NO860007L - PROCEDURE FOR THE PREPARATION OF NEW TRISUBSTITUTED AZACYCLOALKANES, RESP. AZACYKLOALKENER. - Google Patents

Description

The invention relates to a process for the production of new 1,3,4-trisubstituted azacycloalkanes, and azacycloalkenes with the formula

in which R means an optionally substituted 4-indolyl residue,

Z means lower alkylene, which separates the residue R by 1 to 3/preferably 2 carbon atoms from the nitrogen atom, alk means methylene, ethylene or 1,3-propylene, R^ means optionally esterified or amidated carboxy, and R2 means an optionally etherified or acylated hydroxy group, or an optionally acylated amino group, as well as their tautomers and/or salts, especially pharmaceutically usable salts.

The dotted line in formula I then means that between the carbon atoms (C atoms) substituted with R 1 and R 9 , there can be a single or double bond.

Substituents of the 3-indolyl residue include, for example, in -consideration ralphatic hydrocarbon residues such as lower alkyl or lower alkenyl, 4- to even 7-position, likewise optionally esterified or etherified hydroxy groups, such as hydroxy, lower alkanoyloxy, halogen, lower alkoxy, lower erealkenyloxy, or neighboring carbon atoms (C atoms), bonded lower alkyl(ide)dioxide, further trufluoromethyl. Thereby even 4, "especially" 1,2 or 3 of the aforementioned substituents can be present, for example 1 to 3, especially 1 or 2 substituents in the 4- to 7-position, and/or respectively a substituent in 1- and/or 2-position. •Etherated hydroxy R2 is, for example,•lower alkyl or optionally substituted phenyl lower alkyl.

Acyl in acylated hydroxy, resp. amino R 2 .is for example

from an organic carboxylic acid, or a half-ester of carboxylic acid derived acyl.

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

Those derived from acyl half-esters of carboxylic acid, a second hydroxy group is e.g. esterified with an aliphatic or aryl-, such as phenylaliphatic alcohol. As acyl groups derived from half-esters of carboxylic acid, mention may be made, for example, of lower alkoxycarbonyl and optionally substituted phenyl lower oxycarbonyl.

Esterified carboxy means, for example, aliphatic, cycloaliphatic or aryl- such as phenylaliphatic esterified carboxy, for example lower alkoxycarbonyl, optionally substituted phenyllower carboxycarbonyl, 3- to even 8-membered, such as 5- or 6-membered cycloalkoxycarbonyl, i.e. cyclopentyloxy- or cyclohexyloxycarbonyl, further cyclopropyloxy-, cyclo-butyloxy- or cycloheptyloxycarbonyl.

Amidated carboxy means, for example, "unsubstituted" aliphatic N-substituted or N-acylated: carbamyl, such as carbamyl, N-

mono- or N,N-dilower alkylcarbamyl, N,N-lower alkylene or N,N-(aza-, oxa- or thia)lower alkylenecarbamyl or N-acylcarbamyl, in which acyl has, for example, one of the

acyl in acylated hydroxy resp. amino R2 indicated meaning.

Such N-acylcatbamyl groups are, for example: N-lower alkyl carbamyl, N-lower alkyl oxycarbonylcarbamyl, ureidocarbonyl, N'-mono- or N<1>,N'-dilower alkyl ureidocarbonyl or N',N'-lower alkylene- or N',N'-(aza-, oxa- or thia)lower alkylene-ureidocarbonyl.

In the preceding and following can. aryl-, such as phenyl groups

as part of the substituent' of the residue R^ and/or 1*2'

as well as starting materials for the preparation of the compounds I may also be substituted, e.g. with lower alkyl, lower alkoxy, halogen, nitro, and/or trifluoromethyl.

Likewise, if nothing else is indicated, "lower" residues and organic compounds are to be understood as such residues or compounds having up to 7, especially up to 4 C atoms.

The lower alkylene, which separates the radical R from the nitrogen atoms entered 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, can however also be 2,3-butylene.

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

Lower alkenyl is, for example, allyl or methallyl.

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

ILaveraloxy is, for example, methoxy, ethoxy, propyloxy or butyloxy. Lower alkyloxy is, for example, allyloxy.

Lower alkyl (id) endyloxy 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 oxycarbonyl is, for example, methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, secondary butyloxy or tertiary butyloxycarbonyl or a pentyloxy, hexyloxy or heptyloxycarbonyl group.

Cycloalkoxycarbonyl has, for example, 3 to 8, especially 3

to 6 rings, and means e.g. cyclopropyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl or cyclohexyloxycarbonyl.

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

Lower alkylenecarbamyl resp. aza-, oxa- or thialaverealkylenecarbamyl is, for example, pyrrolidinocarbonyl or piperidinocarbonyl, further piperazino- or. N1-lower alkyl-, such as N'-methylpiperazinocarbonyl, morpholinocarbonyl or thio-morpholinocarbonyl.

N<1->mono- or N<1>,N<1->dilaverealkylureidocarbonyl is, for example, N'-methyl-, N'-ethyl-, N<1->propyl-, N<1->butylureidocarbonyl or. N' .,N'-dimethyl- or N1..,N1 -diethylureidocarbonyl.

N',N<1->lower alkylene- resp. N',N'-(aza-, oxa- or thia) lower alkylene ureidocarbonyl is, for example, N-piperidinocarbonylcarbamyl, N-pyrrolidinocarbonylaminocarbamyl, N-morpholino-, N-thiomorpholino or N-piperazino-, resp. N'-(lower alkyl-, such as N<1->methyl)-piperazinocarbonylcarbamyl.

Phenyl lower alkyl is, for example, benzyl, 1- or 2-phenethyl or 3-phenylpropyl. Likewise, phenyl lower alkyloxy, also as a component of phenyl lower alkyl oxycarbonyl, e.g. benzyl-oxy,.1-.or. 2-phenethoxy or 3-phenylpropyloxy. Tautomers of the compounds of formula I are, for example, keto- or ketimine derivatives' of compounds of formula I, in which the azacycloaliphatic ring has a double bond, and R2 means hydroxy or optionally acylated amino, i.e. compounds of formula

wherein R2<1> means oxo or optionally acylated imino. Salts of compounds of formula I are, for example, their pharmaceutically usable acid addition salts, likewise inner salts of compounds of formula I, where R is carboxy, their pharmaceutically usable salts with bases. Pharmaceutically applicable acid addition salts are, for example, salts with suitable mineral acids, such as hydrohalic acids, sulfuric acid or phosphoric acid, e.g. hydrochlorides, hydrobromides, sulphates, hydrogen sulphates or phosphates, or salts of suitable organic carboxylic or sulphonic acids, ..such as. optionally ..hydroxylated aliphatic ..mono- ...or dicarboxylic acids, e.g..acetates, oxalates, succinates, fumarates, maleates, maleates, ascorbinates or citrates, the aliphatic or aromatic sulphonic acids, or N-substituted sulfamic acids, e.g. methanesulfonates, benzenesulfonates, p-toluenesulfonates or N-cyclohexylsulfaminates (cyclamates).

Pharmaceutically usable salts with bases are primarily metal or ammonium salts, such as alkali metal and alkaline earth metal, e.g. sodium, potassium, magnesium or calcium salts. as well as ammonium salts with ammonia or

suitable organic amines, such as lower alkylamines: e.g. triethylamine, hydroxyl lower alkylamines, e.g. 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine or tris-(2-hydroxyethyl)-

amine, basic.aliphatic properties of carboxylic acid, e.g. 4-aminobenzoic acid 2-diethylaminoethyl ester, lower alkylene amines, e.g. 1-ethylpiperidine, cycloalkylamines, e.g. di-cyclohexylamines, or benzylamine, e.g. N,N'-dibenzyl-enediamine, dibenzylamine or N-benzyl-3-phenylethylamine. Compounds of formula I with an acidic and with a basic group can also exist in the form of internal salts, i.e. in zwitterionic form.

Pharmaceutical unsuitable salts can also be used for isolation or purification. For therapeutic use, only the pharmaceutically usable non-toxic salts are therefore preferred.

The compounds of formula I and their pharmaceutically usable salts have valuable pharmacological, especially nootropic, properties. Thus, they decrease in mice in doses from approx. 0.1 mg/kg i.p., as well as p.o. the amnesogenic effect of an electroshock to at least the same degree as after the administration of a nootropically effective dose of piracetam (100 mg/kg i.p.). To influence the nootropic effect, two-compartment tests can be used, for example.

Literature on pharmacological models of this type should be mentioned, for example: S.J. Sara and D. Lefevre, Psycho-pharmacologia 25, .32-40 (1972) , hypoxla-induced amnesia in one-trial learning and pharmacological protection by piracetam^. Boggan W.O., and Schlesinger K. in Behavioral Biology 12, 127-134. (1974).

Furthermore, the compound of formula I shows a strong memory-improving effect in the Step-down Passive Avoidance Test according to Mondadori and Vaer, Psychopharmacology 63, 297-300 (1979). The substances are effective when administered intraperitoneally. 30 minutes. :f before the learning trial, (effective dose 0.1, 1, 10.mg/kg).

.A clear effect can be determined by oral application 60

minutes • before the learning trial (effective doses 0.1, 1.10 mg/kg), as well as by intraperitoneal: application immediately after the learning trial (effective doses 0.1, 1, 10 mg/kg).

The compounds of formula I and their pharmaceutically usable salts can therefore find use as nootropics, for example in the treatment of cerebral dyslexia insufficiency, in particular of memory disorders of different genesis, such as senile dementia or dementia of the Alzheimer type, further of sequelae of brain trauma and apoplexy.

The invention relates, for example, to compounds of formula I, in which R means unsubstituted or in the 5-position with methoxy substituted 3-indolyl, Z and alk means ethylene, R^means methoxycarbonyl and R2 means hydroxy or amino, or if the azacyclic ring does not have a double bond, lower alkanoyloxy with even 4 C atoms, e.g. acetoxy, and their tautomers, and/or salts.

The invention primarily relates to the preparation of compounds of formula I, in which R means unsubstituted or in at least one of positions 1, 2 and 4 to 7 substituted with indo-ylyl f .-j.det.: as ..substituent: i-1 -position comes into consideration lower alkyl or lower alkenyl in the _2-position,, lower alkyl or as substituents or substituents in the 4th to 7-position,

.lower alkyl, lower alkenyl, lower alkoxy, -lower alkenyloxy, hydroxy, halogen, trifluoromethyl, and/or in neighboring C atoms bound lower alkyl(id)endioxy, Z means the lower alkylene, which separates the residue R from the nitrogen atom by 1 to 3, preferably 2 C- atoms, alk means methylene, 1,2-propylene, or above all ethylene, R.^means carboxy, lower alkoxycarbonyl, optionally with.lower alkyl, lower alkoxy, halogen, nitro, and/or trifluoromethyl substituted phenyl lower oxy, carbonyl, ■3- to. 8-membered cycloalkoxycarbonyl, carbamyl, mono-., or diaverealkylcarbamyl, J.averealkylene- resp. aza-, oxa-.or thialaveralalkylenecarbamyl, N-loweralkanoylcarbamyl

myl, N-lower oxycarbonylcarbamyl, ureidocarbonyl, N * - mono- or N',N<1->dilower alkyl ureidocarbonyl, N<1>,N'-lower alkylene- resp. N',N'-(aza-, oxa- or thia)lower alkylureidocarbonyl, and R2 means hydroxy, lower alkoxy, optionally with lower alkyl, lower alkoxy, halogen, trifluromethyl and/or nitro-substituted phenyl lower alkyl, amino, lower alkanoylamino, lower alkoxycarbonylamino, or optionally with lower alkyl , lower alkoxy, . halogen, trifluoromethyl, and/or nitro substituted phenyl lower oxycarbonylamino, with the lower alkylene alk having up to and including 4, the other lower residues together up to and including 7 and in each lower substructure up to and including 4 C atoms, and their tautomers and/or salts . \

The invention relates above all to the preparation of compounds of formula I, in which R means unsubstituted or one or two of the positions 4 to 7 with lower alkyl with 1 with up to and including 4 C atoms, such as methyl, lower alkoxy with up to and including 4 C atoms as methoxy, halogen of atomic number up to and including 35 as chlorine, and/or trifluoromethyl substituted 3-indolyl, Z means the lower alkylene with up to 4 C atoms separated in the residue R

from the nitrogen atom with 1 to 3, preferably 2 C atoms such as methylene,. 1,3-propylene or preferably ethylene, alk means methylene, 1,3-propylene or above all ethylene, R^means carboxy,<:>lower oxycarbonyl with up to 4 C atoms in the alkoxy part, 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-dilower alkylcarbamyl with up to and including 4 C atoms in each alkyl part such as methyl-, ethyl- or dimethylcarbamyl, and R 2 means hydroxy, lower alkoxy with up to and including 4 C atoms such as methoxy, phenyl lower alkyl with 7 to and including 10 C atoms, such as benzyloxy, lower alkanoyloxy with up to and including 4 C atoms, such as acetoxy, amino or lower alkanoylamino with up to and . with 4 C atoms, such as acetylamino, as well as their tautomers and/or salts, especially pharmaceutically usable acid addition salts.

The invention relates in particular to compounds of formula I in which R means substituted or in one or two of the positions 1 and 4 to 7 substituted the 3-indolylphide, the substituents in the 1-position being considered lower alkyl, such as methyl, as substituents/in the 4- to 7 -position, lower alkoxy with up to and including 4 C atoms such as methoxy, halogen of atomic number up to and including 35, such as chlorine, and/or lower alkyl with up to and including 4 C atoms such as methyl, alk means ethylene, Z means 1.1 -, 1,3-or preferably 1,2-lower alkylene with up to and including 4 C atoms such as ethylene, further 1,3-propylene, or methylene, R^means lower alkoxycarbonyl with up to and including 4 C atoms in the lower alkoxy part, which methoxycarbonyl or ethoxycarbonyl, and R 2 means hydroxy or amino, and their tautomers, and/or salts, especially pharmaceutically usable acid addition salts.

The invention preferably relates to the preparation of compounds of formula I, in which R means unsubstituted or 1 or 2 of positions 4 to 7 with lower alkyl with up to and including 4 C atoms such as methyl, and/or halogen with atomic number up to and including 35 such as chlorine, substituted 3-indolyl, Z means linear 1,1-,.1,3- or preferably 1,2-lower alkylene with up to 4 C atoms such as methylene, 1,3-propylene or preferably

-ethylene.; .alk .means ..methyl a well ler -rather than . everything. ethylene, ..R^ .means lower alkoxycarbonyl with .up to 4 C atoms in the alkoxy part, such as methoxy or ethoxycarbonyl and R 2 means hydroxy and their tautomers. and/or salts, especially pharmaceutically usable acid addition salts. The invention primarily relates to the preparation of compounds of formula T, in which R means unsubstituted or in the 4- and 7-position with lower alkyl, with up to 4 C atoms such as methyl, substituted 3-indolyl, Z and alk means ethylene, R 2 means lower alkoxycarbonyl with up to 4 C atoms in the lower alkoxy part, such as methoxycarbonyl or ethoxycarbonyl, and R 2 means hydroxy, as well as their tautomers and/or salts, especially pharmaceutically usable acid addition salts.

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

The invention relates to resp. preferably the preparation of the compounds of formula I, in which the azacycloaliphatic ring is saturated, and R^ are cis-placed to each other.

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

a) for the preparation of the compound of formula I, in which alk means ethylene, is reduced in a compound of formula

in which A Q means an acid anion and R^"...means etherified, acylated or protected hydroxy, or acylated or protected amino, the excess double bond to a single bond and optionally cleaved by the presence of protective groups or

b) a compound of formula

in which X^means a group of formula -CH=R21, -C(X2)'=R2' or cyano, X2 means a cleavable group, or a salt thereof, is cyclized, or

c) a compound of formula

wherein R^ means a in the 3- to 6-position optionally as for

.positions 4 to 7 of the radical R indicated substituted phenyl radical, R^ means hydrogen, or a substituent prescribed for the 1-position of R, and R,- means hydrogen, or a substituent prescribed for the 2-position of R, or a tautomer, and/or a number thereof, are ring-closed to corresponding compounds of formula I or

d) compounds with formula

where X3 means a. nucleofuge cleavable group or their tautomers, and/or salts are reacted with each other, or e) for the preparation of a compound of formula I in which alk means ethylene, a compound of formula or a tautomer or a salt thereof is cyclized, or f) a compound with formula

wherein 1 means one to optionally esterified or amidated

carboxy transferable residue or a tautomer and/or a salt thereof, R^' is optionally transferred to esterified or amidated carboxy, or

g) for the preparation of compound of formula I, in which the azacycloaliphatic residue has a double bond, is condensed

with a compound of formula

in which R' means a 1-position substituted or intermediately protected 3-indolyl residue R and I^"' means a group R^ or intermediately protected hydroxy, or in the case of corresponding keto- or iminotautomers thereof, with a compound of formula R,-Xr(Via), wherein X, means a cleavable

X b b

residue, and optionally the protecting group(s) are split off or

.h) .in a compound with formula

wherein X4 means one to a group with R^transferable residue, X^ is transferred to a group R^, or

_i) . for the preparation of compound of formula I, in which the azacycloaliphatic residue is monounsaturated, R2 means hydroxy, resp. the tautomeric oxo compound rearranges a connecting

see with formula

or

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

with each other, or

k) for the preparation of compound of formula I, wherein

Z separates the residue R from the nitrogen atom with 1 C atom, compounds with formula are condensed

with an oxolave alkane, and

respectively if desired, the compounds obtained according to the method are transferred into another compound of formula I,

an isomer mixture obtained according to the method is divided into components, and the isomer with formula I is isolated a diastereomer mixture obtained according to the method, resp.

an antimer mixture, is split into the diastereomeric resp. one-. enantiomers, and the desired diastereomer resp. enantiomers

is isolated, and/or a free compound obtained according to the method is converted into a salt or a according to the method in the free compound or in another salt.

Method variant a)

The anion A Q is, for example, the anion of a strong protonic acid which is able to transfer alcoholic hydroxy to reactive esterified hydroxy, e.g. a halide ion, such as chloride, bromide or iodide, or a sulphonanion, especially the anion of an aliphatic or aromatic sulphonic acid, e.g. methanesulfonate, ethanesulfonate or methosulfate anion, resp. benzenesulfonate, p-toluenesulfonate or p-bromobenzenesulfonation. I^" is particularly preferred hydroxy R^, or protected hydroxy. The reduction of the excess double bond takes place in the usual way, for example with the action of a dilate metal hydride such as an alkali metal trilavereal oxyaluminum hydride, e.g. of lithium tertiary butyloxyaluminum hydride or a optionally substituted alkali metal borohydride such as lithium borohydride, potassium borohydride, sodium borohydride, or sodium cyanoborohydride. The reaction is preferably carried out in a suitable solvent. Common is, for example, for the reaction with lithium tritertiary butyloxy aluminum hydride an ethereal solvent, such as diethyl ether, dioxane or tetrahydrofuran, and for the reaction with optionally substituted alkali metal borohydrides, especially lower alkanols, such as methanol or ethanol, further water.

Intermediates II can for example be obtained by reaction of compounds, with formula in which A means a reactive esterified hydroxy corresponding to the anion A 0.

Procedure b)

In intermediates III, a cleavable residue X_ means optionally etherified or esterified hydroxy such as hydroxy, aliphatic, araliphatic or aromatic etherified hydroxy, e.g. lower methoxy, phenyl lower oxy or phenoxy, with a carboxylic acid esterified hydroxy, e.g. lower alkanoyloxy, e.g. acetoxy, or halogen, r. exs. chlorine or bromine, or an optionally substituted amino or ammonium group, such as amino, optionally anilino, mono- or diloweralkylamino, e.g. mono- or dimethylamino, or trilower alkylammonio, e.g. trimethylammonio.

The intramolecular condensation takes place in the usual way, for example in the presence of basic condensation agents such as an alcoholate, amide or hydride, an alkali metal or alkaline earth metal, e.g. an alkali metal or alkaline earth metal alcoholate, e.g. of sodium methanolate, magnesium methanolate, sodium methanolate, or potassium tertiary butanolate, an alkali metal amide, f., ex. of sodium amide, lithium diisopropylamide, sodium N-methylanilide or sodium diphenylamide, or of a

-alkali metal-. or -alkaline earth metal hydride, e.g. of sodium hydride or calcium hydride, if necessary during cooling or heating, e.g. at approx. -10°C to +120°C and/or under inert gas, such as nitrogen. In a preferred embodiment of method variant b), for example, a compound with formula

in which R^' means oxo or imino, is subjected to the treatment with one of the aforementioned bases, in particular with an alkali metal

lower alkanolate, e.g. with sodium methanolate or sodium ethanolate. Thereby, the compounds XV are cyclized to a compound of formula I, in which the azacycloaliphatic ring does not have a double bond, and R2 means hydroxy or amino. Starting materials XV are obtained, e.g. being a reactive indol-3-yl alkanol ester of formula

in which X^ means reactive, esterified hydroxy, is condensed with a 3-amino acid compound of the formula r^N-CI^-CH,,-(XVa), and the formed intermediate of formula in which Rg means hydrogen is reacted with acrolein or an optionally functionally modified aldehyde with formula Y^-alk-CH= R2' (XVII, Y, = reactive esterified hydroxy, R2' = optionally acetalized oxo or imino). In another preferred embodiment of method variant b) one is cyclized with the reaction of a compound of formula -R-Z-NH2 (XVIII), with the approximately double molar amount of a compound of formula "Y^—CH^H^-R -^1' (XlXa, Y± = reactive .esterified. hydroxy, R^" esterified. carboxy), resp. CH2=CH-R1" (XlXb, R1" = esterified carboxy), formed compound of formula

e.g. in the presence of a metal base, such as an alkali metal alcoholate, for example, of sodium methanolate, to a compound of formula I<1>, in which R2<1> means oxo, resp. the corresponding tau-.tomer e of formula I... Esterified-carboxy R-^" ±>ether e.g.

■methoxycarbonyl.

For example, compounds of formula I can be obtained, in which

Tl means substituted or .in 5-position with methoxy substituted 3-indolyl, Z and alk means ethylene, R.sup. means methoxycarbonyl, and means hydroxy or amino. or if the azacyclic ring does not have a double bond, lower alkanoyloxy with up to 4 C atoms, e.g. acetoxy, and their tautomers, and/or salts thereof, being a compound of formula

in which R means optionally in the 5-position with methoxy substituted 3-indolyl, Z means ethylene, R^ means methoxycarbonyl, and X-^ means methoxycarbonyl, cyano or a group -CH=R21 , in which R2' means oxo or imino, is cyclized and if desired in a compound obtained according to the method, in which R2 means hydroxy or amino, and the azacycloaliphatic ring has a double bond, resp. in its keto or iminotautomers, the double bond is reduced to the single bond, resp. the oxo or imino group of the hydroxy or amino group, in a compound obtained according to the method, in which R^ means hydroxy and the azacycloaliphatic ring does not have a double bond, the hydroxy group is esterified to lower alkanoyloxy, and, if desired, a a compound obtained according to the method to a salt, or a salt formed according to the method to the free compound or to another salt. Thus one obtains, for example, 4-hydroxy-1-(2-(1H-indol-3-yl)ethyl)2,5,6-pyridine-3-carboxylic acid methyl ester or 1-/~ 2-(1H-indol-3-yl)ethyl 7-piperidin-4-one-3-carboxylic acid methyl ester or a salt thereof,' and isomeric mixtures of cis- and trans-4-hydroxy-1-/ 2- (1H-indol-3-yl)-ethyl 7~piperidin-3-carboxylic acid methyl ester, as well as cis- and trans-4-acetoxy-1-(1H-indol-3-yl)ethyl/-piperidin-3- carboxylic acid methyl ester and.resp..5-methoxy substitution products thereof and their salts.

Method variant c)

The rearrangement, where ammonia is split off in the form of Fischer's indole synthesis, can take place in the usual way, for example by acid treatment, i.e. the effect of a suitable proton or Lewis acid. As protonic acid, mineral acids, such as sulfuric acid, phosphoric acid, likewise hydrogen chloride in a lower alkanol, such as ethanolic hydrochloric acid, organic sulphonic acids, such as lower alkanol, e.g. methanesulfonic acid, or optionally substituted benzenesulfonic acid, such as benzene or p-toluenesulfonic acid, but also organic carboxylic acids, such as lower alkanoic acids, e.g. acetic acid.

Suitable as Lewis acids are, for example, coordinatively unsaturated heavy metal compounds, such as coordinatively unsaturated halides of boron, aluminium, antimony, zinc, copper, nickel, iron, chromium or tin, e.g. zinc chloride, or copper I chloride, resp. - bromide. The turnover is advantageously carried out during heating, e.g. in the temperature range from approx. 60 to 170°C, if necessary under inert gas.

Intermediates IV are preferably produced in situ, as

an optionally correspondingly substituted phenylhydrazine with

- formula H^NrlH^KL, (XXI) is condensed in the usual way with a compound of formula

and if desired, the hydrazone formed is substituted with it. secondary N atom in a residue different from hydrogen<R>4-

Method variant d)

Nucleofuge cleavable groups X^ are, for example, free or

•. reactive esterified hydroxy groups such as hydroxy, halogen, e.g. chlorine, bromine or iodine, or from sulphonic acids. as lower alkane- or optionally substituted benzene-

sulfonic acids, or halosulfonic acids derived sulfonyloxy groups, e.g. methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, p-bromobenzenesulfonyloxy, or fluorosulfonyloxy.

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

Starting materials V can e.g. is produced by reacting the corresponding indole with formaldehyde of a halogen hydrogen acid,

e.g. hydrochloric acid, or is condensed with a reactive diester of a corresponding lower alkane diol, resp. is reacted with epoxy lower alkane, and the formed R-lower alkanol is, if necessary, halogenated, for example by means of thionyl chloride or phosphorus tribromide, resp. is reacted with a sulphonic acid halide, e.g. p-toluenesulfonyl chloride. For the preparation of the "compound V in which alk is - ethylene, the indole derivative can be transferred with the help of oxalyl dichloride 1 corresponding to 3—

chloroxalylindole, this is alcoholized e.g. with ethanol to the corresponding 3-ethoxyallylindole, the oxalic acid ester formed is reduced/ e.g. by means of lithium aluminum hydride in diethyl ether, and the formed 2-(3-indolyl)-lower alkanol if necessary then/- reactively esterified, e.g. by reaction with a halogenating or sulfonylating agent, e.g. by thionyl chloride, phosphorus tribromide or a sulfonic acid chloride, such as p-toluenesulfonic acid chloride.

Starting substance f is VI _can ..f. ex^ .1 the ..compound of formula in which X^means a group of formula -CH=R2<1>, -C(X2)=R2' or cyano, where X2 means a cleavable residue or a salt thereof, is cyclized intramolecularly by treatment with an alkali metal lowereal anolate. However, one can also intramolecularly cyclize a 5-amino-3-R2<1->2-methylene-pentane-1-carboxylic acid or a 2-aminomethyl-3-R2<1->pent-4-1-carboxylic acid, resp. an ester or an amide thereof.

Method variant e)

The cyclization of compound VII takes place spontaneously or

by base treatment, since alkali metal alkanolates, amides or hydrides can be used as bases, e.g. sodium methanolate, potassium tertiary butanolate, sodium hydride, lithium N,N-diisopropylamide or sodium hydride. Suitable solvents are, for example, dimethylformamide.

Intermediate products VII are preferably prepared in situ and -reacted without isolation, according to the invention, as the corresponding 2-halomethyl 1-3-R2'-pent-4-ene-carboxylic acid ..or a. ester or an amine thereof in the presence of a base such as one of those mentioned, e.g. of sodium hydride, N-ethyl-N,N-di-isopropylamine, sodium hydroxide or potassium carbonate, is reacted with a compound of formula R-Z-NH2(XVIII), e.g. in dimethylformamide, N-methylpyrrolidone or dimethylsulfoxide.

The necessary starting materials can be obtained, e.g. whereby a compound with the formula R-Z-X^ (V, X^= bromine) is reacted with ammonia, resp. an acryloylacetic acid ester is ketalized with an orthoformic acid ester, e.g. trimethoxymethane, the ketal formed is heated, under acidic conditions, and the enol ether formed is halogenated on 2-methyl groups, e.g. is brominated using N-bromosuccinimide. However, another 2-methyl-3-R2-penta-1,4-diene-carboxylic acid ester can also be brominated, resp. 2-Methyl-3-R2pent-4-ene carboxylic acid ether with N— bromosuccinimide.

According to method variant f) in any esterified or amidated carboxy transferable residue R^1 is, for example, solvolytically in these transferable residues which are esterified or amidated carboxy R1 variously functionally modified carboxy, for example anhydrous carboxy, trihalo-methyl, esterified hydroxydihalomethyl, e.g. trilower-alkoxydichloromethyl, etherified trihydroxymethyl, e.g. tri-lower oxymethyl, etherified or esterified C-hydroxy-iminomethyl, e.g. C-lower alkyloxyiminomethyl, or 2-oxazinyl groups, such as 4,4- or 5,5-dimethyloxazinyl-(2) or 4,6,6-trimethyldihydro-oxazinyl-(2), C-halogenimino-methyl or cyano.

The solvolysis takes place in the usual way, for example by hydrolysis, alcoholysis, i.e. by reaction with an alcohol or ammonolysis, resp. aminolysis, i.e. reaction with ammonia or an amine that has at least one hydrogen atom.

During the hydrolysis Jean, for example, one of the aforementioned -functional carboxy derivatives is transferred to the carboxylic acids with formula T (R.^ = carboxy), further ortho-anhydride spheres,. ortho ester and

-iminoethers .to esters with formula 1 (R^= etherified carboxy) and iminoesters, amidines resp. nitriles.in amides (Rx = amidated carboxy). The hydrolysis takes place in the usual way by treatment with water, if necessary in the presence of a hydrolysis agent, in a solvent or diluent during cooling or heating, for example in temperature ranges from approx. 0 to 100°C, and/or under inert gas, such as nitrogen, hydrolysis agents are, for example, acidic or basic hydrolysis agents. Acid hydrolysis agents are e.g. protonic acids, such as mineral acids, e.g.

sulfuric acid, such as halogen, e.g. hydrochloric, bromic or hydroiodic acid, or phosphoric acids, sulphonic acids, such as p-toluene sulphonic acid or carboxylic acids, e.g. lower alkanoic acids,

e.g. formic or acetic acid. Basic hydrolysis agents are. for example hydroxides or carbonates of alkaline earth metals, e.g. sodium or potassium hydroxide, sodium or potassium carbonate, or calcium hydroxide, or nitrogen bases, such as ammonia, or organic amines, such as tri-lower alkylamines, piperidine or benzyltriethylammonium hydroxide. Solvents or diluents are, for example, water-miscible organic solvents, alcohols, e.g. lower alkanols, ketones, e.g. di-...lower alkyl ketones, N,N-dilower alkyl lower alkanoic acid amides, resp. N-lower alkyl lower alkanoic acid lactans, e.g. dimethylformamide or N-methylpyrrolidone, or dilave alkyl sulfoxides, e.g. dimethyl sulfoxide.

By hydrolysis, for example, acid anhydrides such as mixed anhydrides with carboxylic acid or inorganic acids can be transferred to esters of formula I (R^ = esterified carboxy).

The alcoholysis takes place in the usual way, if necessary in the presence of a condensing agent, in a solvent under cooling or heating, e.g. in the temperature range from approx. 0° to 150°C, in a closed vessel, and/or under inert gas such as nitrogen. Condensing agents are, for example, acidic condensation agents, such as mineral acids, e.g. sulfuric acid or halogen, such as hydrochloric, bromic or hydroiodic acid, or above all basic condensing agents, such as alkali metal alcohols. of corresponding alcohols such as alkali metal lower alkanolates, e.g. sodium methanolate or sodium ethanolate, alkali metal hydroxides or carbonates, e.g. sodium or potassium hydroxide or potassium carbonate, or tertiary nitrogen bases, such as heteroaromatic nitrogen bases, e.g. pyridine or trilower alkylamines, e.g., triethylamine.

. As solvents, it comes next to a surplus

of the relevant alcohol or the applied tertiary nitro-

gene base, for example in consideration of ethers, such as dilower alkyl or lower alkylene ethers, e.g. diethyl ether, tetrahydrofuran or dioxane, hydrocarbons, such as aromatic or araliphatic hydrocarbons, e.g. benzene, toluene or xylenes, N,N-dilower alkyl lower alkanoic acid amides, resp. N-lower alkyl lower alkanoic acid lactams, e.g. dimethylformamide or N-methylpyrrolidone, or dilave alkyl sulfoxides,

e.g. dimethyl sulfoxide.

In the case of ammono- or aminolysis, for example, acid anhydrides such as mixed anhydrides with carboxylic acid or mineral acids can be transferred into amides of formula I (R^ = amidated carboxy). •Ammono- or the amidolysis takes place in the usual way if necessary in the presence of a condensing agent in a solvent during cooling or heating, e.g. in a temperature range from approx. 0 to 150°C. In a closed vessel and/or inert gas and nitrogen. Condensing agents are, for example, basic condensing agents such as alkali metal hydroxides or carbonates, e.g. sodium or potassium hydroxide or potassium carbonates or tertiary organic nitrogen bases such as heteroaromatic nitrogen bases, e.g. pyridine or tri--lower.ealkylamino.ino, _f....ex:.. triethylamine..--Som. solvent, there is an excess of any organic amine used, e.g. in consideration of ethers - such as dilower alkyl or lower alkylene ethers, - f. e.g. diethyl ether,-tetrahydro- , furan or dioxane, hydrocarbons, such as aromatic, or araliphatic hydrocarbons, e.g. benzene, toluene or xylene, N,N-dilower alkyl lower alkanoic acid amides, resp. N-lower alkyl lower alkanoic acid lactams, e.g. dimethylformamide or N-methylpyrrolidone or dilave alkyl sulfoxides, e.g. dimethyl sulfoxide.

Cyano R^ can further by reaction with a corresponding alcohol or an amine which has at least one hydrogen atom, in the presence of a strong acid, e.g. of hydrochloric or hydrobromic acid is transferred

.to the corresponding amino ether resp. amidino grouping, and then.with mild hydrolysis to esterified carboxy resp. substituted carbamyl R^. However, the formation of the further reaction of the iminoether groupings can also take place in situ, for example when the nitrile is heated in the presence of ammonium chloride in an amount (approx. 1 to 5% by volume) of aqueous alcohol. Further to optionally esterified carboxy transferable residues R^' is, for example, oxidative to these transferable residues as to carboxy R^ oxidizable from organic carboxylic acid derived acyl groups or hydroxymethyl groups, further optionally to the 5-position substituted as dilavereal oxy-.methyl-containing 2-furyl. For carboxy oxidizable from organic carboxylic acids derived acyl R^<1> is, for example, substituted e.g. in the 2-position, in the case of free or functionally modified carboxy, halogen or oxo, and/or in the 2- and/or in the 3-position, hydroxy-containing in a higher position than the 2-position, optionally in addition optionally esterified carboxy or a phenyl group such as substituted lower alkanoyl, respectively lower alkenoyl, such as lower alkanoyl, especially optionally in hydrate form, enol ether form, e.g. as enolets with an alcohol of formula J^-QH, in which Jl .means a Jiy alcohol is a lower alkyl residue, such as acetate, e.g. dilower alkyl or lower alkylene acetal, or acylal, e.g. as dilave alkanoyloxy- or dihalomethyl group present~formyl, further acetyl-propionyl, pivaloyl, etc., optionally functionally modified as esterified or amidated oxalo, e.g. oxalo or lower alkoxy oxalyl, 2-mono-, 2,2-di-, or 2,2,2-tri-halo lower alkanoyl, e.g. mono-, di- or trichlororace-tyl, 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. glycolpyl, or optionally functionally modified, e.g.: esterified or amidated 3-carboxy-2,3-dihydroxypropionyl, such as tartronoyl or lower alkoxy tartonoyl, or optionally with a phenyl group substituted lower alkenoyl, e.g. acryloyl, methacroyl, crotonyl, cinnamoyl, etc. Further groups R1 are etherified hydroxymethyl groups such as lower alkoxymethyl, can be oxidized to esterified carboxy, such as lower alkoxycarbonyl, R-^.

The oxidation takes place in the usual way by reaction with a suitable oxidizing agent, preferably in a solvent or diluent, if necessary during cooling or heating, e.g. at approx. 0 to 10 0°C in a closed vessel, and/or 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, per compounds such as hydrogen peroxide, metal peroxides, e.g. nickel peroxide, percarboxylic acid and their salts or organic peracids, e.g. m-chloroperbenzoic acid, phthalmonoperic acid or peracetic acid, or their salts, oxidizing oxygen acids or their salts or anhydrides, such as hypohalic acids and their salts, e.g. sodium hypochloride, halogen acids and their salts, iodic acids, periodic acids, j.

potassium iodate, sodium periodate or potassium iodate, nitric acid or nitric acid and their salts and anhydrides,

•J:.. eg . potassium nitrate,. sodium nitrite, nitrous oxide, dinitrogen trioxide, or nitrogen dioxide. or oxidized with

heavy metal compounds, such as chromium-YI-, chromium-iv-, ..manganese—IV-, ..manganese-VII-, . silver-II-, copper-II-, mercury-II-, vanadium-'V-, or bismuth-II compounds, e.g. sodium dichromate, potassium dichromate, chromium trioxide, manganese dioxide, potassium permanganate, silver II oxide, copper II oxide, mercury oxide or bismuth oxide. - Inert solvents are, for example, above the resp. for the use of future oxidizing agents inert solvents, such as water, ketones, e.g. acetone, carboxylic acid and their anhydrides, e.g. acetic acid or .acetic anhydride,. halohydrocaxbones, e.g. tetrachloromethane or aromatics or heteroaromatics... e.g., benzene or pyridine or their mixtures.

Optionally, third oxalo R^' with, formula -C(=0)-R can be further oxidized during carbonylation, for example in the presence

of a suitable oxidizing agent, if necessary during cooling or heating, e.g. at approx. 0 to 100°C in an inert solvent in a closed vessel, and/or under an inert gas such as nitrogen. Suitable oxidizing agents are, for example, per compounds, such as hydrogen peroxide or percarboxylic acids, e.g. percarboxylic acid or organic percarboxylic acids, i.a. peracetic acid, permauric acid, perbenzoic acid, etc., further halooxynic acid and their salts, such as hydrochloric acid or alkali metal chlorides, or oxidizing metal compounds such as silver oxide, potassium permanganate or chromium trioxide. Suitable solvents are, for example, optionally water-containing ketones, such as acetone or carboxylic acids, such as acetic acid.

The compounds of formula VIII mentioned as starting materials

can, for example, be prepared as compounds with formula

• wherein means a reactive-esterified hydroxy, e.g. halogen, such as chlorine, bromine or iodine, - is condensed with each other, or a compound of formula in which R<*>means a substituted in the I position, and/or intermediately protected, 3-indolyl residue R, by reaction with a metal base, -.such as ..an alkali metal alkanolate, -hydride or -^arnide, e.g. with sodium methanolate, sodium hydride, sodium

amide or'lithium diisopropylamide, is reacted with phosgene, a lower alkanoyloxycarbonyl chloride, tetrachloromethane, lower alkoxytrihalomethane, trilavereal oxyhalomethane, dicyan, resp. a halogen cyan, an acyl halide or di-acyl oxide of formula R^'-halogen (XXVa), resp. R^-O-R-^<1>(XXVb) with formaldehyde or with a halomethoxy lower alkane. Intermediately protected residues R<1> are, for example, in and of themselves unsubstituted and/or in the 4- to 7-position, hydroxy-containing in the 1-position or by the hydroxy group, with usual protective groups, for example with esterified or etherified hydroxymethyl groups, such as pivaloyloxymethyl, methoxymethyl, 2-chloroethoxymethyl or benzyloxymethyl, tetrahydrofuranyl or trilower alkylsilyl, such as trimethylsilyl, intermediately protected indolyl residues.R. The protecting group is introduced, for example, by reacting the compound VI which is to be protected by a corresponding halogen derivative, resp. with chloroiodomethane (Cl-Cr^I), an alkali metal, e.g. sodium pivalate, -methanolate, -1,2-dichloroethanolate or -benzyl alcoholate and resp. with dihydropyran.

However, compounds with formula can also

wherein one of the residues X_ and Xfi means a metallic residue, e.g.

I II/2 II I

of formula -M ., -M' or -M -Hal, where M means an alkali metal radical, e.g. lithium, M11 means an alkaline earth metal radical, e.g. magnesium, cadmium or zinc, andHal means halogen, such as chlorine, bromine or iodine, others mean reactive esterified hydroxy, e.g. halogen such as chlorine, :bromine or "iodine, or:organic sulfonyloxy, such as lower alkane-"resp. optionally substituted benzenesulfonyloxy, e.g. methane,

benzene- or p-toluenesulfonyloxy,, R2" means etherified or protected hydroxy or protected amino, e.g. etherified hydroxy R2, silyloxy such as trilower alkylsilyloxy, e.g.

trimethylsilyloxy, but also triphenyl lower realoxy, e.g. trityloxy, or silylamino, such as trilower alkylsilylamino, e.g. trimethylsilylamino, however, can also mean phenyl, diphenyl or triphenyl lower alkylamino, such as benzylamino, diphenylmethylamino, tritylamino, and R^ means especially etherified trihydroxymethyl, e.g. lower alkoxymethyl, a 2-oxacinyl group or optionally substituted 2-furyl in the 5-position, are reacted with each other, and the protective groups or

-group splits off.

The compounds VIII, in which R^' means cyano, can further be prepared as a compound of formula

in which X1 means a group of formula -CH=R2' or -C(X2)=R2', X2 means a cleavable residue, e.g. lower alkoxy or halogen, or means cyano, is cyclized in the presence of a metal base, e.g. an alkali metal alcoholate, such as of .sodium methanolate or -ethanolate. This method is particularly suitable for the preparation of compound VIII, in which the azacyclic ring has a double bond, R^1 is cyano, and R2 means amino, in which one starts from compounds XXVIII, in which X^and R^<1>both mean cyano, as well as for the preparation of compounds VIII, in which the azacycloaliphatic residue does not have a double bond, R^1 means formyl or cyano, and R2be-tyre hydroxy, which is assumed from compounds VIII, wherein X^ means formyl, and R^ means formyl or cyano. From compound VIII obtainable according to the first-mentioned method of formation, in which R - means amino, and R1' means cyano, can by mild hydro lyse the corresponding compounds VIII, in which R2 means hydroxy and R11 is cyano, and of these by reaction with ammonium chloride,

or .. "chlorohydrogen and an alcohol are prepared by corresponding compounds VIII, in which R2 means optionally etherified hydroxy, and R^' means etherified C-hydroxyiminomethyl, which further reacts in situ with hydrolysis of R^<1> to esterified carboxy R^.

In starting materials Via according to method variant g), cleavable residues are, for example, the halogen atom or sulfonyloxy groups, e.g. benzene- or p-toluenesulfonyloxy.

Dom compounds Via, for example, halogenocarboxylic acid esters, resp. carbamoyl halides of formula R-^-halogen. Protected hydroxy 1*2"' is, for example, with the meaning given under method variant a), likewise, in the 1-position protected 3-indolyl.

The reaction takes place, for example, in the presence of a basic condensing agent, such as an alcoholate, amide or hydride, an alkali metal or alkaline earth metal, e.g. an alkali metal or alkaline earth metal alcoholate, e.g. of sodium methanolate, magnesium methanolate, sodium ethanolate, or potassium tertiary butanolate, an alkali metal amide, e.g., of sodium amide, lithium diisopropylamide, sodium N-methylanilide or sodium diphenylamide,.or, an alkali metal—.or alkaline earth metal— hydride, ..f . e.g....of sodium hydride or calcium hydride, if -necessary during cooling or heating, e.g. -at approx. -10°C tii"-t-12 0°C, and/or under inert gas and nitrogen.

The starting substances IX can, for example, be obtained when a compound of formula R-Z-X^ (V, X^ .'• = halogen) is condensed with a compound of formula or a tautomer thereof, e.g. with 4-piperidone. Thereby, the residue R and/or hydroxy R2 can be present in a protected form, or protected before the reaction with the reaction components,

e.g. is silylated to trimethylsilyloxy.

Procedure h)

A residue transferable to R2 is, for example, by solvolysis,

i.e. reaction with a compound of formula R2H (XIII) or a salt thereof, to a group of R2transferable residues, for example reactive esterified hydroxy groups, such as halogen atoms with e.g. chlorine, bromine or iodine. To hydroxy transferable residues X., are further diazonium groups, e.g. of the formula -N2 A , where A means the anions -.of a strong acid,

as a mineral acid, e.g. chloride, or sulfate ions, or ethers resp. acylated hydroxy groups R2, resp. optionally acylated amino groups R2.

The solvolysis takes place in the usual way, for example in the presence of

a base, such as an alkali metal or alkaline earth metal hydroxide, e.g. of sodium or potassium hydroxide or a tertiary nitrogen base, e.g. a tri-lower alkylamino, such as tri-ethylamine, or a heteroaromatic nitrogen base such as pyridine, -resp. a quaternary ammonium hydroxide, such as benzyl-trimethyl-ammonium hydroxide, or when compound VIII is used in the form of a metal salt, e.g. of formula. R^ Æ.(.Xllla) , in which M means an alkali metal cation" such as the sodium ion. Preferably one works in the presence of a solvent or diluent, e.g. in an excess of the reaction components XIII and/or one of these miscible inert solvents, if necessary during cooling or heating, for example in a temperature range from approximately 0 to 120°C, and/or under inert gas and nitrogen.

Compound X can, for example, be produced by conversion of

•the connection with the formulas

wherein X means esterified hydroxy, e.g. halogen, in the usual way, for example in the presence of a basic condensing agent, such as a tertiary organic nitrogen base, e.g. of pyridine, or a trilower alkylamine, such as of triethylamine. Compounds X, in which X^means halogen, since halogen or halogen hydrogen is added to a compound with the formula, and in the former cases, halogen hydrogen is split off again. Compound X, in which X^means a diazonium group, is prepared e.g., e.g. wherein a 'compound of formula I,' in which "R^ means amino, is diazotized, e.g. by reaction with nitric acid, or, with ammonium or ..an alkali metal nitrite, e.g. with sodium nitrite in Jiærvær of mineral acids with formula HA.

Method variant i)

The rearrangement of compounds, XI .to compound of formula I, in which the azacycloaliphatic ring has a double bond, and R 2 means hydroxy, resp. to their tautomers of formula I<1>, in which R.,', means oxo, ..takes place for example by acid treatment, especially treatment with Lewis acid, i.e. a coordinatively unsaturated halide of an element from the groups Ilb, IUb or Va from the periodic table, e.g. with zinc chloride, aluminum trichloride, boron trifluoride, or antimony pentachloride, for stepwise with a boron trifluoride etherate, e.g. complex of boron trifluoride with diethyl ether (boron trifluoride etherate), however, can also be effected by treatment with a strong protonic acid such as a mineral acid, e.g. with sulfuric acid or polyphosphoric acid, or with p-toluenesulfonic acid in benzene. If necessary, one works in the presence of an inert solvent, and/or during cooling or heating, e.g. in the temperature range from approx. 0° to 120°C, and/or under inert gas such as nitrogen.

Compounds XI are prepared, for example, as a compound of formula

is usually epoxidized, for example, by reaction with a peroxy compound, such as with hydrogen peroxide or especially an organic hydroperoxide compound, e.g. with ..tertiary butyl hydroperoxide, peracetic acid, perbenzoic acid, m-: ..kloxperbenz osy r e,. -permonof number that ..el 1 is..ii rubbing.

Method variant j)

The reaction of compounds XLI and XIII takes place in the usual way, for example in the presence of a base, such as an alkali metal or alkaline earth metal hydroxide, e.g. of sodium or potassium hydroxide, or a tertiary nitrogen base, e.g. a trilower alkylamino, such as triethylamino, or a heteroaromatic nitrogen base such as pyridine, resp. quaternary ammonium hydroxide, such as benzyl trimethyl ammonium hydroxide or when using compound XIII in the form of a metal salt, e.g.

■ e.g. 3v..formula"R2ejfl® {XIIla) , in which M® means an alkali metal cation, such as the sodium ion. It is advantageous to work in the presence of a solvent or diluent, for example in a

excess of the reaction components XIII and/or an inert solvent miscible with this, if necessary during cooling or heating, e.g. in a temperature range from approx. 0° to 120°C, and/or under inert gas such as nitrogen.

Starting materials XII are obtained, for example, when the compound of formula

in which X^means reactive, esterified hydroxy, e.g. halogen, are condensed with each other in the usual way, for example in the presence of a basic condensing agent such as a tertiary organic nitrogen base, e.g. of pyridine, or a trilower alkylamine such as" of triethylamine.,

Method variant k)

Oxolave alkanes suitable for introduction of the residue Z,

are, for example, lower alkanes, i.e. 1-oxola lower alkanes, can

however, also be dilave alkyl ketones, e.g. "2-oxo-..lower alkanes. The reaction of these with compounds of formula IL. and .VI .takes place in the .usual. way, for example in the presence

amber a protonic acid, such as a mineral acid, e.g., of hydrochloric or carboxylic acid, e.g. of acetic acid, thereby probably forming an intermediate, the corresponding compounds with the formula R-Z-X-o. (V), . in which R x means hydroxy, which then acid-reacts without isolation according to the invention, with reaction component VI. The method variants are thus to be regarded as preferred embodiments of method variant b). ..In starting material f are can .:as-mentioned groups .R but also groups . R^ and/or.R^ resp. R2' present until medially protected form.

. Intermediately protected -residues R are* for example in and for

.seg 1-unsubstituted and/or in the 4- to 7-position hydroxy-containing in the 1-position resp. for the hydroxy groups, usual protective groups, for example, optionally substituted benzyl or benzyloxycarbonyl groups, esterified or

■V" *

ethereal hydroxymethyl groups, such as pivaloyloxymethyl, methoxymethyl, 2-chloroethoxymethyl or benzyloxymethyl, tetrahydropyranyl or trilaverealkylsilyl, such as trimethylsilyl, intermediately protected 3-indolyl residues R. Protecting groups are introduced, for example, by reacting a compound to be protected with a corresponding halogen derivative, resp. with chlorine-. iodomethane (C1-CH2I), an alkali metal, e.g. sodium pivalate,

.:-methane leaf, -1,2-dichloroethanolate, or -benzyl alcoholate, and resp. with' dihydropyran. Analogously, hydroxy-, resp. amino groups R^ or the primary amino group in starting substances, e.g. in compound XXIII, for example intermediately be protected with optionally substituted benzyl or benzyloxycarbonyl groups, esterified or etherified hydroxymethyl groups such as pivaloyloxymethyl, methoxymethyl, 2-chloroethoxy methyl or benzyloxymethyl, tetrahydropyranyl or trilower alkylsilyl, such as trimethylsilyl. Protected hydroxy is, for example, silyloxy, such as . trilower alkylsilyloxy, e.g. /trimethylsilyloxy,.' can, however, also be trifenylvareal oxy, : f v -ex. ••trityloxy. Protected -amino is, for example. silylamino, as .toilavéréalk^ .f .-ex. V^^ethyl-silyl-•amino,- can, however, also be phenyl-, diphenyl- or triphenyl-lower alkylamino, such as benzylamino, diphenylmethylamino, or tritylamino. Intermediately protected residues R^ are, for example, as cyclic iminoethers protected carboxy groups, especially optionally lower alkylenrt 4,5-dihydro-oxazolyl-(2), resp. 5,6-dihydro-oxazinyl(2), as 4,4- or 5,5-dimethyl-4,5-dihydro-oxazolyl-(2), resp. 4,4,6-trimethyl-5,6-dihydrooxazilyl-(2). The one in this too protected group Rj-. is formed in the usual way when going out. from carboxy, e.g. by reaction with -aminoisobutanol, (3-amino-2-methyl-propan-2-ol), or 4-amino-4-methyl-pentan-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-methyl-pentan-2-ol or 2-methyl-pentane-2,4-diol .

Release of intermediately protected residues, i.e. cleavage of the intermediates. 'protecting groups, takes place in the usual way, for example by hydrogenolysis, e.g. in the presence of platinum or palladium catalysts, resp. solvolysis, such as mild hydrolysis, e.g. when treated with water under neutral or slightly acidic conditions, e.g. by the effect of dilute aqueous mineral or carboxylic acids, e.g. de-diluted hydrochloric or acetic acid. During the hydrolysis of dihydro-oxazolyl and dihydro-oxazinyl groups, free carboxy groups are thereby formed.

Compounds obtained according to the method can be converted into other compounds of formula I in the usual way.

Thus, carboxyl groups can be esterified or amidated in the usual way, for example in the presence of a basic or acidic

hydrolyzing agent, such as an alkali metal hydroxide or carbonate, e.g. of sodium hydroxide or potassium carbonate, or a mineral acid, e.g. of hydrochloric or sulfuric acid, is hydrolysed to carboxy.- Esterified carboxy groups can :further

. by . omfores.thing, ie .. treatment, with a. alcohol in the presence of an acidic or basic solvolytic agent, such as a mineral acid, e.g. of sulfuric acid or a corresponding alkali metal alcoholate, or an alkali metal hydroxide, is transferred in other esterified carboxy groups R^, or by reaction with ammonia or with an amine which has at least one hydrogen atom, is transferred in amidated carboxy. Free carboxy R can in the usual way, for example, be treated with a corresponding alcohol in the presence of a mineral acid, e.g. e.g., of sulfuric acid or by transfer to a halide and subsequent reaction with a corresponding alcohol, e.g. in

presence of pyridine or triethylamine,, or by transfer

to an alkali metal salt and subsequent reaction with a reactive ester of the corresponding alcohol as a corresponding halide is transferred to the esterified carboxy.

Free or esterified carboxyl can also by reaction with ammonia or an amine that has at least one hydrogen atom and dehydration of the intermediately formed ammonium salt,

e.g. by heating or by means of N,N-dicyclohexylcarbodiimide, or by transfer into the halide subsequent reaction with ammonia, or an amine which has at least one hydrogen atom, is transferred to amidated carboxy.

Furthermore, etherified or acylated hydroxy groups ~ R^ can be converted to hydroxy, and acylated amino to free amino, for example by hydrolysis, advantageously in the presence of a suitable hydrolysis agent. Such are, for example, acidic hydrolysis agents, such as protonic acids, e.g. mineral acids such as hydrogen or sulfuric acid, for the hydrolysis of an acylated hydroxy-, resp. amino group as well as basic hydrolysis agents, such as alkali metal hydroxides or carbonates, e.g. sodium hydroxide or potassium carbonates. In an analogous way, also in the compound I, in which its azacycloaliphatic residue has a double bond, and R^-rex amino, rresp. where tautomers (I1 , B.^ = imino) are replaced by amino- or imino groups. oxo, • especially:under acidic conditions.. The liberation of.hydroxy from acylated hydroxy. However, R^ can also take place by re-esterification, e.g. by treatment with an alcoholate, e.g. alkali metal lavereal alkanolate, or an alcohol, e.g. lower alkanol, in the presence of one of the aforementioned protonic acids, or a corresponding alkali metal alcoholate. α-phenyl lower real oxy groups R^ can also hydrolytically, e.g. by treatment with hydrogen in the presence of a hydrogenation catalyst such as palladium charcoal, is transferred to hydroxy.

Conversely, hydroxy R^ can be used, resp. hydroxy or amino R2 is acylated. The etherification takes place, for example, with an etherifying agent, such as a reactive ester, e.g. a halohydrogen ester of the corresponding alcohol of formula R 2 H (XIII), e.g. a lower alkyl halide or di lower alkyl sulfate or a corresponding oxonium salt, e.g. a tri-lower alkyl oxonium tetrafluoroborate, or pentachloroantimonate. The acylation takes place, for example, by reaction with a from the corresponding carboxylic acid of formula P^H (XIII) derived anhydride, e.g. with the formula R2~O-R2(XHIb) or R,,-halogen (XIIIc) advantageously in the presence of a basic condensing agent, e.g. an alkali metal hydroxide or carbonate, or a tertiary nitrogen base, e.g. of pyridine or a lower alkyl amine such as triethylamine. Furthermore, in compound I, in which an azacycloaliphatic ring has a double bond, this can be reduced to a single bond, for example by treatment with hydrogen in the presence of a hydrogenation catalyst such as a platinum, palladium or nickel catalyst, e.g. of platinum oxide, or by reaction with a dilate metal hydride, e.g. with sodium borohydride or sodium cyanoborohydride as a reducing agent, cane sugar can also be used in the presence of baker's yeast, as the cis-isomer with 3R,4S configuration is selectively obtained. Assuming a corresponding hydroxide compound, the reduction of the double bond can also be effected by the reaction with a secondary alcohol, e.g. with isopropanol or cyclohexanol, in the presence of an aluminum alcoholate, e.g. of aluminum isopropanolate. Thereby, compound I reacts from the tautomeric form (I',R2' •=.oxo). Conversely, a compound I in which R2 is hydroxy, and the aza-cycloaliphatic ring does not have a double bond, can be oxidized by reaction with a ketone, e.g. with. acetone or cyclohexanone in the presence of a corresponding aluminum alcoholate of the corresponding unsaturated compound or tautomers (I',R2= oxo).

Also, oxo R2' can by reaction with ammonia, e.g. in methanol is transferred to amino.

Furthermore, can. i. J. position. unsubstituted . 3-indolyl residues R in the usual way" are substituted with one of the 1-substituents mentioned at the outset, 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, -lowereal alkanolate, or -hydride. In an analogous way, hydroxy R 2 can also be preferred. Hydroxy, or amino R 2 can be further acylated, for example 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, -lavereal alkanolate, or -hydride, organic carboxylic acids, also in the presence of an organic nitrogen base.Carbonyl can also be N-acylated in an analogous way.

In an analogous manner to R, carbamyl R can also be aliphatically N-substituted, further aliphatic N-monosubstituted carbamyl transferred to aliphatic N,N-disubstituted carbamyl.

Furthermore, hydroxy groups present in the residue R can be esterified, e.g. by treatment with a lower alkane carboxylic acid anhydride, resp. -halide to lower alkanoyloxy or by reaction with a reactive ester, especially bromine or chlorohydrogen ester, a lower alkanol, resp. lower alkenol, is transferred to etherified hydroxy. Two to the vicinal

Hydroxy groups bound to the C atom can also by reaction with

a reactive .diester of .lower alkanediol e.g. dihalo-lower alkane is transferred to lower alkylenedioxy groupings, or by reaction, with an oxolave alkane, i.e. lower alkanes or dilower alkyl ketone, is transferred to lower alkylidenedioxy groupings. Conversely, in esterified or etherified hydroxy groups such as lower alkanoyloxy, lower alkoxy or lower alkyl^ id ) enedioxy, the hydroxy group(s) - are released solvolytically preferably under acidic conditions.

Depending on the choice of starting materials and working methods, the new compounds can exist in the form of one of the possible isomers,

e.g. depending on the number of asymmetric carbon atoms, which

optical isomers, as in the form of an enantiomer, as antipodes resp. diastereomers or as .mixtures thereof, as enantiomeric mixture, ..f. e.g. racemates, diastereomer mixtures or

racemate mixtures.

Formed diastereomer mixtures and racemate mixtures can, due to the physico-chemical differences of the components, be divided in a known manner into the pure diastereomers or racemates, for example by chromatography and/or fractional crystallization. Formed racemates can be further divided into the optical antipodes according to known methods, for example by recrystallization from an optically active reaction agent, with the help of microorganisms, or by reaction in the 1-position and/or with hydroxy- or the amino group R2 unsubstituted, or in at least one of the positions 4- to 7 with hydroxy-:'-sy substituted end substance I in an optically active acid or , an anhydride thereof, resp. a reactive ester of an optically active alcohol, or by reaction of an ester or an acid I (R^ = optionally esterified carboxy), with an ester-forming optically active alcohol with the racemic acid, and resp. separation of the formed diastereomeric substitution product resp. ester, e.g. due to its different solubilities in the diastereomers from which an enantiomer can be liberated by the action of suitable agents. Racemates of salt-forming compounds with formula I can also be split into diastereomer mixtures by reaction with an optically reactive auxiliary compound, e.g. with an optically active acid or base in mixtures with diastereomeric salts and separation of these into diastereomers, from which the enantiomers can be liberated in the respective usual manner.

For this purpose, common optically active bases, resp. acids are e.g. strychnine, cinchonine, optically active alkaloid bases, such as brucine or 1-phenylethylamine, 3-pipecoline, ephedrine, amphetamine, etc. synthetic available optically active bases, resp. optically active carboxylic or sulphonic acids, such as D-or-L-tartaric acid, .di-o-toluyltartaric acid, malic acid, mandelic acid,

camphor sulphonic acid or chinic acid.

Furthermore, formed free salt-forming compounds can be transferred to salts in a manner known per se, e.g. by reacting a solution of the free compound in a suitable solvent, or solvent mixture with a corresponding base, resp. acid or suitable ion exchanger.

Formed salts can be converted in a manner known per se into

the free compounds such as acid addition salts, e.g. by treatment with a base, such as alkali metal hydroxide, a metal carbonate or hydrogen carbonate or ammonia, and base salts, e.g. by reaction with an acid, e.g. with hydrochloric acid.

■.Formed salts can be transferred in a known manner to other salts, acid addition salts, e.g. by treating a salt of an organic acid with a suitable metal salt, such as a sodium, barium or silver salt, of an acid in a suitable solvent, in which an inorganic salt that forms is insoluble, and thus separates from the reaction mixture .

The compound, including its salts, can also be obtained in the form of the hydrates, or including the solvent used for crystallization.

Due to the narrow relationship between the new compounds in free form and in the form of their salts, in the preceding and following free compounds and their salts, the corresponding ones can also possibly be understood: salts, resp. free connections.

The invention also relates to the embodiments of the method according to which, starting from one or the other step of the method as an intermediate compound formed, and carrying out the missing steps, or using a starting material in the form of a salt, or forming it especially under the reaction conditions.

Thus, the intermediates of formula III, VII, resp.

.VIII according to method variant e) resp. f) is formed in

in situ, and T/ide is converted without insulation.

The process for the production of the new starting materials,

e.g. with formula II, III, VIII, IX, X, XII, XVI, XXVII and XXVIII, which were developed especially for the production of the compound according to the invention, especially that of the initially characterized as preferred compound with formula I leading selection of starting materials, process for their production , as well as their use as an intermediate product is also covered by the invention.

In this connection, it is special to mention connection with

-formula XVI, which has similar nootropic properties, although also somewhat less potent than compounds with formula I, and in addition to their use as intermediates can find use in the production of these as medicinally active substances for the treatment of cerebral performance insufficiency, especially of memory disorders of different genesis, such as senile dementia or dementia of the Alzheimer type, further from the sequelae of brain trauma, and apoplexy. The invention therefore also relates to a method for the preparation of a compound with the formula

where R means an optionally substituted 3-indolyl residue, Z means lower alkylene, which separates the residue R by 1 to 3, preferably 2 carbon atoms from the nitrogen atom, R-^ means optionally esterified or amidated carboxy, and R6 means hydrogen or a group of the formula alk- R.^"1, wherein R^"1 has one of the meanings given for R1, or means cyano, hydroxymethyl, or optionally acetalized formyl, such as dilavereal oxy- or lower alkylenedioxymethyl, e.g. dimethoxy- or .diethoxy-metyi,. dioxa-2-yl, or 1, 3-dioxa-2-yl, and. alk means t methylene, ethylene, or 1,3-propylene, as well as their pharmaceutical

"useful salts, for use in/a method for treating the human or 'animal' body, pharmaceutical preparations containing these and their use as medicinally active substances, likewise compounds of formula XVI, in which R, Z, R^ and Rg have above meaning with the precaution that in compounds of formula XVI, in which R is unsubstituted and Rg is hydrogen, Z is different from ethylene, when R^ is methoxycarbonyl or ethoxycarbonyl, and their salts.

As substituents of 3-indolyl residues, for example those mentioned for the compounds of formula I come into consideration. Similarly, Z, alk and R^ have, for example, the preferred meanings indicated for the compounds of formula I, and are salts, for example acid addition resp . base salts of the same type as indicated for the compound of formula I.

The invention relates, for example, to the preparation of a compound of formula XVI, in which R, Z and R^ have the indicated meanings, and Rg means hydrogen, or a group of formula -(CH2)n~R1"1 r in which n means 2, and R^ "<1> means formyl or iminomethyl, or

.if R-^ means free or esterified carboxy, likewise means--free .or..esterified carboxy resp^ if R^ means lower alkoxycarbonyl, means formyl, hydroxymethyl or cyano, with it. precaution that in the context of formula XVI, wherein R is unsubstituted and Rb is hydrogen, Z is different from ethylene

when R 1 means methoxycarbonyl and ethoxycarbonyl, and their salts.

The invention further relates, for example, to the preparation of a compound of formula XVI, in which R means unsubstituted or in the 5-position with methoxy substituted indolyl, Z means ethylene, R^ means methoxycarbonyl and Rg means hydrogen, or a group of the formula - (CH^) n~ Ri"' > in which n means 2, and R-^'" means methoxycarbonyl .or.:formyl with the proviso that a compound of formula XVI in which R is unsubstituted and R 6 c is hydrogen, Z is different from et<y>lene , when R 1 is methoxycarbonyl or ethoxycarbonyl, and their salts.

The invention primarily relates to the preparation of such compounds of formula XVI, in which R means unsubstituted or in at least one of positions 1, 2 and 4 to 7 substituted 3-indolyl, as the substituent in position 1 is taken into account lower alkyl or lower alkenyl, in the 2-position lower alkyl, and as a substituent or substituents in the 4- to 7-position lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, hydroxy, halogen, trifluoromethyl, and/or lower alkyl(id)enedioxy bonded to neighboring C atoms, Z

means the lower alkylene, which separates the residue R from the nitrogen atom 1 to 3, preferably 2 C atoms, R^means carboxy, lower alkoxycarbonyl, optionally with lower alkyl, lower alkoxy, halogen, nitro, and/or trifluoromethyl substituted phenyl lower oxycarbonyl, 3- to 8-membered cycloalkyloxycarbonyl , carbamyl, mono- or dilower alkylcarbamyl, lower alkylene- resp. aza-, oxa-or brilaverealkylethicarbamyl, N-lower alkanoyl-bamyl, N-lower alkoxycarbonylcarbamyl, ureidocarbonyl, N<1->mono- or N',N<*->dilaverealkylureidocarbonyl, N<1>,N'-lower-.alkylene- respectively N',N'-(aza-, oxa- or thia)lower alkyleneurei-•docarbonyl, and R b'v means, hydrogen, :-or a • group of formula

-(CH2)n-R1" ' , _where n .means _1, 2 or 3, and' R1" 1 means .carboxy, .lower oxycarbonyl, optionally with lower alkyl, -lower oxy, halogen, nitro, and/or ..trifluoromethyl substituted phenyl lower alkylcarbamyl, 3- to 8-membered cycloalkoxycarbonyl, carbamyl, mono- or dilower alkylcarbamyl, lower alkylene-, resp. aza-, oxa-, or thialaveralkylenecarbonyl, N-loweralkanoylcarbamyl, ; N-lower oxycarbonylcarbamyl, ureidocarbonyl, N<1->mono- or N<1>,N<1->dilower alkylureido-carbonyl, N',N<1->lower alkylene-, resp. N',N'-(aza-, oxa-, or thia)lower alkylene, ureidocarbonyl, or otherwise cyano, hydroxymethyl, dilavereal oxymethyl or lower alkylene dioxymethyl, the lower alkylene alk having up to and including 4, the other lower residues to together up to and including 7, and in each lower substructure up to and including 4 C atoms, as well as their pharmaceutically usable salts for use in ep method for treating the human and animal body, pharmaceutical preparations containing these, and their use as medicinally active substances, likewise compounds of formula XVI, in which .R, Z, R± , and Rb, have the above meaning, with the precaution that in compounds of formula XVI, in which R is unsubstituted and Rg is hydrogen, Z is different from ethylene, when R 2 is methoxycarbonyl or ethoxycarbonyl, and their salts.

The invention relates above all to the preparation of compounds of formula XVI, in which R means unsubstituted or in one or two of the positions 4 to 7 with lower alkyl with up to and including 4 C atoms, such as methyl, lower alkoxy with up to and including 4 C atoms, which methoxy, halogen with atomic number as well as 35, such as chlorine, and/or trifluoromethyl, substituted 3-indolyl, Z means the lower alkylene with up to and including 4 C atoms separating the residue of R from the nitrogen atom 1 to 3, preferably 2 C atoms, for example methylene, 1,3-propylene, or preferably ethylene, R1 means carboxy, lower alkoxycarbonyl with up to and including 4 C atoms in the alkoxy part, such as methoxy- or ethoxycarbonyl, 3- to 8-, e.g. 5- or 6-membered cycloalkoxy-- carbonyl -scm-jcyclohexyloxycarbonyl, carbamyl.;orj N-mono-...or. N,.N-dilaveréalkylcarbamyl, with resp. even 4 C— atoms, such as methyl-, ethyl- or., dimethylcarbamyl, and Rg means

..hydrogen, or a group of formula -(CH2)n-R<MI>, in which n means 1 or 2, and R^"' means carboxy, lower alkoxycarbonyl with up to 4 C atoms in the alkoxy part, such as methoxy or ethoxycarbonyl . up to and including 4 C atoms, such as methyl, ethyl or dimethylcarbamyl, cyano, hydroxymethyl, formyl, or dilavereal oxymethyl, resp., iaverealkylenedioxymethyl, with resp. up to and including .4 C atoms in each alkoxy or alkylene dioxydel; as dimethoxy- or diethoxymethyl, resp. ethylenedioxymethyl, and ..their pharmaceutically usable salts for use in a method for treating the human or animal body, pharmaceutical preparations containing it, and their use as pharmaceutical active substances, likewise compounds of formula XVI, wherein R, Z, R^ and Rg has the above meaning with the caveat that in connection with formula XVI, in which R is unsubstituted and Rg is hydrogen, Z is different from ethylene when R 1 is methoxycarbonyl or ethoxycarbonyl and their salts.

The invention preferably relates to the preparation of such compounds of formula XVI, in which R means unsubstituted or one or two of the positions 4 to 7, a halogen with an atomic number up to and including 3.5, such as chlorine, and/or lower alkyl with up to and including 4 C atoms as methyl, substituted 3-indolyl, Z means the linear 1,1-, 1,3- or preferably 1,2-lower alkylene with up to 4 carbon atoms such as ethylene, further methylene or 1,3-propylene, R^be - lower alkoxycarbonyl with up to 4 C atoms in the alkoxy part, such as methoxycarbonyl or ethoxycarbonyl, and Rg means hydrogen, or a group of formula ~(CH2^n~Rl"''^lvor:'- n means 1 or 2, andR"<1>has the same meaning as R^, or means cyano, dilavereal oxymethyl with each up to and including 4-alkylenedioxy-C atoms, such as dimethoxy- or diethoxymethyl, lower alkylenedioxymethyl with 2 up to and including 4 .alkylenedioxy-C atoms such as 1/3-.dioxo.lan-2-yl...or 1,3-dioxan-2-yl or N,N-dilaverealkylcarbonyl each having up to and including 4 alkyl-C-• atoms such as diethylcarbamyl, and their pharmaceutically acceptable salts for use.! a method for the treatment of the human or animal body, pharmaceutical preparations containing these, and their use as medicine/similar substances, as well as compounds of formula XVI, in which R, Z, R^, Rg have the above meaning, with the precautionary rule that in compounds of formula XVI, in which R is unsubstituted and Rg is hydrogen, Z is different from ethylene, when R^ means methoxycarbonyl or ethoxycarbonyl, as well as their salts with the method for their preparation.

The invention relates above all to the preparation of such compounds, with formula XVI, in which R means unsubstituted or in the ..other.'series 14- and 7-position with .lower alkyl .with .up to and including 4 C-atoms, such as methyl, resp. in preparation with halogen of atomic number up to and including 35, such as chlorine substituted 3-indolyl,

Z means ethylene, means lower alkoxycarbonyl up to and including

4 C atoms in the lower alkoxy part, such as methoxycarbonyl or ethoxycarbonyl, and Rg means hydrogen or a group of the formula -(CH2)-R1"1, in which n means 1 or 2, or R1"' has the same meaning as R^ or means cyanodilavereal oxymethyl , each up to and including 4 alkoxy C atoms, such as dimethoxy-, or diethoxymethyl, lower alkylenedioxymethyl with 2 up to and including 4 alkylenedioxy C atoms such as 1,3-dioxolan-2-yl or 1,3-dioxan-2- yl, or N/N-dilaveral oxycarbonyl each having up to 4 alkyl-C atoms, such as dimethylcarbamyl, and their pharmaceutically usable salts for use in a method of treating the human or animal body, pharmaceutical preparations containing them , and their use as medicinal substances, likewise compounds of formula XVI, in which R, Z, R1 , and Rb, have the above meaning, with the precaution that in connection with formula XVI, in which R is unsubstituted and Rg is hydrogen, Z is different from ethylene, when R^ is methoxycarbonyl or r ethoxycarbonyl, as well as their salts.

The invention relates to resp. preferably the manufacture of

the compounds of formula XVI, where Rg means hydrogen.

The invention relates in particular to the manufacture, of the i. examples mentioned compounds with formula. _XVI and their salts, especially pharmaceutically usable salts.

The process according to the invention for the preparation of the compounds of formula XVI and their salts,< is charac-

serted by that

1) compounds with formula

R - Z - X5 (XXXII) and Xg - CH2- CH2-^(XXXIII)

wherein one of the residues Xj c and Xc b means a group of formula

—H{Rr)—H, and the other means a nucleofuge, leaving group or their salts, react with each other, or m) compound of formula or their salts react with each other, or n) a compound of formula

in which Rg means a substituted phenyl radical in positions 3 to 6, optionally as indicated for positions 4 to 7 of the residue R, R^ means hydrogen, or one of the substituents prescribed in position 1 of R, and R,, means hydrogen or one of the 2-position of R prescribed substituents, or a tautomer and/or a salt thereof, is ring-closed to the corresponding compound of formula. XVI, or

o) in a connection with formula

in which Rg' means hydrogen or a group with the formula alk-R^', and R^1 means a residue transferable to an optionally esterified or amidated carboxy R^, R^<1> is transferred to an optionally esterified or amidated carboxy, and if desired, the compound obtained according to the method is transferred to another compound of formula XVI, an isomer mixture obtained according to the method is divided into its components, the isomer of formula XVI is isolated, a diastereomer mixture obtained according to the method, resp. enantio-iron mixture, split into the diastereomers resp. enantiomers, - and the desired diastereomer • resp, enantiomers are isolated, and/or a free compound obtained according to the method, is transferred to a salt, or a salt obtained according to the method is transferred to the free compound or to another salt.

Method variant 1)

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

The reaction of compounds XXXII and XXXIII takes place in the usual way, for example in the presence of a basic condensation agent, such as a tertiary organic, nitrogen base, e.g. of pyridine or of a trilower alkylamine, such as of triethylamine. In the reaction, equimolar amounts of both reaction participants are obtained when proceeding from compound XXXII, in which R6 means hydrogen, compounds XVI, in which Rg means hydrogen. If you use reaction component XXXII in at least a double molar excess, then starting from compounds XXXII in which Rg is hydrogen, you arrive at compounds "XVI, in which Rg means a group — (CH^^-I^"1 .in which n hetyr 2, and R^"' .is.identical to R^<1>.

The preparation of compound XXXII, in which X^means a group X^, i.e. of compound V, has already been discussed in process^ - - method variant d) ...Compound XXXVII, in which X_ means a

'5

group -N(Rg)-H and Rg means hydrogen, i.e. compound XXVIII is known, they can also be obtained from the corresponding compounds V by reaction with ammonia. Compound XXXII, wherein Xj. means a group -N(Rg)-H and Rg means a group of formula alk-Rjl1 is prepared by reaction of compounds with. formula H-Z-NH2(XVIII) and X3-alk-R1"' (XXXIIla) resp. CH^CH-R^''

(XXXIIIa) or reaction of compounds R-Z-X^(V) and

H2U-alk-R1'n : (XXXIIIb) .

Following this method variant can, for example, connect

see with formula XVI, in which R, Z and R^ have the indicated meanings, and Rg means hydrogen or a group of formula -(CH2)n~R^"', in which n means 2, and R^"<1>means formyl or iminomethyl, or if R^means free or esterified carboxy, likewise means free or esterified carboxy, resp. if R^ means lower alkoxycarbonyl, means formyl, hydroxymethyl or cyano, or compound of formula XVI in which R means unsubstituted or in the 5-position with methoxy substituted 3-indolyl, Z means ethylene, and R^ means methoxycarbonyl, and Rg means hydrogen or a group of formula.-(CH2)n~R±"1 r in which n means 2 and R^"' means methoxycarbonyl or formyl, and their salts, wherein with a compound of formula

in which X^ means reactive esterified hydroxy, is reacted with a compound of formula

and the formed compound of formula XVI, in which Rb,, means /.hydrogen, is, if -desired, reacted :with acroleln .or .et. aldehyde with formula Y1-CH2CH2-CH=R21 (XVIIa), in which Y± means reactive esterified hydroxy, bg R2J means oxo, and if desired a free compound obtained according to the method is converted into a salt, or a salt obtained according to the method into the free compound or to another salt.

Method variant m)

Reaction of compound XXXVII with compound XXXIV takes place in the usual way, for example in a lower alkanol, such as ethanol, at approx. 0 to approx. 60°C.

"By the conversion of equimolar amounts of both "reaction part-takers" one obtains when proceeding "from compound XXXVII, in which

Rb is hydrogen, compound XVI, in which Rb is hydrogen. If reaction component XXXIV is used in at least a double molar excess, starting from compound (XXXVII) in which Rg means hydrogen, one arrives at compound (XVI), in which R ^means a group -(CH0)-R,"1, wherein n is 2 and R"<1>

bZ Yl L JL

is identical to . R^.

Following this process variant, for example, compounds with formula XVI can be obtained, in which R and Z have the indicated meanings, and Rb means hydrogen or a group with formula

-(CH2)n-R1"<1>, in which n means 2, as R1 and R^'1 mean free or equally esterified carboxy groups, or compounds with ...formula XVI,- in which R means unsubstituted.or for preparation with methoxy substituted indolyl, alk means ethylene, R^ means methoxycarbonyl, and Rc b means hydrogen, or a group of formula ~(CH2)n~Ri"''in which n is 2, and R^"' means methoxycarbonyl and their salts, being a compound with formula

is reacted with the approximately double molar amount of a compound of formula Y^CI^CI^-R " (XlXa) or CH2=CH-R1"

(XlXb), in which Y means reactive, esterified hydroxy, H-^" ..means _free .ell is esterified carboxyl, e.g. methoxycarbonyl, and if desired is converted according to the method obtained free compound into a salt or<_ > according to the method obtained, salt to .the free compound or, another salt.

Method variant n)

The rearrangement which ammonia is split off in Fischer's indole synthesis can take place in the usual way, for example by acid treatment, i.e. the effect of a suitable protonic or Lewis acid. Examples of protonic acids include mineral acids, such as sulfuric acid, phosphoric acids, as well as hydrogen chloride in a lower alkanol, such as ethanolic hydrochloric acid and organic sulphonic acids such as. lower alkane-, e.g. methanesulfonic acid, or optionally substituted benzenesulfonic acid, such as benzene or p-toluenesulfonic acids, but also organic carboxylic acids, such as lower alkane acids, e.g. acetic acid. For example, coordinatively unsaturated heavy metal compounds are suitable as Lewis acids, such as coordinatively unsaturated halides of boron, aluminium, antimony, zinc, copper, nickel, iron, chromium or tin, e.g. zinc chloride or copper I chloride, resp. - bromide. The conversion is preferably carried out during heating, for example in the temperature range from approx. 60 to 170°C, if necessary under inert gas.

Intermediate products XXXV can e.g. is produced as hydrazone

with formula R-,-NH-N=C (CRr-) -CH„-Z-NH~ (XXXVa) is condensed with

o b2 2

compound X,-CH0CH0-R, (XXXIII), X- = halogen), resp. CH =

D2 21 D2. CH2~R1(XXXIV) and if desired then with a compound X3-alk-R1,<M>(XXXIIIa, X3= halogen) resp. CH^CH-R^'1 (XXXIVa) , and if desired, the formed hydrazone with secondary N atom is substituted with a residue R^ different from hydrogen.

Method variant o)

For optionally esterified or amidated carboxy transferable residues R^' are, for example, those for method variant f) specified for R-j^ solvolysable resp. oxidizable groups.

Also the implementation of the solvolysis resp. the oxidation takes place, for example, in an analogous way sonr. stated there.

.The starting materials.XXXVI: can for example be produced as the compound/with formula -R-Z-NH2 (XVIII) or a salt thereof

with a compound of formula-CH„-R ? (XXXVI.II) or

3^1

CH2=CH-R1" (IXL), in which X3 means a nucleofuge cleavable group such as halogen, e.g. chlorine or bromine, and if desired is then reacted with a compound of formula X-^-alk-R^'

(XXXVIIIa), for example in an analogous way as indicated for method variant L. For the preparation of compounds XXXVI, in which R^• means cyano, however, the compound /XVIII can also be reacted with .1, 2- d±functional ethane derivative as a 1,2- dihaloethane, S.. ex. 1,2-dibromomethane, and the reaction product is reacted with an alkali metal cyanide.

As possible secondary reactions in connection with the compound XVI are e.g. to mention the mutual conversions of free, esterified - and "amidated carboxyl groups R1 indicated for the compound I, introduction or modification reactions of substituents of the residue R, mutual conversion of free compounds and salts, as well as separation precautions of formed isomers, all of which are carried out in an analogous manner to that indicated for the compounds I. Also worth mentioning is the possibility of oxidation of hydroxynety1, or formyl R^"<1>

to carboxy, as well as the hydrolysis of cyano R^" to carbamyl or carboxy, which can also be carried out in the usual way.

In particular, a compound XVI obtained according to the method, in which Rg is hydrogen in an analogous manner to method variant 1) or m) indicated by reaction with a compound of formula X^alk-R-^'' (XXXIIIa) , resp. CH2=CH2-R1"<1>(XXXIVa) is transferred to the corresponding compound, wherein R^"' is different from R^.

The new compounds of formulas I and XVI can e.g. find use in the form of pharmaceutical preparations, which contain

.-: therapeutically effective amounts ...of the .active substance, possibly

■together with inorganic or organic solid or "liquid pharmaceutically-usable carriers."which are suitable . for enteral, e.g., oral or parenteral administration. Thus, rman tablets or gelatin capsules are used. which contains the active substance. together with diluents,:.

e.g. lactose, dextrose, sucrose and mannitol, sorbitol, cellulose, and/or lubricants, e.g. diatomaceous earth, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycols. Tablets can also have binders, e.g. magnesium aluminum silicate, starches, corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methylcellulose, • sodium carboxymethylcellulose, and/or polyvinylpyrrolidone, and if desired explosives,

..f. eg, starch, agar, alginic acid or a salt thereof, such as

sodium alginate" and/or" soda mixtures, or adsorbents, dyes, flavorings, and sweeteners. Likewise, the new compound of formula I can be used

respectively XVI in the form of the parenterally administrable preparation, or of infusion solutions. Such solutions are preferably isotonic, aqueous solutions or suspensions, as these, e.g. in the case of lyophilized preparations containing the active substance alone or together with a carrier material, e.g. mannitol, can be prepared before use. The pharmaceutical preparations may be sterilized and/or contain excipients, e.g. preservatives, stabilisers, wetting and/or emulsifiers, solubilizers, salts

.to regulate the osmotic pressure, and/or buffers. Existing pharmaceutical preparations which, if desired, may contain additional pharmacologically active substances, are prepared in a manner known per se, e.g. using conventional mixing, granulating, coating, dissolving or lyophilizing methods | contains from approx. 0.1% more

100%, especially from approx. 1% to approx. 50% lyophilisates, up to 100% of the active substance..

The compounds prepared according to the invention with formula I -.resp...-XVI /.'.used.:-preferably ±~ ±orm. of/pharmaceutical preparations. The dosage may depend on various factors such as application method, type, age, and/or individual condition. The doses to be administered daily are for oral application between approx. 0.5 and approx. 10 mg/kg on warm-blooded animals with a weight of approx. 70 kg, preferably between approx. 20 mg and approx. 50 mg.

The invention will be explained in more detail with the help of some examples, where the temperature is indicated in degrees Celsius and the pressure in mbar.

Example 1

22.4. g 1-bromo-2-(1H-indol-3-yl)-ethane, 15.7 g piperid-4-one-3-

carboxylic acid methyl ester and 39 g of N-ethyl-N,N-diisopropylamine are dissolved under nitrogen in 750 ml of dimethylformamide and stirred

for 16 hours, then evaporate under reduced pressure to approx. 300 ml, add 500 ml of water, and shake out three times with 250 ml of dichloromethane each time. The organic phases are combined and shaken three times with 80 ml of N-hydrochloric acid each time.

The aqueous phases are combined, made basic with 40% caustic soda, and shaken again three times with each time 100 ml of dichloromethane. The new organic phases are combined, washed with water and then with saturated sodium chloride solution, dried over sodium sulfate, and evaporated to dryness. The evaporation residue is dissolved in 100 ml of hot diethyl ether and mixed with 150 ml of N-hexane. After cooling, 4-hydroxy-1-(2-(1H-indol-3-yl)ethyl7-1 crystallizes out in 2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester resp. 1-[2-(1H-indol-3-yl)-ethyl]-piperidin-4-one-3-carboxylic acid methyl ester, which is filtered off and dried, the hydrochloride of which melts at 187°C with decomposition.

Example 2

320.4 g (2 mol) of tryptamine are suspended with stirring for 550

ml of methanol and mixed dropwise over the course of one hour with 378.5

g (4.4 mol) acrylic acid methyl ester. It is left to stir afterwards

' € -hours -at 5 0°C -overnight -over -at -room temperature, :J.nn—

...evaporate ..at ...4 0°C..uinder reduced :pressure..to ..dryness,..take up in .1.5 1 -toluene, add 50 g -aktivkuTI- .Lar. stir it for .30 minutes, - filter:, over diatomaceous earth,. and .evaporate under reduced pressure to dryness. N-^ 2-(1H-indol-3-yl)-ethyl/-imino-di(3-propionic acid) dimethyl ester is obtained as a reddish oil, which analogously to example 10 can be transferred into oxalate of m.p. 98-103°C.

153 g (2.83 mol) of sodium methanolate are dissolved with stirring in 1000 ml of dimethylformamide. A solution of 665 g is then dripped in over the course of 90 minutes. (2 mol) N-^~2-(1H-indol-2-yl)ethyl/-imino-di(3-propionic acid)dimethyl ester in 680 ml of dimethylformamide, heat to 40°C, allow to stir

3 hours below room temperature, and distills off the solvent at 40°C under reduced pressure. The residue remains

at 20 to 35°C entirely in a mixture of 2.1 liters of 5-N hydrochloric acid and 500 ml of toluene. The precipitated 4-hydroxy-1-(2-(1H-indol-3-yl)ethyl 7-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrochloride, resp. ±- £ 2-(1H-indol-3-yl)ethyl 7-piperidin-4-one-3-carboxylic acid ethyl ester hydrochloride, filtered off with suction, washed with cold methanol, and dried at 40°C under reduced pressure. It melts at 185-187°C during cleavage.

Example 3

Analogous to example 2, when starting from 80 g (0.5 mol) tryptamine and 112.g (1.1 mol) acrylic acid ethyl ester in 150 ml ethanol, N-/~2-(lH-indole-3 -yl)ethyl/-imino-di(3-propionic acid)diethyl ester and by reacting 180 g of this with 37.4 g (0.55 mol) sodium methanolate obtain 4-hydroxy-1-/2-(1H-indole -3-yl)ethyl 7-1,3/5,6-tetrahydro-pyridine-3-carboxylic acid ester hydrochloride, resp. 1-(2-(1H-indol-3-yl)ethyl 7-piperidin-4-one-3-carboxylic acid ethyl ester hydrochloride. of m.p. 170-173°C during decomposition.

Example 4

52.6 g (0.15 mol) 4-hydroxy-1-[12-(1H-ind61-3-yl)-ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxyl Ethyl ether hydrochloride is hydrogenated in 2 liters of water with 5 g of platinum oxide at room temperature and normal pressure to absorb 2.8 liters of hydrogen. The catalyst is filtered off, evaporated at 30° C under reduced pressure to dryness. The residue is mixed with 50 ml of acetone. The crude product that immediately crystallizes is filtered off with suction and recrystallized from ethanol, cis-4-hydroxy-1-/ 2-(1H-indol-3-yl)ethyl7 is obtained ~piperidine-3-carboxylic acid ethyl ester hydrochloride of m.p. 207-210°C.

..Analogously .gets;/one knows. hydrogenation of 33.7 g (100 mmol) of 4-hydroxy-1-(2-(1H-indol-3-yl)-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrochloride in the presence of 1.7 g of platinum-

oxide -cis-4-hydroxy-1-(2-(indol-3-yl)ethyl)-piperidine-3-carboxylic acid methyl ester hydrochloride, m.p. 187°C with decomposition.

Example 5

337 g (1 mol) of 4-hydroxy-1-[2-(1H-indol-3-yl)ethyl 7-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester hydrochloride is dissolved in 3, 3 liters of methanol and mixed with stirring at -15 to 5°C over the course of 2 hours in portions with 68 g (1.1 mol) of sodium borohydride. It is left to stir for 1 hour, slowly heated to 40 o C and the solvent is distilled off under reduced pressure. The residue is taken up in a mixture of 1.5 liters of vinegar. and 1 liter. ice water. 50 g of potassium carbonate are added, allowed to stir for 30 minutes, the organic phase is separated, washed neutrally with water, dried over magnesium sulfate, and evaporated under reduced pressure to dryness. 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 is obtained as an oil. This can be separated by flash chromatography on silica gel with dichloromethane/methanol (95:5) into the components, the trans isomer being eluted first. It can be characterized by transfer in the semifumarate of m.p. 208-209°C (cf. example 6).. The later1 isolated.eis-isomer can -by transfer into the ..hydrochloride :of -rsm.-p... 187° during cleavage be characterized

. analogously ..which is ..described in example. 8 .

Example 6

3.16 g (10 mmol) of trans-4-hydroxy-1-^~2-(indol-3-yl)-ethyl 7~piperidine-3-carboxylic acid methyl ester are dissolved in 50 ml of acetone and mixed with 0.6 g (50 mmol ) fumaric acid, dissolved in 10 ml of acetone. After some time, trans-4-hydroxy-1-[2-(indol-3-yl)ethyl 7-piperidine-3-carboxylic acid methyl ester semifumarate crystallizes out. It is filtered off, dried under reduced pressure, m.p. 208-209°C.

Example 7

Analogous to example 5, by reducing 35.3 g (100 mol) of 4-hydroxy-1-[2-(1H-indol-2-yl)ethyl?-1,2,5,6-tetrahydro-pyridine -3-carboxylic acid ethyl ester hydrochloride with 3.8 g

(100 mmol) of sodium borohydride in 300 ml of ethanol and a mixt

of approximately equal parts of cis- and trans-4-hydroxy-1-(2-(1H-indol-3-yl)ethyl 7~piperidine-3-carboxylic acid ethyl ester, up-

separated chromatographically for characterization can be transferred into trans-4-hydroxy-1-[2-(1H-indol-3-yl)ethyl 7-piperidiri-3-carboxylic acid ethyl ester hydrochloride, m.p. 109-112 o C, resp.cis-4<->hydroxy-1-(2-(1H-indol-3-yl)ethyl 7-piperidine-3-carboxylic acid ethyl ester hydrochloride, m.p. 210-213°C (cf. example 8).

Example 8

6.32 g (20 mmol) of trans-4-hydroxy-1-(/~2-(1H-indol-3-yl)-ethyl 7-piperidine-3-carboxylic acid ethyl ester are dissolved in 100 ml of dichloromethane and adjusted to Congo acid with ethereal hydrogen chloride solution. The crystalline precipitate is suctioned off, dried under reduced pressure. Trans-4-hydroxy-1-(2-(1H-indol-3-yl)ethyl 7-piperidine-3-carboxylic acid ethyl ester hydrochloride is obtained from

sm.p. 109-112°C. In an analogous manner, one also obtains cis-4-hydroxy-J.-/~_2-(1H-indol-3-yl)ethyl 7-piperidine-3-carboxylic acid ethyl ester hydrochloride of m.p. "210-213°C during decomposition.

Example 9

30.2 g (100 mmol) of c±s-4-hydroxy-1-[2-(1H-indol-3-yl)-ethyl7-PiPeri^in~3-carboxylic acid methyl ester are dissolved in 150 ml of pyridine, mixed with 75 ml of acetic anhydride, stirred for 15 hours at room temperature. Evaporate under reduced pressure to dryness, take up with a mixture of ice water with saturated potassium carbonate solution and diethyl ether, separate the organic phase, wash neutrally with water, dry over magnesium sulfate and evaporate to dryness. One obtains cis-4-acetoxy-1-£~ 2-(1H-indol-3-yl)-ethyl 7~piperidine-3-carboxylic acid methyl ester of m.p. 93-95°C.

In an exactly analogous manner, trans-4-acetoxy-1-1~ 2-(1H-indol-3-yl)ethyl/piperidine-3-carboxylic acid methyl ester is also obtained as a colorless oil, the oxalate's m.p. (cf. example 10) 189°C.

The above-mentioned compounds can also be obtained by acylating a mixture of equal parts of cis- and trans-4-hydroxy-1-(2-(1H-indol-3-yl)ethyl 7-piperidine-3-carboxylic acid methyl ester in an exactly analogous manner, which mentioned above, and separates the oily mixture formed from equal parts of cis- and trans-4-acetoxy-1-(1H-indol-3-yl)ethyl-piperidine-3-carboxylic acid methyl ester chromatographically into its components. In addition, 2.5 g of the mixture is subjected to flash chromatography of 150 g. at.sell.electricity,. (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-(1H-indol-3-yl)-ethyl?-piperidine-3-carboxylic acid methyl ester is dissolved in 10 ml of acetone and mixed with 0.2 g (2 mmol) of oxalic acid, dissolved in 3 ml of acetone. The trans-4-acetoxy-1-(1-2-(1H-indol-3-yl)ethyl 7-piperidine-3-carboxylic acid methyl ester oxalate, which immediately crystallizes out, is "suctioned off and dried, m.p." 189°C during decomposition.

Example 11

16.9 g (50 mmol) of 4-hydroxy-1-[2-(1H-ihdol-3-yl)ethyl 7-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrochloride are suspended in 100 ml methanol, is mixed with 25 ml of a concentrated aqueous ammonia solution. It is allowed to stir for 2 hours at 40°C, evaporated to dryness under reduced pressure, shaken with 300 ml of dichloromethane and 100 ml of water, the organic phase is separated, washed neutrally with water, dried over magnesium sulfate, evaporated to dryness, and crystallized from diethyl ether r/hec san- .-..Man.foar 4-amino-2-/.2-(1H-indol-3-yl)-ethyl7~1/2, 5 , 6-tetrahydro-pyridine -3-carboxylic acid methyl ester of m.p. 112-113°C.

Example 12

A solution of 14.2 g (50 mmol) 1-(/~2-(1H-indol-3-yl)-ethyl 7~1/2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester

in 150 ml of methanol, mixed with 40 g of ammonia, heated in an autoclave for 12 hours at 100°C as the pressure increases to 22 bar.

It is allowed to cool, evaporated in a water jet pump vacuum to dryness, crystallized from a mixture of 5 ml dichloromethane and a 100 ml diethyl ether, and recrystallized from ethanol. 4-amino-1-([2-(1H-indol-3-yl)ethyl]-piperidin-3-carboxylic acid amide of m.p. 210-212°C is obtained.

The starting material can be prepared as follows:

22.4 g of 1-bromo-2-(1H-indol-3-yl)-ethane, 22.2 g of 1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrobromide (guvacolin hydrobromide) and 39 g of N-ethyl-isopropylamine is dissolved under nitrogen in 750 ml of dimethylformamide and stirred for 16 hours. It is then evaporated under reduced pressure to approx. 300 ml, add 500 ml of water and shake three times with 250 ml of dichloromethane each time. The aqueous phase is made basic with 40% caustic soda and shaken again three times, each time with 100 ml of dichloromethane. The new organic phase is combined, washed with water and. then, with saturated saline solution. dried _over sodium sulfate, .-bg ..evaporated to dryness. The evaporation residue dissolves .J. _100. ml of warm diethyl ether, mix with:; i50 ml N-hexane..After. cooling crystallizes 1-(1H-indolyl-3-yl)ethyl 7-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester, which is filtered off and dried, m.p. 76-77°C.

Example 13

2.82 g (10 mmol) of 4-amino-1-[2-(1H-indol-3-yl)ethyl-7-piperidine-3-carboxylic acid amide are suspended in 35 ml of ethanol and mixed

..to. congo acid„ reaction.with a .diethyl.teric hydrochloric acid solution. When mixed with diethyl ether, 4-amino-1-(2-(1H-indol-3-yl)ethyl7-P-iperidine-3-carboxylic acid precipitates

amide bishydrochloride. It is milled and dried, m.p. 170-180°C.

Example 14

33 g (175 mmol) of 4,6-dimethyltryptamine and 40 ml (368 mmol) of acrylic acid ethyl ester are heated in 100 ml of ethanol for 2 hours under reflux. Evaporate to dryness and chromatograph on silica gel (0.063-0.02 mm) with toluene/isopropanol (99:1)

as eluent. The fractions containing the desired product evaporate and are dried under reduced pressure to give N-^ 2-(4,6-dimethyl-1H-indol-3-yl)ethyl 7-imino-di(3-propionic acid) diethyl ester as a brownish oil .

3.8 g (165 mmol) of sodium are dissolved in 180 ml of ethanol and heated to reflux. 120 ml of ethanol is distilled off, 190 ml of toluene is added, and the mixture is distilled until the distillation temperature has reached 110°C. It is then allowed to cool to 20° C., 64.1 g (165 mmol) of N-[2-(4,6-dimethyl-1H-indol-3-yl)ethyl]-imino-di(3- propionic acid) diethyl ester, dissolved in 170 ml of toluene, let it stir for 2 hours at 100°C. It is allowed to cool to room temperature, acidified with 130 ml conc. hydrochloric acid, suction off the formed precipitate, recrystallize twice from 90% ethanol. One thus obtains 4-:hydroxy-1-[2-(4,6-dimethyl-J_H-indol-2-yl')ethyl7-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester -hydrochloride, resp. .

Analogously, from 19 g of 4,6-dimethyltryptamide and 19 g of acrylic acid methyl ester, N-2-(4,6-dumethyl-1H-indol-3-yl)-ethyl 7-imino-di(3-propionic acid) dimethyl ester (oil ) and starting from 35.6 g of this and 8.44 g of sodium methanolate obtain 4-hydroxy-1-2-(4,6-dimethyl-1H-indol-3-yl)ethyl7~1,2 ,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrochloride, resp. 1- £ 2-(4,6-dimethyl-1H-indol-3-yl)-ethyl 7-piperidin-4-one-3-carboxylic acid methyl ester hydrochloride of m.p. 185-188°C.

Example 15

Analogous to example 14, you want when starting from 58.4 g

(300 mmol) of 5-chlorotryptamine and 65 ml (600 mmol) of acrylic acid ethyl ester give N-[2-(5-chloro-1H-indol-3-yl)-ethyl7-imino-di(3-propionic acid)diethyl ester (oil) and by cyclization of this 4-hydroxy-1-(2-(5-chloro-1H-indol-3-yl)ethyl 7-1,2,5,6-tetrahydropyridine-3-carboxylic acid ethyl ester hydrochloride resp. 1-[2-(5-Chloro-1H-indol-3-yl)ethyl 7-piperidin-4-one-3-carboxylic acid ethyl ester hydrochloride, m.p. 172-174°C.

In an analogous way, starting from 5.7 g of 5-chlorotryptamine and 5.7 g of acrylic acid methyl ester, N-/ 2-(5-chloro-1H-indol-3-yl)ethyl 7-imino-di(3 -propionic acid)dimethyl ester (oil) and by treating 12.4 g of this with 2.9 g of sodium methanolate in 120 ml of dimethylformamide, obtain 4-hydroxy-1-(2-(5-chloro-1H-indol-3-yl) )ethyl 7-1/2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrochloride resp. 1-(5-chloro-1H-indol-3-yl)ethyl-piperidin-4-one-3-carboxylic acid methyl ester hydrochloride of m.p. 195-197°C and when starting from 5-bromo- or 5-Fluorotryptamine and acrylic acid ethyl ester get N-/ 2-(5-bromo-1H-indole 3-yl)ethyl7 resp. N-[2-(5-Fluoro-1H-indol-3-yl)-ethyl]-imino^di-(3-propionic acid) diethyl ester and 4-hydroxy-1[2-(5-bromo-1H-). indol-3-yi)ethyl/- °9'4-hydroxy-1— £~ 2-(5-fluoro-1H-lndol-3--yl)ethyl7'-1 r^2-f 5., 6-tetxahydro -pvridin-3-carboxylic acid ethyl ester resp. ■ 1-/~2-(5-bromo-.1H-indolr-.3-yl)ethyl7- and 2— £2(5-fluoro-1H-indol-3-yl)-ethyl/— piper idin- 4-one-.3-carboxylic acid ethyl ester, analogously also the corresponding methyl ester.

Example 16

In a suspension of 9.5 g (25 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 hydrochloride in 72 ml of methanol and 18 ml of water is introduced at 5 to 10°C over the course of 20 minutes in portions..1.42 g (37.5 mmol) of sodium borohydride. It is left to stir for 20 minutes at 5 to 10°C, mixed with methylene chloride and water, shaken thoroughly, separated from the methylene chloride phase and shaken again with methylene chloride. The combined methylene chloride extracts are dried over magnesium sulfate and evaporated to dryness. The evaporation residue is chromatographed over silica gel (0.063-0.2

mm) with ethyl acetate/isopropanol (7:1) as eluent. First, trans-4-hydroxy-1-(2-(4,6-dimethyl-1H-indol-3-yl)ethyl 7-piperidine-3-carboxylic acid ethyl ester is eluted,

Rf = 0.56 and then cis-4-hydroxy-1-[2-(4,6-dimethyl-1H-indol-3-yl)ethyl 7-piperidine-3-carboxylic acid ethyl ester, Rf =

0.49. Respective fractions are combined, evaporated, and over-

is led by treatment with hydrochloric acid in diethyl ether to the hydrochloride hydrate of m.p. 126-129°C (trans) resp. the hydrochloride hydrate of m.p. 181-183°C (cis)J

Example 17

In an analogous way as in example 16, one will:;when going out

from 10.8 g (28 mmol) 4-hydroxy-1-^~2-(5-chloro-1H-indol-2-yl)-ethyl7~1 r 2,5,6-tetrahydropyridine-3-carboxylic acid ethyl ester by reduction with 1.6 g (42 mmol) sodium borohydride, chromatographic separation of diastereomers gives trans-4-hydroxy-1-1 2-(5-chloro-1H-indol-3-yl)ethyl 7~piperidine-3-carboxylic acid ethyl ester, Rf = 0.42 , and cis-4-hydroxy-1-(2-(5-chloro-1H-±ndol-3-yl)ethyl 7-piperidine-3-carboxylic acid ethyl ester, Rf = 0.27, as well as by subsequent treatment with fumaric acid in their - semifumarates of. syrup. 108-110°C : (trans) resp. 209-211°C (cis).

Analogously, by reacting 6.6 g of 4-hydroxy-1-(2-(5-chloro-1H-indol-2-yl)-ethyl7-1,2,5,6-tetrahydropyridine-3-carbox- syllic acid methyl ester with 3.0 g of sodium borohydride obtain a mixture of cis- and trans-4-hydroxy-1-(2-(5-chloro-1H-indol-3-yl)ethyl)piperidine-3-carboxylic acid methyl ester, which can are divided chromatographically into the components of Rf = 0.39 (trans) resp. 0.26

(cis).

In an analogous way, mari also gets cis- and trans-4-hydroxy-l— £~ 2—

(5-bromo-1H-indol-3-yl)ethyl 7- and cis- and trans-4-hydroxy-1-

1~ 2-(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) 4-hydroxy-1-(2-(4,6-dimethyl-1H-indol-3-yl)ethyl)-1,2,5,6-tetrahydro-pyridine- 3-carboxylic acid ethyl ester is mixed with 0.4 g of platinum oxide and 4 6 ml of ethanol and hydrogenated in a Parr apparatus for 18 hours at room temperature, and a hydrogen overpressure of 4 bar to absorb 160 ml of hydrogen. The reaction mixture is filtered over diatomaceous earth, evaporated

to dryness. Chromatographic purification on silica gel (0.063 -

0.2 mm) with ethyl acetate/isopropanol (7:2) as eluent

■ gives 4-hydroxy-1-[2-(4,6-dimethyl-1H-indol-3-yl)ethyl]-piperidine-2-carboxylic acid ethyl ester as a yellow oil, which according to "<*>"H-NMR -spectrum predominantly contains cisrisomers.

In an analogous way, when starting from 7.3 g of 4-hydroxy-1-12-(4,6-dimethyl-1H-indol-3-yl)ethyl/1,2,5,6-tetrahydro-pyridine- 3-carboxylic acid methyl ester obtain a mixture of cis- and trans-4-hydroxy-1-(2-(4,6-dimethyl-1H-indol-3-yl)ethyl 7-piperidin-3-carboxylic acid methyl ester, which is also predominantly present in cis form.Sm.p. (after recrystallization from isopropanol 138-140°C.

Example 19

A solution of 19.3 (0.1 mol) 4-oxo-piperidine-3-carboxylic acid methyl ester hydrochloride in 60 ml glacial acetic acid is mixed with 8.1 ml 37% aqueous formaldehyde solution and 11 g (0.1 mol) indole . After stirring for 2 hours at room temperature, cool with ice, mix with 300 ml of dichloromethane, neutralize with 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). 1-(1H-indol-3-yl-methyl)-piperidin-4-one-3-carboxylic acid methyl ester or 4-Hydroxy-1-(1H-indol-3-ylmethyl)-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester, as for identification when starting from 14.3 g -by dissolving in acetone a mixture, with 5.8 g of fumaric acid dissolved in 30 ml of acetone, is cooled and suction can be transferred into the fumarate of m.p. 140-14 2°C.

Example 20

Into a solution of 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 introduced while cooling at 0-5°C 1.53 g (4.05 mmol) sodium borohydride in portions.

After 2 hours, the solvent is evaporated, the residue is taken up

in dichloromethane, extracted with water, dried and evaporated to dryness. The residue is chromatographed over silica gel with ethyl acetate/methanol (9:1) as eluent. Trans-4-hydroxy-1-(1H-indol-3-ylmethyl)-piperidin-3-carboxylic acid methyl ester is eluted first and then cis-4-hydroxy-1-(1H-indol-3-ylmethyl)-piperidin-3 -carboxylic acid methyl ester. The uniform fractions are combined and evaporated. The hemifumarate of the trans compound has a m.p. 140-142°C, while cyclamate of the cis compound melts at 170-172°C.

Example 21

A solution of..18.1.- g .(104 mmol). 3-(1H-indol-3-yl)-aminopropane in 150 ml of methanol is mixed dropwise with 22 ml (230 mmol) of acrylic acid methyl ester. After stirring for 15 hours at room temperature, evaporates. one under reduced pressure and thus obtain N- /_ 3-(1H-indol-3-yl)propyl/-imino-di(3-propionic acid)-dimethyl ester as a reddish oil.

Example 22

While cooling, 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 mixed in portions with 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

on ice water, acidify with 2 N hydrochloric acid and extract three times with 100 ml of diethyl ether each time. It is then extracted

aqueous solution four times with each time 500 ml of chloroform, the organic phase is separated, dried over sodium sulphate and evaporated to dryness. From acetone/ether, 1-/~3-(1H-indol-3-yl)propyl7~piperidin:-:4-one^3-carboxylic acid methyl ester hydrochloride resp. 4-Hydroxy-1-(3-(1H-indol-3-yl)propyl 7-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrochloride of m.p. 158-159°C.

Example 2 3

In a solution of 10.5 g (30 mmol) of 4-hydroxy-1-[3-(1H-indol-3-yl)propyl7-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester -hydrochloride in 140 ml of methanol, 2.28 g (60 mmol) of sodium borohydride are introduced in portions while cooling at 0-5°C. After stirring for 1 hour, the solution is evaporated, and the residue is chromatographed over silica gel with ethyl acetate/methanol (95:5) as eluent. In the first place, trans-4-hydroxy-1-[3-(1H-indol-3-yl)propyl-piperidine-3-carboxylic acid methyl ester is eluted (fumarate hydrate melting point 98-100°C during cleavage) and then cis- 4-hydroxy-1-£~ 3-(1H-indol-3-yl)propyl7-piperidin-3-carboxylic acid methyl ester, (melting point of the hydrochloride 217-219° C during decomposition).

Example 24

A solution of 3 g of sodium methanolate in 100 ml is added drop by drop. dimethylformamide a. solution of "15.72 g. 2-(2-(1H-indol-3-yl)ethyl 7-aminomethyl-3-methoxy-penta-2,4-dienecarboxylic acid methyl ester in 150 ml of dimethylformamide, and stirred for 3 hours at room temperature. Man evaporate under reduced pressure to about 150 ml, and pour the residue into a mixture of 100 ml of 2-n hydrochloric acid, and 50 ml of toluene. )ethyl 7-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrochloride or 1-/2-(1H-indol-3-yl)ethyl 7-piperidin-4-one-3-carboxylic acid methyl ester hydrochloride ,..suck off and dry.in vacuum. It melts at 185-187°C during decomposition. The starting material can, for example, be prepared as follows:

A solution of 53.3 g (0.375 mol) of 2-methyl-3-oxo-pent-4-ene-carboxylic acid methyl ester is prepared according to J. A. M. van der Goorbergh and A. van der Gen: Ree. Trot. Chim. Pay-Bas 103, 90 (1984)), 38.5 g of orthoformic acid trimethyl ester, and 300 ml of p-toluenesulfonic acid hydrate in 150 ml of methanol stand for 6 5 hours, then neutralize with 84 ml of sodium methanolate in 3 ml of methanol and distill off the solvent in vacuo. The residue is mixed with 2.5 g of ammonium dihydrogen phosphate and heated to 190°C while the liberated methanol is distilled off. Distillation in bubble tubes gives 2-methyl-3-methoxy-penta-2,4-dienecarboxylic acid methyl ester of boiling point 65-75°C (at 20 mbar). . A well-stirred solution of 39.5 g (0.25 mol) 2-methyl-3-methoxy-penta-2,4-dienecarboxylic acid methyl ester, 44.5 g N-bromosuccinimide and 200 mg azobisisobutyronitrile in 200 ml tetrachloromethane is heated for 12 hours under reflux, the solution being irradiated with a UV lamp. After cooling, succinimide is filtered off, the filter residue is washed twice with 30 ml tetrachloromethane each time, the combined organic phases are washed with sodium carbonate solution and water, dried over sodium sulfate, and the solvent is evaporated in vacuo. ..You get 2-bromomethyl-3-methoxy-penta-2, 4-dienecarboxylic acid methyl ester as an orange-red oil..

A solution of 16 g of 1-amino-_2-(1H-indol-3-yl)-ethane, 23.5 g of bromoethyl-3-methoxy-penta-2,4-dienecarboxylic acid methyl ester and 39 g of N-ethyl-N ,N-diisopropylamine in 500 ml of dimethylformamide, stirred under nitrogen for 16 hours. One evaporates under reduced pressure, set to approx. 250 ml, add 500 ml of water and shake three times with each time 250 ml of dichloromethane. The organic phases are combined, dried over sodium sulphate and evaporated. After purification by chromatography on silica gel with toluene/ethyl acetate 9:1 as eluent, 2-(2-(1H-indol-3-yl)ethyl 7' aminomethyl-3-jnetoxy-penta-2,4-dicarboxylic acid methyl ester is obtained as a yellow oil .

Example 2 5

A solution of 3.8 g (40 mmol) of chloroformic acid methyl ester in 100 ml of dry dichloromethane is mixed with 100 mg (4 mmol) of anhydrous zinc bromide. The solution, cooled at 0°C, is mixed dropwise with 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 100 ml of dichloromethane. After heating to room temperature, the mixture is stirred for 1 hour, then poured into 300 ml of saturated sodium carbonate 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, acidified with methanolic hydrochloric acid solution. After mixing with diethyl ether and cooling, 4-hydroxy-1-(1H-indol-3-yl)ethyl7-1/2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrochloride crystallizes from sm.p. 187°C during decomposition.

The starting material can e.g. produced as follows:

A solution of 10.12 g of diisopropylamine in 100 ml of dry tetrahydrofuran is mixed at ice bath temperature with 62.5 ml of n-butyllithium in n-hexane. After stirring for 30 minutes at room temperature, the solution is cooled again to -15°C and mixed with a solution of 10.9 g (45 mmol) of -1-(2-(indol-3-yl) )ethyl N-piperidin-4-one, prepared according to E. Winterfeldt and P. Strehlke, Chem. Ber.. 98, 2579 (1975) in 100 ml of tetrahydrofuran. After 15 minutes, a solution of 10.9 g (100 mmol) of dimethylchlorosilane in 50 ml of tetrahydrofuran is added dropwise. It is allowed to stir overnight at room temperature, filtered and evaporated under reduced pressure to dryness. Thus, 4-trimethylsilyloxy-1-(2-(1-trimethylsilyl-indol-3-yl)ethyl)-1,2,5,6-tetrahydropyridine is obtained as a pale 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 100 ml glacial acetic acid is heated to reflux for 16 hours. After cooling, evaporate under reduced pressure and distribute between dichloromethane and aqueous sodium carbonate solution, the organic phase is dried and evaporated. The mixture of cis- and trans-4-acetoxy-1-(2-1H-indol-3-yl)ethyl 7-piperidine-3-carboxylic acid methyl ester is separated chromatographically into its components (cf. ex. 9).

The starting material can e.g. produced as follows:

While stirring, 28.4 g (0.1 mol) of 1-(1H-indol-3-yl)ethyl)-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester are introduced portionwise in 150 ml of a 33% solution of hydrogen bromide in glacial acetic acid. After stirring for 18 hours at room temperature, evaporate under reduced pressure and distribute between dichloromethane and aqueous sodium carbonate solution. The organic phase is dried over sodium sulphate and the solvent is evaporated in vacuo. A mixture of cis- and trans 4-bromo-1-(2-(1H-indol-3-yl)ethyl 7-piperidine-3-carboxylic acid methyl ester is obtained as a yellow oil.

Example 27

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

The starting material can be prepared as follows:

25.4 g of 1-bromo-2-(5-methoxy-1-H-indol-3-yl)ethane, 19.2 g of 1,2,5,6-tetrahydropyridine-3-carboxylic acid ethyl ester hydrochloride (guvacine ethyl ester hydrochloride) and 29 g N-ethyl-N,N-diisopropylamine is dissolved under nitrogen in 750 ml of dimethylformamide and stirred for 16 hours. It is then evaporated under reduced pressure to approx. 300 ml, add 500 ml of water and shake three times with 250 ml of dichloromethane each time. The organic phases are combined, shaken three times with each time 80 ml of n-hydrochloric acid. The combined aqueous phases are made basic with 40% caustic soda and shaken again three times with each time 100 ml of dichloromethane. The organic phases are combined, washed with water, dried over sodium sulfate and evaporated to dryness. The residue is dissolved in 100 ml of methanol and mixed with methanolic hydrochloric acid solution. After addition of diethyl ester and cooling, 1-1 2-(5-methoxy-1H-indol-3-yl)ethyl/-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester hydrochloride of m.p. 184-186°C.

Example 28

-5.2 g of the mixture of cis- and trans-4-benzyloxy-1-(2-(5-methoxy-1H-indol-3-yl)ethyl)-piperidin-3-carboxylic acid ethyl ester dissolved. ..in 100 .rn! methanol, mix with 2 g. 10% palladium on charcoal. and . is hydrogenated in . a Parr apparatus..in....l2 hours, 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/acetic acid ethyl ester 9:1 as eluent. The first line is eluted trans-4-hydroxy-1-(2-(5-methoxy-1H-indol-3-yl)-ethyl7~piperidin-3- carboxylic acid ethyl ester and then cis-4-hydroxy-1-(2-(5-methoxy-1H-indol-3-yl)ethyl)piperidine-3-carboxylic acid ethyl ester. The purified fractions are combined, evaporated and transferred by treatment with fumaric acid in acetone to the hemifumarates of m.p. 104-108°C (trans) resp. sm.p. 104-107°C (cis).

Example 29

Analogously to example 14, from 3.8 g (20 mmol) of 5-methoxy-tryptamine and 46 ml (42 mmol) of acrylic acid ethyl ester, N-/ 2-(5-methoxy-1H-indol-3-yl)ethyl7- iminodi(3-propionic acid) diethyl ester, reddish oil, Rf = 0.7 (acetic acid ethyl ester) and by cyclization of this obtain 4-hydroxy-l-/ 2-(5-methoxy-1H-indol-3-yl)ethyl7~l ,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester hydrochloride hemihydrate resp. 1-(2-(5-Methoxy-1H-indol-3-yl)ethyl 7-piperidin-4-one-3-carboxylic acid ethyl ester hydrochloride hemihydrate of m.p. 149-152°C.

Example 3 0

In an analogous manner as described in example 16, starting from 16.2 g (47 mmol) of 4-hydroxy-1H-2-(5-methoxy-1H-indol-3-yl)ethyl7-1,2 ,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester with reduction with 2.7 g (70.5 mmol) of sodium borohydride and chromatographic diastereomer separation obtain trans-4-hydroxy-1-(2-(5-methoxy-1H-indole) -3-yl)ethyl 7~piperidine-3-carboxylic acid ethyl ester, Rf = 0.53 (ethyl acetate/isopropanol 7:2)

and cis-4-hydroxy-1-(2-(5-methoxy-1H-indol-3-yl)ethyl 7-piperidine-3-carboxylic acid ethyl ester, Rf = 0.34, as well as by subsequent treatment with fumaric acid their partially hydrated semifumarates with m.p. 104-108°C (0.27 x H2O, trans) resp. 104-107°C (0.8 x R20,.cis).

Example 31

A boiling solution of 11 g of phenylhydrazine is mixed in

280 ml of methanol and 20 ml of water with a solution of 24.3 g (0.1 mol) of 4-(cis-3-methoxycarbonyl-4-methoxy-piperidino)-butanol in 59 ml of methanol and heat with stirring for 20 hours more backflow. The solvent is evaporated in vacuo and the residue is purified on 500 g of silica gel, chromatographically with toluene/ethyl acetate (9:1). One thus obtains cis-4-methoxy-1-(2-(1H-indol-3-yl)ethyl)piperidine-3-carboxylic acid ethyl ester. Gyklamate's m.p. 144-145°C.

The starting material can e.g. produced as follows:

A resolution of 83,. .6 g (0.5 mol) 4-methoxy-nicotinic acid methyl ester in 200 ml abs. ethanol, mixed with 50 ml of glacial acetic acid and 2 g of platinum oxide and hydrogenated at approx. 3 bar overpressure for 12 hours. The reaction mixture is filtered over diatomaceous earth and evaporated. After adding 200 ml of caustic soda, the mixture is extracted 4 times with 250 ml of diethyl ether each time, the organic phases are combined, dried over sodium sulphate and evaporated. Cis-4-methoxy-piperidine-3-carboxylic acid methyl ester is obtained as a yellow oil. y! ...55 g of 4-chloro-1,1-dimethoxybutane, 73.4 g (0.35 mol) cis-4-methoxy-piperidine-3-carboxylic acid ethyl ester hydrochloride and 136.5 g of N-ethyl-N,N -diisopropylamine is dissolved under nitrogen in 1.2 liters of dimethylformamide and stirred for 16 hours at 50°C.

Evaporate under reduced pressure to approx. 300 ml, add

500 ml of water and shake three times with 250 ml of dichloromethane.

The organic phase is combined and dried over sodium sulfate and evaporated in vacuo. After purification over 1 kg of silica gel with toluene/ethyl acetate (9:1) as eluent, 4-(cis-J-methoxycarbonyl-4-methoxy-piperidino)1,1-dimethoxybutane is obtained

as yellow oil.

A solution of 58 g (0.2 mol) of 4-(cis-.3-methoxycarbonyl-4-methoxy-piperidino)-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 a 10% aqueous oxalic acid solution, and the suspension is dissolved for 3 hours at room temperature. After filtering off, wash with 5% aqueous sodium bicarbonate solution, dry the organic phase with sodium sulfate and evaporate under reduced pressure.

4-(cis-3-methoxycarbonyl-4-methoxy-piperidino)butanal is thus obtained as a yellow oil.

Example 32

A solution of 28.5 g (0.1 mol) 1-(1H-indol-3-yl)ethyl 7-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester in 1,350 ml of dichloromethane, mixed in portions with a total of 52 g of 3,5-dinitroperbenzoic acid, heated for 30 minutes while stirring until reflux. After cooling, it is filtered through a glass filter nut, and the solution is mixed with ice-cooling and good stirring dropwise with 25 ml of boron trifluoride diethyl ether. After 5 minutes, it is mixed with 10 g of anhydrous sodium sulfate, and dropwise with 30 ml of carbon disulfide and then stirred for 2 hours at 0°C and 1 hour at room temperature. After filtration, wash 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, crystalline 4-hydroxy-1-[2-(1H-indol-3-yl)ethyl 7-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester is obtained hydrochloride or 1-(2-(1H-indol-3-yl)ethyl 7-piperidin-4-one-3-carboxylic acid ethyl ester hydrochloride of m.p. 185-187°C during decomposition.

Example 33

A boiling solution of 11 g of phenylhydrazine is mixed in

280 ml of methanol and 20 ml of water with a solution of 26 g (0.1 mol) N-(4-oxobutyl)-imino-di(3-propionic acid)dimethyl ester in ..50 .ml of methanol and heating for .20 hours under reflux . The solvent is evaporated in vacuo, and the residue is chromatographed on 500 g of silica gel with toluene/ethyl acetate (9:1) as eluent. Thus N-(2-(1H-indol-3-yl)ethyl T-imino-di(3-propionic acid) dimethyl ester is obtained as a reddish oil.

Its oxalate has a m.p. at 98-103°C. The starting material can be prepared as follows: 55 g of 4-chloro-1,1-dimethoxybutane, 66.2 g (0.35..mol) imino-di(3-propionic acid)dimethyl ester and 56.5 g.N-ethyl-N,N -diisopropyl alcohol is dissolved under nitrogen in 1 liter of dimethylformamide, and stirred for 16 hours at 50°C. Evaporate under reduced pressure to approx. 250 ml, add 500 ml of water and shake three times with each time 250 ml of dichloromethane. The combined organic phases are dried over sodium sulfate and evaporated in vacuo. N-(4,4-dimethoxybutyl)-imino-di(3-propionic acid) dimethyl ester is thus obtained as an orange-red oil.

A solution of 61.1 g (0.2 mol) 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 J.M. Conia et al. Synthesis 1978, 63 is impregnated with a 10% aqueous oxalic acid solution, and the suspension is stirred for 3 hours at room temperature. After filtration, wash with 5% aqueous sodium bicarbonate solution. The organic phase is dried over sodium sulfate and evaporated to dryness. N-(4-oxobutyl)imino-di(3-propionic acid)dimethyl ester is thus obtained as a yellow oil.

Example 34

40.1 g (0.25 mol) of tryptamine is dissolved in 50 ml of methanol and mixed with stirring at room temperature dropwise with 21/52 g (0.25 mol) acrylic acid methyl ester, 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 mixed with ethereal hydrogen chloride solution to form a weak congo-acidic reaction. f all out N-[2-(1H-.indol-3-yl)ethyl 7-3-alanine methyl ester hydrochloride. For purification, recrystallize once from methanol, the product melts at 168-170°C. In an analogous way, when starting from 40.1 g (0.25 mol) of tryptamine and 25 g (0.25 mol) of acrylic acid ethyl ester in 50 ml of methanol and subsequent mixing with hydrogen chloride, N-^~2 -(1H-indol-3-yl)ethyl 7-B-alanine ethyl ester hydrochloride of m.p. 130-133°C. In an analogous way, starting from 5.7 g of 4,6-dimethyltryptamine and 2.6 g of acrylic acid methyl ester, N-/~ 2-(4,6-dimethyl-1H-indol-3-yl)ethyl7-8 -alanine methyl ester, which by treatment with ethereal hydrochloric acid can be converted into hydrochloride of m.p. 151-155°C.

Example 35

28.3 g (0.1 mol) of N-^~2-(1H-indol-3-yl)ethyl 7-8-alanine methyl ester hydrochloride are mixed in 100 ml of methanol with 10.5 g (0.1 mol) triethylamine and 5.84 g (0.11 mol) acrylonitrile and stirred for 15 hours at room temperature. It is then evaporated in a water jet vacuum, the residue is taken up in ether and washed neutrally with ice water. The ethereal solution is dried over potassium carbonate and evaporated. The residual N-(2-cyanoethyl)-2-(1H-indol-3-yl)-ethyl 7-B-alanine methyl ester is dissolved for transfer to oxalate in 50 ml of acetone and mixed with a solution of 9 g of oxalic acid in 50 ml of acetone. The precipitated oxalate is washed with a little acetone, sucked off and dried. Sm.p. 146-147°C.

Example 36

Analogous to that discussed in example 35, when starting from 28.3 g (0.1 mol) N-(1H-indol-3-yl)ethyl 7-3-alanine methyl ester hydrochloride, 10.5 g (0.1 mol) triethylamino and 10.9 g (0.11 mol) acrylic acid-(N,N-dimethyl)amide in 100 ml of methanol and heating under reflux for 6 hours followed by transfer into the oxalate obtain N-/~2- (1H-indol-3-yl)ethyl 7-N-[2-(N,N-dimethylaminocarbamyl)ethyl 7-B-alanine methyl ester oxalate

.of sm.p...1.53-155°C. during cleavage.

Example 37

Analogous to that described in example 35, when starting from 2.83 g (0>01 mol) N-(1H-indol-3-yl)ethyl 7-8-alanine methyl ester hydrochloride, 2.77 g (0.002 mol) of potassium carbonate and 1.99 g (0.0011 mol) of 2-(2-bromomethyl)-1,3-dioxalane in 20 ml of dioxane, leaving it for 20 hours at a reaction temperature of 80°C , and after the work-up, transfer with oxalic acid to the oxalate to get oxalate of m.p. 159-161°C.

Example 38

Analogous to example 35, when starting from 28.3 g

(0.1 mol) N-[2-(1H-indol-3-yl)ethyl-g-alanine methyl ester hydrochloride, 16.8 g (0.11 mol) bromoacetic acid methyl ester and 29 g (0.21 mol) potassium carbonate in 140 ml of methanol and subsequent transfer into the hydrochloride, obtain N-(methoxycarbonyl-methyl)-N-[2-(1H-indol-3-yl)ethyl]-[alpha]-alanine methyl ester hydrochloride of m.p. . 168°C during decomposition.

Example 39

In an analogous way as in example 35, starting from 29.7 g (0.1 mol), N-/~2-(1H-indol-2--yl)ethyl7-6-alanine-ethyl- ester hydrochloride, 18.4 g (0.11 mol) bromoacetic acid ethyl ester and 29 g (0.21 mol) potassium carbonate in 150 ml of ethanol obtain N-(ethoxycarbonylmethyl)-N-/~2-(1H-indol-3-yl )ethyl 7-8-alanine ethyl ester and its hydrochloride of m.p. 119-121°C.

Example 40

A solution of 6.9 g (20 mmol) N-[2-(1,3-dioxalan-2-yl)ethyl 7-N-[2-(1H-indol-3-yl)ethyl 7-3-alanine methyl ester in 100 ml of dichloromethane is mixed with 30 g of silica gel soml. according to J.M. Conia .-et-al.. Syn the sis 1978, 63, hie..impregnated with.1.0% aqueous oxalic acid solution, and the suspension is stirred for .3 hours at room temperature. After filtering off, wash with a 5% aqueous bicarbonate solution, dry the organic phase with sodium sulphate and evaporate under reduced pressure. The evaporation residue is chromatographed for purification over 300 g of silica gel with toluene/ethyl acetate (9:1) as eluent. N-(3-oxopropyl)-N-2~2-(1H-indol-3-yl)ethyl 7-8-alanine methyl ester is obtained as a yellow oil.

Example 41

A solution of 0.81 g (15 mmol) of sodium ethanolate in 5 ml of dimethylformamide is mixed with a solution of 3.3 g (11 mmol) of N-(3-oxopropyl)-N-(2-(lII -indol-3-yl) ethyl 7-8-alanine methyl ester in 15 ml of N,N-dimethylformamide and stirring for 3 hours at 40°C. The solvent is then evaporated under reduced pressure and the residue is separated in chromatography on 200 g of silica gel with dichloromethane/methanol (95:5) into the components. First eluted trans-4-hydroxy-1-(1H-indol-3-yl)ethyl 7-piperidine-3-carboxylic acid methyl ester (semifumarate m.p.'208 - 209°C) and then cis-4-hydroxy -1-[2-(1H-indol-3-yl)ethyl]-piperidine-3-carboxylic acid methyl ester (hydrochloride m.p. 187°C with decomposition).

Example 4 2

Analogous to that discussed in example 4, one will in hydrogenation

of 4-amino-l-^/~2-(1H-indol-3-yl)ethyl/-l, 2,5, 6-tetrahydro-pyridine-3-carboxylic acid methyl ester obtain cis- and trans-4-amino-l -/~2-(1H-indol-3-yl)ethyl 7-piperidine-3-carboxylic acid methyl ester, which analogously to that discussed in example 8, can be transferred into bis hydrochloride.

Example 43

In a suspension of 19.6 g (15 mmol) of 1-[2-(1H-indol-3-yl)ethyl]-3-methoxycarbonyl-4-methoxy-pyridinium bromide in 250 ml of methanol in a nitrogen atmosphere at 0°C during 90 minutes 3.3 g of 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 mixed 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 mixed with a mixture of 80 ml of 5-n hydrochloric acid and . 20 ml of toluene ..whereupon, upon stirring and cooling, 4-hydroxy-1-(1H-indol-3-yl)ethyl 7-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrochloride crystallizes out , respectively 1-./ 2-(1H-indol-3-yl)ethyl/-piperidin-4-one-3-carboxylic acid methyl ester hydrochloride of m.p. 184-187°C

. during cleavage.

The starting material can e.g. produced as follows:

A solution of 22.4 g (0.1 mol) of 1-bromo-2-(1H-indol-2-yl)-ethane in 100 ml of methanol is mixed with 20.8 g of 4-methoxynicotinic acid methyl ester and let it stand for 3 days at room temperature, whereupon 1-/2-(1H-indol-3-yl)ethyl/-3-methoxycarbonyl-4-methoxy-pyridinium bromide crystallizes out as orange-yellow crystals of m.p. 133-137°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-carboxylic acid nitrile -hydrochloride in 100 ml of 95% methanol is mixed with 1.5 ml of conc. hydrochloric acid, and heated for 15 hours at reflux. After cooling, evaporate under reduced pressure to approx. 30 ml, and the solution is poured into a mixture of 80 ml of 5-n hydrochloric acid and 20 ml of toluene, whereupon 4-hydroxy-1-(2-(1H-indol-3-yl)ethyl)7~1 crystallizes out by stirring and cooling ,2, 5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrochloride resp. 1-(1H-indol-3-yl)ethyl 7-piperidin-4-one-3-carboxylic acid methyl ester hydrochloride of m.p. 185-187°C during decomposition.

The starting material can e.g. produced as follows:

A suspension of 5.73 g approx. 55% sodium hydride d. 100 ml tetrahydrofuran in a nitrogen atmosphere is mixed dropwise with a solution of 12.35 g (-41.-3 mmol) N-(2-cyanoethyl )-N-(1H-indol-3-yl)ethyl 7-B-alanine methyl ester in 200 ml of tetrahydrofuran and stir for 16 hours at room temperature. After adding .70 ml of 2-n aqueous sulfuric acid solution, a yellow solution is obtained. This is mixed with 300 ml of ether and

100 ml of water as two layers are formed. The aqueous layer is extracted three times with 100 ml of ether each time. The combined organic phases are dried over sodium sulfate, evaporated under reduced pressure to approx. 100 ml, and poured into a mixture of 80 ml of .5-n.hydrochloric acid and 20 ml of toluene, after which, upon stirring and cooling, 4-hydroxy-1-/ 2-(1H-indol-3-yl) crystallizes out ethyl/-1,2,5,6-tetrahydropyridine-3-carboxylic acid nitrile hydro-

chloride, resp. 1-7 2-(1H-indol-3-yl)ethyl N-piperidin-4-one-3-carboxylic acid nitrile hydrochloride.

Example 45

A suspension of 10 g of platinum oxide in 100 ml of water is reduced with hydrogen, after which the hydrogen atmosphere is replaced with pure oxygen. A solution of 5.5 g (20 mmol) of cis-4-hydroxy-3-hydroxymethyl-1-(1H-indol-3-yl)ethylpiperidine in 250 ml of acetone is now added, which becomes mixed with 3 g of sodium bicarbonate in 50 ml of water and introducing oxygen for 16 hours, at 58°C. After cooling, the catalyst is filtered off, and the acetone is evaporated in a vacuum. The aqueous phase is extracted three times with 70 ml of dichloromethane each time and acidified with 1-1 hydrochloric acid. After evaporation under reduced pressure, the residue is mixed with methanolic hydrochloric acid (4n), filtered and the solution heated for 3 hours under reflux. After cooling, the solvent is evaporated under reduced pressure, the residue is 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 each time, the combined organic phases are dried over sodium sulphate and evaporated. The residue is purified by chromatography on 250 g of silica gel - with dichloromethane/methanol (95:5) as eluent, obtaining ethyl 7-piperidine-3- carboxylic acid methyl ester as oil,.-m.p....of the hydrochloride is 187°C during decomposition.

The starting material can e.g. produced as follows:

A solution of 31.9 g of mercury(II) acetate in 100 ml of water and 100 ml of tetrahydrofuran is mixed in a nitrogen atmosphere at 5°C with a solution of 25.6 g (0.1 mol) of 3-hydroxymethyl-l-/~ 2-(1H-indol-3-yl)ethyl 7-1,2,5,6-tetrahydro-pyridine in 100 ml: tetrahydrofuran and stir for 1 hour. at 5^. After adding 100 ml of a 3-molar aqueous sodium hydroxide solution, 100 ml of a 0.5-molar sodium borohydride solution is slowly added dropwise to a 3-molar sodium hydroxide solution, stirring for 1 hour at 5°C and filtering. The tetrahydrofuran is evaporated under reduced pressure and the aqueous phase is extracted three times with 100 ml of diethyl ether each time. The combined organic phases dry

es over sodium sulfate and evaporated to dryness. A mixture of cis- and trans-4-hydroxy-3-hydroxymethyl-1-(2-1H-indol-3-yl)ethyl7~piperidine is obtained, which by flash chromatography on 1.5 kg of silica gel with dichloromethane/methanol (9:1) as eluent is divided into the components. The cis-isomer recrystallized from acetonitrile has a m.p. of 159.5-161°C.

Example 46

22.4 g (0.1 mol) ..1-bromo-3-(1H-indol-3-yl)-ethane, 15.5 g B-ala-niethyl ester hydrochloride and 39 g N-ethyl-N, N-diisopropylamine is dissolved under nitrogen in 750 ml of dimethylformamide and stirred for 16 hours at room temperature. It is then evaporated under reduced pressure to approx. 200 ml, mixed with 500 ml of water and shaken three times with 150 ml of dichloromethane each time. The combined organic phases are dried over sodium sulfate and evaporated to dryness. A mixture with ethanolic hydrochloric acid solution and cooling gives N-(1H-indol-3-yl)ethyl 7-B-alanine ethyl ester hydrochloride of m.p. 130-133°C.

Example 47

22.4 g .(0.1:.mol) JL-bromo-2-(1E-indol-3-yl)-ethane, 19 g imino-di(3-propionic acid)dimethyl ester and 39 g N-ethyl-N ,N-diisopropylamine is dissolved under nitrogen in 500 ml of dimethylformamide and stirred for 16 hours at 40°C. One evaporates under reduced pressure

press to approx. 200 ml, add 500 ml of water and shake three times with 250 ml of dichloromethane each time. The organic phases are combined, dried over sodium sulphate and evaporated to dryness. N-N 2-(1H-indol-3-yl) ethyl N-imino-di(3-propionic acid) dimethyl ester is obtained as a reddish oil. Its oxalate has a m.p.

at 98-103°C.

Example 48

22.4 g (0.1 mol) 1-bromo-2-(1H-indol-3-yl)-ethane, 12.5 g imino-di(3-propionic acid)dinitrile and 25 g N-ethyl-N, N-diisopropylamine is dissolved under nitrogen in 500 ml of dimethylformamide and stirred for 16 hours at 60°C. Evaporate under reduced pressure to approx. 200 ml, add 500 ml of water, shake three times with each time 250 ml of dichloromethane. The organic phases are combined, dried over sodium sulfate and evaporated to dryness. N-(1H-indol-3-yl)ethyl/imino-di-(3-propionic acid) dinitrile is obtained as a reddish oil.

A solution of 13.3 g (0.05 mol) of N-[J~2-(1H-indol-3-yl)ethyl]-imino-di-(3-propionic acid)dinitrile in 250 ml of 95% methanol is mixed with 5 ml conc. sulfuric acid and heated for 16 hours at reflux. After cooling, evaporate under reduced pressure to approx. 75 ml, mixed with 200 ml of dichloromethane and 100 ml of water and neutralized with saturated sodium bicarbonate solution. The organic phase is separated, the aqueous phase is further extracted for two hours with 100 ml of dichloromethane each time. The combined organic phases are dried over sodium sulfate and evaporated. N-(1H-indol-3-yl) ethyl 7-imino-di(3-propionic acid) dimethyl ester is obtained. Its oxalate melts at 98-103°C.

Example 49

.18.2 g of 4-{N-benzyl-N-[J~2-(1H-indole-3-yl)ethylaminoj-butyric acid ethyl ester is dissolved! 500 ml of ethanol, mixed with 1.2 g of platinum oxide and hydrogenated in a Parr apparatus at 5 bar overpressure for 18 hours at room temperature and 3 hours at 40-50°C. One filters through diatomaceous earth and mixes the formed ethanolic solution of 4-^N-/_ 2-(1H-indol-3-yl)ethyl7-amino}-butyric acid ethyl ester with stirring dropwise with 4.2 g of acrylic acid ethyl ester in 25 ml of ethanol. It is then allowed to stir for 12 hours at room temperature, evaporated under reduced pressure to 300 ml, cooled to 5°C and acidified with ethereal hydrochloric acid to pH='5.5. The formed crystalline precipitate is sucked off, dried. N-[2-(1H-indol-3-yl)

ethyl N-(3-ethoxycarbonylpropyl)-B-alanine ethyl ester in the form of the hydrochloride. N-(1H-indol-3-yl)ethyl N-(3-methoxycarbonylpropyl)-g-alanine methyl ester and its hydrochloride are also obtained in an analogous manner.

The 4-|N-benzyl-N-/_ 2-(1H-indol-3-yl)ethyl/-amino}-butyric acid ethyl ester used as starting material is prepared by benzylation of 7.5 g of tryptamine with 8.5 g of benzyl bromide and reaction of 13 g of the resulting 1-benzylamino-2-(1H-indol-3-yl)-ethane with 9.7 g of 4-bromobutyric acid ethyl ester.

Example 50

18.2 g of N-/~2-(1H-indol-3-yl)ethyl 7~N-(ethoxycarbonylmethyl)-B-alanine ethyl ester are dissolved in 20 ml of dimethylformamide and added dropwise with stirring over the course of 10 minutes to a suspension of 4, 7 g of sodium ethanolate, in 25 ml of dimethylformamide. The mixture is stirred for 15 hours at room temperature, evaporated under greatly reduced pressure at a bath temperature of 40°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 carefully add 7 g of sodium bicarbonate, separate in a separatory funnel and evaporate the dichloromethane solution under reduced pressure. The residue is recrystallized from 23 ml of ethanol. You get. thus 4-hydroxy-1-[2-(1H-indol-3-yl)ethyl]2,5-dihydro-1H-pyrrole-3-carboxylic acid ethyl ester resp. 1-(2-indol-3-yl)ethyl 7-Pyrrolidin-4-one-3-carboxylic acid ethyl ester of m.p. 122-123°C.

In an analogous way, starting from 19.7 g of N-(1H-indol-3-yl)ethyl 7-(3-ethoxycarbonylpropyl)-B-alanine ethyl ester, 4-hydroxy-1 -//"2-(1H-dinol-3-yl) ethyl 7~1, 2 , 5 , 6-'tetrahydro-7H-azepine-3-carboxylic acid ethyl ester or 1-/~2-(1H-indol-3- yl)ethyl]/-hexahydroazepin-4-one-3-carboxylic acid ethyl ester.

Example 51

12.1 g N-[2-(1H-indol-3-yl)ethyl7-N-(methoxycarbonylmethyl)-B-

alanine methyl ester is dissolved in 10 ml of dimethylformamide and added dropwise with stirring at 20-30°C during 15 minutes to a suspension of 2.8 g of sodium ethanolate in 10 ml of dimethylformamide. It is allowed to stir for 3 hours at room temperature.

turn, evaporates under reduced pressure at a bath temperature of 40°C, dissolves the residue in 150 ml of methanol, and adds at

-5°C a 10% solution of hydrochloric acid gas in ether until pH =

5. The formed 4-hydroxy-1-[2-(1H-indolul-3-yl)ethyl7-2,5-dihydro-1H-pyrrole-3-carboxylic acid methyl ester resp. 1-/ 2-1H-(indolyl-3-yl)-ethyl/-pyrrolidin-4-one-3-carboxylic acid methyl ester can without further purification by adding 7 portions of each 0.4 g sodium borohydride (total 2.8 g) is reduced with stirring at -30°C during 1 hour. After completed, introduction is allowed to stir for 3 hours at room temperature, then evaporated under reduced pressure, the residue is taken up in ether, mixed with water, adjusted with conc. caustic soda at pH = 9. The separated organic phase is washed twice more 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, as the hydrochloride precipitates out. After recrystallization from methanol, 4-hydroxy-1-(1H-indol-3-yl)ethyl 7-pyrrolidih-4-one-.3-carboxylic acid methyl ester hydrochloride is obtained as cis/trans-

ing (ca. 66% cis) with a m.p. of 192-194°C during decomposition which can be separated chromatographically into the components.

Example 52

4.7 g of 1-[2-(1H-indol-3-yl)ethyl]pyrrolidin-4-one-3-carboxylic acid ethyl ester are suspended in 50 ml of ethanol and adjusted to pH 5 with ethereal hydrochloric acid while stirring. Then, during 4 hours at -10°C, 5 portions of 0.2 g each of sodium borohydride are added (1.0 g in total). It is then allowed to stir for 3 hours at 0-3°C, evaporated under reduced pressure, the residue taken up in dichloromethane and shaken with sodium bicarbonate solution. After drying over magnesium sulfate, the cis-trans mixture is evaporated, separated by means of flash chromatography

graphy over silica gel with acetic ester "on eluent. The trans compound is dissolved in a little ethanol and adjusted

with alcoholic hydrochloric acid at pH 4, which crystallizes out trans-4-hydroxy-1-(1H-indol-3-yl)-ethyl-pyrrolidin-4-one-3-carboxylic acid ethyl ester hydrochloride, sm .p. 152-153°C.

The cis compound is isolated as oxalate, m.p. 151-152°C.

In an analogous way, starting from 5.3 g of 4-hydroxy-1-[2-(1H-indol-3-yl)ethyl]-1,2,5,6-tetrahydro-7H-azepin-3 -carboxylic acid ethyl ester get 4-hydroxy-1-/ 2-(1H-indol-3-yl) ethyl/-hexahydroazepine-3-carboxylic acid ethyl ester as a cis/trans mixture.

Example 53

In an analogous manner to that in examples 1-52, the following can be further prepared: 4-amino-1-(2-(1H-indol-3-yl)ethyl 7-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester or a salt, e.g. its bishydrochloride, cis-4-amino-1~2 2-(1H-indol-3-yl)ethyl-7-piperidine-3-carboxylic acid ethyl ester or a salt, e.g. the bishydrochloride thereof, trans-4-amino-1-(2-(1H-indol-3-yl)ethyl 7-piperidine-3-carboxylic acid ethyl ester or a salt, e.g. the bishydrochloride, N-(2-(5-methoxy-1H-indol-3-yl)ethyl 7-inino-di(3-propionic acid)-dimethyl ester or a salt, e.g. its hydrochloride, 4-hydroxy-1-(2-(5-methoxy-1H-indol-3-yl)ethyl 7-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester resp. 1-(2-(5-Methoxy-1H-indol-3-yl)ethyl 7-piperidine-3-carboxylic acid methyl ester or a salt, e.g. its hydrochloride, cis-hydroxy-1-(2-(5-methoxy-1H-indol-3-yl)ethyl 7-piperidine-3-carboxylic acid methyl ester). or .a salt, i. e.g. its hydrochloride,

trans-hydroxy-1-(2-(5-methoxy-1H-indol-3-yl)ethyl/piperidine-

3-carboxylic acid methyl ester or a salt, e.g. the hydrochloride thereof.

Example 5 4

In an analogous way as in examples 6, 8, and 10, one can also prepare fumarates (resp. semifumarates), hydrochlorides and oxalates (resp. hydrogen oxalates) of other compounds according to one of examples 1-53, as well as hydrobromides and cyclamates of the compounds according to a of examples 1-53.

Example 55

Tablets, each containing 50 mg of 4-hydroxy-1-(2-(4,6-dimethyl-1H-indol-3-yl)ethyl 7-1/2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester resp. its hydrochloride can be prepared as follows:

Composition (1000 tablets)

The active substance is mixed with the lactose and 292 g of potato starch, the mixture is moistened with an alcoholic solution of the gelatin and granulated through a sieve. After drying, the rest of the potato starch is mixed with talc, magnesium stearate and the highly dispersed silicon dioxide and the mixture is pressed into tablets of 145.0 mg weight each, and 50.0 mg active substance content, which can be equipped with a partial groove if desired. finer ."to<p>ashing-of the dosage.

Example 56

Lacquer tablets, containing 100 mg of 4-hydroxy-1-(2-(4,6-dimethyl-1H-indol-3-yl)-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester or its hydrochloride can be produced as follows:

Composition (for 1000 tablets)

The active substance, lactose and 40 g of the corn starch are mixed and moistened with glue, prepared from 15 g of corn starch and water (while heating) and granulated. The granulate is dried, the rest of the cornstarch, talc and the calcium stearate are added and mixed with the granulate's J31 andin gene. are pressed into tablets (weight 280 mg) and these are varnished with a solution of hydroxypropylmethylcellulose., and. shellac in. methylene chloride. Final weight of the varnish tablets: 283 g.

Example 57

In an analogous way as in examples 55 and 56, pharmaceutical preparations containing another compound of formula I according to examples 1 to 53 can also be prepared.

Example 58

_20 cane sugar and .19 . g baker's yeast is stirred in. 160 ml. tap water .for 1 hour at 30°C. 3.5 g (10 mmol) of finely powdered 4-hydroxy-1-[2-(1N-indol-3-yl)ethyl 7~1/2.5 are then added,

6-tetrahydro-pyridine-3-carboxylic acid ethyl ester. It is left to stir for 24 hours at room temperature, a 40°C warm solution of 13 g of cane sugar and 65 ml of tap water and a further 4 g of baker's yeast is added, and left to stir for a further 48 hours at room temperature. It is then filtered over diatomaceous earth, made alkaline with potassium carbonate, shaken twice with 100 ml of chloromethane each time. The organic phase is combined, dried over calcium carbonate and evaporated under reduced pressure to dryness. The residue is purified chromatographically (silica gel/acetic ester). 3R,4S,cis-4-hydroxy-1-[2-(1H-indol-3-yl)ethyl 7-piperidine-3-carboxylic acid ethyl ester is obtained, which with the aid of hydrochloric acid can be transferred into the hydrochloride of m.p. 108°C, /"o/p0-= + 46.2+0.6° (C = 1.586 in ethanol).

Claims (10)

1.. Process for the preparation of 1,3,4-trisubstituted azacycloalkanes and azacycloalkenes with formula in which R means an optionally substituted 3-indolyl residue, Z means lower alkylene, which separates the residue R by 1 to 3, preferably 2 carbon atoms from the nitrogen atom, alk means methylene, ethylene or 1,3-propylene, R^ means optionally esterified or amidated carboxy , R2 means an optionally etherified or amidated hydroxy group, or an optionally acylated amino group, as well as their tautomers and/or salts characterized in that a) for the preparation of compounds of formula I, in which alk means ethylene, the excess double bond is reduced by single bonds, in a compound of formula in which A Q means an acid anion and R 2 " means etherified, acylated or protected hydroxy/ or acylated or protected amino, and any protective groups present are removed, orb) a compound of formula in which X^ means a group of formula -CH=R2', -C(X2)=R2' or cyano, X2 means a cleavable residue, or a salt thereof is cyclized. orc) a compound of formula in which R^ means a substituted phenyl residue in positions 3 to 6, optionally as indicated for positions 4 to 7 of the residue R, R^ means hydrogen, or a substituent prescribed for the 1-position of R and R,, means hydrogen or a substituent prescribed for the 2-position of R, or a tautomer and/or salt thereof, ring-closed to a corresponding compound of formula I, or d) compounds with the formulas where. X^ gives a nucleofuge cleavable group, or their tautomers and/or salts react with each other, or e) for the preparation of a compound of formula I, in which alk means ethylene, a compound of formula is cyclized or a tautomer and/or salt thereof,, or f) a compound of formula in which R^' means a residue transferable to an optionally esterified or amidated carboxy or a tautomer and/or salt thereof, R^<1> is transferred to an optionally esterified or amidated carboxy, org) to prepare a compound of formula I, in which the azacycloaliphatic residue has a double bond is condensed to a compound of formula whereinR<1> means a 1-position substituted or intermediately protected 3-indolyl residue R and R2"'/ means a group R2 or intermediately protected hydroxy, or the corresponding keto- or iminotautomer thereof, with a compound of formula R-, -X, (Via), where X- means a cleavable JL b b residue and possibly cleave off the protecting group(s), or. h) in .a compound with formula wherein X4 means a tii a group R2 transferable residue, X^ is transferred to a group. R2, or i) for the preparation of compound of formula I, in which the azacycloaliphatic ring is monounsaturated, and R2 means hydroxy.resp. the tautomeric oxo compound is rearranged in a compound of formula orj) for the preparation of a compound of formula I, in which the azacycloaliphatic ring is saturated, react compounds with the formulas with each other, or k) for the preparation of compound of formula I, in which Z separates the residue R from the nitrogen atom by a C atom, con dense connection with the formulas with an oxolave alkane, and if desired, the compound formed according to the r method is transferred to another compound of formula I, an isomer mixture obtained according to the method is divided into its components and the isomer of formula I is isolated, a diastereomer mixture formed according to the method resp. enantiomeric mixture is separated into the diastereomeric resp. enantiomers and the desired diastereomer or isolate enantiomers, and/or a free compound obtained according to the method is transferred to a salt, or a salt obtained according to the method is transferred to the free compound or another salt. .. 2. Method according to claim 1, characterized in that a compound of formula I is produced, in which R means unsubstituted or in at least one of the positions 1,2 and 4 to 7 substituted 3-indolyl, the substituent in the 1-position being taken into account lower alkyl or lower alkenyl, in the 2-position lower alkyl, and as substituents .in 4 - to the 7-position lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, hydroxy, halogen, trifluoromethyl, and/or to a neighboring C atom bound lower alkyl(ide)dioxide, Z means the lower alkylene, which separates the residue R as a nitrogen atom preferably by 1-3 2 C atoms, alk means methylene, ./ethylene, or 1,2-propylene, R^ means carboxy, lower alkoxycarbonyl, optionally with lower alkyl, lower alkoxy, halogen, nitro, and/or trifluoromethyl substituted phenyl lower oxycarbonyl, 3- to 8-membered cycloalkoxycarbonyl, carbamyl, mono- or dilower alkylcarbamyl, lower alkylene-resp. aza-, oxa- or thialeveralkylenecarbamyl, N-loweralkanoylcarbamyl, N-loweraloxycarbonylcarbamyl, ureidocarbonyl, N <1-> mono- or N',N<1-> diloweralkylureidocarbonyl, N',N<1-> loweralkylene- resp, N < 1>, N'-(aza-, oxa-, or thia) lower alkylene ureidocarbonyl, and R2 means hydroxyl lower alkyl optionally with lower alkyl, lower alkoxy, halogen, trifluoromethyl, and/or nitro substituted phenyl lower alkyl, ..aminolower alkanoylamino,.._lower oxycarbonylamino or optionally- with.lower alkyl, lower alkoxy, halogen, trifluoromethyl, and/or nitro substituted phenyllower oxy- . carbonylamino, the lower alkylene alk having up to and including 4, the other lower residues together up to and including 7, and in each lower partial structure up to and including 4 C atoms or a tautomer and/or salt thereof. 3. Process according to claim 1, characterized in that a compound of formula I is prepared, in which R means unsubstituted or in one or two of the positions 4 to 7. with lower alkyl with. up to and including 4 C atoms, .lower oxy with up to and including 4 C atoms, halogen-.of atomic no. even 35,.and/or trifluoromethyl substituted 3-indolyl, Z means lower alkylene with up to 4 C atoms, which separates the residue R from the nitrogen atom by 1 to 3 C atoms, alk means methylene, ethylene or 1,3-propylene, R 1 means carboxy, lower alkoxycarbonyl with up to 4 C atoms in the alkoxy part. 3- to 8-membered cycloalkoxycarbonyl, carbamyl or N-mono- or N,N-diloweralkylcarbamyl with up to 4 C atoms in each alkyl part, and R^ means hydroxylaverealoxy with up to 4 C atoms, f phenyllaverealoxy with 7 to cg with 10 C atoms[ lower alkanoyloxy with up to 4 C atoms, amino or lower ealkanoy lami no with up to 4 C atoms or a tautomer and/or a salt thereof. 4. Process according to claim 1, characterized in that a compound of formula I is prepared, in which R means unsubstituted or in one or two of positions 4 to 7 with lower alkyl, with up to and including 4 C atoms, and/or halogen of atom murtimer up to and including 35 substituted 3-indolyl, Z means \ linear 1,1-, 1,2- or 1,3-lower alkylidene with up to 4 C atoms, alk means methylene or ethylene, R^ means lower alkoxycarbonyl with to and with 4 C-atoms alkoxy part and R 2 means hydroxy or a tautomer or a salt thereof. _5..... Procedure according to, claim 1,. characterized in that cis-4-hydroxy-1-[2-(1H-indol-3-yl)ethyl]-piperidine-3-carboxylic acid ethyl ester or a salt thereof is produced. 6. Process according to claim 1, characterized in that 4-hydroxy-1-< /~2-(1H-indol-3-yl)ethyl/-1,2,5,6-pyridine-3-carboxylic acid methyl ester is produced resp. 1-(1H-indol-3-yl)ethyl 7-piperidin-4-one-3-carboxylic acid methyl ester, 4-hydroxy-1-[2-(1H-indol-3-yl)ethyl]-1,2,5,6-pyridine-3-carboxylic acid ethyl ester resp. 1-[2-(1H-indol-3-yl)ethyl]-piper- .idin-4-one-3-carboxylic acid ethyl ester, trans-4-hydroxy-1-(2-(1H-indol-3-yl)ethyl 7-piperidin-3-carboxylic acid ethyl ester, cis-4-hydroxy-1-(1H-indol-3-yl) ethyl 7-piperidine-3-carboxylic acid methyl ester; trans-4-hydroxy-1-(1H-indol-3-yl)ethyl 7-piperidin-3-carboxylic acid methyl ester, cis-4-hydroxy-1-(1H-indol-3-yl) ethyl 7-piperidine-3-carboxylic acid methyl ester, trans-4-acetoxy-1-(1H-indol-3-yl)ethyl 7-piperidine-3-carboxylic acid methyl ester, 4-amino-1-(1H-indol- 3-yl)ethyl N-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester, 4-amino-1-[2-(1H-indol-3-yl)ethyl-7-piperidin-3-carboxylic acid amide, 4-hydroxy-1-[2-(4,6-dimethyl-1H-indol- 3-yl)ethyl 7-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester resp. 1-/~2-(4,6-Dimethyl-1H-indol-3-yl)ethyl 7-piperidin-4-one-3-carboxylic acid ethyl ester, 4-hydroxy-1-/~2-(5-chloro-1H- indol-3-yl) ethyl 7~1, 2 , 5 , 6-tetrahydro-pyridine-3-carboxylic acid ethyl ester resp. 1-[2-(5-chloro-1H-indol-3-yl)-ethyl 7-piperidin-4-one-3-carboxylic acid ethyl ester, cis-4-hydroxy-1-[2-(4,5-dimethyl -1H-indol-3-yl)ethyl7~ piperi- .. din-3-carboxylic acid ethyl ester, trans-4-hydroxy-1--/~2-(4,6-dimethyl-1H-indol-3-ryl)ethyl7~ . piperidine-3-carboxylic acid ethyl ester, cis-4-hydroxy-1-(1-2-(5-chloro-JH--indol-3-yl)ethyl)-piperidin- .3-carboxylic acid ethyl ester, trans-4-hydroxy-1-(2-(5-chloro-1H-indol-3-yl)ethyl)piperidine-3-carboxylic acid ethyl ester, 4-hydroxy-1-(1H-indol-3-yl)methyl 7-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester resp. 1-/ (1H-indol-3-yl) methyl 7-piperidin-4-one-3-carboxylic acid methyl ester, trans-4-hydroxy-1-/_ (1H-indol-3-y 1) methyl 7-piperidin-3- carboxyl acid enre ty ester, , 4-Hydroxy-1-(3-(1H-indol-3-yl)propyl 7~1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester resp. 1-/ 3-(1H-indol-3-yl)propyl/-piperidin-4-one-3-carboxylic acid methyl ester, cis-4-hydroxy-1-/~3-(1H-indol-3-yl)propyl7- Piperidine-3-carboxylic acid methyl ester, trans-4-hydroxy-1-(1H-indol-3-yl)propyl-piperidine-3-carboxylic acid methyl ester, cis-4-amino-1-(1H -indol-3-yl)ethyl 7-piperidin-3-carboxylic acid ethyl ester, trans-4-amino-1-(1H-indol-3-yl)ethyl 7-piperidin-3-carboxylic acid ethyl ester, cis- and/or trans-4-benzyloxy-1-(2-(5-methoxy-1H-indol-3-yl)-ethyl 7~ piperidine-3-carboxylic acid ethyl ester, 4-hydroxy-1-/~2-(5 -methoxy-1H-indol-3-yl)ethyl7~lf 2,5,6-tetrahydropyridine-3-carboxylic acid ethyl ester resp. 1-/_ 2-(5-Methoxy-1H-indol-3-yl)ethyl 7-piperidin-4-one-3-carboxylic acid ethyl ester, cis-4-hydroxy-1-/~2-(5-methoxy-1H- indol-3-yl) ethyl/-piperidin-3-carboxylic acid ethyl ester, trans-4-hydroxy-1-/~2-(5-methoxy-1H-indol-3-yl)ethyl7~ piperidine-3-carboxylic acid ethyl ester, 4- hydroxy-1-(2-(5-bromo-1H-indol-3-yl)ethyl 7-1,2,5,6-tetrahydropyridine-3-carboxylic acid ethyl ester resp. 1-/ 2-(5-bromo- 1H-indol-3-yl]f-e ty 17-piperidin-4-one-3-carboxylic acid ty ester, '.-.reis— 4 - hy dr ok sy-1— f. 2— (5-bromo~LH— ±ndol-3 -y 1 )e tyl/-piperidine- .3-carboxylic acid ethyl ester, . trans-4-hydroxy-1-([2-(5-bromo-1H-indol-3-yl)ethyl]-piperidin- ...3-carboxylic acid ethyl ester, 3R, 4S-4-Hydroxy-1/~2 (1H-indol-3-yl) ethyl 7-piperidine-3-carboxylic acid ethyl ester, trans-4-hydroxy-1-/~2-(5-fluoro-1H-indole -3-yl(ethyl 7-piperidin-3-carboxylic acid ethyl ester, 4-hydroxy-1-[2-(5-bromo-(1H-indol-3-yl)ethyl)-7-1,2,5,6-tetrahydropyridin-3 -carboxylic acid methyl ester or 1-(2-(5-bram-1H-indol-3-yl)ethyl)piperidin-4-ca^3-carboxylic acid methyl ester f.4-hydroxy-1-(2-(5-fluoro- lH-indole- - 3-yl)ethyl 7-1,2,5,6H^trahydropyridine-3-carboxylic acid ethyl ester resp. 1-£2-(5-Fluoro-1H-indol-3-yl)ethyl 7-piperidin-4-one-3-carboxylic acid ethyl ester, crs-4-hydroxy-1-(2-(5-fluoro-1H-indole) -3-yl).ethyl 7-piperidin-3-carboxylic acid methyl ester, trans-4-hydroxy-1-(2-(fluoro-1H-indol-3-yl)ethyl)-piperidin-3-carboxylic acid methyl ester, cis-4- hydroxy-1-(2-(5-bromo-1H-indol-3-yl)ethyl)piperidine-3-carboxylic acid methyl ester, 4-hydroxy-1-[2-(5-fluoro-1H-indol-3-yl)ethyl 7-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester resp. 1-[2-(5-fluoro-1H-indol-3-yl)ethyl 7-piperidin-4-one-3-carboxylic acid methyl ester, trans-4-hydroxy-1-[2-(5-bromo-1H- indol-3-yl)ethyl 7-piperidin-3-carboxylic acid methyl ester, 4-hydroxy-1-[2-(4,6-dimethyl-1H-indol-3-yl)ethyl 7-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester resp. 1-/ 2-(4,6-dimethyl-1H-indol-3-yl)ethyl 7-piperidin-4-one-3-carboxylic acid methyl ester, 4-hydroxy-1-/~2-(5-chloro-1H-indole -3-yl)ethyl7~ l/ 2,5,6-tetra-hydropyridine-3-carboxylic acid methyl ester, resp. 1-/ 2-(5-chloro-1H-indol-3-yl)ethyl 7-piperidin-4-one-3-carboxylic acid methyl ester, cis-4-hydroxy-1-/~2T-(5-chloro-1H-indole -(3-yl)ethyl 7-piperidin-3-carboxylic acid methyl ester, trans-4-hydroxy-1-(2-(5-chloro-1H-indol-3-yl)ethyl)piperidine-3-carboxylic acid methyl ester, .cis-4-Hydr.oxy-1-(!2-(4,6-d±methyl.-JLH-J.indol-3.-yl)ethyl 7-piperidine-3-carboxylic acid methyl ester, - +_rans-4-hydroxy-1-(2-(4,6-dimethyl-1H-indol-'3-yl)ethyl 7-piper-idine-3-carboxylic acid methyl ester, cis-4-methoxy-1-(2-(1H-indol-3-yl)ethyl 7-piperidine-3-carboxylic acid methyl ester, 4-hydroxy-1-[2-(5-methoxy-1H-indol-3-yl)ethyl 7-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester resp. 1-/ 2-(5-methoxy-1H-indol-3-yl)ethyl 7~ piperidin-4-one-3-carboxylic acid methyl ester, cis -4-hydroxy-1-/ 2-(5-methoxy-1H-indol- 3-yl) ethyl 7-piperidin-3-carboxylic acid methyl ester, . trans—4-hydroxy—1—/ 2— (5-methoxy-1H-andol—3-yl) ethyl 7-piperidine-3-carboxylic acid methyl ester, 4-Hydroxy-1-[2-(1H-indol-3-yl)ethyl]-2,5-dihydro-1H-pyrrole-3-carboxylic acid ethyl ester resp. l-/~2-(1H-indol-3-yl)ethyl/-pyrrolidin-4-one-3-carboxylic acid ethyl ester, cis-4-amino-1-/2-(1H-indol-3-yl)ethyl7~ Piperidine-3-carboxylic acid methyl ester, transT 4-amino-1-[2-(1H-indol-3-yl)ethyl 7-piperidine-3-carboxylic acid methyl ester, 4-hydroxy-1-[2-(1H-indol-3-yl)ethyl]-2,5-dihydro-1H-pyrrole-3-carboxylic acid methyl ester resp. 1-/~2-(1H-indol-yl)ethyl/-pyrrolidin-4-one-3-carboxylic acid nrethyl ester, cis-4-hydroxy-1-/~2-(1H-indol-3-yl)ethyl7-pyrrolidine -3-carboxylic acid ethyl ester, trans-4-hydroxy-1-/~2-(1H-indol-3-yl)ethyl 7-pyrrolidine-3-carboxylic acid ethyl ester, cis-4-hydroxy-1-/~2-(1H-indole -3-yl)ethyl 7-pyrrolidine-3-carboxylic acid methyl ester, trans-4-hydroxy-1-(1H-indol-3-yl)ethyl 7-pyrrolidine-3-carboxylic acid methyl ester, 4-hydroxy-1-[2-(1H-indol-3-yl)ethyl 7-1,2,5,6-tetrahydro-7H-azepine-3-carboxylic acid ethyl ester resp. 1-/~2-(1H-indol-3-yl)ethyl 7-hexahdyroazepin-4-one-3-carboxylic acid ethyl ester, cis-4-hydroxy-1-/_ 2-(1H~indol-3-yl)ethyl7- hexahydroazepine-3-carboxylic acid ethyl ester, tr.aris-4T-hydroxy--1-(1H-.±ndol--3-i-yl)ethyl-hexahydroazepine-3-carboxylic acid ethyl ester or a salt thereof, f., e.g. in the form of a hydrochloride,. hydrobromide, fumarate, oxalate or cyclamate. 7. Method for preparing compound of formula in which R means an optionally substituted 3-indolyl residue, Z means the lower alkylene which separates the residue R by 1 to 3, preferably 2 carbon atoms from the nitrogen atom, R^ means optionally esterified. or amidated carboxy, and Rc means . hydrogen or a group of formula alk-R^"', where R^"' has one of the meanings given for R^,, or means cyano, hydroxymethyl, or optionally acetalized formyl, and alk means methylene, ethylene or 1,3- propylene, with the proviso that in compounds of formula XVI, in which R is unsubstituted and Rg is hydrogen, Z is different from ethylene, when R^ is methoxycarbonyl or ethoxycarbonyl, and their salts, characterized by that 1) compounds with the formulas .in which one of the residues Xb c and Xb, means a group of the formula -N(Rb,.)-H and the other means a nucleofuge cleavable group or their salts, react with each other, or m) compounds of the formulas or their salts react with each other, or n) a compound of formula in which Rc means a substituted phenyl residue in the 3- to 6-position, optionally as indicated for positions 4 to 7 of the residue R, R4 means hydrogen, or a prescribed substituent in the 1-position of R, and R5_ means hydrogen, or one for 2 -position of R prescribed substituent, or a tautomer and/or salt thereof, is ring-closed to the corresponding compound of formula XVI, or 1 oV-in a compound of formula in which R D ' means hydrogen or a g' rup <p>e with formula alk-Tl^<1> , andR .^ ' means a optionally esterified or amidated carboxy R^ transferable residue/ R^ ' is transferred to optionally' esterified or amidated carboxy, and if desired, the compound obtained according to the method is transferred to another compound of formula XVI, an isomer mixture obtained according to the method is divided into components, and the isomer of formula XVI is isolated, a diastereomer mixture obtained according to the method resp. enantiomer mixture, split into diastereomers resp. enantiomers, and the desired diastereomeric resp. enantiomers are isolated and/or a free compound obtained according to the method is converted into a salt, or a salt obtained according to the method is converted into the free compound or into another salt. 8. Method according to claim 7, characterized in that a compound of formula XVI is prepared wherein R means unsubstituted or in 1 or 2 of positions 4 to 7 with lower alkyl, with up to and including 4 C atoms, lower alkoxy with up to and including 4 C atoms, halogen, of atomic number up to and including 35, and/or trifluoromethyl substituted 3-indolyl,. ...Z. means.;-.J.averealkylene :with to and..with .4 . C atoms. which ..separates the residue R from the nitrogen atom with 1 to 3 C atoms, R^ means carboxy, lower alkoxycarbonyl with up to and including 4 C atoms in the alkoxy part, 3- to 8-membered cycloalkoxycarbo- .. nyl, carbamyl or N-mono- or N,N-diloweralkylcarbamyl having up to 4 C atoms in each alkyl part, and Rr means hydrogen or a group of formula - (CH^) n-R-^n 1 , in which n means 1, 2 or -3, and R 1" 1 means carboxyl lower oxycarbonyl with up to 4 C atoms in the lower alkoxy part, 3- to 8-membered cycloalkoxycarbonyl, carbamyl or N-mono- or N^-dilower alkylcarbamyl with up to 4 C -atoms in each alkyl part, cyano, hydroxymethyl, formyl, dilavereal oxymethyl or lower alkylenedioxymethyl ..with up to and including 4.C atoms, in the alkoxy part, resp.'in the alkylene dioxy part or a salt thereof. 9. Method according to claim 7, character! characterized by the preparation of a compound of formula XVI, in which R means unsubstituted or in the 4- and 7-position with halogen of atomic number up to and including 35, and/or lower alkyl with up to and including 4 C atoms substituted 3-indolyl, Z means ethylene, R^ means lower alkoxycarbonyl with up to 4 C atoms in the lower alkoxy part, and Rb , means hydrogen or a group of formula -(CI^)n~R^"1 > in which .n means 1 or 2, and R^ " <1> has the same meaning as R] _ or means cyanodilavereal oxymethyl with each up to and including 4 alkylenedioxy-C atoms, lower alkylenedioxymethyl with 2 up to and including 4 alkylenedioxy-C atoms, or N,N-diloweralkylcarbamyl with each even 4•alkyl C atoms, or a salt thereof. 10. Process according to claim 7, characterized in that N-(1H-indol-3-yl)ethyl/imino-di(3-propionic acid)dimethyl ester is prepared, N-[2-(1H-indol-3-yl)ethyl]y-imino-di(3-propionic acid) diethyl ester, N-(2-(4,6-dimethyl-1H-indol-3-yl)ethyl 7-amino-di(3-propionic acid) diethyl ester, N-(2-(4,6-dimethyl-1H-indol-3-yl)ethyl 7-imino-di(3-propionic acid)-dimethyl ester, N-/~2— (5-Jdor.-_1H-d.nd ol-3-yl)ethyl.17-imino-di(3-propionic acid) diethyl ester, N-/~2-(5-chloro—1H -indol-3-yl)ethyl/-imino-di(3-propionic acid)dimethyl ester, N-/~3-(1H-indol-3-yl)propyl7~imino-di(3-propionic acid)dimethyl ester, N-(5-methoxy-1H-indol-3-yl)ethyl-imino-di(3-propionic acid)-diethyl ester, 3-/2-(1H-indol-3-yl)ethyl7-N-(2-cyanoethyl)-g-alanine methyl ester, N-/"2-(1H-imdol-3-yl)ethyl7-N-/_ 2 -(1,3-dioxalan-2-yl)ethyl7~B -alanine methyl ester, N-/~2-(2H-indol-3-yl)ethyl7-N-/"2-(N,N-dimethylcarbamyl)ethyl7~ B -alanine methyl ester, N-/~2-(1H-indol-3-yl)ethyl7-N-(methoxycarbonylmethyl)-B-alanine methyl ester, N-/~2-(1H-indol-3-yl)ethyl7~ N -(ethoxycarbonylmethyl)-B-alanine ethyl ester, N-(2-(5-bromo-1H-indol-3-yl)ethyl 7-imino-di(3-propionic acid)diethyl ester, N-(2-(5- bromo-1H -indol-3-yl)ethyl 7~imino-di(3-propionic acid)dimethyl ester, N-(2-(5-Fluoro-1H-indol-3-yl)ethyl 7~imino-di(3-propionic acid) dimethyl ester, N-(2-(5-fluoro-1H-indol-3-yl)ethyl 7-imino-di(3-propionic acid) diethyl ester, N-/~2-(4,6-Dimethyl-1H-indol-3-yl)ethyl 7-B-alanine methyl ester, N-/~2-(1H-indol-3-yl)ethyl7-N-(3-ethoxycarbonylpropyl )-B-alanine ethyl ester, N-/~2-(1H-indol-3-yl)ethyl 7-N-(3-methoxycarbonylpropyl)-B-alanine methyl ester, N-/ 2-(5-Methoxy-1H-indol-3-yl)ethyl7-imino-di(3-propionic acid)-dimethyl ester, N-/~2-(1H-indol-2-yl)ethyl7~ N- (4-oxobutyl)-B-alanine methyl ester or a salt thereof, e.g. in the form of a hydrochloride, hydrobromide, fumarate, oxalate or cyclamate.