DD251131A5 - PROCESS FOR THE PRODUCTION OF NEW TRISUBSTITUTED AZACYCLOALKANES BZW. AZACYCLOALKENE - Google Patents

Abstract

The invention relates to a process for the preparation of novel 1,3,4-trisubstituted Azacycloalkane or Azacycloalkene of formula (I) wherein R is an optionally substituted 3-indolyl, alk is lower alkylene, the radical R by 1 to 3 carbon atoms from the nitrogen atom R 1 is optionally esterified or amidated carboxy and R 2 is an optionally etherified or acylated hydroxy group or an optionally acylated amino group, and their tautomers and / or salts have a nootropic effect and can be used as nootropics. They are prepared, for example, by reacting compounds of the formula (VI), wherein X3 represents a nucleofugic leaving group, or their salts with each other. Formula (I) and (VI)

Description

-7- 251131 Field of application of the invention

The invention relates to a process for the preparation of novel trisubstituted Azacycloalkane or Azacycloalkene with valuable pharmacological properties, in particular with nootropic effect.

The compounds according to the invention are used as medicaments, in particular as nootropics, for example for the treatment of cerebral performance insufficiency, in particular of memory disorders of different origin.

Characteristic of the known technical solutions

There are no known data on which nootropic compounds have been used to treat cerebral insufficiency.

There is also no information available about processes for the preparation of trisubstituted Azacycloalkanen or Azacycloalkenen.

Object of the invention

The aim of the invention is the provision of new compounds with valuable pharmacological properties, in particular with nootropic effect.

Explanation of the essence of the invention

The invention has for its object to find new compounds with the desired properties and processes for their preparation.

According to the invention, new 1,3,4-trisubstituted Azacycloalkane and Azacycloalkene of the formula

alk RZ- / \ -R ₂ (D.

^R l

wherein R is an optionally substituted 3-indolyl radical, Z is lower alkylene which separates the radical R by 1 to 3, preferably 2, carbon atoms from the nitrogen atom, as methylene, ethylene or 1,3-propylene, R ₁ optionally esterified or amidated carboxy and R _{2 is} an optionally etherified or acylated hydroxy group or an optionally acylated amino group, and their tautomers and / or salts, especially pharmaceutically acceptable salts.

The point row in formula I means that between the carbon atoms (C atoms) substituted by R ₁ and R ₂ a single or double bond can be present.

Suitable substituents of the 3-indolyl radical are, for example, aliphatic hydrocarbon radicals, such as lower alkyl or lower alkenyl, optionally also esterified or etherified hydroxy groups in the 4- to 7-position, such as hydroxy, lower alkanoyloxy, halogen, lower alkoxy, lower alkenyloxy or adjacent carbon atoms (C atoms ) Lower alkyl (id) endioxy, further trifluoromethyl, into consideration. Up to and including 4, in particular 1, 2 or 3 of said substituents can be present, for example 1 to and 3, in particular 1 or 2 substituents in the 4 to 7 position and / or 1 substituent in each of 1 and / or 2 2-position.

Etherified hydroxy R ₂ is, for example, lower alkoxy or optionally substituted phenyl-lower alkoxy.

Acyl in acylated hydroxy or amino R ₂ is, for example, acyl derived from an organic carboxylic acid or a half-ester of carbonic acid.

Acyl derived from organic carboxylic acids is, for example, the radical of an aliphatic or monocyclic aromatic carboxylic acid, such as lower alkanoyl or optionally substituted benzoyl, and also pyridoyl.

In acyl halide derived acyl, for example, the second hydroxy group is esterified with an aliphatic or aryl, such as phenylaliphatic, alcohol. Examples of acyl groups derived from half-esters of carbonic acid are lower alkoxycarbonyl and optionally substituted phenyl-lower alkoxycarbonyl.

Esterified carboxy, for example, aliphatic, cycloaliphatic or aryl, such as phenylaliphatic esterified carboxy, ζ. Lower alkoxycarbonyl, optionally substituted phenyl-lower alkoxycarbonyl, 3-bis and 8-membered such as 5- or 6-membered cycloalkoxycarbonyl, d. H. Cyclopentyloxy or cyclohexyloxycarbonyl, furthermore cyclopropyloxy, cyclobutyloxy or cycloheptyloxycarbonyl.

Amidated carboxy, for example, unsubstituted, aliphatic N-substituted or N-acylated carbamyl, such as carbamyl, N-mono or ^ N-Diniederalkylcarbamyl ^ N-lower alkylene or. N, N- (aza, oxa or thia) lower alkylenecarbamyl or N-acylcarbamyl, in which acyl has, for example, one of the meanings given for acyl in acylated hydroxy or amino R 2. Such N-acylcarbamyl groups are, for example: N-lower alkanoylcarbamyl, N-lower alkoxycarbonylcarbamyl, ureidocarbonyl, N'-mono- or Ν ', Ν'-di-lower alkylureidocarbonyl or Ν', Ν'-lower alkylene or N ', N' - (azahydrocarbyl) , Oxa- or thia) lower alkylenureidocarbonyl.

Above and below, aryl, such as phenyl, may also be substituted as a constituent of substituents of the radical R 1 and / or R ₂ and of starting materials for the preparation of compounds I, for example by lower alkyl, lower alkoxy, halogen, nitro and / or trifluoromethyl.

Likewise, unless otherwise stated, "lower" radicals and organic compounds are to be understood as meaning those radicals or compounds which have up to and including 7, in particular up to and including 4, carbon atoms.

Lower alkylene, which separates the radical R from the nitrogen atom shown in formula I by 1 to 3, preferably 2, C atoms, is, for example, methylene, 1,1-ethylene (ethylidene), 1,3-propylene, 2,4-butylene or preferably ethylene, 1,2-propylene or 1,2-butylene, but may also be 2,3-butylene.

Lower alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl or isobutyl, furthermore secondary butyl or tertiary butyl.

Lower alkenyl is, for example, allyl or methallyl.

Halogen is, for example, halogen of the atomic number up to and including 35, such as fluorine, chlorine or bromine.

Lower alkoxy is, for example, methoxy, ethoxy, propyloxy or butyloxy. Lower alkenyloxy is, for example, allyloxy.

Lower alkyl (id) endioxy is, for example, methylenedioxy, ethylidenedioxy, ethylenedioxy, isopropylidenedioxy or 1,3-propylenedioxy.

Lower alkanoyl is, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeroyl or pivaloyl.

Lower alkoxycarbonyl is, for example, methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, secondary butoxy or tertiary-butyloxycarbonyl or a pentyloxy, hexyloxy or heptyloxycarbonyl group.

Cycloalkoxycarbonyl has, for example, 3 to 8, in particular 3 to 6, ring members and means z. Cyclopropyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl or cyclohexyloxycarbonyl.

Mono- or di-lower alkylcarbamyl is, for example, methyl, dimethyl, ethyl, diethyl, propyl, isopropyl, butyl or isobutylcarbamyl.

Lower alkylenecarbamyl or aza-, oxa- or thian-lower alkylcarbamyl is, for example, pyrrolidinocarbonyl or piperidinocarbonyl, furthermore piperazino or N'-lower alkyl, such as N'-methylpiperazinocarbonyl, morpholinocarbonyl or thiomorpholinocarbonyl.

N'-mono- or Ν ', Ν'-di-lower alkylureidocarbonyl is, for example, N'-methyl, N'-ethyl, N'-propyl, N'-butylureidocarbonyl or Ν', Ν'-dimethyl or Ν ' , Ν'-Diethylureidocarbonyl.

Ν ', Ν'-Niederalkylen- or N', N '- (Aza-, Oxa- or Thia) niederalkylenureidocarbonyl is for example N-Piperidinocarbonyicarbamyl, N-Pyrrolidinocarbonylaminocarbamyl, N-morpholino, N-thiomorpholino or N-piperazino or N'-f-lower alkyl, such as N'-methyl-piperazinocarbonylcarbamyl.

Phenyl-lower alkyl is, for example, benzyl, 1- or 2-phenethyl or S-phenylpropyl. Likewise Phenylniederalkoxy, also as a component of Phenylniederalkoxycarbonyl z. B. benzyloxy, 1- or 2-phenethoxy or 3-phenylpropyloxy.

Tautomers of compounds of the formula I are, for example, keto or ketimine derivatives of compounds of the formula I in which the azacycloaliphatic ring has one double bond and R _{2 is} hydroxyl or optionally acylated amino, ie compounds of the formula

wherein R ₂ 'is oxo or optionally acylated imino.

Salts of compounds of formula I are, for example, their pharmaceutically acceptable acid addition salts, as well as internal salts of compounds of formula I in which R _{1 is} carboxy and their pharmaceutically acceptable salts with bases.

Pharmaceutically acceptable acid addition salts include, for example, salts with suitable mineral acids, such as hydrohalic acids, sulfuric acid or phosphoric acid, e.g. Hydrochlorides, hydrobromides, sulfates, hydrogen sulfates or phosphates, or salts with suitable organic carboxylic or sulfonic acids, such as optionally hydroxylated aliphatic mono- or dicarboxylic acids, eg. As acetates, oxalates, succinates, fumarates, maleates, maleates, ascorbinates or citrates, the aliphatic or aromatic sulfonic acids or N-substituted sulfamic acids, eg. As methanesulfonates, benzoisulfonates, p-toluenesulfonates or N-cyclohexylsulfaminates (cyclamates).

Pharmaceutically acceptable salts with bases are primarily metal or ammonium salts such as alkali metal and alkaline earth metal, e.g. For example, sodium, potassium, magnesium or calcium salts, and ammonium salts with ammonia or suitable organic amines, such as lower alkylamines, eg. For example, triethylamine, Hydroxyniederalkylaminen, z. 2-hydroxyethylamine, bis (2-hydroxyethyl) amine or tris (2-hydroxyethyl) amine, basic aliphatic esters of carboxylic acids, e.g.

4-aminobenzoic acid 2-diethylaminoethyl ester, lower alkylene amines, e.g. For example, 1-ethylpiperidine, cycloalkylamines, e.g. B.

Dicyclohexylamine, or benzylamine, e.g. As Ν, Ν'-dibenzylethylenediamine, dibenzylamine or N-benzyl-ß-phenylethylamine.

Compounds of formula I having an acidic and a basic group may also be present in the form of internal salts, i. H. in zwitterionic form.

For isolation or purification it is also possible to use pharmaceutically unsuitable salts. For zosterapeutischen application reach only the pharmaceutically acceptable, non-toxic salts, which are therefore preferred.

The compounds of the formula I and their pharmaceutically acceptable salts have valuable pharmacological, in particular nootropic properties. Thus, they reduce in the mouse in doses from about 0.1 mg / kg i.p. as well as p.o. the amnesiogenic effect of an electric shock to at least the same extent as after administration of a nootropically effective dose of piracetam (100 mg / kg i.p.). To prove the nootropic effect, for example, the TWO-compartment test can be used.

As literature on pharmacological models of this kind, e.g. named: S.J. Sara and D.Lefevre, Psychopharmacologia 25, 32-40 (1972), Hypoxia-induced amnesia in one-trial learning and pharmacological protection by piracetam. Boggan, W. Ο, and Schtesinger, K., in Behavioral Biology 12, 127-134 (1974).

Furthermore, the compounds of the formula I show a strong memory-improving effect in the step-down passive avoidance test according to Mondadori and Wasser, Psychopharmacology 63, 297-300 (1979). The substances are effective in intraperitoneal administration 30 minutes prior to the learning trial (effective doses 0,1,1,10 mg / kg). A significant effect was also

detectable with peroral application 60 minutes before the learning attempt (effective doses 0,1,1,10mg / kg) as well as with intraperitoneal application immediately after the learning attempt (effective doses 0,1,1,10mg / kg).

Accordingly, the compounds of the formula I and their pharmaceutically acceptable salts can be used as nootropics, for example for the treatment of cerebral performance insufficiency, in particular memory disorders of different causes, such as senile dementia or dementia of the Alzheimer type, furthermore of subsequent conditions of brain trauma and apoplexies.

The invention relates, for example, to compounds of the formula I in which R is unsubstituted or 5-methoxy-substituted 3-indolyl, Z and alk are ethylene, R _{1 is} methoxycarbonyl and R _{2 is} hydroxy or amino or, if the azacyclic ring is not a double bond has lower alkanoyloxy with up to and with 4C atoms, z. B.

Acetoxy, and their tautomers and / or salts.

The invention relates in the first place to the preparation of compounds of the formula I in which R is unsubstituted or in at least one of the positions 1, 2 and 4 to 7 substituted 3-indolyl, where as substituent in the 1-position lower alkyl or lower alkenyl, in 2- Lower alkyl and as substituent (s) in 4- to 7-position lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, hydroxy, halogen, trifluoromethyl and / or to adjacent carbon atoms bound lower alkyl (id) endioxy into consideration, Z represents lower alkylene, which represents the radical R from the nitrogen atom by 1 to 3, preferably 2 C atoms, alk methylene, 1,3-propylene or especially ethylene, Ri is carboxy, lower alkoxycarbonyl, optionally lower alkyl, lower alkoxy, halogen, nitro and / or trifluoromethyl substituted phenyl-lower alkoxycarbonyl, 3- to 8-membered cycloalkoxycarbonyl, carbamyl, mono- or di-lower alkylcarbamyl, lower-alkylene or aza-, oxa- or thi-lower alkylene carbene amyl, N-lower alkanoylcarbamyl, N-lower alkoxycarbonylcarbamyl, ureidocarbonyl, N'-mono or Ν ', Ν'-di-lower alkylureidocarbonyl, Ν', Ν'-lower alkylene or N ', N' - (Aza-, Oxa- or Thia ) lower alkylenureidocarbonyl and R _{2 is} hydroxy, lower alkoxy, phenyl-lower alkoxy optionally substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl and / or nitro, amino, lower alkanoylamino, lower alkoxycarbonylamino or phenyl-lower alkoxycarbonylamino optionally substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl and / or nitro, wherein lower alkylene alk to and with 4, the remaining lower radicals have a total up to and with 7 and in each lower part structure to and with 4 C atoms, and their tautomers and / or salts, especially pharmaceutically acceptable acid addition salts.

The invention relates in particular to the preparation of compounds of the formula I in which R is unsubstituted or in one or two of the positions 4 to 7 by lower alkyl having bis and 4 C atoms, such as methyl, lower alkoxy having up to and containing 4 C atoms, such as methoxy, halogen of the atomic number to and with 35, such as chlorine, and / or trifluoromethyl substituted 3-indolyl, Z represents lower alkylene with bis and with 4 C-atoms, which represents the radical R from the nitrogen atom by 1 to 3, preferably 2, C atoms separates, such as methylene, 1,3-propylene or preferably ethylene, alk means, 1,3-propylene or especially ethylene, Ri is carboxy, lower alkoxycarbonyl with up to 4 carbon atoms in the alkoxy, such as Methoxy or ethoxycarbonyl, 3- to 8-, preferably 5- or 6-membered cycloalkoxycarbonyl, such as cyclopentyloxy- or cyclohexyloxycarbonyl, carbamyl or N-mono- or N, N-di-lower alkylcarbamyl having up to and including 4 C atoms in each alkyl moiety, such as methyl -, ethyl or dimethylcarb amyl, and R _{2 is} hydroxy, lower alkoxy having up to and with 4 C atoms, such as methoxy, phenyl-lower alkoxy having 7 to and having 10 C atoms, such as benzyloxy, lower alkanoyloxy with bis and with 4 C atoms, such as acetoxy, amino or Lower alkanoylamino with bis and with 4 C-atoms, such as acetylamino, and their tautomers and / or salts, especially pharmaceutically acceptable acid addition salts.

The invention relates in particular to compounds of the formula I in which R is unsubstituted or substituted in one or two of the positions 1 and 4 to 7 substituted 3-indolyl, where as a substituent in the 1-position lower alkyl, such as methyl, and as substituent (s) in 4 - to 7-position lower alkoxy with bis and with 4 C-atoms, such as methoxy, halogen of the atomic number up to and with 35, such as chlorine, and / or lower alkyl with up to and 4 C atoms, such as methyl, come into consideration, alk Is ethylene, ζ is 1,1-, 1,3- or preferably 1,2-lower alkylene having up to and including 4 C atoms, such as ethylene, furthermore 1,3-propylene or methylene, R _{1 is} lower alkoxycarbonyl with bis and with 4 C atoms in the lower alkoxy part, such as methoxycarbonyl or ethoxycarbonyl, and R _{2 is} hydroxy or amino, and their tautomers and / or salts, in particular pharmaceutically acceptable acid addition salts.

The invention preferably relates to the preparation of compounds of the formula I in which R is unsubstituted or in one or two of the positions 4 to 7 by lower alkyl having up to and including 4 C atoms, such as methyl, and / or halogen of the atomic number up to and including 35, Z is straight-chain 1,1-, 1,3- or preferably 1,2-lower alkylene having up to and including 4 C atoms, such as methylene, 1,3-propylene or, preferably, ethylene, such as chlorine, substituted 3-indolyl, alk is methylene or especially ethylene, R _{1 is} lower alkoxycarbonyl having up to and including 4 C atoms in the alkoxy moiety, such as methoxy- or ethoxycarbonyl, and R _{2 is} hydroxy, and their tautomers and / or salts, in particular pharmaceutically usable acid addition salts.

The invention relates, in the first place, to the preparation of compounds of the formula in which R represents unsubstituted or 3-indolyl substituted in the 4- and 7-positions by lower alkyl having up to and with 4 C atoms, such as methyl, Z and alk represent ethylene, R _{1 is} lower alkoxycarbonyl having up to and including 4 C atoms in the lower alkoxy part, such as methoxycarbonyl or ethoxycarbonyl, and R _{2 is} hydroxy, and their tautomers and / or salts, in particular pharmaceutically usable acid addition salts.

The invention relates in particular to the preparation of the compounds of the formula I and their pharmaceutically acceptable salts, in particular acid addition salts, such as their hydrochlorides, hydrobromides, fumarates, oxalates or cyclamates, which are mentioned in the examples.

The invention preferably relates in each case to the preparation of those compounds of the formula I in which the azacycloaliphatic ring is saturated and R ₁ and R ₂ are cis-continuous with one another.

The method based on known synthesis methods for the preparation of compounds of formula I, including their tautomers and / or salts is characterized in that

a) for the preparation of compounds of the formula I, wherein alk is ethylene, in a compound of the formula

¹ "

wherein Α ^{θ is} an acid anion and R _{2 is} etherified, acylated or protected hydroxy or acylated or protected amino, which reduces excess double bonds to single bonds and splits off any protective groups present, or

b) a compound of the formula

alk-Xi

R-Z-N (III),

• -CH ₂ -Ri

wherein X _{1 represents} a group of the formulas -CH = R ₂ ', -C (X ₂ J = R ₂ ' or cyano, wherein X ₂ denotes a cleavable radical, or a salt thereof cyclized, or

c) a compound of the formula

/ ^al

R ₃ -N- N = C-CH ₂ -ZK, -''- R ₂ (IV),

Rt Rs X-V

where R _{3 is} a phenyl radical which is optionally substituted in the 3 to 6 position as indicated for the positions 4 to 7 of the radical R, R 4 is hydrogen or a substituent provided for the 1 position of R and R _{5 is} hydrogen or a radical Position of R substituents provided, or a tautomer and / or salt thereof, to the corresponding compound of formula I rings, or

d) compounds of the formulas

/ ^al

RZX ₃ (V) and ms · -R ₂ (Vl),

• - ·

in which X ₃ denotes a nucleofuge leaving group, or reacts their tautomers and / or salts with one another, or

e) for the preparation of compounds of the formula I in which alk is ethylene, a compound of the formula

RZ- HN . -Y- " ^Rz (VII)

or a tautomer and / or salt thereof cyclized, or

f) in a compound of the formula

/ ^al

RZ-Nf , * '* -R2 (VIII),

in which R ₁ 'is a radical which can be converted into optionally esterified or amidated carboxy, or in a tautomer and / or salt thereof R ₁ ' is converted into optionally esterified or amidated carboxy, or

g) for the preparation of compounds of the formula I in which the azacycloaliphatic radical has a double bond, a compound of the formula

Z - nf j Ka "'(IX),

wherein R 'is a substituted in 1-position or intermediately protected 3-indolyl R and R ₂ '"is a group R ₂ or intermediately protected hydroxy, or the corresponding keto or iminotautomere thereof with a compound of formula R ₁ -X ₆ (VIa) in which X ₆ denotes a cleavable radical, condenses and, if appropriate, cleaves off the protective group (s), or

h) in a compound of the formula

/ ^al N χ

wherein X _{4 is} a group R ₂ into a convertible radical, X ₄ is converted into a group R2, or

i): for the preparation of compounds of the formula I in which the azacycloaliphatic ring is monounsaturated, and R _{2 is} hydroxy, or the tautomeric oxo compound is a compound of the formula

rearranged, or

j) for the preparation of compounds of the formula I in which the azacycloaliphatic ring is saturated, compounds of the formulas

ZN _z - K y (XU) and R ₂ -H (XIII)

with each other, or

k) for the preparation of compounds of formula I, wherein Z is the radical R is separated from the nitrogen atom by 1 C-atom. Compounds of the formulas

RH (L) and HNT ..0 * ~ ^R 2 (Vl)

condensed with an oxo-lower alkane and, if desired, the process according to available compound converted into another compound of formula I, an isomers according to the invention is separated into the components and isolates the isomers of formula I, a process according to available diastereomer or enantiomeric mixture splits into the diastereomers or enantiomers and isolating the desired diastereomer or enantiomer and / or converting a free compound obtainable by the process into a salt or a salt obtainable according to the process into the free compound or into another salt

Process variant a)

The ation A ^e is, for example, the anion of a strong protic acid capable of converting alcoholic hydroxy to reactive esterified hydroxy, e.g. Example, a halide ion, such as chloride, bromide or iodide, or a sulfonation, in particular the anion of an aliphatic or aromatic sulfonic acid, for example the methanesulfonate, ethanesulfonate or Methosulfato-ion or benzenesulfonate, p-toluenesulfonate or p-Brombenzolsulfonation , R " ₂ is in particular etherified hydroxy R ₂ or protected hydroxy.

The reduction of the excess double bonds is carried out in customary manner, for example by the action of a dileil metal hydride, such as an alkali metal tri-lower alkoxyaluminum hydride, eg. Example of Lithiumtritertiärbutyloxyaluminiumhydrid, or an optionally substituted Alkalimetallborhydrid such as lithium borohydride, potassium borohydride, sodium borohydride or sodium cyanoborohydride. The reaction is preferably carried out in a customary solvent. Conventional solvents are for example for the reaction with Lithiumtritertiärbutyloxyaluminiumhydrid ethereal solvents such as diethyl ether, dioxane or tetrahydrofuran, and for the reaction with optionally substituted Alkalimetallborhydriden especially lower alkanols such as methanol or ethanol, water

 Intermediates II can be prepared, for example, by reacting compounds of the formulas

RZA (XIV) and N ^ ^ -R ₂ (XIVa),

where A is the reactive esterified hydroxy corresponding to the anion Α ^θ

Process variant b)

In intermediates III, a cleavable X ₂ radical optionally etherified or esterified hydroxy, such as hydroxy, aliphatic, araliphatic or aromatic etherified hydroxy, ζ. Lower alkoxy, phenyl-lower alkoxy or phenoxy, hydroxy esterified with a carboxylic acid, 2. B. lower alkanoyloxy, e.g. For example, acetoxy, or halogen, z. As chlorine or bromine, or an optionally substituted amino or ammonio group, such as amino, optionally substituted anilino, mono- or di-lower alkylamino, z. For example, mono- or dimethylamino, or Triniederalkylammonio, z. B. trimethylammonio.

The intramolecular condensation is carried out in customary manner, for example in the presence of a basic condensing agent, such as an alcoholate, amide or hydride, an alkali metal or alkaline earth metal, for example an alkali metal or alkaline earth metal alkoxide, eg. For example, sodium methanoate, magnesium methoxide, sodium ethoxide or potassium tertiary butoxide, an alkali metal amide, e.g. Example of sodium amide, lithium diisopropylamide, sodium N-methyl-anilide or sodium diphenylamide, or an alkali metal or alkaline earth metal hydride, z. As sodium hydride or calcium hydride, if necessary, with cooling or heating, for. B. at about -1O ⁰ C to +120 ⁰ C, and / or under inert gas, such as nitrogen. In a preferred embodiment of process variant b), for example, a compound of the formula

alk-CH = R ₂

IH ₂ - Ri

(XV)

wherein R ₂ 'oxo or imino, the treatment with one of said bases, in particular with an alkali metal lower alkanolate, for example, with sodium methanoate or sodium ethanolate subject. In this case, the compound XV cyclizes to a compound of the formula I in which the azacycloaliphatic ring has no double bond and R _{2 is} hydroxy or amino. Starting materials XV are z. B. obtained by reacting a reactive indole-3-yl-alkanolester.der formula

RZX ₃ (V),

wherein X _{3 is} reactive esterified hydroxy, with an / 3-amino acid compound of the formula H ₂ N-CH ₂ -CH ₂ -Ri (XVa) condensed and the resulting intermediate of the formula

RZN-CH ₂ CH ₂ -R ₁ (XVI),

wherein R _{6 is} hydrogen, with acrolein or an optionally functionally modified aldehyde of the formula Y ^ aIk-CH = R ₂ '(XVII, Y ₁ = reactive esterified hydroxy, R ₂ ' = optionally acetalated oxo or imino). In another preferred embodiment of process variant b), one cyclizes one by reacting a compound of the formula RZ-NH ₂ (XVIII) with the approximately double molar amount of a compound of the formula Y ₁ -CH ₂ CH ₂ -RI "(XIXa; Y ₁ = reactive esterified hydroxy, R ₁ "= esterified carboxy) or CH ₂ = CH-R ₁ "(XIXb; R ₁ "= esterified carboxy) obtainable compound of the formula

Il

-CH ₂ -Ri

R - alk - NT ti. _Yy .

^X. -CH ₂ -Ri ^(XX) '

z. In the presence of a metal base, such as an alkali metal alcoholate, ζ. B. of sodium methanoate, to a compound of formula Γ wherein R ₂ 'is oxo, or to the corresponding tautomers of formula I. Esterified carboxy R ₁ "is, for example, methoxy carbonyl.

For example, compounds of formula I wherein R is unsubstituted or substituted in the 5-position by methoxy 3-indolyl, Z and alk are ethylene, R _{1 is} methoxycarbonyl and R _{2 is} hydroxy or amino or, if the azacyclic ring has no double bond , Lower alkanoyloxy with bis and with 4 C atoms, z. As acetoxy, and their tautomers and / or salts obtained by reacting a compound of formula

-CH ₂ -Xi

R-Z-ΚΓ (IH ')

-CH ₂ -Ri

wherein R is optionally substituted at the 5-position by methoxy-substituted 3-indolyl, Z is ethylene, R _{1 is} methoxycarbonyl and X _{1 is} methoxycarbonyl, cyano or a group -CH = R ₂ 'in which R ₂ ' is oxo or imino, cyclized and, if desired in a compound obtainable by the process in which R _{2 is} hydroxy or amino and the azacycloaliphatic ring has a double bond, or in whose keto or iminotautomers the double bond to the single bond or the oxo or imino group is reduced to the hydroxy or amino group, in a process according to the method A compound obtainable wherein R _{2 is} hydroxy and the azacycloaliphatic ring has no double bond, the hydroxy group esterified to lower alkanoyloxy and, if desired, converting a free compound obtainable by the process into a salt or a salt obtainable according to the process into the free compound or into another salt. Thus, for example, 4-hydroxy-1- [2- (1H-indol-3-yl) -ethyl] -i ^^. E-pyridine-S-carboxylic acid methyl ester or 1- [2- (1H-indole) 3-yl) ethyl] -piperidin-4-one-3-carboxylic acid methyl ester or a salt thereof and isomer mixtures of cis- and trans-4-hydroxy-1- [2- (1H-indol-3-yl) ethyl] - methyl piperidine-3-carboxylate and methyl and cis- and trans-4-acetoxy-1- [2- (1H-indol-3-yl) ethyl] piperidine-3-carboxylate and in each case 5-methoxy substitution products thereof and their salts

Process variant c)

The rearrangement, in which ammonia is split off in the sense of Fischer's indole synthesis, can be carried out in a customary manner, for example by acid treatment, ie the action of a suitable protonic or Lewis acid. As protic acids, for example, mineral acids, such as sulfuric acid, phosphoric acid, as well as hydrogen chloride in a lower alkanol, such as ethanolic hydrochloric acid, and organic sulfonic acids, such as Niederalkan-, z. As methanesulfonic acid, or optionally substituted benzenesulfonic acids, such as benzene or p-toluenesulfonic acid, but also organic carboxylic acids, such as lower alkanoic acids, such as acetic acid, into consideration. As Lewis acids, for example, coordinatively unsaturated heavy metal compounds, such as coordinatively unsaturated halides of boron, aluminum, antimony, zinc, copper, nickel, iron, chromium or tin, z. As zinc chloride or copper-l-chloride or bromide suitable. The reaction is advantageously carried out with heating, for. B. in the temperature range of about 60 to 17O ⁰ C, if necessary under inert gas performed.

Intermediates IV are preferably prepared in situ by reacting an optionally appropriately substituted phenylhydrazine of the formula R ₃ -NH-NH ₂ (XXI) in customary with a compound of the formula

° Ί

- ^Z * \ , f ^ (XXN)

condensed and, if desired, the resulting hydrazone substituted on the secondary N-atom by a radical other than hydrogen R ₄

Process variant d)

Nucleofuge leaving groups X ₃ are, for example, free or reactive esterified hydroxy groups, such as hydroxy, halogen, z. As chlorine, bromine or iodine, or of sulfonic acids, such as lower alkane or optionally substituted benzenesulfonic acids, or halosulfonic acids derived sulfonyloxy groups, eg. For example, methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, p-bromobenzenesulfonyloxy or fluorosulfonyloxy.

The reaction of compounds V and VI is carried out in a customary manner, for example in the presence of a basic condensing agent, such as a tertiary organic nitrogen base, ζ. B. of pyridine or a Triniederalkylamins, such as triethylamine. But you can also alkali metal hydroxides or carbonates, eg. As sodium hydroxide, if necessary in the presence of phase transfer agents (phase transfer catalyst), z. B. of benzyl-trimethyl-ammonium hydroxide. Starting materials V can z. Example, be prepared by reacting a corresponding indole with formaldehyde and a hydrohalic acid, eg. For example, hydrochloric acid, reacted or condensed with a reactive diester of a corresponding Niederalkandiols or reacted with a Epoxyniederalkan and the resulting R-lower alkanol, if necessary, for example by means of thionyl chloride or phosphorus tribromide, halogenated or with a Sulfonsäurehalogenides, z. As p-toluenesulfonyl chloride, reacting. For the preparation of compounds V, wherein alk is ethylene, it is possible to convert the indole precursor by means of oxalyl dichloride into the corresponding 3-chloroxylylindole, this, for. B. with ethanol, alcoholize to the corresponding 3-Ethoxyoxalylindol reduce the resulting oxalic acid ester, z. B. by means of lithium aluminum hydride in diethyl ether, and the resulting 2- (3-indolyl) -niederalkanol if necessary then reactively esterify, for. B. by reaction with a halogenating or sulfonylating agent, for. With thionyl chloride, phosphorus tribromide or a sulfonic acid chloride such as p-toluenesulfonyl chloride

 Starting materials VI be z. B. obtained by reacting a compound of formula

alk-Xi

HN ^ (XXIII),

-CH ₂ -Ri

wherein Χι is a group of the formulas -CH = R ₂ ', -C (X ₂ J = R ₂ ' or cyano, wherein X _{2 is} a leaving group, or a salt thereof, is cyclized intramolecularly by treatment with an alkali metal lower alkoxide but also a B-amino-SR / ^ - methylene-pentane-i-carboxylic acid or a 2-aminomethyl-3-R ₂ 'pent-4-en-1-carboxylic acid or an ester or an amide thereof intramolecular cylation.

Process variant e)

Cyclization of compounds VII occurs spontaneously or by base treatment using as bases, for example, alkali metal alkoxides, amides or hydrides, e.g. Sodium methoxide, potassium tertiary butoxide, sodium amide, lithium N, N-diisopropylamide or sodium hydride can be used. As a solvent, for example, dimethylformamide is suitable.

The intermediates VI are advantageously prepared in situ and further reacted without isolation according to the invention by reacting a corresponding 2-halomethyl-3-R ₂ 'pent-4-ene-carboxylic acid or an ester or an amide thereof, in the presence of a base such as said, z. Example of sodium hydride, N-ethyl-N, N-diisopropylamine, sodium hydroxide or potassium carbonate, with a compound of the formula RZ-NH ₂ (XVIII), z. B. in dimethylformamide, N-methylpyrrolidone or dimethyl sulfoxide.

The necessary starting materials are z. B. obtained by reacting a compound of formula RZX ₃ (V, X ₃ = bromine) with ammonia or acryloylacetic acid ester with a Orthoameisensäuretriester, z. As trimethoxymethane, ketalized, the resulting ketal is heated under acidic conditions and the enol ether formed on the 2-methyl group halogenated, z. B. by means of N-bromo-succinimide, brominated. But you can also another 2-methyl-3-R ₂ -penta-1,4-diencarbonsäureesterbzw. Brominate 2-methyl-3-R ₂ 'pent-4-ene-carboxylic acid ester with N-bromosuccinimide.

In accordance with the process variant f) in optionally esterified or amidated carboxy R ₁ 'are, for example, solvolytically in these convertible radicals, as of esterified or amidated carboxy Ri different functionally modified carboxy, for example anhydridized carboxy, trihalomethyl, etherified Hydroxydihalogenmethyl, z. B. lower alkoxydichloromethyl, etherified trihydroxymethyl, e.g. Tri-lower alkoxymethyl, etherified or esterified C-hydroxyiminomethyl, e.g. C-lower alkoxyiminomethyl, or 2-oxazinyl groups such as 4,4- or 5,5-dimethyloxazinyl- (2) or 4,6,6-trimethyldihydro-oxazinyl- (2), C-haloiminomethyl or cyano.

The solvolysis is carried out in the usual way, for example by hydrolysis, alcoholysis, i. Reaction with an alcohol or ammonolysis or aminolysis, d. H. Reaction with ammonia or having at least one hydrogen atom

By hydrolysis, for example, one of said functional carboxy derivatives in the carboxylic acids of formula I (R ₁ = carboxy), further ortho-anhydride esters, orthoesters and imino ethers in esters of formula I (R ₁ = esterified carboxy) and imino, amidines or nitriles in amides (R ₁ = amidated carboxy).

The hydrolysis is carried out in a conventional manner by treatment with water, if necessary in the presence of a hydrolysis agent, in a solvent or diluent, with cooling or heating, e.g. B. in the temperature range of about 0 to 100 ° C, and / or under inert gas, such as nitrogen, hydrolysis agents are, for example, acidic or basic hydrolysis. Acid

Hydrolyzing agents are, for example, protic acids, such as mineral acids, eg. For example, sulfuric acid, such as halogen, z. As hydrochloric, hydrobromic or hydroiodic acid, or phosphoric acid, sulfonic acids, such as p-toluenesulfonic acid, or carboxylic acids, eg. B. lower alkanoic acids, eg. B. formic or acetic acid. Basic hydrolysis agents are, for example, hydroxides or carbonates of alkaline earth metals, eg. For example, sodium or potassium hydroxide, sodium or potassium carbonate or calcium hydroxide, or nitrogen bases such as ammonia or organic amines such as Triniederalkylamine, pyridine or Benzyltriäthylammoniumhydroxid. Solvents or diluents are, for example, water-miscible organic solvents, such as alcohols, e.g. Lower alkanols, ketones, e.g. Di-lower alkyl ketones, N, N-di-lower alkyl lower alkanoic acid amides and N-lower alkyl lower alkanoic acid lactams, e.g. As dimethylformamide or N-methylpyrrolidone, or di-lower alkyl sulfoxides, z. For example, dimethyl sulfoxide.

By alcoholysis, for example, acid anhydrides, such as mixed anhydrides with carboxylic acids or inorganic acids in esters of formula I (Ri = esterified carboxy) convert.

The alcoholysis is carried out in a customary manner, if necessary in the presence of a condensing agent, in a solvent, with cooling or heating, for. B. in the temperature range of about ^{0 0} C to 15O ⁰ C, in a closed vessel and / or under inert gas, such as nitrogen. Condensation agents include, for example, acidic condensing agents, such as mineral acids, e.g. Example, sulfuric acid or halogen, such as hydrochloric, hydrobromic or hydroiodic acid, or especially basic condensing agents, such as alkali metal alcoholates corresponding alcohols such as Alkalimetallniederalkanolate, z. For example, sodium methoxide or sodium ethoxide, alkali metal hydroxides or carbonates, eg. As sodium or potassium hydroxide or potassium carbonate, or tertiary nitrogen bases, such as heteroaromatic nitrogen bases, ζ. As pyridine, or Triniederalkylamine, z. B. triethylamine. As a solvent in addition to an excess of the alcohol in question or the tertiary nitrogen base used, for example, ether, such as Diniederalkyl- or Niederalkylenäther, z. As diethyl ether, tetrahydrofuran or dioxane, hydrocarbons such as aromatic or araliphatic hydrocarbons, eg. Benzene, toluene or xylenes, N, N-di-lower alkyl lower alkanoic acid amides or N-lower alkyl lower alkanoic acid lactams, e.g. As dimethylformamide or N-methylpyrrolidone, or di-lower alkyl sulfoxides, z. As dimethyl sulfoxide, into consideration. 4th

By means of ammonia or aminolysis, for example, acid anhydrides, such as mixed anhydrides with carboxylic acids or mineral acids, can be converted into amides of the formula I (R ₁ = amidated carboxy).

The ammonia or aminolysis is carried out in customary, if necessary in the presence of a condensing agent, in a solvent, with cooling or heating, e.g. in the temperature range of about 0 to 150 ° C. In a closed vessel and / or under inert gas, such as nitrogen. Condensation agents are, for example, basic condensing agents, such as alkali metal hydroxides or carbonates, z. Sodium or potassium hydroxide or potassium carbonate, or tertiary organic nitrogen bases such as heteroaromatic nitrogen bases, e.g., pyridine, or tri-lower alkylamines, e.g. Triethylamine. Suitable solvents in addition to an excess of an organic amine used, for example, ether, such as Diniederalkyl- or Niederalkylenäther, z. As diethyl ether, tetrahydrofuran or dioxane, hydrocarbons such as aromatic or araliphatic hydrocarbons, eg. B. benzene, toluene or xylenes, Ν, Ν-Diniederalkylniederalkansäureamide or N-Niederalkylniederalkansäurelactame, z. Dimethylformamide or N-methylpyrrolidone, or di-lower alkyl sulphoxides, e.g. Dimethyl sulfoxide, into consideration.

Cyano R ₁ may further be prepared by reaction with a corresponding alcohol or an amine having at least one hydrogen atom in the presence of a strong acid, for. B. of hydrochloric or hydrobromic acid, are converted into a corresponding Iminoether- or Amidinogruppierung and then by mild hydrolysis in esterified carboxy or substituted carbamyl Ri. However, the formation and further reaction of Iminoethergruppierungen can also be done in situ, for example by heating the nitrile in the presence of ammonium chloride with a small amount (about 1 to 5VoI .-%) of water-containing alcohol.

Further radicals FV convertible into optionally esterified carboxy are, for example, oxidizable into these convertible radicals, such as carboxy-Ri oxidizable acyl groups derived from organic carboxylic acids or the hydroxymethyl group, furthermore 2-furyl optionally substituted in the 5-position, such as di-lower alkoxymethyl. Carboxyl-oxidizable, derived from organic carboxylic acyl R ₁ 'is, for example, optionally substituted, for example in the 2-position by free or functionally modified carboxy, halogen or oxo and / or in the 2- and / or 3-position hydroxy exhibiting, in higher than the 2-position optionally additionally substituted by optionally esterified carboxy or a phenyl substituted Niederalkanoyl, or Niederalkenoyl, such as lower alkanoyl, especially optionally in hydrate form, Enolätherform, for example alsEnoläther with an alcohol of the formula R ₀ -OH, wherein R _{0 is} a hydrocarbon radical, such as lower alkyl , means, as acetal, ζ. B. di-lower alkyl or lower alkylene acetal, or acylal, z. B. as Diniederalkanoyloxy- or Dihalogenmethylgruppe present formyl, further acetyl, propionyl, pivaloyl and the like, optionally functionally modified, such as esterified or amidated Oxalo, z. Oxalo or lower alkoxy oxalyl, 2-mono-, 2,2-di- or 2,2,2-trihalo-lower alkanoyl, e.g. For example, mono-, di- or trichloroacetyl, mono-, di- or tribromoacetyl or mono-, di- or triiodoacetyl, 2-oxo-lower alkanoyl or 2-oxo-phenyl-lower alkanoyl such as pyruvoyl or benzoylcarbonyl, 2-hydroxy-lower alkanoyl, e.g. B. glycoloyl, or optionally functionally modified, for. B. esterified or amidated 3-carboxy-2,3-dihydroxypropionyl, such as tartronoyl or Niederalkoxytartronoyl, or optionally substituted by a phenyl lower alkenoyl, z. Acryloyl, methacryloyl, crotonyl, cinnamoyl and the like. Further groups R ₁ are etherified hydroxymethyl groups, such as lower alkoxymethyl, which can be oxidized to esterified carboxy, such as lower alkoxycarbonyl, R ₁ . The oxidation is carried out in customary manner by reaction with a suitable oxidizing agent, advantageously in a solvent or diluent, if necessary with cooling or heating, for example at about 100 ° C., in a closed vessel and / or under inert gas, such as nitrogen. Suitable oxidizing agents are, for example, oxygen, preferably in the presence of a catalyst such as a silver, manganese, iron or cobalt compound, peroxy compounds such as hydrogen peroxide, metal peroxides, e.g. As nickel peroxide, percarbonic acid and its salts or organic peracids, eg. As m-chloroperbenzoic acid, phthalic acid or peracetic acid, or their salts, oxidizing oxygen acids or their salts or anhydrides, such as hypohalous acids and their salts, for. As sodium hypochlorite, halogen acids and their salts, for example, iodic acids, periodic acids, potassium iodate, sodium periodate or potassium chlorate, nitric acid or nitrous acid and their salts and anhydrides, eg. Potassium nitrate, sodium nitrite, nitric oxide, dinitrogen trioxide or nitrogen dioxide, or oxidizing heavy metal compounds,

such as chromium VI, chromium IV, manganese IV, manganese VII, silver II, copper II, mercury II, vanadium V or bismuth II compounds, e.g. As sodium dichromate, potassium dichromate, chromium trioxide, manganese dioxide, potassium permanganate, silver-ll-oxide, copper-ll-oxide, mercury oxide or bismuth oxide. Inert solvents are, for example, inert solvents, such as water, ketones, z. For example, acetone, carboxylic acids and their anhydrides, eg. Acetic acid or acetic anhydride, halohydrocarbons, e.g. As carbon tetrachloride, or aromatics or heteroaromatics, eg. As benzene, or pyridine, or mixtures thereof.

Optionally esterified oxalo R ₁ 'of the formula -CI = O) -R ₁ can also be prepared by decarbonylation, for example in the presence of a suitable oxidizing agent, if necessary with cooling or heating, e.g. B. at about 0 to 100 ⁰ C, in an inert solvent, in a closed vessel and / or under an inert gas, such as nitrogen, are oxidized. Suitable oxidizing agents are, for example, per compounds, such as hydrogen peroxide or percarboxylic acids, for. As percarbonic acid or organic percarboxylic acids, including peracetic acid, performic acid, perbenzoic acid and the like, also halogenated acids and their salts, such as chloric acid or alkali metal chlorites, or oxidizing metal compounds, such as silver oxide, potassium permanganate or chromium trioxide. Suitable solvents are, for example, optionally hydrous ketones, such as acetone, or carboxylic acids, such as acetic acid.

The compounds of the formula VIII mentioned as starting materials can be prepared, for example, by reacting compounds of the formulas

_{V l _{b) /}

R - Z - X ₃ (V) and H <_ ..; - R ₂

wherein X _{3 is} reactive esterified hydroxy, ζ. As halogen, such as chlorine, bromine or iodine, means condensed together or a compound of formula

pl _ 7 - Kr · D

^K \ / ^(XXIV) <

wherein R 'is a substituted in 1-position or intermediately protected 3-indolyl R after reacting with a metal bubble, such as an alkali metal alkoxide, hydride or amide, ζ. With sodium methoxide, sodium hydride, sodium amide or lithium diisopropylamide, with phosgene, a Niederalkanoyloxycarbonylchlorid, carbon tetrachloride, Niederalkoxytrihalogenmethan, Triniederalkoxyhalogenmethan, cyanogen or a cyanogen halide, an acyl halide or Diacyloxid the formula R ^ -halogen (XXVa) or R ^ -OR ₁ ' (XXVb), with formaldehyde or a Halogenmethoxyniederalkan brings to reaction. Intermediate protected radicals R 'are, for example, per se 1-unsubstituted and / or in 4 to 7-position hydroxy, in 1-position or on the hydroxy group by conventional protecting groups, for example by esterified or etherified hydroxymethyl groups such as pivaloyloxymethyl, methoxymethyl, 2 Chloroethoxymethyl or benzyloxymethyl, tetrahydropyranyl or tri-lower alkylsilyl, such as trimethylsilyl, intermediately protected 3-indolyl radicals R. The protective group is prepared, for example, by reacting the compound Vl to be protected with a corresponding halogen derivative or with chloroiodomethane (CI-CH ₂ I), an alkali metal, ζ. As sodium pivalate, -methanolat, -1,2-dichloroethanolate or benzyl alcohol and or with dihydropyran introduced

 But you can also compounds of the formulas

/ ^al

R ¹ - X ₅ (XXVI) and X ₆ -ZN ^ -; - R ₂ "( ^χχνιι >'

wherein one of the radicals X ₅ and X _{6 is} a metallic radical, ζ. For example, the formula M '- M ^{"/ 2} or M" -hal, in which M ¹ is an alkali metal radical, for example, lithium, M "is a Erdalkalimetallradikal, for example, magnesium, cadmium or zinc and Hal represents halogen, such as chlorine, bromine or Iodine, the other is reactive esterified hydroxy, ζ B. is halogen, such as chlorine, bromine or iodine, or organic sulphonyloxy, such as lower alkane or optionally substituted benzenesulfonyloxy, for example methane, benzene or p-butyl. Toluenesulfonyloxy, R _{2 is} etherified or protected hydroxy or protected amino, e.g. As etherified hydroxy R ₂ , silyloxy, such as Triniederalkylsilyloxy, z. B. trimethylsilyloxy, but also Triphenylniederalkoxy, z. Trityloxy, or silylamino such as tri-lower alkylsilylamino, e.g. B. trimethylsilylamino, but can also be phenyl, diphenyl or Triphenylniederalkylamino such as benzylamino, diphenylmethylamino or tritylamino, and R ₁ 'in particular etherified trihydroxymethyl, z. B. tri-lower alkoxymethyl, a 2-oxazinyl group or optionally substituted in the 5-position 2-furyl, react with each other and the protective group (s) split off

Compounds VIII wherein R ₁ 'is cyano can be further prepared by reacting a compound of the formula

alk-Xi

R - Z - N, (XXVIII),

• -CH ₂ -Ri

in the X _{1 is} a group of the formulas -CH = R ₂ 'or-C (X ₂ ) = R ₂ ', where X _{2 is} a leaving group, z. B. lower alkoxy or halogen, represents or is cyano, in the presence of a metal base, for. B. an alkali metal alcoholate, such as sodium methoxide or -ethanolat, cyclized. This process is particularly suitable for the preparation of compound VIII in which the azacyclic ring has a double bond, R ₁ 'is cyano and R _{2 is} amino, starting from compounds XXVIII wherein Χι and R / both are cyano, and for the preparation of Compounds VIII in which the azacycloaliphatic radical has no double bond, R / formyl or cyano and R _{2 is} hydroxyl, which is based on compounds XXVIII, wherein Χι is formyl and R / is formyl or cyano. From Compounds VIII obtainable by the first-mentioned mode of formation, in which R _{2 is} amino and R ₁ 'is cyano, the corresponding compounds VIII, wherein R _{2 is} hydroxy and R ₁ ' is cyano, by mild hydrolysis, and from these by reaction with ammonium chloride or hydrogen chloride and an alcohol, the corresponding compounds VIII, wherein R _{2 is} optionally etherified hydroxy and R ₁ 'etherified C-Hydroxyiminomethyl, are prepared which further react in situ under hydrolysis of R / to esterified carboxy R ₁ . In starting materials VIa according to process variant g) cleavable radicals are, for example, halogen atoms or sulphonyloxy groups, for. B. benzene or p-toluenesulfonyloxy. Suitable compounds Vla are, for example, halocarboxylic acid esters or carbamoyl halides of the formula R.sup.1 halogen. Protected hydroxy R ₂ "'has, for example, the meaning given under process variant a), likewise 3-indolyl protected in the 1-position The reaction takes place, for example, in the presence of a basic condensing agent such as an alcoholate, amide or hydride of an alkali metal or alkaline earth metal, e.g. B. an alkali metal or alkaline earth metal alcoholate, eg of sodium methoxide, magnesium methoxide, sodium ethanolate or potassium tertiary butoxide, of an alkali metal amide, eg of sodium amide, lithium diisopropylamide, sodium N-methylanilide or sodium diphenylamide, or of an alkali metal or alkaline earth metal hydride, eg sodium hydride or calcium hydride, if necessary while cooling or heating, for. example, at about -1O ⁰ C to +120 ⁰ C, and / or under inert gas, such as nitrogen.

The starting materials IX can be obtained, for example, by reacting a compound of the formula RZX ₃ (V; X ₃ = halogen) with a compound of the formula

/ ^al

/ " ^{2 (XXIXI}

or a tautomer thereof, e.g. B. with 4-piperidone condensed. In this case, the radical R and / or hydroxy R _{2 may be} in protected form or protected from reaction with the reaction component, for. B. silylated to trimethylsilyloxy be.

Process variant h)

R ₂ convertible radical X ₄ are for example by solvolysis, ie reaction with a compound of formula R ₂ H (XIII) or a salt thereof, in a group R ₂ convertible radicals, for example reactive esterified hydroxy groups such as halogen atoms, eg. B.Chlor, bromine or iodine. Hydroxy-derivable radicals X ₄ are also diazonium groups, e.g. The formula -Ν ₂ ^Θ Α ^Θ , wherein Α ^{θ is} the anion of a strong acid, such as a mineral acid, e.g. As the chloride or sulfate, means, or etherified or acylated hydroxy groups R ₂ or optionally acylated amino groups R ₂ . The solvolysis is carried out in a customary manner, for example in the presence of a base such as an alkali metal or alkaline earth metal hydroxide, for. As sodium or potassium hydroxide, or a tertiary nitrogen base, for. Example, a Triniederalkylamins such as triethylamine, or a heteroaromatic nitrogen base such as pyridine, or a quaternary ammonium hydroxide such as benzyl-trimethyl-ammonium hydroxide, or by the compound XIII in the form of a metal salt, for. B. the formula R ₂ ^e M® (XIIIa) is used, wherein M® is an alkali metal cation, such as the sodium ion. Advantageously, one works in the presence of a solvent or digestive agent, for. B. in an excess of the reaction component XIII and / or a miscible with these inert solvent, if necessary, with cooling or heating, for. B. in the temperature range of about 0 ⁰ C to 120 ° C, and / or under inert gas, such as nitrogen. Compounds X can be prepared, for example, by reactions of compounds of the formulas

/ ^al

RZX ₃ (V) and m, '· - Xh (XXX),

· - ·

wherein X _{3 is} reactive esterified hydroxy, ζ. B. halogen, in a conventional manner, for example in the presence of a basic condensing agent, such as a tertiary organic nitrogen base, ζ. For example, pyridine or a tri-lower alkylamine, such as triethylamine

Compounds X, wherein X _{4 is} halogen, are further obtained by reacting with a compound of the formula

R - Z - NT y · (XII)

Halogen or hydrogen halide accumulates and splits off again hydrogen halide in the former case.

Compounds X, wherein X _{4 represents} a diazonium group, z. Example, prepared by diazotizing a compound of formula I, wherein R _{2 is} amino, ζ. Example, by reaction with nitrous acid or with ammonium or an alkali metal nitrite, z. B. with sodium nitrite, in the presence of a mineral acid of the formula HA.

Process variant i)

The rearrangement of compounds XI to compounds of the formula I in which the azacycloaliphatic ring has a double bond and R _{2 is} hydroxy, or to their tautomers of the formula Γ wherein R ₂ 'is oxo, takes place, for example, by acid treatment, in particular treatment with a Lewis acid, ie a coordinatively unsaturated halide of an element of the groups lib, INb or Va of the Periodic Table of the Elements, for example with zinc chloride, aluminum trichloride, boron trifluoride or antimony pentachloride, preferably with a boron trifluoride etherate, z. B. the complex of boron trifluoride with diethyl ether (boron trifluoride etherate), but can also by treatment with a strong protic acid such as a mineral acid, eg. B. with sulfuric or polyphosphoric acid, or with p-toluenesulfonic acid in benzene, are effected. If necessary, one works in the presence of an inert solvent and / or under cooling or heating, for. B. in the temperature range of about ^{0 0} C to 12O ⁰ C, and / or under inert gas, such as nitrogen

 Compounds XI are prepared, for example, by reacting a compound of the formula

^R " ^z "

in customary, for example by reaction with a peroxy compound, such as with hydrogen peroxide or in particular with an organic hydroperoxide compound, for. With tertiary butyl hydroperoxide, peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, permonophthalic acid or the like, epoxidized.

Process variant j)

The reaction of compounds XII and XIII is carried out in usually, for example, in the presence of a base such as an alkali metal or alkaline earth metal hydroxide, for. As sodium or potassium hydroxide, or a tertiary nitrogen base, ζ. Β. a tri-lower alkylamine, such as triethylamine, or a heteroaromatic nitrogen base, such as pyridine, or a quaternary ammonium hydroxide, such as benzyltrimethylammonium hydroxide, or by dissolving compound XIII in the form of a metal salt, e.g. B. the formula R ₂ ^e M® (XIlIa) is used, wherein M® is an alkali metal cation, such as the sodium ion. Advantageously, one works in the presence of a solvent or diluent, for. B. in an excess of the reaction component XIII and / or a miscible with these inert solvent, if necessary, with cooling or heating, for. B. in the temperature range of about ^{0 0} C to 12O ⁰ C, and / or under inert gas, such as nitrogen. Starting materials XII are obtained, for example, by reacting compounds of the formulas

R - Z - X ₃ (V) and HN - · _(ΧΧ χΐ _Κ

wherein X _{3 is} reactive esterified hydroxy, ζ. As halogen, means condensed in the usual manner, for example in the presence of a basic condensing agent, such as a tertiary organic nitrogen base, ζ. Β of pyridine or a tri-lower alkylamine, such as triethylamine.

Process variant k)

Oxoniederalkane, which are suitable for the introduction of the radical Z, are for example lower alkanals, ie 1-Oxoniederalkane, but can also Diniederalkylketone, z. B. 2-Oxoniederalkane be. The reaction of the same with compounds of the formulas L and VI is carried out in a customary manner, for example in the presence of a protic acid, such as a mineral acid, for. As hydrochloric acid, or a carboxylic acid, for. As of acetic acid. In this case, the corresponding compound of the formula RZX ₃ (V), where X _{3 is} hydroxyl, is formed as intermediate, which then reacts further without isolation according to the invention with the reaction component Vl.:The process variant is thus to be regarded as a preferred embodiment of process variant d). In starting materials, as mentioned, groups R, but also groups R, and / or R ₂ or R ₂ 'may be present in intermediately protected form.

Intermediate protected radicals R are for example 1-unsubstituted and / or in the 4- to 7-position hydroxy-containing, in 1-position or on the hydroxy group by conventional protecting groups, for example by optionally substituted benzyl or benzyloxycarbonyl, esterified or etherified hydroxymethyl groups such as pivaloyloxymethyl, methoxymethyl, 2-chloroethoxymethyl or benzyloxymethyl, tetrahydropyranyl or tri-lower alkylsilyl, such as trimethylsilyl, intermediately protected 3-indolyl radicals R. The protective group is obtained, for example, by reacting the compound to be protected with a corresponding halogen derivative or with chloroiodomethane (CI-CH ₂ I ), an alkali metal, e.g. B.

Sodium pivalate, -methanolat, -1,2-dichloroethanolate or benzyl alcoholate and or with dihydropyran introduced. Similarly, hydroxy or amino groups R ₂ or the primary amino group in starting materials, ζ. In compounds XVIII, for example by optionally substituted benzyl or benzyloxycarbonyl groups, esterified or etherified hydroxymethyl groups, such as pivaloyloxymethyl, methoxymethyl, 2-chloroethoxymethyl or benzyloxymethyl, tetrahydropyranyl or tri-lower alkylsilyl, such as trimethylsilyl, may be intermediately protected. Protected hydroxy is, for example, silyloxy, such as tri-lower alkylsilyloxy, e.g. B. trimethylsilyloxy, but can also Triphenylniederalkoxy, z. B. be trityloxy. For example, protected amino is silylamino, such as tri-lower alkylsilylamino, e.g. As trimethylsilylamino, but may also be phenyl, diphenyl or Triphenylniederalkylamino, such as benzylamino, diphenylmethylamino or tritylamino. Intermediate protected radicals R ₁ are, for example, carboxy groups which are protected as cyclic iminoethers, in particular optionally lower alkylated 4,5-dihydrooxazolyl (2) or 5,6-dihydro-oxazinyl (2), such as 4,4- or 5,5-dimethyl-4,5-dihydro-oxazolyl- (2), or 4,4,6-trimethyl-5,6-dihydro- oxazinyl (2). The group Ri protected in one of these forms is usually formed starting from carboxy, ζ.B. by reaction with aminoisobutanol (3-amino-2-methylpropan-2-ol) or 4-amino-4-methylpentan-2-ol or by reaction with 2,2-dimethylaziridine and subsequent acid treatment and starting from cyano by reaction with 2- Methyl-propane-1,2-diol, 4-amino-2-methylpentan-2-ol or 2-methyl-pentane-2,4-diol. The release intermediately protected residues, ie cleavage of the intermediate protecting groups, is carried out in customary manner, for example by hydrogenolysis, for. In the presence of platinum or palladium catalysts, or solvolysis, such as mild hydrolysis, e.g. B. treatment with water under neutral or weakly acidic conditions, eg. B. by the action of dilute aqueous mineral or carboxylic acids, eg. B. of dilute hydrochloric or acetic acid. In the hydrolysis of dihydrooxazolyl and dihydro-oxazinyl groups thereby free carboxy groups R _{1 are} formed.

Compounds obtainable according to the process can be converted in a customary manner into other compounds of the formula I. For example, it is possible to use esterified or amidated carboxy groups in customary manner, for example in the presence of a basic or acidic hydrolyzing agent, such as an alkali metal hydroxide or carbonate, ζ. Example of sodium hydroxide or potassium carbonate, or a mineral acid, eg. Hydrochloric acid or sulfuric acid, to hydrolyze to carboxy. Esterified carboxy groups can also be obtained by transesterification, ie treatment with an alcohol in the presence of an acidic or basic solvolysis agent, such as a mineral acid, e.g. B. of sulfuric acid, or a corresponding Alkalimetallalkoholates or an alkali metal hydroxide, converted into other esterified carboxy groups R ₁ or by reaction with ammonia or an amine having at least one hydrogen atom in amidated carboxy.

Free carboxy Ri can be prepared in a conventional manner, for example by treatment with a corresponding alcohol in the presence of a mineral acid, e.g. of sulfuric acid, or by conversion to a halide and subsequent reaction with a corresponding alcohol, for. B. in the presence of pyridine or triethylamine, or by conversion into an alkali metal salt and subsequent reaction with a reactive ester of the corresponding alcohol, such as a corresponding halide, are converted into esterified carboxy. Free or esterified carboxy can also be obtained by reaction with ammonia or an amine having at least one hydrogen atom and dehydration of the ammonium salt formed intermediately, for. B. by heating or by means of! ^, N-Dicyclohexylcarbodiimid, or by conversion into the halide and subsequent reaction with ammonia or an amine having at least one hydrogen atom are converted into amidated carboxy.

Furthermore, it is possible to convert etherified or acylated hydroxy groups R ₂ into hydroxy and acylated amino R ₂ into free amino, for example by hydrolysis, advantageously in the presence of a suitable hydrolysis agent. Such are, for example, acidic hydrolysis agents, such as protic acids, eg. For example, mineral acids such as hydrochloric acid or sulfuric acid, for the hydrolysis of an acylated hydroxy or amino group also basic hydrolyzing agents such as alkali metal hydroxides or carbonates, eg. For example, sodium hydroxide or potassium carbonate. In an analogous manner, in compounds I, wherein the azacycloaliphatic radical has a double bond and R _{2 is} amino, or in their tautomers (Γ, R ₂ = imino), the amino or imino group hydrolytically or by treatment with an alkali metal nitrite Replace hydroxy or oxo, especially under acidic conditions. The release of hydroxy from acylated hydroxy R ₂ can also by transesterification, z. B. by treatment with an alcoholate. B. Alkalimetallniederalkanolat, or an alcohol, for. B. lower alkanol, in the presence of one of said protic acids or a corresponding Alkalimetallalkoholates done. a-Phenylniederalkoxygruppen R ₂ can also hydrogenolysis, z. Example, by treating with hydrogen in the presence of a hydrogenation catalyst, such as palladium carbon, in hydroxy.

Conversely, one can etherify hydroxy R ₂ or acylate hydroxy or amino R ₂ . The etherification is carried out, for example, with an etherifying agent, such as a reactive ester, for. B. a hydrogen halide ester, the corresponding alcohol of the formula R ₂ H (XIII), z. A lower alkyl halide or di-lower alkyl sulfate, or a corresponding oxonium salt, e.g. B. a Triniederalkyl-oxoniumtetrafluorborat or -pentachloroantimonat. The acylation is carried out, for example, by reaction with a derivative of the corresponding carboxylic acid of the formula R ₂ H (XIII) wart of a hydrogenation catalyst, such as a platinum, palladium or nickel catalyst, for. B. of platinum oxide, or by reaction with a Dileichtmetallhydrid, z. B. with sodium borohydride or sodium cyanoborohydride. It is also possible to use cane sugar in the presence of baker's yeast as a reducing agent, whereby the cis isomer with 3R, 4S configuration is obtained selectively. Starting from a corresponding hydroxy compound, the reduction of the double bond can also be carried out by reaction with a secondary alcohol, for. B. with isopropanol or cyclohexanol, in the presence of an aluminum alcoholate, for. As of aluminum, be effected. The compound I reacts from the tautomeric oxoform (Γ, R ₂ '= oxo). Conversely, a compound I in which R _{2 is} hydroxy and the azacycloaliphatic ring has no double bond, by reaction with a ketone, for example with acetone or cyclohexanone, in the presence of a corresponding Aluminiumalkoholates, to the corresponding unsaturated compound or its tautomers (Γ, R ₂ = oxo).

Also you can Oxo R ₂ 'by reaction with ammonia, for. B. in methanol, in amino transfer.

Furthermore, unsubstituted 3-indolyl radicals R can be substituted in the usual way by one of the abovementioned 1-substituents, for example by reaction with a reactive ester of an aliphatic alcohol, preferably in the presence of a base such as an alkali metal hydroxide, lower alkoxide or hydride. In an analogous manner, it is also possible to etherify hydroxy R ₂ . Hydroxy or amino R ₂ can also be acylated z. By reaction with an anhydride or halide of an organic carboxylic acid, preferably in the presence of a base such as an alkali metal hydroxide, lower alkoxide or hydride, organic carboxylic acids also in the presence of an organic nitrogen base. In an analogous manner, carbamyl may also be N-acylated.

In an analogous manner as R can also carbamyl R ₁ aliphatic N-substituted, further convert aliphatic N-monosubstituted carbamyl in aliphatic Ν, Ν-disubstituted carbamyl.

Furthermore, one can esterify existing hydroxy groups in the radical R, z. Bi 'by treatment with a lower alkanecarboxylic anhydride or halide in Niederalkanoyloxy or by reaction with a reactive ester, in particular bromine or hydrochloric acid ester, a lower alkanol or lower alkenol in etherified hydroxy. Two hydroxy groups bonded to vicinal carbon atoms may also be obtained by reaction with a reactive diester of a lower alkanediol, e.g. B. a Dihalogenniederalkan, in Niederalkylendioxygruppierungen or by reaction with a Oxoniederalkan, d. H. Lower alkanal or di-lower alkyl ketone are converted into Niederalkylidendioxygruppierungen.

Conversely, in esterified or etherified hydroxy groups such as lower alkanoyloxy, lower alkoxy or lower alkyl (id) endioxy, one can solvolytically release the hydroxy group (s), preferably under acidic conditions.

The new compounds can, depending on the choice of starting materials and procedures, in the form of one of the possible isomers, ζ-. Example, depending on the number of asymmetric carbon atoms as optical isomers, such as in the form of an enantiomer, such as antipodes or diastereomers or as mixtures thereof, such as mixtures of enantiomers, for. As racemates, diastereomer mixtures or racemate mixtures are present.

Resulting diastereomer mixtures and mixtures of racemates can be separated in a known manner in the pure diastereomers or racemates due to the physico-chemical differences of the constituents, for example by chromatography and / or fractional crystallization. Racemates obtained can furthermore be decomposed by known methods into the optical antipodes, for example by recrystallization from an optically active solvent, by means of microorganisms or by reaction of an unsubstituted in the 1-position and / or on the hydroxy or amino group R ₂ or in at least one of the positions 4 to 7 by hydroxy-substituted end product I with an optically active acid or an anhydride thereof or a reactive ester of an optically active alcohol or by reacting an ester or an acid I (Ri = optionally esterified carboxy) with a with the racemic acid ester-forming optically active alcohol and each separation of the resulting diastereomeric substitution product or ester, for. Due to their different solubilities, into the diastereomers from which the enantiomers can be released by the action of suitable means.

Raeemate salt-forming compounds of formula I can also be prepared by reaction with an optically active auxiliary compound in diastereomer mixtures, for. B. with an optically active acid or base in mixtures of diastereomeric salts, and separation of the same into the diastereomers, from which the enantiomers can be released in the usual manner, are cleaved.

For this purpose, common optically active bases or acids are, for. B. Strichnin, cinchonin, optically active Alkaloidbasen, such as brucine, or 1-phenylethylamine, 3-pipecoline, ephedrine, amphetamine and similar synthetically accessible, optically active bases, or optically active carboxylic or sulfonic acids, such as D- or L-tartaric acid , Di-o-toluenoic, malic, mandelic, camphorsulfonic or quinic acid.

Furthermore, obtained free salt-forming compounds can be converted in a conventional manner into salts, for. Example by reacting a solution of the free compound in a suitable solvent or solvent mixture with a corresponding base or acid or with a suitable ion exchanger.

Salts obtained can be converted in a manner known per se into the free compounds, acid addition salts z. B.

by treating with a base such as an alkali metal hydroxide, a metal carbonate or bicarbonate, or ammonia, and base salts e.g. B. by reaction with an acid, eg. B. with hydrochloric acid.

Salts obtained can be converted in a conventional manner into other salts, acid addition salts z. 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 in which a forming inorganic salt is insoluble and thus precipitates out of the reaction mixture.

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

As a result of the close relationship between the new compounds in free form and in the form of their salts, in the preceding and following among the free compounds or their salts, it will be understood, if appropriate, that they also include the corresponding salts or free compounds.

The invention also relates to those embodiments of the process according to which one starts from an intermediate obtainable at any stage of the process and performs the missing steps or uses a starting material in the form of a salt or in particular forms under the reaction conditions.

Sb intermediate products of the formulas III, VII or VIII according to the process variant e) or f) can be formed in situ and further reacted without isolation.

New starting materials, eg. As the formulas II, III, VIII, IX, X, XII, XVI, XXVII and XXVIII, which were developed specifically for the preparation of the compounds of the invention, in particular to the initially marked as preferred compounds of the formulas I leading source material selection, the method for their preparation and their use as intermediates, also form an object of the invention.

Particular mention should be made in this connection of compounds of formula XVI having similar nootropic properties, albeit in somewhat lower potency, such as the compounds of formula I and besides their use as intermediates for the preparation thereof as pharmaceutical agents for the treatment of cerebral insufficiency, in particular memory disorders of a different nature Genesis of how to use senile dementia or dementia of the Alzheimer's type, furthermore of sequelae of brain trauma and apoplexies. The invention accordingly relates to compounds of the formula as a further subject of the invention

R ₆ RZN-CH ₂ CH ₂ -R ₁ (XVI),

wherein R is an optionally substituted 3-indolyl radical, Z is lower alkylene which separates the radical R by 1 to 3, preferably 2, carbon atoms from the nitrogen atom, R _{1 is} optionally esterified or amidated carboxy and R _{6 is} hydrogen or a group of the formula R, "', wherein R ₁ "' has one of the meanings given for R ₁ or for cyano, hydroxymethyl or optionally acetalated formyl, such as di-lower alkoxy or lower alkylenedioxymethyl, z. Dimethoxy or diethoxymethyl, dioxolan-2-yl or 1, S-dioxan-2-yl, and alk represents methylene, ethylene or 1,3-propylene, and their pharmaceutically acceptable salts for use in a method of treating the human or animal body, pharmaceutical compositions containing them and their use as active pharmaceutical ingredients, as well as compounds of formula XVI, wherein R, Z, R ₁ and R ₆ have the meaning given above, with the proviso that in compounds of formula XVI, wherein R is unsubstituted and R _{6 is} hydrogen, Z is other than ethylene when R _{1 is} methoxycarbonyl or ethoxycarbonyl, and their salts and processes for their preparation.

Suitable substituents of the 3-indolyl radical are, for example, those mentioned for compounds of the formula I. Likewise, Z, alk and R _{1 have,} for example, the preferred meanings given for compounds of formula I and salts are, for example, acid addition salts or base salts of the same type as indicated for compounds of the formula I. The invention relates, for example, to compounds of the formula XVI in which R, Z and R _{1 have} the meanings indicated and R _{6 is} hydrogen or a group of the formula - (CH ₂ J _n -Ri "'in which η 2 represents and R ₁ "'Formyl or iminomethyl or, if R _{1 is} free or esterified carboxy, also free or esterified carboxy or, if R _{1 is} lower alkoxycarbonyl, formyl, hydroxymethyl or cyano, with the proviso that in compounds of formula XVI, wherein R is unsubstituted and R _{6 is} hydrogen, Z is other than ethylene when R _{1 is} methoxycarbonyl or ethoxycarbonyl, and their salts.

The invention further relates, for example, to compounds of the formula XVI in which Run-substituted or 5-methoxy-substituted 3-indolyl, Z is ethylene, R _{1 is} methoxycarbonyl and R _{6 is} hydrogen or a group of the formula - (CH ₂ ) _n - Ri "', in which η is 2 and R ₁ "' is methoxycarbonyl or formyl, with the proviso that in compounds of formula XVI, wherein R is unsubstituted and R _{6 is} hydrogen, Z is other than ethylene when R ₁ Methoxycarbonyl or ethoxycarbonyl, and their salts.

The invention relates in the first place to those compounds of the formula XVI in which R is unsubstituted or substituted in at least one of the positions 1, 2 and 4 to 7, 3-indolyl, where as substituent in the 1-position lower alkyl or lower alkenyl, in the 2-position lower alkyl and as substituent (s) in the 4- to 7-position lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, hydroxy, halogen, trifluoromethyl and / or to lower carbon atoms bound lower alkyl (id) endioxy into consideration, Z is lower alkylene, which is the R 1 is nitrogen from 1 to 3, preferably 2 C atoms, R _{1 is} carboxy, lower alkoxycarbonyl, optionally substituted by lower alkyl, lower alkoxy, halogen, nitro and / or trifluoromethyl substituted phenyl-lower alkoxycarbonyl, 3- to 8-membered cycloalkoxycarbonyl, carbamoyl, mono- or Diniederalkylencarbamyl, lower alkylene or aza-, oxa- or Thianiederalkylencarbamyl, N-lower alkanoylcarbamyl, N-lower alkoxycarbonylcarbamyl, Ure idocarbonyl, N'-mono- or Ν ', Ν'-di-lower alkylureidocarbonyl, Ν', Ν'-lower alkylene or N ', N' - (Aza-, Oxa or Thia) niederalkylenureidocarbonyl and R _{6 is} hydrogen or a Group of the formula - (CH ₂ I _n -R ₁ "', wherein η is 1,2 or 3 and R ₁ "' is carboxy, lower alkoxycarbonyl, optionally substituted by lower alkyl, lower alkoxy, halogen, nitro and / or trifluoromethyl substituted phenyl-lower alkoxycarbonyl, 3 - to 8-membered cycloalkoxycarbonyl, carbamyl, mono- or di-lower alkylcarbamyl, lower-alkylene- or aza-, oxa- or thian-lower-alkylcarbamyl, N-loweralkanoylcarbamyl, N-loweralkoxycarbonylcarbamyl, ureidocarbonyl, N'-mono- or Ν ', Ν'-di-lower alkylureidocarbonyl, Ν' , Ν'-lower alkylene or N ', N' - (aza-, oxa- or Thiajniederalkylenureidocarbonyl or secondarily cyano, hydroxymethyl, di-lower alkoxymethyl or lower alkylenedioxymethyl, wherein lower alkylene alk to and with 4, the remaining lower radicals in total to and with 7 and in j eder lower partial structure up to and including 4 C atoms, and their pharmaceutically acceptable salts for use in a process for the treatment of the human or animal body, pharmaceutical compositions containing them and their use as active pharmaceutical ingredients, as well as compounds of formula XVI, wherein R, Z R ₁ and R ₆ have the significance given above, with the proviso that in compounds of formula XVI wherein R is unsubstituted and R _{6 is} hydrogen, Z is other than ethylene when R _{1 is} methoxycarbonyl or ethoxycarbonyl, and their salts and processes thereof production.

The invention relates in particular to compounds of the formula XVI in which R is unsubstituted or in one or two of the positions 4 to 7 by lower alkyl having bis and with 4C atoms, such as methyl, lower alkoxy with up to and with 4 C atoms, such as methoxy, halogen of Atom number to and with 35, such as chlorine, and / or trifluoromethyl-substituted 3-indolyl, Z is lower alkylene with bis and with 4 C atoms, which separates the radical R from the nitrogen atom by 1 to 3, preferably 2, C atoms, z , Methylene, 1,3-propylene or, preferably, ethylene, R _{1 is} carboxy, lower alkoxycarbonyl having up to and including 4 C atoms in the alkoxy part, such as methoxy or ethoxycarbonyl, 3- to 8-, for example 5- or 6-membered cycloalkoxycarbonyl such as cyclohexyloxycarbonyl, carbamoyl or N-mono or Ν, Ν-di-lower alkylcarbamyl having in each case up to and including 4 C atoms, such as methyl, ethyl or dimethylcarbamyl, and R _{e is} hydrogen or a group of the formula - (CH ₂ J _n -R "'in which η is 1 or 2 and R ₁ "' is carboxy, lower alkoxycarbonyl having up to and including 4 C atoms in the alkoxy part, such as methoxy- or ethoxycarbonyl, 3- to 8-, for example 5- or 6-membered cycloalkoxycarbonyl, such as cyclohexyloxycarbonyl, carbamoyl, N-mono- or Ν, Ν-di-lower alkylcarbamyl having in each case up to and including 4 C atoms, such as methyl, ethyl or dimethylcarbamyl, cyano, hydroxymethyl, formyl or di-lower alkoxymethyl or lower alkylenedioxymethyl with in each case up to and with 4 C atoms, in each alkoxy or alkylenedioxy part, such as Dim ethoxy or

Diethoxymethyl or ethylenedioxymethyl, and their pharmaceutically acceptable salts for use in a process for the treatment of the human or animal body, pharmaceutical compositions containing them and their use as active pharmaceutical ingredients, as well as compounds of the formula XVI, wherein R, Z, R-, and R _{6 are as defined} above, with the proviso that in compounds of formula XVI wherein R is unsubstituted and R _{6 is} hydrogen, Z is other than ethylene when R _{1 is} methoxycarbonyl or ethoxycarbonyl and their salts.

The invention preferably relates to those compounds of formula XVI, wherein R is unsubstituted or in one or two of the positions 4 to 7 by halogen of the atomic number to and with 35, such as chlorine, and / or lower alkyl with up to and 4 C atoms, such as Methyl, substituted 3-indolyl, Z represents straight-chain 1,1-, 1,3- or preferably 1,2-lower alkylene having up to and including 4 C atoms, such as ethylene, furthermore methylene or 1,3-propylene, R _{1 is} lower alkoxycarbonyl having up to and including 4 C atoms in the alkoxy part, such as methoxycarbonyl or ethoxycarbonyl, and R _{6 is} hydrogen or a group of the formula - (CH ₂ I _n -Ri "', where η is 1 or 2 and R"'has the same meaning as Ri, and its pharmaceutically acceptable salts for use in a process for the treatment of the human or animal body, pharmaceutical compositions containing them and their use as drug actives, as well as compounds of the formula XVI, wherein R, Z, R, and R ₆ protrude with the proviso that in compounds of formula XVI wherein R is unsubstituted and R _{6 is} hydrogen, Z is other than ethylene when R _{1 is} methoxycarbonyl or ethoxycarbonyl, and their salts and processes for their preparation.

The invention relates, in particular, to those compounds of the formula XVI in which R is unsubstituted or, secondarily, in the 4- and 7-positions by lower alkyl having bis and 4 C atoms, such as methyl, or in the 5-position by halogen of the atomic number to and Z is 3-indolyl substituted with chlorine, Z is ethylene, R is lower alkoxycarbonyl having up to and including 4 C atoms in the lower alkoxy part, such as methoxycarbonyl or ethoxycarbonyl, and R _{6 is} hydrogen or a group of the formula - (CH ₂ ) _n -Ri "', in which η is 1 or 2 and R ₁ "' has the same meaning as R ₁ or cyano, di-lower alkoxymethyl with up to and with 4 alkoxy C atoms, such as dimethoxy- or diethoxymethyl, lower-alkylenedioxymethyl with 2-bisund with 4-alkylenedioxy- C atoms, such as 1,3-dioxolan-2-yl or 1,3-dioxan-2-yl, or Ν, Ν-di-lower alkylcarbamyl each containing and to 4 alkyl-C-atoms, such as dimethylcarbamyl, and their pharmaceutically acceptable Salts for use in a method of treating the male body or animal body, pharmaceutical compositions containing them and their use as active pharmaceutical ingredients, as well as compounds of the formula XVI, wherein R, Z, R ₁ and R ₆ have the meaning given above, with the proviso that in compounds of the formula XVI, wherein R is unsubstituted and R _{6 is} hydrogen, Z is other than ethylene when R _{1 is} methoxycarbonyl or ethoxycarbonyl, and their salts and processes for their preparation. The invention preferably relates in each case preferably to those compounds of the formula XVI in which R _{6 is} hydrogen. The invention relates in particular to the compounds of the formula XVI mentioned in the examples and their salts, in particular pharmaceutically usable salts.

The process according to the invention for the preparation of compounds of the formula XVI and their salts is characterized in that 1) compounds of the formulas

RZX ₅ (XXXII) and X ₆ -CH ₂ -CH ₂ -R ₁ (XXXIII),

wherein one of X ₆ and X _{6 is} a group of the formula -N (R ₆ ) -H and the other is a nucleofugic leaving group, or their salts are reacted together, or m) compounds of the formulas

RZN (R ₆ ) -H (XXXVII) and CH ₂ = CH-R ₁ (XXXIV)

or their salts are reacted with each other, or n) a compound of the formula

R ₃ -NN = C-CH ₂ -N-CH ₂ CH ₂ -R ₁ (XXXV)

R4 R ₅ R ₆

in which R ₆ denotes a phenyl radical which is optionally substituted in the 3 to 6 position as for positions 4 to 7 of the radical, R _{4 is} hydrogen or a substituent provided for the 1 position of R and R _{5 is} hydrogen or a radical 2 Position of R provided substituents, or a tautomer and / or salt thereof, to the corresponding compound of formula XVI ring, or o) in a compound of formula

R ₆ 'RZN-CH ₂ CH ₂ -R ₁ ', (XXXVI)

in which R ₆ 'is hydrogen or a group of the formula alk-R / and R ₁ ' is a radical which may be converted into optionally esterified or amidated carboxy R ₁ , R ₁ 'is converted into optionally esterified or amidated carboxy and, if desired, the compound obtainable by the process into another Compound of formula XVI transferred, an isomer mixture obtainable by the process is separated into the components and the isomer of formula XVI isolated, a diastereomer mixture or mixture of enantiomers available in the diastereomers or enantiomers splits and isolated the desired diastereomers or enantiomers and / or a process according to available free compound into a salt or a salt obtainable according to the method converts into the free compound or into another salt. Process variant 1)

Nucleofuge leaving groups X ₅ are, for example, reactive esterified hydroxy groups X ₃ , such as halogen, e.g. As chlorine, bromine or iodine, or of sulfonic acids, such as lower alkane or optionally substituted benzenesulfonic acids, or halosulfonic acids derived sulfonyloxy groups, for example methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, p-Brombenzolsufonyloxy or fluorosulfonyloxy.

The reaction of compounds XXXII and XXXIII is carried out in a customary manner, for example in the presence of a basic condensing agent, such as a tertiary organic nitrogen base, for. B. of pyridine or a Triniederalkylamins, such as triethylamine. Reactions of equimolar amounts of both reactants, starting from compounds XXXII, wherein R _{6 is} hydrogen, gives compounds XVI, wherein R _{6 is} hydrogen. If the reaction component XXXII is used in at least a double molar excess, starting from compounds XXXII in which R _{6 is} hydrogen, the compounds XVI are obtained, where R _{6 is} a group - (CH ₂ I _n -Ri '') in which 2 and IV "is identical to R ₁ " The preparation of compounds XXXII in which X 5 is a group X ₃ , ie of compounds V, is already described under process variant d). Compounds XXXVII, wherein X is a group-N (R ₆ IH and R ₆ is hydrogen _5, ie compounds XVIII, are widely known, they can be obtained by reacting with ammonia from the corresponding compounds V. Compounds XXXII wherein X ₅ is a Group -N (R ₆ IH and R _{6 is} a group of the formula alk-R / "can be prepared by reacting compounds of the formulas RZ-NH ₂ (XVIII) and Xy-alk-R,"'(XXXIIIa) or CH ₂ = CH-R ₁ '''(XXXIVa) or reaction of compounds RZX ₃ (V) and H ₂ N-SIk-R ₁ ''(XXXIIIb) According to this process variant, it is possible, for example, to obtain compounds of the formula XVI in which , Z and R _{1 have} the meanings given and R _{6 is} hydrogen or a group of the formula - (CH ₂ ) HR ₁ '", where η 2 represents and R'" is formyl or iminomethyl or, if R _{1 is} free or esterified Represents carboxy, also free or esterified carboxy or, if Ri is lower alkoxycarbonyl, formyl, hydroxymethyl or cyano, or compounds of the formula XVI in which R is unsubstituted or 5-methoxy-substituted 3-indolyl, Z is ethylene, R _{1 is} methoxycarbonyl and R _{6 is} hydrogen or a group of the formula - (CH ₂ I _n R ₁ '"in which η is 2 and R ₁ '" is methoxycarbonyl or formyl, and produce their salts by reacting a compound of the formula

RZX ₃ (V),

wherein X _{3 is} reactive esterified hydroxy, with a compound of the formula

H ₂ N-CH ₂ CH ₂ -R ₁ (XVa)

if desired, reacting with Acrolein or an aldehyde of the formula Y ₁ -CH ₂ CH ₂ -CH = R ₂ '(XVIIa) in which Y _{1 is} reactive esterified hydroxy and R ₂ ' is the compound of formula XVI in which R _{6 is} hydrogen. Oxo means, further reacted and, if desired, converts a free compound obtainable by the process into a salt or a salt obtainable according to the process into the free compound or into another salt.

Process variant m)

The reaction of compounds XXXVII with compounds XXXIV is effected in customary manner, for example in a lower alkanol, such as ethanol, at about 0 C to about 6O ^{c 0} C.

Reactions of equimolar amounts of both reactants, starting from compounds XXXVIII in which R _{6 is} hydrogen, give compounds XVI in which R _{6 is} hydrogen. If the reaction component XXXIV is used in excess of a double molar excess, starting from compounds XXXVII in which R _{6 is} hydrogen, the compounds XVI are obtained, in which R _{6 is} a GrUpPe- (CH ₂ I _n -R ₁ "'in which η 2 and R ₁ '"with R _{1 is} identical.

Examples of these process variants may be compounds of the formula XVI in which R and Z have the meanings indicated and R _{6 is} hydrogen or a group of the formula - (CH ₂ I _n -Ri '"in which η 2 represents where R ₁ and R ₁ '"represent free or identical esterified carboxy groups, or compounds of the formula XVI, wherein R is unsubstituted or substituted in the 5-position by methoxy 3-indolyl, alk is ethylene, Ri is methoxycarbonyl and R _{6 is} hydrogen or a group of the formula - (CH ₂ I _n -Ri '"represents, in which η is 2 and R ₁ '" is methoxycarbonyl, and produce their salts, by reacting a compound of formula

RZ-NH ₂ (XVIII)

with approximately twice the molar amount of a compound of the formula Y ₁ -CH ₂ CH ₂ -R ₁ "(XIXa) or CH ₂ = CH-R ₁ " (XIXb), wherein Yi is reactive esterified hydroxy and R ₁ "is free or esterified carboxy , methoxy-carbonyl, and, if desired, converting a free compound obtainable by the process into a salt or a salt obtainable according to the process into the free compound or into another salt

Process variant n)

The rearrangement, in which ammonia is split off in the sense of Fischer's indole synthesis, can be carried out in a customary manner, for example by acid treatment, ie the action of a suitable protonic or Lewis acid. As protic acids, for example, mineral acids, such as sulfuric acid, phosphoric acid, as well as hydrogen chloride in a lower alkanol, such as ethanolic hydrochloric acid, and organic sulfonic acids, such as Niederalkan-, z. As methanesulfonic acid, or optionally substituted benzenesulfonic acids such as benzene or p-toluenesulfonic acid, but also organic carboxylic acids such as lower alkanoic acids, eg. As acetic acid, into consideration. As Lewis acids, for example, coordinatively unsaturated heavy metal compounds, such as coordinatively unsaturated halides of boron, aluminum, antimony, zinc, copper, nickel, iron, chromium or tin, z. As zinc chloride or copper-l-chloride or bromide suitable. The reaction is advantageously carried out with heating, for. B. in the temperature range of about 60 to 17O ⁰ C, if necessary under inert gas performed. Intermediates XXXV can z. Example, be prepared by reacting a hydrazone of the formula R ₃ -NH-N = C (CR ₅ J-CH ₂ -Z-NH ₂ (XXXVa) with a compound X ₆ -CH ₂ CH ₂ -R ₁ (XXXIII; X ₆ = halogen) or CH ₂ = CH ₂ -R ₁ (XXXIV) and, if desired, subsequently with a compound X ₃ -BIk-R ₁ '"(XXXIIIa, X ₃ = halogen) or CH ₂ = CH-R ₁ '(XXXIVa) is condensed and, if desired, the hydrazone obtained is substituted on the secondary N atom by a radical R _{4 which is} different from hydrogen

Process variant o)

In optionally esterified or amidated carboxyl-transferable radicals R ₁ 'are, for example, for the process variant f) specified to R ₁ solvolysierbaren or oxidizable groups. The solvolysis or oxidation is also carried out, for example, in an analogous manner as indicated there.

The starting materials XXXVI can be prepared, for example, by reacting a compound of the formula RZ-NH ₂ (XVIII) or a salt thereof with a compound of the formula X ₃ -CH ₂ CH ₂ -Ri '(XXXVIII) or CH ₂ = CH- R ₁ '(IXL), wherein X _{3 is} a nucleofugic leaving group, such as halogen, e.g. B. chlorine or bromine, and if desired, then reacted with a compound of formula X ₃ -alk-R ₁ '(XXXVIIIa), for example, in an analogous manner as indicated for process variant 1). For the preparation of compounds XXXVI, wherein R ₁ 'is cyano, but you can also compound XVII with a 1,2-difunctional Ethanderivat such as a 1,2-dihaloethane, z. As 1,2-dibromoethane, react and bring the reaction product with an alkali metal cyanide for reaction.

As optional follow-up reactions in connection with compounds XVI z. As the specified for compounds I mutual conversions of free, esterified and amidated carboxy groups R ₁ , introduction or modification reactions of substituents of the radical R, reciprocal conversions of free compounds and salts as well as separation measures obtained isomers to call all carried out in an analogous manner as indicated for compounds I. To mention is also the possibility of oxidation of hydroxymethyl or formyl R ₁ '"to carboxy and the hydrolysis of cyano R ₁ '" to carbamyl or carboxy, which can also be carried out in the usual manner.

In particular, it is also possible to obtain a compound XVI obtainable in accordance with the process according to the invention in which R _{6 is} hydrogen in analogous manner to process variant I) or m) by reaction with a compound of the formula X ₃ -BIk-R ₁ '"(XXXIII a) or CH ₂ = CH ₂ -R ₁ '"(XXXIVa) into the corresponding compound XVI, in which R ₁ '" is different from R _1. The novel compounds of the formulas I and XVI can be prepared, for example, in the form of pharmaceutical preparations Find use, which contain a therapeutically effective amount of the active substance, optionally together with inorganic or organic, solid or liquid, pharmaceutically acceptable excipients which are suitable for enteral, eg oral or parenteral administration.There are used tablets or gelatin capsules, which comprises the active ingredient together with diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or lubricants, for example silica, talc, stearic acid or Sa These include, for example, magnesium or calcium stearate, and / or polyethylene glycol. Tablets may also bind, 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, disintegrants, e.g. For example, starches, agar, alginic acid or a salt thereof, such as sodium alginate, and / or effervescent mixtures, or adsorbent dyes, flavors, and sweeteners. Furthermore, the novel compound of the formula I or XVI can be used in the form of parenterally administrable preparations or infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, these z. As in lyophilized preparations containing the active substance alone or together with a carrier material, for. As mannitol, can be prepared before use. The pharmaceutical preparations may be sterilized and / or adjuvants, eg. As preservatives, stabilizers, wetting agents 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 conventional manner, for. Example by means of conventional mixing, granulation, coating, solution or lyophilization, prepared and contain from about 0.1% to 100%, in particular from about 1% to about 50%, lyophilizates up to 100% of the active material.

The invention also relates to the use of the compounds of the formula I or XVI, preferably in the form of pharmaceutical preparations. The dosage may depend on various factors, such as route of administration, species, age and / or individual condition. The doses to be administered daily are between about 0.25 and about 10 mg / kg when administered orally and between about 20 mg and about 500 mg for warm-blooded animals weighing about 70 kg.

embodiment

The following examples serve to illustrate the invention; Temperatures are given in degrees centigrade, pressures in mbar.

Example 1: 22.4 g of 1-bromo-2- (1H-indol-3-yl) -ethane, 15.7 g of piperid-4-one-3-carboxylic acid methyl ester and 39 g of N-ethyl-N, N-diisopropylamine are added Dissolved nitrogen in 750 ml of dimethylformamide and stirred for 16 hours. It is then concentrated under reduced pressure to about 300 ml, added 500 ml of water and extracted three times with 250 ml of dichloromethane. The organic phases are combined and extracted by shaking three times with 80 ml each of η-hydrochloric acid. The aqueous phases are combined, made basic with 40% sodium hydroxide solution and shaken again three times with 100 ml dichloromethane. The new organic phases are combined, washed with water and then with saturated brine, dried over sodium sulfate and evaporated to dryness. The evaporation residue is dissolved in 100 ml of warm diethyl ether and mixed with 150 ml of η-hexane. After cooling, the methyl 4-hydroxy-1- [2- (1H-indol-3-yl) ethyl] -1,2,5,6-tetrahydropyridine-3-carboxylate or 1 - [2- (I H- indole-3-yl) ethyl] -piperidin-4-one-3-carboxylic acid methyl ester, which is filtered off and dried; the hydrochloride thereof melts (dec.) at 187 ⁰ C

Example 2: 320.4 g (2 mol) of tryptamine are suspended with stirring in 550 ml of methanol and treated dropwise within one hour with 378.5 g (4,4MoI) of methyl acrylate. The mixture is stirred for 6 hours at 5O ⁰ C and overnight at room temperature, evaporated to 40X under reduced pressure to dryness, taken up in 1.51 toluene, add 50g of activated charcoal, allowed to stir for 30 minutes, filtered through Diatomerenerde and evaporated to dryness under reduced pressure. N- [2- (1H-indol-3-yl) ethyl] -imino-di (3-propionic acid) dimethyl ester is obtained as a reddish oil, which is prepared analogously to Example 10 in the oxalate of mp. 98-103 ° C can be transferred.

153 g (2.83 mol) of sodium methoxide are dissolved with stirring in 1000 ml of dimethylformamide. Then added dropwise within 90 minutes, a solution of 665g (2MoI) N- [2- (1H-indol-3-yl) ethyl] -imino-di (3-propionic acid) dimethyl ester in 680ml dimethylformamide, heated to 40 ° C, stirred for 3 hours at room temperature and the solvent is distilled off at 40 ⁰ C under reduced pressure. The residue is poured at 20 to 35 ⁰ C in a mixture of 2,11 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 methyl ester hydrochloride. 1- [2- (1 H-indol-S-piperidin ^ -one yDethylJ-S-carbonsäuremethylester hydrochloride wirdabgenutscht, washed with cold methanol and dried at 40 ° C under reduced pressure. It melts at 185- 187 ⁰ C ( dec.).

Example 3: Starting from 80 g (0.5 mol) of tryptamine and 112 g (1.1 mol) of ethyl acrylate in 150 ml of ethanol, N- [2- (1H-indol-3-yl) is obtained in an analogous manner. ethyl] -imino-di (3-propionic acid) diethyl ester and by reacting 180 g of this with 37.4 g (0.55 mol) of sodium ethanolate 4-hydroxy-1- [2- (1H-indol-3-yl) ethyl] Ethyl 1,2,2,5-tetrahydro-pyridine-3-carboxylate hydrochloride or ethyl 1- [2- (1H-indol-3-yl) ethyl] -piperidin-4-one-3-carboxylate hydrochloride from m. 170-173 ⁰ C (Zers.).

Example 4: 52.6 g (0.15 mol) of ethyl 4-hydroxy-1- [2- (1H-indol-S-y-ethyl] -j ^ e-tetrahydro-pyridine-S-carboxylate hydrochloride are added in 5 ml of 5g of platinum oxide room temperature and atmospheric pressure until uptake of 3.81 hydrogen hydrogenated. The mixture is filtered off from the catalyst and evaporated at 3O ⁰ C under reduced pressure to dryness. The residue is mixed with 50 ml of acetone. The immediately crystallizing crude product is filtered off and recrystallized from ethanol. This gives cis-4-hydroxy-1- [2- (1 H-indol-S-yl-ethyl-piperidine-S-carboxylic acid ethyl ester hydrochloride, mp. 207-210 ° C.

In an analogous manner, by hydrogenation of 33.7 g (10OmMoI) 4-hydroxy-1- [2- (1H-indol-3-yl) ethyl] -1,2,5,6-tetrahydropyridin-3-carboxylic acid methyl ester- hydrochloride in the presence of 1.7 g of platinum oxide, the cis-4-hydroxy-1- [2- (indol-3-yl) ethyl) piperidine-3-carboxylic acid methyl ester hydrochloride, mp. 187 ° C (dec.).

Example 5: 337 g (1 mol) of 4-hydroxy-1- [2- (1H-indol-S-ylethyl) -j ^^^ -tetrahydropyridine-S-carboxylic acid methyl ester hydrochloride are dissolved in 3.31 methanol and portionwise with stirring at -15 ° to 5 ° C over 2 hours added 68g (1.1 mol) of sodium borohydride. the mixture is stirred for 1 hour slowly warmed to 40 ⁰ C and distilled under reduced pressure, the solvent off. the residue is dissolved in A mixture of 1.51 ethyl acetate and 11 ice water is added, 50 g of potassium carbonate are added, the mixture is stirred for 30 minutes, the organic phase is separated off, washed neutral with water, dried on magnesium sulfate and evaporated to dryness under reduced pressure Mixture of about equal parts of cis- and trans-4-hydroxy-1- [2- (1H-indol-S-y-ethyl-1-piperidine-S-carboxylate as oil, which can be purified by flash chromatography on silica gel with dichloromethane / methanol ( 95: 5) are separated into the components, the transisomer eluie first It can be converted into the semi-fumarate of the type 208-209 ⁰ C (cf. Example 6). The later isolated cis-isomer can be characterized by conversion into the hydrochloride of mp. 187 ⁰ C (dec.) In an analogous manner as described in Example 8.

Examples: 3.16 g (10 mmol) of trans-4-hydroxy-1- [2-indol-3-yl) -ethyl] piperidine-3-carboxylic acid methyl ester are dissolved in 50 ml of acetone, dissolved with 0.6 g (50 mM) fumaric acid in 10 ml of acetone. After some time, the trans-4-hydroxy-1- [2- (indol-3-yl) ethyl] piperidine-3-carboxylic acid methyl ester semifumarate crystallizes out. It is filtered off and dried under reduced pressure; Semp .208-209 ⁰ C.

Example 7: In an analogous manner as described in Example 5, by reduction of 35.3 g (100 mol) of 4-hydroxy-1- [2- (1 H-indol-S-yDethyll-i ^^^ - tetrahydro -pyridine-S-carboxylic acid ethyl ester hydrochloride with 3.8 g (10OmMoI) of sodium borohydride in 300 ml of ethanol a mixture of about equal parts of ice and trans-4-hydroxy-1- [2- (1H-indol-3-yl) ethyl ] -piperidine-3-carboxylic acid ethyl ester, which was separated by chromatography and for characterization in the trans-4-hydroxy-1- [2- (1 H-indol-3-yOethylJ-piperidine-S-carboxylic acid ethyl ester hydrochloride, m.p. 109-112 ⁰ C, and cis-4-hydroxy-1- 210-213 ⁰ [2- (1 H-indol-3-yl) ethyl] piperidine-S-carboxylate hydrochloridjSmp. C, (see. example 8) can be converted ,

Examples: 6.32 g (20 μmol) of trans-4-hydroxy-1- [2- (1H-indol-3-yl) ethyl] -piperidine-3-carboxylic acid ethyl ester are dissolved in 100 ml of dichloromethane and made conglomerate with ethereal hydrogen chloride solution. The crystalline precipitate is filtered off with suction and dried under reduced pressure. The trans-4-hydroxy-1- [2- (1H-indol-3-yl) ethyl] -piperidine-3-carboxylic acid ethyl ester hydrochloride of the mp. 109-112 ⁰ C is obtained in an analogous manner Cis-4-hydroxy-1- [2- (1H-indol-S-y-ethyl-piperidine-S-carboxylic acid ethyl ester hydrochloride, mp 210-213 ⁰ C (dec.).

Example 9: 30.2 g (10OmMoI) of cis-4-hydroxy-1- [2- (1H-indol-3-yl) ethyl] piperidine-3-carboxylic acid methyl ester are dissolved in 150 ml of pyridine, treated with 75 ml of acetic anhydride and 15 Stirred hours at room temperature. It is evaporated to dryness under reduced pressure, taken up in a mixture of ice-water, saturated potassium carbonate solution and diethyl ether, the organic phase is separated off, washed neutral with water, dried over magnesium sulfate and evaporated to dryness. The cis-4-acetoxy-1- [2- (1H-indol-3-yl) ethyl-3-carboxylic acid methyl ester, mp. 93-95 ° C. The trans-4-acetoxy-1- [2- (1H-indol-3-yl) ethyl] -piperidine-3-carboxylic acid methyl ester is obtained in exactly the same way as a colorless oil, mp of the oxalate (compare Example 10) ) 189 ⁰ C.

The two aforementioned compounds can also be obtained by adding a mixture of approximately equal parts of cis- and trans-4-hydroxy-1- [2- (1H-indol-3-yl) ethyl-piperidine-3-carboxylic acid methyl ester in acylated exactly analogous manner as described above and the resulting oily mixture of about equal parts of cis and trans-4-acetoxy-1- [2- (1 H-indol-3-yl) ethyl] piperidine-3-carboxylic acid methyl ester in the chromatographically Separates components. To this is added 2.5 g of the mixture of a flash chromatography on 150 g of silica gel (60, Merck) with trichloromethane / methanol 98: 2) as eluent. The trans-isomer is isolated first, the cis-isomer last.

Example 10: 0.38 g (2 mmol) of trans-4-acetoxy-1- [2- (1H-indol-3-yl) ethyl] -piperidine-3-carboxylic acid methyl ester are dissolved in 10 ml of acetone and treated with 0.2 g (2 mmol) of oxalic acid dissolved in 3 ml of acetone. The trans-4-acetoxy-1- [2- (1H-indol-3-yl) ethyl] -piperidine-3-carboxylic acid methyl ester oxalate, which crystallizes out at once, is filtered off with suction and dried; Mp 189 ° C (decomp.)

Example 11: 16.9 g (50 mM) 4-Hydroxy-1- [2- (1H-indol-S-y-ethyl-1-yl-tetrahydro-pyridine-S-carboxylic acid methyl ester hydrochloride are suspended in 100 ml of methanol and mixed with 25 ml of a The mixture is stirred for 2 hours at 40 ⁰ C, evaporated to dryness under reduced pressure, shaken with 300 ml of dichloromethane and 100 ml of water, the organic phase is separated, washed neutral with water, dried over magnesium sulfate, evaporated Dry and crystallize from diethyl ether / hexane to give methyl 4-amino-2- [2- (1H-indol-3-yl) ethyl] -1,2,5,6-tetrahydropyridine-3-carboxylate, mp 112- 113 ° C.

Example 12: A solution of 14.2 g (50 mM) of methyl 1- [2- (1H-indol-5-y-yl-ethyl) -tetrahydropyridine-S-carboxylate in 150 ml of methanol is mixed with 40 g of ammonia and concentrated The autoclave is heated at 100 ° C. for 12 hours, the pressure rising to 22 bar, allowed to cool, evaporated to dryness on a water jet pump, crystallized from a mixture of 50 ml of dichloromethane and 100 ml of diethyl ether and recrystallized from ethanol 4-amino-1- [2- (1 H-indol-3-yl) ethyl] piperidine-3-carboxamide, mp. 210-212 ⁰ C.

 The starting material can be prepared as follows:

22.4 g of 1-bromo-2- (1H-indol-3-yl) -ethane, 22.2 g of methyl iodo-tetrariydro-pyridine-S-carboxylate hydrobromide (Guvacol® hydrobromide) and 39 g of N-ethyl-N, N-diisopropylamine are dissolved under nitrogen in 750 ml of dimethylformamide and stirred for 16 hours. It is then concentrated under reduced pressure to about 300 ml, added 500ml of water and shaken three times with 250 ml of Diehlormethan from. The aqueous phase is made basic with 40% sodium hydroxide solution and shaken out three times with 100 ml of dichloromethane. The new organic phases are combined, washed with water and then with saturated brine, dried over sodium sulfate and evaporated to dryness. The evaporation residue is dissolved in 100 ml of warm diethyl ether and with 150 ml of η-hexane aqueous phase is made basic with 40% sodium hydroxide solution and shaken again three times with 100 ml of dichloromethane. The new organic phases are combined, washed with water and then with saturated brine, dried over sodium sulfate and evaporated to dryness. The evaporation residue is dissolved in 100 ml of warm diethyl ether and treated with 150 ml of η-hexane. After cooling, the 1- [2- (1H-indolyl-3-yl) ethyl] -1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester crystallizes, which is filtered off and dried; Sin p. 76-77 ⁰ C.

Example 13 2.82 g (10 μmol) of 4-amino-1 [2- (1H-indol-3-yl) ethyl] -piperidine-3-carboxamide are suspended in 35 ml of ethanol and admixed with a diethyl ethereal hydrochloric acid solution until the congenic reaction , By addition of diethyl ether, the 4-amino-1- [2- (1 H-indol-S-yOethylJ-piperidine-S-carboxylic acid amide bishydrochloride is precipitated is filtered off with suction and dried. M.p. 170-180 ⁰ C.

Example 14: 33 g (175 mmol) of 4,6-dimethyltryptamine and 40 ml (368 mmol) of ethyl acrylate are heated to reflux in 1000 ml of ethanol for 72 hours. It is evaporated to dryness and chromatographed on silica gel (0.063-0.02 mm) with toluene / isopropanol (99: 1) as the eluent. The fractions containing the desired product are evaporated and dried under reduced pressure; N- [2- (4,6-dimethyl-1H-indol-3-yl) ethyl] -imino-di (3-propionic acid) diethyl ester is obtained as a brownish oil.

3, 8 g (165 mmol) of sodium are dissolved in 180 ml of ethanol and heated to reflux. Distilled 120 ml of ethanol, adds 180 ml of toluene and distilled until the distillation temperature has reached 110 ⁰ C. Then allowed to cool to 20 ⁰ C, 64.1 g (165 mmol) of N- [2- (4,6-dimethyl-1 H-indol-3-yl) ethyl] -imino-di (3-propionic acid) diethyl ester , dissolved in 270 ml of toluene, and allowed to stir for 2 hours at 100 ⁰ C. The mixture is allowed to cool to room temperature, acidified with 130 ml of concentrated hydrochloric acid, the precipitate is filtered off with suction and recrystallized twice from 90% ethanol. There are thus obtained 4-hydroxy-1- [2- (4,6-dimethyl-1H-indol-S-y-ethyl] -1,3'-B'-tetrahydropyridine S-carboxylic acid ethyl ester hydrochloride or 1- [2- (4,6-dimethyl-1H-indol-S-ylJethylJ-piperidin ^ -on-S-carboxylic acid ethyl ester hydrochloride, mp. 207-209 ⁰ C.

Analogously, 19g of 4,6-dimethyltryptamine and 19 g of methyl acrylate give N- [4,6-dimethyl-1H-indol-3-yl) -ethyl] -imino-di (3-propionic acid) dimethyl ester (oil) and starting from of 35.6 g of the same and 8.44 g of sodium methoxide 4-hydroxy-1- [2- (4,6-dimethyl-1H-indol-S-yOethylJ-I ^ S ^ -tetrahydropyridine-S-carboxylic acid methyl ester hydrochloride or 1 - [2- (4,6-dimethyl-1 H-indol-S-yO-ethyU-piperidin ^ -one-S-carbonsäuremethylesterhydrochlorid, mp 185-188 ⁰ C..

EXAMPLE 15 In a manner analogous to that described in Example 14, starting from 58.4 g (30 μmol) of 5-chlorotryptamine and 65 ml (60 μmol) of ethyl acrylate, N- [2- (5-chloro-1H-indol-3-yl) Ethyl] -imino-di (3-propionic acid) diethyl ester (oil) and by cyclization of the same 4-hydroxy-1- [2- (5-chloro-1H-indol-S-ylJethylJ-I ^ S ^ tetrahydropyridine-S -carboxylic acid ethyl ester hydrochloride or 1- [2- (5-chloro-H-indol-S-y-dimethyl-1-piperidine] -one-S-carboxylic acid ethyl ester hydrochloride of the formula 172-

Starting from 5.7 g of 5-chlorotryptamine and 5.7 g of methyl acrylate, N- [2- (5-chloro-1H-indol-3-yl) ethyl] -imino-di (3-propionic acid) dimethyl ester is obtained in an analogous manner (OI) and by treating 12.4 g of the same with 2.9 g of sodium methoxide in: 120 ml of dimethylformamide 4-hydroxy-1- [2- (5-chloro-1H-indol-3-yl) ethyl] -1,2, Methyl 5,6-tetrahydro-pyridine-3-carboxylate hydrochloride or 1- [2-5-chloro-1H-indole-S-y-ethyl-1-piperidine] -one-S-carboxylic acid methyl ester hydrochloride, mp 195-197 ° C and starting from 5-bromo- or 5-fluortryptamine and ethyl acrylate N- [2- (5-bromo-1H-indol-3-yl) ethyl] or

M- [2- (5-Fluoro-1H-indol-3-yl) -ethyl] -imino-di (3-propionic acid) diethyl ester and 4-hydroxy-1- [2 (5-bromo-1H-indole 3-yl) ethyl] - and 44-hydroxy-1- [2- (5-fluoro-1H-indol-3-yl

Analogously, the reaction is carried out by reacting 6.6 g of methyl 4-hydroxy-1- [2- (5-chloro-1H-indol-3-yl) ethyl] -1,2,5,6-tetrahydropyridine-3-carboxylate with 3 , 0g sodium hydride, a mixture of cis- and trans-4-hydroxy-1- [2- (5-chloro-1H-indol-3-yl) ethyl] piperidine-3-carboxylic acid methyl ester, which chromatographically into the components of R _r value = 0.38 (trans) or 0.26 (ice) can be separated.

In an analogous manner, cis- and trans-4-hydroxy-1- [2- (5-bromo-1H-indol-3-yl) ethyl] and cis- and trans-4-hydroxy-1- [ 2j (5-fluoro-1H-indol-3-yl) ethyl] -piperidine-3-carboxylic acid ethyl ester and the corresponding methyl esters.

Example 18: 2.3 g (6.7 mmol) of 4-hydroxy-1- [2- (4,6-dimethyl-1H-indol-3-yl) -ethyl] -1,2,5,6-tetrahydro- Pyridine-3-carboxylic acid ethyl ester are mixed with 0.4 g of platinum oxide and 46 ml of ethanol and hydrogenated in a Parr apparatus for 18 hours at room temperature and a hydrogen pressure of 4 bar until the intake of 160 ml of hydrogen. The reaction mixture is filtered through diatomaceous earth and evaporated to dryness. Chromatographic purification on silica gel (0; 063-0.02 mm) with ethyl acetate / isopropanol (7: 2) as eluant gives 4-hydroxy-1- [2- (4,6-dimethyl-1H-indol-3-yl) Ethyl] -pJperidin-3-carboxylic acid ethyl ester as a yellow oil, which predominantly contains the cis isomers according to ¹ H-NMR spectrum. Starting from 7.3 g, 4-hydroxy-1- [2- (4,6-dimethyl-1H-indol-3-yl) ethyl] -1,2,5,6-tetrahydropyridine are obtained in an analogous manner. 4-carboxylic acid methyl ester is a mixture of methyl cis and trans-4-hydroxy-1- [2- (4,6-dimethyl-1H-indol-3-yl) ethyl] piperidine-3-carboxylate, which is also predominantly present in the cis- Form is present; M.p. (after recrystallization from isopropanol) 138-14O ⁰ C.

EXAMPLE 19 A solution of 19.3 g (0.1 mol of methyl-oxo-piperidine-S-carboxylate hydrochloride in 60 ml of glacial acetic acid with 8.1 ml of 37% strength aqueous formaldehyde solution and 11 g (0.1 mol) of indole is added. After stirring for 2 hours at room temperature, cooled with ice, treated with 30 ml of dichloromethane and neutralized with η-sodium hydroxide solution The organic phase is separated, washed with water, dried and the solvent evaporated The residue is purified by flash chromatography on silica gel with toluene / ethyl acetate (3: 2) to give 1- (1 H -indol-3-yl-methyl) piperidin-4-one-3-carboxylic acid methyl ester or 4-hydroxy-1- (1 H-indol-3-ylmethyl ) 1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester, for identification starting from 14.3 g by dissolving in acetone and adding 5.8 g of fumaric acid dissolved in 30 ml of acetone, cooling and suction in the fumarate of mp 140-142 ⁰ C.

Example 20: Into a solution 11.59 g (40.5 mmol) of 4-hydroxy-1- (1H-indol-3-ylmethyl) -1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester in 150 ml of methanol is added Cool to 0-5 ⁰ C in portions 1.53g (4.05 mmol) of sodium borohydride entered. After 2 hours, the solvent is evaporated, the residue taken up in dichloromethane, extracted with water, dried and evaporated to dryness. The residue is chromatographed on silica gel with ethyl acetate / methanol (9: 1) as the eluent. First, trans-4-hydroxy-1- (1H-indol-3-ylmethyl) -piperidine-3-carboxylic acid methyl ester and then cis-4-hydroxy-1- (1H-indol-3-ylmethyl) -piperidine-3 -carboxylic acid methyl ester eluted. The uniform fractions are combined and evaporated. DasHemifumarathydratdertrans compound has a mp. 140-142 ⁰ C, while the cyclamate of the cis-compound melts at 170-172 ° C.

Example 21: A solution of 18.1 g (104 mmol) of 3- (1H-indol-3-yl) -aminopropane in 150 ml of methanol is added dropwise with 22 ml of (23OmMoI) methyl acrylate. After stirring for 15 hours at room temperature, the mixture is evaporated under reduced pressure to give N- [3- (1H-indol-3-yl) propyl] -imino-di (3-propionic acid) dimethyl ester as a reddish oil.

EXAMPLE 22 A solution of 12.1 g (35 mmol) of N- [3- (1H-indol-3-yl) -propyl] -imino-di (3-propionic acid) dimethyl ester in 50 ml of dimethylformamide is added in portions to 1, 85 g (38.5 mmol) of sodium hydride (50% suspension in mineral oil). After stirring for 1 hour at room temperature, the solution is poured into ice-water, acidified with 2 N hydrochloric acid and extracted 3 times with 100 ml of diethyl ether. Then the aqueous solution is extracted 4 times with 500 ml of chloroform, the organic phase separated, dried over sodium sulfate and evaporated to dryness. The acetone / ether crystallises the methyl 1- [3- (1H-indole-S-y-propyl-piperidine) -one-S-carboxylic acid ester or 4-hydroxy-1- [3- (1H-indole-3-) yl) propyl] -i ^^^ - tetrahydro-pyridine-S-carboxylic acid methyl ester hydrochloride of mp. 158-159 ° Caus.

Example 23: In a solution of 10.5 g (30 μmol) of 4-hydroxy-1- [3- (1H-indol-3-yl) -propyl] -1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrochloride in 140 ml of methanol are added while cooling to 0-5 ⁰ C in portions 2.28 g (6OmMoI) of sodium borohydride. After stirring for 1 hour, the solution is evaporated and the residue is chromatographed on silica gel with ethyl acetate / methanol (95: 5) as the eluent. First, trans-4-hydroxy-1- [3- (1 H-indol-3-yl) propyl] piperidine-3-carboxylic acid methyl ester (mp of the fumarate hydrate: 98-100 ⁰ C, Zers.) And then Cis-4-hydroxy-1- [3- (1H-indol-3-yl) -propyl] -piperidine-3-carboxylic acid methyl ester, (mp of the hydrochloride: 217-219 ° C, dec.) eluted.

EXAMPLE 24 A solution of 15.72 g of 2- [2- (1H-indol-3-yl) ethyl] -aminomethyl-3-methoxy-penta-2 is added dropwise to a solution of 3 g of sodium methoxide in 100 ml of dimethylformamide. 4-dienecarboxylic acid methyl ester in 150 ml of dimethylformamide and stirred for 3 hours at room temperature. It is concentrated under reduced pressure to about 150 ml and the residue is poured into a mixture of 100 ml of 2N hydrochloric acid and 50 ml of toluene. The slowly crystallizing 4-hydroxy-1- [2- (1H-indol-3-yl) ethyl] -I ^ Ae-tetrahydropyridine-S-carboxylic acid methyl ester hydrochloride or 1- [2- (1 H -indole-3 -yl) ethyl] -piperidin-4-one-3-carboxylic acid methyl ester hydrochloride is filtered off and dried in vacuo. It melts at 185-177 ⁰ C (Zers.). The starting material can be prepared, for example, as follows:

A solution of 53.3 g (0.375 mol) of 2 methyl-S-oxo-penM-encarboxylic acid methyl ester, prepared according to JAM from Goorbergh and A.van the gene: Rec. Trav. Chim. Pays-Bas 103.90 [1984]), 38.5 g of trimethyl orthoformate and 300 ml of p-toluenesulfonic acid hydrate in 150 ml of methanol for 65 hours, then neutralized with 84 mg of sodium methoxide in 3 ml of methanol and the solvent is distilled off in vacuo. The residue is treated with 2.5 g of ammonium dihydrogen phosphate and heated to 190 ⁰ C, wherein the liberated methanol is distilled off. Kugelrohr distillation gives 2-methyl-3-methoxy-penta-2,4-dienecarboxylic acid methyl ester of Kp = 65-75 ⁰ C (at 20mbar). A well-stirred solution of 39.5 g (0.25 mol) of methyl 2-methyl-3-methoxy-penta-2,4-dienecarboxylate, 44.5 g of N-bromosuccinimide and 200 mg of azobisisobutyronitrile in 200 ml of carbon tetrachloride is heated to reflux for 12 hours Solution is irradiated with a UV lamp. After cooling, the mixture is filtered from the succinimide, the filter residue is washed twice with 30 ml of tetrachloromethane, the combined organic phases are washed with sodium carbonate solution and water, dried over sodium sulfate and the solvent is evaporated off in vacuo. 2 ^{l of} methyl bromomethyl-3-methoxy-penta-2,4-dienecarboxylate are obtained as an orange-red oil.

A solution of 16 g of 1-amino-2- (1H-indol-3-yl) -ethane, 23.5 g of methyl bromomethyl-3-methoxy-penta-2,4-dienecarboxylate and 39 g of N-ethyl-N, N-diisopropylamine in 500 ml of dimethylformamide is stirred under nitrogen for 16 hours. Concentrate under reduced pressure to about 250 ml, add 500 ml of water and shake three times with 250 ml of dichloromethane. The organic phases are combined and dried over sodium sulfate and evaporated. Purification by chromatography on silica gel with toluene / ethyl acetate 9: 1 as eluant gives 2- [2- (1H-indol-3-yl) ethyl] -aminomethyl-3-methoxy-penta-2,4-dienecarboxylic acid methyl ester as a yellow oil.

Example 25: A solution of 3.8 g (40 mmol) of methyl chloroformate in 100 ml of dry dichloromethane is mixed with 100 mg (4 mmol) of anhydrous zinc bromide. The solution, cooled to ⁰ ° C., is added dropwise to a solution of 13.5 g (35 mmol) of 4-trimethylsilyloxy-1- [2- (1-trimethylsilylindol-3-yl) ethyl] -1,2,5,6-tetrahydro -pyridine in 100ml dichloromethane. After warming to room temperature, the mixture is stirred for 1 hour, then poured onto 300 ml of saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic phases are dried over magnesium sulfate and evaporated. The residue is dissolved in 150 ml of ethanol and acidified with ethanolic hydrochloric acid solution. After moving

with diethyl ether and cooling crystallized 4-hydroxy-1- [2- (1H-indol-3-yl) ethyl] -1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrochloride of mp. 187 ° C (dec .) out

 The starting material may e.g. be prepared as follows:

A solution of 10.12 g of diisopropylamine in 100 ml of dry tetrahydrofuran is added at ice bath temperature with 62.5 ml of n-butyllithium in η-hexane. After stirring for 30 minutes at room temperature, the solution is again cooled to-15 ⁰ C and a solution of 10.9 g (45mMoi) 1- [2- (indol-3-yl) ethyl] piperidin-4-one , prepared according to E.Winterfeldt and P. Strehlke, Chem. Ber. 98, 2579 (1965) in 100 ml of tetrahydrofuran. After 15 minutes, a solution of 10.9 g (10OmMoI) of trimethylchlorosilane in 50 ml of tetrahydrofuran is added dropwise. The mixture is stirred overnight at room temperature, filtered and evaporated to dryness under reduced pressure. This gives 4-trimethylsilyloxy-1- [2- (1-trimethylsilyl-indol-3-yl) ethyl] -1,2,5,6-tetrahydropyridine as a light yellow oil.

Example 26: A solution of 18.3 g of a mixture of cis- and trans-4-bromo-1- [2- (1H-indol-3-yl) ethyl] -piperidine-3-carboxylic acid methyl ester and 8.2 g of anhydrous sodium acetate in 100mi glacial acetic acid is refluxed for 16 hours. After cooling, the mixture is concentrated under reduced pressure, partitioned between dichloromethane and aqueous sodium carbonate solution, the organic phase is dried and evaporated. The mixture of methyl and trans-4-acetoxy-1- [2- (2-1H-indol-3-yl) ethyl] -piperidine-3-carboxylic acid methyl ester is chromatographed into its components (see Example 9). The starting material can be e.g. produce as follows:

With stirring, 28.4 g (0.1 mol) of 1- [2- (1 H -indol-3-yl) ethyl) -1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester in portions in 150 ml of a 33 % solution of hydrogen bromide in glacial acetic acid. After stirring at room temperature for 18 hours, the mixture is concentrated under reduced pressure and partitioned between dichloromethane and aqueous sodium carbonate solution. The organic phase is dried over sodium sulfate and the solvent evaporated in vacuo. A mixture of ice and trans 4-bromo-1- [2- (1H-indol-S-yl-methyl-piperidine-S-carboxylic acid methyl ester as a yellow oil is obtained.

Example 27 A suspension of 1.2 g of sodium hydride (50% suspension in mineral oil) in 25 ml of dry tetrahydrofuran is treated with a solution of 2.7 g (25 mmol) of benzyl alcohol in 25 ml of tetrahydrofuran and heated to reflux after the evolution of gas has subsided. After cooling, ma η is added dropwise to a solution of 8.2 g (25 m mol) of 1- [2- (5-methoxy-1H-indol-3-yl) ethyl] -1,2,5,6-tetrahydropyridine. Added 3-carboxylic acid ethyl ester in 50ml tetrahydrofuran and heated again for 5 hours to reflux. After cooling, the solvent is evaporated. A mixture of ethyl and trans-4-benzyloxy-1- [2- (5-methoxy-1H-indol-S-yOethylj-piperidine-S-carboxylic acid ethyl ester as an oil

 The starting material can be prepared as follows:

25.4 g of 1-bromo-2- (5-methoxy-1H-indol-3-yl) ethane, 19.2 g of ethyl ^ -tetrahydropyridine-S-carboxylate hydrochloride (guavacin ethyl ester hydrochloride) and 39 g of N- Ethyl N, N-diisopropylamine are dissolved under nitrogen in 750 ml of dimethylformamide and stirred for 16 hours. It is then concentrated under reduced pressure to about 300 ml, added 500 ml of water and extracted three times with 250 ml of dichloromethane. The organic phases are combined and extracted by shaking three times with in each case 80 ml of n-hydrochloric acid. The combined aqueous phases are made basic with 40% sodium hydroxide solution and shaken out three times with 100 ml dichloromethane. The organic phases are combined, washed with water, dried over sodium sulphate and evaporated to dryness. The residue is dissolved in 100 ml of methanol and treated with methanolic hydrochloric acid solution. After addition of diethyl ether and cooling, 1- [2- (5-methoxy-1H-indol-3-yl) ethyl] -1,2,5,6-tetrahydropyridine-3-carboxylic acid ethyl ester hydrochloride, m.p. 6T off.

Example 28: 5.2 g of the mixture of ethyl cis- and trans-4-benzyloxy-1- [2- (5-methoxy-1H-indol-3-yl) ethyl] piperidine-3-carboxylate are dissolved in 100 ml of methanol , mixed with 2 g of 10% palladium on carbon and hydrogenated in a Parr apparatus at room temperature. The reaction mixture is filtered through diatomaceous earth and evaporated to dryness. The evaporation residue is chromatographed over silica gel with toluene / ethyl acetate 9: 1 as eluent. First, trans-4-hydroxy-1- [2- (5-methoxy-1H-indol-S-yOethylj-piperidine-S-carboxylic acid ethyl ester and then cis-4-hydroxy-1- [2- (5-methoxy- 1 H-indole-S-yllethylJ-piperidine-S-carboxylic acid ethyl ester acetate. the purified fractions are combined, evaporated and purified by treatment with fumaric acid in acetone in the Hemifumarate of mp. 104-108 ⁰ C (trans) or mp. 104 107X (ice) convicted.

EXAMPLE 29 Analogously to Example 14, 3.8 g (20 μmol) of 5-methoxytryptamine and 46 ml (42 mmol) of ethyl acrylate N [2- (5-methoxy-1H-indol-3-yl) ethyl] -imino are obtained di (3-propionic acid) diethyl ester; reddish oil, R _f = 0.7 (ethyl acetate) and by cyclization of the same 4-hydroxy-1- [2- (5-methoxy-1H-indol-3-yl) ethyl] -1,2,5,6- ethyl tetrahydropyridine-3-carboxylate hydrochloride hemihydrate or ethyl 1- [2- (5-methoxy-1H-indol-3-yl) ethyl] piperidin-4-one-3-carboxylate hydrochloride hemihydrate of mp. 149- 152 ° C.

EXAMPLE 30 Analogously to Example 16, starting from 16.2 g (47 mmol) of 4-hydroxy-1- [2- (5-methoxy-1H-indol-3-yl) ethyl] -1,2, 5,6-tetrahydro-3-carboxylic acid ethyl ester by reduction with 2,7g (70,5 mmol) sodium borohydride and chromatographic diastereomer separation trans-4-hydroxy-1- [2- (5-methoxy-1H-indol-3-yl) ethyl ] piperidine-3-carboxylic acid ethyl ester, R _f = 0.53 (ethyl acetate / isopropanol 7: 2) and cis-4-hydroxy-1- [2- (5-methoxy-1H-indol-3-yl) ethyl] piperidine-3-carboxylic acid ethyl ester, Rf = 0.34, and by subsequent treatment with fumaric acid whose partially hydrated semifinates of the mp 104-108 ⁰ C (0.27 χ H ₂ O, trans) and 104-107 ⁰ C (0 , 8 χ H ₂ O, ice).

Example 31: A boiling solution of 11 g of phenylhydrazine in 280 ml of methanol and 20 ml of water is added to a solution of 24.3 g (0.1 mmol) of 4- (cis-3-methoxycarbonyl-4-methoxy-piperidino) -butanal in 50 ml Methanol and heated with stirring for 20 hours to reflux. The solvent is evaporated in vacuo and the residue is purified on 500 g of silica gel by chromatography with toluene / ethyl acetate (9: 1). This gives cis-4-methoxy-1- [2- (1H-indol-3-yl) ethyl] piperidine-3-carboxylic acid methyl ester; Mp of the cyclamate: 144-145 ° C.

The starting material may e.g. A solution of 83.6 g iso, 5 mmol) 4-Methoxynikotinsäuremethylester in 200ml absolute ethanol is mixed with 50ml glacial acetic acid and 2g platinum oxide and hydrogenated at about 3bar overpressure for 12 hours. The reaction mixture is filtered through diatomaceous earth and evaporated. After addition of

200 ml of η-sodium hydroxide solution is extracted 4 times with 250 ml of diethyl ether, the combined organic phases, dried over sodium sulfate and evaporated. Cis → -methoxy-piperidine-S-carboxylic acid methyl ester is obtained as a yellow oil. 55 g of 4-chloro-1,1-dimethoxybutane, 73.4 g (0.35 mol of MoOcis ^ -Methoxy-piperidine-S-carboxylic acid methyl ester hydrochloride and 136.5 g of N-ethyl-N, N-diisopropyl-amine under nitrogen in 1 dissolved 2 liters of dimethylformamide and stirred for 16 hours at 5O ⁰ C. The mixture is concentrated to about 300 ml under reduced pressure, adding 500 ml of water and extracted 3 times from each 250ml of dichloromethane. The organic phases are combined, dried over sodium sulfate and concentrated in After evaporation over 1 kg of silica gel with toluene / ethyl acetate (9: 1) as eluent gives 4- (cis-3-methoxycarbonyl-4-methoxypiperidino) -1,1-dimethoxybutane as a yellow oil.

A solution of 58 g (0.2 mol) of 4- (cis-3-methoxycarbonyl-4-methoxypiperidino) -1,1-dimethoxy-butane in 500 ml of dichloromethane is mixed with 250 g of silica gel, which according to J.M. Conia et al. Synthesis 1978, 63 is impregnated with 10% aqueous oxalic acid solution, and the suspension is stirred for 3 hours at room temperature. After filtering off with 5% aqueous sodium bicarbonate solution, the organic phase is dried with sodium sulfate and evaporated under reduced pressure. This gives 4- (cis-3-methoxycarbonyl-4-methoxy-piperidino) butanal as a yellow oil.

Example 32: A solution of 28.5 g (0.1 mol) of 1- [2- (1H-indol-3-yl) ethyl-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester in 350 mL of dichloromethane added in portions with a total of 52 g of 3,5-dinitroperbenzoic acid and heated for 30 minutes with stirring to reflux. After cooling, it is filtered through a Glasfilternutsch and the solution was added dropwise with ice cooling and stirring well with 25 ml of boron trifluoride diethyletherat. After 5 minutes, treated with 10 g of anhydrous sodium sulfate and dropwise with 30 ml of carbon disulfide, and stirred for 2 hours at ^{0 0} C and 1 hour at room temperature. After filtration, it is washed with aqueous sodium carbonate and sodium bisulfite solution, the organic phase is dried and evaporated. After treatment with methanolic hydrochloric acid of the solution of the evaporation residue in methanol is crystalline 4-hydroxy-1- [2- (1 H-indol-S-ylJethylH ^ S ^ -tetrahydro-pyridine-S-carboxylic acid methyl ester hydrochloride or 1- [2 - (1 H-indol-S-yDethyll-piperidin ^ -one-S-carboxylic acid methyl ester hydrochloride, mp. 185-187 ⁰ C (dec.)).

Example 33: A boiling solution of 11 g of phenylhydrazine in 280 ml of methanol and 20 ml of water is added to a solution of 26 g (0.1 mol) of N- (4-oxobutyl) -imino-di (3-propionic acid) dimethyl ester in 50 ml of methanol and heated to reflux for 20 hours. The solvent is evaporated in vacuo and the residue is chromatographed on 500 g silica gel with toluene / ethyl acetate (9: 1) as eluent. This gives N- [2- (1H-indol-3-yl) ethyl] -imino-di (3-propionic acid) dimethyl ester as a reddish oil. Its oxalate has a mp. 98-103 ⁰ C. The starting material can be prepared as follows: 55g 4-chloro-1,1-dimethoxybutane, 66.2 g (0.35 mol) of dimethyl immin (3-propionic acid) and 56.5 g of N-ethyl-N, N-diisopropylamine are dissolved under nitrogen in 1 liter of dimethylformamide and stirred at 50 ^° C. for 16 hours. Concentrate under reduced pressure to about 250 ml, add 500 ml of water and shake 3 χ with 250 ml of dichloromethane. The combined organic phases are dried over sodium sulfate and evaporated in vacuo. This gives N- (4,4-dimethoxybutyl) -imino-di (3-propionic acid) dimethyl ester as an orange-red oil.

A solution of 61.1 g (0.2 mol) of N- (4,4-dimethoxybutyl) -imino-di (3-propionic acid) dimethyl ester in 500 ml of dichloromethane is mixed with 250 g of silica gel, which according to JMConia et al .: Synthesis 1978 , 63 is impregnated with 10% aqueous oxalic acid solution, and the suspension stirred for 3 hours at room temperature. After filtering off with 5% aqueous sodium bicarbonate solution, the organic phase is dried over sodium sulfate and evaporated to dryness. This gives N- {4-oxobutyl) -imino-di (3-propionic acid) dimethyl ester as a yellow oil.

Example 34: 40.1 g (0.25 mol) of tryptamine are dissolved in 50 ml of methanol and admixed dropwise with stirring at room temperature with 21.52 g (0.25 mol) of methyl acrylate, keeping the reaction temperature below 25 ° C. The reaction mixture is then allowed to stand for 15 hours at room temperature, then cooled to 5 ° C and treated with ethereal hydrogen chloride solution until the weakly congous reaction, the N- [2- (1 H -indol-3-yl) ethyl] - / 3-alanine methyl ester hydrochloride precipitates. For purification is recrystallized once from methanol, the product melts at 168-170 ⁰ C. In an analogous manner starting from 40.1 g (0.25 mol) of tryptamine and 25g (0.25 mol) of ethyl acrylate in 50 ml of methanol and subsequent displacement with hydrogen chloride N- [2- (1H-indol-3-yl) ethyl] - / 3-alaninethylester hydrochloride, mp. 130-133 ⁰ C. In an analogous manner, starting from 5.7 g of 4, 6-dimethyltryptamine and 2.6 g of methyl acrylate N- [2- (4,6-dimethyl-1H-indol-3-yl) ethyl] -β-alanine methyl ester, which by treatment with ethereal hydrochloric acid in the hydrochloride, mp. 151 -155 ⁰ C can be transferred.

Example 35: 28.3 g (0.1 mol) of N- [2- (1H-indole-S-y-ethyll-.beta.-alanine methyl ester hydrochloride are dissolved in 100 ml of methanol with 10.5 g (0.1 mol) of triethylamine and 84 g (0.11 mol) of acrylonitrile are added and the mixture is stirred at room temperature for 15 hours, then concentrated in a water-jet vacuum, the residue is taken up in ether and washed neutral with ice-water, the ethereal solution is dried over potassium carbonate and concentrated by evaporation. 2-cyanoethyl) - [2- (1H-indol-3-yl) ethyl] - / 3-alaninsäuremethylester is dissolved in 50 ml of acetone for conversion into the oxalate and treated with a solution of 9g oxalic acid in 50 ml of acetone Oxalate is washed with acetone, filtered off with suction and dried, mp 146-147 ° C.

Example 36 In an analogous manner as described in Example 35, starting from 28.3 g (0.1 mol) of N- [2- (1H-indol-3-y-ethyl-1S-alanine methyl ester hydrochloride, 10.5 g (0 Triethylamine and 10.9 g (0.11 mol) of acrylic acid (N, N-dimethyl) amide in 100 ml of methanol and heated under reflux for 6 hours and subsequent conversion to the oxalate N- [2- (1H-indole) 3-yl) ethyl] -N- [N, N-dimethylaminocarbamyl) ethyl] - / 3-alanine methyl ester-oxalatvomSmp. 153-155 ° C (decomp.).

Example 37: In a manner analogous to that described in Example 35, starting from 2.83 (0.01 mol) of N- [2- (1H-indol-3-yl) ethyl] - / 3 alanine methyl ester hydrochloride, 2.77 g (0.002 mol) of potassium carbonate and 1.99 g (0.0011 mol) of 2- (2-bromoethyl) -1,3-dioxolane in 20 ml of dioxane, being allowed to 20 hours at a reaction temperature of 80 ⁰ C, and after working up with Oxalic acid is converted to the oxalate, N- [2- (1,3-dioxolan-2-yl) ethyl] -N- [2- (1H-indol-3-yl) ethyl] - / 3-alanine methyl ester oxalate from mp. 159-161 ⁰ C.

EXAMPLE 38 In a manner analogous to that described in Example 35, starting from 28.3 g (0.1 mol) of N- [2- (1H-indol-3-yl) ethyl] -3: alanine methyl ester hydrochloride, 16 ° , 8 g (0.11 mol) of methyl bromoacetate and 29 g (0.21 mol) of potassium carbonate in 140 ml of methanol and subsequent transfer into hydrochloride N- (methoxycarbonylmethyl) -N- [2- (1H-indol-3-yl) ethyl] - / 3-Alaninmethylester hydrochloride, mp. 168 ° C (dec.).

EXAMPLE 39 Analogously to Example 35, starting from 29.7 g (0.1 mol) of N- [2- (1H-indol-3-yl) ethyl] - / 3-alanine ethyl ester hydrochloride, 18.4 g (0.11 mol) of ethyl bromoacetate and 29 g (0.21 mol) of potassium carbonate in 150 ml of ethanol N- (ethoxycarbonylmethyl) -N- [2- (1H-indol-3-yl) -ethyl] - / 3- alanine ethyl ester and its hydrochloride of mp. 119-121 ⁰ C.

Example 40: A solution of 6.9 g (20 μmol) N- [2- (1,3-dioxolan-2-yl) ethyl] -N- [2- (1H-indol-3-yl) ethyl] -β -alanine methyl ester in 100 ml of dichloromethane is treated with 30 g of silica gel, which according to JMConia et al .: Synthesis 1978, 63 was impregnated with 10% aqueous oxalic acid solution, and the suspension was stirred for 3 hours at room temperature. After filtering off with 5% aqueous sodium carbonate solution, the organic phase is dried with sodium sulfate and evaporated under reduced pressure. The evaporation residue is chromatographed for purification over 300 g of silica gel with toluene / ethyl acetate (9: 1) as the eluent. N- (3-Oxo-propyl) -N- [2- (1H-indol-yl) ethyl] - / 3-alanine methyl ester is obtained as a yellow oil.

EXAMPLE 41 A solution of 0.81 g (16 mmol) of sodium methoxide in 5 ml of dimethylformamide is treated with a solution of 3.3 g (11 mmol) of N- (3-oxopropyl) -N- [2- (1H-indole) 3-yl) ethyl] - / 3-alanine methyl ester in 15 ml of Ν, Ν-dimethylformamide and stirred for 3 hours at 40 °. Then the solvent is evaporated under reduced pressure and the residue is separated by chromatography on 200 g of silica gel with dichloromethane / methanol (95: 5) in the components. First, trans-4-hydroxy-1- [2- (1H-indol-3-yl) -ethyl] -piperidine-3-carboxylic acid, methyl ester (Semifumarat mp 208-209X) and then cis-4-hydroxy-1- [2 - (1H-indol-3-yl) ethyl] piperidine-3-carboxylic acid methyl ester (hydrochloride mp. 187 ⁰ C, dec.) Eluted.

Example 42 Analogously to Example 4, hydrogenation of 4-amino-1- [2- (1H-indol-3-yl) ethyl] -1,2,5,6-tetrahydropyridine gives 3-carboxylic acid methyl ester cis-undtrans-4-amino-1- [2- (1H-indol-3-yl) ethyl] piperidine-3-carboxylic acid methyl ester, which can be converted into the bis-hydrochlorides in an analogous manner as described in Example 8 ,

Example 43: In a suspension of 19.6 g (5OmMoI) of i-ß-fiH-indol-S-ethyl-S-methoxycarbonyl ^ -methoxypyridinium bromide in 2150 ml of methanol in a nitrogen atmosphere at 0 ⁰ C within 3.3 g 3.3 g Entered sodium borohydride. After stirring for 1 hour at ⁰ ° C. and 2 hours at room temperature, the suspension is evaporated under reduced pressure, the residue is combined with 70 ml of water and extracted three times with 100 ml of dichloromethane each time. The organic phases are combined, dried over magnesium sulfate and evaporated to dryness. The residue is treated with a mixture of 80 ml of 5 N hydrochloric acid and 20 ml of toluene, followed by stirring and cooling 4-hydroxy-1- [2- (1 H-indol-S-yethylH ^ S ^ tetrahydropyridine S -carboxylic acid methyl ester hydrochloride or 1- [2- (1H-indol-3-yl) ethyl] piperidin-4-one-3-carboxylic acid methyl ester hydrochloride of the mp 184-187 ° C (dec.) Crystallized be prepared as follows:

A solution of 22.4 g (0.1 mol) of 1-bromo-2- (1H-indol-3-yl) -ethane in 100 ml of methanol with 20.8 g of 4-Methoxynikotinsäuremethylester and allowed to stand for 3 days at room temperature, whereupon Crystallize 1- [2- (1H-indol-3-yl) ethyl] -3-methoxycarbonyl-4-methoxy-pryridinium bromide as orange-yellow crystals, mp. 133-137 ⁰ C.

Example 44: A solution of 4.55 g (0.015 mol) of 4-hydroxy-1- [2- (1H-indol-3-yl) ethyl] -1,2,5,6-tetrahydro-pyridine-3-carbonitrile. hydrochloride in 100 ml of 95% methanol is added with 1.5 ml of concentrated hydrochloric acid and heated to reflux for 15 hours. After cooling, it is concentrated under reduced pressure to about 30 ml and this solution poured into a mixture of 80 ml of 5N hydrochloric acid and 20 ml of toluene, followed by stirring and cooling 4-hydroxy-1- [2- (1 H-indole-3 -yl) ethyl] -I ^ Se-tetrahydropyridin-S-carbonsäuremethylesterhydrochlorid or 1- [2- (1H-indol-3-yl) ethyl] -piperidin-4-one-3-carbonsäuremethylesterhydrochlorid of mp. 185-187 ⁰ C (Zers.) Crystallized. The starting material can manz. B. produce as follows:

A suspension of 5.73 g of about 55% sodium hydride in 100 ml of tetrahydrofuran in a nitrogen atmosphere is added dropwise with a solution of 12.35 g (41.3 mmol) of N- (2-cyanoethyl) -N- [2- (iH-). indol-3-yl) ethyl] - / 3-alanine methyl ester in 200 ml of tetrahydrofuran and stirred for 16 hours at room temperature. After addition of 70ml 2normaler aqueous sulfuric acid solution gives a yellow solution. It is mixed with 300 ml of ether and 100 ml of water, whereby 2 layers are formed. The aqueous layer is extracted three times with 100 ml of ether. The combined organic phases are dried over sodium sulfate, concentrated under reduced pressure to about 100 ml and poured into a mixture of 80 ml of 5N hydrochloric acid and 20 ml of toluene, followed by stirring and cooling 4-hydroxy-1- [2- (1 H indol-3-yl) ethyl] -1,2,5,6-tetrahydropyridin-3-carbonsäurenitrilhydrochloridbzw. crystallized i-ß-OH-indol-S-yOethyl-piperidine ^ -on-S-carbonitrile hydrochloride.

Example 45: A suspension of 10 g of platinum oxide in 100 ml of water is reduced with hydrogen, whereupon the hydrogen atmosphere is replaced by pure oxygen. Now add a solution of 5.5 g (2OmMoI) cis-4-hydroxy-3-hydroxymethyl-1- [2- (1H-indol-3-yl) ethyl] piperidine in 250 ml of acetone, which with 3g sodium bicarbonate in 50ml Water was added and initiates 16 hours at 58 ° C oxygen. After cooling, the catalyst is filtered off and the acetone is evaporated in vacuo. The aqueous phase is extracted 3 times with 70 ml dichloromethane and acidified with 1 N hydrochloric acid. After evaporation under reduced pressure, the residue is treated with methanolic hydrochloric acid (4N), filtered and the solution heated to reflux for 3 hours. After cooling, the solvent is evaporated under reduced pressure, the residue taken up in 50 ml of water and treated with saturated sodium bicarbonate solution. The thus neutralized solution is extracted three times with 70 ml of dichloromethane, the combined organic phases dried over sodium sulfate and evaporated. The residue is purified by chromatography on 250 g of silica gel with dichloromethane / methanol (95: 5) as eluent to give methyl cis-4-hydroxy-1- [2- (1H-indol-3-yl) ethyl] piperidine-3-carboxylate as an oil is obtained; Mp. Of hydrochloride 187 ⁰ C (dec.).

The starting material can be e.g. produce as follows:

A solution of 31.9 g of mercuric acetate in 100 ml of water and 100 ml of tetrahydrofuran in a nitrogen atmosphere at 5 ° C. is added to a solution of 25.6 g (0.1 mol) of 3-hydroxymethyl-1- [2- (2) 1H-indol-3-yl) ethyl] -1,2,5,6-tetrahydropyridine in 100 ml of tetrahydrofuran and stirred for 1 hour at 5 ° C. After the addition of 100 ml of a 3 molar aqueous sodium hydroxide solution, 100 ml of a 0.5 molar sodium borohydride solution in a 3 molar sodium hydroxide solution are slowly added dropwise, the mixture is stirred at 5 ° C. for 1 hour and filtered. The tetrahydrofuran is evaporated off under reduced pressure and the aqueous phase extracted 3 times with 100 ml of diethyl ether. The combined organic phases are dried over sodium sulfate and evaporated to dryness. A mixture of cis- and trans-4-hydroxy-3-hydroxymethyl-1- [2- (1H-indo-3-yl) ethyl] piperidine, which is obtained by flash chromatography on 1.5 kg silica gel with dichloromethane / Methanol (9: 1) is separated as eluent in the components. The recrystallized from acetonitrile cis-isomers has a mp. Of 159.5-161 ⁰ C on.

Example 46: 22.4 g (0.1 mol) of 1-bromo-2- (1H-indol-3-yl) -ethane, 15.5 g / 3-alanine ethyl ester hydrochloride and 39 g of N-ethyl-N, N-diisopropylamine are dissolved under nitrogen in 750 ml of dimethylformamide and stirred for 16 hours at room temperature. It is then concentrated under reduced pressure to about 200 ml, treated with 500 ml of water and extracted by shaking three times with 150 ml of dichloromethane. The combined organic phases are dried over sodium sulfate and evaporated to dryness. By adding ethanolic hydrochloric acid solution and cooling to give N- [2- (1H-indol-3-yl) ethyl] -ßalaninethylester hydrochloride, mp. 130-133 ⁰ C.

Example 47: 22.4 g (0.1 mol) of 1-bromo-2- (1H-indol-3-yl) -ethane, 19 g of dimethyl imino (3-propionic acid) and 39 g of N-ethyl-N, N- diisopropylamine are dissolved under nitrogen in 500 ml of dimethylformamide and stirred for 16 hours 4O ⁰ C e. Concentrate under reduced pressure to about 200 ml, add 500 ml of water and shake three times with 250 ml of dichloromethane. The organic phases are combined, dried over sodium sulfate and evaporated to dryness. N- [2- (1H-indol-3-yl) ethyl] -imino-di (3-propionic acid) dimethyl ester is obtained as a reddish oil. Its oxalate has a mp of 98-103 ⁰ C.

Example 48: 22.4 g (0.1 mol) of 1-bromo-2- (1H-indo-3-yl) -ethane, 12.5 g of 1-amino-di (3-propionic acid) dinitrile and 25 g of N-ethyl-N , N-Diisopropylamin are dissolved under nitrogen in 500ml dimethylformamide and stirred at 60 ⁰ C for 16 hours. Concentrate under reduced pressure to about 200 ml, add 500 ml of water and shake three times with 250 ml of dichloromethane. The organic phases are combined, dried over sodium sulfate and evaporated to dryness. N- [2- (1H-indol-3-yl) ethyl] imino-di (3-propionic acid) dinitrile is obtained as a reddish oil.

To a solution of 13.3 g (0.05 mol) of N- [2- (1H-indol-3-yl) ethyl] imino-di- (3-pro-dinitrile) dinitrile in 250 mL of 955% methanol is added 5 mL concentrated sulfuric acid and heated to reflux for 16 hours. After cooling, the mixture is concentrated under reduced pressure to about 75 ml, treated with 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 extracted twice more with 100 ml of dichloromethane. The combined organic phases are dried over sodium sulfate and evaporated. This gives N- [2- (1H-indol-3-yl) ethyl] -imino-di (3-propionic acid) dimethyl ester. His oxalate melts at 98-103 ⁰ C.

Example 49: 18.2 g of 4- {N-benzyl-N- [2- (1H-indol-3-yl) ethyl] -amino} -butyric acid ethyl ester are dissolved in 500 ml of ethanol, treated with 1.2 g of platinum oxide and purified in a Parr -Applied at 5bar overpressure 18 hours at room temperature and 3 hours at 40-50 ⁰ C hydrogenated. The mixture is filtered through diatomaceous earth and the resulting desanolic solution of 4 - {} - [2- (1H-indol-3-yl) ethyl] amino] butyric acid ethyl ester is added dropwise with stirring to 4.2 g of ethyl acrylate in 25 ml of ethanol. The mixture is stirred for 12 hours at room temperature, concentrated under reduced pressure to 300 ml, cooled to 5 ° C and acidified with ethereal hydrochloric acid to pH = 5.5 at. The precipitated crystalline precipitate is filtered off with suction and dried. This gives N- [2- (1H-indol-3-yl) ethyl] -N- (3-ethoxycarbonylpropyl) - / 3-alanine ethyl ester in the form of the hydrochloride. Analogously, N- [2- (1H-indol-3-yl) ethyl] -N- (3-methoxycarbonylpropyl) - / 3-alanine methyl ester and its hydrochloride are also obtained. The 4- {N-benzyl-N- [2- (1H-indol-3-yl) ethyl] -amino} -butyric acid ethyl ester used as starting material is obtained by benzylation of 7.5 g of tryptamine with 8.5 g of benzyl bromide and reaction of 12 g of 1-benzylamino-2- (1H-indol-3-yl) -ethane formed with 9.7 g of 4-bromobutyric acid ethyl ester.

Example 50: 18.2 g of N- [2- (1H-indol-3-yl) ethyl] -N- (ethoxycarbonylmethyl) - / 3-alanine ethyl ester are dissolved in 20 ml of dimethylformamide and added with stirring within 10 minutes to a suspension of 4 , 7g sodium ethoxide in 25 ml of dimethylformamide. The mixture is stirred for 15 hours at room temperature, evaporated under strongly reduced pressure at a bath temperature of 40 ⁰ C, the residue is mixed with 150 ml of dichloromethane, some ice and 80 ml of n-hydrochloric acid and stirred for 5 minutes. Then add carefully 7 g of sodium bicarbonate, separating in a separating funnel and evaporating the dichloromethane solution at reduced pressure. The residue is recrystallized from 25 ml of ethanol. This gives ethyl 4-hydroxy-1- [2- (1H-indol-3-yl) -ethyl] -2,5-dihydro-1H-pyrrole-3-carboxylate or 1- [2- (1H- Indole-3-yl) -ethyl] -pyrrolidin-4-one-3-carboxylic acid ethyl ester of mp. 122-123 ⁰ C.

Analogously, starting from 19.7 g of N- [2 (1H-indol-3-yl) ethyl] -N- (3-ethoxycarbonylpropyl) - / 3-alanine ethyl ester, the 4-hydroxy-1- [2- (1H- indol-3-yl) ethyl] -1,2,5,6-tetrahydro-7H-azepin-3-carbonsäureethylesterbzw. 1- [2- (1H-indol-3-yl) ethyl] -hexahydroazepin-4-one-3-carboxylate.

Example 51: 12.1 g of N- [2- (1H-indol-3-yl] -N- (methoxycarbonylmethyl) - / 3-alanine methyl ester are dissolved in 10 ml of dimethylformamide and added with stirring at 20-3O ⁰ C within 15 minutes It is allowed to stir at room temperature for 3 hours, evaporated under reduced pressure at a bath temperature of 40 ⁰ C, the residue is dissolved in 150 ml of methanol and at -5 ° C a 10% pure Solution of hydrochloric acid gas in ether to pH = 5. The resulting 4-hydroxy-1- [2- (1H-indol-3-yl) ethyl] -2,5-dihydro-1H-pyrrole-3-carboxylic acid methyl ester or Methyl 1- [2- (indolyl-3-yl) ethyl] -pyrrolidin-4-one-3-carboxylate can be obtained without further purification by adding 7 portions of 0.4 g sodium borohydride (2.8 g total) with stirring at -30 ° C. within one hour After the entry has been completed, it is allowed to stir at room temperature for 3 hours, then it is evaporated at reduced pressure

251

, the residue is taken up in ether, mixed with water and adjusted with concentrated sodium hydroxide solution to pH = 9. The separated organic phase is washed twice with water, dried over potassium carbonate and evaporated under reduced pressure. The residue is dissolved in 50 ml of acetone and adjusted with stirring to pH = 4 with ethereal hydrochloric acid, wherein the hydrochloride precipitates. After recrystallization from methanol to give the 4-hydroxy-1- [2- (indolyl-3-yl) -ethylJ-pyrrolidine-S-carboxylic acid methyl ester hydrochloride as a cis / trans mixture (about 66% ice) with a mp. from 192-194 ° (dec.), which can be separated into the components by chromatography.

Example 52: 4.7 g of 1- [2- (indolyl-3-yl) -ethyl] -pyrrolidin-4-one-3-carboxylic acid ethyl ester are suspended in 50 ml of ethanol and adjusted to pH = 5 with stirring with ethereal hydrochloric acid. Then, within 4 hours at -10 °, 5 portions of 0.2 g sodium borohydride (1.0 g in total) are added. Then allowed to stir for 3 hours at 0-3 °, evaporated under reduced pressure, the residue is taken up in dichloromethane and extracted with sodium bicarbonate solution. After drying over magnesium sulfate, the mixture is evaporated and the cis-trans mixture is separated by flash chromatography on silica gel with ethyl acetate as eluent. The trans compound is dissolved in a little ethanol and adjusted to pH = 4 with alcoholic hydrochloric acid to crystallize the trans-4-hydroxy-1- [2- (indolyl-3-yl) ethyl] -pyrrolidine-3-carboxylic acid ethyl ester hydrochloride ; mp. 152-153 °

 The cis compound is isolated as an oxalate; Mp 151-152 °.

In an analogous manner starting from 5.3 g 4-hydroxy-1- [2- (1H-indol-3-yl) ethyl] -1,2,5,6-tetrahydro-7H-azepine-3-carboxylic acid ethyl ester den4-hydroxy -1- [2- (1H-indol-3-yl) ethyl] -hexahydroazepin-3-carbonsäureethylesteralscis / trans mixture.

Example 53: In a manner analogous to that described in Examples 1-52, it is also possible to prepare:

Ethyl 4-amino-1- [2- (1H-indol-3-yl) ethyl] -1,2,5,6-tetrahydro-pyridine-3-carboxylate or a salt, e.g. the bishydrochloride, of which;

Cis-4-amino-1 - [2- (1H-indol-3-yl) ethyl] -piperidine-3-carboxylic acid ethyl ester or a salt, e.g. The bishydrochloride, of which; trans-4-amino-1- [2- (1H-indol-3-yl) ethyl] -piperidine-3-carboxylic acid ethyl ester or a salt, e.g. The bishydrochloride, of which; N- [2- (5-methoxy-1H-indol-3-yl) ethyl] -imino-di (3-propionic acid) -dimethyl ester or a salt, e.g. The hydrochloride, of which; 4-Hydroxy-1- [2- (5-methoxy-1H-indol-3-yl) ethyl] -1,2,5,6-tetrahydropyridin-3-carbonsäuremethylesterbzw. Methyl 1- [2- (5-methoxy-1H-indol-3-yl) ethyl] piperidine-3-carboxylate or a salt, e.g. The hydrochloride, of which; methyl cis -hydroxy-1- [2- (5-methoxy-1H-indol-3-yl) ethyl] piperidine-3-carboxylate or a salt, e.g. The hydrochloride, of which;

methyl trans -hydroxy-1- [2- (5-methoxy-1H-indol-3-yl) ethyl] piperidine-3-carboxylate or a salt, e.g. As the hydrochloride, thereof.

Example 54: Fumarates (or semi-fumarates), hydrochlorides and oxalates (or hydrogenoxalates) of other compounds according to any one of Examples 1-53 and hydrobromides and cyclamates of compounds according to. Can also be described in an analogous manner as in Examples 6,8 and 10 one of Examples 1-53 produce.

Example 55 Tablets Containing 50 mg of 4-Hydroxy-1- [2- (4,6-dimethyl-1H-indol-3-yl) ethyl] -1,2,5,6-tetrahydropyridine-3-one carboxylic acid methyl ester or its hydrochloride, can be prepared as follows:

Composition (1 000 tablets) 500.0 g active substance 500.0 g lactose 352.0 g potato starch 8.0 g gelatin 60.0 g talc 10.0 g magnesium stearate 20.0 g Silica (highly dispersed)

Ethanol q.s.

The active ingredient 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, the remainder of the potato starch, talc, magnesium stearate and fumed silica are mixed together and the mixture is compressed into 145.0 mg weight tablets and 50.0 mg active ingredient content, which may optionally be provided with partial scores for finer dosage adjustment.

Example 56: Lacquered tablets containing 100 mg of 4-hydroxy-1- [2- (4,6-dimethyl-1H-indol-3-yl) ethyl] -1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester , its hydrochloride can be prepared as follows:

Composition (for 1 000 tablets) 100.00 g active substance 100.00 g lactose 70.00 g corn starch 8.50 g talc 1.50 g calcium stearate 2.36 g Hydroxypropyl methylcellulose 0.64 g shellac q.s. water q.s. methylene chloride

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 (with heating), and granulated. The granules are dried, the remainder of the corn starch, the talc and the calcium stearate are added and mixed with the granules. The mixture is compressed into tablets (weight: 280 mg) and coated with a solution of the hydroxypropylmethylcellulose and the shellac in methylene chloride; Final weight of the coated tablet: 283 mg.

Example 57: In a manner analogous to that described in Examples 55 and 56, it is also possible to prepare pharmaceutical preparations containing another compound of the formula I according to Examples 1 to 53.

Example 58: 20 g of baker's yeast Rohrzuckerund 19g are stirred in 160ml drinking water for 1 hour at 3O ⁰ C. Then 3.5 g (10 μmol) of finely pulverized ethyl 4-hydroxy-1- [2- (1-indol-3-yl) ethyl] -1,2,5,6-tetrahydropyridine-3-carboxylate are added. It is allowed to stir for 24 hours at room temperature, adds a 4O ⁰ C warm solution of 13g cane sugar in 65 ml of drinking water and another 4g bakers' yeast and allowed to stir for another 48 hours at room temperature. It is then filtered through diatomaceous earth, made alkaline with potassium carbonate and poured twice with 50 ml of dichloromethane. The organic phases are combined, dried over potassium carbonate and evaporated to dryness under reduced pressure. The residue is purified by chromatography (silica gel / ethyl acetate). This gives 3R, 4S-cis-4-hydroxy-1- [2- (1-indol-3-yl) ethyl] -piperidine-3-carboxylic acid ethyl ester, which is converted by means of ethereal hydrochloric acid in the hydrochloride, mp. 108 ⁰ C, α] o ° = + 46.2 ± 0.6 ° C (C = 1.586 in ethanol).

Claims (66)

A process for the preparation of 1,3,4-trisubstituted azacycloalkanes and azacycloalkenes of the formulas RZN ; * -R ₂ (I) wherein R is an optionally substituted 3-indolyl radical, Z is lower alkylene which separates the radical R by 1 to 3, preferably 2, carbon atoms from the nitrogen atom, alk methylene, ethylene or 1,3-propylene, R ₁ optionally esterified or amidated carboxy and R _{2 is} an optionally etherified or acylated hydroxy group or an optionally acylated amino group, and their tautomers and / or salts, characterized in that a) for the preparation of compounds of formula I, wherein alk is ethylene, in a compound of formula ^R " ^Z A /) - ^R 2 (" I) wherein A® is an acid anion and R ₂ "etherified, acylated or protected hydroxy or acylated or protected amino, which reduces excess double bonds to single bonds and optionally splits off existing protective groups, or b) a compound of the formula 8Ik-X ₁ ^R " ^Z " \ (III), • -CH ₂ -Ri wherein Xi is a group of the formulas -CH = R ₂ ', -C (X ₂ ) = R ₂ ' or cyano, wherein X _{2 is} a leaving group, or a salt thereof is cyclized, or c) a compound of the formula R ₃ - N - N = C - CH ₂ - Z - nT Λ Ra (IV), where R _{3 is} a phenyl radical which is optionally substituted in the 3 to 6 position as indicated for the positions 4 to 7 of the radical R, R _{4 is} hydrogen or a substituent intended for the 1-position of R and R _{5 is} hydrogen or a radical Position of R substituents provided, or a tautomer and / or salt thereof, to the corresponding compound of formula I rings, or d) compounds of the formulas / ^al RZX ₃ (V) and HN ^. ·; · -R ₂ (V |), in which X ₃ denotes a nucleofuge leaving group, or reacts their tautomers and / or salts with one another, or e) for the preparation of compounds of formula I wherein alk is ethylene, a compound of formula H ₂ C = *
RZ-HN Λ R ₂ (VIi) or a tautomer and / or salt thereof cyclized, or f) in a compound of the formula κ. ζ - i / i-Ri (VIII), in which R ₁ 'is a radical which can be converted into optionally esterified or amidated carboxy, or in a tautomer and / or salt thereof, R ₁ ' is converted into optionally esterified or amidated carboxy, or g) for the preparation of compounds of the formula I in which the azacycloaliphatic radical has a double bond, a compound of the formula ^al R · z M ^ y · - »» (IX). in which R 'is a 3-indolyl radical R and R ₂ "' which is substituted in the 1-position or is protected as an intermediate, R ₂ or hydroxy protected as intermediate, or the corresponding keto or iminotautomer thereof with a compound of the formula R ₁ -Xo ( Vl a), wherein X _{6 is} a leaving group, condensed and optionally cleaved the protecting group (s), or h) in a compound of formula RZN ^ λ Xn (X), where X _{4 is} a radical convertible into a group R ₂ , X _{4 is converted} into a group R ₂ , or i) for the preparation of compounds of the formula I in which the azacycloaliphatic ring is monounsaturated, and R _{2 is} hydroxy, or tautautomers Oxo compound a compound of the formula / ^al (XI) rearranged, or j) for the preparation of compounds of the formula I in which the azacycloaliphatic ring is saturated, compounds of the formulas / ^al - \ / (XII) with each other, or k) for the preparation of compounds of formula I wherein Z is the radical R is separated from the nitrogen atom by 1 C atom, compounds of the formulas / ^al RH (L) and HN ^ > - R ₂ If desired, the compound obtainable by the process is converted into another compound of the formula I, a isomer mixture of the formula I obtainable according to the process is isolated and the isomer of the formula I is isolated, a diastereomer mixture or enantiomer mixture obtainable according to the process is split into the disastereomers or enantiomers and isolating the desired diastereomer or enantiomer and / or converting a compound which is free from the process into a salt or a salt obtainable according to the process into the free compound or into another salt. 2. A process according to item I, characterized in that a compound of the formula I, in which R is unsubstituted or substituted in at least one of the positions 1, 2 and 4 to 7, is 3-indolyl, where the substituent in the! Position is lower alkyi or lower alkenyl, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, hydroxy, halogen, trifluoromethyl and / or lower alkyl (id) - endioxy bonded to adjacent carbon atoms, Z is lower alkylene which separates the R radical from the nitrogen atom by 2 C atoms, alk is methylene, ethylene or 1,3-propylene, R-, carboxy, lower alkoxycarbonyl, optionally lower alkoxy, lower alkoxy, halogen, nitro and / or trifluoromethyl substituted phenyl-lower alkoxycarbonyl, 3- to 8-membered cycloalkoxycarbonyl, carbamoyl, mono- or di-lower alkylcarbamyl, lower alkylene or aza-, oxa- or thio-lower alkylene carbamyl, N-lower alkanoyl lcarbamyl, N-lower alkoxycarbonylcarbamyl, ureidocarbonyl, N'-mono- or Ν ', Ν'-di-lower alkylureidocarbonyl, Ν', Ν'-lower alkylene or N ', N' - (aza-, oxa- or thia) -dietalylenureadocarbonyl, and R _{2 is} hydroxy, lower alkoxy, phenyl-lower alkoxy, optionally substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl and / or nitro, amino, lower alkanoylamino, lower alkoxycarbonylamino or phenyl-lower alkoxycarbonylamino optionally substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl and / or nitro wherein lower alkylene alk to and with 4, the remainder of the lower residues have a total of up to and including 7 and in each lower substructure up to and including 4 C atoms, or produces a tautomer and / or salt thereof. 3. The method according to item 1 or 2, characterized by reacting a compound of formula I, wherein alk is ethylene and R, Z, R ₁ and R _{2 have} the meanings given in point 1 or 2, or a tautomer and / or salt of it manufactures. 4. The method according to item!, Characterized by reacting a compound of formula!, Wherein R is unsubstituted or in one or two of the positions 4 to 7 by Niederalkyi with up to and with 4 C-atoms, lower alkoxy with bis and with 4 C Atoms, halogen of the atomic number to and with 35 and / or trifluoromethyl substituted 3-indolyl, Z represents lower alkylene with bis and with 4 C-atoms, which separates the radical R from the nitrogen atom by 1 to 3 C-atoms, alk methylene, ethylene or 1,3-propylene, R _{1 is} carboxy, lower alkoxycarbonyl with up to and with 4 C atoms in the alkoxy moiety, 3- to 8-membered cycloalkoxycarbonyl, carbamyl or N-mono- or Ν, Din-di-lower alkylcarbamyl with up to and with 4 C atoms in each alkyl part and R _{2 is} hydroxy, lower alkoxy with up to and with 4 C atoms, lower alkanoyloxy with bis and with 4 C atoms, amino or Niederaikanoylamino means bis and with 4 C atoms, or produces a tautomer and / or salt thereof. 5. The method according to item 1, characterized by reacting a compound of formula I, wherein R is unsubstituted or substituted in one or two of the positions 1 and 4 to 7 substituted 3-indolyl, wherein as a substituent in the 1-position lower alkyl, and as Substituent (s) in the 4- to 7-position lower alkoxy with up to and with 4 C atoms, halogen or atomic number up to and with 35 and / or lower alkyl with up to and with 4 C atoms, alk represents ethylene, Z1, Represents 1-, 1,2- or 1,3-lower alkylene having up to and including 4 C atoms and R ₁ represents lower alkoxycarbonyl having up to and including 4 C atoms in the lower alkoxy part and R ₂ denotes hydroxyl or amino, or a tautomer and / or or salt thereof. 6. The method according to item 1, characterized by reacting a compound of formula I, wherein R is unsubstituted or in one or two of the positions 4 to 7 by lower alkyl having bis and with 4 C-atoms and / or the atomic number to and 35 substituted 3-indolyl, Z is straight-chain 1,1-, 1,2- or 1,3-lower alkylene having up to and with 4 C atoms, alk is methylene or ethylene, Ri is lower alkoxycarbonyl with up to and with 4 C atoms in the Alkoxy part and R _{2 is} hydroxy, or produces a tautomer and / or salt thereof. 7. The method according to item 1, characterized in that one represents a compound of formula I, wherein R is unsubstituted or substituted in the 4- and 7-position by lower alkyl with up to and 4 C-substituted 3-indolyl, Z and alk represent ethylene , R _{1 is} lower alkoxycarbonyl having up to and including 4 C atoms in the lower alkoxy part and R _{2 is} hydroxy, or produces a tautomer and / or salt thereof. 8. The method according to item 1, characterized in that one represents a compound of formula I, wherein R is unsubstituted or substituted in the 5-position by methoxy 3-indolyl, Z and alk are ethylene, R _{1 is} methoxycarbonyl and R _{2 is} hydroxy or Amino, or, if the azacyclic ring has no double bond, lower alkanoyloxy with up to and with 4 C atoms, z. Acetoxy, or a tautomer and / or a salt thereof. 9. The method according to any one of the items 1 to 8, characterized in that compounds of the formula I, wherein R, Z, alk, R ₁ and R _{2 are} each as defined in the points mentioned meanings, the azacycloaliphatic ring has no double bond, and R ₁ and R ₂ are cis-continuous with each other or produce a salt thereof. 10. The method according to item 1, characterized by reacting 4-hydroxy-1- [2- (1 H-indol-3-yl) ethyl] -1,2,5,6-pyridine-3-carboxylic acid methyl ester or 1 [2- (1H-indol-3-yl) ethyl] -piperidin-4-one-3-carboxylic acid methyl ester or a salt thereof. 11. A process according to item 1, characterized in that ethyl 4-hydroxy-1- [2- (1H-indol-3-yl) ethyl] -1,2,5,6-pyridine-3-carboxylate is added. 1- [2- (1H-indol-3-yl) ethyl] -piperidin-4-one-3-carboxylic acid ethyl ester or a salt thereof. 12. The method according to item ↑, characterized in that trans-4-hydroxy-1- [2- (1 H-indol-3-yl) ethyl] piperidine-3-carboxylic acid ethyl ester or a salt thereof. 13. The method according to item 1, characterized by preparing trans-4-hydroxy-1- [2- (1 H-indol-3-yl) ethyl] piperidine-3-carboxylic acid ethyl ester or a salt thereof. 14. The method according to item 1, characterized by preparing cis-4-hydroxy-1- [2- (1 H-indol-3-yl) ethyl] piperidine-3-carboxylic acid methyl ester or a salt thereof. 15. The method according to item 1, characterized by preparing trans-4-hydroxy-1- [2- (1 H-indol-3-yl) ethyl] piperidine-3-carboxylic acid methyl ester or a salt thereof. 16. The method according to item 1, characterized in that cis-4-acetoxy-1- [2- (1 H-indol-3-yl) ethyl] piperidine-3-carboxylic acid methyl ester or a salt thereof is prepared. 17. The method according to item 1, characterized by preparing trans-4-acetoxy-1- [2- (1 H-indol-3-yl) ethyl] piperidine-3-carboxylic acid methyl ester or a salt thereof. 18. A method according to item 1, characterized in that one prepares 4-amino-1- [2- (1 H-indol-3-yl) ethyl] -1 ^, ö ^ tetrahydropyridine-S-carboxylic acid methyl ester or a salt thereof. 19. The method according to item 1, characterized in that one prepares 4-amino-1- [2- (1 H-indol-3-yl) ethyl] piperidine-3-carboxamide or a salt thereof. 20. The method according to item 1, characterized by reacting 4-hydroxy-1- [2- (4,6-dimethyl-1 H-indol-S-yDethyH-i ^^^ - tetrahydro-pyridine-S-carbonsäureethylesterbzw. Ethyl 1- [2- (4,6-dimethyl-1H-indol-3-yl) ethyl] piperidin-4-one-3-carboxylate or a salt thereof. 21. The method according to item 1, characterized in that man4-hydroxy-1- [2- (5-chloro-1 H-indol-3-yl) ethyl] -1,2,5,6-tetrahydropyridine-3 ethylcarboxylate or ethyl 1- [2- (5-chloro-H-indol-3-yl) ethyl] -piperidin-4-one-3-carboxylate or a salt thereof. 22; Process according to item 1, characterized in that cis-4-hydroxy-1- [2- (4,6-dimethyl-1H-indol-S-y-ethyl-1-piperidine-S-carboxylic acid ethyl ester or a salt thereof is prepared. 23s Method according to item 1, characterized in that trans-4-hydroxy-1- [2- (4,6-dimethyl-1 H-indol-S-yOethyll-piperidine-S-carboxylic acid ethyl ester or a salt thereof. 24; Process according to item 1, characterized in that ethyl cis-4-hydroxy-1- [2- (5-chloro-1H-indol-3-yl) ethyl] piperidine-3-carboxylate or a salt thereof is prepared. 25. Process according to item 1, characterized in that trans-4-hydroxy-1- [2- (5-chloro-1H-indol-3-yl) -ethyl] -piperidine-3-carboxylic acid ethyl ester or a salt thereof manufactures. 26. A method according to item 1, characterized in that 4-hydroxy-1 - [(1 H-indol-3-yl) methyl] -1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl esterbzw. Methyl 1 - [(1H-indol-3-yl) methyl] -piperidin-4-one-3-carboxylate or a salt thereof. 27. Process according to item 1, characterized in that trans-4-hydroxy-1 - [(1 H-indol-3-yl) methyl] piperidine-3-carboxylic acid methyl ester or a salt thereof is prepared. 28. The method according to item 1, characterized in that one produces cis-4-hydroxy-1 - [(1 H-indol-3-yl) methyl] piperidine-3-carboxylic acid methyl ester or a salt thereof. Process according to item 1, characterized in that methyl 4-hydroxy-1- [3- (1H-indol-3-yl) propyl] -1,2,5,6-tetrahydro-pyridine-3-carboxylate is used. [1- [3- (1H-indol-3-yl) -propyl] -piperidin-4-one-3-carboxylic acid methyl ester or a salt thereof. 3D. Process according to item 1, characterized in that cis-4-hydroxy-1- [3- (1H-indol-3-yl) -propyl] -piperidine-3-carboxylic acid methyl ester or a salt thereof is prepared. 3 ⁷ I. A method according to item 1, characterized in that trans-4-hydroxy-1- [3- (1 H-indol-3-yl) propyl] piperidine-3-carbonsäuremethylester or a salt thereof is prepared. 32. The method according to item 1, characterized in that cis-4-amino-1- [2- (1 H-indol-3-yl) ethyl] piperidine-3-carboxylic acid ethyl ester or a salt thereof. 33. The method according to item 1, characterized in that trans-4-amino-1 - [2- (1 H-indol-3-yl) ethyl] piperidine-3-carboxylic acid ethyl ester or a salt thereof prepared. 34. A method according to item 1, characterized in that ethyl and / or trans-4-benzyloxy-i- [2- (5-methoxy-1 H-indol-3-yl) ethyl] piperidine-3-carboxylic acid ethyl ester or a Salt of it produces. 35. The method according to item!, Characterized in that4-hydroxy-1- [2- (5-methoxy-1H-indol-3-yl) ethyl] -1,2,5,6-tetrahydropyridine-3-carboxylic acid ethyl ester or 1. 1- [2- (5-methoxy-1H-indol-3-yl) ethyl] -piperidin-4-one-3-carboxylic acid ethyl ester or a salt thereof. 336. The process according to item 1, which comprises preparing cis-4-hydroxy-1- [2- (5-methoxy-1H-indol-S-y-ethyll-piperidine-S-carboxylic acid ethyl ester or a salt thereof. 37. The method according to item 1, characterized in that trans-4-hydroxy-1- [2- (5-methoxy-1 H-indol-S-yO-ethyU-piperidine-S-carboxylic acid ethyl ester or a salt thereof. 38. Process according to item 1, characterized in that 4-hydroxy-1 - [2- (5-bromo-1H-indol-3-yl) ethyl] -1,2,5,6-tetrahydropyridine-3-one carboxylic acid ethyl ester or ethyl 1- [2- (5-bromo-1H-indol-3-yl) ethyl] piperidin-4-one-3-carboxylate or a salt thereof. 39. The method according to item 1, characterized in that cis-4-hydroxy-1- [2- (5-bromo-1 H-indol-3-yl) ethyl] piperidine-3-carboxylic acid ethyl ester or a salt thereof prepared , 40. The method according to item 1, characterized by preparing trans-4-hydroxy-1- [2- (5-bromo-1 H-indol-3-yl) ethyl] piperidine-3-carboxylic acid ethyl ester or a salt thereof , 41. The method according to item 1, characterized in that ethyl cis-4-hydroxy-1- [2- (5-fluoro-1 H-indol-3-yl) ethyl] piperidine-3-carboxylate or a salt thereof prepared , 42. The method according to item 1, characterized in that trans-4-hydroxy-1- [2- (5-fluoro-1 ¹ H-indol-3-yl) ethyl] piperidine-3-carboxylic acid ethyl ester or a salt thereof manufactures. 43. The method according to item 1, characterized in that 4-hydroxy-1- [2- (5-bromo (1 H-indol-3-yl) ethyl] -1,2,5,6-tetrahydropyridine-3 methylcarboxylate or 1- [2- (5-bromo-1H-indol-3-yl) ethyl] -piperidin-4-one-3-carboxylic acid methyl ester or a salt thereof. 44. Method according to item 1, characterized in that 4-hydroxy-1- [2- (5-fluoro-1H-indol-3-yl) ethyl] -1,2,5,6-tetrahydropyridine Ethyl 3-carboxylate or ethyl 1- [2- (5-fluoro-1H-indol-3-yl) ethyl] piperidin-4-one-3-carboxylate or a salt thereof. 45. Method according to item 1, characterized in that cis-4-hydroxy-1- [2- (5-fluoro-1H-indol-3-yl) methyl] -piperidine-3-carboxylic acid methyl ester or a salt thereof is prepared , 46. The method according to item 1, characterized by preparing trans-4-hydroxy-1- [2- (fluoro-1H-indol-3-yl) ethyl] piperidine-3-carboxylic acid methyl ester or a salt thereof. 47. The method according to item 1, characterized in that cis-4-hydroxy-1- [2- (5-bromo-1 H-indol-3-yl) ethyl] piperidine-3-carboxylic acid methyl ester or a salt thereof prepared , 48. Process according to item 1, characterized in that 4-hydroxy-1- [2- (5-fluoro-1H-indol-3-yl) ethyl] -1,2,5,6-tetrahydropyridine-3-one methyl carboxylate or 1- [2- (5-fluoro-1H-indol-3-yl) ethyl] piperidin-4-one-3-carboxylic acid methyl ester or a salt thereof. 49. The method according to item 1, characterized by preparing trans-4-hydroxy-1- [2- (5-bromo-1 H-indol-3-yl) ethyl] piperidine-3-carboxylic acid methyl ester or a salt thereof , 50. The method according to item 1, characterized in that 4-hydroxy-1- [2- (4,6-dimethyl-1H-indol-S-yDethylH ^ S] -tetrahydropyridine-S-carboxylic acid methyl ester or 1- [2- (4,6-dimethyl-1H-indol-3-yl) ethyl] -piperidin-4-one-3-carboxylic acid methyl ester or a salt thereof. 51. The method according to item 1, characterized in that 4-hydroxy-1- [2- (5-chloro-1H-indol-3-yl) ethyl] -1,2,5,6-tetrahydropyridine 3-carboxylic acid methyl ester or 1- [2- (5-chloro-H-indol-3-yl) ethyl] piperidin-4-one-3-carboxylic acid methyl ester or a salt thereof. 52. Method according to item 1, characterized in that cis-4-hydroxy-1- [2- (5-chloro-1H-indol-3-yl) ethyl] piperidine-3-carboxylic acid methyl ester or a salt thereof is prepared , 53. The method according to item 1, characterized in that trans-4-hydroxy-1- [2- (5-chloro-1H-indol-3-y!) Ethyl] piperidine-3-carboxylic acid methyl ester or a salt thereof manufactures. 54. The method according to item 1, characterized in that cis-4-hydroxy-1- [2- (4,6-dimethyl-1 H-indol-S-yD-ethyl-piperidine-S-carboxylic acid methyl ester or a salt thereof manufactures. 55. The method according to item 1, characterized in that trans-4-hydroxy-1 - [2- (4,6-dimethyl-1 H-indol-3-yl) -ethyl] piperidine-3-carboxylic acid methyl ester or a Salt of it produces. 56. Method according to item 1, characterized in that cis-4-methoxy-1- [2- (1H-indol-3-yl) ethyl] -piperidine-3-carboxylic acid methyl ester or a salt thereof is prepared. 57. Process according to item 1, characterized in that 4-hydroxy-1- [2- (5-methoxy-1H-indol-3-yl) ethyl] -1,2,5,6-tetrahydropyridine 3-carboxylic acid methyl ester or 1- [2- (5-methoxy-1 H-indol-3-yl) ethyl] piperidin-4-one-3-carboxylic acid methyl ester or a salt thereof. 58. The method according to item 1, characterized in that one prepares cis-hydroxy-1- [2- (5-methoxy-1H-indol-3-yl) ethyl] piperidine-3-carboxylic acid methyl ester or a salt thereof. 59. The method according to item 1, characterized by preparing trans-hydroxy-1- [2- (5-methoxy-1H-indol-3-yl) -ethyl] - piperidine-3-carboxylic acid methyl ester or a salt thereof , 60. A process according to item 1, characterized in that ethyl 4-hydroxy-1- [2- (1H-indol-3-yl) ethyl] -2,5-dihydro-1H-pyrrole-3-carboxylate or 1- [2- (1H-indol-3-yl) ethyl] -pyrrolindin-4-one-3-carboxylic acid ethyl ester or a salt thereof. 61. The method according to item 1, characterized by preparing cis-4-amino-1- [2- (1 H-indol-3-yl) ethyl] piperidine-3-carboxylic acid methyl ester or a salt thereof. 62. The method according to item 1, characterized by preparing trans-4-amino-1- [2- (1 H-indol-3-yl) ethyl] piperidine-3-carboxylic acid methyl ester or a salt thereof. 63. The method according to item 1, characterized by reacting 4-hydroxy-1- [2- (1 H-indol-3-yl) ethyl] -2,5-dihydro-1 H-pyrrol-3-yl-carboxylic acid methyl ester or 1- [2- (1H-indol-yl) ethyl] -pyrrolidin-4-one-3-carboxylic acid methyl ester or a salt thereof. 64. Method according to item 1, characterized in that cis-4-hydroxy-1- [2- (1 H-indol-3-yl) ethyl] -pyrrolidine-3-carboxylic acid ethyl ester or a salt thereof is prepared. 65. The method according to item 1, characterized by preparing trans-4-hydroxy-1- [2- (1 H-indol-3-yl) ethyl] -pyrrolidin-3-carboxylic acid ethyl ester or a salt thereof. 66. The method according to item 1, characterized in that one prepares cis-4-hydroxy-1- [2- (1 H-indol-3-yl) ethyl] -pyrrolidin-3-carboxylic acid methyl ester or a salt thereof. 67. The method according to item 1, characterized by preparing trans-4-hydroxy-1- [2- (1 H-indol-3-yl) ethyl] -pyrrolidine-3-carboxylic acid methyl ester or a salt thereof. 68. The method according to item ↑, characterized in that 4-hydroxy-1- [2- (1 H-indol-3-yl) ethyl] -1,2,5,6-tetrahydro-7H-azepine-3-carboxylic acid Ethylesterbzw , Ethyl 1- [2- (1H-indol-3-yl) ethyl] -hexahydro-azepine -on-S-carboxylic acid or a salt thereof. 69. The method according to item 1, characterized in that cis-4-hydroxy-1- [2- (1 H-indol-3-yl) ethyl] -hexahydroazepin-3-carboxylic acid ethyl ester or a salt thereof is prepared. 70. The method according to item 1, characterized in that trans-4-hydroxy-1- [2- (1 H-indo-3-yl) ethyl] -hexahydroazepin-3-carboxylic acid ethyl ester or a salt thereof prepared. 71. The method according to item!, Characterized in that one prepares a compound obtainable according to one of the items 1 to 70, in the form of a hydrochloride, hydrobromide, fumarate, oxalate or cyclamates.