CA2055950A1

CA2055950A1 - Pyridyl derivatives, pharmaceutical compositions containing these compounds and processes for preparing them

Info

Publication number: CA2055950A1
Application number: CA002055950A
Authority: CA
Inventors: Rainer Soyka; Wolfgang Eisert; Thomas Muller; Johannes Weisenberger
Original assignee: Individual
Current assignee: Boehringer Ingelheim Pharma GmbH and Co KG
Priority date: 1990-11-22
Filing date: 1991-11-21
Publication date: 1992-05-23
Also published as: HU213676B; IL100097A0; AU8796491A; EP0487095B1; DK0487095T3; NZ240677A; HUT60472A; FI915484A0; NO175634C; PT99571B; ES2084756T3; DE59107462D1; AU640063B2; IL100097A; GR3019783T3; IE914048A1; EP0487095A1; IE74248B1; NO914567D0; PT99571A

Abstract

Abstract Pyridyl Derivatives This invention relates to new pyridyl derivatives of formula I

( I)

Description

2~S5~56~

573~6.539 P~ridyl Derivatives The present invention is concerned with new pyridyl derivatives, the isomers and addition salts thereof.

The compounds according to the invention have valuable pharmacological properties, especially antithrombotic effects. The new compounds are also thromboxane antagonists (T~A) and thromboxane synthesis inhibitors (TSH) and thus also inhibit the effects mediated by thromboxane. Moreover, they also have an effect on PGE2-pxoduction in the lungs and on PGD2-, PGE2 and PGF2~-production in human thrombocytes.

Viewed from one aspect, the present invention provides compounds of formula I

R~ ~

Rl-A-X ~ Rs (I) R3 (cH2)n-co-R6 (wherein n represents an integer 2, 3 or 4;

X represents a carbonyl, thiocarbonyl or sulphonyl group;

R1 represents an opt.ionally phenyl-substituted Cl4-alkyl group, a C47-cycloalkyl group, a naphthyl, biphenylyl, d~phenylmethyl, indolyl, thienyl, chlorothienyl or 5g5~

bromothienyl group, or R1 may represent a phenyl group or, where A does not represent a bond, ~1 may represent a henzoyl or benzenesulphonyl group wherein each phenyl moiety may be substituted by a fluorine, chlorine or bromine atom or by a C14-alkoxy, C14-alkyl, trifluoromethyl, carboxyl, amino or nitro group, and each phenyl moiety may optionally be further substituted by one or two fluorine, chlorine or bromine atoms or by C14 alkyl or C14 alkoxy groups, wherein each substituent may be the same or different;

R2 represents a hydrogen atom or a C14-alkyl group;

R3 represents a pyridyl group;

R4 and R5 each represent a hydrogen atom or R4 and R5 together represent a carbon-carbon bond;

R6 represents a hydroxy or C13-alkoxy group; and A represents a bond, a C34-cycloalkylene or C34-cycloalkylidene group wherein a methylene group may be dichlorinated or A represents a straight-chained, optionally mono- or poly-unsaturated C23-alkylene or oxy-C23-alkylene group, an -R7CR8-, -O-R7CR8-, -NR9--, or -XNR9- group;

(wherein R7 represents a hydrogen atom, a hydroxy, phenyl or C13-alkyl group;

R8 represents a hydrogen atom or a Cl3-alkyl group; and R9 represents a hydrogen atom, or a C14 alkyl or phenyl group)), and 21C5S5~

the isomers and addition salts thereof.

As examples of the definitions of the groups mentioned hereinbefore, R~ may represent, for example, a methyl, ethyl, n~propyl, isopropyl, n-butyl, tert.butyl, benzyl, 2-phenylethyl, 3-phenylpropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzoyl, benzenesulphonyl, fluorophenyl, fluoroben~oyl, fluorobenzenesulphonyl, chlorophenyl, chlorobenzoyl, chlorobenzenesulphonyl, bromophenyl, bromobenzoyl, bromobenzenesulphonyl, methylphenyl, methylbenzoyl, methylbenzenesulphonyl, ethylphenyl, ethylbenzoyl, ethylbenzenesulphonyl, n-propylphenyl, n-propylbenzoyl, n-propylbenzenesulphonyl, isopropylphenyl, isopropylbenzoyl, isopropylbenzene-sulphonyl, n-butylphenyl, n-butylbenzoyl, n-butylbenzenesulphonyl, isobutylphenyl, isobutylbenzoyl, isobutylbenzenesulphonyl, tert.butylphenyl, tert.butyl-benzoyl, tert.butylbenzenesulphonyl, trifluoromethyl-phenyl, trifluoromethylbenzoyl, trifluoromethylbenzene-sulphonyl, nitrophenyl, nitrobenzoyl, nitrobenzene-sulphonyl, aminophenyl, aminobenzoyl, aminobenzene-sulphonyl, carboxyphenyl, carboxybenzoyl, carboxybenzenesulphonyl, methoxyphenyl, methoxybenzoyl, methoxybenzenesulphonyl, ethoxyphenyl, ethoxybenzoyl, ethoxybenzenesulphonyl, isopropoxyphenyl, isopropoxy-benæoyl, isopropoxybenzenesulphonyl, difluorophenyl, difluorobenzoyl, difluorobenzenesulphonyl, dichloro-phenyl, dichlorob~nzoyl, dichlorobenzenesulphonyl, dimethylphenyl, dimethylbenzoyl, dimethylbenzene-sulphonyl, dimethoxyphenyl, dimethoxybenzoyl, dimethoxybenzenesulphonyl, trimethylphenyl, trimethyl-benzoyl, trimethylbenzenesulphonyl, trimethoxyphenyl, trimethoxybenzoyl, trimethoxybenzenesulphonyl, chloro-methylphenyl, chloro-methylbenzoyl, chloro-methylbenzenesulphonyl, chloro-methoxyphenyl, chloro-i59~

methoxybenzoyl, chloro-methoxybenzenesulphonyl, m~thoxy-methylphenyl, methoxy-methylbenzoyl, methoxy-methylbenzenesulphonyl, amino~dichlorophenyl, amino-dichlorobenzoyl, amino-dichlorobenzenesulphonyl, amino-dibromophenyl, amino-dibromobenzoyl, amino--dibromoben~enesulphonyl, naphthyl, biphenyl, biphenylmethyl, indolyl, thienyl, chlorothienyl or bromothienyl group, R2 may represent a hydrogen atom, a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert.-butyl group, R3 may represent a (2)-pyridyl, (3j-pyridyl or (4)-pyridyl group, R6 may represent a hydroxy, methoxy, ethoxy, n-propoxy or isopropoxy group and the -A-X- group may be a carbonyl, methylenecarbonyl, ethylenecarbonyl, n-propylenecarbonyl, ethenylene-carbonyl, ethynylenecarbonyl, sulphonyl, methylene-sulphonyl, ethylenesulphonyl, n~propylenesulphonyl, 1,1-cyclopro~ylenecarbonyl, 1,2-cyclopropylenecarbonyl, 3,3-dichloro-1,1-cyclopropylenecarbonyl, 3,3-dichloro-1,2-cyclopropylenecarbonyl, 1,1-cyclobutylenecarbonyl, 1,2-cyclobutylenecarbonyl, carbonyl-1,2-cyclopropylene carbonyl, carbonyl-1,2-cyclobutylene-carbonyl, oxymethylenecarbonyl, oxy-methylmethylenecarbonyl, oxy-dimethylmethylenecarbonyl, oxy-n-ethylenecarbonyl, oxy-n-propylenecarbonyl, hydroxymethylenecarbonyl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, isobutylaminocarbonyl, phenylamino-carbonyl, aminothiocarbonyl, carbonylaminocarbonyl or sulphonylaminocarbonyl group, whilst the latter carbonyl or sulphonyl yroup is in each case connected to the -NR2 ~5~5~

group.

Preferred compounds according to the invention include those of formula I those wherein n represents an integer 2, 3 or 4;

.
X represents a carbonyl, thiocarbonyl or sulphonyl group;
,~' R1 represents a ph~nyl group or, where A does not represent a bond, R1 may also represent a benzoyl or benzenesulphonyl group wherein each phenyl moiety is optionally substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, phenyl, methoxy, carboxy or nitro group or by a C1~-alkyl group, o:r each phenyl moiety is optionally di-substituted by chlorine or bromine atoms or by methyl groups, wherein each substituent may be the same or different, or, R1 may also represent a cyclohexyl, benzyl, 4-amino-3,5-dichlorophenyl, 4-amino-3,5-dibromophenyl, naphthyl, diphenylmethyl, indolyl, th.ienyl, chlorothienyl or bromothienyl group;

R2 represents a hydrogen atom or a C13-alky~ group;

R3 represents a pyridyl group;

R4 and Rs each represent a hydrogen atom or R4 and R5 together represent a carbon-carbon bond;

R6 represents a hydroxy or C13-alkoxy group; and A represents a bond, a cyclopropylene or - 6 ~
cyclopropylidene group wherein a methylene group may be dichlorinated or A represents an optionally unsaturated ethylene group, or an -R7C~a~, -O-R7CR8 or -NR9- group (wherein R~ represents a hydrogen atom, a hydroxy or a C12-alkyl group;

R~ represents a hydrogen atom or a C12-alkyl group; and R~ represents a hydrogen atom, a C~ 3 alkyl group or a phenyl group), the isomers and addition salts thereof.

Especially preferred compounds accordiny to the invention include those of formula I

wherein n represents an integer 2, 3 or 4;

X represents a carbonyl, thiocarbonyl or sulphonyl group;

R1 represents a phenyl group optionally mono-substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, phenyl, methoxy, carboxy or nitro group or by a C14-alkyl group, or R1 represents a phenyl group di-substituted by chlorine or bromine atoms or methyl groups wherein each substituent may be the same or different, or R1 may represent a benzyl, 4-amino-3,5-dichlorophenyl, naphthyl or chlorothienyl group;

- 7 ~5~35~
R2 represents a hydrogen atom or a methyl group;

R3 represents a 3-pyridyl group;

R4 and R5 each represent a hydrogen atom ox R4 and F~
together represent a carbon-carbon bond;

R6 represents a hydroxy group; and A represents a bond, a cyclopropylene or cyclopropylidene group, an optionally unsaturated ethylene group or an -R7CR8-, -O-R7CR8- or -NR9- group .
: (wherein :`
R7 represents a hydrogen atom or a hydroxy or methyl group;

R8 represents a hydrogen atom or a methyl group; and :~:
~; F~ represents a hydrogen atom or a methyl or phenyl group), the isomers and addition salts thereof.

The most preferred compounds of formula I according to the present invention include: ~

(-)-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-C3-(3-(4-chlorophenyl)-thioureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid;

2~5595;~) 5E-6-[3-(3-(2,4-dichlorophenyl)-l-m~thylthiourei~o)-phenyl]-6-(3-pyridyl)~hex-5-enoic acid; and (-)-SE-6-~4-(Z-2-(4-chlorophenyl)-cyclopropyl-l-carboxamido)-phenyl~-6-(3-pyridyl)-hex-5-enoic acid, and the isomers and addition sal.ts thereof.

Viewed from another aspect, the present invention provides a process for preparing the compounds of the invention, said process comprising one or more of the following steps:

a) acylating a compound of formula II

N ~ 4 R5 (Il) R3 (CH~)n-cO-R6 (wherein R2 to R6 and n are as hereinbefore defined with a compound of formula III

Rt ~ A - X - Z1 (III) (wherein R1 is as hereinbefore defined and Z1 represents a nucleophilic leaving group or, if A
represents an -NR9- group and X represents a carbonyl or thiocarbonyl group, Z1 together with R9 represents another carbon-nitroyen bond);

b~ (to prepare compounds of formula I wherein R6 represents a hydroxy group) cleaving a protecting group from a compound of formula IV

2~5~

~ ( I V ) R ~-A-X
R~ ( CH2 )n-CO-Z2 (wherein R1 to R5, A, X and n are as hereinbefore defined and Z2 represents a hydrolytically, thermolytically or .~ hydrogenolytically cleavable protecting group for a carboxy group or a functional derivative of a carboxy group);

c) (to prepare compounds of formula I wherein R4 and Rs each represent a hydrogen atom) hydrogenating a compound : of formula V
:~ R~
:~ N ~ - I
/ ~ CH-(cH2)n-co-R6 ( V ) ~wherein R1 to R3, R6, A, X and n as are hereinbefore defined);

d) (to prepare compounds of formula I wherein R4 and Rs together represent a carbon-carbon bond) react.ing a compound of formula VI
R~

N ~
/ ~ ,0 (Vl) (wherein 3 R1 to R3, A and X as are hereinbefore defined~ with a - lo - ~5~5~
compound of formula VII

W ~2 ~ (CHz)n - CO - R6 ~VII) (wherein R6 and n are as hereinbefore defined and W represents a triphenylphosphonium halide, dialkylphosphonic acid or magnesium halide group) and if desired subsequently dehydrating the product;

e) alkylating a compound of formula I thus obtained wherein R2 represents a hydrogen atom to form a corresponding compound of formula I wherein R2 represents an alkyl group;

f) esterifying or amidating a compound of formula I
thus obtained wherein R6 represents a hydroxy group to form a corresponding compound of formula I wherein R6 represents an alkoxy, amino, alkylamino or dialkylamino group;

g) resolving a compound of formula I thus obtained wherein R4 and R5 together represent a carbon-carbon bond into the cis- and trans-isomers thereof;

h) resolving a compound of formula I thus obtained may be resolved into the enantiomers thereof; and i) converting a compound of formula I thus obtained into an addition salt thereof.

In reaction step (a), the nucleophilic group Z1 may be such a halogen atom or an alkoxy group, e.g. a chlorine or bromine atom, or a methoxy or ethoxy group.

The reaction of step (a) is preferably carried out in a solvent such as methanol, ethanol, water/methanol, 2~s~s~

dioxane, tetrahydrofuran or chloroform, optionally in the presence of an acid binding agent such as potassium carbonate, triethylamine or pyridine, whilst these latter two may also be used as solvents, conveniently at temperatures between 0 and 50OC, but preferably at ambient temperature.

Examples of hydrolysable groups for use in step (b) include functional derivatives of the carboxy group, such as the unsubstituted or substituted amides, esters~
thioesters, orthoesters, iminoethers, amidines or anhydrides thereof, the nitrile group, ether groups such as the methoxy, ethoxy, tert.butoxy or benzyloxy group or lactones and examples of thermolytically removable groups include esters with tertiary alcohols, e.gO the tert.butylester, and examples of hydrogenolytically removable groups include aralkyl groups, e.g. the benzyl group.

The hydrolysis of reaction step (b) is expediently carried out either in the presence of an acid such as hydrochloric acid, sulphuric 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 -lO and 120C, e.g. at temperatures between ambient temperature and the boiling temperature of the reaction mixture.

If, for example, a compound of formula IV contains a nitrile or aminocarbonyl group, these groups may preerably be converted into the carboxy group using 100% phosphoric acid at temperatures between 100 and 180C, preferably at temperatures between 120 and 160C, or with a nitrite, e.g. sodium nitrite, in the presence of an acid such as sulphuric acid, whilst the latter may ~f~5~95~

convenientLy be used as solvent at the same time, at temperatures between 0 and 50C.

If, for example, a compound of fo~nula IV contains an acid amide group such as the diethylaminocarbonyl or piperidinocarbonyl group, this group may preferably be converted into the carboxy group by hydrolysis in the presence of an acid such as hydrochloric acid, sulphuric 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 120C, e.g. at temperatures between ambient temperature and the boiling temperature of the reaction mixture.

If, for example, a compound of formula IV contains the tert.butyloxycarbonyl group, the tert.butyl group may also be thermally cleaved, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and preferably in the presence of a catalytic quantity of an acid such as p-toluenesulphonic acid, sulphuric acid, phosphoric acid or polyphosphoric acid, preferably at the boiling temperature of the solvent used, e.g. at temperatures between 40 and 100C.

If, for example, a compound of formula IV contains the benzyloxy or benzyloxycarbonyl group, the benzyl group may also be hydrogenolytically cleaved 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, ethyl acetate, dioxane or dimethyl~ormamide, preferably at temperatures between 0 and 50C, e.g. at ambient temperature and under a - 13 - ~ ~5~g5~
hydrogen pressure of from 1 to 5 bar. During hydrogenolysis, a halogen-containin~ compound may be dehalogenated at the same time and any double bond present may be hydrogenated.

The hydrogenation of step (c) is conveniently carried out in a solvent such as methanol, ethanol, dioxane, ethyl acetate or glacial acetic acid with catalytically activated hydrogen, e.g. with hydroyen in the presence of a hydrogenation catalyst such as Raney nickel, palladium, palladium/charcoal, platinum or platinum/charcoal and under a hydrogen pressure of from 1 to 5 bar, or with nascent hydrogen, e.g. in the presence of iron/hydrochloric acid, zinc/glacial acetic acid, tin(II)chloride/hydrochloric acid or iron(II)-sulphate/sulphuric acid, at temperatures between 0 and 50C, preferably at ambient temperature. However, the catalytic hydrogenation may also be carried out stereo-selectively in the presence of a suitable catalyst:.

Any nitro group optionally present in the group R
may be reduced at the same time and any chlorine or bromine atom optionally present in the yroup R1 may be replaced by a hydrogen atom.

For step (d) the reaction is preferably carried out in a solvent such as diethylether, tetrahydrofuran, dioxane or dimethylformamide at temperatures between -30 and 100C, preferably at temperatures between -20 and 25C.

However, the reaction with a triphenylphosphonium halide o~ formula VII is carried out particularly advantayeously in the presence of a base sUch as potassium tert.butoxide or sodium hydride.

I~, during the reaction with a magnesium halide o~

~5S9~

formula VII, in the carbinol which is formed initially in the reaction mixture, the hydroxy group is not cleaved during the reaction, it will be cleaved in the presence of an acid such as hydrochloric acid, sulphuric 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 120C, e.g. at temperatures between ambient temperature and the boiling temperature of the reaction mixture.

The alkylation of step (e) is preferably carried out in a solvent such as methylene chloride, tetra-hydrofuran, dimethylformamide or dimethylsulphoxide in the presence of an alkylating agent such as methyliodide, dimethylsulphate, ethyl bromide, n-propylbromide or isopropylbromide, optionally in the presence of an acid~binding agent such as potassium carbonate at temperatures between 0 and 70C, preferably at temperatures between 20 and 50C.

The esterification or amidation reaction of s~ep (f) is conveniently carried out in a solvent, e.g. in an excess of the alcohol used, such as methanol, ethanol or isopropanol, or an excess of 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 180C, but preferably at the boiling temperature of the reaction mixture.

The compounds of formula I thus obtained wherein R4 and Rs together represent a carbon-carbon bond, may be converted into their cis- and trans-isomers by according to step (g), using conventional methods, e.g. by chromatography on a carrier such as silica gel or by crystallisation.

The compounds of formula I obtained may also be resolved into their enantiomers according to step (h).
Thus, the compounds of formula I obtained which contain only one optically active centre may be resolved into their optical antipodes using methods known ~ se (see Allinger N. L. and Eliel W. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971), e.g. by recrystallisation from an optically active solvent or by reaction with an optically active substance which forms salts with the racemic compound, more particularly a base, and separating the salt mixture thus obtained, e.g. by using their different solubilities, into the diastereomeric salts from which the free antipodes can be liberated by the action of suitable agents. The D- and L-forms of ~-phenyl-ethylamine or cinchonidine are examples of particularly useful optically active bases.

Furthermore, the compounds of formula I obtained having at least 2 asymmetric carbon atoms can be resolved into their diastereomers on the basis of their physical-chemical differences using methods known se, e.g. by chromatography and/or fractional crystallisation. A pair of enantiomers thus obtainPd can subsequently be resolved into the optical antipodes thereof, as described above. If, for examplel a compound of formula I contains two optically active carbon atoms, the corresponding (R R', S S')- and (R S', S R')-forms are obtained.

Furthermore, the new compounds of formula I thus obtained, should they contain a carboxy group, may, if desired, be converted as described in step (i) into the addition salts thereof with inorganic or organic bases, more particularly, for pharmaceutical use, into the physiologically acceptable addition salts thereof.
Examples of bases include sodium hydroxide, potassium hydroxide, cycloh~xylamine, ethanolamine, diethanolamine and triethanolamine.

The compounds of formulae II to VII used as starting mat~rials may be obtained by methods known from the literature or are themselves known from the literature.

A compound o-f formula II used as starting material may be obtained from a corresponding N-acylamino compound by Friedel-Craft acylation, subsequent deacylation, optionally followed by reduction, hydrolysis and/or esterification or by reacting a corresponding magnesium or lithium compound with 2 suitably substituted pyridine compound such as 3-cyano-pyridine, pyridine-3 aldehyde or a pyridine~3-carboxylic acid derivative, optionally followed by oxidation.

The compounds of formulae IV, V and VI used as starting materials may be obtained by reacting a corresponding amino compound with a corresponding halide.

The compounds of formula VII used as starting materials may be obtained by reacting a corresponcling halocarboxylic acid with triphenylphosphine or with a trialkyl-phosphoester.

As already mentioned hereinbefore, the new compounds and the physiologically acceptable addition salts thereof with inorganic or organic bases have valuable pharmacological properties, particularly antithrombotic effects and an inhibitory effect on platelet aggregation. They are also thromboxane antagonists and thromboxane synthesis inhibitors, and it is particul.arly notable that the compounds of formula I
have these effects simultaneously. They also have an - 17 - 2 ~ 5 5 g5 effect on PGE2-production in the lungs and on PGD2-, PGE2- and PGF2a-production in human thrombo~ytes.

Thus, the present invention also provides a pharmaceutical composition comprising a compound of formula I or a physiologically acceptable salt thereof together with at least one pharmaceutically acceptable carrier or diluent.

Such compositions are suitable for the treatment and prevention of thromboembolic disorders, for the prevention of arterio-sclerosis and metastasis and for the treatment of ischaemia, asthma and allergies.
Moreover, the compositions of the present invention may be used in the treatment and prevention of diseases in which a thromboxane-mediated constriction or PGE2-mediated dilation of the capillaries is involved, for reducing the severity of transplant rejection, for reducing the renal toxicity of substances such as cyclosporin, for the treatment of kidney diseases and for the treatment of shock.

One particularly adv~ntageous embodiment encompasses a pharmaceutically acceptable composition of the present invention comprising a PDE-inhibitor or a lysing agent.

Viewed from yet another aspect, the present invention provides the use of a compound of formula I or an isomer or physiologically tolerable salt thereof for tha manufacture of a therapeutic agent for the treatment and prevention of thromboembolic disorders, for the prevention of arterio~sclerosis and metastasis and for the treatment of ischaemia, asthma and allergies.

Viewed from a still further aspect, the present invention provides the use of a compound of formula I or - 18 - ~C5~95~
an isomer or physiologically tolerable salt thereof for the manufacture of a therapeutlc agent for the treatment and prevention of diseases in which a thromboxane-mediated constriction or PGE2-mediated dilation of the capillaries is involved, for reducing the severity of transplant rejection, for reducing the renal toxicity of substances such as cyclosporin, for the treatment of kidney diseases and for the treatment of shock.

Viewed from another aspect, the present invention provides a method of combatting thromboembolic disorders, arterioschlerosis, metastasis, ischaemia, allergies, asthma, thromboxane-medicated capillary constriction, PGE2-medicated capillary dilation, transplant rejection, renal toxicity, kidney diseases or shock of the human or non-human animal body, said method comprising administering to said body a compound of formula I as herein disclosed or an isomer or physiologically tolerable addition salt thereof.

By way of example, the following compounds:

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 were tested for their biological properties as described below. All ratios given are by volume, unless otherwise specified.

~05~5~

1. Antithrombotic_activity Method The thrombocyte aggregation is measured using the Born and Cross method (J. Physiol. 170: 397 (1964)) in platelet~rich plasma taken from healthy volunteers~ To inhibit coagulation the blood is mixed with 3.14% sodium citrate in a ratio by volume of 1:10.

Collaqen-induced a~greqation The pattern of the decrease in optical density of the platelet suspension is photometrically measured and recorded after the addition of the aggregation-triggering substance. The rate of aggregation is concluded from the angle of inclination of the density curve. The point on the curve where there is maximum light transmittance is used to calculate the optical density.

mhe amount of collagen used is as small as possible but sufficient to produce an irreversible reaction curve. Standard commercial collagen produced by Hormonchemie of Munich is used. Before the addition of the collagen the plasma is incubated for 10 minutes with the substance at 37C~

From the measurements obtained an EC50 value is determined graphically, indicating a 50% change in the optical density in terms of the inhibition o~
aggregation.

2. Thromboxane-antaqonistic activity Venous human blood is anti-coagulated with 13 mM Na3 citrate and centrifuged for 10 minutes at 170 x g. The supernatant platelet-rich plasma is passed through a Sepharose 2B column in order to remove the plasma proteins. Aliquots of the platelet suspension obtained are incubated with the test substance, the ligand (3H-- 20 - ~ ~S5~s~
labelled) and a marker (14C-labelled) for 60 minutes at ambient temperature and then centrifu~ed for 20 seconds at 10,000 x g. The supernatant is removed and the pellet is dissolved in NaOH. The 3H activity in the supernatant corresponds to the free ligand, 14C gives the concentration of the marker. 3H in the pellet corresponds to the bound ligand whilst 14C in the pellet is used to correct ~or the ligand in the extracellular space. After the process has been repeated, the displacement curve is determined from the binding values for different concentrations of the test substance and the ICso is determined.

3. etermininq the inhibitorY effect on thromboxane synthetase Venous human blood is anti-coagulated with 13 mM Na3 citrate and centrifuged for 10 minutes at 170 x g. The supernatant platelet-rich plasma is passed through a Sepharose 2B column in order to remove the plasma proteins. Aliquots of the platelet suspension obtained are incubated with the test substance or with a solvent as control for 10 minutes at ambient temperature and after the addition of 14C-labelled arachidonic acid incubation is continued for a further 10 minutes. After the reaction has been stopped with 50 ~1 of citric acid, extraction is carried out with 3 x 500 ~1 of ethyl acetate and the combined extracts are distilled oFf with nitrogen. The residue is taken up in ethyl acetate, placed on TLC film and separated with chloro-form:methanol:glacial acetic acid:water (90:8:1:0.8, v/v/v/v). The dried TLC films are placed on X-ray film for 3 days, the autoradiograms are developed and the active zones are marked on the film using the autoradiograms. After cutting out the portions of radioactive film, the activity is measured in a scintillation counter and the inhibition of the formation of TXB2 is calculated. IC50 is determined by linear interpolation.

- 21 - 2 ~ 5 The Table below contains the values found:

-Example Inhibition of Thromboxane- Inhibition o~
thromboxane antagonistic collagen-induced synthetase activity aggregation ICso ICs~ EC50 A 0.004 ~M/l 0.004 ~M/l n . 5 ~M/l B 0.004 ~M/l 0.008 ~M/l 2.2 ~M/l C 0.032 ~M/l 0.012 ~M/l 0.8 ~M/l D 0.090 ~M/l 0.017 ~M/l 1.2 4- ~sa~L~a~ILEY
The acute toxicity of the substances being tested was determined as a guide on groups of 10 mice after oral administration of a single dose of 250 mg/kg (observation period: 14 days). At this dose, none of the animals died.

In view of their pharmacological properties, the new compounds and the physiologically acceptable addition salts thereof are suitable for the treatment and prevention of thromboembolic disorders such as coronary infarct, cerebral infarct, so-called transient ischaemic attacks, Amaurosis fugax and for the prevention of arteriosclerosis and metastasis and for treating ischasmia, asthma and allergies.

The new compounds and the physiologically acceptable addition salts thereof are also suitable in the treatment of diseases involving thromboxane-mediated constriction or PGE2~mediated dilation of the capillaries, e.g. in pulmonary hypertension. Moreover, these may be used to reduce the severity of a transplant rejection, in order to decrease the renal toxicity of - 22 - 2~S95~
substances such as cyclosporin, in order to treat kidney diseases, more particularly for the therapy or prevention of kidney changec connected with hypertension, systemic lupus or ureter blockages and in cases of shock in conjunction with sepsis, trauma or burns.

The dos~ required to achieve such an effect is expediently 0.3 to 4 mg/kg of body weight, preferably 0 3 to 2 mg/kg of body wei~ht, two to four times a day.
For this purpose, the compounds of formula I according to the invention, opti.onally combined with other active substances, may be made into conventional galenic preparations such as tablets, coated tablets, capsules, powders, suspensions or suppositories, by the use of one or more inert conv~ntional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof.

The present invention further relates to new pharmaceutical compositions containing a compound according to the invention and a PDE- inhibitor or a lysing agent.

Examples of PDE-inhibitors include:

2,6~bis(diethanolamino)-4,8-dipiperidino-pyrimido-[5,4-d]pyrimidine (Dipyridamole), 2,6-bis(diethanolamino)-4-piperidino-pyrimido[5,4-d]-pyrimidine (Mopidamole), 2-(4-methoxy-phenyl)-5(6)-(5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole (Pimobenda~e), 2-(4-hydroxy-phenyl)-s(6)-(s-methyl-3-oxo-4,5 dihydro-2H-6-pyridazinyl)-benzimidazole, l-(1-oxido-thiomorpholino~-3-piperazino-5-methyl-isoquinoline, 6-[4-(3,4-dichlorophenylsulphinyl)-butoxy]-3,4-dihydrocarbostyrile and 5-[4~t2-PYridYlSulphonyl)-butoxy]carbostyrile~

whilst a suitable oral daily dose may be, for example, for dipyridamole is 2.5 to 7.5 mg/kg, preferably 5 mg/kg, for mopidamole it is 15 to 25 mg/kg, preferably 20 mg/kg, for 2-(4-methoxy-phenyl)~5(6)-(5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl)-benzimidaæole, 0.05 to 0.15 mg/kg, preferably 0.08 to 0.10 mg/kg, for 2-(4-hydroxy-phenyl)-5(6)-(5-methyl 3-oxo-4,5- ~
dihydro-2H-6-pyridazinyl)-benzimidazole, 0.05 to 0.15 mg/kg, preferably 0.0~ to 0.10 mg/kg, for l-(l-oxido-thiomorpholino)-3-piperazir.o-5~methyl-isoquinoline it is 0.20 to 2.00 mg/kg, preferably 0.40 to 1.00 mg/kg, for 6-C4-(3,4-flic}llorophenylsulphinyl)-butoxy]-3,4-dihydrocarbostyrile, 0.10 to 1.00 mg/kg, preferably 0.20 to 0.50 mg/kg and 2~5~ S~

for 6-[4-(2-pyridylsulphonyl3-butoxy3carbostyrile, 0.10 to 1.00 mg/kg, preferably 0.20 to O.S0 mg/kg, and suitable lysing agents are plasminogen activators such as t-PA, rt-PA, streptokinase, eminase or urokinase, whilst the lysing agents may be administered parenterally but are preferably given by intravenous route, e.g. t-PA or rt-PA is given in a dosage of between 15 and 100 mg per patient, urokinase is given in a dose between 250,000 and 3,000,000 units per patient, eminase is given in a dose of about 30 mg per patient and streptokinase is given in a dose of between 5 x 104 and 3 x 107 IU within 5 minutes and 24 hours, respectively.

For pharmaceutical use, a new combination containing 1 to 500 mg of a PDE-inhibitor, preferably 2 to 75 mg, together with 10 to 300 mg, preferably 10 to 300 mg, of a compound of formula I or a physiologically acceptable addition salt thereof incorporated together with one or more inert conventional carriers and/or diluents, e.g. corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, cikric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories. These are administered to adults 2 to 4 times a day, preferably 3 to 4 times a day, in order to achieve the desired effect.

Moreover, for pharmaceutical use, there is a new combination containing a lysing agent in the dosages mentioned above together with 10 to 300 mg, preferably ~559~

10 to 200 mg, of a compound of formula I or a physiologically acceptable addition salt thereof incorporated into conventional parenteral preparations, preferably conventional intravenous preparations such as ampoules or infusions, which dosage may be administered within 5 minutes and 2~ hours.

Obviously, the individual active substances of the above-mentioned combinations may also be administered, if desired.

The Examples which follow illustrate the invention:

Preparation of starting compounds:

~m~

Methyl 6-(4-aminophenyl)-6-(3-pyridyl)-hex-5-enoate 3 ~ _ _ a) 4-Acetylaminophenyl-3-pyridyl-ketone 980 g of aluminium trichloride are slowly mixed with 155 ml of dimethylformamide. 342 g of nicotinic acid chloride-hydrochloride and 206 g of N-acetylaniline are added successively to this mixture at 90 to 110C. The reaction mixture is then mixed with 600 ml of ethylene chloride, then poured onto ice and neutralised by the addition of 15 N sodium hydroxide solution, with cooling. The aqueous phase is extracted with methylene chloride. The combined organic phases are concentrated by evaporation and the residue is recrystallised from methanol.
Yield: 44% of theory, Melting point: 189-191C
C14H12N23 (240-26) Calculated: C 69.99 H 5.03 N 11.66 Found: 69.87 5~14 11.58 b) 6~ Acetylaminophenyl)-6-~3~pYridYl)-hex-5-enoic ~cid At -40C, 140 g of 4-acetylaminophenyl-3-pyridyl-ketone are added to a suspension of 307 g of 4-carboxybutyl-triphenylphosphonium bromide and 233 g of potassium tert.butoxide in 2.8 litres of tetrahydrofuran and the mixture is stirred for 2 hours. The reaction mixture is decomposed by the addition of ice water and evaporated down. The residue is taken up in water and washed with ethyl acetate. The aqueous phase is acidified to pH 5 to 6 and extracted with ethyl acetate. The organic phase is evaporated down and the residue is recrystallised from ethyl acetate/diisopropylether.
Yield: 86% of theory, Melting point: 155-156C
C~9H20N2O3 (324.38) Calculated: C 70.35 H 6.21 N 8.64 Found: 70.19 6.27 8.66 c) Methyl 6-(4-amino~henyl)-6-(3-p~ridyl)-hex-5-~noate 65 g of 6-(4-acetylaminophenyl)-6-(3-pyridyl)-hex-5-enoic acid are refluxed for 2 hours in a mixture of 300 ml of methanol and 150 ml of saturated methanolic hydrochloric acid. The reaction mixture is mixed with 500 ml of water, neutralised by the addition of sodium carbonate and extracted with ethyl acetate. The organic phase is washed, dried and evaporated down.
Yield: 71% of theory, Oil, Rf value: 0.72 (silica gel; methylene chloride/acetone = 9:1) C18H20N22 (29~-37) Calculated: C 72.95 H 6.80 N 9.45 Found: 72.83 6.859.23 9~

The following compound is obtained analogously to Example I:

methyl 6-(4-methylaminophenyl)-6-(3-pyridyl)-hex-S-enoate Oil, Rf value: 0.56 (silica gel; methylene chloride/ethanol = 20:1) ClsHz2N202 (310-4~) Calculated: C 73.52 H 7.14 N 9.03 Found: 73.35 7~24 8.91 Exam~le II

Methyl 6-(3-aminophenyl)-6-(3-pyridyl)-hex-5-enoate a) 3-Acetylaminophenyl-3-pyridYlketone 114 g of 3-nitrophenyl-3-pyridylketone are hydrogenated in l,000 ml of acetic acid and 35 g of Raney nickel for 2 hours at 50C under 5 bar of pressure. The catalyst is filtered off and the filtrate is mixed with 80 ml of acetic acid anhydride. After 30 minutes at ambient temperature the mixture is evaporated down and the residue is taken up in ethyl acetate. The organic phase is washed with aqueous potassium carbonate solution and dried over sodium sulphate. The solvent is removed and the residue is recrystallised fr~m ethyl acetate/diiso-propylether.
Yield: 69% of theory, Melting point: 116-117C
C14H12N22 (240.26~
Calculated: C 69.99 H 5.03 N 11.66 Found: 70.01 5.11 11.8~

- 2~ - 205~95~
b) _ ~3-~ t~l5~Lh~henyl)-5-(3-pyridyl)-hex-5-enoic acid At -25'C, g4 g of 3-acetylaminophenyl-3-pyridylketone are added to a mixture of 217 g of 4-carboxybutyl-triphenylphosphonium bromide and lS4 g of potassium tert.butoxide in 1.8 litres of tetrahydrofuran. After 2 hours stirring at ambient temperature, 200 ml of water are added to the reaction mixture and then it is evaporated down. The residue is taken up in 500 ml of water and washed with ethyl acetate. The aqueous phase is then neutralised by the addition of citric acid and extracted with ethyl acetate. The organic phase is evaporated down and the residue is recrystallised from ethyl acetate/acetone.
Yield: 85% of theory, Melting point: 86-89C
C19H20N203 (324.38) Calculated: C 70.35 H 6.21 N 8.64 Found: 70.15 6.36 8~50 c) Mathyl 6-(3-aminopheny~-6-(3-pyridyl)-hex-5-enoate 65 g of 6-(3~acetylaminophenyl)-6-(3-pyridyl)-hex-~-enoic acid are refluxed for 4 hours in a mixture of 400 ml of methanol and 200 ml of methanolic hydrochloric acid. The solvent is eliminated and the residue is taken up in water. The aqueous phase is washed with ethyl acetate and adjusted to pH 8-9 by adding 4N sodium hydroxide solution. The aqueous phase is extracted with ethyl acetate. The organic phase i5 washed, driecl and concentrated by evaporation.
Yield: 71% of theory, Oil, Rf value: 0.55 (silica gel; methylene chloride/ethanol = 9:1) C1~H20N202 (296.37) Calculated: C 72.95 H 6.80 N 9.45 ~Si9S~

Found: 72.83 6.91 9.18 The following compounds are obtained analogously to Example II:

Methyl 5-(3-aminophenyl)-S-( 3 -pyridyl)-pent- 4 -enoate Resin, Rf value: o. 58 (silica gel; methylene chloride/ethanol = 20: 1) C17H18Nzo2 (282 - 34) Calculated: C 72.32 H 6.43 N 9.92 Found: 72.29 6.55 9.70 Methyl 7 - ~ 3 -aminophenyl)-7 - (3 -pyridyl)~hept-6-enoate Resin, Rf value: 0. 63 (silica gel; methylene chloride/ethanol = 20:1) C19H22NzO~ (310.40) Calculated: c 73.52 H 7.14 N 9.03 Found: 73.41 7.18 8.89 Example III

Methyl 6- ~ 3-methylaminophenyl)-6~ (3 -pyridyl)-hex-5-enoate a) N-Acetyl-3-methylaminophenyl-3-pyridYl~etone 17 g of sodium hydride followed by 22 ml of methyliodide are added in batches, with cooling, to 84 g of 3-acetylaminophenyl-3-pyridylketone in 600 ml of dimethylformamide. The mixture is stirred for one hour at ambient temperature and decomposed by the addition of 100 ml of water. The solvent is eliminated and the residue is taken up in ethyl acetate. The organic phase is washed, dried and evaporated down. 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) C15H14N22 (254.29) Calculated: C 70.85 H 5.55 N 11.02 Found: 70.96 5.65 10.92 b) Methyl 6-~3-methylaminophenyl)-6-(3-pyridyl)-hex-5-_noate Prepared from N-acetyl-3-methylaminophenyl-3-pyridyl~
ketone and 4 carboxybutyl-triphenylphosphonium bromide analogously to Example IIb and subsequent esterification analogously to Example IIc.
Oil, Rf value: 0.56 (silica gel; methylene chloride/ethanol = 20:1) C19H22N2O2 (310.40) Calculated: C 73.52 H 7.14 N 9.03 Found: 73.53 7.20 8.~4 Example IV

(+)-E-2-(4-Chlorophenyl)-cyclopropane-l-carboxylic acid a) Ethyl E/Z-2-(4-chlorophenyl)~cyclopropane-1-carboxylate A mixture of 85 g of ethyl diazoacetate and 100 g of 4-chlorostyrene is added dropwise, within 2 hours, to 350 ml of boiling xylene. The mixture is heated for a further hour to 120C and the solvent is eliminated in vacuo. The residue is fractionated under a high vacuum.
Yield: 43% of theory, Boiling point: 105-112C (0.05 Torr) C12H13ClOz (224.69) Calculated: C 64.15 H 5.83 Found: 64.33 6.03 z~

b) E-2-(~-Chlorophenyl)-cyclopropane-l-carboxylic acid nd Z-2- ~- h_ rophenyl)-cyclopropane-~-carboxylic acid Within 5 hours, 160 ml of water are added dropwise to a hoiling mixture of 69 g of ethyl E/Z-~-(4~chlorophenyl)-cyclopropane-l-carboxylate and 8.8 g of sodium hydroxide in 180 ml of ethanol and 50 ml of water, and at the same time 150 ml of ethanol are distilled off. Then the ethyl Z-2-(4-chlorophenyl)-cyclopropane-1-carboxylate is extracted from the reaction mixture using ethyl acetate.
The aqueous phase is made alkaline and extracted with ethyl acetate. The organic phase is evaporated down and the residue is recrystallised from petroleum ether, producing 20 g of E-2 (4-chlorophenyl)-cyclopropane-1-carboxylic acid.

The organic phase which contains ester is evaporated down and the residue is heated to boiling in a mixture I of 8.8 g of sodium hydroxide, lB0 ml of ethanol and 50 ml of water. 160 ml of water are added dropwise within 5 hours to the hoiling reaction mixture and at the same time 150 ml of ethanol are distilled off. Then the reaction solution is acidified and extracted with ethyl acetate. The organic phase is evaporated down and the residue is recrystallised from petrol/ethyl acetate, to yield 10.1 g of Z-2-~4-chlorophenyl)-cyclopropane-1-carboxylic acid.
Melting point (E-isomer): 116-117C
Melting point (Z-isomer): 128 129C
C10H19ClZ (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-c o~_ic acid L-~henyl-qlycinolamide _ At -55C, 1.35 g of isobutylchloroformate are added dropwise to a mixture of 1.96 g of E-2-(4-chlorophenyl)-cyclopropane-l-carboxylic acid and 1.01 g of N-methyl-morpholine in 30 ml of tetrahydrofuran. After 10 minutes, 1.37 g of L-phenylglycinol are added and the mixture is heated to ambient temperature. After 2 hours the reaction mixture is combined with 30 ml of water, evaporated down and the precipitate formed is suction filtered. The product obtained is separated into the diastereomers by column chromatography on silica gel using methylene chloride/acetone (15:1). The pure fractions are subsequently recrystallised from ethyl acetate.
Yield: 30% of theory of diastereomer A and 26~ of theory of diastereomer B
C~8H18ClNO2 (315-80~
Calculated: C 68.46 H 5.74N 4.44 Found: (diastereomer A): 6B.sg 5.86 4.57 Found: (diastereomer B): 68.27 5.81 4.54 d) (+)-E-2-(4-Chlorophenyl)-cyclopropane-1-carboxylic acid l9 g of diastereomer A are dissolved in 200 ml of dioxane and 200 ml of 4N hydrochloric acid and refluxed for 4 hours. The reaction mixture is evaporated down, the precipitate formed is suction fîltered and recrystallised from petroleum ether/ethyl acetate.
Yield: 91% of theory, Melting point: 114-115C
Specific rotation: [~]20 = +351 (c = 1.2;
chloroform) C10H9ClO2 (196.63) Calculated: C 61.08 H 4.61 ~i5~t5~

Founcl: Gl.12 4.64 ~he following compo--nds are obtained analogously to Example IV:

~ E-2-(4-chlorophenyl)-cyclopropane-1-carboxylic acid Melti.ng point: 114-115~C
Specific rotation: [~]DO= -348 ~C = 1.2;
chloroform) C10~C12 (196.63~
Calculated: C 61. 08 H 4. 61 Found: 61.12 4. 55 (+)-Z-2-(4-chlorophenyl)-cyclopropane-1-carboxylic acid Melting point: 95-96C
Specific rotation: [~]D20 = +2.6 (c = 1.2;
chloroform) C10H9Cl02 (196. 63) Calculated: C 61.08 H 4. 61 Found: 61.09 4.64 (-)-Z-2 (4-chlorophenyi)-cyclopropane-1-carboxylic acid Melting point: 95-96C
Specific rotation: [~20= -2.6 (c = 1.2;
chloroform) C10H9Cl02 (196.63) Calculated: C 61.08 H 4. 61 Found: 61.24 ~.64 Preparation of end products:

~3~ 1 6-[4-(4-Methylbenzenesulphonylamino)-phenyl]-6~~3-pyridyl)-hex-5-enoic acid A mixture of 3 g of methyl 6 (4-aminophenyl)-6-(3-- 3~ - 2 ~ ~5 g ~ 0 pyridyl)-hex-5-enoate, 1.9 g of 4-methylbenzene-sulphonic acid chloride and 5 ml of triethylamine in 100 ml of methylene chloride is stirred for one hour at ambient temperature. The organic phase is washed with water, evaporated down and the residue is purified over a silica gel column with ethyl acetate. The product fraction is evaporated down and heated in a mixture of 50 ml of ethanol and 3 ml of lON sodium hydroxide solution to 50C for one hour. The reaction mixture is diluted with water and n~utralised by the addition of citric acid. The aqueous phase is extracted with ethyl acetate, dried and evaporated down. The residue is recrystallised from ethyl acetate/diisopropylether.
Yield: 53% of theory, Melting point: 110-111C
C24H24N24S (436.s3) Calculated: C 66.04 H 5.54 N 6.42 Found: 65.9~ 5.74 6.25 The following compounds are obtained analogously to Example 1:

6-[4-(4-fluorobenzenesulphonylamino)-phenyl~-6-(3-pyridyl)-hex-5-enoic acid Melting point: 95-96C
C23H21FN2O4S (440.50) Calculated: C 62.71 H 4.81 N 6.36 Found: 62.51 5.02 6.15 6-[4-(4-chlorobenzenesulphonylamino)-phenyl]-6-(3 pyridyl)-hex-5-enoic acid Melting point: 109-111C
C23H21ClN2O4S ~456.95) Calculated: C 60.45 H 4.63 N 6.13 Found: 60.23 4.835.96 6-[4-(4-trifluoromethylbenzenesulphony]amino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid Melting point: 116-117C
C24H21FsNz04S (490.50) Calculated: C 58.77 H 4.32 N 5.71 Found: 58.68 4.56 5.67 6-[4-(4-methoxybenzenesulphonylamino)-phenyl3-6-(3-pyridyl)-hex-5-enoic acid Melting point: 129-130C
z~S (452.~3) Calculated: C 63.70 ~ 5.35 N 6.19 Found: 63.~39 5.42 6.34 ~-[4-(4-amino-3,5-dichlorobenzenesulphonylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid Melting point: 233C
C23H21cl2N3O4s (506.41) Calculated: C 54.55 H 4.18 N 8.30 Found: 5~.41 4.26 8.16 6-[4-(2-naphthalenesulphonylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid Melting point: 177-178C
C27~24N24S (472.57) Calculated: C 68.63 H 5.12 N 5.93 Found: 68.45 4.92 5.87 6-[4-(2~(5-chlorothienyl)-sulphonylamino)-phenyl3-6-(3-pyridyl)-hex-5-enoic acid Melting point: 139-141C
C21H19ClN2O4S2 (462.97) Calculated: C 54.48 ~ 4.14 N 6.05 Found: S4.34 4~06 6.20 6-(4-benzenesulphonylaminophenyl)-6-t3-pyridyl) hex-5-enoic acid xoss~s~

Melting point: 1~9-151C
Cz3H22N24S (422.51) Calculated: C 65.38 H 5.25 N 6~63 Found: 65.27 5.10 6.57 6-[4-(1-n-butylsulphonylamino)-phenyl]-6-(3-pyridyl~~
hex-5-enoic acid Melting point: 65C
CZ1H26N204S (402.51) Calculated: C 62.66H 6.51 N 6.96 Found: 62.51 6.69 6.84 6-[3-(4-chlorobenzenesulphonylamino)-phenyl]-6-~3-pyridyl)-hex-5-enoic acid Melting poin'c: 187-188C
C23H21ClN204S (456.95) Calculated: C 60.46 H 4.63 N 6.13 Found: 60.64 4.87 5.96 6-[3-(1-naphthalenesulphonylamino)-phenyl]-6-~3-pyridyl)-hex-5-enoic acid Melting point: 208-209C
Cz7H24N24S (472.56) Calculated: C 68.63 H 5.12 M 5.93 Found: 68.48 5.13 5.96 6-[3-(2-naphthalenesulphonylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid Melting point: 185~186C
Cz7H24N24S (472.56) Calculated: C 68.63 H 5.12 N 5.93 Found: 68.505.305.90 - 37 - ~ ~ 5 e 2 6-[4-(N-Isopropyl-4-chlorobenzenesulphonylamino3--phenyl]-6-(3-pyridyl)-hex-S-enoic acid a) Methyl 6 (4-isopropylaminophenyl)-6-(3-pyridyl)-hex-5-enoate 6 g of methyl 6-(4-aminoph~nyl~-6-(3-pyridyl)-hex-5-enoate, 2.7 g of isopropylbromide, 5 ml of triethylamine and 0.5 g of sodium iodide are heated to 90C in 60 ml of dimethylformamide for 18 hours. The reaction mixture is evaporated down, the residue is taken up in water and extracted with ethyl acetate. The organic phase is evaporated down and the residue i5 chromatographed over a silica gel column using ethyl acetate.
Yield: 27% of theory, Resin, Rf value: 0.35 (silica yel; methylene chloride~acetone - 9:1) C21H26N2O4 (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-chlorobenzenesulphonylamino)-phen~ll-6-(3-pyridyl)-hex-5-enoic acid 2.6 g of methyl 6-(4-isopropylaminophenyl-6-~3-pyridyl)-hex-5-enoate, 3.5 g of 4-chlorobenzenesulphonic acid chloride and 5 ml of triethylamine in 25 ml of methylene chloride is stirred for 3 days at ambient temperature.
Subsequently, the organic phase is washed with water, evaporated and the resulting residue is saponified with lON sodium hydroxide solution analogously to Example 1.
Yield: 41% of theory, Melting point: 169-170~C
C26H27ClN204S t499-~3) Calculated: C 62.58 H 5.45 N 5.61 s~
- 3~ -Found: 62.42 5.52 5.44 Example 3 7-[4-(4-Chlorobenz~nesulphonyl~mino)-phenyl]-7-(3-pyridyl~-hept-6-enoic acid a) 4-(4-Chlorobenzenesulphon,vlaminol-phenyl-3-pyridyl-ketone 24 g of 4-acetylaminophenyl-3-pyridyl-ketone are refluxed for 2 hours in 100 ml of 6N hydrochloric acid.
The reaction mixture is evaporated down and the residue is suspended in 300 ml of methylene chloride. 21 ~ of 4-chlorobenzenesulphonic acid chloride and 60 ml of triethylamine are added successively to this suspension and stirred for 2 hours at ambient temperature. The reaction mixture is washed with water, dried and evaporated down. The residue is purified over a silica gel column with methylene chloride/acetone (19:1~ and then recrystallised from ethanol.
Yield: 40% of theory, Melting point: 196C
C1~H13ClN203S (372-83) Calculated: C 57.99H 3.51 N 7.51 Found: 57.88 3.57 7.69 b) 7-~4-(4-Chlorobenzenesulphonylamino)-phenyll-7--(3-Pvridvl~-hePt-6-enoic acid At -30C, 5.95 g of 3~carboxypropyl-triphenylphosphonium bromide, 4 g of potassium tert.butoxide and 3.7 g of 4-(4-chlorobenzenesulphonylamino)-phenyl-3-pyridyl-ketone are added successively to 150 ml of tetrahydrofuran.
The mixture is stirred for one hour at ambient temperature. The reaction mixture is evaporated down, the rasidue is taken up in water and washed with ethyl - 39 - 2~59~
acetate. The aqueous phase is neutralised by the addition of citric acid and extracted with ethyl acetate/ethanol (9:1). The organic phase is evaporated down and the residue is recrystallised from methylene chloride/diisopropylether.
Yield: 64% of theory, Melting point: 186-187C
C24H23clN204s (470.98) Calculated: C 61.21 H 4.92 N 5.95 Found: 61.14 4.91 5.77 The following compound is obtained analogously to Example 3:

5-[4-(4-chlorob~nzenesulphonylamino)-phenyl]-5-(3-pyridyl)-pent-4-enoic acid Yield: 33% of theory, Melting point: 151-152C
C22H19ClNzO4s (442.93) Calculated: C 59.65 H 4.32 N 6.32 Found: 59.4~ 4.37 6.16 Example 4 6-[4-(4-Methylbenzenesulphonylamino)-phenyl]-6-(3-pyridyl)-hexanoic acid .
1 g of 6-[4-(4-methylbenzenesulphonylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid i~ dissolved in a mixture of 20 ml of methanol and 5 ml of lN sodium hydroxide solution. After the addition of 200 mg of palladium catalyst (10% on charcoal) the mixture is hydrogenated under 5 bar. Then the catalyst is filtered off, the filtrate is neutralised with lN hydrochloric acid and avaporated down. The residue is taken up in ethyl acetate, decocted with activated charcoal, filtered and evaporated down.
Yield: 74% of theory, - ~o ~ 55~5~
Foam, Rf value: 0.5~ (silica gel; ethyl acetate) C24H2hN24S (438.55) Calculated: 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 At 5-10C, 5 ml of triethylamine are added dropwis~ to a mixture of 3 g of methyl 6-(4-aminophenyl)-6-(3-pyridyl)-hex-5-enoate and 2.1 g oP 4-chlorobenzoic acid chloride. A*ter 30 minutes the reaction mixture is washed with water and evaporated down. The residue is mixed with 30 ml of ethanol and 5 ml of lON sodium hydroxide solution and heated to 50~C for 30 minutes.
The reaction mixture is evaporated down and the residue i5 taken up in water. The aqueous phase is washed with ethyl acetate, neutralised by the addition of citric acid and then extracted with ethyl acetate. The organic phase is washed with water, dried and evaporated down and the residue is recrystallised from ethyl acetate/diisopropylether.
Yield: 64% of theory, Melting point: 94-95C
C24H21ClN203 (420~90~ -Calculated: C 68.49 H 5.03 N 6.66 Found: 68.21 5.13 6.60 The following compound~ are obtained analogously to Example 5:

6 [4-(1-naphthoylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid Melting point: 227C
C28H24N2O3 (436.51) Calculated: C 77.04 H 5.54 N 6.42 2~

Found: 76.~3 5.53 G.31 6-[4-(3-chlorobenzoylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid Melting point: 180-182C
Cz4Hz1ClN203 (420-90) Calculated: C 68.49 H 5.03 N 6.66 Found: 68.34 5.02 6.75 6-(~-phenylacetylaminophenyl)-6-(3-pyridyl)-hex-5-enoic acid Melting point: 168-169C
C25H2~N203 (400.48) Calculat~d: C 74.98 H 6.03 N 6.99 Found: 74.85 6.25 7.02 6-[4-(2-phenylhenzoylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid Melting point~ 182-183C
C30H26N203 (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 Melting point: 147-148C
C27~l2sClN23 (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 Melting point: 101-102C
C26H23ClN203 (446.93) Calculated: C 69.87 H 5.19 N 6.27 Found: 69.79 5.376.53 ~55i~1~5~

6-[4-~3-(4-chlorophenyl)-propionylamino)-phenyl~-6-(3-pyridyl)-hex-5-enoic acid Melting point: 148C
C26H2sClN23 (~8-95) Calculated: C 69.56 H 5.61 N 6.24 Found: 69.45 5.62 6.41 6-[4-(4-chlorophenylaeetylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid Melting point: 176-177C
CzsH23ClN2o3 Caleulated: C 69.04 H 5.33 N 6.44 Found: 68.93 5.51 6.31 6-[~-(4-phenylbutanoylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoie aeid Melting point: 144-145C
C27HzsN23 (428-53) Caleulated: C 75.68 H 6.59 N 6.54 Found: 75.64 6.72 6.45 6-[4-(3-phenylpropynoylamino)-phenyl]~6-(3-pyridyl)-hex-5-enoie aeid Melting point: 95-96C
C26H22N203 (410.47) Caleulated: C 76.08 H 5.40 N 6.83 Found: 75.85 5.606.95 6-[4-(E-2-phenyleyelopropyl-1 earboxamido)-phenyl]-6-(3-pyridyl)-hex-5-enoic aeid Melting point: 175-176C
C27H26N203 (426-51) Caleulated: C 76.09 H 6.14 N 6.56 Found: 76.06 6.18 6.48 ~ ' (~)-5E-6-[4-(E-2-(4~ehlorophenyl)-eyelopropyl-1-earboxamido)-phenyl]-6-(3-pyri.dyl)-hex-5-enoie aeid 2~sssa~
- ~3 -Melting point: 167-168C
Specific rotation: ~]20 = ~292 (c = 1.2; methanol) C27H25ClN203 (4~0-96) 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 Melting point: 167-168C
Specific rotation: [~]20= -294 (c = 1.2; methanol) C27H25ClN203 (460.9~) Calculated: C 70.35 H 5.47 N 6.07 Found: 70.2~ 5.56 6.00 (+)-5E-6-[4-(Z-2~(4 chlorophenyl)-cyclopropyl-l-carboxamido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid Melting point: llO-111C
Specific rotation: [~]D20 = +lO. 5 ~c = 1.2; methanol) 03 ~460.96) Calculated: C 70.35 H 5.47 N 6.07 Found: 70.24 5.62 6.22 (-)-5E-~-[4-(Z-2-(4-chlorophenyl)-cyclopropyl-1-carboxamido)-phenyl]-6-(3-pyridyl) hex-5-enoic acid Melting point: llO-111C
Specific rotation: [~]D20= -11 (~ = 1.2; methanol) C27H2sClN203 (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-l-carboxamido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid Melting point: 204-205C
C27H2sBrN203 (505.41) Calculated: C 64.17 H 4.99 N 5.54 Found: 64.00 5.01 5.63 2q~S59~
- 4~ -6-[4-(Z-2-(4-chlorobenzoyl)-cyclopropyl-l-carboxamido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid Melting point: 193-194C
C28HzsClN204 (488.96) Calculated: C 68.78 H 5.15 N 5.72 Found: 68.68 5.23 5.73 6-[4-(N-m~thyl-3-(4-chlorophenyl)-propionylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid Melting point: 87-90C
C27H27ClN203 (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, Rf value: 0.41 (silica gel; methylene chloride/ethanol = 20:1) C28H27ClN203 (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: 148-150C
C28H27ClN203 (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 Melting point: 214-216C
C30H26Nz03 (462.55) Calculated: C 77.90 H 5.67 N 6.06 Found: 77.79 5.86 5.97 ~5S~
- ~5 --6-[3-(E-p-chlorocinnamoylamino)-phenyl]-6-(3-pyridyl)~
hex-5-enoic acid Melting point: 173-174C
Cz6H23ClN203 (446-93) Calculated: 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 Melting point: 186C
C24H21ClNZ03 (420.90) Calculated: C 68.49H 5.03 N 6.66 Found: 68.29 5.1~ 6.55 6-~3-(3-chlorobenzoylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid Melting point: 173C
C24H21ClN23 (420.90) Calculated: C 68.49H 5.03 N 6.66 Found: 68.33 5.13 6.73 6-[3-(E-o-chlorocinnamoylamino)~phenyl]-6-S3-pyridyl)-hex-5-enoic acid Melting point: 199-200C
C26H23ClN203 (446.93) Calculated: 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 Melting point: 187-188C
C26H23ClN203 ~446-93) Calculated: 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 - 46 - 2~55~5~
Melting point: 207-208C
C27H24N2O3 (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 Melting point: 168-170C
C2sH24N2O4 (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 Melting point: 157C
~26H26N23 (414.50) Calculated: C 75.33H 6.32 N 6.76 Found: 75.34 6.35 6.91 6-~3-(4-phenylbenzoylamino)-phenyl]-6-(3-pyridyl) hex-5-enoic acid Melting point: 163-164C
C30H26N2O3 (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, Rf value: 0.33 (silica gel; methylene chloride/
ethanol = 20:1) Specific rotation: [~]D20= +242 (c = 1.2; methanol) C27H2sClN23 (460.96) Calculated: C 70.35 H 5.47 N 6.07 Found: 70.28 5.70 5.83 (-)-5E-6- E 3-(E-2-(4-chlorophenyl)-cyclopropyl-1-carboxamido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid - ~7 ~ 595~
foam, R~ value: 0.33 (silica gel; methylene chloride/
ethanol = 20:1) Specific rotation: [~DQ= -243 (c = 1.2; methanol) C27~lz5ClN203 (460.~6) 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 Melting psint: 221-222C
Spacific rotation: [~]D20= ~87 (c = 1.2; dimethyl~
formamide) C27H2sClN2O3 (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 Melting point: 220-221C
Specific rotation: [~]DO = -87 (c = 1.2; dimethyl-formamide) 27H25ClN23 (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 Melting point: 165-168C
C27HzsBrN2O3 (505-41) 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 Melting point: 149-150~C
Cz7H25clNzo3 (460.96) Calculated: C 70.35 H 5.47 N 6.07 - 48 - Z~ 5~
Found: 70.19 5.59 6.11 6-[3-(3-(4-chlorophenyl)-propionylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid Melting point: 163C
C26H2sClN2Os (448-95) Calculated: C 69.56 H 5.61 N 6.24 Found: 69.56 5.64 6.40 6-[3-(4-chlorophenylacetylamino)-phenyl]-6-(3-pyridyl)-hax-5-enoic acid Melting point: 192-193C
C2sH23ClN2O3 (434.92) Calculated: C 69.04 H 5.33 N 6.44 Found: 68.B7 5.37 6.48 6-[3-(4-phenylbutanoylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic: acid Melting point: 116-117~C
C27H2sN2O3 (42~-53) Calculated: C 75.68 H 5.59 N 6.54 Found: 75.69 5.70 6.42 6-[3-(4-phenylpropynoylamino)-phenyl~-6-(3-pyridyl)-hex-5-enoic acid Melting point: 159-160C
C26H22N2O3 (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 l-carboxamido)-phenyl]-6-(3~pyridyl)-hex-5-enoic acid Melting point: 204-205C
C27H2sBrN2O3 (505.41) Calculated: C 64.17 H a,.99 N 5.54 Found: 64.00 5.01 5.63 Z~S~5~

6-[3-(4-chlorophenylsulphonylaminoacetylamino)-phenyl]-6-(3-pyridyl)-hex-S-enoic acid Melting point: 110-112 D C
C2sH24ClN3O5S (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 C32H30N2O3 (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-~noic acid Melting point: 65C
C27H23Cl3N2O3 (529.85) Calculated: C 61.21 H 4.38 N 5.29 Found: 61.04 4.5~ 5.05 6-[3-(N-methyl-E-o-chlorocinnamoylamino)-phenyl]-6-(3-pyridyl)-~ex-5-enoic acid Melting point: 12~-130DC
C27H2sClN23 (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) C27H27ClN2O3 (462-98) Calculated: C 70.05 H 5.88 N 6.05 Found: 69.88 5.99 5.88 Z~;5~

6-[3-(N-methyl-3-(2-chlorophenyl)-propionylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid Melting point: 122-124C
c27H27ClN203 (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) C33H32N203 (504.63) Calculated: 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 Melting point: 135C
C28H30N204 (458-56) Calculated: C 73~34H 6.59 N 6.11 Found: 73.20 6.70 6.17 ,:, 6-[3-(N-methyl-3-phenylpropynoylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid Melting point: 123-125C
C27H24N203 (424.50) Calculated: C 76.40 H 5.70 N 6.60 Found: 76.30 5.73 6.88 7-[3-(E-2-(~-chlorophenyl)-cyclopropyl-1-carboxamido)-phenyl]-7-(3 pyridyl)-hept-6-enoic acid Foam, Rf value: 0.15 (silica gel; methylene chloride/
aretone = 9:1) C28H27ClN203 (474.99~
Calculated: C 70.80 H 5.73 N 5.90 Found: 70.645.876.00 - 51 - ~ ~S59 7-[3-(3-(4-chlorophenyl)-propionylamino)-phenyl]-7-(3-pyridyl)-hept-6-enoic acid Foam, Rf value: 0.20 (silica gel; ethyl acetate) Cz7H27ClN203 (462-98) Calculat~d: C 70.05 H 5.88 N 6.05 Found: 69.90 5.90 6.06 ~-[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) C26H2sClN203 (448.95) Calculated: C 69.56 H 5.61 N 6.24 Found. 69.37 5.35 6.22 5-[3-(3-(4-chlorophenyl)-pxopionylamino)-phenyl]-5-(3-pyridyl)-pent-4-enoic acid Melting point: 200-201~C
C2sH23clN23 (434.92) Calculated: C 6~.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 methyl 6-(3-aminophenyl)-6-(3-pyridyl)-hex-5-enoate are dissolved in 30 ml of methylene chloride. At O~C, 1.65 g of 4-chlorophenoxyacetic acid chloride and 2.5 ml of triethylamine are added successively to this solution which is then stirxed for 2 hours at ambient temperature. The reaction mixture is washed with water and then evaporated down. The residue is dissolved in a mixture of 20 ml of ethanol and 16 ml of 0.5N sodium hydroxide solution and stirred for 24 hours at ambient temperature. The reaction mixture is evaporated down at ambient temperature, water is added and the resultin~

- 52 - ~ ~5~9S~
mixture is washed with ethyl acetate. The aqueous phase is neutralised by the addition of citric acid and extracted with ethyl acetate. The organic phase is washed with water, dried and evaporated down and the residue is recrystallised from ethyl acetate/diisopropyl ether.
Yield: 49% of theory, Melting point: 178-179C
Cz5H23ClN204 (450-92) Calculated: C 66.59 H 5.14 N 6.21 Found: 66.~3 5.29 5.99 The following compounds are obtained analogously to Example 6:

6-[3-(2-(4-chlorophenoxy)-isobutyroylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid Melting point: 92C
C2~H27ClN204 (478.98) Calculated: C 67.71 H 5.68 N 5.85 Found: 67O56 5.79 5~67 6-[3-(2-chlorophenoxyacetylamino)-phenyl]-6-~3-pyridyl)-hex-5-enoic acid Melting point: 134-136C
C2sH23ClN20~, (450.92) Calculated: 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: 148-150C
C2sH22ClzN204 (485-37) Calculated: C 61.87 H 4.57 N 5.77 Found: 61.74 4.455.81 ,~5S~S~
~ 53 -6-[3-(N-methyl-2-chlorophenoxyacetylamino)--phenyl]-6-(3-pyridyl)-hex-5-enoic acid Melting point: 118-119C
C26~2sClN24 (4~4.95) 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) C28H29ClN204 (493~00) Calculated: C 68.22 H 5.93 N 5.68 Found: 68.10 6.09 5.65 6-[3-tN-methyl-4-chlorophenoxyacetylamino)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid Melting point: 128-132C
04 (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 Melting point: 1~6C
4 (499 40) Calculated: C 62.53H 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 methyl 6-(3-methylaminophenyl)-6-(3-pyridyl)-hex-5-enoate and 1.8 g of carbonyldiimidazole is refluxed for 48 hours in 50 ml of tetrahydrofuran. The 2~35;5i9~

reaction mixture is evaporated down, the residue is taken up in water and extracted with ethyl acetate. The organic phase is evaporated down and the residue is saponified in a mixture of 20 ml of ethanol and 6 ml of 4N sodium hydroxide solution at 50 C for 30 minutes.
The reaction mixture is neutralised by the addition of citric acid and extracted with ethyl acetate. The organic phase is concentrated by evaporation and the residue is recrystallised from ethyl acetate/diiso-propylether.
Yield: 25% of theory, Melting point: 142-144C
C29H29N303 (467.57) 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.~ g of methyl 6-(3-aminophenyl)-6-(3-pyridyl)-hex-5-enoate and 1.5 g of 4-chlorophenylisocyanate are stirred in 50 ml of tetrahydrofuran at ambient temperature for one hour. The reaction mixture is evaporated down, the residue is mixed with water and extracted with ethyl acetate/ethanol (9:1). The organic phase is evaporated down and the residue is saponified in 60 ml of ethanol and 6 ml of 4N sodium hydroxide solution at 50C for one hour. The reaction mixture is evaporated down, the residue is taken up in lO0 ml of water and extracted with ethyl acetate. The aqueous phase is neutralised by the addition of citric acid, whereupon the product is precipitated. The precipitate is suction filtered, washed with water and diisopropylether and recrystallised ~rom ethyl acetate/diisopropylether.
Yield: 52% of theory, Melting point: 172-173C

~1~5~;~5~) C24H22ClN3O3 (~35~91) Caleulated:C 66.13 H 5.09 N 9.64 Found:66.04 5.22 9.71 The following compounds are obtained analogously to Example 8:

6-[3-(3-(3-chlorophenyl)-uraido3-phenyl]-6-(3-pyridyl)-hex-5-enoic acid Melting point: 151-152C
C24H22ClN3O3 (435-91) 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 Melting point: 137C (decomp.), C26H27N3O3 (429.52) Caleulated: C 72.71 H 6.34 N 9.78 Found: 72.5S 6.35 9.75 6-[3-(3-~2-chlorophenyl)-ureido)-phenyl]-6-(3-pyridyl)-hex-5-enoie aeid Melting point: 170-172C
C24~22ClN3O3 (435-91) 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 aeid Melting point: 173C
C2sH2sN33 (451.53) Caleulated: C 74.48H 5.58 N 9.31 Found: 74.32 5.53 9.16 6-[3-(3-(3,4-diehlorophenyl~-ureido)-phenyl]-6-(3-pyridyl)-hex-5-enoie aeid 55~
- 56 ~
Melting point: 178C
C24H21Cl2N34 (~70.36) Calculated: C 61.29 H 4.50 N 8.93 Found: 61.24 4.619.10 6-[3-(3-(2,4-dichlorophenyl)-ureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid Melting point: 126C
C24H21C12N303 (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 Melting pointo 196C
Cz4H2lC12N303 (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 Melting point: 207-208aC
C24H22N40s t446-47) 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 Melting point: from 118C (decomp.), C2sH23N30s (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 Meltiny point: 166 168C

2~S5 !315~
C25H25N303 (415-49) Calculated: C 72.27 H 6.06 N 10.11 Found: 72.10 6.079.91 6-[3-(3-(4-tert.butylphenyl)-ureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid Melting point: 180-182C
Cz8H31N3O3 (457 57~
Calculated: C 73.50 H 6.83 N 9.13 Found: 73.38 6.78 9.20 6-~3-(3-benzoylureido)-phenyl]-6-(3-pyridyl)-hex~5-enoic acid Melting point: 190-191C
C2sH23N304 (429.48) Calculated: C 69.92 H 5.40 N 9.78 Found: 69.72 5.34 9.58 6-[3-( 3-~4-methylbenzenesulphonyl)~ureido)-phenyl~ 6-(3-pyridyl)-hex-5-enoic acid Melting point: 183C (decomp.) C25H25N35S (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 Melting point: 163-164C
C24H29N33 ( 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, dimethyl-formamide and 4-dimethylaminopyridine with heating.
Meltin~ point: 165C

ZOS~9~

C22H27N303 (381.48) Calculated: C 69.27 H 7.13 N 11.02 Found: 69.2~ 7.0510.95 6-t3-(3-(2,4-dichlorophenyl)-1-methylllreido)-phenyl]-6-(3-pyridyl)-hex~5-enoic acid Melting point: 139-141C
C2sH23Cl2N303 (484.3~) 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 using methylene chloride/ethanol (30:1~
Foam, Rf value: 0.52 (silica gel; methylene chloride/ethanol = 20:1) sN35 (459,50) Calculated: C 67.96 H 5.4~ N 9.14 Found- 67.88 5.56 8.96 6-[4-(3-(3-chlorophenyl)-ureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid Melting point: 175-176C
C24H22ClN303 (435-91) Calculated: C 66.13 H 5.09 N 9.64 Found: 65.99 S.14 9.58 6~[4-(3-(2,4-dichlorophenyl)-1-methylureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid Melting point: 150-152C
C2sH23Cl2N303 (484.38) Calculated: C 61.99 H 4.79 N 8.67 Found: 61.88 4.78 8.~9 6-[4-(3-t4-methylbellzenesulphonyl)-ureido)-phenyl~-6-(3-pyridyl)-hex-5-enoic acid ~(~S~i~5~

Melting point: 176C (decomp.) C2sH2sN30sS (479-55) Calculated: C 62.62 H 5.25 N 8.76 Found: 62rS9 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: o.z5 (silica gel; methylene chloride/
ethanol = 19:1) C23H20ClN303 (421.88) Calculated: C 65 ~ 48 H 4.78 N 9.96 Found: 65. 23 4 ~ 87 9O 66 7-[ 3 ~ ( 3 ~ ( 3 chlorophenyl)-ureido)-phenyl]-7-(3-pyr:idyl)-hept 6-enoic acid Melting point: 140-141C
C25H24ClN3O3 (449.94) Calculated: C 66.74 H 5.38 N 9. 34 Found: 66.63 5.34 9.2 Example 9 6-[4-( 3 1 3 ~Diphenylureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid A mixture of 2.4 g of methyl 6-(4-aminophenyl)-6-(3-pyridyl)-hsx-5-enoate and 2.1 g of N,N-diphenyl-carbamoylchloride is stirred in 25 ml of pyridine for 18 hours at ambient temperature. The solvent is eliminated and the residue is taken up in ethyl acetate. The organic phase is washed with water, dried and evaporated down. The residue is saponified in a mixture of 20 ml of ethanol and 6 ml o~ 4N sodium hydroxide solution for 30 minutes at 50C. The reaction solution is diluted with watèr and extracted with ethyl acetate. Then the a~ueous phase is neutralised by the addition of citric Z~ i95~

acid, the precipitate formed is suction filtered and recrystallised from ethyl acetate/isopropanol.
Yield: 55% of theory, Melting point: 155-156C
C30H27N33 (477.56) Calculated: C 75.45 H 5.70 N 8.80 Found- 75.28 5.89 8.68 The following compounds are obtained analogously to Example 9:

6- E 4-(3-methyl-3-phenylureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid Melting point: 118-120~C
C2sH2sN303 (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, Rf value: 0.60 (silica gel; methylene chloride/
ethanol = 20:1) C2~H27N303 (429.52) Calculated: C 72.71 H 6.3~ N g.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) C2hH27N33 (429-52) Calculated: C 72.71 H 6.34 N 9.7~
Found: 72.53 6.349.59 ~55~S~

Example lo 6-[3-(3-(4-Chlorophenyl)-thioureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid _ 2.4 g of methyl 6-(3-aminophenyl)-6-(3-pyridyl)-hex 5-enoate and 1.7 g of 4-chlorophenylisothiocyanate are stirred in 30 ml of tetrahydrofuran for 1.5 hours at ambient temperature. The solvent is eliminated, the residue is taken up in water and extracted with ethyl acetate. The organic phase is evaporated down and the residue is saponified in a mixture of 20 ml of ethanol and 6 ml of 4N sodium hydroxide solution at ambient temperature for 90 minutes. The reaction mixture is diluted with water, extracted with ethyl acetate and then neutralised by the addition of citric acid. The aqueous phase is extracted with ethyl acetate. The organic phase is evaporated down and the residue is purified over a silica gel column using methylene chloride/ethanol (20:1).
Yield: 64% of theory, Foam, Rf value: 0.31 (silica gel; methylene chloride/acetone = 2:1) C24Hz2ClN3O2S (451.98) Calculated: C 63.78 H 4.91 N 9.30 Found: 63.62 5.03 9.11 The following compounds are obtained analogously to Example 10:

6-[3-(3-(3-chlorophenyl)-thioureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid Melting point: 142-144C (ethyl acetate/tert.-butylmethylether) C24H22ClN302S (451.98) Calculated: C 63.78 H 4.91 N 9.30 Found: 63.69 5.11 9.10 2~s~

6-[3-(3-(2-chlorophenyl)-thioureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid Melting point: 146-148C (isopropanol/diisopropylether) Cz4H22clN302s (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 Melting point: 154-155C (ethyl acetate/diiso-propylether) C24H21cl2N302s (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 Melting point: 137~C (ethyl acetate/tert.butylmethyl-ether) C2sH2sN32S ~431.56) Calculated: 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 Melting point: 13~C (isopropanol/dioxane) Cz4H22N404S (462-53) Calculated: C 62.23 H 4.79 N 12.11 Found: 62.08 4.88 i 12.00 6-[3-(3-(tert.butyl)-thioureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid Reaction in a mixture of tetrahydrofuran, dimethyl-formamide and 4-dimethylaminopyridine with heating.
Melting point: 137-139C
C22H27N302S (397 54) Calculated: C 66.47 H 6.85 N 10.57 ss~

Found: 66.~9 6.~5 ~0.48 6-[3-(3-(2,4-dichlorophenyl)-l-methylthioureido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid Melting point: 124-126C (ethyl acetate/diisopropyl-ether) C2sHz3cl2N3o2s (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)-l-methylthioureido)-phenyl~-6-(3-pyridyl)-hex-5-enoic acid Melting point: 127-129C (ethyl acetate/petroleum ether) C25H23Cl2N3o2s(500.44) Calculated:C 60.00H 4.63N 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 methyl 6-(3-methylaminophenyl)-6-~3-pyridyl)-hex-5-enoate, 3.2 g of DL-O-acetylmandelic acid chloride and 3.5 ml of triethylamine are stirred in 50 ml of methylene chloride at ambient temperature for one hour.
The reaction mixture is washed with water and evaporated down. The residue is saponified in a mixture of 30 ml of ethanol and 10 ml of 4N sodium hydroxide solution at 50~C for 30 minutes. The reaction mixture is neutralised by the addition of citric acid and extracted with ethyl acetate. The organic phase is washed with water, evaporated down and the residue is purified over a silica gel column using ethyl acetate.
Yield: 69% of theory, Foam, R~ value: 0.38 (silica gel; methylene chloride/
acetone = 20:1) C26H26N204 (430.50) i595t) - 6~ -Calculated: C 72.54 H 6.09 N 6.51 Found:72.34 6.096.52 Example 12 Methyl 6-t4-(4-methylbenzenesulphonylamino)-phenyl]-6-(3-pyridyl)-hex~5-enoate 3 g of methyl 6-(4-aminophenyl)-6-(3-pyridyl)-hex-5-enoate, 1.9 g of tosylchloride and 5 ml of triethylamine are stirred in 100 ml of methylene chloride at ambient temperature for one hour. The reaction mixture is washed with water, dried and evaporated down. The residue is purified over a silica gel column with ethyl acetate.
Yield: 78% of theory, Oil, Rf value: 0.74 (silica gel; ethyl acetate) CzsH26N24S (450.56) Calculated: C 66.65 H 5.82 N 6.22 Found: 66.53 5~89 6.08 Example 13 Tablets containing I00 mg of (-)-5E-6-~4-(Z-~-(4-chlorophenyl)-cyclopropyl-1-carboxamido) phenyl]-6-(3-pyridyl)-hex-5-enoic acid Composition:
1 tablet contains:
Active substance 100.0 mg Lactose 80.0 mg Corn starch 34.0 mg Polyvinylpyrrolidone4.0 mg Magnesium stearate 2.0 mg 220.0 mg 5~9S~l - ~5 -Preparation:
The active substance, lactose and starch are mixed together and uniformly moistened with an aqueous solution of the polyvinylpyrrolidone. After the moist masses have been screened (2.0 mm mesh size) and dried in a rack dryer at 50C they are screened again (1.5 mm mesh) and the lubricant is added. The mixture produeed is formed into tablets.
Weight of tablet: 220 mg Diameter: 9 mm, biplanar, facetted on both sides and notched on one side.

Example 14 Hard gelatin capsules containing 150 mg of (-)-5E-6-[4-(Z-2-(4-chlorophenyl)-eyclopropyl-1-carboxamido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid 1 eapsule contains:
Aetive substance 150.0 mg Dried corn starch 180.0 mg (approx.) Powdered laetose 87.0 mg (approx.
Magnesium stearate 3.0 mq about 320~0 mg Preparation:
The active substance is mixed with the excipi.ents, passed through a 0.75 mm mesh screen and homogeneously mixed in a suitable apparatus.
The final mixture is paeked into size 1 hard gelatin capsules.
Capsule eontents J about 320 mg Capsule shell: s:ize 1 hard gelatin eapsule.

- 66 - 2 ~ S5 ~5 0 Exam~ 5 Suppositories containing 150 mg of (-)-5E-6-[4-(~-2~(4-chlorophenyl~-cyclopropyl-1-carboxamido~-phenyl]-6-(3-pyridyl)-hex~5-enoic acid 1 suppository contains:
Active substance150.0 mg Polyethyleneglycol (M.W. 1500) 550.0 mg Polyethyleneglycol (M.W. 6000) 460.0 mg Polyethylene sorbitan monostearate 840.0 m~
2 000.0 mg Preparation:
A~ter the suppository masses have been melted the active substance is homogeneously distributed therein and the melt is poured into chilled moulds.

Suspensions containing 50 mg of (-)-5E-6-[4-(Z-2-(4-chlorophenyl)-cyclopropyl-l-carboxamido)-phenyl]-6~(3-pyridyl)-hex-5-enoic acid 100 ml of suspension contain:
Active substance l.0 g Sodium salt of carboxymethylcellulose 0.2 g Methyl p-hydroxybenzoate 0.05 g Propyl p-hydroxybenzoate 0.01 g Glycerol 5.0 g 70% Sorbitol solution 50.0 g Flavouring 0.3 g Distilled water ad 100 ml ~ 67 2~55~
r~ ration:
Distilled water is heated to 70C. The methyl and propyl p-hydroxybenzoates together with the glycerol and sodium salt of carboxymethylcellulose are dissolved therein with stirring. The solution is cooled to ambient temperature and the active substance is added and homogeneously dispersed therein with stirring.
After the addition of the sorbitol solution and flavouring, the suspension is evacuated to eliminate air, with stirring.
5 ml of suspension contain 50 mg of active substance.

Example 17 Tablets containing 150 mg of (-)-5E-6-[4-(Z-2-(4-chlorophenyl)-cyclopropyl-l-carboxamido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid -Composition:
1 tablet contains:
Active substance 150.0 mg Powdered lactose 89.0 mg Corn starch 40.0 mg Colloidal silica 10.0 mg Polyvinylpyrrolidone10.0 mg Magnesium stearate 1.0 mq 300.0 mg PreParation:
The active substance mixed with lactose, corn starch and silica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a 1.5 mm mesh screen. The granules dried at 45C are rubbed through the same screen again and mixed with the speci~ied amount o~ magnesium stearate. Tablets are compressed from the mixture.
Weight of tablet: 300 mg Punch: 10 mm, flat - 68 - ~ ~5595 Example 18 Film-coated tablets containing 75 mg of (-)-5E-6-~4-~Z-2-(4-chlorophenyl~-cyclopropyl-1-carboxamido)-phenyl]-6-~3-pyridyl)-hex-5-enoic acid 1 tablet core contains:
Activ~ substance 75.0 mg Calcium phosphate 93.0 mg corn starch 35.5 mg Polyvinylpyrrolidone10.0 mg Hydroxypropylmethylcellulose 15.0 mg Magnesium stearate 1.5 mq 230.0 mg Preparation:
The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and half the specified amount of magnesium stearate. Using a tablet making machine, compressed tablets are produced about 13 mm in diameter which are then rubbed through a 1.5 mm mesh screen on a suitable machine and mixed with the remaining magnesium stearate. These granules are compressed in a tablet making machine to form tablets of the desired shape.
Weight of core: 230 mg Punch: 9 mm, convex The tablet cores thus produced are coated with a film consisting essentially of hydroxypropylmethyl-cellulose. The finished film coated tablets are glazed with beeswax.
Weight o~ film coated tablet: 245 mg Obviously all the other compounds of general formula I may be used as active substances in the - 6~ -galenic preparations described above. ~S9 Example 19 Film-coated tablets containing 75 mg of ~-) 5E-6-[4-(Z-2-(4-chlorophenyl)-cyclopropyl-1-carboxamido~-phenyl]-6-(3-pyridyl)-hex-5-enoic acid (Substance B) ~ 75 mg of PDE-inhibitor A powdered mixture of Dipyridamole 25%
Substance B 25%
Fumaric acid 15%
Cellulose 20~
Corn starch 8%
Polyvinylpyrrolidone6%

is moistened with water in a mixing vessel and granulated through a screen with a mesh size of 1.5 mm.
After drying and re-screening, 1% magnesium stearate is added and 10 mm biconvex tablets weighing 300 mg are produced. These tablets are sprayed with hydroxypropyl-methylcellulose lacquer until they weigh 312 mg.

Example 20 Hard gelatin capsules, containing 200 mg of (-)-5E-6-[g-(Z-2-(4-chlorophenyl)-cyclopropyl-1-carboxamido) phenyl]-6-(3-pyridyl~-hex-5-enoic acid ~Substance B) +
50 mg of PDE-inhibitor 10 kg of dipyridamole, 20 kg of fumaric acid, 11.5 kg of polyvinylpyrrolidone, 40 kg of substance B, 1.5 kg of silicon dioxide and 0.8 kg o~ magnesium stearate are mixed for 15 minutes in a cube mixer. This mixture is 55~5~

fed through a roller compactor behind which is a dry granulating apparatus with screening means. The fractions measuring 0.25 to 1.0 mm are used. The capsule filling machine is set so that each size 0 capsule contains a quantity of granules corresponding to 50 mg of PDE-inhibitor and 200 mg of substance B.

Example 21 Hard gelatin capsules containing 100 mg of (-)-5E-6-[4-(Z-2-(4-chlorophenyl)-cyclopropyl-1-carboxamido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid (Substance B) 250 mg of PDE-inhibitor -a) Granules 125 kg of mopidamole, 50 kg of fumaric acid and 13.5 kg of lactose are mixed together and moistened with a solution of water/polyethyleneglycol 6000. After granulation through a screen with a mesh size of 1.0 mm and drying at 45~C, 1.4 kg of stearic acid are added.

b) Coated tablets 100 kg of substance B, 7.5 kg of hydroxypropylmethyl-cellulose, 2.5 kg of silicon dioxide and 15 kg of carboxymethylcellulose are moistened with ethanol and granulated through a screen with a mesh siæe of 1.5 mm.
Afker drying, 1 kg of magnesium stearate are added and the granules are compressed to form biconvex tablets weighing 126 mg with a diameter of 5.5 mm.

These cores are coated in several steps with a coating suspension consisting of 5.6 kg of saccharose, 0.5 kg of gum arabic and 3.8 kg of talc until the tablets weigh 135 mg.

c) Packac~ing The quantity of granules corresponding to 250 mg of ~(~5S95~

PDE-inhibitor are packed into a size 0 long hard gelatin capsule in a special capsule filling machine and the coated tablet containing lO0 mg of substance B is placed on top.

Example 22 Suspension containing 10 mg of (-)-5E-6-[4-(Z-2-(4-chlorophenyl)-cyclopropyl-1-carboxamido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid (Substance B) + 100 mg of dipyridamole per 5 g The suspension has the following composition:

(1) Dipyridamole 2.0%
(2) Substance B 0.2%
(3) Sorbitol 20.8%
(4) Cellulose 7.5%
(5) Sodium carboxymethylcellulose 2.5%
(6) Flavour correctors/preservatives 1.8%
(7) Water 65.2%

Ingredients (3) - (6) are stirred into hot water under high shear forces. After cooling, (1), (2) and (7) are incorporated in the viscous suspension.

Example 23 Delayed release preparation containing 50 mg of (-)-5E-6-[4-(Z-2-(4-chlorophenyl)-cyclopropyl-1-carboxamido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid (Substance B) +
200 mg of dipyridamole a~ Pellet I

A mixture o~

2~

Substance B 50.0 kg Lysine 12.5 kg High polymeric hydro~ypropylcellulose 52.5 kg Triacetine 4.0 kg Ethyl cellulose 2.5 kg Magnesium stearate 3.5 kg is kneaded with ethanol in a special extruder and extruded in the form of spaghetti (1 mm in diameter) which is rounded off into pellets in a spheronizer.
These pellets are then dried thoroughly.

b) Pellet II
-300 kg of mixed tartaric acid starter pellets are sprayed in a special container with a suspension consisting of isopropanol, dipyridamole and polyvinyl-pyrrolidone until the pellets of active substance thus produced contain about 45% dipyridamole.

These pellets are sprayed with a lacquer consisting of methacrylic acid/methylmethacrylate copolymer (brand name Eudragit S) and hydroxypropylmethylcellulose-phthalate (brand name HP 55) in a weight ratio of 85:15 to 50:50. The organic lacquer solutions also contain plasticiser and talc. Two pellet components are sprayed with 5 and 7~ coating agents and different proportions -of the lacquer components within the limits specified.
The two components are mixed together so as to give the following in vitro release:

Conditions tcorresponding to USPXXI, Basket Method, 100 rpm, 1st hour: artificial gastric juice, pH 1.2, 2nd to 6th hours: artificial intestinal jui.ce ~phosphate buffer), pH 5.5):

- 73 - 2 ~ ~ 9 Release of active substance per hour:

1st hour about 30%
2nd hour about 25%
3rd hour about 18%
4th hour about 12%
after the 6th hour more than 90% of the dipyridamole has been released.

c) Packa~inq The pellets are mixed together in accordance with the active substance content of pellet components I and II
and the desired dosage, and ar~ packed into size 0 long capsules in a capsule filling machine.

Example 24 I Ampoules containing 5 mg of (-~-5E-6-[4-(Z-2-(4-chlorophenyl)-cyclopropyl 1-carboxamido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid (Substance B) ~ 10 mg of dipyridamole per 5 ml Composition:

(1) Dipyridamole 10 mg (2) Substance B 5 mg (3) Propyleneglycol 50 mg (4) Polyethyleneglycol 5 mg (5) Ethanol 10 mg (6) Water for injections ad5 ml (7) lN HCl ad pH 3 The active substances are dissolved with heating in a solution consisting of ingredients (3) - (7). After the pH has been checked and the mixture filtered sterile, it is poured into suitable ampoules and sterili~ed.

Claims

1. Compounds of formula I

(I) (wherein n represents an integer 2, 3 or 4;

X represents a carbonyl, thiocarbonyl or sulphonyl group;

R1 represents an optionally phenyl-substituted C1-4-alkyl group, a C4-7-cycloalkyl group, a naphthyl, biphenylyl, diphenylmethyl, indolyl, thienyl, chlorothienyl or bromothienyl group, or R1 may represent a phenyl group or, where A does not represent a bond, R1 may represent a benzoyl or benzenesulphonyl group wherein each phenyl moiety may be substituted by a fluorine, chlorine or bromine atom or by a C1-4-alkoxy, C1-4-alkyl, trifluoromethyl, carboxyl, amino or nitro group, and each phenyl moiety may optionally be further substituted by one or two fluorine, chlorine or bromine atoms or by C1-4 alkyl or C1-4 alkoxy groups, wherein each substituent may be the same or different;

R2 represents a hydrogen atom or a C1-4-alkyl group;

R3 represents a pyridyl group;

R4 and R5 each represent a hydrogen atom or R4 and R5 together represent a carbon-carbon bond;

R6 represents a hydroxy or C1-3-alkoxy group; and A represents a bond, a C3-4-cycloalkylene or C3-4-cycloalkylidene group wherein a methylene group may be dichlorinated or A represents a straight-chained, optionally mono- or poly-unsaturated C2-3-alkylene or oxy-C2-3-alkylene group, an -R7CR8-, -O-R7CR8-, -NR9-, -XNR9- group;

(wherein R7 represents a hydrogen atom, a hydroxy, phenyl or C1-3-alkyl group;
R8 represents a hydrogen atom or a C1-3-alkyl group; and R9 represents a hydrogen atom, or a C1-4-alkyl or phenyl group)) and the isomers and addition salts thereof.

2. Compounds of formula I as claimed in claim 1, wherein n represents an integer 2, 3 or 4;

X represents a carbonyl, thiocarbonyl or sulphonyl group;

R1 represents a phenyl group or, where A does not represent a bond, R1 may also represent a benzoyl or benzenesulphonyl group wherein each phenyl moiety is optionally substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, phenyl, methoxy, carboxy or nitro group or by a C1-4-alkyl group, or each phenyl moiety is optionally di-substituted by chlorine or bromine atoms or by methyl groups, wherein each substituent may be the same or different, or, R1 may also represent a cyclohexyl, benzyl, 4-amino-

3,5-dichlorophenyl, 4-amino-3,5-dibromophenyl, naphthyl, diphenylmethyl, indolyl, thienyl, chlorothienyl or bromothienyl group;

R2 represents a hydrogen atom or a C1-3-alkyl group;

R3 represents a pyridyl group;

R4 and R5 each represent a hydrogen atom or R4 and R5 together represent a carbon-carbon bond;

R6 represents a hydroxy or C1-3-alkoxy group; and A represents a bond, a cyclopropylene or cyclopropylidene group wherein a methylene group may be dichlorinated or A represents an optionally unsaturated ethylene group, or an -R7CR8-, -O-R7CR8- or -NR9- group (wherein R7 represents a hydrogen atom, a hydroxy or a C12-alkyl group;
R8 represents a hydrogen atom or a C1-2-alkyl group; and R9 represents a hydrogen atom, a C-3 alkyl group or a phenyl group), the isomers and addition salts thereof.

3. Compounds of formula I as claimed in claim 1, wherein n represents an integer 2, 3 or 4;

X represents a carbonyl, thiocarbonyl or sulphonyl group;

R1 represents a phenyl group optionally mono-substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, phenyl, methoxy, carboxy or nitro group or by a C1-4-alkyl group, or R1 represents a phenyl group di-substituted by chlorine or bromine atoms or methyl groups wherein each substituent may be the same or different, or R1 may represent a benzyl, 4-amino-3,5 dichlorophenyl, naphthyl or chlorothienyl group;

R2 represents a hydrogen atom or a methyl group;

R3 represents a 3-pyridyl group;

R4 and R5 each represent a hydrogen atom or R4 and R5 together represent a carbon-carbon bond;

R6 represents a hydroxy group; and A represents a bond, a cyclopropylene or cyclopropylidene group, an optionally unsaturated ethylene group or an -R7CR8-, -O-R7CRA- or -NR9- group (wherein R7 represents a hydrogen atom or a hydroxy or methyl group;
R8 represents a hydrogen atom or a methyl group; and R9 represents a hydrogen atom or a methyl or phenyl group), the isomers and addition salts thereof.

4. Compounds of formula I as claimed in any of claims 1 to 3, being:

(-)-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, the isomers and addition salts thereof.

5. Compounds as claimed in claim 1 beiny (-)-5E-6-[4-(Z-2-(4-chlorophenyl)-cyclopropyl-1-carboxamido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid, and the isomers and addition salts thereof.

6. Compounds as claimed in any one of claims 1 to 5 being physiologically acceptable addition salts of a compound of formula I with inorganic or organic bases.

7. A pharmaceutical composition comprising a compound of formula I as claimed in any one of claims 1 to 5 or an isomer or physiologically acceptable addition salt thereof together with at least one carrier or diluent.

8. A composition as claimed in claim 7 further comprising a PDE-inhibitor or a lysing agent.

9. Process for preparing compounds as claimed in any one of claims 1 to 6, comprising one or more of the following steps:

a) acylating a compound of formula II

(II) (wherein R2 to R6 and n are as defined in any one of claims l to 5) with a compound of formula III

R1 - A - X - Z1 (III) (wherein R1 is as defined in any one of claims 1 to 5 and Z1 represents a nucleophilic leaving group or, if A
represents an -NR9- group and X represents a carbonyl or thiocarbonyl group, Z1 together with R9 represents another carbon-nitrogen bond);

b) (to prepare compounds of formula I wherein R6 represents a hydroxy group) cleaving a protecting group from a compound of formula IV

(IV) (wherein R1 to R5, A, X and n are as defined in any one of claims 1 to 5 and Z2 represents a hydrolytically, thermolytically or hydrogenolytically cleavable protecting group for a carboxy group or a functional derivative of a carboxy group);

c) (to prepare compounds of formula I wherein R4 and R5 each represent a hydrogen atom) hydrogenating a compound of formula V

(V) (wherein R1 to R3, R6, A, X and n are defined as in any one of claims 1 to 5);

d) (to prepare compounds of formula I wherein R4 and R5 together represent a carbon-carbon bond) reacting a compound of formula VI

(VI) (wherein R1 to R3, A and X are defined as in any one of claims l to 5) with a compound of formula VII

W CH2 ( CH2 ) n CO R6 (VII) (wherein R6 and n are defined as in any one of claims 1 to 5 and w represents a triphenylphosphonium halide, dialkylphosphonic acid or magnesium halide group) and if desired subsequently dehydrating the product;

e) alkylating a compound of formula I thus obtained wherein R2 represents a hydrogen atom to form a corresponding compound of formula I wherein R2 represents an alkyl group;

f) esterifying or amidating a compound of formula I
thus obtained wherein R6 represents a hydroxy group to form a corresponding compound of formula I wherein R6 represents an alkoxy, amino, alkylamino or dialkylamino group;

g) resolving a compound of formula I thus obtained wherein R4 and R5 together represent a carbon-carbon bond into the cis- and trans-isomers thereof;

h) resolving a compound of formula I thus obtained may be resolved into the enantiomers thereof; and i) converting a compound of formula I thus obtained into an addition salt thereof.

10. Use of a compound of formula I as claimed in any one of claims 1 to 5 or an isomer or physiologically tolerable salt thereof for the manufacture of an agent for the treatment and prevention of thromboembolic disorders, for the prevention of arterio-sclerosis and metastasis and for the treatment of ischaemia, asthma and allergies.

11. Use of a compound of formula I as claimed in any one of claims 1 to 5 or an isomer or physiologically tolerable salt thereof for the manufacture of an agent for the treatment and prevention of diseases in which a thromboxane-mediated constriction or PGE2-mediated dilation of the capillaries is involved, for reducing the severity of transplant rejection, for reducing the renal toxicity of substances such as cyclosporin, for the treatment of kidney diseases and for the treatment of states of shock.

12. A method of combatting thromboembolic disorders, arteriosclerosis, metastasis, ischaemia, allergies, asthma, thromboxane-mediated capillary constriction, PGE2 mediated capillary dilation, transplant rejection, renal toxicity, kidney diseases or shock of the human or non-human animal body, said method comprising administering to said body a compound of formula I as claimed in any one of claims 1 to 5 or an isomer or physiologically tolerable addition salt thereof.

13. A compound of formula I (as defined in claim 1) or salt thereof as herein disclosed in any of the Examples.

14. Each and every novel compound, composition, process, use or method as herein disclosed.

15. The use of a compound of formula I as claimed in any one of claims 1 to 5 or a physiologically tolerable acid addition salt thereof for combatting thromboembolic disorders, arterio-sclerosis, metastasis, ischaemia, allergies, asthma, thromboxane-mediated capillary constriction, PGE2-mediated capillary dilation, transplant rejection, renal toxicity, kidney diseases or shock to the human or animal body.

16. A commercial package containing as active pharmaceutical ingredient a compound of formula I as claimed in any one of claims 1 to 5 or a physiologically tolerable acid addition salt thereof, together with instructions for the use thereof for combatting thromboembolic disorders, arterio-sclerosis, metastasis, ischaemia, allergies, asthma, thromboxane-mediated capillary constriction, PGE2-mediated capillary dilation, transplant rejection, renal toxicity, kidney diseases or shock to the human or animal body.