NO175634B - - Google Patents

Abstract

The present invention relates to novel pyridyl derivatives of the general formula <IMAGE> in which R1 to R6, A, X and n are as defined in Claim 1, their enantiomers, their cis- and trans-isomers if R4 and R5 together represent a carbon-carbon bond, and their addition salts, for pharmaceutical use, in particular, their physiologically tolerable addition salts with inorganic or organic bases, if R6 represents a hydroxyl group, which have useful pharmacological properties, in particular antithrombotic effects and effects mediated by thromboxane. In addition, the novel compounds are at the same time thromboxane antagonists (TRA) and thromboxane synthesis inhibitors (TSH). In addition, they also have an effect on PGE2 production.

Description

The present invention relates to methods for the production of new pyridyl derivatives with the general formula

their enantiomers, their cis- and trans-isomers when R^ and R5 together form a carbon-carbon bond, as well as their addition salts, especially for pharmaceutical use, their physiologically acceptable addition salts with inorganic or organic bases when Rg forms a hydroxy group. The compounds exhibit valuable pharmacological properties, especially antithrombotic effects. Moreover, the new compounds are simultaneously thromboxane antagonists (TRA) and thromboxane synthesis inhibitors (TSH) and thus also inhibit thromboxane-mediated effects. Furthermore, the compounds also exhibit an effect on PGE2~ production in the lungs and on PGD2~, PGE2~ and PGF2a~ production in human platelets.

In the general formula given above means

n the number 2, 3 or 4,

X a carbonyl, thiocarbonyl or sulfonyl group,

R1 an optionally phenyl-substituted alkyl group with 1 to 4 carbon atoms, a cycloalkyl group with 5 to 7 carbon atoms, a phenyl group, or if A does not form a bond, also a benzoyl or benzenesulfonyl group, where the phenyl nucleus may be mono-, di- or tri-substituted with fluorine -, chlorine or bromine atoms, alkoxy or alkyl groups with 1 to 4 carbon atoms and where the substituents may be the same or different and one of the substituents may also constitute a trifluoromethyl, carboxyl, amino or nitro group,

a naphthyl, biphenylyl, diphenylmethyl, indolyl, thienyl, chlorothienyl or bromothienyl group,

R2 a hydrogen atom or an alkyl group with 1 to 4 carbon atoms,

R3 a pyridyl group,

R4 and R5 each a hydrogen atom or together an additional carbon-carbon bond,

R 6 is a hydroxy or alkoxy group with 1 to 3 carbon atoms, and

A a bond, a cycloalkylene or cycloalkylidene group, each with 3 or 4 carbon atoms, in which a methylene group may be replaced by a dichloromethylene group, a straight-chain optionally mono- or polyunsaturated alkylene group with 2 or 3 carbon atoms, a -RyCRg-, -0-R7CRQ - or -NRg group, where

R^ is a hydrogen atom, a hydroxy, phenyl or alkyl group of 1 to 3 carbon atoms,

Rg is a hydrogen atom or an alkyl group of 1 to 3 carbon atoms and

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

Current meanings for the residues that are initially defined are, for example

for R1 the meaning methyl-, ethyl-, n-propyl-, isopropyl-, n-butyl-, tert-butyl-, benzyl-, 2-phenylethyl-, 3-phenylpropyl-, cyclobutyl-, cyclopentyl-, cyclohexyl-, phenyl -, benzoyl-, benzenesulfonyl-, fluorophenyl-, fluorobenzoyl-, fluorobenzenesulfonyl-, chlorophenyl-, chlorobenzoyl-, chlorobenzenesulfonyl-,

bromophenyl-, bromobenzoyl-, bromobenzenesulfonyl-, methylphenyl-, methylbenzoyl-, methylbenzenesulfonyl-, ethylphenyl-, ethylbenzoyl-, ethylbenzenesulfonyl-, n-propylphenyl-, n-propylbenzoyl-, n-propylbenzenesulfonyl-, isopropylphenyl-, isopropylbenzoyl-, isopropylbenzenesulfonyl- , n-butylphenyl-, n-butylbenzoyl-, n-butylbenzenesulfonyl-, isobutylphenyl-, isobutylbenzoyl-, iso-butylbenzenesulfonyl-, tert-butylphenyl-, tert-butylbenzoyl-, tert-butylbenzenesulfonyl-, trifluoromethylphenyl-, trifluoromethyl-benzoyl-, Trifluoromethylbenzenesulfonyl, nitrophenyl, nitrobenzoyl, nitrobenzenesulfonyl, aminophenyl, aminobenzoyl, aminobenzenesulfonyl, carboxyphenyl, carboxybenzoyl, carboxybenzenesulfonyl, methoxyphenyl, methoxybenzoyl, methoxybenzenesulfonyl, ethoxyphenyl, ethoxybenzoyl, ethoxybenzenesulfonyl -, isopropoxyphenyl-, isopropoxybenzoyl-, iso-propoxybenzenesulfonyl-, difluorophenyl-, difluorobenzoyl-, di-fluorobenzenesulfonyl-, dichlorophenyl-, dichlorobenzoyl-, dichlorobenzenesulfonyl-, dimethylphenyl-, dimethylbenzoyl -, dimethylbenzenesulfonyl, dimethoxyphenyl, dimethoxybenzoyl, dimethoxybenzenesulfonyl, trimethylphenyl, trimethylbenzoyl, trimethylbenzenesulfonyl, trimethoxyphenyl, trimethoxybenzoyl, trimethoxybenzenesulfonyl, chloromethylphenyl, chloromethylbenzoyl, chloromethylbenzenesulfonyl, chloromethoxyphenyl, chloromethoxy- benzoyl, chloromethoxybenzenesulfonyl, methoxymethylphenyl, methoxymethylbenzoyl, methoxymethylbenzenesulfonyl, aminodichlorophenyl, aminodichlorobenzoyl, aminodichlorobenzenesulfonyl, aminodibromophenyl, aminodibromobenzoyl, aminodibromobenzenesulfonyl, naphthyl, biphenyl, biphenylmethyl, indolyl, thienyl -, the chlorothienyl or bromothienyl group,

for R_ the meaning of the hydrogen atom, the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl group,

for R3 the meaning of the pyridyl-(2), pyridyl-(3) or pyridyl(4) group,

for R6 the meaning of the hydroxy, methoxy, ethoxy, n-propoxy or isopropoxy group and

for the -A-X group the meaning carbonyl-, methylenecarbonyl-, ethylenecarbonyl-, n-propylenecarbonyl-, ethylenecarbonyl-, ethynylenecarbonyl-, sulfonyl-, methylenesulfonyl-, ethylenesulfonyl-, n-propylenesulfonyl-, 1,1-cyclopropylenecarbonyl-, 1 ,2-cyclopropylenecarbonyl-, 3,3-dichloro-1,1-cyclopropylenecarbonyl-, 3,3-dichloro-1,2-cyclopropylenecarbonyl-, 1,1-cyclobutylenecarbonyl-, 1,2-cyclobutylenecarbonyl-, carbonyl-1, 2-cyclopropylenecarbonyl-, carbonyl-1,2-cyclobutylenecarbonyl-, oxymethylenecarbonyl-, oxymethylmethylenecarbonyl-, oxy-dimethylmethylenecarbonyl-, oxy-n-ethylenecarbonyl-, oxy-n-propylenecarbonyl-, hydroxymethylenecarbonyl-, aminocarbonyl-, methylaminocarbonyl -, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, isobutylaminocarbonyl, phenylaminocarbonyl, aminothiocarbonyl, carbonylaminocarbonyl or sulfonylaminocarbonyl, each of the latter carbonyl or sulfonyl groups being linked with - The NR2~ group.

However, preferred compounds of the above formula I are those where

n is the number 2, 3 or 4,

X is a carbonyl, thiocarbonyl or sulfonyl group,

is a phenyl group, or, when A does not form a bond, a benzoyl or benzenesulfonyl group, in which the phenyl nucleus may be monosubstituted with a fluorine, chlorine or bromine atom, with a trifluoromethyl, phenyl, methoxy, carboxy or nitro group or with an alkyl group with 1 to 4 carbon atoms, a phenyl group, or, when A does not form a bond, a benzoyl or benzenesulfonyl group, where the phenyl nucleus is disubstituted with chlorine or bromine atoms or with methyl groups, the substituents may be the same or different, a cyclohexyl, benzyl, 4-amino-3,5-dichlorophenyl, 4-amino-3,5-dibromophenyl, naphthyl, diphenylmethyl, indolyl, thienyl, chlorothienyl or bromothienyl group,

R2 is a hydrogen atom or an alkyl group with 1 to 3 carbon atoms,

R- is a pyridyl group,

R4 and R5 are each a hydrogen atom or together form an additional carbon-carbon bond,

Rg is a hydroxy or alkoxy group with 1 to 3 carbon atoms and

A is a bond, a cyclopropylene or cyclopropylidene group, in which a methylene group can be replaced by a dichloromethylene group, a straight-chain optionally mono- or polyunsaturated alkylene group with 2 carbon atoms, a -R^CRg-,

-O-RyCRg or -NRg group,

in which

R7 constitutes a hydrogen atom, a hydroxy or alkyl group with 1 or 2 carbon atoms,

Rg constitutes a hydrogen atom or an alkyl group with 1 or 2 carbon atoms and

R9 constitutes a hydrogen atom, an alkyl group with 1 or 2 to 3 carbon atoms or a phenyl group,

their enantiomers, their cis- and trans-isomers, to the extent that R4 and Rg together form a carbon-carbon bond, as well as their addition salts with inorganic or organic bases.

Particularly preferred are compounds of formula I, where

n is the number 2, 3 or 4,

X is a carbonyl, thiocarbonyl or sulfonyl group,

R1 is a monosubstituted phenyl group, which is optionally substituted with a fluorine, chlorine or bromine atom, with a trifluoromethyl, phenyl, methoxy, carboxy or nitro group or with an alkyl group with 1 to 4 carbon atoms, a phenyl group which is disubstituted with chlorine or bromine atoms or with methyl groups, where the substituents may be the same or different, a benzyl, 4-amino-3,5-dichlorophenyl, naphthyl or chlorothienyl group,

1*2 is a hydrogen atom or a methyl group,

R, is a 3-pyridyl group,

R4 and R5 are each a hydrogen atom or together form an additional carbon-carbon bond,

Rg is a hydroxy group and

A is a bond, a cyclopropylene or cyclopropylidene group, a straight-chain optionally mono- or polyunsaturated alkylene group with 2 carbon atoms, a -R^CRg-, -O-R7CRg- or

-NRg group, in which

R7 constitutes a hydrogen atom, a hydroxy or methyl group,

Rg constitutes a hydrogen atom or a methyl group and

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

their enantiomers, their cis- and trans-isomers, to the extent that R4 and R5 together form a carbon-carbon bond, as well as their physiologically acceptable addition salts with inorganic or organic bases.

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

a) acylation of a compound of the general formula

where

R2 to Rg and n are as initially defined, with a compound of the general formula

where

R^ is as initially defined and

Z 1 is a nucleophilic leaving group, such as a halogen atom or an alkoxy group, e.g. a chlorine or bromine atom, a methoxy or ethoxy group, or, when A constitutes a -NRg group and X a carbonyl or thiocarbonyl group, Z1 together with Rg constitutes an additional carbon-nitrogen bond.

The reaction is preferably carried out in a solvent such as methanol, ethanol, water/methanol, dioxane, tetrahydrofuran or chloroform, possibly in the presence of an acid-binding agent such as potassium carbonate, triethylamine or pyridine, where the latter two can also be used as a solvent, suitably at temperatures between 0 and 50°C, preferably at room temperature.

b) For the preparation of compounds of the general formula I, where Rg is a hydroxy group: removal of a protecting residue from a compound of the general formula

where

R1 to R5, A, X and n are as initially defined and Z2 constitutes a hydrolytically, thermolytically or hydrogenolytically cleavable protecting group for a carboxy group, or a functional derivative of the carboxy group.

Hydrolysable groups are, for example, functional derivatives of the carboxy group, such as unsubstituted or substituted amides, esters, thioesters, orthoesters, imino-ethers, amidines or anhydrides, the nitrile group, ether groups, such as methoxy-, ethoxy-, tert-butoxy- or benzyloxy- the group, or lactones and

thermolytically cleavable groups are, for example, esters with tertiary alcohols, e.g. tert-butyl ester, and as hydrogenolytically cleavable groups, for example aralkyl groups, e.g. the benzyl group.

The hydrolysis is conveniently carried out in the presence of an acid, such as hydrochloric acid, sulfuric acid, phosphoric acid or trichloroacetic acid, or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, ethanol, water/ethanol, water/isopropanol or water/dioxane at temperatures between -10 and 120°C, e.g. at temperatures between room temperature and the boiling point of the reaction mixture.

If, for example, a compound of formula IV contains a nitrile or aminocarbonyl group, these groups can be transferred into the carboxyl group, preferably with the help of 100% phosphoric acid at temperatures between 100 and 180°C, preferably at temperatures between 120 and 160°C, or also with a nitrite, e.g. sodium nitrite, in the presence of an acid, e.g. sulfuric acid, which can also be used as a solvent, at temperatures between 0 and 50°C.

If, for example, a compound of formula IV contains an acid amide group, such as the diethylaminocarbonyl or piperidinocarbonyl group, this group can be transferred into the carboxy group, preferably hydrolytically in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid or trichloroacetic acid, or in the presence of a base such as sodium hydroxide or potassium hydroxide, in a suitable solvent such as water, water/methanol, ethanol, water/ethanol, water/isopropanol or water/dioxane, at temperatures between -10 and 120°C, e.g. at temperatures between room temperature and the boiling point of the reaction mixture.

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

For example, if a compound of formula IV contains the benzyloxy or benzyloxycarbonyl group, the benzyl group can also be split off hydrogenolytically in the presence of a hydrogenation catalyst such as palladium/charcoal, in a suitable solvent such as methanol, ethanol, methanol/water, ethanol/water, glacial acetic acid, acetic acid ethyl ester, dioxane or dimethylformamide, preferably at temperatures between 0 and 50°C, e.g. at room temperature, and a hydrogen pressure of 1 to 5 bar. During the hydrogenolysis, a halogen-containing compound can be simultaneously dehalogenated and an occurring double bond hydrogenated. c) For the preparation of compounds of the general formula I, where R4 and R5 each constitute a hydrogen atom:

hydration of a compound of the general formula

where

R 1 to R 3 , R 8 , A, X and n are as initially defined.

The hydrogenation is carried out in a suitable solvent such as methanol, ethanol, dioxane, acetic acid ethyl ester or glacial acetic acid, with catalytically activated hydrogen, e.g. with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, palladium, palladium/coal, platinum or platinum/coal, under a hydrogen pressure of 1 to 5 bar, or with nascent hydrogen, e.g. in the presence of iron/hydrochloric acid, zinc/glacial acetic acid, stannous chloride/hydrochloric acid or iron(II) sulphate/sulfuric acid, at temperatures between 0 and 50°C, preferably at room temperature. However, the catalytic hydrogenation can also take place stereoselectively in the presence of a suitable catalyst.

Herein, a possible nitro group in the residue R^ can be simultaneously co-reduced or a possible chlorine or bromine atom in the residue R1 can be replaced with a hydrogen atom. d) For the preparation of compounds of the general formula I, where R^ and R^ together form a carbon-carbon bond:

turnover of a compound with the general formula

where

R1 to R3, A and X are as initially defined, with a compound of the general formula

where

Rg dg n is, as initially defined, and

W means a triphenylphosphonium halide, dialkylphosphonic acid or magnesium halide residue, and optionally subsequent dehydration.

The reaction is preferably carried out in a suitable solvent such as diethyl ether, tetrahydrofuran, dioxane or dimethylformamide, at temperatures between -30 and 100°C, preferably at temperatures between -20 and 25°C.

However, the reaction with a triphenylphosphonium halide of formula VI can be carried out with particular advantage in the presence of a base such as potassium tert-butylate or sodium hydride.

If the hydroxy group in the primarily formed carbinol in the reaction with a magnesium halide of formula VII should not be split off during the reaction, it is split off 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 ethanol, isopropanol or dioxane, at temperatures between 0 and 120°C, e.g. at temperatures between room temperature and the boiling point of the reaction mixture.

If, according to the invention, a compound of formula I is obtained, where R2 constitutes a hydrogen atom, this can be transferred by alkylation into a corresponding compound of formula I, where R2 constitutes an alkyl group,

or

a compound of formula I, where R 6 constitutes a hydroxy group, by esterification, is transferred into a corresponding compound of formula I, where R 6 constitutes an alkoxy group.

The subsequent alkylation is preferably carried out in a solvent such as methylene chloride, tetrahydrofuran, dimethylformamide or dimethylsulfoxide in the presence of an alkylating agent such as methyl iodide, dimethyl sulphate, ethyl bromide, n-propyl bromide or isopropyl bromide, optionally in the presence of an acid binding agent such as potassium carbonate, at temperatures between 0 and 70°C, preferably at temperatures between 20 and 50°C.

The subsequent esterification or amidation is conveniently carried out in a solvent, e.g. in an excess of the alcohol used, such as methanol, ethanol or isopropanol, or the amine used, such as ammonia, methylamine, n-propylamine or dimethylamine, in the presence of an acid activating agent such as thionyl chloride or hydrogen chloride gas, at temperatures between 0 and 180 °C, preferably at the boiling point of the reaction mixture.

The obtained compounds of formula I can also be resolved into their enantiomers. thus the obtained compounds of formula I containing only one optically active center can be resolved into their optical antipodes by known methods (see Allinger N.L. and Eliel W.L. in "Topics in Stereochemistry", Vol. 6., Wiley Interscience, 1971), f .ex. by recrystallization from an optically active solvent or by reaction with an active substance, especially bases, which form salts with the racemic compound, and separating the salt mixture thus obtained, e.g. due to different solubility, in the diastereomeric salts, from which the free antipodes can be liberated by the action of suitable agents. Particularly applicable optically active bases are e.g. The D and L forms of α-phenylethylamine or cinchonidine.

Obtained compounds of formula I with at least two asymmetric carbon atoms can also be resolved into their diastereomers due to their physico-chemical differences, e.g. by chromatography and/or fractional crystallization. A pair of enantiomers thus obtained can then be resolved into their optical antipodes as described above. If, for example, a compound of formula I contains two optically active carbon atoms, the corresponding (R R<1>, S S') and (R S', S R') forms are obtained.

The thus obtained compounds of formula I, where R4 and R5 together form a carbon-carbon bond, can also be transferred into their cis- and trans-isomers using usual methods, for example by chromatography on a support such as silica gel, or by crystallization.

Moreover, the thus obtained new compounds of formula I, if they contain a carboxy group, can optionally then be transferred into their addition salts with inorganic or organic bases, especially for pharmaceutical use, into their physiologically acceptable addition salts. Examples of bases include sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

Starting compounds of formula II to VII are obtained according to methods known from the literature.

A compound of formula II, used as starting material, is obtained from a corresponding N-acylamino compound by acylation according to Friedel-Craft, with subsequent deacylation and possibly subsequent reduction, hydrolysis and/or esterification, or

by reacting a corresponding magnesium or lithium compound with a corresponding substituted pyridine compound such as 3-cyanopyridine, pyridine-3-aldehyde or a pyridine-3-carboxylic acid derivative and possibly subsequent oxidation.

Used starting compounds of formula IV, V and VI are obtained by reacting a corresponding amino compound with a corresponding halide.

Used starting compounds of formula VII are obtained by reacting a corresponding halocarboxylic acid with triphenylphosphine or with a trialkylphosphonic ester.

As already mentioned at the outset, the new compounds and their physiologically acceptable addition salts with inorganic or organic bases exhibit valuable pharmacological properties, in particular antithrombotic effects and an inhibitory effect on platelet aggregation. Moreover, they also constitute thromboxane antagonists and thromboxane synthesis inhibitors, with the remarkable fact that the compounds of formula I simultaneously exhibit these effects. Moreover, the compounds also exhibit an effect on PGE2~ production in the lungs and on PGD2~, PGE2~ and PGF2a production in human platelets.

For example, the new connections were

A = (-)-5E-6-[4-(Z-2-(4-chlorophenyl)-cyclopropyl-1-carboxamido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid,

B = 5E-6-[3-(3-(4-chlorophenyl)-propionylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid,

C = 5E-6-[3-(3-(4-chlorophenyl)-thioureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid, and

D = 5E-6-[3-(3-(2,4-dichlorophenyl)-1-methylthioureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

examined for their biological properties as follows:

1. Antithrombotic effect

Methodology

Platelet aggregation is measured according to the method of Born & Cross (J. Physiol. 170, 397 (1964)) in platelet-rich plasma from healthy subjects. Sodium citrate, 3.14%, in a volume ratio of 1:10 is added to the blood to prevent coagulation.

Collagen-induced aggregation

The course of the decreasing optical density of the platelet suspension is measured and recorded photometrically after the addition of the aggregation-triggering substance. From the angle of inclination of the density curve, the aggregation rate can be determined. The point on the curve where the greatest light transmission exists is used to calculate "optical density".

The amount of collagen is selected as little as possible, but still so that an irreversibly continuous reaction curve is achieved. The commercially available collagen from the company Hormonchemie,

Munich is used.

Before the collagen addition, the plasma is incubated for 10 minutes with the test substance at 37°C.

From the obtained measurement data, an EC5Q value is graphically determined which refers to a 50% change in "optical density" with respect to aggregation inhibition.

2. Thromboxane- antagonistic action

Venous human blood is added to 13 mM Na3~citrate as an anti-coagulant and centrifuged for 10 minutes at 170 x g. The supernatant platelet-rich plasma is added to a Sepharose-2B column to remove the plasma proteins. Aliquots of the obtained platelet suspension are incubated with the test substance, with the ligand ( 3 H-labelled) and a marker ( 14 C-labelled) for 60 minutes at room temperature and then centrifuged for 20 seconds at 10,000 x g. The supernatant liquid is sucked off and the remaining pellet dissolve in NaOH. <3>H activity in the supernatant corresponds to the free ligand, C gives the concentration of the marker. H in the obtained pellet corresponds to the bound ligands, <14>C is used for correction for ligand in the extracellular space. From the binding values for the different concentrations of test substance, the displacement curve is established after iteration and IC5Q is determined.

3. Determination of the inhibitory effect on thromboxane synthetase

Venous human blood is added to 13 mM Na3~citrate which

anticoagulant and centrifuged for 10 minutes at 170 x g. The supernatant platelet-rich plasma is applied to a Sepharose-2B column to remove plasma proteins. Aliquots of the obtained platelet suspension are incubated with the test substance or the solvent as a control, for 10 minutes at room temperature, and, after addition of C-labelled arachidonic acid, the incubation is continued for a further 10 minutes. After interruption with 50 ul of citric acid, extraction is carried out 3 times with 500 ul of ethyl acetate, after which the combined extracts are evaporated with nitrogen.

The residue is taken up in ethyl acetate, placed on TLC foil and separated with chloroform: methanol: glacial acetic acid: water (90:8:1:0.8, parts by volume). The dried TLC foils are placed for 3 days on X-ray film, after which the autoradiograms are developed and with their help the active zones on the foil are marked. After sectioning, the activity is determined in a scintillation counter, after which the inhibition of TXB2 formation is calculated. IC5Q is determined by linear interpolation.

The following table contains the obtained values:

4. Acute toxicity

The acute toxicity of the test compounds was initially determined after oral administration of a single dose of 250 mg/kg to groups of 10 mice (observation time: 14 days). No deaths occurred at this dose.

Due to their pharmacological properties, the new compounds and their physiologically acceptable addition salts are suitable for the treatment and prevention of thromboembolic diseases such as coronary infarction, cerebral infarction, transient ischemic attacks, Amaurosis fugax, as prophylaxis in arteriosclerosis and as metastasis prophylaxis, as well as for the treatment of ischemia , asthma and allergies.

The new compounds and their physiologically acceptable addition salts are also useful in the treatment of diseases in which a thromboxane-mediated constriction or PGE 2 -mediated dilation of the capillaries plays a role, e.g. in pulmonary hypertension. Moreover, these compounds can be used to reduce the degree of graft rejection, reduce the renal toxicity of substances such as cyclosporine, for the treatment of kidney diseases, especially therapeutically or prophylactically in renal changes in connection with hypertension, systemic lupus or ureteral obstructions and in shock states in connection with sepsis, trauma or burns.

The necessary dosage to achieve a desired effect is 2 to 4 daily doses of 0.3 to 4 mg/kg body weight, preferably 0.3 to 2 mg/kg body weight. For this purpose, the new compounds of formula I can optionally be incorporated in combination with other active substances, in one or more inert common excipients and/or diluents, e.g. with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or suitable mixtures thereof, in usual galenic preparations such as tablets, dragees, capsules, powders, suspensions or suppositories.

New drugs may contain a compound of formula I and a PDE inhibitor or a lightening agent.

Current PDE inhibitors are, for example: 2,6-bis(diethanolamino)-4,8-dipiperidino-pyrimido[5,4-d]-pyrimidine (Dipyridamole),

2,6-bis(diethanolamino)-4-piperidino-pyrimido[5,4-d]pyrimidine (Mopidamol),

2-(4-methoxy-phenyl)-5(6)-(5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl)-benzimidazole (Pimobendan),

2-(4-hydroxy-phenyl)-5(6)-(5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl)-benzimidazole,

1-(1-oxido-thiomorpholino)-3-piperazino-5-methyl-isoquinoline,

6-[4-(3,4-dichlorophenylsulfinyl)-butoxy]-3,4-dihydrocarbostyril and

6-[4-(2-pyridylsulfonyl)-butoxy]carbostyril, where the daily oral dose

for Dipyridamole amounts to 2.5 to 7.5 mg/kg, preferably 5 mg/kg,

for Mopidamol 15 to 25 mg/kg, preferably 20 mg/kg,

for 2-(4-riethoxyphenyl)-5 (6)-(5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl)-benzimidazole 0.05 to 0.15 mg/kg, preferably 0 .08 to 0.10 mg/kg,

for 2-(4-hydroxyphenyl)-5(6)-(5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl)-benzimidazole 0.05 to 0.15 mg/kg, preferably 0 .08 to 0.10 mg/kg,

for 1-(1-oxido-thiomorpholino)-3-piperazino-5-methyl-isoquinoline 0.20 to 2.00 mg/kg, preferably 0.40 to 1.00 mg/kg,

for 6-[4-(3,4-dichlorophenylsulfinyl)-butoxy]-3,4-dihydro-carbostyril 0.10 to 1.00 mg/kg, preferably 0.20 to 0.50 mg/kg and

for 6-[4-(2-pyridylsulfonyl)-butoxy]carbostyryl 0.10 to 1.00 mg/kg, preferably 0.20 to 0.50 mg/kg,

and as lysing agent, plasminogen activators such as t-PA, rt-PA, streptokinase, eminase or urokinase, where the lysing agent can be administered parenterally, preferably intravenously, e.g. t-PA or rt-PA in a dosage of between 15 and 100 mg per patient, urokinase in a dose of between 250,000 and 3,000,000

units per patient, eminase in a dosage of approx. 30 mg per patient and streptokinase in a dose of between 5 x 10 to 3 x 10 7 IU which can each be given within a period of o 5 minutes and

24 hours.

For pharmaceutical use, a new combination can be prepared containing 1 to 500 mg of a PDE inhibitor, preferably 2 to 75 mg, plus 10 to 300 mg, preferably 10 to 200 mg of a compound of formula I, as well as their physiologically acceptable addition salts , together with one or more inert common carriers and/or diluents, e.g. corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat, or suitable mixtures thereof, in usual galenic preparations such as tablets, dragees, capsules, powders, suspensions or suppositories. For use in adults to achieve a desired effect, the preparations are given 2 to 4 times a day, preferably 3 to 4 times a day.

For pharmaceutical use, a new combination can be prepared containing a lightening agent in the above dosages plus 10 to 300 mg, preferably 10 to 200 mg, of a compound of formula I, as well as their physiologically acceptable addition salts in usual parenteral, preferably usual intravenous, forms of administration as ampoules or infusion solutions, where the administration can take place within a period of 5 minutes and 24 hours.

If desired, the individual active substances in the aforementioned combinations can of course be given separately.

The following examples shall illustrate the invention in more detail:

Production of output products:

Example I

6-( 4- aminophenyl)- 6-( 3- pyridyl)- hex- 5- enoic acid methyl ester

a) 4-Acetylaminophenyl-3-pyridyl-ketone

980 g of aluminum trichloride is slowly added to 155 ml

dimethylformamide. 342 g of nicotinic acid chloride hydrochloride and then 206 g of N-acetylaniline are added to the mixture at 90-110°C. 600 ml of ethylene chloride is then added to the reaction mixture, after which it is poured onto ice and neutralized during cooling by adding 15N caustic soda. The aqueous phase is extracted with methylene chloride. The combined organic phases are evaporated and the residue is recrystallized from methanol.

Yield: 44% of the theoretical

M.p.: 189-191°C

C14H12N2°3 (240.26)

Calculated: C, 69.99; H, 5.03; N, 11.66;

Found: 69.87; 5.14; 11.58;

b) 6-(4-Acetylaminophenyl)-6-(3-pyridyl)-hex-5-enoic acid

To a suspension of 307 g of 4-carboxybutyl-triphenylphosphonium bromide and 233 g of potassium tert-butylate in 2.8 liters of tetrahydrofuran, 140 g of 4-acetylaminophenyl-3-pyridyl ketone is added at -40°C, after which it is stirred for 2 hours. The reaction mixture is decomposed by adding ice water and evaporated. The residue is taken up in water and washed with acetic acid ethyl ester. The aqueous phase is acidified to pH 5-6 and extracted with ethyl acetate. The organic phase is evaporated and the residue is recrystallized from acetic acid ethyl ester/diisopropyl ether.

Yield: 86% of the theoretical

M.p.: 155-156°C

<C>19H20N2°3 (324.38)

Calculated: C, 70.35; H, 6.21; N, 8.64;

Found: 70.19; 6.27; 8.66;

c) 6-(4-Aminophenyl)-6-(3-pyridyl)-hex-5-enoic acid methyl ester

65 g 6-(4-acetylaminophenyl)-6-(3-pyridyl)-hex-5-enoic acid

boil under reflux in a mixture of 300 ml of methanol and 150 ml of saturated methanolic hydrochloric acid for 2 hours. The reaction mixture is added to 500 ml of water, neutralized by the addition of sodium carbonate and extracted with ethyl acetate. The organic phase is washed, dried and evaporated.

Yield: 71% of the theoretical

Oil, Rf value: 0.72 (silica gel; methylene chloride/acetone = 9:1) C18H20N2°2 (296.37)

Calculated: C, 72.95; H, 6.80; N, 9.45;

Found: 72.83; 6.85; 9.23;

Analogous to Example I, the following compound is obtained: 6-(4-methylaminophenyl)-6-(3-pyridyl)-hex-5-enoic acid methyl ester Oil, Rf value: 0.56 (silica gel; methylene chloride/ethanol = 20:1) C19 <H>22N2°2 (310.40)

Calculated: C, 73.52; H, 7.14; N, 9.03;

Found: 73.35; 7.24; 8.91;

Example II

6-( 3- aminophenyl)- 6-( 3- pyridyl)- hex- 5- enoic acid methyl ester

a) 3- acetylaminophenyl- 3- pyridyl ketone

114 g of 3-nitrophenyl-3-pyridyl ketone in 1000 ml of acetic acid

is hydrated at 5 bar in the presence of 35 g of Raney nickel for 2 hours at 50°C. The catalyst is filtered off and 80 ml of acetic anhydride is added to the filtrate. After 30 minutes at room temperature, the mixture is evaporated, after which the residue is taken up in ethyl acetate. The organic phase is washed with aqueous potassium carbonate solution and dried over sodium sulfate. The solvent is evaporated and the residue is recrystallized from acetic acid ethyl ester/diisopropyl ether.

Yield: 69% of the theoretical

M.p.: 116-117°C

<C>14<H>12<N>2°2 (240.26)

Calculated: C, 69.99; H, 5.03; N, 11.66;

Found: 70.01; 5.11; 11.81

b) 6-(3-Acetylaminophenyl)-6-(3-pyridyl)-hex-5-enoic acid

To a mixture of 217 g of 4-carboxybutyl-triphenylphosphonium bromide and 154 g of potassium tert-butylate in 1.8 liters of tetrahydrofuran, 94 g of 3-acetylaminophenyl-3-pyridyl ketone are added at -25°C. After stirring for 2 hours at room temperature, 200 ml of water is added to the reaction mixture and then evaporated considerably. The residue is taken up in 500 ml of water and washed with ethyl acetate. The aqueous phase is then neutralized by adding citric acid, after which it is extracted with acetic acid ethyl ester. The organic phase is evaporated and the residue is recrystallized from ethyl acetate/acetone.

Yield: 85% of the theoretical

M.p.: 86-89°C

C19H20N2°3 (324.38)

Calculated: C, 70.35; H, 6.21; N, 8.64;

Found: 70.15; 6.36; 8.50;

c) 6-(3-Aminophenyl)-6-(3-pyridyl)-hex-5-enoic acid methyl ester

65 g 6-(3-acetylaminophenyl)-6-(3-pyridyl)-hex-5-enoic acid

is boiled under reflux in a mixture of 400 ml of methanol and 200 ml of methanolic hydrochloric acid for 4 hours. The solvent is evaporated and the residue is taken up in water. The aqueous phase is washed with acetic acid ethyl ester and adjusted to pH 8-9 by adding 4N caustic soda. The aqueous phase is extracted with acetic acid ethyl ester. The organic phase is washed, dried and evaporated.

Yield: 71% of the theoretical

Oil, Rf value: 0.55 (silica gel; methylene chloride/ethanol = 9:1) C18<H>20N2°2 (296'37)

Calculated: C, 72.95; H, 6.80; N, 9.45;

Found: 72.83; 6.91; 9.18;

Analogously to Example II, the following compounds are obtained: 5-(3-aminophenyl)-5-(3-pyridyl)-pent-4-enoic acid methyl ester Resin, Rf value: 0.58 (silica gel; methylene chloride/ethanol =

20:1)

C17H18N2O2 (282.34)

Calculated: C, 72.32; H, 6.43; N, 9.92;

Found: 72.29; 6.55; 9.70;

7-(3-Aminophenyl)-7-(3-pyridyl)-hept-6-enoic acid methyl ester Resin, Rf value: 0.63 (silica gel; methylene chloride/ethanol =

20:1)

C19<H>22N2°2 (310.40)

Calculated: C, 73.52; H, 7.14; N, 9.03;

Found: 73.41; 7.18; 8.89;

Example III

6-( 3- methylaminophenyl)- 6-( 3- pyridyl)- hex- 5- enoic acid methyl ester

a) N-acetyl-3-methylaminophenyl-3-pyridyl ketone

To 84 g of 3-acetylaminophenyl-3-pyridyl ketone in 600 ml

dimethylformamide is added in portions while cooling, 17 g of sodium hydride and then 22 ml of methyl iodide. Stirring is continued for 1 hour at room temperature and the reaction mixture is decomposed by adding 100 ml of water. The solvent is evaporated and the residue is taken up in acetic acid ethyl ester. The organic phase is washed, dried and evaporated. The residue is purified over a silica gel column with methylene chloride/ethanol (30:1).

Oil, Rf value: 0.45 (silica gel; methylene chloride/ethanol = 30:1) C15H14N2°2 (254'29>

Calculated: C, 70.85; H, 5.55; N, 11.02;

Found: 70.96; 5.65; 10.92;

b) 6-(3-methylaminophenyl)-6-(3-pyridyl)-hex-5-enoic acid methyl ester

Prepared from N-acetyl-3-methylaminophenyl-3-pyridyl ketone and 4-carboxybutyl-triphenylphosphonium bromide analogously to Example IIb and subsequent esterification analogously to Example lic. Oil, Rf value: 0.56 (silica gel; methylene chloride/ethanol = 20:1)

C19H22N2°2 (310.40)

Calculated: C, 73.52; H, 7.14; N, 9.03;

Found: 73.53; 7.20; 8.84;

Example IV

(+)-E-2-(4-chlorophenyl)-cyclopropane-1-carboxylic acid

a) E/Z-2-(4-chlorophenyl)-cyclopropane-1-carboxylic acid ethyl ester

A mixture of 85 g of diazoacetic acid ethyl ester and 100 g of 4-chlorostyrene is added dropwise to 350 ml of boiling xylene over the course of 2 hours. After heating for a further 1 hour at 120°C, the solvent is evaporated in vacuo. The residue is fractionated in high vacuum.

Yield: 43% of the theoretical

Boiling point: 105-112°C (0.05 Torr)

C12H13C102 (224.69)

Calculated: C, 64.15; H, 5.83;

Found: 64.33; 6.03;

b) E- 2-(4-chlorophenyl)-cyclopropane-1-carboxylic acid and Z- 2-(4-chlorophenyl)-cyclopropane-1-carboxylic acid

To a boiling mixture of 69 g of E/Z-2-(4-chlorophenyl)-cyclopropane-1-carboxylic acid ethyl ester and 8.8 g of sodium hydroxide in 180 ml of ethanol and 50 ml of water, 160 ml of water is added dropwise over the course of 5 hours while 150 ml of ethanol are distilled off. Z-2-(4-chlorophenyl)-cyclopropane-1-carboxylic acid ethyl ester is then extracted from the reaction mixture with acetic acid ethyl ester. The aqueous phase is acidified and extracted with acetic acid ethyl ester. The organic phase is evaporated and the residue is recrystallized from petroleum ether, whereby 20 g of E-2-(4-chlorophenyl)-cyclopropane-1-carboxylic acid is obtained.

The ester-containing organic phase is evaporated and the residue is heated to boiling in a mixture of 8.8 g of sodium hydroxide, 180 ml of ethanol and 50 ml of water. 160 ml of water are dripped into the boiling reaction mixture over the course of 5 hours, while 150 ml of ethanol is distilled off. The reaction solution is then acidified and extracted with acetic acid ethyl ester. The organic phase is evaporated and the residue is recrystallized from petrol/acetic acid ethyl ester, whereby 10.1 g of Z-2-(4-chlorophenyl)-cyclopropane-1-carboxylic acid is obtained.

M.p.: (E-isomer): 116-117°C

M.p.: (Z-isomer): 128-129°C

C10<H>19ClO2 (196.63)

Calculated: C, 61.08; H, 4.61;

Found (E-isomer: 60.96; 4.66;

Found (Z-isomer): 61.02; 4.76

c) (+)- and (-)-E-2-(4-chlorophenyl)-cyclopropane-1-carboxylic acid-L-phenylglycinolamide

To a mixture of 1.96 g of E-2-(4-chlorophenyl)-cyclopropane-1-carboxylic acid and 1.01 g of N-methylmorpholine in 30 ml of tetrahydrofuran, 1.35 g of chloroformate isobutyl ester is added dropwise at -55°C. After 10 minutes, 1.37 g of L-phenylglycinol is added, after which the mixture is allowed to warm to room temperature. After 2 hours, 30 ml of water is added to the reaction mixture and evaporated, after which the formed precipitate is sucked off. The product obtained is resolved into the diastereomers by column chromatography on silica gel with methylene chloride/acetone (15:1). The pure fractions are then recrystallized from ethyl acetate.

Yield: 30% of the theoretical of diastereomer A and

26% of the theoretical of diastereomer B

<C>18<H>18ClN02 (315.80)

Calcd: C, 68.46; H, 5.74; N, 4.44; Found (diastereomer A): 68.59; 5.86; 4.57; Found (diastereomer B): 68.27; 5.81; 4.54;

d) (+)-E-2-(4-chlorophenyl)-cycloporpan-1-carboxylic acid

19 g of diastereomer A are dissolved in 200 ml of dioxane and 200 ml

4N hydrochloric acid and boil under reflux for 4 hours. The reaction mixture is evaporated, the precipitate is sucked off and recrystallized from petroleum ether/ethyl acetate.

Yield: 91% of the theoretical

M.p.: 114-115°C

Rotation [a]D<20> = +351° (c = 1.2; chloroform)

<C>10<H>9C102 (196.63)

Calculated: C, 61.08; H, 4.61;

Found: 61.12; 4.64;

Analogous to Example IV, the following compounds are obtained: (-)-E-2-(4-chlorophenyl)-cyclopropane-1-carboxylic acid M.p.: 114-115°C

Rotation [a]D<20> = -348° (c = 1.2; chloroform)

C_0H9C102(196.63)

Calculated: C, 61.08; H, 4.61;

Found: 61.12; 4.55;

(+)-Z-2-(4-chlorophenyl)-cyclopropane-1-carboxylic acid M.p.: 95-96°C

Rotation [a]D<20> = + 2.6° (c = 1.2; chloroform)

<C_>0<H>9C102 (196.63)

Calculated: C, 61.08; H, 4.61;

Found: 61.09; 4.64;

(-)-Z-2-(4-chlorophenyl)-cyclopropane-1-carboxylic acid M.p.: 95-96°C

Rotation [a]-.20 = -2.6° (c = 1.2; chloroform)

C10H9C102 (196.63)

Calculated: C, 61.08; H, 4.61;

Found: 61.24; 4.64;

Manufacture of end products:

Example 1

6-[4-(4-methylbenzenesulfonylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

A mixture of 3 g of 6-(4-aminophenyl)-6-(3-pyridyl)-hex-5-enoic acid methyl ester, 1.9 g of 4-methylbenzenesulfonic acid chloride and 5 ml

triethylamine in 100 ml methylene chloride is stirred for 1 hour at room temperature. The organic phase is washed with water and evaporated, after which the residue is purified over a silica gel column with acetic acid

ethyl ester. The product fraction is evaporated and heated to 50°C in a mixture of 50 ml of ethanol and 3 ml of ION caustic soda for 1 hour. The reaction mixture is diluted with water and neutralized by adding citric acid. The aqueous phase is extracted with ethyl acetate, dried and evaporated. The residue is recrystallized from acetic acid ethyl ester/diisopropyl ether.

Yield: 53% of the theoretical

M.p.: 110-111°C

C24H24N_04S (436.53)

Calculated: C, 66.04; H, 5.54; N, 6.42;

Found: 65.98; 5.74; 6.25;

Analogous to Example 1, the following compounds are obtained: 6-[4-(4-fluorobenzenesulfonylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 95-96°C

C23H21ra204B (440<5°)

Calculated: C, 62.71; H, 4.81; N, 6.36;

Found: 62.51; 5.02; 6.15;

6-[4-(4-chlorobenzenesulfonylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 109-111°C

C23H21C1N2°4S (456.95)

Calculated: C, 60.45; H, 4.63; N, 6.13;

Found: 60.23; 4.83; 5.96

6-[4-(4-trifluoromethylbenzenesulfonylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 116-117°C

<C>24<H>21F3N2°4S (490.50)

Calculated: C, 58.77; H, 4.32; N, 5.71;

Found: 58.68; 4.56; 5.67;

6-[4-(4-Methoxybenzenesulfonylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 129-130°C

C24H24N2°5S (452'53)

Calculated: C, 63.70; H, 5.35; N, 6.19;

Found: 63.89; 5.42; 6.34;

6-[4-(4-amino-3,5-dichlorobenzenesulfonylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 233°C

C23H21C12N3°4S (50^41)

Calculated: C, 54.55; H, 4.18; N, 8.30;

Found: 54.41; 4.26; 8.16;

6-[4-(2-naphthalenesulfonylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 177-178°C

C27H_4N204S (472.57)

Calculated: C, 68.63; H, 5.12; N, 5.93;

Found: 68.45; 4.92; 5.87;

6-[4-(2-(5-chlorothienyl)-sulfonylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 139-141°C

C2_H19C1N204S2 (462.97)

Calculated: C, 54.48; H, 4.14, N, 6.05;

Found: 54.34; 4.06; 6.20;

6-(4-benzenesulfonylaminophenyl)-6-(3-pyridyl)-hex-5-enoic acid M.p.: 149-151°C

C23H22N2°4S («2.51).

Calculated: C, 65.38; H, 5.25; N, 6.63;

Found: 65.27; 5.10; 6.57;

6-[4-(1-n-butylsulfonylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 65°C

<C>21<H>26N2°4S (402.51)

Calculated: C, 62.66; H, 6.51; N, 6.96;

Found: 62.51; 6.69; 6.84;

6-[3-(4-chlorobenzenesulfonylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 187-188°C

C23H21C1N2°4S (456.95)

Calcd: C, 60.46; H, 4.63; N, 6.13;

Found: 60.64; 4.87; 5.96;

6-[3-(1-naphthalenesulfonylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 208-209°C

C27H24N_04S (472.56)

Calculated: C, 68.63; H, 5.12; N, 5.93;

Found: 68.48; 5.13; 5.96;

6-[3-(2-naphthalenesulfonylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 185-186°C

C27H24N204S (472.56)

Calculated: C, 68.63; H, 5.12; N, 5.93;

Found: 68.50; 5.30; 5.90;

Example 2

6-[4-(N-isopropyl-4-chlorobenzenesulfonylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

a) 6-(4-isopropylaminophenyl)-6-(3-pyridyl)-hex-5-enoic acid methyl ester

6 g of 6-(4-aminophenyl)-6-(3-pyridyl)-hex-5-enoic acid methyl ester, 2.7 g of isopropyl bromide, 5 ml of triethylamine and 0.5 g of sodium iodide are heated to 90°C in 60 ml of dimethylformamide for 18 hours. The reaction mixture is evaporated and the residue is taken up in water and extracted with ethyl acetate. The organic phase is evaporated and the residue is chromatographed over a silica gel column with acetic acid ethyl ester.

Yield: 27% of the theoretical

Resin, Rf value: 0.35 (silica gel; methylene chloride/acetone = 9:1) C21H26N2°4 (338'45)

Calculated: C, 74.53; H, 7.74; N, 8.28;

Found: 74.52; 7.92; 8.02;

b) 6-[4-(N-isopropyl-4-chlorobenzenesulfonylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

2.6 g of 6-(4-isopropylaminophenyl)-6-(3-pyridyl)-hex-5-enoic acid methyl ester, 3.5 g of 4-chlorobenzenesulfonic acid chloride and 5 ml of triethylamine are stirred in 25 ml of dichloromethane for 3 days at room temperature. The organic phase is then washed with water and evaporated, whereupon the residue obtained is hydrolysed with caustic soda analogously to Example 1.

Yield: 41% of the theoretical

M.p.: 169-170°C

C26H27ClN2°4S (499.03)

Calculated: C, 62.58; H, 5.45; N, 5.61;

Found: 62.42; 5.52; 5.44;

Example 3

7-[4-(4-chlorobenzenesulfonylamino)-phenyl]-7-(3-pyridyl)-hept-6-enoic acid

a) 4-(4-chlorobenzenesulfonylamino)-phenyl-3-pyridyl ketone

24 g of 4-acetylaminophenyl-3-pyridyl ketone are boiled under reflux in 100 ml of 6N hydrochloric acid for 2 hours. The reaction mixture is evaporated and the residue is suspended in 300 ml of methylene chloride. 21 g of 4-chlorobenzenesulphonic acid chloride and then 60 ml of triethylamine are added to the suspension and stirred for 2 hours at room temperature. The reaction mixture is washed with water, dried and evaporated. The residue is purified over a silica gel column with methylene chloride/acetone (19:1) and then recrystallized from ethanol

Yield: 40% of the theoretical

M.p.: 196°C

C18H13ClN2°3S (372.83)

Calculated: C, 57.99; H, 3.51; N, 7.51;

Found: 57.88; 3.57; 7.69;

b) 7-[4-(4-Chlorobenzenesulfonylamino)-phenyl]-7-(3-pyridyl)-hept-6-enoic acid

5.95 g of 3-carboxypropyl-triphenylphosphonium bromide, 4 g of potassium tert-butylate and 3.7 g of 4-(4-chlorobenzenesulfonylamino)-phenyl-3-pyridyl-ketone are added successively to 150 ml of tetrahydrofuran at -30°C. After stirring for 1 hour at room temperature, the reaction mixture is evaporated, after which the residue is taken up in water and washed with ethyl acetate. The aqueous phase is neutralized by adding citric acid and extracted with ethyl acetate/ethanol (9:1). The organic phase is evaporated and the residue is recrystallized from methylene chloride/diisopropyl ether.

Yield: 64% of the theoretical

M.p.: 186-187°C

C24H_3C1N204S (470.98)

Calculated: C, 61.21; H, 4.92; N, 5.95;

Found: 61.14; 4.91; 5.77;

Analogous to Example 3, the following compound is obtained: 5-[4-(4-chlorobenzenesulfonylamino)-phenyl]-5-(3-pyridyl)-pent-4-enoic acid

Yield: 33% of the theoretical

M.p.: 151-152°C

C22H_9C1N204S (442.93)

Calcd: C, 59.65; H, 4.32; N, 6.32;

Found: 59.42; 4.37; 6.16;

Example 4

6-[4-(4-methylbenzenesulfonylamino)-phenyl]-6-(3-pyridyl)-hexanoic acid 1 g 6-[4-(4-methylbenzenesulfonylamino)-phenyl]-6-(3-pyridyl)-hex -5-enoic acid is dissolved in a mixture of 20 ml of methanol and 5 ml of IN caustic soda. After adding 200 mg of palladium catalyst (10% on charcoal), the mixture is hydrated at 5 bar. The catalyst is filtered off, after which the filtrate is neutralized with 1N hydrochloric acid and evaporated. The residue is taken up in acetic acid ethyl ester, boiled with activated carbon, filtered and evaporated.

Yield: 74% of the theoretical

Foam, Rf value: 0.58 (silica gel; ethyl acetate) C24H26N2°4S (438'55>

Calcd: C, 65.73; H, 5.98; N, 6.39;

Found: 65.58; 6.07; 6.35;

Example 5

6-[ 4-( 4- chlorobenzoylamino)- phenyl]- 6-( 3- pyridyl)- hex- 5- enoic acid

To a mixture of 3 g of 6-(4-aminophenyl)-6-(3-pyridyl)-hex-5-enoic acid methyl ester and 2.1 g of 4-chlorobenzoic acid chloride, 5 ml of triethylamine is added dropwise at 5-10°C. After 30 minutes, the reaction mixture is washed with water and evaporated. 30 ml of ethanol and 5 ml of 10N caustic soda are added to the residue and heated to 50°C for 30 minutes. The reaction mixture is evaporated and the residue is taken up in water. The aqueous phase is washed with ethyl acetate, neutralized by adding citric acid and then extracted with ethyl acetate. The organic phase is washed with water, dried and evaporated, after which the residue is recrystallized from acetic acid ethyl ester/diisopropyl ether.

Yield: 64% of the theoretical

M.p.: 94-95°C

C24H21C1N2°3 (420.90)

Calcd: C, 68.49; H, 5.03; N, 6.66;

Found: 68.21; 5.13; 6.60;

Analogous to Example 5, the following compounds are obtained: 6-[4-(1-naphthoylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid M.p.: 227°C

C28<H2>4<N>2°3 (436<51>

Calculated: C, 77.04; H, 5.54; N, 6.42;

Found: 76.83; 5.53; 6.31;

6-[4-(3-chlorobenzoylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid M.p.: 180-182°C

C24H21C1N2°3 (420.90)

Calcd: C, 68.49; H, 5.03; N, 6.66;

Found: 68.34; 5.02; 6.75;

6-(4-phenylacetylaminophenyl)-6-(3-pyridyl)-hex-5-enoic acid M.p.: 168-169°C

C25H24N2°3 (400.48)

Calculated: C, 74.98; H, 6.03; N, 6.99;

Found: 74.85; 6.25; 7.02;

6-[4-(2-phenylbenzoylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid M.p.: 182-183°C

C30<H2>6<N>2°3 (462.55)

Calculated: C, 77.90; H, 5.67; N, 6.06;

Found: 77.80; 5.89; 6.18;

6-[4-(1-(4-chlorophenyl)-cyclopropylcarboxamido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 147-148°C

C27H25<C>1N2°3 (460.96)

Calculated: C, 70.35; H, 5.47; N, 6.08;

Found: 70.54; 5.46; 6.06;

6-[4-(E-m-chlorocinnamoylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 101-102°C

C26H23C1N2°3 (446.93)

Calcd: C, 69.87; H, 5.19; N, 6.27;

Found: 69.79; 5.37; 6.53;

6-[4-(3-(4-chlorophenyl)-propionylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 148°C

C26H25C1N2°3 (448.95)

Calcd: C, 69.56; H, 5.61; N, 6.24;

Found: 69.45; 5.62; 6.41;

6-[4-(4-chlorophenylacetylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 176-177°C

<C>25<H>23<C1N>2°3

Calculated: C, 69.04; H, 5.33; N, 6.44;

Found: 68.93; 5.51; 6.31;

6-[4-(4-phenylbutanoylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid M.p.: 144-145°C

C27H28N2°3 (428.53)

Calculated: C, 75.68; H, 6.59; N, 6.54;

Found: 7 5.64; 6.72; 6.45;

6-[4-(3-phenylpropionylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 95-96°C

C26H22N2°3 (410.47)

Calculated: C, 76.08; H, 5.40; N, 6.83;

Found: 75.85; 5.60; 6.95;

6-[4-(E-2-phenylcyclopropyl-1-carboxamido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 175-176°C

G27H26N2°3 (426.51)

Calculated: C, 76.09; H, 6.14; N, 6.56;

Found: 76.06; 6.18; 6.48;

(+)-5E-6-[4-(E-2-(4-chlorophenyl)-cyclopropyl-1-carboxamido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 167-168°C

Rotation: [a]-.20 = +292° (c = 1.2; methanol)

C_7H25C1N203 (460.96)

Calculated: C, 70.35; H, 5.47; N, 6.07;

Found: 70.18; 5.56; 6.11;

(-)-5E-6-[4-(E-2-(4-chlorophenyl)-cyclopropyl-1-carboxamido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 167-168°C

Rotation: [a]D<20> = -294° (c = 1.2; methanol)

C27H25C1N2°3 (460.96)

Calculated: C, 70.35; H, 5.47; N, 6.07;

Found: 70.28; 5.56; 6.00;

(+)-5E-6-[4-(Z-2-(4-chlorophenyl)-cyclopropyl-1-carboxamido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 110-111°C

Rotation: [ a]^ 20 = +10.5° (c = 1.2; methanol)

C27H25C1N2°3 (460.96)

Calculated: C, 70.35; H, 5.47; N, 6.07;

Found: 70.24; 5.62; 6.22;

(-)-5E-6-[4-(Z-2-(4-chlorophenyl)-cyclopropyl-1-carboxamido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 110-111°C

Rotation: [a]-.20 = -11° (c = 1.2; methanol)

C27H25C1N2°3 (460.96)

Calculated: C, 70.35; H, 5.47; N, 6.07;

Found: 70.20; 5.55; 6.07;

6-[4-(Z-2-(4-bromophenyl)cyclopropyl-1-carboxamido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 204-205°C

C27<H>25BrN2°3 (505'4D

Calculated: C, 64.17; H, 4.99; N, 5.54;

Found: 64.00; 5.01; 5.63;

6-[4-(Z-2-(4-chlorobenzoyl)-cyclopropyl-1-1-carboxamido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 193-194°C

<C>28<H>25C1N2°4 (488.96)

Calculated: C, 68.78; H, 5.15; N, 5.72;

Found: 68.68; 5.23; 5.73;

6-[4-(N-methyl-3-(4-chlorophenyl)-propionylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 87-90°C

C_7H27C1N203 (462.97)

Calculated: C, 70.05; H, 5.88; N, 6.05;

Found. 69.95; 5.87; 5.95;

6-[4-(N-methyl-Z-2-(4-chlorophenyl)-cyclopropyl-1-carboxamido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

Foam, R^ value: 0.41 (silica gel; methylene chloride/ethanol = 20:1) C28H27C1N2°3 (474.99)

Calculated: C, 70.80; H, 5.73; N, 5.90;

Found: 70.71; 5.75; 5.66;

6-[4-(N-methyl-E-2-(4-chlorophenyl)-cyclopropyl-1-carboxamido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

Melting point: 148-150°C

C28H27C1N2°3 (474.99)

Calculated: C, 70.80; H, 5.73; N, 5.90;

Found: 70.60; 5.79; 5.80;

6-[3-(2-phenylbenzoylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid M.p.: 214-216°C

C30H26N2°3 (462.55)

Calculated: C, 77.90; H, 5.67; N, 6.06;

Found: 77.79; 5.86; 5.97;

6-[3-(E-p-chlorocinnamoylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 173-174°C

<C>26<H>23<C1N>2°3 (446.93)

Calcd: C, 69.87; H, 5.19; N, 6.27;

Found: 69.68; 5.27; 6.05;

6-[3-(4-chlorobenzoylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid M.p.: 186°C

C24H21C1N2°3 (420.90)

Calcd: C, 68.49; H, 5.03; N, 6.66;

Found: 68.29; 5.14; 6.55;

6-[3-(3-chlorobenzoylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid M.p.: 173°C

C24H21C1N2°3 (420.90)

Calcd: C, 68.49; H, 5.03; N, 6.66;

Found: 68.33; 5.13; 6.73;

6-[3-(E-o-chlorocinnamoylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

Melting point: 199-200°C

C26H23C1N2°3 (446.93)

Calcd: C, 69.87; H, 5.19; N, 6.27;

Found: 69.67; 5.15; 6.29;

6-[3-(E-m-chlorocinnamoylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 187-188°C

C26H23C1N2°3 (446.93)

Calcd: C, 69.87; H, 5.19; N, 6.27;

Found: 69.67; 5.29; 6.26;

6-[3-(2-naphthoylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid M.p.: 207-208°C

C27H24N2°3 (424.50)

Calculated: C, 76.39; H, 5.70; N, 6.60;

Found: 76.53; 5.64; 6.47;

6-[3-(4-Methoxybenzoylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 168-170°C

C25<H>24N2°4 (416.48)

Calculated: C, 72.10; H, 5.81; N, 6.73;

Found: 71.99; 5.83; 6.80;

6-[3-(3-phenylpropionylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 157°C

C26<H>26N2°3 (414.50)

Calculated: C, 75.33; H, 6.32; N, 6.76;

Found: 75.34; 6.35; 6.91;

6-[3-(4-phenylbenzoylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid M.p.: 163-164°C

C30H26N2°3 (462.55)

Calculated: C, 77.90; H, 5.67; N, 6.06;

Found: 77.83; 5.50; 6.13;

(+)-5E-6-[3-(E-2-(4-chlorophenyl)-cyclopropyl-1-carboxamido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

Foam, Rp value 0 : 0.33 (kis r\elgel; methylene chloride/ethanol = 20:1) Rotation: [a]D = + 242 (c = 1.2; methanol)

<C>27<H>25C1N2°3 (460.96)

Calculated: C, 70.35; H, 5.47; N, 6.07;

Found: 70.28; 5.70; 5.83;

(-)-5E-6-[3-(E-2-(4-chlorophenyl)-cyclopropyl-1-carboxamido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

Foam, Rf value: 0.33 (silica gel; methylene chloride/ethanol = 20:1) Rotation: [a]-.20 = -243° (c = 1.2; methanol)

C27H25C1N2°3 (460.96)

Calculated: C, 70.35; H, 5.47; N, 6.07;

Found: 70.20; 5.67; 5.95;

(+)-5E-6-[3-(Z-2-(4-chlorophenyl)-cyclopropyl-1-carboxamido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 221-222°C

Rotation: [a]-,<20> = +87° (c = 1.2; dimethylformamide) C27H25C1N2°3 (460.96)

Calculated: C, 70.35; H, 5.47; N, 6.07;

Found: 70.38; 5.53; 5.96;

(-)-5E-6-[3-(Z-2-(4-chlorophenyl)-cyclopropyl-1-carboxamido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 220-221°C

Rotation: [a]D<20> = -87° (c = 1.2; dimethylformamide) C27H_5C1N203 (460.96)

Calculated: C, 70.35; H, 5.47; N, 6.07;

Found: 70.21; 5.48; 6.07;

6-[3-(E-2-(4-bromophenyl)-cyclopropyl-1-carboxamido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 165-168°C

C27H25BrN2°3 (505'4D

Calculated: C, 64.17; H, 4.99; N, 5.54;

Found: 64.00; 5.10; 5.69;

6-[3-(1-(4-chlorophenyl)-cyclopropylcarboxamido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 149-150°C

C27<H>25<C>1N2°3 (460.96)

Calculated: C, 70.35; H, 5.47; N, 6.07;

Found: 70.19; 5.59; 6.11;

6-[3-(3-(4-chlorophenyl)-propionylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 163°C

C26H25C1N2°3 (448.95)

Calcd: C, 69.56; H, 5.61; N, 6.24;

Found: 69.56; 5.64; 6.40;

6-[3-(4-chlorophenylacetylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 192-193°C

C25H23C1N2°3 (434.92)

Calculated: C, 69.04; H, 5.33; N, 6.44;

Found: 68.87; 5.37; 6.48: 6-[3-(4-phenylbutanoylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid M.p.: 116-177°C

<C>27H28N2°3 («8.53)

Calculated: C, 75.68; H, 5.59; N, 6.54;

Found: 75.69; 5.70; 6.42;

6-[3-(4-phenylpropionylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 159-160°C

C26H22N2°3 (410.47)

Calculated: C, 76.08; H, 5.40; N, 6.83;

Found: 75.96; 5.50; 7.03;

6-[3-(Z-2-(4-bromophenyl)-cyclopropyl-1-carboxamido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 204-205°C

<C>27<H>25BrN2°3 (505'4D

Calculated: C, 64.17; H, 4.99; N, 5.54;

Found: 64.00; 5.01; 5.63;

6-[3-(4-chlorophenylsulfonylaminoacetylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 110-112°C

C25H24C1N3°5S (514.00)

Calculated: C, 58.42; H, 4.71; N, 8.18;

Found: 58.30; 4.81; 8.05;

6-[3-(3,3-diphenylpropionylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

Foam, Rf value: 0.30 (silica gel; methylene chloride/ethanol = 20:1) <C>32H30N2°3 (490.60)

Calculated: C, 78.34; H, 6.16; N, 5.71;

Found: 78.21; 6.29; 5.67;

6-[3-(E-3,3-dichloro-2-(4-chlorophenyl)-cyclopropyl-1-carboxamido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 65°C

C27H23C13N2°3 (529<85)

Calculated: C, 61.21; H, 4.38; N, 5.29;

Found: 61.04; 4.54; 5.05;

6-[3-(N-methyl-E-o-chlorocinnamoylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

Melting point: 128-130°C

C27H25C1N2°3 (460.96)

Calculated: C, 70.35; H, 5.47; N, 6.08;

Found: 70.32; 5.43; 6.10;

6-[3-(N-methyl-3-(4-chlorophenyl)-propionylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

Oil, Rf value: 0.73 (silica gel; methylene chloride/ethanol = 9:1) C27H27C1N2°3 (462.98)

Calculated: C, 70.05; H, 5.88; N, 6.05;

Found: 69.88; 5.99; 5.88;

6-[3-(N-methyl-3-(2-chlorophenyl)-propionylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 122-124°C

C27H27C1N2°3 (462.98)

Calculated: C, 70.05; H, 5.88; N, 6.05;

Found: 69.85; 5.73; 6.04;

6-[3-(N-methyl-3,3-diphenylpropionylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

Foam, Rf value: 0.46 (silica gel; methylene chloride/ethanol = 20:1) C33H32N2°3 (504.63)

Calcd: C, 78.55; H, 6.39; N, 5.55;

Found: 78.43; 6.49; 5.48;

6-[3-(N-methyl-3-(4-methoxyphenyl)-propionylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 135°C

C28H30N2°4 (458.56)

Calculated: C, 73.34; H, 6.59; N, 6.11;

Found: 73.20; 6.70; 6.17;

6-[3-(N-methyl-3-phenylpropionylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 123-125°C

C27H2<4N>2°3 (424.50)

Calculated: C, 76.40; H, 5.70; N, 6.60;

Found: 76.30; 5.73; 6.88;

7- [3-(E-2-(4-chlorophenyl)-cyclopropyl-1-carboxamido)-phenyl]-7-(3-pyridyl)-hept-6-enoic acid

Foam, R^ value: 0.15 (silica gel; methylene chloride/acetone = 9:1) C28H27C1N2°3 (474.99)

Calculated: C, 70.80; H, 5.73; N, 5.90;

Found: 70.64; 5.87; 6.00;

7-[3-(3-(4-chlorophenyl)-propionylamino)-phenyl]-7-(3-pyridyl)-hept-6-enoic acid

Foam, Rf value: 0.20 (silica gel; ethyl acetate) C27H27C1N2°3 (462.98)

Calculated: C, 70.05; H, 5.88; N, 6.05;

Found: 69.90; 5.90; 6.06;

5-[3-(E-2-(4-chlorophenyl)-cyclopropyl-1-carboxamido)-phenyl]-5-(3-pyridyl)-pent-4-enoic acid

Foam, Rf value: 0.22 (silica gel; methylene chloride/ethanol = 19:1) C26H25C1N2°3 (448.95)

Calcd: C, 69.56; H, 5.61; N, 6.24;

Found: 69.37; 5.35; 6.22;

5- [3-(3-(4-chlorophenyl)-propionylamino)-phenyl]-5-(3-pyridyl)-pent-4-enoic acid

M.p.: 200-201°C

C25H23C1N2°3 (434.92)

Calculated: C, 69.04; H, 5.33; N, 6.44;

Found: 68.86; 5.39; 6.42;

Example 6

6-[3-(4-chlorophenoxyacetylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

2.25 g of 6-(3-aminophenyl)-6-(3-pyridyl)-hex-5-enoic acid methyl ester are dissolved in 30 ml of methylene chloride. 1.65 g of 4-chlorophenoxyacetic acid chloride and then 2.5 ml of triethylamine are added to the solution at 0°C and stirred for 2 hours at room temperature. The reaction mixture is washed with water and evaporated. The residue is dissolved in a mixture of 20 ml of ethanol and 16 ml of 0.5N caustic soda and stirred for 24 hours at room temperature. The reaction mixture is evaporated at room temperature, water is added and washed with ethyl acetate. The aqueous phase is neutralized by adding citric acid and extracted with acetic acid ethyl ester. The organic phase is washed with water, dried and evaporated, after which the residue is recrystallized from acetic acid ethyl ester/diisopropyl ether.

Yield: 49% of the theoretical

M.p.: 178-179°C

C25H23C1N2°4 (450'92)

Calcd: C, 66.59; H, 5.14; N, 6.21;

Found: 66.48; 5.29; 5.99;

Analogous to Example 6, the following compounds are obtained: 6-[3-(2-(4-chlorophenoxy)-isobutyroylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 92°C

C_7H27C1N204 (478.98)

Calculated: C, 67.71; H, 5.68; N, 5.85;

Found: 67.56; 5.79; 5.67;

6-[3-(2-chlorophenoxyacetylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 134-136°C

C25H23C1N2°4 (450<92)

Calcd: C, 66.59; H, 5.14; N, 6.21;

Found: 66.51; 5.13; 6.16;

6-[3-(2,4-dichlorophenoxyacetylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

Melting point: 148-150°C

C25H22C12N2°4 <485'37>

Calculated: C, 61.87; H, 4.57; N, 5.77;

Found: 61.74; 4.45; 5.81;

6-[3-(N-methyl-2-chlorophenoxyacetylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 118-119°C

C26H25C1N2°4 (464'95)

Calculated: C, 67.17; H, 5.42; N, 6.02;

Found: 66.99; 5.46; 5.99;

6-[3-(N-methyl-(2-chlorophenoxy)-isobutyroylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

Foam, Rf value: 0.45 (silica gel; methylene chloride/ethanol = 20:1) C28<H>29<C>1N2°4 (493.00)

Calculated: C, 68.22; H, 5.93; N, 5.68;

Found: 68.10; 6.09; 5.65;

6-[3-(N-methyl-4-chlorophenoxyacetylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 128-132°C

C26<H>25<C>1N2°4 (464.95)

Calculated: C, 67.17; H, 5.42; N, 6.02;

Found: 67.26; 5.32; 6.13;

6-[3-(N-methyl-2,4-dichlorophenoxyacetylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 146°C

<C>26<H>24C12N2°4 (499.40)

Calculated: C, 62.53; H, 4.84; N, 5.61;

Found: 62.47; 4.90; 5.40;

Example 7

6-[3-(N-methyl-3-(3-indolyl)-propionylamino)-phenyl]-6-(3-pyridyl)- hex- 5-enoic acid

A mixture of 1.9 g of 3-(3-indolyl)-propionic acid, 2.3 g of 6-(3-methylaminophenyl)-6-(3-pyridyl)-hex-5-enoic acid methyl ester and 1.8 g of carbonyldiimidazole is boiled under reflux in 50 ml of tetrahydrofuran for 48 hours. The reaction mixture is evaporated, after which the residue is taken up in water and extracted with acetic acid ethyl ester. The organic phase is evaporated and the residue is hydrolysed in a mixture of 20 ml of ethanol and 6 ml of 4N caustic soda for 30 minutes at 50°C. The reaction mixture is neutralized by adding citric acid and extracted with acetic acid ethyl ester. The organic phase is evaporated and the residue is recrystallized from acetic acid ethyl ester/diisopropyl ether.

Yield: 25% of the theoretical

M.p.: 142-144°C

<C>29<H>29N3°3 («7f57)

Calculated: C, 74.50; H, 6.25; N, 8.99;

Found: 74.32; 6.23; 8.85;

Example 8

6-[3-(3-(4-chlorophenyl)-ureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

2.4 g of 6-(3-aminophenyl)-6-(3-pyridyl)-hex-5-enoic acid methyl ester and 1.5 g of 4-chlorophenyl isocyanate are stirred in 50 ml of tetrahydrofuran for 1 hour at room temperature. The reaction mixture is evaporated, the residue is added to water and extracted with ethyl acetate/ethanol (9:1). The organic phase is evaporated, after which the residue is hydrolysed in 60 ml of ethanol and 6 ml of 4N caustic soda for 1 hour at 50°C. The reaction mixture is evaporated, the residue is taken up in 100 ml of water and extracted with ethyl acetate. The aqueous phase is neutralized by adding citric acid, whereby the product is precipitated. The precipitate is suctioned off, washed with water and diisopropyl ether and recrystallized from acetic acid ethyl ester/diisopropyl ether.

Yield: 52% of the theoretical

M.p.: 172-173°C

C24H22C1N3°3 («5.91)

Calculated: C, 66.13; H, 5.09; N, 9.64;

Found. 66.04; 5.22; 9.71;

Analogous to Example 8, the following compounds are obtained: 6-[3-(3-(3-chlorophenyl)-ureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 151-152°C

C24H22C1N3°3 («5.9D

Calculated: C, 66.13; H, 5.09; N, 9.64;

Found: 66.05; 5.18; 9.52;

6-[3-(3-(2,5-dimethylphenyl)-ureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

Mp.: 13 7°C (decomp.)

<C>26<H>27N3°3 (429.52)

Calculated: C, 72.71; H, 6.34; N, 9.78;

Found: 72.58; 6.35; 9.75;

6-[3-(3-(2-chlorophenyl)-ureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 170-172°C

C24H22C1N3°3 (435'9D

Calculated: C, 66.13; H, 5.09; N, 9.64;

Found: 66.03; 5.22; 9.45;

6-[3-(3-(1-naphthyl)-ureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid M.p.: 173°C

C28<H>25N3°3 (451'53)

Calculated: C, 74.48; H, 5.58; N, 9.31;

Found: 74.32; 5.53; 9.16;

6-[3-(3-(3,4-dichlorophenyl)-ureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 178°C

C24H21C12N3°4 (470.36)

Calculated: C, 61.29; H, 4.50; N, 8.93;

Found: 61.24; 4.61; 9,10;

6-[3-(3-(2,4-dichlorophenyl)-ureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 126°C

C24H21C12N3°3 (470'36)

Calculated: C, 61.29; H, 4.50; N, 8.93;

Found: 61.01; 4.69; 8.99;

6-[3-(3-(2,3-Dichlorophenyl)-ureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 196°C

<C>24<H>21<C>12N3°3 (470.36)

Calculated: C, 61.29; H, 4.50; N, 8.93;

Found: 61.14; 4.66; 8.82;

6-[3-(3-(3-nitrophenyl)-ureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 207-208°C

<C>24<H>22N4°5 (446.47)

Calculated: C, 64.57; H, 4.97; N, 12.55;

Found: 64.58; 4.97; 12.36;

6-[3-(3-(4-carboxyphenyl)-ureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: from 118°C (decomp.)

C25<H>23N3°5 (445.48)

Calculated: C, 67.41; H, 5.20; N, 9.43;

Found: 67.27; 5.17; 9.21;

6-[3-(3-benzylureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid M.p.: 166-168°C

C25H25N3°3 (415.49)

Calculated: C, 72.27; H, 6.06; N, 10.11;

Found: 72.10; 6.07; 9.91;

6-[3-(3-(4-tert-butylphenyl)-ureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 180-182°C

C28H31N3°3 (457.57)

Calculated: C, 73.50; H, 6.83; N, 9.18;

Found: 73.38; 6.78; 9.20;

6-[3-(3-benzoylureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid M.p.: 190-191°C

C25H<23N>3°4 (429.48)

Calcd: C, 69.92; H, 5.40; N, 9.78;

Found: 69.72; 5.34; 9.58;

6-[3-(3-(4-methylbenzenesulfonyl)-ureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 183°C (decomp.)

<C>25<H>25N3°5S (479.56)

Calculated: C, 62.62; H, 5.25; N, 8.76;

Found: 62.80; 5.41; 8.68;

6-[3-(3-cyclohexylureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid M.p.: 163-164°C

C24<H>29N3°3 (407.51)

Calculated: C, 70.74; H, 7.17; N, 10.31;

Found: 70.66; 7.36; 10.38;

6-[3-(3-(tert-butyl)-ureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

Reaction in a mixture of tetrahydrofuran, dimethylformamide and 4-dimethylaminopyridine under heating.

M.p.: 165°C

<C>22<H>27N3°3 (381.48)

Calculated: C, 69.27; H, 7.13; N, 11.02;

Found: 69.24; 7.05; 10.95;

6-[3-(3-(2,4-dichlorophenyl)-1-methylureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 139-141°C

C25<H>23C12N3°3 (484.38)

Calculated: C, 61.99; H, 4.79; N, 8.68;

Found: 61.86; 4.91; 8.58;

6-[3-(3-(4-carboxyphenyl)-1-methylureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

Purification by column chromatography on silica gel with methylene chloride/ethanol (30:1)

Foam, R^ value: 0.52 (silica gel; methylene chloride/ethanol = 20:1) <C>26H25N3°5 (459.50)

Calcd: C, 67.96; H, 5.48; N, 9.14;

Found: 67.88; 5.56; 8.96;

6-[4-(3-(3-chlorophenyl)-ureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 175-176°C

C24H22C1N3°3 (435.91)

Calculated: C, 66.13; H, 5.09; N, 9.64;

Found: 65.99; 5.14; 9.58;

6-[4-(3-(2,4-dichlorophenyl)-1-methylureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 150-152°C

C25H23C12N3°3 (484.38)

Calculated: C, 61.99; H, 4.79; N, 8.67;

Found: 61.88; 4.78; 8.49;

6-[4-(3-(4-methylbenzenesulfonyl)-ureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 176°C (decomp.)

C25H25N3°5S (479.55)

Calculated: C, 62.62; H, 5.25; N, 8.76;

Found: 62.59; 5.38; 8.48;

5-[3-(3-(3-chlorophenyl)-ureido)-phenyl]-5-(3-pyridyl)-pent-4-enoic acid

Purification by column chromatography on silica gel with methylene chloride/ethanol (9:1)

Foam, Rf value: 0.25 (silica gel; methylene chloride/ethanol = 19:1)

C23H20C1N3°3 (421.88)

Calcd: C, 65.48; H, 4.78; N, 9.96;

Found: 65.23; 4.87; 9.66;

7-[3-(3-(3-chlorophenyl)-ureido)-phenyl]-7-(3-pyridyl)-hept-6-enoic acid

M.p.: 140-141°C

C25H24C1N3°3 (449.94)

Calcd: C, 66.74; H, 5.38; N, 9.34;

Found: 66.63; 5.34; 9.25;

Example 9

6-[ 4-( 3, 3- diphenylureido)- phenyl]- 6-( 3- pyridyl)- hex- 5- enoic acid

A mixture of 2.4 g of 6-(4-aminophenyl)-6-(3-pyridyl)-hex-5-enoic acid methyl ester and 2.1 g of N,N-diphenylcarbamoyl chloride is stirred in 25 ml of pyridine for 18 hours at room temperature. The solvent is evaporated, after which the residue is taken up in acetic acid ethyl ester. The organic phase is washed with water, dried and evaporated. The residue is hydrolysed in a mixture of 20 ml of ethanol and 6 ml of 4N caustic soda for 30 minutes at 50°C. The reaction solution is diluted with water and extracted with ethyl acetate. The aqueous phase is then neutralized by adding citric acid, after which the formed precipitate is sucked off and recrystallized from ethyl acetate/isopropanol.

Yield: 55% of the theoretical

M.p.: 155-156°C

<C>30<H>27<N>3°3 (477.56)

Calculated: C, 75.45; H, 5.70; N, 8.80;

Found: 75.28; 5.89; 8.68;

Analogous to Example 9, the following compounds are obtained: 6-[4-(3-methyl-3-phenylureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 118-120°C

<C>25H25N3°3 (415.29)

Calculated: C, 72.27; H, 6.07; N, 10.11;

Found: 72.19; 6.16; 10.00;

6-[4-(1,3-dimethyl-3-phenylureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

Resin, R^ value: 0.60 (silica gel; methylene chloride/ethanol =

20:1)

<C>26<H>27N3°3 («9.52)

Calculated: C, 72.71; H, 6.34; N, 9.78;

Found: 72.55; 6.44; 9.54;

6-[3-(1,3-dimethyl-3-phenylureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

Resin, Rf value: 0.40 (silica gel; methylene chloride/ethanol =

20:1)

C26<H>27N3°3 (429.52)

Calculated: C, 72.71; H, 6.34; N, 9.78;

Found: 72.53; 6.34; 9.59;

Example 10

6-[3-(3-(4-chlorophenyl)-thioureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

2.4 g of 6-(3-aminophenyl)-6-(3-pyridyl)-hex-5-enoic acid methyl ester and 1.7 g of 4-chlorophenyl isothiocyanate are stirred in 30 ml of tetrahydrofuran for 1.5 hours at room temperature. The solvent is evaporated, after which the residue is taken up in water and extracted with ethyl acetate. The organic phase is evaporated and the residue is hydrolysed in a mixture of 20 ml of ethanol and 6 ml of 4N caustic soda for 90 minutes at room temperature. The reaction mixture is diluted with water, extracted with ethyl acetate and then neutralized by adding citric acid. The aqueous phase is extracted with acetic acid ethyl ester. The organic phase is evaporated and the residue is purified over a silica gel column with

methylene chloride/ethanol (20:1).

Yield: 64% of the theoretical

Foam, Rf value: 0.31 (silica gel; methylene chloride/acetone = 2:1) C_4H22C1N302S (451.98)

Calculated: C, 63.78; H, 4.91; N, 9.30;

Found: 63.62; 5.03; 9.11;

Analogously to Example 10, the following compounds are obtained: 6-[3-(3-(3-chlorophenyl)-thioureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 142-144°C (ethyl acetate/tert-butyl methyl ether) C24H22C1N3°2<S> (451'98>

Calculated: C, 63.78; H, 4.91; N, 9.30;

Found: 63.69; 5.11; 9,10;

6-[3-(3-(2-chlorophenyl)-thioureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 146-148°C (isopropanol/diisopropyl ether)

C24H22C1N3°2S (451.98)

Calculated: C, 63.78; H, 4.91; N, 9.30;

Found: 63.87; 5.06; 9,10;

6-[3-(3-(2,4-dichlorophenyl)-thioureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 154-155°C (ethyl acetate/diisopropyl ether) C24H21C12N302S (486.41)

Calculated: C, 59.26; H, 4.35; N, 8.64;

Found: 59.18; 4.53; 8.37;

6-[3-(3-(4-methylphenyl)-thioureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 137°C (ethyl acetate/tert-butyl methyl ether) C25H25N3°2S (431.56)

Calcd: C, 69.58; H, 5.84; N, 9.74;

Found: 69.38; 5.92; 9.59;

6-[3-(3-(4-nitrophenyl)-thioureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

M.p.: 139°C (isopropanol/dioxane)

C_4H22N404S (462.53)

Calculated: C, 62.23; H, 4.79; N, 12.11;

Found: 62.08; 4.88; 12.00;

6-[3-(3-(tert-butyl)-thioureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

Reaction in a mixture of tetrahydrofuran, dimethylformamide and 4-dimethylaminopyridine under heating.

M.p.: 137-139°C

C22H27N3°2S <397'54>

Calculated: C, 66.47; H, 6.85; N, 10.57;

Found: 66.49; 6.95; 10.48;

6-[3-(3-(2,4-dichlorophenyl)-1-methylthioureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

mp: 124-126°C (ethyl acetate/diisopropyl ether) C25H23C12N3°2S (500.44)

Calculated: C, 60.00; H, 4.63; N, 8.40;

Found: 59.95; 4.82; 8.25;

6-[4-(3-(2,4-dichlorophenyl)-1-methylthioureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid

mp: 127-129°C (ethyl acetate/petroleum ether) C25H23C12N3°2S (500.44)

Calculated: C, 60.00; H, 4.63; N, 8.40;

Found: 59.87; 4.50; 8.56;

Example 11

6-[3-(N-methyl-2-hydroxy-2-phenylacetylamino)-phenyl]-6-(3-pyridyl)- hex- 5-enoic acid

4.66 g of 6-(3-methylaminophenyl)-6-(3-pyridyl)-hex-5-enoic acid methyl ester, 3.2 g of DL-O-acetylmandelic acid chloride and 3.5 ml of triethylamine are stirred in 50 ml of methylene chloride for 1 hour at room temperature. The reaction mixture is washed with water and evaporated.

The residue is hydrolysed in a mixture of 30 ml of ethanol and 10 ml of 4N caustic soda for 30 minutes at 50°C. The reaction mixture is neutralized by adding citric acid and extracted with acetic acid ethyl ester. The organic phase is washed with water and evaporated, after which the residue is purified over a silica gel column with ethyl acetate.

Yield: 69% of the theoretical

Foam, Rf value: 0.38 (silica gel; methylene chloride/acetone = 20:1) <C>26<H>26N2°4 (430.50)

Calculated: C, 72.54; H, 6.09; N, 6.51;

Found: 72.34; 6.09; 6.52;

Example 12

6-[4-(4-methylbenzenesulfonylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid methyl ester 3 g 6-(4-aminophenyl)-6-(3-pyridyl)-hex-5-enoic acid methyl ester , 1.9 g of tosyl chloride and 5 ml of triethylamine are stirred in 100 ml of methylene chloride for 1 hour at room temperature. The reaction mixture is washed with water, dried and evaporated. The residue is purified over a silica gel column with acetic acid ethyl ester.

Yield: 78% of the theoretical

Oil, Rf value: 0.74 (silica gel; ethyl acetate) <C>25<H>26N2°4S (450.56)

Calculated: C, 66.65; H, 5.82; N, 6.22;

Found: 66.53; 5.89; 6.08;

Claims (3)

1. Analogous method for the preparation of therapeutically active pyridyl derivatives of the general formula where n is the number 2, 3 or 4, X is a carbonyl, thiocarbonyl or sulfonyl group, R1 is an optionally phenyl-substituted alkyl group with 1 to 4 carbon atoms, a cycloalkyl group with 5 to 7 carbon atoms, a phenyl group, or if A does not form a bond, also a benzoyl or benzenesulfonyl group, where the phenyl nucleus may be mono-, di- or tri-substituted with fluorine, chlorine or bromine atoms, or with alkoxy or alkyl groups with 1 to 4 carbon atoms, and where the substituents may be the same or different and one of the substituents may also constitute a trifluoromethyl, carboxyl, amino or nitro group, a naphthyl , biphenylyl, diphenylmethyl, indolyl, thienyl, chlorothienyl or bromothienyl group, R2 is a hydrogen atom or an alkyl group with 1 to 4 carbon atoms, R 3 is a pyridyl group, R4 and R5 each constitute a hydrogen atom or together an additional carbon-carbon bond, Rg is a hydroxy or alkoxy group with 1 to 3 carbon atoms, and A is a bond, a cycloalkylene or cycloalkylidene group, each with 3 or 4 carbon atoms, in which a methylene group may be replaced by a dichloromethylene group, a straight-chain optionally mono- or polyunsaturated alkylene group with 2 or 3 carbon atoms, a -R-CRg-, - O-R-CRg or -NRg group, wherein R7 is a hydrogen atom, a hydroxy, phenyl or alkyl group of 1 to 3 carbon atoms, Rg is a hydrogen atom or an alkyl group of 1 to 3 carbon atoms and Rg is a hydrogen atom, an alkyl group with 1 to 3 carbon atoms or a phenyl group, their enantiomers, their cis- and trans-isomers if R4 and R5 together form a carbon-carbon bond, and their addition salts, characterized in that a) a compound with the general formula where R2 to Rg and n are as defined above, acylated with a compound of the general formula R_ - A - X - Z1 (III) where R1 is defined as above and Z1 is a nucleophilic leaving group or also if A constitutes a -NRg group and X constitutes a carbonyl or thiocarbonyl group, together with Rg constitutes an additional carbon-nitrogen bond, or b) for the preparation of compounds of the general formula I, where Rg constitutes a hydroxy group, a protecting residue is cleaved from a compound with the general formula where R^ to R^, A, X and n are as defined above and Z2 constitutes a hydrolytically, thermolytically or hydrogenolytically cleavable protecting group for a carboxy group, or a functional derivative of the carboxy group, or c) for the preparation of compounds of the general formula I , where R4 and R5 each constitute a hydrogen atom: a compound with the general formula where R1 to R3, Rg, A, X and n are as defined above, hydrogenated, or d) for the preparation of compounds of the general formula I, where R. and Rj. together form a carbon-carbon bond: a compound of the general formula where R1 to R3, A and X are as defined above, is reacted with a compound of the general formula where Rg and n are as defined above and W means a triphenylphosphonium halide- , dialkylphosphonic acid or magnesium halide residue, and then optionally dehydrated, and a thus obtained compound of formula I, where R2 constitutes a hydrogen atom, by alkylation is optionally transferred into a corresponding compound of formula I, where R2 constitutes an alkyl group, or a thus obtained compound with formula I, where Rg constitutes a hydroxy group, by esterification is transferred into a corresponding compound of formula I, where Rg constitutes an alkoxy, amino, alkylamino or dialkylamino group, or a thus obtained compound of formula I, where R4 and R5 together constitute a carbon-carbon bond, splits into its cis and trans isomers, or a thus obtained compound of formula I, is split into its enantiomers, or a thus obtained compound of formula I is transferred in its addition salts, especially in its physiologically acceptable addition salts with inorganic or organic bases. 2. Process according to claim 1 for the preparation of the compounds: (-)-5E-6-[4-(Z-2-(4-chlorophenyl)-cyclopropyl-1-carboxamido)-phenyl]-6-(3-pyridyl) -hex-5-enoic acid 5E-6-[3-(3-(4-chlorophenyl)-propionylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid 5E-6-[3-(3 -(4-chlorophenyl)-thioureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid and 5E-6-[3-(3-(2,4-dichlorophenyl)-1-methylthioureido)- phenyl]-6-(3-pyridyl)-hex-5-enoic acid, their cis- and trans-isomers and their addition salts, characterized using corresponding starting materials. 3. Process according to claim 1 for the preparation of the compound (-)-5E-6-[4-(Z-2-(4-chlorophenyl)-cyclopropyl-1-carboxamido)-phenyl]-6-(3-pyridyl )-hex-5-enoic acid, its cis- and trans-isomers and its addition salts, characterized by the use of corresponding starting materials.