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

FIELD: chemistry.

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

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

16 cl, 3 tbl, 1 dwg, 10 ex

 

This invention relates to new arylsulfonyl-azaheterocyclic compounds, to novel antagonists of serotonin 5-HT6receptors, to new medicinal principles, pharmaceutical compositions, finished dosage forms and methods for their preparation. More specifically, the present invention relates to antagonists of serotonin 5-HT6receptors - new substituted 3-arylsulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidines and substituted 3-arylsulfonyl-5,6,7,8-tetrahydro-pyrazolo[1,5-a]pyrido[4,3-d]pyrimidines, medicinal and pharmaceutical compositions containing the drug began in the form of these compounds, and to a method for treatment and prevention of the development of various conditions and diseases of the Central nervous system (CNS) of humans and warm-blooded animals, 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), diseases of Hantington, schizophrenia, other neurodegenerative diseases, cognitive disorders and obesity.

The use of effective and selective antagonists of serotonin 5-HT6receptors for Les the surveillance of Central nervous system diseases, 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, 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 of serotonin 5-HT6receptor-like material in the rat central nervous system. Brain Research. 1997; 746:207-219]. In addition, it is shown [Dawson L.A., Nguyen H.Q., Li P. The 5-HT(6) receptor antagonist SB-271046 selectively enhances excitatory neurotransmission in the rat frontal cortex and hippocampus. Neuropsychopharmacology.. 2001; 25:662-668]that 5-HT6the receptors are modulators of several neurotransmitter systems, including the cholinergic, noradrenergicheskoy, glutamatergic and dopaminergic. Given the fundamental role of these systems in normal cognitive processes, and their dysfunction in neurodegeneration, it is obvious exceptional role of 5-HT6receptors in the formation of normal or pathological memory. In a large number of modern studies have shown that blocking the 5-HT6receptors leads to a significant increase in memory consolidation in R is slichnih animal models of learning-memory-playback [Foley A.G., Murphy K.J., Hirst W.D., H.C. Gallagher, J.J. Hagan, UptonN., Walsh F.S., Regan C.M. 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; 46:1273-1276. 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"), and then clinches who their 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 IEpix 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
FMPOPreclinica/td> LillyAntipsychotic
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-HT6receptors. Curr. Drug Targets CNSNeurol. 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 selective search and e is effective antagonists of serotonin 5-HT 6receptors appears to be original and promising approach to the creation of new medicines for the treatment of a wide range of neurological and neurodegenerative diseases and cognitive disorders.

In the literature there is a considerable number of publications on various biologically active sulfanilamidnam of azaheterocycles, including serotonin receptor ligands. For example, the famous substituted 1-(2-amino-ethyl)-4-arylsulfonyl-pyrazoles of General formula A1 as ligands serotonin 5-HT2Creceptors [WO 2003057674 A1], and 7-amino-3-arylsulfonyl-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=H; NR4R5= piperazinil.

To develop new highly effective neuroprotective drugs by the authors of the present invention made extensive studies in a series of substituted 3-arylsulfonyl-pyrazolo[1,5-a]pyrido-pyrimidines, resulting in a new found drug began representing antagonis the s 5-HT 6receptors.

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

"Agonist" refers to a ligand that binds with the receptors of this type, actively promote the transfer of these receptors to their inherent specific signal and thereby cause a biological response of a cell.

"Alkyl" means 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+1the aN-, RkaRk+1aNC(=O)-, RkaRk+1aNC(=S)-, RkaRk+1aNSO2-, where Rkaand Rk+1aindependently from each other represent "amino substituents", which is defined in this section, for example, a hydrogen atom, alkyl, aryl, aralkyl, heteroalkyl, heterocyclyl or heteroaryl, or Rkaand Rk+1atogether with the N atom to which they are bound, form a through Rkaand Rk+1a4-7 membered heterocyclyl or heterocyclyl. Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, ISO-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, benzyloxycarbonylation, 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, Anna is new arylheteroacetic.

"Alkyloxy" means alkyl-O - group in which alkyl is defined in this section.

The preferred acyloxy groups are methoxy, ethoxy, n-propoxy, ISO-propoxy and n-butoxy.

"Allyloxycarbonyl" means alkyl-O-C(=O)- group in which alkyl is defined in this section. Preferred alkoxycarbonyl groups are methoxycarbonyl, etoxycarbonyl and tert-butyloxycarbonyl.

"Alkylthio or Alkylsulfonyl" means alkyl-S - group, where alkyl is defined 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" 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 is 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.

"Acyl" means an H-S(=O)- or alkyl-C(=O)-, cycloalkyl-C(=O)-, heterocyclyl-C(=O)-, geterotsiklicheskikh-C(=O)-, aryl-C(=O)- arylalkyl-C(=O)-, heteroaryl-C(=O)-, heteroallyl-C(=O)- group in which alkyl-, cycloalkyl-, heterocyclyl, geterotsiklicheskikh, aryl-arylalkyl, heteroaryl, heteroaromatic is defined in this section.

"Acylamino" means acyl-NH-group, where the acyl 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 OSN which also includes depression, 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, neurological 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.

"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 is; psychogenic disturbances of memory; amnesia; amnestic disorder; transient global amnesia; dissociative amnesia; vascular dementia; light (or moderate) cognitive impairment (mild cognitive his or her, MCI); syndrome of disturbance of attention with hyperactivity (attention deficit hyperactivity disorder, AD/HD); cognitive impairment accompanying psychotic diseases, epilepsy, delirium, autism, psychosis, down syndrome, bipolar disorder and depression; AIDS-associated dementia; dementia with hypothyroidism; dementia induced by alcohol, substances, addictive, and neurotoxins; dementia accompanying neurodegenerative diseases 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 t is aldeasa active beginning of the pharmaceutical composition, used for production and manufacturing of the drug product (tools).

"The drug (the drug), a substance (or mixture of substances in the form of pharmaceutical compositions in the form of tablets, capsules, injections, ointments and other 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 ASO is irovannoe dementia; multi-infarct dementia; frontotemporal dementia; leucoencephalopathy (illness vanishing white matter); chronic neurodegenerative disease; stroke; ischemic and reperfusion of hypoxic brain damage; epilepsy; cerebral ischemia; glaucoma; traumatic brain injury; down syndrome; encephalomyelitis; meningitis; encephalitis; neuroblastoma; schizophrenia; depression. In addition, neurodegenerative diseases include pathological conditions and disorders developing during hypoxia, substance abuse, addictive, when exposed to neurotoxins, infectious and oncological diseases of the brain and neuronal damage associated with autoimmune and endocrine diseases; and other neurodegenerative processes.

"Nootropics" or "nootropic", they neurometabolic stimulants - substances taken to improve mental 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 the Sam is eusto and others); intellectual-mnestic disorders, mania (hypomania, graphomania, kleptomania, magazineline, persecution mania, monomania, pornografiya, erotomania and others); disorder of multiple personality, Amancio, white fever, delirium, delusional syndrome, hallucinatory syndrome, hallucination, hallucinosis, gemicitabine, delirium, delusion, querulant, clinical lycanthropy, macropsia, Manichaean delirium, micropsia, drug addiction, nervous anorexia, oneyroidno syndrome, paranoid, paranoia, paraphrenia, pseudohallucinations, psychosis syndrome Kotar, 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 M is nchhausen, rett syndrome, the syndrome Fregoli, the syndrome of attention deficit and hyperactivity syndrome obsessive-compulsive disorder, syndrome effects of chronic anesthesia, a syndrome of psychic automatism, the syndrome of early infantile autism, delirium, taphophilia, anxiety syndrome Hikikomori, erotographomania and other

"Psychotic illness" are all types of schizophrenia; schizophrenia-like psychosis disease; shizotimichesky disorders; schizoaffective disorders, including bipolar and depressive type; delusional disorders, including delirium relations, 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.

"Sulfonyl" means R-S-group in which R represents Ala is l, cycloalkyl, aryl, heteroaryl, heterocyclyl, annelirovannymi heteroarylboronic, annelirovannymi heteroalicyclic, annelirovannymi heterooligomerization, annelirovannymi heteroalicyclic, annelirovannymi arylchloroalkanes, annelirovannymi aristically, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic, the value of which is determined in this section.

"Sulfonyl" means R-SO2group in which R represents alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, annelirovannymi heteroarylboronic, annelirovannymi heteroalicyclic, annelirovannymi heterooligomerization, annelirovannymi heteroalicyclic, annelirovannymi arylchloroalkanes, annelirovannymi aristically, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic, the value of which is determined in this section.

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

"Anxiety" (anxiety) refers to a generalized (non-specific) anxiety; acute uncontrolled anxiety; panic disorder; phobias, for example, agoraphobe the Yu (strong fear of crowded places) or social phobia (severe fear of humiliation in front of other people) or any specific phobia (severe fear of specific objects animals or situations, in the form of a fear of heights, medical procedures, elevators, open space etc); obsessive-compulsive disorder (obsessive-compulsive disorder); 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.

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

"Pharmaceutical composition" means a composition comprising a compound of formula I and at least one component selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, auxiliary, distributing and vosprinimat the General funds delivery vehicles, 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 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 (the hat 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 perorally, 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 ground solid nose is Telem.

"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 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, of which m is may be the salts of metals, 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 compounds - substituted 3-arylsulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidines of General formulas 1 and substituted 3-arylsulfonyl-5,6,7,8-tetrahydro-pyrazolo[1,5-a]pyrido[4,3-d]pyrimidines of General formula 2 and pharmaceutically acceptable salts and/or hydrates,

where Ar represents a phenyl, optionally substituted by halogen atoms, or 6-membered heteroaryl containing a nitrogen atom in the cycle;

R1represents a hydrogen atom, a C1-C3alkyl, hydroxy, C1-C3alkyloxy group, C1-C3alkylsulfanyl group;

R2represents a hydrogen atom or a C1-C3alkyl;

R3represents a hydrogen atom, optionally substituted C1-C3alkyl or tert-butyloxycarbonyl.

Preferred new compounds are substituted 3-phenylsulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidines of General formula 1.1 and substituted 3-phenylsulfonyl-5,6,7,8-tetrahydro-pyrazolo[1,5-a]pyrido[4,3-d]pyrimidines of General formula 2.1 or their pharmaceutically acceptable salts and/or hydrates,

where R1, R2and R3have the above meaning; R4represents a hydrogen atom, one or two are not necessarily the same halogen atom.

Preferred new compounds are substituted 2-methylsulfanyl-3-phenylsulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidines of General formula 1.2, and substituted 2-methylsulfanyl-3-phenylsulfonyl-5,6,7,8-tetrahydro-pyrazolo[1,5-a]pyrido[4,3-d]pyrimidines of General f is rmula 2.2 or their pharmaceutically acceptable salts and/or hydrates,

where R2, R3and R4have the above value.

More preferred nowymi compounds are 2-methyl-3-phenylsulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine 1.1(1), 2,5-dimethyl-3-phenylsulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine 1.1(2), 2,7-dimethyl-3-phenylsulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine 1.1(3), 2,5,7-trimethyl-3-phenylsulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine 1.1(4), 2-methyl-3-(3-chlorophenylsulfonyl)-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine 1.1 (5), 2,5-dimethyl-3-(3-chlorophenylsulfonyl)-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine 1.1(6), 2,7-dimethyl-3-(3-chlorophenylsulfonyl)-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine 1.1(7), 2,5,7-trimethyl-3-(3-chlorophenylsulfonyl)-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine 1.1(8), 2-methylsulfanyl-3-phenylsulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine 1-2(1), 5-methyl-2-methylsulfanyl-3-phenylsulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine 1.2(2), 7-methyl-2-methylsulfanyl-3-phenylsulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido [3,4-e] pyrimidine 1.2(3), 5,7-dimethyl-2-methylsulfanyl-3-phenylsulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine 1.2(4), 2-methylsulfanyl-3-(3-chlorophenylsulfonyl)-6,7,8,9-tetrahydro-pyrazolo[1,-a]pyrido[3,4-e]pyrimidine 1.2(5), 5-methyl-2-methylsulfanyl-3-(3-chlorophenylsulfonyl)-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine 1.2(6), 7-methyl-2-methylsulfanyl-3-(3-chlorophenylsulfonyl)-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine 1.2(7), 5,7-dimethyl-2-methylsulfanyl-3-(3-chlorophenylsulfonyl)-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine 1.2(8) or their pharmaceutically acceptable salts and/or hydrates,

The object of the present invention is also a method of obtaining new substituted 3-arylsulfonyl-tetrahydro-pyrazolo[1,5-a]-pyrido-pyrimidines of General formulas 1 and 2, which lies in the interaction of 3-amino-4-sulfonyl-2H-pyrazoles of General formula 3 with β-dicarbonyl compounds of General formula 4, followed by separation or separation of the reaction products of General formula 1 and 2 according to the scheme presented below.

where Ar, R1, R2and R3have in sukasana value.

The aim of the present invention is the creation of new antagonists of serotonin 5-HT6receptors.

This goal is achieved by the new antagonists of serotonin 5-HT6receptors represents a substituted 3-arylsulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidines of General formulas 1 and substituted 3-arylsulfonyl-5,6,7,8-tetrahydro-pyrazolo[1,5-a]pyrido[4,3-d]pyrimidines of General formula 2, or their pharmaceutically acceptable salts and/or hydrates.

The subject of the present invention is to provide new molecular tools to study the characteristics of physiologically active compounds that have the property to inhibit serotonin 5-HT6receptors, representing antagonists of serotonin 5-HT6receptors of General formulas 1 and 2 or their pharmaceutically acceptable salts and/or hydrates.

The subject of this invention is also medicinal beginning to pharmaceutical compositions and dosage forms that represent at least one 3-arylsulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine of the General formula 1, 3-arylsulfonyl-5,6,7,8-tetrahydro-pyrazolo[1,5-a]pyrido[4,3-d]pyrimidine of the General formula 2, or their pharmaceutically acceptable salt and/or hydrate.

The subject of this invention is also a pharmaceutical composition is, having the properties of antagonists of serotonin 5-HT6receptors for the treatment and prevention of the development of various conditions and diseases of the Central nervous system of humans and warm-blooded animals containing a pharmaceutically effective amount of a new drug began representing at least one 3-arylsulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine of the General formula 1, 3-arylsulfonyl-5,6,7,8-tetrahydro-pyrazolo[1,5-a]pyrido[4,3-d]pyrimidine of the General formula 2, or their 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. Pharmaceutical composition together with a compound of General formula 1, 2 according to the present invention may include other active principle, provided that they do not cause unwanted effects, such as allergic reactions.

If you want to use the pharmaceutical compositions of the present invention in clinical practice, they can be mixed to produce different forms, however, they can contain conventional pharmaceutical carriers; for example, oral formulations such as tablets, gelatin is 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 3-arylsulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine of the General formula 1, 3-arylsulfonyl-5,6,7,8-tetrahydro-pyrazolo[1,5-a]pyrido[4,3-d]pyrimidine of the General formula 2, or their pharmaceutically acceptable salt and/or hydrate.

The subject of this image is to be placed is also the drug (the drug) in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing, includes drug beginning, representing at least one 3-arylsulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine of the General formula 1, 3-arylsulfonyl-5,6,7,8-tetrahydro-pyrazolo[1,5-a]pyrido[4,3-d]pyrimidine of the General formula 2, or their pharmaceutically acceptable salt and/or hydrate or a pharmaceutical composition comprising a pharmaceutical start, intended for the treatment and prevention of pathological conditions and Central nervous system diseases, pathogenesis of which is associated with impaired activation of serotonin 5-HT6receptors.

According to this invention is preferred remedy for the prevention and treatment of cognitive disorders and neurodegenerative diseases.

According to this invention is preferred remedy for the prevention and treatment of Alzheimer's disease and diseases of Hantington.

According to this invention is preferred remedy for the prevention and treatment of mental disorders and schizophrenia.

According to this invention is preferred also medicinal product (drug), representing nootrop to improve mental abilities.

According to this invention is preferred drug (the drug), which is an anxiolytic for the prevention and treatment of anxiety and frustration.

According to this invention is preferred also medicinal product (drug) for the prevention and treatment of obesity.

The subject of this invention is also a therapeutic cocktail for the prevention and treatment of various diseases, pathogenesis of which is associated with serotoninovymi 5-HT6receptors in animals and humans, including the beginning of a new medication, representing at least one 3-arylsulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine of the General formula 1, 3-aryl-sulfonyl-5,6,7,8-tetrahydro-pyrazolo[1,5-a]pyrido[4,3-d]pyrimidine of the General formula 2, or their pharmaceutically acceptable salt and/or hydrate, or a new pharmaceutical composition comprising a pharmaceutical start, or a new drug (remedy)that includes the specified above the beginning of a new medication or a new pharmaceutical composition.

According to this invention is preferred therapeutic cocktail for the prevention and treatment of neurological disorders, neurodegenerative and cognitive diseases in animals and humans, including the new Le is arctonoe start, representing at least one 3-arylsulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine of the General formula 1, 3-arylsulfonyl-5,6,7,8-tetrahydro-pyrazolo[1,5-a]pyrido[4,3-d]pyrimidine of the General formula 2, or their pharmaceutically acceptable salt and/or hydrate, or a new pharmaceutical composition, or a new drug.

According to this invention is preferred therapeutic cocktail for the prevention and treatment of Alzheimer's disease Hantington, mental disorders, schizophrenia, anxiety disorders, improve mental abilities, hypoxia-ischemia, hypoglycemia, convulsive States, brain injuries, lathyrism, amyotrophic lateral sclerosis, obesity or stroke, including the beginning of a new medication or a new pharmaceutical composition, or a new drug.

Therapeutic cocktails for the prevention and treatment of various diseases, pathogenesis of which is associated with serotonin 5-HT6receptors in animals and humans, including neurological disorders, neurodegenerative and cognitive diseases in animals and humans, including for the prevention and treatment of Alzheimer's disease Hantington, mental disorders and shizophrenia, hypoxia-ischemia, hypoglycemia, convulsive status is of any, brain injuries, lathyrism, amyotrophic lateral sclerosis 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 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(B) receptors (e.g., CGP-36742); monoclonal antibodies (for example, Bapmeuzumab); antioxidants; neurotrophic agents (e.g., Cerebrolysin); antidepressants (eg, Imipramine, Sertraline, etc.) and others.

According to this invention is preferred therapeutic cocktail for lowering excess weight and treatment airen what I including the beginning of a new medication, representing at least one 3-arylsulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine of the General formula 1, 3-arylsulfonyl-5,6,7,8-tetrahydro-pyrazolo[1,5-a]pyrido[4,3-d]pyrimidine of the General formula 2, or their pharmaceutically acceptable salt and/or hydrate, or a new pharmaceutical composition, or a new drug.

Therapeutic cocktails for reducing overweight and obesity along with other drugs in this invention include other drugs 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 cannabinoid antagonists CB-1 receptors (Rimonabant), inhibitors of reuptake of norepinephrine and serotonin (Sibutramine), inhibitors of enzymes of fatty acid synthesis (Orlistat) and others, along with antioxidants, food additives, etc.

The subject of this invention is also a method of prevention and treatment the various diseases of the Central nervous system, the pathogenesis of which is associated with serotonin 5-HT6receptors in animals and humans, including neurological disorders, neurodegenerative and cognitive diseases, anxiety and frustration, improve mental abilities, to reduce overweight and obesity introduction warm-blooded animal or human the beginning of a new drug or a new pharmaceutical composition, or a new drug or a new therapeutic cocktail comprising at least one 3-arylsulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine of the General formula 1, 3-arylsulfonyl-5,6,7,8-tetrahydro-pyrazolo[1,5-a]pyrido[4,3-d]pyrimidine of the General formula 2, or their pharmaceutically acceptable salt and/or hydrate.

Drugs can be administered orally or parenterally (e.g. intravenously, subcutaneously, intraperitoneally or topically). The clinical dosage of the beginning, or pharmaceutical composition or drug containing at least one 3-arylsulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine of the General formula 1, 3-arylsulfonyl-5,6,7,8-tetrahydro-pyrazolo[1,5-a]pyrido[4,3-d]pyrimidine of the General formula 2 or its pharmaceutically acceptable salt and/or hydrate, patients may be adjusted depending on therapeutic e is the efficiency 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 dosage the beginning of the General formula 1 or its pharmaceutically acceptable salt and/or hydrate, preferably 50~300 mg. In accordance with the instructions of the doctor or pharmacist data drugs can be taken several times during a defined time period (preferably from one to six times).

The following examples describe the synthesis of 3-arylsulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidines of General formulas 1, 3-arylsulfonyl-5,6,7,8-tetrahydro-pyrazolo[1,5-a]pyrido[4,3-d]pyrimidines of General formula 2 and pharmaceutically acceptable salts and/or hydrates, their biological tests. The following examples illustrate but do not limit the invention.

Example 1. A common way of obtaining substituted 3-arylsulfonyl-tetrahydro-pyrazolo[1,5-a]-pyrido-pyrimidines of General formulas 1, 2.

Boil 0.005 mol aminopyrazole 3 and 0.0055 mol matched with the appropriate dicarbonyl compounds 4 in 5 ml of acetic acid for 4 hours. The resulting solution is cooled. 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. Output 3-arylsulfonyl-tetrahydro-pyrazolo[1,5-a]-pyrido-pyrimidines is from 30 to 85%. Table 2 presents some examples of the new 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of General formulas 1, 2 and LCMS analyses and NMR spectra.

Table 2
Substituted 3-arylsulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidines of General formulas 1 and substituted 3-arylsulfonyl-5,6,7,8-tetrahydro-pyrazolo[1,5-a]pyrido[4,3-d]pyrimidines of General formula 2
No.FormulaMol. weightLCMS, m/z (M+1)NMR spectra
1(1)388.51389
1(2) 375.47376
1.1(1)328.40329
1.1(2)342.42343
1.1(3)342.42343NMR-1H (CDCl3): 8.45 (s, 1H); 8.12 (d, J=8.0 Hz, 2H); 7.40-7.53 (m, 3H); 3.62 (s, 2H); 3.22 (t, J=5.9 Hz, 2H); 2.83 (t, J=5.9 Hz, 2H); 2.73 (s, 3H); 2.52 (s, 3H).
1.1(3). HCl378.88343
1.1(4)356.45357
1.1(5)362.84363
1.1(6)376.87377
1.1(7)376.87377
1.1(8)390.89391
1.1(9)428.51429
1.1(10)388.45389
1.2(1)360.46361
1.2(2)374.49375
1.2(3)374.49375NMR-1H (CDCl3): 8.39 (s, 1H); 8.15 (d, J=8.0 Hz, 2H); 7.36-7.55 (m, 3H); 3.61 (s, 2H); 3.21 (m, 2H); 2.83 (m, 2H); 2.59 (s, 3H); 2.51 (s, 3H).
1.2(3). HCl410.95375NMR-1H (DMSO-D6, 400 MHz) δ 11,76 (W, 1H), 8,69 (s, 1H), 8,01 (m, 2H), 7,66 (m, 1H), 7,56 (m, 2H), 4,60 (W, 1H), 4,37 (W, 1H), 3,76 (W, 1H), 3,50 (W, 1H), 3,47 (W, 2H), equal to 2.94 (s, 3H), 2,61 (s, 3H).
1.2(4)388.51389
1.2(5)394.90395
1.2(6)408.93409
1.2(7)408.93 409
1.2(8)422.96423
1.2(9)428.94393(DMSO-D6, 400 MHz) δ 11,70 (W, 1H), 8,69 (s, 1H), 8,07 (m, 2H), 7,43 (t, J=8,8 Hz, 2H), 4,60 (W, 1H), to 4.38 (W, 1H), 3.75 to (W, 1H), 3,51 (W, 1H), 3,47 (W, 2N), to 2.94 (s, 3H), 2,61 (s, 3H).
1.2(10)460.58461
1.2(11)450.59451
2.1(1)342.42343NMR-1H (CDCl3): 8.25 (s, 1H); 8.13 (d, J=8.0 Hz, 2H); 7.38-7.54 (m, 3H); 3.59 (s, 2H); 3.21 (t, J=5.9 Hz, 2H); 2.82 (t, J=5.9 Hz, 2H); 2.69 (s, 3H); 2.48 (s, 3H).
2.1(2) 378.88343NMR-1H (DMSO-D6): 11.63 (br.s, 1H); 9.21 (s, 1H); 8.01 (d, J=8.0 Hz, 2H); 7.46-7.66 (m, 3H); 4.43-4.58 (br.m, 1H); 4.22-4.41 (br.m, 1H); 3.63-3.80 (br.m, 1H); 3.43-3.58 (br.m, 1H); 2.91 (s, 3H); 2.61 (s, 3H).
2.1(3)413.33377
2.2(1)374.49375
2.2(2)410.95375NMR-1H (CDCl3): 8.24 (s, 1H); 8.17 (d, J=8.0 Hz, 2H); 7.40-7.54 (m, 3H); 3.58 (s, 2H); 3.20 (t, J=6.3 Hz, 2H); 2.82 (t, J=6.3 Hz, 2H); 2.56 (s, 3H); 2.49 (s, 3H). (DMSO-D6, 400 MHz) δ 11,59 (W, 1H), 9,25 (s, 1H), 8,01 (m, 2H). to 7.67 (m, 1H), 7.57 (m, 2H), 4,51 (W, 1H), 4,35 (W, 1H), 3.75 to (W, 1H), 3.54 (W, 1H), 3,30 (W, 2H), 2.95 and (s, 3H), 2.57 m (s, 3H).
2.2(3)428.94393NMR-1H (DMSO-D6, 400 MHz) δ 11,70 (W, 1H), 8,69 (s, 1H), 8,07 (m, 2H), 7,43 (t, J=8.8 Hz, 2H), 4,60 (W, 1H), to 4.38(W, 1H), 3.75 to (W, 1H), 3,51 (W, 1H), 3,47 (W, 2H), equal to 2.94 (s, 3H), 2,61 (s, 3H).

2.2(4)388.51389

Example 2. Determination of antagonistic activity of the compounds of General formula 1, 2 relative to 5-HT6the receptors. Substances of General formula 1, 2 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.

Tested substituted 3-arylsulfonyl-tetrahydro-pyrazolo[1,5-a]-pyrido-pyrimidines of General formulas 1, 2 (10 μm solutions) inhibited serotonin 5-HT6receptors at 80-100% and was expressed in terms of functional assay antagonistic activity.

the example 3. Determination of the activity of antagonists of serotonin 5-HT6receptors of General formula 1, 2 in a competitive binding to serotonin 5-HT6the receptors. For the screening of substances for their potential ability to interact with serotonin receptor 5-HT6used the method of radioligand binding. This was prepared membrane preparations from HeLa cells expressing recombinant human 5-HT6receptor, by homogenization of recombinant cells in a glass homogenizer followed by the separation of plasmatic membranes from 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 investigated compounds for 120 minutes at 37°C in a medium consisting of 50 mM Tris-HCl, pH 7.4, 150 mm NaCl, 2 mm Ascorbic Acid, 0.001% BSA. The samples after incubation were filtered under vacuum onto glass microfibre filters G/F (Millipor, USA), the filters are washed three times with cold solution environment for the activity was measured using a MicroBeta scintillation counter 340 (PerkinElmer, USA). Nonspecific binding, which was 30% of the total binding was determined by incubation of membrane preparations with radioligand in the presence of 5 μm Serotonin (5-HT). As a positive control was used Methiothepin. Binding of test compounds to the receptor was determined by their ability to displace the radioactive ligand and was expressed as a percentage of displacement. The percentage of displacement was determined by the following formula:

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

For the studied substances were determined by the following formula values pKi (pKi=-lg Ki):

Ki=IC50/(1+[L]/KD)

where IC50the concentration of the analyte, expressed in nm, at which it displaces 50% of the ligand bound to the receptor; [L] is the ligand concentration and KDthe dissociation constant of the ligand.

Tested substituted 3-arylsulfonyl-tetrahydro-pyrazolo[1,5-a]-pyrido-pyrimidines of General formulas 1, 2 have a high affinity for 5-HT6the receptor (table 3).

Table 3
The values of the IC50and Ki3-arylsulfonyl-tetrahydro-pyrazolo[1,5-a]-pyrido-pyrimidines of General formulas 1, 2 in a competitive binding to serotonin 5-HT6receptors
No.IC50, mcmKi, mcm
1.1(3)0.0130.0600
1.1(1)0.004610.00214
1.2(2)0.01660.0077
1.2(3)0.07690.0357
1.2(6)0.02390.0111
2.2(2)0.8010.372
2.2(3)>1

Example 4. Obtaining a medicinal product in the form of tablets. Mix 1600 mg of starch, 1600 mg of powdered lactose, 400 mg of talc and 1000 mg of the hydrochloride of 2-methylsulfanyl-5-methyl-3-phenylsulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine 1.2(2) and pressed in the bar. The resulting block is crushed into granules and p is osuivat through sieves, collecting granules size 14-16 mesh. The obtained granules tabletirujut in a suitable form tablets weighing 560 mg each.

Example 5. Obtaining a medicinal product in the form of capsules. Thoroughly mix hydrochloride 2-methylsulfanyl-5-methyl-3-phenylsulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine 1.2(2) with lactose powder in a 2:1 ratio. Received poroshkoobraznuju mix pack 300 mg in gelatin capsules of suitable size.

Example 6. Obtaining a medicinal product in the form of injectable compositions for intramuscular, intraperitoneal or subcutaneous injection. Mix 500 mg of the hydrochloride of 2-methylsulfanyl-5-methyl-3-phenylsulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine 1.2(2) with 300 mg of chlorobutanol, 2 ml of propylene glycol and 100 ml of injectable water. The resulting solution is filtered and placed in 1 ml ampoules which are sealed.

Example 7. Anti-amnestic activity (nootropic action) compounds of General formula 1, 2.

7.1. Improve memory, disturbed by scopolamine.

7.1.1. Nootropic effect of compounds of General formula 1, 2 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 is Tsekov. 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, 2, for example, the connection 1.2(2), at doses of 0.2 mg/kg the Animals of control group received an injection of saline. Each group used 8 animals.

Animals were placed in the bright compartment and record the latent period of the first entry into the dark chamber. The door between the chambers were closed, and the animal within 3 seconds, was sentenced by a current of 0.6 mA. After that, the animal was returned to a living cell. After 24 hours, the animal was again placed in the light compartment of the Shuttle camera and recorded the latent period of the first entry into the dark chamber, the total time spent in the light 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 expressed in HC is the chances of improving 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 compounds of General formula 1, 2, including 1.2(2), possessed the ability to reduce amnesia (to improve memory)caused by scopolamine.

7.1.2. Nootropic effect of compounds of General formula 1, 2 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 of visits were recorded by an observer. The test was ended when they were 13 entries in the stubs. Criterion approach considered is ü the presence of all four legs of the animal in the chamber.

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

However, this effect of scopolamine was able to prevent intraperitoneal introduction for 60 minutes before the start of training compounds of General formula 1, 2, for example, connection 1.2(2), at doses of 0.05 mg/kg and 0.2 mg/kg

7.2. Improve memory, impaired MK-801.

Nootropic effect of compounds of General formula 1, 2 in the test Passive avoidance in the Shuttle chamber"

The experiment was performed as in example 7.1.1. On the first day experience for 30 mi the ut to study animals were injected intraperitoneally MK-801 (0.1 mg/kg), causing the amnesia. Parallel independent groups of mice prior to the study were injected intraperitoneally with saline, MK-801 in combination with the compound of General formula 1, 2 at doses of 0.2 mg/kg and 1 mg/kg of the Obtained results demonstrate the ability of compounds of General formula 1, 2, including connection 1.2(2), to have a neuroprotective effect.

Example 8. Anxiolytic activity of the compounds of General formula 1, 2 to 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 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 in elevation is 38,5 see

Each mouse was placed in the centre of the maze head to the open sleeve. For 5 minutes recorded the sequence and duration of visits in the 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 describing the alarm condition. In normal animals avoid open sleeves (index their preferences is 0.2-0.3). Substances with anxiolytic activity (anxiolytic activity) increase this rate to 0.5-0.6 or more, and also reduce the number of bowel movements, without changing the overall locomotor activity (total number of visits in the sleeves).

Animals were injected intraperitoneally with placebo, buspirone (5 mg/kg, 30 minutes before training), lorazepam (0.05 mg/kg, 60 minutes before training) or one of the substances of General formula 1, 2, for example, the substance 1.2(2), at doses 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 is imposed which was expressed in the form of a General reduction in exploratory activity (number of visits sleeves during the test).

The results of the experiment showed that the substances of General formula 1, 2, including the connection 1.2(2), standards (Buspirone and Lorazepam) have a marked anxiolytic effects in the test elevated cross maze.

Example 9. Antipsychotic activity of the compounds of General formula 1, 2 in the test "Prepulse inhibition of startle in mice". In the experiments used male mice SHK weighing 24-30, Experiments were performed in light of the daily cycle of animals. Apomorphine hydrochloride, 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. The analyzed compound of General formula 1, 2, for example, the connection 1.2(2), 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 Kama is s, 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 animal experiments to simulate psychoto-like conditions caused a decrease prepulse inhibition of startle that reflects the reduced ability of the CNS to filter touch timely. Haloperidol (1 mg/kg) and studied compounds of General formula 1, 2, including the connection 1.2(2), warned violation prepulse braking wince when the apomorfina.

Example 10. The antidepressant activity of the compounds of General formula 1, 2.

10.1. 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 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 fixed, if not moved 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 test compounds were injected sub-chronic for 4 days intraperitoneally. The results of the experiment showed that the compounds of General formula 1, 2, in particular, the connection 1.2(2), the led intraperitoneally at a dose of 5 mg/kg, reduce the degree of despair, i.e. exhibit antidepressant activity.

10.2. 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 approximately at the height of 400 mm from the surface of the table for 3 minutes, the Animal was considered to be stationary if it didn't do any movements within 1.5 seconds. The studied compounds of General formula 1, 2 was administered intraperitoneally at a dose of 5 mg/kg Comparators (Fluoxetine, Desipramine) was administered intraperitoneally 15 minutes before the start of the test.

In this test the compounds of General formula 1, 2, including the connection 1.2(2), show antidepressant activity comparable with that used by the Comparators Fluoxetine and Desipramine.

1. Substituted 3-sulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidines of General formulas 1 and substituted 3-sulfonyl-5,6,7,8-tetrahydro-pyrazolo[1,5-a]PI is IDO[4,3-d]pyrimidines of General formula 2, or their pharmaceutically acceptable salts and/or hydrates,

where Ar represents a phenyl, optionally substituted by halogen atoms, or 6-membered heteroaryl containing nitrogen atom in a loop;
R1represents a hydrogen atom, a C1-C3alkyl, hydroxys1-C3alkyloxy group, C1-C3alkylsulfanyl group;
R2represents a hydrogen atom or a C1-C3alkyl;
R3represents a hydrogen atom, optionally substituted C1-C3alkyl or tert-butyloxycarbonyl.

2. Compounds according to claim 1, which represents a substituted 3-phenylsulfonyl-6,7,8,9-tetrahydropyrazolo[1,5-a]pyrido[3,4-e]pyrimidines of General formula 1.1 and substituted 3-phenylsulfonyl-5,6,7,8-tetrahydropyrazolo[1,5-a]pyrido[4,3-d]pyrimidines of General formula 2.1 or their pharmaceutically acceptable salts and/or hydrates,

where R1, R2and R3have the above meaning; R4represents a hydrogen atom, one or two are not necessarily the same halogen atom.

3. Compounds according to claim 2, represents a substituted 2-methylsulfanyl-3-phenylsulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidines of General formula 1.2, and substituted 2-methylsulfanyl-3-phenylsulfonyl-5,6,7,8-tetrahydro-pyrazolo[1,5-a]pyrido[4,3-d]pyrim the Dina General formula 2.2 or their pharmaceutically acceptable salts and/or hydrates,

where R2, R3and R4have the above value.

4. Compounds according to claim 1, which represents a 2-methyl-3-phenylsulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine 1.1(1), 2,5-dimethyl-3-phenylsulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine 1.1(2), 2,7-dimethyl-3-phenylsulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine 1.1(3), 2,5,7-trimethyl-3-phenylsulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine 1.1(4), 2-methyl-3-(3-chlorophenylsulfonyl)-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine 1.1(5), 2,5-dimethyl-3-(3-chlorophenylsulfonyl)-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine 1.1(6), 2,7-dimethyl-3-(3-chlorophenylsulfonyl)-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine 1.1(7), 2,5,7-trimethyl-3-(3-chlorophenylsulfonyl)-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine 1.1(8), 2-methylsulfanyl-3-phenylsulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine 1.2(1), 5-methyl-2-methylsulfanyl-3-phenylsulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine 1.2(2), 7-methyl-2-methylsulfanyl-3-phenylsulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine 1.2(3), 5,7-dimethyl-2-methylsulfanyl-3-phenylsulfonyl-6,7,8,9-tetrahydro-pyrazolo [1,5-a] pyrido [3,4-e]pyrimidine 1.2(4), 2-methylsulfanyl-3-(3-chlorophenylsulfonyl)-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]Piri is one 1.2(5), 5-methyl-2-methylsulfanyl-3-(3-chlorophenylsulfonyl)-6,7,8,9-tetrahydro-pyrazolo [1,5-a]pyrido[3,4-e] pyrimidine 1.2(6), 7-methyl-2-methylsulfanyl-3-(3-chlorophenylsulfonyl)-6,7,8,9-tetrahydro-pyrazolo [1,5-a]pyrido[3,4-e] pyrimidine 1.2(7), 5,7-dimethyl-2-methylsulfanyl-3-(3-chlorophenylsulfonyl)-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine 1.2(8) or their pharmaceutically acceptable salts and/or hydrates.



5. Method of preparing compounds according to any one of claims 1 to 4 by the interaction of 3-amino-4-arylsulfonyl-2H-pyrazoles of General formula 3 with the corresponding β-dicarbonyl compounds of General formula 4,

where Ar, R1, R2and R3have the above value.

6. Antagonists of serotonin 5-HT6receptors, which are compounds of General formula 1 and 2 according to any one of claims 1 to 4.

7. Antagonists of serotonin 5-HT6receptor is 6 to study the molecular mechanisms of physiologically active compounds in relation to the inhibition of serotonin 5-HT 6receptors.

8. Substituted tetrahydro-pyrazolo[1,5-a]pyrido-pyrimidines of General formulas 1 and 2 according to any one of claims 1 to 4, having the properties of antagonists of serotonin 5-HT6receptors as drug began to pharmaceutical compositions and medicines.

9. Pharmaceutical composition having the properties of antagonists of serotonin 5-HT6receptors for treating and preventing conditions and disorders of the Central nervous system, containing as an active ingredient pharmaceutically effective amount of a medicinal beginning on item 8.

10. A method of obtaining a pharmaceutical composition according to claim 9 mixing medicinal beginning at step 8 with an inert filler and/or diluent.

11. The drug is in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing, to prevent and treat conditions and diseases of the Central nervous system, the pathogenesis of which is associated with 5-HT6receptors, comprising pharmaceutically effective amount of drug to the beginning of claim 8 or pharmaceutical composition according to claim 9.

12. Drug in claim 11 for the prevention and treatment of cognitive disorders and neurodegenerative diseases.

13. Drug in claim 11 for the prevention and treatment of the mental the ski disorders.

14. Drug in claim 11, having anxiolytic action for the prevention and treatment of anxiety disorders.

15. Drug in claim 11, having a nootropic action to improve mental abilities.

16. 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 of claim 8, or a pharmaceutical composition according to claim 9, or a medicinal product according to any one of § § 11 and 15.



 

Same patents:

FIELD: chemistry.

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

EFFECT: wider field of use of the compounds.

16 cl, 4 tbl, 29 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel antagonists of serotonin 5-HT6 receptors - substituted 2-amino-3-sulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidines of general formula 1 and substituted 2-amino-3-sulfonyl-5,6,7,8-tetrahydro-pyrazolo[1,5-a]pyrido[4,3-d]pyrimidines of general formula 2 or their pharmaceutically acceptable salts and/or hydrates, method of producing said compounds and pharmaceutical compositions, medicinal agents and treatment method. In compounds of formula 1 and general formula 2 , Ar is phenyl which is possibly substituted with halogen atoms, or a 6-member nitrogen-containing heteroaryl; R1 is a hydrogen atom, C1-C3alkyl which is possibly substituted with phenyl, C1-C5alkoxycarbonyl; R2 is a hydrogen atom, halogen or C1-C3alkyl; R13 and R23 are optionally identical substitutes selected from a hydrogen atom, optionally substituted C1-C3alkyl or R13 and R23 together with the nitrogen atom with which they are bonded form a nitrogen-containing 6-member saturated heteroaryl optionally substituted with C1-C5alkoxycarbonyl, where the said heteroaryl has 1-2 heteroatoms selected from nitrogen.

EFFECT: compounds can be used to prevent and treat diseases of the central nervous system, pathogenesis of which is associated with 5-HT6 receptors for enhancing mental capacity.

14 cl, 3 tbl, 19 dwg, 16 ex

FIELD: medicine.

SUBSTANCE: invention refers to method for prevention of mirtazapin sublimation from a pharmaceutical preparative form containing solid enantiomer pure form of mirtazapin, by making the preparative forms by addition of at least one pharmaceutically acceptable adjuvant to the solid form of mirtazapin enantiomer. The enantiomer pure form is pharmaceutically acceptable, nonsublumating and solid salt of S- or R-mirtazapin. There are also described nonsublumating salts of S-mirtazapin and the pharmaceutical preparative form of the latter.

EFFECT: higher efficiency of the composition.

4 cl, 4 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining mirtazapine enantiomer, containing less than 10% of other enantiomer, which includes reaction of closing cycle of compound of formula , where X represents leaving group, said stage includes processing with acid, by means of which mirtazapine with enantiomer excess is obtained by closing cycle R- or S-enantiomer of formula (II) compound by processing with polyphosporic acid in absence of solvent or combination of polyphosphoric acid and N-methylpyrrolidinol or DMF.

EFFECT: stereochemical purity of target product.

10 ex

FIELD: chemistry.

SUBSTANCE: invention refers to imidazoquinolines of formula (I) and (II) , as well as to tetrahydroimidazoquinolines of formula (III) wherein radicals and symbols possess values specified in formula of the invention. The given compounds and based pharmaceutical compositions representing subject of the present invention, can stimulate biosynthesis of various cytokines, particularly, α-interferon and are used in treating certain diseases, including virus diseases and cancerous diseases.

EFFECT: objects of invention are also methods of treating virus and cancerous diseases and intermediate compounds.

41 cl, 2 tbl, 37 ex

Quinolone analogues // 2349586

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds with formula (1): and to their pharmaceutical salts, where B, X, A or V are not present, if Z1, Z2, Z3 or Z4 respectively represent N, and independently H, halogen atom, azido, R2, CH2R2, SR2, OR2 or NR1R2, when Z1, Z2, Z3 or Z4 represent C. In each NR1R2, R1 and R2 together with N there can be formation of an optionally substituted piperidine, pyrrolidine, piperazine or morpholine ring. Z1 represents N and Z2, Z3 and Z4 represent C, or Z1 and Z3 represent N and Z2 and Z4 represent C. W together with N and Z form an optionally substituted thiazole, imidazole or pyrimidine ring, which is condensed with an optionally substituted ring, chosen from a group consisting of: or . U represents NR1R2, NR1-(CR12)n-NR3R4, where in NR3R4, R3 and R4 together with N there can be formation of an optionally substituted piperidine, pyrrolidine, piperazine or morpholine ring. R1 and R3 independently represent H or C1-6alkyl. Each R2 represents H or C1-10alkyl, each optionally substituted with a halogen atom, or C3-6cycloalkyl, aryl, heteroaryl or pyridine, pyrrolidine, piperazine or morpholine ring, where each ring is optionally substituted; or R2 is optionally substituted with piperidine, pyrrolidine, pyridine, piperazine, pyrazine, morpholine or benzimidazole. R2 represents H or C1-10alkyl. Each R5 represents a substitute in any position in ring W, and is H, OR2, amino, alkoxy, amido, halogen atom or cyano; or R5 represents C1-6alkyl, -CONHR1-, each optionally substituted with a halogen atom; or two adjacent R5 are linked with formation of a 5-6-member ring, an optionally substituted heterocyclic ring, chosen piperidine, pyrrolidine, piperazine or morpholine ring. n equals 1-6, and each optionally substituted part can be substituted with one or more halogens, OR2, NR1R2 , carbamate, C1-10alkyl, each optionally substituted with a halogen atom, C=O, cyano, nitro, COR2, NR2COR2, sulphonyl amides, NR2SOOR2; SR2, SOR2, COOR2, CONR22, OCOR2, OCOOR2 or OCONR22. The invention also relates to pharmaceutical compositions, to the method of suppressing proliferation of cells and/or weakening cell proliferative breakdown, to the method of reducing microbe titre and/or weakening microbe infection, to the method of inducing death of cells and/or inducing apoptosis, to compounds, chosen from a group, to pharmaceutical compositions, as well as to the method of producing compounds with formula (1).

EFFECT: obtaining new biologically active compounds, which can suppress proliferation of cells and/or induce apoptosis.

41 cl, 113 ex, 12 tbl

FIELD: chemistry, pharmacology.

SUBSTANCE: described are novel pyridopyrrolizine and pyridoindolizine derivatives of general formula I and their pharmaceutically acceptable salts and hydrates, where A is C1-3alkyl; Ar stands for naphtyl or phenyl optionally substituted with one or two groups, selected from halogen, C1-6alkyl or C1-6alkyl haloid; Q stands for COOH; one of X1, X2, X3 or X4 stands for nitrogen, others are independently selected from CH and C-Rg, where Rg stands for C1-6alkyl or S(O)nC1-6alkyl, where n=0, 2; Y1 stands for S or C(O); Y2 stands for (CRdRe)m, where Rd and Re - hydrogen, m is integer 1 or 2; R1, R2, R3 stands for hydrogen, pharmaceutical composition, containing them, and method of treatment of diseases, mediated by prostaglandin D2.

EFFECT: obtaining novel pyridopyrrolizine and pyridoindolizine derivatives which possess useful properties.

22 cl, 2 tbl, 17 ex

FIELD: chemistry.

SUBSTANCE: novel compounds are selected from group, consisting of: 4-(2-cyclopropyl-ethyl)-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclopropylmethyl-piperazine-1-carboxylic acid 3-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclopropylmethyl-piperazine-1-carboxylic acid 3-fluorine-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-(2-hydroxymethyl-cyclopropylmethyl)-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclopentylmethyl-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclopropylmethyl-piperazine-1-carboxylic acid 3-chlorine-4-(3-methyl- 4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclobutylmethyl-piperazine-1-carboxylic acid 3-chlorine-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclobutylmethyl-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-(2-cyclopropyl-ethyl)-piperazine-1-carboxylic acid 3-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclobutylmethyl-piperazine-1-carboxylic acid 3-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclobutylmethyl-piperazine-1-carboxylic acid 3-fluorine-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclobutylmethyl-piperazine-1-carboxylic acid 2-fluorine-4-(3-methyl-4,10-dihudro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclopropylmethyl-piperazine-1-carboxylic acid 2-fluorine-4-(3-methyl-4,10-dihydro-3H-2,3,4;9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclobutylmethyl-piperazine-1-carboxylic acid 4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclopropylmethyl-piperazine-1-carboxylic acid 3-ethyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclobutylmethyl-piperazine-1-carboxylic acid 2-chlorine-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclopropylmethyl-piperazine-1-carboxylic acid 2-chlorine-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide and 4-cyclobutylmethyl-piperazine-1-carboxylic acid 3-methoxy-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-benzylamide. Invention also relates to pharmaceutical composition and to application of compounds of general formula 1.

EFFECT: obtaining novel biologically active compounds and based on them pharmaceutical composition, possessing antagonistic activity with respect to vasopressin receptors.

60 cl, 153 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the novel compounds with the common formula III: where, if X is selected from the group containing NH and S, R1, R2, R3, R4, R5, R6, R7, R8 and R9, each independently is selected from the group containing H, OH, OR', substituted or unsubstituted aryl, where substitutes independently correspond to H, OH, C1-C12alkoxy; where, if X means O, R1, R2, R3, R4, R5, R6, R7 and R8, each independently, selected from the group containing H, OH, OR', SH, SR', SOR', SO2R', OSO2R', NHR', N(R') CO2R', OC(=O)R'; and R9 independently selected from the group containing H, OR', unsubstituted or substituted with aminogroup or halogen C2-C12 alkenyl, unsubstituted C2- C12 alkenyl, unsubstituted thienyl and halogen; where each of the R' groups are independently selected from the group containing H, substituted or unsubstituted C1-C18 alkyl, substituted or unsubstituted aryl; where substitutes are independently selected from the group containing halogen, OH, CN, C1-C12 alkoxy, phenyl; and the dotted line represents the simple or double bind; or its pharmaceutically compatible salt or complex ether. Other novel lamellarin analogs are described.

EFFECT: compounds have antitumor activity.

24 cl, 2 tbl, 3 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention describes novel substituted pyrazoles of the general formula (I): wherein values of radicals Ar, Ar2, W, G, R5-R8, RZ and n are given in the invention claim. Also, invention relates to a pharmaceutical composition based on these compounds, using this pharmaceutical composition for manufacturing agent designated for treatment of asthma, and a method for inhibition of activity of cathepsin S. Compounds indicated above can be used in medicine.

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

27 cl, 3 tbl, 352 ex

FIELD: chemistry.

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

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

23 cl, 47 ex

FIELD: medicine.

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

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

47 cl, 12 tbl, 2 ex, 4 dwg

FIELD: medicine.

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

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

4 ex

FIELD: food industry.

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

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

9 cl, 4 dwg, 1 tbl, 3 ex

FIELD: chemistry.

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

EFFECT: increased effectiveness of the compounds.

23 cl, 20 ex

FIELD: medicine.

SUBSTANCE: treating of lipidosis and body-weight reduction in the patients with cardiovascular diseases is ensured by diet therapy based on the lacto-vegetarian diet. It involves introduction of proteins in daily amount of 67-79 g, including animal 48-57%, fats in daily amount of 32-49 g, including animal 40-52%, carbohydrates in daily amount of 240-257 g, cholesterol in daily amount of 40-268 mg, cellulose in daily amount of 18-20 g, dietary fibers in daily amount of 150 mg, potassium (K) in daily amount of 4567-6433 mg, magnesium (Mg) in daily amount of 535-693 mg, vitamin E in daily amount of 44-53 mg, arginine in daily amount of 3.9-5.2 g, dehydrated powdered maral meat in daily amount of 1200 mg, microcrystalline cellulose in daily amount of 900 mg. Duration of the diet therapy course is 33 days.

EFFECT: method provides suppression of cholesterol biosynthesis and intensification of excretion thereof that reduces the atherogenic index, reduces manifestations of oxidative stress, with reduced risk of realisation of the modified factors of a cardiovascular pathology.

1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

or

or to their pharmaceutically acceptable salts, where ring A, R2, R3, R4 and X are as defined in the description. The disclosed compounds are useful as 11βHSD1 inhibitor. The invention also relates to a pharmaceutical composition, an agent for treating or preventing pathology related to glucocorticoids, a 11βHSD1 inhibitor containing the disclosed compound or its pharmaceutically acceptable salt, and use of the disclosed compounds.

EFFECT: compounds are highly effective.

40 cl, 48 tbl, 191 ex

FIELD: medicine.

SUBSTANCE: invention relates to compounds of general formula (I) and their pharmaceutically acceptable salts and pharmaceutically acceptable asters, possessing activity with respect to LXRα and/or LXRβ receptors. Compounds can be applied for treatment and prevention of diseases mediated by LXRα and/or LXRβ receptors, namely: increased level of lipids and cholesterol level, atherosclerotic diseases, diabetes, metabolic syndrome, dyslipidermia, sepsis, inflammatory diseases, pancreatitis, liver cholestasis/fibrosis, and diseases which include inflammatory component, such as Alzheimer's disease and reduced/improvable cognitive function. In general formula n represents integer number from 0 to 3; R1 is independently selected from group consisting of halogen, -CN, -NO2, -SO2Me, lower alkyl, -OR11, pyperidinyl and -N(R11)(R11), where R11 is independently selected from lower alkyl and H, X1, X2, X3 and X4 are independently selected from nitrogen and carbon, on condition that, not more than two of X1, X2, X3 and X4 can simultaneously represent nitrogen, and in case when two of X1, X2, X3 and X4 represent nitrogen, n represents 0,1 or 2; k represents integer number 0 or 1; R2 represents H; R3 represents H, lower alkyl or halogen; R4 represents aryl, heteroaryl, lower alkylaryl or lower alkylheteroaryl, each of which is optionally substituted with substituents in amount from one to five, which are independently selected from group consisting of halogen, lower alkyl, -OR41, lower alkinyl and NR42R43, where R41 represents lower alkyl, R42 and R43 independently on each other represent hydrogen or lower alkyl, or NR42R43 represents pyrrolidinyl, or R4 represents lower alkyl; R5 is selected from group, heteroaryl, consisting of and , said aryl and heteroaryl being optionally substituted in one or more positions with one or more substituents, independently selected from group consisting of H, halogen, lower alkyl and (CH2)VR53, where R51 is selected from group consisting of H, lower alkyl, lower alkenyl and lower alkylaryl, said lower alkylaryl is optionally substituted in one or more positions with one or more lower alkyl, -CN, halogen, group -COOR54 and group -CH2OR54, where R54 represents lower alkyl or H; R52 represents lower alkyl or -H; R53 represents H, lower alkyl, C3-C6-cycloalkyl, -COOR55, -N(R55)(R56), -CH2OH, -CN, CF3, -CONH2 or -CH2OR55, where R55 is independently selected from group consisting of lower alkyl, -H, -C(O)aryl or -C(O)-lower alkyl, and R56 is selected from group consisting of H, lower alkyl, -C(O)CF3, -C(O)aryl, -C(O)-lower alkyl and lower alkylaryl, and where said aryl and lower alkylaryl are optionally substituted in one or more positions with one or more lower alkyl, halogen, group COOR57 and group -CH2OR57, where R57 represents lower alkyl or -H, or R55 and R56 together with atom to which they are bound, form ring system; or R53 represents aryl, which can be optionally substituted with benzyloxy, carboxy, lower alkoxycarbonyl, hydroxy-(lower alkyl), halogen, carbamoyl, (lower alkyl)carbamoyl, di-(lower alkyl)carbamoyl, m represents integer number from 0 to 2; v represents integer number from 0 to 4; where term "lower alkyl" separately or in combination with other groups refers to branched or linear monovalent alkyl radical, containing from one to six carbon atoms, where term "aryl" separately or in combination with other groups refers to phenyl or naphthyl, and where term "hetyeroaryl" refers to aromatic 5- or 6-member ring, which can include 1-3 heteroatoms selected from nitrogen, oxygen and/or sulphur, and which can be condensed with phenyl group.

EFFECT: increase of compound application efficiency.

38 cl, 5 dwg, 137 ex

FIELD: medicine.

SUBSTANCE: pharmaceutical compositions include divalent, namely calcium, magnesium or zinc salt, of pravastatin or fluvastatin and omega-3 fat, for prevention, reduction or treatment of increased cholesterol levels, atherosclerosis, hyperlipidemia, cardio-vascular disorders and diseases, coronary heart disease and/or cerebrovascular disease.

EFFECT: improved bioavailability of compositions, easily obtained and introduced.

40 cl, 33 dwg, 2 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel hexafluoroisopropanol substituted derivatives of cyclohexane of formula (I) with LXRα- and/or LXRβ agonist modulation properties, as well as to their pharmaceutically acceptable salts. In formula (I) R1 denotes hydrogen, lower alkyl, fluoro-lower alkyl, lower alkyl-carbonyl, fluoro-lower alkyl-carbonyl, phenyl-lower alkyl, C3-C6-cycloalkyl-lower alkyl, C3-C6-cycloalkylcarbonyl or C3-C6-cycloalkyl-lower alkyl-carbonyl; R2 denotes hydrogen or lower alkyl; R3 denotes lower alkyl, phenyl-lower alkyl, where phenyl is possibly substituted with lower alkoxycarbonyl, lower alkoxycarbonyl, or if X represents a single bond and m is not equal to 0, R3 can also denote a hydroxy group; R4 denotes phenyl or heterocyclyl, where heterocyclyl is a five-member aromatic heterocyclic ring containing two heteroatoms selected from nitrogen and sulphur, optionally substituted with 1-3 substitutes independently selected from a group which includes lower alkyl and halogen; X denotes a single bond, SO2, CO or C(O)O; m equals 0, 1, 2 or 3; n equals 0 or 1. The invention also relates to a pharmaceutical composition containing formula (I) compounds.

EFFECT: novel compounds have useful biological properties.

20 cl, 35 ex

FIELD: medicine.

SUBSTANCE: invention relates to field of medicine and pharmaceutical industry and represents pharmaceutical combination for treatment of cerebral circulatory insufficiency and psychodependent form of erectile dysfunction, including choline alfoscetate in amount 50-600 mg per one intake and hopantenic acid or its pharmaceutically acceptable salt in amount 20-800 mg per one intake.

EFFECT: invention ensures reduction of frequency, duration and intensity of headache, dizziness, fatigability, irritability, improvement of memory for current events and sleep, as well as increase of erectile dysfunction (ED), reduction and fixation of stable positive motivation for quality erection and full orgasm in case of psychodependent form of ED; simultaneously, due to manifestation of synergic effect, which results from the use of claimed combination, it became possible to reduce day dose of hopantenic acid or its salt from 1,5 mg to 0,5 mg.

12 cl, 4 ex, 24 tbl, 4 dwg

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