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

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; R21,R22, R31, R32 independently from each other represent atom of hydrogen or substituent of aminogroup, selected from unnecessarily substituted C1-C4 alkyl, unnecessarily substituted phenyl, or R31 and R32 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 R21 and R22 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

 

This invention relates to new arylsulfonyl-azaheterocyclic compounds, to novel antagonists of serotonin 5-HT6receptors, to new medicinal principles, pharmaceutical compositions, drugs and methods for their preparation. More specifically, the present invention relates to antagonists of serotonin 5-HT6receptor - substituted 4-sulfonylureas and 3-sulfonyl-pyrazolo[1,5-a]pyrimidines, medicinal and pharmaceutical compositions containing the drug began in the form of these compounds, and to a method for treatment and prevention of the development of various cognitive and neurodegenerative diseases. The basis of the pharmacological effect of new drugs began laying their ability to interact with serotonin 5-HT6receptors that play an important role for the treatment of diseases of the Central nervous system (CNS), in particular Alzheimer's disease (AD), diseases of Hantington, schizophrenia, other neurodegenerative diseases, cognitive disorders and obesity.

The use of effective and selective antagonists of serotonin 5-HT6receptors for the treatment of CNS disorders, in particular schizophrenia, ad and other neurodegenerative diseases and cognitive disorders, is a promising direction for the teaching of new drugs [J. Holenz, Pauwels, P.J., J.L. Diaz, Merce R., Codony X., Buschmann H. Medicinal chemistry strategies to 5-HT6receptor ligands as potential cognitive enhancers and antiobesity agents. Drug Disc. Today. 2006; 11:283-299]. These receptors in mammals are found exclusively in the Central nervous system, mainly in the areas of the brain responsible for learning and memory [Ge'rard C., Martres, M.-P., Lefe'vre K., Miquel, M.-C, Verge' D., Lanfumey L., Doucet e, Hamon M., El Mestikawy S. Measurement localisation of serotonin 5-HT6receptor-like material in the rat central nervous system. Brain Research. 1997; 746:207-219]. In addition, it is shown [Dawson L.A., Nguyen H.Q., Li P. The 5-HT(6) receptor antagonist SB-271046 selectively enhances excitatory neurotransmission in the rat frontal cortex and hippocampus. Neuropsychopharmacology.. 2001; 25:662-668]that 5-HT6the receptors are modulators of several neurotransmitter systems, including the cholinergic, noradrenergicheskoy, glutamatergic and dopaminergic. Given the fundamental role of these systems in normal cognitive processes, and their dysfunction in neurodegeneration, it is obvious exceptional role of 5-HT6receptors in the formation of normal or pathological memory. In a large number of modern studies have shown that blocking the 5-HT6receptors leads to a significant increase in memory consolidation in various animal models of learning-memory-playback [Foley A.G., Murphy K.J., Hirst W.D., H.C. Gallagher, J.J. Hagan, Upton N., F.S. Walsh, C.M. Regan The 5-HT(6) receptor antagonist SB-271046 reverses scopolamine-disrupted consolidation f a passive avoidance task and ameliorates spatial task deficits in aged rats. Neuropsychopharmacology.. 2004; 29:93-100. Riemer C., E. Borroni, Levet-Trafit Century, Martin J.R., Poli, S., Porter, R.H., Bos M. Influence of the 5-HT6receptor on acetylcholine release in the cortex: pharmacological characterization of 4-(2-bromo-6-pyrrolidin-l-ylpyridine-4-sulfonyl)phenylamine, a potent and selective 5-HT6receptor antagonist. J. Med. Chem. 2003; 46:1273-1276. King M.V., M.L. Woolley, Topham I.A., Sleight AJ, Marsden CA, Fone K.C. 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]. Also shown significant improvement in cognitive function in aged rats in the model water maze Morrison when exposed to an antagonist of 5-HT6receptors [Foley A.G., Murphy K.J., Hirst W.D., H.C. Gallagher, J.J. Hagan, Upton N., F.S. Walsh, C.M. Regan The 5-HT(6) receptor antagonist SB-271046 reverses scopolamine-disrupted consolidation of a passive avoidance task and ameliorates spatial task deficits in aged rats. Neuropsychopharmacology.. 2004; 29:93-100]. Recently achieved not only a deeper understanding of the role of 5-NT receptors in cognitive processes, but more accurate formation of ideas about possible pharmacophoric properties of their antagonists [Holenz j, Pauwels, P.J., J.L. Diaz, Merce R., Codony X., Buschmann H. Medicinal chemistry strategies to 5-HT6receptor ligands as potential cognitive enhancers and antiobesity agents. Drug Disc. Today. 2006; 11:283-299]. This led to the creation of selective high-affinity ligands ("molecular tools"), then and clinical candidates. Currently, a number of antagonists of 5-HT6receptors are in various stages of clinical trials as drug candidates is s for the treatment of BA, disease Hantington, schizophrenia (antipsychotics) and other neurodegenerative and cognitive diseases (table 1) [http://integrity.prous.com].

Table 1.
Antagonists of 5-HT6receptors as drug candidates.
MedicationClinical phase I trialsDeveloperTherapeutic group
Dimebon™Phase IIIMedivation (USA)Treatment of Alzheimer's disease
SGS-518Phase IILilly, SaegisTreatment of cognitive diseases
SB-742457Phase IIGlaxoSmithKlineTreatment of Alzheimer's disease; Antipsychotic
Dimebon*Phase I/IIAMedivation (USA)Treatment of Hungtinton
Dimebon*Phase II(Russia) Schizophrenia
PRX-07034Phase IEpix Pharm.The treatment of obesity; Antipsychotic; Treatment of cognitive diseases
SB-737050APhase IIGlaxoSmithKlineAntipsychotic
BVT-74316Phase IBiovitrumThe treatment of obesity
SAM-315Phase IWyeth Pharm.Treatment of Alzheimer's disease
SYN-114Phase IRoche, Synosis Ther.Treatment of cognitive diseases
BGC-20-761PreclinicaBTG (London)Antipsychotic; Treatment of cognitive diseases
FMPOPreclinicaLillyAntipsychotic
Dimebon™Preclinica(Russia)Another attractive property of antagonists of 5-HT6receptors is their ability to suppress the appetite, which can lead to the creation on their basis of fundamentally new means to reduce overweight and obesity [Vicker SP, Dourish CT Serotonin receptor ligands and the treatment of obesity. Curr. Opin. Investig. Drugs. 2004; 5:377-388]. This effect is confirmed in many studies [J. Holenz, Pauwels, P.J., J.L. Diaz, Merce R., Codony X., Buschmann H. Medicinal chemistry strategies to 5-HT6receptor ligands as potential cognitive enhancers and antiobesity agents. Drug Disc. Today. 2006; 11:283-299. Davies, S.L. Drag discovery targets: 5-HT6receptor. Drug Of The Future. 2005; 30:479-495], its mechanism is based on inhibition by antagonists of 5-HT6receptor signaling gamma-aminobutyric acid and increase the release of alpha-melanocyte-stimulating hormone, which ultimately reduces the need for food [M.L. Woolley 5-ht6 receptors. Curr. Drug Targets CNSNeurol. Disord. 2004; 3:59-79]. Currently, two antagonist 5-HT6receptors are in the first stage of clinical trials as drug candidates for the treatment of overweight (table 1) [http://integrity.prous.com].

In this regard, the search for selective and effective antagonists of serotonin 5-HT6receptors appears to be original and promising approach to the creation of new medicines for the treatment of a wide range of neurological and neurodegenerative over the olivani and cognitive disorders.

In the literature there is a considerable number of publications on various biologically active sulfanilamidnam of azaheterocycles, including serotonin receptor ligands. For example, the famous substituted 1-(2-amino-ethyl)-4-arylsulfonyl-pyrazoles of General formula A1 as ligands serotonin 5-HT2creceptors [WO 2003057674 A1] and 7-amino-3-sulfanyl-pyrazolo[1,5-a]pyrimidines A2 as antagonists of serotonin 5-HT6receptor [ER 941994 A1, 1999],

A1: R=alkyl, aryl; R1and R2=H, HE, alkyl, alkoxy; R3and R4=H, alkyl, aryl.

A2: Ah=aryl, heterocyclyl; R1=H, alkyl, alkylthio; R2=H, alkyl, halogen; R3=H, alkyl, hydroxyalkyl; R4and R5=N; NR4R5=piperazinil.

To develop new highly effective neuroprotective drugs by the authors of the present invention made extensive studies in a series of substituted 4-sulfonylureas and 3-sulfonyl-pyrazolo[1,5-a]pyrimidines, resulting in a new found drug began representing antagonists of 5-HT6receptors.

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

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

"Azaheterocycle" means an aromatic or non-aromatic monocyclic or polycyclic system containing a loop, at least one nitrogen atom. Azaheterocycle can have one or more cyclic substituents" of the system. "Alkyl" means an aliphatic hydrocarbon of linear or branched group with 1-12 carbon atoms in the chain. Branched means that the alkyl chain has one or more "lower alkyl" substituents. The alkyl may have one or more identical or different substituents ("alkyl substituents including halogen, alkenylacyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkyloxy, Alcoxy, aryloxy, aryloxyalkyl, alkylthio, heteroaromatic, Uralkali, arylsulfonyl, alkylsulfonyl, heteroarylboronic, annelirovannymi heteroarylboronic, annelirovannymi heteroalicyclic, annelirovannymi heterooligomerization, annelirovannymi heteroalicyclic, annelirovannymi arylchloroalkanes, annelirovannymi aristically, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic, alkoxycarbonyl, arelaxation, heteroarylboronic or Rk8Rk+1aN-, RkaRk+1aNC(=O)-, RkaRk+1aNC(=S)-, Rk aRk+1aNSO2-, where Rkaand Rk+1aindependently from each other represent "amino substituents", which is defined in this section, for example a hydrogen atom, alkyl, aryl, aralkyl, heteroalkyl, heterocyclyl or heteroaryl, or Rkaand Rk+1atogether with the N atom to which they are bound, form a through Rkaand Rk+1a4-7-membered heterocyclyl or heterocyclyl. Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, ISO-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, benzyloxycarbonylation, methoxycarbonylmethyl and pyridinedicarboxylate. Preferred "alkyl substituents" are cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, alkoxycarbonyl, Alcoxy, aryloxy, alkylthio, heteroaromatic, Uralkali, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, arelaxation, heteroarylboronic or RkaRk+1aN-, RkaRk+1aNC(=O)-, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic.

"Alkyloxy" means alkyl-O - group in which the alkyl opredelenn this section. The preferred acyloxy groups are methoxy, ethoxy, n-propoxy, ISO-propoxy and n-butoxy.

"Allyloxycarbonyl" means alkyl-O-C(=O) group, in which alkyl is defined in this section. Preferred allyloxycarbonyl groups are methoxycarbonyl, etoxycarbonyl, n-butoxycarbonyl, ISO-propylenecarbonate, tert-butyloxycarbonyl.

"Amino group" means RkaRk+1aN-group, substituted or unsubstituted "Deputy amino group" Rkaand Rk+1awhose value is defined in this section, for example, amino (H2N-), methylamino, diethylamino, pyrrolidino, morpholino, benzylamino or phenethylamine.

"Annelirovannymi cycle" (condensed cycle) means of bi - or polycyclic system, where annelirovannymi cycle and cycle or politics, with whom he "annylirovan have at least two common atom.

"Antagonists" refers to ligands that bind to receptors of a particular type and do not cause active cellular response. Antagonists inhibit the binding of agonists to receptors and thereby block the transmission of specific receptor signal.

"Aryl" means an aromatic monocyclic or polycyclic system containing from 6 to 14 carbon atoms, predominantly from 6 to 10 atmosukarto. Aryl can contain one or more "cyclic system substituents"which may be the same or different. Representatives of aryl groups are phenyl or naphthyl, substituted phenyl or substituted naphthyl. The aryl may be annylirovan with non-aromatic cyclic system or heterocycle.

"Arylsulfonyl" means aryl-SO2group, where aryl is defined in this section.

"Halogen" means fluorine, chlorine, bromine and iodine. Preferred are fluorine, chlorine and bromine.

"Heteroaryl" means an aromatic monocyclic or polycyclic system containing from 5 to 14 carbon atoms, preferably from 5 to 10, in which one or more carbon atoms replaced by a heteroatom or heteroatoms, such as nitrogen, sulfur or oxygen. The prefix "Aza", "oxa" or "thia" before "heteroaryl" means the presence in the cyclic system of nitrogen atom, oxygen atom or sulfur atom, respectively. The nitrogen atom located in heteroaryl, can be oxidized to N-oxide. Heteroaryl may have one or more "cyclic system substituents"which may be the same or different. Representatives of heteroaryl are pyrrolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, isooxazolyl, isothiazolin, tetrazolyl, oxazolyl, thiazolyl, pyrazolyl, furutani, triazolyl, 1,24-thiadiazolyl, pyridazinyl, honokalani, phthalazine, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofuranyl, indolyl, isoindolyl, benzimidazolyl, benzothiazolyl, chinoline, imidazolyl, cyanopyridyl, hintline, thienopyrimidines, pyrrolopyridine, imidazopyridine, ethenolysis, benzoxazinones, 1,2,4-triazinyl, thienopyrrole, properaly and other

"Heterocyclyl" means an aromatic or non-aromatic saturated monocyclic or polycyclic system containing from 3 to 10 carbon atoms, mainly from 5 to 6 carbon atoms, in which one or more carbon atoms 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 nitrogen atom, oxygen atom or sulfur atom, respectively. Heterocyclyl may have one or more "cyclic system substituents"which may be the same or different. Atoms of nitrogen and sulfur, in heterocyclyl, can be oxidized to N-oxide, S-oxide or S-dioxide. Representatives heterocyclyl are piperidine, pyrrolidine, piperazine, morpholine, thiomorpholine, thiazolidine, 1,4-dioxane, tetrahydrofuran, tetrahydrothiophene, etc.

"Hydrate" means the MES, in which water is a molecule or molecules of solvent.

"Deputy" means a chemical which is a mini-radical, which joins scaffold (fragment), for example, Deputy alkyl", "Deputy amino group", "Deputy carbamoyl", "Deputy cyclic system, the values of which are defined in this section.

"Deputy alkyl" means a Deputy, attached to the alkyl, alkenyl, the value of which is determined in this section. Deputy alkyl represents hydrogen, alkyl, halogen, alkenylacyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkyloxy, Alcoxy, aryloxy, aryloxyalkyl, alkylthio, heteroaromatic, Uralkali, arylsulfonyl, alkylsulfonates, annelirovannymi heteroarylboronic, annelirovannymi heteroalicyclic, annelirovannymi heterooligomerization, annelirovannymi heteroalicyclic, annelirovannymi arylchloroalkanes, annelirovannymi aristically, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic, alkoxycarbonyl, arelaxation, heteroarylboronic or RkaRk+1aN-, RkaRk+1aNC(=O)-, RkaRk+1aNSO2-, where Rkaand Rk+1aindependently from each other represent "amino substituents", the value of which is determined in this is the section, for example, a hydrogen atom, alkyl, aryl, aralkyl, heteroalkyl, heterocyclyl or heteroaryl, or Rkaand Rk+1atogether with the N atom to which they are bound, form a through Rkaand Rk+1a4-7-membered heterocyclyl or heterocyclyl. Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, ISO-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, benzyloxycarbonylation methoxycarbonylmethyl and pyridinedicarboxylate. Preferred "alkyl substituents" are cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, alkoxycarbonyl, Alcoxy, aryloxy, alkylthio, heteroaromatic, Uralkali, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, arelaxation, heteroarylboronic or RkaRk+1aN-, RkaRk+1aNC(=O)-, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic. The significance of the "alkyl substituents" defined in this section.

"Deputy amino group" means the Deputy attached to the amino group. Deputy amino group represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, acyl, aroyl, Ala sulfonyl, arylsulfonyl, heteroarylboronic, alkylaminocarbonyl, allumination, heteroelement - carbonyl, heterocyclization, alkylaminocarbonyl, arylamino - carbonyl, heteroarylboronic, heterocyclization, annelirovannymi heteroarylboronic, annelirovannymi heteroalicyclic, annelirovannymi heterooligomerization, annelirovannymi heteroalicyclic, annelirovannymi arylchloroalkanes, annelirovannymi aristically, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic, alkoxycarbonylmethyl, arelaxation alkyl, heteroarylboronic.

"Substituted amino group" means RkaRk+1aN-group, in which Rkaand Rk+1arepresent substituents of the amino group, the value of which is determined in this section.

"Cognitive disorder or cognitive impairment (cognitive disorder)" means a violation of (weakening) of mental abilities, including attention, memory, thinking, cognition, learning, speech, cognitive, Executive and creative abilities, orientation in time and space, in particular cognitive deficits associated with Alzheimer's disease, Parkinson and Huntington; senile dementia; age-related memory disorders (age-assocated his or her memory, AAMI); dysmetabolic encephalopathy; psychogenic disturbances of memory; amnesia; amnestic disorder; transient global amnesia; dissociative amnesia; vascular dementia; light (or moderate) cognitive impairment (mild cognitive his or her, MCI); syndrome of disturbance of attention with hyperactivity (attention deficit hyperactivity disorder, AD/HD); cognitive impairment accompanying psychotic diseases, epilepsy, delirium, autism, psychosis, down syndrome, bipolar disorder and depression; AIDS-associated dementia; dementia with hypothyroidism; dementia induced by alcohol, substances, addictive, and neurotoxins; dementia accompanying neurodegenerative diseases, for example, cerebellar degeneration and amyotrophic lateral sclerosis; cognitive disorders, developing stroke, infectious diseases and cancer of the brain, as well as with traumatic brain injury; cognitive impairment associated with autoimmune and endocrine diseases; and other cognitive disorders.

"Medical home" (drug substance, drug substance, drug-substance) means a physiologically active substance is synthetic or other (biotechnology, plant, animal, microbial or other origin, possessing the E. pharmacological activity and which is the active beginning of the pharmaceutical composition, used for production and manufacturing of the drug product (tools).

"The drug (the drug), a substance (or mixture of substances in the form of pharmaceutical compositions in the form of tablets, capsules, injections, ointments and other fabricated forms intended for restoring, correcting or modifying physiological functions in humans and animals, as well as for treatment and prevention of diseases, diagnostics, anesthesia, contraception, cosmetology and others.

"Ligands" (from the Latin ligo - link) is a chemical (small molecule, an inorganic ion, a peptide, a protein, etc.) capable of interacting with receptors that transform this interaction in specific signal.

"Neurodegenerative disease (NT)" means the specific condition and a disease characterized by damage to the primary and death of populations of nerve cells in certain regions of the Central nervous system. Neurodegenerative diseases include, but are not limited to, Alzheimer's disease and Parkinson's disease; disease (horay) Huntington's, multiple sclerosis, cerebellar degeneration; amyotrophic lateral sclerosis; dementia with calves Levi; spinal muscular atrophy; peripheral neuropathy; spongiform encephalitis ("mad cow disease", Creutzfeld-Jakob Disease); AIDS is associirovannyy dementia; multi-infarct dementia; frontotemporal dementia; leucoencephalopathy (illness vanishing white matter); chronic neurodegenerative disease; stroke; ischemic and reperfusion of hypoxic brain damage; epilepsy; cerebral ischemia; glaucoma; traumatic brain injury; down syndrome; encephalomyelitis; meningitis; encephalitis; neuroblastoma; schizophrenia; depression. In addition, neurodegenerative diseases include pathological conditions and disorders developing during hypoxia, substance abuse, addictive, when exposed to neurotoxins, infectious and oncological diseases of the brain and neuronal damage associated with autoimmune and endocrine diseases; and other neurodegenerative processes.

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

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

"Receptors" (from Latin recipere to receive, to learn) are biological macromolecules that are located on the plasma membrane of cells or intracellular able to interact specifically with a limited set of physiologically active substances (ligands) and transform the signal about this interaction in a specific cellular response.

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

"Pharmaceutical composition" means a composition comprising a compound of formula I and at least one component selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, auxiliary, distributing and perceiving means, means of delivery, such as preservatives, stabilizers, fillers, shredders, moisturizers, emulsifiers, suspendresume agents, thickeners, sweeteners, flavors, fragrances, antibacterial agents, fungicides, lubricants, regulators prolonged delivery,the choice and the value of which depends on the nature and mode of appointment and dosage. Examples suspendida agents are ethoxylated isostearoyl alcohol, polyoxyethylene, sorbitol and sorbitol ester, microcrystalline cellulose, Metagalaxy aluminum, bentonite, agar-agar and tragakant, as well as mixtures of these substances. Protection from the action of microorganisms can be ensured by various antibacterial and antifungal agents such as parabens, chlorobutanol, sorbic acid and similar compounds. The composition may also include isotonic agents such as sugars, sodium chloride and the like. Prolonged action of the composition can be achieved with agents that slow the absorption of the active principle, for example, aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents and delivery vehicles include water, ethanol, polyalcohol, and mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as etiloleat). Examples of fillers are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like. Examples of shredders and distributes funds are starch, aginova acid and its salts, silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulphate, talc, and polyethylene glycol with high is Kim molecular weight. Pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal injection of the active principle, one or in combination with other active early, can be introduced animals and people in the standard form of administration, mixed with conventional pharmaceutical carriers. Usable standard form of introduction include oral forms such as tablets, gelatin capsules, pills, powders, granules, chewing gum and oral solutions or suspensions, sublingual and transbukkalno forms of administration, aerosols, implants, local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular forms of administration and rectal forms of administration.

"Pharmaceutically acceptable salt" refers to the relatively non-toxic organic and inorganic salts of acids and bases, as claimed in the present invention. These salts can be obtained in situ during the synthesis, separation, or purification of compounds or prepared. In particular, salts of bases can be obtained specifically on the basis of the purified free base of the claimed compounds and a suitable organic or inorganic acid. Examples of the thus obtained salts are hydrochloride, hydropram the water, sulfates, bisulfate, phosphates, nitrates, acetates, oxalates, valeriote, oleates, palmitate, stearates, laurate, borate, benzoate, lactates, tozilaty, citrates, maleate, fumarate, succinate, tartratami, mesylates, malonate, salicylates, propionate, econsultancy, bansilalpet, sulfamate and the like. (For a detailed description of the properties of such salts are described in Berge S.M., et al., "Pharmaceutical Salts" J. Pharm. Sci. 1977, 66: 1-19.) Salts of the stated acids can also be specially obtained by the reaction of purified acid with a suitable base, can be synthesized metal salts and amines. The metal include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum, the most desirable of which are sodium and potassium salts. Suitable inorganic bases which can be obtained metal salts are the hydroxide, carbonate, bicarbonate and sodium hydride, hydroxide and bicarbonate of potassium, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide. As organic bases, of which can be obtained salts of the stated acids, selected amines and amino acids with sufficient basicity to form a stable salt, and suitable for use in medical purposes (in particular, they should have a low toxicity). Such amines include ammonia, methylamine, dim is tillin, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, Tris(hydroxymethyl)aminomethane and the like. In addition, for the salt formation can be used tetraalkylammonium hydroxide, such as choline, Tetramethylammonium, tetraethylammonium and the like. As amino acids can be used basic amino acids such as lysine, ornithine and arginine.

The purpose of the present invention is to create a new antagonists of serotonin 5-HT6receptors and new drugs began.

This goal is achieved by antagonists of serotonin 5-HT6receptors of General formula 1 or their pharmaceutically acceptable salts and/or hydrates,

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

R1represents a hydrogen atom, optionally substituted C1-C5alkyl;

R21, R22, R31, R32independently from each other represent a hydrogen atom or Deputy amino group selected from the optional substituted With1-C4of alkyl, for long inogo substituted phenyl, or R31and R32together with the nitrogen atom to which they are bound, form an optional substituted saturated 6-membered heterocyclyl may contain a nitrogen atom in the cycle;

or R1together with the nitrogen atom to which it is linked, and R21and R22together with the nitrogen atom, with cotrim they are bound, form a substituted pyrimidine cycle.

Preferred antagonists of serotonin 5-HT6receptors are substituted 2-amino-3-sulfanyl-pyrazolo[1,5-a]pyrimidines of General formula 1.1 or their pharmaceutically acceptable salts and/or hydrates,

where Ar, R31and R32have the above meaning; R4, R5and R6independently from each other represent a hydrogen atom, optionally substituted C1-C3alkyl or phenyl.

Preferred antagonists of serotonin 5-HT6receptors are substituted 3-arylsulfonyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidines of General formula 1.1.1 or their pharmaceutically acceptable salts and/or hydrates,

where R31and R32have the above meaning; Ri7represents one or two are not necessarily the same Deputy cyclic system selected from and what Ohm hydrogen, With1-C5of alkyl, trifloromethyl or halogen atom.

Preferred antagonists of serotonin 5-HT6receptors 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-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.1(3), 5,7-dimethyl-2-dimethylamino-3-(4-perpenicular)-pyrazolo[1,5-a]the pyrimidine 1.1.1(4), 5,7-dimethyl-2-methylamino-3-(3-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.1(5), 5,7-dimethyl-2-dimethylamino-3-(3-perpenicular)-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) or their pharmaceutically acceptable salts and/or hydrates.

The subject of this invention is also medicinal beginning to pharmaceutical compositions and dosage forms that represent at least one antagonist of serotonin 5-HT6receptors of General formulas 1, 1.1.

The subject of this invention is also a pharmaceutical composition, interacting with serotonin 5-HT6receptors for the treatment and prevention of the development of various conditions and diseases of the Central nervous system of humans and warm-blooded animals containing a pharmaceutically effective amount of a new drug began representing at least one antagonist of serotonin 5-HT6receptors of General formulas 1, 1.1.

The pharmaceutical composition may include pharmaceutically acceptable excipients. Under the pharmaceutically acceptable excipients are meant to be applied in the field of pharmaceutical diluents, auxiliary agents and/or carriers. The pharmaceutical composition along with medicinal beginning of the General formula 1 according to the present invention may include other active ingredients provided that they do not cause unwanted effects, such as allergic reactions.

If you want to use the pharmaceutical compositions of the present invention in clinical practice, they can be mixed to produce different forms, however, they can contain conventional pharmaceutical carriers; for example, oral formulations such as tablets, gelatin capsules, pills, solutions or suspensions); forms for injection (such as solutions or suspensions for injection or dry powder for injection, which will require only the addition of water for injection before use); local forms such as ointments or solutions).

The media used in the pharmaceutical compositions of the present invention, are media that are used in the pharmaceutical industry to obtain common forms, including: oral forms are used binders, lubricating agents, disintegrators, solvents, diluents, stabilizers, suspendresume agents, colorless agents, korrigentami taste; in forms for injection are used antiseptic agents, solubilization, stabilizers; local forms are used bases, diluents, lubricating agents, antiseptic agents.

The subject of this invention is also a method of obtaining a new pharmaceutical composition by mixing with an inert filler and/or solvent medicinal began representing at least one antagonist of serotonin 5-HT6receptors of General formulas 1, 1.1.

The subject of this invention is also a drug in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing, includes drug beginning, representing at least one antagonist of serotonin 5-HT6receptors of General formulas 1, 1.1, or a pharmaceutical composition comprising this medicament is i.i.d. start, intended for the treatment and prevention of pathological conditions and diseases of the Central nervous system, the pathogenesis of which is associated with impaired activation of serotonin 5-HT6receptors.

According to this invention, more preferred are medicines for the prevention and treatment of Alzheimer's disease and diseases of Hantington.

According to this invention, more preferred are also medicines for the prevention and treatment of mental disorders and schizophrenia.

According to this invention, more preferred are also medicines for the prevention and treatment of obesity.

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-HT6receptors in animals and humans, including neurological disorders, neurodegenerative and cognitive diseases, which is the introduction of warm-blooded animal or human a new medicinal product containing medicinal beginning of the General formula 1.

Drugs can be administered orally or parenterally (e.g. intravenously, subcutaneously, intraperitoneally or topically). The clinical dosage of the pharmaceutical composition or the medicinal medium spans the VA, containing medicinal beginning of the General formula 1, patients can be corrected depending on: therapeutic efficiency and bio-availability of active ingredients in the body, the speed of their metabolism and excretion from the body, and depending on age, gender and stage of disease of the patient, the daily dose in adults is usually 10~500 mg, preferably 50~300 mg. Therefore, during the preparation of pharmaceutical compositions of the present invention in the form of dosage units it is necessary to consider the above-mentioned effective dosages, each unit dosage of the drug should contain 10~500 mg dosage the beginning of the General formula 1, preferably 50~300 mg. In accordance with the instructions of the doctor or pharmacist these medications can be taken several times during a defined time period (preferably from one to six times).

The object of the present invention are new substituted 3-sulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1.1 or their pharmaceutically acceptable salts and/or hydrates,

where Ar, R31and R32have the above meaning; R4, R5and R6independently from each other represent a hydrogen atom, optionally substituted C1-C3alkyl or phenyl.

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

where R31and R32have the above meaning; Ri7represents one or two are not necessarily the same Deputy cyclic system selected from a hydrogen atom, a C1-C5of alkyl, trifloromethyl or halogen atom.

More preferred compounds of 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-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.1(3), 5,7-dimethyl-2-dimethylamino-3-(4-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.1 (4), 5,7-dimethyl-2-methylamino-3-(3-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.1(5), 5,7-dimethyl-2-dimethylamino-3-(3-perpenicular)-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,

3-Amino-4-sulfonyl-1H-pyrazoles of General formula 1 (R21=R22-H) is obtained by reaction of 2-aryl(hetaryl)sulfonyl-3-amino-3-methylsulfanyl-Acrylonitrile General formula 2 with hydrazines of General formula 3 according to the scheme presented below:

where Ar, R1, R31and R32have the above meaning; R21and R22represent hydrogen.

The object of the present invention is also a method of obtaining new substituted 3-sulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1.1, 1.1A interaction of 3-amino-4-sulfonyl-2H-pyrazoles of General formula 1 (R1=R21=R22=H) with β-dicarbonyl compounds of General formula 4 according to the scheme presented below:

where Ar, R31, R32, R4, R5and R6have the above value.

If diketones 4 are symmetric (R4=R6), there is only one reaction product 1.1. If diketones 4 are unbalanced, then formed two products re the options 1.1 and 1.1A, who share well-known methods, for example, by using preparative chromatography or recrystallization.

The following examples describe the synthesis of antagonists of serotonin 5-HT6receptors of General formula 1 and their biological tests. The results of antagonists of serotonin 5-HT6receptors of General formula 1 and their biological activity towards serotonin receptors are presented in tables 2-4.

The following examples illustrate but do not limit the invention.

The invention is illustrated by drawings.

Figure 1. The concentration dependence of inhibition by the antagonist of the formula 1.1.1(1) serotonin 5-HT6receptors and Methiothepin as control.

Figure 2. Improve memory in male mice of BALB/c, disturbed by scopolamine, under the action of the antagonist of the formula 1.1.1(1) (CD-008-0216) in the test "Passive avoidance of mice in the Shuttle chamber". The time after which animals make the first entry into the dark chamber. In parentheses indicate the concentration of a substance in mg/kg

Figure 3. Improve memory in male mice of BALB/c, disturbed by scopolamine, under the action of the antagonist of the 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 bright and the camera. In parentheses indicate the concentration is mg/kg

Figure 4. Improve memory in male mice of BALB/c, disturbed by scopolamine, under the action of the antagonist of the formula 1.1.1(1) (CD-008-0216) in the test "Passive avoidance of mice in the Shuttle chamber". The number of visits in a dark chamber. In parentheses indicate the concentration of a substance in mg/kg

Figure 5. Improve memory in male mice of BALB/c, broken MK-801, under the action of the antagonist of the formula 1.1.1(1) (CD-008-0216) in the test "Passive avoidance of mice in the Shuttle chamber". The time after which animals make the first entry into the dark chamber. In parentheses indicate the concentration of a substance in mg/kg

6. Improve memory in male mice of BALB/c, broken MK-801, under the action of the antagonist of the 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 bright and the camera. In parentheses indicate the concentration of a substance in mg/kg

7. Improve memory in male mice of BALB/c, broken MK-801, under the action of the antagonist of the formula 1.1.1(1) (CD-008-0216) in the test "Passive avoidance of mice in the Shuttle chamber". The number of visits in a dark chamber. In parentheses indicate the concentration of a substance in mg/kg

Fig. The behavior of male mice of BALB/c under the action of the antagonist of the formula 1.1.1(1) (CD-008-0216) and Comparators (Buspirone and Lorazepam) to test the Behavior of mice in the elevated cross maze. The time, t is the treatment which the animals are kept in the open sleeves to the time during which the animals are in open and closed sleeves. In parentheses indicate the concentration of a substance in mg/kg

Fig.9. The behavior of male mice of BALB/c under the action of the antagonist of the formula 1.1.1(1) (CD-008-0216) and Comparators (Buspirone and Lorazepam) to test the Behavior of mice in the elevated cross maze. The number of defecations. In parentheses indicate the concentration of a substance in mg/kg

Figure 10. The behavior of male mice of BALB/c under the action of the antagonist of the formula 1.1.1(1) (CD-008-0216) and Comparators (Buspirone and Lorazepam) to test the Behavior of mice in the elevated cross maze. The ratio of the number of calls of animals in open sleeve to the number of visits of animals in open and closed sleeves. In parentheses indicate the concentration of a substance in mg/kg

11. State of immobility during the last 5 min in the Porsolt test. The antagonist of the formula 1.1.1(1) (CD-008-0216) comparison (Fluoxetine, Desipramine) were injected intraperitoneally daily for 4 days at doses of 0.05, 0.2 and 15 mg/kg, respectively. * - p<0.05.

Example 1. The method of obtaining substituted 3,5-diamino-4-sulfonyl-pyrazoles of General formula 1. Heated with stirring in 15 ml of isopropanol 7.85 mmol of 2-aryl(hetaryl)sulfonyl-3-amino-3-methylsulfanyl-Acrylonitrile General formula 2 with 1.2-1.5 EQ. the hydrazine of General formula 3 for 0.5 h (monitoring by LCMS). PEFC the completion of the reaction, the reaction mixture was poured into a mixture of water - ice, the precipitated oil is rapidly solidified, the solid is filtered off, washed with water, cold isopropanol, hexane and recrystallized from a suitable solvent. Receive 3,5-diamino-4-sulfonyl-pyrazoles of General formula 1, are presented in table 2.

Table 2.
Antagonists of serotonin 5-HT6receptors.
No.FormulaMol. weightLCMS, m/z (M+1)% Inhibition of 5-HT6receptor 10 μm antagonist
1(1)296.3529755
1(2)252.2925341
1(3)328.3932960
1(4) 314.3631561
1(5)332.3533359

1(6)418.5241949
1(7)346.3834748
1(8)385.4438644
1(9)523.5452443
1(10)309.3931048
1(11)323.42 32445

1(12)323.4232447
1(13)321.4032250
1(14)407.5040838
1.1(1)406.5140777
1.1(2)378.4637990
1.1(3)378.4637991

1.1(4) 317.3731897
1.1(5)317.3731895
1.1(6)322.4132398
1.1.1(1)316.3831777
1.1.1(2)330.4133186
1.1.1(3)334.3733599

1.1.1(4)348.4034995
1.1.1(5)34.37 33597
1.1.1(6)334.3733597
1.1.1(7)350.83351100
1.1.1(8)364.8636596
1.1.1(9)330.41331104

1.1.1(10)409.9437491
1.1.1(11)423.9738888
1.1.1(12)42.97 38894
1.1.1(13)471.5847263

1.1.1(14)407.9237276
1.1.1(15)421.9538680
1.1.1(16)406.5140770
1.1.1(17)368,8236997

Example 2. A common way of obtaining substituted 2-amino-3-sulfanyl-pyrazolo[1,5-a]pyrimidines of General formula 1.1. Boil 0.005 mol of substituted 3,5-diaminophenol General formula 1 and 0.0055 mol of the corresponding diketone of General formula 4 in 5 ml of acetic acid for 4 hours the resulting solution cooling is so The precipitation 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. Output 3-sulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1.1 is 70-85%. Table 2 presents some examples of new substituted 2-amino-sulfonyl-pyrazolo[1,5-a]pyrimidines of General formula 1.1 and LCMS analysis.

Example 3. Determination of antagonistic activity of the compounds of General formula 1 towards 5-HT6the receptors. Compounds of General formula 1 were tested for their ability to inhibit the activation of 5-HT6the serotonin receptors. Use SOME cells 293 (kidney cells human embryo) with artificially downregulation of the receptor 5-HT6the activation of which is serotonin increases the concentration of intracellular camp. The content of intracellular camp was determined by reagent set LANCE cAMP (PerkinElmer) according to the method described by the manufacturer [http://las.perkinelmer.com/content/Manuals/MAN_LANCEcAMP384KitUser.pdf]. The effectiveness of the compounds assessed on their ability to reduce the amount of intracellular camp induced by serotonin.

Table 2 presents data on the percent inhibition of 5-HT6receptor 10 µm solutions of compounds of the General is the first formula 1. As can be seen from the presented data, the tested compounds exhibit significant activity against serotonin 5-HT6the receptors.

Table 3 presents the concentration dependence of inhibition induced by the serotonin production of intracellular camp by some compounds of General formula 1, demonstrating their antagonistic activity, and the values of the IC50confirming their moderate or high activity in terms of functional assay.

Table 3.
The concentration dependence of inhibition by the compounds of General formula 1 serotonin 5-HT6receptors and values IC50in terms of functional assay.
No.FormulaIC50, nM
1(1)5.667*
1(2)18.840*

1.1.1(1)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
* - IC50, µM

Example 4. Determination of the activity of antagonists of serotonin 5-HT6receptors of General formula 1 in a competitive binding to serotonin 5-HT6the receptors.

For the screening of substances for their potential ability to interact with serotonin receptor 5-HT6using the method of radioligand binding. To do this, prepare membrane preparations from HeLa cells expressing recombinant human 5-HT6receptor, by homogenization of recombinant cells in a glass homogenizer followed by the separation of plasmatic membranes from nuclei, mitochondria and is gunning debris by differential centrifugation. The binding definition of the studied compounds with 5-HT6the receptor is carried out in accordance with the methodology described in Monsma FJ Jr, Shen Y, Ward RP, Hamblin MW and Sibley DR, Cloning and expression of a novel serotonin receptor with high affinity for tricyclic psychotropic drags. Mol. Pharmacol. 43:320-327, 1993. In a preferred execution of the membrane preparations are incubated with labeled ligand (1.5 nM [3H] Lysergic acid diethylamide) without and in the presence of investigated compounds for 120 min at 37°C in a medium consisting of 50 mm Tris-HCl, pH 7.4, 150 mm NaCl, 2 mM Ascorbic Acid, 0.001% BSA. The samples after incubation filtered under vacuum on steklofibrobetonnykh filters G/F (Millipor, USA), the filters are washed three times with cold solution environment and radioactivity was measured using a MicroBeta scintillation counter 340 (PerkinElmer, USA). Nonspecific binding, which was 30% of the total binding is determined by incubation of membrane preparations with radioligand in the presence of 5 μm Serotonin (5-HT). As a positive control, use Methiothepin. Binding of test compounds to the receptor is determined by their ability to displace the radioactive ligand and expressed in percentage of displacement. The percentage of displacement is determined by the following formula:

,

where TA is the total radioactivity in the presence only of the radioactive ligand, CA is radioactivity in the presence of radioligand and joint test and NA - this is radioactivity in the presence of radioligand and serotonin (5 µm).

In table 4 and figure 1 as one example of the results of tests 5,7-dimethyl-2-methylamino-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.1(1) and Methiothepin as a control, showing high activity (4.61 gr) antagonist of serotonin 5-HT6receptors.

Table 4.
The concentration dependence of inhibition by antagonists of General formula 1 serotonin 5-HT6receptors and values IC50and Kiin a competitive assay.
ConnectionConcentration dependenceIC50PMToiPM
Antagonist 1.1.1(1)Cm. 10.5110.237
▪ Control - Methiothepin1.30.603

Example 5. Obtaining medicines in tablet form. Mix 1600 mg of starch, 1600 mg of powdered lactose, 400 mg of talc and 1000 mg of 5,7-dimethyl-2-is ethylamino-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.1(1) and pressed in the bar. The resulting block is crushed into granules and sieved through a sieve, collecting the granules with a size 14-16 mesh. The obtained granules tabletirujut in a suitable form tablets weighing 560 mg each. According to the invention likewise get medicines containing the drug beginning of the other compounds of General formula 1.

Example 6. Obtaining medicines in capsule form. Thoroughly mix 5,7-dimethyl-2-methylamino-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.1(1) with lactose powder in a 2:1 ratio. Received poroshkoobraznuju mix pack 300 mg in gelatin capsules of suitable size.

Example 7. Obtaining medicines in the form of injectable compositions for intramuscular, intraperitoneal or subcutaneous injection. Mix 500 mg of 5,7-dimethyl-2-methylamino-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.1(1) with 300 mg of chlorobutanol, 2 ml of propylene glycol and 100 ml of injectable water. The resulting solution is filtered and placed in 1 ml ampoules which are sealed.

Example 8. Nootropic action (improving memory, disturbed 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". Used Shuttle camera (Ugo Basile, Italy), which consisted of two compartments. All the walls of one of the compartments was the opaque, and the second compartment had a transparent cover. The compartments were connected by the hole, which could be closed by a vertical door. The floor consisted of transverse metal rods, which could be pulsed DC. The experiments were performed on adult male mice of BALB/c mice weighing 20-24 g

On the first day experience for 30 minutes 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 were used at least 8 animals. Animals were placed in the bright compartment and record the latent period of the first entry into the dark chamber. The door between the compartments were closed, and the animal within 3 received punishment by a current of 0.6 mA. After that, the animal was returned to a living cell. After 22-24 h animal was again placed in the light compartment of the Shuttle camera and recorded the latent period of the first entry into the dark compartment, the total time spent in the light compartment and the number of visits in a dark compartment. The duration of observation was 5 minutes

The experiment was carried out in daylight hours in an isolated laboratory environment with the use of "white noise" intensity of 70 dB above the hearing threshold of a person.

Scopolamine causes a disturbance learning (memory)that exp is supplied in the form of increased latent period 1st time in the dark compartment, increase time spent in the light compartment and the decrease in the number of entries into the dark compartment.

The ability of 5,7-dimethyl-2-methylamino-3-phenylsulfonyl-pyrazolo [1,5-a]pyrimidine 1.1.1(1) to improve teaching, disturbed by scopolamine, may be regarded as evidence he may have neuroprotective actions.

The results 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 exert a neuroprotective effect.

Example 9. Nootropic action (improving memory, 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 the Shuttle chamber". The experiment was performed as in example 8. On the first day experience for 30 minutes before training, mice were injected intraperitoneally with saline, MK-801 (0.1 mg/kg). Parallel independent groups of mice to training were injected intraperitoneally with saline, MK-801 in combination with 5,7-dimethyl-2-methylamino-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.1(1).

The results (figure 5-7) demonstrate the capacity 5,7-dimethyl-2-methylamino-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.1(1) to exert a neuroprotective effect.

Example 10. Anxiolytic (anxiolytic) effects of 5,7-dimethyl-2-methylamino-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.11(1) to test the Behavior of mice in the elevated cross maze. The length of the arms of the maze is 30 cm, width 5 cm, height of walls 15 see Two contrasting sleeves closed at the sides and ends of the transparent walls; the other two are lit and open. The mouse was placed in the center of the maze for 5 min recorded the number of entries in open and closed sleeves and the time spent by the animals in the open and closed sleeves. These data were calculated indexes preferences open sleeves as the ratio of the number of entries in open arms, and also the time spent in open arms to the total number of visits to all of the sleeves and the time spent in them. In normal animals avoid open sleeves (index their preferences is 0.2-0.3). Substances with anxiolytic activity (anxiolytic activity) increase this rate to 0.5-0.6 or more, and also reduce the number of bowel movements, without changing the overall locomotor activity (total number of visits in the sleeves).

The results obtained (Fig-10) indicate that 5,7-dimethyl-2-methylamino-3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidine 1.1.1(1) exerts anxiolytic (tranquilizing) activity, comparable with Buspirone and Lorazepam.

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

The behavior of "despair" was asked what Rosatom and other (1977, 1978) as a model of depressive-like state, allowing to test the antidepressant activity of substances. For mice or rats are forced to swim in a restricted space from which they cannot escape, is characteristic of this state of immobility. This behavior is a state of despair, which can be reduced by using substances with antidepressant type of action in humans.

In the experiment used male mice of BALB/c mice (20-30 g). Animal for 15 min was placed in the pool (height 300 mm, the diameter of 480 mm), 70% filled with water with a temperature of ~25°C. after 3-5 min of active swimming intensity of movements begins to decline and be replaced by stationary phases swimming. Fixed an animal was considered in the case, if it did not make any movement for at least 1.5 seconds (this option was used when configuring ANY-maze™). For analysis we used the experimental data obtained during the last 5 min of the test. The results are presented in figure 11.

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

1. Antagonists of serotonin 5-HT6receptors of General formula 1 or their pharmaceutically acceptable salts and/or hydrates,

where Ar is an aryl selected from optionally substituted phenyl or optionally substituted 5-6-membered heteroaryl containing as a heteroatom a nitrogen atom or a sulfur atom;
R1represents a hydrogen atom, optionally substituted C1-C5alkyl;
R21, R22, R31, R32independently from each other represent a hydrogen atom or Deputy amino group selected from the optional substituted C1-C4the alkyl, optionally substituted phenyl, or R31and R32together with the nitrogen atom to which they are bound, form an optional substituted saturated 6-membered heterocyclyl may contain an additional nitrogen atom in the cycle;
or R1together with the nitrogen atom to which it is linked, and R21and R22together with the nitrogen atom to which they are bound, form a substituted pyrimidine cycle.

2. Antagonists according to claim 1, which represents a substituted 2-amino-3-sulfanyl-pyrazolo[1,5-a]pyrimidines of General formula 1.1 or their pharmaceutically acceptable salts and/or hydrates,

where Ar, R31and R32have the above meaning; R4, R5and R6independently from each other represent a hydrogen atom, optionally substituted C1-C3alkyl or phenyl.

3. Antagonists according to claim 2, represents a substituted 3-arylsulfonyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidines of General formula 1.1.1 or their pharmaceutically acceptable salts and/or hydrates,

where R31and R32have the above meaning; Ri7represents one or two are not necessarily the same Deputy cyclic system selected from a hydrogen atom, a C1-C5of alkyl, trifloromethyl or halogen atom.

4. Antagonists according to claim 3, representing 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-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.1(3), 5,7-dimethyl-2-dimethylamino-3-(4-perpenicular)-pyrazolo [1,5-a]pyrimidine 1.1.1(4), 5,7-dimethyl-2-methylamino-3-(3-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.1(5), 5,7-dimethyl-2-dimethylamino-3-(3-perpenicular)-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-chlorine is phenylsulfonyl)-pyrazolo[1,5-a]pyrimidine 1.1.1(8) and their pharmaceutically acceptable salts and/or hydrates

5. Antagonist of serotonin 5-HT6receptors of General formula 1 according to any one of claims 1 to 4 as the drug began to obtain pharmaceutical compositions or dosage forms.

6. Pharmaceutical composition having the properties of antagonists of serotonin 5-HT6receptors for treating and preventing conditions and disorders of the Central nervous system, containing an effective amount of a medicinal beginning according to claim 5.

7. A method of obtaining a pharmaceutical composition according to claim 6 mixture with an inert filler and/or solvent, at least one drug started according to claim 5.

8. Medicinal product which has the properties of antagonists of serotonin 5-HT6receptors intended for treatment and prevent the development of conditions and diseases of the Central nervous system, in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing, including medicinal beginning according to claim 5, or a pharmaceutical composition according to claim 6.

9. Method for the prevention and treatment of diseases of the Central nervous system, Pato is ENES which is associated with serotonin 5-HT 6receptors, which is the introduction of medicinal beginning according to claim 5, or a pharmaceutical composition according to claim 6, or medicinal product of claim 8 in an effective amount.

10. Substituted 2-amino-3-sulfanyl-pyrazolo[1,5-a]pyrimidines of General formula 1.1 or their pharmaceutically acceptable salts and/or hydrates,

where Ar, R31and R32have the above meaning; R4, R5and R6independently from each other represent a hydrogen atom, optionally substituted C1-C3alkyl or phenyl.

11. Connection of claim 10, which represents a substituted 3-arylsulfonyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidines of General formula 1.1.1 or their pharmaceutically acceptable salts and/or hydrates,

where R31and R32have the above meaning; R7irepresents one or two are not necessarily the same Deputy cyclic system selected from a hydrogen atom, a C1-C5of alkyl, trifloromethyl or halogen atom.

12. Compounds according to claim 11, representing 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-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.(3), 5,7-dimethyl-2-dimethylamino-3-(4-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.1(4), 5,7-dimethyl-2-methylamino-3-(3-perpenicular)-pyrazolo[1,5-a]pyrimidine 1.1.1(5), 5,7-dimethyl-2-dimethylamino-3-(3-perpenicular)-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

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

where Ar, R31, R32, R4, R5and R6have the above significance.



 

Same patents:

FIELD: medicine.

SUBSTANCE: there are described new p38 kinase inhibitors that are compounds of general formula (I) (radical values are presented in the patent claim), their pharmaceutically acceptable salts and solvates, a pharmaceutical composition containing thereof, and method for treating inflammatory diseases.

EFFECT: new compounds have effective biological activity.

24 cl, 311 ex

FIELD: medicine.

SUBSTANCE: there are described new isoindole derivatives of general formula (1), wherein A1, A2 and A4 stands for CH, and A3 means N or C-OH; n is equal to 2; R1 represents O; R2-stands for H; and a pharmaceutical composition containing thereof.

EFFECT: new compounds are inhibitors of chaperone protein Hsp90 activity and can be used in chemotherapy of cancerous diseases.

6 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new 2-alkylsufanyl-3-arylsufonyl-cycloalkano[e]pyrazolol[1,5-a]pyrimidines of general formula 1 or 2-alkylsufanyl-3-arylsufonyl-cycloalkano[d]pyrazolo[1,5-a]pyrimidines of general formula 2, which are antagonist of 5-HT6 receptors. In compounds of formula 1

and 2 ,

R1 is a hydrogen atom or C1-C3 alkyl; R2 is C1-C3 alkyl; R3 is a hydrogen atom, one or two optionally identical halogen atoms, C1-C3 alkyl or hydroxyl, optionally substituted with C1-C3 alkyl; n is an integer equal to 1, 2 or 3.

EFFECT: compounds can be used in preventing and treating diseases of the central nervous system, anxiolytics and as compounds with nootropic effect and suitable for enhancing memory.

12 cl, 1 dwg, 4 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a cyclic bioisostere of purine system derivatives, with general structural formula given below , where R = , Li, Na or K, R1 = -H, -NH2, -Br, -Cl, -OH, -COOH; A = -N- for B=-N=, Z = -CH-; A = -CH= for B = -N=, Z = -CH-; A = -CH= for B = -N=, Z = -N=; A = -CH= for B = -CH=, Z - -CH=; A = -CH= for B = -CH=, Z = -N=, except compounds in which A = -CH= for B = -CH=, Z = -CH=, R= Li, Na or K and R1= -NH2 in the 5th position of the benzo[d]-3H-pyridazine-1,4-dione nucleus, and its pharmacologically acceptable salts, with normalising effect on intracellular processes.

EFFECT: obtaining compounds which can be used for normalising intracellular processes in therapy of disorders, caused by intracellular acidosis and/or oxygen deficiency and/or excess formation of free radicals and/or excess formation of free radical forms of oxygen and/or high thrombocyte aggregation and/or erythrocytes and/or adverse effects and/or nitrergic cell mechanism disorder.

17 cl, 14 tbl, 15 dwg

FIELD: chemistry.

SUBSTANCE: new pyrrolotriazine derivatives of general formula (I) are described, where R1 is possibly substituted piperidinyl or piperazinyl; R2 is possibly substituted phenyl; R3 is hydrogen; X is -NH-; Y is -CH2-; as well as their pharmaceutically acceptable salts or steroisomers, and pharmaceutical compositions containing said compounds.

EFFECT: given compounds are kinase inhibitors and can be used in medicine, for example as anticancer agents.

9 cl, 267 ex, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to new derivatives of imidazo[1,2-c]pyrimidinyl acetic acid of formula (I) or to its salts: , where R1 is ,, in which n is an integer ranging from 0 to 6; Y is aryl, where the said aryl is optionally substituted at a substitutable position with one or more substitutes selected from a group which consists of halogen or C1-6alkyl, optionally substituted with mono-, di- or trihalogen; R2 is hydrogen; R3 is hydrogen or halogen; and R4 is hydrogen. The invention also relates to derivatives of imidazo[1,2-c]pyrimidinyl acetic acid of formula (I-i) or to its salts, to a drug, to use of compounds in paragraph 1, as well as to a drug in form of a standard single dosage.

EFFECT: obtaining new biologically active compounds, which are active towards CRTH2.

23 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: in compounds of formula (I) , Q is: (IIa) or (IIb) , R1 is chosen from a group which consists of carboxylic aryl and carboxylic aryl which is substituted with substitute(s) independently chosen from a group which consists of halogen, cyano, nitro, C1-10alkyl, C1-10alkyl which is substituted with substitute(s) independently chosen from a group which consists of halogen, C1-9alkoxy, C1-9alkoxy which is substituted with substitute(s) independently chosen from a group which consists of halogen, mono-C1-5alkylamino, and heterocyclyl or heterocyclyl which is substituted with substitute(s) independently chosen from a group which consists of halogen, C1-5alkyl; R2 is C1-5alkyl, C1-5alkyl which is substituted with halogen, C1-5alkyl which is substituted with carboxylic aryl, C1-5alkoxy, -N(R2a)(R2b); where R2a and R2b are each independently hydrogen, C1-5alkyl or C1-5alkyl, substituted with substitute(s) independently chosen from a group which consists of hydroxyl, carboxylic aryl; L represents formula (IIIa); , where R3 and R4 are each hydrogen; A is a single bond, and B is a single bond or -CH2-; Z1, Z3, and Z4 are each independently hydrogen, halogen, C1-5alkyl, C1-5alkyl, substituted with carboxylic aryl, C1-5alkoxy, mono-C1-5alkylamino, di-C1-5alkylamino, carboxylic aryl, heterocyclyl or substituted heterocyclyl; Z2 is hydrogen, C1-5alkyl, C1-5alkyl which is substituted with carboxylic aryl, C1-5alkoxy, mono-C1-5alkylamino, di-C1-5alkylamino, carboxylic aryl, heterocyclyl or substituted heterocyclyl; Y is -C(O)NH-, -C(O)-, -C(S)NH-, -C(O)O- or -CH2-; where carboxylic aryl is phenyl; heterocyclyl is 1H-indolyl, 9H- xanthenyl, benzo[1,3]dioxolyl, furyl, imidazolyl, isoxazolyl, morpholinyl, piperazinyl, pyridyl, pyrrolidyl; halogen is fluorine, chlorine, bromine or iodine. The invention also relates to a pharmaceutical composition.

EFFECT: compounds can be used for treating central nervous system diseases, and for improving memory functioning, sleep, awakening, diabetes.

16 cl, 8 dwg, 4 tbl, 525 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a tetrazole compound with general formula I , where X3 and X4 are independently N and C, where one of X3 and X4 is certainly C; P is phenyl; m equals 1 or 2, where if m equals 1, R1 is bonded to P through a carbon atom on ring P in the meta-position of ring P relative the point at which P is bonded to X3, and if m equals 2, R1 is bonded to P through a carbon atom on ring P in positions 2 and 5 of ring P; R1 is halogen, C1-6alkyl, OC1-6alkyl or cyano group; X1 is C2-3alkyl, C2-3alkenyl, NR3, O, S, CR3R4, SO, SO2; X2 is a bond, CR3R4, O, S, NR3, SO, SO2; R3 and R4 are independently chosen from a group which consists of hydrogen, hydroxy, C1-6alkyl; Q is triazolyl, piperazinyl, or triazole or imidazole ring, condensed with a 6- or 7-member heterocyclic ring with one or two N atoms as heteroatoms; R is C1-6alkyl, C3-6cycloalkyl, pyridinyl, which can be substituted with a nitro, cyano, halogen or OC1-4alkyl group; phenyl, which can be substituted with a halogen, C1-4alkyl, OC1-4alkyl group; (CO)OC1-4alkyl; pyrimidinyl, which can be substituted with a OC1-4alkyl group; p equals 0, 1 or 2, or pharmaceutically acceptable salt or hydrate thereof.

EFFECT: invention also relates to method of inhibiting activity of mGluR5 receptors.

11 cl, 44 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns novel compounds of formula (1a), formula (1b), formula (1c) and formula (1d), as well as pharmaceutical composition based on them and their application in medicine obtainment. R1-R4, G, W, X, X1, U, V, a, b are defined in the invention claim.

EFFECT: compound with antagonistic effect on vasopressin V1A receptor.

73 cl, 133 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns compounds of the formula and other compounds listed in cl. 1 of invention claim, and pharmaceutical composition based on them, as well as method of mGluR5 receptor activity inhibition involving claimed compounds.

EFFECT: application in treatment and prevention of diseases mediated by mGluR5 receptor activity.

4 cl, 18 dwg, 1009 ex

FIELD: chemistry.

SUBSTANCE: described are derivatives of 5-substituted alkylaminopyrazoles of formula (I) , where R1 stands for CN, W stands for C-halogen; R2 stands for halogen, R3 stands for (C1-C3)-halogenoalkyl, R4 stands for (C1-C6)-alkyl, A stands for (C1-C12)-alkylene, R5 stands for (C1-C6)-alkyl, R6 stands for (C1-C6)-halogenoalkyl, n equals 2, or their pesticidely acceptable salts. Compounds demonstrate insecticidal activity and parasiticidal activity. The method of obtaining formula (I) is described, including interaction of compound of formula (II) with compound of formula (III) R5-O-A-NH2 and interaction on compound obtained with compound of formula (V) R4-L1.

EFFECT: obtaining derivatives which can be applied as pesticides.

3 cl, 6 tbl, 18 ex

FIELD: organic chemistry.

SUBSTANCE: invention describes insecticide-acaricide substance used against extoparasites in dogs and cats. Substance represents derivative of phenylpyrazole of the formula (I) wherein in pyrazole structure cyano-group, trifluoromethylsulfenyl group and amino-group are bound at 3, 4 and 5 positions, respectively, and chlorine atoms are bound to phenyl cycle at 2 and 6 positions, and trichlorosilyl group is bound at 4 position. Substance protects dogs and cats against infection with fleas for 65 days after treatment and for 45 days after treatment of cats, and against infection with mites for 35 days, not less. In acute experiment toxicity of substance is characterized by value LD50 above 1300 mg/kg after its administration in stomach to dogs.

EFFECT: valuable properties of substance.

2 ex

FIELD: organic chemistry, agriculture.

SUBSTANCE: invention relates to 5-substituted alkylaminopyrazole derivatives of formula I , wherein R1 is CN; W is C-halogen; R1 is halogen; R3 is C1-C3-haloalkyl, C1-C3-haloalkoxy; R4 is hydrogen, C1-C6-alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl, COR8; A is C1-C12-alkylene; R5 is hydrogen, C3-C6-alkenyl, -(CH )qR7 or NR10R11; R5 is C1-C6-haloalkyl; as well as method for animal exogenous and endogenous pest controlling; pesticide composition and application of said compounds for production of veterinary drug. 5-Substituted alkylaminopyrazole derivatives are useful in pest controlling, including insects, arachnids and helminthes, such as nematodes.

EFFECT: new pesticide derivatives.

9 cl, 12 tbl, 20 ex

FIELD: organic chemistry, pesticides.

SUBSTANCE: invention relates to production of compounds of formula I

, wherein R1 represents CN or CSNH2; X represents N or CR4; R2 and R4 represent hydrogen or chlorine; and R3 represents halogen, haloalkyl, halooxy or SF5. Claimed method includes reaction of compound of formula II

with aqueous acid solution. Also disclosed are method for production of intermediate of formula II, method for production of compound of formula I including step of production of formula II followed by conversion thereof to target compound. Moreover disclosed are two intermediates for production of target products.

EFFECT: new pesticide compounds and method for production thereof.

13 cl, 2 ex

FIELD: organic chemistry, agriculture.

SUBSTANCE: invention relates to method for production of compounds of general formula I wherein R1 represents CN or CSNH2; X represents N or C each R2 and R4 are independently hydrogen or chlorine; R3 represents halogen, haloalkyl, haloalkoxy or SF3; R5 and R6 are independently alkyl; n = 0, 1 or 2. Claimed method includes reaction of compound of formula II , wherein substituents are as defined above; W represent hydrogen, with metal inorganic salt or organic amine to form salt of compound II as intermediate and further reaction of said salt with alkylating agent of formula III wherein R6 is as defined above; Y represents leaving group. In another embodiment compounds of formula I are obtained by reaction of metal inorganic salt or organic base of formula II with abovementioned alkylating agent of formula III.

EFFECT: essentially decreased formation of side products; target products of high purity.

37 cl, 4 ex

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention elates to novel derivatives of uracil of the formula [I] possessing herbicide activity, a herbicide composition based on thereof and to a method for control of weeds. In derivatives of uracil of the formula [I] the group Q-R3 represents a substituted group taken among:

wherein a heterocyclic ring can be substituted with at least a substitute of a single species taken among the group involving halogen atom, (C1-C6)-alkyl-(C1-C6)-alkoxy; Y represents oxygen, sulfur atom, imino-group or (C1-C3)-alkylimino-group; R1 represents (C1-C3)-halogenalkyl; R2 represents (C1-C3)-alkyl; R3 represents OR7, SR8 or N(R9)R10; X1 represents halogen atom, cyano-group, thiocarbamoyl or nitro-group; X2 represents hydrogen or halogen atom wherein each among R7, R8 and R10 represents independently carboxy-(C1-C6)-alkyl and other substitutes given in the invention claim; R9 represents hydrogen atom or (C1-C6)-alkyl. Also, invention relates to intermediate compounds used in preparing uracil derivatives.

EFFECT: improved preparing method, valuable properties of compounds.

40 cl, 16 sch, 12 tbl, 65 ex

The invention relates to 1-methyl-5-alkylsulfonyl-, 1-methyl-5-alkylsulfonyl - 1-methyl-5-alkylthiomethyl pyrazolylborate and herbicide tool based on them

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of common formula (I) , in which: A, if available, means (C1-C6)-alkyl; R1 means group NR6R7, (C4-C7)-azacycloalkyl, (C5-C9)-azabicycloalkyl, besides, these groups, unnecessarily, are substituted with one or more substituents, selected from (C1-C5)-alkyl or halogen; A-R1 is such that nitrogen of radical R1 and nitrogen in position 1 of pyrazole are necessarily separated at least by two atoms of carbon; R3 means radical H, OH, NH2, ORc, NHC(O)Ra or NHSO2Ra; R4 means phenyl or heteroaryl, unnecessarily, substituted with one or more substituents, selected from halogen, CN, NH2, OH, ORc, C(O)NH2, phenyl, polyfluoroalkyl, linear or ramified (C1-C6)-alkyl, besides these substituents, unnecessarily, are substituted with halogen, and moreover, heteroaryl radicals are 3-10-member, containing one or more heteroatoms, selected from sulphur or nitrogen; R5 means radical H, linear or ramified (C1-C6)-alkyl; Ra means linear or ramified (C1-C6)-alkyl; Rc means linear or ramified (C1-C6)-alkyl, (poly)fluoroalkyl or phenyl; R6 and R7, independently from each other, means hydrogen, (C1-C6)-alkyl; R6 and R7 may create 5-, 6- or 7-member saturated or non-saturated cycle, which includes one heteroatom, such as N, and which, unnecessarily, substituted with one or more atoms of halogen; to its racemates, enantiomers, diastereoisomers and their mixtures, to their tautomers and their pharmaceutically acceptable salts, excluding 3-(3-pyridinyl)-1H-pyrazole-1- butanamine, 4-(3-pyridinyl)-1H-pyrazole-1-butanamine and N-(diethyl)-4-phenyl-1H-pyrazole-1-ethylamine. Invention is also related to methods for production of compounds of formula (I) and to pharmaceutical composition intended for treatment of diseases that appear as a result of disfunction of nicotine receptors α7 or favorably responding to their modulation, on the basis of these compounds.

EFFECT: production of new compounds and pharmaceutically acceptable composition on their basis, which may find application in medicine for treatment, prophylaxis, diagnostics and observance over development of psychiatric or neurological disorders or diseases of central nervous system, when cognitive functions deteriorate or quality of sensor information processing drops.

16 cl, 106 ex

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