JPH09216882A - Hydro-pyrido (4,3-b) indole derivative, production of the same, medicinal composition and treatment - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having an anti-NMDA activity, and useful for the treatment of diseases related to a glutamine agonistic mediator system, especialy chronic degenerative neuropathy, Alzheimer disease, cerebral ischemia, epilepsy, schizophrenia, etc. SOLUTION: This hydro-pyrido [4,3-b]indole derivative is a compound of formula I [broken line is single or double bond; R<1> is H or a lower alkyl; R<2> is 2-(2-N-methyl-N-R<3> -methylamino)ethyl-5-R<1> -indolyl-3-methyl; R<3> is an alkyl, sulfonyl, etc.; X is an anion of an acid; (n) is 0. 1], e.g. 2-methyl-8- isopropyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b]indole hydrochloride. The compound of the formula I is obtained by reacting a compound of formula II [R<11> is a lower alkyl; (k) is 1-4; (t) is 0-2] with an alkylating agent of the formula: R<3> CH2 X in an inert solvent (e.g. hexane) at a room temperature.

Description

Detailed Description of the Invention

The present invention relates to novel hydrogenated pyrido [4,3-b] indole derivatives having pharmacological activity. Especially,
The present invention is directed to substituted tetra- and hexa-hydropyrido [4,3-b] indoles and pharmaceutically acceptable salts thereof, methods for their preparation, pharmaceutical compositions comprising said compounds, and various diseases, especially neurological disorders. Degeneration, eg N
It relates to a method of treatment of Alzheimer's disease (AD) based on its effect on the MDA-receptor and consequently on the activity of glutamate neuromediator system.

The NMDA-receptor represents a subclass of glutamate receptors in the central and peripheral nervous system,
N-methyl-D-aspartic acid (NMDA), the most specific antagonist. In the formation of the receptor-ionopha complex, the NMDA receptor associates with the calcium transport duct of neuromas and its neurological disorders such as ischemic hypoxia, hypoglycemia, convulsions, brain injury and chronic neurodegenerative disorders (especially AD, Its role in the pathogenesis of Huntington's disease, latilism, and amyotrophic lateral sclerosis is determined [JWMcDonald, MVJohnston-Brain Re
s. Rev., 1990, v.15 p p41-70 (and references cited therein)]. The possible regulation of intracellular calcium pools determines the great pharmacological importance of specific antagonists of the NMDA-receptor. Currently many NMDA
Antagonist is an antidepressant [J.Maj, V.Klimek, Z. Rgoez, G.Sk
uza-Pol. J. Pharmacol., 1993, v.45, pp. 549-593; R.
Trullas, P.Skolnic-Eur. J.Pharmacol., 1990, v.18
5, No.1, pp. 1-10], antagonist [RWDunn, R. Corbet,
LLMartin, JFPayack, L.Laws.Ricker, CAWilmot,
DKRush, JFCornfeldt, S. Fielding-Prog. Clin. B
iol. Res., 1990, v.361, (Curr. Future Trends Antico
nvulsant Anxiety, Strok Ther.), pp.495-512], antispasmodics [JMFerkany, WJKrezotarski-Prog. Clin. Bio
l. Res., 1990, v.361, (Curr.Future Trends Anticonvu
lsant Anxiety, Stroke Ther.), pp. 525-541; WJSch
midt, B. Zadow, BDKretschmer-Aminoacids, 1991, v.
1, No.2pp.225-237) and Neuroprotector [S.Field
ing, J.Wilker JC Chernack, V.Ramizer, CAWilmot,
ML Cornfeldt, KARudolphi, LLMartin, JFPayc
k, DKRush-Prog. Clin. Biol. Res., 1990, v.361, p
p.495-512 (Curr.Future Trends Anticonvulsant Anxie
ty, Stroke Ther.); T. Nakao, A. Nishiyama, H. Tanaka,
Y.Morimoto, S.Takehara-Pat.Jap.04, 257, 589 [92,
257, 589] (CO7D495 / 14) February 12, 1991].

Many neuropathies (eg AD, Huntington's chorea, atrophic lateral sclerosis and cerebral ischemia) are associated with excitatotoxic actions (Excitatory A).
minoAcicls and Drug Research, ED, MRSzewczak &
NJHrib, Alan R. Liss, Inc., New York, 1989, p.380
; The NMDA Receptor, EDS.Watkins & CollngridgeG.,
1989, IRL Press). According to the mechanism described above, neuronal hyperexcitation via long-term activation of NMDA-receptors by glutamate results in the excessive transport of calcium ions to cells, which initiates several pathometabolic processes that ultimately lead to neuronal destruction. (DW Choi,
Neurone, 1988, vl pp.623-634). Particularly in the case of AD, massive destruction of neurons is considered to occur as follows. The neurotoxic factor affecting neurodegenerative processes in neurons is the endogenous oligopeptide β-amyloid, which is A
It is contained in a nerve patch freely placed on the surface of the brain of a patient suffering from D (ATPrelli-J. Neurochem, 1988, v. 51, p.
648; yvVanker-Science, 1990, v.250, p.279). According to recent researchers, β-amyloid substantially enhances the glutamate excitatory effect exerted through the NMDA-receptor system (Koh et al., Brain Res., 1990, v.533,
p.315; Mattson et al., J. Nenroschi, 1992, v.12, p.376).
. As a result of the above, concentrations of glutamate mediators, which are non-toxic under normal conditions, are elevated under conditions of β-9 myloidase and become toxic to neurons, thus affecting its destruction.

Therefore, the search for an effective brain NMDA-receptor antagonist capable of preventing the neurotoxic effect of β-amyloid is considered to be an original and developed method for the production of a broad spectrum neuroprotector. To be

SUMMARY OF THE INVENTION As a result of tests carried out on the search for new compounds having anti-NMDA activity, the present inventor has shown that tetra- and hexa-hydro-1H-pyrido [4,3-
b] A large group of indole derivatives was discovered.
The present invention is a novel 2-methyl-5,8-substituted 2,3
4,5-tetra and 2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole,
It relates to its quaternary derivatives having a quaternized nitrogen in the 2-position, as well as to the pharmaceutically acceptable salts thereof described below, which represent one of the aspects of the invention.

Another aspect of the invention is a method for preparing the compounds. A method of treating an illness according to a further aspect of the invention, which comprises administering to the patient an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. In particular, the present invention relates to disorders in the glutamate mediator system, such as neurodegenerative diseases (especially AD, Huntington's chorea), cerebral ischemia, epilepsy, schizophrenia, and some critical conditions (vasospasm, brain disorders, Paralysis) for the treatment of diseases whose etiology is related. A further aspect of the invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention and a therapeutically acceptable inert auxiliary agent such as a carrier, filler or the like.

The object of the present invention is a novel 2-methyl- having the general formula I (having a quaternized nitrogen atom in the 2-position).
5,8-substituted 2,3,4,5-tetra and 2,3
4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole and quaternary salts thereof

Embedded image (In the formula, dotted line and continuous line segment attached to it

Embedded image Is a standard or double bond; R ¹ is H or lower alkyl; R ² is 2- (2-N-methyl-N-R ³ -methylamino) ethyl) -5-R ¹ -indolyl-3. A methyl group, wherein R ¹ is as defined above and R ³ is as defined below, or a group of the general formula

Embedded image (Where: Y is H, halogen, cycloalkyl, ethenyl (optionally mono-, di- or tri-substituted by lower alkyl, mono-substituted by aryl, or β-mono-substituted by COOR ⁴ ). [Wherein R ⁴ is H, alkyl, aralkyl, aryl (optionally mono-, di- or tri-substituted by the substituent A defined below)]; or a group OR ⁴ (wherein R ⁴ is As defined above); alkylsulfonyl; arylsulfonyl; NR ⁵ R ⁶ (wherein R ⁵ and R ⁶ may be the same or different and each independently is H;
Alkyl; cycloalkyl; aralkyl, aryl (optionally mono-, di- or tri-substituted by substituent A as defined below); 2-, 3- or 4-pyridyl; alkylsulfonyl; arylsulfonyl; Or R
^{One of 5} or R ⁶ is COR ⁷ (wherein R ⁷ is H, alkyl, alkoxy, cycloalkyl, aralkyl, aryl (optionally mono-, di- or tri-substituted by a substituent A as defined below). , 2-, 3- or 4-pyridyl); or R ⁵ and R ^{6 taken} together form a group of the general formula: — (CH ₂ ) _2- W— ( CH _{2) 2} (where, W is _{-O -, - (CH 2)} q ( where q =
0, 1 or 2) or

Embedded image (Wherein R ⁸ is H, alkyl, aryl (optionally mono-, di- or tri-substituted by a substituent A as defined below); V is H ₂ or O; r = 0 Or R ⁵ or R ⁶ together with the nitrogen atom to which they are attached is an N-phthalimido group (optionally mono-, di- or tri- or tetra-substituted by the substituent A defined below). COR)); COR
⁹ (wherein R ⁹ is H, alkyl, aralkyl, aryl (optionally mono-, di- or tri-substituted by substituent A as defined below), OH, an alkoxy group, optionally substituted N- Above NR excluding phthalimido group
⁵ R ⁶ , 2-, 3- or 4-pyridyl); CN;
CHal ₃ (wherein Hal is chloro, fluoro or bromo); aryl (optionally mono-, di- or tri-substituted by the substituent A as defined below); 2-3
- and 4-pyridyl (which is mono- or di-substituted by optionally lower alkyl) and 1-R ³ C the corresponding
H ₂ - pyridinium -2, quaternary salts of -3 or -4 (wherein R ³ is as described above); selected from N- azinium the group consisting of N- azolium; trialkylammonium; cycloalkyl ammonium Will be;

Z is O, S or H ₂ ; k is 0 or 1
Is an integer of ~ 4; l, m and n are independently 0 or 1; where: 1) Y may have any of the above definitions only when k + m ≧ 2 and l = 0; 2) When k = 1 = m = 0, Y is halogen, CHa
l ₃ , OR ⁴ , NR ⁵ R ⁶ , other than aryl, trialkylammonium, cycloalkylammonium, N-azinium or N-azolium; 3) Y when k = 1 and l = m = 0. Is halogen, trialkylammonium, cycloalkylammonium, N-azinium or N-azolium; 4) when k = 1, m = 1, and Z = 0, Y is halogen, OH, CN, alkylsulfonyl. , Arylsulfonyl, trialkylammonium, cycloalkylammonium, N-azinium or N-azolium; 5) When k = 1 = 0, m-1, and Z is S, Y is a group NR ⁵ R ⁶ ( wherein R ⁶ is hydrogen) is only; 6) when l = 0, Z is other than _{H 2; 7) k = 0} , and when l = m = 1, It is other than S; R ³ is a group - (CH _{2) k} -Y 'is (wherein Y'
Is as defined for Y and k is as above);

Note that when k = 0, Y'is halogen and the group N
R ⁵ R ⁶ is other than trialkylammonium, cycloalkylammonium, N-azinium or N-azolium; X is an anion of a pharmacologically acceptable acid; Substituent A is independently the following groups. Selected: halogen, lower alkyl, lower alkoxy group, NO ₂ , CN,
COR ⁹ (wherein R ⁹ is as described above except for the pyridyl derivative), CF ₃ , NR ⁵ R ⁶ (wherein R ⁵ and R ⁶
Is as above);

However, a)

Embedded image Is a doublet and when n = 0 and R ¹ is methyl, R ² is H, methyl, benzyl, 2-pyridylmethyl, 2- (6-methyl-3-pyridyl) ethyl, 2-
Other than (4-pyridyl) ethyl, 2- (N, N-dimethylamino) ethyl or 3- (N, N-dimethylamino) propyl; and when R ¹ is H, R ^{2 is} as defined above. Except n-butyl, cyclohexyl, mu-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, general formula R ¹⁰ O- (CH _{2) 2} -
A group of formula (wherein R ¹⁰ is C ₂ -C ₄ alkyl, cyclohexyl or phenyl) or the general formula R ⁵ R ⁶ N- (CH
₂ ) _p- groups, where p = 2 and R ⁵ and R ⁶
Are each ethyl, or R ⁵ and R ⁶ are tetra- or bentamethylene; or p = 3, and R ⁵ and R ⁶ are taken together to form the group — (CH ₂ ) ₂ W (CH
₂ ) _2- (where W is -O-, NCH ₃ , NCH ₂ C ₆ H
₅ )) other than]; b)

Embedded image Is a standard bond and n = 0, when R ¹ is H, R ² is H, methyl, ethyl, benzyl, acetyl,
Chloroacetyl, or (N-morpholino, or N-piperidino or N, N-dimethylamino) acetyl; 3
Other than -chloropropionyl, 3- (3-morpholino) propionyl or 5-chloropentaonyl; when R ¹ is methyl, R ² is H, 2,2,2-trifluoroethyl, 2- (N, N-dimethylamino) ethyl, 3-
(N, N-dimethylamino) propyl, acetyl, 2-
Ethylhexanoyl, other than (E) -2-butenoyl and (E) -cinnamoyl in the case of cis-(−) isomer; c)

Embedded image Is a double bond, and n = 1, R ¹ and R ³
Are each H and X is iodo, R ² is other than H, methyl, ethyl or propyl; R ¹ and R ² are each R, when it is H and X is methylsulfate. ² is other than benzyl; R ¹ is H, R
^{When 3} is methyl and X is iodo, R ² is other than H; when R ¹ is methyl, R ³ is H, and X is iodo, R ² is other than H or methyl; R ¹ is H , R ³ is phenyl, and X is chloro, then R ² is other than H or benzyl; R ¹ is H, R ³ is phenyl, and X
Is iodine, R ² is other than 3- (N, N, N-trimethylammonium) propyliodide) and a pharmaceutically acceptable salt thereof.

The term "halogen" as used herein means chloro, bromo, fluoro or iodo.

The term "lower alkyl" as used in the definitions above and hereinafter refers to an alkyl group having a straight or branched chain containing from 1 to 4 carbon atoms, eg methyl, ethyl, isopropyl. , Butyl, sec-butyl,
tert-butyl and the like.

The term "alkoxy" refers to the group AlkO, where the alkyl component is the alkyl group described above.
Examples of alkoxy groups are methoxy, ethoxy, butoxy and the like.

The term "cyclic alkyl" means a cyclic saturated hydrocarbon group having 5 to 7 ring carbon atoms, examples of which include cyclopentyl, cyclohexyl and the like.

The term "aryl" means an unsubstituted or substituted phenyl or naphthyl group. Substituents in the above groups are halogen (eg chloro, bromo etc.), lower alkyl group (eg methyl, ethyl, isopropyl etc.), lower alkoxy group (eg methoxy, ethoxy, isopropoxy etc.), cyano, nitro, trihalomethyl group. (Eg trifluoromethyl etc.), optionally substituted amino groups (eg amino, dimethylamino, acetylamino N
-Piperidino, N-phthalimido group etc.), acetyl group (e.g. formyl, acetyl, benzoyl etc.), carboxamide group (e.g. N, N-diethylcarboxamide group etc.), carboxy group, carboalkoxy group etc.

The term "aralkyl" means an aryl as defined above appended to an alkyl group as defined above.

The term "cycloalkylammonium" means a substituted ammonium group, of which 2 or 3
The bonds of the book form a non-aromatic mono- or bicyclic ring system, optionally a carbocycle. Examples of suitable substituents are: 1-methylpiperidinium-1; 1,4-dimethyl-1,2,5,6
-Tetrahydropyridinium-1; 4-methylmorpholinium-4; quinuclidinium-1 and the like.

The terms N-azinium and N-azolium respectively represent 6- and 5-membered heteroaromatic cations bound by a quaternization atom and containing no more than two nitrogen atoms in the ring. Meaning, they are also optionally substituted at the free position and optionally annealed. Examples of suitable substituents are: pyridinium-1, iso-quinolinium-2-pyridinium-1,3-methylbenzimidazolinium-1, oxazolinium-3 and the like.

The term "salt with a pharmacologically acceptable acid" is an inorganic type (eg hydrochloric acid type, sulfuric acid type, phosphoric acid type, etc.) and organic type (eg oxalic acid type, citric acid type, tartaric acid type, It includes all pharmacologically acceptable acids of both maleic acid type, succinic acid type, methylsulfonic acid type, p-toluenesulfonic acid type, etc.).

Of the compounds of formula (I) that represent aspects of the present invention, the following formulas (I.1), (I.2) and (I.
Three subgroups of compounds represented by 3) are preferred. Particularly suitable compounds are:

General formula I. 2-methyl-2,3,4,1
5-Tetrahydro-1H-pyrido [4,3-b] indole derivative:

[Chemical 48](Where R¹Is as defined in Formula 1; R^TwoIs
General formula (CH_Two)_kA group of -Y (where Y is H, halo
Gen, cycloalkyl, ethenyl (optionally lower alkyl
Mono-, di-, or tri-substituted by To aryl
More mono-substituted, or COOR^FourBy β-mo
No-substituted [where R^FourIs as defined in Equation 1
Yes]); or OR^Four(Where R ^FourAs defined in Equation 1
Alkylsulfonyl, arylsulfonyl;
NR^FiveR⁶(Where R^FiveAnd R⁶Is as defined in Equation 1
Yes); COR⁹(Where R⁹Is as defined in Equation 1
); CN, CHal_Three(In the formula, Hal is chloro or fluoro.
B or bromo); aryl (optionally in formula 1
Mono-, di- or tri-substituted by the substituent A defined above
2-, 3- and 4-pyridyl (optionally lower
Replaced by rukill) and the corresponding 1-
R^ThreeCH_Two-Quaternary salt (where R^ThreeFormula 1 is as defined
Trialkylammonium; cycloalkyl
Ammonium, N-azinium and N-azolium
K is as described for formula I; where: 1) when k = 0, Y is halogen, CHal_Three, O
R^Four, NR^FiveR⁶, Aryl, trialkylammoniu
Or cycloalkyl ammonium, N-azinium or
Other than N-azolium; 2) when k = 1, Y is halogen, trialkylammonium
Ni, cycloalkyl ammonium, N-azinium
Or other than N-azolium; provided that R¹Is methyl
When, R^TwoIs H, methyl, benzyl, 2-pyridimeti
2-, 6- (6-methyl-3-pyridyl) ethyl, 2-
(4-pyridyl) ethyl, 2- (N, N-dimethylamido)
No) ethyl or 3- (N, N-dimethylamino) propyi
Le; and R¹When is H, R^TwoIs n-butyl
L, cyclohexyl, 4-chlorobenzyl, 2-phenyl
Ruethyl, 2- and 3-pyridyl, 1- (2-pyridyl
) Ethyl, 2- (2-pyridyl) ethyl, 1- (3-
Pyridyl) ethyl, 1- (6-methyl-3-pyridyl)
Ethyl, diethylaminocarbonyl, hydroxymethy
2-methyl-3- (N, N-dimethylamino) pro
Pill, the general formula R above ^FourO- (CH_Two)_Two-Group, or general
Formula R^FiveR⁶N- (CH_Two)_p-Being something other than a base
To be elected) .

General formula I. 2-methyl 2,3,4,4
a, 5,9b-Hexahydro-1H-pyrido [4,3-
b] Indole derivatives:

Embedded image Where R ¹ is as defined in Formula 1; R ² is a group of the general formula:

Embedded image (Where Y, Z, k, l and m are as defined in formula 1); where; 1) when k = 1 = m = 0, Y is halogen, CHa
other than l ₃ , OR ⁴ , NR ⁵ R ⁶ , aryl, trialkylammonium, cycloalkylammonium, N-azinium or N-azolium; 2) Y when k = 1 and l = m = 0. Is other than halogen, tolualkylammonium, cycloalkylammonium, N-azinium or N-azolium; 3) when k = 1, m = 1, and Z is 0, Y is halogen, OH, CN, alkyl. Other than sulfonyl, arylsulfonyl, trialkylammonium, cycloalkylammonium, N-azinium or N-azolium; 4) when k = 1 = 0, m = 1 and Z is S, Y is a group NR ⁵ R ⁶ Only (wherein one of R ⁵ or R ⁶ is hydrogen); 5) when l = 0 and Z is other than H ₂ ; 6) when k = 0, then And when 1 = m = 1, Z is other than S; provided that: when R ¹ is H, R ² is H; methyl;
Ethyl; Hendyl; Acetyl; Chloroacetyl; or (N-morpholino-, N-piperidino- or N, N-diethylamino) acetyl; 3-chloropropionyl; 3
-(N-morpholino) propionyl; or other than 5-chloropentanoyl, and when R ¹ is methyl, R
² is H, 2,2,2-trifluoroethyl, 2- (N,
N-dimethylamino) ethyl, 3- (N, N-dimethylamino) propyl, acetyl, 2-ethylhexanoyl, (E) -2-branoyl and (E)-in the case of cis-(-)-isomer. Other than cinnamoyl).

Formula I. 3-methyl-2-R ³ CH
_{2-2,3,4,5-tetrahydro} - and 2-methyl -
_{^{2-R 3 CH 2 -2,3,4,4a,}} 5, ab- hexahydro -IH- pyrido [4,3-b] quaternary salt of indole (having a line of nitrogen atom at the 2-position):

Embedded image (In the formula, dotted line and continuous line segment attached to it

Embedded image Represents a standard or double bond; R ¹ and X are as defined in formula 1; R ² is 2- (2-N-methyl-NR ³
- methylamino) ethyl) -5-R ¹ - indolyl -3
A methyl group, where R ¹ and R ³ are as described in the formula, and in this case

Embedded image Is a double bond; or a group of the general formula

Embedded image(Where Y, Z, m, l and k are as defined in equation 1)
Note: 1) Y is defined above only when k + m ≧ 2 and l = 0.
2) when k = 1 = m = 0, Y is halogen, CHa
l_Three, OR^Four, NR^FiveR⁶, Aryltrialkyl ane
Monium, cycloalkyl ammonium, N-aziniu
Or N-azolium; 3) when k = 1, m = 1, and Z = 0, Y is
Rogen, OH, CN, alkylsulfonyl, aryls
Rufonyl, trialkylammonium, cycloalkyl
Other than ammonium, N-azinium or N-azolium
4) When k = 1, m = 1, and Z is S, Y is a group
NR^FiveR⁶Only, where R⁶Is hydrogen; 5) when l = 0, Z is H_Two6) When k = 0 and l = m = 1, Z is not S
R; However: R¹And R^ThreeAre each H, and
When X is iodine, R^TwoIs H, methyl, ethyl or pro
Not a pill; R¹And R^ThreeAre H respectively,
And when X is methylsulfate, R ^TwoIs benzyl or less
Outside; R¹Is H, R^ThreeIs methyl and X is iodine
When, R^TwoIs other than H; R¹Is methyl, R^ThreeBut
H, and X is iodine, R^TwoIs other than H or methyl
Yes; R¹Is H, R^ThreeIs phenyl and X is chloro
When R^TwoIs other than H or benzyl; R¹Is H, R
^ThreeIs phenyl and X is iodine, R^TwoIs 3-
(N, N, N-trimethylammonium) propylio
According to the invention (other than zido), the formula I. Of one compound
More preferred compounds of the tetrahydro derivative are: 5- (un) substituted 2-methyl-2 of 1.1,
3,4,5-Tetrahydro-1H-pyrido [4,3-
b] Indore

[Chemical 55](Where R¹Is as defined in equation 1; and Y is
H, cycloalkyl; ethenyl (optionally lower alkyl
By an aryl, mono-, di- or tri-substituted by
Mono-substituted or group (COOR ^FourBy mono
Has been replaced (where R^FourIs as above); 2
-, 3- and 4-pyridyl (optionally with lower alkyl
Mono- or di-substituted).
However, R¹Is methyl, Y is other than H; and
R¹Is H, Y is further cyclohexyl, 2- and 3
-Other than pyridyl).

General formula I. 5- (substituted methyl) of 1.2
-2-methyl-2,3,4,5-tetrahydro-1H-
Pyrido [4,3, -b] indole

Embedded image Wherein R ¹ is as defined in formula 1; Y is H, cycloalkyl; ethenyl (optionally mono-, di- or tri-substituted by lower alkyl, mono-substituted by aryl, COOR ⁴ is β- monosubstituted by (wherein R ⁴ is as defined above)); CN;
CHal ³ (where Hal is chloro, fluoro, or bromo); alkylsulfonyl; arylsulfonyl; aryl (optionally mono-, di-, or tri-substituted by substituent A as defined above); 2-, 3- and 4-
Selected from the group consisting of pyridyl (optionally mono- or di-substituted by lower alkyl); where: when R ¹ is methyl, Y is other than H, phenyl, 2-pyridyl; R ¹ is H Sometimes Y is other than OH and chlorophenyl).

General formula I. 1.3 5- (2-substituted ethyl) -2-methyl-2,3,4,5-tetrahydro-1
H-pyrido [4,3-b] indole:

[Chemical 57](Where R¹Is as defined in formula I; R^TwoIs of formula I.
1 as defined; where: R¹When is methyl,
Y is a dimethylamino group, 6-methyl-3-pyridyl or
Other than -4-pyridyl; R¹When is H, Y is
Phenyl, 2-pyridyl, OR described in formula I^Four, R^FiveR ⁶N
(Where R^FiveAnd R⁶Are each ethyl or
R^FiveAnd R⁶Together with Tetra or pentamethime
Is).

Formula I. The most preferred compounds of 1.3.1 are as follows: 1.3.1 of 5- (2-N-R ⁵ -N ⁶ -R
⁶ -Aminoethyl) -2-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole:

Embedded image Where R ¹ , R ⁵ and R ⁶ are as defined in Formula I; provided that when R ¹ is methyl, R ⁵ and R ⁶ cannot together represent methyl; ^{When 1} is H, R ⁵ and R ⁶ cannot together represent methyl or ethyl, or R ⁵ and R ⁶ together are other than tetra- or pentamethylene).

The general formula I. 5- (2-, 3-) of 1.3
Or 4-pyridylethyl) -2-methyl-2,3,4
5-Tetrahydro-1H-pyrido [4,3-b] indole (I.1.3.2): (wherein R ¹ is as described in formula I; Y is 2-, 3- or 4 -Pyridyl (optionally mono- or di-substituted by lower alkyl); where: when R ¹ is methyl, Y is 6-methyl-
Other than 3-pyridyl or 4-pyridyl; and R ¹
Is H, Y is other than 2-pyridyl).

General formula I. 1.3.3 of 2-methyl-5-
(2-Cyanoethyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole:

Embedded image (Wherein R ¹ is as defined in formula I).

General formula I. 1.3.4 of 5- (2-COR
⁹ -Ethyl) -2-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3, -b] indole

Embedded image Where R ¹ is as defined in Formula 1; R ⁹ is OH,
Alkoxy, NR ⁵ R ⁶ (wherein R ⁵ and R ⁶ are as defined in formula I, except for the phthalimido group).

Formula I. Most preferred of the compounds of general formula I. 1.4 5- (ω-substituted alkyl) -2
-Methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole:

Embedded image Where R ¹ is as defined in Formula I; Y is Formula I.1
As defined above; k represents 3 or 4;
When R ¹ is methyl and k = 3, Y is other than a dimethylamino group; when R ¹ is H and k = 3, Y is a group W
Other than (CH ₂ CH ₂ ) ₂ N (W is O, NC
H ₃ or NCH ₂ Ph), and when k = 4,
Y is other than H).

In accordance with the present invention, the formula I. The most suitable hexahydro derivatives of compounds of formula 2 are: 5- [N-substituted (thio) carbomoyl] -2-methyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole of 2.1:

Embedded image (Wherein R ¹ and R ⁵ are as defined in Formula 1; Z is O or S).

Formula I. 2.2 5- (α- (ω-)-
Substituted alkanoyl-2-methyl-2,3,4,4a,
5,9b-Hexahydro-1H-pyrido [4,3-b]
Indore:

Embedded image (Wherein R ¹ is as described in formula I; Y, k and l
Is of formula I. As defined in 2; where: R ¹ is H, and when l = 0, Y is other than H, N, N-diethylamino or N-piperidino group when k = 1; k = 1 or 2
Is other than N-morpholino group; and when k = 1, 2 or 4 is other than chloro; and when R ¹ is methyl, Y is when k = 1 = 0 or k = 4 and l = 1 , And when Alk is ethyl, it is other than H. )

General formula I. 2-Acyl-substituted-2-methyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole of 2.2.1:

Embedded image Wherein R ¹ is as defined in formula I; Y is H; cycloalkyl; ethenyl (optionally mono-, di- or tri-substituted by lower alkyl, mono-substituted by aryl, COOR ⁴ by β- mono - is substituted (wherein R ⁴ is as defined in formula I); OR ⁴
(Wherein R ⁴ is as defined in formula I, excluding H); N
R ⁵ R ⁶ (wherein 5 ⁵ and R ⁶ are as defined in formula I); COR ⁹ (wherein R ⁹ is as defined in formula I, excluding the OH group); CHal ₃ Wherein Hal is chloro, fluoro or bromo; aryl (optionally defined in formula I. mono-, di- or tri-substituted by substituent A); 2-, 3- and 4-pyridyl ( is mono- or di-substituted by optionally lower alkyl); and the corresponding 1-R ³ CH ₂ - pyridinium -2, -3 or -4 quaternary salt (where R ³ is defined as in formula I And when R ¹ is methyl, Y is other than (E) -propenyl-1 when R ¹ is a cis-(−)-isomer or (E) -2-phenylene. Other than tenil).

General formula 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] indole:

Embedded image R ¹ is as described in formula I; Y is as defined in formula I1.2).

General formula I. 2.2.3 5- (ω-Substituted alkanoyl) -2-methyl-2,3,4,4a, 5
9b-hexahydro-1H-pyrido [4,3-b] indole:

Embedded image Where R ¹ is as defined in Formula I; Y is Formula I.2
Is defined as follows; k represents an integer of 1 to 4; provided that when R ¹ is H, Y is other than H, N, N-diethylamino or N-piperidino when k = 1; k = 1 or Other than N-morpholino group when 2; and other than chloro when k = 1, 2 or 4; and R ¹ is methyl and k =
When 1, Y is other than H).

The next preferred group of hexahydro derivatives consists of: General Formula I. 2.3 5- (ω-substituted alkyl) -2-
Methyl-2,3,4,4a, 5,9b-hexahydro-
1H-pyrido [4,3-b] indole:

Embedded image Where R ¹ is as defined in formula I; k is an integer from 1 to 4; Y is H, ethenyl (optionally mono-, di- or tri-substituted by lower alkyl, COOR ⁴ Β-mono-substituted by wherein R ⁴ is as defined in formula I); CF ₃ ; OR _{4 where} R ⁴ is of formula I
NR ⁵ R ⁶ (in the formula, R ⁵ and R
⁶ is as defined in formula I); where: when R ¹ is H, Y is other than H (when k = 1 or 2) or other than phenyl (when k = 1); and When R ¹ is methyl, Y is other than CF ₃ (when k = 1); and other than a dimethylamino group (when k = 2 or 3)).

The formula I. More preferred quaternary salts of tetrahydro derivatives having 3 are as follows: 3.1 2-methyl -2-R ³ CH ₂ -2,
3,4,5, -Tetrahydro-1H-pyrido [4,3-
b] Quaternary salt of indole (having a quaternized nitrogen atom in the 2-position):

Embedded image Where R ¹ , R ² , R ³ and X are as defined in I; provided that both R ¹ and ³ are H and X is iodo, then R ² is H, methyl, ethyl or Other than propyl; R ¹ and ³ are both H, and when X is methyl sulfonate, R ² is other than benzyl; R ¹ is H,
When R ³ is methyl and X is iodo, R ² is other than H; when R ¹ is methyl, R ³ is H, and X is iodo, R ² is other than H or methyl; 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 iodo, R ² is 3- (N, N, N-trimethyl). Ammonium) other than propyl iodide).

Formula I. Among the derivatives of 3.1, the most preferred groups of compounds are: 3- (un) substituted 2-methyl- of 3.1.1
_2-R ³ CH 2 -2,3,4,5- tetrahydro -1H
A quaternary salt of pyrido [4,3-b] indole:

Embedded image Where R ¹ , R ³ and X are as defined in formula I;
Y is H; cycloalkyl, ethenyl (optionally mono-, di- or tri-substituted by lower alkyl, mono-substituted by aryl, β-mono-substituted by COOR ⁴ , wherein R ⁴ is As above);
Alkylsulfonyl; arylsulfonyl; CN; CO
R ⁹ (wherein R ⁹ is as defined in formula I); 2-,
3- or 4-pyridyl (optionally mono- or di-substituted by lower alkyl); and the corresponding 1-R
³ CH ₂ -Viridinium-2, -3 or -4 is selected from the group consisting of suitable quaternary salts, wherein R ³ is as defined in I: where R ¹ and Y are each H, and when X is iodo, R ³ is other than H or methyl; R ¹ and Y are each H, and when X is chloro, R ³ is other than phenyl; R ³ and Y are each H , And when X is iodo, R ¹ is other than methyl).

Formula I. 3.1.2 5- (substituted methyl) -2-methyl -2-R ³ CH ₂ -2,3,4,5-
Quaternary salt of tetrahydro-1H-pyrido [4,3-b] indole:

Embedded image Where R ¹ , R ³ and X are as defined in formula I;
Y is H, cycloalkyl, ethenyl (optionally mono-, di- or tri-substituted by lower alkyl, mono-substituted by aryl and β-substituted by COOR ⁴ wherein R ⁴ is of the formula I definition. As it is); CN; C
Hal ₃ (where Hal is chloro, fluoro or bromo); alkylsulfonyl; arylsulfonyl;
Aryl (optionally tino, di or tri substituted by a substituent A as described for formula I); OR ⁴ (wherein R
⁴ is as defined in formula I); COR ⁹ (wherein R ⁹
Is as defined in formula I); COR ⁹ (wherein R ⁹ is as defined in formula I); 2-, 3- and 4-pyridyl (optionally mono- or di-substituted by lower alkyl). and has) and the corresponding 1-R ³ CH ₂ - pyridinium -2, quaternary salt of 3 or 4 (wherein R ³ is as defined in formula I); provided that: R ¹ and R ^{When 3} is H and X is iodo, or when R ¹ is methyl and R ³ is H and X is iodo, Y is other than H; and R ¹ and R ³ are H and X, respectively. Is methyl sulfonate, or when R ¹ is H, R ³ is phenyl, and X is chloro, then Y is other than phenyl).

Formula I. 3.1.3 5- (2-substituted ethyl) -2-methyl -2-R ³ CH ₂ -2,3,4,
Quaternary salt of 5-tetrahydro-1H-pyrido [4,3-b] indole:

Embedded image Where R ¹ , R ³ and X are as defined in formula I;
Y is CN, COOAlk; 2-, 3- or 4-pyridyl (optionally being mono- or di-substituted by lower alkyl) and the corresponding 1-R ³ CH ₂ - pyridinium -2, -3 or -4 Is selected from the group consisting of quaternary salts, wherein R ³ is as defined in formula I;
¹ and R ³ are each H, and X is iodine, and Y
Is other than H).

General formula I. 3.1.4 of 5-acyl-2-
Methyl -2-R ³ CH ₂ -2,3,4,5- tetrahydro -1H- pyrido [4,3-b] quaternary salt of indole:

Embedded image Where R ¹ , R ³ and X are as defined in formula I;
Y is cycloalkyl; ethenyl (optionally mono-, di- or tri-substituted by lower alkyl, mono-substituted by aryl, β-mono-substituted by COOR ⁴ where R ⁴ is as defined in formula I) CHal ₃ (wherein Hal is chloro, fluoro or bromo); Aryl (optionally mono-, di- or tri-substituted by the substituent A as defined in formula I); OR ⁴ (wherein R ⁴ is As defined in formula I, with H excluded); NR ⁵ R ⁶ (wherein R ⁵ R ⁶ is as defined in formula I excluding the phthalimido group); COR ⁹ (wherein R ⁹ is OH) as defined in formula I except that); 2-, 3- and 4-pyridyl (optionally being mono- or di-substituted by lower alkyl) and the corresponding 1-R ³ CH ₂ - quaternary salt (as der herein R ₃ is defined as in formula I ) Selected from the group consisting of).

More preferred salts of the hexahydro derivative are: General Formula I. 3.2 5-substituted 2-methyl-2-R ³ C
H ₂ -2,3,4,4a, 5,9b-hexalohydro-
Quaternary salts of 1H-pyrido [4,3-b] indole (having a quaternized nitrogen atom at the 2-position):

Embedded image Where R ¹ , R ³ and X are as defined in formula I;
R ² is a group of the following general formula

Embedded image Where k, l, m and Y are as defined in formula I.3; where: 1) Y has any of the above definitions only when k + m ≧ 2 and l = 0; 2 ) When k = 1, m = 1, Y is halogen, OH,
CN, alkylsulfonyl, arylsulfonyl, trialkylammonium, cycloalkylammonium,
Other than N-azinium or N-azolium; 3) m = 0 only when k = 1 = 0 and Y is alkylsulfonyl, arylsulfonyl or CN).

The most preferred compounds of formula I are: 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-hexamethyleneiminoethyl) -2,
3,4,5-lH-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 iodo; 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-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-trimetal 1-5- (2-ethoxycarboethoxyethyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indolium iodide;

2,2,8-Trimethyl-5- (5-methyl-2- (2-N, N-dimethylaminoethyl) indolyl-3-methyl) -2,3,4,5-tetrahydro-
20. The compound according to claim 19, which is 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-
(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; cis- (±) -2,8
-Dimethyl-5- (N-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, 5,9
b-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- (2
-Promopropionyl) -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-1
H-pyrido [4,3-b] indole bromide.

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; ci
s- (±) -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 crocodile; 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 trihydrochloride; cis- (±) -2,2
8-trimethyl-5-n-carbamoyl-2,3,4
4a, 5,9b-hexahydro-1H-pyrido: [4,
3-b] Indolium iodide.

The compounds of formula I according to the present invention are prepared using procedures known to those skilled in the art for the preparation of similar compounds or using the novel methods described below.

According to the invention, the compounds of the formula I.1 having various substituents in the 5 and 6 positions are represented. The main process for preparing the tetrahydro derivative of pyrido [4,3-b] indole of 1 is carried out according to a novel reaction that builds a tricyclic nucleus utilizing a Fischer condensation process.

According to the method described above, the formula I. Derivatives encompassed by 1 wherein R ² is hydrogen (ie, 5-unsubstituted derivative) or ω- (Y-substituted) alkyl can be prepared.

The Fischer cyclization involves the reaction of a para-substituted phenylhydrazine of formula II (or its salt with a mineral acid) with 1-methylpiperidone-4 (III) according to the following scheme [eg N .Barbulescu, C.Bornaz, C.si
Greff Rev. Chim (Bucresti), 1971, v.22, p.269)

Embedded image (Where R ¹ and R ² are as defined in formula I.1),

The tetrahydro derivatives of formula I in which R ² is other than hydrogen, and the hexahydrogenated and quaternized derivatives are obtained by reaction of the 5-substituted tricyclic derivatives described above.

Formula I. 5- (ω-substituted alkyl)-
2-Methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole has the formula I.I. 5-Substituted derivative of 1a (ie, a compound of formula I.1.1 where Y is H)
And an electrophile IV in the presence of a strong base according to the following scheme (e.g. NF Kucherova,
NMSharkova, VAZagorevsky-USSR Inventor Certificate 2613
86 (CO7C) description]

Embedded image

In Formula IV, the symbol X represents a nucleofugal group (eg halogen, alkyl- or arylsulfonyloxy); Y represents Formula I. 1 as defined, except that each group is unstable under the conditions of the pre-reaction (eg C
OOAlk, N-azinium, N-azolium, etc.), K
Is an integer of 1 to 4.

Formula I. 1.1a of the 5-unsubstituted tetrahydro derivative with an equimolar amount of a strong base (eg sodium, sodium hydride, sodium amide, preferably sodium hydride) and a polar aprotic solvent such as DMFA (dimethylformamide), DMSO (dimethyl. Sulfoxide), HMPTA (hexamethylphosphorum triamide), preferably DMFA, and then the alkylating agent of formula IV is added at a temperature of about 20-170 ° C, preferably at a temperature of about 60-130 ° C. To do.

Formula I. 1.3 'compound (ie, Y is CN
Or an optionally substituted 2-, 3- or pyridyl of Formula I. The compound of formula 1.3 has the formula: 1.1. the same starting compound as a (ie, a compound of formula I.1.1 where Y is H)
Prepared by alkylation according to the following scheme with an electrophilic alkene of formula V in the presence of a catalytic base (eg, NNKamzolova, NFKucherova, VAZagore
vsky's Zh, O, Khim, 1964, v. 34, No. 7, pp
2383-2387 and ANKost, MAJurovskaya, T.
Inventor Certificate USSR367 of V. Melnilova, OlPotanina
049 (COD7) stated on November 2, 1970]

Embedded image In formula V, Y is CN or 2-, 3- or 4-pyridyl, which is optionally mono- or di-substituted by lower alkyl.

According to this reaction scheme, the process is To obtain a derivative of 1.3 '(ie a compound of formula I.1.3 where Y is CN) an excess of the reagent of formula V (room temperature) in the presence of a catalyst (eg a quaternary ammonium alcoholate) ( Where Y is CN). Formula I. 1.3 '(ie, the compound of formula I.1.3 where Y is 2-, 3- or 4-pyridyl) 2-
The reaction of the [2- (3- or 4-) pyridyl] ethyl derivative uses an equivalent amount of the corresponding reagent of Formula V and a suitable strong base (eg, sodium, sodium hydride, sodium ethoxide, etc.), or Polar aprotic solvent (eg DMF
A, DMSO, HMPTA (preferably DMSO).

Formula I. The oxygen-containing derivative of 1.3.4, wherein R ⁹ is OH or alkoxy, has the formula I.2. 1.
It can be prepared via solvolysis of the nitrile of reaction 3.3 in water or a suitable alcohol under standard conditions [eg NNKamzolova, NFKucherova, VAZagore.
vsky's Zh, O, Khim, 1964, v. 34, no. 7, p
p2383-2337].

Formula I. The hexahydro derivative of 2 has formula I. 1
2-methyl-2,3,4,5-tetrahydro-1H-
Pyrido [4,3-b] C _4a by reducing the double bond in the -C _9b, or new hexahydro derivatives useful by conversion those with or already exists in the introduction of functional groups in the indole Is prepared by chemical modification. Formula I. Reduction of the C _4a -C _9b double bond in 2-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole of 1 with the corresponding reducing agent can be carried out. Yes, and (independent of later type)
Formula I. 1-substituted 2-methyl-2,3,4,4a, 5
The cis-isomer of 9b-hexahydro-1H-pyrido [4,3-b] indole (NK Kochetkov, NF Kuchero
va, IGZhukova-Khim, 1961, v. 31 No.
3, pp 924-930 and NF Kucherova, NMSipil
ina, N, N.Novikova, ID Silenko, SG Rosenborg,
VAZagrorevsky-Kh. Get. Soed., 1989, No. 1
0, pp. 1383-1386) or Formula I. against C _4a -C _9b bond 2-substituted 2-methyl-2,3,4,4
a, 5,9b-Hexahydro-1H-pyrido [4,3-
b] the trans isomer of indole is provided (VAZagror
evsky, SG Rosenbers, NMSipilira, LNBikova,
AP Rodionovh-Zh. Vses. Khim. Ob., 1932, v.
27, No. 1, pp. 102-10 4; and JG Ber
ger-Synthesis, 1974, No. 7, p
p. 503-510).

In particular, the formula I. The cis-isomer of 2 is the I.D. 1
From about 2 to about 4 of the tetrahydro derivative of the above in zinc oxide (and similar metals) in a strongly acidic medium (such as hydrochloric acid); or in its carboxylic anhydride (such as trifluoroacetic acid) with its alkali metal borohydride. It is prepared by reduction at a temperature of 100 ° C .; while the trans isomers are borane and the formula I.I. 1 complex with tetrahydro derivative (1: 1) (formed from corresponding base and borane solution (ib
(after sitin or pre-isolation) or the corresponding hydrochloride and sodium borohydride and formed in ether solvent)
It is prepared by heat treatment with a mineral acid (for example, hydrochloric acid).

Formula I. 2.1 ′ N-unsubstituted 5-carbamoyl or 5-thiocarbamoylhexahydro derivatives (ie, compounds of formula I.2.1 where R ⁵ is H) are of formula I.2.
2.3 unsubstituted 5-methyl 2-methyl-2,3,4,4a,
5,9b-Hexahydro-1H-pyrido [4,3-b]
Indole (ie, Formula I.2. Where Y is H and k = 0.
3. Of the compound) and an alkali metal cyanate or thiocyanate of formula VI according to the following Uchime reaction:

Embedded image (In formula VI, M is Na, K; or 0 or S). The reaction is carried out with hot water at 80 to 100 ° C.

Formula I. 2.2. And I. The respective 5-acyl- and 5- (N-substituted (thio) carbamoyl) -2-methyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3- b] indole is of the formula I.I. where Y is H and k = 0. 2.3 Acylating Agent of 5-Unsubstituted 2-methyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido- [4,3-b] indole, Acid Anhydride or Acid Halide And alkyl-cycloalkyl- or aryl-iso (thio) cyanates (e.g. N.
Zh.O.K of K.Kochetkova, NFKucherova, IG Zhukova
him., 1961, v. 31, No. 3, pp924-9
30]].

Formula I. wherein Y is a nucleophilic group (eg an alkoxy, aryloxy, amino, cyano, N-azinium or N-azolium group). The 5- (α- (ω-)-substituted alkanoyl) -hexahydro-derivative of 2.2 is of the formula I.
2.2-5- (α- (ω) -halogen-substituted alkanoyl) -2-methyl-hexahydropyrido [4,3-
b) indole (ie formula I.2.
2 compounds), various C, N or O of halogen
-Prepared by a nucleophilic substitution reaction according to the following scheme with a nucleophile (VII) (e.g. NF Kucherova, I.
G.Zhukova, NNKamzolova, Ml Petruchenko, NM S
harkova, Zh. O. Khim., NK Kochetkov, 1961,
v. 31, No. 3, pp930-936]:

Embedded image In the above formula, k and l are as defined in formula I, with k + 1 ≧ 1 and Y ¹ is chloro, bromo or iodo. The nucleophile can include the following compounds: in a suitable polar solvent (eg benzene, acetonitrile, alcohol, etc.) or in excess of the nucleophile (VII) from about 20 ° C. to the reflux temperature of the reaction mixture. Cyanides and alcoholates of alkali and alkaline earth metals or tetraalkylammoniums, as well as secondary (NHR ⁵ R ⁶ ) or tertiary (Alk ₃ N, azines, azolfamines.

Formula I. The quaternary salt of the tetrahydro-pyrido [4,3-b] indole of 3.1 can be prepared by two methods: Formula I. Corresponding alkylating agent for the 2-methyl-tetrahydro-pyrido [4,3-B] indole of 1 R ³ CH ₂ —X (formula IX) or 2-R ³ CH ₂ —
Reagent Me-X with tetrahydroindole (formula Q ₁ )
According to (Equation VIII) [MA Jurovskaya, LI Rodionov Khim. Geterocycl. Soed. , 198
1, No. 8, pp. 1072-1078] Quaternization according to the following scheme:

Embedded image(Where R¹, R^Two, R^ThreeAnd X is as defined in formula I
Yes, and the substituent R ^TwoAnd R^ThreeIs a quaternized functional group (eg
For example, 2-, 3- or 4-pyridyl, or a substituted amino group
Etc.) must not be included).

According to this scheme, the reaction is carried out at room temperature in a solvent which readily dissolves the starting reagents but does not dissolve the quaternary salt formed (eg benzene, ether, etc.).

The second nucleophilic center is of formula I. When it is in a tetrahydro derivative of 1 and its center is quaternary (eg in the 5- (2-pyridylalkyl) tetrahydro derivative of formula I.1.2.2), the quaternization process is non- Can be selective. In developing the present invention, the inventor investigated alternative methods for the quaternization process.

Therefore, according to a second aspect of the present invention,
I. 5- (ω-pyridylalkyl) base of 1.3a (immediately
Formula I. Compound of 1.3: wherein Y is 2-, 3- or
4-pyridyl, optionally with a lower alkyl mono
-Or di-substituted) alkylating agent R^ThreeCH_Two
-X (formula IX: in the formula, R^ThreeAnd X are as defined in formula I
The starting reagent becomes soluble, but the mono
The quaternized quaternary salt does not dissolve at all in an inert solvent (eg hex
Sun, benzene, etc.) by formula I.I.
3.1 '5- (ω-pyridylalkyl) 2-2-methyi
Le-2-R^ThreeCH _Two-2,3,4,5-tetrahydro-
1H-pyrido [4,3-b] indole (ie, formula I.
Compound of 1.3: wherein Y is 2-, 3- or 4-pyridy
And optionally mono- or di- by lower alkyl.
(Substituted) selective mono-quaternized quaternary salt preparation
A process for manufacturing is proposed, and this process is
It is carried out at room temperature.

Formula I. A 3.1 ″ diquaternized 5- (ω-pyridylalkyl) tetrahydro derivative (ie, Formula I.3.
Compounds of 1 wherein Y is 1-R ³ CH ₂ -pyridinium-2, -3 or -4, optionally mono- or di-substituted by lower alkyl) May be carried out by the process: 5-fold excess of alkylating agent R
³ CH ₂ -X wherein by the action of (formula IX) I. Of the corresponding base 1.3a di - alkylating agent quaternization with or 3-5 fold excess R ³ CH ₂ -X (wherein IX) or R ³ 'CH ₂ -X
Formula I. by the action of (Formula IX '). 3. Depending on either further alkylation of the mono-quaternized derivative of 3.1 '. In the latter case, the asymmetric quaternized derivative I.S. 3.1 "is formed (when R ³ 'and -R ³ are different).

In general, the quaternization process is represented by the following scheme:

Embedded image

In the above equation, R¹, R^ThreeAnd X is the formula
As defined in I, R^Three'Is R ^ThreeDefinition of
And R¹¹Is lower alkyl and k is an integer of 1 to 4
Represents a number and t is 0, 1 or 2.

Formula I. 3.1.3 (where Y is 1-R ³ C
H ₂ -pyridinium-2, -3 or -4) 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 salt of 3-5-fold excess of quaternizing agent R ³ CH ₂ -X ( IX)
The monoquaternized salt is selectively prepared by di-quaternization in a polar solvent (eg, acetonitrile, methanol, etc.) that at least partially dissolves the reaction mixture from about 20 ° C. to the reflux temperature of the reaction mixture. It

Another process according to the invention is the monoacid formula I.I. 3.1 (In the formula, R ² is — (CH ₂ ) ₂ —CN, −
(CH _{2) 2} -COOAlk, a -CONHR ^5,
Where R ⁵ is alkyl, cycloalkyl, aryl, C
OR ¹² wherein R ¹² is an alkyl or alkoxy group) 5-substituted 2-methyl-2-R ³ CH ₂ -2.
3,4,5-Tetrahydro-1H-pyrido [4,3-
b] represents the preparation of a quaternized salt of an indole (having a quaternized nitrogen atom in the 2-position). The process is described in Formula I. Catalyst of 5 Unsubstituted Derivatives of 3.1.1a (ie, Compound of Formula I.3.1.2 where Y is H) with Electrophilic Alkylating Agent or Acylating Agent E (Non-nucleophilic Base) Carried out by reaction according to the above scheme in the presence of:

Embedded image (In the formula, R ¹ , R ³ and X are as defined in formula I.3.1, and R ² is — (CH ₂ ) ₂ —CN, — (CH ₂ ) ₂
-COOAlk, -CONHR ⁵ , COR ¹² , and E
The formula _{CH 2 = CH-CN, CH} 2 = CH-COOAlk
Or R ⁵ —N═C═O (wherein R ⁵ is alkyl, cycloalkyl, aryl), R ¹² —CO—X ′ (wherein R ¹² is an alkyl or alkoxy group, X ′ is halogen or — O-COR ¹² )).

Formula I. 3.1 (In the formula, R ² is-(CH ₂ ).
₂ CN-of (CH ₂₎ a ₂ -COOAlk) 5-
(2-substituted ethyl) -2-methyl -2-R ³ CH ₂ -
2,3,4,5-Tetrahydro-1H-pyrido [4,3
-B] according to the invention and the above scheme to obtain the indolium salt, according to formula I. 5- unsubstituted 2-methyl -2-R of 3.1.1a ³ CH ₂ -2,3,4,5- tetrahydro -1H- pyrido [4,3-b] excess activation of the indolium salt An olefin and 0.5 to 5 mol% of a non-nucleophilic base (eg a highly basic sterically hindered tertiary amine such as ethyldiisopropylamine, DBU (1,8-diazabicyclo [5.4.0] undecene- 7), 1, 2,
The reaction is carried out in the presence of 2,6,6-pentamethylpiperidine, etc.) at about 20 ° C. to the reflux temperature of the reaction mixture.

Formula I. 3.1 (wherein R ² is CONH
R ⁵ : wherein R ⁵ is alkyl, cycloalkyl, aryl) 5- (N-R ⁵ -carbamoyl) -2-methyl-2-R ³ CH ₂ -2,3,4,5-tetrahydro- 1H- pyrido [4,3-b] indolium salt as similar, 5- unsubstituted 2-methyl -2-R ³ CH ₂ -
2,3,4,5-Tetrahydro-1H-pyrido [4,3
-B] Excess amount of indolium isocyanate R ^5-
N—C = 0 (wherein R ⁵ is alkyl, cycloalkyl,
It is prepared by reaction with an aryl) in the presence of 0.5 to 5 mol% of the above non-nucleophilic base as a catalyst at about 20 ° C. to the reflux temperature of the reaction mixture.

When the process according to the invention is carried out with a carboxylic acid derivative as acylating agent E, for example an acid anhydride or an acid halide, the catalyst used is a tertiary amine or the corresponding carboxylic acid salt with an alkali metal. (For example, sodium or potassium salt). Reaction with an acid anhydride is described by Formula I.I. 3.
1.4 of 5 acyl - substituted 2-methyl -2-R ³ CH
_It results in the formation of the 2-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indolium salt.
The reaction is carried out with an excess of reagent, in the presence of a molar equivalent (relative to the original salt) of the catalyst, the acid H liberated during the reaction.
This is done to join X '.

In accordance with the following aspects of the invention, Formula I. 3.1 ″
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--I
H-pyrido [4,3-b] indolium salt (ie R ²
There ^{5-R 1 -2-R 3} CH 2 NMe- (CH 2) 2 - Formula I. indolyl-3-methyl 3.1 compound) is provided. This process is
Formula I. 3.1.1a 5-unsubstituted 2-methyl-2-R ³
CH _{2-2,3,4,5-tetrahydro} -1H- pyrido [4,3-b] indolium salt (i.e., a compound of formula I.3.1.1 Y is H) with a non-nucleophilic base With a heating reaction according to the following scheme:

Embedded image This reaction is carried out in a suitable polar solvent (eg pyridine, DMF).
A, HMPTA and the like; preferably pyridine), 0.5 mol of highly sterically hindered tertiary amine (eg, ethyldiisopropylamine), 1,2,2,6,6-pentamethylpiperidine, DBU, etc.) It is used as a non-nucleophilic base in an equivalent amount and is carried out at a temperature of about 50 to 150 ° C. or at the reflux temperature of the reaction mixture.

Formula I. The 5-reduced hexahydro-1H-pyrido [4,3-b] indole of 3.2 (wherein R is
² is an acceptor substituent) is prepared according to the invention according to a preparation method analogous to the preparation of tetrahydro derivatives. The process of donation, 5- substituted 2-methyl - hexahydro -1H- pyrido - [4,3-b] indole (formula I.3.2) or 5-substituted _2-R ³ CH 2 - hexahydro -1H An excess of the corresponding base of the pyrido [4,3-b] indole (formula Q ₂ ) of the corresponding alkylating agent R ³
Including quaternization with CH ₂ —X (formula IX) or Me—X (VIII) according to the following scheme:

Embedded image (Wherein R ¹ , R ² , R ³ and X are as defined in formula I.3.2).

The reaction is carried out in a suitable inert solvent (eg acetonitrile, benzene, ether etc.) from room temperature to the reflux temperature of the reaction mixture.

Pyrido [4,3 used as a starting compound
Derivatives of b-indoles can in most cases be readily obtained via the above method. Other starting reagents are commercially available and can be purchased primarily from Aldrich Chemical Co.

The invention is illustrated in more detail by the examples for the preparation of representative compounds. The structure of the prepared compound was confirmed by spectral and chemical analysis data, and other physicochemical properties. Melting points are not corrected. NMR spectrum is Brucker CXP-20
Recordings were made using the 0 instrument (at 200 MHz). The multiplet of the signal obtained is abbreviated: (s) -unary,
(D) -doublet, (t) -triplet, (g) -quartet and (m) -multiplet. For some compounds, the molecular weight was determined according to the molecular ion (M ^T ) peak in its mass spectrum. Mass spectra were recorded with a Varian-311 instrument by direct injection of the sample.
These examples are provided for purposes of illustration and are not intended to limit the invention in any way.

[0082]

【Example】

Example 1 2-Methyl-8-isopropyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride (Compound 1) 0.19 g (1 mmol) in 3 ml ethyl alcohol. Of 4
-Isopropylphenylhydrazine hydrochloride and 0.12
1 ml of a mixture of N-methylpiperidone-4 (1 mmol)
After refluxing for 2 hours, 2 ml of ethanol saturated with hydrogen chloride are added and refluxing is carried out for a further 2 hours, the mixture is brought to 0.
Chilled, the precipitate was filtered, washed with a minimal amount of cold water and crystallized from aqueous ethanol. The yield of hydrochloride salt (1) was 0.20 g (75%). m. p. 200
-202 ° C. The free base is prepared by adding to it an aqueous solution of sodium hydrochloride IN adjusted to pH 8-10. Recrystallization is done from aqueous ethanol. MP171-
173 ° C. Found;%; C78.63; H9.25; N12.07. CH ₁₅
H ₂₀ N ₂ . Calculated value,%: C78.92; H8.81; N12.27. PMR
Spectrum _{(CD 3 CN + DMSO-d} 6, ppm, δ): 1.23 (6H, d, (C
H ₃ ) ₂ CH, J = 7Hz); 2.40 (3H, s, NCH ₃ ); 2.74 (4H, m, 3-
and 4-CH ₂ ); 2.88 (1H-septet, (CH ₃ ) ₂ CH, J = 7Hz); 3.
50 (2H, s, 1-CH ₂ ); 9.92 (1H, d, 6-H, J = 7Hz), 7.10
(1H, s, 9-H), 7.20 (1H, d, 7-H, J = 7Hz), 10.17 (1H,
s, NH).

Example 2 2,8-Dimethyl-5- (2,4-dimethylbenzyl)
-2,3,4,5-tetrahydro-1H-pyrido [4,4
3-b] Indole hydrochloride (compound 2) To a suspension of 0.48 g (20 mmol) sodium hydride in 6 ml DMFA 2 g (10 mm) in 10 ml DMFA.
ol) 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole is added dropwise over 30 minutes. Then 1.65 in 10 mmol DMFA
A solution of g (11 mmol) of 2,4-dimethylbenzyl chloride is added. The mixture is stirred at 80 ° C. for 30 minutes. Finally, DMFA is evaporated under vacuum. The residue is extracted with ether (3 x 50 ml), the ether extracts are combined, washed with water and dried over sodium sulfate. The ether is removed by evaporation, the residual oil is dissolved in ethanol and converted to the hydrochloride salt (2) by addition of hydrogen chloride ethanol to saturation, then evaporated in vacuo. The precipitated salt (2) is recrystallized from absolute ethanol. The base yield is 1.42 g (40%). Example;%; N 8.20. CH ₂₂ H ₂₆ N ₂ HCl. Calculated value,
%: N 7.89. PMR spectrum ((CD ₃ ) ₂ CO, ppm, δ): 2.
33; 2.24; 2.40 and 2.46 (12H, 4s, 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 (6
H, m, 6-, 7-, 9-, 3'-, 5'- and 6'-H).

By a similar procedure, the following compound is prepared: 2,8-dimethyl-5- (2-diethylaminoethyl)
-2,3,4,5-tetrahydro-1H-pyrido [4,4
3-b] Indole dihydrochloride (Compound 4); Yield 73
%, M. p. 205-207 ° C. 2,8-Dimethyl-5- (2-piperidinoethyl)-
2,3,4,5-Tetrahydro-1H-pyrido [4,3
-B] indole dihydrochloride (compound 5); yield 54%,
m. p. 264-265 ° C. 2,8-Dimethyl-5- (2-hexamethyleneiminoethyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole dihydrochloride (Compound 6); Yield 47% , M. p. 206-207 ° C. 2,8-Dimethyl-5- (2-dibenzylaminoethyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole dihydrochloride (Compound 7); Yield 71% , M. p. 218-219 ° C.

Example 3 2,8-Dimethyl-5- (2-cyanoethyl) -2,2
3,4,5-Tetrahydro-1H-pyrido [4,3-
b] Indole (Compound 8) 5 g (25 mmol) of 2, in 25 ml of acronitrile.
8-dimethyl-2,3,4,5-tetrahydro-1H-
Slowly into a solution of pyrido [4,3-b] indole,
And while stirring, 1.037 in 3 ml of ethanol.
g (4 mmol) of trimethylphenylammonium benze
Solution obtained by mixing sulfonate.
Add 25 ml, then 0.09 in 2 ml ethanol
2 g (4 mmol) of filtered solution are added. The fever process is over
1 hour later, the acrylonitrile was evaporated.
The residue, filter the residue, and
Wash with ether. Yield 5.21g (67%), m.p. 12
7-128 ℃ (from heptane). Measured value: M⁺253. C₁₆H₁₉
N_Three・ Calculated value: M⁺253. IR spectrum: ν = 2260cm ^-1(C
≡ N). PMR spectrum (CD_ThreeCN, ppm, δ): 2.33 (6H, s,
2-and 8-CH_Three); 2.45 and 2.60 (4H, 2m, 3- and 4-C
H_Two); 2.83 (2H, t, β-CH_Two, J = 7Hz); 3.48 (2H, s, 1-
CH_Two); 4.20 (2H, t, α-CH_Two, 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 9) A mixture of 0.93 g (3.6 mmol) of nitrile 8 and 4 ml of 15% sodium hydroxide in ethanol is refluxed for 5 hours. The ethanol was removed in vacuo and the residue was adjusted to pH 1 with hydrochloric acid.
Acidify and crystallize by evaporation under vacuum. The precipitate is filtered and recrystallized from ethanol. Yield 1 g (89%), mp 170-171 ° C. Found;%; C59.88; H6.62; N 8.48. C ₁₆ H ₂₀ N ₂ O ₂ / HCl
・ 0.75H ₂ O). Calculated value;%: C59.96; h7.05; N8.71. PM
R spectrum (Py-ds, 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 2,8-Dimethyl-5- (2-carboxyethyl)-
2,3,4,5-Tetrahydro-1H-pyrido [4,3
B) Indole hydrochloride (compound 10) 3.6 g (14 mmol) of nitrile 8 are refluxed for 6 hours with an excess of stanol saturated with hydrogen chloride. The alcohol is removed by evaporation and the residue is recrystallized from absolute ethanol. Yield 2.4g (80%),
mp 184-186 ° C. Measured value;%; C63.89; H7.86; N 8.
31. CH ₁₈ H ₂₄ ClN ₂ O ₂ .HCl. Calculated value;%: C64.17; H
7.75; N8.32. IR spectrum: ν = 1200 (CO), 1728 (C =
0) cm ^-1 . PMR spectrum of base (CDCl ₃ , ppm, δ): 1.2
0 (3H, t, CH ₃ -CH ₂ , J = 7Hz); 2.40 (3H, s, 8-CH ₃ ); 2.
54 (3H, s, 2-CH ₃ ); 2.70 (2H, t, β-CH ₂ , J = 8Hz); 2.
86 (4H, m, 3-, and 4-CH ₃ ); 3.62 (2H, s, 1-CH ₂ );
_{4.10 (2H, q, CH 3} -CH 2, J = 7Hz), 4.30 (2H, t, α-CH 2, J = 8
Hz); 6.97 (1H, d, 6-H, J = 8Hz); 7.16 (1H, d, 7-H, J =
8Hz); 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] indole bromide (Compound 10) 0.4 g (20 mmol) of 2.8 in 10 ml of benzene
-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole and 1.13 g (4 mmo
l) N- (4-bromotyl) phthalimide is dissolved with stirring. After 5 days, the precipitate is filtered, washed with benzene and recrystallized from ethanol. Yield 1.02g
(67%), mp 236-238 ° C. Measured value;%; C62.35; H5.
87. C ₂₅ H ₂₈ BrN ₃ O ₂ . Calculated value;%: C61.97; H5.90. 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 = 8Hz); 7.1
7 (1H, s, 9-H), 7.25 (1H, d, J = 8Hz, 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 chloride (compound 11) 0.5 g (1.63 mmol) of 2 in 10 ml of benzene.
-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 mmo
The mixture of methyl iodide from l) is left for 24 hours, the precipitate is filtered, washed with benzene and recrystallized from ethanol and dried in vacuo. Yield 0.61g (85%), mp 20
0-201 ℃. Found;%; C56.27; H5.93. C ₂₁ H ₂₆ IN ₃ .
Calculated value;%: C56.36; H5.86. PMR spectrum (DMSO-d ₆ ,
ppm, δ): 2.38 (3H, s, 6-CH ₃ ); 2.80 (2H, t, 4-C
_{H 2, J = 4Hz);} 3.0 (2H, t, β-CH 2, J = 6Hz); 3.13 (6H,
_{s, N (CH 3) 2} ); 3.70 (2H, t, 3-CH 2, J = 4Hz); 4.33 (23,
t, α−CH ₂ , J = 6Hz); 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 = 8Hz, J = 2Hz); 7.53 (1H, d, 5'-H, J = 8Hz); 8.0
0 (1H, d, 2'-H, J = 2Hz).

Example 8 2,2-Dimethyl-5- [2- (1,6-dimethyl-3
-Pyridinium) ethyl] -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indolium geode (compound 12) 0.306 g (1 mmol) of 2- in 10 ml of methanol.
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)
The methyl iodide solution of was refluxed for 5 hours, the precipitate was filtered,
Wash with methanol and crystallize from ethanol. Yield 0.56g (95%), mp 307-309 ° C. Measured value;
%; C44.89; H5.10. C ₂₂ H ₂₆ I ₂ N ₃ . Calculated value;%: C44.82
H4.96, PMR spectrum (DMSO-d ₆ , ppm, δ): 2.72 (3
H, s, 6-CH ₃ ); 3.16 (4H, m, 4- and β-CH ₂ ); 3.24 (6
H, s, N (CH ₃ ) ₂ ); 3.85 (2H, t, 3-CH ₂ , J = 6Hz); 4.18
(3H, s, 1′-CH ₃ ); 4.41 (2H, t, α-CH ₂ , 7 = 7Hz): 4.75
(2H, s, 1-CH ₂ ); 7.00-7.24 (2H, m, 7- and 8-H); 7.
44 (1H, d, 9-H, J = 8Hz); 7.58 (1H, d, 6-H, J = 8Hz);
7.96 (1H, d, 4'-H, J = 8Hz); 8.30 (1H, d, 5'-H, J = 8
Hz); 9.05 (1H, s, 2'-H).

In a similar manner, the following is prepared: 2,2,8-Trimethyl-5- [2- (1,6-dimethyl-3-pyridinium) ethyl] -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indolium George De (compound 13); yield 90%, m.p. p. 30
6-307 ° 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); 0.61 g (2 mmol) of 2-methyl-5- (2 in 5 ml of benzene.
(6-Methyl-3-pyridyl) ethyl) -2,3,4
5-Tetrahydro-1H-pyrido [4,3-b] indole in 3 ml benzene. 0.56 g (2 mmol) of p
A solution of promofecilpromide is added dropwise without stirring, after 10 hours the precipitate is filtered, washed with benzene and recrystallized from acetone. Yield 1.08g (93%),
mp 177-178 ° C. Found:%: C57.69; H 5.00. C ₂₈ H
₂₉ Br ₂ N ₃ O. Calculated value;%: 57.82; H5.03. PMR spectrum (DMSO-D ₆ , ppm, δ): 2.30 (3H, s, 6-CH ₃ ); 2.99 (4
H, 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, 2s,
1-CH ₂ and NCH ₂ CO, J = 14Hz); 5.38 and 5.56 (2H, 2d, N
CH ₂ CO or 1-CH ₂ , J = 16Hz); 7.00-7.40 (4H, m, 6-, 7
-, 8- and 9-H); 7.41 (1H, dd, 4'-H, J = 8Hz, J = 2Hz)
; 7.50 (1H, d, 5′-H, J = 8Hz); 7.78 (1H, d, 2 meta
-H, J = 8Hz); 7.98 (1H, d, 2other-H, J = 8Hz); 8.12
(1H, s, 2'-H).

In a similar manner, the following is prepared: 2,8-Dimethyl-2-phenacyl 5- [2- (1,6
-Methyl-3-pyridinyl) ethyl] -2,3,4,5-
Tetrahydro-1H-pyrido [4,3-b] indolium bromide (Compound 15); yield 80%, m.p. p. Fifteen
5-160 ° 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 solution of 0.253 g (1 mmol) of nitrile 8 in 20 ml of acetone was added 0.12 ml (2 mmol) of methyl iodide with stirring and after 24 hours. The precipitate is filtered, washed with acetone, recrystallized from ethanol and vacuum dried. Yield 0.358g (90%), mp 284-286 ° C. Measured value;
%: C51.46; H 5.43; N 10.3. C ₁₇ H ₂₁ IN ₃ . Calculated value;
%: 51.65; H5.32; N10.63. PMR spectrum (DMFA-
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 = 7Hz);
5.00 (2H, s, 1-CH ₂ ); 7.08 (1H, d, J = 9Hz); 7.29 (1H,
s, 9-H); 7.63 (1H, d, 6-H, J = 9Hz).

Method B 0.1 g (0.3 mmol) of 2,2,8-trimethyl-
2,3,4,5-Tetrahydro-1H pyrido [4,3-
b) One drop of 1,8-diazabicyclo [5,5] was added to a stirred mixture of indolium iodide and 3 ml of acrylonitrile.
4,0] -Undecene-7 (DBU) is added to dissolve the salt precipitate. Salt is added to the resulting solution in 0.1 g increments until dissolution or completion (total is 0.79 h (2 mmol)), the mixture is heated to 40 ° C. and 15 ml of dry ether are added dropwise with stirring. The precipitate is filtered, washed with ether and crystallized from ethanol Yield 0.65 g (83%), mp 284-286 ° C. The product is identical to the compound obtainable by Method A. Method B
The following is prepared analogously to: 2,2,8-trimethyl-5- (2-carbethoxyethyl) -2,
3,4,5-Tetrahydro-1H-pyrido [4,3-
b] Indolium iodide (Compound 17); Yield 23
%, M. p. 196-198 ° C.

Example 11 2,2,8-Trimethyl-5- [2- (5-methyl-2)
-Dimethylaminoethyl) -indolyl-3-methyl]
-2,3,4,5-tetrahydro-1H-pyrido [4,4
3-b] Indolium iodide (Compound 18); 0.684 g (2 mmol) of 2,2,8-trimethyl-2,3,4,5-tetrahydro-1H pyrido [4,3- in 3 ml of pyridine. b) A mixture of indolium iodide and 0.15 ml (1 mmol) of DBU is added until the dissolution is complete 80
Heat at ~ 100 ° C with stirring and carry out this procedure for a further 30 minutes, cool the mixture, evaporate in vacuo, wash the product with cold water, filter and crystallize twice from water. Let Yield 0.166g (30%), mp 228-
230 ° C (decomposition). Found:%: C60.20; H6.81; N9.8
9. C ₂₈ H ₃₇ IN ₄ . Calculated value;%: 60.43; H6.65. N10.0
7. PMR spectrum (DMFA-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
= 7Hz)); 2.90 (2H, t, α−CH ₂ , J = 7Hz); 3.23 (2H, t,
3-CH ₂ , J = 7Hz); 3.42 (6H, s, N (CH ₃ ) ₂ ); 3.60 (6H,
s, N (CH ₃ ) ₂ ); 4.00 (2H, t, β-CH ₂ J = 7Hz); 4.95 (2
H, s, Ind-CH ₂ -N); 5.50 (2H, s, 1-CH ₂ ); 6.84 (1H,
d, 6'-CH ₂ J = 8Hz); 6.90 (1H, s, 4'-H); 7.02 (1H,
d, 7'-H, J = 8Hz) 7.26 (1H, d, 7-H, J = 8Hz); 7.31 (1H,
s, 9-H); 7.52 (1H, d, 6-H, J = 9Hz); 10, 96 (1H, s
a, NH).

Example 12 2,2,8-Trimethyl-5-methylcarbimoyl-
2,3,4,5-Tetrahydro-1H-pyrido [4,3
-B] indolium iodide (compound 19); 2,2
8-trimethyl-2,3,4,5-tetrahydro-1H
-Pyrido [4,3-b] indolium iodide and 3 ml
1 drop of DBU is added to the stirred mixture of methylisocyanate of and the mixture is carefully heated until the salt dissolves.
Excess methyl isocyanate is evaporated in vacuo, the residue is washed with ether and crystallized from acetonitrile. Yield 0.3g (75%), mp 174-175 ° C.
Found:%: C48.05; H 5.40; N 10.33. C ₁₆ H ₂₂ IN ₃ O.
Calculated value;%: C48.11; H5.65. N10.53. PMR spectrum
(DMSO-d ₆ , ppm, δ): 2.23 (3H, s, 8-CH ₃ ); 2.74 (3H,
s, NCH ₃ ); 0.36 (2H, m, 4-CH ₂ ); 3.13 (6H, s, N (CH
₃ ) ₂ ); 3.67 (2H, s, 3-CH ₂ ); 4.64 (2H, s, 1-CH ₂ );
7.00 (1H, d, 7-H, J-8Hz); 7.14 (1H, s, 9H); 7.50 (1
H, d, 6H, J = 8Hz); 7.88 (1H, broad 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); 0.55 g (2 mmol) cis- (±) -2, in 2 ml hot water.
8-dimethyl-5-carbamoyl-2,3,4,4a,
5,9b-Hexahydro-1H-pyrido [4,3-b]
0.2 g with stirring of the solution of indole dihydrochloride
(2.5 mmol) potassium cyanide is added. The mixture foams and becomes clear. Further 0.08g (1
mmol) potassium cyanide, the solution begins to turn cloudy, a precipitate forms on cooling and the mixture becomes viscous. The precipitate is filtered, washed with water and crystallized from molar ethanol. Yield 0.325g (72%), mp 116-117 ° C.
Found: M ⁺ 249. C ₁₄ H ₂₉ N ₃ O. Calculated: M ⁺ 249. PM
R 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,
m, 2-1-CH ₂ , 9b-H); 4.30 (1H, m, 4a-H); 5.64 (2H, s,
NH ₂ ); 6.89 (1H, d, J = 8Hz; 7, 01 (1H, s, 9H) K 7.61
(1H, d, 6-H, J = 8Hz). Using a similar procedure the following is prepared: cis- (±) -2,8-dimethyl-5-thiocarbamoyl-2,3,4,4a, 5,9b-hexahydro-1
H-pyrido [4,3-b] indole (Compound 21) yield 64%, m.p. p. 156-158 ° C (from acetonitrile).

Example 14 cis- (±) -2,8-dimethyl-5-phenylthio
Carbamoyl-2,3,4,4a, 5,9b-hexahi
Doro-1H-pyrido [4,3-b] indole (compound
22); 2.63 g (13 mm) in 20 ml of anhydrous ether.
ol) cis- (±) -2,8-dimethyl-2,3,3
4,4a, 5,9b-hexahydro-1H-pyrido
To the stirred solution of [4,3-b] indole was added 2 ml of nitric acid.
Isocyanate (1.76 g; 13 mmol) is added dropwise.
After 30 minutes, the precipitated crystals are filtered and washed with ether.
Yield 4.65 g (86%), m.p. 168-169 ° C. Measured value; M⁺34
1. C₂₀H_{twenty three}N_ThreeS. Calculated value: M⁺341. IR spectrum: ν
= 1475 (C = S), 3270 (NH) cm^-1. PMR spectrum: (CDC
l_Three, ppm, δ): 1.60 and 1.97 (2H, 2m, 4-CH_Two); 2.30
And 2.32 (6H, 2s, 2- and 8-CH_Three); 2.38-2.78 and 3.3
2-3.54 (5H, 2m, 3- and 1-CH_Two, 9b-H); 5.20 (1H, m, 4a
-H); 6.99 (1H, D, 7-H, J = 8Hz; 7.12-750 (7H, m, 6-
 And 9-H, C ₆H_Five); 7.80 (1H, s, NH). In the same way
The bottom is adjusted: cis- (±) -2,8-dimethyl-5-cyclohexyl
Luthiocarbamoyl-2,3,4,4a, 5,9b-f
Xahydro-1H-pyrido [4,3-b] indole
(Compound 23) Yield 89%, m.p. p. 165-166 ° C. cis- (±) -2,8-dimethyl-5-butylcarba
Moyl-2,3,4,4a, 5,9b-hexahydro-
1H-pyrido [4,3-b] indole (Compound 24) yield 88%, m.p. p. 157-158 ° C. cis- (±) -2,8-dimethyl-5-phenylcal
Vamoyl-2,3,4,4a, 5,9b-hexahydro
-1H-pyrido [4,3-b] indole (Compound 2
5) Yield 93%, m.p. p. 204-205 ° C.

Example 15 cis- (±) -2,8-dimethyl-5-trifluoroacetyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole ( Compound 2
6); 0.202 g (1 mmi in 2 ml methylene chloride)
l). cis- (±) -2,8-dimethyl-2,3
0.2 g of 4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole (base) in a stirred vessel.
3 g (0.15 ml; 1.1 mmol) trifluoroacetic anhydride are added dropwise. The solvent is slowly evaporated at 60-70 ° C. After cooling, 1 ml of water is added and the mixture is stirred until a precipitate forms. The precipitate is filtered, washed with water and dried. Yield 0.237g (90%),
mp 162-164 ° C. Measured value;%; C74.87; H7.31; N12.
35. C ₁₅ H ₁₇ F ₃ N ₂ O. Calculated value:%; C60.38; H5.75; N
9.39, PMR spectrum (CDCl ₃ , ppm, δ): 1.60-2.56 (4
H, m, 3-CH ₂ , 4CH 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 = 5Hz);
7.12 (1H, s, 9H), 7.93 (1H, d, 6-HJ = 5Hz).

Example 16 cis- (±) -2,8-dimethyl-5- (2-bromobenzoyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] ] Indole hydrochloride (compound 27) 0.202 g (1 mmol) cis- in 2 ml methane chloride
(±) -2,8-dimethyl-2,3,4,4a, 5,9
To a (base) stirred vessel of b-hexahydro-1H-pyrido [4,3-b] indole is added 0.24 g (1.1 mol) of 2-promobenzoyl chloride. The solvent is evaporated in vacuo and the solid residue is washed with ether. Yield 0.37g (95%), mp 190-192 ° C. Found,%: C56.
72; H5.41; N 6.55. C ₂₀ H ₂₁ BrN ₂ O.HCl. Calculated value:
%: C57.13; H5.28; N 6.67. PMR spectrum of base
(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 ). Similarly, the following is prepared: cis- (±) -2,8-dimethyl-5- (2-methylbenzoyl) -2,3,4,4a5,9b-hexahydro-1H-pyrido [4,3- b] indole hydrochloride (compound 28); yield 93%, m.p. p. 241-243 ° C. cis- (±) -2,8-dimethyl-5- (3,4,5
-Trimethoxybenzoyl) -2,3,4,4a5,9
b-Hexahydro-1H-pyrido [4,3-b] indole hydrochloride (Compound 29) Yield 89%, m.p. p. 182-184 ° C.

Example 17 cis- (±) -2,8-dimethyl-5- (2-bromo
Propionyl) -2,3,4,4a, 5,9b-hexa
Hydro-1H-pyrido [4,3-b] indole hydrochloride
Compound 30 6.4 g (32 mmol) ci in 50 ml anhydrous benzene
s- (±) -2,8-dimethyl-2,3,4,4a,
5,9b-Hexahydro-1H-pyrido [4,3-b]
7.88 ml at 0 ° C in a stirred solution of indole (base)
(46 mmol) 2-bromopropionyl chloride was added dropwise.
I do. After 1 hour, the hydrochloride (30) precipitate is filtered. Income
Amount 13.1g (88%), m.p. 150 ℃. (Disassembly). The sediment in water
Dissolve, basify with sodium carbonate and extract with ether
And dry with sodium sulfate. Evaporation of solvent
And the residue is crystallized from anhydrous ether. in this way
The base is generated. m.p. 134 ℃; measured value;%: C57.24;
 H6.38; N 7.98. C₁₆H_{twenty one}BrN_TwoO. Calculated value:%: C57.13
 H6.30; N 8.33. PMR spectrum of hydrochloride (DMSO-d
₆, ppm, δ): 1.56 and 2.30 (2H, 2m, 4-CH_Two); 1.58 (3
H, d, CH_ThreeC, J = 7Hz); 2.32 (3H, s, 8-CH_Three); 2.80
(3H, s, 2-CH_Two); 3.05 and 3.20 (3H, 2m, 1-H and 3-
CH_Three); 3.85 (1H, m, 1-H ′); 4.27 (1H, m, 96-H); 4.
84 (1H, m, 4a-H); 5.24 (1H, m, CHCH_Three); 7.12 (1H, d, 7
-H, J = 8Hz); 7.43 (1H, s, 9-H); 7.90 (1H, s, 6-H,
 J = 8Hz); 9.38 (1H, s, NH). Similarly prepared below
Is: cis- (±) -2,8-dimethyl-5-chloroacetyl
Le-2,3,4,4a5,9b-hexahydro-1H-
Pyrido [4,3-b] indole hydrochloride (Compound 31) yield 90%, m.p. p. 195-205 ° C (alcohol
Ri). cis- (±) -2,8-dimethyl-5-[(E) -2
-Planoyl] -2,3,4,4a5,9b-hexahi
Doro-1H-pyrido [4,3-b] indole (compound
32) Yield 62%, m.p. p. 113-114 ° C.

Example 18 cis- (±) -2,8-dimethyl-5-methoxyacetyl-2,3,4,4a, 5,9b-hexahydro-1
H-pyrido [4,3-b] indole hydrochloride (compound 3
3) 0.63 g (2 mmol) of hydrochloride 31 in a stirred solution of 0.1 g (4.3 mmol) of sodium in 10 ml of methanol.
Is added, then refluxed for 1 hour and cooled. The sodium chloride precipitate is filtered off, the filtrate is evaporated down and 2 ml of water and 10 ml of benzene are added. The organic layer is removed, dried over potassium carbonate, then ethanol saturated with hydrogen chloride is added to pH = 1, evaporated in vacuo and the residue is crystallized from anhydrous isopropanol. Yield 0.34g (55%), mp222-224 ° C; found value;
%: C61.56; H7.60; N 8.95. C ₁₆ H ₂₂ N ₂ O ₂ .HCl. Calculated value;%: C61.19; H7.47; N 9.03. PMR spectrum of base (CDCl ₃ , ppm, δ): 1.80 (2H, m, 4-CH ₂ ); 2.13
And 2.20 (6H, 2s, 2-16and 8CH 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
= 8Hz); 6.74 (1H, d, 6-H, J = 8Hz); 6.81 (1H, s, 9-
H).

Example 19 cis- (±) -2,8-dimethyl-5-N-pyrrolidinoacetyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] Indole (Compound 3
4) To a solution of 0.93 g (3 mmol) of amide 31 in 10 ml of benzene is added an excess of pyrrolidine and the mixture is refluxed for 5 hours. The pyrrolidine hydrochloride is filtered off, the furnace liquid is evaporated down i.vac. And the residue is recrystallized from hexane. Yield 0.65g (69%), mp 108-110
° C. Found;%: C72.9; H8.53; N13.35. C ₁₉ H ₂₇ N ₃ O
. Calculated value;%: C72.79; H8.69; N13.41. PMR spectrum (CD ₃ CN, ppm, δ): 1.35 and 2.00 (2H, 2m, -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 (5
H, m, 1- and 3-CH ₂ , 9b-H); 4.48 (1H, m, 4a-H); 6.95
(1H, d, 70H, J = 8Hz); 7.08 (1H, S, 9-H); 7.84 (1H,
d 6-H, J = 8Hz)

Following the above procedure, the following are prepared: cis- (±) -2,8-dimethyl-5-N-morpholinoacetyl-2,3,4,4a5,9b-hexahydro-1H-pyrido [4,3-b] indole (Compound 3
5) Yield 38%, m.p. p. 150-152 ° C (from hexane). cis- (±) -2,8-dimethyl-5- (2-N-piperidinopropionyl) -2,3,4,4a5,9b-
Hexahydro-1H-pyrido [4,3-b] indole (Compound 36) Yield 14%, m.p. p. 144-145 ° C. (From ether). cis- (±) -2,8-dimethyl-5- (2-N-morpholinopropionyl) -2,3,4,4a5,9b-
Hexahydro-1H-pyrido [4,3-b] indole (Compound 37) Yield 63%, m.p. p. 230 ° C. (From ether; decomposed).

Example 20 cis- (±) -2,8-dimethyl-5- (4-methyl-1-pyridinoacetyl-2,3,4,4a, 5,9b
-Hexahydro-1H-pyrido [4,3-b] indole (compound 38) 0.315 g (1 in 3 ml of stirred 4-methylpyridine)
mmol) hydrochloride 31 and stirring at 60-80 ° C.
For one hour. The mixture is evaporated down i.vac., Washed with isopropanol, recrystallised from ethanol and dried under vacuum. Yield 0.29g (79%), mp 23
4-236 ° C; measured value;%: C67.92; H6.90; N11.12. 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 6.1
1 (2H, 2d, CH ₂ CO, J = 15Hz); 7.08 (1H, d, 7-H, J = 8H
z), 7.38 (1H, s, 9-H); 7.70 (1H, d, 6-H, J = 8Hz);
8.06 (2H, d, 3'- and 5'-H, J = 7Hz); 9.00 (2H, d,
2'- and 6'-H, J = 7Hz). Following the above procedure, the following is prepared: cis- (±) -2,8-dimethyl-5- (1-pyridinioacetyl-2,3,4,4a5,9b-hexahydro-1H-pyrido [4 , 3-b] Indole chloride (Compound 39) yield 80%, mp 280 ° C. (from ethanol; decomposition) cis- (±) -2,8-dimethyl-5-[(2-4-
Methyl-1-pyridinium provinyl-2,3,4,4
a5,9b-Hexahydro-1H-pyrido [4,3-
b] Indole bromide (Compound 40) Yield 70%, m.p. p. 218-220 ° C. (From ethanol).

Example 21 cis- (±) -2,8-dimethyl-5- (3-carboxypropionyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b Indole (compound 41) 0.202 g (2 mmol) of 2,8- in 5 ml of ether
To a stirred vessel of dimethyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole (base) was added 0.11 g (1.1 mmol) of cohanic anhydride. The mixture is heated to reflux, cooled and the precipitate filtered. Recrystallize from ethanol. Yield 0.242g
(80%), mp 156-159 ℃; measured value;%: C67.22; H7.
70; N9.33. C ₁₇ H ₂₂ N ₂ O ₃ . Calculated value;%: C67.51; H7.34
N9.27. PMR spectrum (DSMO-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 = 8Hz); 7.08 (1H, s, 9-
H); 7.83 (1H, d, 6-H, J = 8Hz).

Example 22 cis- (±) -2,8-methyl-5- [2- (6-methyl-pyridyl) ethyl] -2,3,4,4a, 5,9
b-Hexahydro-1H-pyrido [4,3-b] indole trihydrochloride (Compound 42) 0.9 g (2 mmol) of 2 in 10 ml of trifluoroacetic acid.
-Methyl-5- [2 (6-methyl-3-pyridyl) ethyl] -2,3,4,5, -tetrahydro-1H-pyrido [4,3-b] indole sesquisulfate (120 ° C.
0.65 g (10 mmo) with stirring in a vacuum dried solution
Zinc powder from l) is added in small portions, the mixture is heated until completely dissolved and vacuum evaporated. 10 mmol ether and 20% sodium hydroxide solution are added to the residue and the mixture is stirred to dissolve the precipitate. The ether layer is removed and the aqueous layer is extracted with 5 ml ether. The combinations are dried by ether extraction over potassium carbonate, evaporated, dissolved in excess alcohol saturated with hydrogen chloride and evaporated to dryness in vacuo. Wash the residue with anhydrous ether,
Crystallize from ethanol / acetone and vacuum dry.
Yield 0.52g (65%), mp 234-236 ℃; Found:%: C5
8.10; H6.53; N10.05. _{C 10 H 25 N 3 · HCl} . Calculated value;
%: C57.81; H6.80; N10.12. PMR spectrum of base (C
DCl 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 = 7Hz); 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 = 7Hz); 6.64 (1d, s, 9-H, J = 7Hz); 6.88-7.06 (3H,
m, 7-, 8- and 5'-H); 7.31 (1H, dd, 4'-H, J ₁ = 9H
z, J ₂ = 3Hz); 8.29 (1H, d, 2′-H, J = 8Hz).

Example 23 cis- (±) -2,2,8-trimethyl-5-carba
Moyl-2,3,4,4a, 5,9b-hexahydro-
1H-pyrido [4,3-b] indolium iodide
Compound 43) 0.14 g (0.57 mmol) in 2 ml of acetonitrile
To a solution of compound 20 of 0.1 ml (0.15 mmol) of iodine
Add methyl iodide. After 24 hours, the precipitate is filtered and chilled.
Wash with trinitrile and crystallize from ethanol. yield
0.21 g (95%), m.p. 274-276 ° C. Measured value;%: C49.80
 H5.33; N10.45. C_FifteenH_{twenty two}IN_ThreeO. Calculated value;%: C49.63
 H5.39; N10.22. PMR spectrum (DMSO-d₆, ppm,
δ): 1.76 and 2.32 (1H, 2m, 4-CH_Two); 2.23 (3H, s, 8-
CH_Two); 2.92 and 3.20 (6H, 2s, N ⁺(CH_Three)_Two]; 3.35 (2
H, m, 1-CH_Two); 3.71, 3.82 and 4.10 (3H, 3m, 3-CH_Two, 9b
-H); 4.46 (1H, m, 4a-H); 6.54 (2H, s, NH_Two); 7.00
(1H, d, 7-H, J = 8Hz); 7.22 (1H, s, 9-H); 7.70 (1H,
d-6H, J-8Hz).

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

Table 1 2-Methyl-5,8-substituted 2,3,4,5-tetrahydro-1H pyrido [4,3-b] indole (1-9) of formula I, its quaternary salts (10-19) and -2,3,4,4a5,9b-hexahydro-1H-pyrido [4,3-b] indole (20-43).

Embedded image

──────────────────────────────────── No. Com. R ¹ R ² R ^3- CH ₂ -X Q ^* ──────────────────────────────────── 1 Me ₂ CH- H − − HCl 2 Me 2,4-Me ₂ C ₆ H ₃ -CH ₂ ---HCl 3 Me Et ₂ N- (CH ₂ ) ₂ ---2HCl 4 Me (CH ₂ ) ₅ N- (CH ₂ ) _{2- - - 2HCl 5 Me (CH 2} ) 6 N- (CH 2) 2 - - - 2HCl 6 Me (PhCH 2) 2 N- (CH 2) 2 - - - 2HCl 7 Me NC- (CH 2) 2 - - − − 8 Me HOCO- (CH ₂ ) ₂ − − − HCl 9 Me EtOCO- (CH ₂ ) ₂ − − − − HCl 10 Me HC ₆ H ₄ (CO) ₂ N-Br − (CH ₂ ) ₄ − 11 H 6-Me-3-py- ( CH 2) 2 - Me I - 12 H 1, 6-Me 2 -3-Py + - (CH 2) 2 - Me I - (I -) 13 Me 1, 6- ^{_{Me 2 -3-Py + - (}} CH 2) 2 - Me I - (I -) 14 H 6-Me-3-py- (CH 2) 2 - 4-BrC 6 H 4 COCH 2 - Br - 15 Me 6-Me-3-py- ( CH 2) 2 - Ph-C0CH 2 - Br - 16 Me NC- (CH 2) 2 - Me I - 17 Me EtOCO- (CH 2) 2 - Me I 18 Me 5-Me-2- [ Me 2 N- (CH 2) 2] - Me I - indolyl-3-CH 2 - 19 Me MeNH-CO- Me I - 20 * Me H 2 N-CO- - - − 21 Me H ₂ N-CS- − − − 22 Me PhNH-CS- − − − 23 Me cC ₆ H ₁₁ NH-CS- − − − 24 Me n-BuNH-CO- − − − 25 Me PhNH-CO ----26 Me CF ₃ -CO----27 Me 2-BrC ₆ H ₄ -CO---HCl 28 Me 2-MeC ₆ H ₄ -CO---HCl 29 Me 3,4,5- (MeO) ₃ C ₆ H ₂ -CO- − − HCl 30 Me Be-CH (Me) -CO- − − HCl 31 Me ClCH ₂ -CO- − − HCl 32 Me (E) -Me-CH = CH- CO- − − 33 Me MeOCH ₂ -CO- − − HCl 34 Me (CH ₂ ) ₄ N-CH ₂ -CO- − − − 35 Me O (CH ₂ CH ₂ ) ₂ N-CH ₂ CO- − − − 36 Me (CH ₂ ) ₅ N-CH (Me) -CO- − − − 37 Me O (CH ₂ CH ₂ ) ₂ NCH (Me)-− − − CH ₂ CO- 38 Me 4-Me-1-Py _{^{-CH 2 -CO- + - - - (}} Cl -) 39 Me 1-Py + -CH 2 -CO- (Cl -) - - - 40 4-Me 2 -1-Py + -CH (Me) CO- ^{- - - (Br -) 41} Me HOCO- (CH 2) 2 -CO- - - - 42 6-Me-Py-3- (CH 2) 2 - - - 3HCl 43 Me H 2 N-CO- Me I - ^* -20 from up to 43 cis (±) -2,3,4,
4a, 5,9b-hexahydro-1H-pyrido [4,3
-B] indole (ie,

Embedded image Is a standard bond).

The compounds of formula I according to the invention have anti-NMDA activity as demonstrated above by biological test results.

BIOLOGICAL EXPERIMENTAL DATA The experiment was carried out on a male White Mongerel weighing 20-24 g.
Experiments were performed using mice. Test compounds were injected intraperitoneally 40 minutes prior to NMDA injection. 0.2 ml of this compound
5% aqueous dimethyl sulfoxide solution form. The mice were previously anesthetized with ether, the skin graft above the head of the mouse was removed, and the skull was punctured using a fine drill. NMDA was then injected into the lateral ventricles using a microsyringe at a dose of 0.1 μg in a volume of 14 μl. The penetration depth of the microsyringe needle was 2.5 mm.
The accuracy of NMDA capture was controlled by injection of methylene blue. After the operation, the wound was treated with 2% Novocain solution [VV Grigorye
v. VANemanova-Bull. Expert, Boil
Med. , 1989, No. 9, pp. 299-30
2]. The mice showed no signs of pain or tension after anesthesia. The evaluation of the result is 2 of surgery.
It was done after 4 hours.

As an assay animal, one that received a physiological solution was used. In the assay group, lateral ventricular injection of NMDA at a dose of 0.1 μg per mouse resulted in running, jumping, convulsions and subsequent death of the animals. In the experimental group, pre-injection of the test substance prevented the development of convulsions and the death of the animals.

Each substance dose was prepared in groups comprising 6-8 animals.

The activity of the compounds was evaluated as ED ₅₀ value (5
0% of the dose of substances that prevent the onset of seizures and death in animals), the value is Litchfild and Wilcoxon [Litchfild JT, Wilcox
on FJ, J. Phamacol. Exp. Ther.-1949, v.96, pp.99
-114] method was used for evaluation.

The test results are shown in Table 2. 2-Amino-5-phospho antagonistic acid (AP5) was also tested as a standard. It is known as an NMDA-receptor antagonist [Evans et al., Brit J. Pharmacol., 1982, v75, p.65.
]. The data are also reported in Table 2.

From the data shown in Table 2, the compounds of the formula I according to the invention show an anti-NMDA activity upon intraperitoneal injection in the range of ED ₅₀ of 9-46 mg / kg, the standard A
It was 4.2 to 21 times higher than the activity of P5. And, the compounds do not have a significant neurotoxic effect within the active dose range investigated, which means their use in medicine, treatment of diseases in which the glutamate neuromediator system is involved in the pathogenic mechanism and Prevention, especially neurodegenerative diseases such as Alzheimer's disease, Huntington's chorea,
It should be useful for use in cerebral ischemia, infarction, vasospasm, hypoglycemia, cardiac arrest, epilepsy, brain disorders, schizophrenia, paralysis, and other treatments. Table 2 Anti-NMDA activity of hydrogenated derivatives of 1H-pyrido- [4,3-b] indole ──────────────────────────── ───────── Compound No ED ₅₀ (mg / kg) Compound No ED ₅₀ (mg / kg) ──────────────────────── ───────────── 1 30 ± 5 24 17 ± 3 2 35 ± 7 25 23 ± 2 5 36 ± 4 26 45 ± 6 6 42 ± 5 27 32 ± 5 7 46 ± 628 27 ± 4 8 29 ± 4 29 18 ± 2 11 11 ± 2 30 24 ± 4 12 32 ± 4 31 16 ± 4 13 14 ± 2 32 41 ± 4 14 13 ± 3 33 35 ± 0 15 9 ± 2 34 23 ± 2 16 42 ± 5 35 38 ± 4 17 13 ± 2 38 42 ± 5 18 14 ± 2 39 30 ± 5 19 33 ± 4 40 29 ± 5 20 ^# 4 ± 6 41 45 ± 10 22 29 ± 5 43 36 ± 4 23 23 ± 5 AP5 ^{Standard) 190 ± 1 ──────────────────────────────────── # -20~43-} cis- (±) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole.

Determination of Acute Toxicity Acute toxicity of the substance was determined in male White Mongrell mice weighing 22-26 g. The substances were injected intraperitoneally in the form of solutions or suspensions in 1% starch solution. The observation period was 14 days. LD ₅₀ mode of toxicity
Wilcoxon 〔Litchfild JT, Wilcoxon FJ, J. Pharma
col. Exp. Ther-1949, v.96, pp.99-114].

Table 3 shows examples of toxicity of the compound. Table 3 Acute toxicity of some compounds of formula I ──────────────────────── Compound No. LD ₅₀ , mg / kg ───── ─────────────────── 8 150 11 80 80 15 75 75 16 105 21 150 150 22 650 28 28 45 29 29 115 30 800 800 31 350 350 38 70 AP5 1100 ─────── ─────────────────

As a result of the tests carried out, L of the test compound
It has been established that the D ₅₀ is 45-800 mg / kg. According to the toxicity classification of compounds, the compounds can be identified as having moderate and low concentrations of toxicity. While acute toxicity of certain compounds and some exceed slightly from the acute toxicity values for AP5, comparison of the therapeutic index parameters defined as the ratio LD ₅₀ / ED ₅₀ (DNPlutitsky et, -Knim. Pharm. Z
h., 1986, No. 10, pp. 1209-1213) suggests that most of the tested compounds are substantially preferred over AP5.

A second aspect of the invention is a method of treatment and prevention of diseases in which the pathogenic mechanism involves the glutamate neuromediator system, which method comprises treating a patient with an effective amount of a compound of formula I. Consists of

The dosage of the active ingredient (the compound of formula I or a pharmaceutically acceptable salt thereof) depends on many factors, such as the age, sex or weight of the patient, the symptoms and severity of the illness, the particular compound prescribed. , Dosage form, and form of preparation containing the active compound.

As a general rule, the total prescribed dose is 1 per day
~ 200 mg. The total dose is several times, eg 1 per day
It may be divided into 4 administrations. In oral formulations, the total dose range of active agent is 10-200 mg / day, preferably 15-15
Set to 0 mg. For parenteral administration, the prescribed dosage range is 5 to 100 mg, preferably 5 to 50 mg per day, and for intravenous injection, 1 to 50 mg per day, preferably 1 to 2 mg.
Set to 5 mg. The specific dose can be selected by the attending physician.

As well as being used in medicine, it is recommended that the compounds of the formula I according to the invention be used in the form of compositions, which is a further aspect of the invention.

The pharmaceutical compositions of this invention should be prepared utilizing generally accepted procedures known in the art, and a pharmaceutically effective amount of the active agent, ie, Formula I
Or a pharmaceutically acceptable salt thereof (designated as "active compound"),
Its amount is comprised between 5 and 30% by weight, which is combined with one or more pharmacologically acceptable auxiliaries such as diluents, binders, emollients, adsorbents, aroma substances, flavoring agents. ing. According to known methods, pharmaceutical compositions are represented by liquid or solid pharmaceutical forms.

Examples of solid pharmaceutical forms include, for example, tablets, pellets, gelatin, capsules and the like.

Examples of liquid pharmaceuticals for injection and parenteral administration include solutions, emulsions, suspensions and the like.

The compositions are usually prepared using standard procedures involving mixing the active compound with liquid or finely divided solid carriers.

5-30% of the composition according to the invention in tablet form
Of the active compound and a filler or carrier. The latter utilized in tablets are: a) Diluents: sugar, lactose, glucose, sodium chloride, sorbitol, annitol, glycol, disubstituted calcium phosphate;
b) Binders: magnesium aluminum silicate, starch paste, gelatin, gum tragacanth, methylcellulose, carboxymethylcellulose and polyvinylpyrrolidone; c) Relaxants: dextrose, agar, arginine acid or its salts, starch, twins.

Formulation 1 100 g tablets containing 15.0 mg each 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 made by compressing or molding the active ingredient with one or more additional ingredients.

Compressed tablets were prepared in a special facility. 150 g (10,0) of free form active ingredient such as powder or granules
The amount required to prepare 00 tablets is the binding agent tragacanth (20
0 g), with the diluent lactose (400 g) and the emollient arginine acid (200 g) and the flavor citric acid (50 g) are added to this mixture.

In gelatin capsules, colorants and stabilizers are also added. Colorants used are: tetrazine,
Indigo. The stabilizer which can be used may be sodium metabisulfite, sodium benzoate. The proposed gelatin capsule comprises 1-20% active ingredient.

Formulation 2 50 mg capsules containing 50 mg each of compound 31 Compound 31 50.0 mg Glycerol 100.0 mg Sugar syrup 290.0 mg Mint oil 40.0 mg Sodium benzoate 10.0 mg Ascorbic acid 5.0 mg Tetrazine 5.0 mg

500 g of active substance (compound 31) (1
The quantity required to prepare 50,000 tablets) is finely divided and mixed with glycerol (1000 g) and sugar syrup (2900 g) in a mixing tank. After mixing, mint oil (400g), sodium benzoate (100g), ascorbic acid (50g) and tetrazine (50g) are added to the mixture. Gelatin capsules are formed by the drop method. This method involves the simultaneous drop dosing of a pharmaceutical solution and a heated gelatin mass (900 g gelatin) into chilled petrolatum oil. As a result, it is ready for use,
And a spherical lidless capsule is formed which is filled with a drug comprising 50 mg of active substance.

Injectable forms of this composition are preferably represented by isotonic solutions or suspensions. The above forms can be sterilized, and additives such as preservatives: sodium metabisnorphite, benzoic acid, sodium benzoate, mixtures of methylparaben and propylparaben; stabilizers: apricot gum and acacia, dextrin, Starch paste, methylcellulose, twins; may contain osmolality adjusting salts (sodium chloride) or buffers. In addition, this solution may comprise other therapeutic substances.

Formulation 3 2 ml amp containing 20 mg each of compound 24 Compound 24 20.0 mg 0.9% sodium chloride 1.6 ml Benzoic acid 10.0 mg Methylcellulose 10.0 mg Mint oil 0.4 ml

For the preparation of injectable forms, the active compound 24
(20 g; the amount required to prepare 1000 ampoules) was finely divided and mixed with mint oil (400 ml) in a mixing chamber (1000 g), then methylcellulose (10 g) was added, 0.9 % Sodium chloride solution (1600 ml) and finally benzoic acid (10 g) is added. The resulting solution is filled into 2 ml ampoules and sterilized with steam for 30 minutes.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical indication location A61K 31/435 AED A61K 31/435 AED (72) Inventor Andrei Zaharovich Afanashiev Russian Federation, Moskovskaya Oblast , Noginsky Leon, Pozerok Jernogorovka, Prospect Stroiterei, 2, Kvartira 103 (72) Inventor Svetlana Basiliyevna Afanacie Pharos, Russian Federation, Moskovskaya Oblast, Noginski Leon, Pozerok Cjernogorovsky, 102, Prospect Inventor Sergey Oregovich Baturin Russian Federation, Moskovskaya Oblast Noginsky Leon, Pozerok Jernogorovka, Urica Zentralnaya, 4 Be, Kbarchila 47 (72) Inventor Sergei Evgeniewich Trachenko Russian Federation, Moskovskaya Oblast, Noginski Leon, Pozerok Cjellnogorovka, 72, Inventor, Nauriza Vladimir Victorovich Grigoryev Russian Federation, Moskovstaya Oblast, Noginsky Leon, Pozerok Cjellnogolovka, Institutsky Prospect, 13, Kvartilla 60 (72) Inventor Marina Abramokhna Yurovskaya Russian Federation, Moscow, Smakovy ， Kvartilla 42

Claims (51)

[Claims] 1. A quaternized nitrogen atom at the 2-position of general formula I
2-Methyl-5,8-substituted 2,3,4,5- having
Tetra and 2,3,4,4a, 5,9b-hexahydr
Ro-1H-pyrido [4,3-b] indole and its
Quaternary salt [Chemical formula 1](In the formula, a dotted line and a continuous line segment attached to it are shown below.Is a standard or double bond; R¹Is H or lower alkyl
And R^TwoIs 2- (2-N-methyl-NR)^Three-Met
Luamino) ethyl) -5-R¹-Indol-3-Met
Ruki (where R¹Is as above, and R^ThreeIs
As defined below) or a group of the general formula:(Where: Y is H, halogen, cycloalkyl, ethene
(Optionally lower alkyl mono-, di- or tri-substituted
Is substituted, monosubstituted by aryl, or
COOR^FourΒ-mono substituted with [where R^FourIs
H, alkyl, aralkyl, aryl (optionally
Mono-, di- or tri-substituted by the substituent A defined
Or)]); or OR^Four(Where R^FourIs defined above
Alkylsulfonyl; arylsulfo
Nil; NR^FiveR⁶(Where R^FiveAnd R⁶Are the same or different
, And each independently H;
Rualkyl; cycloalkyl; aralkyl, aryl (optional
By the substituent A defined below in a mono, di or tri position
); 2-, 3- or 4-pyridyl; alk
Rsulfonyl; is arylsulfonyl; or R
^FiveOr R⁶One is COR⁷(Where R⁷Is H, Al
Kill, alkoxy, cycloalkyl, aralkyl, ant
(Optionally a mono-, di-
Or tri-substituted), 2-, 3- or 4-pyridy
R); or R^FiveAnd R⁶Together
It forms a group of the general formula:-(CH_Two)_Two -W- (CH_Two)_Two-(Where W is -O-,-(CH_Two)_q(Where q = 0,
1 or 2) or(Where R⁸Is H, alkyl, aryl (optionally
Mono-, di- or tri-substituted by the substituent A defined in
V is H_TwoOr O; at r = 0 or 1
Yes); or R^FiveOr R⁶Is the nitrogen they are adding
N-phthalimido group together with the atom (optionally
The substituent A defined in
Substituted)); COR⁹(here
R⁹Is H, alkyl, aralkyl, aryl (optionally
Mono-, di- or tri-substituted by the substituent A defined below
), OH, alkoxy groups, optionally substituted
The above NR excluding N-phthalimido group^FiveR⁶, 2-3
-Or 4-pyridyl); CN; CHal_Three(here
And Hal is chloro, fluoro or bromo);
(Optionally a mono-, di-
Or tri-substituted); 2-, 3- and 4-pyridy
(Optionally mono- or di-substituted by lower alkyl
And corresponding 1-R^ThreeCH_Two-Pyridiniu
A quaternary salt of M-2, -3 or -4 (where R^ThreeIs above
As is); trialkylammonium; cycloal
Kirammonium; N-azinium and N-azolium
Z is 0, S or H_TwoIs;
k is 0 or an integer from 1 to 4; l, m and n are independently
Is 0 or 1; Note: 1) Y is the above constant only when k + m ≧ 2 and l = 0.
May have any of the meanings; 2) when k = 1, m = 0, Y is halogen, CHa
l_Three, OR^Four, NR^FiveR⁶, Aryl, trialkyl
Ammonium, cycloalkyl ammonium, N-azini
Other than um or N-azolium; 3) when k = 1 and l = m = 0, then Y is halo
Gen, trialkylammonium, cycloalkylan
Monium, N-azinium or N-azolium; 4) when k = 1, m = 1, and Z = 0, Y is
Rogen, OH, CN, alkylsulfonyl, aryls
Rufonyl, trialkylammonium, cycloalkyl
Other than ammonium, N-azinium or N-azolium
5) When k = 1, m−1, and Z is S, Y is a group
NR^FiveR⁶(Where R⁶Is hydrogen) only; 6) when l = 0, Z is H_Two7) When k = 0 and l = m = 1, Z is not S
R;^ThreeIs a group-(CH_Two)_k-Y '(where Y'is
As defined for Y and k as above
Note that when k = 0, Y ′ is halogen and NR.^Five
R⁶, Trialkylammonium, cycloalkylan
Other than monium, N-azinium or N-azolium
X is a pharmacologically acceptable acid anion;
The substituent A is independently selected from the following groups: halogen, low
Primary alkyl, lower alkoxy group, NO_Two, CN, COR
⁹(Where R⁹Is as described above except for the pyridyl derivative
), CF_Three, NR^FiveR⁶(Where R^FiveAnd R⁶Is above
A); however, a)Is a double bond and n = 0, then R¹Is methyl
Come, R^TwoIs H, methyl, benzyl, 2-pyridylmethy
2-, 6- (6-methyl-3-pyridyl) ethyl, 2-
(4-pyridyl) ethyl, 2- (N, N-dimethylamido)
No) ethyl or 3- (N, N-dimethylamino) propyi
Other than Le; and R¹When is H, R^TwoIs the above
N-butyl, cyclohexyl, mu-chlorobut
And 2-phenylethyl, 2- and 3-pyridyl,
1- (2-pyridyl) ethyl, 2- (2-pyridyl) eth
Tyl, 1- (3-pyridyl) ethyl, 1- (6-methyl
-3-pyridyl) ethyl, diethylaminocarbonyl,
Hydroxymethyl, 2-methyl-3- (N, N-dimethyl)
Luamino) propyl, general formula R^TenO- (CH_Two)_Two-Base
(Where R^TenIs C_Two-C_FourAlkyl, cyclohexyl or
Is phenyl) or the general formula R^FiveR⁶N- (CH_Two)_p
-Group [where p = 2 and R^FiveAnd R ⁶Haso
Each is ethyl or R^FiveAnd R⁶Is tetramata
Is pentamethylene; or p = 3, and
R^FiveAnd R⁶Together form the group-(CH_Two) _TwoW (CH_Two)
_Two-(Where W is -O-, NCH_ThreeNCH_TwoC₆H_Fiveso
Other than)); b)Is a standard bond, and n = 0, then R¹Is H
Come, R^TwoIs H, methyl, ethyl, benzyl, acetal,
Chloroacetyl, or (N-morpholino, or N-pi
Peridino or N, N-dimethylamino) acetyl; 3
-Chloropropionyl, 3- (N-morpholino) propion
Other than onyl or 5-chloropentaonyl; R¹But
When methyl, R^TwoIs H, 2,2,2-trifluoroe
Chill, 2- (N, N-dimethylamino) ethyl, 3-
(N, N-dimethylamino) propyl, acetyl, 2-
In the case of ethylhexanoyl, cis-(-)-isomer,
Other than (E) -2-butenoyl and (E) -cinnamoyl
Yes; c)Is a double bond, and n = 1, R¹And R^Three
Are each H, and X is iodine, R^TwoIs
Other than H, methyl, ethyl or propyl; R¹as well as
R^TwoThat of H and X is methylsulfate
R when^TwoIs other than benzyl; R¹Is H, R
^ThreeIs methyl and X is iodine, R^TwoIs other than H
Yes; R¹Is methyl, R^ThreeIs H and X is iodine
Come, R^TwoIs other than H or methyl; R¹Is H, R^ThreeBut
Phenyl, and when X is chloro, R^TwoIs H or Ben
Other than Jill; R¹Is H, R^ThreeIs phenyl, and X
Is iodine, R^TwoIs 3- (N, N, N-trimethyl
Ammonium) other than propyl iodide) and pharmacology
The salt is tolerated. 2. General formula I. 2-methyl-2,3,1
4,5-Tetrahydro-1H-pyrido [4,3-6] i
A compound according to claim 1, which is a ndole derivative:(Where R¹Is as defined in claim 1; R^TwoIs general
The formula (CH_Two)_k-Y group (where Y is H, halogen
Amine, cycloalkyl, ethenyl (optionally lower alkyl
Are mono, di or tri substituted by. By Aryl
Mono-substituted or COOR^FourBy β-mono
-Replaced [where R^FourAs defined in claim 1
]); Or OR^Four(Where R^FourIs defined in claim 1
Alkylsulfonyl, arylsulfo.
Nil; NR^FiveR⁶(Where R^FiveAnd R⁶Is defined in claim 1
); COR ⁹(Where R⁹Is defined in claim 1
As it is meant); CN, CHal_Three(In the formula, Hal is
Chloro, fluoro or bromo); alur (optional
By the substituent A defined in claim 1, mono, di
Or tri-substituted); 2-, 3- and 4-pyridy
(Optionally mono- or di-substituted by lower alkyl
And corresponding 1-R^ThreeCH_Two-Pyridiniu
A quaternary salt of m-2, -3 or 4 (where R^ThreeIs claim 1
Is as defined); trialkylammonium;
Chloalkylammonium, N-azinium and N-a
Zolium, each optionally substituted;
k is as described in claim 1 for formula I;
Note: 1) when k = 0, Y is halogen, CHal_Three, O
R^Four, NR^FiveR⁶, Aryl, trialkylammoniu
Or cycloalkyl ammonium, N-azinium or
Other than N-azolium; 2) when k = 1, Y is halogen, trialkylammonium
Ni, cycloalkyl ammonium, N-azinium
Or other than N-arizolium; provided that R¹When is methyl, R^TwoIs H, methyl, benzyl, ma
-Pyridimethyl, 2- (6-methyl-3-pyridyl) e
Tyl, 2- (4-pyridyl) ethyl, 2- (N, N-di
Methylamino) ethyl or 3- (N, N-dimethylamido)
No) propyl; and R¹When is H, R^TwoIs
Except for the above definitions, n-butyl, cyclohexyl, 4-
Chlorobenzyl, 2-phenylethyl, 2- and 3-pi
Lysyl, 1- (2-pyridyl) ethyl, 2- (2-pyri
Dil) ethyl, 1- (3-pyridyl) ethyl, 1- (6
-Methyl-3-pyridyl) ethyl, diethylaminocalc
Bonyl, hydroxymethyl, 2-methyl-3- (N, N
-Dimethylaminono) propyl, the above general formula R^FourO-
(CH_Two)_TwoA group or a general formula R as defined in claim 2 ^FiveR
⁶N- (CH_Two)_p-It is also other than a group). 3. The general formula I. 2-methyl-2,3,2
4,4a, 5,9b-hydro-1H-pyrido [4,3-
b) a compound according to claim 1, which is a derivative of isindole. Where R ¹ is as defined in claim 1; R ² is a group of the general formula: (Wherein Y, Z, k, l and m are as defined in claim 1); wherein; 1) when k = 1 = m = 0, Y is halogen, CHa
l ₃ , OR ⁴ , NR ⁵ R ⁶ , other than aryl, trialkylammonium, cycloalkylammonium, N-azinium or N-azolium; 2) Y when k = 1 and l = m = 0. Is halogen, tolualkylammonium, cycloalkylammonium, other than N-azinium or N-azonium; 3) when k = 1 = 0, m = 1, and Z is 0, Y is halogen, OH, CN, Other than alkylsulfonyl, arylsulfonyl, trialkylammonium, cycloalkylammonium, N-azinium or N-azolium; 4) when k = 1 = 0, m = 1, and Z is S, Y is a group NR ⁵ R ⁶ is only (where R ⁶ is hydrogen); 5) l = 0 eaves, Z is is other than H _2; 6) when k = 0, and l = m- When, Z is is other than S; provided that: when R ¹ is H R ² is H; methyl;
Ethyl; pentyl; acetyl; chloroacetyl; (N-
Morpholino-, N-piperidino- or N, N-diethylamino) acetyl; 3-chloropropionyl; 3- (N
-Morpholino) propionyl; or other than 5-chloropentanoyl; and when R ¹ is methyl, R ² is H, 2,2,2-trifluoroethyl, 2- (N, N-
Dimethylamino) ethyl, 3- (N, N-dimethylamino) propyl, acetyl, 2-ethylhexanoyl, c
In the case of is (-)-isomer, it is other than (E) -2-branoyl and (E) -cinnamoyl). 4. General formula I. 3-Methyl-2-R^ThreeC
H_Two-2,3,4,5-tetrahydro- and 2-methyl
-2-R^ThreeCH_Two-2,3,4,4a, 5,9b-hex
Sahydro-IH-pyrido [4,3-b] indole (2
Quaternary salt having a nitrogen atom connected to each other)
The compound according to claim 1.(In the formula, dotted line and continuous line segment attached to itRepresents a standard or double bond; R¹And X are in claim 1.
As defined; R^TwoIs 2- (2-N-methyl-N-
R^Three-Methylamino) ethyl) -5-R¹− Indrill
-3-methyl group (in the formula, R¹And R^ThreeIs according to claim 1.
, And in this caseIs a double bond; or a group of the general formula(Where Y, Z, k, l and m are as defined in claim 1)
Yes; 1) Y is defined above only when k + m ≧ 2 and l = 0
2) when k = 1 = m = 0, Y is halogen, CHa
l_Three, OR^Four, NR^FiveR⁶, Aryl, trialkyl
Ammonium, cycloalkyl ammonium, N-azini
Other than um or N-azolium; 3) when k = 1 = 0, m = 1, and Z = 0, Y is
Rogen, OH, CN, alkylsulfonyl, aryls
Rufonyl, trialkylammonium, cycloalkyl
Other than ammonium, N-azinium or N-azolium
4) When k = 1, m = 1, and Z is S, Y is a group
NR^FiveR⁶Only, where R⁶Is hydrogen; 5) when l = 0, Z is H_Two6) When k = 0 and l = m = 1, Z is not S
R; However: R¹And R^ThreeAre each H, and
When X is iodine, R^TwoIs H, methyl, ethyl or pro
Not a pill; R¹And R^ThreeAre H respectively,
And when X is methylsulfate, R ^TwoIs benzyl or less
Outside; R¹Is H, R^ThreeIs methyl and X is iodine
When, R^TwoIs other than H; R¹Is methyl, R^ThreeBut
H, and when X is iodine, R^TwoIs other than H or methyl
And R¹Is H, R^ThreeIs phenyl and X is chloro
When, R^TwoIs other than H or benzyl; R¹Is H,
R^ThreeIs phenyl and X is iodine, R^TwoIs 3-
(N, N, N-trimethylammonium) propylio
Other than Zido). 5. The general formula I. A compound according to claim 2 which is 5-substituted 2-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole of 1.1: Wherein R ¹ and X are as defined in claim 1; and Y is cycloalkyl; ethenyl (optionally mono-, di- or tri-substituted by lower alkyl, mono-substituted by the group COOR ⁴ (Wherein R ⁴ is as defined in claim 1); 2-, 3- and 4-pyridyl (optionally mono- or di-substituted by lower alkyl); Provided that when R ¹ is methyl, Y is other than H; and when R ¹ is H, Y is other than cyclohexyl, 2- and 3-pyridyl). 6. General formula I. 1.2 5- (substituted methyl) -2-methyl-2,3,4,5-tetrahydro-1
3. H-pyrido [4,3, -b] indole.
Compounds described: Where R ¹ is as defined in claim 1; Y is H, cycloalkyl; ethenyl (optionally with lower alkyl to mono,
Di- or tri-substituted, aryl mono-substituted, COOR ⁴ β-mono-substituted (wherein R ⁴ is as defined in claim 1); C
N; CHal ³ (where Hal is chloro, fluoro, or bromo); alkylsulfonyl; arylsulfonyl; aryl (optionally the substituent A according to claim 1).
Mono-, di-, or tri-substituted by;
And 4-pyridyl (optionally mono- or di-substituted by lower alkyl);
When R ¹ is methyl, Y is other than H, phenyl, and 2-pyridyl; when R ¹ is H, Y is also other than OH and chlorophenyl). 7. General formula I. 1.3-5- (2-substituted ethyl) -2-methyl-2,3,4,5-tetrahydro-
A compound according to claim 2 which is 1H pyrido [4,3-b] indole: (Wherein R ¹ is as defined in claim 1; R ² is as defined in claim 2; provided that: when R ¹ is methyl, Y is a dimethylamino group, 6-methyl-3; -Pyridyl or -4
-Other than pyridyl; when R ¹ is H, Y is phenyl, 2-pyridyl, OR ¹⁰ , R ⁵ R ⁶ N according to claim 1 (wherein R ⁵ and R ⁶ are excluded), except as defined above. Are each ethyl or R ⁵ and R ⁶ together are tetra- or pentamethimene). 8. The formula I.I. 1.3.1 of 5- (2-N-
R ⁵ —N—R ⁶ -aminoethyl) -2-methyl-2,
3,4,5-Tetrahydro-1H-pyrido [4,3-
b) indole, the compound according to claim 7: (Wherein R ¹ , R ⁵ and R ⁶ are as defined in claim 1; provided that when R ¹ is methyl, R ⁵ and R ⁶ cannot together represent methyl; When R ¹ is H, R ⁵
And R ⁶ cannot together represent methyl or ethyl, or R ⁵ and R ⁶ together are other than tetra- or pentamethylene). 9. The general formula I.I. 1.3-5- (2-, 3
-Or 4-pyridylethyl) -2-methyl-2,3
The compound according to claim 7, which is 4,5-tetrahydro-1H-pyrido [4,3-b] indole (I.1.3.
2): (wherein R ¹ is as defined in claim 1; Y is 2-, 3- or 4-pyridyl (optionally mono- or di-substituted by lower alkyl); When R ¹ is methyl,
Y is other than 6-methyl-3-pyridyl or 4-pyridyl; and when R ¹ is H, Y is also other than 2-pyridyl). 10. General formula I. 1.3.3 of 2-methyl-
The compound according to claim 7, which is 5- (2-dianoethyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole: (In the formula, R ¹ is as described in claim 1.) 11. General formula I. 1.3.4 of 5- (2-C
OR ⁹ - ethyl) -2-methyl-2,3,4,5-tetrahydro -1H- pyrido [4,3-b] indole a is claim 7 wherein the compound: embedded image (Wherein R ¹ is as defined in claim 1; R ⁹ is OH, alkoxy, NR ⁵ R ⁶ (wherein R ⁵ and R ⁶ are as defined in claim 1 except for the stalimide group). There is)). 12. General formula I. A compound according to claim 2 which is the 4- (ω-substituted alkyl) -2-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole of 1.4: 21] (In the formula, R ¹ are as defined in claim 1; Y are as according to claim 2; k represents 3 or 4; with the proviso that: R ¹
Is methyl and k = 3, Y is other than a dimethylamino group; when R ¹ is H and k = 3, Y is a group N (C
Other than H ₂ CH ₂ ) ₂ w (where W is 0, NCH ₃
Or NCH ₂ Ph), and when k = 4, Y is other than H). 13. General breath I. 5- [N-substituted (thio) carbomoyl] -2-methyl-2,3,4,4 of 2.1
a, 5,9b-Hexahydro-1H-pyrido [4,3-
b) an indole, wherein the compound is: (Wherein R ¹ and R ⁵ are as defined in claim 1; Z is O or S). 14. General formula I. 2.2 5- (α- (ω
-)-Substituted alkanoyl) -2-methyl-2,3,
The compound according to claim 3, which is 4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole. Wherein R ¹ is as defined in claim 1; Y, k and l are as defined in claim 3; provided that: when R ¹ is H and l = 0, then Y is k Other than H, N, N-diethylamino or N-piperidino group when = 1; other than N-morpholino group when k = 1 or 2, and other than chloro when k = 1, 2 or 4; and When R ¹ is methyl,
Y is other than H when k = 1 = 1 = 0 or k = 4 and l = 1, and Alk is ethyl). 15. General formula I. 2.2.1 5-acyl-
Substituted-2-methyl-2,3,4,4a, 5,9b-f
With oxahydro-1H-pyrido [4,3-b] indole
A compound of claim 15 wherein:(Where R¹Is as defined in claim 1; Y is H;
Rukyl; ethenyl (optionally with lower alkyl mono,
Di- or tri-substituted, mono-substituted by aryl
COOR^FourΒ-mono-substituted by
(Where R^FourIs as defined in claim 1); OR ^Four
(Where R^FourIs as defined in claim 1, except H.
); NR^FiveR⁶(Where R^FiveAnd R⁶Is described in claim 1.
As shown); COR⁹(Where R⁹Excludes the OH group
As described in claim 1); CHal_Three(formula
Where Hal is chloro, fluoro or bromo);
Reel (optionally with a substituent A according to claim 1,
Di- or tri-substituted); 2-, 3- and 4-pyri
Dil (optionally mono- or di-substituted by lower alkyl
); And the corresponding 1-R^ThreeCH_Two-Piriji
A quaternary salt of um-2, -3 or -4 (where R is^ThreeIs billed
As described in paragraph 1));
R¹Is methyl, Y is a cis-(-)-isomer
In the case other than (E) -propenyl-1 or (E) -2-f
Other than phenylethenyl). 16. The formula I.I. 2.2.2 5- (α-Substituted alkanoyl) -2-methyl-2-R ³ CH ₂ —
The compound according to claim 14, which is 2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole. R ¹ is as defined in claim 1; Y is as defined in claim 2). 17. The formula I.I. 2.2.3 5- (ω-substituted alkanoyl) -2-methyl-2,3,4,4a,
5,9b-Hexahydro-1H-pyrido [4,3-b]
The compound according to claim 14, which is indole. (In the formula, R ¹ are as claimed in claim 1, wherein; Y are as according to claim 2 wherein; k represents an integer of 1 to 4; provided that: R ¹
Is H, Y is other than H, N, N-diethylamino or N-piperidino when k = 1; N- when k = 1 or 2.
Other than a morpholino group; and other than chloro when k = 1, 2 or 4; and Y is other than H when R ¹ is methyl and k = 1). 18. A compound of general formula I.I. 2.3- (ω-substituted alkyl) -2-methyl-2,3,4,4a, 5,9b
-Hexahydro-1H-pyrido [4,3-b] indole The compound according to claim 3 (Wherein R ¹ is as defined in claim 1; k is an integer from 0 to 4; Y is H; ethenyl (optionally mono-, di- or tri-substituted by lower alkyl, aryl; Monosubstituted or β-mono-substituted by COOR ⁴ , wherein R ⁴ is as defined in claim 1); CF ₃ ; OR _{4 where} R ⁴ is defined in claim 1. NR ⁵ R ⁶ (wherein R ⁵ and R ⁶ are as defined in claim 1); provided that when R ¹ is H, Y is other than H (k = 1 or 2) or other than phenyl (when k = 1); and when R ¹ is methyl,
Y is other than CF ₃ (when k = 1); and other than a dimethylamino group (when k = 2 or 3)). 19. The formula I.I. 3.1-Methyl-2-
R^ThreeCH_Two-2,3,4,5, -tetrahydro-1H-
Pyrido [4,3-b] indole (Quaternized nitrogen atom at 2-position
A compound according to claim 4, which is a quaternary salt of(Where R¹, R^Two, R^ThreeAnd X are as defined in claim 1.
R; However, R¹as well as^ThreeEach is H, and X is yaw
When do, R^TwoIs other than H, methyl, ethyl or propyl
And R¹as well as^ThreeIs H, and X is methylsulfate
R when^TwoIs other than benzyl; R¹Is H, R^Three
Is methyl and X is iodine, R^TwoIs other than H
R; ¹Is methyl, R^ThreeIs H and X is iodine
Come, R^TwoIs other than H or methyl; R¹Is H, R^ThreeBut
Phenyl, and when X is chloro, R^TwoIs H or Ben
Other than Jill; R¹Is H, R^ThreeIs phenyl, and X
Is iodine, R^TwoIs 3- (N, N, N-trimethyl
Other than ammonium) propyl iodide. 20. General formula I. 3.1.1 5- (un) quaternary salts of substituted 2-methyl -2-R ³ CH ₂ -2,3,4,5- tetrahydro -1H- pyrido [4,3-b] indole The compound according to claim 19, which is: (Wherein R ¹ , R ³ and X are as defined in claim 1; Y is H; cycloalkyl; ethenyl (optionally mono-, di- or tri-substituted by lower alkyl, mono by aryl; Substituted, β-mono substituted by COOR ⁴ , wherein R ⁴ is as defined in claim 1); alkylsulfonyl; arylsulfonyl; C
N; COR ⁹ (wherein R ⁹ is as defined in claim 1); 2-, 3- or 4-pyridyl (optionally mono- or di-substituted by lower alkyl); and 1-R ³
Selected from the group consisting of suitable quaternary salts of CH ₂ -viridinium-2, -3 or -4, where R ³ is as defined above: where R ¹ and Y are H and X respectively. Is chloro, R ³ is other than phenyl; R ³ and Y
Are each H and X is iodo, R ¹ is other than methyl). 21. General formula I. 3.1.2 5- (Substitution
Methyl) -2-methyl-2-R^ThreeCH_Two-2, 3, 4,
5-tetrahydro-1H-pyrido [4,3-b] indo
20. The compound according to claim 19, which is a quaternary salt of(Where R¹, R^ThreeAnd X are as defined in claim 1; Y is
H, cycloalkyl, ethenyl (optionally lower alkyl
Mono-, di- or tri-substituted by aryl and aryl-substituted by
Substituted, COOR^FourΒ-mono substituted by
Where R^FourIs as defined in claim 1); C
N; CHal_Three(Where Hal is chloro, fluoro or
Bromo); alkylsulfonyl; arylsulfo
Nyl; aryl (optionally according to the substituent A of claim 1)
Richino, di or tri substituted); OR^Four(here
R^FourIs as defined in claim 1); COR⁹(here
R⁹Is as defined in claim 1); COR⁹(here
R ⁹Is as defined in claim 1); 2-, 3- and 4
-Vyridyl (optionally lower alkyl in mono or di
Has been replaced) and its corresponding 1-R^ThreeCH_Two-Pi
The quaternary salt of ridinium-2, -3 or -4 (where R^Three
Is as defined in claim 1);¹And R^Three
Is H, and X is iodine, or R¹But
Chill and R^ThreeIs H and X is iodine, Y is
Other than H; and R¹And R^ThreeEach is H,
And X is methylsulfate, or R¹Is H, R^Three
Is phenyl and X is chloro, Y is phenyl or less
Outside). 22. General formula I. 3.1.3 5- (2-substituted ethyl) -2-methyl -2-R ³ CH ₂ -2,3,
20. The compound according to claim 19, which is a quaternary salt of 4,5-tetrahydro-1H-pyrido [4,3-b] indole. (Wherein R ¹ , R ³ and X are as defined in claim 1; Y
Is CN, COOAlk; 2-, 3- or 4-pyridyl (optionally lower are mono- or di-substituted by alkyl) and the corresponding 1-R ³ CH ₂ - pyridinium -2, -3 or -4 Quaternary salts (wherein R ³ is claim 1
As described)), where:
R ¹ and R ³ are each H, and X is iodine,
Y is other than H). 23. General formula I. 3.1.4 5-acyl-
2-methyl-2-R ^ThreeCH_Two-2,3,4,5-tetra
Fourth of hydro-1H-pyrido [4,3-b] indole
The compound according to claim 19, which is a graded salt.(Where R¹, R^ThreeAnd X are as defined in claim 1; Y is
Cycloalkyl; ethenyl (optionally with lower alkyl
Mono-, di- or tri-substituted, mono-substituted by aryl
And COOR^FourBy β-mono substitution, where R^Four
Is as defined in claim 1); CHal_Three(Here H
al is chloro, fluoro or bromo); aryl
(Optionally by the substituent A of claim 1, mono, di or
Tri-substituted); OR^Four(Where R^FourIs in the claim
As stated, except H); NR^FiveR⁶(here
In R^FourIs as defined in claim 1 except H); CO
R⁹(Where R⁹Is as defined in claim 1 excluding OH
2-, 3- and 4-pyridyl (optionally lower
Mono- or di-substituted by rukill) and its
1-R^ThreeCH_Two-Quaternary salt (where R_ThreeIs the claim
1 as described in 1)). 24. A compound of the general formula I.I. 3.2 5-substituted 2-me
Chill-2-R^ThreeCH _Two-2,3,4,4a, 5,9b-
Hexahydro-1H-pyrido [4,3-b] indole
With a quaternary salt (having a nitrogenated atom in the 2-position)
A compound of claim 4 wherein:(Where R¹, R^ThreeAnd X are as defined in claim 1; R^TwoIs
Is a group of the following general formula:(In the formula, k, l, m and Y are as defined in claim 4.
Note: 1) Y is defined above only when k + m ≧ 2 and l = 0.
2) when k = 1, m = 1, Y is halogen, OH,
CN, alkylsulfonyl, arylsulfonyl, tri
Alkyl ammonium, cycloalkyl ammonium,
Other than N-azinium or N-azolium; 3) m = 0 only when k = 1 = 0, and Y is
Is rukylsulphonyl, arylsulphonyl or CN
). 25. 2-Methyl-8-isopropyl-2,
3,4,5-Tetrahydro-1H-pyrido [4,3-
The compound according to claim 5, which is b] indole hydrochloride. 26. 2,8-Dimethyl-5- (2,4-dimethylbenzyl) -2,3,4,5-tetrahydro-1
The compound according to claim 6, which is H-pyrido [4,3-b] indole hydrochloride. 27. 2,8-Dimethyl-5- (2-N-hexamethyleneiminoethyl) -2,3,4,5-lH-
The compound according to claim 8, which is pyrido [4,3-b] indole dihydrochloride. 28. 2,8-Dimethyl-5- (2-carboxyethyl) -2,3,4,5-tetrahydro-1H-
A pyrido [4,3-b] indole hydrochloride salt.
2. The compound according to 1. 29. The compound according to claim 22, which is the following compound: 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-trimetal 1-5- (2-carboethoxyethyl) -2,3,4,5-tetrahydro-1H-pyrido [4. 3-b] Indolium iodide. 30. 2,2,8-Trimethyl-5- (5-
20. Methyl-2- (2-N, N-dimethylaminoethyl) indolyl-3-methyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indolium iodo. The described compound. 31. 2,2,8-Trimethyl-5- (N-
24. A compound according to claim 23 which is methylcarbamoyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indolium iodide. 32. The compound according to claim 13, which is the following compound: cis- (±) -2,8-dimethyl-5- (N
-Cyclohexylthiocarbamoyl) -2,3,4,4
a, 5,9b-hexahydro-1H-pyrido: [4,3
-B] indole; cis- (±) -2,8-dimethyl-5- (Nn-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 compound according to claim 15, which is the following compound: 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, 5
9b-Hexahydro-1H-pyrido [4,3-b] indole. 34. The compound according to claim 16, which is the following compound: cis- (±) -2,8-dimethyl-5- (2
-Promopropionyl) -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 compound according to claim 17, which is the following compound: cis- (±) -2,8-dimethyl-5-chloroacetyl-2,3,4,4a, 5,9b-hexahydro-1H-. Pyrido [4,3-b] indole hydrochloride; c
is- ± ()-2,8-dimethyl-5-methoxyacetyl-2,3,4,4a, 5,9b-hexahydro-1
H-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-pyridinumacetyl) -2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indolecrocod; Or cis- (±) -2,8-dimethyl-5-
(3-carboxyprobionyl) -2,3,4,4a,
5,9b-Hexahydro-1H-pyrido [4,3-b]
Indole. 36. cis- (±) -2-methyl-5-
[2- (6-methyl-3-pyridyl) ethyl] -2,
The compound according to claim 18, which is 3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole trihydrochloride. 37. cis- (±) -2,2,8-trimethyl-5-n-carbamoyl-2,3,4,4a, 5
25. The compound according to claim 24 which is 9b-hexahydro-1H-pyrido [4,3-b] indolium iodide. 38. 5- (ω-pyridylalkyl) having the formula:
-2-methyl -2-R ³ CH ₂ -2,3,4,5- tetrahydro -1H- pyrido [4,3-b] indole (2
A mono-quaternized quaternary salt having a quaternized nitrogen atom at position). (Wherein R ¹ , R ³ and X are as defined in claim 19; R ¹¹ is lower alkyl, K is an integer from 1 to 4, and t is 0, 1 or 2): A compound of the formula: (Wherein R ¹ , R ¹¹ , k and t are as described above) and an equimolar amount of the formula R ³ CH ₂ X (wherein R ³ and X are as described above in claim 1). With an alkylating agent of claim 1 in an inert solvent (such as hexane, benzene, ether, etc. claims) which dissolves the starting material but does not dissolve the mono-quaternized salt to be formed, and A method characterized by performing at this step at room temperature. 39. Formula I. 3.1 5-substituted 2-methyl -2-R ³ CH ₂ -2,3,4,5- tetrahydro -1
A method for preparing a quaternary salt of H-pyrido [4,3-b] indole (having a quaternized nitrogen atom at the 2-position): (In the formula, R ¹ , R ³ and X are as defined in claim 19; R ² is (CH ₂ ) _2- CN, — (CH ₂ ) _2- COOA.
lk-CONHR ⁵ (wherein R ⁵ is alkyl, cycloalkyl or aryl) or COR ¹² is an alkyl or alkoxy group Compounds of the formula: (Wherein R ¹ and R ³ and X are as described above) with the formula CH ₂ ═CH—Y, where Y is CN or COOAlk.
A) and an electrophile selected from activated olefins of acid halides or acid anhydrides, respectively, in the presence of a non-nucleophile. 40. R ² is — (CH ₂ ) _2- CN or — (C
H ₂₎ When ₂ -COOAlk, wherein CH ₂ = CH-Y (wherein employing excess electrophilic alkylating reagent to be used, Y
Is CN or COOAlk) with the activation of olefin as an olefin, and the step is adopted at 0.5 to 5 mol% as a non-nucleophilic base. , 2, 2, 6, 6
-Pentamethylpiperidine, DBU, etc.) at a temperature ranging from ambient temperature to the boiling point of the reaction mixture. 41. The formula R ⁵ —N =, wherein R ² is CONHR ⁵ and the electrophilic alkylating agent used is employed in excess.
Isocyanate with C = O (wherein R ⁵ is as defined in claim 39).
As described), and a non-nucleophilic base which is a sterically hindered tertiary amine (eg ethyldiisopropylamine, 1,2,2,2) which employs the steps in an amount of 0.5 to 5 mol%.
6,6-pentamethylpiperidine, DBU, etc.) at a temperature ranging from ambient temperature to the boiling point of the reaction mixture. 42. When R ² is COR ¹² (wherein R ¹² is an alkyl or alkoxy group), the electrophile used is an acid halide of formula R ¹² COX ¹ or oxygen hydrate (wherein R ^{12 is} Is as described above, X ¹ is halogen or R ¹²
40. The method according to claim 39, characterized in that an equimolar amount of non-nucleophilic base is used). 43. The non-nucleophilic base used is a higher tertiary amine (eg triethylamine, ethyldiisopropylamine, DBU, etc.) and the process is carried out at a temperature ranging from ambient temperature to the boiling point of the reaction mixture. And how to. 44. The formula (R ¹² CO) ₂ O, wherein R ¹² is alkyl, wherein the electrophile used is employed in excess.
Carboxylic acid anhydride and the non-nucleophilic base used is the alkali metal (eg sodium or potassium) or alkali metal (eg sodium or potassium) carbonate of the corresponding carboxylic acid, and the step is carried out from 50 ° C. to the reaction mixture. The method is carried out at a temperature in the range of the boiling point of. 45. Formula I. 3.1.2 2-methyl-2-
_{^{R 3 -CH 2 -8-R 1}} -5- (5-R 1 -2-R 3 C
_{H 2 NMe- (CH 2) 2} - indolyl-3-methyl)
-2,3,4,5-tetrahydro-1H-pyrido [4,4
3-b] A method for preparing a quaternary salt of indole, comprising: (Wherein R ¹ R ³ and X are as defined in claim 19), and a compound of the following formula: (Wherein R ¹ R ³ and X are as described above) is reacted with a non-nucleophilic base in a polar solvent while heating. 46. The non-nucleophilic base used is 0.5 molar equivalent of a highly basic basic subject-type tertiary amine (eg, ethyldiisopropylamine, 1,2,2,6,6-pentamethylperidine, DBU). 46) The method according to claim 45, characterized in that 47. The method according to claim 45, wherein the method is carried out in a polar solvent such as pyridine, DMFA, HMPTA and the like. 48. The method of claim 47, wherein the method is performed in pyridine. 49. A process according to claim 45, characterized in that it is carried out at a temperature between 50 ° C. and 150 ° C. or at the boiling point of the reaction mixture. 50. A method of treatment of a disease in which the pathogenic mechanism involves the glutamate neuromediator system, comprising administering to the patient a therapeutically effective amount of a compound that is an NMDA antagonistic amount. This NMD to use
A method wherein the A antagonistic amount is the compound according to claim 1 or a pharmaceutically acceptable salt thereof. 51. A pharmaceutical composition comprising a therapeutically effective amount of an active agent and one or more pharmaceutically acceptable co-additives, wherein the active agent used. A compound of formula I of or a pharmaceutically acceptable salt thereof.