Derivatives of benzothiazole and medicament based on thereof

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention elates to derivatives of benzothiazole of the general formula (I): wherein R means hydrogen atom, -(CH2)n-phenyl optionally substituted with a substitute chosen from the following group: halogen atom, (lower)-alkyl, (lower)-alkoxy-group, trifluoromethyl or -N(R')-C(O)-(lower)-alkyl, -(CH2)n-pyridinyl optionally substituted with (lower)-alkyl, -(CH2)n-(C3-C6)-cycloalkyl optionally substituted with hydroxy-group, -(CH2)n-benzo[1,3]dioxolyl, -(CR'2)-thiophenyl, -(CR'2)n-thiazolyl optionally substituted with (lower)-alkyl, -(CH2)n-C(O)-thiophenyl optionally substituted with halogen atom, -(CH2)-furanyl optionally substituted with (lower)-alkyl, -(CHR')n-benzofuran-1-yl, -(CH2)n-benzo[b]thiophenyl, -(CH2)n-N(R')-C(O)-phenyl optionally substituted with halogen atom or (lower)-alkoxy-group. -(CH2)n-C(O)-phenyl optionally substituted with (lower)-alkoxy-group, -(CH2)n-C(O)-2,3-dihydrobenzo[1,4]dioxine-6-yl, -(CH2)n-N(R')-C(O)-pyridinyl, -(CH2)n-tetrahydrofuranyl, -CH-biphenyl, -CH-(phenyl)pyridinyl, -(CH2)n-1-oxo-(CH2)n-CH-(phenyl)tetrahydropyranyl, -(CH2)n-1-oxo-1,2,3,4-tetrahydroquinoline-3-yl or -(CH2)n-S-[1,3,4]thiadiazol-2-yl optionally substituted with amino-group; R' means hydrogen atom or (lower)-alkyl and independently of one another in case R'2; n = 0, 1, 2, 3 or 4. Also, invention relates to a medicament possessing high affinity to adenosine A2A-receptors and high selectivity with respect to A1-receptors and comprising one or more derivatives of benzothiazole of the formula (I) and pharmaceutically acceptable excipients. Invention provides using derivatives of benzothiazole as ligands of adenosine receptors.

EFFECT: valuable medicinal properties of compounds and medicament.

13 cl, 2 tbl, 3 ex

 

The present invention relates to compounds of General formula

where

R means hydrogen,

-(CH2)nis phenyl, optionally substituted by a Deputy of the series halogen, (ness.)alkyl, (ness.)alkoxy, trifluoromethyl, or-N(R')-C(O)-(ness.)alkyl,

-(CH2)n-pyridinyl, optionally substituted (ness.)the alkyl,

-(CH2)n-C3-C6cycloalkyl, optionally substituted by a hydroxy-group,

-(CH2)n-N(R')-C3-C6cycloalkyl, optionally substituted by a hydroxy-group,

-(CH2)n-benzo[1,3]dioxole,

-(CR'2)n-thiophenyl, optionally substituted (ness.)the alkyl,

-(CR'2)n-thiazolyl, optionally substituted (ness.)the alkyl,

-(CH2)n-C(O)-thiophenyl, optionally substituted with halogen,

-(CH2)n-furanyl, optionally substituted (ness.)the alkyl,

-(CH2)n-C(O)-(CH2)n-thiophenyl,

-(CHR')n-benzofuran-2-yl,

-(CH2)n-benzo[b]thiophenyl, optionally substituted (ness.)the alkyl,

-(CH2)n-N(R')-C(O)-phenyl, optionally substituted with halogen or (ness.)alkoxy,

-(CH2)n-C(O)-phenyl, optionally substituted (ness.)alkoxy,

-(CH2)n-C(O)-2,3-dihydrobenzo[1,4]dioxin-6-yl,

-(CH2)nN(R')-C(O)-pyridinyl,

-(CH2)n-tetrahydrofuranyl,

CH-biphenyl,

-CH-(phenyl)pyridinyl,

-(CH2)n-1-oxo-1,3-dihydroindol-2-yl,

-(CH2)n-1,3-dioxo-1,3-dihydroindol-2-yl,

-(CH2)n-CH-(phenyl)tetrahydropyranyl,

-(CH2)n-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-yl or

-(CH2)n-S-[1,3,4]thiazol-2-yl, optionally substituted amino group,

R' means hydrogen or (ness.)alkyl, independently of each other if R'2a n is 0, 1, 2, 3, or 4, or pharmaceutically acceptable acid additive salts.

It has been unexpectedly found that compounds of General formula I are ligands of the adenosine receptor. In more detail, the compounds of the present invention have high affinity for the receptor And2Aand a high selectivity for receptors A1and a3.

Adenosine modulates a wide range of physiological functions by interacting with surface receptors on specific cells. The use of adenosine receptors as targets of drugs was first described in 1982 in structural and metabolic against adenosine close bioactive nucleotides: adenosine triphosphate (ATP), adenosine diphosphate (ADP), the monophosphate (AMP) and cyclic monophosphate (camp), biochemical m is tiliroside agent of S-adenosyl-L-methionine (SAM), while structurally similar to the coenzymes NAD, FAD, and coenzyme A, and RNA. Adenosine and these related compounds have important roles in regulating many aspects of cellular metabolism and modulation of various types of activity of the Central nervous system.

Receptors adenosine receptors are divided into A1And2AAnd2Band a3belonging to the family of receptors coupled with G-proteins. Activation of adenosine receptors initiates the mechanism of signal transmission. These mechanisms are dependent on G-protein associated with the receptor. Each of the subtypes of adenosine receptors, as a rule, characterized by the adenylate cyclase effector system that uses as a secondary messenger camp. Receptors A1and a3associated with Gi-proteins that inhibit adenylate cyclase, which leads to lower intracellular level of camp, while the receptors A2Aand a2Bpaired with GS-proteins and activate adenylate cyclase, which increases intracellular levels of camp. It is established that the system of receptor-A1includes activation of phospholipase C and modulation of potassium and calcium ion channels. Subspecies receptor And3in addition to binding to adenylate cyclase stimulates the phospholipase C and thus activates calcium ion channels.

This is currently being cloned receptor-a 1(326-328 amino acid residues) of many species (dog, human, rat, dog, chicken, cattle, Guinea pigs), and 90-95% amino acid sequence was identical in many species of mammals. In addition, the cloned receptor-A2A(409-412 amino acid residues) dog, rat, human, Guinea pigs and mice. Cloned the receptor A2B(332 amino acid residue) between human and mouse, and receptor-a2Bman 45% homologous receptors A1and a2Aman. Cloned the receptor And3(317-320 amino acid residues) of human, rat, dog, rabbit and sheep.

It is assumed that the receptor subtypes And1and a2Aplay complementary roles in the regulation of adenosine process of energy production. Adenosine, which is a product of metabolic transformation of ATP diffuses out of the cell and acts on the local level, activating adenosine receptors, which stimulate the reduction of oxygen demand (A1or the increase in the supply of oxygen (A2Aand, thus, regulating the balance between energy production and demand in the tissues. The result of the actions of both subtypes of receptors is to increase the amount of oxygen available to the tissues, and protect cells from damage caused by kratkovremenna the m an imbalance in oxygen supply. One of the important functions of endogenous adenosine is the prevention of damage at the time of injury such as hypoxia, ischemia, hypotension, and seizures.

In addition, it was found that the binding of agonist adenosine receptor with fat cells expressing the receptor And3rats leads to increased concentrations of Insectivora and intracellular calcium, which causes the antigen-induced secretion of inflammatory mediators. Therefore, the receptor And3participates in mediating 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 neural activity changes depending on the behavioral status and (Pato)physiological States. In conditions of high demand and limited flow of energy (such as hypoxia, hypoglycemia, and/or excessive neural activity) adenosine provides an effective protective feedback mechanism. Interaction with adenosine receptors is a promising target for therapeutic intervention for a variety of neurological and psychiatric diseases, such as epilepsy, sleep disorders, disorders of the musculoskeletal system (Parkinson's disease or Huntington's disease), Alzheimer's disease, depression, schizophrenia or drug addiction. The enhanced release of neurotransmitters occurs when an injury such as hypoxia, ischemia and seizures. Finally, these neurotransmitters are responsible for the degeneration of nerve tissue and death of neurons, which leads to brain damage or death. Therefore, agonists of receptor-A1that mimic the inhibitory action of adenosine on cells of the Central nervous system, can be used as neuroprotective agents. It is assumed that adenosine is an endogenous anticonvulsant agent, inhibiting the release of glutamate from the excited neurons and inhibiting inflammation of the neurons. Therefore, agonists of adenosine can be used as antiepileptic agents. Antagonists of adenosine stimulate the activity of the Central nervous system and are effective as enhancers of cognitive abilities. Selective antagonists And2ahave a therapeutic effect in the treatment of various forms of dementia, such as Alzheimer's disease, and neurodegenerative conditions such as stroke. Antagonists of adenosine receptor And2amodulate the activity veins GABAergic neuron is in and manage a calm and coordinated movements, thus opening the possibility of treating the symptoms of Parkinson's disease. In addition, adenosine is involved in several physiological processes, including the effects of sedation, hypnosis, schizophrenia, anxiety, pain, respiration, depression and addiction to narcotic drugs (amphetamine, cocaine, opioids, ethanol, nicotine, cannabinoids). Therefore, medicines acting on adenosine receptors, also have medicinal activity as sedatives, muscle relaxants, antipsychotics, tranquilizers, analgesics, respiratory stimulants, antidepressants, and means for the treatment of substance abuse. In addition, they can be used in the treatment of ADHD (hyperactive condition due to lack of attention).

An important function of adenosine in the cardiovascular system is its cardioprotective action. The level of endogenous adenosine is increased in response to ischemia and hypoxia, as well as provides protection of cardiac tissue during and after injury (pre-processing). When exposed to the receptor And1agonists of receptor-A1can protect against damage caused by myocardial ischemia and reperfusion. The modulating influence of receptors And2aon adrenergic function may be important for a variety of violations, t is such as coronary heart disease and heart failure. Antagonists of the receptor And2acan have a therapeutic effect in cases that require enhanced antiadrenergicheskoe response, such as an acute attack of myocardial ischemia. Selective antagonists of receptor-A2acan also increase the efficacy of adenosine in the suppression of supraventricular arrythmia.

Adenosine modulates many aspects of kidney function, including the release of renin, the rate of glomerular filtration and renal blood flow. Compounds that are antagonists of the actions of adenosine in the kidney, can be used as a renal protective agent. In addition, antagonists And3and/or And2Bcan be used in the treatment of asthma and other allergic responses or in the treatment of diabetes and obesity.

Modern information about adenosine receptors can be found, for example, in the following publications:

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

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

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

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

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

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

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

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, the use of compounds of the formula I and their pharmaceutically acceptable salts for receipt of the drugs, intended for the treatment of diseases mediated by the receptor adenosine A2the methods of obtaining these compounds, medicines on the basis of the compounds according to the invention and the reception, as well as the use of compounds of formula I for the treatment or prevention of diseases associated with the modulation of the adenosine system, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, a neuroprotective effect, schizophrenia, anxiety, pain, respiratory disorder, depression, addiction to narcotic drugs (such as amphetamine, cocaine, opioids, ethanol, nicotine, cannabinoids), 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, anti-epileptics, anticonvulsants and cardioprotective agents for diseases such as coronary heart disease and heart failure. The most preferred indications in the present invention are indications, based on the antagonistic action on the receptor adenosine A2Aand including disorders of the Central nervous system, for example, the treatment or prevention of Alzheimer's disease, some mood the s States, substance abuse, neuroprotective effect, Parkinson's disease and ADHD.

The term "(ness.)alkyl"used in the text of the application, means a saturated alkyl group with straight or branched chain, containing from 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, etc. Preferred (ness.)alkyl groups are groups containing 1 to 4 carbon atoms.

The term "halogen" means chlorine, iodine, fluorine and bromine.

The term "(ness.)alkoxy" means a group in which the alkyl residue has the values listed above, and which is attached via an oxygen atom.

The term "pharmaceutically acceptable acid additive salts" means salts of inorganic and 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, methanesulfonate acid, para-toluensulfonate acid, etc.

Preferred compounds of the present invention are the compounds of formula I in which R signifies hydrogen, for example, the following connection:

amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid.

In addition, preferred compounds of formula I are compounds in to the which R is -(CH 2)nis phenyl, optionally substituted with halogen, (ness.)alkoxy or (ness.)the alkyl, for example, the following connections:

penetrated-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid,

3-Chlorobenzilate 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid,

2-Chlorobenzilate 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid,

2-methoxybenzylamine 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid,

[2-(2-methoxyphenyl)ethyl]amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid,

[2-(3-forfinal)ethyl]amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid,

[2-(4-forfinal)ethyl]amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid,

[2-(4-chlorophenyl)ethyl]amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid,

[2-(2-chlorophenyl)ethyl]amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid,

[2-(3-methoxyphenyl)ethyl]amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid,

[2-(3-chlorophenyl)ethyl]amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid, or

(2-meta-triletal)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid.

Also preferred are such compounds in which R is -(CH2)n-pyridinyl, for example, the following connections:

pyridine-3-alamid 4-methoxy-7-morpholine-4-even thiazol-2-carboxylic acid,

(pyridine-2-ylmethyl)amid-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid, or

(2-pyridin-3-retil)amid-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid.

Also preferred are compounds in which R is -(CHR')n-thiophenyl or -(CH2)n-C(O)-thiophenyl, optionally substituted with halogen, for example, the following connections:

(2-thiophene-2-retil)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid,

(2-thiophene-3-retil)amid-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid,

[2-(3-chlorothiophene-2-yl)-2-oxoethyl] amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid, or

(1-methyl-2-thiophene-2-retil)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid.

In addition, a preferred group of compounds are those compounds in which R is -(CHR')n-thiazolyl, optionally substituted (ness.)the alkyl, for example, the following connection: [1-(4-methylthiazole-2-yl)ethyl]amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid.

These compounds of formula I and their pharmaceutically acceptable salts get known methods, for example, as described below, which includes

a) interaction of the compounds of formula

with the compound of the formula

by the research of the compounds of formula

where R has the meanings indicated above, or

b) cyclization of the compounds of formula

with the formation of the compounds of formula

where R has the meanings indicated above, and

if necessary, the conversion of the compounds obtained into pharmaceutically acceptable acid additive salt.

The compounds of formula I get the options method a) and b)as shown in schemes 1 and 2. In addition, the receipt of 84 compounds according to the invention is described in more detail in the examples.

Scheme 1 R has the values listed above, a CDI means 1,1'-carbonyldiimidazole.

Getting the parent compound of formula (1) described in WO 01/97786.

Scheme 1 the compounds of formula I receive, as described below.

Diethyl ester of oxalic acid (2) is heated to approximately 120°With, very carefully in small portions add 2-methoxy-5-morpholine-4-elfenlied (1) and heated at approximately 180°C for 90 minutes Then the mixture is cooled to room temperature, filter and add n-hexane. The obtained precipitate was separated by filtration, washed with hexane and dried, thus obtain ethyl ester of N-(2-methoxy-5-morpholine-4-ylphenyl)examinados acid (3). Then to the resulting compound of the formula (3) to PADAM xylene for approximately 30 min in small portions add pentasulfide phosphorus, refluxed for 5 min, cooled to room temperature and filtered. The solution is extracted with 1N. NaOH, the aqueous phase is washed with toluene, filtered and at 0-5°add conc. hydrochloric acid to pH 1. The precipitate was separated by filtration, thus obtain (2-methoxy-5-morpholine-4-ilfenomeno)toxocology acid (4).

To a solution of potassium ferricyanide in water, add a solution of (2-methoxy-5-morpholine-4-ilfenomeno)Toxocara acid (4) in 1H. NaOH, keeping the temperature no higher than 10°C. the Mixture was stirred at 10°C for 3 h and add conc. hydrochloric acid to pH 1. The precipitate was separated by filtration and dried, thus obtain 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid (5). A suspension of the compounds of formula (5) and 1,1'-carbonyldiimidazole in dimethylformamide was stirred at room temperature for 1 h, add with stirring a compound of the formula (6), for example, benzylamine, and stirred for another 20 hours and Then water is added and extracted with ethyl acetate. The product was then purified by chromatography on silica gel (eluent: diclomelan/ethyl acetate), thus obtain the connection formula I.

According to scheme 1 are the compounds described in the examples 3-84.

In scheme 2, R has the values listed above.

According to scheme 2, the respective chloracetamide formulas(7) and sulfur in dimethylformamide is treated with triethylamine and the mixture is stirred at room temperature for about 15 hours Then add 2-methoxy-5-morpholine-4-elfenlied (1) and n-propanol and stirred at room temperature for a further 6 hours the mixture is Then refluxed for two days. The crystalline precipitate was separated by filtration and washed with n-propanol, you get a compound of formula (8).

To a solution of potassium ferricyanide in water add a suspension of the compounds of formula (8) in 1H. the sodium hydroxide, the mixture was stirred at 50°C for 30 min and then at room temperature overnight. The precipitate was separated by filtration, dissolved in dichloromethane and purified by chromatography on a column of silica gel (eluent: ethyl acetate/hexane), you get a compound of formula I.

Scheme 2 get compounds described in examples 1 and 2.

Isolation and purification of compounds

Isolation and purification of the above-described compounds and intermediate products is carried out, if necessary, by any suitable methods of separation or purification such as filtration, extraction, crystallization, chromatography on a column chromatography in thin and thick layer of sorbent, preparative liquid chromatography at low or high pressure, or a combination of these techniques. Specific illustrations of suitable separation techniques and allocation is presented below in the Examples section. However, you can also use the SQL and other equivalent methods of separation or selection of substances.

Salts of compounds of formula I

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

Obtaining salts conduct processing at least a stoichiometric amount of the appropriate acid, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. or an organic acid such as acetic 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, para-toluensulfonate acid, salicylic acid, etc. Usually free base dissolved in an inert solvent, such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol and the like, and add acid in the same solvent. The temperature of the support 0°C to 50°C. the Obtained salt precipitates or it can be planted from solution by addition of a less polar solvent.

Acid-edit the main salts of the bases of the compounds of formula I can be converted into the corresponding free base by treatment with at least the stoichiometric amount of the appropriate base, such as sodium hydroxide or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, etc.

The compounds of formula I and their pharmaceutically acceptable additive salts have valuable pharmacological properties. Specifically, it was found that the compounds of the present invention are ligands of adenosine receptors have high affinity for adenosine receptors And2Aand high selectivity in receptor-A1and a3.

The biological activity of the compounds was determined by the following method.

The binding of adenosine receptor A1person

Adenosine receptor-a1man recombinante expressed in egg cells of the Chinese hamster (Cho) using the expression system of the virus Semliki forest. Cells were collected, washed twice by centrifugation, homogenized again and washed by centrifugation. The washed precipitate containing membrane fraction, suspended in a buffer solution of Tris (50 mm, pH 7.4)containing 120 mm NaCl, 5 mm KCl, 2 mm CaCl2and 10 mm MgCl2(buffer solution). Analysis of the binding of [3H]-DPCPX (0,6 nm) ([propyl-3H]-8-cyclopentyl-1,3-dipropylacetic) was performed in 96-well tablets in the presence of 2.5 μg of membrane protein, 0.5 mg of granules SPA, covered with a Ysi-poly-L-lysine, and 0.1% adelaideans in the final volume is 200 ál of buffer A. Nonspecific binding was determined in the presence of related compounds of xanthinuria (KHAS, 2 μm). Binding of the analyzed compounds were determined at 10 concentrations ranging from 10 μm to 0.3 nm. All analyses were performed in repeated experiments that were repeated at least twice. Analytical plates were incubated at room temperature for 1 h, centrifuged, and determined the amount of bound ligand containing radioactive label, on scintillation counter (Packard Topcount). The value of the IC50was calculated using nonlinear regression analysis and software, and the values of Kiwas calculated by the equation of Cheng-Prussoff.

The binding of adenosine receptor And2Aperson

Adenosine receptor And2Aman recombinante expressed in egg cells of the Chinese hamster (Cho) using the expression system of the virus Semliki forest. Cells were collected, washed twice by centrifugation, homogenized again and washed by centrifugation. The washed precipitate containing membrane fraction, suspended in a buffer solution of Tris (50 mm, pH 7.4)containing 120 mm NaCl, 5 mm KCl, 2 mm CaCl2and 10 mm MgCl2(buffer solution). The analysis of binding with [3H]-SCH-58261 (1Nm) (Dionisotti, etc., Br. J. Pharmacol., 121, 353 (1997)) was performed in 96-well tablets in the presence of the tvii 2.5 mg of membrane protein, 0.5 mg granules SPA, covered with a Ysi-poly-L-lysine, and 0.1% adelaideans in the final volume of 200 μl of buffer A. non-specific binding was determined in the presence of related compounds of xanthinuria (KHAS, 2 μm). Binding of the analyzed compounds were determined at 10 concentrations ranging from 10 μm to 0.3 nm. All analyses were performed in repeated experiments that were repeated at least twice. Analitical plates were incubated at room temperature for 1 h, centrifuged, and determined the amount of bound ligand containing radioactive label, on scintillation counter (Packard Topcount). The value of the IC50was calculated using nonlinear regression analysis and software, and the values Toiwas calculated by the equation of Cheng-Prussoff.

It is established that the compounds of formula I have high affinity to the receptor A2Aand high selectivity for receptor A1.

As shown in the table, the preferred compounds of the magnitude of the PKiform>7.5.

13
Example No.hA1(pKi)hA2(pKi)
1of 5.47,6
65,97,7
9of 5.47,8
5,27,5
155,67,7
16of 5.47,5
225,98,4
255,17,6
495,87,5
545,98,2
555,27.6
575,87,7
595,27,5
62the 5.77,5
636,07,7
645,97,6
656,37,6
715,97,6
735,87,5
776,38,3
816,78,9

The compounds of formula I and pharmaceutically acceptable salts of compounds of formula I can be used as medicines, for example, in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally by the way, for example, in the form of pills, tablets in the shell, coated tablets, hard and soft gelatine capsules, solutions, emulsions or su is Pensi. However, it is also effective introduction rectal method, for example, in the form of suppositories, or parenterally way, for example, in the form of injection solutions.

To obtain pharmaceutical preparations of the compounds of formula IA and IB can be processed in a mixture with pharmaceutically inert, inorganic or organic carriers. As such carriers upon receipt of tablets, pills in the shell, coated tablets and hard gelatin capsules are used, for example, lactose, corn starch or its derivatives, talc, stearic acid or its salts and the like are Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like, But in the case of soft gelatin capsules, depending on the nature of the active compounds usually do not require any medium. Suitable carriers upon receipt of solutions and syrups are, for example, water, polyols, glycerol, vegetable oils, etc. are Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols and the like

Moreover, the pharmaceutical preparations can contain preservatives, soljubilizatory, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts changed what I osmotic pressure, buffering agents, masking agents or antioxidants. In addition, they can contain other therapeutically valuable substances.

Drugs containing the compounds of formula I or their pharmaceutically acceptable salt and a therapeutically inert carrier are also an object of the present invention. The object of the invention is also a method of obtaining these drugs, including the processing of one or more compounds of the formula I and/or their pharmaceutically acceptable acid additive salts and optionally one or more other therapeutically valuable substances in the mixture in one or more therapeutically inert carrier in the finished herbal form.

The compounds of formula I of the present invention, and their pharmaceutically acceptable salts, due to the antagonistic action on adenosine receptor are used for treatment or prevention of diseases, such as Alzheimer's disease, Parkinson's disease, a neuroprotective effect, schizophrenia, anxiety, pain, respiratory disorder, depression, 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, protevoepilepticeski what x means, anticonvulsants and cardioprotective agents and to obtain the drugs.

The most preferred indications in the present invention are indications that include violation of the Central nervous system, for example, the treatment or prevention of certain depressive States, a neuroprotective effect and Parkinson's disease.

The dose can vary within wide limits and should be adjusted to the individual requirements in each particular case. In General, when orally administered to adult patients, the daily dose may vary from about 0.01 mg to about 1000 mg of the compounds of General formula I or the corresponding number of its farmatsevticheskii acceptable salt. The daily dose is given as a single dose or divided doses and, in addition, in case of appropriate indications, the upper limit can be exceeded.

125
The composition of the tablets (wet granulation)
Ingredients No.mg in one pill
5 mg25 mg100 mg500 mg
1. The compound of the formula I525100500
2. Lactose anhydrous DTG10530150
3.Sta-Rx 150066630
4. Microcrystalline cellulose303030150
5. Magnesium stearate1111
The total mass167167167831

Method get

1. Components 1, 2, 3 and 4 are mixed and granularit adding purified water.

2. The granules are dried at a temperature of 50°C.

3. The pellets are ground in appropriate mills.

4. Add the component and stirred for 3 min; then pressed tablets on the appropriate tabletirujut equipment.

The capsules
Ingredients No.mg in one capsule
5 mg25 mg100 mg500 mg
1. The compound of the formula I525100500
2. Hydrated lactose159123148-
3. Corn starch 25354070
4. Talc10151025
5. Magnesium stearate1225
The total mass200200300600

Method get

1. Components 1, 2, 3 are mixed in an appropriate mixer for 30 minutes

2. Add components 4 and 5 and mix for 3 minutes

3. The mixture is filled capsules. The invention is illustrated by the following examples without limiting its scope.

Example 1

Amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid

a) 2-(2-Methoxy-5-morpholine-4-ilfenomeno)-2-dioxazine

173 mg (of 1.85 mmol) Chloracetamide and 119 mg (3,70 mmol) of sulfur in 2 ml of dimethylformamide was treated 772 μl (5,55 mmol) of triethylamine and the mixture was stirred at room temperature for 15 hours Then was added 385 mg (of 1.85 mmol) 2-methoxy-5-morpholine-4-ilfenomeno and 10 ml n-propanol was stirred at room temperature for 6 h, and then the mixture is boiled under reflux for two days. The crystalline precipitate was separated by filtration and washed with n-propanol, received 320 mg (59%) of 2-(2-methoxy-5-morpholine-4-ilfenomeno)-2-dioxazine is in the form of crystals of red-brown color. MS: m/e (%) 296 (M+N+, 100).

Elemental analysis:

Rasch. for C13H17N3O3S (295,357): 52,87, N 5,80, N 14,23, S 10.86;

calc.: WITH 52,38, N OF 5.82, N 13,85, S 10,86.

b) Amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid

A suspension of 220 mg (0.75 mmol) of 2-(2-methoxy-5-morpholine-4-ilfenomeno)-2-dioxooleana 2.88 ml of 1N. sodium hydroxide was added to a solution of 813 mg (2,47 mmol) of potassium ferricyanide in 2 ml of water and the mixture was stirred at 50°C for 30 min and then at room temperature overnight. The precipitate was separated by filtration, dissolved in dichloromethane and purified by chromatography on a column of silica gel (eluent: ethyl acetate/hexane, 1:1), to receive amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid (32 mg, 15%) as yellow crystals, tpl.228-230°C. MS: m/e (%) 294 (M+N+, 100).

Example 2

(4-Forfinal)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid

a)N-(4-Forfinal)-2-(2-methoxy-5-morpholine-4-ilfenomeno)-2-dioxazine

919 mg (4,80 mmol) α-chloro-4-fioricetonline and 308 mg (9,60 mmol) of sulfur in 10 ml of dimethylformamide was treated with a 2.01 ml (14.4 mmol) of triethylamine and the mixture was stirred at room temperature for 2 days. Then were added to 1.00 g (4,80 mmol) 2-methoxy-5-morpholine-4-ilfenomeno in 5 ml of dimethylformamide and 25 ml of n-propanol was stirred at room temperature is round for 6 h, and the mixture is then boiled under reflux for 6,5 hours, the Crystalline precipitate was separated by filtration, washed with water and dried, to receive 434 mg (24%) of N-(4-forfinal)-2-(2-methoxy-5-morpholine-4-ilfenomeno)-2-dioxooleana in the form of a powder of red. tpl.206-208°C. MS: m/e (%) 390 (M+N+, 100).

b) (4-Forfinal)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid

A suspension of 100 mg (0.26 mmol) of N-(4-forfinal)-2-(2-methoxy-5-morpholine-4-ilfenomeno)-2-dioxooleana in 3,60 ml of 1N. sodium hydroxide was added to a solution of 285 mg (0.87 mmol) of potassium ferricyanide in 1 ml of water and the mixture was stirred at 50°C for 2 days, and then was extracted with dichloromethane. The product was purified by chromatography on a column of silica gel (eluent: ethyl acetate/hexane, 3:7), when it received 3.5 mg (4-forfinal)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid in the form of crystals off-white color. MS: m/e (%) 388 (M+N+, 100).

Example 3

Benzylamine 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid

a) Ethyl ester of N-(2-methoxy-5-morpholine-4-ylphenyl)assalamou acid

139 ml (1015 mmol) diethyl ester of oxalic acid was heated to 120°cautiously in small portions was added to 30.3 g (145 mmol) of 2-methoxy-5-morpholine-4-ilfenomeno and the mixture was heated at 180°C for 90 minutes Then the mixture is cooled is about room temperature, was filtered and added to 1.5 liters of n-hexane. The precipitate was separated by filtration, washed with hexane and dried, to receive 34.4 g (77%) of ethyl ester of N-(2-methoxy-5-morpholine-4-ylphenyl)assalamou acid in the form of crystals of a greenish color. tpl.95-97°C. MS: m/e (%) 309 (M+N+, 100).

b) (2-Methoxy-5-morpholine-4-ilfenomeno)Toxocara acid

To 33,9 g (110 mmol) of ethyl ester of N-(2-methoxy-5-morpholine-4-ylphenyl)examinados acid 652 ml of boiling xylene in small portions over 30 min was added 8,80 g (40 mmol) of pentasulfide phosphorus, and the mixture was boiled under reflux for 5 h, cooled to room temperature and filtered. The solution sevenfold was extracted with 100 ml of 1N. NaOH. The aqueous phase is twice washed with 100 ml of toluene, filtered and at 0-5°With added conc. hydrochloric acid to pH 1. The precipitate was separated by filtration, it was received by 20.2 g (62%) of (2-methoxy-5-morpholine-4-ilfenomeno)Toxocara acid in the form of yellow crystals. tpl.156-158°C. MS: m/e (%) 297 (M+N+, 100).

C) 4-Methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid

A solution of 10.5 g (of 35.4 mmol) (2-methoxy-5-morpholine-4-ilfenomeno)Toxocara acid in 248 ml (248 mmol) of 1H. NaOH was added dropwise to a solution of 40.1 per g (119 mmol) of potassium ferricyanide in 119 ml of water, keeping the temperature no higher than 10°C. the Mixture premesis what does 10° C for 3 h, and then was added conc. hydrochloric acid to pH 1. The precipitate was separated by filtration and dried, to receive 8,80 g (84%) 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid as yellow crystals. tpl.99-100°C. MS: m/e (%) 295 (M+H+, 100).

d) Benzylamine 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid

Suspension of 29.4 mg (0.10 mmol) of 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid and 18.4 mg (0.11 mmol) of 1,1'-carbonyldiimidazole in 3 ml of dimethylformamide was stirred at room temperature for 1 h and Then added to 12.1 μl (0.11 mmol) of benzylamine and was stirred for 20 hours To the mixture was added 15 ml of water, was extracted with ethyl acetate and the product was purified by chromatography on a column of silica gel (eluent: dichloromethane/ethyl acetate, 95:5), when it got to 31.2 mg (41%) of benzylamine 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid. tpl.156-158°C. MS: m/e (%) 384 (M+N+, 100).

The table below shows the characteristics of the compounds (examples 4-81), synthesized as described in example 3,

Example No.StructureThe systematic nametpl.°CThe original substance
4Phenylamide 4-is ethoxy-7-morpholine-4-eventhorizon-2-carboxylic acid 190-191Aniline
5Cyclohexylamin 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid146-147Cyclohexylamin
6Ventilated 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid50-51Phenylethylamine
74-Chlorobenzilate 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid175-1764-chlorobenzylamino
8Cyclopentolate 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid174-175Cyclopentylamine
9Pyridine-3-alamid 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid220-2213-aminopyridine

Example No.StructureThe systematic nametpl.°CThe original substance
10(4-Way shall Setenil)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid 148Paradisean
11(3-Methoxyphenyl)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid160Methanisation
12(2-Methoxyphenyl)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid191Oreanization
13(Pyridine-2-ylmethyl)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid181-1822-aminomethylpyridine
14(Benzo[1,3]dioxol-5-ylmethyl)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid190-1931,3-benzodioxol-5-methylamine
153-Chlorobenzilate 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid148-1503-chlorobenzylamino

Example No.StructureThe systematic nametpl.°CThe original substance
16 2-Chlorobenzilate 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid114-1162-chlorobenzylamino
174-Forbindelse 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid155-1564-forbindelsen
18(Pyridine-3-ylmethyl)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid181-1843-(aminomethyl)-pyridine
19Pyridine-2-alamid 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid177-1812-aminopyridine
203-Forbindelse 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid152-1533-forbindelsen
212-Forbindelse 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid133-1342-forbindelsen

Example No.StructureThe systematic nametpl.° CThe original substance
22(2-Thiophene-2-retil)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid120-1212-(2-thienyl)-ethylamine
23(Thiophene-2-ylmethyl)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid174-1752-thiophene-methylamine
24Cyclopropylmethyl 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid152-153(aminomethyl)-cyclopropane
252-Methoxybenzylamine 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid186-1882-methoxy-benzylamine
264-Methoxybenzylamine 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid164-1684-methoxybenzylamine
273-Methoxybenzylamine 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid140-1443-methoxybenzylamine

Example No.StructureThe systematic nametpl.°The original substance
28[2-(4-Chlorobenzylamino)ethyl]amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid237-240N-(2-amino-ethyl)-perchlor-benzamid
29[2-(1-Oxo-1,3-dihydroindol-2-yl)ethyl]amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid199-2052-(2-amino-ethyl)-phthalimide
30(4-Vinyltetrahydrofuran-4-ylmethyl)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid144-1484-phenyl-4-methylamino-tetrahydropyran
31(Pyridine-4-ylmethyl)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid207-2094-picolylamine
32[3-(1,3-Dioxo-1,3-dihydroindol-2-yl)-propyl]amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid200-202N-(3-aminopropyl)-phthalimide
33/td> [4-(1,3-Dioxo-1,3-dihydroindol-2-yl)butyl]amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid114-118N-(4-aminobutyl)-phthalimide

Example No.StructureThe systematic nametpl.°The original substance
34[2-(1,3-Dioxo-1,3-dihydroindol-2-yl)ethyl]amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid231-233N-(2-amino-ethyl)-phthalimide
35Cyclohexylmethyl-4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid150-151Cyclohexylethylamine
36(1-Oxo-1,2,3,4-tetrahydroisoquinoline-3-ylmethyl)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid152-1553-(aminomethyl)-3,4-dihydro-1(2H)-athinaikon
37[2-(2-Methoxybenzylamine)ethyl] amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid180-183 N-(2-amino-ethyl)-oreanized
38(2-Pyridine-2-retil)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid184-1852-(2-Pirelli)-ethylamine
39(2-Oxo-2-phenylethyl)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid197-200Aminoacetophenone

Example No.StructureThe systematic nametpl.°The original substance
40(3-Phenylpropyl)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid1473-phenylpropylamine
41(Tetrahydrofuran-2-ylmethyl)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid171-172Tetrahydrofurfuryl-Amin
42(2-Hydroxycyclohexyl)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid178-180CIS-2-amino-ethyl-1-cyclo-hexanol
43(2-Hydroxy-cyclohexylmethyl)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid133-135TRANS-2-amino-ethyl-1-cyclohexanol
44N'-(4-Methoxy-7-morpholine-4-eventhorizon-2-carbonyl)hydrazide nicotinic acid222-224The nicotinic acid hydrazide
45N'-(4-Methoxy-7-morpholine-4-eventhorizon-2-carbonyl)isonicotinic acid hydrazide171-174The nicotinic acid hydrazide

Example No.StructureThe systematic nametpl.°The original substance
46N'-Benzoylhydrazone 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid>260°Benzhydrazide
47Benzhydrylamine 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid166-168α-aminodiphenylamine
48 (2-Pyridine-4-retil)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid185-1884-(2-amino-ethyl)-pyridine
49[2-(2-Methoxyphenyl)ethyl]amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid158-1602-(2-methoxyphenyl)-ethylamine
502-(3-Acetylamino-phenyl)ethyl] amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid165-1662-(3-acetylaminophenol)-ethylamine
51N'-Phenylhydrazide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid226-227 ofThe phenylhydrazine

Example No.StructureThe systematic nametpl.°CThe original substance
52N'-(4-Methoxy-7-morpholine-4-eventhorizon-2-carbonyl)hydrazide pyridine-2-carboxylic acid225-2262-picolinic hydrazide
53Pyridine-4-alamid 4-is ethoxy-7-morpholine-4-eventhorizon-2-carboxylic acid 206-2074-aminopyridine
54(2-Thiophene-3-retil)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid137-1393-thiophene ethylamine
55(2-Pyridin-3-retil)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid160-1633-(2-amino-ethyl)-pyridine
56N'-(4-Methoxy-7-morpholine-4-eventhorizon-2-carbonyl)hydrazide 3,5-dimethoxybenzoic acid146-1483,5-dimethoxy-benzhydrazide
572-(3-Forfinal)ethyl]amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid120-1223-forfinal-ethylamine

Example No.StructureThe systematic nametpl.°CThe original substance
58[2-(2-Forfinal)ethyl]amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid151-1532-forfinal-ethylamine
59[2-(4-Forfinal)ethyl]amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid150-1534-forfinal-ethylamine
60[2-(3-Triptoreline)ethyl]amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid106-1082-(3-triptoreline)-ethylamine
61(2-para-Triletal)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid136-1384-were-ethylamine
62[2-(4-Chlorophenyl)ethyl]amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid153-1542-(4-chlorophenyl)-ethylamine
63[2-(2-Chlorophenyl)ethyl]amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid141-1432-(2-chlorophenyl)-ethylamine

Example No.StructureThe systematic nametpl.°CThe original substance
64 [2-(3-Methoxyphenyl)ethyl]amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid99-1013-methoxyphenethyl-Amin
65[2-(3-Chlorophenyl)ethyl]amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid109-1113-chlorophenyl-ethylamine
66[2-(4-Methoxyphenyl)-2-oxoethyl]amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid176-1782-amino-4'-methoxy-acetophenone
67(Vinylpyridin-2-yl-methyl)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid219-221phenyl-(2-pyridyl)-methylamine
68[2-(4-Methoxyphenyl)ethyl]amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid69-714-methoxyphenethyl-Amin
69(Benzo[b]thiophene-3-ylmethyl)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid187-189benzo(b)thio-Hairdryer-3-ylmethylamino

Example No.
StructureThe systematic nametpl.°CThe original substance
70(5-Methylfuran-2-ylmethyl)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid173-1745-methyl-furfuryl-Amin
71(2-meta-Triletal)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid119-1213-methyl-phenethylamine
72(2-Hydroxycyclohexyl)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid110-115TRANS-2-aminocyclohexanol
73[2-(3-Chlorothiophene-2-yl)-2-oxoethyl]amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid125-1272-(3-chlortan-2-yl)-2-oxo-1-ethanamine
74(2-ortho-Triletal)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid129-1312-methylphenethylamine
75[2-(2,3-Dihydrobis what about[1,4]dioxin-6-yl)-2-oxoethyl]amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid 206-2082-amino-1-(2,3-dihydro-benzo[1,4]-dioxin-6-yl)alanon

Example No.StructureThe systematic nametPL°The original substance
76[2-(3-Methylbenzo[b]thiophene-2-yl)-2-oxoethyl]amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid185-1872-amino-1-(3-methyl-benzo[b]-thiophene-2-yl)-alanon
77[1-(4-Methylthiazole-2-yl)ethyl]amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid175-176α-methyl-2-(4-methyl-thiazole)-methanamine
78(2-Oxo-2-thiophene-2-retil)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid171-1732-amino-1-(2-thienyl)-alanon
79(2-Oxo-2-thiophene-3-retil)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid229-2322-amino-1-(3-thienyl)-alanon
80[1-(2-Methylthiazole-4-yl)ethyl]amide 4-is ethoxy-7-morpholine-4-eventhorizon-2-carboxylic acid 174-1754-(1-amino-ethyl)-2-methylthiazole
81(1-Methyl-2-thiophene-2-retil)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid127-1292-(2-aminopropyl)-thiophene

Example No.StructureThe systematic nametpl.°CThe original substance
82(6-Methylpyridin-3-yl)amide of 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid145-1475-amino-2-methyl-pyridine
83[2-(5-Amino-[1,3,4]thiadiazole-2-ylsulphonyl)ethyl]amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid237-2392-amino-5-[(2-amino-ethyl)-thio]-1,3,4-thiadiazole
84(2-Benzofuran-2-yl-1-methylethyl)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid144-1462-(2-aminopropyl)-benzofuran

1. Derivatives of benzothiazole General formula

where R is hydrogen,

-(CH2)nis phenyl, optionally substituted by a Deputy of the series halogen, (ness.)alkyl, (ness.)alkoxy, trifluoromethyl, or-N(R')-C(O)-(ness.)alkyl,

-(CH2)n-pyridinyl, optionally substituted (ness.)the alkyl,

-(CH2)n-C3-C6cycloalkyl, optionally substituted by a hydroxy-group,

-(CH2)n-benzo[1,3]dioxole,

-(CR'2)n-thiophenyl,

-(CR'2)n-thiazolyl, optionally substituted (ness.)the alkyl,

-(CH2)n-C(O)-thiophenyl, optionally substituted with halogen,

-(CH2)n-furanyl, optionally substituted (ness.)the alkyl,

-(CHR')n-benzofuran-2-yl,

-(CH2)n-benzo[b]thiophenyl,

-(CH2)n-N(R')-C(O)-phenyl, optionally substituted with halogen or (ness.)alkoxy,

-(CH2)n-C(O)-phenyl, optionally substituted (ness.)alkoxy,

-(CH2)n-C(O)-2,3-dihydrobenzo[1,4]dioxin-6-yl,

-(CH2)n-N(R')-C(O)-pyridinyl,

-(CH2)n-tetrahydrofuranyl,

CH-biphenyl,

-CH-(phenyl)pyridinyl,

-(CH2)n-1-oxo-1,3-dihydroindol-2-yl,

-(CH2)n-1,3-dioxo-1,3-dihydroindol-2-yl,

-(CH2)n-CH-(phenyl)tetrahydropyranyl,

-(CH2)n-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-yl or

-(CH2)n-S-[1,3,4]thiadiazole-2-yl, optionally substituted amino group;

R' means hydrogen or (ness.)alkyl, independently of each other if R'2and n is 0, 1, 2, 3, or 4.

2. The compounds of formula I according to claim 1, where R is hydrogen.

3. The compound of formula I according to claim 2, which means amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid.

4. Compounds according to claim 1, where R is -(CH2)nis phenyl, optionally substituted with halogen, (ness.)alkoxy or (ness.)the alkyl.

5. Compounds according to claim 4, the connection means

ventilated 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid,

3-Chlorobenzilate 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid,

2-Chlorobenzilate 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid,

2-methoxybenzylamine 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid,

[2-(2-methoxyphenyl)ethyl]amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid,

[2-(3-forfinal)ethyl]amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid,

[2-(4-forfinal)ethyl]amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid,

[2-(4-chlorophenyl)ethyl]amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid,

[2-(2-chlorophenyl)ethyl]amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid,

[2-(3-methoxyphenyl)ethyl]amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid,

[2-(3-chlorophenyl)ethyl]amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid, or

(2-meta-triletal)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid.

6. Compounds according to claim 1, where R is -(CH2)n-pyridinyl.

7. Compounds according to claim 6, which means

pyridine-3-alamid 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid,

(pyridine-2-ylmethyl)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid, or

(2-pyridin-3-retil)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid.

8. Compounds according to claim 1, where R is -(CHR')n-thiophenyl or -(CH2)n-C(O)-thiophenyl, optionally substituted with halogen.

9. Connection of claim 8, which means

(2-thiophene-2-retil)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid,

(2-thiophene-3-retil)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid,

[2-(3-chlorothiophene-2-yl)-2-oxoethyl]amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid, or

(1-methyl-2-thiophene-2-retil)amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid.

10. Compounds according to claim 1, where R o is means -(CHR') n-thiazolyl, optionally substituted (ness.)the alkyl.

11. Connection of claim 10, where the connection means [1-(4-methylthiazole-2-yl)ethyl]amide 4-methoxy-7-morpholine-4-eventhorizon-2-carboxylic acid.

12. A drug with high affinity for adenosine receptors And2Aand high selectivity for receptor A1containing one or more compounds according to any one of claims 1 to 11, and pharmaceutically acceptable excipients.

13. The drug is indicated in paragraph 12 for the treatment of diseases mediated by adenosine receptor.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 2-oxo-1-pyrrolidine of the formula (I) or their pharmaceutically acceptable salts wherein X means -CA1NR5R6 or -CA1-R8 wherein A1 and A2 mean independently oxygen atom; R1 means hydrogen atom (H), (C1-C20)-alkyl, (C6-C10)-aryl or -CH2-R1a wherein R1a means (C6-C10)-aryl; R3 means H, -NO2, nitrooxy-group, C≡N, azido-group, -COOH, amido-group, (C1-C20)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C6-C10)-aryl, thiazolyl, oxazolyl, furyl, thienyl, pyrrolyl, tetrazolyl, pyrimidinyl, triazolyl, pyridinyl, -COOR11, -COR11 wherein R11 means (C1-C12)-alkyl; R3a means H, (C1-C20)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl or (C6-C10)-aryl; R5 and R6 are similar or different and each means independently H, (C1-C6)-alkyl, and R8 means -OH and wherein each alkyl can be substituted independently with from 1 to 5 substitutes chosen from halogen atom, isothiocyanate, -OH, -NO2, -CN, azido-group, (C3-C6)-cycloalkyl and (C6-C10)-aryl;, and wherein each (C6-C10)-aryl can be substituted independently with from 1 to 5 substitutes chosen from halogen atom, -NH2, -NO2, azido-group, (C1-C6)-alkoxy-group, (C1-C6)-alkyl and (C1-C6)-halogenalkyl, and wherein each alkenyl can be substituted independently with at least one substitute chosen from halogen atom and -OH, and under condition that at least one radical among R and R3a differs from H, and when compound represent a mixture of possible isomers then X means -CONR5R6; A2 means oxygen atom, and R1 means H, -CH3, -C2H5, -C3H7, and when each R1 and R3a means H and A2 means oxygen atom and X means -CONR5R6 then R3 differs from -COOH, -CH, -COOR11, amido-group, naphthyl, phenyl rings substituted with (C1-C6)-alkoxy-group or halogen atom in para-position in naphthyl or phenyl ring. Compounds of the formula (I) can be used in pharmaceutical compositions for treatment of epilepsy, epileptogenesis, convulsions, epileptic seizures, essential tremor and neuropathic pain.

EFFECT: improved method of synthesis, valuable medicinal properties of derivatives and pharmaceutical compositions.

27 cl, 3 tbl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (1):

and their salts wherein ring A comprises optionally heteroatom oxygen (O); dotted lines represent the optional unsaturation; R1 represents (C1-C4)-alkoxy-group; R2 and R3 represent independently hydrogen atom (H), optionally halogenated (C1-C4)-alkyl, optionally substituted aromatic group, or R2 and R3 in common can form substituted or unsubstituted 5-7-membered ring condensed with ring E; k = 0-4; L1 represents a covalent bond or (C1-C6)-alkyl optionally comprising nitrogen atom (N); X represents unsubstituted or substituted carbon © atom or N, or represents O or sulfur (S) atom; Ar represents phenylene; each n = 0-2 independently; each R represents independently H or (C1-C6)-alkyl; Y represents optionally substituted aromatic or heteroaromatic group or 5-11-membered heterocyclic group comprising 1-4 heteroatoms cgosen from N, O and S that are bound with chemokine receptors comprising CXCR4 and CCR5, and elicit the protective affect against damage of host-cells by human immunodeficiency virus (HIV).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds 2,6-di-tert.-butyl-4-{2-[2-(methylamino)ethyl]-1,3-thiazole-4-yl}phenol, 2,6-di-tert.-butyl-4-[4-(hydroxymethyl)-1,3-oxazole-2-yl]phenol, 4-methylphenyl-2-[4-(1,1-biphenyl-4-yl)-1H-imidazole-2-yl]ethylcarbamate and others or their pharmaceutically acceptable salts. Also, invention relates to using these compounds for preparing a medicinal agent possessing one of the following three activities: inhibition of monoamine oxidases activity, inhibition of lipids peroxidation and modulating activity with respect to sodium channels. Proposed derivatives of thiazole, oxazole or imidazole possess one of the following species of pharmacological activity: inhibition of monoamine oxidases activity, inhibition of lipids peroxidation and modulation of sodium channels.

EFFECT: valuable biochemical and biological properties of derivatives.

34 cl, 119 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new benzofuran derivatives of formula 1 , wherein X represents group of formula -N= or -CH=; Y represents optionally substituted amino group, optionally substituted cycloalkyl group, or optionally substituted saturated heterocycle; A represents direct bond, carbon chain optionally containing double bond in molecular or in the end(s) thereof, or oxygen atom; R1 represents hydrogen, halogen, lower alkoxy, cyano, or amino optionally substituted with lower alkyl B represents optionally substituted benzene ring of formula ; and R2 represents hydrogen or lower alkyl; or pharmaceutically acceptable salt thereof. Invention also relates to pharmaceutical composition containing abovementioned compounds, uses thereof and method for thrombosis treatment.

EFFECT: new compounds for thrombosis treatment.

27 cl, 2 tbl, 429 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

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

or their pharmaceutically acceptable salts or esters hydrolyzing in vivo and possessing activity inhibiting the cellular cycle and selective with respect to CDK-2, CDK-4 and CDK-6. Compounds can be used in cancer treatment. In the formula (I) R1 represents halogen atom, amino-group, (C1-C)-alkyl, (C1-C6)-alkoxy-group; p = 0-4 wherein values R1 can be similar or different; R2 represents sulfamoyl or group Ra-Rb-; q = 0-2 wherein values R2 can be similar or different and wherein p + q = 0-5; R3 represents halogen atom or cyano-group; n = 0-2 wherein values R3 can be similar or different; R4 represents hydrogen atom, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, phenyl or heterocyclic group bound with carbon atom wherein R4 can be optionally substituted at carbon atom with one or some groups Rd; R5 and R6 are chosen independently from hydrogen, halogen atom, (C1-C)-alkyl, (C2-C6)-alkenyl or (C3-C8)-cycloalkyl wherein R5 and R6 can be substituted at carbon atom independently of one another with one or some groups Re; Ra is chosen from (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, phenyl, heterocyclic group, phenyl-(C1-C)-alkyl or (heterocyclic group)-(C1-C6)-alkyl wherein Ra can be substituted optionally at carbon atom with one or some groups Rg and wherein if indicated heterocyclic group comprises residue -NH- then its nitrogen atom can be optionally substituted with group chosen from the group Rh; Rb represents -N(Rm)C(O)-, -C(O)N(Rm)-, -S(O)r-, -OC(O)N(Rm)SO2-, -SO2N(Rm)- or -N(Rm)SO2- wherein Rm represents hydrogen atom or (C1-C6)-alkyl, and r = 1-2. Also, invention relates to methods for synthesis of these compounds, a pharmaceutical composition, method for inhibition and using these compounds.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical compositions.

24 cl, 3 sch, 166 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new 2-arylimino-2,3-dihydrothiazole derivatives of formula described in claims having affinity and selectivity to somatostatin receptors and useful as drugs for treatment of pathological conditions or diseases mediated by one or more somatostatin receptors, such as acromegalia, chromophone adenoma, endocrine pancreatic tumor, argentaffinoma syndrome, gastrointestinal hemorrhage, etc.

EFFECT: new agent for treatment of pathological conditions or diseases mediated by somatostatin receptors.

6 cl, 2836 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (I) in racemic form, enantiomer form or in any combinations of these forms possessing affinity to somatostatin receptors. In the general formula (I): R1 means phenyl; R2 means hydrogen atom (H) or -(CH2)p-Z3 or one of the following radicals: and Z3 means (C3-C8)-cycloalkyl, possibly substituted carbocyclic or heterocyclic aryl wherein carbocyclic aryl is chosen from phenyl, naphthyl and fluorenyl being it can be substituted, and heterocyclic aryl is chosen from indolyl, thienyl, thiazolyl, carbazolyl, or radicals of the formulae and and it can be substituted with one or some substitutes, or also radical of the formula: R4 means -(CH2)p-Z4 or wherein Z4 means amino-group, (C1-C12)-alkyl, (C3-C8)-cycloalkyl substituted with -CH2-NH-C(O)O-(C1-C6)-alkyl, radical (C1-C6)-alkylamino-, N,N-di-(C1-C12)-alkylamino-, amino-(C3-C6)-cycloalkyl, amino-(C1-C6)-alkyl-(C3-C6)-cycloalkyl-(C1-C6)-alkyl, (C1-C12)-alkoxy-, (C1-C12)-alkenyl, -NH-C(O)O-(C1-C6)-alkyl, possibly substituted carbocyclic or heterocyclic aryl; p = 0 or a whole number from 1 to 6 if it presents; q = a whole number from 1 to 5 if it presents; X means oxygen (O) or sulfur (S) atom n = 0 or 1. Also, invention relates to methods for preparing compounds of the general formula (I), intermediate compounds and a pharmaceutical composition. Proposed compounds can be used in treatment of pathological states or diseases, for example, acromegaly, hypophysis adenomas, Cushing's syndrome and others.

EFFECT: improved preparing method, valuable medicinal properties of compounds and composition.

11 cl, 2 tbl

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes derivatives of substituted triazoldiamine of the formula (I): wherein R1 represents (C1-C4)-alkyl, phenyl possibly substituted with halogen atom, amino-group substituted with -SO2-(C1-C4)-alkyl, imidazolyl, 1,2,4-triazolyl, imidazolidinone, dioxidoisothiazolidinyl, (C1-C4)-alkylpiperazinyl, residue -SO2- substituted with amino-group, (C1-C4)-alkylamino-group, (C1-C4)-dialkylamino-group, pyridinylamino-group, piperidinyl, hydroxyl or (C1-C4)-dialkylamino-(C1-C3)-alkylamino-group; R2 represents hydrogen atom (H); or R1 represents H and R2 means phenyl possibly substituted with halogen atom or -SO2-NH2; X represents -C(O)-, -C(S)- or -SO2-;R3 represents phenyl optionally substituted with 1-3 substitutes comprising halogen atom and nitro-group or 1-2 substitutes comprising (C1-C4)-alkoxy-group, hydroxy-(C1-C4)-alkyl, amino-group or (C1-C4)-alkyl possibly substituted with 1-3 halogen atoms by terminal carbon atom; (C3-C7)-cycloalkyl possibly substituted with 1-2 groups of (C1-C4)-alkyl; thienyl possibly substituted with halogen atom, (C1-C4)-alkyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C2-C4)-alkenyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, pyrrolyl, pyridinyl or amino-group substituted with -C(O)-C1-C4)-alkyl; (C1-C4)-alkyl substituted with thienyl or phenyl substituted with halogen atom; (C2-C8)-alkynyl substituted with phenyl; amino-group substituted with halogen-substituted phenyl; furyl, isoxazolyl, pyridinyl, dehydrobenzothienyl, thiazolyl or thiadiazolyl wherein thiazolyl and thiadiazolyl are substituted possibly with (C1-C4)-alkyl; to their pharmaceutically acceptable salts, a pharmaceutical composition based on thereof and a method for its preparing. New compounds possess selective inhibitory effect on activity of cyclin-dependent kinases and can be used in treatment of tumor diseases.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and composition.

16 cl, 3 tbl, 26 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds that act as agonists of arginine-vasopressin V2-receptors. Invention describes a derivative of 4,4-difluoro-1,2,3,4-tetrahydro-5H-benzazepine represented by the general formula (I): or its pharmaceutically acceptable salt wherein symbols have the following values: R1 represents -OH, -O-lower alkyl or optionally substituted amino-group; R2 represents lower alkyl that can be substituted with one or more halogen atoms, or halogen atom; among R3 and R4 one of them represents -H, lower alkyl or halogen atom, and another represents optionally substituted nonaromatic cyclic amino-group, or optionally substituted aromatic cyclic amino-group; R5 represents -H, lower alkyl or halogen atom. Also, invention describes a pharmaceutical composition representing agonist of arginine-vasopressin V2-receptors. Invention provides preparing new compounds possessing with useful biological properties.

EFFECT: valuable medicinal properties of compound and composition.

9 cl, 18 tbl, 13 ex

FIELD: organic chemistry, medicine, virology.

SUBSTANCE: invention relates to new derivatives of piperidine of the general formula (II): or their pharmaceutically acceptable salts wherein Xa means -C(R13)2-, -C(R13)(R19)-, -C(O)-, and others; Ra means R6a-phenyl or phenyl substituted with methylsulfonyl; R1 means hydrogen atom or (C1-C6)-alkyl; R2 means R7-, R8-, R9-phenyl wherein R7-, R8 and R9 mean substituted 6-membered heteroaryl and others; R3 means R10-phenyl, pyridyl and others; R4 means hydrogen atom, (C1-C6)-alkyl, fluoro-(C1-C6)-alkyl; R6a means from 1 to 3 substitutes taken among the group involving hydrogen, halogen atom, -CF3 and CF3O-; R7 and R8 mean (C1-C6)-alkyl and others; R9 means R7, hydrogen atom, phenyl and others; R10 means (C1-C6)-alkyl, -NH2 or R12-phenyl wherein R12 means hydrogen atom, (C1-C6)-alkyl and others; R13, R14, R15 and R16 mean hydrogen atom or (C1-C6)-alkyl; R17 and R18 in common with carbon atom to which they are bound form spirane ring comprising from 3 to 6 carbon atoms; R19 means R6-phenyl wherein R6 means R6a or methylsulfonyl; R20, R21 and R22 mean hydrogen atom or (C1-C6)-alkyl; R23 means (C1-C6)-alkyl under condition that if Ra means phenyl substituted with methylsulfonyl then Xa can mean the group only. Compounds of the formula (II) possess properties of CCR5-antagonist and can be used in medicine in treatment of HIV-infection.

EFFECT: improved method for treatment, valuable medicinal properties of compounds and composition.

15 cl, 1 dwg, 12 tbl, 15 ex

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds 2,6-di-tert.-butyl-4-{2-[2-(methylamino)ethyl]-1,3-thiazole-4-yl}phenol, 2,6-di-tert.-butyl-4-[4-(hydroxymethyl)-1,3-oxazole-2-yl]phenol, 4-methylphenyl-2-[4-(1,1-biphenyl-4-yl)-1H-imidazole-2-yl]ethylcarbamate and others or their pharmaceutically acceptable salts. Also, invention relates to using these compounds for preparing a medicinal agent possessing one of the following three activities: inhibition of monoamine oxidases activity, inhibition of lipids peroxidation and modulating activity with respect to sodium channels. Proposed derivatives of thiazole, oxazole or imidazole possess one of the following species of pharmacological activity: inhibition of monoamine oxidases activity, inhibition of lipids peroxidation and modulation of sodium channels.

EFFECT: valuable biochemical and biological properties of derivatives.

34 cl, 119 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new 2-arylimino-2,3-dihydrothiazole derivatives of formula described in claims having affinity and selectivity to somatostatin receptors and useful as drugs for treatment of pathological conditions or diseases mediated by one or more somatostatin receptors, such as acromegalia, chromophone adenoma, endocrine pancreatic tumor, argentaffinoma syndrome, gastrointestinal hemorrhage, etc.

EFFECT: new agent for treatment of pathological conditions or diseases mediated by somatostatin receptors.

6 cl, 2836 ex

FIELD: organic chemistry, medicine, virology.

SUBSTANCE: invention relates to novel 2-cycloalkylimino-5-(4-nitrophenyl)-1,3,4-thiadiazines of the general formula (I): wherein the group represents: piperidino-, pyrrolidino-, methylpiperazino-, hexamethyleneimino-group that possess the biological activity against smallpox virus. Invention provides preparing novel biological active compounds possessing an antiviral effect, in particular, against smallpox virus.

EFFECT: valuable biological and medicinal properties of compounds.

1 cl, 1 tbl, 4 ex

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to derivatives of pyridazinone or triazinone represented by the following formula, their salts or their hydrates: wherein each among A1, A2 and A3 represents independently of one another phenyl group that can be optionally substituted with one or some groups chosen from the group including (1) hydroxy-group, (2) halogen atom, (3) nitrile group, (4) nitro-group, (5) (C1-C6)-alkyl group that can be substituted with at least one hydroxy-group, (6) (C1-C6)-alkoxy-group that can be substituted with at least one group chosen from the group including di-(C1-C6-alkyl)-alkylamino-group, hydroxy-group and pyridyl group, (7) (C1-C6)-alkylthio-group, (8) amino-group, (9) (C1-C6)-alkylsulfonyl group, (10) formyl group, (11) phenyl group, (12) trifluoromethylsulfonyloxy-group; pyridyl group that can be substituted with nitrile group or halogen atom or it can be N-oxidized; pyrimidyl group; pyrazinyl group; thienyl group; thiazolyl group; naphthyl group; benzodioxolyl group; Q represents oxygen atom (O); Z represents carbon atom (C) or nitrogen atom (N); each among X1, X2 and X3 represents independently of one another a simple bond or (C1-C6)-alkylene group optionally substituted with hydroxyl group; R1 represents hydrogen atom or (C1-C6)-alkyl group; R2 represents hydrogen atom; or R1 and R2 can be bound so that the group CR2-ZR1 forms a double carbon-carbon bond represented as C=C (under condition that when Z represents nitrogen atom (N) then R1 represents the unshared electron pair); R3 represents hydrogen atom or can be bound with any atom in A1 or A3 to form 5-6-membered heterocyclic ring comprising oxygen atom that is optionally substituted with hydroxyl group (under condition that (1) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; and each among A1, A2 and A3 represents phenyl group, (2) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o,p-dimethylphenyl group; A2 represents o-methylphenyl group, and A3 represents phenyl group, or (3) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o-methylphenyl group; A2 represents p-methoxyphenyl group, and A3 represents phenyl group, and at least one among R2 and R means the group distinct from hydrogen atom) with exception of some compounds determined in definite cases (1), (3)-(8), (10)-(16) and (19) given in claim 1 of the invention. Compounds of the formula (I) elicit inhibitory activity with respect to AMPA receptors and/or kainate receptors. Also, invention relates to a pharmaceutical composition used in treatment or prophylaxis of disease, such as epilepsy or demyelinization disease, such as cerebrospinal sclerosis wherein AMPA receptors take part, a method for treatment or prophylaxis of abovementioned diseases and using compound of the formula (I) for preparing a medicinal agent used in treatment or prophylaxis of abovementioned diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

32 cl, 10 tbl, 129 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula: or wherein x means 1, 2, 3 or 4; m means 1 or 2; n means 1 or 2; Q represents carbon atom (C) or nitrogen atom (N); A represents oxygen atom (O) or sulfur atom (S); R1 represents lower alkyl; X represents -CH; R2 represents hydrogen (H) or halogen atom; R2a, R2b and R2c can be similar or different and they are chosen from hydrogen atom (H), alkyl, alkoxy-group or halogen atom; R3 represents aryloxycarbonyl or alkoxyaryloxycarbonyl; Y represents -CO2R4 wherein R4 represents hydrogen atom (H) or alkyl, and including all their stereoisomers, their prodrugs as esters and their pharmaceutically acceptable salts. These compounds are useful antidiabetic and hypolipidemic agents and agents used against obesity also.

EFFECT: valuable medicinal properties of compounds.

29 cl, 12 tbl, 587 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to derivatives of dihydronaphthalene represented by the formula (I):

wherein radical values are determined in the description and to its nontoxic salts. The proposed compound is a regulator of receptors activated by a peroxisome proliferator (PPAR) of α- and γ-type. The agent can be useful as a hypoglycemic agent, hypolipidemic agent, agent for prophylaxis and/or treatment of diseases associated with metabolic disturbances, agent increasing the content of HDL-cholesterol and reducing the content of LDL-cholesterol and/or VLDL-cholesterol and agent for weakening diabetes mellitus factor risk, and/or X-syndrome. Also, invention claims derivative of dihydronaphthalene representing 3-{5-{2-[2-(4-methylphenyl)-5-methyloxazol-4-yl]ethoxy}-3,4-dihydronaphthalen-1-yl}propanoic acid.

EFFECT: valuable medicinal properties of compounds and agent.

21 cl, 15 tbl, 14 ex

FIELD: organic chemistry, medicine, oncology.

SUBSTANCE: invention relates to new derivatives of 2-arylimino-2,3-dihydrothiazoles of the general formula (I): wherein radical values R1, R2, R3 and R4 are given in the claim invention. New compounds are useful in treatment of pathological states or diseases wherein one or some somatostatin receptors are implicated, for example, acromegaly, hypophysis adenomas or gastroenteropancreatic endocrine tumors with carcinoid syndrome and gastroenteric bleedings.

EFFECT: improved preparing method, valuable medicinal properties of compounds and compositions.

14 cl, 2825 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of 4-phenylpyridine N-oxides of the general formula (I) and their pharmaceutically acceptable acid-additive salts wherein R means hydrogen atom, lower alkyl or halogen atom; R1 means hydrogen atom; R2 and R2' mean independently of one another hydrogen, halogen atom, trifluoromethyl group, (lower)-alkoxy-group; or R2 and R2' can mean in common the group -CH=CH-CH=CH- optionally substituted with one or two substitutes taken among lower alkyl or (lower)-alkoxy-group; R3 and R3' mean independently of one another hydrogen atom, lower alkyl; R4 and R4' mean independently of one another -(CH2)mOR6 or lower alkyl; or R4 and R4' form in common with N-atom to which they are bound substituted R5-cyclic tertiary amine representing pyrrolidine-1-yl, piperidine-1-yl, piperazine-1-yl, morpholine-4-yl or 1,1-dioxomorpholine-4-yl; R5 means hydrogen atom, hydroxyl, -COOR3, -N(R3)CO-lower alkyl or -C(O)R3; R6 means hydrogen atom, lower alkyl; X means -C(O)N(R6)-, -N(R6)C(O)-; n = 0, 1, 2, 3 or 4; m = 1, 2 or 3. Also, invention describes a medicinal agent comprising these compounds. Compounds can be used as drugs in treatment or prophylaxis of diseases associated with antagonists of NK-1 receptor.

EFFECT: valuable medicinal properties of agent.

6 cl, 32 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to applying compounds of the general formula (1):

as inhibitors of caspase-3 that allows their applying as "molecular tools" and as active medicinal substances inhibiting selectively the scheduling cellular death (apoptosis). Also, invention relates to pharmaceutical compositions based on compounds of the formula (1), to a method for their preparing and a method for treatment or prophylaxis of diseases associated with enhanced activation of apoptosis. Also, invention relates to new groups of compounds of the formula 91), in particular, to compounds of the formulae (1.1):

and (1.2):

. In indicated structural formulae R1 represents inert substitute; R2, R3 and R4 represent independently of one another hydrogen atom, fluorine atom (F), chlorine atom (Cl), bromine atom (Br), iodine atom (J). CF3, inert substitute, nitro-group (NO2), CN, COOH, optionally substituted sulfamoyl group, optionally substituted carbamide group, optionally substituted carboxy-(C1-C6)-alkyl group; R5 represents oxygen atom or carbon atom included in optionally condensed, optionally substituted and optionally comprising one or some heteroatoms; R6 represents hydrogen atom or inert substitute; X represents sulfur atom or oxygen atom.

EFFECT: improved preparing and applying methods, valuable medicinal and biochemical properties of compounds.

3 cl, 1 dwg, 2 tbl, 1 sch, 8 ex

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

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