NO860008L - PROCEDURE FOR THE PREPARATION OF 1,3-DISUBSTITUTED TETRAHYDROPYRIDINE. - Google Patents

Description

The present invention relates to a process for the production of new 1-(3-indolyl)-tetrahydropyridine carboxylic acid esters of the formula

where R stands for hydrogen or methoxy, and salts thereof, especially pharmaceutically acceptable salts.

Salts of the compounds of formula I are e.g. pharmaceutically acceptable acid addition salts thereof.

Pharmaceutically acceptable acid addition salts are, for example, salts with suitable mineral acids, such as halogenated acids, sulfuric acid or phosphoric acid, e.g. hydrochloric acid, hydrogen bromide, sulfates, hydrogen sulfate or phosphates, or salts with suitable organic carboxylic or sulfonic acids, such as optionally hydroxylated aliphatic mono- or dicarboxylic acids, e.g. acetates, oxalates, succinates, fumarates, maleates, maleates, ascorbinates or citrates, or aliphatic or aromatic sulfonic acids or N-substituted sulfamic acids, e.g. methanesulfonate, benzenesulfonates, p-toluenesulfonates or N-cyclohexylsulfaminates (cyclamates).

Pharmaceutically unsuitable salts can also be used for isolation or purification. Only the pharmaceutically tolerable, non-toxic salts are therefore preferred for therapeutic use.

Within the state of the art are certain isomers of the compound

of formula I, where R stands for hydrogen, are known. E.g. is proposed in J. Am. Chem. Soc. B7, page 5 461 - 5 467 (1965) 1-[2-(indol-3-yl)-ethyl]-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester (Isorner A) as an intermediate for the synthesis of the alkaloid dihydro-corynanteol. Further described in J. Am. Pharm. ass. 4_U, page 58 9-590 (iy-51) 1-(indol-3-yl)methyl 1-1,2,5,b-tetrahydropyridin-3-

carboxylic acid ethyl ester (Isomer B) and is proposed, on the basis of an alleged structural braid shaft with the medicinal ergonovine, for investigation of possible corresponding oxytoxin-like properties. Further described in J. Chem. Soc. (C), pages 736-743 (1971) 1-[2-(indol-3-yl)ethyl]-1,2,5,6-tetrahydropyridine-4-carboxylic acid methyl ester (Isomer C) as possible intermediate for 2-methoxycarbonyl -octahydro-indolo[2,3-ajquinolizine, the base of which is found in some alkaloids. The compounds of formula I, on the other hand, are new. Within the state of the art, there is no evidence for a possible effect of 1-(indol-3-yl-alkyl)-tetrahydropyridine-3-carboxylic acid compounds on the central nervous system. The present invention is based on the surprising observation that the compounds of formula I and pharmaceutically acceptable salts thereof have valuable pharmacological effects on the central nervous system, particularly pronounced nootropic properties.

Consequently, the effects are reduced when applied to mice in doses

from approx. 0.1 mg/kg i.p. as well as p.o. the amnesiogenic effect of an electric shock to at least the same degree as that following a nootropic effective dose of Piracetam (100 mg/kg i.p.). To demonstrate the nootropic effect, for example, the two-section experiment can be used. From the literature regarding pharmacological models of this type, e.g. mentioned: S.J. Sara and D. Lefevre, Psychopharmacologia 2_5, 32-40 (1972); "Hypoxia-induced amnesia in one-trial learning and pharmacological protection by piracetam". Boggan, W.O. and Schlesinger, K., in Behavioral Biology Yl, 127-

134 (1974). In this model, 1-[2-(indol-3-yl)ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ester at doses of 0.1 to 1.0 mg/kg e.i. a highly significant (p<0.01) antiamnesiogenic effect. Isomer B shows at 0.1, 1.0 and 10 mg/kg i.p. a similar but less significant (p<0.05) effect. Isomer A certainly shows a certain effect at 1.0 mg/kg (only one-sided significant),

at 0.1 and 10 mg/kg no significant effect, therefore overall an uncertain effect. The isomer C shows at 0.1, 1.0 and 10 mg/kg i.p. no significant amnesiogenic effect.

In particular, the compounds of formula I show a strong memory-enhancing effect in the "Step-down Passive Avoidance Test"

according to Mondadori and Waser, Psychopharmacology 6J3, 297-300 (1979). The substances are effective when administered intraperitoneally 30 minutes before the learning trial (effective dose 0.1, 1, 10 mg/kg). A clear effect could also be determined by oral administration 60 minutes before the learning trial (effective doses 0.1, 1, 10 mg/kg) as well as by intraperitoneal administration immediately after the learning trial (effective doses 0.1, 1, 10 mg/kg) . In this model, 1-[2-(indol-3-yl)ethyl]-1,2,5,6-tetrahydro-pyridinecarboxylic acid methyl ester at 0.1 and 1.0 mg/kg i.p. a significant (p<0.05)

and at 10 mg/kg i.p. a highly significant (p<0.01) memory improvement, while the isomers A, B and C at 0.1 and 1.0 mg/kg i.p. does not show any, and only at 10 mg/kg i.p. shows a significant (p<0.05) effect. From this it appears that to achieve the memory-improving effect of 0.1 mg/kg i.p. of 1-{2-(indol-3-yl)ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester, 10 mg/kg i.p. is needed, i.e. a 100 times greater dose of one of the isomers A, B and C. The significance statements refer, in the same way as the statements in the previous section, to the U-test according to Mann and Whitney.

Above all due to the latter findings, the compounds of formula I and their pharmaceutically acceptable salts are considered to be very suitable for use as nootropics, for example for the treatment of cerebral performance insufficiency, especially for memory disorders of various origins, such as senile dementia or dementia of the Alzheimer type, further of sequelae to brain trauma

and apoplexies. In addition to this, there is also the excellent durability of the compounds.

The invention specifically relates to the preparations of the compounds of formula I indicated in the examples and their pharmaceutically acceptable salts, especially acid addition salts, such as hydrogen chlorides or hydrogen bromides.

The process for the preparation of the compounds of formula I, including salts thereof, is based on synthesis methods known per se and is characterized by the fact that, where A^ means an acid anion, the excess double bonds are reduced to single bonds, or

b) from a compound of the formula

where one of the residues and X2 is hydrogen and the other is a cleavable residue, or a salt thereof, X-^ and X2 cleave to form the double bond, or

c) ring-closes a compound of the formula

or a salt thereof to the corresponding compound of formula

In, or

d) reacts the compounds of the formulas

where X-^ is a nucleofuge leaving group, or salts thereof, with

each other, or

e) ring-closes a compound of the formula

or a salt thereof, or

f) in a derivation of the formula

in

where R-, is a residue which can be transferred to methoxycarbonyl, or a salt thereof, transfers R^ to methoxycarbonyl, or

g) for the preparation of the compound of formula I, where R is methoxy, in a compound of the formula

where X^ is a residue that can be transferred to methoxy or exchanged for methoxy, transfer X4 to methoxy or remove the group for methoxy, and if desired, convert the invention produced according to the method into another compound of formula I, dividing a produced isomer mixture into the individual components and/or transfers a free compound prepared according to the method to a salt or transfers a prepared salt to the free compound or to another salt.

Progress feed variant a)

The anion A is e.g. the anion from a strong protonic acid, which is

capable of transferring alcoholic hydroxy to reactive esterified hydroxy, e.g. a halide ion, such as chloride, bromide or iodide, or a sulfonation, especially the anion of an aliphatic or aromatic sulfonic acid, e.g. methanesulfonate, ethanesulfonate or

methosulfato-ion, or denzensulfonate, p-toluenesulfonate or p-bromobenzenesulfonation.

The reduction of the excess double bonds takes place in the usual way, for example by the action of a di-light metal hydride, such as an alkali metal trilavereal oxyaluminium hydride, e.g. of lithium tritertiary butyloxyaluminum hydride, or an optionally substituted alkali metal borohydride, such as lithium borohydride, potassium borohydride, sodium borohydride or sodium cyanoborohydride. The reaction is preferably carried out in a solvent customary for the purpose. Common is e.g. for the reaction with lithium tri-tertiary butyloxyaluminum hydride etheric solvent media, such as diethyl ether, dioxane or tetrahydrofuran, and for the reaction with optionally substituted alkali metal borohydrides, especially lower alkanols, such as methanol or ethanol, further water.

The intermediates II can, for example, be obtained by reacting a compound of the formula

where A stands for reactive esterified hydroxy corresponding to the anion A<®>, with nicotinic acid methyl ester.

Method variant b)

In intermediates III, the residue X^resp. X^which is different from hydrogen optionally esterified hydroxy, such as hydroxy, with a sulfonic acid, such as alkane or optionally substituted benzenesulfonic acid, esterified hydroxy, e.g. methane, ethane, benzene, p-toluene or p-bromobenzenesulfonyloxy, with a carboxylic acid esterified hydroxy, such as lower alkanoyloxy, e.g. acetoxy, or halogen, e.g. chlorine or bromine, or an optionally substituted amino-, ammonium- or oxidoammonio group, such as amino, optionally substituted anilino, mono- or dilavealkylamino, e.g. mono- or dimethylamino, trilower alkylammonio, e.g. trimethylammonio, or N,N-dilaverealkyl-, e.g. N,N-dimethyl-N-oxido-ammonio. The cleavage of X-^ and X 2 takes place in the usual way, starting from the compounds III, where one of the residues X^ and X 2 is lower alkanoyloxy or an optionally substituted oxidoammonio group, e.g. N,N-dilaverealkyl-N-oxido-ammonio, for example thermally, e.g. in temperature ranges from approx. 60 to approx. 150°C. If the one of the residues X-^ and X2 which is different from hydrogen possibly represents a hydroxy esterified with carboxylic acid or optionally substituted amino, work is required in the presence of an acidic agent, especially a protonic acid, such as a mineral acid, or an acidic salt of this, e.g. of hydrochloric acid or hydrobromic acid, sulfuric acid, or sodium hydrogen sulfate, phosphoric acid or polyphosphoric acid, a lower alkanoic acid, e.g. acetic acid, an organic, sulphonic acid, e.g. p-toluenesulfonic acid, or an acidic ion exchanger. Water, the corresponding carbonic acid, ammonia or the corresponding amine, which is preferably removed physically, e.g. by distillation or azeotropic distillation, or chemical, e.g. by means of a water-attracting agent or formation of ammonium salts, from the reaction mixture.

If the one of the residues X 1 and X 2 which is different from hydrogen stands for trilower alkylamino, a hydroxy esterified with sulphonic acid or a halogen, one preferably works in the presence of a base, such as the hydroxide, carbonate or alcoholate of an alkali metal, e.g. of sodium or potassium hydroxide, potassium carbonate or sodium methanolate, or a tertiary organic amine, e.g. diaza-bicyclononane or diazabicycloundecane.

The intermediate products III can be prepared in a manner known per se, whereby the preparation and further reaction of the compounds is preferably carried out in such a way that the intermediate product III can be further reacted without isolation.

Consequently, one can, for example, submit a compound of the formula

where Y stands for oxo or optionally substituted imino, simultaneous treatment with an acid, especially an aliphatic-carboxylic acid, e.g. acetic acid, and a base, especially an aliphatic amine, such as a mono-, di- or tri-lower alkylamine or lower alkylene- or aza-, oxa- or thialaverealkyleneamine, e.g. triethylamine, piperidine or morpholine. Thereby, the compound XII intermediately cyclizes to an intermediate III, where X stands for hydroxy or optionally monosubstituted amino, which under the reaction conditions reacts further to the final product I. However, the reaction can also be kept at the stage for the intermediate III, by carrying out the cyclization in presence of a metal base, such as a metal alcoholate, e.g. sodium methanolate or -ethanolate. The compounds XII are in turn obtained e.g. by reacting a reactive indol-3-yl alkanol ester of the formula

where X-j stands for reactive esterified hydroxy, first with 6-alanine methyl ester and then with acrolein or an optionally functionally converted aldehyde of the formula Y^CH^-CH^-CH^O (XIII,^ = reactive esterified hydroxy).

Intermediates III, where. X-^ stands for trilower alkylammonio,

can, for example, be achieved by completely lower alkylation of the compounds III, where Xj stands for amino or lower alkylamino, especially when treated with a reactive lower alkanol ester, such as a lower alkyl bromide or iodide. Intermediates III, where X^ is N-dilaverealkyl-N-oxido-ammonio, are obtained in particular by N-oxidation of corresponding dilaverealkyl compounds (III, X-^ = dilaverealkylamino), e.g. by means of organic peroxy compounds.

Intermediates III, where X^ is hydroxy, can also be obtained by reduction of a corresponding compound of the formula

or the corresponding 4-oxo tautomer, for example by catalytic hydrogenation, in particular with platinum oxide, or by reaction with an alkali metal trilavereal oxylithium aluminum hydride or alkali metal borohydride, e.g. with lithium tritertiary butyloxyaluminum hydride, sodium or lithium borohydride or sodium cyanoborohydride. The compounds XIV, in turn, can be prepared by reacting a compound of the formula with an approximately double-molar amount of a compound of the formula Y1-CH2CH2-COOCH3 (XVI,^ = reactive esterified hydroxy) for example acrylic acid methyl ester and ring-closing the reaction product of the formula

e.g. in the presence of a metal base, such as an alkali metal alcoholate, e.g. sodium methanolate.

Intermediates III, where hydroxy is esterified, can e.g. is obtained by esterification of corresponding hydroxy compounds, by reacting these with the anhydride or a halide of a sulphonic or carboxylic acid, such as an alkane or optionally substituted benzenesulphonyl chloride, e.g. with methane, ethane, benzene, p-toluene or p-bromobenzenesulfonyl chloride or a lower alkanoic acid anhydride or halide, e.g. with acetic anhydride, or with thionyl chloride or phosphorus tribromide. If you thereby work in the presence of a base, e.g. potassium carbonate, triethylamine or pyridine, the reaction can be carried out in such a way that the formed ester III directly reacts further to the corresponding end product I.

The intermediate III, where X2 is halogen, can e.g. is obtained by halogenating a compound of the formula

available by reaction of a compound of the formula

where X3 is reactively esterified hydroxy, with piperidine-3-carboxylic acid methyl ester, in the usual manner in the a-position to methoxycarbonyl groups, e.g. by treatment with chlorine or bromine, such as by means of N-chloro- or N-bromosuccinimide.

In this connection, reactive esterified hydroxy is particularly halogen, such as chlorine, bromine or iodine.

Method variant c)

The rearrangement, as expressed by Fischer's indole synthesis splits off ammonia, can take place in the usual way, e.g. by acid treatment, i.e. action of a suitable proton or Lewis acid. As protonic acids, for example mineral acids, such as sulfuric acid, phosphoric acid, as well as hydrochloric acid in a lower alkanol, such as ethanolic hydrochloric acid, and organic sulphonic acids, as a lower alkanol, e.g. methanesulfonic acid, or optionally substituted benzenesulfonic acids, such as benzene or p-toluenesulfonic acid, or also organic carboxylic acids, such as lower alkanoic acids, e.g. acetic acid, in consideration. Son Lewis acids are, for example, coordinatively unsaturated heavy metal compounds, such as coordinatively unsaturated halides of boron, aluminium, antimony, zinc, copper, nickel, iron, chromium or tin, e.g. stannous chloride or copper I chloride, respectively. -bromide suitable. The turnover is preferably carried out during heating, e.g. in the temperature range from approx. 60 to 170°C,

if necessary under inert gas.

The intermediate IV can e.g. produced by condensing

an optionally correspondingly substituted phenylhydrazine in the usual feed with 3-[1-(3-methoxycarbonyl-1,2,5,6-tetrahydropyridyl)]-propionaldehyde.

Method variant d)

Nucleofuge leaving groups X are, for example, reactive esterified hydroxy groups, such as halogen, e.g. chlorine, bromine or iodine, or of sulfonic acids, such as lower alkane or optionally substituted benzenesulfonic acids, or sulfonyloxy groups derived from halosulfonic acids, e.g. methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, p-bromobenzenesulfonyloxy or fluorosulfonyloxy.

The reaction of the compounds V and VI takes place in the usual way, for example in the presence of a basic condensation agent, such as a tertiary organic nitrogen base, e.g. pyridine or a lower alkylamine, such as triethylamine. However, alkali metal hydroxides or carbonates can also be used, e.g. sodium hydroxide, if necessary in the presence of phase transfer agents ("phase transfer catalyst"), e.g. benzyl trimethyl ammonium hydroxide.

The starting substance V can e.g. produced by condensing

a corresponding indole with a 1,2-dihaloethane or a 2-halo-ethanol, with the help of oxalyl chloride to the corresponding 3-chloro-oxalylindole, alcoholizes this e.g. with ethanol to the corresponding 3-ethoxalylindole and reduces the obtained oxalyl acid ester e.g. by means of lithium aluminum hydride in diethyl ether, and the obtained 2-(3-indolyl)-ethanol is then reactively esterified, e.g. by reaction with a halogenating or sulfonylating agent, e.g. with thionyl chloride, phosphorus tribromide or a sulfonic acid chloride, such as p-toluene acid chloride.

The starting substance VI is obtained, e.g. by demethylating arecoline by treatment with a chloroformate alk(en)yl ester, and the resulting 1-alk(en)yloxycarbonyl derivative of VI is hydrolysed to the compound. However, one can also rearrange 6-(p-toluenesulfonyl-oxyimino)-hex-2-ene-carboxylic acid methyl ester with diethylaluminum chloride to the corresponding 5,6-dihydropyridine-3-carboxylic acid methyl ester and reduce this with sodium borohydride to 1,2, 5,6-tetrahydroanalogue compounds.

Method variant e)

The cyclization of the compounds VII takes place spontaneously or by treatment with a base, where alkali metal alkanolates, amides or hydrides can be used as bases, e.g. sodium methanolate, potassium tertiary butanolate, sodium amide, lithium N,N-diisopropylamide or sodium hydride.

The intermediates VII are preferably prepared in situ and, according to the invention, are reacted further without isolation, in which 2-bromo-methyl-penta-2,4-diene-carboxylic acid methyl ester is reacted in the presence of a base, such as one of those mentioned above, e.g. sodium hydride, or an alkali metal hydroxide or carbonate, e.g. of sodium hydroxide or potassium carbonate, with a compound of the formula

e.g. in dimethylformamide, N-methylpyrrolidone or dimethylsulfox-syd. The starting materials required for the reaction are obtained, e.g. by reducing a 2-(5-R-indol-3-yl)-acetonitrile, e.g. with lithium aluminum hydride or diethyl ether or tetrahydrofuran, or reacts a compound of the formula

where X-j e.g. is bromine, with ammonia, resp. condenses acrolein

with a 2-triphenylphosphorylenepropionic acid methyl ester and in the produced 2-methyl-penta-2,4-diene-carboxylic acid methyl ester the 2-methyl group is brominated, e.g. using N-bromosuccinimide.

Method variant f)

The radical R^ which can be transferred to methoxycarbonyl is, for example, carboxy, anhydrous carboxy, esterified carboxy which is different from methoxycarbonyl, trimethoxymethyl, methoxycarbimino of the formula -C(=Nri)-OCH^ or cyano. Anhydrous carboxy is, for example, halocarbonyl, such as chlorocarbonyl. Esterified carboxy which is different from methoxycarbonyl is, for example, esterified carboxy with an aliphatic, araliphatic or aromatic alcohol (except for methanol), such as lower carboxycarbonyl (except for methoxycarbonyl), e.g. ethoxy-, propyloxy-, isopropyloxy- or tertiary butyloxycarbonyl, lower alkenyloxycarbonyl, e.g. vinyloxycarbonyl, phenyl lower oxycarbonyl, e.g. benzyloxycarbonyl, or optionally substituted phenoxycarbonyl, e.g. phenoxy-, p-nitrophenoxy- or 2,4-dinitrophenoxycarbonyl.

The transfer of the aforementioned group R^ to methoxycarbonyl occurs

proceeds in the usual way, for example by hydrolysis or methanolysis. Consequently, one can solvolyse trimethoxymethyl, resp. methoxycarbimino, by hydrolysis under acidic conditions, carboxy by transfer on

a salt-, respectively alkali metal salt form, and reaction with a methylating agent, e.g. with methyl iodide or dimethyl sulfate, or especially reaction with methanol under acidic conditions, anhydrous carboxy by reaction with methanol under basic conditions, esterified carboxy different from methoxycarbonyl by reaction with methanol under acidic or basic conditions, as well as cyano by reaction with methanol in the presence of water under acidic conditions, to methoxycarbonyl.

Solvolysis reactions under acidic conditions are carried out, for example, in the presence of an acidic agent, such as a protonic acid, e.g. a mineral acid such as sulfuric acid, phosphoric acid or a hydrohalic acid, e.g. hydrogen chloride or -bromic acid, respectively an acid salt of such an acid, e.g. ammonium chloride, or an organic sulphonic acid, e.g. p-toluenesulfonic acid, if necessary in the presence of et

solvent or diluent, e.g. one with water, respectively

with methanol, miscible solvent, and/or under heating, e.g. in the temperature range from approx. 20° to approx. 120°C, e.g. around the boiling temperature, i.e. about. 60° to 70°, respectively

90° to 105°C.

In solvolysis reactions under basic conditions, the reaction components VIII are reacted, e.g. with an alkali metal or alkaline earth metal alcoholate, e.g. with sodium ethanolate. However, the basic methanolysis of anhydrous or esterified carboxy groups can also take place in the presence of an alkali metal hydroxide, e.g. potassium hydroxide, the basic methanolysis of anhydrous carboxy also in the presence of an alkali metal carbonate, e.g. sodium or potassium carbonate, or an organic nitrogen base, such as a trilower alkyl or sterically hindered dilower alkylamine, e.g. triethylamine or diisopropylamine, or a tertiary aromatic nitrogen base, e.g. pyrridine. If necessary, one works in the presence of a solvent or diluent, such as a solvent miscible with water or methanol, and/or during cooling or heating, e.g. in the temperature range from approx. -50 to +110°C.

In a preferred embodiment of process variant f) carboxy R. is transferred by esterification, e.g. by reaction with methanol in the presence of a mineral acid, such as sulfuric acid or hydrochloric acid, by transfer into a metal salt, especially an alkali metal salt and subsequent reaction with a methylating agent, for example a reactive ester, i.e. a hydrohalic acid, sulfuric acid or sulphonic acid ester of methanol, e.g. with methyl iodide or methyl bromide, dimethyl sulfate, p-toluenesulfonic acid methyl ester or fluorosulfonic acid methyl ester, or by reaction with diazomethane,

to methoxycarbonyl.

In another preferred embodiment, one starts from a compound VIII, where R^ is cyano and reacts this in the presence of ammonium chloride with approx. 90-99.5%, respectively about. 97-99%, e.g. 98% methanol. Hereby, the cyano group is temporarily transferred to the methoxy-carbimino group, which without isolation is hydrolyzed to methoxycarbonyl.

IN

Another residue R-^ which can be transferred to methoxycarbonyl is the methoxy-methyl group, which oxidatively, e.g. by treatment with a manganese VII or VI compound, e.g. with potassium permanganate or chromium trioxide in aqueous acetone or aqueous pyridine,

or with potassium dichromate in acetic acid or dilute sulfuric acid, can be transferred to methoxycarbonyl R-, . However, you can also

start from a starting material where is hydroxymethyl, and oxidize this in the presence of methanol, for example by treatment with manganese dioxide in methanol as reaction medium.

Starting material f et VIII, where R-^ is optionally esterified carboxy or cyano, is prepared, for example, in the same way as described for the compounds I, where, according to method variants a) to e) or g), starting materials II, III, IV, VI, VII, XII or IX, which instead of the methoxycarbonyl group exhibits

one of the aforementioned groups R^. Then, cyano R- can be transferred by treatment with methanol or a hydrogen halide, such as hydrobromic or hydrochloric acid, or with sulfuric acid in methoxycarbimino and free carboxy, e.g. on treatment with thionyl chloride in the presence of pyridine, to halocarbonyl.

Method variant g)

The radical X^ which can be transferred to methoxy is, for example, hydroxy, which can be transferred by reaction with a methylating agent, such as a hydrogen halide, sulfuric or sulphonic acid ester of methanol, e.g. with a methyl halide, such as methyl bromide or methyl iodide, dimethyl sulfate or an alkanesulfonic acid, optionally substituted benzenesulfonic acid or halosulfonic acid methyl ester, such as methane, ethane, benzene, p-bromobenzene, p-toluene or fluorosulfonic acid methyl ester, in the presence of a base, as an alkali metal or alkaline earth metal hydroxide or carbonate, e.g. sodium or potassium hydroxy or above all potassium carbonate in acrylic alcohol or acetone, to methoxy. Against methoxy exchangeable residues X^

are, for example, halogen atoms, such as chlorine, bromine or iodine, which by reaction with an alkali metal or alkaline earth methanolate, e.g. with sodium methanolate, can be replaced by methoxy.

The starting materials IX are obtained, for example, by condensing a corresponding 5-X^-tryptamine with approximately twice the molar amount of acrylic acid methyl ester, and transferring the reaction product, e.g. as described for method variant b) to the corresponding 1-[(5-X4-indol-3-yl)ethyl]-1,2,5f 6-tetrahydro-pyridine-3-carboxylic acid ethyl ester.

Compounds prepared according to the method can be transferred in the usual way to other compounds of formula I.

For example, free salt-forming compounds can be produced on i

and transferred in a known manner to salts, e.g. by reacting a solution of the free compound in a suitable solvent or a solvent mixture with a corresponding base or acid, or with a suitable ion exchanger.

Prepared salts can be transferred to the free compounds in a manner known per se, e.g. by treatment with a base, such as an alkali metal hydroxide, an alkali metal carbonate or hydrogen carbonate or with ammonia.

Manufactured salts can be transferred in a manner known per se to other salts, acid addition salts, e.g. by treating a salt of an organic acid with a suitable metal salt, such as a sodium, barium or silver salt, an acid in a suitable solvent, the inorganic salt formed being insoluble and thus separated from the reaction mixture.

The compounds, including their salts, can also be obtained in the form of hydrates, or contain the solvent medium used for crystallization.

Because of. the close relationship between the new compounds in free form and in the form of the salts, in the above and in what follows free compounds shall also be understood as salts, and correspondingly under the term salts also be understood free compounds.

The invention also relates to those embodiments of the process where one starts from the intermediate product that occurs at any step in the method and carries out the remaining steps, or uses a starting material in the form of a salt,

or especially forms this under the reaction conditions.

Consequently, intermediates of the formulas III or XIII according to method variant b) or h) is formed in situ and converted further without isolation.

New starting materials, e.g. of formulas II, III, IV, VIII and

IX, which has been developed specifically for the production of the compounds according to the invention, especially compounds which are initially mentioned as starting materials leading to particularly preferred compounds of formula I, the method for producing these compounds as well as their use as intermediates, are also the subject of the present invention.

The new compounds of formula I can e.g. find use in the form of pharmaceutical preparations, which contain a therapeutically effective amount of the active substance, possibly together with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers, which are suitable for enteral administration, e.g. oral or parenteral administration. Consequently, tablets or gelatin capsules are used, which contain the active substance together with diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or lubricants, e.g. diatomaceous earth, talc, stearic acid or salts thereof, such as magnesium

or calcium stearate, and/or polyethylene glycol. Tablets may also contain binders, e.g. magnesium aluminum silicate, starches, such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if desired, explosives, e.g. starch, agar, alginic acid or a salt thereof, such as sodium alginate, and/or effervescent mixtures, or adsorbents, dyes, flavors and sweeteners. Furthermore, the new compounds of formula I can be used in the form of parenterally administrable preparations or infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, whereby these can, for example, be prepared before use by lyophilized

preparations containing the active substance alone or together with a carrier material, e.g. mannite. The pharmaceutical preparations may be sterilized and/or contain excipients, e.g. preservation, stabilization, moisturizing and/

or emulsifiers, solubilizers, salts for regulating the osmotic pressure and/or buffers. The present pharmaceutical preparations, which, if desired, may contain other pharmacologically active substances, are prepared in a manner known per se, e.g. using conventional mixing, granulating, coating, dissolving or lyophilization methods, and contains from approx. 0.1% to 100%, especially from approx. 1% to approx. 50%, lyophilisates up to 100%, of the active substance.

The invention further relates to the use of the compounds of formula I, preferably in the form of pharmaceutical preparations. The dosage may depend on various factors, such as the method of administration, species, age and/or individual condition. The daily dose for oral use is between approx. 5 and approx. 50 mg/kg for warm-blooded mammals with a weight of approx. 70 kg, preferably between approx. 0.3 g and approx. 3.0 g.

The following examples serve to illustrate the invention: Temperatures are indicated in °C, pressure in mbar.

Example 1

22.4 g of 1-bromo-2-(3-indolyl)-ethane, 22.2 g of 1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrogen bromide (Guvacolin hydrogen bromide) and 39 g of N-ethyl -N,N-diisopropylamine is dissolved under nitrogen in 750 ml of dimethylformamide and stirred for 16 hours. It is then evaporated under reduced pressure to approx. 300 ml, 500 ml of water are added and shaken out 3 times, each time with 250 ml of dichloromethane. The organic phases are collected and decanted 3 times, each time with 10 ml of n-hydrochloric acid. The aqueous phases are collected, made basic with 40% caustic soda and decanted again 3 times, each time with 100 ml of dichloromethane. The new organic phases are collected, washed with water and then with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. The evaporation residue

dissolve in 100 ml of hot diethyl ether and mix with 150 ml of n-hexane. After cooling, the 1-[2-(indol-3-yl)-ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester crystallizes out, which is filtered off and dried; mp 76-77°,<1>H-NMR spectrum (250 MHz, CDCl 3 ): Singlet (3H) at 6 = 3.76 pm.

Example 2

25.4 g 1-bromo-2-(5-methoxyindol-3-yl)-ethane, 22.2 g 1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrogen bromide (Guvacolin hydrogen bromide) and 39 g N -ethyl-N,N-diisopropylamine is dissolved under nitrogen in 750 ml of dimethylformamide and stirred for 16 hours. It is then evaporated under reduced pressure to approx. 300 ml, 500 ml of water are added and it is shaken out 3 times, each time with 250 ml of dichloromethane. The organic phases are collected and decanted 3 times, each time with 80 ml of n-hydrochloric acid. The combined aqueous phase is made basic with 40% caustic soda and decanted again 3 times, each time with 100 ml of dichloromethane. The organic phases are collected, washed with water and then with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. The evaporation residue is dissolved in 100 ml of dichloromethane and mixed with 200 ml of diethyl ether. After cooling, the 1-[2-(5-methoxyindol-3-yl)-ethyl |-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester crystallizes out, which is filtered off and dried; melting point 156-158°.

Example 3

21.3 g of 1-[2-(indol-3-yl)-ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester are dissolved in 100 ml of methanol and mixed with stirring with 20 ml of methanolic hydrobromic acid (4n) . 200 ml of diethyl ether are then added. The hydrogen bromide of 1-[2-(indol-3-yl)-ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester with melting point 215-218° is crystallized. In an analogous way, the hydrogen chloride (melting point 208-209°) and the fumarate (melting point 214° during decomposition.

Example 4

15.7 g of 1-[2-(5-methoxyindol-3-yl)-ethyl]-1,2,5,6-tetrahydropyridine 3-carboxylic acid methyl ester is dissolved in 100 ml of methanol and mixed with stirring with 14 ml of methanolic hydrochloric acid (4n ). It is evaporated until

dryness, the residue is taken up in 170 ml of hot acetone, cooled and filtered. The hydrogen chloride of 1-[2-(5-methoxyindol-3-yl)-ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester with melting point 177-178° is obtained.

Example 5

Into a suspension of 6.5 g (18 mmol) 1-[2-(indol-3-yl)-ethyl]-3-methoxycarbonyl-pyridinium bromide in 43 ml of methanol is added with stirring at -10° over the course of 90 minutes , 1.41 g of sodium borohydride. It is reheated for 1 hour at 0°C and 2 hours at room temperature, mixed with 50 ml of water and decanted twice, each time with 100 ml of dichloromethane. The dichloromethane phase is collected,

dried over magnesium sulfate and evaporated to dryness. The crude product is resolved chromatographically on 150 g silica gel (0.063-0.2 mm) with acetic acid ethyl ester as eluent, and is transferred by treating the evaporated main eluate with ethereal hydrochloric acid to 1-[2-(indol-3-yl)-ethyl]-1, 2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrogen chloride with melting point 208-209°.

The starting material can e.g. produced in the following way:

11.2 g (50 mmol) of 2-(indol-3-yl)-1-bromoethane and 9.3 g (67.5 mmol) of nicotinic acid methyl ester are suspended in 50 ml of butan-2-one and heated for 72 hours under stirring until boiling. The mixture is allowed to cool, the solvent is sucked off and it is dried under reduced pressure.

The 1-[2-(indol-3-yl)-ethyl]-3-methoxycarbonyl-pyridinium bromide produced melts at 215-217°.

Example 6

302.4 g of a mixture of cis- and trans-4-hydroxy-1-[2-(indol-3-yl)-ethyl]-piperidine-3-carboxylic acid methyl ester are dissolved in a 2.5 l sulfurization flask with stirrer, dropping funnel and thermometer -hydrogen chloride in 800 ml of pyridine, cooled to 0° to 5°, and mixed with stirring at 0° to 5° dropwise with 137.4 g of methanesulfonyl chloride. It is stirred for 4 hours at room temperature, heated to 53° to 56°, stirred for 4 hours at approx. 55° and allowed to stand overnight. The reaction mass is carried out with 800 ml of acetone, filtered and washed with acetone. This is then carried out with 500 ml of acetonitrile, cooled to 5° and filtered again. The crude 1-[2-(indol-3-yl)-ethyl]-1,2,5,6-tetrahydro-pyr idin-3-carboxylic acid methyl ester produced melts at 108-110°. It is recrystallized from acetone and then melts at 109-110°.

The starting material can be produced in the following way:

153 g of sodium methanolate in 1,000 ml of dimethylformamide are introduced while stirring into a 5 1 sulphurisation flask with stirrer, thermometer and dropping funnel. It is then added drop by drop over the course of 12

hours a solution of 665 g of N-[2-(indol-3-yl)-ethyl]-imino-di(propionic acid) dimethyl ester in 680 ml of dimethylformamide, whereby the reaction temperature rises to approx. 40°. It is stirred for 3 hours at room temperature, the solvent is distilled off under reduced pressure at no more than 40°, the mixture is poured into a mixture of 2,100 ml of 5n-hydrochloric acid and 500 ml of toluene, filtered, washed with cold methanol and dried at 40° under reduced pressure. The 1-[2-(indol-3-yl)-ethyl]-piperidin-4-one-3-carboxylic acid methyl ester or 1-[2-(indol-3-yl)-ethyl]-4-hydroxy-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrogen chloride of melting point 185-187°; Rf = 0.61 (chloroform/methanol 9:1).

In a 6 1 sulfurization flask with stirrer, thermometer and a 250 ml round flask connected via a rubber hose, 337 g of 1-[2-(indol-3-yl)-ethyl]-piperidin-4-one-3-carboxylic acid methyl ester hydrogen chloride are placed in 3 300 ml of methanol. It is cooled with stirring to -15°, and from the round flask of 250 ml, 68 g of sodium borohydride are added in portions over 15 hours at -15 to -5°.

It is stirred for 1 hour at 0°, the solvent is distilled off under reduced pressure at a bath temperature of no more than 40°, it is mixed with 1,500 ml of acetic acid ethyl ester, 1,000 ml of ice water and 50 ml of saturated potassium carbonate solution, and stirred for 30 minutes. The organic phase is separated, dried over magnesium sulphate and evaporated under reduced pressure to dryness. A mixture of cis- and trans-1-[2-(indol-3-yl)-ethyl]-4-hydroxy-piperidine-3-carboxylic acid methyl ester is obtained, Rf = 0.27 and 0.35 (chloroform/methanol 9 :1).

Example 7

In a 1.5 1 sulfurization flask with stirrer and thermometer, 188 g of 1-[2-(indol-3-yl)-ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester are dissolved while stirring in 710 ml of dichloromethane. It is mixed with 53 ml of methanol, cooled to 10° to 15° and slowly added 144 ml of ethereal hydrochloric acid (approx. 17% weight/volume). It is stirred for 15 minutes, filtered, washed twice, each time with 100 ml of dichloromethane and then with 500 ml of diethyl ether and dried for 5 hours under reduced pressure at 50°C. One obtains 1-[2-(indol-3-yl)-ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrogen chloride with melting point 210° (decomposition), Rf = 0.53 (chloroform + methanol + concentrated ammonia; 9:1:1).

Example 8

2.7 g of 1-[2-(5-hydroxyindol-3-yl)-ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrobromide are suspended in 50 ml of acetone, mixed with 5 g of anhydrous potassium carbonate and 0.9 g of dimethyl sulfate and heated to boiling for 5 hours. It is cooled, filtered, the filtrate is evaporated to dryness and recrystallized from dichloromethane/diethyl ether. 1-[2-(5-Methoxyindol-3-yl)-ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester with melting point 157-158° is obtained.

The starting material can be prepared analogously to the description in example 5 starting from 2-(5-hydroxyindol-3-yl)-1-bromoethane and nicotinic acid methyl ester via 1-[2-(5-hydroxyindol-3-yl)-ethyl ]

-3-Methoxycarbonyl-pyridinium bromide.

Example 9

In a suspension of 2.4 g of sodium hydride (55% suspension in mineral oil) in 50 ml of dimethylformamide, a solution of 14.22 g (0.05 mol) of 2-[2-(indole-3- yl)-ethyl ]-aminomethyl-penta-2,4-diene-carboxylic acid methyl ester in 100 ml of dimethylformamide and stirred for 3 hours at room temperature. It is evaporated under reduced pressure to approx. 70 ml, add 150 ml of water and shake out 3 times, each time with 100 ml of dichloromethane. The organic phases are dried over sodium sulphate and the solvent is evaporated. The residue is dissolved in methanol and mixed with methanolic hydrochloric acid. After addition of diethyl ether, 1-[2-(indol-3-yl)-ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester crystallizes out on cooling - hydrogen chloride with melting point 208-209°.

The starting material can e.g. produced in the following way:

A well-stirred solution of 31.5 g (0.25 mol) 2-methyl-penta-2,4-diene-carboxylic acid methyl ester (prepared according to J.L. Belletire and D.R. Walley: Tetrahedron Letters 1983, 1475), 44.5 g of N- bromosuccinimide and 200 mg of azobisisobutyrnitrile in 200 ml of tetrachloromethane are heated for 12 hours to reflux, whereby the solution is irradiated with a 200 W lamp. After precipitation, the precipitated succinimide is filtered off, the filter residue is washed twice, each time with 30 ml of carbon tetrachloride, the combined organic phases are extracted with sodium carbonate solution and water, dried over sodium sulfate, and the solvent is evaporated in vacuo.

2-Bornmethyl-penta-2, 4-diene-carboxylic acid methyl ester is obtained as an orange-red oil. A solution of 16 g of 1-amino-2-(indol-3-yl)-ethane, 20.5 g (0.1 mol) of 2-bromomethyl-penta-2,4-diene-carboxylic acid methyl ester and 39 g of N-ethyl -N,n-diisopropylamine in 500 ml of dimethylformamide is stirred under nitrogen for 16 hours at room temperature.

It is evaporated under reduced pressure to approx. 250 ml, is added

500 ml of water and shake out 3 times, each time with 250 ml of dichloromethane. The organic phases are collected, dried over sodium sulphate and evaporated. After purification by chromatography on silica gel with toluene/ethyl acetate (9:1) as eluent, 2-[2-(1H-indol-3-yl)-ethyl]-aminomethyl-penta-2,4-diene-carboxylic acid methyl ester is obtained as yellow oil.

Example 10

A boiling solution of 4.32 g (40 mmol) of phenylhydrazine in 110 ml of methanol and 10 ml of water is mixed with a solution of 8.45 g (40 mmol) of 4-[1-(3-methoxycarbonyl-1,2,5 , 6-tetrahydr.o)-pyridyl]-butanol in 50 ml of methanol and heating for 20 hours to reflux. The solvent is evaporated in vacuo, the residue is dissolved in hot 0.5% hydrochloric acid solution and filtered over 1 g of activated carbon. The solution is concentrated and the residue is recrystallized from ethanol/diethyl ether. 1-[2-(1H-indol-3-yl)-ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid ethyl ester hydrogen chloride is obtained in this way with a melting point of 208-209 (decomposition).

The starting material can e.g. produced in the following way:

15.5 g 4-chloro-1,1-dimethoxy-butane, 22.2 g 1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrogen bromide (Guvacolin hydrobromide) and 39 g N-ethyl -N,N-diisopropylamine is dissolved under nitrogen in 750 ml of dimethylformamide and stirred for 16 hours at 50°. It is evaporated under reduced pressure to approx. 300 ml, is added

500 ml of water and shake out 3 times, each time with 250 ml of dichloromethane. The organic phases are collected, dried over sodium sulphate and evaporated in vacuo. In this way, 4-[1-(3-methoxycarbonyl-1,2,5,6-tetrahydro)-pyridyl]-1,1-dimethoxy-butane is obtained as a yellow oil.

A solution of 18 g (70 mmol) of 4-[1-(3-methoxycarbonyl-1,2,5,6-tetrahydro)-pyridyl]-1,1-dimethoxy-butane in 200 ml of dichloromethane is mixed with 100 g of silica gel , which is impregnated with 10% aqueous oxalic acid according to J.M. Conia et al., Synthesis 1978,

page 63, and the suspension is stirred for 3 hours at room temperature. After filtration, the mixture is washed with 5% aqueous sodium bicarbonate solution, the organic phase is dried with sodium sulphate and evaporated to dryness. In this way, 4-[1-(3-methoxycarbonyl-1,2,5,6-tetrahydro)-pyridyl]-butanal is obtained as a yellow oil.

Example 11

A solution of 6 g (20 mmol) of 1-[2-(indol-3-yl)-ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester in 100 ml of methanol is mixed with 2.5 ml concentrated sulfuric acid and heated to reflux for 16 hours. After cooling, the solvent is evaporated in vacuo, the residue is taken up in 50 ml of water and treated with saturated sodium bicarbonate solution. The now neutral solution is extracted 3 times, each time with 100 ml of dichloromethane, the combined organic phases are dried over sodium sulphate and evaporated. M.an obtains 1-[2-(indol-3-yl)-ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester which, on treatment with methanolic hydrobromic acid, is converted to the hydrogen bromide with a melting point of 215-218°.

The starting material can, for example, be obtained in the following way:

320.4 g (2 mol) of tryptamine are suspended with stirring in 600 ml of ethanol and added dropwise over the course of 1 hour with 448.0 g (4.4 mol) of acrylic acid ethyl ester. It is then stirred for 6 hours at 50° and overnight at room temperature, evaporated at 40° under reduced pressure to dryness, taken up in 1.5 1 toluene, 50 g of activated carbon are added, stirred for 30 minutes, filtered over diatomaceous earth and evaporated under reduced pressure to dryness. N-[2-(1H-indol-3-yl)-ethyl]-imino-di(3-propionic acid) diethyl ester is obtained as red

like oil.

153 g of sodium ethanolate are dissolved with stirring in 1,000 ml of dimethylformamide. A solution of 721 g (2 mol) N-[2-(1H-indol-3-yl)-ethyl]-imino-di(3-propionic acid) diethyl ester in 680 ml of dimethylformamide is then added dropwise over 90 minutes , heat to 40°, stir for 3 hours at room temperature and distill off the solvent at 40° under reduced pressure. The residue is poured at 20 to 35° into a mixture of 2,100 ml of 5n-hydrochloric acid and 500 ml of toluene. The precipitated 4-hydroxy-1-[2-(1H-indol-3-yl)-ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid ethyl ester hydrogen chloride or 1-[2-(1H-indol-3-yl)-ethyl]-piperidin-4-one-3-carboxylic acid ethyl ester hydrogen chloride is filtered off, washed with cold methanol and dried at 40°C under reduced pressure. It melts at 170-173°

(decomposition).

1 a 5 1 sulfurization flask equipped with a stirrer, thermometer and a 250 ml round flask connected via a rubber hose is filled with 294 g of 1-[2-(indol-3-yl)-ethyl]-piperidin-4-one-3-carboxylic acid ethyl ester- hydrogen chloride in 2,750 ml of methanol. It is cooled with stirring to -15°, and 56.7 g of sodium borohydride are added in portions over the course of 2 hours at -15 to -5° from the 250 ml round flask.

It is stirred for 1 hour at 0°, the solvent is distilled off under reduced pressure at a bath temperature of no more than 40°, mixed with 1,250 ml of acetic acid ethyl ester, 800 ml of ice water and 50 ml of saturated potassium carbonate solution is added and stirred for 30 minutes. The organic phase is separated, dried over magnesium sulphate and evaporated to dryness under reduced pressure. A mixture of cis- and trans-1-[2-(indol-3-yl)-ethyl]-4-hydroxy-piperidine-3-carboxylic acid ethyl ester is obtained, which can be used without further purification.

237.3 g of a mixture of cis- and trans-1-[2-(indol-3--yl)-ethyl]-4-hydroxy-piperidin-3 -carboxylic acid ethyl ester hydrogen chloride in 600 ml of pyridine, cooled to 0° to 5° and mixed with stirring at 0° to 5° dropwise with 103.1 g of methanesulfonyl chloride. It is stirred for 4 hours at room temperature, heated to 53° to 56°, stirred for 4 hours at approx. 55° and allowed to stand overnight. The reaction mass is stirred with 800 ml of acetone, filtered and washed with acetone. The mixture is then stirred with 500 ml of acetonitrile, cooled to 5° and filtered again. The prepared crude 1-[2-(indol-3-yl)-ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester with melting point 151-155° can be used without further purification.

Example 12

A solution of 10 g (0.04 mol) of 1-[2-(indol-3-yl)-ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid nitrile in 200 ml of 95%

methanol is mixed with 4 ml of concentrated sulfuric acid and heated to reflux for 16 hours. After cooling, it is evaporated under reduced pressure to 50 ml, the residue is distributed in 200 ml of dichloromethane and 100 ml of water and neutralized with saturated sodium bicarbonate solution. The organic phase is separated and the aqueous phase is shaken once again with 100 ml of dichloromethane.

The combined organic phases are dried over sodium sulphate and evaporated. After purification by chromatography on 400 g of silica gel with toluene/ethyl acetate (9:1) as eluent, crystallization from diethyl ether/n-hexane yields 1-[2-(indol-3-yl)-ethyl]-1,2,5 ,6-tetrahydropyridine-3-carboxylic acid methyl ester with melting point 75-77°.

The starting material can e.g. produced in the following way:

22.4 g of 1-bromo-2-(3-indolyl)-ethane (0.1 mol), 10.8 g of 1,2,5,6-tetrahydropyridine-3-carboxylic acid nitrile and 20 g of N-ethyl-N, N-diisopropylamine is dissolved under nitrogen in 450 ml of dimethylformamide and stirred for 16 hours. The mixture is then evaporated under reduced pressure to 150 ml, 500 ml of water is added and decanted 3 times, each time with 150 ml of dichloromethane. The organic phases are collected and decanted 3 times, each time with 75 ml of n-hydrochloric acid. The aqueous phases are collected, made basic with 40% caustic soda and decanted

repeat 3 times with 100 ml of dichloromethane. The organic phases are collected,

dried over sodium sulfate and evaporated to dryness. In this way, 1-[2-(indol-3-yl)-ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid nitrile is obtained as a yellow oil.

Example 13

A solution of 15.36 g (60 mmol) of 3-hydroxymethyl-1-[2-(1H-indol-3-yl)-ethyl]1,2,5,6-tetrahydropyridine in 1,000 ml of methanol is mixed while cooling portionwise with 15 g of sodium cyanide,

150 g of activated manganese dioxide and 6 ml of glacial acetic acid and stirs the suspension in a nitrogen atmosphere for 18 hours at room temperature.

After filtering off, the filtrate is evaporated to dryness, the residue is taken up in 300 ml of methylene chloride and this solution is extracted 3 times, each time with 100 ml of water. After purification by chromatography on 500 g of silica gel with toluene/ethyl acetate (9:1) as eluent, after crystallization from diethyl ether/n-hexane 1-[2-(indol-3-yl)-ethyl]-1,2,5 ,6-tetrahydro-pyridine-3-carboxylic acid methyl ester with melting point 76-77°.

Example 14

4.82 g of metallic sodium are dissolved portionwise in a nitrogen atmosphere in 60 ml of dry methanol, this solution is mixed with 100 ml of dimethylformamide, 10 g of copper (I) iodide and 7.26 g (0.02 mol) of 1-[2- (5-bromo-1H-indol-3-yl)-ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester and heat for 16 hours at 130°. After cooling and filtering, mix with 300 ml of ethyl acetate and extract 3 times, each time with 150 ml of water. The organic phase is dried over sodium sulfate and evaporated. After purification by chromatography on 300 g of silica gel with toluene/ethyl acetate (9:1) as eluent, crystallization from dichloromethane/diethyl ether gives 1-[2-(5-methoxy-1H-indol-3-yl)-ethyl]-1 ,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester with melting point 157-158°.

The starting material can be prepared as described in example 6 starting from 2-(5-bromoindole)-1-bromoethane and nicotinic acid methyl ester over 1-[2-(5-bromo-indol-3-yl)-ethyl]-3-methoxycarbonyl -pyridinium bromide.

Example 15

A solution of 7.66 g (25 mmol) 1-[2-(1H-indol-3-yl)-ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid hydrogen chloride in 150 ml methanol is mixed with 1 ml of concentrated sulfuric acid and heated to reflux for 4 hours. After cooling, the solution is evaporated in vacuo, the residue is mixed with 100 ml of dichloromethane and 100 ml of water and neutralized with aqueous sodium carbonate solution. The aqueous phase is separated and extracted again 3 times, each time with 50 ml of dichloromethane. The combined organic phases are dried over sodium sulfate and evaporated under reduced pressure. Analogously to example 3, one obtains with methanolic hydrogen bromide solution (4n) 1-[2-(1H-indol-3-yl)-ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrogen bromide with melting point 215-218°.

The starting material can e.g. produced in the following way:

A solution of 12.8 g (0.05 mol) of 3-hydroxymethyl-1-[2-(1H-indol-3-yl)-ethyl]-1,2,5,6-tetrahydro-pyridine is mixed in 150 ml of tetrahydrofuran with a solution of 2.5 g of sodium hydroxide in 80 ml of water and with 40 g of nickel peroxide trihydrate and stirred for 8 hours at 50° in a nitrogen atmosphere. After cooling, the solution is filtered and evaporated in vacuum to approx. 100 ml. After 3 extractions, each time with 70 ml of dichloroethane, the aqueous phase is acidified with 1N hydrochloric acid and decanted again 3 times, each time with 100 ml of dichloromethane. The combined organic phases are dried over sodium sulfate and evaporated in vacuo. Mixing with methanolic hydrochloric acid and cooling yields 1-[2-(1H-indol-3-yl)-ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid hydrogen chloride with a melting point of 170-171 °.

Example 16

Tablets, each containing 50 mg of 1-[2-(indol-3-yl)-ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester or the hydrogen chloride thereof can be prepared in the following way:

Composition (1,000 tablets)

The active substance is mixed with the lactose and 292 g of potato starch, the mixture is moistened with an alcoholic solution of gelatin and granulated through a sieve. After drying, it is mixed with the rest of the potato starch, talc, magnesium stearate and the highly dispersed silicon dioxide and the mixture is pressed into tablets,

each with a weight of 145.0 mg and an active substance content of 50.0 mg, which, if desired, can be equipped with break lines for finer adjustment of the dose.

Example 17

Lacquer tablets, each containing 100 mg of 1-[2-(indol-3-yl)-ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester, can be prepared as follows:

Composition (for 1,000 tablets)

The active substance, the lactose and 40 g of the corn starch are mixed and moistened with a paste made from 15 g of corn starch and water (while heating) and granulated. The granulate is dried, the rest of the cornstarch, talc and calcium stearate are added and mixed with the granulate. The mixture is pressed into tablets (weight: 280 mg) and these are lacquered with a solution of hydroxypropylmethylcellulose and shellac in methylene chloride; final weight for the varnish tablet: 283 g.

Example 18

In a similar way as described in examples 16 and 17, pharmaceutical preparations containing another compound of formula I according to examples 1 to 15 can also be prepared.

Claims (4)

1. Process for the preparation of new 1-(3-indolyl)-tetrahydropyridines of the formula where R stands for hydrogen or methoxy, and salts thereof, characterized in that mana) in a compound of the formula where A® stands for an acid anion, reduces the excess double bonds to single bonds, eilerb) from a compound of the formula where one of the residues X^ and X2 is hydrogen and the other is a cleavable residue, or a salt thereof, cleaves X-^ and X2 to form the double bond, orc) ring-closes a compound of the formula or a salt thereof, to the corresponding compound of formula I, ord) reacts the compounds of the formulas where X^ stands for a nucleofuge cleavable group, or salts thereof, with each other, or) ring-closing a compound of the formula or a salt thereof, or f) in a compound of the formula where R, represents a residue which can be transferred to methoxycarbonyl, or a salt thereof, transfers R^ to methoxycarbonyl, org) for the preparation of the compound of formula I, where R is methoxy, in a compound of the formula where X, is a residue which can be transferred to methoxy or exchanged for methoxy, transfer X^ to methoxy or exchange this for methoxy, and if desired, the compound prepared according to the method is transferred to another compound of formula I, ad-separate according to isomer mixture produced by the method in the individual components, and/or converts a free compound produced according to the method into a salt, or a salt produced according to the method into the free compound or into another salt. 2. Process according to claim 1, characterized in that 1-[2-(indolyl-3-yl)-ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester or an acid addition salt thereof is prepared. 3. Process according to claim 1, characterized in that 1-[2-(5-methoxyindol-3-yl)-ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester or an acid addition salt thereof is prepared. 4. Method according to claim 1, characterized in that a compound is prepared, which can be prepared according to one of claims 1-3, in the form of hydrogen chloride or hydrogen bromide.