Substituted 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines, serotonin 5-ht6 receptor antagonists, methods of producing and using said compounds

FIELD: chemistry.

SUBSTANCE: present invention relates to novel substituted 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of general formula 1, their pharmaceutically acceptable salts and/or hydrates having serotonin 5-HT6 receptor antagonist properties. The compounds can be used in treating and preventing various diseases of the central nervous system, pathogenesis of which is associated with 5-HT6 receptors, particularly cognitive disorders, neurodegenerative diseases and psychiatric disorders. The compounds have anxiolytic and nootropic effect and can also be used for preventing and treating anxiety disorder and for enhancing metal capacity. In formula 1 , R1 is a hydrogen atom, C1-C3 alkyl, (C1-C3)alkyloxy(C1-C3)alkyl, hydroxy(C1-C3)alkyl, pyridyl; R2 is a hydrogen atom, halogen atom, C1-C3 alkyl, phenyloxy or pyridyloxy; R3 is a hydrogen atom, C1-C3 alkyl, C1-C3 alkyloxy, (C1-C3)alkyloxy(C1-C3)alkyl, hydroxy(C1-C3)alkyl, pyridyl; R4 is C1-C3 alkyl; R5 is a hydrogen atom, one or two halogen atoms, C1-C3 alkyl, C1-C3 alkyloxy or hydroxyl; X is a sulphur atom or thionyl group (SO).

EFFECT: obtaining compounds which can be used in treating and preventing various diseases of the central nervous system.

24 cl, 9 dwg, 4 tbl, 19 ex

 

This invention relates to new substituted 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines, antagonists of serotonin 5-HT6receptors, drug and pharmaceutical compositions containing the drug began in the form of these compounds, and to a method of treating and preventing various diseases of the Central nervous system (CNS), cognitive and neurodegenerative diseases. The basis of the pharmacological effect of new drugs began laying their ability to interact with serotonin 5-HT6receptors that play an important role in the treatment of CNS disorders, in particular Alzheimer's disease (AD), Parkinson's disease, diseases of Hantington, 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 and cognitive disorders, evidence-based and is a very promising trend in modern medicine [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 nervoussystem, mainly in areas of the brain responsible for learning and memory [Ge'rard C., Martres, M.-P., Lefe'vre K., Miquel, M.-C., Verge' D., Lanfumey L., Doucet e, Hamon M., El Mestikawy S. Mipo-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, J.J. Hagan, Upton N., F.S. Walsh, C.M. Regan The 5-HT(6) receptor antagonist SB-271046 reverses scopolamine-dismpted consolidation of a passive avoidance task and ameliorates spatial task deficits in aged rats. Neuropsychopharmacology.. 2004; 29:93-100. Riemer, S., E. Borroni, Levet-Trafit Century, Martin J.R., Poli, S., Porter, R.H., Bos M. Influence of the 5-HT6 receptor on acetylcholine release in the cortex: pharmacological characterization of 4-(2-bromo-6-pyrrolidin-l-ylpyridine-4-sulfonyl)phenylamine, a potent and slective 5-NT receptor 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-HT6 receptor 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 at the effect of the antagonist of 5-HT6receptors [Foley A.G., Murphy K.J., Hirst W.D., H.C. Gallagher, J.J. Hagan, Upton N., F.S. Walsh, C.M. Regan 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]. In recent years, along with the achievement of a deeper understanding of the role of 5-HT6receptors in cognitive processes formed a clearer picture of 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 resulted in the creation of selective high-affinity ligands ("molecular tools"), then and clinical candidates. Currently, a number of antagonists of 5-HT6receptors located at different stages of clinical trials as drug candidates for the treatment of the bronchial asthma, diseases of Hantington, schizophrenia (antipsychotics) and other neurodegenerative and cognitive diseases (table 1) [http://integrity.prous.com].

Table 1
Antagonists of 5-HT6receptors as drug candidates.
MedicationClinical phase I trialsDeveloperTherapeutic group
Dimebon™Phase 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 Huntington
Dimebon*Phase II(Russia)Schizophrenia
PRX-07034Phase IEpix Pharm.Treatment isbutton the first weight; Antipsychotic;
Treatment of cognitive diseases
SB-737050APhase IIGlaxoSmithKlineAntipsychotic
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
DimebonTMPreclinica(Russia)Treatment of stroke

Another attractive property of antagonists of 5-HT6receptors is their ability to suppress appet is t, that can lead to the creation on their basis of fundamentally new means to reduce overweight and obesity [Vicker SP, Dourish C.T. 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 the increase in the emission of alpha melanocytestimulating hormone, which ultimately reduces the need for food [M.L. Woolley 5-HT6receptors. 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 new medicines for the treatment of a wide range of diseases of the Central nervous system, including neurological and neurodegenerative diseases and cognitive disorders.

In the literature there is a considerable number of publications dedicated to the biologically active sulfanilamidnam azaheterocyclic compounds, including serotonin receptor ligands. So, for example, describes 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 medications the authors of the present invention made extensive studies in a series of substituted 3-arylsulfonyl-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 to their inherent specific signal and thereby cause a biological response of a cell.

"Alkyl" means alifaticescoe the 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, alkylsulfonates, annelirovannymi heteroarylboronic, annelirovannymi heteroalicyclic, annelirovannymi heterooligomerization, annelirovannymi heteroalicyclic, annelirovannymi arylchloroalkanes, annelirovannymi aristically, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic, alkoxycarbonyl, arelaxation, heteroarylboronic or RkaRk+1andN-, RkaRk+1aNC(=O)-, RkaRk+1aNC(=S)-, RkaRk+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 relate, form Rkaand Rk+1a4-7-membered heterocyclyl or heterocyclyl. Preferred alkyl groups are methyl, trifluoromethyl, ethyl, propyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, ISO-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, benzyloxycarbonylation, methoxycarbonylmethyl 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.

"Alkylsulfanyl" means CnH2n+1S-group in which the alkyl group defined in this section.

"Alkyloxy" means CnH2n+1O - group in which alkyl is defined in this section. The preferred alkyloxyaryl are methoxy, ethoxy, n-propoxy, ISO-propoxy and n-butoxy.

"Alkyloxyalkyl" means CnH2n+1OCmH2m- group in which alkyl is defined in this times is barely.

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

"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 carbon atoms. 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.

"Halogen" means fluorine, chlorine, bromine and iodine. Preferred are fluorine, chlorine and bromine.

"Hydroxyalkyl" means HOCmH2m- g is the SCP, in which alkyl is defined in this section.

"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, as well as 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 depression; postpartum depression and other depressive conditions accompanying somatic, neurological and other diseases.

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

"Will replace the eh hydroxy-group" means the Deputy, attached to the hydroxy-group, including alkyl, aryl, heteroaryl, aralkyl, heteroalkyl, hydroxyalkyl, acyl, aroyl, alkyloxyalkyl, aryloxyalkyl, geterotsiklicheskikh etc.

"Cognitive disorder or cognitive impairment (cognitive disorder)" means a violation of (weakening) of mental abilities, including attention, memory, thinking, cognition, learning, speech, cognitive, Executive and creative abilities, orientation in time and space, in particular, cognitive disorders associated with Alzheimer's disease, Parkinson's disease and Hantington; 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, accompany the traveler neurodegenerative diseases, for example, 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 with 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 drugs (drug).

"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 ready-made forms, designed to restore, correct or modify 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 procee), capable of interacting with receptors that transform this interaction in specific signal.

"Neurodegenerative disease (NT)" means the specific condition or disease characterized by damage to the primary and death of populations of nerve cells in certain regions of the Central nervous system. Neurodegenerative diseases include, but are not limited to, Alzheimer's disease and Parkinson's disease; disease (horay) Hantington, 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-associated 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 n is of crotoxin, infectious diseases and cancer of the brain, and neuronal damage associated with autoimmune and endocrine diseases and other neurodegenerative processes.

"Lower alkyl" means a linear or branched alkyl with 1-4 carbon atoms.

"Nootropics" or "nootropic", they neurometabolic stimulants - substances taken to improve mental abilities.

"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, parafin the Yu, pseudohallucinations, psychosis syndrome Kotar, schizoaffective 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 coprofilia, 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" is all kinds of schizophrenia; schizophrenia-like psychosis disease; shizotimichesky disorders; schizoaffective disorders, including bipolar and depress wny types; delusional disorders, including delirium relations, persecution, grandeur, jealousy, erotomania, and hypochondriac, somatic, mixed and dedifferentiate delirium; brief psychotic disorder; induced psychotic disorder; induced psychotic substances disorder, and other psychotic disorders.

"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.

"Sulfanilate group" means R-S - group in which R represents alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, annelirovannymi heteroarylboronic, annelirovannymi heteroalicyclic, annelirovannymi heterooligomerization, annelirovannymi heteroalicyclic, annelirovannymi arylchloroalkanes, annelirovannymi aristically, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic, the values of which are defined in this section.

"Sulfonylurea group" means R-SO - group, in which R represents alkyl, cycloalkyl, the reel, heteroaryl, heterocyclyl, annelirovannymi heteroarylboronic, annelirovannymi heteroalicyclic, annelirovannymi heterooligomerization, annelirovannymi heteroalicyclic, annelirovannymi arylchloroalkanes, annelirovannymi aristically, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic, the values of which are defined in this section.

"Sulfonylurea group" means R-SO2group in which R represents alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, annelirovannymi heteroarylboronic, annelirovannymi heteroalicyclic, annelirovannymi heterooligomerization, annelirovannymi heteroalicyclic, annelirovannymi arylchloroalkanes, annelirovannymi aristically, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic, the values of which are defined in this section.

"Therapeutic cocktail" is both 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) denote the generalized (non-specific) anxiety; acute uncontrolled anxiety; panic disorder; phobias, such as agoraphobe the Yu (strong 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); post-traumatic stress disorder and acute stress disorder. In addition to anxiety disorders include anxiety, induced by alcohol or substances; anxiety disorders adaptation, as well as mixed forms of anxiety disorders and depression.

"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 consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, dilute the lei, 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 agent, such as aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents and delivery vehicles include water, ethanol, polyalcohol, and mixtures thereof, 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, alginic 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 introduction of the active agent 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. Pharmaceutical compositions typically obtained using standard procedures involving mixing the active compound with a liquid or finely powdered solid carrier.

"Pharmaceutically acceptable salt" Osnach the et is relatively non-toxic 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 these salts is given in S.M. Berge 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 preferred are the 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, hydroc the ID of 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 object of the present invention are new substituted 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1 and their pharmaceutically acceptable salts and/or hydrates

where R1represents a hydrogen atom, a C1-C3alkyl, C1-C3-alkyloxy1-C3alkyl, hydroxys1-C3alkyl, pyridyl;

R2represents a hydrogen atom, a halogen atom, a C1-C3alkyl, phenyloxy or pyridi is hydroxy;

R3represents a hydrogen atom, a C1-C3alkyl, C1-C3alkyloxy,1-C3alkyloxy(C1-C3)alkyl, hydroxy(C1-C3)alkyl, pyridyl;

R4represents a C1-C3alkyl,

R5represents a hydrogen atom, one or two halogen atom, a C1-C3alkyl, C1-C3alkyloxy or hydroxyl;

X represents a sulfur atom or sulfinyl group (SO),

excluding compounds of General formula 1 in which R1and R3simultaneously represent methyl, R2represents a hydrogen atom, a R4-X represents methylsulfanyl group or ethylsulfonyl group.

Preferred substituted 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1 are compounds of General formula 1.1, and their pharmaceutically acceptable salts and/or hydrates

where R1, R3, R4and R5have the above value.

Preferred substituted 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formulas 1 and 1.1 are substituted 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1.1.1, 1.1.2, 1.1.3, 1.1.4, 1.1.5, 1.1.6, 1.1.7, 1.1.8, 1.1.9, 1.1.10

where R4and R3have the above meaning; R6and R7independently from each other represent hydrogen or C1-C3alkyl; R8represents hydrogen or C1-C3alkyl; R9represents a C1-C3alkyl or pyridyl; PY represents a pyridyl, n takes on the values 1-3.

Preferred substituted 2-methylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formulas 1 and 1.1 are 2-methylsulfanyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.1(1), 2-methylsulfanyl-3-(4-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.1(2), 2-methylsulfanyl-3-(3-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.1(3), 2-methylsulfanyl-3-(3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.1.1(4), 2-methylsulfanyl-3-(4-fluoro-3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.1.1(5), 5-methyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.2(1), 5-methyl-2-methylsulfanyl-3-(4-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.2(2), 5-methyl-2-methylsulfanyl-3-(3-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.2(3), 5-methyl-2-methylsulfanyl-3-(3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimi is in 1.1.2(4), 5-methyl-2-methylsulfanyl-3-(4-fluoro-3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.1.2(5), 7-methyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.3(1), 7-methyl-2-methylsulfanyl-3-(4-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.3(2), 7-methyl-2-methylsulfanyl-3-(3-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.3(3), 7-methyl-2-methylsulfanyl-3-(3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.1.3(4), 7-methyl-2-methylsulfanyl-3-(4-fluoro-3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.1.3(5), 5-methyl-2-methylsulfanyl-7-methoxymethyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.4(1), 5-methyl-2-methylsulfanyl-7-methoxymethyl-3-(4-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.4(2), 5-methyl-2-methylsulfanyl-7-methoxymethyl-3-(3-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.4(3), 5-methyl-2-methylsulfanyl-7-methoxymethyl-3-(3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.1.4(4), 5-methyl-2-methylsulfanyl-7-methoxymethyl-3-(4-fluoro-3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.1.4(5), 7-methyl-2-methylsulfanyl-5-methoxymethyl-3-phenylsulfonyl-pyrazolo[1,5-a] pyrimidine 1.1.5(1), 7-methyl-2-methylsulfanyl-5-methoxymethyl-3-(4-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.5(2), 7-methyl-2-methylsulfanyl-5-methoxymethyl-3-(3-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.5(3), 7-methyl-2-methylsulfanyl-5-methoxymethyl-3-(3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.1.5(4), 7-methyl-2-methylsulfanyl-5-methox the methyl-3-(4-fluoro-3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.1.5(5), 7-hydroxymethyl-5-methyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.6(1), 7-hydroxymethyl-5-methyl-2-methylsulfanyl-3-(4-perpenicular)-pyrazolo[1,5-a] pyrimidine 1.1.6(2), 7-hydroxymethyl-5-methyl-2-methylsulfanyl-3-(3-perpenicular)-pyrazolo[1,5-a] pyrimidine 1.1.6(3), 7-hydroxymethyl-5-methyl-2-methylsulfanyl-3-(3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.1.6(4), 7-hydroxymethyl-5-methyl-2-methylsulfanyl-3-(4-fluoro-3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.1.6(5), 5-hydroxymethyl-7-methyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.7(1), 5-hydroxymethyl-7-methyl-2-methylsulfanyl-3-(4-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.7(2), 5-hydroxymethyl-7-methyl-2-methylsulfanyl-3-(3-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.7(3), 5-hydroxymethyl-7-methyl-2-methylsulfanyl-3-(3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.1.7(4), 5-hydroxymethyl-7-methyl-2-methylsulfanyl-3-(4-fluoro-3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.1.7(5), 5-methyl-2-methylsulfanyl-7-methoxy-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.8(1), 2-methylsulfanyl-7-methoxy-5-(pyridin-2-yl)-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.8(2), 2-methylsulfanyl-7-methoxy-5-(pyridin-3-yl)-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.8(3), 2-methylsulfanyl-7-methoxy-5-(pyridin-4-yl)-3-phenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.1.8(4), 5-methyl-2-methylsulfanyl-7-methoxy-3-(3-florfenicol who were radioactive)-pyrazolo[1,5-a]pyrimidine 1.1.8(5), 2-methylsulfanyl-5-(pyridin-2-yl)-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.9(1), 2-methylsulfanyl-5-(pyridin-3-yl)-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.9(2), 2-methylsulfanyl-5-(pyridin-4-yl)-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.9(3), 2-methylsulfanyl-5-(pyridine-3-yl)-3-(3-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.9(4), 2-methylsulfanyl-5-(pyridin-3-yl)-3-(3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.1.9(5), 7-methyl-2-methylsulfanyl-5-(pyridin-2-yl)-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.9(6), 7-methyl-2-methylsulfanyl-5-(pyridine-3-yl)-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.9(7), 7-methyl-2-methylsulfanyl-5-(pyridin-4-yl)-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.9(8), 7-methyl-2-methylsulfanyl-5-(pyridin-3-yl)-3-(3-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.9(9), 7-methyl-2-methylsulfanyl-5-(pyridin-3-yl)-3-(3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.1.9(10), 2-methylsulfanyl-7-(pyridin-2-yl)-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.10(1), 2-methylsulfanyl-7-(pyridin-3-yl)-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.10(2), 2-methylsulfanyl-7-(pyridin-4-yl)-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.10(3), 2-methylsulfanyl-7-(pyridin-3-yl)-3-(3-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.10(4), 2-methylsulfanyl-7-(pyridin-3-yl)-3-(3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.1.10(5), 5-methyl-2-methylsulfanyl-7-(pyridin-2-yl)-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimido the 1.1.10(6), 5-methyl-2-methylsulfanyl-7-(pyridin-3-yl)-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.10(7), 5-methyl-2-methylsulfanyl-7-(pyridin-4-yl)-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.10(8), 5-methyl-2-methylsulfanyl-7-(pyridin-3-yl)-3-(3-perpenicular)-pyrazolo[1,5-a]the pyrimidine 1.1.10(9), 5-methyl-2-methylsulfanyl-7-(pyridin-3-yl)-3-(3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.1.10(10) and their pharmaceutically acceptable salts and/or hydrates

The object of the present invention is a method for substituted 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1 in which X=S, 1.1, 1.1.1, 1.1.2, 1.1.3, 1.1.4, 1.1.5, 1.1.9, 1.1.10 and their pharmaceutically acceptable salts and/or hydrates interaction of 3-amino-4-sulfonyl-2H-pyrazoles of General formula 2 with the corresponding β-diketones of General formula 3 or their acetals with subsequent isolation or separation of the reaction products (a, b) according to the scheme presented below. If you are using symmetrically samisen the e β-diketones of General formula 3, R1=R3, the reaction product is a 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidine (a=b). If you are using asymmetrically substituted β-diketones of General formula 3 in which R1≠R3to a mixture of isomeric 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines, which is shared by crystallization or chromatography.

where: R1, R2, R3, R4and R5have the above value.

The object of the present invention is a method for substituted 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1 in which X=SO, the oxidation of 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1 in which X=S, by the following schema.

where R1, R2, R3, R4and R5have the above value.

The object of the present invention is also a method of obtaining substituted 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1.1.1 interaction of 3-amino-4-arylsulfonyl-2H-pyrazoles of General formula 2 with tetraacetate malonic aldehyde 3.1 on the following schema.

where R4and R5have the above value.

The subject of this from the retene is also a method of obtaining substituted 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1.1.2 recovery of chlorine substituted General formula 4

where R4, R5and R9have the above value.

The object of the present invention is also a method of obtaining substituted 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1.1.2 and 1.1.3 interaction of 3-amino-4-arylsulfonyl-2H-pyrazoles of General formula 2 with 1-substituted 3,3-dealkylase-propanone 3.2, followed by separation or separation of the reaction products on the following schema.

where R4, R5and R6have the above value.

The object of the present invention is also a method of obtaining acrossamerica 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1.1.4 and 1.1.5 the interaction of 3-amino-4-arylsulfonyl-2H-pyrazoles of General formula 2 with alkoxy-substituted-diketone 3.3, followed by separation or separation of the reaction products on the following schema.

where R4, R5, R6, R7and n have the above meaning.

The object of the present invention is also a method of obtaining substituted 2-alkylsulfanyl-7-(hydroxyalkyl)-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1.1.6 action trichromate boron 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidine obatala 1.1.4

where R4, R5, R6and R7have the above-mentioned value n is 1-3.

The object of the present invention is also a method of obtaining substituted 2-alkylsulfanyl-5-(hydroxyalkyl)-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1.1.7 action trichromate boron 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1.1.5

where R4, R5, R6and R7have the above-mentioned value n is 1-3.

The object of the present invention is also a method of obtaining substituted 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1.1.8 interaction of chlorine substituted General formula 4 with an alkali metal alcoholate of the General formula 6

where R4, R5, R8and R9have the above significance; M represents a cation of an alkali metal.

The object of the present invention is also a method of obtaining pyridylamine 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1.1.9 and 1.1.10 interaction of 3-amino-4-arylsulfonyl-2H-pyrazoles of General formula 2 with a diketone 3.4, followed by separation or separation of the reaction products on the following schema.

where R4, R5, R6and PY have the abovementioned meaning.

The object of the present invention are antagonists of serotonin 5-HT6receptors, which represent 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formulas 1, 1.1, 1.1.1, 1.1.2, 1.1.3, 1.1.4, 1.1.5, 1.1.6, 1.1.7, 1.1.8, 1.1.9, 1.1.10 and their pharmaceutically acceptable salts and/or hydrates.

The purpose of the present invention is to provide new molecular tools used for studying the inhibition of serotonin 5-HT6receptors.

This goal is achieved by antagonists of serotonin 5-HT6receptors represents a substituted 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formulas 1, 1.1, 1.1.1, 1.1.2, 1.1.3, 1.1.4, 1.1.5, 1.1.6, 1.1.7, 1.1.8, 1.1.9, 1.1.10 and their pharmaceutically acceptable salts and/or hydrates.

The subject of this invention is also medicinal beginning to pharmaceutical compositions and medicines, representing at least one 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidine of the General formulas 1, 1.1, 1.1.1, 1.1.2, 1.1.3, 1.1.4, 1.1.5, 1.1.6, 1.1.7, 1.1.8, 1.1.9, 1.1.10, or its pharmaceutically acceptable salt and/or hydrate.

The subject of this invention is also a pharmaceutical composition for treating and preventing various conditions and diseases of the Central nervous system and warm-blooded animals, containing a pharmaceutically effective amount of a new drug began representing at least one 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidine of the General formulas 1, 1.1, 1.1.1, 1.1.2, 1.1.3, 1.1.4, 1.1.5, 1.1.6, 1.1.7, 1.1.8, 1.1.9, 1.1.10, or its pharmaceutically acceptable salt and/or hydrate.

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. The pharmaceutical composition along with the drug early in the present invention may include other active ingredients 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 or suspensions); 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 the drug began representing at least one 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidine of the General formula 1,1 .1, 1.1.1, 1.1.2, 1.1.3, 1.1.4, 1.1.5, 1.1.6, 1.1.7, 1.1.8, 1.1.9, 1.1.10, or its pharmaceutically acceptable salt and/or hydrate with an inert filler and/or diluent.

The subject of this invention is a medicinal product in the form of tablets, capsules, or injections, 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, comprising pharmaceutically effective if estvo medicinal beginning representing at least one 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidine of the General formulas 1, 1.1, 1.1.1, 1.1.2, 1.1.3, 1.1.4, 1.1.5, 1.1.6, 1.1.7, 1.1.8, 1.1.9, 1.1.10, or its pharmaceutically acceptable salt and/or hydrate or pharmaceutical composition containing 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 cognitive disorders and neurodegenerative diseases, containing a pharmaceutically effective amount of a medicinal began representing at least one 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidine of the General formulas 1, 1.1, 1.1.1, 1.1.2, 1.1.3, 1.1.4, 1.1.5, 1.1.6, 1.1.7, 1.1.8, 1.1.9, 1.1.10, or its pharmaceutically acceptable salt and/or hydrate or pharmaceutical composition containing it medicinal beginning.

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 Hantington containing a pharmaceutically effective amount of a medicinal began representing at least one 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidine total of four who uly 1, 1.1, 1.1.1, 1.1.2, 1.1.3, 1.1.4, 1.1.5, 1.1.6, 1.1.7, 1.1.8, 1.1.9, 1.1.10, or its pharmaceutically acceptable salt and/or hydrate or pharmaceutical composition containing 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 mental disorders and schizophrenia, containing a pharmaceutically effective amount of a medicinal began representing at least one 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidine of the General formulas 1, 1.1, 1.1.1, 1.1.2, 1.1.3, 1.1.4, 1.1.5, 1.1.6, 1.1.7, 1.1.8, 1.1.9, 1.1.10, or its pharmaceutically acceptable salt and/or hydrate or pharmaceutical composition containing this drug is started.

More preferred is the drug (anxiolytic or sedative) for the prevention and treatment of anxiety disorders, containing a pharmaceutically effective amount of a medicinal began representing at least one 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidine of the General formulas 1, 1.1, 1.1.1, 1.1.2, 1.1.3, 1.1.4, 1.1.5, 1.1.6, 1.1.7, 1.1.8, 1.1.9, 1.1.10, or its pharmaceutically acceptable salt and/or hydrate or pharmaceutical composition containing a pharmaceutical start.

More preferred is Lekarstvo the e tool (nootropic) for the prevention and treatment of hyperkinetic disorders, in particular to improve mental abilities, containing a pharmaceutically effective amount of a medicinal began representing at least one 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidine of the General formulas 1, 1.1, 1.1.1, 1.1.2, 1.1.3, 1.1.4, 1.1.5, 1.1.6, 1.1.7, 1.1.8, 1.1.9, 1.1.10, or its pharmaceutically acceptable salt and/or hydrate or pharmaceutical composition containing 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 containing a pharmaceutically effective amount of a medicinal began representing at least one 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidine of the General formulas 1, 1.1, 1.1.1, 1.1.2, 1.1.3, 1.1.4, 1.1.5, 1.1.6, 1.1.7, 1.1.8, 1.1.9, 1.1.10, or its pharmaceutically acceptable salt and/or hydrate or pharmaceutical composition containing a pharmaceutical start.

The subject of this invention is also a therapeutic cocktail for the prevention and treatment of various diseases, pathogenesis of which is associated with 5-HT6receptors in animals and humans, containing the drug in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing, including headlight is asepticheski effective amount of drug to the beginning, representing at least one 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidine of the General formulas 1, 1.1, 1.1.1, 1.1.2, 1.1.3, 1.1.4, 1.1.5, 1.1.6, 1.1.7, 1.1.8, 1.1.9, 1.1.10, or its pharmaceutically acceptable salt and/or hydrate or pharmaceutical composition containing 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 Hantington, mental disorders and schizophrenia, hypoxia-ischemia, hypoglycemia, convulsive States, brain injuries, lathyrism, amyotrophic lateral sclerosis, obesity and stroke, containing a pharmaceutically effective amount of a new drug began representing at least one 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidine of the General formula 1, 1.1, 1.1.1, 1.1.2, 1.1.3, 1.1.4, 1.1.5, 1.1.6, 1.1.7, 1.1.8, 1.1.9, 1.1.10, or its pharmaceutically acceptable salt and/or hydrate or pharmaceutical composition containing a pharmaceutical start.

Therapeutic cocktails for the prevention and treatment of neurological disorders, neurodegenerative and cognitive diseases in animals and humans, including for prophylact the Ki and treatment of Alzheimer's disease, Parkinson's disease Hantington, 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 prachi is.

Therapeutic cocktail for reducing overweight and obesity along with medicines by this invention includes other medicines, such as anorexicskin drugs (for example, Farnon, Dezaemon, Mazindol), hormonal agents (such as 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 antagonists of cannabinoid 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 Central nervous system diseases, pathogenesis of which is associated with 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 pharmaceutically effective amount of a medicinal began representing at least one 2-alkylsulfanyl-3-and ylsulphonyl-pyrazolo[1,5-a]pyrimidine of the General formula 1,1 .1, 1.1.1, 1.1.2, 1.1.3, 1.1.4, 1.1.5, 1.1.6, 1.1.7, 1.1.8, 1.1.9, 1.1.10, or its pharmaceutically acceptable salt and/or hydrate or pharmaceutical composition containing a pharmaceutical start.

Drugs can be administered orally or parenterally (e.g. intravenously, subcutaneously, intraperitoneally or topically). The clinical dosage of the beginning, the pharmaceutical composition or the medicinal product (drug), including a pharmaceutically effective amount of a medicinal began representing at least one 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidine of the General formulas 1, 1.1, 1.1.1, 1.1.2, 1.1.3, 1.1.4, 1.1.5, 1.1.6, 1.1.7, 1.1.8, 1.1.9, 1.1.10, or its pharmaceutically acceptable salt and/or hydrate or pharmaceutical composition containing a pharmaceutical start, 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 dose, with each unit d is Siroki product must 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 invention is illustrated by drawings.

Figure 1. The latent period 1st time in the dark compartment within 24 hours after training, mice avoid the dark compartment in the Shuttle chamber (average ± standard error). The number in parentheses is the quantity of the substance in mg/kg of the Studied compounds 1(12) and 1.1.7(1) was administered intraperitoneally 30 minutes prior to the experience. Unlike groups that received scopolamine: * - p<0,05; ** - p<0,01; *** p<0,001.

Figure 2. Duration of stay in the bright compartment within 24 hours after training, mice avoid the dark compartment in the Shuttle chamber (average ± standard error). The number in parentheses is the quantity of the substance in mg/kg of the Studied compounds 1(12) and 1.1.7(1) was administered intraperitoneally 30 minutes prior to the experience. Unlike groups that received scopolamine: * - p<0,05; ** - p<0,01; *** p<0,001.

Figure 3. The number of visits in the dark compartment within 24 hours after training, mice avoid the dark compartment in the Shuttle chamber (average ± standard error). The number in parentheses is the quantity of the substance in mg/kg of the Studied compounds 1(12) and 1.1.7(1) was administered intraperitoneally 30 minutes prior to the experience. Unlike groups that received scopolamine: * - p<0,05; ** - p<0,01; *** p<0,001.

Figure 4. The latent period 1st time in the dark compartment within 24 hours after training, mice avoid the dark compartment in the Shuttle chamber (average ± standard error). The number in parentheses is the quantity of the substance in mg/kg of the Studied compounds 1(12) and 1.1.7(1) was administered intraperitoneally 30 minutes prior to the experience. Unlike groups that received MK-801: * - p<0,05; ** - p<0,01; *** p<0,001.

Figure 5. Duration of stay in the bright compartment within 24 hours after training, mice avoid the dark compartment in the Shuttle chamber (average ± standard error). The number in parentheses is the quantity of the substance in mg/kg of the Studied compounds 1(12) and 1.1.7(1) was administered intraperitoneally 30 minutes prior to the experience. Unlike groups that received MK-801: * - p<0,05; ** - p<0,01; *** p<0,001.

6. The number of visits in the dark compartment within 24 hours after training, mice avoid the dark compartment in the Shuttle chamber (average ± standard error). The number in parentheses is the quantity of the substance in mg/kg of the Studied compounds 1(12) and 1.1.7(1) was administered intraperitoneally 30 minutes prior to the experience. Unlike groups that received MK-801: * - p<0,05; ** - p<0,01; *** p<0,001.

7. The ratio of time spent by animals in open sleeves, to the total time spent in open and closed arms (mean ± standard error). In parentheses are doses of compound 1(11) (mg/kg). Contrast to the group receiving placebo: * p<0,05; ** - p<0,01; *** p&l; 0,001.

Fig. The ratio of the number of inputs into the open sleeve of the total number of inputs in the sleeves of both types (mean ± standard error). In brackets is given the dose of the substance 1(11) (mg/kg). Contrast to the group receiving placebo: * p<0,05; ** - p<0,01; *** p<0,001.

Fig.9. The number of defecations in the test "maze-plus (mean ± standard error). In brackets is given the dose of the substance 1(11) (mg/kg). Contrast to the group receiving placebo: * p<0,05; ** - p<0,01; *** p<0,001.

The following examples illustrate but do not limit the invention.

Example 1. A common way of obtaining substituted 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1 (X=S). Mix 0.005 mol aminopyrazole 2 and 0.0055 mol of the corresponding dicarbonyl compound 3 in 5 ml of acetic acid or other suitable solvent for 4-12 hours at elevated temperatures. The precipitation is filtered off, 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 examples of new 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1 (X=S), 1.1.1, 1.1.2, 1.1.3, 1.1.4, 1.1.5, 1.1.9, 1.1.10 and their salts and LCMS data analysis and NMR spectra.

Example 2. A common way of obtaining substituted 2-alkylsulfanyl the-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1.1.1. Mix 0.005 mol aminopyrazole 2 and 0.0055 mol tetraacetate malonic aldehyde 3.1 in 5 ml of acetic acid for 12 hours at 80°C. Precipitated on cooling the precipitate is filtered off, washed with acetonitrile and dried in vacuum. If necessary, the product is subjected to recrystallization from a suitable solvent or chromatographic purification. Obtain compounds of General formula 1.1.1. Table 2 presents examples of new 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1.1.1 and their salts and LCMS analyses and NMR spectra.

Example 3. A common way of obtaining substituted 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1.1.2 and 1.1.3. To a solution of 0.001 M aminopyrazole 2 in 1 ml of acetic acid under stirring at room temperature was added 1 ml of 6 M solution of model HC1 in ethanol, after 2-3 minutes-pin solution of 0.002 M 1-substituted 3,3-dialkylacrylamide 3.2 in 3 ml of acetic acid. The resulting mixture was left overnight at room temperature and stirring. Evaporated to dryness in vacuo, washed with methanol, then ether. If necessary, the product is subjected to recrystallization from a suitable solvent, chromatographic purification or chromatographic separation. Obtain compounds of General formula 1.1.2 and 1.1.3. Table 2 presents some examples of new 2-and kilalanin-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1.1.2 and 1.1.3 and their salts; data LCMS analyses and NMR spectra.

Example 4. A common way of obtaining substituted 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1.1.4 and 1.1.5. Mix 0.005 mol aminopyrazole 2 and 0.0075 mol of sodium salt of 1-methoxyphenyl-2,4-dione 3.3 in 5 ml of acetic acid for 12 hours at boiling rectional mixture. Precipitated by cooling the precipitate is filtered off, washed with acetonitrile and dried in vacuum. The resulting mixture of isomers is separated chromatographically on silica gel. Obtain compounds of General formula 1.1.4 and 1.1.5. Table 2 presents examples of new 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1.1.4, 1.1.5 and their salts and LCMS analyses and NMR spectra.

Example 5. A common way to obtain pyridylamine 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1.1.9 and 1.1.10. To a solution of 5 mmol of aminopyrazole 2 in 5 ml of acetic acid, add 2 equivalent diketone 3.4; the mixture was incubated at 80°C for 12 hours; cooled to room temperature and evaporated in vacuum. To the residue add 10% aqueous NaOH solution, the precipitation is filtered off, washed with water until neutral and dried. If necessary, the product is subjected to recrystallization from a suitable solvent, chromatographic purification or chromatographic sec is becoming. Obtain compounds of General formula 1.1.9 and 1.1.10. Table 2 presents some examples of new pyridylamine 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1.1.9 and 1.1.10 and their salts; LCMS data analysis and NMR spectra.

Example 6. A common way of obtaining substituted 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1 (X=SO). To a solution of 1 mmol of 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidine of the General formula 1 (X=S) in 10 ml of acetic acid, add 88 μl (1 mmol, 35%) hydrogen peroxide and the mixture is stirred at 80°C for 7 hours the Mixture is evaporated in vacuo and purify the product by the method of column chromatography on silica gel (system chloroform/ethyl acetate = 5:1). Output 75-87%.

Table 2 presents some examples of new 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formulas 1 and LCMS analyses and NMR spectra.

Example 7. A common way of obtaining substituted 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1.1.2. A solution of 0.63 mmol 2-alkylsulfanyl-7-chloro-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidine of the General formula 1 in which R3= Cl, 9 ml Meon and 3 ml of benzene hydronaut over 30 mg of 10% Pd/C at 1 ATM for 12 hours Selection of product spend chromatography on silica gel. Obtain compounds of General formula 1.1.2. Table 2 presents the some examples of new substituted 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1.1.2 and their salts; data LCMS analyses and NMR spectra.

Example 8. A common way of obtaining substituted 2-alkylsulfanyl-3-arylsulfonyl-7-(hydroxyalkyl)-pyrazolo[1,5-a]pyrimidines of General formula 1.1.6 and substituted 2-alkylsulfanyl-3-arylsulfonyl-5-(hydroxyalkyl)-pyrazolo[1,5-a]pyrimidines of General formula 1.1.7. A solution of 0.36 mmol alkyloxyalkyl General formula 1.1.4 or 1.1.5 in 10 ml of distilled methylene chloride was added dropwise at room temperature to a solution of 0.1 ml (0.27 mg) VVG3(3.0 equivalents) in 10 ml of distilled methylene chloride. The reaction mixture was kept at room temperature for 12 hours, then under vigorous stirring there was added 20 ml of water and allowed to mix for 30 minutes. The organic layer is separated and the aqueous layer extracted twice with ether. The combined organic phases, evaporated in vacuo, the residue chromatographic. Obtain compounds of General formula 1.1.6, 1.1.7, examples of which are presented in table 2.

Example 9. A common way of obtaining substituted 2-alkylsulfanyl-3-arylsulfonyl-7-alkoxy-pyrazolo[1,5-a]pyrimidines of General formula 1.1.8. To a solution of 2.5 mmol of sodium alcoholate in 25 ml of a suitable solvent (alcohol, dimethylformamide and the like) is added 2-alkylsulfanyl-3-arylsulfonyl-7-chloro-pyrazolo[1,5-a]pyrimidine of the General formula 4. The reaction mass is kept in a microwave is the first reactor 2 hours at a temperature of 75°C, obladaet, the precipitation hoteltravel, washed with methanol, dissolved in methylene chloride, propustaat through a thin layer of silica gel and evaporated to dryness. If necessary, the resulting product 1.1.8 is recrystallized from a suitable solvent.

Table 2 presents some examples of new substituted 2-alkylsulfanyl-3-arylsulfonyl-7-alkoxy-pyrazolo[1,5-a]pyrimidines of General formula 1.1.8 and LCMS data analysis and NMR spectra.

Table 2
Antagonists of serotonin 5-HT6receptor - 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1
No.FormulaMol. weightLCMS, m/z (M+1)An NMR spectrum
1(1)347.46348
1(2)389.54390
1(3)361.49362
1(4)361.49362
1(5)367.883681H NMR (CDCl3, 400 MHz) δ to 8.20 (m, 2H), 7,46-of 7.55 (m, 3H), 2,85 (s, 3H), of 2.75 (s, 3H), 2,62 (c, 3H).
1(6)412.334131H NMR (CDCl3, 400 MHz) δ to 8.20 (d, J=7.2 Hz, 2H), 7,54 (t, J=7.2 Hz, 1H), of 7.48 (t, J=7.2 Hz, 2H), 2,90 (s, 3H), 2,80 (s, 3H), 2,62 (c, 3H).
1(7)425.534261H NMR (DMSO-D6, 400 MHz) δ 8,63 (d, J=2.4 Hz, 1H), 8,45 (d, J=4,8 Hz, 1H), with 8.05 (m, 2H), 7,76 (DD, J1=2.4 Hz, J2=4,8 Hz, 1H), 7,56-to 7.67 (m, 4H), 2,60 (c, 3H), 2,54 (c, 3H), 2.40 a (c, 3H).

1(8)462.98 4271H NMR (DMSO-D6, 400 MHz) δ 8,63 (d, J=2.4 Hz, 1H), 8,45 (d, J=4,8 Hz, 1H), with 8.05 (m, 2H). 7,76 (DD, J1=8,8 Hz,.J2=2.4 Hz, 1H), 7,56-to 7.67 (m, 4H), 2,60 (s, 3H), of 2.54 (s, 3H), 2.40 a (s, 3H).
1(9)459.554601H NMR (CDCl3): 9.02 (s, 1H); 8.93 (d, J=8.4 Hz, 1H); 8.85-8.88 (m, 1H); 8.72-8.78 (m, 2H); 8.27-8.30 (m, 2H); 7.90-7.98 (m, 2H); 7.43-7.55 (m, 5H); 2.67 (s, 3H).
1(9)·C2H4O2549.59460
1(10)363.46364
1(11)349.433501H NMR (DMSO-D6, 400 MHz) δ 10,46 (W, 1H), to 7.84 (d, J=8.0 Hz, 2H), was 7.36 (s, 1H), 7,07 (s, 1H), 6.87 in (d, J=8.0 Hz, 2H), 2,64 (s, 3H), of 2.56 (s, 6N).
1(12)349.433501 H NMR (DMSO-D6, 400 MHz) δ by 8.22 (m, 2H), 7,58 (m, 1H), 7,51 (m, 2H), to 6.88 (s, 1H), 3,24 (s, 3H), and 2.83 (s, 3H), 2,71 (s, 3H).

381.45
1(13)383.88384
1(14)383.883841H NMR (CDCl3, 400 MHz) δ to 8.20 (m, 2H), to 7.59 (t, J=7,4 Hz, 1H), 7,52 (t, J=7.4 Hz, 2H), 3,25 (s, 3H), 2,99 (s, 3H), 2,82 (s, 3H).
1.1.1(1)305.383061H NMR (DMSO-D6, 400 MHz) δ to 8.70 (DD, J1=1,6 Hz, J2=4.4 Hz, 1H), 8,59 (DD, J1=1,6 Hz, J2=6,8 Hz, 1H), to 8.20 (m, 2H), 7,49-of 7.55 (m, 3H), 6,97 (DD, J1=4.4 Hz, J2=6,8 Hz, 1H), 2,62 (s, 3H).
1.1.1(2)323.373241H NMR (CDCl3, 400 MHz) δ 8,71 (DD, J1=4.4 Hz, J2=2.0 Hz, 1H), 8,61 (DD, J1=6,8 Hz, J2=2.0 Hz, 1H), they were 8.22 (m, 2H), 7,16 (m, 2H), 7,00 (DD, J1=6,8 Hz, J2=4.4 Hz, 1H), 2.63 in (s, 3H).
1.1.1(3)323.37324
1.1.1(4)339.823401H NMR (CDCl3, 400 MHz) δ 8,73 (DD, J1=4.0 Hz, J2=1.2 Hz, 1H), to 8.62 (DD, J1=6,8 Hz, J2=1.2 Hz, 1H), 8,19 (s, 1H), of 8.09 (d, J=7,6 Hz, 1H), 7,51 (d, J=8.0 Hz, 1H), 7,43 (t, J=8.0 Hz, 1H), 7,01 (DD, J1=6,8 Hz, J2=4.4 Hz, 1H), 2.63 in (s, 3H).
1.1.1(5)357.813581H NMR (CDCl3, 400 MHz) δ 8,73 (m, 1H), 8,63 (d, J=7.2 Hz, 1H), 8,29 (DD, J1=6,8 Hz, J2=2.0 Hz, 1H), 8,11 (DDD, J1=6,8 Hz, J2=4.4 Hz, J3=2.0 Hz, 1H), 7,25 (t, J=8,8 Hz, 1H), 7,02 (DD, J1=6,0 Hz, J2=4.4 Hz, 1H), 2.63 in (s, 3H).
1.1.1(6)333.43334
1.1.1(7)319.41320
1.1.2(1)319.413201H NMR (CDCl3, 400 MHz) δ 8.41 (d, J=6,8 Hz, 1H), 8,20-8,23 (m, 2H), 7,54 (m, 1H), of 7.48 (m, 2H), 6,80 (d, J=6,8 Hz, 1H), 2,69 (s, 3H), at 2.59 (s, 3H).
1.1.2(2)337.40338
1.1.2(3)337.40338
1.1.2(4)353.85354
1.1.2(5)371.843721H NMR (CDCl3, 400 MHz) δ 8,44 (d, J=7.2 Hz, 1H), 8,35 (DD, J1=6,8 Hz, J2=2.0 Hz, 1H), 8,11 (DDD, J1=6,4 Hz, J2=4.0 Hz, J3=2.0 Hz, 1H), 7,24 (t, J=8,8 Hz, 1H), 6,85 (d, J=7.2 Hz, 1H), 2,71 (s, 3H), 2,61 (s, 3H).
1.1.3(1)39.41 3201H NMR (CDCl3, 400 MHz) δ to 8.41 (d, J=7.2 Hz, 1H), 8,20-8,23 (m, 2H), 7,54 (m, 1H), 7,49 (m, 2H), 6,80 (d, J=7.2 Hz, 1H), 2,69 (s, 3H), at 2.59 (s, 3H).
1.1.3(2)337.40338
1.1.3(3)337.40338
1.1.3(4)353.85354
1.1.3(5)371.843721H NMR (CDCl3, 400 MHz) δ at 8.60 (d, J=4.4 Hz, 1H), 8,28 (DD, J1=6,4 Hz, J2=2.0 Hz, 1H), 8,11 (DDD, J1=6,4 Hz, J2=4.4 Hz, J3=2.0 Hz, 1H), 7.23 percent (t, J=8,8 Hz, 1H), 6,85 (d, J=4.4 Hz, 1H), and 2.79 (s, 3H), of 2.66 (s, 3H).
1.1.4(1)363.463641H NMR (CDCl3, 400 MHz) δ by 8.22 (m, 2H), 7,45-of 7.55 (m, 3H), of 6.96 (s, 1H), and 85 (s, 2H)and 3.59 (s, 3H), 2,70 (s, 3H), at 2.59 (s, 3H).13With NMR (CDCl3, 75.5 MHz) δ 162,89, 156,15, 147,27, 145,14, 142,98, 132,30, 128,30, 126,45, 106,39, 105,81, 66,88, 59,35, 25,08, 12,88.
1.1.4(2)381.45382
1.1.4(3)381.45382
1.1.4(4)397.91398
1.1.4(5)415.90416
1.1.5(1)363.463641H NMR (CDCl3, 400 MHz) δ to 8.20 (d, J=7.2 Hz, 2H), 7,45-of 7.55 (m, 3H), 7,05 (s, 1H), of 4.66 (s, 2H), 3,52 (s, 3H), of 2.75 (s, 3H), 2.63 in (s, 3H).13With NMR (CDCl3, 75.5 MHz) δ 162,37, 156,32, 147,11, 146,25, 142,99, 132,27, 128,29, 126,51, 106,43, 106,15, 74,42, 58,70, 16,74, 12,87.
1.1.5(2)382
1.1.5(3)381.45382
1.1.5(4)397.91398
1.1.5(5)415.90416
1.1.6(1)349.433501H NMR (DMSO-D6, 400 MHz) δ 8,02 (m, 2H), 7,56-the 7.65 (m, 3H), 7,18 (s, 1H), 5,98 (t, J=5.6 Hz, 1H), 4,90 (d, J=5.6 Hz, 2H), 2,64 (s, 3H), by 2.55 (s, 3H).
1.1.6(2)367.42368
1.1.6(3)367.42368
1.1.6(4) 383.88384
1.1.6(5)401.87402
1.1.7(1)349.433501H NMR (CDCl3, 400 MHz) δ is 8.16 (m, 2H), 7,46-7,56 (m, 3H), for 6.81 (s, 1H), a 4.83 (d, J=4,8 Hz, 2H), of 3.73 (t, J=4,8 Hz, 1H), 2,73 (s, 3H), of 2.64 (s, 3H).
1.1.7(2)367.42368
1.1.7(3)367.42368
1.1.7(4)383.88384
1.1.7(5)401.87402
1.1.8(1)349.43350
1.1.8(2)412.49413
1.1.8(3)412.49413
1.1.8(3) HCl448.89413
1.1.8(3) CH3SO3H508.60413
1.1.8(4)412.49413
1.1.8(5)367.42368
1.1.9(1) 382.47383

1.1.9(2)382.47383
1.1.9(3)382.47383
1.1.9(4)400.46401
1.1.9(5)416.91417
1.1.9(6)396.49397
1.1.9(7)396.493971H NMR (CDCl3): 9.30 (d, J=2.0 Hz, 1H); 8.76 (d, J=5.0 Hz, J=1.5 Hz, 1H); 8.53-8.57 (m, 1H); 8.22-8.26 (m, 2H); 7.46-7.54 (m, 4 Prov.); 7.05 (s, 1H); 2.82 (s, 3H); 2.66 (c, 3H).
1.1.9(8)396.49397
1.1.9(9)414.48415
1.1.9(10)430.94431
1.1.10(1)382.47383
1.1.10(2)
HCl
418.93383
1.1.10(3)382.47383
1.1.10(4)400.46401
1.1.10(5)416.91417
1.1.10(6)396.493971H NMR (CDCl3, 400 MHz) δ 9.17 (d, 1H), 8.81 (d, 1H), 8.37 (d, 1H), 8.25 (d, 2H), 7.53 (Thu, 4H), 6.94 (s, 1H), 2.77 (s, 3H), 2.55 (s, 3H).13With NMR (CDCl3, 75.48 MHz) δ 162.82, 156.50, 151.69, 149.41, 148.22, 142.82, 142.50, 136.46, 132.44, 128.36, 126.64, 125.85, 122.81, 109.18, 106.44, 24.97, 12.96.
1.1.10(6)
HCl
396.493971H NMR (DMSO-D6): 9.26 (d, J=1.5 Hz, 1H); 8.82 (DD, J=5.4 Hz, J=1.5 Hz, 1H); 8.61-8.65 (m, 1H); 8.04-8.08 (m, 2H); 7.72-7.77 (m, 1H); 7.58-7.68 (m, 3H); 7.55 (s, 1H); 2.68 (s, 3H); 2.50 (s, 3H).
1.1.10(7)432.95397
1.1.10(8)396.493971H NMR (CDCl3400 MHz) δ 9.17 (d, 1H), 8.81 (d, 1H), 8.37 (d, 1H), 8.25 (d, 2H), 7.53 (Thu, 4H), 6.94 (s, 1H), 2.77 (s, 3 is), 2.55 (s, 3H).13With NMR (CDCl3, 75.48 MHz) δ 162.82, 156.50, 151.69. 149.41, 148.22, 142.82, 142.50, 136.46, 132.44, 128.36. 126.64, 125.85, 122.81, 109.18, 106.44, 24.97, 12.96.
1.1.10(9)414.48415
1.1.10(10)430.94431

Example 10. Determination of antagonistic activity of the compounds of General formula 1 towards 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 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 IC50antagonis what s the General formula 1 in terms of functional assay inhibition of serotonin 5-HT 6receptors, demonstrating their moderate or high antagonistic activity.

Table 3
The values of the IC50antagonists of General formula 1 in terms of functional assay inhibition of serotonin 5-HT6receptors.
No. antagonistIC50, nM
1(3)24.02
1(5)0.3
1(6)8.4
1(7)>10
1(8)514.4
1(10)4.5
1(11)0.074
1.1.1(1)5.2
1.1.1(3)1.31
1.1.1(4)1.83
1.1.1(6)2.2
1.1.1(7)4.74
1.1.2(1) 2.49
1.1.2(2)0,996
1.1.3(1)1.11
1.1.5(1)0.414
1.1.6(1)0.073
1.1.7(1)0.177
1.1.8(2)30.1

Example 11. Determination of the activity of antagonists of serotonin 5-HT6receptors of General formula 1 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 nuclei, 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 sychotropic 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 only of the radioactive ligand, CA - radioactivity in the presence of radioligand and tested the connection and NA - radioactivity in the presence of radioligand and serotonin (5 µM).

Table 4 presents the test results of some antagonists of serotonin 5-HT6receptors of General formula 1 is a competitive binding to serotonin 5-HT 6receptors, demonstrating their high activity against serotonin 5-HT6the receptors.

Table 4
The values of the IC50antagonists of General formula 1 in a competitive assay inhibition of serotonin 5-HT6receptors
No.IC50, µm
1(5)<0.01
1(6)0.05
1(7)0.05
1(3)1.3
1.1.2(2)0.05
1.1.3(1)0.04
1.1.8(3)<0.01

Presented in tables 3 and 4 indicate the possibility of use of compounds of General formula 1 as "molecular tools for studying characteristics of physiologically active compounds that have the property to inhibit serotonin 5-HT6receptors, and as the drug began to pharmaceutical compositions and cure the funds.

Example 12. Obtaining medicines in tablet form. Mix 1600 mg of starch, 1600 mg of powdered lactose, 400 mg of talc and 1000 mg of the compound 1.1.8(3)·HCl and pressed together 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 13. Obtaining medicines in capsule form. Thoroughly mix the connection 1.1.8(3)·HCl with lactose powder in a 2:1 ratio. The obtained powder mixture is Packed 300 mg in gelatin capsules of suitable size.

Example 14. Obtaining medicines in the form of injectable compositions for intramuscular, intraperitoneal or subcutaneous injection. Mix 500 mg connection 1.1.8(3)·HCl 300 mg chlorbutanol, 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 15. Antiamnesic activity (nootropic action) compounds of General formula 1. Improve memory, disturbed by scopolamine.

15.1. Nootropic effect of compounds of General formula 1 in the test "Passive avoidance of mice in the Shuttle chamber".

The experiments were performed on adult male mice of BALB/c mice weighing 20-25 g or male Wistar rats weighing 200-250 g

In the experiments used is whether the Shuttle chamber (Ugo Basile, Italy), which consisted of two compartments. All the walls of one of the compartments were opaque, and the second compartment had a transparent cover. The compartments were connected by a hole, which can be automatically closed by a vertical door. The floor of the dark compartment consisted of transverse metal rods, which could be pulsed DC.

On the first day experience for 30 minutes before training, animals were injected intraperitoneally scopolamine, which causes memory impairment. Animals of the experimental group additionally injected compound of General formula 1, in particular compound 1(12) and 1.1.7(1), at doses of 0.2 mg/kg the Animals of control group received an injection of saline. Each group used 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 chambers 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 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 chamber, the total time spent in the light compartment and the number of visits in a dark compartment. The follow-up period was 5 minutes.

Animals of the control group, received the punishment in a dark compartment, is displayed on the Wali successful learning, which was reflected in higher latency period of time in the dark compartment, the length of stay in the bright compartment and reducing the number of visits in a dark chamber in comparison with animals from a group not receiving punishment. Scopolamine caused a so-called anterograde amnesia, which is characterized by failure of fixation in long-term memory for new events. This was expressed in the form of a statistically significant increase in the latent period of time in the dark compartment, reducing time spent in the light compartment and increase the number of visits in the dark compartment of the camera.

The results of the experiment are presented in figures 1, 2, 3, from which it follows that the connection 1(12) has the ability to reduce amnesia (to improve memory)caused by scopolamine.

15.2. Nootropic effect of compounds of General formula 1 in the test of Recognition of new objects.

The experiment was performed on adult male mice of SHK. The experiment used a cross-shaped Plexiglas maze, which consisted of 4 stub chambers (numbered 1, 2, 3, 4)which are connected between a fifth Central chamber. The mouse was placed in the Central chamber and allowed her to explore the maze. The floor was cleaned after each animal. The order of visits cameras and time of visits were recorded. The test ended when there was 13 sahada the dead ends. Criterion approach was the presence of all four paws of the animal inside the chamber.

During training, the animal was placed in the maze, in which in each of the four chambers was one of the same Cup. During the test (after 1 hour after training) two oppositely facing cups were replaced flasks, and the animal was allowed to explore the maze. During training and testing, we recorded time spent by the animal in each side chamber. Expected index recognition of new objects as the ratio of time spent in lateral cameras with new objects to the total time of stay in the side chambers. The new facility increases the time spent by the animal in the chamber, compared to the learning phase (the so-called effect of the recognition of new objects). Under the influence of scopolamine dose of 1 mg/kg, introduced intraperitoneally 30 minutes before training, recognition of new objects were broken and index detection was dropped.

However, this effect of scopolamine was able to compensate by intraperitoneal injection of compounds of General formula 1 in doses of 0.05 mg/kg and 0.2 mg/kg for 60 minutes prior to training.

Example 16. Nootropic action (improving memory, impaired MK-801) compounds of General formula 1 in the test "Passive avoidance of mice in the Shuttle chamber". The Provo experiment is either the same as in example 15.1. On the first day experience for 30 minutes before training, mice were injected intraperitoneally with saline, MK-801 (0.1 mg/kg), causing amnesia. Parallel independent groups of mice to training were injected intraperitoneally with saline, MK-801 in combination with the compound of General formula 1, for example 1(12) and 1.1.7(1). The results presented in figure 4, 5 and 6 indicate the ability of the compound 1(12) to have a neuroprotective effect.

Example 17. Anxiolytic (anxiolytic) effects of compounds of General formula 1 in the test the Behavior of mice in the elevated cross maze. In the experiment used male mice of BALB/c mice weighing approximately 25 g Animals were kept in cages (5-7 mice per cage), providing free access to feed and water. No animal was not familiar with the experimental setting. Each experimental group consisted of 8 animals.

The method used was described by Lister, R.G. The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology, 1987; 92:180-185). Plexiglas apparatus consisted of two open sleeves size 30×5 cm and two closed sleeves size 30×5×15 cm Lateral sleeves were closed transparent plexiglass and connected with the Central area the size of 5×5 cm Open sleeve, the Central platform and the floor were made of black plexy the Asa. The device was mounted on the metal base, which was located above the floor level to a height of 38.5 see

The mouse was placed in the center of the maze for 5 minutes recorded the number of entries in open and closed sleeves and the time spent by the animals in the open and closed sleeves. Criterion approach considered when all four paws of the animal in the sleeve. 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. The number of fecal boluses left mouse was considered as an additional parameter describing the alarm condition. 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).

Animals were injected intraperitoneally with placebo, buspirone (5 mg/kg, 30 minutes before training), lorazepam (0.05 mg/kg, 60 minutes before training) or one of the test compounds of General formula 1, for example compound 1(11), at a dose of 0.05 mg/kg and 0.2 mg/kg Buspirone and lorazepam was administered at the maximum effective dose at which no observed adverse sedative effect, which was expressed in the form of a General reduction in exploratory activity (number of visits sleeves during the test).

The experiment results are given in Fig.7, 8 and 9, from which it follows that the standards (buspirone and lorazepam) have a marked anxiolytic effects in the test elevated cross maze, similar action has connection 1(11).

Example 18. Antipsychotic activity of the compounds of General formula 1 in the test "Prepulse inhibition of startle in mice". In the experiments used male mice SHK weighing 24-30, Experiments were performed in light of the daily cycle of animals. Apomorphine hydrochloride was dissolved in 0.1% ascorbic acid solution prepared in sterilized water. Haloperidol was dissolved in sterilized water using an emulsifier tween 80. The analyzed compound of General formula 1 was dissolved in sterilized water. Control animals were injected with 0.1% ascorbic acid solution prepared in sterilized water with Tween 80. Haloperidol was administered for 60 minutes, apomorphine - 15 minutes before the test. The amount of fluid was 10 ml/kg of the tested compounds of General formula 1 was administered subcutaneously at a dose of 1 mg/kg for 60 minutes before the test.

The apparatus consisted of a camera and made of transparent Plexiglas (producer - company Columb is with the instruments, USA), placed on the platform, which was located inside a sound-proof Cabinet. 2 cm from the platform was high-frequency sound column, through which the transmitted sound stimuli. When wince animal there were fluctuations platform, which was located analog Converter and recorded by the computer. Background noise level was 65 dB. Animals received 4 presentation of a single test ("pulse") stimulus duration of 50 MS and a volume of 105 dB or precedes ("pre-pulse") stimulus with a duration of 20 MS, a volume of 85 dB, which after 30 MS pulse followed stimulus duration of 50 MS, a volume of 105 dB. The interval between repeated presentations of the pulse or pre-pulse in combination with the pulse stimulus was 10 C. the Attenuation of startle in response to the pulse stimulus in the presence of a pre-pulse stimulus was calculated in percentage with respect to the amplitude of startle in response to isolated pulse stimulus. The introduction of apomorphine, which is used in animal experiments to simulate psychotropically States, caused a decrease prepulse inhibition of startle that reflects the reduced ability of the CNS to filter sensory stimuli. Haloperidol (1 mg/kg) and studied compounds of General formula 1 warned Nara is giving prepulse braking wince when the apomorfina.

Example 19. The antidepressant activity of the compounds of General formula 1.

19.1. The behavior of mice in the test "Forced the Porsolt swim". The apparatus consisted of a plastic vessel (height 300 mm, the diameter of 480 mm)filled with water at a temperature of 20-22°C up to a height of 18 see the experiment was used male mice of Balb/C mice weighing 20-30, Mice were placed in the water and within 15 minutes were recorded duration fixed hang in the water - so-called behavior ' despair', which is considered a measure depressivnopodobnogo state. After 3-5 min, the activity of swimming began to decline and rotate the phases of movement and stillness. In the test used for automated recognition of motion using video and program Any-maze. After injection intraperitoneally compounds of General formula 1 in a dose of 5 mg/kg despair of the animal decreases, indicating a decrease in time depressivnopodobnogo state.

19.2. The behavior of mice in the test "Hanging by the tail". Test suspension by the tail was described Steri et al. (1985) as a convenient way of exploring the potential of antidepressants. It is assumed that the forced immobility rodents can serve as a model for studies of depressive disorders in humans. Clinically effective antidepressants reduce immobility, which occurs in mylapore futile attempts to break free, when their tail is fixed.

In the experiment we used male mice of Balb/C mice weighing 20-30 g Animals were hung with tape for the tail approximately at the height of 400 mm from the surface of the table for 3 minutes, the Animal was considered to be stationary if it didn't do any movements within 1.5 seconds. The studied compounds of General formula 1 was administered intraperitoneally at a dose of 5 mg/kg Comparators (fluoxetine, desipramine) was administered intraperitoneally 15 minutes before the start of the test. In this test the compounds of General formula 1 exhibit antidepressant activity comparable with that used by the Comparators Fluoxetine and Desipramine.

1. Substituted 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1 and their pharmaceutically acceptable salts and/or hydrates

where R1represents a hydrogen atom, a C1-C3alkyl, (C1-C3)alkyloxy(C1-C3)alkyl, hydroxy(C1-C3)alkyl, pyridyl;
R2represents a hydrogen atom, a halogen atom, a C1-C3alkyl, phenyloxy or pyridyloxy;
R3represents a hydrogen atom, a C1-C3alkyl, C1-C3alkyloxy, (C1-C3)alkyloxy(C1-C3)alkyl, hydroxy(C1-C3)alkyl, pyridyl;
R4represents a C1-C3alkyl;
R 5represents a hydrogen atom, one or two halogen atom, a C1-C3alkyl, C1-C3alkyloxy or hydroxyl;
X represents a sulfur atom or sulfinyl group (SO);
excluding compounds of General formula 1 in which both R1and R3represent methyl, R2represents a hydrogen atom, a R4-X represents methylsulfanyl group and ethylsulfanyl group.

2. Compounds according to claim 1, which represents a substituted 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1.1, and their pharmaceutically acceptable salts and/or hydrates

where R1, R3, R4and R5have the above value.

3. Compounds according to claim 2, represents a substituted 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1.1.1, 1.1.2, 1.1.3, 1.1.4, 1.1.5, 1.1.6, 1.1.7, 1.1.8, 1.1.9, 1.1.10



where R4and R5have the above meaning; R6and R7independently from each other represent hydrogen or C1 3alkyl; R8represents hydrogen or C1-C3alkyl; R9represents a C1-C3alkyl or pyridyl; PY represents a pyridyl; n is 1, 2, 3.

4. Compounds according to claim 3, which represents a 2-methylsulfanyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.1(1), 2-methylsulfanyl-3-(4-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.1(2), 2-methylsulfanyl-3-(3-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.1(3), 2-methylsulfanyl-3-(3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.1.1(4), 2-methylsulfanyl-3-(4-fluoro-3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.1.1(5), 5-methyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.2(1), 5-methyl-2-methylsulfanyl-3-(4-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.2(2), 5-methyl-2-methylsulfanyl-3-(3-perpenicular)-pyrazolo[1,5-a]the pyrimidine 1.1.2(3), 5-methyl-2-methylsulfanyl-3-(3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.1.2(4), 5-methyl-2-methylsulfanyl-3-(4-fluoro-3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.1.2(5), 7-methyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.3(1), 7-methyl-2-methylsulfanyl-3-(4-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.3(2), 7-methyl-2-methylsulfanyl-3-(3-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.3(3), 7-methyl-2-methylsulfanyl-3-(3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.1.3(4), 7-methyl-2-methylsulfanyl-3-(4-fluoro-3-chlorophenylsulfonyl)-irazola[1,5-a]pyrimidine 1.1.3(5), 5-methyl-2-methylsulfanyl-7-methoxymethyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.4(1), 5-methyl-2-methylsulfanyl-7-methoxymethyl-3-(4-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.4(2), 5-methyl-2-methylsulfanyl-7-methoxymethyl-3-(3-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.4(3), 5-methyl-2-methylsulfanyl-7-methoxymethyl-3-(3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.1.4(4), 5-methyl-2-methylsulfanyl-7-methoxymethyl-3-(4-fluoro-3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.1.4(5), 7-methyl-2-methylsulfanyl-5-methoxymethyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.5(1), 7-methyl-2-methylsulfanyl-5-methoxymethyl-3-(4-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.5(2), 7-methyl-2-methylsulfanyl-5-methoxymethyl-3-(3-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.5(3), 7-methyl-2-methylsulfanyl-5-methoxymethyl-3-(3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.1.5(4), 7-methyl-2-methylsulfanyl-5-methoxymethyl-3-(4-fluoro-3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.1.5(5), 7-hydroxymethyl-5-methyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.6(1), 7-hydroxymethyl-5-methyl-2-methylsulfanyl-3-(4-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.6(2), 7-hydroxymethyl-5-methyl-2-methylsulfanyl-3-(3-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.6(3), 7-hydroxymethyl-5-methyl-2-methylsulfanyl-3-(3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.1.6(4), 7-hydroxymethyl-5-methyl-2-methylsulfone the l-3-(4-fluoro-3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.1.6(5), 5-hydroxymethyl-7-methyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.7(1), 5-hydroxymethyl-7-methyl-2-methylsulfanyl-3-(4-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.7(2), 5-hydroxymethyl-7-methyl-2-methylsulfanyl-3-(3-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.7(3), 5-hydroxymethyl-7-methyl-2-methylsulfanyl-3-(3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.1.7(4) and (5-hydroxymethyl-7-methyl-2-methylsulfanyl-3-(4-fluoro-3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.1.7(5), 5-methyl-2-methylsulfanyl-7-methoxy-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.8(1), 2-methylsulfanyl-7-methoxy-5-(pyridine-2-yl)-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.8(2), 2-methylsulfanyl-7-methoxy-5-(pyridin-3-yl)-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.8(3), 2-methylsulfanyl-7-methoxy-5-(pyridin-4-yl)-3-phenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.1.8(4), 5-methyl-2-methylsulfanyl-7-methoxy-3-(3-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.8(5), 2-methylsulfanyl-5-(pyridin-2-yl)-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.9(1), 2-methylsulfanyl-5-(pyridin-3-yl)-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.9(2), 2-methylsulfanyl-5-(pyridin-4-yl)-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.9(3), 2-methylsulfanyl-5-(pyridin-3-yl)-3-(3-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.9(4), 2-methylsulfanyl-5-(pyridin-3-yl)-3-(3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.1.9(5), 7-methyl-2-methylsulfanyl-5-(is iridin-2-yl)-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.9(6), 7-methyl-2-methylsulfanyl-5-(pyridin-3-yl)-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.9(7), 7-methyl-2-methylsulfanyl-5-(pyridin-4-yl)-3-phenylsulfonyl-pyrazolo [1,5-a]pyrimidine 1.1.9(8), 7-methyl-2-methylsulfanyl-5-(pyridin-3-yl)-3-(3-perpenicular)-pyrazolo[1,5-a]the pyrimidine 1.1.9(9), 7-methyl-2-methylsulfanyl-5-(pyridin-3-yl)-3-(3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.1.9(10), 2-methylsulfanyl-7-(pyridin-2-yl)-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.10(1), 2-methylsulfanyl-7-(pyridin-3-yl)-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.10(2), 2-methylsulfanyl-7-(pyridin-4-yl)-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.10(3), 2-methylsulfanyl-7-(pyridin-3-yl)-3-(3-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.10(4), 2-methylsulfanyl-7-(pyridin-3-yl)-3-(3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.1.10(5), 5-methyl-2-methylsulfanyl-7-(pyridin-2-yl)-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.10(6), 5-methyl-2-methylsulfanyl-7-(pyridin-3-yl)-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.10(7), 5-methyl-2-methylsulfanyl-7-(pyridin-4-yl)-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.10(8), 5-methyl-2-methylsulfanyl-7-(pyridin-3-yl)-3-(3-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.10(9), 5-methyl-2-methylsulfanyl-7-(pyridin-3-yl)-3-(3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.1.10(10) and their pharmaceutically acceptable salts and/or hydrates














5. The method of obtaining compounds 1.1.1, 1.1.2, 1.1.3, 1.1.4, 1.1.5, 1.1.9, 1.1.10 according to any one of claims 1 to 4 by the interaction of 3-amino-4-arylsulfonyl-2H-pyrazoles of General formula 2 with the corresponding β-dicarbonyl compounds of General formula 3 or their derivatives

where R1, R2, R3, R4and R5have the above value.

6. The method according to claim 5 obtain the compounds of General formula 1.1.1 according to any one of p and 4 the interaction of 3-amino-4-sulfonyl-2H-pyrazoles of General formula 2 with tetraacetate malonic aldehyde 3.1

where R4and R5have the above value.

7. The method according to claim 5 obtain the compounds of General formula 1.1.2, 1.1.3 on any of PP and 4 the interaction of 3-amino-4-sulfonyl-2H-pyrazoles of General formula 2 with 1-substituted 3,3-dealkylase-propanone 3.2, followed by separation or separation of the reaction products

where R4, R5and R6are above the value.

8. The method according to claim 5 obtain the compounds of General formula 1.1.4, 1.1.5 on any of PP and 4 the interaction of 3-amino-4-sulfonyl-2H-pyrazoles of General formula 2 with alkoxy-substituted-diketone 3.3, followed by separation or separation of the reaction products

where R4, R5, R6, R7and n have the above meaning.

9. The method according to claim 5 obtain the compounds of General formula 1.1.9, 1.1.10 on any of PP and 4 the interaction of 3-amino-4-arylsulfonyl-2H-pyrazoles of General formula 2 with a diketone 3.4, followed by separation or separation of the reaction products

where R4, R5, R6and PY have the abovementioned meaning.

10. The method of obtaining compounds of General formula 1(X=SO) according to claim 1 oxidation 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1(X=S)

where R1, R2, R3, R4and R5have the above value.

11. The method of obtaining substituted 2-effect-free remedy 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1.1.2 according to any one of p and 4 restoration chlorinated General formula 4

where R4, R5and R6have the above value.

12. The method of obtaining compounds of General formula 1.1.6, 1.1.7 what about any of PP and 4 action trichromate boron on the appropriate alkyloxyalkyl compounds of General formula 1.1.4 or 1.1.5.

13. The method of obtaining compounds of General formula 1.1.8 on any of PP and 4 by the interaction of chlorine substituted General formula 4 with an alkali metal alcoholate of the General formula 6

where R4, R5, R8and R9have the above significance; M represents a cation of an alkali metal.

14. Antagonists of serotonin 5-HT6receptors represents a substituted 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1 according to any one of claims 1 to 4.

15. Antagonists of serotonin 5-HT6receptors on 14, designed for studying the selective inhibition of serotonin 5-HT6receptors.

16. Substituted 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines according to any one of claims 1 to 4, having the properties of antagonists of serotonin 5-HT6receptors as drug began to pharmaceutical compositions and medicines.

17. Pharmaceutical composition having the properties of antagonists of serotonin 5-HT6receptors for treating and preventing conditions and disorders of the Central nervous system containing a pharmaceutically effective amount of a medicinal beginning on item 16.

18. A method of obtaining a pharmaceutical composition 17 a mixture of medicinal beginning of the and clause 16 with an inert filler and/or diluent.

19. The drug is in the form of tablets, capsules, or injections, 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, comprising pharmaceutically effective amount of a medicinal beginning on P16 or pharmaceutical compositions by 17.

20. Drug on p.19 for the prevention and treatment of cognitive disorders and neurodegenerative diseases.

21. Drug on p.19 for the prevention and treatment of mental disorders.

22. Drug having anxiolytic effect, according to claim 19 for the prevention and treatment of anxiety disorders.

23. Drug, possess nootropic action on p.19 for improving mental abilities.

24. Method for the prevention and treatment of diseases of the Central nervous system, the pathogenesis of which is associated with 5-HT6receptors, which consists in the introduction of medicinal beginning on clause 16, or the pharmaceutical composition according to 17, or drugs in claim 19 in an effective amount.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to novel 2-alkylamino-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of general formula 1, their pharmaceutically acceptable salts and/or hydrates having serotonin 5-HT6 receptor antagonist properties. The compounds can be used to treat and prevent development of various diseases of the central nervous system, pathogenesis of which is associated with 5-HT6 receptors, particularly Alzheimer's disease, Parkinson's disease, Huntington disease, schizophrenia, other neurodegenerative diseases and cognitive disorders. In general formula 1 , R1 is a hydrogen atom, C1-C3alkyl, C1-C3alkyloxyC1-C3alkyl, hydroxyC1-C3alkyl, adamantyl, optionally substituted phenyl, 5-6-member heterocyclyl containing a nitrogen or oxygen heteroatom, possibly condensed with a benzene ring; R2 is a hydrogen atom, halogen atom, C1-C3alkyl, pyridyloxy; R3 is a hydrogen atom; C1-C3alkyl; optionally substituted amino group selected from amino, mono- or di(C1-C3alkyl)amino, di(C1-C3alkyl)aminoC2-C3alkylamino, N-[di(C1-C3alkyl)aminoC2-C3alkyl]-N-(C1-C3alkyl)-amino; C1-C3alkyloxy, C1-C3alkyloxyC1-C3alkyl, hydroxyC1-C3alkyl; 6-member azaheterocyclyl, possibly containing an extra nitrogen or oxygen atom, a -N(C1-C3alkyl) group; R4 is C1-C3alkyl; R5 is a hydrogen atom, one or two halogen atoms or C1-C3alkyl.

EFFECT: design of a method of obtaining compounds, a pharmaceutical composition and a medicinal agent for treating and preventing various diseases of the central nervous system.

25 cl, 12 dwg, 3 tbl, 20 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 1-(3-morpholinopropyl)-2-phenylimidazo[1,2-a]benzimidazole dihydrochloride of formula I:

having purine P2Y1-receptor antagonist properties, antiaggregant and antithrombotic activity.

EFFECT: obtaining a new compound which can be used in medicine for making a medicinal drug for therapy of diseases accompanied by increase in thrombogenic potential of the blood: atherosclerosis, ischemic heart disease, diabetic angiopathy.

1 cl, 5 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 7H-pyrrol[2,3-d]pyrimidine derivatives of formula I. In compounds of formula R1 is phenyl which is optionally substituted with a halogen, phenylalkyl, where the alkyl contains 1-4 carbon atoms, morpholinoalkyl, where the alkyl contains 1-4 carbon atoms, dialkylaminoalkyl, where the alkyl contains 1-4 carbon atoms, or pyridyl which is optionally substituted with alkyl which contains 1-4 carbon atoms, R2, R3 optionally represent methyl, or R2 and R3 together form a tetramethylene group, R4 is or or where R5 is phenyl which is optionally substituted with 1-3 groups selected from nitro, trifluoromethyl, benzyloxy, hydroxy, alkoxy, alkyl, where the alkyl contains 1-4 carbon atoms, cyano, dialkylamino, where the alkyl contains 1-4 carbon atoms, either a thiophene or naphthyl ring; R6, R7, R8 and R9 independently represent hydrogen, halogen, trifluoromethoxy, sulphonyl or alkyl containing 1-4 carbon atoms, R10 is hydrogen, a nitrile group, or an alkyl containing 1-4 carbon atoms, R11 is tert-butyl or phenyl, or together with X form a tetramethylene ring, or; R12 is phenyl which is possibly substituted with nitro, halogen, alkoxy, or phenyl-alkyl, where the alkyl contains 1-4 carbon atoms, X is carbon, or R11 together with X form a tetramethylene ring, otherwise X denotes nitrogen, methine, methylmethine, ethylmethine, propylmethine, isopropylmethine, tert-butylmethine or phenylmethine. The invention also relates to a pharmaceutical composition and a method of preparation.

EFFECT: obtaining compounds and pharmaceutically acceptable salts which have anti-inflammatory and anaesthetic effect.

10 cl, 3 tbl, 96 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a new pyrazole[1.5-a]pyrimidine derivative of formula [1]: , where ring A is a substituted pyrazole ring condensed with a neighbouring pyrimidine ring having formula , and group E is one of the following groups (ii)-(v): , and the rest of the radicals are defined in the description. The invention also relates to pharmaceutical compositions containing such compounds.

EFFECT: disclosed compositions and compositions have antagonistic effect on CB1 cannabinoid receptor.

19 cl, 82 tbl, 500 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula I. In general formula I A is C or N; B, D and E independently represent CR4, NR5, N, O or S; and a ring containing groups A, B, D, E, selected from thienyl, furan, imidazole, oxazole, isothiazole, thiazole, pyrrol, pyrazole; provided that: b) when A is N, not any of B, D, E can be O or S; and c) when A is C, B is CR4 and one of D or E is N or NR5, when any of D or E cannot be NR5 or N; G is N or C; R1 represents one or more substitutes selected from H, Ra halogen, -OH and -ORa; R2 represents one or more substitutes selected from H, halogen and C1-6-alkyl, and also one of substitutes R2 can be -ORb' , -NRb' Rb', -SRb', -SORb', -SO2Rb', -SO2NRb' Rb'; R3 is H, or Cy, selected from phenyl optionally substituted with one or more substitutes selected from Rc , where Rc independently represents halogen, -ORg', where Rg' independently represents a Rg group, where Rg is C1-6-alkyl; each R4 independently represents H, Re, halogen, -CORe', -CO2Re', -CONRe'Re', -NRe'Re'; R5 independently represents H, Re, -CORe, -CONReRe, -SORe or -SO2Re; each Ra independently represents C1-6-alkyl or halogen- C1-6-alkyl; each R independently represents C1-6-alkyl optionally substituted with one or more substitutes selected from Rd and Rf; each Rb' independently represents H or Rb; each Rc independently represents halogen, -ORg', -CONRg'Rg', -NRg'Rg'; Rd is Cy optionally substituted with one or more Rf substitutes; each Rc independently represents C1-6-alkyl optionally substituted with one or more substitutes selected from Rc and Cy*, or Re is Cy, where any of the groups Cy or Cy* can optionally be substituted with one or more substitutes selected from Rc and Rg ; each Re' independently represents H or Re; each Rf independently represents a halogen, -ORh', -CO2Rh; each Rg independently represents Rd or C1-6-alkyl optionally substituted with one or more substitutes selected from Rd and Rf; each Rg' independently represents H or Rg; each Rh independently represents C1-6-alkyl, halogen-C1-6-alkyl or hydroxy- C1-6-alkyl; each Rh' independently represents H or Rh; and Cy or Cy* given in definitions above is a partially saturated, saturated or aromatic 3-7-member monocyclic carbocyclic ring which optionally contains 1-2 heteroatoms selected from N and O, and where the ring or rings can be bonded to the remaining part of the molecule through a carbon or nitrogen atom.

EFFECT: obtaining formula I compounds with p38-kinase inhibitory properties which can be used in making drugs for treating such diseases as tumour immune and autoimmune diseases etc.

21 cl, 10 dwg, 8 tbl, 57 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to phenylalanine derivatives and their pharmaceutically acceptable salts. In formula (1) R11 is a hydroxyl group, an alkoxyl group having 1-6 carbon atoms, which can be substituted with a methoxy group, cycloalkoxyl group having 3-6 carbon atoms, or a benzyloxy group; R12 and R13 each independently represents a hydrogen atom, alkyl group having 1-6 carbon atoms, cycloalkyl group having 3-6 carbon atoms, acetyl group or methyloxycarbonyl group, or N(R12)R13 is a 1-pyrrolidinyl group, 1-piperidinyl group, 4-morpholinyl group; R14 is a methyl group; R1' is a hydrogen atom, fluorine atom; X1 is -CH(R1a)-, -CH(R1a)CH(R1b)-, -CH(R1a)CH(R1b)CH(R1c)-, -N(R1a)CH(R1b)CH(R1c)-, -OCH(R1a)CH(R1b)-, -OCH(R1a)CH(R1b)CH(R1c)- or 1,3-pyrrolidinylene, where R1a, R1b, each independently represents a hydrogen atom or a methyl group, and R1c is a hydrogen atom; Y11 and Y12 represent any of the combinations (CI, Cl), (CI, Me), (CI, F). Invention also relates to phenylalanine derivatives of formulae (2)-(14), given in the formula of invention.

EFFECT: obtaining a pharmaceutical composition having antagonistic effect on α4-integrin, containing a phenylalanine derivative as an active ingredient, a α4-integrin antagonist and a therapeutic agent.

65 cl, 51 tbl, 244 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new condensed compounds (versions) or their pharmaceutically acceptable salts having inhibitory effect on HER2 and/or EGFR kinase, having the following formula, for example: or , where R1a is a hydrogen atom; R2a is a C1-8alkyl group, C2-8alkenyl group or C2-8alkynyl group, each of which is substituted with substitute(s), R3a is a hydrogen atom or C1-6alkyl group; or R1a and R2a are optionally bonded with formation or R2a and R3a are optionally bonded with formation of C2-4alkylene; Ba is a benzene ring optionally substituted with 1-4 substitutes selected from halogen and optionally halogenated C1-4alkyl; Ca is a phenyl group substituted with 1-5 substitutes selected from (i) halogen, (ii) optionally halogenated C1-4alkyl, (iii) hydroxy- C1-4alkyl, (iv) a 5-8-member heterocycle- C1-4alkyl, where the said 5-8-member heterocycle contains 1-3 heteroatoms selected from a nitrogen atom, oxygen atom and optionally oxidised sulphur atom, (v) optionally halogenated C1-4alkyloxy, (vi) cyano and (vii) carbamoyl, optionally substituted with C1-8alkyl, and, respectively, R2e is a C1-4alkyl group optionally substituted with -O-(CH2)n-OH, where n is an integer from 1 to 4; R3e is a hydrogen atom; Be is a benzene ring optionally substituted with a halogen; and Ce is a phenyl group optionally substituted with halogenated C1-4alkyl.

EFFECT: obtained new compounds can be used for treating cancer.

22 cl, 2 tbl, 280 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and their pharmaceutically acceptable salts of formula (I) where n equals 0, 1 or 2, A is a five- or six-member aromatic ring which optionally contains one or two heteroatoms independently selected from nitrogen, oxygen or sulphur, B is a 5-9-member ring containing 0 or 1 double bonds and optionally contains an additional heteroatom selected from nitrogen and oxygen; where the ring optionally contains one or two substitutes independently selected from a group comprising C1-C6-alkoxy, C1-C6-alkoxycarbonyl, C1-C6-alkyl, carboxy, cyano, hydroxy, hydroxy-C1-C6-alkyl, di-C1-C6-alkylamino-C1-C6-alkyl, (NR4R5)-carbonyl or oxo; R1 is selected from -C(O)NR4R5 - CO2R4, 5-tetrazolyl, cyano; each R2 is independently selected from a group comprising C1-C6-alkyl, amino, benzyloxy, halogen, hydroxyl; R3 is a 5-7-member cycloalkyl ring; values of the rest of the radicals are given in the formula of invention. The invention also relates to a method for synthesis of the said compounds, a method of inhibiting HCV replicon function and a method of inhibiting functioning of the HCV NS5B protein.

EFFECT: wider field of use of the compounds.

16 cl, 4 tbl, 29 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel condensed heterocylic protein kinase modulators of formula I where L1 and L2 independently denote a bond, and R1 and R2 denote a substituted or unsubstituted heteroaryl or a substituted or unsubstituted aryl, as well as to pharmaceutical compositions containing such compounds, and methods of using the compounds to prepare medicine for diseases mediated by protein kinase activity.

EFFECT: increased effectiveness of using the compounds.

24 cl, 20 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel 2-alkylamino-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of general formula 1, their pharmaceutically acceptable salts and/or hydrates having serotonin 5-HT6 receptor antagonist properties. The compounds can be used to treat and prevent development of various diseases of the central nervous system, pathogenesis of which is associated with 5-HT6 receptors, particularly Alzheimer's disease, Parkinson's disease, Huntington disease, schizophrenia, other neurodegenerative diseases and cognitive disorders. In general formula 1 , R1 is a hydrogen atom, C1-C3alkyl, C1-C3alkyloxyC1-C3alkyl, hydroxyC1-C3alkyl, adamantyl, optionally substituted phenyl, 5-6-member heterocyclyl containing a nitrogen or oxygen heteroatom, possibly condensed with a benzene ring; R2 is a hydrogen atom, halogen atom, C1-C3alkyl, pyridyloxy; R3 is a hydrogen atom; C1-C3alkyl; optionally substituted amino group selected from amino, mono- or di(C1-C3alkyl)amino, di(C1-C3alkyl)aminoC2-C3alkylamino, N-[di(C1-C3alkyl)aminoC2-C3alkyl]-N-(C1-C3alkyl)-amino; C1-C3alkyloxy, C1-C3alkyloxyC1-C3alkyl, hydroxyC1-C3alkyl; 6-member azaheterocyclyl, possibly containing an extra nitrogen or oxygen atom, a -N(C1-C3alkyl) group; R4 is C1-C3alkyl; R5 is a hydrogen atom, one or two halogen atoms or C1-C3alkyl.

EFFECT: design of a method of obtaining compounds, a pharmaceutical composition and a medicinal agent for treating and preventing various diseases of the central nervous system.

25 cl, 12 dwg, 3 tbl, 20 ex

Hypolipidemic agent // 2392933

FIELD: medicine, pharmaceutics.

SUBSTANCE: there is offered application of Benzohexonium as a hypolipidemic agent. Previously, Benzohexonium was used as a ganglionic blocking agent in bronchiospasms, peripheral vasospasm, for reduction of hypertensic crisis, for controlled hypotension, in gastric ulcer and duodenal ulcer. It is shown that Benzohexonium reduces concentration of cholesterol and triglycerides in blood, liver, aorta, and considerably decreases the atherogenic index. The intensity of hypolipidemic effect of Benzohexonium enables to consider this agent as close to a common lipid lowering preparation Gemfibrozil and exceeds the fibrate effect of Clofibrate and Probucol.

EFFECT: preclinical trials of Benzohexonium ensure to recommend it as a hypolipidemic agent for prevention and treatment of atherogenic dislipoproteinemia.

4 tbl

FIELD: chemistry.

SUBSTANCE: claimed compounds show effect on receptor activated by peroxysome proliferate δ (PPARδ). In formula I: [Formula I] , [Formula VII] , [Formula VI] , A is R1 is C1-4alkyl group; R3 groups are different and denote halogen atom or C1-4alkyl group substituted or unsubstituted by halogen; R4 is R5 is hydrogen atom or hydroxyl group; the other radicals are as defined in the invention claim. Also invention refers to methods of compound I obtainment, to intermediary compounds VI, VII and methods of their obtainment, to medicines of diabetes, obesity, atherosclerosis, hyperlipidemia treatment and prevention, containing thiazole derivative of the formula I as active component.

EFFECT: enhanced activity of derivatives.

21 cl, 10 tbl, 102 ex

FIELD: chemistry.

SUBSTANCE: invention relates to biologically active analogues of steroid oestrogens. 17,17-dimethyl-D-homo-B-nor-8α-oestrone is synthesised, which has noticeably pronounced hypolipidemic and cardioprotector activity in the absence of uterotropic action. 17,17-dimethyl-D-homo-B-nor-8α-oestrone.

EFFECT: obtaining compounds which can be used in medicine as a basis for designing effective medicinal preparations for treating cardiovascular diseases.

1 cl, 1 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to serotonin 5-HT6 receptor antagonists - new substituted 3-sulphonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[4,3-e]pyrimidines of formula and substituted 3-sulphonyl-5,6,7,8-tetrahydro-pyrazolo[1,5-a]pyrido[4,3-c1]pyrimidines of general formula 2, a medicinal base and pharmaceutical compositions containing the medicinal base in form of the said compounds, as well as to a method of treating and preventing development of different conditions and diseases of the central nervous system of humans and warm-blooded animals. In formulae and Ar is phenyl which is optionally substituted with halogen atoms, or a 6-member heteroaryl which contains a nitrogen atom in the ring; R1 is a hydrogen atom, C1-C3alkyl, hydroxy C1-C3alkyloxy group, C1-C3alkylsulphanyl group; R2 is a hydrogen atom or C1-C3alkyl, R3 is a hydrogen atom optionally substituted C1-C3alkyl or tert-butyloxycarbonyl.

EFFECT: obtaining compounds for preventing development of different conditions and diseases of the central nervous system of humans and warm-blooded animals.

16 cl, 3 tbl, 1 dwg, 10 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) and their pharmaceutically acceptable salts and esters. The disclosed compounds have LXR-alpha and/or LXR-beta agonist properties. In formula (I) R1 is hydrogen, halogen; R2 is lower alkyl, flouro-lower alkyl; R3 is hydrogen, phenyl; R4 is hydrogen, hydroxy; R5 is hydrogen; phenyl; R6 is phenyl, a 5-6-member heteroaryl with one or two heteroatoms selected from nitrogen and sulphur, a 9-member bicyclic heteroaryl with a sulphur atom as a heteroatom, which can be optionally substituted with a halogen, or R6 is , R7 is a lower alkyl; R8 is phenyl which is optionally substituted with one substitute selected from a group consisting of halogen, fluoro-lower alkyl, R9-O-C(O)-, R10R11NC(O)-, phenyl-lower alkoxy; R9, R10, R11 independently represent hydrogen or lower alkyl; L is a single bond, lower alkylene or lower alkenylene; m assumes values from 0 to 3; n is equal to 0 or 1.

EFFECT: obtaining a new compound and a pharmaceutical composition which contains the disclosed compound as an active ingredient for therapeutic and/or preventive treatment of diseases.

23 cl, 47 ex

FIELD: medicine.

SUBSTANCE: invention concerns a composition obtained from a combination of vegetable oil or cod-liver oil with a compound which contains fatty acids analogues resistant to β-oxidation. The invention also concerns animals' fodder produced form a combination of vegetable oil and cod-liver oil containing fatty acids analogues resistant to β-oxidation, to application of the fodder with the purpose of improving the animal's body composition and to the product obtained from the above animals.

EFFECT: production of pharmaceutical or edible composition for prevention and/or treatment of insulin resistance, obesity, diabetes, fatty liver, hypercholesterinemia, dislipidemia, atherosclerosis, coronary heart disease, thrombosis, stenosis, myocardial infarction, apoplexy, hypertension, endothelial dysfunction, hypercoagulability, polycystic ovary syndrome, metabolic syndrome, malignant tumour, inflammatory disorder and poliferous skin lesions.

47 cl, 12 tbl, 2 ex, 4 dwg

FIELD: medicine.

SUBSTANCE: invention belongs to medicine, particularly to hypercholesterinemia correction methods. To that end, probiotic - liquid sporobacterin - is orally administered by 1 ml twice per day for 30 days.

EFFECT: method ensures effective hypercholesterinemia treatment comparable with statins effect, by with no adverse reactions.

4 ex

FIELD: food industry.

SUBSTANCE: invention suggest using edible sorbitan derivative found in the product used for preventing fat absorption. Sorbitan derivative is used for cosmetic control of the body weight.

EFFECT: invention enables to help people suffering from obesity as well as to reduce risks of getting overweight.

9 cl, 4 dwg, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compounds of formula (I) and their pharmaceutically acceptable salts or esters having agonistic effect on PPARδ and/or PPARα, where X1 is selected from a group which includes O and CH2, R1 denotes hydrogen or C1-C7alkyl, R2 denotes C1-C7alkyl, or if X1 denotes CH2, then R2 denotes hydrogen, R3 denotes hydrogen or C1-C7alkyl, R4 and R8 are independently selected from a group which includes hydrogen, C1-C7alkyl, C1-C7alkoxy, halogen, R5, R6 and R7 are independently selected from a group which includes hydrogen, C1-C7alkoxy, halogen, where one of R5, R6 and R7 denotes , where X2 denotes O, R10 denotes hydrogen, R11 denotes hydrogen, one of R12 or R13 is selected from a group which includes hydrogen, C1-C7alkyl and fluoro(C1-C7)alkyl, and the other denotes an unshared electron pair, R14 denotes hydrogen, R15 denotes 4-trifluoromethoxyphenyl, and n equals 1, 2 or 3. The invention also relates to pharmaceutical compositions containing such compounds.

EFFECT: increased effectiveness of the compounds.

23 cl, 20 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel 2-alkylamino-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of general formula 1, their pharmaceutically acceptable salts and/or hydrates having serotonin 5-HT6 receptor antagonist properties. The compounds can be used to treat and prevent development of various diseases of the central nervous system, pathogenesis of which is associated with 5-HT6 receptors, particularly Alzheimer's disease, Parkinson's disease, Huntington disease, schizophrenia, other neurodegenerative diseases and cognitive disorders. In general formula 1 , R1 is a hydrogen atom, C1-C3alkyl, C1-C3alkyloxyC1-C3alkyl, hydroxyC1-C3alkyl, adamantyl, optionally substituted phenyl, 5-6-member heterocyclyl containing a nitrogen or oxygen heteroatom, possibly condensed with a benzene ring; R2 is a hydrogen atom, halogen atom, C1-C3alkyl, pyridyloxy; R3 is a hydrogen atom; C1-C3alkyl; optionally substituted amino group selected from amino, mono- or di(C1-C3alkyl)amino, di(C1-C3alkyl)aminoC2-C3alkylamino, N-[di(C1-C3alkyl)aminoC2-C3alkyl]-N-(C1-C3alkyl)-amino; C1-C3alkyloxy, C1-C3alkyloxyC1-C3alkyl, hydroxyC1-C3alkyl; 6-member azaheterocyclyl, possibly containing an extra nitrogen or oxygen atom, a -N(C1-C3alkyl) group; R4 is C1-C3alkyl; R5 is a hydrogen atom, one or two halogen atoms or C1-C3alkyl.

EFFECT: design of a method of obtaining compounds, a pharmaceutical composition and a medicinal agent for treating and preventing various diseases of the central nervous system.

25 cl, 12 dwg, 3 tbl, 20 ex

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