NO750033L

NO750033L -

Info

Publication number: NO750033L
Application number: NO750033A
Authority: NO
Inventors: P H Derible; J Guillaume; C Dumont
Original assignee: Roussel Uclaf
Priority date: 1974-01-30
Filing date: 1975-01-07
Publication date: 1975-08-25
Also published as: IL46444A0; ES434240A1; HU169259B

Description

Foreliggende oppfinnelse angår en fremgangsmåte ved fremstilling av nye derivater av N-[w-(4'-(3"-indoly1) piperidino) alk-y1]benzamider såvel som syreaddisjonssalter med uorganiske eller organiske syrer, hvilke derivater har generell formel I: The present invention relates to a process for the preparation of new derivatives of N-[w-(4'-(3"-indolyl)piperidino)alk-y1]benzamides as well as acid addition salts with inorganic or organic acids, which derivatives have general formula I:

hvor R betegner et hydrogenatom eller et alkoxyradika1 med 1-3 carbonatomer, R^ og R,, som er lik eller forskjellig, betegner et hydrogenatom eller et alkylradikal med 1-3 carbonatomer, n er lik 2 where R denotes a hydrogen atom or an alkoxy radical with 1-3 carbon atoms, R^ and R, which are the same or different, denote a hydrogen atom or an alkyl radical with 1-3 carbon atoms, n is equal to 2

eller 3, X, betegner et hydrogenatom eller et alkoxyradika1 med 1 - or 3, X, denotes a hydrogen atom or an alkoxy radical1 with 1 -

3 carbonatomer, betegner et hydrogenatom, fluor, klor eller brom, 3 carbon atoms, denotes a hydrogen atom, fluorine, chlorine or bromine,

et aminoradikal eller acetamido og betegner et hydrogenatom eller klor eller et aminosulfonylradikal. an amino radical or acetamido and denotes a hydrogen atom or chlorine or an aminosulfonyl radical.

I formel I og hva som folger, angir uttrykket alkoxy inne-holdende 1-3 carbonatomer f.eks. et methoxyradikal, ethoxyradika1 In formula I and what follows, the term alkoxy denotes containing 1-3 carbon atoms, e.g. a methoxy radical, ethoxy radical1

eller propoxyradikal, uttrykket alkyl med 1-3 carbonatomer beteg- or propoxy radical, the term alkyl with 1-3 carbon atoms denotes

ner f.eks. et methyl-, ethyl-, propyl- eller isopropylradika 1. down e.g. a methyl, ethyl, propyl or isopropyl radical 1.

Addisjonssaltene med uorganiske eller organiske syrer kan The addition salts with inorganic or organic acids can

f.eks. være: salter dannet med saltsyre, hydrobromsyre, hydrojodsy- e.g. be: salts formed with hydrochloric acid, hydrobromic acid, hydroiodic acid

re, salpetersyre, svovelsyre, fosforsyre, eddiksyre, maleinsyre, fu-marsyre, ravsyre, vinsyre, citronsyre, oxalsyre, alkansulfonsyrer, arylsulfonsyrer og a rylearboxylsyrer. re, nitric acid, sulfuric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, alkanesulfonic acids, arylsulfonic acids and alpha carboxylic acids.

Blant de produkter som fremstilles ved fremgangsmåten ifol- Among the products produced by the method according to

ge oppfinnelsen kan i særdeleshet nevnes de derivater som svarer til- ge the invention, in particular, the derivatives that correspond to

den ovenfor angitte formel I såvel som deres syreaddisjonssaIter med the above-mentioned formula I as well as their acid addition sites with

uorganiske eller organiske syrer, hvilke derivater er kjennetegnet ved at R., , .'X,-, .og X0betegner et hydrogenatom, og R« n' oq X^har de tidligere angitte betydninger. inorganic or organic acids, which derivatives are characterized by the fact that R., .'X,-, .and X0 denote a hydrogen atom, and R« n' and X^ have the previously indicated meanings.

Blant disse produkter kan i særdeleshet angis de derivater som svarer til den ovenfor angitte formel I, såvel som deres addisjonssalter med uorganiske eller organiske syrer, hvilke derivater er kjennetegnet ved at R^, X^og X3betegner et hydrogenatom, n er lik 2, X^ betegner et hydrogenatom eller fluor, og R og R^har de tidligere angitte betydninger. Among these products, in particular, the derivatives corresponding to the above-mentioned formula I can be specified, as well as their addition salts with inorganic or organic acids, which derivatives are characterized by the fact that R^, X^ and X3 denote a hydrogen atom, n is equal to 2, X ^ denotes a hydrogen atom or fluorine, and R and R^ have the previously indicated meanings.

Spesielt kan folgende derivater nevnes: In particular, the following derivatives can be mentioned:

4-fluor N-[B-(4'-(3"-indolyl) piperidino) ethyljbenzamid og dets succinat, 4-fluoro N-[B-(4'-(3"-indolyl)piperidino)ethylbenzamide and its succinate,

2-methoxy 4-amino 5-klor N- [ (3 - (4' - (3"-indolyl) piperidino) ethyl] benzamid. 2-Methoxy 4-amino 5-chloro N-[(3-(4'-(3"-indolyl)piperidino)ethyl]benzamide.

Fremgangsmåten ved fremstilling av derivatene av formel I såvel som deres salter er kjennetegnet ved at en forbindelse av formel II: The process for preparing the derivatives of formula I as well as their salts is characterized by the fact that a compound of formula II:

hvor R, R^ og R^ har de tidligere angitte betydninger, omsettes med et halogenid av formel III: hvor n har den tidligere angitte betydning,og Hal betegner et klor-eller bromatom, under dannelse av en forbindelse av formel IV: hvor R, R1?R2og n har de tidligere angitte betydninger, hvorefter dette produkt underkastes en behandling med hydrazinhydrat under dannelse av en forbindelse av formelen V: . hvor R, R^, R2og n har de tidligere angitte betydninger, som omsettes med en forbindelse av formel VI: where R, R^ and R^ have the previously indicated meanings, react with a halide of formula III: where n has the previously indicated meaning, and Hal denotes a chlorine or bromine atom, forming a compound of formula IV: where R , R1?R2 and n have the previously indicated meanings, after which this product is subjected to a treatment with hydrazine hydrate to form a compound of the formula V: . where R, R^, R 2 and n have the previously indicated meanings, which are reacted with a compound of formula VI:

hvor A betegner et halogenatom eller et alkoxyradika1 med 1-3 carbonatomer, X o betegner et hydrogenatom, fluor, klor eller brom, el ler et acetamidoradikal, og X^og X^har de tidligere angitte betydninger, hvorefter enten a) det erholdte derivat av formel I hvor X^ betegner et hydrogenatom, fluor, klor eller brom eller et acetamidoradikal, og R, where A denotes a halogen atom or an alkoxy radical1 with 1-3 carbon atoms, X o denotes a hydrogen atom, fluorine, chlorine or bromine, or is an acetamido radical, and X^ and X^ have the previously indicated meanings, according to which either a) the obtained derivative of formula I where X^ denotes a hydrogen atom, fluorine, chlorine or bromine or an acetamido radical, and R,

R^, R^, n, X^og X^har de tidligere angitte betydninger, iso-leres, og om onsket omsettes med en uorganisk eller organisk sy-re i et organisk opplosningsmiddel under dannelse av det tilsvarende salt, eller R^, R^, n, X^ and X^ have the previously indicated meanings, are isolated, and if desired are reacted with an inorganic or organic acid in an organic solvent to form the corresponding salt, or

b) under forutsetning av å ha fremstillet et derivat av formel I hvor X^betegner et acetamidoradikal, dette derivat hydrolyseres ved hjelp av en uorganisk syre i en alkanol under dannelse av et derivat av formel I i hvilket X9betegner et aminoradika1, og R, R1 . R0, n, X-, og XQhar de tidligere angitte betydninger, og om onsket, at dette derivat omsettes med en uorganisk eller organisk syre i et organisk opplosningsmiddel under dannelse av det tilsvarende salt. b) under the condition of having prepared a derivative of formula I where X^ denotes an acetamido radical, this derivative is hydrolysed with the aid of an inorganic acid in an alkanol to form a derivative of formula I in which X9 denotes an amino radical1, and R, R1 . R0, n, X-, and XQ have the previously indicated meanings, and if desired, this derivative is reacted with an inorganic or organic acid in an organic solvent to form the corresponding salt.

Under de foretrukne betingelser utfores fremgangsmåten på folgende måte: a) Forbindelsen av formel II omsettes med et halogenid av formel III i et organisk opplosningsmiddel slik som isobutylmethylketon eller dimethylformamid ved reaksjonsblandingens koketemperatur og i nærvær av et alkalisk middel slik som et carbonat. b) Den erholdte forbindelse av formel IV omsettes derefter med hydrazinhydrat for å bevirke en hydrazinolyse, og reaksjonen utfores fortrinnsvis i nærvær av et organisk opplosningsmiddel slik som méthanol ved reaksjonsblandingens tilbakeldpstemperatur. c) Den erholdte forbindelse av formel V omsettes derefter med: enten et syreklorid av formel VI (A = Cl) i et vannfritt, organisk opplosningsmiddel slik som benzen, tetrahydrofuran eller methylethylketon, i nærvær av et basisk middel slik som triethylamin eller natriumcarbonat, Under the preferred conditions, the method is carried out as follows: a) The compound of formula II is reacted with a halide of formula III in an organic solvent such as isobutylmethylketone or dimethylformamide at the reaction mixture's boiling temperature and in the presence of an alkaline agent such as a carbonate. b) The obtained compound of formula IV is then reacted with hydrazine hydrate to effect a hydrazinolysis, and the reaction is preferably carried out in the presence of an organic solvent such as methanol at the reflux temperature of the reaction mixture. c) The obtained compound of formula V is then reacted with: either an acid chloride of formula VI (A = Cl) in an anhydrous organic solvent such as benzene, tetrahydrofuran or methyl ethyl ketone, in the presence of a basic agent such as triethylamine or sodium carbonate,

eller en ester av benzoesyre av formel VI (A = alkoxy) i nærvær av en polyalkohol slik som ethylenglycol ved reaksjonsblandingens tilbakelopstemperatur. or an ester of benzoic acid of formula VI (A = alkoxy) in the presence of a polyalcohol such as ethylene glycol at the reflux temperature of the reaction mixture.

d) Når det onskes å fremstille en forbindelse av formel I hvori X? betegner et aminoradika1, fremstilles forst en forbindelse av d) When it is desired to prepare a compound of formula I in which X? denotes an amino radical1, a compound is first prepared from

formel I i hvilken X^betegner et acetamidoradikal, hvorefter dette underkastes behandling med en mineralsyre slik som saltsyre, i nærvær av en alkanol slik som en alkanol med lav molekyl-vekt slik som ethanol. formula I in which X represents an acetamido radical, after which this is subjected to treatment with a mineral acid such as hydrochloric acid in the presence of an alkanol such as a low molecular weight alkanol such as ethanol.

Ifolge en variant av fremgangsmåten ifolge oppfinnelsen kan derivatene av formel I fremstilles ved å gå ut fra en forbindelse av formel V som erholdes ved en fremgangsmåte som er kjennetegnet ved at en forbindelse av formel II: According to a variant of the method according to the invention, the derivatives of formula I can be prepared by starting from a compound of formula V which is obtained by a method characterized in that a compound of formula II:

hvori R, R^og R^ har de tidligere angitte betydninger, omsettes med et derivat av formel VII: hvor Hal betegner et klor- eller bromatom, og n har de tidligere angitte betydninger, under dannelse av en forbindelse av formel VIII: hvor R, R-^, R^og n har de tidligere angitte betydninger, hvorefter dette reduseres under dannelse av forbindelsen av formel V: wherein R, R^ and R^ have the previously indicated meanings, is reacted with a derivative of formula VII: where Hal denotes a chlorine or bromine atom, and n has the previously indicated meanings, forming a compound of formula VIII: where R , R-^, R^ and n have the previously indicated meanings, after which this is reduced to form the compound of formula V:

hvor R, R^, R^og n har de tidligere angitte betydninger. where R, R^, R^ and n have the previously indicated meanings.

I de foretrukne betingelser utfores denne variant på fblgen-de måte: a) Forbindelsen av formel II omsettes med et derivat av formel VII i et organisk opplosningsmiddel slik som dimethylformamid eller methylisobutyIketon ved reaksjonsblandingens tilbakeldpstemperatur og i nærvær av et alkalisk middel slik som triethylamin eller na triumcarbona t.f3In the preferred conditions, this variant is carried out in the following way: a) The compound of formula II is reacted with a derivative of formula VII in an organic solvent such as dimethylformamide or methylisobutyl ketone at the reflux temperature of the reaction mixture and in the presence of an alkaline agent such as triethylamine or na triumcarbona t.f3

b) Det erholdte nitril av formel ¥111 reduseres derefter ved be-. h^nr]] t nn zi\ rlinn" m* nfri"! i 1-Vn' nmnwHri i o -f rii^^r* t->cV nnn ] X o r>-I n ^ eir; i r! _ b) The obtained nitrile of formula ¥111 is then reduced by be-. h^nr]] t nn zi\ rlinn" m* nfri"! i 1-Vn' nmnwHri i o -f rii^^r* t->cV nnn ] X o r>-I n ^ eir; in r! _

del slik som ether. part such as ether.

Derivatene av formel I utviser en basisk karakter. Man kan med fordel fremstille addisjonssaltene av derivatene av formel I ved omsetning av stokiometriske mengder av en uorganisk eller organisk syre med derivatet av formel I. Disse salter kan fremstilles uten å isolere de tilsvarende baser. The derivatives of formula I exhibit a basic character. The addition salts of the derivatives of formula I can be advantageously prepared by reacting stoichiometric amounts of an inorganic or organic acid with the derivative of formula I. These salts can be prepared without isolating the corresponding bases.

Forbindelsene erholdt ved fremgangsmåten ifolge foreliggende oppfinnelse utviser meget interessante farmakologiske egenskaper, de utviser i særdeleshet en bemerkelsesverdig nevrosedativ aktivitet. Eksempler på denne aktivitet er angitt i det efterfolgende. The compounds obtained by the method according to the present invention exhibit very interesting pharmacological properties, in particular they exhibit a remarkable neurosedative activity. Examples of this activity are set out below.

Visse forbindelser utviser ennvidere antipsykotiske egenskaper som ikke er ledsaget av kataleptiske egenskaper; et eksempel på slike er succinatet av 4-fluor N-[ (3-(4' (3"-indoly 1) piperidino) ethyl] benzamid. Certain compounds also exhibit antipsychotic properties that are not accompanied by cataleptic properties; an example of such is the succinate of 4-fluoro N-[(3-(4' (3"-indoly 1) piperidino) ethyl] benzamide.

Derivatene av N-[co-(4'(3u<->indolyl) piperidino) alcyl] benzamider slik som her definert, såvel som deres addisjonssalter med farmasoytisk akseptable syrer er således meget egnet ved behandling av angst, uro, overf dlsomhet, psykomotorisk uro, irritabilitet som ledsages.av søvnforstyrrelser, opphisset tilstand. Visse derivater kan ennvidere anvendes ved behandling av karakterielle forstyrrel-ser, adferdforstyrreiser eller visse psykoser.. The derivatives of N-[co-(4'(3u<->indolyl) piperidino) alkyl] benzamides as defined here, as well as their addition salts with pharmaceutically acceptable acids are thus very suitable for the treatment of anxiety, restlessness, hyperactivity, psychomotor restlessness, irritability accompanied by sleep disturbances, excited state. Certain derivatives can also be used in the treatment of character disturbances, behavioral disturbances or certain psychoses.

Den vanlige dose kan varieres alt efter det anvendte produkt, den pasient som skal behandles og tilstanden, kan f.eks. være 5 - 100 mg/dag administrert oralt til mennesker. The usual dose can be varied depending on the product used, the patient to be treated and the condition, e.g. be 5 - 100 mg/day administered orally to humans.

De nye derivater av formel I og deres addisjonssaIter med farmasoytisk akseptable syrer, erholdt ved fremgangsmåten ifolge oppfinnelsen, kan anvendes ved fremstilling av farmasdytiske komposisjoner omfattende som aktiv bestanddel i det minste étt av disse derivater og salter. Komposisjonene kan fremstilles for å admini-streres oralt eller parenteralt. De kan være faste eller flytende og foreligge som de vanlige farraasdytiske former som anvendes innen den menneskelige medisin, slik som f.eks. enkle eller drasjerte tabletter, kapsler, granuler, stikkpiller, injiserbare preparater, som kan fremstilles efter kjente metoder. The new derivatives of formula I and their addition salts with pharmaceutically acceptable acids, obtained by the method according to the invention, can be used in the preparation of pharmaceutical compositions comprising as active ingredient at least one of these derivatives and salts. The compositions can be prepared to be administered orally or parenterally. They can be solid or liquid and present as the usual farraasdytic forms used in human medicine, such as e.g. simple or coated tablets, capsules, granules, suppositories, injectable preparations, which can be prepared according to known methods.

Den eller de aktive bestanddeler kan være inkorporert i de eksipienter som vanligvis anvendes i farmasoytiske komposisjoner slik som talkum, gummi arabicum, lactose, stivelse, magnesiumstearat, kakaofett. vandige eller ikke vandige bærere, fett av animalsk eller vegetabilsk opprinnelse, pa raffinderivater, glycoler, forskjellige fuktemidler, dispergeringsmidler eller emulgeringsraidler, og konser-veringsmidler . The active ingredient(s) can be incorporated into the excipients that are usually used in pharmaceutical compositions such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa fat. aqueous or non-aqueous carriers, fats of animal or vegetable origin, raffinic derivatives, glycols, various wetting agents, dispersing agents or emulsifying agents, and preservatives.

Fremgangsmåten ifolge foreliggende oppfinnelse tilveiebrin-ger industrielt nye forbindelser som i særdeleshet kan anvendes ved fremstilling av derivatene av formel I, nemlig forbindelser av formel V: The method according to the present invention provides industrially new compounds which can in particular be used in the production of the derivatives of formula I, namely compounds of formula V:

hvor R, R^, R^og n har de tidligere angitte betydninger, og i særdeleshet 4-(3'-indoly1) N-(Gaminoethy1) piperidin, where R, R^, R^ and n have the previously indicated meanings, and in particular 4-(3'-indolyl)N-(Gaminoethyl)piperidine,

4-^3'-indolyl) N-(y-aminopropy1) piperidin og 4-(.2'-methyl-6 '-methoxy 3'-indolyl) N-( S-arainoethy 1) piperidin. 4-(3'-indolyl)N-(γ-aminopropyl)piperidine and 4-(.2'-methyl-6'-methoxy 3'-indolyl)N-(S-arainoethyl)piperidine.

Forbindelsene av formel II som ikke er kjente, kan fremstilles efter den fremgangsmåte som er beskrevet i belgisk patentskrift nr. 802.912. The compounds of formula II which are not known can be prepared according to the method described in Belgian Patent Document No. 802,912.

Denne fremgangsmåte består hovedsakelig i å omsette benzyl-bromid og en forbindelse av formel IX: This process consists essentially in reacting benzyl bromide and a compound of formula IX:

hvor R og R? har de tidligere angitte betydninger, under dannelse av en forbindelse av formel X: hvor R og R^har de tidligere angitte betydninger. Denne forbindelse av formel X omsettes derefter med natriumborhydrid under dannelse av forbindelsen av formel XI: where R and R? have the previously indicated meanings, forming a compound of formula X: wherein R and R 2 have the previously indicated meanings. This compound of formula X is then reacted with sodium borohydride to form the compound of formula XI:

hvori R og R^har de tidligere angitte betydninger, hvorefter, enten produktet av formel XI reduseres med hydrogengass i nærvær av en katalysator basert på palladium under dannelse av forbindelsen av formel II hvori R^betegner et hydrogenatom, og R og R^ har de tidligere angitte betydninger, wherein R and R^ have the previously stated meanings, then either the product of formula XI is reduced with hydrogen gas in the presence of a catalyst based on palladium to form the compound of formula II wherein R^ denotes a hydrogen atom, and R and R^ have the meanings set forth above,

eller or

at forbindelsen av formel XI omsettes med et alkylhalogenid av formelen Hal-R^hvor Hal betegner et halogenatcm og R^ betegner et alkylradikal med opp til 3 carbonatomer i nærvær av natrium-hydrid under dannelse av en forbindelse av formel XII: that the compound of formula XI is reacted with an alkyl halide of the formula Hal-R^, where Hal denotes a halogenate and R^ denotes an alkyl radical with up to 3 carbon atoms in the presence of sodium hydride to form a compound of formula XII:

hvor R^betegner et alkylradikal med opp til 3 carbonatomer, og R og R^har de tidligere angitte betydninger, hvorefter forb i ndelsen av formel XII reduseres med hydrogengass i nærvær av en palladiumkata-lysator under dannelse av forbindelsen av formel II hvor R, R^ og R^har de tidligere angitte betydninger. where R^ denotes an alkyl radical with up to 3 carbon atoms, and R and R^ have the previously indicated meanings, after which the compound of formula XII is reduced with hydrogen gas in the presence of a palladium catalyst to form the compound of formula II where R, R^ and R^ have the previously indicated meanings.

De efterfolgende eksempler illustrerer oppfinnelsen„ The following examples illustrate the invention

Eksempel 1 N-[ G-( 4'-( 3"- xndolyl) piperidino) ethyl] benzamid Example 1 N-[G-(4'-(3"-xindolyl)piperidino)ethyl]benzamide

Tr< nn A * A I O » ... S' n 1 .,1 \ IvT / o •<■" -«-V - "> : — - 3 j .... : ... Tr< nn A * A I O » ... S' n 1 .,1 \ IvT / o •<■" -«-V - "> : — - 3 j .... : ...

En blanding av 10 g 3-(4'-piperidyl) indol og 12,7 g N-(2-brom ethyl) fthalimid i 250 ml isobutylmethylketon ble oppvarmet under omroring til 80 - 90°C. Derefter ble der til den erholdte opp-ldsning tilsatt 10,6 g natriumcarbonat og enkelte krystaller av kali-umjodid, og blandingen ble kokt under tilbakelopskjoling 2 l/2 time. Efter avkjoling ble blandingen heldt over i vann, ekstrahert med ethylacetat, og den organiske fase ble vasket med vann tilsatt natriumklorid, torket, konsentrert til tdrrhet og residuet ble omkrystallisert fra ethylacetat. Der ble erholdt 8 g 4-(3'-indolyl) N-(6-fthalimido ethyl) piperidin. Sm.p. 193°C. A mixture of 10 g of 3-(4'-piperidyl)indole and 12.7 g of N-(2-bromoethyl)phthalimide in 250 ml of isobutylmethylketone was heated with stirring to 80-90°C. Then 10.6 g of sodium carbonate and individual crystals of potassium iodide were added to the solution obtained, and the mixture was boiled under reflux for 2 l/2 hours. After cooling, the mixture was poured into water, extracted with ethyl acetate, and the organic phase was washed with water to which sodium chloride had been added, dried, concentrated to dryness and the residue was recrystallized from ethyl acetate. 8 g of 4-(3'-indolyl)N-(6-phthalimidoethyl)piperidine were obtained. Sm.p. 193°C.

Trinn B: 4-( 31- indolyl) N-( G- amino ethyl) piperidin Step B: 4-(31-indolyl)N-(G-aminoethyl)piperidine

Der ble fremstillet en suspensjon av 7,21 g av produktet fremstillet i trinn A.i 72 ml metbanol, og der ble tilsatt 1,93 ml hydrazinhydrat. Blandingen ble kokt under tilbakelopskjoling under en inert atmosfære i 45 minutter, avkjdlet og tilsatt 72 ral 2 N saltsyre. Blandingen ble filtrert, filtratet ble gjort alkalisk ved tilsetning av 'Na^CO-^-dpplosni-ri-g, ekstrahert med methylenklorid, den organiske fase vasket med vann tilsatt natriumklorid, torket•og konsentrert til torrhet.- Der ble erholdt 4,5 g 4-(3'-indolyl) N-(S-amino ethyl) 'piperidin; sm.p. 132°C. A suspension of 7.21 g of the product prepared in step A was prepared in 72 ml of metbanol, and 1.93 ml of hydrazine hydrate was added thereto. The mixture was refluxed under an inert atmosphere for 45 minutes, cooled and 72 ral of 2N hydrochloric acid was added. The mixture was filtered, the filtrate was made alkaline by the addition of 'Na^CO-^-dpplosni-ri-g, extracted with methylene chloride, the organic phase washed with water to which sodium chloride was added, dried•and concentrated to dryness.- There was obtained 4, 5 g of 4-(3'-indolyl) N -(S-amino ethyl)' piperidine; sm.p. 132°C.

Trinn C: N-[ B( 4'-( 3"- indolyl) piperidino) ethyl] benzamid Step C: N-[B(4'-(3"-indolyl)piperidino)ethyl]benzamide

3,5 g av det fremstillede produkt ifolge trinn B ble innfort i 30 ml tetrahydrofuran, tilsatt 1,44 g natriumcarbonat, avkjolet til 0 - +5°C og tilsatt 1,91 g benzoylklorid. Blandingen fikk anta omgivende temperatur og ble holdt under omroring 15 minutter, tilsatt vann, bunnfalletsentrifugert og vasket med methylenklorid og torket. Der ble efter omkrystallisering fra benzen erholdt 3,33 g N-[B-(4<*->3.5 g of the product prepared according to step B was introduced into 30 ml of tetrahydrofuran, 1.44 g of sodium carbonate was added, cooled to 0 - +5°C and 1.91 g of benzoyl chloride was added. The mixture was allowed to reach ambient temperature and was kept under stirring for 15 minutes, water was added, the precipitate was centrifuged and washed with methylene chloride and dried. After recrystallization from benzene, 3.33 g of N-[B-(4<*->) were obtained

(3"-indolyl) piperidino) ethyl] benzamid..Sm.p. 130°C. (3"-indolyl)piperidino)ethyl]benzamide..M.p. 130°C.

Analyse:<C>22<H>25<N>3° ~ Bere9net: c % 76,05; H % 7,25; N % 12,09 Analysis: <C>22<H>25<N>3° ~ Calculated: c % 76.05; H% 7.25; N% 12.09

Funnet: 75,9 7,3 11,8 Found: 75.9 7.3 11.8

Eksempel 2 Succinat av p- fluor N-[ B-( 4'-( 3"- indoIy1) piperidino) ethyl ]_ bens amid Example 2 Succinate of p-fluoro N-[B-(4'-(3"-indolyl)piperidino)ethyl]-benzamide

I en opplosning av 3,5 g 4-(3'-indolyl) N-(Bamino ethyl) piperidin erholdt under trinn B ifolge eksempel 1, og 1,54 g triethylamin i 25 ml methylethylketon ble ved 0 - +5°C tilsatt en opplosning av 3,6 g p-fluorbenzoylklorid« erholdt ved å gå ut fra 4,9 g p-fluo.r-benzoesyre og 5 g thionylklorid i benzen, i 25 ml methylethylketon. In a solution of 3.5 g of 4-(3'-indolyl) N-(Bamino ethyl) piperidine obtained during step B according to example 1, and 1.54 g of triethylamine in 25 ml of methyl ethyl ketone at 0 - +5°C was added a solution of 3.6 g of p-fluorobenzoyl chloride" obtained by starting from 4.9 g of p-fluoro-r-benzoic acid and 5 g of thionyl chloride in benzene, in 25 ml of methyl ethyl ketone.

Blandingen ble omrdrt 2 timer ved 20°C, opplosningsmidlet ble fordampet, residuet tatt opp i vann og gjort alkalisk med natriumcarbonat. Ether ble tilsatt, og bunnfallet ble filtrert fra, torket og omkrystallisert fra en blanding av benzen-cyclohexan (1 - 1)» Sm.p. 153°C. The mixture was stirred for 2 hours at 20°C, the solvent was evaporated, the residue taken up in water and made alkaline with sodium carbonate. Ether was added, and the precipitate was filtered off, dried and recrystallized from a mixture of benzene-cyclohexane (1-1)» mp. 153°C.

1,4 g p-fluor N-[B-(4'-(3"-indoly1) piperidin ethyljbenzamid ble opplost i 100 ml ethylacetat og tilsatt en opplosning av 0,5 g ravsyre i 100 ml ethylacetat. Det erholdte bunnfall ble sentrifugert, omkrysta Hisert fra isopropanol, og der ble erholdt 1 g av succinatet av p-fluor N-[B-(4'- (3*'-indolyl) piperidin) ethyl] benzamid. Sm.p. 168°C. 1.4 g of p-fluoro N-[B-(4'-(3"-indolyl)piperidine ethylbenzamide was dissolved in 100 ml of ethyl acetate and a solution of 0.5 g of succinic acid in 100 ml of ethyl acetate was added. The precipitate obtained was centrifuged , recrystallized Hisert from isopropanol, and there obtained 1 g of the succinate of p-fluoro N-[B-(4'-(3*'-indolyl)piperidin)ethyl]benzamide, mp 168°C.

Analyse: C^ H^ FN^ Analysis: C^ H^ FN^

Beregnet/%: C 64,58; H 6,25; N 8,69; F 3,93 Calculated/%: C 64.58; H 6.25; N 8.69; F 3.93

Funnet: 64,8 6,3 8,5 4,0 Found: 64.8 6.3 8.5 4.0

Eksempel 3 p- fluor N-[ y-( 4r( 3"- indoly1) piperidin) propylbenzamid Trinn A: 4-( 3'- indolyl) N-( y- fthalimido propyl) piperidin Example 3 p-fluoro N-[y-(4r(3"-indolyl)piperidine)propylbenzamide Step A: 4-(3'-indolyl)N-(y-phthalimidopropyl)piperidine

Man gikk frem som beskrevet i trinn A ifolge eksempel 1 fra One proceeded as described in step A according to example 1 from

8 g 3-(4'-piperidyl) indol og 10,72 g N-(3-brom propyl) fthalimid, 8 g of 3-(4'-piperidyl) indole and 10.72 g of N-(3-bromopropyl) phthalimide,

og der ble erholdt 8,9 g 4-(3'-indolyl) N-(y-fthalimido propyl) piperidin. Sm.p. 170°C. and 8.9 g of 4-(3'-indolyl)N-(γ-phthalimidopropyl)piperidine were obtained. Sm.p. 170°C.

Trinn B: 4-( 3'- indolyl) N-( y- amino propyl) piperidin Step B: 4-(3'-indolyl)N-(γ-aminopropyl)piperidine

Man gikk frem på samme måte som beskrevet i trinn B i eksempel 1 fra 8,9 g av produktet erholdt i det foregående trinn, og 2,4 One proceeded in the same way as described in step B in example 1 from 8.9 g of the product obtained in the previous step, and 2.4

ml hydrazinhydrat, hvorved ble erholdt 5,44 g 4-(3'-indolyl) N-(y~amino propyl) piperidin som ble anvendt som sådant i det efterfolgende trinn. Sm.p. 96°C. ml of hydrazine hydrate, whereby 5.44 g of 4-(3'-indolyl)N-(γ-aminopropyl)piperidine were obtained, which was used as such in the following step. Sm.p. 96°C.

Trinn C: p-fluor N-[y-(4'-(3"-indolyl) piperidin) propyl] Step C: p-fluoro N-[y-(4'-(3"-indolyl) piperidine) propyl]

benzamid benzamide

4,32 g av produktet erholdt i det foregående trinn ble opplost'i 45 ml tetrahydrofuran og tilsatt 1,8 g natriumcarbonat. Blandingen ble avkjdlet til 0 - +5°C og tilsatt 2,5 ml p-fluorbenzoylklorid. Blandingen ble derefter tilsatt vann, ekstrahert med methylenklorid, den organiske fase ble vasket med vann tilsatt natriumklorid, torket og fordampet til torrhet. Det urene produkt ble renset ved kromatografi på silicagel og eluert med en blanding av kloroform-aceton-triethylamin (85--IO-5), og der ble efter omkrystallisering fra benzen erholdt 3,3 g p-fluorN~[y-(4'-(3"-indolyl) piperidin) propyl] benzamid. Sm.p. 133°C„ 4.32 g of the product obtained in the previous step was dissolved in 45 ml of tetrahydrofuran and 1.8 g of sodium carbonate was added. The mixture was cooled to 0 - +5°C and 2.5 ml of p-fluorobenzoyl chloride was added. The mixture was then added to water, extracted with methylene chloride, the organic phase was washed with water to which sodium chloride was added, dried and evaporated to dryness. The impure product was purified by chromatography on silica gel and eluted with a mixture of chloroform-acetone-triethylamine (85--10-5), and after recrystallization from benzene 3.3 g of p-fluoroN~[y-(4 '-(3"-indolyl) piperidine) propyl] benzamide. M.p. 133°C„

Analyse: C23H26FN3° Analysis: C23H26FN3°

Beregnet, %: C 72,80; H 6,91; F 5,01; N 11,07 Calculated, %: C 72.80; H 6.91; F 5.01; N 11.07

Funnet: 72,7 6,8 4,8 11,2 Found: 72.7 6.8 4.8 11.2

- Eksempel 4 p-fluor o-methoxy N-[S-(41 -(3"-indoly1) piperidin) ethyl] benzamid - Example 4 p-fluoro o-methoxy N-[S-(41-(3"-indolyl) piperidine) ethyl] benzamide

Trinn A: 4-( 3'- indolyl) N-( cyano me thyl) piperidin Step A: 4-(3'-Indolyl)N-(cyanomethyl)piperidine

En blanding av 20 g 3-(4'-piperidy1) indol, 180 ml dimethylformamid, 10 g triethylamin, 8,6 g kloracetonitril i 20 ml dimethylformamid ble kokt under ti lbakelripsk jdling i 4 timer. Blandingen ble heldt over i 1 liter koldt vann, det utfeldte produkt ble sentrifugert, vasket med vann og torket. Produktet ble omkrystallisert i 100 ml isopropanol, og der ble erholdt 14,8 g 4-(3r<->indolyl) N-(cyano methyl) piperidin. Sm.p. 132°C. A mixture of 20 g of 3-(4'-piperidyl)indole, 180 ml of dimethylformamide, 10 g of triethylamine, 8.6 g of chloroacetonitrile in 20 ml of dimethylformamide was boiled under reflux for 4 hours. The mixture was poured into 1 liter of cold water, the precipitated product was centrifuged, washed with water and dried. The product was recrystallized in 100 ml of isopropanol, and 14.8 g of 4-(3r<->indolyl)N-(cyano methyl)piperidine were obtained. Sm.p. 132°C.

Trinn B: 4-( 3'- indolyl) N-( B- amino ethyl) piperidin Step B: 4-(3'-indolyl)N-(B-aminoethyl)piperidine

1,9 g aluminiumlithiumhydrid i 50 ml ether ble dråpevis tilsatt i en opplosning av 4,8 g av produktet erholdt i trinn A i 350 ml ether. Blandingen ble kokt under tilbakelopskjoling 20 timer, avkjdlet og langsomt tilsatt 15 ml ethylacetat og derefter en vandig opplosning av natrium og kaliumtartrat. Blandingen ble filtrert, dekantert, den etheriske fase torket, fordampet og residuet omkrystallisert fra benzen under dannelse av 2,8 g 4-(3'-indolyl) N-(S-amino ethyl) piperidin. Sm.p. 132°C. 1.9 g of aluminum lithium hydride in 50 ml of ether was added dropwise to a solution of 4.8 g of the product obtained in step A in 350 ml of ether. The mixture was boiled under reflux for 20 hours, cooled and slowly added 15 ml of ethyl acetate and then an aqueous solution of sodium and potassium tartrate. The mixture was filtered, decanted, the ethereal phase dried, evaporated and the residue recrystallized from benzene to give 2.8 g of 4-(3'-indolyl)N-(S-amino ethyl)piperidine. Sm.p. 132°C.

Trinn C: p-fluor o-methoxy N-[6-(4'-(3"-indolyl) piperidin ethyl] benzamid . ■ Step C: p-fluoro o-methoxy N-[6-(4'-(3"-indolyl) piperidine ethyl] benzamide. ■

2,91 g av produktet erholdt i trinn B ble innfort i 30 ml tetrahydrofuran og tilsatt 1,27 g natriumcarbonat. Blandingen ble avkjdlet til 2°C og dråpevis tilsatt en opplosning av 3,5 g p-fluor o-methoxy benzoesyreklorid erholdt fra 3,06 g av den tilsvarende syre som beskrevet i J. Chem. Soc. 1929, side 1639, og 3 ml thionylklorid i 30 ml tetrahydrofuran. Blandingen ble holdt 2.91 g of the product obtained in step B was placed in 30 ml of tetrahydrofuran and 1.27 g of sodium carbonate was added. The mixture was cooled to 2°C and a solution of 3.5 g of p-fluoro o-methoxy benzoic acid chloride obtained from 3.06 g of the corresponding acid as described in J. Chem. Soc. 1929, page 1639, and 3 ml of thionyl chloride in 30 ml of tetrahydrofuran. The mixture was kept

under omroring ved 0 - +2°C i 30 minutter, fikk derefter anta omgivende temperatur, ble heldt over i vann og ekstrahert med methylenklorid. Den organiske fase ble vasket med vann tilsatt natriumklorid, torket og konsentrert til tdrrhet, hvorefter residuet ble kromatografert på silicagel og eluert med en blanding av kloroform-aceton-triethylamin (80-15-5), hvorved der ble erholdt with stirring at 0 - +2°C for 30 minutes, then allowed to assume ambient temperature, was poured into water and extracted with methylene chloride. The organic phase was washed with water added with sodium chloride, dried and concentrated to dryness, after which the residue was chromatographed on silica gel and eluted with a mixture of chloroform-acetone-triethylamine (80-15-5), whereby there was obtained

3,9 g p-fluor o-methoxy N-[b-(4'-(3"-indoly1) piperidin) ethyl] benzamid. Sm.p. 162°C. 3.9 g of p-fluoro o-methoxy N-[b-(4'-(3"-indolyl) piperidine) ethyl] benzamide. M.p. 162°C.

Analyse: C^H^Fiy^ Analysis: C^H^Fiy^

Beregnet, %: 69,85; H 6,62; F 4,80; N 10,62 Calculated, %: 69.85; H 6.62; F 4.80; N 10.62

Funnet: 69,9 6,4 4,5 10,4 Found: 69.9 6.4 4.5 10.4

Eksempel 5 p-fluor N-[6-(4'-(2"-methy1 6"-methoxy 3"-indolyl) Example 5 p-fluoro N-[6-(4'-(2"-methyl 6"-methoxy 3"-indolyl)

piperidin) ethyl] benzamid piperidine) ethyl] benzamide

Trinn A: 4-(2'-methyl 6'-methoxy 3'-indolyl) N-(S-fthalimido ethyl) piperidin Step A: 4-(2'-methyl 6'-methoxy 3'-indolyl) N-(S-phthalimido ethyl) piperidine

Man gikk frem på lignende måte som beskrevet i trinn A ifolge eksempel 1 fra 12,21 g ■ 2-methyl 3-(4'-piperidy1) 6-methoxy indol og 15 g N-(2-brom ethyl) fthalimid, hvorefter der efter kromatografi av det urene produkt over silicagel og eluer-ing med en blanding av ethylacetat-triethylamin (97-3), ble erholdt 11,15 g amorft 4-(2!-methyl 6'-methoxy 3f<->indolyl) N-(S-fthalimido ethyl) piperidin. One proceeded in a similar way as described in step A according to example 1 from 12.21 g ■ 2-methyl 3-(4'-piperidy1) 6-methoxy indole and 15 g N-(2-bromoethyl)phthalimide, after which after chromatography of the impure product over silica gel and elution with a mixture of ethyl acetate-triethylamine (97-3), 11.15 g of amorphous 4-(2!-methyl 6'-methoxy 3f<->indolyl) N were obtained -(S-phthalimido ethyl) piperidine.

I. R. spektrum: (kloroform). I. R. spectrum: (chloroform).

Nærvær av NH (3459 cm<-1>), C=0 (1778 og 1713 cm<-1>), C=C og aromatisk. Presence of NH (3459 cm<-1>), C=0 (1778 and 1713 cm<-1>), C=C and aromatic.

Trinn B: 4-(2'-methyl 6'-methoxy 3'-indolyl) N-(S-amino ethyl) piperidin Step B: 4-(2'-methyl 6'-methoxy 3'-indolyl) N-(S-amino ethyl) piperidine

Man gikk frem på lignende måte som beskrevet i trinn B i eksempel 1 ut fra 11,15 g av produktet erholdt i det foregående trinn og 2,67 ml hydrazinhydrat, hvorved ble erholdt 6,85 g amorft 4-(2,-methyl 6'-methoxy 3r<->in.dolyl) N-(S-amino ethyl) piperidin. The procedure was similar to that described in step B in example 1, starting from 11.15 g of the product obtained in the previous step and 2.67 ml of hydrazine hydrate, whereby 6.85 g of amorphous 4-(2,-methyl 6 '-methoxy 3<->yndolyl) N-(S-amino ethyl) piperidine.

I. R. spektrum: (kloroform) I. R. spectrum: (chloroform)

Nærvær av NH^ (3378 cm"<1>), NH og aromatisk. Presence of NH^ (3378 cm"<1>), NH and aromatic.

Trinn C: p-fluor N-[S-(4'-(2"-methy1 6"-methoxy 3"-indolyl) Step C: p-fluoro N-[S-(4'-(2"-methyl 6"-methoxy 3"-indolyl)

piperid in) ethyl] benzamid piperid in) ethyl] benzamide

Man gikk frem på lignende måte som beskrevet i trinn C i eksempel 1 ut fra 6,85 g av produktet erholdt i det foregående trinn, 2,43 g natriumcarbonat og 5,5 g p-fluorbenzoylklorid. Det urene produkt ble ekstrahert med methylenklorid og kromatografert på silicagel og eluert med en blanding av kloroform-aceton-triethylamin (60-30-10). The procedure was similar to that described in step C in example 1, starting from 6.85 g of the product obtained in the previous step, 2.43 g of sodium carbonate and 5.5 g of p-fluorobenzoyl chloride. The crude product was extracted with methylene chloride and chromatographed on silica gel and eluted with a mixture of chloroform-acetone-triethylamine (60-30-10).

Der ble efter omkrystallisering fra benzen erholdt 3,2 g p-fluor N-[B- (4' - (2"-methyl 6'<*->methoxy 3"-indolyl) piperidin) ethyl] benzamid. Sm.p. 170°C. After recrystallization from benzene, 3.2 g of p-fluoro N-[B-(4'-(2"-methyl 6'<*->methoxy 3"-indolyl)piperidine)ethyl]benzamide were obtained. Sm.p. 170°C.

Analyse: C^.H FNo0^ Analysis: C 2 . H 2 F No 0 2

24 23 ^2 24 23 ^2

Beregnet, %: 70,39; H 6,89; F 4,63; N 10,26 Calculated, %: 70.39; H 6.89; F 4.63; N 10,26

Funnet: 70,6 6,9 4,3 10,2 Found: 70.6 6.9 4.3 10.2

Utgangsmateria let 6-methoxy 2-methyl 3-(4'-piperidy1) indol erholdes på folgende måte: a) 2- methyl 6- methoxy 3-( 4'- pyridy1) indol• Starting material 6-methoxy 2-methyl 3-(4'-piperidy1)indole is obtained in the following way: a) 2-methyl 6-methoxy 3-(4'-pyridy1)indole•

50 g 2-methyl 6-methoxy indol ble innfort i 230 ml pyri-din. Blandingen ble avkjdlet til -40°C og dråpevis tilsatt 87 g benzoylklorid. Blandingen ble omrdrt 3 dager ved omgivende temperatur og i morke. Pyridinet ble fordampet under vakuum, residuet ble vasket med en vandig opplosning av natriumhydroxyd, og vannet ble fordampet. Det erholdte deigaktige produkt ble opplost i 500 ml kokende methanol, hvorefter der under omroring ble tilsatt 200 ml natriumhydroxyd, og tilslutt to porsjoner 200 ml vann. Blandingen ble omrort 2 timer, fikk stå over natten, methanolen ble fordampet under vakuum, og den vandige fase ble ekstrahert med kloro form. Den organiske fase ble torket over natriumsulfat og fordampet under vakuum. Der ble erholdt lOO g urent produkt som ble renset ved kromatografi over aluminiurnoxyd og eluert med benzen, hvorefter elueringsmidlet ble fordampet under dannelse av 34 g av produktet i form av brune krystaller som ble omkrystallisert fra acetonitril. Der ble erholdt 19,5 g 2-methyl 6-methoxy 3-(4'-pyridy1) indol som smeltet ved 196 - 198°C. 50 g of 2-methyl 6-methoxy indole was introduced into 230 ml of pyridine. The mixture was cooled to -40°C and 87 g of benzoyl chloride were added dropwise. The mixture was stirred for 3 days at ambient temperature and in the dark. The pyridine was evaporated under vacuum, the residue was washed with an aqueous solution of sodium hydroxide, and the water was evaporated. The doughy product obtained was dissolved in 500 ml of boiling methanol, after which 200 ml of sodium hydroxide was added while stirring, and finally two portions of 200 ml of water. The mixture was stirred for 2 hours, allowed to stand overnight, the methanol was evaporated under vacuum, and the aqueous phase was extracted with chloroform. The organic phase was dried over sodium sulfate and evaporated under vacuum. 100 g of impure product was obtained which was purified by chromatography over aluminum oxide and eluted with benzene, after which the eluent was evaporated to form 34 g of the product in the form of brown crystals which were recrystallized from acetonitrile. 19.5 g of 2-methyl 6-methoxy 3-(4'-pyridyl) indole were obtained which melted at 196 - 198°C.

b) Bromid av 1-benzyl 4-(6'-methoxy 2'-methyl 3'- indolyl) pyridinium b) Bromide of 1-benzyl 4-(6'-methoxy 2'-methyl 3'-indolyl)pyridinium

3,4 g 2-methyl 6-methoxy 3-(4r<->pyridyl) indol og 2,65 g 3.4 g of 2-methyl 6-methoxy 3-(4r<->pyridyl) indole and 2.65 g

benzpylbromid ble innfort i 30 ml ethylacetat. Blandingen ble oppvarmet under tilbakelopskjoling i 4 timer. Blandingen ble avkjdlet, de dannede gule krystaller ble sentrifugert og vasket med ethylacetat. Efter tdrking ble erholdt 5,7 g av bromidet av 1-benzyl 4-(6'-methoxy 2'-methyl 3'-indolyl) pyridinium som smeltet ved 244 - 246°C. Benzyl bromide was added to 30 ml of ethyl acetate. The mixture was heated under reflux for 4 hours. The mixture was cooled, the yellow crystals formed were centrifuged and washed with ethyl acetate. After drying, 5.7 g of the bromide of 1-benzyl 4-(6'-methoxy 2'-methyl 3'-indolyl)pyridinium were obtained which melted at 244-246°C.

c) 3-(l'-benzyl 1',2<r>,3',6'-tetrahydro 4'-pyridyl) 6- methoxy 2- methyl indol c) 3-(1'-benzyl 1',2<r>,3',6'-tetrahydro 4'-pyridyl) 6-methoxy 2-methyl indole

20,1 g av bromidet av 1-benzyl 4-(6'-methoxy 2'-methyl 3'-indolyl) pyridinium ble innfort i 165 ml methanol og 70 mlvann, og ble derefter avkjdlet til.25°C og tilsatt i små porsjoner 4 g natriumborhydrid slik at temperaturen ikke overskred 30 - 35°C. 20.1 g of the bromide of 1-benzyl 4-(6'-methoxy 2'-methyl 3'-indolyl)pyridinium was introduced into 165 ml of methanol and 70 ml of water, and was then cooled to 25°C and added in small portions of 4 g of sodium borohydride so that the temperature did not exceed 30 - 35°C.

Blandingen ble omrdrt 2 timer ved omgivende temperatur, tilsatt vann, det dannede bunnfall fraskilt og vasket med vann. Efter tdrking under vakuum ble erholdt 15,4 g 3-(1'-benzyl l',2', 3',6'-tetrahydro 4'-pyridyl) 6-methoxy 2-methyl indol som smeltet ved 142 - 143°C. The mixture was stirred for 2 hours at ambient temperature, water was added, the precipitate formed was separated and washed with water. After drying under vacuum, 15.4 g of 3-(1'-benzyl 1',2',3',6'-tetrahydro 4'-pyridyl)6-methoxy 2-methyl indole were obtained which melted at 142 - 143°C .

d) 6- methoxy 2- methyl 3-( 4'- piperidyl) indol d) 6-methoxy 2-methyl 3-(4'-piperidyl) indole

24 g 3-(l'-benzyl 1',2',3',6'-tetrahydro 4'-pyridyl) 6-methoxy 2-methyl indol, 4 g 10 %'s palladium på carbon ble innfort i 300 ml absolutt ethanol. Blandingen ble oppvarmet til 50°C, og hydrogen ble innfort. Efter 2 timer var 2450 ml hydrogen absorbert. Katalysatoren ble filtrert fra, og 3,0 g 10 %'s palladium på carbon ble pånytt innfort. Hydrogeneringen ble fortsatt i ca.'3.1/2 time hvorunder 3250 ml hydrogen ble absorbert. Katalysatoren ble filtrert fra, ethanol ble fordampet under vakuum, og der ble erholdt 16,6 g 6-methoxy 2-methyl 3-(4'-piperidyl) indol som smeltet ved 166°C 24 g of 3-(1'-benzyl 1',2',3',6'-tetrahydro 4'-pyridyl) 6-methoxy 2-methyl indole, 4 g of 10% palladium on carbon were introduced into 300 ml absolute ethanol. The mixture was heated to 50°C and hydrogen was introduced. After 2 hours, 2450 ml of hydrogen had been absorbed. The catalyst was filtered off, and 3.0 g of 10% palladium on carbon was reintroduced. The hydrogenation was continued for about 3.1/2 hours during which time 3250 ml of hydrogen was absorbed. The catalyst was filtered off, ethanol was evaporated under vacuum, and 16.6 g of 6-methoxy 2-methyl 3-(4'-piperidyl) indole was obtained which melted at 166°C

Eksempel 6 2-methoxy 4-acetamido 5-klor N- [G-(4'-(3"-indoly1) Example 6 2-methoxy 4-acetamido 5-chloro N-[G-(4'-(3"-indolyl)

pip eridin) ethyl] benzamid pip eridine) ethyl] benzamide

4,9 g 4-(3'-indoly1) N~(G-amino ethyl) piperidin og 2,1 g triethylamin ble innfort i 350 ml benzen og langsomt ved 10 - 15°C tilsatt en opplosning av 5,2 g 2-methoxy 4-acetamido 5-klorbenzoe-syreklorid i 450 ml benzen. Blandingen ble holdt under omroring i 18 timer, tilsatt vann og ekstrahert med methylenklorid. Den organiske fase ble vasket, torket og konsentrert til tdrrhet, og residuet ble omkrystallisert fra methylethylketon under dannelse av 8 g 2-methoxy 4-acetamido 5-klor N- [G-(4'-(3n-indolyl) piperidin) 4.9 g of 4-(3'-indolyl) N~(G-amino ethyl)piperidine and 2.1 g of triethylamine were introduced into 350 ml of benzene and slowly at 10 - 15°C added a solution of 5.2 g of 2 -methoxy 4-acetamido 5-chlorobenzoic acid chloride in 450 ml of benzene. The mixture was kept under stirring for 18 hours, water was added and extracted with methylene chloride. The organic phase was washed, dried and concentrated to dryness, and the residue was recrystallized from methyl ethyl ketone to give 8 g of 2-methoxy 4-acetamido 5-chloro N-[G-(4'-(3n-indolyl)piperidine)

ethyl] benzamid med smeltepunkt 208°C. ethyl] benzamide with melting point 208°C.

Analyse: C25<H>2<gC>lN403Analysis: C25<H>2<gC>1N4O3

Beregnet, %: C 64,02; H 6,23; N 11,95; Cl 7,51 Calculated, %: C 64.02; H 6.23; N 11.95; Cl 7.51

Funnet: 63,8 6,4 11,8 7,6 Found: 63.8 6.4 11.8 7.6

Eksempel 7 2-methoxy 4-amino 5-klor N-[G-(4'-(3"-indoly1) Example 7 2-methoxy 4-amino 5-chloro N-[G-(4'-(3"-indolyl)

piperidin) ethyl] benzamid piperidine) ethyl] benzamide

En suspensjon av 8 g av produktet erholdt i eksempel 6 i 50 ml ethanol ble tilsatt 400 ml av en opplosning av 8N saltsyre i A suspension of 8 g of the product obtained in Example 6 in 50 ml of ethanol was added to 400 ml of a solution of 8N hydrochloric acid in

ethanol. Blandingen ble kokt under tilbakelopskjoling i 30 minutter, avkjdlet og holdt ved 20°C i 1 time og derefter konsentrert til tdrrhet. Dihydrokloridet av 2-methoxy 4-amino 5-klor N-[G-(4r<->(3u<->indolyl) piperidin) ethyl] benzamid ble omkrystallisert fra aceton, og ble derefter tatt opp i en blanding av methylenklorid og 2N Na2C03, den organiske fase ble torket og konsentrert til tdrrhet. Residuetble omkrystallisert fra ethanol, og der ble erholdt 1,8 g 2-methoxy 4-amino 5-klor N-[G-(4r<->(3M<->indoly1) piperidin) ethyl] ethanol. The mixture was refluxed for 30 minutes, cooled and held at 20°C for 1 hour and then concentrated to dryness. The dihydrochloride of 2-methoxy 4-amino 5-chloro N-[G-(4r<->(3u<->indolyl)piperidine)ethyl]benzamide was recrystallized from acetone, and then taken up in a mixture of methylene chloride and 2N Na 2 CO 3 , the organic phase was dried and concentrated to dryness. The residue was recrystallized from ethanol, and 1.8 g of 2-methoxy 4-amino 5-chloro N-[G-(4r<->(3M<->indolyl)piperidine)ethyl]

benzamid med smeltepunkt 208°C. benzamide with melting point 208°C.

Analyse:<C2>3H2?C1N402Analysis: <C2>3H2?C1N402

Beregnet, %: C 64,70; H 6,38; Cl 8,30; N 13,12 Calculated, %: C 64.70; H 6.38; Cl 8.30; N 13,12

Funnet: 64,4 6,3 8,3 12,9 Found: 64.4 6.3 8.3 12.9

Eksempel 8 2-methoxy 5-sulfamoyl N-[G-(4'-(3"-indoly1) Example 8 2-Methoxy 5-sulfamoyl N-[G-(4'-(3"-indolyl)

piperidin ) ethyl] benzamid piperidine ) ethyl] benzamide

5 g 4-(3'-indoly1) N-(G-amino ethyl) piperidin ble opplost i 50 ml ethylenglycol, hvorefter der ved 140°C langsomt ble tilsatt 2,4 g 2-methoxy 5-sulfamoylmethylbenzoat fremstillet som beskrevet i Acta Chim (Budapest) 1971 69 (1) 81 - 6. Blandingen ble avkjdlet, tilsatt 50 ml methanol, de erholdte krystaller ble fraskilt, renset ved varm opplosning i dimethylformamid og omkrystallisert ved tilsetning av acetonitril. Der ble således erholdt 2,09 g 2-methoxy 5-sulfamoyl N- [(3- (4' - (3u-indoly 1) piperidin) ethyl] benzamid. Sm.p. 283°C. 5 g of 4-(3'-indolyl) N-(G-amino ethyl) piperidine were dissolved in 50 ml of ethylene glycol, after which at 140°C 2.4 g of 2-methoxy 5-sulfamoylmethylbenzoate prepared as described in Acta Chim (Budapest) 1971 69 (1) 81 - 6. The mixture was cooled, 50 ml of methanol was added, the crystals obtained were separated, purified by hot dissolution in dimethylformamide and recrystallized by the addition of acetonitrile. 2.09 g of 2-methoxy 5-sulfamoyl N-[(3-(4'-(3u-indoly 1)piperidine)ethyl]benzamide were thus obtained.M.p. 283°C.

Analyse: C^H^N^S Analysis: C^H^N^S

Beregnet, %: C 60,51; H 6,18; N 12,27; S 7,02 Calculated, %: C 60.51; H 6.18; N 12.27; S 7.02

Funnet: 60,3 6,3 12,2 6,8 Found: 60.3 6.3 12.2 6.8

Eksempler på farmasdytiske komposisjoner: Examples of pharmaceutical compositions:

c) En injiserbar opplosning ble fremstillet efter fdlgende formulering: c) An injectable solution was prepared according to the following formulation:

Claims

1. Process for the preparation of new derivatives of N-[co-(4'-(3"-indolyl) piperidine) alkyl] benzamide as well as their addition salts with inorganic or organic acids, which derivatives have formula I:

where R denotes a hydrogen atom or an alkoxy radical1 with 1-3 carbon atoms, R^ and R which may be the same or different denote a hydrogen atom or an alkyl radical with 1-3 carbon atoms, n is equal to 2 or 3, X^ denotes a hydrogen atom or a Alkoxy radical 1 with 1-3 carbon atoms, X^ denotes a hydrogen atom, fluorine, chlorine or bromine, an amino radical or acetamido and X^ denotes a hydrogen atom or chlorine or an aminosulfonyl radical 1, characterized in that a compound of formula II:

where R, R 2 and R 2 have the previously stated meanings, is reacted with a halide of formula III:

where n has the previously indicated meaning and Hal denotes a chlorine or bromine atom, forming a compound of formula IV:- where R, R1?R2 and n have the previously indicated meanings, after which the product is subjected to a treatment with hydrazine hydrate, forming a compound of formula V:

where R, R^, R^ and n have the previously indicated meanings, which are then reacted with a compound of formula VI:

where A denotes a halogen atom. or an alkoxy radical 1 with 1-3 carbon atoms, denotes a hydrogen atom, fluorine, chlorine or bromine or an acetamido radical, and X^ and X^ have the previously stated meanings, and either a) the obtained derivative of formula I where X 2 denotes a hydrogen atom, fluorine, chlorine or bromine or an acetamido radical, and R, R^, R2, n, X^ and X^ have the previously indicated meanings are isolated, and if desired the derivative is reacted with an inorganic or organic acid in an organic solvent under formation of the corresponding salt, or b) under the condition of having prepared a derivative of formula I in which X2 denotes an acetamido radical, that this derivative is hydrolysed with an inorganic acid in an alkanol to form a derivative of formula I in which X2 denotes an amino radical, and R, R-^j Rg, n, X, and X^ have the previously indicated meanings, and provided that this derivative is reacted with an inorganic or organic acid in an organic solvent to form the corresponding salt.

2. Method according to claim 1, characterized in that a compound of formula II:

where R, R^.and R^ have the previously stated meanings, are converted with a compound of formula VII:

where Hal denotes a chlorine or bromine atom, and n has the former stated meaning, while forming a compound of formula VIII:

where R, R^, R2 and n have the previously stated meanings, after which this is reduced to form a - compound of formula V:

where R, R-p R2 and n have the previously stated meanings, which are then treated as stated in claim 1.

3. Process for the preparation of derivatives of N-[co-(4'-(3" ('indoly 1)Diocridine) a Ikv 1 ] benzamides of formula T ifolos claim 1 and their addition salts with inorganic or organic acids, characterized by a compound of formula V:

where R, R^, R 2 and n have the previously indicated meanings, is reacted with a compound of formula VI:

where A denotes a halogen atom or an alkoxy radical1 with 1-3 carbon atoms, X2 denotes a hydrogen atom, fluorine, chlorine or bromine or an acetamido radical, and X1 and X3 have the previously stated meanings, and that either a) the obtained derivative of formula I where X2 denotes a hydrogen atom , fluorine, chlorine or bromine or an acetamido radical and R, R 1 , R 2 , n, X 2 and X 2 have the previously indicated meanings are isolated, if it is desired that the derivative obtained is reacted with an organic or inorganic acid in an organic solvent to form the corresponding salt, or b) on condition of having prepared a compound of formula I in which X2 denotes an acetamido radical, that this derivative is hydrolysed with an inorganic acid in an alkanol to form a compound of formula I in which X2 denotes an amino radical, and R, R^ R2, n, X^ ^ and X3 have the previously indicated meanings, and if desired this is reacted with an inorganic or organic acid in an organic solvent to form the corresponding salt.

4. Process according to claim 1, 2 or 3, characterized in that derivatives of formula I according to claim 1 are prepared, as well as their addition salts with inorganic or organic acids, where X^ and X^ denote a hydrogen atom, and R, R^, n and X^ have the previously indicated meanings.

5. Method according to claim 1, 2 or 3, characterized in that compounds of formula I according to claim 1 are prepared, as well as their addition salts with inorganic or organic acids, where R-j , X^ and X^ denote a hydrogen atom, n is equal to 2, X^ denotes a hydrogen atom or fluorine, and R and R^ have the previously indicated meanings.