Derivative of 5-methoxy-8-aryl[1,2,4]-triazole[1,5-a]pyridine

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes a novel derivative of 5-methoxy-8-aryl[1,2,4]-triazole[1,5-a]pyridine of the general formula (I): wherein R1 means hydrogen, halogen atom or lower alkoxy-group; R2 means -C(O)-phenyl wherein ring can be unsubstituted or substituted with one or two substitutes chosen from group consisting of halogen atom, lower alkyl, lower alkoxy-group or trifluoromethyl, or it means -C(O)-furanyl or -C(O)-thiophenyl wherein rings are not substituted or substituted with halogen atom, and its pharmaceutically acceptable salts. Proposed compounds can be used in treatment of diseases associated with adenosine A2 receptors. Also, invention describes a medicinal agent used in treatment of diseases associated with adenosine A2A receptors containing compound of the formula (I) and pharmaceutically acceptable excipients.

EFFECT: valuable medicinal properties of agent.

8 cl, 1 tbl, 1 ex

 

The present invention relates to compounds of General formula

in which

R1represents hydrogen, halogen or lower alkoxy;

R2represents hydrogen or-C(O)-lower alkyl, or-C(O)-phenyl, in which phenyl ring is unsubstituted or substituted by one or two substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy or trifloromethyl, or represents-C(O)-furanyl or-C(O)-thiophenyl, in which the rings are not substituted or substituted with halogen;

and their pharmaceutically acceptable salts.

It has been unexpectedly found that compounds of General formula I are ligands of the adenosine receptor.

Adenosine is a modulator of many physiological functions by interacting with specific receptors on the cell surface. Review possible use of adenosine receptors as targets for drugs was first made in 1982. Both in its structure and metabolism, adenosine close to bioactive nucleotides to adenosine triphosphate (ATP), adenosine diphosphate (ADP), the monophosphate (AMP) and cyclic monophosphate (camp); to biochemical meteorous agent of S-adenosyl-L-methionine (S-AM); and structurally to the coenzymes NAD, FAD, and coffee is the COP And; as well as RNA (ribonucleic acid). As adenosine and specified its derivatives play an important role in regulating many aspects of cell metabolism, as well as in modulation of various kinds of activity of the Central nervous system.

Adenosine receptors are classified as a1And2AAnd2Band a3receptors belonging to the family associated with G-protein receptors. Activation of adenosine receptors adenosine initiates the mechanisms of signal transmission. These mechanisms depend on the type of receptor associated G-protein. Each of the subtypes of adenosine receptor traditionally characterized by adenylyl cyclase effector system in which the camp is used as a secondary messenger. And1and a3receptors associated with GS-proteins that inhibit adenylate cyclase, which leads to decrease in the content of camp in the cells, while A2Aand a2Bthe receptors interact with GS-proteins and activate adenylate cyclase, leading to increased levels of camp in cells. It is known that A1receptor involves activation of phospholipase C and the modulation as potassium, calcium ion channels. The subtype of A3in addition to his Association with adenylate cyclase, also stimulates phospholipase C and thus to enable the t calcium ion channels.

A1receptor (326-328 amino acids) clone from different species (such as dog, human, rat, dog, chicken, bull, Guinea pig) with 90-95% sequence identity among mammalian species. A2Areceptor (409-412 amino acids) clone from dog, rat, human, Guinea-pig and mouse. And2Breceptor (332 amino acids) clone from human and mouse with 45%homologically And2Breceptor of a person relative to A1and A2Areceptors person. A3receptor (317-320 amino acids) clone from human, rat, dog, rabbit and sheep.

Considered to be subtypes - A1and A2Areceptors perform a complementary function in the variable with the participation of adenosine energy transfer. Adenosine, which is a product of the metabolism of ATP diffuses out of the cell and acts locally, activating adenosine receptors, thus lowering oxygen consumption (A1) or by increasing oxygen supply (A2A), and thus restores the balance between energy supply and consumption in the tissues. The action of both subtypes is to increase the number of available tissues of oxygen and protect cells from damage caused by short-term violation of the oxygen balance. One of the important functions of endogenous adenosine is the voiding of damages for injuries such as hypoxia, ischemia, hypotension, and conditions during the attack.

In addition, it is known that the binding of agonist adenosine receptor of mast cells expressing AZ receptor in rats leads to increased content inositoltrifosfata and increasing the calcium concentration inside the cell, which enhances antigen-induced secretion of anti-inflammatory mediators. Thus, As3the receptor acts as a mediator when asthma attacks and other allergic reactions.

Adenosine is a neuromodulator that has exceptional importance in modulating the molecular mechanism underlying many aspects of the physiological functions of the brain and implemented with the participation of adenosine as a mediator of the inhibitory effects of the Central system. Increased release of neurotransmitters leads to injuries, such as hypoxia, ischemia and seizures. These neurotransmitters mainly responsible for the degeneration of the nervous system and death of neurons, which lead to brain damage or death of the individual. Agonists A1receptor adenosine that mimic Central inhibiting effects of adenosine may, therefore, be useful as neuroprotective agents. It was proposed to use adenosine as endogenous protivosudorojna the CSOs agent, inhibiting the release of glutamate from neurons pathogens and inhibits the start of neurons. Agonists of adenosine, thus, can be used as antiepileptic agents. Antagonists of adenosine stimulate the activity of the Central nervous system (CNS) and has been shown to be effective as enhancers of cognitive abilities. Selective A2Aantagonists have therapeutic potential in the treatment of various forms of dementia, for example, in the case of Alzheimer's disease, and can be useful as neuroprotective agents. Antagonists of A2receptor adenosine inhibit the release of dopamine from Central synaptic terminals and reduce locomotor activity, resulting in reduced symptoms in Parkinson's disease. The activity of adenosine in the Central nervous system is also linked with the molecular mechanisms underlying sedation, hypnosis, schizophrenia, anxiety, pain, respiration, depression and the onset of seizures. Therefore, drugs acting on adenosine receptors have therapeutic potential as sedatives, muscle relaxants, agents, relieving or preventing symptoms of psychosis, anxiolytic agents, analgesics, stimulants breathing and antidepressa who you are.

Adenosine plays an important role in the cardiovascular system, as cardioprotection. The content of endogenous adenosine is increased in response to ischemia and hypoxia, which protects the heart tissue during and after injury (stabilization). Therefore, agonists of adenosine are potential cardioprotective agents.

Adenosine is a modulator of many aspects of the functioning of the kidneys, including the release of renin, the impact on the rate of glomerular filtration and renal blood flow. Compounds that inhibit the harmful effects of adenosine in the kidney, are potential agents for the protection of the kidneys. In addition, antagonists of the adenosine A3and/or A2Bcan be useful for the treatment of asthma and other allergic reactions.

The current status of research in the field of adenosine receptor are presented in a large number of documents, for example in the following publications:

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

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

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

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

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

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

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

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

The aim of the present invention are the compounds of formula I and their pharmaceutically acceptable salts as themselves, and as pharmaceutically active compounds, their technology is the manufacture, medicines on the basis of the compounds according to the present invention and their manufacture, and also the use of compounds of formula I for the control or prevention of illnesses based on the modulation of adenosine system, such as Alzheimer's disease, Parkinson's disease, neuroprotection, schizophrenia, anxiety, pain, respiratory failure, depression, asthma, allergic responses, hypoxia, ischemia, seizures, and seizures. In addition, compounds which are the subject of the present invention, can be used as antianxiety agents, muscle relaxants, agents, relieving or preventing symptoms of psychosis, antiepileptic agents, anticonvulsant agents and cardioprotective agents. The most preferred areas of use in accordance with the present invention are those which are based on antagonistic activity against A2Areceptor and which include disorders and disorders of the Central nervous system, such as the treatment and prevention of certain depressive States, neuroprotective and Parkinson's disease.

When used in the text of this application, the term "lower alkyl" means alkyl group with a saturated linear or branched chain containing from 1 to 6 carbon atoms, for example, takuyuki methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl and the like groups. Preferred lower alkyl groups with 1-4 carbon atoms.

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

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

The term "pharmaceutically acceptable salt products join acid" means salts formed with inorganic and organic acids, such as chloromethane acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonate acid, n-toluensulfonate acid and similar acids.

The compounds of formula I according to the present invention, in which R2represents-C(O)-phenyl, substituted by halogen are preferred. For example, these connections:

4-fluoro-N-(5-methoxy-8-phenyl-[1.2.4]triazolo[1.5-a]pyridine-2-yl)benzamid,

4-bromo-N-(5-methoxy-8-phenyl-[1.2.4]triazolo[1.5-a]pyridine-2-yl)benzamid,

4-bromo-N-[5-methoxy-8-(3-methoxyphenyl)-[1.2.4]triazolo[1.5-a]pyridine-2-yl]benzamide,

4-fluoro-N-[8-(4-forfinal)-5-methoxy-[1.2.4]triazolo[1.5-a]pyridine-2-yl]benzamide or

4-N-[5-methoxy-8-(3-methoxyphenyl)-[1.2.4]triazolo[1.5-a]pyridine-2-yl]benzamide.

Also preferred are compounds in which R2represents-C(O)-furanyl, substituted with halogen. Examples of compounds in this group are the following connections:

[8-(3-forfinal)-5-methoxy-[1.2.4]triazolo[1.5-a]pyridine-2-yl]amide 5-bromofuran-2-carboxylic acid, or

[5-methoxy-8-(3-methoxyphenyl)-[1.2.4]triazolo[1.5-a]pyridine-2-yl]amide 5-bromofuran-2-carboxylic acid.

Also preferred compounds of formula I according to the present invention, in which R2represents-C(O)-thiophenyl. For example, the following connection:

[5-methoxy-8-(3-methoxyphenyl)-[1.2.4]triazolo[1.5-a]pyridine-2-yl]amide thiophene-2-carboxylic acid.

The compounds of formula I and their pharmaceutically acceptable salts can be obtained by methods known from the prior art, for example according to the method described below, this method includes

a) interaction of the compounds of formula

with ethoxycarbonylmethylene obtaining thus the compounds of formula

and the cyclization of the compounds of formula III in the presence of hydroxylamine with obtaining thus the compounds of formula

in which R1has the above significance, or

b) interaction of the compounds of formula

with the compound of the formula

R2Cl

obtaining thus the compounds of formula

in which R1and R2are as defined above, and

if necessary, the conversion of the compounds obtained into pharmaceutically acceptable salts of the addition products of acids.

In the examples 1-42 and the following diagram 1 how to obtain compounds of formula I are presented in more detail.

In figure 1 DIPEA means N-ethyldiethanolamine.

In accordance with scheme 1, the compound of formula V (6-amino-5-bromopyridin-2-ol) can be obtained, as described in the article: Kelly, .R.; Jagoe, ST; Gu, Z. Tetrahedron Letters, 1991, v.32, R-4266, as follows. To a solution of 6-aminopyridine-2-ol in acetic acid at room temperature add bromine and stirred for 15 minutes the mixture is diluted with water and the precipitate filtered off. The filtrate is extracted, the combined organic layers dried and evaporated to dryness. Then a suspension of 6-amino-5-bromo-pyridine-2-ol is treated with granules CON and dimethylsulfate. The mixture is stirred for 4 hours at room temperature and evaporated to dryness. The obtained residue purified and receive 3-bromo-6-methoxy-pyridine-2-ylamine (IV). Then a mixture of 3-bromo-6-methoxypyridine-2-ylamine, phenylboronic acid (in which the phenyl ring can be the t to be substituted by the radical R 1), Na2CO3and adduct, sodium dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II dichloromethane in dioxane is heated to 110°C for 2 hours. The concentrate mixture, add the diluted aqueous solution of Na2CO3and extracted. The combined organic phases are dried and evaporated. The resulting residue is purified, thus obtaining the corresponding compound of formula II, for example, 6-methoxy-3-vinylpyridin-2-ylamine. A mixture of 6-methoxy-3-vinylpyridin-2-ylamine (II) and ethoxycarbonylmethylene stirred at room temperature for 2 h, then evaporated to dryness. The obtained compound of formula III is then treated with a mixture of hydroxylamine hydrochloride and N-ethyldiethanolamine (DIPEA). The resulting mixture was heated to 80°C for 16 h, concentrated to dryness, placed in water and extracted with diethyl ether. The combined organic layers dried and evaporated, thus obtaining, for example, 5-methoxy-8-phenyl-[1.2.4]triazolo[1.5-a]pyridine-2-ylamine (Ia). A mixture of 5-methoxy-8-phenyl-[1.2.4]triazolo[1.5-a]pyridine-2-ylamine and the compound of the formula R2Cl, for example, the acid chloride 3-ftorhinolonovy acid, and NEt3in dioxane are heated to 90°C for 16 hours. The resulting mixture was purified, thus obtaining the compound of formula I, for example, 3-fluorescent-N-(5-methoxy-8-phenyl-[1.2.4]triazolo[1.5-a]pyridine-2-yl)benzamide.

Obtaining salts is carried out at room temperature in accordance with methods that are essentially known and familiar to the person skilled in the art. In the scope of the invention includes not only salts with inorganic acids, but also salts formed with organic acids. Examples of these salts are hydrochloride, hydrobromide, sulfates, nitrates, citrates, acetates, maleates, succinate, methanesulfonate, n-toluensulfonate and similar salts.

The compounds of formula I and their pharmaceutically acceptable salts are the addition products of acids have valuable pharmacological properties. Namely, it was found that the compounds that are the subject of the present invention are ligands of the adenosine receptor.

Compounds were investigated in accordance with the tests below.

And2Areceptor adenosine person

A2Areceptor human recombinante Express in ovarian cells of the Chinese hamster (Cho-cells), using the expression system with virus semliki forest". Cells are harvested, washed twice using centrifugation, homogenized and again washed using centrifugation. Fully washed particles membranes suspended in Tris-buffer (50 mm)containing 120 mm NaCl, 5 mm KCl, 2 mm CaCl2and 10 mm MgCl2(pH7,4) (buffer A). Study of the binding of [3H]-SCH-58261 (Dionisotti et al., Br. J. Pharmacol. 1997, v.121, p.353) is carried out in 96-well tablets in the presence of 2.5 μg of membrane protein, 0.5 mg of Ysi-poly-1-lysine-SPA-granules and 0.1 Units adelaideans in the end amount to 200 ál of buffer A. non-specific binding determine using continuingly congener (KHAS; 2 μm). Compounds are tested at 10 concentrations ranging from 10 μm to 0.3 nm. All studies carried out in parallel in two series, and each analysis is repeated at least twice. Before centrifugation tablets used for research, incubated for 1 hour at room temperature, after which the amount of bound ligand is assessed using a scintillation counter Packard Topcount". The values of the IC50calculate, using a non-linear approximation, and the value of Ki is calculated using the equation of Cheng-Prusoff (Cheng-Prussoff).

In accordance with the present invention it was found that the compounds of formula I have high affinity for the receptor And2A.

The following table shows the specific values for the synthesized compounds.

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. F. rmaceuticals drugs can be administered orally, for example in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the introduction can also be effectively carried out rectally, for example in the form of suppositories, parenterally, e.g. in the form of solutions for injection.

The compounds of formula I can be used together with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Can be used lactose, corn starch or its derivatives, talc, stearic acid or their salts and similar substances, for example, as carriers for tablets, coated tablets, dragées and hard gelatin capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like substances. Given the nature of the active substance, in the case of soft gelatin capsules carrier is usually not required. Suitable carrier materials for the manufacture of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and similar substances. Suitable carriers for suppositories are, for example, natural or hydrogenated oils, waxes, fats, semi-solid and liquid polyols and the like substances.

In addition to t the th, the pharmaceutical preparations can contain preservatives, soljubilizatory, stabilizers, humectants, emulsifiers, sweeteners, tinted substances and substances that improve the taste and smell, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. The pharmaceutical preparations can also contain other therapeutically valuable substances.

Drugs, containing a compound of formula I or its pharmaceutically acceptable salt and a therapeutically inert carrier are also an object of the present invention, as the retrieval method, which involves combining one or more compounds of formula I and/or its pharmaceutically acceptable salt is the product of the merger acid and, if necessary, one or more other therapeutic substances with getting the dosage form for administration together with one or more therapeutically inert agent.

In accordance with the invention the compounds of formula I and their pharmaceutically acceptable salts are suitable for regulating the flow, or prevention of disease associated with antagonistic activity against adenosine receptor, such as Alzheimer's disease, Parkinson's disease, neuroprotective, schizophrenia, anxiety, pain, Otradnensky breath, depression, asthma, allergic responses, hypoxia, ischemia, seizures, and seizures. In addition, compounds which are the subject of the present invention may be useful as sedative agents, muscle relaxants, agents, relieving or preventing symptoms of psychosis, protivoepilepticheskih agents, anticonvulsants and cardioprotective agents, for the manufacture of the drugs.

The most preferred indications in accordance with the present invention are those which include disorders or disorders of the Central nervous system, such as the treatment or prevention of certain depressive disorders, reduction or prevention of the symptoms of psychosis and Parkinson's disease. The dosage may vary within wide limits and, of course, it should be adjusted according to the individual requirements in each particular case. In the case of oral administration the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of the compounds of General formula I or the corresponding number of its pharmaceutically acceptable salts. The daily dose can be entered as a single dose or divided into multiple doses, and in addition, the upper limit may be exceeded in the case when it is so far the project.

Example 1

5-Methoxy-8-phenyl-[1.2.4]triazolo[1.5-a]pyridine-2-ylamine

a) 6-Amino-5-bromo-pyridine-2-ol

(Literature: Kelly, .R.; Jagoe, ST; Gu, Z. Tetrahedron Letters, 1991, v.32, R-4266)

To a solution of 11 g (100 mmol) of 6-aminopyridine-2-ol in 220 ml of acetic acid at room temperature add 5,12 ml (100 mmol) of bromine and stirred for 15 minutes the Mixture is diluted with water and the precipitate is filtered off. The filtrate is extracted four times using 400 ml of ethyl acetate. The combined organic layers dried over MgSO4and evaporated to dryness, thus obtaining 12.2 g (65%) indicated in the title compound as a light brown solid.

1H-NMR (400 MHz, DMSO-d6): δ=10,0 (s, wide, 1H, HE), 7,37 (d, J=3 Hz, 1H, H-4), 6,10 (s, Shir, 2H, NH2), to 5.58 (d, J=3 Hz, 1H, H-3).

Mass spectrum: m/e (%): 190 (M+N+, 100).

b) 3-Bromo-6-methoxypyridine-2-ylamine

Suspension 11,58 g (61 mmol) 6-amino-5-bromopyridin-2-ol in 200 ml of acetone is treated using 10.3 g (184 mmol) of pellets of KOH and 10 g (80 mmol) of dimethylsulfate. The mixture is stirred for 4 hours at room temperature and evaporated to dryness. Add 400 ml of water and extracted with a mixture of four times using 300 ml of ethyl acetate. The combined organic phases are dried over MgSO4and evaporated. The resulting residue is purified column rapid chromatography on silica gel, elwira a mixture of hexane/ethyl acetate in sootnoshenie is 1:1, and while receiving 3,455 g (28%) indicated in the title compound as an orange oily substance.

1H-NMR (400 MHz, DMSO-d6): δ=rate of 7.54 (d, J=2 Hz, 1H, H-4), 6,10 (s, Shir, 2H, NH2), 5,90 (d, J=2 Hz, 1H, H-3), 3.75 (s, 3H, och3).

Mass spectrum: m/e (%): 204 (M+N+100).

b) 6-Methoxy-3-vinylpyridin-2-ylamine

A mixture of 330 mg (1,625 mmol) 3-bromo-6-methoxypyridine-2-ylamine, 396 mg (3.25 mmol) of phenylboronic acid, 1 ml of a 2N solution of Na2CO3and 59 mg (0.08 mmol) of the adduct with dichloromethane

dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) in 10 ml of dioxane is heated to 110°C for 2 hours. The mixture is then concentrated, add a dilute aqueous solution of Na2CO3and extracted twice using 100 ml of diethyl ether. The combined organic layers dried over MgSO4and evaporated. The resulting residue is purified column rapid chromatography on silica gel, elwira gradient hexane/ethyl acetate and thereby obtain 230 mg (71%) specified in the connection header.

1H-NMR (400 MHz, DMSO-d6): δ=rate of 7.54 (d, J=2 Hz, 1H, H-4), the 7.43 (m, 5H, Ph), 6,12 (s, Shir, 2H, NH2), of 5.92 (d, J=2 Hz, 1H, H-3), 3.73 (s, 3H, och3).

Mass spectrum: m/e (%): 204 (M+N+100).

g) 3-(3-Forfinal)-6-methoxypyridine-2-ylamine

In accordance with stage b) is listed in the title compound synthesized from 3-bromo-6-methoxypyridine-2-ylamine and 3-ftorhinolonovy acid.

Mass spectrum: m/e (%): 248.7 (M+H+, 100).

d) 3-(4-Forfinal)-6-methoxypyridine-2-ylamine

Rela is availa able scientific C with stage C) is listed in the title compound synthesized from 3-bromo-6-methoxypyridine-2-ylamine and 4-ftorhinolonovy acid.

Mass spectrum: m/e (%): of 218.6 (M+N+, 100).

e) 3-(4-Chlorophenyl)-6-methoxypyridine-2-ylamine

In accordance with stage b) is listed in the title compound synthesized from 3-bromo-6-methoxypyridine-2-ylamine and 4-Chlorfenvinphos acid.

Mass spectrum: m/e (%): 234.7 (M+N+, 100).

g) 6-Methoxy-3-(3-methoxyphenyl)-pyridine-2-ylamine

In accordance with stage b) is listed in the title compound synthesized from 3-bromo-6-methoxypyridine-2-ylamine and 3-methoxyphenylacetic acid.

Mass spectrum: m/e (%): 230.7 (M+N+, 100).

C) 5-Methoxy-8-phenyl-[1.2.4]triazolo[1.5-a]pyridine-2-ylamine

A mixture of 230 mg (1.15 mmol) of 6-methoxy-3-vinylpyridin-2-ylamine and of 142.8 ál ethoxycarbonylmethylene stirred at room temperature for 2 h, then evaporated to dryness. The resulting residue is placed in 20 ml of a mixture of Meon/EtOH ratio of 1:1 and treated using 399 mg (5,74 mmol) of hydroxylamine hydrochloride and 590 μl of N-ethyldiethanolamine. The mixture is heated to 80°C for 16 h, concentrated to obtain the solids are placed in 100 ml of water and extracted using a 3×150 ml of diethyl ether. The combined organic layers dried over MgSO4and evaporated to obtain this 379 mg (80%) specified in the connection header.

1H-NMR (300 MHz, DMSO-d6): δ=8,05 (d, J=8,49 Hz, 2H, phenyl), 7.73 (d, J=8,31 Hz, 1H, H-7), was 7.45 (t, J=7,26 Hz, 2H, phenyl, 7,33 (d, t=7,26 Hz, 1H, phenyl), of 6.52 (d, J=8,31 Hz, 1H, H-6), between 6.08 (s, Shir, 2H, NH2), 4.09 to (s, 3H, och3).

Mass spectrum: m/e (%): 241,3 (M+H+, 100).

Example 2

8-(3-Forfinal)-5-methoxy-[1.2.4]triazolo[1.5-a]pyridine-2-ylamine

In accordance with the methodology described in example 1H), synthesize 8-(3-forfinal)-5-methoxy-[1.2.4]triazolo[1.5-a]pyridine-2-ylamine based on 3-(3-forfinal)-6-methoxy-pyridine-2-ylamine, ethoxycarbonylmethylene, followed by reaction of the corresponding intermediate compounds with hydroxylamine hydrochloride and N-ethyldiethanolamine.

1 H-NMR (300 MHz, AMCO-d6): δ=8,05 (d, J=10.7 Hz, 1H, phenyl), a 7.92 (d, J=10.7 Hz, 1H, phenyl), to 6.88 (d, J=of 8.37 Hz, 1H, 7-H), 7,49 (m, 1H, phenyl), to 7.15 (m, 1H, phenyl), 6,53 (d, J=of 8.37 Hz, 1H, 6-H), 6,14 (s, Shir, 2H, NH2), 4,1 (s, 3H, och3).

Mass spectrum: m/e (%): 259,1 (M+H+, 100).

Example 3

8-(4-Forfinal)-5-methoxy-[1.2.4]triazolo[1.5-a]pyridine-2-ylamine

In accordance with the methodology described in example 1H), synthesize 8-(4-forfinal)-5-methoxy-[1.2.4]triazolo[1.5-a]pyridine-2-ylamine based on 3-(4-forfinal)-6-methoxy-pyridine-2-ylamine, ethoxycarbonylmethylene, followed by reaction of the corresponding intermediate compounds with hydroxylamine hydrochloride and N-ethyldiethanolamine.

1H-NMR (300 MHz, AMCO-d6): μ=8,16 (t, J=5,67 Hz, 2H, phenyl), 7.79 (d, J=by 8.22 Hz, 1H, H-7), 7,34 (t, J=5,67 Hz, 2H, phenyl), to 6.57 (d, J=by 8.22 Hz, 1H, H-6), to 6.19 (s, Shir, 2H, NH2), 4.15 (s, 3H, och3.

Mass spectrum: m/e (%): 259,1 (M+N+100).

Example 4

8-(4-Chlorophenyl)-5-methoxy-[1.2.4]triazolo[1.5-a]pyridine-2-ylamine

In accordance with the methodology described in example 1H), synthesize 8-(4-chlorophenyl)-5-methoxy-[1.2.4]triazolo[1.5-a]pyridine-2-ylamine based on 3-(4-chlorophenyl)-6-methoxy-pyridine-2-ylamine, ethoxycarbonyl isothiocyanate, followed by reaction of the corresponding intermediate compounds with hydroxylamine hydrochloride and N-ethyldiethanolamine.

1H-NMR (300 MHz, DMSO-d6): μ=8,13 (d, J=8,67 Hz, 2H, phenyl), 7.79 (d, J=of 8.37 Hz, 1H, H-7), 7,51 (d, J=8,67 Hz, 2H, phenyl), 6,53 (d, J=of 8.37 Hz, 1H, H-6), 6,11 (s, Shir, 2H, NH2), 4.09 to (s, 3H, och3).

Mass spectrum: m/e (%): 275,2 (M+H+, 100).

Example 5

5-Methoxy-8-(3-methoxyphenyl)-[1.2.41 triazolo[1.5-a]pyridine-2-ylamine

In accordance with the methodology described in example 1H), synthesize 8-(3-methoxyphenyl)-5-methoxy-[1.2.4]triazolo[1.5-a]pyridine-2-ylamine, based on 3-(3-methoxyphenyl)-6-methoxy-pyridine-2-ylamine ethoxycarbonylmethylene, followed by reaction of the corresponding intermediate compounds with hydroxylamine hydrochloride and N-ethyldiethanolamine.

1H-NMR (300 MHz, DMSO-d6): μ=7.76 (d, J=of 8.25 Hz, 1H, H-7), 7,68 (s, 1H, phenyl), a 7.62 (d, J=7,89 Hz, 1H, phenyl), was 7.36 (t, J=7,89 Hz, 1H, phenyl), 6,91 (d, J=7,89 Hz, 1H, phenyl), 6,51 (d, J=of 8.25 Hz, 1H, H-6), 6,07 (s, Shir, 2H, NH2), 4.09 to (s, 3H, och3), a 3.87 (s, 3H, och3).

Mass spectrum: m/e (%): 271,2 (M+N +, 100).

Example 6

3-Fluorescent-N-(5-methoxy-8-phenyl-[1.2.4]triazolo[1.5-a]pyridine-2-yl)benzamid

A mixture of 15 mg (0,062 mmol) 5-methoxy-8-phenyl-[1.2.4]triazolo[1.5-a]-pyridine-2-ylamine, 11 mg (0,068 mmol) of acid chloride of 3-ftorhinolonovy acid and 31.5 μl (0,312 mmol) NEt3in 1 ml of dioxane are heated to 90°C for 16 hours. The mixture was purified preparative GHUR (liquid chromatography high resolution) with reversed phase, elwira gradient acetonitrile/water. After evaporation receive specified in the title compound.

Mass spectrum: m/e (%): 281.7 ((M+CH3CN)+, 100).

Example 7

3-Bromo-N-(5-methoxy-8-phenyl-[1-2 .4]triazolo[1.5-a]pyridine-2-yl)benzamid

In accordance with the methodology described in example 6, is listed in the title compound synthesized from 5-methoxy-8-phenyl-[1.2.4]triazolo[1.5-a]pyridine-2-ylamine and the acid chloride of 3-brompheniramine acid (Mass spectrum: m/e (%): 423,3 (M+N+, 100).

Example 8

4-Fluorescent-N-(5-methoxy-8-phenyl-[1.2.4]triazolo[1.5-a]pyridine-2-yl)benzamid

In accordance with the methodology described in example 6, is listed in the title compound synthesized from 5-methoxy-8-phenyl-[1.2.4]triazolo[1.5-a]pyridine-2-ylamine and the acid chloride of 4-ftorhinolonovy acid. (Mass spectrum: m/e (%): 362,4 (M+N+, 100).

Example 9

3-Methoxy-N-(5-methoxy-8-phenyl-[1.2.4]triazolo[1.5-a]pyridine-2-yl)benzamid

In accordance with methodical is, shown in example 6, is listed in the title compound synthesized from 5-methoxy-8-phenyl-[1.2.4]triazolo[1.5-a]pyridine-2-ylamine and the acid chloride of 3-methoxyphenylacetic acid. (Mass spectrum: m/e (%): 374,4 (M+N+, 100).

Example 10

4-Bromo-N-(5-methoxy-8-phenyl-[1.2.4]triazolo[1.5-a]pyridine-2-yl)benzamid

To a solution of 24 mg (0.1 mmol) of 5-methoxy-8-phenyl-[1.2.4]triazolo[1.5-a]pyridine-2-ylamine in 1 ml of dioxane is added 0.4 ml (0.4 mmol) of 1 M solution AlMe3in toluene and leave the mixture under stirring for 1 hour at room temperature. Add 86 mg (0.4 mmol) of a compound methyl ester 4-brompheniramine acid in 1 ml of dioxane and stirred the mixture for 48 hours at 90°C. Add 0.5 ml of 1N aqueous HCl and the mixture is evaporated to dryness. The resulting residue is placed in 1.5 ml of formic acid and 0.5 ml of methanol, and then subjected to GHUR with reversed phase, elwira gradient of water/acetonitrile. After evaporation of the eluents receive 6 mg (15%) specified in the connection header. Mass spectrum: m/e (%): 423,3 (M+N+, 100).

In accordance with the methodology described in example 10, then synthesize derivatives [1.2.4]triazolo[1.5-a]pyridine. The results of the synthesis are presented in the following table includes examples 11 to 21.

No.cha2A< / br>
KI(h is)
StructureThe connection nameMMMass spectrum: MH+(%)
11884N-(5-Methoxy-8-phenyl-[1.2.4]triazolo[1.5-a]pyridine-2-yl)-4-trifluoromethyl-benzamide412,4413(100)
127764-Bromo-N-[8-(4-forfinal)-5-methoxy-[1.2.4]triazolo[1.5-a]pyridine-2-yl]benzamide441,3442(100)
134804-Bromo-N-[5-methoxy-8-(3-methoxyphenyl)-[1.2.4]triazolo[1.5-a]pyridine-2-yl]benzamide453,3454(100)
149082-Bromo-N-[8-(3-forfinal)-5-methoxy-[1.2.4]triazolo[1.5-a]pyridine-2-yl]-5-methoxybenzamide471,3472(100)
15572 [8-(3-Forfinal)-5-methoxy-[1.2.4]triazolo[1.5-a]pyridine-2-yl]amide 5-bromofuran-2-carboxylic acid431,2432(100)
16560[5-Methoxy-8-(3-methoxyphenyl)-[1.2.4]triazolo[1.5-a]pyridine-2-yl]amide 5-bromofuran-2-carboxylic acid443,3444(100)
17984N-(5-Methoxy-8-phenyl-[1.2.4]triazolo[1,5-a]pyridine-2-yl)-3-methylbenzamide358,4359(100)
No.cha2A< / br>
KI(HM)
StructureThe connection nameMMMass spectrum: MH+(%)
186644-Fluoro-N-[8-(4-forfinal)-5-methoxy-[1.2.4]triazolo[1.5-a]pyridine-2-yl]benzamide380,4381(100)
19748392,4393(100)
207842-Fluorescent-N-[8-(4-forfinal)-5-methoxy-[1.2.4]triazolo[1.5-a]pyridine-2-yl]benzamide380,4381(100)
21516[5-Methoxy-8-(3-methoxyphenyl)-[1.2.4]triazolo[1.5-a]pyridine-2-yl]amide thiophene-2-carboxylic acid380,4381(100)
The tablet formulation (wet granulation)
PositionIngredientmg tablet
5 mg25 mg100 mg500 mg
1.The compound of the formula I525100500
2.Anhydrous lactose DTG125105 30150
3."Sta-Rx 1500"66630
4.Microcrystalline303030150
cellulose
5.Magnesium stearate1111
The total number of167167167831

The method of cooking

1. Mix the components according to the positions 1, 2, 3 and 4 and granularit using purified water.

2. Dry the granules at 50°C.

3. Pass the granules through a suitable equipment for milling.

4. Add the component according to the position 5 and stirred for three minutes; then pressed, using a suitable press.

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

The method of cooking

1. Mixed in a suitable mixer components according to the positions 1, 2 and 3 within 30 minutes.

2. Add components according to the positions 4 and 5 and mix for 3 minutes.

3. Placed in a suitable capsule.

1. Derived 5-methoxy-8-aryl[1,2,4]-triazole[1,5-a]pyridine of General formula I

in which R1means waters of the genus, halogen or lower alkoxy;

R2means-C(O)-phenyl, in which ring may be unsubstituted or substituted by one or two substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy or trifloromethyl, or means-C(O)-furanyl or-C(O)-thiophenyl, in which the rings are not substituted or substituted with halogen;

and its pharmaceutically acceptable salts.

2. Derivative of the formula I according to claim 1, in which R2means-C(O)-phenyl, substituted by halogen.

3. Derivative of the formula I according to claim 2, representing

4-fluorescent-N-(5-methoxy-8-phenyl-[1.2.4]triazolo[1.5-a]pyridine-2-yl)benzamid,

4-bromo-N-(5-methoxy-8-phenyl-[1.2.4]triazolo[1.5-a]pyridine-2-yl)benzamid,

4-bromo-N-[5-methoxy-8-(3-methoxyphenyl)-[1.2.4]triazolo[1.5-a]pyridine-2-yl]benzamide,

4-fluorescent-N-[8-(4-forfinal)-5-methoxy-[1.2.4]triazolo[1.5-a]pyridine-2-yl]benzamide or

4-fluorescent-N-[5-methoxy-8-(3-methoxyphenyl)-[1,2 .4]triazolo[1.5-a]pyridine-2-yl]benzamide.

4. Derivative of the formula I according to claim 1, in which R2means-C(O)-furanyl, substituted with halogen.

5. Derivative of the formula I according to claim 4, representing

[8-(3-forfinal)-5-methoxy-[1.2.4]triazolo[1.5-a]pyridine-2-yl]amide 5-bromofuran-2-carboxylic acid, or

[5-methoxy-8-(3-methoxyphenyl)-[1.2.4]triazolo[1.5-a]pyridine-2-yl]amide 5-bromofuran-2-carboxylic acid.

6. Produced by the water of the formula I according to claim 1, in which R2means-C(O)-thiophenyl.

7. Derivative of the formula I according to claim 6, representing

[5-methoxy-8-(3-methoxyphenyl)-[1.2.4]triazolo[1.5-a]pyridine-2-yl]amide thiophene-2-carboxylic acid.

8. Drug for the treatment of diseases associated with A2Athe adenosine receptor containing derivative of 5-methoxy-8-aryl[1,2,4]-triazole[1,5-a]pyridine of formula I according to any one of claims 1 to 7 and a pharmaceutically acceptable fillers.



 

Same patents:

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

SUBSTANCE: invention relates to a synthetic quinolone agent that is effective as medicinal agents, veterinary preparations, drugs used in fishing industry or as antibacterial preserving agents. Invention describes compound represented by the following general formula (I): as its separate isomers or their mixture, its salt and their hydrates wherein R1 represents cyclic alkyl group comprising 3-6 carbon atoms that can comprise a substitute chosen from halogen atom; R2 represents hydrogen atom; R3 represents hydrogen atom; R4 represents hydrogen atom, amino-group, hydroxyl group; A represents nitrogen atom or part of structure as given in the invention claim; each R5 and R6 represents independently alkyl group comprising 1-6 carbon atoms or hydrogen atom; n means a whole number 1 or 2. Also, invention describes antibacterial agent and therapeutic agent based on compounds of the formula (I) used in treatment of infectious disease, a method for preparing antibacterial agent, a method for preparing a medicinal agent used in treatment of infectious disease and using compound of the formula (I) for preparing an antibacterial agent and using compound of the formula (I) for preparing a medicinal agent used in treatment of infectious disease. Invention provides novel compounds possessing useful biological properties.

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

35 cl, 2 tbl, 15 ex

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention describes derivatives of pyrido[2,1-a]isoquinoline of the formula (I): wherein R1 means (lower)-alkyl, unsubstituted phenyl, phenyl mono-, di- or tri-substituted with (lower)-alkyl or (lower)-alkoxy-group, pyrrolyl, pyridynyl or (lower)-alkyl substituted with cycloalkyl or phenyl; each among R2, R and R4 means independently hydrogen, halogen atom, hydroxy-, (lower)-alkoxy-group or (lower)-alkenyl wherein (lower)-alkoxy-group and (lower)-alkenyl are optionally substituted with groups: (lower)-alkoxycarbonyl, unsubstituted phenyl, phenyl substituted with di-(lower)-alkylamine or cyano-group, thiazolyl substituted with (lower)-alkyl, pyridinyl or morpholino-group; R5 means hydrogen atom, (lower)-alkyl or phenyl optionally substituted with halogen atom, (lower)-alkoxy- or hydroxy-group; R6 means hydrogen atom, (lower)-alkyl or hydroxy-(lower)-alkyl; or R and R6 in common with carbon atoms to which they are bound form phenanthridine; R7 means hydrogen atom or (lower)-alkyl. Also, invention describes a method for synthesis of compounds of the formula (I) and preparing a pharmaceutical composition. Proposed compounds are used in treatment or prophylaxis of diseases associated with enzyme DPP-IV, i. e. dipeptidyl peptidase IV, such as diabetes mellitus and firstly non-insulin dependent diabetes mellitus and disturbed tolerance to glucose.

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

21 cl, 1 tbl, 107 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel derivatives of 8-methoxy[1,2,4]triazolo[1,5-a]pyridine of the general formula (I): wherein R1 means unsubstituted phenyl or phenyl substituted with one substitute chosen from group including halogen atom, trifluoromethyl, (lower)-alkyl, (lower)-alkoxy-, acetylamino-group, acetyl, (lower)-alkenyl, -C(O)O-(lower)-alkyl or thio(lower)-alkyl, or thiophenyl possibly substituted with halogen atom, or indolyl; R2 means unsubstituted phenyl or phenyl substituted with a single substitute chosen from group including halogen atom, (lower)-alkyl, halogen-(lower)-alkyl or (lower)-alkoxy-group, or thiophenyl possibly substituted with (lower)-alkyl, their pharmaceutically acceptable salts, and pharmaceutical preparation based on thereof. Novel compounds possess antagonistic effect on adenosine A2A-receptors and can be used in medicine for stimulation of the central nervous system activity and as enhancers of cognitive ability.

EFFECT: valuable medicinal properties of compounds and pharmaceutical preparation.

10 cl, 1 tbl, 1 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of naphthyridine of the formula (I): or their salts wherein R1 means phenyl or phenyl substituted with one or two substitutes chosen from group including cyano-group, halogen atom, carboxyl, aminocarbonyl group and others; R2 means (C3-C8)-cycloalkyl substituted with carboxyl or (C1-C8)-alkoxycarbonyl. Compounds of the formula (I) and their salts possess inhibitory effect with respect to activity of phosphodiesterase isozyme 4 (PDE4) and can be used for preparing a medicinal agent in treatment of obstructive or inflammatory disease of respiratory ways.

EFFECT: valuable medicinal properties of compounds, improved method of synthesis.

8 cl, 1 tbl, 22 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes 8-amino-[1,2,4]triazolo-[1,5-a]pyridine-6-carboxylic acid amide of the formula (I): wherein R1 means -NR'R'' wherein R'1 and R'' represent independently of one another lower alkyl, -(CH2)n-C(O)NRaRb, -(CH2)n-pyridinyl, -(CH2)n-phenyl, -(CH2)n-CN, -(CH2)n-O-lower alkyl or -(CH2)n-(C3-C8)-cycloalkyl; or R' and R'' form in common with nitrogen atom (N) 5- or 6-membered nonaromatic ring system wherein the latter can comprise additionally one heteroatom - oxygen (O) or sulfur (S) atom and wherein indicated ring system can be unsubstituted or substituted with one or two substitutes chosen from group consisting of lower alkyl, -C(O)NRaRb or group -(CH2)n-O-lower alkyl; each Ra and Rb represents independently hydrogen atom or lower alkyl; R2 means phenyl or heteroaryl representing pyridinyl, furanyl substituted possibly with halogen atom, or lower alkyl, thiophenyl substituted possibly with lower alkyl, or thiazolyl radical, and its pharmaceutically acceptable salts also. Compounds can be used in treatment of disease associated with adenosine A2-receptors.

EFFECT: valuable medicinal properties of compounds.

12 cl, 1 tbl, 108 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to novel derivatives of urea of the general formula (I): and their pharmaceutically acceptable salts wherein A represents -CH- or nitrogen atom; R1 represents (C3-C10)-alkyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkyl-(C1-C10)-alkyl, 6-membered nitrogen-containing heterocycle, 6-membered nitrogen-containing heterocyclyl-(C1-C10)-alkyl, phenyl, phenyl-(C1-C10)-alkyl, 5-10-membered heteroaryl or 5-10-membered heteroaryl-(C1-C10)-alkyl, and others; R2 represents hydrogen atom, (C1-C6)-alkyl, (C0-C2)-alkyl-(C3-C10)-cycloalkyl, (C0-C2)-alkylphenyl, (C3-C10)-cycloalkyl-(C0-C2)-alkyl or phenyl-(C0-C2)-alkyl; R5 represents (C1-C6)-alkyl, (C3-C10)-cycloalkyl, 6-membered nitrogen-containing heterocyclyl, and others; L1 represents -S-, -S(O)-, -S(O2)-, -C(O)-, -N(Rc)-, -CH2-, and others; L2 represents a covalent bond, -O-, -C(O)-, -OC(O)-, -N(Rc)-, and others; W represents oxygen (O) or sulfur (S) atom; Z represents -C(O)ORd wherein Rc, Rd and Re represents hydrogen atom or alkyl; Rb represents -ORe, -NO2, halogen atom, -CN, -CF, (C1-C6)-alkyl; p represents a whole number from 0 to 4. Compounds of the formula (I) and their salts possess antagonistic activity with respect to α4-integrin and can be used in medicine for inhibition or prophylaxis of cellular adhesion in patient body mediated by α4β1- and/or α4β7-integrins.

EFFECT: improved methods of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 2 tbl, 180 ex

FIELD: medicine.

SUBSTANCE: preparation contains chemical compound of formula (I) and new amido-substituted imidazoquinolines of formula (I).

EFFECT: enhanced effectiveness of cytokine biosynthesis.

41 cl, 23 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to imidazopyridine derivatives of the formula (I): that are inhibitors of proton pump. Invention describes compound of the formula (I) or its pharmaceutical acceptable salt wherein Het represents a 5-6-membered aromatic heterocyclic group comprising at least one atom of oxygen or sulfur and substituted with group R3 and group R4 at ortho-positions; R1 represents hydrogen atom (H), -CH3 or -CH2OH; R2 represents -CH3 or -CH2CH3; R3 and R4 are chosen independently from the following group: H, (C1-C6)-alkyl, hydroxylated (C1-C6)-alkyl; R5 and R6 are chosen independently from hydrogen atom, (C1-C6)-alkyl, hydroxylated (C1-C6)-alkyl, (C1-C6)-alkoxy-(C1-C6)-alkyl, hydroxylated (C1-C6)-alkoxy-(C1-C)-alkyl, either R5 and R6 can form morpholine or hydroxylated pyrrolidine in common with nitrogen atom to which they are bound; X represents -NH; R10 represents -CH2-. Also, invention describes intermediate compounds used for their synthesis. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds and medicinal agents.

2 cl, 1 tbl, 23 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes a compound of the formula (I): wherein X means alkylene group; Y means -CO-, -CS- or -SO2-group; Z represents a simple bond or -NR5-group; R1 represents unsubstituted phenyl or phenyl substituted with halogen atom. (C1-C20)-alkyl group; R2 is chosen from -alkyl, -alkyl-O-alkyl; R3 and R4 represent alkyl; R5 represents hydrogen atom or (C1-C10)-alkyl group; Also, invention describes intermediate compounds - derivatives of imidazopyridine-4-amine, 2-phenoxypyridine and 4-phenoxypyridine. Proposed compounds and pharmaceutical compositions are able to stimulate biosynthesis of different cytokines and can be used in treatment of viral and tumor diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

32 cl, 1 tbl, 9 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: medicine.

SUBSTANCE: method involves applying Sarsasapogenin in combination with one or several compounds taken from group consisting of Smilagen and Anzurogenin-D, for preparing composition for treating Parkinson disease or for treating postural hypotension, autism, chronic fatigue syndrome, heavy myasthenia gravis, Lambert-Eaton disease, Gulf War Syndrome and syndrome caused by professional contact with organophosphorous compounds. Sarsasapogenin selectively increases muscarinic receptors M1 activity, contributing to stimulating synaptic transmission, without М2 receptors activity being influenced (which evoke negative feedback and muscarinic transmission interruption).

EFFECT: enhanced effectiveness of treatment.

3 cl, 8 tbl

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

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 proposes using the compound (R/S)-(-/+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chroman or (S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chroman or their salts for preparing a medicinal agent. This agent is used in treatment of extrapyramidal motor disorders, in particular, in treatment of unfavorable effects of anti-parkinsonic preparations and using (S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chroman in combination with an anti-parkinsonic preparation for preparing the combined medicinal agent. Also, invention relates to a pharmaceutical composition for treatment of extrapyramidal disorders and a set of the same designation. Proposed compounds are able to prevent catalepsy caused by usual anti-dopaminergic preparations and they are strong agonists of 5-HT1A-receptors in combination with antagonism to dopamine D2-receptors and interaction with D3-receptors that provides positive effects on extrapyramidal system in treatment of dyskinesia.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

26 cl, 10 ex

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