US 2011 003987OA1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0039870 A1 Vashchenko et al. (43) Pub. Date: Feb. 17, 2011

(54) TETRAHYDRO-PYRAZOLO15-APYRIDO (52) U.S. Cl...... 514/267: 544/251; 435/375 PYRIMDNES ASANTAGONSTS OF (57) ABSTRACT SEROTONIN 5-HT6 RECEPTORS, METHODS FOR THE PRODUCTION AND USE THEREOF The present invention relates to serotonin 5-HT, receptor antagonists-novel substituted 3-sulfonyl-6,7,8,9-tetrahydro (75) Inventors: Andrey Alexandrovich pyrazolo 1.5-alpyrido4.3-epyrimidines and Substituted Ivashchenko, Moscow (RU); 3-sulfonyl-5,6,7,8-tetrahydropyrazolo 1.5-alpyrido4.3-d Volodymyr Mikhailovich Kysil, pyrimidines, drug Substances and pharmaceutical composi tions comprising drug Substances as the mentioned above Kiev (UA); Nikolay Filippovich compounds and to the method of prophylaxis and treatment Savchuk, Rancho Santa Fe, CA of various conditions and diseases of central nervous system (US); Alexander Vasilievich in humans and warm-blooded animals pathogenesis of which Evashchenko, Encinitas, CA (US) is associated with serotonin 5-HT, receptors. Correspondence Address: In formulas 1 and 2 Ivashtchenko Alexander Vasilievich 2874 Cale Rancho Vista Encinitas, CA 92024 (US) RI (73) Assignee: Aleaxnder Vasilievich Ivashtchenko, Encinitas, CA (US) (21) Appl. No.: 12/937,720 (22) PCT Filed: Apr. 30, 2009 \ / N R2 (86). PCT No.: PCT/RU09/00209 A R3 S371 (c)(1), RI (2), (4) Date: Oct. 15, 2010 Air (30) Foreign Application Priority Data May 7, 2008 (RU) ...... 2008117845

Publication Classification (51) Int. Cl. A 6LX 3/59 (2006.01) N CO7D 47L/4 (2006.01) A A6IP 25/00 (2006.01) R3 A6IP 25/28 (2006.01) A6IP 25/6 (2006.01) Ar is optionally substituted aryl or optionally substituted A6IP 25/8 (2006.01) heterocyclyl; R is hydrogen, optionally substituted lower A6IP 25/22 (2006.01) C-C alkyl, Substituted hydroxyl group, Substituted Sulfanyl A6IP3/10 (2006.01) group; R is hydrogen or optionally substituted C-C alkyl: A6IP3/04 (2006.01) R is hydrogen, optionally substituted C-C alkyl or tert CI2N 5/02 (2006.01) butyloxycarbonyl. US 2011/003987.0 A1 Feb. 17, 2011

TETRAHYDRO-PYRAZOLO15-APYRIDO-PYRIMIDhNgsd rats. Neuropsychopharmacology. 2004; 29:93-100; ASANTAGONSTS OF SEROTONN 5-HT6 Riemer C., Borroni E., Levet-Trafit B., Martin J. R., Poli S., RECEPTORS, METHODS FOR THE Porter R. H., Bos M. Influence of the 5-HT6 receptor on PRODUCTION AND USE THEREOF release in the cortex: pharmacological charac terization of 4-(2-bromo-6-pyrrolidin-1-ylpyridine-4-sulfo FIELD OF THE INVENTION nyl)phenylamine, a potent and selective 5-HT, receptor 0001. The invention relates to the novel arylsulfonyl-aza antagonist. J. Med. Chem. 2003; 46:1273-1276; King M. V., heterocyclic compounds, to novel serotonin 5-HT, receptor Woolley M. L., Topham I. A. Sleight A. J., Marsden C. A., antagonists, novel drug Substances, pharmaceutical compo Fone K.C. 5-HT6 receptor antagonists reverse delay-depen sitions, medicaments and methods for preparation thereof. dent deficits in novel object discrimination by enhancing More particular, the present invention is directed to serotonin consolidatione an effect sensitive to NMDA receptor antago 5-HT, receptor antagonists-novel substituted 3-sulfonyl-6.7, nism. Neuropharmacology 2004: 47: 195-204. It was also 8.9-tetrahydropyrazolo 1.5-alpyrido4.3-epyrimidines and demonstrated that considerable enhancement of cognitive substituted 3-sulfonyl-5,6,7,8-tetrahydropyrazolo 1.5-apy functions in aged rats took place under the action of 5-HT rido4.3-dipyrimidines, drug Substances and pharmaceutical receptor antagonists in Morrison's water maze experiment compositions comprising the said compounds as active ingre Foley A. G., Murphy K. J., Hirst W. D., Gallagher H. C., dients, and to methods of prophylaxis and treatment of vari Hagan J.J., Upton N., Walsh F. S., Regan C. M. The 5-HT(6) ous conditions and diseases of central nervous system patho SB-271046 reverses -dis genesis of which is associated with 5-HT, receptors in rupted consolidation of a passive avoidance task and amelio humans and warm-blooded animals. rates spatial task deficits in aged rats. Neuropsychopharma cology. 2004; 29:93-100. Recently more thorough BACKGROUND OF THE INVENTION understanding of 5-HT, receptor function in cognitive pro cesses and more accurate conceptions concerning possible 0002 The origin of pharmacological effect of novel drug pharmacophoric properties of their antagonists were substances is their ability to interact with serotonin 5-HT achieved. Holenz, J., Pauwels P. J., Diaz, J. L., Merce R., receptors playing the key role in treatment of central nervous Codony X., Buschmann H. Medicinal chemistry strategies to system diseases (CNS), in particular, Alzheimer's disease 5-HT, receptor ligands as potential cognitive enhancers and (AD), Huntington's disease, Schizophrenia, other neurode antiobesity agents. Drug Disc. Today. 2006: 11:283-299. generative diseases, cognitive disorders and obesity. This resulted in preparation of highly affine selective ligands 0003 Usefulness of selective antagonists of serotonin (“molecular tools'), and later to clinical candidates. At 5-HT, receptors for treating of CNS diseases, in particular, present a number of 5-HT, receptor antagonists are at various Schizophrenia, AD and other neurodegenerative diseases and phases of clinical investigation as potential drug Substances cognitive disorders was conclusively proved in preclinical for treatment of AD, Huntington's disease, Schizophrenia investigation and is regarded to be very perspective in medi (antipsychotic) and other neurodegenerative and cognitive cine of future. Holenz, J., Pauwels P. J., Diaz, J. L., Merce R., Codony X., Buschmann H. Medicinal chemistry strategies to diseases (Table 1) http://integrity. prous.com. 5-HT, receptor ligands as potential cognitive enhancers and antiobesity agents. Drug Disc. Today. 2006: 11:283-299. At TABLE 1 mammals these receptors are localized exclusively in central 5-HTA Receptor antagonists as drug candidates. nervous system (CNS), and mainly in parts of brain respon sible for training and memory. Gerard C., Martres M.-P. Clinical phase Lefevre K. Miguel M.-C., Verge D., Lanfumey L., Doucet Medicament of testing Developer Therapeutic group E., Hamon M., El Mestikawy S. Immuno-localisation of sero Dimebon TM Phase III Medivation (USA) Alzheimer's disease tonin 5-HT, receptor-like material in the rat central nervous treatmen SGS-518 Phase II Lilly, Saegis Cognitive diseases system. Brain Research. 1997: 746:207-219. Besides, it was treatmen shown Dawson L. A., Nguyen H. Q. Li P. The 5-HT(6) SB-742457 Phase II GlaxoSmithKline Alzheimer's disease receptor antagonist SB-271046 selectively enhances excita treatment; tory neurotransmission in the rat frontal cortex and hippoc Antipsychotic Dimebon Phase IIIa Medivation (USA) Huntington's disease ampus. Neuropsychopharmacology. 2001; 25:662-668), that treatmen 5-HT, receptors are modulators of the whole number of neu Dimebon Phase II (Russia) Schizophrenia romediator Systems including , noradrenergic, PRX-07034 Phase I Epix Pharm. Obesity treatment: and dopaminergic. Taking into account the fun Antipsychotic; Cognitive diseases damental role of these systems in normal cognitive processes treatmen and their dysfunction at neurodegeneration, exclusive role of SB-737OSOA Phase II GlaxoSmithKline Antipsychotic 5-HT, receptors in forming normal and “pathological” BWT-74316 Phase I Bioviltrum Obesity treatment memory becomes obvious. SAM-315 Phase I Wyeth Pharm. Alzheimer's disease treatmen 0004. In a large number of nowadays publications it was SYN-114 Phase I Roche, Synosis Cognitive diseases shown that blocking of 5-HT receptors leads to considerable Ther. treatmen enhancement of memory consolidation in various animal BGC-20-761 Preclinical BTG (London) Antipsychotic; models of training-memorizing-reproduction Foley A. G., Cognitive diseases treatmen Murphy K.J., Hirst W. D., Gallagher H. C., Hagan J.J., Upton FMPO Preclinical Lilly Antipsychotic N., Walsh F. S. Regan C. M. The 5-HT(6) receptor antagonist Dimebon TM Preclinical (Russia) Insult treatment SB-271046 reverses scopolamine-disrupted consolidation of a passive avoidance task and ameliorates spatial task deficits US 2011/003987.0 A1 Feb. 17, 2011

0005. Another attractive property of 5-HT, receptor 3-(sulfonyl)pyrazolo 1.5-alpyrimidines, as a result of which antagonists is their ability to suppress appetite that can lead to novel drug Substances which were 5-HT, receptor antago the development on their basis of essentially novel remedies nists were found. for overweight lowering and obesity treatment. Vicker S. P. Dourish C.T. Serotonin receptor ligands and the treatment of DISCLOSURE OF THE INVENTION obesity. Curr. Opin. Investig. Drugs. 2004; 5:377-388). This 0009. In the context of the invention, the terms are gener effect was confirmed in many investigations Holenz, J., Pau ally defined as follows: wels P. J., Diaz, J. L., Merce R., Codony X., Buschmann H. "' mean ligands being bound to receptors of definite Medicinal chemistry strategies to 5-HT, receptor ligands as type actively promote transferring their specific signal and by potential cognitive enhancers and antiobesity agents. Drug that cause the biological response of the cell. Disc. Today. 2006: 11:283-299. Davies S. L. Drug discovery Alkyl means an aliphatic hydrocarbon straight or branched targets: 5-HT receptor. Drug Future. 2005:30:479–495), its group with 1-12 carbon atoms. Branched means an alkyl mechanism is based on Suppression of Y-aminobutyric acid chain with one or more “lower alkyl substituents. Alkyl signaling by 5-HT, receptor antagonists and increasing of group may have one or more Substituents of the same or C.-melanocyte-stimulating hormone emission, that, finally, different structure (“alkyl substituent’) including halogen, results in lowering of food demand Woolley M. L. 5-htó alkenyloxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, receptors. Curr. Drug Targets CNS Neurol. Disord. 2004: cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, ary 3:59-79. Now two antagonists of 5-HT, receptors are at the loxy, aryloxycarbonyl, alkylthio, heteroarylthio, aralkylthio. first phase of clinical testing as drug candidates for obesity arylsulfonyl, alkylsulfonylheteroaralkyloxy, annelated het treatment (Table 1) http://integrity.prous.com. eroarylcycloalkenyl, annelated heteroarylcycloalkyl, anne 0006. In this context searching for new selective and effec lated heteroarylheterocyclenyl, annelated heteroarylhetero tive serotonin 5-HT, receptorantagonists seems to be original cyclyl, annelated arylcycloalkenyl, annelated arylcycloalkyl, and perspective approach to the development of novel drug annelated arylheterocyclenyl, annelated arylheterocyclyl, Substances for treating of a great number of neurological and alkoxycarbonyl, aralkoxycarbonyl, heteroaralkyloxycarbo neurodegenerative diseases and cognitive disorders. nyl or R'R''N R'R''NC(=O)—, R'R''NC 0007. There are many publications in scientific literature (=S)—, R'R''NSO , where R and R indepen concerning various biologically active Sulfonyl Substituted dently of each other represent “amino group' substituent, the aZaheterocycles, among them ligands of serotonin receptors. meanings thereof which are defined in this section, for For example, substituted 1-(2-aminoethyl)-4-(arylsulfonyl) example, hydrogen, alkyl, aryl, aralkyl, heteroaralkyl, hetero pyrazoles of general formula A1 were described as serotonin cyclyl or heteroaryl, or R." and R together with the 5-HT, receptor ligands WO 2003057674 A1 and substi N-atom, they are attached to, form through R" and R' tuted 7-amino-3-(sulfonyl)pyrazolo 1.5-alpyrimidines A2 as 4-7-membered heterocyclyl or heterocyclenyl. The preferred serotonin 5-HT, receptor antagonists EP 94.1994 A1, 1999 alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, iso-propyl. n-butyl, tent butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, A1 methoxycarbonylmethyl, ethoxycarbonylmethyl, benzy RI loxycarbonylmethyl and pyridylmethyloxycarbonylmethyl. \-At The preferred “alkyl substituents’ are cycloalkyl, aryl, het N 2 V eroaryl, heterocyclyl, hydroxy, alkoxy, alkoxycarbonyl, O aralkoxy, aryloxy, alkylthio, heteroarylthio, aralkylthio. \ 4 alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbo M R2 nyl, heteroaralkyloxycarbonyl or R'R''N R'R''NC R-N (=O)—, annelated arylheterocyclenyl, annelated arylhetero V cyclyl. R3 “Alkoxy' means an alkyl-O-group, wherein alkyl is defined A2 in this section. The preferred alkoxy groups are methoxy, R1 ethoxy, n-propoxy, iso-propoxy and n-butoxy. \-At Alkyloxycarbonyl means an alkyl-O C(=O) group, % V wherein alkyl is defined in this section. The representatives of R5 \ f O alkyloxycarbonyl are: methoxycarbonyl, ethoxycarbonyl, V n-butoxycarbonyl, iso-propoxycarbonyl, benzyloxycarbonyl and phenethyloxycarbonyl. Alkylthio or Alkylsulfanyl' means alkyl-5-group, wherein the meaning of alkyl is defined in this section. "Anxiolytic' (tranquilizer) means a medicament intended for treatment of anxious disorders. A1: Ar-alkyl, aryl; R and R—H, OH, alkyl, alkoxy; Rand Antagonists' mean ligands being bound to definite receptors R—H, alkyl, aryl. do not cause active cellular responses. Antagonists prevent A2: Araryl, heterocyclyl; R'=H, alkyl, alkylthio; R =H, linkage between agonists and receptors and by that block alkyl, halogen; R =H, alkyl, hydroxyalkyl: R* and R=H: specific receptor signal transmission. NR'R' piperazinyl. "’ means a medicament intended for treating 0008. With the aim of working out novel highly effective depression. neuroprotective medicaments the authors of the invention Antipsychotic’ means a remedy intended for treatment of carried out widespread investigation in the field of substituted psychotic diseases. US 2011/003987.0 A1 Feb. 17, 2011

"Aryl means an aromatic mono- or polycyclic system with ity which is an active ingredient of pharmaceutical composi 6-14 carbon atoms, predominantly from 6 to 10 C-atoms. tion employed in production and preparation of medica Aryl may have one or more “cyclic system substituents' of mentS. the same or different structure. Phenyl, substituted phenyl, “Medicament' is a compound or a mixture of compounds naphthyl, or substituted naphthyl are the representatives of representing pharmaceutical composition in the form oftab aryl groups. Aryl could be annelated with nonaromatic cyclic lets, capsules, injections, ointments and other drug products system or heterocycle. intended for restoration, improvement or modification of "Arylsulfonyl' means aryl-SO-group, wherein the meaning physiological functions at humans and animals, and for treat of aryl is defined in this section. ment and prophylaxis of diseases, diagnostics, anesthesia, Acyl' means H C(=O)—or alkyl-C(=O)—, cycloalkyl contraception, cosmetology and others. C(=O)—, heterocyclyl-C(=O)—, heterocyclylalkyl-C "Ligands' (from Latin ligo) represent chemical compounds (=O)—, aryl-C(=O)—, arylalkyl-C(=O)—, heteroaryl-C (Small molecule, peptide, protein, inorganic ion, and so on) (=O)—, heteroarylalkyl-C(=O)—groups, wherein alkyl-, capable to interact with receptors which convert this interac cycloalkyl-, heterocyclyl-, heterocyclylalkyl-, aryl-, aryla tion into specific signal. lkyl-, heteroaryl-, heteroarylalkyl- are defined in this section. “Neurodegenerative diseases' mean specific conditions and Acylamino” means acyl-NH-group, wherein the meaning of diseases, accompanied by damage and primary destruction of acyl is defined in this section. nervous cell populations in certain areas of central nervous "Halogen' means fluorine, chlorine, bromine and iodine. system. Neurodegenerative diseases include but are not lim Preference is given to fluorine, chlorine and bromine. ited by: AB; Parkinson's and Huntington's diseases (chorea); “Hydrate” means stoichiometric or nonstoichiometric com multiocular Sclerosis; cerebellar degeneracy; amyotrophic positions of the compounds or their salts with water. lateral Sclerosis; dementias with Lewy bodies; spinal muscu “Depression” means big depression; incidental, chronic and lar atrophy; peripherical neuropathy; spongy encephalitis recurring form of big depression; dysthymic disorder (dys (Creutzfeld-Jakob Disease); AIDS dementia; multi-infract thymia); cyclotymia; affective disorder; syndrome of sea dementia; frontotemporal dementias; leukoencephalopathy sonal affective disorder; bipolar disorder, including bipolar (spongy degeneration of white matter); chronic neurodegen disorders of I and II type; and other depressive disorders and erative diseases; cerebral crisis; ischemic, reperfusion and conditions. Depression also means the depressions accompa hypoxic brain damage; epilepsy; cerebral ischemia; glau nying AD, Vascular dementia; disorder of mood induced by coma; traumatic brain injury; Down's syndrome; encephalo and substances; schizoaffective disorder of depres myelitis; meningitis; encephalitis; neuroblastoma; schizo sive type; disorder of adaptation. Except for that, depression phrenia; depression. Moreover, neurodegenerative diseases includes depression of oncological patients; depression at include pathological States and disorders associated with Parkinson's disease; depressions after myocardial infarction; hypoxia, Substance abuse, causing dependability, under neu depressions of fruitless women; pediatric depression; postna rotoxins influence; infectious and oncological brain diseases tal depression; the depressions accompanying somatic, neu as well as neuronal damages associated with autoimmune and ralgic and other diseases endocrine diseases and others. “Substituent’ means a chemical radical attached to scaffold “Nootrops’ or "” (neurometabolic stimulates) are (fragment), for example, "alkyl Substituent”, “amino group medicaments taken for cognition enhancing. substituent”, “carbamoyl substituent, and “cyclic system “Psychic disorders, (psychic diseases) are diseases or dis substituent’, the meanings thereofare defined in this section. eased States associated with mental disturbance and/or men "Cognitive disorders or disorders of cognitive functions' tality frustration. “Psychic disorders' include affective disor mean disorders (weakening) of mental abilities including ders (bipolar affective disorders, big depression, hypomania, attentiveness, memory, mentality, cognition, education, Ver minor depression, maniacal syndrome, Cotard's syndrome, bal, mental, executive and creative abilities, time and space cyclothymia, Schizoaffective disorders and so on), intellec orientation; in particular, cognitive disorders associated with tual-mnestic disorders; manias (hypomania, graphomania, AD, Parkinson's and Huntington's diseases, senile dementia; kleptomania, compulsive shopping, mania of persecution, age-associated memory impairment, AAMI; dysmetabolic pornographomania, erotomania and so on); disorder of mul encephalopathy; psychogenous memory impairment; amne tiple personality, amentia, alcoholomania, deliration, sia; amnesic disturbances; transit global amnesia; dissocia delirium syndrome, hallucinosis, hallucinations, lucinatory tive amnesia; vascular dementia; light or mild cognitive effects, homicidomania, delirium, illusion, querulous para impairment (MCI); attention deficit hyperactivity disorder noiaclinical lycanthropy, macropsia, antagonistic delusion, (AD/HD); cognitive impairments, accompanying psychotic micropsia, narcomania; anorexia nervosa, oneiroid syn diseases, epilepsy, delirium, autism, psychosis, Down's Syn drome, paranoid, paranoia, paraphrenia, pseudohallucina drome, bipolar disorders and depression: AIDS-associated tions, psychosis, Cotard's syndrome, Schizoaffective disor dementia; dementias at hypothyroidism; dementia connected der, Schizotypical disorder, Schizophrenia, Schizoaffective with alcohol, Substances causing dependability and neurotox psychosis disorder, Schizophrenomorphic disorder, ins; dementia accompanying neurodegenerative diseases, for Shrebera's syndrome, Daniel Paul's syndrome), phobias example, cerebellar degeneracy and amyotrophic lateral scle (agarophobia, arachnephobia, autophobia, Verminophobia, rosis; cognitive disturbances connected with cerebral crisis, hydrosophobia, hydrophobia, demophobia, Zoophobia, car infectious and oncological brain diseases as well as traumatic cinophobia, claustrophobia, climacophobia, Xenophobia, brain injury; cognitive function damages associated with misophobia, radiophobia, photophobia: Skoliephobia, Scoto autoimmune and endocrine diseases, and others. phobia, social phobia, tetraphobia, triskaidekaphobia, eroto "Drug Substance” means a physiologically active compound phobia); alcoholic psychosis, alcoholic palimpsest, allot of synthetic or other (biotechnological, vegetable, animal, riophagy, aphasia, graphomania, fugue State, microbe and so on) origins exhibiting pharmacological activ dissociative disorders; dysphorias, internet-dependences, US 2011/003987.0 A1 Feb. 17, 2011 hypochondria, hysteria, kopophobia, delirium of persecution, "Pharmaceutical composition” means a composition com melancholy, misanthropy, obsession, panic attacks, Asperg prising, at least, one of compounds of general formula 1 or 2 er's syndrome, Capgras Syndrome, Munchausen's Syn and, at least, one of components selected from pharmaceuti drome, Retta's syndrome, Fregoly’s syndrome, syndrome of cally acceptable and pharmacologically compatible fillers, attention and hyperactivity deficit, obsessive-compulsive dis Solvents, diluents, auxiliary, distributing and sensing agents, order, syndrome of chronic narcotization consequences, Syn delivery agents, such as preservatives, stabilizers, disintegra drome of psychic automatism, syndrome of infantile autism, tors, moisteners, emulsifiers, Suspending agents, thickeners, madness, taphophilia, anxiety conditions, Hikikomory's Syn Sweeteners, flavoring agents, aromatizing agents, antibacte drome, erotographomania and so on. rial agents, fungicides, lubricants, and prolonged delivery “Psychotic diseases” are all types of schizophrenia; schizoaf controllers, the choice and suitable proportions of which fective psychosis; Schizotypical disorders; schizoaffective depend on the nature and way of administration and dosage. disorders, including bipolar and depressive types; delirious Examples of Suitable Suspending agents are: ethoxylated disorders including reference delusion, delusion of persecu isostearyl alcohol, polyoxyethene, sorbitol and sorbitol , tion, megalomania, delusion of jealousy, erotomania, and microcrystalline cellulose, aluminum metahydroxide, bento also hypochondriacal, Somatic, mixed and not differentiated nite, agar-agar and tragacant and mixtures thereof as well. delirium; short-time psychotic disorders; induced psychotic Protection against microorganism action can be provided by frustration; induced by Substances psychotic frustration; and various antibacterial and antifungal agents, such as: parabens, other psychotic disorders. chlorobutanol, Sorbic acid, and similar compounds. Compo “Receptors' (from Latin recipere) represent biological mac sition may also contain isotonic agents, such as: Sugar, romolecules located either on cytoplasm membrane of cellor Sodium chloride, and similar compounds. Prolonged effect of intracellular, capable specifically interact with restricted the composition may be achieved by agents slowing down number of physiologically active compounds (ligands) and absorption of the active ingredient, for example, aluminum transform the signal of this interaction into definite cellular monostearate and gelatin. Examples of Suitable carriers, Sol response. vents, diluents and delivery agents include water, ethanol, "Sulfanyl means R S-group, wherein R represents alkyl, polyalcohols and their mixtures, natural oils (such as olive cycloalkyl, aryl, heteroaryl, heterocyclyl, annelated het oil) and injection-grade organic esters (such as ethyl oleate). eroarylcycloalkenyl, annelated heteroarylcycloalkyl, anne Examples of fillers are: lactose, milk-Sugar, sodium citrate, lated heteroarylheterocyclenyl, annelated heteroarylhetero calcium carbonate, calcium phosphate and the like. Examples cyclyl, annelated arylcycloalkenyl, annelated arylcycloalkyl, of disintegrators and distributors are: starch, alginic acid and annelated arylheterocyclenyl, annelated arylheterocyclyl, the its salts, and silicates. Examples of Suitable lubricants are: meanings of which are defined in this section. Stearate, sodium lauryl Sulfate, talc and polyeth "Sulfonyl' means R SO-group in which R represents ylene glycol of high molecular weight. Pharmaceutical com alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, annelated position for peroral, Sublingval, transdermal, intramuscular, heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, intravenous, Subcutaneous, local or rectal administration of annelated heteroarylheterocyclenyl, annelated heteroarylhet active ingredient, alone or in combination with another active erocyclyl, annelated arylcycloalkenyl, annelated arylcy compound may be administered to humans and animals in cloalkyl, annelated arylheterocyclenyl, annelated arylhetero standard administration form, or in mixture with traditional cyclyl the meanings of which are defined in this section. pharmaceutical carriers. Suitable standard administration “Therapeutic kit' is a simultaneously administered combina forms include peroral forms such as tablets, gelatin capsules, tion of two or more drug substances with different mechanism pills, powders, granules, chewing-gums and peroral Solutions of pharmacological action and aimed at different biotargets or Suspensions, for example, therapeutic kit; Sublingval and taking part in pathogenesis of the disease. transbuccal administration forms; aerosols; implants; local, "Anxiety disorders' means generalized (inconcrete) anxiety; transdermal. Subcutaneous, intramuscular, intravenous, intra acute uncontrolled anxiety; panic disorder, phobia, for nasal or intraocular forms and rectal administration forms. example, agoraphobia (acute fear of crowded place) or social "Pharmaceutically acceptable salt' means relatively nontoxic (acute fear of humiliation at presence of other people) or any both organic and inorganic salts of acids and bases disclosed other phobia (acute fear of particular subjects, animals or in this invention. Salts could be prepared in situ in processes situations, in the form of phobia of height, of medical proce of synthesis, isolation or purification of compounds or they dures, lifts, open space etc.); an obsessional condition (ob could be prepared specially. In particular, Salts of bases could sessive-compulsive disorder); posttraumatic stress disorder be prepared starting from purified bases disclosed in the and acute stress disorder. Besides, anxiety disorders include invention and Suitable organic or mineral acid. Examples of anxiety conditions induced by alcohol or Substances; anxiety salts prepared in this manner include hydrochlorides, hydro under adaptation; as well as mixed forms of anxiety disorders bromides, Sulfates, bisulfates, phosphates, nitrates, acetates, and depression. oxalates, Valeriates, oleates, palmitates, Stearates, laurates, "Schizophrenia' means all known types, forms and variants borates, benzoates, lactates, p-toluenesulfonates, citrates, of the disease, including: simple, hebephrenic, paranoid, maleates, fumarates. Succinates, tartrates, methane Sulpho hypertoxic (pyretic), catatonic, schizoaffective, residual or nates, malonates, salicylates, propionates, ethane Sulpho not differentiated schizophrenia and/or the forms of schizo nates, sulfonates, sulfamates and the like (Detailed phrenia defined in classification of American Psychiatric description of such salt properties is given in: Berge S. M., et Association (American Psychiatric Association, in: Diag al., “Pharmaceutical Salts' J. Pharm. Sci., 1977, 66:1-19). nostic and Statistical Manual of Mental Disorders, IV Edi Salts of disclosed acids may be prepared by reaction of puri tion, Washington D.C. 2000) or in International classification fied acids specifically with suitable base; moreover, metal (International Statistical Classification of Diseases and salts and amine salts may be synthesized too. Metal salts are Related Health Problems) or any other known forms. salts of sodium, potassium, calcium, barium, magnesium, US 2011/003987.0 A1 Feb. 17, 2011 lithium and aluminum; sodium and potassium salts being 0011. The preferred novel compounds are substituted preferred. Suitable inorganic bases from which metal salts 3-phenylsulfonyl-6,7,8,9-tetrahydropyrazolo 1.5-alpyrido can be prepared are: Sodium hydroxide, carbonate, bicarbon 4.3-epyrimidines of the general formula 1.1 and substituted ate and hydride; potassium hydroxide, carbonate and bicar 3-phenylsulfonyl-5,6,7,8-tetrahydropyrazolo 1.5-alpyrido bonate, lithium hydroxide, calcium hydroxide, magnesium 4.3-dpyrimidines of the general formula 2.1 and pharma hydroxide, hydroxide. Organic bases Suitable for prepa ceutically acceptable salts and/or hydrates thereof. ration of disclosed acid salts are amines and amino acids the basicity of which is sufficient enough to produce stable salt and Suitable for use in medical purposes (in particular, they 1.1 are to have low toxicity). Such amines include ammonia, RI e methylamine, dimethylamine, trimethylamine, ethylamine, O diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, , ethylpiperidine, tris(hy -S-Sufi droxymethyl)aminomethane and the like. Besides, salts can \, f \, be prepared using some tetraalkylammonium hydroxides, Such as holine, tetramethylammonium, tetraethylammonium, and the like. Amino acids may be selected from the main aminoacids—lysine, ornithine and arginine. (SN R2 A. 0010. The subject of the present invention is the novel R3 compounds—substituted 3-sulfonyl-6,7,8,9-tetrahydropyra Zolo 1.5-alpyrido4,3-epyrimidines of the general formula 1 and substituted 3-sulfonyl-5,6,7,8-tetrahydropyrazolo 1.5-a pyrido4.3-dpyrimidines of the general formula 2 and phar 2.1 maceutically acceptable salts and/or hydrates thereof. R O e- I 1 y NJR' \, f \,

N A R3

wherein: R", RandR have the above meanings; R" represents hydrogen, one or two optionally identical halo gens, hydroxyl group optionally substituted with C-C alkyl. 0012. The preferred novel compounds are substituted 2-methylsulfanyl-3-sulfonyl-6,7,8,9-tetrahydropyrazolol, 5-alpyrido4.3-epyrimidines of the general formula 1.2 and substituted 2-methylsulfanyl-3-sulfonyl-5,6,7,8-tetrahydro pyrazolo 1.5-alpyrido4.3-dipyrimidines of the general for mula 2.2 and pharmaceutically acceptable salts and/or hydrates thereof

1.2

Hics O e % \ N JiI R' wherein: \ f W Arrepresents optionally substituted aryl or optionally substi N O tuted heterocyclyl: R" represents hydrogen, optionally substituted lower C-C, N alkyl, Substituted hydroxyl group, Substituted Sulfanyl group; \ / N R2 R represents hydrogen or optionally substituted C-C alkyl; A R represents hydrogen, optionally substituted C-C alkyl or R3 tert-butyloxycarbonyl.

US 2011/003987.0 A1 Feb. 17, 2011

0014. The subject of the present invention is also a method representing at least one 3-sulfonyl-6,7,8,9-tetrahydropyra for the preparation of novel substituted 3-sulfonyl-tetrahy Zolo 1.5-alpyrido4.3-epyrimidine of the general formula dropyrazolo 1.5-alpyrido-pyrimidines of the general formu 1.3-sulfonyl-5,6,7,8-tetrahydropyrazolo 1.5-alpyrido4.3-d las 1 and 2 by interaction of 3-amino-4-sulfonyl-2H-pyra pyrimidine of the general formula 2 and pharmaceutically Zoles of the general formula 3 with B-diketones of the general acceptable salt and/or hydrate thereof. formula 4 and Subsequent isolation or separation of com 0018. The subject of the present invention is also a phar pounds 1 and 2 according to the scheme given below. maceutical composition interacting with serotonin 5-HT receptors for prophylaxis and treatment of various conditions and diseases of CNS in humans and warm-blooded animals comprising a pharmaceutically effective amount of a novel drug Substance representing at least one of 3-sulfonyl-6.7.8, 9-tetrahydropyrazolo 1.5-alpyrido4.3-epyrimidines of the general formula 1 or 3-sulfonyl-5,6,7,8-tetrahydropyrazolo 1.5-alpyrido4.3-dpyrimidines of the general formula 2 and pharmaceutically acceptable salts and/or hydrates thereof. 0019 Pharmaceutical compositions may include pharma ceutically acceptable excipients. Pharmaceutically accept able excipients mean diluents, auxiliary agents and/or carriers applied in the sphere of pharmaceutics. According to the invention a pharmaceutical composition together with a drug Substance of general formulas 1, 2 may include other active ingredients provided that they do not give rise to undesirable effects, such as allergic reactions. 0020. If needed, according to the present invention phar maceutical compositions could be used in clinical practice in various forms prepared by mixing the said compositions with traditional pharmaceutical carries, for example, peroral forms (such as, tablets, gelatinous capsules, pills, Solutions or Sus pensions); forms for injections (such as, solutions or suspen sions for injections, or a dry powder for injections which requires only addition of water for injections before utiliza tion); local forms (such as, ointments or Solutions). 0021. According to the present invention the carriers used in pharmaceutical compositions represent carriers which are used in the sphere of pharmaceutics for preparation of com monly used forms. Binding agents, greasing agents, disinte grators, solvents, diluents, stabilizers, Suspending agents, colorless agents, taste flavors are used for peroral forms; antiseptic agents, Solubilizers, stabilizers are used in forms for injections; base materials, diluents, greasing agents, anti septic agents are used in local forms. 0022. The subject of the present invention is also a method for the preparation of novel pharmaceutical composition by mixing withinert excipient and/or solvent of a drug Substance which is at least one of 3-sulfonyl-6,7,8,9-tetrahydropyrazolo 1.5-alpyrido4,3-epyrimidines of the general formula 1 or 3-sulfonyl-5,6,7,8-tetrahydropyrazolo 1.5-alpyrido4.3-d pyrimidines of the general formula 2 or pharmaceutically acceptable salts and/or hydrates thereof. 0023 The subject of the present invention is also a medi cament in the form of tablets, capsules, or injections, placed wherein: in pharmaceutically acceptable packing including a drug Sub Ar, R, R and Rare all as mentioned above. stance which is at least one of 3-sulfonyl-6,7,8,9-tetrahydro 0015 The subject of the present invention is the develop pyrazolo 1.5-alpyrido4.3-epyrimidines of the general for ment of novel serotonin 5-HT, receptor antagonists. mula 1 or 3-sulfonyl-5,6,7,8-tetrahydropyrazolo 1.5-a 0016. The subject in view is achieved by serotonin 5-HT pyrido4.3-dpyrimidines of the general formula 2 and receptor antagonists, which are substituted 3-sulfonyl-6,7,8, pharmaceutically acceptable salts and/or hydrates thereof, or 9-tetrahydropyrazolo 1.5-alpyrido4.3-epyrimidines of the a pharmaceutical composition comprising the said drug Sub general formula 1 and substituted 3-sulfonyl-5,6,7,8-tetrahy stance, intended for prophylaxis and treatment of pathologi dropyrazolo 1.5-alpyrido4.3-dipyrimidines of the general cal conditions and diseases of CNS, pathogenesis of which is formula 2 and pharmaceutically acceptable salts and/or associated with dysfunction of 5-HT, receptors activation. hydrates thereof. 0024. According to the invention the preferable medica 0017. The subject of the present invention is also a drug ment is a medicament intended for treatment and prophylaxis Substance for pharmaceutical compositions and medicaments of cognitive disorders and neurodegenerative disease. US 2011/003987.0 A1 Feb. 17, 2011

0025. According to the invention the preferable medica nooxidase inhibitors MAO-B and/or MAO-A (for example, ment is a medicament intended for treatment and prophylaxis Rasagiline); antiamyloidogenic drugs (for example, Tramip of Alzheimer's disease and Huntington's diseases. rosate); lowering B-amyloidal neurotoxicity compounds (for 0026. According to the invention the preferable medica example, Indole-3-propionic acid); Y- and/or B-secretase ment is a medicament intended for treatment and prophylaxis inhibitors; M1-muscarinic receptor agonists (for example, of psychotic disorders and Schizophrenia. Cevimeline); metalhelates (for example, Clioquinol); GABA 0027. According to the invention the preferable medica (A) receptor antagonists (for example, CGP-36742); mono ment is a medicament, representing a for mental clonal antibodies (for example, BapineuZumab); antioxi ability enhancing. dants; neurotrophic agents (for example, Cerebrolisine); 0028. According to the invention the preferable medica (for example, Imipramine, Sertraline and oth ment is a medicament, representing an anxiolytic for treat ers) and others. ment and prophylaxis of anxiety states and disorders. 0034. According to the invention the preferable therapeu 0029. According to the invention the preferable medica tic kit is a therapeutic kit for overweight lowering and obesity ment is also a medicament for treatment and prophylaxis of treatment, comprising a novel drug Substance which is at least obesity. one 3-sulfonyl-6,7,8,9-tetrahydropyrazolo 1.5-alpyrido4.3- 0030 The subject of the present invention is a therapeutic elpyrimidine of the general formula 1 and/or 3-sulfonyl-5.6, kit intended for treatment and prophylaxis of various diseases 7,8-tetrahydropyrazolo 1.5-alpyrido4.3-dpyrimidine of the pathogenesis of which is associated with serotonin 5-HT general formula 2 or pharmaceutically acceptable salt and/or receptors in humans and animals, including a novel drug hydrate thereof, or a novel pharmaceutical composition, or a substance, which is at least one 3-sulfonyl-6,7,8,9-tetrahy novel medicament. dropyrazolo 1.5-alpyrido4.3-epyrimidine of the general 0035. The therapeutic kit for overweight lowering and formula 1 or 3-sulfonyl-5,6,7,8-tetrahydropyrazolo 1.5-a obesity treatment along with drug Substances disclosed in the pyrido4.3-dpyrimidine of the general formula 2 or pharma invention, may include other active ingredients such as: ceutically acceptable salt and/or hydrate thereof, or a novel anorectic drugs (for example, Fepranon, Desopimon, Masin pharmaceutical composition, comprising the said drug Sub dole), hormone drugs (for example, Tireoidine), hypolipi stance, or a novel medicine, containing the said novel drug demic means Such as fibrates (for example, Fenofibrate), Substance, or a novel pharmaceutical composition. statines (for example, Lovastatine, Simvastatine, Pravastatine 0031. According to the invention the preferable therapeu and Probucol), and also hypoglycemic drugs (sulfonylurea— tic kit is a therapeutic kit for treatment and prophylaxis of for example, Butamide, Glibenclamide; biguanidines—for neurological disorders, neurodegenerative and cognitive dis example, Buformine, Metamorphine) and drugs with some eases in humans and animals comprising a novel drug Sub other , such as CB-1 recep stance which is at least one 3-sulfonyl-6,7,8,9-tetrahydropy tor antagonists (Rimonabant), inhibitors of norepinephrine razolo 1.5-alpyrido4.3-epyrimidine of the general formula and serotonin reuptake (Sibutramine), inhibitors of ferments 1 or 3-sulfonyl-5,6,7,8-tetrahydropyrazolo 1.5-alpyrido4.3- offatty acids synthesis (Orlistat) and others, along with anti dpyrimidine of the general formula 2 or pharmaceutically oxidants, food additives and others. acceptable salt and/or hydrate thereof, or a novel pharmaceu 0036. The subject of the present invention is also a method tical composition, or a novel medicament. for prophylaxis and treatment of various diseases of central 0032. According to the invention the preferable therapeu nervous system pathogenesis of which is associated with tic kit is a therapeutic kit for treatment and prophylaxis of serotonin 5-HT, receptors in humans and animals, among Alzheimer's and Huntington's diseases, psychotic disorders, them neurological disorders, neurodegenerative and cogni Schizophrenia, anxiety states and disorders, mental ability tive diseases, anxiety states and disorders, mental ability enhancing, hypoxia-ischemia, hypoglycemia, convulsive enhancing, for overweight lowering and obesity treatment, states, braininjuries, lathyrism, amyotrophic lateral Sclerosis, which consists in introduction to a warm-blooded animal or a obesity or insult comprising a novel drug Substance, or a human being a novel drug Substance, or a novel pharmaceu novel pharmaceutical composition, or a novel medicament. tical composition, or a novel medicament, or a novel thera 0033. Therapeutic kits for prophylaxis and treatment of peutic kit comprising at least one 3-sulfonyl-6,7,8,9-tetrahy various diseases pathogenesis of which is associated with dropyrazolo 1.5-alpyrido4.3-epyrimidine of the general serotonin 5-HT, receptors in humans and animals, among formula 1 or 3-sulfonyl-5,6,7,8-tetrahydropyrazolo 1.5-a them neurological disorders, neurodegenerative and cogni pyrido4.3-dpyrimidine of the general formula 2, orpharma tive diseases in humans and animals, for prophylaxis and ceutically acceptable salt and/or hydrate thereof. treatment of Alzheimer's disease, Huntington's disease, psy 0037. The medicaments could be introduced peroral or chotic disorders, Schizophrenia, hypoxia-ischemia, hypogly parenterally, for example, intravenously, Subcutaneously, cemia, convulsive states, brain injuries, lathyrism, amyo intraperitoneally or locally. Clinical dose of a drug Substance, trophic lateral sclerosis, obesity or insult, along with drug or a pharmaceutical composition, or medicament comprising Substances disclosed in the invention, may include other at least one 3-sulfonyl-6,7,8,9-tetrahydropyrazolo 1.5-apy active ingredients such as: nonsteroidal anti-inflammatory rido4.3-epyrimidine of the general formula 1 or 3-sulfonyl drugs (Orthophene, Indomethacin, Ibuprophen and others); 5,6,7,8-tetrahydropyrazolo 1.5-alpyrido4,3-dipyrimidine acetyl inhibitors (Tacrine, Amiridine, of the general formula 2 or pharmaceutically acceptable salt FiZostigmine, Aricept, Phenserine and others); estrogens (for and/or hydrate thereof, may be corrected depending on: thera example, Estradiol); NMDA-receptor antagonists (for peutic efficiency and bio-accessibility of active ingredients in example, , Neramexane); nootropic drugs (for patients organism, rate of their exchange and removal from example, Pyracetam, Feni but and others); AMPA receptor organism, and age, sex, and severity of patient's symptoms. modulators (for example, Ampalex); antagonists of cannab Thus, the daily intake for adults normally being 10-500 mg. inoid receptors CB-1 (for example, Rimonabant); monoami preferably 50-300 mg. Accordingly, the above effective US 2011/003987.0 A1 Feb. 17, 2011 10 doses are to be taken into consideration while preparing medi Example 1 cament of the present invention, each dose unit of the medi cament contains 10-500 mg of a drug Substance of the gen 0039. The general method for preparation of substituted eral formulas 1, 2 or its pharmaceutically acceptable salt 3-sulfonyl-tetrahydropyrazolo 1.5-a-pyrido-pyrimidines of and/or hydrate, preferably 50-300 mg. Following the instruc the general formulas 1, 2. tions of physician or pharmacist, the medicaments may be taken several times over specified periods of time (preferably, 0040. A mixture of 0.005 mol of aminopyrazole 3 and from one to six times). 0.0055 mol of the corresponding B-dicarbonyl compound 4 in 5 ml of acetic acid was boiled for 4 hours. After cooling the BEST EMBODIMENT OF THE INVENTION solid precipitated was filtered off, washed with methanol and 0038. The specific examples given below describe synthe water. If necessary, the product was Subjected to recrystalli sis of 3-sulfonyl-6,7,8,9-tetrahydropyrazolo 1.5-alpyrido4. Zation from the proper solvent, or chromatographic purifica 3-epyrimidines of the general formula 1.3-sulfonyl-5,6,7,8- tion or chromatographic separation. Yield of 3-sulfonyl-tet tetrahydropyrazolo 1.5-alpyrido4.3-dpyrimidines of the rahydropyrazolo 1.5-a-pyrido-pyrimidines is within limits general formula 2 and pharmaceutically acceptable salts and/ of 30%-85%. Table 2 represents some examples of novel or hydrates thereof, biological tests thereof. They illustrate 3-sulfonyl-tetrahydropyrazolo 1.5-apyrido-pyrimidines of but not limit the scope of the invention. the general formulas 1, 2, their LCMS and NMR data.

TABLE 2 Substituted 3-sulfonyl-6,7,8,9-tetrahydropyrazolo.1,5-apyrido4,3-epyrimidines of the general formula 1 and substituted 3-arylsulfonyl-5,6,7,8-tetrahydropyrazolo.1,5- rido4,3-dipyrimidines of the general formula 2

LCMS, mz N Formula Mol, w (M + 1) NMR 1(2) sN 375.47 376

o2S1leO s N S HCM N.N - N.N Nea N NCH,

1.1(1) 3.28.40 329

-2' N s n HC M N-N-21

NH

1.1(2) CH 342.42 343 N4 \N 0 \O

US 2011/003987.0 A1 Feb. 17, 2011 12

TABLE 2-continued

Substituted 3-sulfonyl-6,7,8,9-tetrahydropyrazolo.1,5-apyrido4,3-epyrimidines of the general formula 1 and substituted 3-arylsulfonyl-5,6,7,8-tetrahydropyrazolo.1,5- apyrido4,3-dpyrimidines of the general formula 2

LCMS, mz No Formula Mol, w (M + 1) NMR

1.1(6) CH 376.87 377 O

N f O Cl

1.1 (7) CH3 O 376.87 377

\ 0 A-O\, Cl

1.1 (8) SH3 390.89 391

N J.-A-OW \, Cl

1.1 (9) 428.51 429

N O CH3

CH, CH3

US 2011/003987.0 A1 Feb. 17, 2011

TABLE 2-continued Substituted 3-sulfonyl-6,7,8,9-tetrahydropyrazolo.1,5-apyrido4,3-epyrimidines of the general formula 1 and substituted 3-arylsulfonyl-5,6,7,8-tetrahydropyrazolo.1,5- rido4.3-dipwrimidines of the general formula 2

LCMS, mz No Formula Mol, w (M + 1) NMR 2.2(4) 388.51 389

-2' N s n S M \ , N H3C N- 21 YCH, CH

Example 2 (1.5 nM H Lysergic acid diethylamide) without and in the presence of investigated compounds for 120 min at 37°C. in 0041 Antagonistic activity test of compounds of the gen the medium consisting of mM Tris-HCl, pH 7.4, 150 mM eral formulas 1 and 2 towards 5-HT, receptors. Compounds NaCl, 2 mM Ascorbic Acid, 0.001% BSA. After the incuba of general formulas 1 and 2 were tested for their ability to tion the samples were filtered in vacuo on glass-microfiber prevent 5-HT, receptors activation by serotonin. HEK 293 filters G/F (Millipor, USA), filters were washed three times cells (kidney cells of human's embryo) with artificially with cold solution of the medium and radioactivity was mea expressed 5-HT, receptor, activation of which by serotonin sured by scintillation counter MicroBeta 340 (PerkinElmer, leads to increasing the concentration of intracellular cAMP USA). Nonspecific binding which made up 30% of the over were used. Intracellular cAMP content was determined using all binding was determined by incubation of the membrane reagent kit LANCE cAMP (PerkinElmer) according to the preparations with radioligand in the presence of 5 uM Sero method described by the manufacturer of the kit http://las. tonin (5-HT). Methiothepin was used as a positive control. perkinelmer.com/content/Manuals. Binding of the tested compounds with the receptor was deter Effectiveness of compounds was estimated by their ability to mined by their ability to displace the radioligand and was reduce the content of intracellular cAMP induced by seroto expressed in percent of displacement. The percent of dis 1. placement was calculated according to the following equa 0042. The tested substituted 3-sulfonyl-tetrahydropyra tion: Zolo 1.5-alpyrido-pyrimidines of the general formulas 1, 2 (10 uM solutions) inhibited serotonin 5-HT receptors at 80-100% and in the setting of functional assay exhibited high % = TA - CA : antagonistic activity. TA - NA 100, Example 3 wherein: TA was overall radioactivity in the presence of 0043 Activity test of serotonin 5-HT, receptor antago radioligand only, CA was radioactivity in the presence of nists of the general formulas 1, 2 in the setting of competitive radioligand and tested compound and NA was radioactivity binding to serotonin 5-HT, receptors. in the presence of radioligand and Serotonin (5uM). For the 0044 Screening of the disclosed compounds for their compounds investigated values of pKi(pKi=-lg Ki) were cal potential ability to interact with serotonin 5-HT, receptors culated according to the equation shown below: was carried out by the method of radioligand binding. For this purpose membrane species were prepared from HeLa cells expressing recombinant human 5-HT, receptors, by means of wherein: ICso the concentration of the tested compound in cells homogenization in glass homogenizer with Subsequent nM, at which it displaces 50% of the ligand bound to the separation of plasmatic membranes from cell nucli, mito receptor; L-ligand concentration; K, ligand dissocia chondria's and cell wreckages by differential centrifugation. tion constant. Determination of tested compounds binding to 5-HT, recep 0045. The investigated substituted 3-sulfonyl-tetrahydro tors was carried out according to the method described in pyrazolo 1.5-alpyrido-pyrimidines of the general formulas 1, Monsma FJ Jr. Shen Y. Ward RP. Hamblin MW and Sibley 2 exhibit high 5-HT, receptor affinity (Table 3). D R Cloning and expression of a novel serotonin receptor 0046 Table 3. ICs and K values of 3-sulfonyl-tetrahy with high affinity for tricyclic psychotropic drugs. Mol. Phar dropyrazolo 1.5-alpyrido-pyrimidines of the general macol. 43:320-327, 1993. In the preferred embodiment the formulas 1, 2 in the setting of competitive binding to membrane preparations were incubated with the radioligand serotonin 5-HT receptors. US 2011/003987.0 A1 Feb. 17, 2011 19

the animal was taken back to its homecage. In 22-24 hours the same animal was placed again in the light section of the shuttle chamber and latent period of its first entry into the dark No ICso, IM K. LM section, the total time of its stay in the light section and the 1.1(3) O.O13 O.O600 number of entries into the dark section, was registered. Each 1.1(1) O.OO461 O.OO214 monitoring lasted for 5 minutes. 1.2(2) O.O166 O.OO77 0.052 Testing was carried out during the day time in iso 1.2(3) O.0769 0.0357 1.2(6) O.O239 O.O111 lated laboratory using white noise at level of about 70 decibel 2.2(2) O.801 0.372 above human hearing threshold. 2.2(3) >1 0053 Scopolamine causes disturbance of training (memory loss) that results in increased latent period for the first entry into dark section, longer stay in light section, and in Example 4 decreased number of entries into dark section. 0054 The ability of compound 1.2(2) to enhance memory 0047 Preparation of a medicament in a tabloid form. 1600 disturbed by Scopolamine is regarded as manifestation of its mg of starch, 1600 mg of ground lactose, 400 mg of talk and nootropic properties. The data obtained confirm nootropic 1000 mg of 2-methylsulfanyl-5-methyl-3-phenylsulfonyl-6, action of active ingredient 1.2(2). 7,8.9-tetrahydropyrazolo 1.5-alpyrido4.3-epyrimidine hydrochloride 1.2(2) were mixed together and pressed into Example 8 bar. The resultant bar was comminuted into granules and 0055 Nootropic action (memory enhancement disturbed sifted through sieve to collect granules of 14-16 mesh. The by MK-801) of compounds of general formulas 1 and 2 in the granules thus obtained were shaped into tablets of suitable test"Passive Avoidance of mice in the Shuttle Chamber. The form weighing 560 mg each. testing was carried out as in example 7. On the first day of Example 5 testing 30 minutes before training the mice were injected intraintestinally with physiological solution of MK-801 (0.1 0048 Preparation of a medicament in the shape of cap mg/kg). In parallel, physiological solution of MK-801 in sules. 2-Methylsulfanyl-5-methyl-3-phenylsulfonyl-6,7,8,9- combination with active ingredient 1.2(2) was injected tetrahydropyrazolo 1.5-alpyrido4.3-epyrimidine hydro intraintestinally to independent groups of mice before train chloride 1.2(2) and lactose powder were carefully mixed in 1ng. ratio 2:1. The resultant powdery mixture was packed into 0056. The results obtained testify the ability of active gelatin capsules of Suitable size by 300 mg to capsule. ingredient 1.1(3).HCl to produce nootropic effect. Example 6 Example 9 0049 Preparation of a Medicament in Form of Composi 0057 Anxiolytic (tranquilizing) action of compounds of tions for Intramuscular, intraperitoneal or hypodermic injec general formulas 1 and 2 in the test “Mice Behavior in the tions. 500 mg of 2-methylsulfanyl-5-methyl-3-phenylsulfo Elevated Plus Maze'. The length of each arm of the maze is 30 nyl-6,7,8,9-tetrahydropyrazolo 1.5-alpyrido4.3-e cm, width is 5 cm, and height of walls is 15 cm. Two opposite pyrimidine hydrochloride, 1.2(2) 300 mg of chlorobutanol. 2 arms are closed from both sides and end faces by transparent ml of propylene glycol, and 100 ml of injectable water were walls, the other two arms are lit and opened. A mouse was mixed together. The resultant solution was filtered and placed placed in the center of maze, and for the next five minutes the into 1 ml ampoules, which were sealed and sterilized in number of entries into opened and closed arms and the time autoclave. spent in each type of arms were registered. These data were used to calculate the preference indexes for opened arms as Example 7 ratio of the number of opened arm entries, as well as the total time spent there to the whole number of entries to all arms and 0050 Nootropic action of the compounds of the general the total time spent there. The animals usually avoid opened formulas 1 and 2 (enhancement of memory disturbed by arms (the preference index is between 0.2 and 0.3). Com Scopolamine) in the test “Passive Avoidance of mice in the pounds with tranquilizing action increase this index up to Shuttle Chamber. A shuttle chamber (Ugo Basile, Italy) 0.5-0.6 or even more and reduce the number of defecations consisted of two sections was used. The walls of one section without changing the overall motion activity of the mice (the were opaque while the other section had transparent cover. total number of entries to the arms). The sections were connected through a hole which could be 0058. The results obtained testify that active ingredient overlapped by vertical door. The floor was made of transverse 1.2(2) exhibits anxiolytic (tranquilizing) action which is com metal bars on which DC current impulses could be fed. parable with the activity of Buspirone and Lorasepam. Experiments were carried out in aged male mice of BALB/c line weighing 20-24 grams. INDUSTRIAL APPLICABILITY 0051. On the first day of testing 30 minutes before training mice were injected intraintestinally with physiological Solu 0059. The invention could be use in medicine, veterinary, tion, Scopolamine (0.3 mg/kg) or Scopolamine in combina biochemistry. tion with active ingredient 1.2(2). Each group consisted of at 1. Substituted 3-arylsulfonyl-6,7,8,9-tetrahydropyrazolo least 8 animals. The animals were placed in the light section, 1.5-alpyrido4.3-epyrimidines of the general formula 1 and and latent period of the first entry into the dark chamber was substituted 3-arylsulfonyl-5,6,7,8-tetrahydropyrazolo 1.5-a registered. Then the vertical door was closed and the animal pyrido4.3-dpyrimidines of the general formula 2; or phar was punished by 0.6 mA DC current for 3 seconds. After that maceutically acceptable salts and/or hydrates thereof US 2011/003987.0 A1 Feb. 17, 2011 20

-continued 2.1 RI O e N% \ NJR'I WN f \O R2 \ / N

N A R3

wherein: R", RandR have the above meanings; R" is hydrogen, one or two optionally identical halogens, hydroxyl group optionally Substituted with C-C alkyl. 3. Compounds of claim 2 are substituted 2-methylsulfanyl 3-phenylsulfonyl-6,7,8,9-tetrahydropyrazolo 1.5-alpyrido 4.3-epyrimidines of general formula 1.2 and Substituted 2-methylsulfanyl-3-phenylsulfonyl-5,6,7,8-tetrahydropyra Zolo 1.5-alpyrido4.3-dipyrimidines of the general formula 2.2 and pharmaceutically acceptable salts and/or hydrates thereof.

1.2 HC ins e

K l D4 wherein: % SN i-R Ar is optionally substituted aryl or optionally substituted \ f W heterocyclyl: N O R" is hydrogen, optionally substituted lower C-C alkyl, N Substituted hydroxyl group, Substituted Sulfanyl group; \ / R’ is hydrogen or optionally substituted C-C alkyl; N R2 A R is hydrogen, optionally substituted C-C alkyl or tert.- R3 butyloxycarbonyl. 2.2 HC 2. Compounds according to claim 1, representing Substi ins e tuted 3-phenylsulfonyl-6,7,8,9-tetrahydropyrazolo 1.5-apy rido4.3-epyrimidines of the general formula 1.1 and substi tuted 3-phenylsulfonyl-5,6,7,8-tetrahydropyrazolo 1.5-a pyrido4.3-dpyrimidines of the general formula 2.1; or pharmaceutically acceptable salts and/or hydrates thereof.

1.1 2-y-SufiR1 O e \, f \, wherein: R. RandR have the above meanings; 4. Compounds of claim 1 are 2-methyl-3-phenylsulfonyl \ / 6,7,8,9-tetrahydropyrazolo 1.5-alpyrido4,3-epyrimidine N R2 1.1 (1), 2,5-dimethyl-3-phenylsulfonyl-6,7,8,9-tetrahydropy A razolo 1.5-alpyrido4.3-epyrimidine 1.1(2), 2,7-dimethyl R3 3-phenylsulfonyl-6,7,8,9-tetrahydropyrazolo 1.5-alpyrido 4.3-epyrimidine 1.1(3), 2.5,7-trimethyl-3-phenylsulfonyl

US 2011/003987.0 A1 Feb. 17, 2011 22

-continued -continued 1.2(1) 1.2(6) 4N-yO N\ 4 W. Cl

1.2(2) 1.2(7) 4NO N\ 4 W. Cl

M 1.2(3) HC

1.2(8) HCN, K % S

N 1.2(4) \ / N CH M HC

5-20. (canceled) 21. A method of serotonin 5-HT, receptors antagonizing comprising administering into the cell the compounds of the general formula 1 and 2 or pharmaceutically acceptable salts thereof

1.2(5) 2nlyO N\ 4 W. Cl US 2011/003987.0 A1 Feb. 17, 2011 23

-continued -continued 2 2 RI R \-At O\- Ar % V N 2 V \, ( \N / o R2 N R2 \ / N

N A R3

wherein: wherein: Ar is optionally substituted aryl or optionally substituted Ar is an optionally substituted aryl or an optionally Substi heterocyclyl: tuted heterocyclyl: R" is hydrogen, optionally substituted lower C-C alkyl, R" is hydrogen, an optionally substituted lower Substituted hydroxyl group, Substituted Sulfanyl group; C-C alkyl, a Substituted hydroxy group, a Substituted R is hydrogen or optionally substituted C-C alkyl: Sulfanyl group; R is hydrogen, optionally substituted C-C alkyl or tert R’ is hydrogen or an optionally substituted C-C alkyl: butyloxycarbonyl. R is hydrogen, an optionally substituted C-C alkyl or 22. “Molecular tools' for investigation of peculiarities of tert-butyloxycarbonyl. physiologically active compounds possessing the property to 26. The method according to claim 25, wherein said disor inhibit serotonin 5-HT, receptors are the compounds of claim ders and diseases pathogenesis of which is associated with 1 of the general formula 1 and 2 or pharmaceutically accept 5-HT, receptors are Alzheimer's disease, Parkinson's dis able salts thereof. ease, Huntington's disease, psychotic disorders, Schizophre 23. A formulation comprising compounds of the general nia, anxiety disorders, hypoxia-ischemia, hypoglycemia, formula 1 and 2 orpharmaceutically acceptable salts thereof, convulsive states, cerebral damages, lathyrism, amyotrophic of claim 1 and pharmaceutically acceptable carriers, includ lateral Sclerosis, obesity, hyperkinetic disorders, including ing inert excipients and/or solvents. mental ability enhancing. 24. The formulation according to claim 23, which is in the 27. A therapeutic cocktail for treatment and prophylaxis of form of tablet, capsule, or injectable liquid placed in pharma various central nervous system diseases, among them cogni ceutically acceptable packing. tive disorders and neurodegenerative diseases pathogenesis 25. A method of treating and prophylaxis of various central of which is associated with 5-HT, receptors, comprising a nervous system diseases, among them cognitive disorders pharmaceutically effective amount of a medicament includ and neurodegenerative diseases pathogenesis of which is ing the compounds of the general formulas 1 or 2 or pharma associated with 5-HT, receptors, comprising administering to ceutically acceptable salts thereof and pharmaceutically the Subject a pharmaceutically effective amount of the com acceptable carriers, including inert excipients and/or solvents pounds of the general formulas 1 or 2 or pharmaceutically placed in a pharmaceutically acceptable packing acceptable salts thereof.

R' o \-A % V O

N R2 A US 2011/003987.0 A1 Feb. 17, 2011 24

R" is hydrogen, an optionally substituted lower -continued C-C alkyl, a Substituted hydroxyl group, a Substituted Sulfanyl group; 2 R’ is hydrogen or an optionally substituted C-C alkyl: R O R is hydrogen, an optionally substituted C-C alkyl or \- Ar tert-butyloxycarbonyl. N 2 V 28. A method of treating and prophylaxis of various central \ / 'o nervous system diseases, among them cognitive disorders and neurodegenerative diseases pathogenesis of which is associated with 5-HT, receptors, comprising administering to the subject an effective amount of the therapeutic cocktail according to claim 27. 29. The method according to claim 28, wherein said disor ders and diseases pathogenesis of which is associated with 5-HT, receptors are Alzheimer's disease, Parkinson's dis ease, Huntington's disease, psychotic disorders, Schizophre nia, anxiety disorders, hypoxia-ischemia, hypoglycemia, convulsive states, cerebral damages, lathyrism, amyotrophic wherein: lateral Sclerosis, and obesity. Ar is an optionally substituted aryl or optionally Substi tuted heterocyclyl: c c c c c