Substituted 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidine-2,6-diamines, serotonin 5-ht6 receptor antagonists, methods of producing and using said compounds

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidine-2,6-diamines of general formula 1, their pharmaceutically acceptable salts and/or hydrates which have serotonin 5-HT6 receptor antagonist properties and can be used in treating or preventing development of various central nervous system diseases, whose pathogenesis is associated with 5-HT6 receptors, particularly Alzheimer's disease, Parkinson's disease, Huntington disease, schizophrenia, other neurodegenerative diseases, cognitive and anxiety disorders and obesity. In general formula (I): R1, R2 and R4, which are optionally identical, independently denote C1-C3 alkyl; R3 and R4, which are optionally identical, denote: a hydrogen atom, optionally substituted C1-C3 alkyl or acetyl; R5 denotes a hydrogen atom or halogen atom.

EFFECT: high treatment efficiency.

13 cl, 12 dwg, 4 tbl, 12 ex

 

This invention relates to new substituted 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidine-2,6-diamines, 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), the pathogenesis of which is associated with 5-HT6the receptors. 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, neurodegenerative diseases, cognitive and anxiety 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 is, mainly in areas of the brain responsible for learning and memory [Ge'rard C., Martres, M.-P., Lefe'vre K., Miquel, M.-C., Verge' D., Lanfumey L., Doucet e, Hamon M., El Mestikawy S. Immune-localisation of serotonin 5-HT6receptor-like material in the rat central nervous system. Brain Research. 1997; 746:207-219]. In addition, it is shown [Dawson L.A., Nguyen H.Q., Li P. The 5-HT(6) receptor antagonist SB-271046 selectively enhances excitatory neurotransmission in the rat frontal cortex and hippocampus. Neuropsychopharmacology.. 2001; 25: 662-668]that 5-HT6the receptors are modulators of several neurotransmitter systems, including the cholinergic, noradrenergicheskoy, glutamatergic and dopaminergic. Given the fundamental role of these systems in normal cognitive processes, and their dysfunction in neurodegeneration, it is obvious exceptional role of 5-HT6receptors in the formation of normal or pathological memory. In a large number of modern studies have shown that blocking the 5-HT6receptors are a large number of modern studies have shown that blocking the 5-HT6receptors leads to a significant increase in memory consolidation in various animal models of learning-memory-playback [Foley A.G., Murphy K.J., Hirst W.D., H.C. Gallagher, J.J. Hagan, Upton N., F.S. Walsh, C.M. Regan The 5-HT(6) receptor antagonist SB-271046 reverses scopolamine-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-HT6 receptor 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; 46:1273-1276. King M.V., M.L. Woolley, Topham LA., Sleight A.J., 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 are in various stages of clinical trials as drug candidates for the treatment of the bronchial asthma, diseases of Hantington, schizophrenia (antipsychotics) and others who aeroderivative and cognitive diseases (table 1) [http://integrity.prous.com].

Table 1
Antagonists of 5-HT6receptors as drug candidates.
MedicationClinical phase I trialsDeveloperTherapeutic group
Dimebon™Phase IIIMedivation (USA)Treatment of Alzheimer's disease
SGS-518Phase IILilly, SaegisTreatment of cognitive diseases
SB-742457Phase IIGlaxoSmithKlineTreatment of Alzheimer's disease; Antipsychotic
Dimebon*Phase I/IIaMedivation (USA)Treatment of Hantington
Dimebon*Phase II(Russia)Schizophrenia
PRX-07034Phase IEpix Pharm.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
Dimebon™Preclinica(Russia)Treatment of stroke

Another attractive property of antagonists of 5-HT6receptors is their ability to suppress the appetite, which can accommodates the STI to the creation on their basis of fundamentally new means to reduce overweight and obesity [Vicker S.P., 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 the increase in the emission of alpha melanocytestimulating 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 diseases of the Central nervous system, including neurological and neurodegenerative diseases and cognitive disorders.

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

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

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

To develop new highly effective medications the authors of the present invention made extensive studies in a series of substituted 2-alkylamino-3-sulfonyl-pyrazolo[1,5-a]pyrimidines, resulting in a new found drug began representing antagonists of 5-HT6receptors.

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

"Agonist" refers to a ligand that binds with the receptors of this type, actively promote the transfer of these receptors to their inherent 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 mo is et to have one or more "cyclic system substituents".

"Alkyl" means an aliphatic hydrocarbon of linear or branched group with 1-12 carbon atoms in the chain. Branched means that the alkyl chain has one or more "lower alkyl" substituents. The alkyl may have one or more identical or different substituents ("alkyl substituents including halogen, alkenylacyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkyloxy, Alcoxy, aryloxy, aryloxyalkyl, alkylthio, heteroaromatic, Uralkali, arylsulfonyl, alkylsulfonyl, heteroarylboronic, annelirovannymi heteroarylboronic, annelirovannymi heteroalicyclic, annelirovannymi heterooligomerization, annelirovannymi heteroalicyclic, annelirovannymi arylchloroalkanes, annelirovannymi aristically, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic, alkoxycarbonyl, arelaxation, heteroarylboronic or RkaRk+1aN-, RkaRk+1aNC(=O)-, RkaRk+1aNC(=S)-, RkaRk+1andNSO2-, where Rkaand Rk+1aindependently from each other represent "amino substituents", which is defined in this section, for example, a hydrogen atom, alkyl, ar is l, 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, isopropyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, benzyloxycarbonylation and pyridinedicarboxylate. Preferred "alkyl substituents" are cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, alkoxycarbonyl, Alcoxy, aryloxy, alkylthio, heteroaromatic, Uralkali, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, arelaxation, heteroarylboronic or RkaRk+1andN-, RkaRk+1aNC(=O)-, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic.

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

"Alkyloxy" means CnH2n+1O - group is where alkyl is defined in this section.

The preferred acyloxy groups are metiloksi, ethyloxy, n-propyloxy, isopropoxy and n-Butylochka.

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

"Amino group" means RkaRk+1aN - group, a substituted or unsubstituted not necessarily the same substituents of the amino group" Rkaand Rk+1awhose value is defined in this section, for example, amino (H2N-), methylamino, diethylamino, pyrrolidino, morpholino, benzylamino or phenethylamine.

"Aminocarbonyl" means C(=O)N RkaRk+1agroup, substituted or unsubstituted not necessarily the same substituents carbamaepine" Rkaand Rk+1aincluding hydrogen, alkenyl, alkyl, aryl, heteroaryl, heterocyclyl, the value of which is determined in this section.

"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" about the means drug, designed to treat 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 bromine.

"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 also means the depot is assignee state, accompanying 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 values of which are defined in this section.

"Deputy amino group" means the Deputy attached to the amino group. Deputy amino group represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, acyl, aroyl, alkylsulfonyl, arylsulfonyl, heteroarylboronic, alkylaminocarbonyl, allumination, heteroarylboronic, heterocyclization, alkylaminocarbonyl, allumination, heteroarylboronic, heterocyclization, annelirovannymi heteroarylboronic, anneliesa the hydrated heteroalicyclic, annelirovannymi heterooligomerization, annelirovannymi heteroalicyclic, annelirovannymi arylchloroalkanes, annelirovannymi aristically, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic, alkoxycarbonylmethyl, arakaki-carbonylethyl, heteroarylboronic.

"Deputy carbamoyl" means the Deputy attached to aminocarbonyl group, the value of which is defined in this section. Deputy carbamoyl represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonyl, alcoxycarboxylates, heteroarylboronic or RkaRk+1aN-, RkaRk+1aNC(=O)-alkyl, annelirovannymi heteroarylboronic, annelirovannymi heteroalicyclic, annelirovannymi heterooligomerization, annelirovannymi heteroalicyclic, annelirovannymi arylchloroalkanes, annelirovannymi aristically, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic. Preferred substituents carbamaepine" are alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonyl, alcoxycarboxylates, heteroarylboronic or RkaRk+1aN-, RkaRk+1aNC(=O)-alkyl, and melirovanie arylheteroacetic, annelirovannymi arylheteroacetic.

"Deputy cyclic system" means the Deputy attached to aromatic or non-aromatic cyclic system, including hydrogen, alkyl, alkenyl, 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-oxyalkyl, alkylsulfonyl, arylsulfonyl, heterocyclization, alkylsulfonyl, arylsulfonyl, heterocyclization, alkylthio, aaltio, heterocyclic, alkylsulfonates, arylsulfonyl, geterotsiklicheskikh, alkylsulfonates arylsulfonyl, geterotsiklicheskikh, alkylthiomethyl, alltoall, geterotsiklicheskikh, arylalkylamines, geterotsiklicheskie, arylalkylamines, geterotsiklicheskikh, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclyl, amidino, RkaRk+1aN-, RkaN=, RkaRk+1aN-alkyl-, RkaRk+1aNC(=O)- or RkaRk+1aSO2where Rkaand Rk+1arepresent independently of each other "Vice-amino group", the value which is defined in this section, for example, hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroalkyl, or the substituent RkaRk+1aN-, in which Rkacan be acyl or aroyl, and a value of Rk+1adefined above, or "Deputy cyclic system are RkaRk+1aNC(=O)- or Rkak+1aNSO2in 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 disease and Hantington; senile dementia; age-related memory disorders (age-associated memory his or her, AAMI); dysmetabolic encephalopathy; psychogenic disturbances of memory; amnesia; amnestic RA the disorder; transient global amnesia; dissociative amnesia; vascular dementia; light (or moderate) cognitive impairment (mild cognitive his or her, MCI); syndrome of disturbance of attention with hyperactivity (attention deficit hyperactivity disorder, AD/HD); cognitive impairment accompanying psychotic diseases, epilepsy, delirium, autism, psychosis, down syndrome, bipolar disorder and depression; AIDS-associated dementia; dementia with hypothyroidism; dementia induced by alcohol, substances, addictive, and neurotoxins; dementia accompanying neurodegenerative diseases, 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, use the second for the production and manufacture of the medicinal product (drug).

"The drug (the drug), a substance (or mixture of substances in the form of pharmaceutical compositions in the form of tablets, capsules, injections, ointments and other ready-made forms, designed to restore, correct or modify physiological functions in humans and animals, as well as for treatment and prevention of diseases, diagnostics, anesthesia, contraception, cosmetology and others.

"Ligands" (from the Latin ligo - link) is a chemical (small molecule, an inorganic ion, a peptide, a protein, 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; Lachance is alopecia (illness vanishing white matter); chronic neurodegenerative disease; stroke; ischemic and reperfusion of hypoxic brain damage; epilepsy; cerebral ischemia; glaucoma; traumatic brain injury; down syndrome; encephalomyelitis; meningitis; encephalitis; neuroblastoma; schizophrenia; depression. In addition, neurodegenerative diseases include pathological conditions and disorders developing during hypoxia, substance abuse, addictive, when exposed to neurotoxins, infectious and oncological diseases of the brain and neuronal damage associated with autoimmune and endocrine diseases; and other neurodegenerative processes.

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

"Psychotic illness" is all kinds of schizophrenia; schizophrenia-like psychosis disease; shizotimichesky disorders; schizoaffective disorders, including bipolar and 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 the m mechanism of pharmacological action and aimed at different biological target, involved in the pathogenesis of the disease.

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

"Cycloalkyl" means not aromatic mono - or polycyclic system containing from 3 to 10 carbon atoms. Cycloalkyl may have one or more "cyclic system substituents"which may be the same or different. Representatives cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalin, norbornyl, adamant-1-yl, etc. cloaker can be annylirovan with aromatic cycle or a heterocycle. Preferred "what zamestitelyami cyclic systems" are alkyl, arakaki, hydroxy, or RkaRk+1aN, the value of which is determined in this section.

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

"Pharmaceutical composition" means a composition comprising a compound of formula 1 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 way desig the treatment and dosage. Examples suspendida agents are ethoxylated isostearoyl alcohol, polyoxyethylene, sorbitol and sorbitol ester, microcrystalline cellulose, Metagalaxy aluminum, bentonite, agar-agar and tragakant, as well as mixtures of these substances. Protection from the action of microorganisms can be ensured by various antibacterial and antifungal agents such as parabens, chlorobutanol, sorbic acid and similar compounds. The composition may also include isotonic agents such as sugars, sodium chloride and the like. Prolonged action of the composition can be achieved with agents that slow the absorption of the active principle, for example, aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents and delivery vehicles include water, ethanol, polyalcohol, and 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 glycol with high is Kim 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 beginning can be introduced animals and people in the standard form of introduction in the form of a mixture 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 from the eyes of the military free base of the claimed compounds and a suitable organic or inorganic acid. Examples of the thus obtained salts are hydrochloride, hydrobromide, sulphates, bisulfate, phosphates, nitrates, acetates, oxalates, valeriote, oleates, palmitate, stearates, laurate, borate, benzoate, lactates, tozilaty, citrates, maleate, fumarate, succinate, tartratami, mesylates, malonate, salicylates, propionate, econsultancy, bansilalpet, sulfamate and the like. (For a detailed description of the properties of such salts are described in Berge S.M., et al., "Pharmaceutical Salts" J. Pharm. Sci. 1977, 66: 1-19). Salts of the stated acids can also be specially obtained by the reaction of purified acid with a suitable base, can be synthesized metal salts and amines. The metal include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum, the most desirable of which are sodium and potassium salts. Suitable inorganic bases which can be obtained metal salts are the hydroxide, carbonate, bicarbonate and sodium hydride, hydroxide and bicarbonate of potassium, potash, 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 must possess low toxicity). Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, Tris(hydroxymethyl)aminomethane and the like. In addition, for the salt formation can be used tetraalkylammonium hydroxide, such as choline, Tetramethylammonium, tetraethylammonium and the like. As amino acids can be used basic amino acids such as lysine, ornithine and arginine.

The object of the present invention are new substituted 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidine-2,b-diamines of General formula 1 and their pharmaceutically acceptable salts and/or hydrates

where

R1, R2and R4independently from each other are not necessarily the same C1-C3alkyl;

R3and R4are not necessarily the same hydrogen atom, optionally substituted C1-C3alkyl or acetyl;

R5represents a hydrogen atom, or halogen atom.

Preferred substituted 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidine-2,6-diamine of General formula 1 is 5,7,N(2)-trimethyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine-2,6-diamines of General formula 1.1

where

R3and R4have in sukasana value.

More preferred 5,7,N(2)-trimethyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine-2,6-diamine of General formula 1.1 is 5,7N(2)-trimethyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine-2,6-diamine 1.1.1 and 5.7,N(2),N(6)N(6)-pentamethyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine-2,6-diamine 1.1.2.

3-Arylsulfonyl-pyrazolo[1,5-a]pyrimidine-2,6-diamine of General formula 1 are as in the diagram below. When the diketone 3 Raand Rbdifferent alkali, there is a mixture of two N - (3-arylsulfonyl-2-alkylamino)pyrazolo[1,5-a]pyrimidine-6-yl)acetamido 1A, 1B (R3= N, R4= A; Raand Rb= C1-C3alkyl), which is shared by chromatography.

The object of the present invention are antagonists of serotonin 5-HT6receptors represents a substituted 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidine-2,6-diamines of the General formulas 1, 1.1, 1.1.1, 1.1.2 and their pharmaceutically acceptable salts and/or hydrates.

The preferred antagonist of serotonin 5-HT6receptor is 5,7,N(2)-trimethyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine-2,6-diamine 1.1.1 and 5.7,N(2),N(6)N(6)-pentamethyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine-2,6-diamine 1.1.2.

The purpose of the present invention is to create a new "molecular the x tools for studying the interaction of serotonin 5-HT 6the receptors.

This goal is achieved by antagonists of serotonin 5-HT6receptors represents a substituted 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidine-2,6-diamines of the General formulas 1, 1.1, 1.1.1, 1.1.2 and their pharmaceutically acceptable salts and/or hydrates.

The subject of this invention are also substituted 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidine-2,6-diamines of the General formulas 1, 1.1, 1.1.1, 1.1.2 and their pharmaceutically acceptable salts and/or hydrates as the drug began to pharmaceutical compositions and medicines.

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, 1.1.1, 1.1.2 or its pharmaceutically acceptable salt and/or hydrate.

The pharmaceutical composition may include pharmaceutically acceptable excipients. Under the pharmaceutically acceptable excipients are meant to be applied in the field of pharmaceutical diluents, auxiliary agents and/or carriers. The pharmaceutical composition along with the drug early in the present invention may include dragaction ingredients provided what they do not cause unwanted effects, such as allergic reactions.

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

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

The subject of this invention is also a method of obtaining the OIC pharmaceutical composition by mixing with an inert filler and/or solvent medicinal beginning representing at least one of the compounds of General formula 1,1 .1, 1.1.1, 1.1.2 or 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 in warm-blooded animals and humans, representing at least one of the compounds of General formulas 1, 1.1, 1.1.1, 1.1.2 or the pharmaceutically priemlemuyu salt, or a pharmaceutical composition containing the new drug beginning.

More preferred is a drug in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing for the prevention and treatment of cognitive disorders and neurodegenerative diseases, comprising pharmaceutically effective amount of lekarstvenno start representing at least one of the compounds of General formulas 1, 1.1, 1.1.1, 1.1.2 or its pharmaceutically acceptable salt and/or hydrate or pharmaceutical composition containing the new drug beginning.

More preferred is a drug in the form of tablets, capsules, or injections, placed in pharmaceutically reception of the controls package for the prevention and treatment of Alzheimer's disease, Parkinson's disease, diseases of Hantington, comprising pharmaceutically effective amount of a new drug began representing at least one of the compounds of General formulas 1, 1.1, 1.1.1, 1.1.2 or its pharmaceutically acceptable salt and/or hydrate or pharmaceutical composition 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, 1.1.1, 1.1.2 or its pharmaceutically acceptable salt and/or hydrate or pharmaceutical composition containing the new drug beginning.

More preferred is the drug (anxiolytic or sedative) for the prevention and treatment of anxiety disorders, including pharmaceutically effective amount of a medicinal began representing at least one of the compounds of General formulas 1, 1.1, 1.1.1, 1.1.2 or its pharmaceutically acceptable salt and/or hydrate or pharmaceutical composition comprising the TV medicinal 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, 1.1.1, 1.1.2 or its pharmaceutically acceptable salt and/or hydrate or pharmaceutical composition 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, comprising pharmaceutically effective amount of a medicinal began representing at least one of the compounds of General formulas 1, 1.1, 1.1.1, 1.1.2 or its pharmaceutically acceptable salt and/or hydrate or pharmaceutical composition 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, including pharmaceutical the effective amount of drug to the beginning, representing at least one of the compounds of General formulas 1, 1.1, 1.1.1, 1.1.2 or its pharmaceutically acceptable salt and/or hydrate or pharmaceutical composition 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 cognitive diseases in animals and humans, including for the prevention and treatment of Alzheimer's disease, Parkinson's disease, diseases of Hantington, mental disorders and schizophrenia, hypoxia-ischemia, hypoglycemia, convulsive States, brain injuries, lathyrism, amyotrophic lateral sclerosis, obesity and stroke, comprising pharmaceutically effective amount of a medicinal began representing at least one of the compounds of General formulas 1, 1.1, 1.1.1, 1.1.2 or its pharmaceutically acceptable salt and/or hydrate or pharmaceutical composition containing the new drug beginning.

Therapeutic cocktails for the prevention and treatment of neurological disorders, neurodegenerative and cognitive diseases in animals and humans, including for the prevention and treatment of Alzheimer's disease, Parkinson's disease, diseases of Hantington, mental disorders and schizophrenia, hypoxia-ischemia, hypoglycemia, the ship is, the author States, brain injuries, lathyrism, amyotrophic lateral sclerosis, obesity and stroke along with drugs in 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 SV-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(B) receptors (e.g., CGP-36742); monoclonal antibodies (e.g., Bapineuzumab); antioxidants; neurotrophic agents (e.g., Cerebrolysin); antidepressants (eg, Imipramine, Sertraline, etc.) and others.

Therapeutic cocktail for reducing overweight and obesity along with drugs this out is to retenu includes other medicines, such as anorexicskin drugs (for example, Farnon, Dezaemon, Mazindol), hormones (for example, Thyroidin), gipolipidemicheskie tools, such as fibrates (such as Fenofibrate), statins (such as Lovastatin, Simvastatin, pravastatin and probucol), as well as hypoglycemic agents (sulfonylureas 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 synthesis fatty acids (Orlistat) and along with other antioxidants, food additives, etc.

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

Drugs can be administered orally or parenterally (e.g. intravenously, subcutaneously, intraperitoneally or topically). The clinical dosage of the beginning of the (substance), pharmaceutical composition or medicament which military means, including pharmaceutically effective amount of a medicinal beginning, 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 invention is illustrated by drawings.

Figure 1. The latent period 1st time in the dark compartment within 24 hours after training, rats avoid the dark compartment in the Shuttle chamber (average ± standard error). The number in parentheses is the quantity of the substance in mg/kg of the Studied substance 1.1.1 introduced inside 60 minutes prior experience. Unlike groups that received scopolamine: * - p<0,05; ** - p<0,01; *** p<0,001.

Figure 2 Length of stay in the bright compartment 24 cha is and after training rats to avoid the dark compartment in the Shuttle chamber (average ± standard error). The number in parentheses is the quantity of the substance in mg/kg of the Studied substance 1.1.1 introduced inside 60 minutes prior experience. Unlike groups that received scopolamine: * - p<0,05; ** - p<0,01;*** p<0,001.

Figure 3. The number of visits in the dark compartment within 24 hours after training, rats avoid the dark compartment in the Shuttle chamber (average ± standard error). The number in parentheses is the quantity of the substance in mg/kg of the Studied substance 1.1.1 introduced inside 60 minutes prior experience. Unlike groups that received scopolamine: * - p<0,05; *** p<0,001.

Figure 4. The test results on the recognition of new objects in mice (mean ± standard error). Values in parentheses doses of substances in mg/kg of the Studied substance 1.1.1 introduced inside 60 minutes before the test. Unlike groups, which were introduced only scopolamine: * - p<0,05 in accordance with the criterion χ2.

Figure 5. The latent period 1st time in the dark compartment within 24 hours after training, rats avoid the dark compartment in the Shuttle chamber (average ± standard error). The number in parentheses is the quantity of the substance in mg/kg of the Studied substance 1.1.1 introduced inside 60 minutes prior experience. Unlike groups that received MK-801: * - p<0,05; ** - p<0,01; *** p<0,001.

6. Duration of stay in the bright compartment within 24 hours after training, rats avoid the dark compartment in the Shuttle chamber (average ± standard error). Num is in parentheses - the dose of the substance in mg/kg of the Studied substance 1.1.1 introduced inside 60 minutes prior experience. Unlike groups that received MK-801: * - p<0,05; ** - p<0,01;*** p<0,001.

7. The number of visits in the dark compartment within 24 hours after training, rats avoid

dark compartment in the Shuttle chamber (average ± standard error). The number in parentheses is the quantity of the substance in mg/kg of the Studied substance 1.1.1 introduced inside 60 minutes prior experience. Unlike groups that received MK-801: * - p<0,05; *** p<0,001.

Fig. The ratio of time spent by animals in open sleeves, to the total time spent in open and closed arms (mean ± standard error). In parentheses are doses of substances 1.1.1 (mg/kg). Contrast to the group receiving placebo: * p<0,05; ** - p<0,01; *** p<0,001.

Fig.9. The ratio of the number of inputs into the open sleeve of the total number of inputs in the sleeves of both types (mean ± standard error). In parentheses are doses of substances 1.1.1 (mg/kg). Contrast to the group receiving placebo: * p<0,05; ** - p <0,01; *** p<0,001.

Figure 10. The number of defecations in the test "maze-plus (mean ± standard error). In parentheses are doses of substances 1.1.1 (mg/kg). Contrast to the group receiving placebo: * p<0,05; ** - p<0,01; *** p<0,001.

11. The test results prepulse inhibition of startle in mice.

Fig. The results of the test verification of appetite in rats.

Presents lower the examples do not limit the invention.

Example 1. A common way to obtain N-(3-arylsulfonyl-2-alkylamino)pyrazolo[1,5-a]pyrimidine-6-yl)acetamido General formula 1 (R3=N, R4=AC). Stirred at 100°C. for 3 hours 0,637 mol. diketone 3 and 0,606 mol of 4-(arylsulfonyl)-1H-pyrazole-3,5-diamine 2 in 650 ml of Asón. After cooling the reaction mass of precipitated white crystalline precipitate is filtered off, washed with acetic acid and ether and dried in air. Obtain compounds of General formula 1(R3=N, R4=AC) with the release of 80-85%.

Example 2. General method for the preparation of 3-arylsulfonyl-N(2)-alkylpyrazoles[1,5-a]pyrimidine-2,6-diamines of General formula 1 (R3=R4=N). To a suspension of 0.29 g of N-(3-arylsulfonyl-methylamino)pyrazolo[1,5-a]pyrimidine-6-yl)ndimethylacetamide 1.1 (R3=N, R4=Ac) in 1350 ml of a mixture of Meon: N2About (3:1) add 135 g of KOH. The reaction mass is boiled with stirring for 72 hours. After completion of the reaction (monitoring by LC-MS) the precipitate is filtered off and then washed with water. Obtain compounds of General formula 1 (R3=R4=N) with the release of 92-95%.

Example 3. General method for the preparation of 3-arylsulfonyl-N(2),N(6)N(6)-trialkyl-pyrazolo[1,5-d]pyrimidine-2,6-diamines of General formula 1 (R3=R4=CH3). To a suspension of 0.25 mol. 3-arylsulfonyl-N(2)-methylpyrazolo[1,5-a]pyrimidine-2,6-diamines 1.1 (R3=R4=N) 3750 ml of ethyl alcohol add 67 g of sulfuric acid in 230 ml of the odes (3M solution). The resulting suspension is heated to 90°C, and then andadult to room temperature, poured 116,5 g of a 35%solution of formalin. After 30 minutes with vigorous stirring gradually sprinkled in small portions 56 g NaBH4so that the solution temperature remained below 25°C (optionally cooled water bath). After completion of the reaction (monitoring by LC-MS) the precipitate is filtered off and thoroughly washed with water. Alcoholic liquor evaporated in vacuo, and the resulting precipitate well washed with water. The total yield of product 1 (R3=R4=CH3) is 95-97%.

Table 2 presents some examples of the new 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidine-2,6-diamino General formula 1 and LCMS analyses and NMR spectra.

Table 2
Antagonists of serotonin 5-HT6receptor - 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidine-2,6-diamines of General formula 1.
No.FormulaMol. weightLCMS m/z (M+1)An NMR spectrum
1.1.1331.4 3321H NMR (DMSO-D6, 400 MHz) δ 7,98 (d, J=8,4 Hz, 2H), 7,51-to 7.59 (m, 3H), 4,59 (W), 2,89 (s, 2H), by 2.55 (s, 3H), 2,47 (s, 3H).
1.1(1)373.443741H NMR (DMSO-D6, 400 MHz) δ to 9.66 (s, 1H), 8,02 (d, J=6,8 Hz, 2H), 7,56 (m, 3H), 6,39 (kV, J=4,8 Hz, 1H), 2,92 (d, J=4,8 Hz, 3H), of 2.45 (s, 3H), 2,39 (s, 3H), of 2.08 (s, 3H).
1.1(2)365.8366
1.1(3)349.4350
1.1(4)349.4350
1.1(5)345.4346
1.1.2359.4360 1H NMR (DMSO-D6, 400 MHz) δ 8,02 (m, 2H), 7,53-to 7.61 (m, 3H), 6,29 (W, 1H), 2.91 in (s, 3H), 2,74 (C, 6N), to 2.57 (s, 3H).2,49 (s, 3H).

Example 4. Determination of antagonistic activity of the compounds of General formula 1 towards 5-HT6the receptors. Compounds of General formula 1 were tested for their ability to inhibit the activation of 5-HT6the serotonin receptors. Used SOME cells 293 (kidney cells human embryo) with artificially downregulation of the receptor 5-HT6the activation of which is serotonin increases the concentration of intracellular camp. The content of intracellular camp was determined using the reagent kit LANCE cAMP (PerkinElmer)according to the method described by the manufacturer [http://las.perkinelmer.com/content/Manuals/MAN_LANCEcAMP384K.itUser.pdf]. The effectiveness of the compounds were evaluated for their ability to reduce the amount of intracellular camp induced by serotonin. Table 3 presents the antagonistic activity of the compounds of General formula 1 to the serotonin 5-HT6the receptors in terms of functional assay confirming their moderate or high activity.

Table 3.
Antagonistic activity of the compounds of General formula 1 to the serotonin 5-HT6Retz is proram in terms of functional assay.
No. antagonistIC50, nM
1.1.14.3
1.1(1)36.5
1.1.22.3

Example 5. Determination of the activity of the compounds of General formula 1 in a competitive binding to serotonin 5-HT6the receptors. For the screening of substances for their potential ability to interact with serotonin receptor 5-HT6used the method of radioligand binding. This was prepared membrane preparations from HeLa cells expressing recombinant human 5-HT6receptor, by homogenization of recombinant cells in a glass homogenizer followed by the separation of plasmatic membranes from nuclei, mitochondria and cellular debris by differential centrifugation. The binding definition of the studied compounds with 5-HT6the receptor was performed in accordance with the methodology described in [Monsma FJ Jr, Shen Y, Ward RP, Hamblin MW and Sibley DR, Cloning and expression of a novel serotonin receptor with high affinity for tricyclic psychotropic drugs. Mol Pharmacol. 43:320-327, 1993]. In a preferred execution of the membrane preparations were incubated with labeled ligand (1.5 nM [3H] Lysergic acid diethylamide) without and in the presence of ASCS is duemig connections for 120 minutes at 37°C in an environment consisting of 50 mM Tris-HCl, pH 7.4, 150 TM Nad, 2 TM Ascorbic Acid, 0.001% BSA. The samples after incubation were filtered under vacuum on steklofibrobetonnykh filters G/F (Millipor, USA), the filters are washed three times with cold solution environment and radioactivity was measured using a MicroBeta scintillation counter 340 (PerkinElmer, USA). Nonspecific binding, which was 30% of the total binding was determined by incubation of membrane preparations with radioligand in the presence of 5 cm Serotonin (5-HT). As a positive control was used Methiothepin. Binding of test compounds to the receptor was determined by their ability to displace the radioactive ligand and was expressed as a percentage of displacement. The percentage of displacement was determined by the following formula:

,

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

Table 4 presents the test results of the compounds of General formula 1, demonstrating their high activity against serotonin 5-HT6the receptors.

Table 4
The activity is of dinani General formula 1 in relation to the serotonin 5-HT 6receptors in a competitive assay.
No. antagonistKi, nMIC50, nM
I.I.I0.310.67
1.1.20.310.67

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 compounds 1.1.1 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 connection 1.1.1 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 connection 1.1.1 with 300 mg of chlorobutanol, 2 ml of propylene glycol and 100 ml of injectable water. The resulting solution is filtered and placed in 1 ml ampoules which are sealed.

Example 9. Antiamnestic the activity of the compounds of General formula 1 (nootropic effect).

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 connection 1.1.1, 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 is again p who was memali in the light compartment of the Shuttle camera and recorded the latent period of the first entry into the dark chamber, 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, received the 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 presented in figure 1, 2, 3, showed that in the passive avoidance test compounds of General formula 1, including a connection 1.1.1, possessed 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 (pronume avannah 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 of 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 decreased. However, this influence of scopolamine adaval the camping prevent intraperitoneal introduction of Dimebon (0.1 mg/kg) for 5 minutes prior to training, tacrine (10 mg/kg) 30 min before training and compounds of General formula 1 in doses of 0.05 mg/kg and 0.2 mg/kg for 60 minutes prior to training.

From the obtained results, presented in figure 4, it follows that the connection 1.1.1 prevents memory impairment 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 10.1.1. 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.

The experimental results are presented on figure 5, 6 and 7 show that the connection 1.1.1 introduced intraperitoneally prior training in doses of 0.2 mg/kg and 1 mg/kg, has the ability to reduce the amnesia caused by MK-801.

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 giveth contained in the cells (5-7 mice n the cell), 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 apparatus consisted of two open sleeves size 30×5 cm and two closed sleeves size 30×5×15 cm Lateral sleeves were closed transparent plexiglass and connected with the Central area the size of 5×5 cm Open sleeve, the Central platform and the floor 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

Animals were injected intraperitoneally with placebo, buspirone (5 mg/kg 30 minutes before training), lorazepam (0.05 mg/kg for 60 minutes before training) or one of the compounds of General formula 1, for example, the connection 1.1.1, 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).

Each mouse was placed in the centre of the maze head to the open sleeve. For 5 minutes recorded the sequence and duration for the systems in sleeves with the help of computer programs. 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 open chambers, 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 characterizing a state of anxiety.

The test results presented on Fig, 9 and 10 showed that the compounds of General formula 1, including a connection 1.1.1 as standards (buspirone and lorazepam), had a pronounced anxiolytic effects in the test elevated cross maze.

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 dexperimental conducted 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 introduced vnutri uchino 60 minutes before the test. Compounds of General formula 1 was dissolved in sterilized water and were injected subcutaneously 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 vzdragivanie is in response to an isolated pulse stimulus. The introduction of apomorphine, which is used in animal experiments to simulate psychotropically States, caused a decrease prepulse inhibition of startle that reflects the reduced ability of the CNS to filter sensory stimuli. The results of the experiment presented figure 11, show that haloperidol (1 mg/kg) and studied compounds of General formula 1, including a connection 1.1.1 (1 mg/kg), warned violation prepulse braking wince when the apomorfina.

Example 12. Test check of appetite.

Male Wistar rats weighing 230-360 g, were placed in the standard of living cells, where they had free access to food and water except for short periods of food deprivation (16 hours) directly before the test meal. Test appetite spent in individual cells with the top cover of the wire, in a niche in which was placed a portion of the food granules. The weight of the granules was determined every 30 minutes for 3 hours. On the basis of these measurements was estimated food consumption, which is expressed in grams of feed per kilogram of body weight. Placebo and connection 1.1.1. (at a dose of 10 mg/kg) was administered intraperitoneally 60 minutes before the test. Each group contained 10 rats. The substance was dissolved in sterile water. The amount of fluid was 10 ml/kg as a control group is the objects of study were intact animals, not subjected to food deprivation, and animals after food deprivation, which was introduced sterilized water. The results of the experiment presented on Fig show that the studied compounds of General formula 1, including a connection 1.1.1 (10 mg/kg), warned the increased appetite in rats.

1. Substituted 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidine-2,6-diamines of General formula 1 and their pharmaceutically acceptable salts and/or hydrates

where R1, R2and R4not necessarily the same independently of one another represent C1-C3alkyl;
R3and R4not necessarily identical, represent: a hydrogen atom, optionally substituted C1-C3alkyl or acetyl;
R5represents a hydrogen atom or a halogen atom.

2. Compounds according to claim 1, which represents 5,7,N(2)-trimethyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine-2,6-diamines of General formula 1.1

where R3and R4have the above value.

3. Compounds according to any one of claims 1 and 2, representing 5,7,N(2)-trimethyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine-2,6-diamine 1.1.1 and 5.7,N(2),N(6)N(6)-pentamethyl-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine-2,6-diamine 1.1.2.

4. Tool, representing particularly the substituted 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidine-2,6-diamines according to any one of claims 1 to 3, having the properties of antagonists of serotonin 5-HT6receptors.

5. The tool represents a substituted 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidine-2,6-diamines according to any one of claims 1 to 3, for studying the molecular mechanism of interaction with serotonin 5-HT6the receptors.

6. The tool represents a substituted 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidine-2,6-diamines according to any one of claims 1 to 3, as the drug began to pharmaceutical compositions and medicines.

7. 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 drug to the beginning 6.

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

9. 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 drug to the beginning according to claim 6 or a pharmaceutical composition according to claim 7.

10. Drugs the military vehicle according to claim 9 for the prevention and treatment of cognitive disorders and neurodegenerative diseases.

11. The drug according to claim 9 for the prevention and treatment of mental disorders.

12. The drug according to claim 9, having anxiolytic activity, for the prevention and treatment of anxiety disorders.

13. The drug according to claim 9, having neuroprotective activity to improve mental abilities.

14. The drug according to claim 9 for the prevention and treatment of obesity.

15. Method for the prevention and treatment of diseases of the Central nervous system, the pathogenesis of which is associated with 5-HT6receptors, which consists in introducing an effective amount of the drug beginning according to claim 6, or a pharmaceutical composition according to claim 7, or a medicinal product according to any one of PP-14.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing methyl 7-arylcarbamoyl-6-benzoyl-2-methyl-3-phenylpyrazolo[1,5-a]pyrimidine-5-carboxylates of general formula , where Ar denotes 4-chlorophenyl or 4-methoxyphenyl, which can be used as primary products for synthesis of novel heterocyclic systems in pharmacology. Method involves reaction of methyl 1-aryl-3-benzoyl-4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylates with 3-methyl-4-phenyl-1H-pyrazole-5-amine in the medium of an inert aprotic solvent.

EFFECT: method is easy to implement and enables to obtain said compounds with high output.

2 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: described are novel substituted naphthyridines of general formula E: (radicals R1 and R3 are described in the claim), pharmaceutically acceptable salts thereof, a pharmaceutical composition containing said compounds, and use of the novel compounds to prepare a medicinal agent for treating or preventing malignant tumours in mammals.

EFFECT: compounds inhibit Akt acitivity, in particular, the compounds selectively inhibit one or two isoforms of Akt and can be used in medicine.

5 cl, 14 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds (la) of formula applied as tyrosine kinase c-Met inhibitors. , where: LA is selected from ,

or ; RA is selected from:

or each RA2 and RA6 represents hydrogen; RA3 represents RAr; or RA3, RA4 and carbon atoms whereto attached form 6-members aryl, optionally substituted, in the amount up to 4 by independent groups RAr, or a 5-6-members heterocyclyl or heteroaryl ring containing at least one O, N or S atom; R represents -OH; RA5 represents hydrogen or RAr; LB represents a covalent bond or -N(R*)-; RB represents halogen, NH2 or C1-8aliphatic group, optionally substituted by R; a 6-10-members aryl ring; a 3-7-members carbocyclyl ring, a 5-10-members heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulphur atoms, where each said aryl or heteroaryl ring is optionally substituted, in the amount up to five by independent groups RAr; R represents halogen, -R°, -SR°, Ph, optionally substituted R° or -C(O)OR°; each RAr is independently selected from halogen, -R°, -OR°, -SR°, Ph, optionally substituted in the amount up to five by independent groups -R°, -CN, -N(R°)2 or -C(O)OR°; or two adjacent groups RAr taken together, represent 1,2-methylenedixy or 1,2-ethylenedixy; each R* represents hydrogen; and each R° represents independently hydrogen, an optionally substituted C1-6aliphatic radical or an unsubstituted 5-6-members heteroaryl or heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulphur atoms.

EFFECT: invention refers to pharmaceutically acceptable compositions containing the compounds under the invention, and methods of application of the compositions in treatment of various proliferative disorders.

10 cl, 4 tbl, 548 ex, 9 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: there is described new macrocyclic compound of general formula 1-c:

and its pharmaceutically acceptable acid or base addition salts or its stereoisomers (the radical values are presented in the patent claim).

EFFECT: producing the compounds which are hepatitis type C virus inhibitors and can find application in medicine.

9 cl, 1 tbl, 95 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to condensed heterocyclic derivative, represented by formula (I): where ring A represents 5-member monocyclic heteroaryl, containing 1 or 2 heteroatoms, selected from N or S; RA represents lower alkyl group, optionally substituted with hydroxyl group, COW1, COOW1 or CONW2W3, in which W1-W3 independently represent a hydrogen atom or lower alkyl group; m represents integer 0 or 2; ring B represents benzene ring or thiophene ring; RB represents halogen atom, cyano group, lower alkyl group or OW4, in which W4 represents a hydrogen atom or lower alkyl group; n represents integer 0-2; E1 represents an oxygen atom; E2 represents an oxygen atom; U represents a single bond or lower alkelene group; X represents group, represented by Y, -CO-Y, -SO2-Y, -S-L-Y, -O-L-Y, -CO-L-Y, -SO-L-Y, -SO2-L-Y, -S-Z or -O-Z, in which L represents a lower alkylene group optionally substituted with halogen or hydroxy group; Y represents group, represented by Z or -NW7W8, where W7 and W8 independently represent a hydrogen atom, lower alkyl group or Z on condition that W7 and W8 are not simultaneously hydrogen atoms, or W7 and W8 can bind together with adjacent nitrogen atom with formation of cyclic amino group; Z represents cycloalkyl group, optionally condensed with phenyl and optionally substituted with phenyl group, optionally substituted with halogen or alkoxy group; 6-8-member heterocycoalkyl group, which has 1 heteroatom, selected from nitrogen atom or oxygen atom, optionally condensed with phenyl and optionally substituted with phenyl; phenyl group optionally substituted with a substituent, selected from group, consisting of a halogen atom, cyano group, alkyl group, optionally substituted with halogen atom, hydroxy group or alkoxy group, alkoxy group, optionally substituted with halogen atom, hydroxy group, alkoxy group, alkoxy-carbonyl-oxy group or acyloxy group, alkylthio group, carboxy group and alkoxy-carbonyl group; pyridyl; or its pharmaceutically acceptable salt. Invention also relates to pharmaceutical composition possessing antagonistic activity with respect to gonatotropin-releasing hormone, based on the claimed compound.

EFFECT: obtained are novel compounds and based on them pharmaceutical composition, which can be applied in medicine for prevention or treatment of a disease depending on sex hormones, which is selected from group, consisting of benign prostatic hypertrophy, hysteromyoma, endometriosis, premature puberty, prostate cancer, ovarian cancer and breast cancer.

29 cl, 112 tbl, 428 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel crystalline form of a compound of formula (I), which has P2T antagonist properties and can be used to prevent arterial thrombotic complications in patients suffering from coronary artery disease, cerebrovascular and peripheral vascular diseases. The crystalline form of compound (I) is essentially a pure polymorph II, which is essentially in anhydrous form and which is characterised by X-ray powder diffraction pattern, having characteristic base peaks of high intensity at 5.5°(±0.1°), 13.5°(+0.1°), 18.3°(±0.1°), 22.7°(±0.1°) and 24.3°(±0.1°) 2θ, and has characteristic peaks at 5.5°(±0.1°), 6.8°(±0.1°), 10.6°(±0.1o), 13.5°(±0.1°), 14.9°(±0.1°), 18.3°(±0.1°), 19.2°(±0.1°), 22.7°(+0.1°), 24.3°(±0.1°) and 27.1°(±0.1°) 2θ. The differential scanning calorimetry curve of the said crystalline polymorph has melting onset point in the range of 136-139°C.

EFFECT: invention also relates to a method of producing the disclosed polymorph, according to which a compound of formula (I) is crystallised from chloroform.

9 cl, 6 dwg, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula 2: and to its pharmaceutically acceptable salts and their mixtures, where values of R, M, Q, Z, W, D radicals are described in i.1 of the invention formula. Invention also relates to pharmaceutical compositions, which possess inhibiting activity with respect to Btk, based on formula 2 compounds.

EFFECT: obtained are novel compounds and based on them pharmaceutical compositions which can be applied in medicine for treatment of patients with diseases associated with inhibiting Btk activity and/or B-cell activity.

55 cl, 19 ex

FIELD: chemistry.

SUBSTANCE: in formula I' , R denotes -(C=Q)R2a, CN or Y; Y denotes phenyl, or ; Q denotes O; R2a denotes phenyl, OR5 or N(R5)2; R1 denotes H; Z denotes a bond; R3 and R4 denotes H, halogen, C1-6alkoxy, N(R5)2 or Um-V, where m equals 0 or 1; V denotes H, phenyl, 5-6-member heteroaryl containing up to two nitrogen atoms, 5-6-member heterocyclyl containing up to two heteroatoms selected from N or O, or C1-6aliphatic group; U denotes a C1-6alkylidene chain, where up to two methylene links of the chain may be substituted with -CO2-, -C(O)-, -C(O)NH-, -C(O)NR5; R5 denotes H, C0-6alkykphenyl or C1-6aliphatic group, or two R5 groups, taken together with an atom to which they are bonded are optionally bonded to form a 5-7-member heterocyclic ring containing 1-2 heteroatoms selected from N, O or S; JY is selected from N(R9)2, SR9, OR9, halogen, CN, COOR9, -X-OH, phenyl, -X-phenyl, 5-6-member heteroaryl containing up to two nitrogen atoms, -X-(5-6-member heteroaryl containing up to two nitrogen atoms) or X; X denotes a C1-12aliphatic group; R9 denotes H, C1-6aliphatic group, phenyl, C3-6cycloaliphatic group, 4-6-member heterocyclyl containing up to 2 nitrogen atoms. Invention also relates to a pharmaceutical composition and a method of inhibiting Tec or c-Met kinase activity.

EFFECT: high inhibiting activity towards Tec or c-Met kinase.

16 cl, 11 tbl, 20 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or pharmaceutically acceptable salts, solvates or tautomers thereof, where substitute M is selected from groups D1 and D2, having structural formulae given below, and R1, E, A and X are as described in the formula of invention. Disclosed also are pharmaceutical compositions which contain these compounds, methods for synthesis of these compounds, intermediate compounds and synthesis methods thereof, as well as use of compounds of formula (I) in preventing or treating diseases mediated by CDK kinases, GSK-3 kinases or Aurora kinases.

EFFECT: high effectiveness of the compounds.

40 cl, 8 dwg, 18 tbl, 84 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are new compounds of general formula (I): het-X-AB (I) where het is pentamerous N-heteroaryl, additionally containing one O, S or N atom as a heteroatom with heteroaryl with additional O atom being condensed with a benzene ring, or hexamerous N-heteroaryl; X means S; and where N-atom of N- heteroaryl residue and an X group are separated by one carbon atom; AB means 1,2,3-triazolo[4,5-d] pyrimidine-7-yl radical of general formula (II): where R3 is C1-8alkyl, phenyl, benzyl optionally substituted; R5-H, C1-8alkyl or phenyl.

EFFECT: production of new compounds for preparing a pharmaceutical composition either effective for treating cardiovascular, cancer, autoimmune diseases, stroke, neurodegenerative diseases, cystic fibrosis, or used in antithrombotic therapy.

9 cl, 11 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel crystalline forms D1 and D2 of R-(R*,R*)]-2-(4-fluorophenyl)-β, δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, semi-calcium salt, hydrates thereof, which have high stability.

EFFECT: improved methods of producing novel crystalline forms.

15 cl, 4 dwg, 6 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds - benzoquinone derivatives of formula (I): , where each of R1 and R2 is O-C(O)phenyl; where the phenyl is substituted with 1 substitute selected from halide, nitro, C1-C6 alkyl or C1-C6 alkoxy, and pharmaceutically acceptable salts thereof.

EFFECT: low activity of pancreatic lipase based on compounds of the said formula.

6 cl, 3 tbl, 23 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine, namely to chemical-pharmaceutical industry and deals with composition of alpha-lipoic (thioctic) acid in form of solution for infusions and to method of treating diseases selected from group, which includes alcoholic and/or diabetic polyneuropathy, coronary atherosclerosis, Botkin's disease (mild and moderate severity), liver cirrhosis, poisoning with heavy metal salts and intoxications of various etiology.

EFFECT: pharmaceutic composition possesses improved technologic properties and bioavailability, it also preserves stability in long storage.

3 cl, 1 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention enables synthesis of 3-methoxy-2-fluoro-18ethyl-8α-gona-1,3,5(10)-trienes, having osteoprotector and hypocholesteremic activity.

EFFECT: invention has osteoprotector and hypocholesteremic activity and can be used in medicine for hormonal replacement therapy.

1 cl, 3 ex, 1 tbl, 3 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) or pharmaceutically acceptable salts thereof where R1 and R2 together denote a group selected form groups of formula (III-1): , where R9 denotes 1) a lower alkyl group, optionally substituted with a halogen atom or lower alkoxy group, 2) an aryl group, 3) an aralkyl group, 4) a heteroarylalkyl group, 5) a heteroaryl group, where the aryl, aralkyl, heteroarylalkyl and heteroaryl groups can be substituted with a halogen atom, lower alkyl group, optionally substituted with a lower alkoxy group or 1-3 halogen atoms, lower alkoxy group, optionally substituted with 1-3 halogen atoms, cyano group, hydroxy group, alkylsulphonyl group, cycloalkylsulphonyl group, aryl group, heteroaryl group, alkylaminocarbonyl group, alkanoyl amino group, alkyl amino group or dialkylamino group; R10 denotes a lower alkyl group, optionally substituted with 1-3 halogen atoms, or a lower alkylsulphonyl group; X9-X12 denotes a carbon atom or a nitrogen atom, where the carbon atom can be independently substituted with a lower alkyl group, optionally substituted with a halogen atom or a lower alkoxy group, lower alkoxy group, optionally substituted with a halogen atom, or a cyano group or a halogen atom; R3 denotes a) a group of formula (II-1): (ii-U where R4 and R5, taken together with a nitrogen atom, form a 5- or 6-member monocyclic ring, where the monocyclic ring may contain a substitute in form of a lower alkyl group, m1 equals 3; or b) a group of formula (II-2): , where R6 denotes a lower alkyl group or cycloalkyl group; m2 equals 1 or 2; X1-X4 all denote carbon atoms, or one of X1-X4 denotes a nitrogen atom and the rest denote carbon atoms; and where "heteroaryl" in each case relates to a 5- or 6-member aromatic ring containing 1-3 heteroatoms selected from a nitrogen atom, oxygen atom and a sulphur atom. The invention also relates to a histamine H3 receptor antagonist or inverse agonist, as well as a preventive or medicinal agent.

EFFECT: obtaining novel biologically active compounds, having histamine H3 receptor antagonist or inverse agonist activity.

11 cl, 8 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: compound of formula pharmaceutically acceptable salt or solvate of a compound or salt (I), ring Q represents optionally substituted monocyclic or condensed (C6-C12)aryl or optionally substituted monocyclic or condensed heteroaryl where said substitutes are chosen from: halogen; (C1-C6)alkyl optionally substituted by 1-3 halogen atoms; (C1-C6)alkylsulphonyl; phenyl optionally substituted by 1 or 2 substitutes chosen from halogen, (C1-C6)alkyl which can be substituted by 1-3 halogen atoms, groups (C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl and (C1-C6)alkylthio; monocyclic or condensed heteroaryl optionally substituted by halogen; or oxo; Y1 represents a bond or -NR6-CO-, where R6 represents hydrogen, ring A represents optionally substituted a nonaromatic heterocyclyldiyl where said substitutes are chosen from (C1-C6)alkyl optionally substituted by groups hydroxy, (C1-C6)alkylamino, di(C1-C6)alkylamino, morpholino, (C1-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl; cyano; (C3-C6)cycloalkyl; (C1-C6)alkoxy; (C1-C6)alkoxy(C1-C6)alkyl; phenyl; benzyl; benzyloxymethyl; thienyl; 4-8-members monocyclic nonaromatic heterocycle having 1 or 2 heteroatoms chosen from N or O, and optionally substituted by 1 or 2 substitutes chosen from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl and oxo; (C1-C6)alkylamino; di(C1-C6)alkylamino; a group of formula: -Y2Z'- represents a group of formula: [Formula 2] each R7 independently represents hydrogen, (C1-C6)alkyl or (C3-C6)cycloalkyl, each of R8 and R9 independently represents hydrogen or (C1-C6)alkyl, n is equal to an integer 0 to 3, Z1 represents a bond, -O-, -S- or-NR9 - where R9 represents hydrogen, (C1-C6)alkyl, acyl or (C1-C6)alkylsulphonyl, ring B represents optionally substituted aromatic carbocyclediyl or optionally substituted aromatic heterocyclediyl where said substitutes are chosen from (C1-C6)alkyl, halogen, (C1-C6)alkoxy and oxo; Y3 represents a bond optionally substituted (C1-C6)alkylene or (C3-C6)cycloalylene, optionally interrupted -O- or optionally substituted (C2-C6)alkenylene where said substitutes are chosen from (C1-C6)alkyl, (C3-C6)cycloalkyl, halogen and (C1-C6)alkoxycarbonyl; Z2 represents COOR3; R3 represents hydrogen or (C1-C6)alkyl.

EFFECT: preparation of new compounds.

30 cl, 9 tbl, 944 ex

FIELD: medicine.

SUBSTANCE: invention refers to the compound 3-{[5-(azetidine-1-ylcarbonyl)pyrazine-2-yl] oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazine-5-yl)benzamide or to its pharmaceutically acceptable salt. Also, it refers to a pharmaceutical composition for treating insulin-independent diabetes or obesity containing said compound.

EFFECT: there is produced and described a new compound which can be effective in treating insulin-independent diabetes and obesity.

5 cl, 64 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of isothiazole-3(2H)-OH-1,1-dioxides of formula (I) or pharmaceutically acceptable salts thereof, which can increase expression of LXR α and/or β, a pharmaceutical composition based on said derivatives, use thereof in preparing a medicinal agent, as well as novel intermediate compounds of formula (V) or salts thereof. In formulae (I), (V) R2 denotes phenyl, and R1 and R3 are as described in the claim.

EFFECT: improved properties of the derivatives.

7 cl, 9 dwg, 172 ex

FIELD: medicine.

SUBSTANCE: offered is application of a composition substantially consisting of trans-clomiphene or its pharmaceutically acceptable salt for preparing a drug to be introduced in a male patient in a single dose every 3-30 days for treating hypogonadism, lipodystrophy, benign prostatic hypertrophy or prostate cancer (versions). One of side effect of exogenous testosterone, namely decreased biosynthesis level of follicle-stimulating hormone causing reduced sperm formation is compensated. Contrariwise, the product is applied in treating a disorder associated with male hypogonadism and related disturbances, including reduced muscle bulk, body physical capacity limitation, decreased bone density, decreased libido, decreased potency, reduced benign prostatic hyperplasia and infertility.

EFFECT: product increases persistently total testosterone level to a normal range with no abnormal high peaks.

18 cl, 7 dwg, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of general formula (I-B), where values of radicals are described in formula of invention, or to its pharmaceutically acceptable salts, which possess activity of inhibiting cholesterol ester transfer protein, due to which said compounds or salts can be used for prevention and/or treatment of arteriosclerotic diseases, hyperlipemia or dislipidemia or similar diseases.

EFFECT: obtaining pharmaceutical compositions for prevention and treatment of arteriosclerosis, as well as application of formula I-B compounds for manufacturing of medication.

15 cl, 36 tbl, 252 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I, which are HSP90 (heat-shock proteins) inhibitors and can be used to prepare a medicinal agent for treating tumorous diseases affected by HSP90 inhibition. In formula I R1 denotes Hal, H, OA or A, R2, R3 each independently denotes -O-(X)s-Q, -NHCO-(X)s-Q, -CONH-(X)s-Q, -NH(CO)NH-(X)s-Q, -NH(CO)O-(X)s-Q, -NHSOr(X)s-Q, NHCOA, Hal, Het or H, where, if R2=H, then R3≠H, or if R3=H, then R2≠H, R4 denotes H, R5 denotes H, Hal, A, OA, (CH2)nCOOH, (CH2)nCOOA, O(CH2)oCONH2, NHCOOA, NHCO(CH2)nNH2, NHCONHA or O(CH2)oHet1, A denotes a straight or branched alkyl containing 1-10 carbon atoms, in which 1-5 hydrogen atoms may be substituted with F, Cl and/or Br, X denotes a straight or branched C1-C10 alkylene which is unsubstituted or substituted once, twice or thrice by A, O A, OH, Hal, CN, COOH, COOA, CONH2, NH2, NHCOA, NHCOOA, Q denotes H, Ar or Het, Ar denotes phenyl which is unsubstituted or substituted once, twice or thrice with A, OA, OH, NO2, Hal, CN, (CH2)nCOOH, (CH2)nCOOA and/or tetrazole, Het denotes a cyclic saturated or aromatic 5-6-member heterocycle containing 1-2 N and/or O atoms, optionally condensed with a benzene ring which may be substituted once, twice or thrice with A, OA, OH and/or =O (carbonyl oxygen), Het1 denotes a monocyclic saturated, unsaturated or aromatic heterocycle containing 1-2 N and/or O atoms, which may be mono- or disubstituted with A, OA, OH, Hal and/or =O (carbonyl oxygen), Hal denotes F, Cl, Br or I, n equals , 1, 2, 3 or 4, o equals 1, 2 or 3, s equals 0, 1 or 2.

EFFECT: high efficiency of using said derivatives.

4 cl, 4 dwg, 1 tbl, 29 ex

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