CS228910B2 - Method of preparing new substituted alkyleneiminophenylalkyl amides of phenylalkane carboxylic acids - Google Patents

Abstract

Compounds of general formula I <IMAGE> (wherein, in outline, R1 and R2 represent alkyl or cycloalkyl groups or together with the nitrogen atom to which they are attached, represent a cyclic imino group, R3 represents a hydrogen or a halogen atom, an optionally substituted hydroxy, mercapto, amino, carboxy or aminocarbonyl group, or a nitro, alkanoyl, aminosulfonyl, alkyl, trifluoromethyl or cyano group, R4 represents a hydrogen atom or an alkyl group, R5 represents a hydrogen or a halogen atom or an alkyl group, A represents a bond or an optionally substituted methylene, ethylene, cycloalkylidene or vinylidene group, B represents a methylene or ethylene group optionally substituted by an alkyl group and W represents a hydrogen or a halogen atom, a cyano, alkanoyl or nitro group, an optionally substituted amino or aminocarbonyl group, a carboxy group, or an ester thereof, a formyl group or an acetal thereof or an optionally substituted alkyl or alkenyl group); and salts thereof formed with acids and bases. Processes for the preparation of the new compounds as well as pharmaceutical compositions containing them are also objects of this invention. The new compounds show valuable pharmaceutical properties, especially effects on intermediary metabolism and a blood-sugar lowering activity.

Description

The present invention relates to a process for the preparation of novel substituted alkylenimino-phenylalkylamides of phenylalkancarboxylic acids of the general formula I

and salts thereof, in particular their physiologically acceptable salts with inorganic or organic acids and bases.

The compounds have valuable pharmacological properties, in particular they have a metabolic effect, but preferably have the ability to reduce the blood sugar content. For these reasons, the compounds produced according to the invention can be used as active pharmaceutical ingredients.

In the above general formula I, the general symbols have the following meanings:

R1 and R2 which are the same or different from each other denote alkyl groups having 1 to 6 carbon atoms or cycloalkyl groups having 5 to 7 carbon atoms, or

R1 and R2. together with the nitrogen atom therebetween means an unbranched C 3 -C 6 alkyleneimino group optionally substituted by one or two C 1 -C 3 alkyl or hydroxy groups or in which the methylene group is optionally replaced by a carbonyl group , oxygen, sulfur, or imino optionally substituted by C 1 -C 3 alkyl, C 7 -C 10 aralkyl, phenyl, or halophenyl, or in which the ethylene is optionally replaced by o-phenylene a group; further denote unbranched C 4 -C 6 alkenyleneimino, saturated or 1, 2 or 3 double bonds containing C 6 -C 10 azabicycloalkyl, C 6 -C 8 aza-1,4-dioxaspiroalkyl, heptamethylenimino, octamethyleniminoimino, nonamino or decamethyleneimino,

R3 represents a hydrogen atom or, a halogen atom, a trifluoromethyl group, an alkyl group, a hydroxy group, an alkoxy group, an alkanoyloxy group, a mercapto group, an alkylmercapto group, a nitro group, an amino228910

a cyano group, an alkanoyl group, a carboxy group, an alkoxycarbonyl group, an aminocarbonyl group, an alkylaminocarbonyl group, a dialkylaminocarbonyl group, an amino sulfonyl group, an alkylamino group, a dialkylamino group, an alkanoylamino group, an alkoxycarbonylamino group, 3 carbon atoms; 7-C10-phenylalkoxy or phenylcarbonylamino;

Rd represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms,

R 5 represents a hydrogen atom, a halogen atom, or an alkyl group having 1 to 3 carbon atoms,

A represents a bond, optionally methyl, ethyl or isopropyl substituted by methylene or ethylene, by two alkyl groups having 1 to 3 carbon atoms each, substituted by methylene or ethylene group, cycloalkyl having 3 to 7 carbon atoms, hydroxyalkyl group · C 1 -C 3, carboxy, C 1 -C 3 alkoxycarbonyl or phenyl-substituted methylene, C 3 -C 7 cycloalkylidene or vinylidene

R 7 and R 7 represent a hydrogen atom or one of the radicals Re and R 7 represents a methyl group or a cycloalkyl group having 3 to 7 carbon atoms, and the other of the radicals Re or R 7 represents a hydrogen atom or

Re · and R 7 together with the atom. the intervening carbon is a C 5 -C 7 cycloalkylidene group,

B is optionally a C 1 -C 3 alkyl group substituted with a methylene or ethylene group; and

W represents a hydrogen atom or a halogen atom, a nitro group, an alkanoyl group having 1 to 3 carbon atoms substituted by an amino group, optionally a hydroxy group, a carboxy group or an alkoxycarbonyl group or two alkoxycarbonyl groups each having a total of 2 to 4 carbon atoms ; C 2 -C 5 alkenyl, C 1 -C 3 alkanoyl, C 1 -C 3 dialkoxymethyl or C 1 -C 3 trialkoxymethyl or C 1 -C 3 alkoxycarbonyl; an alkyl moiety, an alkylenedioxymethyl group having 2 or 3 carbon atoms in the alkylene moiety, a 1,3-oxazolin-2-yl group or a cyano group, optionally substituted by one or two C 1 -C 4 alkyl groups in each alkyl moiety substituted by an aminocarbonyl group ; an unbranched alkylene- (imino) carbonyl group having a total of 5 to carbon atoms, a morpholino-carbonyl group.

a (C 1 -C 10) dialkyldioxolanyl) alkoxycarbonyl group or a carboxy group or alkyl-, benzyl- or (2,2-dimethyldioxolinyl-4-yl) methyl esters thereof, the alkyl moiety having 1 to carbon atoms and is with the exception of the α-position. optionally substituted with hydroxy, methoxy or diethylamino.

For the above-mentioned meanings in defining individual residues, for example, the following are possible:

for R 1 and R 2 together with a nitrogen atom, there are:

dimethylamino, diethylamino, dipropylamino, dibutylamino, diisobutyl, dipentyl, dihexylamino, N-methyl-N-ethylamino, N-methyl-N-propylamino, N-isopropyl-N-propylamino, · _{N-isobutyl-N-propylaminoskuplna} N methyl-N-isopropylamino; N-methyl-N-butylamino; N-ethyl-N-butylamino, N-ethyl-N-isopropylamino, N-ethyl-N-pentylamino, N-propyl-N-butylamino, N-methyl-1-cyclopentylamino, N-ethyl-N-cyclopentylamino, N- methyl-N-cyclohexylamino, NíethylíNíCyklohexylaminoskupma, NíCykIohexylaminoskupina n-propyl-N-isobutyl-N-cyclohexylamino, * pyrrolidino, piperidino, hexamethyleneimino, tt ^^ ^{^,} ^^ eniminoskupina * heptamethyleniminoskupina, oktamethylenimínoskupina, nonamethyleniminoskupina, dekamethyleniminoskupina, dimethylazetidinoskupina, methylpyrrolidňnoskupina, dimethylpyrrolidňnoskupina, ethylpyrrolidone, methylpiperidino, dimethylpiperidino, ethylpiperidino, diethylpiperidino,

228 9 10 methylethylpiperidino, propylpiperidino, methylpropylpiperidino, isopropylpiperidino, cis-3,5-dimethylpiperidino, trans-3,5-dimethylpiperidino, morpholino, thiomorpholino, piperazino, N-methylpiperazino, N-methylpiperazino, isopropyl] piperazino, N-benzylpiperazino,

N- (2-phenylethyl) piperazino, N- (3-phenylpiropropyl) piperazino, N-phenylpiperazino, N-fluorophenylpiperazino, N-chlorophenylpiperazino, N-bromophenylpiperazino, hydroxypyrrolidinomethyl, hydroxypiperidino, hydroxypiperidino, hydroxypiperidino, hydroxypiperidino, hydroxypiperidino, hydroxypiperidino piperidou-1-yl, hexahydroazepin-1-yl, tetrahydro-4'-di (1H) -quinazolin-2-yl, octahydroiscquinolin-2-yl, decahydroisoquinolin-2-yl, dihydroisoindole-2 4-hydroxy-3-benzazepin-2-yl, octahydroisoindol-2-yl, tetrahydro-3-benzazepin-3-yl, decahydro-3-benzazepin-3-yl, 3-acetyl-3-acetyl-3-acetyl; O] heptan-3-yl, 3-azabicyclo [3.2.0] octan-3-yl, and (abu-Mc) [3,2,2] nonan-3-yl,

1,4-dihydro-7-azaspiro [4.4] nonan-7-yl,

1,4-dio xa-4-azaspiro [4,5] decan-7-yl group,

1,4-dio: α-8-azaspiro [4,5] decan-8-yl group,

1,4-dicyclo-8-azaspiro [4,6] undecan-8-yl, pyrroline or tetrahydropyrrolidine;

R @ 3 for hydrogen, fluorine, chlorine, bromine or iodine, methyl, ethyl, propyl, isopropyl, hydroxy, methoxy, ethoxy, propoxy, isopropyl, hydroxy, propoxy, mercapto, mercapto, mercapto, mercapto, mercapto, mercapto, mercapto , ethylmercapto, propylmercapto, isopropylmercapto, trifluoromethyl, nitro, cyano, formyl, acetyl, propiocnyl, aminosulfinyl, amino, methylamino, ethylamino, di-amino, propylamino, propylamino, , N-methyl-N-isopropylamino, N-ethyl-N-propylamino, formylamino group, acetylamino, propynylamino, methylsulfonylamino, elethylsulfonynylamino, propyl · sulfonylamino, isopropylpropylsulfonylamino coupler, carboxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropylcarbonyl, methoxycarbonylamino, ethoxycarbonylamino, propozycarbonylamino, isopropyl, benzyl, benzyl, benzyl, benzyl, benzyl, benzyl, benzyl, benzyl, benzyl, benzyl, benzyl, benzyl, benzyl, benzyl, benzyl, benzyl, benzyl, benzyl, benzyl, benzyl, benzyl, benzylamino,

1- phenylethoxy,

2-phenylethoxy,

3-phenylpropoxy, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, methylethylaminocarbonyl, or methylpropyl;

for Ri:

a hydrogen atom, a methyl group, an ethyl group, a propyl group or an isopropyl group;

for Rs:

a hydrogen atom, a fluorine atom, a chlorine atom, a bromine or iodine atom, a methyl group, an ethyl group, a propyl group or an isopropyl group;

suitable for A are: single bond, methylene group, ethylidene group, ethylmethylene group, isopropylmethylene group, dimethylmethylene group, diethylmethylene group, dipropylmethylene group, methylethylmethylene group, methylpropylmethylene group, ethylpropylmethylene group, ethylisopropylmethylene group, ethylisopropylmethylene group, ethylisopropylmethylene group, , dimethylethylene, cyclopropylmethylene, cyclobutylmethylene, cyclopentylmethylene, cyclohexylmethylene, cycloheptylmethylene, cyclopropylidene, cyclobutylidene, cyclopentylmethylene, cyclohexylmethylene, cycarbonylmethylene,

1-hydroxyethylmethylene group,

2-hydroxyethylmethylene,

1-hydroxypropylmethylene,

3-hydroxypropylmethylene, vinylidyl, methylvinylidene, cyclopentylvinylidene, cyclohexylvinylidene, cyclopropylidenemethylene, cyclopentylidenemethylene, cyclohexylidenemethylene or cycloheptylidenemethylene;

the following are suitable for B: methylene, ethylene, ethylidene, ethylmethylene, propylmethylene or isopropylmethylene, and for W, there are:

a hydrogen atom, a chlorine atom, a bromine atom or an iodine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a hydroxymethyl group,

1-hydroxyethyl,

2-hydroxyethyl,

1-hydroxypropyl,

3-hydroxypropyl, carboxymethyl,

1-carboxyethyl group,

2-carboxyethyl group,

3-carboxypropyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl,

2-methoxycarbonylethyl,

2-ethoxycarbomylethyl,

3-ethoxycarbonylpropyl, bis- (methoxycarbonyl) methyl, bis- (ethoxycarbonyl) methyl,

2,2-bis- (ethoxycarbonyl) ethyl, carboxyvinyl, carboxypropenyl, carboxypentenyl, methoxycarbonylvinyl, ethoxycarbonylvinyl, propoxycarbonylvinyl, formyl, acetyl, propionyl, dimethoxymethyl, dimethoxymethyl, dimethoxymethyl a group, a triethoxymethyl group,

1,2-ethylenedioxymethyl,

1.3- propylenedioxymethyl, cyano, mitro-group, amino, formylamino, acetamino, propionylamino,

1,3- oxazolin-2-yl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminokarbonylová group, butylaminocarbonyl group, dimethylaminocarbonyl group, diethylaminocarbonyl group, dipropylaminocarbonyl group, dibutylaminocarbonyl group, pyrrolidinocarbonyl, piperidinocarbonyl, hexamethyleniminokarbonylová group, a group heptamethyleniminokarbonylová , morpholinocarbonyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentoxycarbonyl, hexoxycarbonyl, benzylcarbonyl, hydroxy,

2-hydroxypropoxycarbonyl,

3-hydroxypropoxycarbonyl, 2-methoxyethoxycarbonyl, 2-ethoxyethoxycarbonyl, [2,2-dimethyldioxolan-4-yl) methoxycarbonyl, 2-diethylminoethoxycarbonyl.

However, preferred compounds of formula I above are those in which:

Ri and R? together with the intervening nitrogen atom denotes a dialkylamino or N-alkylcyclohexylamino group in which each alkyl moiety may contain 1 to 4 carbon atoms; optionally substituted by one or two methyl groups of a straight-chained (C 3 -C 6) alkyleneimino group, a hydroxypiperidino group, a piperidon-1-yl group, a tetrahydropyridino group, a morpholino group, a thiomolphino group, a N-methylpiperazino group, an N-benzylpiperazino or 1, 2 or 3 double bonds containing up to 9 carbon atoms of azabicycloalkyl, 4 to 6 carbon straight-chain alkylaminoimino in which the ethylene group is replaced by an o-phenylene group, or is a 7-carbon or 1,4-dioxaazaspiroalkyl group ;

R3 is hydrogen, fluorine, chlorine, bromine or iodine, methyl, trifluoromethyl, hydroxy, methoxy, benzyloxy, acetoxy, mercapto, methylmercapto, nitro, amino, dimethylamino, benzyloxy, acetylamino, acetylamino, acetylamino, acetylamino, acetylamino, acetylamino, acetylamino, acetylamino, , carboxy, methoxycarbonyl, ethoxycarboinyl, aminocarbonyl, acetyl or aminosulfonyl,

R1 represents a hydrogen atom or a methyl group,

R 5 represents a hydrogen atom, a chlorine atom or a methyl group,

A represents a bond, optionally methyl, ethyl or isopropyl, phenyl, cyclohexyl, methoxycarbonyl or hydroxymethyl substituted methyl; dimethylmethylene, cyclopropylpropylidene or ethylene or vinylidene group of the general formula

Rs R7 \ / C where

Rg and R-. which may be the same or different from each other are hydrogen atoms or R8 and R8 are hydrogen atoms; together with the intervening carbon atom means a cycloalkylidene radical having 5 or 6 carbon atoms,

V is a methylene, ethylidene or ethylene group; and

W represents a hydrogen atom, a methyl group, an ethyl group, a hydroxymethyl group, a cyano group or a carboxy-vinyl group, or a carboxyl group or a C1-C3 alkyl group substituted by one or two alkoxycarbonyl groups; hydrogen, methyl, ethyl, hydroxy, alkoxy, _(2? 2 dimethyldio; <olan-4-yl) methoxy, benzyloxy, pyridylmethoxy, amino, alkylamino, dialkylamino, piperidino, substituted or morfclinoskupinou. a carbonyl group, wherein each alkyl moiety in the above groups may contain 1 to 3 carbon atoms; or is a radical of formula

O

II

-CO- (C ‰) _n —R ₁ where n is 2, 3 or 4 a

Ra is hydroxy, methoxy, diethylamino, especially those compounds in which the residue is

Ri /

—N \

Ra is at the 2-position and the residue W is at the 4-position, and when these compounds contain an asymmetric carbon atom, their optically active antipodes and salts thereof.

However, the compounds of formula Ia are particularly preferred

—C— in which

R1 and Ra together with the nitrogen atom therebetween are dimethylamino, pyrrolidino, methylpyrrolo228910 dino, piperidino, methylpiperidino, dimethylpiperidino, tetrahydropyridino, 2-octahydroisoindolo or hexamethyleneimino,

R 5 represents a hydrogen atom, a fluorine atom or a chlorine atom or a methyl group,

A is optionally cyclohexyl, phenyl, methoxycarbonyl, ethoxycarbonyl or methyl, ethyl or isopropyl substituted methylene; dimethylmethylene or vinylidene groups of the general formula

whereas

R 6 and R 7 represent hydrogen atoms or together with the carbon atom lying between them represent cyclohexylidene, and

W represents methyl, hydroxymethyl or carboxymethyl, hydrogen, methyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, 2-hydroxyethoxy, 2-methoxyethoxy, (2,2-dimethyldioxolan-4-yl) or methoxy diethylaminoethoxy substituted carbonyl group, their optically active antipodes and their physiologically acceptable salts with inorganic or organic acids or bases.

According to the invention, the novel compounds are prepared by treating the amine of formula II

A and R 1 to R 1 are as defined above, or when A is one of the abovementioned vinylidene groups, its tautomer or its lithium or magnesium halide complex is treated with a carboxylic acid of formula III in an inert organic solvent

HOOC-B

in which

Rs and В have the above meanings and

W 'has the meaning given above for W or is a carboxyl group which is protected by a protecting group or its reactive derivatives, which are optionally produced in the reaction mixture, and optionally the protecting group used is cleaved hydrolytically or by thermolysis in the presence of acid or base at temperatures in the range of -10 ° C to 120 ° C, whereupon the optionally obtained compound of formula (I) is converted into its salts, in particular its physiologically acceptable salts with inorganic or organic acids and with bases.

Suitable reactive derivatives of the compound of formula (III) are, for example, its esters, such as methyl, ethyl or benzyl esters, its thioesters such as methylthioester or ethylthioester, its halides, such as acid chloride, its anhydrides or imidazolides.

The reaction is conveniently carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionally in the presence of an acid activating agent or a water scavenger such as ethyl chloroformate, thionyl chloride, phosphorus trichloride. , phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, a mixture of N, N'-dicyclohexylcarbodiimide and N-hydroxysuccinimide, N, N'-carbonyldiimidazole or N, N'-thionyldiimidazole or a mixture of triphenylphosphine and carbon tetrachloride, or an amine activating agent , 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 of -25 to 250 ° C, preferably at temperatures of -10 ° C to boiling point. solvent. However, the reaction may also be carried out without solvents, and furthermore water formed during the reaction may be separated by azeotropic distillation, for example by heating with toluene, using a water separator or by adding a desiccant such as magnesium sulfate or molecular sieves.

If desired, the following deprotection is preferably carried out hydrolytically, conveniently either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid or trichloroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide: in a suitable solvent such as water, methanol ethanol, a mixture of ethanol and water, a mixture of water and isopropyl alcohol, or a mixture of water and dioxane at temperatures of -10 to 120 ° C, for example at temperatures ranging from room temperature to the boiling point of the reaction mixture.

(III)

The tert-butyl group used as a protecting group can also be cleaved thermally, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or di-ethane, 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, the benzyl group used as a protecting group can also be cleaved hydrogenolytically in the presence of a hydrogenation catalyst such as palladium on carbon in a suitable solvent such as methanol, ethanol, ethanol and water, ice acetic acid, ethyl acetate, dioxane or dimethylformamide.

The compounds of the formula I obtained can be converted to their acid addition salts, in particular to the. their physiologically acceptable salts with inorganic or organic acids or with bases. How ? the acids which may be used 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 the base is sodium hydroxide, potassium hydroxide or cyclohexylamine.

The compounds of the formulas II and III to be used as starting materials are partly known from the literature or are obtained by methods known per se.

Thus, for example, a compound of formula (II) in which A is a bond is obtained by reducing the corresponding nitro compound, for example by catalytically activated or nascent hydrogen or by sodium dithionite or by Hofmann, Curti, Lossen or Schmidt degradation of the corresponding compound.

Thus, for example, a compound of formula II in which A is a vinylidene group or a tautomeric ketimine thereof is obtained by reacting the corresponding nitrile with the corresponding Grignord compound or lithium compound followed by hydrolysis or reaction of the corresponding ketone with the corresponding amine in the presence of titanium tetrachloride. The organometallic complex of ketimine can also be used to further react with the compound of the formula III or its reactive derivatives, in particular its acid chlorides.

Further, for example, a compound of formula II in which A is not a bond or is not a vinylidene group is obtained by reducing the corresponding nitrile with lithium aluminum hydride, reacting the corresponding nitrile with the corresponding Grignard compound or lithium compound and optionally subsequent reduction with lithium aluminum hydride or subsequent hydrolysis to form ketimine. by catalytically activated hydrogen, complex metal hydride or nascent hydrogen, hydrolysis or hydrazinolysis of the corresponding phthalimidoderivative, reaction of the corresponding ketone with ammonium formate and subsequent hydrolysis with optionally the ammonium salt in the presence of sodium cyanoborohydride, reduction of the corresponding lithium aluminum hydride, reduction of the corresponding N-benzyl- or N1-phenylethyl-Schiff base, for example with a complex metal hydride in ether or tetrahedron Ydrofuran at temperatures in the range of -78 ^° C to the boiling point of the solvent and subsequent cleavage of the benzyl or 1-phenylethyl group by catalytic hydrogenation, R 1 -ter reaction of the corresponding alcohol with potassium cyanide in sulfuric acid, or Hofmann, Curtius, Lossen or Schmidt. . The amine of formula (II) thus obtained with a chiral center can be resolved into its enantiomers by resolution of the racemate, for example by fractional crystallization of diastereomeric salts with optically active acids followed by salt decomposition or formation of diastereomeric compounds, their resolution and subsequent resolution. Furthermore, an optically active amine of formula II can also be prepared by enantioselective reduction of the corresponding ketimine with complete borohydrides or alurainium hydrides in which part of the hydride atoms of the hydrogen atom is replaced by optically active alkoxide residues, or hydrogen treatment in the presence of a suitable chiral hydrogenation catalyst, benzyl or, in the case of an optically active N1-phenylethyl-Schiff base, as a starting material and optionally subsequent cleavage of the benzyl or 1-phenethyl radical.

The compound of formula (II) wherein R 1 is lower alkyl is obtained by reduction of the corresponding N-acyl derivative, for example by treatment with lithium aluminum hydride.

As mentioned above, the novel compounds of formula (I) have valuable pharmacological properties, i.e., an effect on the intermediate metabolism, but in particular have the ability to reduce the blood sugar content.

For example, the following compounds have been tested for their ability to lower blood sugar:

A = 4 - [(2-pyrrolidinobenzyl) aminocarbonylmethyl] benzoic acid,

V = 4 - {[1- (2-pyrrolidinophenyl} ethyl) aminocarbonylmethyl benzoic acid,

C 4- _! [1- (5-chloro-2-pyrrolidin-1-yl) -ethyl] -aminocarbonyl-methyl-benzoic acid,

D = 4 - {[(2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid.

Ε = 4 - [[1- (2-piperidinophenyl) ethenyl] aminocarbonylmethyl] benzoic acid,

F = 4- [1- (6-chloro-2-piperidinophenyl) ethenyl] aminocarbonylmethybenzic acid,

G = 4 - {(1- (6-methyl-2-piperidinophenyl) ethenyl] aminocarbonylmethyl] benzoic acid,

H = 4- [1- (2-piperidinophenyl) ethyl] aminocarbonylmethylbenzoic acid,

I = 4 - [[1- (2-Piperidinophenyl) ethyl] aminocarbonylmethyl] benzoic acid ethyl ester,

K = (+) -4 - [[1- (2-Piperidinophenyl) ethyl] amine occarbonylmethylbenzoic acid ethyl ester,

L = (2,2-dimethyldiGxolan-4-yl) methyl 4-yl-1- (2-piperidinophenyl) ethyl] aminocarbonylmethyl-benzoic acid,

M = 4- [1- [2-piperidinophenyl) ethyl] aminocarbonylmethytoluene,

N = 4- [1- 1- (2-piperidinophenyl) ethyl] aminocarbonylmethyl] -benzyl alcohol,

O = 4 - [[1- (2-piperidinophenyl) ethyl] aminocarbonylmethyl] benzaldehyde,

P = 4 - [[1- (2-piperidinophenyl) ethyl] aminocarbonylmethylphenylacetic acid,

Q = 4 - [[1- (4-chloro-2-piperidinophenyl) ethyl] aminocarbonylmethyl] -1H-benzoic acid,

R = 4 - [[1- [5-chloro-2-piperidinophenyl) ethyl] aminocarbonylmethyl] benzoic acid,

S = 4- [1- (6-chloro-2-piperidinophenyl) ethyl] aminocarbonylmethyl | benzoic acid ethyl ester,

T = 4 - [[1- (5-fluoro-2-piperidinophenyl) ethyl] aminocarbonylmethyl] benzoic acid,

U = 4- | [1- [4- (4-Isyl-2- (4-iodo-phenyl) -ethyl] aminocarbonylmethyl] -benzoic acid,

V = 4-1- (5-methyl-2-piperidino.phenyl) ethyl] aminocarbonylmethybenzoic acid,

W = 4- [2--2-piperidinophenyl-2-propyl] aminocarbonylmethybenzoic acid,

X = 4-j (1- (2-piperidinophenyl) -2-methylpropyl) aminocarbonylmethyl] benzoic acid,

Y = 4 - [(2-piperidinobenzhydryl) aminocarbonylmethyl] benzoic acid,

Z = _4-t H2 - l, 2,3,6 - ttrahydropyridinojf phenyl] ethyl {aminokarbonylm.ethyl) benzoic acid

AA = 4- [1- [2- (3-methylpipendino) phenyl] ethyl; aminocarbonylmethyl) benzoic acid,

AB = 4 - [[1- (2-hexahydroazepinophenyl) ethyl] aminocarbonylmethyl] benzoic acid,

AC-4- [1- (2-octahydroisoindolophenyl) ethyl] aminocarbonylbutylmethyl-4-methylbenzoic acid,

4 - [(m-Methoxyphenyl) -4-carbonyl-2 - [(4-carbonyl) amino] carbonylmethyl] benzoic acid AD - ethyl ester;

AE = (+] -4 - {[1- [2-piperidinophenyl) ethyl] aminocarbonylmethylbenzoic acid, as follows:

1. Blood sugar lowering effect

The blood glucose lowering effect of the test compounds was tested in female rats weighing 180-220 g, not fed for 24 hours prior to the start of the experiment. Test compounds are suspended in 1.5% methylcellulose immediately prior to the start of the experiment and applied to the esophagus via a probe.

Blood collection is performed immediately before application of the substance as well as 1, 2, 3 and 4 hours thereafter from retro-orbital venous plexus. To this end, use 50 µl of the sample to which 0.5 ml of 0.33 N perchloric acid is added to remove the proteins and centrifuge the sample. Glucose is determined in the residue by the heKokinase method using photometer analysis. Statistical evaluation was performed according to the d-test (Student) with p = 0.05 as a significant limit.

The following table shows the values found in% compared to the control:

what

him £ 1 Sp ^; with Eí LQ o n <

OJ

what

bo > p ~ W) .with ε I.E O o rH rCl

OJ

OJ CJ co

AND

χφ rH rH CO

H CD CO

CD CO CO ⁰ ri I d II with 1O N '-nn NN CB CM ХИ Хф СО хф СМ Хф хф có rH OD ω d I ^β II ri ю со ь, СО Хф см

CO OJ rH LQ CO rH CO χφ CO CO ^ώ ri

CO LQ χφ O 00 o what co

CO rH φ CO CO ΓСО см тН Хф хф

СО И LC 02 (О гН СО хф хф хф OJ

Χφ co

cd d

χφ OJ χφ rH co CM o Χφ co rH OJ rH LQ co w CO ri I co

OJ

what OJ OJ

LO Cx cO rH rH

LQ OJ χφ CO

WHAT

ID

OO rH

OJ co

CO χφ Ή

OJ OJ CO

TABLE 1

tao AS >> W) .WITH 8 TJ 'o LO OJ

OJ

what LO about what cn what

CM CO tH co 00 CO co CM CO CO CM χφ CO χφ CM CO χφ Φ

CM CM

WHAT drawbar what

oo r>

O] r>.

to χφ CD χφ CM CO

OJ what what what what LO what Φ

OJ 00 χφ χφ ю о

Χφ Χφ o rH CO CD -φ »r> co χφ Χφ CM what co χφ rH o CO rH UD CO χφ * Φ χφ co co

OJ what what what what oοο CO

OO >> OJ co χφ Cd co

ΧΦ fx what what

ΧΦφ ΧΦ CO χφ

LQ co CO χφ χφ Χφ 00 χφ

Χφ rH co χφ oj m oj co co σι r> oj co χφ 00 CO Χφ rH o

Χφ χφ Χφ

O CO OJ

OJ CO χφ

LQ 00 tH OJ Χφ φ co LQ Χφ Ol χφ χφ

CO χφ co χφ CO OJ χφ o drawbar χφ co co

CO CD χφ

CO Χφ Χφ ¹

CO χφ CO ю OJ OJ OJφ χφ Χφ χφ χφ

Explanatory notes: * dose: 20 mg / kg ** dose: 1 mg / kg n., Not statistically significant cd Λί 4- »'СО

2. Acute toxicity

Female and male specimens of 20-26g breeding mice are tested for the toxic effect of compounds H, R and Y after oral administration (suspension in 1% methylcellulose) after a single dose at an observation period of 14 days. The following table contains the found values:

Compound Indicative toxicity

H> 2000 mg / kg p.o. (1 animal out of 10 animals died)

R> 2000 mg / kg p.o. (none of the 10 animals died)

Y> 2000 mg / kg p.o. (none of the 6 animals died)

Owing to their pharmacological properties, the compounds of the formula I and their physiologically tolerable salts produced by the process according to the invention are suitable for the treatment of diabetes mellitus. For this purpose, these substances can be formulated, if appropriate in combination with other active substances, into conventional galenic dosage forms, such as tablets, dragees, capsules, powders or suspensions. The individual dose for adults is 1 to 50 mg, preferably 2.5 to 20 mg, once or twice daily.

The following examples serve to illustrate the invention in greater detail.

Example 1

4 - {[1- (5-chloro-2-dimethylaminophenyl) ethyl] aminocarbonylmethyl) benzoic acid methyl ester

To a solution of 2.00 g (0.0103 mol) of 4-methoxycarbonylphenylacetic acid in 13.5 ml of absolute tetrahydrofuran at 20 ° C was added 1.67 g (0.0103 mol) of carbonyldiimidazole under stirring, followed by reaction the mixture was heated to reflux for 45 minutes under exclusion of moisture. After cooling to room temperature, 2.05 g (0.0103 mol) of 1- (5-chloro-2-dimethylaminophenyl) ethylamine in 7 ml of absolute tetrahydrofuran was added to the reaction mixture, and the mixture was stirred at 20 ° C overnight. The reaction mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (toluene / acetone 10: 1).

Yield: 2.6 g (66.7% of theory).

M.p .: 153-155 ° C (from ether).

Analysis:

calculated:

% H, 6.18;% Cl, 9.46;% N, 7.47.

% C, 64.30;% H, 6.04;% C, 9.70;

In an analogous manner to that described in Example 1, the following compounds were prepared:

4 - [[1- (5-Chloro-2-dipropylaminophenyl) ethyl] aminocarbonylmethyl] benzoic acid methyl ester

Yield: 42%.

135 DEG-137 DEG C. (ether / petroleum ether).

Analysis:

calculated:

% C, 66.83;% H, 7.25;% 8.23;

% C, 66.95;% H, 7.35;% Cl, 8.35;

4 - [[1- (5-Chloro-2-dibutylaminophenyl) ethyl] aminocarbonylmethyl] benzoic acid methyl ester

Yield: 64.8% of theory.

Melting point: 110-112 ° C.

Analysis:

calculated:

68.03% C, 7.69% H, 7.72% Cl, 6.10% N, found:

% C, 67.86;% H, 7.61;% C, 7.73;

4- [1- (5-Chloro-2-N-cyclohexyl-N-methylaminophenyl) ethyl] aminocarbonylmethyl-benzoic acid methyl ester

Yield: 63.9% of theory.

Mp 152-153 ° C (from ether).

Analysis:

calculated:

Found: C, 67.78; H, 7.05; Cl, 8.00.

67.70% C, 6.92% H, 8.24% Cl, 6.46%. N.

4 - [(5-Chloro-2-pyrrolidin-o-, benzyl) aminocarbonylmethyl] benzoic acid methyl ester

Yield: 68.1% of theory.

Melting point 139-141 ° C (from methanol).

Analysis:

calculated:

% C, 65.19;% H, 5.99;% Cl, 9.17;

% C, 65.46;% H, 5.91;% Cl, 9.26;

4 - [[1- (5-Chloro-2-pyrrolidinophenyl) ethyl] aminocarbonylmethyl] benzoic acid methyl ester

Yield: 58.3%.

M.p. 133-135 ° C (from methanol).

Analysis:

calculated:

H, 6.29; H, 8.84; N, 6.99. Found:

66.24% c, 6.19% H, 8.75% Cl,% N.

4 - [(5-Chloro-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid methyl ester

Yield: 75.1% of theory.

Mp 123-125 ° C (from ether).

Analysis:

calculated:

% C, 65.91;% H, 6.29; 6.99 6% N, found:

H, 6.13; H, 8.88; N, 7.21.

4-) [1- (5-Chloro-2-piperidinobenzyl) aminocarbonylmethyl; benzoic acid melthyl ester

Yield: 70.4% of theory.

M.p. 142-144 ^° C (from ether).

Analysis:

calculated:

66.57% C, 6.56% II, 8.55% Cl, 6.75%, found:

% C, 66.50;% H, 6.49;% Cl, 8.44;

4 - {[1- (5-chloro-2-piperidinophenyl) ethyl] aminocarbonylmethyl] benzoic acid methyl ester

Yield: 69.5% of theory.

Melting point 147-149 ^° C (from ether).

Analysis:

calculated:

66.57% C, 6.6% 6% 6I.8.8 (5% Cl, 6.75 6% 6, found:

% C, 66.33;% H, 6.54;% C, 8.67;

4 - () 1- [5-Chloro-2- (3-methylpiperidiino) phenyl, ethylaminocarbonylmethyl / benzoic acid methyl ester

Yield: 54.3% of theory.

Melting point 160-162 ° C (from methanol).

Analysis:

calculated:

67.20% 6.6,, 8% 6H 6.2 ^ 2 ^ 6 / o 6l, 6.521 6/0 _Nj found:

H, 6.81; H, 8.13; N, 6.45.

4- {1- [5-Chloro-2- (3,5-cis-dimethyl-piperidino) -phenyl] -ethyl-aminocarbonylmethyl} -benzoic acid methyl ester

Yield: 44%.

Mp 190-193 ^° C (from methanol).

Analysis:

calculated:

% C, 67.78;% H, 7.05;% C, 8.00 °;

67.50 ° C, 7.05 6% H, 8.25 6% Cl, 6.48 <% N.

4-) [1- [5-Chloro-2-piperidinophenyl) propyl] aminocarbonylmethylbenzoic acid methyl ester

Yield: 65.9% of theory.

M.p. 142-144 ^° C (from ether).

Analysis:

calculated:

67.20% C, 6.81 6% 8, 8.26 6% cl, 6.53 6% N, found:

% C, 67.45;% H, 6.63;% Cl, 8.38%;

4 -) [1- [5-Chloro-2-piperidinophenyl) -2-methylpropyl 1-aminocarbonylmethyl; benzoic acid methyl ester

Yield: 61.4% of theory.

Melting point 156-158 ° C (from ether).

Analysis:

calculated:

67.78% C, 7.05% H 6, 8.00 6% Cl 6.32 _6/0 N Found:

% C, 67.80;% H, 7.17;% Cl, 7.89;

4 - {[1- (5-Chloro-2-morpholino-phenyl) -ethyl] -aminocarbonylmethyl) -benzoic acid methyl ester

Yield: 69.8% of theory.

Melting point 156-158 ° C (from ether).

Analysis:

calculated:

63.38% C 6.04% H 8.50 6% 6 6C 6.72% _N Found:

% C, 63.24;% 6.12;% 6.70;

4 -) [1- (5-Chloro-2-thiomorpholinophenyl) ethyl] aminocarbonylmethyl-4-benzoic acid methyl ester

Yield: 68.2% of theory.

Melting point 167. up to 169 ° C (from ether).

Analysis:

calculated:

% C, 61.03;% H, 5.82;% C, 8.19;

7.41% S, found:

% C, 60.83;% H, 5.77;% Cl, 33;% N, 6.44;% S = 7.39.

4- (11- [5-Chloro-2- (hexahydro-1H-azepino) phenyl] ethylamino-carbonylmethyl) -benzoic acid methyl ester

Yield: 41.7%.

M.p. 146-147 ° C (from methylene chloride / petroleum ether).

Analysis:

calculated:

67.19% C, 6,, 16 / o H, 6.27 6 / o, 6,, 3 6% N, found:

66.90% 6, 6, 6 6% H, 6Д3% Ci, 6, 9-6% N.

4 - {[1- (5-Chloro-2-octahydroazocinophenyl) ethyl] aminocarbonylmethyl] benzoic acid methyl ester

Yield: 30%.

M.p. 154-156 ° C.

Mass spectrum: molecular signal:

calculated: m / e = 442/444 (1 chlorine), found: m / e = 442/444 (1 chlorine).

4 - () 1- [5-Chloro-2- (octahydro-az-azonino) phenyl] ethyl (aminocarbonylmethyl) benzoic acid methyl ester

Yield: 38%.

184 DEG-185 DEG C. (from chloroform-toluene).

Analysis:

calculated:

68.32% C, 7.28% H, 6.13% N, γη Q 1 pry ρ γη

68.10 ° / ο C, 7.30% H, 6.28% N.

4 - {[2- (5-Chloro-2-piperidinophenyl) -2-propyl] amino aminocarbonylmethyl | benzoic acid methyl ester

Yield: 84.4% of theory.

Melting point 162-164 ^° C.

Mass spectrum: molecular signal:

calculated: m / e = 428/430 (1 chlorine), found: m / e = 428/430 (1 chlorine).

4 - {[1- (5-Nitro-2-piperidino-phenyl) -ethyl] -aminocarbonylmethyl] -benzoic acid methyl ester

Yield: 68.3% of theory.

Melting point 178-180 ° C (from toluene).

Analysis:

calculated:

% C, 64.93;% H, 6.40;

H, 6.43; N, 9.87.

4 - [(5-Methyl-2-piperidinobenzyl) amino-carbonylmethyl] -benzoic acid methyl ester

Yield: 32.9%.

Melting point 124-126 ° C (from a mixture of petroleum ether and acetone).

Mass spectrum: molecular signal:

calculated: m / e = 380, found: m / e = 380.

N- (4-nitrophenoacetyl) -N- [1- (2-piperidinophenyl) ethyl] amine

Yield: 62.4%.

Mp 165-167 ° C (from ether).

Analysis:

calculated:

% C, 68.64;% H, 6.86;% N, 11.44.

H, 6.88; H, 11.63;

N- (4-Acetylphenethyl) -N- [1- (2-piperidinophenyl) ethyl] Jamine

Yield: 32.4% of theory.

Melting point 162-164 ° C (from ether).

Analysis:

calculated:

% C, 75.79;% H, 7.74;% N, 7.69%.

75.51 ° C, 7.86 ° C, 7.38% N.

N- (4-acetylphenacetyl) -N- [1- (5-chloro-2-piperidinophenyl) ethyl] amine

Yield: 50.3% of theory.

Mp 162-163 ° C (from ether).

Analysis:

calculated:

% C, 69.24;% H, 6.82;% N, 7.02.

68.88% С, 6.63% H _; 9.79% N.

2 - {[1- (2-Piperidinyl) ethyl] aminocarboinyl-ethoxy-benzoic acid methyl ester

Yield: 82%.

Melting point 107-108 T.

Analysis:

calculated:

% C, 72.60;% H, 7.42;% N, 7.36.

% C, 72.79;% H, 7.38;

Ethyl ester 3 ^J. [1- (2-pipericlinophenyl) ethyl] aminocarbonylmethylhenzoic acid

Yield: 47%.

Mp 155 ° C.

Analysis:

calculated:

% C, 73.07;% H, 7.67;% N, 7.1.0%.

73.30% C, 7.58% II, 7.17% N.

3-Chloro-4-i [1- (2-piperidinophenyl) ethyl] aminocarbonylmethyl] benzoic acid ethyl ester

Yield: 63% of theory

Melting point 123-124 ^° C.

Analysis:

calculated:

% C, 67.20;% H, 6.81;% 8.27;% N, 6.53.

67.28% C, 6.84% I-I, 8.36% Cl, 6.50% N.

4- [1- (2- (1,2,3,4-Tetrahydro-isoquinolin-2-yl) -phenyl] -ethoxy-1-p-carbonylmethyl) -benzoic acid ethyl ester

Yield: 43%.

M.p. 142-144 ^° C.

Analysis:

calculated:

% C, 75.99;% H, 6.83;% N, 6.33.

H, 6.75; N, 6.35.

4 - [[1- (2-piperidimophenyl) ethyl] aminocarbonylmethyl] toluene

Yield: 59% of theory.

Melting point 138-138 ° C.

Analysis:

calculated:

% C, 78.53;% H, 8.39;% N, 8.33.

% C, 78.58;% H, 8.16;

4 - [(5-Chloro-2-piperidinoanilino) carbonylmethyl] benzoic acid methyl ester

Yield: 40.3% of theory.

Melting point 156-158 ° C (from methanol / toluene).

Analysis.:

calculated:

% C, 65.19;% H, 5.99;% Cl, 9.16.

65.20% C _; 6.15% H, 9.40% Cl.

4- [2- (2-Piperidinoanilinocarbonyl) ethyl] benzoic acid methyl ester

Yield: 26.9% of theory.

Mp 71-73 ° C (from petroleum ether).

/ Xnalysis:

calculated:

% C, 72.10;% H, 7.15;% N, 7.65.

% H, 7.09;% N, 7.94.

4-N- [2- (1,2,3,6-tetrahydropyridino) phenyl] ethylaminocarbonylmethyl-benzoic acid ethyl ester

Yield: 63.4% of theory.

Melting point 125-127 ° C (from ether).

Analysis:

calculated:

% C, 73.44;% H, 7.19;% N, 7.14.

H, 7.13; N, 7.13.

Ethyl ester 4 ~! [2- (5-chloro-2-piperidinophenyl) ethyl] aminocarbonylmethyl] benzoic acid

Yield: 68%.

Melting point 95-97 ° C (from ethanol).

Analysis:

calculated:

H, 6.81; H, 8.27; N, 6.53. Found:

H, 6.76; H, 8.22; N, 6.24.

4 - {[1- (5-Fluoro-2-piperidinophenyl) ethyl] aminocarbonylmethyl} benzoic acid ethyl ester

Yield: 47.3% of theory.

M.p. 132-140 ° C (from ether).

Analysis:

calculated:

79.22% C, 7.09% H, 7.79 ° / o N, found:

H, 7.10; N, 7.27.

4 - ((1- (5-Nitro-2-piperidinophenyl) ethyl] aminocarbonylmethyl) benzoic acid ethyl ester

Yield: 56.5%.

M.p. 144-147 ^° C (from ethanol).

Analysis:

calculated:

75.59% C, 7.75 ° / o H, 9.57% N, found:

% C, 75.72;% H, 7.57;% N, 9.73.

4 - ((2- [1- (2-Piperimidophenyl) ethyl] aminocarbonylethyl) benzoic acid methyl ester

Yield: 90%.

Melting point 129-131 ° C.

Analysis:

calculated:

% C, 73.07;% H, 7.77;% N, 7.10.

H, 7.77; N, 7.52.

4 - {[2-Hydroxy-1- (piperidinophenyl) ethyl] aminocarbonylmethyl] benzoic acid ethyl ester

Yield: 44.4% of theory.

M.p. 132-135 ° C (from a mixture of petroleum ether and acetone).

Analysis:

calculated:

% C, 70.22;% H, 7.37;% N, 7.22.

H, 7.25; N, 7.77.

Mass spectrum: molecular signal: calculated: me = · 410 found: mZe = 410.

Ethyl 4 - ((1- (5-hydroxy-2-piperidinophenyl jethyl] -amino ^b onylmethyl ^to Ar (t> ^s enzoov acid

Yield: 74.2%.

M.p. 150-151 ° C (from ether).

Analysis:

calculated:

% C, 70.22;% H, 7.37;% N, 7.22.

ПЯ1Р7РПП ‘

70.37 ° C, 7.17% H, 7.21 ° C.

Mass spectrum: molecular signal: calculated: m / e = 410 found: m / e = <110.

4 - [(α-methoxycarbonyl-2-piperidinobenzyl] aminocarbonylmethyl] benzoic acid ethyl ester

Yield: 59%.

Melting point 110-112 ° C (from a mixture of petroleum ether and acetone).

Analysis:

calculated:

% C, 72.47;% H, 7.90%;

£1 £ 11θΖθΓ1Ο *

72.57 ° C, 7.74% H, 7.47% N.

calculated: m / e = 432 found: m / e = 432.

4- ([1- (5-Chloro-2- (2-methyl-piperidinino) -phenylethyl] aminocarbonylmethyl) -benzoic acid ethyl ester

Yield: 71.3% of theory.

Melting point below 20 ° C.

Mass spectrum: Molecular signal: Calculated: m / e = 442/444 (1 Chloro) Found: m / e = 442/444 (1 Chloro).

4 - ((1- (2-Hexahydroazepinophenyl) ethyl) aminocarbonylmethyl) benzoic acid ethyl ester

Yield: 72%.

145-142 ° C (from toluene).

Analysis:

calculated:

% C, 73.50;% H, 7.90;% N, 7.27.

% C, 73.35;% H, 2.04;% N, 7.29.

4 - [(1- [2- (1,4-Dioxa-2-azaspiro [4.5] dec-8-yl) phenyl] ethyl] aminocarbonylmethyl] benzoic acid ethyl ester

Yield: 64.3%.

143 ^DEG- 145 ^DEG C. (from a mixture of pstrol ether and acetone).

Analysis:

calculated:

69.01% C, 7.13% H, 6.19% N, found:

% C, 69.30;% H, 7.38;

4- / 1- (2- (2-Methyl-pyrrolidino (phenyl); ethylaminocarbonylmethyl, benzoic acid, ethyl 4-ethyl ester)

Yield: 72.0% of theory.

Mp 94-97 ^° C.

Analysis:

calculated:

73.07% C, 7.66% II, 7.10% N, found:

H, 7.67; N, 7.11.

4 - ([1- (2-Piperidinophenyl) ethyl] aminocarbonylmethyrbenzoic acid isopropyl ester

Yield: 45%.

Melting point 141-143 ^c C. (ether).

Analysis:

calculated:

% C, 73.51;% H, 7.90;% N, 6.36.

% C, 73.20;% H, 7.79;% N, 6.70.

4 - ((1- (2-Piperidinophenyl) ethyl) aminocarbonylmethylbenzoic acid butyl ester)

Yield: 49%.

148 ^DEG C. (ether / toluene).

Analysis:

calculated:

% C, 73.90;% H, 8.11;% N, 6.63.

H, 7.99; N, 6.70.

4- [1- (5-Chloro-2-piperidinophenyl) ethyl] aminocarbonylmethyl] -benzoic acid ethyl ester

Yield: 41%.

M.p. 130-133 ° C (from ether).

Analysis: · calculated:

67/21% C, 6.81% H, 8.26% Cl, 6.53% N, found:

% C, 66.90;% H, 6.65;% Cl, 8.32.

4- '[1- (5-Chloro-piperidinophenyl) -ethyl] -amino-carbonylmethyl-benzoic acid butyl ester

Yield: 30.7% of theory.

M.p. 115-118 ° C.

Analysis:

calculated:

68.33% c,% h, 7.75% ci, 6.12% n, found:

% C, 63.20;% H, 7.23;% d, 7.68.

4-Ph '- (b-chloro-2-piperidinophenyl) ethyl' aminocarbonylmethyl, benzoic acid tert-butyl ester

Yield: 20%.

Mass spectrum: molecular signal: calculated: m / e = found: m / e = 4 ^ 3 ^ 6/8.

4-) [1- (2-Piperidinophenyl) ethyl] aminocarbonylmethyl) benzoic acid 2-methoxyethyl ester

Yield: 56%.

Mp 155-157 ° C (from ethyl acetate).

Analysis:

calculated:

% C, 70.74;% H, 7.60;% N, 6.60.

% C, 70.55;% H, 7.38;

[(2,2 ^ ппеШу1 аюао ^ пЧ-у ^ те thyljester)

4-; 1- (2-Piperidino-phenyl) -ethyl] -amino-carbonyl-amino-benzoic acid

Yield: 30.5% of theory.

Mp 110-112 ° C (from ether).

Analysis:

calculated:

% C, 69.98;% H, 7.55;% N, 5.83.

% C, 69.80;% H, 7.50;

Mass Spectrum: Molecular Signal: Calculated: mee = 480 found: mee = 480.

4 - {[1- (2-Piperidinophenyl) ethyl] aminocarbonylmethyl] benzoic acid benzyl ester

Yield; 73.7 ° / o theory.

Melting point 126-124 ° C (from ethyl acetate).

Analysis:

calculated:

Found: C, 76.28; H, 7.86; N, 6.14.

H, 7.28; N, 6.83.

4 - {[1- (2-Piperidinophenyl) ethyl] aminocarbonylmethyl] benzoic acid (2-hydroxyethyl) ester

Yield: 71.4% of theory.

M.p. 128 ^DEG- 129 ^DEG C. (from ethyl acetate / ether).

Analysis:

calculated:

% C, 78.21;% H, 7.36;% N, 6.82.

% C, 78.14;% H, 7.42;% N - 6.78.

Mass spectrum: Molecular signal: Calculated: m / e = 410 Found: m / e = 410.

1,2-bis (4 - {[1- (2-piperidinophenyl) ethyl] aminocarbonylmethyl) benzoyloxy) ethane

Yield: 43.5%.

Mp 188-191 ° C (from toluene).

Analysis:

calculated:

72.88 ° C, 7.17% H, 7.38% N, found:

% H, 7.87;% N, 7.37.

Mass spectrum: molecular signal: calculated: mee = 788 found: mee = 75.

4 - {[1- (2-Piperidinophenyl) ethyl] aminocarbonylmethyl] benzoic acid (2-dimethylaminoethyl) ester

Yield: 56.7% of theory.

Melting point 99-181 ° C (from petroleum ether).

Analysis:

calculated:

72.23 ° C, 8.44 ° C; % N, found:

H, 8.37%; N, 8.95%.

[2- (1,3-dimethylxanthin-7-yl) ethyl] ester

4- [1- (2-Piperidinophenyl) ethyl] aminocarbonylmethyl] benzoic acid

Yield: 48.9% of theory. 121-123 ° C (from ether).

Analysis:

calculated:

% H, 6.34;% N, 14.68.

% C, 64.78;% H, 6.38;

Mass spectrum: Molecular signal: Calculated: mee = 572 Found: m / e = 572.

4 - {[1- (2-Piperidinophenyl) ethyl] aminocarbonylmethyl | benzoic acid methyl ester

Yield: 44.8% of theory. M.p. 146-147 ° C.

Analysis:

calculated:

72.68 o / o C, 7.42 θ / ο H, 7.36% N, found:

72.19% C, 7.33% H, 7.81% N.

4 - {[1- (2-Piperidinophenyl) ethyl] aminocarbonylmethyl] benzoic acid tert-butyl ester

Yield: 8.45 g (19.7% of theory). Melting point 125-127 ° C (from ether).

Analysis:

calculated:

% C, 73.98;% H, 8.11;% N, 6.63.

74.28% C, 8.89% H, 6.77% N.

4- | [1- (2-piperidinophenyl) ethyl] aminocarbonylmethyl] -N-methylbenzamide

Yield: 82% of theory.

Mp 218-228 ° C (from isopropyl alcohol).

Analysis:

calculated:

% C, 72.77;% H, 7.70;% N, 11.07.

% H, 7.67;% N, 10.91.

4 - [[1- (2-piperidinophenyl) ethyl] aminocarbonylmethyl-N, N-dimethylbenzainide

Yield: 52.5%.

M.p. 148-150 ° C (from ethyl acetate).

Analysis:

calculated:

% C, 73.26;% H, 7.94;% N, 10.68.

% C, 73.60;% H, 7.85;% N, 10.73.

4- [1- (2-Piperidinophenyl) ethyl) aminocarbonylmethyl] -N-butylbenzamide

Yield: 71.7% of theory.

Mp 178-181 ^c C (from ethyl acetate).

Analysis:

calculated:

H, 8.37; N, 9.97. Found:

% C, 74.34;% H, 8.26;

4 - {[1- (2-Piperidinophenyl) ethyl] aminocarbonylmethyl'-benzoic acid piperidide

Yield: 73.8% of theory.

Melting point 131-133 ° C (from toluene).

Analysis:

calculated:

74.79% C, 8.14% H, 9.69 ° / o N, found:

H, 7.99; N, 9.48.

Mass spectrum: molecular signal:

calculated: me == 433 found: m / e = 433.

4- [1- (2-Piperidinophenyl) ethyl] aminocarbonylmethyl] benzoic acid morpholide

Yield: 60.5%.

M.p. 148-150 ° C (from ethyl acetate / ether).

Analysis:

calculated:

% C, 71.69;% H, 7.64;% N, 9.65.

71.60% C, 7.80% II, 9.57% N.

4- '[1- (2-Piperidinophenyl) ethyl] aminocarbonylmethylbenzoic acid nitrile

Yield: 55.3% of theory.

Mp 155-157 ° C (from ethyl acetate).

Analysis:

calculated:

% H, 7.25;% N, 12.09.

H, 7.07; N, 11.90.

4 - [[1- (5-Amino-2-3- piperidinophenyl) ethyl] aminocarbonylmethybenzic acid methyl ester

Melting point 140-142 ° C (from toluene).

4- | [1- (SaininoS-piperidinophenyl) ethyl] aminocarbonylmethylmethylbutyric acid ethyl ester

Yield: 97.8% of theory.

M.p. 148-149.5 ° C (from cyclohexane).

Analysis:

calculated:

% C, 70.39;% H, 7.63;% N, 10.26.

% C, 70.20;% H, 7.67;

4 - {[1- (3-Methyl-2-piperidinophenyl) ethyl] aminocarbonylmethyl] benzoic acid ethyl ester

Yield: 39.5% of theory.

Mass spectrum: Molecular signal: Calculated: mee = -408 Found: m / e = 408.

4-) [1- (3-c hl chloro-2-p ipe rdino n oe yl) -ethyl ester ¹ aminokarbonylmethyljbenzoové

Yield: 52.6% of theory.

Mass spectrum: molecular signal: calculated: m / e = 428/430 (1 chlorine) found: m / e = 428/430 (1 chlorine).

Example 2

(+) - 4 - ((1- (2-Piptridinophthyl)) ethyl) aminocarbonylmethyl] benzoic acid ethyl ester

To a solution of 4-ethoxycarbonylphenylacetic acid (290.9 mg, 1.40 mmol) in tetrahydrofuran (6 mL) was added carbonyldiimidazole (231.4 mg, 1.43 mmol) and the reaction mixture was then heated under reflux for 1.5 hours. cooler. After cooling to room temperature, 0.385 ml (ca.

2.78 mmol) triethylamine (dried over potassium hydroxide) and 360 mg (1.30 mmol) of dihydro ochloridu (+) -1- (2-piperidinof phenyl) ethylamine (melting point 242 DEG C. (dec); [a] _D ²⁰ = + 14.8 ° (c = 1; methanol)) together with 2 mL of tetrahydrofuran. The reaction mixture was stirred in an oil bath heated to 50 ^° C for 4 hours. The reaction mixture was then evaporated in vacuo and the residue partitioned between chloroform and water. The chloroform extract was dried over sodium sulfate, filtered through a glass frit (G3j) and the filtrate evaporated in vacuo to dryness. The residue was purified by silica gel column chromatography (using chloroform / methanol 6: 1).

Yield: 229 mg (44.7% of theory).

Mp 89-90 ° C (from ether). ^[:] _D ²⁰ = + 8.2 ° (c = 1, methanol).

Analysis:

calculated:

% C, 73.07;% H, 7.66;% N, 7.10%

H, 7.68; N, 7.14.

Mass spectrum: molecular signal:

calculated: m / e = 394 found: m / e = 394.

In an analogous manner to that described in Example 2:

(-) - 4 - {[1- (2-Piperidinophenyl) ethyl] aminocarbonylmethyl) benzoic acid ethyl ester

(-) - 1- (2-Piperidinophenyl) ethylamine dihydrochloride was used as the starting material; (melting point: 239-242 ° C (dec.); [.alpha.] D @ ²⁰ = -19.6 DEG (c = 1; methanol)).

Yield: 41.1% of theory.

77 DEG-79 DEG C. (from ether / cyclohexane).

[α] _D ²⁰ = -6.2 ° (c = 1; methanol).

Analysis:

calculated:

% C, 73.07;% H, 7.66;% N, 7.10.

Mass spectrum: molecular signal:

calculated: m / e = 394 found: m / e = 394.

Example 3

4 - [[1- (4-Chloro-2-piperidinophenyl) ethyl] aminocarbonylmethyl) benzoic acid ethyl ester

To a solution of 5,5 g (0,023 mol) of 1- (4-chloro-2-piperidinophenyl) ethylamine, 4,8 g (0,023 mol) of 4-ethoxycarbonylphenylacetic acid,

7.3 g (0.028 mol) of triphenylphosphine and 3.2 ml (0.023 mol) of triethylamine in 50 ml of acetonitrile were added 2.3 ml (0.023 mol) of carbon tetrachloride and the reaction mixture was stirred at room temperature for 24 hours. It is then evaporated in vacuo and the residue is partitioned between 100 ml of water and ethyl acetate. The combined organic extracts dried over sodium sulfate were filtered, evaporated in vacuo and the residue purified by silica gel column chromatography (eluting with toluene / ethyl acetate [4: 1]).

Yield: 6.1 g (62% of theory).

Melting point 126-128 ° C.

Analysis:

calculated:

67.20% C, 6.81% H, 8.27% Cl, 6.53% N, found O '

H, 6.97; H, 8.16; N, 6.40.

In an analogous manner to that described in Example 3, the following compounds are obtained:

4 - ((1- (4-Methyl-2-piperidinophenyl) ethyl] aminocarbonylmethyl) benzoic acid ethyl ester

Yield: 48.2% of theory.

Melting point 120-122 ° C.

Analysis:

calculated:

% C, 73.50;% H, 7.89;% N, 6.86.

Пй1Р7РПЛ ·

73.61 θ / ο С, 7.95% Η, 6.73% Ν.

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

Yield: 55.8% of theory.

Melting point: 125 to 128 ° C (from ether).

found: Analysis:

% C, 72.67;% H, 7.75;

calculated:

% C, 73.50;% H, 7.90;% N, 6.86.

Ž2 ^; 8 910 found:

% C, 73.30;% H, 7.99;% N, 7.20.

4 - {[1- (2-Piperidinophenyl) ethyl] aminocarbonylmethyl, benzoic acid ethyl ester

Yield: 71%.

Melting point 147-148 ° C.

Analysis:

calculated:

% C, 73.06;% H, 7.67;% N, 7.10.

H, 8.04; N, 6.95.

4 - [[1- (2-piperidinophenyl) ethyl] aminocarbonylmethylphenylacetic acid

1- (2-Piperidinophenyl) ethylamine and p-phenylenediacetic acid were used as starting materials.

Yield: 27%.

Melting point 186-189 ° C.

Analysis:

calculated:

% C, 72.60;% H, 7.42;% N, 7.36.

% C, 72.75;% H, 7.65;

4 - [(2-Piperidino-benzhydryl) aminocarbonylmethyl] -benzoic acid ethyl ester

Yield: 87.4% of theory.

Mp 160-162 ° C.

Analysis:

calculated:

% H, 7.06;% N, 6.14. Found:

% H, 7.08;% N, 6.17.

4 - [(5-Chloro-2-piperidinobenzhydryl) -aminocarbonylmethyl] -benzoic acid ethyl ester

Yield: 78%.

Mp 202-204 ° C.

Analysis:

calculated:

70.93% C, 6.36% H, 7.22% Cil 5.71% N, found ·

% C, 70.85;% H, 4.0;% 7.11;% N, 5.45.

4 - {[1- (4-Piperidinophenyl) ethyl] ethylcarbonylnipthyl] benzoic acid ethyl ester

Yield: 39%.

Melting point 118-120 ^° C.

Analysis:

calculated:

% C, 73.07;% H, 7.67;% N, 7.10.

H, 7.78; N, 7.11.

4 - ({1- [2- (4-Methyl-piperazino) -phenyl] -ethyl-aminocarbonylmethyl-benzoic acid ethyl ester

Yield: 53%.

Melting point 130-132 ° C.

Analysis:

calculated:

% C, 70.38;% H, 7.63;% N, 10.26.

% C, 70.41;% H, 7.53;% N, 10.12.

4 - ((1- [2- (4-Benzylpiperazino) phenyl) ethylaminocarbonylmethyl) benzoic acid ethyl ester

Yield: 75%.

M.p. 135-136 ^° C.

Analysis:

calculated:

74.20% C, 7.26% H, 8.66% N, found:

H, 7.34; N, 8.54.

4 - ((1- [2- 14-p-Chloro-phenylpiperazino) -phenyl] -thyl) -amino-carbonylmethyl-benzoic acid ethyl ester

Yield: 48.5% of theory.

Melting point: 178-180 ° C.

Analysis:

calculated:

68.83% C. 6.37%% 7.00% d, 8.30% N, found:

68.71%% 8.22% H, 8.88% d, 8.41% N.

4-f (α-Cyclohexyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid ethyl ester

Yield: 75.0% of theory.

Mp 135 ^C C.

Analysis:

calculated ·:

H, 8.28; N, 6.06. Found:

H, 8.13; N, 5.99.

N- (4-chlorophenacetyl) -N- [1- (Z-piperidinophenyl) ethyl] amine

Yield: 79%.

M.p. 150-152 ° C.

Analysis:

calculated:

% C, 70.67;% H, 033;% C, 9.93%;

% C, 70.94;% H, 7.84;% C, 11.09%.

4 - [(2-Pyrrolidinobenzhyddyl) aminocarbonylmethyl] benzoic acid ethyl ester

Yield: 57%.

Mp 163-165 ° C.

Analysis:

calculated:

% C, 75.99;% H, 6.83;% N, 6.33.

% C, 75.45;% H, 6.52;% N, 6.10.

4 - [[2-Hexamethyl-methylbenzhydryl) aminocarbonylmethyl] benzoic acid ethyl ester

Yield: 68%.

Melting point 151-154 ° C.

Analysis:

calculated:

% H, 7.28;% N, 5.95. Found:

H, 7.19; N, 6.01.

Example 4

4 - {[1- (2-piperidinidenyl) ethenyl] aminocarbonylmethyl] benzoic acid ethyl ester To a solution of 10.9 g (0.0539 mol) of freshly produced (2-piperidinyl) methyl ketidine in 110 ml of acetonitrile is gradually stirred 11.2 g (0.0539 mol) of 4-ethoxycarbonylphenylacetic acid, 17 g (0.0647 mol) of triphenylphosphine, 22.6 ml (0.162 mol) of triethylamine and 5.2 ml (0.0539 mol) of carbon tetrachloride are added. After a short period of time a clear solution is formed which is stirred for 20 hours at 20 ^DEG C. The precipitate formed (triethylamine hydrochloride) is then filtered off and the filtrate is evaporated in vacuo. The residue was purified by column chromatography on silica gel with toluene / acetone (10: 1) as the Manual Reagent.

Yield: 15 g (70.1% of theory).

Melting point 112-115 ° C (from ether).

Analysis:

calculated:

% C, 73.44;% H, 7.19;% N, 7.14.

H, 7.32; N, 6.96.

The following compounds are obtained in an analogous manner to that described in Example 4:

4 - [(α-Cyclohexylidene-2-piperidinylbenzyl-aminocarbonylamino) -phthyl] -benzoic acid ethyl ester

Yield: 24%.

Melting point 131-133 ° C.

Analysis:

calculated:

% C, 75.62;% H, 7.88;% N, 6.08.

H, 7.47; N, 6.01.

4 - {[1- (2-Piperidinophrenyl) propenyl] aminocarbonylmethylbenzoic acid ethyl ester

Yield: 65.0% of theory (mixture of E- and Z-isomers).

The melting point of the polar isomers is 82-84 ° C. Analysis: calculated:

% C, 73.86;% H, 7.44;% N, 6.89.

% C, 73.73;% H, 7.57;% N, 7.01%.

Example 5

4 - ((1- (2-Chloro-phenylamino) -ethyl] -aminocarbonylmethyl) -benzoic acid ethyl ester

To a stirred solution of 49.6 g (0.243 mol) of 1- (2-piperidinophenyl) -thylamine (boiling point 100 to 107 ° C / 66.7 Pa, melting point dihydrochloride 234 to 237 ° C (decomposition)) and · 37.3 of triethylamine (0.267 mol) in methylene chloride (245 ml) was added dropwise a solution of 60.6 g (0.267 mol) of 4-gth (methoxycarbonylphmacethyl chloride in 120 ml of methylene chloride) dropwise at 20-30 ° C with slight ice-cooling. The precipitate formed is filtered off, washed once with methyl chloride and the combined methyl chloride phase is extracted successively twice with water, once with 10% aqueous ammonia, twice with water, once with 100 ml.

3% hydrochloric acid and twice with water. The methylene chloride phase was dried over sodium sulfate, filtered and the filtrate evaporated in vacuo. The residue crystallized from ether.

Yield: 88.8 g (92.7% of theory).

M.p. 148-150 ° C.

In an analogous manner to that described in Example 5, the following compounds are obtained:

4 - [(5-Methyl-2-piperidimobenzyl) aminocarbonylmethyl] benzoic acid ethyl ester

Yield: 22.5%.

116.5-117 ^° C (from a mixture of ethanol and petroleum ether).

Analysis:

calculated:

% C, 73.07;% H, 7.66;% N, 7.10.

ПЯ1р7РПП *

H, 7.62; N, 7.15.

4 - {[1- (5-Methyl-2-piperidinophenyl) ethyl] aminocarbonylmethyl] benzoic acid ethyl ester

Yield: 20.2%.

M.p. 132 DEG-132.5 DEG C. (from ethanol).

Analysis:

calculated:

% C, 73.50;% H, 7.90;% N, 6.86.

73.49% C, 7.74% H, 6.94% N.

4 - {[1- (5-Methoxy-2-piperidinophenyl) ethyl] aminocarbonylmethyl] benzoic acid ethyl ester

Analysis:

calculated:

70.73% C, 7.60% H, 6.60% N,

70.98% C, 7.59% H, 6.38% N.

4 - {[1- (2-Piperidinophenyl) ethyl] -N-methylaminocarbonylmethyl) benzoic acid ethyl ester

Yield: 65.2% of theory.

Melting point below 20 ° C.

Analysis:

calculated:

73.50% C, 7.90 o / o H, 6.86 θ / ο N, found *

72.99 ° C, 7.60 θ / ο H, 6.87 θ / ο N,

4 - ((1- [2- (Decahydroisoquinolin-2-yl) phenyl] ethyl´aminocarbonylmethyl) benzoic acid ethyl ester

Yield: 44%.

Melting point 159 C. C.

Analysis:

calculated:

% C, 74.96;% H, 8.08;% N, 6.24.

H, 8.01; N, 6.01.

4 - ((1- (2- (1,2,3,4,5,6,7,8-octahydrolsoquinolin-2-yl) phenyl) ethyl´aminocarbonylmethyl) benzoic acid ethyl ester

Yield: 35%.

Melting point 115-117 ° C.

Analysis:

calculated:

% C, 75.30;% H, 7.67;% N, 6.27

75.18 θ / ο С, 7.37 θ / ο Η, 5.89 θ / ο Ν.

4 - (([1- (2-octahydroisolndol-2-yl) phenyl] ethyl; aminocarbonylmethyl) benzoic acid ethyl ester

Yield: 36%.

Melting point 141 ° C.

Analysis:

calculated:

74.62 θ / ο C, 7.88 θ / ο H, 6.44 θ / ο N, found:

74.70% C, 7.97 θ / ο H, 6.42 θ / ο N.

4 - {[1- (3-Piperidinophenyl) ethyl] aminocarbonylmethyl] -benzoic acid ethyl ester

Yield: 24%.

Melting point 164 ° C.

Analysis:

calculated:

73.07%, C 7.66%, N 7.10%, found:

72.0% C, 7.48% H, 7.13% N.

4 - {[1- (6-Chloro-2-piperidinophenyl) ethyl] aminocarbonylmethyl] benzoic acid ethyl ester

Yield: 17%.

Melting point below 20 ° C.

Analysis:

calculated:

% C, 67.20;% H, 6.81;% 8.26;% N, 6.53.

% C, 67.96;% H, 6.56;% CI = 8.80;

Mass spectrum: molecular signal:

calculated: m / e = 428/30, found: m / e = 428/30.

4 - ([1- (6-Methyl-2-piperidinophenyl) ethyl] aminocarboinylmethyl-benzoic acid ethyl ester

Yield: 3.5%.

Melting point below 20 ^° C.

Analysis:

calculated:

73.49% C, 7.89% H, 6.85% N, Π ΠΑ1Ρ'7ΡΓΊΓΊ "

H, 7.61; N, 7.01.

Mass spectrum: molecular signal:

calculated: m / e = 408, found: m / e = 408.

4 - ((1- (2- (3-Aza-bicyclo [3.2.2] nonan-3-yl) phenyl) ethyl) aminocarbonylmethyl) benzoic acid ethyl ester

Yield: 0.5%.

Melting point below 20 ° C.

Mass spectrum: molecular signal:

calculated: m / e = 434, found: m / e = 434.

N- [1- (5-chloro-2-piperidinophenyl) ethyl] -N-phenacetylamine

Yield: 53.5% of theory.

134 ^DEG- 136 ^DEG C. (from ethanol).

Analysis:

calculated: 70.67% C, 7.06% H, 9.94% Cl, 7.85% N, found *

% C, 70.40;% C, 7.32;% C, 9.77;% N, 7.68.

Example 6

4 - ([1- (2-Piperidinophenyl) ethyl] aminocarbonylmethylbenzoic acid ethyl ester

To a stirred solution of 2.02 g (0.010 mol) of freshly prepared methyl- (2-piperidinophenyl) ketidine and 1.53 ml (0.011 mol) of triethylamine in 10 ml of methylene chloride was added dropwise under ice-cooling at an internal temperature of 1 to 6 ° C over 15 min. A solution of 2.49 g (0.011 mol) of 4-ethoxycarbonylphenacetyl chloride in 10 ml of methylene chloride is stirred for 20 hours at 20 DEG C. and the reaction mixture is then poured into cold sodium bicarbonate solution and extracted several times with methylene chloride, the organic extract. The residue is purified by column chromatography on silica gel (eluting with toluene / acetone [50: 1]).

Yield: 1.86 g (47.7% of theory).

113 DEG-116 DEG C. (from ethanol).

Analysis:

calculated:

73.44% C, 7.19% MH, 7.14% N, παΙρ ^ ρϊίπ ··

H, 6.98; N, 7.22.

Mass spectrum: Molecular signal: Calculated: m / e = 392, Found: m / e = 392.

In an analogous manner to that described in Example 6, the following compounds were prepared: Ethyl ester 4-? [1- (6-chloro-2-piperidinophenyl) ethenyl] aminocarbonylmethyl} benzoic acid

Yield: 37%.

Melting point 102-105 ° C.

Analysis:

calculated:

% C, 67.51;% H, 6.37;% Cl, 8.30;

% H, 6.39;% C, 8.58;% N, 6.23.

Mass spectrum: Molecular signal: Calculated: m / e = 426/28, Found: m / e = 426/28.

4 - ((1- (6-Methyl-2-piperidinophenyl) ethenyl] aminocarbonylmethyl) benzoic acid ethyl ester

Yield: 41%.

Melting point 116-118 ° C.

Analysis:

calculated:

73.86% C, 7.43% H, 6.89% N, γη q 1 ρ * 7ργη ρ ·

73.75% С, 7.43% / ο, 6.77% Ν.

Example 7

4- ((1- (2-Piperidinophenyl) 228910 43 ethenyl) aminocarbonylmethylbenzoic acid ethyl ester

To a suspension of 2.20 g (6.24 mmol) of iodomagnesium [methyl- (2-piperidinophenyl) ketimino] complex in 15 ml of methylene chloride was added dropwise a solution of 1.55 g (6.86 mmol) of 4-ethoxycarbonylphenacetyl chloride in 15 ml. 5 mL of methylene chloride. the internal temperature rose from 20 C. to 30 ^C. the reaction mixture was stirred for 2 hours at room temperature, then added with stirring, water and repeatedly extracted with methylene chloride. the methylene chloride solution was washed with water, dried over sodium sulfate The residue was purified by column chromatography on silica gel (eluting with toluene / acetone [50: 2]).

Yield: 1.1 g (45.8% of theory).

115 DEG-118 DEG C. (from ethanol).

Analysis:

calculated:

% C, 73.44;% H, 7.19;% N, 7.14.

H, 7.06; N, 7.16.

In an analogous manner to that described in Example 7, 4 - {[1- (5-chloro-2-piperidinophenyl) ethenyl] aminocarbonylmethyl} benzoic acid ethyl ester is obtained.

Yield: 39.5% of theory.

M.p. 142-145 ° C (from ethanol).

Analysis: Calculated: C, 67.51; H, 6.37; Cl, 8.30; U, 6.56.

67.51 ° C, 6.37% H, 8.36% Cl, 6.49% N.

Example 8

4 - {[1- (5-chloro-2-dimethylaminophenyl) ethyl] aminocarbonylmethyl] benzoic acid

A solution of 2.0 g (0.00534 mol) of 4 - {[1- (5-chloro-2-dimethylaminophenyl) ethyl] aminocarbonylmethyl-benzoic acid methyl ester and 0.32 g (0.00801 mol) of sodium hydroxide in 23 ml of ethanol and 7 ml of water are stirred at 50 ° C for 2 hours. The reaction mixture was then evaporated in vacuo, taken up in water, adjusted to pH 6 with 2N hydrochloric acid and extracted with ethyl acetate. The organic phase is shaken with water, dried over sodium sulphate, filtered and evaporated in vacuo. The residue was recrystallized from ether.

Yield: 1.7 g (88% of theory).

Mp 190-192 ° C.

Analysis:

calculated:

% C, 63.24;% H, 5.87;% C, 9.83;% N, 7.76.

62.90% C ,. % H, 5.81;% N, 11.02.

In an analogous manner to the example

8, the lymphocytes are:

4 - {[1- (5-Chloro-2-dipropylamino-phenyl) -ethyl] -amino-carbonylmethyl-benzoyl acid

Yield: 87.6% of theory.

Mp 203-205 ° C.

Analysis:

calculated:

% C, 66.25;% H, 7.01;% C, 8.50;% N, 6.72.

H, 6.96; Cl, 8.52; N, 6.55.

4-j [1- (5-chloro-2-dibutylaminophenyl) ethyl] aminocarbonylmethyl] benzoic acid

Yield: 77.3% of theory.

Melting point 200-202 ° C.

Analysis:

calculated:

% C, 67.47;% H, 48;% C, 7.97;% N, 6.30.

% C, 67.45;% H, 7.60;% 8.28;

4 - {[1- (5-chloro-2-N-chlorobenzyl-N-methoxyphenyl) ethyl] amino-carbonylmethyl-benzoic acid

Yield: 88.2% of theory.

Melting point 198-200 ° C (from ether).

Analysis:

calculated:

67.20% C, 6.31 O / o H, 8.27% Cl, 6.53% N, found:

H, 6.73; Cl, 8.16; N, 6.47.

4- [[5-5-chloro-2-2-fluoro-benzyl: amino-carbonylmethyl] -benzoic acid

Yield: 84.2% of theory.

208 ^DEG- 210 ^DEG C. (from ethyl acetate).

Analysis:

calculated:

% C, 64.42;% H, 5.68;% Cl, 9.51;% N, 7.51.

% C, 64.70;% H, 5.68;% Cl, 9.58.

4-f [1- (5-chloro-2-pyrrolidinophenyl) ethyl] aminocarbonylmethylphenzoic acid

Yield: 81.1% of theory.

M.p. 202-204 ° C (from ethyl acetate).

Analysis:

calculated:

% C, 65.20;% H, 5.99;% Cl, 9.17;% N, 7.24.

% C, 65.02;% H, 6.12;% Cl, 9.32;

4 - [[5-chloro-2-piperidinobenzyl] aminocarbonylmethyl] benzoic acid

Yield: 78%.

Melting point 164-166 ° C.

Analysis:

calculated:

% C, 65.19;% H, 5.99;% C, 9.17%;

C 65.50, H 5.76, Cl 9.24, N 7.36.

4-f [1- (5-chloro-2-piperidinobenzyl) aminocarbonyl] ethyl} benzoic acid

Yield: 81.1% of theory.

M.p. 213-216 ° C (from acetone / ether).

Analysis:

calculated:

% H, 6.29;% H, 8.84;% N, 6.99.

% C, 66.30;% H, 6.40;% C, 9.00;

4-f [1- (5-chloro-2-piperidinophenyl) ethyl] aminocarbonylmethyl] benzoic acid

Yield: 84.9% of theory.

Mp 213-215 ° C (from ether).

Analysis:

calculated:

H, 6.29; H, 8.85; N, 6.99. Found *

% C, 66.18;% H, 6.19;% C, 8.88;

4 - ({1- [5-chloro-2- (3-methylpiperidino) phenyl] ethyl} aminocarbonylmethyl) benzoic acid

Yield: 69.2% of theory.

Mp 208-210 ° C (from ethyl acetate).

Analysis:

calculated:

Found: C, 66.57; H, 6.56; Cl, 8.55; N, 6.75.

% C, 66.36;% C, 6.77;% C, 8.58;

4 - ({1- [5-chloro-2- [3,5-cis-dimethylpiperidino) phenyl] ethylaminocarbonylmethyl) benzoic acid

Yield: 82.2% of theory.

212-214 ° C (from ether).

Analysis:

calculated:

67.20% C, 6.81% H, 8.26% Cl, 6.53 θ / ο N, found *

66.95 _0/0 C, 6.69% H, 8.43% Cl, 6.68% N.

4-f [1- (5-chloro-2-piperidinophenyl) propyl) aminocarbonylmethylphenzoic acid

Yield: 81.5% of theory.

Melting point 200-203 ° C (from ether).

Analysis:

calculated:

% C, 66.57;% H, 6.56;% C, 8.55;% N, 6.75.

% C, 66.74;% H, 6.35;% C, 8.59;

4-f [1- (5-chloro-2-piperidinophenyl) -2-methylpropyl) aminocarbonylmethyl} benzic acid

Yield: 82.7% of theory.

Mp 236-240 ^° C (from ethyl acetate).

Analysis:

calculated:

67.20 ° C, 6.81% H, 8.27% Cl, 6.53% N, found:

C, 67.19; H, 6.56; H, 8.14; N, 6.39.

4-f [1- [5-chloro-2-morpholinylphenyl] ethyl] aminocarbonylmethyl] benzoic acid

Yield: 85.6% of theory.

Mp 201-203 ° C (from ether).

Analysis:

calculated:

% C, 62.60;% H, 5.75;% Cl, 8.80;

% C, 62.30;% H, 8.8; Cl, 8.83; N. 6.85.

4 - {[1- (5-chloro-2-thiomorpholinylphenyl) ethyl] aminocarbonylmethyl] benzoic acid

Yield: 87.6% of theory.

Mp 216-217 ^° C (from ether).

Analysis:

calculated:

% C, 60.20;% H, 5.53;% 8.46;% N, 6.69.

% C, 59.90;% H, 11.1;% C, 8.61;

4- [1- [5-chloro-2- (hexahydro-1H-azepino) phenyl] ethyl] amino-carbonylmethyl) benzoic acid

Yield: 81.2% of theory.

M.p. 202-204 ° C (from chloroform-toluene).

Analysis:

calculated:

% C, 66.58;% H, 6.56;% C, 8.55;% N, 6.75.

% C, 66.60;% H, 6.37;% C, 8.50;

4 - [[1- (5-chloro-2-octahydroazocinophenyl) ethyl] aminocarbonylmethyl] benzoic acid

Yield: 44.4% of theory.

Melting point 196-197 ° C (from a mixture of chloroform and petroleum ether).

Analysis:

calculated:

% C, 67.19;% H, 6.81;% N, 6.53.

H, 6.97; N, 6.37.

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

Yield: 74.7% of theory.

Mp 204-206 ° C (from ethyl acetate / petroleum ether).

Analysis:

calculated:

Found: C, 67.78; H, 7.05; N, 6.32.

H, 7.03; N, 6.04.

4-f [2- (5-chloro-2-piperidinophenyl) -2-propyl] aminocarbonylmethyl] benzoic acid

Yield: 82.9% of theory.

Melting point 227-229 ° C (from acetone).

Analysis:

calculated:

66.57% 8, 6.55% H, 8.55% 8, 6.77% H, found:

% C, 66.03;% H, 6.66;% Cl, 8.67.

4- | [1- (5-nitro-2-piperidincphenyl) ethyl] aminocarbonylmethyl] benzoic acid

Yield: 95.6% of theory.

Mp 252-254 ^° C (from ether).

Analysis:

calculated:

% C, 64.22;% H, 6.12;% N / 10.21.

% C, 64.20;% H, 6.17;

4-f [1- (2-piperidinophenyl) ethyl) aminocarbonylmethyl] benzoic acid

Yield: 85%.

Melting point 170-172 ° C.

Analysis:

calculated:

% C, 72.11;% H, 7.15;% N, 7.64.

% H, 7.03;% N, 7.72.

4-f [2- (2-piperidinophenyl) -2-propyl) aminocarbonylmethyl] benzoic acid

Yield: 72.7% of theory.

Mp 213-215 ° C.

Analysis:

calculated:

% C, 72.61;% H, 7.42;% N, 7.36.

% H, 7.31;% N, 7.45.

4 - [(5-methyl-2-plperidinobenzyl) aminocarbonylmethyl] benzoic acid

Yield: 64.6%.

Melting point 120-122 ° C.

Analysis:

calculated:

% C, 72.11;% H, 7.15;% N, 7.64.

72.42% C, 7.38% H, 7.45% N.

Mass spectrum: molecular signal:

Calcd .: m / e = 366 found: m / e = 366.

Melting point of hydrochloride: 266 ° C (dec.).

Analysis:

calculated:

% C, 65.58;% H, 6.76;% CC, 8.88%;

H, 6.62; Cl, 9.40; N, 7.00.

4 - [(2-piperidinoanilino) carbomylmethyl] benzoic acid. 0.25 HCl

Yield: 72.5% of theory.

Mp 216-217 ° C.

Analysis:

calculated · (. 0.25 HCl):

69.11% C. 6. 44% N, 6.255 84) CC 6.00% H, found:

69.40% C6 C633 CC6 CI.600.6 CC 6.33% CI.

4 - {[2- (2-piperidinophenyl) -2-propyl] aminocarbonylmethyl] benzoic acid

Yield: 68.5% of theory.

Mp 213-215 ° C.

Analysis:

calculated:

72.61% C, 7.42% H, 7.36% N, found:

% C, 72.43;% H, 7.25;

4 - [[1- (2-dimethylaminophenyl) ethyl] aminocarbonylmethylbenzoic acid

Yield: 53.3%.

Melting point 165-168 ° C (from acetone / petroleum ether).

Analysis:

calculated:

% C, 69.92;% H, 6.79;% N, 8.59.

% H, 6.83;% N, 8.49.

4 - [(2-pyrrolidinohenzyl) aminocarbonynylmethyl] benzoic acid

Yield: 55%.

212 DEG-215 DEG C. (from methanol).

Analysis:

calculated:

% C, 70.99;% H, 6.55;% N, 8.28.

H, 6.91; N, 8.15.

4 - ((1- (2-pyrrolidinophenyl) ethyl) aminocarbonylmethybenzoic acid

Yield: 25%.

Mp 155-157 ° C (from acetone / ether).

Analysis:

calculated:

71.57% C, 6.86 ° / o H, N 7.95%, found:

71.22 O / _o C, 6.75% H, 8.42% N.

4 - [(2-piiperidinobenzyl) aminocarbonylmethyl] benzoic acid

Yield: 60.4% of theory.

Melting point 175-177 ° C (from acetone).

Analysis:

calculated:

% C, 71.57;% H, 6.86;% N, 7.95.

% C, 71.48;% H, 7.00;% N, 8.09.

4- | [2- (2-Piperidinophenyl) ethyl] aminocarbonylmethylibenzoic acid

Yield: 60.4% of theory.

164-166 ° C (from ethyl acetate).

Analysis:

calculated:

% C, 72.11;% H, 7.15;% N, 7.64.

% C, 72.35;% H, 7.18;% N, 7.76.

4 - ((1- [2- (2-Methylpiperidino) phenyl] ethyl | aminocarbonylmethyl) benzoic acid

Yield: 90.9% of theory.

Melting point 171-173 ° C (from a mixture of petroleum ether and acetone).

Analysis:

calculated:

% C, 72.61;% H, 7.42;% N, 7.36.

% C, 72.30;% H, 7.39;

4 - ((1- [2- (3-methylpiperidino (phenyl) ethyl) aminocarbonylmethyl) benzoic acid Yield: 86.3% of theory.

Melting point 170-173 ° C (from a mixture of petroleum ether and acetone).

Analysis:

calculated:

H, 7.42; N, 7.36. Found:

72.20 θ / ο C, 7.28 θ / ο H, 7.12% N.

4 - {[1- (2-dipropylaminophenyl) ethyl] aminocarbonylmethylbenzoic acid

Yield: 51.1% of theory.

Melting point 175-178 ° C (from ethyl acetate).

Analysis:

calculated:

72.22% C, 7.91 θ / ο H, 7.32% N, found:

% C, 72.10;% H, 8.05;

4 - {[1- (2-piperidinophenyl) -2-methylpropyl] aminocarbonylmethyl | benzoic acid

Yield: 68%.

Mp 215-217 ^° C (from acetone).

Analysis:

calculated:

% C, 73.06;% H, 7.67;% N, 7.10.

H, 7.55; N, 6.99.

4- ([1- (2-Piperidinophenyl) ethyl] aminocarbonylmethyl] benzoic acid methyl ester

4 - {[1- (5-Chloro-2-piperidinophenyl) ethyl] aminocarbonylmethyl-benzoic acid methyl ester was used as starting material.

Yield: 37.2% of theory.

Melting point 145-147 ° C.

Analysis:

calculated:

% C, 72.61;% H, 7.42;% N, 7.36.

% C, 72.47;% H, 7.30;

4 - [(2-Piperidinoanilino) carbonylmethyl] benzoic acid methyl ester

4 - [(5-Chloro-2-piperidinyl) carbonylmethyl] benzoic acid methyl ester was used as starting material.

Yield: 60%.

85-86 ° C (from toluene / petroleum ether).

Analysis:

calculated:

% C, 71.57;% H, 6.86;% N, 7.96.

% C, 71.48;% H, 6.92;

N-Phenacetyl-N- [1- (2-piperidinophenyl) ethyl] amine

N- [1- (5-chloro-2-piperidinophenyl) ethyl] -N-phenacetylamine was used as starting material.

Yield: 54.6% of theory.

Melting point 120-121 ° C (from a mixture of petroleum ether and acetone).

Analysis:

calculated:

% C, 78.22;% H, 8.13;% N, 8.69%

% C, 77.90;% H, 8.24;

4 - [(5-chloro-2-piperidinoanilino) carbonylmethyl] benzoic acid hydrochloride

Yield: 51.3% of theory.

232 DEG C. (decomposition).

Analysis:

calculated:

58.68% C, 42% H, 17.32 θ / ο Cl, 6.84 θ / ο N, found:

% H, 44%;% N, 6.74%.

4- (2- (2-Piperidinoanilinocarbonylmethylbenzoic acid) semi-hydrate)

Yield: 69.9% of theory.

151-153 ° C (from petroleum ether / acetone).

Analysis:

calculated (0.5 H2O):

69.78 O / o C, 6.97 θ / ο H, 7.75 θ / ο N, found:

% C, 69.30;% H, 6.82;

4- {2- [1- (2-Piperidinophenyl) ethyl] aminocarbonylethyl] benzoic acid. 0.2 H2O

Yield: 71.4% of theory.

Melting point 171-172 ° C (from acetone / petroleum ether).

Analysis:

calculated (.0.2 H-O):

% C, 71.91;% H, 7.45;% N, 7.29.

% C, 71.90;% H, 7.30;

Example 9

4 - {[1- (5-Benzyloxy-2-piperidinophenyl) ethyl] aminocarbonylmethylbenzoic acid

244 mg (0.487 mmol) of 4 - (((1-5-benzyloxy-2-piperidinophenyl) ethyl) aminocarbonylmethylbenzoic acid ethyl ester in 2.5 mL of ethanol was heated with stirring with 0.73 mL of 1 N sodium hydroxide solution in a bath at temperature 50 [deg.] C. until the presence of the ester is no longer detectable by thin layer chromatography (0.73 ml) of 1N hydrochloric acid solution is added, the mixture is evaporated in vacuo and the residue is partitioned between ethyl acetate and water. It was dried over sodium sulfate, filtered and evaporated in vacuo.

Yield: 191 mg (83% of theory).

Melting point 220-222 ° C.

Analysis: ·. ' calculated:

% C, 73.71;% H, 6.83;% N, 5.93%

73.21% C, 6.67% H, 5.80% N.

In an analogous manner to that described in Example 9, the following compounds are obtained:

4 ([1- (- hexaazdrazepinophenyl) ethyl l aminocarbonylmetayl] benzoic acid

Yield: 68.5% of theory.

174 DEG-176 DEG C. (from ethyl acetate).

Analysis:

calculated:

% C, 72.61;% H, 7.42;% N, 7.36.

% H, 7.34;% N, 7.38.

4 - ((1- [2- (1,2,3,6 ^ ύ: 4 ^ άΓοργΓ1ΰΐηο) phenyl) ethanediocarbonylmethyl) benzoic acid

Yield: 68.2% of theory.

M.p. 158-160 ° C (from ethyl acetate).

Analysis:

l calculated:

% C, 72.51;% H, 6.64;% N, 7.69.

% C, 72.20;% H, 6.66;% N, 7.74.

4 - ([2- (5-chloro-piperidinophenyl) ethyl) aminocarbonylmetaylbenzoic acid

Yield: 75%.

Mp 192-195 ° C (from ethyl acetate).

Analysis:

calculated:

65.91% S, 0 6.9 0% 0, 08.4 0% 01, 0.99 ° Sat 0, found:

66.39% 0c 0.11 0Ό 0, 0.44 0ί> 0, 0.77 0ί) 0.

4 - ([1- (5-fluoro-4-piperidinophenyl) ethyl] aminocarbonylmethylbenzoic acid

Yield: 52.9% of theory.

174 DEG-176 DEG C. (from ethyl acetate).

Analysis:

calculated:

% C, 68.73;% H, 6.55;% N, 7.29

% C, 68.30;% H, 6.48;% N, 7.45.

4 - [(S-methyl-1-piperidinobenzyl) aminocarbonylmethyl] benzoic acid

Yield: 53.9% of theory.

Melting point 120-122 ° C (from ethanol).

Analysis:

calculated:

% C, 72.11;% H, 7.15;% N, 7.64.

% H, 7.04;% N, 7.64.

Mass spectrum: Molecular signal: Calculated: m / e = 0 366, found: m / e = 366.

4-j [1- (5-cyano (- piperidinophenyl) ethyl] aminocarbonylmethyl] benzoic acid

Yield: 71.6% of theory.

Melting point 198-200 ° C (from ether).

Analysis:

calculated:

70.57 θ / ο C, 6.44% H, 10.73% N, found:

H, 6.38; N, 11.00.

4 - {[1- (5-carboxy-2-piperidinophenyl) ethyl] aminocarbonylmethyl] benzoic acid

They are prepared from the corresponding diethyl ester by saponification with 2.5 equivalents of sodium hydroxide.

Yield: 73.5% of theory.

260 DEG C. (decomposition).

Analysis:

calculated:

% C, 67.30;% H, 6.38;% N, 6.82.

67.76 θ / ο C, 6.62 θ / ο H, 6.85% N.

4 - ((1- [2- (1,4-Dioxa-8-azaspiro [4,5] decan-8-yl) phenyl) ethyl] aminocarbonylmethyl / benzoic acid semi-hydrate

Yield: 85.7% of theory.

M.p. 130-135 ° C (from a mixture of petroleum ether and acetone).

Analysis:

calculated (.0.5 H2O):

% C, 66.49;% H, 6.74;% N, 6.46.

66.56% C, 6.65% H, 6.46% N.

4- ([2-Hydroxy-1- (2-piperldinophenyl) ethyl] aminocarbonylmethyl) benzoic acid

Yield: 65%.

Mp 155-157 ° C (dec. (Petroleum ether / acetone)).

Mass spectrum: Molecular signal: Calculated: m / e = 382, Found: m / e = 382.

4 - ((1- [5-chloro-2- (2-methylplperidino) phenyl] ethyl] aminocarbonylmethyl) benzoic acid

Yield: 64.1% of theory.

Mp 195-198 ° C (from ethyl acetate).

Analysis:

calculated:

66.57% C, 6.56% H, 8.54% Cl, 6.75% N, found ·

% C, 66.01;% H, 6.25;% Cl, 8.32.

4 - {[1- (5-aminocarbonyl-2-piperidinophenyl) ethyl] aminocarbonylmethyl] benzoic acid

Yield: 86%.

Mp 231-235 ° C (from ethyl acetate).

Analysis:

calculated:

67.46% C, 6.65 θ / ο H, 10.26% N, found *

67.96% C, 6.68% H, 10.11% N.

4 - ((1- [2- (4-Methylpiperidino) phenyl] ethyl) aminocarbonylmethyl / benzoic acid

Yield: 67.7% of theory.

Melting point 173-175 ° C (from chloroform).

Analysis:

calculated:

72.61% C, 7.42 θ / ο H, 7.36 θ / ο N,

ΓΊ A 1 Ρ7ΡΤΊ fV

H, 7.36; N, 7.45.

4 - {[1- (2-Piperidinophenyl) ethyl] -N-methylaminocarbonylmethyl] benzoic acid hydrochloride

Conversion of the viscous betaine (72% crude) to the hydrochloride is carried out with hydrogen chloride in a solution of isopropyl alcohol.

Yield: 32%.

222 DEG-230 DEG C. [decomposition (from ethanol).

Analysis:

calculated:

% C, 66.25;% H, 7.01;% C, 8.50;% N, 6.71.

66.07%, C 6.96%, 8.37% Cl, 6.58% N.

2 - ((1- (2-piperidinophenyl) ethyl) aminocarbonylmethyl) benzoic acid

Yield: 7%.

Melting point 135 ° C (dec.).

Analysis:

calculated:

72.10% C, 7.15% H, 7.64 ° / o N, found:

% H, 7.03;% N, 7.37.

3 - {[1- (2-piperidinophenyl) ethyl] aminocarbonylmethyl] benzoic acid

Yield: 86%.

Mp 205-207 ^° C.

Analysis:

calculated:

% C, 72.11;% H, 7.15;% N, 7.64.

% H, 7.29;% N, 7.71.

3-chloro-4 - [[1- (2-piperidinophenyl) ethyl] aminocarbonylmethylbenzoic acid

Yield: 38%.

Melting point from 175 ° C to south, from 190 ° C clear melt.

Analysis:

calculated:

% C, 65.91;% H, 6.69;% N, 8.84;% N, 6.69;

C, 65.42; H, 6.32; Cl, 9.05; N, 6.77.

4 - ((1- [2- (1,2,3,4-Etrahydroisoquinolin-2-yl) phenyl] ethyl} aminocarbonylmethyl) benzoic acid

Yield: 59%.

Mp 207-209 ° C.

Analysis:

calculated:

% C, 75.34;% H, 6.32;% N, 6.76.

% H, 6.29;% N, 6.67.

4- [1- (3-Piperidinophthyl) ethyl] aminocarbonylmethyl] benzoic acid

Yield: 33%.

Mp 206-208 ° C.

Analysis:

calculated:

% C, 72.09;% H, 7.15;% N, 7.64.

H, 7.14; N, 7.57.

4-) [1- (6-chloro-2-piperidinophenyl) ethyl] aminocarbonylmethylbenzoic acid

Yield: 35% of theory.

M.p. 148-150 ° C.

Analysis:

calculated:

H, 6.28; H, 8.84; N, 6.9.8. Found:

% C, 65.45;% H, 6.36;% Cl, 9.63.

4-j [1- (6-methyl-2-piperidinophenyl) ethyl] aminocarbonylmethylbenzoic acid

Yield: 33%.

Melting point 170 ° C.

Analysis:

calculated:

% C, 72.60;% H, 7.41;% N, 7.36.

% H, 7.34;% N, 7.32.

4 - ({[1- (2-octahydroisoindol-2-yl (phenyl) ethyl) aminocarbonylmethyl) benzoic acid

Yield: 64%.

Melting point 130 ° C.

Analysis:

calculated:

% C, 73.86;% H, 7.43;% N, 6.89.

73.60 ° C, 7.47% H, 6.72% N.

4- (| [1- (2-decahydroisoquinolin-2-yl (phenyl) ethyl) aminocarbonylmethyl) benzoic acid

Yield: 71%.

Mp 220-221 ^° C.

Analysis:

calculated:

% C, 74.25;% H, 7.66;% N, 6.66.

H, 7.50; N, 6.58.

Mass spectrum: molecular signal: calculated m / e = 420, found: m.'c =% 400.

4 - ((1- [2- (1,2,3,4,5,6,7,8-octahydroiscquinolin-4-yl) phenyl] ethyl) aminocarbonylmethyl / benzoic acid semi-hydrate

Yield: 99%.

Melting point 70 ° C (dec.).

Analysis:

calculated (0.5 H2O):

H, 7.30; N, 6.54.

73.00 θ / ο С, 7.16 θ / ο Η, 5.98 θ / ο Ν.

Mass spectrum: Molecular signal: Calculated: m / e = 418, Found: m / e = 418.

4- | [1- (4-Chloro-2-piperidinophenyl) ethyl] aminocarbonylmethyl] benzoic acid

Yield: 82.1% of theory. Melting point 200-202 ° C.

Analysis:

calculated:

% C, 65.91;% H, 6.29;% Cl, 8.84;

% C, 66.06;% H, 6.40;

4 - [[1- (4-methyl-2-piperidinophenyl) ethyl] aminocarbonylmethyl] benzoic acid

Yield: 66.5% of theory.

Melting point 110-115 ° C.

Analysis:

calculated:

% C, 72.60;% H, 7.42;% N, 7.36.

% C, 72.50;% H, 7.52;% N, 7.46.

4 - [(2-piperidinobenzhydryl) aminocarbonylmethyl] benzoic acid

Yield: 88%.

Mp 232-234 ° C.

Analysis:

calculated:

% C, 75.68;% H, 6.59;% N, 6.54.

ΤΊΑ1Ρ7ΡϊΊΠ

75.16 θ / ο С, 6.52 θ / ο Η, 6.74 θ / ο Ν.

4 - [(5-chloro-2-piperidinobenzhydryl) aminocarbonylmethyl] benzoic acid

Yield: 78.5% of theory. Mp 255-260 ° C.

Analysis:

calculated:

70.05% C, 5.88 θ / ο H, 7.66 θ / o Cl, 6.05 θ / ο N, found *

C 70.50, H 6.76, Cl 7.36, N 6.06.

4 - [[1- (5-amino-2-piperidinophenyl) ethyl] aminocarbonylmethyl] benzoic acid

Yield: 85.7% of theory.

Melting point 223-225 ° C (from ether).

Analysis:

calculated:

69.27% C, 7.13% H, 11.02 θ / ο N, found:

% H, 7.04;% N, 11.35.

4- | [1- (4-Piperidinophenyl) ethyl) aminocarbonylmethyl] benzoic acid

Yield: 81%.

Mp 208-210 ^° C.

Analysis:

calculated:

% C, 72.11;% H, 7.15;% N, 7.64.

72.24% C, 7.26% H, 7.54% N.

4 - ({1- [2- (4-methylpiperazino) phenyl] ethyl] aminocarbonylmethyl) benzoic acid

Yield: 65% of theory.

M.p. 150-153 ° C.

Analysis:

calculated:

69.27% C, 7.13% H, 11.02% N, found *

% C, 69.62;% H, 7.65;

4 - ({1- [2- [4-Benzylpiperazino) phenyl] ethyl] aminocarbonylmethyl) benzoic acid hydrochloride

Yield: 32%.

Melting point 180 ° C.

Analysis:

calculated:

68.07 θ / o C, 6.53% H, 7.18% Cl, 8.51% N, found *

67.85% C, 6.56% H, 7.18% Cl, 8.51% N.

4 - ({1- [2- (4-p-chlorophenylpiperazino) phenyl] ethyl-aminocarbonylmethyl) benzoic acid

Yield: 75%.

212 ° C (dec.).

Analysis:

calculated:

% C, 67.84;% H, 5.90;% Cl, 7.42;% N, 8.79.

H, 6.22; H, 7.59; N, 8.82.

4 - [(α-cyclohexyl-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid

Yield: 33%.

Melting point 199-202 ° C.

Analysis:

calculated:

74.62% C, 7.89% H, 6.45% N, found ·

74.60% C, 7.54% H, 6.68% N.

(+) -4- [1- (2-piperidinophenyl) ethyl] aminocarbonylmethyl] benzoic acid.

. 0.3 HzO

Yield: 40%.

Melting point 107 ° C (dec.) (From isopropanol / ether).

[.alpha.] D @ ²⁰ = + 7.3 DEG (c = 1; methanol).

Analysis:

calculated (0.3 H2O):

71.02% C, 7.25% H, 7.52% / N, less ·

70.90 θ / ο С, 7.22 θ / ο Η, 7.42 θ / ο Ν.

Mass spectrum: Molecular signal: Calculated: m / e = 366 Found: m / e = 366.

(-) - 4 - {[1- (2-Piperidinophenyl) ethyl] aminocarbonylmethyl] benzoic acid, sodium salt

Yield of crude product based on betaine: 77% of theory.

Mass spectrum: Molecular signal: Calculated: m / e = 366 Found: m / e = 366.

Conversion to the sodium salt is carried out with 1 equivalent of sodium hydroxide in ethanol.

Melting point of sodium salt 190 ° C (decomposition).

4- [1- (2-piperidinophenyl) ethenyl] aminocarbonylmethylphenzoic acid

Yield: 53.6% of theory.

M.p. 158-160 ° C (from ethanol).

Analysis:

calculated:

72.51% C, 6.64 θ / ο H, 7.69 θ / ο N, и л1р7Рпа ·

72.40 θ / ο C, 6.34 θ / ο H, 7.51 θ / ο N.

4-f [1- (5-chloro-2-piperidinophenyl) ethenyl] aminocarbonylmethyl] benzoic acid

Yield: 78.7% of theory.

Melting point 198-200 ° C (from acetone).

Analysis:

calculated:

% C, 66.24;% H, 5.81;% C, 8.88%;

65.74% C, 5.72 θ / ο H, 9.37 θ / ο Cl, 7.10 »/ o N.

4 - [(α-cyclohexylidene-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid

Yield: 21% of theory.

Mp 213-216 ° C.

Analysis:

calculated:

74.97 θ / ο C, 7.46 θ / ο H, 6.48 θ / ο N, пя1р7Рпп *

74.73 θ / ο С, 7.52 θ / ο Η, 6.48 θ / ο Ν.

4 - ((1- (6-chloro-2-piperidinophenyl) ethenyl] aminocarbonylmethyl) benzoic acid

Yield: 39%.

Melting point 162 ° C.

Analysis:

calculated:

66.24 θ / o C, 5.81 θ / ο H, 8.88 θ / ο Cl, 7.02 θ / ο N, found:

66.48% C, 5.84% H, 8.88% Cl, 6.85% N.

Mass spectrum: Molecular signal: Calculated: m / e = 398/400 Found: m / e = 398/400.

4-f [1- (6-methyl-2-plperidinophenyl) ethenyl] aminocarbonylmethyl] benzoic acid

Yield: 49%.

Mp 128-130 ° C.

Mass spectrum: Molecular signal: Calculated: m / e = 378 Found: m / e = 378.

4 - ((1- (2-piperidinophenyl) propenyl) aminocarbonylmethyl) benzoic acid

Yield: 65% of theory.

Melting point: E-form: 185-187 ° C (from ethyl acetate).

Analysis:

calculated:

72,99 θ / ο C, 6,92 θ / ο H, 7,40 θ / ο N,

ΓΊЯ 1 Ρ7ΡΓΊ Π

73.10% С, 6.99% Η, 7.56% Ν.

Melting point of the Z-form: 108-110 ° C.

4 - ((1- (5-Hydroxy-2-piperidinophenyl) ethyl) aminocarbonylmethyl) benzoic acid semi-hydrate

The saponification is carried out with 2.5 equivalents of sodium hydroxide.

Yield: 55.9% of theory.

Foam (ether).

Analysis:

calculated (.0.5 H2O):

H, 6.95; N, 7.16.

ΤΊΡ 1θ7ΡΠίΊ *

67.11 ° C, 7.15% H, 6.87% N.

4 - ((1- [2- (2-methylpyrrolidolido) phenyl) ethyl (amnocarbonylmethyl) benzoic acid

Yield: 62%.

Melting point 169-172 ° C.

Analysis:

calculated:

H, 7.15; N, 7.64.

ΤΊΑ 1Ο7ΡΤ1Ω *

71.96 ° C, 6.82% H, 7.51% N.

4 - [[1- (5-Aminosulfonyl-2-piperidinophenyl) ethyl] aminocarbonylmethyl] benzoic acid

Yield: 19.2%.

210 ^DEG C. (decomposition).

Analysis:

calculated:

% C, 59.30;% H, 6.11;% N, 9.43.

% C, 58.80;% H, 5.87;% N, 9.06.

Mass spectrum: Molecular signal: Calculated: m / e = 445 Found: m / e = 445.

4 - {[1- (2-Piperidinophenyl) propyl] aminocarbonylmethylbenzoic acid

Yield: 71.4% of theory.

208 DEG-210 DEG C. (from ethanol).

Analysis:

calculated:

% C, 72.61;% H, 7.42;% N, 7.36.

% C, 72.30;% H, 7.44;

Example 10

4 - [[1- (2-piperidinophenyl) ethyl] aminocarbonylmethyl-benzoic acid

To 88.8 g (0.225 mol) of 4 - ((1- (2-piperidinophenyljethyl laminocarbonylmethyl) benzoic acid ethyl ester in 890 ml of ethanol) was added a solution of 13.5 g (0.338 mol) of sodium hydroxide in 50 ml of water and the reaction mixture was stirred at an internal temperature of 60 ^DEG C. until the presence of the starting material can be detected by thin layer chromatography (about 45 minutes), then 400 ml of water are added and the pH is adjusted to about 25 ^DEG C. with dilute hydrochloric acid (1: 1). It is adjusted to pH 5.8 with a pH meter.

The reaction mixture is left to stand overnight at 20 ^DEG C. and then the precipitated crystalline product is filtered off, washed several times with water, dissolved in methylene chloride and separated from the aqueous phase. The methylene chloride solution was dried over sodium sulfate, filtered, evaporated in vacuo to give a solid residue (57.5 g).

The filtrate in ethanolic HCl (pH = 5.8) is adjusted to pH 5.0 with dilute hydrochloric acid (1: 1), and then ethanol is distilled off in vacuo where possible, and the concentrated solution is cooled with ice. The precipitate formed is filtered off, methylene chloride is dissolved, the aqueous phase is separated, the methylene chloride solution is dried, filtered and evaporated in vacuo. The evaporation solid weighed 13.0 g. Both evaporators (together 70.5 g) were recrystallized from a 5-6-fold amount of ethanol / water (80:20) with the addition of activated carbon.

Yield: 62%.

Mp 163-164 ° C.

Analysis:

calculated:

% C, 72.11;% H, 7.15;% N, 7.64.

% C, 72.13;% H, 7.25;% N, 7.75.

If, after completion of the saponification, the pH is immediately adjusted to 5.0 after addition of water and cooling to 25 DEG C., 75.9% of a dried residue is obtained, as described above, but without treatment of the filtrate in ethanolic hydrogen chloride. it provides the correct elemental analysis values before the next recrystallization.

M.p. 172-176 ° C.

Analysis:

calculated:

% C, 72.11;% H, 7.15;% N, 7.64.

% C, 71.90;% H, 7.08;

In an analogous manner to that described in Example 10, the following compounds are obtained:

4 - [[1- (5-methyl-2-piperidinoienyl) ethyl] aminocarbonylmethyl] benzoic acid

Yield: 56.6% of theory.

215 ^DEG- 217 ^DEG C. (from ethanol).

Analysis:

calculated:

% C, 72.61;% H, 7.42;% N, 7.36.

% C, 72.71;% H, 7.49;% N, 7.25.

4 - [(α-carboxy-2-piperidinobenzyl) aminocarbonylmethyl] benzoic acid. . 0.66 H2O

This compound is produced by saponification of 4 - [(α-methoxycarbonyl-2-piperidinobenzyl) amino-carbonylmethyl-1-benzoic acid ethyl ester with 2.5 equivalents of sodium hydroxide.

Yield: 72.2% of theory.

235 DEG-240 DEG C. (decomposition) (from methanol / chloroform).

Analysis:

calculated · (. 0.66 H2O):

% C, 64.69;% H, 6.33;% N, 6.85.

% C, 64.64;% H, 6.23;% N, 6.61.

Example 11

4- [1- (2-Piperidinophenyl) ethyl) aminocarbonylmethyl (1 H, 4 H) -benzoic acid monohydrate

500 mg (1.26 mmol) of 4- (1- (2-piperidinophenyl) ethyl) aminocarbonylmethylbenzoic acid ethyl ester in 5 ml of ethanol are stirred together with 1.26 ml of 1 N sodium hydroxide solution for 1 hour at 50 ° C. The mixture is cooled to 0 ° C, the precipitated crystalline product is filtered off and washed with cold ethanol and ether.

Yield: 238 mg (48.6% of theory).

Mp 245-250 ° C.

Analysis:

calculated (1 H 2 O):

% C, 65.01;% H, 6.69;% N, 6.89.

% C, 65.40;% H, 6.83;

In an analogous manner to that described in Example 11, the sodium salt monohydrate is prepared 1- 1- (5-Methoxy-2-piperidinophenyl) ethyl laminocarbonylmethyl-benzoic acid:

Yield: 17.5% of theory.

Mp 212-215 ° C.

Analysis:

calculated (1 HzO):

% C, 63.28;% H, 6.70;% N, 6.42.

% H, 6.82;% N, 6.51.

From the sodium salt following an analogous procedure to that described in Example 9, the corresponding acid is obtained in the form of the monohydrate:

Mp 187-189 ° C (from ethanol / water).

Analysis:

calculated (1 H 2 O):

66.40% C, 7.29% H, 6.76% N, found:

H, 6.97; N, 6.80.

Example 12

4 - [1- (2-Piperidinophenyl) ethyl] aminocarbonylmethylbenzoic acid, sodium salt

8.4 g (0.0222 mol of 4 - (- 1- (2-piperidinedioethyl) ethyl) aminocarbonylmethyl-benzoic acid) are dissolved at 60 to 65 ° C in 80 ml of ethanol, then 22.9 ml of 1 N are added with stirring sodium hydroxide solution and the reaction mixture is stirred for a further 30 minutes, after which the reaction mixture is cooled to 20 ° C, whereupon a precipitate forms, the mixture is cooled to 0 ° C, filtered and washed with cold ethanol and ether. m.p. 250 DEG-251 DEG C., recrystallized from ethanol / water (7: 3).

Yield: 7.2 g (78.6% of theory).

Mp 253-255 ° C.

Analysis:

calculated (0.6 HzO):

% C, 66.18;% H, 6.61;% N, -7.02.

% C, 66.10;% H, 6.64;

Example 13

4-f [1- (2-piperidinophenyl) ethyl] aminocarbonylmethylbenzoic acid

100 mg (0.237 mmol) of tert-butyl 4 - ([1- (2-piperidinophenyl) ethyl] aminocarbonylmethylphenzoic acid) tert-butyl ester were heated to reflux in 5 ml of benzene together with several crystals of p-trifluorosulfonic acid hydrate for half a day. there is no starting material present in the thin layer chromatogram and only the desired product is present according to the Rf value and the mass spectrum.

Mp 163-165 ° C.

Mass spectrum: molecular signal:

calculated: m / e = 366 found: m / e = 366.

Example 14

4-f [1- (2-piperidinophenyl) ethyl] aminocarbonylmethyl] benzoic acid

0.46 g (1 mmol) of 4 - {[1- (2-piperidinophenyl) ethyl) aminocarbonylmethyl-benzoic acid benzyl ester in 20 ml of ethanol is hydrogenated in the presence of 0.25 g of palladium on carbon (10%) at 50 ° C and at 50 ° C. pressure of 0.5 MPa. After 5 hours, the catalyst was filtered off through a filter aid and the filtrate was evaporated in vacuo. The residue is recrystallized from a mixture of ethanol and water (8: 2).

Yield: 0.26 g - (71% of theory).

Mp 163-165 ° C.

Analysis:

calculated:

% C, 72.11;% H, 7.15;% N, 7.64.

% C, 72.30;% H, 7.25;% N, 7.81.

Example 15

4-f [1- (5-chloro-2-piperidinophenyl) ethyl] aminocarbonylmethylbenzoic acid

To a stirred solution of 1 g (5.55 mmol) of 4-carboxyphenylacetic acid and 1.32 g (5.55 mmol) of 1- (5-chloro-2-piperidinophenyl) ethylamine in 10 ml of absolute pyridine was added dropwise 0.4 ml ( 5.55 mmol) of thionyl chloride, the internal temperature rising from 20 to ° C. The deep brown reaction mixture was stirred for 3 hours at 20 ° C and then evaporated in vacuo. The residue was partitioned between water (at pH = 3 after addition of 2 N hydrochloric acid) and chloroform. The organic extract was dried and filtered and the filtrate evaporated in vacuo. The residue was purified by silica gel column chromatography using a 10: 1 mixture of chloroform and methanol as eluent.

Yield: 1.06 g (48% of theory).

Mp 212-214 ° C (from ether).

Analysis:

calculated:

Found: C, 65.91; H, 6.29; Cl, 8.85;

% C, 65.79;% H, 6.01;% C, 8.69;

In an analogous manner to that described in Example 15, the following compounds are obtained:

4-f [1- (2-piperidinophenyl) ethyl] aminocarbonylmethylbenzoic acid

Yield: 52%.

Melting point 169-171 ° C.

Analysis:

calculated:

% C, 72.11;% H, 7.15;% N, 7.64.

% H, 6.87;% N, 7.72.

4 - ((1- [2- (4-oxo-piperidino) phenyl) ethylfaminocarbonylmethyl / benzoic acid)

Yield: 32%.

Melting point: 177 to 180 ° C (decomposition) (from a mixture of acetone and petroleum ether).

Analysis:

calculated:

% C, 69.46;% H, 6.36;% N, 7.36.

H, 6.41; N, 7.50.

4 - ((1- (2- (4-hydroxypiperidino) phenyl) ethyl) aminocarbonylmethyl / benzoic acid. 0.66 HzO

Yield: 23.5%.

M.p. 176-179 ° C (dec.) (Acetone / petroleum ether).

Analysis:

calculated (0.55 HzO):

% C, 66.97;% H, 6.81;% N, 7.10.

H, 6.78; N, 7.26.

4 - [[1- (2-piperidinophenyl) ethyl) aminocarbonylmethyl] benzonitrile

This compound is produced using 4-cyanophenylacetic acid.

Yield: 51%.

Mp 155-157 ° C (from ethyl acetate).

Analysis:

calculated:

H, 7.25; N, 12.09. Found:

H, 7.10; N, 12.20.

N- (4-Aminopheneacetyl) -N- [1- (4-piperidinophenyl) ethyl] amine dihydrochloride semi-hydrate

This compound is produced using 4-aminophenylacetic acid.

Yield: 17.5% of theory.

238 ° C (dec.).

Analysis:

calculated (2 HCl, 0.5 H2O):

60.12% C, 7.21% H, 16.91% Cl, found:

C, 60.52; H, 7.52; Cl, 17.05.

4 - ([1- (2-piperidinophenyl) ethyl] aminocarbonylmethyl) benzyl alcohol

This compound is produced using 4-hydroxymethylphenylacetic acid.

Yield: 39%.

Melting point 104-106 ° C.

Analysis:

calculated:

74.96% C, 8.00. % H, 7.94% N, found:

74.80% C, 7.80% H, 7.80 a / o N.

4- | [1- (2-Piperidinophenyl) ethyl 1-aminocarbonylmethyl] benzaldehyde

This compound is produced using 4-formylphenyl acetic acid.

Yield: 10%.

Mp 159 ° C.

Analysis:

calculated:

% C, 75.40;% H, 7.48;% N, 7.99.

H, 7.24; N, 7.60.

Claims (5)

SUBJECT A process for the preparation of novel substituted alkylenimino-phenylalkylamides of phenylalkancarboxylic acids of the general formula I in which: R 1 and R 2, which are the same or different from each other, denote alkyl groups having 1 to 6 carbon atoms or cycloalkyl groups having 5 to 7 carbon atoms, or R 1 and R 2 together with the intervening nitrogen atom denote an unbranched C 3 -C 6 alkyleneimino group which is optionally substituted by one or two C 1 -C 3 alkyl or hydroxy groups, or in which the methylene invention is optional is replaced by a carbonyl group, an oxygen atom or a sulfur atom, or an imino group which is optionally substituted by an alkyl group having 1 to 3 carbon atoms, an aralkyl group having 1-6 carbon atoms. C 7 to 10 carbon atoms, phenyl 6 or halophenyl, or in which the ethylene group is optionally replaced by an o-phenylene group, further represents an unbranched alkenyleneimino group. (C až-C 6), saturated or 1, 2 or 3 double bonds containing (C až-C az) azabicycloalkyl, (Cza-C-1,4) 1,4-dioxaspiroalkyl, heptamethyleneimino, octamethylenimino, nonamethylenimino or decamethylenimino, R3 is hydrogen or halogen, trifluoromethyl, alkyl, hydroxy, alkoxy, alkanoyloxy, mercapto, alkylmercapto, nitro, amino, cyano, alkanoyl, carboxy, alkoxycarbonyl, aminocarbonyl, aminocarbonyl, an alkylamino group, a dialkylamino group, an alkanoylamino group, an alkoxycarbonylamino group or an alkylsulfonylamino group, each alkyl moiety in the abovementioned groups having in each case 1 to 3 carbon atoms, furthermore 7 to 10 phenylalkoxy or phenylcarbonylamino, R 1 represents a hydrogen atom or a C 1 -C 3 alkyl group, R 5 represents a hydrogen atom, a halogen atom, or an alkyl group having 1 to 3 carbon atoms, A represents a bond, optionally substituted by methylene or ethylene or isopropyl, methylene or ethylene, methylene or ethylene substituted by two alkyl groups of 1 to 3 carbon atoms, C3-C7 cycloalkyl, 1 to 3 hydroxyalkyl carbon atoms, carboxy, C 1 -C 3 alkoxycarbonyl or phenyl-substituted methylene, C 3 -C 7 cycloalkylidene or woollidene of the general formula R 6 R 7 C / c - where R 6 and R 2 are hydrogen or one of the radicals R e and R 7 is a methyl or cycloalkyl group having 3 to 7 carbon atoms, and the other of the radicals R e or R 7 is a hydrogen atom or R 8 and R 7 together with the intervening carbon atom represent a C 5 -C 7 cycloalkylidene group, B is optionally a C 1 -C 3 alkyl group substituted with a methylene or ethylene group; and W represents a hydrogen atom or a halogen atom, a nitro group or an alkanoyl group having 1 to 3 carbon atoms substituted by an amino group, optionally a hydroxy group, a carboxy group or an alkoxycarbonyl group or two alkoxycarbonyl groups each having a total of 2 to 4 carbon atoms carbon, carboxy or C 2 -C 4 alkoxycarbonyl substituted C 2 -C 5 alkenyl, C 1 -C 3 alkanoyl, dialkoxymethyl or C 1 -C 3 trialkoxymethyl in each alkyl moiety, alkylenedioxymethyl a group having 2 or 3 carbon atoms in the alkylene moiety, a 1,3-oxazolin-2-yl group or a cyano group, or optionally one or two alkyl groups having from 1 to 4 carbon atoms in each of the alkyl moieties substituted by an aminocarbonyl group; C5-C8 uppentine, morpholinocarbonyl, (C7 -C10) dialkyldioxolanyl) alkoxycarbonyl or carboxy or its alkyl, benzyl or (2,2-dimethyldioxolan-4-yl) methyl esters, wherein the alkyl moiety contains from 1 to 6 carbon atoms and is optionally substituted by a hydroxy, methoxy or diethylamino group, as well as their optically active antipodes and salts thereof, in particular their physiologically acceptable salts with inorganic or organic acids or bases, characterized by: by treating the amine of formula II A and R 1 to R 4 are as defined above, or when A is one of the abovementioned vinylidene groups, its tautomer or its lithium or magnesium halide complex is treated with a carboxylic acid of formula III (III) in an inert organic solvent wherein: R 5 and B have the meanings given above and W ‘is as defined above for W or is a carboxyl group which is protected by a protecting group or its reactive derivatives, optionally produced in the reaction mixture, and optionally the protecting group used is cleaved hydrolytically or. by thermolysis in the presence of an acid or a base at temperatures in the range of -10 ° C to 120 ° C, whereupon the optionally obtained compound of formula I is converted into its optically active antipodes or salts, in particular their physiologically acceptable salts with inorganic or organic acids and bases. production of merchandise 2. The process of item 1 of the formula (Ia) Rž.a (la.) (Ha.) In which B is as defined in point 1, R 1 _and R 2a, which are the same or different from each other, denote alkyl groups having 1 to 6 carbon atoms or cycloalkyl groups having 5 to 7 carbon atoms, or R1 _and R2 _and together. with a nitrogen atom therebetween are optionally one or two alkyl groups having from 1 to 2, respectively. 3 carbon atoms substituted with 4 to 10 carbon alkyleneimino, morpholino or thiomorpholino groups, R 3a represents a hydrogen or halogen atom, a trifluoromethyl group, an alkyl group, an hydroxy group, an alkoxy group, a mercapto group, an alkylmercapto group, a cyano group, a nitro group, an amino group, an aminocarbonyl group, alkylamino group, dialkylamino group; up to 3 carbon atoms, and Aa optionally represents one or two alkyl groups having from 1 to 3 carbon atoms each substituted by a methylene or ethylene group, as well as 1 alkyl, benzyl, or (2,2-dimethylhydroxy-7-alan-4-yl) methyl esters, the alkyl moiety containing 1 is optionally substituted with hydroxy, methoxy or diethylamino, their optically active antipodes and their salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases, characterized in that the amine of the formula Ila in which Aa and R 1a to R _3a have the previously defined meanings; HOOC-B Ηζ _ / - № (HiaJ in which B has the meaning defined in point 1 a Wa is a carboxyl group optionally protected by a protecting group, or reactive derivatives thereof, optionally produced in a reaction mixture, whereupon the optionally used protecting group is cleaved by hydrolytic or thermolysis in the presence of an acid or a base at temperatures between -10 ^° C and 120 ° C and optionally the compound of formula (Ia) obtained is converted to its optically active antipodes or salts, in particular to its physiologically acceptable salts with inorganic or organic acids and bases. 3. The process according to claim 1, wherein the reaction is carried out in the presence of an acid activating agent or a water scavenger and optionally in the presence of an inorganic or tertiary organic base. 4. The process according to claim 1, wherein the reaction is carried out in the presence of an amine activating agent and optionally in the presence of an inorganic or tertiary organic base. 5. A process according to any one of claims 1 to 4, wherein the reaction is carried out at temperatures of -25 to 250 [deg.] C. preferably at temperatures in the range of -10 ° C to the boiling point of the solvent used.