Benzothiazol derivatives as adenosine receptor ligands

FIELD: chemistry.

SUBSTANCE: invention refers to benzothiazol derivatives of general formula (I) and to their pharmaceutically acceptable acid-additive salts as adenosine receptor ligands and to based medicinal agent. In general formula (I) , R1 represents 1,4-dioxepanyl or tetrahydropyran-4-yl; R2 represents -N(R)-(CH2)n-5- or 6-merous nonaromatic heterocycle containing 1-2 nitrogen heteroatoms optionally substituted with one-two substitutes chosen from group, consisting of C1-C6alkyl or -NR2, or represents -(CH2)n-5- or 6-merous nonaromatic heterocycle containing 1-2 heteroatoms chosen of N, S or O, optionally substituted with group -(CH2)n-OH, C1-C6alkyl, C1-C6alkoxy, or represents -(CH2)n-5-or 6-merous aromatic heterocycle containing 1-2 nitrogen heteroatoms optionally substituted with the following group: C1-C6alkyl, C1-C6alkoxy, halogen, halogen-(C1-C6alkyl), -CH2N(R)(CH2)2OCH3, -N(R)(CH2)2OCH3, - CH2-morpholinyl or -CH2-pyrrolidinyl or represents (CH2)n-C3-C6cycloalkyl optionally substituted with group hydroxy, or represents -N(R)-C3-C6cycloalkyl optionally substituted with group hydroxy or C1-C6alkyl, or represents phenyl optionally substituted with group C1-C6alkoxy, halogen, halogen-(C1-C6alkyl), C1-C6alkyl, -CH2-pyrrolidine-1-yl, CH2N(R)(CH2)2OCH3 or -CH2-N(R)C(O)-(C1-C6alkyl), or represents 1,4-dioxa-8-azaspiro[4,5]decane, or 2-oxa-5-azabicyclo[2,2,1]heptane, or 1-oxa-8-azaspiro[4,5]decane, or -N(R)-7-oxabicyclo[2,2,1]hept-2-yl, or 2-azabicyclo[2,2,2]octane; R represents hydrogen or C1-C6alkyl; n stands for 0 or 1.

EFFECT: compounds can be applied for treatment and prevention of diseases mediated by adenosine A2A and A1 receptors, eg Alzheimer's disease, some depressions, toxicomania, Parkinson's disease.

8 cl, 3 dwg, 61 ex

 

The present invention relates to compounds of General formula

where R1represents 1,4-dioxetanes or tetrahydropyran-4-yl;

R2represents-N(R)-(CH2)n-5-or 6-membered nonaromatic a heterocycle, optionally substituted by one or more substituents selected from the group consisting of lower alkyl, or-NR2or

represents -(CH2)n-5 - or 6-membered nonaromatic a heterocycle, optionally substituted by a group -(CH2)nHE, lower alkyl, lower alkoxy, or

represents -(CH2)n-5-or 6-membered aromatic heterocycle, optionally substituted by a group of lower alkyl, lower alkoxy, halogen, halogen-lower alkyl), -CH2N(R)(CH2)2OCH3, -N(R)(CH2)2OCH3, -CH2-morpholinyl or-CH2-pyrrolidinyl or

represents (CH2)n-cycloalkyl, optionally substituted by hydroxy group, or

represents-N(R)-cycloalkyl, optionally substituted by hydroxy group or a group of lower alkyl, or

represents phenyl, optionally substituted by a group of lower alkoxy, halogen, halogen-(lower alkyl), lower alkyl, -CH2-pyrrolidin-1-yl, -CH2-morpholinyl, -CH2N(R)(CH2)2OCH3 or-CH2-N(R)C(O)-(lower alkyl), or

means 1,4-dioxa-8 azaspiro[4,5]decane, or

mean 2-oxa-5-azabicyclo[2,2,1]heptane, or

mean 1-oxa-8-azaspiro[4,5]decane, or

means-N(R)-7-oxabicyclo[2,2,1]hept-2-yl, or

mean 2-azabicyclo[2,2,2]octane;

R represents hydrogen or lower alkyl;

n means 0 or 1; and

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 Aiand 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-triphosphate (ATP), adenosine diphosphate (ADP), a monophosphate (AMP) and cyclic monophosphate (camp); with biochemical mahilyowskaya 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 channels. Subtype And3in addition to the Association with adenylate cyclase, stimulates phospholipase C and thus activates calcium ion CA is Aly.

Cloned A1receptor (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 A2Breceptor (332 amino acids) of human and mouse, while there has been a 45%gomologichnosti sequence of the receptor And2Bperson in relation to A1and a2Freceptors 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 is to increase the number of tissues of oxygen and in the protection of cells from damage caused by short-term imbalances in the post is tion 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, receptor-a3plays 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 effects in the case of a variety of neurological and psychiatric C the problems 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 A1simulating 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 A2aantagonists have therapeutic potential in the treatment of various forms of dementia, such as Alzheimer's disease, and not rodegenerative 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 providing 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 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 injury (stabilization). Pose the ETS impact on A 1receptor agonists adenosine A1can provide protection from 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 reactions or in the treatment of diabetes and obesity.

The current status of research in the field of adenosine receptors reflects many published documents, n is the sample 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 are the 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 modulation of 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, ischaemia, seizure and substance abuse. In addition, the compounds according to the present invention can be useful as CE is exploring means, 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).

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. A preferred group of the lower alkyl represents a group containing 1-4 carbon atoms.

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

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

The term "cycloalkyl" means a saturated carbocyclic group containing 3-7 carbon atoms.

The term "5-or 6-membered nonaromatic a heterocycle" means a ring system such as morpholine, piperazine, piperidine, tetrahydropyran or tetrahydrofuran.

The term "5-or 6-membered aromatic heterocycle" means a ring system, such as thiophene, imidazole, pyrazole, or pyridine.

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 are those compounds of formula I, where R1represents 1,4-dioxan-6-yl, and R2is such as described above, for example, the following connections:

(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide morpholine-4-carboxylic acid,

(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide piperidine-1-carboxylic acid,

1-cyclohexyl-3-(7-[1,4]dioxan-6-yl-4-IU is oxybisethanol-2-yl)-1-metalmachine,

(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide of 4-hydroxymethyl-piperidine-1-carboxylic acid,

3-(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)-1-methyl-1-(1-methyl-piperidine-4-yl)urea,

(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide 1,4-dioxa-8-Aza-Spiro[4,5]decane-8-carboxylic acid,

(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide of 4-hydroxypiperidine-1-carboxylic acid,

(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide 5-methylthiophene-2-carboxylic acid,

N-(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)-4-methoxybenzamide,

N-(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)-4-perbenzoic,

(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide cyclohexanecarbonyl acid,

N-(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)-2-(tetrahydropyran-4-yl)acetamide", she

(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide(R)-tetrahydrofuran-2-carboxylic acid,

(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide 3-methyl-3H-imidazole-4-carboxylic acid,

N-(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)isonicotinamide,

N-(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)-2-methoxy-isonicotinamide,

TRANS-1-(4-hydroxycyclohexyl)-3-(4-methoxy-7-[1,4]dioxan-6-yl-benzothiazol-2-yl)-1-metalmachine,

(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide and(1S,4S)-oxa-5-azabicyclo[2,2,1]heptane-5-carboxylic acid,

(7-[,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide of 4-methoxypiperidine-1-carboxylic acid,

4-chloromethyl-N-(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)-benzamid,

(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide 1-methyl-1H-pyrazole-4-carboxylic acid,

N-(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)-4-[(methyl-propionyl amino)methyl]benzamide or

N-(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)-2-pyrrolidin-1-yl-isonicotinamide.

In addition, preferred compounds according to the present invention are those compounds of formula I, where R1represents tetrahydropyran-4-yl, and R2is such as described above, for example, the following connections:

3-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea,

TRANS-1-(4-hydroxycyclohexyl)-3-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]-1-metalmachine,

CIS-1-(4-hydroxycyclohexyl)-3-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]-1-metalmachine,

1-(4-CIS-hydroxy-4-methylcyclohexyl)-3-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]-1-metalmachine,

3-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]-1-methyl-1-(tetrahydropyran-4-yl)urea,

3-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]-1-methyl-1-(tetrahydrofuran-3-ylmethyl)urea,

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

(rat)(endo)-3-[4-methods the si-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]-1-methyl-1-(7-oxa-bicyclo[2,2,1]hept-2-yl)urea,

[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]amide of 4-isopropyl-piperazine-1-carboxylic acid,

[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]amide of 1,4-dioxa-8-Aza-Spiro[4,5]decane-8-carboxylic acid,

[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]amide of 4-hydroxy-4-methyl-piperidine-1-carboxylic acid,

[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]amide and (1S,4S)-2-oxa-5-Aza-bicyclo[2,2,1]heptane-5-carboxylic acid,

[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]amide of 2-Aza-bicyclo[2,2,2]octane-2-carboxylic acid,

N-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]-2-(tetrahydropyran-4-yl)acetamide", she

N-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]-2-morpholine-4-ilmmilmismiliemi,

2-[(2-methoxyethylamine)methyl]-N-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]isonicotinamide,

(TRANS)-2-(4-hydroxycyclohexyl)-N-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]acetamide", she

[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]amide of 4-hydroxyethylpiperazine-1-carboxylic acid,

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

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

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

a) interaction of the compounds of formula

with the compound of the formula

obtaining thus 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 thus the compounds of formula

where R1and R are as defined above, L is tsepliaeva group, such as halogen, -O-phenyl or O-lower alkyl, and R3represents -(CH2)n-5 - or 6-membered nonaromatic a heterocycle, optionally substituted by one or more substituents selected from the group consisting of lower alkyl, or-NR2or is cycloalkyl, optionally substituted by a hydroxy radical or lower alkyl, or represents a 7-oxa-bicyclo[2,2,1]hept-2-yl; and if necessary, converting the compounds obtained into pharmaceutically acceptable acid additive salt.

In the examples 1-56 and the following schemes 1-3 obtaining compounds of formula I are described in more under the window.

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

Obtaining compounds of formula I

Obtaining the compounds of formula Ia can be described as follows:

Scheme 1

Obtaining compounds of formula (XI)

Intermediate compound 7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-ylamine of formula (XI) can be obtained from 6-(4-methoxy-3-nitrophenyl)-[1,4]dioxetane (X) in accordance with the methods disclosed in published international application WO 01/97786. Obtaining compounds of formula 1A are also described in published international application WO 01/97786 and in the specific examples of the synthesis. Obtaining compounds of formula (VIII), (IX) and (X) described in more detail in examples 36, 37 and 38.

Obtaining the intermediate of formula XVII can be represented as follows:

Scheme 2

Obtaining compounds of formula (XIV)

Derivatives arilbred formula (XIII) is subjected to interaction with a slight excess of bis(pinacolato)diboron in an organic solvent, preferably dimethyl sulfoxide, containing a palladium catalyst, preferably the adduct dichloro(1,1'-bis(diphenylphosphino)ferrocene)-palladium(II) dichloromethane and an excess of potassium acetate. Maintains deistvie is carried out at elevated temperature, preferably at approximately 80°C. for about 2-24 hours, preferably for about 2 hours. The resulting product of formula (XIV) was isolated according to standard techniques, and preferably purified by chromatography or recrystallization.

Obtaining compounds of formula (XV)

One way of preparing compounds of the formula (XV) is in the handling of the compounds of formula (XIV) derived vinylmania, vinylidine or vinestreet in the presence of a palladium catalyst, preferably such as 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 at about 80°C., for about 0.1 to 2 hours, preferably for about 20 minutes. The resulting product of the formula (XV) was isolated according to standard techniques, and preferably purified by chromatography or recrystallization. The parent compound derivatives vinylmania, vinylidine or vinestreet may be commercially available, for example, from the firm "Fluka", or can be obtained according to methods known from preceding the adequate level of technology.

Obtaining compounds of formula (XVI)

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

Obtaining compounds of formula (XVII)

The intermediate compound 4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-ylamine of formula (XVII) can be obtained from 2-methoxy-5-(tetrahydropyran-4-yl)phenylamine (XVI) in accordance with the techniques disclosed in published international application WO 01/97786. Obtaining compounds of formula Ib using intermediate compounds of formula (XVII) are also described in published international application WO 01/97786.

Scheme 3

where R1and R are as defined above, L is tsepliaeva group, such as halogen, -O-phenyl or O-lower alkyl, and 3represents -(CH2)n-5 - or 6-membered nonaromatic a heterocycle, optionally substituted by one or more substituents selected from the group consisting of lower alkyl, or-NR2or is cycloalkyl, optionally substituted by a hydroxy radical or lower alkyl, or represents a 7-oxa-bicyclo[2,2,1]hept-2-yl;

In accordance with scheme 3, the compounds of formula Ic can be obtained in the usual manner from the intermediate compounds of formula IV are known compounds described in published international application WO 01/97786), as described in more detail in the examples.

Isolation 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 implement is placed below in the 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 acid additive salt (product of accession acid).

The transformation is implemented by processing at least the stoichiometric amount of the appropriate acid, such as chloromethane acid, Hydrobromic acid, 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, for example, that ka is 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°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, sodium bicarbonate, ammonia, and similar reasons.

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 what exploits 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. The tablets, which conduct research, 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 7.5 to 9.0. For the preferred compounds of the pKi values>8,5.

When is EP No. hA2(pKi)Example No.hA2(pKi)
89,0318,9
98,7328,7
108,9338,8
118,6348,7
149,0358,8
158,7398,8
208,6439,4
218,6448,6
228,6468,6
238,70 8,6
248,5529,0
269,0558,9
298,8568,5

Example No.hA2(pKi)Example No.hA2(pKi)
308,9

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. 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 farmatsevticheskii 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 are, 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 antioxid antes. They can also contain the 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 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 for the affected 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 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 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 mg 100 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 of167167 167831

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 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
1.The connection formulas1525100500
2.Water lactose159123148-
3.Corn starch 25354070
4Talc10151025
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.

Following preparation examples and examples serve only to illustrate the invention and are assumed not to limit the scope of the present invention.

Example 1

(7-[1,4]Dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide morpholine-4-carboxylic acid

7-[1,4]Dioxan-6-yl-4-methoxybenzothiazole-2-ylamine first subjected to interaction with phenylcarbamates, as described in relation benzyl EPE is a (4-methoxy-7-phenyl-benzothiazol-2-yl)carbamino acid in published international application WO 01/97786, and then morpholine. After the usual selection preparative reversed-phase GHUR and the final freeze-drying receive specified in the title compound as light brown powder. Mass spectrum: m/e=394(M+N+).

In accordance with the General procedure described in example 1, to obtain compounds according to examples 2-7.

Example 2

(7-[1,4]Dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide piperidine-1-carboxylic acid

Using 7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-ylamine, phenylchloropyruvate and piperidine specified in the title compound obtained as a light yellow powder. Mass spectrum: m/e=392(M+N+).

Example 3

1-Cyclohexyl-3-(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)-1-metalmachine

Using 7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-ylamine, phenylchloropyruvate and cyclohexylethylamine specified in the title compound obtained as a light not quite white powder. Mass spectrum: m/e=420(M+H+).

Example 4

(7-[1,4]Dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide of 4-hydroxyethylpiperazine-1-carboxylic acid

Using 7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-ylamine, phenylchloropyruvate and 4-hydroxyethylpiperazine specified in the title compound obtained as not quite white powder. Mass spectrum: m/e=422(M+H+).

Example 5

3-(7-[1,4]Dioxan-6-yl-4-methoxy shall isothiazol-2-yl)-1-methyl-1-(1-methyl-piperidine-4-yl)urea

Using 7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-ylamine, phenylchloropyruvate and 1-methyl-4-(methylamino)piperidine specified in the title compound obtained as a light brown powder. Mass spectrum: m/e=435(M+H+).

Example 6

(7-[1,4]Dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide 1,4-dioxa-8-Aza-Spiro[4,5]decane-8-carboxylic acid

Using 7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-ylamine, phenylchloropyruvate and 1,4-dioxa-8-Aza-Spiro[4,5]decane specified in the title compound obtained as not quite white powder. Mass spectrum: m/e=450(M+H+).

Example 7

(7-[1,4]Dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide of 4-hydroxypiperidine-1-carboxylic acid

Using 7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-ylamine, phenylchloropyruvate and 4-hydroxypiperidine specified in the title compound obtained as not quite white powder. Mass spectrum: m/e=408(M+N+).

Example 8

(7-[1,4]Dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide 5-methylthiophene-2-carboxylic acid

7-[1,4]Dioxan-6-yl-4-methoxybenzothiazole-2-ylamine and 5-methylthiophene-2-carboxylic acid is subjected to interaction, as described in relation to N-(4-methoxy-7-phenyl-benzothiazol-2-yl)benzamide in published international application WO 01/9786. After the usual selection preparative reversed-phase GHUR and the final freeze-drying is obtained from asanee the title compound as a white powder. Mass spectrum: m/e=405 (M+N+).

Compounds according to examples 9-16 receive in accordance with the General procedure described in example 1.

Example 9

N-(7-[1,4]Dioxan-6-yl-4-methoxybenzothiazole-2-yl)-4-methoxybenzamide

Using 7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-ylamine and 4-methoxybenzoic acid specified in the title compound obtained as a white powder. Mass spectrum: m/e=415(M+N+).

Example 10

N-(7-[1,4]Dioxan-6-yl-4-methoxybenzothiazole-2-yl)-4-perbenzoic

Using 7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-ylamine and 4-fermenting acid specified in the title compound obtained as a white powder. Mass spectrum: m/e=403(M+N+).

Example 11

(7-[1,4]Dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide cyclohexanecarbonyl acid

Using 7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-ylamine and cyclohexanecarbonyl acid specified in the title compound obtained as a white powder. Mass spectrum: m/e=391(M+N+).

Example 12

N-(7-[1,4]Dioxan-6-yl-4-methoxybenzothiazole-2-yl)-2-(tetrahydropyran-4-yl)ndimethylacetamide

Using 7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-ylamine and tetrahydropyran-4-yl acetic acid specified in the title compound obtained as a white powder. Mass spectrum: m/e=407(M+N+).

Example 13

(7-[1,4]Dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide(R)-tetr hydrofuran-2-carboxylic acid

Using 7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-ylamine and (R)-tetrahydrofuran-2-carboxylic acid specified in the title compound obtained as a white powder. Mass spectrum: m/e=379(M+N+).

Example 14

(7-[1,4]Dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide 3-methyl-3H-imidazole-4-carboxylic acid

Using 7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-ylamine and 3-methyl-3H-imidazole-4-carboxylic acid, receive specified in the header connection. Mass spectrum: m/e=389(M+H+).

Example 15

N-(7-[1,4]Dioxan-6-yl-4-methoxybenzothiazole-2-yl)-isonicotinamide

Using 7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-ylamine and isonicotinoyl acid, receive specified in the header connection. Mass spectrum: m/e=386(M+H+).

Example 16

N-(7-[1,4]Dioxan-6-yl-4-methoxybenzothiazole-2-yl)-2-methoxy-isonicotinamide

Using 7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-ylamine and 2-methoxyethylamine acid, receive specified in the header connection. Mass spectrum: m/e=416(M+H+).

Compounds according to examples 17-34 receive in accordance with the General procedure described in example 1.

Example 17

TRANS-(4-Hydroxycyclohexyl)-3-(4-methoxy-7-[1,4]dioxan-6-yl-benzothiazol-2-yl)-1-metalmachine

Using 7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-ylamine, phenylchloropyruvate and TRANS-4-methylenecycloartanol, shown is in the title compound obtained as not quite white solid. Mass spectrum: m/e=452(M+H+).

Example 18

(7-[1,4]Dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide and (1S,4S)-2-oxa-5-Aza-bicyclo[2,2,1]heptane-5-carboxylic acid

Using 7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-ylamine, phenylchloropyruvate and (1S,4S)-oxa-5-Aza-bicyclo[2,2,1]heptane specified in the title compound obtained as not quite white solid. Mass spectrum: m/e=422(M+H+).

Example 19

(7-[1,4]Dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide of 4-methoxypiperidine-1-carboxylic acid

Using 7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-ylamine, phenylchloropyruvate and 4-methoxypiperidine specified in the title compound obtained as not quite white solid. Mass spectrum: m/e=438(M+H+).

Example 20

3-[4-Methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea

Using 4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-ylamine, phenylchloropyruvate and 1-methyl-4-(methylamino)piperidine specified in the title compound obtained as white crystals (yield 56%). Mass spectrum: m/e=419(M+H+), so pl. 152-155°C.

Example 21

TRANS-1-(4-Hydroxycyclohexyl)-3-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]-1-metalmachine

Using 4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-ylamine, phenylchloropyruvate and (TRANS)-4-methylenecycloartanol specified in the header of the is & SMS receive in the form of white crystals, so pl. 160°C (yield 76%). Mass spectrum: m/e=420(M+H+), so pl. 160°C.

Example 22

CIS-1-(4-Hydroxycyclohexyl)-3-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]-1-metalmachine

Using 4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-ylamine, phenylchloropyruvate and (CIS)-4-methylenecycloartanol specified in the title compound obtained as white solid (yield 70%). Mass spectrum: m/e=420(M+H+), so pl. 191-193°C.

Example 23

1-(4-CIS-Hydroxy-4-methylcyclohexyl)-3-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]-1-metalmachine

Using 4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-ylamine, phenylchloropyruvate and (CIS)-1-methyl-4-methylenecycloartanol specified in the title compound obtained as a white powder (yield 64%). Mass spectrum: m/e=434(M+H+), so pl. 211-213°C.

Example 24

3-[4-Methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]-1-methyl-1-(tetrahydropyran-4-yl)urea

Using 4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-ylamine, phenylchloropyruvate and methyl-(tetrahydropyran-4-yl)amine indicated in the title compound obtained as white solids (yield 16%). Mass spectrum: m/e=406(M+H+), so pl. 237-238°C.

Example 25

3-[4-Methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]-1-methyl-1-(tetrahydrofuran-3-ylmethyl)urea

Using 4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-ylamine,phenylchloropyruvate and methyl-(tetrahydrofuran-3-ylmethyl)amine, specified in the title compound obtained as white crystals (yield 80%). Mass spectrum: m/e=406(M+H+), so pl. 185-186°C.

Example 26

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

Using 4-methoxy-7-(tetrahydropyran-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 white crystals (yield 93%). Mass spectrum: m/e=418(M+H+), so pl. 197-200°C.

Example 27

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

Using 4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-ylamine, phenylchloropyruvate and (endo)-methyl-(7-oxa-bicyclo[2,2,1]hept-2-yl)amine indicated in the title compound obtained as white crystals (yield 45%). Mass spectrum: m/e=418(M+H+), so pl. 214-216°C.

Example 28

[4-Methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]amide of 4-isopropylpiperazine-1-carboxylic acid

Using 4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-ylamine, phenylchloropyruvate and 1-isopropylpiperazine specified in the title compound obtained as light yellow crystals (yield 36%). Mass spectrum: m/e=419(M+H+), so pl. 200-204°C.

Example 29

[4-Methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]amide of 1,4-dioxa-8 azaspiro[4,5]decane-8-arbonboy acid

Using 4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-ylamine, phenylchloropyruvate and 1,4-dioxa-8-Aza-Spiro[4,5]decane specified in the title compound obtained as white crystals (yield 53%). Mass spectrum: m/e=434(M+H+), so pl. 208-209°C.

Example 30

[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]amide of 4-hydroxy-4-methyl-piperidine-1-carboxylic acid

Using 4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-ylamine, phenylchloropyruvate and 4-hydroxy-4-methylpiperidin specified in the title compound obtained as not quite white solid (yield 56%). Mass spectrum: m/e=406(M+H+), so pl. 90-95°C.

Example 31

[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]amide and (1S,4S)-2-oxa-5-Aza-bicyclo[2,2,1]heptane-5-carboxylic acid

Using 4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-ylamine, phenylchloropyruvate and (1S,4S)-2-Aza-5-oxabicyclo-[2,2,1]heptane specified in the title compound obtained as white crystals (yield 52%). Mass spectrum: m/e=390(M+H+), so pl. 193-197°C.

Example 32

[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]amide of 2-Aza-bicyclo[2,2,2]octane-2-carboxylic acid

Using 4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-ylamine, phenylchloropyruvate and 2-Aza-bicyclo[2,2,2]octane, specified in the title compound obtained as off-white crystals (yield 53%). Mass spectrum: m/e=402(M+H+), t square 237-239°C.

Example 33

N-[4-Methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]-2-(tetrahydropyran-4-yl)ndimethylacetamide

Using 4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-ylamine and (tetrahydropyran-4-yl)acetic acid specified in the title compound obtained as light yellow crystals (yield 17%). Mass spectrum: m/e=391(M+H+), so pl. 218-220°C.

Example 34

N-[4-Methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]-2-morpholine-4-ilmmilmismiliemi

2-Chloromethyl-N-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]-isonicotinamide (300 mg, 0.7 mmol) and morpholine (2.1 ml, 25 mmol) is heated to 30°C for 30 minutes and Then the mixture is cooled to room temperature, treated with dichloromethane (15 ml) and saturated aqueous sodium carbonate (15 ml), the phases are separated and the resulting aqueous layer is extracted twice with dichloromethane. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. After rapid chromatography (silica gel, eluent a mixture of chloroform/ethyl acetate, then the mixture chloroform/methanol) get mentioned in the title compound as a white solid (yield 60%). Mass spectrum: m/e=469(M+H+), so pl. 199-201°C.

Example 35

2-[(2-Methoxyethylamine)methyl]-N-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]isonicotinamide

Specified in the header of the connection get is-chloromethyl-N-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]isonicotinamide and 2-methoxy-ethylamine in exactly the same way, as described in relation to N-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]-2-morpholine-4-ylmethyl-isonicotinamide, the connection obtained as yellow solid (yield 60%). Mass spectrum: m/e=457(M+H+), so pl. 93-95°C.

2-Chloromethyl-N-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]-isonicotinamide obtained from 4-methoxy-7-(tetrahydropyran-4-yl)benzothiazole-2-ylamine and 2-chloromethylisothiazolinone acid in exactly the same way as described in relation (7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide 5-methylthiophene-2-carboxylic acid, thus obtaining a light yellow solid (yield 60%). Mass spectrum: m/e=419(M+H+).

Example 36

(7-[1,4]Dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide 1-oxa-8-azaspiro[4,5]decane-8-carboxylic acid

Using 7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-ylamine, phenylchloropyruvate and 1-oxa-8-azaspiro[4,5]decane specified in the title compound obtained as a light brown powder. Mass spectrum: m/e=448(M+H+).

Example 37

(7-[1,4]Dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide of 4-hydroxymethyl-4-methyl-piperidine-1-carboxylic acid

Using 7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-ylamine, phenylchloropyruvate and 4-hydroxymethyl-4-methyl-piperidine specified in the title compound obtained as a light brown powder. Mass spectrum: m/e=436(M+H+).

Example 38

N-(7-[1,4]D is oxepin-6-yl-4-methoxybenzothiazole-2-yl)-4-fluoro-3-methyl-benzamide

Using 7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-ylamine and 4-fluoro-3-methylbenzoic acid specified in the header connection receive exactly the same way as described for (7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide 5-methylthiophene-2-carboxylic acid, the compound obtained as light brown powder. Mass spectrum: m/e=417(M+H+).

Example 39

4-Chloromethyl-N-(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)-benzamide

Using 7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-ylamine and 4-chloromethylbenzene acid specified in the header connection receive exactly the same way as described in relation (7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide 5-methylthiophene-2-carboxylic acid, the compound obtained as light brown powder. Mass spectrum: m/e=434(M+H+).

Example 40

N-(7-[1,4]Dioxan-6-yl-4-methoxybenzothiazole-2-yl)-4-pyrrolidin-1-ylmethylene

4-Chloromethyl-N-(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)-benzamide and pyrrolidin subjected to interaction thus, as described in relation to N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-4-pyrrolidin-1-ylmethyl-benzamide in published international application WO 01/9786. After the usual selection preparative reversed-phase GHUR and the final freeze-drying receive specified in the title compound as light brown is orosco. Mass spectrum: m/e=468(M+H+).

Example 41

2-Chloromethyl-N-(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)-isonicotinamide

Using 7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-ylamine and 2-chloromethylisothiazolinone acid specified in the header connection receive exactly the same way as described in relation (7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide 5-methylthiophene-2-carboxylic acid, the compound obtained as a brown solid. Mass spectrum: m/e=435(M+H+).

Example 42

N-(7-[1,4]Dioxan-6-yl-4-methoxybenzothiazole-2-yl)-4-{[(2-methoxy-ethyl) - methyl-amino]methyl}benzamide

4-Chloromethyl-N-(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)-benzamide and N-(2-methoxyethyl)methylamine are interacting in the same way as described in relation to N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-4-pyrrolidin-1-iletilmesine in published international application WO 01/97786. After the usual selection preparative reversed-phase GHUR and the final freeze-drying receive specified in the title compound as light brown powder. Mass spectrum: m/e=486(M+H+).

Example 43

(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide 1-methyl-1H-pyrazole-4-carboxylic acid

Using 7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-ylamine and 1-methyl-1H-pyrazole-4-carboxylic acid specified in the header of the is & SMS receive exactly the same way, as described in relation (7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide 5-methylthiophene-2-carboxylic acid, the compound obtained as white solid. Mass spectrum: m/e=389(M+H+).

Example 44

N-(7-[1,4]Dioxan-6-yl-4-methoxybenzothiazole-2-yl)-4-[(methyl-propionamido)methyl]benzamide

Sodium hydride (4.8 mg, 60%dispersion in mineral oil, 0.2 mmol) are added to N-methylpropionamide (1 ml, 11 mmol), and then add 4-chloromethyl-N-(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)benzamide (50 mg, 1 mmol), after which the resulting reaction mixture is heated to 55°C for 3 hours. After cooling, the mixture was diluted with water (5 ml) and extracted twice with ethyl acetate (5 ml). The combined organic phases are dried with magnesium sulfate, filtered and evaporated. After final purification using preparative GHUR and the final freeze-drying receive specified in the title compound as a white solid (23 mg, yield 42%). Mass spectrum: m/e=484(M+H+).

Example 45

N-(7-[1,4]Dioxan-6-yl-4-methoxybenzothiazole-2-yl)-2-[(2-methoxy-ethyl)methylamino]isonicotinamide

N-(7-[1,4]Dioxan-6-yl-4-methoxybenzothiazole-2-yl)bromine-isonicotinamide and N-(2-methoxyethyl)methylamine are interacting in such a way as described in relation to 2-(2-methoxyethylamine)-N-(4-methoxy-7-morpholine-4-yl-benzo is a thiazol-2-yl)isonicotinamide in published international application WO 03/043636. After the usual selection preparative reversed-phase GHUR and the final freeze-drying receive specified in the title compound as a light brown solid. Mass spectrum: m/e=473(M+H+).

Example 46

N-(7-[1,4]Dioxan-6-yl-4-methoxybenzothiazole-2-yl)-2-pyrrolidin-1-yl-isonicotinamide

N-(7-[1,4]Dioxan-6-yl-4-methoxybenzothiazole-2-yl)bromine-isonicotinamide and pyrrolidin subjected to interaction thus, as described in relation to 2-(2-methoxy-ethylamino)-N-(4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)isonicotinamide in published international application WO 03/043636. After the usual selection preparative reversed-phase GHUR and the final freeze-drying receive specified in the title compound as a light brown solid. Mass spectrum: m/e=455(M+H+).

Example 47

NM-(7-[1,4]Dioxan-6-yl-4-methoxybenzothiazole-2-yl)-2-pyrrolidin-1-ilmmilmismiliemi

2-Chloromethyl-N-(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)-isonicotinamide and N-(2-methoxyethyl)methylamine are interacting in the same way as described in relation to 2-{[(2-methoxyethyl)methylamino]-methyl}-N-(4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)-isonicotinamide in published international application WO 03/043636. After the usual selection preparative reversed-phase GHWR and final su is limacina drying receive specified in the title compound as a pale yellow solid (yield 48%). So pl. 108-111°C., mass spectrum: m/e=469(M+H+).

Example 48

N-(7-[1,4]Dioxan-6-yl-4-methoxybenzothiazole-2-yl)-2-{[(2-methoxyethyl)methylamino]methyl}isonicotinamide

2-Chloromethyl-N-(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)-isonicotinamide and pyrrolidin subjected to interact in the same way as described in relation to 2-{[(2-methoxyethyl)methylamino]methyl}-N-(4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)isonicotinamide in published international application WO 03/043636. After the usual selection preparative reversed-phase GHUR and the final freeze-drying receive specified in the title compound as light brown solid (yield 56%). So pl. 100-107°C., mass spectrum: m/e=487(M+H+).

Example 49

2-Bromo-N-(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)-isonicotinamide

Using 7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-ylamine and 2-bromo-isonicotinoyl acid specified in the header of the connection receives the same way as described in relation (7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide 5-methylthiophene-2-carboxylic acid, the compound obtained as not quite white powder. Mass spectrum: m/e=452(M+H+).

Example 50

(TRANS)-2-(4-Hydroxycyclohexyl)-N-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]ndimethylacetamide

Using 4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-ylamine and (4-hydroxy shall illogical)acetic acid, specified in the header of the connection receives the same way as described in relation to N-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]-2-(tetrahydropyran-4-yl)ndimethylacetamide, connection get in the form of white crystals (yield 25%). So pl. 120-145°C., mass spectrum: m/e=405 (M+H+).

Example 51

[4-Methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]amide (R)-tetrahydrofuran-2-carboxylic acid

Using 4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-ylamine and (R)-tetrahydrofuran-2-carboxylic acid specified in the header of the connection receives the same way as described in relation to N-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]-2-(tetrahydropyran-4-yl)ndimethylacetamide, the connection will get not quite a white solid (yield 62%). So PL-161°C, mass spectrum: m/e=363(M+H+).

Example 52

[4-Methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]amide of 4-hydroxyethylpiperazine-1-carboxylic acid

Using 4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-ylamine, phenylchloropyruvate and 4-hydroxymethyl-piperidine specified in the title compound obtained as white crystals (yield 87%). So pl. 202-203,5°C, mass spectrum: m/e=406(M+H+).

Example 53

1-(1-Dimethylpiperidin-4-yl)-3-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]-1-metalmachine

Using 4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-ylamine, vanillaroma the MIAT and N,N,N'-trimethyl-piperidine-1,4-diamine, specified in the title compound obtained as white crystals (yield 77%). So pl. 167-170°C., mass spectrum: m/e=448(M+H+).

Example 54

N-[4-Methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]-2-(tetrahydrofuran-2-yl)ndimethylacetamide

Using 4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-ylamine and (tetrahydrofuran-2-yl)acetic acid specified in the header of the connection receives the same way as described in relation to N-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]-2-(tetrahydropyran-4-yl)ndimethylacetamide, the compound obtained as white solids (yield 50%). So pl. 170-174°C., mass spectrum: m/e=377(M+N+).

Example 55

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

Using 4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-ylamine, phenylchloropyruvate and (Exo)methyl-(7-oxabicyclo[2,2,1]hept-2-yl)amine specified in the header connection receive in the form of a racemate. After chiral separation using Chiralpak AD (eluent 20% EtOH in heptane) receive the first eluruumis isomer as white crystals (yield 39%). So pl. 185-188°C., mass spectrum: m/e=418(M+H+).

Example 56

(Exo)-(-)-3-[4-Methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]-1-methyl-1-(7-oxabicyclo[2,2,1]hept-2-yl)urea

Using 4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-ylamine, phenylchloropyruvate and (Exo)m is Teal-(7-oxa-bicyclo[2,2,1]hept-2-yl)amine, specified in the header connection receive in the form of a racemate. After chiral separation using Chiralpak AD (eluent 20% EtOH in heptane) to receive the second eluruumis isomer as a white solid (yield 29%). So pl. 155-190°C, mass spectrum: m/e=418(M+H+).

Intermediate compounds

Example 57

6-(4-methoxyphenyl)-[1,4]-dioxan-6-ol (VIII)

Magnesium (1.27 g, 0,053 mol) dried thermostat for 1 hour at 75°C, stirred with THF (125 ml) in a three-neck flask with a capacity of 500 ml by heating under reflux. Add a crystal of iodine, and then added dropwise a solution of 4-methoxypropanol in THF (50 ml) for 15 minutes After adding 10 ml of the solution begins the interaction. After adding the whole, the mixture is refluxed for 2 hours. The obtained gray solution is cooled to 0°C and then added dropwise a solution of 1,4-dioxan-6-it (thus obtained, as described in U.S. patent 4410354) (5,08 g 0,044 mol) in THF (25 ml). The reaction mixture was stirred at room temperature overnight, then evaporated. The resulting residue is acidified to pH 1 using 1 N HCl, and then extracted with ether (2×250 ml). The ether extracts are washed with water, dried (MgSO4), filtered and concentrated, thus obtaining a sticky brown solid (9.45 in). This connection is clean out column chromatography on silica gel, elwira a mixture of ethyl acetate-hexane. The appropriate fractions are concentrated, thus obtaining the target product (6,21 g, yield 63%).

Example 58

6-(4-methoxyphenyl)-[1,4]dioxan (IX)

To a solution of 6-(4-methoxyphenyl)-[1,4]-dioxan-6-ol (6.20 g, 0,028 mol) in CH2Cl2add triethylsilane (3,53 g 0,031 mol) and triperoxonane acid (35.1 g, 0.31 mol). The reaction mixture was stirred over night. Then the reaction mixture was alkalinized using the solution To2CO3up to pH 10. The organic layer is dried (MgSO4), filtered and evaporated to dryness, thus obtaining the target product as a red oily substance (of 5.84 g, yield 100%).

Example 59

6-(4-Methoxy-3-nitrophenyl)-1,4-dioxan (X)

A solution of 6-(4-methoxyphenyl)-1,4-dioxetane (of 5.84 g, 0,028 mol) and acetic anhydride (40 ml) in a three-neck flask with a capacity of 100 ml was heated to 65°C. the Heating stop and add portions of nitrate copper(II) (7,7 g 0,033 mol) for 2 hours, until the temperature reaches 60-70°C (caution: exothermic reaction). After adding the blue suspension was stirred at 65°C. additionally for 1.5 hours, water is Added (400 ml) and stirred the reaction mixture for 1 hour, then add the solid To2CO3to pH 10. The resulting mixture was extracted with ethyl acetate (3×150 ml). The combined organic layers dried (MgSO4), fil the shape and evaporated, while receiving a red oily substance (7,37 g). The crude product is purified column chromatography, elwira a mixture of 20%-30% EtOAc-hexane. The appropriate fractions are combined and concentrated, thus obtaining the target product as an orange oily substance (5,80 g, yield 83%). Mass spectrum: m/e=254(M+H+).

Example 60

7-[1,4]Dioxan-6-yl-4-methoxybenzothiazole-2-ylamine (XI)

Specified in the title compound is obtained from 6-(4-methoxy-3-nitrophenyl)-1,4-dioxetane according to the same method as described in published international application WO 01/97786 against 4-methoxy-7-phenoxybenzamine-2-yl-amine, yield 57% (3.7 g). Mass spectrum: m/e=281(M+H+).

Example 61

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

a) 2-(4-Methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolan

To a stirred solution of 1.30 g (the ceiling of 5.60 mmol) 4-bromo-2-nitroanisole in 25 ml of DMSO type of 1.57 g (6,16 mmol) of bis(pinacolato)diboron, 123 mg (0,17 mmol) of 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 the rapid-chromatography (ethyl acetate/is exan in the ratio of½, then ethyl acetate) to obtain 1.39 g of 2-(4-methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane as 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

To mix the solution 4,36 g (15.6 mmol) of 2-(4-methoxy-3-nitro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane 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°C and added dropwise to 16.5 ml (33.0 mmol) of 2 M aqueous solution of sodium carbonate. The reaction mixture is stirred for 20 minutes at 80°C 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 the rapid-chromatography (ethyl acetate/hexane in a ratio of 1/4) receive a 2.00 g (yield 60%) of 4-(4-methoxy-3-nitrophenyl)-3,6-dihydro-2H-Piran in the form of a light yellow solid. Mass spectrum (ES-MS): m/e (%): 253 (M+NH4+, 100), 236 (M+N+, 24).

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

To mix the solution 3,30 g (14.0 mmol) of 4-(4-methoxy-3-nitrophenyl)-3,6-dihydro-2H-Piran in 70 ml of methanol and 70 ml of dichloromethane add Aut at the tip of the spatula 10%palladium on carbon and then the resulting mixture was stirred for 20 minutes at room temperature in a hydrogen atmosphere. The resulting mixture is filtered, washed with dichloromethane and the obtained filtrate was concentrated in vacuo, while receiving a 2.75 g (yield 95%) of 2-methoxy-5-(tetrahydropyran-4-yl)phenylamine as 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

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 the resulting mixture is refluxed for 10 minutes. Then add dropwise a solution of 2.75 g (13.3 mmol) of 2-methoxy-5-(tetrahydropyran-4-yl)phenylamine in 30 ml of acetone and the reaction mixture is refluxed additionally within 10 minutes. Then the mixture is 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 a ratio of 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+H, 100).

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

For mixed races is the thief 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. The resulting mixture was then 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 substance. Mass spectrum (ES-MS): m/e (%): 267 (M+N+, 100).

e) 4-Methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl-amine

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 min at 80°C. and Then added dropwise to 0.56 ml (7.85 mmol) of DMSO and the reaction mixture is additionally stirred for 30 min 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. Uterine fluid are separated and the organic phase was concentrated in vacuo to a volume of 5 ml. Received a second batch of crystals are collected by filtration and combined with the first batch, while receiving 920 mg (Ihad 49%) 4-methoxy-7-(tetrahydropyran-4-yl)benzothiazole-2-ylamine in the form of a white solid. ES-MS m/e (%): 265 (M+H+, 100).

1. Compounds of General formula:

where R1represents 1,4-dioxetanes or tetrahydropyran-4-yl;
R2represents-N(R)-(CH2)n-5 - or 6-membered nonaromatic a heterocycle containing 1-2 heteroatoms of nitrogen, optionally substituted by one or two substituents selected from the group consisting of C1-C6the alkyl or-NR2or
represents -(CH2)n-5 - or 6-membered nonaromatic a heterocycle containing 1-2 heteroatoms selected from N, S or O, optionally substituted by a group -(CH2)nHE, C1-C6alkyl, C1-C6alkoxy, or
represents -(CH2)n-5 - or 6-membered aromatic heterocycle containing 1-2 heteroatoms of nitrogen, optionally substituted by the following group: C1-C6alkyl, C1-C6alkoxy, halogen, halogen-(C1-C6alkyl), -CH2N(R)(CH2)2OCH3, -N(R)(CH2)2OCH3, -CH2-morpholinyl or-CH2-pyrrolidinyl, or represents (CH2)n-C3-C6cycloalkyl, optionally substituted by hydroxy group, or
represents-N(R)-C3-C6cycloalkyl, optionally substituted by hydroxy group or a C1-C6alkyl, or
represents the t a phenyl, optionally substituted C1-C6alkoxy, halogen, halogen-(C1-C6alkyl), C1-C6alkyl, -CH2-pyrrolidin-1-yl, -CH2N(R)(CH2)2OCH3or-CH2-N(R)C(O)-(C1-C6alkyl), or
represents 1,4-dioxa-8 azaspiro[4,5]decane, or
is a 2-oxa-5-azabicyclo[2,2,1]heptane, or
is a 1-oxa-8-azaspiro[4,5]decane, or
represents-N(R)-7-oxabicyclo[2,2,1]hept-2-yl, or
is a 2-azabicyclo[2,2,2]octane;
R represents hydrogen or C1-C6alkyl;
n means 0 or 1;
and pharmaceutically acceptable acid additive salts of these compounds.

2. Compounds according to claim 1 of General formula

where R1represents 1,4-dioxetanes and
R2represents-N(R)-(CH2)n-5 - or 6-membered nonaromatic a heterocycle containing 1-2 heteroatoms of nitrogen, optionally substituted by one or two substituents selected from the group consisting of C1-C6the alkyl, or
represents -(CH2)n-5 - or 6-membered nonaromatic a heterocycle containing 1-2 heteroatoms selected from N, S or O, optionally substituted by a group -(CH2)nHE or
represents -(CH2)n-5 - or 6-membered aromatic heterocycle, containing the th 1-2 heteroatoms of nitrogen, optionally substituted C1-C6the alkyl, C1-C6alkoxy or the group-CH2-pyrrolidinyl, or
represents a C3-C6cycloalkyl, or
represents-N(R)-C3-C6cycloalkyl, optionally substituted by hydroxy group, or
represents phenyl, optionally substituted C1-C6alkoxy, halogen, -(CH2)npyrrolidinyl or-CH2-N(CH3)C(O)-(C1-C6alkyl), or
represents 1,4-dioxa-8-Aza-Spiro[4,5]decane, or
is a 2-oxa-5-Aza-bicyclo[2,2,1]heptane, or
is a 1-oxa-8-Aza-Spiro[4,5]decane;
or
R1represents tetrahydropyran-4-yl and
R2represents-N(R)-(CH2)n-5 - or 6-membered nonaromatic a heterocycle containing 1-2 heteroatoms of nitrogen, optionally substituted C1-C6alkyl, or
represents -(CH2)n-5 - or 6-membered nonaromatic a heterocycle containing 1-2 heteroatoms selected from N, S or O, or
represents-N(R)-C3-C6cycloalkyl, optionally substituted by hydroxy group or a C1-C6alkyl, or
represents piperidine-1-yl, substituted by a hydroxy group and C1-C6the alkyl in the 4-position, or
represents piperazine-1-yl, substituted and what propylon in the 4-position, or represents pyridin-4-yl, substituted by a group-CH2-morpholinyl, or
represents pyridin-4-yl, substituted by a group-CH2NH(CH2)2Och3or
represents-N(R)-7-oxabicyclo[2,2,1]hept-2-yl, or
is a 2-oxa-5-azabicyclo[2,2,1]heptane, or
is a 2-azabicyclo[2,2,2]octane, or
represents 1,4-dioxa-8 azaspiro[4,5]decane;
R represents hydrogen or C1-C6alkyl;
n means 0 or 1; and
and pharmaceutically acceptable acid additive salts of these compounds.

3. The compounds of formula I according to claim 1, where R1represents 1,4-dioxan-6-yl, and R2so, as stated in claim 1.

4. The compounds of formula I according to claim 2, which represent the following connections:
(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide morpholine-4-carboxylic acid,
(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide piperidine-1-carboxylic acid,
1-cyclohexyl-3-(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)-1-metalmachine,
(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide of 4-hydroxymethyl-piperidine-1-carboxylic acid,
3-(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)-1-methyl-1-(1-methyl-piperidine-4-yl)urea,
(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide 1,4-dioxa-8-Aza-Spiro[4,5]decane-8-carboxylic acid,
(7-[1,4]dioxan-6-yl-4-ethoxybenzothiazole-2-yl)amide of 4-hydroxypiperidine-1-carboxylic acid,
(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide 5-methylthiophene-2-carboxylic acid,
N-(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)-4-methoxybenzamide,
N-(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)-4-perbenzoic,
(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide cyclohexanecarbonyl acid,
N-(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)-2-(tetrahydropyran-4-yl)acetamide", she
(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide (R)-tetrahydrofuran-2-carboxylic acid,
(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide 3-methyl-3H-imidazole-4-carboxylic acid,
N-(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)isonicotinamide,
N-(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)-2-methoxy-isonicotinamide,
TRANS-1-(4-hydroxycyclohexyl)-3-(4-methoxy-7-[1,4]dioxan-6-yl-benzothiazol-2-yl)-1-metalmachine,
(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide and(1S,4S)-oxa-5-azabicyclo[2,2,1]heptane-5-carboxylic acid,
(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide of 4-methoxypiperidine-1-carboxylic acid,
4-chloromethyl-N-(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)-benzamid,
(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)amide 1-methyl-1H-pyrazole-4-carboxylic acid,
N-(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)-4-[(methyl-propionyl amino)methyl]benzamide or
N-(7-[1,4]dioxan-6-yl-4-methoxybenzothiazole-2-yl)-2-pyrrolidin-1-yl-ison codenamed.

5. The compounds of formula I according to claim 1, where R1represents tetrahydropyran-4-yl, and R2so, as stated in claim 1.

6. The compounds of formula I according to claim 5, which represent the following connections:
3-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea,
TRANS-1-(4-hydroxycyclohexyl)-3-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]-1-metalmachine,
CIS-1-(4-hydroxycyclohexyl)-3-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]-1-metalmachine,
1-(4-CIS-hydroxy-4-methylcyclohexyl)-3-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]-1-metalmachine,
3-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]-1-methyl-1-(tetrahydropyran-4-yl)urea,
3-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]-1-methyl-1-(tetrahydrofuran-3-ylmethyl)urea,
(rat)-(Exo)-3-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]-1-methyl-1-(7-oxabicyclo[2,2,1]hept-2-yl)urea,
(rat)(endo)-3-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]-1-methyl-1-(7-oxa-bicyclo[2,2,1]hept-2-yl)urea,
[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]amide of 4-isopropyl-piperazine-1-carboxylic acid,
[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]amide of 1,4-dioxa-8-Aza-Spiro[4,5]decane-8-carboxylic acid,
[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]amide of 4-hydroxy-4-methyl-piperidine-1-carbon is Oh acid,
[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]amide and (1S,4S)-2-oxa-5-Aza-bicyclo[2,2,1]heptane-5-carboxylic acid,
[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]amide of 2-Aza-bicyclo [2,2,2] octane-2-carboxylic acid,
N-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]-2-(tetrahydropyran-4-yl)acetamide", she
N-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]-2-morpholine-4-ilmmilmismiliemi,
2-[(2-methoxyethylamine)methyl]-N-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]isonicotinamide,
(TRANS)-2-(4-hydroxycyclohexyl)-N-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]acetamide", she
[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]amide of 4-hydroxyethylpiperazine-1-carboxylic acid,
(Exo)-(+)-3-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]-1-methyl-1-(7-oxa-bicyclo[2,2,1]hept-2-yl)urea or
(Exo)-(-)-3-[4-methoxy-7-(tetrahydropyran-4-yl)benzothiazol-2-yl]-1-methyl-1-(7-oxa-bicyclo[2,2,1]hept-2-yl)urea.

7. Drug, possessing properties of ligand adenosine receptor (A2Acontaining one or more compound according to any one of claims 1 to 6, and pharmaceutically acceptable excipients.

8. The drug according to claim 7 for the treatment of diseases associated with adenosine receptor And2A.



 

Same patents:

The invention relates to a neuroprotective (anti-ischemic and excited by blocking amino acid receptor) analogues 5-(1-hydroxy-2-piperidinophenyl)-2-(1H, 3H)-indole-defined formula (I), (II) and (III) below; their pharmaceutically acceptable salts; method of using these compounds in the treatment of stroke, traumatic brain injury or degenerative diseases of the CNS (Central nervous system), such as disease Alzheimer, senile dementia Alzheimers.com type, Huntington's disease and Parkinson's disease; and some of their intermediates

FIELD: chemistry; pharmacology.

SUBSTANCE: compounds of formula (I) as inhibitors of phosphotyrosine phosphotase 1B and their pharmaceutically acceptable salts, their application, based pharmaceutical composition and method of production. In general formula (I) , R1 indicates phenyl, naphthyl, thionaphthyl, pyridyl. Phenyl, naphthyl, thionaphthyl and pyridyl can be single- or multiple-substituted with F, Cl, Br, (CH2)0-2OH, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkinyl, CF3, OCF3, N(R9)(R10), piperidinone, piperazine, piperazinone, N-(C1-C6-alkylene)-piperazine, N-(C1-C6-alkylene)-piperazinone, morpholine, thiomorpholine, NO2, CN, O-(C1-C6)-alkyl, S(O)0-2-(C1-C6)-alkyl, SO2-N(R9)(R10), CO-(C1-C6)-alkyl, -COOH, (C1-C6)-alkylene-COOH, COO(C1-C6)-alkyl, (C1-C6)-alkyleny-COO(C1-C6)-alkyl, (C3-C10)-cycloalkyl, phenyl. These piperidinone, piperazine, piperazinone, N-(C1-C6-alkylene)-piperazine, N-(C1-C6-alkylene)-piperazinone, morpholine, thiomorpholine, and phenyl rings can be single- or multiple-substituted with F, Cl, Br, (CH2)0-2OH, COOH, CN, NO2, O-(C1-C6)-alkyl, -NH-O-(C1-C6)-alkyl, -(CO)-NH-O-(C1-C6)-alkylene-N(R9)(R10), -(CO)-(C1-C6)-alkyl, -(C1-C6)-alkyl, CF3, OCF3, N(R9)(R10); R2 indicates H, (C1-C6)-alkyl, COOH, (C1-C6)-alkylene-COOH, COO(C1-C6)-alkyl, (C1-C6)-alkylene-COO(C1-C6)-alkyl; R3 indicates H, (C1-C6)-alkyl, (C1-C6)-alkylenphenyl, -C(O)-phenyl, (C1-C6)-alkylenheterocycle, where heterocycle represents 5-6-merous heterocyclic ring containing 1-2 heteroatoms, chosen of nitrogen and oxygen, CO-(C1-C6)alkyl; R4, R5 indicate H; R6 indicates H, R9 indicates H, (C1-C4)-alkyl; R10 indicates H, (C1-C4)-alkyl.

EFFECT: applications for treating diseases mediated with phosphotyrosine phosphotase 1B activity, such as diabetes type II, lipidosis and carbohydrate metabolic imbalance, insulin resistivity, reduced sugar content in blood.

9 cl, 2 tbl, 1 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: new compounds of formula (I) and its pharmaceutically acceptable salts. Offered compounds possess properties of bacterial gyrase and Topo-IV activity inhibitor. In general formula (I) , W is chosen from CH or CF; X represents CH; Z represents O or NH; R1 represents phenyl or 5-6-merous heteroaryl ring containing 1-3 nitrogen atoms where R1 is substituted with 0-3 groups independently chosen from -(T)y-Ar, R', oxo, C(O)R', OR', N(R')2, SR', CN or C(O)N(R')2; R2 is chosen from C1-3alkyl and C3-7-cycloalkyl; and ring A represents 5-6-merous heteroaryl ring containing 1-3 heteroatoms, independently chosen of nitrogen, oxygen or sulphur provided the specified ring has hydrogen bond acceptor in position adjacent to that of joining to B ring where ring A is substituted with 0-3 groups independently chosen from R', oxo, CO2R', OR', N(R')2, halogen, CN, C(O)N(R')2, NR'C(O)R', or NR'SO2R', and where two substitutes in adjacent positions of ring A, together can form 6-merous saturated heterocyclic or heteroaryl ring containing 1-2 nitrogen atoms.

EFFECT: pharmaceutical compositions with properties of bacterial gyrase and Topo-IV activity inhibitor containing disclosed compound as active component, method of gyrase and/or Toro IV-activity inhibition, method of bacteria number reduction.

25 cl, 3 tbl, 4 dwg, 29 ex

FIELD: medicine.

SUBSTANCE: formula bond

or it pharmaceutically comprehensible salt where value of radicals are specified in the invention formula is described. The bonds are effective as inhibitors of protein kinases FLT-3 or KIT. A way of inhibition of activity kinases FLT-3 or KIT in the biological sample in vitro and application of bonds for manufacture of a medical product, suitable for treatment or simplification of gravity of disease or a condition, the chosen acute myelogenetic leukosis, acute progranulocytic leukemia or acute lymphocytic leukosis or cancer of ovaries are described also.

EFFECT: rising of efficiency of a composition and the method of treatment.

11 cl, 86 ex

FIELD: medicine.

SUBSTANCE: invention offers analogues of quinazoline of the formula I

where A is bound at least with one of atoms of carbon in position 6 or 7 of the dicyclic ring; X represents N. A represents the group Q or Z including tautomeric group Z form where Q and Z, have the formulas resulted more low in which symbols and radicals, have the value specified in item 1 of the formula of the invention. R1 represents phenyl, substituted -(G)nOAr or -O(G)nAr and where phenyl is unessentially replaced by halogen or C1-C10alkyl; where G represents C1-C4alkylene, n is peer 0 or 1. And Ar represents phenyl either pyridyl or thiazolyl where Ar is unessentially substituted by 1-2 substituents chosen from halogen or C1-C10alkyl; R2 and R3 represent N. The bonds of the formula I are inhibitors of the receptor tyrosine kinases of type 1. The invention includes also a way of treatment of hyperproliferative diseases, such as a cancer, application of bonds of the formula 1 in manufacture of medical products and pharmaceutical composition on the basis of these bonds.

EFFECT: rising of efficiency of a composition and the method of treatment.

14 cl, 6 dwg, 63 ex

FIELD: chemistry.

SUBSTANCE: compounds of the invention have chemokine antagonistic properties and can be applied in treatment of immunoinflammatory diseases, such as atherosclerosis, allergy diseases. In general formula (I) R1 is hydrogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxyl, cyclopropylmethoxy group, (C1-C4)-alkylthio group; R2 is halogen atom, (C1-C8)-alkyl, perfluoro-(C1-C4)-alkyl, (C3-C10)-cycloalkyl, phenyl, (C1-C8)-alkoxyl, values of the other radicals are indicated in the claim of the invention.

EFFECT: improved properties.

14 cl, 7 tbl, 20 dwg, 17 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I) and their pharmaceutically acceptable salts. Claimed compounds have antibacterial effect. In formula (I) , X is ; R1 is i) hydrogen, ii) (CH2)nNR5R6, iv) NRCO2R, v) (C1-6alkyl)CN, CN, (CH2)pOH; Y is NR*, O or S(O)p; is phenyl or 5-6-member heteroaryl with N or S as heteroatoms; R3 is NR(C=X2)R12, NR*R12, or -(O)n-5-6-member heteroaryl with 1-3 heteroatoms selected out of N, O, which can be linked over either carbon atom or heteroatom; the indicated 5-6-member heteroaryl can be optionally substituted by 1-3 groups of R7; R4, R4a, R4b and R4c are independently i) hydrogen, ii) halogen; other radicals are defined in the claim.

EFFECT: pharmaceutical composition containing effective volume of the claimed compound.

13 cl, 1 dwg, 194 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: 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; pharmacology.

SUBSTANCE: invention refers to new benzofuran and benzothiophen derivatives of general formula I, , wherein X is chosen from O and S; R1 is chosen from H, (C1-C6)alkyl, C(O)(C1-C6) alkyl and benzoyl; R2 is chosen from phenyl optionally substituted with 1 or 2 substitutes, each independently chosen from CN, NO2, (C1-C6)alkyl, (C1-C6)alkoxy, halogen, halogen(C1-C6)alkyl, pyridyl or benzo[1,3]dioxolyl optionally substituted with (C1-C6)alkyl. There are disclosed pharmaceutical composition based on compounds I and method of treatment.

EFFECT: compounds can be used to treat or prevent diseases associated with malignant cell proliferation.

26 cl, 7 tbl, 365 ex

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

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

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