EA014100B1 - 2,4-diaminopyridine derivatives, pharmaceutical composition, medicament based thereon for treating and preventing diseases and disorders caused by nmda-receptors hyperactivation and/or as stimulators of cognitive function and method of treatment - Google Patents

Abstract

The invention relates to novel 2,4-diaminopyridines, pharmaceutically acceptable salts and/or solvates thereof, compositions, medicaments comprising novel 2,4-aminopyridine derivatives and use thereof as NMDA receptors blockers, and also as stimulators of cognitive functions. The novel derivatives combine properties of highly-affine antagonist of NMDA receptors with properties of medium inhibitors of acetylcholinesterase and properties highly affine agonists of nicotine cholino receptors and sympathomimetics, stimulating their complex normalizing action on a disbalance of several neurotransmiting systems, including glutamatergic, cholinergic and adrenergic systems not displaying undesirable side effects earlier expressed in known NMDA antagonists. They do not only cause disorders of mental capacities, attention and memory typical for known NMDA –receptor antagonists, but on the contrary, can be suitable for treating and preventing some diseases or disorders associated with disorders of cognitive functions and ability to teaching. The invention also relates to a method of treating or preventing diseases and disorders associated with increased activation of glutamatergic system and/or affection of intellectually-mnestic functions.

Description

FIELD OF THE INVENTION

The invention relates to the field of chemistry, medicine and the pharmaceutical industry and relates to new derivatives of 2,4-diaminopyridine of the general formula (I), their pharmaceutically acceptable salts and / or solvates, which are active against the central nervous system, the method for their preparation, compositions, drugs containing new derivatives of 2,4-aminopyridine, and their use as blockers of ΝΜΌΆ-receptors, as well as as stimulants of cognitive functions.

State of the art

Detailed studies of the last decade have significantly expanded our understanding of the structure and numerous functions of the glutamatergic system.

It is proved that the glutamatergic system is the main exciting neurotransmitter system involved in the implementation of all the basic physiological functions of the brain, including maintaining its tone, wakefulness, psychological and physical activity, in the perception of sensory information of various modality, especially sensitive and pain impulses. She also has one of the leading roles in the implementation of synaptic plasticity and higher integrative functions of the brain, including the ability to learn, form and function of memory, and regulate behavior (Bobde I. ExcpAyu Ltsho As1bk ίη NsaPb apb I1keake. 1. XVPSu & 8opk: C1ps11S51sg . 1988; Χνίκαί N., TNotrkop A. - ExsPogu Atsho As1bk apb 8uparRs TgapkiNkkup. Asabetyu Rgekk: Lopbop, 1991).

Glutamatergic mechanisms of transmission of nerve impulses are present in approximately 40% of nerve cells, and the remaining part falls on the share of all other mediators (norepinephrine, serotonin, acetylcholine, dopamine, etc.) (A. Boldyrev. Neuronal receptors in the cells of the immune system // Nature, 2005, No. 7 (1079), p. 3-8).

The receptors of the main excitatory neurotransmitter, glutamate, are divided into two main classes: ionotropic and metabotropic.

Ionotropic receptors are structurally associated with ion channels, their activation by glutamate or agonists that mimic the action of glutamate leads to the depolarization of cell membranes and the opening of ion channels and, as a result, to the generation of an exciting postsynaptic potential.

Metabotropic receptors are a family of receptors conjugated with O-proteins that act on the ion channel indirectly through a chain of biochemical reactions, in particular through the activation of a system of secondary messengers.

Ionotropic receptors are divided into 3 subtypes, named after the corresponding selective agonists: AMPA (2-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor), CA (kainic acid receptor) and ΝΜΩΛ (Ν-methyl receptor -I-aspartate) (Aa1kshk 1., Kgodkdaagb-Bagkep R, Nopog T 81gns1ngse ac (1U11u teiayopkirk Le Beeuyorshep1 o! Ekspayuuuuuuuuuuuuuuuuuuuyuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuu). 33). Metabotropic glutamate receptors are divided into three groups (Molecular lactobacillus oleraceae glutamate. Appi Kem RNukyu1 54: 507-536) Sopp R. 1., Rs 1. R. RnattasoLdu apb LpsRopk o! Te1aLo1hor1s d1i1ata1e geseryugk // Appi. Keu. Rnagtaso Toxuo1., 1997, 37, p.205-237).

Activation of ionotropic receptors causes the electrical activity of the neuron, while metabotropic ones regulate its size and duration (A. Boldyrev. Functional interactions between glutamate receptors of different classes // Bull. Expert. Biol. And Med., 2000, v. 130, No. 9, p. 244252).

The processes of neuronal excitability and synaptic plasticity are largely based on mechanisms in which the IMIA receptor complex plays a key role. The opening of the channel associated with the IMIA receptor complex leads to an increase in the concentration of intracellular calcium. In turn, this changes the functional activity of the neuron, since it is precisely with an increase in the content of intracellular calcium that synaptic transmission of excitatory signals is associated (CoPiap Ον., Vpbdek K.1., Taie 1.8. E! A1. Not the only one! petuoik kuk1et p1a811s11u apb raLo1od // 1. ΝΙΗ Kek., 1987, ν. 1, p. 65-74).

The activity of the IMIA receptor is regulated by a variety of modulator sites that can be targets for selective agonists and antagonists (MsVash S.1., Maueg M.I.-teFuEe-acragPc ac1b geserGuyisle apb LpsRop // RNukyu. Ke / '., 1994 , ν. 74, No. 3, pp. 723-760; Ishd1ebsche K., Vogdek K., Wo \\ 1e I., Ttaupeyk 8.B. Tne 61 and KashirUser 1op SNapp1k // Rnagtaso Reu., 1999, ν. 51, No. 1, p. 7-62).

With glutamatergic neurotransmission, normal activation of the IMIA receptor causes a short-term opening of the calcium channel. However, under certain conditions, the glutamate IMIA receptors are overactivated, causing prolonged neuronal excitation and leading to excessive intake of calcium ions into the neurons.

Excessive or prolonged stimulation of glutamatergic IMIA receptors leads to dysfunction and subsequent death of neurons by means of a mechanism known as excitotoxicity (from English exhoLhuyu - toxicity that develops upon excitation (Koltap, 8. M., O1peu, 1. V. // Tpebq w Yeitoksg., 1987, 10, No. 7, p. 299-302; NeLada Igkotbegk o! Atsho Asgbk Me! ^^! ^, Ie \ t Watk:

- 1 014100

MashShap, 1989, p. 501-512). In accordance with this mechanism, depolarization of neuronal membranes during pathological activation of ΝΜΌΑ receptors leads to disruption of calcium homeostasis in nerve cells, which causes activation of a number of enzymes that initiate a cascade of biochemical reactions fatal for the cell. It was found that calcium overload of neurons is able to induce the formation of nitric oxide (N0), reactive oxygen species, primarily superoxide anionradical and hydroxyl radical, which, in turn, causes mitochondrial dysfunction and other pathophysiological changes, ultimately leading to cell death (Ско1 Ω. \ ν. С1и1аша1с peigo! oh1syu ίη coP1sa1 se11 siige 18 sa1sht berebep! // No. gig8s1. Bey., 1985, ν. 58, No. 3, p. 293-297; Bibka 1.M. , Ko! Ktap 8.M. 1p1gase11i1ag sa1stsht sopsep1gayop8 bigshd siesh1sa1 kurokh1a apb exhyo! Okhu peigopa shchchg // 1.Noigotsk, 1991, ν. 11, No. 8, pp. 2545-2551; Sagrep! Er Ό. ΝΜΌΑ geser1og8 apb! Ke tosi1ag teska Ш8Ш8 ok exxio1oh1syu // 0x1bayue 8! Ge88 a! еνе18, Еb8 Р.1окп8оп, A. Во1буге \ ^g . Ke8eagsk 81про8 !, TgAapbgit, 2002, pp. 77-88; Vabshd N., Ssh1u Ό.Ό., Sgepepgd M.E. Ked1a! peigop8 bw! 18hf! sa1ssht 81dpakpd ra! k ^ ay8 // 8s1epse, 1993, ν. 260, No. 5105, p. 181-186; Bo1e A. Tke Ko1e ok Exxio! ohuyu w No need for more than 18ea8e: 1t1 Tkegaru // Rkagtasoodu apb Tkegareijs8, 1999, ν.81, No. 3, p. 163-221).

It is assumed that excitotoxicity is a universal molecular mechanism for the development of any neurodegenerative process, since it is observed in the most diverse etiology of neurological and psychiatric diseases associated with neuronal death or impaired function (Bespalov A.Yu., Zvartau E.E. Neuropsychopharmacology of antagonists NΜ ^ Α -receptors, St. Petersburg: Nevsky dialect, 2000, 297 pp .; Vpap 8. Me1bgit S1i1ata1e a8 a Noigo! hap8ty! eh sh! ke Vgash: Ke \ ze \\ · ok Rku8yuodu apb Ra! koododa // 1oita1 ok Mtspbop .. 2000,130, p. 1007-1015; MsBopa1b E8. A1, Mesiash8t8 ok peigo! Okhu shschgu apb se11 bea! To // No. 1. C1sh., 2000, Hades, 18 (3), p. 525-540; KiYp BB, no. 1 se11 bea! K: ap irba! Eb νΐο ^ // Year of your school Ke8., 1998, 117, pp. 3-8; Sko1 Ό.ν. S1i1ata1e peigo! oh1syu apb b18ea8e8 ok! ke peguos 8u81et // Noigop, 1988, ν. 1, p. 623-634).

It has also been established that hyperactivation of the glutamatergic system is the primary cause of neuronal degeneration during cerebral ischemia, stroke, and injuries of the brain and spinal cord (Maish, B.E. a1. No. IHebedepegayop sh eksyu! : And regresure ia oper kop1pbiyop8 ok aror! O818 apb pesgo818 // Vgash Ke8. Vi11., 1998, 1i1 1, 46 (4), pp. 281-309), Alzheimer's disease (^ a1k1pz apb Sospdpbde. Tk NΜ ^ Α Keser! Og, Ohkoggb: 1KB Рge88, 1989; Ouagabagfap 8. е! А1. Κеν ^ еν: А1хкекпег'5 ау1о1б Бе1а-рреййбе-a88ос1а! Еб кее габюа1 Oh1ba1п'е 8! Ge88 apb peigo! Yuyu // 1. 81gis !. Vu1., 2000, 1ip, 130 (2-3), p. 184-208), Parkinson's disease (K1oskde! keg T. Tig8k1 B. Tgepb8 No.igo8s1. 1989, 12, 285- 286; kagoos. | Sh and Noggosk8, Vgash Ke8. Κν., 1991, 16, 171; Co! Ktap, 8. M. apb O1peu, 1. V., Tgepb8 sh No.igo8sg, 1987.10 (7), 299 -302; Eo1eu R., Shebegeg R. 1pk1iepse ok peigo! Ohsh8 apb oh | ba1Be 81ge88 op! Ke op8e! Apb rogge88yup ok Ragksh8op'8 b18ea8e // 1. No. 1, 2000, Arg, 247, 8irr1 2, p .1182-1194), some forms of epilepsy (Pshd1e e! A1., Exhia! ogu atsho as1b geser! og8 sh oberkhu. Tgebb8 Rkagtaso 1. 8sk, 1990, 11, 334; Vgabkogb N.E. S1i1ata! E, SAVA, apb erier8u // Rg. No. 1, 1995, ν. 47, No. 6, p. 477-511), anxiety and depressive states (^ beu apb Pak! E. Prg1111shsa1 eva1ia! ^ Oη ok note! Ku1-e-a8rag1a! E ap! Adosh8! 8 kog apyapkh1e1u ekkes! 8: A ge \ e \\ - // Mi1yr1e 81dta apb RSR Keser! Og Ydapb8: Meskash8t8 kog No.igotobiayop apb No.igorg! Esyop, 1992, No. P Vook8, App Agog, Myuidap, p. 801-815).

The development of Huntington's chorea and amyotrophic lateral sclerosis is associated with excitotoxicity. ) Ehsya! Ogu Atsho Ac1b8 apb Aegis Ke8eagsk. Fuck LU M.K8khe \ hskhak & KBNsh. A1ap K.B188, bs. No. \ ν Wagk, 1989, p. 380; Tke NΜ ^ Α Keser! Eb8. ^ A1ksh8 & CoSpdpbde S., 1989, 1KB Rge88), schizophrenia, increased pain sensitivity (Pyukep8op, And sigog kog \\ zpb-ir: NΜ ^ Α geser! Og ap! Adop18! 8 a8 po! Epy1 ap8de8U8. Rkagtaso. 1.

In a large number of experiments simulating the most diverse neuropathological situations, it was also shown that compounds acting as competitive or non-competitive antagonists of the NΜ ^ Α receptor, as a result of binding to the receptor, block its function and thus weaken or suppress excitotoxicity caused by hyperactivation of the glutamatergic system .

The discovery of the phenomenon of excitotoxicity and the identification of a universal mechanism of the pharmacological action of NΜ ^ Α receptor antagonists resulted in the creation of new therapeutic strategies for the treatment and prevention of a wide variety of diseases of the central nervous system.

Possible therapeutic indications for NΜ ^ Α receptor antagonists include acute forms of neurodegenerative diseases caused, for example, by cerebral ischemia, stroke, hypoxia, hypoglycemia, brain injury or spinal cord injury; chronic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, epilepsy, multi-infarct dementia, Huntington's chorea, multiple sclerosis, amyotrophic lateral sclerosis; degenerative diseases of the retina, neurodegenerative diseases associated with bacterial or viral infections, neurological disorders and diseases including sensation

- 014100 causeless anxiety, psychosis, depression, schizophrenia, migraine, muscle cramps, urinary incontinence or paralysis; drug, drug or alcohol dependence, withdrawal syndrome; acute or chronic pain (EP1313703, A61K31 / 445, publ. 05.28.2003; AO 9511244, A61K31 / 50, publ. 04/27/1995; AO 0234718, A61K31 / 404, publ. 02.05.2002; AO 9505175, A61K31 / 44, publ. 23.02.1995; I84902695, С07О217 / 16, publ. 02.20.1990; I8 5192751, A61K31 / 4427, publ. 03/09/1993; AO 9606081, A61K31 / 40, publ. 02.29.1996; Ragkopk S.6., Οηηνκζ A., Onask 6. 61i1asha1e ίη ΟΝ8 Pkotkesh a ha Tagde! £ from Egad Peue1orshep1: Up Irka1e // Egadk No. \\ Regk !, !, 1998, ν. 11, No. 9, p. 523-580).

In accordance with this, the search for compounds capable of preventing or blocking the overactivation of NΜ ^ A receptors is one of the highest priorities in the development of drugs for the treatment of diseases of the central nervous system (Illarioshkin S. N. et al. Preventive neuroprotection in neurodegenerative diseases: use glutamate receptor antagonists (literature review and own experience) // Neurological journal, 2006, vol. 11, No. 5, pp. 47-54; Le1 8.N. e! a1. Ca2 + p eνeηΐ8 peigo1oh1syu // Vtash. Keck., 1992, ν. 598, № 1 -2, p. 196-202).

To date, a large number of compounds have been synthesized that belong to different chemical groups that are capable of blocking the function of NΜ ^ A receptors.

In particular, polyamines are described as antagonists of NΜ ^ A receptors in patent publications (AO 9312777, A61K 31/13, publ. 08.07.1993); arylalkylamines (AO 9856752, С07С 211/32, publ. 17.12. 1998); polycyclic alkaloids (AO 9703979, A61K 31/135, publ. 06.02.1997); amide derivatives of carboxylic acids (I8 4968678, С07Э 401/06, publ. 06/11/1990; EP 0539057, A61K 31/675, publ. 07/16/1997; AO 0234718, A61K 31/404, publ. 02.05. 2002); derivatives of alkylthioureas (VI 2252936, С07С 335/12, publ. 27.05.2005); 3-substituted derivatives of carboxyindoles (AO 9216205, С07О2 09/42, publ. 01.10.1992); derivatives of hydrogenated pyrido / 3,4-b / indoles (VI2106864, A61K31 / 437, publ. 03.20.1998); pyridine derivatives (AO 03040128, С07О 401/04, publ. 15.05. 2003); substituted hydroxypyridines (AO 9525721; AO 0075109; EP 824098; 2272027, 2178412); piperidine derivatives (AO 9117156, A61K31 / 425, publ. 11/14/1991; EP441506, A61K 31/445, publ. 14.08. 1991; AO 9302052, A61K 31/445, publ. 04.02.1993; AO 9637226, A61K 45/06 , publ. 11/28/1996); quinoxaline derivatives (AO 9113878, A61K 31/495, publ. 09/19/1991; AO 9518616, S07E 487/04, publ. 07/13/1995); derivatives of decahydroisoquinoline (I8 4902695, S07E 217/16, 02.20.1990); imidazopyridine derivatives (EP0092458, А61К 31/435, publ. 26.10.1983; AO 9108211, А61К 31/435, publ. 13.06. 1991); derivatives of piperidinoalkanols (AO 9014088, С07Э 451/02, publ. 11/29/1990; AO 9606081, А61К 31/40, publ. 02/29/1996; AO 9707098, С07О211 / 52, publ. 02/27/1997; AO 0247685, С07О 211 / 52, publ. 06/20/2002); benzyl derivatives (AO 0228814, А61К 31/00, publ. 11.04.2002); derivatives of 4-substituted piperidines (AO 9723216, S07E211 / 14. publ. 03.07.1997; AO 0000197, A61K 31/435, publ. 06.01. 2000); Ν-substituted non-aryl heterocyclic compounds (EP 1379520, A61K 31/444, publ. 14.01.2004); derivatives of adamantane (I8 5061703, A61K 31/13, publ. 10/29/1991; AO 0208219, publ. 01/31/2002).

The disadvantage of most known NΜ ^ A receptor antagonists is the presence of side effects, including impaired coordination of movements, stimulation of the sympathetic nervous system, dizziness, headache, hallucinations, dysphoria and mental impairment and memory, manifested in doses at which the known compounds exert their antagonistic effect on NΜ ^ A receptors.

The closest structural analogues of the claimed compounds are derivatives of 4aminopyridine, including 4-aminopyridine (fampridine), 3,4-diaminopyridine, 2,4-diaminopyridine used in anesthesiology, as well as for the treatment of certain neuromuscular and neurodegenerative diseases (I8 4562196, A61K 31/44 , publ. 12/31/1985).

However, these compounds do not have antagonistic activity against NΜ ^ Areceptors. In addition, the known 4-aminopyridine derivatives have not found wide clinical use due to serious side effects.

SUMMARY OF THE INVENTION

In this regard, one of the objectives of the invention is the creation of new chemical compounds that would have strong antagonistic activity against NΜ ^ A receptors, but would not cause adverse side effects characteristic of known NΜ ^ A antagonists.

The objective of the invention is the development of new pharmaceutical compositions, drugs, methods for their use, which would be effective and safe for the treatment of neurodegenerative and psychiatric diseases and disorders caused by hyperactivation of the glutamatergic system.

The technical result of the invention is to obtain new pharmaceutically active compounds in the series of derivatives of 2,4-diaminopyridine, pharmaceutical compositions and medicines based on them, suitable for the treatment and prevention of neurological and psychiatric diseases and disorders and unexpectedly combining the properties of the high affinity antagonist of NΜ ^ Areceptors with properties moderate acetylcholinesterase inhibitors and high affinity properties

- 3,011,100 agonists of nicotinic cholinergic receptors and sympathomimetics, which leads to their complex normalizing effect on the imbalance of several neurotransmitter systems, including glutamatergic, cholinergic and adrenergic, without manifesting undesirable side effects previously observed in known ΝΜΌΆ-antagonists, as well as as activators of cognates.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to new biologically active derivatives of 2,4 diaminopyridine of General formula (I)

γ

I where In ¹ means hydrogen,

In ² means hydrogen or optionally substituted benzyl, or

B ¹ and B ² together with the atom Ν to which they are attached mean piperidino, morpholino, Ν methylpiperazino,

In ^3, phenyl or substituted phenyl, X is hydrogen, Υ is hydrogen, a cyano group, a carboxyl group, their pharmacologically acceptable salts and / or solvates.

The term “pharmaceutically acceptable salts of a compound of formula (I)” means any salts of an inorganic or organic acid or base that possess the necessary pharmacological activity of the parent compound. These salts can be obtained with ίη 8Yi during the synthesis, isolation or purification of the compounds of formula (I) or specially prepared. Examples of the salt formed by the acid are salts of mineral acids, in particular hydrohalic (hydrofluoric, hydrobromic, hydroiodic or hydrochloric acid), nitric, perchloric, carbonic, sulfuric or phosphoric acids; salts of alkyl sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid and ethanesulfonic acid; salts of arylsulfonic acids such as benzenesulfonic acid or paratoluenesulfonic acid; salts of organic carboxylic acids, such as acetic, fumaric, tartaric, oxalic, maleic, malic, succinic, benzoic, mandelic, ascorbic, lactic, gluconic, citric acid, etc. The compounds of formula (I) according to the invention can be used in the form of various solvates , including in the form of a hydrate.

The most preferred compounds are 2-amino-4-phenylaminopyridine, 2-morpholino-3-cyano-4-phenylaminopyridine, 2-U-methylpiperazino-3-cyano-4-phenylaminopyridine, 2-U-methylpiperazino-4-phenylaminopyridine, 2- benzylamino-3-cyano-4-phenylaminopyridine, 2-benzylamino-4 phenylaminopyridine, 2-morpholino-4-p-chlorophenylaminopyridine.

The compounds of formula (I) and their physiologically acceptable salts or solvates possess an unexpected combination of complementary pharmacological properties that determine their complex effect on the central nervous system.

The new derivatives of 2,4-diaminopyridine are high-affinity receptor antagonists, additionally combining the properties of moderate acetylcholinesterase inhibitors and high-affinity agonists of nicotinic cholinergic receptors and, in addition, possessing the properties of sympathomimetics (i.e., have affinity for the adrenergic system and a low degree of affinity )

Due to the unique combination of these types of activity, the compounds of the present invention possess the therapeutic potential of ΝΜΌΆ receptor antagonists, but at the same time do not exhibit the adverse and undesirable side effects characteristic of the known ΝΜΌΆ receptor antagonists. In particular, the compounds of the present invention have less pronounced psychostimulating properties and exhibit them in doses 10 times higher than therapeutic doses, do not have a potentially adverse effect on blood pressure, respiration and heart rate, bioelectric activity of the heart, tone of bronchial muscles and periodic bowel activity .

Unlike the known antagonists of ΝΜΌΆ receptors, the compounds of the present invention not only do not impair cognitive ability, but also possess the properties of nootropics and activators of cognitive functions that contribute to the development of memory, mental and behavioral abilities. Thus, the compounds of the present invention improve the learning ability of animals in the development of simple and complex instrumental defensive reflexes (URAI and passive avoidance reaction), contribute to the consolidation and preservation of the memorial trail. The new compounds stimulate cognitive functions in animals with learning deficits and have an anti-amnestic effect in experimental memory impairment with the cholinolytic drug scopolamine and maximum electroshock (MES). In experiments on old animals, they have an activating effect on the bioelectric activity of the brain, restore impaired functional asymmetry between its hemispheres, and reduce

- 4 014100 damaging effect of hypoxia on the higher parts of the brain; facilitate the solution of the experimental extrapolation problem by animals in a stressful situation, which may indicate an improvement in their associative functions of the brain.

The pharmacological activity of the compounds of the present invention was determined using tests adopted to evaluate new pharmacological substances ("Guide to the experimental (preclinical) study of new pharmacological substances", Moscow, 2000). At the same time, studies of the receptor activity of new derivatives of 2,4-diaminopyridine were carried out in accordance with the standard recommendations of MOUNTAIN (Szhye ίο Reser1og5 apy Syappey, 8.R.N. A1ehapyeg, A. Mines apy J.A. Re1eg8, SR, ν.147, 8irr 1.3, 2006). The ability of compounds to bind competitively to ΝΜΌΑ glutamate receptors was determined on the basis of a radioligand binding assay using tritium-labeled ligands of the glutamate receptors [C-3H] -MK-801 (disocylpin) (see Νο \ ν; · ι1 <C., Trn11a5 I ., Laueg Ya., 8k1shk R., apy Rai1 I. AjarGeo siapdez ίη 1Ne NoTeLu1-O-A8rayae geserlog sotr1ekh ayeg sygoshs 1gea1tep1, νίί1ι 1t1rgatte apy 1-apocentiocomp. , p. 1380-1386). The activity of the compounds against dopamine receptors was determined using tritium-labeled ligands [C-3H] -8CH-23390 for the D1 type of dopamine receptor and [C-3H] spiroperidol (spiropril) for the D2 type of dopamine receptor (8ip U. , С ^ ηоνа ^ ί К, Ko E., 8etap R., e1 a1., Ιη νίνυ е \ Зеепсе и йорате-теФа1ей 1п (епп11ха (1 st О2-гесер1ог5 айег атрее1йейрёпе1пешепе1пешепе1пе1пе1пе1пе1епе [3H] 8p1regope. Mo1 Ryagtaso 63 (2): 456-62, 2003).

To study the affinity of the compounds of formula (I) for cholinergic receptors, experiments were carried out on radioligand binding using tritium-labeled (±) nicotine with a specific activity of 140 Ci / mmol obtained by solid-phase labeling (Kovalev G.I. Mammalian CNS presynaptic receptors as an object of pharmacological effects Moscow, VINITI, v. 15, pp. 5-61, 1987).

The pharmacological activity of the compounds of formula (I) as activators of cognitive functions was demonstrated in amnesia models and behavioral experiments 1n νί \ Ό (experimental animals - mice, rats).

The activity of the compounds of formula (I) as sympathomimetics was confirmed on standard models, such as tests on the effect on behavioral reactions, on the deprimative effect of reserpine.

The effectiveness of new 2,4-diaminopyridine derivatives for the treatment of multiple sclerosis I was demonstrated on experimental allergic encephalomyelitis (EAE) models, which are generally accepted when testing new agents for the treatment of demyelinating and other neurodegenerative diseases in humans (Nayeg, E.A. apy Ueteg, N. . // [type 1 companionship 1 ν ν ^ ν 8 8, 1995, 144, p. 75).

The inventive compounds can be obtained by the method illustrated by reaction scheme 1 below.

Scheme 1

- 5 014100 where KZ-K ⁵ , X and Υ have the meanings indicated above.

The results of the synthesis, biochemical studies and testing of the pharmacological activity of the compounds of formula (I) are given in the corresponding examples, which illustrate but do not limit the scope of the present invention.

A subject of the invention is also a pharmaceutical composition which contains, as an active ingredient, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, taken in an effective amount in a mixture with pharmaceutically acceptable excipients.

The term “effective amount” means an amount of an active ingredient that, when administered to a patient, provides prevention or amelioration of the disease and the symptoms of the disease to be prevented or treated.

As pharmaceutically acceptable excipients in the pharmaceutical composition according to the invention, any pharmaceutically acceptable components that are compatible with the active ingredient and do not harm patients, traditionally used for the preparation of dosage forms, for example fillers, binding agents, granulating agents, solubilizing agents, glidants, stabilizers, diluents, adjuvants, preservatives, components of buffer systems, solvents, di dispersing agents, preservatives, lubricants, flavoring agents, thickeners, food colors, emulsifiers, delayed delivery regulators, and the like.

Pharmaceutically acceptable adjuvants are, for example, lactose, inositol, glucose, mannitol, dextran, cyclodextrin, sorbitol, starch and its modifications, sucrose, magnesium aluminum silicate, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethyl cellulose, hydroxypropylated starch, carboxymethyl cellulose, ion exchange methyl cellulose, gelatin, gum arabic, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, alginic acid, algin t of sodium, anhydrous silicic acid, magnesium stearate, talc, carboxyvinyl polymer, titanium oxide, fatty acid ester of sorbitol, sodium lauryl sulfate, glycerin, glycerol fatty acid ester, lanolin, glycerol gelatin, polysorbate, macrogol, vegetable oil, propylene glycol, wax, para , polyethylene glycol, water, ethanol, polyalcohols, polyoxyethylene hydrogenated castor oil, sodium chloride, sodium hydroxide, hydrochloric acid, dibasic sodium phosphate, monobasic sodium phosphate, citric acid, glutamic acid, benz silt alcohol, methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate and the like.

The pharmaceutical compositions of the present invention can be in the form of an oral administration form, for example, in the form of tablets, granules, beads, powders, capsules, suspensions, syrups, emulsions, etc .; in injection form; suppository for rectal or vaginal administration; aerosols, spray, transdermal, intranasal, intraocular forms of administration, etc. Solid forms of pharmaceutical compositions for oral administration and solutions for injection are preferred.

The pharmaceutical compositions may be prepared by any known method in the art using one or more pharmaceutically acceptable excipients. For example, in the manufacture of tablets, the active ingredient is mixed with traditional tablet ingredients, such as fillers, binders, disintegrants, granulating agents, lubricants and glidants, followed by compression of the resulting mixture in a tablet machine. As fillers and disintegrants, lactose, sodium citrate, calcium carbonate and dicalcium phosphate, and the like can be used; binding agents - starch or its derivatives, gelatin, glucose, lactose, natural or synthetic gums, such as gum arabic, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, wax, sodium lauryl sulfate and talc, etc. Lubricants used in these dosage forms include, but are not limited to, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. If desired, tablets may be coated with sugar, gelatin, film, or intestinal coatings by standard methods, for example, a tablet may include an inner core containing the active ingredient and an outer layer in the form of a shell covering the core. The outer shell can serve to protect against disintegration in the stomach, which will allow the inner core to pass intact into the duodenum and slowly release. A variety of substances can be used to form such protective layers or shells, including a number of polymeric acids and mixtures of polymeric acids with common substances, such as alkali, cetyl alcohol and cellulose acetate. Sweeteners and flavorings may be added to improve the taste of the oral form.

A pharmaceutical composition in the form of capsules can be prepared by mixing the active ingredient with excipients, such as, for example, sorbitol or lactose, and packaging the resulting mixture in capsules.

A pharmaceutical composition in the form of oral medicines, elixirs or syrups may contain water, polyols, sucrose as pharmaceutically acceptable excipients,

- 6 014100 inverted sugar, glucose, edible oils, such as cottonseed oil, sesame oil, coconut oil or peanut oil, food flavorings, colorings, etc. Potions, elixirs or syrups may additionally contain suspending agents and thickeners, such as synthetic and natural gums (tragacanth, Arabian gum), alginate, dextran, sodium carboxymethyl cellulose, gelatin, glycerin, methyl cellulose or polyvinyl pyrrolidone, or preservatives, for example.

A pharmaceutical composition in an injection form can be prepared by dissolving the active ingredient and possible adjuvants in part of the injection solvent, preferably in sterile water, adjusting the resulting solution to the desired volume, optionally adding a pH adjusting agent, solubilizer, stabilizer or antiseptic sterilizing the resulting solution and filling it with suitable ampoules or containers. As a solvent, physiological saline, alcohols, polyols, glycol ethers, for example, polyoxyethylene sorbitan, monolaurate, monooleate or monostearate, glycerin, vegetable oils, etc. can be used.

Pharmaceutically acceptable excipients in the preparation of a pharmaceutical composition in the form of suppositories are, for example, natural or hardened oils, for example, cocoa butter, waxes, fats, glycerol and saturated fatty acid esters, glycerogelatin, macrogol, semi-liquid or liquid polyols, triglycerides, etc. . The suppository base may also include a surfactant or stabilizer.

The composition according to the invention may also contain such components that provide a quick, sustained or delayed release of the active ingredient after administration by patients. The prolonged action of the composition can be achieved using agents that slow down the absorption of the active principle, for example aluminum monostearate and gelatin.

Preferably, the active ingredient is included in the pharmaceutical composition of the present invention in unit dosage form.

The term in unit dose means any effective amount of an active ingredient which, in combination with pharmaceutically acceptable excipients, is contained in a dosage form of a pharmaceutical composition used for single administration to a patient.

The pharmaceutical composition of the present invention in a single unit dose may contain the active ingredient in an amount of from 0.01 to 100 mg, preferably in an amount of from 0.1 to 10 mg of the active ingredient. Of course, an effective amount of the active ingredient in some compositions may go beyond the above boundaries.

The following formulation examples are illustrative only and do not limit the scope of the present invention.

The invention also relates to a medicament containing a compound of formula (I), its pharmaceutically acceptable salts, solvates as such or in the form of a pharmaceutical composition, for treating and preventing diseases or disorders of the central nervous system associated with increased activation of the glutamatergic system and / or intellectual impairment functions.

Diseases or disorders to be treated or prevented with the drugs of the present invention include acute forms of neurodegenerative disorders or diseases associated with sudden damage to neurons or impairment of their functions, including, but not limited to, cerebrovascular insufficiency, cerebral ischemia, stroke, neuropathies caused by hypoxia or hypoglycemia, brain injury or damage to the spinal cord and the like; chronic neurodegenerative disorders or diseases associated with damage to motor neurons, including, but not limited to, amyotrophic lateral sclerosis, spinocerebellar degeneration, degenerative ataxia, cortico-basal degeneration, the Guam complex (amyotrophic lateral sclerosis-parkinsonism-dementia complex), subacute sclerosalitis ; chronic neurodegenerative demyelinating diseases associated with the destruction or impairment of the formation of the myelin sheath of the nerve conduits, including, but not limited to, multiple (multiple) sclerosis, multiple encephalomyelitis, Schilder’s sclerosis, inflammatory and vascular myelinopathy, inflammatory demyelinating disease, polymyelinus disease, polymyelinus syndrome, -Bignami, central pontine myelinolysis, neurooptomyelitis, Devic's syndrome, Balo's disease, myelopathy in HIV, secondary demyelinating diseases such as CNS lupus erythematosus, polyarteritis nodosa, Sjogren's syndrome, sarcoidosis, localized cerebral vasculitis and the like; chronic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multi-infarction dementia, Huntington's disease; neurodegenerative diseases associated with bacterial or viral infections; neurological and psychiatric disorders and diseases associated with excitotoxic neuronal damage, including, but not limited to, feelings of causeless anxiety, psychosis, depression, schizophrenia, epilepsy, migraine, muscle cramps, urinary incontinence, paralysis,

- 7 014100 drug, drug or alcohol dependence, withdrawal syndrome; conditions with acute or chronic pain syndrome; acute or chronic neurodegenerative disorders or diseases associated with impaired cognitive function, learning ability, memory impairment, remembering, impaired attention, which may result from age-related changes, mental retardation, stroke, trauma, alcohol or drug use, or any other acute or chronic neurodegenerative diseases, for example, such as Alzheimer's disease, Parkinson's disease and the like.

The therapeutic and prophylactic effect of the drugs of the present invention is based on several complementary mechanisms, which are based on the neuroprotective and cognitively activating effects of the new derivatives of 2,4-diaminopyridine.

Due to the presence of strong antagonistic activity against ΝΜΌΑ-receptors, the proposed drugs are able to block overactivity of ΝΜΌΑ-receptors and suppress the pathological influx of calcium into neurons associated with this process, thereby protecting neurons from pathological activation and excitotoxicity, which makes them suitable for treatment and prevention of various neurodegenerative and psychiatric diseases caused by hyperactivity of the glutamatergic system.

The cognitive activity of the drugs of the present invention is associated with the stimulation of cholinergic processes in the brain by the activation of nicotinic cholinergic receptors, as well as the inhibition of acetylcholinesterase. Compounds that activate nicotinic receptors or block the activity of acetylcholinesterase are known to compensate for the deficiency of hypofunction of the cholinergic system and can have an antiamnestic and nootropic effect and can be used in the treatment of cognitive disorders (V.G. Granik, “Medicines”, 2006, M ., "University Book", pp. 173-177).

For the compounds of the present invention, the presence of sympathomimetic activity is also shown. The presence of this activity determines the activation of cognitive functions (along with a psychostimulating effect), antidepressant effects and increased performance.

The compounds of the present invention possess the above activities, as a result of which they not only do not cause disturbances in mental abilities, attention and memory, characteristic of known antagonists of ΝΜΌΑ-receptors, but, moreover, may be suitable for the treatment and prevention of a number of diseases or disorders related with impaired cognitive function and learning ability. (Lups, 2003; Uogoshp, Syegiysh, 2003; Rerey, Syuapshsh, 2004; Me8i1ash, 2004). (Rerey 1. apb M.L. Syuapsh, Leagpd & Metogu, 11: 21-27; 2004.). (Egapaz R.T., A1ap Μ Ra1teg, Muaye1 8pare apb Sogbop K EDbskosk, 1. No. 1. No. hyposigd. RzusYaPu; 66: 137-147, 1999, O. Gozkt L.R. apb R.A. Sgookk, GRET 298: 395-402, 2001; Feziat, Μ., Lägshpd & Μeto ^ u, 11: 43-49; 2004). (Νίδΐιίζηΐίί T., T ^ a ^^ ka, T. # tsha, e! A1., Μο1.Rya ^ taso1., 53: 1-5; 1998. N ^ zyzak ^ T., T.Μaΐzioka, T. Shtiga e! A1., Vgash Kez., 826 (2): 281-288; 1999. Νί31ιίζη1 <ί Т, Μаΐзіёка Т, №tiga Т, Kopboy T, EDa! Aye 8, 8yyu! Ash T, Wuzil Μ ANyeteg Ό13 Azzos O | zogb 2000; 14 8irr1 1: 882-94). (8sype1beg 1.8., 1. R. Tshkeg, E. ηеηζадй ^ apb S.K. L1oub, 1ET 306: 401-406, 2003).

Thus, on the basis of the action profile, the drugs according to the invention have a complex normalizing effect on the imbalance of several neurotransmitter systems, including glutamatergic, cholinergic, adrenergic systems, have an extremely low degree of affinity for dopamine receptors, and therefore can be more effective for the treatment or prevention of a number of diseases or disorders of the central nervous system without manifesting undesirable side effects, previously observed vshihsya have known ΝΜΌΑantagonistov.

The invention also relates to a method for the treatment or prophylaxis of diseases and disorders associated with increased activation of the glutamatergic system and / or impairment of intellectual functions, by administering to the patient an effective dose of a compound of formula (I), a pharmaceutically acceptable salt, hydrate, pharmaceutical composition or drug thereof basis.

A compound of formula (I), pharmaceutically acceptable salts, solvates, a pharmaceutical composition or a medicament based thereon, are administered to the patient by conventional methods well known to those skilled in the art, for example, orally, rectally, intravaginally, transdermally, intranasally, intraocularly or parenterally . A preferred method of administration of the invention is oral or parenteral administration.

The dose and course of administration prescribed to treat or prevent the above diseases or disorders can vary widely. In each case, the choice of the appropriate dosage depends on the age, body weight of the patient, method of administration, the particular type of disease to be treated or prevented, as well as the severity of the disease or condition of the patient. The recommended daily dose for an adult patient is 0.01-300 mg / day, a dose of 0.01-30 mg / day is preferred for all of the above indications. The full daily dose may be administered in a single dose, or the daily dose may be given in divided doses of two, three or four

- 8 014100 times a day.

Specialists in this field it is clear that it is easy to determine the optimal dosage and course of treatment that will provide a therapeutic or preventive effect in each case.

The invention is illustrated, but not limited to the following examples.

Example 1. 2-amino-3-cyano-4-phenylaminopyridine.

To 25.5 g of 2-chloro-3-cyano-4-phenylaminopyridine (compound II), 200 ml of alcohol ammonia (ammonia concentration 13 ± 1%) was added and heated in an autoclave at 200-210 ° C for 9 hours. The mixture was cooled 100 ml of alcohol are distilled off and kept at 0 ° C for 2 hours. The precipitate is filtered off, washed with 50 ml of water, dried, and 20 g of technical 2-amino-3-cyano-4-phenylaminopyridine are obtained (compound of formula (I), where P ¹ = B ² = X = H. Y = CH, B ³ = Pb, hereinafter referred to as compound 1b), the yield is 85.7%, so pl. 194-197 ° C. After recrystallization from methanol, so pl. 194-196 ° C.

Found,%: C 68.68, H 5.05, N 26.67; C1 ₂ H ₁₀ S ₄ ;

Calculated,%: C 68.57, H 4.76, N 26.67;

Mass spectrum: M ⁺ 210; IR spectrum, ν cm ^-1 : 2200 (SC), 3195, 3310, 3400 (ΝΗ, ΝΗ ₂ ).

Example 2. 2-amino-4-phenylaminopyridine.

To 10 g of compound 1b obtained in Example 1, 10 g of KOH, 8 ml of ethylene glycol and 1.5 ml of water are added, the mixture is boiled for 7 hours, cooled, 500 ml of water are added and the mixture is kept for 0.5 h at + 2 ° С. 3.9 g (44.3%) of 2-amino-4-phenylaminopyridine (compound of formula (I), where Ρ ^Ι = Ρ ² = Χ = Υ = H, B ³ = Pb, is subsequently filtered off, hereinafter referred to as compound I; ) and the precipitate is washed with water. The aqueous mother liquor was extracted with chloroform (2 times 70 ml), the chloroform extracts were dried with CaCl ₂ , filtered, evaporated, the residue was triturated with petroleum ether, and an additional 0.3 g (3.4%) of compound b was filtered off. The total yield of compound I; equal to 4.2 g (47.7%), mp 164-166 ° C (from hexane).

Found,%: C 70.96, H 5.99, N 22.94; Scn ^ s;

Calculated,%: C 71.30, H 5.95, N 22.70;

Mass spectrum: M ′ 185, IR spectrum, ν cm ^-1 : 3400, 3495 (NН, NΗ ₂ );

¹ NMR spectrum (DMF b7), ppm: 5.74 (2H, br s, N1 ^); 6.30 (2H, m. 3-H, 5-H); 7.00-7.40 (5H, m, Pb); 7.70 (1H, d, ³ 15-H, _6-H = 5.9 Hz, 6-H); 8.52 (1 H, broad s, NΗ).

Example 3. 2-amino-4-phenylaminopyridine-3-carboxylic acid.

A) The aqueous layer remaining after the extraction of compound b in Example 2 was acidified with concentrated HCl to pH 5-6 and 4.2 g (38.5%) of 2-amino-4-phenylaminopyridine-3-carboxylic acid was filtered off (compound of the formula ( I), where B ¹ = B ² = X = H, Υ ^ В, B ³ = Pb, hereinafter referred to as compound K), washed with water, so pl. 258-260 ° C (from dimethylformamide).

Found,%: C 62.90, H 4.97, N 18.21; C ^ NccOD

Calculated,%: C 62.88, H 4.80, N 18.34;

Mass spectrum: M ⁴ 229, IR spectrum, ν cm ^-1 : 1660 (СО), 3400, 3495 (1 \ 1Н, ^ Д;

NMR spectrum (SG ₃ SOOI), ppm: 6.41 (1H, d,% _-6 = 7.6 Hz, 5-H); 7.25-7.65 (6H, m. 6H, Pb).

B) To 5 g of compound F, 15 g of KOH, 20 ml of diethylene glycol are added and heated at 130-140 ° C for 7 hours, the mixture is cooled, 100 ml of water are added and 0.18 g (18.2%) of compound I is filtered off; . The mother liquor is acidified with a solution of H ₂ 8O ₄ and 3 g of compound K (55%) is filtered off.

A mixture of 2 g of compound K and 100 ml. ethylene glycol is boiled for 4 hours, cooled, 100 ml of water are added, incubated for 1 hour at 2 ° C, 1.3 g of compound I are filtered off; (80.5%).

Example 4. 2-amino-4-phenylaminopyridine phosphate.

1.5 ml of water are added to a solution of 1 g of compound b in 8.5 ml of alcohol, cooled to 0 ° C and 0.7 g of 100% orthophosphoric acid in 3 ml of alcohol are added dropwise with stirring in 0.5 ml and water (8.5: 1.5), incubated for 2 hours at 0 ° C and then 3 days at 2 ° C. The precipitate formed is filtered off, washed with 10 ml of acetone, and 1.2 g (78.5%) of 2-amino-4-phenylaminopyridine phosphate are obtained, so pl. 196199 ° C.

Found,%: C 46.62, H 4.94, N 14.48, P 10.95; Spn ^ KO ^;

Calculated,%: C 46.64, H 4.95, N 14.84, P 10.95;

Mass spectrum: M ⁴ 185;

'H NMR spectrum (I ₂ O), ppm: 6.06 (1H, s. With resolution, ⁴ 13-H-5-H = 2.2 Hz, 3-H); 6.35 (1H, with cleavage, ³ 15-n-6-n, = 7.3 Hz, 5-H); 7.42 (1 H, doublet. 6-H); 7.15-7.50 (5H, m, pb).

Example 5. 2-amino-4-phenylaminopyridine hydrobromide.

30 ml of 20% HBg are added to 3 g of compound b, the reaction mass is brought to a boil, the precipitate is dissolved, cooled, evaporated, the residue is triturated with acetonitrile, 2.6 g (60.3%) of 2-amino are obtained -4-phenylaminopyridine hydrobromide, mp 175-176 ° C (from isopropanol: acetonitrile 1: 1).

Found,%: Vg 30.36; CnH ^ Br; Calculated%: Vg 30.08.

Example 6. 2-Morpholino-3-cyano-4-phenylaminopyridine.

15 ml of morpholine are added to 1 g of compound II and the mixture is heated for 10 hours at 200-210 ° C in an autoclave.

- 9 014100 ve, the mixture is cooled, 100 ml of 92% alcohol are added, filtered, the alcohol is distilled off in vacuo, the residue is triturated with water, the product is filtered off, recrystallized from hexane, 1.2 g (98%) of 2-morpholino-3 are obtained -cyano-4-phenylaminopyridine (compound of formula (I), where Υ = 0'0. K ³ = Py, X = H, K ¹ , K ² = morpholino, hereinafter referred to as compound I), so pl. 152-154 ° C.

Found,%: C 68.64; H, 5.80; N, 20.09; C ₁₆ H ₁₆ ^ O;

Calculated,%: C 68.57, H 5.71, N 20.00; Mass spectrum: M '280.

Example 7. 2-No.Metylpiperazino-3-cyano-4-phenylaminopyridine.

The reaction is carried out analogously to example 6, but 15 ml of N-methylpiperazine are taken per 1 g of compound II, heated for 10 hours at 200-210 ° in an autoclave, 1.04 g of 2-N-methylpiperazino-3-cyano-4-phenylaminopyridine is obtained (compound of formula (I) , where K ³ = Pu, Υ ^ Ν, X = H, K ¹ , K ² = No. methylpiperazino, hereinafter referred to as compound k), 94% yield, mp. 123-125 ° C (from heptane).

Found,%: C 69.80; H, 6.57; N, 23.65; C ₁₆ H ₂₁ ^;

Calculated,%: C 69.62, H 6.48, N 23.89; Mass spectrum: M ⁺ 293.

Example 8. 2-No.Metylpiperazino-4-phenylaminopyridine.

g of compound K is heated in polyphosphoric acid for 4 hours at 160-170 ° C (PFC; prepared from 15 g of phosphoric acid and 15.7 g of P ₂ O ₅ ), cooled, 75 ml of water are added, alkalinized with 4% No. 1OH to pH 8, extracted with chloroform and 0.87 g (95%) of 2-methylpiperazino-4-phenylaminopyridine (compound of formula (I), where K ³ = Pb, Υ = X = H, K ¹ , are obtained from the chloroform extract by the usual procedure K ² = No. methylpiperazino, hereinafter referred to as compound II), so pl. 160-162 ° C (from heptane).

Found,%: C 71.67, H 7.73, N 21.21; ZDL

Calculated,%: C 71.64, H 7.63, N 20.90; Mass spectrum: M '268.

Example 9. 2-Morpholino-4-phenylaminopyridine.

To 1 g of compound I, 1 g of KOH and 8 ml of ethylene glycol are added and the mixture is boiled for 6.5 hours. After the usual work-up similar to that used to obtain compound E1 in Example 2, 0.8 g (88%) of 2-morpholino -4-phenylaminopyridine (compound of formula (I), where K ³ = Py, Υ = Χ = 4, K ¹ , K ² = morpholino, hereinafter referred to as compound [β), so pl. 160-162 ° C (from heptane).

Found,%: C 70.49, H 6.72, N 16.47; C. 11 · N, 0;

Calculated,%: C 70.59, H 6.67, N 16.47; Mass spectrum: M '268.

Example 10. 2-Piperidino-4-phenylaminopyridine.

The reaction is carried out analogously to example 9, but take 1 g of the compound 2-piperidino-3-cyano-4 phenylaminopyridine, 1 g KOH and 8 ml of ethylene glycol and the mixture is boiled for 6.5 hours and 0.8 g of 2 piperidino-4-phenylaminopyridine is obtained (compound of the formula ( I), where K ³ = Py, Υ = Χ = 4, K ¹ , K ² = piperidino, hereinafter referred to as compound III). Yield 87%, mp. 181-183 ° C (from heptane).

Found,%: C 75.68, H 7.60, N 16.60; SKDe ^;

Calculated,%: C 75.90, H 7.51, N 16.60; Mass spectrum: M ⁺ 253.

Example 11. 2-Benzylamino-3-cyano-4-phenylaminopyridine.

1 ml of benzylamine and 20 ml of absolute alcohol are added to 1 g of compound II, the mixture is heated for 10 hours at 200-210 ° C in an autoclave, cooled, the precipitate is filtered off, recrystallized from absolute alcohol, 1.3 g (99%) of 2-benzylamino are obtained -3-cyano-4-phenylaminopyridine (compound of formula (I), where Υ ^^ K ³ = Py, X = K ¹ = H, K ² = benzylamino, hereinafter referred to as compound B), mp 163165 ° C.

Found,%: C 75.96, H 5.30, N 18.74; C ₁₉ H ₁₆ ^;

Calculated,%: C 76.00, H 4.95, N 14.84, P 10.95; Mass spectrum: M '280.

Example 12. 2-Benzylamino-4-phenylaminopyridine.

The reaction is carried out analogously to example 9, but 1 g of compound II is taken, 1 g of KOH and 8 ml of ethylene glycol are added and the mixture is boiled for 6.5 hours and 0.84 g of 2-benzylamino-4-phenylaminopyridine is obtained (compound of formula (I), where Υ = Η, K ³ = Pb, X = K ^! = H, K ² = benzylamino, hereinafter referred to as compound III). Yield 90%, mp. 111-113 ° C (from heptane).

Found,%: C 78.72, H 6.40, N 15.15; C ₁₈ H ₁₇ ^;

Calculated,%: C 78.55, H 6.18, N 15.27; Mass spectrum: M ⁺ 275.

Example 13. 2-Morpholino-3-cyano-4-p-chlorophenylaminopyridine.

The reaction is carried out analogously to example 11, but take 1 g of 2-chloro-3-cyano-4-p-chlorophenylamino pyridine, 1 ml of morpholine and 20 ml of absolute alcohol, the mixture is heated for 10 hours at 200-210 ° C in an autoclave and get 2- morpholino-3-cyano-4-p-chlorophenylaminopyridine (compound of formula (I), where Υ ^^ K ³ = p-chlorophenyl, X = H, K ¹ , K ² = morpholino, hereinafter referred to as compound Tm). Yield 75%, mp. 161-163 ° C (from heptane).

Found,%: C 61.20, H 4.97, N 17.86, C1 11.39; C1 ₈ H ₁₇ ^;

Calculated,%: C 61.05, H 4.77, N 17.81, C1 11.29;

Mass spectrum: M ⁺ 314.

Example 14. 2-Morpholino-4-p-chlorophenylaminopyridine.

The reaction is carried out analogously to example 9, but take 1 g ^, 1 g KOH and 8 ml of ethylene glycol and a mixture

- 10 014100 boil for 6.5 hours and get 2-morpholino-4-p-chlorophenylaminopyridine (compound of formula (I), where Υ = Η, B ³ = p-chlorophenyl, X = H, B ¹ , B ² = morpholino, hereinafter referred to as the connection Ση). Yield 97%, mp. 148-149 ° C (from heptane).

Found,%: C 62.23, H 5.52, Ν 14.39, 12.16; C ₁₈ H ₁₇ S ₃ C1;

Calculated,%: C 62.18, H 5.53, Ν 14.51, C1 12.26; Mass spectrum: M ⁺ 289.

Example 15. 2-amino-3-cyano-4-p-methoxyphenylaminopyridine.

The synthesis is carried out analogously to example 11, but in the reaction with 1 g of 2-chloro-3-cyano-4-methoxyphenylaminopyridine take 20 ml of alcohol ammonia, the mixture is heated for 10 hours at 200-210 ° C in an autoclave and get 2-amino-3-cyano -4-p-methoxyphenylaminopyridine (compound of formula (I), where Υ ^ Ν, B ^! = X = B ² = H, B ³ = p-methoxyphenyl, hereinafter referred to as the compound! O). Yield 76%, mp. 211-213 ° C (from isopropanol).

Found,%: C 78.72, H 6.40, Ν 15.15; C1 ₈ H ₁₇ S ₃ ;

Calculated,%: C 61.20, H 4.97, Ν 17.98; Mass spectrum: M ⁺ 314.

Example 16. 2-amino-4-p-methoxyphenylaminopyridine.

The reaction is carried out analogously to example 9, but take 1 g! O. 1 g of KOH and 8 ml of ethylene glycol are added and the mixture is boiled for 6.5 hours to obtain 2-amino-4-p-methoxyphenylaminopyridine (compound of formula (I), where Υ = Η, B ^! = X = B ² = H, B ³ = p-methoxyphenyl, hereinafter referred to as the compound Σρ). Yield 56%, mp. 154-156 ° C (from benzene).

Found,%: C 66.72, H 6.04, Ν 19.74; C1 ₈ H ₁₇ S ₃ ;

Calculated,%: C 66.98, H 6.05, Ν 19.53; Mass spectrum: M '215.

Example 17. Determination of the activity of compounds with respect to the ΝΜΌΆ receptor.

The compounds of formula (I) are tested for ΝΜΌΆ-antagonistic activity in a model of membrane preparations by radioligand analysis based on the competitive binding of the test compound or selective labeled ligand to the ΝΜΌΆ receptor. As the ligand, tritium-labeled compound MK-801 (disocylpin), a known antagonist of β receptors, is used. The affinity of the tested compounds for the ΝΜΌΆ receptor and their antagonistic activity are evaluated by a value of ^ ₅₀ , which reflects the ability of the compounds to displace the labeled ligand from the phencyclidine binding site to the ΝΜΌΆ receptors.

For the preparation of membrane preparations of ΝΜΌΆ receptors, the hippocampus and cerebellum isolated from rat brain frozen in liquid nitrogen are used. The tissue is thoroughly homogenized in a Potter homogenizer (Teflon-glass) in 10 volumes of 5 mM HEPE8 / 4.5 tM Tris buffer (pH 7.6) containing 0.32 M sucrose (buffer No. 1). The homogenate is diluted to 50 volumes with 5 mM HEPE8 / 4.5 shI Tris buffer (pH 7.6) (buffer No. 2) and centrifuged for 10 min at 1000 d.

The supernatant was removed and centrifuged again for 20 minutes at 25,000 d. The pellet was homogenized in 50 volumes of buffer No. 2 and centrifuged for 20 minutes at 8,000 days. The supernatant and its soft, unsteady superlayer were removed and centrifuged for 20 minutes at 25,000 days.

The resulting precipitate was suspended in 5 mM HEPE8 / 4.5 mM Tris buffer containing 1 mM Na4EOTL (pH 7.6) (buffer No. 3), and the suspension was again centrifuged. This washing procedure is carried out four times, and at the last washing, EOTL is excluded from the buffer. The final precipitate was resuspended in 5 volumes of buffer No. 2 and stored in liquid nitrogen.

In the experiment on receptor binding using labeled with tritium MK-801 with a specific activity of 210 Ci / mol. The reaction mixture (final volume 0.5 ml) contains 200 μl of buffer No. 2, 50 μl of labeled ligand (50 nM solution) and 250 μl of a suspension of membranes. Nonspecific binding is determined in the presence of 50 μl of unlabeled ligand.

The reaction mixture is incubated at room temperature for 2 hours in the presence of calculated concentrations of the test compounds of formula (I). At the end of the incubation, the samples are filtered through OE / B glass fiber filters (^ ka! Tap) pre-soaked in 0.3% polyethylene emine for 2 hours at 4 ° C. Each tube was washed once with cold buffer No. 2, then the filters were washed three times with the same volume of buffer. The filters are dried in air until completely dry and transferred to scintillation vials. The filters are filled with 5 ml of a scintillation mixture containing 4 g of PPO (2,5-diphenyloxazole), 0.2 g of POPOP [1,4-bis (5-phenyl-2-oxazolyl) benzene)] per 1 liter of toluene. Radioactivity is recorded on a \ Wa11as1411 scintillation counter with a counting efficiency of about 46%.

Protein in all experiments is determined by the Lowry method. In statistical and graphical processing, special software packages are used: §1a118Ysa 6.0, 81dta Р1о1 9.0, OgarkRab Prgyp 4.

For tested compounds, a value of ^ _{50 is} determined. As a result of these tests, it was found that the value of Κ \ ₀ for the most active compound E1 of the present invention is 2.4 μM, which indicates a high degree of affinity for ΝΜΌΆ receptors and strong antagonistic activity in relation to this subtype of glutamate receptors.

Example 18. Determination of the activity of compounds against dopamine receptors.

To obtain membrane preparations of dopamine receptors, striatums from 4 animals are thoroughly homogenized in 10 ml of ice-cold (0-4 ° C) 50 mM Tg-HC1 buffer (pH 7.4 at 4 ° C) using a Teflon-glass homogenizer. The resulting suspension is centrifuged at 40,000 d for 20 min in

- 11 014100 ultracentrifuge “Orbta B-70K” (Vesktap Soiyeg).

After centrifugation, the supernatant is drained, the pellet is resuspended by repeated homogenization in the same volume of the buffer, then centrifuged again. The washing procedure is carried out three times, the resulting precipitate is resuspended in 10 ml of 50 MM TPZ-HC'1 incubation buffer (pH 7.4 at 37 ° C) with the addition of salts (120 MM No. 1Cl. 5 MM KCl, 2 MM CaCl ₂ -2 N ₂ О, 1 ММ МДС1 ₂ -6Н ₂ О) and use 250 μl each in the indicated binding procedure of [6-3Н] -8СН-23390 (D1 type of dopamine receptor) and [C-3H] spiroperidol (D2 type of dopamine receptor )

Radioligand analysis. The resulting membrane fraction is incubated with [C-3H] -ligand, which is added to the incubation mixture in a volume of 50 μl at a final concentration of 0.1 nM for 20 min at 37 ° C using a solid-state thermostat "Termite" (NPO DNA -diagnostics"). Nonspecific binding is determined in the presence of 50 μl of unlabeled spiroperidol (20 μM) or - 8CH23390, which on average does not exceed 12-14% of the total. Specific binding is calculated as the difference between total and non-specific binding.

1С ₅₀ with respect to [С-3Н] -spipeperidol (specific activity 95 Ci / mmol) or | С-3Н | 8СН23390 (specific activity 60 BSi / mmol) is determined by adding 50 μl of the studied compounds to the incubation medium at final concentrations in the range 10 ^-3 -10 ^-10 M. The volume of the incubation mixture is 500 μl. The binding process is stopped by adding 2 ml of ice-cold 50 mM TPS-HC'1 buffer and rapid filtration through CE / B type glass fiber filters (^ ba! Tap) followed by washing with ice-cold buffer with a total volume of 14 ml. The filters are pre-wetted before the experiment in ice-cold 50 mM TPS-HC'1 buffer for 3 hours.

The filters are then dried for 12 hours at room temperature, then placed in a scintillation fluid (Bray reagent) with a volume of 4 ml and used for scintillation counting. The radioactivity of each sample is measured for 2 min on a scintillation counter ^ a11aC 1411. The counting efficiency for tritium is 40-45%. Determination of protein content in samples is carried out according to the Lowry method. The optical density (X = 700 nm) is measured on an SF-46 spectrophotometer (LOMO). The results are processed using standard statistical programs with the calculation of the arithmetic mean and 8EM.

For all tested compounds determine the value of the indicator 1C ₅₀ . The test results indicate that the compounds of formula (I) under ίη νίΐτο conditions do not exhibit neurochemically significant tropism for D1-dopamine and D2-dopamine rat striatum receptors. The value of 1C ₅₀ with respect to the D1-dopamine receptor, for example for compound 1a, is 220 μM, and the value of 1C ₅₀ with respect to the D2-dopamine receptor is 195 μM.

Example 19. Determination of the activity of compounds against cholinergic receptors.

To study the affinity of the compounds of the present invention to nicotinic type acetylcholine receptors, radioligand binding experiments of the test compound and the radioactive selective ligand with rat brain membranes are performed. As a ligand, tritium-labeled (±) Nicotine with a specific activity of 140 Ci / mmol obtained by solid-phase labeling is used.

Isolation of plasma membranes of the brain is carried out according to the method of Votapo S. apb A.6o1bz1et, (8s1epse, 1980, 210, p. 647-650). In this case, outbred male rats weighing 200-250 g are decapitated, the whole brain is extracted and homogenized in 10 volumes of “ice” buffer (Via, 50 tM; NaCl, 118 mm; CaCl ₂ , 2.5 mm; KCl, 4.8 mm; Md ₄ , 1.2 mM; pH 7.4) in a Teflon-glass homogenizer. The homogenate is centrifuged for 30 min at 17500 d. The resulting precipitate is suspended in 20 volumes of cold distilled water and left for an hour for osmotic destruction. The resulting suspension is again centrifuged for 30 min at 17500 d. The resulting precipitate is suspended in buffer and again precipitated under the same mode. The pellet was resuspended in buffer to a final concentration (40 mg of starting tissue per 1 ml of buffer).

Radioligand analysis. The tubes are filled with a reaction mixture containing in a final volume of 50 μl of [3H] (±) Nicotine, 250 μl of buffer and 200 μl of a protein suspension of membranes prepared as described above. Nonspecific binding is determined by adding unlabeled ligand in a concentration range from 10 ^-10 to 10 ^-4 M in triplicates.

Tubes with the reaction mixture are incubated with constant shaking at 37 ° C for 40 minutes. The tubes are then quickly immersed in ice to stop the reaction. After 20 minutes, the contents of the tubes are ultrafiltered through CE / C filters, previously incubated for 24 hours in a 0.3% solution of polyethyleneimine at 4 ° C. After washing with cold buffer, the filters are transferred to vials and dioxane-based scintillation fluid is added. The radioactivity of the samples is determined on a scintillation counter "\ Уа11ас 1411" with a counting efficiency of about 40-44%.

The results are processed using the specialized program SVARNRAE Rkht.

The test results indicate that the compounds of formula (I) are characterized by a high degree of affinity for the binding sites of [3H] nicotine with rat brain membranes. The concentration dependence of the effect of nicotine on the binding of a labeled ligand is described by a classical curve with a 1C ₅₀ value of 0.13 μM. Compound 1a shifts the concentration curve to the right to values

- 12 014100

1C ₅₀ equal to 3.20 μM. This concentration range is considered as a high degree of receptor affinity.

Example 20. Determination of anticholinesterase activity of the compounds.

The anticholinesterase activity of the compounds of formula (I) was studied in experiments ίη νίΐτο using a standard set of reagents for the determination of cholinesterase (CE) of the company Basjeta (Czech Republic). The principle of the method is that CE cleaves the butyryl-thiocholinium iodide substrate into butyric acid and thiocholinium iodide, which reacts with dithio-bisnitrobenzoic acid to form a yellow color. The determination is carried out on the FEK model KF-2-UHL-4.2 (Russia). To determine the ability to inhibit CE, the test compounds are added to a solution containing the CE enzyme and substrate, and the color change is observed in comparison with the control. Inhibitory activity is expressed in the IC ₅₀ concentration of the inhibitor, in which the enzyme activity is blocked by 50% compared with the control.

Table 1 presents the results of determining the anticholinesterase activity of the most active compounds of this invention in comparison with the most well-known drugs of this pharmacological group.

Table 1. Anticholinesterase activity of compound 1a in comparison with eserin, proserin and galantamine

A drug IR ₅₀ (g / ml), concentration causing 50% inhibition of cholinesterase activity Negative logarithm of concentration, IC50 Compound 1a 6.4x10 ' ⁵ 4.93 Compound 1a 5.3 x 10 ' ⁵ 4.28 Eserin 3.0 x 10 ' ⁸ 7.52 Prozerin 3.2 x 10 ' ⁸ 7.50 G alantamine 7.4 x 10 · ⁶ 5.13 4-aminopyridine 4.4 x 10’- 2,36

Example 21. Determination of the activity of compounds in relation to the adrenergic system.

The activity of the compounds of the present invention with respect to the adrenergic system has been studied in a number of behavioral tests using pharmacological analyzers that allow changing the normal level of neurotransmitters in the pathological direction: the effect on the depriving effects of reserpine, the hypodynamic effect of α-methyl-p-tyrosine.

It is known that the main mediator of adrenergic (sympathetic) transmission is norepinephrine (HA), which performs a mediator function in the peripheral nerve endings and in the synapses of the central nervous system. According to modern concepts, norepinephrine released during the nerve impulse from the presynaptic nerve endings activates the norepinephrine-sensitive adenylate cyclase of the cell membrane of the adrenoreceptor system, which leads to increased formation of a secondary cAMP mediator and further the implementation of adrenergic physiological effects.

The central sympathomimetic effect is due to the excitation of norepinephrine and dopaminergic brain structures and is expressed in behavioral hyperactivity, acceleration of the mnemonic and cognitive functions of the brain, activation of electroencephalographic (EEG) indicators - the electrical activity of the brain.

Another way of activating the noradrenergic system is characteristic of indirect sympathomimetics such as amphetamine and other drugs of the β-phenylethylamine series, which cause the release of norepinephrine from the depot, which already further affects adrenoreceptors. This is typical for most drugs with the psychostimulating effect of the amphetamine series and structurally similar drugs - indirect sympathomimetics.

In the experiment, the central sympathomimetic action is evaluated by the rate of increase in spontaneous motor activity and behavioral reactions. These effects are analyzed under conditions of blockade of the synthesis of mediators using α-methyl-p-tyrosine, an inhibitor of the synthesis of HA and dopamine (DA), as well as under conditions of emptying the neuronal depot of mediators by reserpine, as described below.

A. Effect of compounds on behavior and spontaneous motor activity.

Locomotor activity in animals placed in a new environment consists of an orientation-research reaction (OIR) during the first 4-6 minutes and locomotion, which is caused by cycles of behavioral activity. The introduction of substances having psychostimulating activity increases the level of locomotion, i.e. transfers spontaneous locomotion to the level of locomotor hype

- 13 014100 activity, bypassing OIR.

The study was carried out on male mice weighing 20-22 g and male rats weighing 180-200 g. The registration of spontaneous motor activity of mice was carried out using an Opto-varimex actometer (Columbus, USA) according to the method of 8sup550p. Tych (1969).

Motor activity is recorded every 10 min for 2-4 hours before and after administration of the test compound. The test compounds are administered in doses of 1-10-12.5-25-50 and 100 mg / kg. At the same time, the locomotor activity of control animals is recorded, to which the corresponding volume of physiological saline is injected. Using the method of probit analysis calculate the value of the ED ₂₀₀ dose, causing an increase in motor activity by 2 times (200%) in relation to the control.

In the table. 2 presents the results of determining the motor activity of the most active compounds of this invention in comparison with well-known drugs of this pharmacological group.

The test results indicate that the compound of formula (I) when administered to mice subcutaneously, starting with a dose of 5 mg / kg, increases the spontaneous locomotor activity of animals. Increasing the dose to 10-20 mg / kg leads to increased motor excitation, which with a further increase in doses (up to 30-40 mg / kg) is replaced by depression, the appearance of stereotypical and convulsive manifestations. When injected into mice, similar manifestations of the central stimulatory activity of compound 1a are manifested in a higher dose range (12.5-100 mg / kg). The fact of the presence of indirect sympathomimetic action indicates that it substantially compensates for those side effects that are characteristic of ΝΜΌΆ receptor inhibitors.

B. Investigation of behavioral reactions in an open field test.

The effect on behavioral reactions in rats is studied using the open field method using a Varimex actometer (Columbus, USA). The severity of stereotypic behavioral reactions is scored, and spontaneous motor activity is measured in absolute values of the device counter for 10 minutes within 2-4 hours after administration of the test compound in doses of 1-12.5-25-50 and 100 mg / kg, inside. In comparative experiments, phenamine and sydnocarb are used. The results of the study are presented in table.2.

In comparative experiments with phenamine and sydnocarb, compound 1a, when administered subcutaneously, is inferior in strength to the central stimulating effect of phenamine, and when administered orally, it is more than 3 times weaker than phenamine and close to sydnocarb. According to the severity of locomotor excitation in mice, the effect of compound 1a is similar to the effects of phenamine and sydnocarb.

Compounds (I G-Ιι), when administered orally to animals in a dose range of up to 100 mg / kg, have a central excitatory effect comparable to that of compound 1a.

Table 2. Comparative activity of compound 1a, phenamine and sydnocarb according to tests of locomotor arousal in mice and stereotype in rats

A drug Locomotor agitation in mice, ED200, mg / kg ** Stereotype in rats, ED ₅₀ , mg / kg * subcutaneously inward subcutaneously inward Compound 1a 13.1 (12.5 - 14.1) 31.5 (25.0-38.1) 17.5 (12.5-21.0) 30,0 (20.8 - 36.2) Phenamine 7.5 (6.8-8.3) 9.3 (8.5-10.1) 5.0 (3.0-7.1) 21.0 (16.0-24.5) Sydnocarb 18.6 (17.1-20.0) 24.3 (22.6-26.0) - 31.5 (21.1-41.2)

ED ₅₀ - the dose causing the appearance of stereotypic reactions in 50% of rats;

ED200 - a dose that causes a 2-fold increase in spontaneous motor activity in mice.

B. The effect of the compounds on the depriving effect of reserpine in mice.

The ability of the compounds of formula (I) to release HA from neuronal depots (indirect sympathomimetic effect) is studied in the antireserpine test (when emptying these depots with reserpine).

The study is carried out on male mice weighing 18-20 g, which are administered intraperitoneally with reserpine at a dose of 2 mg / kg. Reserpine has a depressive effect on the central nervous system, causing a decrease in motor activity (hypolocomotion), ptosis and hypothermia. Hypolocomotion is recorded using an Opto-Varimex actometer (Columbus, USA), ptosis is evaluated visually in points on a 4-point scale, hypothermia is determined using a TPEM-1 electrothermometer by temperature in the rectum.

The test compounds are administered orally and subcutaneously at doses of 1, 5 and 10 mg / kg.

Administration of reserpine to mice at a dose of 2 mg / kg (intraperitoneally) after 2 h causes a decrease in spontaneous motor activity of animals by more than 80%, ptosis with a severity of 3.4 ± 0.4 points and a decrease in rectal temperature by 2.8 ± 0.6 ° FROM.

Connection! A. administered at a dose of 10 mg / kg (subcutaneously) 2 hours after reserpine, restores

- 14 014100 reduced motor activity of mice to the level of activity of animals of the control group, reduces ptosis by more than 70% and completely eliminates the hypothermic effect of reserpine, translating it into hyperthermic.

Compound 1a acts on the effects of reserpine about 2 times weaker than phenamine (in an equal dose). Sydnocarb at a dose of 25 mg / kg in these experiments has a negligible effect on the effects of reserpine.

Compounds (I G-11), when administered orally to animals in a dose range of up to 100 mg / kg, change the severity of the depriving effects of reserpine (inactivity, ptosis, hypothermia) similar to compound 1a.

The results of the antireserpine test of the most active compounds of this invention in comparison with known drugs of this pharmacological group are presented in table. 3.

Thus, experiments performed on mice showed that in the central action of the compounds of the present invention there is a component associated with indirect sympathomimetic properties, expressed in antagonism to the effects of reserpine. At the same time, according to the severity of the indicated properties, the compounds of formula (I) are significantly inferior to phenamine, the psychostimulating effect of which is associated with the effect on the release of the mediator from the rapidly renewable (labile) NA depot in the presynaptic region of the neuron.

Table 3. The effect of compound 1A on the deprimative effects of reserpine in mice in comparison with phenamine and sydnocarb

A drug Dose, mg / kg, s / c Locomotor activity in 30 min in% to control Ptosis value in points Change in rectal temperature to baseline The control - one hundred 0 0 Reserpine 2 15.7 3.4 ± 0.4 -2.8 ± 0.6 Reserpine + Compound 1a 10 82.8 1.0 ± 0.3 +3.4 ± 0.8 Reserpine + phenamine 10 177.0 0.5 ± 0.1 +3.3 ± 0.8 Reserpine + Sydnocarb 25 thirty 3.1 ± 0.5 0.7 ± 0.2

D. Effect of compounds on the hypodynamic effect of α-methyl-p-tyrosine in mice.

The central action mechanism of the studied compounds is also evaluated in experiments using an α-methyl-p-tyrosine (alpha-MT) inhibitor of the tyrosine hydroxylase enzyme involved in the biosynthesis of dopamine from tyrosine in nerve endings as a pharmacological analyzer.

The experiments were carried out on male mice weighing 18-20 g, which was administered α-methyl-p-tyrosine at a dose of 250 mg / kg, intraperitoneally. The introduction of α-methyl-p-tyrosine causes a decrease in locomotor activity of animals by more than 6 times, which reflects a decrease in the level of dopamine in the brain.

6 hours after the injection of α-methyl-p-tyrosine, the animals were injected subcutaneously with the studied compounds at a dose of 10 mg / kg and recorded motor activity. Registration of motor activity is carried out on an Opto-Varimex actometer (Columbus, USA). Phenamine (10 mg / kg, subcutaneously) and Sydnocarb (25 mg / kg, subcutaneously) are used as a comparison drug. The results of the study are presented in table. 4.

Against the background of the preliminary administration of α-methyl-p-tyrosine, compound I; ·! it has a weak effect on physical inactivity, which differs from phenamine and even more so from sydnocarb, which - the first partially and the second completely - eliminate the changes in the motor activity of animals caused by the introduction of a tyrosine hydroxylase inhibitor. Compounds (I G-1), when administered orally in a dose range of up to 100 mg / kg, exhibit an effect similar to compound 1a.

Thus, the experiments performed show that the compounds of formula (I) have practically no effect on the effect of α-methyl-p-tyrosine in mice and differ in this respect from phenamine and sydnocarb. In particular, the compounds of the invention are inferior to phenamine in influencing the spontaneous motor activity of animals, do not cause disorganization of targeted activity, but are superior to phenamine in the strength and duration of the activating effect on EEG in rats. In addition, they do not have a significant peripheral sympathomimetic effect.

Given the presence of psychostimulating properties in the studied doses in the compounds of the invention, it can be assumed that the mechanism of their central action is not determined by the influence of dopamine on the neurotransmitter biosynthesis and its conversion into norepinephrine with subsequent accumulation in

- 15 014100 stable depots in the nerve endings, which shows the absence of negative effects associated with psychostimulating activity in the studied compounds.

Table 4. The effect of compound 1A on physical inactivity induced by alpha-methyl paratyrosine in mice compared to phenamine and sydnocarb

A drug Dose mg / kg Locomotor activity through 30 min subcutaneously after drug administration in absolute figures for 10 min in% of control Control, nat. rr - 957 (806-1107) one hundred alpha MT * - 153 (105-201) 16.1 compound 1a 10 1659 (1398-1920) one hundred alpha-MT + compound 1A 243 (97-389) 14.6 Phenamine 10 1960 (1749-2170) one hundred alpha MT + Phenamine 428 (284-572) 21.8 Sydnocarb 25 1997 (1517-2426) one hundred alpha MT + Sydnocarb 1040 (868-1211) ** 52.0

# - alpha-MT, - α-methyl-p-tyrosine, 250 mg / kg, intraperitoneally;

* - difference with control (alpha-MT) is significant at P <0.05, ** - at P = 0.05.

Example 22. Evaluation of the neuroprotective activity of compounds in a model of multiple sclerosis.

The ability of the compounds of formula (I) to have a neuroprotective effect in the treatment or prevention of neurodegenerative diseases was determined ίη νίνο in an experimental model of human multiple sclerosis. Such a model is experimental autoimmune (allergic) encephalomyelitis (EAE) - myelin antigens induced by T cells and an autoimmune disease in laboratory animals that is similar in clinical and histological signs to multiple human sclerosis (81е1птп,.. , ν.14, p. 79-93). The methodology for assessing the effect of the compounds of formula (I) on reducing the severity of EAE in experimental animals is presented below.

A. Inhibition of the development of EAE in mice. Effect on the course of neuroinflammation in EAE in mice.

In the experiment, mice of the 81b / 1 line at the age of 6-7 weeks were used, which were kept in the laboratory for one week before the start of the study in the absence of non-specific pathogenic flora, with free access to food and water, to adapt to the environment. All procedures are carried out in accordance with the rules of ΙηδΙίΙυΙίοηαΙ Ashta1 Sat apb Ize about £ 111e and atz £ o Ca1ap1a, Pa1y. One control group and three experimental groups of animals are formed, each of which consists of 7-8 animals.

In all animals of the control and experimental groups, EAE was induced by the method of 1. 8ΐ. Εοιιίδ e! a1. (Ροδί 8, е! А1 .// No. ig8C1epse, 2006,142, pp. 1303-1315). To do this, mice are immunized with 75 μg of myelin lipoprotein protein (hereinafter referred to as PF) emulsified with Freund's adjuvant (CP A) and 0.6 mg / ml Cusobacilli ^^ and Fetci ^ intrinsic H37KA (E &amp;C; 1: 1 ratio. PbP was synthesized by Sepeteb 8nl8e818 (8nap P ^ aηc ^ 8co CA). Each mouse receives a subcutaneous injection of 200 μl of the emulsion, divided into 4 parts, into the axillary region and inguinal lymph nodes. As a co-adjuvant, pertussis toxin is used (Ret1i8818 Juht, Ca1yusyet, Nooΐΐyat, IR), which is administered intragastrically at a dose of 200 ng / mouse 0 and 2 days after immunization.

Starting from the second day after immunization, the animals of the experimental groups are administered an orally tested compound of the formula (I) 6 times a week: to the 1st experimental group - at a dose of 1.0 mg / kg; The 2nd experimental group - at a dose of 3.0 mg / kg; The 3rd experimental group at a dose of 5.0 mg / kg Treatment with the test compound is carried out for 30 days.

The mice of the control and experimental groups were observed daily for 30 days after immunization, the clinical signs of EAE were weighed and recorded.

Depending on the severity of the clinical signs of EAE, animals are sorted using the following scale: 0 - no symptoms (no disease); 1 - lowering the tone of the tail; 2 weakening of the muscles of the hind limbs, impaired gait (moderate paraparesis); 3 - hind limb paralysis (severe paraparesis); 4 - complete paralytic immobility (state of dying); 5 death of an animal.

- 16 014100

Primary critical points: average clinical cumulative indicators (average indicators of drug accumulation in the animal’s body), attack, duration of illness.

Statistical analysis for significant differences in clinical indicators is carried out by ΑΝΟνΑ for unpaired data. P value <0.05 is accepted as statistically significant.

Studies have shown that the compounds of formula (I) have a significant neuroprotective effect, because have the ability to inhibit the development of EAE in mice.

It was found that in the control group of animals the average cumulative values of the clinical parameters of EAE within 2 weeks after immunization are 87.5%. This is the standard level of manifestations of EAE in the control in the range of 2 weeks after immunization. In the experimental groups of mice, the studied compounds of formula (I) have a dose-dependent way to positively influence the development of the disease in comparison with the control group. For example, compound 1a in a high dose (5.0 mg / kg) significantly reduces the cumulative effects of EAE, which are observed only in 33.3% (2 out of 6) mice during the 30-day observation period. In low and medium doses, compound I; also causes a decrease in the level of manifestations of the disease, which is in the groups of 60 and 71.4%, respectively. At these doses, there is also a decrease in cumulation and the duration of the manifestations of the disease.

Thus, according to the clinical estimates, a significant deviation (p <0.05) was established between the experimental groups (from 33.3%) and the control group (87.5%), confirming that the studied compounds suppress the symptoms of EAE. In addition, the average day of onset of the disease in the experimental groups is from 4.2 days to 6 days depending on the dose of the test compound, which is significantly higher than in the control group. This suggests that the expression of symptoms tends to slow down in the experimental groups and that the compounds of formula (I) inhibit the onset of symptoms of EAE. In animals to which the test compounds were introduced, the general condition almost returned to normal, while in control animals the state of complete development of the disease was stable and lasted until the end of the experiment.

These results show that the compounds of formula (I) can be effective agents in the treatment of human multiple sclerosis, as it helps to prevent the development of EAE.

Example 23. Determination of the effect of compounds on the activation of cognitive functions.

The cognitive-stimulating activity of the compounds of the present invention is evaluated in a number of behavioral experiments on animals by their ability to improve memory and learning in mice, as well as exert anti-amnestic effects in animals with experimentally induced amnesia.

A. Evaluation of the anti-amnestic effect of the compounds in the test of the conditioned reflex of passive avoidance in a living model of scopolamine-induced amnesia.

An assessment of the effect of compounds on the ability of animals to learn and reproduce skills is carried out under the conditions of developing simple conditioned reflex reactions using passive avoidance reaction (conditioned reflex of passive avoidance). Violation of training and information storage is modeled using the amnestic action of the central anticholinergic scopolamine.

The experiments are carried out on male mice weighing 20-22 g, forming groups of 10-12 animals for each study dose. Passive avoidance reaction is produced by the method 81er 6ο \ νπ. in an illuminated chamber with an electrode floor and a rescue platform in the middle. Under new conditions, the behavior of an animal when it is placed in a chamber (new environment) is expressed in the form of tentative research activity (examination of the chamber). As soon as the animal descends from the platform to the electrode floor, it receives an electric shock on its paws (50 V for 3-5 s), after which it is returned back to the living cage. The training is carried out in three sessions, the criterion for the training of animals is to stay on the platform for 1 min. The functional state of memory is evaluated by the ability of mice to reproduce the developed passive avoidance reaction skill when an animal is placed in a chamber on a rescue platform 2 hours after the development of a conditioned reflex reaction and amnestic effect.

To simulate amnesia, scopolamine is administered to mice at a dose of 1 mg / kg, intraperitoneally, 15-20 minutes before the administration of the test compounds. Scopolamine is a central M-anticholinergic drug that causes memory impairment (amnesia) and reduces learning ability. The test compounds are administered orally, at a dose of 10 mg / kg, 40 minutes before training. The basis for the use of these doses is the initial active dose of the compound Pg taken as a comparison drug, and a component of 3 mg / kg, orally.

Studies have shown that in groups of mice treated with a compound of formula (1), animals capable of learning were 1.5-2.5 times more than in the control group.

The results of the study are presented in table. 5, which shows that the compounds of the present invention significantly reduce the severity of the amnestic effect of scopolamine and activate the production and reproduction of passive avoidance reaction under conditions of scopolamine-induced amnesia.

- 17 014100

Table 5. The effect of the compounds of formula (I) on learning and memory in the passive avoidance reaction test in mice

Test compounds Effect on the amnestic effect of scopolamine (1 mg / kg, ip) Doses, mg / kg, bp % of animals with passive passive avoidance reaction Scopolamine (control group) - 27.5 Compound 1a + scopolamine 3.0 62.5 Compound 1d + scopolamine 10 66.6 The compound of formula I (K3 = Pb, K.6 = Me) + scopolamine 10 50,0 The compound of formula 1 (K1 = K2 = H, Χ = Υ = ϋΝ, KZ = Pb) + scopolamine 10 40,0

B. Activity of compounds in comparison with known nootropic drugs.

A comparative assessment of the cognitive-stimulating activity of the compounds of the present invention and known nootropics is carried out in mice and rats using standard tests such as passive avoidance reaction, URAI (conditional reflex test of active avoidance), on the model of amnesia caused by electroshock (MES), the model of scopolamine amnesia and in electrophysiological experiments. Piracetam, meclofenoxate (centrophenoxin) and tacrine are used as reference preparations. The results of comparative tests are presented in table. 6.

As can be seen from the table. 6, the compounds of the present invention have a positive effect on cognitive functions in animals with learning disabilities, as well as on amnesia models caused by the administration of the cholinolytic drug scopolamine (1.0 mg / kg, s / c) and the effect of maximum electroshock. In terms of effective doses, compound 1a, when developing URAI and passive avoidance reaction, surpasses the nootropic drugs piracetam and meclofenoxate. Unlike piracetam and acefen, compound 1a has a positive effect on cognitive functions in both normal animals and animals with learning deficits, whereas nootropic drugs act mainly in conditions of impaired function. Under the influence of compound 1a, an improvement in the associative functions of the brain is observed, as evidenced by the results of experiments to solve the extrapolation problem in animals under stressful conditions, in which it also exceeded piracetam and acefen.

In electrophysiological experiments, compound 1a has an activating effect on the EEG of old rats, increasing the power of its spectrum and restoring the impaired functional asymmetry between the cerebral hemispheres characteristic of young animals, which is different from piracetam, which causes the opposite effect.

Table 6. Cognitive-stimulating activity of compounds of formula (I) in comparison with known nootropics

Equivalent Doses (mg / kg, by mouth) #

Test compounds (preparations) Impact on Learning Anti-amnestic action URAI (rats) Passive avoidance reaction (mouse) Extra apol solution. tasks (rats) MES (mouse) Scopol - min (rats) Compound 1a 0.5-3 one 1-3 0.5-3 0.5-1 * 0.5 Piracetam 200-500 > 500 200-500 200 200-500 * 200-500 Acefen > 200 > 200 > 200 one hundred 100-200 * 200 Tacrine - - - 10-50 * -

# - doses of drugs that have an equally pronounced effect> 50%)

Example 24. Determination of the antidepressant activity of the compounds.

The antidepressant activity of the compounds is evaluated by their effect on the psychoemotional and behavioral characteristics of animals in standard tests simulating the development of an emotional stress state. The stress state in animals is caused when they are placed in a chamber with water equipped with a rotating ribbed wheel. After unsuccessful attempts to get out of the water

- 18 014100 people take a characteristic motionless pose, which is regarded as a manifestation of depression, “despair”. The antidepressant effect of the studied compounds is established by increasing the activity of animals relative to the control group in the experiment, as described below.

A. Evaluation of the antidepressant effect of the compounds on a rotating wheel model.

The experiments were performed on male mice weighing 20-22 g. The test compound was administered subcutaneously to experimental animals at doses of 5 and 10 mg / kg. The control group of animals injected with saline in the same doses. For each dose, 8-10 animals are taken. One hour after the introduction of compounds or physiological saline, experimental and control animals were placed in a chamber with water (with a temperature of 24-26 ° C) equipped with a rotating built-in ribbed wheel with a counting output. The wheel rotation intensity is recorded by the number of wheel rotations when trying to get out of the water. Registration is carried out within 1 h. The results are evaluated at the 6th and 12th minutes of the experiment.

The research results are presented in table. 7, from which it is seen that the compounds of formula (I) significantly increase the intensity of rotation of the ribbed wheel, which indicates a pronounced antidepressant effect. So, 1 hour after the administration of the studied compounds, the rotation intensity increased 1.5-2 times for the 6th minute and 5 times for the 12th minute of observation compared to the control. In terms of activity, the compounds of the present invention are comparable to phenamine (used in an equivalent dose) and are 2–3 times higher than meridyl (by the 12th minute).

Table 7. Evaluation of the antidepressant effect of the compounds on a rotating wheel model

Test compounds, preparations Dose mg / kg The number of wheel rotations 1 hour after drug administration On the 6th min On the 12th Dean The control - 47.6 ± 4.1 10.3 ± 1.6 Compound 1a 5,0 61.6 ± 7.2 29.6 ± 5.1 Compound 1a 10.0 78.3 ± 8.5 33.6 ± 8.1 Phosphate Compound 1a 10.0 80.3 ± 8.0 36.0 ± 8.8 Hydrobromide of compound 1a 10.0 76.0 ± 7.5 35.2 ± 7.5 Meridil fifty 60.0 ± 8.0 15.6 ± 8.2 Phenamine 2,5 90.5 ± 8.4 32.8 ± 9.2

Example 25. The effect of connections on health.

An assessment of the effect of the compounds of formula (I) on physical performance is examined in a swimming test. The experiments are carried out on mice. The test compound is administered to experimental animals subcutaneously in doses of 5-15 mg / kg. The control group of animals injected with saline in the same doses. For each dose, 8-10 animals are taken. After 30 minutes and 1 hour after the administration of compounds (experimental group) or physiological solution (control group), a load of 7.5% of body weight was recorded on each animal and placed in a chamber with water at a water temperature of 24-26 ° С . The time during which the mouse is able to stay on the surface of the water is recorded. The activity of the studied compounds is evaluated by the increase in the duration of swimming mice with cargo in comparison with the control. The results of the study are presented in table. 8.

Table 8. Assessment of the effect of compounds on the performance of animals in a swimming test

Test compounds Dose "mg / kg, sc Duration of sailing with cargo, min The control - 5.0 ± 0.45 Compound 1a * 15.0 14.2 ± 2.2 Phosphate compound 1a 5,0 9.6 ± 1.1 Phosphate compound 1a 10.0 15.7 ± 2.0 Hydrobromide of compound 1a 5,0 9.2 ± 1.3 Hydrobromide of compound 1a 10.0 15.0 ± 2.0 Meridil fifty 15.2 ± 1.4 Phenamine 2.5 ** 8.9 ± 0.8

* - Compound O was administered orally due to insolubility in water. ** - Dose of ~ 0.1 of LD ₅₀ .

- 19 014100

Example 26. Obtaining a pharmaceutical composition in the form of a tablet containing 0.1 mg of the active ingredient.

As the active ingredient, take the compound of formula (I) obtained in examples 1, mixed with the calculated amount of microcrystalline cellulose, silicon dioxide, stearic acid, mix thoroughly and compress to obtain tablets weighing 52 mg each.

Get tablets of the following composition, mg (per tablet):

The compound of formula (I) - 0.1 mg

Microcrystalline cellulose - 30 mg

Silicon Dioxide - 20 mg

Stearic acid - 1.9 mg

The weight of the tablet is 52 mg.

Example 27. Obtaining a pharmaceutical composition in the form of tablets containing 1 mg of the active ingredient.

A compound of formula (I) is taken as the active ingredient, mixed with the calculated amount of corn starch, microcrystalline cellulose, lactose, povidone, croscarmellose sodium, magnesium stearate, mixed thoroughly and pressed to obtain tablets weighing 90 mg each.

Get tablets of the following composition, mg (per tablet):

The compound of formula (I) - 1.0 mg

Lactose - 46.9 mg

Corn Starch - 23.5 mg

Povidone - 1.8 mg

Microcrystalline cellulose - 14.4 mg

Croscarmellose sodium type A - 1.8 mg

Magnesium Stearate - 0.6 mg

The weight of the tablet is 90.0 mg.

Example 28. Obtaining a pharmaceutical composition in the form of a tablet containing 2.5 mg of the active ingredient.

A compound of formula (I) is taken as the active ingredient, mixed with the calculated amount of milk sugar, polyvinylpyrrolidone of low molecular weight potato starch, calcium stearate, mixed thoroughly and pressed to obtain tablets weighing 80 mg each.

Get tablets of the following composition, mg (per tablet):

The compound of formula (I) - 2.5 mg

Milk sugar - 50.0 mg

Polyvinylpyrrolidone -. 2.5 mg

Calcium Stearate - 0.5 mg

Potato starch - 24.5 mg

The weight of the tablet is 80.0 mg.

Example 29. Obtaining a pharmaceutical composition in the form of a tablet containing 5 mg of the active ingredient.

As the active ingredient, a compound of formula (I) is taken, mixed with the calculated amount of corn starch, lactose, hydroxypropylcellulose and crystalline cellulose. Hydroxypropyl cellulose dissolved in water is added and thoroughly mixed again. The resulting mixture was dried, granulated and magnesium stearate and light anhydrous silicic acid were added and pressed to obtain tablets weighing 70 mg. The tablets are then coated in the usual manner with a film coating using hydroxypropyl cellulose.

Get tablets of the following composition, mg (per tablet):

The compound of formula (I) 5 mg

Corn Starch 20 mg

Lactose 19 mg

Crystalline Cellulose 10 mg

Hydroxypropylcellulose 15mg

Magnesium Stearate 0.5 mg

Anhydrous Silicic Acid 0.5 mg

The mass of the core tablets 70 mg.

Example 30. Preparation of tablets containing 10 mg of active ingredient.

A compound of formula (I) is taken as the active ingredient, mixed with the calculated amount of milk sugar, polyvinylpyrrolidone of low molecular weight potato starch, calcium stearate, mixed thoroughly and pressed to obtain tablets weighing 320 mg each.

- 20 014100

Get tablets of the following composition, mg (per tablet):

The compound of formula (I) - 10 mg

Milk Sugar - 200 mg

Polyvinylpyrrolidone 20 mg

Calcium Stearate - 2 mg

Potato starch - 98 mg

The weight of the tablet is 320 mg.

Example 31. Preparation of tablets containing 100 mg of active ingredient.

A compound of formula (I) is taken as the active ingredient, mixed with the calculated amount of starch, crushed lactose, talc, mixed thoroughly and pressed into a block.

The resulting bar is crushed into granules and sieved through sieves. The granules obtained are tabletted into a suitable tablet form weighing 460 mg each.

According to this scheme, tablets of the following composition are obtained, mg (per tablet):

The compound of formula (I) - 100 mg

Lactose -160 mg

Corn starch - 160 mg

Talc - 40 mg

The weight of the tablet is 460 mg.

Example 32. Preparation of tablets containing 60 mg of active ingredient.

The active ingredient (compound of formula 1), starch and cellulose are passed through a sieve and mixed thoroughly. The resulting powder is mixed with a solution of polyvinylpyrrolidone and granulated. The granules are dried at 50 ° C and combined with sodium carboxymethyl, magnesium stearate and talc. Thoroughly mixed and pressed in a machine for the manufacture of tablets to obtain tablets weighing 150 mg each.

Get tablets of the following composition, mg (per tablet):

The compound of formula (I) - 60 mg

Starch - 45 mg

Microcrystalline cellulose - 35 mg

Polyvinylpyrrolidone - 4 mg

Carboxymethyl Sodium - 4.5 mg

Magnesium Stearate - 0.5 mg

Talcum - 1 mg

The weight of the tablet is 150 mg.

Example 33. Obtaining a pharmaceutical composition in the form of suppositories.

A compound of formula (I) is taken as the active ingredient, mixed with the calculated amount of lanolin and melted cocoa butter and mixed thoroughly. The manufacture of suppositories is carried out on machines with the necessary technological conditions by molding.

According to the above scheme, suppositories of the following composition are obtained, mg (per suppository):

The compound of formula (I) - 25 mg

Anhydrous lanolin - 1800 mg

Cocoa Butter - 1200 mg.

Example 34. Obtaining a pharmaceutical composition in the form of a capsule containing 5 mg of the active ingredient.

A compound of formula (I) is taken as the active ingredient, mixed with the calculated amount of crystalline lactose and corn starch, mixed thoroughly. Next, talc and magnesium stearate are added and mixed again. The resulting mixture is filled in hard gelatin capsules of the appropriate size.

Capsules of the following composition are obtained, mg (per capsule):

The compound of formula (I) - 5 mg

Lactose - 159 mg

Starch - 25 mg

Talcum - 10 mg

Magnesium Stearate - 1 mg

The mass of the contents of the capsule is 200 mg.

Example 35. Obtaining a pharmaceutical composition in the form of a capsule containing 50 mg of the active ingredient.

A compound of formula (I) is taken as the active ingredient, mixed with the calculated amount of crystalline lactose and microcrystalline cellulose to a homogeneous state, sieved, and then talc and magnesium stearate are mixed. Hard or soft gelatin capsules of the appropriate size are filled with the finished mixture.

Capsules of the following composition are obtained, mg (per capsule):

- 21 014100

The compound of formula (1) - 50 mg

Lactose - 60 mg

Microcrystalline Cellulose - 34 mg

Talcum - 5 mg

Magnesium Stearate - 1 mg

The mass of the contents of the capsule is 150 mg.

Example 36. Obtaining a pharmaceutical composition in the form of solutions for intramuscular, intraperitoneal or subcutaneous injection.

As the active ingredient, take the compound of formula (I), mix with the calculated amount of excipients. The resulting solution is filtered and poured into ampoules of the appropriate size, which are sealed and sterilized in an autoclave.

A. Get a solution for injection containing 1 ml:

The compound of formula (I) - 0.5 mg

Sorbitol - 5.1 mg

Acetic acid - 0.08 mg

Water for injection - up to 1 ml.

B. Get a solution for injection containing 5 ml:

The compound of formula (1) - 100 mg

Mannitol - 100 mg and sodium hydroxide - 200 μl

Purified water - up to 5 ml.

C. An injection solution containing 1 ml is obtained:

The compound of formula (I) - 0.2 mg sodium lactate - 1.67 mg sodium chloride - 8.1 mg (P, B) lactic acid - 1.44 mg distilled water - up to 1 ml.

Ό. An injection solution containing 10 ml is obtained:

The compound of formula (1) - 50 mg

Citric Acid - 210 mg

Ό-mannitol - 100 mg distilled water - up to 10 ml.

Example 37. Obtaining a pharmaceutical composition in aerosol form.

A compound of formula (I) is taken as the active ingredient, mixed with the calculated amount of ethanol, a dispersant of chlorodifluoromethane cooled to -30 ° C is added, and aerosol cans are filled.

The content of components, wt. % (per spray):

The compound of formula (I) - 0.25

Ethanol - 29.75 chlorodifluoromethane - 70.00

Total - 100.00.

Claims (14)

CLAIM 1. The compound of General formula (I) I where K ¹ means hydrogen, K ² means hydrogen or optionally substituted benzyl or K ¹ and K ² together with the atom Ν to which they are attached mean piperidino, morpholino, Ν methylpiperazino, K ³ is phenyl or substituted phenyl, X is hydrogen Υ means hydrogen, cyano group, carboxyl group, their pharmacologically acceptable salts and / or solvates. 2. The compound according to claim 1, selected from the group comprising 2-amino-4-phenylaminopyridine, 2morpholino-3-cyano-4-phenylaminopyridine, 2-methylpiperazino-3-cyano-4-phenylaminopyridine, 2-methylpiperazino-4- phenylaminopyridine, 2-benzylamino-3-cyano-4-phenylaminopyridine, 2-benzylamino-4-phenylaminopyridine, 2-morpholino-4-p-chlorophenylaminopyridine. - 22 014100 3. A pharmaceutical composition for the treatment of diseases associated with hyperactivation of receptors, containing an effective amount of a compound or its pharmaceutically acceptable salt or solvate according to any one of claims 1 to 2, mixed with pharmaceutically acceptable excipients. 4. The composition according to claim 3, having antagonistic activity against ΝΜΌΆ glutamate receptors. 5. The composition according to claim 3, having cognitively stimulating activity. 6. The composition according to claim 3, having agonistic activity against nicotinic cholinergic receptors. 7. The composition according to claim 3, having the activity of an acetylcholinesterase inhibitor. 8. The composition according to claim 3, showing the properties of sympathomimetics. 9. An agent for treating or preventing diseases and disorders associated with hyperactivation of β receptors, comprising a compound or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 2, or a pharmaceutical composition according to any one of claims 3 to 8. 10. The tool according to claim 9, where the specified disease and disorder is selected from the group including cerebrovascular insufficiency, cerebral ischemia, stroke, neuropathies caused by hypoxia or hypoglycemia, brain injury or damage to the spinal cord, amyotrophic lateral sclerosis, spinocerebellar degeneration, degenerative ataxia cortico-basal degeneration, Guam complex, subacute sclerosing panencephalitis, multiple (multiple) sclerosis, multiple encephalomyelitis, Schilder's sclerosis, myelinopathy inflammatory nasal and vascular nature, inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, Markiafava disease Bignami, central pontine myelinolysis, neurooptomyelitis, Devic's syndrome, Balo's disease, myelopathy with HIV, lupus erythematosus central nervous system, lupus erythematosus, nodular polyarteritis, sjögeren's disease, lacarizolezaris syndrome, Cerebrospinalis syndrome Alzheimer's, Parkinson's disease, multi-infarct dementia, Huntington's disease; neurodegenerative diseases associated with bacterial or viral infections; neurological and psychiatric disorders and diseases associated with excitotoxic neuronal damage, including a sense of causeless anxiety, psychosis, depression, schizophrenia, epilepsy, migraine, muscle cramps, urinary incontinence, paralysis, drug, drug or alcohol dependence, withdrawal syndrome; conditions with acute or chronic pain syndrome. 11. An agent for treating or preventing diseases and disorders associated with impaired cognitive function, learning ability, memory impairment, memorization or impaired attention, containing the compound or its pharmaceutically acceptable salt or solvate according to any one of claims 1 to 2, or the pharmaceutical composition according to to any of claims 3-8. 12. The tool according to claim 11, where the specified disease and disorder is selected from the group including acute or chronic neurodegenerative disorders associated with age-related dementia, vascular dementia, dementia of endocrine or metabolic origin, traumatic dementia and diffuse brain damage, mental retardation, alcohol intake or narcotic drugs, Alzheimer's disease, Parkinson's disease. 13. A method of treating or preventing diseases and disorders caused by hyperactivation of β receptors, comprising administering to a patient a compound, a pharmaceutically acceptable salt or solvate according to any one of claims 1 to 2, or an agent according to any one of claims 9 to 10. 14. A method of treating or preventing diseases and disorders associated with impaired cognitive function, learning ability, memory impairment, remembering or impaired attention, comprising administering to a patient a compound, a pharmaceutically acceptable salt or solvate according to any one of claims 1 to 2, or an agent according to any from paragraphs 11-12. 4 ^^ Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2