NO820046L - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE CARBOXYLIC ACID DERIVATIVES - Google Patents

Description

This invention relates to the preparation of new carboxylic acid derivatives: by the general formula

and their addition salts, in particular their physiologically compatible salts with inorganic or organic acids and also bases when Z represents a carboxy group.

• New 2-amino-carboxylic acid derivatives are also described here

the general formula

their addition salts, especially their salts with inorganic or organic acids and also bases'when W means a carboxy-

group, and method for its preparation and use of the new 2-amino-carboxylic acid derivatives, among other things, as intermediates for the preparation of the new compounds or the general formula I.

The new compounds with the general formulas I and Ia and

their optically active antipodes, although they contain an asym-

tric carbon atom, exhibits valuable pharmacological properties,

namely an effect on the intermediate metabolism. Thus, the compounds of the general formula I in particular have a blood-sugar-lowering and/or lipid-lowering effect and the compounds of the general formula Ia a lipid-lowering effect.

In the above general formulas I and Ia mean

m the number 0 or 1,

n the number 1 or 2,

R a hydrogen atom or an alkyl group with 1 to 3 carbon

atoms,

R^et^hydrogen, fluorine, chlorine, bromine or iodine atom, an alkyl or alkoxy group with each 1 to 4 carbon atoms, cyano, hydroxy or trifluoromethyl group or one optionally with an alkyl group with 1 to 3 carbon atoms,' a fluorine, chlorine or bromine substituted phenyl group,

R 2 and R 3 together with the intervening nitrogen atom a piperidino-, 3,5-dimethyl-piperidino-, octahydro-1H-azonino-, decahydro-azecino-, 1,3-dihydro-isoindolo-, hexahydro-isoindolo- or octahydro- isoindolo group, a piperidino group substituted with an alkyl group of 5 to 10 carbon atoms, an azabicycloalkyl group of 7 to 12 carbon atoms in the bicycloalkane ring, which may be substituted with one or more alkyl groups of 1 to 3 carbon atoms each, or one with a halogen atom, an alkoxy group with 1 to 3 carbon atoms or an amino group substituted 1,3-dihydro-isoindolo group or also when m means the number'1, a pyrrolidino-, hexamethyleneimino- or

heptamethyleneimino group,

X a CH group or a nitrogen atom,

Z and W each an optionally esterified carboxy group,

R^ a hydrogen or "halogen atom, an amino-, cyano-, hydroxy-,

carboxy or acetamino group, an alkyl or alkoxy group each having 1 to 4 carbon atoms,

Rg and R^ together with the intervening nitrogen atom a piperidino group substituted with an alkyl group of 5 to 10 carbon atoms, an azabicycloalkyl group of 7 to 12 carbon atoms in the bicycloalkane ring, which may be substituted with one or more alkyl groups of 1 to 3 carbon atoms, an octahydro -1H-azonino-, 1,3-dihydro-isoindolo-, hexahydro-isoindolo- or octahydro-isoindolo group or one with a halogen atom, an alkoxy group of 1 to 3 carbon atoms or an amino group

substituted 1,3-dihydro-isoindolo group, and

Rg is a hydrogen atom, an alkyl group of 1 to 3 carbon atoms or an aryl group.

Among the initially stated meanings for the residues R, R^ to Rg and Z resp. For example, W comes into consideration

for R the meaning of a hydrogen atom, a methyl, ethyl, propyl or isopropyl group,

for R^meaning a hydrogen, fluorine, chlorine, bromine or iodine atom, a methyl, ethyl, propyl, isopropyl, butyl, iso-

butyl-, tert.butyl-, hydroxy-, methoxy-, ethoxy-, propoxy-, isopropoxy-, butoxy-, isobutoxy-, cyano-, trifluoro-methyl-, phenyl-, methylphenyl-, ethylphenyl-, iso-propylphenyl- , fluorophenyl, chlorophenyl or bromophenyl group,

for R^ and together with the intervening nitrogen atom the meaning a pyrrolidino-, piperidino-, 3,5-dimethyl-piperidino-, pentyl-(3)-piperidino-, nonyl-(5)-piperidino-, hexamethyleneimino-, octahydro-lH -azonino-, 1,3-dihydro-isoindolo-, hexahydro-isoindolo-, octahydro-isoindolo-, chloro-1,3-dihydro-isoindolo-, bromo-1,3-dihydro-isoindolo-, methoxy-1,3 -dihydro-isoindolo-, ethoxy-1,3-dihydro-iso-indolp-, isopropoxy-1,3-dihydro-isoindolo-, amino-1,3-dihydro-isoindolo- or 2-azabicyclo-nonan-2-yl -group, for Z and W each meaning a carboxy-, methoxycarbonyl-,

ethoxycarbonyl-, propoxycarbonyl-, isopropoxycarbonyl-, butoxycarbonyl-, isobutoxycarbonyl-, tert.butoxycarbonyl-, pentoxycarbonyl-, hexoxycarbonyl-, heptoxycarbonyl-, allyloxycarbonyl-, phenoxycarbonyl-, benzyloxycarbonyl-, phenylethoxycarbonyl-, cyclopropoxycarbonyl-, cyclopentoxycarbonyl, cyclohexyloxycarbonyl - or cycloheptoxycarbonyl group,

for R^ the meaning of a hydrogen, fluorine, chlorine, bromine or iodine atom, a methyl, ethyl, cyano, hydroxy, methoxy, carboxy, amino or acetamino group,

for Rg and R^ together with the intervening nitrogen atom the meaning a pentyl-(3)-piperidino-, nonyl-(5)-piperidino-, 2-azabicyclo-nonan-2-yl-, 1,3-dihydro-isoindolo-, chloro-1,3-dihydro-isoindolo-, -bromo-1,3-dihydro-isoindolo-, methoxy-1,3-dihydro-isoindolo-, ethoxy-1,3-dibydro-isoindolo-, isopropoxy-1,3 -dihydro-isoindolo-, amino-1,3-dihydro-isoindolo-, hexahydro-isoindolo- or octahydro-isoindolo group, and

for Rg meaning a hydrogen atom, a methyl-, ethyl-, propyl-,

isopropyl or phenyl group.

Preferred compounds of the above general formulas I and Ia are those where

m is the number 0 or 1,

n is the number 1 or 2,

X is a CH group or a nitrogen atom,

R is a hydrogen atom or a methyl group,

R1 is a hydrogen, fluorine, chlorine, bromine or iodine atom, a cyano, trifluoromethyl, hydroxy, methoxy, methyl, methylphenyl, chlorophenyl or bromophenyl group,

R2 and R^ together with the intervening nitrogen atom is a piperidino group substituted in bi-position with an alkyl group with 5 to 9 carbon atoms, a optionally substituted 1,3-dihydro-isoindolo group with a methoxy or amino group, a chlorine or a bromine atom, a hexahydro-isoindolo- or 2-aza-bicyclo-nonan-2-yl group or

an octahydro-lH-azonino group when

m is the number 1 or

m is the number 0,

R^ is a hydrogen, fluorine or iodine atom or a methyl group, and X is a CH group, or '

m is the number 0,

X is a nitrogen atom and

R^ is not a hydrogen atom, or

a decahydro-1H-azecino group, when

m is the number 1 or

m is the number 0,

R^ is a methyl group, a hydrogen, fluorine, bromine or iodine atom,

and

X -.is a CH group, or

m is the number 0,

X . is a nitrogen atom, and

R^ is not a hydrogen atom, or

a piper idinogroup, when

m is the number 1 or

m is the number 0,

X is a nitrogen atom, and

R^ is not a hydrogen atom, or

m is the number 0,

X is a CH group, and

R-^ is not a hydrogen atom, or

an octahydro-isoindolo group, when

m is the number 1 or

m is the number 0,

is a hydrogen, fluorine, bromine or iodine atom, a methyl,

hydroxy, methoxy or cyano group, and

X is a CH group, or

m is the number 0 and X is a nitrogen atom, or

a 3,5-dimethyl-piperidino group, when

m is the number 1 or

m is the number 0,'

R is a hydrogen, chlorine or bromine atom,

R is a methyl group, and

X is a nitrogen atom, or

m is the number 0,.

Rj is a methyl, hydroxy or cyano group, a fluorine or

iodine atom and

X is a CH group, or

also a pyrrolidone, hexamethyleneimino or heptamethyleneimino group, when

nr is the number 1,

Rg is a hydrogen atom, a methyl or phenyl group,

Z and W are each a carboxy or , an alkoxycarbonyl group with

a total of 2 to 4 carbon atoms,

R^ is a hydrogen, fluorine, chlorine, bromine or iodine atom, an alkyl group with 1 to 4 carbon atoms, a hydroxy, methoxy, amino, cyano, carboxy or acetamino group,

Rg and R^ together with the intervening nitrogen atom are one in 4 -

position with an alkyl group with 5 to 9 carbon atoms substituted piperidino group, one optionally with a chlorine or bromine atom,

a methoxy or an amino group substituted 1,3-dihydro-isoindolo group, a hexahydro-isoindolo- or 2-aza-bicyclo-nonan-2-yl group or also an octahydro-isoindolo group, when m means the number 1 or

X is a nitrogen atom or

m the number 0,

R^ is a hydrogen, fluorine, bromine or iodine atom, an alkyl group of 1 to 4 carbon atoms, a hydroxy, methoxy, cyano, carboxy or acetamino group, and

X is a CH group., and

if they contain an asymmetric carbon atom, their opt

active antipodes and their salts.

Particularly preferred compounds with the above general formulas I and Ia are, however, those where

m is the number 0 or 1,

n is the number 2,

X is a CH group,

Z is a carboxy or alkoxycarbonyl group with a total of 2 more

4 carbon atoms,

W is a carboxy group,

R is a hydrogen atom,

R-^ in the 5-position is a fluorine, chlorine, bromine or iodine atom or a methyl group or also a hydrogen atom, when R£ and R^ together with the intervening nitrogen atom is an octahydro-1H-azonino group,

■'in the 5-position is a hydrogen, chlorine or bromine atom,

R2 and R^ respectively. Rg and R^ together with the intervening nitrogen atom is a piperidino group substituted in the 4-position with an alkyl group with 5 to 9 carbon atoms, a 1,3-dihydro-isoindolo group optionally substituted with a chlorine or bromine atom,

a 2-aza-bicyclo-nonan-3-yl or hexahydro-isoindolo group, or

R 2 and R 4 together with the intervening nitrogen atom is an octahydro-1H-azonino group, when

m is the number 1, or

m is: the number 0 and

R-^ is a methyl group, a hydrogen, fluorine or iodine atom,

or

Rg and R_, together with the intervening nitrogen atom is an octahydro-isoindolo group, when

m is the number 1, or

m is the number 0 and

Rg is a bromine atom, or-

R2 and R^ together with the intervening nitrogen atom is a pyrrolidino, piperidino, hexamethyleneimino or heptamethyleneimino group, when

m is the number 1, and

Rg is a hydrogen atom, a methyl or phenyl group, and

if they contain an asymmetric carbon atom, their opt

active antipodes and their physiologically compatible addition salts with inorganic or organic acids or also bases when Z or W is a carboxy group.

The new compounds are prepared as follows:

1. Preparation of the 2-aminocarboxylic acid derivatives or the general formula Ia: a) For the preparation of compounds, or the general formula Ia where W is a carboxy group: Hydrolysis of a compound of the general formula

where R, Rg to Rg, m and X are as indicated at the outset, and A is a group which can be transferred to a carboxy group by hydrolysis.'

As such hydrolysable groups come into consideration, for example, a nitrile group, functional derivatives of the carboxy group such as its unsubstituted or substituted amides, esters, thioesters, orthoesters, iminoethers, amidines

or anhydrides, a malonester-(1)-yl group, a tetrazolyl group, an optionally substituted 1,3-oxazol-(2)-yl or dihydro-1,3-oxazol-(2)-yl group .

The hydrolysis is conveniently carried out 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, ethanol, water/ethanol, water/isopropanol or water /dioxane at temperatures between -10 and 12 0°C, for example at temperatures between room temperature and

the boiling temperature of the reaction mixture.

If.B means a cyano group in a compound of the general formula II, the reaction is conveniently carried out in the presence of ethanol/hydrogen chloride. In this way, the corresponding imino- and orthoester resp. are formed in the reaction mixture. after addition of water the corresponding ester, which is hydrolysed after addition of water. b) For the preparation of compounds of the general formula Ia where R5 denotes an amino group: Reduction of a nitro compound of the general formula where R, Rg to Rg, m, W and X are as indicated at the outset. The reduction is conveniently carried out in a solvent such as methanol, ethanol, water, water/ethanol, dioxane, methanol/dioxane, ethyl acetate, dimethylformamide or dioxane/dimethylformamide with catalytically activated hydrogen, ■ for example with hydrogen in the presence of a hydrogenation catalyst such as palladium/coal, platinum or Raney nickel at a hydrogen pressure of 1 to 10 bar; with hydrazine in the presence of Raney nickel, with nascent hydrogen, for example with zinc/acetic acid, stannous/hydrochloric acid or ferric/hydrochloric acid, or with a metal salt, for example stannous chloride/hydrochloric acid or ferric (II )-sulphate/sulphuric acid, at temperatures between 0 and 50°C, preferably at room temperature. c) For the preparation of compounds of the general formula Ia where R^ is a hydroxy group, a cyano group, a hydrogen,

fluorine, chlorine or bromine atom:

Reaction of a compound with the general formula where R, Rg to Rg, m, - W and X are as indicated at the outset, with a nitrite and subsequent heating of the thus obtained diazonium salts, possibly in the presence of copper or a suitable copper(I) salt. The reaction is carried out, conveniently by a compound of the general formula IV in a suitable solvent, for example in water/hydrochloric acid, methanol/hydrochloric acid or dioxane/hydrochloric acid, being transferred to a diazonium salt at lower temperatures, for example at temperatures between -10 and 5 °C, with a nitrite, for example sodium nitrite or an ester of nitric acid.

The corresponding diazonium salt thus obtained is then transferred, for example as fluoroborate, as hydrosulphate in sulfuric acid, as hydrochloride in the presence of copper or in the presence of a suitable copper (I) salt such as copper (I) chloride/hydrochloric acid, copper (I) bromide /hydrobromic acid or tri-sodium copper(I) tetracyanide at pH 7, by heating, for example at temperatures between 15 and 90°C, to the desired compound. d) For the preparation of compounds of the general formula Ia where Rg means a hydrogen atom: Dehalogenation of a compound of the general formula

where R, Rg to Rg, m, X and W are as indicated at the outset, and Hal means a halogen atom, for example a chlorine, bromine or iodine atom.

The dehalogenation is preferably carried out in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, using catalytically activated hydrogen, for example with hydrogen in the presence of platinum, palladium/coal or Raney nickel, at temperatures between 0 and 75°C, preferably at room temperature, and at a hydrogen pressure of 1-5 bar. e) For the preparation of compounds with the general formula Ia where W means a carboxy group: Reaction of one organometallic compound with the general formula

where R, Rg to Rg, m and X are as indicated at the outset, and Me is an alkali atom, preferably a lithium atom, or an alkaline earth halide residue, preferably a magnesium chloride or magnesium bromide residue, with carbon dioxide.

The reaction is preferably carried out by adding a compound of the general formula VI, optionally dissolved in an inert solvent such as diethyl ether or tetrahydrofuran, to solid carbon dioxide. f) For the preparation of compounds of the general formula Ia where X represents a nitrogen atom: Reaction of a compound of the general formula

where R, Rg, Rg, W and m are as indicated at the outset, and B means a replaceable residue such as a halogen atom or an alkylsulfonyl group, for example a chlorine or bromine atom, a methyl or ethylsulfonyl group, with an amine of the general formula

where R b and R l are as indicated at the outset.

The reaction is carried out, suitably in a solvent such as water, water/methanol, water/ethanol, water, n/iso-propanol, dimethylformamide or in an excess of the amine used with the general formula VIII, possibly in the presence of an inorganic or tertiary organic base, optionally in the presence of a reaction accelerator such as copper, and optionally in a pressure vessel at temperatures between 20 and 150°C, preferably at the boiling temperature of the reaction mixture, for example at temperatures between 80 and

100°C. However, the turnover can also be carried out without a solvent1.

g) For the preparation of compounds with the general formula

Ia where R^ means an alkoxy group with 1 to 4 carbon atoms: Alkylation of a hydroxy compound of the general formula

where. R, Rg to Rg, W, X and m are, as indicated at the outset,

by a compound with the general formula

where R5' means an alkyl group with 1 to 4 carbon atoms,

and D a nucleophilic leaving group or, together with the adjacent H atom in the residue R^' a diazo group, and if necessary subsequent hydrolysis.

For example, a chlorine, bromine or iodine atom or a sulphonyloxy group such as a methanesulphonyloxy, p-toluenesulphonyloxy or metoxy-sulphonyloxy group comes into consideration as a leaving group.

The reaction is suitably carried out in a solvent such as ether, tetrahydrofuran, ethanol, acetone, dimethylformamide or dimethylsulfoxide, optionally in the presence of a base such as sodium carbonate, potassium carbonate, barium hydroxide, sodium ethylate or potassium tert-butylate with, an alkylating agent such as diazomethane, diazoethane, methyl iodide, ethyl iodide, isopropyl bromide, butyl bromide, dimethyl sulfate, diethyl sulfate or p-toluenesulfonic acid methyl ester at temperatures between 0 and 100°C, preferably at temperatures between 15 and 70°C.

If W here means a carboxy group, this is simultaneously esterified by the alkylation with a diazoalkane or by the alkylation in the presence of a strong base. The ester thus obtained is then optionally transferred by hydrolysis in the presence of an acid or base to the corresponding carboxylic acid.

A prepared compound of the general formula Ia where W means an alkoxycarbonyl group can then be transferred by hydrolysis to a corresponding compound of the general formula Ia where W means a carboxy group.

The subsequent hydrolysis is preferably carried out in a water-miscible solvent such as methanol, ethanol, dioxane, water/ethanol or water/tetrahydrofuran in the presence of an acid. such as hydrochloric or sulfuric acid, or a base such as sodium or potassium hydroxide at elevated temperatures, for

for example at the boiling temperature of the reaction mixture.

2%. Preparation of the carboxylic acid derivatives of the general formula I:

a) Reaction of a carboxylic acid with the general formula

where R, R^, R2, R3, Rg, X and m are as indicated at the outset, or its optionally produced* reactive derivative in the reaction mixture, with an amine of the general formula

where Z and n are as indicated at the outset, or with an N-activated amine of the general formula XII formed in the reaction mixture, when a carboxylic acid of the general formula XI is used and when Z in an N-activated amine of the general formula XII is not means a carboxy group.

The method thus relates to the acylation of an amine of the general formula XII with a carboxylic acid of the general formula XI in the presence of an acid-activating or water-attracting agent, or with its functional derivatives, or

reaction of a carboxylic acid of the general formula XI with an amine of the general formula XII where Z does not represent a carboxy group, in the presence of an amino group-activating agent, or with reactive derivatives thereof.

As possibly functional derivatives produced in the reaction mixture: of a carboxylic acid of the general formula XI, for example its alkyl,

aryl or aralkyl esters or thioesters such as the methyl, ethyl, phenyl or benzyl ester, its imidazolides,

its acid halides such as the acid chloride or bromide, its anhydrides, its mixed anhydrides with aliphatic or aromatic carboxylic, sulfenic, sulfinic or sulfonic acids or carboxylic acid esters, for example with acetic>propionic acid, p-toluenesulfonic acid or O-ethylcarboxylic acid, its O-triphenylphosphonium or copper complexes, its N-acyloxyimides, its azides or nitriles or the corresponding amino-thiocarboxylic acid derivatives, and which optionally produced in the reaction mixture reactive derivatives of an amine of the general formula XII, where X does not mean a carboxy group , its phosphazo derivatives.

As acid-activating and/or water-attracting agents, for example, a chloroformic acid ester such as chloroformic acid ethyl ester, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N,N1 -dicyclohexylcarbodiimide, .N,N'-carbonyl diimidazole, N,N'-thionyldiimidazole, boron trifluoride etherate

or triphenylphosphine/carbon tetrachloride.

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 inorganic base such as sodium carbonate or a tertiary organic base

such as triethylamine or pyridine, which can simultaneously serve as a solvent, and optionally in the presence of an acid activating agent at temperatures between -25 and 250°C, preferably at temperatures between -10°C and the boiling temperature of the solvent used. It is not necessary to isolate any functional derivative of a compound of the general formula XI or XII formed in the reaction mixture, and furthermore the reaction can also be carried out without a solvent. In addition, water formed during the reaction can be removed by azeotropic distillation, for example by heating with toluene on a water separator, or by adding a drying agent such as magnesium sulfate or molecular sieve. b) For the preparation of compounds of the general formula I where

X means ehCH group, and m means the number 0:

Reaction of a compound with the general formula

where R, R^, Z and n are as indicated at the outset, and E means a replaceable residue such as a halogen atom, with an amine of the general formula

where R 2 and R 3 are as indicated at the outset.

The term "a halogen atom" which is used in the definition of the replaceable residue E, is to be understood in particular as a chlorine or bromine atom.

The reaction is suitably carried out in a solvent such as water, water/methanol, water/ethanol, water/isopropanol, dimethylformamide or in an excess of the amine used with the general formula XIV, optionally in the presence of an inorganic or tertiary organic base, optionally in the presence

of the reaction accelerator such as copper, and optionally in a pressure vessel at temperatures between 20 and 150°C, preferably at the boiling temperature of the reaction mixture, for example at 100°C. However, the reaction can also be carried out without a solvent.

c) For the preparation of compounds of the general formula I where Z means a carboxy group: Oxidation of a compound of the general formula

where R, R-^ to R^, Rg, X^ nr and n are as indicated at the outset, and G means a group which can be transferred to a carboxy group by oxidation.

As such an oxidizable group comes into consideration, for example, a formyl group and its aetals, a hydroxymethyl group and its ethers, an unsubstituted or substituted acyl group such as an acetyl-, chloroacetyl-, propionyl-

or malonic acid-(1)-yl group or a malonester-(1)-yl group.

The reaction is carried out with an oxidizing agent in a suitable solvent such as water, glacial acetic acid, pyridine or carbon tetrachloride, at temperatures between 0 and 100°C, suitably at temperatures between 20 and 50°C. However, the reaction is preferably carried out with silver oxide/sodium hydroxide solution, manganese dioxide/acetone or methylene chloride, hydrogen peroxide/sodium hydroxide solution, bromine or chlorine/sodium hydroxide solution or potassium hydroxide solution or chromium trioxide/pyridine. ■ d) For the preparation of compounds of the general formula I where Z means a carboxy group:

Hydrolysis of a compound with the general formula

where R, R^ to R^ , Rg , X, m and n are as indicated at the beginning, and Q means a group which can be transferred to a carboxy group by hydrolysis.

As such hydrolyzable groups come into consideration, for example, a nitrile group, functional derivatives of the carboxy group such as its unsubstituted or substituted amides, esters, thioesters, orthoesters, iminoethers, amidines or anhydrides, a malonester-(1)-yl group, a tetrazolyl - group, an optionally substituted 1,3-oxazol-(2)-yl- or dihydro-1,3-oxazol-(2)-yl group.

The hydrolysis is suitably carried out 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, ethanol, water/ethanol, water/isopropanol or water/- dioxane at temperatures between -10 and 12 0°C, for example at temperatures between room temperature and the boiling temperature of the reaction mixture.

If Q means a cyano group in a compound of the general formula XVI, the reaction is suitably carried out in the presence of ethanol/hydrogen chloride, and in the reaction mixture the corresponding imino- and ortho-ester resp. after addition of water the corresponding ester, which is hydrolysed after addition of water. e) For the preparation of compounds with the general formula I where X means a CH group and m the number 0: ... Reaction of an amide with the general formula

where R and R^ to R^ are as initially indicated, or its alkali salt, with a compound of the general formula

where Z and n are as initially indicated, and Y means a nucleophilic leaving group such as a halogen atom or a sulfonyloxy group.

The reaction is conveniently carried out in a solvent such as tetrahydrofuran, dioxane, toluene, dimethylformamide, dimethylsulfoxide or hexamethylphosphoric acid triamide, optionally in the presence of a base such as sodium hydride or potassium tert.butylate at temperatures between 20 and 180°C, preferably at temperatures between 50 and 150°C. f) For the preparation of compounds of the general formula I where X means a CH group and Z a carboxy group: Acylation of a compound of the general formula

where R> R^ to R^, Rg, m and n are as initially stated, with an oxalyl halide or phosgene in the presence of a Lewis acid.

The Friedel force acylation is conveniently carried out in a solvent such as nitrobenzene or carbon disulphide in the presence of a Lewis acid such as aluminum chloride, at temperatures between 0 and 80°C, preferably at temperatures between 20 and 60°C. g) For the preparation of compounds of the general formula I where X means a CH group and Z a carboxy group:

Reaction of a compound with the general formula

where R, R^ to R^, Rg, m and n are as stated at the outset, with any hypohalogenite produced in the reaction mixture.

The reaction is conveniently carried out in a solvent such as water/tetrahydrofuran or water/dioxane at temperatures between 0 and 80°C, preferably at temperatures between 25 and 50°C.

If the method yields a carboxylic acid amide of the general formula I where Z means a carboxy group, this can optionally be transferred by esterification to a corresponding compound of the general formula I where Z is an esterified carboxy group.

The subsequent esterification is conveniently carried out in a suitable solvent, for example in a corresponding alcohol, pyridine, toluene or dioxane, in the presence of an acid-activating and/or water-attracting agent such as thionyl chloride, chloroformic acid ethyl ester, N,N'-dicyclohexylcarbodiimide or carbonyldiimidazole, or by transesterification, for example with a corresponding carboxylic acid diester, at temperatures between 0 and 50°C, preferably at room temperature.

The obtained compounds of the general formulas I and Ia can further be transferred to their physiologically compatible salts with inorganic or organic acids and also bases when W or Z means a carboxy group. As acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid or fumaric acid, and as bases sodium hydroxide, potassium hydroxide or cyclohexylamine come into consideration.

The compounds used as starting materials or the general formulas II to XX are known from the literature, or they can be prepared by methods known per se. Thus you get, for example, a compound with the general formula II by reduction of a corresponding nitro compound and optionally subsequent Sandmeyer reaction and optionally subsequent alkylation.

A compound of the general formula III is obtained, for example, by nitration of a corresponding compound, by reaction of a corresponding organometallic compound with carbon dioxide or by reaction of a corresponding benzyl halide with potassium cyanide and - possibly subsequent hydrolysis and/or esterification.

A compound with the general formula IV or XI is obtained. for example by reacting a corresponding 2-chloro- or 2-bromo-nitrocarboxylic acid or its derivatives with a corresponding amine, subsequent reduction of the nitro group in a thus obtained 2-amino compound by means of catalytically activated hydrogen, by means of nascent hydrogen, by by means of metals or metal salts, and' transfer of the salted.s obtained amino group over a corresponding diazonium salt to a corresponding compound of the general formula IV or XI. For the preparation of a starting compound of the general formula XI, where R 1 denotes an alkoxy group, a hydroxy carboxylic acid thus prepared is then alkylated and, if necessary, then hydrolysed.

For example, you get a connection with the general formula

V by Sandmeyer reaction of a corresponding amino compound, a compound of the general formula VI by metalation of a corresponding halogen compound, a compound of the general formula VII by halogenation of a corresponding pyridine compound, and a compound of the general formula. IX by boiling in a corresponding diazonium salt.

A compound of the general formula XI where R.^ denotes an alkyl or trifluoromethyl group is obtained, for example, by reduction of a corresponding nitrobenzene derivative, Sandmeyer reaction of the obtained amino compound with copper (I) bromide, metallation of the obtained bromine compound with butyl -lithium and subsequent reaction with carbon dioxide.

A compound of the general formula XII is obtained, for example, by reacting a corresponding 4-bromomethylbenzene derivative with sodium cyanide and subsequent catalytic hydrogenation of the cyano compound thus obtained.

A compound with the general formulas XIII, XV to XVII, XIX and XX used as starting material is obtained by reacting a corresponding carboxylic acid with a corresponding amine in the presence of an acid-activating or water-attracting agent.

A compound of the general formula XVIII used as starting material is obtained by halogenating a corresponding alcohol or reacting a sulfonic acid halide with a corresponding alcohol in the presence of a base.

As mentioned at the beginning, they show new connections with

the general formulas I and Ia have valuable pharmacological properties, namely an effect on intermediate metabolism. Thus, the compounds of the general formula I in particular have a blood sugar-lowering and/or lipid-lowering effect and the compounds of the general formula Ia a lipid-lowering effect. Moreover, the compounds of the general formula Ia represent valuable intermediates for the production of the new compounds of the general formula I..

"'As examples were the compounds

Å = 4-[2-[2-(2-azabicyclo[3.3.1]nonan-2-yl)-5-chloro-benzoylamino]-ethyl]benzoic acid,

B = 4-[2-[5-fluoro-2-(octahydro-1H-azonino)-benzoylamino]ethyl]-benzoic acid,

C = 4-[2-[5-chloro-2-(cis-3,5-dimethylpiperidino)-nicotinoylaminoj-ethyl]benzoic acid and

D = 4-[2-[5-methyl-2-(octahydro-1H-azonino)-benzoylamino]-ethyl]-benzoic acid

compared with

E = 4-[2-(2-ethylamino-5-chloro-benzoylamino)-ethyl]benzoic acid

(see example 5 in Belgian patent 837 311)

investigated for its blood sugar-lowering properties,

and the connections

F 5-chloro-2-[4-(3-pentyl)-piperidino]benzoic acid,

G = 5-bromo-2-(octahydro-isoindol-2ryl)-benzoic acid,

H = 5-chloro-2-(2,3,'3a,4,7,7a-hexahydro-1H-isoindol-2-yl)-benzoic acid and

I = 5-chloro-2-(octahydro-isoindol-2-yl)-nicotinic acid

and was investigated for its lipid-lowering properties as follows:

1. Blood sugar-lowering effect:

The hypoglycaemic effect of the test compounds was investigated on female rats of own breeding with a weight of 180-220 g, which were fasted 24 hours before the start of the experiment. The test compounds were suspended in 1.5% methylcellulose immediately before the start of the experiment and administered via a throat tube. Blood samples were taken immediately before administration of the test compound and likewise 1, 2, 3 and 4 hours thereafter/in each case from the retroorbital venous plexus. From 50^ul of. in each of these samples, proteins were removed with 0.5 ml of 0.33 N perchloric acid, and the samples were centrifuged. In the liquid on top, glucose was determined by the hexokinase method using an analytical photometer. The statistical assessment was carried out using the t-test according to Student with p = 0.05 as the significance limit. D. the following table contains the values found in percentage compared to the control.

2. Lipid-lowering effect:

Literature: P.E. Schurr et al. in Atherosclerosis Drug Discovery (1976) , Publisher: CE. Day;

Plenum-, New York, page 215.

Young male rats with an average weight of 100 g were fed a diet (consisting of 10% coconut fat, 1.5% cholesterol, 0.5% cholic acid, 0.2% choline chloride and 15% sucrose) for four days to become hyperlipemic . While maintaining the diet, the test compound in methyl cellulose was added in suspension via a throat tube on two consecutive days. The animals were then kept fasting overnight, and 4 and 24 hours after the last administration of the test compound, blood samples were taken to obtain serum.

In the serum, the total amount of cholesterol (Boehringer Mannheim Testkombination 187.313) and triglycerides (Boehringer Mannheim Testkombination 126.039) was determined enzymatically. The S-lipoproteins were determined nephelometrically after precipitation with Ca and heparin in an Autoanalyzer.

The calculation of the percentage lowering was done in comparison with a control group.

The following table contains the values found:

The changes are statistically significant at p = 0.05.

3. Acute toxicity:

The toxic effect of the compounds was investigated on female and male mice of own breeding with a weight of 20-26 g. oral administration (suspension in 1% methylcellulose) of a single dose with an observation period of at least 7 days. The following table contains the values found:

Due to their pharmacological properties, the compounds of formula In prepared according to the invention and their physiological

■compatible salts suitable for the treatment of Diabetes mellitus. For this purpose, they can, possibly in combination 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 1-50 mg, preferably 2.5-20 mg,

1 or 2 times daily.

Furthermore, due to their pharmacological properties, the compounds of the general formula Ia are suitable for the treatment of hyperlipidaemias, particularly of type Ila, Ilb and IV, and hence conditional arteriosclerotic changes in the vascular system, and can, possibly in combination with other active substances, be incorporated in the usual pharmaceutical preparation forms such as dragées, tablets, capsules, suppositories, suspensions or solutions. The single dose is 5-200 mg, preferably 5-50 mg, and the daily dose 10-500 mg, preferably 15-150 mg.

The following examples shall serve to further illustrate the invention: Example A

2-( 2- azabicyclo[ 3. 3. 1] nonan- 2- yl)- 5- nitro- benzoic acid

In 600 ml of ethanol, 40 g (320 nuMol) of 2-azabicyclo[3.3.1]-nonane, 64.5 g (320 mmol) of 2-chloro-5-nitro-benzoic acid and 74.3 g of sodium carbonate are heated for 4 days to reflux temperature . After distilling off the ethanol, the evaporation residue is dissolved in 800 ml of water, adjusted to pPT 4 with 2 N hydrochloric acid and then shaken out with chloroform. The chloroform phases are dried over sodium sulfate, and the evaporation residue is purified chromatographically over a silica gel column with toluene/acetic acid ethyl ester (6:4) as eluent.

Yield: 11.6 g (12.5% of the theoretical)

Melting point: 167°C

Example B

5-nitro-2-[4-(3-pentyl)-piperidino]benzoic acid

Prepared analogously to example A from 2-chloro-5-nitro-benzoic acid and 4-(3-pentyl)-piperidine.

Yield: 60% of the theoretical

Melting point: 146°C

Example C

5-nitro"o-2-[4-(5-nonyl)-piperidino]benzoic acid

Prepared analogously to example A from 2-chloro-5-nitro-benzoic acid and 4-(5-nonyl)-piperidln.

Yield: 73% of the theoretical

Melting point: 150-152°C

Example D

5-nitro-2-(octahydro-isoindol-2-yl)-benzoic acid

Prepared analogously to example A from 2-chloro-5-nitro-benzoic acid and octahydro-isoindole.

Yield: 77.5% of the theoretical

Melting point: 188-190°C

Example E

3-bromo-4-(octahydro-1H-azonino)-toluene

12.0 g (52 mmol) of 5-methyl-2-(octahydro-1H-azonino)-aniline (prepared by reduction of 3-nitro-4-(octahydro-1H-azonino)-toluene) is dissolved in 200 ml 48% ig aqueous hydrobromic acid and diazotized at 5°C by dropwise addition of a solution of 3.8 g (55 mmol) sodium nitrite in 10 ml of water. The diazonium salt solution thus obtained is then rapidly added dropwise to a suspension of 10.75 g (75 mmol) copper (I) bromide and 4.0 g copper powder in 100 ml 48% aqueous hydrobromic acid. The mixture is stirred for one hour at 40°C, the mixture is made alkaline, extracted with methylene chloride, the extracts are dried over sodium sulphate, filtered and evaporated.

Yield: 10.1. g (66% of the theoretical),

Melting point: <20°C.

Example F

3-bromo-4-(octahydro-isoindol-2-yl)-toluene

Prepared by Sandmeyer reaction analogously to example E starting from 3-amino-4-(octahydro-isoindol-2-yl)-toluene.

Yield: 20% of the theoretical,

Melting point: 116°C

Example G

(5-nitro-2-piperidino-phenyl)acetic acid

55 g (260 mmol) (2-chloro-5-nitrophenyl)acetic acid [prepared by nitration of (2-chlorophenyl)-acetic acid with nitric acid,. melting point: 127°C] is heated with 230 ml of piperidine for 48 hours to reflux temperature. After adding 400 ml of water, adjust the pH value to 5.5 with hydrochloric acid. Thereby the reaction product is precipitated, which is then washed with after extraction. acetone and ether. Yield: 64 g (93% of theoretical),

Melting point: 119°C

Example H

( 2- octahydro- 1H- azonino- 5- nitro- phenyl) acetic acid

50 g (240 mmol) of (2-chloro-5-nitro-phenyl)acetic acid are heated with 260 ml of octahydro-1H-azonine for -24 hours to 110-120°C. After evaporation to dryness, the residue is dissolved in 400 ml of water, the solution is adjusted to pH 2-3 with hydrochloric acid and shaken out with chloroform. The combined chloroform phases are shaken with diluted caustic soda, and then the aqueous phase is extracted with chloroform after renewed acidification. After drying and distilling off the chloroform, the crystallisate formed is washed with petroleum ether/ether = 5:1.

Yield: 31 g (42% of the theoretical),

Melting point: 100-103°C

Example I

[ 2-( octahydro- isoindol- 2- yl)- 5- nitro- phenyl]- acetic acid

Prepared analogously to example H from (2-chloro-5-nitro-phenyl)-acetic acid and octahydro-isoindole.

Yield: 53% of the theoretical,

Melting point: 228°C

Example K•

2-(2,3,3a,4,7,7a-hexahydro-1H-isoindol-2-yl)-5-nitro-benzoic acid Prepared analogously to example A from 2-chloro-5-nitro-benzoic acid. and 2,3,3α,4,7,7α-hexahydro-1H-isoindole.

Yield: 85% of the theoretical,

Melting point: 231°C

Example L

2-( 1, 3- dihydro-isolndol- 2- yl)- 5- nitro- benzoic acid

Prepared analogously to example A from 2-chloro-5-nitro-benzoic acid and 1,3-dihydroisoindole.

Yield: 52% of the theoretical,

Melting point: 185-186°C

Example M

DL-2-(2-chloro-5-nitro-phenyl) propionic acid

■To 2.9 g (157 mmol) of DL-2-(2-chlorophenyl)propionic acid, dissolved in 70 ml of concentrated sulfuric acid, add at "15°C 23.5 ml of nitric acid (7.5 ml of fuming nitric acid with specific gravity 1 .5 and 16 ml of concentrated sulfuric acid) so slowly that the temperature does not rise above 0°C. After the addition is finished and further stirring for one hour at room temperature, the reaction mixture is poured into ice water. The precipitated acid is filtered off with suction, dissolved in chloroform and washed with water. The chloroform extracts dried, and the evaporation residue is crystallized with petroleum ether/ether.

Yield: 95% of the theoretical,

Melting point: 129-131°C

Analogously, the following compounds were prepared:

DL-2-[2-(octahydro-isoindol-2-yl)-5-nitro-phenyl]propionic acid DL-2-(2-octahydro-1H-azonino-5-nitro-phenyl)-propionic acid

DL-2-(5-nitro-2-piperidino-phenyl)-propionic acid

Example N

2-(5-chloro-1,3-dihydro-isoindol-2-yl)-5- nitro-benzoic acid

Prepared analogously to example A from 2-chloro-5-nitro-benzoic acid and 5-chloro-1,3-dihydro-isoindole.

Yield: 27% of the theoretical,

Melting point:' 163°C

Example 0

2-(1,3-dihydro-5-methoxy-isoindol-2-yl)-5-nitro-benzoic acid Prepared analogously to example A from 2-chloro-5-nitro-benzoic acid and 5-methoxy-1,3-dihydro -isoiridol.

Yield: 57% of the theoretical,

Melting point: 152°C

Example P

(5-nitro-2-pyrrolidino-phenyl)acetic acid

Prepared analogously to example G from (2-chloro-5-nitrc-phenyl)-acetic acid and pyrrolidine.

Yield: 90% of the theoretical,

Melting point: 2 0 8°C.

Example Q

(2-hexamethyleneimino-5-nitro-phenyl) acetic acid

Prepared analogously to, example H from (2-chloro-5-nitro-phenyl)-acetic acid and hexamethylene imine.

Yield: 96% of the theoretical,

Melting point: 144°C

Example R

(2-heptamethyleneimino-5-nitro-phenyl) acetic acid

Prepared analogously to example H from (2-chloro-5-nitro-phenyl)-acetic acid and heptamethyleneimine.

Yield: 9 5% of the theoretical,

Melting point: 136°C

Example S 2,5-dichloronicotinic acid

a) A mixture of 52.1 g (0.3 mol) 5-chloro-2-hydroxy-nicotinic acid and 68.7 g (0.33 mol) phosphorus pentachloride is stirred for 30 minutes at

140°C. 500 ml of toluene are then added, undissolved components are suctioned off, and the filtrate is evaporated in vacuo. The residue is distilled

in high-vacuum. Yield: 40.1 g (63.5% of the theoretical),

Boiling point: 72.74°C at 0.05 mbar.

b) 2, 5-dichloro-nicotinic acid

72.2 g (0.343 mol) of 2,5-dichloronicotinic acid chloride add

is added dropwise under cooling and vigorous stirring to aqueous caustic soda (from 13.7 g (0.343 mol) sodium hydroxide and 200 ml water). After 1.5 hours, the precipitate is suctioned off and washed with water. The crystals obtained are triturated with acetonitrile and suctioned off. Yield: 62.7 g (95.2% of the theoretical),

Melting point: 153-155°C

Example T

[ 2-piperidinopyridyl-(3)] acetonitrile

a) [2-chloro-pyridyl-(3)] acetonitrile

A solution of 35.8 g (0.267 mol) of 3-cyanomethyl-pyridine-N-oxide in 360 ml of phosphorus oxychloride is slowly heated to reflux temperature with stirring. After 2 hours, the reaction mixture is evaporated in vacuo, the residue is added to ice water and brought to pH 3 with caustic soda. After extraction with chloroform, purification is carried out by column chromatography over silica gel in eluent toluene/ethyl acetate = 10:1,

Yield: 8.5 g (21% of the theoretical),

Melting point: 82-84°C

b) [2-piperidinopyridyl-(3)]acetonitrile

Prepared from [2-chloro-pyridyl-(3)]acetonitrile and piperidine

analogous to example H.

Yield: 57% of the theoretical,

Melting point: <20°C

.Calculated: Mole peak: m/e = 201

Found: Mole top: m/e = 201

Example 1

4-[ 2- f 2-( 2- azabicyclo[ 3. 3. 1] nonan- 2- yl)- 5- chloro- benzoylamino] ethyl]-benzoic acid ethyl ester

To a solution of 3.7 g (13 mmol) 2-(2-aza'bicyclo[3.3.1]-nonan-2-yl)-5-chloro-benzoic acid in 20 ml absolute pyridine is added

2.3 (13 mmol) N,N'-carbonyldiimidazole. After 5 hours of heating to 80°C, the imidazolide has been formed quantitatively. 3.1 g (16 mmol) of 4-(2-amino-ethyl)-benzoic acid ethyl ester, dissolved in 50 ml of pyridine, are then added, and the whole is heated for 16 hours to 90°C with stirring. After distilling off

the pyridine on a rotary evaporator, the ester is purified chromatographically over a silica gel column with toluene/acetic acid ethyl ester (9:1) as eluent.

Yield: 1.8 g (30% of the theoretical),

Melting point: <20°C

Example 2 4-[2-[5-chloro-2-(4-(3-pentyl)-piperidino)-benzoylamino] ethyl]-benzoic acid ethyl ester

Prepared analogously to example 1 from 5-chloro-2-(4-(3-pentyl)-piperidino)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester. Yield: 62% of the theoretical,

Melting point: 95-96°C

Example 3

4"- [ 2- [ 5- chloro- 2 - ( 4 - ( 5- nonyl) - piperidino ) - benzoylamino] ethyl] - benzoic acid ethyl ester

Prepared analogously to example 1 from 5-chloro-2-(4-(5-nonyl)-piperidino)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester. Yield: 79% of the theoretical,

Melting point: 49-50°C

Example 4 4-[2-[5-bromo-2-(octahydro-isoindol-2-yl)-benzoylamino] ethyl]-benzoic acid ethyl ester

Prepared analogously to example 1 from 5-bromo-2-(octahydro-isoindol-2-yl)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester.

Yield: 67.7% of the theoretical,

Melting point: 178-179°C

Example 5

4 - [ 2- [ 2- ( 2- azabicyclo[ 3. 3. 1] nonan- 2- yl)- 5- chloro- benzoylamino] - ethyl] benzoic acid

1.3 g (2.9 mmol) of 4-[2-[2-(2-azabicyclo[3.3.1]nonan-2-yl)-5-chloro-benzoylamino]ethyl]benzoic acid ethyl ester is dissolved in 40 ml of a mixture of methanol/dioxane (1:1). After adding 0.65 g (12 mmol) of potassium hydroxide, dissolved in 5 ml of water, 100 ml of water is added so slowly at room temperature that no precipitation of the ester occurs. After a few hours, the organic solvent is distilled off on a rotary evaporator, the aqueous phase is shaken out with chloroform, and the aqueous phase is adjusted to pH 5.5 with 2 N hydrochloric acid. After extraction with chloroform, drying over sodium sulphate, distillation of the chloroform and digestion with petroleum ether, the acid is obtained.

Yield: 1 g (80% of the theoretical),

Melting point: 217°C

Example 6

4-[ 2-[ 5- chloro- 2-( 4-( 3- pentyl)-piperidino)- benzoylamino] ethyl]-benzoic acid

Prepared analogously to example 5 by alkaline hydrolysis

of 4-[2-[5-chloro-2-(4-(3-pentyl)-piperidino)-benzoylamino]ethyl]-benzoic acid ethyl ester.

Yield: 20% of the theoretical,

Melting point: 130-132°C

Example 7

4-[ 2-[ 5- chloro- 2-( 4-( 5- nonyl)-piperidino)- benzoylamino] ethyl]-benzoic acid

Prepared analogously to example 5 by alkaline hydrolysis

of 4-[2-[5-chloro-2-(4-(5-nonyl)-piperidino)-benzoylamino]ethyl]-benzoic acid ethyl ester.

Yield: 68% of the theoretical,

Melting point: 12 9-130°C

Example 8

4-[ 2-[ 5- bromo- 2-( octahydro- isoindol- 2- yl)- benzoylamino] ethyl] benzoic acid

Prepared analogously to example 5 by alkaline hydrolysis

of 4-[2-[5-bromo-^2-(octahydro-isoindol-2-yl)-benzoylamino] ethyl ]-benzoic acid ethyl ester.

Yield: 86.3% of the theoretical,

Melting point: 23 5°C

. Example 9 4-[2-(5-iodo-2-(octahydro-1H-azonino)-benzoylamino)ethyl]benzoic acid ethyl ester

2.9 g (7.8 mmol) of 5-iodo-2-(octahydro-1H-azonino)-benzoic acid are dissolved in 20 ml of absolute pyridine and quantitatively transferred to the imidazolide at 50°C with 1.5 g (8.5 mmol ) N,N<1->carbonyldiimidazole during. 3 hours. After adding 1.75 g (9 mmol) of 4-(2-amino-ethyl)-benzoic acid ethyl ester, the reaction mixture is heated for 8 hours to 90°C, and the pyridine is then distilled off in a rotary evaporator. The ester is purified chromatographically over a silica gel column with toluene/acetic acid ethyl ester (9:1) as eluent.

Yield: 1.3 g (30% of the theoretical),

Melting point: <20°C

Example 10

4- [ 2- ( 5- fluoro- 2-.( octahydro- 1H- azonino) - benzoylamino) ethyl] benzoic acid ethyl ester

Prepared analogously to example 9 from 5-fluoro-2-(octahydro-1H-azonino)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester. Yield: 60% of the theoretical,

Melting point: <20°C

Example 11

4-[ 2-( 5- methyl- 2-( octahydro- 1H- azonino)- benzoylamino) ethyl]-benzoic acid ethyl ester

Prepared analogously to example 9 from 5-methyl-2-(octahydro-1H-azonino)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester. Yield: 90% of the theoretical,

Melting point: <20°C

Example 12

4-[ 2-[ 5-( 2-tolyl)- 2-( octahydro- 1H- azonino)- benzoylamino] ethyl]-benzoic acid ethyl ester

Prepared analogously to example 9 from 5-(2-tolyl)-2-(octa-.hydro-1H-azonino)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester.

Yield: 11% of the theoretical,

Melting point: <2 0°C

Example 13

4-[ 2-[ 5-( 4- chlorophenyl)- 2- piperidino- benzoylamino] ethyl] benzoic acid ethyl ester

Prepared analogously to example 9 from 5-(4-chlorophenyl)-2-piperidino-benzoic acid and 4-(2-amino-ethyl)benzoic acid ethyl ester.

Yield: 24% of the theoretical

Melting point: 129-130°C

Example 14

4-[ 2-[ 5- trifluoromethyl- 2-( octahydro- 1H- azonino)- benzoylamino]-ethyl] benzoic acid ethyl ester

Prepared analogously to example 9 from 5-trifluoromethyl->2-(octahydro-1H-azonino)benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester.

Yield: 80% of the theoretical,

Melting point: <20°C

Analogous to the above examples 9-14, the following compounds were prepared: 4-[2-(5-isopropyl-2-(octahydro-1H-azonino)-benzoylamino)ethyl]-benzoic acid ethyl ester

4-[2-[5-tert.butyl-2-(octahydro-1H-azonino)-benzoylamino]ethyl]-benzoic acid ethyl ester■

4-[2-[5-Butyl-2-(octahydro-1H-azonino)-benzoylamino]ethyl]-benzoic acid ethyl ester

4-[2-[5-fluoro-2-(decahydro-azecino)-benzoylamino]ethyl]benzoic acid ethyl ester

4-[2-[5-Bromo-2-(decahydro-azecino)-benzoylamino]ethyl]benzoic acid ethyl ester

4-[2-[5-iodo-2-(decahydro-azecino)-benzoylamino]ethyl]benzoic acid ethyl ester

4-[2-[5-cyano-2-(decahydro-azecino)-benzoylamino]ethyl]benzoic acid ethyl ester

4-[2-[5-methyl-2-(decahydro-azecino)-benzoylamino]ethyl]benzoic acid ethyl ester

4-[2-[5-Methoxy-2-(decahydro-azecino)-benzoylamino]ethyl]benzoic acid ethyl ester

Example 15 ..

4-[ 2-[ 5-iodo- 2-( octahydro-1H- azonino)- benzoylamino] ethyl] benzoic acid 1 g (1.8 mmol) 4-[,2-[ 5-iodo-2-(octahydro-1H -azonino)-benzoylamino] ethyl] benzoic acid ethyl ester is pre-saponified in 20 ml dioxane/methanol (1:1) at room temperature with 0.4 g (7.2 mmol) potassium chloride, dissolved in 50 ml water. After distilling off the organic solvent, shaking is carried out with chloroform, the aqueous phase is adjusted to pH 4.5 with 2 N hydrochloric acid and shaken with chloroform. The dry residue from the chloroform extracts is rubbed with petroleum ether, whereby the product crystallizes out.

Yield: 0.45 g (48% of theoretical),

Melting point: 7 3°C (sintering)

Example 16

4-[ 2-[ 5- fluoro- 2-( octahydro- 1H- azonino)- benzoylamino] ethyl] benzoic acid

Prepared analogously to example 15 by alkaline hydrolysis of 4-[2-(5-fluoro-2-(octahydro-1H-azonino)-benzoylamino)ethyl]-benzoic acid ethyl ester.

Yield: 85% of the theoretical,

Melting point: 166-168°C

Example 17

4-[ 2-[ 5- methyl- 2-( octahydro- 1H- azonino)- benzoylamino] ethyl] benzoic acid

■■' Prepared analogously to example 15 by alkaline hydrolysis of 4-[2-(5-methyl-2-(octahydro-1H-azonino)-benzoylamino)ethyl]-benzoic acid ethyl ester.

Yield: 81% of the 'theoretical,

Melting point: 145-147PC

Example 18

4 - [ 2-[ 5-( 4- chlorophenyl)- 2- piperidino- benzoylamino] ethyl] benzoic acid

Prepared analogously to example 15 by alkaline hydrolysis of 4-[2-[5-(4-chlorophenyl)-2-piperidino-benzoylamino]ethyl]benzoic acid ethyl ester.

Yield: 73% of the.theoretical,

Melting point: 249-252°C

Example 19 4-[2-[5-trifluoromethyl-2-(octahydro-1H-azonino)-benzoylamino]-ethyl]benzoic acid

Prepared analogously to example 15 by alkaline hydrolysis

of 4-[2-[5-trifluoromethyl-2-(octahydro-1H-azonino)-benzoylamino]-ethyl] benzoic acid ethyl ester .■

Yield: 48% of the theoretical,

Melting point: 149-150°C

Analogous to examples 15-19, the following compounds were prepared: 4-[2-[5-isopropyl-2-(octahydro-1H-azonino)-benzoylamino].ety 1]-benzoic acid

4-[2-[5-tert.butyl-2-(octahydro-1H-azonino)-benzoylamino]ethyl]-benzoic acid 4-[2-[5-butyl-2-(octahydro-1H-azonino)-benzoylamino] ethyl]-benzoic acid

4-[2-[5-(2-tolyl)-2-piperidino-benzoylamino]ethyl]benzoic acid 4-[2-[5-fluoro-2-(decahydro-azecino)-benzoylamino]ethyl]benzoic acid

4 - [2-[5-bromo-2-(decahydro-azecino)-benzoylamino]ethyl]benzoic acid

4-[2-[5-iodo-2-(decahydro-azecino)-benzoylamino]ethyl]benzoe-

acid

4-[2-[5-cyano-2-(decahydro-azecino)-benzoylamino]ethyl]benzoic acid

4-[2-[5-methyl-2-(decahydro-azecino)-benzoylamino]ethyl]benzoic acid

4-[2-[5-Methoxy-2-(decahydro-azecino)-benzoylamino]ethyl]benzoic acid

Example 20

4-[ 2-( 5- chloro- 6- methyl- 2- piperidino- nicotinoylamino)- ethyl]-benzoic acid methyl ester

2.5 g (13.7 mmol) 5-chloro-6-methyl-2-piperidino-nicotinic acid, 3.0 g (13.7 mmol) 4-(2-amino-ethyl)-benzoic acid methyl ester hydrochloride and 5.0 g (19.25 mmol) of triphenylphosphine are stirred in 150 ml of absolute acetonitrile and then 1.4 ml (1.4 mmol) of carbon tetrachloride and 8.3 ml (60 mmol) of triethylamine are added. The suspension thus obtained is stirred for 2 days at room temperature, then evaporated, water is added and extracted several times with chloroform. The chloroform extracts are dried over sodium sulfate and evaporated and purified by column chromatography over silica gel with toluene/ethyl acetate (2:1) as eluent

mean..

Yield: 3.35 g (58.8% of the theoretical),

Melting point: 88-90°C

Example 21

4-[ 2-( 6- methyl- 2- piperidino-nicotinoylamino) ethyl] benzoic acid methyl ester

Prepared analogously to example 20 from 6-methyl-2-piperidi-nicotinic acid and 4-(2-amino-ethyl)-benzoic acid methyl ester hydrochloride. Yield: 72.4% of the theoretical,

Melting point: 92-94°C

Example 2 2

4-[ 2-( 5- chloro- 2-( octahydro- 1H- azonino)- nicotinoylamino) ethyl]-■ benzoic acid ethyl ester

Prepared analogously to Example 20 from 5-chloro-2-(octahydro-1H-azonino)-nicotinic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester hydrochloride.

Yield: 31% of the theoretical,

Melting point: <2 0°C

Example 23

4-[ 2-( 5- bromo- 2- piperidino-nicotinoylamino) ethyl] benzoic acid ethyl ester

Prepared analogously to example 20 from 5-bromo-2-piperidinonicotinic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester hydrochloride. Yield: 41.8% of the theoretical,

Melting point: 93r95°C

Example 24-4-[2-[5-chloro-2-(cis-3,5-dimethyl-piperidino)-nicotinoylamino]-ethyl]benzoic acid ethyl ester

Prepared analogously to Example 20 from 5-chloro-2-(cis-3,5-dimethyl-piperidino)-nicotinic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester hydrochloride. Yield: 4 2.4% of the theoretical,

Melting point: 94-96°C

Example 25

4-[2-(5-chloro-2-piperidino-nicotinoylamino)ethyl]benzoic acid-. methyl ester

Prepared analogously to example 20 from 5-chloro-2-piperidinenicotinic acid and 4-(2-amino-ethyl)-benzoic acid methyl ester hydrochloride.

Yield: 49% of the theoretical,

Melting point: '113-115°C

Example 26

4 -[ 2-( 5- bromo- 6- methyl- 2- piperidino- nicotinoylamino) ethyl] benzoic acid ethyl ester

Prepared analogously to example 20 from 4-(2-amino-ethyl)-benzoic acid ethyl ester hydrochloride and 5-bromo-6-methyl-2-piperidino-nicotinic acid.

Yield: 54.6% of the theoretical.

Melting point: <20°C

Example 27 4-[2-['5-chloro-2-(3,5-cis-dimethyl-piperidino)-6-methyl-nicotinoylamino]ethyl]benzoic acid ethyl ester

Prepared analogously to example 20 from 5-chloro-2-(3,5-cis-dimethyl-piperidino)-6-methyl-nicotinic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester hydrochloride.

Yield: 51% of the theoretical,

Melting point: <2 0°C

Example 28

4-[ 2-[ 5- bromo- 2-( 3, 5- cis- dimethyl-piperidino)- 6- methyl- nicotinoyl-3m"i nn 1 of ul 1 Vicin 7nacurc»- cifiri opf ov

Prepared analogously to example 20 from 5-bromo-2-(3,5-cis-dimethyl-piperidino)-6-methyl-nicotinic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester hydrochloride.

Yield: 43% of the theoretical,

Melting point: <2 0°C

Example 2 9

4-[2-(5-Chloro-6-methyl-2-piperidino-nicotinoylamino)ethyl]-benzoic acid

1.65 g (3.97 mmol) of 4-[2-(5-chloro-6-methyl-2-piperidino-nicotinoylamino)ethyl]benzoic acid methyl ester is dissolved in 100 ml of methanol and stirred for 12 hours at 40°C after addition of 25 ml of 1 N caustic soda. It is then evaporated in a vacuum. The evaporation residue is dissolved in water, filtered, and 25 ml of IN hydrochloric acid is added to the filtrate. The formed precipitate is suctioned off and recrystallized from acetonitrile.

Yield: 1.1 g (58.75% of theoretical),

Melting point: 18.5-187°C

Example 3 0

4-[2-(6-methyl-2-piperidino-nicotinoylamino)ethyl]benzoic acid Prepared analogously to example 29 by alkaline saponification of 4-[2-(6-methyl-2-piperidino-nicotinoylamino)ethyl]benzoic acid methyl ester.

Yield: 92% of the theoretical,

Melting point: . 152-154°C

Example 31

4-[ 2-( 5- chloro- 2-( octahydro- 1H- azonino)- nicotinoylamino) ethyl]-benzoic acid

Prepared analogously to example 29 from 4-[2-(5-chloro-2-(octahydro-1H-azonino)-nicotinoylamino)ethyl]benzoic acid ethyl ester by alkaline saponification.

Yield: 83.3% of the theoretical,

Melting point: 169-170°C

Example 32

4-[ 2-( 5- bromo- 2- piperidino-nicotinoylamino) ethyl] benzoic acid

Prepared analogously to example 29 from 4-[2-(5-bromo-2-piperidino-nicotinoylamineb)ethyl]benzoic acid ethyl ester by alkaline saponification.

Yield: 93.5% of the theoretical,

Melting point: 175-177°C

Example 33

4-[ 2-[ 5- chloro- 2-( cis- 3, 5- dimethyl-piperidino)- nicotinoylamino]-ethyl] benzoic acid

Prepared analogously to example 29 by alkaline saponification of 4-[2-[5-chloro-2-(cis-3,5-dimethyl-piperidino)-nicotinoylamino] ethyl ] benzoic acid ethyl ester.

Yield: 76% of the theoretical,

Melting point: 191-193°C

Example 34 4.-. L2 - ( 5- chloro- 2- piper idino-nicotinoylamino) ethyl ] benzoic acid

Prepared analogously to example 29 by alkaline saponification of 4-[2-(5-chloro-2-piperidino-nicotinoylamino)ethyl]benzoic acid methyl ester.

Yield: 82% of the theoretical,

Melting point: 164-166°C

Example 35 4-[2-(5-bromo-6-methyl-2-piperidino-nicotinoylamino)ethyl]benzoic acid.

Prepared analogously to example 29 from 4-[2-(5-bromo-6-methyl-2-piperidirio-nicotinoylamino)ethyl]benzoic acid ethyl ester by alkaline saponification.

Yield: 85.5% of the theoretical,

Melting point: 199-201°C

Example 36

4-[ 2-[ 5- chloro- 2-( 3, 5- cis- dimethyl- piperidino)- 6- methyl- nicotinoylamino] ethyl] benzoic acid

Prepared analogously to example 29 from 4-[2-[5-chloro-2-(3,5-cis-dimethyl-piperidino)-6-methyl-nicotinoylamino]ethyl]benzoic acid ethyl ester by alkaline saponification.

Yield: 71% of the theoretical,

Melting point: 192-193°C

Example 37

4-[ 2-[ 5- bromo- 2-( 3, 5- cis- dimethyl- piperidino)- 6- methyl- nicotinoylamino] ethyl] benzoic acid

Prepared analogously to example 29 from 4-[2-[5-bromo-2-(3,5-cis-dimethyl-piperidino)-6-methyl-nicotinoylamino]ethyl]benzoic acid ethyl ester by alkaline saponification.

Yield: 99% of the "theoretical,

Melting point: 203-204°C

Example 38

4-[ 2-[( 2- piperidino- pyridyl- 3) acetylamino] ethyl] benzoic acid ethyl ester

Prepared from [2-piperidino-pyridyl-(3)]acetic acid and 4-(2-amino-ethyl)benzoic acid ethyl ester analogously to example 20. Yield: 84% of the theoretical,

Melting point: 103-104°C

Example 3 9

4-[(2-piperidino-pyridyl-3)acetylamino-methyl]benzoic acid ethyl ester.

Prepared from [2-piperidino-pyridyl-(3)]acetic acid and 4-amino-methyl-benzoic acid ethyl ester analogously to example 20. Yield: 86% of the theoretical,

Melting point: 68-71°C

Example 4 0

4-[ 2-[( 5- chloro- 2- piperidino- pyridyl- 3) acetylamino] ethyl] benzoic acid ethyl ester

Prepared from [5-chloro-2-piperidino-pyridyl-(3)]acetic acid

and 4-(2-aminoethyl)-benzoic acid ethyl ester analogously to example 20. Yield: 86% of the theoretical,

Melting point: 115-117°C

Example 41

4-[ 2-[( 2- piperidino- pyridyl- 3) acetylamino] ethyl] benzoic acid

Prepared from 4-[2-[(2-piperidino-pyridyl-3)acetylamino]-ethyl]benzoic acid ethyl ester by alkaline saponification analogously to example 29.

Yield: 60% of the theoretical,

Melting point: 153-155°C

Example 4 2

4-[(2-piperidino-pyridyl-3)acetylaminomethyl]benzoic acid Prepared by alkaline saponification of 4-[(2-piperidino-pyridyl-3)acetylaminomethyl]benzoic acid ethyl ester analogously to example 29.

Yield: 74% of the theoretical,

Melting point: 180-182°C

Example 4 3 4— [2-[(5-chloro-2-piperidino-pyridyl-3)acetylamino]ethyl]benzoic acid

Prepared by alkaline saponification of 4-[2-[(5-chloro-2-piperidino-pyridyl-3)acetylamino]ethyl]benzoic acid ethyl ester analogously to example 29.

Yield: 85% of the theoretical,

Melting point: 182-184°C

Example 4 4 4-[(5-chloro-^2-piperidino-phenyl)-acetylamino-methyl]benzoic acid ethyl ester

Prepared analogously to example 1 from (5-chloro-2-piperidino-phenyl)acetic acid and 4-aminomethyl-benzoic acid ethyl ester.

Yield:' 64. % of the theoretical,

Melting point: 112°C

Example 45

4-[ 2-[( 5- chloro- 2- piperidino- phenyl)- acetylamino] ethyl] benzoic acid ethyl ester

Prepared analogously to example 1 from (5-chloro-2-piperidino-phenyl)acetic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester. Yield: 74% of the theoretical,

Melting point: 187-18 9°C

Example 4 6

4-[(5-chloro-2- octahydro-1H-azonino-phenyl)-acetylaminomethyl]-benzoic acid ethyl ester

Prepared analogously to example 1 from (5-chloro-2-octahydro-1H-azonino-phenyl)acetic acid and 4-amino-methyl-benzoic acid ethyl ester. Yield: 85% of the theoretical,

Melting point: <2 0°C

Example 47

4-[ 2-[( 5- chloro- 2- octahydro- 1H- azonino- phenyl)- acetylamino] ethyl]-benzoic acid ethyl ester

Prepared analogously to example 1 from (5-chloro-2-octahydro-1H-azonino-phenyl)acetic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester. Yield: 59% of the theoretical,

Melting point: <2 0°C

Calculated: -Moltop: m/e = 47 0/2

Found: Mole top: m/e = 470/2

Calculated: C 68.84 H 7.49 N 5.95

Found: 68.17 7.14 5.75

Example 48

4- [ ( 5- chloro- 2-( octahydro- isoindol- 2- yl)- phenyl)- acetylaminomethyl] benzoic acid ethyl ester

Prepared analogously to example 1 from [5-chloro-2-(octahydro-isoindol-2-yl)-phenyl]acetic acid and 4-amino-methyl-benzoic acid ethyl ester. Yield: 45% of the theoretical,

Melting point: 17 2°C

Example 49 4-[ 2-[(5-chloro-2-(octahydro-isoindol-2-y1)-phenyl)-acetylamino]-ethyl] benzoic acid ethyl ester.-Prepared analogously to example 1 from [5-chloro-2 -(octahydro-isoindol-2-yl)-phenyl]acetic acid and 4-(2-aminoethyl)benzoic acid ethyl ester.

Yield: 12.5% of the theoretical,

Melting point: 102°C

Calculated: Mole top: m/e - 468/2 .

Found: Mole top: m/e = 4 68/2

Example 5 0

DL- 4- [ ( 2-( 5^- chloro- 2- piperidino- phenyl) propionylamino) methyl] - benzoic acid ethyl ester

Prepared analogously to example 20 from 2-(5-chloro-2-piperidino-phenyl)propionic acid and 4-aminomethyl-benzoic acid ethyl ester. Yield: 46% of the theoretical,

Melting point: <20°C

Calculated: Mole top: m/e = 428/3 0

Found: Mole top: m/e = 428/30

Example 51 DL- 4-[ 2- [ 2-( 5- chloro- 2- piperidino^- phenyl) propionylamino] ethyl] - benzoic acid ethyl ester

Prepared analogously to example 20 from 2-(5-chloro-2-piperidino-phenyl)propionic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester. Yield: 52% of the theoretical,

Melting point: <20°C

Calculated: Mole top: m/e = 442/44

Found: Mole top: m/e = 4 4 2/4 4

Example 52

DL- 4-[ 2-[ 2-( 5- chloro- 2- octahydro- 1H- azonino- phenyl)- propionyl-■ amino] ethyl] benzoic acid ethyl ester

Prepared analogously to example 1 from 2-(2-octahydro-1H-azonino-5-chloro-phenyl)propionic acid and 4-(2-aminoethyl)benzoic acid ethyl ester.

Yield: 43% of the theoretical,

Melting point: <2 0°C

Example 53

DL- 4-[ 2-[( 2- piperidino-diphenyl)- acetylamino] ethyl] benzoic acid ethyl ester

Prepared from (2-piperidino-diphenyl)-acetic acid and 4-(2-aminoethyl)benzoic acid ethyl ester analogously to example 20. Yield: 36% of the" theoretical,

Melting point: 84-85°C

Example 54

DL- 4-[( 2- piperidino- diphenyl)- acetylamino- methyl] benzoic acid ethyl ester

Prepared from .(2-piperidino-diphenyl)acetic acid and 4-amino-methyl-benzoic acid ethyl ester analogously to example 20. Yield: 43% of the theoretical,

Melting point: 137-139°C

Example 55

4-[ 2-[( 5- chloro- 2- pyrrolidino- phenyl)- acetylamino] ethyl] benzoic acid ethyl ester

Prepared analogously to example 1 from (5-chloro-2-pyrrolidino-phenyl)-acetic acid and 4-(2-aminoethyl)benzoic acid ethyl ester. Yield: 75% of the theoretical,

Melting point: 126-127°C

Example 56 4-[2-[(5-chloro-2-hexamethyleneimino-phenyl)-acetylamino] ethyl]-benzoic acid ethyl ester

Prepared analogously to example 1 from (5-chloro-2-hexamethylene-iminophenyl)-acetic acid and 4-(2-amino-ethyl)benzoic acid ethyl ester. Yield: 51% of the theoretical,

Melting point: 102-104°C

Example 57

4- [ 2-[( 5- chloro- 2- heptamethyleneimino- phenyl) acetylamino] ethyl]-benzoic acid ethyl ester

Prepared analogously to example 1 from (5-chloro-2-heptamethyleneimino-phenyl)-acetic acid and 4-(2-amino-ethyl)benzoic acid ethyl ester. Yield: 57% of the theoretical,

Melting point: 95.96°C

Example 58

4-[ 2-( 2- octahydro- 1H- azonino- benzoylamino) ethyl] benzoic acid ethyl ester

Prepared analogously to example 1 from 2-octahydro-1H-azonino-benzoic acid and 4-(2-amino-ethyl)benzoic acid ethyl ester. Yield: 53% of the theoretical,

Melting point: <20°C

Calculated: Mole top: m/e =4 22

Found: Mole top: m/e =4 22

Example 59

4-[ 2-( 5- chloro- 2-( 2, 3, 3a, 4, 7, 7a- hexahydro- 1H- isoindol- 2- yl)-benzoylamino) ethyl] benzoic acid ethyl ester

Prepared analogously to example 1 from 5-chloro-2-(2,3,3a,4,7,7a-hexahydro-1H-isoindol-2-yl)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid- ethyl ester.

Yield: 57% of the theoretical,

Melting point: 17 2°C

Example 6 0 4-[2-(5-chloro-2-(1,3-dihydro-isoindol-2-yl)-benzoylamino)ethyl]-benzoic acid ethyl ester Prepared analogously to example 1 from 5-chloro-2-( 1,3-dihydroisoindol-2-yl)-benzoic acid and 4-(2-amino-ethyl)benzoic acid ethyl ester. Yield: 40% of the theoretical, Melting point: 158°C

Example 61

4-[(5-chloro-2-piperidino-phenyl)-acetylaminomethyl]benzoic acid

Prepared analogously to example 5 by alkaline hydrolysis of 4-[(5-chloro-2-piperidino-phenyl)-acetylaminomethyl]benzoic acid ethyl ester.

Yield: 92% of the theoretical,

Melting point: 18 7-18 9°C

Example 62

4-[(2-piperidino-phenyl)-acetylaraino-methyl]benzoic acid

1 g (2.6 mmol) of 4-[(5-chloro-2-piperidino-phenyl)-acetylaminomethyl] benzoic acid is dissolved in 100 ml of methanol and hydrogenated at a hydrogen pressure of 5 bar at room temperature. 10% palladium/coal is used as a catalyst. After completion of hydrogen absorption, the catalyst is separated, the solvent is distilled off

on a rotary evaporator, and the dry residue is dissolved in water. Extraction is carried out at pH 6 with chloroform, and after drying, the chloroform evaporation residue is treated with petroleum ether/ether. Yield: 0.5 g (55% of theoretical),

Melting point: 18 0°C

Example 63

4-[ 2-[( 5-chloro-2-piperidino-phenyl)-acetylamino] ethyl] benzoic acid Prepared analogously to example 5 by alkaline hydrolysis of

4— [ 2— [" ( 5-chloro-2-piperidino-phenyl)-acetylamino] ethyl ] benzoic acid ethyl ester.

Yield: 95% of the theoretical, Melting point: 16 9-17 0°C

Example 64

4-[ 2-[( 2- piperidino-phenyl)- acetylamino] ethyl] benzoic acid

Prepared analogously to example 62 by catalytic dehalogenation of 4-[2-[(5-chloro-2-piperidino-phenyl)-acetylamino]-ethyl]-benzoic acid.

Yield: 55% of the'theoretical,

Melting point: 154°C

Example 65

4-[(5-chloro-2-octahydro-1H-azonino-phenyl)-acetylaminomethyl]-benzoic acid

Prepared analogously to example 5 by alkaline hydrolysis of 4-[(5-chloro-2-octahydro-1H-azonino-phenyl)-acetylaminomethyl]-benzoic acid ethyl ester.

Yield: 91% of the theoretical,

Melting point: 191°C

Example 66

4-[( 2- octahydro- 1H- azonino- phenyl)- acetylaminomethyl] benzoic acid

Prepared analogously to example 6 2 by catalytic dehalogenation of 4-[(5-chloro-2-octahydro-1H-azonino-phenyl)-acetylaminomethyl]benzoic acid.

Yield: 55% of the theoretical,

Melting point: 150°C

Example 67

4-[ 2-[( 5- chloro- 2- octahydro- 1H- azonino- phenyl)- acetylamino] ethyl]-benzoic acid

Prepared analogously to example 5 by alkaline hydrolysis of 4-[2-[(5-chloro-2-octahydro-1H-azonino-phenyl)-acetylamino]ethyl]-benzoic acid ethyl ester.

Yield: 88% of the theoretical,

Melting point: 179°C

Example 68

4-[2-[(2-octahydro-1H-azonino-phenyl)-acetylamino]ethyl]benzoic acid Prepared analogously to example 62 by catalytic dehalogenation of 4-[2-[(5-chloro-2-octahydro-1H-azonino) -phenyl)-acetylamino]ethyl]benzoic acid.. Yield: .55% of the theoretical,

Melting point: 154°C

Example 6 9

4 - [ ( 5- chloro- 2- ( ok. tahydro- isoindol- 2- yl) - phenyl) - acetylaminomethyl ] benzoic acid-

Prepared analogously to example 5 by alkaline hydrolysis of 4-[(5-chloro-2-(octahydro-isoindol-2-yl)-phenyl)-acetylaminomethyl]benzoic acid ethyl ester.

Yield: 78% of the theoretical,

Melting point: 200°C

Example 70

DL- 4- [ ( 2- ( 5- chloro- 2- piperidino- phenyl) propionylamino)' methyl ] - benzoic acid

Prepared analogously to example 5 by alkaline hydrolysis of 4-[(2-(5-chloro-2-piperidino-phenyl)propionylamino)methyl]benzoic acid ethyl ester.

Yield: 65% of the theoretical,

Melting point: 170°C

Example 71

DL- 4-[ 2-( 2-piperidino-phenyl) propionylamino) methyl] benzoic acid Prepared analogously to example 62 by catalytic hydrogenation of 4-[(2-(5-chloro-2-piperidino-phenyl)propionylamino)- methyl]benzoic acid.

Yield: 60% of the theoretical,

Melting point: 12 5°C

Example 7 2

DL- 4-[ 2-[ 2-( 5- chloro- 2- piperidino- phenyl) propionylamino] ethyl] benzoic acid

Prepared analogously to example 5 by alkaline hydrolysis of DL-4-[2-[2-(5-chloro-2-piperidino)-phenyl)propionylamino]ethyl]-benzoic acid ethyl ester.

Yield: 73% of the theoretical,

Melting point: 174°C

Example 73

DL- 4-[ 2-[ 2-( 2-piperidino-phenyl) propionylamino] ethyl] benzoic acid

Prepared analogously to Example 62 by catalytic dehalogenation of DL-4-[2-[2-(5-chloro-2-piperidino-phenyl)propionylamino]ethyl]benzoic acid.

Yield: 7 0% of the theoretical,

Melting point: 151°C

Example 7 4 DL- 4-[ 2-[ 2-( 5- chloro- 2- octahydro- 1H- azonino- phenyl)- propionylamino] ethyl] benzoic acid

Prepared analogously to example 5 by alkaline hydrolysis of DL-4-[2-[2-(5-chloro-2-octahydro-1H-azonino-phenyl)propionylamino]ethyl]benzoic acid ethyl ester.

Yield: 65% of the theoretical,

Melting point: 1.68-170°C

Example 75

DL- 4-[ 2-[ 2-( 2- octahydro- 1H- azonino- phenyl) propionylamino] ethyl]-benzoic acid

Prepared analogously to example 62 by catalytic dehalogenation of DL-4-[2-[2-(5-chloro-2-octahydro-1H-azonino-phenyl)-propionylamino]ethyl]benzoic acid.

Yield': 64% of the theoretical,

Melting point: 152-154°C

Example 7 6 DL- 4-[ 2-[(2-piperidino-diphenyl)-acetylamino] ethyl] benzoic acid-Prepared by alkaline saponification of 4-[2-[(2-piperidino-diphenyl)-acetylamino] ethyl] benzoic acid -ethyl ester analogously to example 29.

Yield: 64% of the theoretical,

Melting point: 166-168°C

Example 77

DL- 4 - ( 2- piperidino-diphenyl)- acetylaminomethyl) benzoic acid

Prepared by alkaline saponification of 4-(2-piperidino-diphenyl)-acetylaminomethyl)benzoic acid ethyl ester analogously to example 29.

Yield: 75% of the theoretical,

Melting point: 2 2 0-222°C

Example 78

4-[2-[(5-chloro-2-hexamethyleneimino-phenyl)-acetylamino]'ethyl]-benzoic acid

Prepared analogously to example 5 by alkaline hydrolysis of 4-[2-[(5-chloro-2-hexamethyleneimino-phenyl)-acetylamino]ethyl]-benzoic acid ethyl ester.

Yield: 42% of the theoretical,

Melting point: 168°C

Example 7 9

4-[ 2-[( 2- hexamethyleneimino-phenyl)- acetylamino] ethyl] benzoic acid

Prepared analogously to example 62 by catalytic dehalogenation of 4-[2-[(5-chloro-2-hexamethyleneimino-phenyl)-acetyl-

aminoj ethyl]benzoic acid.

Yield: 70% of the theoretical,

Melting point: 14 4°C

Example 8 0

4-[ 2- [ ( 5- chloro- 2- pyrrolidino- phenyl)- acetylamino] ethyl] benzoic acid

Prepared analogously to example 5 by alkaline hydrolysis of 4-[2-[(5-chloro-2-pyrrolidino-phenyl)-acetylamino]ethyl]benzoic acid ethyl ester.

Yield: 86% of the theoretical,

Melting point: 174-176°C

Example 81

4-[ 2-[( 2- pyrroiidino- phenyl)- acetylamino] ethyl] benzoic acid

Prepared analogously to example 62 by catalytic dehalogenation of 4-[2-[(5-chloro-2-pyrrolidino-phenyl)-acetylamino]-ethyl]benzoic acid.

Yield: 3-7% of the theoretical,

Melting point: 150-152°C

Example 82

4-[ 2-[( 5- chloro- 2- heptamethyleneimino- phenyl)- acetylamino] ethyl]-benzoic acid

Prepared analogously to example 5 by alkaline hydrolysis of 4-[2-[(5-chloro-2-heptamethyleneimino-phenyl)-acetylamino]ethyl]-benzoic acid ethyl ester.

Yield: 43% of the theoretical,

Melting point: 188<Q>C

Example 83

4-[ 2-[( 2- heptamethyleneimino-phenyl)- acetylamino] ethyl] benzoic acid

Prepared analogously to example 62 by catalytic dehalogenation of 4-[2-[(5-chloro-2-heptamethyleneimino-phenyl)-acetylamino] ethyl ] benzoic acid.

Yield: 73% of the theoretical,

Melting point: 152-154°C

Example 84

DL- 4-[ 2-[ 2-( 2- pyrrolidino-phenyl) propionylamino] ethyl] benzoic acid ethyl ester

Prepared from DL-2-(2-pyrrolidino-phenyl)propionic acid and 4-(2-aminoethyl)benzoic acid ethyl ester analogously to example 1. Yield: 64% of the theoretical,

Melting point: <20°C

Calculated: Mole top: m/e =3 94

Found: Mole top: m/e =3 94

Example 8 5

DL- 4-[[ 2-( 2- pyrrolidino-phenyl) propionylamino] methyl] benzoic acid ethyl ester

Prepared from DL-2-(2-pyrrolidino-phenyl)propionic acid and 4-amino-methyl-b.enzoic acid ethyl ester analogously to example 1. Yield: 58% of the theoretical,

Melting point: <20°C Calculated: Mole peak: m/e =38 0

Found: Mole top: m/e = 380

Example 8 6

DL- 4-[ 2-[ 2-( 2- hexamethyleneimino-phenyl) propionylamino] ethyl]-benzoic acid ethyl ester

Prepared from DL-2-(2-hexamethyleneimino-phenyl)propionic acid and 4-(2-amino-ethyl)benzoic acid ethyl ester analogously to example 1. Yield: 72% of the theoretical,

Melting point: <2 0°C

Calculated: Mole top: m/e = 422

Found: Mole top: m/e = 422

Example 87

DL- 4-[[ 2-( 2- hexamethyleneimino-phenyl) propionylaminojmethyl]-benzoic acid ethyl ester

Prepared from DL-2-(2-hexamethyleneimino-phenyl)propionic acid and 4-(aminomethyl)benzoic acid ethyl ester analogously to example I. Yield: 6 9% of the theoretical,

Melting point: <2 0°C

Calculated: Mole top: m/e =4 08

Found: Mole top: m/e =4 08

Example 88 DL- 4-[ 2-[( 2-pyrrolidino-diphenyl)-acetylamino] ethyl] benzoic acid ethyl ester Prepared from (2-pyrrolidino-diphenyl)-acetic acid and 4-(2-aminoethyl)benzoic acid ethyl ester analogously to example 20. Yield: 51% of theoretical, Melting point: 89-92°C

Example 89

DL- 4-[ 2-[( 2- hexamethyleneimino- diphenyl)- acetylamino] ethyl]-benzoic acid ethyl ester

Prepared from (2-hexamethyleneimino-diphenyl)-acetic acid and 4-(2-aminoethyl)-benzoic acid ethyl ester analogously to example 20.

Yield: 49% of the theoretical,

Melting point: 8 0-8 3°C

Example 90

4- [ 2- ( 2- octahydro- 1H- az. onino- benzoylamino) ethyl ] benzoic acid

Prepared analogously to example 5 by alkaline hydrolysis of 4-[2-(2-octahydro-1H-azonino-benzoylamino)ethyl]benzoic acid ethyl ester.

Yield: 71% of the theoretical,

Melting point: 154-156°C

Example 91

4-[ 2-( 5- chloro- 2-( 2, 3, 3a, 4, 7, 7a- hexahydro- 1H- isoindol- 2- yl)-benzoylamino) ethyl] benzoic acid hemihydrate

Prepared analogously to example 5 by alkaline hydrolysis of 4-[2-N5-chloro-2-(2,3,3a,4,7,7a-hexahydro-1H-isoindol-2-yl)-benzoylamino)ethyl]benzoic acid -ethyl ester.

Yield: 86% of the theoretical,

Melting point: 90°C decomposition

Example 92

4-[ 2-( 5- chloro- 2-( 1, 3- dihydro- isoindol- 2- yl)- benzoylamino) ethyl] benzoic acid

Prepared analogously to example 5 by alkaline hydrolysis of 4-[2-(5-chloro-2-(1,3-dihydro-isoindol-2-yl)-benzoylamino)ethyl]-benzoic acid ethyl ester.

Yield: 74% of the theoretical,

Melting point: 224-226°C

Example 93

5- amino- 2-( 2- azabicyclo[ 3. 3. 1] nonan- 2- yl)- benzoic acid

11 g of 2-(2-azabicyclo-[3.3.1]nonan-2-yl)-5-nitro-benzoic acid are dissolved in 100 ml of dimethylformamide, and hydrogenated at a hydrogen pressure of 5 bar with 10% palladium charcoal as a catalyst at room temperature. After completion of hydrogen absorption, the catalyst is filtered off, the solvent is distilled in vacuum, and the residue is brought to crystallization with ethanol/petroleum ether. Yield: 7.5 g (76% of theoretical),

Melting point: 215-217°C

Example 94 5-amino-2-[4-(3-pentyl)-piperidino]benzoic acid Prepared analogously to example 93 by catalytic hydrogenation of 5-nitro-2-[4-(3-pentyl)-piperidino]benzoic acid. Yield: 94.1% of the theoretical, Melting point: 218°C

Example 9 5

5-amino-2-[4-(5-nonyl)-piperidino]benzoic acid

Prepared analogously to example 93 by catalytic hydrogenation of 5-nitro-2-[4-(5-nonyl)-piperidino]benzoic acid. Yield: 85% of the theoretical,

Melting point: 130°C

Example 9 6

5-amino-2-(octahydro-isoindol-2-yl)-benzoic acid

Prepared analogously to example 93 by catalytic hydrogenation of 5-nitro-2-(octahydro-isoindol-2-yl)-benzoic acid. Yield: 78.7% of the theoretical,

Melting point: 244-245°C

Example 97 5-amino-2-(1,3-dihydro-isoindol-2-yl)-benzoic acid Prepared by catalytic hydrogenation of 2-(1,3-dihydroisoindol-2-yl)-5-nitro-benzoic acid analogously to example 93. Yield: 54% of theoretical, Melting point: 26 0°C

Example 98

5- amino- 2-( 2, 3, 3a, 4, 7, 7a- hexahydro- 1H- isoindol- 2- yl)- benzoic acid

3.4 g (11.8 mmol) of 2-(2,3,3a,4,7,7a-hexahydro-1H-isoindol-2-yl)-5-nitro-benzoic acid are suspended in 32 ml of a mixture of concentrated hydrochloric acid and methanol 1:1 and reduced at 0°C in portions with 15.6 g (69 mmol) tin (II) chloride dihydrate. After the addition has been completed, the mixture is stirred for a few hours at room temperature, diluted with 300 ml H20, the pH value is adjusted to 4 with caustic soda, and extraction is carried out with chloroform. The chloroform extracts are dried, and after distilling off the chloroform in a vacuum, the residue is brought to crystallization in acetone/ether. Yield: 2.3 g (75% of theoretical),

Melting point: 287°C

Calculated: Mole top: m/e =2 58

Found: Mole top: m/e = 258

Example 9 9

(5-amino-2-pyrrolidino-phenyl)acetic acid

Prepared by catalytic hydrogenation of (5-nitro-2-pyrrolidino-phenyl)acetic acid analogously to example 93.

Yield: 7 2% of the theoretical,

Melting point: 158°C

Example 100

. (5-amino-2-heptamethyleneimino-phenyl) acetic acid

Prepared by catalytic hydrogenation of (5-nitro-2-heptamethyleneimino-phenyl)acetic acid analogously to example 93. Yield: 42% of the theoretical,

Melting point: 152-154°C

Example 101

[ 5- amino- 2-( octahydro- isoindol- 2- yl)- phenyl] acetic acid

Prepared by catalytic hydrogenation of [2-(octahydro-isoindol-2-yl)-5-nitro-phenyl]-acetic acid analogously to example 93. Yield: 92% of the theoretical,

Melting point: 202-203°C

Example 102 [5-amino-2-(octahydro-1H-azonino)-phenyl]acetic acid Prepared by catalytic hydrogenation of [2-(octahydro-1H-azonino)-5-nitro-phenyl]acetic acid analogous to example 93. Yield : 74% of the theoretical, Melting point: 187-189°C

Oak. simple 103

(5-amino-2-hexamethyleneimino-phenyl)-acetic acid

Prepared by catalytic hydrogenation of (2-hexamethyleneimino-5-nitrophenyl)-acetic acid analogously to example 93. Yield: 48% of the theoretical,

Melting point: 156°C

(5-amino-2-piperidino-phenyl)-acetic acid

Prepared by catalytic hydrogenation of (5-nitro-2-piperidino-phenyl)-acetic acid analogously to example 93.. Yield: 65% of the theoretical,

Melting point: 179-181°C

Example 105

DL-2-(5-amino-2-piperidino-phenyl)-propionic acid

Prepared from DL-2-(5-nitro-2-piperidino-phenyl)-propionic acid by catalytic hydrogenation analogous to example 93. Yield: 40% of the theoretical,

Melting point: 2 0 7°C

Example 106

DL- 2-( 5- amino- 2- octahydro- 1H- azonino- phenyl)- propionic acid

Prepared from DL-2-(5-nitro-2-octahydro-1H-azonino-phenyl)-propionic acid by catalytic hydrogenation analogously to example 93.

Yield: 19% of the theoretical, Melting point: 218°C

Example 107 DL-2-[5-amino-2-(octahydro-isoindol-2-yl)-phenyl]-propionic acid Prepared by catalytic hydrogenation of DL-2-[5-nitro-2-(octahydro-isoindol-2- yl)-phenyl]propionic acid analogously to example 93.

Yield: 21% of the theoretical,

Melting point: 24 3°C

Example 108

5- chloro- 2-( 2- azabicyclo[ 3. 3. 1] nonan- 2- yl)- benzoic acid

6.5 g (25 mmol) of 5-amino-2-(2-azabicyclo[3.3.1]nonan-2-yl)-benzoic acid are dissolved in 90 ml of semi-concentrated hydrochloric acid and diazotized at 0°C with a solution of 1.5 g (27 mmol) of sodium nitrite in 18 ml of water. The diazonium solution is added dropwise with stirring to a solution of 3 g (30 mmol) of copper (I) chloride in 45 ml of concentrated hydrochloric acid. After the end of nitrogen development, stirring continues for 2 to 3 hours. The chlorine compound is shaken off with chloroform and purified over a silica gel column with

acetic acid ethyl ester as eluent.

Yield: 5.2 g (75% of theoretical),

Melting point: 85-87°C

Example 109

5-chloro-2-[4-(3-pentyl)-piperidino]-benzoic acid

Prepared analogously to example 108 by Sandmeyer reaction starting from 5-amino-2-[4-(3-pentyl)-piperidino]benzoic acid. Yield: 60.6% of the theoretical,

Melting point: 150°C

Example 110

5-chloro-2-[4-(5-nonyl)-piperidino]benzoic acid

Prepared analogously to example 108 by Sandmeyer reaction starting from 5-amino-2-[4-(5-nonyl)-piperidino]benzoic acid. Yield: 58% of the theoretical,

Melting point: 148-150°C

Example 111

5-bromo-2-(octahydro-isoindol-2-yl)-benzoic acid

Prepared analogously to example 108 by Sandmeyer reaction starting from 5-amino-2-(octahydro-isoindol-2-yl)-benzoic acid. Yield: 21% of the theoretical,

Melting point: 176°C

Example 112

5-iodo-2-(octahydro-isoindol-2-yl)-benzoic acid

Prepared analogously to example 108 by Sandmeyer reaction starting from 5-amino-2-(octahydro-isoindol-2-yl)-benzoic acid. Yield: 19% of the theoretical,

Melting point: 174°C

Example 113

5- cyano- 2-( octahydro- isoindole- 2- y1)- benzoic acid

Prepared analogously to example 108 by Sandmeyer reaction starting from 5-amino-2-(octahydro-isoindol-2-yl)-benzoic acid. Dividend: . 33% of the theoretical,

Melting point: 190°C

Example 114

5-fluoro-2-(octahydro-isoindole-2-y1)-benzoic acid

Prepared from 5-amino-2-(octahydro-isoindol-2-yl)-benzoic acid over [5-diazonium-2-(octahydro-isoindol-2-yl)-benzoic acid]tetrafluoroborate [Yield 73%, Melting point: 173°C (decomposition)] and subsequent thermal decomposition.

Yield: 2% of the theoretical,

Calculated: Moltop m/e = 263

Found: Moltop m/e = 263

Example 115

5-hydroxy-2-(octahydro-isoindol-2-yl)-benzoic acid

Prepared from 5-amino-2-(octahydro-isoindol-2-yl)-benzoic acid by diazotization and subsequent boiling of the diazonium salt in 50% sulfuric acid at 80-90°C.

Yield: 61% of the theoretical,

Melting point: 222-223°C

Example 116

5- methoxy- 2-( octahydro- isoindol- 2- yl)- benzoic acid methyl ester

1 g (3.8 mmol) of 5-hydroxy-2-(octahydro-isoindol-2-yl)-benzoic acid in 10 ml of absolute dimethylformamide is transferred to the disodium salt with 0.19 g (8 mmol) of a 50% sodium hydride dispersion and then alkylated with 1.66 g (11.7 mmol) of methyl iodide. Yield: 0.9 g (82% of theoretical),

Melting point: 6 6-6 8°C

Example 117

5-Methoxy-2-(octahydro-isoindol-2-yl)-benzoic acid

Prepared analogously to example 5 by alkaline hydrolysis of 5-methoxy-2-(octahydro-isoindol-2-yl)-benzoic acid methyl ester. Yield: 91% of the theoretical,

Melting point: 132-134°C

Example 118

5-methyl-2-(octahydro-isoindol-2-yl)-benzoic acid

Prepared analogously to example 135 from 3-bromo^4-(octahydro-isoindol-2-yl)-toluene (Melting point: 110-112°C) with butyllithium and subsequent carboxylation.

Yield: 46% of the theoretical,

Melting point: 157-159°C

Example 119

5- chloro- 2-( 2, 3, 3a, 4, 7, 7a- hexahydro- 1H- isoindoi- 2- y1)- benzoic acid

Prepared by Sandmeyer reaction analogous to example 108 starting from 5-amino-2-(2,3,3a,4,7,7a-hexahydro-1H-isoindol-2-yl)-benzoic acid.

Yield: 12% of the theoretical,

Melting point: 201°C

Example 120

2-(2,3,3a,4,7,7a-hexahydro-1H-isoindol-2-yl)-benzoic acid

Prepared from 5-amino-2-(2,3,3a,4,7,7a-hexahydro-1H-isoindol-2-yl)-benzoic acid by diazotization with sodium nitrite and subsequent reduction with copper/hydrochloric acid.

Yield: 5% of the theoretical,

Melting point: 156°C

Example 121

5-acetamino-2-(2,3,3a,4,7,7a-hexahydro-1H-isoindol-2-yl)-benzoic acid

Prepared from 5-amino-2-(2,3,3a,4,7,7a-hexahydro-1H-isoindol-2-yl)benzoic acid by acylation with acetyl chloride in pyridine. Yield: 76% of the theoretical,

Melting point: 226-227°C

Example 122

5- chloro- 2-( 1, 3- dihydro- isoindol- 2- yl)- benzoic acid

Prepared analogously to example 108 by Sandmeyer reaction starting from 5-amino-2-(1,3-dihydro-isoindol-2-yl)-benzoic acid.

Yield: 37% of the theoretical,

Melting point: 16 2°C

Example 123

5- bromo- 2-( 1, 3- dihydro- isoindol- 2- yl)- benzoic acid

Prepared analogously to example 108 by Sandmeyer reaction starting from 5-amino-2-(1,3-dihydro-isoindol-2-yl)-benzoic acid.

Yield: 63% of the theoretical,

Melting point: 178°C

Example 124

2-(1,3-dihydro-isoindol-2-yl)-benzoic acid

Prepared analogously to example 62 by catalytic dehalogenation. of 5-chloro-2-(1,3-dihydro-isoindol-2-yl)-benzoic acid. Yield: 68% of the theoretical,

Melting point: 146-148°C

Example 125

5- amino- 2-( 1, 3- dihydro- 5- chloro- isoindole- 2- yl- benzoic acid

Prepared analogously to example 93 by reduction of 2-(1,3-dihydro-5-chloro-isoindol-2-yl)-5-nitro-benzoic acid with stannous chloride.

Yield: 23% of the theoretical, Melting point: 235°C

Example 126 5-chloro-2-(1,3-dihydro-5-chloro-isoindol-2-yl)-benzoic acid

Prepared analogously to example 108 by Sandmeyer reaction starting from 5-amino-2-(1,3-dihydro-5-chloro-isoindol-2-yl)-benzoic acid.

Yield: 18% of the theoretical, Melting point: 157°C

Example 127 5-amino-2-(1,3-dihydro-5-methoxy-isoindol-2-yl)-benzoic acid

Prepared analogously to example 93 by catalytic hydrogenation of 2-(1,3-dihydro-5-methoxy-isoindol-2-yl)-5-nitro-benzoic acid.

Yield: 75% of the theoretical,

Melting point: 2 02°C

Example 128 5-chloro-2-(1,3-dihydro-5-methoxy-isoindol-2-yl)-benzoic acid

Prepared analogously to example 108 by Sandmeyer reaction starting from 5-amino-2-(1,3-dihydro-5-methoxy-isoindol-2-yl)-benzoic acid.

Yield: 34% of the theoretical,

Melting point: 148°C

Example 12 9 2-(1,3-dihydro-5-me.toxy-isoindol-2-yl)-benzoic acid Prepared analogously to example 62 by catalytic dehalogenation of 5-chloro-2-(1,3-dihydro -5-Methoxy-isoindol-2-yl)-benzoic acid.

Yield: 64% of the theoretical,

Melting point: 14 0°C

Example 13 0

2-[4-(3-pentyl)-piperidino]-benzoic acid

Prepared analogously to example 62 by catalytic dehalogenation of 5-chloro-2-[4-(3-pentyl)-piperidino]benzoic acid. Yield: 31% of the theoretical,

Melting point: 134-136°C

Example 131

5- bromo-- 2-- [ 4- ( 3- pentyl)-piperidino] benzoic acid

Prepared analogously to example 108 by Sandmeyer reaction starting from 5-amino-2-[4-(3-pentyl)-piperidino]benzoic acid. Yield: 21% of it., theoretical ,

Melting point: 157-158°C

Example 132

5-cyano-2-[4-(3-pentyl)-piperidino]benzoic acid

Prepared analogously to example 108 by Sandmeyer reaction starting from 5-amino-2-[4-(3-pentyl)-piperidino]benzoic acid. Yield: 19% of the theoretical,

Melting point: 171°C

Example 13 3

4-[4-(3-pentyl)-piperidino]-isophthalic acid

Prepared by alkaline saponification of 5-cyano-2-[4-(3-pentyl)-piperidino]-benzoic acid analogously to example 5.

Yield: 27.% of the theoretical,

Example 134

5- acetamino- 2-[ 4-( 3- pentyl)-piperidino]- benzoic acid

Prepared from 5-amino-2-[4-(3-pentyl)-piperidino]-benzoic acid by acetylation with acetic anhydride.

Yield: 23% of the theoretical,

Melting point: 26 0-2 63°C

Example 135-

5?methyl-2-(octahydro-1H-azonino)-benzoic acid

3.1 g (10.5 mmol) of 3-bromo-4-(octahydro-1H-azonino)-toluene are dissolved in 100 ml of absolute ether. Under nitrogen, 20 ml of a 15% butyllithium solution in hexane is added dropwise at -50°C. The reaction mixture is then allowed to come to room temperature. The reaction mixture is then quickly added dropwise to a suspension of solid carbon dioxide in absolute ether, and it is stirred overnight. Water is then added, and the pH value is adjusted to 4-5 with diluted hydrochloric acid. After extraction with chloroform, column chromatographic purification is carried out over silica gel (eluent: toluene/acetic acid ethyl ester = 1:1).

Yield: 1.35 g (49.3% of the theoretical),

Melting point: ' 87°C

• Example 136

DL-2-(5-chloro-2-piperidino-phenyl)-propionic acid

Prepared analogously to example 108 by Sandmeyer reaction starting from DL-2-(5-amino-2-piperidino-phenyl)-propionic acid. Yield: 45% of the theoretical,

Melting point: 134-135°C

Example 137

DL- 2-( 5- chloro- 2- octahydro- 1H- azonino- phenyl)- propionic acid

Prepared analogously to example 108 by Sandmeyer reaction starting from DL-2-(5-amino-2-octahydro-1H-azonino-phenyl)-propionic acid.

Yield: 17% of the theoretical,

Melting point: 139-140°C

Example 138

DL- 2-[ 5- chloro- 2-( octahydro- isoindol- 2- yl)- phenyl]- propionic acid

Prepared analogously to example 108 by Sandmeyer reaction starting from DL-2-[5-amino-2-(octahydro-isoindol-2-yl)-phenyl]-propionic acid.

Yield: 27% of the theoretical,

Melting point: 151-152°C

Example 13 9

(5-chloro-2-octahydro-1H-azonino-phenyl)-acetic acid

Prepared analogously to example 108 by Sandmeyer reaction starting from (5-amino-2-octahydro-1H-azonino-phenyl)-acetic acid.

Yield: 58% of the theoretical,

Melting point: 63-65°C

Example 140

(5-chloro-2-heptamethyleneimino-phenyl)-acetic acid

...Prepared analogously to example 108 by Sandmeyer reaction starting from (5-amino-2-heptamethyleneimino-phenyl)-acetic acid. Yield: 43% of the theoretical,

Melting point: 78°C

Calculated: Mole top m/e = 280/2

Found: Mole top m/e = 2 80/2

Example 141

(5-chloro-2-hexamethyleneimino-phenyl)-acetic acid

Prepared analogously to example 108 by Sandmeyer reaction starting from (5-amino-2-hexamethyleneimino-phenyl)-acetic acid. Yield: 77% of the theoretical,

Melting point:' <20°C

Example 142

(5-chloro-2-piperidino-phenyl)-acetic acid

Prepared analogously to example 108 by Sandmeyer reaction

starting from (5-amino-2-piperidino-phenyl)-acetic acid.

Yield: 63% of the theoretical,

Melting point: 105°C

Example 14 3

(5-chloro-2-pyrrolidino-phenyl)-acetic acid

Prepared analogously to example 108 by Sandmeyer reaction starting from (5-amino-2-pyrrolidino-phenyl)-acetic acid. Yield: 54% of the theoretical,

Melting point: 105-107°C

Example 144

[5-chloro-2-(octahydro-isoindol-2-yl)-phenyl]-acetic acid Prepared analogously to example 108 by Sandmeyer reaction starting from f5-amino-2-(octahydro-isoindol-2-yl) )-phenyl]-acetic acid.

Yield: 40% of the theoretical,

Melting point: 156-157°C

Example 14 5

[ 2-( octahydro-isoindol-2-yl)-phenyl]-acetic acid

Prepared analogously to Example 120 from [5-amino-2-(octahydro-indol-2-yl)-phenyl]-acetic acid.

Yield: 15% of the theoretical,

Melting point: 135-136°C

Example 14 6

[ 5- chloro- 2-(- 4-( 3- pentyl)-piperidino)-phenyl]-acetic acid

Prepared analogously to example 108 by Sandmeyer reaction starting from [5-amino-2-(4-(3-pentyl)-piperidino)-phenyl]-acetic acid.

Yield: 17% of the theoretical,

Melting point: <2 0°C

Example 147 .

( 2- piperidino-diphenyl) acetic acid hydrochloride

a) (2-piperidino-diphenyl)acetonitrile

To 17.0 g (52.8 mmol) of 2-piperidino-benzhydryl chloride^

hydrochloride (produced from 2-piperidino-benzhydryl alcohol by treatment with thionyl chloride); 8.5 g (0.17 mol) of sodium cyanide are added to 200 ml of dimethyl sulphoxide and the mixture is stirred for 2 hours at 60-70°C. Cold, diluted caustic soda is then added and extracted with methylene chloride. After adding some activated charcoal, the evaporated extracts are extracted in a warm state with petroleum ether (90-110°C). After evaporation of the petroleum ether extracts, a yellow oil remains.

Yield: 12.7 g (87% of theory), oil.

b) (2-piperidino-diphenyl)-acetic acid hydrochloride

1.5 g (5.4 mmol) of '(2-piperidino-diphenyl)-acetonitrile is boiled

under reflux for 3 hours with 50 ml of concentrated hydrochloric acid. It is then evaporated to dryness and recrystallized from 2 N hydrochloric acid.

Yield: 1.2 g (75.2% of the theoretical),

Melting point: 195-200°C (decomposition)

Example 148

2-( octahydro- i soindol- 2- yl)- nicotinic acid

3.15 g (20 mmol) of 2-chloronicotinic acid and 2.5 g (20 mmol) of octahydroisoindole in 50 ml of ethanol are heated for 18 hours under reflux together with 5.2 g (40 mmol) of N -ethyldiisopropylamine. The reactive ion mixture is then evaporated. taken up in water and 20 mmol of glacial acetic acid are added. Then extract with chloroform.

The dried chloroform extracts are evaporated, and the crystalline residue obtained is recrystallized from acetonitrile.

Yield: 1.8. g (37% of the theoretical),

Melting point: 217-218°C

Example 14 9 5-chloro-2-(octahydro-isoindol-2-yl)-nicotinic acid

Prepared from 2,5-dichloro-nicotinic acid and octahydro-isoindole analogously to example 148.

Yield: 36% of the theoretical,

Melting point: 23 3-23 5°C

Example 150

6- methyl- 2- piperidino- nicotinic acid

Prepared from 2-chloro-6-methyl-nicotinic acid and piperidine analogously to example 148.

Yield: 68% of the theoretical, Melting point: 120-122°C

Example 151

5- Chloro- 6- Methyl- 2- Piperidinenicotinic acid

Prepared from 2,5-dichloro-6-methyl-nicotinic acid and piperidine analogously to example 148.

Yield: 56% of the theoretical,

Melting point: 130-132°C

Example 152

5- chloro- 2- octahydro- 1H- azonino- nicotinic acid

Prepared from 2,5-dichloro-nicotinic acid and octahydro-1H-azonine analogously to Example 148.

Yield: 57% of. the theoretical,

Melting point: 154-156°C

Example 153

5-chloro-2-(cis-3,5-dimethyl-piperidino)-nicotinic acid

Prepared from 2,5-dichloronicotinic acid and cis-3,5-dimethyl-piperidine analogously to example 14 8. Yield: 40% of the theoretical,

Melting point: 78-80°C

Example 154

5-chloro-2-piperidino-nicotinic acid

Prepared from 2,5-dichloronicotinic acid and piperidine analogously to example 14 8.

Yield: 63% of the theoretical,

Melting point: 149-152°C

Example 155

5- bromo- 6- methyl- 2- piperidino- nicotinic acid

Prepared from 5-bromo-2-chloro-6-methyl-nicotinic acid and piperidine

. analogous to example 148.

Yield: 35% of the theoretical,

Melting point: 108-111DC

Example 156

5- bromo- 2- piperidino- nicotinic acid

Prepared from 5-br6m-2-chloro-nicotinic acid and piperidine analogously to example 14 8.

Yield: 43% of the theoretical,

Melting point: . 172-174°C

Example 157

[ 2- Piperidino- pyridyl-(3) acetic acid

Prepared by alkaline saponification of [2-piperidino-pyridyl-(3)]acetic acid ethyl ester with melting point <20°C (prepared from

[2-piperidino-pyridyl-(3)]-acetonitrile by boiling with ethanolic hydrochloric acid) analogously to example 5.

Dividend:. 81% of the theoretical,

Melting point: 112-115°C

Example 158

[5-chloro-2-piperidino-pyridyl-(3)]acetic acid

Prepared by alkaline saponification of [5-chloro-2-piperidino-pyridyl-(3)]acetic acid ethyl ester of melting point <20°C (prepared from [5-chloro-2-piperidino-pyridyl-(3)]acetonitrile by boiling with ethanolic hydrochloric acid) analogously to example 5.

Yield: 89% of the theoretical,

Melting point: 12 4-12 6°C

Example 159

5- chloro- 6- methyl- 2-( cis- 3, 5- dimethyl- piperidino) nicotinic acid

Prepared from 2,5-dichloro-6-methyl-nicotinic acid and cis-3,5-dimethyl-piperidine analogously to example 14 8.

Yield: 18% of the theoretical,

Melting point: <2 0°C

Example 160 5-bromo-6-methyl-2-(cis-3,5-dimethyl-piperidino)nicotinic acid

Prepared from 5-bromo-2-chloro-6-methyl-nicotinic acid and cis-3,5-dimethyl-piperidine analogously to example 14 8.

Yield: 28% of the.theoretical,

Melting point: <20°C

Example 161

1- methyl- 2- piper idino- benzoic acid

Prepared analogously to example 135 by reaction of 3-brorn-2-piperidino-toluene with butyllithium and subsequent carboxylation with carbon dioxide.

Yield: 64% of the theoretical,

Melting point: . 126-128°C

Calculated: Mole top: m/e = 219

Found: Mole top: m/e = 219

Example 162

3-chloro-2-piperidino-benzoic acid

Prepared analogously to example 108 by Sandmeyer reaction starting from 3-amino-2-piperidino-benzoic acid. Yield: 54% of the theoretical,

Calculated: Mole peak: m/e = 239/241 (1 Cl)

Found: Mole top: m/e = 23 9/2 41 (1 Cl)

Example 16 3

3-methyl-2-(octahydro-isoindol-2-yl)-benzoic acid

Prepared analogously to example 135 by reacting 3-bromo-2-(octahydro-isoindol-2-yl)-toluene with butyllithium and subsequent carboxylation with carbon dioxide.

Yield: 53% of the theoretical,

Calculated: C 74.10 H 8.16 N 5.40

Found: 74.27 8.29 5.53

Calculated: Moltop m/e =2 59

Found: Moltop m/e = 259

Example 164

3-chloro-2-(octahydro-isoindol-2-yl)-benzoic acid

Prepared analogously to example 108 by Sandmeyer reaction starting from '3-amino-2-(octahydro-isoindol-2-yl)-benzoic acid. Yield: 59% of the theoretical,

Calculated: C 64.40 H 6.48 Cl 12.67 N 5.00

Found: 64, 27 .6,40 12 , 49! 5.12

Calculated: Mole peak m/e = 279/281 (1 Cl)

Found: Mole peak m/e = 279/281 (1 Cl)

Claims (5)

1. Analogous method for the preparation of therapeutically active carboxylic acid amides of the general formula where m is the number 0 or 1, n. is the number 1 or 2, R is a hydrogen atom or an alkyl group of 1 to 3 carbons atoms, R^ is a hydrogen, fluorine, chlorine, bromine or iodine atom, an alkyl or alkoxy group with 1 to 4 carbon atoms each, a cyano, hydroxy or trifluoromethyl group or one optionally with an alkyl group as well. 1 to 3 carbon atoms, a fluorine, chlorine or bromine atom substituted phenyl group, R 2 and R 3 together with the intervening nitrogen atom are one piperidino-, 3,5-dimethyl-piperidino-, octahydro-1H-azonino-, decahydro-azecino-, 1,3-dihydro-isoindolo-, hexahydro-iso-""' indolo- or octahydro-isoindolo group, one with a alkyl group of 5 to 10 carbon atoms substituted-piperidino group, an azabicycloalkyl group of 7 to 12 carbon atoms in the bicycloalkane ring which may be substituted with one or more alkyl groups of each 1 to 3 carbon atoms; or one optionally with a halogen atom, an alkoxy group with 1 to 3 carbon atoms or an amino group substituted 1,3-dihydroisoihdolo group, or also, when m means the number 1, a pyrroli dino, hexamethyleneimino or heptamethyleneimino group, X is a CH group or a nitrogen atom, Rg is a hydrogen atom, an alkyl group of 1 to 3 carbon atoms or an aryl group, and Z is an optionally esterified carboxy group, and their optically active antipodes, provided they contain an asymmetric carbon atom and their addition salts, especially their physiologically compatible salts with inorganic or organic acids and also bases when Z means a carboxy group, characterized by ata) a carboxylic acid with the general formula ■where R, R-^, R2 / R3 f Rg # X and m are as indicated at the outset, or any reactive derivative thereof produced in the reaction mixture, is reacted with an amine of the general formula where Z and n are as indicated at the outset, or with an N-activated amine of the general formula XII formed in the reaction mixture when a carboxylic acid of the general formula XI is used and when Z in an N-activated amine of the general formula XII does not mean a carboxy group, or b) for the preparation of compounds of the general formula I where X means a CH group and m the number 0, a compound with the general formula is reacted where R, R^, Z and n are as indicated at the outset, and..E means a replaceable residue such as a halogen atom, with an amine of the general formula where 1*2 and R., is as indicated at the outset, or c) for the preparation of compounds of the general formula I where Z means a carboxy group, a compound of the general formula is oxidized where R, R, to R.,, RT0, X, m and n are as indicated at the beginning, and G means a group which can be transferred to a carboxy group by oxidation, or d) for the preparation of compounds of the general formula I.where Z means a carboxy group, one is hydrolysed for bond with the.general formula where R, R^ to R^ , Rg, X, m and n are as indicated at the outset, and Q is a group which can be transferred to a carboxy group by hydrolysis, or e) for the preparation of compounds with the general formula I where X means a CH group and m is 0, an amide with the general formula is reacted where R and R, to R., are as stated at the outset, or its alkali salt, with a connection with.the general formula where Z and n are as indicated at the outset, and Y means a nucleophilic leaving group such as a halogen atom or a sulfonyloxy group, or f) for the preparation of compounds of the general formula I where X means a CH group and Z a carboxy group, a compound of the general formula is acylated Ten where R, R^ to R^ , Rg, m and n are as initially indicated, with an oxalyl halide or phosgene in the presence of eri Lewis acid, or g) for the preparation of compounds of the general formula I where X means a CH groupb g Z a carboxyl group, a compound with the•general formula is reacted where R, R^ to R^/ Rg/ m and n are as indicated at the beginning, with any hypohalogenite produced in the reaction mixture, and a thus prepared compound of formula I where Z is a carboxy group is optionally then transferred by esterification to a corresponding compound of the general formula I where Z means an esterified carboxy group, and/or a prepared compound of the general formula I is optionally transferred to its acid addition salts, in particular to its physiologically compatible salts with inorganic or organic acids and also bases when Z means a carboxy group. 2. Method as stated in claim 1, characterized in that compounds of formula I are prepared where m is the number 0 or 1, n is the number 2, X is a CH group, Z is a carboxy or alkoxycarbonyl group with a total of 2 to 4 carbon atoms, R is a hydrogen atom, Rg is a hydrogen atom, a methyl or phenyl group, R^ in 5-position . is a methyl group, a fluorine or chlorine atom, and R>2 and R^ together with the intervening nitrogen atom is a 2-aza-bicyclo[3.3.1]nonan-2-yl or octahydro-1H-azonino group, their optically active antipodes if they contain an asymmetric carbon atom, and their physiological compatible addition salts with inorganic or organic acids and also bases when Z represents a carboxy group. 3. Process as stated in claim 1, characterized in that 4-[2-[2-(2-azabicyclo[3.3.1]nbnan-2-yl)-5-chloro-benzoylamino]ethyl]benzoic acid, its alkyl esters with 1 to 3 carbon atoms and its addition salts. 4. Process as stated in claim 1, characterized in that 4-[2-[5-fluoro-2-(octahydro-1H-azonino)-benzoylamino]ethyl]-benzoic acid, its alkyl esters with 1 to 3 carbon atoms and its addition salts. 5. Process as set forth in claim 1, characterized by preparing 4-[2-[5-methyl-2-(octahydro-1H-azonino)-benzoylamino]ethyl]-benzoic acid, its alkyl esters with 1 to 3 carbon atoms and its addition salts.