Benzothiazole derivatives and their application in treatment of diseases related to adenosine a2a receptors

FIELD: chemistry.

SUBSTANCE: invention concerns benzothiazole derivatives of general formula (1) and their pharmaceutically acceptable acid-additive salts as adenosine receptor ligands with high affinity to A2A adenosine receptor, and based medicine. Compounds can be applied in treatment and prevention of diseases mediated by A2A adenosine receptors, such as Alzheimer's disease, some depressive states, toxicomania, Parkinson's disease. In general formula (I) , R is C5-C6-cycloalkyl non-substituted or substituted by hydroxy group, or is ethyl or isobutyl, or is tetrahydropyrane-4-yl or -(CH2)n-tetrahydrofurane-2 or 3-yl or is 5-hydroxybicyclo[2,2,1]hept-2-yl; X is CH or N; n is 0 or 1.

EFFECT: enhanced efficiency of composition and treatment method.

12 cl, 2 dwg, 14 ex

 

The present invention relates to compounds of General formula

where R represents a C5-C6-cycloalkyl, unsubstituted or substituted by hydroxy group, or

represents ethyl, isobutyl, or

represents tetrahydropyran-4-yl, or

represents -(CH2)n-tetrahydrofuran-2 or 3-yl, or

represents a 5-hydroxybenzyl[2,2,1]hept-2-yl;

X represents CH or N;

n means 0 or 1;

and their pharmaceutically acceptable acid additive salts (salts and the addition products of acids).

It has been unexpectedly found that compounds of General formula I are ligands of adenosine receptor. Namely, the compounds according to the present invention have significant affinity for And2A-receptor and a high selectivity to A1and And3-receptors. Adenosine is a modulator of a large number of physiological functions that are performed through interaction with specific cell-surface receptors. Review the possible use of adenosine receptors as targets for drugs, was first performed in 1982. Adenosine is related structurally and metabolically with biologically active nucleotide adenusi what triphosphate (ATP), adenosine diphosphate (ADP), a monophosphate (AMP) and cyclic monophosphate (camp); biochemical meteorous agent of S-adenosyl-L-mational (SAM) and structurally with the coenzymes NAD, FAD, and coenzyme A; and RNA. Adenosine and related compounds play an important role in regulating many aspects of cellular metabolism and modulation of various kinds of activity of the Central nervous system.

Adenosine receptors are classified as A1, A2AAnd2Band a3receptors belonging to the family of receptors coupled with G-proteins. Activation of adenosine receptors adenosine initiates the transmission system signal. These mechanisms are mediated by G-protein associated with the receptor. Each subtype adenosine receptor usually is characterized by the adenylate cyclase effector system in which as a second messenger is cyclic amp. A1and a3receptors associated with Giproteins that inhibit adenylate cyclase, which leads to decrease in the content of camp in the cells, while A2Aand a2Breceptors coupled with Gsproteins 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 and calcium ion is s channels. Subtype And3in addition to the Association with adenylate cyclase, stimulates phospholipase C and thus activates calcium ion channels.

Cloned And1receptor (326-328 amino acids) of different types (the family dog, human, rat, dog, chicken, cattle, Guinea pigs), while in mammals observed 90-95%sequence identity. Cloned A2Areceptor (409-412 amino acids) family dog, rat, human, Guinea pigs and mice. Cloned And2Breceptor (332 amino acids) of human and mouse, while there has been a 45%gomologichnosti sequence of the receptor And2Bperson in relation to A1and A2Areceptors person. Cloned And3receptor (317-320 amino acids) of human, rat, dog, rabbit and sheep.

It is assumed that the receptor subtypes A1and A2Acomplement each other in the regulation of adenosine process of providing energy. Adenosine, which is a product of metabolic transformation of ATP diffuses from the cell and locally affects the activation of adenosine receptors, reducing the need for oxygen (A1or increasing the supply of oxygen (A2Aand so maintaining a balance between energy supply and consumption in the tissues. The action of both subtypes for luchetta in increasing the number of tissue oxygen and in the protection of 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, injury such as hypoxia, ischemia, hypotension, and seizures.

In addition, it is known that the binding of agonist adenosine receptor with fat cells expressing the receptor And3rats, increases the level of Insectivora and the calcium concentration inside the cell, which enhances antigen-induced secretion of mediators of the inflammatory response. Therefore, the receptor And3plays an important role as a mediator in case of asthma attacks and other allergic reactions.

Adenosine is a neuromodulator that can modulate various aspects of physiological activity of the brain. Endogenous adenosine, the Central link between energy metabolism and neuronal activity, changes in accordance with behavioral state and (Pato)physiological conditions. In the context of increasing demand and decreasing availability of energy (such as hypoxia, hypoglycemia, and/or excessive neuronal activity), adenosine provides an effective protective feedback mechanism. Interaction with adenosine receptors is a promising therapeutic alongside the effects in the case of a variety of neurological and psychiatric diseases, such as epilepsy, disorders and sleep disorders, and motor activity (Parkinson's disease or Huntington's disease (Huntington), Alzheimer's disease, depression, schizophrenia or addiction.

The increase in the rate of neurotransmitter release occurs with trauma, such as hypoxia, ischemia and seizures. These neurotransmitters ultimately responsible for the degeneration and death of neurons, which leads to brain damage or death of the organism. Thus, agonists of adenosine receptor And1simulating the inhibitory processes in the Central nervous system (CNS)caused by adenosine, can be used as neuroprotective agents. Adenosine is supposed to be used as an endogenous anticonvulsant agent that inhibits the release of glutamate from the excited neurons and inhibitory stimulation of neurons. Thus, agonists of adenosine can be used as antiepileptic agents.

Antagonists of adenosine stimulate the activity of the Central nervous system and, as installed, are effective reinforcing agents in relation to cognitive (cognitive) abilities. Selective And2Aantagonists have therapeutic potential in the treatment of various forms of dementia, for example, in the case of Alzheimer's disease, on neurodegenerative diseases, for example, when the cerebral circulation. Antagonists of adenosine A2Areceptor modulate the activity stroitelnyh GABA-eliteskin neurons and regulate smooth movement and coordination, thus, provide an opportunity to treat the symptoms observed in parkinsonism.

Adenosine is also involved in several physiological processes underlying sedation, hypnosis, schizophrenia, anxiety, pain, lack of breath, depression, drug abuse and drug addiction (amphetamine, cocaine, opioids, ethanol, nicotine, cannabinoids). Therefore, drugs acting on adenosine receptors have therapeutic potential as a sedative agents, muscle relaxants, antipsychotics, tranquilizers, analgesics, respiratory stimulants and antidepressants in the treatment of drug abuse and drug addiction. They can also be used to treat disorders and disorders related to attention deficit and hyperactivity disorder (ADHD).

In the cardiovascular system adenosine plays an important role as cardioprotector (cardioboxing funds). The level of endogenous adenosine is increased in response to ischemia and hypoxia, which protects the heart tissue at the injury and after the injury (the camera is the zation). Through the influence of A1receptor agonists adenosine A1can provide protection from damage caused by myocardial ischemia and reperfusion. The modulating effects of A2areceptors on adrenergic function may be important in the case of various diseases, such as coronary artery disease and heart failure. And2Aantagonists may be of interest for therapy in such situations, when necessary increased adrenergic reactions, such as acute myocardial infarction. Selective antagonists with respect to A2areceptors may also increase the efficacy of adenosine in non-recurrent supraventricular (supraventricular) arrhythmias.

Adenosine is a modulator of many aspects of the functioning of the kidneys, including the release of renin, the rate of glomerular (glomerular filtration and renal blood flow. Compounds that counteract the effects of adenosine on the kidneys, are protective agents for the kidneys. In addition, antagonists of adenosine receptors And3and/or A2Bcan be useful in the treatment of asthma and other allergic reactions or in the treatment of diabetes and obesity.

The current status of research in the field of adenosine receptors reflects many of the published documents, for example, the following publications:

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

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

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

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

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

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

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

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

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

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

The aim of the present invention to provide compounds of formula I themselves, the use of compounds of the formula I and their pharmaceutically acceptable salts to obtain drugs intended for treatment of diseases associated with adenosine A2receptor, receipt, medicines based on compounds according to the present invention, and receipt of them, and also the use of compounds of formula I for the control or prevention of diseases associated with the work of the adenosine system, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, neuroprotective effect, schizophrenia, anxiety, pain, lack of breath, depression, addiction to drugs and medicines, such as amphetamine, cocaine, opioids, ethanol, nicotine, cannabinoids, or use of asthma, allergic responses, hypoxia, ischaemia, seizure and abuse of alcohol or drug.

In addition, the compounds according to the present image is the shadow can be useful as sedatives, muscle relaxants, antipsychotics, anti-epileptics, anticonvulsants and cardioprotective funds in such diseases, such as coronary artery disease and heart failure. The most preferred indications in accordance with the present invention are those that are based on antagonistic activity against A2Areceptor and which include disorders of the Central nervous system, for example, the treatment or prevention of Alzheimer's disease, some depressive disorders or disorders, drug addiction, drug addiction, neuroprotective effect and Parkinson's disease, and disorders and disorders related to attention deficit and hyperactivity disorder (ADHD).

The term "pharmaceutically acceptable additive salts with acids" (salt - addition products of acids) include salts 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.

Preferred compounds according to the present invention t is Auda such compounds of the formula I, where R represents a C5-C6-cycloalkyl, optionally substituted by hydroxy group, for example the following compounds:

4-hydroxy-cyclohexyloxy ether (TRANS)-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]carbamino acid,

cyclohexyloxy ether (4-methoxy-7-morpholine-4-eventhorizon-2-yl)carbamino acid,

4-hydroxycyclohexyl ether (TRANS)-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)carbamino acid,

4-hydroxycyclohexyl ether (CIS)-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)carbamino acid or

3-hydroxycyclopent ether (CIS/TRANS)-(4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)carbamino acid.

Additionally preferred are such compounds of formula I in which R represents ethyl, isobutyl or methoxyethyl, for example, the following connections:

ethyl ester [4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]carbamino acid,

isobutyl ether (4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)carbamino acid.

Preferred compounds according to the present invention are those compounds of formula I in which R represents tetrahydropyran-4-yl or -(CH2)n-tetrahydrofuran-2 or 3-yl, for example the following compounds:

tetrahydropyran-4-silt ether (4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)carbamino acid,

tetrahydrofuran-3-silt ether (R)-(4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)carbamino acid,

tetrahydrofuran-2-yl-methyl ester [4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]carbamino acid or

(S)-(tetrahydrofuran-3-yl)new ester [4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]carbamino acid.

Also preferred are those compounds of formula I in which R represents a 5-hydroxybenzyl[2,2,1]hept-2-yl, for example the following connection:

5-hydroxybenzyl[2,2,1]hept-2-silt ether (rat)-(Exo,Exo)-(4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)carbamino acid.

The compounds of formula I according to the present invention and their pharmaceutically acceptable salts may be obtained using methods known from the prior art, for example, by the method described below. This method includes:

a) interaction of the compounds of formula

with the compound of the formula

obtaining the compounds of formula

in which R and X have the meanings given above, or

b) interaction of the compounds of formula

with the compound of the formula

getting connection f is rmula

in which R and X are as defined above, L is tsepliaeva group, such as halogen, -O-phenyl or O-lower alkyl, and, if necessary, converting the compounds obtained into pharmaceutically acceptable acid additive salt.

In examples 1-13 and the following schemes 1 and 2 obtain compounds of formula I are described in more detail.

Source materials are known compounds or can be obtained according to methods known from the prior art.

Obtaining compounds of formula I

The intermediate 7-(morpholine-4-yl)-4-methoxybenzothiazole-2-ylamine and 7-(tetrahydropyran-4-yl)-4-methoxybenzothiazole-2-ylamine can be obtained in accordance with the methods disclosed in published international application WO 01/97786. Obtaining compounds of formula (I) using the intermediate compounds of formula (II) are also described in published international application WO 01/97786.

Scheme 1

Obtaining compounds of formula (VII)

Derivatives arilbred formula (VI) is subjected to interaction with a slight excess of bis(pinacolato)diboron in an organic solvent, preferably dimethylsulfoxide, containing a palladium catalyst, preferably such as adduct dichloro(1,1'-bis(l is phenylphosphino)ferrocene)palladium(II) - dichloromethane and an excess of potassium acetate. The interaction is carried out at elevated temperature, preferably at about 80°With, for about 2-24 hours, preferably about 2 hours. The resulting product of formula (VII) was isolated according to standard techniques, and preferably purified by chromatography or recrystallization.

Obtaining compounds of formula (VIII)

One way of preparing compounds of the formula (VIII) is in the handling of the compounds of formula (VII) derivative vinylmania, vinylidine or vinestreet in the presence of a palladium catalyst, preferably in the presence of the adduct dichloro(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloromethane, and inorganic bases, preferably such as sodium carbonate. The interaction is carried out in a mixture of solvents, preferably in a mixture of ethanol, toluene and water. The interaction is carried out at elevated temperature, preferably about 80°With, for about 0.1 to 2 hours, preferably about 20 minutes. The resulting product of formula (VIII) was isolated according to standard techniques, and preferably purified by chromatography or recrystallization. Source derivatives vinylmania, vinylidine or vinestreet may be commercially available, for example obtained is from the company "Fluka", or can be obtained in accordance with methods known from the prior art.

Obtaining compounds of formula (IX)

The compounds of formula (IX) can be obtained by hydrogenation of compounds of formula (VIII) in the presence of a hydrogenation catalyst, preferably 10%palladium on carbon. These interactions may be held in various organic solvents, such as methanol, ethanol or tetrahydrofuran, preferably in methanol at room temperature and at a pressure equal to atmospheric or above atmospheric, preferably at a pressure equal to one atmosphere, for 16-72 hours, preferably about 72 hours. The resulting product of formula (IX) was isolated according to standard techniques, and preferably purified by chromatography or recrystallization.

Obtaining the compounds of formula (X)

To a solution of ammonium thiocyanate in acetone added benzoyl chloride and a solution of 2-methoxy-5-(tetrahydropyran-4-yl)phenylamine (IX). The interaction is carried out at boiling under reflux for about 20 minutes. The resulting product is 1-benzoyl-3-[2-methoxy-5-(tetrahydropyran-4-yl)phenyl]thiourea (X) was isolated according to standard techniques.

Obtaining the compounds of formula (XI)

To a solution of 1-benzoyl-3-[2-methoxy-5-(tetrahydrate is an 4-yl)phenyl]thiourea (X) in methanol is added a solution of sodium methylate and continue stirring for about 1 h at room temperature. The resulting product (XI) [2-methoxy-5-(tetrahydropyran-4-yl)phenyl]thiourea allocate according to standard techniques.

Obtaining the compounds of formula (XII)

To a solution of 1-[2-methoxy-5-(tetrahydropyran-4-yl)phenyl]thiourea (XI) in acetic acid is added Hydrobromic acid and then continue stirring for approximately 30 minutes at 80°C. Then added dropwise DMSO and the reaction mixture is additionally stirred for 30 minutes at 80°C. the resulting product (XII) - 4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-ylamine - allocate according to standard techniques.

Obtaining the compounds of formula (IB)

4-Methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-ylamine (XII) is first subjected to interaction with phenylcarbamates thus, as described in relation to the benzyl ether (4-methoxy-7-phenylbenzothiazole-2-yl)carbamino acid in published international application WO 01/97786 and then with N-ethyldiethanolamine and the corresponding alcohol of the formula HO-R in dimethyl sulfoxide at about 50°C for 2 h, as shown in scheme 2.

Scheme 2

R and X are as described above, L means tsepliaeva group, such as halogen, -O-phenyl or O-lower alkyl.

Isolation and purification of compounds

Isolation and purification of the compounds and the intermediate connection the developments described in the text of the present application may be performed, if necessary, using any suitable methods of separation or purification such as filtration, extraction, crystallization, column chromatography, thin layer chromatography, chromatography in a thick layer preparative chromatography low or high resolution or liquid chromatography under high pressure, or using combinations of these methods.

Specific illustrations of the use of suitable methods of division and separation can be found in the section devoted to the synthesis and examples of specific performance in the following text of this application. But, of course, can be used and other equivalent methods of division and separation.

Salts of compounds of formula I

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

The transformation is implemented by processing at least the stoichiometric amount of the appropriate acid, such as chloromethane acid, Hydrobromic to the slot, sulfuric acid, nitric acid, phosphoric acid and similar acids, such as organic acid, for example 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 (β-phenylacrylate) acid, mandelic acid, methanesulfonate acid, econsultancy acid, n-toluensulfonate acid, salicylic acid and similar acids. Usually the free base is dissolved in an inert organic solvent, such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol and the like, and add the acid in this solvent. The temperature maintained within the range from 0 to 50°C. the Obtained salt precipitates spontaneously or can be extracted from the solution with a less polar solvent.

Additive salts with acids of the compounds of the basic character of the formula I can be converted into the corresponding free base by processing at least a stoichiometric equivalent of a suitable base, such as sodium hydroxide or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, and similar reasons.

Link the formula I and their pharmaceutically acceptable additive salts with acids have valuable pharmacological properties. Namely, it was shown that the compounds according to the present invention are ligands of adenosine receptor and have a high affinity to the adenosine A2Athe receptor.

Compounds were investigated in accordance with the following testing methods.

Adenosine A2Areceptor human

Adenosine A2Areceptor human recombinante Express in cells of the Chinese hamster ovary (Cho) using the expression system of the virus semliki forest. Cells are harvested, washed twice by centrifugation, homogenized and washed again by centrifugation. The washed precipitate the membrane fraction suspended in Tris-buffer solution (50 mm)containing 120 mm NaCl, 5 mm KCl, 2 mm CaCl2and 10 mm MgCl2(pH of 7.4) (buffer A). Study of the binding of [3H]-SCH-58261 (Dionisotti et al., 1997, Br J Pharmacol, 121, 353; 1 nm) 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 final volume of buffer And average of 200 μl. The nonspecific binding determined with the use of compounds of the same class of xanthinuria (KHAS; 2 μm). Compounds assayed at 10 concentrations ranging from 10 μm to 0.3 nm. All research is carried out in two parallel series, and the analysis is repeated at least twice. PL is nsity, in which conduct the study, incubated for 1 hour at room temperature before centrifugation and then bound ligand was determined using a scintillation counter Packard Topcount". The values of the IC50calculated using nonlinear approximation and the values of Ki are calculated according to the equation of Cheng-Prusoff.

The pKi values for the compounds according to the present invention are in the range of 7.6 to 8.7. For the most preferred compounds of the pKi values>8,0.

Example No.hA2(pKi)Example No.hA2(pKi)
18,788,1
28,398,4
37,9107,6
47,6117,8
58,1127,9
68,2138,4
78,0

The compounds of formula I and pharmaceutical salts of the compounds of formula I can be used as medicines, for example, in the form of pharmaceutical preparations is impressive. The pharmaceutical preparations can be administered orally, for example in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions. In addition, the introduction can 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 pharmaceutical compositions. As carriers for tablets, coated tablets, dragées and hard gelatin capsules can be used, for example, lactose, corn starch or its derivatives, talc, stearic acid or their salts and similar compounds. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like compounds. However, depending on the nature of the active compounds in the case of soft gelatin capsules the media may not be used. Suitable carrier materials for obtaining of solutions and syrups are, for example, water, polyols, glycerine, vegetable oil, and the like compounds. Suitable carrier materials for obtaining of solutions and syrups are, for example, water, poly the crystals, glycerin, vegetable oil, and similar substances. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like compounds. However, depending on the nature of the active compounds in the case of soft gelatin capsules the media may not be used.

Pharmaceutical compositions can also contain preservatives, soljubilizatory, stabilizers, agents for improving wettability, emulsifiers, sweeteners, tinted agents, agents for improving taste and smell, salts for regulating the osmotic pressure, buffers, masking agents or antioxidants. They can also contain other therapeutically important compounds.

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 well as the way they are received, which includes the introduction of one or more compounds of formula I and/or pharmaceutically acceptable additive salts with an acid and, if necessary, one or more therapeutic substances in the composition of a medicinal product, together with one or more therapeutically inert carrier.

In accordance with the present invention with the organisations of the formula I, and their pharmaceutically acceptable salts can be used to control or prevent diseases associated with agonistic activity against adenosine receptor, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, neuroprotective effect, schizophrenia, anxiety, pain, lack of breath, depression, asthma, allergic responses, hypoxia, ischaemia, seizure and substance abuse. In addition, the compounds according to the present invention can be useful as sedatives, muscle relaxants, antipsychotics, anti-epileptics, anticonvulsants and cardioprotective funds and to obtain the drugs.

The most appropriate evidence in accordance with the present invention are indications, which include disorders or disorders of the Central nervous system, such evidence as the treatment or prevention of certain depressive disorders, neuroprotection and Parkinson's disease.

The dosage may vary within wide limits and will, of course, be adjusted depending on the individual requirements in each particular case. In the case of oral administration the dosage for adults can vary from approximately 0,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 dosage may be entered as a single dose or divided into multiple doses and, in addition, may be exceeded, if it is found that it is necessary according to the testimony.

Manufacturing of tablets (wet granulation)
PositionIngredientsmg tablet
5 mg25 mg100 mg500 mg
1The compound of the formula I525100500
2Anhydrous lactose DTG12510530150
3Sta-Rx 150066630
4Microcrystalline cellulose303030150
5Magnesium stearate1111
The total number of167167167831

Method get

1. Mixed connection positions 1, 2, 3 and 4 and carry out granulation using treated in the control.

2. Dry the granules at 50°C.

3. Pass the granules through a suitable device for grinding.

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

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

The method of cooking

1. Mixed connection positions 1, 2 and 3 in a suitable mixer for 30 minutes.

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

3. Placed in a suitable capsule.

The following procedures and examples illustrate the invention but they should not be construed as limiting the scope of the present invention.

Example 1

4-Hydroxycyclohexyl ether (TRANS)-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]carbamino acid

4-Methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-ylamine (69 mg, 0.26 mmol) is first subjected to interaction with phenylcarbamates thus, as described in relation to the benzyl ether (4-methoxy-7-phenylbenzothiazole-2-yl)carbamino acid in published international application WO 01/97786, and then N-ethyldiethanolamine (0,090 ml, 0.5 mmol) and (TRANS)-cyclohexane-1,4-diola (60 mg, 0.5 mmol) in dimethyl sulfoxide (10 ml) at 50°C for 2 hours Then add 100 ml of dichloromethane, the mixture is extracted with saturated aqueous sodium carbonate and the organic phase is dried and evaporated. After cleaning, Express chromatography (silica gel, elution with a mixture of dichloromethane/methanol) get mentioned in the title compound as a white solid (yield 7%). Mass spectrum: m/e=407(M+N+), TPL 282-284°C.

In accordance with the General methodology described in example 1, to obtain compounds according to examples 211.

Example 2

Ethyl ester [4-methoxy-7-(tetrahydropyran-4-yl)benzoate the evils-2-yl]carbamino acid

Using 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and ethanol, is listed in the title compound obtained as white solids (yield 35%). Mass spectrum: m/e= 337(M+N+), TPL 170-174°C.

Example 3 (not included in the scope of the present invention)

2-Methoxyethylamine ether (4-methoxy-7-morpholine-4-eventhorizon-2-yl)carbamino acid

Using 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and 2-methoxyethanol specified in the title compound obtained as not quite white solids (yield 52%). Mass spectrum: m/e= 368(M+N+), TPL 149-152°C.

Example 4

Isobutyl ether (4-methoxy-7-morpholine-4-eventhorizon-2-yl)carbamino acid

Using 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and Isobutanol, specified in the title compound obtained as yellow crystals (yield 12%). Mass spectrum: m/e=366(M+N+), so pl. 164-168°C.

Example 5

Cyclohexyloxy ether (4-methoxy-7-morpholine-4-eventhorizon-2-yl)carbamino acid

Using 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and cyclohexanol specified in the title compound obtained as white solids (yield 60%). Mass spectrum: m/e= 392(M+N+), TPL 177-179°C.

Example 6

4-Hydroxycyclohexyl ether (TRANS)-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)carbamino acid

Using 4-methoxy-7-morpholine-yl-benzothiazol-2-ylamine and (TRANS)-cyclohexane-1,4-diol, specified in the title compound obtained as a white foam substance (yield 14%). Mass spectrum: m/e=408(M+H+), TPL 176-179°C. Mass spectrum: m/e=407,49(M+H+).

Example 7

4-Hydroxycyclohexyl ether (CIS)-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)carbamino acid

Using 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and (CIS)-cyclohexane-1,4-diol, is listed in the title compound obtained as colorless crystals (yield 40%). Mass spectrum: m/e=408(M+N+), TPL 204-206°C.

Example 8

Tetrahydropyran-4-silt ether (4-methoxy-7-morpholine-4-eventhorizon-2-yl)carbamino acid

Using 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and tetrahydropyran-4-ol that is listed in the title compound obtained as white solids (yield 7%). Mass spectrum: m/e=394(M+N+), TPL 187-188°C.

Example 9

(rat)-(Exo,Exo)-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)carbamino acid 5-hydroxybenzyl[2,2,1]hept-2-silt ether

Using 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and (rat)-(Exo, Exo)-bicyclo[2,2,1]heptane-2,5-diol, specified in the title compound obtained as white solids (yield 10%). Mass spectrum: m/e=420(M+H+), TPL 193-194°C.

Example 10

Tetrahydrofuran-3-silt ether (R)-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)carbamino acid

Using 4-methox the-7-morpholine-4-eventhorizon-2-ylamine and (R)-tetrahydrofuran-3-ol, specified in the title compound obtained as white crystals (yield 33%). Mass spectrum: m/e=380(M+N+), TPL 198-200°C.

Example 11

3-Hydroxycyclopent ether (CIS/TRANS)-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)carbamino acid

Using 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and (CIS/TRANS)-cyclopentane-1,3-diol, specified in the title compound obtained as white solids (yield 42%). Mass spectrum: m/e=394(M+N+), TPL 188-189°C.

Example 12

Tetrahydrofuran-2-ymetray ester [4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]carbamino acid

Using 7-(tetrahydropyran-4-yl)-4-methoxybenzothiazole-2-ylamine and (tetrahydrofuran-2-yl)methanol specified in the title compound obtained as white solids (yield 8%). Mass spectrum: m/e=393(M+N+), TPL 175-180°C.

Example 13

(S)-(Tetrahydrofuran-3-yl)new ester [4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]carbamino acid

Using 7-(tetrahydropyran-4-yl)-4-methoxybenzothiazole-2-ylamine and (S)-tetrahydrofuran-3-ol, specified in the title compound obtained as white solids (yield 13%). Mass spectrum: m/e=379(M+N+), TPL 195-200°C.

Intermediate compounds

Example 14

4-Methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-ylamine (X)

a) 2-(4-Methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl,3,2]dioxaborolan (VII)

To a stirred solution of 1.30 g (the ceiling of 5.60 mmol) 4-bromo-2-nitroanisole (VI) in 25 ml DMSO type of 1.57 g (6,16 mmol) of bis(pinacolato)diboron, 123 mg (0,17 mmol) adduct dichloro(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloromethane and of 1.65 g (16,8 mmol) of potassium acetate. The resulting mixture is heated at 80°C for 2 h and then cooled to room temperature, poured into water and extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. After rapid chromatography (mixture of ethyl acetate/hexane in a ratio of 1:2, then ethyl acetate) to obtain 1.39 g of 2-(4-methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl[1,3,2]dioxaborolane (VII) in the form of not-quite-white solid. Mass spectrum (ES-MS): m/e (%) 280 (M+N+, 100).

b) 4-(4-Methoxy-3-nitrophenyl)-3,6-dihydro-2H-Piran (VIII)

To mix the solution 4,36 g (15.6 mmol) of 2-(4-methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl[1,3,2]dioxaborolane (VII) and 3.30 g (14 mmol) of 3,6-dihydro-2H-Piran-4-silt ether triftormetilfullerenov acid in 33 ml of ethanol and 82 ml of toluene added 580 mg (0.71 mmol) of adduct dichloro(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) - dichloromethane.

The resulting mixture is heated at 80°and added dropwise to 16.5 ml (33.0 mmol) of 2 M aqueous sodium carbonate. The reaction mixture is stirred for 20 minutes at 80°and then cooled to the room for the Noah temperature, poured into water and extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. After rapid chromatography (mixture of ethyl acetate/hexane in the ratio 1:4) receive a 2.00 g (yield 60%) of 4-(4-methoxy-3-nitrophenyl)-3,6-dihydro-2H-Piran (VIII) as a pale yellow solid. Mass spectrum (ES-MS): m/e (%) 253 (M+NH4+, 100), 236 (M+N+, 24).

a) 2-Methoxy-5-(tetrahydropyran-4-yl)phenylamine (IX)

To mix the solution 3,30 g (14.0 mmol) of 4-(4-methoxy-3-nitrophenyl)-3,6-dihydro-2H-Piran (VIII) in 70 ml of methanol and 70 ml of dichloromethane added at the tip of the spatula 10%palladium on carbon and the resulting mixture is then stirred for 20 minutes at room temperature under hydrogen pressure about one atmosphere.

The resulting mixture was then filtered, washing with dichloromethane, and then the filtrate was concentrated in vacuo, while receiving a 2.75 g (yield 95%) of 2-methoxy-5-(tetrahydropyran-4-yl)phenylamine (IX) in the form of not quite white solid crystalline substances. Mass spectrum (ES-MS): m/e (%) 208 (M+N+, 100).

g) 1-Benzoyl-3-[2-methoxy-5-(tetrahydropyran-4-yl)phenyl]thiourea (X)

To a stirred solution of 1.11 g (14.6 mmol) of ammonium thiocyanate in 60 ml of acetone is added dropwise and 1.54 ml (13.3 mmol) of benzoyl chloride and then the mixture is refluxed in t the value of 10 minutes. Add dropwise a solution of 2.75 g (13.3 mmol) of 2-methoxy-5-(tetrahydropyran-yl)phenylamine in 30 ml of acetone. The reaction mixture is refluxed additionally within 10 minutes. The resulting mixture was then cooled to room temperature, poured into sodium bicarbonate solution and extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. After the rapid-chromatography (ethyl acetate/hexane in the ratio 1:1) followed by rubbing in the air get 3.25 g (yield 66%) of 1-benzoyl-3-[2-methoxy 5-(tetrahydropyran-4-yl)phenyl]thiourea as a white solid. Mass spectrum (ES-MS): m/e (%) 371 (M+N+, 100).

d) [2-Methoxy-5-(tetrahydropyran-4-yl)phenyl]thiourea (XI)

To a stirred solution of 3.25 g (8,77 mmol) of 1-benzoyl-3-[2-methoxy-5-(tetrahydropyran-4-yl)phenyl]thiourea in 45 ml of methanol is added dropwise 0.25 ml (1.3 mmol) of 5.3 M solution of sodium methylate and continue stirring for 1 h at room temperature. Then, the resulting mixture was poured into water and extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. After the rapid-chromatography (ethyl acetate) to obtain 1.90 g (yield 81%) of [2-methoxy-5-(tetrahydropyran-4-yl)phenyl]thiourea as a white foam in the society. Mass spectrum (ES-MS): m/e (%) 267 (M+N+, 100).

e) 4-Methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-ylamine (XII)

To a stirred solution of 1.90 g (7,13 mmol) [2-methoxy-5-(tetrahydropyran-4-yl)phenyl]thiourea in 20 ml of acetic acid, heated to 80°C, is added dropwise to 1.45 ml (of 8.27 mmol) Hydrobromic acid (5,7 M solution in acetic acid) and continue stirring for 30 minutes at 80°C. is Added dropwise of 0.56 ml (7.85 mmol) of DMSO and the reaction mixture is stirred additionally for 30 minutes at 80°C.

The resulting mixture was then cooled to room temperature, slowly poured into a sodium bicarbonate solution and add ethyl acetate. The resulting mixture was stirred for 10 minutes at room temperature and the resulting crystals are collected by filtration, washing with ethyl acetate. Mother liquor is subjected to separation, the organic phase is concentrated in vacuo to 5 ml of the Obtained second batch of crystals are collected by filtration and combined with the first batch, while receiving 920 mg (yield 49%) of 4-methoxy-7-(tetrahydropyran-4-yl)benzothiazole-2-ylamine in the form of a white solid. Mass spectrum (ES-MS): m/e (%) 265 (M+N+, 100).

1. Compounds of General formula

in which

R represents a C5-C6-cycloalkyl, resumes the config or substituted by hydroxy group, or represents ethyl or isobutyl, or represents tetrahydropyran-4-yl or -(CH2)n-tetrahydrofuran-2 or 3-yl, or represents 5-hydroxybenzyl[2,2,1]hept-2-yl;

X represents CH or N;

n means 0 or 1,

and their pharmaceutically acceptable acid additive salt.

2. Compounds of General formula according to claim 1

in which

R represents a C5-C6-cycloalkyl, unsubstituted or substituted by hydroxy group, or represents ethyl or isobutyl, or represents tetrahydropyran-4-yl or tetrahydrofuran-3-yl, or represents 5-hydroxybenzyl[2,2,1]hept-2-yl;

X represents CH or N;

and their pharmaceutically acceptable acid additive salt.

3. The compounds of formula I according to claim 1, where R represents a C5-C6-cycloalkyl, optionally substituted by a hydroxy group.

4. The compounds of formula I according to claim 3, which represent the following connections:

4-hydroxycyclohexyl ether (TRANS)-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]carbamino acid,

cyclohexyloxy ether (4-methoxy-7-morpholine-4-eventhorizon-2-yl)carbamino acid,

4-hydroxycyclohexyl ether (TRANS)-(4-methoxy-7-morpholine-4-albenza eazol-2-yl)carbamino acid,

(CIS)-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)carbamino acid 4-hydroxy-cyclohexyloxy ether or

3-hydroxycyclopent ether (CIS/TRANS)-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)carbamino acid.

5. The compounds of formula I according to claim 1, where R represents ethyl or isobutyl.

6. The compounds of formula I according to claim 4, which represent the following connections:

ethyl ester [4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]carbamino acid or

isobutyl ether (4-methoxy-7-morpholine-4-eventhorizon-2-yl)carbamino acid.

7. The compounds of formula I according to claim 1, where R is tetrahydropyran-4-yl or -(CH2)n-tetrahydrofuran-2 or 3-yl.

8. The compounds of formula I according to claim 7, which represent the following connections:

tetrahydropyran-4-silt ether (4-methoxy-7-morpholine-4-eventhorizon-2-yl)carbamino acid,

tetrahydrofuran-3-silt ether (R)-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)carbamino acid,

tetrahydrofuran-2-ymetray ester [4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]carbamino acid or

(S)-(tetrahydrofuran-3-yl)new ester [4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]carbamino acid.

9. The compounds of formula I according to claim 1, where R represents a 5-hydroxybenzyl[2,2,hept-2-yl.

10. The compound of formula I according to claim 9, which is the following connection:

5-hydroxybenzyl[2,2,1]hept-2-silt ether (rat)-(Exo,Exo)-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)carbamino acid.

11. Drug, possessing properties of ligand adenosine receptors and high affinity to the receptor adenosine A2Acontaining one or more compounds according to any one of claims 1 to 10 and a pharmaceutically acceptable fillers.

12. Drug in claim 11 for the treatment of diseases associated with adenosine receptor And2A.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention concerns method of treatment, alleviation and/or prevention of neurological state, particularly neurodegenerative disorders, involving administration of effective quantity of compound with formula I: . Also invention concerns application of compound of the formula I as neurotherapeutical, neuroprotective or antimyloid agent, pharmaceutical or veterinary composition for treatment, alleviation and/or prevention of neurological states, and compounds of the formula I on the following additional terms: (b) if R3, R and R' are H, and R2 is (CH2)2NR9R10, then both R9 and R10 are not ethyl or methyl; (c) if R3, R and R' are H, and R2 is (CH2)2NR9R10, then both R9 and R10 are not hydrogen or ethyl; (d) if R3, R and R' are H, and R2 is NR11R12, then both R11 and R12 are not hydrogen; (e) if R3, R and R' are H, and R2 is COR6, then R6 is not H, OH or CH2Cl; (f) if R3, R and R' are H, and R2 is not CH3 or CH2Cl; (g) if R3, R and R' are H, and R2 is HCNN R9R10, then both R9 and R10 are not H.

EFFECT: efficient treatment, alleviation and prevention of neurological state.

24 cl, 14 tbl, 21 ex, 14 dwg

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the formula I , where R0 is 1) monocyclic 6-14-member aryl, where aryl is independently mono-, di- or trisubstituted by R8, 2) heterocyclyl out of group of benzothiazolyl, indazolyl, pyridyl, where the said heterocyclyl is independently non-substituted or mono-, di- or trisubstituted by R8, and other radicals referred to in point 1 of the claim; R8 is halogen; on condition that R8 is at least one halogen atom if R0 is monocyclic 6-14-member aryl; substructure in the formula I is 4-8-member saturated, partly non-saturated or aromatic cyclic group including 0, 1 heteroatom selected out of nitrogen or sulfur, and is non-substituted or substituted 1, 2, 3 times by R3; Q is -(C0-C2)alkylene-C(O)NR10-, methylene; R1 is hydrogen atom, -(C1-C4)alkyl, where alkyl is non-substituted or substituted one to three times by R13; R2 is a direct link; R1-N-R2-V can form 4-8-member cyclic group selected out of piperazine or piperidine group; R14 is halogen, =O, -(C1-C8)alkyl, -CN; V is 1) 6-14-member aryl, where aryl is independently non-substituted or mono-, di- or trisubstituted by R14, and other radicals referred to in point 1 of the claim; G is direct link, -(CH2)m-NR10, where m is 0 and R10 is hydrogen, -(CH2)m-C(O)-(CH2)n-, where m is 0 or 1, and n is 0, -(CH2)m-C(O)-NR10-(CH2)n-, where m is 0 or 1, and n is 0, 1 or 2, -(CH2)m-, where m is 1; M is 1) hydrogen atom, 2) 6-14-member aryl, and other radicals referred to in point 1 of the claim; R3 is 1) hydrogen atom, 2) halogen atom, 3) -(C1-C4)alkyl, where alkyl is non-substituted, and other radicals referred to in point 1 of the claim; R11 and R12 are independently the same or different and are 1) hyfrogen atom, 2) -(C1-C6)alkyl, where alkyl is non-substituted or monosubstituted by R13, and other radicals referred to in point 1 of the claim; or R11 and R12 can form 4-8-member monocyclic heterocyclic ring together with nitrogen atoms to which they are linked, and beside the nitrogen atom the ring can include one or two similar or different ring heteroatoms selected out of oxygen, sulfur and nitrogen; where the said heterocyclic ring is independently non-substituted or mono-, disubstituted by R13; R13 is halogen, =O, -OH, -CF3, -(C3-C8)cycloalkyl, -(C0-C3)alkylene-O-R10; R10 is hydrogen, -(C1-C6)alkyl; R15 and R16 are independently hydrogen, -(C1-C6)alkyl; R17 is -(C1-C6)alkyl, -(C3-C8)cycloalkyl; in all stereoisomer forms and their mixes at any ratio, and physiologically tolerable salts. Compounds of the formula I are reversible inhibitors of enzyme factor Xa (FXa) and/or factor VIIa (FVIIa) of blood clotting, and can be generally applied in states accompanied by undesirable factor Xa and/or factor VIla activity, or supposing factor Xa and/or factor VIla inhibition for treatment or prevention. In addition, invention concerns methods of obtaining compounds of the formula I, their application as agents in pharmaceutical compositions.

EFFECT: obtaining compounds applicable as agents in pharmaceutical compositions.

19 cl, 1 tbl, 169 ex

FIELD: chemistry.

SUBSTANCE: description is given of a piperidine derivative with general formula (I) , where L represents CH or N; M represents CH or N; under the condition that, L and M both do not represent CH; R1 represents phenyl (possibly substituted with a halogen or C1-4alkyl), S(O)2(C1-4alkyl), S(O)2(C1-4fluroalkyl), S(O)2phenyl (possibly substituted with CF3 or OCF3), benzyl, benzoyl (possibly substituted with a halogen) or C(O)NHphenyl (possibly substituted with a halogen); R2 represents phenyl, possibly substituted with a halogen; R3 represents hydrogen or C1-4alkyl; R4 represents methyl or ethyl; R5 represents phenyl-NH, phenyl (C1-2alkyl), phenyl(C1-C2)alkyl-NH or pyridyl(C1-2alkyl). The phenyl can be substituted with a halogen, cyano, C1-4alkyl, C1-4alkoxy, S(O)k(C1-4alkyl) or S(O)2NR8R9; k is equal to 2; R8 and R9 represent hydrogen or its pharmaceutical salts. The compound is a modulator of the activity of the CCR5 receptor. Description is given of the method of obtaining the compound, where L represents N, and the pharmaceutical composition based on a compound with formula (I).

EFFECT: design of a method of obtaining a compound, where L represents N, and a pharmaceutical composition based a compound with formula (I).

7 cl, 7 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to derivatives of 4-[1-arylimidazol-4-yl ethynyl]-2-alkylpyridine and 4-[1-heteroarylimidazol-4-yl ethynyl]-2-alkylpyridine of general formula I having general formula I in which R1 stands for C1-C6alkyl; R2 stands for C1-C6alkyl or C3-C12cycloalkyl; R3 stands for aryl or heteroaryl, where aryl or heteroaryl are unsubstituted or contain substituents, selected from group, including halogen, C1-C6alkyl, S-C1-C6alkyl, C1-C6alkylhlogen, C1-C6alkoxygroup, halogen- C1-C6lkoxygroup, C3-C12cycloalkyl, C2-C11heterocycloakyl, C1-C6alkylminogroup,di- C1-C6alkylaminogroup, C1-C6alkoxyaminogroup, (C1-C6 alkoxy) C1-C6alkylaminogroup, C3-C12cycloalkylaminogroup, benzylaminogroup and cyanogroup, where said "aryl" represents phenyl, and said " heteroaryl" represents aromatic 5- or 6- member ring or one or more condensed rings, containing one or more heteroatoms, selected from group, which includes nitrogen, oxygen and sulfur; and R4 stands for hydrogen, C(O)H or CH2R5 , where R stands for hydrogen or its pharmaceutically acceptable salt. Invention also relates to method of obtaining compounds of general formula I, their application as anxiolytic, to based on them pharmaceutical composition and method of treatment or prevention of disorders, fully or partly mediated by metabotropic glutamate receptor of subtype 5.

EFFECT: obtaining novel heterocyclic compounds possessing useful biological properties.

15 cl, 18 ex

FIELD: medicine; pharmacology.

SUBSTANCE: compounds of this invention possess properties of protein kinase inhibitors. In the general formula p means integer within 0 to 2; R and R1 mean O; A1 and A2 mean single bond, (C1-C6)alkyl; B2 means monocyclic or bicyclic, saturated or unsaturated heterocyclic radical including 1 to several identical or different heteroatoms, chosen among O, S, N and NR7, probably substituted with one or several identical or different substitutes.

EFFECT: inhibiting effect on protein kinase, effective application of compounds of formula for medical products.

49 cl, 1 tbl, 6 dwg, 334 ex

FIELD: chemistry.

SUBSTANCE: in general formula I

R1 is phenyl or 5-6-member heterocycle, containing one N atom and/or one O atom; R2 is imidazole or annelated imidazole, selected from group, including a), b), c), d) and e); and R3 stands for hydrogen, phenyl, 2,3-dihydrobenzo[1,4]dioxin-6-yl, benzo[b]thiophen-3-yl, 3-methylbenzo[b] thiophen-2-yl, thiophen-2-yl or thiophen-2-ylmethyl, R4 is hydrogen or lower alkyl, R5 is hydrogen, lower alkyl, halogen, morpholinyl, -NR'R", piperydinyl, optionally substituted with hydroxy-group, or is pyrrolidin-1-yl; R6 is hydrogen or -(CH2)nO-lower alkyl, R7 is hydrogen, -C(O)O-lower alkyl, -C(O)-C6H4-halogen, -C(O)-C6H4-lower alkyl, -C(O)-lower alkyl, -C(O)-cycloalkyl, -C(O)-NR'R", -C(O)-(CH2)nO-lower alkyl, -S(O)2-lower alkyl, -(CH2)nO-lower alkyl, -C(O)-pyridin-4-yl, whose ring can contain as substituents lower alkyl, halogen-lower alkyl or pyrrolidin-1-ylmethyl or is -(CH2)n-C(O)-NR'R"; R'/R" independently on each other stand for hydrogen, lower alkyl or -(CH2)n-tetrahydropyran-4-yl, X is -CH2-, -NR'''- or -O-; R''' is hydrogen, -C(O)-lower alkyl, -C(O)O-lower alkyl, -C(O)-C6H4CH3 or benzyl; n is 1 or 2.

EFFECT: increase of composition and treatment method efficiency.

14 cl, 56 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to new derivatives of 2-pyridinecarboxamide and their pharmaceutical salts, which have glucokinase activating properties. In formula (I): D represents O or S; R2 and R3 each represents a hydrogen atom; formula (II) represents triazole group, imidazole group, thiazole group and pyridine group, which can have in the ring, 1 or 2 substitutes; formula (III) represents a thiazole group, thiadiazole group, isoxazolyl group, pyrazine group, pyridothiazolyl group or pyridyl group, ring B can have 1 or 2 substitutes. The invention also relates to pharmaceutical compositions based on the invented compounds.

EFFECT: new derivatives can be used for treating such diseases as sugar diabetes.

19 cl, 5 tbl, 165 ex

FIELD: chemistry.

SUBSTANCE: new compounds with formula Ia are proposed, where: P represents pyridine or pyrimidine; R1 represents hydrogen; R2 is chosen from halogen, nitro, C0-6alkylheteroaryl, (CO)OR4, trifluoromethyl, C0-6alkylcyano, C0-6alkylNR4R5, OC1-6alkylNR4R5, C0-6alkylCONR4R5, C0-6alkyl(SO2)NR4R5 and X1R6 group, where X1 represents a direct link; R6 represents a 5- or 6-member heterocyclic group, containing one or two heteroatoms, independently chosen from N, O, and S, for which the given heterocyclic group can be unsaturated and can be substituted with by one substitute, chosen from W; m equals 0, 1, or 2; R3 is chosen from CO(OR4), C0-6alkylNR4R5, C0.6alkylCONR4R5, OC1-6alkylNR4R5 C1-6alkyl(SO2)NR4R5; n equals 1 or 2; R4 is chosen from hydrogen, C1-6alkyl; R5 is chosen from hydrogen, C1-6 alkyl, C0-6 alkyl C3-6 cycloalkyl, C0-6 alkylaryl, C0-6alkylheteroaryl and C1-6alkylNR14R15 or R4 and R5 together can form a 4-, 5-, 6- or 7-member heterocyclic group, containing one or more heteroatoms, independently chosen from N and O, where the given heterocyclic group can be substituted by group Y; and where any C1-6alkyl, indicated in defining R2-R5, can be substituted with one or more one Z group; R14 and R15 together can form a 5-member heterocyclic group, containing one or more heteroatoms, independently chosen from N and O; W and Z are independently chosen from halogen, CN, OR16, C1-6alkyl, trifluoromethyl, trifluoromethoxy, 5-member heterocyclic group, containing one heteroatom, independently chosen from N, for which the given heterocyclic group can be substituted with group Y; Y is chosen from oxo, halogen, C1-6alkyl, C0-6alkylaryl, NR16R17, phenyl, C0-6alkylaryl, where the phenyl and C0-6alkylaryl groups can be substituted with nitro, trifluoromethyl; R16 and R17 are independently chosen from hydrogen and C1-6alkyl, or where R16 and R17 together can form a 5-member heterocyclic group, containing one heteroatom, chosen from N; in form of a free base or pharmaceutical salt. Formula Ia compounds have inhibiting effect to glycogen-synthase-kinase-3 (GSK3). The invention also relates to the method of obtaining the proposed compounds and to new intermediate compounds, used in them, pharmaceutical compositions, containing the given therapeutically active compounds, and use of the given active compounds in therapy for treating conditions, related to GSK3.

EFFECT: new method of obtaining indole derivatives.

33 cl, 1 tbl, 112 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to new compounds with general formula: , where R is -(CH2)n-A, where A: where each of B and C independently represent phenyl or phenyl substituted with 1-3 substitutes, independently chosen from a halogen, -CN, -CHO, -CF3, -OCF3, -OH, -C1-C6alkyl, C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -NH-C(O)-(C1-C6alkyl) and -NO2; or n equals an integer from 0 to 3; n1 equals an integer from 1 to 3; n2 equals an integer from 0 to 4; n3 equals an integer from 0 to 3; n4 equals an integer from 0 to 2; X1 is chosen from a chemical bond -S-, -S(O)2-, -NH-, -NHC(O)- and -C=C-, R1 is chosen from C1-C6alkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, tetrahydropyranyl, CN, -N(C1-C6alkyl)2, phenyl, pyridinyl, pyrimidinyl, furyl, thienyl, naphtyl, morpholinyl, triazolyl, pyrazolyl, piperidinyl, pyrrolidinyl, imidazolyl, piperizinyl, thiazolydinyl, thiomopholinyl, tetrazolyl, benzoxazolyl, imidazolidine-2-thionyl, 7,7-dimethylbicyclo[2.2.1]heptane-2-onyl, benzo[1.2.5]oxadiazolyl, 2-oxa-5-azabicyclo[2.2.1]heptyl and pyrrolyl, each of which can be optionally substituted with 1-3 substitutes, independently chosen from a halogen, -CN, -CHO, -CF3, OCF3, -OH, -C1-C6alkyl, C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -NO2, -SO2(C1-C3alkyl), -SO2NH2, -SO2N(C1-C3alkyl)2, -COOH, -CH2-COOH, pyridyl, 2-methylazolyl, morpholino, 1-chloro-2-methylpropyl, phenyl, (optionally substituted with one or more halogens), benzyloxy, and , X2 selected from -O-, -CH2-, -S-, -SO-, -SO2-, -NH- and , R2 represents a ring group, chosen from a phenyl or thienyl group. Each ring group is substituted with a group with formula -(CH2)n4-CO2H; and besides that, the ring group can optionally be substituted with 1 or 2 extra substitutes, independently chosen from halogen, - C1-C6alkyl and -C1-C6alkoxy; R3 is chosen from H, halogen and -NO2; R4 is chosen from H, halogen and morpholino; or its salt form, used in pharmaceuticals. The invention also relates to pharmaceutical compositions, to methods of treatment, and to compounds with formula (A).

EFFECT: obtaining new biologically active compounds and pharmaceutical compositions based on them, which have inhibiting effect on cytosolic phospholipase A2.

45 cl, 300 ex

Amid derivative // 2336273

FIELD: chemistry.

SUBSTANCE: invention relates to amid derivatives of formula (I), method of disease treatment and pharmaceutical composition based on them. Compounds can be applied in treatment of different herpes virus infections. In general formula (I) , Z: 1,2,4-oxydiazol-3-yl, 4-oxazolyl, 1,2,3-triazol-2-yl or 2-pyridyl, A: phenyl, which can have a substitute (substitutes) selected from group, including lower alkyl, halogen, halogen-substituted lower alkyl, O-lower alkyl, O-lower alkylene -OH, CN, OH, O-lower alkylene-phenyl, O-lower alkylene-O-lower alkyl, NH2, NH-lower alkyl, N-(lower alkyl)2 ,NH-lower alkylene-OH, NH-lower alkylene-O-lower alkyl, O-lower alkylene- NH2, O-lower alkylene-NH-lower alkyl and O-lower alkylene-N(lower alkyl)2; heteroaryl, representing monocyclic 6-member ring, which contains nitrogen atom as heteroatom or bicyclic 9-member ring, containing 1-2 heteroatoms selected from nitrogen and/or sulfur, which can have a substitute (substitutes), selected from lower alkyl; or phenyl group, condensed with saturated 5-member hydrocarbon cycle; or phenyl group, condensed with saturated 5-member heterocyclic cycle, which contains 1-2 heteroatoms, selected from nitrogen and/or oxygen, which can have a substitute (substitutes), selected from group, including lower alkyl, halogen, -C(O)-lower alkyl, lower alkylene-O-lower alkyl, on condition, that aryl group, condensed with saturated hydrocarbon cycle or aryl group, condensed with saturated heterocyclic cycle is bound with nitrogen atom through carbon atom in aromatic cycle, X: CO, R3: C3-C6cycloalkyl, which can have a substitute (substitutes), selected from group, which includes oxo, OH, halogen, CN, O-lower alkyl, -C(O)-NH2, -C(O)-NH-lower alkyl, -C(O)-N(lower alkyl)2, lower alkylene-OH, lower alkylene-O-lower alkyl; aryl, selected from phenyl, naphtyl, which can have a substitute (substitutes), selected from halogen; pyridyl; 9-member bicyclic heteroaryl, containing 1-3 heteroatoms, selected from S, N, O; or saturated heterocyclic group, representing monocyclic 6-member group, which contains 1-2 heteroatoms selected from S, SO, SO2, N, O, which can have a substitute (substitutes), selected from halogen.

EFFECT: obtaining amid derivatives that can be applied for treating various herpes virus infections.

17 cl, 26 tbl, 125 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to a compound with general formula where R' stands for phenyl, unsubstituted or substituted with one or more substitutes, chosen from a group comprising alkyl, alkoxy group, halogen, -(CH2)oOH, -C(O)H, CF3, CN, S-alkyl, -S(O)1,2-alkyl, -C(O)NR'R", -NR'R"; R2 and R3 independently stand for hydrogen, halogen, alkyl, alkoxy group, OCHF2, OCH2F, OCF3 or CF3 and R4 and R5 independently stand for hydrogen, -(CH2)2SCH3, -(CH2)2S(O)2CH3, -(CH2)2S(O)2NHCH3, -(CH2)2NH2, -(CH2)2NHS(O)2CH3 or -(CH2)2NHC(O)CH3, R' stands for hydrogen, alkyl, -(CH2)oOH, -S(O)2- alkyl, -S(O)-alkyl, -S-alkyl; R" stands for hydrogen or alkyl; o stands for 0, 1, 2 or 3. The invention also relates to use of formula I compounds in making medicinal preparations for treating schizophrenia, for treating positive and negative symptoms of schizophrenia and medicine for treating schizophrenia.

EFFECT: obtaining new compounds with useful biological properties.

55 cl, 421 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention claims derivatives of pyridazin-3(2H)-one of formula (I), where R1, R2 and R4 are organic radicals described in the claim 1, R3 is cyclic group described in the claim, and R5 is phenyl or heteroaryl group described in the claim. Compounds of formula (I) inhibit phosphodiesterase 4 (PDE-4) and can be applied in treatment of various diseases or pathological states alleviated by PDE-4 inhibition, and in medicine production for treatment of aforesaid diseases. Also invention claims method of obtaining these compounds and intermediate compounds for their obtainment.

EFFECT: obtaining compounds which can be used in treatment of various diseases or pathological states and in medicine production for treatment of aforesaid diseases.

25 cl, 28 tbl, 243 ex

FIELD: chemistry.

SUBSTANCE: in general formula I

R1 is phenyl or 5-6-member heterocycle, containing one N atom and/or one O atom; R2 is imidazole or annelated imidazole, selected from group, including a), b), c), d) and e); and R3 stands for hydrogen, phenyl, 2,3-dihydrobenzo[1,4]dioxin-6-yl, benzo[b]thiophen-3-yl, 3-methylbenzo[b] thiophen-2-yl, thiophen-2-yl or thiophen-2-ylmethyl, R4 is hydrogen or lower alkyl, R5 is hydrogen, lower alkyl, halogen, morpholinyl, -NR'R", piperydinyl, optionally substituted with hydroxy-group, or is pyrrolidin-1-yl; R6 is hydrogen or -(CH2)nO-lower alkyl, R7 is hydrogen, -C(O)O-lower alkyl, -C(O)-C6H4-halogen, -C(O)-C6H4-lower alkyl, -C(O)-lower alkyl, -C(O)-cycloalkyl, -C(O)-NR'R", -C(O)-(CH2)nO-lower alkyl, -S(O)2-lower alkyl, -(CH2)nO-lower alkyl, -C(O)-pyridin-4-yl, whose ring can contain as substituents lower alkyl, halogen-lower alkyl or pyrrolidin-1-ylmethyl or is -(CH2)n-C(O)-NR'R"; R'/R" independently on each other stand for hydrogen, lower alkyl or -(CH2)n-tetrahydropyran-4-yl, X is -CH2-, -NR'''- or -O-; R''' is hydrogen, -C(O)-lower alkyl, -C(O)O-lower alkyl, -C(O)-C6H4CH3 or benzyl; n is 1 or 2.

EFFECT: increase of composition and treatment method efficiency.

14 cl, 56 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula II as neuropeptide FF receptor antagonist, their pharmaceutically acceptable acid-additive salts, medication based on them, as well as their application. Compounds can be applied for treatment and prevention of diseases mediated by activity of neuropeptide FF receptor, such as pain, hyperalgesia, enuresis, for elimination of syndromes arising in case of alcohol, psychotropic and nicotine addiction, for regulation of insulin release, digestion, memory functions, blood pressure or electrolytic and energy exchange. In general formula II , A together with thiazole ring forms 4,5,6,7-tetrahydrobenzothiazole, 5,6,7,8-tetrahydro-4H-cycloheptathiazole, 5,6-dihydro-4H-cyclopentathiazole fragments; R1 represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tret-butyl, 1,1-dimethylpropyl or phenyl; R2-R6 each represents hydrogen or methyl.

EFFECT: obtaining solutions, which ca be used for treatment and prevention of diseases, mediated by activity of neuropeptide FF receptor.

6 cl, 4 tbl, 106 ex

FIELD: chemistry, pharmaceuticals.

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

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

33 cl, 85 dwg, 101 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the bonds of the formula (I) and their pharmaceutically acceptable salts in the capacity of modulators of receptors CB1 and to the pharmacological composition on their basis. Bonds can be used for treatment and prophylaxis of diseases, which are associated with the modulation of receptor CB1, for example, obesity and diabetes of type II. In the general formula (I) R1 means hydrogen or the lowest alkyl; R2 means hydrogen, the lowest alkyl, the lowest alkenyl, the lowest alkoxy-lowest alkyl, the lowest alkoxycarbonilamino-group or - (CH2)m-R2a; or R1 and R2 form together with atom of nitrogen to which they are attached, a 5-or 6-member saturated heterocyclic ring; R2a means cycloalkyl, which is not necessarily mono- or tetra-substituted independently by hydroxy-group, the lowest alkyl; C3-6cycloalkenyl, 5- or 6-member monovalent saturated heterocyclic ring, which contains from one to two heteroatoms, independently selected from nitrogen and oxygen; 5- or 6-member monovalent heteroaromatic ring, which contains from one to two heteroatoms, independently selected from nitrogen and oxygen, here note that the said heteroaromatic ring is not necessarily mono-substituted independently with the lowest alkyl; or phenyl which is not necessarily mono- or di-substituted independently with the lowest of the alkoxy group, halogen, halogenated lowest alkyl, halogenated lowest alkoxy group or nitro-group; R3 means the lowest alkyl, the lowest alkoxy-lowest alkyl, diphenyl-lowest alkyl or - (CH2)n-R3a; R3a means C3-6cycloalkyl which can be not necessarily condensed with the phenol ring; or C3-6cycloalkyl, which can be not necessarily mono-, di- or trisubstituted independently hydroxy-group, the lowest alkyl, C3-6cycloalkenyl, 5- or 6-member monovalent saturated heterocyclic ring, which contains from one to two heteroatoms, independently selected from nitrogen and oxygen, here note that the said heterocyclic rings are not necessarily mono-substituted independently by the lowest alkyl, 5- or 6-member monovalent heteroaromatic ring containing one heteroatom, independently selected from oxygen and sulfur, the aforesaid heteroaromatic ring being not necessarily mono-substituted independently with the lowest alkyl, or the phenyl, which can be not necessarily mono-, di- or trisubstituted independently by the hydroxy-group, lowest alkyl, lowest alkoxy-group, halogen, halogenated lowest alkyl, halogenated lowest alkoxy-group or nitro-group; R4 means the lowest alkyl the lowest alkoxycarbonyl; C3-6 cycloalkyl, 5- or 6-member monovalent heteroaromatic ring, which contains one or two heteroatoms, independently selected from nitrogen, the said heteroaromatic ring being not necessarily mono-substituted independently with the lowest alkyl, lowest alkoxy-group; phenoxy-lowest alkyl, in which the phenyl part is not necessarily mono-, di- or trisubstituted independently by the lowest alkoxy-group; or the phenyl, which not necessarily can be mono-, di- or trisubstituted independently, by the lowest alkyl, by the lowest alkoxy-group, by halogen, halogenated lowest alkyl, halogenated lowest alkoxy-group or nitro-group; or two adjusted substitutes of the said phenyl remainder indicate together -O-(CH2)p-O- or -(CH2)2-O-; R5 and R6 each indicates a substitute independently selected from hydrogen of lowest alkyl; R7 indicates hydrogen; m indicates 0,1 or 2; n indicates 1.

EFFECT: new bonds possess useful biological properties.

28 cl, 4 dwg, 380 ex

FIELD: chemistry.

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

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

23 cl, 603 ex

FIELD: chemistry; oxa-and thiazole derivatives.

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

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

10 cl, 30 dwg, 12 tbl, 584 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes novel derivatives of 1,2,4-triazole of the general formula (I): wherein A and b can be taken separately or in common being when they are taken separately then A means (C1-C6)-alkyl or phenyl, and B means (C1-C6)-alkyl; A and B taken in common mean (C2-C5)-alkanediyl, and they form with C-atoms 3-6-membered cycle optionally substituted with (C1-C4)-alkylene, oxo, ethylenedioxy group, (C1-C4)-alkyl, 1-2 halogen atoms, (C1-C3)-alkoxy-(C1-C3)-alkoxy or hydroxy group; each R1 means independently hydrogen atom, -OH, halogen atom, (C3-C6)-cycloalkyl, (C1-C6)-alkyl optionally substituted with 1-3 halogen atoms; or two R1 groups near adjacent carbon atoms form 6-membered aryl cycle; R2 and R3 can be taken in common or separately, and when they are taken in common then they represent (C3-C8)-alkanediyl that forms condensed 5-10-membered nonaromatic cycle; when R2 and R3 are taken separately then R2 means (C1-C6)-alkyl possibly substituted with 1-3 halogen atoms or cyclopropyl, and R3 means cyclopropyl possibly substituted with (C1-C4)-alkyl, naphthyl, phenyl possibly substituted with halogen atom, -OH, (C1-C6)-alkyl wherein indicated (C1-C6)-alkyl is optionally substituted with 1-3 halogen atoms, -O-(C1-C6)-alkyl wherein indicated -O-(C1-C6)-alkyl is optionally substituted with 1-3 halogen atoms, phenyl or benzyloxy group, dihydrobenzofuranyl, benzothiadiazolyl or benzoimidazolyl possibly substituted with (C1-C6)-alkyl, their pharmaceutically acceptable salts or solvates, and pharmaceutical composition based on thereof. Proposed compounds are inhibitor of 11β-hydroxysteroid dehydrogenase I, and can be used in medicine in treatment of diabetes mellitus, obesity and dyslipidemia.

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

19 cl, 17 tbl, 4 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): and/or stereomer form of compound of the formula (I), and/or physiologically compatible salt of compound of the formula (I) wherein X and M are similar or different and mean independently of one another nitrogen atom (N) or -CH; R1 and R11 are similar or different and mean independently of one another: (1.) hydrogen atom; (2.) fluorine (F), chlorine (Cl), iodine (J) or bromine (Br) atom; R2 means: (1.) heteroaryl residue of group comprising 1,3,4-oxadiazole, oxadiazolylidinedione, oxadiazolone, thiazole, and heteroaryl residue is unsubstituted or 1-3-times substituted independently of one another: (1.1.) keto-group; (2) -C(O)-R5 wherein R5 means hydrogen atom or -(C1-C4)-alkyl, or (3.) -C(O)-N(R7)-R8 wherein R7 and R8 mean independently of one another hydrogen atom, -(C1-C4)-alkyl-OH, -O-(C1-C4)-alkyl or -(C1-C4)-alkyl; R3 means hydrogen atom or -(C1-C4)-alkyl; R4 means: (1.) heteroaryl residue of group comprising thiazole, isothiazole, pyridine, pyrazine, pyrimidine wherein heteroaryl residue is unsubstituted or 1-3-times substituted independently of one another with -(C1-C5)-alkyl, halogen atom, trifluoromethyl, or (2.) aryl residue of group comprising phenyl. Also, invention relates to a method for preparing a medicinal agent and to using compounds based on the formula (I) possessing activity with respect to IkB kinase. Invention provides synthesis of novel compounds possessing useful biological properties.

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

6 cl, 67 ex

FIELD: chemistry.

SUBSTANCE: this invention refers to new compounds of formula (Ia) and to their pharmaceutically acceptable salts. Compounds of this invention are characterised by CB1 receptor antagonist properties. In formula (Ia) , R1 means phenyl independently mono-, di- or tri-substituted with haloid, (lower)alkoxy, (lower)alkyl, halogenated (lower)alkoxy or di(lower)alkylamino; R2 means phenyl, independently mono-, di- or tri-substituted with haloid, halogenated (lower)alkyl, nitro or cyano; R3 means hydrogen, nitro, amino, -NHSO2-R3a or -NHCO-R3b; R3a means (lower)alkyl, di(lower)alkylamino, benzyl, phenyl or phenyl monosubstituted with (lower)alkyl; R3b means benzyl or phenyl monosubstituted with (lower)alkyl.

EFFECT: application of compounds thereof as therapeutically active substance with CB1 receptor agonist properties and to relevant pharmaceutical composition.

18 cl, 1 dwg, 5 tbl, 70 ex

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