors, for example, the following publications:

Bioorganic & Medicinal Chemistry, 6, (1998), 619-641,

Bioorganic & Medicinal Chemistry, 6, (1998), 707-719,

J Med. Chem., (1998), 41, 2835-2845,

J. Med. Chem., (1998), 41, 3186-3201,

J. Med. Chem., (1998), 41, 2126-2133,

J. Med. Chem., (1999), 42, 706-721,

J. Med. Chem., (1996), 39, 1164-1171,

Arch. Pharm. Med. Chem., 332, 39-41, (1999),

Am. J. Physiol., 276, H1113-1116, (1999) or

Naunyn Schmied, Arch. Pharmacol. 362, 375-381, (2000).

Objects of the present invention are the compounds of formula I, as such, the use of compounds of the formula I and their pharmaceutically acceptable salts for the production of medicaments for the treatment of diseases associated with a2receptor, their manufacture, medicaments based on a compound in accordance with the invention, and receipt of them, and also the use of compounds of formula I for the control or prevention of illnesses based on the modulation adenozinovmi system, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, neuroprotection, schizophrenia, fear, pain, lack of breath, depression, drug addiction (amphetamine, cocaine, opioids, ethanol, nicotine, organic substances derived from cannabis), or asthma, allergic responses, hypoxia, ischaemia, seizure and substance abuse. In addition, the compounds of the present invention can be used as sedatives, muscle relaxants, antipsychotics, ANTIEPILEPTICS funds, anticonvulsants and cardioprotective agents in such disorders as coronary arter the social disease and heart failure. The most preferred indications in connection with the present invention are such that based on antagonistic activity relative to A2Areceptor, and which include disorders of the Central nervous system, for example, the treatment or prevention of Alzheimer's disease, Central depressive disorder, drug addiction, neuroprotection and Parkinson's disease, and ADHD.

Used in this description, the term "lower alkyl" denotes an alkyl group with a linear or branched chain containing from 1 to 6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, n-butyl, ISO-butyl, 2-butyl, tert.-butyl and the like. Preferred lower alkyl groups are groups containing from 1 to 4 carbon atoms.

The term "halogen" denotes chlorine, iodine, fluorine or bromine.

The term "lower alkoxy group" means a group in which the alkyl residue is as defined above attached through an oxygen atom.

The term "pharmaceutically acceptable acid additive salt" includes salts of inorganic or organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-tol is alsultany acid and the like.

Preferred compounds of the present invention are the compounds of formula I in which R1denotes 4-forfinal. Such compounds are:

2-Chloromethyl-N-[7-(4-forfinal)-4-methoxybenzimidazole-2-yl]isonicotinamide,

N-[7-(4-Forfinal)-4-methoxybenzimidazole-2-yl]-2-methylethanolamine,

N-[7-(4-Forfinal)-4-methoxybenzimidazole-2-yl]-6-nicotine amide,

4-Fluoro-N-[7-(4-forfinal)-4-methoxybenzimidazole-2-yl]benzamide,

N-[7-(4-Forfinal)-4-methoxybenzimidazole-2-yl]-2-morpholine-4-yl-isonicotinamide or

N-[7-(4-Forfinal)-4-methoxybenzimidazole-2-yl]-2-methoxymethyl-isonicotinamide.

Further preferred are the compounds of formula I, in which R denotes unsubstituted phenyl, for example the following compounds:

4-Fluoro-N-(4-methoxy-7-phenylbenzoxazole-2-yl)benzamide or

4-{[(2-Methoxyethyl)methylamino]methyl}-N-(4-methoxy-7-phenylbenzoxazole-2-yl)-benzamide.

Further preferred are compounds where R1means tetrahydropyran-4-yl, for example the following compounds:

N-[4-Methoxy-7-(tetrahydropyran-4-yl)benzooxazol-2-yl]-6-nicotine amide or

N-[4-Methoxy-7-(tetrahydropyran-4-yl)benzooxazol-2-yl]-2-methylethanolamine.

These compounds of formula I and their pharmaceutically acceptable salts can be obtained by known prior art methods, for example by the method described the data below, which includes the processes of:

a) reaction of compounds of formula

with the compound of the formula

or

with the compound of the formula

with the formation of the compounds of formula

in which R1denotes phenyl, unsubstituted or substituted with halogen, or

b) reaction of compounds of formula

with the compound of the formula

or with the compound of the formula

with the formation of the compounds of formula

in which R1denotes unsubstituted or substituted with halogen phenyl,

or

b) hydrogenation of the compounds of formula

by H2/Pd/C

with the formation of connections

or

g) reaction of compounds of formula

with NaOH and then with the compound of the formula

or with the compound of the formula

with the formation of the compounds of formula

or

d) reaction of compounds of formula

with NaOH and then with compounds is receiving formula

or with the compound of the formula

with the formation of the compounds of formula

or

e) reaction of compounds of formula

with the compound of the formula

or with the compound of the formula

with the formation of connections

or

g) the modification of one or more of the substituents R1or R within the above definitions

and,

if desirable, the transformation obtained above in connection pharmaceutically acceptable acid additive salt.

The compounds of formula I can be obtained in accordance with the following scheme:

Obtaining compounds of the formula I, in which R1denotes phenyl or phenyl substituted by halogen

One method of preparing compounds of the formula I, in which R1denotes phenyl or phenyl substituted by halogen, comes from the intermediate of formula (5)as shown below in scheme 2. Obtaining the intermediate of formula (5) shown below in reaction scheme 1.

where R1denotes phenyl or substituted by halogen phenyl and R above.

Obtaining the intermediate of the formula (2)

The original 2-nitroresorcinol formula (1) are available commercially (from the firm Aldrich) or can be obtained according to methods well known in the prior art.

2-Nitroresorcinol formula (1) hydronaut in the presence of a hydrogenation catalyst, preferably 10%palladium on coal. This reaction may proceed in different solvents, such as methanol, ethanol, dioxane or tetrahydrofuran, preferably in methanol at room temperature and pressures of 1 ATM or higher, preferably at 1 ATM, for 2-24 hours, preferably for about 18 hours the Product formula (2), 2-aminoethanol, preferably used in the next stage without purification.

Obtaining the intermediate of formula (3)

The intermediate of formula (2) is reacted with a slight excess of canidrome in a mixture of an aqueous solvent, preferably in a mixture of lower alcohol and water, preferably in a mixture of methanol and water. The reaction preferably proceeds at room temperature for about 2 hours the Product benzoxazole compound of the formula (3), isolated by standard methods, and preferably purified by chromatography or recrystallization.

Obtaining the intermediate of formula (4)

A method of obtaining the intermediate of formula (4) is in the treatment of intermediate of formula (3) slight excess of a strong base, PR is doctitle of sodium hydride in an aprotic solvent, preferably tetrahydrofuran, at elevated temperature, preferably about 50°C for about 1 h; an intermediate connection are processed in order methyliodide, preferably with about 1 equivalent of methyliodide, at elevated temperature, preferably about 50°With, for 1-5 hours, preferably about 3 hours, the Product of formula (4) was isolated by standard methods, and preferably purified by chromatography or recrystallization.

Obtaining the intermediate of formula (5)

The intermediate of formula (4) is reacted with a slight excess of methylchloroform in an organic solvent, preferably dichloromethane. The reaction proceeds in the presence of an amine base, such as pyridine, triethylamine or N-ethyldiethanolamine, preferably pyridine, at a temperature below room temperature, preferably at 0°With, for 0.25 to 4 hours, the Product of formula (5) was isolated by standard methods, and preferably purified by chromatography or recrystallization.

Obtaining the intermediate of formula (6)

The intermediate of formula (5) is reacted with a slight excess jodorowski reagent, preferably of atmosohere, in an organic solvent, preferably acetic acid, at room temperature, for about 2-30 h, predpochtitelney 16 PM The product of formula (6) was isolated by standard methods, and preferably purified by chromatography or recrystallization.

Obtaining compounds of formula I (8) and/or formula (9)

Source tributylstannyl the compounds of formula (7) are commercially available, for example, from the company Fluka or can be obtained by methods well known in the prior art.

The intermediate of formula (6) is reacted with an excess of tributylstannyl formula (7) in an organic solvent, preferably in N,N-dimethylformamide, containing a palladium catalyst, preferably Tris(dibenzylideneacetone)dipalladium(0), a catalytic amount of phosphine or arsenova ligand, preferably triphenylarsine, and excess Cu(I) salt, preferably CuI. The reaction proceeds at elevated temperature, preferably about 80°With, for 2-24 hours, preferably about 16 hours the Product(s) was isolated by standard methods, and preferably purified by chromatography or recrystallization. Depending on the reaction parameters such as temperature and reaction time, the main reaction product may be a compound of formula I (8), in other cases, the main reaction product may be a compound of the formula (9), or the reaction can be obtained a mixture of products of formula I (8) and (9).

Alternative getting is soedinenii formula I (8) and/or formula (9)

The original connection Bronevoy acid of the formula (10) are available commercially, for example, from the company Fluka or can be obtained by methods well known in the prior art.

The compounds of formula I (8) or equation (9) alternative can be obtained by treating the intermediate of formula (6) excess connections Bronevoy acid of the formula (10). The reaction proceeds in an aqueous solvent, preferably a mixture of water, dioxane and 1,2-diethoxyethane, containing a palladium catalyst, preferably tetrakis(triphenylphosphine)palladium(0), the excess lithium salt, preferably lithium chloride, and inorganic base, preferably sodium carbonate. The reaction proceeds preferably at the boiling temperature of the solvent, preferably about 100°With, for 2-24 hours, preferably about 16 hours the Product(s) was isolated by standard methods, and preferably purified by chromatography or recrystallization. Depending on the reaction parameters such as temperature and reaction time, the main reaction product may be a compound of formula I (8), in other cases, the main reaction product may be a compound of the formula (9), or the reaction can be obtained a mixture of products of formula I (8) and (9).

Obtain intermediates of formula (9) compounds of formula I (8)

The compounds of formula I (8) can the be converted into the corresponding intermediates of formula (9) by reaction with excess aqueous base, such as lithium hydroxide, sodium hydroxide or potassium hydroxide, preferably sodium hydroxide. The reaction proceeds in an aqueous solvent, preferably a mixture of water and a miscible organic solvent, such as dioxane, tetrahydrofuran or ethylene glycol, preferably ethylene glycol at elevated temperature, preferably at the boiling temperature of the solvent, for 2-16 hours, preferably about 16 hours the Product of formula (9) was isolated by standard methods, and preferably purified by chromatography or recrystallization.

Obtaining compounds of formula I, where R1denotes phenyl or halogen-substituted phenyl

One method of preparing compounds of formula I, where R1denotes phenyl or halogen-substituted phenyl, is in the handling of the intermediate of formula (9) a slight excess of the corresponding acylchlorides formula (11), which is commercially available or can be obtained by methods well known in the prior art. Can also be used such catalyst as N,N-dimethyl-4-aminopyridine. The reaction proceeds in an aprotic organic solvent, preferably a mixture of dichloromethane and tetrahydrofuran, containing a base, preferably N-ethyldiethanolamine or triethylamine, at temperatures between room temperature and the pace is atural boiling solvent for 2-24 h, preferably 16 hours, the Product of formula I, where R1denotes phenyl or halogen-substituted phenyl, isolated by standard methods, and preferably purified by chromatography or recrystallization.

Alternative obtaining the compounds of formula I, where R1denotes phenyl or halogen-substituted phenyl

An alternative method of preparing compounds of formula I where R1denotes phenyl or halogen-substituted phenyl, includes the treatment of the corresponding carboxylic acid of formula (12) stoichiometric equivalent of the reagent for condensing with the peptide, preferably O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethyluronium hexaflurophosphate (HATU), in an ethereal solvent, preferably tetrahydrofuran, containing a base, preferably N-ethyldiethanolamine at room temperature for 30-90 minutes, preferably 1 hour the Mixture is then processed by the intermediate of formula (9) in a mixture of solvents, preferably in a mixture of tetrahydrofuran, dioxane and N,N-dimethylformamide at room temperature for 16-24 hours, preferably 16 hours, the Product of formula I, where R1denotes phenyl or halogen-substituted phenyl, isolated by standard methods, and preferably purified by chromatography or recrystallization.

Obtaining compounds of formula I, where R1denotes a 36-dihydro-2H-Piran-4-yl or tetrahydropyran-4-yl

One method of preparing compounds of formula I, where R1indicates 3,6-dihydro-2H-Piran-4-yl or tetrahydropyran-4-yl, comes from the intermediate of formula (6), as shown below in scheme 3.

where R the above.

Obtaining compounds of formula I (15)

Source tributylstannyl the compounds of formula (13) can be obtained by methods well known in the prior art.

The intermediate of formula (6) is reacted with an excess of tributylstannyl formula (7) in an organic solvent, preferably dioxane, containing a palladium catalyst, preferably Tris(dibenzylideneacetone)dipalladium(0), a catalytic amount of phosphine or arsenova ligand, preferably three(2-furyl)phosphine. The reaction proceeds at elevated temperature, preferably about 100°With, for about 2-24 hours, preferably about 16 hours the Product of formula I (15) was isolated by standard methods, and preferably purified by chromatography or recrystallization.

Alternative obtaining the compounds of formula I (15)

The original connection Bronevoy acid of formula (14) can be obtained by methods well known in the prior art.

The compounds of formula I (15) alternative can be obtained by treating the intermediate of formula (6) excess connections Bronevoy acid f is rmula (14). The reaction proceeds in an aqueous solvent, preferably a mixture of water, dioxane and 1,2-diethoxyethane, containing a palladium catalyst, preferably tetrakis-(triphenylphosphine)palladium(0), and an inorganic base, preferably sodium carbonate. The reaction proceeds preferably at the boiling temperature of the solvent, preferably about 100°With, for about 2-24 hours, preferably about 16 hours the Product of formula I (15) was isolated by standard methods, and preferably purified by chromatography or recrystallization.

Obtaining compounds of formula I (16)

The compounds of formula I (15) can be transformed into the compounds of formula I (16) by hydrogenation in the presence of a hydrogenation catalyst, preferably 10%palladium on charcoal. This reaction proceeds in various organic solvents, such as methanol, ethanol, dioxane, tetrahydrofuran or dichloromethane, preferably in a mixture of methanol and dichloromethane, at room temperature, at a pressure of 1 ATM or higher, preferably at 1 ATM, for 2-24 hours, preferably about 18 hours, the Product of formula I (16) was isolated by standard methods, and preferably purified by chromatography or recrystallization.

Obtaining compounds of formula I, where R1indicates 3,6-dihydro-2H-Piran-4-yl (Ia)

The compounds of formula I, g is e R 1indicates 3,6-dihydro-2H-Piran-4-yl, can be obtained from compounds of the formula I (15) methods, is completely analogous to the methods described above to obtain compounds of the formula I from intermediates of formula (8). The product of formula I, where R1indicates 3,6-dihydro-2H-Piran-4-yl (Ia), isolated by standard methods, and preferably purified by chromatography or recrystallization.

Obtaining compounds of formula I, where R1means tetrahydropyran-4-yl (IB)

The compounds of formula I, where R1means tetrahydropyran-4-yl, can be obtained from compounds of the formula I (16) methods, is completely analogous to the methods described above to obtain compounds of the formula I from intermediates of formula (8). The product of formula I, where R1means tetrahydropyran-4-yl (Ia), isolated by standard methods, and preferably purified by chromatography or recrystallization.

Obtaining compounds of formula I, where R1means morpholine-4-yl

One method of preparing compounds of formula I, where R1means morpholine-4-yl, comes from the intermediate of formula (5)as shown below in scheme 4.

where R the above.

Obtaining the intermediate of formula (17)

The intermediate of formula (5) is injected into the reaction nitrous agent, preferably with microneutralisation, in a polar organic solvent, preferably nitromethane. The reaction proceeds in the temperature range from 0°to room for about 2-24 hours, preferably about 18 hours, the Product of formula (17) was isolated by standard methods, and preferably purified by chromatography or recrystallization.

Obtaining the intermediate of formula (18)

The intermediate of formula (17) can be transformed into an intermediate of formula (18) by hydrogenation in the presence of a hydrogenation catalyst, preferably 10%palladium on charcoal. This reaction proceeds in various organic solvents, such as methanol, ethanol, dioxane, tetrahydrofuran or dichloromethane, preferably in a mixture of methanol and dichloromethane, at room temperature, at a pressure of 1 ATM or higher, preferably at 1 ATM, for 2-24 hours, preferably about 18 hours, the Product of formula (18) was isolated by standard methods, and preferably purified by chromatography or recrystallization.

Obtaining the intermediate of formula (19)

The intermediate of formula (18) can be transformed to the corresponding intermediate of formula (19) by reaction with excess aqueous base such as lithium hydroxide, sodium hydroxide or potassium hydroxide, preferably sodium hydroxide. The reaction proceeds in an aqueous solvent, predpochtitel what about in a mixture of water and a miscible organic solvent, such as dioxane, tetrahydrofuran or ethylene glycol, preferably in a mixture of water, dioxane and ethylene glycol at elevated temperature, preferably at the boiling temperature of the solvent, for about 2-16 hours, preferably about 4 hours, the Product of formula (19) was isolated by standard methods, and preferably purified by chromatography or recrystallization.

Obtaining the intermediate of formula (20)

The intermediate of formula (19) is injected into the reaction digitalcinema compound of formula (21), which can be obtained by methods well known in the prior art, in an organic solvent, preferably in N,N-dimethylformamide, containing a base, preferably potassium carbonate. The reaction proceeds in the range between room temperature and the boiling temperature of the solvent, preferably about 60°With, for about 1-48 hours, preferably about 48 hours Product formula (20) was isolated by standard methods, and preferably purified by chromatography or recrystallization.

Obtaining compounds of formula IB (R1means morpholine-4-yl)

The compounds of formula I, where R1means morpholine-4-yl, can be obtained from the intermediate of formula (20) methods, is completely analogous to the methods described above for preparing compounds of formula I of intermediates f is rmula (9). The product of formula I, where R1means morpholine-4-yl, isolated by standard methods, and preferably purified by chromatography or recrystallization.

Conversion of compounds of the formula I into other compounds of formula I, having the modified R Deputy

If the compound of formula I contains R Deputy, having chemically reactive functional group, for example, when R contains halodendron functional group or 2-haloperidol functional group, the compound of the formula I can be converted into another compound of formula I, having the modified R Deputy, through reactions involving reactive functional group contained in the original R the Deputy. Such transformations can be carried out according to methods well known in the prior art, and specific examples can be found in several examples below. For example, the compounds of formula I having the R substituents bearing halodendron or 2-haloperidol functional groups that can react with nucleophilic alcohol or amine reagents, forming the compounds of formula I containing R substituents having respectively benzyl ether or benzyl amine functional group, or a pyridyl-2-yl-ether or pyridyl-2-yl-amine functional g is PI.

Isolation and purification of compounds

Isolation and purification of the compounds and intermediates described herein, can be carried out, if necessary, by any suitable method of isolation and purification, such as filtration, extraction, crystallization, column chromatography, thin layer chromatography, chromatography in a thick layer preparative chromatography low or high pressure, or a combination of these methods. Suitable methods of division and separation in pure form can be illustrated by referring to preparation methods and examples below. However, other equivalent methods of division and separation in pure form can, of course, also be used.

Salts of compounds of formula I

The compounds of formula I can be basic, for example, in cases where the residue R contains a basic group, such as aliphatic or aromatic amine fragment. In such cases, the compounds of formula I can be converted into the corresponding acid additive salt.

The transformation is carried out by processing at least the stoichiometric amount of the appropriate acid, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as kasna acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonate acid, econsultancy acid, p-toluensulfonate acid, salicylic acid and the like. Usually the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol and the like, and then add the acid in the same solvent. The temperature is maintained in the range from 0 to 50°C. the Resulting salt spontaneously precipitates, or can be extracted from a solution of the less polar solvent.

Acid additive salts of basic compounds of formula I can be converted into the corresponding free base by treatment, at least a stoichiometric equivalent of a suitable base type of the hydroxides of sodium or potassium, potassium carbonate, sodium bicarbonate, ammonia and the like.

The compounds of formula I and their pharmaceutically acceptable salts possess various pharmacological properties. In particular, it was found that the compounds of the present invention are ligands of the adenosine receptor is (A 2A). In addition, it was shown that the preferred compounds of formula I exhibit good selectivity with respect to A1receptor in the field from 26 to 650.

Compounds were investigated in accordance with the tests below.

And2Areceptor adenosine person

A2Areceptor adenosine person recombinante Express in cells of the Chinese hamster ovary (Cho)using a viral expression system "Semliki forest" (semliki forest). Cells harvestroad, washed twice by centrifugation, homogenized and washed again by centrifugation. Finally the washed membrane residue suspended in Tris (50 ml) buffer containing 120 mm NaCl, 5 mm KCl, 2 mm CaCl2and 10 mm MgCl2(pH of 7.4) (buffer A). [3H]-SCH-58261 (Dionisotti and others, 1997, Br. J. Pharmacol. 121, 353; 1 nM) analysis of the binding is carried out in 96-well tablets in the presence of 2.5 μg of membrane protein, 0.5 mg of Ysi-poly-1-lysine SPA granules and 0.1 U adenosine deaminase in a total volume of 200 μl of buffer. Non-specific binding determine using continuin conger eel (KHAS; 2 μm). Compounds are tested at 10 concentrations ranging from 10 μm to 0.3 nm. All analyses were duplicated and repeated at least twice. Before centrifugation, analytical tablets were incubated for 1 h at room temperature and then related ligands were determined with the use of what Finance scintillation counter Packard Topcount. IC50values were calculated using a suitable nonlinear curve, and Ki values were calculated using the equation of Cheng-Prussoff.

Preferred compounds mattered R Ki>7.5. The following table presents the affinity And2Areceptor and selectivity to A1the receptor for these compounds.

ExamplehA2apKiThe selectivity to hA1
1a 7.9226
2the 7.65137
57,66140
97,66351
13of 7.64227

ExamplehA2apKiThe selectivity to hA1
147,80134
177,89242
188,19120
208,07650
217,5296

The compounds of formula I and pharmaceutically acceptable salts of compounds of formula I can be used as medicaments, for example in the form of pharmaceutical preparations. F. rmaceuticals drugs can be administered orally for example in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions and suspensions. The administration can also be carried out rectally, for example in the form of suppositories, or parenterally, for example in the form of injection solutions.

The compounds of formula I can be combined with pharmaceutically inert, inorganic or organic carriers for pharmaceutical drugs. Can be used lactose, corn starch or derivatives thereof, talc, stearic acid or their salts and the like, for example, as carriers for tablets, coated tablets, dragées and hard gelatin capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. However, depending on the nature of the active substance may not require any of the carriers normally used in the case of soft gelatin capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or solid oils, waxes, fats, semi-solid and liquid polyols and the like.

In addition, pharmaceutical products m which may contain preservatives, solvents, stabilizers, softening agents, emulsifiers, sweeteners, colorants, odorants, salts to adjust osmotic pressure, buffers, masking agents or antioxidants. They can also contain other therapeutically valuable substances.

Medicaments containing a compound of formula I or its pharmaceutically acceptable salt and a therapeutically inert carrier are also an object of the present invention, as the method of production thereof, which comprises applying one or more compounds of the formula I and/or pharmaceutically acceptable acid additive salts and, if desired, one or more other therapeutically valuable substances in herbal dosage form together with one or more therapeutically inert carriers.

In accordance with the invention the compounds of formula I and their pharmaceutically acceptable salts, are used for control or prevention of diseases associated with antagonistic activity of the adenosine receptor, such as Alzheimer's disease, Parkinson's disease, neuroprotection, schizophrenia, fear, pain, deficits of breath, depression, asthma, allergic responses, hypoxia, ischaemia, seizure and substance abuse. In addition, the compounds of the present invention can be used as sedatives, muscle re is Axundov, antipsychotics, ANTIEPILEPTICS funds, anticonvulsants and cardioprotective agents and for the production of corresponding medicaments.

The most preferred indications for the use in accordance with the present invention are those which include disorders of the Central nervous system, for example, the treatment or prevention of Central depressive disorders, neuroprotection and Parkinson's disease.

The dosage may vary within wide limits and, of course, must be adjusted in accordance with the individual requirements in each particular case. In the case of oral administration the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of the compounds of General formula I or the corresponding number of its pharmaceutically acceptable salts. The daily dose can be entered as a single dose or divided into multiple doses and, in addition, the upper limit may be exceeded if there are indications.

Manufacturing of tablets (wet granulation)
Component Ingredientmg tablet
5 mg25 mg100 mg 500 mg
1.The compound of the formula I525100500
2.Anhydrous lactose DTG12510530150
3.Sta-Rx 150066630
4.Microcrystal. cellulose303030150
5.Magnesium stearate1111
The total number of167167167831

The production process

1. The mixture of components 1, 2, 3 and 4 and granulation with purified water.

2. Drying of the granules at 50°C.

3. Passing the granules through a suitable milling equipment.

4. Add a component 5 and mix for 3 min; pressing on a suitable press.

Manufacturing capsules
Component Ingredientmg/capsule
5 mg25 mg100 mg500 mg
1.The compound of the formula I525100500
2.Water lactose159123148-
3.Corn starch25354070
4.Talc10151025
5.Magnesium stearate1225
The total number of200200300600

The production process

1. The mixing of components 1, 2 and 3 in a suitable mixer for 30 minutes

2. Adding components 4 and 5 and stirring for 3 minutes

3. The filling of the respective capsules.

The following examples illustrate the invention, without having in mind the limitation of its scope.

Examples

Example 1: 4-Fluoro-N-(4-methoxy-7-phenylbenzoxazole-2-yl)benzamid

a) 2-Aminobenzothiazole-4-ol

To a mixed solution of 30 g (193 mmol) of 2-nitroresorcinol in 900 ml of methanol added to 2.00 g of 10%palladium on charcoal and the mixture is then stirred for 18 h at room temperature in a hydrogen atmosphere. The mixture is ATEM filtered and the filtrate, containing 2-aminoethanol, is added dropwise to a stirred solution of 22.5 g (213 mmol) of canidrome in 230 ml of methanol and 100 ml of water. Stirring is continued for 2 h at room temperature, and the mixture is then concentrated in vacuo. To the residue add aqueous sodium bicarbonate solution and three times extracted with a mixture of ethyl acetate. The combined organic phases are washed with saturated brine, dried over sodium sulfate and concentrated in vacuo. Express chromatography (ethyl acetate), followed by rubbing with ether, the yield of 27.0 g (93%) 2-aminobenzothiazole-4-ol as a beige crystalline solid. EI-MS m/e (%): 150 (M+, 100), 107 (28).

b) 4-Methoxybenzothiazole-2-ylamine

To mix a solution of 10 g (66 mmol) of 2-aminobenzothiazole-4-ol in 100 ml THF at room temperature add portions 3,49 g (79,9 mmol) of sodium hydride (55%oil dispersion) and the mixture is then stirred for 1 h at 50°C. add dropwise a solution of 14.5 ml (233 mmol) of iodomethane in 500 ml of THF for 3 h, keeping the temperature of the reaction mixture at 50°C. the Mixture is then poured into water and extracted three times with ethyl acetate. The combined organic phases are washed with saturated brine, dried over sodium sulfate and concentrated in vacuo. Express chromatography (dichloromethane, then met the Nol/dichloromethane in the ratio of 2:98) to give 7.5 g (69%) 4-methoxybenzothiazole-2-ylamine in the form of a brown crystalline solid. EI-MS m/e (%): 164 (M+, 100), 149 ([M-CH3]+, 23), 135 (46).

C) Methyl ester of (4-methoxybenzothiazole-2-yl)carbamino acid

To a stirred solution of 6.5 g (40 mmol) 4-methoxybenzothiazole-2-ylamine and 4.5 ml (56 mmol) of pyridine in 250 ml of dichloromethane at 0°With added dropwise a solution of 4.1 ml (49 mmol) of methylchloroform in 50 ml of dichloromethane and continue stirring for 3.5 h the Mixture was then poured into water and extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. Express chromatography (dichloromethane) to give 4.7 g (54%) in the form of almost white crystalline solid. EI-MS m/e (%): 222 (M+, 100), 190 (27), 163 (23).

d) Methyl ester (7-iodine-4-methoxybenzimidazole-2-yl)carbamino acid

To a stirred solution of 4.0 g (18 mmol) of the methyl ester (4-methoxybenzothiazole-2-yl)carbamino acid and 4.4 g (54 mmol) of sodium acetate in 20 ml of acetic acid is added dropwise at room temperature of 8.8 g (54 mmol) of atmosohere and continue stirring for 30 hours the Mixture was then poured into water and extracted three times with ethyl acetate. The combined organic phases are washed with 1-molar sodium thiosulfate solution, then dried over sodium sulfate and concentrated in vacuo. Rubbing with ether to give 4.1 g (65%) of methyl ester (7-th is d-4-methoxybenzimidazole-2-yl)carbamino acid as a white crystalline solid. EI-MS m/e (%): 349 (M+N+, 100).

d) 4-Methoxy-7-phenylbenzoxazole-2-ylamine

To a stirred solution of 820 mg (2.36 mmol) of the methyl ester (7-iodine-4-methoxybenzimidazole-2-yl)carbamino acid in 20 ml of N,N-dimethylformamide are added at 1.17 ml (3.58 mmol) of phenyl(tri-n-butyl)stannane, 65 mg (0.21 mmol) triphenylarsine and 208 mg (1,09 mmole) iodide, copper(I). The mixture is heated at 80°C for 16 h, then poured into water and extracted three times with ethyl acetate. The combined organic phases are washed with saturated brine, dried over sodium sulfate and concentrated in vacuo. Express chromatography (methanol/dichloromethane in the ratio of 1: 99), followed by rubbing in the air, giving 200 mg of 4-methoxy-7-phenylbenzoxazole-2-ylamine in the form of a white solid. ES-MS m/e (%): 241 (M+N+, 100).

e) 4-Fluoro-N-(4-methoxy-7-phenylbenzoxazole-2-yl)benzamid

To a stirred solution of 100 mg (0.42 mmol) of 4-methoxy-7-phenylbenzoxazole-2-ylamine, 0,087 ml of 0.62 mmol) of triethylamine and 5.1 mg N,N-dimethyl-4-aminopyridine in 5 ml of THF at room temperature is added dropwise a solution 0,064 ml (0.54 mmol) of 4-tormentilla in 2 ml of THF and continue stirring for 16 h at 65°C. the Reaction mixture was then concentrated in vacuo. To the residue was added water and the mixture extracted three times with dichloromethane. The combined organic phases are dried over su is hatom sodium and concentrated in vacuo. Express chromatography (ethyl acetate/hexane in a ratio of 1:4, then 4:1), followed by rubbing in the air, give 50 mg (33%) 4-fluoro-N-(4-methoxy-7-phenylbenzoxazole-2-yl)benzamide in the form of a slightly yellow crystalline solid. EI-MS m/e (%): 362 (M+, 90), 123 (FC6H4CO+, 100).

A similar method is received:

Example 2: 4-{[(2-Methoxyethyl)methylamino]methyl}-N-(4-methoxy-7-phenylbenzoxazole-2-yl)benzamid

From 4-methoxy-7-phenylbenzoxazole-2-ylamine, 4-{[(2-methoxyethyl)methylamino]methyl}benzoyl chloride, triethylamine and N,N-dimethyl-4-aminopyridine in THF. ES-MS m/e (%): 446 (M+N+, 100).

Example 3: Methyl ether [7-(3,6-dihydro-2H-Piran-4-yl)-4-methoxybenzimidazole-2-yl]carbamino acid

To a stirred solution of 3.50 g (10.1 mmol) of the methyl ester (7-iodine-4-methoxybenzimidazole-2-yl)carbamino acid in 50 ml of dioxane is added 5,63 g (15.1 mmol) tributyl(3,6-dihydro-2H-Piran-4-yl)stannane, 173 mg (0,30 ml) bis(dibenzylideneacetone)palladium(0), 374 mg (1,61 mmol) three(2-furyl)phosphine. The mixture is heated at 100°C for 22 h, then poured into water and extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. Express chromatography (methanol/dichloromethane in the ratio of 2:98, 5:95)followed by rubbing in dichloromethane yield of 1.30 g (42%) of metropoleopera [7-(3,6-dihydro-2H-Piran-4-yl)-4-methoxybenzimidazole-2-yl]carbamino acid as a white solid. ES-MS m/e (%): 305 (M+N+, 100).

Example 4: 2-Bromo-N-[4-methoxy-7-(tetrahydropyran-4-yl)benzooxazol-2-yl]isonicotinamide

a) Methyl ester [4-methoxy-7-(tetrahydropyran-4-yl]benzooxazol-2-yl]carbamino acid

To a stirred solution of 1.30 g (4,27 mmol) methyl ester [7-(3,6-dihydro-2H-Piran-4-yl)-4-methoxybenzimidazole-2-yl]carbamino acid in 250 ml of methanol and 250 ml of dichloromethane added to 1.00 g of 10%palladium on coal and the mixture then mix for 10 h at room temperature in a hydrogen atmosphere. The mixture was then filtered, washed with a mixture of dichloromethane/methanol in the ratio of 1:1 and the filtrate was concentrated in vacuo, obtaining of 1.30 g (100%) methyl ester [4-methoxy-7-(tetrahydropyran-4-yl)benzooxazol-2-yl]carbamino acid in the form of an almost white solid. ES-MS m/e (%): 307 (M+N+, 100).

b) 4-Methoxy-7-(tetrahydropyran-4-yl)benzooxazol-2-ylamine

To a stirred solution of 1.30 g (4,24 mmol) methyl ester [4-methoxy-7-(tetrahydropyran-4-yl)benzooxazol-2-yl]carbamino acid in 90 ml of dioxane and 30 ml of ethylene glycol added 90 ml of 5 normal aqueous sodium hydroxide solution and heat the mixture at 100°C for 16 hours After cooling to room temperature the mixture is then poured into water and extracted four times with ethyl acetate. The combined organic phases are dried over sulfate intothree and concentrated in vacuo. Express chromatography (dichloromethane, then methanol/dichloromethane in the ratio 5:95) gives 0,78 g (74%) of 4-methoxy-7-(tetrahydropyran-4-yl)benzooxazol-2-ylamine in the form of a brown solid. ES-MS m/e (%): 249 (M+N+, 100).

a) 2-Bromo-N-[4-methoxy-7-(tetrahydropyran-4-yl)benzooxazol-2-yl]isonicotinamide

To a stirred solution of 106 mg (0.52 mmol) of 2-bromoisonicotinic acid in 5 ml of THF added 230 mg (0,60 mmol) HATU and 0.10 ml (0,60 mmol) of N-ethyldiethanolamine and continue stirring at room temperature for 5 hours Then add 100 mg (0.40 mmol) of 4-methoxy-7-(tetrahydropyran-4-yl)benzooxazol-2-ylamine in 5 ml of dioxane and 1 ml of DMF) and continue stirring at 40°C for 72 h, the Reaction mixture was then poured into water and shaken out three times with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. Express chromatography (dichloromethane, then methanol/dichloromethane in the ratio 20:80), followed by rubbing in the air, give 146 mg (84%) of 2-bromo-N-[4-methoxy-7-(tetrahydropyran-4-yl)benzooxazol-2-yl]isonicotinamide in the form of a white crystalline solid. ES-MS m/e (%): 434 (M{81Br}+H+, 95), 432 (M{79Br}+H+, 100).

A similar method is received:

Example 5: 4-Fluoro-N-[4-methoxy-7-(tetrahydropyran-4-yl)benzooxazol-2-yl]benzamide

4-perbenzoic the Oh of the acid, HATU and N-diethylethanolamine in THF, then treatment 7-(tetrahydropyran-4-yl)benzooxazol-2-aluminum in dioxane and DMF. ES-MS m/e (%): 371 (M+N+, 100).

Example 6: N-[4-Methoxy-7-(tetrahydropyran-4-yl)benzooxazol-2-yl]-6-nicotine amide

6 methylnicotinic acid, HATU and N-diethylethanolamine in THF, then treatment 4-methoxy-7-(tetrahydropyran-4-yl)benzooxazol-2-aluminum in dioxane and DMF. ES-MS m/e (%): 368 (M+N+, 100).

Example 7: N-[4-Methoxy-7-(tetrahydropyran-4-yl)benzooxazol-2-yl]-2-methylethanolamine

2 methylethanolamine acid, HATU and N-diethylethanolamine in THF, then treatment 4-methoxy-7-(tetrahydropyran-4-yl)benzooxazol-2-aluminum in dioxane and DMF. ES-MS m/e (%): 368 (M+N+, 100).

Example 8: 2-Chloromethyl-N-[4-methoxy-7-(tetrahydropyran-4-yl)benzooxazol-2-yl]isonicotinamide

2 chloromethylisothiazolinone acid, HATU and N-diethylethanolamine in THF, then treatment 4-methoxy-7-(tetrahydropyran-4-yl)benzooxazol-2-aluminum in dioxane and DMF. ES-MS m/e (%): 404 (M{37Cl}+H+, 30), 402 (M{35Cl}+H+, 100).

Example 9: N-[4-Methoxy-7-(tetrahydropyran-4-yl)benzooxazol-2-yl]-2-morpholine-4-yl-isonicotinamide

Stir the suspension 460 g (1.06 mmol) of 2-bromo-N-[4-methoxy-7-(tetrahydropyran-4-yl)benzooxazol-2-yl]isonicotinamide, 693 g (2,13 mmol) of cesium carbonate and a few crystals of 2,6-di-tert.-butyl-p-cresol ,78 ml (3,19 mmol) research and 2 ml of N-methylpyrrolidone heated at 140° C for 24 h in a thick-walled glass tube for high pressure, equipped with a Teflon lid. The reaction mixture is then cooled to room temperature and poured into water and then extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. Express chromatography (methanol/dichloromethane in the ratio of 2:98), followed by rubbing in the air, give 136 mg (29%) of N-[4-methoxy-7-(tetrahydropyran-4-yl)benzooxazol-2-yl]-2-morpholine-4-yl-isonicotinamide in the form of a white crystalline solid. ES-MS m/e (%): 439 (M+N+, 100).

Example 10: 2-Methoxymethyl-N-[4-methoxy-7-(tetrahydropyran-4-yl)benzooxazol-2-yl]isonicotinamide

To a stirred solution of 0.05 ml (1,24 mmol) of methanol in 5 ml of dioxane and 1 ml of N,N-dimethylformamide at room temperature is added 27 mg (of 0.62 mmol) of sodium hydride (55%dispersion in mineral oil) and the mixture heated for 1 h at 50°C. Then add 50 mg (0.12 mmol) of 2-chloromethyl-N-[4-methoxy-7-(tetrahydropyran-4-yl)benzooxazol-2-yl] isonicotinamide and heat the mixture at 50°C for 20 hours, the Reaction mixture was then cooled to room temperature and poured into water. The mixture is acidified with 1 normal aqueous solution of hydrochloric acid, and then extracted three times with dichloromethane. The combined organic is the cue phase is dried over sodium sulfate and concentrated in vacuo. Express chromatography (dichloromethane), followed by rubbing in ether to give 32 mg (65%) 2-methoxymethyl-N-[4-methoxy-7-(tetrahydropyran-4-yl)benzooxazol-2-yl] isonicotinamide in the form of a white crystalline solid. ES-MS m/e (%): 398 (M+N+, 100).

Analogously to example 4 obtained:

Example 11: N-[4-methoxy-7-(tetrahydropyran-4-yl)benzooxazol-2-yl]-2-phenylacetamide

Of phenylacetic acid, HATU and N-diethylethanolamine in THF, then treatment 4-methoxy-7-(tetrahydropyran-4-yl)benzooxazol-2-aluminum in dioxane and DMF. ES-MS m/e (%): 367 (M+N+, 100).

Example 12: 2-Bromo-N-[4-methoxy-7-(tetrahydropyran-4-yl)benzooxazol-2-yl]isonicotinamide

a) Methyl ether [7-(4-forfinal)-4-methoxybenzimidazole-2-yl]carbamino acid

To a stirred solution of 3.00 g (8,62 mmol) methyl ester (7-iodine-4-methoxybenzimidazole-2-yl)carbamino acid in 20 ml of dioxane and 60 ml of 1,2-dimethoxyethane add 731 mg (17,2 mmol) of lithium chloride, 299 mg (0.26 mmol) of tetrakis(triphenylphosphine)palladium(0), 1,45 g (10.3 mmol) of p-ferbinteanu acid and 18 ml of 1N aqueous sodium bicarbonate solution. The mixture is heated at 100°C for 24 h, and then poured into water and extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. Rubbing in the air give 2.67 g (98%) of methyl ester of 7-(4-forfinal)-4-methoxybenzimidazole-2-yl]carbamino acid in the form of an almost white solid. ES-MS m/e (%): 317 (M+N+, 100).

b) 7-(4-Forfinal)-4-methoxybenzimidazole-2-ylamine

To mix the solution 2,80 g (cent to 8.85 mmol) methyl ester [7-(4-forfinal)-4-methoxybenzimidazole-2-yl]carbamino acid in 100 ml of dioxane and 30 ml of ethylene glycol was added 100 ml of 5N aqueous sodium hydroxide solution and the mixture is heated at 100°C for 16 hours, the Reaction mixture was then cooled to room temperature and poured into water and then extracted three times with ethyl acetate. The combined organic phases are washed with brine, dried over sodium sulfate and concentrated in vacuo. Rubbing in the air, gives 0.95 g (42%) of 7-(4-forfinal)-4-methoxybenzimidazole-2-ylamine as an almost white solid. ES-MS m/e (%): 259 (M+N+, 100).

a) 2-Bromo-N-[7-(4-forfinal-4-methoxybenzimidazole-2-yl]isonicotinamide

To a stirred solution of 203 mg (1.00 mmol) 2-bromoisonicotinic acid in 5 ml of THF added 442 mg (1,16 mmol) HATU and 0.20 ml (1,16 mmol) of N-ethyldiethanolamine and continue stirring at room temperature for 5 hours Then add a solution of 200 mg (0.77 mmol) of 7-(4-forfinal)-4-methoxybenzimidazole-2-ylamine in 5 ml of dioxane and 1 ml of DMF) and continue stirring at 40°C for 16 hours, the Reaction mixture was then poured into 100 ml of water and shaken out three times with ethyl acetate. The combined organic phases are dried over self the volume of sodium and concentrated in vacuo. Rubbing in a mixture of ether/ethyl acetate in the ratio of 4: 1, give 233 mg (68%) of 2-bromo-N-[7-(4-forfinal)-4-methoxybenzimidazole-2-yl]isonicotinamide in the form of almost white crystalline solid. ES-MS m/e (%): 444 (M{81Br}+H+, 90), 442 (M{79Br}+H+, 100).

A similar method is received:

Example 13: 2-Chloromethyl-N-[7-(4-forfinal)-4-methoxybenzimidazole-2-yl]isonicotinamide

2 chloromethylisothiazolinone acid, HATU and N-diethylethanolamine in THF, then treatment 7-(4-forfinal)-4-methoxybenzimidazole-2-aluminum in dioxane and DMF. ES-MS m/e (%): 414 (M{37Cl}+H+, 30), 412 (M{35Cl}+H+, 100).

Example 14: N-[7-(4-Forfinal)-4-methoxybenzimidazole-2-yl]-2-methylethanolamine

2 methylethanolamine acid, HATU and N-diethylethanolamine in THF, then treatment 7-(4-forfinal)-4-methoxybenzimidazole-2-aluminum in dioxane and DMF. ES-MS m/e (%): 378 (M+N+, 100).

Example 15: N-[7-(4-Forfinal)-4-methoxybenzimidazole-2-yl]-2-propionamide

From propionic acid, HATU and N-diethylethanolamine in THF, then treatment 7-(4-forfinal)-4-methoxybenzimidazole-2-aluminum in dioxane and DMF. ES-MS m/e (%): 315 (M+N+, 100).

Example 16: N-[7-(4-Forfinal)-4-methoxybenzimidazole-2-yl]-2-methoxyacetate

From methoxybutanol acid, HATU and N-diethylethanolamine in THF, then treatment 7-(4-forfinal)-4-methoxybenzimidazole-2-aluminum in dioxane and D Is F. ES-MS m/e (%): 331 (M+N+, 100).

Example 17: N-[7-(4-Forfinal)-4-methoxybenzimidazole-2-yl]-6-nicotine amide

6 methylnicotinic acid, HATU and N-diethylethanolamine in THF, then treatment 7-(4-forfinal)-4-methoxybenzimidazole-2-aluminum in dioxane and DMF. ES-MS m/e (%): 378 (M+N+, 100).

Example 18: N-[7-(4-Forfinal)-4-methoxybenzimidazole-2-yl]benzamide

4-fermenting acid, HATU and N-diethylethanolamine in THF, then treatment 7-(4-forfinal)-4-methoxybenzimidazole-2-aluminum in dioxane and DMF. ES-MS m/e (%): 381 (M+N+, 100).

Example 19: N-[7-(4-Forfinal)-4-methoxybenzimidazole-2-yl]-2-phenylacetamide

Of phenylacetic acid, HATU and N-diethylethanolamine in THF, then treatment 7-(4-forfinal)-4-methoxybenzimidazole-2-aluminum in dioxane and DMF. ES-MS m/e (%): 377 (M+N+, 100).

Analogously to example 9 received:

Example 20: N-[7-(4-Forfinal)-4-methoxybenzimidazole-2-yl]-2-morpholine-4-yl-isonicotinamide

From 2-bromo-N-[7-(4-forfinal)-4-methoxybenzimidazole-2-yl]isonicotinamide with cesium carbonate and morpholine N-organic. ES-MS m/e (%): 449 (M+N+, 100).

Analogously to example 9 received:

Example 21: N-[7-(4-Forfinal)-4-methoxybenzimidazole-2-yl]-2-methoxynicotinate

From 2-chloromethyl-N-[7-(4-forfinal)-4-methoxybenzimidazole-2-yl]isonicotinamide with sodium hydride and ethanol in dioxane and DMF. ES-MS m/e (%): 408 (M+N+, 10).

Example 22: 2-Chloromethyl-N-(4-methoxy-7-morpholine-4-eventuality-2-yl)isonicotinamide

a) Methyl ester of (4-methoxy-7-nitrobenzoxazole-2-yl)carbamino acid

To a stirred solution of 780 mg (3,51 mmol) methyl ether (4-methoxybenzothiazole-2-yl)carbamino acid in 40 ml of nitromethane at 0°add 699 mg (5,27 mmol) nitrosoanatabine and continue stirring for 18 hours, allowing the reaction mixture to gradually warm to room temperature. The mixture is then concentrate in vacuo. Express chromatography gives 300 mg (32%) of the methyl ester (4-methoxy-5-nitrobenzoxazole-2-yl)carbamino acid in the form of a solid orange substance and 220 mg (32%) of the methyl ester (4-methoxy-7-nitrobenzoxazole-2-yl)carbamino acid as a yellow solid. ES-MS m/e (%): 268 (M+N+, 100).

b) Methyl ester (7-amino-4-methoxybenzothiazole-2-yl)carbamino acid

To a stirred solution of 220 mg (0.82 mmol) of the methyl ester (4-methoxy-7-nitrobenzoxazole-2-yl)carbamino acid in 25 ml of methanol and 45 ml of dichloromethane added at the tip of the spatula 10%palladium on coal and continue stirring for 18 h at room temperature in a hydrogen atmosphere. The mixture is filtered and then concentrate under vacuum. Express chromatography (methanol/dichloromethane in the ratio of 2:98) to give 114 mg (58%)of methyl ester (7-amino-4-methoxybenzothiazole-2-yl)carbamino acid as a white crystalline solid. ES-MS m/e (%): 238 (M+N+, 100).

C) 4-Methoxybenzothiazole-2,7-diamine

To a stirred solution of 100 mg (0.42 mmol) of the methyl ester (7-amino-4-methoxybenzothiazole-2-yl)carbamino acid in 15 ml of dioxane and 5 ml of ethylene glycol is added 15 ml of 5N aqueous sodium hydroxide solution and the mixture is heated at 100°C for 4 h, the Reaction mixture was then cooled to room temperature and poured into water and then extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. Express chromatography (methanol/dichloromethane in the ratio of 5:95, then methanol/dichloromethane/triethylamine in the ratio of 10:89:1), followed by rubbing in the air, give 15 mg (20%) 4-methoxybenzothiazole-2,7-diamine as a brown solid. ES-MS m/e (%): 180 (M+N+, 100).

d) 4-Methoxy-7-morpholine-4-eventuality-2-ylamine

To a mixed solution of 800 mg (4,47 mmol) 4-methoxybenzothiazole-2,7-diamine in 40 ml of DMF added at room temperature 2,47 g (to 17.9 mmol) of potassium carbonate and 2.18 g (6,70 mmol) 1-iodine-2-(2-iodoxy)ethane and heat the mixture at 60°C for 48 hours the Reaction mixture is then cooled to room temperature and poured into water and then extracted three times with ethyl acetate. The combined organic phases are washed with brine, dried over sodium sulfate will contentresult in vacuum. Express chromatography (methanol/dichloromethane in the ratio of 2:98, then methanol/dichloromethane in the ratio 10:90), give 585 mg (53%) 4-methoxy-7-morpholine-4-eventuality-2-ylamine in the form of a slightly brown solid. ES-MS m/e (%): 250 (M+N+, 100).

d) 2-Chloromethyl-N-(4-methoxy-7-morpholine-4-eventuality-2-yl)isonicotinamide

To a stirred solution of 72 mg (0.42 mmol) 2-chloromethylisothiazolinone acid in 5 ml of THF added 183 mg (0.48 mmol) HATU and 0.08 ml (0.48 mmol) of N-ethyldiethanolamine and continue stirring at room temperature for 5 hours Then add a solution of 80 mg (0.32 mmol) 4-methoxy-7-morpholine-4-eventuality-2-ylamine in 5 ml of dioxane and 1 ml of DMF) and continue stirring at 40°C for 48 hours the Reaction mixture is then poured into 50 ml of water, acidified with 1M th water solution of hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. Express chromatography (methanol/dichloromethane in the ratio of 3:97, then methanol/dichloromethane in the ratio 10:90)followed by rubbing in the air, give 8 mg (6%) of 2-chloromethyl-N-(4-methoxy-7-morpholine-4-eventuality-2-yl)isonicotinamide in the form of almost white crystalline solid. ES-MS m/e (%): 405 (M{37Cl}+H+, 35), 403 (M{35Cl}+H+, 100).

Similar is the second method received:

Example 23: N-(4-Methoxy-7-morpholine-4-eventuality-2-yl)-6-nicotine amide

6 methylnicotinic acid, HATU and N-diethylethanolamine in THF, then treatment 4-methoxy-7-morpholine-4-eventuality-2-aluminum in dioxane and DMF. ES-MS m/e (%): 369 (M+N+, 100).

Example 24: 4-Fluoro-N-(4-methoxy-7-morpholine-4-eventuality-2-yl)benzamid

4-fermenting acid, HATU and N-diethylethanolamine in THF, then treatment 4-methoxy-7-morpholine-4-eventuality-2-aluminum in dioxane and DMF. ES-MS m/e (%): 372 (M+N+, 100).

Analogously to example 9 received:

Example 25: N-(4-Methoxy-7-morpholine-4-eventuality-2-yl)-2-morpholine-4-yl-isonicotinamide

2 bromoisonicotinic acid, HATU and N-diethylethanolamine in THF, followed by treatment of 4-methoxy-7-morpholine-4-eventuality-2-aluminum in dioxane and DMF, followed by treatment with cesium carbonate and morpholine N-organic. ES-MS m/e (%): 440 (M+N+, 100).

Example 26: N-[7-(4-Forfinal)-4-methoxybenzimidazole-2-yl]-2-pyrrolidin-1-ilmmilmismiliemi

A mixture of 100 mg (0.24 mmol) of 2-chloromethyl-N-[7-(4-forfinal)-4-methoxybenzimidazole-2-yl]-2-pyrrolidin-1-ilmmilmismiliemi and 0.35 g (a 4.86 mmol) pyrrolidine exposed to ultrasound at room temperature for 10 minutes, the Reaction mixture was then poured into water and extracted three times with ethyl acetate. The combined organic phases visas who live over sodium sulfate and concentrated in vacuo. Rubbing in a mixture of ether/ethyl acetate in a ratio of 5:1 give 56 mg (52%) of N-[7-(4-forfinal)-4-methoxybenzimidazole-2-yl]-2-pyrrolidin-1-ilmmilmismiliemi in the form of a yellow crystalline solid. ES-MS m/e (%): 447 (M+H+, 100).

A similar method is received:

Example 27: N-[7-(4-Forfinal)-4-methoxybenzimidazole-2-yl]-2-morpholine-4-ilmmilmismiliemi

From 2-chloromethyl-N-[7-(4-forfinal)-4-methoxybenzimidazole-2-yl]isonicotinamide and research. ES-MS m/e (%): 463 (M+N+, 100).

1. The compounds of formula

where R denotes phenyl, unsubstituted or substituted with halogen or-CH2N(CH3)(CH2)nOch3or denotes benzyl, lower alkyl, lower alkoxy group, -(CH2)nOch3or denotes pyridine-3 - or-4-yl, unsubstituted or substituted lower alkyl, halogen, morpholinyl, -(CH2)n-halogen, -(CH2)nOch3, -(CH2)n-morpholine-4-yl, or -(CH2)n-pyrrolidin-1-yl;

R1denotes phenyl, unsubstituted or substituted with halogen tetrahydropyran-4-yl, 3,6-dihydro-2H-Piran-4-yl or morpholine-4-yl;

n denotes independently from each other 1 or 2,

and their pharmaceutically acceptable acid additive salt.

2. The compounds of formula I according to claim 1, where R1means forfinal and R defined in claim 1.

3. The compounds of formula I according to claim 2, representing the following connections:

2-Chloromethyl-N-[7-(4-forfinal)-4-methoxybenzimidazole-2-yl]isonicotinamide,

N-[7-(4-Forfinal)-4-methoxybenzimidazole-2-yl]-2-methylethanolamine,

N-[7-(4-Forfinal)-4-methoxybenzimidazole-2-yl]-6-nicotine amide,

4-Fluoro-N-[7-(4-forfinal)-4-methoxybenzimidazole-2-yl]benzamide,

N - [7-(4-Forfinal)-4-methoxybenzimidazole-2-yl]-2-morpholine-4-yl-isonicotinamide

or

N - [7-(4-Forfinal)-4-methoxybenzimidazole-2-yl]-2-methoxynicotinate.

4. The compounds of formula I according to claim 1, where R1denotes unsubstituted phenyl and R described in claim 1.

5. The compounds of formula I according to claim 4, which represent the following compounds: 4-Fluoro-N-(4-methoxy-7-phenylbenzoxazole-2-yl)benzamide or

4-{[(2-Methoxyethyl)methylamino]methyl}-N-(4-methoxy-7-phenylbenzoxazole-2-yl)benzamide.

6. The compounds of formula I according to claim 1, where R1means tetrahydropyran-4-yl and R described in claim 1.

7. The compounds of formula I according to claim 6, representing the following connections:

N-[4-Methoxy-7-(tetrahydropyran-4-yl)benzooxazol-2-yl]-6-nicotine amide or

N-[4-Methoxy-7-(tetrahydropyran-4-yl)benzooxazol-2-yl]-2-methylethanolamine.

8. The compound of formula I according to any one of claims 1 to 7, having the properties of ligand adenosine receptor.

9. The pharmaceutical is Skye composition, having the properties of ligand adenosine receptor containing one or more compounds according to any one of claims 1 to 7 and a pharmaceutically acceptable fillers.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to the new compounds presented by the following formula (I), or to the pharmaceutically acceptable salts: , where R1 and R2 represent substitutes, adjoining with each other and with two carbonic atoms, to each of which they are adjoined forming the group presented by the following formula: 1) , or

2) , , , , , , , , or

3) or

4) , , or

where hydrogen atom in each cyclic group can be substituted bi 1-4 substitutes selected fro the following group of substitutes B1, R3 represents hydrogen atom or methyl group; and R6 represents substitute selected from the following group of A1 substitutes, the group of A1 substitutes: (1) hydrogen atom, (2) C1-C6 alkoxy group; substitute B1 group: (1) hydrogen atom, (2) hydroxyl group, (3) oxo group, (4) C1-C6 alkanoyl group, (5) C3-C8 cycloalkyl group, (6) C1-C6 alkyl group (where C1-C6 alkyl group can be substituted by C1-C6 alkoxy group), (7) C1-C6 alkoxy group, (8) C1-C6 alkoxyimino group, (9) C5-C6 cycloalkyl group, derived by two C1-C3 alkyl groups joined to the same carbonic atom with hydrogen atom and the carbons. The invention is also relates to the pharmaceutical composition.

EFFECT: production of the new biologically active compounds and pharmaceutical compositions on their basis having inhibitor potency towards to serotonine1A receptor.

34 cl, 73 ex, 12 tbl, 4 dwg

FIELD: chemistry, pharmaceuticals.

SUBSTANCE: invention pertains to compounds with formula (I), their pharmaceutical salts or N-oxide used as an inhibitor to replication and/or proliferation of HCV, to the method of inhibiting replication or proliferation of hepatitis C virion using formula (I) compounds, as well as to pharmaceutical compositions based on them. The compounds can be used for treating or preventing infections, caused by hepatitis C virus. In general formula (I) cycle B is an aromatic or non-aromatic ring, which contains two heteroatoms, where X and Y, each is independently chosen from C, CH, N or O, under the condition that, both X and Y are not O and that, both X and Y are not N; U and T represent C; Z represents -CH-; A represents N or -CR2-; B represents -CR3-; D represents N or -CR4-; E represents N or -CR5-; G represents N or -CR6-; J represents N or -CR14-; K represents -CR8-; L represents N or -CR9-; M represents N or -CR10-; R2 and R6, each is independently chosen from a group, consisting of hydrogen, halogen, C1-C6alkyl, substituted C1-C6alkyl, C1-C6alkoxy, C1-C6substituted alkoxy, C1-C6alkoxycarbonyl, cycloheteroalkyl, substituted cycloheteroalkyl, -O-carbamoil, substituted -O-carbamoil, halogen C1-C6alkyl, diC1-C6alkylamino, substituted diC1-C6alkylamino and sylye ethers, where cycloheteroalkyl is a 3-7-member ring, containing 1-2 heteroatoms, chosen from N and O, under the condition that, one of R2 and R6 is not hydrogen; R3 and R5, each is independently chosen from a group, consisting of hydrogen, halogen; R4 represents hydrogen; R7 represents - NR11C(O)R12; R8, R9, R10 and R14, each is independently represents hydrogen; R11 represents hydrogen, C1-C6alkyl; and R12 is chosen from a group, consisting of halogen C1-C6alkyl; where each substituted group is substituted with one or more groups, chosen from -Q, -R40, -OR40, -C(O)R40, -C(O)OR40, where each Q independently represents halogen, R40 and R41 are independently chosen from a group consisting of hydrogen, C1-C6alkyl, C1-C6alkoxy, under the condition that: (i) at least one of A, D, E, G, J, L or M represents N; (ii) not more than one of A, D, E or G represents N; and (iii) not more than one of J, L or M represents N.

EFFECT: obtaining pyridyl-substituted heterocycles for treating and preventing infections, caused by hepatitis C virus.

33 cl, 85 dwg, 101 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the general formula: , where R1 is an inferior alkyl, -(CH2)n-aryl, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl, inferior alkoxy-, halogen or trifluormethyl, or pyridine; R2 is an inferior alkyl, -(CH2)n- aryl, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl, inferior alkoxy-, halogen or trifluoromethyl, nitro-, cyano-, -NR'R", hydroxy-, or heteroaryl group that is a monovalent heterocyclic 5- or 6-membered aromatic radical with N atoms, either R2 is a heteroaryl that is monovalent heterocyclic 5- or 6-membered aromatic radical where heteroatoms are chosen from N, O or S group, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl or halogen; R3 is pyridine or aryl, unsubstituted or substituted by a halogen or inferior alkyl; R4 is hydrogen or hydroxy-. A is -S(O)2- or -C(O)-; X, Y are -CH2- or -O- independently from each other, though both X and Y should not be -O- at the same time; R'R" are hydrogen or inferior alkyl independently from each other; n is 0, 1 or 2. Also the invention concerns pharmaceutically acceptable additive salts and acids of the compounds, and a medicine based on it.

EFFECT: new biologically active compounds show inhibition effect in glycine absorption.

21 cl, 214 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the new derivatives of imide indolylmaleic acid with the formula I , where Ra denotes H; C1-4alkyl or C1-4alkyl, with substituted OH, NH2, NH(C1-4 alkyl) or H(C1-4alkyl)2; Rb denotes H or C1-4alkyl; R denotes a radical of the formula (d) or (e) , where each one from R8 and R11 independently denotes OH; heterocyclic residue; NR16R17, where each from R16 and R17 independently denotes H or C1-4alkyl, or R16 and R17 together with a nitrogen atom; to which they are joined, form a heterocyclic residue; or a radical of the formula -X-RC-Y (α) where X denotes a covalent bond, O, S or NR18, where R18 denotes H or C1-4alkyl; Rc denotes C1-4alkylen or C1-4alkylen, in which one CH2 has been changed with the group CRxRy, whereby one of Rx and Ry denotes H, and the other denotes CH3, each of the Rx and Ry denote CH3 or Rx and Ry together form the group -CH2-CH2-, and Y is joined with the terminal carbon atom and is selected from OH, -NR19R20, where each one of R19 and R20 independently denotes C1-4alkyl; each one of R9, R10, R12, R13 independently denotes H, halogen, C1-4alkyl, OH, NH2, C1-4alkoxy, NH(C1-4alkyl) or N(C1-4alkyl)2 or each E denotes -N= and G denotes -CH= or E denotes -CH= and G denotes -N=, and cycle A is unsubstituted, monosubstituted, where the substitute is selected from a group containing halogen, OH, C1-4alkoxy, C1-4alkyl, NO2, NH2, NH(C1-4alkyl) or N(C1-4alkyl)2 or CN; where the heterocyclic residue is 3-8 member saturated, heterocyclic rings, containing 1-2-heteroatoms, of which one is N, and the other N or O, possibly substituted with one or more carbon atoms in the cycle and/or with a nitrogen atom in the cycle, if it is in the ring; where the substitutes of the carbon atom ring, if they exist, are selected from the group which contains C1-4alkyl, C3-C6cycloalkyl, it is optional to further substitute C1-4alkyl; , where p denotes 1, 2 or 3; and where the substitutes on the nitrogen atom ring if they exist, are selected from a group which contains C1-4alkyl, C3-C6cycloalkyl, C3-C6cycloalkyl C1-4alkyl, phenyl, phenylC1-4alkyl, heterocyclic residue and the residue from the formula β: -R21-Y' (β) R21 - denotes C1-C4alkylen, a Y' denotes OH, NH2, NH(C1-4alkyl) or N(C1-4alkyl)2, where the heterocyclic residue is of importance, as stated above, or its pharmaceutically acceptable salts.

EFFECT: bonds possess an action, which has an inhibitory activity on proteinkinase C and can be used in a pharmaceutical composition for treatment or prophylaxis of acute or chronic rejection of allo or xenotransilants of organs or tissues.

10 cl, 7 tbl, 182 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to derivatives of phtalazine with general formula (I) , in which R represents a methyl or difluromethyl group; R1 represents phenyl or oxazolyl or thiophenyl, chemically bonded to a phtalazine ring through a carbon-carbon bond. Both phenyl and the above mentioned heterocycle are substituted with a carboxylic group, and optionally with a second functional group, chosen from methoxy-, nitro-, N-acetylamino-, N-metanesulphonylamino- group. The invention also relates to pharmaceutical salts of such derivatives. The given compounds with general formula (I) are inhibitors of phosphodiesterase.

EFFECT: objective of the invention is also the method of obtaining compounds with general formula (I) and pharmaceutical compositions for treating allergies and antiphlogistic diseases based on the given compounds.

9 cl, 9 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new bonds in the formula (I-0): or its pharmaceutically acceptable salts, where X represents a carbon atom or nitrogen atom; X1, X2, X3 and X4, each independently, represents a carbon atom or a nitrogen atom; ring A of the formula (II): represents tiazolil, imidazolil, izotiazolil, tiadiazolil, triazolil, oxazolil, oxadiazolil, izoxazolil, pirazinil, piridil, piridazinil, pirazolil or pirimidinil; R¹ represents aryl or represents a 4-10- membered monocyclic or bicyclic heteroring, which has in the ring from 1 to 4 heteroatoms, selected from the group, consisting of a nitrogen atom, sulphur atom and an oxygen atom, and R¹ can be independently substituted with 1-3 R4, and, when the specified heteroring is an aliphatic heteroring, then it can have 1 or 2 double bonds; R² independently represents hydroxy, formyl, -CH3-aFa, -OCH3-aFa, amino, CN, halogen, C1-6 alkyl or -(CH2)1-4OH; R3 represents -C1-6 alkyl, -(CH2)1-6-OH, -C(O)-OC1-6 alkyl, -C(O)-OC1-6 alkyl, -(CH2)1-6-NH2, cyano, -C(O)-C1-6 alkyl, halogen, -C2-6 alkenyl, -OC1-6 alkyl, -COOH, -OH or oxo; R4 independently represents -C1-6 alkyl, and the alkyl can be substituted with identical or different 1-3 hydroxyls, halogens, -OC(O)-C1-6 alkyls, and the alkyl can be substituted with 1-3 halogens or -OC1-6 alkyls, -C3-7 cycloalkyl, -C2-6 alkenyl, -C(O)-N(R51)R52, -S(O)2-N(R51)R52,-O-C1-6 alkyl, and C1-6 alkylcan be substituted with a halogen or N(R51)R52, -S(O)0-2-C1-6 alkyl, -C(O)-C1-6 alkyl, and C1-6 alkyl can be substituted with a halogen, amino, CN, hydroxy, -O-C1-6 alkyl, -CH3-aFa, -OC(O)-C1-6 alkyl, -N(C1-6 alkyl)C(O)O-C1-6 alkyl, -NH-C(O)O-C1-6 alkyl, phenyl, -N(R51)R52, -NH-C(O)-C1-6 alkyl, -N(C1-6 alkyl)-C(O)-C1-6 alkyl or -NH-S(O)0-2-C1-6 alkyl, -C(S)-C3-7 cycloalkyl, -C(S)- C1-6 alkyl, -C(O)-O- C1-6 alkyl, -(CH2)0-4-N(R53)-C(O)-R54, -N(R53)-C(O)-O-R54,-C(O)-aryl, it is optional to substitute the halogen, -C(O)-aromatic heteroring, -C(O)-aliphatic heteroring, heteroring, and the heteroring can be substituted with C1-6 alkyl, optionally substituting the halogen or -O-C1-6 alkyl, phenyl, optionally substituting the halogen, -C1-6 alkyl, -O-C1-6 alkyl, halogen, CN, formyl, COOH, amino, oxo, hydroxy, hydroxyamidine or nitro; R51 and R52, each independently, represents a hydrogen atom, C1-6 alkyl or a nitrogen atom, R51 and R52 together form 4-7-member heteroring; R53 represents a hydrogen atom or C1-6 alkyl, R54 represents -C1-6 alkyl or alkyls for R53 and R54 and -N-C(O)- together form 4-7-member hydrogen containing heteroring, or alkyls for R53 and R54 and -N-C(O)-O- together form 4-7-member hydrogen containing aliphatic heteroring and an aliphatic heteroring can be substituted with oxo, or an aliphatic heteroring can have 1 or 2 double bonds in the ring; X5 represents -O-, -S-, -S(O)-, -S(O)2-, a single bond or -O-C1-6 alkyl; a independently denotes a whole number 1, 2 or 3; q denotes a whole number from 0 till 2; m denotes a whole number from 0 till 2, except in the case when one of the X5 represents -O-, -S-, -S(O)- or -S(O)2-, and the other from X5 represents a single bond, and R1 represents aryl, optionally substituted with 1-3 R4, or a hydrogen containing aromatic heteroring, consisting of from 1 to 4 heteroatoms, selected from the group, comprising of a hydrogen atom, sulphur atom and an oxygen atom, in the case, when X5, both represent single bonds or in cases, when R1, both represent aliphatic heteroring. The invention also relates to the bonding in the formula (I-12), and also to the bonding in the formula (I-0), to the pharmaceutical composition, to the glucokinase activator and to the medication.

EFFECT: getting new bioactive compounds which can be used for treatment and/or prophylaxis of diabetes or obesity.

23 cl, 603 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to non-peptide antagonists GnRH, with general formula 1 , where each of A1, A2 and A3 are independently chosen from A5 and A6; and A4 represents either a covalent bond, or A5; under the condition that, if A4 is a covalent bond, then one of A1-A3 represent A6, and the other two represent A5, and that, if A4 represents A5, then all of A1-A3 represent A5; A5 is chosen from C-R13 and N; A6 is chosen from N-R14, S and O; R1 is chosen from H, NHY1 and COY2, and R2 represents H; or and R1, and R2 represents methyl or together represent =O; each of R3, R4 and R5 independently represents H or low alkyl; each of R6, R7, R8, R9, R10, R11 and R12 are independently chosen from H, NH2, F, CI, Br, O-alkyl and CH2NMe2; R13 is chosen from H, F, CI, Br, NO2, NH2, OH, Me, Et, OMe and NMe2; R14 is chosen from H, methyl and ethyl; W is chosen from CH and N; X is chosen from CH2, O and NH; Y1 is chosen from CO-low alkyl, CO(CH2)bY3, CO(CH2)bCOY3 and CO(CH2)bNHCOY3; Y2 is chosen from OR15, NRI6R17 and NH(CH2)cCOY3; Y3 is chosen from alkyl, OR15 and NR16R17; R15 represents H; each of R16 and R17 is independently chosen from H, low alkyl and (CH2)aR18, or together represent -(CH2)2-Z-(CH2)2-; R18 is chosen from OH, pyridyl, pyrizinyl and oxadiazolyl; Z represents NH; a represents 0-4; and b and c represent 1-3. The invention also relates to use of formula 1 a compound as a therapeutic agent and pharmaceutical composition, with antagonistic effect to GnRH receptor. Description is also given of the method of obtaining compounds with the given formula.

EFFECT: obtaining new compounds, with useful biological properties.

27 cl, 70 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new derivatives of benzimidazol of the general formula I R1 designates phenyl group which unessentially contains up to three substitutors independently chosen of the group including F, Cl, Br, J, R4; R2 designates monocyclic or bicyclic 5-10-terms heteroaryl group which contains 1-2 heteroatoms, chosen of N, S and O; R3 designates H; R4 designatesC1-6alkyl; A designates C2-6 alkylene group; B designates group COOH, CONH2, CONHR5 or CONR5R5, in each case attached to atom of carbon of group A; R5 and R5 ' independently designate the residue chosen from group includingC1-6 alkyl where one C-atom can be replaced by O, and(C0-3 alkandiil-C3-7 cycloalkyl); and to their pharmaceutically acceptable salts, except for following compounds: 6 [[1-phenyl-2 (pyridine-4-il)-1H-benzimidazol-6-il] oxi] hexanic acid and 6 [[1-phenyl-2 (benzothien-2-il)-1H-benzimidazol-6-il] oxi] hexanic acid. The invention relates also to pharmaceuticals and to application of compounds of general formula I.

EFFECT: new biologically active compounds possess inhibiting effect on activation of microglia.

10 cl, 34 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of 2- pyrrolidine-2-yl-[1, 3, 4]oxadiazole with common formula I where R1 is aryl or heteroaryl, aryl here being phenyl unsubstituted or substituted with F, Cl, O-alkyl or phenyl, whereas heteroaryl is pyridinyl or thyenyl, R2 designates H, SO2R3 or COR4 where R3 and R4 independently designate C1-C10alkyl, C3-C10cycloalkyl, (C1-C6alkyl)-C3-C10cycloalkyl, aryl, (C1- C6alkyl)aryl, heterocyclyl, carboxylate residues with 3-10 C-atoms, dimethylamide or NR5R6, C1-C10alkyl at that being methyl, propyl, butyl, butenyl, isobutyl, amyl, pent-3-yl, hept-3-yl, hept-4-yl, 2,2-dimethylpropyl, CH2OCH3, CH2O(CH2)2OCH3 or CH(benzyl)MSO2C6H4CH3, C3-C10cycloalkyl is cyclopropyl, cyclobutyl, cycloamyl, adamantane-1-yl, 2-phenylcyclopropyl or 4,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-3-on-1-yl, (C1-C6alkyl)-C3-C10cycloalkyl is CH2-cycloamyl, (CH2)2-cycloamyl or 7,7-dimethyl-1-methylbicyclo[2.2.1]heptane-2-on, aryl is phenyl, benzyl or naphthyl unsubstituted, monosubstituted or polysubstituted with identical or different substitutes, namely: phenyl, NO2, C1-C6alkyl, O-alkyl, CO2-alkyl, C(=O)C1-C6alkyl, CH2OC(=O)C6H5, F, Cl, Br, N(CH3)2, OCF3, CF3 or (C=O)CH3, (C1-C6alkyl)aryl is 3,4-dimethoxyphenyl-CH2, 4-chlorophenoxy-CH2, phenyl-CH=CH, benzyl-OCH2, phenyl-(CH2)2, 2-bromphenyl-CH2, 1-phenylpropyl, 2-chlorophenyl-CH=CH, 3-trifluorinemethylhenyl-CH=CH, phenoxy-CH2, phenoxy-(CH2)3 or phenoxy-CH(CH3), heterocyclyl is pyridinyl, isoxazole, thienyl, furanyl, triazole, benzoxadiazole, thiadiazole, pyrazole or isoquinoline unsubstituted, monosubstituted or polysubstituted with identical or different substitutes, namely: Cl, C1-C6alkyl, phenyl, in their turn unsubstituted or mono- or polysubstituted with identical or different substitutes, namely: Cl or C1-C6alkyl, CF3, carboxylate residues with 3-10 C-atoms are CH3OC(=O)CH2, CH3OC(=O)(CH2)3, CH3CH2OC(=O)CH2, CH3CH2OC(=O)(CH2)2, CH3C(=O)OCH2, CH3C(=O)OC(CH3)2 or CH3C(=O)OCH(C6H5), and R5 and R6 independently designate H or aryl, aryl at that being benzyl or phenyl respectively mono- or polysubstituted with identical or different substitutes, namely: F, C1, O-alkyl, CN, CF3. Invention also relates to method of obtaining, to medicament and to use of compounds with common formula I.

EFFECT: obtaining of new biologically active compounds and medicinal agents based on the above formulas.

9 cl, 248 ex, 2 tbl

Indanol derivatives // 2323937

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I): (where R1 and R2 may be identical or different, and each is a 1,3-substituted aryl with substituents from group α; R3 stands for any of the following groups: -CO-R4, -CO-O-R4, -CO-NH-R4, -CO-CH2-N(Ra)Rb, -(CH2)m-CO-R5, -(CH2)m-R5, -CO-NH-CO-N(Ra)Rb, -CO-NH-SO2-N(Ra)Rb, -CO-NH-CO-(CH2)m-N(Ra)Rb, or -CO-NH2; R4 stands for a lower alkyl, cycloalkyl, cycloalkyl substituted with 1-3 substituent from group α, lower alkenyl, lower alkynyl, halogen-substituted lower alkyl, hydroxyl-substituted lower alkyl, lower alkoxyalkyl, lower aliphatic acyloxyalkyl or lower alkoxycarbonylalkyl; R5 stands for hydroxyl, -OR4 or -N(Ra)Rb; Rа and Rb may be identical or different, each of them stands for hydrogen, hydroxyl, lower alkoxy group, hydroxyl-substituted lower alkoxyl, hydroxyl-substituted lower alkoxyalkyl, lower alkoxy lower alkoxyalkyl, cyano lower alkyl, cyano lower alkoxyalkyl, carboxy lower alkyl, carboxy lower alkoxyalkyl, aliphatic lower alkoxycarbonyl lower alkoxyalkyl, carbamoyl lower alkyl group, carbamoyl lower alkoxyalkyl, lower aliphatic acylamino lower alkyl, lower aliphatic acylamino lower alkoxyalkyl, lower alkylsulphonylamino lower alkyl, lower alkylsulphanylamino lower alkoxyalkyl, (N-hydroxy-N-methylcarbamoyl) lower alkyl, (N-hydroxy-N-methylcarbamoyl) lower alkoxyalkyl, (N-lower alkoxy-N-methylcarbamoyl) lower alkyl, (N-lower alkoxy-14-methylcarbamoyl) lower alkoxyalkyl or R4, or both, including associated nitrogen, stand for nitrogen-containing heterocyclic group or nitrogen-containing 1-3 substituted heterocyclic group with substituents from group α; m is an integer from 1 to 6; А stands for carbonyl; В stands for straight bond; D stands for oxygen atom; Е stands for С14 alkylene; n is an integer from 1 to 3; and α group is a group of substituents, which consist of halogen atoms, lower alkyls, hydroxy lower alkyls, halogen lower alkyls, carboxy lower alkyls, lower alkoxyls, hydroxy lower alkoxyls, hydroxy lower alkoxyalkyls, lower alkoxycarbonyls, carboxyls, hydroxyls, lower aliphatic acyls, lower aliphatic acylamines, (N-hydroxy-N-methylcarbamoyl) lower alkyls, (N-lower alkoxy-N-methylcarbamoyl) lower alkyls, hydroxy lower aliphatic acylamines, amines, carbamoyls and cyano groups), or pharmacologically suitable salt thereof. Invention also relates to pharmaceutical composition and method for disease prevention and treatment.

EFFECT: preparation of novel biologically active compounds.

18 cl, 117 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I) and their pharmaceutically acceptable salts. The compounds claimed by the invention have inhibition effect on VR1 receptor activation and can be applied in pain prevention or treatment. In the general formula (I) , or , L is a low alkylene, E cycle is benzene or 5-membered heteroaromatic ring containing sulfur atom as a heteroatom, D cycle is a monocyclic or bicyclic hydrocarbon cycle optionally condensed with C5-7 cycloalkyl, 6-membered monocyclic heteroaromatic cycle containing nitrogen atom as heteroatom or 9-11-membered bicyclic heteroaromatic cycle containing 1 to 3 equal or different heteroatoms selected out of the group including N, S and O, G cycle is a 5-7-membered monocyclic saturated or partially saturated heterocycle or 10-membered bicyclic heterocycle containing 1 to 3 equal or different heteroatoms selected out of the group including N, S and O. The invention also concerns pharmaceutical composition based on the said compounds, and application thereof in obtaining pain prevention or treatment medication, and a method of pain prevention or treatment.

EFFECT: obtaining prevention or treatment medium against pain.

24 cl, 470 ex, 41 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: derivatives possess antiproliferative activity and stimulate an apoptosis in cells where absence of normal regulation of development of a cell and its destruction is observed. The derivatives are applied as a part of pharmaceutical compositions in combination with pharmaceutically acceptable mediums. The pharmaceutical compositions can be applied for treatment of diseases caused by hyperproliferation, including tumour growth, lymphoproliterative diseases and angiogenesis. Invention compounds pertain to the group of replaced pyrazoles and Pyrazolinums characterised by the formula of the invention.

EFFECT: derivatives possess useful biological properties.

56 cl, 115 ex

FIELD: chemistry.

SUBSTANCE: invention concerns a compound of the formula (I) where A ring is (C3-C8)-cycloalkyl or (C3-C8)-cycloalkenyl where two carbon atoms in the cycloalkyl ring can be substituted by oxygen atoms; R1, R2 are H, F, Cl, Br, OH, CF3, OCF3, (C1-C6)-alkyl or O-(C1-C6)-alkyl independently from each other; R3 is H or (C1-C6)-alkyl; R4, R5 are H, (C1-C6)-alkyl independently from each other; X is (C1-C6)-alkyl where one carbon atom in the alkyl group can be substituted by oxygen atom; Y is (C1-C6)-alkyl where one carbon atom in the alkyl group can be substituted by oxygen atom; and its pharmaceutically acceptable salts. The invention also concerns such compounds as (+)-cis-2-(3-(2-(4-fluorphenyl)oxazole-4-ylmethoxy)cyclohexyloxymethyl)-6-methylbenzoic acid of the formula 6b , 2-{3-[2-(3-methoxyphenyl)-5-methyloxazole-4-ylmethoxy]cyclohexyl-oxymethyl}-6-methylbenzoic acid of the formula 53 and 2-methyl-6-[3-(5-methyl-2-n-tolyloxazole-4-ylmethoxy)cyclohexylomethyl]benzoic acid of the formula 70 , or their enantiomers. The invention also concerns pharmaceutical composition exhibiting PPARα agonist effect, including one or more compounds of the formula (I) as an active component together with a pharmaceutically acceptable carrier. The pharmaceutical composition is obtained by mixing of active compound of the formula (I) with a pharmaceutically acceptable carrier and rendering it a form viable for introduction.

EFFECT: obtaining of diarylcycloalkyl derivatives applicable as PPAR-activators.

9 cl, 2 tbl, 67 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the general formula: , where R1 is an inferior alkyl, -(CH2)n-aryl, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl, inferior alkoxy-, halogen or trifluormethyl, or pyridine; R2 is an inferior alkyl, -(CH2)n- aryl, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl, inferior alkoxy-, halogen or trifluoromethyl, nitro-, cyano-, -NR'R", hydroxy-, or heteroaryl group that is a monovalent heterocyclic 5- or 6-membered aromatic radical with N atoms, either R2 is a heteroaryl that is monovalent heterocyclic 5- or 6-membered aromatic radical where heteroatoms are chosen from N, O or S group, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl or halogen; R3 is pyridine or aryl, unsubstituted or substituted by a halogen or inferior alkyl; R4 is hydrogen or hydroxy-. A is -S(O)2- or -C(O)-; X, Y are -CH2- or -O- independently from each other, though both X and Y should not be -O- at the same time; R'R" are hydrogen or inferior alkyl independently from each other; n is 0, 1 or 2. Also the invention concerns pharmaceutically acceptable additive salts and acids of the compounds, and a medicine based on it.

EFFECT: new biologically active compounds show inhibition effect in glycine absorption.

21 cl, 214 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to the obtaining of the new derivatives of benzamide of the formulas (I), which possess the activating influence on glucokinase, which can be used for treating of diabetes and obesity: where X1 and X2 represent oxygen, R1 represents alkylsufonyl, alkaneyl, halogen or hydroxyl; R2 represents alkyl or alkenyl, R3 represents alkyl or hydroxyalkyl, ring A represents phenyl or pyridyl, the ring B represents thiazolyl, thiadiazolil, isoxazoleyl, pyridothiazolyl or pyrazolyl, in which the atom of carbon of ring B, which is connected with the atom of nitrogen of the amide group of the formula(I), forms C=N bond with ring B.

EFFECT: obtaining new bioactive benzamides.

12 cl, 166 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the new pyridine and new pyrimidine derivative, their pharmaceutically accepted salt or hydrate of the general formula (I): . The invention also relates to the pharmaceutical composition, which possesses the inhibiting activity with respect to the receptor of the growth factor of hepatocytes; to the inhibitor of the receptor of the growth factor of hepatocytes, the inhibitor of angiogenesis, the antitumor drug, the inhibitor of cancerous metastatic spreading, that contains the pharmacologically effective dose of the said compounds, its pharmaceutically acceptable salt or hydrate.

EFFECT: inhibitory activity.

27 cl, 45 tbl, 540 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the compounds of the formula (I) where: X is O; Y represents a bond, CH2, NR35, CH2NH, CH2NHC(O), CH(OH), CH(NHC(O)R33), CH(NHS(O)2R34), CH2O or CH2S; Z is C(O), or if Y is a bond, then Z can also be S(O)2; R1 could be substituted with phenyl; R4 is hydrogen, C1-6-alkyl (substituted possibly by C3-6-pilkoalkyl) or C3-6-cycloalkyl; R2, R3, R5, R6, R7 and R8 are independently hydrogen, C1-6-alkyl or C3-6-cycloalkyl; type independently indicate 0 or 1; R9 could possibly be substituted with an aryl or heterocycle; R10, R32 and R35 are independently hydrogen, C1-6-alkyl or C3-6-cycloalkyl; R33 and R34 are C1-6-alkyl or C3-6-cycloalkyl; where the aforesaid aryl and heterocyclic groups, when possible, can be substitute with: halogen cyanogens, nitro, hydroxyl, oxo, S(O)Kr12, OC(O)NR13R14, NR15R16, NR17C(O)R18, NR19C(O)NR20R21, S(O)2NR22R23, NR24S(O)2R25, C(O)NR26R27, C(O)R28, CO2R29, NR30CO2R31, by C1-6-alkyl (which itself can be monosubstituted with NHC(O)phenyl), C1-6-halogenalkyl, C1-6-alkoxy(C1-6)alkyl, C1-6-alkoxy, C1-6-halogenaloxy, C1-6-alkoxy(C1-6)-alkoxy, C1-6-alkylthio, C2-6-alkenyl, C2-6-alkinil, C3-10-cycloalkyl, methylenedioxy, difluoromethylenedioxy, phenyl, phenyl(C1-4)alkyl, phenoxy, phenylthio, phenyl(C1-4)alkyl, morpholinyl, heteroaryl, heteroaryl(C1-4)alkyl, heteroarylhydroxy of heteroaryl(C1-4)alkoxy, where any of the said phenyl and heteroaryl groups can be substituted by halogen, hydroxyl, nitro, S(O)r(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-.4-alkyl)2, cyanogens, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4-alkyl), CO2H, CO2(C1-4-alkyl), NHC(O)( C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)( C1-4-alkyl), CF3 or OCF3; k and r independently mean 0, 1 or 2; R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R26, R27, R29 and R30 independently represent hydrogen, C1-6-alkyl (probably replaced by halogen, hydroxyl or C3-10-cycloalkyl), CH2(C2-6-alkenyl), C3-6-cycloalkyl, phenyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4-alkyl), NH(C1-4-alkyl)2, S(O)2(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2, cyanogen, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4-alkyl), C(O)N(C1-4-alkyl)2, CO2H, CO2(C1-4-alkyl), NHC(O)(C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)(C1-4-alkyl), CF3 or OCF3) or heterocyclyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4-alkyl), N(C1-4-alkyl)2, S(O)2)(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2, cyanogen, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4-alkyl), C(O)N(C1-4-alkyl)2, CO2H5 CO2(C1-4-alkyl), NHC(O)( C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)( C1-4-alkyl), CF3 or OCF3); alternatively, NR13R14, NR15R16, NR20R21, NR22R23, NR26R27 can independently form 4-7-member heterocyclic ring, selected from the group, which includes: azetidine (which can be substituted by hydroxyl or C1-4-alkyl), pyrrolidine, piperidine, azepine, 1,4-morpholine or 1,4-piperazine, the latter is probably substituted by C1-4-alkyl on the peripheral nitrogen; R12, R25, R28 and R31 are independently C1-6-alkyl (possibly substituted by halogen, hydroxyl or C3-10-cycloalkyl), CH2(C2-6-alkenyl), phenyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4- alkyl), N(C1-4-alkyl)2, (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), S(O)2(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2 (and these alkyl groups can connec to form a ring as described hereabove for R13 and R14), cyanogen, C1-4- alkyl, C1-4- alkoxy, C(O)NH2, C(O)NH(C1-4- alkyl), C(O)N(C1-4-alkyl)2 (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), CO2H, CO2(C1-4-alkyl), NHC(O)(C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)(C1-4-alkyl), NHC(O)(C1-4-alkyl), CF3 or OCF3) or heterocyclyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4-alkyl), N(C1-4-alkyl)2, (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), S(O)2(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2 (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), cyanogen, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4- alkyl), C(O)N(C1-4-alkyl)2 (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), CO2H, CO2(C1-4-alkyl), NHC(O)(C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)(C1-4-alkyl), CF3 or OCF3); or its N-oxide; or its pharmaceutically acceptable salt, solvate or solvate of its salt, which are modulators of activity of chemokines (especially CCR3); also described is the pharmaceutical composition on their basis and the method of treating the chemokines mediated painful condition.

EFFECT: obtaining new compounds possessing useful biological properties.

13 cl, 238 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the tetrahydroquinolin derivatives with the common formula (I) or their pharmaceutically acceptable salts, where R1 and R2 are H or Me; R3 is H, hydroxy or (1-4C)alkoxi; R4 is H, OH, (1-4C)alkoxi; R5 is OH, (1-4C)alkoxi or R7; provided the R4 is H, then R5 differs from OH or (1-4C)alkoxi; R6 is (2-5C)heteroaryl, not necessarily substituted with one or more substitutes, selected from (1-4C)alkyla, bromine or chlorine; (6C)aryl, not necessarily substituted with one or more substitutes, selected from (1-4C)alkyla, (1-4)C-alkoxi, bromine, chlorine, phenyl or (1-4C) (di)alkylamino; (3-8C)cycloalkyl, (2-6C)heterocycloalkyl or (1-6C)-alkyl; R7 is amino, (di)(1-4C)alkylamino, (6C)arylcarbonylamino, (2-5C)heteroarylcarbonylamino, (2-5C)heteroaryl-carbonylokxi, R8-(2-4C)alkoxi, R9-methylamino or R9-methoxi; R8 is amino, (1-4C)alkoxi, (di)(1-4C)-alkylamino, (2-6C)-heterocycloalkyl, (2-6C)heterocycloalkylcarbonylamino or (1-4C)-alkoxicarbonylamino; and R9 is aminocarbonyl, (di)(1-4C)alkylaminocarbonyl, (2-5C)heteroaryl or (6C)aryl. The invention also relates to the pharmaceutical composition which contains the said derivatives, and to the application of the derivatives in fertility modulating.

EFFECT: novel tetrahydroquinolin derivatives with follicle-stimulating hormone receptors modulating activity are obtained.

15 cl, 51 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to the tetrahydroquinolin derivatives with the common formula (I) , or their pharmaceutically acceptable salts, where R1 and R2 are H, Me; R3 is (2-6C)-hetercycloalkyl(1-4C)alkyl, (2-5C)heteroaryl(1-4C)alkyl, (6C)aryl(1-4C)-alkyl, (2-6C)hetercycloalkylcarbonylamino(2-4C)alkyl, R5-(2-4C)alkyl or R5-carbonyl(1-4C)alkyl; R4 is (2-5C)heteroaryl (6C)aryl, not necessarily substituted with one or more substitutes selected from bromine, chlorine, nitro, phenyl, (1-4C)alkyl, trufluoromethyl, (1-4C)alkoxi or (1-4C)alkylamino; or (2-6C)hetercycloalkyl; R5 is (di (1-4C)alkylamino, (1-4C)alkoxi, amio, hydroxy, (6C)arylamino, (di)(3-4C)alkenylamino, (2-5C)heteroaryl(1-4C)alkylamino, (6C)aryl(1-4C)alkylamino, (di)[(1-4C)alkoxi(2-4C)alkyl]amino, (di)[(1-4C)alkylamino2-4C)alkyl]amino, (di)[amino(2-4C)alkyl]amino or (di)[hydroxy(2-4C)alkyl]amino. The invention also relates to the pharmaceutical composition based on the compound with formula (I) and to the application of the compound with the formula (I).

EFFECT: novel tetrahydroquinolin derivatives with follicle-stimulating hormone receptors modulating activity are obtained.

10 cl, 44 ex

FIELD: chemistry; oxa-and thiazole derivatives.

SUBSTANCE: oxa- and thiazole derivatives have general formula . Their stereoisomers and pharmaceutical salts have PPARα and PPARγ activity. The compounds can be used for treating diseases, eg. diabetes and anomaly of lipoproteins through PPARα and PPARγ activity. In the general formula, x has value of 1, 2, 3 or 4; m has value of 1 or 2; n has value of 1 or 2; Q represents C or N; A represents O or S; Z represents O or a bond; R1 represents H or C1-8alkyl; X represents CH; R2 represents H; R2a, R2b and R2c can be the same or different and they are chosen from H, alkoxy, halogen; R3 represents aryloxycarbonyl, alkyloxycarbonyl, alkyl(halogen)aryloxycarbonyl, cycloalkylaryloxycarbonyl, cycloalkyloxyaryloxycarbonyl, arylcarbonylamino, alkylsulphonyl, cycloheteroalkyloxycarbonyl, heteroarylalkenyl, alkoxyaryloxycarbonyl, arylalkyloxycarbonyl, alkylaryloxycarbonyl, halogenalkoxyaryloxycarbonyl, alkoxycarbonylaryloxycarbonyl, arylalkenyloxycarbonyl, aryloxyarylalkyloxycarbonyl, arylalkenylsulphonyl, heteroarylsulphonyl, arylsulphonyl, arylalkenylarylalkyl, arylalkoxycarbonyl-heteroarylalkyl, heteroaryloxyarylalkyl, where alkyl is in form of C1-8alkyl; Y represents CO2R4, where R4 represents H or C1-8alkyl; including all their stereoisomers and pharmaceutical salts, under the condition that, if A is O, then R3 is not aryloxycarbonyl or alkoxyaryloxycarbonyl.

EFFECT: the compounds can be used in curing such diseases as diabetes and lipoprotein anomalies.

10 cl, 30 dwg, 12 tbl, 584 ex

FIELD: chemistry, pharmaceuticals.

SUBSTANCE: invention pertains to compounds with formula (I), their pharmaceutical salts or N-oxide used as an inhibitor to replication and/or proliferation of HCV, to the method of inhibiting replication or proliferation of hepatitis C virion using formula (I) compounds, as well as to pharmaceutical compositions based on them. The compounds can be used for treating or preventing infections, caused by hepatitis C virus. In general formula (I) cycle B is an aromatic or non-aromatic ring, which contains two heteroatoms, where X and Y, each is independently chosen from C, CH, N or O, under the condition that, both X and Y are not O and that, both X and Y are not N; U and T represent C; Z represents -CH-; A represents N or -CR2-; B represents -CR3-; D represents N or -CR4-; E represents N or -CR5-; G represents N or -CR6-; J represents N or -CR14-; K represents -CR8-; L represents N or -CR9-; M represents N or -CR10-; R2 and R6, each is independently chosen from a group, consisting of hydrogen, halogen, C1-C6alkyl, substituted C1-C6alkyl, C1-C6alkoxy, C1-C6substituted alkoxy, C1-C6alkoxycarbonyl, cycloheteroalkyl, substituted cycloheteroalkyl, -O-carbamoil, substituted -O-carbamoil, halogen C1-C6alkyl, diC1-C6alkylamino, substituted diC1-C6alkylamino and sylye ethers, where cycloheteroalkyl is a 3-7-member ring, containing 1-2 heteroatoms, chosen from N and O, under the condition that, one of R2 and R6 is not hydrogen; R3 and R5, each is independently chosen from a group, consisting of hydrogen, halogen; R4 represents hydrogen; R7 represents - NR11C(O)R12; R8, R9, R10 and R14, each is independently represents hydrogen; R11 represents hydrogen, C1-C6alkyl; and R12 is chosen from a group, consisting of halogen C1-C6alkyl; where each substituted group is substituted with one or more groups, chosen from -Q, -R40, -OR40, -C(O)R40, -C(O)OR40, where each Q independently represents halogen, R40 and R41 are independently chosen from a group consisting of hydrogen, C1-C6alkyl, C1-C6alkoxy, under the condition that: (i) at least one of A, D, E, G, J, L or M represents N; (ii) not more than one of A, D, E or G represents N; and (iii) not more than one of J, L or M represents N.

EFFECT: obtaining pyridyl-substituted heterocycles for treating and preventing infections, caused by hepatitis C virus.

33 cl, 85 dwg, 101 ex

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