UA80968C2 - Polycyclic compounds as potent alpha-2 adrenoceptor antagonists - Google Patents

Abstract

The invention provides a compound of formula I, wherein X, Z, R1 to R10, R15, R16, m, n, r and t are as defined in claim I, or a pharmaceutically acceptable salt or ester thereof, useful as an alpha-2 antagonist. The compounds of formula I can be used for the treatment of diseases or conditions where antagonists of alpha-2 adrenoceptors are indicated to be effective. I

Description

Description of the invention

The present invention relates to pharmacologically active derivatives of arylquinolysine and related compounds, to their 2 pharmaceutically acceptable salts and esters, as well as to pharmaceutical compositions containing them, and to their use as alpha? antagonists

Certain compounds exhibiting alpha adrenergic activity are well known in the art. As is also well known and accepted in the art, such compounds can be used to treat a large number of diseases and conditions of the peripheral and central nervous system (CNS). 70 Alpha adrenergic receptors can be divided on a pharmacological basis into alpha!1- and alpha?-adrenoceptors, both of which can be divided into subtypes. Three genetically encoded subtypes, namely, alpha-A, alpha-B, and alpha-2C adrenoceptors, have been identified in humans. Accordingly, human alpha2-adrenoceptors have been divided into three pharmacological subtypes, known as alpha?A-, alpha2B-, and alpha?C-adrenoceptors. A fourth, pharmacologically defined subtype, alpha2O, is known in rodents and some 12 other mammals and corresponds to the genetically defined alpha 2A adrenoceptors.

Subtypes of alpha2-adrenoceptors have different distribution in tissues and functional roles. For example, whereas alphaγA adrenoceptors are widely expressed in various tissues, alpha?2C adrenoceptors are concentrated in the CNS and apparently play a role in modulating specific, CNS-mediated behavioral and physiological responses.

Compounds that are non-specific to any of the above alpha subtypes? and compounds that are specific to certain alpha2 subtypes are already known. For example, is atipamezole a non-specific alpha? antagonist. Atipamezole is described (for example, in EP-A-183492 (compare p. 13, compound XM) and Naaraipp,

A. ei aI.,, Mashpup-Z5sptiederegu from Agsp. RIagtasoi. 356 (1997) 570-5821. (US patent Mo5902807)| describes compounds that are selective antagonists of the alpha subtype? and can be used in the treatment of mental diseases, p 29 for example, mental disorders induced by stress. Such compounds include, for example, MK-912 and VAM-1303. Gee)

In addition, (MMO-A-99 28300| describes substituted imidazole derivatives having agonist-like activity against alphaH2HB- or 28/2C-adrenoceptors. In addition, (MO 01/64645) refers to quinoline derivatives useful as alpha? antagonists, and to selective alpha2C antagonist agents.The descriptions of all documents cited above in this section are incorporated herein by reference.

A number of arylquinolysine derivatives and related compounds have been described in the literature, some of which have useful pharmaceutical activity. (For example, US Pat. Nos. 4,806,545 and 4,044,012 describe 1,1-disubstituted indolo(|2,3-o)quinolizidines useful as vasodilators and antihypoxic agents. Further, substituted arylquinolisine derivatives are described (eg, in US Pat. No. 4,686,226)| , possessing alpha2-adrenoceptor. "3 antagonistic activity, are useful, for example, as antidepressants, hypotensive or antidiabetic agents, or platelet aggregation inhibitors. In addition, (US patent Mo3492303| refers to indolo(|2,3-quinolizidines, useful as suppressors of the central nervous system. molecular modeling of targets for the synthesis of alphatA and alpha?selective ligands is discussed by Sgiyyi, K. eyi ai., 5.

Sotryi.-Aided Moi. Oevzidp 13 (1999) 69-78). 20 The purpose of this invention is to provide novel alpha2-adrenoceptor antagonists that can be used to treat diseases or conditions of the peripheral or central nervous system in which alpha2-antagonists have been shown to be beneficial. Accordingly, it is an object of the present invention to provide novel compounds for use as alpha2-antagonist agents in the treatment of mammals, including humans and animals.

The invention also provides compounds that are useful as alpha2C antagonist agents for the treatment of various disorders or conditions of the central nervous system for which alpha?C antagonists have been shown to be useful. oo Figla and B show the results of two separate locomotor activity tests, where the locomotor activity of mice was studied after injections of solvent (vehicle) or amphetamine (amp) (4 micromol/kg). Mice were pre-treated (20 minutes before amphetamine) with a solvent, a subtype of the selective alpha2-antagonist atipamezole (Imicromol/kg) or alpha?C-antagonists, compound K (Zmicromol/kg) (Fig.a) or compound G! (Zmicromole/kg) (Fig. rv). "p«0.05, ""p«e0.01 and ireb0.001 in comparison with the solvent-narf group - (one-sided AMOMACHI 50 - test). (2) Fig. 2 shows the alpha2-agonist-induced sedative effect (measured as motor inhibition) in mice.The non-selective alpha2-antagonist atipamezole (Aty, Aii) antagonized the sedative effects of the alpha2-subtype of the non-selective agonist dexmedetomidine (Dex; 5Onmol/kg b/w), whereas selective alpha-agonists had no significant effects (solvent-solvent) . (""p«0.001, in comparison with Dextrosolvent).

Fig. 3 shows the effect of alpha2C-selective antagonists compound K (Zmicromole/kg) and compound HH. (Zmicromol/kg), non-selective antagonist atipamezole (1Omicromol/kg) and standard antidepressants desipramine (F) (1Omicromol/kg) and fluoxetine (1Omicromol/kg) in the forced swimming test in rats. All compounds, except

GI atipamezole increased activity (""ra" 0.001, compared to the solvent).

Figures 4a and 45 show the effect of compounds K and I on the startle reflex and its anticipatory inhibition in rats. in (Solvent-solvent). Asterisks as in Fig. 1; a comparison was made between FCC (PCP, phenylcyclidine) solvent and

FCKEsCompounds Ki her.

Figures 5a and 55 show the effect of the non-selective antagonist atipamezole (Aty) on the startle reflex and its anticipatory inhibition in rats in the presence of phenylcyclidine (FCC); (solvent-solvent). Asterisks as in Fig. 1, comparison with the solvent-FCC group. 65 One embodiment of the present invention covers the use of compounds of the formula

!

Sq

Kk; (Tuesday also - x 7 I

IN;

IS,

Zh k B, 70 E; where

X represents SKK", O, Z or MK"; 7 represents - SNK 8-(СНа)- or a simple bond;

Cu represents hydroxy, (C 1-Cv)alkyl, (C4-Cv)alkyl, halogen, halogen(C.4-Cv)alkyl, (C4-Cv) alkoxy-CO-, CM,

MO», MH», mono- or di(C4-Sev) alkylamino or carboxyl;

Co and Co are independently H, hydroxy or (C 41-Cv)alkyl or Co and Co" form, together with the carbon atoms that form the ring to which they are attached, a carbonyl group;

Kz is H, hydroxy, (Co 4-Cv)alkyl, (Co-Cv)alkenyl, hydroxy(C--Cv)alkyl, (C.--Cv)alkyl, (C.4-Cv)alkyl (C.4 -Cv)alkyl, hydroxy(C4-Cv)alkyl (C.--Cv)alkyl, (C3-Cv)cycloalkyl, (C3-C7)cycloalkyl(C.--Cv)alkyl, aryl, aryl(Cv) )alkyl, aryloxy, aryl(C.--Cv)alkyl, aryloxy(C--Cv)alkyl, aryl(C.--Cv)alkyl(C.4-Cv)alkyl, halo(C 4-Cv)alkyl . (С4-Св)alkyl-СО-О-, (С1-Св)alkyl-СО-О-(Си-Св)alkyl,) SM (С.-Св)alkyl-СО-, (С.4-Св) Alkoxy-CO-(C.4-Cv)alkyl, (C--Cv)Alkoxy-CO-(C4-Cv)Alkoxy(Ci-Cv)alkyl, carbamoyl, or mono or di(C--Cv)alkylcarbamoyl, carboxyl or (C.4-C)alkyl-5-(C.4-C)alkyl, where said (C.53-C)cycloalkyl or aryl is unsubstituted or substituted by 1 or 2 substituents, each of which is independently hydroxy, (C.4- C1-alkyl, halogen, (C4-C1) alkoxy, MNo, CM or MO", or one of Kz or EK, and Ke together form a bond between the atoms of the ring to which they are attached; co

KE. represents H, hydroxy, (C4-Cv)alkyl, hydroxy(C.--Cv)alkyl, (C4-Cv)alkyl, or (C.4-Cv)alkyl(C4-Cv)alkyl; "co

K represents H, hydroxy, (C 4-Cv)alkyl, (Co-Cv)alkenyl, (C.i-Cv)alkyl, (C.4-Cv) alkoxy(C4-Cv)alkyl, (C3-C7 )cycloalkyl, (C3-C7)cycloalkyl(C.--Cv)alkyl, aryl, aryl(C--Cv)alkyl, aryloxy, aryl(C.--Cv)alkyloxy, (o) aryloxy(C.4- C4-alkyl, aryl(C4-C4) alkoxy (C4-C4) alkyl, halo(C4-C4) alkyl, (C4-C4) alkyl-CO-O-, o (C4-C4) alkyl-CO- O-(C.Cv)alkyl, (C4-Cv)Alkoxy-CO-(C4-Cv)Alkoxy(C4-Cv)alkyl, carbamoyl, Mono or di(C4i-Cv)alkylcarbamoyl, carboxyl or (C.- C1)alkyl-5-(C4-C8)alkyl, where the specified (C3-C7)cycloalkyl or aryl 00 is substituted or unsubstituted by 1 or 2 substituents, each of which is independently hydroxy, (C4-C8)alkyl, halogen, (Ci-Cv)alkoxy, МНо, СМ or MO», or K, and K5 form, together with the ring-forming carbon atoms to which they are attached, a condensed five-seven-membered saturated carbocyclic ring, substituted with 1- 3 "Co substituents, each of which independently represents hydroxy, (Co 4-Cv)alkyl, halogen, MH", MO", (C5-CU)cycloalkyl, hydroxy(C-i-Cv)alkyl, halogen(C- -Sv)alkyl , amino(C.i-Cv)alkyl, mono-or di(C.--Cv)alkylamino, mono- or di(Ci-Cv)alkylamino(C 4-Cv)alkyl, (C4-Cv)alkyl , (C41-Cv)alkyl(C4-Cv)alkyl, carboxyl, h (C4-Cv)alkyl-CO-, (C41-Cv)alkyl-CO-O-, (C4-Cv)alkyl-CO- , (C4-C) alkoxy-CO-(C4-C) alkyl, carbamoyl mono- or di(C-C) alkylcarbamoyl or oxo;

Ke represents H, hydroxy, (C 4-Cv)alkyl, (Ci-Cv)alkyl or (C.4-Cv)alkyl(C.i-Cv)alkyl or K; forms a bond between the atom of the ring to which it is attached and the atom of the ring to which K»7 is attached; (ee) K; represents H, hydroxy, (C4-Cv)alkyl, hydroxy(C.--Cv)alkyl, (C4-Cv)alkyl, or (C.4-Cv)alkyl(C4-Cv)alkyl; o Ka represents H, hydroxy, (C 4-Cv)alkyl, hydroxy(C--Cv)alkyl, (C4-Cv)alkyl, or (C-4-Cv)alkoxy(C--Cv)alkyl or, in in the case when n is 0, K and Ka form together with the carbon atoms that form the ring to which they are attached, a condensed five-seven-membered saturated carbocyclic ring, unsubstituted or substituted with 1-3 b 50 substituent(s) ) Kio, each of which is independently a hydroxy, (Co 4-Cv)alkyl, halogen, MH", MO", (C3-C7)cycloalkyl, hydroxy(C.-i-Cv)alkyl, halogen(C.- C1-alkyl, amino(C1-C1)alkyl, mono- or di(C1-C1)alkylamino, co-mono- or di(C1-C1)alkylamino(C1-C1)alkyl, (C4-C1) Alkoxy, (C4-Cv)Alkoxy(C.4-Cv)alkyl, carboxyl, (C4-Cv)Alkyl-CO-, (C4-Cv)Alkyl-CO-O-, (C4-Cv)Alkoxy-CO- . oo Kiv is H, (Co 4-Cv)alkyl, (Co-Cv)alkenyl, hydroxy(C.i-Cv)alkyl, (C.4-Cv) alkoxy(C.4-Cv)alkyl,

Gee! hydroxy(C 1-Cv)alkyl(C4-Cv)alkyl, halogen(C.4-Cv)alkyl, amino(C.--Cv)alkyl, mono- or di(C4i-Cv)alkylamino(C 4-Cv) )alkyl, (C4-Cv)alkyl-CO-, (C4-Cv)alkyl-CO-O-(C4-Cv)alkyl, (C4-Cv)alkyl-CO-, where (C4-Cv)alkyl-CO -(C4-Cv)alkyl, (C4-Cv)alkyl-C0-(C4-Cv)alkyl (C-Cv)alkyl, carbamoyl, mono- or di(C-Cv)alkylcarbamoyl or carboxyl; because Kv represents M or (C.4-Sev)alkyl;

KE; and Ka are attached to carbon atoms of rings that are adjacent; t is equal to 0-2; and n is 0 or 1, or a pharmaceutically acceptable salt or ester thereof, provided that the compound is not 65 1,2,3,4,5,10p-hexahydro-10-thia-Za-azacyclopenta|a|fluorine, to obtain a medicinal product for the treatment of diseases or conditions in which alpha2-antagonists have been shown to be effective.

In a possible subgroup of compounds of formula I, X represents MK".

In another possible subgroup of compounds of the formula I, t is 0, n is 0, Ko is H, Kz is H, hydroxy, (C.4-Cv)alkyl, hydroxy(C--Cv)alkyl, (C4-Cv) alkoxy(C.4-Cv)alkyl, (C3-Cv)cycloalkyl, halo(C.--Cv)alkyl, 500 (C1-Cv)alkyl-CO-, (Ci-Cv)alkyl-CO-O-( C4-Cv)alkyl, (C4-Cv)alkyl-CO- or (C.-Cv)alkyl-CO-(C.-Cv)alkyl, Ku represents H, hydroxy, (C 4-Cv)alkyl or hydroxy (C.i-Cv)alkyl, Co represents H, hydroxy, (C 4-Cv)alkyl or (C4-Cv)alkyl, Co represents M or (C.4-Cv)alkyl and K; is H, (C.4-Cv)alkyl or hydroxy(C.-Cv)alkyl.

In another possible subgroup of compounds of the formula | Kz is M or (C 4 -C 4 )alkyl and K 4 is hydroxy or hydroxy (C 4 -C 4 )alkyl. 70 In another possible subgroup of compounds of formula | K, and K5 form, together with the carbon atoms that form the ring to which they are attached, a condensed six-membered saturated carbocyclic ring.

In another possible subgroup of compounds of formula I, K and Ko together form a bond between the atoms of the ring to which they are attached, or K; forms a bond between the atom of the ring to which it is attached and the atom of the ring to which K is attached."

In yet another possible subgroup of compounds of formula I, the compound is 1To-ethyl-1,2,3,4,6,7,12,126 D-octahydroindolo!|2,3-o)quinolisin-1-ol, (T-ethyl- 1,2,3,4,6,7,12,125 y-octahydroindolo|2,3-odhinolisin-1-ilumethanol, 1o-methyl-1,2,3,4,6,7,12,125 p-octahydroindolo|2, 3- d) quinolysin-1-ol, (To-methyl-1,2,3,4,6,7,12,125 p-octahydroindolo|2,3- odhinolysin-1-ilumethanol or

ZA4mdar,5,6,7,8,13,136 D,1Zso-decahydro-2H-ba,13-diazaindeno|1,2-c|phenanthren-1-one.

In another possible subgroup of compounds of formula I, X represents SCC".

In the next possible subgroup of compounds of formula I, X is 5.

In yet another possible subgroup of compounds of formula I, X is 0.

When X is O, one possible subgroup of compounds of the formula | includes K 5 and Co, as defined in the description of the use of compounds of formula I above. at

Another possible subgroup of compounds of formula I, when X is 0, is one where K5 is H, hydroxy, (C4-C8)alkyl, (C4-C8)alkenyl, (C4-C8)alkoxy, (C4-C8) alkoxy(C.4-C)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C-C)alkyl, aryl, aryl(C.--Cv)alkyl, aryloxy, aryl(C--Cv) )alkoxy, aryloxy(C4-Cv)alkyl, aryl(C.-Cv)alkyl(C.--Cv)alkyl, halogen(C.--Cv)alkyl, (C--Cv)alkyl-CO-O- . or di(C--Cv)alkylcarbamoyl, carboxyl or "co(C-Cv)alkyl-C-(Ci-Cv)alkyl and Ka; is H, hydroxy, (C 1 -C 2 )alkyl, (C 2 -C 2 )alkyl or (C 4 -C 2 )alkyl (C 4 -C 2 )alkyl. Me)

Another embodiment of the invention is provided by the compound of formula IA: o

IA (ee)

Sq

E 5 « (vit y x Zx IA 8 s V h E, "» Kk B,

E, ' (ee) where o X represents the SCC", O or 5; o 2, Kk, Ko, K", Ka-Kuo, Kv and Kv, t and n are as defined above, or their pharmaceutically acceptable salt or ester, provided that (22) a) when X represents 0, t equals 0 and n equals 0, then Kz-Ka are not all hydrogen at the same time; c B) the compounds are not 1,2,3,4,5,10p-hexahydro-10-thia-Za-azacyclopenta(a|)fluorene; 1,3,4,5,6,11p6-hexahydro-2H-11-thia-4a-azabenzo|(a|fluorene; 1-(1,3,4,5,6,11p-hexahydro-2H-11- thia-4a-azabenzo(a|fluoren-1-yl)uethanone or 1,3,4,5,6,11p6-hexahydro-2H-11-thia-4a-azabenzo(a|fluoren-1-carboxylic acid) methyl ester ; for example, where X represents the SCC"; or

F) where X is 0; or where X represents 5; or where Kz is hydroxy, (C 1-C) alkyl, hydroxy(C 4-C) alkyl, (C 4-C) oxy(C 4-C) alkyl, (C 4-C) oxy-CO-vo or ( C4-Cv)alkyl-CO-O-(C.4-Cv)alkyl and K; represents H, (C.-Cv)alkyl or hydroxy(C.--Cv)alkyl; or where Kz is hydroxy, hydroxy(C 4 -C 4 )alkyl or (C 4 -C 4 ) alkoxy (C 4 -C 4 )alkyl and K; is (C4-C8)alkyl; or where K and K5 form, together with the carbon atoms of the rings to which they are attached, a condensed six-membered saturated carbocyclic ring; or 65 where the compound is 1y-methyl-1,3,4,5,6,11p-hexahydro-2H-11-oxa-4a-azabenzo(a|fluoren-1-ol, (To-methyl-1,3 ,4,5,6,116 p-hexahydro-2H-11-oxa-4a-azabenzo(a|)fluoren-1-yl)methanol,

(Y-To-methyl-1,3,4,5,6,116 p-hexahydro-2H-11-oxa-4a-azabenzo|a|fluoren-1-yl)methanol, (4-(To-methyl-1, 3,4,5,6,1165 p-hexahydro-2H-11-oxa-da-azabenzo|a|fluoren-1-yl)methanol, 1o-isopropyl-1,3,4,5,6,11p-hexahydro -2H-11-oxa-4a-azabenzo(a|)fluoren-1-ol, 1o-ethyl-1,3,4,5,6,115 p-hexahydro-2H-11-oxa-4a-azabenzo(a|fluorene -1-ol, (To-ethyl-1,3,4,5,6,116 p-hexahydro-2H-11-oxa-4a-azabenzo|(a|fluoren-1-yl)methanol, 1-methyl-1o, ,3,4,6,116 p-hexahydro-2H-11-oxa-da-azabenzo|a|fluorene, (1-hydroxymethyl-1,3,4,5,6,11 p-hexahydro-2H-11-oxa- 4a-azabenzo(a|fluoren-1-yl)-methanol, 1-methoxymethyl-1o-methyl-1,3,4,5,6,116 p-hexahydro-2H-11-oxa-4a-azabenzo|a|fluorene, 70 (-)-1-methoxymethyl-1o-methyl-1,3,4,5,6,116 p-hexahydro-2H-11-oxa-4a-azabenzo|a|)fluorene, ()-1-methoxymethyl-1o- methyl-1,3,4,5,6,115 p-hexahydro-2H-11-oxa-4a-azabenzo|(a|)fluorene, ethyl ether To-methyl-1,3,4,5,6,116 p-hexahydro- 2H-11-oxa-4a-azabenzo(a|)fluorene-1-carboxylic acid, 1-ethoxymethyl-1u-methyl-1,3,4,5,6,116u-hexahydro-2H-11- oxa-4a-azabenzo(a|fluorene, (To-methyl-1,3,4,5,6,116 y-hexahydro-2H-11-oxa-4a-azabenzo|a|fluoren-1-yl)methanol, (- -(1o-methyl-1,3,4,5,6,116 y-hexahydro-2H-11-oxa-4a-azabenzo|a|fluoren-1-yl)methanol, (43-(To-methyl-1,3 . 2H-11-oxa-4a-azabenzo(a|fluorene-1-carboxylic acid, 1-methoxymethyl-1o-methyl-1,3,4,5,6,115 y-hexahydro-2H-11-oxa-4a-azabenzo( a|fluorene, (-)U-1-methoxymethyl-1o-methyl-1,3,4,5,6,1165 o-hexahydro-2H-11-oxa-4a-azabenzo(a|fluorene, (4)- 1-methoxymethyl-1u-methyl-1,3,4,5,6,115u-hexahydro-2H-11-oxa-4a-azabenzo(a|fluorene, (To-ethyl-1,3,4,5,6,116u -hexahydro-2H-11-oxa-4a-azabenzo|(a|fluoren-1-yl)methanol, 15-methyl-1,3,4,5,6,116 d-hexahydro-2H-11-oxa-4a-azabenzo |(a|)fluoren-1-ylmethyl ester of acetic acid or c (To-methyl-1,2,3,4,6,7,12,1265 d-octahydroindeno|2,1-a)quinolisin-1-yl )umethanol. Go)

Another embodiment of the invention provides new compounds of the formula IV:

IV

Kr

Kr so (bi | M me) - x 7 IV o ko

Be so ki

Well, where are you?

X represents ME 2; c E»o is a (C.4-Ceu)alkyl; :z» 2, Ki, K8-Kio, Ki, Kv, t and n are as defined above, or a pharmaceutically acceptable salt and ester thereof, provided that a) when t is 0 or K is methoxy and K. represents H or ethyl, oo then Kz is not methoxy-CO;

B) the compound is not 12-methyl-1,2,3,4,6,7,12,12p-octahydroschdoloi|2,3-o)quinolysine; o i-ethyl-12-methyl-1,2,3,4,6,7,12,12p-octahydroindolo|2,3-od)quinolysine;

Ge) 2,3-diethyl-12-methyl-1,2,3,4,6,7,12,12p-octahydroindolo|2,3-oi)quinolysine;

F 50 12-methyl-1,2,3,4,6,7,12,12p-octahydroindolo|2,3-aquinolisin-1-ol; 2-(1-ethyl-12-methyl-1,2,3,4,6,7,12,12p-octahydroindole|2,3-a)quinolisin-1-yl)ethanol; (Che 11-methyl-2,3,5,6,11,11p-hexahydro-1H-indolizinoi|8, 7-b)indole; (11-methyl-2,3,5,6,11,11p-hexahydro-1H-indolizino|8,7-B|indol-1-yl)umethanol; (1,11-diethyl-2,3,5,6,11,11p-hexahydro-1H-indolizinoi8,7-indol-1-yl)umethanol or methyl ether

C-(1-ethyl-12-methyl-1,2,3,4,6,7,12,12p-octahydroindolo|2,3-a)quinolisin-1-yl)propionic acid; for example, where Kz is hydroxy, (C.4-Cv)alkyl, hydroxy(C.4-Cv)alkyl or (C.4-Cv)alkyl(C.--Cv)alkyl and K; is

F, H, (C4-Cv)alkyl or hydroxy(C.--Cv)alkyl; or where the compound is 1o-ethyl-12-methyl-1,2,3,4,6,7,1265p-octahydroindolo|2,3-aquinolisin-1-ol or 1o-ethyl-12-ethyl- 1,2,3,4,6,7,12b p-octahydroindolo|2,3-a)quinolisin-1-ol. 60 Another embodiment of the invention provides new compounds of formula IS: b5

IS

Square in; (you /shshhk x their s

Vo in, (Kg KE 70 From de

X represents ME 2;

Ko represents H; 7 represents -СНЕв8-(СНо)- or a simple bond; n is equal to 0;

Ru, Ez, Ke-Kao, Kv, Kv and t are as defined above; r is from 1 to 3; or their pharmaceutically acceptable salts and esters, provided that the compound is not 10-methyl-5,7,7a,8,9,10,11,11a,116,12-decahydro-6H-ba,12-diazaindeno| 1,2-a) fluorene; methyl ether

C-hydroxy-1,2,3,4 4a,5,6,7,8,13,130,1C-dodecahydro-ba, 13-diazaindeno|1,2-c|renanthrene-4-carboxylic acid; methyl-3-ethyl-1,2,Za,4,6,7,120,12c-octahydro-ZH,12H-indolo|2,3-9)cyclopent(Ia)indolizine-2-carboxylate; methyl-1,2,3a,4,6,7,126, 12c-octahydro-ZH, 12H-indolo|2,3-9)cyclopent(Ia)|indolizine-2-carboxylate or Ha 12c-ethyl-1,Za, 4,6,7,120,12c-octahydrocyclopent/(1,2|indolizinoi|8,7-b|indol-3(2H)-one; for example, where r is 1 and Kz is H, hydroxy, (С4-Св) alkyl or hydroxy(C.-C.v.)alkyl; or where the compound is 3,4,4a p,5,6,7,8,13,136 D,1Zso-decahydro-2H-ba,13-diazaindeno|1,2 -c|phenanthrene-1-one, 1,2,3,4,5,6,7,8,13, 13p-decahydro-ba, 13-diazaindenoi|1,2-c|phenanthrene, 1a,2,3 ... ,4ar, 5,6,7,8,13,13Br,1Zro-bodecahydro-ba,13-diazaindeno|1,2-c|renanthren-1-yl ester of acetic acid.

Another embodiment of the invention provides new compounds of formula IU: (2) c) o

Kv (ee)

IN

(Street | M. « x 7

В (В 0Ю Z s 1-3 . v/s ;z2 В. со 45 de

X represents ME 2; av | E»o is H; 7 represents -CH-(CHa)-; (se) I . n is equal to 0;

Ge) 50 Ko, Ka-Kcio, Kv; K and t are as defined above; co Y is equal to from 0 to Z; or their pharmaceutically acceptable salts and esters, provided that the compound is not 1,2,3,4 4a,5,6,11,116,12,13,1Za-dodecahydro-4p,11-diazaindeno|2,1-a Renanthrene; 1,2,3,4 4α,5,6,11,116,12-decahydro-4β,11-diazaindeno|2,1-α|)renanthrene; 9-methoxy-1,2,3,4 4a,5,6,11,116,12-decahydro-4p,11-diazaindeno|2,1-a)renanthrene or

HF) methyl ether t 1-hydroxy-1,2,3,4 4a,5,6,11,116,12,13,13a-dodecahydro-4B,11-diazaindeno|2,1-a|)phenanthrene-2-carbon acid

Another embodiment of the invention provides new compounds of formula IE: b5

IE

Sq

KE. , 2 (vii still p

IE

IN; I am in her place

X represents ME 2;

E»o is H; 2, Ka, Ka-Kcho, Kui5, Kv and t are as defined above; n equals 1, or their pharmaceutically acceptable salts and esters, provided that the compound is not 2,3,4,5,7,8,13,13p-octahydro-2,3-diethyl-1H-azegano|1" ,2"1,2|pyridoyiZ,4-c)indole; 2,3,4,5,7,8,13,13p-octahydro-1H-azepino|1,271,2|pyridoZ,4-in|indol-2-ylmethyl ester of acetic acid; 2,3,4,5,7,8,13,13p-octahydro-1H-azegano|1",2":1,2|garidoi|3,4-indole-2-Cphenylmethoxy)methyl)| or 2,3,4,5,7,8,13,13p-octahydro-1H-azepino|1",27:1,2|pyrido33,4-indole-4-ethyl-2-phenylmethoxy)methylome; for example where the compound is 2,3,4,5,7,8,13,13p-octahydro-1H-azepino|1",2":1,2|pyridoy|3,4-v|indole.

Another variant of the invention provides new compounds, which are c 29 2p-methoxy-1,2,3,4,6,7,12,12a-octahydroindolo!|2,3-a)quinolysine, He) g2oa-netoxy-1, 2,3,4,6,7,12,125 o-octahydroindolo|2,3-a) quinolysine,

Thi-ethyl-2o-methyl-1,2,3,4,6,7,12,12 or-octahydroindolo|2,3-a)quinolisin-1-ol, 1o-isopropyl-1,2,3,4 ,6,7,12,12B5 p-ectahydroindolo|2,3-a)quinolisin-1-ol, with zo (-)-To-isopropyl-1,2,3,4,6,7,12,1265 p -octahydroindolo|2,3-a)quinolisin-1-ol, (u)-Th-isopropyl-1,2,3,4,6,7,12,125 p-octahydroindolo|2,3-a)quinolisin-1- olom, ix, 1p-isopropyl-1,2,3,4,6,7,12,125 p-ectahydroindolo|2,3-a)quinolysine, Ge") (To-isopropyl-1,2,3,4,6 ,7,12,125 p-octahydroindolo|2,3-a)quinolisin-1-yl)umethanol, o (To-y-propyl-1,2,3,4,6,7,12,125 p-octahydroindolo|2,3 -a)quinolisin-1-ylmethanol, 2-(1o00,2,3,4,6,7,12,126p-ectahydroindolo|2,3-a)quinolisin-1-yl)butan-2-ol, (ee) 1-(1,20,3,4,6,7,12,1200-ectahydroindolo|2,3-a)quinolisin-2-yl)upropan-1-ol, 2-(1002,3,4,6, 7,12,126 p-Ectahydroindolo!|2,3-a)quinolisin-1-ylpropan-2-ol, 1-tert-butyl-1,2,3,4,6,7,12,12b p-eccahydroindole|2 ,3-a)quinolisin-1-ol, « 1-cyclohexyl-1,2,3,4,6,7,12,126 D-ectahydroindolo|2,3-a)quinolisin-1-ol, C7Z 70 9-fluoro -1o-isopropyl-1,2,3,4,6,7,12,125 p- octahydroindolo|2,3-a)quinolisin-1-ol, c (To-methyl-1,2,3,4,6,7,12,125 p-octahydroindolo|2,3-a)quinolisin-1-ilumethanol, ; R. (Y-To-methyl-1,2,3,4,6,7,12,125 p-ectahydroindolo|2,3-a)quinolisin-1-ylmethanol, (9)-(To-methyl-1,2 . a) quinolysine-1-ilumethanol, (ee) ZB, 4o-bimethyl-1,2,3,4,6,7,12,125 r-ectahydroindolo|2,3-a)quinolysine, o (1,20,3, 4,6,7,12,120 O-ectahydroindolo|2,3-a)quinolisin-2-yl)upropan-2-ol, (1,20,3,4,6,7,12,126 D-ectahydroindolo|2,3 -a)quinolisin-2-yl)upropan-2-ol, se) (2a-ethyl-1,2,3,4,6,7,12,126 x-octahydroindolo|2,3-a)quinolisin-2-ylmethanol ,

F 20 (2o-ethyl-1,2,3,4,6,7,12,126 p-octahydroindolo|2,3-a)quinolisin-2-ylmethanol, ethyl ether (1-o-ethyl-1,2,3 ,4,6,7,12,126 p-octahydroindolo|2,3-a)quinolisin-1-ylmethoxy)acetic acid, so 1-(2oa-ethyl-1,2,3,4,6,7,12,126 u- octahydroindolo|2,3-a)quinolisin-2-yl)uethanone, 1-(2o-ethyl-1,2,3,4,6,7,12,125 y-octahydroindolo|2,3-a)quinolisin-2- yl)ethanol, 2-(2o-ethyl-1,2,3,4,6,7,12,126 y-octahydroindolo|2,3-a)quinolisin-2-yl)upropan-2-ol, 2-(3Z -ethyl-1,20,Zoa.,4,6,7,12,12α-ectahydroindolo|2,3-a)quinolisin-2-yl)upropan-2-ol, (F) (3-ethyl-2- methyl-1o,2p8,38,4,6,7,12,126 p-staghydroindolo|2,3-a)quinolisin-1-ylmethanol, co 3-ethyl-1,2-dimethyl-1o,2p,3p8,4, 6,7,12,126 p-octahydroindolo|2,3-a)quinolysine, 1,2-dimethyl-1,2,3,4,6,7,12,125 p-octahydroindolo|2,3-a)quinolysine-1 d -ol, in (1-ethyl-2-methyl-ir,2rf,Zr,4,6,7,12,126.-ectahydroindolo|2,3-a)quinolisin-3-ylmethanol, methyl ether 1-D-hydroxymethyl- i-methyl-1,2,3,4,6,7,12,12b p-octahydroindolo!|2,3-a)quinolysine-6 d-carboxylic acid, 5,6,7,7ar . decahydro-IN-13-oxa-ba-azaindeno|1,2-s|phenanthrene, bo 2,3,4,4ar,5,6,7,8,13ra,13s p-decahydro-1H-13-oxa- ba-azaindene|1,2-s|renanthrene,

2,3,4,4ar,5,6,7,8,13,136 p-secahydro-1H-ba,13-diazaindeno|1,2-c|phenanthrene-1Zs p-ol, ()-2,3,4 ,4ar,5,6,7,8,13,136 p-becahydro-1H-ba,13-diazaindeno|1,2-s|phenanthrene-1Zs p-ol, (k)-2,3,4,4ar,5 . 13,13B p-secahydro-1H-ba,13-diazaindeno|1,2-s|phenanthrenyl)-13c p-methanol or 5,6,7,7a, 11,116,12-decahydro-ba,12-diazaindeno|1 ,2-a)fluorene-11a-ol.

The terms used in this description have the following meanings:

The term "halogen", as used herein, as such or as part of another group, refers to chlorine, bromine, fluorine or iodine.

The term "carboxyl" as used herein refers to the group COOH.

The term "oxo" as used herein refers to the group -0.

The term "(C.--Cv)alkyl", as used herein as such or as part of another group, refers to a straight or branched carbon chain having 1-6 carbon atoms. Typical examples of (C-C)alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, 75 isobutyl, t-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n - hexyl and the like.

The term "(Co-Cv)alkenyl", as used herein either alone or as part of another group, refers to a radical with a straight or branched carbon chain having 2-6 carbon atoms and containing a double bond(s) and).

The term "(C3-C7)cycloalkyl", as used herein as such or as part of another group, refers to a saturated cyclic hydrocarbon group containing 3-7 carbon atoms. Typical examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutane, cyclopentane, cyclohexyl, and the like.

The term "(C3-C7)cycloalkyl(C--Cv)alkyl", as used in this description, refers to a (C3-C7)cycloalkyl group, as defined in this description, attached to a fragment of the parent molecule by means of (C.4- C) alkyl group, as defined in this description. Ge

The term "aryl" as used herein, as such or as part of another group, refers to (5) a monocyclic or bicyclic aromatic group containing 6-12 carbon atoms. Typical examples of aryls include, but are not limited to, phenyl, naphthyl, and the like.

The term "aryl(C 1 -C 10 )alkyl" as used herein, either as such or as part of another group, refers to an aryl group, as defined herein, attached to a fragment of the parent molecule via (ee) (S. -Cv)alkyl group, as defined in this description. co

The term "aryloxy", as used herein, as such or as part of another group, refers to an aryl group, as defined herein, attached to a fragment of the parent molecule by (o) an -O- group. at

The term "aryl(C 1 -C 6 ) alkoxy" as used herein, either as such or as part of another group, refers to an aryl group, as defined herein, attached to a fragment of the parent molecule via (ee) (C. 4-Cv)Alkoxy groups, as defined in this description.

The term "aryloxy(C-i-Cv)alkyl, as used in this description, refers to an aryloxy group, as defined in this description, attached to a fragment of the parent molecule by means of a (C.4-Cv)alkyl group," as defined in this description .

The term "aryl(C.sub.--Cv)alkyl(C.sub.1-Cv)alkyl, as used in this description, refers to - aryl(C.sub.--Cv)alkyl, as defined in this description, attached to a fragment of the main molecule by and a (C 4 -C 6 )alkyl group as defined herein. The term "hydroxy" as used herein, either as such or as part of another group, refers to the OH group.

The term "hydroxy(C--Cv)alkyl" as used herein, either as such or as part of another group, (ee) refers to at least one hydroxy group, as defined herein, attached to a moiety of the parent molecule by (C .i-Cv)alkyl group as defined herein. Typical examples of hydroxy(C1-C1)alkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, (se)3-hydroxypropyl, 1-hydroxypropyl, 1-methyl-1-hydroxyethyl, 1-methyl- 1-hydroxypropyl and the like.

Fu 50 The term "halo(Ci-Cv)alkyl", as used herein, refers to one or more halogens, as defined herein, attached to a moiety of the parent molecule via a 42) (C4-Cv)alkyl group, as defined in this description. Typical examples of halo(C 1 -C 1 )alkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoroethyl, 2-chloroethyl, 3-bromopropyl, and the like.

The term "amino", as used in this description, as such or as part of another group, refers to the MH 2 group. o The term "amino(C.--Cv)alkyl", as used in this description, refers to an amino group, as defined in this description, attached to a fragment of the main molecule by means of a (C.4-Cv)alkyl group, as defined in this description. Typical examples of amino(Ci-Cv)alkyl include, but are not limited to, aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 2-aminopropyl, 4-aminobutyl, 1-methyl-1-aminoethyl, and the like. 60 The term "mono- or di(C 1 -C 4 )alkylamino" as used herein, either as such or as part of another group, refers to one or two (C 1 -C 4 )alkyl group(s), as defined in this description, attached to a fragment of the main molecule by means of an amino group, as defined in this description. Typical examples of mono- or di(C 1 -C 2 )alkylamino include, but are not limited to, methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino, M-ethyl-M-diethylamino, and the like. 65 The term "mono- or di(C.-4-Cv)alkylamino(C.sub.4-Cv)alkyl", as used herein, refers to a mono- or di(Ci-Cv)alkylamino group, as defined herein, attached to to the fragment of the main molecule with the help of a (C.i.i.-Cv)alkyl group, as defined in this description. Typical examples of mono- or di(C 1 -C 1 )alkylamino(C 1 -C 2 )alkyl include, but are not limited to, M,M-dimethylaminomethyl,

M,M-diethylaminomethyl, M-methylaminoethyl, M-methylaminopropyl, M-ethyl-M-methylaminomethyl and the like.

The term "(C 1 -C 10 )alkyl" as used herein, either as such or as part of another group, refers to (C 1 -C 4 )alkyl, as defined herein, attached to a fragment of the parent molecule by means of - O- groups. Typical examples of (C--Cb)alkyl include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.

The term "(C 4 -C 10 )alkyl(C 1 -C 10 )alkyl", as used herein, either as such or as part of another 7/0 Group, refers to at least one (C 1 -C 15 )alkyl group as defined in this description, attached to the fragment of the main molecule with the help of a (C.4-Cv)alkyl group, as defined in this description. Typical examples of (C 1 -C 1 )alkyl (C 1 -C 1 )alkyl include, but are not limited to, methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 3,3-dimethoxypropyl, 2,4-dimethoxybutyl, and the like.

The term "hydroxy(C--Cv) alkoxy" as used herein, either as such or as part of another group, refers to a hydroxy group, as defined herein, attached to a fragment of the parent molecule by means of a (C-4-Cv) alkoxy group , as defined in this description.

The term "hydroxy(C.4-Cv)alkyl(C.--Cv)alkyl, as used in this description, refers to a hydroxy(C.-Cv)alkyl group, as defined in this description, attached to a fragment of the parent molecule by means of ( C.4-Cv)alkyl group, as defined in this description.

The term "carbamoyl", as used in this description, as such or as part of another group, refers to the -SOMN" group.

The term "mono- or di(C4-C8)alkylcarbamoyl", as used herein, refers to one or two (C1-C8)alkyl group(s), as defined herein, attached to a fragment of the parent molecule by groups - NMSO- or -МСО-. Typical examples of mono- or di(C 4 -C 4 )alkylcarbamoyl include, but are not limited to, M-methylcarbamoyl, M-ethylcarbamoyl, M-propylcarbamoyl, M,M-dimethylcarbamoyl,

M,M-diethylcarbamoyl and the like. (8)

Compounds of formulas I and IA, IV, IC, IJU and IE, as well as their pharmaceutically acceptable salts and esters, are referred to below as compounds of the invention, unless otherwise indicated.

The scope of the invention includes all possible stereoisomers of the compounds, including geometric isomers, for example, isomers (cis- and trans-isomers), its optical isomers, for example, diastereoisomers and enantiomers. In addition, the invention includes both individual isomers and any mixtures thereof, for example, racemic mixtures. Individual isomers can be obtained using the corresponding isomeric forms of the starting material or they can be separated after obtaining the final compound according to conventional separation methods. To separate optical isomers, for example, enantiomers, from their mixture, conventional methods of separation can be used, for example, fractional crystallization. Gee)

Pharmaceutically acceptable salts, for example acid addition salts with organic and inorganic acids, are well known in the field of pharmaceuticals. Non-limiting examples of such salts include chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates, and ascorbates. Pharmaceutically acceptable esters, when used, can be obtained by known "methods using pharmaceutically acceptable acids, which are common in the field of pharmaceuticals and which retain the pharmacological properties of the free form. Non-limiting examples of such an ester include an ester of aliphatic or aromatic alcohols, for example, methyl, ethyl, propyl, "" isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl esters.

Compounds according to the invention can be obtained similarly or according to methods known in the literature using acceptable starting substances. The starting substances of the formulas II, PI and IM are commercially available or can be obtained using a number of known synthesis routes known in the literature. For example, the starting substances used are arylalkylamines of the formula (II)

Ge») | i U mam so Kn t z

HF) where K. is as defined above and X is MH, 0, CH" or 5.

Ge When X is O, amines of formula (II) can be prepared, for example, according to the method (described in the description of US patent No. 4,710,504|I. When X is CH 5, compounds of formula (I) can be prepared as (described in U. Med. Spec. 10 (1967) 856-859).When X is 5, compounds of formula (II) can be obtained by decarboxylation of the corresponding 3-(thianaphthen-3-yl)-I-alanine.

Other starting substances used are compounds of the formula (HER) b5

PI

A, in (Ш) 70 where Kz is as defined above and K./4 is OH or halogen. In addition, the starting substances used are compounds of the formula (IM)

IM about a

And: in, in. in

E, ah) where Ka-K»7 and 7 are as defined above and y is O or MM. Compounds of formula (IM) can be obtained according to methods (described in Tejapyedgoop 33 (1977) 1803-1808). Similarly, the corresponding anhydrides can be used instead of the lactones (0). When Kz and K5 form a ring, compounds of formula (IM) are obtained by partial reduction of their corresponding anhydrides. with

In general, compounds of formula (I), where X represents MH, O or 5, can be obtained, for example, analogously to Ge) or according to the following reaction scheme 1:

Scheme 1

That's it. - SO -- y x C p y x s

V z 'of (by M z F - | «v)

Х р ше Х M--2, B; x in the village

Х В В и ШЯ в в (У) (Upu

M-1,

In, and FU with s amy she

F in ;" de Ku, Ka-K; and 7 are as defined above.

According to the scheme | amides (M), which are obtained as a result of alkylation of amines (II) with compounds of the formula CO 75 (IP), are converted into enamines (MI) through beta carbolines (M) by the Bischler-Napieralski reaction for the formation of the O ring, under the influence of compounds of the formula (MI) from 1 ,3-dihaloalkanes under basic conditions (as described in bag2. Spit. Mai. (av) PI (1981) 257-267). At the last stage, compounds of formula (I) are obtained by 1) oxidation of enamines (MI) using potassium iodide, iodine and air or 2) interaction of enamines (MII) with formaldehyde in the presence of Hoenig's base at 6020. (o) 20 Another way of obtaining compounds of the formula (I), where X represents MK", O, CH" or 5, illustrated in scheme 2: so Scheme 2

F) name) 60 b5

S Zh di in z sten sya she SHE S Bu sennya

I am ve Be! and. what

This is also where X represents MK", O, CH" or 5, K.-K" and 7 are as defined above.

In Scheme 2, arylalkylamines of formula (II), where X is MM, O, CH 5 or 5, are reacted with compounds of formula (IM) or the corresponding anhydride to give amides (MI), as described in Teiggapedop 33 (1977) 1803 -1808)|. The Bischler-Napieralski cyclization reaction of intermediates (MI) leads to enamines (IX), which are converted into compounds of formula (1).

Compounds of the formula (I), where X represents MH, can be alkylated by alkyl halides in the presence of a suitable base at room temperature (He(egosusiez 27 (1988) 1179-11901 according to the following scheme 3:

Scheme Z

Jehemi o gi vi r: ше и сие - ш ше Ге) where K4-K; and 7 are as defined above. at

The following method of obtaining compounds of formula (I) is illustrated in scheme 4: so

Scheme 4

Vg M

So". o- - ma: shi s " s . t - p VI - 4 y; yes" U u-- oh, but M - (ee) ! v y v nn ("v) ho ss) se) -- so si 5 - so s kt M

Eat me; and

In, in, Kk,

Spo) ЧО) И " o where Ko represents VOS and K., Kb and Ko are as defined above.

In Scheme 4, pyridine is alkylated with tryptophyll bromides (X) to obtain pyridine salts (XI), which are then subjected to partial reduction to obtain the compound of formula (XII). Protection of compounds of formula (XIII) using di-t-butyl bicarbonate under basic conditions gives compounds of formula (XIII). The Polonowski-Poitier reaction of the obtained 60 intermediates and their cyclization using Meon/Nsi gives compounds of formula (1).

The following method of obtaining compounds of formula (I), where X is O, 5 or MH, K 4 and K 43-Ka are as defined above, is shown in the following scheme 5:

Scheme 5 b5

I s i KE x a V - I "a x sne 7 oz I bi a, x. pe 170 z I sh v, y

In scheme 5, the oxidative cyclization of the derivative (CHM) with mercuric acetate according to the method described in

Neuroscience 32 (1991) 489-497), gives enamine (HM). This intermediate product can be oxidized or treated with formaldehyde, as in scheme 1, or reduced with sodium borohydride to obtain compounds of formula (1).

The following method of obtaining compounds of formula (I), where Kb and K7 form a bond, is illustrated in Scheme 6:

Scheme 6

Va yen da m svsoos hi ushu U |)

X x

EK, Kk, V soosnsn,

Uh FUSH) : s o x

In Gya snn o so where X represents MH and Kz represents lower alkyl. "at

Application of the method (described in y). Ogd. Spent 52 (1987) 353-356), the Diels-Alder hetero-reaction

of 3,4-dihydro-p-carboline (HMI) with a diene ester (HMI) obtained by the Wittig reaction as described in

Sap. 9. He sang. 65 (1987) 670-682), gives compounds of formula (CHMIII), which are then reduced to alcohols of formula (1). at

The following method of obtaining compounds of formula (I) is illustrated in scheme 7.

From Scheme 7 so and V

In 7 vumikh U " « in x c) V x on 1 vo ! Va VI Ko - s sah) 2) ts ; "" where X, Ku, Kz, K, and 2 are as defined above. Ki" can be M or OSN" and K/z can be an alkyl or aryl group.

In Scheme 7, compounds of formula (XIX), when Ki" represents H, are obtained as (described in y). Spent boss, speth (oo) Sottype. (1995) 2317-23181, and compounds of formula (XIX), when K./o is OSN with, are obtained as (described in .). about Spet. boss. (C) (1971) 736-743). Compounds of formula (XIX) are subjected to interaction with Grignard reagents to obtain compounds of formula (I). When Ki" in formula (XIX) represents H, other Kz groups in formula (I) are also H. (Ce) A new method of obtaining certain compounds of formula (I) is shown in Scheme 8.

Scheme 8 (22)

ИЧ f) и и со I - so. in h vi o v/ r'4 v/ trgo ome ome oo) min

F) x 9-1

Х х 60 в ВЩЧ/ Вы ОМе В В вы ОН (СХ Fo where X, Ku, Kz and 2 are as defined above. K.44 represents a lower alkyl group.

In Scheme 8, tetrahydropyridine (XX) obtained according to the method described in y). Spent Zos. (3) (1971) 65 736-743), is deprotonated by a strong base to give anion (XXI). This anion is alkylated and then cyclized with an acid to give compounds of formula (XXIII). Reduction of (XXII) HIATN then gives compounds of formula (1).

The separation of racemic compounds of formula (I) can be carried out, for example, by converting compounds of formula (I) into a mixture of salts of their diastereoisomers by reaction with an optically active acid, such as U-tartaric acid, dibenzoyl-O-tartaric acid, etc., and by separation of diastereoisomers by crystallization.

It is obvious to a person skilled in the art that in the aforementioned reactions any starting materials or intermediates can be protected, if necessary, in a manner well known in the field of chemistry. Any protected functional group is subsequently deprotected in the usual manner.

It should be noted that the above-mentioned synthetic routes are intended to illustrate the preparation of compounds according to the invention and such preparation does not mean its limitation, that is, other synthetic methods that are within the general knowledge of the expert are also possible.

The compounds of the invention can be converted, if necessary, into their pharmaceutically acceptable salt or ester form using methods well known in the art.

The present invention will be explained in more detail by the following examples. The examples are intended for illustrative purposes only and do not limit the scope of the invention defined in the claims.

Example 1 1-propyl-4,9-dihydro-ZH-rd-carbonyl 8.00 g (50.00 mmol) of tryptamine was dissolved in 150 ml of ethyl acetate and 4.800 ml (52.0 mmol) of n-butyric acid was slowly added. After standing for 4 hours. at 0 C, the reaction mixture was filtered to obtain 12.30 g (49.5 mmol) of tryptamine butyrate, which was molten. The melt was heated at 2002 and kept at ЗОхв. at this temperature. The water that formed was removed using the device

Dean Stark. After cooling, the melt was mixed with 120 ml of toluene, 23.5 ml (257.7 mmol) of freshly distilled phosphorus oxychloride was added, and the reaction mixture was refluxed for 4 hours.

The solution was evaporated in vacuo and the dark oil was mixed with 2095 acetic acid solution (3x5Oml). The solid was filtered off, the aqueous solution was made alkaline with 2595 ammonium hydroxide while cooling, and the CM was extracted with dichloromethane (3x5Oml). The combined organic phases were dried over sodium sulfate, the drying agent (5) was filtered off and the filtrate was evaporated to give the title compound, which was purified by column chromatography (silica gel, dichloromethane/methanol, 95:5).

NMR: 1.00 (t, 3H), 1.75 (m, 2H), 2.66 (t, 2H), 2.87 (t, 2H), 3.90 (t, 2H), 7.00 -7.62 (m, 4H), 8.94 (width, 1H).

MS: 212 (2895), 211 (1296), 197 (25906), 184 (10095), 169 (13905). co

Example 2 "so 1-isobutyl-4,9-dihydro-ZN-B-carboline

The procedure of example 1 was repeated, using isovaleric acid instead of n-butyric acid. (at)

NMR: 0.98 (d, EN), 2.16 (m, 1H), 2.54 (d, 2H), 2.86 (t, 2H), 3.89 (t, 2H), 7.00 -7.62 (m, 4H), 8.60 (width, 1H). at

MS: 226 (1695), 211 (1895), 184 (100965), 169 (1396).

Example C (ge) 1-butyl-4,9-dihydro-ZN-p-carbonyl

The procedure of example 1 was repeated, using n-valeric acid instead of n-butyric acid.

NMR: 1.00 (t, ZN), 7.00-7.62 (m, 4H), 8.64 (b, 1H). "

MS: 226 (1895), 211 (1895), 184 (100965), 169 (1496).

Example 4 o, c 1-(2-methylbutyl)-4,9-dihydro-ZH-d-carbonyl "z The procedure of example 1 was repeated, using 3-methylvaleric acid instead of n-butyric acid. " NMR: 0.84 ( t, ZN), 0.87 (d, ZN), 7.05-7.60 (m, 4H), 12.2 (width, 1H).

MS: 240 (996), 225 (10905), 211 (10965), 185 (1390), 184 (10095), 183 (1495), 155 (24905).

Example 5 with 1-cyclohexylmethyl-4,9-dihydro-ZH-dD-carboline av! The procedure of example 1 was repeated, using 3-cyclohexylacetic acid instead of n-butyric acid. ish NMR: 1.0-1.9 (m, 11H), 2.56 (d, 2H), 2.85 (m, 2H), 3.88 (m, 2H), 7.14-7.63 (m, 4H), 8.55 (width, 1H), b 20 MS: 266 (896), 185 (1595), 184 (10090), 183 (1290), 155 (1790).

Example 6 with 1p-isopropyl-1,2,3,4,6,7,12,126p-octahydroindolo|2,3-a)quinolysine 2.56g (11.5mmol) 4,9-dihydro-1-isobutyl-3 -H-pyrido|Z3,4-B|indole (example 2), 2 ml of M-ethyldiisopropylamine and 1.35 ml (13.mmol) of 1-bromo-Z3-chloropropane were dissolved in 5 ml of acetonitrile. The mixture was boiled with reflux at 99°C in an argon atmosphere for 8 hours. After evaporation of the solvent, 20 ml of methanol was added and

HF) 1.3 g (34.5 mmol) of sodium borohydride. The reaction mixture was stirred for an hour. at room temperature, and then 20 ml of water was added. The reaction mixture was extracted with dichloromethane (3x5Oml). The combined organic phases were dried over sodium sulfate, the drying agent was filtered off, and the filtrate was evaporated to give the title compound, which was purified by column chromatography (silica gel, dichloromethane/methanol, 95:5).

NMR: 1.02 (b, 6H), 7.11 (t, 1H), 7.18 (t, 1H), 7.35 (d, 1H), 7.48 (d, 1H), 7 .85 (width, 1H).

MS: 267 (100965), 253 (2095), 197 (35905), 170 (3095), 169 (30905).

Example 7 2-(10,2,3,4,6,7,12,12Br-octahydroindolo!|2,3-aquinolisin-1-yl)butan-2-ol 65 To a solution of 190 mg (0.7 mmol) of 1- (1,2,3,4,6,7,12,12p-octahydroindolo|2,3-a)quinolisin-1-yl)uethanone

(Geigapedop Gei. 30 (1989) 719-722| 0.11 ml (0.8 mmol) of ethylmagnesium bromide (1.0 M) was added to 1 ml of dichloromethane at 602. The reaction mixture was stirred for 30 minutes at this temperature and for 2 hours at room temperature.

Then water (10 ml) was added and the reaction mixture was extracted with dichloromethane (3x50 ml). The combined organic phases were dried over sodium sulfate, the drying agent was filtered off, and the filtrate was evaporated to give the title compound, which was purified by column chromatography (silica gel, dichloromethane/methanol, 95:5).

NMR: 0.97 (t, ЗН), 1.30 (z, ЗН), 4.69 (width с, 1Н), 7.00-7.50 (m, 4Н), 8.36 (width with, 1H).

MS: 297 (10096), 281 (3095), 269 (35905), 225 (28905), 197 (4590), 170 (3595), 169 (34905).

Example 8 2-10, 2,3,4,6,7,12,12π-octahydroindolo|2,3-a)quinolisin-1-yl)upropan-2-ol

The procedure of example 7 was repeated, using methylmagnesium bromide (excess) instead of ethylmagnesium bromide.

NMR: 1.37 (3, ZN), 1.42 (3, ZN), 4.73 (width s, 1H), 7.00-7.50 (m, 4H), 8.18 (width with, 1H).

MS: 283 (100965), 267 (42905), 225 (33905), 197 (60905), 170 (5095), 169 (5095).

Example 9

To-isopropyl-1,2,3,4,6,7,12,126 p-octahydroindolo|2,3-aquinolisin-1-ol (compound A) 5.13g (23,00mmol) 4,9-dihydro-1- isobutyl-3-N-pyrido3,4-b)indole, 4 ml of M-ethyldisopropylamine and 2.7 ml (27.6 mmol) of 1-bromo-33-chloropropane were dissolved in 1000 ml of acetonitrile. The mixture was refluxed in an argon atmosphere for 8 hours. The dark solution was concentrated to oil, which was treated with 2090 sodium hydroxide. After 10 minutes stirring, the solution was extracted with dichloromethane (C x 5 Oml). The combined organic phases were dried over sodium sulfate, the drying agent was filtered off, and the filtrate was evaporated to obtain the corresponding enamine, which was dissolved in 1000 ml of acetonitrile. 7.0g (27.bmol) of iodine and 4.6g (27.bmol) of potassium iodide were added. The reaction mixture was stirred in the dark in air for s

According to After evaporation of the solvent, 50ml of methanol and, upon cooling, 2.bg (b9mmol) of sodium borohydride were added. The reaction mixture was stirred for an hour. at room temperature and then added 20 ml of water. The reaction mixture was extracted with dichloromethane (3x5Oml). The combined organic phases were dried over sodium sulfate, the drying agent was filtered off, and the filtrate was evaporated to give the title compound, which was purified by column chromatography (silica gel, dichloromethane/methanol, 95:5). co

NMR: 0.47 (d, ЗН), 0.90 (d, ЗН), 3.48 (width с, 1Н), 7.00-7.50 (m, 4Н), 8.92 (width with, 1H). "co

MS: 284 (1495), 239 (1390), 171 (10095), 170 (1695), 169 (33905).

Example 10 b» 1To-ethyl-2o-methyl-1,2,3,4,6,7,12,12B5 rD-octahydroindolo|2,3-a)quinolisin-1-ol (Compound B) o

The procedure of example 9 was repeated, using 4,9-dihydro-1-propyl-ZN-pyrido|Z3,4-Z|indole instead

From 4,9-dihydro-1-isobutyl-3-H-pyrido|3,4-b|indole and 1,3-dibromobutane instead of 1-bromo-3-chloropropane. co

NMR: 0.69 (t, ЗН), 1.00 (d, ЗН), 3.20 (width с, 1Н), 7.00-7.60 (m, 4Н), 9.04 (width with, 1H).

MS: 284 (596), 267 (15906), 225 (10095), 210 (1595), 195 (1595), 182 (72905), 171 (4195), 170 (2295), 169 (32905).

Example 11 « 9-fluoro-1o-isopropyl-1,2,3,4,6,7,12,125 p-octahydroindolo|2,3-a)quinolisin-1-ol 50 The procedure of example 9 was repeated, using b-fluoro- 1-isobutyl-4,9-dihydro-ZN-pyrido|3,4-v|indole Z c (obtained from 5-fluorotryptamine as described in example 2), instead of 4,9-dihydro-1-isobutyl-ZN- pyrido|3,4-in|indole. z» NMR: 0.45 (d, ЗН), 0.89 (d, ЗН), 3.32 (3, 1Н), 6.8-7.25 (m, ЗН), 8.94 (width with, 1H).

MS: 302 (2695), 203 (1395), 189 (100965), 161 (2696).

Example 12 1-tert-butyl-1,2,3,4,6,7,12,12b p-octahydroindolo|2,3-a)quinolisin-1-ol (mixture of isomers) (Compound C) co The procedure of the example was repeated 9, using 1-(2-methylbutyl)-4,9-dihydro-3H-pyridoyl3,4-b|indole

And av | instead of 4,9-dihydro-1-isobutyl-ZN-pyridoyZ,4-c)|indole.

NMR: 0.48 (d, ZN, major isomer), 0.69 (t, ZN, minor isomer), 0.82 (t, ZN, major isomer), 0.92 i-o (d, ZN, minor isomer), 3.30 (z, 1H), 7.0-7.5 (m, 4H), 8.88 (lat.s, IN, secondary isomer), 8.93 (He) 50 (lat.s , 1H, the main isomer).

MS: 298 (2396)-172 (2490), 171 (10095), 170 (1595), 169 (23965), 14-3 (2996). so Example 13 1-cyclohexyl-1,2,3,4,6,7,12,12B6 D-octahhydroindolo|2,3-a)quinolisin-1-ol

The procedure of example 9 was repeated, using 1-cyclohexylmethyl-4,9-dihydro-ZN-pyridoyZ,4-v|indole 59 instead of 4,9-dihydro-1-isobutyl-ZN-pyridoyZ,4-v)|indole.

HF) NMR: 3.35 (width s, 1H), 7.02-7.55 (m, 4H), 8.98 (width s, 1H). 7 MS: 324 (2195), 172 (1290), 171 (10095), 170 (1095), 169 (1595), 143 (22905).

Example 14 (To-isopropyl-1,2,3,4,6,7,12,125 p-octahydroindolo|2,3-a)quinolisin-1-ylmethanol 60 The method of example 9 was repeated, using iodine and potassium iodide instead of oxidation , the obtained enamine was treated with 40956 aqueous formaldehyde, the reaction mixture was refluxed for and the solvent was evaporated. The precipitate was diluted with ethyl acetate and washed with saturated salt solution. The organic phase was dried over sodium sulfate, the desiccant was filtered off, and the filtrate was evaporated to give the title compound, which was purified by column chromatography (silica gel, dichloromethane/methanol, 98:2).

NMR: 0.58 (wt.s, ЗН), 0.82 (d, WT), 3.07 (wt.s, 1H), 3.62 (d, 1H), 4.13 (d, 71H) , 7.00-7.50 (m, 4H), 9.41 (width, 1H).

MS: 298 (100965), 297 (5595), 281 (6095), 170 (7595), 169 (52905).

Example 15 (Th-y-propyl-1,2,3,4,6,7,12,125 p-octahydroindolo|2,3-a)quinolisin-1-yl)umethanol

The procedure of example 14 was repeated, using 4,9-dihydro-1-butyl-ZN-pyridoYZ,4-N|indole instead of 4,9-dihydro-1-isobutyl-ZN-pyridoYZ,4-N|indole.

NMR: 0.81 (t, ZH), 3.34 (b, 1H), 3.65 (d, 1H), 3.82 (d, 1H), 7.00-7.50 (m, 4H), 10.07 (width, 1H). 70 MS: 298 (100965), 297 (6595), 281 (67905), 170 (7595), 169 (52905).

Example 16 (T-methyl-1,2,3,4,6,7,12,125 p-octahydroindolo|2,3-yl)quinolisin-1-yl)umethanol

The procedure of example 14 was repeated, using 1-ethyl-4,9-dihydro-ZN-pyrido|Z,4-Z|indole instead of 4,9-dihydro-1-isobutyl-ZN-pyridoZ,4-indole. 15 NMR: 0.91 (z, ЗН), 3.37 (b, 1H), 3.70 (d, 1H), 3.76 (d, 1H), 7.0-7.6 (m , 4H), 9.78 (width, 1H).

MS: 270 (9795), 269 (10095), 253 (53905), 197 (48905), 170 (6895), 169 (6295).

Example 17 (To-ethyl-1,4,6,7,12,12pp-hexahydroindolo|2,3-a)quinolisin-1-yl)umethanol

A mixture of 0.34 g (2.0 mmol) of 3,4-dihydro-d-carboline and 0.39 g (2.5 mmol) of ethyl 2-ethylpenta-2,4-dienoate in 5 ml of 20 chlorobenzene was refluxed for 16 hours. The solvent was evaporated and the precipitate was subjected to column chromatography (silica gel, dichloromethane/methanol, 99:1) to obtain an intermediate ester product. This product was reduced by the usual method with lithium aluminum hydride in dry tetrahydrofuran to obtain the title compound.

NMR: 0.82 (t, 3H), 3.69 (d, 1H), 3.70 (b, 1H), 3.90 (d, 1H), 5.42 (ddd, 1H), 5 .97 (ddd, 1H), 7.0-7.5. YDC C 25 (m, 4H), 10.02 (width s, 1H). (5)

MS: 282 (3195), 171 (1495), 170 (100965), 169 (5296).

Example 18 28B-netoxy-1,2,3,4,6,7,12,12α-octahydroindolo|2,3-a)quinolysine and c 30 2o-cetoxy-1,2,3,4,6,7 ,12,12α-octahydroindolo|2,3-α)quinolysine (Compound 0) with 1.16 g (14.7 mmol) of pyridine and 3.0 g (13.4 mmol) of tryptophyll bromide was dissolved in 15 ml of dry diethyl ether.

The reaction mixture was heated with stirring at 602C until the evaporation of the solvent was complete. Then the mixture (22) was heated to 1002C for 2 hours. with obtaining the corresponding pyridine bromide salt. It was dissolved in 100 ml of methanol and 1.52 g (40.1 mmol) of sodium borohydride was added in portions while cooling. The reaction mixture was stirred for 3 hours at room temperature for 4 hours, followed by the addition of 20 ml of water. The reaction mixture was extracted with dichloromethane (300 mL). The combined organic phases were dried over sodium sulfate, the drying agent was filtered off, and the filtrate was evaporated. The precipitate was dissolved in 100 ml of dry dichloromethane and 2.91 g (13.3 mmol) of di-t-butyl bicarbonate and 0.149 g (1.2 mmol) of 4-(dimethylamino)pyridine were added. "

The reaction mixture was stirred for 2 hours. at room temperature in an argon atmosphere. Solvent Z7Z was evaporated and the precipitate was purified by column chromatography (silica gel, dichloromethane/methanol, 98:2). The resulting viscous oil was dissolved in 40 ml of dichloromethane and 2.54 g (13.3 mmol) of tSRBA was added. The solution was stirred for an hour at 0 9С, then the solvent was evaporated and the crude product was purified by column chromatography (silica gel, dichloromethane/methanol, 98:2) to obtain Bos Mr oxide.

To the stirred solution, 0.59 g (1.7 mmol) of Bos M oxide in 15 ml of dichloromethane at 09C was slowly added with 3.0 ml of trifluoroacetic anhydride. The cooling bath was removed and stirring was continued for 2 hours. at kt, then the solvent was evaporated. Methanol saturated with gaseous hydrogen chloride (α) (20 ml) was added, and the mixture was refluxed for 2 hours. Treatment with alkali and purification by column chromatography (silica gel, dichloromethane/methanol, 98:2) afforded two simple esters. 2p8-cetoxy-1,2,3,4,6,7,12,12B o-octahydroindolo|2,3-a)quinolysine: (22) NMR: 1.54 (ddd, 1H), 3.24 (dd , 1H), 3.38 (dddd, 1H), 3.43 (z, ЗН), 7.00-7.50 (m, 4H), 7.77 (width s, 1H). "with MS: 256 (100965), 255 (8695), 255 (5995), 197 (35905), 169 (30905). g2oa-netoxy-1,2,3,4,6,7,12,125 o-octahydroindolo|2,3-a)quinolysine:

NMR: 3.41 (z, ZN), 3.67 (b, 1H), 3.68 (b, 1H), 7.00-7.50 (m, 4H), 7.72 ( width s, 1H).

MS: 256 (10095), 255 (75905), 255 (70905), 223 (4590), 197 (40905), 170 (4595), 169 (65905).

Example 19 (F; 1-(1,20,3,4,6,7,12,126 59-ectahydroindolo|2,3-a)quinolisin-2-yl)upropan-1-ol to a solution of 0.086 bg (0, Zmmol) 1,2,3,4,6,7,12,12p0-octahydroindolo|2,3-a)Equinolisine-2-carbaldehyde |U. SpNet.

Zos. Spent Sottype 22 (1995) 2317-2318) 0.22 ml (1.7 mmol) of 1M ethylmagnesium bromide was added to 2 ml of dichloromethane at -606C. The reaction mixture was stirred for 4 hours. in an argon atmosphere. Treatment with aqueous sodium hydroxide, followed by extraction with dichloromethane and purification by column chromatography (silica gel, dichloromethane/methanol, 98:2) afforded the title compound.

NMR: 1.02 (t, ЗН), 1.93 (bt, 1H), 2.30 (bt, 1H), 6.80-7.40 (m, 4H).

MS: 284 (9595), 283 (100965), 225 (8095), 169 (3696). 65 Example 20 (1,20,3,4,6,7,12,1200-ectahydroindolo|2,3-a)quinolisin-2-yl)upropan-2-ol

To a solution of 88 mg (0.3 mmol) of methyl ether 1,20,3,4,6,7,12,1265 d-octahydroindolo|2,3-a)quinolysine-2-carboxylic acid in 3 ml of dry tetrahydrofuran, 1 ml was added dropwise ( 3,00 mmol) solutions of methylmagnesium chloride (ZM in tetrahydrofuran). Then the resulting solution was refluxed for 10 minutes. Then the mixture was processed as in example 7 to obtain crude alcohol, which was purified by column chromatography (silica gel, dichloromethane/methanol, 95:5) to obtain the title compound.

NMR: 1.20 (z, ZN), 1.25 (z, ZN), 3.28 (l, 1H), 7.0-7.5 (m, 4H),

MS: 284 (8695), 283 (65905), 225 (10096).

Example 21 (1,20,3,4,6,7,12,126 p-ectahydroindolo|2,3-a)quinolisin-2-yl)upropan-2-ol

As in example 20, 1 mg (0.23 mmol) of methyl ester of 1,20,3,4,6,7,12,125 p-octahydroindolo|2,3-a)quinolysine-2-carboxylic acid in 3 ml of dry tetrahydrofuran and

0.7 ml (2.1 mmol) of methylmagnesium chloride solutions (ZM in tetrahydrofuran) were refluxed for 10 minutes. Workup as above afforded, after column chromatography (silica gel, dichloromethane/methanol, 90:10), the title compound.

NMR: 1.17 (z, ZN), 1.18 (z, ZN), 4.57 (bt.s, 1H), 7.0-7.5 (m, 4H), 8.65 (bt. s, 1H),

MS: 284 (5895), 283 (5390), 225 (10096).

Example 22 (2α-ethyl-1,2,3,4,6,7,12,126 y-octahydroindolo|2,3-a)quinolisin-2-yl)umethanol

To a stirred solution of 0.36 g (33 mmol) of diisopropylamine in 4 mL of dry tetrahydrofuran at -5020 was added 2.00 mL (3. mmol) of n-butyllithium (1.8 M in hexanes). The mixtures were allowed to heat up to -302C (15 min.), then cooled to -702C. At this temperature, 0.64 g (3 ppm) of hexamethylphosphoramide was added.

Stirring was continued during ZOkhv. at this temperature, then 0.42 g (1.48 mmol) of methyl c 29 1-(2-(3-indolyl)ethyl/-1,2,5,6-tetrahydropyridine-4-carboxylate in 7 ml of tetrahydrofuran was added. After stirring He ) within 20 minutes. at -70 C, the mixture was allowed to heat up to -409 C (15 min.). At this temperature, 0.3 g (3.0 mmol) of ethyl iodide was added and stirring was continued for an hour. Then the cooling bath was removed after an additional 15 minutes. the mixture was quenched with 595 ammonia. The aqueous layer was extracted with dichloromethane (3 x 2 Oml) and the combined organic layers were washed with water at 20°C. Drying over sodium sulfate, filtration and evaporation of the solvent gave the crude enamine, which was dissolved in 5 Oml of methanol saturated with hydrogen chloride, and (Ce) the resulting solution was stirred for 16 hours at room temperature. The solvent was evaporated and the FU precipitate was treated with aqueous sodium bicarbonate. After the usual extraction (dichloromethane), the solvent was evaporated to obtain the crude product, which was subjected to column chromatography (silica gel, dichloromethane/methanol, (a) with 98:2) to obtain the intermediate product of the complex ether, methyl ether of 2α-ethyl-1,2, 3,4,6,7,12,12α-octahydroindolo|2,3-a)quinolysine-2-carboxylic acid. This compound was then treated with lithium aluminum hydride in dry tetrahydrofuran in the usual manner to give, after column chromatography, (silica gel, dichloromethane/methanol, 95:5) the title alcohol.

NMR: 0.90 (t, 3H), 3.29 (d, 1H), 3.43 (d, 1H), 3.52 (width, d, 1H), 7.0-7.5 (m, 48), MS: 284 (10095), 283 « 20 (9890), 253 (3390), 197 (3790), 170 (33905), 169 (4095), 156 (34905). -in

Example 23 c (2o-ethyl-1,2,3,4,6,7,12,125p-octahydroindolo[2,3-a]quinolisin-2-yl)umethanol:c» Solution of 51 mg (0.1 mmol) of the intermediate product of the ester obtained in example 22 (methyl ether of 2o-ethyl-1,2,3,4,6,7,12,126 o-octahydroindolo|2,3-a-quinolysine-2-carboxylic acid) in 4 ml of trifluoroacetic acid

The acids were refluxed in an argon atmosphere for 16 h. The acid was evaporated and the precipitate was treated with aqueous sodium bicarbonate. After conventional extraction (dichloromethane), a crude mixture (20:80) of two diastereomers, methyl ether o 2o-ethyl-1 ,2,3,4,6,7,12,125 d-octahydroindolo|2,3-ai)(quinolisine-2-carboxylic acid and methyl ether (Ce) 2a-ethyl-1,2,3,4,6,7 ,12,125 d-Octahydroindole|2,3-aHyquinolisine-2-carboxylic acid The latter isomer was separated by column chromatography (silica gel, dichloromethane/methanol, 99:1) and then reduced in the usual way

Lithium aluminum hydride in dry tetrahydrofuran. Purification, as indicated above, then gave the indicated in the title

IR f) alcohol.

NMR: 0.87 (t, 3H), 3.51 (d, 1H), 3.78 (d, 1H), 7.0-7.5 (m, 4H).

MS: 284 (9595), 283 (10095), 253 (30905), 197 (30905), 170 (17905), 169 (2395), 156 (19905).

Example 24 1-(2o-ethyl-1,2,3,4,6,7,12,1200-ectahydroindolo|2,3-a)quinolisin-2-yl)ethanone o 2-(2o-ethyl-1, 2,3,4,6,7,12,126 a-ectahydroindolo|2,3-a)quinolisin-2-yl)upropan-2-ol ime) As in example 20, 230 mg (0.74 mmol) of ester intermediates, obtained in example 22 (methyl ether of 2o-ethyl-1,2,3,4,6,7,12,125 o-octahydroindolo|2,3-a-quinolizine-2-carboxylic acid) in dry 60 tetrahydrofuran (Uml) and 3.7 ml (11.1 mmol) of methylmagnesium chloride (ZM in tetrahydrofuran) was refluxed overnight. Conventional workup gave, after column chromatography (silica gel, dichloromethane/methanol, 98:2-95:5), a 5:1 mixture of the two compounds. 1-(2o-ethyl-1,2,3,4,6,7,12,125 y-octahydroindolo|2,3-a)quinolisin-2-yl)ethanone:

NMR: 0.82 (t, ZN), 2.14 (3, ZN), 3.44 (width, 1H), 7.05-7.50 (m, 4H), 8.05 (width with, 1H). b5 MS: 296 (8395), 295 (62905), 253 (10095), 184 (9596).

2-(2α-ethyl-1,2,3,4,6,7,12,12α-octahydroindolo|2,3-α)quinolisin-2-yl)propan-2-ol:

NMR: 1.05 (t, ЗН), 1.24 (3, 6Н), 3.42 (width, 1Н), 7.05-7.50 (m, 4Н), 7.88 (width with, 1H).

MS: 312 (4895), 311 (3790), 253 (10096).

Example 25 1-(2α-ethyl-1,2,3,4,6,7,12,12α-octahydroindole|2,3-α)quinolisin-2-yl)ethanol

The ketone obtained in the above reaction was reduced with sodium borohydride in methanol in the usual manner to obtain the title alcohol as an inseparable mixture of diastereomers.

NMR: 0.95 (t, ЗН, secondary), 1.18 (t, ЗН, main), 3.61 (sq., Ш, secondary), 3.67 (sq., 1Н, main). 70 MS: 298 (100965), 297 (64965), 253 (87906).

Example 26 2,3,4,5,7,8,13,13p-octahydro-1H-azepino|1",271,2|pyridoZ,4-vindole (Compound E)

0.14 g (1.2 mmol) of ε-caprolactam was added to a solution of 0.20 g (1.2 mmol) of tryptamine in 5.0 ml of xylene. The mixture was refluxed for 7 hours. After evaporation of the solvent, the precipitate was dissolved in 5.0 ml of 75 toluene, 0.5 ml of freshly distilled phosphorus oxychloride was added, and the reaction mixture was refluxed for 10 minutes. The solution was evaporated in a vacuum and the precipitate was mixed with a 2095 solution of acetic acid (3x1Oml). The solid was filtered off, and the aqueous solution was made alkaline (pH11) with 2595 ammonium hydroxide under cooling and extracted with dichloromethane (3x20ml). 6 ml of 4M sodium hydroxide was added to the combined organic layers, and this mixture was refluxed for an hour. The organic phase was dried over sodium sulfate for 20 minutes, the drying agent was filtered off, and the filtrate was concentrated to obtain an oil that was dissolved in 3 ml of methanol. 0.2 g (5 mmol) of sodium borohydride was added to the cold solution. The mixture was stirred at room temperature for an hour. Water was added slowly and the reaction mixture was extracted with dichloromethane (3x20ml). The combined organic phases were dried over sodium sulfate, the drying agent was filtered off, and the solvent was evaporated to give the title compound, which was purified by Ge! 25 by column chromatography (silica gel, dichloromethane/methanol, 95:5). (5)

NMR: 4.03 (bd, 1H), 7.11-7.46 (m, 4H), 8.05 (bd, 1H).

MS: 240 (5295), 239 (100965), 198 (10965), 170 (2496).

Example 27 1To-ethyl-12-methyl-1,2,3,4,6,7,125 p-octahydroindolo|2,3-a)quinolisin-1-ol (ge) 30 To a solution of 0.05 g (0.mmol) 1o-ethyl-19-hydroxy-1,2,3,4,6,7,12,1265 p-octahydroindolo|2,3-a)quinolysine and 0.05g (0.9mmol) KOH in 1.00ml 0.02 ml (0.3 mmol) of iodomethane was added to acetone. The reaction mixture was stirred at RT for an hour. Water was added slowly and the reaction mixture was extracted with dichloromethane (3 x 200 ml). (22)

The combined organic phases were dried over sodium sulfate, the drying agent was filtered off, and the filtrate was evaporated to give the title compound, which was purified by column chromatography (silica gel,

With dichloromethane/methanol, 95:5). co

NMR: 0.71 (t, ZH), 1.01 (m, 2H), 3.59 (b, 1H), 3.72 (z, ZH), 7.00-7.50 (m, 4H).

MS: 284 (2195), 283 (10095), 185 (60905), 170 (10965).

Example 28 "1o-ethyl-12-ethyl-1,2,3,4,6,7,125 p-ectahydroindolo|2,3-a)quinolisin-1-ol 70 The procedure of example 27 was repeated, using iodethane instead of iodomethane. 8 s NMR: 0.71 (t, 3H), 1.00 (m, 2H), 1.07 (t, 3H), 3.60 (z, 1H), 4.20 (m, 1H), 4 .64 (m, 1H), 7.00-7.50 (m, 4H). from» MS: 298 (2995), 297 (1995), 199 (100965), 171 (33965).

Example 29 1o;--methyl-1,3,4,5,6,11p-hexahydro-2H-11-oxa-4a-azabenzo|(a|fluoren-1-ol

0.34 g (3.00 mmol) of o-methyl-5-valerolactone was added to a solution of 0.48 g (3 mmol) of 2-(3-benzo|p|furanylethylamine in 5 mL of xylene. The mixture was refluxed for 7 5 hours. After (c) evaporation of the solvent, the precipitate was dissolved in b.Oml of toluene, 0.72 ml of freshly distilled phosphorus oxychloride was added, and the reaction mixture was refluxed for 11 hours. The solution was evaporated under vacuum and the resulting oil was mixed with a 2095 solution of acetic acid (3x2Oml). The solid substance (2) was filtered, the aqueous solution was made alkaline (pH 11) with 2595 ammonium hydroxide under co-cooling and extracted with dichloromethane (3x20ml). 12.5ml of 4M sodium hydroxide was added to the combined organic phases and this mixture was boiled refluxed for 1 h. The organic phase was dried over sodium sulfate, the drying agent was filtered off, and the filtrate was concentrated to obtain the corresponding enamine 5B, which was oxidized as described in Example 9.

NMR: 1.18 (z, ZN), 3.25 (lat, 1H), 7.10-7.50 (m, 4H). (F. MS: 257 (25905), 242 (10905), 172 (10096). ka Example 30 (To-methyl-1,3,4,5,6,116 p-hexahydro-2H-11-oxa-4a-azabenzo |(α|fluoren-1-yl)umethanol The procedure of Example 29 was repeated, except that 4090 aqueous formaldehyde was slowly added to the enamine formed.The reaction mixture was refluxed for 3.5 h and the solvent was evaporated The precipitate was diluted with ethyl acetate and washed with brine. The organic phase was dried over sodium sulfate, the drying agent was filtered off, and the filtrate was evaporated to give the title compound, which was purified by column chromatography (silica gel, dichloromethane/methanol, 98:2). 65 NMR: 0 ...

MS: 271 (6995), 270 (10095), 198 (4595), 171 (52905), 170 (60905).

Example 31 1o-isopropyl-1,3,4,5,6,11p-hexahydro-2H-11-oxa-4a-azabenzo(a| fluoren-1-ol

The procedure of example 9 was repeated, using 2-(3-benzo|(p|furanyl)ethylamine instead of tryptamine.

NMR: 1.00 (m, EN), 7.25 (m, 2H), 7.44 (m, 2H).

MS: 285 (2395), 242 (10905), 198 (1096), 186 (2390), 172 (100905).

Example 32 1o;ethyl-1,3,4,5,6,11pp-hexahydro-2H-11-oxa-4a-azabenzo|(a|fluoren-1-ol

The procedure of example 29 was repeated, using α-ethyl-5-valerolactone 70 instead of 9-methyl-5-valerolactone.

NMR: 0.73 (t, ЗН), 3.22 (b, 1H), 7.00-7.30 (m, 2H), 7.40-7.55 (m, 2H).

MS: 271 (1595), 186 (1890), 173 (11905), 172 (10095), 170 (2895).

Example 33 (To-ethyl-1,3,4,5,6,116 p-hexahydro-2H-11-oxa-4a-azabenzo(a|fluoren-1-yl)methanol

The method of example 3 was repeated, using os-ethyl-5-valerolactone instead of d-methyl-5-valerolactone.

NMR: 0.62 (t, ЗН), 3.48 (b, 1H), 3.52 (d, 1H), 4.06 (d, 1H), 7.00-7.30 (m, 2H), 7.40-7.55 (m, 2H).

MS: 285 (5695), 284 (10095), 268 (1995), 198 (36905), 172 (20905), 171 (4495), 170 (54905).

Example 34 5,6,7,7a,11,116,12-decahydro-ba,12-diazaindeno[/1,2-a)fluoren-11a-ol

The procedure of example 29 was repeated, using tryptamine and hexahydroisobenzofuran-1-one instead of /2-(3-benzo|b|furanyl)ethylamine and d-methyl-5-valerolactone.

NMR: 4.45 (b, 1H), 7.00-7.60 (m, 4H), 9.11 (b, 1H).

MS: 296 (896), 143 (10095), 130 (81905). high school

Example 35 Ge) 1,2,3,44a, 5,6,7,8,13-decahydro-ba,13-diazaindeno|1,2-c|renanthrene

A solution of 1.6 g of mercuric acetate and 1.88 g of disodium ethylenediaminetetraacetic acid dihydrate in 400 ml of water was added to a solution of 0.356 g (1.2 mmol) of M-(2-(33-indolyl)ethyl)|decahydroisoquinoline in 20 ml of ethanol, and the resulting mixture was boiled with a reflux condenser during the Agreement. The cooled mixture was made basic with 09 diluted ammonium hydroxide (pH11) and then extracted with dichloromethane (3x30ml). The combined organic layers were dried over sodium sulfate, filtered, and the solvent was evaporated to obtain the crude enamine (mixture of regioisomers), which was directly used in the next step (see example 36). Pure enamine F could be obtained by column chromatography (silica gel, dichloromethane/methanol/triethylamine, 98:1:1). (av)

Example 36 2,3,4,4ar,5,6,7,8,13,136 p-secahydro-1H-ba,13-diazaindeno|1,2-c|phenanthrene-1Zc p-ol (Compound E) 09

As in example 9, 0.42 g (1.51 mmol) of the crude enamine of example 35 was treated with 0.21 g of potassium iodide and 0.32 g of iodine in 30 ml of acetonitrile. After recovery of 0.29 g of sodium borohydride in 30 ml of methanol, the crude product was purified by column chromatography (silicon dioxide, dichloromethane/methanol, 99:11) to obtain pure alcohol. with s NMR: 3.18 (width s, 1H), 7.0-7.55 (m, 4H), 9.18 (width s, 1H).

MS: 296 (2595), 295 (1095), 185 (1595), 171 (10096). :z» Example 37 (2,3,4,4ar,5,6,7,8,13,1 Zpp-decahydro-1H-ba, 13-diazaindeno|1,2-c|phenanthrenyl)-13c p-methanol

A solution of 15 mg (1.5 mmol) of the above-mentioned pure enamine (from example 35), 2 ml of 3695 aqueous formaldehyde and 0.2 ml of M-ethyldiisopropylamine in 1 ml of acetonitrile was refluxed for 10 minutes. After treatment, the crude product was purified by column chromatography (silica gel, dichloromethane/methanol, 98:2) to obtain pure alcohol. o NMR: 3.29 (b, 1H), 3.98 (d, 1H), 4.17 (d, 1H), 7.0-7.5 (m, 4H), 10.05 (b .c, 1H).

MS: 310 (8895), 309 (10095), 293 (34905), 197 (67905), 184 (35905), 170 (9095), 169 (77905). (o) Example 38 with ZB,4o-bimethyl-1,2,3,4,6,7,12,125 p-octahydroindolo|2,3-a)quinolysine

To a solution of 0.422 g (1.65 mmol) of M-(2'-(3-indolyl)ethyl)|1-2,3-dimethylpiperidine in 25 ml of ethanol was added 2.1 g of mercuric acetate and 2.46 g of the disodium salt of ethylenediaminetetraacetic acid in 5 Oml of water and the resulting mixture was boiled under reflux for 10 minutes. The cooled mixture was made basic with dilute ammonium hydroxide and then extracted with dichloromethane. Drying over sodium sulfate, (F) filtration and evaporation of the solvent gave the crude enamine, which was dissolved in 3 mL of methanol and cooled in an ice bath. A few drops of acetic acid were added, followed by the addition of 0.322 g of sodium borohydride in portions. After stirring for 1.5 hours, the mixture was processed in the usual way to give the crude product, which was purified by column chromatography (silica gel, dichloromethane/methanol 98.5:1.5).

NMR: 0.89 (d, ЗН), 0.96 (d, ЗН), 3.76 (width d, 1Н), 7.0-7.5 (m, 4Н), 7.71 (width with, 1H).

MS: 254 (9595), 253 (10095), 239 (30905), 170 (3195), 169 (36905).

Example 39 65 Ethyl ether (To-ethyl-1,2,3,4,6,7,12,12b p-octahydroindolo|2,3-a)quinolisin-1-ylmethoxy)acetic acid

A solution of 0.02 g (0.07 mmol) of (1p-ethyl-1,2,3,4,6,7,12,12B o-octahydroindolo|2,3-a)quinolisin-1-ilumethanol (bag.

Sleep May PI (1981) 257-267) in a mixture of M,M-dimethylformamide-toluene (ml, 1:1) was added to 6b.8mg (0.28mmol) of sodium hydride, previously washed with heptane. The reaction mixture was stirred at RT for an hour. and then ethyl bromoacetate (0.009ml, 0.084mmol) in toluene (1ml) was added dropwise. Stirring continued during the Accords. at kt.

Water was added slowly and the reaction mixture was extracted with dichloromethane (3x2Oml). The combined organic phases were dried over sodium sulfate, the drying agent was filtered off, and the filtrate was evaporated to give the title compound, which was purified by column chromatography (silica gel, dichloromethane/methanol, 5:5). 70 NMR: 0.61 (t, 3H), 1.28 (t, 3H), 3.49 (z, 1H), 4.25 (d, 1H), 4.30 (q., 2H), 4 .55 (d, 1H), 6.93 (t, 1H), 7.03 (t, 1H), 7.35 (d, 1H), 7.38 (d, 1H), 10.64 (s, 1H).

MS: 370 (4095), 369 (3090), 283 (12906), 267 (10095), 197 (1290), 170 (1290), 169 (16905)

Example 40 5,6,7,7ar,8,9,10,11,11arf3,11B6o,-becahydro-12-oxa-ba-azaindeno|1,2-a|fluorene

0.13 g (0.87 mmol) of cis-1,2-cyclohexanedicarboxylic anhydride was added to a solution of 0.70 g (0.4 mmol) of 2-(3-benzo|B|furanyl)ethylamine in 30 ml of chlorobenzene. The mixture was irradiated in a microwave oven (1000 W,

T-1302С) during ЗОхв. Chlorobenzene was replaced by ethanol (5 ml) and 82.7 mg (2.18 mmol) of sodium borohydride was added. The mixture was stirred at RT for 18 hours, then water was added and the product was isolated in the usual way.

Trifluoroacetic acid (0.12 ml, 1.53 mmol) in dichloromethane (1 ml) was added and the reaction mixture was stirred for 2 hours. at kt. Treatment with alkali (4 M sodium hydroxide) gave an amide intermediate, which was dissolved in diethyl ether (1 bml), 0.1 g (2.63 mmol) of lithium aluminum hydride was added, and the reaction mixture was refluxed for 1.5 h. Water was slowly added while cooling. After conventional extraction, the crude product was purified by column chromatography (silica gel, dichloromethane/methanol, 90:10). Gee!

NMR: 1.77 (m, 2H), 2.07 (m, 1H), 2.29 (m, 1H), 2.48 (m, 1H), 3.04 (m, 1H), 3.20 (m, 1H), 4.13 (z, 1H), o 7.18 7.50 (m, 4H).

MS: 267 (4695), 266 (100965), 185 (52905), 170 (1296).

Example 41 1-methyl-1o,,3,4,6,1165 rD-hexahydro-2H-11-oxa-4a-azabenzo|(a|fluorene (Compound b) (ee)

The procedure of example 26 was repeated, using o-rethyl-5-valerolactone and c 2-(3-benzo|v|furanyl)ethylamine instead of e-caprolactam and tryptamine, respectively.

NMR: 0.88 (d, ZH), 3.34 (b, 1H), 7.19-7.43 (m, 4H). Me)

MS: 241 (4095), 240 (50965), 226 (10095), 198 (1095), 170 (68905), 170 (24905). at

Example 42

Zo (1-hydroxymethyl-1,3,4,5,6,11p-hexahydro-2H-11-oxa-4a-azabenzo(a|fluoren-1-yl)-methanol co

The procedure of example 41 was repeated, using o-valerolactone instead of o-methyl-5-valerolactone, and the resulting enamine was treated with formaldehyde, as in example 14.

NMR: 3.30 (d, 1H), 3.76 (d, 1H), 3.79 (d, 1H), 3.82 (z, 1H), 4.31 (d, 1H), 7.18 -7.50 (m, 4H). "

MS: 287 (5695), 286 (6090), 270 (40965), 256 (10095), 198 (34905), 172 (26905), 170 (54905).

Example 43 in c 1-methoxymethyl-1o-methyl-1,3,4,5,6,116 dD-hexahydro-2H-11-oxa-4a-azabenzo|(a)fluorene

From" A solution of 173.1 mg (0.6 b4 mmol) of the alcohol described in example 30 in 5 ml of tetrahydrofuran was added to 153.0 mg (6.3 mmol) of sodium hydride, previously washed with heptane. The reaction mixture was stirred at 359 for 1 hour. followed by the dropwise addition of a solution of 0.04 ml (0.64 mmol) of iodomethane in tetrahydrofuran (bml). 15 Stirring was continued for an hour. Water was added slowly and the reaction mixture was extracted with dichloromethane (3x20ml). The combined organic phases were dried over sodium sulfate, the drying agent (a) was filtered off, and the filtrate was evaporated to give the title compound, which was purified by column chromatography (silica gel, dichloromethane/methanol, 90:10).

NMR: 0.74 (z, ЗН), 3.29 (z, ЗН), 3.36 (d, 1Н), 3.89 (d, 1Н), 7.20-7.52 (m, 4Н) . (o) 20 MS: 285 (8095), 284 (10095), 270 (2095), 254 (9895), 198 (35905), 171 (82905), 170 (70905). so Example 44 2,3,4,4ar,5,6,7,8,136 D,1Zsr-decahydro-IN-13-oxa-ba-azaindeno|1,2-c|phenathrene and 2,3,4,4ar, 5,6,7,8,13Bo,,1Zpp-decahydro-1H-13-oxa-ba-azaideno|1,2-s|phenanthrene

The procedure of example 41 was repeated, using cis-octahydroisochromen-1-one instead of o-methyl-5-valerolactone. The two isomers were separated by column chromatography (silica gel,

F) ethyl acetate/heptane, 70:30). ko 2,3,4,4ar,5,6,7,8,136 V, 1Zpp-decahydro-IN-13-oxa-ba-azaindenoi|1,2-s|phenanthrene:

NMR: 3.28 (3, 1H), 7.17-7.53 (m, 4H). in MS: 281 (4095), 280 (10095), 238 (1595), 198 (12905), 170 (24905). 2,3,4,4ar,5,6,7,8,136 o, 1Zpp-decahydro-1H-13-oxa-ba-azaindeno|1,2-s|phenanthrene:

NMR: 2.75 (d, 1H), 7.15-7.43 (m, 4H).

MS: 281 (3895), 280 (100965), 198 (16905), 170 (3096).

Example 45 65 Ethyl ether of 1-9-methyl-1,3,4,5,6,116 y-hexahydro-2H-11-oxa-4a-azabenzo(a|fluorene-1-carboxylic acid

0.56 g (2.33 mmol) of 5-chloro- of 2-ethoxycarbonyl-2-methylvaleroyl chloride (obtained according to the method described for the corresponding 2-ethyl derivative in (U. Ogu. Spet. 45 (1980) 32-341) in dichloromethane (4 ml). After stirring at rt for 45 min. was added water, and the mixture was extracted with dichloromethane.

The pure amide (0.3 g, 0.82 mmol) was dissolved in toluene (3 ml) and 0.38 ml (4.1 mmol) of phosphorus oxychloride was added.

The mixture was refluxed for 2 hours, then evaporated to dryness. The precipitate was dissolved in methanol (3 mL) and 57 mg (1.5 mmol) of sodium borohydride was added in portions. After stirring for 7/0 h. water was added and the mixture was extracted with ethyl acetate. Drying over sodium sulfate, followed by filtration and evaporation gave the crude ester, which was purified by column chromatography (silica gel, ethyl acetate/heptane, 1:1).

NMR: 0.65 (t,,ZN), 1.55 (z, ZN), 3.30 (b, 1H), 7.16-7.50 (m, 4H).

MS: 313 (7095), 312 (10095), 284 (22905), 240 (32905), 198 (8095), 171 (3595), 170 (95905).

Example 46 1-ethoxymethyl-1o-methyl-1,3,4,5,6,116 d -hexahydro-2H-11-oxa-4a-azabenzo|(a| fluorene

The procedure of example 43 was repeated, using iodethane instead of iodomethane.

NMR: 0.74 (s, ЗН), 1.17 (t, ЗН), 3.37 (s, 1Н), 3.38 (d, 1Н), 3.54 (q., 2Н), 3, 96 (d, 1H), 7.10-7.60 (m, 4H).

MS: 299 (7095), 298 (9290), 270 (40965), 254 (10095), 198 (34905), 171 (8695), 170 (72905).

Example 47 (To-methyl-1,3,4,5,6,116 x-hexahydro-2H-11-oxa-4a-azabenzo(a|fluoren-1-yl)umethanol

To a suspension of 0.31 g (8.2 mmol) of lithium aluminum hydride in dry tetrahydrofuran (1 mL), 0.86 g (2.74 mmol) of the ester described in example 45 in dry tetrahydrofuran (1 mL) was added. The reaction mixture was refluxed for one hour. Water was added slowly and the reaction mixture was extracted with Na ethyl acetate (3x20ml). The combined organic phases were dried over sodium sulfate, filtered, and the filtrate was evaporated to obtain the desired product, which was purified by column chromatography (silica gel, ethyl acetate/heptane 50:50).

NMR: 1.30 (s, 3H), 2.98 (b, 1H), 3.21 (d, 1H), 3.69 (d, 1H), 4.33 (s, 1H), 7 ,15-7,55 (m.4H).

MS: 271 (5295), 270 (10095), 198 (34905), 172 (20905), 171 (4495), 170 (66905). with

Example 48.

The procedures described in examples 45 and 47 were repeated, using 2-(ZH-inden-1-yl)ethylamine instead of F) 2-(3-benzo|p|furanyl)ethylamine. at

NMR: 0.82 (z, 3H), 3.07 (b, 1H), 3.23 (d, 1H), 3.39 (d, 1H), 3.52 (d, 1H), 3 .70 (d, 1H), 7.05-7.35 (m, 4H).

MS: 269 (4395), 268 (10695), 252 (2995), 196 (3695), 168 (40905). (uh)

Example 49

Methyl ether of 1o-ethyl-1,3,4,5,6,115 y-hexahydro-2H-11-oxa-4a-azabenzo(a|fluorene-1-carboxylic acid.

The procedure of example 45 was repeated, using 5-chloro-2-ethoxycarbonyl-2-ethylvaleroyl chloride instead of 5-chloro-2-ethoxycarbonyl-2-methylvaderoyl chloride.

NMR: 0.90 (t, ZN), 6.90-7.58 (m, 4H). t s MS: 327 (7290), 326 (10095), 312 (2095), 298 (20905), 254 (30905), 198 (54905), 172 (6095), 170 (9095). h Example 50 -» 1-methoxymethyl-10-methyl-1,3,4,5,6,115 y-hexahydro-2H-11-oxa-4a-azabenzo|(a|fluorene

The procedure of example 43 was repeated, using the alcohol described in example 47 as the starting compound.

NMR: 1.44 (z, ZN), 2.99 (d, 1H), 3.15 (b, 1H), 3.22 (s, ZN), 3.70 (d, 1H), 7 ,18-7,50 (m, 4H). with MS: 285 (8495), 284 (10095), 270 (1495), 254 (92905), 198 (34905), 171 (74905), 170 (50905). o Example 51 (To-ethyl-1,3,4,5,6,116 y-hexahydro-2H-11-oxa-4a-azabenzo|(a|fluoren-1-yl)umethanol and, Repeated the procedure of example 47, using a complex the ether described in example 49 as the starting material

Fu 20 compound.

NMR: 1.00 (t, 3H), 2.93 (m, 2H), 3.29 (s, 1H), 7.15-7.60 (m, 4H). with MS: 286 (9095), 285 (6890), 284 (10095), 268 (1695), 198 (22905), 171 (22905), 170 (36905).

Example 52

Methyl ether 52 1-p-hydroxymethyl-1-methyl-1,2,3,4,6,7,12,1265 p-octahydroindolo|2,3-a)quinolysine-br-carboxylic acid

GF) We repeated the method of obtaining 7 (1-d-ethyl-1,2,3,4,6,7,12,125 o-ectahydroindolo|2,3-a)quinolisin-1-ilumethanol ISag. Sleep may SH (1981) 257-267), using the methyl ester of I-tryptophan instead of tryptamine. in NMR: 0.74 (z, ZN), 3.39 (s, ZN), 3.46 (d, 1H), 3.97 (d, 1H), 4.38 (bt, 1H), 7.00-7.50 (m, 4H), 8.90 (width, 1H).

MS: 328 (2695), 327 (10095), 299 (3895), 268 (3290), 170 (1095), 169 (24905).

Example 53

Separation of 1o-isopropyl-1,2,3,4,6,7,12,125 p-octahydroindolo|2,3-a)quinolisin-1-ol

A solution of 0.3 g (1, Thymmol) (5)-Th-isopropyl-1,2,3,4,6,7,12,125 p-octahydroindolo|2,3-a)quinolisine-y-ol and 0.16 g 65 (1.Tmmol) of I -tartaric acid in 15 ml of acetone was refluxed for 30 minutes. When standing at room temperature during the night, 2000 mg of solid matter precipitated. After double recrystallization from methanol, the collected I-tartrate salt was separated between dichloromethane and 1095 sodium hydroxide solution, dried over sodium sulfate and evaporated to obtain 116.bmg of (-)-To-isopropyl-1,2,3,4,6,7, 12.125 r-ectahydroindolo|2,3-a)quinolisin-1-ol with (0)0--64.52 (c, 0.011 in SNSY5). Another enantiomer is (k)-To-isopropyl-1,2,3,4,6,7,12,126 p-octahydroindolo|2,3-a)quinolisin-1-ol. (odr--64.59 (with 0.011 in CHO)) was isolated from the uterine fluid in the same way.

Example 54

Separation of (To-methyl-1,3,4,5,6,116 rD-hexahydro-2H-11-oxa-4a-azabenzo(a)fluoren-1-yl)umethanol

The procedure of example 53 was repeated using anhydride (k)-diacetyl-i! -tartaric acid and isopropanol 70 instead of I-tartaric acid and acetone. The optical purity of the separated enantiomers was confirmed by chiral HPLC (column: OAISEI SNEMISAG IMOOZTAKIE5, TO SNIKASEI 0), dimensions O.46bsm " 25cm, flow: O.5ml/min., mobile phase: n-hexane (Megsk MOmazo! for spectroscopy/isopropanol ( Kairigp, for gradient HPLC) (100:20), UV determination at 272 nm, retention time: 8.8 min (9)-(To-methyl-1,3,4,5,6,116 p-hexahydro-2H-11- oxa-4a-azabenzo(a|fluoren-1-yl)methanol) and 11.1 min 15. 1-(1o-methyl-1,3,4,5,6,116 d-hexahydro-2H-11-oxa-4a -azabenzo(|(a|)fluoren-1-yl)umethanol.

Example 55

Separation of (1o-methyl-1,3,4,5,6,11B o-hexahydro-2H-11-oxa-4a-azabenzo|(a|fluoren-1-yl)umethanol

The procedure of example 53 was repeated using (-)di-p-toluoyl-II-tartaric acid monohydrate and ethyl acetate instead of I-tartaric acid and acetone.

The optical purity of the separated enantiomers was confirmed by chiral HPLC (column: OAISEI SNEMISAG.

IMOOBTACHE5, HTO SNIKASEI 0), dimensions 0.46 bcm "25 cm, flow: 0.vml/min., mobile phase: n-hexane (Metgsk Omazoi for spectroscopy)/zopropanol (Kaibygp, for gradient HPLC) (180:20), determination of UV at 254 nm, retention time: 7.8 min. fluoren-1-yl)methanol)| and 12.6 bw. -1-yl)methanol. c 29 Example 56 Ge)

Enantiomers of 1-methoxymethyl-1o-methyl-1,3,4,5,6,116 dD-hexahydro-2H-11-oxa-4a-azabenzo|a|fluorene

The procedure of example 43 was repeated using pure enantiomers, (5-(To-methyl-1,3,4,5,6,115 d-hexahydro-2H-11-oxa-4a-azabenzo(a|fluoren-1-yl)umethanol and (-- so zo (10-methyl-1,3,4,5,6,1165 p-hexahydro-2H-11-oxa-4a-azabenzo(a|fluoren-1-yl)umethanol, respectively, from example 54 instead of the alcohol described in example 30. The optical purity of the products was confirmed by chiral HPLC (column: ke,

KOSKI AMO TESNMOG OSIE5, IM OSTKOM E5-OMM, dimensions 4.bsm " 15cm, flow: O.vml/min., mobile phase: 0.04M Ge"!

KM2PO4 (rna,b)acetonitrile (Megsk Ispgovoi Ivosgais class for liquid chromatography) (90:10), retention time 3.8 min. |(-)-1-methoxymethyl-1 o-methyl-1,3,4,5,6,1165 p-hexahydro-2H-11-oxa-4a-azabenzo(a|fluorene and o 5, entry I( k)-1-methoxymethyl-1o-methyl-1,3,4,5,6,116 dD-hexahydro-2H-11-oxa-4a-azabenzo|a|fluorene. (ee)

Example 57

Enantiomers of 1-methoxymethyl-1o-methyl-1,3,4,5,6,116 o-hexahydro-2H-11-oxa-4a-azabenzo(a|)fluorene

The procedure of example 43 was repeated using pure enantiomers, "(95-(To-methyl-1,3,4,5,6,11B5 y-hexahydro-2H-11-oxa-4a-azabenzo(a|fluoren-1-yl )methanol and 40. (3-(19-methyl-1,3,4,5,6,116 y-hexahydro-2H-11-oxa-4a-azabenzo(a| fluoren-1-yl)umethanol, respectively, from the example With p 55 instead of the alcohol described in example 30. The optical purity of the products was confirmed by chiral HPLC "" (column: OAISEI SNEMISAG IMOOZTAKIE5, TO SNIKASEI 0), dimensions O.46bsm " 25cm, flow: O.vml/min., mobile " phase : n-hexane (Megsk Omazoi for spectroscopy), retention time 5.6 bhv.

I(--1-methoxymethyl-1 d-methyl-1,3,4,5,6,116 y-hexahydro-2H-11-oxa-4a-azabenzo(a|fluorene and b, Ref. so 395 I-)- 1-methoxymethyl-1u-methyl-1,3,4,5,6,116u-hexahydro-2H-11-oxa-4a-azabenzo(|(a|fluorene.

The following known compounds can be obtained similarly or according to methods known in the literature. (a) 1o-cetyl-1,2,3,4,6,7,12,125 p-octahydroindolo|2,3-a|quinolisin-1-ol (Compound H) The procedure of example 6 was repeated using 1-ethyl- 4,9-dihydro-ZN-pyrido/Z,4-B|indole |U. Spent os, Regkip Tgapez I (1977) 2109-2115) instead of 1-isobutyl-4,9-dihydro-ZN-pyrido|3,4-in|indole. (o) 2p-methyl-1,2,3,4,6,7,12,125 D-octahydroindolo|2,3-a)quinolisin-2-ol and c 2o-methyl-1,2,3,4,6 ,7,12,125 p-octahydroindolo|2,3-a)yquinolisin-2-ol was obtained following the methods described in

IM. Oh Spent 56 (1991) 2701-2712 and Spet. Veg 106 (1973) 3106-3118). 1,2,3,4,6,7,12,12b p-ectahydroindolo|2,3-a)quinolisin-1 y-ol and 1,2,3,4,6,7,12,126 p-octahydroindolo|2 ,3-a) Echinolysin-1 D-ol was obtained according to the method described in Spet.

RIagt. howl 34 (1986) 3713-3721. o 1,2,3,4,6,7,12,12p-octahydroindolo|2,3-a|ychinolysine was obtained according to the method described in M.Spet. ko os, Spet Sott., (1972) 4611. 1,4,6,7,12,12b-hexahydroindolo|2,3-α-quinolysine (Compound I) was obtained according to the method described in Teganedhop 45 (1989) 3975-3992. 3,4,6,7,12,12p-hexahydroindolo|2,3-a)quinolysine and 1-ethyl-3,4,6,7,12,12p-hexahydroindolo|2,3-a)quinolysine were obtained according to the method described in (Viyi. Zos. Spit. Rg. 7-8 (1976) 12221.

To-ethyl-1,2,3,4,6,7,12,126 D-octahydroindolo|2,3-a)quinolysine and 1d-ethyl-1,2,3,4,6,7,12,125 p-ectahydroindolo| 2,3-Alquinolysine (Compound .) was obtained according to the method described in |Tegapedagop 45 (1989) 7615-7630).

To-ethyl-1,2,3,4,6,7,12,126 rD-octahydroindolo|2,3-a)quinolisin-1-ol (Compound YuK) and

(1d-ethyl-1,2,3,4,6,7,12,12α-octahydroindolo|2,3-a)quinolisin-1-yl)umethanol (Compound 1!) was obtained according to the method described in |Zag2 . Sleep May I (1981) 257-267). (1d-ethyl-1,2,3,4,6,7,12,1265p-octahydroindolo|2,3-aquinolizin-1-yl)umethanol (Compound M) was obtained

According to the method described in |paiap 9. Spet., Zesi. U 22 (1983) 5311.

3-ethyl-2-methyl-1,4,6,7,12,12p-hexahydroindolo|2,3-a)quinolysine (Compound M) and

Zo-ethyl-2o-methyl-1,2,3,4,6,7,12,12p-octahydroindolo|2,3-a)quinolysine was obtained according to the method described in |Tegngapedop 46 (1990) 2633-2650) . 2,3,5,6,7,11,11p-hexahydro-1H-indolizine|8,7-B|indole was obtained according to the method described in (|). 70 Oh. Spent 53 (1988) 42361). (1p8,2,9,4,6,7,12,12α-octahydroindolo|2,3-a)quinolisin-1-yl)umethanol (Compound OO) was obtained by reduction of the corresponding complex ester, the synthesis of which is described in Geigapedop 52 ( 1996) 9925). 1-4102,2,3,4,6,7,12,126 D-ectahydroindolo|2,3-a)quinolisin-1-yl)ethanol (Compound P) was obtained by reduction of its corresponding ketone, the synthesis of which is described in . 30 (1989) 719). 1d-propyl-1,2,3,4,6,7,12,125p-octahydroindolo|2,3-a)quinolysine was obtained according to the method described in Y3U. Oh Spent 34 (1969) 330). 1o-ethyl-1r-methyl-1,2,3,4,6,7,12,125-rectohydroindolo|2,3-a)quinolysine was obtained according to the method described in |U. Spent Kez. (5) (1995) 3821. 2p-tert-butyl-1,2,3,4,6,7,12,125p-octahydroindolo|2,3-a)quinolysine and 2rf-tert-butyl-1,2,3 ,4,6,7,12,12B5 o-octahydroindolo|2,3-a|quinolysine (Compound C) was obtained according to the method described in |Tei(gapeadgop 45 (1989) 39751. 2-tert-butyl-1, 4,6,7,12,12B-hexahydroindolo|2,3-a)quinolysine and 2-tert-butyl-3,4,6,7,12,12b-hexahydroindolo|2,3-a)quinolysine were obtained according to the method, described in (Teigapedop 47 (1991) 2879-2894). ch 29 (-)-To-ethyl-1,2,3,4,6,7,12,1265 p-octahydroindolo|2,3-a)quinolisin-1-ol and Ge) ()-To-ethyl- 1,2,3,4,6,7,12,125 p-octahydroindolo|2,3-a|quinolisin-1-ol was obtained by separating their racemic mixture (Compound K).

As already indicated above, the compounds according to the present invention show interesting pharmacological properties, and in particular, they show affinity for alpha2 adrenoceptors. The indicated pharmacological activity of the compounds according to the invention is demonstrated by means of the pharmacological tests presented below. is),

Experiment I: Binding of radioactive ligand to alpha2-adrenoceptors o

Examples of the alpha2-adrenoceptor binding capacity of the compounds included in the present invention are shown in Table 1. Most of these compounds are high affinity ligands for all alpha?-receptors, but some of them ("c") show selectivity for the alpha2C subtype . d) studies of the binding of radioactive "ligands" using cells that express subtypes of human alpha2g-adrenoceptors. » in | yuyu 1 so posts and tone NO o

Ф 78 vv do not die out 22

Fu 2 yuyu so o 1 z yuyu a | ml | lu | wow

Experiment II: Antagonism of ip migo alpha2-adrenoceptors

The functional activity of two compounds (K and Y) showing alpha2-selectivity in binding experiments was determined as the ability of the compounds to inhibit epinephrine-stimulated binding of 358-ZTRU5Z to 0 proteins Yuazreg, U.K. ei aI.,, Viospet. RIaptasoi. 55(7) (1998) 1035-44 in the membranes of CHO cells stably transfected with subtypes of human alpha2-adrenoceptors. Antagonistic activity of compound K and compound Y.

presented in Table 2. The results show that these compounds are selective antagonists of alpha2C subtypes. activity (Kv) of compound K and compound I. on subtypes of human alpha2-adrenoceptors

The compound is

Ip mimo effect of alpha2C-selective compounds

At present, it is not known in this field what effects of ip mimo can be caused by selective alpha?C antagonism. Based on available knowledge and previous experience, the authors selected two different behavioral models, namely the d-amphetamine-stimulated locomotor model and the forced swim test, in order to demonstrate the specific alpha2C-antagonistic action in the CNS of mice and rats i.p. mimo. The choice of these methods is mainly based on published hypotheses about the theoretical effects of alpha2?C-antagonists; in the absence of acceptable ligands, these hypotheses were based on studies involving mice with genetically altered expression of the alpha2C-adrenoceptor |Zspeipip, M. ei ai., I Me 5si 68(19-20) (2001) 2277-85).

Experiment III: Test of O-amphetamine-stimulated motor activity

Genetically modified mice with non-functioning alpha2C-adrenoceptors (alpha2C-knockout; alpha2C-KO) are more sensitive to the motor-enhancing action of the psychostimulant d-amphetamine and, on the other hand, increased expression of alpha?2C-adrenoceptor in of mice (airpa2O-OE) leads to the opposite effect, that is, to a decrease in the effect of the stimulator. Therefore, a hypothesis can be proposed that alpha2C antagonists will enhance the motor effect of α-amphetamine. Gee)

The aforementioned forcing was tested by administering to groups of mice (n-10-12/dose group) amphetamine (4 micromol/kg b/w) alone or together with alpha2C antagonists (2 micromol/kg b/w) according to the present invention or with an alpha-subtype non-selective strong alpha-antagonist (1 Imicromol/kg p/w) (Naaraippa, A. ei ai.,

Mashypup-Zsptiedereguz Agsp. RPaptasoiy. 356 (1997). As expected, both alpha?C-selective antagonists tested increased the activity of mice (Fig. Lazhnr), as expected for (22) alphag2gC antagonists. A subtype of non-selective alpha2g antagonist also potentiated the effects of 4d-amphetamine. The tested compounds did not affect the initial locomotor activity of the mouse (in doses between 0.1 1Omg/kg/h).

Zo IM experiment: Antagonism of the sedative effect induced by an alpha2-agonist so

One of the obvious effects of non-selective alpha?-agonists in rodents is their ability to cause a strong sedative effect. This effect, measured as motor inhibition by the alpha2-agonist dexmedetomidine, did not change in mice with genetically altered expression of alpha?C | ZsNeipip, M. ei ai., I Mbe Zsi 68(19-20) (2001) « 2277-851. On the other hand, the alpha2-agonist did not have a sedative effect in mice with a genetically impaired alpha?A-adrenoceptor | (Nipieg, 9.S. ei ai., Vgyivy doshigpa! oi Rpagtasoiodo 122(7) (1997) 1339-44). Therefore, since the sedative effect of alpha?-agonists is usually related to the alpha2-adrenoceptor, it was expected that "» alpha?C-antagonists would not significantly modulate the sedative effect induced by alpha?2-agonists. This " assumption was tested in an experiment where dexmedetomidine was administered to mice that had previously received alpha?C-antagonists of compound K or compound GI, or a subtype of the non-selective antagonist atipamezole INaaraippa, A. eyi a)., Mashpup-Zsptiederegu in Agsp. Riagtasoi 356 (1997) 570-582). As expected, alpha?2C-antagonists did not have a clear effect, while atipamezole effectively counteracted the effect of dexmedetomidine. This result demonstrates the absence of alpha?gA-antagonism in the alpha2C-selective compounds of the present invention (Fig. 2).

Experiment C: Forced swimming test (se) Forced swimming test (TPP (E5T) i.e. Porsolt test) is usually used in b 20 pharmacological screening of new antidepressants. In this test, antidepressants increase the activity of animals compared to untreated controls. It turned out that alpha?C-KO mice are more active, and alpha2C-OE mice are less active in TPP (US patent Mo5902807 and ZsNeipip, M. ei ai., Me si 68(19-20) (2001) 2277- 85). Therefore, it was investigated whether a selective alpha2C antagonist has antidepressant-like activity (for example, the property of increasing activity) in TPN. Figure 3 shows how both alpha2C compounds increased activity in this test, as expected based on studies on transgenic mice.

GF! ei a!.,, I Me Zsi 68(19-20) (2001) 2277-85) and as reported on a recently developed alpha?C-antagonist

YIMUO 01/64645)Yi. Also, the positive control substances desipramine and fluoxetine (clinically effective antidepressants) were active. The non-selective alpha2-antagonist subtype atipamezole did not have an antidepressant-like effect as expected (MO 01/64645). bo Experiment MI: Anticipatory inhibition of the startle reflex

Anticipatory inhibition (PI) of the startle reflex refers to the reduction of the startle response elicited by a low-intensity, non-fearful stimulus (anticipatory pulse) presented shortly before the fear-inducing stimulus. VI can be used as a working measure of sensorimotor conduction and is probably present in all mammals, including rats and humans |Zmegaudomu, M.K. Hey, yeah, that's why I'm a depega! rzuspiayu 51 (1994) 139-154th. A normally functioning VI can be disrupted by psychostimulants such as d-amphetamine or phenylcyclidine (PCC) and reversed by clinically effective antipsychotic agents.

In a previous study, the alpha?C-KO mutation was associated with attenuated VI, whereas alpha2C-OEE showed increased VI. In other words, genetically altered expression of alpha 2C in mice was associated with changes in VI, suggesting that alpha2C reduces VI. 85). Such a hypothesis was tested with compounds K and G. separately and against violation of VI FCK.

Groups of rats (n-10/group) were injected with alpha?C antagonists for 20 minutes, and FCC or solvent for 10 minutes. to measure the sound reactivity of fright and VI in the test system created for the study of fright |ZK-I AV,

Zap Oiedo Ipzigitepiv, SA, OBZA). It was found that alpha2C-antagonists were able to weaken the 7/0 violation of VI caused by FCC (Fig. 3). This was unexpected and contradicted the hypothesis based on transgenic studies. The non-selective alpha2-antagonist atipamezole produced effects different from those observed with selective alpha2C-antagonists: atipamezole did not enhance Vi, but it increased the startle reflex per se (ie, startle without anticipatory stimuli) (Fig. 4).

In conclusion, the results presented in this section indicate that such antagonists, which are classified as alpha2C-selective according to ip mygo experiments, are likely to function as alpha 2C-selective antagonists also ip mimo in the same way as predicted on the basis of available knowledge alpha?C-antagonism. However, the finding that alpha2C antagonists do not lower VI as expected, but instead increase VI, could be considered unexpected and adds new value to the currently proposed applicability of the compounds of this invention.

The compounds of this invention can be used to treat any disease or condition in which alpha2 antagonists have been shown to be effective. The compounds may also be used to reverse the effects induced by alpha2 agonists. Accordingly, the compounds of the invention may be useful in the treatment of various central nervous system (CNS) disorders, i.e. various neurological, psychiatric and cognitive disorders (such as depression, anxiety disorders, post-traumatic stress disorder, schizophrenia, schizophrenia

Parkinson's and other movement disorders). Moreover, they can be used in the treatment of various peripheral disorders, for example, diabetes, orthostatic hypotension, lipolytic disorders (such as obesity), disease (8)

Raynaud's and male and female sexual dysfunctions.

The selective alpha?C antagonists of the present invention can be used to treat various disorders or conditions of the central nervous system where alpha?2C antagonists have been shown to be useful, for example, in alleviating co

Of the symptoms of various mental disorders caused by stress, Parkinson's disease, depression, negative symptoms of schizophrenia, attention deficit hyperactivity disorder, post-traumatic stress disorder and anxiety disorders. b

In addition, due to the new and previously unpublished effects of these alpha?2C-antagonists on FCC-disturbed

VI, alpha?2C-selective compounds can also be used to treat disorders and conditions associated with sensorimotor selection deficits, particularly disorders and conditions where sensorimotor selection deficits lead to sensory immersion and cognitive decay, causing attentional and sensory dysfunction. . Such disorders and conditions include, but are not limited to, schizophrenia, obsessive-compulsive disorder,

Tourette's, blepharospasm and other focal dystonia, temporal lobe epilepsy with psychosis, drug-induced psychoses (for example, psychosis caused by chronic use of dopaminergic "agents") IVgai, O.S. eg a, Rvusporpaptasoydu (Ve) 156(2-3) (2001) 234-258), Hettington's disease, pl)s Parkinson's disease, disorders caused by fluctuations in sex hormone levels (such as premenstrual syndrome) and panic disorders. ;" Further, symptoms commonly associated with the above disorders or conditions include, but are not limited to, hallucinations, delusions, parathymia, anxious agitation, psychotic cognitive impairment (including deficits in thought and language), social withdrawal, and withdrawal symptoms ( including delirium) associated with cessation of cigarette smoking or alcohol or drug abuse. Such symptoms can also be observed in animals in unusual circumstances, for example, when parting with their owners or during transportation.

Ge) Because of the selectivity of their action, alpha2C antagonists according to the invention have fewer or no undesirable side effects inherent in non-selective alpha2?-antagonism, such as increased blood pressure,

Me, the frequency of heart contractions, saliva secretion, secretion of the gastrointestinal tract, anxiety and starting reactivity as such | KiyoYo, K.K. Tohisoi! 32 (1993) 243-279).

The compound according to the invention can be administered, for example, enterally, topically or parenterally with the help of any pharmaceutical composition applicable for the specified administration, and which contains at least one active compound of the formula | in pharmaceutically acceptable and effective amounts together with pharmaceutically acceptable diluents, carriers and/or excipients known in the art. Getting these

F) pharmaceutical compositions are well known in this field. A therapeutic dose for administration to a patient in need of treatment will vary depending on the compound being administered, the species, age and sex of the subject being treated, the particular condition being treated, and the route and method of administration and will be readily determined by one skilled in the art. in this field. Accordingly, a typical dosage for oral administration is from 5mcg/kg to 100mg/kg per day and for parenteral administration from 00.5mcg/kg to 1mg/kg for an adult mammal.

The present invention further provides a compound of the invention or an ester or salt thereof for use as an alpha?g2 antagonist. Also provided are methods of treating diseases or conditions in which 65 alpha antagonists have been shown to be beneficial, such as methods of treating diseases or conditions of the central nervous system. In such a method, a therapeutically effective amount of a compound of the invention is administered to a subject,

in need of such treatment. They also provide the use of compounds according to the invention to obtain a medicinal product for use in the above-mentioned conditions.

A specialist in this field should take into account that the embodiments of the invention described in this application

Can be modified without deviation from the general idea of the invention. It will also be apparent to a person skilled in the art that the invention is not limited to certain described embodiments, but is also intended to include modifications of the embodiments that do not change the nature and are within the scope of the invention.

Claims (27)

The formula of the invention 1. Application of the compound of the formula I Kv I, Kv (vit M. Kk and Ez E and Kk, in Re t where X represents SKK", O, Z or MK"; 72 represents -СНК-(СНо)- or a simple bond; Ku represents hydroxy, (C 1-Cv)alkyl, (C4-Cv) alkoxy, halogen, halogen (C.4-Cv)alkyl, (C4-Cv) alkoxy-CO-, CM, cm MO», MH» , mono- or di(C.4-C) alkylamino or carboxyl group; Ho) EC" and Co are independently H, hydroxy or (C 4-Cv)alkyl, or Co and Co" form, together with the carbon atoms that form the ring to which they are attached, a carbonyl group; Kz represents H, hydroxy, (Co 4-Cv)alkyl, (Co-Cv)alkenyl, hydroxy(C--Cv)alkyl, (C.--Cv)alkyl, co zo (C4-Cv)alkyl(C1 -Cv) alkyl, hydroxy(C4-Cv) hydroxy(C.--Cv) alkyl, (C3-C7) cycloalkyl, (C3-C7) cycloalkyl(C-Cv) alkyl, aryl, aryl(C.--Cv) )alkyl, aryloxy, aryl(C--Cv)alkyl, aryloxy(Ci-Cv)alkyl, aryl(C--Cv)alkyl(C-Cv)alkyl,) "(0 halogen(C 4-Cv)alkyl . СО-, (С4-Св)alkyl-СО-О-, (С4-Св)alkyl-СО-О-(С.-Св)alkyl, (С41-Св)alkyl-СО-, (С.4-Св )Alkoxy-CO-(C.4-Cv)alkyl, (C.4-Cv)Alkoxy-CO-(C.4-Cv)Alkoxy(C--Cv)alkyl, carbamoyl, "3 mono- or di( C-i-Ci)alkylcarbamoyl, carboxyl or (Ci-Ci)alkyl-5-(Ci-Ci)alkyl, where the specified (Ci-Ci)cycloalkyl co or aryl is unsubstituted or substituted by 1 or 2 substituents, each of which independently represents hydroxy, (C4-C8) alkyl, halogen, (Ci-C8) alkoxy, MH, CM or MO", or one of K»z or K, and K; together form a bond between ring atoms, to which in we are attached; KE. represents H, hydroxy, (C4-Cv)alkyl, hydroxy(C.--Cv)alkyl, (C4-Cv)alkyl, or (C.4-Cv)alkyl(C4-Cv)alkyl; « du K is H, hydroxy, (C 4-Cv)alkyl, (Co-Cv)alkenyl, (C.i-Cv) alkoxy, (C.4-Cv) oxy(C4-Cv)alkyl, - c (C3-C7) cycloalkyl, (C3-C7) cycloalkyl(C.--Cv) alkyl, aryl, aryl(C--Cv) alkyl, aryloxy, aryl(C.--Cv) alkoxy, aryloxy(C.4 -Cv)alkyl, aryl(C.-Cv)alkyl(C4-Cv)alkyl, halogen(C.-Cv)alkyl, (C4-Cv)alkyl-CO-O-, ; with" (C4-Cv)alkyl-CO-O-(C.-Cv)alkyl, (C4-Cv)alkyl-CO-(C4-Cv)alkyl (C4-Cv)alkyl, carbamoyl, MOono- or di( C--Ci)alkylcarbamoyl, carboxyl or (C.4-Ci)alkyl-5-(C.4-Ci)alkyl, where the specified (Ci-C)cycloalkyl or aryl is unsubstituted or substituted by 1 or 2 substituents, each of which are independently represented by hydroxy, (C 1-Cv)alkyl, y and co halogen, (Ci-Cv)alkoxy, МНо, СМ or МО», or K, and K5 form, together with the carbon atoms that form the ring, to to which they are attached, a condensed five-seven-membered saturated carbocyclic ring substituted by 1-3 (ab) Co substituent(s), each of which is independently hydroxy, (Co | 4-Cv)alkyl, halogen, MH»o, MO», c (C3-C7)cycloalkyl, hydroxy(C.-Ci-Cv)alkyl, halogen(Ci-Ci)alkyl, amino(Ci-Ci)alkyl, mono- or di(Ci-Ci) alkylamino, mono- or di(C--Cv)alkylamino(C 1-Cv)alkyl, (C4-Cv)alkyl, (C4-Cv)alkyl(C.4-Cv)alkyl, carboxyl, (o) 20 ( C4-Cv)alkyl-CO-, (C4-Cv)alkyl-CO-O-, (C4-Cv)alkyl-CO-, (C4-Cv)alkyl-CO-(C4-Cv)alkyl, carbamoyl mono- or so di(C--Cv)alkyl arbamoyl or oxo; Ke represents H, hydroxy, (C 4-Cv)alkyl, (Ci-Cv)alkyl or (C.4-Cv)alkyl(C.i-Cv)alkyl or K; forms a bond between the atom of the ring to which it is attached and the atom of the ring to which K»7 is attached; K; represents H, hydroxy, (C4-Cv)alkyl, hydroxy(C.--Cv)alkyl, (C4-Cv)alkyl, or (C.4-Cv)alkyl(C4-Cv)alkyl; 59 Ka represents H, hydroxy, (C 4-Cv)alkyl, hydroxy(C--Cv)alkyl, (C4-Cv)alkyl, or (C.4-Cv)alkyl(C--Cv)alkyl HF) or , in the case when n is equal to 0, K and Ka form, together with the carbon atoms that form the ring to which HF they are attached, a condensed five-seven-membered saturated carbocyclic ring, unsubstituted or substituted by 1-3 substituent(s) Co , each of which independently represents a hydroxy, (Co 4-Cv)alkyl, halogen, MH", MO", in (C3-C7)cycloalkyl, hydroxy(C.-i-Cv)alkyl, halogen (C.-Cv) )alkyl, amino(Ci-Cv)alkyl, mono- or di(C.i-Cv)alkylamino, mono- or di(C--Cv)alkylamino(C 1-Cv)alkyl, (C4-Cv)alkyl, (С4-Св)Alkoxy(С4-Св)alkyl, carboxyl, (С4-Св)alkyl-СО-, (С4-Св)alkyl-СО-О-, (С4-Св)Alkoxy-СО-, ( C.-Ci)alkyl-CO-(Ci-Ci)alkyl, carbamoyl, mono- or di(Ci-Ci)alkylcarbamoyl or oxo; Ki5 is NN, (Co 4-Cv)alkyl, (Co-Cv)alkenyl, hydroxy(C--Cv)alkyl, (C4-Cv) alkoxy(C.4-Cv)alkyl, hydroxy(C 1-Cv )alkoxy(C4-Cv)alkyl, halo(C.4-Cv)alkyl, amino(C.--Cv)alkyl, MOono- or 65 di(C4i-Cv)alkylamino(C 4-Cv)alkyl, (C4 -Cv)alkyl-CO-, (C4-Cv)alkyl-CO-O-(C4-Cv)alkyl, (C4-Cv)alkyl-CO-, (C4-Cv)Alkoxy-CO-(C4-Cv)alkyl, (C4-Cv)Alkoxy-CO-(C4-Cv)Alkoxy(C-Cv)alkyl, carbamoyl, MOono- or di(C--Cv) alkylcarbamoyl or carboxyl; Kv represents H or (C-C-C) alkyl; KE; and Ka are attached to carbon ring atoms that are adjacent; t is equal to 0-2; and n is 0 or 1, or a pharmaceutically acceptable salt or ester thereof, provided that the compounds are not 1,2,3,4,5,10p-hexahydro-10-thia-Za-azacyclopenta(α|fluorene, for obtaining a medicinal product that is/o antagonist of alpha-2 adrenoceptors for the treatment of diseases or conditions. 2. Use of the compound according to claim 1, where X represents MK". 3. Use of a compound according to any of claims 1 or 2, where t is 0, n is 0, K» represents H, Kz represents H, hydroxy, (Co 4-Cv)alkyl, hydroxy(Ci-Cv) )alkyl, (C4-Cv)alkyl (C.--Cv)alkyl, (C3-C7)cycloalkyl, halo(C1-Cv)alkyl, (C4-Cv)alkyl-CO-, (C1-Cv)alkyl -CO-O-(C.4-Cv)alkyl, (C4-Cv)alkyl-CO- or 75. "C1-Cv) alkoxy-CO-(C-Cv) alkyl, Ki represents H, hydroxy, (C 1-Cv) alkyl or hydroxy(C--Cv) alkyl, Kb represents H, hydroxy, (C4i-Cv)alkyl or (C.4-Cv)alkyl, Co represents H or (C/-Cv)alkyl and K represents H, (C4-Cv)alkyl or hydroxy(C--Cv)alkyl . 4. Use of a compound according to any of claims 1-3, where K is H or (C-Cb)alkyl and K is hydroxy or hydroxy(C.4-Cb)alkyl. 5. Use of a compound according to any of claims 1 or 2, where K; and K5 form, together with the ring-forming carbon atoms to which they are attached, a condensed six-membered saturated carbocyclic ring. 6. Use of a compound according to any of claims 1 or 2, where K and Ke together form a bond between the atoms of the ring to which they are attached, or Co forms a bond between the atom of the ring to which it is attached and the atom the ring to which K is attached". with 7. Use of a compound according to any of claims 1-5, where the compound is ""-ethyl-1,2,3,4,6,7,12,125 in octahydroindolo|2,3-a)quinolisin-1-ol ) ,4,6,7,12,126 8-octahydroindolo|2,3-a)quinolisin-1-ol, (7"-methyl-1,2,3,4,6,7,12,12r. в-octahydroindolo| 2,3-a)quinolisin-1-yl)umethanol or 3,4,4a 8,5,6,7,8,13,136 6,13c 2-decahydro-2H-ba,13-diazaindeno|1,2 -c|phenanthrene-1-one. 8. Application of the compound according to claim 1, where X is a SCoK". ise) 9. Application of the compound according to claim 1, where X represents 0. Gee! 10. Use of the compound according to claim 1, where X is 5. 11. Use of a compound according to any one of claims 1-10 for obtaining a medicinal product for the treatment of disorders of the central nervous system, diabetes, orthostatic hypotension, lipolytic disorders, Raynaud's disease or male or female sexual dysfunction. 12. Use according to claim 11, wherein the central nervous system disorder is depression, anxiety disorders, post-traumatic stress disorders, schizophrenia, Parkinson's disease or other movement disorders. 13. Use of the compound according to any one of claims 1-10 to obtain a medicinal product for use as a selective alpha-2 C antagonist. from the village 14. Application according to claim 13 for obtaining a medicinal product for the treatment of mental disorders caused by stress, Parkinson's disease, depression, negative symptoms of schizophrenia, attention deficit hyperactivity disorder, post-traumatic stress disorder and anxiety disorders. 15. The compound of the formula IA Kv IA, o Re o (vit | A (Se) x Ty vu ez E 42) and ve B where X represents SKK", O or 5; 72 represents -СНК-(СНо)- or a simple bond; (F. Ku represents hydroxy, (C 4-Cv)alkyl, (C4-Cv)alkyl, halogen, halogen (C.-Cv)alkyl, (C4-Cv)alkyl-CO-, CM, g MO» MH", mono- or di(C.4-C) alkylamino or carboxyl group; EK" and Co are independently H, hydroxy or (C 4-C) alkyl, or Co and Co" form, together with boron carbon atoms , which form the ring to which they are attached, a carbonyl group; Kz represents H, hydroxy, (Co 4-Cv)alkyl, (Co-Cv)alkenyl, hydroxy(C--Cv)alkyl, (C--Cv) )alkoxy, (C4-Cv)alkyl (C.4-Cv)alkyl, hydroxy(C4-Cv)alkyl (C.--Cv)alkyl, (C3-Cv)cycloalkyl, (C3-C7)cycloalkyl (C. --Cv)alkyl, aryl, aryl(Ci-Cv)alkyl, aryloxy, aryl(C.--Cv)alkyl, aryloxy(C--Cv)alkyl, aryl(C.--Cv)alkyl (C.4 -Cv)alkyl, halogen(C 4-Cv)alkyl, MH», amino(C.-Cv)alkyl, mMono- or di(C4i-Cv)alkylamino, mMono- or 65 di(C1-Cv)alkylamino(C 1-Cv)alkyl, (C4-Cv)alkyl-CO-, (C4-Cv)alkyl-CO-O-, (C4-Cv)alkyl-CO-O-(C1-Cv)alkyl, (C4-Cv) )alkoxy-CO-, (C4-Cv)alkoxy-CO-(C4-Cv)alkyl, (C4-Cv)alkoxy-CO-(C4-Cv)alkyl (Ci-Cv)alkyl, carbamoyl, mono- or di(C-i-Cv)alkylcarbamoyl, carboxyl or (Ci-Ci)alkyl-5-(C4-Ci)alkyl, where the specified (C5-Ci)cycloalkyl or aryl is unsubstituted or substituted by 1 or 2 substituents , each of which is independently hydroxy, (C4-C8)alkyl, halogen, (Ci-C8)alkoxy, MH», CM or MO», or one of Kz or K, and Ko together form a bond between the ring atoms , to which they are attached; KE. represents H, hydroxy, (C4-Cv)alkyl, hydroxy(C.--Cv)alkyl, (C4-Cv)alkyl, or (C.4-Cv)alkyl(C4-Cv)alkyl; K represents H, hydroxy, (C 4-Cv)alkyl, (Co-Cv)alkenyl, (C.i-Cv)alkyl, (C.4-Cv) alkoxy(C4-Cv)alkyl, (C3-C7 )cycloalkyl, (C3-C7)cycloalkyl(C.--Cv)alkyl, aryl, aryl(C--Cv)alkyl, aryloxy, aryl(C.--Cv)alkoxy, aryloxy(C.4-Cv)alkyl , aryl(C.-Cv)alkyl(C4-Cv)alkyl, halogen(C.-Cv)alkyl, (C4-Cv)alkyl-CO-O-, 70. "C1-Cv)alkyl-CO-0O-(C.-Cv)alkyl, (C4-Cv)alkyloxy-CO-(C4-Cv)alkyl (C4-Cv)alkyl, carbamoyl, MOono- or di( C--Ci)alkylcarbamoyl, carboxyl or (C.4-Ci)alkyl-5-(C.4-Ci)alkyl, where the specified (Ci-C)cycloalkyl or aryl is unsubstituted or substituted by 1 or 2 substituents, each of which independently represents hydroxy, (C 1-C) alkyl, halogen, (Ci-C) alkoxy, МНо, СМ or МО», or K, and K5 form, together with the carbon atoms that form the ring to which they are attached , a condensed five-seven-membered saturated carbocyclic ring, substituted with 1-3 Co substituent(s), each of which is independently hydroxy, (Cy claim 4-C)alkyl, halogen, MH»o, MO», (C3- C7)cycloalkyl, hydroxy(C.-i-Cv)alkyl, halo(C.i-Cv)alkyl, amino(Ci-Ci)alkyl, mono- or di(C.i-Ci)alkylamino, MOono- or di( C--Cv)alkylamino(C 1-Cv)alkyl, (C4-Cv)alkyl, (C4-Cv)alkyl (C.4-Cv)alkyl, carboxyl, (C4-Cv)alkyl-CO-, (C41 -Cv)alkyl-CO-O-, (C4-Cv)alkyl-CO-, (C4-Cv)alkoxy-CO-(C4-Cv)alkyl, carbamoyl mono- or di(C-Cv)alkylcarbamoyl or ox at; Ke represents H, hydroxy, (C 4-Cv)alkyl, (Ci-Cv)alkyl or (C.4-Cv)alkyl(C.i-Cv)alkyl or K; forms a bond between the atom of the ring to which it is attached and the atom of the ring to which K»7 is attached; K; represents H, hydroxy, (C4-Cv)alkyl, hydroxy(C.--Cv)alkyl, (C4-Cv)alkyl, or (C.4-Cv)alkyl(C4-Cv)alkyl; Ka represents H, hydroxy, (C 4 -C 8 )alkyl, hydroxy(C 1 -C 8 )alkyl, (C 4 -C 8 )alkyl, or (C 4 -C 8 )alkyl (C 1 -C 8 )alkyl or, only when n is 0, K; and Ka form, together with the ring-forming carbon atoms to which they are attached, a condensed five-seven-membered saturated ring, unsubstituted or substituted by 1-3 substituent(s) K 0, each of which is independently hydroxy, (Cy claim 4-Cv)alkyl, halogen, MH", MO", (C3-C7)cycloalkyl, (8) hydroxy(C.4-Cv)alkyl, halogen(C--Cv)alkyl, amino(C- -Cv)alkyl, mono- or di(C--Cv)alkylamino, mono- or di(C--Cv)alkylamino(C.i-Cv)alkyl, (C--Cv)alkyl, (Ci- C.i.i.Cv)alkyl -Sv) alkoxi-so- (p.4-s), carbamoyl, moon- or io- or io zi di (C4-CV) alkylcarbamyl or oxogroup; Ki5 is NN, (Co 4-Cv)alkyl, (Co-Cv)alkenyl, hydroxy(C--Cv)alkyl, (C4-Cv) oxy(C.4-Cv)alkyl, ise) hydroxy(C 1 -C 4 -C 4 -Alkyl, halogen (C 4 -C 4 )alkyl, amino (C 4 -C 4 )alkyl, MOono- or He! di(C4i-Cv)alkylamino(C.-Cv)alkyl, (C.--Cv)alkyl-CO-, (C.4-Cv)alkyl-CO-O-(C4-Cv)alkyl, (C. --C 4 -C 6 -Alkoxy-Co, (C 4 -C )Alkoxy-CO-(C 4 -C )alkyl, (C 4 -C )Alkoxy -CO-(C 4 -C )Alkoxy (C -C )Alkyl, Carbamoyl, MOono- or F di(C-C)alkylcarbamoyl or a carboxyl group; co Kv represents H or (C 1-C )alkyl; KE; and Ka are attached to carbon ring atoms that are adjacent; t is equal to 0-2; and n is 0 or 1, "or a pharmaceutically acceptable salt or ester thereof, provided that in c a) when X is 0, t is 0 and n is 0, then Kz-Ka are not all hydrogen at the same time; . B) the compound is not 1,2,3,4,5,10p-hexahydro-10-thia-Za-azacyclopenta(a|fluorene; i? 1,3,4,5,6,11p6-hexahydro-2H-11 -thia-4a-azabenzo|(a|fluorene; 1-(1,3,4,5,6,11p-hexahydro-2H-11-thia-4a-azabenzo(a|fluoren-1-yl)uethanone or methyl ether of 1,3,4,5,6,11p6-hexahydro-2H-11-thia-4a-azabenzo(a|fluorene-1-carboxylic acid. Go! 16. The compound according to claim 15, where X represents SCoK". 17. Compound according to claim 15, where X represents 0. o 18. Compound according to claim 15, where X represents 5. Ge) 19. The compound according to any of claims 15-18, where K is hydroxy, (C 4-Cv)alkyl, hydroxy(C.4-Cv)alkyl, "C1-Cv)alkoxy(C1-Cv)alkyl , (C4-Cv) alkoxy-CO- or (C4-Cv) alkyl-CO-O-(C.i-Cv) alkyl and Ku; is H, Me, (C4-Cv)alkyl or hydroxy(C--Cv)alkyl. with 20. The compound according to any one of claims 15-19, where K represents hydroxy, hydroxy((C 4-C)alkyl or (C 4-C)alkoxy(C 4-C)alkyl and K; represents ( C.4-Cv)alkyl. 21. A compound according to any one of claims 15-18, where K and K5 form, together with the carbon atoms forming the ring to which they are attached, a condensed six-membered saturated carbocyclic ring. 22. Compound according to any Kk! claims 15-21, where the compound is (F) ""-methyl-1/3,4,5,6,11p-hexahydro-2H-11-oxa-4a-azabenzo(a|fluoren-1-ol, ka (71x -methyl-1,3,4,5,6,116 P -hexahydro-2H-11-oxa-4a-azabenzo(a|)fluoren-1-yl)umethanol, (3-0 12 -methyl-1,3 . hexahydro-2H-11-oxa-4a-azabenzo|(a|fluoren-1-yl)methanol, 1"-Isopropyl-1,3,4,5,6,11p-hexahydro-2H-11-oxa-4a- azabenzo(a|)fluoren-1-ol, T« -ethyl-1,3,4,5,6,116 in -hexahydro-2H-11-oxa-4a-azabenzo|a|fluoren-1-ol, (1« -ethyl-1,3,4,5,6,11p6 2-hexahydro-2H-11-oxa-4a-azabenzo|(a|fluoren-1-yl)methanol, 1-methyl-!«,3,4, 6,116 P-hexahydro-2H-11-oxa-4a-azabenzo(|(a|fluorene, 65 (1-hydroxymethyl-1,3,4,5,6,11p-hexahydro-2H-11-oxa-4a-azabenzo (a|fluoren-1-yl)methanol, 1-methoxymethyl-"g-methyl-1,3,4,5,6,115 P -hexahydro-2H-11-oxa-4a-azabenzo(|a|fluorene, (-)-1-methoxymethyl-"g-methyl-1,3,4,5,6,115 P-hexahydro-2H-11-oxa-4a-azabenzo(a|fluorene, (4)-1-methoxymethyl-"is -methyl-1,3,4,5,6,116.b-hexahydro-2H-11-oxa-4a-azabenzo|(a|fluorene, ethyl ether is -methyl-1,3,4,5,6,116 "-hexahydro -2H-11-oxa-4a-azabenzo(a|ifluorene-1-carboxylic acid, 1-ethoxymethyl-"is -methyl-1,3,4,5,6,116 P -hexahydro-2H-11-oxa-4a- azabenzo(|(a|fluorene, (7-methyl-1,3,4,5,6,116 2-hexahydro-2H-11-oxa-4a-azabenzo|(a|fluoren-1-yl)methanol, (-) -( 7 -methyl-1,3,4,5,6,1165 2-hexahydro-2H-11-oxa-4a-azabenzo|(a|fluoren-1-yl)methanol, (9-(1x -methyl- 1,3,4,5,6,115 "-hexahydro-2H-11-oxa-4a-azabenzo(a|fluoren-1-yl)methanol, methyl ether "g-ethyl-1,3,4,5,6,116 - hexahydro-2H-11-oxa-4a-azabenzo(a|)fluorene-1-carboxylic acid, 70 1-methoxymethyl-"e-methyl-1,3,4,5,6,116 2-hexahydro-2H-11-oxa -4a-azabenzo|(a|fluorene, (-)-1-methoxymethyl-"x-methyl-1,3,4,5,6,116"-hexahydro-2H-11-oxa-4a-azabenzo|(a|fluorene , (4-1-methoxymethyl-"is -methyl-1,3,4,5,6,116 --hexahydro-2H-11-oxa- 4a-azabenzo|(a|fluorene, (7x-ethyl-1,3,4,5,6,116-hexahydro-2H-11-oxa-4a-azabenzo(a|fluoren-1-yl)methanol, 1"-methyl -1,3,4,5,6,116. β-hexahydro-2H-11-oxa-4a-azabenzo(a|ifluoren-1-ylmethyl acetic acid ester or (7-methyl-1,2,3,4,6,7,12,1265 e-octahydroindeno|2 ,1-a)quinolisin-1-yl)umethanol. 23. Compound according to any Kk! claims 15-22, where the compound is KU-(7-methyl-1,3,4,5,6,115P-hexahydro-2H-11-oxa-4a-azabenzo(a|fluoren-1-yl)methanolomi). 24. Compound according to any Kk! claims 15-22, where the compound is -)-1-methoxymethyl- "" -methyl-1,3,4,5,6,116 U -hexahydro-2H-11-oxa-4a-azabenzo(|a|fluorene. 25. A pharmaceutical composition with alpha-2 adrenoceptor antagonist activity, containing at least one compound according to any one of claims 15-24 as an active agent in an effective amount and a pharmaceutically acceptable diluent, carrier and/or excipient. 26. A compound according to any one of claims 15-24 for use as a medicinal product. 27. A method of treating a disease or condition with an antagonist of alpha-2 adrenoceptors, which includes administering to a mammal in need of it an effective amount of at least one compound according to claim 1. ((c) se) b 50 IR e) F) ime) 60 b5