Substituted 2-alkylsulfanyl-3-sulfonyl-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 2-alkylsulfanyl-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. In general formula 1 , R1 and R3 independently denote optionally identical C1-C3 alkyl, and R2 is a -(CH2)nX group or R1 and R3 independently denote different substitutes selected from C1-C3 alkyl or a -(CH2)nX group, and R2 is a hydrogen atom or C1-C3 alkyl; R4 is C1-C3 alkyl; Ri5 is a hydrogen atom, one or two identical or different halogen atoms, C1-C3 alkyl; equals 0, 1 or 2; n equals 0, 1, 2 or 3; X is a carboxyl CO2H, C1-C3 alkyloxycarbonyl, aminocarbonyl CONR6R7 or amino group NR6R7; except compounds in which R3 is a -(CH2)nX group, where X is an amino group NR6R7 and n equals 0; R6 and R7 are optionally identical and denote a hydrogen atom, optionally substituted C1-C5 alkyl or R6 and R7 together with the nitrogen atom with which they are bonded form an optionally substituted 6-member azaheterocyclyl containing 1-2 nitrogen atoms in the ring, where the substitute is selected from C1-C3 alkyl.

EFFECT: obtaining compounds which can be used in treating diseases of the central nervous system during prevention or treatment of cognitive disorders, neurodegenerative diseases, psychiatric disorders, have anxiolytic and nootropic effect and can be used to prevent and treat anxiety disorders and enhance mental capacity.

25 cl, 2 tbl, 12 ex

 

The invention relates to new substituted 2-alkylsulfanyl-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 for 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, is a promising direction for new drugs [Holenz j, Pauwels, P.J., J.L. Diaz, Merce R., Codony X., Buschmann H. Medicinal chemistry strategies to 5-HT6receptor ligands as potential cognitive enhancers and antiobesity agents. Drug Disc. Today. 2006; 11:283-299]. These receptors in mammals are found exclusively in the Central nervous system, moreover, is mainly in the 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. Measurement localisation ofserotonin 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., Gallagher H.C-, 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. Riemer, S., E. Borroni, Levet-Trafit Century, Martin J.R., Poli, S., Porter, R.H., Bos M. Influence of the 5-HT6receptor on acetylcholine release in the cortex: pharmacological characterization of 4-(2-bromo-6-pyrrolidin-l-ylpyridine-4-sulfonyl)phenylamine, a potent and selective 5-HT6receptor antagonist. J. Med. Chem. 2003; 46:1273-127. King M.V., M.L. Woolley, Topham I.A., Sleight AJ, Marsden CA, Fone K.C. 5-HT6receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing consolidation e an effect sensitive to NMDA receptor antagonism. Neuropharmacology 2004; 47:195-204]. Also shown significant improvement in cognitive function in aged rats in the model water maze Morrison when exposed to an antagonist of 5-HT6receptors [Foley A.G., Murphy K.J., Hirst W.D., H.C. Gallagher, J.J. Hagan, Upton N.. 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]. Recently achieved not only a deeper understanding of the role of 5-HT6receptors in cognitive processes, but a clearer concept about possible pharmacophoric properties of their antagonists [Holenz j, Pauwels, P.J., J.L. Diaz, Merce R., Codony X., Buschmann H. Medicinal chemistry strategies to 5-HT6receptor ligands as potential cognitive enhancers and antiobesity agents. Drug Disc. Today. 2006; 11:283-299]. This led to the creation of selective high-affinity ligands ("molecular tools"), then and clinical candidates. Currently, 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
DimebonTMPhase IIIMedivation (USA)Treatment of Alzheimer's disease
SGS-518Phase IILilly, SaegisTreatment of cognitive diseases
SB-742457Phase IIGlaxoSmithKlineTreatment of Alzheimer's disease; Antipsychotic
Dimebon*Phase I/IIaMedivation (USA)Treatment of Hantington
Dimebon*Phase II(Russia)Schizophrenia
PRX-07034Phase IEpi Pharm. The treatment of obesity; 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 the appetite, which can lead to the creation on their basis of fundamentally new means to reduce overweight and obesity [Vicker SP, Dourish CT Serotonin receptor ligands and the treatment of obesity. Curr. Opin. Investig. Drugs. 2004; 5:377-388]. This effect is confirmed in many studies [J. Holenz, Pauwels, P.J., J.L. Diaz, Merce R., Codony X., Buschmann H. Medicinal chemistry strategies to 5-HT6receptor ligands as potential cognitive enhancers and antiobesity agents. Drug Disc. Today. 2006; 11:283-299. Davies, S.L. Drug discovery targets: 5-HT6receptor. Drug Of The Future. 2005; 30:479-495], its mechanism is based on inhibition by antagonists of 5-HT6receptor signaling gamma-aminobutyric acid and increase the release of alpha-melanocyte-stimulating hormone, which ultimately reduces the need for food [M.L. Woolley 5-ht6 receptors. Curr. Drug Targets CNS Neurol. Disord. 2004; 3:59-79]. Currently, two antagonist 5-HT6receptors are in the first stage of clinical trials as drug candidates for the treatment of overweight (table 1) [http://integrity.prous.com].

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

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

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

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

To develop new highly effective medicines by the authors of the present invention made extensive studies in a series of substituted 2-alkylsulfanyl-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 that the receptors specific specific signal and thereby cause a biological response of a cell.

"Azaheterocycle" means an aromatic or non-aromatic monocyclic or polycyclic system containing a loop, at least one nitrogen atom. Azaheterocycle can have one or more cyclic substituents" of the system.

"Alkyl" means an aliphatic hydrocarbon of linear or branched group with 1-12 carbon atoms in the chain. Branched means that the alkyl chain has one or more "lower alkyl" substituents. The alkyl may have one or more identical or different substituents ("alkyl substituents including halogen, alkenylacyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkyloxy, Alcoxy, aryloxy, aryloxyalkyl, alkylthio, heteroaromatic, Uralkali, arylsulfonyl, alkylsulfonyl, heteroarylboronic, annelirovannymi heteroarylboronic, annelirovannymi heteroalicyclic, annelirovannymi heterooligomerization, annelirovannymi heteroalicyclic, annelirovannymi arylchloroalkanes, annelirovannymi aristically, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic, alkoxycarbonyl, arelaxation, heteroarylboronic or RkaRk+1aN-, RkaRk+1aN(=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 are bound, form a through 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.

"Alkylamino" means CnH2n+1N - or (C nH2n+1)(CnH2n+1)N-group in which alkyl is defined in this section. The preferred alkylaminocarbonyl are methylamino, ethylamino, n-propylamino, out-propylamino and n-butylamine.

"Alkyloxy" means CnH2n+1O-group in which alkyl is defined in this section. The preferred acyloxy groups are metiloksi, ethyloxy, n-propyloxy, out-propyloxy and n-Butylochka.

"Allyloxycarbonyl" means-C(O)OCnH2n+1-group in which alkyl is defined in this section.

"Alkylsulfanyl" means alkyl-S-group in which alkyl is defined in this section. Preferred alkylsulfonyl groups are methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, out-propylsulfonyl and n-butylsulfonyl.

"Amino" means-NR6R7the group in which R6and R7are not necessarily the same hydrogen atom, optionally substituted lower alkyl, or R6and R7together with the nitrogen atom to which they are bound, form an optionally substituted azaheterocyclic.

"Aminocarbonyl" means-CONR6R7the group in which R6and R7are not necessarily the same hydrogen atom, optionally substituted lower alkyl, or R6and R7together with the nitrogen atom to which they are related is s, form an optionally substituted azaheterocyclic.

"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, preimushestvenno 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 b is the Ohm.

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

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

"Deputy" means a chemical moiety that is attached to scaffold (fragment), for example, "Deputy alkyl", "Deputy amino group", "Deputy carbamoyl", "Deputy cyclic system, the value of which is determined in this time is barely.

"Deputy cyclic system" means the Deputy attached to aromatic or non-aromatic cyclic system, including hydrogen, alkylaryl, quinil, aryl, heteroaryl, aralkyl, heteroalkyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkoxy, aryloxy, acyl, aroyl, halogen, nitro, cyano, carboxy, alkoxycarbonyl, aryloxyalkyl, arelaxation, alkyloxyalkyl, aryloxyalkyl, geterotsiklicheskikh, arylalkylamines, geterotsiklicheskikh, alkylsulfonyl, arylsulfonyl, heterocyclyl-sulfonyl, alkylsulfonyl, arylsulfonyl, heterocyclization, alkylthio, aaltio, heterocyclic, alkylsulfonates, arylsulfonyl, geterotsiklicheskikh, alkylsulfonates, arylsulfonyl geterotsiklicheskikh, alkylthiomethyl, alltoall, geterotsiklicheskikh, arylalkylamines, geterotsiklicheskie, arylalkylamines, geterotsiklicheskikh, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclyl, amidino,represent independently from each other "Vice-amino group", which is defined in this section, for example, hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroaryl is, or Deputy RkaRk+1aN-, in which Rkacan be acyl or aroyl, and a value of Rk+1adefined above, or "Deputy cyclic system is RkaRk+1aNC(=O)- or RkaRk+1aNSO2-, in which Rkaand Rk+1atogether with the nitrogen atom to which they are bound, form a through Rkaand Rk+1a4-7 - membered heterocyclyl or heterocyclyl.

"Carboxyl" means the group-CO2H.

"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 and Huntington; senile dementia; age-related memory disorders (age-associated memory his or her, AAMI); dysmetabolic encephalopathy; psychogenic disturbances of memory; amnesia; amnestic disorder; transient global amnesia; dissociative amnesia; vascular dementia; light (or moderate) cognitive impairment (mild cognitive his or her, MCI); deficit disorder attention hyperactivity disorder (attentiondeficit hyperactivity disorder, AD/HD); cognitive impairment accompanying psychotic diseases, epilepsy, delirium, autism, psychosis, down syndrome, bipolar disorder and depression; AIDS-associated dementia; dementia with hypothyroidism; dementia induced by alcohol, substances, addictive, and neurotoxins; dementia accompanying neurodegenerative diseases, 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, MAZ is th etc. the finished form, intended for restoring, correcting or modifying physiological functions in humans and animals, as well as for treatment and prevention of diseases, diagnostics, anesthesia, contraception, cosmetology and others.

"Ligands" (from the Latin ligo - link) is a chemical (small molecule, an inorganic ion, a peptide, a protein, etc.) capable of interacting with receptors that transform this interaction in specific signal.

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

"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 is, pornografiya, erotomania and others); disorder of multiple personality, Amancio, white fever, delirium, delusional syndrome, hallucinatory syndrome, hallucination, hallucinosis, gemicitabine, delirium, delusion, querulant, clinical lycanthropy, macropsia, Manichaean delirium, micropsia, drug addiction, nervous anorexia, oneyroidno syndrome, paranoid, paranoia, paraphrenia, pseudohallucinations, psychosis syndrome Kotar, schizoaffective disorder, schizotypical disorder, schizophrenia, schizophrenia-like psychosis disorder, isoprenaline disorder, syndrome Schreber, Daniel Paul; phobias (agoraphobia, arachnophobia, autophobia, verminophobia, hydrocodobe, the hydrophobicity demophobia, zoophobia, cancerophobia, claustrophobic, climacophobia, xenophobia, misophobia, primarily, photophobia, scoleciphobia, scotophobia, social phobia, tetraphobia, triskaidekaphobia, erotophobia); alcoholic psychosis, alcoholic palimpsest, allotriophagy, aphasia, graphomania, dissociative Fugue, dissociative disorders, dysphoria, Internet addiction, hypochondria, hysteria, koprofilia, persecution mania, melancholy, misanthropy, obsession, panic attacks, Asperger's syndrome, Capgras syndrome, Munchausen syndrome, rett syndrome, the syndrome Fregoli, the syndrome of attention deficit and hyperactivity syndrome obsessive-compulsive disorder, syndrome poles the Vij chronic anesthesia, the 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 depressive type; 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.

"Therapeutic cocktail" is simultaneously SKOLKOVO initiative combination of two or more drugs with different mechanisms of pharmacological action and aimed at different biomes is no, involved in the pathogenesis of the disease.

"Anxiety" (anxiety) refers to a generalized (non-specific) anxiety; acute uncontrolled anxiety; panic disorder; phobias, such as agoraphobia (a severe fear of crowded places) or social phobia (severe fear of humiliation in front of other people) or any specific phobia (severe fear of specific objects, animals or situations, in the form of a fear of heights, medical procedures, elevators, open space etc); obsessive-compulsive disorder (obsessive-compulsive disorder); 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 Menial Disorders, IV Edition, Washington D.C. 2000) or the International classification (International Statistical Classification of Diseases and Relted 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, diluents, carriers, auxiliary, distributing and perceiving means, means of delivery, such as preservatives, stabilizers, fillers, shredders, moisturizers, emulsifiers, suspendresume agents, thickeners, sweeteners, flavors, fragrances, antibacterial agents, fungicides, lubricants, regulators prolonged delivery, the choice and the value of which depends on the nature and mode of appointment and dosage. Examples suspendida agents are ethoxylated isostearoyl alcohol, polyoxyethylene, sorbitol and sorbitol ester, microcrystalline cellulose, Metagalaxy aluminum, bentonite, agar-agar and tragakant, as well as mixtures of these substances. Protection from the action of microorganisms can be ensured by various antibacterial and antifungal agents such as parabens, chlorobutanol, sorbic acid and similar compounds. The composition may also include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged action of the composition mo is et to be achieved through agents, slowing down the absorption of the active principle, for example, aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents and delivery vehicles include water, ethanol, polyalcohol, and 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, aginova acid and its salts, silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulphate, talc, and polyethylene with high molecular weight. Pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal injection of the active principle, one or in combination with other active early, can be introduced animals and people in the standard form of administration, mixed with conventional pharmaceutical carriers. Usable standard form of introduction include oral forms such as tablets, gelatin capsules, pills, powders, granules, chewing gum and oral solutions or suspensions, sublingual and transbukkalno forms of administration, aerosols, implants,local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular forms of administration and rectal forms of administration. Pharmaceutical compositions typically obtained using standard procedures involving mixing the active compound with a liquid or finely powdered solid carrier.

"Pharmaceutically acceptable salt" refers to the relatively non-toxic organic and inorganic salts of acids and bases, as claimed in the present invention. These salts can be obtained in situ during the synthesis, separation, or purification of compounds or prepared. In particular, salts of bases can be obtained specifically on the basis of the purified free base of the claimed compounds and a suitable organic or inorganic acid. Examples of the thus obtained salts are hydrochloride, hydrobromide, sulphates, bisulfate, phosphates, nitrates, acetates, oxalates, valeriote, oleates, palmitate, stearates, laurate, borate, benzoate, lactates, tozilaty, citrates, maleate, fumarate, succinate, tartratami, mesylates, malonate, salicylates, propionate, econsultancy, bansilalpet, sulfamate and the like. (For a detailed description of the properties of such salts are described in Berge S.M., et al., "Pharmaceutical Salts" J. Pharm. Sci. 1977, 66: 1-19). Salts of the stated acids can also be specially recip is by the reaction of purified acid with a suitable base, this can be synthesized metal salts and amines. The metal include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum, the most desirable of which are sodium and potassium salts. Suitable inorganic bases which can be obtained metal salts are the hydroxide, carbonate, bicarbonate and sodium hydride, hydroxide and bicarbonate of potassium, potash, lithium hydroxide, 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 Deputy is on 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1 and their pharmaceutically acceptable salts and/or hydrates,

where

R1and R3independently from each other are not necessarily identical With1-C3alkyl, and R2represents a group -(CH2)nX or

R1and R3independently from each other represent different substituents selected from C1-C3the alkyl or the group -(CH2)nX, a, R2represents a hydrogen atom or a C1-C3alkyl;

R4represents a C1-C3alkyl;

Ri5represents a hydrogen atom, one or two identical or different halogen atom, a C1-C3alkyl;

i represents the number 0, 1 or 2;

n represents the number 0, 1, 2 or 3;

X represents carboxyl CO2H1-C3allyloxycarbonyl, aminocarbonyl CONR6R7or amino group NR6R7; excluding the compounds in which R3represents a group -(CH2)nX, where X represents the amino group NR6R7and n is 0;

R6and R7are not necessarily the same hydrogen atom, optionally substituted C1-C5alkyl, or R6and R7together with the nitrogen atom to which they are bound, form an optionally substituted 6-membered azaheterocyclic containing 1-2 atoms AZ is that in a loop, where the Deputy is selected from C1-C3the alkyl.

Preferred substituted 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1 are the esters of General formula 1.1, 1.2 or 1.3,

where n and Ri5have the above value.

Preferred substituted 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1 are the acids of General formula 1.4, 1.5 or 1.6,

where n and Ri5have the above value.

Preferred substituted 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1 are amides of the General formula 1.7, 1.8 or 1.9,

where n, Ri5, R6and R7have the above value.

Preferred substituted 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1 are amines of General formula 1.10, 1.11 or 1.12,

where nR6and R7have the above value.

More PR is doctitle amines of General formula 1.10, 1.11 and 1.12 are 6-amino-5,7-dimethyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.10(1), 6-aminomethyl-5,7-dimethyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.10(2), 6-(2-amino-ethyl)-5,7-dimethyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.10(3), 6-(3-aminopropyl)-5,7-dimethyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.10(4), 6-aminomethyl-5,7-dimethyl-2-methylsulfanyl-3-(3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.10(5), 6-aminomethyl-5,7-dimethyl-2-methylsulfanyl-3-(3-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.10(6), 6-aminomethyl-5,7-dimethyl-2-methylsulfanyl-3-(4-fluoro-3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.10(7), 6-(2-amino-ethyl)-5,7-dimethyl-2-methylsulfanyl-3-(3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.10(8), 6-(2-amino-ethyl)-5,7-dimethyl-2-methylsulfanyl-3-(3-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.10(9), 5,7-dimethyl-6-dimethylaminomethyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.10(10), 5,7-dimethyl-6-dimethylaminomethyl-2-methylsulfanyl-3-(3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.10(11), 5,7-dimethyl-6-dimethylaminomethyl-2-methylsulfanyl-3-(3-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.10(12), 5,7-dimethyl-6-dimethylaminomethyl-2-methylsulfanyl-3-(4-fluoro-3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.10(13), 5,7-dimethyl-6-(2-dimethylaminoethyl)-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine(14), 5,7-dimethyl-6-(2-dimethylaminoethyl)-2-methylsulfanyl-3-(3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.10(15), 5,7-dimethyl-6-(2-dimethylaminoethyl)-2-methylsulfanyl-3-(3-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.10(16), 5,7-dimethyl-6-(2-dimethylamino-ethyl)-2-methylsulfanyl-3-(4-fluoro-3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.10(17), 5-aminomethyl-7-methyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.11(1), 5-(2-amino-ethyl)-7-methyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.11(2), 5-dimethylaminomethyl-7-methyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.11(3), 5-dimethylaminomethyl-7-methyl-2-methylsulfanyl-3-(4-fluoro-3-chloro-phenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.11(4), 5-(2-dimethylaminoethyl)-7-methyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.11(5), 7-aminomethyl-5-methyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.12(1), 7-(2-amino-ethyl)-5-methyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.12(2), 7-dimethylaminomethyl-5-methyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.12(3), 7-dimethylaminomethyl-5-methyl-2-methylsulfanyl-3-(4-fluoro-3-chloro-phenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.12(4), 7-(2-dimethylaminoethyl)-5-methyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.12(5) and their pharmaceutically acceptable salts and/or hydrates,

The object of the present invention is a method of producing esters of the General formula 1.1 the interaction of 3-amino-4-sulfonyl-2H-pyrazoles of General formula 2 with the corresponding β-dicarbonyl compounds of General formula 3 according to the scheme presented below.

in which n, R1, R3, R4and Ri5have the above value.

The object of the present invention is also a method of producing esters of the General formula 1.2, 1.3 interaction of 3-amino-4-sulfonyl-2H-pyrazoles of General formula 2 with the corresponding β-dicarbonyl compounds of General fo the mules 4, followed by separation and purification or separation of the reaction products according to the scheme, below.

in which n, R1, R3, R4and Ri5have the above value.

The object of the present invention is also a method of producing acids of General formula 1, 1.4, 1.5, 1.6 hydrolysis of the corresponding esters of the General formulas 1, 1.1, 1.2, 1.3.

The object of the present invention is also a method for obtaining the amides of General formula 1.7, 1.8, 1.9 interaction of the corresponding acids of General formula 1.4, 1.5, 1.6, or derivatives thereof, with amines of General formula 5,

in which R6and R7have the above value.

The object of the present invention is also a method for obtaining the amides of General formula 1.7 interaction of 3-amino-4-sulfonyl-2H-pyrazoles of General formula 2 with the corresponding β-dicarbonyl compounds of General formula 6,

in which n, R1, R3, R4, Ri5R6and R7have the above value.

The object of the present invention is also a method for obtaining the amides of General formula 1.8, 1.9 interaction of 3-amino-4-sulfonyl-2H-pyrazoles of General formula 2 with the corresponding β-dicarbonyl compounds of General formula 7 with subsequent isolation and purification or separation of the reaction products is about the schema, below.

in which n, R1, R3, R4, Ri5, R6and R7have the above value.

The object of the present invention is also a method of obtaining amines of General formula 1.10, 1.11, 1.12 and their pharmaceutically acceptable salts and/or hydrates serial conversion of the acids of General formula 1.4, 1.5, 1.6 in appropriate arylazide General formula 1.13, 1.14, 1.15 under the action of sodium azide, obtained by thermal decomposition of azides in the isocyanates of General formula 1.16, 1.17, 1.18 and hydrolysis of the latter in the amines of General formula 1.10, 1.11, 1.12, respectively, according to the diagrams below.

in which n, R1, R3, R4and Ri5have the above value.

The object of the present invention is also a method of obtaining amines of General formula 1.10, 1.11, 1.12 reductive alkylation of amines 1.10, 1.11, 1.12, in which R6and R7represent a hydrogen atom, carbonyl compounds of General formula 8,

where R8and R9are not necessarily the same hydrogen atom, optionally substituted C1-C3alkyl, or R8and R9together with the carbon atom to which they are bound, form an optionally substituted 5-C7cycloalkyl or heterocycle, including one heteroatom and 4-6 carbon atoms.

The object of the present invention is also 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formulas 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, 1.11, 1.12 and their pharmaceutically acceptable salts and/or hydrates having the properties of antagonists of serotonin 5-HT6receptors.

Preferred 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines as antagonists of serotonin 5-HT6receptors are amines with 1.10(1) 1.10(17) and their pharmaceutically acceptable salts and/or hydrates.

The object of the present invention is also 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1 and the compound 1.10(1) 1.10(17), 1.11(1) 1.11(5), 1.12(1) 1.12(5) and their pharmaceutically acceptable salts and/or hydrates as a "molecular tools for studying the molecular mechanism of interaction with serotonin 5-HT6the receptors.

The object of the present invention is also 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formulas 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, 1.11, 1.12 and their pharmaceutically acceptable salts and/or hydrates, as the drug began to pharmaceutical compositions and medicines.

More predpochtitel the diversified compounds as medicinal beginning are compound 1.10(1)-1.10(17), 1.11(1)-1.11(5), 1.12(1)-1.12(5) and their pharmaceutically acceptable salts and/or hydrates.

The subject of this invention is also a pharmaceutical composition for treating and preventing conditions and disorders of the Central nervous system of humans and warm-blooded animals containing a pharmaceutically effective amount of a new drug began representing at least one of the compounds of General formulas 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, 1.11. 1.12 and its pharmaceutically acceptable salt and/or hydrate or at least one of the compounds 1.10(1)-1.10(17), 1.11(1)-1.11(5), 1.12(1)-1.12(5) and 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 include traditional farm is septicemia media; 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 with an inert filler and/or solvent medicinal began representing at least one of the compounds of General formulas 1, 1.1, 1.2, 1.3, 1.4, 1.5. 1.6, 1.7, 1.8, 1.9, 1.10, 1.11, 1.12 and its pharmaceutically acceptable salt and/or hydrate or at least one of the compounds of formula 1.10(1) 1.0(17), with 1.11(1) 1.11(5), 1.12(1) 1.12(5) and its pharmaceutically acceptable salt and/or hydrate.

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 amount of a medicinal began representing at least one of the compounds of General formulas 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, 1.11, 1.12 and its pharmaceutically acceptable salt and/or hydrate or at least one of the compounds of formula 1.10(1) 1.10(17), 1.11(1) 1.11(5), 1.12(1) 1.12(5) and 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, comprising pharmaceutically effective amount of a new drug started.

More preferred is a drug in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing, for the prevention and treatment of Bo is esni Alzheimer's disease, Parkinson's disease Hantington, comprising pharmaceutically effective amount of a medicinal began representing at least one antagonist of General formulas 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, 1.11, 1.12 and its pharmaceutically acceptable salt and/or hydrate or at least one antagonist of formula 1.10(1) 1.10(17), 1.11(1) 1.11(5), 1.12(1) 1.12(5) and its pharmaceutically acceptable salt and/or hydrate or pharmaceutical compositions containing the new drug beginning.

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, comprising pharmaceutically effective amount of a medicinal began representing at least one of the compounds of General formulas 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, 1.11, 1.12 and its pharmaceutically acceptable salt and/or hydrate, or at least one of the compounds of formula 1.10(1) 1.10(17), 1.11(1) 1.11(5), 1.12(1) 1.12(5) and its pharmaceutically acceptable salt and/or hydrate or pharmaceutical compositions containing the new drug beginning.

More preferred is the drug (anxiolytic or sedative) for the prevention and treatment of anxiety Rosstroy is in, including pharmaceutically effective amount of a medicinal began representing at least one of the compounds of General formulas 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, 1.11, 1.12 and its pharmaceutically acceptable salt and/or hydrate, or at least one of the compounds of formula 1.10(1) 1.10(17), 1.11(1) 1.11(5), 1.12(1) 1.12(5) and its pharmaceutically acceptable salt and/or hydrate or pharmaceutical compositions containing the new drug beginning.

More preferred is the drug (nootropic) for the prevention and treatment of hyperkinetic disorders, in particular to improve mental abilities, including a pharmaceutically effective amount of a medicinal began representing at least one of the compounds of General formulas 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, 1.11, 1.12 and its pharmaceutically acceptable salt and/or hydrate, or at least one of the compounds of formula 1.10(1) 1.10(17), 1.11(1) 1.11(5), 1.12(1) 1.12(5) and its pharmaceutically priemlemuyu salt and/or hydrate or pharmaceutical compositions containing the new drug beginning.

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, including the pharmacist in the český effective amount of drug to the beginning, representing at least one of the compounds of General formulas 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, 1.11, 1.12 and its pharmaceutically acceptable salt and/or hydrate, or at least one of the compounds of formula 1.10(1) 1.10(17), 1.11(1) 1.11(5), 1.12(1) 1.12(5) and its pharmaceutically acceptable salt and/or hydrate, or pharmaceutical compositions containing the new drug beginning.

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, comprising a drug in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing, comprising a pharmaceutically effective amount of a medicinal began representing at least one of the compounds of General formulas 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, 1.11, 1.12 and its pharmaceutically acceptable salt and/or hydrate, or at least one of the compounds of formula 1.10(1) 1.10(17), 1.11(1) 1.11(5), 1.12(1) 1.12(5) and its pharmaceutically acceptable salt and/or hydrate or pharmaceutical compositions containing the new drug beginning.

The subject of this invention is also a therapeutic cocktail for the prevention and treatment of neurological disorders, neurodegenerative and Kohn the tive diseases in animals and people 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, comprising pharmaceutically effective amount of a medicinal began representing at least one antagonist of General formulas 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, 1.11, 1.12 and its pharmaceutically acceptable salt and/or hydrate, or, at least one antagonist of formula 1.10(1) 1.10(17), 1.11(1) 1.11(5), 1.12(1) 1.12(5) and its pharmaceutically acceptable salt and/or hydrate or pharmaceutical composition containing the beginning of a new medication or a new medication, comprising pharmaceutically effective amount of a medicinal began representing at least one antagonist of General formulas 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, 1.11, 1.12 and its pharmaceutically acceptable salt and/or hydrate, or at least one antagonist of formula 1.10(1) 1.10(17), 1.11(1) 1.11(5), 1.12(1) 1.12(5) and its pharmaceutically acceptable salt and/or hydrate or pharmaceutical compositions containing the new drug beginning.

Therapeutic cocktails for the prevention and treatment of neurological disorders, neurodegenerative the x and cognitive diseases in animals and people including for the prevention 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 M1 receptors (for example, Cevimeline); chelators of metals (for example, Clioquinol); antagonists of GABA(C) receptors (e.g., CGP-36742); monoclonal antibodies (e.g., Bapineuzumab); antioxidants; neurotrophic agents (e.g., Cerebrolysin); antidepressant (for example, Imipramine, Sertraline, etc.) and others.

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), hormones (for example. The thyroidin), gipolipidemicheskie tools, such as fibrates (such as Fenofibrate), statins (such as Lovastatin, Simvastatin, pravastatin and probucol), as well as hypoglycemic agents (sulfonylureas such as Butamid, Glibenclamide; biguanides - for example, Buformin, Metmorfin) and drugs with a different mechanism of action, such as antagonists of cannabinoid CB-1 receptor (Rimonabant), inhibitors of reuptake of norepinephrine and serotonin (Sibutramine), inhibitors of enzymes of fatty acid synthesis (Orlistat) and others, along with antioxidants, food additives, etc.

In accordance with this invention a method of prevention and treatment of various diseases, pathogenesis of which is associated with 5-HT6receptors in animals and humans, is the introduction of pharmaceutically effective amounts of new medicinal beginning pharmaceutically effective amount of new pharmaceutical composition, pharmaceutically effective amounts of new medicines is whether pharmaceutically effective amount of a new therapeutic cocktail.

Drugs can be administered orally or parenterally (e.g. intravenously, subcutaneously, intraperitoneally or topically). The clinical dosage of the active agent, the pharmaceutical compositions or drugs patients may be adjusted depending on therapeutic efficacy and bioavailability of the active ingredients in the body, the speed of their metabolism and excretion from the body, and depending on age, gender and stage of disease of the patient, the daily dose in adults is usually 10~500 mg, preferably 50~300 mg. Therefore, during the preparation of pharmaceutical compositions of the present invention in the form of dosage units it is necessary to consider the above-mentioned effective dosages, each unit dosage of the drug should contain 10~500 mg, 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 following examples illustrate but do not limit the invention.

Example 1. A common method of obtaining 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1.1, 1.2, 1.3, and 1.7, 1.8 and 1.9. Mix 0.005 mol aminopyrazole 2 and 0.0055 mol of the corresponding dicar analnogo connection 3, 4, 6, or 7 in 5 ml of acetic acid or other suitable solvent for 4-12 hours. The precipitation is filtered, washed with methanol and water. If necessary, the product is subjected to recrystallization from a suitable solvent, or chromatographic purification, or chromatographic separation. Table 2 presents some examples of new 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1.1, 1.2, 1.3, and 1.7, 1.8 and 1.9 and LC-MS analysis and NMR spectra.

Example 2. A common method of obtaining 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1.4, 1.5 and 1.6. To 2.0 mmol of the ester of General formula 1.1, 1.2 or 1.3 in 50 ml of ethanol is added a solution of 4.0 mmol (263 mg) of 85% KOH in 20 ml of water and stirred the mixture at room temperature for 6-18 hours Completeness of reaction control method LC MS. From the reaction mass is distilled ethanol in vacuo, the residue diluted with water to a volume of 200 ml. of the resulting solution is acidified with hydrochloric acid to pH 4-5. The resulting white precipitate is filtered off, washed with water and dried in air. Table 2 presents some examples of new 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1.4, 1.5 and 1.6 and LC-MS analysis and NMR spectra.

Example 3. A common method of obtaining 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]feast is Malinov General formula 1,7, 1.8 and 1.9. To a solution of 0,902 mmol of the acid of General formula 1.4, 1.5, 1.6 in 5 ml of dimethylformamide add 259 mg carbodiimide (0,992 mmol). The reaction mass is stirred at a temperature of 75°C for 1 hour, add 0,992 mmol amine of General formula 5 and incubated over night at a temperature of 75°C. the Completeness of the reaction control method LC MS. After completion of the reaction the reaction mass is poured into 5% sodium carbonate solution. The product is extracted with dichloromethane. The extract is dried with anhydrous sodium sulfate, evaporated in vacuum. Get amides of the General formula of 1.7, 1.8 and 1.9, which without additional purification is used to produce salts. Table 2 presents some examples of new 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1.7, 1.8 and 1.9 and LC-MS analysis and NMR spectra.

Example 4. A common method of obtaining 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1.10, 1.11, 1.12.

A. To a mixture of 1.0 mmol of the appropriate acid of General formula 1.4, 1.5, 1.6 in 10 ml of acetone are added dropwise successively a solution of 139 μl (101 mg, 1.18 mmol) of triethylamine in 1 ml of acetone and the solution 109 μl (123 mg, 1,29 mmol) ethoxycarbonylphenyl in 1 ml of acetone. The resulting mixture was stirred at 0°C for 30 min, then added dropwise a solution of 109 mg (1.53 mmol) of sodium azide in 0.35 ml of water and stirred at 0°C for the of hours. The resulting reaction mass is then poured into 30 ml of ice water. The product is extracted with cooled to 0°C. dichloromethane, the solvent evaporated in vacuo to a volume of 2-3 ml at room temperature. The resulting solution acylated General formula 1.13, 1.14, 1.15 diluted with dioxane to a volume of 5 ml. of This solution is added dropwise in 20 ml of boiling dioxane. After adding azide reaction mass is boiled for 1 hour. The resulting solution of the isocyanate of General formula 1.16, 1.17, 1.18 cooled to 70°C, add 5 ml of 20% aqueous hydrochloric acid solution, stirred at a temperature of 80°C for 3 h to complete the hydrolysis of the isocyanate (control method LC-MS). The product of General formula 1.10, 1.11, 1.12 falls hydrochloride after cooling the reaction mass.

B. To a solution of 1 mmol of the corresponding amine of General formula 1.10, 1.11, 1.12, in which R6and R7represent a hydrogen atom, in 10 ml of dichloroethane added 3 mmol of carbonyl compounds of General formula 8 and 2.5 mmol of triacetoxyborohydride sodium. The mixture is stirred for 3 h at room temperature. Control reactions carried out by LC MS. To bring the reaction to the end add another 3 mmol of carbonyl compounds of General formula 8 and 2.5 mmol of triacetoxyborohydride sodium and stirred for 12 hours the Mixture is diluted with water and extracted with dichloromethane, washed with 10% solution of potash, the tub sodium sulfate and privault General formula 1.10, 1.11, 1.12 allocate the method of column chromatography on silica gel (system hexane:ethyl acetate:triethylamine = 30:10:1). The hydrochloride is obtained by adding an excess of HCl in dioxane to a solution of amine in acetone, if necessary, planted ether.

Table 2 presents some examples of new 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1.10, 1.11, 1.12, and their salts and LC-MS analysis and NMR spectra.

Table 2
Antagonists of serotonin 5-HT6receptor - 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1
No.FormulaMol. weightLCMS m/z (M+1)An NMR spectrum
1.1(1)406.51407
1.1(2)447.58448
1.1(3) 433.55434
1.1(4)461.61462

1.1(5)433.55434
1.2(1)374.443751H NMR (CDCl3, 400 MHz) δ 8,29 (m, 2H). 7,47-EUR 7.57 (m, 4H), 4,07 (s, 3H), 2,82 (d, J=0.4 Hz, 3H), of 2.66 (s, 3H).
1.3(1)374.443751H NMR (CDCl3, 400 MHz) δ 8,01 (m, 2H), EUR 7.57-to 7.67 (m, 4H), of 3.97 (s, 3H), of 2.66 (s, 3H), of 2.56 (s, 3H).
1.4(1)378.45379
1.4(2) 388.45389
1.5(1)333.35334

1.6(1)333.35334
1.7(1)·HCl526.12490
1.7(2)·HCl524.11488
1.8(1)·HCl484.04448
1.9(1)·HCl484.04448
1.10(1) 348.45349

1.10(2)·HCl398.943631H NMR (DMSO-D6, 400 MHz) δ 8,15 (s, 3H), 8,02 (m, 2H). of 7.60 (m, 3H), 4,23 (s, 2H),. 2,82 (s, 3H), of 2.72 (s, 3H), 2,60 (s, 3H).
1.10(2)·CH3SO3H458.59363
1.10(3)·HCl412.96377
1.10(4)·HCl426.99391
1.10(5)·HCl433.38397

1.10(6)·HCl416.93/td> 381
1.10(7)·HCl451.37415
1.10(8)·HCl447.41411
1.10(9)·HCl430.95395
1.10(10)·HCl426.99391

1.10(11)·HCl461.43425
1.10(12)·HCl444.98409
1.10(13)·HCl 479.43443
1.10(14)·HCl441.02405
1.10(15)·HCl475.46440

1.10(16)·HCl459.01423
1.10(17)·HCl493.45457
1.10(18)·HCl441.02405
1.11(1)·HCl394.91349
1.11(2)·HCl 398.94363

1.11(3)·HCl412.96377
1.11(4)·HCl465.40429
1.11(5)·HCl426.99391
1.12(1)·HCl394.91349
1.12(2)·HCl398.94363
1.12(3)·HCl412.96377

1.12(4)·HCl 465.40429
1.12(5)·HCl426.99391

Example 5. Determination of antagonistic activity of the compounds of General formula 1 towards 5-HT6the receptors. Substances 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.

It is established that the percentage of inhibition of the serotonin 5-HT6receptors in terms of functional assay 1 µm compounds of General formula 1, as a rule, varies 95-107%, and their activity to a serotonin 5-HT6cocktail recipes. who am in terms of functional assay ranges from IC 50=5 nM to IC50=500 nM.

Example 6. 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 1.10(2)·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 7. Obtaining medicines in capsule form. Thoroughly mix the compound 1.10(2)·HCl with lactose powder in a 2:1 ratio. The obtained powder mixture is Packed 300 mg in gelatin capsules of suitable size.

Example 8. Obtaining medicines in the form of injectable compositions for intramuscular, intraperitoneal or subcutaneous injection. Mix 500 mg of the compound 1.10(2)·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 9. Anti-amnestic activity (nootropic action) compounds of General formula 1.

9.1. Improve memory, disturbed by scopolamine.

9.1.1. Nootropic effect of compounds of General formula 1 in the test Passive avoidance 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 experiment used 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 the hole, which was closed automatic 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, for example, the compound 1.10(2)·HCl at doses of 0.2 mg/kg the Animals of control group received an injection of saline. In each group, 8 animals were used.

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 chamber and the number of visits in a dark chamber. The follow-up period was 5 minutes.

Animals of the control group, receiving what their punishment in a dark compartment, demonstrated 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 showed that in the passive avoidance test, the compounds of General formula 1, including a connection 1.10(2)·HCl had the ability to reduce amnesia (to improve memory)caused by scopolamine.

9.1.2. 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 a 4-dead-end chambers (numbered 1, 2, 3, 4), connected to each other via a fifth Central chamber. The mouse was placed in the Central chamber and allowed to explore the maze. The floor was cleaned after each animal. The order of visits cameras and time the visits were recorded by an observer. The test was ended when they were 13 entries in the stubs. 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 averted 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. The results imply that the compounds of General formula 1, for example, the compound 1.10(2)·HCl, warn Nara is giving memory caused by scopolamine.

9.2. Improve memory, impaired MK-801.

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

The experiment was carried out as described in example 9.1.1. On the first day experience for 30 minutes before training, animals were injected intraperitoneally MK-801 (0.1 mg/kg), causing amnesia. The pretreatment with MK-801 significantly reduces the effect of learning, that is, causes anterograde amnesia. Parallel independent groups of mice to study intraperitoneally injected MK-801 in combination with the investigational compounds of General formula 1, for example, the compound 1.10(2)·HCl.

The results indicate the ability of the compound 1.10(2)·HCl to exert a neuroprotective effect.

Example 10. Anxiolytic activity of the 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. None of the animals was not to familiar with this experimental setup. Each experimental group consisted of 8 animals.

The method used was previously described by Lister, R.G. The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology, 1987; 92:180-185). Plexiglas installation consisted of the two open sleeves size 30×5 cm and two closed sleeves size 30×5×15 cm Side 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 was made of black Plexiglas. The device was mounted on the metal base, which was located above the floor level to a height of 38.5 see

Each mouse was placed in the centre of the maze head to the open sleeve. For 5 minutes to register 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. Expected preference index as the ratio of time spent by the animal in the open arms and the number of entries into the open sleeve, to the total time spent in open and closed sleeves or, respectively, to the total number of visits in the sleeves of both types. 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 with notriptyline 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, the compound 1.10(2)·HCl 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 action, which was expressed in the form of a General reduction in exploratory activity (number of visits sleeves during the test).

The results showed that compounds of General formula 1, including a connection 1.10(2)·HCl, exhibit a pronounced anxiolytic activity in the test elevated cross maze, comparable with the standards (Buspirone and Lorazepam),

Example 11. Antipsychotic activity of the compounds of General formula 1 in the test "Prepulse inhibition of startle in mice". In the experiments used mice of SHK weighing 24-30, Experiments were performed in light of the daily cycle of animals. Apomorphine hydrochloride, and haloperidol were obtained from Sigma chemicals, USA. Apomorphine hydrochloride was dissolved in 0.1% ascorbic acid solution prepared in sterilized water, and was administered subcutaneously 15 minutes before the test. Haloperidol was dissolved in sterilized water using an emulsifier tween 80 and administered intraperitoneally 60 minutes before the test. Compounds of General Faure the uly 1 was dissolved in sterilized water and were injected subcutaneously at a dose of 1 mg/kg for 60 minutes before the test. The amount of fluid was 10 ml/kg Control animals were injected with 0.1% ascorbic acid solution prepared in sterilized water with Tween 80.

The apparatus consisted of a camera and made of transparent Plexiglas (producer - company Columbus 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 the experts who the cops on animal models of psychoto-like States, caused a decrease prepulse inhibition of startle that reflects the reduced ability of the CNS to filter sensory stimuli.

The results of the experiment show that haloperidol (1 mg/kg) and studied compounds of General formula 1, including a connection 1.10(2)·HCl (1 mg/kg), warned violation prepulse inhibition of startle, when the apomorfina.

Example 12. The antidepressant activity of the compounds of General formula 1.

12.1. The behavior of mice in the test "Forced the Porsolt swim". In the Porsolt test and others (1977, 1978) as a model study of the antidepressant activity was proposed expression of despair in behavior. That is, the behavior of the mouse or rat in the indoor pool from which the animal cannot escape, characterizes the degree of despair, which can be reduced by taking antidepressants.

In the experiment we used male mice of Balb/C mice weighing 20-30 g of the Animals at 15 min was placed in the tank (height 300 mm, the diameter of 480 mm)filled with 70% water at 25°C. After 3-5 min the activity of swimming began to decline and rotate the phases of movement and stillness. The animal was considered to be stationary if it did not move for 1.5 seconds. Data from the last 5 min was used for analysis. In the test used for automated recognition of motion using video and program Any-maze.

The results of the experiment showed that the compounds of General formula 1, for example, the compound 1.10(2)·HCl, administered intraperitoneally at a dose of 0.5 mg/kg for 4 days, reduce the degree of despair, i.e. exhibit antidepressant activity.

12.2. 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 mice after fruitless attempts to escape, 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 on a tripod above the horizontal surface approximately at the height of 40 cm and within 3 minutes was recorded the total duration of the episodes of complete immobility. The animal was considered to be stationary if it didn't do any movements within 1.5 seconds. In the test used for automated recognition of motion using video and program Any-maze. The studied compounds of General formula 1 was administered intraperitoneally at a dose of 0.5 mg/kg for 4 days. Comparators (fluoxetine, desipramine) enter and intraperitoneally 15 minutes before the start of the test.

In this test the compounds of General formula 1, including a connection 1.10(2)·HCl, exhibit antidepressant activity comparable to drugs comparison of Fluoxetine and Desipramine.

1. Substituted 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1 and their pharmaceutically acceptable salts and/or hydrates

where R1and R3independently from each other are not necessarily the same C1-C3alkyl, and R2represents a group -(CH2)nX, or
R1and R3independently from each other represent different substituents selected from C1-C3the alkyl or the group -(CH2)nX, and R2represents a hydrogen atom or a C1-C3alkyl;
R4represents a C1-C3alkyl;
Ri5represents a hydrogen atom, one or two identical or different halogen atom, a C1-C3alkyl;
i represents the number 0, 1 or 2;
n represents the number 0, 1, 2 or 3;
X represents carboxyl CO2H, C1-C3allyloxycarbonyl, aminocarbonyl CONR6R7or amino group NR6R7; excluding the compounds in which R3represents a group -(CH2)nX, where X represents the amino group NR6R7 and n is 0;
R6and R7are not necessarily the same hydrogen atom, optionally substituted C1-C5alkyl, or R6and R7together with the nitrogen atom to which they are bound, form an optionally substituted 6-membered azaheterocyclic containing 1-2 nitrogen atom in the cycle where the Deputy is selected from C1-C3the alkyl.

2. Compounds according to claim 1, which represents the esters of General formula 1.1, 1.2 and 1.3 and their pharmaceutically acceptable salts and/or hydrates

where n and Ri5have the above value.

3. Compounds according to claim 1, which represents an acid of General formula 1.4, 1.5 and 1.6 and their pharmaceutically acceptable salts and/or hydrates

where n and Ri5have the above value.

4. Compounds according to claim 1, which represents the amides of General formula 1.7, 1.8 and 1.9 and their pharmaceutically acceptable salts and/or hydrates

where n, Ri5, R6and R7have the above value.

5. Compounds according to claim 1, which represents the amines of General formula 1.10, 1.11 and 1.12 and their pharmaceutically acceptable salts and/or igrati

where n, Ri5, R6and R7have the above value.

6. Compounds according to claim 5, representing 6-amino-5,7-dimethyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.10(1), 6-aminomethyl-5,7-dimethyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.10(2), 6-(2-amino-ethyl)-5,7-dimethyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.10(3), 6-(3-aminopropyl)-5,7-dimethyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.10(4), 6-aminomethyl-5,7-dimethyl-2-methylsulfanyl-3-(3-chlorophenylsulfonyl)-pyrazolo[1,5-a] pyrimidine 1.10(5), 6-aminomethyl-5,7-dimethyl-2-methylsulfanyl-3-(3-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.10(6), 6-aminomethyl-5,7-dimethyl-2-methylsulfanyl-3-(4-fluoro-3-chlorophenylsulfonyl)-pyrazolo[1,5-a] pyrimidine 1.10(7), 6-(2-amino-ethyl)-5,7-dimethyl-2-methylsulfanyl-3-(3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.10(8), 6-(2-amino-ethyl)-5,7-dimethyl-2-methylsulfanyl-3-(3-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.10(9), 5,7-dimethyl-6-dimethylaminomethyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.10(10), 5,7-dimethyl-6-dimethylaminomethyl-2-methylsulfanyl-3-(3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.10(11), 5,7-dimethyl-6-dimethylaminomethyl-2-methylsulfanyl-3-(3-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.10(12), 5,7-di is ethyl-6-dimethylaminomethyl-2-methylsulfanyl-3-(4-fluoro-3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.10(13), 5,7-dimethyl-6-(2-dimethylamino-ethyl)-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.10(14), 5,7-dimethyl-6-(2-dimethylamino-ethyl)-2-methylsulfanyl-3-(3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.10(15), 5,7-dimethyl-6-(2-dimethylamino-ethyl)-2-methylsulfanyl-3-(3-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.10(16), 5,7-dimethyl-6-(2-dimethylamino-ethyl)-2-methylsulfanyl-3-(4-fluoro-3-chlorophenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.10(17), 5-aminomethyl-7-methyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine hydrochloride 1.11(1), 5-(2-amino-ethyl)-7-methyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine hydrochloride 1.11(2), 5-dimethylaminomethyl-7-methyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine hydrochloride 1.11(3), 5-dimethylaminomethyl-7-methyl-2-methylsulfanyl-3-(4-fluoro-3-chloro-phenylsulfonyl)-pyrazolo[1,5-a]pyrimidine hydrochloride 1.11(4), 5-(2-dimethylaminoethyl)-7-methyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine hydrochloride 1.11(5), 7-aminomethyl-5-methyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine hydrochloride 1.12(1), 7-(2-amino-ethyl)-5-methyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine hydrochloride 1.12(2), 7-dimethylaminomethyl-5-methyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine hydrochloride 1.12(3), 7-dimethylaminomethyl-5-methyl-2-methylsulfanyl-3-(4-fluoro-3-chloro-phenylsulfonyl)-pyrazolo[1,5-a]pyrimidine Hydra is chloride 1.12(4), 7-(2-dimethylaminoethyl)-5-methyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine hydrochloride 1.12(5), their pharmaceutically acceptable salts, if they are not specified above, and/or hydrates,






7. The method of producing esters of the General formula 1.1 according to claim 2 interaction 3-amino-4-sulfonyl-2H-pyrazoles of General formula 2 with the corresponding β-dicarbonyl compounds of General formula 3

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

8. The method of producing esters of the General formula 1.2, 1.3 on p. the interaction of 3-amino-4-sulfonyl-2H-pyrazoles of General formula 2 with the corresponding β-dicarbonyl compounds of General formula 4, followed by separation and purification or separation of the reaction products

where n, R1, R3, R4and Ri5have the above value.

9. The method of obtaining the acids of General formula 1.4, 1.5, 1.6 according to claim 3 by hydrolysis of the corresponding esters of the General formula 1.1, 1.2, 1.3.

10. The method of obtaining the amides of General formula 1.7, 1.8, 1.9 according to claim 4 interaction of the corresponding acids of General formula 1.4, 1.5, 1.6, or derivatives thereof, with amines of General formula 5

where R6and R7have the above value.

11. The method of obtaining the amides of General formula 1.7 according to claim 4 interaction of 3-amino-4-sulfonyl-2H-pyrazoles of General formula 2 with the corresponding β-dicarbonyl compounds of General formula 6

where n, R1, R3, R4, Ri5, R6and R7have the above value.

12. The method of obtaining the amides of General formula 1.8, 1.9 according to claim 4 interaction of 3-amino-4-sulfonyl-2H-pyrazoles of General formula 2 with the corresponding β-dicarbonyl compounds of General formula 7 with subsequent isolation and purification or separation of the reaction products

where n, R1, R3, R4, Ri5, R6and R7have the above value.

13. The method of obtaining amines of General formula 1.10, 1.11, 1.12 on either the from pp.5 and 6 serial conversion of the acids of General formula 1.4, 1.5, 1.6 in appropriate arylazide General formula 1.13, 1.14, 1.15 under the action of sodium azide, obtained by thermal decomposition of azides to the corresponding isocyanates of General formula 1.16, 1.17, 1.18 and hydrolysis of the latter in the amines of General formula 1.10, 1.11, 1.12, respectively


where n, R1, R3, R4and Ri5have the above value.

14. The method of obtaining amines of General formula 1.10, 1.11, 1.12 on any of pp.5 and 6 reductive alkylation of amines 1.10, 1.11, 1.12, in which R6and R7represent a hydrogen atom, carbonyl compounds of General formula 8

where R8and R9are not necessarily the same hydrogen atom, optionally substituted C1-C3alkyl.

15. Substituted 2-alkylamino-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines according to any one of claims 1 to 6, having the properties of antagonists of serotonin 5-HT6receptors.

16. Connection 15 for studying the molecular mechanism of interaction with serotonin 5-HT6the receptors.

17. Connection 15 as the drug began to obtain pharmaceutical compositions and dosage is rest.

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

19. A method of obtaining a pharmaceutical composition according p mixture with an inert filler and/or solvent medicinal beginning on 17.

20. 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 17 or pharmaceutical composition according p.

21. Drug in claim 20, for the prevention and treatment of cognitive disorders and neurodegenerative diseases.

22. Drug in claim 20, for the prevention and treatment of mental disorders.

23. Drug in claim 20, having anxiolytic action for the prevention and treatment of anxiety disorders.

24. Drug in claim 20, having a nootropic action to improve mental abilities.

25. Method of prevention and treatment of diseases of the heart is through the nervous system, the pathogenesis of which is associated with 5-HT6receptors, which consists in introducing an effective amount of the drug beginning at 17, or the pharmaceutical composition according p, or drugs on any of PP-24.



 

Same patents:

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

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: medicine.

SUBSTANCE: invention refers to medicine, particularly to gastroenterology, and concerns a reducing diet therapy. A patient takes a saline laxative and stops food intake. Stating from first day of fast, 1.5-2 l of purified water is introduced daily in equal portions, with administering at the end of the day a cleansing enema of 1.5-2 l of purified water with colloidal silver added at 10 drops per 1 l. Psychotherapeutic discussion, walks for 30-40 minutes 2-3 times a day and Nishi gymnastics are practiced. Starting from the second day of fast, for 16 days, daily at 7:30 the patient takes 1/3 teaspoons of a vegetative organic sorbent dissolved in a glass of water with another glass of water taken in half an hour thereafter. At 9:30 and 18:30, an herbal antihelmintic drug is administered; 9:40 and 18:40, 1 capsule of an herbal preparation "Catrel" is taken. At 10:00 and every night at bedtime, colloidal silver is taken in amount 1 teaspoon, held in a mouth for 6 minutes, then swallowed and also instilled 1 drop in each eye and 1 drop in nose. During a day, herbal tea "Pohudey-ka", "Cleansing", and every night at bedtime, 2 tablets of "Senade" are prescribed. On 3rd, 6th, 10th, 13th, 16th days of fast, every night at bedtime, liver and gall bladder flush is performed. The course involves 3-5 procedures of hydrocolonotherapy. The first days of the recovery period, the patient consumes fresh juices, vegetables, fruits, bacterial preparation "Bacteriobalance", with a vegetarian salt-free diet for a month. Starting from the third day, vitamin-mineral and microelement complexes containing organic calcium, selenium, iodine, polyunsaturated fat acids, and essential amino acids are prescribed.

EFFECT: method provides effective complex normalisation of digestive organs activity and thereby health improvement.

4 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention refers to novel compounds with affinity to MC4 receptors, of the general formula (I): , where A is -CH2- or -C(O)-; R1 is (C1-C8)alkyl; R2 is (C1-C8)alkyl; R3 is radical of the formula -(CH2)s-R'3; R'3 is 5-6-member heterocycloalkyl containing one or two nitrogen atoms and possibly one oxygen atom possibly substituted with (C1-C6)alkyl or benzyl; or radical of the formula -NW3W'3; W3 is hydrogen atom or (C1-C8)alkyl; W'3 is radical of the formula -(CH2)s'-Z3; Z3 is hydrogen atom, (C1-C8)alkyl; s and s' are independently an integer within 0 to 6; B is 5-6-member monocyclic unsaturated, aromatic or non-aromatic radical which can be condensed with 5-6-member unsaturated, aromatic or non-aromatic radical forming bicyclic condensed system, and B is possibly containing one or more equal or different heteroatoms selected out of O, S and N, and possibly substituted with one or more equal or different radicals selected out of halogen atom, nitro group, cyano group, oxy group, -XB-YB and phenyl possibly substituted with one substitute selected out of halogen atom and (C1-C6)alkyl; XB is a covalent bond, -O-, -S-, -C(O)-, -C(O)-O-; YB is (C1-C6)alkyl; or pharmaceutically acceptable salt of claimed compounds.

EFFECT: improved obtainment and application efficiency of compounds for production of drug for treatment of diseases related to MC4 receptor activation.

20 cl, 4 dwg, 2 tbl, 81 ex

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 refers to compounds of the formula (I) and pharmaceutically acceptable salts, where R1-R7 mean the same as provided in the invention description and claim. Compounds of the formula (I) are specific inhibitors of 11b-HSD1. They can be applied in treatment and/or prevention of diseases caused by dysfunctions related to 11b-HSD1 enzyme, particularly in treatment and/or prevention of metabolic diseases, obesity, dyslipidemia, hypertension and/or diabetes, especially diabetes type "П". Additionally subject matter includes pharmaceutical composition for treatment and/or prevention of the said diseases.

EFFECT: improved efficiency of derivatives.

21 cl, 1 tbl, 146 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to cyclic derivatives of aminobenzoic acid and to their pharmaceutically acceptable salts of general formula , in which ring Ar is a phenyl group, a 5-member aromatic heterocyclic group containing 1-2 heteroatoms selected from nitrogen, sulphur and oxygen, or a benzothiazolyl group; where the said groups can have 1-2 substitutes selected from a group comprising lower alkyl; a phenyl group; a phenyl group substituted with 1-2 halogens; a phenyl group substituted with a lower alkoxy group; a phenyl group substituted with a halogen-substituted lower alkyl group; a phenoxy group substituted with a halogen; a halogen; Z is an oxygen atom or -(CH2)-n (where n equals 0, 1 or 2); Y is C1-C4 alkylene, C2-C4 alkenylene or general formula (2) -T-A-U- (2) in which T is a single bond, C1-C4 alkylene or C2-C4 alkenylene; U is single bond, C1-C4 alkylene; values of the rest of radicals are given in the formula of invention.

EFFECT: obtaining a PPARα, agonist which contains an active ingredient in form of at least one cyclic derivative of aminobenzoic acid, and an agent which reduces the level of lipids which contains an active ingredient in form of at least one cyclic derivative of aminobenzoic acid.

12 cl, 16 tbl, 184 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I , where R1 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl and lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl, which can be substituted with a halogen; R2 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl or lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl which can be substituted with a halogen; or R1 and R2 together with the nitrogen atom to which they are bonded form a 4-, 5- or 6-member saturated or partially unsaturated heterocyclic ring which optionally contains the same heteroatom selected from oxygen or sulphur, where the said saturated or partially heterocyclic ring is unsubstituted or substituted with one or two groups independently selected from a group consisting of lower alkyl, halogen, halogenalkyl, cyano group, hydroxy group, lower hydroxyalkyl, lower alkoxy group, oxo group; A is selected from , and , where m equals 0 or 1; R3 is a lower alkyl; n equals 0; R4 is a lower alkyl; p equals 1; q equals 0, 1 or 2; R5 is hydrogen; and their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition based on formula I compounds.

EFFECT: new quinoline derivatives are obtained, which have antagonistic effect on histamine 3 receptors (H3 receptors).

18 cl, 4 tbl, 86 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel dibenzosuberone derivatives of formula , where R1 and R2 each independently represent hydrogen or halogen. These compounds are used for treating and/or preventing diseases related to CB1 receptor modulation. The invention also relates to a pharmaceutical composition based on these compounds.

EFFECT: obtaining novel dibenzosuberone derivatives.

5 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula , in which: Ra and Ra' denote hydrogen, R1 denotes cycloalkyl; R2 denotes a group of formula -(CH2)x-(CO)y-Y or -(CO)y-(CH2)x-Y, in which x=0, y=1, Y denotes -N-R11R12;- R11 and R12 denote alkyl; R3 denotes a halogen atom; R5 denotes a hydrogen atom; R4 is selected from: (1) a group of formula : in which each of the rings in formulae (a) and (b) can be substituted in any position with 1-4 R7 groups which are identical or different from each other, and in which: a=0; p=0, 1, 2 or 3; m=1; X is an oxygen or sulphur atom or a C(R6)(R7)- or -N(R10)- group; R6 is selected from: a hydrogen atom; a -(CH2)x-NR8R9 group in which x=0, aryl, alkylaryl; R7 is selected from hydrogen atoms; aryl, alkylaryl groups; -OR group; -NRR' groups; R8 and R9 are selected from a hydrogen atom; R10 is selected from: hydrogen atom; aryl, alkylaryl; R and R' denote a hydrogen atom; (2) a group of formula -A-R18, -A-CH=N-R19, in which A denotes a straight or branched alkyl; R18 denotes a halogen atom or a -NH2 group; R19 denotes hydroxyl; (3) a group of formula : in which r equals 1; s equals 1, and one of U, V and W denotes a nitrogen atom while the others denote a methylene group; or (4) -(CH2)r-heteroaryl, where r equals 1; where the heteroaryl denotes a 5-6-member aromatic group containing 1-2 heteroatoms such as nitrogen, oxygen, in form of a base or additive acid salt. The invention also relates to a method for synthesis of formula (I) compounds, to compounds of formulae (IV) and (V), to a medicinal agent, to a pharmaceutical composition, as well as to use of formula (I) compounds.

EFFECT: obtaining new biologically active compounds having melanocortin receptor agonist activity.

11 cl, 28 ex, 1 tbl

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 a method of treating one or more drug dependences, nicotine addiction and/or obesity, involving administration of an effective amount of the compound, sufficient for lowering production and/or secretion of dopamine, where the said compound has general formula: and its pharmaceutically acceptable salts, where R1 is hydrogen or methyl when R2 is Cy; R2 is hydrogen or methyl when R1 is Cy; and where Cy is a group which is optionally substituted with -R, -OR, -NR2 or a halogen, where each R is independently optionally substituted with a lower alkyl, aryl or heteroaryl. The invention also relates to methods of treating one or more drug dependences, nicotine addiction or obesity.

EFFECT: novel methods of treating addictions.

5 cl, 14 ex

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

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