NO159590B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE PHENYLEDIC ACID DERIVATIVES. - Google Patents

Description

This invention relates to a process for the production of new phenylacetic acid derivatives with the general formula

their enantiomers and their salts, especially their physiologically compatible salts with inorganic or organic acids or bases.

The new compounds exhibit valuable pharmacological properties, in particular an effect on the metabolism, preferably a blood pressure-lowering effect.

In the above general formula I, A means a group of the formulas

where R3 is an alkyl group with 1 to 3 carbon atoms substituted with an alkoxy group with 1 to 3 carbon atoms or with a phenyl group, an n-propyl group, an alkyl group with 4 to 6 carbon atoms, an alkenyl group with 3 to 5 carbon atoms, a cyano group, an optionally with alkyl groups with each 1 to 3 carbon atoms in the alkyl part mono- or disubstituted aminocarbonyl group, an optionally with halogen atoms, with alkyl, hydroxy, alkoxy, phenyl alkoxy, alkylsulfenyl, alkylsulfinyl and/or alkylsulfonyl groups mono- or disubstituted aryl group with 6 to 10 carbon atoms, as the substituents can be the same or different and the alkyl part in each case can contain 1 to 3 carbon atoms, or a pyridyl group, or also a methyl group, when R^means a piperidino group and R2 in the 4-position a fluorine atom and W a carboxy or alkoxycarbonyl group, where the alkyl part may contain 1 to 3 carbon atoms,

or also a phenyl group, when R± means a piperidino group substituted in the 2- or 3-position with a methyl group, R2 a hydrogen atom and W a carboxy or alkoxycarbonyl group, where the alkyl part can contain 1 to 3 carbon atoms, or when R^ means a piperidino group , R 2 in the 3-, 4- or 6-position a chlorine atom or in the 4- or 6-position a methyl group and W a carboxy or alkoxycarbonyl group, where the alkyl part may contain 1-3 carbon atoms, or when R^ denotes a piperidino group, R 2 a hydrogen atom and W a formyl group or a 2-carboxyethenyl group,

R4 and R5 together with the intermediate carbon atom is an alkylidene group with 3 to 9 carbon atoms or a phenylalkylidene group with 1 to 3 carbon atoms in the alkylidene part,

R^means an optionally with alkyl groups with 1 to 3 carbon atoms mono- or disubstituted, unbranched alkyleneimino group with 4 to 8 carbon atoms,

R 2 means a hydrogen, fluorine, chlorine or bromine atom, a hydroxy, trifluoromethyl, nitro, amino, piperidino, alkyl, alkoxy, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, phenylalkoxy, alkanoyloxy, alkanoylamino -, alkylamino or dialkylamino group, the alkyl part in each case may contain 1 to 3 carbon atoms,

W means a carboxy group or an alkoxycarbonyl group with a total of 2 to 5 carbon atoms, in which the alkyl part may be substituted with a phenyl group and from the ø-carbon atom with 1 or 2 hydroxy groups, an alkoxy-, alkanoyloxy-, or pyridine-carbonyloxy group, where each alkyl part in each case may contain 1 to 3 carbon atoms; an alkyl group with 1 to 3 carbon atoms, a hydroxymethyl-, formyl-, cyano-, amino-carbonyl-, carboxymethyl-, 2-carboxyethyl-, 2-carboxy-ethenyl-, 2- carboxyl-carbonyl-ethyl- or 2-alkoxycarbonyl -ethenyl group, where the alkoxy group can in each case contain 1 to 3 carbon atoms.

Particularly preferred are phenylacetic acid derivatives of the general formula I where R 3 means an n-propyl group, an alkyl group with 4 to 5 carbon atoms, a methyl group, a phenyl group substituted with a fluorine or chlorine atom or a pyridyl group,

R4 and R5 together with the intermediate carbon atom means an alkylidene group with 3 to 5 carbon atoms or a phenylalkylidene group with 1 to 3 carbon atoms in the alkylidene part,

Ri means a piperidino group optionally substituted with one or two methyl groups,

R 2 means a hydrogen, fluorine or chlorine atom, a methyl or methoxy group, and

W means a carboxy group or an alkoxycarbonyl group with a total of 2 to 4 carbon atoms,

their optically active antipodes and their salts with inorganic or organic acids or bases.

Particularly preferred single compounds are 4-[(1-(2-piperidino-phenyl)-1-butyl)aminocarbonylmethyl]benzoic acid and 4-[(1-(2-piperidino-phenyl)-1-pentyl)aminocarbonylmethyl]benzoic acid, their alkyl esters of 1 to 3 carbon atoms, their optically active antipodes and their salts.

According to the invention, the new compounds are produced by the following methods:

a) Reaction of an amine of the general formula where A, R 2 and R 2 are as initially indicated, resp., when A means one of the initially indicated vinylidene groups, its tautomers or its lithium or magnesium halide complex, with a carboxylic acid of the general formula

where W has the meanings given for W at the beginning or is a carboxyl group protected with a protective residue, or with its possibly reactive derivatives produced in the reaction mixture, and if necessary, subsequent cleavage of an applied protective residue.

As reactive derivatives of a compound of the general formula III come into consideration, for example, its esters such as the methyl, ethyl or benzyl ester, its thioesters such as the methylthio or ethyl thioester, its halides such as the acid chloride, its anhydrides or imidazolides.

The reaction is conveniently carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionally in the presence of an acid activating agent or a water-attracting agent, e.g. in the presence of chloroformate ethyl ester, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N'-carbonyldiimidazole or N,N</->thionyldiimidazole or triphenylphosphine /carbon tetrachloride, or an amino group-activating agent, e.g. phosphorus trichloride, and optionally in the presence of an inorganic base such as sodium carbonate, or a tertiary organic base such as triethylamine or pyridine, which can simultaneously serve as a solvent, at temperatures between -25 and 250°C, preferably at temperatures between -10 and the boiling temperature of the solvent used. The reaction can also be carried out without a solvent, and further water formed during the reaction can be removed by azeotropic distillation, e.g. by heating with toluene on a water separator, or by adding a drying agent such as magnesium sulfate or molecular sieves.

If necessary, the subsequent cleavage of a protective residue is carried out preferably hydrolytically, suitably either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid or trichloroacetic acid, or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, methanol, ethanol, ethanol/water, water/isopropanol or water/dioxane at temperatures between -10 and 120°C, e.g. at temperatures between room temperature and the boiling temperature of the reaction mixture.

A tert.buty1 residue used as a protective residue can optionally also be cleaved off thermally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane, and preferably in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid.

Furthermore, a benzyl residue can be used as a protective residue,

is also cleaved hydrogenolytically in the presence of a hydrogenation catalyst, such as palladium/charcoal, in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide.

b) For the preparation of a compound of the general formula I, where W means a carboxy, carboxymethyl, 2-carboxyethyl or 2-carboxyethenyl group, a compound of the general formula is transferred

where

R1>R2°9A is as indicated at the outset, and B means a group which can be transferred to a carboxy-, carboxymethyl-, 2-carboxyethyl- or 2-carboxyethenyl group, for example functional derivatives of carboxy-, carboxymethyl-, 2-carboxyethyl- or the 2-carboxyethenyl group, such as their unsubstituted or substituted amides, their nitriles, esters, thiol esters, ortho-esters, iminoethers, amidines or anhydrides, a malonester-(1)-yl group, a tetrazolyl group, an optionally substituted 1,3 -oxazol-2-yl or 1,3-oxazolin-2-yl group, and for example esters with tertiary alcohols, such as a tert. butyl ester, and for example esters with aralkanols, such as a benzyl ester, to the corresponding carboxy compound by hydrolysis, thermolysis or hydrogenolysis.

The hydrolysis is conveniently carried out either in the presence of a

acid such as hydrochloric acid, sulfuric acid, phosphoric acid or trichloroacetic acid, or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, ethanol, water/ethanol, water/isopropanol or water/dioxane at temperatures between -10 and 120°C, for example

at temperatures between room temperature and the boiling temperature of the reaction mixture.

If B in a compound of the general formula IV means a cyano or aminocarbonyl group, these groups can also be transferred to a carboxyl group with a nitrite, for example sodium nitrite, in the presence of an acid such as sulfuric acid, this being suitably used at the same time as a solvent, at temperatures between 0 and 50°C.

If B in a compound of the general formula IV, for example, means a tert.butyloxycarbonyl group, the tert.butyl group can also be cleaved off thermally, possibly in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane, and preferably in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid, preferably at the boiling temperature of the solvent used, e.g. at temperatures between 40 and 100°C.

If B in a compound of the general formula IV,

e.g. means a benzyloxycarbonyl group, the benzyl group can also be removed hydrogenolytically in the presence of a hydrogenation catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, acetic acid ethyl ester, dioxane or dimethylformamide, preferably at temperatures between 0 and 50°C , e.g. at room temperature, and a hydrogen pressure of 1 to 5 bar. During the hydrogenolysis, other residues can be co-reduced at the same time, for example a nitro group to an amino group,

a benzyloxy group to a hydroxy group, a vinylidene group to the corresponding alkylidene group or a cinnamic acid group to the corresponding phenylpropionic acid group, or is replaced by hydrogen atoms, e.g. a halogen atom with a hydrogen atom.

c) For the preparation of a compound of the general formula I, where A means a group of the formula

R3' I - CH - ,

where R3', with the exception of an alkenyl group and a cyano group, have the meanings given for R3 at the beginning, a compound with the general formula is reduced

where

Rl»R2°9 w is as indicated at the outset, and

D means a group with the formulas

where R3" with the exception of a cyano group have the meanings given for R3 at the beginning, and R4' and R5' together with the intermediate carbon atom mean a propylidene group, an alkylidene group with 4 to 6 carbon atoms or a phenylalkylidene group with 1 to 3 carbon atoms in the alkylidene part, with hydrogen in the presence of a hydrogenation catalyst.

The reduction is preferably carried out with hydrogen in the presence of a hydrogenation catalyst such as palladium/charcoal or Raney nickel, in a suitable solvent such as methanol, ethanol, isopropanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane, tetrahydrofuran, dimethylformamide, benzene or benzene/ ethanol at temperatures between 0 and 100°C, preferably at temperatures between 20 and 50°C, and a hydrogen pressure of 1 to 5 bar. By using a suitable chiral hydrogenation catalyst such as a metal-ligand complex, e.g. a complex of \ x .^'-dichloro-bis-[1,5-cyclooctadiene-rhodium] and (+)- or (-)-0,0-isopropylidene-2,3-dihydroxy-1,4-bis- (diphenylphosphino)-butane (=DIOP), the hydrogen addition occurs enantioselectively. Furthermore, in the catalytic hydrogenation, other groups can be co-reduced, e.g. a nitro group to an amino group, a benzyloxy group to a hydroxy group or a cinnamic acid group to a phenyl-propionic acid group, or is replaced by hydrogen atoms, e.g. a halogen atom with a hydrogen atom.

d) For the preparation of compounds of the general formula I, where R3 with the exception of a cyano group have the meanings given for R3 at the beginning, a compound of the general formula is reacted

where

R 3 " is as above indicated, and R 3 and R 2 are as initially indicated, with a compound of the general formula

where

W is as indicated at the outset.

The reaction is carried out in the presence of a strong acid which can also serve as a solvent, preferably in concentrated sulfuric acid, at temperatures between 0 and 150°C, preferably at temperatures between 20 and 100°C.

e) For the preparation of compounds with the general formula I where R2 means a hydrogen atom and A a group with the formula

where R 3 is as indicated at the outset, a compound of the general formula is dehalogenated

where

, A and W are as indicated at the outset, and Hal means a fluorine, chlorine, bromine or iodine atom.

The dehalogenation is conveniently carried out in a solvent such as methanol, ethanol, ethyl acetate, glacial acetic acid or dimethylformamide, with catalytically activated hydrogen, e.g. with hydrogen in the presence of platinum or palladium/carbon, at temperatures between 0 and 100°C, preferably at room temperature, and at a hydrogen pressure of 1 to 5 bar. During the dehalogenation, other groups can be co-reduced at the same time, e.g. a benzyloxy group to a hydroxy group, a vinylidene group to the corresponding alkylidene group or a cinnamic acid group to the corresponding phenylpropionic acid group, or is replaced by hydrogen atoms, e.g. a halogen atom with a hydrogen atom.

f) For the preparation of compounds of the general formula I where A means a group of the formula

where R3 means an alkyleneiminocarbonyl group with 4 to 6 carbon atoms in the alkylene ring or an optionally with alkyl or phenylalkyl groups with each 1 to 3 carbon atoms in the alkyl part mono- or disubstituted aminocarbonyl group, a compound with the general formula is reacted

where

R 1 and R 2 are as indicated at the beginning, and W" has, with the exception of a carboxy-, carboxy-methyl-, 2-carboxyethyl-, 2-carboxy-ethenyl- or 2,2-bis-(carboxy)ethyl group, those for W at the beginning indicated meanings, with an amine of the general formula

where

R6 means an alkyleneimino group with 4 to 6 carbon atoms or an optionally with alkyl or phenylalkyl groups with each 1 to 3 carbon atoms in the alkyl part mono- or disubstituted amino group.

The amidation is conveniently carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, preferably in the presence of an acid-activating agent or a water-attracting agent, e.g. in the presence of chloroformate ethyl ester, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N''-carbonyldiimidazole, N,N'-thionyldiimidazole or triphenylphosphine/carbon tetrachloride, or an amino group activating agent, e.g. phosphorus trichloride, and optionally in the presence of an inorganic base such as sodium carbonate, or a tertiary organic base such as triethylamine or pyridine, which can simultaneously serve as a solvent, at temperatures between -25 and 250°C, preferably at temperatures between -10°C and the boiling point of the solvent used.

g) For the preparation of compounds of the general formula I where W means a carboxy group, a compound of the general formula is oxidized

where

RltR2 and R3 are as indicated at the outset, and

E means a group which by oxidation can be transferred to a carboxy group, for example a fbrmyl group and acetals thereof, a hydroxymethyl group and ethers thereof, an unsubstituted or substituted acyl group such as an acetyl-, chloroacetyl-, propionyl-, malonic acid-(1)- yl or malonester-(1)-yl group.

The reaction is carried out with an oxidizing agent in a suitable solvent such as water, glacial acetic acid, methylene chloride, dioxane or glycol dimethyl ether, at temperatures between 0 and 100°C, suitable at temperatures between 20 and 50°C. However, the reaction is preferably carried out with silver oxide/sodium hydroxide, manganese dioxide/acetone or methylene chloride, hydrogen peroxide/sodium hydroxide, bromine or chlorine/sodium hydroxide or potassium hydroxide, chromium trioxide/pyridine or pyridinium chlorochromate.

h) For the preparation of compounds of the general formula I, where W means an alkoxycarbonyl group with a total of 2 to

5 carbon atoms, where the alkyl part from the P carbon atom can be substituted with 1 or 2 hydroxy groups or with an alkoxy group with 1 to 3 carbon atoms, a carboxylic acid with the general formula is esterified

where , R 2 and A are as indicated at the outset, or its possibly produced derivatives in the reaction mixture, with an alcohol of the general formula

where

R7 means an alkyl group with 1 to 4 carbon atoms which can be substituted from the e-carbon atom with 1 or 2 hydroxy groups or an alkoxy group with 1 to 3 carbon atoms.

As reactive derivatives of a compound with the general formula XII come e.g. considering its halides such as the acid chloride, its anhydrides or imidazolides.

The reaction is suitably carried out in the corresponding alcohol as solvent, or in a suitable solvent such as methylene chloride, chloroform, ether, tetrahydrofuran,

dioxane, benzene or toluene, optionally in the presence of an acid-activating agent or a water-attracting agent, e.g. in the presence of hydrogen chloride, sulfuric acid, chloroformate ethyl ester, thionyl chloride, carbon tetrachloride/triphenylphosphine, carbonyl

diimidazole or N,N'-dicyclohexylcarbodiimide or isourine ethers thereof, optionally in the presence of a reaction accelerator such as copper chloride, and optionally in the presence of an inorganic base such as sodium carbonate, or a tertiary organic base such as triethylamine or pyridine, or by transesterification , e.g. with a suitable carbonic acid diester, at temperatures between -20 and 100°C, preferably at temperatures between -10 and the boiling point of the solvent used.

i) For the preparation of a compound of the general formula I, where W means an alkoxycarbonyl, 2-alkoxycarbonyl-ethyl or 2-alkoxycarbonyl-ethenyl group, and A is a group of the formula

where R3", with the exception of a cyano group, have the meanings given for R3 at the beginning, a compound with the general formula is transferred

where R 1 and R 2 are as indicated at the beginning, with the exception of a cyano group, R 3 " has the meanings given for R 3 at the beginning, and W" means a cyano, 2-cyanoethyl or 2-cyano-ethenyl group, to a corresponding ester.

The alcoholysis is conveniently carried out in a corresponding alcohol as solvent, such as methanol, ethanol or propanol, preferably in the presence of an acid such as hydrochloric or sulfuric acid, at temperatures between 20°C and the boiling temperature of the solvent used, preferably at temperatures between 50 and 100° C.

Optionally, a prepared compound of the general formula I, where W means a carboxy or alkoxycarbonyl group, can be transferred by reduction to a corresponding compound of the general formula I, where W means a formyl or hydroxymethyl group, and/or

a prepared compound of the general formula I, where W means a carboxy group, is converted by transfer to a sulfonic acid hydrazide and subsequent disproportionation to a corresponding compound of the general formula I, where W means a formyl group, and/or

a prepared compound of the general formula I, where W means a formyl group, is converted by condensation and possibly subsequent hydrolysis and/or decarboxylation into a corresponding compound of the general formula I, where W means a 2-alkoxycarbonylethenyl or 2-carboxyethenyl group, and /or

a prepared compound of the general formula I, where W means a 2-carboxyetheny1- or 2-alkoxycarbonyl-ethenyl group, is transferred by catalytic hydrogenation to a corresponding compound of the general formula I, where W means a 2-carboxyethyl- or 2 -Alkoxycarbonyl-ethyl group, and/or

a prepared compound of the general formula I, where W means an alkoxycarbonyl group, which from the ω-carbon atom is substituted with a hydroxy group, is transferred by acylation with a pyridine carboxylic acid to a corresponding (pyridinecarbonyloxy-alkoxy)-carbonyl compound of the general formula I, and/ or

a prepared compound of the general formula I, where W means a hydroxymethyl group, after transfer to a corresponding halomethyl compound and subsequent reaction with a malonic acid diester, is converted into a corresponding compound of the general formula I, where W means an ethyl group substituted with two alkoxycarbonyl groups, and /or

a prepared compound of the general formula I, where W means an ethyl group substituted with two alkoxycarbonyl groups, is converted by hydrolysis into a corresponding compound of the general formula I, where W means an ethyl group substituted with two carboxy groups, and/or

a prepared compound of the general formula I, where W means an ethyl group substituted with two alkoxycarbonyl groups, is converted by hydrolysis and decarboxylation into a corresponding compound of the general formula I, where W means a 2-carboxy-ethyl group, and/or

a prepared compound of the general formula I, where R2 denotes a nitro group, is converted by reduction into a corresponding compound of the general formula I, where R2 denotes an amino group, and/or

a prepared compound of the general formula I, where R2 is an amino group, is converted over a corresponding diazonium salt into a corresponding compound of the general formula I, where R2 is a hydrogen, fluorine, chlorine or bromine atom, a hydroxy, alkoxy or alkylsulfenyl group, and/or

a prepared compound of the general formula I, where R 2 means a benzyloxy acid residue and/or R 3 means an aryl residue substituted with a benzyloxy acid residue, is converted by debenzylation into a corresponding compound of the general formula I, where R 2 means a hydroxy group and/or R 3 means a substituted with a hydroxy group aryl residue, and/or

a prepared compound of the general formula I, where R 3 means an aminocarbonyl group, is converted by dehydration into a corresponding compound of the general formula I, where R 3 means a cyano group.

The subsequent reduction is preferably carried out with a metal hydride, e.g. with a complex metal hydride such as lithium aluminum hydride, in a suitable solvent such as diethyl ether, tetrahydrofuran or dioxane at temperatures between 0 and 100°C, preferably at temperatures between 20 and 60°C.

The subsequent disproportionation of a sulphonic acid hydrazide, which is obtained by reacting a corresponding hydrazine with a corresponding, reactive carboxylic acid derivative, is carried out in the presence of a base such as sodium carbonate in a solvent such as ethylene glycol, at temperatures between 100 and 200°C, preferably at 160 to 170°C.

The subsequent condensation of a formyl compound is conveniently carried out in a solvent such as pyridine or tetrahydrofuran, with malonic acid, with a malonic acid ester, with a dialkylphosphonoacetic acid ester or an alkoxycarbonylmethylenetriphenylphosphorane, optionally in the presence of a base as a condensing agent, e.g. in the presence of piperidine, potassium tert-butylate or sodium hydride, at temperatures between 0 and 100°C; and by subsequent acidification, e.g. by hydrochloric acid or sulfuric acid, resp. by subsequent alkaline hydrolysis, the desired compound is obtained.

The subsequent catalytic hydrogenation is conveniently carried out in a solvent such as methanol, ethanol, acetic acid ethyl ester, glacial acetic acid or dimethylformamide, with hydrogen in the presence of a hydrogenation catalyst such as platinum or platinum/charcoal, at temperatures between 0 and 75°C, preferably at room temperature, and at a hydrogen pressure of 1 to 5 bar.

The subsequent O-acylation is conveniently carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, preferably with a reactive derivative of the acid, e.g. a halide such as the acid chloride, an anhydride or imidazolide, and optionally in the presence of an inorganic base such as sodium carbonate, or a tertiary organic base such as triethylamine or pyridine, which can simultaneously serve as a solvent, at temperatures between -25 and 250°C , preferably at temperatures between -10 and the boiling temperature of the solvent used.

The subsequent transfer of a hydroxymethyl group to a halomethyl group is carried out with a halogenating agent such as thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride, in a solvent such as methylene chloride, carbon tetrachloride, benzene or nitrobenzene, and its subsequent reaction with a malonic acid ester, e.g. with the alkali salt of malonic acid diethyl ester, is carried out at temperatures between 0 and 100°C, preferably at temperatures between 50 and 80°C.

The subsequent hydrolysis or hydrolysis and decarboxylation is suitably carried out in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid or trifluoroacetic acid, in a suitable solvent such as water, ethanol, water/ethanol, water/isopropanol or water/dioxane, at elevated temperature, e.g. at the boiling temperature of the reaction mixture.

The subsequent reduction of the nitro compound is preferably carried out in a solvent such as water, water/ethanol, methanol, glacial acetic acid, ethyl acetate or dimethylformamide, suitably with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, platinum or palladium/charcoal, with metals such as such as iron, tin or zinc in the presence of an acid, with salts such as iron (II) sulphate, tin (II) chloride or sodium dithionite or with hydrazine in the presence of Raney nickel at a temperature between 0 and 50°C, preferably at room temperature.

The subsequent reaction of a diazonium salt, e.g. the fluoroborate, the fluoride in 40% hydrofluoric acid, the hydrosulphate in sulfuric acid or the hydrochloride, possibly in the presence of copper or a suitable copper (I) salt such as copper (I) chloride/hydrochloric acid or copper (I) bromide/hydrobromic acid, is carried out at slightly elevated temperatures , e.g. at temperatures between 15 and 100°C. The subsequent reaction with hypophosphorous acidification is preferably carried out at -5 to 0°C. The required diazonium salt is conveniently prepared in a suitable solvent, e.g. in water/hydrochloric acid, methanol/hydrochloric acid, ethanol/hydrochloric acid or dioxane/hydrochloric acid, by diazotizing a corresponding amino compound with a nitrite, e.g. sodium nitrite or an ester of nitric acid, at lower temperatures, e.g. at temperatures between -10 and 5°C.

The subsequent debenzylation is conveniently carried out in a solvent such as methanol, ethanol, ethyl acetate, glacial acetic acid or dimethylformamide, with catalytically activated hydrogen, e.g. with hydrogen in the presence of platinum or palladium/carbon, at temperatures between 0 and 75°C, preferably at room temperature, and at a hydrogen pressure of 1 to 5 bar.

The subsequent dehydration is carried out with a water-attracting agent such as phosphorus pentoxide, sulfuric acid or p-toluenesulfonic acid chloride, possibly in a solvent such as methylene chloride or pyridine, at temperatures between 0 and 100°C, preferably at temperatures between 20 and 80°C.

If the obtained compounds of the general formula I contain a chiral center, they can be separated into their enantiomers by conventional methods. This separation takes place by column chromatography on a chiral phase.

The obtained compounds of the general formula I can also be converted into their addition salts, in particular their physiologically compatible salts with inorganic or organic acids or also bases. As acids come e.g. considering hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid or fumaric acid, and as bases e.g. considering sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine, triethanolamine or ethylenediamine.

The compounds of the general formulas II to XIV used as starting materials are known from the literature or can be prepared by methods known from the literature.

Thus, you get e.g. a connection with the general

formula II, where A is a group of the formula

respectively its tautomeric ketimine, by reaction of a corresponding nitrile with an appropriate Grignard or lithium compound and subsequent hydrolysis, or by reaction of a corresponding ketone with ammonia in the presence of titanium tetrachloride. For further reaction with a compound of the general formula III or its reactive derivatives, especially its acid chlorides, the organometallic ketimine complex can also be used. A compound of the general formula II, where A means a group of the formula

where R3 with the exception of one

cyano or aminocarbonyl group, is as indicated at the outset, you get e.g. by reaction of a corresponding nitrile with an appropriate Grignard or lithium compound and optionally subsequent lithium aluminum hydride reduction and subsequent hydrolysis to the ketimine, which is then reduced with catalytically activated hydrogen, with a complex metal hydride or with nascent hydrogen; by hydrolysis or by hydrazinolysis of a corresponding phthalimido compound, by reaction of a corresponding ketone with ammonium formate and subsequent hydrolysis resp. with an ammonium salt in the presence of sodium cyanoborohydride, by reduction of a corresponding oxime with lithium aluminum hydride or with catalytically activated or nascent hydrogen, with reduction of a corresponding N-benzyl or N-(1-phenylethyl)ketimine, e.g. with catalytically activated hydrogen or with a complex metal hydride in ether or tetrahydrofuran at temperatures between -78°C and the solvent used

boiling temperature and subsequent cleavage of the benzyl or 1-phenylethyl group by catalytic hydrogenation, by Ritter reaction of a corresponding alcohol with potassium cyanide in sulfuric acid, or by Hofman, Curtius, Lossen or Schmidt decomposition of a corresponding compound.

A compound of the general formula II, where A represents the group

is obtained by reacting a corresponding aldehyde with ammonium cyanide or by reacting a corresponding cyanohydrin with ammonia. An amine thus obtained of the general formula II with a chiral center, where A means a group of the formula

where R3, with the exception of a cyano group, is as indicated at the outset, can by racemate cleavage, e.g. by fractional crystallization of the diastereomeric salts with optically active acids and subsequent cleavage of the salts or by column chromatography on a chiral phase, or by formation of diastereomeric compounds, separation and subsequent cleavage of these, are separated into the enantiomers.

Furthermore, an optically active amine of the general formula II can also be prepared by enantio-selective reduction of a corresponding ketimine with complex boron or aluminum hydrides, in which part of the hydride hydrogen atoms are replaced with optically active alcohol residues, or with hydrogen in the presence of a suitable chiral hydrogenation catalyst or analogously by starting from a suitable N-benzyl- or N-(1-phenethyl)-ketimine or from a corresponding N-acyl-ketimine resp. enamide and possibly subsequent cleavage of the benzyl, 1-phenethyl or acyl residue.

Furthermore, an optically active eimine with the general formula II can also be prepared by diastereoselective reduction of a corresponding ketimine or hydrozone which is chirally substituted on the nitrogen atom, with complex or also non-complex boron or aluminum hydrides, in which possibly part of the hydride hydrogen atoms have been replaced with suitable alcoholate, phenolate or also alkyl residues, or with hydrogen in the presence of a suitable hydrogenation catalyst and possibly subsequent cleavage of the chiral auxiliary residue by catalytic hydrogenolysis or hydrolysis.

Furthermore, an optically active amine with the general formula II can also be prepared by diastereo-selective addition of a suitable organometallic compound, preferably a Grignard or a lithium compound, to a corresponding aldimine which is chirally substituted on the nitrogen atom, by subsequent hydrolysis and optionally subsequent cleavage of the chiral auxiliary residue by catalytic hydrogenolysis or hydrolysis.

The compounds of the general formulas IV, VIII, IX, XI, XII and XIV used as starting materials are obtained by reacting a corresponding amine with a corresponding compound of the general formula III or their reactive derivatives and possibly subsequent hydrolysis.

A compound with the general formula V used as starting material is preferably obtained by acylation of a corresponding ketimine or its organometallic complex with a suitable carboxylic acid or reactive derivatives thereof.

As mentioned at the outset, the new compounds with the general formula I exhibit valuable pharmacological properties, namely an effect on intermediate metabolism, in particular a blood pressure-lowering effect, partly also an effect on the cardiovascular system.

As examples were the compounds

A = (Z)-4-[(1-(2-piperidino-phenyl)-1-buten-1-yl)-amino-carbonylmethyl]-benzoic acid,

B = (Z)-4-[(1-(2-piperidino-phenyl)-1-buten-1-yl)-amino-carbonylmethyl]-benzoic acid ethyl ester,

C = (E)-4-[(1-(2-piperidino-phenyl)-1-buten-1-yl)-amino-carbonylmethyl]-benzoic acid,

D = 4-[(2-methyl-1-(2-piperidino-phenyl)-1-propen-1-yl)-amino-carbonylmethyl]-benzoic acid,

E = (Z)-4-[(1-(2-piperidino-phenyl)-1-hexen-1-yl)-amino-carbonylmethyl]-benzoic acid ethyl ester,

F = (Z)-4-[(3-phenyl-1-(2-piperidino-phenyl)-1-propen-1-yl)amino-carbonylmethyl]-benzoic acid,

G (Z)-4-[(1-(2-(3,3-dimethyl-piperidino)-phenyl)-1-buten-1-yl)-aminocarbonylmethyl]-benzoic acid,

H 4-[(1-(2-pyrrolidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoic acid,

J (±)-4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoic acid,

K (+)-4-t(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoic acid,

L (+)-4[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoic acid ethyl ester,

M = 4-[(1-(2-hexahydroazepino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoic acid,

N = 4-[(1-(2-piperidino-phenyl)-1-hexyl)-aminocarbonyl-methyl]-benzoic acid,

0 = 4-[(3-phenyl-1-(2-piperidino-phenyl)-1-propyl)-amino-carbonylmethyl]-benzoic acid,

P = 4-[(2-methoxy-1-(2-piperidino-phenyl)-1-ethyl)-amino-carbonylmethyl]-benzoic acid,

Q = 4-[(α-cyano-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid,

R = 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzyl alcohol,

S = 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-phenylacetic acid,

T = 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-cinnamic acid,

U = 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid (2,3-dihydroxy-propyl) ester,

V = 4-[(1-(4-fluoro-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoic acid,

W = 4-[(1-(4-methoxy-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoic acid,

X = 4-[(1-(2-octahydroazonino-phenyl)-1-ethenyl)-aminocarbonyl-methyl]-benzoic acid,

Y = 4-[(1-(3-chloro-2-piperidino-phenyl)-1-ethyl)-aminocarbonyl-methyl]-benzoic acid,

Z = 4-[(1-(3-methyl-2-piperidino-phenyl)-1-ethyl)-aminocarbonyl-methyl]-benzoic acid,

AA = 4-[(α-(4-methyl-phenyl)-2-piperidino-benzyl)-aminocarbonyl-methyl]-benzoic acid,

AB = 4-[(a-(3-methyl-phenyl)-2-piperidino-benzyl)-aminocarbonyl-methyl]-benzoic acid,

AC = 4-[(α-(4-fluoro-phenyl)-2-piperidino-benzyl)-aminocarbonyl-methyl]-benzoic acid,

AD = 4-[(a-(2-fluoro-phenyl)-2-piperidino-benzyl)-aminocarbonyl-methyl]-benzoic acid,

AE = 4-[(α-(4-chloro-phenyl)-2-piperidino-benzyl)-aminocarbonyl-methyl]-benzoic acid,

AF = 4-t(a-(3-chloro-phenyl)-2-piperidino-benzyl)-aminocarbonyl-methyl]-benzoic acid,

AG = 4-[(2-piperidino-α-(2-pyridyl)-benzyl)-aminocarbonyl-methyl]-benzoic acid,

AH = 4-[(2-piperidino-α-(4-pyridyl)-benzyl)-aminocarbonyl-methyl]-benzoic acid,

AJ = 4-[(6-chloro-α-phenyl-2-piperidino-benzyl)-aminocarbonyl-methyl]-benzoic acid,

AK = 4-[(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-cinnamic acid,

AL = 3-[4-[(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-phenyl]-propionic acid,

AM = 4-[(4-chloro-α-phenyl-2-piperidino-benzyl)-aminocarbonyl-methyl]-benzoic acid,

AN = 4-[(6-methyl-α-phenyl-2-piperidino-benzyl)-aminocarbonyl-methyl]-benzoic acid,

AO = 4-[(4-methyl-α-phenyl-2-piperidino-benzyl)-aminocarbonyl-methyl]-benzoic acid,

AP = 4-t(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzaldehyde,

AQ = 4-[(2-(2-methyl-piperidino)-α-phenyl-benzyl)-aminocarbonyl-methyl ]-benzoic acid,

AR = 4-[(2-(3-methyl-piperidino)-α-phenyl-benzyl)-aminocarbonyl-methyl]-benzoic acid and

AS = 4-[(3-chloro-α-phenyl-2-piperidino-benzyl)-aminocarbonyl-methyl]-benzoic acid

examined with respect to its properties as follows:

1. Blood pressure-lowering effect

The blood pressure-lowering effect of the test compounds was investigated on female rats of own breeding with a weight of 180-220 g, which were fasted for 24 hours before the start of the experiment. The test compounds were immediately before the beginning of the experiment suspended in 1.5% methylcellulose and administered via throat probe.

Blood samples were taken immediately before administration of the test compound and likewise 1, 2, 3 and 4 hours thereafter, each time from the retro-orbital venous plexus. From 50 µl of each of these, proteins were removed with 0.5 ml of 0.33N perchloric acid and they were centrifuged. In the liquid on top, glucose was determined according to the hexokinase method using an analytical photometer. The statistical assessment was carried out according to the t-test according to Student with p = 0.05 as the significance limit.

The following table contains the values found in percentage compared to control:

2. Acute toxicity:

On female and male mice of own breeding weighing 20-26 g, the toxic effect was investigated after oral administration (suspension in 1% methylcellulose) of a single dose with a post-observation period of 14 days:

Due to their pharmacological properties, the new compounds of the general formula I and their physiologically compatible salts are suitable for the treatment of diabetes mellitus. For this purpose, they can, optionally together with other active substances, be incorporated into the usual galenic preparation forms such as tablets, dragees, capsules, powders or suspensions. The single dose for adults is here 1-50 mg, preferably 2.5-20 mg, 1 or 2 times a day.

The following examples shall further illustrate the invention:

Example 1

4-[N-[α-(4-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonyl-methyl]-benzoic acid ethyl ester

To 4.2 g (15 mmol) α-(4-methyl-phenyl)-2-piperidino-benzylamine and 3.4 g (16.5 mmol) 4-ethoxycarbonyl-phenylacetic acid, dissolved in 40 ml of acetonitrile, is added order 4.7 g (18 mmol) triphenylphosphine, 3 g (30 mmol) triethylamine and 1.5 ml (15 mmol) carbon tetrachloride. The reaction mixture is stirred for 2 hours at 50°C, then evaporated, and after acidification with 6N hydrochloric acid, it is extracted with ethyl acetate. The acidic, aqueous phase is then extracted several times with methylene chloride. The methylene chloride extracts are washed with sodium bicarbonate solution, dried over magnesium sulfate and evaporated. The evaporation residue is triturated with ethanol and suctioned off. Yield: 4.55 g (65% of the theoretical).

Melting point: 177-178°C

Analogous to example 1 was produced:

(a) 4-[N-[α-(3-methyl-phenyl)-2-piperidino-benzyl]-amino-carbonyl-methyl]-benzoic acid ethyl ester.

Yield: 48% of the theoretical.

Melting point: 159-16 0°C

(b) 4-[N-[α-(2-methyl-phenyl)-2-piperidino-benzyl]-amino-carbonylmethyl]-benzoic acid ethyl ester.

Yield: 3 5.4% of the theoretical.

Melting point: 196-198°C

(c) 4-[N-[α-(4-methoxy-phenyl)-2-piperidino-benzyl]-amino-carbonylmethyl]-benzoic acid ethyl ester.

Yield: 4 5% of the theoretical.

Melting point: 16 7-168°C

(d) 4-[N-1 α-(4-benzyloxy-phenyl)-2-piperidino-benzyl]-amino-carbonylmethyl]-benzoic acid ethyl ester.

Yield: 96% of the theoretical.

Melting point: 154-155°C

(e) 4-[N-[a-(4-fluoro-phenyl)-2-piperidino-benzyl]-amino-carbonylmethyl]-benzoic acid ethyl ester

Yield: 58% of the theoretical.

Melting point: 174-176°C

(f) 4-[N-[α(2-fluoro-phenyl)-2-piperidino-benzyl]-amino-carbonylmethyl]-benzoic acid ethyl ester.

Yield: 83% of the theoretical.

Melting point: 173-175°C

(g) 4-[N-[α-(4-chloro-phenyl)-2-piperidino-benzyl]-amino-carbonylmethyl]-benzoic acid ethyl ester.

Yield: 57% of the theoretical.

Melting point: 178-181°C.

(h) 4-[N-[α-(3-chloro-phenyl)-2-piperidino-benzyl]-amino-carbonylmethyl]-benzoic acid ethyl ester.

Yield: 71% of the theoretical.

Melting point: 153-156°C

(i) 4-[N-[α-(2-chloro-phenyl)-2-piperidino-benzyl]-amino-carbonylmethyl]-benzoic acid ethyl ester.

Yield: 66% of the theoretical.

Melting point: 196-198°C

(k) 4-[N-[α-(4-methylmercapto-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzoic acid ethyl ester.

Yield: 84% of the theoretical.

Melting point: 173-175°C.

(1) 4-[N-[5-chloro-α-(2-chloro-phenyl)-2-piperidino-benzyl]-amino-carbonylmethyl]-benzoic acid ethyl ester Yield: 92% of theoretical.

Melting point: 213-215°C

(m) 4-[N-[2-piperidino-α-(2-pyridyl)-benzyl]-aminocarbonyl-methyl]-benzoic acid ethyl ester.

Yield: 51% of the theoretical

Melting point: 158-159°C

(n) 4-[N-[2-piperidino-α-(3-pyridyl)-benzyl]-aminocarbonyl-methyl ]-benzoic acid ethyl ester

Yield: 85% of the theoretical.

Melting point: 172°C

(o) 4-[N-[2-piperidino-α-(4-pyridyl)-benzyl]-aminocarbonyl-methyl]-benzoic acid ethyl ester

Yield: 20% of the theoretical.

Melting point: 150-152°C

(p)4-[N-(6-chloro-a-phenyl-2-piperidino-benzyl)-aminocarbonyl-methyl]-benzoic acid ethyl ester.

Yield: 12% of the theoretical.

Melting point: oil

Calculated: Mole top m/e = 490/492

Found : Mole top m/e = 490/492

(g) 4-[N-(4-chloro-α-phenyl-2-piperidino-benzyl)-aminocarbonyl-methyl]-benzoic acid ethyl ester.

Yield: 37% of the theoretical.

Melting point: 148-150°C.

(r) 4-[N-(3-chloro-α-phenyl-2-piperidino-benzyl)-aminocarbonyl-methyl]-benzoic acid ethyl ester.

Yield: 74% of the theoretical.

Melting point: 176-178°C

(s) 4-[N-(6-methyl-α-phenyl-2-piperidino-benzyl)-aminocarbonyl-methyl]-benzoic acid ethyl ester.

Yield: 65% of the theoretical.

Melting point: oil.

Calculated: Moltop m/e = 470

Found: Mole top m/e = 4 70

(t) 4-[N-(4-methyl-α-phenyl-2-piperidino-benzyl)-aminocarbonyl-methyl]-benzoic acid ethyl ester.

Yield: 76% of the theoretical.

Melting point: 133-135°C

( u ) 4-[N-[5-chloro-2-(2-methyl-piperidino)-α-phenyl-benzyl]-aminocarbonylmethyl]-benzoic acid ethyl ester.

Yield: 36.5% of the theoretical.

Melting point: 171-173°C

Example 2

4-[N-1 α-(4-chloro-phenyl)-2-piperidino-benzyl]-aminocarbonyl-methyl ]-benzoic acid ethyl ester

To a solution of 6.02 g (20 mmol) α-(4-chloro-phenyl)-2-piperidino-benzylamine and 3.5 ml (25 mmol) triethylamine in 50 ml chloroform, a solution of 5 g (22.1 mmol) of 4-ethoxycarbonyl-phenylacetyl chloride in 20 ml of chloroform. The mixture is stirred for 2 hours at room temperature, water is then added and extracted with chloroform. The extracts are dried and evaporated. The evaporation residue is chromatographed on silica gel with toluene/acetic acid ethyl ester 5:1 as developing agent. Yield: 5.6 g (57% of theoretical).

Melting point: 178-181°C

Analogous to example 2 was produced:

(a) 4-[N-[5-chloro-2-(3-methyl-piperidino)-α-phenyl-benzyl]-aminocarbonylmethyl]-benzoic acid ethyl ester.

Yield: 54% of the theoretical.

Melting point: 178-180°C

Example 3

4-[N-[α-(4-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonyl-1-methyl]-benzoic acid

4.4 g (9.35 mmol) of 4-[N-[α-(4-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzoic acid ethyl ester are dissolved in 150 ml of ethanol while heating. Then add 20 ml of 1N caustic soda and stir for 3 hours at 50°C. 20 ml of 1N hydrochloric acid is then added to the reaction mixture and excess ethanol is removed by evaporation on a rotary evaporator. The remaining aqueous suspension is filtered, and the precipitate is washed well with water. It is then recrystallized from acetonitrile.

Yield: 2.45 g (59.3% of the theoretical).

Melting point: 226-228°C

Analogous to example 3 was produced:

(a) 4-[N-[α(3-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonyl-methyl]-benzoic acid.

Yield: 72% of the theoretical.

Melting point: 202-203°C

(b) 4-[N-[α-(2-methyl-phenyl)-2-piperidino-benzyl]-amino-carbonylmethyl]-benzoic acid.

Yield: 4 2.6% of the theoretical.

Melting point: 285-290°C

(c) 4-[N-[α-(4-methoxy-phenyl)-2-piperidino-benzyl]-amino-carbonylmethyl]-benzoic acid.

Yield: 72.4% of the theoretical.

Melting point: 228-230°C

(d) 4-[N-[α-(4-benzyloxy-phenyl)-2-piperidino-benzyl]-amino-carbonylmethyl]-benzoic acid.

Yield: 57% of the theoretical.

Melting point: 219-221°C

(e) 4-[N-[α-(4-Fluoro-phenyl)-2-piperidino-benzyl]-aminocarbonyl-methyl]-benzoic acid.

Yield: 75% of the theoretical.

Melting point: 238-240°C

(f) 4-[N-[α-(2-fluoro-phenyl)-2-piperidino-benzyl]-amino-carbonylmethyl]-benzoic acid.

Yield: 87% of the theoretical.

Melting point: 280-283°C

(g) 4-[N-[α-(4-chloro-phenyl)-2-piperidino-benzyl]-amino-carbonylmethyl]-benzoic acid.

Yield: 89% of the theoretical.

Melting point: 241-242°C

(h) 4-[N-[α-(3-chloro-phenyl)-2-piperidino-benzyl]-aminocarbonyl-methyl]-benzoic acid.

Yield: 53% of the theoretical.

Melting point: 223-225°C

(i) 4-[N-[α(2-chloro-phenyl)-2-piperidino-benzyl]-aminocarbonyl-methyl]-benzoic acid.

Yield: 98% of the theoretical.

Melting point: 303-305°C

(k) 4-[N-[α-(4-methylmercapto-phenyl)-2-piperidino-benzyl]-amino-carbonylmethyl]-benzoic acid.

Yield: 84.6% of the theoretical.

Melting point: 225-227°C

(1) 4-[N-[5-chloro-α-(2-chloro-phenyl)-2-piperidino-benzyl]-amino-carbonylmethyl]-benzoic acid.

Yield: 90% of the theoretical.

Melting point: 317-320°C

(m) 4-[N-[2-piperidino-α-(2-pyridyl)-benzyl]-aminocarbonyl-methyl]-benzoic acid.

Yield: 81% of the theoretical.

Melting point: 16 0-161°C

(n) 4-[N-[2-piperidino-α-(3-pyridyl)-benzyl]-aminocarbonyl-methyl]-benzoic acid.

Yield: 72% of the theoretical.

Melting point: 252-253°C

(o) 4-[N-[2-piperidino-α-(4-pyridyl)-benzyl]-aminocarbonyl-methyl]-benzoic acid.

Yield: 68.5% of the theoretical.

Melting point: from 26 0°C (decomposition)

(p) 4-[N-(6-chloro-a-phenyl-2-piperidino-benzyl)-aminocarbonyl-methyl]-benzoic acid.

Yield: 82% of the theoretical.

Melting point: 91-94°C

(g) 4-[N-(4-chloro-α-phenyl-2-piperidino-benzyl)-aminocarbonyl-methyl]-benzoic acid.

Yield: 61% of the theoretical.

Melting point: 221-223°C

(r) 4-[N-(3-chloro-α-phenyl-2-piperidino-benzyl)-aminocarbonyl-methyl]-benzoic acid.

Yield: 83% of the theoretical.

Melting point: 210-213°C

(s) 4-[N-(6-methyl-α-phenyl-2-piperidino-benzyl)-aminocarbonyl-methyl]-benzoic acid.

Yield: 64% of the theoretical.

Melting point: 165-170°C (sintering from 150°C)

(t) 4-[N-(4-methyl-α-phenyl-2-piperidino-benzyl)-aminocarbonyl-methyl]-benzoic acid.

Yield: 96% of the theoretical.

Melting point: 202-203°C

(u ) 4-[N-[5-chloro-2-(2-methyl-piperidino)-a-phenyl-benzyl]-aminocarbonylmethyl]-benzoic acid..

Yield: 52% of the theoretical.

Melting point: 280-282°C

(v ) 4-[N-[5-chloro-2-(3-methyl-piperidino)-α-phenyl-benzyl]-arainocarbonylmethyl]-benzoic acid..

Yield: 66% of the theoretical.

Melting point: 246-248°C

Example 4

4-[N-[a-(4-Hydroxy-phenyl)-2-piperidino-benzyl]-aminocarbonyl-methyl]-benzoic acid

1.1 g (2 mmol) of 4-[N-[a-(4-benzyloxy-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzoic acid is suspended in 200 ml of ethanol and catalytically debenzylated at 50°C and a hydrogen pressure at 5 bar in the presence of 0.4 g of 10% palladium/charcoal. The catalyst is then filtered off, and the reaction mixture is evaporated and recrystallized from acetonitrile.

Yield: 720 mg (66.7% of the theoretical).

Melting point: 202-204°C

Example 5

4-[N-[α-(4-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonyl-methyl]-benzyl alcohol

2.5 g (5.3 mmol) of 4-[N-[α-(4-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzoic acid ethyl ester are added portionwise to a suspension of 0.5 g ( 13.2 mmol) of lithium aluminum hydride in 50 ml of absolute tetrahydrofuran. It is stirred for a further 30 minutes at room temperature, decomposed by the dropwise addition of 4N caustic soda and the sodium aluminate formed is filtered off. The filtrate is evaporated, and the residue is recrystallized from a little toluene.

Yield: 0.98 g (43% of theoretical).

Melting point: 144-146°C

Example 6

4-[N-[α-(4-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonyl-methyl]-benzaldehyde

8.85 g (20 mmol) 4-[N-[a-(4-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzoic acid and 3.25 g (20 mmol) N,N'-carbonyldiimidazole heated in 100 ml of absolute tetrahydrofuran for 2 hours under reflux. Evaporation is then carried out and, after adding 50 ml of pyridine and 3.7 g (20 mmol) of 4-toluenesulfonic acid hydrazide, it is boiled for a further 2 hours under reflux. Ice water is then added, suction is carried out, and the precipitate is dried. The thus obtained crude toluenesulfonic acid hydrazide of the carboxylic acid used is added to 20 g of anhydrous sodium carbonate and heated in 50 ml of ethylene glycol for 2 hours to 170°C. Water is then added and extracted with chloroform. The evaporated extracts are purified by column chromatography on silica gel with toluene/ethyl acetate 5:1 as developing agent.

Yield: 1.73 g (21% of the theoretical).

Melting point: 144-146°C

Analogous to example 6 was produced:

(a) 4-[N-[α-phenyl-2-piperidino-benzyl]-aminocarbonylmethyl]-benzaldehyde.

Yield: 29% of the theoretical.

Melting point: 168-170°C

Example 7

4-[N-[α-(4-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonyl-methyl]-benzaldehyde

0.5 g (1.2 mmol) of 4-[N-[a-(4-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzyl alcohol is added to a suspension of 0.4 g (1, 5 mmol) pyridinium chlorochromate in 2 ml

chloroform. After 12 hours at room temperature, ether is added, the evaporated filtrate is filtered and purified by column chromatography on silica gel (developing agent: toluene/ethyl acetate = 5:1).

Yield: 0.3 g (60% of the theoretical).

Melting point: 145-146°C

Analogous to example 7 was produced:

(a) 4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzaldehyde.

Yield: 40% of the theoretical.

Melting point: 170°C

Example 8

4-[N-[a-(4-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonyl-methyl]-cinnamic acid ethyl ester

427 mg (1 mmol) of 4-[N-[a-(4-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzaldehyde is added to an ethereal solution of 450 mg (2 mmol) diethylphosphonoacetic acid ethyl ester and 100 rag ( 2 mmol) 50% sodium hydride. After stirring overnight, water is added and extraction is carried out with chloroform and purification is carried out by column chromatography on silica gel with toluene/acetic acid ethyl ester 5:1 as developing agent.

Yield: 0.18 g (36% of theoretical).

Melting point: 176-180°C

Analogous to example 8 was produced:

(a) 4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-cinnamic acid ethyl ester.

Yield: 28.6% of the theoretical.

Melting point: 159-161°C

Example 9

4-[N-[a-(4-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonyl-methyl]-cinnamic acid

Prepared by alkaline saponification of 4-[N-[a-(4-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-cinnamic acid ethyl ester analogously to example 3.

Yield: 84% of the theoretical.

Melting point: 173-176°C

Analogous to example 9 was produced:

(a) 4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-cinnamic acid.

Yield: 75% of the theoretical.

Melting point: 177-180°C

Example 10

4-[N-[α-(3-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonyl-methyl]-benzoic acid ethyl ester

A mixture of 0.22 g (0.8 mmol) a-(3-methyl-phenyl)-2-piperidino-benzyl alcohol is added dropwise at room temperature to 1.5 ml of o-dichlorobenzene and 1.5 ml of concentrated sulfuric acid and 0.15 g (0.8 mmol) of 4-cyanomethyl-benzoic acid ethyl ester in 2 ml of o-dichlorobenzene. After stirring for 2 hours, ice water is added, extracted once with ether, the reaction mixture made alkaline with dilute caustic soda and extracted with chloroform. The chloroform extract is evaporated, and the residue is recrystallized from ethanol.

Yield: 0.22 g (60% of theoretical).

Melting point: 158-159°C

Example 11

4-[N-[a-(4-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonyl-methyl ]-benzoic acid

240 mg (5 mmol) of 4-[N-[5-chloro-a-(4-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzoic acid is catalytically dehalogenated in 80 ml of ethanol/dioxane 1/1 in the presence of 0.1 g of palladium on charcoal (10%) at 50°C and a hydrogen pressure of 5 bar. After cooling, the catalyst is filtered off. The filtrate is evaporated, and the residue is recrystallized from ethanol.

Yield: 0.16 g (72% of theoretical).

Melting point: 226-228°C

Analogous to example 11 was produced:

(a) 4-[N-[2-(2-methyl-piperidino)-α-phenyl-benzyl]-amino-carbonylmethyl]-benzoic acid,

from 4-[N-[5-chloro-2-(2-methyl-piperidino)-α-phenyl-benzyl]-aminocarbonylmethyl]-benzoic acid.

Yield: 68% of the theoretical.

Melting point: 246-248°C

(b) 4-[N-t 2-(3-methyl-piperidino)-α-phenyl-benzyl]-amino-carbonylmethyl ]-benzoic acid,

from 4-[N-[5-chloro-2-(3-methyl-piperidino)-α-phenyl-benzyl]-aminocarbonylmethyl]-benzoic acid.

Yield: 43% of the theoretical.

Melting point: 228-230°C

Example 12

4-[N-[o-(4-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonyl-methyl]-benzoic acid ethyl ester

To a solution of 2.78 g (10 mmol) of newly prepared (4-methyl-phenyl)-(2-piperidino-phenyl)-ketimine in 50 ml of methylene chloride is added 1.5 ml (11 mmol) of triethylamine and then under ice-cooling dropwise a solution of 2.5 g (11 mmol) of 4-ethoxycarbonyl-phenylacetic acid chloride in 20 ml of methylene chloride. After 1 hour at room temperature, ice water is added and extracted with methylene chloride. The extracts are dried and evaporated, and the evaporation residue is purified by column chromatography on silica gel (developing agent: toluene/ethyl acetate 10:1). The crude acylimine is dissolved in dimethylformamide and hydrogenated at room temperature after adding 0.5 g of palladium (10% on charcoal) at 5 bar hydrogen pressure. After absorption of the calculated amount of hydrogen, the catalyst is filtered off, the reaction mixture is evaporated, and the residue is recrystallized from a little alcohol. Yield: 2.8 g (60% of the theoretical).

Melting point: 175-177°C

Example 13

4-[N-[α-(4-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonyl-methyl]-benzonitrile

Prepared from α-(4-methyl-phenyl)-2-piperidino-benzylamine and 4-cyano-phenylacetic acid analogously to example 1.

Yield: 64% of the theoretical.

Melting point: 144-146°C

Example 14

4-[N-[α-(4-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonyl-methyl ]-benzoic acid ethyl ester

4.2 g (10 mmol) of 4-[N-[a-(4-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzonitrile are boiled under reflux with 50 ml of ethanolic hydrochloric acid for 24 hours. Then evaporate, add sodium bicarbonate solution to the evaporation residue and extract with chloroform. The chloroform extract is evaporated, and the residue is triturated with ethanol and suctioned off. Yield: 2.9 g (61.6% of the theoretical).

Melting point: 177-179°C

Example 15 4-[N-[5-chloro-a-(2-chloro-phenyl)-2-piperidino-benzyl]-amino-carbonylmethyl]-benzoic acid ethyl ester 10 mmol 4-[N-[a-(2- chloro-phenyl)-5-nitro-2-piperidino-benzyl]-aminocarbonylmethyl]-benzoic acid ethyl ester is dissolved in 50 ml of dimethylformamide and hydrogenated after adding 1 g of Raney nickel at 60°C and a hydrogen pressure of 6 bar. The catalyst is then filtered off, the filtrate is evaporated, and the residue, which consists of 4-[N-[5-amino-α-(2-chloro-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl]-benzoic acid ethyl ester, is dissolved in 100 ml of concentrated hydrochloric acid. Under ice cooling, a solution of 1.0 g (14 mmol) of sodium nitrite in 10 ml of water is now added dropwise, and further stirring is carried out for 1 hour at 0-5°C. The reaction mixture is then added dropwise to a solution of 3 g of copper (I) chloride in 25 ml of concentrated hydrochloric acid. After 1 hour of further stirring, the reaction mixture is made alkaline with caustic soda and extracted with chloroform. The evaporated chloroform extracts are purified by column chromatography on silica gel in toluene/ethyl acetate 5:1 as developing agent. Yield: 1.5 g (28.6% of the theoretical).

Melting point: 213-215°C

Example 16

3-[4-[N-(a-(4-methyl-phenyl)-2-piperidino-benzyl)-aminocarbonyl-methyl 3-phenyl J-propionic acid

0.91g (2 mmol) 4-[N-(a-(4-methyl-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl]-cinnamic acid is dissolved in 50 ml methanol and catalytically hydrogenated at room temperature and a hydrogen pressure of 3 bar after adding 0.5 g of palladium (10% on charcoal). After completion of hydrogen absorption, the catalyst is filtered off, and recrystallization is carried out from a little acetonitrile.

Yield: 0.68 g (74% of theoretical).

Melting point: 146-148°C

Example 17

4-[N-(a-(4-methyl-phenyl)-2-piperidino-benzyl)-aminocarbonyl-methyl]-benzoic acid sodium salt

Dissolve 442 mg (1 mmol) of 4-[N-(a-(4-methyl-phenyl)-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid in 25 ml of ethanol and add 1 ml of 1N caustic soda. The mixture is then evaporated in vacuo, 20 ml of acetone is added, the precipitate is filtered off with suction and the mixture is washed with acetic acid ethyl ester.

Yield: 410 mg (85% of the theoretical).

Melting point: 295-300°C

Analogous to example 17 was produced:

(a) 4-[N-(α-(4-methyl-phenyl)-2-piperidino-benzyl)-amino-carbonylmethyl]-benzoic acid ethanolamine salt.

Yield: 75% of the theoretical.

Melting point: 188-191°C

(b) 4-[N-(α-(4-methyl-phenyl)-2-piperidino-benzyl)-amino-carbonylmethyl]-benzoic acid diethanolamine salt. Yield: 81% of the theoretical.

Melting point: 178-180°C

(c) 4-[N-(α-(4-methyl-phenyl)-2-piperidino-benzyl)-amino-carbonylmethyl]-benzos<y>re-triethanolamine salt. Yield: 76% of the theoretical. Melting point: 16 0-165°C (d) 4-[N-(a-(4-methyl-phenyl)-2-piperidino-benzyl)-amino-carbonylmethyl]-benzoic acid ethylenediamine salt. Yield: 6 5% of the theoretical.

Melting point: 160-163°C

Example 18

4-[(2-Methoxy-1-(2-piperidino-phenyl)-ethyl]-aminocarbonyl-methyl]-benzoic acid ethyl ester

To a solution of 0.55 g (2.34 mmol) of 2-methoxy-1-(2-piperidino-phenyl)-ethylamine in 5 ml of acetonitrile, 0.49 g (2.34 mmol) of 4-ethoxycarbonyl -phenylacetic acid, 0.73 g (2.78 mmol) triphenylphosphine, 0.50 ml (3.66 mmol) triethylamine and 0.23 ml (2.34 mmol) carbon tetrachloride and stir for 20 hours at room temperature. It is then evaporated in a vacuum and partitioned between ethyl acetate and water. The organic extract is dried and filtered and evaporated in a vacuum. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 10/2).

Yield: 0.45 g (45% of the theoretical).

Melting point: 122-123°C

Analogously to example 18, the following was prepared: (a) 4-[(1-(3-chloro-2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoic acid ethyl ester.

Yield: 55% of the theoretical.

Melting point: 141-14 3°C

(b) 4-[(1-(6-chloro-2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoic acid ethyl ester.

Yield: 73.9% of the theoretical.

Melting point: 79-82°C

(c) 4-[(1-(4-bromo-2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoic acid ethyl ester.

Yield: 62.1% of the theoretical.

Melting point: 116-118°C

(d) 4-t(1-(4-nitro-2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoic acid ethyl ester.

Yield: 74.6% of the theoretical.

Melting point: 127-130°C

(e) 4-[(1-(3-methyl-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoic acid ethyl ester.

Yield: 68% of the theoretical.

Melting point: 14 5-147°C

(f) 4-[(1-(4-methyl-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoic acid ethyl ester.

Yield: 54.7% of the theoretical.

Melting point: 113-114°C

(g) 4-[(1-(5-methyl-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoic acid ethyl ester.

Yield: 67.9% of the theoretical.

Melting point: 149-150°C

(h) 4-t(1-(6-methyl-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoic acid ethyl ester.

Yield: 47% of the theoretical.

Melting point: 92-93°C

(i) 4-[(1-(2-pyrrolidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoic acid ethyl ester.

Yield: 57.3% of the theoretical.

Melting point: 122-125°C

(k) 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid ethyl ester.

Yield: 71.5% of the theoretical.

Melting point: 12 7-128°C

(1) 4-[(1-(2-(4-methyl-piperidino)-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoic acid ethyl ester.

Yield: 51.1% of the theoretical.

Melting point: 153-155°C

(m) 4-[(1-(2-hexahydroazepino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoic acid ethyl ester.

Yield: 42.7% of the theoretical.

Melting point: 145-147°C

(n) 4-[(1-(5-fluoro-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoic acid ethyl ester.

Yield: 55% of the theoretical.

Melting point: 128-130°C

(o) 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid methyl ester.

Yield: 63.2% of the theoretical.

Melting point: 147-148°C

(p) 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid n-butyl ester.

Yield: 50.9% of the theoretical.

Melting point: 117-119°C (ether).

(q) 4-[(1-(2-piperidino-phenyl)-4-penten-1-yl)-aminocarbonyl-methyl]-benzoic acid ethyl ester.

Yield: 18.9% of the theoretical.

Melting point: 103-105°C

Example 19

4-[(1 -(5-nitro-2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]- benzoic acid ethyl ester

To a stirred solution of 15.1 g (54.4 mmol) of 1-(5-nitro-2-piperidino-phenyl)-1-butylamine and 8.46 ml (61.4 mmol) of triethylamine in 55 ml of dry methylene chloride is added a solution of 14.6 g (64.6 mmol) of 4-ethoxycarbonyl-phenyl-acetic acid chloride in 20 ml of methylene chloride is added dropwise over the course of 30 minutes so that the temperature does not exceed 30°C. The mixture is stirred for a further 2 hours at room temperature, 300 ml of methylene chloride are added and decanted twice with 50 ml of water each time. The organic phase is dried over sodium sulphate, filtered and evaporated in a vacuum. The reddish-brown, oily evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 10/1).

Yield: 17.7 g (69.7% of the theoretical).

Melting point: 135-137°C (ether).

Analogous to example 19, the following compounds were prepared: (a) 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid ethyl ester.

Yield: 80.2% of the theoretical.

Melting point: 127-129°C

(b) 4-[(1-(4-hydroxy-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoic acid ethyl ester.

Yield: 13.5% of the theoretical.

Melting point: 178-180°C

(c) 4-[(1-(5-Hydroxy-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzos<y>re-ethyl ester.

Yield: 37.4% of the theoretical.

Melting point: 188-190°C

Example 20

4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-phenylacetic acid

3.0 g (15.45 mmol) of p-phenylenediacetic acid and 10 ml of thionyl chloride are heated for 90 minutes under reflux and then evaporated in vacuo. The crude diacid chloride is dissolved in 100 ml of methylene chloride. A solution of 3.6 g (15.45 mmol) of 1-(2-piperidino-phenyl)-1-butylamine is slowly added dropwise with stirring to this solution at an internal temperature of 10-15°C. After 2 hours at room temperature, the mixture is evaporated in vacuo and the evaporation residue is distributed between 100 ml of ice-cold 5% caustic soda and ethyl acetate. Mein filters through diatomaceous earth and separates the organic phase. The alkaline-aqueous phase is adjusted to pH 5.5 with semi-concentrated hydrochloric acid and extracted with ethyl acetate. It is dried over sodium sulphate, filtered and the filtrate evaporated in a vacuum. The evaporation residue is purified by column chromatography on silica gel (chloroform/methanol = 20/1).

Yield: 0.10 g (1.6% of theoretical).

Melting point: 136-140°C (acetonitrile/ether)

Example 21

4-t-(2-methyl-1-(2-piperidino-phenyl)-1-propen-1-yl)-amino-carbonylmethyl]-benzoic acid ethyl ester

To a solution of 6.17 g (26.8 mmol) of freshly prepared isopropyl-(2-piperidino-phenyl)-ketimine in 62 ml of acetonitrile, 5.58 g (26.8 mmol) of 4-ethoxycarbonyl-phenylacetic acid are added in sequence, 8.43 g (32.2 mmol) of triphenylphosphine, 11.2 ml (80.4 mmol) of triethylamine and 2.6 ml (0.0268 mol) of carbon tetrachloride and stirred for 20 hours at room temperature. It is then evaporated in a vacuum and partitioned between ethyl acetate and water. The dried and filtered ethyl acetate extract is evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/ethyl acetate = 5/1).

Yield: 3.0 g (26.6% of the theoretical).

Melting point: 82-84pC (ether).

Analogous to example 21, the following compounds were prepared: (a) 4-[(1-(2-piperidino-phenyl)-1-penten-1-yl)-aminocarbonyl-methyl]-benzoic acid ethyl ester.

Yield: 16% of the theoretical.

Melting point: 94-97°C (ethanol).

(b) 4-[(1-(2-piperidino-phenyl)-1-hexen-1-yl)-aminocarbonyl-methyl]-benzoic acid ethyl ester.

Yield: 27.4% of the theoretical.

Melting point: 83-85°C (ethanol).

(c) 4-[(1-(2-piperidino-phenyl)-1-buten-1-yl)-aminocarbonyl-methyl]-benzoic acid ethyl ester.

Yield (most lipophilic isomer; probably E-form):

4.1% of the theoretical.

Melting point: < 20°C

Calculated: m/e = 420

Found : m/e = 4 20

Yield (least lipophilic isomer; probably Z-form):

51.9% of the theoretical.

Melting point: 115-117°C (ethanol).

(d) 4-[(2-phenyl-1-(2-piperidino-phenyl)-ethen-1-yl)-amino-carbonylmethyl]-benzoic acid ethyl ester.

Yield (most lipophilic isomer; probably E-form): 4% of theory.

Melting point: 75-77°C (ether/petroleum ether).

Yield (least lipophilic isomer; probably Z-form):

42.7% of the theoretical.

Melting point: 157-160°C (ethanol)

Found : C 77.19 H 6.95 N 6.02 (e) 4-[(3-phenyl-1-(2-piperidino-phenyl)-1-propen-1-yl)-amino-carbonylmethyl]-benzoic acid -ethyl ester.

Yield: 62.6% of the theoretical.

Melting point: < 20°C

Calculated: m/e = 482

Found: m/e = 482

(f) 4-[(1-(2-(3,3-dimethyl-piperidino)-phenyl)-1-buten-1-yl)-aminocarbonylmethyl]-benzoic acid ethyl ester.

Yield: 33% of the theoretical.

Melting point: 113-116°C (ethanol).

(g) 4-[(1-(6-methyl-2-piperidino-phenyl)-1-buten-1-yl)-aminocarbonylmethyl]-benzoic acid ethyl ester.

Yield: 60.4% of theoretical (probably Z-form). Melting point: 95-96°C

Example 22

4-t(1-(2-piperidino-phenyl)-1-buten-1-yl)-aminocarbonylmethyl]-benzoic acid ethyl ester

A stirred solution of 19.0 g (82.46 mmol) of newly prepared (2-piperidino-phenyl)-propylketimine and 11.5 ml (82.46 mmol) of triethylamine in 190 ml of anhydrous toluene is heated at an internal temperature of 85°C, then add dropwise over 10 minutes a solution of 18.7 g (82.46 mmol) of 4-ethoxycarbonyl-phenylacetic acid chloride in 95 ml of anhydrous toluene and stir for 30 minutes at an internal temperature of 95°C. Cool to 20°C and decant twice with water. The organic phase is dried over sodium sulphate, filtered and evaporated in a vacuum. The evaporation residue is purified by column chromatography several times (toluene/acetone = 20/1 and 50/1).

Yield (most lipophilic isomer; probably E-form): 11.2 g (23.6% of theory).

Melting point: < 20°C (honey-yellow, viscous oil)

Calculated: C 74.26 H 7.67 N 6.66

Found : 73.90 7.92 6.91

Yield (least lipophilic isomer; probably Z form): 15.9 g (33.5% of theory).

Melting point: 114-116°C

Found: C 74.02 H 7.69 N 6.85

Example 23

(E)- and (Z)-4-[(1-(2-piperidino-phenyl)-1-buten-1-yl)-amino-carbonylmethyl]-benzoic acid ethyl ester

1.0 g of Z-ester (see example 21c) is heated in a pre-heated oil bath at 230°C for 30 minutes. After cooling, the product obtained is purified by column chromatography on silica gel (toluene/acetone = 20/1).

Yield (E-ester): 0.365 g (36.5% of theory).

Melting point: < 20°C

Yield (Z-ester): 0.380 g (38.0% of theory). Melting point: 115-117°C

By heating the E-ester for 3.5 hours with catalytic amounts of iodine in benzene, a thin-layer chromatographic examination (toluene/acetone = 10/1) gives a 1/1 mixture of (E)- and (Z)-ester.

Analogous to example 2 3, the following compound was prepared: (a) (E)- and (Z)-4-[(1-(6-methyl-2-piperidino-phenyl)-1-buten-1-yl)-aminocarbonylmethyl ]-benzoic acid ethyl ester From the (Z)-ester (see example 21g), according to the thin-layer chromatogram, a 1/1 mixture of the (E)- and (Z)-ester is obtained.

Upper spot (E): Calculated: m/e = 434 Found: m/e = 434

Lower spot (Z): Found : m/e = 4 34

Example 24

4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid ethyl ester

2.9 g (6.90 mmol) of 4-[(1-(2-piperidino-phenyl)-1-buten-1-yl)-aminocarbonylmethyl]-benzoic acid ethyl ester in 100 ml of ethanol are hydrogenated over 0.77 g palladium/coal (10%) at 50°C and 1 bar hydrogen. After 2 hours, the catalyst is filtered off over diatomaceous earth and evaporated in a vacuum. The evaporation residue is crystallized from ethanol.

Yield: 1.5 g (51.5% of the theoretical).

Melting point: 126-128°C.

Analogous to example 24, the following compounds were prepared: (a) 4-[(1-(2-piperidino-phenyl)-1-pentyl)-aminocarbonylmethyl]-benzoic acid ethyl ester.

Yield: 45% of the theoretical.

Melting point: 117-120°C (ether).

(b) 4-[(1-(2-piperidino-phenyl)-1-hexyl)-aminocarbonylmethyl]-benzoic acid ethyl ester.

Yield: 50% of the theoretical.

Melting point: 108-110°C (ether).

(c) 4-[(2-phenyl-1-(2-piperidino-phenyl)-1-ethyl)-aminocarbonyl-methyl]-benzoic acid ethyl ester.

Yield: 87.6% of the theoretical.

Melting point: 161-162°C (ethanol).

(d) 4-[(3-phenyl-1-(2-piperidino-phenyl)-1-propyl)-amino-carbonylmethyl]-benzoic acid ethyl ester.

Yield: 57.6% of the theoretical.

Melting point: 118-119°C (ethanol).

(e) 4-[(1-(2-(3,3-dimethyl-piperidino)-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoic acid ethyl ester.

Yield: 36.5% of the theoretical.

Melting point: 140-141°C (ethanol).

Example 25

4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid

A mixture of 1.2 g (2.84 mmol) of 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid ethyl ester and 4.26 ml of 1N caustic soda is stirred in 12 ml ethanol for 1 hour at 60°C, then neutralize with 4.26 ml of 1N hydrochloric acid and evaporate the ethanol in vacuo. Partitioning is carried out between ethyl acetate and water, the organic extract is dried and filtered and evaporated in a vacuum. The evaporation residue is crystallized from ethanol.

Yield: 0.50 g (44.6% of the theoretical).

Melting point: 213-215°C

Analogous to example 25, the following compounds were prepared: (a) 4-[(1-(2-piperidino-phenyl)-1-pentyl)-aminocarbonylmethyl]-benzoic acid.

Yield: 70.2% of the theoretical.

Melting point: 213-215°C (acetone).

(b) 4-[(1-(2-piperidino-phenyl)-1-hexyl)-aminocarbonylmethyl]-benzoic acid.

Yield: 7 2.6% of the theoretical.

Melting point: 197-200°C (acetone).

(c) 4-[(2-phenyl-1-(2-piperidino-phenyl)-1-ethyl)-aminocarbonyl-methyl]-benzoic acid.

Yield: 68.7% of the theoretical.

Melting point: 214-215°C (ethanol).

(d) 4-[(3-phenyl-1-(2-piperidino-phenyl)-1-propyl)-amino-carbonylmethyl]-benzoic acid.

Yield: 67.7% of the theoretical.

Melting point: 167-170°C (ethyl acetate).

(e) 4-[2-Methoxy-1-(2-piperidino-phenyl)-1-ethyl)-amino-carbonylmethyl]-benzoic acid.

Yield: 60.8% of the theoretical.

Melting point: 196-198°C (ether)

(f) 4-1-(1-(2-piperidino-phenyl)-4-penten-1-yl)-aminocarbonyl-methyl]-benzoic acid x 0.67 H 2 O.

Yield: 30.7% of the theoretical.

Melting point: 193-197°C (ether/petroleum ether).

Calculated: C 71.74 H 7.38 N 6.69 Found : 71.63 7.21 6.34 (g) 4-[(1-(2-(3,3-dimethyl-piperidino)-phenyl)- 1-butyl)-amino-carbonylmethyl]-benzoic acid.

Yield: 48.2% of the theoretical.

Melting point: 168-170°C (petroleum ether).

(h) 4-[(1-(3-methyl-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoic acid.

Yield: 53% of the theoretical.

Melting point: 179-182°C

(i) 4-[(1-(4-methyl-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoic acid.

Yield: 85.6% of the theoretical.

Melting point: 170-172°C

(k) 4-[(1-(5-methyl-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoic acid.

Yield: 6 2.1% of the theoretical.

Melting point: 219-221°C

(1) 4-[(1-(6-methyl-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl] benzoic acid x 0.3 H 2 O.

Yield: 89% of the theoretical.

Melting point: 158-160°C

(m) 4-[(1-(3-chloro-2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoic acid.

Yield: 70% of the theoretical.

Melting point: 189-191°C

(n) 4-[(1-(4-chloro-2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoic acid.

Yield: 57.8% of the theoretical.

Melting point: 188-189°C

(o) 4-[(1-(5-chloro-2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoic acid.

Yield: 81.6% of the theoretical.

Melting point: 226-229°C

(p) 4-[(1-(6-Chloro-2-piperidino-phenyl)-1-butyl)^aminocarbonyl-methyl]-benzoic acid.

Yield: 69.4% of the theoretical.

Melting point: 150-153°C

(q) 4-[(1-(4-bromo-2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoic acid.

Yield: 84.4% of the theoretical.

Melting point: 198-201°C

(r) 4-[(1-(5-bromo-2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoic acid.

Yield: 90.7% of the theoretical.

Melting point: 232-235°C

(s) 4-[(1-(4-nitro-2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoic acid.

Yield: 70.9% of the theoretical.

Melting point: 188-190°C

(t) 4-[(1-(5-nitro-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoic acid. Yield: 90.7% of the theoretical.

Melting point: 225-227°C

(u) 4-[(1-(4-hydroxy-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoic acid x 0.5 H 2 O.

Dividend; 85.7% of the theoretical.

Melting point: softening from 70°C (foam)

(v) 4-[(1-(5-hydroxy-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoic acid.

Yield: 89.3% of the theoretical.

Melting point: 186-190°C

(w) 4-[(1-(4-Methoxy-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoic acid.

Yield: 78.6% of the theoretical.

Melting point: 185-187°C

(x) 4-[(1-(5-Methoxy-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoic acid.

Yield: 75% of the theoretical.

Melting point: 182-185°C (decomp).

(y) 4-[(1-(2-pyrrolidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid.

Yield: 64.5% of the theoretical.

Melting point: 200-203°C

(z) 4-[(1-(2-(4-methyl-piperidino)-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoic acid.

Yield: 81.4% of the theoretical.

Melting point: 197-201°C

(aa) 4-[(1-(2-hexahydroazepino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoic acid.

Yield: 6 5.6% of the theoretical.

Melting point: 199-202°C

(ab) 4-[(1-(4-fluoro-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoic acid.

Yield: 87.1% of the theoretical.

Melting point: 204-207°C

(ac) N-(1-(5-Fluoro-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoic acid.

Yield: 53.9% of the theoretical.

Melting point: 200-202°C

Example 26

4-[(2-methyl-1-(2-piperidino-phenyl)-1-propen-1-yl)-amino-carbonylmethyl]-benzoic acid

A mixture of 3.5 g (8.3 mmol) 4-[(2-methyl-1-(2-piperidino-phenyl)-1-propen-1-yl)-aminocarbonylmethyl]-benzoic acid ethyl ester and 12 .5 ml of 1N caustic soda in 35 ml of ethanol for 2 hours at 60°C. Neutralize with 12.5 ml of 1N hydrochloric acid, evaporate in vacuo and partition between ethyl acetate and water. The dried, filtered, organic extract is evaporated in a vacuum. The evaporation residue is crystallized from ethanol. Yield: 2.4 g (73.6% of the theoretical).

Melting point: 188-191°C

Analogous to example 26, the following compounds were prepared: (a) (E)-4-[(1-(2-piperidino-phenyl)-1-buten-1-yl)-amino-carbonylmethyl]-benzoic acid.

Yield: 71.5% of the theoretical.

Melting point: 188-190°C

Olefinic proton: H-NMR (CDC13>: 6= 6.42 ppm (b) (Z)—4—t(1—(2-piperidino-phenyl)-1-buten-1-yl)-amino-carbonylmethyl] -benzoic acid.

Yield: 57.8% of the theoretical.

Melting point: 174-175°C (ethanol).

Olefinic proton: H-NMR (CDC 13 ): δ = 5.60 ppm.

(c) (E)-4-[(2-phenyl-1-(2-piperidino-phenyl)-ethen-1-yl)-amino-carbonylmethyl]-benzoic acid x 0.4 H 2 O.

Yield: 33.2% of the theoretical.

Melting point 165-167°C (ether/petroleum ether).

Olefinic proton: H-NMR (CDC 13 ): 6 > 6.9 ppm

(d) (Z)-4-[(2-phenyl-1-(2-piperidino-phenyl)-ethen-1-yl)-amino-carbonylmethyl]-benzoic acid x 1 H 2 O.

Yield: 72% of the theoretical.

Melting point: 182-185°C (methanol).

Olefinic proton: H-NMR |CDC 13 ): 6 = 6.50 ppm

(e) 4-[(3-phenyl-1-(2-piperidino-phenyl)-1-propen-1-yl)-amino-carbonylmethyl]-benzoic acid.

Yield: 48.3% of the theoretical.

Melting point: 162-164°C (ether); probably (Z) form.

Olefinic proton: H-NMR (CDC 13 ): δ = 5.80 ppm

(f) 4-[(1-(2-(3,3-dimethyl-piperidino)-phenyl)-1-buten-1-yl)-aminocarbonylmethyl]-benzoic acid.

Yield: 64.1% of the theoretical.

Melting point: 152-153°C (ethyl acetate); probably (Z) form

Olefinic proton:<*>H-NMR (CDCl 3 ) : 6 = 5.55 ppm (g) (Z)-4-[(1-(6-methyl-2-piperidino-phenyl)-1-butene-1- yl)-aminocarbonylmethyl]-benzoic acid.

Yield: 53.3% of the theoretical.

Melting point: 142-145°C

Calculated: C 73.66 H 7.44 N 6.89

Found : 73.56 7.73 7.15

Olefinic proton: 1 H-NMR (CDCl 3 ): δ = 5.38 ppm

Example 27

4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid

200 mg (0.51 mmol) of 4-[(1-(2-piperidino-phenyl)-1-buten-1-yl)-aminocarbonylmethyl]-benzoic acid is hydrogenated in 10 ml of absolute ethanol over 100 mg of palladium/charcoal (10 %) at 50°C and 1 bar hydrogen while shaking. After 1.5 hours, filter and evaporate in a vacuum.

Yield: 68% of the theoretical.

Melting point: 213-214°C

The yield is 56% of the theoretical when hydrogenating at 50°C and 1 bar of hydrogen on Raney nickel.

Example 28

4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid sodium salt x 0.5 ^0

10.0 g (25.35 mmol) of 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid are dissolved at 50°C in 200 ml of ethanol and 25.35 ml of 1N are added baking soda. Evaporate to dryness in a vacuum and dissolve the evaporation residue while heating on a steam bath in the minimal amount of ethanol. Cool in an ice bath, filter off the precipitated crystals, wash them with ether and dry them at 140°C/15 torr.

Yield: 9 g (85.3% of the theoretical).

Melting point: 280-285°C (decomp.); Softening from 255°C

Example 29

(+)-4-t(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid ethyl ester

To a stirred solution of 2.58 g (11.1 mmol) (+)-1-(2-piperidino-phenyl)-1-butylamine [K n _,:<8>7°C;

ee = 86 (HPLC, after derivatization with (+ )-1-phenethyl isocyanate)] in 26 ml of acetonitrile, at 20°C, 2.31 g (11.1 mmol) of 4-ethoxycarbonyl-phenylacetic acid are successively placed,

3.50 g (13.3 mmol) triphenylphosphine, 4.60 ml (33.9 mmol) triethylamine and 1.03 ml (11.1 mmol) carbon tetrachloride. After 14 hours at 20°C and 1.5 hours at 40°C, the mixture is evaporated in a vacuum and partitioned between water and ether. The organic phase is dried over sodium sulphate, filtered and evaporated in a vacuum. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 6:1).

Yield: 2.63 g (56% of the theoretical).

Melting point: 118-120°C

[a]2)°= + 9.2° (c = 1; methanol)

Analogous to example 29, the following compound was prepared: (a) (-)-4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl ]-benzoic acid ethyl ester

Prepared from (-)-1-(2-piperidino-phenyl)-1-butylamine x 1.4 HCl tta]<2>)<0>= -20.0° (c = 1 , methanol), Melting range: 90 -100°C; ee = 80 (HPLC, after derivatization of the base with (+)-1-phenethyl isocyanate)] Yield: 52.6% of theoretical.

Melting point: 115-120°C

[a]jj°=-9.0° (c = 1, methanol)

Example 30

( + )- 4-1 (1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid ethyl ester

1.0 g (3.27 mmol) of (+)-1-(2-piperidino-phenyl)-1-butylamine dihydrochloride [[a]^° = + 18.7° is suspended

(c = 1, methanol); melting point: from 115°C decomposition;

ee = 91.6 (HPLC, after derivatization of the base with (+)-1-phenethyl isocyanate)] in 6 ml of methylene chloride, add with stirring 1.4 ml (10 mmol) of triethylamine and then add dropwise a solution of 0, 82 g (3.64 mmol) of 4-ethoxycarbonyl-phenylacetic acid chloride in 2.4 ml of methylene chloride, so that the reaction temperature rises from 22 to 38°C. Stir for 6 hours at room temperature and shake out one after the other:

twice with 10 ml of water each time,

once with 10 ml of 2N hydrochloric acid, and

once with 10 ml of water.

The organic phase is dried over sodium sulphate, filtered and evaporated in a vacuum. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 6/1). Yield: 0.53 g (38.2% of theoretical).

Melting point: 120-122°C

[a]2.0 = + 9.0° (c = 1, methanol)

Example 31

(+)-4-1(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid

2.0 g (4.73 mmol) of (+)-4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid ethyl ester [[a]<2>,< 0>= + 9.2° (c = 1, methanol)] in 20 ml of ethanol together with 7.0 ml of 1N caustic soda for 2.5 hours in a bath at 65°C. It is cooled and 7.0 ml of 1N hydrochloric acid is added. The crystals which separate slowly are filtered off, washed with water and dried at 100°C/4 torr.

Yield: 1.65 g (88.2% of the theoretical).

Melting point: 185-187°C

[a]<g>° = + 7.9° (c = 1, methanol)

Analogous to example 31, the following compound was prepared: (a) (-)-4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoic acid.

Yield: 80% of the theoretical.

Melting point: 187-190°C

[a]2<0>=-7.9° (c = 1, methanol)

Example 32

4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzonitrile

Prepared from 1-(2-piperidino-phenyl)-1-butylamine and 4-cyano-phenylacetic acid analogously to example 19. Yield: 57.3% of the theoretical.

Melting point: 14 7-148°C

Analogously to Example 32, the following compound was prepared: (a) 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-toluene.

Made with 4-tolyl acetic acid.

Yield: 60.4% of the theoretical.

Melting point: 150-153°C

Example 33

4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid ethyl ester

Prepared from 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzonitrile with ethanolic hydrochloric acid analogously to Example 14.

Yield: 58% of the theoretical.

Melting point: 127-128°C

Example 34

4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid ethyl ester

Prepared analogously to example 10 from 1-(2-piperidino-phenyl)-1-butanol and 4-cyanomethyl-benzoic acid ethyl ester with concentrated sulfuric acid in o-dichlorobenzene at room temperature. Yield: 21% of the theoretical.

Melting point: 126-128°C

Analogous to example 34, the following compound was prepared: (a) 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid.

Prepared from 1-(2-piperidino-phenyl)-1-butanol and 4-cyanomethyl-benzoic acid. Extraction at pH 5.5.

Yield: 29% of the theoretical.

Melting point: 215-217°C

Example 35 4-[(1-(4-amino-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid x 0.5 f^O 0.60 g (1.365 mmol) of 4- [ (1-(4-nitro-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid in 10 ml dimethylformamide over 0.1 g palladium/charcoal (10%) for 3 hours at 25°C and 1 bare hydrogen. The catalyst is filtered off over diatomaceous earth and evaporated in a vacuum. The evaporation residue is crystallized from ether.

Yield: 0.41 g (73.2% of theoretical).

Melting point: 118-120°C

Analogous to example 35, the following compounds were prepared: (a) 4-[(1-(4-amino-2-piperidino-^phenyl)-1-butyl)-amino-carbonylmethyl]-benzoic acid ethyl ester.

Yield: 81.7% of the theoretical.

Melting point: 145-146°C (ether/petroleum ether).

(b) 4-[(1-(5-amino-2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoic acid.

Yield: 64% of the theoretical.

Melting point: 227-230°C

(c) 4-[(1-(5-amino-2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoic acid ethyl ester.

Yield: 84.3% of the theoretical.

Melting point: 16 2-165°C

Example 3 6

4-[(1-(5-chloro-2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoic acid ethyl ester

From 2.0 g (4.57 mmol) of 4-[ (1 -(5-amino-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid ethyl ester in 4.8 ml of semi-concentrated hydrochloric acid and 0.315 g (4.57 mmol) of sodium nitrite in 1.66 ml of water is prepared at 0°C a diazonium salt solution. This is added dropwise at 0-5°C to a stirred mixture of 0.59 g (5.94 mmol) copper (I) chloride and 2.4 ml concentrated hydrochloric acid and then heated in a bath at 50°C. After gas evolution has ended (approx. 15 minutes), cool, introduce the reaction mixture into ice/concentrated ammonia and extract four times with 100 ml of ethyl acetate each time. The combined organic extracts are decanted with water, dried and filtered and evaporated in a vacuum. The evaporation residue is purified by column chromatography on silica gel (toluene/ethyl acetate = 10/1).

Yield: 0.80 g (40% of the theoretical).

Melting point: 137-140°C (ether).

Analogous to example 36, the following compounds were prepared: (a) 4-[(1-(4-chloro-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoic acid ethyl ester.

Yield: 21.9% of the theoretical.

Melting point: 123-125°C

(b) 4-[(1-(5-bromo-2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoic acid ethyl ester.

Yield: 53.8% of the theoretical.

Melting point: 140-142°C

(c) 4-[(1-(4-fluoro-2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoic acid ethyl ester.

Yield: 21.6% of the theoretical.

Melting point: 110-112°C

In addition, a further 40% of 4-[(1-(4-hydroxy-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid ethyl ester (solid foam) is isolated. (d) 4-[(1-(5-fluoro-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoic acid ethyl ester.

Yield: 2% of the theoretical.

Melting point: 127-129°C

Calculated: m/e = 440

Found: m/e = 440

(e) 4-[(1-(4-fluoro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl]-benzoic acid.

Yield: 16.9% of the theoretical.

Melting point: 172-175°C

Example 37

4-[(1 -(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid

1.0 g (2.33 mmol) of 4-[(1-(5-chloro-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid is hydrogenated in 40 ml of absolute ethanol over 0.5 g of palladium /coal (10%) at 50°C and 5 bar hydrogen. After 2 hours, the catalyst is filtered off over diatomaceous earth and evaporated in a vacuum. The evaporation residue is distributed at pH 6 between water and ethyl acetate. The organic extract is washed with water, dried and filtered and evaporated in a vacuum.

Yield: 0.61 g (66% of theoretical).

Melting point: 213-215°C

The same compound is also obtained from the corresponding 4-chloro-, 3-chloro- or 6-chloro substituted starting materials.

Example 38

4-[(1-(4-Methoxy-2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoic acid ethyl ester

A solution of 5.0 g (11.4 mmol) 4-[(1-(4- hydroxy-2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid ethyl ester in 45 ml of absolute dimethylformamide. The mixture is stirred for 15 minutes and a solution of 0.71 ml (11.4 mmol) of methyl iodide in 8 ml of absolute dimethylformamide is then slowly added dropwise. The mixture is stirred for a further 2.5 hours at room temperature, evaporated in vacuo and partitioned between water and ether. The ether phase is dried and filtered and evaporated in a vacuum. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 20/1). Yield: 1.8 g (34.9% of the theoretical).

Melting point: 115-117°C

Analogous to example 36', the following compound was prepared: (a) 4-[(1-(5-methoxy-2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoic acid ethyl ester.

Yield: 68.4% of the theoretical.

Melting point: 142-145°C

Example 39

4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid-(2,3-dihydroxy-propyl) ester

A solution of 2.0 g (5.07 mmol) 4 — [(1 —

(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid and 0.85 g (5.27 mmol) of N,N'-carbonyldiimidazole in 20 ml of absolute tetrahydrofuran for 1 hour under reflux, adding 3.7 ml (50.7 mmol) of glycerol and heat for an additional 15 hours under reflux. Evaporate in a vacuum, partition between water and ethyl acetate, dry and filter the organic solution and evaporate it in a vacuum. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 1/1).

Yield: 1.1 g (46.2% of the theoretical).

Melting point: 120-122°C

Analogous to example 39, the following compounds were prepared: (a) 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoic acid-(2-hydroxy-ethyl)ester.

Yield: 80% of the theoretical.

Melting point: 125-127°C

(b) 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-benzoic acid-(2-methoxy-ethyl) ester.

Yield: 55.9% of the theoretical.

Melting point: 120-123°C

Example 4 0

4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid-(2- nicotinoyloxy-ethyl) ester

To a stirred solution of 2.0 g (4.56 mmol) 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid-(2-hydroxy-ethyl)ester in 40 ml methylene chloride and 0.7 ml (4.81 mmol) triethylamine, a solution of 0.7 g (4.68 mmol) nicotinic acid chloride in 20 ml methylene chloride is quickly added dropwise. Stir for 2.5 hours at 20°C, decant with water, dry and filter the organic phase and evaporate it in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 5/1).

Yield: 1.1 g (44% of the theoretical).

Melting point: 132-135°C

Example 41

4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzyl alcohol

A solution of 5.0 g (11.83 mmol) 4-[(1 -(2-piperidino-phenyl)-1-butyl)-amino-carbonylmethyl]-benzoic acid ethyl ester in 75 ml of absolute tetrahydrofuran. Stir for 20 hours at room temperature, cool to 0°C and slowly add enough 4N caustic soda drop by drop that a filterable precipitate is formed. The precipitate is filtered off and boiled several times with ether. The combined organic solutions are evaporated in a vacuum. The evaporation residue is distributed between water and ether. The ether phase is dried and filtered and evaporated in a vacuum. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 5/1). Yield: 1.0 g (22% of theoretical).

Melting point 152-154°C

Example 42

4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzaldehyde

6.6 g (62 mmol) of sodium carbonate are heated together with 6 2 ml of ethylene glycol in a bath at 170°C and, with vigorous stirring, 6.2 g (11 mmol) of N<1->[4- [-(1-(2-piperidino-phenyl)-1-butyl)aminocarbonylmethyl]-benzoyl]-N<2->tosyl-hydrazine with a melting point of 195°C (decomp.), during which a strong evolution of gas is observed. The mixture is then heated for a further 2.5 minutes at 170°C and the reaction mixture is immediately poured onto ice. Extract with ether, dry, filter and evaporate the ether solution in a vacuum. The evaporation residue is purified by column chromatography on silica gel (chloroform/acetone = 20/1).

Yield: 2.2 g (52.9% of the theoretical).

Melting point: 142-145°C

Example 43

4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-cinnamic acid ethyl ester

To 0.60 g (12.5 mmol) of sodium hydride (50% in oil) in 15 ml of absolute dimethylformamide, a solution of 2.80 g (12.5 mmol) of diethylphosphonoacetic acid ethyl ester in 10 ml of absolute dimethylformamide is added dropwise at room temperature. It is stirred for 15 minutes (until gas evolution ceases) and then a solution of 2.4 g (6.34 mmol) 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]- is added dropwise benzaldehyde in 10 ml of absolute dimethylformamide. The reaction mixture is stirred for 2 hours at room temperature, evaporated in vacuo and partitioned between water and ether. The ether phase is dried and filtered and evaporated in a vacuum. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone = 10/1).

Yield: 0.85 g (29.9% of the theoretical).

Melting point: 135-137°C (ether/petroleum ether).

Example 4 4

4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-cinnamic acid

Prepared by alkaline saponification of 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-cinnamic acid ethyl ester analogously to example 25.

Yield: 64% of the theoretical.

Melting point: 180-183°C

Example 45

3-[4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-phenyl]-propionic acid ethyl ester

0.60 g (1.34 mmol) of 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-cinnamic acid ethyl ester in 10 ml of ethanol is hydrogenated over 0.20 g of palladium/charcoal ( 10%) at room temperature and 5 bar hydrogen. Filter and evaporate in a vacuum.

Yield: 0.53 g (88% of theoretical).

Melting point: 98-99°C (petroleum ether).

Analogous to example 45, the following compound was prepared: (a) 3-[4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonyl-methyl]-phenyl]-propionic acid.

Yield: 63% of the theoretical.

Melting point: 131-133°C

Example 46

3-[4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-phenyl]-propionic acid

Prepared by alkaline saponification of 3-[4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-phenyl]-propionic acid ethyl ester analogously to example 25.

Yield: 50% of the theoretical.

Melting point: 131-133°C

Example 47

4-[(α-aminocarbonyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid ethyl ester

To a stirred solution of 2.0 g (4.7 mmol) 4-[(α-carboxy-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid ethyl ester x 0.167 H 2 O; (melting point 156-159°C) in 20 ml of anhydrous tetrahydrofuran is placed at 20°C 0.90 g (5.5 mmol) N,N'-carbonyldiimidazole and then heated for half an hour in a bath at 80°C. It is then cooled to 60°C and, at this temperature, a strong stream of possibly dry ammonia is introduced for half an hour. One then evaporates in a vacuum, distributes between water and chloroform, decants the combined chloroform extracts with a little water, dries, filters and evaporates in a vacuum. The evaporation residue is purified by column chromatography on silica gel (chloroform/methanol = 5/1).

Yield: 1.0 g (50.2% of theoretical).

Melting point: 160-16 2°C (acetone).

Example 4 8

4-[(α-cyano-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid ethyl ester

To 520 mg (1.22 mmol) of 4-[(α-aminocarbonyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid ethyl ester in 0.22 ml of pyridine, add in two portions 234 mg (1.22 mmol) 4 -toluene sulphochloride and heat to 50°C. After 2 hours and after a further hour, the same amounts of pyridine and 4-toluene sulphochloride are added again and heated for a further 1 hour at 50°C. After standing for 2 days at 20°C, 2N ammonia is added and extracted with chloroform. The chloroform solution is decanted twice with water. After drying and filtering, it is evaporated in a vacuum. The evaporation residue is purified by column chromatography on silica gel (chloroform/methanol = 10/1).

Yield: 325 mg (65.7% of the theoretical).

Melting point: 114-117°C (ether/petroleum ether).

Example 49

4-[(α-cyano-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid

1.5 g (3.7 mmol) of 4-[(α-cyano-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid ethyl ester are stirred in 15 ml of dioxane together with 3.7 ml of 1N caustic soda for 45 minutes in a bath at 60°C and a further 45 minutes in a bath at 80°C. After cooling with ice, 3.7 ml of 1N hydrochloric acid is added, dioxane is evaporated in vacuo and partitioned between water and chloroform. The organic solution is decanted with a little water, dried and filtered and evaporated in a vacuum. The evaporation residue is purified by column chromatography on silica gel (chloroform/ethanol = 5/1).

Yield: 0.50 g (35.7% of the theoretical).

Melting point: 176-180°C (decomp.)

Example 50

4-[(1 -(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid x H^ SO^

To a solution of 1.0 g (2.53 mmol) of 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid in 50 ml of ethanol is added 5 ml (2.50 mmol ) 1N sulfuric acid, evaporate to dryness in vacuo and rub with acetone. Yield: 0.80 g (65% of the theoretical).

Melting point: 192-197°C (decomp.)

Analogous to example 50, the following addition salt was prepared: a) 4-[(1 -(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid x 0.5 H 2 SO 4 x 1.5 H 2 O

Prepared with half the amount of sulfuric acid analogously to example 50.

Yield: 59.3% of the theoretical.

Melting point: 180-185°C; decomp. at 207-210°C

Claims (4)

1. Analogy method for the preparation of therapeutic active phenylacetic acid derivatives with the general formula where A means a group with the formulas where R3 is an alkyl group with 1 to 3 carbon atoms, an n-propyl group, an alkyl group with 4 to 6 carbon atoms, an alkenyl group with 3 to 5 carbon atoms, a cyano group, an optionally with alkyl groups with each 1 to 3 carbon atoms in the alkyl part mono- or disubstituted aminocarbonyl group, an optionally with halogen atoms, with alkyl, hydroxy, alkoxy, phenyl alkoxy, alkylsulfenyl, alkylsulfinyl and/or alkylsulfonyl groups mono- or disubstituted aryl group with 6 to 10 carbon atoms, the substituents can be the same or different and the alkyl part in each case can contain 1 to 3 carbon atoms, or a pyridyl group, or also a methyl group, when Rj means a piperidino group and R2i 4-position a fluorine atom and W a carboxy or alkoxycarbonyl group, where the alkyl part can contain 1 to 3 carbon atoms, or also a phenyl group, when R^ denotes a piperidino group substituted in the 2- or 3-position with a methyl group, R 2 a hydrogen atom and W a carboxy or alkoxycarbonyl group, where the alkyl part may contain 1 to 3 carbon atoms, or when R^ denotes a piperidino group, R 2 in the 3-, 4- or 6-position a chlorine atom or in the 4- or 6-position a methyl group and W a carboxy or alkoxycarbonyl group, where the alkyl part may contain 1-3 carbon atoms, or when R x means a piperidino group, R 2 a hydrogen atom and W a formyl group or a 2-carboxyethenyl group, R4 and R5 together with the intermediate carbon atom is an alkylidene group with 3 to 9 carbon atoms or a phenylalkylidene group with 1 to 3 carbon atoms in the alkylidene part, R±means an optionally with alkyl groups with 1 to 3 carbon atoms mono- or disubstituted, unbranched alkyleneimino group with 4 to 8 carbon atoms, R 2 means a hydrogen, fluorine, chlorine or bromine atom, a hydroxy, trifluoromethyl, nitro, amino, piperidino, alkyl, alkoxy, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, phenylalkoxy, alkanoyloxy, alkanoylamino -, alkylamino or dialkylamino group, the alkyl part in each case may contain 1 to 3 carbon atoms, W means a carboxy group or an alkoxycarbonyl group with a total of 2 to 5 carbon atoms, in which the alkyl part may be substituted with a phenyl group and from the P-carbon atom with 1 or 2 hydroxy groups, an alkoxy, alkanoyloxy, or pyridine-carbonyloxy group, where each alkyl part in each case may contain 1 to 3 carbon atoms; an alkyl group with 1 to 3 carbon atoms, a hydroxymethyl, formyl, cyano, amino-carbonyl, carboxymethyl, 2-carboxyethyl, 2-carboxyethenyl, 2-alkoxycarbonyl-ethyl or 2-alkoxycarbonyl-ethenyl group , where the alkoxy group in each case may contain 1 to 3 carbon atoms, and their optically active antipodes and their salts with inorganic or organic acids or bases, characterized by a) an amine of the general formula where A, Ri and R2 are as stated at the beginning, resp. when A is one of the initially indicated vinylidene groups, its tautomers, its lithium or magnesium halide complex, is reacted with a carboxylic acid of the general formula where W has the meanings given for W at the beginning or is a carboxy group protected with a protective residue, or with its possibly reactive derivatives produced in the reaction mixture, and if necessary, the protective residue used is cleaved off, or b) for the preparation of a compound of the general formula I, where W means a carboxy, carboxymethyl, 2-carboxyethyl or 2-carboxyethenyl group, a compound of the general formula is transferred where R1'R2°9A is as indicated at the outset, and B means a group which can be transferred to a carboxy-, carboxymethyl-, 2-carboxyethyl- or 2-carboxyethenyl group, for example functional derivatives of carboxy-, carboxymethyl-, 2-carboxyethyl- or the 2-carboxyethenyl group, such as their unsubstituted or substituted amides, their nitriles, esters, thiol esters, ortho-esters, iminoethers, amidines or anhydrides, a malonester-(1)-yl group, a tetrazolyl group, an optionally substituted 1,3 -oxazol-2-yl or 1,3-oxazolin-2-yl group, and for example esters with tertiary alcohols, such as a tert. butyl ester, and for example esters with aralkanols, such as a benzyl ester, to the corresponding carboxy compound by hydrolysis, thermolysis or hydrogenolysis, or c) for the preparation of a compound of the general formula I, where A means a group of the formula where R3', with the exception of an alkenyl group and a cyano group, have the meanings given for R3 at the beginning, a compound with the general formula is reduced where Rl»R20<? w is, as indicated at the beginning, and D means a group with the formulas where R3" with the exception of a cyano group have the meanings given for R3 at the beginning, and R4' and R$' together with the intermediate carbon atom mean a propylidene group, an alkylidene group with 4 to 6 carbon atoms or a phenylalkylidene group with 1 to 3 carbon atoms in the alkylidene part, with hydrogen in presence of a hydrogenation catalyst, or d) for the preparation of compounds of the general formula I, where R3 with the exception of a cyano group has the meanings given for R3 at the beginning, a compound of the general formula is reacted where R 3 " is as above indicated, and R 3 and R 2 are as initially indicated, with a compound of the general formula where W is as indicated at the outset, or e) for the preparation of compounds of the general formula I where R 2 means a hydrogen atom and A a group of the formula where R 3 is as indicated at the outset, a compound of the general formula is dehalogenated where Rl, A and W are as indicated at the outset, and Hal means a fluorine, chlorine, bromine or iodine atom, or f) for the preparation of compounds of the general formula I where A means a group of the formula where R3 means an alkyleneiminocarbonyl group with 4 to 6 carbon atoms in the alkylene ring or an optionally with alkyl or phenylalkyl groups with each 1 to 3 carbon atoms in the alkyl part mono- or disubstituted aminocarbonyl group, a compound with the general formula is reacted where R 1 and R 2 are as indicated at the outset, and W" has with the exception of a carboxy-, carboxy-methyl-, 2-carboxyethyl-, 2-carboxy-ethenyl- or 2,2-bis-(carboxy)ethyl group those for W meanings given at the outset, with an amine of the general formula where R6 represents an alkyleneimino group with 4 to 6 carbon atoms or an optionally with alkyl or phenylalkyl groups with each 1 to 3 carbon atoms in the alkyl part mono- or disubstituted amino group or g) for the preparation of compounds of the general formula I where W means a carboxy group, a compound is oxidized with the general formula where R!, R 2 and R 3 are as indicated at the beginning, and E means a group which can be transferred to a carboxy group by oxidation, for example a formyl group and acetals thereof, a hydroxymethyl group and ethers thereof, an unsubstituted or substituted acyl group such as an acetyl-, chloroacetyl- , propionyl, malonic acid-(1)-yl or malonester-(1)-yl group, or h) for the preparation of compounds of the general formula I, where W means an alkoxycarbonyl group with a total of 2 to 5 carbon atoms, where the alkyl part from the P-carbon atom can be substituted with 1 or 2 hydroxy groups or with an alkoxy group with 1 to 3 carbon atoms, a carboxylic acid is esterified with the general formula where Rj_, R2 and A are as indicated at the outset, or its possibly produced derivatives in the reaction mixture, with an alcohol of the general formula where R7 means an alkyl group with 1 to 4 carbon atoms which from the P-carbon atom can be substituted with 1 or 2 hydroxy groups or an alkoxy group with 1 to 3 carbon atoms, or i) for the preparation of a compound of the general formula I, where W means an alkoxycarbonyl- , 2-Alkoxycarbonylethyl or 2-Alkoxycarbonylethenyl group, and A is a group of the formula where R3", with the exception of a cyano group, have the meanings given for R3 at the beginning, a compound with the general formula is transferred where R 1 and R 2 are as indicated at the beginning, with the exception of a cyano group, R 3 " has those for R 3 indicated at the beginning meanings, and W" means a cyano-, 2-cyanoethyl- or 2-cyano-ethenyl group, to a corresponding ester, and optionally then: a prepared compound of the general formula I, where W means a carboxy or alkoxycarbonyl group, is transferred by reduction to a corresponding compound of the general formula I, where W means a formyl or hydroxymethyl group, and/or a prepared compound ; with the general formula I, where W means a carboxy group, is converted by transfer to a sulfonic acid hydrazide and subsequent disproportionation to a corresponding compound with the general formula I, where W means a formyl group, and/or a prepared compound with the general formula I, where W means a formyl group, is converted by condensation and possibly subsequent hydrolysis and/or decarboxylation into a corresponding compound of the general formula I, where W means a 2-alkoxycarbonylethenyl or 2-carboxyethenyl group, and/or a prepared compound of the general formula I , where W means a 2-carboxyethenyl or 2-alkoxycarbonylethenyl group, is transferred by catalytic hydrogenation to a corresponding compound of the general formula I, where W means a 2-carboxyethyl or 2-alkoxycarbonylethyl group, and/or a prepared compound of the general formula I, where W means an alkoxycarbonyl group, which from the P-carbon atom is substituted by a hydroxy group , is transferred by acylation with a pyridine carboxylic acid to a corresponding (pyridinecarbonyloxy-alkoxy)-carbonyl compound of the general formula I, and/or a prepared compound of the general formula I, where W means a hydroxymethyl group, after transfer to a corresponding halomethyl compound and subsequent reaction with a malonic acid diester, is converted to a corresponding compound of the general formula I, where W means an ethyl group substituted with two alkoxycarbonyl groups, and/or a prepared compound of the general formula I, where W means an ethyl group substituted with two alkoxycarbonyl groups, is converted by hydrolysis to a corresponding compound of the general formula I, where W means an ethyl group substituted with two carboxy groups, and/or a prepared compound of the general formula I, where W means an ethyl group substituted with two alkoxycarbonyl groups, is converted by hydrolysis and decarboxylation into a corresponding compound of the general formula I, where W means a 2-carboxy-ethyl group, and/or a prepared compound of the general formula I, where R2 is a nitro group, is converted by reduction into a corresponding compound of the general formula I, where R2 is an amino group, and/or a prepared compound of the general formula I, where R2 is an amino group, is converted over a corresponding diazonium salt into a corresponding compound of the general formula I, where R2 is a hydrogen, fluorine, chlorine or bromine atom, a hydroxy, alkoxy or alkylsulfenyl group, and/or a prepared compound of the general formula I, where R 2 means a benzyloxy acid residue and/or R 3 means an aryl residue substituted with a benzyloxy acid residue, is converted by debenzylation into a corresponding compound of the general formula I, where R 2 means a hydroxy group and/or R 3 means a substituted with a hydroxy group aryl residue, and/or a prepared compound of the general formula I, where R3 is an aminocarbonyl group, is converted by dehydration into a corresponding compound of the general formula I, where R3 is a cyano group, and/or a prepared compound of the general formula I, if it contains a chiral center, is resolved into its enantiomers by chromatography on chiral phases, and/or a prepared compound of the general formula I is converted into its salts, in particular its physiologically compatible salts, with inorganic or organic acids or bases. 2. Method according to claim 1 for the production of phenylacetic acid derivatives with the general formula I where R3 means an n-propyl group, an alkyl group with 4 to 5 carbon atoms, a methyl group, a phenyl group substituted with a fluorine or chlorine atom or a pyridyl group, R4 and R5 together with the intermediate carbon atom means an alkylidene group with 3 to 5 carbon atoms or a phenylalkylidene group with 1 to 3 carbon atoms in the alkylidene part, R^ means a piperidino group optionally substituted with one or two methyl groups, R 2 means a hydrogen, fluorine or chlorine atom, a methyl or methoxy group, and W means a carboxy group or an alkoxycarbonyl group with a total of 2 to 4 carbon atoms, their optically active antipodes and their salts with inorganic or organic acids or bases, characterized by the use of corresponding starting materials. 3. Process according to claim 1 for the production of 4-[(1-(2-piperidino-phenyl)-1-butyl)aminocarbonylmethyl]-benzoic acid, its alkyl esters with 1 to 3 carbon atoms, its optically active antipodes and its salts, characterized by the use of corresponding starting materials. 4. Process according to claim 1 for the production of 4-[(1-(2-piperidino-phenyl)-1-pentyl)aminocarbonylmethyl]benzoic acid, its alkyl esters with 1 to 3 carbon atoms, its optically active antipodes and its salts, characterized by the use of corresponding starting materials.