RU2421456C1 - SUBSTITUTED 3-ARYLSULFONYL-PYRAZOLO[1,5-a]PYRIMIDINE-2,6-DIAMINES, SEROTONIN 5-HT6 RECEPTOR ANTAGONISTS, METHODS OF PRODUCING AND USING SAID COMPOUNDS - Google Patents

Abstract

FIELD: chemistry.

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

R¹, R² and R⁴, which are optionally identical, independently denote C₁-C₃ alkyl; R³ and R⁴, which are optionally identical, denote: a hydrogen atom, optionally substituted C₁-C₃ alkyl or acetyl; R⁵ denotes a hydrogen atom or halogen atom.

EFFECT: high treatment efficiency.

13 cl, 12 dwg, 4 tbl, 12 ex

Description

This invention relates to new substituted 3-arylsulfonyl-pyrazolo [1,5-a] pyrimidine-2,6-diamines, serotonin 5-HT ₆ receptor antagonists, drug principles and pharmaceutical compositions containing drug substances in the form of these compounds, and to a method of treating and preventing the development of various diseases of the central nervous system (CNS), the pathogenesis of which is associated with 5-HT ₆ receptors. 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, neurodegenerative diseases, cognitive and anxiety 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. Immune-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 works have shown that blocking 5-HT ₆ receptors; a large number of modern works 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 LA., 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 ™ 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 ™ 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. Thus, for example, substituted 1- (2-aminoethyl) -4-arylsulfonylpyrazoles of the general formula A1 are known as ligands for serotonin 5-HT _2c receptors [WO 2003057674 A1] and 7-amino-3-sulfonyl pyrazolo [1,5 -a] pyrimidines of the general formula 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-alkylamino-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 system 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} ^and 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, isopropyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethylmethyl, 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 H2 _{n + 1} ) N— group in which alkyl is defined in this section. Preferred alkylamino groups are methylamino, ethylamino, n-propylamino, isopropylamino 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, isopropyloxy and n-butyloxy.

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

“Amino group” means R _k ^a R _{k + 1} ^a N is a group substituted or unsubstituted with optionally the same “amino group substituents” R _k ^a and R _{k + 1} ^a , the meaning of which is defined in this section, for example, amino (H ₂ N- ), methylamino, diethylamino, pyrrolidino, morpholino, benzylamino or phenethylamino.

"Aminocarbonyl" means C (= O) NR _k ^a R _{k + 1} ^a is a group substituted or unsubstituted with optionally the same "carbamoyl substituents" R _k ^a and R _{k + 1} ^a , including hydrogen, alkenyl, alkyl, aryl, heteroaryl, heterocyclyl, the meaning of which is defined in this section.

"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 amino group”, “substituent carbamoyl”, “substituent of the cyclic system”, the meanings of which are defined in this section.

“Substituent amino group” means a substituent attached to an amino group. Amino group substituent represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, acyl, aroyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, geterotsiklilaminokarbonil, alkylaminothiocarbonyl, arylaminothiocarbonyl, heteroarylaminothiocarbonyl, heterocyclylaminothiocarbonyl, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl annelated heteroaryl heterocyclyl annelirs arylcycloalkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, heteroaralkyloxycarbonylalkyl.

“Carbamoyl substituent” means a substituent attached to an aminocarbonyl group, the meaning of which is defined in this section. The carbamoyl substituent is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, heteroaralkyloxycarbonylalkyl or R _k ^a R _{k + 1} ^a N-, R _k ^a R _{k + 1} ^a NC (= O) -alkyl, heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated heteroarylheterocyclyl, annelated arylcycloalkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylget. Preferred carbamoyl substituents are alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, heteroaralkyloxycarbonylalkyl or R _k ^a R _{k + 1} ^a N-, R _k ^a R _{k + 1} ^a NC (= O) -alkyl, arylheterocyclenyl, annelated arylheterocyclyl.

“Substituent cyclic system” means a substituent attached to an aromatic or non-aromatic cyclic system, including hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkoxy, aryloxy, acyl, aroyl, halogen , nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkyloxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, arylalkyloxyalkyl, heterocyclylalkyl-hydroxyalkyl, alkylsulfonyl, arylsulfonyl, heterocylalkyl lfinil, arylsulfinyl, geterotsiklilsulfinil, alkylthio, arylthio, heterocyclylthio, alkylsulfonylalkyl, arylsulfonylalkyl, geterotsiklilsulfonilalkil, alkylsulfinylalkyl, arylsulfinylalkyl, geterotsiklilsulfinilalkil, alkylthioalkyl, arylthioalkyl geterotsikliltioalkil, arilalkilsulfonilalkil, geterotsiklilalkilsulfonilalkil, arilalkiltioalkil, geterotsiklilalkiltioalkil, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, amidino, R _k ^a R _{k + 1} ^a N-, R _k ^a N =, R _k ^a R _{k + 1} ^a N-alkyl-, R _k ^a R _{k + 1} ^a NC (= O) - or R _k ^a R _{k + 1} ^a SO 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, 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 _{k + 1} ^a NSO _2, wherein R _k ^a and R _{k + 1} ^a together with the nitrogen atom to which they are attached to, form through R _k ^a and R _{k + 1} ^a 4-7-membered geterotsik yl 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; 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.

"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, Asperg's 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.

“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. icloalkyl 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 non-differentiable schizophrenia and / or forms of schizophrenia defined in the classification of the American Psychiatric Association (American Psychiatric Association; in: Diagnostic and Statistical Manual of Mental Disorders, IV Edition, Washington DC 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 1 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 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 is novel substituted 3-arylsulfonyl-pyrazolo [1,5-a] pyrimidin-2, b-diamines of general formula 1 and their pharmaceutically acceptable salts and / or hydrates

Where

R ¹ , R ² and R ⁴ independently from each other are optionally the same C ₁ -C ₃ alkyl;

R ³ and R ⁴ are optionally the same hydrogen atom, optionally substituted C ₁ -C ₃ alkyl or acetyl;

R ⁵ represents a hydrogen atom, or a halogen atom.

A preferred substituted 3-arylsulfonyl-pyrazolo [1,5-a] pyrimidin-2,6-diamine of general formula 1 is 5.7, N (2) -trimethyl-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine- 2,6-diamines of the general formula 1.1

Where

R ³ and R ⁴ have the above meaning.

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

3-Arylsulfonyl-pyrazolo [1,5-a] pyrimidin-2,6-diamine of general formula 1 is prepared according to the scheme below. In the case where a diketone 3 R _a and R _b are different alkyls, then a mixture of two N (3-arylsulfonyl-2-alkylamino) pyrazolo [1,5- a] pyrimidin-6-yl) acetamides 1A, 1B (R ³ = H, R ⁴ = A; R _a and R _b = C ₁ -C ₃ alkyl), which is separated by chromatography.

The subject of the present invention are also antagonists of serotonin 5-HT ₆ receptors, which are substituted 3-arylsulfonyl-pyrazolo [1,5-a] pyrimidin-2,6-diamines of the general formula 1, 1.1, 1.1.1, 1.1.2 and their pharmaceutically acceptable salts and / or hydrates.

A more preferred antagonist of serotonin 5-HT ₆ receptors is 5.7, N (2) -trimethyl-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine-2,6-diamine 1.1.1 and 5.7, N ( 2), N (6), N (6) -pentamethyl-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidin-2,6-diamine 1.1.2.

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

This goal is achieved by antagonists of serotonin 5-HT ₆ receptors, which are substituted 3-arylsulfonyl-pyrazolo [1,5-a] pyrimidine-2,6-diamines of the general formula 1, 1.1, 1.1.1, 1.1.2 and their pharmaceutically acceptable salts and / or hydrates.

The subject of this invention are also substituted 3-arylsulfonyl-pyrazolo [1,5-a] pyrimidin-2,6-diamines of the general formula 1, 1.1, 1.1.1, 1.1.2 and their pharmaceutically acceptable salts and / or hydrates as a medicinal product beginning for pharmaceutical compositions and medicines.

The subject of this invention is also a pharmaceutical composition for the treatment and prevention of 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, representing at least one of the compounds of general formula 1, 1.1, 1.1.1, 1.1 .2 or a pharmaceutically acceptable salt and / or hydrate thereof.

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 solutions or suspensions for injection 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 the present invention is also a method for preparing a new pharmaceutical composition by mixing with an inert excipient and / or solvent of a medicinal agent, which is at least one of the compounds of the general formula 1.1.1, 1.1.1, 1.1.2 or a pharmaceutically acceptable salt thereof and / or hydrate.

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, in warm-blooded animals and humans, which is at least at least one of the compounds of general formula 1, 1.1, 1.1.1, 1.1.2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing 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 cognitive disorders and neurodegenerative diseases, comprising a pharmaceutically effective amount of a medicinal agent, representing at least one of the compounds of general formula 1, 1.1, 1.1.1, 1.1.2 or a pharmaceutically acceptable salt and / or hydrate thereof, or a pharmaceutical composition containing a new drug substance.

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 new drug beginning, representing at least one of the compounds General formula 1, 1.1, 1.1.1, 1.1.2 or its pharmaceutically acceptable salt and / or hydrate, or pharmaceutical composition containing a new drug start.

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, 1.1.1, 1.1.2 or a pharmaceutically acceptable salt and / or hydrate thereof, or a pharmaceutical composition containing a new drug substance.

More preferred is a medicament (anxiolytic or tranquilizer) for the prophylaxis 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, 1.1.1, 1.1.2 or its pharmaceutically an acceptable salt and / or hydrate, or pharmaceutical composition containing a new drug start.

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, 1.1.1, 1.1. 2 or its pharmaceutically acceptable salt and / or hydrate, or a pharmaceutical composition containing a new drug beginning.

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, 1.1.1, 1.1.2 or a pharmaceutically acceptable salt and / or hydrate thereof, or a pharmaceutical composition containing a new drug substance.

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, 1.1.1, 1.1.2 or its pharmaceutically acceptable salt and / or hydrate, or pharmaceutical w composition comprising a novel drug substance.

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 of the compounds of general formula 1, 1.1, 1.1.1, 1.1.2 or its pharmaceutically acceptable salt and / or hydrate, or a pharmaceutical composition containing a new drug beginning.

Therapeutic cocktails for the prevention and treatment of neuralgic 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, along with the medicines of this invention may include other medicines, such as: steroidal anti-inflammatory drugs (Ortofen, indomethacin, ibuprofen and the like); 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 cannabinoid CB-1 receptor antagonists (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 of the central nervous system, the pathogenesis of which is associated with 5-HT ₆ receptors in animals and humans, is to introduce a pharmaceutically effective amount of a new drug source, a new pharmaceutical composition, a new drug or a new therapeutic cocktail .

Medicines can be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically). The clinical dosage of the drug substance (s), pharmaceutical composition or drug, including a pharmaceutically effective amount of the drug substance, 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, and also depending on the age, gender, 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 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 invention is illustrated by drawings.

Figure 1. The latent period of the first entry into the dark compartment 24 hours after training the rats to avoid the dark compartment in the shuttle chamber (average value ± standard error). The number in parentheses is the dose of the substance in mg / kg. The studied substance 1.1.1 was administered orally 60 minutes before the experiment. Difference from the scopolamine group: * - p <0.05; ** - p <0.01; *** - p <0.001.

Figure 2: Duration of stay in the bright compartment 24 hours after training the rats to avoid the dark compartment in the shuttle chamber (mean ± standard error). The number in parentheses is the dose of the substance in mg / kg. The studied substance 1.1.1 was administered orally 60 minutes before the experiment. Difference from the scopolamine group: * - p <0.05; ** - p <0.01; *** - p <0.001.

Figure 3. The number of entries into the dark compartment 24 hours after training the rats to avoid the dark compartment in the shuttle chamber (mean ± standard error). The number in parentheses is the dose of the substance in mg / kg. The studied substance 1.1.1 was administered orally 60 minutes before the experiment. Difference from the scopolamine group: * - p <0.05; *** p <0.001.

Figure 4. Test results for recognition of new objects in mice (mean ± standard error). In parentheses are the doses of substances in mg / kg. The studied substance 1.1.1 was administered orally 60 minutes before the test. Difference from the group to which only scopolamine was administered: * - p <0.05 in accordance with the χ ² criterion.

Figure 5. The latent period of the first entry into the dark compartment 24 hours after training the rats to avoid the dark compartment in the shuttle chamber (average value ± standard error). The number in parentheses is the dose of the substance in mg / kg. The studied substance 1.1.1 was administered orally 60 minutes before the experiment. Difference from the group receiving MK-801: * - p <0.05; ** - p <0.01; *** - p <0.001.

6. Duration of stay in the bright compartment 24 hours after training the rats to avoid the dark compartment in the shuttle chamber (mean ± standard error). The number in parentheses is the dose of the substance in mg / kg. The studied substance 1.1.1 was administered orally 60 minutes before the experiment. Difference from the group receiving MK-801: * - p <0.05; ** - p <0.01; *** - p <0.001.

7. The number of entries in the dark compartment 24 hours after training rats to avoid

dark compartment in the shuttle chamber (average value ± standard error). The number in parentheses is the dose of the substance in mg / kg. The studied substance 1.1.1 was administered orally 60 minutes before the experiment. Difference from the group receiving MK-801: * - p <0.05; *** p <0.001.

Fig. 8. The ratio of time spent by animals in open arms to the total time spent in open and closed arms (mean ± standard error). In parentheses are doses of the substance 1.1.1 (in mg / kg). Difference from placebo groups: * - p <0.05; ** - p <0.01; *** - p <0.001.

Fig.9. The ratio of the number of entrances to open arms to the total number of entrances to both types of arms (mean ± standard error). In parentheses are doses of the substance 1.1.1 (in mg / kg). Difference from placebo groups: * - p <0.05; ** - p <0.01; *** - p <0.001.

Figure 10. The number of bowel movements in the labyrinth-plus test (mean ± standard error). In parentheses are doses of the substance 1.1.1 (in mg / kg). Difference from placebo groups: * - p <0.05; ** - p <0.01; *** - p <0.001.

11. Test results for prepulse inhibition of flinching in mice.

Fig. 12. Rat appetite test results.

The following examples do not limit the invention.

Example 1. General method for producing N- (3-arylsulfonyl-2-olkylamino) pyrazolo [1,5-a] pyrimidin-6-yl) acetamides of general formula 1 (R ³ = H, R ⁴ = Ac). Stirred at 100 ° C for 3 hours 0.637 mol. diketone 3 and 0.606 mol of 4- (arylsulfonyl) -1H-pyrazole-3,5-diamine 2 in 650 ml of AcOH. After cooling the reaction mass, the precipitated white crystalline precipitate is filtered off, washed with acetic acid, ether and dried in air. Get the compounds of General formula 1 (R ³ = N, R ⁴ = Ac) with a yield of 80-85%.

Example 2. General method for producing 3-arylsulfonyl-N (2) -alkylpyrazolo [1,5-a] pyrimidin-2,6-diamines of general formula 1 (R ³ = R ⁴ = H). To a suspension of 0.29 g of N- (3-arylsulfonyl2-methylamino) pyrazolo [1,5-a] pyrimidin-6-yl) acetamide 1.1 (R ³ = H, R ⁴ = Ac) in 1350 ml of a mixture of MeOH: H ₂ O ( 3: 1) 135 g of KOH are added. The reaction mass is boiled with stirring for 72 hours. After completion of the reaction (LC-MS control), the precipitate formed is filtered off and then washed with water. Get the compounds of General formula 1 (R ³ = R ⁴ = N) with a yield of 92-95%.

Example 3. General method for the preparation of 3-arylsulfonyl-N (2), N (6), N (6) -trialkyl-pyrazolo [1,5-d] pyrimidin-2,6-diamines of the general formula 1 (R ³ = R ⁴ = CH ₃ ). To a suspension of 0.25 mol. 3-arylsulfonyl-N (2) -methylpyrazolo [1,5-a] pyrimidin-2,6-diamines 1.1 (R ³ = R ⁴ = H) in 3750 ml of ethyl alcohol add 67 g of sulfuric acid in 230 ml of water (3M solution). The resulting suspension is heated to 90 ° C, and then cooled to room temperature, 116.5 g of a 35% formalin solution are added. After 30 minutes, with vigorous stirring, 56 g of NaBH _{4 are} gradually sprinkled in small portions so that the temperature of the solution remains no higher than 25 ° C (if necessary, cooled with a water bath). After the reaction (LC-MS control), the precipitate is filtered off and washed thoroughly with water. The mother liquor is evaporated in vacuo, and the resulting precipitate is also washed with water. The total yield of product 1 (R ³ = R ⁴ = CH ₃ ) is 95-97%.

Table 2 presents some examples of the new 3-arylsulfonyl-pyrazolo [1,5-a] pyrimidin-2,6-diamines of general formula 1 and the data of their LCMS analyzes and NMR spectra.

table 2 Antagonists of serotonin 5-HT ₆ receptors are 3-arylsulfonyl-pyrazolo [1,5-a] pyrimidin-2,6-diamines of the general formula 1. No. Formula Like the weight LCMS m / z (M + 1) NMR spectrum 1.1.1

331.4 332 ¹ H NMR (DMSO-D ₆ , 400 MHz) δ 7.98 (d, J = 8.4 Hz, 2H), 7.51-7.59 (m, 3H), 4.59 (w), 2 89 (s, 2H); 2.55 (s, 3H); 2.47 (s, 3H). 1.1 (1)

373.44 374 ¹ H NMR (DMSO-D ₆ , 400 MHz) δ 9.66 (s, 1H), 8.02 (d, J = 6.8 Hz, 2H), 7.56 (m, 3H), 6.39 (q, J = 4.8 Hz, 1H), 2.92 (d, J = 4.8 Hz, 3H), 2.45 (s, 3H), 2.39 (s, 3H), 2.08 (s, 3H). 1.1 (2)

365.8 366 1.1 (3)

349.4 350 1.1 (4)

349.4 350 1.1 (5)

345.4 346 1.1.2

359.4 360 ¹ H NMR (DMSO-D ₆ , 400 MHz) δ 8.02 (m, 2H), 7.53-7.61 (m, 3H), 6.29 (w, 1H), 2.91 (s, 3H), 2.74 (s, 6H), 2.57 (s, 3H). 2.49 (s, 3H).

Example 4. Determination of the antagonistic activity of compounds of General formula 1 in relation to 5-HT ₆ receptors. Compounds of general formula 1 were tested for their ability to inhibit 5-HT ₆ receptor activation 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_LANCEcAMP384K.itUser.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 antagonistic activity of the compounds of general formula 1 to serotonin 5-HT ₆ receptors under the conditions of a functional essay, confirming their moderate or high activity.

Table 3. Antagonistic activity of compounds of general formula 1 to serotonin 5-HT ₆ receptors under conditions of functional essay. Antagonist number IC ₅₀ , nM 1.1.1 4.3 1.1 (1) 36.5 1.1.2 2.3

Example 5. Determination of the activity of compounds of General formula 1 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, the 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 a medium consisting of 50 mM Tris-HCl, pH 7.4, 150 tM Nad, 2 tM Ascorbic Acid, 0.001% BSA. Samples after incubation were filtered under vacuum on a G / F fiberglass filter (Millipor, USA), the filters were washed three times with a cold medium solution 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 mM 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 the 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 compounds of General formula 1, indicating their high activity in relation to serotonin 5-HT ₆ receptors.

Table 4 The activity of compounds of the general formula 1 with respect to serotonin 5-HT ₆ receptors under conditions of competitive essay. Antagonist number K _i , nM IC ₅₀ , nM I.I.I 0.31 0.67 1.1.2 0.31 0.67

Example 6. Obtaining a drug in the form of tablets. 1600 mg of starch, 1600 mg of crushed 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 7. 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 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 1.1.1 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 9. Antiamnestic activity of compounds of General formula 1 (nootropic effect).

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 the general formula 1, for example, compound 1.1.1, at 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 into the dark compartment 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 results of the experiment, shown in figures 1, 2, 3, showed that in the passive avoidance test the compounds of general formula 1, including compound 1.1.1, had the ability 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 dimebon (0.1 mg / kg) 5 minutes before the start of training, tacrine (10 mg / kg) 30 minutes before the start of training and compounds of the general formula 1 in doses of 0.05 mg / kg and 0.2 mg / kg 60 minutes before training.

From the results presented in figure 4, it follows that the connection 1.1.1 prevents 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 10.1.1. 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 test compounds of general formula 1.

The experimental results presented in FIGS. 5, 6 and 7 indicate that compound 1.1.1, administered intraperitoneally before training at doses of 0.2 mg / kg and 1 mg / kg, has the ability to reduce amnesia caused by MK-801.

Example 10. The anxiolytic activity of compounds of General formula 1 in the test "Behavior of mice in an elevated cruciform maze."

In the experiment, male BALB / c mice weighing approximately 25 g were used. Animals were kept in cages (5-7 mice per cage), providing free access to food 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.

Animals were given an intraperitoneal placebo, buspirone (5 mg / kg 30 minutes before training), lorazepam (0.05 mg / kg 60 minutes before training), or one of the compounds of general formula 1, for example, compound 1.1.1, 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).

Each mouse was placed in the center of the maze with its head toward the open sleeve. For 5 minutes, the sequence and duration of entries into the arms were recorded using a computer program. 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 open chambers, as well as the number of visits to open sleeves, to the total time spent in open and closed sleeves or, respectively, to the total number of visits to both types of sleeves. The number of fecal boluses left by the mouse was considered as an additional parameter characterizing the state of anxiety.

The test results presented in Figs. 8, 9 and 10 showed that the compounds of the general formula 1, including compound 1.1.1, as well as the standards (buspirone and lorazepam), had a pronounced anxiolytic effect in the elevated cross-maze test.

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 during daylight hours 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. The compounds of general formula 1 were dissolved in sterilized water and administered subcutaneously 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 apparatus consisted of a chamber made of transparent plexiglass (manufactured by Columbus Instrument, USA), placed on a platform that was located inside a soundproofing 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 test (“pulse”) stimulus lasting 50 ms and a loudness of 105 dB or a preceding (“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 model psychotropic 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 experimental results presented in Fig. 11 show that haloperidol (1 mg / kg) and the studied compounds of general formula 1, including compound 1.1.1 (1 mg / kg), prevented impaired inhibition of trembling by the administration of apomorphine.

Example 12. An appetite test.

Male Wistar rats weighing 230-360 g were placed in standard living cages, where they had constant free access to water and food with the exception of short periods of food deprivation (16 hours) immediately before the appetite test. An appetite test was carried out in individual cells with a top cover made of wire, in a niche of which a portion of food granules was placed. The mass of granules was determined every 30 minutes for 3 hours. Based on these measurements, food intake was estimated, which was expressed in grams of feed per kilogram of body weight. Placebo and Compound 1.1.1. (at a dose of 10 mg / kg) was administered intraperitoneally 60 minutes before the test. There were 10 rats in each group. The substances were dissolved in sterile water. The volume of fluid introduced was 10 ml / kg. As control groups were used intact animals that were not subjected to food deprivation, and animals after food deprivation, which were injected with sterilized water. The experimental results presented in Fig. 12 show that the studied compounds of general formula 1, including compound 1.1.1 (10 mg / kg), prevented an increase in appetite in rats.

Claims (15)

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

where R ¹ , R ² and R ⁴ optionally the same independently from each other are C ₁ -C ₃ alkyl;
R ³ and R ⁴ optionally the same are: a hydrogen atom, optionally substituted C ₁ -C ₃ alkyl or acetyl;
R ⁵ represents a hydrogen atom or a halogen atom. 2. The compounds according to claim 1, which are 5,7, N (2) -trimethyl-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidin-2,6-diamines of the general formula 1.1

where R ³ and R ⁴ have the above meaning. 3. The compounds according to any one of claims 1 and 2, representing 5,7, N (2) -trimethyl-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine-2,6-diamine 1.1.1 and 5, 7, N (2), N (6), N (6) -pentamethyl-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidin-2,6-diamine 1.1.2.

4. The tool is a substituted 3-arylsulfonyl-pyrazolo [1,5-a] pyrimidin-2,6-diamine according to any one of claims 1 to 3, having antagonist properties of serotonin 5-HT ₆ receptors. 5. The tool is a substituted 3-arylsulfonyl-pyrazolo [1,5-a] pyrimidine-2,6-diamine according to any one of claims 1 to 3, to study the molecular mechanism of interaction with serotonin 5-HT ₆ receptors. 6. The agent, which is a substituted 3-arylsulfonyl-pyrazolo [1,5-a] pyrimidin-2,6-diamine according to any one of claims 1 to 3, as a drug source for pharmaceutical compositions and medicines. 7. 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 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 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 6 or the pharmaceutical composition according to claim 7. 10. The drug according to claim 9 for the prevention and treatment of cognitive disorders and neurodegenerative diseases. 11. The drug according to claim 9 for the prevention and treatment of mental disorders. 12. The drug according to claim 9, with anxiolytic activity, for the prevention and treatment of anxiety disorders. 13. The drug according to claim 9, having nootropic activity, to improve mental abilities. 14. The drug according to claim 9 for the prevention and treatment of obesity. 15. 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 6, or the pharmaceutical composition according to claim 7, or the drug according to any one of claims. 9-14.

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