RU2393159C1 - SUBSTITUTED 2-ALKYLSULFANYL-3-SULFONYL-PYRAZOLO[1,5-a]PYRIMIDINES, SEROTONIN 5-HT6 RECEPTOR ANTAGONISTS, METHODS OF PRODUCING AND USING SAID COMPOUNDS - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: present invention relates to novel substituted 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of general formula 1, their pharmaceutically acceptable salts and/or hydrates having serotonin 5-HT₆ receptor antagonist properties. In general formula 1

, R¹ and R³ independently denote optionally identical C₁-C₃ alkyl, and R² is a -(CH₂)_nX group or R¹ and R³ independently denote different substitutes selected from C₁-C₃ alkyl or a -(CH₂)_nX group, and R² is a hydrogen atom or C₁-C₃ alkyl; R⁴ is C₁-C₃ alkyl; R_i ⁵ is a hydrogen atom, one or two identical or different halogen atoms, C₁-C₃ alkyl; equals 0, 1 or 2; n equals 0, 1, 2 or 3; X is a carboxyl CO₂H, C₁-C₃ alkyloxycarbonyl, aminocarbonyl CONR⁶R⁷ or amino group NR⁶R⁷; except compounds in which R³ is a -(CH₂)_nX group, where X is an amino group NR⁶R⁷ and n equals 0; R⁶ and R⁷ are optionally identical and denote a hydrogen atom, optionally substituted C₁-C₅ alkyl or R⁶ and R⁷ together with the nitrogen atom with which they are bonded form an optionally substituted 6-member azaheterocyclyl containing 1-2 nitrogen atoms in the ring, where the substitute is selected from C₁-C₃ alkyl.

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

25 cl, 2 tbl, 12 ex

Description

The invention relates to new substituted 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo [1,5-a] pyrimidines, antagonists of serotonin 5-HT ₆ receptors, pharmaceutical principles and pharmaceutical compositions containing medicinal principles in the form of these compounds, and also to a method of treatment and preventing the development of various diseases of the central nervous system (CNS), cognitive and neurodegenerative diseases. The pharmacological effect of new drugs is based on their ability to interact with serotonin 5-HT ₆ receptors, which play an important role in the treatment of central nervous system diseases, in particular Alzheimer's disease (AD), Parkinson's disease, Huntington's disease, schizophrenia, other neurodegenerative diseases, cognitive disorders and obesity.

The use of effective and selective antagonists of serotonin 5-HT ₆ receptors for the treatment of central nervous system diseases, in particular schizophrenia, asthma and other neurodegenerative diseases and cognitive disorders, is a promising area for the development of new drugs [Holenz J., Pauwels PJ, Diaz JL, Merce R. , Codony X., Buschmann H. Medicinal chemistry strategies to 5-HT ₆ receptor ligands as potential cognitive enhancers and antiobesity agents. Drug Disc. Today. 2006; 11: 283-299]. These mammalian receptors are located exclusively in the central nervous system, and 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. Immuno-localization ofserotonin 5-HT ₆ receptor-like material in the rat central nervous system. Brain Research. 1997; 746: 207-219]. In addition, [Dawson LA, Nguyen HQ, 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-HT ₆ receptors are modulators of several neurotransmitter systems, including cholinergic, noradrenergic, glutamatergic and dopaminergic. Given the fundamental role of these systems in normal cognitive processes, as well as their dysfunction in neurodegeneration, the exceptional role of 5-HT ₆ receptors in the formation of normal or “pathological” memory becomes apparent. A large number of modern studies have shown that blocking 5-HT ₆ receptors leads to a significant increase in memory consolidation in various animal learning-memorizing-reproduction models [Foley AG, Murphy KJ, Hirst WD, Gallagher HC-, Hagan JJ, Upton N., Walsh FS, Regan CM The 5-HT (6) receptor antagonist SB-271046 reverses scopolamine-disrupted consolidation of a passive avoidance task and ameliorates spatial task deficits in aged rats. Neuropsychopharmacology. 2004; 29: 93-100. Riemer C., Borroni E., Levet-Trafit B., Martin JR, Poli S., Porter RH, Bos M. Influence of the 5-HT ₆ receptor on acetylcholine release in the cortex: pharmacological characterization of 4- (2- bromo-6-pyrrolidin-l-ylpyridine-4-sulfonyl) phenylamine, a potent and selective 5-HT ₆ receptor antagonist. J. Med. Chem. 2003; 46: 1273-1276. King MV, Woolley ML, Topham IA, Sleight AJ, Marsden CA, Fone KC 5-HT ₆ receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing consolidation e an effect sensitive to NMDA receptor antagonism. Neuropharmacology 2004; 47: 195-204]. Significant improvement in cognitive function in old rats was also shown in the Morrison water maze model when exposed to a 5-HT ₆ receptor antagonist [Foley AG, Murphy KJ, Hirst WD, Gallagher HC, Hagan JJ, Upton N. .. Walsh FS, Regan CM The 5- HT (6) receptor antagonist SB-271046 reverses scopolamine-disrupted consolidation of a passive avoidance task and ameliorates spatial task deficits in aged rats. Neuropsychopharmacology. 2004; 29: 93-100]. Recently, not only a deeper understanding of the role of 5-HT ₆ receptors in cognitive processes, but a clearer formation of ideas about the possible pharmacophore properties of their antagonists [Holenz J., Pauwels PJ, Diaz JL, Merce R., Codony X., Buschmann H. Medicinal chemistry strategies to 5-HT ₆ receptor ligands as potential cognitive enhancers and antiobesity agents. Drug Disc. Today. 2006; 11: 283-299]. This led to the creation of high-affinity selective ligands (“molecular tools”), and then clinical candidates. Currently, a number of 5-HT ₆ receptor antagonists are at different stages of clinical trials as drug candidates for the treatment of AD, Huntington's disease, schizophrenia (antipsychotics) and other neurodegenerative and cognitive diseases (table 1) [http://integrity.prous.com ].

Table 1 5-HT ₆ receptor antagonists as drug candidates Medicine Clinical trial phase Developer Therapeutic group Dimebon _TM Phase III Medivation (USA) Alzheimer's Disease Treatment SGS-518 Phase II Lilly saegis Cognitive Disease Treatment SB-742457 Phase II GlaxoSmithKline Treatment of Alzheimer's disease; Antipsychotic Dimebon * Phase I / IIa Medivation (USA) Huntington's Disease Treatment Dimebon * Phase II (Russia) Schizophrenia PRX-07034 Phase I Epix Pharm. Overweight treatment; Antipsychotic; Cognitive Disease Treatment SB-737050A Phase II GlaxoSmithKline Antipsychotic BVT-74316 Phase I Biovitrum Overweight treatment SAM-315 Phase I Wyeth Pharm. Alzheimer's Disease Treatment SYN-114 Phase I Roche, Synosis Ther. Cognitive Disease Treatment BGC-20-761 Preclinic BTG (London) Antipsychotic; Cognitive Disease Treatment FMPO Preclinic Lilly Antipsychotic Dimebon ^TM Preclinic (Russia) Stroke treatment

Another attractive property of 5-HT ₆ receptor antagonists is their ability to suppress appetite, which can lead to the creation on their basis of fundamentally new means for reducing excess weight and obesity [Vicker SP, Dourish S.Т. Serotonin receptor ligands and the treatment of obesity. Curr. Opin. Investig. Drugs 2004; 5: 377-388]. This effect has been confirmed in many studies [Holenz J., Pauwels PJ, Diaz JL, Merce R., Codony X., Buschmann H. Medicinal chemistry strategies to 5-HT ₆ receptor ligands as potential cognitive enhancers and antiobesity agents. Drug Disc. Today. 2006; 11: 283-299. Davies SL Drug discovery targets: 5-HT ₆ receptor. Drug Future. 2005; 30: 479-495], its mechanism is based on the suppression of 5-HT ₆ antagonists of gamma-aminobutyric acid signaling receptors and an increase in the release of alpha-melanocyte-stimulating hormone, which ultimately leads to a decrease in food requirements [Woolley ML 5-ht6 receptors . Curr. Drug Targets CNS Neurol. Disord 2004; 3: 59-79]. Currently, two 5-HT ₆ receptor antagonists are in the first stage of clinical trials as drug candidates for overweight treatment (Table 1) [http://integrity.prous.com].

In this regard, the search for selective and effective antagonists of serotonin 5-HT ₆ receptors seems to be an original and promising approach to the creation of new drugs for the treatment of a wide range of central nervous system diseases, including neurological and neurodegenerative diseases and cognitive disorders.

There are a significant number of publications in the literature on various biologically active sulfonyl derivatives of azaheterocycles, including serotonin receptor ligands. For example, substituted 1- (2-aminoethyl) -4-arylsulfonyl-pyrazoles of general formula A1 are known as ligands of serotonin 5-HT _2c receptors [WO 2003057674 A1] and 7-amino-3-sulfonyl-pyrazolo [1,5 -a] pyrimidines A2, as antagonists of serotonin 5-HT ₆ receptors [EP 941994 A1, 1999]

A1: Ar = alkyl, aryl; R ¹ and R ² = H, OH, alkyl, alkoxy; R ³ and R ⁴ = H, alkyl, aryl.

A2: Ar = aryl, heterocyclyl; R ¹ = H, alkyl, alkylthio; R ² = H, alkyl, halogen; R ³ = H, alkyl, hydroxyalkyl; R ⁴ and R ⁵ = H; NR ⁴ R ⁵ = piperazinyl.

In order to develop new highly effective drugs, the authors of this invention carried out extensive studies in the series of substituted 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo [1,5-a] pyrimidines, as a result of which new drug principles, which are antagonists of 5-HT ₆ receptors, were found .

The following are definitions of terms that are used in the description of this invention:

“Agonists” means ligands that, by binding to receptors of a given type, actively promote the transmission of their specific signal by these receptors and thereby elicit a biological response from the cell.

“Azaheterocycle” means an aromatic or non-aromatic monocyclic or polycyclic system containing at least one nitrogen atom in a ring. An azaheterocycle may have one or more “cyclic” substituents.

"Alkyl" means an aliphatic hydrocarbon 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. Alkyl may have one or more identical or different substituents (“alkyl substituents”), including halogen, alkenyloxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl, alkylthio, heteroarylthio, aralkylthio, arylsulfonyl, alkylsulfonyl, heteroaralkyloxy, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroaryl heterocyclenyl, annelated heteroaryl heterocyclyl, annelated aero kloalkenil, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl, alkoxycarbonyl, aralkoxycarbonyl, geteroaralkiloksikarbonil or R _k ^a R _{k + 1} ^a N-, R _k ^a R _{k + 1} ^a NC _{(= O) -, R k} a R k + ₁ ^a NC (= S) -, R _k ^a R _{k + 1} ^a NSO ₂ -, where R _k ^a and R _{k + 1} ^{a are} independently “amino substituents”, the meaning of which is defined in this section, for example, a hydrogen atom, alkyl, aryl, aralkyl, heteroaralkyl, heterocyclyl or heteroaryl, or R _k ^a and R _{k + 1} ^a together with the N atom to which they are bonded, form through R _k ^a and R _{k + 1} ^a 4-7- member get erocyclyl or heterocyclenyl. Preferred alkyl groups are methyl, trifluoromethyl, ethyl, propyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl benzyloxycarbonylmethyl, methoxycarbonylmethyl and pyridylmethyloxycarbonylmethyl. The preferred "alkyl substituents" are cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, alkoxycarbonyl, aralkoxy, aryloxy, alkylthio, heteroarylthio, aralkylthio, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, geteroaralkiloksikarbonil or R _k ^a R _{k + 1} ^a N- , R _k ^a R _{k + 1} ^a NC (= O) -, annelated arylheterocyclenyl, annelated arylheterocyclyl.

“Alkylamino” means C _n H _{2n + 1} NH— or (C _n H _{2n + 1} ) (C _n H _{2n + 1} ) the N-group in which alkyl is defined in this section. Preferred alkylamino groups are methylamino, ethylamino, n-propylamino, iso-propylamino and n-butylamino.

“Alkyloxy” means a C _n H _{2n + 1} O-group in which alkyl is defined in this section. Preferred alkyloxy groups are methyloxy, ethyloxy, n-propyloxy, iso-propyloxy and n-butyloxy.

“Alkyloxycarbonyl” means —C (O) OC _n H _{2n + 1 -} group in which alkyl is defined in this section.

“Alkylsulfanyl” means an alkyl-S-group in which alkyl is defined in this section. Preferred alkylsulfanyl groups are methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, iso-propylsulfanyl and n-butylsulfanyl.

“Amino group” means a —NR ⁶ R ⁷ group in which R ⁶ and R ⁷ are optionally the same hydrogen atom, optionally substituted lower alkyl, or R ⁶ and R ^7, together with the nitrogen atom to which they are attached, form an optionally substituted azaheterocyclyl.

“Aminocarbonyl” means a —CONR ⁶ R ⁷ group in which R ⁶ and R ⁷ are optionally the same hydrogen atom, optionally substituted lower alkyl, or R ⁶ and R ^7, together with the nitrogen atom to which they are bonded, form optionally substituted azaheterocyclyl.

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

“Antagonists” means ligands that bind to receptors of a particular type and do not elicit an active cellular response. Antagonists inhibit the binding of agonists to receptors and thereby block the transmission of a specific receptor signal.

"Antidepressant" means a medication intended to treat depression.

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

“Aryl” means an aromatic monocyclic or polycyclic system comprising from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms. Aryl may contain one or more “cyclic system substituents”, which may be the same or different. Representative aryl groups are phenyl or naphthyl, substituted phenyl or substituted naphthyl. Aryl can be annelated with a non-aromatic ring system or heterocycle.

"Arylsulfonyl" means aryl-SO ₂ - a group in which the meaning of aryl is defined in this section.

“Halogen” means fluoro, chloro, bromo and iodo. Fluorine, chlorine and bromine are preferred.

"Hydrate" means a solvate in which water is a molecule or molecules of a solvent.

“Depression” means major depression; episodic, chronic and recurrent forms of major depression; dysthymic disorder (dysthymia); cyclotymia; affective disorders; seasonal affective disorder syndrome; bipolar disorders, including type I and type II bipolar disorders; as well as other depressive disorders and conditions. The term depression also means the depressive conditions accompanying Alzheimer's disease, vascular dementia; mood disorders induced by alcohol and substances; schizoaffective disorder of the depressive type; adaptation disorders. In addition, depression includes depressive states of cancer patients; with Parkinson's disease; depression after myocardial infarction; depression of infertile women; pediatric depression; postpartum depression; as well as other depressive conditions accompanying somatic, neuralogical and other diseases.

“Substituent” means a chemical radical that is attached to a scaffold (fragment), for example, “substituent alkyl”, “substituent of an amino group”, “substituent of carbamoyl”, “substituent of a cyclic system”, the meanings of which are defined in this section.

представляют собой независимо друг от друга «заместители аминогруппы», значение которых определено в данном разделе, например, водород, необязательно замещенный алкил, необязательно замещенный арил, необязательно замещенный аралкил или необязательно замещенный гетероаралкил, или заместитель R_k ^aR_k+1 ^aN-, в котором R_k ^a может быть ацил или ароил, а значение R_k+1 ^a определено выше, или «заместителем циклической системы» является R_k ^aR_k+1 ^aNC(=O)- или R_k ^aR_k+1 ^aNSO₂-, в котором R_k ^a и R_k+1 ^a вместе с атомом азота, с которым они связаны, образуют через R_k ^a и R_k+1 ^a 4-7- членный гетероциклил или гетероцикленил."Substituent cyclic system" means a substituent attached to an aromatic or non-aromatic cyclic system, including hydrogen, alkylalkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroalkyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkoxy, aryloxy, acyl, aroyl, halogen, nitro , cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkyloxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, arylalkyloxyalkyl, heterocyclylalkyloxyalkyl, alkylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, finil, arylsulfinyl, geterotsiklilsulfinil, alkylthio, arylthio, heterocyclylthio, alkylsulfonylalkyl, arylsulfonylalkyl, geterotsiklilsulfonilalkil, alkylsulfinylalkyl, arylsulfinylalkyl, geterotsiklilsulfinilalkil, alkylthioalkyl, arylthioalkyl geterotsikliltioalkil, arilalkilsulfonilalkil, geterotsiklilalkilsulfonilalkil, arilalkiltioalkil, geterotsiklilalkiltioalkil, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, amidino,

independently represent “amino substituents”, the meanings of which are defined in this section, for example, hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or a substituent R _k ^a R _{k + 1} ^a N- in which R _k ^a may be acyl or aroyl, and the value of R _{k + 1} ^{a is} defined above, or the “cyclic system substituent” is R _k ^a R _{k + 1} ^a NC (= O) - or R _k ^a R _{k + 1} ^a NSO ₂ -, in which R _k ^a and R _{k + 1} ^a together with the nitrogen atom to which they are bonded, form through R _k ^a and R _{k + 1} ^a 4-7 membered heterocyclyl or heterocyclenyl.

"Carboxyl" means a group -CO ₂ H.

“Cognitive impairment or cognitive disorder” means impaired (weakened) mental capabilities, including attention, memory, thinking, cognition, learning, speech, cognitive, executive and creative abilities, orientation in time and space, in particular cognitive Alzheimer's, Parkinson's and Huntington's disease disorders; senile dementia; age-related memory impairment (AAMI); dysmetabolic encephalopathies; psychogenic memory impairment; amnesia; amnestic disorders; transient global amnesia; dissociative amnesia; vascular dementia; mild (or moderate) cognitive impairment (mild cognitive impairment, MCI); attention deficit hyperactivity disorder (AD / HD); cognitive impairment accompanying psychotic diseases, epilepsy, delirium, autism, psychosis, Down syndrome, bipolar disorder and depression; AIDS-related dementia; dementia with hypothyroidism; dementia induced by alcohol, addictive substances, and neurotoxins; dementia accompanying neurodegenerative diseases, for example, cerebellar degeneration and amyotrophic lateral sclerosis; cognitive disorders that develop with stroke, infectious and oncological diseases of the brain, as well as with traumatic brain injuries; cognitive impairment associated with autoimmune and endocrine diseases; and other cognitive disorders.

“Medicinal substance” (drug substance, drug substance, drug-substance) means a physiologically active substance of synthetic or other (biotechnological, plant, animal, microbial and other) origin, having pharmacological activity and is an active principle of the pharmaceutical composition used for the manufacture and manufacture medicinal product (preparation).

“Medicinal product (preparation)” - a substance (or a mixture of substances in the form of a pharmaceutical composition) in the form of tablets, capsules, injections, ointments and other formulations intended to restore, correct or alter physiological functions in humans and animals, as well as treatment and prevention of diseases, diagnosis, anesthesia, contraception, cosmetology and other things.

"Ligands" (from Latin ligo - bind) are chemicals (small molecule, inorganic ion, peptide, protein, etc.) that can interact with receptors that transform this interaction into a specific signal.

“Neurodegenerative disease (ND)” means a specific condition and disease characterized by damage and primary death of populations of nerve cells in certain areas of the central nervous system. Neurodegenerative diseases include, but are not limited to, Alzheimer's and Parkinson's disease; Huntington's disease (chorea); multiple sclerosis; cerebellar degeneration; amyotrophic lateral sclerosis; dementia with Levy bodies; spinal muscular atrophy; peripheral neuropathy; spongiform encephalitis ("mad cow disease", Creutzfeld-Jakob Disease); AIDS-related dementia; multi-infarct dementia; frontotemporal dementia; leukoencephalopathy (white matter disappearance disease); chronic neurodegenerative diseases; stroke; ischemic, reperfusion, and 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 that develop with hypoxia, abuse of addictive substances when exposed to neurotoxins, infectious and oncological diseases of the brain, as well as neuronal damage associated with autoimmune and endocrine diseases; and other neurodegenerative processes.

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

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

“Mental disorders” (mental illness) are illnesses or illnesses associated with a mental disorder and / or disorder. Mental disorders include affective disorders (bipolar affective disorders, major depression, hypomania, minor depression, manic syndrome, Cotard syndrome, cyclothymia, schizoaffective disorder, etc.); intellectual and mnestic disorders, mania (hypomania, graphomania, kleptomania, shop-mania, persecution mania, monomania, pornography, erotomania, etc.); Disorder of multiple personality, amentia, delirium tremens, delirium, delusional syndrome, hallucinatory syndrome, hallucinations, hallucination, gomitsidomaniyu, delirium, illusion querulant, clinical lycanthropy, macropsia, Manichean delusions micropsia, drug addiction, anorexia nervosa, oneiroid syndrome, paronoid, paranoia , paraphrenia, pseudo-hallucinations, psychosis, Cotard's syndrome, schizoaffective disorder, schizotypal disorder, schizophrenia, schizophrenia-like disorder, schizophrenomorphic disorder, Schreber syndrome, Daniel Pau la; phobias (agarophobia, arachnophobia, autophobia, verminophobia, hydrosophobia, hydrophobia, demophobia, zoophobia, carcinophobia, claustrophobia, climacophobia, xenophobia, pseudophobia, celophobia, celophobia, celophobia, celophobia, celophobia, celophobia, celophobia, celophobia, celophobia, celophobia, celophobia, celophobia, celophobia, celophobia, celophobia, celophobia, celophobia, celophobia, celophobia, celophobia, celophobia, celophobia, trichobia) alcoholic psychoses, alcoholic palimpsest, allotriophagy, aphasia, graphomania, dissociative fugues, dissociative disorders, dysphoria, Internet addiction, hypochondria, hysteria, coprofemia, persecution mania, melancholy, misanthropy, obsession, panic attacks, Kapusgra syndrome, Aspergus syndrome , Rett syndrome, Fregoli syndrome, attention deficit hyperactivity disorder, obsessive states syndrome, chronic anesthesia effects syndrome, mental automatism syndrome, early childhood syndrome tism, madness, taphophilia, anxiety, Hikikomori syndrome, erotomomaniyu, etc.

“Psychotic diseases” are all types of schizophrenia; schizophrenic diseases; schizotypal disorders; schizoaffective disorders, including bipolar and depressive types; delusional disorders, including delusions of attitude, persecution, greatness, jealousy, erotomania, as well as hypochondriacal, somatic, mixed and undifferentiated delusions; short-term psychotic disorders; induced psychotic disorders; substance-induced psychotic disorders; as well as other psychotic disorders.

“Receptors” (from the Latin recipere - to receive, to recognize) are biological macromolecules located on the cytoplasmic membrane of a cell or intracellular, capable of specifically interacting with a limited set of physiologically active substances (ligands) and transforming the signal about this interaction into a specific cellular response.

A “therapeutic cocktail” is a simultaneously administered combination of two or more drugs with a different mechanism of pharmacological action and aimed at different biological targets involved in the pathogenesis of the disease.

“Anxiety” (anxiety) means generalized (non-specific) anxiety; acute uncontrolled anxiety; panic disease; phobias, for example, agoraphobia (a strong fear of crowded places) or social phobia (a strong fear of humiliation before other people) or any specific phobia (a strong fear of specific objects, animals or situations, in the form of a fear of heights, medical procedures, elevators, open space, etc. .P.); obsessive states (obsessive-compulsive disorder); post-traumatic stress disorder and acute stress disorder. In addition, anxiety disorders include anxiety conditions induced by alcohol or substances; anxiety in adaptation disorders; 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, hypertoxic (febrile), catatonic, schizoaffective, residual or non-differentiable schizophrenia and / or forms of schizophrenia defined in the classification of the American Psychiatric Association { Psychiatric Association; in: Diagnostic and Statistical Manual of Menial Disorders, IV Edition, Washington D.C. 2000) or in the International Statistical Classification of Diseases and Related Health Problems' or any other known forms

"Pharmaceutical composition" means a composition comprising a compound of formula I and at least one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, excipients, distributing and perceiving agents, agents delivery, such as preservatives, stabilizers, fillers, grinders, moisturizers, emulsifiers, suspending agents, thickeners, sweeteners, perfumes, flavors, antibacterial agents, fungicides, lubricants, prolonged delivery regulators, the choice and ratio of which depends on the nature and method of administration and dosage. Examples of suspending agents are ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, as well as mixtures of these substances. Protection against the action of microorganisms can be provided with a variety of antibacterial and antifungal agents, for example, parabens, chlorobutanol, sorbic acid and the like. The composition may also include isotonic agents, for example, sugars, sodium chloride and the like. The prolonged action of the composition can be achieved using agents that slow down the absorption of the active principle, for example, aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols, and also mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Examples of excipients are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like. Examples of grinders and distributors are starch, alginic acid and its salts, silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycol. The pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal administration of the active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard administration form, in the form of a mixture with traditional pharmaceutical carriers. Suitable unit dosage forms include oral forms such as tablets, gelatine capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, implants, local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms. Pharmaceutical compositions are generally prepared using standard procedures involving the mixing of the active compound with a liquid or finely divided solid carrier.

“Pharmaceutically acceptable salt” means the relatively non-toxic organic and inorganic salts of the acids and bases of the present invention. These salts can be obtained in situ during the synthesis, isolation or purification of the compounds or prepared specially. In particular, base salts can be prepared on the basis of the purified free base of the claimed compound and a suitable organic or inorganic acid. Examples of salts thus obtained are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valeriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, maleates, fumarates, succinates, tartrates mesylates, malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like. (A detailed description of the properties of such salts is given in Berge S. M., et al., "Pharmaceutical Salts" J. Pharm. Sci. 1977, 66: 1-19). Salts of the claimed acids can also be specially prepared by reacting the purified acid with a suitable base, and metal and amine salts can be synthesized. Metal salts include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum salts, the most desirable of which are sodium and potassium salts. Suitable inorganic bases from which metal salts can be obtained are hydroxide, carbonate, sodium bicarbonate and hydride, potassium hydroxide and bicarbonate, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide. As organic bases from which salts of the claimed acids can be obtained, amines and amino acids are selected that are sufficiently basic to form a stable salt and are suitable for medical use (in particular, they should have 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, tetraalkylammonium hydroxides, for example, such as choline, tetramethylammonium, tetraethylammonium and the like, can be used for salt formation. As amino acids, the main amino acids can be used - lysine, ornithine and arginine.

The subject of the present invention are novel substituted 2-alkylsulfanyl-3-arylsulfonylpyrazolo [1,5-a] pyrimidines of the general formula 1 and their pharmaceutically acceptable salts and / or hydrates,

Where

R ¹ and R ³ independently from each other are optionally the same C ₁ -C ₃ alkyl, and R ² represents a group - (CH ₂ ) _n X or

R ¹ and R ³ independently from each other are different substituents selected from C ₁ -C ₃ alkyl or a group - (CH ₂ ) _n X, and R ² represents a hydrogen atom or C ₁ -C ₃ alkyl;

R ⁴ represents C ₁ -C ₃ alkyl;

R _i ⁵ represents a hydrogen atom, one or two identical or different halogen atoms, C ₁ -C ₃ alkyl;

i represents the number 0, 1 or 2;

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

X represents carboxyl CO ₂ H, C ₁ -C ₃ alkyloxycarbonyl, aminocarbonyl CONR ⁶ R ⁷ or an amino group NR ⁶ R ⁷ ; excluding compounds in which R ³ represents a group - (CH ₂ ) _n X, where X represents an amino group NR ⁶ R ⁷ and n is 0;

R ⁶ and R ⁷ are optionally the same hydrogen atom, optionally substituted C ₁ -C ₅ alkyl, or R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form an optionally substituted 6-membered azaheterocyclyl containing 1-2 nitrogen atoms in a cycle where the substituent is selected from C ₁ -C ₃ alkyl.

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

where n and R _i ⁵ have the above meaning.

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

where n and R _i ⁵ have the above meaning.

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

where n, R _i ⁵ , R ⁶ and R ⁷ have the above meaning.

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

R⁶ и R⁷ имеют вышеуказанное значение.where n

R ⁶ and R ⁷ have the above meaning.

More preferred amines of the general formula 1.10, 1.11 and 1.12 are 6-amino-5,7-dimethyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine 1.10 (1), 6-aminomethyl-5.7 -dimethyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine 1.10 (2), 6- (2-aminoethyl) -5,7-dimethyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo [1 5-a] pyrimidine 1.10 (3), 6- (3-aminopropyl) -5,7-dimethyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine 1.10 (4), 6-aminomethyl -5,7-dimethyl-2-methylsulfanyl-3- (3-chlorophenylsulfonyl) pyrazolo [1,5-a] pyrimidine 1.10 (5), 6-aminomethyl-5,7-dimethyl-2-methylsulfanyl-3- ( 3-fluoro enylsulfonyl) pyrazolo [1,5-a] pyrimidine 1.10 (6), 6-aminomethyl-5,7-dimethyl-2-methylsulfanyl-3- (4-fluoro-3-chlorophenylsulfonyl) pyrazolo [1,5-a ] pyrimidine 1.10 (7), 6- (2-aminoethyl) -5,7-dimethyl-2-methylsulfanyl-3- (3-chlorophenylsulfonyl) pyrazolo [1,5-a] pyrimidine 1.10 (8), 6- ( 2-aminoethyl) -5,7-dimethyl-2-methylsulfanyl-3- (3-fluorophenylsulfonyl) pyrazolo [1,5-a] pyrimidine 1.10 (9), 5,7-dimethyl-6-dimethylaminomethyl-2-methylsulfanyl -3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine 1.10 (10), 5,7-dimethyl-6-dimethylaminomethyl-2-methylsulfanyl-3- (3-chlorophenylsulfonyl) -pyrazolo [1,5-a] pyrimidine 1.10 (11), 5,7-dimethyl-6-dimethylamino ethyl-2-methylsulfanyl-3- (3-fluorophenylsulfonyl) pyrazolo [1,5-a] pyrimidine 1.10 (12), 5,7-dimethyl-6-dimethylaminomethyl-2-methylsulfanyl-3- (4-fluoro-3 -chlorophenylsulfonyl) -pyrazolo [1,5-a] pyrimidine 1.10 (13), 5,7-dimethyl-6- (2-dimethylaminoethyl) -2-methylsulfanyl-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine 1.10 (14), 5,7-dimethyl-6- (2-dimethylaminoethyl) -2-methylsulfanyl-3- (3-chlorophenylsulfonyl) pyrazolo [1,5-a] pyrimidine 1.10 (15), 5,7-dimethyl- 6- (2-dimethylaminoethyl) -2-methylsulfanyl-3- (3-fluorophenylsulfonyl) pyrazolo [1,5-a] pyrimidine 1.10 (16), 5,7-dimethyl-6- (2-dimethylaminoethyl) - 2-methylsulfanyl-3- (4-fluoro-3-chlorophenyls ulphonyl) pyrazolo [1,5-a] pyrimidine 1.10 (17), 5-aminomethyl-7-methyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine 1.11 (1), 5- ( 2-aminoethyl) -7-methyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine 1.11 (2), 5-dimethylaminomethyl-7-methyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo [1 , 5-a] pyrimidine 1.11 (3), 5-dimethylaminomethyl-7-methyl-2-methylsulfanyl-3- (4-fluoro-3-chloro-phenylsulfonyl) -pyrazolo [1,5-a] pyrimidine 1.11 (4) 5- (2-dimethylaminoethyl) -7-methyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine 1.11 (5), 7-aminomethyl-5-methyl-2-methylsulfanyl-3-phenylsulfonyl pyraz lo [1,5-a] pyrimidine 1.12 (1), 7- (2-aminoethyl) -5-methyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine 1.12 (2), 7- dimethylaminomethyl-5-methyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine 1.12 (3), 7-dimethylaminomethyl-5-methyl-2-methylsulfanyl-3- (4-fluoro-3-chloro -phenylsulfonyl) -pyrazolo [1,5-a] pyrimidine 1.12 (4), 7- (2-dimethylaminoethyl) -5-methyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine 1.12 (5 ) and their pharmaceutically acceptable salts and / or hydrates,

An object of the present invention is a method for producing esters of general formula 1.1 by reacting 3-amino-4-sulfonyl-2H-pyrazoles of general formula 2 with the corresponding β-dicarbonyl compounds of general formula 3 according to the scheme below.

in which n, R ¹ , R ³ , R ⁴ and R _i ⁵ have the above meaning.

The subject of the present invention is also a process for preparing esters of general formula 1.2, 1.3 by reacting 3-amino-4-sulfonyl-2H-pyrazoles of general formula 2 with the corresponding β-dicarbonyl compounds of general formula 4, followed by isolation and purification or separation of reaction products according to the scheme shown below.

in which n, R ¹ , R ³ , R ⁴ and R _i ⁵ have the above meaning.

The subject of the present invention is also a method for producing acids of the general formula 1, 1.4, 1.5, 1.6 by hydrolysis of the corresponding esters of the general formula 1, 1.1, 1.2, 1.3.

The subject of the present invention is also a process for preparing amides of the general formula 1.7, 1.8, 1.9 by reacting the corresponding acids of the general formula 1.4, 1.5, 1.6 or their derivatives with amines of the general formula 5,

in which R ⁶ and R ⁷ have the above meaning.

The subject of the present invention is also a process for preparing amides of the general formula 1.7 by reacting 3-amino-4-sulfonyl-2H-pyrazoles of the general formula 2 with the corresponding β-dicarbonyl compounds of the general formula 6,

in which n, R ¹ , R ³ , R ⁴ , R _i ⁵ R ⁶ and R ⁷ have the above meaning.

The subject of the present invention is also a method for producing amides of the general formula 1.8, 1.9 by reacting 3-amino-4-sulfonyl-2H-pyrazoles of the general formula 2 with the corresponding β-dicarbonyl compounds of the general formula 7, followed by isolation and purification or separation of the reaction products according to the scheme shown below.

in which n, R ¹ , R ³ , R ⁴ , R _i ⁵ , R ⁶ and R ⁷ have the above meaning.

The subject of the present invention is also a method for producing amines of the general formula 1.10, 1.11, 1.12 and their pharmaceutically acceptable salts and / or hydrates by successive conversion of acids of the general formula 1.4, 1.5, 1.6 to the corresponding acyl azides of the general formula 1.13, 1.14, 1.15 by the action of sodium azide, by thermal decomposition of the obtained azides into isocyanates of the general formula 1.16, 1.17, 1.18 and hydrolysis of the latter into amines of the general formula 1.10, 1.11, 1.12, respectively, according to the schemes presented below.

in which n, R ¹ , R ³ , R ⁴ and R _i ⁵ have the above meaning.

The subject of the present invention is also a process for preparing amines of the general formula 1.10, 1.11, 1.12 by reductive alkylation of amines 1.10, 1.11, 1.12, in which R ⁶ and R ⁷ represent a hydrogen atom, carbonyl compounds of the general formula 8,

where R ⁸ and R ⁹ are optionally the same hydrogen atom, optionally substituted C ₁ -C ₃ alkyl, or R ⁸ and R ⁹ together with the carbon atom to which they are attached form an optionally substituted C ₅ -C ₇ cycloalkylene or heterocycle, including one heteroatom and 4-6 carbon atoms.

The subject of the present invention are also 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo [1,5-a] pyrimidines of the general formula 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, 1.11, 1.12 and their pharmaceutically acceptable salts and / or hydrates having antagonists of serotonin 5-HT ₆ receptors.

More preferred 2-alkylsulfanyl-3-arylsulfonylpyrazolo [1,5-a] pyrimidines as serotonin 5-HT ₆ receptor antagonists are amines 1.10 (1) to 1.10 (17) and their pharmaceutically acceptable salts and / or hydrates.

The subject of the present invention are also 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo [1,5-a] pyrimidines of the general formula 1 and compounds 1.10 (1) to 1.10 (17), from 1.11 (1) to 1.11 (5), from 1.12 (1) to 1.12 (5) and their pharmaceutically acceptable salts and / or hydrates as “molecular tools” for studying the molecular mechanism of interaction with serotonin 5-HT ₆ receptors.

The subject of the present invention are also 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo [1,5-a] pyrimidines of the general formula 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, 1.11, 1.12 and their pharmaceutically acceptable salts and / or hydrates, as a drug source for pharmaceutical compositions and drugs.

More preferred compounds as a medicament are compounds 1.10 (1) -1.10 (17), 1.11 (1) -1.11 (5), 1.12 (1) -1.12 (5) and their pharmaceutically acceptable salts and / or hydrates.

The subject of this invention is also a pharmaceutical composition for treating and preventing the development of conditions and diseases of the central nervous system of humans and warm-blooded animals, containing a pharmaceutically effective amount of a new drug source, which is at least one of the compounds of the general formula 1, 1.1, 1.2, 1.3, 1.4 , 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, 1.11. 1.12 and its pharmaceutically acceptable salt and / or hydrate, or at least one of compounds 1.10 (1) -1.10 (17), 1.11 (1) -1.11 (5), 1.12 (1) -1.12 (5) and its a pharmaceutically acceptable salt and / or hydrate.

The pharmaceutical composition may include pharmaceutically acceptable excipients. By pharmaceutically acceptable excipients are meant diluents, excipients and / or carriers used in the pharmaceutical field. The pharmaceutical composition along with the drug beginning of the present invention may include other active ingredients, provided that they do not cause undesirable effects, for example, allergic reactions.

If it is necessary to use the pharmaceutical compositions of the present invention in clinical practice, they can be mixed for the manufacture of various forms, while they can include traditional pharmaceutical carriers; for example, oral forms (such as tablets, gelatine capsules, pills, solutions or suspensions); injection forms (such as injectable solutions or suspensions, or dry powder for injection, which only requires the addition of water for injection before use); local forms (such as ointments or solutions).

The carriers used in the pharmaceutical compositions of the present invention are carriers that are used in the pharmaceutical field to obtain common forms, including: in oral forms, binders, lubricants, disintegrants, solvents, diluents, stabilizers, suspending agents, colorless are used agents, flavoring agents of taste; antiseptic agents, solubilizers, stabilizers are used in injection forms; in local forms, bases, diluents, lubricants, antiseptic agents are used.

The subject of this invention is also a method for preparing a new pharmaceutical composition by mixing with an inert excipient and / or solvent of a drug substance, which is at least one of the compounds of the general formula 1, 1.1, 1.2, 1.3, 1.4, 1.5. 1.6, 1.7, 1.8, 1.9, 1.10, 1.11, 1.12 and its pharmaceutically acceptable salt and / or hydrate, or at least one of the compounds of the formula 1.10 (1) to 1.10 (17), 1.11 (1) to 1.11 (5), from 1.12 (1) to 1.12 (5), and a pharmaceutically acceptable salt and / or hydrate thereof.

The subject of this invention is a medicament in the form of tablets, capsules or injections, placed in a pharmaceutically acceptable package, for the prophylaxis and treatment of diseases of the central nervous system, the pathogenesis of which is associated with 5-HT ₆ receptors, including a pharmaceutically effective amount of the drug substance, which is, according to at least one of the compounds of the general formula 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, 1.11, 1.12 and a pharmaceutically acceptable salt and / or hydrate thereof, or at least one of compounds f formulas 1.10 (1) to 1.10 (17), 1.11 (1) to 1.11 (5), 1.12 (1) to 1.12 (5) and a pharmaceutically acceptable salt and / or hydrate thereof, or a pharmaceutical composition containing this drug Start.

More preferred is a drug in the form of tablets, capsules or injections in a pharmaceutically acceptable package for the prevention and treatment of cognitive disorders and neurodegenerative diseases, including a pharmaceutically effective amount of a new drug start.

More preferred is a medicament in the form of tablets, capsules or injections in a pharmaceutically acceptable package for the prophylaxis and treatment of Alzheimer's disease, Parkinson's disease, Huntington's disease, comprising a pharmaceutically effective amount of a medicinal agent, representing at least one antagonist of the General formula 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, 1.11, 1.12 and its pharmaceutically acceptable salt and / or hydrate or at least one antagonist of the formula 1.10 (1) to 1.10 (17), from 1.11 (1) to 1.11 (5), from 1. 12 (1) to 1.12 (5) and a pharmaceutically acceptable salt and / or hydrate thereof, or a pharmaceutical composition containing a new drug onset.

A subject of the invention is also a medicament in the form of tablets, capsules or injections in a pharmaceutically acceptable package for the prevention and treatment of mental disorders and schizophrenia, comprising a pharmaceutically effective amount of a medicinal agent, representing at least one of the compounds of general formula 1 , 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, 1.11, 1.12 and its pharmaceutically acceptable salt and / or hydrate, or at least one of the compounds of formula 1.10 (1) to 1.10 (17), from 1.11 (1) to 1.11 (5), from 1.12 (1) n 1.12 (5) and its pharmaceutically acceptable salt and / or hydrate thereof, or a pharmaceutical composition comprising a novel drug substance.

More preferred is a medicament (anxiolytic or tranquilizer) for the prevention and treatment of anxiety disorders, comprising a pharmaceutically effective amount of the drug beginning, representing at least one of the compounds of General formula 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, 1.11, 1.12 and its pharmaceutically acceptable salt and / or hydrate, or at least one of the compounds of the formula 1.10 (1) to 1.10 (17), 1.11 (1) to 1.11 (5 ), from 1.12 (1) to 1.12 (5) and its pharmaceutically acceptable salt and / or hydrate, or pharmaceutical compo itsii comprising a novel drug substance.

More preferred is a drug (nootropic) for the prevention and treatment of hyperkinetic disorders, in particular for improving mental abilities, including a pharmaceutically effective amount of the drug beginning, representing at least one of the compounds of General formula 1, 1.1, 1.2, 1.3, 1.4 , 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, 1.11, 1.12 and its pharmaceutically acceptable salt and / or hydrate, or at least one of the compounds of formula 1.10 (1) to 1.10 (17), 1.11 ( 1) according to 1.11 (5), from 1.12 (1) to 1.12 (5) and its pharmaceutically acceptable salt / Or hydrate thereof, or a pharmaceutical composition comprising a novel drug substance.

The subject of the present invention is also a medicament in the form of tablets, capsules or injections in a pharmaceutically acceptable package for the prevention and treatment of obesity, comprising a pharmaceutically effective amount of a medicinal agent, representing at least one of the compounds of general formula 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, 1.11, 1.12 and its pharmaceutically acceptable salt and / or hydrate, or at least one of the compounds of the formula 1.10 (1) to 1.10 (17 ), from 1.11 (1) to 1.11 (5), from 1.12 (1) to 1.12 (5) and its pharmaceutically an acceptable salt and / or hydrate, or pharmaceutical composition containing a new drug beginning.

The subject of this invention is also a therapeutic cocktail for the prevention and treatment of various diseases, the pathogenesis of which is associated with 5-HT ₆ receptors in animals and humans, including the drug in the form of tablets, capsules or injections, placed in a pharmaceutically acceptable package, including a pharmaceutically effective amount of the drug beginning, representing at least one of the compounds of General formula 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, 1.11, 1.12 and its pharmaceutically acceptable salt and / or hydra t, or at least one of the compounds of the formula 1.10 (1) to 1.10 (17), 1.11 (1) to 1.11 (5), 1.12 (1) to 1.12 (5) and a pharmaceutically acceptable salt thereof and / or a hydrate, or a pharmaceutical composition containing a new drug start.

The subject of this invention is also a therapeutic cocktail for the prevention and treatment of neurological disorders, neurodegenerative and cognitive diseases in animals and humans, including the prevention and treatment of Alzheimer's disease, Parkinson's disease, Huntington’s disease, mental disorders and schizophrenia, hypoxia-ischemia, hypoglycemia, convulsive conditions, brain injuries, latirism, amyotrophic lateral sclerosis, obesity and stroke, including a pharmaceutically effective amount of the drug on ozal, representing at least one antagonist of the general formula 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, 1.11, 1.12 and its pharmaceutically acceptable salt and / or hydrate, or, at least one antagonist of the formula 1.10 (1) to 1.10 (17), 1.11 (1) to 1.11 (5), 1.12 (1) to 1.12 (5), and a pharmaceutically acceptable salt and / or hydrate thereof, or a pharmaceutical composition containing a new drug start, or a new drug, comprising a pharmaceutically effective amount of a drug beginning, representing at least one antagonist formulas 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, 1.11, 1.12 and its pharmaceutically acceptable salt and / or hydrate, or at least one antagonist of the formula with 1.10 (1) according to 1.10 (17), from 1.11 (1) to 1.11 (5), from 1.12 (1) to 1.12 (5) and its pharmaceutically acceptable salt and / or hydrate, or a pharmaceutical composition containing a new drug beginning.

Therapeutic cocktails for the prevention and treatment of neurological disorders, neurodegenerative and cognitive diseases in animals and humans, including for the prevention and treatment of Alzheimer's disease, Parkinson's disease, disease. Huntington, mental disorders and schizophrenia, hypoxia-ischemia, hypoglycemia, convulsive conditions, brain injuries, latirism, amyotrophic lateral sclerosis, obesity and stroke, along with the drugs of this invention may include other drugs, such as non-steroidal anti-inflammatory drugs ( Ortofen, Indomethacin, Ibuprofen, etc.); acetylcholinesterase inhibitors (Tacrine, Amiridine, Physostigmine, Arisept, Phenserine, etc.); estrogens (e.g., estradiol); NMDA receptor antagonists (e.g., Memantine, Neramexane); Nootropic drugs (e.g., Piracetam, Phenibut, etc.); AMPA receptor modulators (e.g. Ampalex); CB-1 cannabinoid receptor antagonists (e.g. Rimonabant); MAO-B and / or MAO-A monoamine oxidase inhibitors (e.g. Rasagiline); anti-amyloidogenic drugs (e.g., Tramiprosate); substances that reduce the neurotoxicity of beta-amyloid (for example, Indole-3-propionic acid); gamma and / or beta secretase inhibitors; muscarinic M1 receptor agonists (e.g., Cevimeline); metal chelators (e.g. Clioquinol); GABA (B) receptor antagonists (e.g., CGP-36742); monoclonal antibodies (e.g., Bapineuzumab); antioxidants; neurotrophic agents (e.g., cerebrolysin); antidepressants (e.g., imipramine, sertraline, etc.) and others.

The therapeutic shake for overweight and obesity along with the drugs of this invention includes other drugs, such as anorexic drugs (e.g., Fepranon, Desopimon, Mazindol), hormonal drugs (e.g., Thyroidin), lipid-lowering drugs, such as fibrates ( e.g. Fenofibrate), statins (e.g. Lovastatin, Simvastatin, Pravastatin and Probucol), as well as hypoglycemic drugs (sulfonylureas - e.g. Butamide, Glibenclamide; biguanides - Nap imer, Buformin, Metmorfin) and drugs with a different mechanism of action, such as antagonists of cannabinoid CB-1 receptors (Rimonabant), norepinephrine and serotonin reuptake inhibitors (Sibutramine), fatty acid synthesis enzyme inhibitors (Orlistat) and others, along with antioxidants, food additives etc.

In accordance with this invention, a method for the prevention and treatment of various diseases, the pathogenesis of which is associated with 5-HT ₆ receptors in animals and humans, is the introduction of a pharmaceutically effective amount of a new drug start, a pharmaceutically effective amount of a new pharmaceutical composition, a pharmaceutically effective amount of a new drug or a pharmaceutically effective amount of a new therapeutic cocktail.

Medicines can be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically). The clinical dosage of the active principle, pharmaceutical composition or drug in patients can be adjusted depending on the therapeutic efficacy and bioavailability of the active ingredients in the body, their metabolic rate and excretion from the body, as well as on the age, sex and stage of the patient’s disease, the dose in adults is usually 10 ~ 500 mg, preferably 50 ~ 300 mg. Therefore, during the preparation of the pharmaceutical compositions of the present invention as dosage units, the above effective dosage must be taken into account, with each dosage unit containing 10 ~ 500 mg, preferably 50 ~ 300 mg. In accordance with the instructions of a doctor or pharmacist, these drugs can be taken several times during certain periods of time (preferably from one to six times).

The following examples demonstrate but do not limit the invention.

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

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

Example 3. The General method for producing 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo [1,5-a] pyrimidines of the general formula 1,7, 1.8 and 1.9. To a solution of 0.902 mmol of the acid of the general formula 1.4, 1.5, 1.6 in 5 ml of dimethylformamide, 259 mg of carbodiimidazole (0.992 mmol) is added. The reaction mass is stirred at a temperature of 75 ° C for 1 hour, add 0.992 mmol of amine of General formula 5 and incubated overnight at a temperature of 75 ° C. The completeness of the reaction is monitored by the LC MS method. After completion of the reaction, the reaction mass is poured into a 5% sodium carbonate solution. The product is extracted with dichloromethane. The extract was dried with anhydrous sodium sulfate and evaporated in vacuo. Amides of the general formula 1.7, 1.8 and 1.9 are obtained, which are used to obtain salts without further purification. Table 2 presents some examples of the new 2-alkylsulfanyl-3-arylsulfonylpyrazolo [1,5-a] pyrimidines of the general formula 1.7, 1.8 and 1.9 and their LC MS analyzes and NMR spectra.

Example 4. General method for producing 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo [1,5-a] pyrimidines of the general formula 1.10, 1.11, 1.12.

A. To a mixture of 1.0 mmol of the corresponding acid of the general formula 1.4, 1.5, 1.6 in 10 ml of acetone, a solution of 139 μl (101 mg, 1.18 mmol) of triethylamine in 1 ml of acetone and a solution of 109 μl (123 mg, 1.29 mmol) of ethoxycarbonyl chloride in 1 ml of acetone. The resulting mixture was stirred at 0 ° C for 30 minutes, then a solution of 109 mg (1.53 mmol) of sodium azide in 0.35 ml of water was added dropwise and stirred at 0 ° C for one hour. The resulting reaction mass is poured into 30 ml of ice water. The product was extracted with dichloromethane cooled to 0 ° C, the solvent was evaporated in vacuo to a volume of 2-3 ml at room temperature. The resulting acyl azide solution of the general formula 1.13, 1.14, 1.15 is diluted with dioxane to a volume of 5 ml. This solution was added dropwise in 20 ml of boiling dioxane. After adding azide, the reaction mass is boiled for 1 hour. The resulting isocyanate solution of the general formula 1.16, 1.17, 1.18 is cooled to 70 ° C, 5 ml of a 20% aqueous hydrochloric acid solution are added, stirred at 80 ° C for 3 hours until the hydrolysis of the isocyanate is complete (LC MS control). The product of General formula 1.10, 1.11, 1.12 falls out in the form of hydrochloride after cooling the reaction mass.

B. To a solution of 1 mmol of the corresponding amine of general formula 1.10, 1.11, 1.12, in which R ⁶ and R ⁷ represent a hydrogen atom, 3 mmol of a carbonyl compound of general formula 8 and 2.5 mmol of sodium triacetoxyborohydride are added in 10 ml of dichloroethane. The mixture was stirred for 3 hours at room temperature. Reaction control is carried out according to LC MS. To bring the reaction to the end, another 3 mmol of the carbonyl compound of the general formula 8 and 2.5 mmol of sodium triacetoxyborohydride are added and stirred for 12 hours. The mixture is diluted with water and extracted with dichloromethane, washed with 10% potash solution, dried with sodium sulfate and evaporated. The product of general formula 1.10, 1.11, 1.12 are isolated by column chromatography on silica gel (hexane: ethyl acetate: triethylamine = 30: 10: 1 system). The hydrochloride is prepared by adding an excess of a solution of HCl in dioxane to a solution of the amine in acetone, and if necessary, precipitated with ether.

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

table 2 Antagonists of serotonin 5-HT ₆ receptors - 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo [1,5-a] pyrimidines of the general formula 1 No. Formula Like the weight LCMS m / z (M + 1) NMR spectrum 1.1 (1)

406.51 407 1.1 (2)

447.58 448 1.1 (3)

433.55 434 1.1 (4)

461.61 462

1.1 (5)

433.55 434 1.2 (1)

374.44 375 ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.29 (m, 2H). 7.47-7.57 (m, 4H), 4.07 (s, 3H), 2.82 (d, J = 0.4 Hz, 3H), 2.66 (s, 3H). 1.3 (1)

374.44 375 ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.01 (m, 2H), 7.57-7.67 (m, 4H), 3.97 (s, 3H), 2.66 (s, 3H) 2.56 (s, 3H). 1.4 (1)

378.45 379 1.4 (2)

388.45 389 1.5 (1)

333.35 334

1.6 (1)

333.35 334 1.7 (1) HCl

526.12 490 1.7 (2) HCl

524.11 488 1.8 (1) HCl

484.04 448 1.9 (1) HCl

484.04 448 1.10 (1) 348.45 349

1.10 (2) HCl

398.94 363 ¹ H NMR (DMSO-D ₆ , 400 MHz) δ 8.15 (s, 3H), 8.02 (m, 2H). 7.60 (m, 3H); 4.23 (s, 2H). 2.82 (s, 3H), 2.72 (s, 3H), 2.60 (s, 3H). 1.10 (2) CH ₃ SO ₃ H

458.59 363 1.10 (3) HCl

412.96 377 1.10 (4) HCl

426.99 391 1.10 (5) HCl

433.38 397

1.10 (6) HCl

416.93 381 1.10 (7) HCl

451.37 415 1.10 (8) HCl

447.41 411 1.10 (9) HCl

430.95 395 1.10 (10) HCl

426.99 391

1.10 (11) HCl

461.43 425 1.10 (12) HCl

444.98 409 1.10 (13) HCl

479.43 443 1.10 (14) HCl

441.02 405 1.10 (15) HCl

475.46 440

1.10 (16) HCl

459.01 423 1.10 (17) HCl

493.45 457 1.10 (18) HCl

441.02 405 1.11 (1) HCl

394.91 349 1.11 (2) HCl

398.94 363

1.11 (3) HCl

412.96 377 1.11 (4) HCl

465.40 429 1.11 (5) HCl

426.99 391 1.12 (1) HCl

394.91 349 1.12 (2) HCl

398.94 363 1.12 (3) HCl

412.96 377

1.12 (4) HCl

465.40 429 1.12 (5) HCl

426.99 391

Example 5. Determination of the antagonistic activity of compounds of General formula 1 in relation to 5-HT ₆ receptors. Substances of general formula 1 were tested for their ability to inhibit the activation of 5-HT ₆ receptors by serotonin. We used HEK 293 cells (human embryonic kidney cells) with an artificially expressed 5-HT ₆ receptor, activation of which by serotonin leads to an increase in the concentration of intracellular cAMP. The content of intracellular cAMP was determined using the LANCE cAMP reagent kit (PerkinElmer) according to the procedure described by the kit manufacturer [http://las.perkinelmer.com/content/Manuals/MAN_LANCEcAMP384KitUser.pdf].

The effectiveness of the compounds was evaluated by their ability to reduce the content of intracellular cAMP induced by serotonin.

It has been established that the percentage inhibition of serotonin 5-HT ₆ receptors under functional essay 1 μM by compounds of the general formula 1, as a rule, ranges from 95-107%, and their activity to serotonin 5-HT ₆ receptors under functional essay ranges from from IC ₅₀ = 5 nM to IC ₅₀ = 500 nM.

Example 6. Obtaining a drug in the form of tablets. 1600 mg of starch, 1600 mg of powdered lactose, 400 mg of talc and 1000 mg of compound 1.10 (2) · HCl are mixed and pressed into a block. The resulting bar is crushed into granules and sieved through sieves, collecting granules with a size of 14-16 mesh. The granules obtained are tabletted into a suitable tablet form weighing 560 mg each.

Example 7. Obtaining a drug in the form of capsules. Compound 1.10 (2) · HCl is thoroughly mixed with lactose powder in a 2: 1 ratio. The resulting powder mixture is packaged in 300 mg in a suitable size gelatin capsule.

Example 8. Obtaining a medicinal product in the form of injection compositions for intramuscular, intraperitoneal or subcutaneous injection. 500 mg of compound 1.10 (2) · HCl are mixed with 300 mg of chlorobutanol, 2 ml of propylene glycol and 100 ml of injection water. The resulting solution is filtered and placed in 1 ml ampoules, which are sealed.

Example 9. Anti-amnestic activity (nootropic effect) of compounds of General formula 1.

9.1. Improving memory impaired by scopolamine.

9.1.1. Nootropic effect of compounds of the general formula 1 in the test “Passive avoidance in the shuttle chamber”. The experiments were performed on adult male BALB / c mice weighing 20-25 g or male Wistar rats weighing 200-250 g

The experiment used a shuttle camera (Ugo Basile, Italy), which consisted of two compartments. All walls of one of the compartments were opaque, and the second compartment had a transparent cover. The compartments were connected by an opening, which was closed by an automatic vertical door. The floor of the dark compartment consisted of transverse metal rods to which direct current pulses could be supplied.

On the first day of the experiment, scopolamine, which causes memory impairment, was injected intraperitoneally 30 minutes before training. The animals of the experimental group were additionally administered a compound of general formula 1, for example, compound 1.10 (2) · HCl, in doses of 0.2 mg / kg Animals of the control group received an injection of saline. In each group, 8 animals were used.

Animals were placed in the bright compartment and the latent period of the first entry into the dark chamber was recorded. At the same time, the door between the chambers was closed, and the animal was punished with a current of 0.6 mA for 3 seconds. After that, the animal was returned to the living cage. After 24 hours, the animal was again placed in the bright compartment of the shuttle chamber and the latent period of the first entry into the dark chamber, the total residence time in the bright chamber and the number of entries into the dark chamber were recorded. The duration of observation was 5 minutes.

Animals of the control group that received punishment in the dark compartment showed successful learning, which was expressed in an increase in the latent period of entry into the dark compartment, the duration of stay in the light compartment, and a decrease in the number of entries in the dark chamber compared to animals from the group that did not receive punishment. Scopolamine caused the so-called anterograde amnesia, which is characterized by impaired fixation in the long-term memory of new events. This was expressed as a statistically significant increase in the latent period of entry into the dark compartment, a decrease in the time spent in the bright compartment, and an increase in the number of entries into the dark compartment of the camera.

The experimental results showed that in the passive avoidance test, the compounds of general formula 1, including compound 1.10 (2) · HCl, were able to reduce amnesia (improve memory) caused by scopolamine.

9.1.2. Nootropic effect of compounds of general formula 1 in the test "Recognition of new objects."

The experiment was performed on adult male SHK mice. In the experiment, a cross-shaped plexiglass labyrinth was used, which consisted of 4 dead-end side chambers (numbered 1, 2, 3, 4), interconnected through the fifth central chamber. The mouse was placed in a central chamber and allowed to explore the maze. The floor was cleaned after each animal. The order of visits to the cameras and the time of visits were recorded by the observer. The test ended when there were 13 entries to dead ends. The criterion of entry was the presence of all four paws of the animal inside the chamber.

During training, the animal was placed in a labyrinth in which in each of the four side chambers there was one identical cup. During the test (1 hour after training), two opposing cups were replaced with flasks, and the animal was allowed to explore the maze. During training and testing, the time spent by the animal in each side chamber was recorded. The index of recognition of new objects was calculated as the ratio of the time spent in the side chambers with new objects to the total time spent in the side chambers. The appearance of a new object increases the time spent by the animal in the chamber compared to the training phase (the so-called recognition effect of new objects). Under the action of scopolamine at a dose of 1 mg / kg, administered intraperitoneally 30 minutes before the start of training, the recognition of new objects was impaired, and the recognition index decreased.

However, this effect of scopolamine was prevented by the intraperitoneal administration of compounds of the general formula 1 at doses of 0.05 mg / kg and 0.2 mg / kg 60 minutes before the start of training. From the obtained results it follows that compounds of general formula 1, for example, compound 1.10 (2) · HCl, prevent memory impairment caused by scopolamine.

9.2. Improving memory impaired MK-801.

Nootropic effect of compounds of the general formula 1 in the test “Passive avoidance in the shuttle chamber”.

The experiment was carried out as described in example 9.1.1. On the first day of the experiment, MK-801 (0.1 mg / kg), which caused amnesia, was injected intraperitoneally 30 minutes before training. The preliminary introduction of MK-801 significantly reduces the learning effect, that is, it causes anterograde amnesia. In parallel to independent groups of mice, MK-801 was administered intraperitoneally before training in combination with the studied compounds of general formula 1, for example, compound 1.10 (2) · HCl.

The results obtained indicate the ability of compound 1.10 (2) · HCl to have a nootropic effect.

Example 10. The anxiolytic activity of compounds of General formula 1 in the test "Behavior of mice in an elevated cruciform maze." Male BALB / c mice weighing approximately 25 g were used in the experiment. Animals were kept in cages (5-7 mice per cage), providing free access to feed and water. None of the animals were previously familiar with the experimental setup. Each experimental group included 8 animals.

The method used was previously described by Lister (Lister R. G. The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology, 1987; 92: 180-185). The plexiglass installation consisted of two open sleeves measuring 30 × 5 cm and two closed sleeves measuring 30 × 5 × 15 cm. The lateral sleeves were closed with transparent plexiglass and connected to a central platform measuring 5 × 5 cm. The open sleeves, the central platform and the floor were made from black plexiglass. The device was mounted on a metal base, which was located above the floor at a height of 38.5 cm.

Each mouse was placed in the center of the maze with its head toward the open sleeve. Over the course of 5 minutes, the number of entries into open and closed arms and the time spent by animals in open and closed arms were recorded. The criterion of entry was considered to be the location of all four paws of the animal in the sleeve. The preference index was calculated as the ratio of the time spent by the animal in the open sleeves, as well as the number of visits to the open sleeves, to the total time spent in the open and closed sleeves, or, respectively, to the total number of visits to the sleeves of both types. The number of fecal boluses left by the mouse was considered as an additional parameter characterizing the state of anxiety. Normally, animals avoid open sleeves (their preference index is 0.2-0.3). Substances with anxiolytic activity (tranquilizing activity) increase this indicator to 0.5-0.6 or more, and also reduce the number of bowel movements without changing the overall motor activity (total number of entries into the arms).

Placebo, buspirone (5 mg / kg, 30 minutes before training), lorazepam (0.05 mg / kg, 60 minutes before training) or one of the tested compounds of general formula 1, for example, compound 1.10 (2), was administered to the animals intraperitoneally. · HCl, at a dose of 0.05 mg / kg and 0.2 mg / kg. Buspirone and lorazepam were administered at the maximum effective dose, at which no adverse sedation was observed, which was expressed as a general decrease in research activity (the number of visits to the arms during the test).

The results showed that compounds of general formula 1, including compound 1.10 (2) · HCl, exhibit pronounced anxiolytic activity in the elevated cruciform labyrinth test, comparable to the standards (Buspirone and Lorazepam),

Example 11. Antipsychotic activity of compounds of General formula 1 in the test "Pre-pulsed inhibition of trembling in mice." In the experiments, SHK mice weighing 24-30 g were used. The experiments were carried out in the daytime of the daily cycle of animals. Apomorphine hydrochloride and haloperidol were obtained from Sigma Chemicals, USA. Apomorphine hydrochloride was dissolved in a 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 a Tween 80 emulsifier and was administered intraperitoneally 60 minutes before the test. Compounds of general formula 1 were dissolved in sterilized water and administered subcutaneously at a dose of 1 mg / kg 60 minutes before the test. The volume of fluid introduced was 10 ml / kg. Control animals were injected with a 0.1% ascorbic acid solution prepared in sterilized water with Tween 80.

The device consisted of a camera made of transparent plexiglass (manufacturer - Columbus Instruments, USA), placed on a platform that was located inside a soundproof cabinet. 2 cm from the platform was a high-frequency speaker through which sound stimuli were transmitted. When the animal shuddered, platform vibrations arose, which were captured by an analog transducer and recorded by a computer. The background noise level was 65 dB. Animals received 4 presentations of a single testing (“pulse”) stimulus lasting 50 ms and a loudness of 105 dB or a preliminary (“pre-pulse”) stimulus lasting 20 ms with a loudness of 85 dB, followed by a pulse stimulus of 50 ms loudness 105 after 30 ms db The interval between repeated presentations of a pulse or pre-pulse in combination with a pulse stimulus was 10 s. The weakening of the startle in response to a pulse stimulus in the presence of a pre-pulse stimulus was calculated as a percentage of the amplitude of the startle in response to an isolated pulse stimulus. The introduction of apomorphine, which is used in animal experiments to simulate psycho-like conditions, caused a decrease in prepulse inhibition of trembling, which reflects a decrease in the central nervous system's ability to filter sensory stimuli.

The results of the experiment show that haloperidol (1 mg / kg) and the studied compounds of general formula 1, including compound 1.10 (2) · HCl (1 mg / kg), prevented impaired inhibition of trembling when injected with apomorphine.

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

12.1. The behavior of mice in the test "Forced swimming Porsolt." In the test of Porsolt et al. (1977, 1978), an expression of despair in behavior was proposed as a model for studying antidepressant activity. That is, the behavior of a mouse or rat in an indoor pool, from which the animal cannot get out, characterizes the degree of its despair, which can be reduced by taking antidepressants.

In the experiment, male Balb / C mice weighing 20-30 g were used. Animals were placed for 15 min in a reservoir (height 300 mm, diameter 480 mm) filled with 70% water at 25 ° C. After 3-5 minutes, swimming activity began to decrease and alternate between the phases of movement and immobility. An animal was considered immobile if it did not move for 1.5 seconds. The data of the last 5 minutes were used for analysis. The test used automated motion recognition using the video system and the Any-maze program.

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

12.2. The behavior of mice in the test "Hanging by the tail."

A tail suspension test has been described by Steri et al. (1985) as a convenient way to study potential antidepressants. It is suggested that forced rodent immobility can serve as a model for the study of depressive disorders in humans. Clinically effective antidepressants reduce the immobility that occurs in mice after unsuccessful attempts to free themselves when their tail is fixed.

In the experiment, male Balb / C mice weighing 20-30 g were used. The animals were hung with adhesive tape by the tail on a tripod above a horizontal surface at a height of about 40 cm and the total duration of episodes of complete immobility was recorded for 3 minutes. An animal was considered motionless if it did not make any movements within 1.5 seconds. The test used automated motion recognition using the video system and the Any-maze program. The studied compounds of general formula 1 were administered intraperitoneally at a dose of 0.5 mg / kg for 4 days. Comparison preparations (fluoxetine, desipramine) were administered intraperitoneally 15 minutes before the test.

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

Claims (25)

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

where R ¹ and R ³ independently from each other are optionally the same C ₁ -C ₃ alkyl, and R ² represents a group - (CH ₂ ) _n X, or
R ¹ and R ³ independently from each other are different substituents selected from C ₁ -C ₃ alkyl or a group - (CH ₂ ) _n X, and R ² represents a hydrogen atom or C ₁ -C ₃ alkyl;
R ⁴ represents C ₁ -C ₃ alkyl;
R _i ⁵ represents a hydrogen atom, one or two identical or different halogen atoms, C ₁ -C ₃ alkyl;
i represents the number 0, 1 or 2;
n represents the number 0, 1, 2 or 3;
X represents carboxyl CO ₂ H, C ₁ -C ₃ alkyloxycarbonyl, aminocarbonyl CONR ⁶ R ⁷ or an amino group NR ⁶ R ⁷ ; excluding compounds in which R ³ represents a group - (CH ₂ ) _n X, where X represents an amino group NR ⁶ R ⁷ and n is 0;
R ⁶ and R ⁷ are optionally the same hydrogen atom, optionally substituted C ₁ -C ₅ alkyl, or R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form an optionally substituted 6-membered azaheterocyclyl containing 1-2 atoms nitrogen in a cycle where the substituent is selected from C ₁ -C ₃ alkyl. 2. The compounds according to claim 1, which are esters of the General formula 1.1, 1.2 and 1.3 and their pharmaceutically acceptable salts and / or hydrates

where n and R _i ⁵ have the above meaning. 3. The compounds according to claim 1, which are acids of the general formula 1.4, 1.5 and 1.6 and their pharmaceutically acceptable salts and / or hydrates

where n and R _i ⁵ have the above meaning. 4. The compounds according to claim 1, which are amides of the general formula 1.7, 1.8 and 1.9 and their pharmaceutically acceptable salts and / or hydrates

where n, R _i ⁵ , R ⁶ and R ⁷ have the above meaning. 5. The compounds according to claim 1, which are amines of the general formula 1.10, 1.11 and 1.12 and their pharmaceutically acceptable salts and / or hydrates

where n, R _i ⁵ , R ⁶ and R ⁷ have the above meaning. 6. The compounds according to claim 5, which are 6-amino-5,7-dimethyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine 1.10 (1), 6-aminomethyl-5,7- dimethyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine 1.10 (2), 6- (2-aminoethyl) -5,7-dimethyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo [1, 5-a] pyrimidine 1.10 (3), 6- (3-aminopropyl) -5,7-dimethyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine 1.10 (4), 6-aminomethyl- 5,7-dimethyl-2-methylsulfanyl-3- (3-chlorophenylsulfonyl) pyrazolo [1,5-a] pyrimidine 1.10 (5), 6-aminomethyl-5,7-dimethyl-2-methylsulfanyl-3- (3 -fluorophenylsulfonyl) -pyrazolo [1 , 5-a] pyrimidine 1.10 (6), 6-aminomethyl-5,7-dimethyl-2-methylsulfanyl-3- (4-fluoro-3-chlorophenylsulfonyl) pyrazolo [1,5-a] pyrimidine 1.10 (7) , 6- (2-aminoethyl) -5,7-dimethyl-2-methylsulfanyl-3- (3-chlorophenylsulfonyl) pyrazolo [1,5-a] pyrimidine 1.10 (8), 6- (2-aminoethyl) -5 , 7-Dimethyl-2-methylsulfanyl-3- (3-fluorophenylsulfonyl) pyrazolo [1,5-a] pyrimidine 1.10 (9), 5,7-dimethyl-6-dimethylaminomethyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine 1.10 (10), 5,7-dimethyl-6-dimethylaminomethyl-2-methylsulfanyl-3- (3-chlorophenylsulfonyl) pyrazolo [1,5-a] pyrimidine 1.10 (11), 5 , 7-dimethyl-6-dimethylaminomethyl-2-methylsulfanyl-3- (3- fluorophenylsulfonyl) pyrazolo [1,5-a] pyrimidine 1.10 (12), 5,7-dimethyl-6-dimethylaminomethyl-2-methylsulfanyl-3- (4-fluoro-3-chlorophenylsulfonyl) pyrazolo [1,5-a ] pyrimidine 1.10 (13), 5,7-dimethyl-6- (2-dimethylaminoethyl) -2-methylsulfanyl-3-phenylsulfonylpyrazolo [1,5-a] pyrimidine 1.10 (14), 5,7-dimethyl -6- (2-dimethylamino-ethyl) -2-methylsulfanyl-3- (3-chlorophenylsulfonyl) pyrazolo [1,5-a] pyrimidine 1.10 (15), 5,7-dimethyl-6- (2-dimethylamino ethyl) -2-methylsulfanyl-3- (3-fluorophenylsulfonyl) pyrazolo [1,5-a] pyrimidine 1.10 (16), 5,7-dimethyl-6- (2-dimethylamino-ethyl) -2-methylsulfanyl-3 - (4-fluoro-3-chlorophenylsulfonyl) pyrazolo [1,5-a] irimidine 1.10 (17), 5-aminomethyl-7-methyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine hydrochloride 1.11 (1), 5- (2-aminoethyl) -7-methyl-2 Methylsulfanyl-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine hydrochloride 1.11 (2), 5-dimethylaminomethyl-7-methyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine hydrochloride 1.11 ( 3), 5-dimethylaminomethyl-7-methyl-2-methylsulfanyl-3- (4-fluoro-3-chloro-phenylsulfonyl) pyrazolo [1,5-a] pyrimidine hydrochloride 1.11 (4), 5- (2-dimethylaminoethyl ) -7-methyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine hydrochloride 1.11 (5), 7-aminomethyl-5-methyl-2 methylsulfanyl-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine hydrochloride 1.12 (1), 7- (2-aminoethyl) -5-methyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine hydrochloride 1.12 (2), 7-dimethylaminomethyl-5-methyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine hydrochloride 1.12 (3), 7-dimethylaminomethyl-5-methyl-2-methylsulfanyl- 3- (4-fluoro-3-chloro-phenylsulfonyl) -pyrazolo [1,5-a] pyrimidine hydrochloride 1.12 (4), 7- (2-dimethylaminoethyl) -5-methyl-2-methylsulfanyl-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine hydrochloride 1.12 (5), pharmaceutically acceptable salts thereof, if not indicated higher and / or hydrates,

7. A method for producing esters of general formula 1.1 according to claim 2 by reacting 3-amino-4-sulfonyl-2H-pyrazoles of general formula 2 with the corresponding β-dicarbonyl compounds of general formula 3

where n, R ¹ , R ³ , R ⁴ and R ⁵ have the above meaning. 8. The method of producing esters of general formula 1.2, 1.3 according to claim 2, by reacting 3-amino-4-sulfonyl-2H-pyrazoles of general formula 2 with the corresponding β-dicarbonyl compounds of general formula 4, followed by isolation and purification or separation of reaction products

where n, R ¹ , R ³ , R ⁴ and R _i ⁵ have the above meaning. 9. The method of producing acids of the general formula 1.4, 1.5, 1.6 according to claim 3 by hydrolysis of the corresponding esters of the general formula 1.1, 1.2, 1.3. 10. The method of producing amides of the general formula 1.7, 1.8, 1.9 according to claim 4 by reacting the corresponding acids of the general formula 1.4, 1.5, 1.6 or their derivatives with amines of the general formula 5

where R ⁶ and R ⁷ have the above meaning. 11. The method of producing amides of general formula 1.7 according to claim 4 by reacting 3-amino-4-sulfonyl-2H-pyrazoles of general formula 2 with the corresponding β-dicarbonyl compounds of general formula 6

where n, R ¹ , R ³ , R ⁴ , R _i ⁵ , R ⁶ and R ⁷ have the above meaning. 12. The method of producing amides of general formula 1.8, 1.9 according to claim 4, by reacting 3-amino-4-sulfonyl-2H-pyrazoles of general formula 2 with the corresponding β-dicarbonyl compounds of general formula 7, followed by isolation and purification or separation of reaction products

where n, R ¹ , R ³ , R ⁴ , R _i ⁵ , R ⁶ and R ⁷ have the above meaning. 13. A method for producing amines of the general formula 1.10, 1.11, 1.12 according to any one of claims 5 and 6 by successive conversion of the acids of the general formula 1.4, 1.5, 1.6 to the corresponding acyl azides of the general formula 1.13, 1.14, 1.15 under the action of sodium azide, by thermal decomposition of the obtained azides into corresponding isocyanates of the general formula 1.16, 1.17, 1.18 and hydrolysis of the latter into amines of the general formula 1.10, 1.11, 1.12, respectively

where n, R ¹ , R ³ , R ⁴ and R _i ⁵ have the above meaning. 14. A method of producing amines of the general formula 1.10, 1.11, 1.12 according to any one of claims 5 and 6 by reductive alkylation of amines 1.10, 1.11, 1.12, in which R ⁶ and R ⁷ represent a hydrogen atom, carbonyl compounds of the general formula 8

where R ⁸ and R ⁹ are optionally the same hydrogen atom, optionally substituted C ₁ -C ₃ alkyl. 15. Substituted 2-alkylamino-3-arylsulfonyl-pyrazolo [1,5-a] pyrimidines according to any one of claims 1 to 6, having antagonist properties of serotonin 5-HT ₆ receptors. 16. The compounds of claim 15 for studying the molecular mechanism of interaction with serotonin 5-HT ₆ receptors. 17. The compound of claim 15 as a medicament for the manufacture of pharmaceutical compositions and drugs. 18. A pharmaceutical composition having the properties of antagonists of serotonin 5-HT ₆ receptors, suitable for the treatment and prevention of the development of conditions and diseases of the central nervous system, containing a pharmaceutically effective amount of the drug beginning according to 17. 19. The method of obtaining the pharmaceutical composition according to p. 18 by mixing with an inert excipient and / or solvent of the drug substance according to claim 17. 20. A drug in the form of tablets, capsules or injections in a pharmaceutically acceptable package for the prevention and treatment of diseases of the central nervous system, the pathogenesis of which is associated with 5-HT ₆ receptors, including the pharmaceutically effective amount of the drug substance according to claim 17 or the pharmaceutical composition according to claim 18. 21. The drug according to claim 20 for the prevention and treatment of cognitive disorders and neurodegenerative diseases. 22. The drug according to claim 20 for the prevention and treatment of mental disorders. 23. The drug according to claim 20, with anxiolytic effect, for the prevention and treatment of anxiety disorders. 24. The drug according to claim 20, having a nootropic effect, to improve mental abilities. 25. A method for the prevention and treatment of diseases of the central nervous system, the pathogenesis of which is associated with 5-HT ₆ receptors, which consists in administering in an effective amount of the drug substance according to claim 17, or the pharmaceutical composition according to claim 18, or the drug according to any one of claims. 20-24.