Derivatives of benzothiazole as adenosine receptor ligands and medicinal agent

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzothiazole of the general formula (I): and their pharmaceutically acceptable acid-additive salts used as ligands of adenosine receptors and to a medicinal agent based on thereof. In compound of the general formula (I) R means phenyl, pyridine-2-yl, -C(O)-O-(lower)-alkyl, -C(O)-(lower)-alkyl, -C(O)-morpholinyl, -C(O)-NR'2, -(CH2)n-NR'2 or -(CH2)n-O-(lower)-alkyl; R' means hydrogen atom or (lower)-alkyl. Compounds can be used in treatment and prophylaxis of diseases mediated by adenosine receptors A2A and A1, for example, in Alzheimer's disease, some depressive states, toxicomania, Parkinson's disease.

EFFECT: valuable medicinal properties of compounds.

15 cl, 3 sch, 6 ex

 

The present invention relates to compounds of General formula

where

R is phenyl, pyridin-2-yl, -C(O)-O-(ness.)alkyl, -C(O)-(ness.)alkyl, -C(O)-morpholinyl, -C(O)-NR'2, -(CH2)n-NR'2or -(CH2)n-O-(ness.)alkyl, and R' means hydrogen or (ness.)alkyl,

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 more detail, the compounds of the present invention have high affinity for the receptor, A2Aand a high selectivity for receptors A1and A3and, in addition, these compounds are soluble in water.

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 meteorous agent of S-adenosyl-L-methionine (S-AM), and structurally close to the coenzymes NAD, FAD, and coenzyme A, and RNA. Hell is sin 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 A1, A2AAnd2Band 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 A3besides binding to adenylate cyclase, stimulates the phospholipase C and thus activates calcium ion channels.

Currently, the cloned receptor-a1(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 Lampedusa. In addition, the cloned receptor-A2A(409-412 amino acid residues) dog, rat, human, Guinea pigs and mice. Cloned the receptor And2B(332 amino acid residue) between human and mouse, and the receptor And2Bman 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 A1and 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 energy demand of 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 short-term imbalances in the flow of oxygen. 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 to the, it is established that the binding of agonist adenosine receptor with fat cells expressing the receptor of A3rats leads to increased concentrations of Insectivora and intracellular calcium, which causes antigonadotropin the 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. Increase wisweb is the origin of neurotransmitters occurs when the 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 effect 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 neurons 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 in the action of sedatives, 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 receptor-a1agonists 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 disorders, such as ischemic heart disease and heart failure. Antagonists of receptor-A2Acan have a therapeutic effect in cases that require enhanced antiadrenergics the th response, such as an acute attack of myocardial ischemia. Selective antagonists of the receptor And2Acan 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 renal actions of adenosine, 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 obtaining a drug intended for the treatment of diseases mediated by the receptor adenosine A2the methods of obtaining the criminal code of the related 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 depression, substance abuse, neuroprotective effect, Parkinson's disease and ADHD.

The term "(ness.)alkyl"used in the text of the statements and, 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 1-4 carbon atoms.

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 compounds in which R is phenyl, pyridin-2-yl, -C(O)-O-CH2CH3-C(O)-CH2CH3-C(O)-morpholinyl or-C(O)-N(CH3)2for example the following compounds:

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 1-benzyl-2-oxo-1,2-dihydropyridines-4-carboxylic acid,

ethyl ester [4-(4-methoxy-7-morpholine-4-eventhorizon-2-ylcarbonyl)-2-oxo-2H-pyridin-1-yl]acetic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 2-oxo-1-(2-oxobutyl)-1,2-dihydropyridines-4-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 2-oxo-pyridine-2-ylmethyl-1,2-dihydropyridines-4-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 1-(2-morpholine-4-yl-2-oxoethyl)-2-oxo-1,2-dihydropyridines-4-carboxylic acid, or

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 1-dimethylcarbamoyl-2-oxo-1,2-dihydropyridines-4-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

with the formation of the compounds of formula

where R is phenyl, pyridyl, -C(O)O-(ness.)alkyl or-C(O)-(ness.)alkyl, or

b) interaction of the compounds of formula

with the compound of the formula

or

with the formation of the compounds of formula

where R is-C(O)-morpholinyl, -(CH2)n-O-(ness.)alkyl, -(CH2)nNR'2or-C(O)NR'2and

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

Obtaining compounds of formula I, where R is phenyl, pyridyl, -C(O)O-(ness.)alkyl or-C(O)-(ness.)alkyl

In the first method, the compounds of formula I, where the R is phenyl, pyridyl, -C(O)O-(ness.)alkyl or-C(O)-(ness.)alkyl, is obtained from the intermediate 2-methoxyethylamine formula (6), as shown below in schemes 1 and 2.

Scheme 1

In figure 1 the following abbreviations are used:

HATU means hexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylrhodamine

Scheme 2

Figure 2 R is phenyl, pyridyl, -C(O)O-(ness.)alkyl or-C(O)-(ness.)alkyl.

Obtaining compounds of formula (2)

The parent compound, 2-horizontina acid or 2-bromsalicilova acid of formula (1)are commercial products (for example, are delivered by the company Maybridge Chemicals) or you can get them known methods.

2 halogencontaining acid of formula (1) you can get the appropriate derived acylhomoserine formula (2) in the interaction of the compounds of formula (1) with an excess of halogenation agent, such as oxacillin or oxalipatin, or thionyl chloride or thienylboronic, in the presence of a catalyst such as N,N-dimethylformamide or pyridine, in an organic solvent, preferably in dichloromethane or dichloroethane at room temperature for 2-16 h, preferably for 16 hours the Product formula (2) was isolated by known methods, and preferably use the following is Tadei without additional purification.

Obtaining compounds of formula (4)

The original connection, 2-aminobenzothiazole formula (3), can be obtained by the methods described in EP 00113219.0.

The compounds of formula (4) are obtained by the reaction of 2-aminobenzothiazole formula (3) with a slight excess of acylhomoserine formula (2) in an aprotic organic solvent, preferably in a mixture dichlorethane and tetrahydrofuran containing base, preferably N-ethyldiethanolamine or triethylamine, at room temperature for 2-24 hours, preferably within 24 hours Product formula (4) was isolated by known methods, and preferably purified by chromatography or recrystallization.

Alternative methods of producing compounds of the formula (4)

The compounds of formula (4) can also be obtained directly from compounds of formula (1). In this case, the compound of formula (1) is treated with a stoichiometric amount of the condensing agent used in the chemistry of peptides, preferably of hexaflurophosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylrhodamine (HATU), in an ethereal solvent, preferably tetrahydrofuran, containing a base, preferably N-ethyldiethanolamine at room temperature for 30-90 minutes and Then the resulting mixture was treated with 2-aminobenzothiazole formula (3) in a mixture of solvents, preferably in a mixture tetrahedr is furan, dioxane and N,N-dimethylformamide at room temperature for 16-24 hours, preferably 24 hours Product formula (4) was isolated by known methods, and preferably purified by chromatography or recrystallization.

Obtaining compounds of formula (6)

The first method of obtaining compounds of formula (6) is the interaction of the compounds of formula (4) with an excess of methanol in the presence of a metal hydride, preferably sodium hydride or potassium hydride. These reactions are conducted in an ethereal solvent such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, preferably dioxane, optionally containing co-solvent, such as N,N-dimethylformamide, at a temperature of from room temperature to the boiling point of the solvent, preferably at about 100°within 2-72 hours, preferably for 16 hours, the Product of formula (6) was isolated by known methods, and preferably purified by chromatography or recrystallization.

The compounds of formula (6) is treated with excess allylbromide formula (7), which is a commercial product or can be obtained by the known methods according to the method described in Synthetic. Commun., 29, 4051-4059 (1999). The above reaction is carried out in a polar organic solvent such as acetonitrile or N,N-dimethylformamide, preferably in N,N-dimethylformamide, when p is increased the temperature, preferably at the boiling temperature of the solvent, for 2-18 hours, preferably for 16 hours, the Product of formula I, where R is phenyl, pyridyl, -C(O)O-(ness.)alkyl or-C(O)-(ness.)alkyl, isolated by known methods, and preferably purified by chromatography or recrystallization.

Obtaining compounds of formula I, where R is-C(O)-morpholinyl, -(CH2)n-NR'2, -(CH2)n-O-(ness.)alkyl or-C(O)NR'2.

The compounds of formula I, where R is-C(O)-morpholinyl, -(CH2)n-NR'2, -(CH2)n-O-(ness.)alkyl or-C(O)NR'2receive from the intermediate compounds, amide 2-oxo-1,2-dihydropyridines-4-carboxylic acid of formula (8), the receipt of which is shown in the following scheme 3.

Scheme 3

Figure 3 R is-C(O)-morpholinyl, -(CH2)n-NR'2, -(CH2)n-O-(ness.)alkyl or-C(O)NR'2a TMSI means attributively.

Obtaining compounds of formula (8)

The compound of formula (6) is treated with excess of attributively in halogenated organic solvent, preferably chloroform, at room or higher temperatures, preferably at the boiling temperature of the solvent, for 2-16 h, preferably for about 8 hours Then the reaction mixture is treated with alcohol, prefer the Ino methanol, at room or higher temperatures, preferably at the boiling temperature of the mixture of solvents, for 2-18 hours, preferably for 16 hours, the Product of formula (8) was isolated by known methods, and preferably purified by chromatography or recrystallization.

Obtaining compounds of formula I, where R is-C(O)-morpholinyl, -(CH2)n-NR'2, -(CH2)n-O-(ness.)alkyl or-C(O)NR'2

The compound of formula (8) is treated with excess allylbromide formula (7) or alkylchloride formula (9), which are commercial products or can be obtained by the known methods. When using alkylchloride formula (9) the reaction is carried out in the presence of stoichiometric amount of lithium bromide. The above reaction is carried out in a polar organic solvent such as dioxane or N,N-dimethylformamide, preferably in a mixture of N,N-dimethylformamide/dioxane, at temperatures from room temperature to the boiling temperature of the solvent for 2-18 hours, preferably for 16 hours, the Product of formula I distinguish known means, and preferably purified by chromatography or recrystallization.

Isolation and purification of the products obtained

Isolation and purification of the above-described compounds and intermediate products is carried out, if necessary, by any suitable methods in the division or cleaning, 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 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, e is alsultanova acid, pair-toluensulfonate acid, salicylic acid, etc. Usually the base is dissolved in an inert organic 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 from 0 to 50°C. the Obtained salt precipitates or it can be planted from solution by addition of a less polar solvent.

Acid additive 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 quantity sootvetstvuyuschego 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 receptor (A2Aand high selectivity for receptor A1.

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

The binding of adenosine receptor And1person

Adenosine receptor-a1man recombinante expressed in egg cells of the Chinese hamster (Cho) if IP is the use of the expression system, 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 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. 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 by nonlinear curve using the software, and the values Toiwas calculated by the equation of Cheng-Prussoff.

The binding of adenosine receptor And2Aperson

Adenosine receptor-a2Aman is ka 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]-SCH-58261 (1 nm) (Dionisotti and other Br. J. Pharmacol., 121, 353 (1997)) 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 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. 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 by nonlinear curve using the 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 in respect to the research Institute of the receptor And 1.

As shown below, the preferred compounds of the magnitude of the PKiform >7,2.

Example No.hA1(pKi)hA2(pKi)
15,908,67
25,188,19
35,188,24
45,188,10
55,18of 7.23
65,187,30

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 suspensions. However, it is also effective introduction rectal way, 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 I can be processed in a mixture with pharmaceutically inert, inorganic or organic carriers. As such carriers when is poluchenii tablets tablets 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, flavoring agents, salts for modifying the osmotic pressure, buffer substances, 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 the criminal code of the related drugs, involving 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 a mixture with one or more therapeutically inert carriers 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, anti-epileptics, 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 the x limits and must meet the individual requirements in each particular case. In General, when orally administered to adult patients, the daily dose varies from about 0.01 mg to about 1000 mg of the compounds of General formula I or the corresponding number of its pharmaceutically acceptable salts. 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.

The tablet formulation (wet granulation)

Ingredients No.mg in one pill
5 mg25 mg100 mg500 mg
1. The compound of the formula I525100500
2. Lactose anhydrous DTG12510530150
3. Sta-Rx 150066630
4. Microcrystalline cellulose303030150
5. Magnesium stearate1111
The total mass167167167831

Method get

1. Components 1, 2, 3, and 4) the t 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 5 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 lactose59123148-
3. Corn starch25354070
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 illustrates the I following examples, not limiting its scope.

Example 1

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide 1-benzyl-2-oxo-1,2-dihydropyridines-4-carboxylic acid

To a solution of 85 mg (0,21 mmole) of 2-methoxy-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide in 2 ml of acetonitrile under stirring was added 73 mg (0.43 mmole) of sodium iodide, 0.05 ml (0.43 mmole) of benzylbromide and the mixture is boiled under reflux for 16 hours Then the reaction mixture was cooled to room temperature, diluted with ethyl acetate and then washed with water and brine. The organic phase was dried over sodium sulfate and has given concerts in vacuum. The product was purified Express chromatography (eluent: ethyl acetate/toluene 2:1), received 32 mg (32%) (4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 1-benzyl-2-oxo-1,2-dihydropyridines-4-carboxylic acid as yellow crystals. MS (ES): m/e (%) 499 (M+Na+, 14), 477 (M+H+, 100).

The following compounds were obtained in the same way as described in example 1.

Example 2

Ethyl ester [4-(4-methoxy-7-morpholine-4-eventhorizon-2-ylcarbonyl)-2-oxo-2H-pyridin-1-yl]acetic acid

The specified connection was obtained by the reaction of 2-methoxy-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide with sodium iodide and ethyl ether bromoxynil acid in DMF. MS (ES): m/e (%) 495 (M+Na+, 25), 473 (M+H , 100).

Example 3

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide 2-oxo-1-(2-oxobutyl)-1,2-dihydropyridines-4-carboxylic acid

The specified connection was obtained by the reaction of 2-methoxy-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide with sodium iodide and 1-bromo-2-butanone in DMF. MS (ES): m/e (%) 479 (M+Na+, 32), 457 (M+H+, 100).

Example 4

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide 2-oxo-1-pyridin-2-ylmethyl-1,2-dihydropyridines-4-carboxylic acid

The specified connection was obtained by the reaction of 2-methoxy-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide with sodium iodide and the hydrobromide of 2-(bromacil)pyridine in DMF. MS (ES): m/e (%) 500 (M+Na, 30), 478 (M+H+, 100).

Example 5

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide 1-(2-morpholine-4-yl-2-oxoethyl)-2-oxo-1,2-dihydropyridines-4-carboxylic acid

To a solution of 200 mg (0.52 in mmole) (4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 2-oxo-1,2-dihydropyridines-4-carboxylic acid in 1 ml DMF and 4 ml of 1,2-dimethoxyethane under stirring was added 44 mg (1.04 million mmole) of sodium hydride (60% dispersion in mineral oil). After stirring at room temperature for 15 min was added 90 mg (1.04 million mmole) of lithium bromide and stirred for a further 15 minutes and Then was added 95 mg (of 0.58 mmole) of 4-(2-chloroacetyl)of the research and the mixture was stirred at room temperature for 16 hours actionnow mixture was diluted with ethyl acetate and sequentially washed with 0.5 M hydrochloric acid, a saturated solution of sodium bicarbonate and saline. The combined aqueous phase was filtered, the filter cake was washed with ether, resuspendable in toluene and concentrated in vacuum. The product was purified Express chromatography (eluent: MeOH/CH2Cl2) and triturated in ethyl acetate, was received 83 mg (31%) (4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 1-(2-morpholine-4-yl-2-oxoethyl)-2-oxo-1,2-dihydropyridines-4-carboxylic acid as yellow crystals. MS (ES): m/e (%) 536 (M+Na+, 25), 514 (M+N+, 100).

The following compound was obtained in the same way as described in example 5.

Example 6

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide 1-dimethylcarbamoyl-2-oxo-1,2-dihydropyridines-4-carboxylic acid

The specified connection was received during the interaction (4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 2-oxo-1,2-dihydropyridines-4-carboxylic acid with sodium hydride, lithium bromide and 2-chloro-N,N-dimethylacetamide in 1,2-dimethoxyethane and DMF. MS (ES): m/e (%) 494 (M+Na+, 22), 472 (M+H+, 100).

1. Compounds of General formula

where R is phenyl, pyridin-2-yl, -C(O)-O-(ness.)alkyl, -C(O)-(ness.)alkyl, -C(O)-morpholinyl, -C(O)-NR'2, a R' means hydrogen or (ness.)alkyl, and their pharmaceutically acceptable acid additive salt.

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

3. The compounds of formula I according to claim 2, where the connection means (4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 1-benzyl-2-oxo-1,2-dihydropyridines-4-carboxylic acid.

4. Compounds according to claim 1, where R is-C(O)O-(ness.)alkyl.

5. Compounds according to claim 4, where the connection means ethyl ester [4-(4-methoxy-7-morpholine-4-eventhorizon-2-ylcarbonyl)-2-oxo-2H-pyridin-1-yl]acetic acid.

6. Compounds according to claim 1, where R is-C(O)-(ness.)alkyl.

7. Compounds according to claim 6, where the connection means (4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 2-oxo-1-(2-oxobutyl)-1,2-dihydropyridines-4-carboxylic acid.

8. Compounds according to claim 1, where R is pyridinyl.

9. Connection of claim 8, where the connection means (4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 2-oxo-1-pyridin-2-ylmethyl-1,2-dihydropyridines-4-carboxylic acid.

10. Compounds according to claim 1, where R is-C(O)-morpholinyl.

11. Connection of claim 10, where the connection means (4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 1-(2-morpholine-4-yl-2-oxoethyl)-2-oxo-1,2-dihydropyridines-4-carboxylic acid.

12. Compounds according to claim 1, where R is-C(O)-NR'2.

13. The connection section 12, where the connection means (4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 1-dimethylcarbamoyl-2-oxo-1,2-dihydropyridines-4-carboxylic acid.

14. A drug that has affinity to the receptors of adenosine A2Aand selectivity of the receptor A 1and a3containing one or more compounds according to any one of claims 1 to 13 and pharmaceutically acceptable excipients.

15. Drug for 14 suitable for the treatment of diseases mediated by adenosine receptors And2Aand a1.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of nicotine- or isonicotine-benzothiazole of general formulas (IA) and (IB) their pharmaceutically acceptable acid-additive salts and a medicinal agent based on thereof. In compounds of general formula (IA) and (IB) R1 means phenyl, piperidine-1-yl or morpholine; A means -O-; R means -(CH2)n-N(R'')-C(O)-lower alkyl, -(CH2)n-O-lower alkyl, -(CH2)n-O-(CH2)n-O-lower alkyl, lower alkyl, -(CH2)n-morpholinyl, -(CH2)n-phenyl, -(CH2)n-N(R''), -(CH2)n-pyridinyl, -(CH2)n-CF3, -(CH2)n-2-oxopyrrolidinyl or (C4-C6)-cycloalkyl; R'' mean(s) independently of one another hydrogen atom or lower alkyl; n= 1 or 2; A means -N(R')-; R means lower alkyl, (C4-C6)-cycloalkyl, -(CH2)n-O-lower alkyl, -(CH2)n-pyridinyl, -(CH2)n-piperidinyl, -(CH2)n-phenyl, -(CH2)n-N(R'')-C(O)-lower alkyl, -(CH2)n-morpholinyl or -(CH2)n-N(R'')2; R' and R'' mean independently of one another hydrogen atom or lower alkyl; n = 1 or 2; or A means -CH2-; R means -N(R'')-(CH2)m-O-lower alkyl, -N(R'')2, S-lower alkyl, or R means azethidinyl, pyrrolidinyl or piperidinyl that are substituted optionally with hydroxy-group or lower alkoxy-group; or R means morpholinyl, -N(R'')-(CH2)m-(C4-C6)-cycloalkyl, -N(R'')-(CH2)m-C(O)-O-lower alkyl, -O-(CH2)m-O-lower alkyl or alkoxy-group; R'' mean(s) independently of one another hydrogen atom or lower alkyl; m = 1, 2 or 3; or A means -S-; R means lower alkyl, or A-R mean in common piperazinyl substituted with alkyl, -C(O)-lower alkyl or oxo-group, or group A-R means piperidinyl substituted with lower alkoxy-group or hydroxy-group, or group A-R means morpholinyl substituted with lower alkyl, or group A-R means (C4-C6)-cycloalkyl, azethidine-1-yl optionally substituted with hydroxy-group or lower alkoxy-group, or group A-R means thiomorpholinyl-1,1-dioxo-group, tetrahydropyrane or 2-oxa-5-azabicyclo[2.2.1]hept-5-yl. Proposed compounds can be used in treatment of diseases mediated by adenosine A2A-receptors, for example, Alzheimer disease, some depressive states, toxicomania and Parkinson's disease.

EFFECT: valuable medicinal properties of compounds and agent.

37 cl, 10 sch, 109 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to using compounds represented by the general formula (II): wherein Ra and Rb are chosen independently from hydrogen atom, alkyl, cycloalkyl, aryl (optionally substituted with a group chosen from alkyl, halogen atom and alkoxy-group), -(Z)n-aryl (optionally substituted with a group chosen from alkyl, halogen atom and alkoxy-group), -(Z)nC(O)OR3; Z is chosen independently from -C(R3)(R4)-; R3 and R4 are chosen independently from hydrogen atom, alkyl and 6-membered cycle with nitrogen atom as a heteroatom; n has values 0, 1 or 2; X and Y are chosen independently from =O, =S and =N(R3). These compounds are active component in preparing a pharmaceutical composition designated in treatment of diseases wherein glycogen synthase-kinase 3-beta (GSK-3) is involved. Also, invention relates to compounds represented by the general formula (II) wherein Ra is chosen from -CH2Ph, -CH2CO2Et, 4-OMePh, 4-MePh and 4-BrPh; Rb is chosen from Me and -CH2CO2Et; X and Y represent =O. Also, invention relates to a pharmaceutical composition possessing GSK-3-inhibitory activity and containing compound of the general formula (II) as an active component. Invention provides using heterocyclic inhibitors of glycogen synthase-kinase-3β.

EFFECT: valuable biochemical and medicinal properties of inhibitors.

17 cl, 5 tbl, 5 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of piperidine of the general formula (I): or their pharmaceutically acceptable salts wherein rings A and B represent optionally substituted benzene rings; R1 represents alkyl, hydroxyl, thiol, carbonyl, sulfinyl, unsubstituted or substituted sulfonyl group and others; R2 represents hydrogen atom, hydroxyl, amino-group, alkyl, unsubstituted or substituted carbonyl group or halogen atom; Z represents oxygen atom or group -N(R3)- wherein R3 and R4 represent hydrogen atom or alkyl group under condition that N-acetyl-1-benzyloxycarbonyl-2-phenyl-4-piperidineamine is excluded. Compounds of the formula (I) or their salts possess antagonistic activity with respect to tachykinin NK1-receptors and can be used in medicine in treatment and prophylaxis of inflammatory, allergic diseases, pain, migraine, diseases of central nervous system, digestive organs and others.

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

18 cl, 138 tbl, 527 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, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted indoles or its pharmaceutically acceptable salts of the formula (I): , wherein R1 means hydrogen (H) atom, halogen atom, -CN, nitro-group, -SO2R4, -OH, -OR4, -SO2NR5R6, -CONR5R6, -COOH, -COOCH3, -NR5R6, phenyl, naphthyl or (C1-C6)-alkyl wherein the latter group is possibly substituted with one or more substitutes chosen independently from halogen atom, -OR8 and -NR5R6 wherein x = 2; R2 means (C1-C7)-alkyl; R3 means phenyl, naphthyl or heteroaryl and each of them is possibly substituted with one or more substitutes chosen independently from H, halogen atom, -CN, -OH, -SO2R4, -OR4, -SO2NR5R6, -CONR5R6, phenyl, naphthyl, (C1-C6)-alkyl wherein the latter group is possibly substituted with one or more substitutes chosen independently from halogen atoms, -OR8 and -NR5R6, -S(O)xR7 wherein x = 2; R4 means (C1-C6)-alkyl; R5 and R6 mean independently H, (C1-C6)-alkyl, or R5 and R6 in common with nitrogen atom to which they are bound can form 6-membered saturated heterocyclic ring comprising one atom chosen from -NR16; R7 means (C1-C6)-alkyl; R8 means H, (C1-C6)-alkyl; R16 means H, -COY-(C1-C4)-alkyl wherein Y means oxygen atom (O) and wherein alkyl group in the substitute group can be direct, branched or cyclic, and wherein heteroaryl means 5-6-membered heteroaromatic ring comprising from 1 to 3 heteroatoms chosen from nitrogen (N), oxygen (O) and sulfur (S) atoms, or means 6,6-condensed bicyclic aromatic ring system comprising one nitrogen atom. Compounds of the formula (I) can be used in production of a medicinal agent used in treatment of asthma and chronic obstructive disease.

EFFECT: valuable medicinal properties of compounds.

7 cl, 2 tbl, 59 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention relates to a compound of the general formula [I]: wherein R1 and R2 can be similar or different and each represents (C1-C10)-alkyl group; each among R3 and R4 represents hydrogen atom; R5 and R6 can be similar or different and each represents hydrogen atom or (C1-C10)-alkyl group; Y represents 5-6-membered aromatic heterocyclic group or condensed aromatic heterocyclic group comprising one or some heteroatoms chosen from nitrogen atom, oxygen atom and sulfur atom wherein heterocyclic group can be substituted with 0-6 of similar or different groups chosen from the following group of substitutes α, and so on; n means whole values from 0 to 2; [Group of substitutes α]: hydroxyl group, halogen atoms, (C1-C10)-alkyl groups, (C1-C10)-alkyl groups wherein each group is monosubstituted with group chosen from the following group of substitutes β, (C1-C4)-halogenalkyl groups, (C3-C8)-cycloalkyl groups, (C1-C10)-alkoxy-groups, (C1-C10)-alkoxy-groups wherein each group is monosubstituted with group chosen from the following group of substitutes and so on; [Group of substitutes β]: hydroxyl group, (C3-C8)-cycloalkyl groups that can be substituted with halogen atom or alkyl group, (C1-C10)-alkoxy-group, (C1-C10)-alkylthio-groups, (C1-C10)-alkylsulfonyl groups, (C1-C10)-alkoxycarbonyl groups, amino-group, carbamoyl group (wherein its nitrogen atom can be substituted with similar or different (C1-C10)-alkyl groups), (C1-C6)-acyl groups, (C1-C10)-alkoxyimino-groups, cyano-group, optionally substituted phenyl group; [Group of substitutes γ]: optionally substituted phenyl group, optionally substituted aromatic heterocyclic groups, cyano-group. Also, invention relates to herbicide comprising derivative of isoxazoline of the formula [I] as an active component or its pharmaceutically acceptable salt. Invention provides the development of isoxazoline derivative possessing the herbicide activity with respect to resistant weeds, selectivity for cultural crop and weed.

EFFECT: valuable herbicide properties of substances.

18 cl, 24 tbl, 106 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new polymorphous crystalline forms of 5-[4-[2-[N-methyl-N-(2-pyridyl)-amino]-ethoxy]-benzyl]-thiazolidine-2,4-dione maleate of formula and stereomers thereof.

EFFECT: polymorphous crystalline forms of high stability.

12 cl, 1 tbl, 13 dwg, 5 ex

FIELD: medicine, organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to compounds of formula I , or pharmaceutically acceptable salt or solvates thereof, wherein X and Z represent CH or N; Y represents O; R1, R2, and R3 are identical or different and represent hydrogen atom, C1-C6-alkoxy; R5 represents hydrogen atom; R5, R6, R7, and R8 are identical or different and represent hydrogen atom, halogen atom, C1-C4-alkyl, trifluoromethyl; R9 and R10 represent hydrogen atom; R11 represents optionally substituted azolyl. Also disclosed are pharmaceutical composition with inhibiting activity in relates to KDR phosphorylation and method for inhibiting of target blood-vessel angiogenesis.

EFFECT: new pharmaceuticals useful in treatment of tumors, diabetic retinopathy, chronic rheumatism, psoriasis, arteriosclerosis, and Kaposi's sarcoma.

33 cl, 5 tbl, 75 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compound of the formula (IA) wherein X means -NH; R5a represents optionally substituted 5-membered heteroaromatic ring chosen from the group of the following formulae: (a) (b) (c) (d) (e) (f) (g) (h) (i) or (j) wherein * means the addition position to the group X in the formula (IA); R60 and R61 from group of the formula (k) wherein p and q mean independently 0 or 1; R1' and R1'' represent independently hydrogen atom, hydroxy-group wherein T represents C=O, sulfur atom (S), -C(=NOR)CO, -C(O)C(O) wherein R represents hydrogen atom, (C1-C6)-alkyl and phenyl; V represents independently hydrogen atom, hydroxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy-, (C2-C6)-alkenyloxy-group, trifluoromethyl, phenyl optionally substituted with (C1-C6)-alkoxy- or (C1-C6)-alkanoyloxy-group or (C3-C7)-cycloalkyl; or V represents -N(R63)R64 wherein one of R63 and R64 is chosen independently from hydrogen atom, (C1-C10)-alkyl optionally substituted with hydroxy-group, (C1-C6)-alkoxycarbonyl and (C1-C6)-alkoxyl; and (C2-C6)-alkenyl and another represents (C1-C6)-alkyl optionally substituted 1 or 2 with (C1-C4)-alkoxyl, cyano-group, (C1-C4)-alkoxycarbonyl, (C2-C4)-alkanoyloxy- or hydroxy-group; heteroaryl-(C1-C6)-alkyl wherein heteroaryl represents 5-6-membered ring comprising 1-2 heteroatoms chosen from oxygen (O), sulfur (S) and nitrogen (N) atoms and optionally substituted with (C1-C6)-alkyl; phenyl or phenyl-(C1-C6)-alkyl optionally substituted with 1, 2 or 3 groups chosen from halogen atom, N,N-di-(C1-C6)-alkyl)-amino-, N-(C1-C6)-alkyl)-amino-, (C1-C6)-alkoxy-group, (C2-C6)-alkanoyl, trifluoromethyl, cyano-group, (C1-C6)-alkyl optionally substituted with hydroxy- or cyano-group, carbamoyl, hydroxy-, trifluoromethoxy-, nitro-, (C1-C6)-alkylthio-, amino-group, -O-(C1-C3)-alkyl-O- and (C1-C6)-alkylcarbonyl; heteroaryl chosen from pyridyl, furanyl and indolyl optionally substituted with 1 or 2 hydroxy-groups, halogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; (C3-C7)-cycloalkyl or (C3-C7)-cycloalkyl-(C1-C6)-alkyl optionally substituted with hydroxy-group; or R63 and R64 in common with nitrogen atom to which they are bound form 5-6-membered ring that can comprise additionally heteroatom N or O and can be optionally substituted with (C1-C6)-alkyl, hydroxy-group, hydroxy-(C1-C6)-alkyl or carbamoyl; R62 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl or carbamoyl; R1' represents hydrogen atom; R2' represents (C1-C5)-alkoxy-group; R3' represents -X1R9 wherein X1 represents -O- and R9 is chosen from the following groups: (1) (C1-C5)-alkyl; (2) (C1-C5)-alkyl-X3R20 wherein X3 represents -NR25- wherein R25 represents hydrogen atom or (C1-C3)-alkyl; R20 represents (C1-C3)-alkyl, cyclopentyl and (C1-C3)-alkyl group can comprise 1 or 2 substitutes chosen from oxo-, hydroxy-group, halogen atom and (C1-C4)-alkoxy-group; (3) represents (C1-C5)-X4-(C1-C5)-alkyl-X5R26 wherein each among X4 and X5 represents -NR31- wherein R31 represents hydrogen atom or (C1-C3)-alkyl; R26 represents hydrogen atom or (C1-C3)-alkyl; (4) (C1-C5)-alkyl-R32 wherein R32 represents 5-6-membered saturated heterocyclic group bound through carbon or nitrogen atom with 1-2 heteroatoms chosen independently from O and N and wherein heterocyclic group can comprise 1 or 2 substitutes chosen from hydroxy-group, (C1-C4)-alkyl and (C1-C4)-hydroxyalkyl; (5) (C1-C3)-alkyl-X9-(C1-C3)-alkyl-R32 wherein X9 represents -NR57- wherein R57 represents hydrogen atom or (C1-C3)-alkyl and R32 is given above; R4' represents hydrogen atom; or to its pharmaceutically acceptable salts. Compounds are inhibitors of kinase aurora 2 and can be used for preparing a medicinal agent used in treatment of proliferative diseases, in particular, in cancer treatment. Except for, invention relates to a pharmaceutical composition possessing the abovementioned activity and a method for preparing compounds of the formula (IA).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

14 cl, 30 tbl, 477 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention proposes compounds of the general formula (1): wherein X is chosen from sulfur atom and methylene group; X1 is chosen from sulfur atom and methylene group; X2 is chosen from oxygen (O), sulfur (S) atoms and methylene group; X3 means -NR5 or carbonyl group; R1 means hydrogen atom or nitrile group; R and R3 are chosen independently from hydrogen atom (H) and (C1-C6)-alkyl; R4 means R4A when X3 means -NR5 and R4B when X3 means carbonyl group; R4A is chosen from -R6R7NC(=O), -R6R7NC(=S), -R8(CH2)qC(=O), -R8(CH2)qC(=S), -R8(CH2)qSO2 and -R8(CH2)qOC(=O); R4B means -R6R7N; R5 means hydrogen atom (H); R6 and R7 are chosen independently from -R8(CH2)q, or they form in common -(CH2)2-Z1-(CH2)2- or -CHR9-X2-CH2-CHR10-; R8 is chosen from hydrogen atom (H), (C1-C4)-alkyl, cycloalkyl group condensed with benzene ring, acyl, dialkylcarbamoyl, dialkylamino-group, N-alkylpiperidyl, optionally substituted aryl, optionally substituted α-alkylbenzyl, optionally substituted aroyl, optionally substituted arylsulfonyl and optionally substituted heteroaryl representing monocyclic 5- and 6-membered ring aromatic group with one or two heteroatoms chosen from nitrogen, oxygen and sulfur atoms, and derivatives of abovementioned rings condensed with benzene; R9 and R10 are chosen independently from hydrogen atom (H), hydroxymethyl and cyanomethyl groups; Z1 is chosen from -(CH2)r-, -O-, and -N((CH2)q)R8)-; Z2 means optionally the substituted ortho-phenylene group; m = 1-3; n = 0-4; p = 2-5; q = 0-3, and r = 1 or 3. Proposed compounds are inhibitors of dipeptidyl-peptidase IV and can be used in preparing pharmaceutical compositions designated for treatment of different diseases, among them, diabetes mellitus of type 2.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

22 cl, 8 tbl, 453 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of nicotine- or isonicotine-benzothiazole of general formulas (IA) and (IB) their pharmaceutically acceptable acid-additive salts and a medicinal agent based on thereof. In compounds of general formula (IA) and (IB) R1 means phenyl, piperidine-1-yl or morpholine; A means -O-; R means -(CH2)n-N(R'')-C(O)-lower alkyl, -(CH2)n-O-lower alkyl, -(CH2)n-O-(CH2)n-O-lower alkyl, lower alkyl, -(CH2)n-morpholinyl, -(CH2)n-phenyl, -(CH2)n-N(R''), -(CH2)n-pyridinyl, -(CH2)n-CF3, -(CH2)n-2-oxopyrrolidinyl or (C4-C6)-cycloalkyl; R'' mean(s) independently of one another hydrogen atom or lower alkyl; n= 1 or 2; A means -N(R')-; R means lower alkyl, (C4-C6)-cycloalkyl, -(CH2)n-O-lower alkyl, -(CH2)n-pyridinyl, -(CH2)n-piperidinyl, -(CH2)n-phenyl, -(CH2)n-N(R'')-C(O)-lower alkyl, -(CH2)n-morpholinyl or -(CH2)n-N(R'')2; R' and R'' mean independently of one another hydrogen atom or lower alkyl; n = 1 or 2; or A means -CH2-; R means -N(R'')-(CH2)m-O-lower alkyl, -N(R'')2, S-lower alkyl, or R means azethidinyl, pyrrolidinyl or piperidinyl that are substituted optionally with hydroxy-group or lower alkoxy-group; or R means morpholinyl, -N(R'')-(CH2)m-(C4-C6)-cycloalkyl, -N(R'')-(CH2)m-C(O)-O-lower alkyl, -O-(CH2)m-O-lower alkyl or alkoxy-group; R'' mean(s) independently of one another hydrogen atom or lower alkyl; m = 1, 2 or 3; or A means -S-; R means lower alkyl, or A-R mean in common piperazinyl substituted with alkyl, -C(O)-lower alkyl or oxo-group, or group A-R means piperidinyl substituted with lower alkoxy-group or hydroxy-group, or group A-R means morpholinyl substituted with lower alkyl, or group A-R means (C4-C6)-cycloalkyl, azethidine-1-yl optionally substituted with hydroxy-group or lower alkoxy-group, or group A-R means thiomorpholinyl-1,1-dioxo-group, tetrahydropyrane or 2-oxa-5-azabicyclo[2.2.1]hept-5-yl. Proposed compounds can be used in treatment of diseases mediated by adenosine A2A-receptors, for example, Alzheimer disease, some depressive states, toxicomania and Parkinson's disease.

EFFECT: valuable medicinal properties of compounds and agent.

37 cl, 10 sch, 109 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, medicine, pharmacy.

SUBSTANCE: invention relates to triheterocyclic compound of the formula (I): wherein X represents carbon atom; Y represents carbon or nitrogen atom; W represents carbon or nitrogen atom; U represents -CR2, and Z represents -CR2 or nitrogen atom; ring A represents (C5-C6)-cycloalkyl ring or 5-membered heterocyclic ring comprising one nitrogen, oxygen or sulfur atom; R1 represents alkyl, alkenyl, alkynyl, -NR4R5, -OR6 and others; R3 represents phenyl ring substituted with 1-3 substitutes or pyridyl or 1,3-dioxoindanyl ring substituted with 1-2 substitutes, and its pharmaceutically acceptable salts and pharmaceutical composition containing thereof as an active component. Also, invention relates to derivatives of pyrazolopyrimidine and derivatives of pyrrolopyrimidine. Compounds of the formula (I) show antagonistic activity with respect to corticotropin-releasing factor receptors. The compound can be used in treatment and/or prophylaxis of depression, anxiety state, disorders in food intake, post-traumatic stress, ulcerous disease, irritable bowel syndrome, Alzheimer's disease, abuse in drugs using or alcoholic syndrome dependence.

EFFECT: valuable medicinal properties of compounds and pharmaceutical agent.

7 cl, 1 dwg, 24 ex

Fumaric acid amides // 2290946

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to medicinal agents, namely, to using fumaric acid amides of the formula (I): These compounds are used in preparing a medicinal agent designated for treatment of autoimmune diseases, response reactions "transplant against host", treatment of diseases mediated by NfkappaB, and to fumaric acid amides of the formula (I) and to a medicinal agent comprising fumaric acid amide of the formula (I) taken in the dose corresponding to 1-500 mg of fumaric acid as measured for a single dose and designated for treatment abovementioned diseases. Fumaric acid amides and a medicinal agent comprising thereof are characterized by absence of systemic adverse effect of body and resistance against hydrolysis that allows avoiding their multiply dosing.

EFFECT: valuable medicinal properties of agents.

19 cl, 2 tbl, 3 ex

FIELD: medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition comprising the medicinal preparation "Noopept" as an active component. Pharmaceutical composition for preparing solid medicinal formulations of the preparation comprises "Noopept", microcrystalline cellulose, polyvinylpyrrolidone, stearic acid or stearate as tablets. The medicinal preparation "Noopept" representing N-phenylacetyl-L-prolylglycine ethyl ester elicits the nootropic and neuroprotective activity in broad ranges of doses. The composition comprises small amounts of special additives, tablet release active component easily and invention provides its high bioavailability. Tablets satisfy all requirements of the State Pharmacopoeia of XI edition.

EFFECT: improved and valuable pharmaceutical and medicinal properties of pharmaceutical composition.

7 cl, 1 tbl, 3 ex

FIELD: medicine, pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a method for preparing rosavine possessing the nootropic activity. Method for preparing rosavine involves three-fold extraction of rosewort (Rhodiola rosea L.) milled rhizomes with 70-90% ethyl alcohol in the definite ratio raw : extractant, evaporation of combined extracts under vacuum to obtain dense residue, chromatography separation on silica gel, evaporation of eluates and crystallization wherein the first extraction is carried out at definite temperature and two other extractions are carried out at definite temperature with reflux condenser. Proposed method provides increasing the yield of the end product from rosewort rhizomes and reducing duration of the technological process.

EFFECT: improved preparing method.

3 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: method involves introducing tacrolimus derivative of known formula (1) for stimulating nerve cell growth or regeneration. Another method is suggested for repairing transected peripheral nerve or spinal cord by making contact of the transected peripheral nerve ends or spinal cord with the compound (1) or by introduced the compound (1) to the patient and transplanting a transplant into peripheral nerve or spinal cord.

EFFECT: sharp growth of regenerated myelinated axons; improved motor function of feet; high neurotropic and low immunosuppressive activity level.

17 cl, 8 tbl

FIELD: internal diseases.

SUBSTANCE: patient is administered diet including 0.3-0.5 g/kg/day animal for 10 days followed by increase to dose 0.8-1 g/kg/day during 1 month, after which 5% glucose solution is administered intravenously in dose 400-500 ml for 1 weak, lactulose in dose 60-90 ml divided into 2-3 intakes for 4 weeks, and probiotics over a 2-weak period 30 min before meal time. Simultaneously, L-ornithine-L-aspartate is given during 10 days in dose 30-40 g a day divided into 2-3 intakes followed by dose 5-7 g thrice a day during 10 days.

EFFECT: achieved involution of neurological and psychical manifestations of encephalopathy, reduced hepatic coma development incidence, and increased protein tolerance in patients.

4 cl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrimidine of the general formula (I) that possess properties of antagonists to adenosine A2-receptors and can be effective in relieve, for example, of defecation. In compound of the general formula (I) each R1 and R2 represents hydrogen atom; R3 represents hydrogen atom, halogen atom, amino-group, cyano-group, alkyl group comprising 1-6 carbon atoms, alkoxy-group comprising 1-6 carbon atoms, alkenyloxy-group comprising 2-6 carbon atoms, phenyl group that can be substituted with halogen atom, pyridyl group, furyl group or thienyl group; R4 represents pyridyl that can be substituted with a substitute chosen from the group comprising: hydrogen atom, halogen atom, amino-group, mono- or dialkylamino-group, aminoalkylamino-group wherein each has in alkyl residue from 1 to 6 carbon atoms, alkyl group comprising from 1 to 6 carbon atoms that can be substituted with halogen atom, hydroxy-group, amino-group, mono- or dialkylamino-group, alkoxycarbonyl wherein each has in alkyl residue from 1 to 6 carbon atoms, alkoxy-group comprising in alkyl group from 1 to 6 carbon atoms substituted with phenyl or pyridyl, hydroxyalkoxy-group comprising in alkyl residue from 1 to 6 carbon atoms, hydroxycarbonyl, alkoxycarbonyl comprising from 1 to 6 carbon atoms in alkyl residue, alkenyl group comprising from 2 to 6 carbon atoms, alkynyl group comprising from 2 to 6 carbon atoms, piperidinyl group that can be substituted with hydroxyl group, or represents group of the formula (IV): R5 represents phenyl that can be substituted with halogen atom, pyridyl group, thienyl or furyl group.

EFFECT: valuable biological properties of derivatives.

16 cl, 2 tbl, 185 ex

FIELD: organic chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of pyrimidine of the general formula (I) and their pharmaceutically acceptable acid-additive salts possessing properties of neurokinin-1 (NK) receptors antagonists. In the general formula (I): R1 means lower alkyl, lower alkoxyl, pyridinyl, pyrimidinyl, phenyl, -S-lower alkyl, -S(O2)-lower alkyl, -N(R)-(CH2)n-N(R)2, -O-(CH)n-N(R)2, -N(R)2 or cyclic tertiary amine as a group of the formula: R1 means lower alkyl, lower alkoxyl, pyridinyl, pyrimidinyl, phenyl, -S-lower alkyl, -S(O2)-lower alkyl, -N(R)-(CH2)n-N(R)2, -O-(CH)-N(R)2, -N(R)2 or cyclic tertiary amine of the formula: that can comprise additional heteroatom chosen from atoms N, O or S, and wherein this group can be bound with pyrimidine ring by bridge -O-(CH2)n-; R2 means hydrogen atom, lower alkyl, lower alkoxyl, halogen atom or trifluoromethyl group; R3/R3' mean independently of one another hydrogen atom or lower alkyl; R4 means independently of one another halogen atom, trifluoromethyl group or lower alkoxyl; R means hydrogen atom or lower alkyl; R means independently of one another hydrogen atom or lower alkyl; X means -C(OH)N(R)- or -N(R)C(O)-; Y means -O-; n = 1, 2, 3 or 4; m means 0, 1 or 2. Also, invention relates to a pharmaceutical composition comprising one or some compounds by any claim among claims 1-19 and pharmaceutically acceptable excipients. Proposed compounds can be used in treatment, for example, inflammatory diseases, rheumatic arthritis, asthma, benign prostate hyperplasia, Alzheimer's diseases and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

21 cl, 1 tbl, 76 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of nicotine- or isonicotine-benzothiazole of general formulas (IA) and (IB) their pharmaceutically acceptable acid-additive salts and a medicinal agent based on thereof. In compounds of general formula (IA) and (IB) R1 means phenyl, piperidine-1-yl or morpholine; A means -O-; R means -(CH2)n-N(R'')-C(O)-lower alkyl, -(CH2)n-O-lower alkyl, -(CH2)n-O-(CH2)n-O-lower alkyl, lower alkyl, -(CH2)n-morpholinyl, -(CH2)n-phenyl, -(CH2)n-N(R''), -(CH2)n-pyridinyl, -(CH2)n-CF3, -(CH2)n-2-oxopyrrolidinyl or (C4-C6)-cycloalkyl; R'' mean(s) independently of one another hydrogen atom or lower alkyl; n= 1 or 2; A means -N(R')-; R means lower alkyl, (C4-C6)-cycloalkyl, -(CH2)n-O-lower alkyl, -(CH2)n-pyridinyl, -(CH2)n-piperidinyl, -(CH2)n-phenyl, -(CH2)n-N(R'')-C(O)-lower alkyl, -(CH2)n-morpholinyl or -(CH2)n-N(R'')2; R' and R'' mean independently of one another hydrogen atom or lower alkyl; n = 1 or 2; or A means -CH2-; R means -N(R'')-(CH2)m-O-lower alkyl, -N(R'')2, S-lower alkyl, or R means azethidinyl, pyrrolidinyl or piperidinyl that are substituted optionally with hydroxy-group or lower alkoxy-group; or R means morpholinyl, -N(R'')-(CH2)m-(C4-C6)-cycloalkyl, -N(R'')-(CH2)m-C(O)-O-lower alkyl, -O-(CH2)m-O-lower alkyl or alkoxy-group; R'' mean(s) independently of one another hydrogen atom or lower alkyl; m = 1, 2 or 3; or A means -S-; R means lower alkyl, or A-R mean in common piperazinyl substituted with alkyl, -C(O)-lower alkyl or oxo-group, or group A-R means piperidinyl substituted with lower alkoxy-group or hydroxy-group, or group A-R means morpholinyl substituted with lower alkyl, or group A-R means (C4-C6)-cycloalkyl, azethidine-1-yl optionally substituted with hydroxy-group or lower alkoxy-group, or group A-R means thiomorpholinyl-1,1-dioxo-group, tetrahydropyrane or 2-oxa-5-azabicyclo[2.2.1]hept-5-yl. Proposed compounds can be used in treatment of diseases mediated by adenosine A2A-receptors, for example, Alzheimer disease, some depressive states, toxicomania and Parkinson's disease.

EFFECT: valuable medicinal properties of compounds and agent.

37 cl, 10 sch, 109 ex

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