Substituted cycloalkano[e or d]pyrazolo[1,5-a]pyrimidine-antagonists of serotonin 5-ht6 receptors, method of producing said compounds and use

FIELD: chemistry.

SUBSTANCE: invention relates to new 2-alkylsufanyl-3-arylsufonyl-cycloalkano[e]pyrazolol[1,5-a]pyrimidines of general formula 1 or 2-alkylsufanyl-3-arylsufonyl-cycloalkano[d]pyrazolo[1,5-a]pyrimidines of general formula 2, which are antagonist of 5-HT6 receptors. In compounds of formula 1

and 2 ,

R1 is a hydrogen atom or C1-C3 alkyl; R2 is C1-C3 alkyl; R3 is a hydrogen atom, one or two optionally identical halogen atoms, C1-C3 alkyl or hydroxyl, optionally substituted with C1-C3 alkyl; n is an integer equal to 1, 2 or 3.

EFFECT: compounds can be used in preventing and treating diseases of the central nervous system, anxiolytics and as compounds with nootropic effect and suitable for enhancing memory.

12 cl, 1 dwg, 4 tbl, 9 ex

 

This invention relates to new 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines, to new antagonists of serotonin 5-HT6receptors, to new medicinal principles, pharmaceutical compositions, finished dosage forms and methods for their preparation. More specifically, the present invention relates to antagonists of serotonin 5-HT6receptor - substituted 2-alkylsulfanyl-3-arylsulfonyl-cycloalkane[e or d]pyrazolo[1,5-a]pyrimidines, medicinal and pharmaceutical compositions containing the drug began in the form of these compounds, as well as to new medicines and treatment and prevent the development of Central nervous system diseases, pathogenesis of which is associated with 5-HT6the receptors. The basis of the pharmacological effect of new drugs began laying their ability to interact antagonistically with serotonin 5-HT6receptors that play an important role for the treatment of diseases of the Central nervous system (CNS), in particular Alzheimer's disease (AD), a disease of Hungtinton, schizophrenia, other neurodegenerative diseases, cognitive disorders and obesity.

The use of effective and selective antagonists of serotonin 5-HT6receptors for the treatment of CNS disorders, in particular schizophrenia, ad and other neurodegenerative diseases is the third and cognitive disorders, is a promising direction for new drugs [Holenz j, Pauwels, P.J., J.L. Diaz, Merce R., Codony X., Buschmann H. Medicinal chemistry strategies to 5-HT6receptor ligands as potential cognitive enhancers and antiobesity agents. Drug Disc. Today. 2006; 11:283-299]. These receptors in mammals are found exclusively in the Central nervous system, mainly in the areas of the brain responsible for learning and memory [Ge'rard C, Martres, M.-P., Lefe'vre K., Miquel, M., Verge' D., Lanfumey L., Doucet e, Hamon M., El Mestikawy S.Immuno-localisation of serotonin 5-HT6receptor-like material in the rat central nervous system. Brain Research. 1997; 746:207-219]. In addition, it is shown [Dawson L.A., Nguyen H.Q., Li P. The 5-HT(6) receptor antagonist SB-271046 selectively enhances excitatory neurotransmission in the rat frontal cortex and hippocampus. Neuropsychopharmacology.. 2001; 25:662-668]that 5-HT6the receptors are modulators of several neurotransmitter systems, including the cholinergic, noradrenergicheskoy, glutamatergic and dopaminergic. Given the fundamental role of these systems in normal cognitive processes, and their dysfunction in neurodegeneration, it is obvious exceptional role of 5-HT6receptors in the formation of normal or pathological memory. In a large number of modern studies have shown that blocking the 5-HT6receptors leads to a significant increase in memory consolidation in various animal models of learning-memory-playback [Foley A.G., Murphy K.J., Hirst W.D., H.C. Gallagher, Hagn J.J., Upton N., Walsh F. S., Regan CM. The 5-HT(6) receptor antagonist SB-271046 reverses scopolamine-disrapted consolidation of a passive avoidance task and ameliorates spatial task deficits in aged rats. Neuropsychopharmacology.. 2004; 29:93-100. Riemer C, Borroni e, Levet-Trafit Century, Martin J.R., Poll, S., Porter, R.H., Bos M. Influence of the 5-HT6receptor on acetylcholine release in the cortex: pharmacological characterization of 4-(2-bromo-6-pyrrolidin-1-ylpyridine-4-sulfonyl)phenylamine, a potent and selective 5-HT6receptor antagonist. J. Med. Chem. 2003; 46:1273-1276. King M.V., M.L. Woolley, Topham I.A., Sleight AJ, Marsden CA, Fone K.C. 5-HT6receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing consolidation e an effect sensitive to NMDA receptor antagonism. Neuropharmacology 2004; 47:195-204]. Also shown significant improvement in cognitive function in aged rats in the model water maze Morrison when exposed to an antagonist of 5-HT6receptors [Foley A.G., Murphy K.J., Hirst W.D., H.C. Gallagher, J.J. Hagan, Upton N., Walsh F. S., Regan CM. The 5-HT(6) receptor antagonist SB-271046 reverses scopolamine-disrupted consolidation of a passive avoidance task and ameliorates spatial task deficits in aged rats. Neuropsychopharmacology.. 2004; 29:93-100]. Recently achieved not only a deeper understanding of the role of 5-HT6receptors in cognitive processes, but a clearer concept about possible pharmacophoric properties of their antagonists [Holenz j, Pauwels, P.J., J.L. Diaz, Merce R., Codony X., Buschmann H. Medicinal chemistry strategies to 5-HT6receptor ligands as potential cognitive enhancers and antiobesity agents. Drug Disc. Today. 2006; 11:283-299]. This led to the creation of selective high-affinity ligands ("molecular tools"), then and clinical candidates. Currently lying is the number of antagonists of 5-HT 6receptors are in various stages of clinical trials as drug candidates for the treatment of the bronchial asthma, diseases of Hungtinton, schizophrenia (antipsychotics) and other neurodegenerative and cognitive diseases (table 1) [http://integrity.prous.com.].

Dimebon*
Table 1
Antagonists of 5-HT6receptors as drug candidates.
MedicationClinical phase I trialsDeveloperTherapeutic group
DimebonTMPhase IIIMedivation (USA)Treatment of Alzheimer's disease
SGS-518Phase IILilly, SaegisTreatment of cognitive diseases
SB-742457Phase IIGlaxoSmithKlineTreatment of Alzheimer's disease; Antipsychotic
Dimebon*Phase I/IIAMedivation (USA)Treatment of Hungtinton
Phase II(Russia)Schizophrenia
PRX-07034Phase IEpix Pharm.The treatment of obesity; Antipsychotic; Treatment of cognitive diseases
SB-737050APhase IIGlaxo SmithKlineAntipsychotic
BVT-74316Phase IBiovitrumThe treatment of obesity
SAM-315Phase IWyeth Pharm.Treatment of Alzheimer's disease
SYN-114Phase IRoche, Synosis Ther.Treatment of cognitive diseases
BGC-20-761PreclinicaBTG (London)Antipsychotic; Treatment of cognitive diseases
FMPOPreclinicaLillyAntipsychotic
DimebonTM Preclinica(Russia)Treatment of stroke

Another attractive property of antagonists of 5-HT6receptors is their ability to suppress the appetite, which can lead to the creation on their basis of fundamentally new means to reduce overweight and obesity [Vicker SP, Dourish CT Serotonin receptor ligands and the treatment of obesity. Curr. Opin. Investig. Drugs. 2004; 5:377-388]. This effect is confirmed in many studies [J. Holenz, Pauwels, P.J., J.L. Diaz, Merce R., Codony X., Buschmann H. Medicinal chemistry strategies to 5-HT6receptor ligands as potential cognitive enhancers and antiobesity agents. Drug Disc. Today. 2006; 11:283-299. Davies, S.L. Drug discovery targets: 5-HT6receptor. Drug Of The Future. 2005; 30:479-495], its mechanism is based on inhibition by antagonists of 5-HT6receptor signaling gamma-aminobutyric acid and increase the release of alpha-melanocyte-stimulating hormone, which ultimately reduces the need for food [M.L. Woolley 5-ht6 receptors. Curr. Drug Targets CNS Neurol. Disord. 2004; 3:59-79]. Currently, two antagonist

5-HT6receptors are in the first stage of clinical trials as drug candidates for the treatment of overweight (table 1) [http://integrity.prous.com.].

In this regard, the search for selective and effective antagonists of serotonin 5-HT6receptors appears to be original and promising approach to the creation of a new drug is for the treatment of a wide range of neurological and neurodegenerative diseases and cognitive disorders.

In the literature there is a considerable number of publications on various biologically active sulfanilamidnam of azaheterocycles, including serotonin receptor ligands. For example, the famous substituted 1-(2-amino-ethyl)-4-arylsulfonyl-pyrazoles of General formula A1 as ligands serotonin 5-HT2Creceptors [WO 2003057674 A1] and 7-amino-3-sulfanyl-pyrazolo[1,5-a]pyrimidines A2, as antagonists of serotonin 5-HT6receptor [ER 941994 A1, 1999]

A1:Ar=alkyl, aryl; R1and R2=H, HE, alkyl, alkoxy; R3and R4=H, alkyl, aryl.

A2:Ar=aryl, heterocyclyl; R1=H, alkyl, alkylthio; R2=H, alkyl, halogen; R3=H, alkyl, hydroxyalkyl; R4and R5=N; NR4R5=piperazinil.

To develop new highly effective neuroprotective drugs by the authors of the present invention made extensive studies in a series of substituted 3-sulfonyl-pyrazolo[1,5-a]pyrimidines, resulting in a new found drug began representing antagonists of 5-HT6receptors.

Below are definitions of terms used in the description of this invention:

"Agonist" refers to a ligand that binds with the receptors of this type, actively promote the transfer of these receptors are peculiar to them is specificheskogo signal and thereby cause a biological response of a cell.

"Azaheterocycle" means an aromatic or non-aromatic monocyclic or polycyclic system containing a loop, at least one nitrogen atom. Azaheterocycle can have one or more cyclic substituents" of the system. "Alkyl" means an aliphatic hydrocarbon of linear or branched group with 1-12 carbon atoms in the chain. Branched means that the alkyl chain has one or more "lower alkyl" substituents. The alkyl may have one or more identical or different substituents ("alkyl substituents including halogen, alkenylacyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkyloxy, Alcoxy, aryloxy, aryloxyalkyl, alkylthio, heteroaromatic, Uralkali, arylsulfonyl, alkylsulfonyl, heteroarylboronic, annelirovannymi heteroarylboronic, annelirovannymi heteroalicyclic, annelirovannymi heterooligomerization, annelirovannymi heteroalicyclic, annelirovannymi arylchloroalkanes, annelirovannymi aristically, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic, alkoxycarbonyl, arelaxation, heteroarylboronic or RkaRk+1aN-, RkaRk+1aNC(=O)-, RkaRk+1aNC(=S)-, Rk aRk+1aNSO2where Rkaand Rk+1aindependently from each other represent "amino substituents", which is defined in this section, for example, a hydrogen atom, alkyl, aryl, aralkyl, heteroalkyl, heterocyclyl or heteroaryl, or Rkaand Rk+1atogether with the N atom to which they are bound, form a through Rkaand Rk+1a4-7 membered heterocyclyl or heterocyclyl. Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, ISO-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, benzyloxycarbonylation and pyridinedicarboxylate. Preferred "alkyl substituents" are cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, alkoxycarbonyl, Alcoxy, aryloxy, alkylthio, heteroaromatic, Uralkali, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, arelaxation, heteroarylboronic or RkaRk+1aN-, RkaRk+1aNC(=O)-, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic.

"Alkyloxy" means alkyl-O-group in which the alkyl groups defined in this RA matter. The preferred alkyloxyaryl are methoxy, ethoxy, n-propoxy, ISO-propoxy and n-butoxy.

"Alkylthio or Alkylsulfonyl" means alkyl-S-group in which the alkyl group defined in this section. Preferred alkylsulfonyl groups are methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, out-propylsulfonyl.

"Anxiolytic" or "Tranquilizer" means a drug intended for the treatment of anxiety disorders.

"Annelirovannymi cycle" (condensed cycle) means of bi - or polycyclic system, where annelirovannymi cycle and cycle or politics, with whom he "annylirovan have at least two common atom.

"Antagonists" refers to ligands that bind to receptors of a particular type and do not cause active cellular response. Antagonists inhibit the binding of agonists to receptors and thereby block the transmission of specific receptor signal.

"Antidepressant" means a drug intended for the treatment of depression.

"Antipsychotic" means a drug intended for the treatment of psychotic diseases.

"Aryl" means an aromatic monocyclic or polycyclic system containing from 6 to 14 carbon atoms, predominantly from 6 to 10 atoms of plastics technology : turning & is Yes. Aryl can contain one or more "cyclic system substituents"which may be the same or different. Representatives of aryl groups are phenyl or naphthyl, substituted phenyl or substituted naphthyl. The aryl may be annylirovan with non-aromatic cyclic system or heterocycle. "Arylsulfonyl" means aryl-SO2group, where aryl is defined in this section.

"Hydrate" means the MES, in which water is a molecule or molecules of solvent.

"Depression" means great depression; episodic, chronic and recurrent forms of major depression; delimitable disorder (dysthymia); cyclothymia; affective disorders; syndrome of seasonal affective disorder; bipolar disorders including bipolar disorder type I and II; and other depressive disorders and conditions. The term depression refers also depression that accompany Alzheimer's disease, vascular dementia; mood disorders induced by alcohol and substances; schizoaffective disorder depressive type; adjustment disorders. In addition, the depression includes depression in cancer patients; Parkinson's disease; depression after myocardial infarction; depression of infertile women, pediatric depr is a Russia; postpartum depression or other depressive conditions accompanying somatic, nevrologicheskie and other diseases.

"Deputy" means a chemical moiety that is attached to scaffold (fragment), for example, Deputy alkyl", "Deputy amino group", "Deputy carbamoyl", "Deputy cyclic system, the values of which are defined in this section.

"Deputy alkyl" means a Deputy, attached to the alkyl, alkenyl, the value of which is determined in this section. Deputy alkyl represents hydrogen, alkyl, halogen, alkenylacyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkyloxy, Alcoxy, aryloxy, aryloxyalkyl, alkylthio, heteroaromatic, Uralkali, arylsulfonyl, alkylsulfonyl, heteroarylboronic, annelirovannymi heteroarylboronic, annelirovannymi heteroalicyclic, annelirovannymi heterooligomerization, annelirovannymi heteroalicyclic, annelirovannymi arylchloroalkanes, annelirovannymi aristically, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic, alkoxycarbonyl, arelaxation, heteroarylboronic or RkaRk+1aN-, RkaRk+1aNC(=O)-, Rka, R k+1aNSO2-, where Rkaand Rk+1aindependently from each other represent "amino substituents", which is defined in this section, for example a hydrogen atom, alkyl, aryl, aralkyl, heteroalkyl, heterocyclyl or heteroaryl, or Rkaand Rk+1atogether with the N atom to which they are bound, form a through Rkaand Rk+1a4-7 membered heterocyclyl or heterocyclyl. Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, ISO-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, benzyloxycarbonylation and pyridinedicarboxylate. Preferred "alkyl substituents" are cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, alkoxycarbonyl, Alcoxy, aryloxy, alkylthio, heteroaromatic, Uralkali, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, arelaxation, heteroarylboronic or RkaRk+1aN-, RkaRk+1aNC(=O)-, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic. The significance of the "alkyl substituents" defined in this section.

"Cognitive disorders, or drug is the relationship of cognitive function (cognitive disorder)" means the violation (weakening) of the mental abilities including attention, memory, thinking, cognition, learning, speech, cognitive, Executive and creative abilities, orientation in time and space, in particular cognitive deficits associated with Alzheimer's disease, Parkinson's and Huntington; senile dementia; age-related memory disorders (age-associated memory his or her, AAMI); dysmetabolic encephalopathy; psychogenic disturbances of memory; amnesia; amnestic disorder; transient global amnesia; dissociative amnesia; vascular dementia; light (or moderate) cognitive impairment (mild cognitive his or her, MCI); syndrome of disturbance of attention with hyperactivity (attention deficit hyperactivity disorder, AD/HD); cognitive impairment accompanying psychotic diseases, epilepsy, delirium, autism, psychosis, down syndrome, bipolar disorder and depression; AIDS-associated dementia; dementia with hypothyroidism; dementia induced by alcohol, substances, addictive, and neurotoxins; dementia accompanying neurodegenerative diseases such as cerebellar degeneration and amyotrophic lateral sclerosis; cognitive disorders, developing stroke, infectious diseases and cancer of the brain, as well as with traumatic brain injury; cognitive impairment associated the autoimmune and endocrine diseases; and other cognitive disorders.

"Medical home" (drug substance, drug substance, drug-substance) means a physiologically active substance is synthetic or other (biotechnology, plant, animal, microbial or other origin, possessing pharmacological activity and which is the active beginning of the pharmaceutical composition used for the production and manufacture of the medicinal product (tools).

"The drug (the drug), a substance (or mixture of substances in the form of pharmaceutical compositions in the form of tablets, capsules, injections, ointments and other fabricated forms intended for restoring, correcting or modifying physiological functions in humans and animals, as well as for treatment and prevention of diseases, diagnostics, anesthesia, contraception, cosmetology and others. "Ligands" (from the Latin ligo - link) is a chemical (small molecule, an inorganic ion, a peptide, a protein, etc.) capable of interacting with receptors that transform this interaction in specific signal.

"Neurodegenerative disease (NT)" means the specific condition and a disease characterized by damage to the primary and death of populations of nerve cells in certain areas of the centre is Inoi nervous system. Neurodegenerative diseases include, but are not limited to, Alzheimer's disease and Parkinson's disease; disease (horay) Huntington's, multiple sclerosis, cerebellar degeneration; amyotrophic lateral sclerosis; dementia with calves Levi; spinal muscular atrophy; peripheral neuropathy; spongiform encephalitis ("mad cow disease", Creutzfeld-Jakob Disease); AIDS-assotsiirovannye dementia; multi-infarct dementia; frontotemporal dementia; leucoencephalopathy (illness vanishing white matter); chronic neurodegenerative disease; stroke; ischemic and reperfusion of hypoxic brain damage; epilepsy; cerebral ischemia; glaucoma; traumatic brain injury; down syndrome; encephalomyelitis; meningitis; encephalitis; neuroblastoma; schizophrenia; depression. In addition, neurodegenerative diseases include pathological conditions and disorders developing during hypoxia, substance abuse, addictive, when exposed to neurotoxins, infectious and oncological diseases of the brain and neuronal damage associated with autoimmune and endocrine diseases; and other neurodegenerative processes.

"Nootropics" or "nootropic", they neurometabolic stimulants - substances taken to improve mental with whom osobnosti.

"Receptors" (from Latin recipere to receive, to learn) are biological macromolecules that are located on the plasma membrane of cells or intracellular able to interact specifically with a limited set of physiologically active substances (ligands) and transform the signal about this interaction in a specific cellular response.

"Mental disorder" (mental illness) - these are the diseases or conditions associated with the violation and/or mental disorder. Mental disorders include affective disorders (bipolar disorder, major depression, gipomania, shallow depression, manic syndrome, Kotar, cyclothymia, schizoaffective disorder, and others); intellectual-mnestic disorders, mania (hypomania, graphomania, kleptomania, magazineline, persecution mania, monomania, pornografiya, erotomania and others); disorder of multiple personality, Amancio, white fever, delirium, delusional syndrome, hallucinatory syndrome, hallucination, hallucinosis, gemicitabine, delirium, delusion, querulant, clinical lycanthropy, macropsia, Manichaean delirium, micropsia, drug addiction, nervous anorexia, oneyroidno syndrome, paranoid, paranoia, paraphrenia, pseudohallucinations, psychosis syndrome Kotar, shiz is affective disorder, schizotypical disorder, schizophrenia, schizophrenia-like psychosis disorder, isoprenaline disorder, syndrome Schreber, Daniel Paul); phobia (agoraphobia, arachnophobia, autophobia, verminophobia, hydrocodobe, the hydrophobicity, demophobia, zoophobia, cancerophobia, claustrophobic, climacophobia, xenophobia, misophobia, primarily, photophobia, scoleciphobia, scotophobia, social phobia, tetraphobia, triskaidekaphobia, erotophobia); alcoholic psychosis, alcoholic palimpsest, allotriophagy, aphasia, graphomania, dissociative Fugue, dissociative disorders, dysphoria, Internet addiction, hypochondria, hysteria, koprofilia, persecution mania, melancholy, misanthropy, obsession, panic attacks, Asperger's syndrome, Capgras syndrome, Munchausen syndrome, rett syndrome, the syndrome Fregoli, the syndrome of attention deficit and hyperactivity syndrome obsessive-compulsive disorder, syndrome effects of chronic anesthesia, a syndrome of psychic automatism, the syndrome of early infantile autism, delirium, taphophilia, anxiety syndrome Hikikomori, erotographomania and other

"Psychotic illness" are all types of schizophrenia; schizophrenia-like psychosis disease; shizotimichesky disorders; schizoaffective disorders, including bipolar and depressive type; delusional disorders, including delirium relations, harassment, is Alicia, jealousy, erotomania, and hypochondriac, somatic, mixed and dedifferentiate delirium; brief psychotic disorder; induced psychotic disorder; induced psychotic substances disorder, and other psychotic disorders.

"Therapeutic cocktail" is simultaneously SKOLKOVO initiative combination of two or more drugs with different mechanisms of pharmacological action and aimed at different biological target involved in the pathogenesis of the disease.

"Anxiety" (anxiety) refers to a generalized (non-specific) anxiety; acute uncontrolled anxiety; panic disorder; phobias, such as agoraphobia (a severe fear of crowded places) or social phobia (severe fear of humiliation in front of other people) or any specific phobia (severe fear of specific objects, animals or situations, in the form of a fear of heights, medical procedures, elevators, open space etc); obsessive-compulsive disorder (obsessive-compulsive disorder); posttraumatische stress disorder and acute stress disorder. In addition to anxiety disorders include anxiety, induced by alcohol or substances; anxiety disorders adaptation; and mixing the nnye forms of anxiety disorders and depression.

"Cycloalkyl" means a non-aromatic mono - or polycyclic system containing from 3 to 10 carbon atoms. Cycloalkyl may have one or more "cyclic system substituents"which may be the same or different. Representatives cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalin, norbornyl, adamant-1-yl, etc. Cycloalkyl can be annylirovan with aromatic cycle or a heterocycle. Preferred "cyclic system substituents" are alkyl, Alcoxy, hydroxy, or RkaRk+1aN, the value of which is determined in this section.

"Schizophrenia" means all known types, forms and variants of the disease, including simple, hebephrenic, paranoid, gipertoksicheskaya (febrile), catatonic, schizoaffective disorder, residual or dedifferentiate schizophrenia and/or form of schizophrenia that is defined in the classification of the American Psychiatric Association (American Psychiatric Association; in: Diagnostic and Statistical Manual of Mental Disorders, IV Edition, Washington D.C. 2000) or the International classification (International Statistical Classification of Diseases and Related Health Problems) or any other known form.

"Pharmaceutical composition" means a composition comprising a compound of formula I and at least one component selected from the group, ostoja of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, auxiliary, distributing and perceiving means, means of delivery, such as preservatives, stabilizers, fillers, shredders, moisturizers, emulsifiers, suspendresume agents, thickeners, sweeteners, flavors, fragrances, antibacterial agents, fungicides, lubricants, regulators prolonged delivery, the choice and the value of which depends on the nature and mode of appointment and dosage. Examples suspendida agents are ethoxylated isostearoyl alcohol, polyoxyethylene, sorbitol and sorbitol ester, microcrystalline cellulose, Metagalaxy aluminum, bentonite, agar-agar and tragakant, as well as mixtures of these substances. Protection from the action of microorganisms can be ensured by various antibacterial and antifungal agents such as parabens, chlorobutanol, sorbic acid and similar compounds. The composition may also include isotonic agents such as sugars, sodium chloride and the like. Prolonged action of the composition can be achieved with agents that slow the absorption of the active principle, for example, aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents and delivery vehicles include water, ethanol, polyalcohol, and the mixture vegetable oils (such as olive oil) and injectable organic esters (such as etiloleat). Examples of fillers are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like. Examples of shredders and distributes funds are starch, aginova acid and its salts, silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulphate, talc, and polyethylene with high molecular weight. Pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal injection of the active principle, one or in combination with other active early, can be introduced animals and people in the standard form of administration, mixed with conventional pharmaceutical carriers. Usable standard form of introduction include oral forms such as tablets, gelatin capsules, pills, powders, granules, chewing gum and oral solutions or suspensions, sublingual and transbukkalno forms of administration, aerosols, implants, local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular forms of administration and rectal forms of administration.

"Pharmaceutically acceptable salt" means a relatively netoc the ranks of organic and inorganic salts of acids and bases, claimed in the present invention. These salts can be obtained in situ during the synthesis, separation, or purification of compounds or prepared. In particular, salts of bases can be obtained specifically on the basis of the purified free base of the claimed compounds and a suitable organic or inorganic acid. Examples of the thus obtained salts are hydrochloride, hydrobromide, sulphates, bisulfate, phosphates, nitrates, acetates, oxalates, valeriote, oleates, palmitate, stearates, laurate, borate, benzoate, lactates, tozilaty, citrates, maleate, fumarate, succinate, tartratami, mesylates, malonate, salicylates, propionate, econsultancy, bansilalpet, sulfamate and the like. (For a detailed description of the properties of such salts are described in Berge S.M., et al., "Pharmaceutical Salts" J. Pharm. Sci. 1977, 66: 1-19.). Salts of the stated acids can also be specially obtained by the reaction of purified acid with a suitable base, can be synthesized metal salts and amines. The metal include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum, the most desirable of which are sodium and potassium salts. Suitable inorganic bases which can be obtained metal salts are the hydroxide, carbonate, bicarbonate and sodium hydride, hydroxide and bicarbonate of potassium, potash, g is droxia lithium calcium hydroxide, magnesium hydroxide, zinc hydroxide. As organic bases, of which can be obtained salts of the stated acids, selected amines and amino acids with sufficient basicity to form a stable salt, and suitable for use in medical purposes (in particular, they should have a low toxicity). Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, Tris(hydroxymethyl)aminomethane and the like. In addition, for the salt formation can be used tetraalkylammonium hydroxide, such as choline, Tetramethylammonium, tetraethylammonium and the like. As amino acids can be used basic amino acids such as lysine, ornithine and arginine.

The purpose of the present invention is to create a new 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines, new antagonists of serotonin 5-HT6receptors of new drugs started and pharmaceutical compositions containing the drug began in the form of these compounds, as well as to new medicines and treatment and prevention of the development of various Central nervous system diseases, including neurodegenerative diseases and when ativnyh, neuralgic and anxiety disorders of humans and warm-blooded animals.

This goal is achieved by substituted 2-alkylsulfanyl-3-arylsulfonyl-cycloalkane[e]pyrazolo[1,5-a]pyrimidines of General formulas 1 and substituted 2-alkylsulfanyl-3-arylsulfonyl-cycloalkane [d]pyrazolo [1,5-a]pyrimidines of General formula 2

where R1represents a hydrogen atom or a C1-C3alkyl;

R2represents a C1-C3algil;

R3represents a hydrogen atom, one or two are not necessarily the same halogen atom, a C1-C3alkyl or optionally substituted C1-C3the alkyl hydroxyl; n is an integer 1, 2 or 3.

More preferred compounds of General formula 1 are 2-alkylsulfanyl-3-arylsulfonyl-7,8-dihydro-6N-cyclopent[f]pyrazolo[1,5-a]pyrimidines of General formula 1.1, 2-alkylsulfanyl-3-arylsulfonyl-6,7,8,9-tetrahydro-cyclohexano[e]pyrazolo[1,5-a]pyrimidines of General formula 1.2 and 2-alkylsulfanyl-3-arylsulfonyl-7,8,9,10-tetrahydro-6N-cyclohepta[e]pyrazolo[1,5-a]pyrimidines of General formula 1.3

where R1, R2and R3have the above value.

More preferred compounds of General formula 1 are 2-methylsulfanyl-3-phenylsulfonyl-7,8-dihydro-6N-is clopant[e]pyrazolo[1,5-a]pyrimidine 1.1(1), 2-methylsulfanyl-3-(3-perpenicular)-7,8-dihydro-6N-cyclopent[f]pyrazolo[1,5-a]pyrimidine 1.1(2), 2-methylsulfanyl-3-(3-chlorophenylsulfonyl)-7,8-dihydro-6N-cyclopent[f]pyrazolo[1,5-a]pyrimidine 1.1(3), 2-methylsulfanyl-3-(3-chloro-4-perpenicular)-7,8-dihydro-6N-cyclopent[f]pyrazolo[1,5-a]pyrimidine 1.1(4), 2-methylsulfanyl-3-phenylsulfonyl-6,7,8,9-tetrahydro-cyclohexano[e]pyrazolo[1,5-a]pyrimidine 1.2(1), 2-methylsulfanyl-3-(3-chlorophenylsulfonyl)-6,7,8,9-tetrahydro-cyclohexano[e]pyrazolo[1,5-a]pyrimidine 1-2(2), 5-methyl-2-methylsulfanyl-3-phenylsulfonyl-6,7,8,9-tetrahydro-cyclohexano[e]pyrazolo[1,5-a]pyrimidine 1.2(3), 5-methyl-2-methylsulfanyl-3-(3-perpenicular)-6,7,8,9-tetrahydro-cyclohexano[e]pyrazolo[1,5-a] pyrimidine 1.2(4), 5-methyl-2-methylsulfanyl-3-(3-chlorophenylsulfonyl)-6,7,8,9-tetrahydro-cyclohexano[e]pyrazolo[1,5-a]pyrimidine 1.2(5), 5-methyl-2-methylsulfanyl-3-(3-chloro-4-perpenicular)-6,7,8,9-tetrahydro-cyclohexano[e]pyrazolo[1,5-a]pyrimidine 1.2(6), 2-methylsulfanyl-3-phenylsulfonyl-7,8,9,10-tetrahydro-6N-cyclohepta[e]pyrazolo[1,5-a]pyrimidine 1.3(1) and 2-methylsulfanyl-3-(3-chlorophenylsulfonyl)-7,8,9,10-tetrahydro-6N-cyclohepta[e]pyrazolo[1,5-a]pyrimidine 1.3(2)

The object of the present invention is a method for substituted 2-alkylsulfanyl-3-arylsulfonyl-cyclo is lcano[e]pyrazolo[1,5-a]pyrimidines of General formula 1, 1.1, 1.2, 1.3 and substituted 2-alkylsulfanyl-3-arylsulfonyl-cycloalkane[d]pyrazolo[1,5-a]pyrimidines of General formula 2 by the interaction of 3-amino-4-arylsulfonyl-2H-pyrazoles of General formula 3 with the corresponding β-dicarbonyl compounds of General formula 4 or their derivatives of General formula 5, followed by separation or separation of the reaction products of General formulas 1, 1.1, 1.2, 1.3, 2 according to the scheme presented below:

where R1, R2, R3and n have the above meaning.

The purpose of the present invention is to provide new molecular tools to study the characteristics of physiologically active compounds that have the property to inhibit serotonin 5-HT6the receptors.

This goal is achieved by antagonists of serotonin 5-HT6receptors represents a substituted 2-alkylsulfanyl-3-arylsulfonyl-cycloalkane[e]pyrazolo[1,5-a]pyrimidines of General formulas 1, 1.1, 1.2, 1.3 and substituted 2-alkylsulfanyl-3-arylsulfonyl-cycloalkane[d]pyrazolo[1,5-a]pyrimidines of General formula 2.

The subject of this invention is also medicinal beginning to pharmaceutical compositions and medicines, representing at least one 2-alkylsulfanyl-3-arylsulfonyl-cycloalkane[e]pyrazolo[1,5-a]pyrimidine of the General formulas 1, 1.1, 1.2, 1. or 2-alkylsulfanyl-3-arylsulfonyl-cycloalkane[d]pyrazolo[1,5-a]pyrimidine of the General formula 2.

The subject of this invention is also a pharmaceutical composition for treating and preventing various conditions and diseases of the Central nervous system of humans and warm-blooded animals containing a pharmaceutically effective amount of a new drug began representing at least one 2-alkylsulfanyl-3-arylsulfonyl-cycloalkane[e]pyrazolo[1,5-a]pyrimidine of the General formulas 1, 1.1, 1.2, 1.3 or 2-alkylsulfanyl-3-arylsulfonyl-cycloalkane[d]pyrazolo[1,5-a]pyrimidine of the General formula 2.

The pharmaceutical composition may include pharmaceutically acceptable excipients. Under the pharmaceutically acceptable excipients are meant to be applied in the field of pharmaceutical diluents, auxiliary agents and/or carriers. Pharmaceutical composition, along with the medicinal beginning, according to the present invention may include other active compounds, provided that they do not cause unwanted effects, such as allergic reactions.

If you want to use the pharmaceutical compositions of the present invention in clinical practice, they can be mixed to produce different forms, however, they can contain conventional pharmaceutical carriers; for example, oral formulations such as tablets, gelatin capsules, pills, solutions Il the suspension); forms for injection (such as solutions or suspensions for injection or dry powder for injection, which requires only the addition of water for injection before use); local forms such as ointments or solutions).

The media used in the pharmaceutical compositions of the present invention, are media that are used in the pharmaceutical industry to obtain common forms, including: oral forms are used binders, lubricating agents, disintegrators, solvents, diluents, stabilizers, suspendresume agents, colorless agents, korrigentami taste; in forms for injection are used antiseptic agents, solubilization, stabilizers; local forms are used bases, diluents, lubricating agents, antiseptic agents.

The subject of this invention is also a method of obtaining a new pharmaceutical composition by mixing with an inert filler and/or solvent medicinal began representing at least one 2-alkylsulfanyl-3-arylsulfonyl-cycloalkane[e]pyrazolo[1,5-a]pyrimidine of the General formulas 1, 1.1, 1.2, 1.3 or 2-alkylsulfanyl-3-arylsulfonyl-cycloalkane[d]pyrazolo[1,5-a] pyrimidine of the General formula 2.

The subject of this invention is a medicinal product in the form of tablets, capsules fruit is or injection, placed in pharmaceutically acceptable packing, for the prevention and treatment of diseases of the Central nervous system, the pathogenesis of which is associated with 5-HT6receptors, including neurodegenerative diseases and cognitive, neurological and anxiety disorders of humans and warm-blooded animals, including drug started representing at least one 2-alkylsulfanyl-3-arylsulfonyl-cycloalkane[e]pyrazolo[1,5-a]pyrimidine of the General formulas 1, 1.1, 1.2, 1.3 or 2-alkylsulfanyl-3-arylsulfonyl-cycloalkane[d]pyrazolo[1,5-a]pyrimidine of the General formula 2, or a pharmaceutical composition comprising a pharmaceutical start.

More preferred is a drug in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing, for the prevention and treatment of Alzheimer's disease, Parkinson's disease, diseases of Hartington, comprising pharmaceutically effective amount of a medicinal began representing at least one 2-alkylsulfanyl-3-arylsulfonyl-cycloalkane[e]pyrazolo[1,5-a]pyrimidine of the General formulas 1, 1.1, 1.2, 1.3 or 2-alkylsulfanyl-3-arylsulfonyl-cycloalkane[e]pyrazolo[1,5-a]pyrimidine of the General formula 2, or a pharmaceutical composition comprising a pharmaceutical start.

The subject of this invention is also Leka is a significant tool in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing for the prevention and treatment of mental disorders and schizophrenia, comprising pharmaceutically effective amount of a medicinal began representing at least one 2-alkylsulfanyl-3-arylsulfonyl-cycloalkane[e]pyrazolo[1,5-a]pyrimidine of the General formulas 1, 1.1, 1.2, 1.3 or 2-alkylsulfanyl-3-arylsulfonyl-cycloalkane[d]pyrazolo[1,5-a]pyrimidine of the General formula 2, or a pharmaceutical composition comprising a pharmaceutical start.

More preferred is the drug (anxiolytic or sedative) for the prevention and treatment of anxiety disorders, including pharmaceutically effective amount of a medicinal began representing at least one 2-alkylsulfanyl-3-arylsulfonyl-cycloalkane[e]pyrazolo[1,5-a]pyrimidine of the General formulas 1, 1.1, 1.2, 1.3 or 2-alkylsulfanyl-3-arylsulfonyl-cycloalkane[d]pyrazolo[1,5-a]pyrimidine of the General formula 2, or a pharmaceutical composition comprising a pharmaceutical start.

More preferred is the drug (nootropic) for the prevention and treatment of hyperkinetic disorders, in particular to improve mental abilities, including a pharmaceutically effective amount of drug to the beginning-what about the other, at least one 2-alkylsulfanyl-3-arylsulfonyl-cycloalkane [e] pyrazolo [1,5-a] pyrimidine of the General formulas 1, 1.1, 1.2, 1.3 or 2-alkylsulfanyl-3-arylsulfonyl-cycloalkane[d]pyrazolo[1,5-a]pyrimidine of the General formula 2, or a pharmaceutical composition comprising a pharmaceutical start.

The subject of this invention is also a drug in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing, for the prevention and treatment of obesity, comprising pharmaceutically effective amount of a medicinal began representing at least one 2-alkylsulfanyl-3-arylsulfonyl-cycloalkane [e] pyrazolo [1,5-a] pyrimidine of the General formulas 1, 1.1, 1.2, 1.3 or 2-alkylsulfanyl-3-arylsulfonyl-cycloalkane[d]pyrazolo[1,5-a]pyrimidine of the General formula 2, a pharmaceutical composition comprising a pharmaceutical the beginning.

The subject of this invention is also a therapeutic cocktail for the prevention and treatment of various Central nervous system diseases, pathogenesis of which is associated with 5-HT6receptors in animals and humans, comprising a drug in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing, comprising a pharmaceutically effective amount of a medicinal began representing at least one 2-alkyls hanil-3-arylsulfonyl-cycloalkane[e]pyrazolo[1,5-a]pyrimidine of the General formula 1, 1.1, 1.2, 1.3 or 2-alkylsulfanyl-3-arylsulfonyl-cycloalkane[d]pyrazolo[1,5-a]pyrimidine of the General formula 2, a pharmaceutical composition comprising a pharmaceutical start.

The subject of this invention is also a therapeutic cocktail for the prevention and treatment of neurological disorders, neurodegenerative and cognitive diseases in animals and humans, including for the prevention and treatment of Alzheimer's disease, Parkinson's disease, diseases of Hartington, mental disorders and schizophrenia, hypoxia-ischemia, hypoglycemia, convulsive States, brain injuries, lathyrism, amyotrophic lateral sclerosis, obesity and stroke, comprising a drug in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing, comprising a pharmaceutically effective amount of a medicinal began representing at least one 2-alkylsulfanyl-3-arylsulfonyl-cycloalkane[e]pyrazolo[1,5-a]pyrimidine of the General formulas 1, 1.1, 1.2, 1.3 or 2-alkylsulfanyl-3-arylsulfonyl-cycloalkane[e]pyrazolo[1,5-a]pyrimidine of the General formula 2, a pharmaceutical composition comprising a pharmaceutical start.

Therapeutic cocktails for the prevention and treatment of neurological disorders, neurodegenerative and cognitive diseases in animals and humans, including the profilaktiki and treatment of Alzheimer's disease, Parkinson's disease Hungtington, mental disorders and schizophrenia, hypoxia-ischemia, hypoglycemia, convulsive States, brain injuries, lathyrism, amyotrophic lateral sclerosis, obesity and stroke, along with medicines by this invention, may include other medicinal agents, such as nonsteroidal anti-inflammatory drugs (Ortofen, Indomethacin, Ibuprofen and the like); acetylcholinesterase inhibitors (Taken, Amiridin, Physostigmine, Aricept, Phenserine, etc.); estrogens (eg, Estradiol); antagonists of NMDA receptors (for example, Memantine, Neramexane); nootropic drugs (for example, Piracetam, Phenibut, etc.); modulators of AMPA receptors (such as Ampalex); antagonists of cannabinoid receptors CB-1 (e.g., Rimonabant); inhibitors of monoamine oxidase MAO-B and/or MAO-A (e.g., Rasagiline); antiamyloidogenic drugs (for example, Tramiprosate); substance reduce the neurotoxicity of beta-amyloid (e.g., Indole-3-propionic acid); inhibitors of gamma and/or beta-Secretase; agonists of muscarinic receptors Ml (for example, Cevimeline); chelators of metals (for example, Clioquinol); antagonists of GABA(B) receptors (e.g., CGP-36742); monoclonal antibodies (e.g., Bapineuzumab); antioxidants; neurotrophic agents (e.g., Cerebrolysin); antidepressants (eg, Imipramine, Sertraline, etc.) and others.

Therapeutic cocktail for reducing overweight and obesity, along with drugs in this invention includes other medicines, such as anorexicskin drugs (for example, Farnon, Dezaemon, Mazindol), hormones (for example, Thyroidin), gipolipidemicheskie tools, such as fibrates (such as Fenofibrate), statins (such as Lovastatin, Simvastatin, pravastatin and probucol), as well as hypoglycemic agents (sulfonylureas, for example Butamid, Glibenclamide; biguanides such as Buformin, Metmorfin) and drugs with a different mechanism of action, such as cannabinoid antagonists CB-1 receptors (Rimonabant), inhibitors of reuptake of norepinephrine and serotonin (Sibutramine), inhibitors of enzymes of fatty acid synthesis (Orlistat) and others, along with antioxidants, food additives, etc.

In accordance with this invention a method of prevention and treatment of various diseases, pathogenesis of which is associated with serotonin 5-HT6receptors in animals and humans, is the introduction of the drug in the form of tablets, capsules or injections containing as the active ingredient of the drug beginning, representing at least one 2-alkylsulfanyl-3-arylsulfonyl-cycloalkane[e]pyrazolo[1,5-a]pyrimidine General the th formula 1, 1.1, 1.2, 1.3 or 2-alkylsulfanyl-3-arylsulfonyl-cycloalkane[d]pyrazolo[1,5-a]pyrimidine of the General formula 2, or a pharmaceutical composition comprising a pharmaceutical start.

Drugs can be administered orally or parenterally (e.g. intravenously, subcutaneously, intraperitoneally or topically. The clinical dosage of the pharmaceutical composition or drug containing medicinal beginning of the General formula 1 or 2, patients may be adjusted depending on therapeutic efficacy and bioavailability of the active ingredients in the body, the speed of their metabolism and excretion from the body, and depending on age, gender and stage of disease of the patient, the daily dose in adults is usually 10~500 mg, preferably 50~300 mg. Therefore, during the preparation of pharmaceutical compositions of the present invention in the form of dosage units it is necessary to consider the above-mentioned effective dosages, each unit dosage of the drug should contain 10~500 mg drug beginning, preferably 50~300 mg. In accordance with the instructions of the doctor or pharmacist these medications can be taken several times during a defined time period (preferably from one to six times).

The examples below demonstrate, but is not limited icipat this invention.

Example 1. A common way of obtaining substituted 2-alkylsulfanyl-3-arylsulfonyl-cycloalkane[e]pyrazolo[1,5-a]pyrimidines of General formulas 1, 1.1, 1.2, 1.3 and 2-alkylsulfanyl-3-arylsulfonyl-cycloalkane[d]pyrazolo[1,5-a]pyrimidines of General formula 2. Mix 0.005 mol aminopyrazole 3 and 0.0055 mol of the corresponding p-dicarbonyl compounds of General formula 4 or a derivative of General formula 5 in 5 ml of acetic acid or other suitable solvent for 4-12 hours. The precipitation is filtered, washed with methanol and water. If necessary, the product is subjected to recrystallization from a suitable solvent, or chromatographic purification, or chromatographic separation.

Table 2 presents some examples of new 2-alkylsulfanyl-3-arylsulfonyl-cycloalkane[e]pyrazolo[1,5-a]pyrimidines of General formulas 1, 1.1, 1.2, 1.3 and 2-alkylsulfanyl-3-arylsulfonyl-cycloalkane[d]pyrazolo[1,5-a]pyrimidines of General formula 2, LCMS data analyses and NMR spectra.

Table 2. Antagonists of serotonin 5-HT6receptor - 2-alkylsulfanyl-3-arylsulfonyl-cycloalkane[e]pyrazolo[1,5-a]pyrimidines of General formulas 1 and 2-alkylsulfanyl-3-arylsulfonyl-cycloalkane[d]pyrazolo[1,5-a]pyrimidines of General formula 2.

No.Formula Mol. weightLCMS, m/z (M+1)An NMR spectrum
1.1(1)345.44346(DMSO-D6, 400 MHz) δ 8,69 (s, 1H), 8,00 (m, 2H), to 7.59 (m, 3H), of 3.28 (t, J=7,6 Hz, 2H), 3.04 from (t, J=7.2 Hz, 2H), 2,58 (s, 3H), of 2.21 (t, J=7,6 Hz, 2H).
1.1(2)363.44364
1.1(3)379.89380
1.1(4)351.79352
1.2(1)359.47360(DMSO-D6, 400 MHz) δ 8,55 (s, 1H), 7,99 (m, 2H), 7.62mm (t, J=7.2 Hz, 1H), 7,56 (t, J=7,6 Hz, 2H), 3,03 (t, J=6 Hz, 2H), was 2.76 (t, J=6 Hz, 2H), 2,58 (s, 3H), of 1.87 (m, 2H), 1,76 (m, 2H).
1.2(2) 393.92394
1.2(3)373.50374(CDCl3, 400 MHz) δ by 8.22 (m, 2H), 7,44-7,52 (m, 3H), is 3.08 (t, J=5.6 Hz, 2H), to 2.67 (t, J=5.6 Hz, 2H), 2,60 (s, 3H), at 2.59 (s, 3H), 1.91 a (m, 4H).
1.2(4)391.49
1.2(5)407.94408
1.2(6)425.93426
1.3(1)373.50374
1.3(2)407.94408
2(1) 359.47360(DMSO-D6, 400 MHz) δ 8,96 (s, 1H), 8,01 (m, 2H), to 7.61 (m, 3H), 2.95 points (t, J=6.4 Hz, 2H), was 2.76 (t, J=6,8 Hz, 2H), 2,53 (s, 3H), of 1.86 (m, 2H), of 1.75 (m, 2H).
2(2)373.50374(CDCl3, 400 MHz) 5 8,21 (m, 2H), 7,43-7,53 (m, 3H), 3,06 (W, 2H), 2,75 (W, 2N), of 2.66 (s, 3H), 2,62 (s, 3H), 1,90 (W, 4H).

Example 2. Determination of antagonistic activity of the compounds of General formula 1 and 2 in relation to 5-HT6the receptors. Compounds of General formula 1 were tested for their ability to inhibit the activation of 5-HT6the serotonin receptors. Used SOME cells 293 (kidney cells human embryo) with artificially downregulation of the receptor 5-HT6the activation of which is serotonin increases the concentration of intracellular camp. The content of intracellular camp was determined using the reagent kit LANCE cAMP (PerkinElmer) according to the method described by the kit manufacturer

[http://las.perkinelmer.com/content/Manuals/MAN_LANCEcAMP384KitUser.pdf].

The effectiveness of the compounds were evaluated for their ability to reduce the amount of intracellular camp induced by serotonin.

Table 3 presents the values of the IC50compounds of General formula 1 and 2 the conditions of functional assay inhibition of serotonin 5-HT 6receptors, demonstrating their moderate or high antagonistic activity.

Table 3. The values of the IC50compounds of General formula 1 and 2 in terms of functional assay inhibition of serotonin 5-HT6receptors.
No.IC50, nM
1.1(1)27.0
1.2(1)35.0
1.2(3)32.0
2(1)479
2(2)7.8

Example 3. Determination of the activity of the compounds of General formula 1 and 2 in a competitive binding to serotonin 5-HT6the receptors. For the screening of substances for their potential ability to interact with serotonin receptor 5-HT6used the method of radioligand binding. This was prepared membrane preparations from HeLa cells expressing recombinant human 5-HT6receptor, by homogenization of recombinant cells in a glass homogenizer followed by the separation of plasmatic membranes from I the EP, mitochondria and cellular debris by differential centrifugation. The binding definition of the studied compounds with 5-HT6the receptor was performed in accordance with the methodology described in [Monsma FJ Jr, Shen Y, Ward RP, Hamblin MW and Sibley DR, Cloning and expression of a novel serotonin receptor with high affinity for tricyclic psychotropic drugs. Mol Pharmacol. 43:320-327, 1993]. In a preferred execution of the membrane preparations were incubated with labeled ligand (1.5 nM [3H] Lysergic acid diethylamide) without and in the presence of investigated compounds for 120 minutes at 37°C in a medium consisting of 50 mM Tris-HCl, pH 7.4, 150 mm NaCl, 2 mm Ascorbic Acid, 0.001% BSA. The samples after incubation were filtered under vacuum onto glass microfibre filters G/F (Millipor, USA), the filters are washed three times with cold solution environment and radioactivity was measured using a MicroBeta scintillation counter 340 (PerkinElmer, USA).

Nonspecific binding, which was 30% of the total binding was determined by incubation of membrane preparations with radioligand in the presence of 5 μm Serotonin (5-HT). As a positive control was used Methiothepin. Binding of test compounds to the receptor was determined by their ability to displace the radioactive ligand and was expressed as a percentage of displacement. The percentage of displacement was determined by the following formula:

where TA is the total radioactivity in the presence of only R of the radioactive ligand, SA is radioactivity in the presence of radioligand and tested the connection and NA is radioactivity in the presence of radioligand and serotonin (5 µm).

Table 4 presents the test results of some compounds of General formula 1 and 2 in a competitive binding to serotonin 5-HT6receptors, demonstrating their high activity against serotonin 5-HT6the receptors.

Table 4 Values IC50compounds of General formula 1 and 2 in a competitive assay inhibition of serotonin 5-HT6receptors.
No.IC50PMToiPM
1.1(1)0.9860.458
1.2(1)1.180.549
1.2(3)0.9480.44
2(1)17.27.97
2(2)1.460.68

Presented in tables 3 and 4 indicate in which of moznosti compounds of General formula 1 and 2 be used as Molecular tools to study the characteristics of physiologically active compounds, having the property of inhibiting serotonin 5-HT6receptors, and as the drug began to pharmaceutical compositions and medicines.

Example 4. Obtaining a medicinal product in the form of tablets. Mix 1600 mg of starch, 1600 mg of powdered lactose, 400 mg of talc and 1000 mg of compound 1.2(3) and pressed in the bar. The resulting block is crushed into granules and sieved through a sieve, collecting the granules with a size 14-16 mesh. The obtained granules tabletirujut in a suitable form tablets weighing 560 mg each.

Example 5. Obtaining a medicinal product in the form of capsules. Thoroughly mix the connection 1.2(3) with lactose powder in a 2:1 ratio. Received poroshkoobraznuju mix pack 300 mg in gelatin capsules of suitable size.

Example 6. Obtaining a medicinal product in the form of injectable compositions for intramuscular, intraperitoneal or subcutaneous injection. Mix 500 mg of compound 1.2(3) with 300 mg of chlorobutanol, 2 ml of propylene glycol and 100 ml of injectable water. The resulting solution is filtered and placed in 1 ml ampoules which are sealed.

Example 7. Nootropic action (improvement of memory disturbed by scopolamine) compounds of General formula 1, 2 in the test "Passive avoidance of mice in the Shuttle chamber". Used Shuttle camera (Ugo Basile, Italy), which consisted of the TLD the compartments. All the walls of one of the compartments were opaque, and the second compartment had a transparent cover. The compartments were connected by the hole, which could be closed by a vertical door. The floor consisted of transverse metal rods, which could be pulsed DC. The experiments were performed on adult male mice of BALB/c mice weighing 20-24 g

On the first day experience for 30 minutes before training, mice were injected intraperitoneally with saline, scopolamine (0.3 mg/kg) or scopolamine in combination with compound 1.2(3). In each group were used at least 8 animals. Animals were placed in the bright compartment and record the latent period of the first entry into the dark chamber. The door between the compartments were closed, and the animal within 3 seconds, was sentenced by a current of 0.6 mA. After that, the animal was returned to a living cell. After 22-24 hours, the animal was again placed in the light compartment of the Shuttle camera and recorded the latent period of the first entry into the dark compartment, the total time spent in the light compartment and the number of visits in a dark compartment. The follow-up period was 5 minutes.

The experiment was carried out in daylight hours in an isolated laboratory environment with the use of "white noise" intensity of 70 dB above the hearing threshold of a person.

Scopolamine causes a disturbance learning (memory), ivory is itself expressed in the form of increased latent period 1st time in the dark compartment, increase time spent in the light compartment and the decrease in the number of entries into the dark compartment.

The ability of connection 1.2(3) to improve teaching, disturbed by scopolamine, may be regarded as evidence of their neuroprotective actions.

The results indicate the ability of the compound 1.2(3) to provide more effective nootropic action.

Example 8. Nootropic action (improved memory impaired MK-801) compounds of General formula 1, 2 in the test "Passive avoidance of mice in the Shuttle chamber". The experiment was performed as in example 5. On the first day experience for 30 minutes before training, mice were injected intraperitoneally with saline, MK-801 (0.1 mg/kg). Parallel independent groups of mice to training were injected intraperitoneally with saline, MK-801 in combination with compound 1.2(3). The results indicate the ability of the compound 1.2(3) to exert a neuroprotective effect.

Example 9. Anxiolytic (anxiolytic) effects of compounds of General formula 1, 2 to test the Behavior of mice in the elevated cross maze. The length of the arms of the maze is 30 cm, width 5 cm, height of walls 15 see Two contrasting sleeves closed at the sides and ends of the transparent walls; the other two are lit and open. The mouse was placed in the center of the maze for 5 minutes registered number : the species in open and closed sleeves and time held animals in open and closed sleeves. These data were calculated indexes preferences open sleeves as the ratio of the number of entries in open arms, and also the time spent in open arms, to the total number of visits to all of the sleeves and the time spent in them. In normal animals avoid open sleeves (index their preferences is 0.2-0.3). Substances with anxiolytic activity (anxiolytic activity) increase this rate to 0.5-0.6 or more, and also reduce the number of bowel movements, without changing the overall locomotor activity (total number of visits in the sleeves).

The results obtained indicate that the connection 1.2(3) exerts anxiolytic (tranquilizing) activity, comparable with Buspirone and lorazepam.

1. 2-Alkylsulfanyl-3-arylsulfonyl-cycloalkane[e]pyrazolo[1,5-a]pyrimidines of General formulas 1 and 2-alkylsulfanyl-3-arylsulfonyl-cycloalkane[d]pyrazolo[1,5-a] pyrimidines of General formula 2

where R1represents a hydrogen atom or a C1-C3alkyl;
R2represents a C1-C3alkyl;
R3represents a hydrogen atom, one or two are not necessarily the same halogen atom, a C1-C3alkyl or optionally substituted C1-C3the alkyl guide is oxyl;
n represents the integer 1, 2 or 3.

2. Compounds according to claim 1, which represents a 2-alkylsulfanyl-3-arylsulfonyl-7,8-dihydro-6N-cyclopent[f]pyrazolo[1,5-a]pyrimidines of General formulas (1.1), 2-alkylsulfanyl-3-arylsulfonyl-6,7,8,9-tetrahydrocyclopent[e]pyrazolo[1,5-a]pyrimidines of General formula (1.2) and 2-alkylsulfanyl-3-arylsulfonyl-7,8,9,10-tetrahydro-6N-cyclohepta[e]pyrazolo[1,5-a]pyrimidines of General formula (1.3)

where R1, R2and R3have the above value.

3. Compounds according to claim 2, representing a 2-methylsulfanyl-3-phenylsulfonyl-7,8-dihydro-6N-cyclopent[f]pyrazolo[1,5-a]pyrimidine 1.1(1),
2-methylsulfanyl-3-(3-perpenicular)-7,8-dihydro-6N-cyclopent[f]pyrazolo[1,5-a]pyrimidine 1.1(2), 2-methylsulfanyl-3-(3-chlorophenylsulfonyl)-7,8-dihydro-6N-cyclopent[f]pyrazolo[1,5-a]pyrimidine 1.1(3), 2-methylsulfanyl-3-(3-chloro-4-perpenicular)-7,8-dihydro-6N-cyclopent[f]pyrazolo[1,5-a]pyrimidine 1.1(4), 2-methylsulfanyl-3-phenylsulfonyl-6,7,8,9-tetrahydro-cyclohexano[e]pyrazolo[1,5-a]pyrimidine 1.2(1), 2-methylsulfanyl-3-(3-chlorophenylsulfonyl)-6,7,8,9-tetrahydro-cyclohexano[e]pyrazolo[1,5-a]pyrimidine 1.2(2), 5-methyl-2-methylsulfanyl-3-phenylsulfonyl-6,7,8,9-tetrahydro-cyclohexano[e]pyrazolo[1,5-a]pyrimidine 1.2(3), 5-methyl-2-methylsulfanyl-3-(3-florfenicol who were radioactive)-6,7,8,9-tetrahydro-cyclohexano[e]pyrazolo[1,5-a]pyrimidine 1.2(4), 5-methyl-2-methylsulfanyl-3-(3-chlorophenylsulfonyl)-6,7,8,9-tetrahydro-cyclohexano [e] pyrazolo [1,5-a] pyrimidine 1.2(5), 5-methyl-2-methylsulfanyl-3-(3-chloro-4-perpenicular)-6,7,8,9-tetrahydro-cyclohexano[e]pyrazolo[1,5-a]pyrimidine 1.2(6), 2-methylsulfanyl-3-phenylsulfonyl-7,8,9,10-tetrahydro-6N-cyclohepta[e]pyrazolo[1,5-a]pyrimidine 1.3(1) and 2-methylsulfanyl-3-(3-chlorophenylsulfonyl)-7,8,9,10-tetrahydro-6N-cyclohepta[e]pyrazolo[1,5-a]pyrimidine 1.3(2)

4. The method of obtaining compounds of General formula (1) and (2) according to any one of claims 1 to 3 by the interaction of 3-amino-4-arylsulfonyl-2H-pyrazoles of General formula (3) with the corresponding β-dicarbonyl compounds of General formula (4) or their derivatives of General formula (5) with subsequent isolation or separation of the reaction products

where R1, R2, R3and n have the above meaning.

5. "Molecular tools for studying characteristics of physiologically active compounds, the region is giving the property to inhibit serotonin 5-HT 6receptors, which are compounds of General formula (1) or (2) according to any one of claims 1 to 3.

6. Substituted 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidine of the General formula (1) or (2) according to any one of claims 1 to 3 as the drug began to pharmaceutical compositions and medicines possessing properties of antagonists of 5-HT6receptors.

7. Pharmaceutical composition having the properties of antagonists of 5-HT6receptors that are suitable for treating and preventing conditions and disorders of the Central nervous system containing a pharmaceutically effective amount of drug to the beginning 6.

8. A method of obtaining a pharmaceutical composition according to claim 7 mixture with an inert filler and/or solvent medicinal beginning 6.

9. Drug, possessing properties of antagonists of 5-HT6receptors that are suitable for the prevention and treatment of diseases of the Central nervous system in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing, including medicinal beginning according to claim 6 or a pharmaceutical composition according to claim 7 in an effective amount.

10. The drug according to claim 9, having anxiolytic activity.

11. The drug according to claim 9, having neuroprotective activity and suitable for str is Ksenia memory.

12. Method for the prevention and treatment of diseases of the Central nervous system, the pathogenesis of which is associated with 5-HT6receptors, which is the introduction of medicinal beginning according to claim 6, or a pharmaceutical composition according to claim 7, or a medicinal product according to claim 9 in an effective amount.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a cyclic bioisostere of purine system derivatives, with general structural formula given below , where R = , Li, Na or K, R1 = -H, -NH2, -Br, -Cl, -OH, -COOH; A = -N- for B=-N=, Z = -CH-; A = -CH= for B = -N=, Z = -CH-; A = -CH= for B = -N=, Z = -N=; A = -CH= for B = -CH=, Z - -CH=; A = -CH= for B = -CH=, Z = -N=, except compounds in which A = -CH= for B = -CH=, Z = -CH=, R= Li, Na or K and R1= -NH2 in the 5th position of the benzo[d]-3H-pyridazine-1,4-dione nucleus, and its pharmacologically acceptable salts, with normalising effect on intracellular processes.

EFFECT: obtaining compounds which can be used for normalising intracellular processes in therapy of disorders, caused by intracellular acidosis and/or oxygen deficiency and/or excess formation of free radicals and/or excess formation of free radical forms of oxygen and/or high thrombocyte aggregation and/or erythrocytes and/or adverse effects and/or nitrergic cell mechanism disorder.

17 cl, 14 tbl, 15 dwg

FIELD: chemistry.

SUBSTANCE: new pyrrolotriazine derivatives of general formula (I) are described, where R1 is possibly substituted piperidinyl or piperazinyl; R2 is possibly substituted phenyl; R3 is hydrogen; X is -NH-; Y is -CH2-; as well as their pharmaceutically acceptable salts or steroisomers, and pharmaceutical compositions containing said compounds.

EFFECT: given compounds are kinase inhibitors and can be used in medicine, for example as anticancer agents.

9 cl, 267 ex, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to new derivatives of imidazo[1,2-c]pyrimidinyl acetic acid of formula (I) or to its salts: , where R1 is ,, in which n is an integer ranging from 0 to 6; Y is aryl, where the said aryl is optionally substituted at a substitutable position with one or more substitutes selected from a group which consists of halogen or C1-6alkyl, optionally substituted with mono-, di- or trihalogen; R2 is hydrogen; R3 is hydrogen or halogen; and R4 is hydrogen. The invention also relates to derivatives of imidazo[1,2-c]pyrimidinyl acetic acid of formula (I-i) or to its salts, to a drug, to use of compounds in paragraph 1, as well as to a drug in form of a standard single dosage.

EFFECT: obtaining new biologically active compounds, which are active towards CRTH2.

23 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: in compounds of formula (I) , Q is: (IIa) or (IIb) , R1 is chosen from a group which consists of carboxylic aryl and carboxylic aryl which is substituted with substitute(s) independently chosen from a group which consists of halogen, cyano, nitro, C1-10alkyl, C1-10alkyl which is substituted with substitute(s) independently chosen from a group which consists of halogen, C1-9alkoxy, C1-9alkoxy which is substituted with substitute(s) independently chosen from a group which consists of halogen, mono-C1-5alkylamino, and heterocyclyl or heterocyclyl which is substituted with substitute(s) independently chosen from a group which consists of halogen, C1-5alkyl; R2 is C1-5alkyl, C1-5alkyl which is substituted with halogen, C1-5alkyl which is substituted with carboxylic aryl, C1-5alkoxy, -N(R2a)(R2b); where R2a and R2b are each independently hydrogen, C1-5alkyl or C1-5alkyl, substituted with substitute(s) independently chosen from a group which consists of hydroxyl, carboxylic aryl; L represents formula (IIIa); , where R3 and R4 are each hydrogen; A is a single bond, and B is a single bond or -CH2-; Z1, Z3, and Z4 are each independently hydrogen, halogen, C1-5alkyl, C1-5alkyl, substituted with carboxylic aryl, C1-5alkoxy, mono-C1-5alkylamino, di-C1-5alkylamino, carboxylic aryl, heterocyclyl or substituted heterocyclyl; Z2 is hydrogen, C1-5alkyl, C1-5alkyl which is substituted with carboxylic aryl, C1-5alkoxy, mono-C1-5alkylamino, di-C1-5alkylamino, carboxylic aryl, heterocyclyl or substituted heterocyclyl; Y is -C(O)NH-, -C(O)-, -C(S)NH-, -C(O)O- or -CH2-; where carboxylic aryl is phenyl; heterocyclyl is 1H-indolyl, 9H- xanthenyl, benzo[1,3]dioxolyl, furyl, imidazolyl, isoxazolyl, morpholinyl, piperazinyl, pyridyl, pyrrolidyl; halogen is fluorine, chlorine, bromine or iodine. The invention also relates to a pharmaceutical composition.

EFFECT: compounds can be used for treating central nervous system diseases, and for improving memory functioning, sleep, awakening, diabetes.

16 cl, 8 dwg, 4 tbl, 525 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a tetrazole compound with general formula I , where X3 and X4 are independently N and C, where one of X3 and X4 is certainly C; P is phenyl; m equals 1 or 2, where if m equals 1, R1 is bonded to P through a carbon atom on ring P in the meta-position of ring P relative the point at which P is bonded to X3, and if m equals 2, R1 is bonded to P through a carbon atom on ring P in positions 2 and 5 of ring P; R1 is halogen, C1-6alkyl, OC1-6alkyl or cyano group; X1 is C2-3alkyl, C2-3alkenyl, NR3, O, S, CR3R4, SO, SO2; X2 is a bond, CR3R4, O, S, NR3, SO, SO2; R3 and R4 are independently chosen from a group which consists of hydrogen, hydroxy, C1-6alkyl; Q is triazolyl, piperazinyl, or triazole or imidazole ring, condensed with a 6- or 7-member heterocyclic ring with one or two N atoms as heteroatoms; R is C1-6alkyl, C3-6cycloalkyl, pyridinyl, which can be substituted with a nitro, cyano, halogen or OC1-4alkyl group; phenyl, which can be substituted with a halogen, C1-4alkyl, OC1-4alkyl group; (CO)OC1-4alkyl; pyrimidinyl, which can be substituted with a OC1-4alkyl group; p equals 0, 1 or 2, or pharmaceutically acceptable salt or hydrate thereof.

EFFECT: invention also relates to method of inhibiting activity of mGluR5 receptors.

11 cl, 44 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns novel compounds of formula (1a), formula (1b), formula (1c) and formula (1d), as well as pharmaceutical composition based on them and their application in medicine obtainment. R1-R4, G, W, X, X1, U, V, a, b are defined in the invention claim.

EFFECT: compound with antagonistic effect on vasopressin V1A receptor.

73 cl, 133 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns compounds of the formula and other compounds listed in cl. 1 of invention claim, and pharmaceutical composition based on them, as well as method of mGluR5 receptor activity inhibition involving claimed compounds.

EFFECT: application in treatment and prevention of diseases mediated by mGluR5 receptor activity.

4 cl, 18 dwg, 1009 ex

FIELD: medicine.

SUBSTANCE: according to the invention there is provided substituted indolequinoxalines of the formula (I), where R1 represents hydrogen or represents one or more similar or different substituent in positions from 7 to 10, selected of the group of halogen, low alkyl/alkoxy, hydroxy, triflouromethyl, trichloromethyl, triflouromethoxy, R2 represents similar or different C1-C4 alkyl substituents, X represents CO or CH2, Y represents OH, NH2, NH-(CH2)n-R3, where R3 represents low alkyl, OH, NH2, NHR4 or NR5R6, where R4, R5 and R6 represent low alkyl or cycloalkyl independently and n represents integer from 2 to 4 provided that X represents CH2, Y represents OH or NH-(CH2)n-OH and its pharmaceutically acceptable salt. There is also provided pharmaceutical composition, containing these compounds, methods of compound producing, formula (I).

EFFECT: compounds are applied as medicine for treatment and prevention of autoimmune diseases.

15 cl, 1 ex, 5 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to antagonists of serotonin 5-HT6 receptors - substituted 4-sulphonylpyrazoles and 3-sulphonyl-pyrazolo[1,5-a]pyrimidines of general formula 1 or general formula 1.2. These compounds can be used for treating and preventing development of different cognitive and neurodegenerative diseases of the central nervous system. In general formulae 1 and 1.2, 1 1.2 respectively, Ar is optionally substituted phenyl or optionally substituted 5-6-member heteroaryl, containing a nitrogen, oxygen or sulphur atom as a heteroatom; R1 is a hydrogen atom, optionally substituted C1-C5 alkyl, lower acyl or optionally substituted phenyl; R2 is an optionally substituted amino group or substituted hydroxy group or R1, together with the nitrogen atom to which it is bonded, and R2, together with the carbon atom to which it is bonded, form a substituted pyrimidine ring; R3 is a hydrogen atom, optionally substituted C1-C5alkyl, substituted hydroxyl group or substituted sulphanyl group, R5 is a hydrogen atom, optionally substituted C1-C5alkyl, substituted hydroxyl group or substituted sulphanyl group, R7 and R9 independently represent a hydrogen atom, C1-C3alkyl or phenyl, R8 is a hydrogen atom.

EFFECT: new compounds have useful biological properties.

13 cl, 2 dwg, 4 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: new derivative of diaminopyrroloquinazolines of formula (I) and their pharmaceutically acceptable salts possess properties of proteintyrosine posphatase PTP1 inhibitors which can be used for treating the diseases mediated by action of the latter, particularly for decreasing glucose content in blood. In formula (I) , A stands for 6-membered aromatic ring, or 5- or 6-membered aromatic ring which contains 1 or 2 heteroatoms chosen from S, N and O; R1 is specified from the group including the following radicals: C1-6alkyl, hydroxyC1-6alkyl, mono- or dihydroxy-substituted C1-6alkyl, phenyl-(C1-6alkyl), benzyloxyC1-6alkyl and phenyl-(C1-6alkoxy)C1-6alkyl; R2 is specified from the group including the following radicals: hydrogen, C1-6alkyl, hydroxyC1-6alkyl, mono- or dihydroxy-substituted C1-6alkyl, phenyl-(C1-6alkyl) and phenyl-(C1-6alkoxy)C1-6alkyl; R3 represents hydrogen or methyl; Ra is specified from the group including the following radicals: hydrogen, C1-6alkyl, C1-6alkoxy, hydroxyC1-6alkyl, mono- or dihydroxy-substituted C1-6alkyl, phenyl(C1-6alkyl), benzyloxyC1-6alkyl or ; R10 represents hydrogen or ; x and y separately stand for integers 0 to 4; Rb and Rc are separately specified from the group including the following radicals: hydrogen, C1-6alkyl, perfluorochemical C1-6alkyl, substituted C1-6alkyl, C1-6alkoxy, phenoxy, halogen, (unsubstituted C1-6alkyl)-(substituted phenyl)-(C1-6alkyl), phenyl-(C1-6alkoxy) or ; R11 represents hydrogen, phenyl or unsubstituted C1-6alkyl; p stands for integer 0 to 1; Rd represents hydrogen, substituted C1-6alkyl or perfluorochemical C1-6alkyl; Re represents hydrogen, halogen, substituted C1-6alkyl and perfluorochemical C1-6alkyl; Rf represents hydrogen or C1-6alkyl; the substitutes found in alkyl groups are independently specified from the following groups: hydroxy, C1-6alkoxy, C1-6alkanoyl; and the substitutes found in substituted phenyl as Rb and Rc, are independently specified from the following groups: C1-6alkyl, C1-6alkoxy, hydroxyC1-6alkyl, hydroxyl, hydroxylC1-6alkoxy, halogen, perfluorC1-6alkyl and C1-6alkanoyl.

EFFECT: improved properties of the derivatives.

29 cl, 2 dwg, 48 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I), their R and S isomers; or a mixture of R and S isomers; or pharmaceutically acceptable salts. Disclosed compounds can be used as a medicinal agent with agonist properties towards PPAR. In formula (I) and L represents (II) or (III); R1, R2, R3, Ya, R4a, R", Yb, R4b are hydrogen; R and R' are independently hydrogen, C1-C4alkoxy; n equals 0, 1 or 2; m equals 0, 1 or 2; X1 is a -Z-(CH2)P-Q-W group; X2 is -CH2-, -C(CH3)2-, -O- or -S-.

EFFECT: invention relates to a pharmaceutical composition, which contains the disclosed compound, to use of the pharmaceutical composition as a medicinal agent, to use of the disclosed compound in making the pharmaceutical composition.

13 cl, 35 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new nitro-derivatives of blockers of angiotensin II receptors of formula R-(Y-ONO2)s (I), (values of radicals R, Y and s are given in the formula of invention) with broad pharmacological effect and high transferability.

EFFECT: obtaining compounds which can be used for treating cardiovascular diseases, kidney diseases, chronic liver diseases and inflammatory processes.

6 cl, 6 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, particularly to the technology of producing selenoxanthenes and can be used in producing food additives, medicinal agents and cosmetic agents, which exhibit broad biological activity. An agent is described, which is an α-crystalline form of 9-phenyl-sym-octahydroselenoxanthene, which has antixodant, detoxication, immunomodulating, antiatherogenic, antisclerotic, anabolic, hypolipid action, and the corresponding structural formula with powder X-ray pattern obtained on Cu-K radiation sources with characteristic reflection indices expressed in degrees of the diffraction angle 2θ: 6.0 12.0 15.0 17.0 19.0 20.0 21.5, 21.7, 20.9 25.0 27.0 28.0 29.0 37.0 and melting temperature 96.8°C, as well as to a method of producing said agent, involving crystallisation of the corresponding 9-R-sym-hydroselenoxanthene from low-polar or non-polar solvent, preferably hexane, chloroform or isopropyl alcohol.

EFFECT: design of an efficient method of producing selenoxanthenes.

3 cl, 1 dwg, 1 tbl

FIELD: medicine.

SUBSTANCE: invention relates to medicine, particularly to cardiology, and concerns treatments of cardiovascular diseases that is ensured by introduction of a composition containing stem cells and undifferentiated precursors prepared of adipose tissue by separating mature adipocytes and connective tissue.

EFFECT: that ensures restoration of blood circulation in ischemic region.

28 cl, 7 ex, 12 dwg

FIELD: medicine.

SUBSTANCE: invention concerns medicine, namely application of sodium thiosulphate as a hypolipidemic and antiatherosclerotic agent for oral introduction to treat dislipoproteinemia and atherosclerosis.

EFFECT: there is disclosed hypolipidemic and antiatherosclerotic agent.

5 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medical products and concerns a pharmaceutical tablet, contains a therapeutically effective dose of crystalline telmisartan sodium salt of fusion temperature 245±5°C and diuretic hydrochlorothiaside, as well as one or more adjuvants used to prepare medical products. There is also disclosed method for making thereof. According to the invention, the pharmaceutical tablets are storage-stable.

EFFECT: intended for prevention or treatment of diseases wherein application of angiotensin II antagonists ensures the therapeutic effect.

23 cl, 7 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine and can be used for treatment of neural diseases. The invention represents a combined antihypoxic medical product characterised by that it contains vinpocetine and succinic acid in the relation 1:2-50. Succinic acid potentiates antihypoxic action of vinpocetine.

EFFECT: invention provides extended range of medical products used for treating various ischemic conditions of central nervous system.

5 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine and pharmacology and presents a pharmaceutical composition based on alpha-lipoic acid as an aqueous solution for injections, for treatment and/or prevention of a disease chosen from group including alcoholic and/or diabetic polyneuropathy, coronary atherosclerosis, hyperlipidemia, hyperlipoproteinemia, mild and moderate viral hepatitis type A, hepatic cirrhosis, heavy metal salts poisoning, intoxications of various aetiologies, differing that it contains ethylenediamine, propylene glycol, solubiliser presented with plasdone, water for injection or 0.9% NaCI solution for injection in a certain relation components in the composition.

EFFECT: invention provides improved stability and absence of sediment in the solution, as well as extended range of products.

5 cl, 1 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: use of disodium salt of 4,4'-di(sulphophenyl) sulphone as a hypolipidemic and an antiatherosclerotic agent during treatment of dislipoproteinemia of atherogenic nature and atherosclerosis of various localisation is proposed. The proposed preparation reduces level of cholesterol and triglycerides in blood plasma (hypolipidemic action), reduces cholesterol content in the aorta and degree of its atherosclerotic damage (antiatherosclerotic action).

EFFECT: preparation exhibits low toxicity and efficiency during oral administration.

5 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to therapy, and concerns treatment of chronic arterial insufficiency. That is ensured by introduction of the preparation Antistax once a day in a dose 720 mg within 10 days, and then in a dose 320 mg within 20 days in addition to the conventional therapy involving antiaggregants, anticoagulants and vasodilators. Besides, Xymedone is introduced in a daily dose 1 g within 10 days in combination with machine pneumatic massage in mode "running wave" at duration of procedure 45 minutes and more and maximum pressure in chambers 100 mm Hg and less.

EFFECT: such complex of pharmacological aids introduced in developed doses and modes in combination with pneumatic massage provides effective treatment ensured by improved microcirculation and normalised lymphatic and venous blood flow.

3 ex

Diabetes treatment // 2363465

FIELD: medicine.

SUBSTANCE: present group of inventions relates to medicine, particularly to endocrinology. For this purpose sufficient amounts of a compound which inhibits HIF hydroxylase activity are introduced.

EFFECT: design of a method of treating diabetes and other conditions, related to glucose pathometabolism, through stabilisation of HIFα.

8 cl, 12 dwg

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