RU2376291C1 - SUBSTITUTED 3,5-DIAMINO-4-SULFONYL-PYRAZOLES AND 2-AMINO-3-SULFONYL-PYRAZOLO-[1,5-a]PYRIMIDINES-ANTAGONISTS OF SEROTONIN 5-HT6 RECEPTORS, METHODS FOR THEIR PRODUCTION AND USE - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention is related to antagonists of serotonin 5-HT₆ receptors of common formula 1 and their pharmaceutically acceptable salts and/or hydrates, pharmaceutical compositions, dosage forms and methods of production. Invention also includes new compounds of formula 1.1. In formulae 1

and 1.1

, Ar represents aryl, selected from unnecessarily substituted phenyl or unnecessarily substituted 5-6-member heteroaryl, which contains atom of nitrogen or atom of sulfur and heteroatom; R¹ represents atom of hydrogen, unnecessarily substituted C₁-C₅ alkyl; Ar represents aryl, selected from unnecessarily substituted phenyl or unnecessarily substituted 5-6-member heteroaryl, which contains atom of nitrogen or atom of sulfur as heteroatom; R¹ represents atom of hydrogen, which is unnecessarily substituted C₁-C₅ alkyl; R² ₁,R² ₂, R³ ₁, R³ ₂ independently from each other represent atom of hydrogen or substituent of aminogroup, selected from unnecessarily substituted C₁-C₄ alkyl, unnecessarily substituted phenyl, or R³ ₁ and R³ ₂ together with atom of nitrogen, to which they are bound, create unnecessarily substituted saturated 6-member heterocycle, possibly containing atom of nitrogen in cycle; or R¹ together with atom of nitrogen, to which it is bound, and R² ₁ and R² ₂ together with atom of nitrogen, to which they are bound, create substituted pyrimidine cycle. In formula 1.1 R⁴, R⁵ and R⁶ independently from each other represent atom of hydrogen, unnecessarily substituted C₁-C₃ alkyl or phenyl.

EFFECT: compounds of invention may find application for treatment and prevention of development of conditions and disorders of central nervous system.

13 cl, 11 dwg, 4 tbl, 11 ex

Description

This invention relates to new arylsulfonyl-azaheterocyclic compounds, to new antagonists of serotonin 5-HT ₆ receptors, to new drug principles, pharmaceutical compositions, drugs and methods for their preparation. More specifically, the present invention relates to antagonists of serotonin 5-HT ₆ receptors - substituted 4-sulfonylpyrazoles and 3-sulfonyl-pyrazolo [1,5-a] pyrimidines, pharmaceutical principles and pharmaceutical compositions containing pharmaceutical principles in the form of these compounds, as well as to a method of treating and preventing the development of various cognitive and neurodegenerative diseases. The pharmacological effect of new drugs is based on their ability to interact with serotonin 5-HT ₆ receptors, which play an important role in the treatment of diseases of the central nervous system (CNS), in particular Alzheimer's disease (AD), Huntington's disease, schizophrenia, other neurodegenerative diseases, cognitive disorders and obesity.

The use of effective and selective antagonists of serotonin 5-HT ₆ receptors for the treatment of central nervous system diseases, in particular schizophrenia, asthma and other neurodegenerative diseases and cognitive disorders, is a promising area for the development of new drugs [Holenz J., Pauwels PJ, Diaz JL, Merce R. , Codony X., Buschmann H. Medicinal chemistry strategies to 5-HT ₆ receptor ligands as potential cognitive enhancers and antiobesity agents. Drug Disc. Today. 2006; 11: 283-299]. These receptors in mammals are located exclusively in the central nervous system, and mainly in the areas of the brain responsible for learning and memory [Ge′rard C., Martres M.-P., Lefe′vre K., Miquel M.-C, Verge ′ D., Lanfumey L., Doucet E., Hamon M., El Mestikawy S. Immuno-localization 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 learning-memorizing-reproduction models [Foley AG, Murphy KJ, Hirst WD, Gallagher HC, Hagan JJ, Upton N., Walsh FS, Regan CM The 5-HT (6) receptor antagonist SB-271046 reverses scopolamine-disrupted consolidation of a passive avoidance task and ameliorates spatial task deficits in aged rats. Neuropsychopharmacology. 2004; 29: 93-100. Riemer C., Borroni E., Levet-Trafit B., Martin JR, Poli S., Porter RH, Bos M. Influence of the 5-HT ₆ receptor on acetylcholine release in the cortex: pharmacological characterization of 4- (2- bromo-6-pyrrolidin-l-ylpyridine-4-sulfonyl) phenylamine, a potent and selective 5-HT ₆ receptor antagonist. J. Med. Chem. 2003; 46: 1273-1276. King MV, Woolley ML, Topham IA, Sleight AJ, Marsden CA, Fone KC 5-HT6 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-HT6 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, 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) 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 ™ 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 Drag 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 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 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: R = 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 carried out extensive studies in the series of substituted 4-sulfonylpyrazoles and 3-sulfonyl-pyrazolo [1,5-a] pyrimidines, as a result of which new drug principles, which are 5-HT ₆ antagonists, were found receptors.

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

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

“Azaheterocycle” means an aromatic or non-aromatic monocyclic or polycyclic system containing at least one nitrogen atom in a ring. An azaheterocycle may have one or more “cyclic” substituents. "Alkyl" means an aliphatic hydrocarbon linear or branched group with 1-12 carbon atoms in the chain. Branched means that the alkyl chain has one or more "lower alkyl" substituents. Alkyl may have one or more identical or different substituents (“alkyl substituents”), including halogen, alkenyloxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl, alkylthio, heteroarylthio, aralkylthio, arylsulfonyl, alkylsulfonyl, heteroaralkyloxy, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroaryl heterocyclenyl, annelated heteroaryl heterocyclyl, annelated aero kloalkenil, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl, alkoxycarbonyl, aralkoxycarbonyl, geteroaralkiloksikarbonil ⁸ or R _k 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 goethe rocyclyl 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.

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

“Alkyloxycarbonyl” means an alkyl-O — C (═O) group in which alkyl is defined in this section. Preferred alkyloxycarbonyl groups are methoxycarbonyl, ethoxycarbonyl, n-butoxycarbonyl, iso-propyloxycarbonyl, tert-butyloxycarbonyl.

“Amino group” means R _k ^a R _{k + 1} ^a N-group substituted or unsubstituted with “amino group substituent” 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.

“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.

“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.

“Heteroaryl” means an aromatic monocyclic or polycyclic system comprising from 5 to 14 carbon atoms, preferably from 5 to 10, in which one or more carbon atoms are substituted with heteroatoms or heteroatoms such as nitrogen, sulfur or oxygen. The prefix "aza", "oxa" or "thia" before "heteroaryl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. The nitrogen atom in the heteroaryl can be oxidized to an N-oxide. Heteroaryl may have one or more “ring system substituents”, which may be the same or different. Representative heteroaryl compounds are pyrrolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, isoxazolyl, isothiazolyl, tetrazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, triazolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinazole, quinazole -a] pyridinyl, imidazo [2,1-b] thiazolyl, benzofurazanil, indolyl, azaindolyl, benzimidazolyl, benzothiazenyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidinyl, pyrrolopyridine, imidazoinazole, azidazinoidinazole , thienopyrrolyl, furopyrrolyl, etc.

“Heterocyclyl” means an aromatic or non-aromatic saturated monocyclic or polycyclic system comprising from 3 to 10 carbon atoms, preferably from 5 to 6 carbon atoms, in which one or more carbon atoms are replaced by a heteroatom such as nitrogen, oxygen, sulfur. The prefix "aza", "oxa" or "thia" before heterocyclyl means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Heterocyclyl may have one or more “cyclic system substituents,” which may be the same or different. The nitrogen and sulfur atoms in the heterocyclyl can be oxidized to N-oxide, S-oxide or S-dioxide. Representatives of heterocyclyl are piperidine, pyrrolidine, piperazine, morpholine, thiomorpholine, thiazolidine, 1,4-dioxane, tetrahydrofuran, tetrahydrothiophene, etc.

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

“Substituent” means a chemical radical that is attached to a scaffold (fragment), for example, “substituent alkyl”, “substituent of an amino group”, “substituent carbamoyl”, “substituent of a 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, methoxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethoxymethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethoxymethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonyl . 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.

“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, geteroarilamino- carbonyl geterotsiklilaminokarbonil, alkylaminothiocarbonyl, arilaminotio- carbonyl, heteroarylaminothiocarbonyl, heterocyclylaminothiocarbonyl, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated heteroarylheterocyclyl, annelir ovany arylcycloalkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl, alkoxycarbonylalkyl, aralkoxycarbonyl alkyl, heteroaralkyloxycarbonylalkyl.

“Substituted amino group” means R _k ^a R _{k + 1} ^a N-group in which R _k ^a and R _{k + 1} ^a are amino substituents as 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, Parkineon 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, 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 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 formulations intended to restore, correct or alter physiological functions in 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.

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

“Sulfonyl” means R — SO ₂ - a group in which R is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, annelated heteroarylcycloalkenyl, annelated heteroaryl heterocyclylalkylalkylalkylalkylalkylalkylalkylalkylalkylalkylalkyl the meaning of which is defined in this section.

"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.

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

“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 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, when this can be synthesized metal salts and amines. 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 purpose of the present invention is to create new antagonists of serotonin 5-HT ₆ receptors and new drug principles.

This goal is achieved by antagonists of serotonin 5-HT ₆ receptors of General formula 1 or their pharmaceutically acceptable salts and / or hydrates,

where Ar is aryl selected from optionally substituted phenyl or optionally substituted 5-6 membered heteroaryl containing a nitrogen atom or a sulfur atom as a heteroatom;

R ¹ represents a hydrogen atom, optionally substituted C ₁ -C ₅ alkyl;

R ² ₁ , R ² ₂ , R ³ ₁ , R ³ ₂ independently represent a hydrogen atom or an amino substituent selected from optionally substituted C ₁ -C ₄ alkyl, optionally substituted phenyl, or R ³ ₁ and R ³ ₂ together with the nitrogen atom to which they are attached form an optionally substituted saturated 6-membered heterocyclyl, possibly containing a nitrogen atom in the ring;

or R ¹ together with the nitrogen atom to which it is bonded, and R ² ₁ and R ² ₂ together with the nitrogen atom to which they are bonded form a substituted pyrimidine ring.

Preferred antagonists of serotonin 5-HT ₆ receptors are substituted 2-amino-3-sulfonyl-pyrazolo [1,5-a] pyrimidines of the general formula 1.1 or their pharmaceutically acceptable salts and / or hydrates,

where Ar, R ³ ₁ and R ³ ₂ have the above meaning; R ⁴ , R ⁵ and R ⁶ independently from each other represent a hydrogen atom, optionally substituted C ₁ -C ₃ alkyl or phenyl.

More preferred antagonists of serotonin 5-HT ₆ receptors are substituted 3-arylsulfonyl-5,7-dimethyl-pyrazolo [1,5-a] pyrimidines of the general formula 1.1.1 or their pharmaceutically acceptable salts and / or hydrates,

where R ³ ₁ and R ³ ₂ have the above meaning; R _i ⁷ represents one or two optionally identical substituents of the cyclic system selected from a hydrogen atom, C ₁ -C ₅ alkyl, trifluoromethyl or a halogen atom.

More preferred antagonists of serotonin 5-HT ₆ receptors are 5,7-dimethyl-2-methylamino-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine 1.1.1 (1), 5,7-dimethyl-2-dimethylamino 3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine 1.1.1 (2), 5,7-dimethyl-2-methylamino-3- (4-fluorophenylsulfonyl) -pyrazolo [1,5-a] pyrimidine 1.1.1 (3), 5,7-dimethyl-2-dimethylamino-3- (4-fluorophenylsulfonyl) pyrazolo [1,5-a] pyrimidine 1.1.1 (4), 5,7-dimethyl-2-methylamino-3- (3-fluorophenylsulfonyl) pyrazolo [1,5-a] pyrimidine 1.1.1 (5), 5,7-dimethyl-2-dimethylamino-3- (3-fluorophenylsulfonyl) pyrazolo [1,5-a] pyrimidine 1.1 .1 (6), 5,7-dimethyl-2-methyl but-3- (3-chlorophenylsulfonyl) pyrazolo [1,5-a] pyrimidine 1.1.1 (7), 5,7-dimethyl-2-dimethylamino-3- (3-chlorophenylsulfonyl) pyrazolo [1,5- a] pyrimidine 1.1.1 (8) or their pharmaceutically acceptable salts and / or hydrates.

The subject of this invention is also a pharmaceutical principle for pharmaceutical compositions and dosage forms, which is at least one antagonist of serotonin 5-HT ₆ receptors of the general formula 1, 1.1.

The subject of this invention is also a pharmaceutical composition that interacts with 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 source, which is at least one serotonin antagonist 5-HT ₆ receptors of the general formula 1, 1.1.

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 pharmaceutical principle of the general formula 1 of the present invention may include other active ingredients, provided that they do not cause undesirable effects, such as allergic reactions.

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

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

The subject of the present invention is also a method for preparing a new pharmaceutical composition by mixing with an inert excipient and / or a solvent of a drug substance, which is at least one antagonist of serotonin 5-HT ₆ receptors of the general formula 1, 1.1.

The subject of this invention is also a medicament in the form of tablets, capsules or injections, placed in a pharmaceutically acceptable package, comprising a medicament comprising at least one serotonin 5-HT ₆ receptor antagonist of the general formula 1, 1.1 or a pharmaceutical composition comprising this drug substance, intended for treatment and prevention of pathological states and CNS diseases pathogenesis of which is associated with impaired activation of serotonin 5-HT ₆ D eptorov.

According to this invention, more preferred are drugs for the prevention and treatment of Alzheimer's disease and Huntington's disease.

Drugs for the prevention and treatment of mental disorders and schizophrenia are also more preferred according to the invention.

Drugs for the prevention and treatment of obesity are also more preferred according to the invention.

The subject of this invention is also a method for the prevention and treatment of diseases of the central nervous system, the pathogenesis of which is associated with serotonin 5-HT ₆ receptors in animals and humans, including neurological disorders, neurodegenerative and cognitive diseases, which consists in introducing a new medicinal product to a warm-blooded animal or human funds containing the medicinal beginning of the General formula 1.

Medicines can be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically). The clinical dosage of a pharmaceutical composition or medicament containing a pharmaceutical principle of general formula 1 in patients can be adjusted depending on: therapeutic efficacy and bioavailability of the active ingredients in the body, their metabolic rate and excretion from the body, as well as on age, gender and stage diseases of the patient, with a daily dose in adults is usually 10 ~ 500 mg, preferably 50 ~ 300 mg. Therefore, during the preparation of the pharmaceutical compositions of the present invention as dosage units, the above effective dosage must be taken into account, with each dosage unit of the preparation containing 10 ~ 500 mg of the drug substance of the general formula 1, 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 subject of the present invention is novel substituted 3-sulfonyl-pyrazolo [1,5-a] pyrimidines of the general formula 1.1 or their pharmaceutically acceptable salts and / or hydrates,

where Ar, R ³ ₁ and R ³ ₂ have the above meaning; R ⁴ , R ⁵ and R ⁶ independently from each other represent a hydrogen atom, optionally substituted C ₁ -C ₃ alkyl or phenyl.

A subject of the present invention are also new substituted 3-arylsulfonyl-5,7-dimethyl-pyrazolo [1,5-a] pyrimidines of the general formula 1.1.1 or their pharmaceutically acceptable salts and / or hydrates,

where R ³ ₁ and R ³ ₂ have the above meaning; R _i ⁷ represents one or two optionally identical substituents of the cyclic system selected from a hydrogen atom, C ₁ -C ₅ alkyl, trifluoromethyl or a halogen atom.

More preferred compounds of the general formula 1.1.1 are 5,7-dimethyl-2-methylamino-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine 1.1.1 (1), 5,7-dimethyl-2-dimethylamino-3 -phenyl sulfonyl-pyrazolo [1,5-a] pyrimidine 1.1.1 (2), 5,7-dimethyl-2-methylamino-3- (4-fluorophenylsulfonyl) -pyrazolo [1,5-a] pyrimidine 1.1.1 (3), 5,7-dimethyl-2-dimethylamino-3- (4-fluorophenylsulfonyl) pyrazolo [1,5-a] pyrimidine 1.1.1 (4), 5,7-dimethyl-2-methylamino-3- (3-fluorophenylsulfonyl) pyrazolo [1,5-a] pyrimidine 1.1.1 (5), 5,7-dimethyl-2-dimethylamino-3- (3-fluorophenylsulfonyl) pyrazolo [1,5-a] pyrimidine 1.1 .1 (6), 5,7-dimethyl-2-methylamino-3- (3-chlorophen lsulfonyl) pyrazolo [1,5-a] pyrimidine 1.1.1 (7), 5,7-dimethyl-2-dimethylamino-3- (3-chlorophenylsulfonyl) pyrazolo [1,5-a] pyrimidine 1.1.1 ( 8) and their pharmaceutically acceptable salts and / or hydrates,

3-amino-4-sulfonyl-1H-pyrazoles of the general formula 1 (R ² ₁ = R ² ₂ -H) are prepared by reacting 2-aryl (hetaryl) sulfonyl-3-amino-3-methylsulfanyl-acrylonitriles of the general formula 2 with hydrazines of the general formula 3 according to the scheme below:

where Ar, R ¹ , R ³ ₁ and R ³ ₂ have the above meaning; R ² ₁ and R ² ₂ are hydrogen.

The subject of the present invention is also a process for preparing new substituted 3-sulfonyl-pyrazolo [1,5-a] pyrimidines of the general formula 1.1, 1.1a by reacting 3-amino-4-sulfonyl-2H-pyrazoles of the general formula 1 (R ¹ = R ² ₁ = R ² ₂ = H) with β-dicarbonyl compounds of the general formula 4 according to the scheme below:

where Ar, R ³ ₁ , R ³ ₂ , R ⁴ , R ⁵ and R ⁶ have the above meaning.

If diketones 4 are symmetric (R ⁴ = R ⁶ ), then only one reaction product 1.1 is formed. If diketones 4 are asymmetric, then two reaction products 1.1 and 1.1a are formed, which are separated by well-known methods, for example, using preparative chromatography or recrystallization.

The following examples describe the synthesis of serotonin 5-HT ₆ receptor antagonists of general formula 1 and their biological tests. The results of the analysis of antagonists of serotonin 5-HT ₆ receptors of General formula 1 and their biological activity in relation to serotonin receptors are presented in tables 2-4.

The following examples demonstrate but do not limit the invention.

The invention is illustrated by drawings.

Figure 1. Concentration dependences of the inhibition by the antagonist of formula 1.1.1 (1) of serotonin 5-HT ₆ receptors and methiotepine as a control.

Figure 2. Improvement of memory in male BALB / c mice impaired by scopolamine under the action of an antagonist of formula 1.1.1 (1) (CD-008-0216) in the test “Passive avoidance of mice in the shuttle chamber”. The time after which the animals make their first entry into the dark chamber. The concentration of the substance in mg / kg is indicated in parentheses.

Figure 3. Improvement of memory in male BALB / c mice impaired by scopolamine under the action of an antagonist of formula 1.1.1 (1) (CD-008-0216) in the test “Passive avoidance of mice in the shuttle chamber”. The time during which the animals are in a bright chamber. The parentheses indicate the concentration of the substance in mg / kg.

Figure 4. Improvement of memory in male BALB / c mice impaired by scopolamine under the action of an antagonist of formula 1.1.1 (1) (CD-008-0216) in the test “Passive avoidance of mice in the shuttle chamber”. The number of visits to the dark chamber. The concentration of the substance in mg / kg is indicated in parentheses.

Figure 5. Improving memory in male BALB / c mice, disturbed by MK-801, under the action of an antagonist of formula 1.1.1 (1) (CD-008-0216) in the test "Passive avoidance of mice in the shuttle chamber". The time after which the animals make their first entry into the dark chamber. The concentration of the substance in mg / kg is indicated in parentheses.

6. Improving memory in male BALB / c mice, disturbed by MK-801, under the action of an antagonist of formula 1.1.1 (1) (CD-008-0216) in the test "Passive avoidance of mice in the shuttle chamber". The time during which the animals are in a bright chamber. The concentration of the substance in mg / kg is indicated in parentheses.

7. Improving memory in male BALB / c mice, disturbed by MK-801, under the action of an antagonist of formula 1.1.1 (1) (CD-008-0216) in the test "Passive avoidance of mice in the shuttle chamber". The number of visits to the dark chamber. The parentheses indicate the concentration of the substance in mg / kg.

Fig. 8. Behavior of male BALB / c mice under the action of an antagonist of formula 1.1.1 (1) (CD-008-0216) and comparison preparations (Buspirone and Lorazepam) in the test “Behavior of mice in an elevated cruciform maze”. The ratio of the time during which animals are in open sleeves to the time during which animals are in open and closed sleeves. The concentration of the substance in mg / kg is indicated in parentheses.

Fig.9. Behavior of male BALB / c mice under the action of an antagonist of formula 1.1.1 (1) (CD-008-0216) and comparison preparations (Buspirone and Lorazepam) in the test “Behavior of mice in an elevated cruciform maze”. The number of bowel movements. The parentheses indicate the concentration of the substance in mg / kg.

Figure 10. Behavior of male BALB / c mice under the action of an antagonist of formula 1.1.1 (1) (CD-008-0216) and comparison preparations (Buspirone and Lorazepam) in the test “Behavior of mice in an elevated cruciform maze”. The ratio of the number of calls of animals in open sleeves to the number of calls of animals in open and closed sleeves. The parentheses indicate the concentration of the substance in mg / kg.

11. The state of immobility over the past 5 minutes in the Porsolt test. The antagonist of formula 1.1.1 (1) (CD-008-0216) and the comparison compound (Fluoxetine, Desipramine) were administered intraperitoneally daily for 4 days at doses of 0.05, 0.2 and 15 mg / kg, respectively. * - p <0.05.

Example 1. A method of obtaining substituted 3,5-diamino-4-sulfonyl-pyrazoles of the general formula 1. Heated with stirring in 15 ml of isopropanol 7.85 mmol of 2-aryl (hetaryl) sulfonyl-3-amino-3-methylsulfanyl-acrylonitrile of the general formula 2 from 1.2-1.5 equiv. hydrazine of the general formula 3 for 0.5 h (LCMS control). After completion of the reaction, the reaction mixture was poured onto a water-ice mixture, the precipitated oil quickly solidified, the solid was filtered off, washed with water, cold isopropanol, hexane and recrystallized from a suitable solvent. Get 3,5-diamino-4-sulfonyl-pyrazoles of General formula 1, are presented in table 2.

Table 2. Antagonists of serotonin 5-HT ₆ receptors. No. Formula Like the weight LCMS, m / z (M + 1) % Inhibition of 5-HT ₆ receptors 10 μM antagonist 1 (1)

296.35 297 55 1 (2)

252.29 253 41 1 (3)

328.39 329 60 1 (4)

314.36 315 61 1 (5)

332.35 333 59

1 (6)

418.52 419 49 1 (7)

346.38 347 48 1 (8)

385.44 386 44 1 (9)

523.54 524 43 1 (10)

309.39 310 48 1 (11)

323.42 324 45

1 (12)

323.42 324 47 1 (13)

321.40 322 fifty 1 (14)

407.50 408 38 1.1 (1)

406.51 407 77 1.1 (2)

378.46 379 90 1.1 (3)

378.46 379 91

1.1 (4)

317.37 318 97 1.1 (5)

317.37 318 95 1.1 (6)

322.41 323 98 1.1.1 (1)

316.38 317 77 1.1.1 (2)

330.41 331 86 1.1.1 (3)

334.37 335 99

1.1.1 (4)

348.40 349 95 1.1.1 (5)

334.37 335 97 1.1.1 (6)

334.37 335 97 1.1.1 (7)

350.83 351 one hundred 1.1.1 (8)

364.86 365 96 1.1.1 (9)

330.41 331 104

1.1.1 (10)

409.94 374 91 1.1.1 (11)

423.97 388 88 1.1.1 (12)

423.97 388 94 1.1.1 (13)

471.58 472 63

1.1.1 (14)

407.92 372 76 1.1.1 (15)

421.95 386 80 1.1.1 (16)

406.51 407 70 1.1.1 (17)

368.82 369 97

Example 2. General method for producing substituted 2-amino-3-sulfonyl-pyrazolo [1,5-a] pyrimidines of the general formula 1.1. 0.005 mol of the substituted 3,5-diaminopyrazole of general formula 1 is boiled and 0.0055 mol of the corresponding diketone of general formula 4 in 5 ml of acetic acid for 4 hours. The resulting solution is cooled. 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. The yield of 3-sulfonyl-pyrazolo [1,5-a] pyrimidines of the general formula 1.1 is 70-85%. Table 2 presents some examples of the new substituted 2-amino3-sulfonyl-pyrazolo [1,5-a] pyrimidines of the general formula 1.1 and the data of their LCMS analyzes.

Example 3. Determination of the antagonistic activity of the 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. HEK 293 cells (human embryonic kidney cells) with an artificially expressed 5-HT ₆ receptor are used, the activation of which by serotonin leads to an increase in the concentration of intracellular cAMP. The content of intracellular cAMP is 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 is evaluated by their ability to reduce the content of intracellular cAMP induced by serotonin.

Table 2 presents data on the% inhibition of 5-HT ₆ receptors by 10 μM solutions of compounds of the general formula 1. As can be seen from the data presented, the tested compounds exhibit noticeable activity with respect to serotonin 5-HT ₆ receptors.

Table 3 shows the concentration dependences of the inhibition of serotonin-stimulated production of intracellular cAMP by some compounds of the general formula 1, indicating their antagonistic activity, and IC ₅₀ values confirming their moderate or high activity under functional essay.

Table 3. Concentration dependences of inhibition of serotonin 5-HT ₆ receptors by compounds of the general formula 1 and IC ₅₀ values under functional essay conditions. No. Formula IC50, nM 1 (1)

5.667 * 1 (2)

18.840 *

1.1.1 (1)

5,0 1.1.1 (2)

11.77 1.1.1 (3)

6.0 1.1.1 (5)

5,0 1.1.1 (7)

2.0 1.1.1 (17)

4.0 * - IC ₅₀ , µM

Example 4. Determination of the activity of antagonists of serotonin 5-HT ₆ receptors 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 is used. For this, membrane preparations are 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 is 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 drags. Mol. Pharmacol 43: 320-327, 1993. In a preferred embodiment, the membrane preparations are incubated with a labeled ligand (1.5 nM [ ³ H] Lysergic acid diethylamide) without and in the presence of the test compounds for 120 min 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 are filtered under vacuum on G / F glass microfiber filters (Millipor, USA), the filters are washed three times with cold medium and radioactivity is measured using a MicroBeta 340 scintillation counter (PerkinElmer, USA). Non-specific binding, which accounted for 30% of total binding, is determined by incubation of membrane preparations with a radioligand in the presence of 5 μM Serotonin (5-HT). Methiothepin is used as a positive control. The binding of the test compounds to the receptor is determined by their ability to displace the radioactive ligand and expressed as a percentage of displacement. The percentage of displacement is 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).

In table 4 and figure 1 as one example presents the results of tests of 5,7-dimethyl-2-methylamino-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine 1.1.1 (1) and methiotepine as a control, indicating a high activity (4.61 nM) of this antagonist of serotonin 5-HT ₆ receptors.

Table 4. Concentration dependences of the inhibition of serotonin 5-HT ₆ receptors by antagonists of the general formula 1 and IC ₅₀ and K _i values under conditions of competitive essay. Compound Concentration dependencies IC ₅₀ , nM K _i , nM

Антагонист 1.1.1(1)

Antagonist 1.1.1 (1) See FIG. 1 0.511 0.237 ▪ Control - Methotepine 1.3 0.603

Example 5. Obtaining a drug in the form of tablets. 1600 mg of starch, 1600 mg of ground lactose, 400 mg of talc and 1000 mg of 5,7-dimethyl-2-methylamino-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine 1.1.1 (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. According to the invention, drugs are likewise prepared containing other compounds of general formula 1 as a medicament.

Example 6. Obtaining a drug in the form of capsules. 5,7-Dimethyl-2-methylamino-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine 1.1.1 (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 7. Obtaining a medicinal product in the form of injection compositions for intramuscular, intraperitoneal or subcutaneous injection. 500 mg of 5,7-dimethyl-2-methylamino-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine 1.1.1 (1) is 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 8. Nootropic effect (improvement of memory impaired by scopolamine) 5,7-dimethyl-2-methylamino-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine 1.1.1 (1) 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 min before training, mice were injected intraperitoneally with saline, scopolamine (0.3 mg / kg) or scopolamine in combination with 5,7-dimethyl-2-methylamino-3-phenylsulfonyl-pyrazolo [1,5-a ] pyrimidine 1.1.1 (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. At the same time, the door between the compartments was closed, and the animal was punished with a current of 0.6 mA for 3 s. 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 observation duration 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 5,7-dimethyl-2-methylamino-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine 1.1.1 (1) to improve learning disrupted by scopolamine is considered as evidence of its nootropic effect.

The results obtained, presented in figure 2, 3 and 4, indicate the ability of 5,7-dimethyl-2-methylamino-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine 1.1.1 (1) to have a nootropic effect.

Example 9. Nootropic effect (memory improvement, impaired MK-801) 5,7-dimethyl-2-methylamino-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine 1.1.1 (1) in the test "Passive avoidance of mice in shuttle camera. " The experiment was carried out as in example 8. On the first day of the experiment, 30 min before training the mice, physiological saline solution MK-801 (0.1 mg / kg) was injected intraperitoneally. Before training, independent groups of mice were injected intraperitoneally with physiological saline solution MK-801 in combination with 5,7-dimethyl-2-methylamino-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine 1.1.1 (1).

The results obtained (FIGS. 5-7) indicate the ability of 5,7-dimethyl-2-methylamino-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine 1.1.1 (1) to have a nootropic effect.

Example 10. The anxiolytic (tranquilizing) effect of 5,7-dimethyl-2-methylamino-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine 1.1.1 (1) in the test “Behavior of mice in an elevated cross-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 labyrinth, the number of entries into open and closed arms and the time spent by animals in open and closed arms were recorded for 5 min. 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 residence time 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 (Figs. 8-10) indicate that 5,7-dimethyl-2-methylamino-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine 1.1.1 (1) exhibits anxiolytic (tranquilizing) activity, comparable to Buspirone and Lorazepam.

Example 11. The antidepressant effect of 5,7-dimethyl-2-methylamino-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine 1.1.1 (1) in the test "Porsolt forced swimming in mice."

The behavior of “despair” was proposed by Porsolt et al. (1977, 1978) as a model of a depression-like state that allows testing the antidepressant activity of substances. For mice or rats forced to swim in a limited space from which they are not able to get out, a state of immobility is characteristic. Such behavior is a state of despair that can be alleviated with substances that have an antidepressant type of action in humans.

Male BALB / c mice (20-30 g) were used in the experiment. The animal was placed in a pool for 15 min (height 300 mm, diameter 480 mm) 70% filled with water at a temperature of ~ 25 ° C. After 3-5 minutes of active swimming, the intensity of movement begins to decrease and is replaced by phases of motionless swimming. An animal was considered stationary if it did not make any movement for at least 1.5 s (this parameter was used when setting up the ANY-maze ™ program). For analysis, we used experimental data obtained during the last 5 min of the test. The results are presented in Fig.11.

The results obtained (Fig. 11) indicate that 5,7-dimethyl-2-methylamino-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine 1.1.1 (1), administered intraperitoneally daily for 4 days in dose of 0.2 mg / kg, shows a high antidepressant activity, comparable to the activity of Fluoxetine (Prozac) and Desipramine (Norpramin).

Claims (13)

1. Antagonists of serotonin 5-HT ₆ receptors of General formula 1 or their pharmaceutically acceptable salts and / or hydrates,

where Ar is aryl selected from optionally substituted phenyl or optionally substituted 5-6 membered heteroaryl containing a nitrogen atom or a sulfur atom as a heteroatom;
R ¹ represents a hydrogen atom, optionally substituted C ₁ -C ₅ alkyl;
R ² ₁ , R ² ₂ , R ³ ₁ , R ³ ₂ independently represent a hydrogen atom or an amino substituent selected from optionally substituted C ₁ -C ₄ alkyl, optionally substituted phenyl, or R ³ ₁ and R ³ ₂ together with the nitrogen atom to which they are attached form an optionally substituted saturated 6-membered heterocyclyl, possibly containing an additional nitrogen atom in the ring;
or R ¹ together with the nitrogen atom to which it is bonded and R ² ₁ and R ² ₂ together with the nitrogen atom to which they are bonded form a substituted pyrimidine ring. 2. The antagonists according to claim 1, which are substituted 2-amino-3-sulfonyl-pyrazolo [1,5-a] pyrimidines of the general formula 1.1 or their pharmaceutically acceptable salts and / or hydrates,

where Ar, R ³ ₁ and R ³ ₂ have the above meaning; R ⁴ , R ⁵ and R ⁶ independently from each other represent a hydrogen atom, optionally substituted C ₁ -C ₃ alkyl or phenyl. 3. The antagonists according to claim 2, which are substituted 3-arylsulfonyl-5,7-dimethyl-pyrazolo [1,5-a] pyrimidines of the general formula 1.1.1 or their pharmaceutically acceptable salts and / or hydrates,

where R ³ ₁ and R ³ ₂ have the above meaning; R _i ⁷ represents one or two optionally identical substituents of the cyclic system selected from a hydrogen atom, C ₁ -C ₅ alkyl, trifluoromethyl or a halogen atom. 4. The antagonists according to claim 3, which are 5,7-dimethyl-2-methylamino-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine 1.1.1 (1), 5,7-dimethyl-2-dimethylamino 3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine 1.1.1 (2), 5,7-dimethyl-2-methylamino-3- (4-fluorophenylsulfonyl) -pyrazolo [1,5-a] pyrimidine 1.1.1 (3), 5,7-dimethyl-2-dimethylamino-3- (4-fluorophenylsulfonyl) pyrazolo [1,5-a] pyrimidine 1.1.1 (4), 5,7-dimethyl-2-methylamino-3- (3-fluorophenylsulfonyl) pyrazolo [1,5-a] pyrimidine 1.1.1 (5), 5,7-dimethyl-2-dimethylamino-3- (3-fluorophenylsulfonyl) pyrazolo [1,5-a] pyrimidine 1.1 .1 (6), 5,7-dimethyl-2-methylamino-3- (3-chlorophenylsulfonyl) pyrazolo [1,5- a] pyrimidine 1.1.1 (7), 5,7-dimethyl-2-dimethylamino-3- (3-chlorophenylsulfonyl) pyrazolo [1,5-a] pyrimidine 1.1.1 (8) and their pharmaceutically acceptable salts and / or hydrates

5. An antagonist of serotonin 5-HT ₆ receptors of the general formula 1 according to any one of claims 1 to 4 as a drug source for obtaining a pharmaceutical composition or dosage form. 6. A pharmaceutical composition having the properties of antagonists of serotonin 5-HT ₆ receptors for treating and preventing the development of conditions and diseases of the central nervous system, containing an effective amount of the drug beginning according to claim 5. 7. The method of obtaining the pharmaceutical composition according to claim 6 by mixing with an inert excipient and / or solvent of at least one drug substance according to claim 5. 8. A drug having the properties of antagonists of serotonin 5-HT ₆ receptors, intended for the treatment and prevention of the development of conditions and diseases of the central nervous system, in the form of tablets, capsules or injections, placed in a pharmaceutically acceptable package, including the medicinal product according to claim 5 or The pharmaceutical composition according to claim 6. 9. A method for the prevention and treatment of diseases of the central nervous system, the pathogenesis of which is associated with serotonin 5-HT ₆ receptors, which consists in the introduction of the drug beginning according to claim 5, or the pharmaceutical composition according to claim 6, or the drug according to claim 8 in an effective quantity. 10. Substituted 2-amino-3-sulfonyl-pyrazolo [1,5-a] pyrimidines of the general formula 1.1 or their pharmaceutically acceptable salts and / or hydrates,

where Ar, R ³ ₁ and R ³ ₂ have the above meaning; R ⁴ , R ⁵ and R ⁶ independently from each other represent a hydrogen atom, optionally substituted C ₁ -C ₃ alkyl or phenyl. 11. The compounds of claim 10, which are substituted 3-arylsulfonyl-5,7-dimethyl-pyrazolo [1,5-a] pyrimidines of the general formula 1.1.1 or their pharmaceutically acceptable salts and / or hydrates,

where R ³ ₁ and R ³ ₂ have the above meaning; R ⁷ _i represents one or two optionally identical substituents of the cyclic system selected from a hydrogen atom, C ₁ -C ₅ alkyl, trifluoromethyl or a halogen atom. 12. The compounds of claim 11, which are 5,7-dimethyl-2-methylamino-3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine 1.1.1 (1), 5,7-dimethyl-2-dimethylamino 3-phenylsulfonyl-pyrazolo [1,5-a] pyrimidine 1.1.1 (2), 5,7-dimethyl-2-methylamino-3- (4-fluorophenylsulfonyl) -pyrazolo [1,5-a] pyrimidine 1.1.1 (3), 5,7-dimethyl-2-dimethylamino-3- (4-fluorophenylsulfonyl) pyrazolo [1,5-a] pyrimidine 1.1.1 (4), 5,7-dimethyl-2-methylamino-3- (3-fluorophenylsulfonyl) pyrazolo [1,5-a] pyrimidine 1.1.1 (5), 5,7-dimethyl-2-dimethylamino-3- (3-fluorophenylsulfonyl) pyrazolo [1,5-a] pyrimidine 1.1 .1 (6), 5,7-dimethyl-2-methylamino-3- (3-chlorophenylsulfonyl) pyrazolo [1,5- ] pyrimidine 1.1.1 (7), 5,7-dimethyl-2-dimethylamino-3- (3-chlorophenylsulfonyl) pyrazolo [1,5-a] pyrimidine 1.1.1 (8) and their pharmaceutically acceptable salts and / or hydrates

13. A method of producing substituted 3-sulfonyl-pyrazolo [1,5-a] pyrimidines of the general formula 1.1 according to any one of claims 10-12 by reacting 3,5-diamino-4-sulfonyl-2H-pyrazoles of the general formula 1 with β-dicarbonyl compounds of General formula 4,

where Ar, R ³ ₁ , R ³ ₂ , R ⁴ , R ⁵ and R ⁶ have the above meaning.

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