2-aminobenzothiazolylureas as adenosine modulators

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to using compounds of the general formula (I): and their pharmaceutically acceptable acid-additive salts. Compounds are used for preparing medicinal agents used in treatment diseases and state associated with system of adenosine receptors A2A, such as Alzheimer's disease, Parkinson's diseases, Huntington's syndrome, schizophrenia, anxiety state, pain, depression, narcomania to such substances as amphetamine, cocaine, opioides, ethyl alcohol, nicotine, cannabinoids, or in treatment of hypoxia, ischemia, epileptic attack. Also, proposed compounds exert neuroprotective effect and can be used as sedative, antipsychotic or anti-epileptic agents.

EFFECT: valuable medicinal properties of compounds.

18 cl, 1 tbl, 49 ex

 

The present invention relates to the use of compounds of General formula

in which

R is lower alkoxygroup or a halogen atom;

R1and R2independently from each other represent a hydrogen atom, lower alkyl, tetrahydropyran-4-yl or cycloalkyl, which is unsubstituted or substituted by one or two substituents selected from the group consisting of halogen atom, lower alkoxy - or hydroxy-group, or

R1and R2together with the nitrogen atom N to which they are linked, form a heterocyclic ring selected from the group consisting of

2-oxa-5-azabicyclo[2.2.1]heptane,

3-endo-hydroxy-8-azabicyclo[3.2.1]octane

2-azabicyclo[2.2.2]octane

1-oxo-2,8-diazaspiro[4.5]decane,

3 azaspiro[5.5]undecane,

8 azaspiro[4.5]decane,

1-oxa-8-azaspiro[4.5]decane,

1,8,8-trimethyl-3-azabicyclo[3.2.1]octane

[1.4]oxazepan,

2-oxa-5-azabicyclo[2.2.2]octane

8-oxa-3-azabicyclo[3.2.1]octane

1,4-diazabicyclo[3.2.1]octane

2-azabicyclo[2.2.1]heptane,

3-azabicyclo[3.2.1]octane

moreover, these rings can be unsubstituted or substituted lower alkyl, or a ring selected from piperazinil, unsubstituted or substituted by one or two groups lower alkyl, phenyl or oxo, or are they selected from piperidine-1-yl, substituted what Rupay -(CH 2)n-NR′S(O)2-(lower)alkyl, -C(O)NR′2or -(CH2)n-phenyl, in which phenyl ring is unsubstituted or substituted lower alkyl;

R′ means a hydrogen atom or lower alkyl, independently of each other in the case of R′2;

X is the group-O - or-CH2and

n is 0, 1, 2, 3,or 4

and to pharmaceutically acceptable acid additive salts of these compounds to obtain drugs for the treatment of diseases associated with the system adenosine receptor And2. Such diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, neuroprotective effect, schizophrenia, anxiety, pain, respiratory disorder, depression, addiction to drugs, such as amphetamine, cocaine, opioids, ethanol, nicotine, cannabinoids, or asthma, allergic responses, hypoxia, ischaemia, seizure and substance abuse. In addition, the compounds of the present invention can be used as sedatives, muscle relaxants, antipsychotic, antiepileptic, anticonvulsant and cardioprotector funds for such violations as coronary artery disease and heart failure. In accordance with the present invention, the most preferred are the testimony to the which is based on the activity of the receptor antagonist A 2Aand which include disorders of the Central nervous system, for example, the treatment or prevention of Alzheimer's disease, some depressive disorders, addiction to drugs, neuroprotective effect, Parkinson's disease, and ADHD (defeat of attention - hyperkinesis).

It has been unexpectedly found that compounds of General formula I are ligands of adenosine receptor. Specifically, the compounds of the present invention have a good affinity And2A-receptor and high selectivity in a1and And3-receptors.

Adenosine modulates a wide range of physiological functions by interacting with specific cell surface receptors. The potential of adenosine receptors in the quality of medicines was first considered in 1982 Adenosine in the structural and metabolic relation associated with biologically active nucleotide - triphosphate (ATP), adenosine diphosphate (ADP), a monophosphate (AMP) and cyclic monophosphate (camp); biochemical meteorous agent

S-adenosyl-L-mational (SAM); and structurally connected with the coenzymes NAD, FAD, and coenzyme A; and RNA. Adenosine together with those of related compounds plays an important role in the regulation of many types of cellular metabolism and in modelirovanie the various activities of the Central nervous system.

Receptors for adenosine were classified as A1, A2AAnd2Band A3receptors belonging to the family of receptors coupled to protein G. the Activation of adenosine receptors adenosine triggers the mechanism of transduction (transfer) signal. These mechanisms depend on G protein associated with the receptor. Each subtype of adenosine receptors traditionally characterized by a system of nerve endings of adenylate cyclase, cyclic amp acts as a second RNA intermediary. Receptors A1and A3coupled with protein Gi, inhibit adenylate cyclase, which leads to decrease in the content of cellular camp, while A2Aand a2Breceptors coupled with G proteinssand activate adenylate cyclase, resulting in increased levels of cellular camp. It is known that the receptor system A1includes activation of phospholipase C and the modulation of ion channels potassium, and calcium. The subtype of A3besides the Association with adenylate cyclase, also stimulates phospholipase C and, thus, are activated ion channels calcium.

Receptor-a1(326-328 amino acids) is cloned from different species (dog, human, rat, chicken, cow, Guinea pig) with 90-95% sequence identity among these mammalian species. Receptor-a2A(409-412 the amino acid is t) is cloned from the dog, rat, human, Guinea-pig and mouse. Receptor And2B(332 amino acids) cloned from human and mouse when 45% of gomologichnosti human receptor And2Bhuman receptors A1and A2A. Receptor-a3(317-320 amino acids) cloned from human, rat, dog, rabbit and sheep.

I believe that subtypes A1and A2Areceptors play an additional role in the regulation of energy supply by using adenosine. Adenosine, which is a product of the metabolism of ATP diffuses from the cell and locally activates adenosine receptors, reducing oxygen consumption (A1or increasing the flow of oxygen (A2Aand, thus, supported the balance between income and consumption of energy within the tissue. Both subtype perform the following functions: increase the number of available oxygen to the tissues and protects cells from damage caused by short-term imbalance of oxygen. One of the important functions of endogenous adenosine is to prevent damage in such diseases as hypoxia, ischemia, hypotension, and seizures.

In addition, it is known that the binding of agonist adenosine receptor with fat cells, expressing And3receptor in rats leads to increased concentrations of Inositol triphosphate and wew is kletochnogo calcium, that increases the secretion of inflammatory mediators induced by antigen. Thus, As3the receptor plays a role in the transmission of asthma attacks and other allergic reactions.

Adenosine is a neuromodulator that is able to adjust many aspects of the physiological activity of the brain. Endogenous adenosine as a Central link between energy metabolism and neural activity changes in accordance with the state of the reaction and (Pato)physiological conditions. In conditions of increased demand and reduced availability of energy (such as hypoxia, hypoglycemia, and/or excessive neural activity), adenosine provides a powerful protective mechanism with feedback. Interaction with adenosine receptors is a promising target for therapeutic intervention in a number of neurological and psychiatric diseases, such as epilepsy, drowsiness, impaired movement (Parkinson's disease or Huntington's, Alzheimer's, depression, schizophrenia, or substance abuse. Diseases such as hypoxia, ischemia and seizures, can be traced by the increased secretion of neurotransmitter. Ultimately, these neurotransmitters are responsible for the degradation and destruction of the nerve, which causes brain damage Il is the death of the individual. Therefore, adenosine A1agonists that mimic Central inhibitory action of adenosine, can be used as neuroprotective agents. Adenosine has been proposed as an endogenous anti-convulsants, inhibiting the secretion of glutamate from stimulating neurons and inhibiting inflammation of the neurons. Therefore, agonists of adenosine can be used as anti-epileptics. Antagonists of adenosine stimulate the activity of the Central nervous system (CNS), and found that these antagonists are an effective means of enhancing cognitive activity. Election And2Aantagonists have therapeutic potential in the treatment of various forms of dementia, such as Alzheimer's disease, and neurodegenerative disorders such as stroke. Antagonists of adenosine A2areceptor correct activity striped gamma aminomalononitrile-eliteskin neurons and regulate smooth and well-coordinated movement, providing, thus, a potential therapy of symptoms of Parkinson's disease. Adenosine is also involved in a number of physiological processes associated with sedation, hypnosis, schizophrenia, anxiety, pain, respiration, depression and drug addiction (addiction to amphetamine, is akainu, opioids, ethyl alcohol, nicotine, cannabinoids). Therefore, drugs acting on adenosine receptors have therapeutic potential as sedatives, muscle relaxants, antipsychotics, tranquilizers, analgesics, respiratory stimulants, antidepressants, and in the treatment of substance abuse. In addition, they can be used in the treatment of ADHD (defeat of attention - hyperkinesis).

The important role of adenosine in the cardiovascular system lies in its cardiotoxins action. In response to ischemia and hypoxia increased the content of endogenous adenosine, which protects cardiac tissue during and after damage (preprocessing). Influencing And1receptor, agonists of the adenosine A1can protect the body from damage caused by myocardial ischemia and reperfusion. Corrective influence And2Areceptors on adrenergic function may be of importance in many disorders, such as ischemia coronary artery disease and heart failure. Antagonists of A2acan be used therapeutically in situations where it is desired increased antiadrainergicakimi reaction, as, for example, in acute myocardial ischemia. In addition, selective antagonists at receptors And2Acan improve the efficiency of adeno is in for the termination of supraventricular arrhythmia.

Adenosine corrects many factors of renal function, including renin secretion, glomerular filtration rate and renal blood flow. Compounds that resist the effects of adenosine on the kidneys, are potential agents for the protection of the kidneys. In addition, adenosine A3and/or And2Bantagonists can be used in the treatment of asthma and other allergic reactions or (and) in the treatment of diabetes and obesity.

The modern level of knowledge about adenosine receptors is reflected in numerous documents, for example in the following publications:

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

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

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

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

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

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

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

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

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

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

In addition, in the application WO 01/57008 described derivative benzothiazolinone and their use as inhibitors of protein kinases. These compounds are used as tyrosine kinase inhibitors that have value in the treatment of hyperproliferative diseases, especially cancer, and in the process of angiogenesis. The following compounds of formulas IA and IB are not included in the scope of the invention WO 01/57008,

Thus, the present invention also relates to new the compounds of formula IA

in which

R means a lower alkoxygroup or halogen atom;

R11and R21together with the nitrogen atom to which they are linked, form a heterocyclic ring selected from the group consisting of

2-oxa-5-azabicyclo[2.2.1]heptane,

3-endo-hydroxy-8-azabicyclo[3.2.1]octane

2-azabicyclo[2.2.2]octane

1-oxo-2,8-diazaspiro[4.5]decane,

3-Aza-Spiro[5.5]undecane,

8-Aza-Spiro[4.5]decane,

1-oxa-8-azaspiro[4.5]decane,

1,8,8-trimethyl-3-Aza-bicyclo[3.2.1]octane

[1.4]oxazepan,

2-oxa-5-azabicyclo[2.2.2]octane

8-oxa-3-azabicyclo[3.2.1]octane

1,4-diazabicyclo[3.2.1]octane

2-azabicyclo[2.2.1]heptane,

3-azabicyclo[3.2.1]octane

moreover, these rings can be nenamesceni or substituted lower alkyl,

or choose from

piperidine-1-yl, substituted by a group -(CH2)n-NR′S(O)2-(lower)alkyl, -C(O)NR′2or -(CH2)n-phenyl, in which phenyl ring may be unsubstituted or substituted lower alkyl;

R′ means a hydrogen atom or lower alkyl, independently of each other in the case of R′2;

X is-O - or-CH2-; and

n is 0, 1, 2, 3 or 4 and

to pharmaceutically acceptable acid additive salts of these compounds.

In addition, the present invention relates to new compounds of the Fort is uly IB

in which

R means a lower alkoxygroup or halogen atom;

R12is lower alkyl and

R22means cycloalkyl substituted by one or two substituents, and these substituents selected from the group consisting of halogen atom, lower alkoxygroup or hydroxy;

X is-O - or-CH2-;

The new compounds of the formula IA in which X is-O-, are, for example, the following:

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide-endo-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide-methyl-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide-oxo-2,8-diazaspiro[4.5]decane-8-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide-benzyl-4-hydroxyethylpiperazine-1-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide-azaspiro[5.5]undecane-3-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide-azaspiro[4.5]decane-8-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 2-Aza-bicyclo[2.2.2]octane-2-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 1-oxa-8-azaspiro[4.5]de is an-8-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide (R)-4-(1-hydroxyethyl)piperidine-1-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide (S)-4-(1-hydroxyethyl)piperidine-1-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 4-(methanesulfonylaminoethyl)-piperidine-1-carboxylic acid,

4-amide-1-[(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide]piperidine-1,4-dicarboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide (1R)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane-3-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 2-oxa-5-azabicyclo[2.2.2]octane-5-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 1,4-diazabicyclo[3.2.1]octane-4-carboxylic acid, or

(4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)amide and (1S,4R)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid.

In addition, the new compounds of the formula IA are those in which x is the group-CH2for example, the following:

(4-methoxy-7-piperidine-1-eventhorizon-2-yl)amide 1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid,

(4-chloro-7-piperidine-1-eventhorizon-2-yl)amide of 4-hydroxy-4-(4-methylbenzyl)piperidine-1-carboxylic acid, or

(4-chloro-7-piperidine-1-eventhorizon-2-yl)amide of 4-benzylpiperidine-1-carboxylic acid.

The new compounds of the formula IB in which X is-O-, are, for example, the following:

1-(4-qi is forcelogix)-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine,

1-(4,4-diverticulosis)-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine,

(CIS)-1-(4-methoxycyclohexyl)-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine,

(TRANS)-1-(4-hydroxycyclohexyl)-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine,

(CIS)-1-(4-hydroxycyclohexyl)-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine or

(TRANS)-1-(4-methoxycyclohexyl)-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine.

Objects of the present invention are the compounds of formula IA or IB, the use of compounds of the formula I and their pharmaceutically acceptable salts to obtain drugs for the treatment of diseases associated with adenosine A2receptor receiving them, drugs are based on compounds according to the invention and the reception, as well as the use of compounds of formula I for the inhibition or prevention of illnesses based on the modulation of adenosine system, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, neuroprotective effect, schizophrenia, anxiety, pain, respiratory disorder, depression, drug addiction (for example, addiction to such substances, such as amphetamine, cocaine, opioids, ethanol, nicotine, cannabinoids, or asthma, allergic responses, hypoxia, ischaemia, seizure Prip the dock and substance abuse. In addition, the compounds of the present invention can be used as sedatives, muscle relaxants, antipsychotic, antiepileptic, anticonvulsant and cardioprotective funds for such violations as coronary artery disease and heart failure. According to the present invention, the most preferred indications are those that are based on activity of antagonist And2Areceptor and which include disorders of the Central nervous system, for example the treatment or prevention of Alzheimer's disease, some depressive disorders, drug addiction, neuroprotective effect and Parkinson's disease, and ADHD.

Used in this invention, the term "(lower) alkyl" means a saturated alkyl group with a normal or branched chain, containing from 1 to 6 carbon atoms, for example methyl, ethyl, propyl, isopropyl,

n-butyl, isobutyl, 2-butyl, tert-butyl and the like, the Preferred lower alkyl groups contain 1-4 carbon atoms.

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

The term "(lower) alkoxy" means a group in which the alkyl residues have the above values and which are joined through an oxygen atom.

The term "pharmaceutically acceptable acid additive salts" embraces salts reorga the systematic 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, p-toluensulfonate acid, etc.

Preferred compounds of the present invention for use against diseases associated with a2Areceptor, are compounds of the formula I, in which X is-O-, for example the following compounds:

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide and (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 3-endo-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 2-methyl-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide of 4-benzyl-4-hydroxyethylpiperazine-1-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 3-azaspiro[5.5]undecane-3-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 8-azaspiro[4.5]decane-8-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 2-azabicyclo[2.2.2]octane-2-carboxylic acid,

(4-methox the-7-morpholine-4-eventhorizon-2-yl)amide 1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide (R)-4-(1-hydroxyethyl)piperidine-1-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide (S)-4-(1-hydroxyethyl)-piperidine-1-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 4-(methanesulfonylaminoethyl)-piperidine-1-carboxylic acid,

4-amide-1-[(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide]piperidine-1,4-dicarboxylic acid,

1-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-3-(tetrahydropyran-4-yl)urea,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide of 4-isopropylpiperazine-1-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide of 4-phenylpiperazin-1-carboxylic acid,

1-cyclohexyl-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine,

1-(4-CIS-forcelogix)-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine,

1-(4-CIS-forcelogix)-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine,

(CIS)-1-(4-methoxycyclohexyl)-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine,

(TRANS)-1-(4-hydroxycyclohexyl)-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide[1.4]oxazepan-4-carboxylic acid,

(CIS)-1-(4-hydroxycyclohexyl)-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)am the d 2-oxa-5-azabicyclo[2.2.2]octane-5-carboxylic acid,

(TRANS)-1-(4-methoxycyclohexyl)-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide and (1S,4R)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid,

3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-methyl-1-(tetrahydropyran-4-yl)urea,

1-cycloheptyl-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine,

1-cyclopentyl-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine or

1-cyclopentyl-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)urea.

In addition, preferred compounds of the present invention for use against diseases associated with a2Areceptor, are the compounds of formula I, in which X stands for a group-CH2-for example, the following connections:

(4-methoxy-7-piperidine-1-eventhorizon-2-yl)amide 1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid,

(4-chloro-7-piperidine-1-eventhorizon-2-yl)amide of 4-hydroxy-4-(4-methylbenzyl)piperidine-1-carboxylic acid,

(4-chloro-7-piperidine-1-eventhorizon-2-yl)amide of 4-benzylpiperidine-1-carboxylic acid,

(4-methoxy-7-piperidine-1-eventhorizon-2-yl)amide of 4-methyl-3-oxopiperidin-1-carboxylic acid, or

1-(4-chloro-7-piperidine-1-eventhorizon-2-yl)-3-cyclohexylamino.

In the present invention the compounds of formula IA or IB and their pharmaceutically acceptable salts can be obtained, the IP is by using known from the prior art methods, for example, the following methods, which are that

a) compound of the formula

interacts with phenylcarbamates and then with the compound of the formula HNR11R21(3A) or HNR11R22(3B),

forming a compound of the formula

which are, as indicated above, and R11and R21together with the nitrogen atom to which they are linked, form a heterocyclic ring selected from the group consisting of 2-oxa-5-azabicyclo[2.2.1]heptane, 3-endo-hydroxy-8-azabicyclo[3.2.1]octane, 2-azabicyclo[2.2.2]octane, 1-oxo-2,8-diazaspiro[4.5]decane, 3-azaspiro[5.5]undecane, 8-azaspiro[4.5]decane, 1-oxa-8-azaspiro[4.5]decane, 1,8,8-trimethyl-3-azabicyclo[3.2.1]octane, [1.4]oxazepan, 2-oxa-5-azabicyclo[2.2.2]octane, 8-oxa-3-azabicyclo[3.2.1]octane, 1,4-diazabicyclo[3.2.1]octane, 2-azabicyclo[2.2.1]-heptane or 3-azabicyclo [3.2.1]octane, and these rings may be unsubstituted or substituted lower alkyl, or are they selected from piperidine-1-yl, substituted by the groups -(CH2)n-phenyl, -(CH2)n-NR′S(O)2-(lower) alkyl, -C(O)NR′2or -(CH2)n-phenyl, in which phenyl ring is unsubstituted or substituted by lower alkyl and R′ means a hydrogen atom or lower alkyl, independently of each other in the case of R′ and the value of n indicated above,

and R12means alkyl and R22is cycloalkyl substituted by one or two substituents, and these substituents selected from the group consisting of halogen atom, lower alkoxy or hydroxy groups; or

if it is desirable to make the compounds obtained into pharmaceutically acceptable acid additive salt.

The compounds of formula IA and IB can be obtained in accordance with variant a) of the method according to the following scheme 1. Scheme 2 illustrates the production of intermediate compounds of the formula (2). In addition, obtaining compounds of formula IA and IB are described in more detail in 37 examples.

in which the substituents such as described above.

Obtaining the compounds of formula IA or IB

Into a solution of the compounds of formula (2), for example 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine, in dichloromethane successively added pyridine and phenylcarbamate and the resulting solution stirred for 45 min at ambient temperature. Then add the compound of the formula (3A) or (3B), for example, (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane, and the mixture was stirred at ambient temperature for 15 minutes and at 40°within 2.5 hours After cooling to ambient temperature, add saturated aqueous solution of sodium carbonate, the PR is onicescu phase is separated and dried.

Obtaining a starting compound of the formula (2) described in the patent EP 00113219.0 as follows:

in which figures 1-5 have the following meanings:

1 morpholine or piperidine, base, Pd-catalyst

2 H2and Pd-C or H2and Raney Ni, or TiCl3or Fe,

3 Ph(CO)NCS,

4 sodium methylate,

5 Br2.

Here R means lower alkoxygroup or halogen atom, and R3means piperidine-1-yl or morpholinyl.

Isolation and purification of compounds

Optionally, the isolation and purification of the compounds described in the invention, intermediate compounds can be carried out using any suitable methods of separation or purification such as filtration, extraction, crystallization, column chromatography, thin layer chromatography, chromatography in a thick layer, preparative liquid chromatography at low or high pressure, or by combinations of these methods. Specific examples of suitable methods of division and separation can be provided below with references to Drugs and Examples of the invention. But, of course, can also be used by other equivalent methods of separation or selection.

Salts of compounds of formula IA or IB

The main groups of compounds of formula IA or IB can be converted into the corresponding acid hell is iTune salt. This transformation is carried out by processing at least a stoichiometric amount of a suitable acid, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. and organic acids 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, p-toluensulfonate acid, salicylic acid, etc. Usually the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethyl alcohol or methyl alcohol, etc. and add acid in the same solvent. The temperature of the support between 0 and 50°C. the Resulting salt precipitates spontaneously or can be deduced from the solution with a less polar solvent.

Acid additive salts of basic compounds of formula I can be converted into the corresponding free base by treating at least a stoichiometric equivalent of a suitable base, such as sodium hydroxide or potassium, to rbonate potassium, sodium bicarbonate, ammonia, etc.

The compounds of formula I 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 the adenosine A2Areceptor and a good selectivity in receptor And1and a3.

Compounds were tested in accordance with test procedure below.

Adenosine A2Areceptor human

Adenosine A2Areceptor human recombinante is expressed in cells of the Chinese hamster ovary (Cho) using the expression system of the virus semliki forest. Cells are harvested, washed twice by centrifugation, homogenized and washed again by centrifugation. Finally the washed precipitate centrifugation suspended in Tris buffer solution (50 mmol/l)containing 120 mmol/l (mM) NaCl, 5 mM KCl, 2 mM CaCl2and 10 mM MgCl2(pH of 7.4) (buffer A). Analysis of the binding is carried out with labeled substrate [3H]-SCH-58261 (Dionisotti et al., 1997, Brit.J.Pharmacol. 121, 353; 10-9mol/l) plates with 96 wells in the presence of 2.5 μg membrane protein, 0.5 mg of beads antigenic complex of Ysi-poly-1-lysine protecting stroma, and 0.1% adenosine-deaminase in a final volume of 200 μl is upernova solution A. Non-specific binding determine using continuingly representative of the same genus (KHAS; 2 µmol/l). Tests were conducted for 10 concentrations of compounds in the range of 10-5-0,3·10-9mol/L. All tests are conducted with duplicate and repeated at least twice. The analyzed tablets allowed to stand for 1 hour at room temperature before centrifugation and then determine the amount of bound ligand using a scintillation counter Packard Topcount. Concentrations of 50% inhibition (IC50) calculated using a nonlinear program for the construction of the empirical curve, and Ki values calculated using the equation of Cheng-Prussoff.

Preferred compounds have a pKi value>7.5.

Example No.hA2(pKi)Example No.hA2(pKi)
18,5198,4
27,9208,5
38,1218,6
48,2227,8
58,2238,1
67,7248,0
78,1 257,7
88,4277,9
97,9287,9
108,0297,9
118,2308,3
128,6327,6
138,6338,3
148,1347,8
158,1357,9
167,8368,1
177,7378,1
187,7

The compounds of formula I and pharmaceutically acceptable salts of compounds of formula I can be used as medicines, for example in the form of pharmaceutical preparations. These pharmaceutical preparations can be administered orally, for example in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the introduction can also be carried out rectally, for example, by suppository, parenteral, for example, in the form of solutions for injection.

To obtain the headlight is aceticacid preparations of compounds of formula I can be processed with pharmaceutically inert, inorganic or organic carriers. As such carriers for tablets, coated tablets, dragées and hard gelatin capsules can be used, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and other Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like, However, depending on the nature of the active substance, in the case of soft gelatin capsules usually do not require any medium. To obtain solutions and syrups are suitable carriers are, for example, water, polyols, glycerine, vegetable oil, etc. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like

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

Drugs, containing a compound of formula I or its pharmaceutically acceptable salt and a therapeutically inert carrier, t is the train are the object of the present invention, as the retrieval method, which is that make one or more compounds of the formula I and/or their pharmaceutically acceptable acid additive salts and, optionally, one or more other therapeutically important substances in a pharmaceutical formulation, together with one or more therapeutically inert carriers.

According to the invention the compounds of formula I and their pharmaceutically acceptable salts are used in the suppression or prevention of the disease caused by the activity of the antagonist of adenosine receptor, such as Alzheimer's disease, Parkinson's disease, neuroprotective effect, schizophrenia, anxiety, pain, breathing problems, depression, asthma, allergic responses, hypoxia, ischaemia, seizure and substance abuse. In addition, the compounds of the present invention can be used as sedatives, muscle relaxants, antipsychotic, antiepileptic, anticonvulsant and cardioprotective funds and to obtain the drugs.

According to the present invention the most preferred indications are those that include disorders of the Central nervous system, for example, the treatment or prevention of certain depressive disorders, neuroprotective effect and shall Olesen Parkinson.

The dosage may vary within wide limits and, of course, must be tailored to suit the individual requirements in each particular case. In the case of oral assignments daily dosage for adults can vary from about 0.01 to 1000 mg of the compounds of General formula I or the corresponding number of pharmaceutically acceptable salts of this compound. The daily dosage may be administered in a single dose or in separate doses and, in addition, the upper limit may be exceeded when it is medically necessary.

The tablet formulation (wet granulation)
Item Componentsin mg (pill)
5 mg25 mg100 mg500 mg
1. The compound of the formula I525100500
2. Anhydrous lactose DTG12510530150
3. Sta-Rx 1500 (starch)66630
4. Microcrystalline cellulose303030150
5. Walls is at magnesium 1111
Only167167167831

The method of cooking

1. Mix components 1, 2, 3 and 4 and the mixture granularit with purified water.

2. Dry the granules at 50°C.

3. Pass the granules through the appropriate grinding device.

4. Add the component 5 and mix for 3 min; tabletirujut on the appropriate media.

Recipe capsules
Item Componentsin mg (per capsule)
5 mg25 mg100 mg500 mg
1. The compound of the formula I525100500
2. Water lactose159123148-
3. Corn starch25354070
4. Talc10151025
5. Magnesium stearate1225
Only200200300600

The method of cooking

1. Mix components 1, 2 and 3 in an appropriate mixer for 30 minutes

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

3. Fill in the appropriate capsule.

The following preparations and examples illustrate this invention, but they are not intended to limit the scope of the invention.

Example 1

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide and (1S,4S)-2-oxa-5-azabicyclo-[2.2.1]heptane-5-carboxylic acid

To a solution of 4-methoxy-7-morpholine-4-eventhorizon-2-ylamine (265 mg, 1.0 mmol) in dichloromethane (15 ml) was successively added pyridine (of 0.24 ml, 3.0 mmol) and phenylcarbamate (0.15 ml, 1.2 mmol) and the resulting solution stirred for 45 min at ambient temperature. Then add (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane (490 mg, 3.6 mmol) and the mixture was stirred at ambient temperature for 15 min and at 40°within 2.5 hours After cooling to ambient temperature, add saturated aqueous solution of sodium carbonate (15 ml); the organic phase is separated, dried and the solvent is evaporated in vacuum. Using flash chromatography (silica, eluent: dichloromethane containing methyl alcohol (gradient from 0 to 5%)), get mentioned in the title compound as white crystals (135 mg, 35% yield). Mass spectrum (MS): m/e=391 (M+N+).

Sledueoschey the method of example 1, there were obtained compounds of examples 2-37.

Example 2

1-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-3-(tetrahydropyran-4-yl)urea

Using tetrahydropyran-4-ylamine, get mentioned in the title compound as white crystals with a yield of 62%. MS: m/e=393 (M+H+).

Example 3

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide 3-endo-hydroxy-8-aspecto[3.2.1]octane-8-carboxylic acid

Using 8-azabicyclo[3.2.1]Octan-3-endo-ol, get mentioned in the title compound as white crystals with a yield of 49%. MS: m/e=419 (M+N+).

Example 4

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide 2-methyl-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylic acid

Using 4-Spiro-[3-(N-methyl-2-pyrrolidinone)]piperidine, get mentioned in the title compound as white crystals with a yield of 43%. MS: m/e=460 (M+H+).

Example 5

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylic acid

Using 4-Spiro-[3-(2-pyrrolidinone)]piperidine, get mentioned in the title compound as white crystals with a yield of 40%. MS: m/e=446 (M+N+).

Example 6

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide of 4-isopropylpiperazine-1-carboxylic acid

Using 1-(2-propyl)piperazine, get mentioned in the title compound as white crystals with a yield of 62%. MS: m/e=420 (M+H+).

Example

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide of 4-phenylpiperazin-1-carboxylic acid

Using 1-phenylpiperazine receive specified in the title compound in the form of white crystals with a yield of 53%. MS: m/e=454 (M+H+).

Example 8

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide of 4-benzyl-4-hydroxyethylpiperazine-1-carboxylic acid

Using (4-benzylpiperidine-4-yl)methyl alcohol, get mentioned in the title compound as light brown solid with a yield of 6%. MS: m/e=497 (M+N+).

Example 9

1-Cyclohexyl-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine

Using cyclohexylethylamine receive specified in the title compound in the form of white crystals with a yield of 73%. MS: m/e=405 (M+H+).

Example 10

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide 3-azaspiro[5.5]undecane-3-carboxylic acid

Using 3-azaspiro[5.5]undecane, get mentioned in the title compound as white crystals with a yield of 38%. MS: m/e=445 (M+H+).

Example 11

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide 8-azaspiro[4.5]decane-8-carboxylic acid

Using 8-azaspiro[4.5]decane, get mentioned in the title compound as white crystals with a yield of 48%. MS: m/e=431 (M+H+).

Example 12

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide 2-azabicyclo[2.2.2]octane-2-carboxylic acid

IP is by using 2-azabicyclo[2.2.2]octane, get listed in the title compound as white crystals with a yield of 47%. MS: m/e=403 (M+H+).

Example 13

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide 1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid

Using 1-oxa-8-azaspiro[4.5]decane, get mentioned in the title compound as white crystals with a yield of 40%. MS: m/e=433 (M+H+).

Example 14

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide (R)-4-(1-hydroxyethyl)piperidine-1-carboxylic acid

Using (R)-4-(1-hydroxyethyl)piperidine, get mentioned in the title compound as white crystals with a yield of 21%. MS: m/e=421 (M+N+).

Example 15

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide (S)-4-(1-hydroxyethyl)piperidine-1-carboxylic acid

Using (S)-4-(1-hydroxyethyl)piperidine, get mentioned in the title compound as white crystals with a yield of 53%. MS: m/e=421 (M+H+).

Example 16

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide 4-(methanesulfonylaminoethyl)piperidine-1-carboxylic acid

Using tert-butyl ether piperidine-4-iletilerinindeki acid, receive tert-butyl ether [1-(4-methoxy-7-morpholine-4-eventhorizon-2-ylcarbonyl)piperidine-4-ylmethyl]carbamino acid as a white solid. Subsequent removal of the protective group triperoxonane acid and interacting with the mixture methanol villoria/pyridine in the standard conditions are specified in the title compound in the form of white crystals with a total yield of 44%. MS: m/e=482 ([M-H+]-).

Example 17

4-Amide-1-[(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide]piperidine-1,4-dicarboxylic acid

Using amide piperidine-4-carboxylic acid, receive specified in the title compound in the form of white crystals with a yield of 44%. MS: m/e=420 (M+N+).

Example 18

(4-Methoxy-7-piperidine-1-eventhorizon-2-yl)amide of 4-methyl-3-oxopiperidin-1-carboxylic acid

Using 4-methoxy-7-piperidine-1-eventhorizon-2-ylamine and 4-methyl-3-oxopiperidin get mentioned in the title compound as a yellow solid with a yield of 84%. MS: m/e=404 (M+N+).

Example 19

(4-Methoxy-7-piperidine-eventhorizon-2-yl)amide 1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid

Using 4-methoxy-7-piperidine-1-eventhorizon-2-ylamine and 1-oxa-8-azaspiro[4.5]decane, get mentioned in the title compound in the form of beige crystals with a yield of 52%. MS: m/e=431 (M+N+).

Example 20

(4-Chloro-7-piperidine-1-eventhorizon-2-yl)amid-hydroxy-4-(4-methylbenzyl)piperidine-1-carboxylic acid

Using 4-chloro-7-piperidine-1-eventhorizon-2-ylamine and 4-hydroxy-4-(4-methylbenzyl)piperidine, get mentioned in the title compound as a white solid with a yield of 70%. MS: m/e=431 (M+N+).

Example 21

1-(4-Chloro-7-piperidine-1-eventhorizon-2-yl)-3-cyclohexylamino

Using 4-chloro-7-piperidine-1-yl is isothiazol-2-ylamine and cyclohexylamine, get listed in the title compound as a white solid with a yield of 73%. MS 394 (M+N+).

Example 22

(4-Chloro-7-piperidine-1-eventhorizon-2-yl)amide of 4-benzylpiperidine-1-carboxylic acid

Using 4-chloro-7-piperidine-1-eventhorizon-2-ylamine and 4-benzylpiperidine get mentioned in the title compound as a white solid with a yield of 80%. MS 470 (M+H+).

Example 23

1-(4-CIS-Forcelogix)-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine

Using (CIS)-(4-forcelogix)methylamine, get mentioned in the title compound as white crystals (yield 24%); melting temperature (tPL) 201-204°C. MS: m/e=423 (M+H+).

Example 24

1-(4,4-Diverticulosis)-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine

Using (4,4-diverticulosis)methylamine, get mentioned in the title compound as white crystals (yield 44%), tPL189-192°C. MS: m/e=441(M+H+).

Example 25

(CIS}-1-(4-Methoxycyclohexyl)-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine

Using (CIS)-(4-methoxycyclohexyl)methylamine, get mentioned in the title compound as white crystals (yield 39%), tPL198-200°C. MS: m/e 435 (M+H+).

Example 26

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide (1R)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane-3-carboxylic to the slots

Using campagin get mentioned in the title compound as white crystals (yield 75%), tPL185-189°C. MS: m/e=445 (M+H+).

Example 27

(TRANS}-1-(4-Hydroxy-cyclohexyl)-3 -(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine

Using (TRANS)-(4-hydroxycyclohexyl)methylamine, get mentioned in the title compound as a whitish solid (yield 44%), tPL158-162°C. MS: m/e=421 (M+N+).

Example 28

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide [1.4]oxazepan-4-carboxylic acid

Using [1.4]oxazepan get mentioned in the title compound as a pale yellow solid (yield 57%), tPL171-172°C. MS: m/e=393 (M+N+).

Example 29

(CIS}-1-(4-Hydroxycyclohexyl)-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine

Using (CIS)-(4-hydroxycyclohexyl)methylamine, get mentioned in the title compound as a white solid (yield 66%), tPL169-171°C. MS: m/e=421 (M+H+).

Example 30

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide 2-oxa-5-azabicyclo[2.2.2]octane-5-carboxylic acid

Using 2-oxa-5-azabicyclo[2.2.2]octane, get mentioned in the title compound as a white solid (yield 69%), tPL164-170°C. MS: m/e=405 (M+H+).

Example 31

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)am the d 1,4-diazabicyclo[3.2.1]octane-4-carboxylic acid

Using 1,4-diazabicyclo[3.2.1]octane, get mentioned in the title compound as light-yellow crystals (yield 51%). MS: m/e=404 (M+N+).

Example 32

(TRANS}-1-(4-Methoxycyclohexyl)-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine

Using (TRANS)-(4-methoxycyclohexyl)methylamine, get mentioned in the title compound as a white solid (yield 48%), tPL211-213°C. MS: m/e=435 (M+H+).

Example 33

(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)amide and (1S,4R)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid

Using (1S,4R-2-azabicyclo[2.2.1]heptane, get mentioned in the title compound as white crystals (yield 67%), tPL149°C. MS: m/e=389 (M+N+).

Example 34

3-(4-Methoxy-7-morpholine-4-eventhorizon-2-yl)-1-methyl-1-(tetrahydropyran-4-yl)urea

Using (4-tetrahydropyranyl)methylamine, get mentioned in the title compound as a white solid (yield 56%), tPL240-242°C. MS: m/e=407 (M+H+).

Example 35

1-Cycloheptyl-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine

Using cycloheptylamine get mentioned in the title compound as a white solid (yield 70%), tPL198-200°C. MS: m/e=419 (M+H+).

Example 36

1-Cyclopentyl-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine

COI is lsua cyclopentylmethyl, get listed in the title compound as a white solid (yield 48%), tPL110-125°C. MS: m/e=391 (M+H+).

Example 37

1-Cyclopentyl-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)urea

Using cyclopentylamine get mentioned in the title compound as white crystals (yield 57%), tPL191-194°C. MS: m/e=377 (M+N+).

Drugs intermediates for examples 1-22

Example 38

4-Benzyl-4-hydroxyethylpiperazine

1,4-Dibenzyl-4-hydroxyethylpiperazine (1.0 g, 3.4 mmol) in dichloromethane (20 ml) is treated with 1-chloritisation (of 0.48 ml, 4.3 mmol, dissolved in 1.5 ml dichloromethane)and the resulting solution stirred at 0°C for 30 minutes the Solvent is removed in vacuo and the resulting residue is boiled in methyl alcohol (20 ml) for 40 min After removal of volatiles in vacuo specified in the title compound allocate using flash chromatography (silica, eluent - dichloromethane/methyl alcohol/the triethylamine (9:1:0.1, then 4:1:0,1, then 3:1:0,1)) in the form of a brown resin with a yield of 40%. MS 206 (M+N+).

Example 39

1.4-Dibenzyl-4-hydroxyethylpiperazine

This compound is obtained from ethyl ether 1,4-dibenzylpiperazine-4-carboxylic acid (J.Chem.Soc., Perkin TRANS 1996, 20, 2545-2551), restoring aired sociallyengaged in tetrahydrofuran (THF) in Antartic conditions; yield 81%. MS 296 (M+H+).

Example 40

3 Azaspiro[5.5]undecane

Derived from 3,3-tetramethyleneglutaric, restoring the imide sociallyengaged in tetrahydrofuran under standard conditions. Using flash chromatography (silica, eluent - dichloromethane/methyl alcohol/triethylamine 10:2:0,1) get mentioned in the title compound as a colourless oil (yield 94%). MS 140 (M+N+).

Example 41

8 Azaspiro[4.5]Decan

Derived from 3,3-pentamethylheptane by restoring sociallyengaged in tetrahydrofuran under standard conditions. Flash chromatography (silica, eluent - dichloromethane/methyl alcohol/triethylamine 10:2:0,1) gives specified in the title compound as a pale yellow oil (yield >95%). MS 154 (M+N+).

Example 42

(TRANS)-(4-Hydroxycyclohexyl)methylamine

Specified in the title compound is obtained from (TRANS)-(4-hydroxycyclohexyl)-amine as a result of interaction with di-tert-BUTYLCARBAMATE in aqueous sodium hydroxide solution under standard conditions and the subsequent restoration by sociallyengaged in THF under standard conditions.

Unless otherwise noted, other N-methylated amines get the same way.

Example 43

(CIS)-(4-Forcelogix)methylamine

Specified in the title compound is obtained from benzyl ether (CIS)-(4-FPO is cyclohexyl)carbamino acid by reduction with sociallyengaged under standard conditions, yield 91%.

Example 44

Benzyl ether (CIS)-(4-forcelogix)carbamino acid

Benzyl ether of (TRANS)-(4-hydroxycyclohexyl)carbamino acid (900 mg, 3.6 mmol) dissolved in dichloromethane (30 ml) and treated with diethylamino-sulfur TRIFLUORIDE (1 ml, 7.2 mmol). After 1 h at room temperature, add 5%aqueous solution of sodium hydrogen carbonate (15.3 g, 7.2 mmol) and stirring is continued for another hour. The layers separated, the aqueous phase is twice extracted with dichloromethane (20 ml), the combined organic layers dried with magnesium sulfate and evaporated. Flash chromatography (silica, eluent - hexane, containing from 0 to 30% ethyl acetate) gives specified in the title compound as light-yellow crystals (yield 14%),

tPL105-107°C. MS: m/e=252 (M+H+).

Example 45

(4,4-Diverticulosis) methylamine

Specified in the title compound is obtained from 4,4-diverticulectomy (prepared from 8,8-debtor-1,4-dioxaspiro[4.5]decane by removing the protection of sulfuric acid under standard conditions) and methylamine by the reaction of reductive amination under standard conditions (palladium hydroxide in methyl alcohol, 1 ATM hydrogen) with a yield of about 50%. By recrystallization of the hydrochloride from a mixture of ethanol/diethyl ether to obtain analytically pure substance. Light brown TV is Joe substance, tPL137-144°C. MS: m/e=186 (M+H+).

Example 46

8,8-Debtor-1,4-dioxaspiro[4.5]Decan

1,4-Dioxaspiro[4.5]decane-8-he (9.0 g, 56 mmol) and (diethylamino)sulfur TRIFLUORIDE (19 g, 112 mmol) interact in dichloromethane (180 ml) for 2 h at room temperature. The mixture was poured into water (300 ml), the layers separated and the aqueous phase is twice subjected to back extraction with dichloromethane (50 ml). The combined organic phases are dried with magnesium sulfate and evaporated. In the distillation under reduced pressure on a column of get in the Game mentioned in the title compound as a colourless liquid (6.0 g, 60%), tKip65-72°at a pressure of 1.32 to 1.42 in kPa (0,013-0,014 bar), MS: m/e=186 (M+), with admixture (˜30%) of 8-fluoro-1,4-dioxaspiro[4.5]Dec-7-ene, MS: m/e=158 (M+).

Example 47

2-oxa-5-azabicyclo[2.2.2]Octan

Specified in the title compound is obtained from 2-oxa-5-azabicyclo[2.2.2]Octan-6-she (J.Polymer Sci. 1990, 28, 3251-60) by restoring sociallyengaged in standard conditions; yield 84%. MS: m/e=113(M+).

Example 48

1,4-Diazabicyclo [3.2.1] octane

This connection get the technique, published in the patent US 3954766 (1976). MS: m/e=112 (M+).

Example 49

(1S,4R)-2-Azabicyclo[2.2.1]heptane

Specified in the title compound is obtained from (1S,4R)-2-azabicyclo[2.2.1]heptane-3-it is by restoring sociallyengaged in standard conditions; yield 8%. MS: m/e=97 (M+).

1. The use of compounds of General formula

in which R means1-C6-alkoxygroup or halogen;

R1and R2independently of one another denote hydrogen, C1-C6-alkyl, cycloalkyl, or tetrahydropyran-4-yl,

or R1and R2together with the N atom to which they are linked, form a heterocyclic ring selected from the group consisting of

2-oxa-5-azabicyclo[2.2.1]heptane,

3-endo-hydroxy-8-azabicyclo[3.2.1]octane

2-azabicyclo[2.2.2]octane

1-oxo-2,8-diazaspiro[4.5]decane,

3 azaspiro[5,5]undecane,

8 azaspiro[4.5]decane,

1-oxa-8-azaspiro[4.5]decane,

1,8,8-trimethyl-3-azabicyclo[3.2.1]octane

[1.4]oxazepan,

2-oxa-5-azabicyclo[2.2.2]octane

8-oxa-3-azabicyclo[3.2.1]octane

1,4-diazabicyclo[3.2.1]octane

2-azabicyclo[2.2.1]heptane,

3-azabicyclo[3.2.1]octane

moreover, these rings can be unsubstituted or substituted C1-C6-alkyl, or a ring selected from piperazinil, unsubstituted or mono - or disubstituted by C1-C6-alkyl, phenyl or oxopropoxy or their selected from piperidine-1-yl, substituted by a group -(CH2)n-NR′S(O)2-(C1-C6)-al the sludge, -C(O)NR′2or -(CH2)n-phenyl, in which phenyl ring is unsubstituted or substituted With1-C6-alkyl;

R′ means a hydrogen atom or a C1-C6-alkyl, independently of each other in the case ofR′2;

X is the group-O - or-CH2-; and

n is 0, 1, 2, 3,or 4

and pharmaceutically acceptable acid additive salts of these compounds to obtain drugs for the treatment of diseases associated with the system adenosine receptor (A2A.

2. The use of compounds of the formula I according to claim 1, in which these diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, neuroprotective effect, schizophrenia, anxiety, pain, depression, drug addiction, i.e. addiction to such substances, such as amphetamine, cocaine, opioids, ethanol, nicotine, cannabinoids, or hypoxia, ischemia, seizures, and these compounds can be used as a sedative, antipsychotic or anti-epileptics.

3. The use of compounds of the formula I according to claim 1 or 2, in which X represents-O-.

4. The use of compounds of the formula I according to claim 3, which is a

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide and (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbon is th acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 3-endo-hydroxy-8-Aza-bicyclo[3.2.1]octane-8-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 2-methyl-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylic acid,

(4-methoxy-7-morpholine-4-yl-benzothiazol-2-yl)amide of 4-benzyl-4-hydroxymethyl-piperidine-1-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 3-Aza-Spiro[5.5]undecane-3-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 8-azaspiro[4.5]decane-8-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 2-azabicyclo-[2.2.2]octane-2-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 1-oxa-8-azaspiro-[4.5] decane-8-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide (R)-4-(1-hydroxyethyl)-piperidine-1-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide (S)-4-(1-hydroxyethyl)-piperidine-1-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide of 4-(methanesulfonyl-aminomethyl)piperidine-1-carboxylic acid,

4-amide-1-[(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-amide]piperidine-1,4-dicarboxylic acid,

1-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-3-(tetr gidropony-4-yl)urea,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide of 4-isopropylpiperazine-1-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide of 4-phenylpiperazin-1-carboxylic acid,

1-cyclohexyl-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine,

1-(4-CIS-forcelogix)-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine,

1-(4-CIS-forcelogix)-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine,

(CIS)-1-(4-methoxycyclohexyl)-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine,

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

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide [1.4]oxazepan-4-carboxylic acid,

(CIS)-1-(4-hydroxycyclohexyl)-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 2-oxa-5-azabicyclo-[2.2.2]octane-5-carboxylic acid,

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

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide and (1S,4R)-2-azabicyclo-

[2.2.1]heptane-2-carboxylic acid,

3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-methyl-1-(tetrahydropyran-4-yl)-urea,

1-cycloheptyl-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-is amylocaine,

1-cyclopentyl-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine or

1-cyclopentyl-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)urea.

5. The use of compounds of the formula I according to claim 1 or 2, in which X is a group-CH2-.

6. The use of compounds of the formula I according to claim 5, which represent

(4-methoxy-7-piperidine-eventhorizon-2-yl)amide 1-oxa-8-azaspiro-[4.5]decane-8-carboxylic acid,

(4-chloro-7-piperidine-1-eventhorizon-2-yl)amide of 4-hydroxy-4-(4-methyl-benzyl)piperidine-1-carboxylic acid,

(4-chloro-7-piperidine-1-eventhorizon-2-yl)amide of 4-benzylpiperidine-1-carboxylic acid,

(4-methoxy-7-piperidine-1-eventhorizon-2-yl)amide of 4-methyl-3-oxo-piperazine-1-carboxylic acid, or

1-(4-chloro-7-piperidine-1-eventhorizon-2-yl)-3-cyclohexylamino.

7. The compounds of formula

in which R is C1-C6-alkoxygroup or halogen;

R1and R2together with the N atom to which they are linked, form a heterocyclic ring selected from the group consisting of 2-oxa-5-azabicyclo[2.2.1]heptane,

3-endo-hydroxy-8-azabicyclo[3.2.1]octane

2-azabicyclo[2.2.2]octane

1-oxo-2,8-diazaspiro[4.5]decane,

3 azaspiro[5.5]undecane,

8 azaspiro[4.5]decane,

1-oxa-azaspiro[4.5]decane,

1,8,8-trimethyl-3-azabicyclo[3.2.1]octane

[1.4]oxazepan,

2-oxa-5-azabicyclo[2.2.2]octane

8-oxa-3-azabicyclo[3.2.1]octane

1,4-diazabicyclo[3.2.1]octane

2-azabicyclo[2.2.1]heptane,

3-azabicyclo[3.2.1]octane

moreover, these rings can be unsubstituted or substituted C1-C6-alkyl, or a ring selected from piperidine-1-yl, substituted by a group -(CH2)n-NR′S(O)2-(C1-C6)-alkyl, -C(O)NR′2or -(CH2)n-phenyl, in which phenyl ring is unsubstituted or substituted C1-C6-alkyl; R′ means a hydrogen atom or a C1-C6-alkyl, independently of each other in the case ofR′2;

X represents the group-O - or-CH2-; and

n is 0, 1, 2, 3,or 4

and pharmaceutically acceptable acid additive salts of these compounds.

8. The compounds of formula IA according to claim 7, in which X represents-O-.

9. The compounds of formula IA of claim 8, which represent

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide and (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 3-endo-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 2-methyl-1-oxo-2,8-diazep the ro[4.5]decane-8-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 1-oxo-2,8-diazaspiro-[4.5]decane-8-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide of 4-benzyl-4-hydroxyethylpiperazine-1-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 3-azaspiro[5.5]undecane-3-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 8-azaspiro[4.5]decane-8-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 2-azabicyclo-[2.2.2]octane-2-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 1-oxa-8-azaspiro-[4.5]decane-8-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide (R)-4-(1-hydroxyethyl)-piperidine-1-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide (S)-4-(1-hydroxyethyl)-piperidine-1-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide of 4-(methanesulfonyl-aminomethyl)-piperidine-1-carboxylic acid,

4-amide-1-[(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide]piperidine-1,4-dicarboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide (1R)-1,8,8-trimethyl-3-azabicyclo [3.2.1]octane-3-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 2-oxa-5-azabicyclo-[2.2.2]octane-5-carboxylic acid,

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)amide 1,4-databits the CLO-[3.2.1]octane-4-carboxylic acid, or

(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-amide and (1S,4S)-2-azabicyclo-[2.2.1]heptane-2-carboxylic acid.

10. The compounds of formula IA according to claim 7, in which X stands for a group-CH2-.

11. The compounds of formula IA of claim 10, which represent

(4-methoxy-7-piperidine-1-eventhorizon-2-yl)amide 1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid,

(4-chloro-7-piperidine-1-eventhorizon-2-yl)-amide 4-hydroxy-4-(4-methylbenzyl)piperidine-1-carboxylic acid, or

(4-chloro-7-piperidine-1-eventhorizon-2-yl)amide of 4-benzylpiperidine-1-carboxylic acid.

12. The compounds of formula

in which R means1-C6-alkoxygroup or halogen atom;

R12is C1-C6-alkyl; and

R22means cycloalkyl substituted by one or two substituents and these substituents are selected from the group consisting of a halogen atom, a C1-C6-alkoxy - or hydroxy-group;

X is-O - or-CH2-,

and their pharmaceutically acceptable acid additive salt.

13. The compounds of formula IB according to item 12, in which X is-O-.

14. The compounds of formula IB according to item 13, which are

1-(4-CIS-forcelogix)-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine,

1-(4,4-diverticles is)-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine,

(CIS)-1-(4-methoxycyclohexyl)-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine,

(TRANS)-1-(4-hydroxycyclohexyl)-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine,

(CIS)-1-(4-hydroxycyclohexyl)-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine or

(TRANS)-1-(4-methoxycyclohexyl)-3-(4-methoxy-7-morpholine-4-eventhorizon-2-yl)-1-metalmachine.

15. Drug for the treatment of diseases associated with adenosine receptor (A2Acontaining one or more compounds according to one of claims 7 to 14 and a pharmaceutically acceptable fillers.

16. The drug is indicated in paragraph 15 for the treatment of diseases associated with adenosine receptor (A2A.

17. The use of compounds of the formula I according to claim 1 for the treatment of diseases associated with adenosine receptor (A2A.

18. The use of compounds of the formula I according to claim 1 to obtain drugs for the treatment of diseases associated with adenosine, receptora A2A.



 

Same patents:

FIELD: organic chemistry.

SUBSTANCE: invention relates to new compounds of general formula I , wherein one from V or X is N and another is CRa or both V and X are CRa (each CRa is independently hydrogen atom); Y is O, S; Z is N(R2)(R3); R1 is hydrogen, C1-C10-alkyl, C3-C7-cycloalkyl, etc.; R4 is hydrogen, C1-C6-alkyl, C3-C7-cycloalkyl, etc.; A is hydrogen, C1-C10-alkyl, halo-C1-C6-alkyl, etc.; B is optionally substituted 5-membered aromatic ring containing at least one nitrogen atom and 0-3 additional heteroatoms; U is -NR5; meanings of the rest substituents are as defined in specification, and pharmaceutically acceptable salts thereof. Also disclosed are pharmaceutical composition and intermediates of formula I.

EFFECT: new biologically active compounds and pharmaceutical compositions based on the same having inhibition activity in relates to IKK-β enzyme.

26 cl, 13 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein R1 means hydrogen atom or lower alkyl; R2 means lower alkyl, -(CH2)n-O-lower alkyl, -(C3-C6)-cycloalkyl or -(CH2)n-NR'2 wherein R' means hydrogen atom, lower alkyl or -(CH2)n-O-lower alkyl independently of one another for R'2; or R'2 in common with nitrogen atom can form pyrrolidine ring, and wherein n = 1, 2 or 3. Also, invention relates to a pharmaceutical composition possessing antagonistic activity with respect to A2 receptors and containing one or some compounds of the general formula (I) and its pharmaceutically acceptable excipients. Invention provides synthesis of compound of the general formula (I) possessing antagonistic activity with respect to A2 receptors.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

11 cl, 19 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an improved method for synthesis of 2-(3',5'-diamino-1',2',4'-triazol-1'-yl)-4-R1-5-R2-1,3-thiazoles of the general formula (I): , wherein R1 represents hydrogen atom (H), direct or branched (C1-C4)-alkyl or COO-(C1-C4)-alkyl or phenyl optionally substituted with one or some substitutes chosen from halogen atom; R2 represents H, direct or branched (C1-C4)-alkyl, COO-(C1-C4)-alkyl. Method for synthesis involves addition to aqueous solution of 4-R1-5-R2-1-hydrazino-1,3-thiazole hydrochloride of the formula (II): , wherein R1 and R2 have above given values of N-cyanoguanidine of the formula (III): in the mole ratio (II) : (III) = (1.10-1.20):100. Prepared mixture is heated at temperature 80-95°C followed by its neutralization, filtering off and recrystallization. Method provides preparing 2-(3',5'-diamino-1',2',4'-triazol-1'-yl)-4-R1-5-R2-1,3-thiazole from inexpensive and available raw and without using complex technological procedures. Synthesized compounds can be used in synthesis of medicinal and biologically active substances.

EFFECT: improved method of synthesis.

10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative compound of carboxylic acid represented by the formula (I): , wherein each X and Y represents independently (C1-C4)-alkylene; Z means -O-; each R1, R2, R3 and R4 means independently hydrogen atom or (C1-C8)-alkyl; R5 means (C2-C8)-alkenyl; A means -O- or -S-; D means D1, D2, D3, D4 or D5 wherein D1 means (C1-C8)-alkyl; D2 means compound of the formula: wherein ring 1 represents saturated 6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom chosen from oxygen, sulfur and nitrogen atoms; D3 means compound of the formula: wherein ring 2 represents (1) completely saturated (C3-C10)-monocarboxylic aryl, or (2) optionally saturated 5-membered monoheteroaryl comprising 3 atoms chosen from nitrogen and sulfur atoms, or completely saturated 6-membered monoheteroaryl comprising 1 heteroatom representing oxygen atom; D4 means compound of the formula: ; D5 means compound of the formula: ; R6 represents (1) hydrogen atom, (2) (C1-C8)-alkyl, (3) -NR7R8 wherein R7 or R8 represent hydrogen atom or (C1-C8)-alkyl, or R7 and R8 taken in common with nitrogen atom to which they are added form saturated 5-6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom representing oxygen atom; E means -CH or nitrogen atom; m means a whole number 1-3, or its nontoxic salt. Invention relates to a regulator activated by peroxisome proliferator receptor, agent used in prophylaxis and/or treatment of diseases associated with metabolism disorders, such as diabetes mellitus, obesity, syndrome X, hypercholesterolemia or hyperlipoproteinemia, hyperlipidemia, atherosclerosis, hypertension, diseases coursing with circulation disorder, overeating or heart ischemic disease, and to an agent that increases cholesterol level associated with HDL, reduces cholesterol level associated with LDL and/or VLDL, eliminates risk factor in development of diabetes mellitus and/or syndrome X and comprising a compound represented by the formula (I) or its nontoxic salt as an active component and a carrier, excipient or solvent optionally. Invention proposes derivative compounds of carboxylic acid possessing the modulating activity with respect to peroxisome proliferator receptor (PPAR).

EFFECT: valuable medicinal properties of compounds.

15 cl, 5 tbl, 48 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 3-oxo-1-cyclobutene of the general formula (I): and their salts, solvates, hydrates and N-oxides wherein R1 represents group of the formula: Ar1L2Ar2Alk wherein Ar1 represents aromatic or heteroaromatic group; L2 represents a covalent bond or -O-, -NH- or -CONH-; Ar2 represents arylene or heteroarylene group; Alk represents chain -CH2CH(R) or -CH(CH2R)- wherein R represents -CO2H or -COOAlk7 wherein Alk7 represents (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C3-C8)-heterocycloalkyl group and others; X represents group -N(R2)- wherein R2 represents hydrogen atom or (C1-C6)-alkyl group; V represents oxygen atom; Rx, Ry and Rz represent atom or group -L1(Alk1)n(R3)v wherein L1 represents covalent bond or -O-, -S-, -Se-, -S(O)-, -NH- or -N(CH3)-; Alk1 represents aliphatic group; R3 represents hydrogen, halogen atom, group -OR3a, -SR3a and others wherein R3a represents hydrogen atom, (C1-C6)-alkyl and others; n = 0 or 1; v = 1, 2 or 3 under condition that if n = 0 and L1 represents covalent bond then v = 1; or Rz represents atom or group given above, and Rx and Ry taken together form spiro-bound cycloaliphatic or heterocycloaliphatic group. Compounds of the formula (I) possess inhibitory activity with respect to α4-integrin and can be used in medicine.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

26 cl, 216 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

Benzothiazoles // 2293736

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein R1 represents 3,6-dihydro-2H-pyran-4-yl, 5,6-dihydro-4H-pyran-3-yl, 5,6-dihydro-4H-pyran-2-yl, tetrahydropyran-2,3- or 4-yl, cyclohex-1-enyl, cyclohexyl, or it represents 1,2,3,6-tetrahydropyridin-4-yl or piperidin-4-yl that are optionally substituted with -C(O)CH3 or -C(O)OCH3 in position 1 at nitrogen atom (N); R2 represents lower alkyl, piperidin-1-yl substituted with hydroxy-group optionally, or it represents phenyl optionally substituted with -(CH2)n-N(R')-C(O)-(CH2)n-NR'2, -(CH2)n-halogen, lower alkyl or -(CH2)n-N(R')-(CH2)n-O-lower alkyl, or it represents morpholinyl or pyridinyl that is substituted optionally with halogen atom, -N(R')-(CH2)n-O-lower alkyl, lower alkyl, lower alkoxy-group, morpholinyl or -(CH)n-pyrrolidinyl; n = 0, 1 or 2; R' represents hydrogen atom or lower alkyl, and to their pharmaceutically acceptable acid-additive salts. Also, invention relates to a medicament possessing affinity to adenosine A2A-receptors and containing one or some compounds of the general formula (I) and pharmaceutically acceptable excipients.

EFFECT: valuable medicinal properties of compounds.

17 cl, 47 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: 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, 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, medicine, pharmacy.

SUBSTANCE: invention describes novel nitrogen-containing aromatic derivatives of the general formula (I): wherein X1 means nitrogen atom (N) or group -CR10= wherein R10 means hydrogen atom (H), halogen atom or -CN; X2 means N or group -CR11= but X1 and X2 can't mean N simultaneously; Y means oxygen atom (O) or group -NRY- wherein RY means hydrogen atom or (C1-C6)-alkyl group; R1 means phenoxy-group, group -NR12aR12b, group , group and other values; each radical among R3, R4, R5, R6 and R11 means hydrogen atom; R7 means hydrogen atom or (C1-C6)-alkyl group; R8 means hydrogen atom or (C1-C6)-alkyl group; R10 means hydrogen atom, halogen atom or cyano-group; R9 means group -NR16aR16b or group of the formula: wherein T2 means pyrrolidine, piperazine ring possibly substituted with (C1-C6)-alkyl group, or morpholine ring; R12a and R12b mean independently hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group; R2 means hydrogen atom or (C1-C6)-alkyl; R16a means hydrogen atom or (C1-C6)-alkyl, and R16b means (C1-C6)-alkyl possibly substituted with phenyl, (C1-C6)-alkoxy-group, (C1-C6)-alkylthio-group or di-(C1-C6)-alkylamino-group, (C3-C6)-alkynyl, (C3-C8)-cycloalkyl, phenyl possibly substituted with halogen atom, thiazolyl or piperidinyl possibly substituted with (C1-C6)-alkyl, and their salts or hydrates. Also, invention describes a pharmaceutical composition, method for treatment or prophylaxis of tumor diseases and using the novel compounds for preparing an agent useful in treatment abovementioned diseases.

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

26 cl, 17 tbl, 221 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to pharmaceutical compositions possessing inhibitory effect with respect to MC2R-receptors, for preparing medicinal preparations as tablets, granules, capsules, suspensions, solutions or injections placed into pharmaceutically acceptable package. As active substance the composition comprises azaheterocyclic compound of general formulas (1.1.1) , (1.2.1) or (1.3.1) , wherein R1 in the general formula (1.1.1) represents substituted alkyl, aryl, heteroaryl, heterocyclyl, or R1 in the general formula (1.2.1) represents a substitute of amino-group chosen from hydrogen atom or possibly substituted lower alkyl or lower acyl; each R2, R3 and R4 represents independently of one another a substitute of cyclic system chosen from hydrogen atom, azaheterocyclyl, possibly substituted lower alkyl, possibly substituted hydroxy-group, carboxy-group, cycloalkyl; or R3 and R4 in common with carbon atoms to which they are bound form azaheterocycle, or R1 in common with nitrogen atom to which it is bound, and R3 and R4 in common with carbon atoms to which they are bound form azaheterocycle through R1, R3 and R4; R18 and R19 represent independently of one another substitutes of amino-group chosen from hydrogen atom or lower alkyl substituted with azaheterocycle as their racemates, optically active isomers or their pharmaceutically acceptable salts and/or hydrates; R20 and R21 in common with nitrogen atom to which they are bound form possibly substituted azaheterocycle. Also, invention relates to a method for preparing a pharmaceutical composition and using compounds and compositions for preparing medicinal preparations and for treatment or prophylaxis of diseases associated with enhanced activation of adrenocorticotropic hormone for compounds of general formulas (1.1.1), (1.2.1) and (1.3.1), and for using compounds for experimental investigations of indicated processes in vitro or in vivo also.

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

15 cl, 1 dwg, 4 tbl, 5 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel polycyclic compounds of the formula (I): wherein radicals and symbols have values given in the invention claim. Compounds of the formula (I) possess properties of H3 receptors antagonist. Also, invention relates to a pharmaceutical composition containing compounds of the formula (I). Also, invention relates to a method for treatment of disease of group comprising difficulty in nasal breath, obesity, somnolence, narcolepsy, attention deficiency with hyperactivity, Alzheimer's disease and schizophrenia that involves using compounds of the formula (I) and, optionally, in combination of H receptor antagonist.

EFFECT: valuable medicinal properties of compound and pharmaceutical composition.

39 cl, 3 tbl, 31 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to compound of the formula (I): wherein R1, R2, R3, R4, R5, R6, R7 and R8 represent hydrogen atom or (C1-C6)-alkyl; T represents oxygen atom; V represents N<; X1 represents phenyl substituted with 1-2 substitutes chosen from group comprising (C1-C6)-alkyl, (C1-C6)-alkoxy-group, halogen atom, cyano-group or trifluoromethyl; X2 represents a bicyclic heteroaryl comprising 7 carbon atoms and 1-2 heteroatoms chosen from oxygen (O), nitrogen (N) and sulfur (S) atoms optionally substituted with (C1-C6)-alkyl, (C3-C6)-cycloalkyl, phenyl or phenyl substituted with halogen atom; Y represents monocyclic heteroarylenyl comprising 3-5 carbon atoms and 1-3 heteroatoms chosen from N and O; Z1 and Z2 represent independently (C1-C4)-alkylene. Compounds of the formula (I) are used in preparing a pharmaceutical composition used in treatment of morbid state in mammal that can be relieved using inhibitor of oxidation of aliphatic acids. Also, invention relates to a pharmaceutical composition inhibiting oxidation of aliphatic acids and comprising at least one pharmaceutically acceptable excipient and the therapeutically effective dose of compound of the formula (I). Invention provides using substituted piperazine compounds as inhibitors of oxidation of aliphatic acids.

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

19 cl, 22 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel compounds of the general formula (I) wherein p, R1, R2, R3 and A are determined in the invention description, their individual isomers and their pharmaceutically acceptable salts. Proposed compounds possess antagonistic effect with respect to muscarinic receptors that allows their using in treatment and prophylaxis of diseases yielding to treatment with muscarinic receptor antagonist. Also, invention describes a pharmaceutical composition containing these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 22 ex

FIELD: organic chemistry, medicine, hematology, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): in all their stereoisomeric forms and their mixtures taken in any ratio and their physiologically acceptable salts possessing properties of inhibitors of factor Xa and/or factor VIIa, and to a medicinal agent based on thereof. Also, invention relates to a method for synthesis of these compounds and their using for preparing pharmaceutical agents for inhibition of activity of factor Xa and/or factor VIIa or for their effect on blood coagulation or fibrinolysis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

10 cl, 1 tbl, 276 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of derivatives of indolinone of the general formula (VI): wherein R1, R2, R3 and R4 are chosen independently from group consisting of hydrogen atom (H) and halogen atom; each R5 means independently (C1-C12)-alkyl; R6 means -NR8-(CH2)mR9, -NR10R11 under condition that from 1 to 4 groups -CH2- can be substituted optionally with -OH; R8 means H; R9 means -NR10R11 wherein R10 and R11 mean (C1-C12)-alkyl, or R10 and R11 in common with nitrogen atom to which they are bound can form a heterocyclic group chosen from morpholinyl, pyrrolidinyl and piperidinyl under condition that the heterocyclic group can be substituted optionally with morpholino-group; J means -NH; L means carbon atom (C), and group -C(O)R6 is bound with L; K and M means -CR5; m = 1, 2, 3 or 4; p = 2. Method for synthesis of these compounds involves the addition reaction of compound of the general formula (III): wherein R* means R with compound of the formula (IV): wherein values R1, R2, R3 and R4 are given above with amine of the general formula (V): HR6 (V) wherein R6 is given above to form indolinone of the general formula (VI). Method provides synthesis of indolinone derivatives with the yield 25-85%.

EFFECT: improved method of synthesis.

20 cl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrimidine of the general formula (I): or its pharmaceutically acceptable salts or esters hydrolyzed in vivo and possessing properties of selective inhibitor of cyclin-dependent kinases, such as CDK-2, and inhibiting proliferation of cells. Compounds can be used in preparing medicinal agents used in treatment of cancer diseases. In compounds of the formula (I) R1 represents halogen atom; p = 0 or 1; R2 represents sulfamoyl or group B-E-; q = 0 or 1 wherein p + q = 1; R3 represents hydrogen atom, (C1-C6)-alkyl wherein R3can be substituted optionally at carbon atom with one or some M; R4 represents (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl wherein R4 can be substituted optionally with one or some M; or R3 and R4 taken with nitrogen atom to which they are bound form heterocyclic ring substituted optionally at carbon atom with one or some M wherein if indicated heterocyclic ring comprises group -NH then nitrogen atom can be substituted optionally with group chosen from Q; B is chosen from (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl or (heterocyclic group)-(C1-C6)-alkyl wherein B can be substituted optionally at carbon atom with one or some D and wherein indicated heterocyclic group comprises group -NH- then nitrogen atom can be substituted optionally with group chosen from G; E represents -S(O)r- or -N(Ra)SO2- wherein Ra represents hydrogen atom or (C1-C6)-alkyl and r = 2; D is chosen independently from halogen atom, nitro-, cyano-, hydroxy-, amino-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-, N-(C1-C6)-alkylamino-, N,N-((-C1-C6)-alkyl)2-amino-, (C1-C6)-alkanoylamino-group, (C1-C6)-alkyl-S(O)a wherein a = 0-2, wherein D can be substituted optionally at carbon atom with one or some V; M is chosen independently from halogen atom, nitro-, cyano-, hydroxy-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-, N,N-((C1-C6)-alkyl)2-amino-group, (C1-C6)-alkoxycarbonyl, (C3-C8)-cycloalkyl or heterocyclic group wherein M can be substituted optionally at carbon atom with one or some P; P, X and Y are chosen independently from hydroxy-group, methyl, methoxy-, dimethylamino-group; G and Q are chosen independently from (C1-C4)-alkyl, (C1-C4)-alkylsulfonyl, (C1-C4)-alkoxycarbonyl wherein Q can be substituted optionally at carbon atom with one or some X. Also, invention relates to methods for synthesis of compounds, preparing pharmaceutical compositions based on thereof and to a method for inhibition of proliferation of cells.

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

15 cl, 2 sch, 133 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel aromatic compounds that can be used in treatment of diseases or pathological states accompanying by inflammation, for example, chronic inflammation diseases. Invention describes compound of the formula (II): wherein G means phenyl, pyridinyl, pyrazolyl and wherein G is substituted with one or some groups R1, R2 or R3; Ar means naphthyl; X means (C5-C8)-cycloalkyl or cycloalkenyl optionally substituted with 1-2 oxo-groups, phenyl, furanyl, pyridinyl or pyrazolyl; Y means a bond or saturated either unsaturated branched or unbranched (C1-C4)-carbon chain wherein one or some methylene groups are optionally and independently substituted with oxygen (O) or nitrogen (N) atoms; Y is optionally substituted with oxo-group; Z means phenyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, morpholinyl, thiomorpholinyl, piperidinyl, piperidinonyl, piperazinyl, pentamethylenesulfoxidyl wherein each of them is optionally substituted with 1-3 (C1-C6)-alkyls or group -CONH2, (C1-C6)-alkyl, nitrile, hydroxy-group, (C1-C6)-alkoxy-group, secondary or tertiary amine wherein amine nitrogen is bound covalently with (C1-C3)-alkyl or (C1-C5)-alkoxyalkyl, tetrahydrofuranyl-(C1-C3)-alkyl, nitrile-(C1-C3)-alkyl, carboxamide-(C1-C3)-alkyl; R1 means independently in each case (C1-C10)-alkyl which is optionally partially or completely halogenated and optionally substituted with 1-3 hydroxy-groups, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl wherein each of them is optionally substituted with 1-3 groups -CN, halogen atom, (C3-C6)-alkynyl branched or unbranched carbon chain and one or some methylene groups is optionally replaced for atom O and indicated alkynyl group is optionally substituted with one or some (C1-C4)-alkyl groups; R2 means branched or unbranched (C1-C6)-alkyl that is optionally partially or completely halogenated, branched or unbranched (C1-C4)-alkoxy-group that in each case is optionally partially or completely halogenated, halogen atom, (C1-C6)-alkoxy-group, hydroxy-group, mono- or di-(C1-C4)-alkyl-amino-group, group -OR6, nitro-group or group mono- or di-(C1-C4)-alkyl-amino-S(O)2 that is optionally partially or completely halogenated, or group -H2NSO2; R3 in each case means independently phenyl, pyridinyl, pyrimidyl, pyrrolidinyl, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, (C1-C4)-alkynyl group or branched or unbranched (C1-C6)-alkoxy-group wherein each of them is optionally partially halogenated, -OR18 or (C1-C6)-alkyl optionally substituted with group -OR18, amino-group or mono- either di-(C1-C5)-alkyl-amino-group, (C2-C6)-alkynyl branched or unbranched carbon chain wherein one or some methylene groups are optionally replaced for atom O, and indicated alkynyl group is optionally substituted with one or some (C1-C4)-alkyl groups; R6 means (C1-C4)-alkyl that is optionally partially or completely halogenated; in each case R18 means independently hydrogen atom, (C1-C4)-alkyl; W means atom O, and its pharmaceutically acceptable derivatives. Also, invention describes a pharmaceutical composition containing these compounds and a method for treatment of disease mediated by cytokines and based on indicated compounds. Invention provides synthesis of novel compounds possessing valuable biological properties.

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

12 cl, 1 tbl, 38 ex

FIELD: organic chemistry, insecticides.

SUBSTANCE: invention describes compound of the formula (I): wherein B represents oxygen atom (O) or -NR1; J represents 5-membered heteroaromatic ring representing group of the formula (J-1): optionally substituted with 1-2 radicals R5 wherein Q represents -NR5; each X, Y and Z represents independently nitrogen atom (N), -CH or - CR5; B1 represents O; R2 represents hydrogen atom (H) or (C1-C6)-alkyl optionally substituted with one halogen atom, or (C2-C6)-alkynyl; or R1 and R2 taken in common form a binding chain consisting of 2-3 members and comprising at least one carbon atom, optionally comprising one carbon atom as -C(=O), optionally substituted with R3 wherein R3 represents (C1-C2)-alkyl; each R represents independently H, (C1-C6)-alkyl, halogen atom or -CN; each R5 represents independently (C1-C6)-halogenalkyl or halogen atom, or each ring is substituted with one R6; each R6 represents independently halogen atom; n represents a whole number 1 or 2. Also, invention describes a composition used for control of insects and comprising the biologically effective dose of compound of the formula (I) and at least one additional component chosen from group comprising surface-active substances, solid and liquid diluting agents, and methods for control of insects with using compositions based on compounds of the formula (I) and compounds of the formula (I). Proposed compounds of the formula (I) possess insecticide activity and can be used in agriculture.

EFFECT: valuable insecticide properties of compounds and compositions.

11 cl, 26 tbl, 4 ex

The invention relates to new compounds of the formula (I), where a represents the group CH2or atom That denotes H or halogen, D is CH2, OCH2, NHCH2CH2CH2, R denotes phenyl, benzothiazolyl, indolyl, indazoles, purinol, pyridyl, pyrimidyl, thiophenyl, each of these groups may be substituted or unsubstituted
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