RU2377244C1 - 2-ALKYLAMINO-3-ARYLSULPHONYLCYCLOALKANO [e OR d]PYRAZOLO[1,5-a] PYRIMIDINES SEROTONIN 5-HT6 RECEPTOR ANTAGONISTS, METHODS FOR MAKING AND APPLYING THEREOF - Google Patents

Abstract

FIELD: pharmacology.

SUBSTANCE: invention refers to new 2-alkylamino-3-arylsulphonylcycloalkano[e]pyrazolo[1,5-a]pyrimidines of general formula 1 and 2-alkylamino-3-arylsulphonylcycloalkano[d]pyrazolo[1,5-a]pyrimidines of general formula 2 with properties of serotonin 5-NT₆ receptor antagonists, to pharmaceutical compositions containing specified compounds as a principle, medical products and method of treatment and the prevention of CNS diseases. In general formulae

1 and

2, R¹ represents hydrogen atom or C₁-C₃ alkyl; R² represent C₁-C₃ alkyl; R³ represent hydrogen atom, one or two optionally substituted identical halogen atoms, C₁-C₃ alkyl or hydroxyl optionally substituted with C₁-C₃alkyl; n represents an integer 1, 2 or 3. The invention also relates to the method for making the compounds of general formula 1 or 2 by interaction of 3-amino-4-arylsulphonyl-2H-pyrazoles of general formula 3 with relevant β-dicarbonyl compounds of general formula 4 or their derivatives of general formula 5.

3,

4,

5, where: R¹, R², R³ and n have said values.

EFFECT: new 2-alkylamino-3-arylsulphonyl-cycloalkano[e or c1]pyrazolo[1,5]pyrimidines - serotonin 5-NT₆ receptor antagonists, methods of making and applying thereof.

12 cl, 1 dwg, 4 tbl, 9 ex

Description

This invention relates to new 3-arylsulfonyl-pyrazolo [1,5-a] pyrimidines, to new antagonists of serotonin 5-HT ₆ receptors, to new drug principles, pharmaceutical compositions, finished dosage forms and methods for their preparation. More specifically, the present invention relates to antagonists of serotonin 5-HT ₆ receptors - substituted 2-alkylamino-3-arylsulfonyl-cycloalkano [e or d] pyrazolo [1,5-a] pyrimidines, pharmaceutical principles and pharmaceutical compositions containing pharmaceutical principles in the form of these compounds, as well as to new drugs and a method for treating and preventing the development of various cognitive and neurodegenerative diseases. The pharmacological effect of the new drugs is based on their ability to antagonistically interact with serotonin 5-HT ₆ receptors, which play an important role in the treatment of diseases of the central nervous system (CNS), in particular Alzheimer's disease (AD), Gangnton’s disease, schizophrenia, and other neurodegenerative diseases, cognitive impairment 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 (CNS), 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 of serotonin 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 models of learning-memorization-reproduction [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 has been achieved, but also 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, Gangnton’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 ™ 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) Gangnton 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 CT 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 creating new drugs for the treatment of a wide range of neurological and neurodegenerative diseases and cognitive disorders.

There are a significant number of publications in the literature on biologically active sulfonyl derivatives of azaheterocycles, including serotonin receptor ligands. For example, substituted 1- (2-aminoethyl) -4-arylsulfonylpyrazoles of the 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.

With the aim of developing new highly effective neuroprotective drugs, the authors of this invention performed extensive studies in the series of substituted 3-sulfonyl-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, alkylsulfonylheteroaralkyloxy, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroaryl heterocyclenyl, annelated heteroaryl heterocyclyl, annelated aero cycloalkenyl, 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, an atom hydrogen, alkyl, aryl, aralkyl, heteroalkyl, heterocyclyl or heteroaryl, or R _k ^a and R _{k + 1} ^a, together with the N atom to which they are bonded, form ^a 4-7 membered via R _k ^a and R _{k + 1} ^a getter cyclic or heterocyclenyl. Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, benzyloxycarbonylmethylmethylcarbonylmethylmethylcarbonylmethylmethylcarbylmethylmethylcarbonylmethylmethylcarbonylmethylmethylcarbonylmethylmethylcarbonylmethylmethylcarbonylmethylmethylcarbonylmethylmethylcarbonylmethylmethylcarbonylmethyl Preferred "alkilnshi 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.

“Alkyloxy” means an alkyl-O-group in which alkyl groups are defined in this section. Preferred alkyloxy groups are methoxy, ethoxy, n-propoxy, iso-propoxy and n-butoxy.

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

“Annelated cycle” (condensed ring) means a bi- or polycyclic system in which the annelated cycle and the cycle or polycycle with which it is “annelated” have at least two atoms in common.

“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 anelated 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.

"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, neurological and other diseases.

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

“Substituent alkyl” means a substituent attached to alkyl, alkenyl, the meaning of which is defined in this section. Alkyl substituent is hydrogen, alkyl, halogen, alkenyloxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl, alkylthio, heteroarylthio, aralkylthio, arylsulfonyl, alkilsulfonilgeteroaralkiloksi, annelated heteroarylcycloalkenyl , annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated heteroarylheterocyclyl, annelated arylcycloalkenyl, annelated arylcycloalkyl, anneliro arylheterocyclenyl, annelated arylheterocyclyl, alkoxycarbonyl, aralkoxycarbonyl, heteroaralkyloxycarbonyl 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 NSO ₂ -, where R _k ^a and R _{k + 1} ^{a are} independently “amino substituents”, the meanings of which are 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 a} 4-7 membered heterocyclyl or heterocyclenyl. 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, benzyloxycarbonylmethylene 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. The meaning of “alkyl substituents” is defined in this section.

“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 disorders associated with Alzheimer's, Parkinson's and Huntington's diseases; 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, such as 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 principle” (medicinal ingredient, medicinal substance, drug-substance) means a physiologically active substance of synthetic or other (biotechnological, plant, animal, microbial and other) origin, having pharmacological activity and being the active principle of the pharmaceutical composition used for the manufacture and manufacture medicinal product (means).

“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 finished forms, intended to restore, correct or alter the physiological functions of humans and animals, as well as for treatment and disease prevention, diagnosis, anesthesia, contraception, cosmetology and more.

"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 (a disease of endangered white matter); 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, substance abuse, exposure to neurotoxins, infectious and oncological diseases of the brain, as well as neuronal damage associated with autoimmune and endocrine diseases; and other neurodegenerative processes.

"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.

"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 achieved using a variety of antibacterial and antifungal agents, for example, such as 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 or 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.

“Pharmaceutically acceptable salt” means the relatively non-toxic organic or inorganic salts of acids and bases of the 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 SM, 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.

“Cycloalkyl” means a non-aromatic mono- or polycyclic system containing from 3 to 10 carbon atoms. Cycloalkyl may have one or more “ring system substituents”, which may be the same or different. Representative cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalin, norbornyl, adamant-1-yl and the like. Cycloalkyl can be annelated with an aromatic ring or heterocycle. Preferred “cyclic substituents” are alkyl, aralkoxy, hydroxy or R _k ^a R _{k + 1} ^a N, the meaning of which is defined in this section.

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

The purpose of the present invention is to create new 3-arylsulfonyl-pyrazolo [1,5-a] pyrimidines, new antagonists of serotonin 5-HT ₆ receptors, new drugs and pharmaceutical compositions containing drugs in the form of these compounds, as well as new drugs and methods for treating and preventing the development of various diseases of the central nervous system, including cognitive and neurodegenerative diseases.

This goal is achieved by substituted 2-alkylamino-3-arylsulfonyl-cycloalkano [e] pyrazolo [1,5-a] pyrimidines of the general formula 1 and substituted 2-alkylamino-3-arylsulfonyl-cycloalkano [d] pyrazolo [1,5-a] pyrimidines of the general formula 2,

where R ¹ represents a hydrogen atom or C ₁ -C ₃ alkyl;

R ² represents C ₁ -C ₃ alkyl;

R ³ represents a hydrogen atom, one or two optionally identical halogen atoms, C ₁ -C ₃ alkyl or optionally substituted C ₁ -C ₃ alkyl hydroxyl;

n is an integer of 1, 2 or 3.

More preferred compounds of the general formula 1 are 2-alkylamino-3-arylsulfonyl-7,8-dihydro-6H-cyclopenta [e] pyrazolo [1,5-a] pyrimidines of the general formula 1.1, 2-alkylamino-3-arylsulfonyl-6, 7,8,9-tetrahydro-cyclohexano [e] pyrazolo [1,5-a] pyrimidines of the general formula 1.2 and 2-alkylamino-3-arylsulfonyl-7,8,9,10-tetrahydro-6H-cyclohepta [e] pyrazolo [1,5-a] pyrimidines of the general formula 1.3,

where R ¹ , R ² and R ³ have the above meaning.

More preferred compounds of the general formulas 1.1, 1.2 and 1.3 are 2-methylamino-3-phenylsulfonyl-7,8-dihydro-6H-cyclopenta [e] pyrazolo [1,5-a] pyrimidine 1.1 (1), 2-methylamino-3 - (3-chlorophenylsulfonyl) -7,8-dihydro-6H-cyclopenta [e] pyrazolo [1,5-a] pyrimidine 1.1 (2), 5-methyl-2-methylamino-3-phenylsulfonyl-7,8-dihydro -6H-cyclopenta [e] pyrazolo [1,5-a] pyrimidine 1.1 (3), 5-methyl-2-methylamino-3- (3-chlorophenylsulfonyl) -7,8-dihydro-6H-cyclopenta [e] pyrazolo [1,5-a] pyrimidine 1.1 (4), 2-methylamino-3-phenylsulfonyl-6,7,8,9-tetrahydrocyclohexano [e] pyrazolo [1,5-a] pyrimidine 1.2 (1), 2-methylamino -3- (3-chlorophenyls lphonyl) -6,7,8,9-tetrahydrocyclohexano [e] pyrazolo [1,5-a] pyrimidine 1.2 (2), 5-methyl-2-methylamino-3-phenylsulfonyl-6,7,8,9-tetrahydrocyclohexano [e] pyrazolo [1,5-a] pyrimidine 1.2 (3), 5-methyl-2-methylamino-3- (3-fluorophenylsulfonyl) -6,7,8,9-tetrahydrocyclohexano [e] pyrazolo [1,5 -a] pyrimidine 1.2 (4), 5-methyl-2-methylamino-3- (3-chlorophenylsulfonyl) -6,7,8,9-tetrahydrocyclohexano [e] pyrazolo [1,5-a] pyrimidine 1.2 (5) , 5-methyl-2-methylamino-3- (3-chloro-4-fluorophenylsulfonyl) -6,7,8,9-tetrahydrocyclohexano [e] pyrazolo [1,5-a] pyrimidine 1.2 (6), 2-methylamino -3-phenylsulfonyl-7,8,9,10-tetrahydro-6H-cyclohepta [e] pyrazolo [1,5 -a] pyrimidine 1-3 (1) and 2-methylamino-3- (3-chlorophenylsulfonyl) -7,8,9,10-tetrahydro-6H-cyclohepta [e] pyrazolo [1,5-a] pyrimidine 1.3 ( 2).

The subject of the present invention is a method for producing substituted 2-alkylamino-3-arylsulfonyl-cycloalkano [e] pyrazolo [1,5-a] pyrimidines of the general formula 1, 1.1, 1.2, 1.3 and substituted 2-alkylamino-3-arylsulfonyl-cycloalkano [d ] pyrazolo [1,5-a] pyrimidines of the general formula 2 by the interaction of 3-amino-4-arylsulfonyl-2H-pyrazoles of the general formula 3 with the corresponding β-dicarbonyl compounds of the general formula 4 or their derivatives of the general formula 5, followed by isolation or separation of the reaction products General formula 1, 1.1, 1.2, 1.3, 2 according to the scheme below .

where R ¹ , R ² , R ³ and n have the above meaning.

The purpose of the present invention is to create new "molecular tools" for studying the characteristics of physiologically active compounds with the property to inhibit serotonin 5-HT ₆ receptors.

This goal is achieved by antagonists of serotonin 5-HT ₆ receptors, which are substituted 2-alkylamino-3-arylsulfonyl-cycloalkano [e] pyrazolo [1,5-a] pyrimidines of the general formula 1, 1.1, 1.2, 1.3 and substituted by 2-alkylamino 3-arylsulfonyl-cycloalkano [d] pyrazolo [1,5-a] pyrimidines of the general formula 2.

The subject of the present invention is also a pharmaceutical principle for pharmaceutical compositions and medicines, comprising at least one 2-alkylamino-3-arylsulfonyl-cycloalkano [e] pyrazolo [1,5-a] pyrimidine of the general formula 1, 1.1, 1.2, 1.3 or 2-alkylamino-3-arylsulfonyl-cycloalkano [d] pyrazolo [1,5-a] pyrimidine of the general formula 2.

The subject of this invention is also a pharmaceutical composition having the properties of antagonists of serotonin 5-HT ₆ receptors for treating and preventing 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 beginning, which is at least one 2-alkylamino -3-arylsulfonyl-cycloalkano [e] pyrazolo [1,5-a] pyrimidine of the general formula 1, 1.1, 1.2, 1.3 or 2-alkylamino-3-arylsulfonyl-cycloalkano [d] pyrazolo [1,5-a] pyrimidine total f formulas 2.

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 principles, 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 oral agents using binders, lubricants, disintegrants, solvents, diluents, stabilizers, suspending agents, colorless 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 the present 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 2-alkylamino-3-arylsulfonyl-cycloalkano [e] pyrazolo [1,5-a] pyrimidine general formula 1, 1.1, 1.2, 1.3 or 2-alkylamino-3-arylsulfonyl-cycloalkano [d] pyrazolo [1,5-a] pyrimidine general formula 2.

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, which is at least at least one 2-alkylamino-3-arylsulfonyl-cycloalkano [e] pyrazolo [1,5-a] pyrimidine of the general formula 1, 1.1, 1.2, 1.3 or 2-alkylamino-3-arylsulfonyl-cycloalkano [d] pyrazolo [1,5 pyrimidi m of General formula 2, or a pharmaceutical composition containing this medicinal beginning.

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 the drug, which is at least one 2-alkylamino-3 -arylsulfonyl-cycloalkano [e] pyrazolo [1,5-a] pyrimidine of the general formula 1, 1.1, 1.2, 1.3 or 2-alkylamino-3-arylsulfonyl-cycloalkano [(1] pyrazolo [1,5-a] pyrimidine of the general formula 2, or a pharmacist a chemical composition containing this beginning.

A 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 mental disorders and schizophrenia, comprising a pharmaceutically effective amount of a medicinal agent comprising at least one 2-alkylamino-3 -arylsulfonyl-cycloalkano [e] pyrazolo [1,5-a] pyrimidine of the general formula 1, 1.1, 1.2, 1.3 or 2-alkylamino-3-arylsulfonyl-cycloalkano [d] pyrazolo [1,5-a] pyrimidine of the general formula 2 , or pharmaceutical tab containing a start.

More preferred is a medicament (anxiolytic or tranquilizer) for the prophylaxis and treatment of anxiety disorders, comprising a pharmaceutically effective amount of a drug onset of at least one 2-alkylamino-3-arylsulfonyl-cycloalkano [e] pyrazolo [1,5-a] pyrimidine of the general formula 1, 1.1, 1.2, 1.3 or 2-alkylamino-3-arylsulfonyl-cycloalkano [d] pyrazolo [1,5-a] pyrimidine of the general formula 2, or a pharmaceutical composition containing this principle.

More preferred is a drug (nootropic) for the prophylaxis and treatment of hyperkinetic disorders, in particular for improving mental abilities, including a pharmaceutically effective amount of the drug, representing at least one 2-alkylamino-3-arylsulfonyl-cycloalkano [e] pyrazolo [1 , 5-a] pyrimidine of the general formula 1, 1.1, 1.2, 1.3 or 2-alkylamino-3-arylsulfonyl-cycloalkano [d] pyrazolo [1,5-a] pyrimidine of the general formula 2, or a pharmaceutical composition containing this principle.

A 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 comprising at least one 2-alkylamino-3-arylsulfonyl-cycloalkano [ e] pyrazolo [1,5-a] pyrimidine of the general formula 1, 1.1, 1.2, 1.3 or 2-alkylamino-3-arylsulfonyl-cycloalkano [d] pyrazolo [1,5-a] pyrimidine of the general formula 2, or a pharmaceutical composition, containing this medicine real beginning.

In accordance with this invention, a method for the prophylaxis and treatment of diseases of the central nervous system, the pathogenesis of which is associated with 5-HT ₆ receptors in animals and humans, is to administer a drug in the form of tablets, capsules or injections containing at least one as a drug 2-alkylamino-3-arylsulfonyl-cycloalkano [e] pyrazolo [1,5-a] pyrimidine of the general formula 1, 1.1, 1.2, 1.3 or 2-alkylamino-3-arylsulfonyl-cycloalkano [d] pyrazolo [1,5-a ] pyrimidine of general formula 2 in a pharmaceutically effective amount, or a pharmaceutical composition containing this drug substance. Medicines can be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically). The clinical dosage of the pharmaceutical composition or drug can be adjusted depending on the therapeutic efficacy and bioavailability of the active ingredients in the body, their metabolic rate and excretion, as well as on the age, sex and stage of the patient’s disease, with a daily dose in adults usually being 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 should be taken into account, with each dosage unit of the drug containing 10 ~ 500 mg of the drug, which is at least one 2-alkylamino-3-arylsulfonyl-cycloalkano [ e] pyrazolo [1,5-a] pyrimidine of the general formula 1, 1.1, 1.2, 1.3 or 2-alkylamino-3-arylsulfonyl-cycloalkano [d] pyrazolo [1,5-a] pyrimidine of the general formula 2, or a pharmaceutical composition, containing this medicinal start, 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. General method for producing substituted 2-alkylamino-3-arylsulfonyl-cycloalkano [e] pyrazolo [1,5-a] pyrimidines of the general formula 1, 1.1, 1.2, 1.3 and 2-alkylamino-3-arylsulfonyl-cycloalkano [d] pyrazolo [1,5-a] pyrimidines of the general formula 2. 0.005 mol of aminopyrazole of the general formula 3 and 0.0055 mol of the corresponding β-dicarbonyl compound of the general formula 4 or its derivative of the general formula 5 are mixed in 5 ml of acetic acid or other suitable solvent for 4- 12 hours. The precipitate formed is filtered off, washed with methanol and water. If necessary, the product is subjected to recrystallization from a suitable solvent or chromatographic purification, or chromatographic separation.

Table 2 presents some examples of the new 2-alkylamino-3-arylsulfonyl-cycloalkano [e] pyrazolo [1,5-a] pyrimidines of the general formula 1, 1.1, 1.2, 1.3 and 2-alkylamino-3-arylsulfonyl-cycloalkano [d] pyrazolo [1,5-a] pyrimidines of the general formula 2 and the data of their LCMS analyzes and NMR spectra.

table 2 2-Alkylamino-3-arylsulfonyl-cycloalkano [e] pyrazolo [1,5-a] pyrimidines of the general formula 1 and 2-alkylamino-3-arylsulfonyl-cycloalkano [d] pyrazolo [1,5-a] pyrimidines of the general formula 2. No. Formula Like the weight LCMS, m / z
(M + 1) NMR spectrum 1.1 (1)

328.40 329 (DMSO-D ₆ , 400 MHz) δ 8.44 (s, 1H), 8.00 (m, 2H), 7.56 (m, 3H), 6.43 (q, J = 4.8 Hz, 1H), 3.17 (t, J = 7.6 Hz, 2H), 2.96 (t, J = 7.6 Hz, 2H), 2.92 (d, J = 4.8 Hz, 3H) 2.15 (n, J = 7.6 Hz, 2H). 1.1 (2)

362.84 363 1.1 (3)

342.42 343 (CDCl ₃ ): 8.14 (d, J = 8 Hz, 2H); 7.37-7.52 (m, 3H); 6.01 (br.q, J = 4.5Hz, 1H); 3.22 (t, J = 7.6 Hz, 2H); 3.02 (d, J = 4.5Hz, 3H): 2.93 (t, J = 7.3Hz, 2H); 2.51 (s, 3H); 2.18-2.28 (m, 2H). 1.1 (4)

376.87 377 1.2 (1)

342.42 343 (DMSO-D ₆ , 400 MHz) δ 8.32 (s, 1H), 7.99 (d, J = 8 Hz, 2H), 7.59 (t, J = 7.2 Hz, 1H), 7 54 (t, J = 7.6 Hz, 2H), 6.37 (q, J = 4.8 Hz, 1H), 2.93 (m, 5H), 2.7 (t, J = 6 Hz , 2H), 1.84 (m, 2H), 1.73 (m, 2H). 1.2 (2)

376.87 377 1.2 (3)

356.45 357 1.2 (4)

374.44 375 1.2 (5)

390.89 391 1.2 (6)

408.89 409 1.3 (1)

356.45 357 1.3 (2)

390.89 391 2 (1)

342.42 343 (DMSO-D ₆ , 400 MHz) δ 8.71 (s, 1H), 8.00 (d, J = 6.8 Hz, 2H), 7.57 (m, 3H), 6.32 (q, J = 4.8 Hz, 1H), 2.87 (m, 5H), 2.69 (t, J = 6.4 Hz, 2H), 2.53 (s, 3H), 1.82 (m, 2H), 1.72 (m, 2H). 2 (2)

356.45 357 2 (3)

328.4 329 2 (4)

342.42 343

Example 2. Determination of the antagonistic activity of compounds of General formula 1 and 2 in relation to 5-HT ₆ receptors. Compounds of general formula 1 and 2 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. Table 3 presents the IC ₅₀ values of antagonists of the general formula 1 and 2 under the conditions of a functional essay of inhibition of serotonin 5-HT ₆ receptors, indicating their high antagonistic activity.

Table 3 IC ₅₀ values of antagonists of the general formula 1 and 2 under conditions of a functional essay of inhibition of serotonin 5-HT ₆ receptors. Antagonists of the general formula 1 and 2 IC ₅₀ , nM 1.1 (1) 4.8 1.1 (3) 7.0 1.2 (1) 4.4 2 (1) 7.5 2 (2) 15.5

Example 3. Determination of the activity of antagonists of serotonin 5-HT ₆ receptors of General formula 1 and 2 under conditions of competitive binding to serotonin 5-HT ₆ receptors. To screen substances for their potential ability to interact with the 5-HT ₆ serotonin receptor, the radioligand binding method was used. For this, membrane preparations were prepared from HeLa cells expressing the recombinant human 5-HT ₆ receptor by homogenizing the recombinant cells in a glass homogenizer, followed by separating the plasma membranes from the nuclei, mitochondria, and cell fragments by differential centrifugation. The binding of the studied compounds to the 5-HT ₆ receptor was determined in accordance with the procedure 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 embodiment, membrane preparations were incubated with a labeled ligand (1.5 nM [ ³ H] Lysergic acid diethylamide) without and in the presence of the test compounds for 120 minutes at 37 ° C in an environment consisting of 50 mM Tris-HCl, pH 7.4, 150 mM NaCl, 2 mM Ascorbic Acid, 0.001% BSA, Samples after incubation were filtered under vacuum on a G / F glass-microfiber filter (Millipor, USA), the filters were washed three times with cold medium and radioactivity was measured using a MicroBeta 340 scintillation counter (PerkinElmer, USA ) Non-specific binding, which accounted for 30% of total binding, was determined by incubation of membrane preparations with a radioligand in the presence of 5 μM Serotonin (5-HT). Methiothepin was used as a positive control. The binding of the test compounds to the receptor was determined by their ability to displace the radioactive ligand and was expressed as a percentage of displacement. The crowding out percentage was determined by the following formula:

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

Table 4 presents the test results of some serotonin 5-HT ₆ receptor antagonists of the general formula 1 and 2 under conditions of competitive binding to serotonin 5-HT ₆ receptors, indicating their high activity with respect to serotonin 5-HT ₆ receptors.

Table 4 IC ₅₀ values of antagonists of general formulas 1 and 2 under conditions of competitive essay of inhibition of serotonin 5-HT ₆ receptors. Antagonists of the general formula 1 and 2 IC ₅₀ , nM K _i, nM 1.1 (1) 0.157 0.073 1.1 (3) 0.436 0.202 1.2 (1) 0.241 0.112 1.2 (3) 1.05 0.49 2 (1) 1.07 0.499 2 (2) 0.551 0.256

The data presented in tables 3 and 4 indicate the possibility of using compounds of the general formula 1 and 2 as “Molecular Instruments” for studying the characteristics of physiologically active compounds with the property of inhibiting serotonin 5-HT ₆ receptors, and as medicinal principles for pharmaceutical compositions and medicinal funds.

Example 4. Obtaining a drug in tablet form. 1600 mg of starch, 1600 mg of ground lactose, 400 mg of talc and 1000 mg of compound 1.1 (1) 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 5. Obtaining a drug in the form of capsules. Compound 1.1 (1) is thoroughly mixed with lactose powder in a 2: 1 ratio. The resulting powdery mixture is packaged in 300 mg in a suitable size gelatin capsule.

Example 6. Obtaining a medicinal product in the form of compositions for intramuscular, intraperitoneal or subcutaneous injection. 500 mg of compound 1.1 (1) 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 7. Nootropic effect (improvement of memory impaired by scopolamine) of compounds of the general formula 1 and 2 in the test “Passive avoidance of mice in the shuttle chamber”. A shuttle camera (Ugo Basile, Italy) was used, 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 that could be closed by a vertical door. The floor consisted of transverse metal rods to which direct current pulses could be supplied. The experiments were conducted on adult male BALB / c mice weighing 20-24 g.

On the first day of the experiment, 30 minutes before the training, mice were injected intraperitoneally with physiological saline, scopolamine (0.3 mg / kg) or scopolamine in combination with drug 1.1 (1). In each group, at least 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. The door between the compartments 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 22-24 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 compartment, the total residence time in the bright compartment and the number of entries into the dark compartment were recorded. The duration of observation was 5 minutes.

The experiment was conducted during daylight hours in an isolated laboratory room using "white noise" with an intensity of about 70 dB above the threshold of human hearing.

Scopolamine causes learning disruption (memory), which is expressed as an increase in the latent period of the first entry into the dark compartment, an increase in the time spent in the bright compartment, and a decrease in the number of visits to the dark compartment.

The ability of the drug source 1.1 (1) to improve learning disrupted by scopolamine is considered as evidence of the presence of a nootropic effect. The results obtained indicate the ability of the drug source 1.1 (1) to have a nootropic effect.

Example 8. Nootropic effect (improving memory impaired MK-801) of compounds of General formula 1 and 2 in the test "Passive avoidance of mice in the shuttle chamber". The experiment was carried out as in example 7. On the first day of the experiment, 30 minutes before training the mice were injected intraperitoneally with physiological saline solution MK-801 (0.1 mg / kg). Before training, independent groups of mice were injected intraperitoneally with physiological saline solution MK-801 in combination with drug 1.1 (1). The results obtained indicate the ability of compound 1.1 (1) to have a nootropic effect.

Example 9. Anxiolytic (tranquilizing) effect of compounds of the general formula 1 and 2 in the test “Behavior of mice in an elevated cruciform maze”. The length of the labyrinth sleeves is 30 cm, the width is 5 cm, the height of the walls is 15 cm. Two opposite sleeves are closed from the sides and ends with transparent walls; the other two are lit and open. The mouse was placed in the center of the maze, the number of visits to the open and closed arms and the time spent by the animals in the open and closed arms were recorded for 5 minutes. Based on these data, preference indices for open arms were calculated as the ratio of the number of visits to open arms, as well as the time spent in open arms, to the total number of visits to all arms and the time spent in them. 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).

The results obtained indicate that compound 1.1 (1) exhibits anxiolytic (tranquilizing) activity comparable with Buspirone and Lorazepam.

Claims (12)

1. 2-Alkylamino-3-arylsulfonylcycloalkano [e] pyrazolo [1,5-a] pyrimidines of the general formula 1 and 2-alkylamino-3-arylsulfonylcycloalkano [d] pyrazolo [1,5-a] pyrimidines of the general formula 2

where R ¹ represents a hydrogen atom or C ₁ -C ₃ alkyl;
R ² represent C ₁ -C ₃ alkyl;
R ₃ represents a hydrogen atom, one or two optionally identical halogen atoms, C ₁ -C ₃ alkyl or optionally substituted C ₁ -C ₃ alkyl hydroxyl;
n is an integer of 1, 2 or 3. 2. The compounds according to claim 1, which are 2-alkylamino-3-arylsulfonyl-7,8-dihydro-6H-cyclopenta [e] pyrazolo [1,5-a] pyrimidines of the general formula 1.1, 2-alkylamino-3-arylsulfonyl -6,7,8,9-tetrahydrocyclohexano [e] pyrazolo [1,5-a] pyrimidines of the general formula 1.2 and 2-alkylamino-3-arylsulfonyl-7,8,9,10-tetrahydro-6H-cyclohepta [e] pyrazolo [1,5-a] pyrimidines of the general formula 1.3

where R ¹ , R ² and R ³ have the above meaning. 3. The compounds according to claim 2, which are 2-methylamino-3-phenylsulfonyl-7,8-dihydro-6H-cyclopenta [e] pyrazolo [1,5-a] pyrimidine 1.1 (1), 2-methylamino-3- (3-chlorophenylsulfonyl) -7,8-dihydro-6H-cyclopenta [e] pyrazolo [1,5-a] pyrimidine 1.1 (2), 5-methyl-2-methylamino-3-phenylsulfonyl-7,8-dihydro 6H-cyclopenta [e] pyrazolo [1,5-a] pyrimidine 1.1 (3), 5-methyl-2-methylamino-3- (3-chlorophenylsulfonyl) -7,8-dihydro-6H-cyclopenta [e] pyrazolo [ 1,5-a] pyrimidine 1.1 (4), 2-methylamino-3-phenylsulfonyl-6,7,8,9-tetrahydrocyclohexano [e] pyrazolo [1,5-a] pyrimidine 1.2 (1), 2-methylamino 3- (3-chlorophenylsulfonyl) -6,7,8,9-tetrahydro-cyclo Exano [e] pyrazolo [1,5-a] pyrimidine 1.2 (2), 5-methyl-2-methylamino-3-phenylsulfonyl-6,7,8,9-tetrahydrocyclohexano [e] pyrazolo [1,5-a] pyrimidine 1.2 (3), 5-methyl-2-methylamino-3- (3-fluorophenylsulfonyl) -6,7,8,9-tetrahydrocyclohexano [e] pyrazolo [1,5-a] pyrimidine 1.2 (4), 5- methyl-2-methyl-amino-3- (3-chlorophenylsulfonyl) -6,7,8,9-tetrahydro-cyclohexano [e] pyrazolo [1,5-a] pyrimidine 1.2 (5), 5-methyl-2- methylamino-3- (3-chloro-4-fluorophenylsulfonyl) -6,7,8,9-tetrahydrocyclohexano [e] pyrazolo [1,5-a] pyrimidine 1.2 (6), 2-methylamino-3-phenylsulfonyl-7, 8,9,10-tetrahydro-6H-cyclohepta [e] pyrazolo [1,5-a] pyrimidine 1.3 (1) and 2-methylamino -3- (3-chlorophenylsulfonyl) -7,8,9,10-tetrahydro-6H-cyclohepta [e] pyrazolo [1,5-a] pyrimidine 1.3 (2).

4. A method for producing compounds of general formula 1 or 2 according to any one of claims 1 to 3 by reacting 3-amino-4-arylsulfonyl-2H-pyrazoles of general formula 3 with the corresponding β-dicarbonyl compounds of general formula 4 or their derivatives of general formula 5, followed by isolation or separation of reaction products

where R ¹ , R ² , R ³ and n have the above meaning. 5. “Molecular instruments” for studying the characteristics of physiologically active compounds having the property of inhibiting serotonin 5-HT ₆ receptors, which are compounds of the general formula 1 or 2 according to any one of claims 1-3. 6. Substituted 2-alkylamino-3-arylsulfonyl-pyrazolo [1,5-a] pyrimidine of the general formula 1 or 2 according to any one of claims 1 to 3 as a drug principle for pharmaceutical compositions and drugs having serotonin 5- antagonist properties NT ₆ receptors. 7. A pharmaceutical composition having the properties of serotonin 5-HT ₆ receptor antagonists for treating and preventing the development of conditions and diseases of the central nervous system, comprising a pharmaceutically effective amount of a drug substance according to claim 6. 8. The method of obtaining the pharmaceutical composition according to claim 7 by mixing with an inert excipient and / or solvent of the drug substance according to claim 6. 9. A medicine having the properties of antagonists of serotonin 5-HT ₆ receptors, intended for the prevention and treatment of diseases of the central nervous system, in the form of tablets, capsules or injections, placed in a pharmaceutically acceptable package, comprising the drug substance according to claim 6 or the pharmaceutical composition according to Claim 7 in an effective amount. 10. The drug according to claim 9, with anxiolytic activity. 11. The drug according to claim 9, with nootropic activity and suitable for improving memory. 12. 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 the introduction of the drug beginning according to claim 6, or the pharmaceutical composition according to claim 7, or the drug according to claim 9 in an effective amount .