Derivatives of nicotine- or isonicotine-benzothiazole and medicinal agent

FIELD: organic chemistry, medicine, pharmacy.

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

EFFECT: valuable medicinal properties of compounds and agent.

37 cl, 10 sch, 109 ex

 

The present invention relates to compounds of General formula

where

R1means phenyl, piperidine-1-yl or morpholinyl,

A represents-O-, and

R is -(CH2)n-N(R")-C(O)-(ness.)alkyl, -(CH2)n-O-(ness.)alkyl, -(CH2)n-O-(CH2)n-O-(ness.)alkyl, (ness.)alkyl, -(CH2)n-morpholinyl, -(CH2)n-phenyl, (CH2)n-N(R')2, -(CH2)n-pyridinyl, -(CH2)n-CF3, -(CH2)n-2-oxopyrrolidin or4-C6-cycloalkyl,

R" independently of one another denotes hydrogen or (ness.)alkyl, and

n is 1 or 2, or

A represents-N(R')-, a

R means (ness.)alkyl, C4-C6-cycloalkyl, -(CH2)n-O-(ness.)alkyl, -(CH2)n-pyridinyl, -(CH2)n-piperidinyl, -(CH2)n-phenyl, -(CH2)n-N(R")-C(O)-(ness.)alkyl, -(CH2)n-morpholinyl or -(CH2)n-N(R')2,

R' and R" independently of one another denote hydrogen or (ness.)alkyl, and

n is 1 or 2, or

And means-CH2-and

R is-N(R")-(CH2)m-O-(ness.)alkyl, -N(R')2S-(ness.)alkyl or R means azetidinol, pyrrolidinyl or piperidinyl, are not substituted by hydroxyl or (ness.)alkoxygroup, or R means morpholinyl, -N(R")-(CH2/sub> )m-(C4-C6)cycloalkyl, -N(R")-(CH2)m-C(O)O-(ness.)alkyl, -N(R")-(CH2)m-C(O)OH, -2-oxopyrrolidin, -N(R")-C(O)O-(ness.)alkyl, -O(CH2)m-O-(ness.)alkyl or alkoxy,

R" independently of one another denote hydrogen or (ness.)alkyl, and

m is 1, 2 or 3, or

A represents-S-, and

R means (ness.)alkyl, or

A-R together imply piperazinil, substituted (ness.)by alkyl, -C(O)-(ness.)the alkyl or exography, or A group-R means piperidinyl, substituted (ness.)alkoxygroup or hydroxy-group, or group A-R means morpholinyl, substituted (ness.)the alkyl, or A group-R means-From4-C6-cycloalkyl, azetidin-1-yl, optionally substituted by a hydroxy-group or (ness.)alkoxygroup, or A group-R means thiomorpholine-1,1-dioxo, tetrahydropyran or 2-oxa-5-azabicyclo[2.2.1]hept-5-yl,

and their pharmaceutically acceptable acid additive salts.

It has been unexpectedly found that compounds of General formula I are ligands of the adenosine receptor. In more detail, the compounds of the present invention have high affinity for the receptor And2Aand a high selectivity for receptors And1and a3.

Adenosine modulates a wide range of physiological functions by interacting with surface receptors on specific cells. The possibility of use the of adenosine receptors as targets of drugs was first described in 1982 In structural and metabolic against adenosine close bioactive nucleotides: adenosine triphosphate (ATP), adenosine diphosphate (ADP), the monophosphate (AMP) and cyclic monophosphate (camp), biochemical meteorous agent of S-adenosyl-L-methionine (S-AM), and structurally close to the coenzymes NAD, FAD, and coenzyme A, and also RNA. Adenosine and these related compounds have important roles in regulating many aspects of cellular metabolism and modulation of various types of activity of the Central nervous system.

Receptors adenosine receptors are divided into A1, A2AAnd2Band a3belonging to the family of receptors coupled with G-proteins. Activation of adenosine receptors initiates the mechanism of signal transmission. These mechanisms are dependent on G-protein associated with the receptor. Each of the subtypes of adenosine receptors, as a rule, characterized by the adenylate cyclase effector system that uses as a secondary messenger camp. Receptors A1and a3associated with Gi-proteins that inhibit adenylate cyclase, which leads to lower intracellular level of camp, while the receptors And2Aand a2Bpaired with GS-proteins and activate adenylate cyclase, which increases intracellular levels of camp. It is established that the system is a receptor A 1includes activation of phospholipase C and modulation of potassium and calcium ion channels. Subspecies receptor And3in addition to binding to adenylate cyclase stimulates the phospholipase C and thus activates calcium ion channels.

Currently, the cloned receptor And1(326-328 amino acid residues) of many species (dog, human, rat, dog, chicken, cattle, Guinea pigs), and 90-95% amino acid sequence was identical in many species of mammals. In addition, the cloned receptor And2A(409-412 amino acid residues) dog, rat, human, Guinea pigs and mice. Cloned the receptor A2B(332 amino acid residue) between human and mouse, and the receptor And2B45% homologous receptors A1and a2Aman. Cloned the receptor And3(317-320 amino acid residues) of human, rat, dog, rabbit and sheep.

It is assumed that the receptor subtypes A1and a2Aplay complementary roles in the regulation of adenosine process of energy production. Adenosine, which is a product of metabolic transformation of ATP diffuses out of the cell and acts on the local level, activating adenosine receptors, which stimulate the reduction of oxygen demand (A1or the increase in the supply of keys is oredom (A 2Aand, thus, regulating the balance between energy production and demand in the tissues. The result of the actions of both subtypes of receptors is to increase the amount of oxygen available to the tissues, and protect cells from damage caused by short-term imbalances in the flow of oxygen. One of the important functions of endogenous adenosine is the prevention of damage at the time of injury such as hypoxia, ischemia, hypotension, and seizures.

In addition, it was found that the binding of agonist adenosine receptor with fat cells expressing the receptor And3rats leads to increased concentrations of Insectivora and intracellular calcium, which causes the antigen-induced secretion of inflammatory mediators. Therefore, the receptor And3participates in mediating asthma attacks and other allergic reactions.

Adenosine is a neuromodulator that is able to modulate many aspects of the physiological functions of the brain. Endogenous adenosine, the Central link between energy metabolism and neural activity changes depending on the behavioral status and (Pato)physiological States. In conditions of high demand and limited flow of energy (such as hypoxia, hypogly the Accademia and/or excessive neural activity) adenosine provides an effective protective feedback mechanism. Interaction with adenosine receptors is a promising target for therapeutic intervention for a variety of neurological and psychiatric diseases, such as epilepsy, sleep disorders, disorders of the musculoskeletal system (Parkinson's disease or Huntington's disease), Alzheimer's disease, depression, schizophrenia or drug addiction. The enhanced release of neurotransmitters occurs when an injury such as hypoxia, ischemia and seizures. Finally, these neurotransmitters are responsible for the degeneration of nerve tissue and death of neurons, which leads to brain damage or death of the individual. Therefore, agonists of the receptor And1that mimic the inhibitory action of adenosine on cells of the Central nervous system, can be used as neuroprotective agents. It is assumed that adenosine is an endogenous anticonvulsant agent, inhibiting the release of glutamate from the excited neurons and inhibiting inflammation of the neurons. Therefore, agonists of adenosine can be used as antiepileptic agents. Antagonists of adenosine stimulate the activity of the Central nervous system and are effective as enhancers of cognitive abilities. Selective antagonists And2ahave a therapeutic effect in the treatment of various formsubmit, for example, Alzheimer's disease, and neurodegenerative conditions such as stroke. Antagonists of adenosine receptor And2Amodulate the activity veins GABAergic neurons and manage a calm and coordinated movements, thus opening the possibility of treating the symptoms of Parkinson's disease. In addition, adenosine is involved in several physiological processes, including the effects of sedation, hypnosis, schizophrenia, anxiety, pain, respiration, depression and addiction to narcotic drugs (amphetamine, cocaine, opioids, ethanol, nicotine, cannabinoids). Therefore, medicines acting on adenosine receptors, also have medicinal activity as sedatives, muscle relaxants, antipsychotics, tranquilizers, analgesics, respiratory stimulants and antidepressants for the treatment of substance abuse. In addition, they can be used in the treatment of ADHD (hyperactive condition due to lack of attention).

An important function of adenosine in the cardiovascular system is its cardioprotective action. The level of endogenous adenosine is increased in response to ischemia and hypoxia and protects cardiac tissue during and after injury (pre-processing). When exposed to eceptor A 1agonists may protect against damage caused by myocardial infarction and reperfusion. The modulating influence of receptors A2aon adrenergic function may be important for a variety of disorders, such as ischemic heart disease and heart failure. Antagonists of receptor-A2acan have a therapeutic effect in situations that require enhanced antiadrenergicheskoe response, such as an acute attack of myocardial infarction. Selective antagonists of receptor-A2acan also increase the efficacy of adenosine in the suppression of supraventricular arrythmia.

Adenosine modulates many aspects of kidney function, including the release of renin, the rate of glomerular filtration and renal blood flow. Compounds that are antagonists of the renal actions of adenosine, can be used as a renal protective agent. In addition, antagonists And3and/or A2Bcan be used in the treatment of asthma and other allergic responses.

Modern information about adenosine receptors can be found, for example, in the following publications:

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

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

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

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

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

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

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

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

Am. J. PhysioL, 276, HI 113-1116 (1999) or

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

Objects of the present invention are compounds of formulas IA and IB, the use of compounds of formulas IA and IB and their pharmaceutically acceptable salts for obtaining a drug intended for the treatment of diseases mediated by the receptor adenosine A2the methods of obtaining these compounds, medicines on the basis of the compounds according to the invention and the reception, as well as the use of compounds of formulas IA and IB for the treatment or prevention of diseases associated with the modulation of the adenosine system, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, a neuroprotective effect, schizophrenia, anxiety, pain, respiratory disorder, depression, addiction to narcotic drugs (such as amphetamine, cocaine, opioids, ethanol, nicotine, cannabinoids), asthma, allergic responses, hypoxia, ischaemia, seizure and substance abuse. In addition, the compounds of the present invention can be used as sedatives, muscle relaxants, antipsychotics, anti-epileptics, anticonvulsants and cardioprotective agents for diseases such as coronary heart disease and heart failure. The most preferred and the indications of the present invention are indications, based on the antagonistic action on the receptor adenosine A2Aand including disorders of the Central nervous system, for example the treatment or prevention of Alzheimer's disease, some depression, substance abuse, neuroprotective effect, Parkinson's disease and ADHD.

The term "(ness.)alkyl"used in the text of the application, means a saturated alkyl group with straight or branched chain, containing from 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, etc. Preferred (ness.)alkyl groups are groups containing 1-4 carbon atoms.

The term "cycloalkyl" means a saturated carbocyclic group containing 4-6 carbon atoms.

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

The term "(ness.)alkoxy" means a group in which the alkyl residue has the values listed above, and which is attached via an oxygen atom.

The term "pharmaceutically acceptable acid additive salts" means salts of inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonate acid, a pair of toluensulfonate the I acid, etc.

Preferred compounds of the present invention are the compounds of formula IA, in which R1means morpholinyl, and a represents-O-. More preferred are compounds in which R means cycloalkyl, -(CH2)n-NHC(O)CH3, -(CH2)n-N(R')2, -(CH2)n-O-(ness.)alkyl or (ness.)alkyl, for example the following compounds:

2-(2-methoxyethoxy)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2 ethoxy-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2-methoxy-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2 isopropoxy-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2 cyclohexyloxy-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2 cyclopentyloxy-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2-(2-dimethylaminoethoxy)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide or

2-(2-acetylbenzoate)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide.

Also preferred are compounds of formula IA, in which R1means morpholinyl, And means-O-and R is -(CH2)n-pyridinyl, -(CH2)n-morpholinyl or -(CH2)n-2-oxopyrrolidin, for example, the following connections:

2-benzyloxy-N-(4-methoxy-7-morpholine-4-Elbe societal-2-yl)isonicotinamide,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(pyridine-2-ylethoxy)isonicotinamide,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-[2-(2-oxopyrrolidin-1-yl)ethoxy]isonicotinamide or

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(2-morpholine-4-ylethoxy)isonicotinamide.

Also preferred are compounds of formula IA, in which R1means morpholinyl, And means-NR'-, a R is -(CH2)n-pyridinyl, -(CH2)n-piperidinyl or -(CH2)n-phenyl, or -(CH2)n-morpholinyl, for example, the following connections:

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-[methyl-(2-pyridin-2-retil)amino]isonicotinamide,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(2-pyridin-2-ylethylamine)isonicotinamide,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-[(pyridine-2-ylmethyl)amino]isonicotinamide,

2-[ethyl-(2-pyridin-2-retil)amino]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(2-morpholine-4-ylethylamine)isonicotinamide,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-[methyl(2-piperidine-1-retil)amino]isonicotinamide,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(2-piperidine-1-ylethylamine)isonicotinamide,

2 benzylamino-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

2-(benzylmethylamine)-N-(4-methoxy-7-morpholine-eventhorizon-2-yl)isonicotinamide,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(methylphenethylamino)isonicotinamide or

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-ventilatorassociated.

Also preferred are compounds of formula IA, in which R1means morpholinyl, And means-NR'-, a R means (ness.)alkyl, cycloalkyl, -(CH2)n-O-(ness.)alkyl, -(CH2)n-N(R')2or -(CH2)n-NR"-C(O)-(ness.)alkyl, for example the following compounds:

2-[(2-methoxyethyl)methylamino]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2-(2-methoxyethylamine)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2-[ethyl-(2-methoxyethyl)amino]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2-(2-ethoxyethylene)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2-(2-acetylaminofluorene)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2 cyclohexylamino-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2 cyclopentylamine-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2 cyclobutylamine-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2-(2-diethylaminoethylamine)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-propylaminoethyl.

N-(4-methoxy-7-morpho is in 4-eventhorizon-2-yl)-2-(methylpropylamine)isonicotinamide,

2-(cyclohexylethylamine)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide or

2-[(2-dimethylaminoethyl)methylamino]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide.

Also preferred are compounds of formula IA, in which R1means morpholinyl, And means-CH2-, a R is-N(R")-(CH2)m-O-(ness.)alkyl, S-(ness.)alkyl, -N(R')2, -N(R")-(CH2)m-cycloalkyl or-N(R")-(CH2)m-C(O)O-(ness.)alkyl, for example the following compounds:

2-[(2-methoxyethylamine)methyl]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2-[(2-ethoxyethylene)methyl]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2-[(butylmethylamine)methyl]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2-butylaminoethyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2-diethylaminomethyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-methylaminoanthraquinone,

2-ethylaminomethyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2-[(cyclopropylamino)methyl]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

tert-butyl ether 4-{[4-(4-methoxy-7-morpholine-4-eventhorizon-2-ylcarbonyl)pyridine-2-ylmethyl]amino} butyric acid,

methyl ether [-(4-methoxy-7-morpholine-4-eventhorizon-2-ylcarbonyl)pyridine-2-ylmethyl]methylcarbamate acid,

2-ethylsulfanyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2-{[(2-ethoxyethyl)methylamino]methyl}-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide.

Also preferred are compounds of formula IA, in which R1means morpholinyl, And means-CH3-, a R means pyrrolidinyl, 2-oxopyrrolidin, piperidinyl, which is optionally substituted (ness.)alkoxy or hydroxy-group, or R means morpholinyl or alkoxy, for example the following compounds:

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-pyrrolidin-1-ilmmilmismiliemi,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(2-oxopyrrolidin-1-ylmethyl)isonicotinamide,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(4-methoxypiperidine-1-ylmethyl)isonicotinamide,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-piperidine-1-ilmmilmismiliemi,

2-(4-hydroxypiperidine-1-ylmethyl)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-morpholine-4-ilmmilmismiliemi or

2-methoxymethyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide.

Preferred compounds of the present invention are the compounds of formula IA, in which R means morpholinyl, And mean-S is, for example, the following connections:

N-(4-methoxy-7-morpholine-4-Ivens is a thiazol-2-yl)-2-methylsulfonylmethane or

2-ethylsulfanyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide.

Preferred compounds of the present invention are the compounds of formula IA, in which R1means morpholinyl, a a-R together imply piperazinil, substituted (ness.)by alkyl, -C(O)-(ness.)the alkyl or exography, or A group-R means piperidinyl, substituted (ness.)alkoxy or hydroxy-group, or group A-R means morpholinyl, substituted (ness.)the alkyl, or A group-R is cyclohexyl, azetidin-1-yl, optionally substituted by a hydroxy-group or (ness.)alkoxy, or A group-R means tetrahydropyran, 1,1-diocletianopolis or 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, for example the following compounds:

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide,

2-(4-acetylpiperidine-1-yl)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(4-methyl-3-oxopiperidin-1-yl)isonicotinamide,

2-(4-ethyl-3-oxopiperidin-1-yl)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2-[(2R,6S)-2,6-dimethylmorpholine-4-yl]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2-cyclohexyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2 azetidin-1-yl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

N-(4-methoxy-7-morpholine-4-Elbe societal-2-yl)-2-(4-methoxypiperidine-1-yl)isonicotinamide,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(3-methoxypiperidine-1-yl)isonicotinamide,

2-(3-hydroxypiperidine-1-yl)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(tetrahydropyran-4-yl)isonicotinamide,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-{(1S,4S)-2-oxa-5-azabicyclo [2.2.1]hept-5-1-yl}isonicotinamide,

2-(1,1-dioxo-6-thiomorpholine-4-yl)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2-(3-hydroxyazetidine-1-yl)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2-(3-methoxyisatin-1-yl)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide or

2-(3-ethoxyacetylene-1-yl)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide.

Preferred compounds of the present invention are the compounds of formula IA, in which R1means piperidinyl, a a-R together imply piperazinil, substituted (ness.)the alkyl, for example, the following connection:

N-(4-methoxy-7-piperidine-4-eventhorizon-2-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide.

Preferred compounds of the present invention are the compounds of formula IA, in which R1means phenyl, a represents-O-, a R means (ness.)alkyl, for example, the following connection:

2-methoxy-N-(4-methoxy-7-phenylbenzothiazole-2-yl)isonicotinamide.

Preferable with what disiniame of the present invention are the compounds of formula IA, in which R1means piperidinyl. Preferred above all such compounds in which a represents-CH2-, a R means pyrrolidinyl or morpholinyl, for example, the following connections:

N-(4-methoxy-7-piperidine-1-eventhorizon-2-yl)-2-pyrrolidin-1-ilmmilmismiliemi or

N-(4-methoxy-7-piperidine-1-eventhorizon-2-yl)-2-morpholine-4-ilmmilmismiliemi.

Also preferred are compounds of formula IB, for example, such compounds in which R1means morpholinyl, And means-O-, and R means (ness.)alkyl, -(CH2)2-O-(ness.)alkyl or cycloalkyl, for example, the following connections:

6-methoxy-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)nicotinamide,

6 isopropoxy-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)nicotinamide,

6-(2-methoxyethoxy)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)nicotinamide or

6 cyclohexyloxy-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)nicotinamide.

The above compounds of formulas IA and IB and their pharmaceutically acceptable salts get known methods, for example as described below, which includes

a) interaction of the compounds of formula

with the compound of the formula

in the presence of a base to form compounds of formula

where R is -(CH2)n-N(R")-C(O)-(ness.)alkyl, -(CH2)n-O-(ness.)alkyl,(CH2)n-O-(CH2)n-O-(ness.)alkyl, (ness.)alkyl, -(CH2)n-morpholinyl, -(CH2)n-phenyl, (CH2)n-N(R')2, -(CH2)n-pyridinyl, -(CH2)n-CF3, -(CH2)n-2-oxopyrrolidin or4-C6cycloalkyl, Y represents chlorine or bromine, a represents O or S, a n is 1 or 2,

b) interaction of the compounds of formula

with the compound of the formula

with the formation of the compounds of formula

where R means (ness.)alkyl, C4-C6cycloalkyl, -(CH2)n-O-(ness.)alkyl, -(CH2)n-pyridinyl, -(CH2)n-piperidinyl, -(CH2)n-phenyl, -(CH2)n-N(R")-C(O)-(ness.)alkyl, -(CH2)n-morpholinyl or -(CH2)n-N(R')2or R and R' together with the nitrogen atom form the following groups: piperazinil, optionally substituted (ness.)the alkyl, C(O)-(ness.)the alkyl or oxopropoxy; piperidinyl, optionally substituted (ness.)alkoxy or hydroxy group; morpholinyl, optionally substituted (ness.)by alkyl; azetidin-1-yl, optionally substituted by a hydroxy-group or (NISS)alkoxy; or thiomorpholine-1,1-dioxo or oxabicyclo[2.2.1]hept-5-yl,

R' and R" independently of one another denote hydrogen or (ness.)alkyl, Y represents chlorine or bromine, and n is 1 or 2, or

C) the interaction of the compounds of formula

with the compound of the formula

with the formation of the compounds of formula

where R is-N(R")-(CH2)m-O-(ness.)alkyl, -N(R')2, -S-(ness.)alkyl or R means azetidinol, pyrrolidinyl or piperidinyl, are not substituted by a hydroxy-group or (ness.)alkoxy, or R means morpholinyl, N(R")-(CH2)m-(C4-C6)cycloalkyl, -N(R")-(CH2)m-C(O)O-(ness.)alkyl, -N(R")-(CH2)m-C(O)HE-2-oxopyrrolidin, -N(R")-C(O)O-(ness.)alkyl, -O(CH2)m-O-(ness.)alkyl or alkoxy,

R" independently of one another denote hydrogen or (ness.)alkyl, a m is 1, 2 or 3, or

g) the interaction of the compounds of formula

with the compound of the formula

with the formation of the compounds of formula

where R is -(CH2)m-O-(ness.)alkyl or (ness.)alkyl, and m is 1, 2 or 3, or

d) the interaction of the compounds of formula

with the compound of the formula

Bu3Sn-A'-R/cut or IN(OH)2-And'-R/cat.

with the education of the compounds of formula

where A'-R together denote With4-C6cycloalkenyl or dihydropyran, a Y means bromine,

followed by the interaction of the compounds of formula IA4 or IB4 with hydrogen in the presence of a catalyst with the formation of the compounds of formula

where A-R together denote With4-C6cycloalkyl or tetrahydropyran, and

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

Compounds of formula IA or IB receive options method a)-d)as shown in schemes 1-10.

The formation of compounds of formula IA or IB, where a represents-O - or-S-, a R is -(CH2)n-N(R")-C(O)-(ness.)alkyl, -(CH2)n-O-(ness.)alkyl, -(CH2)n-O-(CH2)n-O-(ness.)alkyl, (ness.)alkyl, -(CH2)n-morpholinyl, -(CH2)n-phenyl, (CH2)n-N(R')2, -(CH2)n-pyridinyl, -(CH2)n-CF3, -(CH2)n-2-oxopyrrolidin or4-C6cycloalkyl, and n is 1 or 2.

In the first method, compounds of formula IA or IB, where a represents oxygen or sulphur, are obtained from the intermediate derivatives of 2-chloro - or 2-bromosalicylic formula (4A) or intermediate derivatives of 2-chloro-or 2-bromonicotinate formula (4B), as shown below in schemes 1 and 2.

Schemes which 1

In the diagram 1R means -(CH2)n-N(R")-C(O)-(ness.)alkyl, -(CH2)n-O-(ness.)alkyl, -(CH2)n-O-(CH2)n-O-(ness.)alkyl, (ness.)alkyl, -(CH2)n-morpholinyl, -(CH2)n-phenyl, -(CH2)n-N(R')2, -(CH2)n-pyridinyl, -(CH2)n-CF3, -(CH2)n-2-oxopyrrolidin or4-C6cycloalkyl, And means O or S, a n is 1 or 2.

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

Scheme 2

Figure 2 R is -(CH2)n-N(R")-C(O)-(ness.)alkyl, -(CH2)n-O-(ness.)alkyl, -(CH2)n-O-(CH2)n-O-(ness.)alkyl, (ness.)alkyl, -(CH2)n-morpholinyl, -(CH2)n-phenyl, -(CH2)n-N(R')2, -(CH2)n-pyridinyl, -(CH2)n-CF3, -(CH2)n-2-oxopyrrolidin or4-C6cycloalkyl, And means O or S, a n is 1 or 2.

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

Obtaining compounds of formula (2A) or (2B)

The parent compound, 2-horizontina acid or 2-bromsalicilova acid of the formula (1A) or 2-chloronicotinic acid or 2-bromonicotinic acid of the formula (1B), whom are ironscheme drugs (for example, are delivered by the company Maybridge Chemicals) or you can get them known methods.

2 halogencontaining acid of the formula (1A) or 2-halogenating acid of the formula (1B) can be obtained corresponding derived acylhomoserine formula (2A) or (2B) in the interaction of the compounds of formula (1A) or (1B) with an excess of halogenation agent, such as oxacillin or oxalipatin or thionyl chloride or thienylboronic, in the presence of a catalyst such as N,N-dimethylformamide or pyridine, in an organic solvent, preferably dichloromethane or dichloroethane at room temperature for 2-16 h, preferably for 16 hours the Product formula (2) are known ways and preferably used in the next stage without additional purification.

The formation of compounds of the formula (4A) or (4B)

The source of the derived series 2-aminobenzothiazole formula (3) can be obtained by the methods described in EP 00113219.0.

Compounds of formula (4A) or (4B) get in the interaction of derivatives of 2-aminobenzothiazole formula (3) with a slight excess of acylhomoserine formula (2A) or (2B) in an aprotic organic solvent, preferably in a mixture dichlorethane and tetrahydrofuran containing base, preferably N-ethyldiethanolamine or triethylamine, at room temperature for 2-24 h, predpochtitel is but within 24 hours The product of formula (4A) or (4B) was isolated by known methods, and preferably purified by chromatography or recrystallization.

Alternative methods of producing compounds of the formula (4A) or (4B)

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

Obtaining compounds of formula IA1 or IB1 (a represents oxygen or sulfur)

The first method of obtaining compounds of formula IA1 or IB1 is the interaction of the compounds of formula (4A) or (4B) with an excess of the appropriate alcohol or thiol of the formula (5), which is a commercial product, or which can be obtained with known methods and which are selected from primary or secondary aliphatic alcohol or thiol or of an aromatic alcohol or thiol. In each case, the reaction is carried out in the presence of a metal hydride, preferably sodium hydride or potassium hydride. These reactions are conducted in an ethereal solvent such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, preferably dioxane, optionally containing co-solvent, such as N,N-dimethylformamide, at a temperature of from room temperature to the boiling point of the solvent, preferably at about 100°within 2-72 hours, preferably for 16 hours, the Product of formula I, where a represents oxygen or sulfur, isolated by known methods, and preferably purified by chromatography or recrystallization.

Obtaining compounds of formula IA2 and IB2, where a represents-N(R')-, a R means (ness.)alkyl, C4-C6cycloalkyl, -(CH2)n-O-(ness.)alkyl, -(CH2)n-pyridinyl, -(CH2)n-piperidinyl, -(CH2)n-phenyl, -(CH2)n-N(R")-C(O)-(ness.)alkyl, -(CH2)n-morpholinyl or -(CH2)n-N(R')2or R and R' together with the nitrogen atom form the following groups: piperazinil, optionally substituted (ness.)the alkyl, C(O)-(ness.)the alkyl or oxopropoxy; piperidine, optionally substituted (ness.)alkoxy or hydroxy-group; morpholinyl, optionally substituted (ness.)by alkyl; azetidin-1-yl, optionally substituted by a hydroxy-group or(NISS)alkoxy; or thiomorpholine-1,1-dioxo or 2-oxabicyclo[2.2.1]hept-5-yl.

R' and R" independently of one another denote hydrogen or (ness.)alkyl, Y represents bromine, and n is 1 or 2.

In the first method, the compound of formula IA1 or IB1 derived from the intermediate derivatives of 2-bromosalicylic formula (4A) or 2-chloro - or 2-bromonicotinate formula (4B), as shown below in schemes 3 and 4.

Scheme 3

Figure 3 R means (ness.)alkyl, C4-C6cycloalkyl, -(CH2)n-O-(ness.)alkyl, -(CH2)n-pyridinyl, -(CH2)n-piperidinyl, -(CH2)n-phenyl, -(CH2)n-N(R")-C(O)-(ness.)alkyl, -(CH2)n-morpholinyl or -(CH2)n-N(R')2or R and R' together with the nitrogen atom form the following groups: piperazinil, optionally substituted (ness.)the alkyl, C(O)-(ness.)the alkyl or oxopropoxy; piperidinyl, optionally substituted (ness.)alkoxy or hydroxy-group; morpholinyl, optionally substituted (ness.)by alkyl; azetidin-1-yl, optionally substituted by a hydroxy-group or (NISS)alkoxy; or thiomorpholine-1,1-dioxo or 2-oxabicyclo[2.2.1]hept-5-yl, R' and R" independently of one another denote hydrogen or (ness.)alkyl, Y represents bromine, and n is 1 or 2.

Scheme 4

Scheme 4 R means (ness.)alkyl, C4-C6cycloalkyl, -(With the 2)n-O-(ness.)alkyl, -(CH2)n-pyridinyl, -(CH2)n-piperidinyl, -(CH2)n-phenyl, -(CH2)n-N(R")-C(O)-(ness.)alkyl, -(CH2)n-morpholinyl or -(CH2)n-N(R')2or R and R' together with the nitrogen atom form the following groups: piperazinil, optionally substituted (ness.)the alkyl, C(O)-(ness.)the alkyl or oxopropoxy;

piperidinyl, optionally substituted (ness.)alkoxy or hydroxy-group; morpholinyl, optionally substituted (ness.)by alkyl; azetidin-1-yl, optionally substituted by a hydroxy-group or (NISS)alkoxy; or thiomorpholine-1,1-dioxo or 2-oxabicyclo[2.2.1]hept-5-yl, R and R" independently of one another denote hydrogen or (ness.)alkyl, Y represents chlorine or bromine, and n is 1 or 2.

To obtain the compounds of formula IA2 or IB2 2-bromosalicylic formula (4A) or 2-chloro - or 2-bromonicotinate formula (4B) is treated with a large excess of the appropriate amine of formula (6), which is a commercial product, or which is obtained by the known methods and which are selected from primary or secondary aliphatic amine or aromatic amine. In each case, the reaction is carried out in the presence of metal carbonate, preferably cesium carbonate. The above reaction is carried out in the absence of solvent, or optionally in the presence of a solvent, such is AK N,N-dimethylformamide or N-organic, at elevated temperature, preferably at approximately 140°within 2-48 hours, preferably within 24 hours Product formula IA2 or IB2, where a represents nitrogen, isolated by known methods, and preferably purified by chromatography or recrystallization.

The formation of compounds of formula IA or IB, where a represents-CH2-, a R is-N(R")-(CH2)m-O-(ness.)alkyl, -N(R')2, -S-(ness.)alkyl, or R means azetidinol, pyrrolidinyl or piperidinyl, are not substituted by a hydroxy-group or (ness.)alkoxy, or R means morpholinyl, -N(R")-(CH2)m-(C4-C6)cycloalkyl, -N(R")-(CH2)m-C(O)O-(ness.)alkyl, -N(R")-(CH2)m-C(O)HE-2-oxopyrrolidin, -N(R")-C(O)O-(ness.)alkyl, -O(CH2)m-O-(ness.)alkyl or alkoxy, R" independently of one another denote hydrogen or (ness.)alkyl, a m is 1, 2 or 3.

In the first method, compounds of formula IA or IB, where a represents-CH2-receive from the intermediate derivatives of 2-chlorotryptamine formula (A) or 2-chloromethylketone formula (4B-1), as shown below in schemes 5 and 6.

Scheme 5

In scheme 5, compounds of formula IA3-1 R is-N(R")-(CH2)m-O-(ness.)alkyl, -N(R')2, -S-(ness.)alkyl, or R means azetidinol, pyrrolidinyl or piperidinyl that are not necessarily Zam is disposed hydroxy-group or (ness.)alkoxy, or R means morpholinyl, -N(R")-(CH2)m-(C4-C6)cycloalkyl, -N(R")-(CH2)m-C(O)O-(ness.)alkyl, -N(R")-(CH2)m-C(O)HE-2-oxopyrrolidin or-N(R")-C(O)O-(ness.)alkyl, R" independently of one another denote hydrogen or (ness.)alkyl, m is 1, 2 or 3, and in this scheme, the compounds of formula IA3-2 R is -(CH2)m-O-(ness.)alkyl or alkyl.

Scheme 6

In scheme 6, compounds of formula IB3-1 R is-N(R")-(CH2)m-O-(ness.)alkyl, -N(R')2, -S-(ness.)alkyl, or R means azetidinol, pyrrolidinyl or piperidinyl, are not substituted by a hydroxy-group or (ness.)alkoxy, or R means morpholinyl, -N(R")-(CH2)m-(C4-C6)cycloalkyl, -N(R")-(CH2)m-C(O)O-(ness.)alkyl, -N(R")-(CH2)m-C(O)HE-2-oxopyrrolidin, -N(R")-C(O)O-(ness.)alkyl, R" independently of one another denote hydrogen or (ness.)alkyl, m is 1, 2 or 3, and compounds of the formula IB3-2 R is -(CH2)m-O-(ness.)alkyl or alkyl and m is 1, 2 or 3.

In the first method, compounds of formula IA3-1 or IA3-2 and IB3-1 or IB3-2 is obtained from the respectively derived benzothiazol-2-ylamine (3) and 2-chloromethylisothiazolinone (A) or 2-chloromethylisothiazolinone formula (V), as shown below in schemes 7 and 8.

Scheme 7

Scheme

The formation of compounds of formula IA or IB, where a represents-CH2-, a R means O(CH2)m-O-(ness.)alkyl or alkoxy

In the first method, compounds of formula IA3-1, IA3-2, IB3-1 or IB3-2 is produced by treating compound of formula (A) or (B) the excess of the appropriate alcohol of formula (5), which is a commercial product, or which is obtained by the known methods and which are selected from primary or secondary aliphatic alcohol or an aromatic alcohol. In each case, the reaction is carried out in the presence of a metal hydride, preferably sodium hydride or potassium hydride. These reactions are conducted in an ethereal solvent such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, preferably dioxane, optionally containing co-solvent, such as N,N-dimethylformamide, or in the corresponding alcohol, at a temperature of from room temperature to the boiling point of the solvent, preferably at about 100°within 2-72 hours, preferably for 16 hours, the Product of formula I, where a represents CH2Oh, there are the well-known means, and preferably purified by chromatography or recrystallization.

The formation of compounds of formula IA or IB, where a represents-CH2-, a R is-N(R")-(CH2)m-O-(ness.)alkyl, -N(R')2azetidinol, pyrrole inil or piperidinyl, which optionally substituted by a hydroxy-group or (ness.)alkoxy, or R means morpholinyl, -N(R")-(CH2)m-(C4-C6)cycloalkyl, -N(R")-(CH2)m-C(O)O-(ness.)alkyl, -N(R")-(CH2)m-C(O)OH, -2-oxopyrrolidin, -N(R")-C(O)O-(ness.)alkyl, R" independently of one another denote hydrogen or (ness.)alkyl, a m is 1, 2 or 3.

To obtain the compounds of formula IA or IB, where a represents-CH2-2-chlorisondamine formula (A) or (B) is treated with a large excess of the appropriate amine of formula (9), which is a commercial product, or which is obtained by the known methods and which are selected from primary or secondary aliphatic amine or aromatic amine. The above reaction is carried out in the absence of solvent, or optionally in the presence of a solvent such as N,N-dimethylformamide or N-organic, at elevated temperature, preferably at about 60°within 2-48 hours, preferably for 4 hours, the Product of formula I, where a represents-CH2-allocate known means, and preferably purified by chromatography or recrystallization.

Obtaining compounds of formula I, where A-R together denote With4-C6cycloalkyl or tetrahydropyran

The method of obtaining compounds of formula IA4 or IB4 and IA5 or IB5 shown below in schemes 9 and 10.

Schemes is 9

Figure 9 A'-R together denote With4-C6cycloalkenyl or dihydropyran, and A-R together denote With4-C6cycloalkyl or tetrahydropyran.

Scheme 10

Figure 10 A'-R together denote With4-C6cycloalkenyl or dihydropyran, and A-R together denote With4-C6cycloalkyl or tetrahydropyran.

Obtaining compounds of formula IA4 and IB4

The original tributylstannyl formula (7) are commercial products (for example, are made by the company Fluka), or get them known methods.

Compounds of formula IA4 or IB4 are treated as intermediate derivatives of 2-bromosalicylic formula (4A) or intermediate derivatives of 2-bromonicotinate formula (4B) the excess of tributylstannyl formula (7) in an organic solvent, preferably in N,N-dimethylformamide, containing a catalyst based on palladium, preferably chloride bis(triphenylphosphine)palladium (II), in the presence of other additives, such as triphenylphosphine, lithium chloride and 2,6-di-tert-butyl-4-METHYLPHENOL. The reaction is carried out at elevated temperature, preferably at about 100°C for approximately 16-96 h, preferably for about 72 hours Product formula IA4 or IB4 produce by known methods and preferably about what isout chromatography or recrystallization.

Alternative methods of producing compounds of formula IA4 or IB4

Source derived Baranovich acids of the formula (8) are commercial preparations (for example, are made by the company Fluka), or get them known methods.

The compounds of formula IA4 or IB4 are treated as intermediate derivatives of 2-bromosalicylic formula (4A) or intermediate derivatives of 2-bromonicotinate formula (4B) surplus derived Bronevoy acid of formula (8). The reaction is carried out in an aqueous solvent, preferably a mixture of water and dioxane, containing a catalyst based on palladium, preferably chloride bis(triphenylphosphine)palladium (II), and inorganic base, preferably sodium carbonate. The reaction is preferably carried out in the presence of other additives such as triphenylphosphine, lithium chloride and 2,6-di-tert-butyl-4-METHYLPHENOL. The reaction preferably is carried out at the boiling temperature of the solvent, preferably at about 100°With, for approximately 16-96 h, preferably for about 48 hours Product formula IA4 or IB4 allocate known means, and preferably purified by chromatography or recrystallization.

Obtaining compounds of formula IA5 and IB5

Compounds of formula IA5 or IB5 is produced by hydrogenation of compounds of formula IA4 or IB4 in the presence of a catalyst to guide the financing, preferably 10% palladium on coal. the above reaction is carried out in a mixture of organic solvents, preferably in a mixture of methanol and dichloromethane, at room temperature and at a pressure of 1 atmosphere or higher, preferably at one atmosphere, within 2-48 hours, preferably for approximately 16 hours the Product formula IA5 or IB5, where a represents a carbon atom, there are the well-known means, and preferably purified by chromatography or recrystallization.

Isolation and purification of the products obtained

Isolation and purification of the above-described compounds and intermediate products is carried out by any suitable methods of separation and purification such as filtration, extraction, crystallization, chromatography on a column chromatography in thin and thick layer of sorbent, preparative liquid chromatography at low and high pressure, or a combination of these techniques. Specific illustrations of suitable separation techniques and allocation is presented below in the Examples section. However, you can also use other equivalent methods of separation or selection of substances.

Salts of compounds of formulas IA and IB

The compounds of formula IA or IB are the reason, for example, if the remainder is A-R contains a basic group, such as aliphatic or aromatic amine. In such cases, the compounds of formula A or IB can be converted into the corresponding acid additive salt.

Obtaining salts conduct processing at least a stoichiometric amount of the appropriate acid, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. or an organic acid such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonate acid, econsultancy acid, para-toluensulfonate acid, salicylic acid, etc. Usually the base is dissolved in an inert solvent, such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol and the like, and add acid in the same solvent. The temperature of the support 0°C to 50°C. the Obtained salt precipitates, or can be planted from solution by addition of a less polar solvent.

Acid additive salts of the bases of the compounds of formulas IA and IB can be converted into the corresponding free base by treatment with at least the stoichiometric quantity sootvetstvuyuschego base, such as sodium hydroxide or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, etc.

The connection is of the formulae IA and IB and their pharmaceutically acceptable additive salts have valuable pharmacological properties. Specifically, it was found that the compounds of the present invention are ligands of adenosine receptor and have high affinity for adenosine receptor (A2A.

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

The binding of adenosine receptor And2Aperson

Adenosine receptor And2Aman recombinante expressed in egg cells of the Chinese hamster (Cho) using the expression system of the virus Semliki forest. Cells were collected, washed twice by centrifugation, homogenized again and washed by centrifugation. The washed precipitate containing membrane fraction, suspended in a buffer solution of Tris (50 mm, pH 7.4)containing 120 mm NaCl, 5 mm KCl, 2 mm CaCl2and 10 mm MgCl2(buffer solution). The analysis of binding with [3H]-SCH-58261 (1 nm) (Dionisotti and others, Br.J. Pharmacol, 121, 353 (1997)) was performed in 96-well tablets in the presence of 2.5 μg of membrane protein, 0.5 mg of granules SPA, covered with a Ysi-poly-L-lysine and 0.1% adelaideans in the final volume of 200 μl of buffer A. non-specific binding was determined in the presence of related compounds of xanthinuria (KHAS, 2 μm). Binding of the analyzed compounds were determined at 10 concentrations ranging from 10 μm to 0.3 nm. All analyses were performed in repeated experiments that were repeated at least DV is GDI. Analytical plates were incubated at room temperature for 1 h, centrifuged, and determined the amount of bound ligand containing radioactive label, on scintillation counter (Packard Topcount). The value of the IC50was calculated by nonlinear curve using the software, and the values Toiwas calculated by the equation of Cheng-Prussoff.

The preferred compounds of the magnitude of the PKimake up >to 8.5. The magnitude of the pKifor some compounds, reflecting the affinity to the receptor adenosine hA2, are given in the table.

85
Example No.HA2(pKi)Example No.2(PKi)
18,5073a total of 8.74
38,51748,87
48,58758,72
58,58768,76
68,94778,54
88,75808,68
109,14818,62
138,81838,76
158,728,53
178,6386of 9.30
18of 9.21879,07
248,65889,34
269,02898,83
319,00908,76
358,70928,80
408,99938,97
44charged 8.52948,92
478,6958,72
528,8968,79
548,7978,65
568,89which 9.22
588,71008,81
628,81018,90
658,51028,70
708,91038,80
718,71048,50

Compounds of formulas IA and IB and pharmaceutically acceptable salts of compounds of formulas IA and IB can be used is in the quality of medicines, for example, in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally by the way, for example, in the form of pills, tablets in the shell, coated tablets, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, it is also effective introduction rectal method, for example, in the form of suppositories, or parenterally way, for example, in the form of injection solutions.

To obtain pharmaceutical preparations of the compounds of formulas IA and IB can be processed in a mixture with pharmaceutically inert, inorganic or organic carriers. As such carriers upon receipt of tablets, pills in the shell, coated tablets and hard gelatin capsules are used, for example, lactose, corn starch or its derivatives, talc, stearic acid or its salts and the like are Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like, But in the case of soft gelatin capsules, depending on the nature of the active compounds usually do not require any medium. Suitable carriers upon receipt of solutions and syrups are, for example, water, polyols, glycerol, vegetable oils, etc. are Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, W is ture, semi-solid or liquid polyols and the like

Moreover, the pharmaceutical preparations can contain preservatives, soljubilizatory, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for modifying the osmotic pressure, buffer substances, masking agents or antioxidants. In addition, they can contain other therapeutically valuable substances.

Drugs, containing compounds of formulas IA and IB, or their pharmaceutically acceptable salt and a therapeutically inert carrier are also an object of the present invention. The object of the invention is also a method of obtaining these drugs, including the processing of one or more compounds of the formulae IA and IB and/or their pharmaceutically acceptable acid additive salts and optionally one or more other therapeutically valuable substances in a mixture with one or more therapeutically inert carrier in the finished herbal form.

Compounds of formulas IA and IB of the present invention, and their pharmaceutically acceptable salts due to the antagonistic action on adenosine receptor are used for treatment or prevention of diseases, such as Alzheimer's disease, Parkinson's disease, a neuroprotective effect, schizophrenia, anxiety, pain, respiratory disorder, depression, is STMA, allergic responses, hypoxia, ischaemia, seizure and substance abuse. In addition, the compounds of the present invention can be used as sedatives, muscle relaxants, antipsychotics, anti-epileptics, anticonvulsants and cardioprotective agents, and to obtain the drugs.

The most preferred indications in the present invention are indications that include violation of the Central nervous system, for example the treatment or prevention of certain depressive States, a neuroprotective effect and Parkinson's disease.

The dose can vary within wide limits and should be adjusted to the individual requirements in each particular case. In General, when orally administered to adult patients is sufficient daily dose from about 0.01 mg/day to about 1000 mg/day of the compounds of General formula I or the corresponding number of its pharmaceutically acceptable salts. The daily dose is given as a single dose or divided doses and, in addition, in case of appropriate indications, the upper limit can be exceeded.

The composition of the tablets (wet granulation)
Ingredients N mg in one pill
5 mg25 mg100 mg500 mg
1. The compound of formula IA or IB525100500
2. Lactose anhydrous DTG12510530150
3. Starch Sta-Rx 150066630
4. Microcrystalline cellulose303030150
5. Magnesium stearate1111
The total mass167167167831

Method get

1. Components 1, 2, 3 and 4 are mixed and granularit adding purified water.

2. The granules are dried at a temperature of 50°C.

3. The pellets are ground in appropriate mills.

4. Add the component 5 and stirred for 3 min; then pressed tablets on the appropriate tabletirujut equipment.

The capsules

100 mg
Ingredients No.mg in one capsule
5 mg25 mg500 mg
1. The compound of formula IA or IB525100500
2. Hydrated lactose159123148---
3. Corn starch25354070
4. Talc10151025
5. Magnesium stearate1225
The total mass200200300600

Method get

1. Components 1, 2, 3 are mixed in an appropriate mixer for 30 minutes

2. Add components 4 and 5 and mix for 3 minutes

3. The mixture is filled capsules.

Example 1

2-(2-Methoxyethoxy)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

a) 2-Chloro-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

To a stirred solution of 10.8 g (40,8 mmole) of 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine and 17.3 ml (102 mmole) of N-ethyldiethanolamine in 500 ml of THF at 5°C for 90 min was added dropwise a solution of 7.90 g (44,9 mmole) of 2-horizontalvelocity in 250 ml of dichloromethane and the mixture was stirred at room tempera is ur over 16 PM Then the reaction was stopped by adding 30 ml of methanol and the solution was concentrated in vacuum. The remainder resuspendable in ethyl acetate and sequentially washed with a saturated solution of sodium bicarbonate, 0.5 M hydrochloric acid and saturated saline. Then the organic phase was dried over sodium sulfate and concentrated in vacuo to approximately 100 ml of the resulting suspension is kept at room temperature for 72 h, was added 100 ml of ether and stirred at room temperature for 1 h, the Crystals were separated by filtration and dried in vacuum, to receive 9,79 g (59%) of 2-chloro-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide in the form of a crystalline substance brown. MC(ES): m/e (%) 429 (M{37Cl}+Na+, 11), 427 (M{35Cl}+Na+, 30), 407 (M{37Cl}+H+, 30), 405 (M{35Cl}+H+, 100).

b) 2-(2-Methoxyethoxy)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

To mix the solution 0,058 ml (0,74 mmole) of 2-methoxyethanol in 2 ml of dioxane at room temperature was added 49 mg (1,24 mmole) of sodium hydride (60% dispersion in mineral oil) and stirred for 10 minutes To the mixture was added 200 mg (0,49 mmole) of 2-chloro-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide and the mixture was heated at 115°C for 16 hours Then the reaction mixture was cooled to whom atoi temperature, was diluted with ethyl acetate and sequentially washed with 1 M hydrochloric acid and saturated saline. The organic phase was dried over sodium sulfate and concentrated in vacuum. After cleaning substances Express chromatography (eluent: ethyl acetate/toluene 2:1) received 109 mg (50%) of 2-(2-methoxyethoxy)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide in the form of a crystalline substance is yellow. MC(ES): m/e (%) 467 (M+Na+, 16), 445 (M+N+, 100).

The following compound was obtained in the same way as described above:

Example 2

2-[2-(2-Methoxyethoxy)ethoxy]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound, MC(ES): m/e (%) 511 (M+Na+, 13), 489 (M+N+, 100), was obtained from 2-chloro-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide in the presence of sodium hydride and nanometrology ether of diethylene glycol in dioxane.

Example 3

2 Ethoxy-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

a) 2-Bromsalicilova acid

To a stirred solution of 29.0 g (169 mmol) of 2-bromo-4-methylpyridine in 150 ml of concentrated sulfuric acid portions were added to 67.9 g (231 mmol) of potassium bichromate and the reaction mixture was cooled in an ice bath, keeping the temperature in the range of 20-50°C. After completion of addition of reagents, the mixture was stirred at room temperature is in for another 2 hours Then the reaction mixture was slowly poured into 2 l of ice water and stirred for 1 h at room temperature. The obtained crystals were separated by filtration, washed with water until its discoloration and dried in vacuum, to receive 30.0 g (88%) 2-bromoisonicotinic acid in the form of a crystalline substance of white color. MC(EI): m/e (%) 203 (M{81Br}+, 100), 201 (M{79Br}+, 93), 122 ([M-Br]+, 98).

b) 2-Bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

To mix the solution 3,81 g (18,8 mmole) 2-bromoisonicotinic acid in 50 THF was added 7,16 g (18,8 mmole) of HATU and 3.21 ml (18,8 mmole) of N-ethyldiethanolamine and stirred at room temperature for 90 minutes Then to the mixture was added a solution of 5.00 g (18,8 mmole) of 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine in 50 ml of dioxane and 10 ml of DMF and stirred at room temperature for a further 16 hours the Reaction mixture was poured into 300 ml of 1M hydrochloric acid and the mixture was stirred for 20 minutes the resulting crystals were separated by filtration, washed with water, then with ether, and dried in vacuum, to receive 7,53 g (89%) of 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide in the form of a crystalline substance is yellow. MS(EI): m/e (%) 473 (M{81Br}+Na+, 30), 471 (M{79Br}+Na+, 34), 451 (M{81Br}+H+, 100), 449 (M{79Br}+H+, 80).

C) 2-Ethoxy-N(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

To a stirred solution of 0.52 ml (8,90 mmole) of ethanol in 30 ml of dioxane at room temperature was added 486 mg (11.1 mmole) of sodium hydride (55% dispersion in mineral oil) and the mixture was heated at 50°C for 30 minutes To the mixture was added to 1.00 g (of 2.23 mmole) of 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide and the mixture was heated at 115°C for 72 h and Then the reaction mixture was cooled to room temperature and concentrated in vacuum. The remainder resuspendable in dichloromethane and then washed with water and saturated salt solution. The organic phase was dried over sodium sulfate and concentrated in vacuum. The remainder resuspendable in methanol and concentrated in vacuo to 2 ml, was added 20 ml of ether, the obtained crystals were separated by filtration and dried in vacuum, to receive 410 mg (44%) 2 ethoxy-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide in the form of a crystalline substance is light yellow in color. MC(ES): m/e (%) 437 (M+Na+, 24), 414 (M+N+, 100).

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

Example 4

2-Benzyloxy-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound, MC(ES): m/e (%) 499 (M+Na+, 40), 477 (M+N+, 100), was obtained from 2-chloro-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide the presence of sodium hydride and benzyl alcohol in dioxane.

Example 5

2-Methoxy-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound, MC(ES) m/e (%): 423 (M+Na+, 31), 401 (M+N+, 100), was obtained from 2-chloro-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide in the presence of sodium hydride and methanol in dioxane and DMF.

Example 6

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(pyridine-2-ylethoxy)isonicotinamide

Specified in the title compound, MC(ES) m/e (%): 500 (M+Na+, 23), 478 (M+N+, 100), was obtained from 2-chloro-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide in the presence of sodium hydride and 2-hydroxymethylpropane in dioxane.

Example 7

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-2-[methyl(2-pyridin-2-retil)amino]isonicotinamide

Stir a suspension of 200 mg (0.45 mmole) of 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide, 1.23 ml (8,90 mmole) of 2-(2-methylaminomethyl)pyridine and 290 mg (0,89 mmole) of cesium carbonate were placed in a thick-walled glass pressure-resistant test tube with a Teflon stopper and heated at 140°C for 24 h Then the reaction mixture was cooled to room temperature and poured into water. The mixture was extracted three times with dichloromethane, the combined organic phase was washed with saturated saline solution, dried over sodium sulfate and concentrated in vacuum. The resulting product PTS who attended the Express chromatography (eluent: methanol/dichloromethane, from 0:100 to 2.5:97,5) and triturated in ether to receive 160 mg (71%) of N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-[methyl(2-pyridin-2-retil)amino]isonicotinamide in the form of a crystalline substance is light yellow in color. MC(ES): m/e (%) 505 (M+N+, 100).

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

Example 8

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(2-pyridin-2-ylethylamine)isonicotinamide

Specified in the title compound, MC(ES): m/e (%) 491 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinic-amide in the presence of cesium carbonate and 2-(2-amino-ethyl)pyridine in NMP (N-organic).

Example 9

2-[(2-Methoxyethyl)methylamino]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound, MC(ES): m/e (%) 458 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide in the presence of cesium carbonate and N-(2-methoxyethyl)methylamine.

Example 10

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide

Specified in the title compound, MC(ES): m/e (%) 469 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide in the presence of cesium carbonate and 1-methylpiperazine.

Example 11

2-(2-Methoxyethylamine)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound, MC(ES): m/e (%) 444 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide in the presence of cesium carbonate and 2-methoxyethylamine.

Example 12

2-(4-acetylpiperidine-1-yl)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound, MC(ES): m/e (%) 519 (M+Na+, 32), 497 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide in the presence of cesium carbonate and 1-acetylpiperidine.

Example 13

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-2-[(pyridine-2-ylmethyl)amino]isonicotinamide

Specified in the title compound, MC(ES): m/e (%) 477 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)ISO-nicotinamide in the presence of cesium carbonate and 2-picolylamine.

Example 14

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-2-[methyl(2-piperidine-1-retil)amino]isonicotinamide

Specified in the title compound, MC(ES): m/e (%) 511 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide in the presence of cesium carbonate and methyl(2-piperidine-1-retil)-amine.

Example 15

2-(2-Acetylaminofluorene)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound, MC(ES): m/e (%) 493 (M+Na+, 19), 471 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isoniazid is tinamidae in the presence of cesium carbonate and N-acetylethylenediamine.

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

Example 16

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(2,2,2-triptoreline)isonicotinamide

Specified in the title compound, MC(ES): m/e (%) 491 (M+Na+, 81), 469 (M+N+, 100), was obtained from 2-chloro-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide in the presence of sodium hydride and 2,2,2-triptoreline in dioxane and DMF.

Example 17

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-2-[2-(2-oxopyrrolidin-1-yl)ethoxy]isonicotinamide

Specified in the title compound, MC(ES): m/e (%) 520 (M+Na+, 47), 498 (M+N+, 100), was obtained from 2-chloro-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide in the presence of sodium hydride and 1 -(2-hydroxyethyl)-2-pyrrolidone in dioxane.

The following compounds were obtained in the same way as described in example 7.

Example 18

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(2-morpholine-4-ylethylamine)isonicotinamide

Specified in the title compound, MC(ES): m/e (%) 499 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide in the presence of cesium carbonate and 4-(2-amino-ethyl)research.

Example 19

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(2-piperidine-1-ylethylamine)isonicotinamide

Specified in the title compound, MC(ES): m/e (%) 497 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-eventhorizon-2-yl)isonicotinamide in the presence of cesium carbonate and 1-(2-amino-ethyl)piperidine.

Example 20

2-[Ethyl(2-pyridin-2-retil)amino]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound, MC(ES): m/e (%) 519 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide in the presence of cesium carbonate and 2-[2-(ethylamino)ethyl]pyridine.

Example 21

2-[Ethyl(2-methoxyethyl)amino]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound, MC(ES): m/e (%) 472 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide in the presence of cesium carbonate and N-(2-methoxyethyl)ethylamine.

Example 22

2-(2-Ethoxyethylene)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound, MC(ES): m/e (%) 458 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide in the presence of cesium carbonate and 2-ethoxyethylene.

Example 23

2-[(2R,6S)-2,6-Dimethylmorpholine-4-yl]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound, MC(ES): m/e (%), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide in the presence of cesium carbonate and CIS-2,6-dimethylmorpholine.

Example 24

2-Cyclohexyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

a) 2-Cyclohex-1-enyl-N-(4-methoxy-7-morpholine-4-benzothiazol-2-yl)isonicotinamide

To a stirred solution of 400 mg (0,89 mmole) of 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide in 10 ml of DMF was added 661 mg (1,78 mmole) of tri-N-butylcyclohexyl-1-Edelstenne, 75 mg (0.11 mmole) chloride bis(triphenylphosphine)palladium (II), 140 mg (of 0.53 mmole) of triphenylphosphine, 317 mg (of 7.48 mmol) of lithium chloride and at the tip of a spatula of 2,6-di-tert-butyl-4-methyl-phenol. The mixture was heated at 100°C for 72 h, and then concentrated in vacuum. After cleaning, Express chromatography (eluent: methanol/dichloromethane, 2:98) received 520 mg solid orange color, consisting mainly of 2-cyclohex-1-enyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide, which was used in the next stage without additional purification. MC(ES): m/e (%) 451 (M+N+, 100).

b) 2-Cyclohexyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

To a stirred solution of 585 mg (theoretical maximum number of 1.30 mmole) of the crude 2-cyclohex-1-enyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide in 5 ml of methanol and 10 ml of dichloromethane was added 500 g of 10% palladium on coal and the resulting mixture was stirred for 16 h at room temperature in a hydrogen atmosphere. The mixture was filtered, washed with dichloromethane and the filtrate was concentrated in vacuum. The resulting substance was purified Express chromatography (eluent: methane is/dichloromethane, 1:19) and triturated in ether and pentane, to receive 125 mg (21%) 2-cyclohexyl-N-(4-methoxy-7-morpholine-4-albenza-thiazol-2-yl)isonicotinamide in the form of crystalline substances off-white color. MC(ES): m/e (%) 475 (M+Na+, 26), 453 (M+N+, 100).

The following compounds were obtained in the same way as described in example 7.

Example 25

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(4-methyl-3-oxo-piperazine-1-yl)isonicotinamide

Specified in the title compound, MC(ES): m/e (%) 505 (M+Na+, 31), 483 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide in the presence of cesium carbonate and 1-methylpiperazin-2-it.

Example 26

2 azetidin-1-yl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound, MC(ES): m/e (%) 426 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide in the presence of cesium carbonate and azetidine.

Example 27

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(4-methoxypiperidine-1-yl)isonicotinamide

Specified in the title compound, MC(ES): m/e (%) 484 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide in the presence of cesium carbonate and 4-methoxypiperidine.

Example 28

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(3-methoxypiperidine-1-yl)isonicotinamide

Specified in the header is the connection, MC(ES): m/e (%) 484 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide in the presence of cesium carbonate and 3-methoxypiperidine.

Example 29

2-(4-Ethyl-3-oxopiperidin-1-yl)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound, MC(ES): m/e (%) 519 (M+Na+, 28), 497 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide in the presence of cesium carbonate and 1-ethylpiperazin-2-it).

The following compound was obtained in the same way as described in example 24.

Example 30

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(tetrahydropyran-4-yl)isonicotinamide

Specified in the title compound, MC(ES): m/e (%) 477 (M+Na+, 16), 455 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide in the presence of tri-N-butyl-(3,6-dihydro-2H-Piran-4-yl)stannane, chloride bis(triphenylphosphine)palladium (II), triphenylphosphine, lithium chloride and 2,6-di-tert-butyl-4-METHYLPHENOL in DMF, and then was first made in the presence of palladium on coal in methanol and dichloromethane.

The following compounds were obtained in the same way as described in example 7.

Example 31

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-2-{(1S,4S)-2-oxa-5-azabicyclo [2.2.1] hept-5-yl}isonicotinamide

Specified in the title compound, MC(ES): m/e (%) 590 (M+Na+, 17), 468 (M+N+,100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide in the presence of cesium carbonate hydrochloride and (1S,4S)-(+)-2-Aza-5-oxabicyclo[2.2.1]heptane.

Example 32

2-(3-Hydroxypiperidine-1-yl)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound, MC(ES): m/e (%) 470 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide in the presence of cesium carbonate and 3-hydroxypiperidine.

Example 33

2-(4-Hydroxypiperidine-1-yl)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound, MC(ES): m/e (%) 470 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide in the presence of cesium carbonate and 4-hydroxypiperidine.

Example 34

6 Ethoxy-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)nicotinamide

a) 6-Chloro-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)nicotinamide

To a stirred solution of 1.89 g (7,54 mmole) of 6-chloronicotinic acid in 20 ml of THF was added 2,87 g (7,54 mmole) of HATU and 1.28 ml (7,54 mmole) of N-ethyldiethanolamine and the mixture was stirred at room temperature for 30 minutes Then to the mixture was added a solution of 2.00 g (7,54 mmole) of 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine in 20 ml of dioxane and 4 ml of DMF and stirring continued at room temperature for 16 hours the Reaction to shift the b was poured into 350 ml of water and stirred within 30 minutes The obtained crystals were separated by filtration, washed with methanol and ether, dried in vacuum, to receive 3.03 g (99%) 6-chloro-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)nicotinamide as a crystalline substance is yellow. MC(EI): m/e (%) 429 (M{37Cl}+Na+, 15), 427 (M{35Cl}+Na+, 38), 407 (M{37Cl}+H+, 40), 405 (M{35Cl}+H+, 100).

b) 6-Ethoxy-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)nicotinamide

To a stirred solution of 0.24 ml (4,94 mmole) of ethanol in 5 ml of dioxane at room temperature was added 270 mg (6,18 mmole) of sodium hydride (55% dispersion in mineral oil) and the mixture was heated at 50°C for 30 minutes To the mixture was added 500 mg (1,23 mmole) of 2-chloro-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)nicotinamide and the mixture was heated at 80°C for 16 hours Then the reaction mixture was cooled to room temperature and poured into water. The mixture was extracted three times with dichloromethane, the combined organic phases were dried over sodium sulfate and concentrated in vacuum. The obtained product was purified Express chromatography (eluent: methanol/dichloromethane, 1:99) and triturated in ether, was obtained 270 mg (53%) 6 ethoxy-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)nicotinamide as a crystalline substance of white color. MC(ES): m/e (%) 437 (M+Na+, 26), 415 (M+N+, 100).

The following connection recip is whether the same as explained above.

Example 35

6-Methoxy-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)nicotinamide

Specified in the title compound, MC(ES): m/e (%) 423 (M+Na+, 15), 401 (M+N+, 100), was obtained from 6-chloro-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)nicotinamide in the presence of sodium hydride and methanol in dioxane and DMF.

Example 36

6-(4-acetylpiperidine-1-yl)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)nicotinamide

Stir a suspension of 200 mg (0,49 mmole) of 6-chloro-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)nicotinamide, 2,53 ml (19,8 mmole) 1-acetylpiperidine and 290 mg (0,89 mmole) of cesium carbonate in 4 ml of NMP, placed in a thick-walled glass pressure-resistant test tube with a Teflon tube, was heated at 120°C for 24 h Then the reaction mixture was cooled to room temperature and poured into water. The mixture was extracted three times with dichloromethane, the combined organic phase was washed with saturated saline solution, dried over sodium sulfate and concentrated in vacuum. The obtained product was purified Express chromatography (eluent: methanol/dichloromethane, 0:99-4:96) and triturated in ether, was obtained 77 mg (31%) of 6-(4-acetylpiperidine-1-yl)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)nicotinamide as a crystalline substance of white color. MC(ES): m/e (%) 519 (M+Na+, 26), 417 (M+N+, 100).

The following compound was obtained the same way as described in example 34.

Example 37

6-(2-Methoxyethoxy)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)nicotinamide

Specified in the title compound, MC(ES): m/e (%) 467 (M+Na+, 24), 445 (M+N+, 100), was obtained from 6-chloro-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)nicotinamide in the presence of sodium hydride and 2-methoxyethanol in dioxane and DMF.

The following compounds were obtained in the same way as described in example 36.

Example 38

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-6-(4-methylpiperazin-1-yl)nicotinamide

Specified in the title compound, MC(ES): m/e (%) 469 (M+N+, 100), was obtained from 6-chloro-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)nicotinamide in the presence of cesium carbonate and 1-methylpiperazine in NMP.

Example 39

6-[(2R,6S)-2,6-Dimethylmorpholine-4-yl]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)nicotinamide

Specified in the title compound, MC(ES): m/e (%) 506 (M+Na+, 31), 484 (M+N+, 100), was obtained from 6-chloro-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)nicotinamide in the presence of cesium carbonate and CIS-2,6-dimethylmorpholine in NMP.

Example 40

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-6-[(pyridine-2-ylmethyl)amino] nicotinamide

Specified in the title compound, MC(ES): m/e (%) 499 (M+Na+, 19), 477 (M+N+, 100), was obtained from 6-chloro-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)nicotinamide in the presence of cesium carbonate and 2-picolylamine the NMP.

Example 41

6-(2-Methoxyethylamine)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)nicotinamide

Specified in the title compound, MC(ES): m/e (%) 444 (M+N+, 100), was obtained from 6-chloro-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)nicotinamide in the presence of cesium carbonate and 2-methoxyethylamine in NMP.

The following compounds were obtained in the same way as described in example 34.

Example 42

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-6-propoxyimino

Specified in the title compound, MC(ES): m/e (%) 429 (M+N+, 100), was obtained from 6-chloro-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)nicotinamide in the presence of sodium hydride and propanol in dioxane and DMF.

Example 43

6 Butoxy-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)nicotinamide

Specified in the title compound, MC(ES): m/e (%) 465 (M+Na+, 40), 443 (M+N+, 100), was obtained from 6-chloro-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)nicotinamide in the presence of sodium hydride and butanol in dioxane and DMF.

Example 44

6 Isopropoxy-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)nicotinamide

Specified in the title compound, MC(ES): m/e (%) 451 (M+Na+, 20), 429 (M+N+, 100), was obtained from 6-chloro-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)nicotinamide in the presence of sodium hydride and isopropanol in dioxane and DMF.

Example 45

6 Cyclohexyloxy-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)n is codenamed

Specified in the title compound, MC(ES): m/e (%) 491 (M+Na+, 24), 469 (M+N+, 100), was obtained from 6-chloro-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)nicotinamide in the presence of sodium hydride and cyclohexanol in dioxane and DMF.

Example 46

2-{[(2-Methoxyethyl)methylamino]methyl}-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

2-Chloromethyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide (240 mg, 0.55 mmole) was dissolved in N-(2-methoxyethyl)methylamine (1.0 g, 12 mmol) and the mixture was heated at 60°C for 1 h the Volatile components were removed in vacuo, the residue was purified by chromatography on SiO2(eluent:dichloromethane/ethanol 19:1). Specified in the title compound was obtained as yellow crystals (170 mg, 71%yield). MS: m/e 472 (M+N+).

Compounds described in the examples 47-62, obtained according to the General procedure described in example 46.

Example 47

2-[(2-Methoxyethylamine)methyl]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound was obtained from 2-methoxyethylamine in the form of yellow crystals (yield 68%). MS: m/e 458 (M+N+).

Example 48

2-{[Ethyl(2-methoxyethyl)amino]methyl}-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound was obtained from N-ethyl(2-methoxyethyl)amine in the form of a solid off-white color (yield 76%). MS: m/e 486 (MN +).

Example 49

2-{[(Ethoxyethyl)ethylamino]methyl}-N-(4-methoxy-7-morpholine-4-albenza-thiazol-2-yl)isonicotinamide

Specified in the title compound was obtained from N-(2-ethoxyethyl)ethylamine in the form of a solid brown color (yield 67%). MS: m/e 500 (M+N+).

Example 50

2-[(2-Ethoxyethylene)methyl]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound was obtained from 2-ethoxyethylene in the form of a solid yellow (yield 44%). MS: m/e 472 (M+N+).

Example 51

2-[(Butylmethylamine)methyl]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound was obtained from N-butylmethylamine in the form of a solid yellow (yield 70%). MS: m/e 470 (M+N+).

Example 52

2-Butylaminoethyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound was obtained from butylamine in a solid yellow (yield 58%). MS: m/e 456 (M+N+).

Example 53

2-Diethylaminomethyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound was obtained from diethylamine in the form of solid light yellow (yield 55%). MS: m/e 456 (M+N+).

Example 54

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-2-pyrrolidin-1-ilmmilmismiliemi

Specified in is the head of the connection received from pyrrolidine in the form of yellow crystals (yield 63%). MS: m/e 454 (M+N+).

Example 55

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-2-piperidine-1-ilmmilmismiliemi

Specified in the title compound was obtained from piperidine in the form of a solid off-white color (yield 56%). MS: m/e 468 (M+N+).

Example 56

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-2-morpholine-4-ilmmilmismiliemi

Specified in the title compound was obtained from piperidine in the form of a solid light brown color (yield 76%). MS: m/e 470 (M+N+).

Example 57

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(4-methoxypiperidine-1-ylmethyl)isonicotinamide

Specified in the title compound was obtained from 4-methoxypiperidine in the form of a solid light brown color (yield 99%). MS: m/e 498 (M+N+).

Example 58

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-2-methylamino-methylethanolamine

Specified in the title compound was obtained from methylamine in the form of yellow crystals (yield 30%). MS: m/e 414 (M+N+).

Example 59

2-Ethylaminomethyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound was obtained from ethylamine in the form of yellow crystals (yield 70%). MS: m/e 428 (M+N+).

Example 60

2-[(Cyclopropylamino)methyl]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the header is compound was obtained from C-cyclopropanemethylamine in the form of yellow crystals (yield 70%). MS: m/e 454 (M+N+).

Example 61

2 azetidin-1-ylmethyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound was obtained from azetidine in the form of yellow crystals (yield 24%). MS: m/e 440 (M+N+).

Example 62

tert-Butyl ether 4-{ [4-(4-methoxy-7-morpholine-4-eventhorizon-2-ylcarbonyl)pyridine-2-ylmethyl]amino}butyric acid

Specified in the title compound was obtained from tert-butyl ether 4-amino-butyric acid in the form of a solid light brown color (yield 43%). MS: m/e 542 (M+N+).

Example 63

4-{[4-(4-Methoxy-7-morpholine-4-eventhorizon-2-ylcarbonyl)pyridine-2-ylmethyl]amino}butyric acid

Specified in the title compound was obtained in the form of a solid light brown color (yield >95%), MS: m/e 486 (M+N+), when processing tert-butyl ester 4- {[4-(4-methoxy-7-morpholine-4-eventhorizon-2-ylcarbonyl)-pyridine-2-ylmethyl]-amino} butyric acid (214 mg, 0.40 mmole) triperoxonane acid (1.0 ml, 13 mmole).

Example 64

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(2-oxopyrrolidin-1-ylmethyl)isonicotinamide

2-pyrrolidinone (2.0 ml, 26 mmol) was added sodium hydride (45 mg, 1.1 mmole, 60% suspension in mineral oil)in 15 min was added 2-chloromethyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide (210 mg, of 0.50 mmole) and poluchennymi was stirred at 80° C for 3 hours Then the mixture was treated with water (15 ml) and evaporated to dryness. The obtained product was purified Express chromatography (SiO2, eluent: dichloromethane/methanol, 19:1) and recrystallized from dichloromethane/ethanol to receive specified in the title compound as yellow crystals (129 mg, yield 55%). MS: m/e 486 (M+N+).

Example 65

Methyl ester [4-(4-methoxy-7-morpholine-4-eventhorizon-2-ylcarbonyl)pyridine-2-ylmethyl]methylcarbamate acid

A solution of N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-methylamino-methylethanolamine (180 mg, of 0.44 mmole) in tetrahydrofuran (15 ml) was sequentially treated with pyridine (52 μl, 0.65 mmole) and methylchloroform (43 μl, 0.31 in mmole) and stirred at room temperature for 15 hours Then to the mixture was added an additional amount of pyridine (25 μl, 0.31 in mmole) and methylchloroform (20 μl, of 0.26 mmole) and stirred for another 1 hour To the mixture was added a saturated solution of sodium bicarbonate (15 ml) and the mixture was extracted four times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and evaporated to dryness. The obtained product was purified Express chromatography (SiO2, eluent: dichloromethane/methanol, 19:1), to receive specified in the title compound as yellow crystals (115 mg, yield 56%). MS: m/e 472 (M+N+).

2-(2-Methoxyethoxymethyl)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

2-Methoxyethanol (2,6 ml, 48 mmol) was treated at 0°With sodium hydride (38 mg, 0.95 mmole, 60% suspension in mineral oil) and the resulting solution was heated to room temperature over 1 h Then the solution was added a solution of N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-methylaminoanthraquinone (200 mg, 0.48 mmole) in tetrahydrofuran (2.0 ml)and the mixture was stirred at 80°C for 15 hours the Mixture was evaporated to dryness, and treated with a saturated solution of sodium carbonate (20 ml) and four 20 ml was extracted with dichloromethane. The combined organic phase was dried and evaporated. The obtained product was purified Express chromatography (SiO2, eluent: dichloromethane/methanol, 20:0-19:1), to receive specified in the title compound in the form of crystals pale yellow (104 mg, yield 48%). MS: m/e 459 (M+N+).

Example 67

2-Methoxymethyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

A solution of N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-methylaminomethyl-isonicotinamide (200 mg, 0.48 mmole) in tetrahydrofuran (5.0 ml) was treated with sodium methoxide (81 mg, 1.4 mmole) at 0°and the mixture was heated at 50°C for 15 h the Reaction was stopped by adding a saturated solution of sodium carbonate (4.0 ml), caterer the IDT portions 15 ml was extracted with dichloromethane, the combined organic phase was dried and evaporated. The obtained product was purified Express chromatography (SiO2first eluent: dichloromethane/methanol, 0-5%, then dichloromethane/ethyl acetate, from 30% to 60%), while the received specified in the title compound in the form of crystals pale yellow (49 mg, yield 25%). MS: m/e 415 (M+N+).

Obtaining intermediates for the compounds described in the examples 46-67

Example 68 (intermediate compound)

2-Chloromethyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

To a solution of 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine (2.3 g, 87 mmole) in tetrahydrofuran (80 ml) was added N-ethyldiethanolamine (6,0 ml, 35 mmol) and the solution was cooled to 0°C. Then the mixture for 15 min was added a solution of 2-chloro-methylisothiourea (2.4 g, 10.5 mmol) in tetrahydrofuran (50 ml) and the mixture was heated at 70°C for 1 h the Volatile components were evaporated, the residue was dissolved in ethyl acetate and the water was filtered and the residue was combined with the residue obtained after drying and evaporation of the organic phase. After recrystallization from dichloromethane/ethyl acetate has been specified in the title compound in the form of solid light brown color (2.9 g, yield 81%). MS: m/e 420 (M+N+).

Example 69

2-Chloromethylisothiazolinone (intermediate compound)

Marked the th ether 2-chloromethylisothiazolinone acid (obtained, as described Scopes and others; J. Med. Chem. (1992) 35, 492) hydrolyzed in the presence of LiOH in Meon and water. The obtained acid was treated with oxalylamino/dimethylformamide in dichloromethane, to receive specified in the title compound in the form of butter, light brown (yield about 80%)which was used without further purification.

Example 70

N-(4-Methoxy-7-piperidine-1-eventhorizon-2-yl)-2-pyrrolidin-1-yl-methylethanolamine

Specified in the title compound was obtained as crystals, light yellow (yield 67%), MS: m/e 452 (M+N+), from 2-chloromethyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide and pyrrolidine as described in example 46.

Example 71

N-(4-Methoxy-7-piperidine-1-eventhorizon-2-yl)-2-morpholine-4-yl-methylethanolamine

Specified in the title compound was obtained as crystals, light yellow (yield 54%), MS: m/e 468 (M+N+), from 2-chloromethyl-N-(4-methoxy-7-piperidine-1-eventhorizon-2-yl)isonicotinamide and research, as described in example 46.

Obtaining intermediates for the compounds described in examples 70 and 71

Example 72

2-Chloromethyl-N-(4-methoxy-7-piperidine-1-eventhorizon-2-yl)isonicotinamide

Specified in the title compound was obtained as yellow crystals (yield 70%), MS: m/e 417 (M+N+), from 4-methoxy-7-piperidine-1-eventhorizon-2-ylamine is, as described in obtaining 2-chloromethyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide.

Example 73

2-(1,1-Dioxo-6-thiomorpholine-4-yl)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

a) N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-thiomorpholine-4-isonicotinamide

Stir a suspension of 500 mg (1,11 mmole) of 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide and 1.15 g (11.1 mmole) thiomorpholine and 725 mg (2,23 mmole) of cesium carbonate, placed in a thick-walled glass pressure-resistant test tube with a Teflon tube, was heated at 140°C for 48 hours Then the reaction mixture was cooled to room temperature and poured into water. The mixture was extracted three times with ethyl acetate, the combined organic phase was washed with saturated saline solution, dried over sodium sulfate and concentrated in vacuum. The obtained product was purified Express chromatography (eluent: methanol/dichloromethane, 1:99) and triturated in ether/ethyl acetate/hexane, to receive 290 mg (55%) of N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-thiomorpholine-4-isonicotinamide in the form of crystalline substances off-white color. MC(ES): m/e (%) 472 (M+N+, 100).

b) 2-(1,1-Dioxo-6-thiomorpholine-4-yl)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

To a stirred solution of 500 mg (of 1.06 mmole) of N-(4-methoxy-7-morpholine-4-IV societal-2-yl)-2-thiomorpholine-4-isonicotinamide in 5 ml methanol and 5 ml of dichloromethane at room temperature was added 652 mg (1,06 mmole) axona and was stirred for 60 hours Then the reaction was stopped by the careful addition of 5 ml saturated aqueous Hydrosulphite solution of sodium was added sodium bicarbonate solution until the desired pH values. Then the mixture was extracted three times with dichloromethane, the combined organic phases were dried over sodium sulfate and concentrated in vacuum. The obtained product was purified Express chromatography (eluent: methanol/dichloromethane and 0.5:99,5) and triturated in ether to receive 90 mg (17%) of 2-(1,1-dioxo-6-thiomorpholine-4-yl)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide in the form of a crystalline substance is yellow. MC(ES): m/e (%) 504 (M+N+, 100).

The following compound was obtained in the same way as described in example 7.

Example 74

2-(3-Hydroxyazetidine-1-yl)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound, MC(ES): m/e (%) 442 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide in the presence of cesium carbonate and azetidin-3-ol in NMP.

Example 75

2-(3-Methoxyisatin-1-yl)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound, MS (ES): m/e (%) 456 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide hydrochloride and 3-methoxyaniline in the presence of cesium carbonate in NMP.

Example 76

2-3-Ethoxyacetylene-1-yl)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound, MS (ES): m/e (%) 470 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide hydrochloride and 3-ethoxyacetylene in the presence of cesium carbonate in NMP.

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

Example 77

2 Isopropoxy-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound, MS (ES): m/e (%) 429 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide and isopropanol in the presence of sodium hydride in dioxane and DMF.

Example 78

2 Cyclohexyloxy-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound, MS (ES): m/e (%) 469 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide and cyclohexanol in the presence of sodium hydride in dioxane and DMF.

The following compound was obtained in the same way as described in example 7.

Example 79

2 Cyclohexylamino-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound, MS (ES): m/e (%) 468 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide and cyclohexylamine in the presence of cesium carbonate in NMP.

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

Example 80

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-methylsulfonylmethane

Specified in the title compound, MS (ES): m/e (%) 417 (M+H+,100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide and methanolate sodium in dioxane and DMF.

Example 81

2-Ethylsulfanyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound, MS (ES): m/e (%) 431 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide and attentionate sodium in dioxane and DMF.

Example 82

2-Butylsulfonyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound, MS (ES): m/e (%) 459 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide and butanethiol in the presence of sodium hydride in dioxane and DMF.

The following compound was obtained in the same way as described in example 7.

Example 83

2 Benzylamino-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound, MS (ES): m/e (%) 476 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide and benzylamine in the presence of cesium carbonate.

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

Example 84

2 Isobutoxy-N-(4-methoxy-7-Maur the Olin-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound, MS (ES): m/e (%) 443 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide and 2-methylpropanol in the presence of sodium hydride in dioxane and DMF.

Example 85

2 Cyclopentyloxy-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound, MS (ES): m/e (%) 455 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide and Cyclopentanol in the presence of sodium hydride in dioxane and DMF.

Example 86

2-(2-Dimethylaminoethoxy)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound, MS (ES): m/e (%) 458 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide and 2-dimethylaminoethanol in the presence of sodium hydride in dioxane and DMF.

Example 87

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(2-morpholine-4-ylethoxy)isonicotinamide

Specified in the title compound, MS (ES): m/e (%) 500 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide and N-(2-hydroxyethyl)the research in the presence of sodium hydride in dioxane and DMF.

The following compounds were obtained in the same way as described in example 7.

Example 88

2-(2-Diethylaminoethylamine)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide/p>

Specified in the title compound, MS (ES): m/e (%) 457 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide and 2-diethylaminoethylamine in the presence of cesium carbonate.

Example 89

2 Cyclopentylamine-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound, MS (ES): m/e (%) 454 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide and cyclopentylamine in the presence of cesium carbonate.

Example 90

2 Cyclobutylamine-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound, MS (ES): m/e (%) 440 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide and cyclobutylamine in the presence of cesium carbonate.

The following compound was obtained in the same way as described in example 36.

Example 91

6-[Ethyl(2-methoxyethyl)amino]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)nicotinamide

Specified in the title compound, MS (ES): m/e (%) 472 (M+N+, 100), was obtained from 6-chloro-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)nicotinamide and N-(2-methoxyethyl)ethylamine in the presence of cesium carbonate.

The following compound was obtained in the same way as described in example 1.

Example 92

2-(2-Acetylbenzoate)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinate is d

Specified in the title compound, MS (ES): m/e (%) 472 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide and N-acetylethanolamine in the presence of sodium hydride in dioxane.

The following compounds were obtained in the same way as described in example 7.

Example 93

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-propylaminoethyl

Specified in the title compound, MS (ES): m/e (%) 428 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide and Propylamine in the presence of cesium carbonate.

Example 94

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(methylpropylamine)isonicotinamide

Specified in the title compound, MS (ES): m/e (%) 442 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide and N-methyl-N-Propylamine in the presence of cesium carbonate in DMF.

Example 95

2-(Cyclohexylethylamine)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound, MS (ES): m/e (%) 482 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide and N-methylcyclohexylamine in the presence of cesium carbonate.

Example 96

2-(Benzylmethylamine)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound, MS (ES): m/e (%) 490 (M+N+, 10), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide and N-methylbenzylamine in the presence of cesium carbonate.

Example 97

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(methylphenethylamino)isonicotinamide

Specified in the title compound, MS (ES): m/e (%) 504 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide and N-methyl-2-phenethylamine in the presence of cesium carbonate.

Example 98

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-ventilatorassociated

Specified in the title compound, MS (ES): m/e (%) 490 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide and phenethylamine in the presence of cesium carbonate.

Example 99

2-[(2-Dimethylaminoethyl)methylamino]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound, MS (ES): m/e (%) 471 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide and N,NN'-trimethylethylenediamine in the presence of cesium carbonate.

Example 100

N-(4-methoxy-7-piperidine-1-eventhorizon-2-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide

Specified in the title compound, MS (ES): m/e (%) 467 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-piperidine-1-eventhorizon-2-yl)isonicotinamide and N-methylpiperazine in the presence of cesium carbonate.

Trace the abuser compound was obtained in the same way as described in example 1.

Example 101

2-Methoxy-N-(4-methoxy-7-phenylbenzothiazole-2-yl)isonicotinamide

Specified in the title compound, MS (ES): m/e (%) 392 (M+N+, 100), was obtained from 2-bromo-N-(4-methoxy-7-phenylbenzothiazole-2-yl)isonicotinamide and methanol in the presence of sodium hydride in dioxane.

The following compound was obtained from intermediate 68 (2-chloromethyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide) in the same way as described in example 46.

Example 102

2-(4-Hydroxypiperidine-1-ylmethyl)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound was obtained as yellow crystals (yield 68%), tpl.125°S, MS: m/e 484 (M+N+when using 4-hydroxypiperidine.

Example 103

2-Ethylsulfanyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound was obtained as crystals light brown (yield 41%), tpl.158-159°S, MS: m/e 445 (M+N+when using ethanthiol, N-ethyldiethanolamine (1.1 EQ.) and methanolate sodium (1 EQ.).

Example 104

2-{[(2-Ethoxyethyl)methylamino]methyl}-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound was obtained as yellow crystals (yield 41%), tpl.l59-160°C, MS: m/e 486 (M+N+), PR is the use of N-(2-ethoxy)methylethylamine.

Example 105

(S)-2-(2-Methoxypiperidine-1-ylmethyl)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound was obtained in the form of a solid yellow (yield 45%), tpl.110-113°S, MS: m/e 498 (M+N+), using (S)-2-methoxypiperidine.

Example 106

(S)-2-(3-Methoxypiperidine-1-ylmethyl)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound was obtained in the form of solid light yellow (yield 30%), tpl.93-96°C, MS: m/e 498 (M+N+), using (S)-3-methoxypiperidine.

Example 107

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(2-Mei-1-ylmethyl)isonicotinamide

Specified in the title compound was obtained in the form of a solid light brown color (yield 87%), tpl.264-265°S, MS: m/e 465 (M+N+when using 2-methylimidazole and dioxane.

Example 108

2-[(Acetylecholine)methyl]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

N-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-2-methylaminoanthraquinone (207 mg, 0.5 mmole) was dissolved in dichloromethane (10 ml) and treated with pyridine (0,07 ml of 0.85 mmole), acetylchloride (0.05 ml, 0.7 mmole) and stirred at room temperature for 16 hours Then was added a saturated solution of gidrokarbonatnaja (10 ml), the layers were separated and the aqueous phase twice with 10 ml was extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate and evaporated. The product was recrystallized from ethyl acetate, to receive Specified in the title compound in the form of solid light yellow (yield 80%), tpl.228-230°C. MS: m/e 456 (M+N+).

The following compound was obtained in the same way as described in example 108.

Example 109

2-[(Methoxyethylamine)methyl]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide

Specified in the title compound was obtained in the form of a solid yellow (yield 73%), tpl.210°C, MS: m/e 486 (M+N+when using the acid chloride methoxybutanol acid.

1. Compounds of General formula

where R1means phenyl, piperidine-1-yl or morpholinyl, And means-O-and

R is -(CH2)n-N(R")-C(O)-lower alkyl, -(CH2)n-O-lower alkyl, -(CH2)n-O-(CH2)n-O-lower alkyl, lower alkyl, -(CH2)n-morpholinyl, -(CH2)n-phenyl, -(CH2)n-N(R')2, -(CH2)n-pyridinyl, -(CH2)n-CF3, -(CH2)n-2-oxopyrrolidin or4-C6-cycloalkyl,

R" independently will dragoncat hydrogen or lower alkyl, and

n is 1 or 2, or

A represents-N(R')-, a

R means a lower alkyl, C4-C6-cycloalkyl, -(CH2)n-O-lower alkyl, -(CH2)n-pyridinyl, -(CH2)n-piperidinyl, -(CH2)n-phenyl, -(CH2)n-N(R")-C(O)-lower alkyl, -(CH2)n-morpholinyl or -(CH2)n-N(R')2,

R' and R" independently of one another denote hydrogen or lower alkyl, and

n is 1 or 2, or

And means-CH2-, a

R is-N(R")-(CH2)m-O-lower alkyl, -N(R')2, S-lower alkyl, or R means azetidinol, pyrrolidinyl or piperidinyl, are not substituted by a hydroxy-group or lower alkoxy, or R means morpholinyl, -N(R")-(CH2)m-(C4-C6)cycloalkyl, -N(R")-(CH2)m-C(O)O-lower alkyl, -N(R")-(CH2)m-C(O)OH, -2-oxopyrrolidin, -N(R")-C(O)O-lower alkyl, -O(CH2)m-O-lower alkyl or alkoxy,

R" independently of one another denote hydrogen or lower alkyl, and

m is 1, 2 or 3, or

A represents-S-, and

R means a lower alkyl, or

A-R together imply piperazinil, substituted lower alkyl, -C(O)-lower alkyl or exography, or A group-R means piperidinyl, substituted lower alkoxy or hydroxy-group, or group A-R means morpho is inil, substituted lower alkyl, or A group-R means4-C6-cycloalkyl, azetidin-1-yl, optionally substituted by a hydroxy-group or lower alkoxy, or A group-R means thiomorpholine-1,1-dioxo, tetrahydropyran or 2-oxa-5-azabicyclo[2.2.1]hept-5-yl,

and their pharmaceutically acceptable acid additive salt.

2. The compounds of formula IA according to claim 1.

3. Compounds according to claim 2, where R' denotes morpholinyl.

4. Compounds according to claim 3, where a represents-O-.

5. Compounds according to claim 4, where R is cycloalkyl, -(CH2)n-NHC(O)CH3, -(CH2)n-N(R')2, -(CH2)n-O-lower alkyl or lower alkyl.

6. Compounds according to claim 5, which means

2-(2-methoxyethoxy)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2 ethoxy-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2-methoxy-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2 isopropoxy-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2 cyclohexyloxy-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2 cyclopentyloxy-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2-(2-dimethylaminoethoxy)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide or

2-(2-acetylbenzoate)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)ison codenamed.

7. Compounds according to claim 4, where R is -(CH2)n-pyridinyl, -(CH2)n-morpholinyl or -(CH2)n-2-oxopyrrolidin.

8. Compounds according to claim 7, which means:

2-benzyloxy-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(pyridine-2-ylethoxy)isonicotinamide,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-[2-(2-oxopyrrolidin-1-yl)ethoxy]isonicotinamide or

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(2-morpholine-4-ylethoxy)isonicotinamide.

9. Compounds according to claim 3, where a represents-N(R')-.

10. Compounds according to claim 9, where R is -(CH2)n-pyridinyl, -(CH2)n-piperidinyl, -(CH2)n-phenyl, or -(CH2)n-morpholinyl.

11. Connection of claim 10, which means:

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-[methyl(2-pyridin-2-retil)amino] isonicotinamide,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(2-pyridin-2-ylethylamine)isonicotinamide,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-[(pyridine-2-ylmethyl)amino]isonicotinamide,

2-[ethyl-(2-pyridin-2-retil)amino]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(2-morpholine-4-ylethylamine)isonicotinamide,

N-(4-methoxy-7-morpholine-4-avanzati the evils-2-yl)-2-[methyl(2-piperidine-1-retil)amino]isonicotinamide,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(2-piperidine-1-ylethylamine)isonicotinamide,

2 benzylamino-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2-(benzylmethylamine)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(methylphenethylamino)isonicotinamide or

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-ventilatorassociated.

12. Compounds according to claim 9, where R is lower alkyl, cycloalkyl, -(CH2)n-N(R')2, -(CH2)n-O-lower alkyl or -(CH2)n-NR"-C(O)-lower alkyl.

13. Connection 12, which means:

2-[(2-methoxyethyl)methylamino]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-

Il)isonicotinamide,

2-(2-methoxyethylamine)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2-[ethyl(2-methoxyethyl)amino]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2-(2-ethoxyethylene)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2-(2-acetylaminofluorene)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2 cyclohexylamino-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2 cyclopentylamine-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2-cyclobutyl the but-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2-(2-diethylaminoethylamine)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-propylaminoethyl,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(methylpropylamine)isonicotinamide,

2-(cyclohexylethylamine)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide or

2-[(2-dimethylaminoethyl)methylamino]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide.

14. Compounds according to claim 3, where a represents-CH2-.

15. Connection 14, where R is-N(R")-(CH2)m-O-lower alkyl, -N(R')2, -N(R")-(CH2)m-cycloalkyl, -S-lower alkyl or-NR"-(CH2)m-C(O)O-lower alkyl.

16. Connection 15, which means:

2-[(2-methoxyethylamine)methyl]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2-[(2-ethoxyethylene)methyl]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2-[(butylmethylamine)methyl]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2-butylaminoethyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2-diethylaminomethyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-methylaminoanthraquinone,

2-ethylaminomethyl-N-(4-methoxy-7-Maur the Olin-4-eventhorizon-2-yl)isonicotinamide,

2-[(cyclopropylamino)methyl]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

tert-butyl ether 4-{[4-(4-methoxy-7-morpholine-4-eventhorizon-2-ylcarbonyl)pyridine-2-ylmethyl]amino} butyric acid,

methyl ester [4-(4-methoxy-7-morpholine-4-eventhorizon-2-ylcarbonyl)pyridine-2-ylmethyl]methylcarbamate acid,

2-ethylsulfanyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2-{[(2-ethoxyethyl)methylamino]methyl}-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

17. Connection 14, where R is pyrrolidinyl, 2-oxopyrrolidin, piperidinyl, which is optionally substituted by lower alkoxy or hydroxy-group, or R means morpholinyl or lower alkoxy.

18. Connection 17, which means:

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-pyrrolidin-1-ilmmilmismiliemi,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(2-oxopyrrolidin-1-ylmethyl)isonicotinamide,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(4-methoxypiperidine-1-ylmethyl)isonicotinamide.

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-piperidine-1-ilmmilmismiliemi,

2-(4-hydroxypiperidine-1-ylmethyl)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-morpholine-4-yl is utilizedabolished,

2-methoxymethyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide or

19. Compounds according to claim 3, where a represents-S-.

20. Compounds according to claim 19, which means:

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-methylsulfonylmethane or

2-ethylsulfanyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide.

21. Compounds according to claim 3, where A-R together imply piperazinil, substituted lower alkyl, -C(O)-lower alkyl or exography, or A group-R means piperidinyl, substituted lower alkoxy or hydroxy-group, or group A-R means morpholinyl, substituted lower alkyl, or A group-R is cyclohexyl, azetidin-1-yl, optionally substituted by a hydroxy-group or lower alkoxy, or A group-R means tetrahydropyran, 1,1-dioxothiazolidine or 2-oxa-5-azabicyclo[2.2.1]hept-5-Il.

22. Compounds according to item 21, which means:

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide,

2-(4-acetylpiperidine-1-yl)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(4-methyl-3-oxopiperidin-1-yl)isonicotinamide,

2-(4-ethyl-3-oxopiperidin-1-yl)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2-[(2R,65)-2,6-dimethylmorpholine-4-yl]-N-(4-methoxy-7-morpholine-4-eventhorizon-2-is)isonicotinamide,

2-cyclohexyl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2 azetidin-1-yl-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(4-methoxypiperidine-1-yl)isonicotinamide,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(3-methoxypiperidine-1-yl)isonicotinamide,

2-(3-hydroxypiperidine-1-yl)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-(tetrahydropyran-4-yl)isonicotinamide,

N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-2-{(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl}isonicotinamide,

2-(1,1-dioxo-6-thiomorpholine-4-yl)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2-(3-hydroxyazetidine-1-yl)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide,

2-(3-methoxyisatin-1-yl)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide or

2-(3-ethoxyacetylene-1-yl)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)isonicotinamide.

23. Compounds according to claim 2, where R is piperidinyl.

24. Compounds according to item 23, where a represents-CH2-, and R means pyrrolidinyl or morpholinyl.

25. Connection point 24, which means:

N-(4-methoxy-7-piperidine-1-eventhorizon-2-yl)-2-pyrrolidin-1-ilmmilmismiliemi or

N-(4-methoxy-7-piperidin-1-eventhorizon-2-yl)-2-morpholine-4-ilmmilmismiliemi.

26. The compounds of formula IB according to claim 1.

27. Connection p, where R1means morpholinyl.

28. Compounds according to item 27, where a represents-O-, and R means a lower alkyl, -(CH2)2-O-lower alkyl or cycloalkyl.

29. Connection p, which means:

6-methoxy-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)nicotinamide,

6 isopropoxy-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)nicotinamide,

6-(2-methoxyethoxy)-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)nicotinamide or

6 cyclohexyloxy-N-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)nicotinamide.

30. Compounds according to item 23, where A-R together imply piperazinil, substituted lower alkyl.

31. Connection item 30, which means:

N-(4-methoxy-7-piperidine-1-eventhorizon-2-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide.

32. Compounds according to claim 2, where R is phenyl, a represents-O-and R is lower alkyl.

33. Connection p, which means:

2-methoxy-N-(4-methoxy-7-phenylbenzothiazole-2-yl)isonicotinamide.

34. The drug that has the property of ligand adenosine receptors and high affinity to the receptor adenosine A2Acontaining one or more compounds according to any one of claims 1 to 33 and pharmaceutically acceptable excipients.

35. Drug at 34, is suitable for the treatment of diseases, oposredovany the x adenosine receptor And 2A.



 

Same patents:

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound represented by the structural formula: or its pharmaceutically acceptable salt wherein Z represents -(CH2)n-; double dotted line represents a double bond; n = 0-2; R1 and R2 are chosen independently from the group comprising hydrogen atom (H), alkyl with 1-6 carbon atoms; R3 means H, hydroxy-, alkoxy-group with 1-6 carbon atoms, -C(O)OR17 or alkyl with 1-6 carbon atoms; Het means monocyclic heteroaromatic group consisting of 6 atoms and comprising 5 carbon atoms and one heteroatom chosen from nitrogen atom (N) and wherein Het is bound through ring carbon atom and wherein Het-group has one substitute W chosen independently from the group comprising bromine atom (Br), heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N; heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N substituted with OH-substituted alkyl with 1-6 carbon atoms or =O; R21 -aryl-NH-; -C(=NOR17)R18; R21-aryl; R41-heteroaryl representing group consisting of 5-6 atoms comprising 3-5 carbon atoms and 1-4 heteroatoms chosen independently from the group: N, S and O; R8 and R10 are chosen independently from group comprising R1; R9 means H; R11 is chosen from group comprising R1 and -CH2OBn wherein Bn means benzyl; B means -(CH2)n4CR12=CR12a(CH2)n5; n4 and n5 mean independently 0; R12 and R12a are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; X means -O-; Y means =O; R15 is absent as far as double dotted line mean a simple bond; R16 means lower alkyl with 1-6 carbon atoms; R17 and R18 are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; R21 means 1-3 substituted chosen independently from group comprising hydrogen atom, -CN, -CF3, halogen atom, alkyl with 1-6 carbon atoms and so on; R22 is chosen independently from group comprising hydrogen atom; R24-alkyl with 1-10 carbon atoms; R25-aryl and so on; R23 is chosen independently from group comprising hydrogen atom, R24-alkyl with 1-10 carbon atoms, R25-aryl and -CH2OBn; R24 means 1-3 substitutes chosen independently from group comprising hydrogen atom, halogen atom, -OH, alkoxy-group with 1-6 carbon atoms; R25 means hydrogen atom; R41 means 1-4 substitutes chosen independently from group comprising hydrogen atom, alkyl with 1-6 carbon atoms and so on. Also, invention relates to a pharmaceutical composition possessing the inhibitory activity with respect to receptors activated by protease and comprising the effective dose of derivative of nor-seco-chimbacine of the formula (I) and a pharmaceutically acceptable excipient. Also, invention relates to methods for inhibition of thrombin and cannabinoid receptors comprising administration in mammal derivative of nor-seco-chimbacine of the formula (I) in the effective dose as active substance. Invention provides derivatives of nor-seco-chimbacine as antagonists of thrombin receptors.

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

8 cl, 1 tbl, 18 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention elates to derivatives of benzothiazole of the general formula (I): wherein R means hydrogen atom, -(CH2)n-phenyl optionally substituted with a substitute chosen from the following group: halogen atom, (lower)-alkyl, (lower)-alkoxy-group, trifluoromethyl or -N(R')-C(O)-(lower)-alkyl, -(CH2)n-pyridinyl optionally substituted with (lower)-alkyl, -(CH2)n-(C3-C6)-cycloalkyl optionally substituted with hydroxy-group, -(CH2)n-benzo[1,3]dioxolyl, -(CR'2)-thiophenyl, -(CR'2)n-thiazolyl optionally substituted with (lower)-alkyl, -(CH2)n-C(O)-thiophenyl optionally substituted with halogen atom, -(CH2)-furanyl optionally substituted with (lower)-alkyl, -(CHR')n-benzofuran-1-yl, -(CH2)n-benzo[b]thiophenyl, -(CH2)n-N(R')-C(O)-phenyl optionally substituted with halogen atom or (lower)-alkoxy-group. -(CH2)n-C(O)-phenyl optionally substituted with (lower)-alkoxy-group, -(CH2)n-C(O)-2,3-dihydrobenzo[1,4]dioxine-6-yl, -(CH2)n-N(R')-C(O)-pyridinyl, -(CH2)n-tetrahydrofuranyl, -CH-biphenyl, -CH-(phenyl)pyridinyl, -(CH2)n-1-oxo-(CH2)n-CH-(phenyl)tetrahydropyranyl, -(CH2)n-1-oxo-1,2,3,4-tetrahydroquinoline-3-yl or -(CH2)n-S-[1,3,4]thiadiazol-2-yl optionally substituted with amino-group; R' means hydrogen atom or (lower)-alkyl and independently of one another in case R'2; n = 0, 1, 2, 3 or 4. Also, invention relates to a medicament possessing high affinity to adenosine A2A-receptors and high selectivity with respect to A1-receptors and comprising one or more derivatives of benzothiazole of the formula (I) and pharmaceutically acceptable excipients. Invention provides using derivatives of benzothiazole as ligands of adenosine receptors.

EFFECT: valuable medicinal properties of compounds and medicament.

13 cl, 2 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 2-oxo-1-pyrrolidine of the formula (I) or their pharmaceutically acceptable salts wherein X means -CA1NR5R6 or -CA1-R8 wherein A1 and A2 mean independently oxygen atom; R1 means hydrogen atom (H), (C1-C20)-alkyl, (C6-C10)-aryl or -CH2-R1a wherein R1a means (C6-C10)-aryl; R3 means H, -NO2, nitrooxy-group, C≡N, azido-group, -COOH, amido-group, (C1-C20)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C6-C10)-aryl, thiazolyl, oxazolyl, furyl, thienyl, pyrrolyl, tetrazolyl, pyrimidinyl, triazolyl, pyridinyl, -COOR11, -COR11 wherein R11 means (C1-C12)-alkyl; R3a means H, (C1-C20)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl or (C6-C10)-aryl; R5 and R6 are similar or different and each means independently H, (C1-C6)-alkyl, and R8 means -OH and wherein each alkyl can be substituted independently with from 1 to 5 substitutes chosen from halogen atom, isothiocyanate, -OH, -NO2, -CN, azido-group, (C3-C6)-cycloalkyl and (C6-C10)-aryl;, and wherein each (C6-C10)-aryl can be substituted independently with from 1 to 5 substitutes chosen from halogen atom, -NH2, -NO2, azido-group, (C1-C6)-alkoxy-group, (C1-C6)-alkyl and (C1-C6)-halogenalkyl, and wherein each alkenyl can be substituted independently with at least one substitute chosen from halogen atom and -OH, and under condition that at least one radical among R and R3a differs from H, and when compound represent a mixture of possible isomers then X means -CONR5R6; A2 means oxygen atom, and R1 means H, -CH3, -C2H5, -C3H7, and when each R1 and R3a means H and A2 means oxygen atom and X means -CONR5R6 then R3 differs from -COOH, -CH, -COOR11, amido-group, naphthyl, phenyl rings substituted with (C1-C6)-alkoxy-group or halogen atom in para-position in naphthyl or phenyl ring. Compounds of the formula (I) can be used in pharmaceutical compositions for treatment of epilepsy, epileptogenesis, convulsions, epileptic seizures, essential tremor and neuropathic pain.

EFFECT: improved method of synthesis, valuable medicinal properties of derivatives and pharmaceutical compositions.

27 cl, 3 tbl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (1):

and their salts wherein ring A comprises optionally heteroatom oxygen (O); dotted lines represent the optional unsaturation; R1 represents (C1-C4)-alkoxy-group; R2 and R3 represent independently hydrogen atom (H), optionally halogenated (C1-C4)-alkyl, optionally substituted aromatic group, or R2 and R3 in common can form substituted or unsubstituted 5-7-membered ring condensed with ring E; k = 0-4; L1 represents a covalent bond or (C1-C6)-alkyl optionally comprising nitrogen atom (N); X represents unsubstituted or substituted carbon © atom or N, or represents O or sulfur (S) atom; Ar represents phenylene; each n = 0-2 independently; each R represents independently H or (C1-C6)-alkyl; Y represents optionally substituted aromatic or heteroaromatic group or 5-11-membered heterocyclic group comprising 1-4 heteroatoms cgosen from N, O and S that are bound with chemokine receptors comprising CXCR4 and CCR5, and elicit the protective affect against damage of host-cells by human immunodeficiency virus (HIV).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds 2,6-di-tert.-butyl-4-{2-[2-(methylamino)ethyl]-1,3-thiazole-4-yl}phenol, 2,6-di-tert.-butyl-4-[4-(hydroxymethyl)-1,3-oxazole-2-yl]phenol, 4-methylphenyl-2-[4-(1,1-biphenyl-4-yl)-1H-imidazole-2-yl]ethylcarbamate and others or their pharmaceutically acceptable salts. Also, invention relates to using these compounds for preparing a medicinal agent possessing one of the following three activities: inhibition of monoamine oxidases activity, inhibition of lipids peroxidation and modulating activity with respect to sodium channels. Proposed derivatives of thiazole, oxazole or imidazole possess one of the following species of pharmacological activity: inhibition of monoamine oxidases activity, inhibition of lipids peroxidation and modulation of sodium channels.

EFFECT: valuable biochemical and biological properties of derivatives.

34 cl, 119 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new benzofuran derivatives of formula 1 , wherein X represents group of formula -N= or -CH=; Y represents optionally substituted amino group, optionally substituted cycloalkyl group, or optionally substituted saturated heterocycle; A represents direct bond, carbon chain optionally containing double bond in molecular or in the end(s) thereof, or oxygen atom; R1 represents hydrogen, halogen, lower alkoxy, cyano, or amino optionally substituted with lower alkyl B represents optionally substituted benzene ring of formula ; and R2 represents hydrogen or lower alkyl; or pharmaceutically acceptable salt thereof. Invention also relates to pharmaceutical composition containing abovementioned compounds, uses thereof and method for thrombosis treatment.

EFFECT: new compounds for thrombosis treatment.

27 cl, 2 tbl, 429 ex

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

SUBSTANCE: invention relates to compounds of the formula (I)

or their pharmaceutically acceptable salts or esters hydrolyzing in vivo and possessing activity inhibiting the cellular cycle and selective with respect to CDK-2, CDK-4 and CDK-6. Compounds can be used in cancer treatment. In the formula (I) R1 represents halogen atom, amino-group, (C1-C)-alkyl, (C1-C6)-alkoxy-group; p = 0-4 wherein values R1 can be similar or different; R2 represents sulfamoyl or group Ra-Rb-; q = 0-2 wherein values R2 can be similar or different and wherein p + q = 0-5; R3 represents halogen atom or cyano-group; n = 0-2 wherein values R3 can be similar or different; R4 represents hydrogen atom, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, phenyl or heterocyclic group bound with carbon atom wherein R4 can be optionally substituted at carbon atom with one or some groups Rd; R5 and R6 are chosen independently from hydrogen, halogen atom, (C1-C)-alkyl, (C2-C6)-alkenyl or (C3-C8)-cycloalkyl wherein R5 and R6 can be substituted at carbon atom independently of one another with one or some groups Re; Ra is chosen from (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, phenyl, heterocyclic group, phenyl-(C1-C)-alkyl or (heterocyclic group)-(C1-C6)-alkyl wherein Ra can be substituted optionally at carbon atom with one or some groups Rg and wherein if indicated heterocyclic group comprises residue -NH- then its nitrogen atom can be optionally substituted with group chosen from the group Rh; Rb represents -N(Rm)C(O)-, -C(O)N(Rm)-, -S(O)r-, -OC(O)N(Rm)SO2-, -SO2N(Rm)- or -N(Rm)SO2- wherein Rm represents hydrogen atom or (C1-C6)-alkyl, and r = 1-2. Also, invention relates to methods for synthesis of these compounds, a pharmaceutical composition, method for inhibition and using these compounds.

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

24 cl, 3 sch, 166 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new 2-arylimino-2,3-dihydrothiazole derivatives of formula described in claims having affinity and selectivity to somatostatin receptors and useful as drugs for treatment of pathological conditions or diseases mediated by one or more somatostatin receptors, such as acromegalia, chromophone adenoma, endocrine pancreatic tumor, argentaffinoma syndrome, gastrointestinal hemorrhage, etc.

EFFECT: new agent for treatment of pathological conditions or diseases mediated by somatostatin receptors.

6 cl, 2836 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (I) in racemic form, enantiomer form or in any combinations of these forms possessing affinity to somatostatin receptors. In the general formula (I): R1 means phenyl; R2 means hydrogen atom (H) or -(CH2)p-Z3 or one of the following radicals: and Z3 means (C3-C8)-cycloalkyl, possibly substituted carbocyclic or heterocyclic aryl wherein carbocyclic aryl is chosen from phenyl, naphthyl and fluorenyl being it can be substituted, and heterocyclic aryl is chosen from indolyl, thienyl, thiazolyl, carbazolyl, or radicals of the formulae and and it can be substituted with one or some substitutes, or also radical of the formula: R4 means -(CH2)p-Z4 or wherein Z4 means amino-group, (C1-C12)-alkyl, (C3-C8)-cycloalkyl substituted with -CH2-NH-C(O)O-(C1-C6)-alkyl, radical (C1-C6)-alkylamino-, N,N-di-(C1-C12)-alkylamino-, amino-(C3-C6)-cycloalkyl, amino-(C1-C6)-alkyl-(C3-C6)-cycloalkyl-(C1-C6)-alkyl, (C1-C12)-alkoxy-, (C1-C12)-alkenyl, -NH-C(O)O-(C1-C6)-alkyl, possibly substituted carbocyclic or heterocyclic aryl; p = 0 or a whole number from 1 to 6 if it presents; q = a whole number from 1 to 5 if it presents; X means oxygen (O) or sulfur (S) atom n = 0 or 1. Also, invention relates to methods for preparing compounds of the general formula (I), intermediate compounds and a pharmaceutical composition. Proposed compounds can be used in treatment of pathological states or diseases, for example, acromegaly, hypophysis adenomas, Cushing's syndrome and others.

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

11 cl, 2 tbl

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes derivatives of substituted triazoldiamine of the formula (I): wherein R1 represents (C1-C4)-alkyl, phenyl possibly substituted with halogen atom, amino-group substituted with -SO2-(C1-C4)-alkyl, imidazolyl, 1,2,4-triazolyl, imidazolidinone, dioxidoisothiazolidinyl, (C1-C4)-alkylpiperazinyl, residue -SO2- substituted with amino-group, (C1-C4)-alkylamino-group, (C1-C4)-dialkylamino-group, pyridinylamino-group, piperidinyl, hydroxyl or (C1-C4)-dialkylamino-(C1-C3)-alkylamino-group; R2 represents hydrogen atom (H); or R1 represents H and R2 means phenyl possibly substituted with halogen atom or -SO2-NH2; X represents -C(O)-, -C(S)- or -SO2-;R3 represents phenyl optionally substituted with 1-3 substitutes comprising halogen atom and nitro-group or 1-2 substitutes comprising (C1-C4)-alkoxy-group, hydroxy-(C1-C4)-alkyl, amino-group or (C1-C4)-alkyl possibly substituted with 1-3 halogen atoms by terminal carbon atom; (C3-C7)-cycloalkyl possibly substituted with 1-2 groups of (C1-C4)-alkyl; thienyl possibly substituted with halogen atom, (C1-C4)-alkyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C2-C4)-alkenyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, pyrrolyl, pyridinyl or amino-group substituted with -C(O)-C1-C4)-alkyl; (C1-C4)-alkyl substituted with thienyl or phenyl substituted with halogen atom; (C2-C8)-alkynyl substituted with phenyl; amino-group substituted with halogen-substituted phenyl; furyl, isoxazolyl, pyridinyl, dehydrobenzothienyl, thiazolyl or thiadiazolyl wherein thiazolyl and thiadiazolyl are substituted possibly with (C1-C4)-alkyl; to their pharmaceutically acceptable salts, a pharmaceutical composition based on thereof and a method for its preparing. New compounds possess selective inhibitory effect on activity of cyclin-dependent kinases and can be used in treatment of tumor diseases.

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

16 cl, 3 tbl, 26 ex

FIELD: organic chemistry, biochemistry.

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

EFFECT: valuable biochemical and medicinal properties of inhibitors.

17 cl, 5 tbl, 5 ex

FIELD: organic chemistry, medicine, pharmacy.

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

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

18 cl, 138 tbl, 527 ex

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

FIELD: organic chemistry, medicine, pharmacy.

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

EFFECT: valuable medicinal properties of compounds.

7 cl, 2 tbl, 59 ex

FIELD: organic chemistry, herbicides.

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

EFFECT: valuable herbicide properties of substances.

18 cl, 24 tbl, 106 ex

FIELD: organic chemistry.

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

EFFECT: polymorphous crystalline forms of high stability.

12 cl, 1 tbl, 13 dwg, 5 ex

FIELD: medicine, organic chemistry, pharmaceuticals.

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

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

33 cl, 5 tbl, 75 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

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

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

14 cl, 30 tbl, 477 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

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

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

22 cl, 8 tbl, 453 ex

FIELD: organic chemical, pharmaceuticals.

SUBSTANCE: invention relates to new compounds having JAK3 kinase inhibitor activity, methods for production thereof, intermediates, and pharmaceutical composition containing the same. In particular disclosed are aromatic 6,7-disubstituted 3-quinolinecarboxamide derivatives of formula I and pharmaceutically acceptable salts thereof useful in production of drugs for treatment of diseases mediated with JAK3. In formula n = 0 or 1; X represents NR3 or O; Ar is selected from phenyl, tetrahydronaphthenyl, indolyl, pyrasolyl, dihydroindenyl, 1-oxo-2,3-dihydroindenyl or indasolyl, wherein each residue may be substituted with one or more groups selected from halogen, hydroxy, cyano, C1-C8-alkoxy, CO2R8, CONR9R10 C1-C8-alkyl-O-C1-C8-alkyl, etc., wherein R-groups are independently hydrogen atom or C1-C8-alkyl; meanings of other substitutes are as define in description.

EFFECT: new compounds having value biological properties.

17 cl, 222 ex

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

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