RU2140417C1 - Derivatives of hydrogenated pyrido[4,3-b]indoles, methods of their synthesis, pharmaceutical composition and method of patient treatment - Google Patents

Abstract

FIELD: organic chemistry, pharmacy. SUBSTANCE: invention describes new substituted 2,3,4,5-tetra- and 2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indoles, their quaternary derivatives with quaternized nitrogen atom at position 2 and their salts with pharmacologically acceptable acids of the formula (I)

also where R¹, R², R³ and X are given in p. 1 of the invention claim. Invention describes also methods of their synthesis and the use and pharmaceutical compositions. Indicated compounds show an anti-NMDA-activity and can be useful for treatment of patients with diseases associated with the damage of glutamateergic mediatory system: chronic neurodegenerative illnesses, for example, Alzheimer's disease, cerebral ischemia, epilepsy, schizophrenia and others. Also, invention describes a method of treatment of patients with diseases where glutamateergic mediatory system takes part as a mechanism of pathogenesis and this method of treatment involves the use of compounds of the formula (I). EFFECT: new compounds indicated above, improved method of synthesis, enhanced curative effectiveness of compounds. 46 cl, 2 tbl, 26 ex

Description

 This invention relates to new derivatives of hydrogenated pyrido [4,3-b] indoles having pharmacological activity. More specifically, the present invention relates to substituted tetra- and hexahydropyrido [4,3-b] indoles and their pharmaceutically acceptable salts, to methods for their preparation, pharmaceutical compositions containing these compounds, and to a method for treating various diseases, including neurodegenerative , for example, Alzheimer's disease (AD), which are based on the effect on NMDA receptors and, as a consequence, the regulation of the glutamatergic neurotransmitter system.

 NMDA receptors are a subclass of glutamate receptors in the central and peripheral nervous system, for which N-methyl-D-aspartate (NMDA) is the most specific agonist. In the form of a receptor-ionophore complex, NMDA receptors are associated with calcium transporting channels of neuronal membranes, which determines their role in the pathogenesis of neurological 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) [J. W. McDonald, M.V. Johnston - Brain Res. Rev. 1990, v. 15, pp. 41-70 (and references therein)]. The ability to regulate the pool of intracellular calcium determines the great pharmacological significance of specific NMDA receptor antagonists. Currently, a number of NMDA antagonists have been proposed as antidepressants [J. Maj, V. Klimek, Z. Rogoz, G. Skuza - Pol. J. Pharmacol., 1993, v. 45, pp. 549-553; R. Trullas, P. Skolnick - Eur. J. Pharmacol. , 1990, v. 185, N 1, pp. 1-10], anxiolytics [R.W. Dunn, R. Corbet, L.L. Martin, J.F. Payack, L. Laws-Ricker, C.A. Wilmot, D.K. Rush, J. F. Cornfeldt, S. Fielding - Prog. Clin. Biol. Res., 1990, v. 361, (Curr, Future Trends Anticonvulsant Anxiety, Stroke Ther.), Pp. 495-512], anticonvulsants [J.M. Ferkany, W.J. Krezotarski - Prog. Clin. Biol. Res. , 1990, v. 361 (Curr. Future Trends Anticonvulsant Anxiety, Stroke Ther.), Pp. 525-541; W.J. Schmidt, B. Zadow, B.D. Kretshmer. - Aminoacids, 1991, v. 1, N 2, pp. 225-237)] and neuroprotective agents (S. Fielding, J. Wilker, JC Chernack, V. Ramizer, CA Wilmot, ML Cornfeldt, KA Rudolphi, LL Martin, JF Payck, DK Rush-Prog. Clin. Biol. Res., 1990, v. 361, pp. 495-512 (Curr. Future Trends Anticolvunsant Anxiety, Stroke Ther.); T. Nakao, A. Nishiyama, H. Tanaka, Y. Morimot, S. Takehara - Pat. Jap. 04,257,589 [ 92,257,589] (C 07 D 495/14) dated 12/02/1991).

 It is known that a wide range of neurological diseases (such as AD, Huntington's chorea, amyotrophic lateral sclerosis, and also cerebral ischemia) are associated with the ixitotoxic effect of neurotransmitter excitatory amino acids (VAC) - glutamate and aspartate (Excitatory Amino Acids and Drug Research, Ed. By MR Szewczak & NJ Hrib, Alan R. Liss, Inc., New York, 1989, p. 380; The NMDA Receptor, Eds. Watkins & Collngridge G., 1989, IRL Press). In accordance with this mechanism, neuronal hyper-excitation during prolonged activation of their NMDA receptors by glutamate leads to excessive entry of calcium ions into the cell, which initiates a number of pathological metabolic processes that ultimately cause nerve cell death (DW Choi, Neurone, 1988, v. 1 , p. 623-634).

 In particular, in the case of AD, the mass death of neurons is supposed to be as follows. The neurotoxic factor causing neurodegenerative processes in neurons is the endogenous β-amyloid oligopeptide contained in neurotic plaques abundantly located on the brain surface of AD patients (AT Prelli - J. Neurochem., 1988, v. 51, p. 648; YV Yanker - Science, 1990, v. 250, p. 279). Recent studies have shown that β-amyloid significantly enhances the xytotoxic effect of glutamate via the NMDA receptor system (Koh et al., Brain Res., 1990, v. 533, p. 315; Mattson et al., J. Neuroschi. 1992, v. 12, p. 376). As a result of this, concentrations of glutamate mediator non-toxic under normal conditions become toxic to neurons under the conditions of developing β-amyloidosis and cause their death.

 In this regard, the search for effective antagonists of NMDA brain receptors that can inhibit the implementation of the neurotoxic action of β-amyloid is considered an original and promising approach to the creation of broad-spectrum neuroprotectors.

 As a result of studies aimed at searching for compounds with anti-NMDA activity, the inventors discovered a wide group of tetra- and hexahydro-1H-pyrido [4,3-b] indole derivatives, which are characterized by this type of activity.

 The present invention relates to new 2-methyl-5.8-substituted 2,3,4,5-tetra- and 2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indoles their quaternary derivative with a quaternized nitrogen atom in position 2, and their salts with pharmaceutically acceptable acids, described in detail below, which constitute one aspect of the present invention.

 Another aspect of the invention includes methods for producing these compounds.

 A further aspect of the invention is a method of treating a number of diseases, which is to administer to patients to receive an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. In particular, the invention provides for the treatment of diseases whose pathogenesis mechanism is associated with a violation of the glutamatergic mediator system - such as chronic neurodegenerative diseases (including AD, Huntington's chorea), cerebral ischemia, epilepsy, schizophrenia, and some critical conditions (including angiospasm, brain injury, paralysis).

 An additional aspect of the invention is the provision of pharmaceutical compositions comprising a therapeutically effective amount of a compound of the invention and therapeutically acceptable inert adjuvants, such as carriers, excipients, etc.

в которой:
пунктирная линия с сопровождающей ее сплошной линией

представляет одинарную или двойную связь;
R¹ представляет H или низший алкил;
R² представляет 2-(2-(N-метил-N-R³ метиламино)этил)-5-R¹-индолил-3-метильную группу, в которой R¹ имеет значения, определенные выше, а R³ определен ниже; или группу общей формулы:

в которой: Y выбран из группы, состоящей из:
H,
галогена,
циклоалкила,
этенила, необязательно моно-, ди- или тризамещенного низшим алкилом,
монозамещенного арилом или β- монозамещенного группой COOR⁴ (в которой R⁴ представляет H, алкил, аралкил, арил (необязательно моно-, ди- или тризамещенный заместителями A, определенными ниже),
группы OR⁴ (в которой R⁴ имеет значения, определенные выше);
алкилсульфонила;
арилсульфонила;
группы NR⁵R⁶ (в которой R⁵ и R⁶ могут быть одинаковыми или различными,
и каждый независимо представляет:
H; алкил; циклоалкил; аралкил; арил (необязательно моно-, ди- или тризамещенный заместителями A, определенными ниже);
2-, 3- или 4-пиридил;
алкилсульфонил;
арилсульфонил; или
один из заместителей R⁵ или R⁶ может представлять группу
COR⁷ (в которой R⁷ представляет:
H, алкил, алкокси, циклоалкил, аралкил, арил, необязательно моно-, ди- или тризамещенный заместителями A, определенными ниже,
2-, 3- или 4-пиридил); или
R⁵ и R⁶, взятые вместе, представляют группу общей формулы:
-(CH₂)₂-W-(CH₂)₂-,
[в которой W представляет -O-, -(CH₂)_q- (в которой q = 0, 1 или 2); или

(в которой R⁸ представляет H, алкил, арил, необязательно моно-, ди- или тризамещенный заместителями A, определенными ниже;
V представляет H₂ или O; r = 0 или 1)]; или
R⁵ и R⁶ вместе с атомом азота, к которому они присоединены, образуют N-фталимидо группу, необязательно моно-, ди-, три- или тетразамещенную заместителями A, определенными ниже;
группы COR⁹ (в которой R⁹ представляет: H, алкил, аралкил, арил, необязательно моно-, ди- или тризамещенный заместителями A, определенными ниже; OH, алкокси группу, группу NR⁵R⁶, определенную выше, кроме необязательно замещенной N-фталимидо группы, 2-, 3- или 4-пиридил);
CN;
CHal₃ (в которой Hal представляет хлор, фтор или бром);
арила (необязательно моно-, ди- или тризамещенного заместителя A, определенными ниже);
2-, 3- и 4-пиридила (необязательно моно- или дизамещенного низшим алкилом) и соответствующих им четвертичных солей 1-R⁴CH₂-пиридиния-2, -3 или -4 (где R³ имеет значения, определенные ниже);
триалкиламмония;
циклоалкиламмония;
N-азиния и N-азолия;
Z представляет O, S или H₂;
k представляет 0 или целое число от 1 до 4;
l, m и n независимо представляют 0 или 1;
причем:
1) Y может иметь любое из указанных значений только, когда k+m ≥ 2, а l = 0;
2) когда k = l = m = 0,
тогда Y является отличным от галогена, CHal₃, OR⁴, NH⁵R⁶, арила, триалкиламмония, циклоалкиламмония, N-азиния или N-азолия;
3) когда k = 1, а l = m = 0,
тогда Y имеет значения, отличные от галогена, триалкиламмония, циклоалкиламмония, N-азиния или N-азолия;
4) когда k = l = 0, m = 1 и Z представляет O,
тогда Y является отличным от галогена, OH, CN, алкилсульфонила, арилсульфонила, триалкиламмония, циклоалкиламмония, N-азиния или N-азолия;
5) когда k = l = 0, m = 1 и Z представляет S,
тогда Y представляет только группу NR⁵R⁶, в которой R⁶ представляет водород;
6) когда l = 0, тогда Z является отличным от H₂;
7) когда k = 0, а l = m = 1, тогда Z является отличным от S;
R³ представляет группу -(CH₂)_k-Y' (в которой Y' имеет значения, определенные выше для Y, и k имеет значения, определенные выше),
причем:
когда k = 0, тогда Y' является отличным от галогена, группы NR⁵R⁶, триалкиламмония, циклоалкиламмония, N-азиния и N-азолия;
X^- представляет анион фармакологически приемлемой кислоты;
заместители A выбраны независимо из следующей группы: галоген, низший алкил, низшая алкокси группа, NO₂, CN, группа COR⁹ (в которой R⁹ имеет значения, определенные выше, за исключением производных пиридила), CF₃, NR⁵R⁶ (в которой R⁵ и R⁶ имеют значения, определенные выше);
при условии, что
a) если

представляет двойную связь и n = 0, то, когда R¹ представляет метил, тогда R² является отличным от: H, метила, бензила, 2-пиридилметила, 2-(6-метил-3-пиридил)этила, 2-(4-пиридил)этила, 2-(N,N-диметиламино)этила или 3-(N,N-диметиламино)пропила;
а когда R¹ представляет H,
тогда R² помимо указанных выше является отличным также от: н-бутила, циклогексила, 4-хлорбензила, 2-фенилэтила, 2- и 3-пиридила, 1-(2-пиридил)этила, 2-(2-пиридил)этила, 1-(3-пиридил)этила, 1-(6-метил-3-пиридил)этила, диэтиламинокарбонила, гидрокси-метила, 2-метил-3-(N,N-диметиламино)пропила, от группы общей формулы: R¹⁰O-(CH₂)₂- (в которой R¹⁰ представляет C₂-C₄ алкил, циклогексил или фенил); или от группы общей формулы: R⁵R⁶N-(CH₂)_p- [в которой p = 2 и R⁵ и R⁶ каждый представляет этил, или R⁵ и R⁶ вместе представляют тетра- или пентаметилен; или p = 3 и R⁵ и R⁶ вместе представляют группу -(CH₂)₂W(CH₂)₂- (в которой W представляет -O-, NCH₃, NCH₂C₆H₅)];
б) если

представляет одинарную связь и n = 0, то, когда R¹ представляет H, тогда R² является отличным от H, метила, этила, бензила, ацетила, хлорацетила или (N-морфолино-, или N-пиперидино-, или N,N-диэтиламино)ацетила, 3-хлорпропионила, 3-(N-морфолино)пропионила или 5-хлорпентаноила;
когда R¹ представляет метил, тогда R² является отличным от: H, 2,2,2-трифторэтила, 2-(N, N-диметиламино)этила, 3-(N,N-диметиламино)пропила, ацетила, 2-этилгексаноила, (E)-2-бутеноила в случае цис(-) изомера, (E)-циннамоила;
в) если

представляет двойную связь и n = 1, то, когда каждый из R¹ и R³ представляет H и X представляет иод, тогда R² является отличным от H, метила, этила или пропила;
когда каждый R¹ и R³ представляет H, и X представляет метилсульфат, тогда R² является отличным от бензила;
когда R¹ представляет метил, H, R³ представляет метил и X представляет иод, тогда R² отличен от H;
когда R¹ представляет метил, R³ представляет H и X представляет иод, тогда R² отличен от H или метила;
когда R¹ представляет H, R³ представляет фенил и X представляет хлор, тогда R² отличен от H или бензила;
когда R¹ представляет H, R³ представляет фенил и X представляет иод, тогда R² отличен от иодида 3-(N,N,N-триметиламмонио)пропила;
а также солей производных формулы I с фармакологически приемлемыми кислотами;
Под используемым здесь термином "галоген" имеется в виду хлор, бром, фтор или иод.The aim of the present invention is the provision of new 2-methyl-5,8-substituted 2,3,4,5-tetra- and 2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indoles and their quaternary salts (with a quaternized nitrogen atom in position 2) of the general formula (I):

wherein:
dashed line with a solid line accompanying it

represents a single or double bond;
R ¹ represents H or lower alkyl;
R ² represents a 2- (2- (N-methyl-NR ³ methylamino) ethyl) -5-R ¹ -indolyl-3-methyl group in which R ¹ is as defined above and R ^{3 is} defined below; or a group of the general formula:

in which: Y is selected from the group consisting of:
H
halogen
cycloalkyl
ethenyl optionally mono-, di- or trisubstituted with lower alkyl,
monosubstituted with aryl or β-monosubstituted with a COOR ⁴ group (in which R ⁴ is H, alkyl, aralkyl, aryl (optionally mono-, di- or trisubstituted with A substituents as defined below),
groups OR ⁴ (in which R ⁴ has the meanings defined above);
alkylsulfonyl;
arylsulfonyl;
groups NR ⁵ R ⁶ (in which R ⁵ and R ⁶ may be the same or different,
and each independently represents:
H; alkyl; cycloalkyl; aralkyl; aryl (optionally mono-, di- or trisubstituted with substituents A as defined below);
2-, 3- or 4-pyridyl;
alkylsulfonyl;
arylsulfonyl; or
one of the substituents R ⁵ or R ⁶ may represent a group
COR ⁷ (in which R ⁷ represents:
H, alkyl, alkoxy, cycloalkyl, aralkyl, aryl, optionally mono-, di- or trisubstituted with substituents A as defined below,
2-, 3- or 4-pyridyl); or
R ⁵ and R ⁶ taken together represent a group of the general formula:
- (CH ₂ ) ₂ -W- (CH ₂ ) ₂ -,
[in which W represents —O—, - (CH ₂ ) _q - (in which q = 0, 1 or 2); or

(in which R ⁸ represents H, alkyl, aryl, optionally mono-, di- or trisubstituted with substituents A as defined below;
V represents H ₂ or O; r = 0 or 1)]; or
R ⁵ and R ^6, together with the nitrogen atom to which they are attached, form an N-phthalimido group, optionally mono-, di-, tri- or tetra-substituted with substituents A as defined below;
COR ⁹ groups (in which R ⁹ represents: H, alkyl, aralkyl, aryl, optionally mono-, di- or trisubstituted with substituents A as defined below; OH, alkoxy group, NR ⁵ R ⁶ group as defined above, except for optionally substituted N -phthalimido groups, 2-, 3- or 4-pyridyl);
CN;
CHal ₃ (in which Hal is chloro, fluoro or bromo);
aryl (optionally mono-, di- or trisubstituted substituent A, as defined below);
2-, 3- and 4-pyridyl (optionally mono- or disubstituted with lower alkyl) and their corresponding quaternary salts of 1-R ⁴ CH ₂ -pyridinium-2, -3 or -4 (where R ³ has the meanings defined below);
trialkylammonium;
cycloalkylammonium;
N-azinium and N-azolium;
Z represents O, S or H ₂ ;
k represents 0 or an integer from 1 to 4;
l, m and n independently represent 0 or 1;
moreover:
1) Y can have any of the indicated values only when k + m ≥ 2, and l = 0;
2) when k = l = m = 0,
then Y is different from halogen, CHal ₃ , OR ⁴ , NH ⁵ R ⁶ , aryl, trialkylammonium, cycloalkylammonium, N-azinium or N-azolium;
3) when k = 1, and l = m = 0,
then Y has values other than halogen, trialkylammonium, cycloalkylammonium, N-azinium or N-azolium;
4) when k = l = 0, m = 1 and Z represents O,
then Y is different from halogen, OH, CN, alkylsulfonyl, arylsulfonyl, trialkylammonium, cycloalkylammonium, N-azinium or N-azolium;
5) when k = l = 0, m = 1 and Z represents S,
then Y represents only the group NR ⁵ R ⁶ in which R ⁶ represents hydrogen;
6) when l = 0, then Z is different from H ₂ ;
7) when k = 0, and l = m = 1, then Z is different from S;
R ³ represents a group - (CH ₂ ) _k —Y ′ (in which Y ′ has the meanings defined above for Y and k has the meanings defined above),
moreover:
when k = 0, then Y 'is other than halogen, a group NR ⁵ R ⁶ , trialkylammonium, cycloalkylammonium, N-azinium and N-azolium;
X ^- represents the anion of a pharmacologically acceptable acid;
substituents A are independently selected from the following group: halogen, lower alkyl, lower alkoxy group, NO ₂ , CN, group COR ⁹ (in which R ⁹ has the meanings defined above, with the exception of pyridyl derivatives), CF ₃ , NR ⁵ R ⁶ ( in which R ⁵ and R ⁶ have the meanings defined above);
provided that
a) if

represents a double bond and n = 0, then when R ¹ is methyl, then R ² is different from: H, methyl, benzyl, 2-pyridylmethyl, 2- (6-methyl-3-pyridyl) ethyl, 2- (4 -pyridyl) ethyl, 2- (N, N-dimethylamino) ethyl or 3- (N, N-dimethylamino) propyl;
and when R ¹ represents H,
then R ² in addition to the above is also different from: n-butyl, cyclohexyl, 4-chlorobenzyl, 2-phenylethyl, 2- and 3-pyridyl, 1- (2-pyridyl) ethyl, 2- (2-pyridyl) ethyl, 1- (3-pyridyl) ethyl, 1- (6-methyl-3-pyridyl) ethyl, diethylaminocarbonyl, hydroxymethyl, 2-methyl-3- (N, N-dimethylamino) propyl, from the group of the general formula: R ¹⁰ O- (CH ₂ ) ₂ - (in which R ¹⁰ represents C ₂ -C ₄ alkyl, cyclohexyl or phenyl); or from a group of the general formula: R ⁵ R ⁶ N- (CH ₂ ) _p - [wherein p = 2 and R ⁵ and R ^{6 are} each ethyl, or R ⁵ and R ⁶ together are tetra- or pentamethylene; or p = 3 and R ⁵ and R ⁶ together represent a group - (CH ₂ ) ₂ W (CH ₂ ) ₂ - (in which W represents —O—, NCH ₃ , NCH ₂ C ₆ H ₅ )];
b) if

represents a single bond and n = 0, then when R ¹ represents H, then R ² is other than H, methyl, ethyl, benzyl, acetyl, chloroacetyl or (N-morpholino, or N-piperidino, or N, N -diethylamino) acetyl, 3-chloropropionyl, 3- (N-morpholino) propionyl or 5-chloropentanoyl;
when R ¹ is methyl, then R ² is different from: H, 2,2,2-trifluoroethyl, 2- (N, N-dimethylamino) ethyl, 3- (N, N-dimethylamino) propyl, acetyl, 2-ethylhexanoyl , (E) -2-butenoyl in the case of the cis (-) isomer, (E) -cinnamoyl;
c) if

represents a double bond and n = 1, when each of R ¹ and R ³ represents H and X represents iodine, then R ² is other than H, methyl, ethyl or propyl;
when each R ¹ and R ³ is H and X is methyl sulfate, then R ² is other than benzyl;
when R ¹ is methyl, H, R ³ is methyl and X is iodine, then R ² is other than H;
when R ¹ represents methyl, R ³ represents H and X represents iodine, then R ² is other than H or methyl;
when R ¹ represents H, R ³ represents phenyl and X represents chlorine, then R ² is other than H or benzyl;
when R ¹ represents H, R ³ represents phenyl and X represents iodine, then R ² is different from 3- (N, N, N-trimethylammonio) propyl iodide;
as well as salts of derivatives of formula I with pharmacologically acceptable acids;
The term “halogen” as used herein means chlorine, bromine, fluorine or iodine.

 As used in the above definitions and the following description, the term “lower alkyl” means a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, examples of which are methyl, ethyl, isopropyl, butyl, sec-butyl, tert-butyl and the like. .

 The term “alkoxy” means an AlkO— group in which the alkyl moiety is as defined above as an alkyl group. Examples of alkoxy groups include methoxy, ethoxy, butoxy and similar groups.

 The term “cycloalkyl” means a cyclic saturated hydrocarbon group with 5-7 ring carbon atoms, examples thereof include cyclopentyl, cyclohexyl and the like.

 The term “aryl” means an unsubstituted or substituted phenyl or naphthyl group. Substituents of these groups may be halogens (e.g. chlorine, bromine and the like), lower alkyl groups (e.g. methyl, ethyl, iso-propyl and the like), lower alkoxy groups (e.g., methoxy, ethoxy, iso-propoxy and the like), cyano, nitro, trihalomethyl groups (e.g. trifluoromethyl and the like), optionally substituted amino groups (e.g. amino, dimethylamino, acetylamino, N-piperidino, N-phthalimido groups and the like), acyl groups (e.g. formyl, acetyl, benzoyl and the like ), carboxamide groups (for example , N, N-diethylcarboxamido group and the like), carboxy groups, carbalkoxy groups, and the like.

 The term “aralkyl” means the aryl described above, to which the alkyl group described above is attached.

 The term “cycloalkylammonium” means a substituted ammonium group, two or three bonds of which form a non-aromatic mono- or bicyclic system, optionally carbocyclic. Examples of suitable substituents include: 1-methylpiperidinium-1; 1,4-dimethyl-1,2,5,6-tetrahydropyridinium-1; 4-methylmorpholinium-4; quinuclidinium-1, etc.

 The terms N-azinium and N-azolium mean respectively a 6-membered and 5-membered heteroaromatic cation attached via a quaternized nitrogen atom and containing no more than two nitrogen atoms in the ring, which is optionally substituted in free positions and optionally annelated. Examples of suitable substituents are: pyridinium-1, iso-quinolinium-2, pyrimidinium-1,3-methylbenzimidazolium-1, oxazolium-3, etc.

 The term “salts with pharmacologically acceptable acids” includes salts of all pharmacologically acceptable acids, such as inorganic (for example, hydrochloric, sulfuric, phosphoric, etc.); and organic (such as, for example, oxalic, citric, tartaric, maleic, succinic, methylsulfuric, p-toluenesulfonic acid, etc.).

в которой: R¹ имеет значения, определенные выше для формулы I,
R² представляет группу общей формулы -(CH₂)_k-Y, в которой Y выбран из группы, состоящей из:
H,
галогена,
циклоалкила,
этенила (необязательно моно-, ди- или тризамещенного низшим алкилом, монозамещенного арилом или β- монозамещенного группой COOR⁴, в которой R⁴ имеет значения, определенные выше для формулы I);
OR⁴ (в которой R⁴ имеет значения, определенные выше для формулы I);
алкилсульфонила,
арилсульфонила;
группы NR⁵R⁶ (в которой R⁵ и R⁶ имеют значения, определенные выше для формулы I);
группы COR⁹ (в которой R⁹ имеет значения, определенные выше для формулы I);
CN;
CHal₃ (в которой Hal - хлор, фтор или бром);
арила (необязательно моно-, ди- или тризамещенного заместителями A, определенными выше для формулы I);
2-, 3- и 4-пиридила, необязательно моно- или дизамещенного низшим алкилом, и соответствующих ему 1-R³CH₂-четвертичных солей (в которой К³ имеет значения, определенные выше для формулы I);
триалкиламмония;
циклоалкиламмония;
N-азиния и N-азолия;
и k имеет значения, определенные выше для формулы I
причем:
1) когда k = 0,
тогда Y является отличным от галогена, CHal₃, OR⁴, NR⁵R⁶, арила, триалкиламмония, циклоалкиламмония, N-азиния, N-азолия;
2) когда k = 1, тогда Y имеет значения отличные от галогена, триалкиламмония, циклоалкиламмония, N-азиния или N-азолия;
при условии, что
когда R¹ представляет метил, тогда R² является отличным от: H, метила, бензила, 2-пиридилметила, 2-(6-метил-3-пиридил)этила, 2-(4-пиридил)этила, 2-(N,N-диметиламино) этила или 3-(N,N-диметиламино)пропила;
а когда R¹ представляет H, тогда R² является отличным также от: н-бутила, циклогексила, 4-хлорбензила, 2-фенилэтила, 2- и 3-пиридила, 1-(2-пиридил)этила, 2-(2-пиридил)этила, 1-(3-пиридил)этила, 1-(6-метил-3-пиридил)этила, диэтиламинокарбонила, гидроксиметила, 2-метил-3-(N,N-диметиламино)пропила, от группы общей формулы: R⁴O-(CH₂)₂- или от группы общей формулы
R⁵R⁶N-(CH₂)_p-;
I.2 2-метил-2,3,4,4a,5,9b-гексагидро-1H-пиридо[4,3-b]индола общей формулы:

в которой R¹ имеет значения, определенные выше для формулы I, R² представляет группу общей формулы:

в которой Y, Z, m, l и k имеют значения, указанные при определении формулы I;
причем:
1) когда k = l = m = 0,
тогда Y является отличным от галогена, CHal₃, OR⁴, NR⁵R⁶, арила, триалкиламмония, циклоалкиламмония, N-азиния, N-азолия;
2) когда k = 1, а l = m = 0,
тогда Y имеет значения отличные от галогена, триалкиламмония, циклоалкиламмония, N-азиния или N-азолия;
3) когда k = l = 0, m = 1 и Z представляет O,
тогда Y является отличные от галогена, OH, CN, алкилсульфонила, арилсульфонила, триалкиламмония, циклоалкиламмония, N-азиния или N-азолия;
4) когда k = l = 0, m = 1 и Z представляет S,
тогда Y представляет только группу NR⁵R⁶, в которой один из заместителей R⁵ или R⁶ представляет водород;
5) когда l = 0,
тогда Z является отличным от H₂;
4) когда k = 0, а l = m = 1,
тогда Z является отличным от S;
при условии, что:
когда R¹ представляет H,
тогда R² является отличным от H, метила, этила, бензила, ацетила, хлорацетила или (N-морфолино-, или N-пиперидино-, или N,N-диэтиламино)ацетила, 3-хлорпропионила, 3-(N-морфолино)пропионила или 5-хлорпентаноила;
а когда R¹ представляет метил,
тогда R² является отличным от: H, 2,2,2-трифторэтила, 2-(N,N-диметиламино)этила, 3-(N,N-диметиламино)пропила, ацетила, 2-этилгексаноила, (E) 2-бутеноила в случае цис(-) изомера и (E)-циннамоила,
I. 3 Четвертичные соли 2-метил-2-R³CH₂-2,3,4,5- тетрагидро- и 2-метил-2-R³CH₂-2,3,4,4a, 5,9b-гексагидро- 1H-пиридо[4,3-b] индолов (с кватернизованным атомом азота в положении 2) общей формулы:

в которой: пунктирная линия с сопровождающей ее сплошной линией

представляет одинарную или двойную связь; и
R¹ и X^- имеют значения, определенные выше для формулы I:
R² представляет 2-(2-(N-метил-N-R³метиламино)этил)-5-R¹-индолил-3- метильную группу, в которой R¹ и R³ определены выше для формулы I (при этом

представляет двойную связь)
или группу общей формулы:

в которой Y, Z, m, l и k имеют значения, указанные при определении формулы I;
причем:
1) Y может иметь любое из указанных значений только когда k + m ≥ 2, а l = 0;
2) когда k = l = m = 0,
тогда Y является отличным от галогена, CHal₃, OR⁴, NR⁵R⁶, арила, триалкиламмония, циклоалкиламмония, N-азиния, N-азолия;
3) когда k = l = 0, m = 1 и Z представляет O,
тогда Y является отличным от галогена, OH, CN, алкилсульфонила, арилсульфонила, триалкиламмония, циклоалкиламмония, N-азиния или N-азолия;
4) когда k = l = 0, m = 1 и Z представляет S,
тогда Y представляет только группу NR⁵R⁶, в которой R⁶ представляет водород;
5) когда l = 0,
тогда Z является отличным от H₂;
6) когда k = 0, а l = m = 1,
тогда Z является отличным от S;
при условии, что:
когда R¹ и R³ каждый представляет H и X представляет иод, тогда R² является отличным от H, метила, этила или пропила;
когда R¹ и R³ каждый представляет H, и X представляет метилсульфат, тогда R² является отличным от бензила;
когда R¹ представляет H, R³ представляет метил и X представляет иод, тогда R² отличен от H;
когда R¹ представляет метил, R³ представляет H и X представляет иод, тогда R² отличен от H или метила;
когда R¹ представляет H, R³ представляет фенил и X представляет хлор, тогда R² отличен от H или бензила;
когда R¹ представляет H, R³ представляет фенил и X представляет иод, тогда R² отличен от иодида 3-(N,N,N-триметиламмонио)пропила.Preferred Embodiments
Among the compounds of formula (I) constituting one of the objects of the present invention, the following three subgroups of compounds are preferred, which can be represented by formulas (I.1), (I.2) and (I.3) below. Particularly preferred compounds are:
I.1 2-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indoles of the general formula:

in which: R ¹ has the meanings given above for formula I,
R ² represents a group of the general formula - (CH ₂ ) _k —Y, in which Y is selected from the group consisting of:
H
halogen
cycloalkyl
ethenyl (optionally mono-, di- or trisubstituted with lower alkyl, monosubstituted with aryl or β-monosubstituted with COOR ⁴ in which R ⁴ is as defined above for formula I);
OR ⁴ (in which R ⁴ has the meanings defined above for formula I);
alkylsulfonyl,
arylsulfonyl;
groups NR ⁵ R ⁶ (in which R ⁵ and R ⁶ are as defined above for formula I);
groups COR ⁹ (in which R ⁹ is as defined above for formula I);
CN;
CHal ₃ (in which Hal is chloro, fluoro or bromo);
aryl (optionally mono-, di- or trisubstituted with substituents A as defined above for formula I);
2-, 3- and 4-pyridyl, optionally mono- or disubstituted with lower alkyl, and the corresponding 1-R ³ CH ₂ quaternary salts (in which K ³ has the meanings defined above for formula I);
trialkylammonium;
cycloalkylammonium;
N-azinium and N-azolium;
and k has the meanings given above for formula I
moreover:
1) when k = 0,
then Y is different from halogen, CHal ₃ , OR ⁴ , NR ⁵ R ⁶ , aryl, trialkylammonium, cycloalkylammonium, N-azinium, N-azolium;
2) when k = 1, then Y has values other than halogen, trialkylammonium, cycloalkylammonium, N-azinium or N-azolium;
provided that
when R ¹ is methyl, then R ² is different from: H, methyl, benzyl, 2-pyridylmethyl, 2- (6-methyl-3-pyridyl) ethyl, 2- (4-pyridyl) ethyl, 2- (N, N-dimethylamino) ethyl or 3- (N, N-dimethylamino) propyl;
and when R ¹ represents H, then R ² is also different from: n-butyl, cyclohexyl, 4-chlorobenzyl, 2-phenylethyl, 2- and 3-pyridyl, 1- (2-pyridyl) ethyl, 2- (2- pyridyl) ethyl, 1- (3-pyridyl) ethyl, 1- (6-methyl-3-pyridyl) ethyl, diethylaminocarbonyl, hydroxymethyl, 2-methyl-3- (N, N-dimethylamino) propyl, from the group of the general formula: R ⁴ O- (CH ₂ ) ₂ - or from a group of the general formula
R ⁵ R ⁶ N- (CH ₂ ) _p -;
I.2 2-methyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole of the general formula:

in which R ¹ has the meanings given above for formula I, R ² represents a group of the general formula:

in which Y, Z, m, l and k have the meanings indicated in the definition of formula I;
moreover:
1) when k = l = m = 0,
then Y is different from halogen, CHal ₃ , OR ⁴ , NR ⁵ R ⁶ , aryl, trialkylammonium, cycloalkylammonium, N-azinium, N-azolium;
2) when k = 1, and l = m = 0,
then Y has values other than halogen, trialkylammonium, cycloalkylammonium, N-azinium or N-azolium;
3) when k = l = 0, m = 1 and Z represents O,
then Y is other than halogen, OH, CN, alkylsulfonyl, arylsulfonyl, trialkylammonium, cycloalkylammonium, N-azinium or N-azolium;
4) when k = l = 0, m = 1 and Z represents S,
then Y represents only the group NR ⁵ R ⁶ in which one of the substituents R ⁵ or R ⁶ represents hydrogen;
5) when l = 0,
then Z is different from H ₂ ;
4) when k = 0, and l = m = 1,
then Z is different from S;
provided that:
when R ¹ represents H,
then R ² is different from H, methyl, ethyl, benzyl, acetyl, chloroacetyl or (N-morpholino-, or N-piperidino-, or N, N-diethylamino) acetyl, 3-chloropropionyl, 3- (N-morpholino) propionyl or 5-chloropentanoyl;
and when R ¹ is methyl,
then R ² is different from: H, 2,2,2-trifluoroethyl, 2- (N, N-dimethylamino) ethyl, 3- (N, N-dimethylamino) propyl, acetyl, 2-ethylhexanoyl, (E) 2- butenoyl in the case of the cis (-) isomer and (E) -cinnamoyl,
I. 3 Quaternary salts of 2-methyl-2-R ³ CH ₂ -2,3,4,5-tetrahydro and 2-methyl-2-R ³ CH ₂ -2,3,4,4a, 5,9b- hexahydro-1H-pyrido [4,3-b] indoles (with a quaternized nitrogen atom in position 2) of the general formula:

in which: a dashed line with an accompanying solid line

represents a single or double bond; and
R ¹ and X ^- have the meanings given above for formula I:
R ² represents a 2- (2- (N-methyl-NR ³ methylamino) ethyl) -5-R ¹ -indolyl-3-methyl group in which R ¹ and R ^{3 are as} defined above for formula I (wherein

represents a double bond)
or a group of the general formula:

in which Y, Z, m, l and k have the meanings indicated in the definition of formula I;
moreover:
1) Y can have any of the indicated values only when k + m ≥ 2, and l = 0;
2) when k = l = m = 0,
then Y is different from halogen, CHal ₃ , OR ⁴ , NR ⁵ R ⁶ , aryl, trialkylammonium, cycloalkylammonium, N-azinium, N-azolium;
3) when k = l = 0, m = 1 and Z represents O,
then Y is different from halogen, OH, CN, alkylsulfonyl, arylsulfonyl, trialkylammonium, cycloalkylammonium, N-azinium or N-azolium;
4) when k = l = 0, m = 1 and Z represents S,
then Y represents only the group NR ⁵ R ⁶ in which R ⁶ represents hydrogen;
5) when l = 0,
then Z is different from H ₂ ;
6) when k = 0, and l = m = 1,
then Z is different from S;
provided that:
when R ¹ and R ³ each represents H and X represents iodine, then R ² is other than H, methyl, ethyl or propyl;
when R ¹ and R ³ each represents H, and X represents methyl sulfate, then R ² is other than benzyl;
when R ¹ represents H, R ³ represents methyl and X represents iodine, then R ² is other than H;
when R ¹ represents methyl, R ³ represents H and X represents iodine, then R ² is other than H or methyl;
when R ¹ represents H, R ³ represents phenyl and X represents chlorine, then R ² is other than H or benzyl;
when R ¹ represents H, R ³ represents phenyl and X represents iodine, then R ² is different from 3- (N, N, N-trimethylammonio) propyl iodide.

в которой R¹ имеет значения, определенные выше для формулы I,
а Y выбран из группы, состоящей из:
H,
циклоалкила,
этенила [необязательно моно-, ди- или тризамещенного низшим алкилом, монозамещенного арилом или β- монозамещенного группой COOR⁴ (в которой R⁴ имеет значения, определенные выше)],
2-, 3- и 4-пиридила (необязательно моно- или дизамещенного низшим алкилом),
при условии, что:
когда R¹ представляет метил, тогда Y является отличным от H,
а когда R¹ представляет H, тогда Y дополнительно является отличным также от циклогексила, 2- и 3-пиридила;
I. 1.2 5-(замещенный метил)-2-метил-2,3,4,5-тетрагидро-1H-пиридо [4,3-b] индолы общей формулы:

в которой R¹ имеет значения, определенные для формулы I,
Y выбран из группы, состоящей из:
H,
циклоалкила,
этенила (необязательно моно-, ди- или тризамещенного низшим алкилом, монозамещенного арилом, β- замещенного COOR⁴, в которой R⁴ имеет значения, определенные выше),
CN,
CHal₃ (в которой Hal представляет хлор, фтор или бром),
алкилсульфонила,
арилсульфонила,
арила (необязательно моно-, ди- или тризамещенного заместителя A, определенными выше);
COR⁹ (в которой R⁹ имеет значения, определенные выше),
2-, 3- и 4-пиридила (необязательно моно- или дизамещенного низшим алкилом),
при условии, что:
когда R¹ представляет метил,
тогда Y имеет значения, отличные от H, фенила, 2-пиридила;
когда R¹ представляет H,
тогда Y отличен также от OH и 4-хлорфенила;
I. 1.3 5-(замещенный этил)-2-метил-2,3,4,5-тетрагидро-1H-пиридо [4,3-b] индолы общей формулы:

в которой R¹ имеет значения, определенные для формулы I,
Y имеет значения, определенные для формулы I.1;
при условии что:
когда R¹ представляет метил,
тогда Y имеет значения, отличные от диметиламино группы, 6-метил-3-пиридила или 4-пиридила;
когда R¹ представляет H,
тогда Y отличен также от фенила, 2-пиридила, от группы OR⁴, определенной для формулы I, от группы R⁵R⁶N (в которой R⁵ и R⁶ каждый представляет этил; или R⁵ и R⁶ вместе представляют тетра- или пентаметилен).Even more preferred compounds according to the present invention from tetrahydro derivatives of compounds of formula I.1 are:
I. 1.1 5- (un) substituted 2-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indoles of the general formula:

in which R ¹ has the meanings given above for formula I,
and Y is selected from the group consisting of:
H
cycloalkyl
ethenyl [optionally mono-, di- or trisubstituted with lower alkyl, monosubstituted with aryl or β-monosubstituted with COOR ⁴ (in which R ⁴ is as defined above)],
2-, 3- and 4-pyridyl (optionally mono- or disubstituted with lower alkyl),
provided that:
when R ¹ is methyl, then Y is other than H,
and when R ¹ is H, then Y is further different from cyclohexyl, 2- and 3-pyridyl;
I. 1.2 5- (substituted methyl) -2-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indoles of the general formula:

in which R ¹ has the meanings defined for formula I,
Y is selected from the group consisting of:
H
cycloalkyl
ethenyl (optionally mono-, di- or trisubstituted with lower alkyl, monosubstituted with aryl, β-substituted with COOR ⁴ in which R ⁴ is as defined above),
CN
CHal ₃ (in which Hal is chloro, fluoro or bromo),
alkylsulfonyl,
arylsulfonyl,
aryl (optionally mono-, di- or trisubstituted substituent A, as defined above);
COR ⁹ (in which R ⁹ has the meanings defined above),
2-, 3- and 4-pyridyl (optionally mono- or disubstituted with lower alkyl),
provided that:
when R ¹ is methyl,
then Y has values other than H, phenyl, 2-pyridyl;
when R ¹ represents H,
then Y is also different from OH and 4-chlorophenyl;
I. 1.3 5- (substituted ethyl) -2-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indoles of the general formula:

in which R ¹ has the meanings defined for formula I,
Y is as defined for formula I.1;
provided that:
when R ¹ is methyl,
then Y has values other than a dimethylamino group, 6-methyl-3-pyridyl or 4-pyridyl;
when R ¹ represents H,
then Y is also different from phenyl, 2-pyridyl, from the group OR ⁴ defined for formula I, from the group R ⁵ R ⁶ N (in which R ⁵ and R ⁶ each represents ethyl; or R ⁵ and R ⁶ together represent tetra- or pentamethylene).

в которой R¹, R⁵ и R⁶ имеют значения, определенные выше для формулы I;
при условии, что:
когда R¹ представляет метил, тогда R⁵ и R⁶ не могут одновременно быть метилами;
когда R¹ представляет H, тогда дополнительно R⁵ и R⁶ не могут одновременно быть метилами или этилами, или R⁵ и R⁶, взятые вместе, отличны от тетра- или пентаметилена;
I. 1.3.2 5-(2-, 3- или 4-пиридилэтил)- 2-метил-2,3,4,5-тетрагидро-1H-пиридо[4,3-b]индолы общей формулы I.1.3, указанной выше,
в которой:
R¹ имеет значения, определенные выше для формулы I;
Y представляет 2-, 3- или 4-пиридил (необязательно моно- или дизамещенный низшим алкилом),
при условии что:
когда R¹ представляет метил,
тогда Y имеет значения, отличные от 6-метил-3-пиридила или 4-пиридила;
а когда R¹ представляет H,
тогда Y отличен также от 2-пиридила.Of the compounds of formula I.1.3, the most preferred are:
I. 1.3.1 5- (2-NR ⁵ -NR ⁶ amino) ethyl) - 2-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indoles of the general formula:

in which R ¹ , R ⁵ and R ⁶ have the meanings defined above for formula I;
provided that:
when R ¹ is methyl, then R ⁵ and R ⁶ cannot simultaneously be methyl;
when R ¹ represents H, then additionally R ⁵ and R ⁶ cannot simultaneously be methyl or ethyl, or R ⁵ and R ⁶ taken together are different from tetra- or pentamethylene;
I. 1.3.2 5- (2-, 3- or 4-pyridylethyl) - 2-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indoles of the general formula I.1.3, above
wherein:
R ¹ has the meanings given above for formula I;
Y represents 2-, 3- or 4-pyridyl (optionally mono- or disubstituted with lower alkyl),
provided that:
when R ¹ is methyl,
then Y has values other than 6-methyl-3-pyridyl or 4-pyridyl;
and when R ¹ represents H,
then Y is also different from 2-pyridyl.

в которой R¹ имеет значения, определенные выше для формулы I;
I. 1.3.4 5-(2-COR⁹-этил)- 2-метил-2,3,4,5-тетрагидро-1H-пиридо[4,3-b] индолы общей формулы

в которой R¹ имеет значения, определенные для формулы I;
R⁹ представляет OH, алкокси, NR⁵R⁶ (в которой R⁵ и R⁶ имеют значения, определенные выше для формулы I, кроме N-фталимидо группы).I. 1.3.3 2-methyl-5- (2-cyanoethyl) - 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indoles of the general formula:

in which R ¹ has the meanings defined above for formula I;
I. 1.3.4 5- (2-COR ⁹ -ethyl) - 2-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indoles of the general formula

in which R ¹ has the meanings defined for formula I;
R ⁹ represents OH, alkoxy, NR ⁵ R ⁶ (in which R ⁵ and R ⁶ are as defined above for formula I, except for the N-phthalimido group).

в которой: R¹ имеет значения, определенные выше для формулы I; Y имеет значения, определенные выше для формулы I.1, и k = 3 или 4,
при условии, что:
когда R¹ представляет метил, и k = 3, тогда Y отличен от диметиламино группы;
когда R¹ представляет H, и k = 3, тогда Y отличен также от группы W(CH₂CH₂)₂N-, в которой W представляет O, NCH₃ или NCH₂Ph;
а когда k = 4, тогда Y отличен от H.Another more preferred group of compounds of formula I.1 are:
I. 1.4 5 - (ω-substituted alkyl) - 2-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indoles of the general formula:

in which: R ¹ has the meanings given above for formula I; Y has the meanings given above for formula I.1, and k = 3 or 4,
provided that:
when R ¹ is methyl, and k = 3, then Y is other than a dimethylamino group;
when R ¹ represents H, and k = 3, then Y is also different from the group W (CH ₂ CH ₂ ) ₂ N-, in which W represents O, NCH ₃ or NCH ₂ Ph;
and when k = 4, then Y is different from H.

в которой R¹ и R⁵ имеют значения, определенные выше для формулы I;
Z представляет O или S;
I. 2.2 5 -(α-(ω-)- замещенный алканоил)- 2-метил-2,3,4,4a,5,9b-гексагидро-1H-пиридо[4,3-b]индолы общей формулы:

в которой R¹ имеет значения, определенные выше для формулы I;
Y, k и l имеют значения, указанные выше при определении формулы I.2,
при условии, что:
когда R¹ представляет H, и l = 0,
тогда Y является отличным от:
H, N,N-диэтиламино или N-пиперидино группы, когда k = 1;
от N-морфолино группы, когда k = 1 или 2; и
от хлора, когда k = 1, 2 или 4;
а когда R¹ представляет метил,
тогда Y является отличным от H,
когда k = 1 или l = 0 или
когда k = 4, и l = 1 и Alk представляет этил.More preferred hexahydro derivatives of the compounds of formula I.2 according to the present invention are:
I. 2.1 5- [N-substituted (thio) carbamoyl] - 2-methyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indoles of the general formula:

in which R ¹ and R ⁵ have the meanings defined above for formula I;
Z represents O or S;
I. 2.2 5 - (α- (ω -) - substituted alkanoyl) - 2-methyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indoles of the general formula:

in which R ¹ has the meanings defined above for formula I;
Y, k and l have the meanings given above in the definition of formula I.2,
provided that:
when R ¹ represents H, and l = 0,
then Y is different from:
H, N, N-diethylamino or N-piperidino groups when k = 1;
from an N-morpholino group when k = 1 or 2; and
from chlorine when k = 1, 2 or 4;
and when R ¹ is methyl,
then Y is different from H,
when k = 1 or l = 0 or
when k = 4 and l = 1 and Alk represents ethyl.

в которой R¹ имеет значения, определенные выше для формулы I;
Y выбран из группы, состоящей из:
H,
циклоалкила;
этенила (необязательно моно-, ди- или тризамещенного низшим алкилом, монозамещенного арилом или β- монозамещенного группой COOR⁴, в которой R⁴ имеет значения, определенные выше для формулы I):
OR⁴ (в которой R⁴ имеет значения, определенные выше для формулы I, кроме H);
группы NR⁵R⁶ (в которой R⁵ и R⁶ имеют значения, определенные выше для формулы I);
группы COR⁹ (в которой R⁹ имеет значения, определенные выше для формулы I, кроме OH группы);
CHal₃ (в которой Hal - хлор, фтор или бром);
арила (необязательно моно-, ди- или тризамещенного заместителями A, определенными выше для формулы I);
2-, 3- и 4-пиридила (необязательно моно- или дизамещенного низшим алкилом), и соответствующих им четвертичных солей 1-R³CH₂-пиридиния-2-, -3 или -4 (в которой R³ имеет значения, определенные выше для формулы I);
при условии, что:
когда R¹ представляет метил, тогда Y отличен от (E)-пропенила-1 в случае цис(-)изомера или от (E) 2-фенилэтенила.Of the compounds of formula I.2.2, more preferred are:
I. 2.2.1 5-acyl-substituted 2-methyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indoles of the general formula:

in which R ¹ has the meanings defined above for formula I;
Y is selected from the group consisting of:
H
cycloalkyl;
ethenyl (optionally mono-, di- or trisubstituted with lower alkyl, monosubstituted with aryl or β-monosubstituted with COOR ⁴ , in which R ⁴ has the meanings defined above for formula I):
OR ⁴ (in which R ⁴ has the meanings defined above for formula I, except for H);
groups NR ⁵ R ⁶ (in which R ⁵ and R ⁶ are as defined above for formula I);
groups COR ⁹ (in which R ⁹ has the meanings defined above for formula I, except for the OH group);
CHal ₃ (in which Hal is chloro, fluoro or bromo);
aryl (optionally mono-, di- or trisubstituted with substituents A as defined above for formula I);
2-, 3- and 4-pyridyl (optionally mono- or disubstituted with lower alkyl), and their corresponding quaternary salts of 1-R ³ CH ₂ -pyridinium-2-, -3 or -4 (in which R ³ has the meanings defined above for formula I);
provided that:
when R ¹ is methyl, then Y is different from (E) -propenyl-1 in the case of the cis (-) isomer or from (E) 2-phenylethenyl.

в которой R¹ имеет значения, определенные для формулы I;
Y имеет значения, указанные выше при определении формулы I.2.I. 2.2.2 5- (α-substituted alkanoyl) - 2-methyl-2-R ³ CH ₂ - 2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indoles general formula:

in which R ¹ has the meanings defined for formula I;
Y has the meanings given above in the definition of formula I.2.

в которой R¹ имеет значения, определенные для формулы I,
Y имеет значения, указанные выше для формулы I.2,
k представляет целое число от 1 до 4;
при условии, что:
когда R¹ представляет H, тогда Y является отличным от:
H, N, N-диэтиламино или N-пиперидино группы, если k = 1; от N-морфолино группы, если k = 1 или 2; и от хлора, если k = 1, 2 или 4;
а когда R¹ представляет метил и k = 1, тогда Y является отличным от H.I. 2.2.3 5 - (ω-substituted alkanoyl) - 2-methyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indoles of the general formula:

in which R ¹ has the meanings defined for formula I,
Y has the meanings given above for formula I.2,
k represents an integer from 1 to 4;
provided that:
when R ¹ represents H, then Y is different from:
H, N, N-diethylamino or N-piperidino groups, if k = 1; from an N-morpholino group if k = 1 or 2; and from chlorine, if k = 1, 2 or 4;
and when R ¹ is methyl and k = 1, then Y is different from H.

в которой R¹ имеет значения, определенные для формулы I;
k представляет целое число от 1 до 4;
Y выбран из группы, состоящей из:
H;
этенила (необязательно моно-, ди- или тризамещеного низшим алкилом, монозамещенного арилом или

монозамещенного группой COOR⁴, в которой R⁴ имеет значения, определенные выше для формулы I);
CF₃;
OR⁴ (в которой R⁴ имеет значения, определенные выше для формулы I);
NR⁵R⁶ (в которой R⁵ и R⁶ имеют значения, определенные выше для формулы I);
при условии, что:
когда R¹ представляет H,
тогда Y является отличным от H (при k = 1 или 2), или фенила (при k = 1);
а когда R¹ представляет метил,
тогда Y является отличным от CF₃ (при k = 1); и от диметиламиногруппы (при k = 2 или 3).The following preferred group of hexahydro derivatives are:
I. 2.3 5 - (ω-substituted alkyl) - 2-methyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indoles of the general formula:

in which R ¹ has the meanings defined for formula I;
k represents an integer from 1 to 4;
Y is selected from the group consisting of:
H;
ethenyl (optionally mono-, di- or trisubstituted with lower alkyl, monosubstituted with aryl or

monosubstituted by COOR ⁴ group, in which R ⁴ has the meanings defined above for formula I);
CF ₃ ;
OR ⁴ (in which R ⁴ has the meanings defined above for formula I);
NR ⁵ R ⁶ (in which R ⁵ and R ⁶ are as defined above for formula I);
provided that:
when R ¹ represents H,
then Y is different from H (for k = 1 or 2), or phenyl (for k = 1);
and when R ¹ is methyl,
then Y is different from CF ₃ (for k = 1); and from dimethylamino group (at k = 2 or 3).

в которой R¹, R², R³ и X имеют значения, указанные выше при определении формулы I;
при условии, что:
когда R¹ и R³ оба одновременно представляют H и X представляет иод,
тогда R² является отличным от H, метила, этила или пропила;
когда R¹ и R³ оба одновременно представляют H, и X представляет метилсульфат,
тогда R² является отличным от бензила;
когда R¹ представляет H, R³ представляет метил и X представляет иод,
тогда R² отличен от H;
когда R¹ представляет метил, R³ представляет H и X представляет иод,
тогда R² отличен от H или метила;
когда R¹ представляет H, R³ представляет фенил и X представляет хлор,
тогда R² отличен от H или бензила;
когда R¹ представляет H, R³ представляет фенил и X представляет иод,
тогда R² отличен от иодида 3-(N,N,N-триметиламмонио)пропила.More preferred quaternary salts of tetrahydro derivatives according to the present invention of formula I.3 are:
I. 3.1 Quaternary salts of 2-methyl-2-R ³ CH ₂ - 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indoles (with a quaternized nitrogen atom in position 2) of the general formula:

in which R ¹ , R ² , R ³ and X have the meanings indicated above in the definition of formula I;
provided that:
when R ¹ and R ³ both simultaneously represent H and X represents iodine,
then R ² is other than H, methyl, ethyl or propyl;
when R ¹ and R ³ both represent H and X represents methyl sulfate,
then R ² is other than benzyl;
when R ¹ represents H, R ³ represents methyl and X represents iodine,
then R ² is other than H;
when R ¹ represents methyl, R ³ represents H and X represents iodine,
then R ² is other than H or methyl;
when R ¹ represents H, R ³ represents phenyl and X represents chlorine,
then R ² is other than H or benzyl;
when R ¹ represents H, R ³ represents phenyl and X represents iodine,
then R ² is different from 3- (N, N, N-trimethylammonio) propyl iodide.

в которой R¹, R³ и X имеют значения, определенные выше для формулы I;
Y выбран из группы, состоящей из:
H,
циклоалкила,
этенила [необязательно моно-, ди- или тризамещенного низшим алкилом, монозамещенного арилом, β- монозамещенного группой COOR⁴ (в которой R⁴ имеет значения, определенные выше)],
алкилсульфонила;
арилсульфонила,
CN,
COR⁹ (в которой R⁹ имеет значения, определенные выше для формулы I);
2-, 3- или 4-пиридила (необязательно моно- или дизамещенного низшим алкилом) и соответствующих им четвертичных солей 1-R³CH₂-пиридиния-2, -3, или -4 (где R³ имеет значения, определенные выше для формулы I);
при условии, что:
когда R¹ и Y каждый представляет H, и X представляет иод,
тогда R³ является отличным от H или метила;
когда R¹ и Y каждый представляет H, и X представляет хлор,
тогда R³ является отличным от фенила;
когда R³ и Y каждый представляет H и X представляет иод,
тогда R¹ является отличным от метила.Moreover, from the derivatives of I.3.1, the following groups of compounds are most preferred:
I.3.1.1 Quaternary salts of 5- (un) substituted 2-methyl-2-R ³ CH ₂ -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indoles of the general formula:

in which R ¹ , R ³ and X have the meanings defined above for formula I;
Y is selected from the group consisting of:
H
cycloalkyl
ethenyl [optionally mono-, di- or trisubstituted with lower alkyl, monosubstituted with aryl, β-monosubstituted with COOR ⁴ (in which R ⁴ is as defined above)],
alkylsulfonyl;
arylsulfonyl,
CN
COR ⁹ (in which R ⁹ has the meanings given above for formula I);
2-, 3- or 4-pyridyl (optionally mono- or disubstituted with lower alkyl) and their corresponding quaternary salts of 1-R ³ CH ₂ -pyridinium-2, -3, or -4 (where R ³ has the meanings defined above for formula I);
provided that:
when R ¹ and Y each represents H, and X represents iodine,
then R ³ is other than H or methyl;
when R ¹ and Y each represents H, and X represents chlorine,
then R ³ is other than phenyl;
when R ³ and Y each represents H and X represents iodine,
then R ¹ is other than methyl.

в которой R¹, R³ и X имеют значения, определенные выше для формулы I;
Y выбран из группы, состоящей из:
H,
циклоалкила,
этенила [необязательно моно-, ди- или тризамещенного низшим алкилом, монозамещенного арилом, β- монозамещенного группой COOR⁴ (в которой R⁴ имеет значения, определенные выше)],
CN;
CHal₃ (в которой Hal - хлор, фтор или бром);
алкилсульфонила;
арилсульфонила;
арила (необязательно моно-, ди- или тризамещенного заместителем A, определенным выше для формулы I),
OR⁴ (в которой R⁴ имеет значения, определенные выше для формулы I),
COR⁹ (в которой R⁹ имеет значения, определенные выше для формулы I),
2-, 3- и 4-пиридила (необязательно моно- или дизамещенного низшим алкилом), и соответствующих им четвертичных солей 1-R³CH₂-пиридиния-2, -3 или -4 (где R³ имеет значения, определенные выше для формулы I);
при условии, что:
когда R¹ и R³ каждый представляет H и X представляет иод, или R¹ представляет метил, а R³ представляет H и X представляет иод, тогда Y отличен от H;
а когда R¹ и R³ каждый представляет H и X представляет метилсульфат, или R¹ представляет H, R³ представляет фенил, и X представляет хлор, тогда Y отличен от фенила.I.3.1.2 Quaternary salts of 5- (substituted methyl) -2-methyl-2-R ³ CH ₂ -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indoles of the general formula:

in which R ¹ , R ³ and X have the meanings defined above for formula I;
Y is selected from the group consisting of:
H
cycloalkyl
ethenyl [optionally mono-, di- or trisubstituted with lower alkyl, monosubstituted with aryl, β-monosubstituted with COOR ⁴ (in which R ⁴ is as defined above)],
CN;
CHal ₃ (in which Hal is chloro, fluoro or bromo);
alkylsulfonyl;
arylsulfonyl;
aryl (optionally mono-, di- or trisubstituted with substituent A as defined above for formula I),
OR ⁴ (in which R ⁴ has the meanings defined above for formula I),
COR ⁹ (in which R ⁹ has the meanings given above for formula I),
2-, 3- and 4-pyridyl (optionally mono- or disubstituted with lower alkyl), and their corresponding quaternary salts of 1-R ³ CH ₂ -pyridinium-2, -3 or -4 (where R ³ has the meanings defined above for formula I);
provided that:
when R ¹ and R ³ each represents H and X represents iodine, or R ¹ represents methyl, and R ³ represents H and X represents iodine, then Y is different from H;
and when R ¹ and R ³ each represents H and X represents methyl sulfate, or R ¹ represents H, R ³ represents phenyl, and X represents chlorine, then Y is different from phenyl.

в которой R¹, R³ и X имеют значения, определенные выше для формулы I;
Y выбран из группы, состоящей из:
CN,
COOAlk,
2-, 3- и 4-пиридила (необязательно моно- или дизамещенного низшим алкилом), и соответствующих им четвертичных солей 1-R³CH₂-пиридиния-2, -3, или -4 (где R³ имеет значения, определенные выше для формулы I);
при условии, что:
когда R¹ и R³ каждый представляет H, а X представляет иод,
тогда Y отличен от H.I.3.1.3 Quaternary salts of 5- (2-substituted ethyl) -2-methyl-2-R ³ CH ₂ -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indoles of the general formula:

in which R ¹ , R ³ and X have the meanings defined above for formula I;
Y is selected from the group consisting of:
CN
COOAlk,
2-, 3- and 4-pyridyl (optionally mono- or disubstituted with lower alkyl), and their corresponding quaternary salts of 1-R ³ CH ₂ -pyridinium-2, -3, or -4 (where R ³ has the meanings defined above for formula I);
provided that:
when R ¹ and R ³ each represents H, and X represents iodine,
then Y is different from H.

в которой R¹, R³ и X имеют значения, определенные выше для формулы I;
Y выбран из группы, состоящей из:
циклоалкила,
этенила [необязательно моно-, ди или тризамещенного низшим алкилом, монозамещенного арилом, β- монозамещенного группой
COOR⁴ (в которой R⁴ имеет значения, определенные выше для формулы I), CHal₃ (в которой Hal представляет хлор, фтор или бром),
арила (необязательно моно-, ди- или тризамещенного заместителем A, определенным выше для формулы I),
группы OR⁴ (в которой R⁴ имеет значения, определенные выше для формулы I, кроме H),
группы NR⁵R⁶ (в которой R⁵ и R⁶ имеют значения, определенные выше для формулы I, кроме фталимидо группы),
группы COR⁹ (в которой R⁹ имеет значения, определенные выше для формулы I, кроме OH),
2-, 3- и 4-пиридила (необязательно моно- или дизамещенного низшим алкилом), и соответствующих им четвертичных солей 1-R³CH₂-пиридиния-2, -3 или -4 (где R³ имеет значения, определенные выше).I.3.1.4 Quaternary salts of 5-acyl-2-methyl-2-R ³ CH ₂ -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indoles of the general formula:

in which R ¹ , R ³ and X have the meanings defined above for formula I;
Y is selected from the group consisting of:
cycloalkyl
ethenyl [optionally mono-, di or trisubstituted by lower alkyl, monosubstituted by aryl, β-monosubstituted by
COOR ⁴ (in which R ⁴ has the meanings given above for formula I), CHal ₃ (in which Hal represents chlorine, fluorine or bromine),
aryl (optionally mono-, di- or trisubstituted with substituent A as defined above for formula I),
group OR ⁴ (in which R ⁴ has the meanings defined above for formula I, except for H),
groups NR ⁵ R ⁶ (in which R ⁵ and R ⁶ have the meanings defined above for formula I, except for the phthalimido group),
groups COR ⁹ (in which R ⁹ has the meanings defined above for formula I, except OH),
2-, 3- and 4-pyridyl (optionally mono- or disubstituted with lower alkyl), and their corresponding quaternary salts of 1-R ³ CH ₂ -pyridinium-2, -3 or -4 (where R ³ has the meanings defined above) .

в которой R¹, R³ и X имеют значения, определенные выше для формулы I;
R² представляет группу общей формулы:

в которой k, l, m и Y имеют значения, определенные выше для формулы I.3
причем:
1) Y имеет любое из указанных значений, только когда k+m ≥ 2 и l = 0;
2) когда k = l = 0, m = 1, тогда Y являетсчя отличным от галогена, OH, CN, алкилсульфонила, арилсульфонила, триалкиламмония, циклоалкиламмония, N-азиния или N-азолия.More preferred salts of hexahydro derivatives are:
I. 3.2 Quaternary salts of 5-substituted 2-methyl-2-R ³ CH ₂ -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indoles (with a quaternized nitrogen atom in position 2) of the general formula:

in which R ¹ , R ³ and X have the meanings defined above for formula I;
R ² represents a group of the general formula:

in which k, l, m and Y have the meanings defined above for formula I.3
moreover:
1) Y has any of the indicated values only when k + m ≥ 2 and l = 0;
2) when k = l = 0, m = 1, then Y is very different from halogen, OH, CN, alkylsulfonyl, arylsulfonyl, trialkylammonium, cycloalkylammonium, N-azinium or N-azolium.

 3) m = 0 only when k = l = 0 and Y is alkylsulfonyl, arylsulfonyl or CN.

The most preferred compounds of formula I are the following:
2-methyl-8-isopropyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride;
2,8-dimethyl-5- (2,4-dimethylbenzyl) - 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride;
2,8-dimethyl-5- [2- (N-hexamethyleneimino) ethyl] 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole dihydrochloride;
2,8-dimethyl-5- (2-carboxyethyl) - 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride;
2,2-dimethyl-5- [2- (6-methyl-3-pyridyl) ethyl] 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indolium iodide;
2,2,8-trimethyl-5- [2- (1,6-dimethyl-3-pyridinium) ethyl] 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indolium diiodide;
2-methyl-2- (4-bromophenacyl) -5- [2- (6-methyl-3-pyridyl) ethyl] - 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indolium bromide;
2,8-dimethyl-2-phenacyl-5- [2- (6-methyl-3-pyridyl) ethyl] 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indolium bromide;
2,2,8-trimethyl-5- (2-ethoxycarbonylethyl) 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indolium iodide;
2,2,8-trimethyl-5- [5-methyl-2- (2-N, N-dimethylamino) ethyl) indolyl-3-methyl] -2,3,4,5-tetrahydro-1H-pyrido [4 , 3-b] indolium iodide;
2,2,8-trimethyl-5-N-methylcarbamoyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indolium iodide;
cis (±) -2,8-dimethyl-5-cyclohexylthiocarbamoyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole;
cis (±) -2,8-dimethyl-5-n-butylcarbamoyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole;
cis (±) -2,8-dimethyl-5-phenylcarbamoyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole;
cis (±) -2,8-dimethyl-5- (2-methylbenzoyl) - 2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole hydrochloride;
cis (±) -2,8-dimethyl-5- (2-bromopropionyl) 2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole hydrochloride;
cis (±) -2,8-dimethyl-5-chloroacetyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole hydrochloride;
cis (±) -2,8-dimethyl-5 - [(E) -2-butenoyl] - 2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole;
cis (±) -2,8-dimethyl-5-methoxyacetyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole hydrochloride;
cis (±) -2,8-dimethyl-5- (N-pyrrolidinoacetyl) - 2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole;
cis (±) -2,8-dimethyl-5- [2- (4-methylpyridinium-1) propionyl] - 2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole bromide;
cis (±) -2,8-dimethyl-5- (3-carboxypropionyl) 2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole;
cis (±) -2-methyl-5- [2- (6-methyl-3-pyridyl) ethyl] - 2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole hydrochloride;
cis (±) -2,2,8-trimethyl-5-carbamoyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indolium iodide.

 The compounds of formula I according to the invention are prepared using methods known in the art for the preparation of similar substances or new methods described below.

 The basis for the preparation of new compounds according to the invention is a method for producing tetrahydro derivatives of pyrido [4,3-b] indoles of the formula I.1 with various substituents in 5- and 8-positions, carried out according to the well-known reaction of constructing a tricyclic core using Fischer condensation.

Using this method, derivatives encompassed by Formula I.1 can be prepared in which R ² is hydrogen (i.e., 5-unsubstituted derivatives) or ω- (Y-substituted) alkyl.

в которой R¹ и R² имеют значения, указанные выше при определении формулы I.1.Fischer cyclization involves the reaction of a para-substituted phenylhydrazine of formula II (or its salts with mineral acids) and 1-methylpiperidone-4 (III), as, for example, described by N. Barbulescu, C. Bornaz, C. si Greff - Rev . Chim. (Bucuresti), 1971, v. 22, p. 269, according to the scheme:

in which R ¹ and R ² have the meanings indicated above in the definition of formula I.1.

Tetrahydro derivatives of formula I, in which R ² is other than hydrogen, as well as hexahydrated and quaternized derivatives, are prepared by reactions using the 5-unsubstituted tricyclic compounds mentioned above.

В формуле IV X - уходящая группа (такая как галоген, алкил- или акрилсульфонилокси); Y имеет значения, указанные при определении формулы I.1 за исключением групп, неустойчивых в условиях данной реакции (таких как COOAlk, N-азиний, N-азолий и аналогичные), k - целое число от 1 до 4.5 - (ω-substituted alkyl) -2-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indoles of formula I.1 are obtained by alkylation of 5-unsubstituted derivatives of formula I.1.1a ( i.e., compounds of formula I.1.1, in which Y represents H) by electrophilic reagents IV in the presence of a strong base, as, for example, described in the work of N.F. Kucherova, N.M. Sharkova, V.A. Zagorevsky - Author. testimonial. USSR, 261386 (C 07 C), dated 6.07.1965) according to the scheme:

In formula IV, X is a leaving group (such as halogen, alkyl or acrylsulfonyloxy); Y has the meanings given in the definition of formula I.1 with the exception of groups that are unstable under the conditions of this reaction (such as COOAlk, N-azinium, N-azolium and the like), k is an integer from 1 to 4.

The 5-unsubstituted tetrahydro derivatives of Formula I.1.1a are heated with an equimolar amount of a strong base (e.g. sodium, sodium hydride, sodium amide, preferably sodium hydride) in a polar aprotic solvent such as DMF (dimethylformamide), DMSO (dimethyl sulfoxide), HMPTA (hexametamide ), preferably in DMF, followed by the addition of an alkylating agent IV at a temperature of 20-170 ^o C, preferably at 60-130 ^o C.

В формуле V Y представляет CN или 2-, 3- или 4-пиридил, необязательно моно- или дизамещенный низшим алкилом.A compound of formula I. 1.3 '(i.e., a compound of formula I.1.3 in which Y is CN or optionally substituted 2- (3- or 4-) pyridyl, is prepared by alkylation of the same starting compounds of formula I.1.1a (t ie a compound of formula I.1.1, in which Y represents H) - by electrophilic V alkenes in the presence of a base catalyst, as, for example, described in the works of N. N. Kamzolova, N. F. Kucherova, V. A. Zagorevsky - Zhokh, 1964, v. 34, No. 7, pp. 2383-2387 and A.N. Kosta, M.A. Yurovskaya, T.V. Melnikova, O.I. Potanina - Auth. Of the USSR, 367094 (C 07 D) from 2.11.1970, according to the scheme:

In the formula, VY represents CN or 2-, 3- or 4-pyridyl, optionally mono- or disubstituted with lower alkyl.

 According to the scheme, the reaction is carried out using excess reagent V (in which Y is CN) at room temperature under the influence of a catalyst (such as a quaternary ammonium alcoholate) and leads to the formation of derivatives I. 1.3 '(i.e., compounds of formula I.1.3, where Y represents CN). The reaction for producing 2- [2- (3- or 4-) pyridyl] ethyl derivatives I.1.3 '(i.e., a compound of formula I.1.3 (in which Y is 2-, 3- or 4-pyridyl, optionally mono- or disubstituted with lower alkyl) is carried out using the equivalent of the corresponding reagent V and a suitable strong base (such as sodium, sodium hydride, sodium ethylate and the like), or in a polar aprotic solvent [such as DMF, DMSO, HMFTA (preferably in DMSO)].

Oxygen derivatives of formula I.1.3.4 (in which R ⁹ is OH or alkoxy) can be obtained by solvolysis of the corresponding nitrile of formula I. 1.3.3 in water or the corresponding alcohols under ordinary conditions, as, for example, described in the work of N. N. Kamzolova, N.F. Kucherova, V.A. Zagorevsky - Zhokh, 1964, v. 34, No. 7, pp. 2383-2387.

Hexahydro derivatives of formula I. 2 are prepared by reduction of a C _4a- C _9b double bond in 2-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indoles of formula I.1 or chemical modification prepared hexahydro derivatives by introducing a new or transformation of existing functional groups.

The reduction of the C _4a- C _9b double bond in 2-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indoles of the formula I.1 can be carried out using suitable reducing agents and can be selected selectively (depending from their type) to the cis isomers of substituted 2-methyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indoles of formula I.2 (see N.K. Kochetkov , N.F. Kucherova, I.G. Zhukova - ZhOKh, 1961, Vol. 31, No. 3, pp. 924-930 and N.F. Kucherova, N.M. Sipilina, N.N. Novikova, I. D. Silenko, S. G. Rozenberg, V. A. Zagorevsky - CHS, 1980, N 10, p. 1383-1386) or to the trans isomers of substituted 2-methyl-2,3,4,4a, 5,9b-hexahydro -1H-pyrido [4,3-b] indole forms Uly I.2 (see V.A. Zagorevsky, S.G. Rozenberg, N.M. Sipilina, L.U. Bykova, A.P. Rodionov - ZhVKhO, 1982, v. 27, No. 1, p. 102-104; and JG Berger - Synthesis, 1974, No. 7, pp. 508-510) regarding the C _4a- C _9b bond.

In particular, the cis isomers of I.2 are obtained by reduction of the tetrahydro derivatives of I.1 with zinc (and similar metals in a strongly acidic medium (for example, in hydrochloric acid and the like); or alkali metal borohydrides in anhydrous carboxylic acids (for example, in trifluoroacetic acid and the like ) at a temperature of 20-100 ^o C; while the trans-isomers of I.2 are obtained by treatment of complexes (1: 1) of borane with tetrahydro derivatives of formula I. 1 [obtained from the corresponding bases and a solution of borane (in situ or after preliminary highlight) or from the corresponding hydrochlorides and sodium borohydride in ether solvents] with mineral acids (for example, hydrochloric acid and the like) when heated.

В формуле VI M представляет Na, K; Z представляет O или S.N-unsubstituted 5-carbamoyl or 5-thiocarbamoyl hexahydro derivatives of formula I.2.1 '(i.e., compounds of formula I.2.1 in which R ⁵ is H) are prepared by the reaction of 5-unsubstituted 2-methyl-2,3 dihydrochlorides, 4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indoles of formula I. 2.3a (ie, compounds of formula I.2.3 in which Y represents H and k = 0) with cyanates or alkali metal rhodanides of formula VI according to the scheme:

In formula VI, M represents Na, K; Z represents O or S.

The reaction proceeds in water at a temperature of 80-100 ^o C.

 5-acyl- and 5- (N-substituted (thio) carbamoyl) -2- methyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indoles of the formula I.2.2 and I.2.1, respectively, are prepared by the reaction of 5-unsubstituted 2-methyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indoles of formula I. 2.3, in which Y represents H and k = 0, with acylating agents, respectively, anhydrides or halides of carboxylic acids and alkyl, cycloalkyl, or aryl-iso (thio) cyanates, as, for example, described in the work: N.K. Kochetkova, N.F. Kucherova, I.G. Zhukova - Zhokh, 1961, v. 31, No. 3, pp. 924-930.

В приведенных выше формулах k и l имеют значения, указанные при определении формулы I, при условии, что k+l ≥ 1; а Y' представляет хлор, бром или иод. В качестве примеров нуклеофильных реагентов можно привести: цианиды и алкоголяты щелочных и щелочноземельных металлов или тетраалкиламмония и амины - вторичные (HNR⁵R⁶) или третичные (Alk₃N, азины, азолы) в подходящем полярном растворителе (таком как бензол, ацетонитрил, спирт и аналогичные) или в избытке нуклеофильного реагента (VII) при температуре от 20^oC до температуры кипения реакционной смеси.5-α- (ω-) substituted alkanoyl) - hexahydro derivatives of formula I.2.2, in which Y represents a nucleophilic group (such as alkoxy, aryloxy, amino, cyano, N-azinium or N-azolium groups), obtained by the reaction nucleophilic substitution of halogen in 5 - (α- (ω -) - halogen substituted alkanoyl) -2-methyl-hexahydro-pyrido [4,3-b] indoles of formula I.2.2a (ie, compounds of formula I.2.2, in which Y represents halogen) under the action of various types of C, N and O-nucleophilic reagents (VII) (as, for example, described in the work of N.F. Kucherova, I.G. Zhukova, N.N. Kamzolova, M.I. .Pet uchenko, N.M.Sharkovoy, N.K.Kochetkova - ZHOH, 1961, 31 m, N 3, pp 930-936 according to the scheme:..

In the above formulas, k and l have the meanings indicated in the definition of formula I, provided that k + l ≥ 1; and Y 'represents chlorine, bromine or iodine. Examples of nucleophilic reagents include: cyanides and alkoxides of alkali and alkaline earth metals or tetraalkylammonium and amines — secondary (HNR ⁵ R ⁶ ) or tertiary (Alk ₃ N, azines, azoles) in a suitable polar solvent (such as benzene, acetonitrile, alcohol and similar) or in excess nucleophilic reagent (VII) at a temperature of from 20 ^o C to the boiling point of the reaction mixture.

где R¹, R², R³ и X имеют значения, указанные при определении формулы I, причем заместители R² и R³ должны быть свободны от способных к кватернизации функциональных групп (таких как 2-, 3- или 4-пиридильная, замещенная амино группа и аналогичные).The quaternary salts of tetrahydropyrido [4,3-b] indoles of formula I.3.1 can be obtained in two ways: by quaternization: 2-methyl-tetrahydropyrido [4,3-b] indoles of formula I.1 with an excess of the corresponding alkylating agent R ³ CH ₂ -X (formula IX) or 2-R ³ -CH ₂ -tetrahydro indoles (formula Q ₁ ) with Me-X reagent (formula VIII), as described in the work of M. Yurovskaya, L. I. Rodionov - HGS, 1981, N 8, p. 1072-1078, according to the scheme:

where R ¹ , R ² , R ³ and X have the meanings indicated in the definition of formula I, and the substituents R ² and R ³ should be free from quaternizable functional groups (such as 2-, 3- or 4-pyridyl, substituted amino group and the like).

 According to the scheme, the reaction proceeds in a solvent that dissolves the starting reagents well, but completely does not dissolve the quaternary salts formed (such as benzene, ether and the like) at room temperature.

 In the presence of a second nucleophilic center capable of quaternization in tetrahydro derivatives I.1 (for example, in 5- (2-pyridylalkyl) tetrahydro derivatives of formula I.1.3.2), quaternization can proceed nonselectively. During the creation of the present invention, the inventors have found a selective way to implement quaternization.

Accordingly, according to a further aspect of the invention, there is provided a method for producing selectively mono-quaternized quaternary salts of 5 - (ω-pyridylalkyl) -2-methyl-2-R ³ CH ₂ -2,3,4,5-tetrahydro-1H-pyrido [4,3-b ] indoles of formula I.3.1 '(ie, compounds of formula I.3.1 in which Y is 2-, 3- or 4-pyridyl, optionally mono- or disubstituted with lower alkyl) by alkylation of 5 - (ω-pyridylalkyl) bases of formula I.1.3a (i.e., compounds of formula I.1.3 in which Y is 2-, 3- or 4-pyridyl, optionally mono- or disubstituted with lower alkyl) is equivalent with a linear amount of an alkylating agent R ³ CH ₂ -X (formula IX in which R ³ and X have the meanings given above for formula I) in an inert solvent capable of dissolving the starting reagents, but completely not dissolving the resulting mono-quaternized quaternary salt (such as hexane, benzene, ether and the like), and the process is carried out at room temperature.

В приведенных выше формулах R¹, R³ и X имеют значения, определенные выше для формулы I, R^3' имеет значения, определенные выше для R³, R¹¹ представляет низший алкил, k представляет целое число от 1 до 4, t представляет 0, 1 или 2.Obtaining quaternary 5 - (ω-pyridylalkyl) -tetrahydro derivatives of formula I. 3.1 ″ (i.e., compounds of formula I.3.1, in which Y represents 1-R ^{3 ′} CH ₂ -pyridinium-2, -3, or - 4, optionally mono- or disubstituted with lower alkyl) is possible in two ways: either by diquaternization of the corresponding bases of formula I.1.3a under the action of a 3-5-fold molar excess of the alkylating agent R ³ CH ₂ -X (formula IX), or by further alkylation of mono-quaternized derivatives of formula I.3.1 'under the action of a 3-5-fold molar excess of an alkylating agent R ³ CH ₂ X (ph formula IX), or R ³ CH ₂ X (formula IX '), in the latter case, an asymmetrically quaternized derivative of I. 3.1''is formed (when R ^3' and R ³ are different). In general, quaternization processes are presented in the following diagram:

In the above formulas, R ¹ , R ³ and X have the meanings given above for formula I, R ^{3 '} has the meanings given above for R ³ , R ¹¹ represents lower alkyl, k represents an integer from 1 to 4, t represents 0 , 1 or 2.

пиридилалкильных соединений формулы I.3.1.2 под действием 3-5-кратного избытка кватернизующего агента R³CH₂-X (IX) в полярном растворителе, по крайней мере частично растворяющем монокватернизованную соль (таком, например, как ацетонитрил, метанол и аналогичные), при температуре 20^oC до температуры кипения реакционной смеси.2-methyl-2-R ³ CH ₂ -5- (ω- (1-R ³ CH ₂ - pyridinium) alkyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indolium salts of formula I.3.1.3 (in which Y is 1-R ³ CH ₂ -pyridinium-2, -3 or -4) are selectively obtained by 5- (

pyridylalkyl compounds of formula I.3.1.2 under the action of a 3-5-fold excess of a quaternizing agent R ³ CH ₂ -X (IX) in a polar solvent that at least partially dissolves the mono-quaternized salt (such as, for example, acetonitrile, methanol and the like) at a temperature of 20 ^o C to the boiling point of the reaction mixture.

в которой R¹, R³ и X определены выше для формулы I.3.1, R² представляет - (CH₂)₂-CN, (CH₂)₂-COOAlk, -CONHR⁵, -COR¹², E представляет реагент формулы CH₂= CH-CN, CH₂=CH-COOAlk, R⁵-N=C=O (где R⁵ представляет алкил, циклоалкил, арил), R¹²-CO-X' (где R¹² представляет алкил или алкокси группу, X' представляет галоген или -O-COR¹²).Another method according to the invention provides for the preparation of quaternary salts of 5-substituted 2-methyl-2-R ³ CH ₂ -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indoles (with a quaternized nitrogen atom in position 2) of the general formula I.3.1 (in which R ² represents - (CH ₂ ) ₂ —CN, - (CH ₂ ) ₂ —COOAlk, —CONHR ⁵ (where R ⁵ represents alkyl, cycloalkyl, aryl), COR ¹² ( where R ¹² represents an alkyl or alkoxy group)). This method is carried out by the reaction of 5-unsubstituted derivatives of formula I.3.1.1a (i.e., compounds of formula I.3.1.1 in which Y represents H) with electrophilic alkylating or acylating reagents E in the presence of a catalyst (non-nucleophilic base) according to scheme:

in which R ¹ , R ³ and X are defined above for formula I.3.1, R ² is - (CH ₂ ) ₂ —CN, (CH ₂ ) ₂ —COOAlk, —CONHR ⁵ , —COR ¹² , E is a reagent of formula CH ₂ = CH-CN, CH ₂ = CH-COOAlk, R ⁵ -N = C = O (where R ⁵ represents alkyl, cycloalkyl, aryl), R ¹² -CO-X '(where R ¹² represents an alkyl or alkoxy group, X 'is halogen or —O — COR ¹² ).

For the preparation of 5- (2-substituted-ethyl) -2-methyl-2-R ³ CH ₂ -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole salts of formula I.3.1 (in which R ² represents - (CH ₂ ) ₂ —CN or - (CH ₂ ) ₂ —COOAlk, according to the method of the invention according to the above scheme, 5-unsubstituted 2-methyl-2-R ³ CH ₂ -2,3,4,5-tetrahydro 1H-pyrido [4,3-b] indolium salts of formula I.3.1.1a are reacted with activated olefins, taken in excess, in the presence of 0.5-5 mol.% Non-nucleophilic base (such as a highly basic sterically hindered tertiary amine for example ethyldiisopropylamine, DBU (1,8-diazabicyclo [5.4.0] undecene-7), 1,2, 2,6,6-pentamethylpiperidine and others) at a temperature of from 20 ^o C to the boiling point of the reaction mixture.

5- (NR ⁵ carbamoyl) -2- methyl-2-R ³ CH ₂ -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole salts of formula I. 3.1 [in which R ² represents CONHR ⁵ (where R ⁵ represents alkyl, cycloalkyl, aryl)] are obtained in a similar manner by the reaction of 5-unsubstituted 2-methyl-2-R ³ CH ₂ -2,3,4,5-tetrahydro-1H-pyrido [4 , 3-b] indole salts of formula I. 3.1.1a with isocyanates R ⁵ -N = C = O (where R ⁵ is alkyl, cycloalkyl, aryl) taken in excess at a temperature of from 20 ^o C to the boiling point of the reaction mixture in the presence of 0.5-5 mol.% of the above non-nucleophilic base as a catalyst.

When carrying out the process of the invention using carboxylic acid derivatives — anhydrides or halides as acylating reagents E — tertiary amines or salts of the corresponding carboxylic acids with alkali metals (for example, sodium or potassium) are used as catalysts. In the reaction with anhydrides, 5-acyl substituted 2-methyl-2-R ³ CH ₂ -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole salts of the formula I.3.1.4 are formed . The reaction is carried out in excess of reagent in the presence of a molar equivalent (with respect to the starting salt) of the catalyst in order to bind the acid HX ′ liberated in the reaction.

Реакция проводится в подходящих полярных растворителях (таких, как пиридин, ДМФА, ГМФТА и аналогичные, предпочтительнее в пиридине) с использованием в качестве ненуклеофильных оснований высокоосновных стерических затрудненных третичных аминов (таких, как этилдиизопропиламин, 1,2,2,6,6-пентаметилпиперидин, DBU и аналогичные) в количестве 0,5 моль эквивалента при температуре 50-150^oC или при температуре кипения реакционной смеси.According to a further aspect of the invention, there is provided a process for the preparation of 2-methyl-2-R ³ CH ₂ -8-R ¹ -5- (5-R ¹ -2- R ³ CH ₂ NMe- (CH ₂ ) ₂ -indolyl-3-methyl ) - 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indolium salts of the formula I.3.1 ″ (i.e., a compound of the formula I.3.1 in which R ² is ⁵ -R ¹ -2-R ³ CH ₂ NMe- (CH ₂ ) _2- indolyl-3-methyl-). This method involves the reaction of 5-unsubstituted 2-methyl-2-R ³ CH ₂ - 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole salts of formula I. 3.1.1a (i.e. Compounds of formula I.3.1.21, in which Y represents H) with non-nucleophilic bases when heated according to the scheme:

The reaction is carried out in suitable polar solvents (such as pyridine, DMF, GMFTA and the like, preferably pyridine) using highly basic steric hindered tertiary amines (such as ethyldiisopropylamine, 1,2,2,6,6-pentamethylpiperidine as non-nucleophilic bases) , DBU and the like) in an amount of 0.5 mol equivalent at a temperature of 50-150 ^o C or at the boiling point of the reaction mixture.

где R¹, R², R³ и X имеют значения, определенные выше для формулы I.3.2.The quaternary salts of 5-substituted hexahydro-1H-pyrido [4,3-b] indoles according to the invention of formula I.3.2 (in which R ² is an acceptor substituent) are obtained using a similar method for preparing the corresponding tetrahydro derivatives. This method involves the quaternization of the corresponding bases of 5-substituted 2-methyl-hexahydro-1H-pyrido [4,3-b] indoles (formula I. 3.2) or 5-substituted 2-R ³ CH ₂ - hexahydro-pyrido [4,3 -b] indoles (formula Q ₂ ) with an excess of the corresponding alkylating agent — R ³ CH ₂ -X (formula IX) or Me-X (formula VIII) according to the scheme:

where R ¹ , R ² , R ³ and X have the meanings defined above for formula I.3.2.

 The reaction is carried out in a suitable inert solvent (such as acetonitrile, benzene, ether and the like) at a temperature from room temperature to the boiling point of the reaction mixture.

 The pyrido [4,3-b] indole derivatives used as starting materials in most cases are readily prepared by methods known in the literature. Other starting reagents are commercially available and are manufactured primarily by Aldrich Chemical Co.

Below the invention is described in more detail using examples of the preparation of specific compounds. The structures of the obtained compounds were confirmed by chemical, spectral analysis and other physicochemical characteristics; melting points are not fixed. PMR spectra were recorded on a Brucker CXP-200 instrument (200 MHz). The multiplicities of the observed signals are indicated in abbreviated form: (s) - singlet, (e) - doublet, (t) - triplet, (k) - quadruplet and (m) - multiplet. For a number of compounds, the molecular weight was determined from the peak of the molecular ion (M ⁺ ) in the mass spectrum. Mass spectra were obtained on a Varian-311 instrument with direct sample input.

 The following examples illustrate but do not limit the invention.

 Example 1

)₂CH, J = 7 Гц), 2,40 (3H, с, NCH₃), 2,74 (4H, м, 3- и 4-CH₂); 2,88 (1H, септет, (CH₃)₂C

J = 7 Гц), 3,50 (2H, с, 1-CH₂), 6,92 (1H, д, 6-H, J = 7 Гц), 7,10 (1H, с, 9-H), 7,20 (1H, д, 7-H, J = 7 Гц), 10,17 (1H, с, NH).2-Methyl-8-isopropyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride (compound 1):
A mixture of 0.19 g (1 mmol) of 4-isopropylphenylhydrazine hydrochloride and 0.12 ml (1 mmol) of N-methylpiperidone-4 in 3 ml of alcohol is boiled for 1 hour, 2 ml of alcohol saturated with hydrogen chloride is added and boiled in for 2 hours, cooled to 0 ^o C, the precipitate is filtered off, washed with a minimum volume of cold water, crystallized from aqueous alcohol. The yield of hydrochloride (1) - 0.20 g (75%), so pl. 200 - 202 ^o C. By alkalizing it with an aqueous solution of 1N sodium hydroxide to a pH of 8-10 receive a free base. Recrystallized from aqueous alcohol. Mp 171 - 173 ^o C. Found,%: C 78.63; H 9.25; N, 12.07. C ₁₅ H ₂₀ N ₂ . Calculated,%: C 78.92; H 8.81; N, 12.27. PMR spectrum (CD ₃ CN + DMSO-d ₆ , ppm, δ): 1.23 (6H, d, (C

) ₂ CH, J = 7 Hz), 2.40 (3H, s, NCH ₃ ), 2.74 (4H, m, 3- and 4-CH ₂ ); 2.88 (1H, septet, (CH ₃ ) ₂ C

J = 7 Hz), 3.50 (2H, s, 1-CH ₂ ), 6.92 (1H, d, 6-H, J = 7 Hz), 7.10 (1H, s, 9-H) 7.20 (1H, d, 7-H, J = 7 Hz); 10.17 (1H, s, NH).

 Example 2

2,8-Dimethyl-5- (2,4-dimethylbenzyl) - 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride (compound 2):
To a suspension of 0.48 g (20 mmol) of sodium hydride in 6 ml of DMF was added dropwise a solution of 2 g (10 mmol) of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3- b] indole in 10 ml of DMF for 30 minutes A solution of 1.65 g (11 mmol) of 2,4-dimethylbenzyl chloride in 10 ml of DMF is then added. The mixture was stirred for 30 minutes at 80 ^° C. After completion of the reaction, DMF was distilled off in vacuo. The residue was extracted with ether (3 x 50 ml), the ether extracts were combined, washed with water, dried over sodium sulfate. The ether was evaporated, the remaining oil was dissolved in alcohol and converted to hydrochloride 2, adding alcohol saturated with hydrogen chloride and evaporated in vacuo. The precipitated salt is recrystallized from absolute alcohol, so pl. 240 ^o C. The yield of base is 1.42 g (40%). Found,%: N 8.20. C ₂₂ H ₂₆ N ₂ • HCl. Calculated,%: N 7.89. PMR spectrum ((CD ₃ ) ₂ CO, ppm, δ): 2.23; 2.34, 2.40 and 2.46 (12H, 4c, 2-, 8-, 2'- and 4'-CH ₃ ); 2.69 (4H, m, 3-CH ₂ and 4-CH ₂ ), 3.61 (2H, s, 1-CH ₂ ), 5.17 (2H, s, 5-CH ₂ ), 6.08 -7.20 (6H, m, 6-, 7-, 9-, 3'-, 5'- and 6'-H).

The following method was obtained:
2,8-Dimethyl-5- (2-diethylaminoethyl) - 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole dihydrochloride (compound 3):
Yield 73%, mp. 205 - 207 ^o C.

2,8-Dimethyl-5- (2-piperidinoethyl) - 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole dihydrochloride (compound 4):
Yield 54%, mp. 264 - 265 ^o C.

2,8-Dimethyl-5- (2-hexamethyleneiminoethyl) - 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole dihydrochloride (compound 5):
Yield 47%, mp. 206 - 207 ^o C.

2,8-Dimethyl-5- (2-dibenzylaminoethyl) - 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole dihydrochloride (compound 6):
Yield 71%, mp. 218 - 219 ^o C.

 Example 3

2,8-Dimethyl-5- (2-cyanoethyl) - 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole (compound 7):
To a solution of 5 g (25 mmol) of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole in 25 ml of acrylonitrile is slowly added with stirring, 1.25 ml of the solution obtained by mixing solutions of 1.037 g (4 mmol) of trimethylphenylammonium besolnosulfonate in 3 ml of ethanol and 0.092 g (4 mmol) of sodium in 2 ml of ethanol and filtering. One hour after the end of the exothermic reaction, the acrylonitrile was evaporated, the residue was filtered off and washed with ether. Yield 5.21 g (67%), mp. 127 - 128 ^o C (from heptane). Found: M ⁺ 253. C ₁₆ H ₁₉ N ₃ . Calculated: M ⁺ 253. IR spectrum: ν = 2260 cm ^-1 (C ≡ N). 1 H-NMR spectrum (CD ₃ CN, ppm, δ): 2.33 (6H, s, 2- and 8-CH ₃ ), 2.45 and 2.60 (4H, 2m, 3- and 4-CH ₂ ), 2.83 (2H, t, β-CH ₂ , J = 7 Hz), 3.48 (2H, s, 1-CH ₂ ), 4.20 (2H, t, α-CH ₂ , J = 7 Hz), 6.95 - 7.37 (3H, m, 6-, 7- and 9-H).

 Example 4

2,8-Dimethyl-5- (2-carboxyethyl) - 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride (compound 8):
A mixture of 0.93 g (3.6 mmol) of nitrile 7 and 40 ml of a 15% alcohol solution of sodium hydroxide is boiled for 5 hours. The alcohol is distilled off in vacuo, the residue is acidified with hydrochloric acid to pH 1 and evaporated in vacuo until crystallization begins. The precipitate was filtered off and recrystallized from alcohol. Yield 1 g (89%), mp. 170 - 171 ^o C. found,%: C 59.88; H 6.62; N, 8.48. C ₁₆ H ₂₀ N ₂ O ₂ • HCl • 0.75H ₂ O. Calculated,%: C 59.96; H 7.05; N, 8.71. 1 H-NMR spectrum (Py-d ₅ , ppm, δ): 2.40 (3H, s, 8-CH ₃ ), 2.94 (5H, m, 2-CH ₃ , 4-CH ₂ ), 3.44 (4H, m, β-CH ₂ , 3-CH ₂ ), 4.40 (4H, m, 1-CH ₂ , α-CH ₂ ), 7.00 (3H, m, 6-, 7- and 9-H).

 Example 5

CH₂, J = 7 Гц), 2,40 (3H, с, 8-CH₃), 2,54 (3H, с, 2-CH₃), 2,70 (2H, т, β-CH₂, J = 8 Гц), 2,86 (4H, м, 3- и 4-CH₂), 3,62 (2H, с, 1-CH₂), 4,10 (2H, к, CH₃

, J = 7 Гц), 4,30 (2H, т, α-CH₂, J = 8 Гц), 6,97 (1H, д, 6-H, J = 8 Гц), 7,16 (1H, д, 7-H, J = 8 Гц), 7,18 (1H, с, 9-H).2,8-Dimethyl-5- (2-carbethoxyethyl) - 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride (compound 9):
3.6 g (14 mmol) of nitrile 7 are refluxed with an excess of ethanol saturated with hydrogen chloride for 6 hours. The alcohol is evaporated, the residue is recrystallized from absolute alcohol. Yield 2.4 g (80%), mp. 184 - 186 ^o C. Found,%: C 63.89; H 7.86; N, 8.31. C ₁₈ H ₂₄ ClN ₂ O ₂ • HCl. Calculated,%: C 64.17; H 7.75; N, 8.32. IR spectrum: ν = 1200 (CO), 1728 (C = O) cm ^-1 . PMR spectrum of the base (CDCl ₃ , ppm, δ): 1.20 (3H, t,

CH ₂ , J = 7 Hz), 2.40 (3H, s, 8-CH ₃ ), 2.54 (3H, s, 2-CH ₃ ), 2.70 (2H, t, β-CH ₂ , J = 8 Hz), 2.86 (4H, m, 3- and 4-CH ₂ ), 3.62 (2H, s, 1-CH ₂ ), 4.10 (2H, q, CH ₃

, J = 7 Hz), 4.30 (2H, t, α-CH ₂ , J = 8 Hz), 6.97 (1H, d, 6-H, J = 8 Hz), 7.16 (1H, d, 7-H, J = 8 Hz), 7.18 (1H, s, 9-H).

 Example 6

2,8-Dimethyl-2- (4-N-phthalimidobutyl) - 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indolium bromide (compound 10):
In 10 ml of benzene, 0.4 g (2 mmol) of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole and 1.13 g (4 mmol) are dissolved with stirring ) N- (4-bromobutyl) phthalimide. After 5 days, the precipitate is filtered off, washed with benzene and recrystallized from alcohol. Yield 1.02 g (67%), mp. 236 - 238 ^o C. Found,%: C 62.35; H 5.87. C ₂₅ H ₂₈ BrN ₃ O ₂ . Calculated,%: C 61.97; H 5.90. PMR spectrum (DMSO-d ₆ , ppm, δ): 1.65 (2H, m, γ-CH ₂ ); 1.93 (2H, m, β-CH ₂ ); 2.35 (3H, s, 8-CH ₃ ); 3.10 (3H, s, 2-CH ₃ ); 3.17 (2H, m, 4-CH ₂ ); 3.48 (2H, m, δ-CH ₂ ); 3.65 and 3.80 (4H, 2m, α-CH ₂ and 3-CH ₂ ); 4.66 (2H, s, 1-CH ₂ ); 6.93 (1H, d, 7-H, J = 8 Hz); 7.17 (1H, s, 9-H); 7.25 (1H, d, J = 8 Hz, 6-H); 8.80 (4H, s, phthalimide); 10.03 (1H, s, NH).

 Example 7

2,2-Dimethyl-5 [2- (6-methyl-3-pyridyl) ethyl] - 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indolium iodide (compound 11):
A mixture of 0.5 g (1.63 mmol) of 2-methyl-5- [2- (6-methyl-3-pyridyl) ethyl] - 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole and 0.1 ml (1.63 mmol) of methyl iodide in 10 ml of benzene are left for a day, the precipitate is filtered off, washed with benzene and recrystallized from alcohol. Dried in a vacuum. Yield 0.61 g (85%), mp. 200 - 201 ^o C. Found,%: C 56.27; H 5.93. C ₂₁ H ₂₆ IN ₃ . Calculated,%: C 56.36; H 5.86. 1 H-NMR spectrum (DMSO-d ₆ , ppm δ): 2.38 (3H, s, 6'-CH ₃ ), 2.80 (2H, t, 4-CH ₂ , J = 4 Hz), 3 00 (2H, t, β-CH ₂ , J = 6 Hz), 3.13 (6H, s, N (CH ₃ ) ₂ ), 3.70 (2H, t, 3-CH ₂ , J = 4 Hz), 4.33 (2H, t, α-CH ₂ , J = 6 Hz), 4.70 (2H, s, 1-CH ₂ ), 7.00 - 7.24 (4H, m, 6- 7-, 8- and 9-H), 7.41 (1H, dd, 4'-H, J = 8 Hz, J = 2 Hz), 7.53 (1H, d, 5'-H, J = 8 Hz), 8.00 (1H, d, 2'-H, J = 2 Hz).

 Example 8

2,2-Dimethyl-5- [2- (1,6-dimethyl-3-pyridinium) ethyl] 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indolium diiodide (compound 12 ):
A solution of 0.306 g (1 mmol) of 2-methyl-5- [2- (6-methyl-3-pyridyl) ethyl] -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole and 0.2 ml (3.2 mmol) of methyl iodide in 10 ml of methanol is boiled for 5 hours, the precipitate is filtered off, washed with methanol and crystallized from acetonitrile. Yield 0.56 g (95%), mp. 307-309 ^o C. Found,%: C 44.89; H 5.10. C ₂₂ H ₂₆ I ₂ N ₃ . Calculated,%: C 44.82; H 4.96. PMR spectrum (DMSO - d ₆ , ppm, δ): 2.72 (3H, s, 6'-CH ₃ ), 3.16 (4H, m, 4- and β-CH ₂ ), 3, 24 (6H, s, N (CH ₃ ) ₂ ), 3.85 (2H, t, 3-CH ₂ ), J = 6 Hz), 4.18 (3H, s, 1'-CH ₃ ), 4 41 (2H, t, α-CH ₂ , J = 7 Hz), 4.75 (2H, s, 1-CH ₂ ), 7.00 - 7.10 (2H, m, 7- and 8-H ), 7.44 (1H, d, 9-H, J = 8 Hz), 7.58 (1H, d, 6-H, J = 8 Hz), 7.96 (1H, d, 4'-H , J = 8 Hz), 8.30 (1H, d, 5'-H, J = 8 Hz), 9.05 (1H, s, 2'-H).

A similar method was obtained:
2,2,8-Trimethyl-5- [2- (1,6-dimethyl-3-pyridinium) ethyl] - 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indolium diiodide ( connection 13):
Yield 90%, mp. 306 - 307 ^o C.

 Example 9

2-Methyl-2- (4-bromophenacyl) -5- [2- (6-methyl-3-pyridinyl) ethyl] 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indolium bromide (compound 14):
To 0.61 g (2 mmol) 2-methyl-5- (2- (6-methyl-3-pyridyl) ethyl] - 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole in 5 ml of benzene is added dropwise with stirring a solution of 0.56 g (2 mmol) of p-bromophenacyl bromide in 3 ml of benzene, after 10 hours the precipitate is filtered off, washed with benzene and recrystallized from acetonitrile. Yield 1.08 g (93%), t. mp 177 - 178 ^o C. found,%: C 57.69; H 5.00. C ₂₈ H ₂₉ Br ₂ N ₃ O. Calculated,%: C 57.82; H 5.03. PMR spectrum (DMSO - d ₆ , ppm, δ): 2.30 (3H, s, 6'-CH ₃ ), 2.99 (4H, m, 4- and β-CH ₂ ), 3.33 (3H, s, NCH ₃ ), 3.90 - 4.42 (4H, m, 3- and α-CH ₂ ), 4.97 and 5.08 (2H, 2d, 1-CH ₂ or NCH ₂ CO, J = 14 Hz), 5.38 and 5.56 (2H, 2d, NCH ₂ CO or 1-CH ₂ , J = 16 Hz), 7.00 - 7.40 (4H, m, 6-, 7-, 8 - and 9-H), 7.42 (1H, dd, 4'-H, j = 8 Hz, J = 2Hz), 7.50 (1H, d, 5'-H, J = 8 Hz), 7.78 (1H, d, 2 meta-H, J = 8 Hz), 7.98 (1H, d, 2 ortho-H, J = 8 Hz), 8.12 (1H, s, 2'-H).

A similar method was obtained:
2,8-Dimethyl-2-phenacyl-5- [2- (6-methyl-3-pyridinyl) ethyl] - 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indolium bromide ( connection 15):
Yield 80%, mp. 155 - 160 ^o C.

 Example 10

2,2,8-Trimethyl-5- (2-cyanoethyl) - 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indolium iodide (compound 16):
Method a
To a stirred mixture of 0.1 g (0.3 mmol) of 2,2,8-trimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indolium iodide and 3 ml of acrylonitrile, ≈ 0 , 01 g of 1,8-diazabicyclo [5.4.0] undecene-7 (DBU), as a result of which the salt precipitate dissolves. Salt is added to the resulting solution in 0.1 g portions until dissolution stops [total 0.79 g (2 mmol)], the mixture is heated to 40 ^° C. and 15 ml of dry ether are added dropwise with stirring. The precipitate was filtered off, washed with ether and crystallized from ethanol. Yield 0.65 g (83%), mp. 284 - 286 ^o C. Found,%: C 51.46; H 5.43; N, 10.3. C ₁₇ H ₂₁ IN ₃ . Calculated,%: C 51.65; H 5.32; N, 10.63. PMR spectrum (DMF-d ₇ , δ): 2.38 (3H, s, 8-CH ₃ ); 3.16 (2H, t, β-CH ₂ ); 3.50 [6H, s, N (CH ₃ ) ₂ ]; 3.56 (2H, m, 4-CH ₂ ); 4.20 (2H, m, 3-CH ₂ ); 4.70
(2H, t, α-CH ₂ , J = 7 Hz); 5.00 (2H, s, 1-CH ₂ ); 7.08 (1H, d, 7-H, J = 9 Hz), 7.29 (1H, s, 9-H), 7.63 (1H, d, 6-H, J = 9 Hz).

Method B
To a solution of 0.253 g (1 mmol) of nitrile 7 in 2 ml of acetone, 0.12 ml (2 mmol) of methyl iodide was added with stirring, after a day the precipitate was filtered off, washed with acetone, recrystallized from alcohol, dried in vacuo. Yield 0.358 g (90%), mp. 284 - 286 ^o C.

 The product is identical to the compound obtained according to method A.

Similarly, using method A, we obtained:
2,2,8-Trimethyl-5- (2-carbethoxyethyl) - 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indolium iodide (compound 17):
Yield 23%, mp. 196 - 198 ^o C.

 Example 11

-N), 5,50 (2H, с, 1-СH₂), 6,84 (1H, д, 6'-H, J = 8 Гц), 6,90 (1H, с, 4'-H), 7,02 (1H, д, 7'-H, J = 8 Гц), 7,26 (1H, д, 7-H, J = 8 Гц), 7,31 (1H, с, 9-H), 7,52 (1H, д, 6-H, J = 8 Гц), 10,96 (1H, с, NH).2,2,8-Trimethyl-5- [5-methyl-2- (2-N, N-dimethylaminoethyl) indolyl-3-methyl] -2,3,4,5-tetrahydro-1H-pyrido [4.3 -b] indolium iodide (compound 18):
A mixture of 0.684 g (2 mmol) of 2,2,8-trimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indolium iodide and 0.15 ml (1 mmol) of DBU in 3 ml of pyridine is heated with stirring at 80 - 100 ^o C until dissolved, and the procedure is continued for another 30 minutes, the mixture is cooled, evaporated in vacuo, the product is washed with cold water, filtered and crystallized twice from water. Yield 0.166 g (30%), mp. 228 - 230 ^o C (decomp.). Found,%: C 60.20; H 6.81; N, 9.89. C ₂₈ H ₃₇ IN ₄ . Calculated,%: C 60.43; H 6.65; N, 10.07. PMR spectrum (DMF-d ₇ , ppm, δ): 2.18 and 2.36 (6H, 2s, 8-CH ₃ and 6'-CH ₃ ), 2.43 (2H, t, 4- CH ₂ , J = 7 Hz), 2.90 (2H, t, α-CH ₂ , J = 7 Hz), 3.23 (2H, t, 3-CH ₂ , J = 7 Hz), 3.42 (6H, s, N (CH ₃ ) ₂ ), 3.60 (6H, s, N (CH ₃ ) ₂ ), 4.00 (2H, t, β-CH ₂ , J = 7 Hz), 4, 95 (2H, s, Ind-C

-N), 5.50 (2H, s, 1-CH ₂ ), 6.84 (1H, d, 6'-H, J = 8 Hz), 6.90 (1H, s, 4'-H) 7.02 (1H, d, 7'-H, J = 8 Hz), 7.26 (1H, d, 7-H, J = 8 Hz), 7.31 (1H, s, 9-H) 7.52 (1H, d, 6-H, J = 8 Hz); 10.96 (1H, s, NH).

 Example 12

2,2,8-Trimethyl-5-N-methylcarbamoyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indolium iodide (compound 19):
To a stirred mixture of 0.342 g (1 mmol) of 2,2,8-trimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indolium iodide and 3 ml of methyl isocyanate add 1 drop of DBU, carefully heat before dissolving the salt. The excess methyl isocyanate was evaporated in vacuo, the residue was washed with ether, and crystallized from acetonitrile. Yield 0.3 g (75%), mp. 174 - 175 ^o C. Found,%: C 48.05; H 5.40; N, 10.33. C ₁₆ H ₂₂ IN ₃ O. Calculated,%: C 48.21; H 5.56; N, 10.53. PMR spectrum (DMSO-d ₆ , ppm, δ): 2.23 (3H, s, 8-CH ₃ ), 2.74 (3H, s, NCH ₃ ), 3.06 (2H, m, 4-CH ₂ ), 3.13 (6H, s, N (CH ₃ ) ₂ ), 3.67 (2H, m, 3-CH ₂ ), 4.64 (2H, s, 1-CH ₂ ), 7.00 (1H, d, 7-H, J = 8 Hz), 7.14 (1H, s, 9-H), 7.50 (1H, d, 6-H, J = 8 Hz), 7 88 (1H, br.s. NH).

 Example 13

cis ((±)) - 2,8-Dimethyl-5-carbamoyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole (compound 20):
To a solution of 0.55 g (2 mmol) of cis dihydrochloride ((±)) 2,8-dimethyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole in 2 ml of hot water is added with stirring 0.2 g (2.5 mmol) of potassium cyanate. The mixture foams, the solution becomes clear. Another 0.08 g (1 mmol) of potassium cyanate is added, the solution becomes cloudy, a precipitate forms upon cooling, and the mixture thickens. The precipitate is filtered off, washed with water, crystallized from alcohol. Yield 0.325 g (72%), mp 116 - 117 ^o C. Found: M ⁺ 249. C ₁₄ H ₁₉ N ₃ O. Calculated: M ⁺ 249. PMR spectrum ((CD ₃ ) ₂ CO + CDCl ₃ , ppm, δ): 1.55 and 1.90 (2H, 2m, 4-CH ₂ ), 2.23 and 2.28 (6H, 2s, 2- and 8-CH ₃ ), 2.40 (2H, m, 3-CH ₂ ), 2.69 and 3.42 (3H, 2m, 1-CH ₂ , 9b-H), 4.30 (1H, m, 4a-H), 5.64 (2H, s, NH ₂ ), 6.89 (1H, d, 7-H, J = 8 Hz), 7.01 (1H, s, 9-H), 7.61 (1H, d, 6-H, J = 8 Hz).

Using a similar technique, we obtained:
cis ((±)) 2,8-Dimethyl-5-thiocarbamoyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole (compound 21):
Yield 64%, mp. 156 - 158 ^o C (from acetonitrile).

Example 14
cis ((±)) 2,8-Dimethyl-5-phenylthiocarbamoyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole (compound 22):
To a solution of 2.63 g (13 mmol) cis ((±)) - 2,8-dimethyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole in 20 ml of absolute ether, 2 ml (1.76 g, 13 mmol) of phenylisothiocyanate are added dropwise with stirring. After 30 minutes, the precipitated crystals are filtered off, washed with ether. Yield 4.65 g (86%), mp. 168 - 169 ^o C. Found: M ⁺ 341. C ₂₀ H ₂₃ N ₃ S. Calculated: M ⁺ 341. IR spectrum: ν = 1475 (C = S), 3270 (NH) cm ^-1 . 1 H-NMR spectrum (CDCl ₃ , ppm, δ): 1.60 and 1.97 (2H, 2m, 4-CH ₃ ), 2.30 and 2.32 (6H, 2s, 2- and 8-CH ₃ ), 2.38 - 2.78 and 3.32 - 3.54 (5H, 2m, 3- and 1-CH ₂ , 9b-H), 5.20 (1H, m, 4a-H), 6 99 (1H, d, 7-H, J = 8 Hz), 7.12 - 7.50 (7H, m, 6- and 9-H, C ₆ H ₅ ), 7.80 (1H, s, NH).

The following method was obtained:
cis (±) -2,8-dimethyl-5-cyclohexylthiocarbamoyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole (compound 23):
Yield 89%, mp. 165 - 166 ^o C.

cis (±) -2,8-dimethyl-5-n-butylcarbamoyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole (compound 24):
Yield 88%, mp. 157 - 158 ^o C.

cis (±) -2,8-dimethyl-5-phenylcarbamoyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole (compound 25):
Yield 93%, mp. 204 - 205 ^o C.

cis (±) -2,8-dimethyl-5-N-benzenecarbamoyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole (compound 26):
Yield 96%, mp. 230 - 233 ^o C.

Example 15
cis (±) -2,8-dimethyl-5-trifluoroacetyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole (compound 27):
To a solution of 0.202 g (1 mmol) cis (±) -2,8-dimethyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole (base) in 2 ml with methylene chloride, 0.23 g (0.15 ml; 1.1 mmol) of trifluoroacetic anhydride are added dropwise with stirring. The solvent is slowly evaporated at 60 - 70 ^o C. After cooling, add 1 ml of water, triturated to form a precipitate. The precipitate is filtered off, washed with water and dried. Yield 0.237 g (90%), mp. 162 - 164 ^o C. Found,%: C 74.87; H 7.31; N, 12.35. C ₁₅ H ₁₇ F ₃ N ₂ O. Calculated,%: C 60.38; H 5.75; N, 9.39. 1H-NMR spectrum (CDCl ₃ , ppm, δ): 1.60 - 2.56 (4H, m, 3-CH ₂ , 4-CH ₂ ), 2.32 and 2.38 (6H, 2s, 2 - and 8-CH ₃ ), 2.75 (1H, m, 9b-H), 3.46 (2H, m, 1-CH ₂ ), 4.56 (1H, m, 4a-H), 7, 06 (1H, d, 7-H, J = 5 Hz), 7.12 (1H, s, 9-H), 7.93 (1H, d, 6-H, J = 5 Hz).

 Example 16

cis (±) -2,8-dimethyl-5- (2-bromobenzoyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole hydrochloride (compound 28):
To a solution of 0.202 g (1 mmol) cis (±) -2,8-dimethyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole (base) in 2 ml methylene chloride is added with stirring 0.24 g (1.1 mmol) of 2-bromobenzoyl chloride. The solvent was evaporated in vacuo, the solid residue was washed with ether. Yield 0.37 g (95%), mp. 190 - 192 ^o C. Found,%: C 56.72; H 5.41; N, 6.55. C ₂₀ H ₂₁ BrN ₂ O • HCl. Calculated,%: C 57.13; H 5.28; N, 6.67. 1 H-NMR spectrum (CDCl ₃ , ppm, δ): 2.8 - 3.2 (4H, m, 3-CH ₂ , 4-CH ₂ ), 2.28 (6H, 2s, 2- and 8- CH ₃ ), 4.00 and 5.60 (4H, 2m, 1-CH ₂ , 4a-H, 9b-H), 6.7 - 7.8 (7H, m, C ₆ H ₅ ).

The following method was obtained:
cis (±) -2,8-dimethyl-5- (2-methylbenzoyl) - 2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole hydrochloride (compound 29):
Yield 93%, mp. 241 - 243 ^o C.

cis (±) -2,8-dimethyl-5- (3,4,5-trimethoxybenzoyl) - 2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole hydrochloride ( connection 30):
Yield 89%, mp. 182 - 184 ^o C.

cis (±) -2,8-dimethyl-5- (1-naphthylacetyl) - 2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole hydrochloride (compound 31):
Yield 81%, mp. 191 - 193 ^o C.

cis (±) -2,8-dimethyl-5-methylsulfonyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole hydrochloride (compound 32):
Yield 85%, mp. 216 - 217 ^o C.

cis (±) -2,8-dimethyl-5- (2-nitrophenylsulfonyl) - 2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole hydrochloride (compound 33):
Yield 88%, mp. 222 - 224 ^o C.

cis (±) -2,8-dimethyl-5- (3-pyridylsulfonyl) - 2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole hydrochloride (compound 34):
Yield 92%, mp. 239 - 241 ^o C.

CH₃), 7,12 (1H, д, 7-H, J = 8 Гц), 7.43 (1H, с, 9-H), 7,90 (1H, д, 6-H, J = 8 Гц), 9,38 (1H, с, NH).Example 17
cis (±) -2,8-dimethyl-5- (2-bromopropionyl) - 2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole hydrochloride (compound 35):
To a solution of 6.4 g (32 mol) cis (±) -2,8-dimethyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole (base) in 50 ml of absolute benzene, while cooling to 0 ^° C and stirring, are added dropwise 7.88 ml (46 mmol) of 2-bromopropionyl chloride. After 1 hour, the precipitate of hydrochloride (35) is filtered off. Yield 13.1 g (88%), mp. 150 ^o C (decomp.). The precipitate is dissolved in water, alkalinized with sodium carbonate, extracted with ether, dried with sodium sulfate. The solvent was evaporated, the residue was crystallized from absolute ether. Get the base 35, so pl. 134 ^o C. Found,%: C 57.24; H 6.38; N, 7.98. C ₁₆ H ₂₁ BrN ₂ O. Calculated,%: C 57.13; H 6.30; N, 8.33. PMR spectrum of hydrochloride (DMSO-d ₆ , ppm, δ): 1.56 and 2.30 (2H, 2m, 4-CH ₂ ), 1.58 (3H, d, CH ₃ C, J = 7 Hz), 2.32 (3H, s, 8-CH ₃ ), 2.80 (3H, s, 2-CH ₃ ), 3.05 and 3.20 (3H, 2m, 1-H and 3-CH ₂ ), 3.85 (1H, m, 1-H '), 4.27 (1H, m, 9b-H), 4.84 (1H, m, 4a-H), 5.24 (1H, m , C

CH ₃ ), 7.12 (1H, d, 7-H, J = 8 Hz), 7.43 (1H, s, 9-H), 7.90 (1H, d, 6-H, J = 8 Hz) 9.38 (1H, s, NH).

The following method was obtained:
cis (±) -2,8-dimethyl-5-chloroacetyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole hydrochloride (compound 36):
Yield 90%, mp. 195 - 205 ^o C (from alcohol).

cis (±) -2,8-dimethyl-5 - ((E) -2-butenoyl) - 2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole (compound 37):
Yield: 62% mp. 113 - 114 ^o C.

Example 18
cis (±) -2,8-dimethyl-5-methoxyacetyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole hydrochloride (compound 38):
To a solution of 0.1 g (4.3 mol) of sodium in 10 ml of methanol, 0.63 g (2 mmol) of hydrochloride 36 is added with stirring, boiled for 1 hour, cooled. The precipitate of sodium chloride is filtered off, the filtrate is evaporated and 2 ml of water and 10 ml of benzene are added. The organic layer was separated, dried with potassium carbonate, ethanol saturated with hydrogen chloride was added to pH 1, evaporated in vacuo, crystallized from absolute isopropanol. Yield 0.34 g (55%), mp. 222 - 224 ^o C. Found,%: C 61.56; H 7.60; N, 8.95. C ₁₆ H ₂₂ N ₂ O ₂ • HCl. Calculated,%: C 61.91; H 7.47; N 9.03. 1 H-NMR spectrum of the base (CDCl ₃ -d ₆ , ppm, δ): 1.80 (2H, m, 4-CH ₂ ), 2.13 and 2.20 (6H, 2s, 2- and 8-CH ₃ ), 2.32 (3H, s, OCH ₃ ), 2.60 - 3.10 (5H, m, 3-CH ₂ , 1-CH ₂ , 9b-H), 3.34 (2H, m, CH ₂ O), 3.70 (1H, m, 4a-H), 6.50 (1H, d, 7-H, J = 8 Hz), 6.74 (1H, d, 6-H, J = 8 Hz), 6.81 (1H, s, 9-H).

H); 6,95 (1H, д, 7-H, J = 8 Гц); 7,08 (1H, с, 9-H); 7,84 (1H, д, 6-H, J = 8 Гц).Example 19
cis (±) -2,8-dimethyl-5-N-pyrrolidinoacetyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole (compound 39):
To a solution of 0.93 g (3 mol) of amide 36 in 10 ml of benzene, an excess of pyrrolidine was added and boiled for 5 hours. Pyrrolidine hydrochloride is filtered off, the filtrate is evaporated in vacuo, the residue is recrystallized from hexane. Yield 0.65 g (69%), mp. 108 - 110 ^o C. Found,%: C 72.9; H 8.53; N 13.35. C ₁₉ H ₂₇ N ₃ O. Calculated,%: C 72.79; H 8.69; N, 13.41. 1 H-NMR spectrum: (CD ₃ CN, ppm, δ): 1.35 and 2.00 (2H, m, 4-CH ₂ ); 1.74 (4H, m, (CH ₂ ) ₂ ); 2.18 and 2.25 (6H, 2s, 2- and 8-CH ₃ ); 2.58 (4H, m, (CH ₂ ) ₂ N); 3.20 - 3.57 (5H, m, 1- and 3-CH ₂ , 9-β-H); 4.48 (1H, m, 4

H); 6.95 (1H, d, 7-H, J = 8 Hz); 7.08 (1H, s, 9-H); 7.84 (1H, d, 6-H, J = 8 Hz).

Following this technique, receive:
cis (±) -2,8-dimethyl-5-morpholinoacetyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole (compound 40):
Yield 38%, mp. 150 - 152 ^o C (from hexane).

cis (±) -2,8-dimethyl-5- (2-N-piperidinopropionyl) 2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole (compound 41) :
Yield 14%, mp. 144-145 ^° C (from ether).

cis (±) -2,8-dimethyl-5- (2-N-morpholinopropionyl) - 2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole (compound 42) :
Yield 63%, mp. 230 ^o C (from ether decomp.).

 Example 20

cis (±) -2,8-dimethyl-5- (4-methyl-1-pyridinium acetyl) - 2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole chloride ( connection 43):
0.315 g (1 mmol) of hydrochloride 36 is added to 3 ml of 4-methylpyridine with stirring, stirred at 60 - 80 ^o C for 1 hour. The mixture was evaporated in vacuo, washed with isopropanol, recrystallized from alcohol and dried in vacuo. Yield 0.29 g (79%), mp. 234 - 236 ^o C. Found,%: C 67.92; H 6.90; N 11.12. C ₂₁ H ₂₆ ClN ₃ O. Calculated,%: C 67.89; H 7.06; N, 11.32. PMR spectrum: (DMSO-d ₆ , ppm, δ): 1.64 (2H, m, 4-CH ₂ ), 2.30 and 2.62 (6H, 2s, 2- and 8-CH ₃ ), 2.83 (3H, s, 4'-CH ₃ ), 3.00 - 3.87 (4H, m, 1- and 3-CH ₂ ), 4.24 (1H, m, 9b-H) 4.90 (1H, m, 4a-H), 6.05 and 6.11 (2H, 2d, CH ₂ CO, J = 15 Hz), 7.08 (1H, d, 7-H, J = 8 Hz), 7.38 (1H, s, 90-H), 7.70 (1H, d, 6-H, J = 8 Hz), 8.06 (2H, d, 3'- and 5'- H, J = 7 Hz), 9.00 (2H, d, 2'- and 6'-H, J = 7 Hz).

Following this technique, receive:
cis (±) -2,8-dimethyl-5- (1-pyridinium acetyl) - 2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole chloride (compound 44):
Yield 80%, mp. 280 ^° C (from alcohol, decomp.).

cis (±) -2,8-dimethyl-5- [2- (4-methyl-1-pyridinium) propionyl [- 2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3- b] indole bromide (compound 45):
Yield 70%, mp. 218 - 220 ^o C (from alcohol).

Example 21
cis (±) -2,8-dimethyl-5- (3-carboxypropionyl) - 2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole (compound 46):
To a solution of 0.202 g (2 mmol) of 2,8-dimethyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole (base) in 5 ml of ether is added with stirring , 11 g (1.1 mmol) of succinic anhydride, heated to a boil, cooled, the precipitate was filtered off. Recrystallized from alcohol. Yield 0.242 g (80%), mp. 156 - 159 ^o C. Found,%: C 67.22; H 7.70; N, 9.33. C ₁₇ H ₂₂ N ₂ O ₃ . Calculated,%: C 67.51; H 7.34; N, 9.27. PMR spectrum: (DMSO-d ₆ , ppm, δ): 1.30 and 2.00 (2H, 2m, 4-CH ₂ ), 2.18 and 2.27 (6H, 2s, 2- and 8-CH ₃ ), 2.44 (4H, m, COCH ₂ CH ₂ CO), 2.80 (1H, m, 1-H), 3.41 (4H, m, 1'-H, 9b-H and 3-CH ₂ ), 4.45 (1H, m, 4a-H), 6.95 (1H, d, 7-H, J = 8 Hz), 7.08 (1H, s, 9-H) 7.83 (1H, d, 6-H, J = 8 Hz).

Example 22
cis (±) 2-Methyl-5- [2- (6-methyl-3-pyridyl) ethyl] - 2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole trihydrochloride (compound 47):
To a solution of 0.9 g (2 mmol) of vacuum-dried at 120 ^° C. sesquioxide of 2-methyl-5- [2- (6-methyl-3-pyridyl) ethyl] - 2,3,4,5-tetrahydro 1H-pyrido [4,3-b] indole in 10 ml trifluoroacetic acid was added with stirring in small portions 0.65 g (10 mmol) of zinc powder, heated to dissolve and evaporated in vacuo. 10 ml of ether and 10 ml of 20% sodium hydroxide are added to the residue, stirred until the precipitate is dissolved. The ether layer was separated, the aqueous was extracted with 5 ml of ether. The combined ether extracts were dried with potassium carbonate, evaporated, dissolved in excess alcohol saturated with hydrogen chloride, and evaporated to dryness in vacuo. The residue was washed with absolute ether, crystallized from alcohol with acetone, dried in vacuo. Yield 0.52 g (65%), mp. 234 - 236 ^o C. Found,%: C 58.10; H 6.53; N, 10.05. C ₂₀ H ₂₅ N ₃ • 3HCl. Calculated,%: C 57.81; H 6.80; N 10.12. 1 H-NMR spectrum of the base (CDCl ₃ , ppm, δ): 1.76 (2H, m, 4-CH ₂ ), 2.10 and 2.41 (6H, 2s, 2-CH ₃ and 6'-CH ₃ ), 2.58 - 2.77 (4H, t + m, β- and 3-CH ₂ , J = 7 Hz), 3.00 - 3.30 (5H, m, α- and 1-CH ₂ 9b-H), 3.48 (1H, m, 4a-H), 6.40 (1H, d, 6-H, J = 7 Hz), 6.64 (1H, d, 9-H, J = 7 Hz), 6.88 - 7.06 (3H, m, 7-, 8- and 5'-H), 7.31 (1H, dd, 4'-H, J ₁ = 9 Hz, J ₂ = 3 Hz), 8.29 (1H, d, 2'-H, J = 8 Hz).

)₂], 3,35 (2H, м, 1-CH₂), 3,71 , 3,82 и 4,10 (3H, 3м, 3-CH₂, 9b-H), 4,46 (1H, м, 4a-H), 6,54 (2H, с, NH₂), 7,00 (1H, д, 7-H, J = 8 Гц), 7,22 (1H, с, 9-H), 7,70 (1H, д, 6-H, J = 8 Гц).Example 23
cis (±) -2,2,8-trimethyl-5-carbamoyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indolium iodide (compound 48):
To a solution of 0.14 g (0.57 mmol) of compound 20 in 2 ml of acetonitrile, 0.1 ml (1.5 mmol) of methyl iodide was added. After 24 hours, the precipitate is filtered off, washed with cold acetonitrile. Yield: 0.21 g (95%), mp. 274 - 276 ^o C (from alcohol). Found,%: C 49.80; H 5.33; N, 10.45. C ₁₅ H ₂₂ IN ₃ O. Calculated,%: C 49.63; H 5.39; N, 10.22. PMR spectrum (DMSO-d ₆ , ppm, δ): 1.76 and 2.32 (1H, 2m, 4-CH ₂ ), 2.23 (3H, s, 8-CH ₃ ), 2, 92 and 3.20 [6H, 2s, N ⁺ (C

) ₂ ], 3.35 (2H, m, 1-CH ₂ ), 3.71, 3.82 and 4.10 (3H, 3m, 3-CH ₂ , 9b-H), 4.46 (1H, m, 4a-H), 6.54 (2H, s, NH ₂ ), 7.00 (1H, d, 7-H, J = 8 Hz), 7.22 (1H, s, 9-H), 7.70 (1H, d, 6-H, J = 8 Hz).

Following this technique, receive:
cis (±) -2,8-dimethyl-2- (2,4-dimethylbenzyl) 5-carbamoyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indolium chloride (compound 49):
Yield 80%, mp. 205 - 206 ^o C.

 The synthesized compounds of formula I are shown in Table 1.

 As noted above, the compounds of formula I according to the invention have anti-NMDA activity, which is confirmed by the results of biological tests.

Experiment
The experiments were carried out on male white outbred mice weighing 20-24 g. The test compound was administered intraperitoneally 40 minutes before the introduction of NMDA. The compound was used as a solution in 0.2 mol of 5% aqueous dimethyl sulfoxide. Mice previously under ether anesthesia removed the skin flap on their heads and made a hole in the skull with a thin drill. Then, NMDA was injected into the lateral ventricle of the brain using a microsyringe in a dose of 0.1 μg in a volume of 1.4 μl. The depth of immersion of the needle of the microsyringe was 2.5 mm. The accuracy of the NMDA was controlled by the introduction of methylene blue. After surgery, the wound was treated with a 2% solution of novocaine [Grigoryev V.V., Nemanova V.A. - Bull. Expert. Biol. Honey., 1989, No. 9, pp. 299-302]. After exiting anesthesia, the mice showed no signs of pain or anxiety. Evaluation of the results was carried out 2-4 hours after surgery.

 As a control, we used animals that received saline. In the control group, the introduction of NMDA into the lateral ventricle at a dose of 0.1 μg per mouse caused running, jumping, cramps, and then the death of the animal. In the experimental group, the preliminary administration of the test substances prevented the development of seizures and the death of the animal.

Each dose of the substance was tested on a group of 6-8 animals. The activity of the compounds was expressed as the ED ₅₀ value (dose of a substance that prevents the development of seizures and the death of 50% of animals), which was determined by the method of Litchfield and Wilcoxon [Litchfild JT, Wilcoxon FJ Pharmacol. Exp. Ther. - 1949, v. 96, pp. 99 - 114].

 The results of the tests are presented in Table 2 below. As a standard substance, 2-amino-5-phosphovalerianic acid (AP5), which is known to be an antagonist of NMDA receptors, was also tested in experiments [Evans et al. - Brit J. Pharmacol., 1982, v. 75, p. 65]. These data are also presented in Table 2.

From the data shown in Table 2, it can be seen that the compounds of formula I according to the invention exhibit anti-NMDA activity when administered intraperitoneally in the range of ED ₅₀ from 9 to 46 mg / kg and superior to the standard substance AP5 in 4.2 to 21 times. However, they do not have a noticeable neurotoxic effect in the range of active studied doses, which makes them valuable for use in medicine, in the treatment and prevention of diseases, the glutamatergic neurotransmitter system is involved in the pathogenesis mechanism, and especially in the treatment of neurodegenerative diseases, such as Alzheimer's disease , Huntington's chorea, cerebral ischemia, heart attack, angiospasm, hypoglycemia, cardiac arrest, epilepsy, brain injuries, schizophrenia, paralysis, etc.

Acute toxicity experiment
Acute toxicity of substances was determined on male outbred mice weighing 22-26 g. Substances were administered intraperitoneally in the form of a solution or suspension in a 1% starch solution. The observation period was 14 days. Toxicity in the form of LD _{50 was} calculated by the method of Litchfield and Wilcoxon. [Litchfild JT, Wilcoxon FJ, J. Pharmacol. Exp. Ther., 1949, v. 96, pp. 99-114].

 Examples of toxicity of the claimed compounds are shown in table 3.

As a result of tests, it was found that the LD _{50 of the} investigated compounds is from 45 to 800 mg / kg In accordance with the classification of toxicity of chemicals, these compounds are classified as moderately and low toxic substances. Although the acute toxicity of these compounds slightly exceeds the value of acute toxicity of AP5, a comparison of the parameters of the therapeutic index, defined as the ratio of LD ₅₀ / ED ₅₀ (D.N. Plutitsky et al., - Chem. Pharm. J., 1986, N 10, 1209 - 1231), shows that most of the compounds tested have a significant advantage over AP5.

 A further aspect of the invention is a method for the treatment and prevention of diseases in which glutamatergic neurotransmitter system is involved in the pathogenesis mechanism, which provides for the administration to patients in need of treatment an effective amount of a compound of formula I.

 The dose to be administered for the active ingredient (the compound of formula I or its pharmaceutically acceptable salts) varies depending on many factors, such as the age, gender, weight of the patient, symptoms and severity of the disease, the compound specifically prescribed, the method of administration, the form of the preparation in which active connection is assigned.

 Usually, the total prescribed dose is from 1 to 200 mg per day. The total dose can be divided into several doses, for example, for taking from 1 to 4 times a day. For oral administration, the range of total doses of the active substance is from 10 to 200 mg per day, preferably from 15 to 150 mg. For parenteral administration, the prescribed dosage range is from 5 to 100 mg per day, preferably from 5 to 50 mg, and for intravenous injections from 1 to 50 mg per day, preferably from 1 to 25 mg. The exact dose can be chosen by the attending physician.

 As is commonly accepted in medicine, the compounds of formula I according to the present invention are recommended to be used in the form of compositions constituting respectively the next aspect of the invention.

 The pharmaceutical composition according to the invention is prepared using methods generally accepted in the art and includes a pharmacologically effective amount of an active agent representing a compound of formula I or a pharmaceutically acceptable salt thereof (hereinafter referred to as "active compound"), typically from 5 to 30% by weight, in in combination with one or more pharmaceutically acceptable adjuvants, such as diluents, binders, disintegrating agents, adsorbents, flavoring agents, flavoring agents Options. In accordance with known methods, pharmaceutical compositions may be in various liquid or solid forms.

 Examples of solid dosage forms include, for example, tablets, pills, gelatine capsules, etc.

 Examples of liquid dosage forms for injection and parenteral administration include solutions, emulsions, suspensions, etc.

 Compositions, as a rule, are obtained using standard procedures involving the mixing of the active compound with a liquid or finely divided solid carrier.

 Compositions according to the invention in the form of tablets contain from 5 to 30% of the active compound and a filler (s) or carrier (s). As such for tablets, the following are used: a) diluents: beet sugar, lactose, glucose, sodium chloride, sorbitol, mannitol, glycol, disubstituted calcium phosphate; b) binders: aluminum magnesium silicate, starch paste, gelatin, tragacanth, methyl cellulose, carboxymethyl cellulose and polyvinylpyrrolidone; c) disintegrants: dextrose, agar, alginic acid or its salts, starch, tween.

 Example 1

100 mg tablets containing 15.0 mg of compound 9
Compound 9 - 15.0 mg
Lactose - 40.0 mg
Alginic acid - 20.0 mg
Citric Acid - 5.0 mg
Tragacanth - 20.0 mg
A tablet may be formed by compressing or molding the active ingredient with one or more additional ingredients.

 Obtaining pressed tablets is carried out on a special installation. The active ingredient in free form, such as powder or granules, in an amount of 150 g (the amount of substance required to obtain 10,000 tablets) is mixed with a binder - tragacanth (200 g), mixed with a diluent - lactose (400 g), in a mixture loosening agent is added - alginic acid (200 g) and fragrance - citric acid (50 g).

 For gelatin capsules, colorants and stabilizers are additionally used. As dyes are used: tetrazine, indigo; as stabilizers can be represented: sodium metabisulfite, sodium benzoate. The proposed gelatin capsules contain from 1 to 20% of the active ingredient.

 Example 2

500 mg tablets containing 50 mg of compound 31
Compound 31 - 50.0 mg
Glycerin - 100.0 mg
Sugar syrup - 290.0 mg
Peppermint Oil - 40.0 mg
Sodium benzoate - 10.0 mg
Ascorbic acid - 5.0 mg
Tetrazine - 5.0 mg
500 g of the active substance (compound 31) (the amount needed to prepare 10,000 capsules) is precisely ground and mixed in a mixer with glycerin (1000 g) and sugar syrup (2900 mg). After stirring, peppermint oil (400 g), sodium benzoate (10 g), ascorbic acid (50 g) and tetrazine (50 g) are added to the mixture. Gelatin capsules are prepared by the drip method. This method allows simultaneous drip dosing of a solution of a medicinal substance and heated gelatinous mass (900 g of gelatin) in chilled paraffin oil. As a result, seamless spherical gelatin capsules are formed, filled with a medicinal mixture, completely ready for use, containing 50 mg of the active substance.

 Injectable forms of the composition are preferably isotonic solutions or suspensions. The above forms may be sterilized and contain additives such as preservatives: sodium metabisulfite, benzoic acid, sodium benzoate, a mixture of methylparaben and propylparaben; stabilizers: apricot and gum arabic, dextrin, starch paste, methyl cellulose, twin; salts regulating the osmotic pressure (sodium chloride), or buffers. In addition, they may contain other therapeutically useful substances.

 Example 3

2 ml ampoules containing 20 mg of compound 24
Compound 24 - 20.0 mg
Sodium chloride 0.9% - 1.6 ml
Benzoic acid - 10.0 mg
Cellulose - 10.0 mg
Peppermint Oil - 0.4 ml
For the preparation of injection forms, the active compound 24 (20 g; the amount required for the manufacture of 1000 ampoules) is ground finely and mixed in a mixer with peppermint oil (400 ml), then methyl cellulose (10 g) is added, mixed with a 0.9% sodium chloride solution (1600 ml) and benzoic acid (10 g) is added. The resulting solution is packaged in 2 ml ampoules and steam sterilized for 30 minutes.

Claims (48)

1. 2-Methyl-5,8-substituted 2,3,4,5-tetra- and 2,3,4,4a, 5,9b-hexahydro-1H-pyrido (4,3-b) indoles and their quaternary salts with a quaternized nitrogen atom in position 2 of the general formula I

in which the dashed line with the solid line accompanying it

represents a single or double bond;
R ¹ is H or lower alkyl;
R ² - 2- (2-N, N-dimethylaminoethyl) -5-R ¹ -indolyl-3-methyl group (in which R ¹ has the meanings defined above), provided that

represents a double bond, and R ³ is H; or a group of the general formula

in which Y is selected from the group consisting of H, halogen, cycloalkyl, ethenyl, optionally mono-, di- or trisubstituted with lower alkyl; groups OR ⁴ (in which R ⁴ is H, lower alkyl), alkylsulfonyl, arylsulfonyl, groups NR ⁵ R ⁶ (in which R ⁵ and R ⁶ may be the same or different and each independently represents H, lower alkyl, cycloalkyl, benzyl, phenyl (optionally mono-, di- or trisubstituted with substituents A as defined below), or one of the substituents R ⁵ and R ⁶ represents a COR ⁷ group (in which R ⁷ is phenyl), or R ⁵ and R ⁶ taken together represent a group of the general formula (CH ₂ ) ₂ - W - (CH ₂ ) ₂ (in which W represents —O—, (CH ₂ ) _q , where q = 0.1 or 2); COR ⁸ groups (in which R ⁸ - lower alkyl, OH; alkoxy na, phenyl); CN, CHal ₃ (in which Hal - chloro, fluoro or bromo), aryl (optionally mono- or di- or tri- substituents A, defined below), 2-, 3- and 4-pyridyl (optionally mono - or disubstituted with lower alkyl) and its corresponding quaternary salts of 1-R ³ CH ₂ -pyridinium-2, -3, or -4 (in which R ³ has the meanings defined below); trialkylammonium;
cycloalkylammonium; N-azinium and N-azolium; z is O, S, H ₂ ; k = 0, 1, 2, 3, 4; l, m and n = 0, 1, and 1) Y can have any of the indicated values only when k + m = 2 - 5, and l = 0; 2) when k = l = m = 0, then Y is different from halogen, CHal ₃ , OR ⁴ , NR ⁵ R ⁶ , aryl, trialkylammonium, cycloalkylammonium, N-azinium or N-azolium; 3) when k = 1, and l = m = 0, then Y has values other than halogen, trialkylammonium, cycloalkylammonium, N-azinium or N-azolium; 4) when k = l = 0, m = 1 and z represents O, then Y is different from halogen, OH, CN, alkylsulfonyl, arylsulfonyl, trialkylammonium, cycloalkylammonium, N-azinium or N-azolium; 5) when k = l = 0, m = 1 and z represents S, then Y represents only the group NR ⁵ R ⁶ in which R ⁶ is hydrogen; 6) when l = 0, then z is different from H ₂ ; 7) when k = 0, and l = m = 1, then Z is different from S;
R ³ represents a group - (CH ₂ ) _k Y'-, in which Y 'is H, phenyl, benzoyl or N-phthalimidogroup, k has the meanings defined above;
X represents an anion of a pharmacologically acceptable acid;
substituents A are independently selected from the following group: halogen,
lower alkyl, lower alkoxy group, NO ₂ ; provided that a) if

represents a double bond and n = 0, then when R ¹ is methyl, then R ² is other than H, methyl, benzyl, 2-pyridylmethyl, 2- (6-methyl-3-pyridyl) ethyl, 2- (4-pyridyl ) ethyl, 2- (N, N, dimethylamino) ethyl or 3- (N, N-dimethylamino) propyl, and when R ¹ is H, then R ^2, in addition to the above, is also different from n-butyl, cyclohexyl, 4 -chlorobenzyl, 2-phenylethyl, 2- and 3-pyridyl, 1- (2-pyridyl) ethyl, 2- (2-pyridyl) ethyl, 1- (3-pyridyl) ethyl, 1- (6-methyl-3- pyridyl) ethyl, diethylaminocarbonyl, hydroxymethyl, 2-methyl-3- (N, N, dimethylamino) propyl, from the group of the general formula R ⁴ O- (CH ₂ ) ₂ - (in which R ⁴ - C ₂ - C ₄ -alkyl) or from a group of the general formula R ⁵ R ⁶ N- (CH ₂ ) _p - (in which p = 2, R ⁵ and R ^{6 are} each ethyl or R ⁵ and R ⁶ together represent tetra - or pentamethylene, or p = 3 and R ⁵ and R ⁶ together represent the group - (CH ₂ ) ₂ O (CH ₂ ) ₂ -); b) if

represents a single bond and n = 0, then when R ¹ is H, then R ² is other than H, methyl, ethyl, benzyl, acetyl, chloroacetyl or (N-morpholino, or N-piperidino, or N, N- diethylamino) acetyl, 3-chloropropionyl, 3- (N-morpholino) propionyl or 5-chloropentanoyl when R ¹ is methyl, then R ² is other than H, 2,2,2-trifluoroethyl, 2- (N, N- dimethylamino) ethyl,
3- (N, N-dimethylamino) propyl, acetyl, 2-ethylhexanoyl, (E) 2-butenoyl in the case of the cis (-) isomer; c) if

represents a double bond and n = 1, then when each of R ¹ and R ³ is H and X is iodine, then R ² is other than H, methyl, ethyl or propyl; then when each R ¹ and R ³ is H and X is methyl sulfate, then R ² is different from benzyl, when R ¹ is H, R ³ is methyl and X is iodine, then R ² is different from H; when R ¹ is methyl, R ³ is H and X is iodine, then R ² is other than H or methyl; when R ¹ is H, R ³ is phenyl and X is chloro, then R ² is other than H or benzyl; when R ¹ is H, R ³ is phenyl and X is iodine, then R ² is different from 3- (N, N, N-trimethylammonio) propyl iodide,
and their salts with pharmacologically acceptable acids. 2. The compounds according to claim 1, which are derivatives of 2-methyl-2,3,4,5-tetrahydro-1H-pyrido (4,3-b) indole of the general formula I.1

in which R ¹ has the meanings defined in claim 1;
R ² represents a group of the general formula - (CH ₂ ) _k —Y, in which Y is selected from the group consisting of H, halogen, cycloalkyl, ethenyl, optionally mono-, di- or trisubstituted with lower alkyl; OR ⁴ (in which R ⁴ has the meanings defined in claim 1); groups NR ⁵ R ⁶ (in which R ⁵ and R ⁶ have the meanings defined in claim 1); groups COR ⁸ (in which R ⁸ has the meanings defined in paragraph 1); CN; CHal ₃ (in which Hal is chloro, fluoro or bromo); aryl (optionally mono-, di- or trisubstituted with substituents A as defined above); 2-, 3- and 4-pyridyl, optionally mono- or disubstituted with lower alkyl, and the corresponding quaternary salts of 1-R ³ CH ₂ -pyridinium-2, -3, or -4 (in which R ³ has the meanings defined in p. 1); trialkylammonium; cycloalkylammonium; N-azinium and N-azolium;
k has the meanings defined in claim 1 for formula I, and 1) when k = 0, then Y is different from halogen, CHal ₃ , OR ⁴ , NR ⁵ R ⁶ , aryl, trialkylammonium, cycloalkylammonium, N-azinium or N -asolium;
2) when k = 1, then Y has values other than halogen, trialkylammonium, cycloalkylammonium, N-azinium or N-azolium, provided that when R ¹ is methyl, then R ² is other than H, methyl, benzyl, 2-pyridylmethyl, 2- (6-methyl-3-pyridyl) ethyl, 2- (4-pyridyl) ethyl, 2- (N, N, dimethylamino) ethyl, or 3- (N, N-dimethylamino) propyl, and when R ¹ is H, then R ² in addition to the above is also different from n-butyl, cyclohexyl, 4-chlorobenzyl, 2-phenylethyl, 2- and 3-pyridyl, 1- (2-pyridyl) ethyl, 2- ( 2-pyridyl) ethyl, 1- (3-pyridyl) ethyl, 1- (6-methyl-3-pyridyl) ethyl, diethylaminocarbonyl, guide roxymethyl, 2-methyl-3- (N, N, dimethylamino) propyl, from the group of the general formula R ⁴ O- (CH ₂ ) ₂ - (in which R ⁴ is C ₂ - C ₄ -alkyl) or from the group of the general formula R ⁵ R ⁶ N- (CH ₂ ) _p - defined in claim 1. 3. The compounds of claim 1, which are derivatives of 2-methyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido (4,3-b) indole of the general formula I.2

in which R ¹ has the meanings defined in claim 1;
R ² represents a group of the general formula

in which Y, Z, k, l and m have the meanings defined in claim 1; moreover, 1) when k = l = m = 0, then Y is different from halogen, CHal ₃ , OR ⁴ , NR ⁵ R ⁶ , aryl, trialkylammonium, cycloalkylammonium, N-azinium or N-azolium; 2) when k = 1 and l = m = 0, then Y has values other than halogen, trialkylammonium, cycloalkylammonium, N-azinium or N-azolium; 3) when k = l = 0, m = 1 and Z is O, then Y is different from halogen, OH, CN, alkylsulfonyl, arylsulfonyl, trialkylammonium, cycloalkylammonium, N-azinium or N-azolium; 4) when k = l = 0, m = 1, and Z represents S, then Y represents only the group NR ⁵ R ⁶ in which R ⁶ is hydrogen; 5) when l = 0, then Z is different from H ₂ ; 6) when k = 0, and l = m = 1, then Z is different from S; with the proviso that when R ¹ is H then R ² is other than H, methyl, ethyl, benzyl, acetyl, chloroacetyl, (N-morpholino, N-piperidino or N, N-diethylamino) acetyl, 3-chloropropionyl , 3- (N-morpholino) propionyl or 5-chloropentanoyl, and when R ¹ is methyl,
then R ² is other than H, 2,2,2-trifluoroethyl, 2- (N, N-dimethylamino) ethyl, 3- (N, N-dimethylamino) propyl, acetyl, 2-ethylhexanoyl, (E) -2- butenoyl in the case of the cis (-) isomer. 4. The compounds according to claim 1, representing the quaternary salts of 2 methyl-2-R ³ CH ₂ - 2,3,4,5-tetrahydro and 2-methyl-2-R ³ CH ₂ - 2,3,4,4a , 5,9b-hexahydro-1H-pyrido (4,3-b) indoles (with a quaternized nitrogen atom in position 2) of the general formula I.3

in which the dashed line with the solid line accompanying it

represents a single or double bond;
R ¹ and X are as defined in claim 1;
R ² represents a 2- (2-N, N-dimethylaminoethyl) -5-R ¹ -indolyl-3-methyl group (in which R ¹ is as defined above), provided that

represents a double bond, and R ³ is H; or a group of the general formula

in which Y, Z, k, l and m have the meanings defined in claim 1; moreover, 1) Y can have any of the indicated values only when k + m = 2 - 5, and l = 0, 2) when k = 1, m = 0, then Y is different from halogen, CHal ₃ , OR ⁴ , NR ⁵ R ⁶ , aryl, trialkylammonium, cycloalkylammonium, N-azinium or N-azolium; 3) when k = l = 0, m = 1 and Z is O, then Y is different from halogen, OH, CN, alkylsulfonyl, arylsulfonyl, trialkylammonium, cycloalkylammonium, N-azinium or N-azolium; 4) when k = l = 0, m = 1, and Z represents S, then Y represents only the group NR ⁵ R ⁶ in which R ⁶ is hydrogen; 5) when l = 0, then Z is different from H ₂ ; 6) when k = 0, and l = m = 1, then Z is different from S; with the proviso that when R ¹ and R ^{3 are} each H and X is iodine, then R ² is other than H, methyl, ethyl, or propyl; when R ¹ and R ³ are H and X is methyl sulfate, then R ² is other than benzyl; when R ¹ is H, R ³ is methyl and X is iodine, then R ² is other than H; when R ¹ is methyl, R ³ is H and X is
iodine, then R ² is other than H or methyl; when R ¹ is H, R ³ is phenyl and X is chloro, then R ² is other than H or benzyl; when R ¹ is H, R ³ is phenyl and X is iodine, then R ² is different from 3- (N, N, N-trimethylammonio) propyl iodide. 5. The compounds according to claim 2, representing 5-substituted 2-methyl-2,3,4,5-tetrahydro-1H-pyrido (4,3b) indoles of the general formula I.1.1:

in which R ¹ has the meanings defined in claim 1;
Y is selected from the group consisting of H, cycloalkyl, ethenyl, optionally mono-, di- or trisubstituted with lower alkyl, 2-, 3- and 4-pyridyl (optionally mono- or disubstituted with lower alkyl), provided that when R ¹ is methyl, then Y is different from H, and when R ¹ is H, then Y is additionally also different from cyclohexyl, 2- and 3-pyridyl. 6. The compounds of claim 2, representing 5- (substituted methyl) -2-methyl-2,3,4,5-tetrahydro-1H-pyrido (4,3-b) indoles of the general formula I.1.2

in which R ¹ has the meanings defined in claim 1;
Y is selected from the group consisting of H, cycloalkyl, ethenyl, optionally mono-, di- or trisubstituted with lower alkyl, CN, CHal ₃ (in which Hal is chloro, fluoro or bromo); aryl (optionally mono-, di- or trisubstituted with substituents A as defined in claim 1); COR ⁸ (in which R ⁸ has the meanings defined in claim 1); 2-, 3- and 4-pyridyl (optionally mono- or disubstituted with lower alkyl), provided that when R ¹ is methyl, then Y has values other than H, phenyl, 2-pyridyl; when R ¹ is H, then Y is also different from OH and 4-chlorophenyl. 7. The compounds of claim 2, representing 5- (2-substituted ethyl) -2-methyl-2,3,4,5-tetrahydro-1H-pyrido (4,3-b) indoles of the general formula I.1.3

in which R ¹ has the meanings defined in claim 1;
Y has the meanings defined in clause 2;
with the proviso that when R ¹ is methyl, then Y has values other than a dimethylamino group, 6-methyl-3-pyridyl or 4-pyridyl; when R ¹ is H, then Y, in addition to the above, is also different from phenyl, 2-pyridyl, from the group OR ⁴ (in which R ⁴ is C ₂ - C ₄ -alkyl), from the group R ⁵ R ⁶ N (in which R ⁵ and R ^{6 are} each ethyl or R ⁵ and R ⁶ together represent tetra- or pentamethylene). 8. The compounds according to claim 7, representing 5- (2-NR ⁵ -NR ⁶ amino-ethyl) -2-methyl-2,3,4,5-tetrahydro-1H-pyrido (4,3-b) indoles total formulas I.1.3.1

in which R ¹ , R ⁵ and R ⁶ have the meanings defined in paragraph 7; provided that when R ¹ is methyl, then R ⁵ and R ⁶ cannot simultaneously be methyl; when R ¹ is H, then R ⁵ and R ⁶ cannot additionally be simultaneously methyl or ethyl, or R ⁵ and R ⁶ taken together are different from tetra- or pentamethylene. 9. The compounds according to claim 7, representing 5- (2-, 3- or 4-pyridylethyl) -2-methyl-2,3,4,5-tetrahydro-1H-pyrido (4,3-b) indoles of the general formula I.1.3 of the above (I.1.3.2.), In which R ¹ has the meanings defined in claim 1, Y represents 2-, 3- or 4-pyridyl (optionally mono- or disubstituted with lower alkyl), when provided that when R ¹ is methyl, then Y has values other than 6-methyl-3-pyridyl or 4-pyridyl, and when R ¹ is H, then Y is also different from 2-pyridyl. 10. The compounds according to claim 7, representing 2-methyl-5- (2-cyanoethyl) -2,3,4,5-tetrahydro-1H-pyrido (4,3-b) indoles of the general formula I.1.3.3

in which R ¹ has the meanings defined in claim 1. 11. The compounds of claim 7, representing 5- (2-COR ⁸ -ethyl) -2-methyl-2,3,4,5-tetrahydro-1H-pyrido (4,3-b) indoles of the general formula I.1.3.4

in which R ¹ has the meanings defined in claim 1;
R ⁸ is OH, alkoxy. 12. The compounds according to claim 2, representing 5- (ω-substituted alkyl) -2-methyl-2,3,4,5-tetrahydro-1H-pyrido (4,3-b) indoles of the general formula I.1.4

in which R ¹ has the meanings defined in claim 1;
Y has the meanings defined in clause 2;
k = 3 or 4,
provided that when R ¹ is methyl and k = 3, then Y is different from the dimethylamino group, when R ¹ is H and k = 3, then Y is also different from the group N (CH ₂ CH ₂ ) ₂ O, and when k = 4, Y is different from H. 13. The compounds according to claim 3, representing 5- (N-substituted (thio) carbamoyl) -2-methyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido (4,3-b) indoles general formula I.2.1

in which R ¹ and R ⁵ have the meanings defined in claim 3; Z represents O or S. 14. The compounds according to claim 3, representing 5- (α- (ω -) - substituted alkanoyl) -2-methyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido (4,3-b ) indoles of the general formula I.2.2

in which R ¹ has the meanings defined in claim 1;
Y, k and l have the meanings indicated in clause 3,
provided that R ¹ is H and l = 0, then Y is different from H, N, N-diethylamino or N-piperidino group, if k = 1, from the N-morpholino group, if k = 1 or 2, and from chlorine, if k = 1, 2 or 4; and when R ¹ is methyl, then Y is different from H if k = 1 and l = 0 or if k = 4 and l = 1 and Alk is ethyl. 15. The compounds of claim 14, which are 5-acyl substituted 2-methyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido (4,3-b) indoles of the general formula I.2.2.1

in which R ¹ has the meanings defined in claim 1;
Y is selected from the group consisting of H, cycloalkyl, ethenyl, optionally mono-, di- or trisubstituted with lower alkyl, OR ⁴ (in which R ⁴ has the meanings defined in clause 14 except for H), the group NR ⁵ R ⁶ ( in which R ⁵ and R ⁶ have the meanings defined in clause 14), CHal ₃ (in which Hal is chlorine, fluorine or bromine), aryl (optionally mono-, di- or trisubstituted with substituents A as defined above),
with the proviso that when R ¹ is methyl, then Y is different from the (E) -penyl-1 in the case of the cis (-) isomer. 16. The compounds of claim 14, representing 5- (α-substituted alkanoyl) -2-methyl-2-R ³ CH ₂ -2,3,4,4a, 5,9b-hexahydro-1H-pyrido (4.3 -b) indoles of the general formula I. 2.2.2

wherein
R ¹ has the meanings given in claim 1;
Y has the meanings defined in clause 14. 17. The compounds of claim 14, representing 5- (ω-substituted alkanoyl) -2-methyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido (4,3-b) indoles of the general formula I .2.2.3

in which R ¹ has the meanings defined in claim 1;
Y has the meanings defined in clause 14;
k = 1 - 4, an integer,
with the proviso that when R ¹ is H then Y is different from H, N, N-diethylamino or N-piperidino, if k = 1; from the N-morpholino group if k = 1 or 2, and from chlorine if k = 1, 2 or 4; and when R ¹ is methyl and k = 1, then Y is H. 18. The compounds according to claim 3, representing 5- (ω-substituted alkyl) -2-methyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido (4,3-b) -indoles of the general formula I.2.3

in which R ¹ has the meanings defined in claim 1;
k = 0 - 4, an integer;
Y is selected from the group consisting of H, ethenyl, optionally mono-, di- or trisubstituted with lower alkyl, CF ₃ , OR ⁴ (in which R ⁴ is as defined in claim 1), NR ⁵ R ⁶ (in which R ⁵ and R ⁶ have the meanings defined in paragraph 1), provided that when R ¹ is H, then Y is different from H (for k = 1 or 2) or phenyl (for k = 1), and when R ¹ is methyl, then Y is different from CF ₃ (at k = 1) and from a dimethylamino group (at k = 2 or 3). 19. The compounds of claim 4, representing the quaternary salts of 2-methyl-2-R ³ CH ₂ -2,3,4,5-tetrahydro-1H-pyrido (4,3-b) -indoles (with a quaternized nitrogen atom in position 2) of the general formula I.3.1

in which R ¹ , R ² , R ³ and X have the meanings defined in paragraph 4,
with the proviso that when R ¹ and R ³ are simultaneously H and X are iodine, then R ² is other than H, methyl, ethyl or propyl; when R ¹ and R ^{3 are} both H and X both methyl sulphate, then R ² is other than benzyl; when R ¹ is H, R ³ is methyl and X is iodine, then R ² is other than H; when R ¹ is methyl, R ³ is H and X is iodine, then R ² is other than H or methyl; when R ¹ is H, R ³ is phenyl and X is chloro, then R ² is other than H or benzyl; when R ¹ is H, R ³ is phenyl and X is iodine, then R ² is different from 3- (N, N, N-trimethylammonio) propyl iodide. 20. The compounds according to claim 19, representing the quaternary salts of 5-substituted-2-methyl-2-R ³ CH ₂ -2,3,4,5-tetrahydro-1H-pyrido (4,3-b) -indoles of the General formula I. 3.1.1

in which R ¹ , R ³ and X have the meanings defined in claim 1;
Y is selected from the group consisting of H, cycloalkyl, ethenyl, optionally mono-, di- or trisubstituted with lower alkyl, 2-, 3- or 4-pyridyl (optionally mono- or disubstituted with lower alkyl) and their corresponding 1-R quaternary salts ³ CH ₂ -pyridinium-2,3- or -4- (where R ³ is as defined above); provided that when R ¹ and Y are each H and X is iodine, then R ³ is other than H or methyl; when R ¹ and Y are each H and X is chloro, then R ³ is other than phenyl; when R ³ and Y are each H and X is iodine, then R ¹ is other than methyl. 21. The compounds according to claim 19, representing the quaternary salts of 5- (substituted methyl) -2-methyl-2-R ³ CH ₂ -2,3,4,5-tetrahydro-1H-pyrido (4,3-b) - indoles of the general formula I.3.1.2

in which R ¹ , R ³ and X have the meanings defined in claim 1;
Y is selected from the group consisting of H, cycloalkyl, ethenyl, optionally mono-, di- or trisubstituted with lower alkyl, CN, CHal ₃ (in which Hal is chloro, fluoro or bromo), alkylsulfonyl, arylsulfonyl, aryl (optionally mono, di- or trisubstituted with substituent A as defined above), OR ⁴ (in which R ⁴ is as defined in claim 1), COR ⁸ (in which R ⁸ is as defined in claim 1), 2-, 3 - and 4-pyridyl (optionally mono- or disubstituted with lower alkyl) and the corresponding quaternary salts of 1-R ³ CH ₂ -pyridinium-2, -3 or -4- (where R ³ is as defined given in claim 1), provided that when R ¹ and R ^{3 are} each H and X is iodine or R ¹ is methyl and R ³ is H and X is iodine, then Y is different from H; and when R ¹ and R ^{3 are} each H and X is methyl sulfate or R ¹ is H, R ³ is phenyl and X is chlorine, then Y is different from phenyl. 22. The compounds according to claim 19, representing the quaternary salts of 5- (2-substituted methyl) -2-methyl-2-R ³ CH ₂ -2,3,4,5-tetrahydro-1H-pyrido (4,3-b ) -indoles of the general formula I.3.1.3

in which R ¹ , R ³ and X have the meanings defined in claim 1;
Y is selected from the group consisting of CN, COOAlk, 2-, 3- and 4-pyridyl (optionally mono- or disubstituted with lower alkyl) and its corresponding quaternary salts of 1-R ³ CH ₂ -pyridinium-2, 3 or -4- (where R ³ has the meanings defined in claim 1), provided that when R ¹ and R ^{3 are} each H and X is iodine, then Y is different from H. 23. The compounds according to claim 19, representing the quaternary salts of 5-acyl-2-methyl-2-R ³ CH ₂ -2,3,4,5-tetrahydro-1H-pyrido (4,3-b) -indoles of the General formula I. 3.1.4

in which R ¹ , R ³ and X have the meanings defined in claim 1,
Y is selected from the group consisting of cycloalkyl, ethenyl, optionally mono-, di- or trisubstituted with lower CHal ₃ (in which Hal is chloro, fluoro or bromo), aryl (optionally mono-, di- or trisubstituted with A, as defined in .1), groups OR ⁴ (in which R ⁴ - has the meanings defined in claim 1, except for H), NR ⁵ R ⁶ (in which R ⁵ and R ⁶ have the meanings defined in clause 1). 24. The compounds of claim 4, representing the quaternary salts of 5-substituted 2-methyl-2-R ³ CH ₂ -2,3,4,4a, 5,9b-hexahydro-1H-pyrido (4,3-b) - indoles (with a quaternized nitrogen atom in position 2) of the general formula I.3.2

in which R ¹ , R ³ and X have the meanings defined in claim 1,
R ² represents a group of the general formula

in which k, l and m have the meanings indicated in paragraph 4; moreover, 1) Y has any of the indicated values only when k + m = 2 - 5, and l = 0; 2) when k = l = 0, m = 1, then Y is different from halogen, OH, CN, alkylsulfonyl, arylsulfonyl, trialkylammonium, cycloalkylammonium, N-azinium or N-azolium; 3) m = 0 only when k = l = 0 and Y is alkylsulfonyl, arylsulfonyl or CN.  25. The compound according to claim 5, representing 2-methyl-8-isopropyl-2,3,4,5-tetrahydro-1H-pyrido (4,3-b) indole hydrochloride.  26. The compound according to claim 6, representing 2,8-dimethyl-5- (2,4-dimethylbenzyl) -2,3,4,5-tetrahydro-1H-pyrido (4,4-b) indole hydrochloride.  27. The compound of claim 8, representing 2,8-dimethyl-5- (2-N-hexamethyleneimino-ethyl) -2,3,4,5-tetrahydro-1H-pyrido (4,3-b) indole dihydrochloride.  28. The compound according to claim 11, representing 2,8-dimethyl-5- (2-carboxyethyl) -2,3,4,5-tetrahydro-1H-pyrido (4,3-b) indole hydrochloride. 29. The compound according to item 22, representing
2,2-dimethyl-5- [2- (6-methyl-3-pyridyl) ethyl] -2,3,4,5-tetrahydro-1H-pyrido (4,3-b) indolium iodide;
2,2,8-trimethyl-5- [2- (1,6-dimethyl-3-pyridinium) ethyl / -2,3,4,5-tetrahydro-1H] pyrido (4,3-b) indolium diiodide ;
2-methyl-2- (4-bromophenacyl) -5- [2- (6-methyl-3-pyridyl) ethyl] -2,3,4,5-tetrahydro-1H-pyrido (4,3-b) indolium bromide;
2,8-dimethyl-2-phenacyl-5- [2- (6-methyl-3-pyridyl) ethyl] -2,3,4,5-tetrahydro-1H-pyrido (4,3-b) indolium bromide or
2,2,8-trimethyl-5- (2-carbethoxyethyl) -2,3,4,5-tetrahydro-1H-pyrido (4,3-b) indolium iodide.  30. The compound according to claim 19, representing 2,2,8-trimethyl-5- (5-methyl-2- (2-N, N-dimethylaminoethyl) indolyl-3-methyl) -2,3,4,5- tetrahydro-1H-pyrido (4,3-b) indolium iodide.  31. The compound according to item 23, representing 2,2,8-trimethyl-5- (N-methylcarbamoyl) -2,3,4,5-tetrahydro-1H-pyrido (4,3-b) indolium iodide.  32. The compounds of claim 13, which are cis (±) -2,8-dimethyl-5- (N-cyclohexylthiocarbamoyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido (4,3- b) indole, cis (±) -2,8-dimethyl-5- (N-n-butylcarbamoyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido (4,3-b) indole or cis (±) -2,8-dimethyl-5- (N-phenylcarbamoyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido (4,3-b) indole.  33. The compounds of claim 15, representing cis (±) -2,8-dimethyl-5- (2-methylbenzoyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido (4,3- b) indole hydrochloride or cis (±) -2,8-dimethyl-5 / (E) -2-butenoyl / -2,3,4,4a, 9b-hexahydro-1H - pyrido (4,3-b) indole.  34. The compounds of claim 16, which represent cis (±) -2,8-dimethyl-5- (2-bromopropionyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido (4,3- b) indole hydrochloride or cis (±) -2,8-dimethyl-5- (2- (4-methyl-1-pyridinium) propionyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido (4,3-b) indole bromide.  35. The compounds of claim 17, representing cis (±) -2,8-dimethyl-5-chloroacetyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido (4,3-b) indole hydrochloride ; cis (±) -2,8-dimethyl-5-methoxyacetyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido (4,3-b) indole hydrochloride; cis (±) -2,8-dimethyl-5- (N-pyrrolidinoacetyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido (4,3-b) indole; cis (±) -2,8-dimethyl-5- (4-methyl-1-pyridinium acetyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido (4,3-b) indole chloride or cis (±) -2,8-dimethyl-5- (3-carboxypropionyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido (4,3-b) indole.  36. The compound according to p. 18, representing cis (±) - [2-methyl-5- [2- (6-methyl-3-pyridyl) ethyl] -2,3,4,4a, 5,9b-hexahydro -1H-pyrido (4,3-b) indole trihydrochloride.  37. The compound according to paragraph 24, representing cis (±) -2,2,8-trimethyl-5-n-carbamoyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido (4,3- b) indolium iodide. 38. A method of obtaining selectively mono-quaternized quaternary salts of 5-ω-pyridylalkyl) -2-methyl-2-R ³ CH ₂ -2,3,4,5-tetrahydro-1H-pyrido (4,3-b) indoles (with quaternized a nitrogen atom in position 2) of formula I.3.1 '

in which R ¹ , R ³ , X have the meanings defined in claim 1;
R ¹⁰ is lower alkyl;
t is 0.1 or 2;
k = 1 - 4, an integer,
characterized in that the compound of formula I.1.3a

in which R ¹ , R ¹⁰ , k and t have the above meanings,
react with an equimolar amount of an alkylating agent of the formula R ³ CH ₂ X (in which R ³ and X are as defined above) in an inert solvent capable of dissolving the starting reagents but not dissolving the resulting mono-quaternized quaternary salt (such as hexane, benzene, ether and the like) and the process is carried out at room temperature. 39. The method of obtaining the quaternary salts of 5-substituted 2-methyl-R ³ CH ₂ -2,3,4,5-tetrahydro-1H-pyrido (4,3-b) indoles (with a quaternized nitrogen atom in position 2) of the formula I .3.1

in which R ¹ , R ³ and X have the meanings defined in claim 1;
R ² represents - (CH ₂ ) ₂ —CN or —CONHR ⁵ (where R ⁵ is alkyl, aryl or a COR ¹² group in which R ¹² is alkyl),
characterized in that the compound of formula I.3.1.1a

in which R ¹ , R ³ and X have the above meanings,
subjected to a reaction with an appropriate electrophilic reagent selected from an activated olefin of the formula CH ₂ = CH-Y (in which Y is CN) or an isocyanate of the formula R ⁵ —N = C = O (in which R ⁵ is as defined above) in the presence of a non-nucleophilic bases, such as a sterically hindered third amine. 40. The method according to p. 39, characterized in that when R ² is - (CH ₂ ) ₂ —CN, an activated olefin of the formula CH ₂ = CH — Y (in which Y is CN) taken in in excess, the process is carried out in the presence as a non-nucleophilic base of a highly basic sterically hindered tertiary amine (such as ethyldiisopropylamine, 1,2,2,6,6-pentamethylpiperidine, DBU and the like), taken in an amount of 0.5 to 5 mol.% at room temperature to the boiling point of the reaction mixture. 41. The method according to § 39, wherein R ² is CONHR ⁵ , as the electrophilic acylating reagent, an isocyanate of the formula R ⁵ —N = C = O (in which R ⁵ has the meanings specified in § 39) is used, taken in excess, and the process is carried out in the presence as a non-nucleophilic base of a highly basic sterically hindered tertiary amine (such as ethyldiisopropylamine, 1,2,2,6,6-pentamethylpiperidine, DBU and the like) in an amount of 0.5 to 5 mol.% at room temperature to the boiling point of the reaction mixture. 42. The method of obtaining 2,2-dimethyl-8-R'-5- (2- (2-N, N-dimethylamino ethyl) -5-R'-indolyl-3-methyl) -2,3,4,5 -tetrahydro-1H-pyrido (4,3-b) indole salts of the formula I.3.1 ''

in which R ¹ and X have the meanings defined in claim 1,
characterized in that 5-unsubstituted 2,2-dimethyl-2,3,4,5-tetrahydro-1H-pyrido (4,3-b) indolium salts of the formula I.3.1.1b

in which R ¹ and X have the above meanings,
react with a non-nucleophilic base, such as a tertiary amine (e.g. ethyldiisopropylamine, 1,8-diazabicyclo (5.4.0) undecene-7 (DBU) and the like), in polar solvents when heated.  43. The method according to § 42, wherein a non-nucleophilic base is a highly basic sterically hindered tertiary amine (such as ethyldiisopropylamine, 1,2,2,6,6-pentamethylpiperidine, DBU and the like), in an amount of 0.5 molar equivalent.  44. The method according to § 42, wherein the process is carried out in polar solvents, such as pyridine, DMF, HMPA and the like.  45. The method according to item 44, wherein the process is carried out in pyridine. 46. The method according to p. 42, characterized in that the process is carried out at 50 - 150 ^o C or at the boiling point of the reaction mixture.  47. A method of treating diseases in which the glutamatergic neurotransmitter system is involved in the method of administering to patients a therapeutically effective amount of a compound that is an NMDA antagonist, characterized in that the compound according to claim 1 of formula I or a salt thereof with pharmaceutically acceptable ones is used as an NMDA antagonist acids in an amount of 1 to 200 mg per day.  48. A pharmaceutical composition intended for the treatment of neurodegenerative diseases in the pathogenesis of which the glutamatergic neurotransmitter system is involved, comprising an active agent and one or more pharmaceutically acceptable auxiliary additives, characterized in that the compound of formula I according to claim 1 is used as an active agent or salt with pharmaceutically acceptable acids in an amount of 0.25 to 50.0 mg.

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