NO874724L - PROCEDURE FOR THE PREPARATION OF HYDRATED 1-PHENOXYLYCYLPYRIDINE-3-CARBOXYLIC ACID COMPOUNDS. - Google Patents

Description

The present invention relates to a method for the production of new dehydrogenated 1-phenoxyalkylpyridine-3-carboxylic acid compounds of the formula:

in which Ri stands for lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl, N,N-dilower alkylcarbamyl or optionally acylated hydroxymethyl, Eg stands for hydrogen, an optionally etherified or acylated hydroxy group or an optionally acylated amino group, alk stands for lower alkylene, ring A is unsubstituted or single - or polysubstituted by hydroxy, lower alkoxy, lower alkanoyloxy, cyano, halogen, lower alkyl and/or trifluoromethyl and the dashed line shall express the presence of a single or double bond, their tautomers and/or salts, the use of these compounds and pharmaceutical preparations containing a compound of formula I or a tautomer and/or a pharmaceutically usable salt thereof.

Ethered hydroxy, Eg, is, for example, lower alkoxy or optionally substituted phenyl lower oxy.

Acyl in acylated hydroxymethyl E^ as well as in acylated hydroxy or amino Eg is, for example, an acyl derived from a carboxylic or sulfonic acid.

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

Acyl derived from an organic sulphonic acid is, for example, lower alkanesulphonyl.

The invention relates, for example, to a process for the preparation of compounds of formula I, in which stands for lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl or N,N-dilower alkylcarbamyl, Rg stands for hydrogen, an optionally etherified or acylated hydroxy group or an optionally acylated amino group, alk stands for the lower alkylene, the ring A is unsubstituted or mono- or poly-substituted with hydroxy, lower alkoxy, lower alkanoyloxy, cyano, halogen, lower alkyl and/or trifluoromethyl and the dashed line shall express the presence of a single or a double bond, tautomers and/or salts thereof, the use of these compounds and pharmaceutical preparations containing such a compound of formula I or a tautomer and/or a pharmaceutically usable salt thereof.

Tautomeric forms of the compound of formula I exist e.g. when Rg stands for hydroxy or amino and the dashed line shall express that there is a double bond. That is the enols and enamines of formula I are in equilibrium with the corresponding keto and ketimine tautomers of the formula

wherein R£ stands for oxo or imino. Representatives of both tautomeric forms can be isolated.

The compounds of formula I can also exist in the form of stereoisomers. Since the compounds of formula I, if the dashed line represents a single bond, have at least one chiral carbon atom (C atom) (e.g. the atom C3 in the piperidine residue), they can e.g. present as pure enantiomers or enantiomer mixtures, as racemates, and if at least one further chiral center is present (e.g. the C4 atom of a 4-substituted piperidine residue) also as diastereomers, diastereomer mixtures or racemate mixtures. Consequently, for example in the case of and Rg, geometric isomers such as cis-, i.e. 3R,4S- and 3S,4R-, and trans-, i.e. 3R,4R- and 3S,4S-isomers can be formed, if Rg is different from hydrogen.

Salts of compounds of formula I or their tautomers are particularly corresponding acid addition salts, preferably pharmaceutically usable acid addition salts. These are mixed, for example, with strong inorganic acids, such as mineral acids, e.g. sulfuric acid, a phosphoric acid or a hydrohalic acid, with strong organic carboxylic acids, such as lower alkane carboxylic acids, e.g. acetic acid as optionally unsaturated dicarboxylic acids, e.g. malonic, maleic or furmaric acid, or as hydroxycarboxylic acids, e.g. tartaric or citric acid, or with sulfonic acids, such as lower alkane or optionally substituted benzenesulfonic acids, e.g. methane or p-toluenesulfonic acid. If R^, for example, stands for hydroxymethyl, corresponding compounds can form salts with bases. Suitable salts with bases are, for example, corresponding alkali metal or alkaline earth metal salts, e.g. sodium, potassium or magnesium salts, pharmaceutically usable transition metal salts, such as zinc or copper salts, or salts with ammonia or organic amines, such as cyclic amines, such as mono-, di- or trilower alkylamines, such as hydroxyl lower alkylamines, e.g. mono-, di- or trihydroxy lower alkyl amines, hydroxyl lower alkyl lower alkyl amines or polyhydroxy lower alkyl amines. Cyclic amines are e.g. morpholine, thiomorpholine, piperidine or pyrrolidine. As monolower alkylamines, for example, ethyl or t-butylamine, as dlower alkylamine, for example diethyl or diisopropylamine, as trilower alkylamine, for example trimethyl or triethylamine can come into consideration. Corresponding hydroxyl lower alkylamines are e.g. mono-, di-, respectively triethanolamine, and hydroxyl lower alkyl lower alkyl amines are e.g. N,N-dimethylamino- or N,N-diethylamino-ethanol, as polyhydroxy lower alkylamine, e.g. glucosamine in speech.

Also included are salts that are unsuitable for pharmaceutical applications, as these can for example be used for isolation or purification of free compounds of formula I as well as their pharmaceutically usable salts.

In the above and following, residues or compounds denoted by "lower", unless otherwise stated, are to be understood in particular as containing up to and including 7, above all up to and including 4 carbon atoms.

Low-area coke is e.g. C 1 -C 4 -Alkoxy, such as methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy and tert-butyloxy.

Lower alkyl is e.g. C^-C^-alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl and further includes C5-Cy-alkyl, such as pentyl, hexyl and heptyl residues .

Lower alkylene alk is e.g. The C-^-C^-alkylene, which bridges the two heteroatoms 0 and N entered in formula I primarily by means of 2 to 4 C atoms, and can e.g. be ethylene, 1,3-propylene or 1,4-butylene, but also methylene, 1,2-propylene, 1,2- or 1,3-(2-methyl)-propylene or 1,2- or 1,3 -butylene.

Lowerealkanoyl is e.g. Cg-Cg-alkanoyl, such as acetyl, propionyl, butyryl, isobutyryl or pivaloyl.

Lower alkanoyloxy is e.g. Cg-Cg-alkanoyloxy, such as acetyloxy, propionyloxy, butyryloxy, isobutyryloxy or pivaloyloxy.

Lower oxycarbonyl is e.g. C 6 -C 8 -Alkoxycarbonyl, such as methoxy-, ethoxy-, n-propyloxy-, isopropyloxy-, n-butyloxy-, isobutyloxy- or tert-butyloxycarbonyl.

N-lower alkylcarbamyl is e.g. N-C1-C4-alkylcarbyl, such as N-methyl-, N-ethyl-, N-(n-propyl)-, N-isopropyl-, N-(n-butyl)-, N-isobutyl- or N-tert -butylcarbamyl.

N,N-dilaverealkylcarbamyl, is e.g. N,N-di-C-^-C4-alkylcarbamyl, whereby in any case the two N-alkyl groups may be the same or different, such as N,N-dimethyl-, N,N-diethyl-, N,N-diisopropyl- or N-butyl-N-methylcarbamyl.

Optionally substituted phenyl lower real oxy is e.g. optionally substituted in the phenyl part phenyl-C 1 -C 4 - alkoxy, such as benzyloxy, p-chlorobenzyloxy, 1-phenylethoxy or 1-(p-bromophenyl)-n-butyloxy.

Optionally substituted benzoyl is e.g. benzoyl, p-chloro-benzoyl or p-nitrobenzoyl.

Lower alkanesulfonyl are e.g. C 1 -C 4 -alkanesulfonyl, such as methane or ethanesulfonyl.

Halogen is particularly those with an atomic number up to and including 35, such as fluorine, chlorine and bromine, and further includes iodine.

The compounds of formula I, their tautomers and/or their pharmaceutically usable salts exhibit, for example, valuable pharmacological, especially nootropic, properties. Consequently, they cause e.g. in the "Two-Compartment Passive Avoidance" trial model of Mondadori and Classen, Acta Neurol. Send. 69, suppl. 99, 125 ( 1984 ) in doses from approx. 0.1 mg/kg i.p. as well as p.o. in mice, a reduction of the amnesic effect of a cerebral electroshock.

Furthermore, the compounds of formula I have a significant memory-enhancing effect, which can be determined in the "Step-down Passive Avoidance" test according to Mondadori and Vaser, Psychopharmacol. jb3, 297 (1979 ) from a dose of approx. 0.1 mg/kg i.p. as well as p.o. in mice.

Accordingly, the compounds of formula I respectively their tautomers and/or their pharmaceutically usable salts can be used as pharmaceuticals, e.g. nootropics, for example for therapeutic and/or prophylactic treatment of cerebral insufficiency conditions, especially memory disorders. A further object of the invention is therefore the use of the compounds of formula I, their tautomers and/or their pharmaceutically usable salts for the preparation of drugs, in particular nootropics, for the treatment of cerebral insufficiency states, in particular memory disorders. This may also include the industrial preparation of the active substances.

The invention primarily relates to a process for the preparation of compounds of formula I, in which E-^ stands for lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl, N,N-dilower alkylcarbamyl, hydroxymethyl, lower alkanoyloxymethyl, lower alkanesulfonyloxymethyl, benzoyloxymethyl or pyridoyloxymethyl, Eg stands for hydrogen, hydroxy, lower alkoxy, benzyloxy, lower alkanoyloxy, lower alkanesulfonyloxy, benzoyloxy, pyridoyloxy, amino, lower alkanoylamino, lower alkanesulfonylamino, benzoylamino or pyridoylamino, alk stands for the lower alkylene, which bridges the two heteroatoms 0 and N entered in formula I, primarily at 2 to and with 4 C atoms, the ring A is unsubstituted or is singly, doubly or multi-substituted with hydroxy, lower alkoxy, lower alkanoyl, cyano, halogen, lower alkyl and/or trifluoromethyl and the dashed line shall express that there is a single or a double bond, for example a method for producing compounds of formula I in which R^ is lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl or N,N-dilower alkylcarbamyl, R 2 is hydrogen, hydroxy, lower alkoxy, benzyloxy, lower alkanoyloxy, lower alkanesulfonyloxy, benzoyloxy, pyridoyloxy, amino, lower alkanoylamino, benzoylamino or pyridoylamino, alk is for the lower alkyl that bridges the two heteroatoms 0 and N entered in formula I, primarily at 2 to 3 C atoms, the ring A is unsubstituted or singly, doubly or polysubstituted by hydroxy, lower alkoxy, lower alkanoyloxy, cyano , halogen, lower alkyl and/or trifluoromethyl and the dashed line shall express the presence of a single or a double bond, and their tautomers and/or salts.

The invention primarily relates to a process for the preparation of compounds of formula I in which R^ stands for C 1 -C 4 alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, n-butyloxycarbonyl or tert-butyloxycarbonyl, carbamyl, N-C 1 -C 4 -alkylcarbamyl, as N-methylcarbamyl , N ,N-di-C]_-C4~ alkylcarbamyl , as N,N-diethylcarbamyl, hydroxymethyl or Cg-Cg-alkanoyloxymethyl, as acetoxymethyl, Rg stands for hydrogen, hydroxy or amino, alk stands for C The ^-C4-alkylene which bridges the two heteroatoms 0 and N entered in formula I, primarily at 2 to 4 C atoms, such as ethylene, 1,3-propylene or 1,4-butylene, the ring A may be unsubstituted or mono-, di- or poly-substituted with C-L~C4 alkoxy such as methoxy, cyano, halogen with an atomic number up to and including 35, such as fluorine and/or chlorine, C^-C4 alkyl, such as methyl, and/ or trifluoromethyl and the dashed line must express that there is a single or a double bond, for example a method for producing a v compounds of formula I, in which R^ stands for C^-C4-alkoxycarbonyl, such as methoxycarbonyl or carbamyl, R2 stands for hydrogen or hydroxy, alk stands for the C^-C4~ alkylene which forms a bridge across the two heteroatoms entered in formula I 0 and N, primarily with 2 to 3 C atoms, such as ethylene or 1,3-propylene, the ring A being unsubstituted or mono-, di- or poly-substituted with C 1 -C 6 alkoxy, such as methoxy, cyano, halogen with an atomic number up to and including 35, such as fluorine and/or chlorine, C^-C^j alkyl, such as methyl, and/or trifluoromethyl and the dashed line shall express the presence of a double bond, and their tautomers and/or salts.

The invention relates in particular to a process for the preparation of compounds of formula I, in which R represents C1-C4 alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl or carbamyl, Rg represents hydrogen or hydroxy, alk represents C1-C4 alkylene which form a bridge over the two heteroatoms 0 and N entered in formula I, primarily with 2 to even 3 C atoms, such as ethylene or 1,3-propylene, the ring A is singly substituted with C 1 -C 4 alkoxy, which methoxy, C 1 -C 4 -alkyl, such as methyl or trifluoromethyl or doubly substituted with halogen with an atomic number up to and including 35, such as chlorine or C 1 -C 4 -alkyl, such as methyl or C 1 -C 4 -alkyl such as methoxy, as well as C 2 - C4-alkyl as methyl, and the dashed line shall express that there is a single or a double bond, and their tautomers and/or salts.

The invention primarily relates to a process for the preparation of compounds of formula I in which R^ stands for C^-C4-Alkoxycarbonyl, such as methoxycarbonyl, Rg stands for hydrogen, alk stands for ethylene, the ring A is singly substituted with C-L-C4-Alkoxy, such as methoxy, or trifluoromethyl or doubly substituted with an atomic number up to and including 35, such as chlorine, and the dashed line shall express the presence of a double bond, and tautomers and/or salts thereof.

The invention primarily relates to a method for producing the new compounds of formula I and their tautomers and/or salts indicated in the examples.

The object of the present invention is a process for the preparation of compounds of formula I, their tautomers and salts, e.g. characterized by the fact that man

a) reacts a compound of the formula

or a salt thereof with a compound of the formula

a tautomer and/or a salt thereof, whereby either Z^ is a group alk-X} and Zg is hydrogen, or Z^ is hydrogen and Zg a group alk-X^ in each case with as hydroxy or reactively esterified hydroxy, or

b) in a compound of the formula

a tautomer and/or a salt thereof, in which X2 represents a residue that can be transferred to , transfers the residue X2 to R^, or c) for the preparation of a compound of formula I, a tautomer and/or a salt thereof, in which R2 represents

hydroxy or amino, and in which R^ in particular stands for

lower alkoxycarbonyl, ring-closes a compound of the formula

in which Yj_ stands for a group of the formula -CH=R£, -C(Y2)=R^, -CH(Yg)-R2 or cyano, whereby R^ stands for oxo or imino and Y2 stands for a cleavable residue, or a salt thereof, or d) for the preparation of a compound of formula I', a tautomer and/or a salt thereof, in which R^ stands for oxo or imino and the dashed line shall express that there is a single mixture, and in which R^ in particular stands for lower alkoxycarbonyl, reacts a compound of the formula or a tautomer or a salt thereof with a compound of the formula

or a salt thereof, in which X3 stands for halogen or lower alkoxy, or

e) for the preparation of a compound of formula I, a tautomer and/or a salt thereof, where R2 is different

from hydrogen, in a compound of the formula

or a salt thereof, in which X4 stands for a residue that can be transferred to R2 , transfers X4 to R2 or f) especially for the preparation of a compound of formula I, a tautomer and/or a salt thereof, in which R2 stands for

hydrogen, in a compound of the formula

in which A- stands for the anion of an acid, and R^ stands for hydrogen, etherified, esterified or protected hydroxy or acylated or protected amino, reduces the excess double bond to a single bond and cleaves off any protective group present and, if desired, transfers one according to the invention or on otherwise obtained compound to another compound of formula I, separates an isomer mixture obtained according to the invention into its components, splits an enantiomer or diastereomer mixture obtained according to the invention into the enantiomers or diastereomers, transfers a free compound of formula I obtained according to the invention to a salt and/ or converts an obtained salt into the free compound of formula I or into another salt.

The transactions described above and in the variants below are carried out in a manner known per se, e.g. in the absence, or usually in the presence, of a suitable solvent or diluent or a mixture of such, whereby, as required, one works under cooling, at room temperature or under heating, e.g. in a temperature range from approx. -10°C to the boiling point of the reaction medium, preferably from approx. 20°C to approx. 150°C, and if necessary, in a closed container, under pressure, in an inert gas atmosphere and/or working under anhydrous conditions.

The starting materials of the formulas Ia and Ilb, III, IV, Va and Vb, VI and VII indicated above and in the following, which have been developed for the preparation of compounds of the formula I, their tautomers and salts are in part known or can be prepared by known methods procedures, e.g. analogously to the method variants indicated above.

Starting materials with basic centers can e.g. exist in the form of acid addition salts, for example with the above-mentioned acids, while starting compounds with acidic groups can form salts with bases, e.g. of the type specified above. Furthermore, the starting compounds can exist in the form of tautomers, especially in the case of compounds of formula IIb, when R2 stands for hydroxy and the dashed line shall indicate that a double bond is present.

Variant a):

Reactively esterified hydroxy means especially with a strong inorganic acid or organic sulfonic acid esterified hydroxy, for example halogen, such as chlorine, bromine or iodine, sulfonyloxy, such as hydroxysulfonyloxy, halogensulfonyloxy, e.g. fluorosulfonyloxy, optionally, e.g. with halogen, substituted lower alkanesulfonyloxy, e.g. methane- or trifluoromethanesulfonyloxy, cycloalkanesulfonyloxy, e.g. cyclohexane-sulfonyloxy, or optionally, e.g. with lower alkyl or halogen, substituted benzenesulfonyloxy, e.g. p-bromophenyl or p-toluenesulfonyloxy. The N-alkylation is carried out in particular in the presence of a condensing agent, such as a suitable base. Bases include, for example, alkali metal hydroxides, hydrides, amides, alkanolates, carbonates, triphenylmethylides, dilower alkyl amides, amino lower alkyl amides or lower alkyl silyl amides, naphthalene amines, lower alkyl amines, basic heterocyclic compounds, ammonium hydroxides such as carbocyclic amines. Examples include sodium hydroxide, -hydride, -amide, -ethylate, potassium tert-butylate, -carbonate, lithium tri-phenylmethylide, lithium diisopropylamide, potassium 3-(aminopropyl)-amide, -bis-(trimethylsilyl)-amide, dimethylaminonaphthalene, di- or triethylamine, pyridine, benzyl-trimethyl-ammonium hydroxide, 1,5-diaza-bicyclo[4.3.0]non-5-ene (DBN) and 1,5-diaza-bicyclo[5.4.0]undec -5-en (DBU ).

The starting materials of the formulas Ila and Ilb are partially known or can be prepared analogously to known starting materials.

Variant, b ):

A residue Xg transferable to Ri is, for example, a carboxy functionally derived from R^differently, such as cyno, anhydridized carboxy or from esterified or amidated carboxy R-^differently esterified or amidated carboxy.

Anhydridized carboxy is, for example, carboxy that is anhydridized with a mineral acid, such as hydrohalic acid, or with a carboxylic acid, such as an optionally substituted lower alkane or benzoic acid or a carboxylic acid halide lower alkyl half-ester. Examples may be mentioned of halogenocarbonyl, such as chlorocarbonyl, lower alkanoyloxycarbonyl, such as acetyloxycarbonyl, or loweralkyloxycarbonyl, such as ethoxycarbonyloxycarbonyl.

X2 can, for example, be transferred to R^ by solvolysis. Solvolysis agents are, for example, lower alkanols corresponding to the desired esterified carboxy R^, ammonia or amines corresponding to the desired amidated carboxy group R^. The treatment with a solvolytic agent is optionally carried out in the presence of an acid or base. Acids include, for example, inorganic or organic protonic acids, such as mineral acids, e.g. sulfuric acid or hydrogen halide acids, for example citric acid, such as sulphonic acids, e.g. lower alkane or optionally substituted benzenesulfonic acid, for example methane- or p-toluenesulfonic acid, or as carboxylic acids, e.g. lower alkane carboxylic acids, for example acetic acid in question, while as bases possibly those indicated under variant a) can be used, especially sodium or potassium hydroxide.

Cyano, anhydridized carboxy and from esterified or amidated carboxy R-^differently esterified or amidated carboxy is alcoholized, for example, with a suitable lower alkanol to esterified carboxy R} and cyano and anhydridized carboxy ammono-, respectively, is aminolyzed, for example, with ammonia or an amine corresponding to the amidated carboxy R ^.

The starting material of formula III can be prepared analogously to the method mentioned under variant a) by reacting a compound of the formula

with a compound of the formula

a tautomer and/or a salt thereof in the presence of one of said bases.

Variant c):

Cleavable residues Y2 in the groups of formula -CfYg)»!^ or-CH(Y2)-R2 are e.g. etherified or reactive esterified hydroxy groups, such as lower alkoxy, halogen or sulfonyloxy.

The cyclization can, for example, be carried out analogously to the Dieckmann reaction, especially in the presence of one of the bases specified under variant a) and during subsequent hydrolytic work-up.

In a preferred embodiment, one can, for example, submit a compound of the formula

wherein R 2 stands for oxo or imino, treatment with one of the aforementioned bases, in particular with an alkali metal low-alkanolate, e.g. with sodium methanolate or sodium ethanolate. The compound IVa is thereby ring-closed to a compound of formula I, in which the dashed line indicates that there is no double bond and R2 stands for hydroxy or amino. Starting materials IVa are obtained, e.g. by reacting a reactive phenoxyethyl ester of the formula in which Z-l stands for a group of the formula alk-X^, in which hydroxy is reactively esterified with a compound of the formula H2N-CH2-CH2-Ri (IVb) and the obtained intermediate of the formula

is reacted with acrolein or an optionally functionally derived aldehyde of the formula Y1-CH2-CH2-CH=R^ (IVd; Y±= reactive esterified hydroxy; R£ = oxo or imino).

In another preferred embodiment of variant c) a compound of formula IV is ring-closed, in which Y]_ and R^ stand for lower alkoxycarbonyl, i.e. in which Y^ stands for a group of the formula -C(Y2)=R£, in which R£ is oxo and the cleavable radical Y2 is shown as etherified hydroxy a lower alkoxy group, to the corresponding compound of formula I', in which R£ is oxo.

For the production of the latter starting compounds of formula IV, one can for example proceed from compounds of the formula

or salts thereof, such as e.g. can be obtained by reduction of the corresponding nitriles, and these are reacted with at least 2 mol of a compound of the formula

Variant d):

The C-acylation according to the invention can in particular take place in the presence of one of the bases mentioned under variant a). The reaction of a compound of the formula with a compound of the formula

or a salt thereof, analogously leads to the N-alkylation according to variant a) in the presence of one of the aforementioned bases to starting material of formula Va.

Variant e):

Residues X4 that can be transferred to Rg are, for example, residues that can be transferred to a group Rg by solvolysis, i.e. reaction with a compound of the formula RgH or a salt thereof, for example reactive esterified hydroxy groups, such as halogen atoms, e.g. chlorine, bromine or iodine. Residues X4 which can be transferred to hydroxy are further diazonium groups, e.g. of the formula -N2<+>A~, where A~ is the anion of a strong acid, such as a mineral acid, e.g. the chloride or sulfate ion.

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. sodium or potassium hydroxide, or a tertiary nitrogen base, e.g. a trilower alkylamine, such as triethylamine, or a heteroaromatic nitrogen base, such as pyridine, respectively a quaternary ammonium hydroxide, such as benzyl trimethyl ammonium hydroxide, or by using the compound Via in the form of a metal salt, e.g. of the formula R2~M<+>(VIb), where M<+>is an alkali metal cation, such as the sodium ion. It is advantageous to work in the presence of a solvent or diluent, e.g. in an excess of the reaction component Via and/or an inert solvent miscible with it, if necessary during cooling or heating, e.g. in the temperature range from approx. 0°C to approx. 120° C, and/or under inert gas, such as nitrogen.

The solvolysis of the residues X4 to groups R2 may optionally be combined with the solvolytic transfer of solvolysable groups R 1 to other groups R^ according to the invention, for example, in the ammonolysis of the residue X4 to amino R2, lower alkoxycarbonyl groups R-^ or other groups R^ which can be solvolyzed to carbamyl is simultaneously ammonolysed to carbamyl groups R^.

For the preparation of the starting compounds of formula VI and their salts, one starts, for example, from compounds of formula Ila

and reacts this with a corresponding compound of the formula

or a salt thereof in the presence of one of the above-mentioned bases, whereby e.g. proceeds in a similar way as described under method variant a).

In a preferred embodiment, compound VI is obtained, in which X4 represents halogen and the dotted line represents a single bond, and salts thereof, by reacting a compound of formula I, in which R2 represents hydroxy and the dotted line represents a single bond, or a salt thereof with a halogenating agent, such as phosphotri- or -pentachloride or thionyl chloride, whereby the corresponding compounds I and their salts can for example be obtained in a similar manner as described under method variant a).

Variant f):

The anion A" is, for example, the anion of a strong protonic acid, e.g. a halide ion, such as a chloride, bromide or iodide ion, or a sulfonate ion, such as an optionally substituted lower alkane or benzene sulfonate, e.g. methanesulfonate, ethanesulfonate or p-bromophenylsulfonate or p-toluenesulfonation. Rg* is in particular hydrogen, etherified hydroxy Rg or protected hydroxy. Protected hydroxy is, for example, silyloxy, such as tr ilaverealkylsilyloxy, e.g. methylsilyloxy, but can also be trif enyllaverealoxy, eg trityloxy Protected amino is for example silylamino, such as trilower alkylsilylamino, eg trimethylsilylamino, but can also be phenyl, diphenyl or triphenyl lower alkylamino, such as benzylamino, diphenylamino or tritylamino.

The reduction of the excess double bond takes place by treatment with a suitable reducing agent, for example by hydrogenation in the presence of a hydrogenation catalyst, by reduction with a hydride-transferring reagent or by reduction with a metallic reduction system of metal and proton-releasing agent.

As hydrogenation catalysts, e.g. elements from the VIII. the side group in the periodic table of the elements or their derivatives in question, such as palladium, platinum, platinum oxide, ruthenium, rhodium, tris(triphenylphosphane)-rhodium-I-halide, e.g. -chloride, or Raney nickel, which is optionally applied to a carrier material, such as activated carbon, alkali metal carbonate or -sulphate or a silica gel. Suitable hydride-transferring reagents include, for example, light metal hydrides, in particular alkali metal aluminum hydrides respectively

-borohydrides in question, such as lithium aluminum hydride, lithium triethylborohydride, sodium borohydride, sodium cyanoborohydride or tin hydrides, such as triethyl or tributyltin hydrate, or diborane. The metal component of the metallic reduction system is, for example, a base metal, such as alkali or alkaline earth metal, e.g. lithium, sodium, potassium, magnesium or calcium, or transition metal1, e.g. zinc, tin, iron or titanium, while as a proton-releasing agent e.g. protonic acids of the above-mentioned type, such as hydrochloric or acetic acid, lower alkanols, such as ethanol and/or amines and/or ammonia are used. Such systems are, for example, sodium/ammonia, zinc/hydrochloric or acetic acid or zinc/ethanol. The production of the starting compounds of formula VII takes place, for example, by reacting compounds of the formula

in which Zi represents a group of the formula alk-A, in which A is the anion A~ of the corresponding reactively esterified hydroxy, with compounds of the formula

or a salt thereof, whereby one e.g. can proceed in a similar way as described under method variant a).

In the starting substances of the formulas IIb, III and IIIa, a hydroxy group Rg can be present in the ether, respectively a hydroxy or amino group Rg also in intermediately protected form. Protected hydroxy is, for example, trimethylsilyloxy, but can also be triphenyllower oxy, e.g. trityloxy. Protected amino is, for example, silylamino, so trilower alkylsilylamino, e.g. trimethylsilylamino, but can also be phenyl, diphenyl or triphenyl lower alkylamino, such as benzylamino, diphenylmethylamino or tritylamino.

The release of intermediately protected residues Rg , i.e. cleavage of the intermediate protective groups, takes place in the usual way, for example by solvolysis, as mild hydrolysis, e.g. treatment with water under neutral or slightly acidic conditions, e.g. by the influence of dilute aqueous mineral or carboxylic acids, e.g. of dilute hydrochloric or acetic acid. In a similar way, the release of intermediately protected hydroxy or amino groups Rg1 takes place in starting substances of the formulas VII and Vila respectively.

Compounds of formula I according to the invention or obtained in another way can be transferred to other compounds of formula I in the usual way.

Consequently, one can e.g. transfer esterified carboxy groups R^ to other esterified carboxy groups in the usual way by transesterification, i.e. treatment with an alcohol in the presence of an acidic or basic solvolytic agent, such as a mineral acid, e.g. sulfuric acid, respectively a corresponding alkali metal alcoholate or alkali metal hydroxide, or by reaction with ammonia or a corresponding amine containing at least one hydrogen atom to amidated carboxy R^.

Furthermore, optionally present hydroxy groups can be esterified, e.g. by treatment with a lower alkane carboxylic acid anhydride respectively transfer -halide to lower alkanoyloxy or by reaction with a reactive ester, especially hydrogen bromide or hydrogen chloride ester, transfer a lower alkanol to corresponding etherified hydroxy. Conversely, from esterified or etherified hydroxy, such as lower alkanoyloxy or lower alkoxy, the hydroxy groups can be solvolytically set free, preferably under acidic conditions. In a similar way, one can also hydrolyze etherified or acylated hydroxy Rg t:i-1 hydroxy.

Correspondingly, one can further esterify hydroxymethyl R^, e.g. on treatment with a lower alkane carboxylic acid anhydride, respectively, -halide is transferred to lower alkanoyloxymethyl Rj^. Conversely, one can from acylated hydroxymethyl, e.g. lower alkanoyloxymethyl, R^ solvolytically set the hydroxy groups free, preferably under acidic conditions.

Furthermore, hydroxymethyl R-^ can be transferred in the usual way to lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl or N,N-dilower alkylcarbamyl R-^, whereby one e.g. proceeds in such a way that hydroxymethyl R-^ is first oxidized to carboxy in the usual way, e.g. in the presence of an oxidizing agent, such as potassium permanganate or potassium dichromate, and then the carboxy group is transferred in the usual manner, e.g. by treatment with a corresponding alcohol in the presence of a mineral acid, e.g. of sulfuric acid, or by transfer to a halide and subsequent reaction with a corresponding alcohol, e.g. in the 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, or using a dehydrating agent, such as N,N'-dicyclohexylcarbodiimide, with a corresponding alcohol to lower alkoxycarbonyl R^, or by reaction with ammonia or an amine which exhibits at least one hydrogen atom and dehydration of the intermediate danked ammonium salt, e.g. by heating or by means of a dehydrating agent, such as N,N'-dicyclohexylcarbodiimide or by transfer to the halide and subsequent reaction with ammonia or an amine containing at least one hydrogen atom to amidated carboxy R^. Furthermore, acylated hydroxymethyl R^ can be transferred to esterified or amidated carboxy R^, by first solvolytically setting the acylated hydroxy methyl group free, e.g. as described above, and then transfers the obtained free hydroxymethyl group, as described above, to a carboxyl group and further converts the latter to an esterified or amidated carboxyl group. Conversely, esterified or amidated carboxyl groups R^ can be transferred to optionally acylated hydroxymethyl R^, by first hydrolyzing the esterified or amidated carboxyl group R^ in the usual way, for example in the presence of a basic or acidic hydrolysis agent, such as an alkali metal hydroxide or -carbonate, e.g. sodium hydroxide or potassium carbonate, or a mineral acid, e.g. hydrochloric or sulfuric acid, to carboxy and then reducing the carboxy group obtained in the usual way, e.g. in the presence of a reducing agent, for example of the type mentioned above, to hydroxymethyl Rj, whereby if desired the latter, as described above, can then be transferred to acylated hydroxymethyl R^.

If the dashed line present in compounds that can be obtained according to the invention means a double bond, this can e.g. in a manner known per se by means of a reducing agent, e.g. of the type specified under variant f) is hydrogenated to a single bond.

Furthermore, an obtained compound according to the invention in which the dashed line represents a double bond and Rg represents hydrogen, e.g. in a manner known per se by addition of than compound Rg-H, in which Rg stands for an optionally etherified or acylated hydroxy group or an optionally acylated amino group, is transferred to a corresponding piperidine compound according to the invention. The addition is carried out in particular in the presence of a suitable base, e.g. of the type specified under variant a).

Obtained compounds according to the invention in which the dashed line represents a single bond:! ng can vice versa, e.g. by eliminating a compound Rg-H, in which Rg is an optionally etherified or acylated hydroxy group or an optionally acylated amino group, is transferred in a manner known per se to corresponding tetrahydro-pyridine compounds according to the invention, in which Rg stands for hydrogen. Cleavable groups Rg which are poorly suited for an elimination, e.g. hydroxy, can thereby beforehand, e.g. in situ, is transferred to honor suitable leaving groups Rg, e.g. lower alkanesulfonyloxy, such as methanesulfonyloxy or halogen, such as chlorine, bromine or iodine. The elimination thereby takes place particularly in the presence of a suitable base, e.g. of the type specified under variant a).

Salts of compounds of formula I or their tautomers can be prepared in a manner known per se. Consequently, one obtains, for example, acid addition salts of compounds of formula I by treatment with an acid or a suitable ion-exchange reagent. Salts can be transferred in the usual way to the free compounds, acid addition salts e.g. by treatment with a suitable basic agent.

Depending on the method or the reaction conditions, the compounds obtained according to the invention can be obtained with salt-forming, especially basic properties, in free form or in the form of salts.

Due to the close relationship between the new compounds in free form and in the form of salts, in the preceding and following terms, free compound must also be understood as salts, and under salts respectively also the corresponding free compounds.

The new compounds that can be obtained according to the invention including their salts of salt-forming compounds can also be obtained in the form of hydrates or include other solvents, such as e.g. is used for crystallization of compounds that are in solid form.

The new compounds obtained according to the invention may, depending on the choice of starting materials and working methods, be in the form of one of the possible isomers or as a mixture of these. Depending on the molecular symmetry, e.g. of the number, absolute and relative configuration of the chirality centers, such as asymmetric C atoms, these can be obtained as pure isomers, e.g. pure enantiomers and/or pure diastereomers, such as pure cis/trans isomers or meso compounds. Similarly, as mixtures of isomers, e.g. present enantiomeric mixtures, such as racemates, diastereomer mixtures or racemate mixtures.

Obtained diastereomer mixtures and racemate mixtures can, on the basis of the physico-chemical differences between the components, be divided into the pure diastereomers or racemates in a known manner, for example by fractional crystallization.

Obtained enantiomer mixtures, such as racemates, can be separated into the enantiomers by known methods, for example by recrystallization from an optically active solvent, chromatography on chiral adsorbents, with the help of suitable microorganisms, by cleavage with specific immobilized enzymes, by formation of inclusion compounds, e.g. under use of chiral crown ethers, whereby only one enantiomeric complex is found, or by transfer to diastereomeric salts, e.g. by reacting a basic end product racemate with an optically active acid, such as carboxylic acid, e.g. tartaric or malic acid, or sulphonic acid, e.g. camphorsulfonic acid, and separation of the diastereomer mixture thus obtained, e.g. on the basis of different solubilities, in the diastereomers, from which the desired enantiomer can be set free by the action of suitable agents. Preferably, the most active enantiomer is isolated.

The invention also relates to those embodiments of the method where one starts from a compound obtained as an intermediate in any step of the method and carries out the missing steps, or uses a starting material in the form of a derivative or salt and/or its racemate or enantiomers, or especially form these under the reaction conditions.

In the method according to the present invention, such starting materials are preferably used which lead to the compounds which are indicated at the outset as particularly valuable. The process for the production of new starting materials, which has been developed specifically for the production of the compounds according to the invention and their use, also forms the subject of the present invention, whereby the variables R , R , and alk as well as the substituents on the ring A have the meanings indicated for the preferred compound groups of formula I.

The invention also relates to the use of compounds of formula I, their tautomers and/or pharmaceutically usable salts of such compounds with salt-forming properties, especially as pharmacological, primarily nootropically active substances. Hereby, they can, preferably in the form of pharmaceutical preparations, be used in a method for prophylactic and/or therapeutic treatment of humans or animals, especially as nootropics, e.g. for the treatment of cerebral insufficiency 1 conditions, especially memory disorders.

The invention also relates to pharmaceutical preparations containing a compound of formula I or a tautomer and/or a pharmaceutically usable salt thereof as active substance, as well as methods for their preparation.

The pharmaceutical preparations according to the invention, which contain a compound of formula I or a tautomer and/or a pharmaceutically usable salt thereof, are those for enteral, such as oral, further rectal, and parenteral administration to warm-blooded animals, whereby the pharmacological the active substance is available alone or together with common pharmaceutical excipients.

The new pharmaceutical preparations contain e.g. from approx. 10 to approx. 80$, preferably from approx. 20 to approx. 60$, of the active substance. Pharmaceutical preparations according to the invention for enteral or parenteral administration are e.g. preparations in such dosage unit forms as dragées, tablets, capsules or suppositories, further ampoules. These are produced in a manner known per se, e.g. using conventional mixing, granulating, coating, dissolving or lyophilizing methods. Consequently, pharmaceutical preparations for oral use can be obtained by mixing the active substance with solid carriers, an obtained mixture is optionally granulated and the mixture or the granulate is processed, if desired or necessary, after the addition of suitable excipients, into tablets or dragé cores.

Suitable carriers are especially fillers, such as sugar, e.g. lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphate, e.g. tricalcium phosphate or potassium hydrogen phosphate, further binders, such as starch glue, using e.g. corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and/or polyvinylpyrrolidone, if desired, explosives, such as the above-mentioned starches, further carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Aids are primarily flow agents, regulating and lubricating agents, e.g. silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Dragon cores are equipped with suitable, possibly gastric juice-resistant covers, whereby one e.g. use concentrated sugar solutions which possibly contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the production of gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate. The tablets or dragé coatings may have added dyes or pigments, e.g. for identification or indication of different doses of active substance.

Further orally usable pharmaceutical preparations are gelatin suppositories, as well as soft, closed capsules of gelatin and a plasticizer, such as glycerol or sorbitol. The capsules can contain the active substance in the form of a granule, e.g. in a mixture with fillers, such as lactose, binders, such as starches, and/or lubricants, as well as talc or magnesium stearate, and possibly stabilizers. In soft capsules, the active substance is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, to which stabilizers may possibly be added.

As rectally applicable pharmaceutical preparations, e.g. suppositories in consideration, consisting of a combination of the active substance with a suppository base. As a suppository base material, e.g. natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. Furthermore, gelatin rectal capsules can also be used which contain a combination of the active substance with a base substance. As base materials come e.g. liquid triglycerides, polyethylene glycols or paraffin hydrocarbons in question.

For parenteral administration, primarily aqueous solutions of an active substance in water-soluble form are suitable, e.g. a water-soluble salt, further suspensions of the active substance as corresponding oily injection suspensions, whereby suitable lipophilic solvents or carriers are used, such as fatty oils, e.g. sesame oil, or synthetic fatty acid esters, e.g. ethyl oleate or triglycerides, or aqueous injection suspensions containing viscosity-increasing substances, e.g. sodium carboxymethylcellulose, sorbitol and/or dextran and optionally also stabilizers.

The dosage of the active substance may depend on various factors, such as method of administration, species of warm-blooded animal, age and/or individual condition. Normally, for a warm-blooded animal of approx. 75 kg when used orally, an approximate daily dose from approx. 20 to approx. 500 mg, especially from approx. 25 to approx. 250 mg, preferably divided into several equal partial doses, recommended.

The following, non-limiting, examples shall illustrate the above-mentioned invention.

Due to the close relationship between a compound of formula I and the corresponding tautomeric compound of formula I', in the examples with a compound of formula I the tautomeric compound of formula I' must also be understood. The same applies to a compound of formula I', as well as to salts of the compounds of formulas I and I'.

Example 1

2.54 g (10 mmol) 1-bromo-2-(2,4-dichlorophenoxy)-ethene and 2.66 g (12 mmol) 1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrobromide are dissolved in 20 ml of absolute dimethylformamide. A solution of 2.84 g (22 mmol) of N-ethyl-N,N-diisopropylamine in 20 ml of absolute toluene is then added dropwise at room temperature. The mixture is allowed to stand for 48 hours at room temperature and is then stirred for 12 hours at 50°C. For processing, the solvents are removed in vacuum or high vacuum at a maximum of 40-50°C, and the obtained residue is dissolved in 30 ml of 2N hydrochloric acid. The acidic, aqueous solution is decanted with diethyl ether, the aqueous phase is separated and the organic phase is washed with water. The pooled aqueous extracts

or synthetic fatty acid esters, e.g. ethyl oleate or triglycerides, or aqueous injection suspensions containing viscosity-increasing substances, e.g. sodium carboxymethylcellulose, sorbitol and/or dextran and optionally also stabilizers.

The dosage of the active substance may depend on various factors, such as method of administration, species of warm-blooded animal, age and/or individual condition. Normally, for a warm-blooded animal of approx. 75 kg when used orally, an approximate daily dose from approx. 20 to approx. 500 mg, especially from approx. 25 to approx. 250 mg, preferably divided into several equal partial doses, recommended.

The following, non-limiting, examples shall illustrate the above-mentioned invention.

Due to the close relationship between a compound of formula I and the corresponding tautomeric compound of formula I', in the examples with a compound of formula I the tautomeric compound of formula I' must also be understood. The same applies to a compound of formula I', as well as to salts of the compounds of formulas I and I'.

Example 1

2.54 g (10 mmol) 1-bromo-2-(2,4-dichlorophenoxy)ethene and 2.66 g (12 mmol) 1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrobromide are dissolved in 20 ml of absolute dimethylformamide. A solution of 2.84 g (22 mmol) of N-ethyl-N,N-di in sopropylamine in 20 ml of absolute toluene is then added dropwise at room temperature. The mixture is allowed to stand for 48 hours at room temperature and is then stirred for 12 hours at 50°C. For processing, the solvents are removed in vacuum or high vacuum at a maximum of 40-50°C, and the obtained residue is dissolved in 30 ml of 2N hydrochloric acid. The acidic, aqueous solution is decanted with diethyl ether, the aqueous phase is separated and the organic phase is washed with water. The pooled aqueous extracts

made basic in the cold state with saturated sodium hydrogen carbonate solution and decanted four times with diethyl ether/dichloromethane (3:1). The organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo. The obtained oil, consisting of crude 1-[2-(2,4-dichlorophenoxy)ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester is crystallized from diethyl ether/pentane to give the pure compound of m.p. 63-66°C. 30 g (9.08 mmol) of pure 1-[2-(2,4-dichlorophenoxy)-ethyl]-1,2,5,6-tetrahydro-pyrldine-3-carboxylic acid methyl ester are dissolved in a little isopropanol and mixed until a strongly acidic reaction with ethereal hydrochloric acid. The precipitated product is filtered off and recrystallized from isopropanol/methanol/diethyl ether. The pure 1-Å2-(2,4-dichlorophenoxy)ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrochloride (yield: 90% of theory) melts at 172-175°C.

Example 2

Analogous to example 1 is obtained from 2.31 g (10 mmol) of 1-bromo-2-(o-methoxyphenoxy)-ethane, 2.66 g (12 mmol) of 1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester -hydrobromide and 2.84 g (22 mmol) of N-ethyl-N,N-diisopropylamine the crude 1-[2-(o-methoxyphenoxy)-ethyl]-1,2,5,6-tetrahydro-pyridine -3-carboxylic acid methyl ester. The crude base is purified with cyclohexane on "Florisil" and then transferred in isopropanol/diethyl ether to the oxalate (yield: 77$ of theoretical). The pure 1-[2-(o-methoxyphenoxy)ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester oxalate melts at 128-131°C.

Example 3

Analogous to example 1 is obtained from 2.31 g (10 mmol) of 1-bromo-2-(m-methoxyphenoxy)-ethane, 2.66 g (12 mmol) of 1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester -hydrobromide and 2.84 g (22 mmol) of N-ethyl-N,N-diisopropyl-amine 1-[2-(m-methoxyphenoxy)-ethyl]-1,2,5,6-tetrahydro-pyridine-3- carboxylic acid methyl ester. From the free base, the hydrochloride is precipitated with ethereal hydrochloric acid and recrystallized from isopropanol/diethyl ether. The pure 1-[2-(m-methoxyphenoxy)ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrochloride is obtained in a yield of 82% of theory and melts at 155-157°C.

Example 4

Analogous to example 1 is obtained from 2.35 g (10 mmol) of 1-bromo-2-(p-chlorophenoxy)-ethane, 2.66 g (12 mmol) of 1,2,5,6-tetrahydro-pyridine-3- carboxylic acid methyl ester hydrobromide and 2.84 g (22 mmol) N-ethyl-N,N-diisopropylamine 1-[2-(p-chlorophenoxy)ethyl]-1,2,5,6-tetrahydro-pyridine-3 -carboxylic acid methyl ester. From the free base, the hydrochloride is precipitated with ethereal hydrochloric acid and this is recrystallized from isopropanol/diethyl ether. The pure 1-[2-(p-chlorophenoxy)ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrochloride melts at 158-160°C (yield: 74% of theory).

Example 5

Analogous to example 1 is obtained from 5.78 g (25 mmol) of 1-bromo-2-(p-methoxyphenoxy)-ethane, 6.66 g (30 mmol) of 1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester -hydrobromide and 7.10 g (55 mmol) N-ethyl-N,N-diisopropyl-amine 1-[2-(p-methoxyphenoxy)-ethyl]-1,2,5, 6-tetrahydro-pyridine-3- carboxylic acid methyl ester. The free base is transferred to the hydrochloride with ethereal hydrochloric acid and this is recrystallized from isopropanol/diethyl ether. The pure 1-[2-(p-methoxyphenoxy)ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrochloride (yield: 77% of theory), containing 0.25 equivalents of water of crystal, melt at 131-134°C.

Example 6

Analogous to example 1 is obtained from 5.65 g (25 mmol) of 1-bromo-2-(p-cyanophenoxy)-ethane, 6.66 g (30 mmol) of 1,2,5,6-tetrahydro-pyridin-3- carboxylic acid methyl ester hydrobromide and 7.10 g (55 mmol) N-ethyl-N,N-diisopropylamine the crude l-[2-(p-cyano-phenoxy)ethyl]-1,2,5,6-tetrahydro- pyridine-3-carboxylic acid methyl ester. The crude base is recrystallized from toluene/hexane to give the pure 1-[2-(p-cyanophenoxy)ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester in a yield of 80% of theory (m.p. 81-83°C).

Example 7

Analogous to example 1 is obtained from 13.5 g (50 mmol) of 1-bromo-2-(m-trifluoromethylphenoxy)-ethane, 13.3 g (60 mmol) of 1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester -hydrobromide and 14.2 g (1.10 mmol) of N-ethyl-N,N-diisopropylamine the crude 1-[2-(m-trifluoromethylphenoxy)ethyl]-1,2,5,6-tetrahydro-pyridine-3 -the carboxylic acid methyl ester. The crude product is purified with 12 g "Florisil" cyclohexane. The hydrochloride is then prepared with ethereal hydrochloric acid from the purified base, and recrystallized from isopropanol/diethyl ether. The pure 1-[2-(m-trifluoromethylphenoxy)ethyl]-1,2,5,6-tetrahydro-pyr in the din-3-carboxylic acid methyl ester hydrochloride is obtained in a yield of 60$ of theoretical (melting point 144-147° C).

Example 8

Analogous to example 1 is obtained from 6.45 g (30 mmol) of 1-bromo-2-(p-methylphenoxy)-ethane, 8.0 g (36 mmol) of 1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester -hydrobromide and 8.53 g (66 mmol) of N-ethyl-N,N-diisopropylamine the crude 1-[2-(p-methyl-phenoxy)ethyl]-1,2,5,6-tetrahydro-pyridine -3-carboxylic acid - methyl ester. From the crude base, the hydrochloride is prepared with ethereal hydrochloric acid and this is recrystallized from isopropanol/diethyl ether. The pure 1-[2-(p-methylphenoxy)ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrochloride which crystallizes with 0.5 equivalents of water of crystal, melts at 140-143° C (yield: 73$ of theoretical).

Example 9

4.8 g (14 mmol) of N,N-bis(2-methoxycarbonylethyl)-N-[2-(p-chlorophenoxy)ethyl]-amine are dissolved in 50 ml of absolute toluene and added at 40-50°C dropwise to a suspension of 0.8 g (16.8 mmol) sodium hydride (50$ suspension in mineral oil) in 50

ml of toluene. The separation mixture is heated for 3 hours to 80°C. Then a mixture of toluene and methanol is distilled off at an internal temperature of 110°C. The obtained residue is poured onto an ice/hydrochloric acid mixture. The organic phase is separated and the acidic aqueous phase is made alkaline with saturated sodium bicarbonate solution. The mixture is decanted four times with diethyl ether/dichloromethane (3:1) and the organic phases are washed with saturated sodium chloride solution and dried over magnesium sulfate. The solvent is removed in vacuo, the oily residue is purified with chlorohexane from 5 g of "Florisil". The obtained the eluate is evaporated to dryness and the residue is mixed with ethereal hydrochloric acid. The precipitated hydrochloride is recrystallized from a little isopropanol/diethyl ether. The pure 1-[2-(p-chlorophenoxy)ethyl]-4-hydroxy-1,2,5,6-tetrahydro- pyr in the din-3-carboxylic acid methyl ester hydrochloride respectively the 1-[2-(p-chlorophenoxy)ethyl]-4-oxo-piperidine-3-carboxylic acid methyl ester hydrochloride melt at 163-164°C (yield 71$ of theoretical).

N,N-bis(2-methoxycarbonylethyl)-N-[2-(p-chlorophenoxy)ethyl]-amine can e.g. is obtained in the following way: 17.1 g (100 mmol) of 2-(p-chlorophenoxy)ethylamine and 21.5 g (250 mmol) of acrylic acid methyl ester are dissolved in 200 ml of methanol and boiled for 12 hours under reflux. The reaction mixture is then evaporated under reduced pressure to dryness. The crude, oily N,N-bis(2-methoxycarbonylethyl)-N-[2-(p-chlorophenoxy)ethyl]-amine is used further (yield: 100$ of theoretical).

Example 10

From 6.79 g (20 mmol) N,N-bis(2-methoxycarbonylethyl)-N-[2-(p-methoxy enoxy )ethyl]-amine and 1.15 g (24 mmol) sodium hydride dispersion (50$ in mineralol; prepared analogously to example 9 1 - [2 - ( p-methoxy enoxy ) ethyl j -4-hydroxy-1 ,2,5, 6- tetrahydro-pyridine-3-carboxylic acid methyl ester hydrochloride respectively l-[ 2-(p-Methoxyphenoxy)ethyl]-4-oxo-piper In the din-3-carboxylic acid methyl ester hydrochloride in a yield of 60% of theory (m.p. 170-172°C).

N,N-bis(2-methoxycarbonylethyl)-N-[2-(p-methoxyphenoxy)ethyl]-amine can e.g. is prepared in the following way: 8.06 g (50 mmol) of 2-(p-methoxyphenoxy)ethylamine and 12.9 g (150 mmol) of acrylic acid methyl ester are dissolved in 100 ml of methanol and boiled for 12 hours under reflux. After removal of the solvent under reduced pressure, the crude N,N-bis(2-methoxycarbonylethyl)-N-[2-(p-methoxyphenoxy)ethyl]-amine is obtained as a viscous oil in a yield of 100% of theory.

Example 11

From 10.81 g (30 mmol) of N,N-bis-(2-methoxycarbonylethyl)-N-[2-(o-methoxyphenoxy)ethyl]-amine and 1.73 g (36 mmol) of sodium hydride dispersion (50$ in mineral oil ) is obtained analogously to example 9 1-[2-(o-methoxyphenoxy)ethyl]-4-hydroxy-1,2,5,6-tetrahydro-pyr idin-3-carboxylic acid methyl ester hydrochloride, where 1-[2 -(o-methoxyphenoxy)ethyl]-4-oxo-piperidine-3-carboxylic acid methyl ester hydrochloride in a yield of 60% of theory (m.p. 138-140°C).

N,N-bis-(2-methoxycarbonylethyl)-N-[2-(o-methoxyphenoxy)ethyl]-amine can e.g. is prepared as follows: 8.06 g (50 mmol) of 2-(o-methoxyphenoxy)ethylamine and 12.9 g (150 mmol) of acrylic acid methyl ester are dissolved in 100 ml of methanol and boiled for 12 hours under reflux. After removal of the solvent under reduced pressure, the crude N,N-bis(2-methoxycarbonylethyl)-N-[2-(o-methoxyphenoxy)ethyl]-amine is obtained in the form of an oil in 100% yield.

Example 12

From 7.82 g (20 mmol) of N,N-bis(2-methoxycarbonylethyl)-N-[3-(rn-trifluoromethylphenoxy)propyl]-amine and 1.15 g (24 mmol) of sodium hydride dispersion (50$ in mineral oil ) is obtained analogously to example 9 4-hydroxy-1-[3-(m-trifluoromethylphenoxy)propyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrochloride respectively 4-oxo-1-[3- (m-trifluoromethylphenoxy)-propyl]-piperidine-3-carboxylic acid methyl ester hydrochloride.

N,N-bis-(2-methoxycarbonylethyl)-N-[3-(m-trifluoromethyl-phenoxy)-propyl]-amine can e.g. is prepared as follows: 39.1 g (100 mmol) of 1-bromo-3-(m-trifluoromethylphenoxy)-propane and 7.8 g (120 mmol) of sodium azide are dissolved in 50 ml of absolute dimethyl sulfoxide and stirred for 12 hours at 80-100 °C. The reaction mixture is then poured into 200 ml of ice water. It is shaken with diethyl ether and the ether-containing phases are washed with saturated sodium chloride solution. The organic phases are dried over magnesium sulphate and the solvent is removed in vacuo. The obtained oily residue, consisting of crude 1-azido-3-(m-trifluoromethylphenoxy)-propane is used further without further purification. 20 g (81.5 mmol) of 1-azido-3-(m-trifluoromethylphenoxy)-propane (crude product) are dissolved in 100 ml of absolute diethyl ether and added dropwise at reflux temperature to a suspension of 1.5 g (40 mmol) of 1 lithium aluminum hydride in 150 ml absolute diethyl ether. The reaction mixture is boiled for 6 hours under reflux and then decomposed under ice cooling with 7.5 ml of 0.5 N caustic soda. The white precipitate formed is filtered off and boiled twice with diethyl ether. The combined ether solutions are dried over magnesium sulfate and evaporated in vacuo to dryness. The oil obtained is 3-(m-trifluoromethylphenoxy)-propylamine, which can optionally be purified via its hydrogen chloride. 15 g (68 mmol) of 3-(m-trifluoromethylphenoxy)propylamine and 14.6 g (170 mmol) of acrylic acid methyl ester are dissolved in 150 ml of methanol and boiled for 12 hours under reflux. After removing the solvent under reduced pressure, the crude N,N-bis(2-methoxycarbonylethyl)-N-[3-(m-trifluoromethylphenoxy)-propyl]-amine is obtained, which can be used further without further purification.

Example 13

In a similar way as in example 9, one obtains from 6.47 g (20 mmol) N,N-bis(2-methoxycarbonylethyl)-N-[2-(p-methyl-phenoxy)ethyl]-amine and 1.15 g (24 mmol) sodium hydride (50$ suspension in mineral oil) 4-hydroxy-1-[2-(p-methylphenoxy)-ethyl]-1,2,5, 6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrochloride respectively l- The [2-(p-methylphenoxy)ethyl]-4-oxo-piperidine-3-carboxylic acid methyl ester hydrochloride in a yield of 80% of theory (m.p. 168-169°C).

N,N-bis(2-methoxycarbonylethyl)-N-[2-(p-methylphenoxy)ethyl]-amine can e.g. is obtained in the following way: 15.1 g (100 mmol) of 2-(p-methylphenoxy)ethylamine is dissolved in 200 ml of methanol and mixed with 21.8 g (250 mmol) of acrylic acid methyl ester. The mixture is boiled for 12 hours under reflux and then evaporated to dryness after cooling at reduced pressure. The crude, oily N,N-bis(2-methoxycarbonylethyl)-N-[2-(p-methylphenoxy)ethyl]-amine is used further (yield: 90$ of theoretical ).

Example 14

6.32 g (20 mmol) 4-hydroxy-1-[2-(p-methylphenoxy)ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acids ethyl ester hydrochloride respectively -[2-(p-methylphenoxy)ethyl]-4-oxo-piperidine-3-carboxylic acid methyl ester hydrochloride is dissolved in 100 ml of methanol. At a temperature of -20°C to -10°C, 1.5 g (40 mmol) of sodium borohydride are introduced in portions. The reaction mixture is then stirred for one hour without cooling, whereby the temperature rises to 0°C. The reaction mixture is then mixed, under renewed cooling, until a strongly acidic reaction with 2N sodium chloride and then evaporated under reduced pressure to dryness. The residue is dissolved in ice water and the solution is mixed until an alkaline reaction with saturated potassium carbonate solution

and drained with vinegar. The combined organic phases are washed neutral with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness. The 4-hydroxy-1-[2-(p-methylphenoxy)-ethyl]-piperidine-3-carboxylic acid methyl ester obtained in the form of a viscous oil (yield: 90% of theory; cis- and trans-diastereomer mixture) is used further without further cleansing. For this purpose, 5.28 g (18 mmol) of this product and 13.7 g (90 mmol) of 1,5-diaza-bicyclo[5,4,0]undec-5-ene are dissolved in 90 ml of toluene. At 0°C, a solution of 2.47 g (21.6 mmol) of methanesulfonic acid chloride in 15 ml of toluene is added with stirring over the course of 30 minutes. The reaction mixture is then stirred for 18 hours at room temperature and then mixed with 100 ml of ice water and 50 ml of 2N hydrochloric acid. The acidic aqueous phase is separated and the toluene phase is decanted twice, each time with 50 ml 1N hydrochloric acid. The combined acidic, aqueous phases are mixed with solid sodium bicarbonate until an alkaline reaction and then decanted with dichloromethane. The dichloromethane extracts are washed with saturated sodium chloride solution and dried over magnesium sulfate. After removal of the solvent, a viscous oil is obtained as a residue. This oil is dissolved in a little isopropanol. The solution is mixed with ethereal hydrochloric acid and the precipitated crystals are filtered off. The pure 1-[2-(p-methylphenoxy)-ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrochloride, which crystallizes with 0.25 equivalents of water of crystal, melts at 140-143° C (Profit: 70$ of theoretical).

Example 15

3.16 g (10 mmol) 1-[2-(p-methylphenoxy)ethyl]-1,2,5,6-tetrahydro-pyr idin-3-carboxylic acid methyl ester hydrochloride containing 0.25 equivalents of crystal water , dissolve in 50 ml of absolute methanol and hydrate with the addition of 1.0 g of palladium on activated charcoal under normal pressure at room temperature. The catalyst is filtered off and the filtrate is evaporated to dryness. The residue obtained is dissolved in 50 ml of water and the solution is mixed with saturated sodium bicarbonate solution until alkaline

reaction and decanted with dichloromethane. The dichloromethane phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The remaining oily crude 1-[2-(p-methylphenoxy)ethyl]-piperidine-3-carboxylic acid methyl ester is purified with cyclohexane on "Florisil" and then transferred in isopropanol/diethyl ether to the oxalate (Yield: 75$ of theoretical). The pure i-[2-(p-methylphenoxy)ethyl]-piperidine-3-carboxylic acid methyl ester oxalate melts at 146-148°C.

Example 16

In a similar manner as described in example 1, from 5.66 g (20 mmol) of 1-bromo-3-(m-trifluoromethylphenoxy)-propane, 5.33 g (24 mmol) of 1,2,5,6-tetrahydro are obtained -pyridine-3-carboxylic acid methyl ester hydrobromide and 5.68 g (44 mmol) N-ethyl-N,N-diisopropylamine 1-[3-(m-trifluoromethylphenoxy)propyl]-1,2,5,6- tetrahydro-pyridine-3-carboxylic acid methyl ester. From the free base, the hydrochloride is precipitated with ethereal hydrochloric acid. After recrystallization from isopropanol/diethyl ether, the pure 1-[3-(m-trifluoromethylphenoxy)propyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrochloride is obtained in a yield of 77$ of the theoretical ( melting point 186-188°C).

Example 17

From 7.55 g (20 mmol) N,N-bis-(2-methoxycarbonylethyl)-N-[2-(m-trifluoromethylphenoxy)ethyl]-amine and 1.15 g (24 mmol) sodium hydride (50$ suspension in mineral oil) is obtained analogously to example 9 4-hydroxy-1-[2-(m-trifluoromethylpheoxy)ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acids tyles terhydrochlor i respectively the 4-oxo-1-[2-(rn-trifluoromethylphenoxy)ethyl]-piperidine-3-carboxylic acid nrethyl ester hydrochloride which exhibits a melting point of 151-153°C (yield: 53$ of theoretical).

N,N-bis-(2-methoxycarbonylethyl)-N-[2-(m-trifluoromethyl-phenoxy)-ethyl]-amine can e.g. is produced as follows.

20.5 g (100 mmol) of 2-(m-trifluoromethylphenoxy)ethylarnine are dissolved in 200 ml of methanol and boiled with 21.73 g (250 mmol) of acrylic acid methyl ester for 1 24 hours under reflux. The reaction mixture is evaporated after cooling to dryness under reduced pressure. The oily residue is purified on 10 g of magnesium silicate with dichloromethane as eluent. After removal of the solvent in vacuo, the N,N-bis(2-methoxycarbonylethyl)-N-[2-(m-trifluoromethylphenoxy)-amine is obtained in a yield of 98$ of theoretical.

Example 18

In a similar way as described in example 1, the following compounds can also be prepared from 1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrobromide: By reaction with l-bromo-2-(3, 4-dichlorophenoxy)-ethane 1-[2-(3,4-dichlorophenoxy)ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrochloride of melting point 205-208°C (from isopropanol /diethyl ether);

By reaction with l-bromo-2-(2,5-dimethylphenoxy)-ethane l-[2-(2,5-dimethylphenoxy)ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester oxalate of melting point 132-134°C (from isopropanol);

By reaction with l-bromo-2-(m-methylphenoxy)-ethane l-[2-(m-methylphenoxy)ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxy 1-acid methyl ester- hydrochloride of m.p. 153-155°C (from isopropanol/diethyl ether);

By reaction with l-bromo-2-(o-methylphenoxy)-ethane l-[2-(o-methylphenoxy)ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester oxalate of melting point 165- 167°C (from isopropanol/methanol) and

By reaction with l-bromo-2-(3,4-dimethylphenoxy)-ethane l-[2-(3,4-dimethylphenoxy)ethyl]-1,2,5,6-tetrahydro-pyr idine-3-carboxylic acid methyl ester hydrochloride of melting point 184-186°C (from isopropanol).

Example 19

5.4 g (20 mmol) of 1-bromo-2-(m-trifluoromethylphenoxy)ethane and 3.5 g (22 rnmol) of piperidine-3-carboxylic acid ethyl ester are dissolved in 20 ml of absolute dimethylformamide. At room temperature, a solution of 3.2 g (25 mmol) of N-ethyl-N,N-diisopropylamine in 20 ml of toluene is added dropwise. The reaction mixture is then kept under stirring for days at 50°C and then freed in high vacuum at 40-50°C of solvent. The obtained oily residue is dissolved in 20 ml of 2N hydrochloric acid. The solution is decanted with diethyl ether and the ether-containing phase is washed with water. The acidic aqueous extracts are made alkaline with saturated sodium bicarbonate solution and decanted with diethyl ether/dichloromethane (2:1). The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The oily residue obtained is purified with cyclohexane as an eluent on magnesium silicate. After removal of the solvent, the remaining oily 1-[2-(m-trifluoromethyl-phenoxy)ethyl]-piperidine-3-carboxylic acid ethyl ester is dissolved in a little diethyl ether and the oxalate is precipitated from the solution with ethereal oxalic acid. After recrystallization from methanol/isopropanol, the pure 1-[2-(m-trifluoromethylphenoxy)-ethyl]-piperidine-3-carboxylic acid ethyl ester oxalate exhibits a melting point of 143-145°C (yield: 62$ of theoretical).

Example 20

In a similar manner as described in example 19, 5.7 g (20 mmol) of 1-bromo-3-(m-trifluoromethylphenoxy)-propane, 3.5 g (22 mmol) of piperidine-3-carboxylic acid ethyl ester and 3.2 g (25 mmol) N-ethyl-N,N-diisopropylamine 5.6 l-[3-(m-trifluoromethyl-phenoxy)propyl]-piperidine-3-carboxylic acid ethyl ester in the form of a colorless oil. The crude base is dissolved in diethyl ether and the hydrochloride is precipitated from the solution with ethereal hydrochloric acid. After recrystallization from isopropanol/diethyl ether, the pure 1-[3-(m-trifluoromethylphenoxy)propyl]-piperidine-3-carboxylic acid ethyl ester hydrochloride melts at 155-157°C (yield: 67% of theory).

Example 21

In a similar way as described in example 19, 4.3 g (20 mmol) of 1-bromo-2-(p-methylphenoxy)-ethane, 3.5 g (22 mmol) of piperidine-3-carboxyl ethyl ester and 3.2 g ( 25 mmol) N-ethyl-N,N-diisopropylamine after standing for 4 days at room temperature 4.6 g of oily 1-[2-(p-methylphenoxy)ethyl]-piperidine-3-carboxylic acid ethyl ester. The crude base is dissolved in diethyl ether and the oxalate is precipitated from the solution with ethereal oxalic acid. After recrystallization from isopropanol/diethyl ether, the pure 1-[2-(p-methylphenoxy)ethyl]-piperidine-3-carboxylic acid ethyl ester oxalate melts at 114-116°C (yield: 70% of theory).

Example 22

In a similar way as described in example 19, the following compounds can also be obtained from piperidine-3-carboxylic acid ethyl ester: By reaction with l-bromo-2-(2,4-dichlorophenoxy)-ethane l-[2-(2,4-dichloro Enoxy)ethyl]-piperidin-3-carboxylic acid ethyl ester oxalate of melting point 132-134°C (from isopropanol/diethyl ether);

By reaction with l-bromo-2-(3,4-dichlorophenoxy)-ethane l-[2-(3,4-dichlorophenoxy)ethyl]-piperidine-3-carboxylic acid ethyl ester oxalate of melting point 142-144°C (from isopropanol/diethyl ether );

By reaction with l-bromo-2-(2,5-dimethylphenoxy)-ethane l-[2-(2,5-dlmethylphenoxy)ethyl]-piperidine-3-carboxylic acid ethyl ester oxalate of melting point 125-126°C (from isopropanol /diethyl ether );

By reaction with l-bromo-2-(m-methylphenoxy)-ethane l-[2-(m-methylphenoxy) e ty 1 ]-piperidine-3-carboxylic acid ethyl ester oxalate of melting point 116-118°C (from isopropanol/diethyl ether );

By reaction with l-bromo-2-(o-methylphenoxy)-ethane l-[2-(o-methylphenoxy)ethyl]-piperidine-3-carboxylic acid ethyl ester oxalate of melting point 144-146°C (from isopropanol/diethyl ether);

By reaction with l-bromo-2-(34-dimethylphenoxy)-ethane l-[2-(3,4-dimethylphenoxy)ethyl]-piperidine-3-carboxylic acid ethyl ester oxalate of melting point 139-140°C (from isopropanol/diethyl ether ) and

By reaction with l-bromo-4-(m-trifluoromethylphenoxy)-butane 1-[4 - (m-trifluoromethylphenoxy)butyl]-piperidln-3-carboxylic acid ethyl ester hydrochloride of melting point 124-126°C (from isopropanol /diethyl ether ).

Example 23

From 4.9 g (20 mmol) 1-bromo-2-(2-methoxy-5-methylphenoxy)-ethane, 3.45 g (22 mmol) piperidine-3-carboxylic acid ethyl ester and 3.23 g (25 mmol) N -ethyl-N,N-diisopropylamine is obtained analogously to example 19 1-[2-(2-methoxy-5-methylphenoxy)ethyl]-piperidine-3-carboxylic acid ethyl ester in the form of an oil (yield: 60% of theoretical) . 1-Bromo-2-(2-methoxy-5-methylphenoxy)-ethane is prepared, for example, as follows: 13.8 g (100 mmol) of 2-methoxy-5-methyl-phenol is dissolved in 113 g (0.6 mol) 1,2-dibromoethane and mixed with 20.8 g (150 mmol) of powdered potassium carbonate. While stirring, the reaction mixture is refluxed for 2 days. After cooling, the precipitate is filtered off and the filter residue is thoroughly washed with dichloromethane. The filtrate is shaken out with 100 ml of 2N caustic soda, washed neutrally with saturated sodium chloride solution and dried over magnesium sulphate. After removal of the solvent under reduced pressure, 1-bromo-2-(2-methoxy-5-methyl-phenoxy)-ethane is obtained in the form of a yellow oil (yield: 60% of theory).

Example 24

4.37 g (15 mmol) of 1-[2-(p-methylphenoxy)ethyl]-piperidine-3-carboxylic acid ethyl ester are dissolved in 30 ml of n-butanol and mixed with a solution of 1.8 g (18 mmol) of concentrated sulfuric acid in 20 ml of n-butanol. The reaction mixture is kept for 12 hours with stirring at 80°C and then evaporated under reduced pressure. The oily residue is dissolved in 50 ml of water, mixed with saturated sodium bicarbonate solution until an alkaline reaction and extracted with dichloromethane. The combined organic phases are decanted with saturated sodium chloride solution and dried over magnesium sulphate. After removal of the solvent under reduced pressure, the oil obtained as a residue is purified with cyclohexane as eluent on 5 g of magnesium silicate. The eluate is evaporated to dryness under reduced pressure. The oily residue is mixed with ethereal oxalic acid. The precipitated crystals are recrystallized from isopropanol/diethyl ether. The pure 1-[2-(p-methylphenoxy)ethyl]-piperidine-3-carboxylic acid n-butyl ester oxalate thus obtained melts at 103-105°C (yield: 80$ of theoretical).

Example 25

From 5.5 g (16 mmol) 1-[2-(m-trifluoromethylphenoxy)ethyl]-piperidine-3-carboxylic acid ethyl ester, 1.8 g (18 mmol) concentrated sulfuric acid and 50 ml n-butanol is obtained in a similar way as described in example 24 1-[2-(m-trifluoromethyl-phenoxy)-ethyl]-piperidine-3-carboxylic acid n-butyl ester oxalate of melting point 115-117°C (yield: 83$ of theoretical).

Example 26

4.3 g (20 mmol) of 1-bromo-2-(p-methylphenoxy)-ethane and 3.0 g (22 mmol) of piperidine-3-carboxylic acid amide are dissolved in 20 ml of dimethyl-

formamide. A solution of 3.2 g (25 mmol) of N-ethyl-N,N-diisopropylamine in 20 ml of toluene is added to the solution. The mixture is heated with stirring for 48 hours to 50° C. and then evaporated to dryness under high vacuum. The residue is dissolved in IN hydrochloric acid, and the solution is decanted with diethyl ether. The ethereal phase is washed with water. The combined acidic, aqueous extracts are made alkaline with 2N caustic soda and then extracted with diethyl ether/dichloromethane (2:1), washed with saturated sodium chloride solution and dried over magnesium sulfate. After removal of the solvent under reduced pressure, the crystalline residue is recrystallized from toluene/petroleum ether. The pure 1-[2-(p-methylphenoxy)ethyl]-piperidine-3-carboxylic acid compound melts at 115-117°C (yield: 62% of theoretical).

Example 27

From 5.4 g (20 mmol) of 1-bromo-2-(m-trifluoromethylphenoxy)ethane, 3.0 g (22 mmol) of piperidine-3-carboxylic acid amide and 3.2 g (25 mmol) of N-ethyl-N, N-diisopropylamine is obtained in a similar way as described in example 26, the oily 1-[2-(m-trifluoromethylphenoxy)-ethyl]-piperidine-3-carboxylic acid amide. This gives, after reaction with ethereal oxalic acid and recrystallization from methanol/isopropanol, the pure 1-[2-(m-trifluoromethylphenoxy)ethyl]-piperidine-3-carboxylic acid amide oxalate of melting point 163-165°C in a yield of $50 of theoretical.

Example 28

In a similar way as described in examples 26 and 27, the following compounds can also be obtained from piperidine-3-carboxylic acid amide: By reaction with l-bromo-2-(2,4-dichlorophenoxy)-ethane l-[2-(2,4 -dichlorophenoxy)ethyl]-piper in di-3-carboxylic acid eam id of melting point 83-85°C (from cyclohexane/petroleum ether);

By reaction with l-bromo-3-(m-trifluoromethylphenoxy)-propane

1-[3-(m-trifluoromethylphenoxy)propyl]-p i per i dyne-3-carboxy 1-acid amide of melting point 57-59°C (from toluene/petroleum ether) and

By reaction with 1-bromo-2-(3,4-dimethylphenoxy)-ethane 1-[2-(3,4-dimethylphenoxy)ethyl]-piperidine-3-carboxylic acid amide of melting point 108-110°C (from cyclohexane/petroleum ether ).

Example 29

4.3 g (20 mmol) of 1-bromo-2-(p-methylphenoxy)-ethane and 4.1 g (22 mmol) of piperidine-3-carboxylic acid-N,N-diethylamide are dissolved in 20 ml of dimethylformamide and mixed with a solution of 3.2 g (25 mmol) of N-ethyl-N,N-diisopropylamine in 20 ml of toluene. The reaction mixture is heated with stirring for 3 days to 50°C and then evaporated to dryness under high vacuum. The residue obtained is dissolved in 50 ml of 1N hydrochloric acid. The solution is decanted with diethyl ether, and the ether-containing phase is washed with water. The combined acidic, aqueous phases are made alkaline with 2N caustic soda and decanted with diethyl ether/dichloromethane (2:1). The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and freed from solvent under reduced pressure. The oily residue obtained is chromatographed on 120 g of silica gel (Merck 0.04-0.063 mm) with dichloromethane/methanol (9:1) as eluent. Fractions 1-5 are collected and the solvent is removed under reduced pressure. The oily residue is mixed with ethereal hydrochloric acid. The precipitated crystals are filtered off and recrystallized from acetic acid ethyl ester/diethyl ether. The thus obtained pure 1-[2-(p-methylphenoxy)ethyl]-piperidine-3-carboxylic acid-N,N-diethylamide hydrochloride melts at 149-151°C (yield: 27% of theory).

Example 30

In a similar way as described in example 29, the following compounds can also be obtained from piperidine-3-carboxylic acid-N,N-diethylamide: By reaction with l-bromo-2-(3,4-dimethylphenoxy)-ethane 1-[2- (3,4-Dimethylphenoxy)ethyl]-piperidine-3-carboxylic acid N,N-diethylamidoxolate of melting point 128-129°C;

By reaction with l-bromo-2-(rn-trifluoromethylphenoxy)-ethane 1-[2-(m-trifluoromethylphenoxy)ethyl]-piperidine-3-carboxylic acid-N,N-diethylamide hydrochloride of melting point 120-122 °C and

On reaction with l-bromo-2-(2,4-dichlorophenoxy)-ethane 1-[2-(2,4-dichlorophenoxy)ethyl]-piperidine-3-carboxylic acid-N,N-diethylamide hydrochloride of melting point 201- 204°C.

Example 31

In a similar manner as described in example 19, 5.9 g (20 mmol) of 1-bromo-4-(m-trifluoromethylphenoxy)-butane, 2.6 g (22 mmol) of 3-hydroxymethylpiperidine and 3.2 g (25 mmol) N-ethyl-N,N-diisopropyl-amine after purification on "Florisil" the oily 1-[4-(m-trifluoromethylphenoxy)butyl]-3-hydroxymethyl-piperidine. From the crude base, the oxalate is precipitated with ethereal oxalic acid and this is recrystallized from isopropanol/diethyl ether. The pure 1-[4-(m-trifluoromethylphenoxy)-butyl]-3-hydroxymethyl-piperidine oxalate melts at 128-130°C.

Example 32

4.9 g (20 mmol) of 1-[2-(p-methylphenoxy)ethyl]-3-cyano-piperidine are dissolved in 160 ml of absolute ethanol. At a temperature of +5°C, hydrogen chloride gas is introduced into the solution until saturation. The mixture is then allowed to stand for 24 hours at room temperature. The excess hydrogen chloride gas and the solvent are then removed under reduced pressure. The obtained crystalline residue is dissolved in 50 ml of water and the solution is allowed to stand for 2 hours at room temperature and is then made alkaline with sodium bicarbonate. The mixture is shaken out with diethyl ether and the organic phase is washed with saturated sodium chloride solution and dried over magnesium sulphate. After removing the solvent under reduced pressure, the obtained is mixed

the oil with ethereal oxalic acid and the oxalate is recrystallized from isopropanol/diethyl ether. The pure 1-[2-(p-methylphenoxy)-ethyl]-piperidine-3-carboxylic acid ethyl ester oxalate melts at 114-116°C.

1-[2-(p-methylphenoxy)ethyl]-3-cyano-piperidine is prepared, e.g. as follows: 11.0 g (100 mmol) of 3-cyanopiperidine, 21.5 g (100 mmol) of 1-bromo-2-(p-methylphenoxy)-ethane and 16.2 g (125 mmol) of N-ethyl-N ,N-diisopropylamine is dissolved in 50 ml of toluene and 50 ml of dimethylformamide and allowed to stand for 48 hours at room temperature. The solvent is then removed under high vacuum at 40-50°C, and the oily residue obtained is dissolved in 2N hydrochloric acid. After decanting with diethyl ether, the acidic aqueous phase is made alkaline with sodium bicarbonate and decanted with diethyl ether/dichloromethane (2:1). The organic phases are washed with saturated sodium chloride solution and dried over magnesium sulfate. The solvent is removed under reduced pressure. The obtained residue is purified with cyclohexane as eluent on 30 g of "Florisil". The 1-[2-(p-methylphenoxy)ethyl]-3-cyano-piperidine obtained is further used in the crude state.

Example 33

4.7 g (20 mmol) of 1-[2-(p-methylphenoxy)ethyl]-4-oxo-piperidine are dissolved in 20 ml of diethylene glycol dimethyl ether (diglyme) and the solution is added dropwise at 50°C with stirring to a mixture of 3.6 g (40 mmol) dimethyl carbonate and 1.2 g (25 mmol) sodium hydride dispersion in mineral oil ($50) in 20 ml diethylene glycol dimethyl ether (diglyme). The reaction mixture is then boiled for 12 hours under reflux, then cooled, diluted with 50 ml of toluene and mixed dropwise with 1.5 g of glacial acetic acid while cooling. The solvent is then largely removed under reduced pressure. The residue is dissolved in diethyl ether and the solution is decanted with 2N hydrochloric acid. The acidic aqueous phase is made alkaline with sodium bicarbonate and decanted with diethyl ether/dichloromethane (2:1). The organic phases are dried

over magnesium sulfate and free from solvent. The residue is mixed with ethereal hydrochloric acid. The precipitated hydrochloride is recrystallized from isopropanol/diethyl ether. The pure 4-hydroxy-1-[2-(p-methylphenoxy)ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrochloride respectively 1-[2-(p-methylphenoxy)ethyl] The -4-oxo-piperidine-3-carboxylic acid methyl ester hydrochloride melts at 168-169°C. 1-[2-(p-methylphenoxy)ethyl]-4-oxo-piperidine is prepared, for example, in the following way: In a similar way as described in example 19, 4.3 g (20 mmol) of 1-bromo-2-(p-methylphenoxy) are obtained )-ethane, 3.4 g (22 mmol) of 4-piperidone hydrate hydrochloride and 5.7 g (44 mmol) of N-ethyl-N,N-diisopropylamine the crude 1-[2-(p-methylphenoxy )ethyl]-4-oxo-piperidine as an orange-yellow oil. After purification of the crude product over "Florisil" with cyclohexane as eluent, the oxalate is precipitated with ethereal oxalic acid and this is recrystallized from a little ethanol/diethyl ether. The pure 1-[2(p-methylphenoxy)ethyl]-4-oxo-piperidine oxalate, which crystallizes with 0.125 equivalents of crystal water, melts at 157-159°C.

Example 34

6.2. g (20 mmol) of 4-chloro-1-[2-(p-methylphenoxy)ethyl]-piperidine-3-carboxylic acid methyl ester is dissolved in 20 ml of methanol. At room temperature, 40 ml (140 mmol) of a 3.5N solution of ammonia in methanol are added dropwise. The mixture is allowed to stand for 24 hours at room temperature. The solvent is then removed under reduced pressure. The residue obtained is dissolved in dichloromethane, the solution is decanted with 2N hydrochloric acid and the acidic aqueous phase is separated, made alkaline with sodium bicarbonate and extracted with diethyl ether/dichloromethane (2:1). The organic extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and freed from solvent under reduced pressure. The residue obtained is chromatographed on basic silica gel with dichloromethane/methanol

(99:1) as eluent. The eluate is evaporated to dryness and the residue treated with ethereal hydrochloric acid. Thereby the pure 4-amino-1-[2-(p-methylphenoxy)ethyl]-piperidine-3-carboxylic acid amide dihydrochloride is obtained.

The 4-chloro-1-[2-(p-methylphenoxy)ethyl]-piperidine-3-carboxyl acid methyl ester can be obtained, for example, in the following way:

16.35 g (50 mmol) 4-hydroxy-1-[2-(p-methylphenoxy)ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrochloride respectively 1-[2 -(p-methylphenoxy)ethyl]-4-oxo-piperidine-3-carboxylic acid methyl ester hydrochloride (preparation see example 13) is introduced over the course of one hour in portions at -20°C in a solution of 5.6 g (150 mmol) of sodium borohydride in 300 ml of methanol. The mixture is then stirred for 3 hours at -20°C and allowed to cool to room temperature over 4 hours. Then, while cooling, the mixture is mixed dropwise with 70 ml IN hydrochloric acid. The methanol is then removed as far as possible under reduced pressure. The residue is washed with diethyl ether and the acidic aqueous phase is made alkaline with sodium bicarbonate and extracted with diethyl ether/dichloromethane (2:1). The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate and freed from solvent under reduced pressure. The obtained residue, consisting of crude 4-hydroxy-1-[2-(p-methylphenoxy)ethyl]-piperidine-3-carboxylic acid methyl ester is used further without working up.

8.8 g (30 mmol) of 4-hydroxy-1-[2-(p-methylphenoxy)ethyl]-piperidine-3-carboxylic acid methyl ester and 3.6 g (36 mmol) of triethylamine are dissolved in 100 ml of dichloromethane. At room temperature, 3.92 g (33 mmol) of thionyl chloride are added dropwise while stirring. The mixture is stirred for 4 hours at room temperature. The precipitated triethylamine hydrochloride is then filtered off, and the filtrate is decanted cold with saturated sodium hydrogen carbonate solution. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate and freed from solvent under reduced pressure. It

The obtained 4-chloro-1-[2-(p-methylphenoxy)ethyl]-piperidine-3-carboxylic acid methyl ester is further used in the crude state.

Example 35

7.0 g (20 mmol) of 1-[2-(p-methylphenoxy)ethyl]-pyridinium-3-carboxylic acid methyl ester bromide is added at -15°C over the course of one hour in portions with stirring to a solution of 2.3 g (60 mmol) of sodium borohydride in 200 ml of methanol. The mixture is then stirred for one hour at -10°C. The reaction solution is then stirred for one hour at room temperature and boiled for a further hour under reflux. After complete cooling, 50 ml IN hydrochloric acid is added slowly and dropwise and then the methanol is removed under reduced pressure. The residue is decanted with diethyl ether, and the acidic aqueous phase is made alkaline under cooling with sodium bicarbonate and extracted with diethyl ether/dichloromethane (2:1). The organic extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and freed from solvent under reduced pressure. The oily residue obtained is mixed with ethereal hydrochloric acid and the precipitated hydrochloride is recrystallized from isopropanol/diethyl ether. The 1-[2-(p-methylphenoxy)-ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrochloride thus obtained, which crystallizes with 0.25 equivalents of water of crystal, melts at 140-143° C.

The 1-[2- (p-methylphenoxy)ethyl]-pyridinium-3-carboxylic acid methyl 1-ester bromide is prepared, e.g. as follows: 6.45 g (30 mmol) of 1-bromo-2-(p-methylphenoxy)-ethane and 4.47 g (30 mmol) of pyridine-3-carboxylic acid methyl ester are dissolved in 50 ml of absolute trichloromethane and heated for 24 hours with stirring to 50°C. The precipitated 1[2-(p-methylphenoxy)ethyl]-pyridinium-3-carboxylic acid methyl ester bromide is filtered off and further used in the crude state.

Example 36

In a similar way as described in examples 1 to 35, the following compounds and their pharmaceutically usable salts can also be obtained: 1-[2- (p-trifluoromethylphenoxy)ethyl]-1,2,5,6-tetrahydro-pyridine- the 3-carboxylic acid methyl ester; 1-[2-(5-Methoxy-2-methyl-phenoxy)ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester; 4-hydroxy-1-[2-(5-methoxy-2-methyl-phenoxy)ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester respectively 1-[2-(5-methoxy-2 -methyl-phenoxy)ethyl]-4-oxo-piperidine-3-carboxylic acid methyl ester; 4-Hydroxy-1-[2-(2,5-dimethoxyphenoxy)ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester respectively 1-[2-(2,5-dimethoxyphenoxy) )ethyl]-4-oxo-piperidine-3-carboxylic acid methyl ester; 1-[2-(2,5-dimethoxyphenoxy)ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester; 1-[4-(m-trifluoromethylphenoxy)butyl]-piperidine-3-carboxy 1-acid amide of melting point 124-128°C;

1-[2-(p-cyanophenoxy)ethyl]-piperidine-3-carboxylic acid amide of melting point 152-154°C and

1-[2-(p-methylphenoxy)ethyl]-3-hydroxymethyl-piperidine of melting point 149-150°C.

Example 37

Tablets, containing 25 mg of active substance, e.g. 1-[2-(2,4-dichlorophenoxy)-ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrochloride can be prepared in the following way:

Ingredients (for 1000 tablets):

Manufacturing:

All solid components are first passed through a sieve with a mesh size of 0.6 mm. The active substance, lactose, talc, magnesium stearate and half of the starch are then mixed in. The other half of the starch is suspended in 40 ml of water and this suspension is added to a boiling solution of the polyethylene glycol in 100 ml of water. The obtained starch paste is added to the main quantity and the mixture is granulated, if necessary with the addition of water. The granulate is dried overnight at 35°C, driven through a sieve with a mesh size of 1.2 mm and pressed into tablets that are concave on both sides and have a diameter of approx. 6 mm.

Example 38

Tablets, containing 50 mg of the active substance, e.g. 1-[2-(2,4-Dichlorophenoxy)-ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrochloride is prepared as follows:

Composition (for 10,000 tablets):

A mixture of the active substance, the lactose and 194.70 g of potato starch is moistened with an ethanolic solution of the stearic acid and granulated through a sieve. After drying, the remaining potato starch, talc, magnesium stearate and colloidal silicon dioxide are mixed and the mixture is pressed into tablets, each weighing 0.1 g, which, if desired, can be equipped with dividing lines for finer adjustment of the dosage.

In a similar way, 100 mg of active substance can be incorporated.

Example 39

Capsules, containing 0.025 g of the active substance, e.g. 1-[2-(2,4-dichlorophenoxy)-ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrochloride can be prepared in the following way:

Composition (for 1000 capsules):

The active substance is mixed with the lactose, the mixture is regularly moistened with an aqueous solution of gelatin and granulated through a sieve with a mesh size of 1.2 to 1.5 mm. The granulate is mixed with the dried malt starch and talc and portions of 300 mg are filled into hard gelatin capsules (size 1).

Example 40

In a similar way as described in examples 37 to 39, pharmaceutical preparations can also be prepared containing another compound of formula I or a tautomer and/or a pharmaceutically usable salt thereof, for example according to examples 1 to 36.

Claims (11)

1. Procedure for the preparation of a compound of the formula: in which represents lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl, N,N-dllower alkylcarbamyl or optionally acylated hydroxymethyl, R2 represents hydrogen, an optionally etherified or acylated hydroxy group or an optionally acylated amino group, alk represents lower alkylene, ring A is unsubstituted or single- or polysubstituted with hydroxy, lower alkoxy, lower alkanoyloxy, cyano, halogen, lower alkyl and/or trifluoromethyl and the dashed line shall express that there may be a single or a double bond, or a tautomer and/or a salt thereof, characterized in that mana) reacts a compound of the formula: or a salt thereof with a compound of the formula • a tautomer and/or a salt thereof, whereby either Z| represents a group alk-X^ and Z2 represents hydrogen, or Z^ represents hydrogen and Z2 represents a group alk-X^ in which in any case X^ represents hydroxy or reactively esterified hydroxy, or h) in a compound of the formula a tautomer and/or a salt thereof, in which X2 represents a residue that can be transferred to , transfers X2 to R^ , or c) for the preparation of a compound of formula (I), a tautomer and/or a salt thereof, in which R2 stands for hydroxy or amino, and in which R^ in particular stands for lower alkoxycarbonyl, ring-closing a compound of the formula in which Yi stands for a group of the formula -CH=R^, -C(Y2)=R2', -CH(Y2 )-R2 or cyano, whereby R<$ stands for oxo or imino and Y2 stands for a cleavable residue, or a salt thereof, or d) for the preparation of a compound of formula (I'), a tautomer and/or a salt thereof, in which R^ stands for oxo or imino and the dashed line expresses that there is a single bond, and in which R^ in particular stands for lower alkoxycarbonyl , reacts a compound of the formula or a tautomer or salt thereof with a compound of the formula or a salt thereof, wherein X3 stands for halogen or lower alkoxy, or e) for the preparation of a compound of formula (I), a tautomer and/or a salt thereof, where Rg is different from hydrogen, 1 a compound of the formula or a salt thereof, wherein X4 represents a residue that can be transferred to Rg, transfers X4 to Rg or f) especially for the preparation of a compound of formula (I), a tautomer and/or a salt thereof, in which Rg stands for hydrogen, reduces the excess double bond to a single bond in a compound of the formula in which A~ stands for the anion of an acid, and Rg" stands for hydrogen, etherified, esterified or protected hydroxy or acylated or protected amino, and in any case cleaves off any protective group present and, if desired, transfers a compound according to the invention or otherwise obtained to another compound of formula (I ), divides an isomer mixture obtained according to the invention into its components, splits an enantiomer or diastereomer mixture obtained according to the invention into the enantiomers or diastereomers, transfers a free compound of formula (I) obtained according to the invention into a salt and/or converts a salt obtained according to the invention into the free compound of formula (I) or to another salt. 2. Method according to claim 1 for the preparation of a compound of formula (I), in which R^ stands for lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl or N,N-dilower alkylcarbamyl, Rg and alk have the indicated meanings, ring A is unsubstituted or single- or polysubstituted as stated above and the dashed line shall indicate that there is a single or a double bond, a tautomer and/or a salt thereof, characterized in that in a compound of formula (I) in which Rji stands for hydroxymethyl or acylated hydroxymethyl, first transfers any acylated hydroxymethyl R^ to hydroxymethyl R^ , then oxidizes hydroxymethyl R^ to carboxy and then esterifies the obtained carboxy group to lower alkoxycarbonyl Ri or amidates to carbamyl, N-lower alkylcarbamyl or N ,N-dilower alkylcarbamyl R-^ and in any case cleaves off a possibly present protecting group and, if desired, one is transferred according to the invention or otherwise obtained dd compound to another compound of formula (I), an isomer mixture obtained according to the invention is divided into its components, an enantiomer or diastereomer mixture obtained according to the invention is split into the enantiomers or diastereomers, a free compound of formula (I) obtained according to the invention is transferred to a salt and/or a salt obtained according to the invention is converted to the free compound of formula (I) or to another salt. 3. Process according to claim 1 or 2, characterized in that a compound of formula (I) is prepared, in which stands for lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl, N,N-dilower alkylcarbamyl, hydroxymethyl, lower alkanoyloxymethyl, lower alkanesulfonyloxy, benzoyloxymethyl or pyridoyloxymethyl, Eg stands for hydrogen, hydroxy, lower alkoxy, benzyloxy, lower alkanoyloxy, lower alkanesulfonyloxy, benzoyloxy, pyridoyloxy, amino, lower alkanoylamino, lower alkanesulfonylamino, benzoylamino or pyridoylamino, alk stands for the lower alkyl that forms a bridge over the two heteroatoms 0 and N entered in formula (I), in the first row with 2 up to and including 4 C atoms, the ring A is unsubstituted or singly, doubly or polysubstituted by hydroxy, lower alkoxy, lower alkanoyloxy, cyano, halogen, lower alkyl and/or trifluoromethyl and the dashed line shall express that there is a single or a double bond, or a tautomer and/or a salt thereof. 4. Method according to claim 1 or 2, characterized in that a compound of formula (I) is prepared in which E^ stands for lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl or N,N-dilower alkylcarbamyl, Rg stands for hydrogen, hydroxy, lower alkoxy, benzyloxy, lower -alkanoyloxy, lower alkanesulfonyloxy, henzoyloxy, pyridoyloxy, amino, lower alkanoylamino, benzoylamino or pyridoylamino, alk stands for the lower alkylene which bridges the two in formula (I) The heteroatoms 0 and N, primarily with 2 to 3 C atoms , the ring A is unsubstituted or mono-, double- or multi-substituted with hydroxy, lower alkoxy, lower alkanoyloxy, cyano, halogen, lower alkyl and/or trifluoromethyl and the dashed line shall express that there is a single or a double bond, or a tautomer and/ or a salt thereof. 5. Method according to claim 1 or 2, characterized in that a compound of formula (I) is prepared in which R 1 stands for C-L-C 2 - alkoxycarbonyl, carbamyl, N-C 1 -C 2 -alkylcarbamyl, N ,N-di-C 2 -C 4 -alkylcarbamyl, hydroxymethyl or Cg-Cg-alkanoyloxymethyl, Rg stands for hydrogen, hydroxy or amino, alk stands for the C-^-C4-alkylene which forms a bridge over the two heteroatoms 0 and N entered in formula (I), primarily with 2 up to and including 4 C atoms, the ring A is unsubstituted or mono-, di-, or poly-substituted with C 1 -C 4 -alkoxy, cyano, halogen with an atomic number up to and including 35, C 1 -C 4 -alkyl, and/ or trifluoromethyl and the dashed line shall express that there is a single or a double bond, or a tautomer and/or a salt thereof. 6. Method according to claim 1 or 2, characterized in that a compound of formula (I) is prepared, in which R^ stands for C^-C4 -Alkoxycarbonyl or carbamyl, Rg stands for hydrogen or hydroxy, alk stands for C1-C4-alkylene which forms a bridge over the two heteroatoms 0 and N entered in formula (I), primarily with 2 to even 3 C atoms, the ring A is unsubstituted or singly, doubly or polysubstituted with C 1 -C 4 -alkyloxy, cyano, halogen with an atomic number up to and including 35, C 1 -C 4 -alkyl and/or trifluoromethyl and the dashed line shall express the presence of a double bond, or a tautomer and/or a salt thereof. / . Method according to claim 1 or 2, characterized in that a compound of formula (I) is prepared, in which R1 stands for C1 -C4 -Alkoxycarbonyl or carbamyl, R2 stands for hydrogen or hydroxy, alk stands for the C1 -C4 -alkylene which forms bridging the two heteroatoms 0 and N inscribed in formula (I), primarily with 2 to even 3 C atoms, the ring A is singly substituted with C 1 -C 4 -alkyl, C 1 -C 4 -alkyl or trifluoromethyl or doubly substituted with halogen with an atomic number up to and including 35 or C^ -C^ -alkyl or C^ -C4~ alkoxy as well as Ci -C4~ alkyl and the dashed line shall express that there is a single or a double bond, or a tautomer and /or a salt thereof. 8. Process according to claim 1 or 2, characterized in that a compound of formula (I) is prepared, in which R^ stands for C^ -C4 -Alkoxycarbonyl, Rg stands for hydrogen, alk stands for ethylene, the ring A is singly substituted with C^ - C4 -Alkoxy or trifluoromethyl or doubly substituted with halogen with an atomic number up to and including 35 and the dashed line shall express the presence of a double bond, or a tautomer and/or a salt thereof. 9. Process according to claim 1 or 2, characterized in that 1-[2-(p-methylphenoxy)-ethyl]-piperidine-3-carboxylic acid amide or a salt thereof is produced. 10. Process according to claim 1 or 2, characterized in that 1-[2-(2,4-dichlorophenoxy)ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester is produced, 1-[2 - (o-methoxyphenoxy)-ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester, 1-[2-(m-trifluoromethylphenoxy)ethyl]-1,2,5,6 -tetrahydro-pyridine-3-carboxylic acid ethyl ester, 1-[2-(p-methylphenoxy)ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester, 4-hydroxy-1- [2-(p-methylphenoxy)ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxyl-acid methyl ester respectively 1-[2-(p-methylphenoxy)ethyl]-4-oxo-piperidine-3- carboxylic acid methyl ester, 4-hydroxy-1-[2-(m-trifluoromethylphenoxy)ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester respectively 4-oxo-1-[2-(m-trifluoro- methylphenoxy )ethyl]-piperidine-3-carboxylic acid methyl ester, 1-[2-(m-trifluoromethylphenoxy)ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester, 1-[3-(m-trifluoromethylphenoxy) propyl]-piperidine-3-carboxylic acid ethyl ester, 1-[2-(2-methoxy-5-meth ylphenoxy)ethyl]-piperidin-3-carboxylic acid ethyl ester, 1-[2-(3, 4-dichlorophenoxy)ethyl]-piperidine-3-carboxylic acid ethyl ester or l-[2-(3, 4-Dimethylphenoxy)ethyl]-piperidine-3-carboxylic acid ethyl ester or a salt thereof. 11. Method according to claim 1 or 2, characterized in that l-[2-(m-methoxyphenoxy)-ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester is produced, l-[2-(p- chlorophenoxy)ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester, 1-[2-(p-methoxyphenoxy)ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester , 1-[2-(p-cyanophenoxy)ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester, 1-[2-(p-chlorophenoxy)ethyl]-4-hydroxy-1,2 ,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester respectively 1-[2-(p-chlorophenoxy)ethyl]-4-oxo-piperidine-3-carboxylic acid methyl ester , 1-[2-(p-methoxyphenoxy)ethyl] -4-hydroxy-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester respectively 1-[2-(p-methoxyphenoxy)ethyl]-4-oxo-piperidine-3-carboxylic acid methyl ester, l-[2-( o-Methoxyphenoxy)ethyl]-4-hydroxy-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester respectively 1-[2-(o-methoxyphenoxy)ethyl]-4-oxo-piperidine-3-carboxylic acid methyl ester, 4- hydroxy-1-[3-(m-trifluoromethyl-phenoxy)propyl]-1,2,5,6-tetra hydro-pyridine-3-carboxylic acid methyl ester respectively 4-oxo-1-[3-(m-trifluoromethylphenoxy)-propyl]-piperidine-3-carboxylic acid methyl ester, 1-[2-(p-methyl-phenoxy)-ethyl]- Piperidine-3-carboxylic acid methyl ester, 1-[3-(m-trifluoromethylphenoxy)propyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester, 1-[2-(2,4-dichlorophenoxy)ethyl ]-piperidine-3-carboxylic acid ethyl ester, 1-[2-(3,4-dichlorophenoxy)-ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester, 1-[2-(2,5- dimethyl phenoxy)ethyl]-piper in di-3-carboxy 1 acid ethyl ester, 1-[2-(2,5-dimethylphenoxy)ethyl]-1,2,5,6-tetrahydro-pyridine -3-carboxylic acid methyl ester, 1-[2-(m-methylphenoxy)-ethyl]-piperidine-3-carboxylic acid methyl ester, 1-[2-(m-methyl-phenoxy)ethyl]-1,2,5,6-tetrahydro- Pyridine-3-carboxylic acid methyl ester, 1-[2-(o-methylphenoxy)ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester, 1-[2-(3,4-dimethylphenoxy) -ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester, 1-[2-(p-methylphenoxy)ethyl]-piperidine-3-carboxylic acid n-butyl ester, 1-[2-(m-trifluoromethylphenoxy)ethyl]-piperidine-3-carboxylic acid anide, 1-[2-(m- trifluoromethylphenoxy)-ethyl]-piperidine-3-carboxylic acid n-butyl ester, l-[2-(2,4-dichlorophenoxy)ethyl]-piperidine-3-carboxylic acid amide, 1-[3-(m-trifluoromethylphenoxy)propyl]- piper in din-3-carboxylic acid amide, l-[2-(3,4-dimethylphenoxy)ethyl]-piperidine-3-carboxylic acid amide, 1-[4-(m-trifluoromethylphenoxy)butyl]-piperidine-3-carboxylic acid methyl ester, 1-[2-(3,4-dimethylphenoxy)ethyl]-piperidine-3-carboxylic acid-N,N-diethylamide, 1 -[2-(m-trifluoromethylphenoxy)-ethyl]-piperidine-3-carboxylic acid-N,N-diethylamide, 1-[2-(p-methylphenoxy)ethyl]-piperidine-3-carboxylic acid-N,N -diethylamide, 1- [2 - ( 2 , 4-dichlorophenoxy)ethyl]-piperidine-3-carboxylic acid-N,N-diethylamide, 1-[4-(m-trifluoromethylphenoxy)butyl]-3-hydroxymethyl -piperidine , 4- amino-1-[2-(p-methylphenoxy)ethyl]-piperidine-3-carboxylic acid amide, 1-[2-(p-trifluoromethylphenoxy)-ethyl]-1,2,5,6-tetrahydro-pyridine-3 -carboxylic acid methyl ester, l-[2-(5-methoxy-2-methyl-phenoxy)ethyl]-1,2,5 , 6-tetrahydro-pyridine-3-carboxylic acid methyl ester, 4-hydroxy-l-[2-(5- methoxy-2-methyl-phenoxy)ethyl]-1,2,5,6-tetrahydro-pyr idin-3-carboxylic acid methyl ester respectively l-[2-(5-methoxy-2-methyl-phenoxy)ethyl]- 4-oxo-piperidin-3-carboxylic acid methyl ester, 4-hydroxy-1-[2-(2,5-dimethoxyphenoxy)ethyl]-1,2,5,6-tetrahydro-pyr ldine-3-carboxylic acid methyl ester respectively l-[2 -(2,5-dimethoxyphenoxy)ethyl]-4-oxo-piperidine-3-carboxylic acid methyl ester, 1-[2-(2,5-dimethoxyphenoxy)ethyl]-1,2,5,6-tetrahydro-pyridine-3 -carboxylic acid methyl ester , 1-[4-(m-trifluoro-methylphenoxy)butyl]-piperidine-3-carboxylic acid amide, 1-[2-(p-cyanophenoxy)ethyl]-piperidine-3-carboxylic acid reamide or 1-[2-(p-methylphenoxy)ethyl]-3-hydroxymethyl-piperidine or a portion thereof.