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

FIELD: chemistry.

SUBSTANCE: invention concerns benzothiazole derivatives of general formula (I) and their pharmaceutically acceptable salts as adenosine receptor ligands and based medicinal product. 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 the general formula (I) , R1 is C5-C6-cycloalkyl substituted by CF3 group, lower alkyl, -(CH2)nOH or -(CH2)n-O- lower alkyl, or is 1-bicyclo[2,2,1]hept-2-yl, 1-(7-oxa-bicyclo[2,2,1]hept-2-yl, 1-(5-exo-hydroxybicyclo[2,2,1]hept-2-exo-yl, 1-(5-exo-hydroxybicyclo[2,2,1]hepto-2-endo-yl, or is 1-adamantane-1-yl; R2 is lower alkyl; or R1 and R2 together with N atom form 8-oxa-3-aza-bicyclo[3,2,1]octane group, n is 0 or 1.

EFFECT: improved efficiency of treatment.

9 cl, 2 dwg, 15 ex

 

The present invention relates to compounds of General formula

in which

R1represents a C5-C6-cycloalkyl substituted by a group of CF3, lower alkyl, -(CH2)nHE or -(CH2)n-O-lower alkyl, or represents

1-bicyclo[2,2,1 ]hept-2-yl,

1-(7-oxa-bicyclo[2,2,1]hept-2-yl,

1-(5-Exo-hydroxybutyl[2,2,1]hept-2-Exo-yl,

1-(5-Exo-hydroxybutyl[2,2,1]hept-2-endo-yl

or represents a 1-adamantane-1-yl;

R2represents a lower alkyl or

R1and R2together with the N atom form a group of 8-oxa-3-Aza-bicyclo[3,2,1]octane;

n means 0 or 1;

and their pharmaceutically acceptable acid additive salts.

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 high selectivity to And1and 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 drug media is TV, was first performed in 1982. Adenosine is related structurally and metabolically with biologically active nucleotide-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-And2A-And2Band And3receptors 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. And1and And3receptors associated with Gi-proteins that inhibit adenylate cyclase, which leads to decrease in the content of camp in the cells, while A2Aand And2Breceptors coupled with Gs-proteins and activate adenylate cyclase, which leads to higher the s content of camp in the cells. It is known that the system And1-receptor involves activation of phospholipase C and the modulation as potassium and calcium ion channels. Subtype And3in addition to the Association with adenylate cyclase, stimulates phospholipase C and thus activates calcium ion channels.

Cloned And1-receptor (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 And2A-receptor (409-412 amino acids) family dog, rat, human, Guinea pigs and mice. Cloned And2B-receptor (332 amino acids) of human and mouse, while there has been a 45%gomologichnosti sequence of the receptor And2Bperson in relation to a1and And2Areceptors person. Cloned And3-receptor (317-320 amino acids) of human, rat, dog, rabbit and sheep.

It is assumed that the receptor subtypes And1and 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 what olorado (A 2Aand so maintaining a balance between energy supply and consumption in the tissues. The action of both subtypes is to increase the number of tissues of 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 increases antigennegative the 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, is hypoglycemia and/or excessive neuronal activity), adenosine provides an effective protective feedback mechanism. Interaction with adenosine receptors is a promising therapeutic 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 effectively the positive 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 and neurodegenerative diseases, for example, when the cerebral circulation. Antagonists of adenosine A2A-modulate receptor 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, respiration, 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 has an important function is 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 injury (stabilization). Through the influence And1-receptor agonists adenosine A1-can protect against damage caused by myocardial ischemia and reperfusion. Modulation effects And2Areceptors 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 reaction, for example, in acute myocardial infarction. Selective antagonists against And2Areceptors 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 And2Bcan be useful in the treatment of asthma and other allergic R. the shares or in the treatment of diabetes and obesity.

The current status of research in the field of adenosine receptors reflects many 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 in asthma, allergic responses, hypoxia, is samii, seizures and abuse of alcohol or drugs.

In addition, the compounds according to the present invention 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 A2A-receptor 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).

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

The term "pharmaceutically acceptable acid additive salts" includes salts with neo is organic 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 preferred compounds are such compounds where R1represents a C5-C6-cycloalkyl substituted by a group of CF3, lower alkyl, -(CH2)nHE or -(CH2)n-O-lower alkyl, for example, the following connections:

3-(4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)-1-methyl-1-(4-tripterocalyx)urea,

(TRANS)-3-(4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)-1-methyl-1-(4-methylcyclohexyl)urea,

(TRANS)-1-(4-hydroxymethylcellulose)-3-(4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)-1-metalmachine,

(TRANS)-1-(4-methoxymethylethoxy)-3-(4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)-1-metalmachine or

(rat),(CIS)-1-(3-hydroxymethylglutaryl)-3-(4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)-1-metalmachine.

Also preferred are such compounds where R1is a 1-bicyclo[2,2,1]hept-2-yl, 1-(7-oxa-bicyclo[2,2,1]hept-2-yl, 1-(5-Exo-hydroxybutyl[2,2,1]hept-2-Exo-yl, 1-(5-Exo-hydroxybutyl[2,2,1]hept-2-endo-yl or 1-adamantane-1-yl, for example, after the respective connection:

1-(endo)-(rat)-bicyclo[2,2,1]hept-2-yl-3-(4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)-1-metalmachine,

(Exo)-(+)-3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-1-(7-oxa-bicyclo[2,2,1]hept-2-yl)urea,

(Exo)-(-)-3-(4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)-1-methyl-1-(7-oxa-bicyclo[2,2,1]hept-2-yl)urea,

(rat)(endo)-3-(4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)-1-methyl-1-(7-oxa-bicyclo[2,2,1]hept-2-yl)urea,

(rat)-1-(5-Exo-hydroxybutyl[2,2,1]hept-2-Exo-yl)-3-(4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)-1-metalmachine,

(rat)-1-(5-Exo-hydroxybutyl[2,2,1]hept-2-endo-yl)-3-(4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)-1-metalmachine or

1-adamantane-1-yl-3-(4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)-1-metalmachine.

Examples of compounds in which R1and R2together with the N atom form a group of 8-oxa-3-Aza-bicyclo [3,2,1] octane, is the connection (4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)amide 8-oxa-3-azabicyclo[3,2,1]octane-3-carboxylic acid.

The compounds of formula I according to the present invention and their pharmaceutically acceptable salts can be obtained in accordance with methods well known from the prior art, for example, using 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

where R1and R2have the meanings given above, or

b) interaction of the compounds of formula

with the compound of the formula

obtaining the compounds of formula

where R1and R2are as defined above, L is a leaving group such as halogen, -O-phenyl or O-lower alkyl, and,

if necessary, the conversion of 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 substances, which are known compounds, can be obtained in accordance with methods known from the prior art.

Obtaining compounds of formula I

Intermediate compound 7-(morpholine-4-yl)-4-methoxybenzothiazole-2-ylamine (II) can be obtained in accordance with the techniques 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.

One way of preparing compounds of formula (I) implementing tlaut according to scheme 1 as follows: to a solution of the compounds of formula (II) in dichloromethane sequentially add the base, for example, such as pyridine or diisopropylethylamine, and the compound of formula (III), then the resulting solution is stirred for about 45 min at ambient temperature. Add saturated aqueous sodium bicarbonate solution, the organic phase is separated and dried.

Scheme 1

R1and R2are as described above.

Another method of preparing compounds of formula (I) as follows: to the solution of the derivative compounds of formula (IV), which can be obtained in accordance with methods well known from the prior art and which are described in published international application WO 01/97786, in an inert solvent such as dichloromethane, successively added base, such as pyridine or diisopropylethylamine, and the compound of formula (V), then the resulting solution is stirred for approximately 45 minutes at 45°C. After cooling to ambient temperature, add saturated aqueous the sodium bicarbonate solution, the organic phase is separated and dried.

Scheme 2

R1and R2are as described above, L is a leaving group such as halogen, -O-phenyl or-O-lower alkyl.

Vyd the separation and purification of compounds

Isolation and purification of the compounds and intermediates 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 techniques. 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, e.g. the measures such as chloromethane acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and similar acids, such as organic acid, e.g. 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 of 0°C 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, b is sodium carbonate, ammonia, and the like of the base.

The compounds of 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 - continuin the (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. The tablets, which conduct research, incubated for 1 hour at room temperature before centrifugation, and then the 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 from 7.3 to 8.5, as shown in the table below.

Example No.hA2(pKi)Example No.hA2(pKi)
17,788,0
27,897,9
37,8108,1
47,7118,1
58,4127,3
68,1138,0
78,5

Connect the Oia formula I and pharmaceutical salts of the compounds of formula I can be used as medicines, for example, in the form of pharmaceutical preparations. 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 carriers for suppositories, not only is jut a, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like compounds.

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 retrieval method, 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 the compounds of formula I and their pharmaceutically acceptable salts can be used to control or prevent diseases associated with agonistic activity against adenosine receptor, such as illness, Alzhei the EPA, 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, for example, such evidence as the treatment or prevention of certain depressive disorders or disorders, neuroprotective effect 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 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 dosage may be entered as a single dose or divided the Oh at several doses and, in addition to this, you 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
1.The compound of the formula I525100500
2.Anhydrous lactose DTG12510530150
3.Sta-Rx 150066630
4.Microcrystalline cellulose303030150
5.Magnesium stearate1111
The total number of167167167831

Method get

1. Mixed connection positions 1, 2, 3 and 4 and carry out granulation, using purified water.

2. Dry the granules at 50°C.

3. Pass the granules through approach is a General 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
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 connection positions 1, 2 and 3 in a suitable mixer for 30 minutes.

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

3. Placed in a suitable capsule.

the listed below preparative examples and examples serve only to illustrate the invention and, assumed not to limit the scope of the present invention.

Example 1

3-(4-Methoxy-7-morpholine-4-yl-benzothiazol-2-yl)-1-methyl-

1-(4-tripterocalyx)urea

4-Methoxy-7-morpholine-4-yl-benzothiazol-2-ylamine first subjected to interaction with phenylcarbamates thus, as described in relation to the benzyl ether (4-methoxy-7-phenyl-benzothiazol-2-yl)carbamino acid in published international application WO 01/97786 and then with methyl-(4-tripterocalyx)amine. After the usual allocation Express chromatography (silica gel, eluent a mixture of dichloromethane/methanol) and a final evaporation of the solvent receive specified in the title compound as white crystals (yield 96%), TPL 157-167°C. Mass spectrum: m/e=473(M+H+).

In accordance with the General procedure described in example 1, to obtain compounds according to examples 2 to 12.

Example 2

(TRANS)-3-(4-Methoxy-7-morpholine-4-yl-benzothiazol-2-yl)-1-methyl-1-(4-methylcyclohexyl)urea

Using 4-methoxy-7-morpholine-4-yl-benzothiazol-2-ylamine, phenylchloropyruvate and (TRANS)-methyl-(4-methylcyclohexyl)amine indicated in the title compound obtained as off-white crystals (yield 70%), TPL 171-173°C. Mass spectrum: m/e=420(M+H+).

Example 3

(TRANS)-1-(4-Hydroxymethylcellulose)-3-(4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)-1-methyl who Icewine

Using 4-methoxy-7-morpholine-4-yl-benzothiazol-2-ylamine, phenylcarbamate and (TRANS)-(4-hydroxymethylcellulose)methylamine specified in the title compound obtained as light brown crystals (yield 42%). Mass spectrum: m/e=436(M+H+), TPL 190°C (With decomp.).

Example 4

(TRANS)-1-(4-Methoxymethylethoxy)-3-(4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)-1-metalmachine

Using 4-methoxy-7-morpholine-4-yl-benzothiazol-2-ylamine, phenylcarbamate and (TRANS)-(4-methoxymethylethoxy)methylamine specified in the title compound obtained as white solids (yield 73%), TPL 141-143°C. Mass spectrum: m/e=450(M+H+).

Example 5

(rat),(CIS)-1-(3-Hydroxymethylglutaryl)-3-(4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)-1-metalmachine

Using 4-methoxy-7-morpholine-4-yl-benzothiazol-2-ylamine, phenylcarbamate and (rat)-(CIS)-(3-methylaminomethyl)methanol specified in the title compound obtained as a light yellow solid (yield 58%), TPL 115-118°C. Mass spectrum: m/e=421(M+N+).

Example 6

1-(endo)-(rat)-Bicyclo[2,2,1]hept-2-yl-3-(4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)-1-metalmachine

Using 4-methoxy-7-morpholine-4-yl-benzothiazol-2-ylamine, phenyl chloroformate and (endo)-(rat)-(bicyclo[2,2,1]hept-2-yl)methylamine specified in the title compound obtained as white solids (Ihad 65%), TPL 199-202°C. Mass spectrum: m/e=417(M+H+).

Example 7

(Exo)-(+)-3-(4-Methoxy-7-morpholine-4-yl-benzothiazol-2-yl)-1-methyl-1-(7-oxa-bicyclo[2,2,1]hept-2-yl)urea

Using 4-methoxy-7-morpholine-4-yl-benzothiazol-2-ylamine, phenylcarbamate and (-)-(Exo)methyl-(7-oxabicyclo[2,2,1]hept-2-yl)amine indicated in the title compound obtained as light yellow crystals (yield 82%), TPL 202-204°C. Mass spectrum: m/e=419(M+H+).

Example 8

(Exo)-(-)-3-(4-Methoxy-7-morpholine-4-yl-benzothiazol-2-yl)-1-methyl-1-(7-oxa-bicyclo[2,2,1]hept-2-yl)urea

Using 4-methoxy-7-morpholine-4-yl-benzothiazol-2-ylamine, phenylchloropyruvate and (+)-(Exo)methyl-(7-oxabicyclo[2,2,1]hept-2-yl)amine indicated in the title compound obtained as light yellow crystals (yield 82%), TPL 202-203°C. Mass spectrum: m/e=419(M+H+).

Example 9

(rat)-(endo)-3-(4-Methoxy-7-morpholine-4-yl-benzothiazol-2-yl)-1-methyl-1-(7-oxa-bicyclo[2,2,1]hept-2-yl)urea

Using 4-methoxy-7-morpholine-4-yl-benzothiazol-2-ylamine, phenylcarbamate and (rat)-(endo)methyl-(7-oxabicyclo[2,2,1]hept-2-yl)amine indicated in the title compound obtained as white crystals (yield 47%), TPL 191-193°C. Mass spectrum: m/e=419(M+H+).

Example 10

(rat)-1-(5-Exo-Hydroxy-bicyclo[2,2,1]hept-2-Exo-yl)-3-(4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)-1-metalmachine

Using 4-methoxy-7-morpholine-4-yl-benzothiazol--ylamine, phenylcarbamate and 5-(Exo)methylamino-bicyclo[2,2,1]heptane-2-(Exo)-ol, specified in the title compound obtained as white crystals (yield 10%). Mass spectrum: m/e=433(M+N+), TPL 189°C.

Example 11

(rat)-1-(5-Exo-Hydroxybutyl[2,2,1]hept-2-endo-yl)-3-(4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)-1-metalmachine

Using 4-methoxy-7-morpholine-4-yl-benzothiazol-2-ylamine, phenylcarbamate and 5-(endo)methylaminomethyl[2,2,1]heptane-2-(Exo)-ol, specified in the title compound obtained as white crystals (yield 12%). Mass spectrum: m/e=433(M+N+), TPL 189°C.

Example 12

1-Adamantane-1-yl-3-(4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)-1-metalmachine

Using 4-methoxy-7-morpholine-4-yl-benzothiazol-2-ylamine, phenyl chloroformate and adamantane-1-yl-methylamine specified in the title compound obtained as white crystals (yield 76%), TPL 165-176°C. Mass spectrum: m/e=458(M+H+).

Example 13

8-oxa-3-Aza-bicyclo[3,2,1]octane-3-carboxylic acid (4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)amide

Using 4-methoxy-7-morpholine-4-yl-benzothiazol-2-ylamine, phenyl chloroformate and 8-oxa-3-Aza-bicyclo[3,2,1]octane specified in the title compound obtained as white crystals (yield 67%), TPL 229-231°C. Mass spectrum: m/e=405(M+N+).

The intermediate connection:

Example 14

Methyl-(4-tripterocalyx)Amin

Specified in the title compound is obtained from triftormetilfullerenov (patent DE 2630562) through the introduction of ethoxycarbonyl group under standard conditions (ethylchloride/diisopropylethylamine) and final restoration with the use of lithium aluminum hydride in tetrahydrofuran under standard conditions, while receiving specified in the title compound as a pale yellow oily substance. Mass spectrum: m/e=168(M+N+). Specified in the title compound can be obtained in the form of its crystalline hydrochloride when using ethanol solution of hydrogen chloride. White crystals, TPL 202-204°C.

Example 16

1-Methyl-4-(CIS)methylamino cyclohexanol

Specified in the title compound can be obtained from (CIS)-4-amino-1-methylcyclohexanol (WO 9607657) in accordance with the same method as described in relation to methyl-(4-tripterocalyx)amine. White crystals, TPL 123-124°mass spectrum: m/e=144(M+N+).

Example 15

(-)-(Exo)-Methyl-(7-oxabicyclo[2,2,1]hept-2-yl)aminogidrohlorid

Specified in the title compound is obtained from (rat)-(Exo)methyl-(7-oxa-bicyclo[2,2,1]hept-2-yl)amine (J.Med.Chem. 1971, 14, 698) by benzylidene under standard conditions (benzylbromide/aminobutiramida-Etalon is n) followed by chiral separation by preparative chiral GHUR (liquid chromatography high-resolution ("Chiralpak AD", eluent of 2% isopropanol in heptane) and the final removal of the protective group under standard conditions (chloroethylphosphonic/methanol), while receiving specified in the title compound as a white solid. [α]D=is 6.2 (C=0,23, dichloromethane).

The enantiomer (+)-(Exo)methyl-(7-oxa-bicyclo[2,2,1]hept-2-yl)amine hydrochloride obtained from previously buervenich fractions of the separation process.

1. Compounds of General formula

in which

R1represents a C5-C6-cycloalkyl substituted by a group of CF3, lower alkyl, -(CH2)nHE or -(CH2)n-O-lower alkyl, or means of 1-bicyclo[2,2,1]hept-2-yl, 1-(7-oxa-bicyclo[2,2,1]hept-2-yl, 1-(5-Exo-hydroxybutyl[2,2,1]hept-2-Exo-yl, 1-(5-acao-hydroxybutyl[2,2,1]hept-2-endo-yl, or means 1-adamantane-1-yl;

R2represents lower alkyl; or

R1and R2together with the N atom form a group of 8-oxa-3-Aza-bicyclo [3,2,1] octane,

n means 0 or 1;

and pharmaceutically acceptable salts of these compounds.

2. The compounds of formula I according to claim 1, where R1represents a C5-C6cycloalkyl substituted by a group of CF3, lower alkyl, -(CH2)nHE or -(CH2)nO-lower alkyl.

3. The compounds of formula I according to claim 2, the cat is who represent the following compounds:

3-(4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)-1-methyl-1-(4-tripterocalyx)urea,

(TRANS)-3-(4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)-1-methyl-1-(4-methylcyclohexyl)urea,

(TRANS)-1-(4-hydroxymethylcellulose)-3-(4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)-1-metalmachine,

(TRANS)-1-(4-methoxymethylethoxy)-3-(4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)-1-metalmachine or

(rat),(CIS)-1-(3-hydroxymethylglutaryl)-3-(4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)-1-metalmachine.

4. The compounds of formula I according to claim 1, where R1represents a

1-bicyclo[2,2,1]hept-2-yl,

1-(7-oxa-bicyclo[2,2,1]hept-2-yl,

1-(5-Exo-hydroxybutyl[2,2,1]hept-2-Exo-yl),

1-(5-Exo-hydroxybutyl[2,2,1]hept-2-endo-yl) or 1-adamantane-1-yl.

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

1-(endo)-(rat)-bicyclo[2,2,1]hept-2-yl-3-(4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)-1-metalmachine,

(Exo)-(+)-3(4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)-1-methyl-1-(7-oxabicyclo[2,2,1]hept-2-yl)urea,

(Exo)-(-)-3-(4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)-1-methyl-1-(7-oxa-bicyclo[2,2,1]hept-2-yl)urea,

(rat)-(endo)-3-(4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)-1-methyl-1-(7-oxa-bicyclo[2,2,1]hept-2-yl)urea,

(rat)-1-(5-Exo-hydroxybutyl,2,1]hept-2-Exo-yl)-3-(4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)-1-metalmachine,

(rat)-1-(5-Exo-hydroxybutyl[2,2,1]hept-2-endo-yl)-3-(4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)-1-metalmachine or

1-adamantane-1-yl-3-(4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)-1-metalmachine.

6. The compounds of formula I according to claim 1, where R1and R2together with the N atom form a group of 8-oxa-3-azabicyclo[3,2,1]octane.

7. The compounds of formula I according to claim 6, where the compound is a (4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)amide 8-oxa-3-Aza-bicyclo[3,2,1]octane-3-carboxylic acid.

8. Drug, possessing properties of ligand adenosine receptor And2Acontaining one or more compound according to any one of claims 1 to 7 and a pharmaceutically acceptable fillers.

9. The drug of claim 8 for the treatment of diseases associated with adenosine receptor And2A.



 

Same patents:

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

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: 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

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

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: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an improved method for synthesis of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole. Method involves the following successive steps: (i) interaction of bromine with 4-acetamidocyclohexanone an aqueous solution to yield 2-bromo-4-acetamidocyclohexanone; (ii) addition of thiourea to yield 6-acetylamino-2-amino-4,5,6,7-tetrahydrobenzothiazole; (iii) addition of hydrobromic acid an aqueous solution to yield 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole without isolation of 6-acetylamino-2-amino-4,5,6,7-tetrahydrobenzothiazole synthesized at stage (ii); (iv) isolation of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole and if necessary separation of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole isolated at stage (iv) for R-(+)- and S-(-)-enantiomers, and isolation of R-(+)- and/or S-(-)-enantiomer. 2,6-Diamino-4,5,6,7-tetrahydrobenzothiazole is used for synthesis of pramipexole. Also, invention relates to a method for synthesis of pramipexole by synthesis of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole by using the method said and its conversion to pramipexole and if necessary by separation of pramipexole for its R-(+)- and S-(-)-enantiomers and isolation of R-(+)- and/or S-(-)-enantiomer.

EFFECT: improved method of synthesis.

15 cl, 1 sch, 3 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compounds that possess affinity for adenosine A2A-receptors and represent compounds of the general formula: wherein R1 and R2 represent independently hydrogen atom, lower alkyl, tetrahydropyrane-2,3- or 4-yl, -(CH2)n-O-lower alkyl, -C(O)-lower alkyl, -(CH2)n-C(O)-lower alkyl, -(CH2)n-C(O)-NR'R'', -(CH2)n-phenyl substituted optionally with lower alkyl, lower alkoxy-group or -(CH2)n-pyridinyl, -(CH2)n-tetrahydropyrane-2,3- or 4-yl, -C(O)-piperidine-1-yl; or R1 and R2 in common with nitrogen atom (N) to which they are added form the ring 2-oxa-5-azabicyclo[2,2,1]hept-5-yl; R3 represents lower alkoxy-group, phenyl substituted optionally with halogen atom, -(CH2)n-halogen or -(CH2)n-N(R')-(CH2)n+1-O-lower alkyl, or represents pyridinyl substituted optionally with lower alkyl, halogen atom or morpholinyl; n means 1 or 2; R'/R'' represent independently of one another hydrogen atom or lower alkyl, and their pharmaceutically acceptable acid-additive salt. Except for, invention relates to a medicinal agent showing affinity to adenosine A2A-receptors containing one or some compounds by any claims 1-11, and pharmaceutically acceptable excipients.

EFFECT: valuable medicinal properties of compounds and agents.

13 cl, 38 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing a substituted alkylamine derivative from the 2-aminothiophenol compound with high industrial yield that can be used as an intermediate compound used in medicine or in agriculture. Invention proposes a method for preparing substituted alkylamine derivative represented by the following general formula (3): wherein X mean halogen atom, alkyl group, alkoxy-group, cyano-group or nitro-group; n means a whole number from 1 to 4; each R1 and R2 means independently hydrogen atom of phenyl-substituted, or unsubstituted alkyl group that can in common form 5- or 6-membered cycle, or its additive acid salt. Method involves addition of 2-aminothiophenol derivative salt represented by the following formula (1): wherein X and n have abovementioned values to acid to provide pH value 6 or less and to convert salt to free 2-aminothiophenol derivative of the general formula (1) followed by addition of 2-aminothiophenol derivative with amino-N-carboxyanhydride to the reaction represented by the following general formula (2): wherein each R1 and R2 have abovementioned values. Invention provides the development of a method for unimpeded preparing 1-(2-benzothiazolyl)-alkylamine derivative, i. e. substituted alkylamine derivative from the 2-aminothiophenol derivative with the satisfactory industrial yield and without pollution of the environment.

EFFECT: improved preparing method, valuable properties of compound.

8 cl, 13 ex

FIELD: medicine, organic chemistry.

SUBSTANCE: the present innovation deals with new benzothiazole derivatives and medicinal preparation containing these derivatives for treating diseases mediated by adenosine receptor A2.A.. The present innovation provides efficient treatment of the above-mentioned diseases.

EFFECT: higher efficiency of therapy.

14 cl, 354 ex

The invention relates to new derivatives of benzothiazole General formula (I) or its salt, where p denotes 1; X1and X2together form =O; R1denotes hydrogen, halogen, alkyl, alkoxy; R2denotes hydrogen; R3denotes a-Z4-R6, -Z13-NR7R8; Z4denotes a-Z11-C(O)-Z12-, -Z11-C(O)-O-Z12-; Z11and Z12represent a simple bond or alkylene; Z13denotes a-Z11-C(O)-Z12-; R4denotes hydrogen; R5denotes phenyl, substituted groups Z1, Z2selected from alkyl, halogen, nitro, -HE, hydroxyalkyl, -C(O)Z6, -C(O)OZ6-Z4-NZ7Z8where Z4represents a simple bond; biphenyl, substituted alkyl; naphthalenyl, which optionally can be substituted-HE; chinoline, substituted alkyl; heterocyclics; Z6denotes alkyl which may be optionally substituted by a group-Z4-NZ7Z8, morpholinium; Z7, Z8each independently represents alkyl; R6denotes alkyl optionally substituted by cyano, methoxy, phenyl, -Z4-NZ7Z8and so on; R7denotes hydrogen, alkyl; R8denotes alkyl, the long is Z4-NZ7Z8; and t

The invention relates to the production of derivatives of 3-amino-2-mercaptobenzoic acid of the formula I, in which X represents fluorine, n = 0 or 1, Z represents CO-a or CS-A1A represents hydrogen, halogen, OR1or SR2, A1denotes hydrogen or or1, R1and R2denote hydrogen, substituted or unsubstituted, saturated or unsaturated hydrocarbon radical with an open chain, containing not more than 8 carbon atoms; the interaction of the compounds of formula II in which T represents hydrogen, C1-C6alkyl, C3-C6alkenyl,3-C6quinil,3-C6cycloalkyl or substituted or unsubstituted phenyl, benzyl or phenethyl; with aqueous strong base

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

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