DD210907A5 - PROCESS FOR THE PREPARATION OF PHENYL ACID DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of phenylacetic acid derivatives for use as medicaments. The aim of the invention is the provision of new compounds with stronger blood pressure lowering effect. According to the invention, new phenylacetic acid derivatives d. in which, for example: A represents a group -CH- and the like; R 4 is an optionally substituted alkyl group having 1 to 3 carbon atoms and the like; R 1 is a monoblocksubstituted or disubstituted by alkyl groups having 1 to 3 carbon atoms or less. al .; R deep 2 is a hydrogen, fluorine, chlorine, bromine, iodine atom u. al .; R deep 3 is an alkyl group having 1 to 3 carbon atoms, among others; W is a carboxy group, an alkoxycarbonyl group, among others. The compounds of the formula I can according to analog Verbindg. conventional methods are produced.

Description

Dorlin, 17.11.1983

AP C 07 D / 252 755 62 554/12

Process for the preparation of phenylacetic acid derivatives Field of application of the invention

The invention relates to a process for the preparation of JK

Novon phonylacetic acid derivatives with valuable pharmaco- "

logical properties, in particular with effect on the metabolism, preferably with hypotensive action. The compounds according to the invention are used as medicaments, for example for the treatment of diabetes mellitus,

Characteristic of the known technical solutions

The Journal of Medicinal Chemistry 22_, 750-752 (1979) describes the most similar known compound, namely the two enantiomers of 4-N- / "1- (5-fluoro-2-methoxyphenyl) -oethylamycamoylmethylbenzoic acid.

Based on the above-mentioned reference and 3E-PS 837,311, the methods of the present application are so-called, analogy methods.

Object of the invention

The aim of the invention is the provision of new compounds .with. stronger hypotensive effect,

Presentation of the essence the invention

The invention is based on the object, new compounds

-Ia-

17/11/1983

AP C 07 D / 252 755

62 554/12

with the desired properties and processes for their production.

According to the invention, new phenylacetic acid derivatives of the general formula

Λ - Ml! - CO - CH,

(I)

prepared, their enantiomers and their salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases,

The new compounds have valuable pharmacological properties, in particular an effect on the metabolism, but preferably a blood glucose lowering effect,

In the above general formula 1

A is a group of formulas

R /

CH -

or

-C-

,in which

R. An alkyl group having 1 to 3 carbon atoms optionally substituted by an alkoxy group having 1 to 3 carbon atoms or by a phenyl group, an alkyl group having 4 to 7 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, a cyano or alkyleneiminocarbonyl group having 4 to 6 carbon atoms in the alkylene part, an optionally substituted by alkyl or phenylalkyl groups each having 1 to 3 carbon atoms in the alkyl moiety mono- or disubstituted aminocarbonyl, optionally by Haloqenatome, by alkyl, hydroxy, alkoxy, phenylalkoxy, alkylsulfenyl, alkylsulfinyl and / or Alkylsulfonyl groups mono- or disubstituted aryl group having 6 or 10 carbon atoms, wherein the substituents may be the same or different and each alkyl part may contain 1 to 3 carbon atoms, or a 1 or 2 nitrogen atoms containing heteroaryl group having 4, 5, 8 or 9 carbon atoms,

R and R, which may be the same or different, 5 6

Hydrogen atoms or alkyl groups having 1 to 5 carbon atoms or

r_ and R together with the intermediate coal-5 6,

represent a phenylalkylidene group having 1 to 4 carbon atoms in the alkylidene part,

R is a linear or monosubstituted or disubstituted by alkyl groups having 1 to 3 carbon atoms or alkylenimino group having 4 to 9 carbon atoms or a dialkylamino group each having 1 to 5 carbon atoms in each alkyl part,

R is a hydrogen, fluorine, chlorine, bromine or iodine atom, a hydroxy, trifluoromethyl, nitro, amino, piperidino, alkyl, alkoxy, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, phenylalkoxy, , Alkanoyloxy, alkanoylamino, alkylamino or dialkylamino group, wherein the alkyl portion may each contain 1 to 3 carbon atoms,

R is an alkyl group having 1 to 3 carbon atoms, a hydrogen or halogen atom and

W is a carboxy group or an alkoxycarbonyl group having a total of 2 to 6 carbon atoms, in which the alkyl moiety may be substituted by a phenyl group and from the β-carbon atom by one or two hydroxy groups, by an alkoxy, alkanoyloxy, dialkylamino, alkylenimino or pyridinecarbonyloxy group wherein each alkyl moiety may contain from 1 to 3 carbon atoms and the alkylenimino group may contain from 4 to 6 carbon atoms, an alkenyloxycarbonyl group having from 4 to 6 carbon atoms in total, an alkyl group having from 1 to 3 carbon atoms, hydroxymethyl, formyl, cyano, aminocarbonyl, carboxy methyl, 2-carboxyethyl, 2-carboxy-ethyl, 2,2-bis (carboxy) ethyl, alkoxycarbonyl-methyl, 2-alkoxycarbonyl-ethyl, 2-alkoxycarbonyl-ethenyl or 2, 2-bis (alkoxycarbonyl) ethyl group, wherein the alkoxy group may each contain 1 to 3 carbon atoms.

For the meanings mentioned in the definition of the radicals R ₁ to R _g and W, for example

for R, which is the dimethylamino, diethylamino, di-n-propylamino, di-n-butylamino, di-n-pentylamino, diisobutylamino, N-methyl-ethylamino, N-methyl-n-propylamino -, N-methyl-isopropylamino, N-isopropyl-n-propylamino, N-isobutyl-n-propylamino, N-methyl-n-butylamino, N-ethyl-n-butylamino, N-ethyl-isopropylamino , N-ethyl-n-pentylamino, N-propyl-n-butylamino, pyrrolidino, piperidino, hexamethyleneimino, heptamethyleneimino, octamethyleneimino,

-A-

Nonamethyleneimino, methylpyrrolidino, dimethylpyrrolidino, ethylpyrrolidino, methylpiperidino, ethylpiperidino, dimethylpiperidino, diethylpiperidino, methylethylpiperidino, n-propylpiperidino, methyl -n-propylpiperidino, isopropyl-piperidino or di-n-propyl-piperidino group,

for R _2, those of the hydrogen, fluorine, chlorine, bromine or iodine atom, the methyl, ethyl, n-propyl, isopropyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, , Trifluoromethyl, nitro, amino, piperidino, methylmercapto, ethylmercapto, η-propylmercapto, isopropylmercapto, methylsulfinyl, ethylsulfinyl, methylsulfonyl, n-propylsulfonyl, benzyloxy, 1-phenylethoxy, 2-phenylethoxy, 3-phenylpropoxy, acetoxy, propionyloxy, formylamino, acetylamino, propionylamino, methylamino, ethylamino, n-propylamino, dimethylamino, diethylamino, di-n- propylamino or methyl-ethylamino group,

for Ro, the hydrogen, fluorine, chlorine or bromine atom, the methyl, ethyl, n-propyl or isopropyl group,

for R _4, the methyl, ethyl, n-propyl, isopropyl, η-butyl, n-pentyl, n-hexyl, methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, 2- Methoxyethyl, 2-ethoxy-ethyl, 3-methoxy-propyl, benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenyl-n-propyl, 2-phenyl-npropyl, 3-phenylpropyl- , Allyl, 3-buten-1-yl, 2-butene-1

yl, 4-penten-1-yl, cyano, carboxy, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, di-n-propylaminocarbonyl, benzylaminocarbonyl, 2-Phenylethylaminocarbonyl, pyrrolidinocarbonyl, piperidinocarbonyl, hexamethyleneiminocarbonyl, phenyl, naphthyl, fluorophenyl, chlorophenyl, bromophenyl, methylphenyl, ethylphenyl, isopropylphenyl, hydroxyphenyl, methoxyphenyl, ethoxyphenyl, n-propoxyphenyl , Benzyloxyphenyl, 2-phenylethoxy-phenyl, 3-phenylpropoxy-phenyl, methylsulfenyl

phenyl, ethylsulfenyl-phenyl, methylsulfinyl-phenyl, n-propylsulfinyl-phenyl, methylsulfonyl-phenyl, ethylsulfonyl-phenyl, isopropylsulfonyl-phenyl, methylnaphthyl, hydroxy-naphthyl, methoxynaphthyl, Dichlorophenyl, chlorobromophenyl, dimethylphenyl, diisopropylphenyl, chloromethylphenyl, dimethoxyphenyl, methylmethoxyphenyl, chloro-methoxy-phenyl, bromomethoxy phenyl, pyridyl, pyrimidyl, quinolyl, isoquinolyl or quinazolyl group,

for R ₁ . and R is the hydrogen atom, the methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, see. Butyl or n-pentyl group,

for R _r and R together with the intermediate 5 6

Carbon atom of the benzylidene, 1-phenyl-ethylidene, 2-phenyl-ethylidene, 1-phenyl-n-propylidene, l-phenyl-2,2-propylidene or 3-phenyl-n-propylidengruppe and

for W, the hydroxymethyl, formyl, carboxy, carboxymethyl, 2-carboxy-ethyl, 2-carboxy-ethyl, 2,2-bis (carboxy) -ethyl, methoxycarbonyl, ethoxycarbonyl, n -Propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, n-pentoxycarbonyl, allyloxycarbonyl, crotyloxycarbony.l, (2-hydroxyethoxy) carbonyl, (2-hydroxy-propoxy) carbonyl, (1-hydroxy -2-propoxy) carbonyl, (2-methoxyethoxy) carbonyl, (2-ethoxyethoxy) carbonyl, (2-n-propoxyethoxy) carbonyl, (2-nicotinoyloxyethoxy) carbonyl, (2-isonicotinoyloxy) ethoxy) carbonyl, (2,3-dihydroxy-n-propoxy) carbonyl, (2-dimethylamino-ethoxy) carbonyl, (2-diethylaminoethoxy) carbonyl, (2-piperidinoethoxy) carbonyl, methyl, Ethyl, n-propyl, isopropyl, cyano, aminocarbonyl, methoxycarbonyl-methyl, ethoxycarbonyl-methyl, n-propoxycarbonyl-methyl, 2-methoxycarbonyl-ethyl, 2-ethoxycarbonyl-ethyl, 2- isopropoxycarbonyl

ethyl, 2-methoxycarbonyl-ethenyl, 2-ethoxycarbonyl-ethenyl, 2-n-propoxycarbonyl-ethenyl, 2,2-bis (methoxycarbonyl) -ethyl, 2,2-bis (ethoxycarbonyl) -ethyl - or 2,2-bis (isopropoxycarbonyl) ethyl group into consideration.

Preferred compounds of the above general formula I are those in which

A is a group of formulas

^R 4 ^C

I Il

CH- or - C -, where

R _{4 is} an alkyl group having 1 to 3 carbon atoms substituted by an alkoxy group having 1 to 3 carbon atoms or by a phenyl group, an n-propyl group, an alkyl group having 4 to 6 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, a cyano or An aminocarbonyl group, one by halogen atoms, by alkyl, hydroxy, alkoxy, phenylalkoxy and / or Alkylsulfenylgruppen mono- or disubstituted aryl group having 6 or 10 carbon atoms, wherein the substituents may be identical or different and the alkyl moiety each containing 1 to 3 carbon atoms may be a naphthyl, pyridyl, quinolyl or isoquinolyl group,

r_ and R _r together with the intervening coal 5 b

represent an alkylidene group having 3 to 9 carbon atoms or a phenylalkylidene group having 1 to 3 carbon atoms in the alkylene,

R _{1 is} an unbranched alkylenimino group having 4 to 8 carbon atoms or a piperidino group mono- or disubstituted by alkyl groups having in each case 1 to 3 carbon atoms,

R is a hydrogen, fluorine, chlorine or bromine atom, a nitro, alkyl or alkoxy group each having 1 to 3 carbon atoms or also,

if R ₁ - and R ,. the meanings mentioned above on

and R _{4 is} an alkyl group having 1 to 3 carbon atoms substituted by an alkoxy group having 1 to 3 carbon atoms or a phenyl group, an n-propyl group, an alkyl group having 4 to 6 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, a nitrile or Represents aminocarbonyl group,

an iodine atom, a hydroxy or amino group,

r_ is a hydrogen or chlorine atom and

W is a methyl, hydroxymethyl, formyl, cyano, carboxy, carboxymethyl, 2-carboxy-ethyl or 2-carboxy-ethenyl group, an alkoxycarbonyl group having a total of 2 to 5 carbon atoms, in which the alkyl part from β-carbon atom may be substituted by one or two hydroxy groups, by an alkoxy group having 1 to 3 carbon atoms or by a pyridinecarbonyloxy group, an alkoxycarbonyl-methyl, 2-alkoxycarbonyl-ethyl or 2-alkoxycarbonyl-ethenyl group, wherein the Alkoxy group may contain 1 to 3 carbon atoms, mean, and

4- [N- (6-chloro-a-phenyl-2-piperidino-benzyl) -aminocarbonylmethyl] -benzoic acid and its alkyl ester having 1 to 3 carbon atoms,

4- [N- (α-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] cinnamic acid and its alkyl ester having 1 to 3 carbon atoms,

3- [4 - [(N- (α-phenyl-2-piperidino-benzyl) aminocarbonylmethyl] -phenyl] -propionic acid and its alkyl ester having 1 to 3 carbon atoms,

4- [N- (4-chloro-a-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid and its alkyl ester having 1 to 3 carbon atoms,

4- [N- (3-chloro-a-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid and its alkyl ester having 1 to 3 carbon atoms,

4- [N- (6-methyl-a-phenyl-2-piperidino-benzyl) -aminocarbonylmethyl] -benzoic acid and its alkyl ester having 1 to 3 carbon atoms,

4- [N- (4-methyl-a-phenyl-2-piperidino-benzyl) -aminocarbonyl-methyl] -benzoic acid and its alkyl ester having 1 to 3 carbon atoms,

4- [N- (2- (2-methyl-piperidino) -a-phenyl-benzyl) -aminocarbonylmethyl] -benzoic acid and its alkyl ester having 1 to 3 carbon atoms,

4- [N- (2- (3-methylpiperidino) -α-phenylbenzyl) aminocarbonylmethyl] benzoic acid and its alkyl esters having 1 to 3 carbon atoms,

4- [N- (ct-phenyl-2-piperidino-benzyl) aminocarbonylmethyl] benzaldehyde,

4 - [(1- (4-fluoro-2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl] -benzoic acid and its alkyl ester having 1 to 3 carbon atoms,

4 - [(1- (3-chloro-2-piperidino-phenyl) ethyl) aminocarbonylmethyl] -benzoic acid and its alkyl esters having 1 to 3 carbon stoffatomeh] and

4 - [(1- (3-methyl-2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl] -benzoic acid and its alkyl ester having 1 to 3 carbon atoms,

but especially those compounds of general formula I in which

A is a group of formulas

- CH - or C -, where

R is an alkyl group having 1 to 3 carbon atoms substituted by a methoxy or phenyl group, an n-propyl, cyano or aminocarbonyl group, an alkyl group having 4 to 6 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, one represented by a fluoro, chloro or bromine atom, phenyl group or a pyridyl group substituted by a methyl, hydroxy, methoxy, benzyloxy or methylsulfenyl group,

R _r and R. together with the intervening coal

5 6 atom of an alkylidene group having 3 to 9 carbon atoms

or a phenylalkylidene group with 1 to 3 carbon 'atoms in the alkyl moiety,

R is a straight-chain alkyleneimino group having 4 to 8 carbon atoms or a piperidino group mono- or disubstituted by methyl groups,

R is a hydrogen, fluorine, chlorine or bromine atom, a methyl or methoxy group or, if R _r meanings ^{and R} ^ th ^e above-mentioned ascending

5 6 and R _{4 is} a by a methoxy or phenyl group

substituted alkyl group having 1 to 3 carbon atoms, an n-propyl, nitrile or aminocarbonyl group, an alkyl group having 4 to 6 carbon atoms or alkenyl! group having 3 to 5 carbon atoms, an iodine atom, a hydroxy or amino group,

R is a hydrogen or chlorine atom and

W is a methyl, hydroxymethyl, formyl, cyano, carboxy, carboxymethyl, 2-carboxy-ethyl or 2-carboxy-ethenyl group, an alkoxycarbonyl group having a total of 2 to 5 carbon atoms, in which the alkyl part from β-carbon atom may be substituted by one or two hydroxy groups, by an alkoxy group having 1 to 3 carbon atoms or by a pyridinecarbonyloxy group, an alkoxycarbonyl-methyl, 2-alkoxycarbonyl-ethyl or 2-alkoxycarbonyl-ethenyl group, wherein the alkoxy group respectively May contain 1 to 3 carbon atoms, as well as

4_ [ _N _ (6-chloro-a-phenyl-2-piperidino-benzyl) -aminocarbonyl-methyl] -benzoic acid and its alkyl ester having 1 to 3 carbon atoms,

4_ [ν- (ct -phenyl-2-piperidinobenzyl) aminocarbonylmethyl] 15; cinnamic acid and its alkyl esters having 1 to 3 carbon atoms,

3- [4 - [(N- (α-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] -: phenyl] propionic acid and its alkyl ester having 1 to 3 carbon atoms,

4- [N- (4-chloro-a-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid and its alkyl ester having 1 to 3 carbon atoms,

4- [N- (3-chloro-a-phenyl-2-piperidinobenzyl) -aminocarbonylmethyl] -benzoic acid and its alkyl ester having 1 to 3 carbon atoms,

4_ [N- (6-methyl-a-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid and its alkyl ester having 1 to 3 carbon atoms,

4_ [N- (4-methyl-a-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid and its alkyl esters having 1 to 3 carbon atoms,

4- [N- (2- (2-methylpiperidino) -α-phenylbenzyl) aminocarbonylmethyl] benzoic acid and its alkyl esters having 1 to 3 carbon atoms,

4- [N- (2- (3-methyl-piperidino) -α-phenyl-benzyl) -aminocarbonyl-methyl] -benzoic acid and its alkyl ester with 1 to 3 carbon atoms

4- [N- (a-phenyl-2-piperidino-benzyl) aminocarbonylmethyl] -Taenzaldehyd,

: 4 - [(1- (4-fluoro-2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl] -benzoic acid and its alkyl esters having 1 to 3 carbon atoms, '. ^^ "'''' ΐ '\ ^: -

4 - [(1- (3-chloro-2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl] -benzoic acid and its alkyl esters having 1 to 3 carbon atoms and

15ΐ 4 - [(1- (3-methyl-2-piperidino-phenyl) -ethyl) -aminocarbonyl-imethyl] -benzoic acid and its alkyl esters having 1 to 3 carbon atoms,

i.

ideren optically active antipodes and their salts, especially ideren physiologically acceptable salts with inorganic or organic acids or bases.

Make another group of preferred compounds. however, those are those in which A, R, to R and W are as defined above, especially those in which

25iw represents a carboxy group or an alkoxycarbonyl group having a total of 2 to 5 carbon atoms', wherein the alkylite may be substituted by one or two hydroxy groups from the β-carbon atom, and their optically active antipodes and their salts, in particular their physiologically acceptable salts with inorganic or organic acids

i atoms, i

od ^ -

Particularly preferred compounds of the above general formula I are those in which

A is a group of formulas

R ₄ C

ι π

- CH- or - C -, where

R represents an n-propyl group, an alkyl group having 4 or 5 carbon atoms, a phenyl group substituted by a methyl group, by a fluorine or chlorine atom, or a pyridyl group, r_ and R- together with the carbon atom therebetween.

, DD

represents an alkylidene group having 3 to 5 carbon atoms 10, or a phenylalkylidene group having 1 to 3 carbon atoms in the alkylene,

R _{1 represents} an optionally substituted by one or two methyl groups piperidino group,

] R is a hydrogen, fluorine or chlorine atom, the methyl-15: or methoxy group,

R_ is a hydrogen atom and

W is a carboxy group or an alkoxycarbonyl group having a total of 2 to 4 carbon atoms, especially those in which

A is a group of formulas

- CH - or - C -, where R is an n-propyl group or an alkyl group with 4 or 5

Carbon atoms and R ₅ and R _g together with the intervening carbon atom, an alkylidene group having up to 5 carbon atoms or a phenylalkylidene having 1 to 3 carbon atoms in Alkylidenteil, their optically active antipodes and their salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases ,

According to the invention, the novel compounds are obtained by the following processes:

a) reaction of an amine of the general formula

A-NH,

(II)

in the "* '";"

A, R ₁ and R are as defined above, or, if A represents one of the initially mentioned vinylidene groups, its tautomers or its lithium or magnesium halide complex with a carboxylic acid of the general formula

, (III)

HO-CO-CH

in the R ₃ as defined above and

W has the meanings mentioned for W or represents a protected by a protective carboxy group, or with their reactive derivatives optionally prepared in the reaction mixture and, if necessary, subsequent cleavage of a used protective moiety.

Reactive derivatives of a compound of the general formula III are, for example, their esters such as! Methyl, ethyl or benzyl esters, their thioesters such as the methylthio or ethylthioester, their halides like the! Acid chloride, their anhydrides or imidazolides into consideration.

The reaction is conveniently carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, if appropriate in the presence of a ^!

\ Acid activating agent or dehydrating agent, for example in the presence of ethyl chloroformate, thionyl chloride, phosphorus trichloride, phosphorus pentoxide,; N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide, N-hydroxy-succinimide, N, N'-carbonyldiimidazole or J, N'-thionyldiimidazole or triphenylphosphine / carbon tetrachloride, or an amino group activating agent, For example, phosphorus trichloride, and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or jj pyridine, which may serve as a solvent, at temperatures between -25 C and 250 C, but preferably at temperatures between -10 C and The reaction can also be carried out without a solvent through-I, furthermore, water formed during the reaction can be separated off 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 ,

If necessary, the subsequent spin-off of a

j protective moiety preferably carried out hydrolytically, purposefully

; moderately either in the presence of an acid such as Saiz

I acid, sulfuric acid, phosphoric acid or trichloroacetic acid

\ Or in the presence of a base such as sodium hydroxide or

Potassium hydroxide in a suitable solvent such as water,

Methanol, ethanol, ethanol / water, water / isopropanol or water / dioxane at temperatures between -10 C and 120 C, e.g. at temperatures between room temperature and the boiling temperature of the reaction mixture.

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

Furthermore, a benzyl radical used as a protective radical can also be removed by hydrogenolysis in the presence of a hydrogenation catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide.

b) For the preparation of a compound of the general formula I in which W represents a carboxy, carboxymethyl, 2-carboxyethyl or 2-carboxyethyl group: cleavage of a compound of the general formula

A-NH-CO-CH

R 3

in the

R, to R, A and X are as defined above and

B represents a group convertible by hydrolysis, thermolysis or hydrogenolysis into a carboxy, carboxymethyl, 2-carboxyethyl or 2-carboxyethyl group.

Suitable hydrolyzable groups are, for example, functional derivatives of the carboxy, carboxymethyl, 2-carboxy groups.

ethyl or 2-carboxy-phenyl group, such as their unsubstituted or substituted amides, their nitriles, esters, thiol esters, orthoesters, imino ethers, amidines or anhydrides, a malonic ester (1) -yl group, the tetrazolyl group, an optionally substituted 1,3-oxazole -2-yl or 1,3-oxazolin-2-yl group, and

as thermally cleavable groups, for example, esters with tertiary alcohols, e.g. the tert. Buty! Ester, and

as hydrogenolytically cleavable groups, for example esters with aralkanols, e.g. the benzyl ester, into consideration.

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, water / methanol, ethanol, water / ethanol, water / isopropanol or Water / dioxane at temperatures

ο o between -10 C and 120 C, e.g. at temperatures between room temperature and the boiling temperature of the reaction mixture, carried out.

If B in a compound of the general formula IV denotes a cyano or aminocarbonyl group, these groups may also be reacted with a nitrite, e.g. Sodium nitrite, in the presence of an acid such as sulfuric acid, which is suitably used simultaneously as a solvent, be converted at temperatures between O and 50 C in the carboxy group.

j is B in a compound of general formula IV, for example, the tert. Butyloxycarbonylgruppe, so the tert. Butyl also thermally optionally in one

inert solvents such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane, and preferably in the presence of a catalytic amount of an acid such as

p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid, preferably at the boiling temperature of the solvent used, e.g. at temperatures between 40 C and 100 C, be split off.

If B in a compound of general formula IV, for example, the benzyloxycarbonyl group, the benzyl group can also be hydrogenolysis in the presence of a hydrogenation catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at temperatures be split off between 0 and 50 ⁰ C, for example at room temperature, and a hydrogen pressure of 1 to 5 bar. In the hydrogenolysis, other radicals, eg a nitro group to the amino group, a benzyloxy group to the hydroxy group, a vinylidene group to the corresponding alkylidene group or a cinnamic acid group to the corresponding phenyl-propionic acid group, can be simultaneously reduced or replaced by hydrogen atoms, eg a halogen atom by a hydrogen atom.

c) For the preparation of a compound of the general formula I in which A is a group of the formula

CH - represents, where

R 'with the exception of the alkenyl group and the cyano group has the meanings mentioned for R. above:

Reduction of a compound of the general formula

D-CO-CH ₂

in the

R, to R ~ and W are as defined above and D is a group of formulas

R. "R 'R.'

4 5 - ^ ^ y 6

^: ' ^: '; ·. ' ·. ... c

- C or "

S-c

N

H

in which R ₄ ^11, with the exception of the cyano group, has the meanings mentioned for R ₄ above and R ₅ ¹ and Rg 'together with the intervening carbon atom denote an alkylidene group having 1 to 7 carbon atoms or a phenylalkylidene group having 1 to 3 carbon atoms in the alkylidentical part.

The reduction is preferably carried out with hydrogen in the presence of a hydrogenation catalyst such as palladium / carbon or Raney nickel in a suitable solvent such as methanol, ethanol, isopropanol, ethanol / water, glacial acetic acid, ethyl acetate, dioxane, tetrahydrofuran, dimethylformamide, benzene or benzene / ethanol at temperatures between 0 and 100 ° C, but preferably carried out at temperatures between 20 C and 50 C, and a hydrogen pressure of 1 to 5 bar. When using a suitable chiral hydrogenation catalyst such as a metal ligand complex, e.g. a complex of μ, μ'-dichloro-bis [1,5-cyclooctadiene-rhodium] and (+) - or (-) 0,0-isopropylidene-2,3-dihydroxy-1,4-bis (diphenylphosphino) - butane (= DIOP), the hydrogen addition takes place enantioselectively. Furthermore, in catalytic hydrogenation, other groups, e.g. a

Nitro group to the amino group, a benzyloxy group to the hydroxy group or a cinnamic acid group to the phenylpropionic acid group, mitreduziert or by hydrogen atoms, e.g. a halogen atom is replaced by a hydrogen atom.

d) For the preparation of compounds of the general formula I in which R ', with the exception of the cyano group, has the meanings mentioned at the outset for R.;

Reaction of a compound of the general formula

CH - OH K .T

in the ·.-.·.. · · . .. ·. · ->. v. · .. R. ' as defined above, and R ₁ and R "are as defined above, with a compound of the general formula. , , ,

in the ' .- -

R and W are as defined above.

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

ν iff

e) Dehalogenation of a compound of the general formula

Hal

A-NH-CO-CH

W, (VIII)

in the

R ₁ , R, A and W are as defined above and • Hai represents a fluorine, chlorine, bromine or iodine atom.

The dehalogenation is conveniently carried out in a solvent such as methanol, ethanol, ethyl acetate, glacial acetic acid or dimethylformamide using catalytically-promoted hydrogen, e.g. with hydrogen in the presence of platinum or palladium / carbon, at temperatures between 0 and 100 C, but preferably at room temperature, and carried out at a Wasserstöffdruck 1-5 bar. In the dehalogenation, other groups, e.g. a benzyloxy group to the hydroxy group, a vinylidene group to the corresponding alkylidene group or a cinnamic acid group to the corresponding phenyl-propionic acid group, mitreduziert or by hydrogen atoms, e.g. a halogen atom is replaced by a hydrogen atom.

f) For the preparation of compounds of the general formula I in which R. represents an alkyleneiminocarbonyl group having 4 to 6 carbon atoms in the alkylene ring or an aminocarbonyl group optionally mono- or disubstituted by alkyl or phenylalkyl groups each having 1 to 3 carbon atoms in the alkyl moiety:

Reaction of a compound of the general formula COOH

CH - NH - CO - CH - (f * \ _ _w " _(ΊΧ \

in the

R ,, R and R-. as defined above and W "with the exception of the carboxy group has the meanings mentioned for W, with an amine of the general

formula

H - R ₇ , (X)

in the

R represents an alkyleneimino group having 4 to 6 carbon atoms or an amino group mono- or disubstituted by alkyl or phenylalkyl groups each having 1 to 3 carbon atoms in the alkyl moiety. : _(] ,

The amidation is conveniently carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, preferably in the presence of an acid activating agent or a dehydrating agent, for example in the presence of ethyl chloroformate, thionyl chloride, phosphorus trichloride , phosphorus pentoxide, NJN '^ Dicyclohexylcärbödiimid, Ν, Ν'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N'-carbonyldiimidazole, N, N'-thionyldiimidazole or triphenylphosphine / carbon _{tetrachloride:} or the amino group activating agent, for example phosphorus trichloride, and if appropriate 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 solvent, at temperatures

doors between -25 ° C and 250 ° C, but preferably at temperatures between -10 ⁰ C and the boiling temperature of the solvent used, performed.

g) For the preparation of compounds of general formula I in which W represents the carboxy group:

Oxidation of a compound of general formula R.

CH - NH - CO - CH.

• in the

R ₁ to R are as defined above and E is a convertible by oxidation in a carboxy group

Group represents.

As such an oxidizable group, for example, the formyl group and its acetals, the hydroxymethyl group and their ethers, an unsubstituted or substituted acyl group such as the acetyl, chloroacetyl, propionyl, the malonic acid (1) -yl group or a malonic ester - (1) -yl group into consideration.

The reaction is carried out with an oxidizing agent in a suitable solvent such as water, glacial acetic acid, methylene chloride, dioxane or glycol dimethyl ether at temperatures between 0 and 100 ° C, but expediently at temperatures between 20 C 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 / soda or potassium hydroxide, Ehromtrioxid / pyridine or pyridinium chlorochromate.

h) For the preparation of compounds of the general formula I in which W represents an alkoxycarbonyl group having a total of 2 to 4 carbon atoms, in which the alkyl portion may be substituted by one or two hydroxyl groups or by an alkoxy group having 1 to 3 carbon atoms from the β-carbon atom:

Esterification of a carboxylic acid of the general formula

A - NH - CO - CH

WZ, (XII)

in the

R to R and A are as defined above, or their reactive derivatives optionally prepared in the reaction mixture, with an alcohol "of the general formula

HO

in the ι

R _{q represents} an alkyl group having 1 to 5 carbon atoms, which may be substituted from the β-carbon atom by one or two hydroxy groups or an alkoxy group having 1 to 3 carbon atoms.

As reactive "derivatives of a compound of the general formula XiI are, for example, their halides such as the acid chloride, their anhydrides or imidazolides into consideration.

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

furan, dioxane, benzene or toluene, optionally in the presence of an acid activating agent or a dehydrating agent, for example in the presence of hydrogen chloride, sulfuric acid, ethyl chloroformate, thionyl chloride, carbon tetrachloride / triphenylphosphine, carbonyldiimidazole or ^, N'-dicyclohexylcarbodiimide or its isourea, optionally in the presence of a reaction accelerator such as cupric chloride, and optionally:. .. if in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine, or by transesterification, for example with a corresponding carbonic acid diester, at temperatures between -20 ° C and 100 ⁰ C, but preferably at temperatures between -10 C. and the boiling temperature of the used; Solvent, performed.

! i) For the preparation of a compound of the general formula I, in which W is an alkoxycarbonyl, alkoxycarbonyl-methyl-; 2-alkoxycarbonyl-ethyl or 2-alkoxycarbonyl-ethenyl group and R ₄ ¹ except for the cyano group has the meanings mentioned for R above:

! Alcoholysis of a compound of the general formula

CH - NH - CO -

* ¹ :

in the

R · as defined above and R ₁ to

! 4. , -....: ι

  R are as defined above and w "represents a cyano, cyanomethyl, 2-cyanoethyl or 2-cyano-ethyl-phenyl group.

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

, .If according to the invention

a compound of the general formula I, in which W represents a carboxy or alkoxycarbonyl group, may be converted into a formyl or hydroxymethyl group by reduction to a corresponding compound of the general formula I in which W represents /or

a compound of general formula I in which W represents the carboxy group, it may be converted by means of conversion into a sulfonic acid and subsequent "disproportionation into a corresponding compound of general formula I, in which W represents the formyl group, and /or

a compound of general formula I in which W represents a formyl group, this may be prepared by condensation and optionally subsequent hydrolysis and / or decarboxylation in a corresponding compound of general formula I in which W is a 2-Älköxycarbönyl-ethenyl ^ or ' represents a, 2-carboxy-ethenyl group, be converted, and / or

a compound of general formula I in which W is a, 2-carboxy-ethyl or 2-alkoxycarbonyl-ethenyl group, it may be by means of catalytic hydrogenation in a corresponding compound of general formula I in which W is a 2-carboxy ethyl or 2-alkoxycarbonyl-ethyl group, and / or ^{rr: v} " ^r:

a compound of the general formula I in which W represents an alkoxycarbonyl group which is substituted by a hydroxy group starting from the .beta.-carbon atom, this can be converted by acylation by a pyridinecarboxylic acid into a corresponding (pyridoxycarbonyloxyalkoxy) * -carbonyl compound of the general formula Formula I are transferred, and / or

, a compound of the general formula I in which W represents a hydroxymethyl group, it may, after conversion into a corresponding halomethyl compound, by reaction with a Malonsäurediester into a corresponding compound of the general formula I, in the W represents a substituted by two alkoxycarbonyl ethyl group , be transferred, and / or

a compound of the general formula I in which W is an ethyl group substituted by two alkoxycarbonyl groups, this can be converted by hydrolysis into a corresponding compound of the general formula I in which W is an ethyl group substituted by two carboxy groups, and / or

a compound of the general formula I in which W represents an ethyl group substituted by two alkoxycarbonyl groups, this can be converted by hydrolysis and decarboxylation into a corresponding compound of the general formula I in which W represents a 2-carboxyethyl group, and or

a compound of the general formula I in which R 2 represents a nitro group can be converted by reduction into a corresponding compound of the general formula I in which R p is an amino group, and / or

a compound of the general formula I in which R "represents an amino group, this may be converted via a corresponding diazonium salt into a corresponding compound of the general formula I in which R is a hydrogen or halogen atom, a hydroxy, alkoxy or alkyl sulfenyl represents group, be transferred, and / or

a compound of general formula I in which R _{2 represents} a hydroxy group, so this can be prepared by alkylation in a corresponding compound of general formula Ί, ^ 0 jn the R _? represents an alkoxy group, "

and or ,..,,-

a compound of the general formula I in which R _{2 represents} a benzyloxy radical and / or R represents an aryl radical substituted by a benzyloxy radical, this radical can be converted into a corresponding compound of the alicemeinic formula I in which R 1 is debenzylation _{2 represents} the hydroxy group and / or R. represents an aryl radical substituted by a hydroxy group, and / or

a compound of general formula I, ^ n is the R. represents a Aminocarbcnylgruppe, this can by dehydration into a corresponding compound of general formula I, ₄ in which R represents a cyano group, ^over-: be performed '·

The subsequent reduction is preferably carried out with a metal hydride, e.g. with a complex metal hydride, such as lithium aluminum hydride, in a suitable solvent

Such as diethyl ether, tetrahydrofuran or dioxane at temperatures between 0 and 100 C, but preferably at Tempe-

o 'ο., temperatures between 20 C and 60 C, - carried out.

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

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

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

The subsequent O-acylation is conveniently carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene,

Toluene, acetonitrile or dimethylformamide, preferably with a reactive derivative of the acid, for example a halide such as the acid chloride, an anhydride or imidazolide and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine which may simultaneously serve as a solvent, at temperatures between -25 C and 250 C, but preferably at temperatures between -10 C and the boiling temperature of the solvent used, carried out.

The subsequent conversion of a hydroxymethyl group to a halomethyl group is carried out with a halogenating agent such as thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride in a solvent such as methylene chloride, carbon tetrachloride, benzene or nitrobenzene and their subsequent reaction with a malonic acid ester, e.g. with an alkali salt of Malonsäurediäthyl-

    '' ο

at temperatures between 0 and 100 C, preferably

> ο ο

However, at temperatures between 50 C and 80 C, carried out.

The subsequent hydrolysis or hydrolysis and decarboxylation is conveniently carried out in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid

  or trifluoroacetic acid in a suitable solvent

such as water, ethanol, water / ethanol, water / isopropanol or water / dioxane at elevated temperatures, e.g. at the boiling point of the Reaktiönsgemisches performed.

The subsequent reduction of the nitro compound is preferably in a solvent such as water, water / ethanol, methanol, glacial acetic acid, ethyl acetate or "dimethylformamide expediently with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, platinum or palladium / carbon, with metals such as iron, tin or Zinc in

Presence of an acid, with salts such as iron (II) sulfate, stannous chloride or sodium dithionite or with hydrazine in the presence of Raney nickel at temperatures between 0 and 50 C, but preferably at room temperature performed.

Subsequent reaction of a diazonium salt, e.g. the fluoroborate, the fluoride in 40% hydrofluoric acid, the hydrosulfate in sulfuric acid or the hydrochloride, if necessary in the presence of copper or a corresponding copper (I) salt such as copper (I) chloride / hydrochloric acid or 1C copper (I. ) bromide / hydrobromic acid, at slightly elevated temperatures, eg at temperatures between 15 C and 100 C, carried out; the subsequent implementation with

○ hypophosphorous acid is preferably carried out bex -5 C to 0 C. The required diazonium salt is conveniently dissolved in a suitable solvent, e.g. in water / hydrochloric acid, methanol / hydrochloric acid, ethanol / hydrochloric acid or dioxane / hydrochloric acid, by diazotization of a corresponding amino compound with a nitrite, e.g. Sodium nitrite or an ester of nitrous acid, at low temperatures, e.g. 1 produced.

ο ο doors, e.g. at temperatures between -10 C and 5 C,

The subsequent O-alkylation is conveniently carried out with a corresponding halide, sulfonic acid ester or diazoalkane, e.g. with methyl iodide, dimethyl sulfate, ethyl bromide, p-TcluolEulfonsäure-ethyl ester, methanesulfonic acid isopropyl ester or diazomethane, optionally in the presence of a base such as sodium hydride, potassium hydroxide or potassium tert.butyl t and preferably in a solvent such as diethyl ether, tetrahydrofuran, dioxane, Methanol, ethanol, pyridine or dimethylformamide at temperatures between 0 and 75 C, preferably at room temperature, carried out.

The subsequent debenzylation is advantageously carried out in a Lösungsiritttel such as methanol, ethanol, ethyl acetate, glacial acetic acid or dimethylformamide by means of catalytically excited

- ~ 3Γ-

Hydrogen, e.g. with hydrogen in the presence of platinum or palladium / carbon, at temperatures between 0 and 75 C, but preferably at room temperature, and carried out at a hydrogen pressure of 1-5 bar.

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

The resulting compounds of the general formula I, if they have a chiral center, can furthermore be separated into their enantiomers by customary methods. This separation is carried out by column chromatography on a chiral phase.

The resulting compounds of general formula I can be further converted into their addition salts, in particular in their physiologically acceptable salts with inorganic or organic acids or bases. Suitable acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid or fumaric acid and bases sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine, triethanolamine or ethylenediamine into consideration.

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

Thus, for example, a compound of general formula II, in which A is a group of the formula

^R5 ^ / ^R6

 I

or their tautomeric ketimine by reacting a corresponding nitrile with a corresponding Grignard or lithium compound and subsequent hydrolysis or by reacting a corresponding ketone with ammonia in the presence of titanium tetrachloride. For further reaction with a compound of general formula III or their reactive derivatives, especially their acid chlorides, the organometallic ketimine complex can also be used.

A compound of the general formula II in which A is a group of the formula

^R 4

- CH -, wherein R except for the cyano and aminocarbonyl group as

15! is defined above, is obtained for example by reacting a corresponding nitrile with a corresponding Grignard or lithium compound and optionally subsequent lithium aluminum hydride reduction or subsequent hydrolysis to ketimine, which is then reduced with catalytically excited hydrogen, with a complex, metal hydride or with nascent hydrogen is, by hydrolysis or by hydrazinolysis of a corresponding phthalimido compound, by reacting a corresponding ketone with ammonium formate and subsequent hydrolysis or with an ammonium salt in the presence of sodium cyanoborohydride, by reduction of a corresponding

OxiiTis with lithium aluminum hydride or with catalytically excited or nascent hydrogen, by reduction of a corresponding N-benzyl- or N- (1-phenyl-ethyl) -ketimine, eg with catalytically-promoted hydrogen or with a complex metal hydride in ether or tetrahydrofuran at 5- temperatures between - 78 C and the boiling temperature of the solvent used and subsequent removal of the benzyl or 1-Phenyla'thylgruppe by catalytic .Hydrierung, by Ritter reaction of a corresponding alcohol with potassium cyanide in sulfuric acid, or by Hofmann, Curtius, Lossen or Schmidt Removal of a corresponding Connection. ''

A compound of general formula II in which A is the group

CN

- CH - is obtained by reacting a corresponding aldehyde with ammonium cyanide or by reacting a corresponding cyanohydrin with ammonia.

A thus obtained amine of the general formula II having a chiral center, in which A is a group of the formula

^R 4

- CH - represents, where

R, with the exception of the cyano group as defined above, may be prepared by resolution, e.g. by fractional crystallization of the diastereomeric salts with optically active acids and subsequent decomposition of the salts or by

Column chromatography on a chiral phase, or by formation of diastereomeric compounds, their separation and subsequent cleavage are separated into the enantiomers.

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

Furthermore, an optically active amine of the general formula II can also by diastereo-selective reduction of a corresponding chirally substituted at the nitrogen ketimine or hydrazone by means of complex or non-complex boron or aluminum hydrides, in which optionally a portion of the hydrogen hydrides by appropriate alkoxide, phenolate or also alkyl radicals is replaced, or be prepared by means of hydrogen in the presence of a suitable hydrogenation catalyst and optionally subsequent cleavage of the chiral auxiliary radical by catalytic hydrogenolysis or hydrolysis.

Furthermore, an optically active amine of the general formula II may also be prepared by diastereo-selective addition of a corresponding organometallic compound, preferably a Grignard or a lithium compound, to a corresponding aldimine chirally substituted on the nitrogen atom, by subsequent hydrolysis and optionally subsequent cleavage of the chiral auxiliary radical by catalytic Hydrogenolysis or hydrolysis are produced.

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

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

As already mentioned, the novel compounds of the general formula I have valuable pharmacological properties, namely an effect on the intermediary metabolism, but in particular a blood glucose lowering effect, in part also an effect on the cardiovascular system.

For example, the compounds were

A 5 = (Z) -4 - ^ (1- (2-piperidino-phenyl) -1-buten-1-yl) -aminocar-

bonylmethy / - benzoic acid,

j B- (Z) -A- / (1- (2-piperidino-phenyl) -1-buten-1-yl) -aminocar-

ethylmonoyl ethylbenzoate,

C = (E) -4- ^ "(1- (2-piperidino-phenyl) -1-buten-1-yl) -aminocarbonyl-benzoic acid,

D - 4- (2-methyl-1- (2-piperidino-phenyl) -1-propen-1-yl) -aminocarbonyl-methyl-benzoic acid;

E = (Z) -4 - / "(1- (2-piperidino-phenyl) -l-hexen-1-yl) -aminocarbonylmethyl-7-benzoic acid ethyl ester,

F = (Z) -4- / 73-phenyl-1- (2-piperidino-phenyl) -1-propen-1-yl) -aminocarbonyl-methyl / benzoic acid,

Q = (z) -4- / (1- (2- (3,3-dimethyl-piperidino) -phenyl) -1-buten-1-yl) -aminocarbonylmethylZ-benzoic acid,

η = 4 - / ((1- (2-pyrrolidino-phenyl) -1-butyl) -aminocarbonyl-methyl / benzoic acid,

j = (4) _4_ £ - (i - (2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl-7-benzoic acid,

K = (+) - 4 - / | 7l- (2-piperidino-phenyl) -1-butyl) -aminocarbonyl- . methyl / benzoic acid,

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

- (2-hexahydroazepino-phenyl) -1-butyl) -aminocarbonylmethyl / -benzoic acid,

ν = 4- (II-piperidino-phenyl) -l-hexyl) -aminocarbonyl-1-methyl-benzoic acid,

= 4- / T3-phenyl-1- (2-piperidino-phenyl) -lt-propyl) -aminocarbonylmethyl / benzoic acid,

P s; 4- / T2-methoxy-1- (2-piperidino-phenyl) -1-ethyl) -aminocarbonylmethyl / 'benzoic acid,

Q = 4- / 7a-cyano-2-piperidinobenzyl) aminocarbonylmethyl / benzoic acid,

R = 4- / 7l- (2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl / -benzyl alcohol,

S = 4 -, / (1- (2-piperidino-phenyl) -1-butyl) -aminocarbonylmethylj-phenylacetic acid,

T = 4- / I1- (2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl-cinnamic acid ,

/ 5U = 4- / 71- (2-piperidino-phenyl) -1-butyl) -aminocarbonylmethylZ-benzoic acid (2,3-dihydroxypropyl) ester,

V = 4 - / _ (1- (4-fluoro-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethylbenzoic acid,

"W = 4 - / _ (1- (4-methoxy-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethylbenzoic acid,

X = 4- / 1- (2- (2-octahydroazonino-phenyl) -l-ethenyl) -anti- carbonylmethylbenzoic acid,

γ = 4 - ^ / Jl- (3-chloro-2-piperidino-phenyl) -1-ethyl) -aminocarbonylmethyl / benzoic acid,

, Z = 4 - ^ (1- (3-methyl-2-piperidino-phenyl) "1-ethyl) -aminocarbonylmethyl / benzoic acid,

AA = 4 - / (α- (4-methyl-phenyl) -2-piperidino-benzyl) -aminocarbphenylmethyl-7-benzoic acid,

AB - 4- / Ta- (3-methyl-phenyl) -2-piperidino-benzyl) -aminocarbonylmethyl-7-benzoic acid _f

AC = 4- (1a-4-fluoro-phenyl) -2-piperidino-benzyl) -aminocarbonylmethyl-benzoic acid,

AD = A- [Ja (2-fluoro-phenyl) -2-piperidino-benzyl] -aminocarbonylmethyl-benzoic acid,

AE = 4 s -, / Yes (4-chloro-phenyl) -2-piperidino-benzyl) ^-aminocar-: bonylmethylj-benzoic acid,

AF = 4 - / _ (α- (3-chloro-phenyl) -2-piper-idino-benzyl) -aminocar-; bonylmethy / - benzoic acid,

S AG »4 - / ^ (2-piperidino-a- (2-pyridyl) -benzyl) aminocarbonylmethyl / benzoic acid,

AH = 4 - / _ (2-piperidino-a- (4-pyridyl) benzyl) aminocarbonylmethyl / benzoic acid,

AJ = 4 - ^ (6-chloro-a-phenyl-2-piperidinobenzyl) aminocarbonylmethyl / benzoic acid,

AK = 4- / 7 "a-phenyl-2-piper-idino-benzyl) -aminocarbonylmethyl-cinnamic acid,

AL = 3- / 4 - / (α-phenyl-2-piperidino-benzyl) -aminocarbonyl-methyl-phenyl / propionic acid,

AM = 4- (4-chloro-a-phenyl-2-piperidinobenzyl) aminocarbonylmethyl / '- benzoic acid,

AN = 4 - / (6-methyl-a-phenyl-2-piperidinobenzyl) aminocarbonylmethyl / benzoic acid,

AO = 4- _i / _ (4-methyl-a-phenyl-2-piperidino-benzyl) aminocarbonylmethyl / benzoic acid,

AP = 4α, / 7a.-phenyl-2-piperidinobenzyl) aminocarbonylmethyl / benzaldehyde,

AQ = 4 - ^ (2- (2-methylpiperidino) -α-phenylbenzyl) aminocarbonylmethylbenzoic acid,

AR - 4- _< / "(2- (3-methyl-piperidino) - <x-phenyl-benzyl) -aminocarbonyl-methyl-benzoic acid and

AS = 4- (3-chloro-a-phenyl-2-piperidinobenzyl) aminocarbonylmethylbenzoic acid

on their properties as follows: 1. Hypoglycemic effect

The hypoglycemic effect of the substances to be tested was tested on female rats of their own breed weighing 180-220 g, which were fasted 24 hours before the start of the experiment. The substances to be examined were suspended immediately before the start of the experiment in 1: 5% methyl cellulose and applied by gavage.

Blood was taken immediately before administration of the substance and 1, 2, 3 and 4 hours later, respectively, from the retroorbital venous plexus. Of these, each 50 μΐ were de-infected with 0.5 ml of 0.33 N perchloric acid and centrifuged. In the supernatant, glucose was determined by the hexokinase method using an analysis photometer. The statistical evaluation was carried out according to the student t-test with ρ = 0.05 as the significance limit.

The following table contains the values found in percent over control:

5 1 mg / kg 3 4 1 1 2 mg / kg 4 substance 2 -43 -40 3 -35 A -44 -26 -35 -39 -19 -33 -30 B -39 -43 -43 -26 -38 C -36 -32 -37 -25 D -46 -38 -26 -23 -23 -27 -18 e -43 -40 -39 -32 -12 F -42 -44 -42 -31 G -50 -44 -45 -37 H -44 -46 -42 -42 -38 -32 -29 J -37 -41 -43 -34 -31 K -42 -31 -22 -14 -18 -38 n.s. L -46 -45 -40 -36 -33 -30 -14 n.s. M -42 -43 -37 -33 -21 N -38 ⁺ -42 n.s. n.s. O -49 -3I ⁺ -34 -22 -37 -19 n.s. P -28 -43 n.s. n.s. n.s. Q -38 -13 -35 -29 -39 -34 -24 R -49 -40 -30 -17 -29 -20 -29 n.s. S -48 -42 -42 -40 -42 -42 -10 -32 T -43 -46 -49 -45 -39 -35 -40 -24 U -45 -43 -46 -40 -37 -23 -29 -18 ν -46 -41 -39 -37 -36 -25 -30 n.s. W -34 ⁺ -45 -17 ⁺ -14 ⁺ -16 'X -32 -2I ⁺ -16 -18 y -22 -24 -28 -26 Z -30 -33 -14 n.s. -15 -15 n.s. AA -43 -33 -36 -27 -26 -15 -13 n.s. FROM -36 -38 -36 -33 n.s. AC -28 -37 -27 -28 -16 -20 -14 AD -30 -32 -39 -36 -'21 -20 -17 n.s. AE -28 -22

5 1 mg / kg 3 4 1 1 2 mg / kg 4 substance -43 2 -30 -26 -17 -19 3 n.s. AF -49 ⁺ -39 -36 ⁺ -3I ⁺ -18 n.s. n.s. n.s. AG -41 -5O ⁺ -20 n.s. -26 -14 n.s. n.s. AH -44 -37 -39 -40 -35 -34 n.s. -20 AJ -48 ⁺ -40 -4O ⁺ -45 ⁺ -32 -19 -28 -17 AK -43 ⁺ -47 ⁺ -38 ⁺ -34 ⁺ -40 -31 -10 -12 AL -34 -4I ⁺ -32 -29 -11 -13 -23 n.s. AT THE -39 -35 -27 -26 -27 -24 n.s. n.s. ON -37 -35 -32 -31 -21 -17 n.s. -11 AO -34 -26 -28 -15 -17 AP -32 -24 -19 -16 -11 -22 n.s. AQ -35 -31 -29 -31 -13 - 9 n.s. n.s. AR -45 -30 -42 -32 -21 -13 n.s. n.s. AS -44 n.s.

+ = at 10 mg / kg

n.s. = not statistically significant

2. Acute toxicity;

In female and male mice of their own breed weighing 20-26 g, the toxic effect after oral administration (suspension in 1% methylcellulose) of a single dose at a follow-up of 14 days was tested:

17/11/1903

ΛΡ C 07! 1/252 755

62 554/12

substance 1 000 000 orienting acute toxicity P .0. (O from 6 animals died) Λ 000 0OC mg / kg P .O. (O from 6 animals died) W 500 000 mg / kg P .O. (O from 6 animals died) < ü 000 Mg / kg P .O. (O from 10 animals died) \ D 1 GOC mg / kg P .O. (O from 10 animals died) j 1 000 mg / kg P _{# # #} (O from I died of animals) i , \O 1000 mg / kg P .O. (O from 10 animals raised) j 1 mg / kg P .O. (O from 10 animals died) / Λ0 1 mg / kg P .O. (O from / 10 animals died) · 1 mg / kg P .O. (O from 10 animals died) _... - .. - .\G mg / kg

Because of their pharmacological properties, the compounds of the general formula I and their physiologically tolerated salts are suitable for the treatment of diabetes mellitus. For this purpose, they can be mixed, if appropriate in combination with other active substances, into the customary galenic formulation such as tablets. Incorporate dragees, capsules, powders or suspensions. The single dose e, r; i nr.vachsenon is in this case 1 to 5 mg, but preferably 2.5 to 20 mg, 1 or 2 times a day.

by the way

The following examples are intended to explain the interpretation

- 43 Example 1

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

To 4.2 g (15 mmol) of α- (4-methylphenyl) -2-piperidinobenzylamine and 3.4 g (16.5 mmol) of 4-ethoxycarbonylphenylacetic acid dissolved in 40 ml of acetonitrile are added successively -4 ^ 7 g (18 mmol) of triphenylphosphine, 3 g (30 mmol) of triethylamine and 1.5 ml (15 mmol) of carbon tetrachloride. The reaction mixture is stirred for 2 hours at 50 ° C, then concentrated and extracted after acidification with 6N hydrochloric acid with ethyl acetate. The acidic aqueous phase is then extracted several times with methylene chloride. The methylene chloride extracts are washed with sodium bicarbonate solution, dried over magnesium sulfate and concentrated. The concentration residue is triturated with ethanol and filtered with suction. Yield: 4.55 g (65% of theory), m.p .: 177-178 ° C. Calc .: C, 76.57, H, 7.28, N, 5.95, Found: 76.19, 7.16, 5.82

Analogously to Example 1 were prepared:

(a) 4- [N- [α- (3-Methyl-phenyl) -2-piperidino-benzyl] -aminocarbonyl-methyl] -benzoic acid ethyl ester. Yield: 48% of theory, m.p .: 159-160 ° C

Calc .: C 76.57 H 7.28 N 5.95 F .: 76.80 7.35 5.76

(b) 4- [N- [α- (2-Methylphenyl) -2-piperidino-benzyl] -aminocarbonylmethyl] -benzoic acid ethyl ester Yield: 35.4% of theory, m.p .: 196-198 ° C

Calc .: C 76.57 H 7,28 N 5,95 Found: 76,65 7,35 5,90

(C) 4- [N- [α- (4-Methoxy-phenyl) -2-piperidino-benzyl] -aminocarbonylmethyl] -benzoic acid ethyl ester. Yield: 45% of theory, m.p .: 167-168 ° C

Calc .: C 74.05 H 7.04 N 5.76 Found: 73.72 6.99 5.62

(d) 4- [N- [α- (4-Benzyloxyphenyl) -2-piperidino-benzyl] -aminocarbonylmethyl] -benzoic acid ethyl ester

Yield: 96% of theory,

Melting point: 154-155 ° C

Ber. C, 76.84, 6.81, N, 4.98

Gef .: 76.82 6.68 5.03

(e) 4- [N- [Ct- (4-Fluoro-phenyl) -2-piperidino-benzyl] -aminocarbonylmethyl] -benzoic acid ethyl ester. Yield: 58% of theory, m.p .: 174-176 ° C

Calc .: C 73.40 H 6.58 N 5.90 F .: 73.55 6.72 5.91

(f) 4- [N- [α- (2-fluoro-phenyl) -2-piperidino-benzyl] -aminocarbonylmethy1] -benzoic acid ethyl ester Yield: 83% of theory, Melting point: 173-175 ⁰ C.

Calc .: C 73.40 H 6.58 N 5.90 F .: 73.61 6.62 5.85

(g) 4- [N- [α- (4-Chloro-phenyl) -2-piperidino-benzyl] -aminocarbonylmethyl] -benzoic acid ethyl ester. Yield: 57% of theory, m.p .: 178-181 ° C

Calcd .: C, 70.94, H, 6.36, N, 5.71, Cl, 7.22, Found: 71.10, 6.56, 5.26, 7.11

(h) 4- [N- [α- (3-chloro-phenyl) -2-piperidino-benzyl] -amino

carbonylmethyl] -benzoic acid ethyl ester Yield: 71% of theory, Melting point: 153-156 ⁰ C.

Calc .: C, 70.94, H, 6.36; N, 5.71; Cl, 7.22, Found: 70.86, 6.26, 5.65, 7.25

(i) 4- [N- [α- (2-Chloro-phenyl) -2-piperidino-benzyl] -aminocarbonylmethyl] -benzoic acid ethyl ester Yield: 66% of theory, m.p .: 196-198 ° C

Calcd .: C, 70.94, H, 6.36, N, 5.71, Cl, 7.22, Found: 70.90, 6.30, 5.61, 7.10

(k) ethyl 4- [N- [ot- (4-methylmercapto-phenyl) -2-piperidino-benzyl] -aminocarbonylmethyl] -benzoate Yield: 84% of theory, m.p .: 173-175 ° C

Calcd .: C, 71.68, H, 6.82, N, 5.57, S, 6.38, F, 71, 92, 6.97, 5.45, 6.21

(1) 4- [N- [5-chloro-a- (2-chloro-phenyl) -2-piperidino-benzyl] -aminocarbonylmethyl] -benzoic acid ethyl ester Yield: 92% of theory,

Melting point: 213-215 ° C

Calc .: C 66.28 H 5.75 N 5.33 Cl 13.49 F .: 66.45 5.86 5.25 13.51

(m) 4- [N- [2-Piperidino-a- (2-pyridyl) -benzyl] -aminocarbonylmethyl] -benzoic acid ethyl ester Yield: 51% of theory, m.p .: 158-159 ° C

Be r. : C 73 50 H 6 , 83 N 9 , 18 Found .: 73 40 6 95 9 10

(n) 4- [N- [2-piperidino-a- (3-pyridyl) benzyl] aminocarbonylmethyl] -benzoic acid ethyl ester Yield: 85% of theory, Melting point: 172 ⁰ C.

Calc .: C 73.50 H 6.83 N 9.18

F .: 73.42 6.76 9.25

(o) 4- [N- [2-piperidino-a- (4-pyridyl) benzyl] aminocarbonylmethyl] -benzoic acid ethyl ester Yield: 20% of theory, Melting point: 150-152 ⁰ C.

Ber. : C 73 50 H 6 , 83 N 9 , 18 Gef .: C 73 , 61 6 91 9 15

(p) Ethyl 4- [N- (6-chloro-a-phenyl-2-piperidino-benzyl) -aminocarbonylmethyl] -benzoate Yield: 12% of theory, m.p .: oil Calc .: Molpeak m / e = 490 / 492 Found: Molpeak m / e = 490/492

(q) 4- [N- (4-chloro-a-phenyl-2-piperidino-benzyl) -aminocarbo-

nylmethyl] -benzoic acid ethyl ester • yield: 37% of theory, Melting point: 148-150 ⁰ C.

Ber. : C 70 , 94 H 6 , 36 N 5 , 71 Cl 7 , 22 Gef .: 70 , 81 6 25 5 , 61 7 12

(r) Ethyl 4- [N- (3-chloro-a-phenyl-2-piperidinobenzyl) aminocarbonyloxy] benzoate Yield: 74% of theory, m.p .: 176-178 ° C

5 calc .: C 70.94 H 6.36 N 5.71. Cl 7,22 Gef .: 70,59 6,25 5,68 7,16

(s) Ethyl 4- [N- (6-methyl-a-phenyl-2-piperidino-benzyl) -aminocarbonylmethyl] -benzoate Yield: 65% of theory, 10 Melting point: oil

Ber .: Molpeak m / e = 470 Gef .: Molpeak m / e = 470

(t) 4- [N- (5-methyl-a-phenyl-2-piperidino-benzyl) -aminocarbo-

methyl nylmethyl] benzoate Yield: 48% of theory, m.p .: 171-173 ° C

Calc .: C 76.57 H 7.28 N 5.95

Gef .: 76.75 7.35 5.72

(u) 4- [N- (4-Methyl-a-phenyl-2-piperidino-benzyl) -aminocarbo-20-nylmethyl] -benzoic acid ethyl ester

Yield: 76% of theory, '. Melting point: 133-135 ° C calc .: C

Found .:

25 (v) 4- [N- (5-methoxy-a-phenyl-2-piperidino-benzyl) -aminocarbo ⁱ nylmethyl] -benzoic acid ethyl ester -

Yield: 10% of theory, melting point: 122-125 ° C Calc .: Molpeak m / e = 486 Ft .: Molpeak m / e = 486

76 , 57 H 7 , 28 N 5 95 76 , 51 7 16 5 , 83

(w) Ethyl 4- [N- (6-methoxy-a-phenyl-2-piperidino-benzyl) aminocarbonylmethyl] -benzoate Yield: 97% of theory, m.p .: oil Calc. M.p. m / e = 486 .: Molpeak m / e = 486

(x) methyl 3-chloro-4- [N- (α-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoate. Yield: 42% of theory, m.p .: 175-176 ° C. Calc .: C 70, 93 H 6,36 N 5,71 Cl 7,22 Found: 70,65 6,36 5,50 7,29

(y) 4- [N- (2-Dimethylamino-α-phenyl-benzyl) -aminocarbonylmethyl] -benzoic acid ethyl ester. Yield: 67% of theory, m.p .: 116-118 ° C

Gef .:

(z) 4- [N- (2-Di-n-propylamino-a-phenyl-benzyl) -aminocarbonyl-

Methyl] -benzoic acid ethyl ester 20 Yield: 76% of theory, m.p .: 138-139 ° C Ber. : C

Found .:

(aa) 4- [N- [2- (Octahydro-1H-azonino) -a-phenyl-benzyl] -aminocarbonylmethyl] -benzoic acid ethyl ester. Yield: 71% of theory, m.p .: oil Ber .: Molpeak m / e = 498 Gef .: Molpeak m / e = 498

74 97 H 6 77 N 6 , 73 75 13 6 60 6 , 78

76 24 H 7 , 68 N 5 , 93 76 , 41 7 , 79 5 , 81

(ab) 4- [N- [5-chloro-2- (2-methyl-piperidino) -a-phenyl-benzyl] -aminocarbonylmethyl] -benzoic acid ethyl ester Yield: 36.5% of theory,

Melting point: 171-173 ° C

Calcd .: C, 71.24, H, 6.58, N, 5.54, Cl, 7.01, Found: 71.45, 6.68, 5.59, 7.20

(ac) 4- [N- [2- (3,3-Dimethyl-piperidino) -α-phenyl-benzyl] -aminocarbonylmethyl] -benzoic acid ethyl ester

Yield: 91% of theory,

Melting point: 146-148 ° C

Calc .: C 76.82 H 7.49 N 5.78

Gef .: 76.91 '7.55 5.61

Example 2

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

To a solution of 6.02 g (20 mmol) of α- (4-chloro-phenyl) -2-piperidino-benzylamine and 3.5 ml (25 mmol) of triethylamine in 50 ml of chloroform is added dropwise, with ice cooling, a solution of 5 g (22.1 mmol) of 4-ethoxycarbonyl-phenylacetyl chloride in 20 ml of chloroform. The mixture is stirred at room temperature for two hours, then added to water and extracted with chloroform. The extracts are dried and concentrated. The concentration residue is chromatographed on silica gel with toluene / ethyl acetate 5: 1 as eluent.

Yield: 5.6 g (57% of theory), m.p .: 178-181 ° C

Calcd .: C, 70.94, 6.36, N, 5.71, Cl, 7.22, Found: 71.09, 6.47, 5.61, 7.10

- 50 was prepared analogously to Example 2:

(a) 4- [N- [5-chloro-2- (3-methyl-piperidino) -a-phenyl-benzyl] aminocarbonylmethyl] -benzoic acid ethyl ester Yield: 54% of theory, Melting point: 178-180 ⁰ C.

Calc .: C 71.24 H 6.58 N 5.54 Cl 7.01 Found: 70.91 6.64 5.75 7.01

Example 3

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

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

Yield: 2.45 g (59.3% of theory), m.p .: 226-228 ° C

Calc .: C, 75.99, H, 6.83; N, 6.33, Found: 75.60, 6.75, 6.29

Analogously to Example 3 were prepared:

(a) 4- [N- [α- (3-methylphenyl) -2-piperidinobenzyl] aminocarbonylmethyl] benzoic acid. Yield: 72% of theory,

Melting point: 202-203 ° C Calc .: C 75.99 H 6.83 N 6.33 Found: 75.64 6.91 6.37

(b) 4- [N- [α- (2-methyl-phenyl) -2-piperidino-benzyl] aminocarbonylmethyl] -benzoic acid Yield: 42.6% of theory, Melting point: 285-290 ⁰ C.

Calc .: C 75 99 H 6 , 83 N 6 , 33 Found .: 76 , 05 6 , 98 6 25

Ber. : C 73 , 34 H 6 , 59 N (Tl , 11 Gef .: 73 , 22 6 , 61 6 13

(c) 4- [N- [α- (4-methoxy-phenyl) -2-piperidino-benzyl] -aminocar · bonylmethyl] -benzoic acid Yield: 72.4% of theory, Melting point: 228-230 ⁰ C.

(d) 4- [N- [α- (4-benzyloxy-phenyl) -2-piperidino-benzyl] aminocarbonylmethyl] -benzoic acid Yield: 57% of theory, Melting point: 219-221 ⁰ C.

Ber. : C 76 , 38 H (Ti , 41 N 5 24 Gef .: 76 , 05 6 , 44 5 24

(e) 4- [N- [α- (4-Fluoro-phenyl) -2-piperidino-benzyl] -aminocarbonylmethyl] -benzoic acid. Yield: 75% of theory, m.p .: 238-24O ⁰ C

Ber. : C 72 , 63 H 6 , 09 N 6 , 27 Gef .: 72 , 98 6 , 29 6 , 32

(f) 4- [N- [α- (2-fluoro-phenyl) -2-piperidino-benzyl] -aminocarbonylmethyl] -benzoic acid. Yield: 87% of theory,

Melting point: 280-283 ° C Calc .: C 72.63 H 6.09 N 6.27 F .: 72.70 6.10 6.37

(g) 4- [N- [α- (4-Chloro-phenyl) -2-piperidino-benzyl] -aminocarbonylmethyl] -benzoic acid. Yield: 89% of theory, m.p .: 241-242 ° C

Ber. : C 70 , 05 H 5 , 88 N 6 , 05 Cl 7 , 66 Gef .: 69 , 74 6 , 05 6 , 01 7 , 64

Ber. : C 70 , 05 H 5 , 88 N 6 , 05 Cl 7 , 66 Gef .: 70 , 28 5 , 98 5 , 78 7 , 84

(h) 4- [N- [α- (3-chloro-phenyl) -2-piperidino-benzyl] aminocarbonylmethyl] -benzoic acid Yield: 53% of theory, Melting point: 223-225 ⁰ C.

(i) 4- [N- [α- (2-chloro-phenyl) -2-piperidino-benzyl] aminocarbonylmethyl] -benzoic acid Yield: 98% of theory, Melting point: 303-305 ⁰ C.

Calc .: C 70 , 05 H 5 , 88 N 6 , 05 Cl 7 , 66 Found .: 69 , 88 6 , 05 5 , 87 7 , 74

(k) 4- [N- [α- (4-Methylmercaptophenyl) -2-piperidinobenzyl] aminocarbonylmethyl] benzoic acid. Yield: 84.6% of theory, m.p .: 225-227 ° C

Calc .: C, 70.86, H, 6.37; N, 5.90; S, 6.75, F .: 70.34, 6.37, 5.68, 6.82

(1) 4- [N- [5-chloro-a- (2-chloro-phenyl) -2-piperidino-benzyl] aminocarbonylmethyl] -benzoic acid Yield: 90% of theory, Melting point: 317-320 ⁰ C.

C 65 19 - H 53 - N 5, 63 Cl 14 25 Ber. : 64 , 87 5, 27 5, 69 14 , 22 Gef .: 5, 34

(m) 4- [N- [2-piperidino-a- (2-pyridyl) benzyl] -aminocarbonylme · thyl] benzoic acid yield: 81% of theory, Melting point: 160-161 ⁰ C.

Calc .: C 72 , 71 H 6 , 34 N 9 , 78 Found .: 72 , 43 6 , 39 10 00

j (n) 4- [N- [2-Piperidino-a- (3-pyridyl) -benzyl] -aminocarbonylmethane

thyl] benzoic acid

Yield: 72% of theory,

Melting point: 252-253 ⁰ C calc .: C 72.71 H 6.34 N 9.78

j Gef .: 72.56 6.53 9.60

(o) 4- [N- [2-Piperidino-a * (4-pyridyl) -benzyl] -aminocarbonylmethane

ethyl] benzoic acid yield: 68.5% of theory,

j melting point: from 260 ^° C. (decomposition)

Calc .: C, 72.71, H, 6.34, N, 9.78, F, 72.31, 6.29, 9.63

ι ν -:

(p) 4- [N- (6-chloro-a-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid. Yield: 82% of theory, m.p .: 91-94 ° C

25

Calc .: C 70 , 04 H 5 , 88 N 6 , 05 Cl 7 , 66 Found .: 69 , 61 5 77 5 96 7 , 78

(q) 4- [N- (4-chloro-a-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid. Yield: 61% of theory, m.p .: 221-223 ° C

Calc .: C 70 , 05 H 5 , 88 N 6 , 05 Cl 7 , 66; Found .: 69 , 73 5 , 89 5 , 87 7 , 52

(r) 4- [N- (3-chloro-a-phenyl-2-piperidino-benzyl) aminocarbonylmethyl] -benzoic acid Yield: 83% of theory, Melting point: 210-213 ⁰ C.

Ber. : C 70 , 05 H 5 , 88 N 6 , 05 Cl 7 , 66 Found .: 70 , 31 6 , 03 5 90 7 , 79

(s) 4- [N- (6-methyl-a-phenyl-2-piperidino-benzyl) aminocarbonylmethyl] -benzoic acid Yield: 64% of theory, Melting point: 165-170 ⁰ C (sintering from 150 ⁰ C) CALC .: C, 75.99, H, 6.83, N, 6.33, Found: 75.73, 6.96, 6.14

(t) 4- [N- (5-Methyl-a-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid. Yield: 97% of theory, m.p .: 243-245 ° C

Ber. : C 75 99 H 6 , 83 N 6 , 33 Gef .: 75 60 7 , 01 6 , 31

(u) 4- [N- (4-methyl-ct-phenyl-2-piperidino-benzyl) -aminocarbonylmethyl] -benzoic acid

Yield: 96% of theory, Melting point: 202-203 ⁰ C.

Ber. : C 75 99 H 6 , 83 N 6 , 33 Gef .: 76 , 04 6 , 78 6 , 23

(v) 4- [N- (5-Methoxy-a-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid

Yield: 27% of theory, Melting point: 217-220 ⁰ C (sintering from 203 ⁰ C) Calc .: C 73.34 H 6.59 N 6.11 Found .: 72.92 6.68 5.99

(w) 4- [N- (6-methoxy-a-phenyl-2-piperidino-benzyl) aminocarbonylmethyl] -benzoic acid Yield: 51.5% of theory, Melting point: 90-95 ⁰ C

Calc .: C 73.34 H 6.59 N 6.11 Found: 73.03 6.42 5.86

(x) 4- [N- [5-Chloro-2- (3,5-cis -dimethyl-piperidino) -α-phenylbenzyl] -aminocarbonylmethyl] -benzoic acid. Yield: 81% of theory, m.p .: 253-255 ° C

Calcd .: C, 70.93, H, 6.36, N, 5.71; Cl, 7.22, Found: 70.68, 6.51, 5.73, 7.36

(y) 4- [N- (2-Dimethylamino-α-phenylbenzyl) aminocarbonylmethyl] benzoic acid

Yield: 83% of theory, melting point: 183-184 ° C

Calc .: C 74,20 H 6,23 N 7,21 F .: 74,31 6,27 7,16

(z) 4- [N- (2-Di-n-propylamino-α-phenylbenzyl) aminocarbonylmethyl] benzoic acid

Yield: 79% of theory, Melting point: 202-204 ⁰ C.

Ber. : C 75 , 64 H 7 , 26 N 6 30 Gef .: 75 , 74 7 , 31 6 15

(aa) 4- [N- [5-chloro-2- (2-methylpiperidino) -α-phenylbenzyl] aminocarbonylmethyl] benzoic acid. Yield: 52% of theory,

Melting point: 280-282 ⁰ C

Calc .: C 70.50 H 6,13 N 5,87 Cl 7,43 F .: 70,14 6,10 5,75 7,45

(ab) 4- [N- [5-Chloro-2- (3-methyl-piperidino) -α-phenyl-benzyl] -aminocarbonylmethyl] -benzoic acid Yield: 66% of theory, m.p .: 246-248 ° C

Calc .: C 70.50 H 6,13 N 5,87 Cl 7,43 F .: 70,16 6,07 5,87 7,30

(ac) 4- [N- [2- (3,3-dimethyl-piperidino) -α-phenyl-benzyl] aminocarbonylmethyl] -benzoic acid Yield: 59% of theory, Melting point: 238-240 ⁰ C.

Calc .: C 76.28 H 7.07 N 6.14 Found: 76.38 7.28 6.11

(ad) 3-Chloro-4- [N- (α-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid

Yield: 56% of theory, melting point: 236-239 ° C

Calc .: C 70.04 H 5.88 N 6.05 Cl 7.66 F .: 69.88 5.77 5.86 7.81

(ae) 4- [N- [2- (3,5-cis-dimethyl piperidino) -5-nitro-a-phenylbenzyl] aminocarbonylmethyl] -benzoic acid Yield: 81% of theory, Melting point: from 255 ⁰ C ( Decomposition) Calc .: C, 69.44, H, 6.23, N, 8.38, Found: 68.95, 6.44, 8.53

, (af) 4- [N- [2- (octahydro-1H-azoneino) -α-phenyl-benzyl] -aminocarbonylmethyl] -benzoic acid. Y Yield: 62.5% of theory, m.p .: 235-237 ° C

Ber. : C 76 , 56 H 7 , 28 N 5 95 Found .: 76 50 7 30 5 , 94

(aq) 4- [N- (5-hydroxy-a-phenyl-2-piperidino-benzyl) aminocarbonylmethyl] -benzoic acid Yield: 71% of theory, Melting point: 98-101 ⁰ C.

Be r. » C 72 95 H 6 35 N 6 30 Gef. 4 72 , 98 6 40 6 , 47 example

4- [N- [α- (4-Hydroxy-phenyl) -2-piperidino-benzyl] -aminocarbonylmethyl] -benzoic acid

1.1 g (2 mmol) of 4- [N- [α- (4-benzyloxy-phenyl) -2-piperidinobenzyl] -aminocarbonylmethyl] -benzoic acid are suspended in 200 ml of ethanol and at 50 ⁰ C and a hydrogen pressure of 5 bar catalytically debenzylated in the presence of 0.4 g of 10% palladium / carbon. The catalyst is then filtered off, concentrated and recrystallized from acetonitrile. Yield: 720 mg (66.7% of theory), Melting point: 202-204 ⁰ C.

Calc .: C 72.95 H 6.35 N 6.30 F .: 72.65 6.17 6.20

Analogously to Example 4 was prepared:

(a) 4- [N- (5-Hydroxy-a-phenyl-2-piperidino-benzyl) -aminocarbonylmethyl] -benzoic acid ethyl ester Yield: 93% of theory, m.p .: 191-193 ° C

Calc .: C 73.70 H 6.82 N 5.93 F .: 73.52 6.57 5.61

Example 5

4- [N- [α- (4-methylphenyl) -2p: -> eridinobenzyl] aminocarbonylmethyl] benzyl alcohol ,

2.5 g (5.3 mmol) of ethyl 4- [N- [α- (4-methylphenyl) -2-piper-id-5-yl] -aminocarbonylmethyl] -benzoate are added in portions to a suspension of 0 , 5 g (13.2 mmol) of lithium aluminum hydride in 50 ml of absolute tetrahydrofuran. The mixture is stirred for a further 30 minutes at room temperature, decomposed by dropwise addition of 4 N sodium hydroxide solution and filtered from the sodium aluminate formed. The filtrate is concentrated and the residue is recrystallized from a little toluene. Yield: 0.98 g (43% of ⁿ ? Fore),

Melting point: 144-146 ° C;

Calc .: C 78.47 H 7.53 N 6.54 Γ

Gef .: 78,20 7,39 6,58 |

    , ·. · ..-. ' ι

Analogously to Example 5 was prepared:

(a) 4- [N- [α-phenyl-2-piperidine-benzyl) -aminocarbonylmethyl] -

benzyl alcohol, ^c

Yield: 31.5? theory, *. · << * ϊ · ~ \ -. /,

Melting point: 143-145 ° C - ""'i'

Calc .: C 78.23 H 7.29 N 6.76 -j 1 *

Gef .: 78,13 7,30 6,62 : \ '

Example 6

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

8.85 g (20 mmol) of 4- [N-fα- (4-methylphenyl) -2-piperidinobenzyl] aminocarbonylmethyl] benzoic acid and 3.25 g (20 mmol)

Ν, Ν'-Carbonyldiimidazol be heated in 100 ml of absolute tetrahydrofuran for 2 hours at reflux. It is then concentrated and boiled for a further 2 hours after addition of 50 ml of pyridine and 3.7 g (20 mmol) of 4-toluenesulfonic acid hydrazide at reflux. Then you are on ice water, filtered off with suction and dried the precipitate. The thus obtained crude Toluolsulfonsäurehydrazid the carboxylic acid used is mixed with 20 g of anhydrous sodium carbonate and heated to 170 ⁰ C in 50 ml of ethylene glycol for two hours. Then add water and extract with chloroform. The concentrated extracts are purified by column chromatography on silica gel with toluene / ethyl acetate 5: 1 as eluant. Yield: 1.73 g (21% of theory), m.p .: 144-146 ° C

Calc .: C 78.84 H 7.09 N 6.57 G .: 78.95 7.19 6.50

Analogously to Example 6 was prepared:

(a) 4- [N- [α-Phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzaldehyde

Yield: 29% of theory, melting point: 168-170 ⁰ C.

Calc .: C 78.61 H 6.84 N 6.79 G .: 78.60 7.00 6.72

Example 7

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

0.5 g (1.2 mmol) of 4- [N- [α- (4-methyl-phenyl) -2-piperidino-benzyl] -aminocarbonylmethyl] -benzyl alcohol is added to a suspension of 0.4 g (1, 5 mmol) of pyridinium chlorochromate in 2 ml of chloroform. After 12 hours at room temperature with

Ether added, filtered and the concentrated filtrate on silica gel purified by column chromatography (eluent: toluene / ethyl acetate = 5: 1)

 Yield: 0.3 g (60% of theory), m.p .: 145-146 ° C

Calc .: C 78.84 H 7.09 N 6.57 V .: 78.97 7.12 6.57

Analogously to Example 7 was prepared:

(a) 4- [N- (α-Phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzaldehyde

Yield: 40% of theory, melting point: 170 ^° C.

Ber. : C 78 , 61 H 6 , 84 N 6 , 79 Gef .: 78 , 59 6 , 87 6 , 61

Example 8

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

427 mg (1 mmol) of 4- [N- [α- (4-methylphenyl) -2-piperidinobenzyl] aminocarbonylmethyl] benzaldehyde are added to an ethereal solution of 450 mg (2 mmol) of diethylphosphonoacetic acid.

acid ethyl ester and 100 mg (2 mmol) of 50% sodium hydride]. After stirring overnight, it is decomposed with water and extracted with chloroform and purified by column chromatography on silica gel with toluene / ethyl acetate: acid 5: 1 as eluent.

Yield: 0.18 g (36% of theory), Melting point: 176-180 ⁰ C.

Calc .: C 77.39 H 7.31 N 5.64 F .: 77.64 7.25 5.71

- 61 was prepared analogously to Example 8:

(a) 4- [N- (α-Phenyl-2-piperidinobenzyl) aminocarbonylmethyl] cinnamic acid ethyl ester. Yield: 28.6% of theory, m.p .: 159-161 ° C

Calc .: C 77.14 H 7.10 N 5.80 F .: 77.28 7.21 5.65

Example 9

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

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

 Yield: 84% of theory,! Melting point: 173-176 ° C

Calc .: C 76.90 H 6.88 N 5.98 F .: 77.24 7.01 5.64

Analogously to Example 9 was prepared:

(a) 4- [N- (α-Phenyl-2-piperidinobenzyl) aminocarbonylmethyl] cinnamic acid

Yield: 75% of theory, Melting point: 177-180 ⁰ C.

Calc .: C 76.62 H 6.65 N 6.16 F .: 76.75 6.57 6.07

- 62 Example 10

4- [N- [α- (3-Methyl-phenyl) -2-piperidino-benzyl] -aminocarbon, γ-methyl] -benzoic acid ethyl ester

A mixture of 0.22 g (0.8 mmol) of α- (3-methylphenyl) -2-piperidinobenzyl alcohol and 0, at room temperature is added dropwise to 1.5 ml of o-dichlorobenzene and 1.5 ml of concentrated sulfuric acid. 15 g (0.8 mmol) of ethyl 4-cyanomethylbenzoate in 2 ml of o-dichlorobenzene. After stirring for 2 hours, it is added to ice-water, extracted once with ether, made alkaline with dilute sodium hydroxide solution and extracted with chloroform. The chloroform extract is concentrated and the residue is recrystallized from ethanol.

Yield: 0.22 g (60% of theory), m.p .: 158-159 ° C. Calc .: C 76.57 H 7.28 N 5.95 Found: 76.41 7.39 5.76

The following compound was prepared analogously to Example 10:

(a) 4- [N- [2- (3,5-cis -dimethyl-piperidino) -5-nitro-a-phenylbenzyl] -aminocarbonylmethyl] -benzoic acid ethyl ester Yield: 57% of theory, m.p .: 170-173 ⁰ C

Calc .: C 70.30 H 6.66 N 7.93 F .: 70.05 6.68 7.81

Example 11

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

240 mg (5 mmol) of 4- [N- [5-chloro-a- (4-methylphenyl) -2-piperidinobenzyl] aminocarbonylmethyl] benzoic acid are dissolved in 80 ml of ethanol / dioxane 1/1 in the presence of 0.1 g of palladium

on carbon (10%) at 50 ⁰ C and a hydrogen pressure of bar catalytically dehalogenated. After cooling, the catalyst is filtered off. The filtrate is concentrated and the residue is recrystallized from ethanol. Yield: 0.16 g (72% of theory), m.p .: 226-228 ° C. Calc .: C, 75.99, H, 6.83, N, 6.33, Found: 75.81, 6.73, 6.10

Analogously to Example 11 were prepared:

(a) 4- [N- [2- (2-Methyl-piperidino) -ot-phenyl-benzyl] -aminocarbonylmethyl] -benzoic acid from 4- [N- [5-chloro-2- (2-methyl-piperidino) -α-phenylbenzyl] -aminocarbonylmethyl] -benzoic acid Yield: 68% of theory, m.p .: 246-248 ° C Calc .: C, 75.99, H, 6.83, N, 6.33, Foth .: 75.57, 7.10 6, 44

(b) 4- [N- [2- (3-Methylpiperidino) -a-phenyl-benzyl] -aminocarbonylmethyl] -benzoic acid from 4- [N- [5-chloro-2- (3-methyl-piperidino) -a-phenyl-benzyl] aminocarbonylmethyl] -benzoic acid yield: 43% of theory, melting point: 228-230 ⁰ C Calc .: C 75.99 H 6.83 N 6.33 Found .: 75.91 6.82 6.33

Example 12

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

A solution of 2.78 g (10 mmol) of freshly prepared (4-methyl-phenyl) - (2-piperidino-phenyl) -ketimin in 50 ml of methylene chloride is treated with l _r 5 ml (11 mmol) of triethylamine, then under ice-cooling dropwise with a solution of 2.5 g (11 mmol) of 4-ethoxycarbonyl-phenylacetic acid chloride in 20 ml of methylene chloride. After 1 hour at Raumtempertur are added to ice-water and extracted with methylene chloride. The extracts are dried and concentrated, and the concentration residue on silica gel is purified by column chromatography (eluent: toluene / ethyl acetate 10: 1). The crude acylimine is dissolved in dimethylformamide and hydrogenated after addition of 0.5 g of palladium (10% on charcoal) at 5 bar hydrogen pressure at room temperature. After taking up the calculated amount of hydrogen is filtered off from the catalyst, concentrated and the residue recrystallized from a little alcohol.

Yield: 2.8 g (60% of theory), m.p .: 175-177 ° C

Calc .: C 76.57 H 7.28 N 5.95 F .: 76.41 7.19 5.76

Example 13

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

Prepared from α- (4-methylphenyl) -2-piperidinobenzylamine and 4-cyano-phenylacetic acid analogously to Example 1.

Yield: 64% of theory, melting point: 144-146 ° C

Calc .: C 79.40 H 6.90 N 9.92 F .: 79.10 6.90 9.78

Analogously to Example 13 was prepared:

(a) 4- [N- (α-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzonitrile

Yield: 53% of theory, melting point: 178-181 ° C

Ber. : C 79 , 18 H 6 65 N 10 , 26 Found .: 78 , 84 6 , 55 10 24

Example 14

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

4.2 g (10 mmol) of 4- [N- [α- (4-methyl-phenyl) -2-piperidino-benzyl] -aminocarbonylmethyl] -benzonitrile are refluxed with 50 ml of ethanolic hydrochloric acid for 24 hours The reaction mixture is mixed with aqueous sodium bicarbonate solution and extracted with chloroform, the chloroform extract is concentrated and the residue is triturated with ethanol and filtered with suction to yield 2.9 g (61.6% of theory), m.p .: 177-179 ° C. .: C 76.57 H 7.28 N 5.95 F .: 76.41 7.35 5.76

Analogously to Example 14 was prepared:

(a) 4- [N- (5-Methyl-a-phenyl-2-piperidino-benzyl) -aminocarbonyl-methyl] -benzoic acid ethyl ester

Yield: 57% of theory, Melting point: 170-173 ⁰ C.

Calc .: C 76.57 H 7.28 N 5.95

Gef.i 76.41 7.19 5.65

Example 15

J- [N- [5-chloro-a- (2-chloro-phenyl) -2-piperidino-behzyl] -minino- carbony! -Methyl] -benzoic-acid-a-thyate ~

10 mmol of 4- [N- [α- (2-chloro-phenyl) -5-nitro-2-piperidino-benzyl] -aminocarbonylmethyl] -benzoic acid ethyl ester are dissolved in 50 ml of dimethylformamide and, after addition of 1 g of Raney nickel hydrogenated at 60 ⁰ C and a hydrogen pressure of 6 bar. The catalyst is then filtered off, the filtrate is concentrated and the residue consisting of 4- [N- [5-amino-a- (2-chloro-phenyl) -2-piperidino-benzyl] -aminocarbonylraethyl] -benzoic acid ethyl ester in 100 Dissolved ml of concentrated hydrochloric acid. Under ice-cooling, a solution of 1.0 g (14 mmol) of sodium nitrite in 10 ml of water is then added dropwise and stirred at 0 - 5 ° C for 1 hour. The reaction mixture is then added dropwise to a solution of g of copper (I) chloride in 25 ml of concentrated hydrochloric acid.

After one hour of stirring is made alkaline with sodium hydroxide solution and extracted with chloroform. The concentrated chloroform extracts are purified by silica gel chromatography on silica gel in eluent toluene / ethyl acetate 5: 1 *

Yield: 1.5 g (28.6% of theory), m.p .: 213-215 ° C

Calc .: C 66.28 H 5.75 N 5.33 Cl 13.49: Found: 66.40 5.91 5.41 13.40

- 67 was prepared analogously to Example 15:

(a) 4- [N- [5-Chloro-2- (3,5-cis -dimethyl-piperidino) -α-phenylbenzyl) -aminocarbonylmethyl] -benzoic acid ethyl ester Yield: 28% of theory, m.p .: 188-191 ⁰ C

Calc .: C 71.72 H 6.80 N 5.40 Cl 6.83 Found: 71.95 6.85 5.35 6.77

Example 16

3- [4- [N- (α- (4-methylphenyl) -2-piperidino-benzyl) aminocarbonylmethyl] phenyl] propionic acid

0.91 g (2 mmol) of 4- [N- (α- (4-methylphenyl) -2-piperidinobenzyl) aminocarbonylmethyl] cinnamic acid are dissolved in 50 ml of methanol and, after addition of 0.5 g of palladium (10 % on carbon) at room temperature and a hydrogen pressure of 3 bar catalytically hydrogenated. After completion of the hydrogen uptake, the catalyst is filtered off and recrystallized from a little acetonitrile. Yield: 0.68 g (74% of theory), m.p .: 146-148 ° C

Calc .: C 76.57 H 7.28 N 5.95 F .: 76.41 7.19 5.61

Analogously to Example 16 was prepared:

(a) 3- [4- [N- (α-Phenyl-2-piperidino-benzyl) -aminocarbonylmethyl] -phenyl] -propionic acid

 Yield: 65% of theory, melting point: 97-99 ° C

Calc .: C 76.30 H 7.06 N 6.13 F .: 76.35 6.95 5.91

Example 17

4- [N- (α- (4-Methylphenyl) -2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid, sodium salt

442 mg (1 mmol) of 4- [N- (α- (4-methyl-phenyl) -2-piperidino-benzyl) -aminocarbonylmethyl] -benzoic acid are dissolved in 25 ml of ethanol and admixed with 1 ml of 1 N sodium hydroxide solution. Then concentrated in vacuo, mixed with 20 ml of acetone, filtered off with suction from the precipitate and washed with ethyl acetate

Yield: 410 mg (85% of theory), Melting point: 295-300 ⁰ C.

Calc .: C 72.40 H 6,29 N 6,03 Found: 72,15 6,46 5,93

Analogously to Example 17 were prepared:

(a) 4- [N- (α- (4-Methyl-phenyl) -2-piperidino-benzyl) -aminocarbonylmethyl] -benzoic acid ethanolamine salt. Yield: 75% of theory, m.p .: 188-191 ° C 71.55 H 7.41 N 8.34 F .: 71.16 7.48 8.52

(b) 4- [N- (α- (4-methylphenyl) -2-piperidino-benzyl) aminocarbonylmethyl] -benzoic acid diäthanolaminsalz Yield: 81% of theory, Melting point: 178-180 ⁰ C.

Calc .: C 70.70 H 6.86 N 7.73 F .: 70.25 6.75 7.58

(c) 4- [N- (α- (4-methylphenyl) -2-piperidino-benzyl) aminocarbonylmethyl] -benzoic acid triethanolamine salt Yield: 76% of theory, Melting point: 160-165 ⁰ C.

Calc .: C 69.01 H 7.67 N 7.10 F .: 68.91 7.64 7.45

(d) 4- [N- (α- (4-methylphenyl) -2-piperidino-benzyl) aminocarbonylmethyl] -benzoic acid äthylendiaminsalz Yield: 65% of theory, Melting point: 160-163 ⁰ C.

Calc .: C 71.69 H 7.62 N 11.15 F .: 72.04 7.80 10.96

Example 18

Ethyl 4- [N- (5-methoxy-a-phenyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoate

472 mg (1 mmol) of ethyl 4- [N- (5-hydroxy-a-phenyl-2-piperidino-benzyl) -aminocarbonylmethyl] -benzoate are dissolved in 25 ml of absolute dimethylformamide. After addition of 50 mg of 50% sodium hydride is stirred for 30 minutes. Then added dropwise 0.5 g of methyl iodide and stirred overnight. For workup, it is added to ice-water and extracted with methylene chloride. The concentrated extracts are purified by column chromatography on silica gel with toluene / ethyl acetate 4: 1 as eluent, ι yield: 260 mg (53% of theory),: melting point: 123-125 ⁰ C.

! Calc .: C 74.05 H 7.04 N 5.76: Gef .: 73.86 6.95 5.61

Example 19

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

To a solution of 0.55 g (2.34 mmol) of 2-methoxy-1- (2-piperidino-phenyl) ethylamine in 5 ml of acetonitrile is added successively 0.49 g (2.34 mmol). 4-ethoxycarbonyl-phenylacetic acid, 0.73 g (2.78 mmol) of triphenylphosphine, 0.50 ml (3.66 mmol) of triethylamine and 0.23 ml (2.34 mmol) of carbon tetrachloride, and stirred for 20 hours at room temperature.

It is then evaporated in vacuo and partitioned between ethyl acetate and water. The organic extract is dried, filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene / acetone = 10/2).

Yield: 0.45 g (45% of theory), Melting point: 122-123 ⁰ C.

! Calc .: C 70.73 H 7.60 N 6.60! Gef. 71.04 7.48 6.39

Analogously to Example 19, the following compounds were obtained:

I (a) Ethyl 4 - [(1- (3-chloro-2-piperidino-phenyl) -l-butyl) -aminocarbonylmethyl] -benzoate Yield: 55% of theory, m.p .: 141-143 ° C

(b) 4 - [(1- (6-chloro-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester Yield: 73.9% of theory,

Melting point: 79-82 ° C Calc .: C 68.33 H 7,28 Cl 7,76 N 6,13 F .: 68,45 7,24 7,80 6,09

Ber. : C 68 , 33 H 7 , 28 Cl 7 , 76 N 6 13 Found .: 68 30 7 8th , 03 6 20

(c) 4 - [(1- (4-Bromo-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester Yield: 62.1% of theory, m.p .: 116-118 ° C

Calc .: C 62 , 27 H 6 , 63 br 15 , 93 N 5 , 58 Found .: 62 , 53 6 48 15 , 98 5 , 66

(d) 4 - [(1- (4-nitro-2-piperidino-phenyl) -1-butyl) aminocarbonylmethyl] -benzoic acid ethyl ester Yield: 74.6% of theory, Melting point: 127-130 ⁰ C.

Calc .: C 66.79 H 7> 11 N 8.99 Found: · 66.88 7.08 9.15

(e) 4 - [(1- (3-Methyl-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester. Yield: 68% of theory, m.p .: 145-147 ° C

Calc .: C 74.28 H 8,31 N 6,42 ^! Gef .: 74.40 8.30 6.41

(f) 4 - [(1- (4-Methyl-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester. Yield: 54.7% of theory, m.p .: 113-114 ° C

Calc .: C 74.28 H 8, * 31 N 6.42 F .: 74.23 8.30 6.55

(g) 4 - [(1- (5-methyl-2-piperidino-phenyl) -1-butyl) aminocarbonylmethyl] -benzoic acid ethyl ester Yield: 67.9% of theory, Melting point: 149-150 ⁰ C.

(h) 4 - [(1- (6-Methyl-2-piperidino-phenyl) -1-butyl) -aminocarbo-, nylmethyl] -benzoic acid ethyl ester

Ber. : C 74 , 28 H 8th , 31 N 6 , 42 Found .: 74 , 38 8th , 21 6 , 49

Yield: 47% of theory, melting point: 92-93 ° C. Calc .: C 74.28 H 8.31. Foth .: 74.50 8.46

N 6,42 6,48

(i) 4 - [(1- (2-Pyrrolidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester. Yield: 57.3% of theory, m.p .: 122-125 ° C

Ber. : C 73 50 H 7 90 N 6 , 86 Gef .: 73 , 63 8th , 07 7 , 01

(k) Ethyl 4 - [(1- (2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoate Yield: 71.5% of theory, m.p .: 127-128 ° C

Calc .: C 73 90 H 8 ', Il N 6 , 63 Found .: 73 90 8.06 6 72

(1) 4 - [(1- (2- (4-Methyl-piperidino) -phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester Yield: 51.1% of theory, m.p .: 153-155 ° C

Calc .: C 74.28 H 8.31 N 6.42

Gef .: 74.55 8.33 6.45

(m) 4 - [(1- (2-hexahydroazepino-phenyl) -1-butyl) -aminocarbo

nylmethyl] -benzoic acid ethyl ester: Yield: 42.7% of theory,! Melting point: 145-147 ° C

j Ber .: C 74.28 H 8,31 N 6,42 L-Fe: 73,98 8,26 6,58

'. (n) ethyl 4 - [(1- (5-fluoro-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoate Yield: 55% of theory,

Melting point: 128-130 ° C. Calc .: C 70.88 H 7.55 N 6.36 V .: 71.14 7.57 6.49

(o) Methyl 4 - [(1- (2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoate Yield: 63.2% of theory, m.p .: 147-148 ° C

Calc .: C 73 50 H 7 90 N 6 , 86 Found .: 73 , 66 7 , 88 6 80

.10 (p) 4- [(1- (2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid n-butyl ester. Yield: 50.9% of theory, m.p .: 117-119 ° C ( Ether) Calc .: C 74.63 H 8.50 N 6.22 Found: 74.49 8.46 6.14

(q) Ethyl 3-chloro-4 - [(1- (2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoate Yield: 14.9% of theory, m.p .: <2O ⁰ C m / e = 456/458 (1 chlorine) F: m / e = 456/458 (1 chlorine)

(r) 4 - [(1- (2-piperidino-phenyl) -4-penten-l-yl) -aminocarbonylme thyl] benzoic acid ethyl ester Yield: 18.9% of theory, Melting point: 103-105 ⁰ C.

Ber. : C 74 , 62 H 7 , 89 N 6 45 Gef .: 75 , 01 8th 10 6 , 26

(s) 4 - [(1- (3-Chloro-2-piperidino-phenyl) -1-ethyl) -aminocarbonylmethyl] -benzoic acid ethyl ester. Yield: 58.0% of theory, m.p .: 166-168 ° C

20 C 67 20 H - 74 - Cl 8th , 27 N 6 , 53 Ber. : 67 17 6 8th 17 6 45 Gef .: 6 example , 81 85

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

To a stirred solution of 15.1 g (54.4 mmol) of 1- (5-nitro-2-piperidino-phenyl) -1-butylamine and 8.46 ml (61.4 mmol) of triethylamine in 55 ml of dry methylene chloride is added dropwise the solution of 14.6 g (64.6 mmol) of 4-Äthoxycarbonyl-phenylessigsäurechlorid in 20 ml of methylene chloride within 30 minutes so that the temperature of 30 ⁰ C is not exceeded. The mixture is stirred for 2 hours at room temperature, 300 ml of methylene chloride are added and shaken twice with 50 ml of water. The organic phase is dried over sodium sulfate, filtered and evaporated in vacuo. The red-brown, oily evaporation residue is purified by column chromatography on silica gel (toluene / acetone = 10/1). Yield: 17.7 g (69.7% of theory), m.p .: 135-137 ° C. (ether)

Calc .: C 66.79 H 7.11 N 8.99 F .: 66.73 6.99 9.09

The following compounds were obtained analogously to Example 20:

(a) Ethyl 4 - [(1- (2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoate Yield: 80.2% of theory, m.p .: 127-129 ° C

Ber. : C 73 90 H 8th , 11 N 6 , 63 Gef .: 73 , 98 8th , 26 6 , 89

(b) 4 - [(1- (4-hydroxy-2-piperidino-phenyl) -1-butyl) aminocarbonylmethyl] -benzoic acid ethyl ester Yield: 13.5% of theory, Melting point: 178-180 ⁰ C.

Calc .: C 71.21 H 7.81 N 6.39 F .: 71.27 7.82 6.40

(c) 4 - [(1- (5-hydroxy-2-piperidino-phenyl) -1-butyl) aminocarbonylmethyl] -benzoic acid ethyl ester Yield: 37.4% of theory, Melting point: 188-190 ⁰ C.

Calc .: C 71.21 H 7.81 N 6.39 F .: 71.34 7.89 6.38

Example 21

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

3.0 g (15.45 mmol) of p-phenylene-diacetic acid and 10 ml of thionyl chloride are refluxed for 90 minutes and then evaporated in vacuo. The crude diacid chloride is dissolved in 100 ml of methylene chloride. To this solution is added dropwise to the solution of 3.6 g (15.45 mmol) of 1- (2-piperidinophenyl) -1-butylamine slowly at an internal temperature of 10-15 ⁰ C with stirring. After 2 hours at room temperature, the mixture is evaporated in vacuo and the evaporation residue is partitioned between 100 ml of ice-cold 5% sodium hydroxide solution and ethyl acetate. It is filtered through diatomaceous earth and the organic phase is separated; from. The alkaline-aqueous phase is adjusted to pH 5.5 with half-concentrated hydrochloric acid and extracted with ethyl acetate. It is dried over sodium sulfate, filtered and the filtrate is evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform / methanol = 20/1).

Yield: 0.10 g (1.6% of theory), Melting point: 136-140 ⁰ C (acetonitrile / ether) Calc .: C 73.50 H 7.90 N 6.86 Found .: 73.17 8 10 6.85

Example 22

A- [ (2-Methyl-1- (2-piperidino-phenyl) -1-propen-1-yl) -amino- carbonylmethyl] -benzoic acid ethyl ester

To a solution of 6.17 g (26.8 mmol) of freshly prepared isopropyl (2-piperidino-phenyl) -ketimine in 62 ml of acetonitrile are added successively 5.58 g (26.8 mmol) of 4-ethoxycarbonylphenylacetic acid, 8, 43 g (32.2 mmol) of triphenylphosphine, 11.2 ml (80.4 mmol) of triethylamine and 2.6 ml (0.0268 mol) of carbon tetrachloride and stirred for 20 hours at room temperature. It is then evaporated in vacuo and partitioned between ethyl acetate and water. The dried and filtered ethyl acetate extract is evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene / ethyl acetate = 5/1). Yield: 3.0 g (26.6% of theory), m.p .: 82-84 ° C (ether)

Calc .: C 74.26 H 7.67 N 6.66 F .: 74.20 7.49 6.56

The following compounds were obtained analogously to Example 22:

(a) 4 - [(1- (2-piperidino-phenyl) -1-penten-1-yl) -aminocarbonylmethyl] -benzoic acid ethyl ester

Yield: 16% of theory; Melting point: 94-97 ° C (ethanol)

Ber. : C 74 , 62 H 7 , 89 N 6 45 Ge f .: 74 75 7 , 71 6 24

(b) 4 - [(1- (2-piperidino-phenyl) -1-hexen-l-yl) aminocarbonylmethyl] -benzoefiäure acid ethyl ester Yield: 27.4% of theory, Melting point: 83-85 ⁰ C (ethanol )

Calc .: C 74 97 H 8th , 09 N 6 24 Found .: 75 , 42 7 95 6 00

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

Yield (more lipophilic isomer, probably E-form): 4.1% of theory,

Melting point: <2O ⁰ C Ber .: m / e = 420 Gef .: m / e = 420

Yield (less lipophilic isomers, probably Z-form): 51.9% of theory,

Melting point: 115-117 ⁰ C (ethanol); Calc .: C 74.26 H 7.67 N 6.66 'F .: 73.85 7.59 6.44

(d) 4 - [(2-Phenyl-1- (2-piperidino-phenyl) -äthen-1-yl) -aminocarbonylmethyl] -benzoic acid ethyl ester

Yield (more lipophilic isomer, probably E-form):

4% of theory,

Melting point: 75-77 ° C (ether / petroleum ether) Calc .: C, 76.90, H, 6.88, N, 5.98, V, 77.31, 7.20, 5.93

Yield (less lipophilic isomers, likely Z-form): 42.7% of theory,

Melting point: 157-16O ⁰ C (ethanol) Found: C 77.19 H 6.95 N 6.02

(e) ethyl 4 - [(3-phenyl-1- (2-piperidino-phenyl) -1-propen-1-yl) -aminocarbonylmethyl] -benzoate Yield: 62.6% of theory,

Melting point: <20 ^° C. Ber .: m / e = 482 Gef .: m / e = 482

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

[Yield: 33% of theory,

Melting point: 113-116 ° C (ethanol) Calc .: C 74.97 H 8.09 N 6.24

Gef .: 75.37 7.93 6.03

,

j (g) 4 - [(1- (6-Methyl-2-piperidino-phenyl) -1-buten-1-yl) -amino

carbonylmethyl] -benzoic acid ethyl ester 15 Yield: 60.4% of theory (probably Z-form),

Melting point: 95-96 ° C

Calc .: 74.74 8.00 6.59 m / e = 434

Example 23

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

A stirred solution of 19.0 g (82.46 mmol) of freshly prepared (2-piperidino-phenyl) -propyl ketimine and 11.5 ml (82.46 mmol) of triethylamine in 190 ml of anhydrous toluene is heated to an internal temperature of 85 ° C, then added dropwise within 10 minutes, the solution of 18.7 g (82.46 mmol) of 4-Äthoxycarbonyl-phenylessigsäurechlorid in 95 ml of anhydrous toluene and stirred for 30 minutes at an internal temperature of 95 ° C. It is cooled to 20 ⁰ C and shaken twice with water

out. The organic phase is dried over sodium sulfate, filtered and evaporated in vacuo. The evaporation residue is purified by multiple column chromatography (toluene / acetone = 20/1 and 50/1)

 Yield (more lipophilic isomer, probably E-form):

11.2 g (23.6% of theory),

Melting point: <20 ⁰ C (honey-yellow, viscous oil) Calc .: C 74.26 H 7.67 N 6.66 Found .: 73.90 7.92 6.91

Yield (less lipophilic isomers, likely

Z-form): 15.9 g (33.5% of theory), Melting point: 114-116 ⁰ C. Found .: C 74.02 H 7.69 N 6.85

Example 24

Ethyl (E) - and (Z) -4- [(1- (2-piperidino-phenyl) -β-buten-1-yl) -aminocarbonyl-methyl] -benzoate

1.0 g of Z-ester (see Example 22c) is heated in a preheated oil bath at 230 ^° C. for 30 minutes. After cooling, the product obtained is purified by column chromatography on silica gel (toluene / acetone = 20/1). Yield (E-ester): 0.365 g (36.5% of theory), melting point: <20 ^° C.

Yield (Z-ester): 0.380 g (38.0% of theory), m.p .: 115-117 ° C

; When the (E) -ester is heated for 3.5 hours with catalytic amounts of iodine in benzene, a 1/1 mixture of (E) and (Z) esters is obtained by thin-layer chromatographic analysis (toluene / acetone = 10/1).

The following compounds were obtained analogously to Example 24:

(a) (E) - and (Z) -4 - [(1- (6-methyl-2-piperidino-phenyl) -1-

buten-1-yl) -aminocarbonylmethyl] -benzoic acid ethyl ester ; From (Z) ester (see Example 22g), a 1/1 mixture of (E) and (Z) esters is obtained by thin layer chromatography.

upper spot (E): Ber .: m / e = 434

Gef .: m / e 434 lower spot (Z); Gef .: m / e = 434

: Example 25

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

2.9 g (6.90 mmol) of ethyl 4 - [(1- (2-piperidino-phenyl) -1! -Butene-1-yl) -aminocarbonylmethyl] -benzoate in 100 ml of ethanol are hydrogenated to 0.77 g palladium / carbon (10%) at 50 ⁰ C ' and 1 bar of hydrogen. After 2 hours, the catalyst is filtered through kieselguhr and evaporated in vacuo. The evaporation residue is crystallized from ethanol.

Yield: 1.5 g (51.5% of theory), m.p .: 126-128 ° C. Calc .: C 73.90 H 8.11 N 6.63 F .: 73.97 8.22 6.57

The following compounds were obtained analogously to Example 25:

(a) Ethyl 4 - [(1- (2-piperidino-phenyl) -l-pentyl) -aminocarbonylmethyl] -benzoate Yield: 45% of theory, m.p .: 117-12O ⁰ C (ether) Calc. C 74 , 2B H 8,31 N 6,42 Gef .: 74,60 8,13 6,27

(b) 4 - [(1- (2-piperidino-phenyl) -1-hexyl) aminocarbonylmethyl] -benzoic acid ethyl ester Yield: 50% of theory, Melting point: 108-110 ⁰ C (ether) Calc .: C 74 , 63 H 8.50 N 6.22 Gef .: 74.85 8.33 6.01

(c) 4- [(2-phenyl-l- (2-piperidino-phenyl) -1-ethyl) aminocarbonylmethyl] -benzoic acid ethyl ester Yield: 87.6% of theory, Melting point: 161-162 ⁰ C (ethanol ) Calc .: C 76.57 H 7.28 N 5.95 F .: 76.71 7.19 5.99

(d) Ethyl 4-t (3-phenyl-1- (2-piperidino-phenyl) -1-propyl) -amcnocarbonylmethyl] benzoate. Yield: 57.6% of theory, m.p .: 118-119 ° C ( ethanol)

Calc .: C 76.83 H 7.49 N 5.78 F .: 76.70 · 7.49 5.90

; (e) 4 - [(1- (2- (3,3-dimethyl-piperidino) phenyl) -1-butyl) aminocarbonylmethyl] "rbenzoesäure ethyl ester 'Yield: 36.5% of theory,' Melting point: 140 -141 ⁰ C (ethanol) Calc .: C 74.63 H 8.50 N 6.22 Found .: 74.30 8.23 6.12

Example 26

: 4 - [(1- (2-piperidino-phenyl) -1-butyl) -amcnocarbonylmethyl] -benzoic acid _i __

The mixture is stirred from 1.2 g (2.84 mmol) of 4 - [(1- (2-piperidino-phenyl) -1-butyl) -amxnocarbonylmethyl] -benzoic acid ethyl ester and 4.26 ml of 1 N sodium hydroxide in 12 ml of ethanol for 1 hour

at 60 ⁰ C, then neutralized with 4.26 ml of 1N hydrochloric acid and evaporated in vacuo from the ethanol. It is divided between ethyl acetate and water; The organic extract is dried, filtered and evaporated in vacuo. The evaporation residue is crystallized from ethanol. Yield: 0.50 g (44.6% of theory), m.p .: 213-215 ° C

Calc .: C 73.07 H 7.66 N 7.10 F .: 73.18 7.51 7.10

The following compounds were obtained analogously to Example 26:

(a) 4 - [(1- (2-Piperidino-phenyl) -1-pentyl) -aminocarbonylmethyl] -benzoic acid

Yield: 70.2% of theory, Melting point: 213-215 ⁰ C (acetone) Calc .: C 73.50 H 7.90 N 6.86 Found .: 73.71 7.70 6.90

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

Yield: 72.6% of theory, Melting point: 197-200 ⁰ C (acetone) Calc .: C 73.90 H 8.11 N 6.63 Found '.: 73.83 7.93 6.77

(c) 4 - [(2-Phenyl-1- (2-piperidino-phenyl) -1-ethyl) -aminocarbonylmethyl] -benzoic acid

Yield: 68.7% of theory,

Melting point: 214-215 ° C (ethanol) [ calc .: C, 75.99; H, 6.83, N, 6.33; V: 75.70, 6.60, 6.32

(d) 4 - [(3-phenyl-1- (2-piperidino-phenyl) -1-propyl) -aminocarbonylmethyl] -benzoic acid. Yield: 67.7% of theory,

Melting point: 167-170 ° C (ethyl acetate) Calc .: C 76.29 H 7.06 N 6.14 Found: 76.56 7.06 6.23

(e) 4- [2-methoxy-l- (2-piperidino-phenyl) -1-ethyl) aminocarbonylmethyl] -benzoic acid Yield: 60.8% of theory, Melting point: 196-198 ⁰ C (ether)

Calc .: C 69 , 68 H 7 12 N 7 , 07 Found .: 69 72 6 , 52 6 , 71

(f) 4 - [(1- (2-Piperidino-phenyl) -4-penten-1-yl) -aminocarbonylmethyl] -benzoic acid χ 0.67 HpO Yield: 30.7% of theory, m.p .: 193-197 ° C (ether / petroleum ether) Calc .: C, 71.74, H, 7.38, N, 6.69, F, 71.63, 7.21, 6.34

: (g) 4 - [(1- (2- (3,3-Dimethyl-piperidino) -phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid. Yield: 48.2% of theory, m.p .: 168- 170 ⁰ C (petroleum ether) Calc .: C 73.91 H 8.11 N 6.63 Found .: 73.51 7.89 6.32

: (h) 4 - [(1- (3-methyl-2-piperidino-phenyl) -1-butyl) -aminocarboxylic , bonylmethyl] -benzoic acid; Yield: 53% of theory, 25; Melting point: 179-182 ° C

j Ber .: C 73.50 H 7.90 N 6.86! Gef .: 73.50 7.82 7.01

; (i) 4 - [(1- (4-methyl-2-piperidino-phenyl) -1-butyl) aminocarbonylmethyl] -benzoic acid Yield: 85.6% of theory, Melting point: 170-172 ⁰ C.

Calc .: C 73.50 H 7.90 N 6.86 F .: 73.25 7.64 6.89

(k) 4 - [(1- (5-Methyl-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid. Yield: 62.1% of theory, m.p .: 219-221 ° C

Calc .: C 73 50 H 7 90 N 6 , 86 Found .: 73 20 7 , 74 6 , 89

(1) 4 - [(1- (6-methyl-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] benzoic acid χ 0.3 I ^ O. Yield: 89% of theory, melting point: 158- 160 ⁰ C

Ber. : C 72 , 53 H 7 , 93 N 6 77 Found .: 72 40 7 91 6 , 92

(m) 4 - [(1- (3-Chloro-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid. Yield: 70% of theory, m.p .: 189-191 ° C

Calc .: C 67 20 H 6 , 81 Cl 8th , 27 N 6 , 53 Gef .: 67 30 6 85 8th , 36 6 , 58

(n) 4 - [(1- (4-Chloro-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid. Yield: 57.8% of theory, m.p .: 188-189 ° C

Ber. : C 67 20 H 6 , 81 Cl 8th , 27 N 6 , 53 Gef .: 66 90 7 00 8th , 22 6 , 53

(o) 4 - [(1- (5-chloro-2-piperidino-phenyl) -1-butyl) aminocarbonylmethyl] -benzoic acid Yield: 81.6% of theory, Melting point: 226-229 ⁰ C.

Ber. : C 67 20 H 6 , 81 Cl 8th , 27 N 6 , 53 Gef .: 67 17 6 , 59 8th , 51 6 60

(ρ) 4 - [(1- (6-chloro-2-piperidino-phenyl) -l-butyl) aminocarbonylmethyl] -benzoic acid Yield: 69.4% of theory, Melting point: 150-153 ⁰ C Calc .: C 67.20 H 6.81 Cl 8.27 N 6.53 Gef.i 67.18 6.91 8.42 6.77

(q) 4 - [(1- (4-bromo-2-piperidino-phenyl) -l-butyl) aminocarbonylmethyl] -benzoic acid Yield: 84.4% of theory, Melting point: 198-201 ⁰ C.

Calc .: C 60 , 89 H 6 17 br 16 , 88 N 5 , 92 Found .: 60 , 88 5 R98 17 20 5 , 98

(r) 4 - [(1- (5,3-Bromo-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid. Yield: 90.7% of theory, m.p .: 232-235 ° C

, Calc .: C 60.89 H 6.17 Br 16.88 N 5.92 F .: 60.96 6.13 16.85 5.90

(S) 4 - [(1- (4-nitro-2-piperidino-phenyl) -1-butyl) aminocarbonylmethyl] -benzoic acid Yield: 70.9% of theory, Melting point: 188-190 ⁰ C Calc .: C 65.59 H 6.65 N 9.56 Found: 65.30 6.44 9.53

(t) 4 - [(1- (5-nitro-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid

Yield: 90.7% of theory; Melting point: 225-227 ° C \ Re: C 65.59 H 6.65 N 9.56: Found: 65.80 6.61 9.72

(u) 4 - [(1- (4-Hydroxy-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid χ 0.5 1 ^ 0 Yield: 85.7% of theory, melting point: softening 70 ⁰ C (foam) Calc .: (x 0.5 H ₂ O) C 68.71 H 7.45 N 6.68 Found .: 68.63 7.55 6.26

(v) 4 - [(1- (5-hydroxy-2-piperidino-phenyl) -1-butyl) aminocarbonylmethyl] -benzoic acid Yield: 89.3% of theory, Melting point: 186-190 ⁰ C.

Calc .: C 70 , 22 H 7 , 37 N 6 , 82 Found .: 70 , 31 7 , 58 6 , 51

(w) 4 - [(1- (4-methoxy-2-piperidino-phenyl) -1-butyl) aminocarbonylmethyl] -benzoic acid Yield: 78.6% of theory, Melting point: 185-187 ⁰ C.

Ber. : C 70 , 73 H 7 60 N 6 60 Found .: 70 , 46 7 77 6 , 56

(x) 4 - [(1- (5-methoxy-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid. Yield: 75% of theory, Melting point: 182-185 ° C (decomp.) Calc .: C 70.73 H 7.60 N 6.60 F .: 70.52 7.50 6.70

(y) 4 - [(1- (2-pyrrolidino-phenyl) -1-butyl) -aminocarbonyl-; methyl] -benzoic acid

Yield: 64.5% of theory,

; Melting point: 200-203 ⁰ C

Calc .: C 72.61 H 7.42 N 7.36 3Q Found: 72.64 7.50 7.38

(ζ) 4 - [(1- (2- (4-methyl-piperidino) phenyl) -1-butyl) aminocarbonylmethyl] -benzoic acid Yield: 81.4% of theory, Melting point: 197-201 ⁰ C.

Calc .: C 73 50 H 7 90 N 6 , 86 Found .: 73 90 8th , 06 7 00

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

Yield: 6 5 , 6 % the Theory ie, N 6 , 86 Melting point: 199-202 ⁰ C 6 , 76 Ber. : C 73 50 H 7,90 Found .: 73 50 7.90

(ab) 4 - [(1- (4-fluoro-2-piperidino-phenyl) -1-butyl) aminocarbonylmethyl] -benzoic acid Yield: 87.1% of theory, Melting point: 204-207 ⁰ C.

Calc .: C 69 , 88 H 7 , 09 N 6 , 79 Found .: 70 25 7 , 02 7 12

(ac) 4 - [(1- (5-fluoro-2-piperidino-phenyl) -1-butyl) aminocarbonylmethyl] -benzoic acid Yield: 53.9% of theory, Melting point: 200-202 ⁰ C.

Calc .: C 69 , 88 H 7 , 09 N 6 , 79 Found .: 69 , 67 7 24 6 90

j (ad) 3-chloro-4 - [(1- (2-piperidino-phenyl) -1-butyl) -aminocarbene

bonylmethyl] benzoic acid

j Yield: 51% of theory,

! Melting point: 165-168 ⁰ C

j Ber .: C 67.20 H 6.81 N 6.53 m / e = 428/430 (1 chlorine)

30; Gef .: 66.92 6.69 6.55 m / e = 428/430 (! Chlorine)

(ae) 4 - [(1- (3-methyl-2-piperidino-phenyl) -1-ethyl) -aminocar bonylmethyl] -benzoic acid Yield: 79% of theory, Melting point: 230-231 ⁰ C.

Calc .: C 72 60 H 7 , 42 N 7 , 36 Found .: 72 75 7 , 58 7 30

(af) 4 - [(1- (3-chloro-2-piperidino-phenyl) -1-ethyl-aminocarbo-

nylmethyl] benzoic acid

Yield: 54% of theory, m.p .: 192-195 ° C (75% aqueous ethanol) Calc .: C, 65.91, H, 6.28, Cl, 8.84, N, 6.99 Found: 66.00, 6.44 8 , 67 6.78

Example 27

4-t (2-methyl-1- (2-piperidino-phenyl) -1-propen-1-yl) -aminocarbonylmethyl] benzoic acid

The mixture is stirred from 3.5 g (8.3 mmol) of ethyl 4 - [(2-methyl-1- (2-piperidino-phenyl) -1-propen-1-yl) -aminocarbonylmethyl] benzoate and 12, 5 ml of iN-sodium hydroxide solution in 35 ml of ethanol for 2 hours at 60 ⁰ C. The mixture is neutralized with 12.5 ml of 1 N SaIz-! acid, evaporated in vacuo and partitioned between ethyl acetate and water. The dried filtered organic extract is evaporated in vacuo. The evaporation residue is crystallized from ethanol

 j Yield: 2.4 g (73.6% of theory),

j Melting point: 188-191 ° C

j Ber .: C 73.44 H 7,19 N 7,14! Gef .: 73,60 7,19 7,02

The following compounds were obtained analogously to Example 27:

(a) (E) -4 - [aminocarbonylmethyl 1- (2-piperidino-phenyl) -1-buten-l-yl ()] -benzoic acid Yield: 71.5% of theory, Melting point: 188-190 ⁰ C.

Calc .: C 73 , 44 H 7 19 N 7 , 14 Found .: 73 15 7 13 7 10

Olefinic proton: ¹ H-NMR (CDCl ₃ ): S - 6.42 ppm

(b) (Z) -4 - [(1- (2-Piperidino-phenyl) -1-buten-1-yl) -aminocarbonylmethyl] -benzoic acid. Yield: 57.8% of theory, m.p .: 174-175 ° C (ethanol) Calc .: C 73.44 H 7.19 N 7.14 Found .: 73.54 6.97 7.17 olefinic proton: H-NMR _(CDCl3): ^ = 5.60 ppm

15; (C) (E) -4 - [(2-phenyl-1- (2-piperidino-phenyl) -äthen-1-yl) -; aminocarbonylmethyl] benzoic acid χ 0.4 H ₂ O Yield: 33.2% of theory, m.p .: 165-167 ° C (ether / petroleum ether) Ber. (x 0.4 H ₂ O): C 75.11 H 6.48 N 6.26 F .: 75.22 6.39 6.26

Olefinic proton: ¹ H-NMR (CDCl ₃ ): £> 6.9 ppm

(d) (Z) -4 - [(2-Phenyl-1- (2-piperidino-phenyl) -äthen-1-yl) -aminocarbonylmethyl] -benzoic acid χ 1 H ₂ O Yield: 72% of theory, ' m.p. : 182-185 ° C (methanol) Ber. (x 1 H ₂ O): C 73.34 H 6,60 N 6,11 F .: 73,55 6,45 6,00

Olefinic proton: H-NMR (CDClO): i = 6.50

ppm

(e) 4- [(3-Phenyl-1- (2-piperidino-phenyl) -1-propen-1-yl) -aminocarbonylmethyl] -benzoic acid. Yield: 48.3% of theory, m.p .: 162-164 ° C (Ether); probably (Z) form: C, 76.63, H, 6.65, N, 6.16

Gef .: 76.30 6.47 6.31. · '. Olefinic proton: ¹ H-NMR (CDCl ₃ ): f = 5.80 ppm

(f) 4 - [(1- (2- (3,3-Dimethyl-piperidino) -phenyl) -1-buten-1-yl) -aminocarbonylmethyl] -benzoic acid. Yield: 64.1% of theory; Melting point: 152-153 ° C (ethyl acetate); probably

: (Z) shape

Calc .: C 74.26 H 7.67 N 6.67

: Found .: 73.93 7.57 6.50 15: olefinic proton: H-NMR (CDCl _3): i = 5.55 ppm

(g) (Z) -4 - [(1- (6-Methyl-2-piperidino-phenyl) -1-buten-1-yl) -! aminocarbonylmethyl] benzoic acid! Yield: 53.3% of theory,: Melting point: 142-145 ° C Calc .: C 73.66 H 7.44 N 6.89 Found: 73.56 7.73 7.15! "Olefinic proton: H-NMR _(CDCl3): ί = 5.38 ppm

Example 28

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

200 mg (0.51 mmol) of 4 - [(1- (2-piperidino-phenyl) -1-buten-1-yl) -aminocarbonylmethyl] -benzoic acid are hydrogenated in 10 ml of absolute ethanol over 100 mg of palladium / carbon (10 %) at 50 ^° C. and 1 bar of hydrogen with shaking. After 1.5 hours, filtered and evaporated in vacuo.

Yield: 68% of theory, melting point: 213-214 ° C

Calc .: C 73.07 H 7.66 N 7.10 F .: 73.21 7.82 7.02

The yield is 56% of theory when hydrogenated at 50 ⁰ C and 1 bar of hydrogen to Raney nickel.

Example 29

4 - [(1- (2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid sodium salt χ 0.5 H 2 O.

Dissolve 10.0 g (25.35 mmol) of 4 - [(1- (2-piperidino-phenyl) -1-butyl) aminocarbonylmethyl] benzoic acid at 50 ⁰ C in 200 ml ethanol and added 25.35 ml of 1 Add sodium hydroxide solution. It is evaporated to dryness in vacuo and the evaporation residue is dissolved under heating on the steam bath in the minimum amount of ethanol. It is cooled in an ice bath, filtered from the precipitated crystals, washed with ether and dried at 140 ° C / 15 Torr.

Yield: 9 g (85.3% of theory), Melting point: 280-285 ⁰ C (dec.); Softening from 255 ° C i Ber. (x 0.5 H ₂ O): C 67.74 H 6.87. N 6.58 V .: 67.86 7.13 6.49

Example 30

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

To a stirred solution of 2.58 g (11.1 mmol) of 1- (2-piperidino-phenyl) -1-butylamine [K _{n η} ~: 87 ^° C;

ρ U fUJ

ee = 86 (HPLC, after derivatization with (+) - 1-phenethyl isocyanate) in 26 ml of acetonitrile are added at 2O ⁰ C in succession 2.31 g (11.1 mmol) of 4-Äthoxycarbonyl-phenylacetic acid, 3.50 g (13.3 mmol) of triphenylphosphine, 4.60 ml (33.9 mmol) of triethylamine and 1.03 ml (11.1 mmol) of carbon tetrachloride. After 14 hours at 20 ⁰ C and 1.5 hours at 40 ⁰ C evaporated in vacuo and distributed between water and ether. The organic phase is dried over sodium sulfate, filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene / acetone = 6: 1).

Yield: 2.63 g (56% of theory), Melting point: 118-120 ⁰ C Calc .: C 73.90 H 8.11 N 6.63

Found: 74.02 7.97 6.51 ι [a] p ° = + 9.2 ° (c = 1, methanol)

The following compound was obtained analogously to Example 30:

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

Prepared from (-) - 1- (2-piperidino-phenyl) -1-butylamine

20 x 1.4 HCl [[a] p = -20.0 ° (c = 1, methanol),

Melting range: 90-100 ⁰ C; ee = 80 (HPLC, after derivatization of the base with (+) - 1-phenethyl isocyanate)] Yield: 52.6% of theory; Melting point: 115-120 ⁰ C; Calc .: C 73.90 H 8.11 N 6.63

Found: 73.83 8.01 6.47 20 J = -9.0 ° (c = 1, methanol)

- 93 Example 31

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

1.0 g (3.27 mmol) of (+) - 1- (2-piperidino-phe-

20 nyl) -1-butylamine dihydrochloride t [a] _D = + 18.7 ° (c = 1, methanol); Melting point: from 115 ° C decomposition; ee = 91.6 (HPLC, after derivatization of the base with (+) - l-phenethyl isocyanate)] in 6 ml of methylene chloride, 1.4 ml (10 mmol) of triethylamine are added with stirring and then the solution is dropped from 0, 82 g (3.64 mmol) of 4-Äthoxycarbonyl-phenylacetic acid chloride in 2.4 ml of methylene chloride, wherein the reaction temperature of 22 ° C to 38 ° C increases. It is stirred for 6 hours at room temperature and shaken demand \ each of: twice with 10 ml of water,

once with 10 ml of 2N hydrochloric acid and once with 10 ml of water.

; The organic phase is dried over sodium sulfate, filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel: (toluene / acetone = 6/1).

Yield: 0.53 g (38.2% of theory), Melting point: 120-122 ⁰ C Calc .: C 73.90 H 8.11 N 6.63

Gef .: 73.96 7.98 6.61

r τ ²⁰ ; ^laJ D = + 9.0 ° (c = 1, methanol)

- 94 Example 32 .

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

2.0 g (4.73 mmol) of (+) - A- [ (1- (2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester are stirred

[[α] ²⁰ = + 9.2 ° (c = 1, methanol)] in 20 ml of ethanol - together with 7.0 ml of 1N sodium hydroxide solution for 2.5 hours in the bath at 65 ° C. It is cooled and 7.0 ml of 1 N hydrochloric acid are added. The slowly precipitating crystals are filtered off, washed with water and dried at 100 ° C / 4 Torr. Yield: 1.65 g (88.2% of theory), melting point: 185-187 ° C calc .: C, 73.07, H, 7.66, N, 7.10, viz., 72.90, 7.80, 7.17

20; [α] ρ = + 7.9 ° (c = 1, methanol)

The following compound was obtained analogously to Example 32:

(a) (-) - 4 - [(1- (2-piperidino-phenyl) -1-butyl) -aminocarbonylme thyl] benzoic acid yield: 80% of theory, Melting point: 187-190 ⁰ C.

Calc .: C 73.07 H 7.66 N 7.10 F .: 72.98 7.44 7.22. [A] |; = -7.9 ° (c = 1, methanol)

- 95 Example 33

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

Prepared from 1- (2-piperidino-phenyl) -1-butylamine and 4-cyano-phenylacetic acid analogously to Example

Yield: 57.3% of theory, "Melting point: 147-148 ⁰ C Calc .: C 76.76 H 7.78 N 11.19 Found .: 76.46 7.81 11.10

The following compound was obtained analogously to Example 33:

(a) 4 - [(1- (2-piperidino-phenyl) -1-butyl) -aminocarbonylmethane

: thyl] toluene

; Made with 4-tolyl-acetic acid.

Yield: 60.4% of theory, Melting point: 150-153 ⁰ C.

Calc .: C, 79.08, H, 8.85, N, 7.68

j Gef .: 78.97 8.58 7.77

Example 34

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

Prepared from 4 - [(1- (2-piperidino-phenyl) -1-butyl) amino-; carbonylmethyl] benzonitrile with ethanolic hydrochloric acid analogously to Example Yield: 58% of theory,! Melting point: 127-128 ° C Calc .: C 73.90 H 8.11 N 6.63 F .: 74.07 8.23 6.87

- 96 Example 35

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

Prepared analogously to Example 10 from 1- (2-piperidino-phenyl) 1-butanol and 4-cyanomethyl-benzoic acid ethyl ester with

concentrated sulfuric acid in o-dichlorobenzene at room temperature.

Yield: 21% of theory),. Melting point: 126-128 ° C

Calc .: C 73.90 H 8.11 N 6.63 F .: 74.12 8.20 6.45

The following compound was obtained analogously to Example 35:

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

Prepared from 1- (2-piperidino-phenyl) -1-butanol and 4-cyanomethylbenzoic acid. Extraction at pH 5.5. Yield: 29% of theory, m.p .: 215-217 ° C

Calc .: C 73.07 H 7.66 N 7.10 F .: 72.82 7.69 6.95

Example 36

j 4 - [(1- (4-Amino-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid χ 0.5 H ₂ O.

Hydrogenates 0.60 g (1.365 mmol) of 4 - [(1- (4-nitro-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoic acid in 10 ml of dimethylformamide over 0.1 g of palladium / carbon (10%). ig) 3 hours

at 25 ° C and 1 bar of hydrogen. The catalyst is filtered through kieselguhr and evaporated in vacuo. The evaporation residue is crystallized from ether.

Yield: 0.41 g (73.2% of theory), Melting point: 118-120 ⁰ C.

Ber. (x 0.5 H ₂ O): C, 68.87, H, 7.71, N, 10.04

Gef .: 68.62 7.64 10.08

The following compounds were obtained analogously to Example 36:

(a) 4 - [(1- (4-amino-2-piperidino-phenyl) -1-butyl) -aminocar · bonylmethyl] -benzoic acid ethyl ester Yield: 81.7% of theory, Melting point: 145-146 ⁰ C. (Ether / petroleum ether) j Ber .: C 71.37 H 8.06 N 9.60 Found: 71.50 8.08 9.68

(b) 4 - [(1- (5-amino-2-piperidino-phenyl) -1-butyl) -aminocar · bonylmethyl] -benzoic acid Yield: 64% of theory, Melting point: 227-230 ⁰ C.

Calc .: C 70 , 39 H 7 , 63 N 10 , 26 Found .: 70 , 54 7 , 54 10 , 36

(c) 4 - [(1- (5-Amino-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester. Yield: 84.3% of theory, m.p .: 162-165 ° C

Calc .: C 71.37 H 8.06 N 9.60 F .: 71.58 7.83 9.65

Example 37

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

Prepare 2.0 g (4.57 mmol) of A- [ (1- (5-amino-2-piperidino)

no-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester in 4.8 ml of half-concentrated hydrochloric acid and 0.315 g - (4.57 mmol) of sodium nitrite in 1.66 ml of water, an O ⁰ C-cold diazonium salt solution forth , This is added dropwise at 0-5 ° C in a stirred mixture of 0.59 g (5.94 mmol) of copper (I) -10; chloride and 2.4 ml conc. Hydrochloric acid and then heated in the bath of 50 ⁰ C. After completion of gas evolution (about 15 minutes) is cooled, carries the reaction mixture in ice / conc. Ammonia and extracted four times with 100 ml of ethyl acetate. The combined organic extracts are extracted with water, dried, filtered and evaporated

put them in a vacuum. The evaporation residue is purified by column chromatography on silica gel (toluene / ethyl acetate = Ϊ 10/1).

! Yield: 0.80 g (40% of theory), Melting point: 137-140 ⁰ C (ether)

Calc .: C 68.32 H 7.27 Cl 7.75 N 6.13 F .: 68.42 7.09 8.06 6.05

The following compounds were obtained analogously to Example 37:

(a) 4-t (1- (4-Chloro-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester Yield: 21.9% of theory, m.p .: 123-125 ° C

Ber. : C 68 , 32 H 7 , 27 Cl 7 75 N 6 13 Found .: 68 70 7 , 18 7 77 6 , 08

(b) 4- [(1- (5-bromo-2-piper idino-phenyl) -1-butyl) aminocarbonylmethyl] -benzoic acid ethyl ester Yield: 53.8% of theory, Melting point: 140-142 ⁰ C.

5l calc .: C 62.27 H 6.63 Br 15.93 N 5.58 'F .: 62.39 6.78 15.85 5.59

(c) 4 - [(1- (4-Fluoro-2-piperidino-phenyl) -1-butyl) -aminocarboxylyl-ethyl] -benzoic acid ethyl ester

Yield: 21.6% of theory, 10: Melting point: 110-112 ⁰ C.

j Ber .: C 70.88 H 7.55 N 6.36 Found: 71.01 7.53 6.21

In addition, 40% of 4 - [(1- (4-hydroxy-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid are isolated! ethyl ester (solid foam).

: (d) 4 - [(1- (5-fluoro-2-piperidino-phenyl) -1-butyl) -aminocar-; Ethyl bonylmethyl] benzoate \ Yield: 2% of theory, mp: 127-129 ° C Calc .: m / e = 440 Found: m / e = 440

: (e) 4 - [(1- (4-Fluoro-2-piperidino-phenyl) -ethyl) -aminocarbonylmethyl] -benzoic acid. Yield: 16.9% of theory, 25; Melting point: 172-175 ° C

Calc .: C 68 , 73 H 6 , 55 N 7 , 29 Found .: 68 , 78 6 , 62 7 , 31

Example 38

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

Hydrogenated 1.0 g (2.33 mmol) of 4- [(1- (5-chloro-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid in 40 ml of absolute ethanol over 0.5 g of palladium / Coal (10%)

Hr 50 ⁰ C and 5 bar hydrogen. After'2 hours, the catalyst is filtered through kieselguhr and evaporated in vacuo. The evaporation residue is distributed at pH 6 between water ι and ethyl acetate. The organic extract is washed with water, dried and filtered and evaporated in vacuo. Yield: 0.61 g (66% of theory),

j Melting point: 213-215 ⁰ C.

Calc .: C 73.07 H 7.66 N 7.10! Gef .: 73.18 7.42 7.27

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

j Example 39

Ethyl 4- [(1- (4-methoxy-2-piperidinophenyl) -1-butyl) aminocarbonylmethyl] benzoate

To 548 mg (11.4 mmol) of sodium hydride (50% in oil) in 10 ml of absolute dimethylformamide was added dropwise with stirring at room temperature the solution of 5.0 g (11.4 mmol) 4 - [(1- (4- Hydroxy-2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid ethyl ester in 45 ml of absolute dimethylformamide. The mixture is stirred for 15 minutes and then added dropwise the solution of 0.71 ml (11.4 mmol) of methyl iodide in 8 ml of absolute dimethyl

' - 101 -

formamide slowly. It is stirred for another 2.5 hours at room temperature! temperature, evaporated in vacuo and distributed between water! and ether. The ether phase is dried, filtered and concentrated in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene / acetone = j 20/1).

Yield: 1.8 g (34.9% of theory), m. Melting point: 115-117 ° C

Re: C 71.65 H 8.02 N 6.19 1Oi Gef .: 71.47 7.86 6.19

Analogously to Example 39, the following compound was obtained:

j (a) 4 - [(1- (5-methoxy-2-piperidino-phenyl) -l-butyl) -amino]

j carbonylmethyl] benzoic acid ethyl ester

j Yield: 68.4% of theory,

j Melting point: 142-145 ° C

; Calc .: C 71.65 H 8.02 N 6.19

I: 71.87 8.06 6.38

I Example 40 4 - [(1- (2-Piperidino-phenyl) -l-butyl) -aminocarbonyl] -

benzoic acid ester (2,3-dihydroxy-propyl)

Heat the solution of 2.0 g (5.07 mmol) of 4- [(1- (2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid and 0.85 g (5.27 mmol) of N , N'-Carbonyldiimidazol in 20 ml of absolute tetrahydrofuran for 1 hour at reflux, adds 3.7 ml of 25J (50.7 mmol) of glycerol and heated for a further 15 hours to ι reflux. It is evaporated in vacuo, partitioned between water I and ethyl acetate, dried, and the organic solution is filtered and concentrated by evaporation in vacuo. The evaporation residue j is purified by column chromatography on silica gel (toluene / acetone = 1/1).

Yield: 1.1 g (46.2% of theory), Melting point: 120-122 ⁰ C.

Calc .: C 69.21 H 7.74 N 5.98 Gef.:. 69.23 7.78 5.93

The following compounds were obtained analogously to Example 40

(a) 4 - [(1- (2-piperidino-phenyl) -l-butyl) -aminocarbonylme

thyl] -benzoic acid (2-hydroxyethyl) ester Yield: 80% of theory, ^e Melting point: 125-127 ° C

Calc .: C, 71.21, H, 7.81, N, 6.39, F, 71.35, 7.54, 6.33

(b) 4 - [(1- (2-Piperidino-phenyl) -l-butyl) -aminocarbonyl-methyl] -benzoic acid (2-methoxy-ethyl) ester. Yield: 55.9% of theory, m.p .: 120- 123 ⁰ C

Calc .: C 71.65 H 8.02 N 6.19 Found: 72.03 8.03 6.24

Example 41

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

To a stirred solution of 2.0 g (4.56 mmol) of 4 - [(1- (2-pi-1-peridino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoic acid (2-I-hydroxy-ethyl) ester in 40 ml of methylene chloride and 0.7 ml ΓΤ4.81 mmol) of triethylamine is added dropwise the solution of: 0.7 g (4.68 mmol) of nicotinic acid chloride in 20 ml of methylene chloride. The mixture is stirred for 2.5 hours at 20 ⁰ C, shaken out with j water, dried and filtered the organic phase and I evaporated it in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene / acetone = j 5/1).

j Yield: 1.1 g (44% of theory),! Melting point: 132-135 ⁰ C

Calc .: C 70.70 H 6.86 N 7.73 j. F .: 70.82 6.82 7.91

Example 42

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

To a stirred suspension of 0.68 g (17.95 mmol) Li! thiumaluminum hydride in 25 ml of absolute tetrahydrofuran

j is added dropwise the solution of 5.0 g (11.83 mmol) of 4 at an internal temperature of 0 ⁰ C - [(1- (2-piperidino-phenyl) -1-butyl) aminocarbonylmethyl] -benzoic acid ethyl ester in 75 ml of absolute tetrahydrofuran. The mixture is stirred for 20 hours at room temperature, cooled to ^{0 0} C and slowly added dropwise as much 4 N sodium hydroxide solution until a filterable precipitate is formed.

It is filtered off and the precipitate is repeatedly extracted with ether. The combined organic solutions are evaporated in vacuo. The evaporation residue is distributed between water and ether. The ether phase is dried, filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene / acetone = 5/1).

 Yield: 1.0 g (22% of theory),

melting point: 152-154 ° C

j Ber .: C 75,75 H 8,48 N 7,36 -! θ! Gef .: 75.90 8.45 7.28

Example 43

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

6.6 g (62 mmol) of sodium carbonate are heated together with 62 ml of ethylene glycol in the bath of 17O ⁰ C and under rapid stirring within 1 minute 6.2 g (11 mmol) of N ¹ - [4 - [(1- -Piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -benzoyl] -

2 N -tosyl-hydrazine of melting point 195 ° C (dec.) To, wherein a vigorous evolution of gas observed. Then heated for a further 2.5 minutes at 170 ⁰ C and then poured immediately on ice. It is extracted with ether, dried, filtered and the ether solution is evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform / acetone = 20/1).

 Yield: 2.2 g (52.9% of theory), m.p .: 142-145 ° C

Re: C 76.16. H 7,99 N 7,40 F .: 76,26 7,96 7,37

- 105 Example 44

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

I To 0.60 g (12.5 ml of) of sodium hydride (50% in oil) in 15 ml of absolute dimethylformamide is added dropwise at room temperature ^; Solution of 2.80 g (12.5 mmol) of diethylphosphonoacetic acid L-ethyl ester in 10 ml of absolute dimethylformamide. Stir: 15 minutes (until gas evolution ceases) and then drip; the solution of 2.4 g (6.34 mmol) of 4 - [(1- (2-piperidino-phe-

10; nyl) -1-butyl) -aminocarbonylmethyl] -benzaldehyde in 10 ml of absolute dimethylformamide. The mixture is stirred for 2 hours at room temperature, evaporated in vacuo and partitioned between water and ether. The ether phase is dried, filtered I and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene / acetone = 10/1).

I Yield: 0.85 g (29.9% of theory), m. Melting point: 135-137 ° C (ether / petroleum ether) i Calc .: C 74.97 H 8.09 N 6.24

20! Gef .: 74,91 7,89 6,29

Example 45

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

Prepared by alkaline saponification of 4 - [(1- (2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] cinnamic acid ethyl ester analogously to Example 26.

Yield: 64% of theory, Melting point: 180-183 ⁰ C Calc .: C 74.26 H 7.67 Found .: 74.03 7.47

N 6.66 6.80

Example 46

Ethyl 3- [4 - [(1- (2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -phenyl] -propionate

Is hydrogenated 0.60 g (1.34 mmol) of 4 - [(1- (2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] cinnamic acid ethyl ester in

10 l 10 m ethanol to 0.20 g palladium / carbon (10%) at room temperature and 5 bar hydrogen. It is filtered and evaporated in vacuo.

Yield: 0.53 g (88% of theory), Melting point: 98-99 ⁰ C (petroleum ether) Calc .: C 74.63 H 8.50 N 6.22 Found .: 74.64 8.58 6.23

Analogously to Example 46, the following compound was obtained:

(a) 3- [4 - [(1- (2-piperidino-phenyl) -1-butyl) -aminocarbonylmethyl] -phenyl] -propionic acid 20; Yield: 63% of theory, Melting point: 131-133 ⁰ C Be r:. C

Found .:

73 90 H 8th 30 N 6 , 63 73 r96 8th 6 , 56

- 107 Example 47

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

Prepared by alkaline saponification of 3- [4- [(1- (2-piperidino-phenyl) -l-butyl) -aminocarbonylmethyl] -phenyl] -propionic acid ethyl ester analogously to Example 26. Yield: 50% of theory, melting point : 131-133 ° C

Calc .: C 73.90 H 8.11 N 6.63 10 | Gef .: 73.82 8.07 6.41

Example 48

j 4 - [(α-aminocarbonyl-2-piperidino-benzyl) -aminocarbonylme-! thyl] benzoic acid ethyl ester

To the stirred solution of 2.0 g (4.7 mmol) of ethyl 4- [(a-carboxy-2-piperidinobenzyl) aminocarbonylmethyl] benzoate

0.167 H ₂ O; (Mp 156-159 ° C) in 20 ml of anhydrous tetrahydrofuran are added at 2O ⁰ C 0.90 g (5.5 mmol) Ν, Ν'-carbonyldiimidazole and then heated for half an hour in the bath of 80 ⁰ C. Then cool It is cooled to ^60.degree. C. and, at this temperature, for half an hour a vigorous stream of dry ammonia is introduced. It is then evaporated in vacuo, partitioned between water and chloroform, the combined chloroform extracts are extracted with a little water, dried, filtered and evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform / methanol - 5/1). Yield: 1.0 g (50.2% of theory), Melting point: 160-162 ⁰ C (acetone) Calc .: C 68.07 H 6.90 N 9.92 Found .: 68.40 6.92 9 , 84

- IQS -

Example 49

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

To 520 mg (1.22 mmol) of 4 - [(α-aminocarbonyl-2-piperidino-benzyl) aminocarbonylmethyl] -benzoic acid ethyl ester in 0.22 ml of pyridine is added in 2 portions 234 mg (1.22 mmol) of 4 -Toluenesulfochlorid and heated to 50 ⁰ C. After 2 hours and after another hour, each again the same amounts of pyridine and ^ -toluenesulfochloride and 10! heated for another hour at 50 ⁰ C. After two days

; Standing at 20 ⁰ C, 2 N-ammonia is added and extracted with chloroform. The chloroform solution is extracted twice with water. After drying and filtration, they are evaporated in vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform / methanol 10/1). Yield: 325 mg (65.7% of theory), Melting point: 114-117 ⁰ C (ether / petroleum ether) Calc .: C 71.09 H 6.71 N 10.36 Found .: 70.79 6.56 10 10

Example 50

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

1.5 g (3.7 mmol) of ethyl 4-1 (α-cyano-2-piperidinobenzyl) -aminocarbonylmethyl] -benzoate in 15 ml of dioxane are stirred together with 3.7 ml of 1N sodium hydroxide solution for 45 minutes Bath of 60 ⁰ C and a further 45 minutes in the bath of 80 ⁰ C After cooling with ice is treated with 3.7 ml of 1 N hydrochloric acid, the dioxane is evaporated in vacuo and partitioned between water and j chloroform. The organic solution is shaken out with a little ι water, dried and filtered and evaporated it in the

- 109 -

 .

Vacuum. The evaporation residue is purified by column chromatography on silica gel (chloroform / ethanol = 5/1). ! Yield: 0.50 g (35.7% of theory) /! Melting point: 176-18O ⁰ C (dec.) 5 | Calc .: C 70.01 H 6,14 N 11,13 Found: 70,02 6,19 11,05

Example 51

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

10: To dissolve 1.0 g (2.53 mmol) of 4 - [(1- (2-piperidino-phenyl) 1-butyl) -aminocarbonylmethyl] -benzoic acid in 50 ml of ethanol, 5 ml (2.50 mmol ) 1 N sulfuric acid, evaporated to dryness in vacuo and triturated with acetone. j Yield: 0.80 g (65% of theory), 15! Melting point: 192-197 ⁰ C (dec.)

Calcd .: C 58.53 H 6.55 N 5.69 S 6.49 F .: 58.05, 6.54, 5.49, 6.35

The following addition salt was obtained analogously to Example 51:

2025

(a) 4 - [(1- (2-piperidino-phenyl) -1-butyl-aminocarbonyl- methyl] -benzoic acid χ 0.5 EU SO, χ 1.5 H ₀ O.

2nd Hc ti.-

Made with half the amount of sulfuric acid analog

Example 51.

Exploits 59.3% of theory _s

Melting point; 180-185 ⁰ Cy Zers »at 207-21O ⁰ Ce Calc .: C 61.26 H 7.28 N 5.95 S 3.40 Gef .; 61.28 6.99 6.10 3.23

Claims (18)

an alkyl group optionally substituted by an alkoxy group having from 1 to 3 carbon atoms or by a phenyl group is from 1 to 3 carbon atoms, an alkyl group having from 4 to 7 carbon atoms, an alkenyl group having from 3 to 5 carbon atoms, a cyano or alkyleniminocarbonyl group having from 4 to 6 carbon atoms in the alkylene part optionally mono- or disubstituted by alkyl or phenylalkyl groups each having 1 to 3 carbon atoms in the alkyl moiety Amlnocarbonylgruppe, optionally substituted by halogen atoms, by alkyl, hydroxy, alkoxy, phenylalkoxy, alkylsulfenyl, alkylsulfinyl and / or alkylsulfonyl mono- or disubstituted aryl group having 6 or 10 carbon atoms, wherein the substituents may be the same or different and the 17.11.1983 AP C 07 D / 252 755 - Ill - 62 554/12 Alkyl part can contain in each case 1 to 3 carbon atoms, or.a 1 or 2 nitrogen atoms containing heteroaryl group with 4, 5, 8 or 9 carbon atoms, R and R _are the same or different. Hydrogen atoms or alkyl groups having 1 to 5 carbon atoms or R ₁ . and R- together with the intervening carbon atom represent a phenylalkylidene group having 1 to 4 carbon atoms in the alkylidene part, R 1 is a mono- or disubstituted by alkyl groups having 1 to 3 carbon atoms unbranched Alkyleniminogruppe, having 4 to 9 carbon atoms or eino Dialkylamlnogruppe each having 1 to 5 carbon atoms in each alkyl part, R _{2 is} a hydrogen, fluorine, chlorine, bromine or oxygen atom, a hydroxy, trifluoromethyl, nitro, amino, piperidino, alkyl, alkoxy, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, phenylalkoxy , Alkanoyloxy, alkanoylamino, alkylamino or dialkylamino group, wherein the alkyl portion may each contain 1 to 3 carbon atoms, R is an alkyl group having 1 to 3 carbon atoms, a hydrogen or halogen atom and IV a carboxy group or a AlkoxycarbonyIgrjppe with 17.11 * 1983 AP C 07 D / 252 755 - 112 - 62 554/12 total of 2 to 6 carbon atoms, in which the alkyl moiety may be substituted by a phenyl group and from the β-carbon atom by one or two hydroxy groups, by an alkoxy, alkanoyl-oxy, dialkylamino, alkyleneimino or pyridinecarbonyloxy group; Each alkyleneimino group may contain 4 to 6 carbon atoms, an alkenylbxycarbonyl group having a total of 4 to 6 carbon atoms, an alkyl group having 1 to 3 carbon atoms, a hydroxymethyl, formyl, cyano, aminocarbonyl ', carboxy-methyl, 2-carboxy-ethyl, ^ -carboxy-äthenyl-, 2 _# 2-bis (carboxy) -äthyl-, alkoxycarbonyl-methyl-, 2-alkoxycarbonyl-ethyl - ^ - alkoxycarbonyl-äthenyl- or 2,2-bis (alkoxycarbonyl) -ethyl group, where the alkoxy group can contain in each case 1 to 3 carbon atoms, mean and their optically active antipodes and their salts with inorganic or organic acids or bases, characterized in that a) an atnine of the general formula A - NH ₂ in the A, R ^ and R _{2 are} as defined above or, if A is one of the above-mentioned vinylidene groups, whose 17/11/1983 AP C 07 D / 252 755 62 554/12 Tautomeres whose lithium or magnesium halide complex with a carboxylic acid of the general formula HO - CO CH (HI). in which R- is as defined above and W has the meanings mentioned above for W or represents a carboxy group protected by a protective group, or reacts with their reactive derivatives optionally produced in the reaction mixture mixture, and, if necessary, the protective group used is split off, or b) for the preparation of a compound of the general formula I, in which VV represents a carboxy, carboxymethyl, 2-carboxyethyl or 2-carboxyäthenylgrupp ©, a compound of the general formula R. A - NH - CO - CH in the R ₁ to R ₃ and A are as defined above and B is one in a carboxy, carboxymethyl, 2-carboxyethyl or 2-carboxy 17.11.1983 AP C 07 D / 252 - 114 - 62 554/12 äthenylgruppe represents transferable group is converted into the corresponding carboxy compound by means of hydrolysis, thermolysis or hydrogenolysis, or c) for the preparation of a compound of the general formula I in which A is a group of the formula R *, where -CH- R 'except for the alkenyl group and the cyano group has the meanings mentioned for R. above, a compound of the general formula in the R ₁ to R ₃ and W are as defined above and D is a group of the formulas _{5 6} • II - C or - C N ~ N - I H where R ", with the exception of the cyano group, has the meanings mentioned for R. above and R 'and 17.11.1983 AP C 07 D / 252 755 115 - 62 554/12 R 'together with the intervening carbon atom is an alkylidene group having 1 to 7 carbon atoms or a phenylalkylidene group having 1 to 3 carbon atoms in the alkylidenteil, is reduced, or d) for the preparation of compounds of general formula I in which R "except for the cyano group has the meanings mentioned above for R., a compound of the general formula CH -OH (VI) in the R. "as defined above, and R and R _{2 are} as defined above, with a compound of the general formula H = C - CH ₂ ~ ( _vy > -W (VII), in the R_ and Vl are as defined above, implemented _s or _s e) a compound of the general formula 17/11/1983 AP C 07 D / 252 755 έ2 554/12 Hal A - NH - CO - CH, (VIII). in the R ₁ R ₇₁ A and W are as defined above and Hai represents a fluorine, chlorine, bromine or dodentate, is dehalogenated, or f) for the preparation of compounds of general formula I ₁ in the R. an alkyleniminocarbonyl group having 4 to 6 carbon atoms in the alkylene ring or an optionally mono- or disubstituted by alkyl or phenylalkyl groups each having 1 to 3 carbon atoms in the alkyl moiety aminocarbonyl, a compound of general formula COOH CH - NH - CO - CH, in the R-, R ₂ and R are as defined above and VV "except for the carboxy group for VV in the beginning has mentioned meanings, with an amine of the general formula 17,11.1983 AP C 07 D / 252 755 62 554/12 MR in the R _{7 is} an alkyleneimxno group having 4 to 6 carbon atoms or an alkyl or »
Represents phenylalkyl groups each having 1 to 3 carbon atoms mono- or disubstituted amino group in the alkyl moiety,
is implemented, or g) for the preparation of compounds of general formula I in which W represents the carboxy group,
a compound of the general formula CH - NH -CO- (XI) in the R ₁ to R are as defined above and
E represents a group convertible by oxidation into a carboxy group,
is oxidized, or h) for the preparation of compounds of general formula I, in which VV represents an alkoxycarbonyl group having a total of 2 to 6 carbon atoms, in which the alkyl part from the ß-carbon atom by one or two 17/11/1983 AP C 07 D / 252 755 62 554/12 Hydroxy groups or by an alkoxy group having 1 3 carbon atoms may be substituted, a carboxylic acid of the general formula to A - NH - CO - CH, COOH in the R ₁ to R_ and A are as defined above _f or their derivatives optionally prepared in the reaction mixture with an alcohol of the general formula HO - (XIII) ₁ in the R represents an alkyl group having 1 to 5 carbon atoms which may be esterified from the β-carbon atom by one or two hydroxy groups or an alkoxy group having 1 to 3 carbon atoms, or i) for preparing a compound of the general formula I "in which W methyl- an alkoxycarbonyl, alkoxycarbonyl," 2-alkoxycarbonyl-ethyl or 2-Alkoxycarbonyläthenylgruppe and R 'with the exception of the cyano group has the above mentioned meanings for R, a compound of the general formula 17/11/1933 07 C07 D / 252 755 62 554/12 CH - MH - CO - CH, (XIV) in the R to R "are as defined above and Represents 17 "'a cyano, cyanomethyl, 2-cyanoethyl or 2-cyanoäthenylgruppe,
is converted into an appropriate ester, and then optionally, a compound of general formula I obtained according to the invention in which W represents a carboxy or alkoxycarbonyl group is converted by reduction into a corresponding compound of general formula I in which IV represents a formyl or hydroxymethyl group, and / or a erfindungsgerräß obtained compound of general formula I _t in the V / represents the carboxy group, converted by means of conversion into a sulfonic acid and subsequent disproportionation into a corresponding compound of general formula I, in which W represents the formyl group, and / or a erfindungsgemäii obtained compound of the general formula I, in which IV represents a formyl group, by means of condensation and optionally subsequent hydrolysis 17.11.1983 AP C 07 D / 252 755 - 120 - 62 554/12 and / or decarboxylation into a corresponding compound of the general formula I, in which VV represents a 2-alkoxycarbonyl-ethenyl or a 2-carboxy-ethyl-butyl group, and / or a compound according to the invention of general formula I _# in which W represents a 2-carboxy-ethyl or 2-alkoxycarbonyl-ethenyl group, by means of catalytic hydrogenation in a corresponding compound of general formula I ₄ in the VV a 2-carboxy-ethyl represents - or 2-alkoxycarbonyl-ethyl group, is converted, and / or a compound according to the invention of general formula I ₁ in which V represents an alkoxycarbonyl group which is substituted by a hydroxy group starting from the β-carbon atom, by acylation by a pyridinecarboxylic acid into a corresponding (pyridinecarbonyloxyalkoxy) carbonyl compound of general formula I. is transferred, and / or a compound of the general formula I according to the invention, in which .7 represents a hydroxymethyl group, is converted, after conversion into a corresponding halomethyl compound, by reaction with a malonic acid diester into a corresponding compound of the general formula I in which W represents an ethyl group substituted by two alkoxycarbonyl groups , and or a compound obtained according to the invention of the general 17/11/1983 AP C 07 D / 252 755 ; - 121 - <'' ^: '_; / 62 554/12. : ' ^: ..'... NEN Formula 1, in which Ö represents a ßthylgruppe substituted by two Alkoxycarbönylgruppen, is converted by hydrolysis into a corresponding compound of general formula I »in which W is substituted by two carboxy groups ο Athylgfuppe, is transferred, and / or a compound of general formula I obtained according to the invention in which W represents a vithyl group substituted by two alkoxycarbonyl groups is converted by hydrolysis and decarboxylation into a corresponding compound of general formula I in which W represents a carboxyethyl group; / or a compound of the general formula I according to the invention, in which R _{2 represents} a nitro group, is converted by reduction into a corresponding compound of the general formula I, in which R _{2 represents} an amino group, and / or a compound of general formula 1 according to the invention in which R _{2 represents} an amino group, via a corresponding diazonium salt in a corresponding compound of general formula I in which R _{2 is} a hydrogen or halogen atom, a hydroxy, alkoxy or alkylsulfenyl group represents, is transferred, and / or a compound of the general formula I obtained according to the invention, in which R _{2 represents} a hydroxy group, by means of 17.11.1983 AP C 07 D / 252 755 - 122 - 62 554/12 Alkylation is converted into a corresponding compound of the general formula I, in which Ro ^e * ⁿ e alkoxy group is converted, and / or a compound of general formula I obtained according to the invention in which R "represents a benzyloxy radical and / or R represents an aryl radical substituted by a benzyloxy radical, by debenzylation into a corresponding compound of general formula I, R ₂ represents hydroxy group and / or R. represents an aryl radical substituted by a hydroxy group, and / or a compound of general formula I obtained according to the invention in which R _{4 is} an aminocarbonyl group is converted by dehydration into a corresponding compound of general formula I in which R. represents a cyano group, and / or a compound of the general formula I obtained in accordance with the invention, if it contains a chiral center, is separated into its enantiomers by means of chromatography on chiral phases, and / or a Verbini obtained according to the invention of the general formula I in their salts, especially in their physiologically acceptable salts with inorganic or organic acids or bases is transferred « , Process according to item 1, characterized in that the reaction is carried out in a solvent. 17.11.1983 AP C07 D / 252 755 - 123 - 62 554/12 3. Process according to points 1a and 2, characterized in that the reaction is carried out in the presence of an acid-activating or dehydrating agent, if appropriate in the presence of an inorganic or tertiary organic base. 4. Method according to points la and 2 _t, characterized in that the reaction is carried out in the presence of an amine-activating agent, if appropriate in the presence of an inorganic or tertiary organic base, 5. The method according to the points la and 2, characterized in that the water formed during the reaction is removed by azeotropic distillation or by adding a desiccant « 6 «method according to the points la and 2 to 5, characterized in that" the reaction at temperatures between -25 and 120 ⁰ C, preferably at temperatures between -10 ⁰ C and the boiling temperature of the solvent used, is performed. 7 "Process according to points 1 b and 2, characterized in that the hydrolysis or thermolysis is carried out in the presence of an acid or a base" 8, processes according to items 1 b and 2 _t, characterized in that the reaction is carried out in the presence of a nitrite, for example, sodium nitrite, and in the presence of an acid, such as sulfuric acid, when B is the nitrile or aminocarbonyl group. 17.11.1983 AP C 07 D / 252 755 " 124 - 62 554/12 9 »process according to the points Ib, 2 and 7, characterized in that the reaction at temperatures between -10 and 120 ⁰ C, preferably at temperatures between room temperature and the boiling temperature of Reaktlons ~ mixture is performed, 10, process according to the points lc, Ie and 2, characterized in that the reduction or, the dehalogenation is carried out with hydrogen in the presence of a hydrogenation catalyst, 11, Process according to the points lc, Ie, 2 and 10, characterized in that the reaction at temperatures between 0 and 100 ⁰ C, preferably at temperatures between 20 and 50 ⁰ C, and a VVasserstoffdruck of 1 to 5 bar is performed, 12, processes according to the points Id and 2, characterized in that the reaction in the presence of a strong acid, z, B, sulfuric acid, carried out, 13 «method according to the items Id, 2 and 12, characterized in that the reaction at temperatures between 0 and 150 ⁰ C, preferably 20 and 100 ⁰ C, carried out 'is. 14, method according to the points If, lh and 2, characterized in that the reaction in the presence of an acid activating or a dehydrating agent is optionally carried out in the presence of an inorganic or tertiary organic base. 17.11.1983 ΛΡ C 07 D / 252 755 - 125 - 62 554/12 15. Method according to points 1 and 2, characterized in that the reaction is carried out in the presence of an amine-activating agent, if appropriate in the presence of an inorganic or tertiary organic base, 16. The method according to the points If ₁ 2, 14 and 15, characterized in that the reaction at temperatures between -25 and 250 ° C _# but preferably at temperatures between -10 ⁰ C and the boiling temperature of the solvent used, is performed » 17 * Process according to points Ig and 2, characterized in that the oxidation is carried out with silver oxide / sodium hydroxide solution, manganese dioxide, hydrogen peroxide / sodium hydroxide solution, chromium trioxide / pyridine, pyridinium chlorochromate / bromine or chlorine / soda paler Kalilaugo _e IG. The method according to the points Ig, 2 and 17, characterized in that the Urasetzurig is carried out at temperatures between 0 and 100 ⁰ C but preferably at temperatures between 20 and 50 ^ C ;, in " 19, process according to the points lhy 2 and 14, characterized in that the reaction at temperatures between -20 and 100 ⁰ C, but preferably at temperatures between ~> 10 C and the boiling temperature of the solvent used, carried out « 20, method according to points Ii and 2, characterized 17,11.1983
AP C 07 D / 252 755
- 126 - 62 554/12 through, dap. the reaction in the presence of an acid like
Hydrogen chloride or sulfuric acid is performed. 21, method according to the points li _# 2 and 20, characterized in that the reaction at temperatures between
20 ⁰ C and the boiling temperature of the solvent used, preferably at temperatures between 50 and 100 ⁰ C _{1 is} performed *