WO2008026965A1 - Substituted pyrrolo[4,3-b]indoles, combinatorial and focused libraries, pharmacological composition and a method for the production and use thereof - Google Patents

Abstract

The invention relates to synthesising novel chemical agents, to searching novel physiologically active substances, leading compounds, 'molecular tools' and drug candidates produced by screening combinatorial and focused libraries of compounds, to a pharmaceutical composition and to methods for the production and use thereof. The invention claims hydrated pyrrolo[4,3-b]indoles of general formula 1, the racemates, optical and geometrical isomers and the pharmaceutically acceptable salts and/or hydrates thereof, wherein a dotted line with an unbroken line associated therewith (__----) is a single or double bond; R1 and R2 independently of one another represent aminogroup substituents, selected from hydrogen, of possibly substituted C1-C6 alkyl, possibly substituted by aryl, by hydrogen-containing heteroaryl; from C1-C6 alkoxycarbonyl, possibly substituted phenyl, possibly carbonylamino or tiocarbonylamino substituted, substituted acyl, possibly substituted arylsulphonyl; R in is one or more like or different substituents of cyclic system, which are selected from hydrogen, alkyl, aryl, ciano, halogen and 5-6-membered nitrogen-containing azaheterocyclyl.;

Description

 Substituted pippolo [4,3-b] indoles, combinatorial and focused libraries, pharmaceutical composition, methods for their preparation and use

Technical field

The present invention relates to the synthesis of new chemicals, the search for new physiologically active substances, leader compounds, “molecular tools)) and drug candidates obtained from screening of combinatorial and focused libraries of compounds, as well as to a pharmaceutical composition, methods for their preparation and use.

More specifically, the present invention relates to new annelated azaheterocycles - hydrogenated pippolo [4,3-b] indoles, their optical and geometric isomers, mixtures of isomers, their pharmaceutically acceptable salts and / or hydrates, to methods for their preparation, pharmaceutical compositions containing these compounds in the form of active substances, as well as to a method for the treatment and prevention of the development of various diseases, including neurodegenerative diseases, for example, Alzheimer's disease (AD), associated with excessive entry of calcium ions into the nerve cells, which initiates a number of pathological metabolic processes that ultimately cause the death of neurons [D.W. Schoi, Neurope, 1988; 1: 623-634].

State of the art

The pharmacological effect of the hydrogenated pirpolo [4,3-b] indoles is based on their ability to effectively lower the cytosolic concentration of calcium ions when the intracellular content of Ca ^{+ 2} ions becomes excessive as a result of various pathological processes. Another pharmacological property of hydrogenated pyrpolo [4,3-b] indoles and azepino [4,3-b] indoles is their highly effective antihistamine effect, which allows the use of these substances in the form of these pharmaceutical compositions for the treatment of a wide range of allergic and autoimmune diseases, including hay fever, urticaria, bronchial asthma, atopic dermatitis, neurodermatitis, angioedema, Quincke's edema, eczema, burn toxemia, as well as allergic reactions caused by drugs, food, cosmetics their agents, household dust, insect bites, etc.

Maintaining a low concentration of calcium ions is extremely important for the normal functioning of the cell, since a long-term increase in the level of calcium in the cytosol leads to cell death. Such a mechanism of cell death is a characteristic feature of all neurodegenerative diseases, and the search for pharmacological agents that impede the excess entry of Ca ^{+ 2} ions into neurons seems to be one of the most important directions for the creation of neuroprotectors [Kiwert C, Nartmapp J., Stoll J., Tekkumkara TJ., Vap der Schuf CJ., Klein J. NGPl-Ol is a Brain-Permeable Dual Blacker Neutral-Apd Ligapd-Orcel Calcium Chappels. Neuroset Res. 2006 Mau 3; Еруб ахед оf ррипt]. The concentration of cytosolic calcium in eukaryotic cells is regulated by transmembrane transport and cytoplasmic binding of calcium [Sauer RJ. Iptacellular Ca2 + haplipg. Adv Exp Med Biol. 2002; 513: 183-96]. In this case, the following complex interrelated processes occur: the transport of calcium ions by two families of Ca ^{+ 2} channels, namely: calcium channels of the cell membrane and calcium channels located in the endo (capco) membrane of the plasma reticulum (ER or CP), which form the pathways of calcium entry into cytoplasm; the removal of calcium from the cytoplasm due to the activity of calcium plasmalemma pumps and / or calcium exchangers; accumulation of calcium ions by intracellular calcium depots and mitochondria. The latter serve as calcium buffer systems capable of accumulating and accumulating it, thus supporting calcium homeostasis in the cytoplasm. Most Ca ²⁺ - regulated processes in the cell occur when the Ca ²⁺ concentration changes in the range 10 ^{~ 7} - 10 ^' M, while its concentration in the extracellular medium is close to 10 ^"3 M. It is obvious that various proteins that support calcium homeostasis in cytoplasm play an exceptional role in the pathogenesis of neuralogical disorders such as hypoxia-ischemia, hypoglycemia, convulsive conditions, brain injuries, as well as chronic neurodegenerative diseases (including AD, Huntington's chorea, latirism, amyotrophic lateral sclerosis) [JW M Dopal, MV Johstop - Brain Res. Rev., 1990; 15: 41-70; Stus R.K. Geperal mechapisms оf ahopal damagde its its reveptiop. J Neurool Sci. 2005; 233 (1-2): 3-13] The ability to regulate the pool of intracellular calcium determines the great pharmacological importance of selective blockers / activators of various voltage-gated calcium channels (eg, T-, L-, N-, P-, Q-, R-channels) and specific ligand-controlled antagonists / modulators channels (for example, NMDA, AMPA, pAShR, P2X receptors) [Valu PH, Lupsh JW Ligapd-gathed chappels. IEEE Traps Napiosioce. 2005; 4 (l): 70-80]. Currently, an extensive range of these calcium transport effectors has been proposed as highly effective. medicines. For example, calcium antagonists are a group of drugs that combines the ability to reversibly block the flow of calcium through voltage-dependent calcium channels. According to the chemical structure, these drugs are divided into two large subgroups - dihydropyridines (Nifedipine, Amlodipine, Felodipine, etc.), in the properties of which the effect of peripheral vasodilation predominates, and nedihydropyridines (Verapamil and Diltiazem), in the properties of which the negative chrono- and inotropic effect predominates as well as the ability to reduce atrioventricular conductivity [Si D.A. PHARCASOTHERARU REVIEW: CALCIUM CHAIMEL BLOSKERS. J Slip Nurerteps (Greepwish). 2006; 8 (l): 53-6]. An example of a drug that blocks the excess entry of calcium ions into neurons through ligand-controlled channels (NMDA) is Memantine, currently widely used to treat Alzheimer's disease [Rogawski MA, Wepk GL Theothermalysis biophase therapy, Alzheimer disеasе. CNS Drig Rev. 2003; 9 (3): 275-308]. Almost all of these drugs prevent the excess entry of calcium ions into the cells, but to date, modulators of calcium homeostasis have not been known that can effectively reduce the concentration of cytosolic calcium, which has become excessive due to any of the many possible pathological processes.

In this regard, the search for effective neuroprotective agents that can inhibit the neurotoxic effect of excess cytoplasmic calcium seems to be an original and promising approach to the creation of new drugs for the treatment of a wide range of neurological and neurodegenerative diseases.

At the same time hydrogenated pyrrolo [4,3-b] ind ^'oly moleno regarded as closest analogues of compounds of series hydrogenated pyrido [4,3-b] indoles. Hydrogenated pyrido [4,3-b] indoles include antihistamines Dimebon and Diazolin [Mashkovsky M. D. Medicines. Ed. 13. Kharkov: Torsing, 1998.p. from. 280-281], as well as a neuroprotective agent, antioxidant and antiarrhythmic agent Stobadin, which is in the second stage of clinical trials, [Nokakova L., Stoels S. Aptiokhidapt apd pharmacodupamis effof of ruriodipodole stobadipe. Gep Rhartasol. 1998; 30 (5): 627-38]. Dimebon and Diazolin are blockers of Hl receptors and have a pronounced antihistamine and partial antiserotonin effect. Antiarrhythmic properties were found in Dimebon [Galepko-Iaroshevskii P. A., Schekapova O.A., Skibitskii VV, Cartashevis VV, Khapkova AI, Rolisova T. L. Apthiarthusperr of dimmebop. Vill Expr YOU Med. 1995; 119 (4): 375-7], as well as neuroprotective and cognitive-stimulating properties [Vashurip S., Vukatipa E., Lermoptova N., Tkaskhepko S., Afapasiev A., Grigoriev V., Grigorieva L., Yvapov Y., Szblip S., Zefiróv N. Pharmaceutical and educational Dimépop as well as a comprehensive test and social programming. App NY Acad Sсi. 2001; 939: 425-35], it turned out to be an effective neuroprotector in animal models of Alzheimer's disease [Lermoptova NN, Lukovapov NV, Serkova TP, Lukowapova EA, Hurip S. O. Dimebepelimpelimpelimpelimp. BuIl EXP YOU MED. 2000, 129 (6), 544-546. Zefiróv, NS; Afapasiev, AZ; Afapasiеvf, SV; Vasuri, SE; Tkaskhepko, S.Е ,; Grigoriev, VV; Jurovskaua, MA; Сhetvеrikоv, VP; Bukatipa, EE ;; Grigoriev, LV. US 6187785, 2001].

In order to develop new highly effective neuroirotective, antihistamine and antiarrhythmic drugs, the authors of this invention carried out extensive studies of chemical compounds of the class of hydrogenated pirpolo [4,3-b] indoles, carried out directed modifications of many positions of the structure, and as a result a series of new derivatives of hydrogenated pirpolo was synthesized [ 4,3-b] indoles, which effectively improve memory and inhibit and inhibit the development of various diseases, including neurodegenerative diseases associated with ytochnym entry of calcium ions into nerve cells, initiating a number of pathological metabolic processes finally causing the death of neurons [DW Shoi, Neirope, 1988; 1: 623-634], for example, Alzheimer's disease (BA) and others. Another pharmacological property of hydrogenated pippolo [4,3-b] indoles is their highly effective antihistamine effect, which allows the use of these substances in the form of these pharmaceutical compositions for the treatment of a wide range of allergic and autoimmune diseases, including hay fever, urticaria, asthma, atopic dermatitis, neurodermatitis, angioedema, Quincke's edema, eczema, burn toxemia, and also allergic reactions caused by drugs, food, cosmetics, house dust, insect bites, etc.

In the literature there are few data on hydrogenated pippolo [4,3-b] indoles, presented in table 1.

где: пунктирная линия с сопровождающей ее сплошной линией (^) представляет одинарную или двойную связь.1 H-Pyrrole o [4, 3-b] indoles

where: the dashed line with the solid line accompanying it (^) represents a single or double bond.

Table 1. Known hydrogenated pippolo [4,3-b] indoles

It has been shown that l, 2,3,8-tetrahydro-ipsyl [4,3-b] indoles are of interest as biologically active compounds. In particular, it was found that 7-ftop-4- (4-fluorophenyl) -pprolo [3,4-b] indoles (Table 1, N ° 8) are orally active antipsychotic agents.

As a result of the studies, the inventors discovered a large group of hydrogenated pippolo [4,3-b] indoles having physiological activity.

A further aspect of the invention is the provision of pharmaceutical compositions comprising a therapeutically effective amount of a compound according to the invention and therapeutically acceptable inert auxiliary agents such as carriers, excipients, etc.

Disclosure of invention

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

“Aheterocycle” means an aromatic or non-aromatic monocyclic or polycyclic system containing at least one nitrogen atom in a cycle. An azaheterocycle may have one or more “replaceable cyclic” systems. "Aliphatic" radical means a radical obtained by removing a hydrogen atom from a non-aromatic C-H bond. An aliphatic radical may additionally contain substituents — aliphatic or aromatic radicals defined in this section. Representatives of aliphatic radicals include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aralkenyl, aralkiloksial- keel, aralkiloksikarbonilalkil, aralkyl, aralkynyl, aralkiloksialkenil, nile geteroaralke-, heteroaralkyl, geteroaralkiloksialkenil, reteroaralkiloksialkil, nile geteroaralke-, annelated arylcycloalkyl, annelated heteroarylcycloalkyl, annelated arylcycloalkenyl, annelated heteroarylcycloalkenyl, annelated arylheterocyclyl, annelated heteroarylhetero iklil, annelated arylheterocyclenyl, annelated heteroarylheterocyclenyl.

“Alkenyl” means an aliphatic linear or branched hydrocarbon group containing from 2 to 7 carbon atoms and including a carbon-carbon double bond. Branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. An alkyl group may have one or more substituents, for example, such as halogen, alkenyloxy, cycloalkyl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl, alkylthio, heteroaraalkyloxy, heterocyclyl, heterocyclylalkyloxy, alkoxycarboxyloxycarbyl carbonyl or R _k ^a R _{k + 1} ^a N-, R _k ^a R _{k +} i ^a NC (= O>, R _k ^a R _{k + 1} ⁸ NSO ₂ -, where R _k ^a and R _{k +} i ^{a are} independently other are “amino acid substitutes”, the meaning of which is defined in this section, for example, a hydrogen atom, alkyl, aryl, aral keel, heteroaralkyl, heterocyclyl or heteroaryl, or R _k ^a and R _{k +} i, ^a, together with the N atom to which they are bonded, form 4 to 7 membered heterocyclyl or heterocyclenyl via R _k ^a and R _{k +} i ^a . methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n- pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, benzyloxycarbonylmethyl and pyridylmethyloxycarbonylmethyl. Preferred alkenyl groups are ethenyl, propenyl, n-butenyl, isobutenyl, 3-methylbut-2-enyl, n-pentenyl and cyclohexylbutenyl.

“Alkenyloxy” means an alkenyl-O— group in which alkenyl is defined in this section. Preferred alkenyloxy groups are allyloxy and 3-butenyloxy. “Alkenyloxyalkyl” means an alkenyl-O-alkyl group in which alkyl and alkenyl are defined in this section.

где R_k ^a и R_k+i^a независимо друг от друга представляют собой «зaмecтитeли аминогруппы)), значение которых определено в данном разделе, например, атом водорода, алкил, арил, аралкил, гетероаралкил, гетероциклил или гетероарил, или R_k ^a и R_k+ϊ ^a вместе с атомом N, с которым они связаны, образуют через R_k ^a и R_k+i^a 4 - 7 членный гетероциклил или гетероцикленил. Предпочтительными алкильными группами являются метил, трифторметил, циклопропилметил, циклопентил- метил, этил, н-пропил, изо-пропил, н-бутил, трет-бутил, н-пентил, 3-пeнтил, метоксиэтил, карбоксиметил, метоксикарбонилметил, этоксикарбонилметил, бензилокси- карбонилметил, метоксикарбонилметил и пиридилметилоксикарбонилметил. Предпочтительными «aлкильными заместителями)) являются циклоалкил, арил, гетероарил, гетероциклил, гидрокси, алкокси, алкоксикарбонил, аралкокси, арилокси, алкилтио, гетероарилтио, аралкилтио, алкилсульфонил, арилсульфонил, алкоксикарбонил, аралкоксикарбонил, гетероаралкилоксикарбонил или R_k ^aR_k+i^aN-, Rk^aRk₊i^aNC(=O)-, аннелированный арилгетероцикленил, аннелированный арилгетероциклил. «Aлкилoкcиaлкил» означает алкил-О-алкил группу, в которой алкильные группы независимы друг от друга и определены в данном разделе. Предпочтительными алкилоксиалкильными группами являются метоксиэтил, этоксиметил, н-бутоксиметил, метоксипропил и изо-пропилоксиэтил.“Alkyl” means an aliphatic hydrocarbon linear or branched group with 1-12 carbon atoms in the chain. Branched means that the alkyl chain has one or more “lower alkyl” substituents. Alkyl may have one or more identical or different substituents (“alkyl substituents))), including halogen, alkenyloxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl. , alkylthio, heteroarylthio, aralkylthio, arylsulfonyl, alkylsulfonylheteroaralkyloxy, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated heteroaryl heterocyclyl cycloalkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl, alkoksikar- Bonilla, aralkoxycarbonyl, geteroaralkiloksikarbonil or ^{_{R k a Rk + i a N-}} , Rk a Rk + ϊ a NC (= O) -, R k a R k + i a NC (= S) -,

where R _k ^a and R _{k +} i ^a independently represent “amino group substituents)), the meanings of which are defined in this section, for example, a hydrogen atom, alkyl, aryl, aralkyl, heteroaralkyl, heterocyclyl or heteroaryl, or R _k ^a and R _{k + ϊ} ^a together with the N atom to which they are bonded, form through R _k ^a and R _{k +} i ^a 4 - 7 membered heterocyclyl or heterocyclenyl. Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentyl methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, benzyloxy carbonylmethyl, methoxycarbonylmethyl and pyridylmethyloxycarbonylmethyl. The preferred "alkyl substituents)) are cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, alkoxycarbonyl, aralkoxy, aryloxy, alkylthio, heteroarylthio, aralkylthio, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, geteroaralkiloksikarbonil or ^{_{R k a R k + i a}} N- , Rk ^a Rk ₊ i ^a NC (= O) -, annelated arylheterocyclenyl, annelated arylheterocyclyl. “Alkyloxyalkyl” means an alkyl-O-alkyl group in which the alkyl groups are independent of each other and are defined in this section. Preferred alkyloxyalkyl groups are methoxyethyl, ethoxymethyl, n-butoxymethyl, methoxypropyl and isopropyloxyethyl.

“Alkyloxycarbonyl” means an alkyl-O — C (= O) group in which alkyl groups are defined in this section. Preferred alkyloxycarbonyl groups are methoxycarbonyl, ethoxycarbonyl, n-butoxycarbonyl, iso-propyloxycarbonyl, benzylcarbonyl and phenethylcarbonyl.

“Alkylthio” means an alkyl-S group in which an alkyl group is defined in this section.

“Alkoxy” means an alkyl-O— group in which alkyl is defined in this section.

Preferred alkyloxy groups are methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.

“Alkoxycarbonyl” means alkyl-OC (= ^: O), the group in which alkyl is defined in this section. Preferred alkoxycarbonyl groups are methoxycarbonyl, ethoxycarbonyl and tert-butyloxycarbonyl.

"Alkoxycarbonylalkyl" means an alkyl-O-C (= O) -alkyl group in which alkyl is defined in this section. Preferred alkoxycarbonylalkyl groups are: methoxy-carbonylmethyl, ethoxy-carbonylmethyl, methoxy-carbonyl-ethyl, ethoxy-carbonylethyl.

“Aminograppa” means R _k ^a R _{k +} i ^a N is a group substituted or unsubstituted

“Noticeable amino groups” R _k ^a and R _{k +} ^, the meaning of which is defined in this section, for example, amino (H ₂ N-), methylamino, diethylamino, pyrrolidine, morpholine, benzylamino or phenethylamino.

“Amino acid” means a natural amino acid or a non-natural amino acid, the meaning of which is defined in this section. Preferred amino acids are amino acids containing an α or β amino group. Examples of natural amino acids are α-amino acids, they can be alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, series, threonine and cysteine.

“Amino-cyano-methylene” means (NR _k ^a Rk ₊ i ^a ) (CN) C = a group (radical) substituted or unsubstituted “substituent of the amino group” Rk ^a and Rк ₊ Д, the meaning of which is defined in this section, for example, amino. “Annelized cycle” (condensed cycle) means a bi- or polycyclic system in which the annelated cycle and the cycle or polycyclic with which it is “annealed” have at least two common atoms. ''

“Annelated apylheterocycloalkenyl” means annelated aryl and heterocycloalkenyl, the meaning of which is defined in this section. Annelated arylheterocycloalkenyl can bind through any possible atom of the ring system. The prefix "aza", "okca" or "tia" before "heterocycloalkenyl" means the presence of a nitrogen atom, atom, oxygen or sulfur atom in the cyclic system, respectively. Annelated arylheterocycloalkenyl may have one or more “cyclic system substitutes,” which may be the same or different. The nitrogen and sulfur atoms in the heterocycloalkenyl moiety may be oxidized to N-oxide, S-oxide or S-dioxide. Representatives of annelated arylheterocycloalkenyls are indolinyl, Ш-2-oxoquinolinyl, 2H-1-oxoisoquinolinyl, 1,2-dihydroxinolinyl, and the like.

“Annelated apylheterocycloalkyl” means annelated aryl and heterocycloalkyl, the meaning of which is defined in this section. Annelated arylheterocycloalkyl can bind through any possible atom of the cyclic system. The prefix "aza", "okca" or "tia" before "heterocycloalkyl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Annelated arylheterocycloalkyl may have one or more “cyclic system substitutes,” which may be the same or different. The nitrogen and sulfur atoms in the heterocycloalkyl moiety can be oxidized to N-oxide, S-oxide or S-dioxide. Representatives of annelated arylheterocycloalkyls are indolyl, 1,2,3,4-tetrahydroisoxinoline, 1,3-benzodiocol, and the like. “Annelated apylcycloalkenyl” means annelated aryl and cycloalkenyl, the meanings of which are defined in this section. Annelated arylcycloalkenyl can bind through any possible atom of the cyclic system. Annelated arylcycloalkenyl may have one or more “cyclic system substitutes,” which may be the same or different. Representatives of annelated arylcycloalkenyls are 1,2-dihydro-naphthalene. inden, etc.

“Annelated apylcycloalkyl” means annelated aryl and cycloalkyl, the meanings of which are defined in this section. Annelated arylcycloalkyl can bind through any possible atom of the cyclic system. Annelated arylcycloalkyl may have one or more “cyclic system substituents)), which may be the same or different. Representatives of annelated arylcycloalkyls are indanine, 1,2,3,4-tetrahydronaphthalene, 5,6,7,8-tetrahydronaphth-l-yl, and the like.

“Annelated heteroapylcycloalkenyl” means annelated heteroaryl and cycloalkenyl, the meanings of which are defined in this section. Annelated heteroarylcycloalkenyl can bind through any possible atom of the cyclic system. The prefix "aza", "okca" or "tia" before "heteroapyl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Annelated heteroarylcycloalkenyl may have one or more “ring system substituents)), which may be the same or different. The nitrogen atom in the heteroaryl moiety may be oxidized to N-oxide. Representatives of annelated heteroarylcycloalkenyls are 5,6-dihydroquinolinyl, 5,6-dihydroisoxinolinyl, 4,5-dihydro-III-benimidazolyl, and the like. “Annelated heteroapylcycloalkyl” means annelated heteroaryl and cycloalkyl, the meanings of which are defined in this section. Annelated heteroarylcycloalkyl can bind through any possible atom of the cyclic system. The prefix "aza", "okca" or "tia" before "heteroapyl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Annelated heteroarylcycloalkyl may have one or more “ring system substituents)), which may be the same or different. The nitrogen atom in the heteroaryl moiety may be oxidized to N-oxide. Representatives of annelated heteroarylcycloalkyls are 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoxinolinyl, 4,5,6,7-tetrahydro-S-benzimidazole and the like. “Annelated heteroapylheterocycle” means annelated heteroaryl and heterocyclenyl, the meanings of which are defined in this section. Annelated heteroarylheterocyclenyl can bind through any possible atom of the ring system. The prefix "aza", "okca" or "tia" before "heteroapyl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Annelated heteroarylheterocyclenyl may have one or more “substituent ring systems)), which may be the same or different. The nitrogen atom in the heteroaryl moiety may be oxidized to N-oxide. The nitrogen and sulfur atoms in the heterocyclenyl moiety can be oxidized to N-oxide, S-oxide or S-dioxide. Representatives annellated heteroarylheterocyclenyls are l, 2-dihydropo [2,7] naphthyridinyl, 7,8-dihydro [l, 7] naphthyridinyl, 6,7-dihydro-3H-imidazo [4,5-c] pyrvinyl, and the like.

“Annelated heteroapylheterocyclyl” means annelated heteroaryl and heterocyclyl, the meanings of which are defined in this section. Annelated heteroaryl heterocyclyl can bind through any possible atom of the ring system. The prefix "aza", "okca" or "tia" before "heteroapyl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively.

Annelated heteroaryl heterocyclyl may have one or more

“Substitutes for a cyclic system)), which may be the same or different.

The nitrogen atom in the heteroaryl moiety can be oxidized to N-oxide.

The nitrogen and sulfur atoms in the heterocyclyl moiety can be oxidized to

N-oxide, S-oxide or S-dioxide. Representatives of annelated heteroaryl heterocyclyls are 2,3-dihydro-III-pyrpolo [3,4-b] quinolin-2-yl, 2,3-dihydro-III-pyrpolo [3,4-b] indol-2-yl, l, 2,3,4-tetrahydro [l, 5] naphthyridinyl and the like.

“Aralkenyl” means an aryl-alkenyl group in which the meanings of aryl and alkenyl are defined in this section. For example, 2-phenethyl is an aralkenyl group.

“Aralkyl” means an alkyl group substituted with one or more aryl groups, in which the meanings of aryl and alkyl are defined in this section.

Examples of aralkyl groups are benzyl, 2,2-diphenylethyl or phenethyl.

“Aralkylamino” means an aryl-alkyl-NH-group in which the meanings of aryl and alkyl are defined in this section.

“Aralkylcylfinyl” means an aralkyl-SO— group in which the meaning of aralkyl is defined in this section.

“Aralkylcylphonyl” means aralkyl-SO ₂ —the group in which the meaning of aralkyl is defined in this section.

“Aralkylthio” means an aralkyl-S- group in which the meaning of aralkyl is defined in this section.

“Aralkoxy” means an aralkyl-O— group in which the meaning of aralkyl is defined in this section. For example, benzyloxy or 1- or 2-naphthylenmethoxy are aralkyloxy groups.

“Aralkoxyalkyl” means an aralkyl-O-alkyl group in which the meanings of aralkyl and alkyl are defined in this section. An example of an aralkyl-O-alkyl group is benzyloxyethyl. “Aralkoxycarbonyl” means aralkyl-OC (= O), the group in which the meaning of aralkyl is defined in this section. An example of an aralkoxycarbonyl group is benzyloxycarbonyl.

“Aralkoxycarbonylalkyl” means an aralkyl-O — C (= O) -alkyl- group in which the meanings of aralkyl and alkyl are defined in this section. An example of an aralkoxycarbonylalkyl group is benzyloxycarbonylmethyl or benzyloxycarbonylethyl.

"Apyl" means an aromatic monocyclic or polycyclic system comprising from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms.

Aryl may contain one or more “cyclic system substitutes,” which may be the same or different. Representative aryl groups are phenyl or naphthyl, substituted phenyl or substituted naphthyl. Aryl can be annelated with a non-aromatic ring system or heterocycle.

“Apylcarbamoyl” means apyl-NHC (= O), the group in which the aryl value is defined in this section.

“Apyloxy” means an aryl-O- group in which the meaning of aryl is defined in this section. Representatives of the aryloxy groups are phenoxy and 2-naphthyloxy.

“Apyloxycarbonyl” means apylo-O-C (= O) —the group in which the aryl value is defined in this section. Representative aryloxycarbonyl groups are phenoxycarbonyl and 2-naphthoxycarbonyl.

“Apylcylfinyl” means an aryl-SO— group in which the meaning of aryl is defined in this section.

“Apylcylphone” means aρyl-SO ₂ —the group in which the meaning of aryl is defined in this section.

"Apilthio" means an aryl-S- group in which the meaning of aryl is defined in this section. Representative arylthio groups are phenylthio and 2-naphthylthio.

“Apoylamino” means an aroyl-NH group in which the meaning of aroyl is defined in this section.

“Apoyl" means apyl-C (= O), the group in which the meaning of aryl is defined in this section. Examples of aroyl groups are benzoyl, 1st 2nd naphthoyl.

“Aromatic” radical means a radical obtained by removing a hydrogen atom from an aromatic CH bond. The “aromatic” radical includes the aryl and heteroaryl rings defined in this section. Aryl and heteroaryl rings may additionally contain substituents - aliphatic or aromatic radicals defined in this section. Representative aromatic radicals include aryl, annelated cycloalkenylaryl, annelated cycloalkylaryl, annelated heterocyclylaryl, annelated heterocyclylaryl, heteroaryl, annelated cycloalkylheteroaryl, annelated cycloalkenylheteroaryl heteroeryl heteroaryl. “Aromatic cycle” means a planar cyclic system in which all atoms of the cycle participate in the formation of a single conjugation system including, according to the Hückel rule, (4n + 2) π-electrons (n is a non-negative integer). Examples of aromatic cycles are benzene, naphthalene, anthracene and the like. In the case of “hetero matric cycles”, π electrons and p electrons of heteroatoms participate in the conjugation system; their total number also equals (4n + 2). Examples of such cycles are pyridine, thiophene, pyrrole, furan, thiazole and the like. An aromatic ring may have one or more “replaceable cyclic” systems and may be annelated with a non-aromatic ring, heteroaromatic or heterocyclic system.

“Acyl” means HC (= O) - or alkyl-C (= O) -, cycloalkyl-C (= 0) -, heterocyclyl-C (= O) -, heterocyclyl-C (= O) -, apyl-C (= O) - apylalkyl-C (= O) -, heteroapyl-C (= O) - or heteroapylalkyl-C (= 0) - a group in which alkyl-, cycloalkyl-, heterocyclyl-, heterocyclylalkyl, aryl-, arylalkyl , heteroaryl, heteroarylalkyl are defined in this section.

“Acylamino” means an acyl-NH— group in which the meaning of acyl is defined in this section.

"Bifunctional reagent" means a chemical compound having two reaction centers participating simultaneously or sequentially in the reactions. Examples of bifunctional reagents are reagents containing a carboxyl group and an aldehyde or ketone group, for example, 2-formylbenzoic acid, 2- (2-oxo-ethylcarbamoyl) -benzoic acid, 2- (3-formyl-thiophen-2- and ) -benzoic acid or 2- (2-formylphenyl) -thiophene-3-carboxylic acid. “1,2-Vinyl radical” means a —CH═CH— group which contains one or more identical or different “alkyl substituents”, the meanings of which are defined in this section.

"Halogen" means fluorine, chlorine, bromine and iodine. Fluorine, chlorine and bromine are preferred. “Hetero-linked loop” means that a loop that attaches (annelates or condenses) to another loop or polycycle contains at least one heteroatom.

“Heteroapalkenyl” means a heteroaryl alkenyl group in which heteroaryl and alkenyl are defined in this section. Preferably, heteroarylalkenyl includes a lower alkenyl group. Representatives of heteroarylalkenyls are 4-pyridshi-vinyl, thienyl-ethenyl, imidazolylenethenyl, pyrazinyl-ethenyl, etc. “Heteroapalkyl” means a heteroaryl-alkyl group in which heteroaryl and alkyl are defined in this section. Representative heteroarylalkyls are pyridylmethyl, thienylmethyl, furylmethyl, imidazolylmethyl, pyrazinylmethyl, and the like. “Heteroapalkyloxy” means a heteroarylalkyl-O— group in which heteroarylalkyl is defined in this section. Representatives of heteroarylalkyloxy groups are 4-pyridylmethyloxy, 2-thienylmethyloxy and the like.

“Heteroapyl” means an aromatic monocyclic or polycyclic system comprising from 5 to 14 carbon atoms, preferably from 5 to 10, in which one or more carbon atoms are substituted with heteroatoms or heteroatoms such as nitrogen, sulfur or oxygen. The prefix "aza", "okca" or "tia" before "heteroapyl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. The nitrogen atom in the heteroaryl may be oxidized to N-oxide. Heteroaryl may have one or more “cyclic system substitutes,” which may be the same or different. Representatives of heteroaryl are pyrrolyl,. furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, isoxoxazolyl, isothiazolyl, tetrazolyl, ochazolyl, thiazolyl, pyrazolyl, furazanyl, triazolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, lidylazinyl imidazo [2, lb] tiazolil, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzotiazenil, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidinyl, pyrrolopyridine, imidazopyridyl, isoquinolinyl, benzoazaindolil, 1,2,4-tpiazinil, tienopirrolil, furopirrolil et al. "Getepoapilcylfonilkapbamoil" means a heteroaryl-Sθ ₂ -NH-C (= O) - group, otorrhea heteroaryl is defined herein.

“Heteroapoyl” means heteroapyl-C (= O), the group in which heteroaryl is defined in this section. Representative heteroaroyls are nicotinoyl, thienoyl, pyrazoloyl, etc. “Heterocycle” means a non-aromatic monocyclic or polycyclic system comprising from 3 to 13 carbon atoms, preferably from 5 to 13 carbon atoms, in which one or more carbon atoms are replaced by a hetero atom, such as nitrogen, oxygen, sulfur, and which contains at least at least one carbon-carbon double bond or carbon-nitrogen double bond. The prefix "aza", "okca" or "thia" before heterocyclenyl means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Heterocyclenyl may have one or more “substituents of the cyclic system)), which may be the same or different. The nitrogen and sulfur atoms in heterocyclenyl can be oxidized to N-oxide, S-oxide or S-dioxide. Representative heterocyclenyls are 1,2,3,4-tetrahydropyridine, 1,2-dihydropopyridine, 1,4-dihydropyridine, 2-pyrpolinyl, 3-pyrrolinyl, 2-imidazolyl, 2-pyrazolinyl, dihydrofuranyl, dihydrothiophenyl and the like. “Heterocyclyl” means an aromatic or non-aromatic saturated monocyclic or polycyclic system comprising from 3 to 10 carbon atoms, preferably from 5 to 6 carbon atoms, in which one or more carbon atoms are replaced by a heteroatom such as nitrogen, oxygen, sulfur. The prefix "aza", "okca" or "tia" before heterocyclyl means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Heterocyclyl may have one or more substituents of the cyclic system)), which may be the same or different. The nitrogen and sulfur atoms in the heterocyclyl can be oxidized to N-oxide, S-oxide or S-dioxide. Representatives of heterocyclyl are piperidine, pyrrolidine, piperazine, morpholine, thiomorpholine, thiazolidine, 1,4-dioxane, tetrahydrofuran, tetrahydrothiophene, etc.

“Heterocyclyloxy” means a heterocyclyl-O— group in which heterocyclyl is defined in this section.

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

“Hydroxyalkyl” means a HO-alkyl group in which alkyl is defined in this section.

“Substituent” means a chemical radical that is attached to a scaffold (fragment), for example, ((substituent alkyl ”, ((substituent of amino group)), ((substituent of carbamoyl”, ((substituent of cyclic system)), the meanings of which are defined in this section . Alkyl substituent "means a substituent attached to alkyl, alkenyl, the meaning of which is defined in this section. Alkyl substituent is hydrogen, alkyl, halogen, alkenyloxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, ariloksikarbnil, alkylthio, heteroarylthio, aralkylthio, arylsulfonyl, alkilsulfonilgeteroaralkiloksi, annelated heteroarylcycloalkenyl annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated heteroarylheterocyclyl, annelated arylcycloalkenyl, annelated arylcycloalkyl, anneliro arylheterocyclenyl, annelated arylheterocyclyl, alkoxycarbonyl, aralkoxycarbonyl, heteroaralkyloxycarbonyl or R _k ^a R _{k + 1} ^a N-, R _k ^a R _{k + 1} ^a NC (= O) -, R _k ^a R _{k + 1} ^a NSO ₂ -, where R _k ^a and R _{k + 1} ^a independently represent “amino group substituents)), the meanings of which are defined in this section, for example, a hydrogen atom, alkyl, aryl, aralkyl, heteroaralkyl, heterocyclyl or heteroaryl, or R _k ^a and R _k V together with the N atom to which they are bonded form through R _k ^a and R _{k +} ^ 4 - 7 membered heterocyclyl or heterocyclenyl. Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentil, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, benzyloxycarbonylmethyl methoxycarbonylmethyl and pyridyl - methyloxycarbonylmethyl. The preferred "alkyl substituents)) are cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, alkoxycarbonyl, aralkoxy, aryloxy, alkylthio, heteroarylthio, aralkylthio, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, geteroaralkiloksikarbonil or R _k ^a Rk ₊ i ^a N- , R _k ^a R _{k + 1} ^a NC (= O) -, annelated arylheterocyclenyl, annelated arylheterocyclyl. The meaning of “alkyl substituents)) is defined in this section. Amino group substituent "means a substituent attached to an amino group. Amino group substituent represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, acyl, aroyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylaminocarbonyl, arylaminocarbonyl, geteroarilamino- carbonyl geterotsiklilaminokarbonil, alkylaminothiocarbonyl, arilaminotiokar- Bonilla, heteroarylaminothiocarbonyl, heterocyclylaminothiocarbonyl, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated heteroarylheterocyclyl, annelir ovany arylcycloalkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, heteroaralkyloxycarbonylalkyl. The meaning of “Amino Acceptable Substances” is defined in this section.

“Carbamoyl substituent” means a substituent attached to a carbamoyl group, the meaning of which is defined in this section. The carbamoyl substituent is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, heteroaralkyloxycarbonylalkyl or R _k ^a Riq.i ^a N-, R _k ^a R _{k + 1} ^a NC (= O) acylalkyl - alkenyl, annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated heteroarylheterocyclyl, annelated arylcycloalkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl. Preferred "zamectitelyami kapbamoilnymi" are alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonylalkyl, aralkoksikarbonilalkil, geteroaralkiloksikarbonilalkil or ^{_{R k a R k + i a}} N-, R k a R k + i a NC (= O) -alκil, annelated arylheterocyclenyl, annelated arylheterocyclyl. The meaning of “carbamoyl substitutes” is defined in this section.

"Nucleophilic substituent" means a chemical radical that is attached to scaffold by reaction with a nucleophilic reagent, for example, selected from the group of primary or secondary amines, alcohols, phenols, mercaptans and thiophenols.

“Ring system substituent” means a substituent attached to an aromatic or non-aromatic ring system, including hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkoxy, aryloxy, acyl, , nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkyloxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, arylalkyloxyalkyl, heterocyclylalkyloxyalkyl, alkylsulfonyl, arylsulfonyl, heterocylalkyl yl, arylsulfonic finil, geterotsiklilsulfinil, alkylthio, arylthio, heterocyclylthio, heterocyclylthio, alkylsulfonylalkyl, arylsulfonylalkyl, geterotsiklilsulfonilalkil, alkilsul- finilalkil, arilsulfinilalisil, geterotsiklilsulfinilalkil, alkylthioalkyl, arylthioalkyl geterotsikliltioalkil, arilalisilsulfonilalkil, heterocyclyl- alkylsulfonylalkyl, arilalkiltioalkil, geterotsiklilalkiltioalkil, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, amidino, R _k ^a R _{k +} i ^a N-, R _k ^a N =, R _k ^a R _{k +!} ^a N- alkyl-, Ri _< ^a Rk + ₁ ^a NC (= O) - or R _k ^a R _{k +} i ^a NSO ₂ -, where Rk ^a and R _{k + 1} ^a are independently “amino substituents”, the value of which is determined in this section, for example, hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, or optionally substituted heteroaralkyl, or a substituent R _k ^a R _{k +} i ^a N-, in which R / may be acyl or aroyl, and the value R _{k +} i ^{a is} defined above, or the “substituent of the cyclic system” is Rk ^a R _{k +} i ^a NC (= O) - or R / Rк ₊ ^ NSОг-, in which Rk ^a and Rk + i ^a together with the nitrogen atom with which nor are attached to via R / and R _{k +} ϊ ^a 4-7 membered heterocyclyl or heterocyclenyl.

“Electrophilic substituent” means a chemical radical that attaches to scaffold by reaction with an electrophilic reagent, for example, selected from the group of organic acids or their derivatives (anhydrides, imidazolides, halides), organic sulfonic acid esters or organic sulfonyl chlorides, organic halides, organic isocyanides organic isothiocyanates.

“Substituted amino group” means an Rk ^a R _{k +} i ^a N group in which Rk ^a and Rk + i ^a are amino substituents, the meaning of which is defined in this section.

“Substituted carboxyl” means a C (O) OR group. The substituted carboxyl has an R ₅ substituent including alkenyl, alkyl, aryl, heteroaryl, heterocyclyl, the meaning of which is defined in this section.

“Substituted mercapto group” means an SR, S (O) R or S (O ₂ ) R group in which the substituent R is alkenyl, alkyl, aryl, heteroaryl, heterocyclyl, the meaning of which is defined in this section.

“Protection group” (PG) means a chemical radical that attaches to a scaffold or intermediate to temporarily protect the amino group in multifunctional compounds including, but not limited to: an amide substituent such as formyl, optionally substituted acetyl (eg trichloroacetyl, trifluoroacetyl, 3-phenylpropionyl et al.) optionally substituted benzoyl et al .; a carbamate substituent, such as optionally substituted Ci-C ₇ alkyloxycarbonyl, for example, methyloxycarbonyl, ethyloxycarbonyl, tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (Fmoc), etc .; optionally substituted Ci-C ₇ alkyl substituent, for example, tert-butyl, benzyl, 2,4- dimethoxybenzyl, 9-phenylphyloinyl and others; sulfonyl substituent, for example, benzenesulfonyl, p-toluenesulfonyl, etc.

“Protected primary or secondary amine” means a group of the formula Rk ^a R _{k +} i ^a N-, in which R _k ^a is a PG protecting group and R _{k + 1} ^a is hydrogen, “a substituent of the amino group)), the meaning of which is defined in in this section, for example, alkenyl, alkyl, aralkyl, aryl, annelated arylcycloalkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl, cycloalkyl, cycloalkenyl, heteroaralkyl, heteroaryl, annilated heteroalkyl, arylated heteroalkyl nelirovanny heteroarylheterocyclenyl, annelated geteraarilgeterotsiklil, heterocyclenyl or heterocyclyl.

“Imino group” means R _k ^a N = a group substituted or unsubstituted with “a substituent of the amino group)) R _k ^a , the meaning of which is defined in this section, for example, imino (HN =), methylimino (CH ₃ N =), ethylimino (C ₂ H ₅ N =), benzylimino (PhCH ₂ N =) or phenethylimino (PhCH ₂ CH ₂ N =).

“Inert substituent (or“ non-interfering)), “Nopperfer substitupt”) means a low or non-reactive radical, including but not limited to Cj - C ₇ alkyl, C ₂ - C ₇ alkenyl, C ₂ - _. C ₇ alkynyl, C ₁ - C ₇ alkoxy, C ₇ - C ₁₂ aralkyl substituted with inert aralkyl substituents, C ₇ - C ₁₂ heterocyclylalkyl substituted with inert substituents heterocyclylalkyl, C ₇ - C ₁₂ alkaryl, C ₃ - C _1O cycloalkyl, C ₃ - C ₁₀ cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl, C ₂ - C ₁₂ alkoxyalkyl, C ₂ - C ₁₀ alkylsulfinyl, C ₂ - C ₁₀ alkylsulfonyl, (CH ₂ ) _m -O- (C ₁ - C ₇ alkyl), - (CH _{2) m} -N (Ci - C ₇ alkyl) _n, aryl substituted with halogen, aryl inert substituents, substituted by inert substituents alkoxy, fluoroalkyl, aryloxyalkyl, heterocyclyl, substituted by inert Vice-heterocyclic and nitroalkyl; where m and n are from 1 to 7. Preferred "inert substituents" are C ₁ - C ₇ alkyl, C ₂ - C ₇ alkenyl, C ₂ - C ₇ alkynyl, C ₁ - C ₇ alkoxy, C ₇ - C ₁₂ aralkyl, C ₇ - C ₁₂ alkaryl, C ₃ - C ₁₀ cycloalkyl, C ₃ - Cyu cycloalkenyl, substituted with inert substituents C ₁ - C ₇ alkyl, phenyl substituted with inert substituents phenyl, (CH ₂ ) _m -O- ( C ₁ - C ₇ alkyl), - (CH ₂ ) _m —N (C ₁ - C ₇ alkyl) _n , aryl substituted with inert substituents aryl, heterocyclyl and substituted with inert substituents heterocyclyl. “Kambamoyl” means C (= O) NR _k ^a R _{k +} i ^a is a group. Carbamoyl may have one or more identical or different carbamoyl substituents R _k ^a and Rk + ϊ ^a including hydrogen, alkenyl, alkyl, aryl, heteroaryl, heterocyclyl, the meaning of which is defined in this section.

“Carbamoylheterocycle” means an azaheterocycle containing as

“Substituent of the cyclic system)), at least one carbamoyl group.

The meanings “hetero-cycle”, “substituent of the cyclic system)) and“ carbamoyl group)) are defined in this section.

“Carboxyl” means an HOC (= O) - (carboxyl) group.

“Carboxyalkyl” means the HOC (= O) -alkyl group in which the meaning of alkyl is defined in this section.

“Kapbocycle” means a mono- or polycyclic system consisting only of carbon atoms. Carbocycles can be either aromatic or alicyclic.

Alicyclic polycycles may have one or more common atoms. In the case of one common atom, spiro-carbocycles are formed (for example, spiro [2.2] pentane), in the case of two

- various condensed systems (for example, decalin), in the case of three - bridging systems (for example, bicyclo [3.3.1] nonon), in the case of a larger number - various polyhedral systems (for example, adamantane). Alicycles can be

“Saturated”, for example, as cyclohexane, or “partially saturated)), for example, as tetralin.

“Combinative library” means a collection of compounds obtained by parallel synthesis designed to search for a hit or leader compound, as well as to optimize the physiological activity of a hit or leader, each library compound corresponding to a common scaffold and the library is a collection of related homologs or analogues.

“Methylene radical” means —CH ₂ — a group that contains one or two identical or different ((alkyl substituents ”, the meaning of which is defined in this section.

“Non-aromatic cycle” (saturated cycle or partially saturated cycle) means a non-aromatic cyclic or polycyclic system formally formed as a result of complete or partial hydrogenation of unsaturated C = C ι or C = N bonds. A non-aromatic ring may have one or more ((cyclic substituents)) systems and may be annelated with aromatic, heteroaromatic or heterocyclic systems. Examples of non-aromatic rings are cyclohexane or piperidine, examples of a partially saturated ring are cyclohexene or piperidein. “Non-natural amino acid” means an amino acid of a non-nucleic nature.

Examples of unnatural amino acids include the D-isomers of natural α-amino acids, aminobutyric acid, 2-aminobutyric acid, γ-aminobutyric acid, N-α-alkylated amino acids, 2,2-dialkyl-α-amino acids, 1-amino-cycloalkyl carboxylic acids, β-Alanine, 2-Alkyl-β-Alanines, 2-Cycloalkyl-β-Alanines,

2-apyl-β-alanines, 2-heteroapyl-β-alanines, 2-heterocyclyl-β-alanines and (1-amino-cycloalkyl) -cyclic acids in which the meanings of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are defined section.

Optional aromatic cycle "means a cycle that can be either an aromatic or a non-aromatic cycle, the meanings of which are defined in this section.

“Optionally substituted radical” means a radical without substituents or containing one or more substituents.

Optional annelated (condensed) cycle "means a condensed, non-condensed cycle, the meanings of which are defined in this section.

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

“Parallel synthesis” means a method for conducting chemical synthesis of a combinatorial library of individual compounds.

“1,3-Propylene radical” means —CH ₂ —CH ₂ —CH ₂ — a group that contains one or more identical or different “alkyl substituents”, the meanings of which are defined in this section.

“Leader-compound” (“leader”) means a compound with outstanding (maximum) physiological activity associated with a specific biological target related to a specific (or several) pathology or disease.

“Compound-hit” (“hit”) means a compound that exhibits the desired physiological activity during the initial screening process.

“Family group” means Rk ^a Rk ₊ i ^a NSO ₂ is a group substituted or unsubstituted “a substituent of the amino group)) R _k ^a and Rk ₊ D whose values are defined in this section.

"Cylphonyl" means R-SO ₂ - a group in which R represents alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated heteroarylheterocyclyl, annelated arylcycloalkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl, the meaning of which is defined in this section. “Template” means the general structural formula of a group of compounds or compounds included in the “combination library)).

“Thiocarbamoyl” means Ri _c ^a R _{k + 1} ^a NC (= S) is a group. Thiocarbamoyl may have one or more of the same or different ((amino substituents)) R _k ^a and R _{k +} A, the meaning of which is defined in this section, for example, including alkenyl, alkyl, aryl, heteroaryl, heterocyclyl, the meaning of which is defined in this section. “Cycloalkyl” means a non-aromatic mono- or polycyclic system containing from 3 to 10 carbon atoms. Cycloalkyl may have one or more ((substituents on the cyclic system)), which may be the same or different. Representatives of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalin, norbornyl, adamant-1-yl and the like. Cycloalkyl can be annelated with an aromatic ring or heterocycle. Preferred ((cyclic substituents)) are alkyl, aralkoxy, hydroxy or R _k ^a R _{k +} i ^a N, the meaning of which is defined in this section.

“Cycloalkylcarbonyl” means cycloalkyl-C (= O), the group in which the meaning of cycloalkyl is defined in this section. Representatives of cycloalkylcarbonyl groups are cyclopropylcarbonyl or cyclohexylcarbonyl.

“Cycloalkoxy” means a cycloalkyl-O— group in which the meaning of cycloalkyl is defined in this section.

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

“Pharmaceutically acceptable salt” means the relatively non-toxic organic and inorganic salts of the acids and bases of the present invention. These salts can be prepared in situ during the synthesis, isolation or purification of compounds or prepared specially. In particular, base salts can be prepared specifically based on the purified free base of the claimed compound and a suitable organic or inorganic acid. Examples of salts thus obtained are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valeriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, maleates, fumarates, succinates, tartrates, mesylates, malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like (A detailed description of the properties of such salts is given in Werge SM, et al, “Pharmaceut Salts J. Pharm. 19). Salts of the claimed acids can also be specially prepared by reacting the purified acid with a suitable base, and metal and amine salts can be synthesized. Metal salts include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum salts, the most desirable of which are sodium and potassium salts. Suitable inorganic bases from which metal salts can be obtained are hydroxide, carbonate, sodium bicarbonate and hydride, potassium hydroxide and bicarbonate, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide. As organic bases from which salts of the claimed acids can be obtained, amines and amino acids are selected that are sufficiently basic to form a stable salt and are suitable for medical use (in particular, they should have low toxicity). Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, tris (hydroxymethyl) aminomethane and the like. In addition, tetraalkylammonium hydroxides, for example, such as choline, tetramethylammonium, tetraethylammonium and the like, can be used for salt formation. As amino acids, basic amino acids can be used - lysine, ornithine and arginine.

“Focussed library” means a combinatorial library, or a collection of several combinatorial libraries, or a collection of libraries and substances specially organized to increase the likelihood of finding hits and leaders or to increase the efficiency of their optimization. The design of focused libraries, as a rule, is associated with a directed search for effectors (inhibitors, activators, agonists, antagonists, etc.) of specific biological targets (enzymes, receptors, ion channels, etc.).

“Fragment” (scaffold) means the structural formula of a part of a molecule characteristic of a group of compounds or a molecular framework characteristic of a group of compounds or compounds included in a “combination library)).

“1,2-Ethylene radical” means —CH ₂ —CH ₂ — a group that contains one or more identical or different “alkyl substituents”, the meanings of which are defined in this section. The aim of the present invention are unknown previously substituted hydrogenated pippolo [4,3-b] indoles having biological activity.

This goal is achieved by hydrogenated pyrpo [4,3-b] indoles of general formula 1, their racemates, their optical isomers, their geometric isomers, mixtures of their optical or geometric isomers, their pharmaceutically acceptable salts and / or hydrates.

1 where: the dashed line with the accompanying solid line (™) represents a single or double bond; R ¹ and R ² independently of one another are amino substituents selected from hydrogen, optionally substituted C ₁ -C ₆ alkyl, optionally substituted with aryl, nitrogen-containing heteroaryl; C ₁ -C ₆ alkoxycarbonyl, possibly substituted phenyl, possibly substituted carbonylamino or thiocarbonylamino, substituted acyl, possibly substituted arylsulfonyl, with the substituents in said R and R being independently selected from C ₁ -C ₆ alkyl, halogen atoms, nitro, carboxy, alkoxy aryl;

R ' _n represents one or more identical or different substituents of the cyclic system selected from hydrogen, alkyl, aryl, cyano, halogen, 5-6-membered nitrogen-containing tetroaryl; excluding: l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indole A (I), 2-methyl-A (2), 2-butyl-A (3), 2-cyclohexyl-A ( 4), 2-phenethidine-A (5), 2- (l-methyl-2-phenyl-ethyl) - A (6), 2-carbethoxy-A (7) and 2-benzyl-4-phenyl-l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indole A (8); 3- (2-butyl-A (9) and 3- (2-cyclohexyl-l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indol-4-yl) -proponitrile A (IO); 2-butyl-4- (2-dimethylaminoethyl) - A (Il), 3- (2-cyclohexyl-4- (2-dimethylaminoethyl) - A (12), 2-butyl-4- [3- (4-methylpiperazine -l-yl) propyl] - A (13) and 2-cyclohexyl-4- [3- (4-methylpiperazin-1-yl) propyl] -1, 2,3,4-tetrahydro-pyrpolo [4,3- b] indole A (14); 2-isopropyl-A (15), 2-tert-butyl-A (16), 2-benzyl-A (17) and 2- (4-methoxybenzyl) -4- phenylcylphonyl-1, 2,3,4-tetrahydro-pyrpolo [4,3-b] indole A (18); 2-carbetoxy-7-ftop-A (19), 7-ftop-4- (4-fluorophenyl) - A (20), 2-carbetoxy-7-fluoro-4- (4-fluoro-phenyl) - A (21), 2-methyl-7-fluoro-4- (4-fluoro-phenyl) - A (22), 2- propyl-7-fluoro-4- (4-fluoro-phenyl) - A (23), 2- (3,3-dimethyl-butyl) -7 ~ fluoro-4- (4-fluoro-phenyl) - A (24), 2-pheno-phenyl 7 -ftop-4- (4-fluorophenyl) - A (25), 2-benzyl-7-fluoro-4- (4-fluoro-phenyl) - A (26), 2-propionyl-7-fluoro-4- (4-fluoro-phenyl) - A (27), 2- ( 3,3-dimethylbutanoyl) -7-fluoro-4- (4-fluoro-phenyl) - A (28), 2- [4-oxo-4- (4-fluorophenyl)] - A (29), 2- (4- hydroxy-4-phenyl) - A (30) ₅ 2- [4 ~ hydroxy-4- (4-fluorophenyl)] - A (31), 2- [5-oxo-5- (4-fluorophenyl)] - A (32) and 2- [5-hydroxy-5- (4-fluorophenyl)] - 1,2,3,4-tetrahydro-pyrpolo [4,3-b] indole A (33); cis-l, 2,3,3a, 4,8b-hexahydro-pyrpolo [4,3-b] indole A (34); 7-methyl-2-benzyl-l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indole A (35).

A: R * = H (1.20); CH ₃ (2.21); C ₄ H ₉ (3,9,11,13); C ₆ H ₅ -CH ₂ CH ₂ (4.24); C ₆ H ₅ -CH ₂ (5.17.25); cyclohexyl (6,10,12,14); CO ₂ C ₂ H ₅ (7.28); iso-C ₃ H ₇ (15); mp. -C ₄ H ₉ (16); 4-CH ₃ OC ₆ H ₄ (18); C ₃ H ₇ (22,); (CHa) ₃ CH ₂ CH ₂ CH ₂ (23); CH ₃ CH ₂ CO (26); (CH ₃ ) ₃ CH ₂ CH ₂ CO (27); 4-F-C ₆ H ₄ -C (O) CH ₂ CH ₂ CH ₂ (29); C ₆ H ₅ -C (OH) CH ₂ CH ₂ CH ₂ (30); 4-FC ₆ H ₄ -C (OH) CH ₂ CH ₂ CH ₂ (31); 4-FC ₆ H ₄ -C (O) CH ₂ CH ₂ CH ₂ CH ₂ (32); 4-FC ₆ H ₄ -C (OH) CH ₂ CH ₂ CH ₂ CH ₂ (33).

More preferred hydrogenated pyrpolo [4,3-b] indoles are g / wc-l, 2,3,3a, 4,8b-hexahydro-pyrpolo [4,3-b] indoles of general formula 1.2.

1.2 where: R ¹ , R ² and R ' _n have the above meaning.

More preferred hydrogenated pyrpolo [4,3-b] indoles are l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indoles of the general formula 1.1.1, 1.1.2, 1.1.3 or cis-l, 2,3,3a, 4,8b-hexahydro-pyrpolo [4,3-b] indoles of the general formula 1.2.1, 1.2.2, 1.2.3.

1.1.3, 1.2.3 где: пунктирная линия с сопровождающей ее сплошной линией (^₁), R¹, R² и R'_n имеют вышеуказанное значение.1.1.1, 1.2.1

1.1.3, 1.2.3 where: the dashed line with the accompanying solid line (^ ₁ ), R ¹ , R ² and R ' _n have the above meaning.

More preferred hydrogenated pyrpolo [4,3-b] indoles are pyrpol [4,3-b] indoles of the general formula 1.1.4 - 1.1.15, 1.2.4 - 1.2.15.

1.1.10, 1.2.10 1.1.11, 1.2.11 1.1.12, 1.2.12

где: R¹, R² и R_n ¹ имеют вышеуказанное значение; R⁴ представляет собой возможно замещенный алкил, возможно замещенный арилом, карбоксиалкилом, возможно замещенный арил; R⁵ представляет собой CN, возможно замещенный арил или гетероциклил, карбоксиалкил; R представляет собой карбоксиалкил, карбамоил, CN, возможно замещенный арил или возможно замещенный гетероциклил; R⁷ представляет собой возможно замещенный алкил, возможно замещенный арил или возможно замещенный гетероциклил.

1.1.10, 1.2.10 1.1.11, 1.2.11 1.1.12, 1.2.12

where: R ¹ , R ² and R _n ¹ have the above meaning; R ⁴ represents a possibly substituted alkyl, possibly substituted by aryl, carboxyalkyl, possibly substituted aryl; R ⁵ represents CN, possibly substituted aryl or heterocyclyl; carboxyalkyl; R represents carboxyalkyl, carbamoyl, CN, optionally substituted aryl or optionally substituted heterocyclyl; R ⁷ represents an optionally substituted alkyl, an optionally substituted aryl or an optionally substituted heterocyclyl.

The aim of the present invention are methods for producing hydrogenated pirpolo [4,3-b] indoles of general formula 1, their racemates, their optical isomers, their geometric isomers, their pharmaceutically acceptable salts and / or hydrates.

According to the invention, a method for preparing compounds of general formula 1 consists in reacting phenylhydrazines of general formula 2 (or their salts) with an N-substituted pyppolidin-3-one of general formula 3 in an organic solvent.

где: R , R и R_n ¹ имеют вышеуказанное значение.

where: R, R and R _n ¹ have the above meaning.

According to the invention, a process for the preparation of z / wc-l, 2,3,3a, 8,8a-hexahydro-pippolo [4,3-b] indoles of the general formula 1.2 consists in hydrogenation of a double bond СЗа'Сδа ^{in the} corresponding l, 2,3, The 8-tetrahydro-pyrpolo [4,3-b] indole of general formula 1 with hydrogen in the presence of PtO ₂ in an organic solvent medium.

где: R ₅ R и R_n имеют вышеуказанное значение.

where: R ₅ R and R _n have the above meaning.

According to the invention, a method for producing compounds of the general formula 1.1.4 - 1.1.9, 1.2.4 - 1.2.9, excluding compounds in which R ¹ = H, consists in reacting the corresponding compounds 1.1.1 or 1.2.1 in an organic solvent with electrophilic reagents selected from: alkyl, aryl or heterocyclyl halides of the general formula 5 in the presence of a base; electrophilic alkenes of the general formula 6 in the presence of a base as a catalyst; aldehydes of the general formula 7 and NaBH (AcO) ₃ ; carboxylic acid anhydrides or halides formula 8 in the presence of a base; from (thio) cyanides of the general formula 9 or sulfonyl chlorides of the general formula 10 in the presence of a base.

где: R¹, R², R⁴, R⁵ _j R⁶ _, R⁷ и R_n ¹ имеют вышеуказанное значение, исключая R¹ = H; X представляет собой атом галогена; Y представляет собой атом галогена, гидроксид 3H- имидaзoл-1-иyмa, R⁷-C(O)O.

where: R ¹ , R ² , R ⁴ , R ⁵ _j R ⁶ _, R ⁷ and R _n ¹ have the above meaning, excluding R ¹ = H; X represents a halogen atom; Y represents a halogen atom, 3H-imidazol-1-ima hydroxide, R ⁷ -C (O) O.

According to the invention, a method for producing compounds of the general formula 1.1.2, 1.1.3, 1.2.2, 1.2.3, including 1.1.4 - 1.1.9, 1.2.4 - 1.2.9, in which R ¹ = H, by hydrolysis of the protective group in the corresponding compounds 1.1.4 - 1.1.9, 1.2.4 - 1.2.9, in which R ¹ represents a protective group, such as a 2-ethyl-oxocarbonyl group (R ¹ = CO ₂ C ₂ H ₅ ) or 2-tert-butyl-oxo-carbonyl group (R ¹ = CO ₂ C (CH ₃ ) ₃ ).

1.1.4 - 1.1.9, 1.2.4 - 1.2.9: 1.1.2, 1.1.3, 1.1.4 - 1.1.9, 1.2.2, 1.2.3, R ¹ = CO ₂ C ₂ H ₅ 1.2 .4 - 1.2.9: R ¹ = H

According to the invention, a method for producing compounds of the general formula 1.1.2, 1.1.3, 1.2.2, 1.2.3, including 1.1.4 - 1.1.9, 1.2.4 - 1.2.9, in which R ¹ = CH ₃ , by reduction of the protective group with lithium aluminum hydride in the corresponding compounds 1.1.4 - 1.1.9, 1.2.4 - 1.2.9, in which R ¹ represents a protective group, such as a 2-ethyl-oxocarbonyl group (R ¹ = CO ₂ C ₂ H ₅ ) .

1.1.4 - 1.1.9, 1.2.4 - 1.2.9: 1.1.2, 1.1.3, 1.1.4 - 1.1.9, 1.2.2, 1.2.3, R ¹ = CO ₂ C ₂ H ₅ 1.2 .4 - 1.2.9: R ¹ = CH ₃

According to the invention, a method for producing compounds of the general formulas 1.1.10 - 1.1.15, 1.2.10 - 1.2.15 consists in reacting the corresponding compounds 1.1.2, 1.1.3 or 1.2.2, 1.2.3 in an organic solvent with electrophilic reagents, selected from: alkyl, aryl or heterocyclyl halides of the general formula 5 in the presence of a base; electrophilic alkenes of the general formula 6 in the presence of a base as a catalyst; aldehydes of the general formula 7 and NaBH (AcO) ₃ , anhydrides or halides of the carboxylic acids of the general formula 8 in the presence of a base; from (thio) cyanides of the general formula 9 or sulfonyl chlorides of the general formula 10 in the presence of a base.

1.1.10, 1.2.10 1.1.11, 1.2.11 1.1.12, 1.2.12

1.1.13, 1.2.13 1.1.14, 1.2.14 1.1.15, 1.2.15

where: R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R _n ¹ , X and Y have the above meaning.

Compounds of formula 1 are prepared using methods known in the art to produce similar materials or novel methods described below.

According to the invention, a method for producing new l, 2,3,8-tetrahydro-pyrpo [4,3-b] indoles of general formula 1 with various substituents, carried out according to the well-known reaction of constructing a tricyclic nucleus using Fischer condensation, including the phenylhydrazine reaction of formula 2 ( or its salts with mineral acids) and N-substituted pyppolidin-3-one 3, is described in [Waelsh, WM; Narbert, C. A. J. Med. Chet., 1980 23, (b), 704-707].

Using this method, 1,2,3,8-tetrahydro-pippololo [4,3-b] indoles of the general formula 1 in which R ¹ is an amino substituent, N-protecting groups, for example, ethoxycarbonyl or tert can be obtained. - butoxycarbonyl group, which by known reactions can be transformed into other substituents, including hydrogen; R ¹ represents hydrogen of a secondary amino group, which, by known reactions, can be transformed into a substituted secondary amino group in which R ¹ represents an amino group substituent; R _n 'represents a substituent of the cyclic system.

Reduction of the Cz _a- Cg _a double bond in l, 2,3,8 ~ tetrahydro ~ pippolo [4,3-b] indole of general formula 1 is carried out using suitable reducing agents and selectively substituted z / wc-l, 2,3, 3a, 8,8a-recarcaridropipyrpolo [4,3-b] indoles 1.2 [V.A. Zagorevsky, S.G. Rosenberg, N.M. Sipilina, L.Y. Bykova, A.P. Rodionov - ZhVHO, 1982, v. 27, No. 1, pp. 102-104; and JG Verger, Supsisis, 1974, No. 7, pp. 508-510] relative to the Sza-Cδa bond.

The various amino substituents R ¹ and R ² , along with the methods discussed above, are introduced into the hydrogenated pppolo [4,3-b] indoles 1 and 1.2:

- alkyl derivatives are obtained by alkylation of the corresponding hydrogenated pyr [[4,3-b] indoles 1, 1.2 with electrophilic reagents R ⁴ -X of formula 5 in the presence of a strong base in a polar aprotic solvent such as DMF (dimethylformamide), DMSO (dimethyl sulfoxide), HMPA ( hexamethylphospho-triamide), for example, by analogy with [N.F. Kucherova, N.M. Sharkova, V.A. Zagorevsky Auth. testimonial. USSR, 261386, 1965];

- a compound containing a substituted ethyl group in which R ⁵ is CN or optionally substituted 2-, 3- or 4-pyridyl, is obtained by alkylation of the corresponding hydrogenated pirpolo [4,3-b] indoles 1, 1.2 with electrophilic alkenes of formula 6 in the presence of catalyst base, as, for example, described in the works of [N.N. Kamzolova, N.F. Kucherova, V.A. Zagorevsky, Zhokh, 1964, 34, (7), 2383-2387; A.N. Coast, M.A. Yurovskaya, T.V. Melnikova, O.I. Potanin - Auth. testimonial. USSR, 367094, 1970]. The reaction is carried out using excess reagent 6 (Y = CN) at room temperature under the influence of a catalyst, for example, quaternary ammonium or sodium alcoholate, sodium hydride, sodium ethylate and others, in a polar aprotic solvent such as DMF, DMSO or HMFTA;

- alkyl derivatives are also obtained by reduction of the reaction products of the corresponding hydrogenated pirpolo [4,3-b] indoles 1, 1.2 with aldehydes of the formula 7;

- acyl derivatives, (thio) carbamide derivatives and sulfamoyl derivatives are prepared by reacting the corresponding hydrogenated pyrpolo [4,3-b] indoles 1, 1.2 with acylating agents, respectively anhydrides or halides carboxylic acids of formula 8, alkyl, cycloalkyl or apyl-iso (thio) cyano compounds of formula 9 or sulfochlorides of formula 10, for example, by analogy, as described in [HK Kochetkov, N.F. Kucherova, I.G. Zhukov, Zhokh, 1961, 31, (3), 924-930].

Hydrogenated pppolo [4,3-b] indoles of the general formula 1 of the present invention may form hydrates or pharmaceutically acceptable salts. Inorganic acids and organic acids, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid, maleic acid, tartaric acid, methanesulfonic acid can be used to obtain salts. , benzenesulfonic acid, paratoluenesulfonic acid.

The subject of this invention is also a combinatorial library of compounds with neuroprotective, cognitively stimulating and antihistamine effects for determining hit compounds and leaders, consisting of compounds of general formula 1.

The subject of this invention is also a focused library of compounds with neuroprotective, cognitively stimulating and antihistamine effects for the determination and / or optimization of leader compounds, containing at least one compound of the general formula 1.

According to the present invention, hydrogenated pippolo [4,3-b] indoles of general formula 1, their racemates, their optical isomers, their geometric isomers, their pharmaceutically acceptable salts and / or hydrates can be used as an active ingredient in the manufacture of medicaments for the treatment of and prevention of various diseases.

The subject of this invention is also a pharmaceutical composition having a neuroprotective, cognitively stimulating and antihistamine effect, for treating diseases whose pathogenesis is associated with excessive intracellular content of Ca ^{+ 2} ions in animals and humans, and / or diseases associated with impaired histaminergic mediator system, in the form of tablets, capsules or injections in a pharmaceutically acceptable package containing, as an active substance, a pharmaceutically effective amount, according to ayney least one hydrogenated pyrrolo [4,3-b] indola general formula 1 or a racemate or an optical isomer or a geometric isomer or a pharmaceutically acceptable salt and / or hydrate. The subject of this invention is also a method for producing a pharmaceutical composition, which consists in mixing the active substance with an inert excipient and / or solvent, the distinguishing feature of which is that a pharmacologically effective amount of at least one hydrogenated pippol is used as the active substance [4, 3-b] indole of general formula 1 or its racemate, or its optical isomer, or its geometric isomer, or its pharmaceutically acceptable salt and / or hydrate.

The subject of this invention is the use of a pharmaceutical composition for the preparation of drugs for the treatment and prevention of various diseases of warm-blooded animals and humans, the pathogenesis of which is associated with excessive intracellular content of Ca ions in animals and humans and / or diseases associated with impaired histaminergic mediator system.

According to this invention, it is more preferable to use a pharmaceutical composition for the preparation of drugs for the treatment and prevention of the development of neurological disorders (in particular, hypoxia-ischemia, hypoglycemia, convulsive conditions, brain injuries, etc.), as well as neurodegenerative diseases (including Alzheimer's disease, Huntington's chorea, latirism, amyotrophic lateral sclerosis, etc.).

The use of a pharmaceutical composition for the preparation of medicaments for the treatment of allergic and autoimmune diseases, including hay fever, hives, bronchial asthma, atopic dermatitis, neurodermatitis, angioedema, Quincke edema, eczema, burn toxemia, and also allergic reactions, is more preferred according to this invention. due to medicines, food, cosmetics, house dust, insect bites, etc.

The subject of this invention is also a method for improving the processes of memorization and reproduction of memorized (cognitive stimulation) in humans and warm-blooded animals by introducing a pharmaceutical composition.

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

The carriers used in the pharmaceutical compositions of the present invention are carriers that are used in the pharmaceutical field to obtain common forms, including: in oral forms, binders, lubricants, disintegrants, solvents, diluents, stabilizers, suspending agents, colorless are used agents, flavoring agents of taste; antiseptic agents, solubilizers, stabilizers are used in injection forms; in local forms, bases, diluents, lubricants, antiseptic agents are used. Pharmaceutical preparations may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally or topically). If any medicinal substance in the stomach is not stable, you can use it for the manufacture of tablets, coated with a film of a substance soluble in the stomach and intestines.

In addition, the clinical dosage of hydrogenated pippolo [4,3-b] indoles of general formula 1 or their racemates, or their optical isomers, or their geometric isomers, or their pharmaceutically acceptable salts and / or hydrates in patients can be adjusted depending on: therapeutic the effectiveness and bioavailability of the active ingredients in the body, their metabolic rate and excretion from the body, as well as depending on the age, sex and stage of the patient’s disease, while the daily dose in adults is usually 10 ~ 500 mg, preferably 50 ~ 300 mg. Therefore, during the preparation of the pharmaceutical compositions of the present invention in dosage units, the aforementioned effective dosage must be considered, with each dosage unit containing 10 ~ 500 mg of the compound of general formula 1, preferably 50 ~ 300 mg. In accordance with the instructions of a doctor or pharmacist, these drugs can be taken several times during certain periods of time (preferably from one to six times).

The subject of this invention are also compounds of the general formula 1 possessing neuroprotective, cognitively stimulating and antihistamine properties, as well as the ability to regulate the cytosolic concentration of calcium ions in nerve cells, intended for experimental study of physiological processes of ip vivo and ip vitro as "pharmacological agents". The best embodiment of the invention

The following are specific examples that illustrate but do not limit the scope of the invention.

Example 1. Obtaining 2 ~ carbethoxy-l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indoles 1 (R ^ CO ₂ C ₂ H ₅ ).

A. Preparation of 2-carbetoxy-l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indoles 1 (R ^{1 =} CO ₂ C ₂ H ₅ ). Substances are obtained from the corresponding hydrazines 2 and N-carbethoxy-3-pyrrolidinone 3 (R ^ CO ₂ C ₂ Hs) according to the procedure described for 2-carbethoxy-7-fluoro-1, 2,3,4-tetrahydro-pyrpolo [4 , 3-b] indole 1.1.1 (3) [Well, WM, Narbert, CA, Weissmap, AJ Med. Chet. 1980, 23, 704-707], including: 2-carbetoxy-1,2,3, 4-tetrahydro-pippolo [4,3-b] indole 1.1.1 (1), LC-MS: m / z 231 [M + H]; 2-carbetoxy-7 ~ methyl-l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indole 1.1.1 (2), LC-MS: m / z 245 [M + H]; 2-carbetoxy-7-fluoropl, 2,3,4-tetrahydro-pyrpolo [4,3-b] indole 1.1.1 (3), LC-MS: m / z 249 [M + H]; 7-bromo-2-carbethoxy-l, 2,3,4-tetrahydro-propyl [4,3-b] indole 1.1.1 (4), LC-MS: m / z 310 [M + H] and others.

1.1.1 (1) 1.1.1 (2) 1.1.1 (3) 1.1.1 (4)

B. Preparation of 2-carbetoxy-l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indol-7-carbonitrile 1.1.1 (5). A mixture of 0.2 mmol of the bromine derivative 1.1.1 (4), 36 mg (0.4 mmol) of CuCN and 2 ml of DMF was stirred for 24 hours at 130 ⁰ C in an inert atmosphere. The reaction mass is cooled to 4 ^° C and 15 ml of ammonia and 15 ml of chloroform are added with stirring. The organic layer was separated, washed with water, dried over Na ₂ SO ₄ , filtered, the resulting solution was stirred for 15 minutes with activated carbon, filtered and concentrated. The precipitate is filtered off and recrystallized from methanol or, if necessary, flash chromatographed. Get 2-carbetoxyl, 2,3,4-tetrahydro-propripo [4,3-b] indol-7-carbonitrile 1.1.1 (5), LC-MS: m / z 256 [M + H].

В. Получение 7-apил- и 7-гeтapил-2-кapбэтoкcиЛ,2,3,4-тeтpaгидpo-пиppoлo[4,3- b]индoлoв 1 (R^CO₂O₂Hs). Смесь 0.5 ммоль бромпроизводного 1.1.1(4), 0.6 ммоль арил- или гетарилбороновой кислоты, 70 мг (0.1 ммоль) PdCl₂(PPh₃)₂, 652 мг (2 ммоль) Cs₂(CCb)₂ в 5 мл дегазированного DME нагревают в микроволновой печи при 140⁰C 30 мин, реакционную смесь фильтруют через селит, промывают осадок на фильтре DME, объединенный фильтрат упаривают досуха, остаток несколько раз обрабатывают 2N HCl, всякий раз доводя до легкого кипения при перемешивании и декантируя водный слой со смолистого остатка. К объединенному водному раствору добавляют активированный уголь, доводят до кипения, фильтруют горячим через селит, фильтрат охлаждают и обрабатывают избытком водного раствора NH₃. Выпавший осадок после охлаждения отфильтровывают, промывают большим количеством воды, получают 7-apил- и 7- гeтapил-2-кapбэтoкcи-l,2,3,4-тeтpaгидpo-пиppoлo[4,3-b]индoлы 1 (R^CO₂C₂Hs), которые, при необходимости дополнительно подвергают флэш-хроматографии, в том числе: 7-(3-мeтилфeнил)-2-кapбэтoкcи-l,2,3,4-тeтpaгидpo-пиppoлo[4,3-b]индoл 1.1.1(6), LC-MS: m/z 321[M+H]; 7-(3-пиpидил)-2-кapбэтoкcи-l,2,3,4-тeтpaгидpo-пиppoлo[4,3- bjиндол 1.1.1(7), LC-MS: m/z 308 [М+Н] и другие.

B. Preparation of 7-apyl- and 7-heteryl-2-carbetoxyl, 2,3,4-tetrahydro-pyrpolo [4,3-b] indoles 1 (R ^ CO ₂ O ₂ Hs). A mixture of 0.5 mmol of the bromine derivative 1.1.1 (4), 0.6 mmol of aryl or hetarylboronic acid, 70 mg (0.1 mmol) PdCl ₂ (PPh ₃ ) ₂ , 652 mg (2 mmol) Cs ₂ (CCb) ₂ in 5 ml of degassed DME heated in a microwave oven at 140 ^° C for 30 minutes, the reaction mixture was filtered through celite, the precipitate was washed with a DME filter, the combined filtrate was evaporated to dryness, the residue was treated several times with 2N HCl, each time bringing to a slight boil with stirring and decanting the aqueous layer from the resinous residue . Activated carbon is added to the combined aqueous solution, brought to a boil, filtered hot through celite, the filtrate is cooled and treated with an excess of an aqueous solution of NH ₃ . After cooling, the precipitate formed is filtered off, washed with a large amount of water, and 7-apyl- and 7-heteryl-2-carbetoxy-l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indoles 1 (R ^ CO ₂ C ₂ Hs), which, if necessary, is additionally subjected to flash chromatography, including: 7- (3-methylphenyl) -2-carbethoxy-l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indole 1.1.1 (6), LC-MS: m / z 321 [M + H]; 7- (3-pyridyl) -2-carbetoxy-l, 2,3,4-tetrahydro-pyrpolo [4,3-bjindole 1.1.1 (7), LC-MS: m / z 308 [M + H] and others.

1.1.1 (6) 1.1.1 (7)

Example 2. The General method of obtaining 2-methyl-, l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indoles 1 (R ^{1 =} CH 3). Substances are obtained from the corresponding 2-carbethoxy-1,2,3,4-tetrahydro-pyrpolo [4,3-b] indoles 1 (R ^ COgCαHs) according to the procedure described for 7-fluoro-4- (4-fluorophenyl) - 2-methyl-l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indole [Welsh, WM, Narbert, CA, Weissmap, A. J Med. Chet. 1980, 23, 704-707], including: 2-methyl-l, 2,3,8-tetrahydro-pyrpolo [4,3-b] indole 1.1.1 (8), LC-MS: m / z 173 [M + H]; 2,7-dimethyl-1,2,3,4-tetrahydro-pippolo [4,3-b] indole 1.1.1 (9), LC-MS: m / z 187 [M + H], ¹ H NMR ( 400 MHz, DMSO-d ₆ ): 10.87 (br.s, IH), 7.26 (m, IH), 7.15 (s, IH), 6.89 (m, IH), 3.90 (m, 4H), 2.62 (s, 3H), 2.39 (s, 3H); 2-methyl-7-fluorop-l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indole 1.1.1 (10), LC-MS: m / z 191 [M + H]; 7-bromo-2-methyl-l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indole 1.1.1 (11), LC-MS: m / z 252 [M + H]; 2-methyl-l, 2,3,4-tetrahydro-pyrolo [4,3-b] indol-7-carbonitrile 1.1.1 (12), LC-MS: m / z 198 [M + H]; 2-methyl-7- (3-methylphenyl) -l, 2,3,4-tetrahydro- pppolo [4,3-b] indole 1.1.1 (13), LC-MS: m / z 249 [M + H]; 2-methyl-7- (3-pyridyl) -1,2,3,4-tetrahydro-pyrpolo [4,3-b] indole 1.1.1 (14), LC-MS: m / z 250 [M + H ] and others.

1.1.1 (12) 1.1.1 (13) 1.1.1 (14)

Example 3. General method for the preparation of l, 2,3,8-tetrahydro-propripo [4,3-b] indoles 1.1.3. Substances are prepared according to the procedure described for 7-fluorop 4- (4-fluorophenyl) -l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indole [Welsh, WM, Narbert, CA, Weissmap, AJ Honey. Chet. 1980, 23, 704-707], including: l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indole 1.1.3 (1), LC-MS: m / z 159 [M + H]; 7-methyl-l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indole 1.1.3 (2), LC-MS: m / z 172 [M + H]; 7-fluorop-l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indole 1.1.3 (3), LC-MS: m / z 177 [M + H]; 7-bromo-l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indole 1.1.3 (4), LC-MS: m / z 237 [M + H]; l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indol-7-carbonitrile 1.1.3 (5), LC-MS: m / z 184 [M + H]; 7- (3-methylphenyl) -l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indole 1.1.3 (6), LC-MS: m / z 235 [M + H]; 7- (3-pyridyl) -l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indole 1.1.3 (7), LC-MS: m / z 236 [M + H] and others.

1.1.3 (1) 1.1.3 (2) 1.1.3 (3) 1.1.3 (4)

1.1.3 (5) 1.1.3 (6) 1.1.3 (7) Example 4. General method for producing l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indoles 1.

A. Preparation of pyrrolo [4.3-b] indoles 1.1.4. Vigorously stirred for 6 hours at 5O ⁰ C, a mixture of 2 mmol of pyrolo [4,3-b] indole 1.1.1, 2.5 mmol of an alkyl halide, for example, iodide or bromide, and 750 mg of Cs ₂ CO ₃ in 10 ml of N methyl pyrrolidone (NMP). At the end of the reaction (control according to LC MS), reaction products are isolated. Compounds 1.1.4 are obtained in a yield of 50-80%, including: 2-ethoxycarbonyl-l ethyl ester, 2,3,8-tetrahydro-pyrpolo [4,3-b] indol-4-yl) -uccinic acid 1.1 .4 (1): LC-MS, t / z 317 (M + H); 4,7-dimethyl-l, 2,3,8-tetrahydro-propylpol [4,3-b] indol-2-carboxylic acid ethyl ester 1.1.4 (2): LC-MS, t / z 259 (M + H) ; 4-methyl-7-fluoro-l ethyl ester, 2,3,8-tetrahydro-pyrpolo [4,3-b] indol-2-carboxylic acid 1.1.4 (3): LC-MS, t / z 363 ( M + H); 4-benzyl-7-methyl-l ethyl ester, 2,3,8-tetrahydro-pyrpolo [4,3-b] indol-2-carboxylic acid 1.1.4 (4): LC-MS, t / z 335 ( M + H); 2,4,7-trimethyl-l, 2,3,8-tetrahydro-propylpol [4,3-b] indole 1.1.4 (5): LC-MS, t / 201, M (H +) and others.

B. Preparation of pippolo [4,3-b] indoles 1.1.4. Prepared from the corresponding [4,3-b] indoles 1.1.1 and aryl or heteroaryl halides according to the procedure described for 7-fluoro-4- (4-fluoro-phenyl) -l, 2,3,4-tetrahydropo-pyro [4 , 3-b] indole [Welch, WM, Barbert, CA, Weissmap, A. J Med. Chet. 1980, 23, 704-707], including: 4- (2,4-diferephenyl) -2-carbetoxy-7-methyl-1, 2,3,8-tetrahydro-pyrpolo [4,3-b] indole 1.1.4 (6), LC-MS: m / z 356 [M + H]; 2,7-dimethyl-4- (4-carboxy-2-nitrophenyl) -l, 2,3,8-tetrahydropypropyl [4,3-b] indole 1.1.4 (7), LC-MS: z 352 [M + H] and others.

1.1.4 (6) 1.1.4 (7)

B. Preparation of pippolo [4,3-b] indoles 1.1.5. Stir 1 mmol of pppolol [4.3-b] indole 1.1.1, 1200 μl of dimethyl sulfoxide, 300 μl of water, 3 mmol of the corresponding freshly distilled vinyl derivative 6 and 3 mmol of MeONa or 2,3,4,6,7,8,9 , 10-octahydro-pyrimido [l, 2-a] azepine (DBU) in an argon atmosphere at 80-100 ⁰ C for 2-48 hours. After completion of the reaction (control LC MS), the reaction mass was dissolved in 50 ml of dichloromethane, which was washed twice with a weak aqueous solution of potash, dried over Na ₂ SO ₄ , evaporated, and the residue was chromatographed on a silica gel column impregnated with triethylamine. Compounds 1.1 were obtained, including: 2,5-dimethyl-8- (2-pyridin-2-yl-ethyl) -l, 2,3,8-tetrahydro-pyrpolo [4,3-b] indole 1.1.5 (1) LC-MS: m / z 292 [M + H], ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.48 (m, IH), 7.57 (m, IH), 7.22 (m, IH ), 7.18 (m, IH), 7.05 (m, IH), 7.01 (m, IH), 6.82 (m, IH), 4.36 (m, 2H), 3.74 (br.s, 2H), 3.58 (br. s, 2H), 3.07 (m, 2H), 2.45 (s, 3H), 2.30 (s, 3H); 2,5-dimethyl-8- [2- (6-methyl-pyridin-3-yl) -ethyl] - l, 2,3,8-tetrahydropyrpolo [4,3-b] indole 1.1.5 (2 ), LC-MS: m / z 306 [M + H], ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.16 (m, IH), 7.37 (m, 2H), 7.15 (m, 2H), 6.93 (m, IH), 4.28 (m, 2H), 3.81 (m, 2H), 3.59 (m, 2H), 2.98 (m, 2H), 2.51 (s, 3H), 2.44 (s, 3H), 2.40 (s, 3H); 2,5-dimethyl-8- (2-pyridin-4-yl-ethyl) -l, 2,3,8-tetrahydro-pyrpolo [4,3-b] indole 1.1.5 (3), LC-MS: m / z 292 [M + H], ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.45 (m, 2H), 7.38 (m, IH), 7.15 (m, 3H), 6.93 (m, IH), 4.35 (m, 2H), 3.84 (br.s, 2H), 3.67 (br.s, 2H), 3.04 (m, 2H), 2.54 (s, 3H), 2.39 (s, 3H) and others.

Г. Получение пиppoлo[4,3-b]индoлoв 1.1.7. К раствору 0.16 ммоль пиppoлo[4,3- b]индoлa 1.1.1 в 3 мл тетрагидрофурана добавляют 0.2 ммоль триэтиламина и при перемешивании добавляют 0.2 ммоль соответствующего ацилирующего реагента общей формулы 8, например, хлорангидрида. Смесь перемешивают 2-6 ч при комнатной температуре. После окончания реакции (контроль по LC MS) выпавший хлористый триэтиламин отфильтровывают (промывают осадок на фильтре дополнительно 10 мл тетрагидрофурана). Раствор соединений 1 в тетрагидрофуране упаривают в вакууме. Остаток хроматографируют на силикагеле, импрегнированном триэтиламином, смесью гексан-хлороформ-триэтиламин (5:4:1). Получают соединения 1.1.7 с выходом 65-75%, в том числе: 4-aцeтил-2-кapбэтoкcи-7-мeтил-l ,2,3,8-тeтpaгидpo-пиppoлo[4,3-b]индoл 1.1.7(1), LC-MS: m/z 287 [М+Н]; 4-aцeтил-2,7-димeтил-l,2,3,8-тeтparидpo-пиppoлo[4,3- b]индoл 1.1.7(2), LC-MS: m/z 228 [М+Н]; 4-бeнзoил-2-мeтил-7-фтop-l,2,3,8-тeтpaгидpo- пиpρoлo[4,3-b]индoл 1.1.7(3), LC-MS: m/z 295 [М+Н] и другие.

D. Preparation of pippolo [4,3-b] indoles 1.1.7. 0.2 mmol of triethylamine is added to a solution of 0.16 mmol of pippolo [4.3-b] indole 1.1.1 in 3 ml of tetrahydrofuran, and 0.2 mmol of the corresponding acylating reagent of general formula 8, for example, acid chloride, is added with stirring. The mixture is stirred for 2-6 hours at room temperature. After the completion of the reaction (control according to LC MS), the precipitated triethylamine chloride is filtered off (the filter cake is washed with an additional 10 ml of tetrahydrofuran). A solution of compounds 1 in tetrahydrofuran was evaporated in vacuo. The residue was chromatographed on silica gel impregnated with triethylamine with hexane-chloroform-triethylamine (5: 4: 1). Compounds 1.1.7 are obtained in a yield of 65-75%, including: 4-acetyl-2-carbetoxy-7-methyl-l, 2,3,8-tetrahydro-pyrpolo [4,3-b] indole 1.1.7 (1) LC-MS: m / z 287 [M + H]; 4-acetyl-2,7-dimethyl-l, 2,3,8-tetrahydro-pyrpolo [4,3-b] indole 1.1.7 (2), LC-MS: m / z 228 [M + H]; 4-benzoyl-2-methyl-7-fluorop-l, 2,3,8-tetrahydropypropyl [4,3-b] indole 1.1.7 (3), LC-MS: m / z 295 [M + H ] and others.

1 .1.7 (1) 1. 1.7 (2) 1 .1.7 (3)

D. Preparation of pippolo [4,3-b] indoles 1.1.8. To a solution of 0.16 mmol of pippolo [4.3-b] indole 1.1.1 in 3 ml of THF, 0.2 mmol of isocyanate or isothiocyanate of the general formula 9 are added with stirring. The mixture is stirred for 4 hours at room temperature. After completion of the reaction (control according to LC MS), the solution was evaporated in vacuo. The residue was chromatographed on silica gel impregnated with triethylamine with hexane-chloroform-triethylamine (5: 4: 1). Compounds 1.1.8 are obtained with a yield of 55-80%, including: 2-carbetoxy-7-methyl-4- (4-fluorophenylcarbamoyl) - 1,2,3, 8-tetrahydro-pyrpolo [4,3-b] indole 1.1.8 (1), LC-MS: m / z 382 [M + H]; 2,7-dimethyl-4- (2,4-dichlorophenylthiocarbamoyl) -1,2,3,8-tetrahydro-pyrpolo [4,3-b] indole 1.1.8 (2), LC-MS: m / z 390 [M + H] and others.

E. Preparation of pippolo [4,3-b] indoles 1.1.9. 0.2 mmol of triethylamine is added to a solution of 0.16 mmol of pippolo [4.3-b] indole 1.1.1 in 3 ml of tetrahydrofuran, and 0.2 mmol of the corresponding sulfochloride of general formula 10 is added with stirring. The mixture is stirred for 2-6 hours at 5O ⁰ C. After completion of the reaction (LC MS control) the precipitated triethylamine chloride is filtered off (the filter cake is washed with an additional 10 ml of tetrahydrofuran). A solution of compound 1 in tetrahydrofuran was evaporated in vacuo. The residue was chromatographed on silica gel impregnated with triethylamine with hexane-chloroform-triethylamine (5: 4: 1). Compounds 1.1.9 are obtained in a yield of 62-85%, including: 2-carbetoxy-7-methyl-4-p-tolylcylphonyl-l, 2,3,8-tetrahydro-pyrpolo [4,3-b] indole 1.1 .9 (1), LC-MS: m / z 399 [M + H]; 2,7-dimethyl-4-phenylcylphonyl-l, 2,3,8-tetrahydro-pyrpolo [4,3-b] indole 1.1.9 (2), LC-MS: m / z 327 [M + H] and others.

Example 5. General method for producing l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indoles 1.

A. Preparation of pippolo [4,3-b] indoles 1.1.11. Stirred 1 mmol of pippolo [4,3-b] indole 1.1.2, 1200 μl of dimethyl sulfoxide, 300 μl of water, 3 mmol of the corresponding freshly distilled vinyl derivative of the formula 6 and 3 mmol of MeONa or 2.3, 4,6,7,8, 9, 10-octahydro-pyrimido [l, 2-a] azepine (DBU) in an argon atmosphere at 80-100 ⁰ C for 2-48 hours. After the completion of the reaction (control LC MS), the reaction mass was dissolved in 50 ml of dichloromethane, which was washed twice with weak aqueous potash solution, dried over Na ₂ SO ₄ , evaporated, and the residue is chromatographed on a silica gel column impregnated with triethylamine. Compounds 1.1 were prepared, including: 8-methyl-2- (2-pyridin-4-yl-ethyl) -5-fluoro-1, 2,3,4-tetrahydro-pyrpolo [4,3-b] indole 1.1.11 (1) LC-MS: m / z 282 [M + H]; 3- (4-benzyl-7-methyl-1,2,3, 4-tetrahydropypropyl ethyl ether [4,3-b] indol-2-yl) -propanoic acid 1.1.11 (2), LC-MS : m / z 363 [M + H] and others.

B. Preparation of Pyrpol [4,3-b] indoles 1. To a solution of 0.04 mol of pirpol [4,3-b] indole 1.1.2 or 1.1.3 in 600 ml of ethanol add 3.6 ml of aqueous formalin. Stirred for 30 minutes. at room temperature. Fill the flask with argon and add 600 mg of PtO _{2 to it} . Then, with stirring, the flask was purged with hydrogen and stirring was continued in an atmosphere of hydrogen at room temperature for 48 hours (LCMS control). After completion of the reaction, the solution is filtered. The filtrate was evaporated in vacuo, the residue was washed on the filter with water and dried in vacuo. If necessary, the substance is purified chromatographically on silica gel impregnated with triethylamine. Elution is carried out with a 10% solution of triethylamine in dichloromethane. The corresponding 2-methyl derivatives 1. are obtained with a yield of 61-75%, including: 2,7-dimethyl-l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indole 1.1.1 (9), LC-MS: m / z 187 [M + H], ¹ H NMR (400 MHz, DMSO-d ₆ ): 10.87 (br.s, IH), 7.26 (m, IH) ₃ 7.15 (s, IH), 6.89 (m, IH), 3.90 (m, 4H), 2.62 (s, 3H), 2.39 (s, 3H); 2-methyl-4- (3-methylbenzyl) -7-fluoro-l, 2,3,4 ~ tetrahydro-pyrpropyl [4,3-b] indole 1.1.4 (8), LC-MS: m / z 295 [M + H] and others.

В. Получении пиppoлo[4,3-b]индoлoв 1.1.12. К раствору 0.32 ммоля пиppoлo[4,3- b]индoлa 1.1.2 или 1.1.3 в 3 мл дихлорэтана прибавляют 0.4 ммоля соответствующего альдегида 7 и 170 мг (0.8 ммоля) NaBH(AcO)₃. Смесь перемешивают при комнатной температуре 2-6 часов (контроль по LC MS). После окончания реакции добавляют 10 мл воды и 1 мл 10% водного поташа. Органическую фазу сушат поташом и упаривают. Продукт из остатка выделяют методом препаративной хроматографии на силикагеле, импрегнированном триэтиламином, элюируя смесью гексан-этилацетат-триэтиламин (7:2:1). Получают соединения 1.1.12 с выходом 60-70%, в том числе: 2-(3- пиpидинилмeтил)-l,2,3,4-тeтpaгидpo-пиppoлo[4,3-b]индoл 1.1.12(1), LC-MS: m/z 250 [М+Н]; 7-мeтмл-2-(3-фтopбeнзил)-l,2,3,4-тeтpaгидpo-пиppoлo[4,3-b]индoл 1.1.12(2), LC- MS: m/z 281 [М+Н]; 2-(3-мeтoкcибeнзил)-7-фтop-l,2,3,4-тeтpaгидpo-пиppoлo[4,3-b]индoл 1.1.12(3), LC-MS: m/z 297 [М+Н]; 2-бeнзил-7-бpoм-l,2,3,4-тeтpaгидρo-пиppoлo[4,3- b]индoл 1.1.12(4), LC-MS: m/z 328 [М+Н]; 2-(4-пиρидинилмeтил)-7-фeнил-l,2,3,4- тeтpaгидpo-пиppoлo[4,3-b]индoл 1.1.12(5), LC-MS: m/z 326 [М+Н]; 2-бeнзил-7-(3- пиpидинил)-l,2,3,4-тeтpaгидpo-пиppoлo[4,3-b]индoл 1.1.12(6), LC-MS: m/z 326 [М+Н] и другие.

B. Preparation of [4.3-b] indoles 1.1.12. 0.4 mmoles of the corresponding aldehyde 7 and 170 mg (0.8 mmoles) of NaBH (AcO) _{3 are} added to a solution of 0.32 mmol of pippolo [4.3-b] indole 1.1.2 or 1.1.3 in 3 ml of dichloroethane. The mixture was stirred at room temperature for 2-6 hours (LC MS control). After the reaction, add 10 ml of water and 1 ml of 10% aqueous potash. The organic phase is dried with potash and evaporated. The product is isolated from the residue by preparative chromatography on silica gel impregnated with triethylamine, eluting with a mixture of hexane-ethyl acetate-triethylamine (7: 2: 1). Compounds 1.1.12 are obtained in a yield of 60-70%, including: 2- (3-pyridinylmethyl) -l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indole 1.1.12 (1), LC-MS: m / z 250 [M + H]; 7-methyl-2- (3-fluorobenzyl) -l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indole 1.1.12 (2), LC-MS: m / z 281 [M + H ]; 2- (3-Methoxybenzyl) -7-fluoro-l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indole 1.1.12 (3), LC-MS: m / z 297 [M + H ]; 2-benzyl-7-bromo-l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indole 1.1.12 (4), LC-MS: m / z 328 [M + H]; 2- (4-pyridinylmethyl) -7-phenyl-l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indole 1.1.12 (5), LC-MS: m / z 326 [M + H ]; 2-benzyl-7- (3-pyridinyl) -l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indole 1.1.12 (6), LC-MS: m / z 326 [M + H ] and others.

1.1.12 (4) 1.1.12 (5) 1.1.12 (6)

D. Preparation of pippolo [4,3-b] indoles 1.1.13. To a solution of 0.16 mmol of pippolo [4.3-b] indole 1.1.2 or 1.1.3 in 3 ml of tetrahydrofuran is added 0.2 mmol of triethylamine and 0.2 mmol of the corresponding acylating reagent 8, for example, acid chloride, is added with stirring. The mixture is stirred for 2-6 hours at room temperature. After completion of the reaction (control according to LC MS), the precipitated triethylamine chloride is filtered off (the filter cake is washed with an additional 10 ml terahydrofuran). A solution of compounds 1.1.13 in tetrahydrofuran was evaporated in vacuo. The residue was chromatographed on silica gel impregnated with triethylamine with hexane-chloroform-triethylamine (5: 4: 1). Compounds 1.1.13 are obtained in a yield of 65-75%, including: 7-methyl-2-nicotinyl-l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indole 1.1.13 (1), LC-MS: m / z 278 [M + H]; 2-carboxy-ipem.-butyl-7-methyl-l, 2,3,4-tetrahydro-p-ppprol [4,3-b] indole 1.1.13 (2), LC-MS: m / z 257 [M + H]; 4-benzyl-2-benzoyl-l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indole 1.1.13 (3), LC-MS: m / z 353 [M + H] and others.

D. Preparation of pippolo [4,3-b] indoles 1.1.14. To a solution of 0.16 mmol of pippolo [4.3-b] indole 1.1.2 or 1.1.3 in 3 ml of THF, 0.2 mmol of an isocyanate or isothiocyanate of the general formula 9 is added with stirring. The mixture is stirred for 4 hours at room temperature. After completion of the reaction (control according to LC MS), the solution was evaporated in vacuo. The residue was chromatographed on silica gel impregnated with triethylamine with hexane-chloroform-triethylamine (5: 4: 1). Compounds 1.1.14 are obtained with a yield of 55-80%, including: 7-methyl-2- (2,4-dichlorophenylcarbamoyl) -l, 2,3,4-tetrahydro-pyrpropole [4,3-b] indole 1.1 .14 (1), LC-MS: m / z 360 [M + H] and others.

1.1.14 (1)

E. Preparation of pippolo [4,3-b] indoles 1.1.15. To a solution of 0.16 mmol of pippolo [4.3-b] indole 1.1.2 or 1.1.3 in 3 ml of tetrahydrofuran, 0.2 mmol of triethylamine is added and 0.2 mmol of the corresponding sulfochloride 10 is added with stirring. The mixture is stirred for 2-6 hours at 5O ⁰ C. After the end of the reaction (control according to LC MS) the precipitated triethylamine chloride is filtered off (the filter cake is washed with an additional 10 ml of tetrahydrofuran). A solution of compound 1.1.15 in tetrahydrofuran evaporated in vacuo. The residue was chromatographed on silica gel impregnated with triethylamine with hexane-chloroform-triethylamine (5: 4: 1). Compounds 1.1.15 are obtained in a yield of 62-85%, including: 7-methyl-2-p-tolylcylphosphonyl - 1,2,3, 4-tetrahydropyrpipolo [4,3-b] indole 1.1.15 (1 ), LC-MS: m / z 327 [M + H] and others.

1.1.15 (1)

Example 6. General methods for producing z / wc ~ l, 2,3,3a, 4,8b-hexahydro-pyrpolo [4,3-b] indoles of the general formula 1.2.

A. General Method for the Preparation of Substituted z / wc-l, 2,3,3a, 8,8a-hexahydro-pippololo [4,3-b] indoles 1.2. Stir in an atmosphere of hydrogen 2.7 mmol of 1,2,3,8-tetrahydro-pippolo [4,3-b] indole 1 and 150 mg of PtO ₂ in 20 ml of ethanol for 12-48 hours at 2O ⁰ C. After completion of hydrogenation (control by LC MS) the reaction mixture is filtered, evaporated in vacuo, chromatographed on silica gel impregnated with Et ₃ N. Get tyme-l, 2,3,3a, 4,8b-hexcaridpo-pippolo [4,3-b] indoles 1.2 including: cgιc-2,7-dimethyl-l, 2,3,3a, 4,8b-hexahydro-pyrpolo [4,3-b] indole 1.2.1 (1), LC-MS: m / z 189 [M + H], ¹ H NMR (400 MHz ₅ DMSO-db): 6.75 (s, IH), 6.68 (d, IH, J = 7.8 Hz), 6.25 (d, IH, J = 7.8 Hz), 5.42 (br.s, IH), 4.21 (m, IH) ₅ 3.71 (m, IH) ₅ 2.67 (m, 2H), 2.46 (m, IH) ₅ 2.30 (m, IH), 2.16 (s, 3H) 2.14 (s, 3H); g / wc-2- (pyridin-3-ylmethyl) -l ₅ 2,3, Зa ₅ 4,8b-hexacaride-pyrpolo [4,3-b] indole 1.2.1 (2), LC-MS: m / z 252 [M + H]; g / ms-7-methyl-2- (3-fluorobenzyl) -l, 2 ₅ 3 ₅ Za, 4.8b-hexahydro-pyrpolo [4.3-b] indole 1.2.1 (3), LC-MS: m / z 283 [M + H]; cuc-2- (3-methoxybenzyl) -7-fluor-l, 2,3, 3a, 4,8b-hexahydro-pyrpolo [4,3-b] indole 1.2.1 (4), LC-MS: m / z 298 [M + H]; g / is-2- (pyridin-4-ylmethyl) -7-phenyl-l, 2,3, 3a, 4,8b-hexahydro-pippolo [4,3-b] indole 1.2.1 (5), LC- MS: m / z 328 [M + H]; g ^ c ~ 2-benzyl-7- (3-pyridinyl> I, 2.3 ₅ 3a ₅ 4.8b-hexahydro-pyrpolo [4.3-b] indole 1.2.1 (6), LC-MS: m / z 328 [M + H]; gμιc-2,4,7-trimethyl-l, 2,3,3a, 4,8b-hexahydro-pyrpolo [4,3-b] indole 1.2.4 (1), LC -MS: m / z 203 [M + H]; g / wc-7-methyl-2- (p-tolylcylphonyl) -l, 2,3, Za, 4,8b-hexahydro-pippolo [4,3-b ] indole 1.2.15 (1), LC-MS: m / z 329 [M + H]; z / wc-2,7-dimethyl-4-pyridin-3-ylmethyl-l, 2,3 ₅ Зa ₅ 4 , 8b-hexaradro-pippolo [4,3-b] indole 1.2.6 (1), LC-MS: m / z 280 [M + H], ¹ H NMR (400 MHz, DMSO-db): 8.51 (s , IH), 8.45 (d, IH, J = 4.1 Hz), 7.67 (d, IH, J = 7.7 Hz), 7.33 (m, IH), 6.79 (s, IH), 6.71 (d, IH, J = 8.0 Hz), 6.18 (d, IH, J = 8.0 Hz), 4.40 (m, 2H), 4.17 (m, IH), 3.77 (m, IH), 2.72 ( m, 2H), 2.45 (m, 2H), 2.17 (s, 3H) ₅ 2.13 (s, ^' 3H); z / is-2,7-dimethyl-4- [2- (6-methylpyridin-3-yl) ethyl] -l, 2,3,3a, 4,8b-hexahydro-pippo-llo [4,3-b ] indole 1.2.5 (1), LC-MS: m / z 308 [M + H], ¹ H NMR (400 MHz, DMSO-db): 8.33 (s, IH), 7.58 (m, IH), 7.16 (m, IH), 6.74 (m, 2H), 6.24 (m, IH), 4.14 (m, IH), 3.74 (m, IH), 3.21-3.32 (m, 3H), 2.80-2.64 (m, 4H ), 2.42 (s, 3H), 2.28 (m, IH), 2.17 (s, 3H), 2.14 (s, 3H); g / is-2,7-dimethyl-4- [2- (4-pyridinyl) ethyl] -l, 2,3,3a, 4,8b-hexahydro-pyrpolo [4,3-b] indole 1.2.5 (2) LC-MS: m / z 294 [M + H], cis-4-acetyl-2,7-dimethyl-l, 2,3, Za, 4,8b-hexahydro-pyrpolo [4,3- b] indole 1.2.7 (1), LC-MS: m / z 231 [M + H]; g / ms-2,7-dimethyl-4- (4-chlorobenzoyl) -l, 2,3, 3a, 4,8b-hexahydro-pyrpolo [4,3-b] indole 1.2.7 (2), LC- MS: m / z 327 [M + H] and others.

B. A General Method for the Preparation of Hydrogenated Pyrpolo [4,3-b] Indoles of the General Formula 1.2.5. Mix 1 mmol g / w> l, 2,3,3a, 4,8b-hexahydro-pyrpolo [4,3-b] indole 1.2.1, 1200 μl of dimethyl sulfoxide, 300 μl of water, 3 mmol of the corresponding freshly distilled vinyl derivative of the formula 6 and 3 mmol of MeONa or 2,3,4,6,7,8,9,10-octahydro-pyrimido [l, 2-a] azepine (DBU) in an argon atmosphere at 80- 100 ⁰ C for 2-48 hours. After completion of the reaction (control LC MS), the reaction mass was dissolved in 50 ml of dichloromethane, which was washed twice with a weak aqueous solution of potash, dried over Na ₂ SO ₄ , evaporated, and the residue was chromatographed on a silica gel column impregnated with triethylamine. Compounds 1.2.5 are prepared, including: z / wc-2,7-dimethyl-4- [2- (6-methylpyridin-3-yl) ethyl] - 1, 2,3, 3 a, 4, 8b- hexaradro-pippolo [4,3-b] indole 1.2.5 (1), LC-MS: m / z 308 [M + H], ¹ H NMR (400 MHz, DMSO-db): 8.33 (s, IH), 7.58 (m, W), 7.16 (t, IH), 6.74 (t, 2H), 6.24 (t, IH), 4.14 (t, IH), 3.74 (t, IH), 3.21- 3.32 (t , 3H), 2.80-2.64 (t, 4H), 2.42 (s, 3H), 2.28 (t, IH), 2.17 (s, 3H), 2.14 (s, 3H); and others.

B. General method for the production of hydrogenated pyrpolo [4,3-b] indoles of the general formula 1.2.4, 1.2.6. A mixture containing 0.32 mmol z / wc-l, 2,3,3a, 4,8b-hexahydro-pippololo [4,3-b] indole 1.2.1, 0.4 mmol of the corresponding aldehyde of the formula 7, 170 mg (0.8 mmol) NaBH (AcO) ₃ and 3 ml of dichloroethane, stirred at room temperature for 2-6 hours (control according to LC MS). After the reaction, add 10 ml of water and 1 ml of 10% aqueous potash. The organic phase is dried with potash and evaporated. The product from the residue is isolated by preparative chromatography on silica gel impregnated with triethylamine, with a mixture of hexane-ethyl acetate-triethylamine (7: 2: 1). Hydrogenated pipolo [4,3-b] indoles 1.2.6 are obtained with a yield of 60-70%, including: g / ms-2,4,7-trimethyl-l, 2,3, Za, 4,8b-hexahydro -ppro [4.3-b] indole 1.2.4 (1), LC-MS: m / z 203 [M + H]; g / ms-4-benzyl-2,7-dimethyl-l, 2,3, Za, 4,8b-hexahydro-pyrpolo [4,3-b] indole 1.2.6 (2), LC-MS: m / z 279 [M + H] and others.

Г. Общий способ получения гидрированных пирроло [4,3 -b] индолов общей формулы 1.2.7. К раствору 0.16 ммоль г/иc-l,2,3,3a,4,8b-гёкcaгидpo-пиppoлo[4,3-b]индoлa 1.2.1 в 3 мл тетрагидрофурана добавляют 0.2 ммоль триэтиламина и при перемешивании добавляют 0.2 ммоль соответствующего ацилирующего реагента формулы 8, например, хлорангидрида. Смесь перемешивают в течение 2-6 часов при комнатной температуре. После окончания реакции (контроль по LC MS) выпавший хлористый триэтиламин отфильтровывают (промывают осадок на фильтре дополнительно 10 мл тетрагидрофурана). Полученный раствор упаривают в вакууме. Остаток хроматографируют на силикагеле, импрегнированном триэтиламином, смесью гексан- хлороформ-триэтиламин (5:4:1). Получают соединения 1.2.7 с выходом 65-75%, в том числе: г/wc-4-aцeтил-2,7-димeтил~l ,2,3,3a,8,8a-гeкcaгидpo-пиppoлo[4,3-b]индoл 1.2.7(1), LC-MS: m/z 231 [М+Н]; z/wc-4-бeнзoил-2,7-димeтил-l,2,3,Зa,8,8a-гeкcaгидpo-пиppoлo[4,3- b]индoл 1.2.7(3), LC-MS: m/z 293 [М+Н] и другие.1.2.4 (1)

D. A General Method for the Preparation of Hydrogenated Pyrrolo [4.3-b] Indoles of the General Formula 1.2.7. To a solution of 0.16 mmol g / ic-l, 2,3,3a, 4,8b-hydroxyhydro-pyrpolo [4,3-b] indole 1.2.1 in 3 ml of tetrahydrofuran, 0.2 mmol of triethylamine is added and 0.2 mmol of the corresponding acylating agent is added with stirring a reagent of formula 8, for example, an acid chloride. The mixture is stirred for 2-6 hours at room temperature. After the completion of the reaction (control according to LC MS), the precipitated triethylamine chloride is filtered off (the filter cake is washed with an additional 10 ml of tetrahydrofuran). The resulting solution was evaporated in vacuo. The residue was chromatographed on silica gel impregnated with triethylamine with hexane-chloroform-triethylamine (5: 4: 1). Compounds 1.2.7 are obtained in a yield of 65-75%, including: g / wc-4-acetyl-2,7-dimethyl ~ l, 2,3,3a, 8,8a-hexahydro-pyrpolo [4,3- b] indole 1.2.7 (1), LC-MS: m / z 231 [M + H]; z / wc-4-benzoyl-2,7-dimethyl-l, 2,3, Za, 8,8a-hexahydro-pyrpolo [4,3-b] indole 1.2.7 (3), LC-MS: m / z 293 [M + H] and others.

1.2.7 (1) 1.2.7 (3)

D. General method for the production of hydrogenated pyrpolo [4,3-b] indoles of the general formula 1.2.8. To a solution of 0.16 mmol g / ms-l, 2,3,3a, 4,8b-hexahydro-pyrpolo [4,3-b] indole 1.2.1 in 3 ml of THF, 0.2 mmol of isocyanate or isothiocyanate of the general formula 9 are added with stirring. The mixture was stirred for 4 hours at room temperature. After completion of the reaction (control according to LC MS), the solution was evaporated in vacuo. The residue was chromatographed on silica gel impregnated with triethylamine with hexane-chloroform-triethylamine (5: 4: 1). Compounds 1.2.8 are obtained with a yield of 55-80%, including: g / ωc-2,7-dimethyl-4-phenylcarbamoyl-l, 2,3, Za, 8,8a-hexahydro-pippolo [4,3- b] indole 1.2.8 (1), LC-MS: m / z 308 [M + H] and others.

E. Общий способ получения гидрированных пиppoлo[4,3-b]индoлoв общей формулы 1.2.9. К раствору 0.16 ммоль г/мc-l,2,3,3a,4,8b-гeкcaгидρo-пиppoлo[4,3-b]индoлa 1.2.1 в 3 мл тетрагидрофурана добавляют 0.2 ммоль триэтиламина и при перемешивании добавляют 0.2 ммоль соответствующего сульфохлорида формулы 10. Смесь перемешивают 2-6 ч при 5O⁰C. После окончания реакции (контроль по LC MS) выпавший хлористый триэтиламин отфильтровывают (промывают осадок на фильтре дополнительно 10 мл тетрагидрофурана). Полученный раствор упаривают в вакууме. Остаток хроматографируют на силикагеле, импрегнированном триэтиламином, смесью гексан-хлороформ-триэтиламин (5:4:1). Получают соединения 1.2.9 с выходом 62-85%, в том числе: z/wc-4-фeнилcyльфoнил-2,7-димeтил-l,2,3,Зa,8,8a-гeкcaгидpo-пиppoлo[4,3- bjиндол 1.2.9(1), LC-MS: m/z 329 [М+Н] и другие.

E. General Method for the Preparation of Hydrogenated Pirpolo [4,3-b] Indoles of the General Formula 1.2.9. To a solution of 0.16 mmol g / ms-l, 2,3,3a, 4,8b-hexahydro-pyrpolo [4,3-b] indole 1.2.1 in 3 ml of tetrahydrofuran, 0.2 mmol of triethylamine is added and 0.2 mmol of the corresponding sulfonyl chloride is added with stirring of the formula 10. The mixture is stirred for 2-6 hours at 5 ^° C. After the reaction (LC MS control), the precipitated triethylamine chloride is filtered off (the filter cake is washed with an additional 10 ml of tetrahydrofuran). The resulting solution was evaporated in vacuo. The residue was chromatographed on silica gel impregnated with triethylamine with hexane-chloroform-triethylamine (5: 4: 1). Compounds 1.2.9 are obtained with a yield of 62-85%, including: z / wc-4-phenylcylphonyl-2,7-dimethyl-l, 2,3, Za, 8,8a-hexahydro-pyrpolo [4,3- bjindole 1.2.9 (1), LC-MS: m / z 329 [M + H] and others.

Example 7. General methods for producing salts. A solution of ~ 4-8 equivalents of acid in anhydrous dioxane or tetrahydrofuran is added to 1 equivalent of base 1 or 1.2 in dioxane. The precipitated white precipitate was separated, washed with dioxane or tetrahydrofuran and dried in vacuum. Compounds 1 or 1.2 are obtained in the form of salts, including: dichlorohydrates ^ wc-2,7-dimethyl-4-pyridin-3-ylmethyl-l, 2,3, Za, 4,8b-hexahydro-pippolo [4,3 -b] indole 1.2.6 (I) HCl ₅ LC-MS: m / z 280 [M + H]; ywe-2,7-dimethyl-4- [2- (6-methylpyridin-3-yl) ethyl] - 1, 2,3, 3 a, 4, 8b-hexahydro-pippo lo [4,3 -b] indole 1.2.5 (I) HCl, LC-MS: m / z 308 [M + H]; z / wc-2,7-dimethyl-4- [2- (4-pyridinyl) ethyl] - l, 2,3,3a, 4,8b-hexahydro-pyrupolo [4,3-b] indole 1.2.5 (2) HC1, LC-MS: m / z 294 [M + H] and others.

Example 8. Testing the biological activity of compounds of the general formula 1. In order to determine the physiological activity of the compounds, a focused library was prepared including compounds of the general formula 1, some of which are presented in Table 2 below. The compounds were tested as potential antagonists of the histamine Hl receptor, and also their ability to regulate the cytosolic concentration of calcium ions in cells by blocking calcium channels regulated by intracellular calcium depots was determined. SK-N-SH cells (ATCC, USA) were grown on DMEM medium (Ivitrogep, USA) containing 10% fetal calf serum (FBS) and penicillin-streptomycin antibiotics in a CO ₂ incubator (5% CO ₂ ) until a density was reached IxIO cells ⁵ cells / cm. Cells were removed from the surface of the flask with the TURLE Express reagent (Ivitrogep, USA), collected by centrifugation and resuspended in Hybridoma Segam Free Medium (HSFM, Sigma, USA) at a concentration of 4x10 ⁶ cells / ml. To measure the intracellular concentration of calcium, the cells were loaded with a Fura 2 AM calcium-sensitive fluorescent dye (Ipvitrogep, USA) by incubating the cells with the dye in suspension for 30 minutes at room temperature. Cells were harvested by centrifugation, resuspended in HSFM, incubated in suspension for 15 minutes, harvested by centrifugation, washed twice in HSFM and resuspended in HSFM at a concentration of ⁴ x 10 ⁶ cells / ml.

Calcium fluxes in the cells were recorded using a Shimadzu-RF5301PC spectrofluorimeter. Cells were diluted in working buffer (NaCl 0.145 M, KCl 0.0054 M, NaH ₂ PO ₄ 0.001 M, MgSO ₄ 0.0008 M, CaCl ₂ 0.0018 M, HEPES 0.03 M, D-glucose 0.0112 M pH 7.4) to IxIO ⁵ cells / ml in measuring cuvette with a magnetic stirrer and began recording fluorescence in the two-wave excitation mode (340 and 380 nm, respectively) at an emission wavelength of 510 nm (Fl and F2, respectively). Twenty seconds after the start of recording, a 10 mM solution of histamine in water was added (final concentration 10 μM). After another 30 seconds, after reaching a peak in intracellular calcium concentration, a solution of the test compound in DMSO was added and recording continued for 3 minutes. To determine the biological activity of the compounds, serial dilutions in dimethyl sulfoxide (DMSO) were prepared and the dependence of the effect of the compound on its concentration on histamine-induced calcium flow was determined.

Transformation of the fluorescent signal into calcium concentration was carried out using the equation built into the Super IoProbe program (Smadzu), for which the maximum content of free calcium was determined by adding digitonin (Sigma, USA) to 0.1 mg / ml, and zero calcium content by adding ethylene diamine tetraacetate (EDTA) up to 10 mm.

The kinetic curves of the decrease in intracellular calcium after the addition of the test compound against the background of histamine were calculated using a single-phase exponential model using the Prism 4 program (GrhRad Software, Ips):

[Ca] = [Ca] _max x exp (-K x T) + [Ca] _min where T is the time after addition of the test compound, [Ca] _max and [Ca] _n U _n correspond to the maximum (peak value after addition of histamine) and minimum (the equilibrium level to which the curve tends after adding the test compound) concentration of intracellular calcium, and K - this is the rate constant for decreasing intracellular calcium concentration, which is calculated by minimizing the least squares of the deviations. Based on the calculated calcium decay rate constants (K), their dependence on the concentration of the test compound was constructed (Q, and using this Prism 4 program, the EC ₅₀ value was determined (the concentration of the test compound corresponding to the half-maximal increase in the rate constant of the decrease in intracellular calcium concentration) using four parametric the equation

£ = £ „,„ + ^ -

EC ₅₀ ^N + C ^N '^' where Kв _kg and K _max are the rate constants for decreasing the concentration of intracellular calcium without and in the presence of an infinitely high concentration of the test compound, respectively, and N is the Hil coefficient. Table 2 shows the values corresponding to the inverse logarithm of EC ₅₀ (-LogEC ₅ o = pEC ₅₀ ), which were used as an indicator of the activity of the test compound.

Table 2. The activity of the tested compounds of General formula 1

As can be seen from table 2, the compounds of general formula 1 are effective blockers of the histamine receptor (Phase 1 - substances block the entry of calcium ions into cells due to the antagonistic effect on Hl receptors), and also accelerate the excretion of intraplasmic calcium (Phase 2), which indicates their neuroprotective cognitive-stimulating and antihistamine action.

Example 9. Testing the effect of compounds of the general formula 1 on spatial memory in a test for recognizing new localization. The object recognition test is based on the fact that rats and mice spontaneously examine a new object or a new localization of an object for more time than a known or known localization of an object. This test was first used in rats [A. Ermaseur and J. Delacour, and the first opera-test test for the periurbiological studio of the method of rats. ₁ 1: Behavioral dat. Behav. Vraip Res. 1988, 31, 47-59; J.S. Dodart, S. Matis and A. Upgerer, Sorolamipe-ipodsef defitsit and two-trial obbesestpogopitask ip miise. NeuroRorort 1997, S, 1173-1178; S. Messier, Objest Resource IP Mice: Imperative of the Method of Glucose. Neurobiol. Learp. Mum. 1997, 67, 172-175; S. Rittepger, YY Nuapg, RF Raletzki, R. Worthshouladze, H. Saplip, S. Vronskaya et al., Reversible inhibition of CRED / ATF transcription factors in the region CAl of thе dorsal hirrosmrus disruprts hirrosamrus-derept sratial mémoru. Neurop 2002, 34, 447-462; A.E. Ruaibipip, M.N. Miller and S. Durrapt, Effects of acute alcohol admixture on recognition of learning in C57BL / 6J mix. Pharmacol. Bioshem. Behav. 2002, 71, 307-312; F. Sargolipi, P. Rowlett, A. Oliverio and A. MeIe, Effects of iptr-assumbeps fosl add-ons of glutamate apoptists on objest recognition method and mix. Behav. Vraip Res. 2003, 138, 153-163].

The object recognition test is divided into two tests. This is a test for recognizing a new localization of an object, which is used to study spatial memory, and a test for recognizing a new object - for exploring non-spatial memory [D. Gaffap, Ampèsia forcomcomplex naturalistic scenes and forbjests forwillip forpix transaction in the Rhesus mopke. EUR. J. Neurosi. 1992, 4, 381-388; B. KoIb, K. Wuhrmärm, R. McDopal and R. Suthérlapd, Dissociátiop of thé mediál prefoptál, apostorítorípariétal, apd póstério’s temperámáparutápárápátápait Serb. Sortech 1994, 6, 664-680; T. Stäckler, W.N.I.M. Drippekburgh, A. Sahgal apd J.P. Agglétop, Recognition method and rats. I. Contents app. Rog. Neurobiol. 1998, 54, 289-311. T. Stäckler, W.N.I.M. Drippekburgh, A. Sahgal apd J.P. Agglétop, Recognition method and rats P. Neuroapatomicl substrates. Rog. Neurobiol. 1998, 54, 313-332].

Research Methods. The experiments were carried out on male mice of 3–5 months of age of the C57BL / 6 line weighing 20–24 g. Animals were kept in a vivarium of 5 pieces per cage under a light regime of 12 x 12 hours with a light part from 8 to 20 hours at free access to water and food. The observation camera was made of white opaque organic glass 48x38x30 cm in size. Brown glass vials with a diameter of 2.7 cm and a height of 5.5 cm were used as objects for examination. For 2 - 3 minutes. Before placing the animal, the camera and the objects to be examined were wiped with 85% alcohol. Animals were always placed in the center of the chamber.

40 mg of the compound of general formula 1 was dissolved in 0.2 ml of DMSO, followed by addition to the required concentration of distilled water. Solutions were prepared immediately before the experiment. All experiments were performed on two groups of animals of 10 pieces each. Substances were administered intragastrically at doses of 1 and 5 mg / kg 1 hour before training in a volume of 0.05 ml per 10 g of animal weight. Control animals were injected with an appropriate volume of distilled water.

The order of the experiment. Familiarization with the behavioral camera. On the first day, the mice were brought to the research room and acclimatized for 20-30 minutes. After that, each animal was placed for 10 minutes. into an empty, pre-treated with alcohol, behavioral chamber for review. Then the animal was put into a cage and carried to the vivarium.

Workout. The next day, these same mice were brought to the research room, 20-30 minutes. acclimatized and then introduced an intragastric solution of the analyte. 1 hour after the substance was introduced, the animal was placed in a behavioral chamber, on the bottom of which two identical objects (glass bottles) were placed diagonally at a distance of 14.5 cm from the corners (glass bottles) for recognition. The duration of the training of each animal is 15 minutes After 15 minutes, he was put into a cage and returned to the vivarium.

Testing. Testing was performed 48 hours after training. For this, after acclimatization, the animal was placed for 1 min. into the camera for re-familiarization. After a minute, it was removed and one object was placed at the bottom of the chamber in a location known to the animal, and the other in a new one. Using two electronic stopwatch, the time of examination of each object separately for 10 minutes was recorded, with an accuracy of 0.1 sec. The behavior of animals was observed through a mirror. As a positive reaction for examining the object, a targeted approach of the animal’s nose to the object at a distance of 2 cm or direct touching of the object with the nose was considered. The left object is in a known location, and the right one is in a new one.

Statistical processing of results. Due to the fact that in this test significant fluctuations in the time of examination of objects between animals are observed, the percentage of examination time for each mouse was calculated by the formula tHl / (tIl + tNl) x 100. For 100%, the total time spent on examining two objects was taken. Further processing of the results was carried out according to the student method using the t-test. Acute toxicity study.

The acute toxicity of the test compounds was determined on male C57BL / 6 mice. The substance was administered to six mice intragastrically once at a dose of 100 mg / kg. The observation period is 14 days.

The following are the test results for some of the pyro [4,3-b] indoles of general formula 1: - animals that were injected with 2,5-dimethyl-8- [2- (6-methyl-pyridin-3-yl) -ethyl] -l, 2,3,8-tetrahydro-pyrpolo [4,3 ~ b] indole 1.1.5 (2) at a dose of 1 mg / kg spent on examination of the object in a new location 58.7 ± 9.7% of the time, and in the known one - 41.3 ± 9.7% (P = 0.03). With an increase in dose to 5 mg / kg, mice examined the object in a new location of 58.8 ± 11D% of the time, and in the known location 41.2 ± CD% (P = 0.04). These results indicate that compound 1.1.5 (2) has a stimulating effect on memory and this effect is equally pronounced at doses of 1 and 5 mg / kg;

- animals that were injected with g / wc-2,7-dimethyl-4- [2- (4-pyridinyl) ethyl] -l, 2,3, Za, 4,8b-hexahydro-pyrpolo [4,3-b ] indole 1.2.5 (2) at a dose of 5 MG / KG, examined the object in a new location 60.9 ± 8.3% of the time, and in the known location 39.1 ± 8.3% (P = 0.005). The results obtained in the group of animals to which the test compound was administered at a dose of 1 mg / kg practically did not differ from the control. These results indicate that compound 1.2.5 (2) has a stimulating effect on memory only at a dose of 5 mg / kg;

- animals that were injected with g / wc-4-benzyl-2,7-dimethyl-l, 2,3, 3a, 4,8b-hexahydro-pippolo [4,3-b] indole 1.2.6 (2) in a dose 5 MG / KG, 66.3 ± 9.3% of the time spent on the examination of the object in the new location, and 33.7 ± 9.3% (P = O ₅ OOl) in the known location. A dose of 1 mg / kg did not affect the duration of the examination of the object in a known and new location. These results indicate that compound 1.2.6 (2) has an activating effect on memory only at a dose of 5 mg / kg;

- compounds 1.1.5 (2), 1.2.5 (2) and 1.2.6 (2) do not cause death of animals within 14 days of observation after a single introduction to the stomach at a dose of 100 mg / kg. Therefore, these compounds are low toxic - their LD ₅₀ more than 100 mg / kg;

- animals to which g / wc-2,7-dimethyl-4- [2- (4-pyridinyl) ethyl] -l, 2,3, Za, 4,8b ~ hexahydro-pyrpolo [4,3-b ] indole 1.2.5 (2) in doses of 100 and 50 mg / kg.

The test results of the compounds in mice showed that pippolo [4,3-b] indoles of general formula 1:

- have an activating effect on the memory of animals in the test of recognition of the new localization of a known object in doses of 1 and 5 mg / kg;

- non-toxic and have LDso tested compounds more than 100 mg / kg.

Example 10. An example illustrating the preparation of tablets containing 100 mg of the active ingredient. 1600 mg of starch, 1600 mg of ground lactose, 400 mg of talc and 1000 mg of 2,5-dimethyl-8- [2- (6-methyl-pyridin-3-yl) ethyl] -l, 2,3,8- are mixed tetrahydro-pyrpolo [4,3-b] indole 1.1.5 (2) and pressed into a block. Received bar crushed into granules and sieved through sieves, collecting granules with a size of 14-16 mesh. The granules obtained are tabletted into a suitable tablet form weighing 560 mg each. According to the invention, pharmaceutical compositions in the form of tablets are likewise prepared containing other substituted pippolo [4,3-b] indoles as the active ingredient.

Example 11. Capsules containing 200 mg of Is-4-benzyl-2,7-dimethyl-l, 2,3, 3a, 4,8b-hexahydro-pippolo [4,3-b] indole 1.2.6 (2) , according to the invention, are obtained by thoroughly mixing compound 1.2.6 (2) with lactose powder in a ratio of 2: 1. The resulting powdery mixture is packaged in 300 mg in a suitable size gelatin capsule.

Example 12. Injectable compositions for intramuscular, intraperitoneal or subcutaneous injection can be prepared by mixing 500 mg of the active ingredient with a suitable solubility, for example, z / ms-4-benzyl-2,7-dimethyl-l, 2,3, Za, 4 hydrochloride , 8b-rehydro-pyrpolo [4,3-b] indole 1.2.6 (2), with 300 mg of chlorobutanol, 2 ml of propylene glycol and 100 ml of injection water. The resulting solution is filtered and placed in 1 ml ampoules, which are sealed and sterilized in an autoclave.

Industrial applicability

Can the invention be used in medicine _? veterinary medicine, biochemistry.

Claims

CLAIM 1. Hydrogenated pppolo [4,3-b] indoles of general formula 1, their racemates, their optical isomers, their geometric isomers, their pharmaceutically acceptable salts and / or hydrates.

1 where: the dashed line with the accompanying solid line (™) represents a single or double bond; R ¹ and R ² independently from each other are amino substituents; selected from hydrogen, optionally substituted C ₁ -C ₆ alkyl, optionally substituted with aryl, nitrogen-containing heteroaryl; C ₁ -C ₆ alkoxycarbonyl, possibly substituted phenyl, possibly substituted carbonylamino or thiocarbonylamino, substituted acyl, possibly substituted arylsulfonyl, with the substituents in said R ¹ and R ^{2 being} independently selected from C ₁ -C ₆ alkyl, halogen atoms, nitro, carboxy alkoxy aryl; R ' _n represents one or more identical or different substituents of the cyclic system selected from hydrogen, alkyl, aryl, cyano, halogen, 5-6 membered nitrogen-containing heteroaryl; excluding: l, 2,3,4-tetrahydro-propyl [4,3-b] indole A (I), 2-methyl-A (2), 2-butyl-A (3), 2-cyclohexyl-A (4) , 2-phenethidine-A (5), 2- (l-methyl-2-phenyl-ethyl) - A (6), 2-carbethoxy-A (7) and 2-benzyl-4-phenyl-l, 2, 3,4-tetrahydro-propippolo [4,3-b] indql A (8); 3- (2-butyl-A (9) and 3- (2-cyclohexyl-l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indol-4-yl) -proponitrile A (IO); 2-butyl-4- (2-dimethylaminoethyl) - A (Il), 3- (2-cyclohexyl-4- (2-dimethylaminoethyl) - A (12), 2-butyl-4- [3- (4-methylpiperazine -l-yl) propyl] - A (13) and 2-cyclohexyl-4- [3- (4-methylpiperazin-l-yl) propyl] -l, 2,3,4-tetrahydro-pyrpolo [4,3- b] indole A (14); 2-isopropyl-A (15), 2-tert-butyl-A (16), 2-benzyl-A (17) and 2- (4-methoxybenzyl) -4- phenylsulfonyl-1, 2,3,4-tetrahydro-pyrpolo [4,3-b] indole A (18); 2-carbetoxy-7-fluoro-A (19), 7-fluoro-4- (4-fluoro phenyl> A (20), 2-carbetoxy-7-fluoro-4- (4-fluoro-phenyl) - A (21), 2-methyl-7-fluoro-4- (4-fluoro-phenyl) - A (22), 2-propyl -7-fluoro-4- (4-fluoro-phenyl) - A (23), 2- (3,3-dimethyl-butyl) -7-fluoro-4- (4-fluoro-phenyl) - A (24), 2-pheno-7 -f op-4- (4-fluoro-phenyl) - A (25), 2-benzyl-7-fluoro-4- (4-fluoro-phenyl) - A (26), 2-propionyl-7-fluoro-4- (4-fluoro-phenyl) ) - A (27), 2- (3,3-dimethylbutanoyl) -7-fluoro-4- (4-fluoro-phenyl) - A (28), 2- [4-oxo-4- (4-fluorophenyl)] - A (29), 2- (4-hydroxy-4-phenyl) - A (30), 2- [4-hydroxy-4- (4-fluorophenyl)] - A (31), 2- [5-oxo-5- (4-fluorophenyl)] - A (32) and 2- [5-hydroxy-5- (4-fluorophenyl)] - l, 2,3,4- tetrahydro-pyppolo [4,3-b] indole A (33); cisL, 2,3,3a, 4,8b-hexahydro-pyrpolo [4,3-b] indole A (34); 7-methyl-2-benzyl-l, 2,3,4-tetrahydro-pyrpolo [4,3-b] indole A (35).

A (15-18) A (20-33) A: R ¹ HH (1.20); CH ₃ (2.21); C ₄ H ₉ (3,9,11,13); C ₆ H ₅ -CH ₂ CH ₂ (4.24); C ₆ H ₅ -CH ₂ (5.17.25); cyclohexyl (6,10,12,14); CO ₂ C ₂ H ₅ (7.28); iso-C ₃ H ₇ (15); mp. -C ₄ H ₉ (16); 4-CH ₃ OC ₆ H ₄ (18); C ₃ H ₇ (22,); (CH ₃ ) ₃ CH ₂ CH ₂ CH ₂ (23); CH ₃ CH ₂ CO (26); (CH ₃ ) ₃ CH ₂ CH ₂ CO (27); 4-F-C ₆ H ₄ -C (O) CH ₂ CH ₂ CH ₂ (29); C ₆ H ₅ -C (OH) CH ₂ CH ₂ CH ₂ (30); 4-FC ₆ H ₄ -C (OH) CH ₂ CH ₂ CH ₂ (31); 4-FC ₆ H ₄ -C (O) CH ₂ CH ₂ CH ₂ CH ₂ (32); 4-FC ₆ H ₄ -C (OH) CH ₂ CH ₂ CH ₂ CH ₂ (33). 2. The compounds of claim 1, which are z / we-l, 2,3,3a, 4,8b-hexahydro-pippololo [4,3-b] indoles of the general formula 1.2.

1 9 i where where :. R ts. ,, R ts. and and R xs. _nn and immeyuyutt in ышysheyuuuk & anzάaishn.ntvoves with knowledge .. 3. Compounds according to any one of paragraphs. 1, 2, which are 1,2,3,4-tetrahydro-pippolol [4,3-b] indoles of the general formula 1.1.1, 1.1.2, 1.1.3 or g / wol, 2,3,3a, 4 , 8b-hexahydro-pyrrolo [4.3-b] indoles of the general formula 1.2.1, 1.2.2, 1.2.3.

1.1.1, 1.2.1

1.1.3, 1.2.3 where: the dashed line with the solid line accompanying it (^, R ¹ , R »2 ^2. And R ' _n have the above meaning. 4. Compounds according to any one of paragraphs. 1, 2, which are hydrogenated pyrpolo [4,3-b] indoles of the general formula 1.1.4 - 1.1.9, 1.2.4 - 1.2.9.

where: R and R _n ¹ have the above meanings; R ⁴ represents a possibly substituted alkyl, possibly substituted by aryl, carboxyalkyl, possibly substituted aryl; R ⁵ represents CN, optionally substituted aryl or heterocyclyl, carboxyalkyl; R ⁶ represents carboxyalkyl, carbamoyl, CN, optionally substituted aryl or optionally substituted heterocyclyl; R ⁷ represents an optionally substituted alkyl, an optionally substituted aryl or an optionally substituted heteroaryl. 5. Compounds according to any one of paragraphs. 1, 2, which are hydrogenated pyrpolo [4,3-b] indoles of the general formula 1.1.10 - 1.1.15, 1.2.10 - 1.2.15.

1.1.10, 1.2.10 1.1.11, 1.2.11

where: R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R _n ¹ have the above meanings. 6. A method for producing compounds of general formula 1 according to claim 1 by reacting phenylhydrazines of general formula 2 (or their salts) with an N-substituted pyppolidin-3-one of general formula 3.

where: R ¹ , R ^g and R _n ¹ have the above meaning. 7. A method for producing compounds of general formula 1.2 according to claim 2 by hydrogenating the corresponding compounds of general formula 1 with hydrogen in the presence of PtO ₂ in an organic solvent medium. 8. The method of producing compounds according to claim 4, excluding compounds in which R ¹ = H, by reacting the corresponding compounds 1.1.1 or 1.2.1 in an organic solvent with electrophilic reagents selected from: alkyl, aryl or heterocyclyl halides of the general formula 5 in the presence of a base; electrophilic alkenes of the general formula 6 in the presence of a base as a catalyst; aldehydes of the general formula 7 and NaBH (AcO) ₃ , anhydrides or halides of the carboxylic acids of the general formula 8 in the presence of a base; from (thio) cyanides of the general formula 9 or sulfonyl chlorides of the general formula 10 in the presence of a base. R ⁴ -X CH ₂ = CH-R ⁵ R ^b -CHO R ⁷ -C (O) YR ⁷ -NCO (S) R ⁷ -SO ₂ C1 5 6 7 8 9 10 where: R ⁴ , R ⁵ , R ⁶ and R ⁷ have the above meaning, X represents a halogen atom; Y represents a halogen atom, hydroxide 3H-imidazol-1-ima, R —C (O) O. 9. The method of producing compounds according to claim 4, in which R ¹ = H, by hydrolysis of the protective group in the corresponding compounds according to claim 4, in which R ¹ represents a protective group, such as a 2-ethyl-oxocarbonyl group (R ¹ = CO ₂ C ₂ H ₅ ) or 2-tert-butyloxycarbonyl group (R ¹ = CO ₂ C (CH ₃ ) ₃ ). 10. The method of producing compounds according to claim 4, in which R ¹ = CH ₃ , by reduction of the protective group with lithium aluminum hydride in the corresponding compounds according to claim 4, in which R ¹ represents a protective group, such as a 2-ethyloxycarbonyl group (R ¹ = CO ₂ C ₂ H ₅ ). 11. The method of producing compounds according to claim 5 by reacting the corresponding compounds 1.1.2, 1.1.3 or 1.2.2, 1.2.3 in an organic solvent medium with electrophilic reagents selected from: alkyl, aryl or heterocyclyl halides of the general formula 5 in the presence of a base; electrophilic alkenes of the general formula 6 in the presence of a base as a catalyst; aldehydes of the general formula 7 and NaBH (AcO) ₃ , anhydrides or halides of the carboxylic acids of the general formula 8 in the presence of a base; from (thio) cyanides of the general formula 9 or sulfonyl chlorides of the general formula 10 in the presence of a base. R ⁴ -X CH ₂ = CH-R ⁵ R ⁶ -CHO R ⁷ -C (O) YR ⁷ -NCO (S) R ⁷ -SO ₂ C1 5 6 7 8 9 10 where: R ⁴ , R ⁵ , R ⁶ , R ⁷ , X and Y have the above meaning. 12. A combinatorial library of compounds with neuroprotective, cognitively stimulating and antihistamine effects for the determination of hit compounds and leaders, consisting of compounds of general formula 1 according to claim 1. 13. A focused library of compounds with neuroprotective, cognitively stimulating and antihistamine effects for determining and / or optimizing leader compounds, containing at least one compound of general formula 1 according to claim 1. 14. A pharmaceutical composition having a neuroprotective, cognitively stimulating and antihistamine effect, in the form of tablets, capsules or injections in a pharmaceutically acceptable package containing a pharmaceutically effective amount of at least one hydrogenated pippolo as an active substance [4,3-b ] an indole of general formula 1 according to claim 1, or their racemate, or their optical isomer, or their geometric isomer, or their pharmaceutically acceptable salt and / or hydrate. 15. The method of obtaining the pharmaceutical composition according to p. 14, which consists in mixing the active substance with an inert excipient and / or solvent, characterized in that the pharmacologically effective amount of at least one hydrogenated pippol is used as the active substance [4,3-b ] indole general formula 1 according to claim 1, or its racemate, or its optical isomer, or its geometric isomer, or its pharmaceutically acceptable salt and / or hydrate. 16. The use of the pharmaceutical composition according to p. 14 for the preparation of medicines for the treatment and prevention of the development of various diseases of warm-blooded animals and people whose pathogenesis is associated with excessive intracellular content of Ca ⁺² ions in animals and people and / or diseases associated with impaired histaminergic mediator system. 17. The use according to claim 16 for the treatment of neuralogical disorders (in particular, hypoxia-ischemia, hypoglycemia, convulsive conditions, brain injuries, etc.), as well as neurodegenerative diseases (including Alzheimer's disease, Huntington's chorea, latirism, lateral amyotrophic sclerosis, etc.). 18. The use according to claim 16 for the treatment of allergic and autoimmune diseases, including hay fever, urticaria, bronchial asthma, atopic dermatitis, neurodermatitis, angioedema, Quincke's edema, eczema, burn toxemia, as well as allergic reactions caused by drugs, food, cosmetic means, house dust, insect bites, etc. 19. A way to improve the processes of memorization and reproduction of memorized (cognitive stimulation) in humans and warm-blooded animals by introducing the pharmaceutical composition according to p. 14. 20. Compounds of general formula 1 according to claim I ₅ possessing neuroprotective, cognitive-stimulating and antihistamine properties, intended for experimental study of physiological processes in vivo and in vitro as “pharmaceutical tools *.