USOO8829009B2

(12) United States Patent (10) Patent No.: US 8,829,009 B2 Vashtchenko et al. (45) Date of Patent: Sep. 9, 2014

(54) SUBSTITUTED (56) References Cited 2-AMINO-3-(SULFONYL)PYRAZOLO15 APYRIMIDINES - SEROTONIN 5-HT FOREIGN PATENT DOCUMENTS RECEPTOR ANTAGONISTS, METHOD FOR USE THEREOF EP O94.1994 3, 1999 EP 1354.884 10, 2003 WO WO97/11075 9, 1996 (71) Applicants: Alexander Vasillevich Ivashtchenko, WO WOO3,057674 T 2003 Encinitas, CA (US); Andrey OTHER PUBLICATIONS Alexandrovich Ivashchenko, Moscow (RU); Nikolay Filippovich Savchuk, Woolley M.L.: 5-HT6 receptors. Curr. Drug Targets CNS Neurol. Rancho Santa Fe, CA (US) Disord. vol. 3, 2004, pp. 59-79. Vicker S.P.; Dourish C.T.: Serotonin receptor ligands and the treat ment of obesity. Curr. Opin. Investig. Drugs. vol. 5, 2004, pp. 377 (72) Inventors: Alexander Vasillevich Ivashtchenko, 388. Encinitas, CA (US); Andrey Davies S.L.: Drug discovery targets: 5-HT6 receptor. Drug Future Alexandrovich Ivashchenko, Moscow vol. 30, 2005, pp. 479–495. (RU); Nikolay Filippovich Savchuk, Primary Examiner — Jeffrey H Murray Rancho Santa Fe, CA (US) (57) ABSTRACT The present invention relates to novel substituted 2-amino-3- (*) Notice: Subject to any disclaimer, the term of this (arylsulfonyl)pyrazolo 1.5-alpyrimidines of general formula patent is extended or adjusted under 35 1, to serotonin 5-HT, receptor antagonists, to novel drug U.S.C. 154(b) by 115 days. Substances and pharmaceutical compositions, to medica ments, methods for preparation thereof, and to methods for (21) Appl. No.: 13/573,818 prophylaxis and treatment of various CNS diseases, patho genesis of which is associated with disturbance of monoam (22) Filed: Oct. 9, 2012 inergic signaling pathways, more specifically over- or hypo activation of serotonin 5-HT, receptors. (65) Prior Publication Data In general formula 1 US 2013 FOOT935O A1 Mar. 28, 2013

Related U.S. Application Data (62) Division of application No. 12/812,733, filed as application No. PCT/IB2009/050272 on Jan. 23, 2009, now Pat. No. 8,309,559. (30) Foreign Application Priority Data Jan. 24, 2008 (RU) ...... 2008102154 May 7, 2008 (RU) ...... 2008117846 R" and Rindependently of each other represent C-C alkyl (51) Int. C. or phenyl; R represents hydrogen or C-C alkyl; R. R. AOIN 43/90 (2006.01) independently of each other represent hydrogen, optionally A 6LX3/59 (2006.01) substituted C-C alkyl or optionally substituted phenyl, or CO7D 487/00 (2006.01) RandR together with the nitrogenatom they are attached CO7D 487/04 (2006.01) to form optionally substituted heterocyclyl; Aris aryl selected (52) U.S. C. from phenyl, optionally substituted with R, that is one or two CPC ...... C07D487/04 (2013.01) optionally identical Substituents selected from hydrogen, USPC ...... 514/259.3:544/281 lower alkyl, trifluoromethyl or halogen; or optionally substi (58) Field of Classification Search tuted 5-6-membered heteroaryl, containing as the heteroatom None nitrogen or Sulfur atom. See application file for complete search history. 3 Claims, 2 Drawing Sheets U.S. Patent Sep. 9, 2014 Sheet 1 of 2 US 8,829,009 B2

5 O i 4. O

ravaar Ps N

le-5 le-4 1e-3 le-2 le-l e--0 Concentration (uM) Fig. 1. U.S. Patent Sep. 9, 2014 Sheet 2 of 2 US 8,829,009 B2

|-||||||||||||||||||| |||||||||||||||||||||||||||||||| — 1.1 (1)

Fig. 3. US 8,829,009 B2 1. 2 SUBSTITUTED It was shown in a large number of nowadays publications 2-AMINO-3-(SULFONYL)PYRAZOLO15 that blocking of 5-HT receptors leads to considerable APYRIMIDINES - SEROTONIN 5-HT enhancement of memory consolidation in various animal RECEPTOR ANTAGONISTS, METHOD FOR models of training-memorizing-reproduction Foley A. G., USE THEREOF Murphy K.J., Hirst W. D., Gallagher H. C., Hagan J.J., Upton N., Walsh F. S. Regan C. M. The 5-HT(6) CROSS REFERENCE TO RELATED SB-271046 reverses -disrupted consolidation of APPLICATIONS a passive avoidance task and ameliorates spatial task deficits in aged rats. Neuropsychopharmacology. 2004; 29:93-100. This application is a Division of application Ser. No. 10 Riemer C., Borroni E., Levet-Trafit B., Martin J. R., Poli S., 12/812,733, filed Jul. 13, 2010 now U.S. Pat. No. 8,309,559 Porter R. H., Bos M. Influence of the 5-HT6 receptor on which claims benefit of priority to the International applica release in the cortex: pharmacological charac tion PCT/IB2009/050272 filed Jan. 23, 2009, which claims terization of 4-(2-bromo-6-pyrrolidin-1-ylpyridine-4-sulfo benefit of foreign priorities to the Russian Federation appli nyl)phenylamine, a potent and selective 5-HT, receptor 15 antagonist. J. Med. Chem. 2003; 46:1273-1276. King M. V., cations RU 2008117846 of May 7, 2008 and RU 2008102154 Woolley M. L., Topham I. A. Sleight A. J., Marsden C. A., of Jan. 24, 2008. The priority applications are hereby incor Fone K.C. 5-HT6 receptor antagonists reverse delay-depen porated by reference in their entirety. dent deficits in novel object discrimination by enhancing consolidatione an effect sensitive to NMDA receptor antago FIELD OF THE INVENTION nism. Neuropharmacology 2004: 47: 195-204. It was also demonstrated that considerable enhancement of cognitive The invention relates to novel (arylsulfonyl)pyrazolo 1.5- functions in aged rats in Morrison's water maze experiment apyrimidines, novel serotonin 5-HT, receptor antagonists, to took place under the action of 5-HT, receptor antagonists novel drug Substances, pharmaceutical compositions, medi Foley A. G., Murphy K. J., Hirst W. D., Gallagher H. C., caments, methods for their preparation and use. More specifi 25 Hagan J.J., Upton N., Walsh F. S., Regan C. M. The 5-HT(6) cally, the invention relates to serotonin 5-HT receptor receptor antagonist SB-271046 reverses scopolamine-dis antagonists—Substituted 2-amino-3-(sulfonyl)pyrazolo 1.5- rupted consolidation of a passive avoidance task and amelio apyrimidines, to drug Substances, to pharmaceutical compo rates spatial task deficits in aged rats. Neuropsychopharma sitions, comprising the said compounds as active ingredients, cology. 2004; 29:93-100. Recently more thorough and to methods of treatment and prophylaxis of various cog 30 understanding of 5-HT, receptor function in cognitive pro nitive and neurodegenerative diseases. The origin of pharma cesses and more accurate conceptions concerning possible cological effect of novel drug substances is their ability to pharmacophoric properties of their antagonists were interact with serotonin 5-HT receptors playing the key role achieved. Holenz, J., Pauwels P. J., Diaz, J. L., Merce R., in treatment of central nervous system diseases (CNS), in Codony X., Buschmann H. Medicinal chemistry strategies to particular, Alzheimer's disease (AD), Huntington's disease, 35 5-HT, receptor ligands as potential cognitive enhancers and Schizophrenia, other neurodegenerative diseases, cognitive antiobesity agents. Drug Disc. Today. 2006: 11:283-299. disorders and obesity. This resulted in preparation of highly affine selective ligands (“molecular tools'), and afterwards clinical candidates. At PRIOR ART present a number of 5-NT receptor antagonists are at various 40 phases of clinical investigation as potential ingredients for Usefulness of selective antagonists of serotonin 5-HT treatment of AD, Huntington's disease, Schizophrenia (antip receptors for treating of CNS diseases, in particular, Schizo sychotic) and other neurodegenerative and cognitive diseases phrenia, AD and other neurodegenerative diseases and cog (Table 1) http://integrity. prous.com. nitive disorders was proved conclusively in clinical practice and is regarded to be very perspective in medicine of future 45 TABLE 1 Holenz. J., Pauwels P. J., Diaz. J. L., Merce R., Codony X. Buschmann H. Medicinal chemistry strategies to 5-HT 5-HT6 Receptor antagonists as drug candidates. receptor ligands as potential cognitive enhancers and antiobe Clinical phase sity agents. Drug Disc. Today. 2006: 11:283-299. Medicament of testing Developer Therapeutic group At mammals these receptors are localized exclusively in 50 central nervous system (CNS), and mainly in parts of brain Dimebon TM Phase III Medivation (USA) Alzheimer's disease treatinent responsible for training and memory Gérard C., Martres SGS-518 Phase II Lilly, Saegis Cognitive diseases M.-P. Lefevre K. Miguel M.-C., Verge D., Lanfumey L. treatinent Doucet E., HamonM., El Mestikawy S. Immuno-localization SB-742457 Phase II GlaxoSmithKline Alzheimer's disease 55 treatment; of serotonin 5-HT, receptor-like material in the rat central Antipsychotic nervous system. Brain Research. 1997: 746:207-219. Dimebon Phase IIIa Medivation (USA) Huntington's disease Besides, it was shown Dawson L.A., Nguyen H.Q., Li P. treatinent The 5-HT(6) receptor antagonist SB-271046 selectively Dimebon Phase II (Russia) Schizophrenia PRX-07034 Phase I Epix Pharm. Obesity treatment: enhances excitatory neurotransmission in the rat frontal cor Antipsychotic; tex and hippocampus. Neuropsychopharmacology. 2001; 60 Cognitive 25:662-668), that 5-HT receptors are modulators of the diseases treatment whole number of neuromediator Systems including cholin SB-737OSOA Phase II GlaxoSmithKline Antipsychotic ergic, noradrenergic, and dopaminergic. Tak BWT-74316 Phase I Bioviltrum Obesity treatment SAM-315 Phase I Wyeth Pharm. Alzheimer's disease ing into account the fundamental role of these systems in treatinent normal cognitive processes and their dysfunction at neurode 65 SYN-114 Phase I Roche, Synosis Ther. Cognitive diseases generation, exclusive role of 5-HT, receptors informing nor treatinent mal and “pathological memory becomes obvious. US 8,829,009 B2 3 4 TABLE 1-continued -continued A2 R 5-HT6 Receptor antagonists as drug candidates. O\-A N 2 V Clinical phase Medicament of testing Developer Therapeutic group R \,N f 'o Y. N BGC-20-761 Preclinical BTG (London) Antipsychotic; 10 ( \ A Cognitive diseases treatinent FMPO Preclinical Lilly Antipsychotic A1: Ar-alkyl, aryl; R and R-H, OH, alkyl, alkoxy; R and Dimebon TM Preclinical (Russia) Blood stroke R=H, alkyl, aryl. 15 A2: Araryl, heterocyclyl; R =H, alkyl, alkylthio; R =H. treatinent alkyl, halogen; R-H, alkyl, hydroxyalkyl: R* and R-H; NRR- piperazinyl. With the aim of working out novel highly effective neuro Another attractive property of 5-HT, receptor antagonists protective medicaments the authors of the invention carried is their ability to suppress appetite that can lead to preparation out widespread investigation in the field of substituted 3-(sul on their basis of essentially novel remedies for overweight fonyl)pyrazolo 1.5-alpyrimidines, as a result of which novel lowering and obesity treatment. Vicker S. P. Dourish C. T. drug Substances which were 5-HT, receptor antagonists have Serotonin receptor ligands and the treatment of obesity. Curr: been found. Opin. Investig. Drugs. 2004; 5:377-388). This effect was confirmed in many investigations Holenz, J., Pauwels P. J., 25 DISCLOSURE OF THE INVENTION Diaz. J. L., Merce R., Codony X., Buschmann H. Medicinal chemistry strategies to 5-HT, receptor ligands as potential In the context of the present invention, the terms are gen cognitive enhancers and antiobesity agents. Drug Disc. erally defined as follows: Today. 2006: 11:283-299. Davies S. L. Drug discovery tar "' mean ligands being bound to receptors of definite gets: 5-HT, receptor. Drug Future. 2005; 30:479–495; its 30 type actively promote transferring their specific signal and by mechanism is based on Suppression of Y-aminobutyric acid that cause biological response of the cell. signaling by 5-HT, receptor antagonists and increasing of “Alkyl means aliphatic hydrocarbon straight or branched C.-melanocyte-stimulating hormone emission, that, finally, group with 1-12 carbon atoms. Branched means alkyl chain results in lowering of food demand Woolley M. L. 5-HT with one or more “lower alkyl substituents. Alkyl group may 35 have one or more substituents of the same or different struc receptors. Curr. Drug Targets CNS Neurol. Disord. 2004: ture (“alkyl Substituent”) including halogen, alkenyloxy, 3:59-79. Now two 5-HT, receptor antagonists are at the first cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, phase of clinical testing as drug candidates for obesity treat hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, ary ment (Table 1) http://integrity prous.com. loxycarbonyl, alkylthio, heteroarylthio, aralkylthio, arylsul In this context searching for new selective and effective 40 fonyl, alkylsulfonylheteroaralkyloxy, annelated heteroaryl serotonin 5-HT, receptorantagonists seems to be original and cycloalkenyl, annelated heteroarylcycloalkyl, annelated perspective approach to the development of novel drug Sub heteroarylheterocyclenyl, annelated heteroarylheterocyclyl, stances for treating of a great number of neurological and annelated arylcycloalkenyl, annelated arylcycloalkyl, anne neurodegenerative diseases and cognitive disorders. lated arylheterocyclenyl, annelated arylheterocyclyl, alkoxy 45 carbonyl, aralkoxycarbonyl, heteroaralkyloxycarbonyl or There are many publications in scientific literature describ R'R''N R'R''NC(=O)—, R'R''NC(=S)—, ing various biologically active arylsulfonyl Substituted aza RR, NSO, , where R." and R' independently of heterocycles, among them serotonin receptor ligands. For each other represent "amino group'Substituent, the meanings example, Substituted 1-(2-aminoethyl)-4-(arylsulfonyl)pyra thereof are defined in this section, for example, hydrogen, Zoles of general formula A1 were described as serotonin 50 alkyl, aryl, aralkyl, heteroaralkyl, heterocyclyl or heteroaryl, 5-HT, receptor ligands WO 2003057674A1 and substituted or R." and R together with the N-atom, they are attached 7-amino-3-(Sulfonyl)pyrazolo 1.5-alpyrimidines A2 as sero to, form through RandR '4-7-membered heterocyclyl or tonin 5-HT receptor antagonists EP 94.1994 A1, 1999 heterocyclenyl. The preferred alkyl groups are methyl, trif luoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, 55 n-propyl, iso-propyl. n-butyl, tert-butyl, n-pentyl, 3-pentyl, A1 methoxyethyl, carboxymethyl, methoxycarbonylmethyl, RI O ethoxycarbonylmethyl, benzyloxycarbonylmethyl and pyridylmethyloxycarbonylmethyl. The preferred “alkyl sub 2 \-A stituents' are cycloalkyl, aryl, heteroaryl, heterocyclyl, N \ 60 hydroxy, alkoxy, alkoxycarbonyl, aralkoxy, aryloxy, alky \, ( lthio, heteroarylthio, aralkylthio, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, heteroaralkyloxycarbo --S1 R2 nyl or R'R''N R'R''NC(=O)—, annelated aryl W R3 heterocyclenyl, annelated arylheterocyclyl. 65 “Alkoxy' means alkyl-O-group, wherein alkyl is defined in this section. The preferred alkoxy groups are methoxy, ethoxy, n-propoxy, iso-propoxy and n-butoxy. US 8,829,009 B2 5 6 “Amino group” means R'R''N-group Substituted or not by (AD/HD); cognitive impairments, accompanying psychotic “amino group Substituent R." and R', the meanings diseases, epilepsy, delirium, autism, psychosis, Down's Syn thereofare defined in this section, for example, amino (NH), drome, bipolar disorders and depression: AIDS-associated methylamino, diethylamino, pyrrolidino, morpholino, ben dementia; dementias at hypothyroidism; dementia connected Zylamino or phenethylamino. with , Substances causing dependability and neurotox Annelated cycle' (condensed cycle) means bi- or poly-cy ins; dementia accompanying neurodegenerative diseases, for clic system wherein annelated cycle and cycle or polycycle example, cerebellar degeneracy and amyotrophic lateral scle with which it is annelated has, at least, two common atoms. rosis; cognitive disturbances connected with cerebral crisis, Antagonists' mean ligands being bound to definite receptors infectious and oncological brain diseases as well as traumatic do not cause active cellular responses. Antagonists prevent 10 brain injury; cognitive function damages associated with binding between agonists and receptors and by that block autoimmune and endocrine diseases, and others. specific receptor signal transmission. "Drug Substance' means physiologically active compound of "Aryl means aromatic mono- or polycyclic system with 6-14 synthetic or other (biotechnological, vegetable, animal, carbon atoms, mainly from 6 to 10 C-atoms. Aryl may have microbe and so on) origin exhibiting pharmacological activ one or more “cyclic system substituents of the same or 15 ity and being an active ingredient of pharmaceutical compo different structure. Phenyl, substituted phenyl, naphthyl, or sition employed in production and preparation of medica Substituted naphthyl are representatives of aryl groups. Aryl mentS. could be annelated with nonaromatic cyclic system or hetero “Medicament' is compound or mixture of compounds rep cycle. resenting pharmaceutical composition in the form of tablets, "Arylsulfonyl' means aryl-SO-group, wherein the meaning capsules, injections, ointments and other finished pharma of aryl is defined in this section. products intended for restoration, improvement or modifica “Heterocyclyl means aromatic or nonaromatic monocyclic tion of physiological functions at humans and animals, and or polycyclic system comprising 3-10 carbon atoms, pre for treatment and prophylaxis of diseases, diagnostics, anes dominantly 5-6 carbon atoms, in which one or more carbon thesia, contraception, cosmetology and others. atoms are replaced by nitrogen, oxygen, or Sulfur. The prefix 25 "Ligands' (from Latin ligo) represent chemical compounds “aza”, “oxa' or “thia” before heterocyclyl means the occur (Small molecule, peptide, protein, inorganic ion, and others) rence in cyclic system nitrogen, oxygen or Sulfur atoms, capable to interact with receptors which convert this interac respectively. Heterocycyl may have one or more “cyclic sys tion into specific signal. tem substituens' of the same or different structure. N- And “Neurodegenerative diseases' means specific conditions and S-atoms of heterocyclic fragment could be oxidized to N-ox 30 diseases, accompanied by damage and primary destruction of ide, S-oxide and S-dioxide. The representatives of heterocy nervous cell populations in the certain areas of central ner clyl are: piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, vous system. Neurodegenerative diseases include but are not thiomorpholinyl, thiazolidinyl, 1,4-dioxan-2-yl, tetrahydro limited by: AD; Parkinson's and Huntington's diseases (cho furanyl, tetrahydrothiophenyl and others. rea); multiocular Sclerosis; cerebellar degeneracy; amyo “Hydrate” means stoichiometric or nonstoichiometric com 35 trophic lateral sclerosis; dementias with Lewy bodies; spinal positions of the compounds or their salts with water. muscularatrophy; peripherical neuropathy; spongy encepha “Substituent’ means chemical radical attached to scaffold litis (Creutzfeld-Jakob Disease); AIDS dementia; multi-in (fragment), for example, "alkyl Substituent”, “amino group fract dementia; frontotemporal dementias; leukoencephal substituent”, “carbamoyl substituent, and “cyclic system opathy (spongy degeneration of white matter); chronic neuro substituent’, the meanings thereofare defined in this section. 40 degenerative diseases; cerebral crisis; ischemic, reperfusion “Amino group Substituent’ means Substituent attached to and hypoxic brain damage; epilepsy; cerebral ischemia; glau amino group. Amino group Substituent represents hydrogen, coma; traumatic brain injury; Down's syndrome; encephalo alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, acyl, aroyl, myelitis; meningitis; encephalitis; neuroblastoma; Schizo alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylami phrenia; depression. Moreover, neurodegenerative diseases nocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, 45 include pathological States and disorders associated with heterocyclylaminocarbonyl, alkylaminothiocarbonyl, ary hypoxia, Substance abuse, causing dependability under neu laminothiocarbonyl, heteroarylaminothiocarbonyl, heterocy rotoxins influence; infectious and oncological brain diseases clylaminothiocarbonyl, annelated heteroarylcycloalkenyl, as well as neuronal damages associated with autoimmune and annelated heteroarylcycloalkyl, annelated heteroarylhetero endocrine diseases and others. cyclenyl, annelated heteroarylheterocyclyl, annelated arylcy 50 “Substituted sulfonyl means R SO-group wherein R cloalkenyl, annelated arylcycloalkyl, annelated arylhetero could be selected from alkyl, cycloalkyl, aryl, heteroaryl, cyclenyl, annelated arylheterocyclyl alkoxycarbonylalkyl, heterocyclyl, annelated heteroarylcycloalkenyl, annelated aralkoxycarbonylalkyl, heteroaralkyloxycarbonylalkyl. heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, “Substituted amino group” means R'R''N— group annelated heteroarylheterocyclyl, annelated arylcycloalk wherein RandR representamino group Substituents the 55 enyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, meanings thereof are defined in this section. annelated arylheterocyclyl, the meanings thereof are defined "Cognitive disorders” or disorders of cognitive functions' in this section. mean disorders (weakening) of mental abilities including “Receptors' (from Latin recipere) represent biological mac attentiveness, memory, mentality, cognition, education, Ver romolecules located either on cytoplasmic cell membrane or bal, mental, executive and creative abilities, time and space 60 intracellular, capable specifically interact with restricted orientation; in particular, cognitive disorders associated with number of physiologically active compounds (ligands) and AD, Parkinson's and Huntington's diseases, senile dementia; transform the signal of this interaction into definite cellular age-associated memory impairment, AAMI; dysmetabolic response. encephalopathy; psychogenous memory impairment; amne “Therapeutic cocktail is simultaneously administered com sia; amnesic disturbances; transit global amnesia; dissocia 65 bination of two or more drug substances with different tive amnesia; vascular dementia; light or mild cognitive mechanism of pharmacological action and aimed at different impairment (MCI); attention deficit hyperactivity disorder biotargets taking part in pathogenesis of the disease. US 8,829,009 B2 7 8 "Pharmaceutical composition” means composition compris can be prepared are: sodium hydroxide, carbonate, bicarbon ing, at least, one of compounds of general formula 1 and, at ate and hydride; potassium hydroxide, carbonate and bicar least, one of components selected from pharmaceutically bonate, lithium hydroxide, calcium hydroxide, acceptable and pharmacologically compatible fillers, Sol hydroxide, hydroxide. Organic bases Suitable for prepa vents, diluents, auxiliary, distributing and sensing agents, ration of disclosed acid salts are amines and amino acids the delivery agents, such as preservatives, stabilizers, disintegra basicity of which is sufficient enough to produce stable salt tors, moisteners, emulsifiers, Suspending agents, thickeners, and Suitable for use in medical purposes (in particular, they Sweeteners, flavoring agents, aromatizing agents, antibacte are to have low toxicity). Such amines include ammonia, rial agents, fungicides, lubricants, and prolonged delivery methylamine, dimethylamine, trimethylamine, ethylamine, controllers, the choice and suitable proportions of which 10 diethylamine, triethylamine, benzylamine, dibenzylamine, depend on the nature and way of administration and dosage. Examples of Suitable Suspending agents are: ethoxylated dicyclohexylamine, , ethylpiperidine, tris(hy isostearyl alcohol, polyoxyethene, sorbitol and sorbitol , droxymethyl)aminomethane and the like. Besides, salts can microcrystalline cellulose, aluminum metahydroxide, bento be prepared using some tetraalkylammonium hydroxides, nite, agar-agar and tragacant and mixtures thereof as well. 15 Such as holine, tetramethylammonium, tetraethylammonium, Protection against microorganism action can be provided by and the like. Amino acids may be selected from the main various antibacterial and antifungal agents, such as: parabens, aminoacids—lysine, ornithine and arginine. chlorobutanol, Sorbic acid, and similar compounds. Compo The subject of the present invention is novel substituted sition may also contain isotonic agents, such as: Sugar, 2-amino-3-(Sulfonyl)pyrazolo 1.5-alpyrimidines of general Sodium chloride, and similar compounds. Prolonged effect of formula 1 and pharmaceutically acceptable salts and/or the composition may be achieved by agents slowing down hydrates thereof, absorption of the active ingredient, for example, aluminum monostearate and gelatin. Examples of Suitable carriers, Sol vents, diluents and delivery agents include water, ethanol, R4 R4 polyalcohols and their mixtures, natural oils (such as olive 25 oil) and injection-grade organic esters (such as ethyl oleate). In 1 o Examples of fillers are: lactose, milk-Sugar, Sodium citrate, \- Ar calcium carbonate, calcium phosphate and the like. Examples N 2 V of disintegrators and distributors are: starch, alginic acid and \N / 'o its salts, and silicates. Examples of Suitable lubricants are: 30 magnesium Stearate, sodium lauryl Sulfate, talc and polyeth R1 N ylene glycol of high molecular weight. Pharmaceutical com \ / position for peroral, Sublingual, transdermal, intramuscular, intravenous, Subcutaneous, local or rectal administration of R2 R3 active ingredient, alone or in combination with another active 35 compound may be administered to humans and animals in wherein: standard administration form, or in mixture with traditional R" and R independently of each other are C-C alkyl or pharmaceutical carriers. Suitable standard administration phenyl: forms include peroral forms such as tablets, gelatin capsules, R’ is hydrogen or C-C alkyl; pills, powders, granules, chewing-gums and peroral Solutions 40 R. R. independently of each other are hydrogen, optionally or Suspensions, for example, Therapeutic cocktail; Sublingual substituted C-C alkyl or optionally substituted phenyl; or and transbuccal administration forms; aerosols; implants; RandR together with the nitrogenatom they are attached local, transdermal, Subcutaneous, intramuscular, intravenous, to form optionally substituted heterocyclyl: intranasal or intraocular forms and rectal administration Ar is aryl selected from phenyl, optionally substituted with forms. 45 R, that is one or two optionally identical substituents selected "Pharmaceutically acceptable salt' means relatively nontoxic from hydrogen, lower alkyl, trifluoromethyl or halogen; or both organic and inorganic salts of acids and bases disclosed optionally substituted 5-6-membered heteroaryl, containing in this invention. Salts could be prepared in situ in processes as the heteroatom nitrogen or Sulfur atom. of synthesis, isolation or purification of compounds or they The preferred substituted 2-amino-3-(sulfonyl)pyrazolo.1, could be prepared specially. In particular, Salts of bases could 50 5-alpyrimidines are substituted 5,7-dimethyl-3-(arylsulfo be prepared starting from purified bases disclosed in the nyl)pyrazolo 1.5-alpyrimidines of general formula 1.1 or invention and Suitable organic or mineral acid. Examples of pharmaceutically acceptable salts and/or hydrates thereof, salts prepared in this manner include hydrochlorides, hydro bromides, Sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, Valeriates, oleates, palmitates, Stearates, laurates, 55 1.1 borates, benzoates, lactates, p-toluenesulfonates, citrates, maleates, fumarates. Succinates, tartrates, methane Sulpho *s-, e nates, malonates, salicylates, propionates, ethane Sulpho nates, sulfonates, sulfamates and the like (Detailed description of such salt properties is given in: Berge S. M., et 60 ^-\al al., “Pharmaceutical Salts' J. Pharm. Sci., 1977, 66:1-19). \ f W. R. Salts of disclosed acids may be prepared by reaction of puri fied acids specifically with suitable base; moreover, metal H3C \ / salts and amine salts may be synthesized too. Metal salts are salts of sodium, potassium, calcium, barium, magnesium, 65 CH lithium and aluminum; sodium and potassium salts being preferred. Suitable inorganic bases from which metal salts US 8,829,009 B2 9 10 wherein: -continued R" and R', are all as mentioned above; R, represents one or 1.1(5) two optionally identical Substituents selected from hydrogen, lower alkyl, trifluoromethyl or halogen. The preferable compounds of general formula 1.1 are: 2 2-methylamino-5,7-dimethyl-3-(phenylsulfonyl)pyrazolo.1, N 5-alpyrimidine 1.1 (1), 2-dimethylamino-5,7-dimethyl-3- N f Alu (phenylsulfonyl)pyrazolo 1.5-alpyrimidine 1.1(2), 2-methy lamino-5,7-dimethyl-3-(4-fluorophenylsulfonyl)pyrazolo1, 10 5-alpyrimidine 1.1(3), 2-dimethylamino-5,7-dimethyl-3-(4- fluorophenylsulfonyl)pyrazolo 1.5-alpyrimidine 1.1(4), 2-methylamino-5,7-dimethyl-3-(3-fluorophenylsulfonyl) 1.1 (6) pyrazolo 1.5-alpyrimidine 1.1 (5), 2-dimethylamino-5,7- n 1 dimethyl-3-(3-fluorophenylsulfonyl)pyrazolo 1.5-alpyrimi 15 dine 1.1(6), 2-methylamino-5,7-dimethyl-3-(3- chlorophenylsulfonyl)pyrazolo 1.5-alpyrimidine 1.1(7), 2-dimethylamino-5,7-dimethyl-3-(3-chlorophenylsulfonyl) N f F N Alu pyrazolo 1.5-alpyrimidine 1.1 (8) or pharmaceutically acceptable salts and/or hydrates thereof, H3C N /

1.1 (1) 25 1.1 (7)

2 N f O 2 30 f Alu C H3C \ /

1.1(2) 35 CH n 1 1.1 (8) HC n 1. CH N N Alu 40 Cl H3 C N N Alu / & H3C c N 1.1(3) 45

F 2 The subject of the present invention is also method for N preparation of novel Substituted 2-amino-3-(sulfonyl)pyra \ f Alu 50 Zolo 1.5-alpyrimidines of general formula 1 by interaction of substituted 3-amino-4-(sulfonyl)-2H-pyrazoles of general formula 2 with B-diketones of general formula 3 and subse quentisolation or separation of the reaction products (1A, 1B) 55 according to scheme given below. 1.1 (4) H3C n 1 F R4 'N -R' N O O O 2 60 A. N 2 \ - Ar -- -e- \ f W R1 R3 O N 2 H3 C N H R & /f NH2 3 65 US 8,829,009 B2 11 12 4 -continued 4 tegrators, Solvents, diluents, stabilizers, Suspending agents, colorless agents, taste flavors are used for peroral forms; R N-R's R N-R's antiseptic agents, Solubilizers, stabilizers are used in forms for injections; base materials, diluents, greasing agents, anti % \ - Ar % KS-Ar septic agents are used in local forms. V f W \ f W The subject of the present invention is also method for N O -- N O preparation of pharmaceutical composition by mixing drug Substance which is, at least, one of Substituted 2-amino-3- RI \ / R3 \ / (sulfonyl)pyrazolo 1.5-alpyrimidines of general formulas 1, 10 1.1, or compounds of formulas 1.1 (1), 1.1(2), 1.1(3), 1.1 (4), R2 R3 R2 R1 1.1 (5), 1.1(6), 1.1 (7), 1.1 (8) or pharmaceutically acceptable salts and/or hydrates thereof with inert exicipient and/or sol 1A 1B Vent. The Subject of the present invention is also a medicament in wherein: Ar, R. R. R. R. and R', are all as mentioned 15 the form of tablets, capsules, or injections, placed in pharma above. ceutically acceptable packing intended for treatment and pro If diketones 3 are symmetrical compounds (R'-R), only phylaxis of CNS diseases pathogenesis of which is associated with the disturbance of serotonin 5-HT, receptor activation, one product of the reaction could be obtained. If diketones comprising drug Substance which is, at least, one of Substi used are unsymmetrical (R'zR), mixture of two isomeric tuted 2-amino-3-(sulfonyl)pyrazolo 1.5-alpyrimidines of products of the reaction 1A and 1B are usually formed, which general formulas 1, 1.1, 1.1 (1), 1.1(2), 1.1(3), 1.1(4), 1.1 (5), could be separated by well known methods, for example, 1.1(6), 1.1(7), 1.1 (8) or pharmaceutically acceptable salts recrystallization or preparative chromatography. and/or hydrates thereof, orpharmaceutical composition com The subject of the present invention is the development of prising this drug Substance. novel serotonin 5-HT, receptor antagonists and novel bio 25 According to the present invention the preferable medica logically active Substances. ment is a medicament intended for prophylaxis and treatment The subject in view is achieved by serotonin 5-HT recep of Alzhheimer's disease and Huntington's disease. tor antagonists, which are substituted 2-amino-3-(sulfonyl) According to the invention the preferable medicament is a pyrazolo 1.5-alpyrimidines of general formulas 1, 1.1, 1.1 medicament intended for prophylaxis and treatment of psy (1), 1.1(2), 1.1(3), 1.1(4), 1.1 (5), 1.1(6), 1.1(7), 1.1 (8) or 30 chic disorders and Schizophrenia. pharmaceutically acceptable salts and/or hydrates thereof. According to the invention the preferable medicament is a The subject of the present invention is a drug substance for medicament intended for prophylaxis and treatment of obe pharmaceutical compositions and medicaments which is, at S1ty. least, one of substituted 2-amino-3-(sulfonyl)pyrazolo 1.5-a The subject of the present invention is also therapeutic pyrimidines of general formulas 1, 1.1, 1.1 (1), 1.1(2), 1.1(3), 35 cocktail for prophylaxis and treatment of various diseases 1.1 (4), 1.1 (5), 1.1(6), 1.1(7), 1.1 (8) or pharmaceutically pathogenesis of which is associated with serotonin 5-HT acceptable salts and/or hydrates thereof. receptors at humans and animals comprising novel medica The Subject of the present invention is also a pharmaceu ment or drug Substance of general formulas 1.1, 1.1, 1.1 (1), tical composition interacting with serotonin 5-HT, receptors 1.1(2), 1.1(3), 1.1 (4), 1.1 (5), 1.1(6), 1.1 (7), 1.1 (8) or pharma for prophylaxis and treatment of various conditions and dis 40 ceutical composition including this drug Substance. eases of CNS of humans and warmblooded animals compris According to the present invention the preferable therapeu ing pharmaceutically effective amount of novel drug Sub tic cocktail is a therapeutic cocktail for prophylaxis and treat stance which is, at least, one of 2-amino-3-(sulfonyl)pyrazolo ment of neurologic disorders, neurodegenerative and cogni 1.5-alpyrimidines of general formulas 1, 1.1, 1.1 (1), 1.1(2), tive diseases at humans and animals comprising novel 1.1(3), 1.1 (4), 1.1(5), 1.1(6), 1.1 (7), 1.1 (8) or pharmaceuti 45 medicament or drug Substance of general formulas 1.1, 1.1 cally acceptable salts and/or hydrates thereof. (1), 1.1(2), 1.1(3), 1.1 (4), 1.1 (5), 1.1(6), 1.1(7), 1.1 (8) or Pharmaceutical compositions may include pharmaceuti pharmaceutical composition including this drug Substance. cally acceptable excipients. Pharmaceutically acceptable According to the present invention the preferable therapeu excipients mean diluents, auxiliary agents and/or carriers tic cocktail is a therapeutic cocktail for prophylaxis and treat applied in the sphere of pharmaceutics. According to the 50 ment of AD, Huntington's disease, psychic disorders, Schizo invention pharmaceutical composition together with a drug phrenia, hypoxia-ischemia, hypoglycemia, convulsive states, Substance of general formula 1 may contain other active brain injuries, lathyrism, amyotrophic lateral Sclerosis, obe ingredients provided that they do not give rise to undesirable sity or blood stroke, comprising novel medicament or drug effects, for example, allergic reactions. Substance of general formulas 1, 1.1, 1.1 (1), 1.1(2), 1.1(3), If needed, according to the present invention pharmaceu 55 1.1 (4), 1.1(5), 1.1(6), 1.1(7), 1.1 (8), or pharmaceutical com tical compositions can be used in clinical practice in various position including this drug Substance. forms prepared by mixing the said compositions with tradi The therapeutic cocktail for prophylaxis and treatment of tional pharmaceutical carries; for example, peroral forms various diseases, pathogenesis of which is associated with (such as, tablets, gelatinous capsules, pills, Solutions or Sus serotonin 5-HT, receptors at humans and animals, among pensions); forms for injections (such as, Solutions or Suspen 60 them neurological disorders, neurodegenerative and cogni sions for injections, or a dry powder for injections which tive diseases, for prophylaxis and treatment of AD, Hunting requires only addition of water for injections before utiliza ton's disease, psychotic disorders and Schizophrenia, tion); local forms (such as, ointments or solutions). hypoxia-ischemia, hypoglycemia, convulsive states, brain According to the present invention the carriers used in injuries, lathyrism, amyotrophic lateral Sclerosis, and blood pharmaceutical compositions represent carriers which are 65 stroke, along with drug Substances disclosed in the invention, used in the sphere of pharmaceutics for preparation of com may include other active ingredients such as: nonsteroidal monly applied forms. Binding agents, greasing agents, disin anti-inflammatory drugs (Orthophene, Indomethacin, Ibu US 8,829,009 B2 13 14 prophen and others); acetyl inhibitors (3-chlorophenylsulfonyl)pyrazolo 1.5-alpyrimidine, and (Tacrine, Amiridine, Fizostigmine, Aricept, Phenserine and 5,7-dimethyl-2-dimethylamino-3-(3-chlorophenylsulfonyl) others); estrogens (for example, Estradiol); NMDA-receptor pyrazolo 1.5-alpyrimidine, or a pharmaceutically acceptable antagonists (for example, , Neramexane); nootro salt thereof. The best embodiment is the method, wherein said pic drugs (for example, Pyracetam, Fenibut and others); disease is obesity. AMPA receptor modulators (for example, Ampalex); antago The best embodiment is the method, wherein said disease nists of receptors CB-1 (for example, Rimona selected from Alzhheimer's disease or Huntington's disease. bant); monoaminooxidase inhibitors MAO-Band/or MAO-A The best embodiment is the method, wherein said disease (for example, Rasagiline); antiamyloidogenic drugs (for selected from psychotic disorder or schizophrenia. The best embodiment is the method, wherein said disease example, Tramiprosate); lowering B-amyloide neurotoxicity 10 selected from the group, consisting of neurological disorder, compounds (for example, Indole-3-propionic acid); Y- and/or hypoxia-ischemia, hypoglycemia, convulsive state, brain B-secretase inhibitors; M1-muscarinic receptor agonists (for injury, lathyrism, amyotrophic lateral Sclerosis, and blood example, Cevimeline); metal helates (for example, Clio stroke. quinol); GABA(A) receptor antagonists (for example, CGP A compound of formula 1 could be administered peroral or 36742); monoclonal antibodies (for example, Bapineu 15 parenterally (for example, intravenously, Subcutaneously, Zumab); antioxidants; neurotrophic agents (for example, intraperitoneally or locally). The clinical dose of pharmaceu Cerebrolisine); (for example, Imipramine, tical composition or medicament comprising drug Substance Sertraline and others) and others. of general formulas 1, 1.1, 1.1 (1), 1.1(2), 1.1(3), 1.1 (4), 1.1 According to the present invention the preferable therapeu (5), 1.1(6), 1.1 (7), 1.1 (8) may be corrected depending on: tic cocktail is a therapeutic cocktail for overweight lowering therapeutic efficiency and bio-accessibility of active ingredi and obesity treatment. The therapeutic cocktail for over ents in patients organism, rate of their exchange and removal weight lowering and obesity treatment along with drug Sub from organism, and age, gender, and severity of patients stances disclosed in the invention, may include other active symptoms. Thus, the daily intake for adults normally being ingredients such as: anorectic drugs (for example, Fepranon, 10-500 mg, preferably 50-300 mg. Accordingly, the above Desopimon, Masindole); hormone drugs (for example, Tire 25 effective doses are to be taken into consideration while pre oidine); hypolipidemic means such as fibrates (for example, paring medicament of the present invention, each dose unit of Fenofibrate); statines (for example, Lovastatine, Simvasta the medicament contains 10-500 mg of compound of general tine, Pravastatine and Probucol); hypoglycemic drugs (sulfo formulas 1, 1.1, 1.1 (1), 1.1(2), 1.1(3), 1.1 (4), 1.1 (5), 1.1(6), nylureas—for example, Butamide, Glibenclamide; bigu 1.1 (7), 1.1 (8), preferably 50-300 mg. Following the instruc anidines—for example, Buformine, Metamorphine) and 30 tions of physician or pharmacist, the medicaments may be drugs with Some other , such as cannab taken several times over specified periods of time (preferably, inoid CB-1 receptor antagonists (Rimonabant), inhibitors of from one to six times). norepinephrine and serotonin reuptake (Sibutramine), inhibi tors of ferments offatty acids synthesis (Orlistat) and others, BEST EMBODIMENT OF THE INVENTION along with antioxidants, food additives and others. 35 The subject of the present invention is also a method of The invention is illustrated by the following figure treating disease of CNS, pathogenesis of which is associated FIG. 1. Concentration dependence of serotonin 5-HT with 5-HT, receptors, in human or warm blooded animal receptor and Methiothepin (control) inhibition by drug sub comprising administering an effective dose of a compound of stance 1.1 (1). formula 1, or a pharmaceutically acceptable salt thereof, to 40 FIG. 2. Test results for appetite checkup in rats. A with human or animal, wherein: out starvation, O starvation 16 h with placebo, X starva R" and R independently of each other are C-C alkyl or tion 16 h with 1 mg/kg of 1.1 (1). phenyl: FIG. 3. The influence of compound 1.1 (1) on prepulse R is hydrogen or C-C alkyl; inhibition in reply to acoustic stimulus. Difference from the R. R. independently each other are hydrogen, option 45 group of animals received placebo: *—according to LS ally substituted C-C alkyl or optionally substituted phenyl: Fisher-test, & according to chi square test. or R and R, together with the nitrogen atom they are Below the invention is described by means of specific attached to form optionally substituted heterocyclyl: examples, which illustrate but not limit the scope of the inven Aris aryl selected from phenyl, optionally substituted with tion. R, that is one or two optionally identical substituents selected 50 from hydrogen, lower alkyl, trifluoromethyl or halogen; oran EXAMPLE 1. optionally substituted 5-6-membered heteroaryl, containing as the heteroatom nitrogen or Sulfur atom. General method for preparation of substituted 2-amino-3- The best embodiment is the method, wherein said com (sulfonyl)pyrazolo 1.5-alpyrimidines of general formulas 1, pound is the compound of formula 1.1, or a pharmaceutically 55 1.1. Mixture of 0.005 mol of substituted 3,4-diamino-pyra acceptable salt thereof. Zole 2 and 0.0055 mol of corresponding diketone 3 in 5 ml of The best embodiment is the method, wherein said com acetic acid was boiled for 4 hours. After cooling the solid pound is selected from the group, consisting of 5,7-dimethyl precipitated was filtered off, washed with methanol and 2-methylamino-3-(phenylsulfonyl)pyrazolo 1.5-alpyrimi water. If necessary, the product was Subjected to recrystalli dine, 5,7-dimethyl-2-dimethylamino-3-(phenylsulfonyl) 60 Zation from proper Solvent, or chromatographic purification pyrazolo 1.5-alpyrimidine, 5,7-dimethyl-2-methylamino-3- or chromatographic separation. Yield of 3-(sulfonyl)pyrazolo (4-fluorophenylsulfonyl)pyrazolo 1.5-alpyrimidine, 5,7- 1.5-alpyrimidines of general formulas 1, 1.1 was 70%-85%. dimethyl-2-dimethylamino-3-(4-fluorophenylsulfonyl) Some of novel substituted 2-amino-3-(sulfonyl)pyrazolo.1, pyrazolo 1.5-alpyrimidine, 5,7-dimethyl-2-methylamino-3- 5-alpyrimidines of general formulas 1, 1.1, 1.1 (1), 1.1(2), (3-fluorophenylsulfonyl)pyrazolo 1.5-alpyrimidine, 5,7- 65 1.1(3), 1.1(4), 1.1(5), 1.1(6), 1.1(7), 1.1 (8), their LCMS and dimethyl-2-dimethylamino-3-(3-fluorophenylsulfonyl) NMR data, and% inhibition of 5-HT, receptors are presented pyrazolo 1.5-alpyrimidine, 5,7-dimethyl-2-methylamino-3- in Table 2.

US 8,829,009 B2 25 26 TABLE 2-continued

2-Amino-3-(sulfonyl)pyrazolo 15-a rimidines of general formulas 1, 1.1. LCMS, m/z H NMR, DMSO-d6, No Formula Mol. W. (M + 1) 8, ppm: 9* 1.1 (8) H3CN-CH3 364.86 365 96 N K

N f \O Cl

"- CH 1.1 (9) H3CN 368.82 369 H NMR (CDC1,400 97 NH F MHz): 88.32 (dd, J = K 6.8 Hz, J2 = 2.4 Hz, 1H), 8.11 (dd, J = 6.8 Hz, % \ J2 = 4.4 Hz, J = 2.4 Hz, W f W. Cl 1H), 7.21 (t, J = 8.8 Hz, N 1H), 6.58 (s, 1H), 5.95 (q, J = 5.2 Hz, 1H), 3.05 H3C N N (d, J = 5.2 Hz, 3H), 2.62 / (s, 3H), 2.57 (s, 3H). CH *%inhibition of5-HT6 receptors by 10uMsolutions of substituted 2-amino-3-(sulfonyl)pyrazolo15-alpyrimidines of general formulas 1, 1.1.

EXAMPLE 2 TABLE 3-continued Determination of antagonistic activity of compounds of ICso inhibition of serotonin 5-HT6 receptors by compounds of general formula 1 in the Setting of functional assay. general formula 1 towards 5-HT receptors. Compounds of 35 general formula 1 were tested for their ability to prevent No substance ICso, nM 5-HT, receptor activation by serotonin. HEK 293 cells (cells of human embryo's kidney) with artificially expressed 5-HT 1.1 (7) 2.O receptor, activation of which by serotonin leads to increasing 1.1 (9) 4.0 the concentration of intracellular cAMP were used. The con 40 tent of intracellular cAMP was determined using reagent kit LANCE cAMP (PerkinElmer) according to the method EXAMPLE 3 described by the manufacturer of the kit http://las perkinelm er.com/content/Manuals/ Activity determination of serotonin 5-HT receptor MAN LANCEcAMP384KitUser.pdf). 45 antagonists of the general formula 1 in the setting of competi Effectiveness of compounds was estimated by their ability tive binding to serotonin 5-HT, receptors. to reduce the content of intracellular cAMP induced by sero Screening of the disclosed compounds for their potential tonin. ability to interact with serotonin 5-HT, receptors was carried Table3 presents data on%inhibition of 5-HT receptors by out by method of radioligand binding. For this purpose mem 10 uM solutions of compounds of general formula 1. As can 50 brane species were prepared from expressing recombinant be seen from the data given, tested compounds show observ human 5-HT, receptors HeLa cells by means of their homog able activity towards serotonin 5-HT, receptors. enization in glass homogenizer with Subsequent separation of Table 3 shows values of ICso inhibition of intracellular plasmatic membranes from cell nucli, mitochondria's and cAMP production stimulated by serotonin by some com cell wreckages by differential centrifugation. Determination pounds of general formula 1, testifying antagonistic activity 55 of tested compounds binding with 5-HT, receptors was car thereof in the setting of functional assay. ried out according to the method described in Monsma FJJr. Shen Y. Ward RP. Hamblin MW and Sibley DR, Cloning and TABLE 3 expression of a novel serotonin receptor with high affinity for tricyclic psychotropic drugs. Mol Pharmacol. 43:320-327. ICso inhibition of serotonin 5-HT6 receptors by compounds of 60 1993. In the preferable embodiment membrane preparations general formula 1 in the Setting of functional assay. were incubated with radioligand (1.5 nM H Lysergic acid No substance ICso, nM diethylamide) without and in the presence of investigated compounds for 120 min at 37°C. in medium consisting of 1.1(1) S.O 1.1(2) 1177 mM Tris-HCl, pH 7.4, 150 mM NaCl, 2 mM Ascorbic Acid, 1.1(3) 6.0 65 0.001% BSA. After incubation the samples were filtered in 1.1(5) vacuo on glass-microfiber filters G/F (Millipor, USA), filters were washed three times with cold solution of medium and US 8,829,009 B2 27 28 radioactivity was measured by scintillation counter Micro EXAMPLE 7 Beta 340 (PerkinElmer, USA). Nonspecific binding which made up 30% of overall binding was determined by incuba Appetite control test. Male rats of Vistar line weighing tion of membrane preparations with radioligand in the pres 230-360 g were housed in standard home cages with water ence of 5 uM Serotonin (5-HT). Methiothepin was used as and food available with the exception of short periods of food positive control. Binding of tested compounds to the receptor deprivation (16hs) just before the Appetite test. The Appetite was determined by their ability to displace the radioligand test was carried out in individual cages with overhead cover and expressed in percent of displacement. The percent of made of wire in the niches of which a portion of food granules displacement was calculated according to the following equa was inserted. Mass of the granules was examined every 30 tion: 10 minutes for 3 h. On the basis of these measurements food consumption was estimated and stated in grams of food per kilogram of body mass. Placebo and the compound 1.1 (1) % = TA - CA : (dose 10 mg/kg) were injected intraperitoneally 60 minutes TA - NA 100, 15 before the test. Each experimental group of animals consisted of 10 rats. Compound was dissolved in sterilized water. The wherein: TA was overall radioactivity in the presence of injection Volume was 10 ml/kg. Intact animals which were radioligand only, CA was radioactivity in the presence of not undergone food deprivation, and animals after food dep radioligand and tested compound and NA was radioactivity rivation, but injected with sterilized water, were used as con in the presence of radioligand and Serotonin (5uM). trol. Intact animals which were not undergone food depriva Table 4 and FIG. 1 present, as one of the examples, the test tion and injected with sterilized water, were used as control. results for 5,7-dimethyl-2-methylamino-3-(phenylsulfonyl) Test results show (FIG. 2) that the compound 1.1(1) is capable pyrazolo 1.5-alpyrimidine 1.1 (1) and Methiothepin (control to prevent appetite rising in rats. compound), which testify the high activity (4.61 nM) of this serotonin 5-HT, receptor antagonist. 25 EXAMPLE 8

TABLE 4 Antipsychotic activity of compounds of the general for mula 1 in “Prepulse inhibition of the startle response in mice’ Concentration dependence of serotonin 5-HT6 receptor test. Mice of SHK line weighing about 24-30 g were used in inhibition by drug Substance of formula 1.1(1) and 30 ICsa and K. values in the setting of competitive binding. the test. Experiments were carried out during light period of animal's diurnal. hydrochloride and Haloperi Compound Concentration dependences ICso, nM K, nM dol were received from Sigma Chemicals Company, (USA). Substance 1.1 (1) FIG. 1. O.S11 0.237 Apomorphine hydrochloride was dissolved in 0.1% solution s Control- 1.3 O.603 ofascorbic acid prepared with sterilized water; it was admin Methiothepin 35 istered subcutaneously 15 minutes before the test. Haloperi dol was dissolved in sterilized water using emulsifier Twin 80, it was administered intraperitoneally 60 minutes before EXAMPLE 4 the test. The compound 1.1(1) was dissolved in sterilized 4 water, it was introduced subcutaneously 60 minutes before Medicament preparation in the form of tablets. 1600 mg Of the test. Injection volume was 10 ml/kg. Solution of ascorbic starch, 1600 mg of ground lactose, 400 mg of talk and 1000 acid prepared with sterilized water and Twin 80 were injected mg of 5,7-dimethyl-2-methylamino-3-(phenylsulfonyl)pyra to control group of animals. Zolo 1.5-alpyrimidine 1.1(1) were mixed together and The test instrument consisted of a chamber made of trans pressed into bar. The resultant bar was comminuted into gran 45 parent plexiglass (manufacturer Columbia Instruments ules and sifted through sieve to collect granules of 14-16 Company, USA) and placed on a platform the latter was mesh. The granules thus obtained were shaped into tablets of lodged inside the Sound insulating chamber. High frequency Suitable form weighing 560 mg each. Sound column transmitting acoustic stimulus was located 2 cm away from the platform. Startle of animal resulted in EXAMPLE 5 50 vibrations of platform, which were detected by analog con Verter and registered by computer. Level of background noise Medicament preparation in the form of capsules. 5,7-Dim made up 65 dB. Each animal received 4 stimuli of single ethyl-2-methylamino-3-(phenylsulfonyl)pyrazolo 1.5-apy testing (pulse) stimulus of 50 ms duration and 105 dB or rimidine 1.1 (1) and lactose powder were carefully mixed in prepulsory stimulus (pre-pulse) of 20 ms duration and 85 dB, ratio 2:1. The resultant powdery mixture was packed into 55 after which in 30 ms pulse stimulus of 50 ms duration and 105 gelatin capsules of Suitable size by 300 mg to capsule. dB followed. Time interval between repeated pulse or prepulse in combination with pulse stimuli made up 10 S. EXAMPLE 6 Inhibition of the startle in reply to prepulse-plus-pulse stimu lus was calculated in percentage towards amplitude of startle Medicament preparation of in the form of compositions for 60 in response to isolated pulse stimulus. Administering Apo intramuscular, intraperitoneal or hypodermic injections. 500 , which is used in experiments on animals for mod mg of 5,7-dimethyl-2-methylamino-3-(phenylsulfonyl)pyra elling of psychoto-like conditions, caused reduction of Zolo 1.5-alpyrimidine 1.1 (1), 300 mg of chlorobutanol, 2 ml prepulse inhibition of startle, which reflected the lowering of of propylene glycol, and 100 ml of injectable water were CNS ability to filter sensory stimulus. The results of the mixed together. The resultant solution was filtered and placed 65 experiment show (FIG. 3) that Haloperidol (1 mg/kg) and the into 1 ml ampoules, which were sealed and sterilized in tested compound 1.1 (1) (1 mg/kg) prevented disturbance of autoclave. prepulse inhibition of startle caused by Apomorphine. US 8,829,009 B2 29 30 INDUSTRIAL APPLICABILITY 2. The method of claim 1, wherein said compound is the compound of formula 1.1, or a pharmaceutically acceptable The invention could be used in medicine, veterinary, bio salt thereof, chemistry. The invention claimed is: 1. A method for treating obesity or a psychotic disorder, 1.1 pathogenesis of which is associated with 5-HT, receptors, in human or warm blooded animal, comprising administering an effective dose of a compound of formula 1, or a pharma ceutically acceptable salt thereof, to a subject in need thereof, 10

15 % V CH3 \ 3. The method of claim 2, wherein said compound is selected from the group, consisting of 5,7-dimethyl-2-me thylamino-3-(phenylsulfonyl)pyrazolo 1.5-alpyrimidine, 5,7-dimethyl-2-dimethylamino-3-(phenylsulfonyl)pyra Zolo 1.5-alpyrimidine, 5,7-dimethyl-2-methylamino-3-(4-fluorophenylsulfonyl) wherein: R" and R independently of each other are C-C alkyl or 25 pyrazolo 1.5-alpyrimidine, phenyl: 5,7-dimethyl-2-dimethylamino-3-(4-fluorophenylsulfo R is hydrogen or C-C alkyl; nyl)pyrazolo 1.5-alpyrimidine, R. R. independently of each other are hydrogen, option 5,7-dimethyl-2-methylamino-3-(3-fluorophenylsulfonyl) ally substituted C-C alkyl or optionally substituted pyrazolo 1.5-alpyrimidine, phenyl: or R and R, together with the nitrogen atom 30 5,7-dimethyl-2-dimethylamino-3-(3-fluorophenylsulfo they are attached to form optionally substituted hetero nyl)pyrazolo 1.5-alpyrimidine, cyclyl, 5,7-dimethyl-2-methylamino-3-(3-chlorophenylsulfonyl) Aris aryl selected from phenyl, optionally substituted with pyrazolo 1.5-alpyrimidine, and R, that is one or two optionally identical substituents selected from hydrogen, lower alkyl, trifluoromethyl or 35 5,7-dimethyl-2-dimethylamino-3-(3-chlorophenylsulfo halogen; or an optionally substituted 5-6-membered het nyl)pyrazolo 1.5-alpyrimidine, or a pharmaceutically eroaryl, containing as the heteroatom nitrogen or Sulfur acceptable salt thereof. atOm. k k k k k