NO165837B

NO165837B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE INDEX DERIVATIVES AND ACID ADDITION SALTS THEREOF.

Info

Publication number: NO165837B
Application number: NO861235A
Authority: NO
Inventors: Jens Kristian Perregaard
Original assignee: Lundbeck & Co As H
Priority date: 1985-04-10
Filing date: 1986-03-26
Publication date: 1991-01-07
Also published as: LV5743B4; NO165837C; MX9203347A; DE3669153D1; ZA862615B; ES553807A0; GR860927B; ATE50564T1; NZ215507A; ES8707499A1; LV5743A4; IL78136A; DE19775090I2; NO1998009I1; IL78136A0; PT82348B; GB8509164D0; PT82348A; NO861235L

Description

Oppfinnelsen vedrører analogifremgangsmåter ved fremstilling av nye indolderivater og syreaddisjonssalter derav, hvilke indolderivater har interessante farmako-dynamiske effekter som antyder tydelig aktivitet i behandlingen av ulike psykoser og som samtidig har en lav grad av uønskede bieffekter. The invention relates to analogous methods for the production of new indole derivatives and acid addition salts thereof, which indole derivatives have interesting pharmacodynamic effects that suggest clear activity in the treatment of various psychoses and which at the same time have a low degree of unwanted side effects.

De nye indolderivater har følgende formel I: The new indole derivatives have the following formula I:

hvori R er fenyl eventuelt substituert med halogen eller trifluormetyl, eller en aromatisk gruppe så som 2-tienyl, 3-tienyl, 2-tiazolyl, 2-pyridyl, 3-pyridyl eller 4-pyridyl; R<1 >er hydrogen, halogen, lavere alkyl, nitro, trifluormetyl eller amino; "A" er nitrogen eller karbon, og den stiplete linje indikerer - når A er karbon - en eventuell binding, R<2 >er hydrogen, lavere alkyl eventuelt substituert med en hydroksygruppe, hvorved enhver foreliggende hydroksygruppe kan eventuelt være forestret med en alifatisk karboksylsyrerest som har fra 2 til 24 karbon-atomer eller R<2> er gruppen wherein R is phenyl optionally substituted with halogen or trifluoromethyl, or an aromatic group such as 2-thienyl, 3-thienyl, 2-thiazolyl, 2-pyridyl, 3-pyridyl or 4-pyridyl; R<1 >is hydrogen, halogen, lower alkyl, nitro, trifluoromethyl or amino; "A" is nitrogen or carbon, and the dashed line indicates - when A is carbon - a possible bond, R<2> is hydrogen, lower alkyl optionally substituted with a hydroxy group, whereby any hydroxy group present may optionally be esterified with an aliphatic carboxylic acid residue having from 2 to 24 carbon atoms or R<2> is the group

hvor "n" er et helt tall fra 2-4. X er oksygen eller svovel eller >C=X kan utgjøre gruppen CH= når Y er =N- eller =CH-, Y er oksygen, CH2 eller NH, Z er _(CH2)m -, hvorved m where "n" is an integer from 2-4. X is oxygen or sulfur or >C=X can form the group CH= when Y is =N- or =CH-, Y is oxygen, CH2 or NH, Z is _(CH2)m -, whereby m

er 2 eller 3, eller Z er -CH=CH-, U er nitrogen eller karbon med den forutsetning at når R<1> er klor, A er nitrogen og R<2 >er metyl eller cykloheksyl, kan R ikke være fenyl; samt deres farmasøytisk akseptable syreaddisjonssalter. is 2 or 3, or Z is -CH=CH-, U is nitrogen or carbon with the proviso that when R<1> is chlorine, A is nitrogen and R<2> is methyl or cyclohexyl, R cannot be phenyl; as well as their pharmaceutically acceptable acid addition salts.

Det har tidligere vært funnet at flere indolderivater som er substituert på nitrogenatomet med en karboksylsyrerest, er i besittelse av analgetiske og anti-inflammatoriske egenskaper. Nylig ble det foreslått i tysk utlegningsskrift nr. 2811031 at også indoler som har en fenylsubstituent på nitrogenatomet, kan ha de ønskede analgetiske eller anti-inflammatoriske virkninger, men ingen data ble gitt for 1-fenyl-5-klor-3-metylpiperazin-indol eller l-fenyl-5-klor-3 -cykloheksylpiperazin-indol som omtales i beskrivelsen. Førstnevnte av disse forbindelser (Lu 23-015) ble fremstilt og ble funnet at den var uten interessante effekter i de farmakologiske forsøk som ble utført i våre laboratorier. I Europeisk Patentsøknad med publ. nr. 22705 ble noen derivater av tetrahydropyridinyl-indoler som har enten hydrogen eller alkyl (1-3 C-atomer), i 1-stilling beskrevet å være neuroleptika. De farmakologiske data som gis i beskrivelsen indikerer dog kun svak til moderat neuroleptisk aktivitet. It has previously been found that several indole derivatives which are substituted on the nitrogen atom with a carboxylic acid residue possess analgesic and anti-inflammatory properties. Recently, it was suggested in German explanatory document No. 2811031 that also indoles having a phenyl substituent on the nitrogen atom may have the desired analgesic or anti-inflammatory effects, but no data were given for 1-phenyl-5-chloro-3-methylpiperazine-indole or 1-phenyl-5-chloro-3-cyclohexylpiperazine-indole as mentioned in the description. The first of these compounds (Lu 23-015) was prepared and was found to be without interesting effects in the pharmacological experiments carried out in our laboratories. In European Patent Application with publ. No. 22705, some derivatives of tetrahydropyridinyl indoles having either hydrogen or alkyl (1-3 C atoms) in the 1-position were described as neuroleptics. However, the pharmacological data given in the description indicate only weak to moderate neuroleptic activity.

Der er blitt fremstilt en av disse forbindelser, 5-klor-3(l-(2-hydroksyetyl)-1,2,3,6-tetrahydropyrid-4-yl)indol (Lu 23-14 3) og det ble funnet at den var nesten inaktiv sammen-lignet med forbindelsen med formel I. One of these compounds, 5-chloro-3(1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyrid-4-yl)indole (Lu 23-14 3) has been prepared and it was found that it was almost inactive compared to the compound of formula I.

Det er nå overraskende blitt funnet at de nye indolderivater med formel I er sterke dopaminergiske antagonister i farmakologiske forsøk, både in vivo og in vitro, når de sammenlignes med velkjente neuroleptika som vanligvis benyttes ved behandlingen av psykoser, og særlig meget langvarige effekter - opp til flere dager - ble observert med mange av forbindelsene med formel I. I tillegg ble de fleste av indolene med formel I sterke 5-HT antagonister både periferisk og sentralt, hvilket betraktes å være viktig ved behandlingen av psykiske forstyrrelser og kardiovasku-lære sykdommer. It has now surprisingly been found that the new indole derivatives of formula I are strong dopaminergic antagonists in pharmacological tests, both in vivo and in vitro, when compared to well-known neuroleptics that are usually used in the treatment of psychoses, and especially very long-lasting effects - up to several days - was observed with many of the compounds of formula I. In addition, most of the indoles of formula I became strong 5-HT antagonists both peripherally and centrally, which is considered to be important in the treatment of mental disorders and cardiovascular diseases.

Uttrykket lavere alkyl, lavere alkoksy, lavere alkyltio og lavere alkylsulfonyl betegner slike grupper som har fra 1 til 4 karbonatomer. Eksempler på slike grupper er metyl, etyl, n-propyl, iso-propyl, n-butyl, sec.butyl, metoksy, etoksy, butoksy, metyltio, etyltio, propyltio, metylsulfo-nyl, etylsulfonyl eller lignende. The term lower alkyl, lower alkoxy, lower alkylthio and lower alkylsulfonyl denotes such groups having from 1 to 4 carbon atoms. Examples of such groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec.butyl, methoxy, ethoxy, butoxy, methylthio, ethylthio, propylthio, methylsulfonyl, ethylsulfonyl or the like.

Uttrykket lavere alkenyl betegner alkenyl grupper som har fra to til fire karbonatomer, for eksempel etenyl, 1-prop-enyl, 2-butenyl og lignende. The term lower alkenyl denotes alkenyl groups having from two to four carbon atoms, for example ethenyl, 1-prop-enyl, 2-butenyl and the like.

Denne oppfinnelse omfatter også farmasøytisk akseptable salter av forbindelsene med formel I dannet med ikke-toksiske syrer. Slike salter kan med letthet dannes i henhold til teknikkens stand. This invention also encompasses pharmaceutically acceptable salts of the compounds of formula I formed with non-toxic acids. Such salts can easily be formed according to the state of the art.

Basen omsettes enten med den beregnende mengde av organisk eller uorganisk syre i et løsningsmiddel som er blandbart med vann, så som aceton eller etanol, med isolasjon av saltet ved konsentrering eller avkjøling eller med et overskudd av syren i et løsningsmiddel som ikke er blandbart med vann, så som etyleter eller kloroform, slik at det ønskede salt utskilles direkte. The base is reacted either with the calculated amount of organic or inorganic acid in a solvent that is miscible with water, such as acetone or ethanol, with isolation of the salt by concentration or cooling or with an excess of the acid in a solvent that is not miscible with water , such as ethyl ether or chloroform, so that the desired salt is separated directly.

Eksempler på slike organiske salter er de med.malein-, fumar-, benzoe-, askorbin-, embon-, rav-, oxal-, bis-met-ylensalicyl-, metansulfon-, etandisulfon-, eddik-, prop-ion-, vin-, salicyl-, sitron-, glukon-, melke-, eple-, mandel-, kanel-, citrakon-, asparagin-, stearin-, palmitin-, itakon-, glykol-, p-aminobenzo-, glutamin-, benzensulfon-og teofyllineddiksyre, samt 8-halogenteofylliner, for eksempel 8-brom-teofyllin. Eksempler på slike uorganiske salter er de med saltsyre, hydrobromsyre, svovelsyre, sulfaminsyre, fosforsyre og salpetersyre. Naturligvis kan disse salter også fremstilles ved den klassiske metode med dobbel spaltning av egnede salter, hvilket er velkjent i faget. Examples of such organic salts are those with maleic, fumaric, benzoic, ascorbic, embonic, amber, oxal, bis-methylenesalicyl, methanesulphonic, ethanedisulphonic, acetic, propionic- , wine-, salicylic-, lemon-, glucone-, milk-, apple-, almond-, cinnamon-, citracone-, asparagine-, stearine-, palmitin-, itacone-, glycol-, p-aminobenzo-, glutamine- , benzenesulphonic and theophylline acetic acid, as well as 8-halotheophyllines, for example 8-bromo-theophylline. Examples of such inorganic salts are those with hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid. Naturally, these salts can also be prepared by the classic method of double cleavage of suitable salts, which is well known in the art.

De indoler med formel I hvori R<1> er klor, fluor, trifluormetyl, metyl, salpeter eller amino i 5-stillingen, R er fenylsubstituert med fluor i 4'- eller 2<1->stillingen, R<2> er metyl, hydroksyetyl eller 3-hydroksypropyl, og A er som definert ovenfor, har vist særlig fordelaktige effekter i de farmakologiske forsøk og har også få uønskede bieffekter . The indoles of formula I in which R<1> is chlorine, fluorine, trifluoromethyl, methyl, nitrate or amino in the 5-position, R is phenyl substituted with fluorine in the 4'- or 2<1-> position, R<2> is methyl , hydroxyethyl or 3-hydroxypropyl, and A is as defined above, has shown particularly beneficial effects in the pharmacological trials and also has few unwanted side effects.

Spesielt foretrukne forbindelser er Particularly preferred compounds are

1-(4<1->fluorfenyl-3-(4-(2-hydroksyetyl)-piperazin)-5-trifluormetyl-lH-indol (Lu 21-152), 1-(4<1->fluorophenyl-3-(4-(2-hydroxyethyl)-piperazine)-5-trifluoromethyl-1H-indole (Lu 21-152),

1-(4'-fluorfenyl-5-nitro-3-(1-metyl-l,2,3,6-tetrahydropyridin-4-yl)-lH-indol (Lu 22-135), 1-(4'-fluorophenyl-5-nitro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (Lu 22-135),

5-klor-l-(4'-fluorfenyl-3-(1-metyl-l,2,3,6-tetrahydropyridin-4-yl)-lH-indol (Lu 22-117), 5-chloro-1-(4'-fluorophenyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (Lu 22-117),

1-(4'-fluorfenyl-3-(1-(2-hydroksyetyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-lH-indol (Lu 23-150), 1-(4<1->fluorfenyl-3-(1-(2-hydroksyetyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-trifluormetyl-lH-indol (Lu 23-156), 5-fluor-1-(4<1->fluorfenyl-3-(1-(3-hydroksypropyl)-1,2,3,6-tetrahydropyridin-4-yl)-lH-indol (Lu 23-175), 1-(4'-fluorophenyl-3-(1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1H-indole (Lu 23-150), 1- (4<1->fluorophenyl-3-(1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-trifluoromethyl-1H-indole (Lu 23-156), 5- fluoro-1-(4<1->fluorophenyl-3-(1-(3-hydroxypropyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (Lu 23-175),

Disse forbindelsenes gode farmakologiske effekter fremgår av tabell 1. The good pharmacological effects of these compounds can be seen in table 1.

Oppfinnelsen vedrører en fremgangsmåte ved fremstilling av de nye indoler ved formel I, hvilken fremgangsmåte består av The invention relates to a process for the production of the new indoles of formula I, which process consists of

a) å omsette et indolderivat med den følgende formel: a) to react an indole derivative with the following formula:

hvori R<1> er R som definert ovenfor med en 4-piperidon med wherein R<1> is R as defined above with a 4-piperidone with

formel: formula:

hvori R<2> er som definert ovenfor, eller wherein R<2> is as defined above, or

b) redusere en forbindelse med den følgende formel: b) reduce a compound with the following formula:

hvori R<1>, R og R<2> er som definert ovenfor, eller wherein R<1>, R and R<2> are as defined above, or

c) omsette en forbindelse med den følgende formel: hvori R<1>, R<2> og A er som definert ovenfor med en forbindelse med formel: hvori R er som definert ovenfor og "hal" er halogen, i nærvær av en metallkatalysator, eller d) omsette en forbindelse med den følgende formel: c) reacting a compound with the following formula: wherein R<1>, R<2> and A are as defined above with a compound of formula: wherein R is as defined above and "hal" is halogen, in the presence of a metal catalyst, or d) reacting a compound of the following formula:

hvori R<1>, R og A er som definert som ovenfor, med et lavere wherein R<1>, R and A are as defined as above, with a lower

alkylhalogenid eller et oksyd med formel alkyl halide or an oxide of formula

er hydrogen, metyl eller etyl, eller is hydrogen, methyl or ethyl, or

R hvori R<1 >e) redusere en forbindelse med den følgende formel: hvori R<1>, R og A er som definert ovenfor og R<4> er hydrogen, lavere alkyl (1-3 C-atomer) eller lavere alkoksy (1-3 C-atomer), eller f) oppvarme en forbindelse med den følgende formel: hvori R<1> og R er som definert ovenfor, med et piperazin med formel: R in which R<1>e) reduce a compound with the following formula: wherein R<1>, R and A are as defined above and R<4> is hydrogen, lower alkyl (1-3 C atoms) or lower alkoxy (1-3 C atoms), or f) heating a compound with the following formula: wherein R<1> and R are as defined above, with a piperazine of formula:

hvori R<2> er som definert ovenfor, eller wherein R<2> is as defined above, or

g) redusere en forbindelse med den følgende formel: g) reduce a compound with the following formula:

hvori R<1>, R og R<2> er som definert ovenfor, med et egnet wherein R<1>, R and R<2> are as defined above, with a suitable

reduksjonsmiddel, hvoretter indolet med formel I isoleres i form av den frie base eller som et farmasøytisk akseptabelt syreaddisjonssalt derav og hvis gruppen R<2> inneholder en hydroksylgruppe hvis ønsket å acylere en slik hydroksygruppe med et reaktivt derivat av en alifatisk karboksylsyre som har fra 2 til 24 karbon atomer, og isolere den dannede ester som den frie base eller et farmasøytisk akseptabel syre-addis j onssalt derav. reducing agent, after which the indole of formula I is isolated in the form of the free base or as a pharmaceutically acceptable acid addition salt thereof and if the group R<2> contains a hydroxyl group if desired to acylate such a hydroxyl group with a reactive derivative of an aliphatic carboxylic acid having from 2 to 24 carbon atoms, and isolating the ester formed as the free base or a pharmaceutically acceptable acid addition salt thereof.

Med fremgangsmåte a) utføres reaksjonen ved sterkt sure betingelser ved oppvarming. Trifluoreddiksyre eller HC1 i etanol er foretrukket som syrekatalysatorer. Utgangsfor-bindelsene med formel II fremstilles hensiktsmessig i henhold til fremgangsmåten beskrevet i litteraturen, for eksempel ved reduksjon av R substituerte isatiner eller oksin-doler ved fremgangsmåten beskrevet i H.Sirowej et al. i. Synthesis 1972. 84, i henhold til det følgende reaksjons- With method a), the reaction is carried out under strongly acidic conditions by heating. Trifluoroacetic acid or HCl in ethanol are preferred as acid catalysts. The starting compounds with formula II are suitably prepared according to the method described in the literature, for example by reduction of R-substituted isatins or oxindoles by the method described in H. Sirowej et al. i. Synthesis 1972. 84, according to the following reaction-

Isatiner og oksyindoler fremstilles ved en Fiedel-Craft ringslutning under standardbetingelser fra henholdsvis N-oksalylklor- eller N-(2-kloracetyl)difenylaminer. Forbindelsene med formel II kan alternativt fremstilles ved arylering av N-usubstituerte indoler i henhold til fremgangsmåten beskrevet av M.A. Khan og E.K. Rocha, Chem. Isatins and oxyindoles are prepared by a Fiedel-Craft ring closure under standard conditions from N-oxalylchloro- or N-(2-chloroacetyl)diphenylamines, respectively. The compounds of formula II can alternatively be prepared by arylation of N-unsubstituted indoles according to the method described by M.A. Khan and E.K. Rocha, Chem.

Pharm.Bull 25 (11), 3110-3114 (1977). Pharm. Bull 25 (11), 3110-3114 (1977).

En alternativ måte å fremstille mellomproduktene med formel II går ut fra en indoksyl-2-karboksylester som skissert nedenfor: An alternative way to prepare the intermediates of formula II starts from an indoxyl-2-carboxyl ester as outlined below:

I fremgangsmåte b) utføres reduksjonen fortrinnsvis ved lave hydrogentrykk (3 atm.) i nærvær av platina eller palladium på kull. In method b), the reduction is preferably carried out at low hydrogen pressure (3 atm.) in the presence of platinum or palladium on charcoal.

I fremgangsmåte c) utføres aryleringen fortrinnsvis ved ca. 160 -210° C i aprotisk polare løsningsmidler så som for eksempel N-metyl-2-pyrrolidon eller heksametylfosfortriamid med K2CC>3 som base og kobber som katalysator. In method c), the arylation is preferably carried out at approx. 160 -210° C in aprotic polar solvents such as for example N-methyl-2-pyrrolidone or hexamethylphosphoric triamide with K2CC>3 as base and copper as catalyst.

I fremgangsmåte e) utføres reduksjonen fortrinnsvis med LiAlH4 i THF eller dietyleter eller med diboran i THF. In method e), the reduction is preferably carried out with LiAlH4 in THF or diethyl ether or with diborane in THF.

Fremgangsmåte f) er en to-trinns prosedyre i hvilken forbindelse VII først dekarboksyleres i nærvær av et uorganisk salt så som for eksempel LiCl eller MgCl2 i et polart løsningsmiddel så som for eksempel diglyme, heksametylfos-forsyretriamid eller N-metyl-2-pyrrolidon ved forhøyet temperatur (120 - 150° C). Endelig tilsettes det tilsvarende piperazin og temperaturen heves til ca. 200° C og holdes der til det tilsvarende indoksyl er forsvunnet i henhold til TLC-analyse. Forbindelsene med formel VII fremstilles hensiktsmessig i henhold til fremgangsmåtene beskrevet av P.C Unangst og M.E. Carethers, J.Heterocyclic Chem. 21, 709 (1984). Method f) is a two-step procedure in which compound VII is first decarboxylated in the presence of an inorganic salt such as for example LiCl or MgCl2 in a polar solvent such as for example diglyme, hexamethylphosphoric acid triamide or N-methyl-2-pyrrolidone by elevated temperature (120 - 150° C). Finally, the corresponding piperazine is added and the temperature is raised to approx. 200° C and held there until the corresponding indoxyl has disappeared according to TLC analysis. The compounds of formula VII are conveniently prepared according to the methods described by P.C. Unangst and M.E. Carethers, J. Heterocyclic Chem. 21, 709 (1984).

I fremgangsmåte g) er det hensiktsmessig å anvende diboran In method g) it is appropriate to use diborane

i THF som reduksjonsmiddel. Forbindelsene med formel VIII fremstilles fra de tilsvarende R-substituerte isatiner i henhold til det følgende reaksjons skjema: in THF as reducing agent. The compounds of formula VIII are prepared from the corresponding R-substituted isatins according to the following reaction scheme:

Fremgangsmåten i henhold til oppfinnelsen skal illustreres i det følgende ved noen eksempler: The method according to the invention shall be illustrated in the following by some examples:

Eksempel 1 Example 1

(Metode a) (Method a)

1-(4'-fluorfenyl)-5-metyl-3-(1-metyl-l,2,3,6-tetrahydropyridin-4-yl)-lH-indol, hydroklorid ( Lu 20- 089). 1-(4'-fluorfenyl)-5-metyl-lH-indol (4.5 g) og l-metyl-4-piperidon (5 g) ble oppløst i 25 ml eddiksyre og dråpevis tilsatt til 50 ml trifluoreddiksyre holdt nesten på koke-punktet. Blandingen ble forsiktig kokt under tilbakeløp i en halv time. Overskudd av trifluoreddiksyre ble fordampet og reaksjonsblandingen ble tilsatt til 50 ml 6M HCL og 50 ml eter. Den utfelte tittelforbindelse ble filtrert og tørket. Utbytte: 3.1 g(43%). Smp 262-266° C. 1-(4'-fluorophenyl)-5-methyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, hydrochloride ( Lu 20-089). 1-(4'-Fluorophenyl)-5-methyl-1H-indole (4.5 g) and 1-methyl-4-piperidone (5 g) were dissolved in 25 ml of acetic acid and added dropwise to 50 ml of trifluoroacetic acid kept almost at boiling the point. The mixture was carefully refluxed for half an hour. Excess trifluoroacetic acid was evaporated and the reaction mixture was added to 50 mL 6M HCL and 50 mL ether. The precipitated title compound was filtered and dried. Yield: 3.1 g (43%). mp 262-266° C.

På korresponderende måte ble de følgende tetrahydropyridin Correspondingly, they became the following tetrahydropyridine

-4-ylindoler fremstilt: 5-fluor-l-(4'fluorfenyl)-3-(1-metyl-l,2,3,6-tetrahydropyridin-4-yl)-lH-indol, hydroklorid. ( Lu 21- 018). Smp 256° C. 1-(4-fluorfenyl)-3-(1-metyl-l,2,3,6-tetrahydropyridin-4-yl) -lH-indol, oksalat. ( Lu 21- 120). Smp 228-229° C. 1-(4<1->fluorfenyl)-5-nitro-3-(1-metyl-l,2,3,6-tetrahydropyridin-4-yl)-lH-indol. ( Lu 22- 135). Smp 168-170° C. 1-(3<1->fluorfenyl)-5-nitro-3-(1-metyl-l,2,3,6-tetrahydropyridin-4-yl)-lH-indol, maleat. ( Lu 24- 004). Smp 216-217° C. 1-(2<1->fluorfenyl)-5-nitro-3-(1-metyl-l,2,3,6-tetrahydropyridin-4-yl)-lH-indol, maleat. ( Lu 24- 003). Smp 208° C. 3-(l-(2-hydroksyetyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-(41 - trifluormetylfenyl-lH-indol, fumarat. ( Lu 24- 012). Smp 174-175° C. 1-(4<1->fluorfenyl)-3-(1-metyl-l,2,3,6-tetrahydropyridin-4-yl)-lH-indol, hydroklorid. ( Lu 23- 083). Smp 268-270° C. 1-(4'-fluorfenyl)-5-nitro-3-(1,2,3,6-tetrahydropyridin-4-yl)-lH-indol, maleat. ( Lu 23- 133). Smp 204-205° C. 5-klor-l-(4'-fluorfenyl)-3-(1-(2-hydroksyetyl)-1,2,3,6-tetrahydropyridin-4-yl)-lH-indol, hydroklorid. ( Lu 23- 146). Smp 280-282° C. 5-klor-l-(4<1->fluorfenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl) -lH-indol. ( Lu 23- 147). Smp 105-107° C. -4-ylindoles prepared: 5-fluoro-1-(4'fluorophenyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, hydrochloride. (Lu 21-018). M.p. 256° C. 1-(4-fluorophenyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, oxalate. (Lu 21-120). Mp 228-229° C. 1-(4<1->fluorophenyl)-5-nitro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole. (Lu 22-135). Mp 168-170° C. 1-(3<1->fluorophenyl)-5-nitro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, maleate. (Lu 24-004). mp 216-217° C. 1-(2<1->fluorophenyl)-5-nitro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, maleate. (Lu 24-003). Mp 208°C. 3-(1-(2-Hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-(41-trifluoromethylphenyl-1H-indole, fumarate. (Lu 24-012). Mp 174-175 °C. 1-(4<1->fluorophenyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, hydrochloride. (Lu 23-083). Mp 268-270° C. 1-(4'-fluorophenyl)-5-nitro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, maleate. (Lu 23-133). Mp 204-205° C. 5-Chloro-1-(4'-fluorophenyl)-3-(1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, hydrochloride. (Lu 23-146). Mp 280-282° C. 5-chloro-1-(4<1->fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole. (Lu 23-147). Mp 105-107° C.

1-(4'-fluorfenyl)-3-1-(2-hydroksyetyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-lH-indol. ( Lu 23- 150). Smp 151-152° C. 1-(4'-fluorophenyl)-3-1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1H-indole. (Lu 23-150). Mp 151-152° C.

1-(4<1->fluorfenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)-5-trifluormetyl-lH-indol. ( Lu 23- 155). Smp 128-130° C. 1-(4<1->fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)-5-trifluoromethyl-1H-indole. (Lu 23-155). mp 128-130° C.

1-(4'-fluorfenyl)-3-(1-(2-hydroksyetyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-trifluormetyl-lH-indol. ( Lu 23- 156). Smp 140-141° C. 1-(4'-fluorophenyl)-3-(1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-trifluoromethyl-1H-indole. (Lu 23-156). Mp 140-141° C.

5-fluor-l-(4<1->fluorfenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)-lH-indol. ( Lu 23- 159). Smp 75-77° C. 5-fluoro-1-(4<1->fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole. (Lu 23-159). mp 75-77° C.

5-fluor-1-(4'-fluorfenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)-lH-indol, oksalat. ( Lu 23- 160). Smp 180-184° C. 5-fluoro-1-(4'-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, oxalate. (Lu 23-160). Mp 180-184° C.

5-fluor-1-(4•-fluorfenyl)-3-(1-(2-propyl)-1,2,3,6-tetrahydropyridin-4-yl)-lH-indol, fumarat. ( Lu 23- 167). Smp 190-195° 5-fluoro-1-(4•-fluorophenyl)-3-(1-(2-propyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, fumarate. (Lu 23-167). mp 190-195°

C. C.

1-(4<1->fluorfenyl)-3-(1-(3-hydroksypropy1)-1,2,3,6-tetrahydropyridin-4-yl)-5-trifluormetyl-lH-indol. ( Lu 23- 171). Smp 159-161° C. 1-(4<1->fluorophenyl)-3-(1-(3-hydroxypropyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-trifluoromethyl-1H-indole. (Lu 23-171). Mp 159-161° C.

5-fluor-1-(4'-fluorfenyl)-3-(1-(3-hydroksypropyl)-1,2,3,6-tetrahydropyridin-4-yl)-lH-indol, oksalat. ( Lu 23- 175). Smp 173-175° C. 5-fluoro-1-(4'-fluorophenyl)-3-(1-(3-hydroxypropyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, oxalate. (Lu 23-175). Mp 173-175° C.

Eksempel 2 Example 2

(Metode b) (Method b)

1-(4'-fluorfenyl)-3-(l-metyl-4-piperidyl)-5-trifluormetyl-lH-indol, oksalat. ( Lu 21- 131). 1-(4'-fluorophenyl)-3-(1-methyl-4-piperidyl)-5-trifluoromethyl-1H-indole, oxalate. (Lu 21-131).

Forbindelse Lu 21-120, oxalat (2.5 g) oppløses i etanol (200 ml), og Pt02 (0.2 g) tilsettes. Hydrogenisasjonen fort-setter i 3 timer ved 3 atm. Katalysatoren ble deretter filtrert av, etanol fordampet og tittelforbindelsen krystallisert fra aceton/eter. Utbytte: 1.2 g(48%). Smp 251-252° C. Compound Lu 21-120, oxalate (2.5 g) is dissolved in ethanol (200 ml), and PtO 2 (0.2 g) is added. The hydrogenation continues for 3 hours at 3 atm. The catalyst was then filtered off, the ethanol evaporated and the title compound crystallized from acetone/ether. Yield: 1.2 g (48%). mp 251-252° C.

På lignende måte fremstilles også: 1-(4'-fluorfenyl)-3-(1-(2-imidazolidinon-l-yletyl)-4-piper-idyl)-lH-indol. ( Lu 23- 086). Smp 174-175° C. 1-(4<1->fluorfenyl)-3-(1-(l-pyrrolidin-2-onyletyl)-4-piperi-dyl)5-trifluormetyl-lH-indol, fumarat. ( Lu 23- 158). Smp 240-241° C. 5-klor-l-(4'-fluorfenyl)-3-(1-(2-imidazolidinon-l-yletyl)-4 -piperidyl)-lH-indol, maleat. ( Lu 23- 174). Smp 155-160° C. Also prepared in a similar way: 1-(4'-fluorophenyl)-3-(1-(2-imidazolidinone-1-ylethyl)-4-piperidyl)-1H-indole. (Lu 23-086). Mp 174-175° C. 1-(4<1->fluorophenyl)-3-(1-(1-pyrrolidin-2-onyletyl)-4-piperidyl)5-trifluoromethyl-1H-indole, fumarate. (Lu 23-158). Mp 240-241° C. 5-Chloro-1-(4'-fluorophenyl)-3-(1-(2-imidazolidinon-1-ylethyl)-4-piperidyl)-1H-indole, maleate. (Lu 23-174). mp 155-160° C.

Eksempel 3 Example 3

(Metode c) (Method c)

3-(1-metyl-l,2,3,6-tetrahydropyridin-4-yl)-5-nitro-l-pyridin-3-yl-lH-indol. ( Lu 24- 016). 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1-pyridin-3-yl-1H-indole. (Lu 24-016).

3-(1-metyl-l,2,3,6-tetrahydropyridin-4-yl)-5-nitro—lHindol (4.5 g), 3-brompyridin (6.0 g), CuBr (4.5 g) og K2C03 (8.0 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1Hindole (4.5 g), 3-bromopyridine (6.0 g), CuBr (4.5 g) and K2CO3 (8.0

g) ble oppvarmet under røring ved 160° C i 2.5 time. Etter avkjøling ble reaksjonsblandingen helt på fortynnet NH40H g) was heated with stirring at 160° C for 2.5 hours. After cooling, the reaction mixture was poured onto dilute NH 4 OH

(500 ml) og ekstrahert med etylacetat (2 x 3 00 ml). De kombinerte organiske faser ble tørket (MgS04) og oppløs-ningsmiddelet fordampet. Tittelforbindelsen ble oppnådd ved (500 ml) and extracted with ethyl acetate (2 x 300 ml). The combined organic phases were dried (MgSO 4 ) and the solvent evaporated. The title compound was obtained by

omkrystallisering fra aceton. Utbytte: 3.4.g (58%). Smp 175-177°C. recrystallization from acetone. Yield: 3.4.g (58%). M.p. 175-177°C.

På lignende måte fremstilles også: 3-(1-metyl-l,2,3,6-tetrahydropyridin-4-yl)-5-nitro-l-pyridin-2-yl-lH-indol. ( Lu24- 015). Smp. 134°C. Also prepared in a similar way: 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1-pyridin-2-yl-1H-indole. (Lu24-015). Temp. 134°C.

3-(1-metyl-l,2,3,4-tetrahydropyridin-4-yl)-5-nitro-l-(2-tiazolo-lH-indol. Lu24- 022). Smp. 204-206°C. 3-(1-methyl-1,2,3,4-tetrahydropyridin-4-yl)-5-nitro-1-(2-thiazolo-1H-indole. Lu24-022). Temp. 204-206°C.

5-klor-3-(1-metyl-l,2,3,6-tetrahydropyridin-4-yl)-1-(3-tienyl)-lH-indol, maleat. ( Lu 24- 001). Smp. 168-170°C. 5-Chloro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(3-thienyl)-1H-indole, maleate. (Lu 24-001). Temp. 168-170°C.

3-(1-metyl-l,2,3,6-tetrahydropyridin-4-yl)-5-nitro-l-(2-tienyl)-lH-indol, maleat. ( Lu 24- 014). Smp. 206-208°C. 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1-(2-thienyl)-1H-indole, maleate. (Lu 24-014). Temp. 206-208°C.

Eksempel 4 Example 4

(metode c og e) (method c and e)

5-klor-l-(4<1->fluorfenyl)-3-(1-metyl-l,2,3,6-tetrahydropyridin-4-yl)-lH-indol, hydrobromid. ( Lu 22- 117). 5-Chloro-1-(4<1->fluorophenyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, hydrobromide. (Lu 22-117).

5-klor-3-(1-karbetoksy-l,2,3,6-tetrahydropyridin-4-yl)-1H-indol (10 g), 1,4-fluorjodbenzen (15 g), CuBr (10 g) og K2C03 (15 g) i HMPA (50 ml) ble oppvarmet (180-200°C) under røring i 3 timer. Etter avkjøling ble reaksjonsblandingen helt på H20 (1 liter) og etylendiamin (100 ml). Råproduktet ble oppnådd ved ekstrahering to ganger med eter/etylacetat (2:1). De kombinerte organiske faser ble tørket (MgS04) og oppløsningsmiddelet fordampet. Det rene 5-klor-l-(41 - fluorfenyl)-3-(1-karbetoksy-l ;2,3,6tetrahydropyridin-4-yl)-lH-indol ble oppnådd ved kolonnekromatografi på silikagel (eluent 30% eter i diklormetan). Utbytte: 8,9 g (68%). Smp. 120-122°C. Karbetoksyforbindelsen som så ble oppnådd (3 g) ble oppløst i tørr THF (50 ml) og LiAlH4-pellets (2g) ble tilsatt. Blandingen ble kokt under tilbakeløp i 1 time, avkjølt, og H20/THF ble tilsatt for å ødelegge overflødig 5-chloro-3-(1-carbethoxy-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (10 g), 1,4-fluoroiodobenzene (15 g), CuBr (10 g) and K 2 CO 3 (15 g) in HMPA (50 mL) was heated (180-200 °C) with stirring for 3 h. After cooling, the reaction mixture was poured onto H 2 O (1 L) and ethylenediamine (100 mL). The crude product was obtained by extraction twice with ether/ethyl acetate (2:1). The combined organic phases were dried (MgSO 4 ) and the solvent evaporated. The pure 5-chloro-1-(41-fluorophenyl)-3-(1-carbethoxy-1;2,3,6tetrahydropyridin-4-yl)-1H-indole was obtained by column chromatography on silica gel (eluent 30% ether in dichloromethane ). Yield: 8.9 g (68%). Temp. 120-122°C. The carbethoxy compound thus obtained (3 g) was dissolved in dry THF (50 ml) and LiAlH 4 pellets (2 g) were added. The mixture was refluxed for 1 h, cooled, and H 2 O/THF was added to destroy excess

LiAlH4. Presipitatet ble filtrert av og THF fordampet. Den gjenværende olje ble oppløst i aceton, og tittelforbindelsen ble utskilt, som hydrobromidsalt. Utbytte: 2,4 g (75%). LiAlH4. The precipitate was filtered off and the THF evaporated. The remaining oil was dissolved in acetone and the title compound separated as the hydrobromide salt. Yield: 2.4 g (75%).

Smp. 285°C. Temp. 285°C.

På lignende måte fremstilles også: 5-klor-l-(4<1->fluorfenyl)-3-(1-isobutyl-l,2,3,6-tetrahydropyridin-4-yl)-lH-indol, hydrobromid. ( Lu 22- 134). Also prepared in a similar way: 5-chloro-1-(4<1->fluorophenyl)-3-(1-isobutyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, hydrobromide. (Lu 22-134).

Smp. 285-286°C. Temp. 285-286°C.

5-fluor-3-(1-metyl-l,2,3,6-tetrahydropyridin-4-yl)-1-(2-tiazolo)-lH-indol, fumarat. ( Lu 24- 013). Smp. 190194°C. 5-fluoro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(2-thiazolo)-1H-indole, fumarate. (Lu 24-013). Temp. 190194°C.

Eksempel 5 Example 5

(metode d) (method d)

5-fluor-1-(4'-fluorfenyl)-3-(1-^-imidazolidinon-l-yletyl)-1,2,3,6-tetrahydropyridin-4-yl)-lH-indol, oksalat. ( Lu 21-046) . 5-Fluoro-1-(4'-fluorophenyl)-3-(1-^-imidazolidinon-1-ylethyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, oxalate. (Lu 21-046).

5-fluor-1-(4<1->fluorfenyl)-3-(1,2,3,6-tetrahydropyridin4-yl)-lH-indol (2g) fremstilt som beskrevet i eksempel 1; 1-kloretyl-2-imidazolidinon (2g), K2CO3 (3g) og en liten krystall av Kl ble kokt under tilbakeløp i metyl isobutyl-keton (50 ml) i 16 timer. Reaksjonsblandingen ble helt på H20 og CH2Cl2 (2 00 ml) ble tilsatt. Den organiske fase ble separert, tørket (MgS04) og oppløsningsmiddelet fordampet. Råproduktet ble oppløst i aceton og utskilt som et oksalat-salt. Utbytte: 1,2 g (36%). Smp. 186-189°C. 5-fluoro-1-(4<1->fluorophenyl)-3-(1,2,3,6-tetrahydropyridin4-yl)-1H-indole (2g) prepared as described in Example 1; 1-Chloroethyl-2-imidazolidinone (2g), K2CO3 (3g) and a small crystal of K1 were refluxed in methyl isobutyl ketone (50ml) for 16h. The reaction mixture was poured onto H 2 O and CH 2 Cl 2 (200 mL) was added. The organic phase was separated, dried (MgSO 4 ) and the solvent evaporated. The crude product was dissolved in acetone and separated as an oxalate salt. Yield: 1.2 g (36%). Temp. 186-189°C.

På lignende måte fremstilles de følgende indoler: 1-(4'-fluorfenyl)-3-(4-(2-imidazolidinon-l-yletyl)-1-pipe-razino)-5-trifluormetyl-lH-indol, dihydrobromid. ( Lu 23-001). Smp. 262-263°C. In a similar manner, the following indoles are prepared: 1-(4'-fluorophenyl)-3-(4-(2-imidazolidinone-1-ylethyl)-1-piperazino)-5-trifluoromethyl-1H-indole, dihydrobromide. (Lu 23-001). Temp. 262-263°C.

1-(4'-fluorfenyl)-3-(4-(2-pyrrolidin-2-onyletyl)-1-pipe- 1-(4'-fluorophenyl)-3-(4-(2-pyrrolidin-2-onylethyl)-1-pipe-

razino)-5-trifluormetyl-lH-indol. ( Lu 22- 133). Smp. 224-227°C. razino)-5-trifluoromethyl-1H-indole. (Lu 22-133). Temp. 224-227°C.

1-(4<1->fluorfenyl)-5-nitro-3-(l-pyrrolidin-2-onyletyl)-1,2-3,6-tetrahydropyridin-4-yl)-lH-indol, hydroklorid ( Lu 2 3-024). Smp. 263-265°C. 1-(4<1->fluorophenyl)-5-nitro-3-(1-pyrrolidin-2-onyethyl)-1,2-3,6-tetrahydropyridin-4-yl)-1H-indole, hydrochloride ( Lu 2 3-024). Temp. 263-265°C.

1-(4'-fluorfenyl)-3-(1-(2-imidazolidinon-l-yletyl)-1,2,36-tetrahydropyridin-4-yl)-lH-indol, hydroklorid. ( Lu 2 3-075). Smp. 259-262°C. 1-(4'-Fluorophenyl)-3-(1-(2-imidazolidinon-1-ylethyl)-1,2,36-tetrahydropyridin-4-yl)-1H-indole, hydrochloride. (Lu 2 3-075). Temp. 259-262°C.

1-(4<1->fluorfenyl)-5-nitro-3-(1-(2-oksazolidinon-3-yletyl)-1,2,3,6-tetrahydropyridin-4-yl)-lH-indol, maleat. ( Lu 23-134). Smp. 128-130°C. 1-(4<1->fluorophenyl)-5-nitro-3-(1-(2-oxazolidinon-3-ylethyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, maleate . (Lu 23-134). Temp. 128-130°C.

1-(4<1->fluorfenyl)-3-(1-(2-imidazolidinon-l-yletyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-lH-indol. ( Lu 23- 142). Smp. 177-179°C. 1-(4<1->fluorophenyl)-3-(1-(2-imidazolidinon-1-ylethyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1H-indole. (Lu 23-142). Temp. 177-179°C.

5-klor-l-(4<1->fluorfenyl)-3-(1-(2-imidazolidinon-l-yletyl) - 1,2,3,6-tetrahydropyridin-4-yl)-lH-indol. ( Lu 23- 148). Smp. 138-140°C. 5-chloro-1-(4<1->fluorophenyl)-3-(1-(2-imidazolidinon-1-ylethyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole. (Lu 23-148). Temp. 138-140°C.

1-(4'-fluorfenyl)-3-(1-(2-imidazolidinon-l-yletyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-trifluormetyl-lH-indol. ( Lu 23-157) . Smp. 164-165"C". 1-(4'-Fluorophenyl)-3-(1-(2-imidazolidinon-1-ylethyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-trifluoromethyl-1H-indole. (Lu 23-157). Temp. 164-165"C".

1-(2'-fluorfenyl)-3-(1-(2-imidazolidinon-l-yletyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-lH-indol, maleat. ( Lu 24-024). Smp. 200°C. 1-(2'-Fluorophenyl)-3-(1-(2-imidazolidinon-1-ylethyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1H-indole, maleate. (Lu 24-024). Temp. 200°C.

Eksempel 6 Example 6

(Metode e) (Method e)

1-(4'fluorfenyl)-3-(l-pyrrol-2-etyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-trifluormetyl-lH-indol, maleat. ( Lu 23-172) . 1-(4'Fluorophenyl)-3-(1-pyrrole-2-ethyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-trifluoromethyl-1H-indole, maleate. (Lu 23-172).

1-(4<1->fluorfenyl)-3-(l-pyrrol-2-aceto)-1,2,3,6-tetrahydro- 1-(4<1->fluorophenyl)-3-(1-pyrrole-2-aceto)-1,2,3,6-tetrahydro-

pyridin-4-yl)-5-trifluormetyl-lH-indol (2,5 g) ble oppvarmet under tilbakeløp med LiAlH4 (lg) i tørr THF (50 ml) i 1,5 timer. Etter avkjøling ble H20/THF tilsatt for å ødelegge overflødig LiAlH4. Presipitatet ble filtrert av og THF inndampet. Den gjenværende olje ble oppløst i 2-propanol og tittelforbindelsen ble utskilt som et maleat. Utbytte: 1,3 g (42%). Smp. 194-195°C. pyridin-4-yl)-5-trifluoromethyl-1H-indole (2.5 g) was heated under reflux with LiAlH 4 (1g) in dry THF (50 mL) for 1.5 h. After cooling, H 2 O/THF was added to destroy excess LiAlH 4 . The precipitate was filtered off and the THF was evaporated. The remaining oil was dissolved in 2-propanol and the title compound separated as a maleate. Yield: 1.3 g (42%). Temp. 194-195°C.

På lignende måte fremstilles også: 1-(4<1->fluorfenyl)-3-(1-(2-metyl-l-imidazol-2-etyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-trifluormetyl-lH-indol, di-fumarat. ( Lu 23- 173). Smp. 189-191°C. Also prepared in a similar way: 1-(4<1->fluorophenyl)-3-(1-(2-methyl-1-imidazol-2-ethyl)-1,2,3,6-tetrahydropyridin-4-yl) -5-trifluoromethyl-1H-indole, di-fumarate. (Lu 23-173). Temp. 189-191°C.

1-(4'fluorfenyl)-3-(1-(l-imidazol-2-etyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-trifluormetyl-lH-indol, dimaleat. ( Lu 24- 002). Smp. 165-167°C. 1-(4'Fluorophenyl)-3-(1-(1-imidazol-2-ethyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-trifluoromethyl-1H-indole, dimaleate. (Lu 24-002). Temp. 165-167°C.

Eksempel 7 Example 7

(metode f) (method f)

1- ((4'-fluorfenyl)-3-(4-metylpiperazin)-5-trifluormetyllH-indol, dihydroklorid. ( Lu 21- 12 3). 1- ((4'-fluorophenyl)-3-(4-methylpiperazine)-5-trifluoromethyl 1H-indole, dihydrochloride. ( Lu 21- 12 3).

2- karboksymetyl-l-(4 »-fluorfenyl)-5-trifluormetylindolin3-on (15 g) og MgCl2.6 H20 (30 g) i HMPA (100 ml) ble oppvarmet under N2 ved 120-140°C i time og til slutt ved 150°C i ytterligere 1/2 time. 1-metylpiperazin (25 ml) ble tilsatt, og blandingen ble kokt under tilbakeløp under N2 ved en oljebadtemperatur på 200°C i 16 timer. Blandingen ble avkjølt og helt på 1 liter H20 og ekstrahert med eter (3 x 200 ml). De kombinerte eterekstrakter ble vasket med 0,5 M HC1 (3 x 300 ml). Den sure H20-fase ble gjort alkalisk og reekstrahert med eter (2 x 2 00 ml). Den kombinerte organiske fase ble tørke (MgS04) og eter fordampet. Den gjenværende olje ble oppløst i aceton og tittelforbindelsen ble utskilt som et dihydroklorid. 2-Carboxymethyl-1-(4»-fluorophenyl)-5-trifluoromethylindolin3-one (15 g) and MgCl2.6H2O (30 g) in HMPA (100 ml) were heated under N2 at 120-140°C for 1 hour and finally at 150°C for another 1/2 hour. 1-Methylpiperazine (25 mL) was added and the mixture was refluxed under N 2 at an oil bath temperature of 200°C for 16 hours. The mixture was cooled and poured into 1 L of H 2 O and extracted with ether (3 x 200 mL). The combined ether extracts were washed with 0.5 M HCl (3 x 300 mL). The acidic H 2 O phase was made alkaline and back-extracted with ether (2 x 200 mL). The combined organic phase was dried (MgSO 4 ) and the ether evaporated. The remaining oil was dissolved in acetone and the title compound separated as a dihydrochloride.

Utbytte: 6,7 g (35%). Smp. 245-247°C. Yield: 6.7 g (35%). Temp. 245-247°C.

På lignende måte fremstilles de følgende 3-piperazin-indoler: 1-(4<1->fluorfenyl)-3-(4-(2-hydroksyetyl)piperazino-5-trifluormetyl-lH-indol. Lu 21- 152) . Smp. 168°C. The following 3-piperazine-indoles are prepared in a similar manner: 1-(4<1->fluorophenyl)-3-(4-(2-hydroxyethyl)piperazino-5-trifluoromethyl-1H-indole. Lu 21-152). Temp. 168°C.

1-(4<1->fluorfenyl)-3-piperazino-5-trifluormetyl-lH-indol. 1-(4<1->Fluorophenyl)-3-piperazino-5-trifluoromethyl-1H-indole.

( Lu 21- 153) . Smp. 168-17CTC. (Lu 21-153). Temp. 168-17CTC.

1-(4'-fluorfenyl)-3-(4-isopropyl-piperzin)-5-trifluormetyl-lH-indol, dihydroklorid. ( Lu 23- 016). Smp. 278280°C. 1-(4'-Fluorophenyl)-3-(4-isopropyl-piperzine)-5-trifluoromethyl-1H-indole, dihydrochloride. (Lu 23-016). Temp. 278280°C.

5-klor-3-(4-metylpiperazino)-1-fenyl-lH-indol. ( Lu 23015). Smp. 174-175°C. 5-Chloro-3-(4-methylpiperazino)-1-phenyl-1H-indole. (Lu 23015). Temp. 174-175°C.

Eksempel 8 Example 8

(metode g) (method g)

1-(4'-fluorfenyl)-5-metyl-3-(l-metyl-4-piperidyl)-lH-indol, hydrobromid. ( Lu 21- 037). 1-(4'-Fluorophenyl)-5-methyl-3-(1-methyl-4-piperidyl)-1H-indole, hydrobromide. (Lu 21-037).

Til 14 g Mg-spon ble det tilsatt 4-klor-l-metyl -pyridin (35 To 14 g of Mg shavings was added 4-chloro-1-methyl-pyridine (35

g) i tørr THF (500 ml). Blandingen ble kokt under tilbake-løp i 1 time og filtrert under N2 til en isavkjølt oppløs-ning av 1-(4'-fluorfenyl)-5-metylisatin (60 g) i tørr THF (500 ml). Blandingen ble oppvarmet under tilbakeløp og helt på H20 (1 liter) mettet med NH4C1 og ekstrahert med eter (2 x 300 ml). De kombinerte organiske faser ble tørket (MgS04), eteren fordampet og ga 48,5 g (58%) av l-(4'-fluorfenyl)-3-hydroksy-5metyl-3-(l-metyl-4-piperidyl)-indolin-2-on. Blandingen ble kokt under tilbakeløp i 1 time, overflødig LiAlH4 ble ødelagt ved tilsetning av H20 THF og filtrert; og 2 M HC1 (500 ml) ble tilsatt til filtratet og forsiktig oppvarmet. H20-fasen ble gjort alkalisk og produktet ekstrahert med eter (2 x 300 ml). De kombinerte eterfaser ble tørket (MgS04) og eteren fordampet. Den gjenværende olje ble oppløst i aceton, og 1-(4'-fluor-fenyl ) -5-metyl-3- (l-metyl-4piperidyl) indolin-2-on ble utskilt som et oksalat. Utbytte: 2,0 g (66%). Smp. 222°C. Til en oppløsning av B2H6 i THF (100 ml) holdt under N2 ved 0°C ble det tilsatt 11,0 g av oksalatsaltet fremstilt som ovenfor. Blandingen ble sakte oppvarmet til 50'C og holdt der i 2 timer. Den ble til slutt helt på is (1 liter) og ekstrahert med eter (2 x 200 ml). De kombinerte eterfaser ble tørket (MgS04) og eteren fordampet. Den gjenværende olje ble oppløst i 2-propanol, og tittelforbindelsen ble utskilt som et hydrobromidsalt. Utbytte: 3,7 g (36%). g) in dry THF (500 mL). The mixture was refluxed for 1 hour and filtered under N 2 to an ice-cooled solution of 1-(4'-fluorophenyl)-5-methylisatin (60 g) in dry THF (500 mL). The mixture was heated under reflux and poured into H 2 O (1 liter) saturated with NH 4 Cl and extracted with ether (2 x 300 mL). The combined organic phases were dried (MgSO 4 ), the ether evaporated to give 48.5 g (58%) of 1-(4'-fluorophenyl)-3-hydroxy-5methyl-3-(1-methyl-4-piperidyl)- indolin-2-one. The mixture was refluxed for 1 h, excess LiAlH 4 was destroyed by addition of H 2 O THF and filtered; and 2 M HCl (500 mL) was added to the filtrate and gently warmed. The H 2 O phase was made alkaline and the product extracted with ether (2 x 300 mL). The combined ether phases were dried (MgSO 4 ) and the ether evaporated. The remaining oil was dissolved in acetone, and 1-(4'-fluoro-phenyl)-5-methyl-3-(1-methyl-4-piperidyl)indolin-2-one was separated as an oxalate. Yield: 2.0 g (66%). Temp. 222°C. To a solution of B 2 H 6 in THF (100 ml) maintained under N 2 at 0°C was added 11.0 g of the oxalate salt prepared as above. The mixture was slowly heated to 50°C and held there for 2 hours. It was finally poured onto ice (1 L) and extracted with ether (2 x 200 mL). The combined ether phases were dried (MgSO 4 ) and the ether evaporated. The remaining oil was dissolved in 2-propanol and the title compound separated as a hydrobromide salt. Yield: 3.7 g (36%).

Smp. 254256"C. Temp. 254256"C.

Eksempel 9 Example 9

5-amino-l-(4'-fluorfenyl)-3-(1-metyl-l,2,3,6-tetrahydropyridin-4-yl)-lH-indol, fumarat. ( Lu 23- 149). 5-amino-1-(4'-fluorophenyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, fumarate. (Lu 23-149).

1-(4'-fluorfenyl)-3-(1-metyl-l,2,3,6-tetrahydropyridin4-yl)-5-nitro-lH-indol (Lu 22-135) (10 g) i 90% etanol (150 1-(4'-fluorophenyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin4-yl)-5-nitro-1H-indole (Lu 22-135) (10 g) in 90% ethanol (150

ml) ble oppvarmet under tilbakeløp, og fortynnet HC1 (2 ml) og Fe-pulver (5g) ble tilsatt i løpet av 0,5 timer. Koking under tilbakeløp fortsatte ytterligere en time. Reaksjonsblandingen ble filtrert, avkjølt og deretter helt på 1 mL) was heated under reflux, and dilute HCl (2 mL) and Fe powder (5 g) were added over 0.5 h. Boiling under reflux continued for another hour. The reaction mixture was filtered, cooled and then poured into 1

liter NH4OH og ekstrahert med etylacetat (2 x 400 ml). Den gjenværende olje ble renset ved kolonnekromatografi på silikagel (eluert med etylacetat/metanol 1:1 inneholdende 2% trietylamin). Tittelforbindelsen ble til slutt utskilt som et fumarat fra etanol/aceton (1:1). Utbytte 4,2 g (34%). Smp.. 128-134°C. liter of NH4OH and extracted with ethyl acetate (2 x 400 ml). The remaining oil was purified by column chromatography on silica gel (eluted with ethyl acetate/methanol 1:1 containing 2% triethylamine). The title compound was finally isolated as a fumarate from ethanol/acetone (1:1). Yield 4.2 g (34%). M.p. 128-134°C.

Eksempel 10 l-(4'-fluorfenyl)-3-(4-(2-(pyrrolidin-2-tion-l-yl)-etyl)-1-piperazino)-5-trifluormetyl-lH-indol ( Lu 23- 018) . Example 10 1-(4'-fluorophenyl)-3-(4-(2-(pyrrolidin-2-thion-1-yl)-ethyl)-1-piperazino)-5-trifluoromethyl-1H-indole ( Lu 23- 018).

Pyrrolidonylindolderiva:;et (Lu 22-133) 2,8 g) fremstilt i eksempel 4 og p-metoksyfenyltionofosfinsulfid-dimer (2,0 g) Pyrrolidonylidene derivative (Lu 22-133) 2.8 g) prepared in Example 4 and p-methoxyphenylthiophosphine sulphide dimer (2.0 g)

(Lawesson reagens) ble oppvarmet i HMPA (25 ml) ved 110 "C i 1 time. Reaksjonsblandingen ble helt på H20 (500 ml) og (Lawesson's reagent) was heated in HMPA (25 mL) at 110 °C for 1 h. The reaction mixture was poured onto H 2 O (500 mL) and

K2C03 (10 g) ble tilsatt. Produktet ble ekstrahert med eter inneholdende 10% etylacetat (2 x 200 ml). De kombinerte organiske faser ble tørket (MgS04), oppløsningsmiddelet fordampet, og det resulterende krystallinske produkt ble rekrystallisert fra etanol som ga utbytte 2,1 g (73%) av tittelforbindelsen. Smp. 199-201°C. K 2 CO 3 (10 g) was added. The product was extracted with ether containing 10% ethyl acetate (2 x 200 ml). The combined organic phases were dried (MgSO 4 ), the solvent evaporated, and the resulting crystalline product was recrystallized from ethanol to yield 2.1 g (73%) of the title compound. Temp. 199-201°C.

Eksempel 11 Example 11

3-(4-(1-acetyloksyetyl)-1-piperazino)-1-(4<1->fluorfenyl)5-trifluormetyl-lH-indol. ( Lu 23- 161). 3-(4-(1-acetyloxyethyl)-1-piperazino)-1-(4<1->fluorophenyl)5-trifluoromethyl-1H-indole. (Lu 23-161).

1-(4<1->fluorfenyl)-3-(4-(2-hydroksyetyl)-1-piperazino)-5-trifluormetyl-lH-indol (Lu 21-152) (5g) ble oppvarmet under tilbakeløp i aceton (50 ml). Acetylklorid (2 ml) ble sakte tilsatt. Koking under tilbakeløp fortsatte i 1,5 timer. Oppløsningsmiddelet ble fordampet, og den gjenværende olje ble ekstrahert med CH2C12 (2 x 200 ml) fra NH4OH ved pH 10. De kombinerte organiske faser ble tørket (MgS04) og oppløsningsmiddelet fordampet. Tittelforbindelsen ble utskilt fra eter. Utbytte: 3,7 g (72%). Smp. 129-131°C. 1-(4<1->fluorophenyl)-3-(4-(2-hydroxyethyl)-1-piperazino)-5-trifluoromethyl-1H-indole (Lu 21-152) (5g) was heated under reflux in acetone ( 50 ml). Acetyl chloride (2 mL) was slowly added. Refluxing continued for 1.5 hours. The solvent was evaporated and the remaining oil was extracted with CH 2 Cl 2 (2 x 200 mL) from NH 4 OH at pH 10. The combined organic phases were dried (MgSO 4 ) and the solvent was evaporated. The title compound was isolated from ether. Yield: 3.7 g (72%). Temp. 129-131°C.

På lignende måte ble de følgende esterifiserte indolderivater fremstilt: 3-(4-(1-dekanoyloksyetyl)-1-piperazino)-1-(4'-fluorfenyl)5-trifluormetyl-lH-indol. ( Lu 23- 162). Smp. 71-73°C. l-(4'-fluorfenyl)-3-(4-(1-oleyloksyetyl)-1-piperazino)-5-trifluormetyl-lH-indol, dihydroklorid. (Lu 23-163). Smp. 158-162°C. In a similar manner, the following esterified indole derivatives were prepared: 3-(4-(1-decanoyloxyethyl)-1-piperazino)-1-(4'-fluorophenyl)5-trifluoromethyl-1H-indole. (Lu 23-162). Temp. 71-73°C. 1-(4'-fluorophenyl)-3-(4-(1-oleyloxyethyl)-1-piperazino)-5-trifluoromethyl-1H-indole, dihydrochloride. (Lu 23-163). Temp. 158-162°C.

Forbindelsene med formel I ble testet i henhold til polit-lige og velkjente farmakologiske forsøk som følger: The compounds of formula I were tested according to political and well-known pharmacological tests as follows:

1. Metvlfenidat antagonisme 1. Metvlphenidate antagonism

Den hemmende effekt av testsubstansene på den metylfenidat-induserte gnaging i mus bestemmes som beskrevet av Pedersen og Christensen (1972). The inhibitory effect of the test substances on methylphenidate-induced gnawing in mice is determined as described by Pedersen and Christensen (1972).

Testsubstansen gis intraperitonealt i forskjellige doser, mens metylfenidat gis subkutant i dosen 60 mg/kg, 1/2, 2 eller 24 timer etter injeksjon av forsøkssubstansen. Pr. dose av forsøkssubstansen anvendes 3x2 mus ( , 18-25 g). Resultatene gis i fraksjoner: 0/3, 1/3, 2/3 og 3/3, der 0, 1. 2 og 3 er antall par hvilke ikke begynte gnaging etter mottak av forsøkssubstansene. The test substance is given intraperitoneally in different doses, while methylphenidate is given subcutaneously in a dose of 60 mg/kg, 1/2, 2 or 24 hours after injection of the test substance. 3x2 mice ( , 18-25 g) are used per dose of the test substance. The results are given in fractions: 0/3, 1/3, 2/3 and 3/3, where 0, 1, 2 and 3 are the number of pairs which did not start gnawing after receiving the test substances.

Ref: Ref:

Pedersen, V. og Christensen, A.V.: Acta Pharmacol. et toxicol. 31, 488-496, 1972. Pedersen, V. and Christensen, A.V.: Acta Pharmacol. a toxicol. 31, 488-496, 1972.

2. Katalepsi 2. Catalepsy

Evaluering av katalepsi gjøres i henhold til Arnt (1983). Rotten plasseres på et vertikalt ståltrådnett (nettdiameter 12 mm) og betraktes som kataleptisk hvis den forblir immobil i mer enn 15 sekunder. Antall kataleptiske rotter i liver dosegruppe bestemmes hver time, 1-6 timer og 24 timer etter peritoneal administrering av forsøksforbindelsen. Det maksimale antall kataleptiske rotter i hver av minst 3 dosegrupper som hver består av minst 4 rotter, nedtegnes. Dette antall anvendes ved beregningene av ED5g-verdiene ved log-probit-analyse. Evaluation of catalepsy is done according to Arnt (1983). The rat is placed on a vertical wire mesh (mesh diameter 12 mm) and considered cataleptic if it remains immobile for more than 15 seconds. The number of cataleptic rats in the liver dose group is determined every hour, 1-6 hours and 24 hours after peritoneal administration of the test compound. The maximum number of cataleptic rats in each of at least 3 dose groups, each consisting of at least 4 rats, is recorded. This number is used in the calculations of the ED5g values by log-probit analysis.

Ref. : Ref. :

Arnt, J.: European J. Pharmacol. 90, 47-55, 1983. Arnt, J.: European J. Pharmacol. 90, 47-55, 1983.

3. Quipazinhemminq 3. Quipazinehemminq

Quipazin og en rekke andre forbindelser som øker 5-HT2-reseptor aktiviteten i det sentrale nervesystem, induserer en karakteristisk rask risting (rykking) av hodet. Denne respons hemmes av 5-HT2-reseptor antagonister (Vetulani et al. 1980, Arnt et al. 1984). Quipazine and a number of other compounds that increase 5-HT2 receptor activity in the central nervous system induce a characteristic rapid shaking (jerking) of the head. This response is inhibited by 5-HT2-receptor antagonists (Vetulani et al. 1980, Arnt et al. 1984).

Testforbindelsen eller en saltoppløsning injiseres subkutant 2 timer før en subkutan injeksjon av quipazinhemi-maleat (15 pmol/kg) . Minst 3 doseringsgrupper, hver bestå-ende av minst 4 rotter, benyttes. Rottene plasseres indivi-duelt i observasjonsbur (12 x 25 cm), og antall hode rykninger telles 30-40 minutter etter quipazin administrer-ingen. Hemming av hoderykninger uttrykkes i prosent pr. antall hoderykninger i kontrollgruppen. ED50 verdiene be-regnes ved log-probit analyse. The test compound or a saline solution is injected subcutaneously 2 hours before a subcutaneous injection of quipazine hemi-maleate (15 pmol/kg). At least 3 dosage groups, each consisting of at least 4 rats, are used. The rats are placed individually in observation cages (12 x 25 cm), and the number of head twitches is counted 30-40 minutes after quipazine administration. Inhibition of head twitching is expressed as a percentage per number of head twitches in the control group. The ED50 values are calculated by log-probit analysis.

Ref. : Ref. :

Vetulani, J., B.B. Beduarczyk, K. Reichenberg og A. Rokost: Neuropharmacology 19., 155-158, 1983. Vetulani, J., B.B. Beduarczyk, K. Reichenberg and A. Rokost: Neuropharmacology 19., 155-158, 1983.

Arnt, J., J. Hyttel og J.-J. Larsen: Acta pharmacol. et toxicol. 55, 363-372, 1984. Arnt, J., J. Hyttel and J.-J. Larsen: Acta pharmacol. a toxicol. 55, 363-372, 1984.

4. 3 H- spiroperidol bindin<g>er 4. 3 H- spiroperidol bindin<g>er

Affiniteten av forbindelser til dopamin (DA) D-2-reseptorer og serotonin2~(5-HT2)-reseptorer ble bestemt ved hjelp av in vitro reseptorbindingsteknikker. Binding av <3>H-spiroperidol til DA-D-2-reseptorer i rotte-striatalmembraner og til 5-HT2 reseptorer i rotte-kortikalmembraner ble bestemt som beskrevet detaljert av Arnt et al. (1984). The affinity of compounds for dopamine (DA) D-2 receptors and serotonin2~(5-HT2) receptors was determined using in vitro receptor binding techniques. Binding of <3>H-spiroperidol to DA-D-2 receptors in rat striatal membranes and to 5-HT2 receptors in rat cortical membranes was determined as described in detail by Arnt et al. (1984).

Ref. : Ref. :

Arnt, J., J. Hyttel og J.-J. Larsen: Acta phamacol. et toxicol. 55, 363-372, 1984. Arnt, J., J. Hyttel and J.-J. Larsen: Acta phamacol. a toxicol. 55, 363-372, 1984.

Konklusjon til tabell 1 Conclusion to table 1

Forsøkene metylfenidatantagonisme (MePh Antg.), katalepsi og <3>H-spiroperidolbinding (Da-2) er alle undersøkelse av DA-antagonistisk virkning og dermed av neuroleptisk virkning. Resultatene av disse forsøk i tabell 1 viser at de nye forbindelser har sterk DA-antagonistisk virkning (samme som referanseforbindelsene klorpromazin, cis(Z)flupentixol, haloperidol, tefludazin). Virkningen av forbindelsene sees også å være langt sterkere enn virkningen av den nærmest beslektede forbindelse 5-klor-3-(l-(2-hydroksyetyl)-1,2,3,6-tetrahydropipid-4-yl)-indol (Lu 23-143) (EP publ. nr. 22705) som er angitt å være neuroleptisk. Heller ikke 1-fenyl-5-klor-3-metylpiperazinindol (Lu 23-015) (tysk utlegn.skrift nr. 2811031) som er tillagt analgetiske og anti-inflammatoriske egenskaper, har interessante effekter i disse forsøk. The experiments methylphenidate antagonism (MePh Antg.), catalepsy and <3>H-spiroperidol binding (Da-2) are all investigations of DA-antagonistic action and thus of neuroleptic action. The results of these tests in table 1 show that the new compounds have strong DA-antagonistic action (same as the reference compounds chlorpromazine, cis(Z)flupentixol, haloperidol, tefludazine). The effect of the compounds is also seen to be far stronger than the effect of the closely related compound 5-chloro-3-(1-(2-hydroxyethyl)-1,2,3,6-tetrahydropipid-4-yl)-indole (Lu 23 -143) (EP publ. no. 22705) which is indicated to be neuroleptic. Nor does 1-phenyl-5-chloro-3-methylpiperazineindole (Lu 23-015) (German publication no. 2811031), which has been attributed analgesic and anti-inflammatory properties, have interesting effects in these experiments.

Forsøkene quipazinhemming og <3>H-spiroperidolbinding (5HT2) er tester på affinitet til 5HT2-reseptorer. Resultatene av disse forsøk viser at de nye forbindelser har sterk 5HT2-antagonistisk virkning, like sterk som referanseforbindelsene og meget sterkere enn Lu 23-143. The experiments quipazine inhibition and <3>H-spiroperidol binding (5HT2) are tests of affinity to 5HT2 receptors. The results of these tests show that the new compounds have strong 5HT2-antagonistic action, as strong as the reference compounds and much stronger than Lu 23-143.

Claims

1. Analogy method for the preparation of a therapeutically active indole derivative with the following general formula: wherein R is phenyl, optionally substituted with halogen, trifluoromethyl or an aromatic group, such as 2-thienyl, 3-thienyl, 2-thiazolyl, 2-pyridyl, 3-pyridyl or 4-pyridyl; R<1> is hydrogen, halogen, lower alkyl, nitro, trifluoromethyl or amino; "A" is nitrogen or carbon, and the dashed line indicates - when A is carbon - a possible bond, R<2> is hydrogen, lower alkyl optionally substituted with a hydroxy group, whereby any hydroxy group present may optionally be esterified with an aliphatic carboxylic acid residue having from 2 to 24 carbon atoms or R<2> is the group where "n" is an integer from 2-4, X is oxygen or sulfur, or C=X can form the group CH= when Y is =N-or =CH-, Y is oxygen, CH2 or NH, Z is - (CH2)m-, "m" is 2 or 3 and Z is -CH=CH-, U is nitrogen or carbon with the proviso that when R<1> is chlorine, A is nitrogen and R<2> is methyl, R cannot be phenyl, as well as their pharmaceutically acceptable acid addition salts, characterized by a) reacting an indole derivative with the following formula: wherein R<1> is R as defined above with a 4-piperidone of formula: wherein R<2> is as defined above, or b) reduce a compound of the following formula: wherein R<1>, R and R<2> are as defined above, or c) reacting a compound of the following formula: wherein R<1>, R<2> and A are as defined above with a compound of formeir wherein R is as defined above and "hal" is halogen, in the presence of a metal catalyst, or d) reacting a compound of the following formula: wherein R<1>, R and A are as defined above, with a lower alkyl halide or an epoxide of formula R<1> is hydrogen, methyl or ethyl, or wherein e) reduce a compound of the following formula: wherein R<1>, R and A are as defined above, and R<4> is hydrogen, lower alkyl (1-3 C atoms) or lower alkoxy (1-3 C atoms), or f) heating a compound with the following formula: wherein R<1>, and R is as defined above, with a piperazine of formula: wherein R<2> is as defined above, or g) reduce a compound of the following formula: wherein R<1>, R and R<2> are as defined above, with a suitable reducing agent, after which the indole of formula I is isolated in the form of the free base or as a pharmaceutically acceptable acid addition salt thereof and if the group R<2> contains a hydroxyl group, if desired, to acylate such a hydroxyl group with an active derivative of an aliphatic carboxylic acid having from 2 to 24 carbon atoms, and to isolate the ester formed as the free base or a pharmaceutically acceptable acid addition salt thereof.

2. Analogous method according to claim 1 in the preparation of the following compounds: 1-(4'-fluorophenyl)-3-(4-(2-hydroxyethyl)-piperazino)-5-trifluoromethyl-1H-indole. 1-(4'-fluorophenyl)-5-nitro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole. 5-Chloro-1-(4'-fluorophenyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole. 1-(4'-fluorophenyl)-3-(1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1H-indole. 1-(4'-fluorophenyl)-3-(1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-trifluoromethyl-1H-indole. 5-fluoro-1-(4'-fluorophenyl)-3-(1-(3-hydroxypropyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole as well as pharmaceutically acceptable acid addition salts thereof, characterized by the use of correspondingly substituted starting materials.