NO860918L - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE SULPHONYLAMINOETHYL COMPOUNDS. - Google Patents

Description

In the Japanese off. document 124.279/78 (see CA. 90, 168.635t (1979)) describes, among other things, the compounds with the formula

where

R means a hydrogen atom or a methyl group, which exhibits valuable pharmacological properties, including an inhibitory effect on platelet aggregation and the antithrombotic effects.

In addition, DE-A-3,000,377 describes 4-(benzenesulfonamidoethyl)-benzoic acids, benzenesulfonamidoethyl-acetic acids, -propionic acids and -acrylic acids as well as their esters, which exhibit a lipid-lowering and a platelet aggregation-inhibiting effect.

It was now found that the new compounds with the general formula

and their physiologically tolerable salts with inorganic or organic bases, if E contains a hydroxycarbonyl group, exhibit superior pharmacological properties, especially antithrombotic effects, moreover, the new compounds are thromboxane antagonists.

The object of the present invention is thus the production of the new compounds with the above general formula I, their addition salts with inorganic or organic bases, especially their physiologically compatible addition salts. (1)-yl-, 5-hydroxycarbonyl-n-pentanone-(1)-yl-, 2-hydroxycarbonyl-2-methyl-ethanon-(1)-yl-, 3-hydroxycarbonyl-2-methyl-n-propanone -(1)-yl-, 3-hydroxycarbonyl-3-methyl-n-propanone-(1)-yl-, 4-hydroxycarbonyl-2-methyl-n-butanone-(1)-yl-, 4- hydroxycarbonyl- 3-methyl-n-butanone-(1)-yl-, 4-hydroxycarbonyl-4-methyl-n-butanone-(1)-yl-, 2-hydroxycarbonyl-2-ethyl-ethanone-(1)-yl- , 2-hydroxycarbonyl-2-n-propyl-ethanon-(1)-yl-, 2-hydroxycarbonyl-2-ethyl-n-propanone-(1)-yl-, 3-hydroxycarbonyl-3-ethyl-n-propanone -(1)-yl-, 3-hydroxycarbonyl-2-methyl-n-propanone-(1)-yl-, 3-hydroxycarbonyl-3-methyl-n-propanone-(1)-yl-, 4-hydroxycarbonyl- n-buten-2-one-(1)-yl-, 5-hydroxycarbonyl-n-penten-2-one-(1)-yl-, 2-hydroxycarbonyl-1-hydroxy-ethyl-, 3-hydroxycarbonyl-1 -hydroxy-n-propyl-, 4-hydroxycarbonyl-1-hydroxy-n-butyl-, 5-hydroxycarbonyl-1-hydroxy-n-pentyl-, 2-hydroxycarbonyl-2-methyl-1-hydroxy-ethyl-, 2 - hydroxycarbonyl-2-ethyl-1-hydroxy-ethyl-, 2-hydroxycarbonyl-2-isopropyl-1-hydroxy-ethyl-, 3-hydroxycarbonyl- 2-methyl-1-hydroxy-n-propyl-, 3-hydroxycarbonyl-2-ethyl-1-hydroxy-n-propyl-, 3-hydroxycarbonyl-3-methyl-1-hydroxy-n-propyl-, 3-hydroxycarbonyl -3-ethyl-1-hydroxy-n-propyl-, 4-hydroxycarbonyl-2-methyl-1-hydroxy-n-butyl-, 4-hydroxycarbonyl-3-methyl-1-hydroxy-n-butyl-, 4- hydroxycarbonyl-4-methyl-1-hydroxy-n-butyl-, 2-methoxycarbonyl-ethanon-(1)-yl-, 2-(2-methoxyethoxycarbonyl)-ethanon-(1)-yl-, 3-methoxycarbonyl-n -propanone-(1)-yl-, 3-ethoxycarbonyl-n-propanone-(1)-yl-, 3-(2-ethoxyethoxycarbonyl)-n-propanone-(1)-yl-, 3-(3-methoxy -n-propoxycarbonyl)-n-propanone-(1)-yl-, 3-n-propoxycarbonyl-n-propanone-(1)-yl-, 4-ethoxycarbonyl-n-butanone-(1)-yl-, 5 - ethoxycarbonyl-n-pentanone-(1)-yl-, 2-ethoxycarbonyl-2-methyl-ethanon-(1)-yl-, 3-ethoxycarbonyl-2-methyl-n-propanone-(1)-yl-, 3-ethoxycarbonyl-3-methyl-n-propanone-(1)-yl-, 4-ethoxycarbonyl-2-methyl-n-butanone-(1)-yl-, 4-ethoxycarbonyl-3-methyl-n-butanone- (1)-yl-, 4-ethoxycarbonyl-4-methyl-n-butanone-(1)yl-, 2-ethoxycarbonyl-2-ethyl-ethanone-(1)-yl-, 2-eto oxycarbonyl-2-n-propyl-ethanon-(1)-yl-, 3-ethoxycarbonyl-2-ethyl-n-propanone-(1)-yl-, 3-ethoxycarbonyl-3-ethyl-n-propanone-(1 )-yl-, 3-ethoxycarbonyl-n-propanone-(1)-yl-, 3-ethoxycarbonyl-2-methyl-n-propanone-(1)-yl-, 3-ethoxycarbonyl-3-methyl-n-propanone -(1)-yl, 4-ethoxycarbonyl-n-buten-2-one-(1)-yl-, 5-ethoxycarbonyl-n-penten-2-one-(1)-yl-, ethoxycarbonyl-hydroxymethyl-, 2-ethoxycarbonyl-1-hydroxyethyl-, 3-ethoxycarbonyl-1-hydroxy-n-propyl-, 4-ethoxycarbonyl-1-hydroxy-n-butyl-, 5-ethoxycarbonyl-1-hydroxy-n-pentyl-, 2- ethoxycarbonyl-2-methyl-1-hydroxy-ethyl-, 2-ethoxycarbonyl-2-ethyl-1-hydroxy-ethyl-, 2-ethoxycarbonyl-2-isopropyl-1-hydroxy-ethyl-, 3-ethoxycarbonyl-2-methyl -1-hydroxy-n-propyl-, 3-ethoxycarbonyl-1-2-ethyl-1-hydroxy-n-propyl-, 3-ethoxycarbonyl-3-methyl-1-hydroxy-n-propyl-, 3-ethoxycarbonyl-3- ethyl-1-hydroxy-n-propyl-, 4-ethoxycarbonyl-2-methyl-1-hydroxy-n-butyl-, 4-ethoxycarbonyl-3-methyl-1-hydroxy-n-butyl-, 4-ethoxycarbonyl-4 -methyl-1-hydroxy-n-butyl-, 3-(2-methoxy-ethoxycarbonyl). 1)-n-propanone-(1)-yl-, 3-(2-ethoxy-ethoxycaronyl)-n-propanone-(1)-yl-, 3-(2-isopropoxy-ethoxycarbonyl)-n-propanone-( 1)-yl-, 3-(3-methoxy-n-propoxycarbonyl)-n-propanone-(1)-yl-, 3-(3-n-propoxy-n-propoxycarbonyl)-n-propyl-(1) -yl-, 4,5-dihydro-pyridazin-3-on-6-yl-, 4,5-dihydro-5- methyl-pyridazin-3-on-6-yl-, 4,5-dihydro-5- ethyl-pyridazin-3-on-6-yl-, 4,5-dihydro-5-n-propyl-pyridazin-3-on-6-yl-, 4,5-dihydro-5,5-dimethyl-pyridazin- 3-on-6-yl-, pyridazin-3-on-6-yl-, 5-methyl-pyridazin-3-on-6-yl-, 5-ethyl-pyridazin-3-on-6-yl-, 5-n-propyl-pyridazin-3-on-6-yl or 5-isopropyl-pyridazin-3-on-6-yl group.

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

R. means a phenyl group which is optionally substituted with a methyl group, with a fluorine, chlorine or bromine atom, a 4-biphenyl group which is optionally substituted with a fluorine or chlorine atom, a naphthyl, pyridyl or thienyl group,

R2 a hydrogen atom or a methyl group,

A a methylene or methyleneoxy group, whereby the oxygen atom is linked to the neighboring residue B,

B is 1,4-phenylene or 1,4-naphthylene group, and

E a hydroxycarbonyl or alkoxycarbonyl group with a total of 2 or 3 carbon atoms which is attached over a linear or branched alkylene group with 2 to 4 carbon atoms or over a linear or branched alkenylene group with 3 or 4 carbon atoms, whereby a methylene group in the aforementioned alkylene or alkenylene groups, which must be linked to the residue B, are replaced with a hydroxymethylene or carbonyl group and an ethoxycarbonyl group can be substituted in the 2-position with a methoxy group, whereby however E cannot be a hydroxy-carbonylmethylenecarbonyl group which is optionally substituted in the a-position with a methyl or ethyl group, or a 4,5-dihydro-pyridazin-3-on-6-yl or pyridazin-3-on-6-yl group which is optionally substituted in the 5-position with a methyl group.

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

R.j means a phenyl group which is optionally substituted with a chlorine atom or a methyl group,

<R>2 a hydrogen atom,

A a methylene or methyleneoxy group,

B a 1,4-phenylene group and

E a hydroxycarbonyl or alkoxycarbonyl group with a total of 2 or 3 carbon atoms which are bonded over an n-propylene group, whereby a methylene group in the aforementioned propylene group, which must be linked to the residue B, is replaced with a hydroxymethylene or carbonyl group and an ethoxycarbonyl group can be substituted in the 2-position with a methoxy group, or a 4,5-dihydro-pyridazin-3-on-6-yl group which is optionally substituted in the 5-position with a methyl group.

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

a.) Acylation of a compound with the general formula

where

R 2 , A, B and E are as defined at the outset, whereby a hydroxy group in the residue E may be protected with a hydrolytic or hydrogenolytic, cleavable protecting group, such as an alkoxy or benzyloxy group, with a phenylsulfonic acid derivative of the general formula

where

R.J is as defined at the outset, and

X is a leaving group such as a halogen atom or an alkoxy group, for example a chlorine or bromine atom, a methoxy or ethoxy group, and possibly subsequent cleavage of a protective residue used.

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

The eventual subsequent cleavage of an applied protective residue preferably takes place hydrolytically in an aqueous solvent, for example in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as hydrochloric acid or sulfuric acid or in the presence of an alkali base such as sodium hydroxide or potassium hydroxide at temperatures between 0 and 100°C, preferably at the boiling temperature of the reaction mixture. However, the removal of a benzyl residue preferably takes place hydrogenolytically, for example with hydrogen in the presence of a catalyst such as palladium/charcoal in a solvent such as methanol, ethanol, acetic acid ethyl ester or glacial acetic acid, possibly with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50°C , but preferably at room temperature, and a hydrogen pressure of 1 to 7 bar, preferably however from 3 to 5 bar.

b.) For the preparation of compounds of the general formula I, in which E is a hydroxycarbonyl group bonded over an alkylene or alkenylene group:

Cleavage of a protecting residue from a compound of the general formula

where

, R^/A and B are as defined initially and

E.J has the meanings mentioned at the outset for E, whereby, however, the carboxyl group is protected with a hydrolytically, thermolytically or hydrogenolytically cleavable protective group or a functional derivative of the carboxyl group and/or the residue E contains a hydroxy group that is protected with a protective residue.

Examples of hydrolyzable groups include functional derivatives of the carboxy group, such as their unsubstituted or substituted amides, esters, thioesters, orthoesters, iminoethers, amidines or anhydrides, the nitrile group, ether groups such as the methoxy or benzyloxy group or lactones and

as thermolytically cleavable groups, for example esters

with tertiary alcohols, for example the tertiary butyl ester, and as hydrogenolytically cleavable groups, for example aralkyl groups, for example the benzyl group, in consideration.

The hydrolysis is conveniently carried out either in the presence of

an acid such as hydrochloric acid, sulfuric acid, phosphoric acid or trichloroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, ethanol, water/ethanol, water/isopropanol or water/dioxane at temperatures between -10 and 120°C, for example at temperatures between room temperature and the boiling temperature of the reaction mixture.

If a compound with the general formula IV, for example, contains a nitrile or aminocarbonyl group,

then these groups can preferably be transferred to the carboxy group preferably with the help of 100% phosphoric acid at temperatures between 100 and 180°C, preferably at temperatures between 120 and 160°C, or also with a nitrite, for example sodium nitrite, in the presence of an acid such as sulfuric acid, whereby these are suitably used at the same time as a solvent, at temperatures between 0 and 50°C.

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

If a compound with the general formula IV, for example, contains the benzyloxy or benzyloxycarbonyl group, then the benzyl group can also be removed hydrogenolytically in the presence of a hydrogenation catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, methanol/water, ethanol/water, glacial acetic acid , acetic acid ethyl ester, dioxane or dimethylformamide, preferably at temperatures between 0 and 50°C, for example at room temperature and a hydrogen pressure of 1 to 5 bar. During hydrogenolysis, a halogen-containing compound can be dehalogenated and a double bond present can be hydrogenated at the same time.

c.) For the preparation of compounds of the general formula I, in which E contains a carbonyl group as a neighbor

the rest B:

acylation of a compound of the general formula

in which

, R 2 , A and B are as defined initially, with a compound of the general formula

in which

E2 has the meanings mentioned at the beginning for E, whereby, however, E must contain a carbonyl group which is a neighbor of Y and at the same time a possibly present hydroxycarbonyl group can be protected by a hydrolytically or hydrogenolytically cleavable protective residue, such as an alkoxy or benzyl group, and

Y is a nucleophilic leaving group such as a halogen atom, for example a chlorine, bromine or iodine atom, or their anhydride in the presence of a Lewis acid and optionally subsequent cleavage of an applied protecting residue.

The Friedel-Craft acylation is preferably carried out in a solvent such as ethylene chloride or nitrobenzene in the presence of a Lewis acid such as aluminum chloride, boron trifluoride or zinc chloride, suitably at temperatures between 0 and 50°C, but preferably at room temperature.

The eventual subsequent cleavage of an applied protective residue preferably takes place hydrolytically in an aqueous solvent, for example in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as hydrochloric acid or sulfuric acid or in the presence of an alkali base such as sodium hydroxide or potassium hydroxide at temperatures between 0 and 100°C, preferably at the boiling temperature of the reaction mixture. However, the cleavage of a benzyl residue preferably takes place hydrogenolytically, for example with a hydrogen in the presence of a catalyst such as palladium/charcoal in a solvent such as methanol, ethanol, acetic acid ethyl ester or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50°C, but preferably at room temperature, and a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar. d.) For the preparation of compounds of the general formula I, in which E contains a hydroxymethylene group adjacent to the residue B:

Reduction of a compound with the general formula

in which

<R>^,<R>2/A and B are as defined initially and

E^ has the meanings mentioned at the outset for E, whereby, however, E must contain a carbonyl group.

The reduction is carried out in a suitable solvent such as methanol, ethanol, ether, tetrahydrofuran, dioxane or glacial acetic acid in the presence of catalytically activated hydrogen, for example by hydrogen in the presence of platinum or palladium/coal, and optionally in the presence of an acid such as hydrochloric acid or perchloric acid or in the presence of a metal hydride such as sodium borohydride, lithium borohydride or lithium aluminum hydride at temperatures between 0 and 100°C, preferably at temperatures between 20 and 80°C.

For the preparation of a compound of the general formula I, in which E contains a hydroxymethylene group, the reaction is preferably carried out with sodium borohydride in methanol and at room temperature.

If a compound with the general formula VII contains a double bond in the residue E, this can be simultaneously hydrogenated with a hydrogen in the presence of catalytically activated hydrogen.

e.) For the preparation of compounds of the general formula I, in which E is the initially mentioned, saturated residues:

Hydrogenation of a compound with the general formula

in which

, R2, A and B are as defined initially and

E^represents an unsaturated residue which is initially mentioned for E.

The hydrogenation is carried out in a suitable solvent such as methanol, ethanol, dioxane, ethyl acetate or glacial acetic acid with catalytically activated hydrogen or with nascent hydrogen at temperatures between 0 and 50°C, preferably at room temperature. Hereby, a carbonyl group which may be present in the residue E can be simultaneously transferred to a hydroxymethylene group.

For the preparation of a compound of the general formula I, in which E contains a carbonyl group, the reaction is preferably carried out in the presence of zinc/glacial acetic acid and at room temperature.

f.) For the preparation of compounds with the general formula I, in which E is one of the initially mentioned hydroxy-carbonyl groups which are bonded over a saturated alkylene group: Decarboxylation of a possibly in the reaction mixture

prepared compound with the general formula

in which

R.J , R2, A and B are as defined initially and

E,- are two hydroxycarbonyl groups which are bound to the same carbon atom via a linear or branched alkylene group with 1 to 5 carbon atoms, whereby a methylene group in the residue E^, which must be linked to the residue B, is replaced with a hydroxymethylene or carbonyl group.

The decarboxylation is preferably carried out in the presence of an acid such as hydrochloric acid, sulfuric acid, hydrobromic acid or phosphoric acid, which can simultaneously serve as a solvent, in a solvent such as water, ethanol/water, glacial acetic acid/water, dioxane/water or diethylene glycol dimethyl ether at elevated temperatures , preferably at the boiling temperature of the reaction mixture, for example at temperatures between 80 and 100°C.

g.) For the preparation of compounds of the general formula I, in which E is a pyridazinone ring:

Reaction of a compound with the general formula

in which

R.j , R^ / A and B are as defined initially,

R6 and R7, which may be the same or different, are hydrogen atoms or alkyl groups, whereby R^ and R^ together may contain a total of 1 to 3 carbon atoms, and W is each a hydrogen atom or together is an additional bond, or their reactive derivatives such as their esters, amides or halides with hydrazine.

The reaction is conveniently carried out in a solvent such as methanol, ethanol, isopropanol, glacial acetic acid, propionic acid and/or in an excess of hydrazine or hydrazine hydrate at temperatures between 0 and 200°C, for example at temperatures between 20 and 150°C, but preferably at the boiling temperature of the reaction mixture, and optionally in the presence of an acid as condensing agent, such as sulfuric acid or p-toluenesulfonic acid. However, the turnover can also be carried out without solvent.

h.) For the preparation of compounds of the general formula I, in which A is a methyleneoxy group:

Reaction of a compound with the general formula

in which

R.J and R 2 are as defined initially and

Z means a nucleophilic leaving group such as a halogen atom or a sulfonyloxy group, for example a chlorine or bromine atom, a methanesulfonyloxy or p-toluenesulfonyloxy group, with a compound of the general formula

in which

B and E are as defined at the outset, whereby a hydroxy group which is optionally present in the residue E can be protected with a hydrolytically cleavable protecting group, such as an alkoxy or benzyloxy group, optionally subsequent removal of an applied protective residue and optionally subsequent transfer of a obtained ester of the general formula I to the corresponding carboxylic acid.

The reaction is preferably carried out in a solvent such as methanol, ethanol, water/methanol, dioxane, tetrahydrofuran or dimethylsulfoxide, preferably in the presence of an anhydrous, acid-binding agent such as potassium carbonate or triethylamine, whereby triethylamine can also be used as a solvent, suitably at temperatures between 25 and 100 °C, but preferably at temperatures between 40 and 80°C.

The possibly subsequent cleavage of an applied protective residue or the transfer of an obtained ester with the general formula I to the corresponding carboxylic acid preferably takes place hydrolytically in an aqueous solvent, for example in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in presence of an acid such as hydrochloric acid or sulfuric acid or in the presence of an alkali base such as sodium hydroxide or potassium hydroxide at temperatures between 0 and 100°C, preferably at the boiling temperature of the reaction mixture. However, the removal of a benzyl residue preferably takes place hydrogenolytically, for example with hydrogen in the presence of a catalyst such as palladium/charcoal in a solvent such as methanol, ethanol, acetic acid ethyl ester or glacial acetic acid, possibly with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50°C , but preferably at room temperature, and a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar. i.) For the preparation of compounds with the general formula I, in which E is an alkoxycarbonylmethylenecarbonyl group which is optionally substituted in the a-position with a methyl or ethyl group: Reaction of an acetophenone with the general formula

in which

, R2, A and B are as defined initially and

RQ is a hydrogen atom, a methyl or ethyl group, with a carbon dialkyl ester in the presence of a base.

The reaction is carried out in the presence of a base such as potassium tert-butylate or sodium hydride and in a solvent such as toluene, but preferably in an excess of the carbon dialkyl ester used, at temperatures between 50 and 150°C, preferably at temperatures between 75 and 100°C.

The new compounds of the general formula I thus obtained, if these contain a carboxy group, can then be transferred, if desired, to their addition salts with inorganic or organic bases, especially for the pharmaceutical use of their physiologically compatible addition salts. As a base, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine,

diethanolamine and triethanolamine.

The compounds with the general formulas II to XIII which are used as starting materials are obtained according to methods known in the literature, respectively are known from the literature.

A compound of the general formula II used

as starting material, is obtained from a corresponding N-acyl-amino-alkyl-phenyl compound by acylation according to Friedel-Craft, subsequent de-acylation and possibly subsequent reduction, hydrolysis and/or esterification.

The compounds of the general formulas IV, V, VII,

VIII, IX, X and XIII, which are used as starting materials, are obtained

by reacting a corresponding amino compound with a corresponding sulfonyl halide.

As already mentioned at the outset, the new compounds and their physiologically compatible addition salts with inorganic or organic bases exhibit valuable pharmacological properties, in particular antithrombotic effects and an inhibitory effect on platelet aggregation. In addition, they exhibit an inhibitory effect on tumor metastasis and are thromboxane antagonists. In addition, the pyridazinones of the general formula I exhibit an inhibitory effect on phosphodiesterase.

For example, the new connections were:

A = 3-[4-(2-(4-chlorobenzenesulfonyl)-aminoethyl)-benzoyl]- propionic acid,

B = 3-[4-(2-benzenesulfonylaminoethyl)-benzoyl]propionic acid p-methoxyethyl ester,

C = 6-[4-(2-benzenesulfonylaminoethyl)-phenyl]-4,5-dihydro-pyridazin-(2H)-3-one,

D = 6-[4-(2-(p-toluenesulfonyl)-aminoethyl)-phenyl]-5-methyl-4,5-dihydro-pyridazin-(2H)-3-one,

E = 6-[4-(2-benzenesulfonylaminoethoxy)-phenyl]-4,5-dihydro-pyridazin-(2H)-3-one, and

F = 3-[4-(2-benzenesulfonylaminoethyl)-benzoyl]propionic acid investigated for their biological properties as follows:

1. Antithrombotic effect

Methodology

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

Collagen-induced aggregation

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

The amount of collagen is chosen as small as possible, but in such a way that an irreversibly continuous reaction curve is achieved. The commercially available collagen from the company Hormonchemie, Munich, is used.

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

From the obtained measurement figures, an EC^q is calculated graphically, which refers to a 50% change in "optical density" as an expression of an inhibition of aggregation.

The following table contains the results found:

2. Determination of the prolongation of the bleeding time.

Preface

The human organism, as well as warm-blooded ones, has an intricate mechanism to protect it from blood loss in the event of injury. This system consists of the platelets (thrombocytes), which, with the help of their adhesive properties, should quickly "plug up" a heart defect, and thus bring about the primary hemostasis. Next to this purely cellular blood status mechanism, the body has a blood clotting system. With this system, the plasma factors (proteins) are brought into an effective form, which finally allows the liquid plasma fibrinogen to become a fibrin clot.

The system of primary hemostasis, which is essentially stopped by the platelets, and the storage system complement each other in the common goal of effectively protecting the body against blood loss.

In the case of many diseases, delivery processes as well as clumping of platelets can also occur with an intact vascular system. The weakening of the coagulation system by coumarins or heparin is known and can be easily measured using known coagulation tests, which show a prolongation under the influence of the preparation (plasma recalcification time, Quick determination, thrombin time, etc.).

Since the first rapid blood position occurs with platelets in the event of an injury, the function of the platelets can be easily determined by measuring the bleeding time using a standardized injury. The normal bleeding time in humans amounts to approx. 1 to 3 minutes, but this requires platelets with performance and in sufficient numbers. With a normal platelet count, a prolonged bleeding time indicates impaired platelet function. This occurs, for example, in some congenital platelet function disorders. If, on the other hand, drugs are used to prevent the tendency to spontaneous clumping of the platelets with the resulting blockage of cartilage in the arterial system, then the bleeding time in a successful platelet-active therapy must therefore be extended under the influence of substances. With a platelet-active substance, an extension of the bleeding time can therefore be expected and, as the plasmatic storage system is not affected, a normal blood

delivery time.

Literature: W.D. Keidel: Kurzgefasstes Lehrbuch der Physiologie,

Georg Thieme Verlag Stuttgart 1967, page 31:

DerBlutstillungsvorgang.

To determine the bleeding time, the substances to be examined are administered to awake mice in a dose of 10 mg/kg p.o. After 1 hour, the tip of the tail of each animal was cut off

about. 0.5 mm and the emerging blood gently blotted up with a filter paper at intervals of 30 seconds until the bleeding stopped. The number of blood drops thus obtained provides a measure of the bleeding time (5 animals per experiment). The following figures mean percentage extension compared to controls without substance addition:

3. Acute toxicity

The acute toxicity of the substances to be investigated was determined as a guideline for groups of every 10 mice after oral administration of a single dose (observation time: 14 days):

Due to its pharmacological properties, the new compound and its physiologically compatible addition salts are suitable for the treatment and for the prophylaxis of thromboembolic diseases such as coronary infarction, cerebral infarction, so-called "transient ischemic attacks", Amaurosis fugax, for the prophylaxis of arteriosclerosis and for the prophylaxis of metastases .

The dosage necessary to achieve a similar effect is suitably 0.3 to 4 mg/kg body weight, preferably 0.3 to 2 mg/kg body weight, 2 to 3 times a day. For this purpose, the compounds of the general formula I, which are produced according to the invention, possibly in combination with other active substances, can be incorporated together with one or more inert, common carriers and/or diluents, for example with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethyl cellulose or fatty substances such as tallow or their suitable mixtures, in normal, galenic preparations such as tablets, dragees, capsules, powders, suspensions or suppositories.

The following examples will explain the invention in more detail: Example A

3-[ 4-( 2- aminoethyl)- benzoyl] propionic acid methyl ester hydrochloride

51.5 g (0.2 mol) of 3-[4-(2-aminoethyl)-benzoyl]propionic acid hydrochloride are suspended in 200 ml of methanol. Chlorine hydrogen gas is introduced to this suspension to saturation and heated under reflux for 30 minutes. 31.5 g of ester hydrochloride crystallises from the filtered solution. When working up the mother liquor, a further 4.4 g is obtained.

Yield: 35.5 g (66% of the theoretical),

melting point: 191°C

C13H17N03 x HC1 (271.75)

Ber.: C, 57.46; H, 6.68; N, 5.15; Cl, 13.05

Findings: 57.33; 6.42; 5.02; 13.06

Example B

3-[ 4-( 2-aminoethyl)-benzoyl] butyric acid ethyl ester

a. ) 4-(2-acetylaminoethyl)-2'-chloro-propiophenone

Prepared from N-acetyl-3-phenethylamine and 2-chloropropionic acid chloride in the presence of anhydrous aluminum chloride.

Yield: 82% of the theoretical,

melting point: 81-85°C.

b. ) 3-[ 4-( 2-aminoethyl)-benzoyl] butyric acid

The chloroketone obtained according to Example Ba) is reacted with malonic acid diethyl ester and potassium tert.butanolate in dimethyl sulfoxide to 2-carbethoxy-3-[4-(2-acetyl-aminoethyl)-benzoyl]butyric acid ethyl ester. This is hydrolysed alkaline and the free acid obtained therefrom is transferred by heating in diethylene glycol diethyl ether to 3-[4-(2-acetylamino)-benzoyl]-butyric acid with a melting point of 147-152°C. 3-[4-(2-amino-ethyl)-benzoyl]butyric acid hydrochloride is then obtained by boiling with semi-concentrated hydrochloric acid for 6 hours. c. ) By esterification of the compound obtained according to Example Bb), 3-[4-(2-aminoethyl)-benzoyl]butyric acid ethyl ester is obtained.

Oil, Rf value: 0.7 (on Alox plates with chloroform-methanol-concentrated ammonia (9:1:0.1).

Example C

4-[4-(2-benzenesulfonylaminoethyl)-phenyl]-4-hydroxy-butene-(3)-acid actone

10.8 g of 3-[4-(2-benzenesulfonylaminoethyl)-benzoyl]propionic acid is heated in 25 ml of acetic anhydride for 1 hour until boiling, whereby a clear solution is produced after 10 minutes. The acetic anhydride is then distilled off in a vacuum, the crystalline residue is expelled with ether and recrystallized from 60 ml of ethylene chloride.

Yield: 7.8 g (76% of theoretical),

melting point: 155-157°C

C18H17N04S (343.41)

Ber.: C, 62.96; H, 4.99; N, 4.08; S, 9.34;

Findings: 62.85; 5.14; 4.16; 9.18

Example D

4-(2-benzenesulfonylaminoethyl)-2'-chloropropiophenone

Prepared analogously to Example B from N-benzenesulfonyl-3-phenethylamine and 2-chloropropionic acid chloride in the presence of anhydrous aluminum chloride in ethylene chloride.

Example E

4-(2-benzenesulfonylaminoethyl)-acetophenone

30 g (0.15 mol) of 4-(2-aminoethyl)-acetophenone hydrochloride are suspended in 150 ml of pyridine and 39.7 g (0.225 mol) of benzenesulphonic acid chloride are added slowly. After stirring for 1 hour, ice and hydrochloric acid are added and the precipitated reaction product is suctioned off. It is recrystallized from 200 ml of ethanol and 100 ml of water. Yield: 20.6 g (44% of the theoretical),

melting point: 138-140°C.

Example F

Benzenesulfonic acid-(N~ 3~ phenylethyl)- amide

A solution of 24.2 g (0.2 mol) 3-phenethylamine in 100 ml dioxane is sublayered with 100 ml of an aqueous solution of potassium carbonate (from 50 ml saturated potassium carbonate and 100 ml water) and it is added dropwise with vigorous stirring 4 2, 4 g (0.24 mol) of benzene sulfochloride. It is stirred for 1 hour at room temperature, the organic precipitate is suctioned off, the aqueous phase is separated and the dioxane solution is evaporated in vacuo.

The residue dissolved in chloroform is washed with water. After the drying of the organic phase, it is evaporated and the residue obtained is recrystallized from 120 ml of toluene and 160 ml of cyclohexane. Yield: 41.0 g (78% of theoretical),

melting point: 66-68°C.

Example G

3-[4-(2-acetylaminoethyl)-benzoyl]propionic acid

504.3 g (3.78 mol) of anhydrous aluminum chloride are suspended

in 1.3 liters of ethylene chloride and 189.2 g (1.89 mol) succinic anhydride and 280.2 g (0.172 mol) N-acetyl-3-phenylethylamine are added in sequence while stirring and cooling with ice water. It is stirred for 2 hours at room temperature and then ice and 550 ml of concentrated hydrochloric acid are added. A precipitate falls out, which is filtered off and distributed between chloroform and 2n-sodium hydroxide. The alkaline-aqueous phase is acidified. The precipitated acid is suctioned off and recrystallized from 1200 ml of water.

Yield: 109 g (24% of the theoretical),

melting point: 14 5-147°C.

Example H

3-[ 4-( 2-aminoethyl)-benzoyl] propionic acid hydrochloride

55.9 g of 3-[4-(2-acetylaminoethyl)-benzoyl]propionic acid are boiled

in 200 ml of semi-concentrated hydrochloric acid for 22 hours in an oil bath. The clear solution is evaporated in vacuo and the residue is crystallized from 200 ml of n-propanol.

Yield: 49.8 g (92% of theoretical),

melting point: 163-166°C (decomposition).

Example 1

3-[4-(2-benzenesulfonylaminoethyl)-benzoyl]propionic acid potassium salt

A solution of 1.9 g (0.033 mol) of potassium hydroxide in 25 ml of methanol and then 400 ml of ether are added. The potassium salt which precipitates as crystals is filtered off after 1 hour and recrystallized after drying from 200 ml of n-propanol.

Yield: 9.3 g (78% of theoretical),

melting point: 165-167°C.

<C>18<H>18<K>N05(399.52)

Ber.: N, 3.51; S, 8.03

Findings: 3.39; 8.05

Example 2

3- [4-(2-(4-fluorobenzenesulfonyl)-aminoethyl)-benzoyl]-propionic acid methyl ester

13.6 g (0.05 mol) of 3-[4-(2-aminoethyl)-benzoyl]propionic acid methyl ester hydrochloride are suspended in 70 ml of pyridine. 10.6 g (0.1 mol) of triethylamine and 200 mg of 4-dimethylaminopyridine are added and then, while cooling with ice-cold sodium chloride, 11.7 g (0.06 mol) of 4-fluorobenzenesulphonic acid chloride. Then stir for 1 hour at room temperature. For processing, dilute with ice water, add hydrochloric acid and suction off the reaction product. It is recrystallized from 50 ml of methanol.

Yield: 18.7 g (94% of theoretical),

melting point: 92-94°C

C19H2QFN05S (393.30)

Ber.: N, 3.56; S, 8.15

Findings: 3.63; 8.24

Example 3

3-[ 4-( 2-fluorobenzenesulfonyl)- aminoethyl)- benzoyl]- propionic acid

9.8 g (0.025 mol) of the ester obtained according to

Example 2, heat with 30 ml of aqueous 2N sodium hydroxide solution to boiling. This creates a clear solution. This is acidified and the reaction product is suctioned off. After drying, recrystallize from 60 ml of n-propanol.

Yield: 8.0 g (84% of theoretical),

melting point: 132-134°C

C18<H>18<F>N05S (379.42)

Ber.: C, 56.98; H, 4.78; N, 3.69; S, 8.45

Findings: 56.74; 4.77; 3.82; 8.41

Example 4

3-[4-(2-(4-chlorobenzenesulfonyl)-aminoethyl)-benzoyl]-propionic acid methyl ester

Prepared analogously to Example 2 from 3-[4-(2-aminoethyl)-benzoyl]propionic acid methyl ester hydrochloride and 4-chlorobenzenesulfonic acid chloride.

Melting point: 111-113°C (from methanol/water).

<C>19<H>2QC1N05S (409.90)

Ber.: C, 55.67; H, 4.92; N, 3.42; S, 7.82

Findings: 55.67; 4.98; 3.24; 7.59

Example 5

3-[ 4-( 2-( 4- chlorobenzenesulfonyl)- aminoethyl)- benzoyl]- propionic acid

Prepared analogously to Example 3 from 3-[4-(2-(4-chloro-benzenesulfonyl)aminoethyl)-benzoyl]-propionic acid methyl ester.

Melting point: 150-152°C (from carbon tetrachloride)

C18HlgClN05S (395.87)

Ber.: C, 54.61; H, 4.58; Cl, 8.96; N, 3.54; S, 8.10 Find.: 54.90; 4.66; 9.26; 3.30; 8.22

Example 6

3-[4-(2-(p-toluenesulfonyl)-aminoethyl)-benzoyl]-propionic acid methyl ester

Prepared analogously to Example 2 from 3-[4-(2-aminoethyl)-benzoyl]propionic acid methyl ester hydrochloride and toluenesulfonic acid chloride.

Melting point: 120-122°C (from methanol/water).

Example 7

3-[ 4-( 2-( p-toluenesulfonyl)- aminoethyl)- benzoyl] propionic acid

Prepared analogously to Example 3 from 3-[4-(2-(p-toluene-sulfonyl)-aminoethyl)-benzoyl]propionic acid methyl ester. Melting point: 13 0-13 2°C.

Cl9<H>21N05S (375.45)

Ber.: C, 60.78; H, 5.64; N, 3.73; S, 8.54

Findings: 60.42; 5.62; 3.91; 8.61

Example 8

3-[4-(2-(3-pyridinesulfonyl)-aminoethyl)-benzoyl]propionic acid methyl ester

Prepared analogously to Example 2 from 3-[4-(2-aminoethyl)-benzoyl]propionic acid methyl ester hydrochloride and 3-pyridine sulfonic acid chloride.

Yield: 85% of the theoretical,

melting point: 111-113°C.

<C>18<H>20<N>2°5<S>(376'344>

Ber.: C, 57.43; H, 5.36; N, 7.44; S, 8.52

Findings: 57.20; 5.33; 7.49; 8.48

Example 9

3-[ 4-( 2-( 3- pyridinesulfonyl)- aminoethyl)- benzoyl]- propionic acid

Prepared analogously to Example 3 from 3-[4-(2-(3-pyridine-sulfonyl)-aminoethyl)-benzoyl]propionic acid methyl ester.

Yield: 71% of the theoretical,

melting point: 158-160°C (from n-propanol).

<C>17<H>18<N>205<S>(362.42)

Func.: C, 56.34; H, 5.01; N, 7.73; S, 8.85

Fun.: 56.09; 5.02; 7.53: 8.83

Example 10

3-[4-(2-(2-thiophenesulfonyl)-aminoethyl)-benzoyl]propionic acid methyl ester

Prepared analogously to Example 2 from 3-[4-(2-aminoethyl)-benzoyl]propionic acid methyl ester hydrochloride and 2-thiophene-sulfonic acid chloride id .

Yield: 80% of the theoretical,

oil, Rf value: 0.2 (Silica gel-Polygram plates with cyclohexane-ethyl acetate =2:1).

Example 11

3-[ 4-( 2-( 2- Thiophenesulfonyl)- aminoethyl)- benzoyl] propionic acid

Prepared analogously to Example 3 from 3-[4-(2-(2-thiophene-sulfonyl)-aminoethyl)-benzoyl]propionic acid methyl ester.

Yield: 60% of the theoretical,

melting point: 141-143°C (from isopropanol)

Cl6H17N05S2(367.46)

Ber.: C, 52.30; H, 4.66; N, 3.81

Found.: 52.31 4.89; 3.94

Example 12

3-[4-(2-(2<1->fluoro-4-biphenylyl-sulfonyl)-aminoethyl)-benzoyl]-propionic acid

A suspension of 7.7 g (0.03 mol) of 3-[4-(2-aminoethyl)-benzoyl]propionic acid hydrochloride in 25 ml of pyridine is added

100 mg of 4-dimethylaminopyridine and then, under ice-cooling, 9.7 g (0.036 mol) of 2<1->fluoro-4-biphenylsulfonic acid chloride. After 1 hour, dilute with water, acidify and the reaction product is recrystallized from ethylene chloride.

Yield: 7.7 g (56% of theoretical),

melting point: 160-162°C

C24H22FN05S (455/51)

Ber.: C, 63.28; H, 4.87; N, 3.08; S, 7.07

Findings: 63.44; 4.95; 3.28; 7.36

Example 13

4-[ 4-( 2- benzenesulfonylaminoethyl)- phenyl]- 4- hydroxy- butyric acid

7.2 g (0.02 mol) of 3-[4-(2-benzenesulfonylaminoethyl)-benzoyl]-propionic acid are dissolved in 15 ml of 2N sodium hydroxide and 0.4 g (0.01 mol) of sodium borohydride are added. The mixture is stirred for 1 hour at room temperature, then acidified and the reaction product is extracted with ethyl acetate. This is purified by chromatography on a Lobar (R) ready column from the company Merck A.G. with ethylene chloride-ethanol (25:1).

Yield: 4.0 g (55% of theoretical),

oil, Rf value: 0.3 (Silica gel-Polygram plates with ethylene chloride-ethanol 10:1) .

C18H21N05S (363.44)

Ber.: C, 59.49; H, 5.83; N, 3.85; S, 8.82

Fun.: 59.40; 5.59; 3.68; 8.67

Example 14

3-[4-(2-benzenesulfonylaminoethyl)-benzoyl]acrylic acid

60 g (0.45 mol) of anhydrous aluminum chloride are suspended in

120 ml of ethylene chloride and 22.1 g (0.225 mol) of maleic anhydride and 39.2 g (0.15 mol) of benzenesulfonic acid (N-3-phenyl-ethyl)-amide are added under vigorous stirring and cooling with ice water in sequence. It is stirred for 2 hours at room temperature, ice is added, the solvent is distilled off with steam and the reaction product is isolated.

Yield: 87% of the theoretical,

melting point: 139-141°C (from ethylene chloride)

C18H1?N05S (359.41)

Ber.: C, 60.15; H, 4.77; N, 3.90; S, 8.92

Fun.: 60.20; 4.72; 4.07; 8.89

Example 15

3-[4-(2-benzenesulfonylaminoethyl)-benzoyl]butyric acid ethyl ester

Prepared analogously to Example 2 from 3-[4-(2-aminoethyl)-benzoyl]butyric acid ethyl ester and benzenesulfonic acid chloride in pyridine. Oil, Rf value: 0.6 (Silica gel-Polygram plates with cyclohexane-ethyl acetate 1:1).

Example 16

3-[4-(2-benzenesulfonylaminoethyl)-benzoyl]butyric acid

Prepared analogously to Example 3 from 3-[4-(2-benzenesulfonylaminoethyl)-benzoyl]butyric acid ethyl ester.

Yield: 90% of the theoretical,

melting point: 84-87°C (from diisopropyl ether).

C19H21N05S (375.45)

Ber.: C, 60.78; H, 5.64; N, 3.73; S, 8.54

Fun.: 61.00; 5.51; 3.66; 8.41

Example 17

3-[4-(2-p-Chlorobenzenesulfonylaminoethyl)-benzoyl]butyric acid

Prepared analogously to Example 2 from 3-[4-(2-aminoethyl)-benzoyl]butyric acid ethyl ester and 4-chlorobenzenesulfonic acid chloride in pyridine and triethylamine and subsequent hydrolysis.

Yield: 56% of the theoretical,

melting point: 65-68°C (from dioxane-cyclohexane).

Example 18

3-[4-(2-p-toluenesulfonylaminoethyl)-benzoyl]butyric acid ethyl ester

Prepared analogously to Example 2 from 3-[4-(2-aminoethyl)-benzoyl]butyric acid ethyl ester.

Oil, Rf value: 0.6 (Merck-Silica gel plates with cyclohexane-ethyl acetate 1:1 as eluent).

Example 19

3-[4-(2-p-toluenesulfonylaminoethyl)-benzoyl]butyric acid

Prepared analogously to Example 3 from 3-[4-(2-p-toluene-sulfonylaminoethyl)-benzoyl]butyric acid ethyl ester.

Yield: 55% of the theoretical,

melting point: 109-112°C (from ethyl acetate-diisopropyl ether).

C20H23NO5S (389'47)

Ber.: C, 61.68; H, 5.95; N, 3.60; S, 8,23

Fun.: 61.90; 6.16; 3.63; 8.01

Example 20

3-[ 4-( 2-( 3- pyridylsulfonyl)- aminoethyl)- benzoyl] butyric acid

Prepared analogously to Example 2 from 3-[4-(2-aminoethyl)-benzoyl]butyric acid ethyl ester and pyridine-3-sulfonic acid chloride and subsequent hydrolysis.

Yield: 37% of the theoretical,

melting point: 130-132°C (from ethyl acetate).

<C>18<H>20<N>2°5<S><376'43)

Ber.: C, 57.43; H, 5.36; N, 7.44; S, 8.52

Fun.: 5 7.20; 5.38; 7.20; 8.52

Example 21

6-[4-(2-benzenesulfonylaminoethyl)-phenyl]-4,5-dihydro-pyridazin-(2H)-3-one

To a suspension of 54.2 g (0.15 mol) of 3-[4-(2-benzenesulfonylaminoethyl)-benzoyl] propionic acid in 200 ml of glacial acetic acid, 41.3 g (0.825 mol) of 99% hydrazine hydrate are added dropwise and the then heat for 1 hour until boiling. Then cool. The crystallized reaction product is isolated and purified by recrystallization from n-butanol.

Yield: 43.6 g (81% of theoretical),

melting point: 173-175°C.

<C>18<H>19N3°3S (357'44>

Ber.: C, 60.48; H, 5.36; N, 11.76; S, 8.9 7

Fun.: 60.90; 5.32; 11.80; 9,10

Example 22

6-[4-(2-(4-fluorobenzenesulfonyl)-aminoethyl)-phenyl]-4,5-dihydro-pyridazin-(2H)-3-one

Prepared analogously to Example 21 from 3-[4-(2-(4-fluoro-benzenesulfonyl)-aminoethyl)-benzoyl]propionic acid and hydrazine hydrate in glacial acetic acid.

Dividend; 65% of the theoretical,

melting point: 172-174°C (from n-butanol).

C18H18FN303S (375.43)

Ber.: C, 57.59; H, 4.83; N, 11.19; S, 8.54

Fun.: 57.90; 4.92; 11.30; 8.68

Example 23

6-[4-(2-benzenesulfonylaminoethyl)-phenyl]-5-methyl-4,5-dihydro-pyridazin-(2H)-3-one

Prepared analogously to Example 21 from 3-[4-(2-benzenesulfonylaminoethyl)-benzoyl] butyric acid and hydrazine hydrate in glacial acetic acid.

Yield: 75% of the theoretical,

melting point: 120-125°C (from isopropanol-tetrachlorocarbon).

Example 2 4

6-[4-(2-(p-toluenesulfonyl)-aminoethyl)-phenyl]-5-methyl-4,5-dihydro- pyridazine-(2H)- 3- one

7.0 g of 3-[4-(2-(p-toluenesulfonyl)-aminoethyl)-benzoyl]-butyric acid ethyl ester and 2 g of 99% strength hydrazine hydrate are boiled in 25 ml of glacial acetic acid for 5 hours. It is evaporated in vacuo, the residue is distributed between aqueous sodium carbonate solution and methylene chloride. The organic phase is evaporated and the residue is recrystallized from 65 ml of ethyl acetate.

Yield: 4.0 g (62% of theoretical),

melting point: 147-150°C

<C>20<H>23N3O3S (385.49).

Ber.: C, 62.32; H, 6.01; N, 10.90; S, 8.32

Fun.: 62.48; 5.97; 10.77; 8.32

Example 25

6-[4-(2-(p-chlorobenzenesulfonyl)-aminoethyl)-phenyl]-5-methyl-4,5-dihydro- pyridazine-(2H)- 3- one

Prepared analogously to Example 24 from 3-[4-(2-(p-chloro-benzenesulfonyl)-aminoethyl)-benzoyl]butyric acid ethyl ester and hydrazine hydrate in glacial acetic acid.

Yield: 48% of the theoretical,

melting point: 152-154°C.

Example 26

6-[4-(2-(3-pyridinesulfonyl)-aminoethyl)-phenyl]-5-methyl-4,5-dihydro-pyridazin-(2H)-3-one

Prepared analogously to Example 24 from 3-[4-(2-(3-pyridine-sulfonyl)aminoethyl)-benzoyl]butyric acid ethyl ester and hydrazine hydrate in glacial acetic acid.

Yield: 40% of the theoretical,

melting point: 120-122°C (from isopropanol).

<C>18<H>20<N>4°3S <372'46>

Ber.: C, 58.05; H, 5.41; N, 15.04; S, 8.61

Fun.: 58.00; 5.41; 14.51; 8.53

Example 2 7

3-[ 4-( 2- N- benzenesulfonyl- N- methyl- aminoethyl)- benzoyl] propionic acid

Prepared analogously to Example 14 from N-benzenesulfonyl-N-methyl-3-phenylethylamine and succinic anhydride in the presence of aluminum chloride in ethylene chloride.

Yield: 37% of the theoretical,

melting point: 123-125°C (from isopropanol).

Cl9H21N05S (375.45)

Ber.: C, 60.78; H, 5.64; N, 3.73; S, 8.54

Fun.: 60.82; 5.62; 3.61; 8.65

Example 28

6-[4-(2-N-benzenesulfonyl-N-methyl-aminoethyl)-phenyl]-4,5-dihydro- pyridazine-(2H)- 3- one

Prepared analogously to Example 21 from 3-[4-(2-N-benzenesulfonyl-N-methyl-aminoethyl)-benzoyl]propionic acid and hydrazine hydrate in glacial acetic acid.

Yield: 66% of the theoretical,

melting point: 181-183°C

<C>19<H>21<N>3°3<S><371'47>

Ber.: C, 61.43; H, 5.70; N, 11.31; S, 8.63

Fun.: 61.40; 5.85; 11.38; 8.70

Example 29

3-[4-(2-benzenesulfonylaminoethoxy)-benzoyl]-propionic acid methyl ester

9.8 g (37 mmol) N-benzenesulfonyl-N-3-bromomethylamine (J. Indian chem. Soc. V7, 567 (1940)) and 7.7 g (37 mmol) 3-(4-hydroxybenzoyl)-propionic acid -methyl ester (melting point: 119-120°C; J. Chem. Soc. London 1944, 548) is heated together with 5.1 g of dry potassium carbonate in 50 ml of dimethylsulfoxide for 6 hours at 50-60°C with stirring. 150 ml of water is then added, decanted from the precipitated oil, this is extracted with ethyl acetate and the organic phase is washed with dilute sodium hydroxide solution. After drying and evaporation, 3-[4-(2-benzenesulfonylaminoethoxy)-benzoyl]propionic acid methyl ester is obtained as an oil.

Rf value: 0.6 (Silica gel ready plates from the company Merck with ethylene chloride, ethyl acetate, glacial acetic acid = 100:30:5 as eluent).

Yield: 11.8 g (81% of theory).

Example 3 0

3-[4-(2-oenesulfonylaminoethoxy)-benzoyl]propionic acid

Prepared analogously to Example 3 by alkaline hydrolysis of 3-4-(2-benzenesulfonylaminoethoxy)-benzoyl propionic acid methyl ester.

Yield: 9.8 g (86% of theoretical),

melting point: 139-141°C (from n-butanol)

C18HigN06S (377.43)

Ber.: C, 57.28; H, 5.07; N, 3.71; S, 8.50

Fun.: 57.31; 5.16 4.07;. 8.82

Example 31

3-[4-(2-p-toluenesulfonylaminoethoxy)-benzoyl]propionic acid

Prepared analogously to Example 29 from N-3-toluenesulfonyl-N-3-bromomethyl-amine and 3-(4-hydroxybenzoyl)-propionic acid methyl ester and subsequent, alkaline hydrolysis of 3-[4-(2-p-toluenesulfonylaminoethoxy)- benzoyl]propionic acid methyl ester. Yield: 32% of the theoretical,

melting point: 166-167°C (from n-butyl acetate).

Example 32

6-[4-(2-benzenesulfonylaminoethoxy)-phenyl]-4,5-dihydro-pyridazine-(2H)-3-one

Prepared analogously to Example 21 from 3-[4-(2-benzenesulfonylaminoethoxy)-benzoyl]propionic acid and hydrazine hydrate in glacial acetic acid.

Yield: 87% of the theoretical,

melting point: 156-157°C (from n-butanol).

Example 33

5-[4-(2-benzenesulfonylaminoethyl)-benzoyl]pentanoic acid ethyl ester

To a suspension of 16.7 g (125 mmol) of anhydrous aluminum chloride in 80 ml of ethylene chloride, 9.3 g (48 mmol) of adipic acid chloride monoethyl ester and then 12.6 g (48 mmol) of N-benzenesulfonyl-N-3-phenethyl- amine and stirred for 4 hours at room temperature. Ice and hydrochloric acid are added, the reaction product is isolated and purified by column chromatography on 650 g silica gel with cyclohexane-ethyl acetate 1:1.

Yield: 12.5 g (62% of the theoretical),

oil, Rf value: 0.6 (Silica gel-Polygram plates with cyclohexane-ethyl acetate 1:1).

Example 34

5-[4-(2-benzenesulfonylaminoethyl)-benzoyl]pentanoic acid

5.5 g (13 mmol) of 5-[4-(2-benzenesulfonylaminoethyl)-benzoyl]-pentanoic acid ethyl ester is boiled with sodium hydroxide in ethanol for 2 hours. It is evaporated, taken up in water, the aqueous solution is washed with ether and acidified. The precipitated reaction product is recrystallized from 40 ml of ethyl acetate.

Yield: 2.4 g (4 7% of theoretical),

melting point: 129-130°C

C20H23NO5S <389'47)

Ber.: C, 61.68; H, 5.95; N, 3.60; S, 8,23

Fun.: 61.55; 5.87; 3.50; 8.18

Example 3 5

3-[4-(2-(1-Naphthalenesulfonyl)aminoethyl)-benzoyl]propionic acid methyl ester

Prepared analogously to Example 2 from 3-[4-(2-aminoethyl)-benzoyl]propionic acid methyl ester hydrochloride and 1-naphthalene sulfonic acid chloride in pyridine and triethylamine.

Yield: 66% of the theoretical,

melting point: 130-132°C (from n-propanol-water).

Example 3 6

3-[ 4-( 2-( 1- Naphthalenesulfonyl)- aminoethyl)- benzoyl] propionic acid

Prepared by alkaline hydrolysis from 3-[4-(2-(1-naphthalene-sulfonyl)-aminoethyl)-benzoyl]propionic acid methyl ester.

Yield: 56% of the theoretical,

melting point: 156-158°C (from n-propanol-water).

C22H21N05S (411'48)

Ber.: C, 64.22; H, 5.15; N, 3.40; S, 7.79

Fun.: 64.30; 5.12; 3.26; 8.0 7

Example 3 7

3-[ 4-( 2- benzenesulfonylaminoethyl)- naphthoyl-( 1) 3- propionic acid

Prepared analogously to Example 14 from N-benzenesulfonyl-N-3-1-naphthylethylamine and succinic anhydride in ethylene chloride in the presence of aluminum chloride.

Yield: 35% of the theoretical,

melting point: 53-56°C (from methanol/water).

Example 38

3-[ 4-( 2- Benzenesulfonylaminoethyl)- benzoyl] propionic acid ethyl ester

7.8 g of 4-[4-(2-benzenesulfonylamino-ethyl)-phenyl]-4-hydroxy-butene-(3)-acid lactone are boiled in 20 ml of ethanol in the presence of a catalytic amount of p-toluenesulfonic acid for 1 hour. It is evaporated, the residue is dissolved in chloroform, washed with sodium hydrogen carbonate solution and water, dried and evaporated. It is recrystallized from 25 ml of toluene.

Yield: 7.0 g (80% of theoretical),

melting point: 85-87°C.

C20H23NO5S (389.48)

Ber.: C, 61.68; H, 5.95; N, 3.60; S, 8,23

Fun.: 61.94; 5.91; 3.62; 8.08

Example 39

3-[ 4-( 2- Benzenesulfonylaminoethyl)- benzoyl] propionic acid methyl ester

Prepared analogously to Example 38 from 4-[4-(2-benzenesulfonylaminoethyl)-phenyl]-4-hydroxy-butene-(3)-acid lactone and methanol.

Yield: 84% of the theoretical,

melting point: 92-94°C (from methanol).

C1<9H>21N05S (375'45>

Ber.: N, 3.73; S, 8.54

Fun.: 3.77; 8.3 0

Example 4 0

3-[4-(2-benzenesulfonylaminoethyl)-benzoyl]propionic acid 3-methoxyethyl ester

Prepared analogously to Example 38 from 4-[4-(2-benzenesulfonylaminoethyl)-phenyl]-4-hydroxy-butene-(3)-acid lactone and glycol monomethyl ether.

Yield: 63% of the theoretical,

melting point: 62-64°C (from ethyl acetate/diisopropyl ether).

C21H25N06S (419/5°)

Ber.: C, 60.13; H, 6.01; N, 3.34; S, 7.64

Fun.: 6 0.17; 6.12; 3.45; 7.59

Example 41

6-[4-(2-(4-chlorobenzenesulfonyl)-aminoethyl)-phenyl]-4,5-dihydro-pyridazin-(2H)-3-one

Prepared analogously to Example 21 from 3-[4-(2-(4-chloro-benzenesulfonyl)-aminoethyl)-benzoyl]propionic acid and hydrazine hydrate in glacial acetic acid.

Yield: 68% of the theoretical,

melting point: 174-176°C (from n-propanol)

<C>18<H>18<C>1N303S (391.89)

Ber.: C, 55.17; H, 4.63; N, 10.72; S, 8.18; Cl, 9.05 Fun.: 55.24; 4.85; 10.62; 8.26; 9,10

Example 4 2

6-[4-(2-(p-toluenesulfonyl)-aminoethyl)-phenyl]-4,5-dihydro-pyridazin-(2H)-3-one

Prepared analogously to Example 21 from 3-[4-(2-(p-toluene-sulfonyl)-aminoethyl)-benzoyl]propionic acid and hydrazine in glacial acetic acid. • Yield: 54% of the theoretical,

melting point: 169-171°C (from n-propanol)

<C>19<H>21N3°3<S><371'47)

Ber.: C, 61.44; H, 5.70; N, 11.31; S, 8.63

Fun.: 61.42; 5.40; 11.70; 8.49

Example 43

-6-[4-(2-benzenesulfonylaminoethyl)-naphthyl]-(1)]-4,5-dihydro-pyridazin-(2H)-3-one

Prepared analogously to Example 21 from 3-[4-(2-benzenesulfonylaminoethyl)-naphthoyl-(1)]-propionic acid and hydrazine hydrate in glacial acetic acid.

Yield: 43% of the theoretical,

oil, Rf value: 0.45 (Silica gel-Polygram plates with benzene-ethanol-concentrated ammonia = 80:20:1).

Example 4 4

3-[4-(2-benzenesulfonylaminoethyl)-benzoyl]propionic acid

3.6 g (0.01 mol) of 3-[4-(2-benzenesulfonylaminoethyl)-benzoyl]acrylic acid are dissolved in 100 ml of ethanol, Raney nickel is added and hydrogenated at room temperature at 5 bar hydrogen pressure. After absorption of 1 equivalent of hydrogen, the reaction stops. The catalyst is suctioned off, it is evaporated and the residue is recrystallized from 20 ml of ethanol.

Yield: 2.6 g (72% of theoretical),

melting point: 152-154°C.

Example 4 5

3-[4-(2-benzenesulfonylaminoethyl)-benzoyl]propionic acid

3.6 g (0.01 mol) of 3-[4-(2-benzenesulfonylaminoethyl)-benzoyl]acrylic acid is added to 3 g of zinc dust in 50 ml of glacial acetic acid and heated for 5 hours on a steam bath with occasional shaking. Unreacted zinc is filtered off, the filtrate is added to 100 ml of water, the reaction product is filtered off with suction and recrystallized from ethanol. Yield: 2 g (56% of theoretical),

melting point: 150-152°C

Example 4 6

3-[4-(2-benzenesulfonylaminoethyl)-benzoyl]butyric acid.

35.2 g (0.1 mol) 4-(2-benzenesulfonylaminoethyl)-2<1->chloro-propiophenone are reacted with 18 g (0.11 mol) malonic acid diethyl ester and 22.4 g (0.2 mol) potassium tert.butanol in dimethyl sulfoxide to 2-carbethoxy-3-[4-(2-benzenesulfonylaminoethyl)-benzoyl]-butyric acid ethyl ester, an oil. This oil is saponified by boiling for 1 hour with an excess of sodium hydroxide in ethanol. After evaporation, dissolution in water and acidification, 2-carboxy-3-[4-(2-benzenesulfonylaminoethyl)-benzoyl]-butyric acid is obtained therefrom, which is heated in diethylene glycol diethyl ether to 120°C. After completion of C02 evolution, it is diluted with water, the reaction product is extracted with chloroform. The crude reaction product is converted by boiling with methanolic hydrogen chloride to the oily 3-[4-(2-benzenesulfonylaminoethyl)-benzoyl]-butyric acid methyl ester. This ester is chromatographed for purification on silica gel with cyclohexane-ethyl acetate = 1:1 and then hydrolyzed with sodium hydroxide. The free acid thus obtained is recrystallized from diisopropyl ether.

Yield: 8 g (20% of the theoretical),

melting point: 8 5-88°C.

Example 4 7

[ 4-( 2- Benzenesulfonylaminoethyl)- benzoyl] acetic acid ethyl ester

A suspension of 24.7 g (0.22 mol) of potassium tert-butylate

in 50 ml of carbonic acid diethyl ester is heated with stirring and under light vacuum to 80-90°C. A suspension of 29.8 g (0.098 mol) 4-(2-benzenesulfonylamino-ethyl)-acetofenone in 200 ml of carbonic acid diethyl ester is added to this in portions. The ethanol produced by the reaction is continuously distilled off. After 5 hours at 80-90°C, all carbonic acid diethyl ester is distilled off at 12 mm Hg, the residue is dissolved in ice water and acidified. The reaction product is extracted with ether, washed and dried. After evaporation, the residue is recrystallized twice from ethanol. Yield: 14.3 g (39% of the theoretical),

melting point: 8 0-8 2°C.

Example 48

6-[ 4-( 2- benzenesulfonylaminoethyl)- phenyl]- pyridazine-( 2H)- 3- one

5.4 g (0.015 mol) of 3-[4-(2-benzenesulfonylaminoethyl)-benzoyl]acrylic acid and 4.1 g of 99% strength hydrazine hydrate are heated for 1 hour in 15 ml of glacial acetic acid to boiling. The reaction product is precipitated with water, extracted with chloroform, purified by recrystallization from chloroform/ethanol and from n-butanol.

Yield: 0.6 g (11% of theoretical),

melting point: 168-170°C

<C>1<gH>l7<N>303<S>(355.43)

Ber.: C, 60.83; H, 4.82; N, 11.82; S, 9.02

Findings: 60.87; 5.13; 11.87; 8.76

Example 4 9

4- hydroxy- 4-[ 4-( 2- benzenesulfonylaminoethyl)- phenyl]- crotonic acid

7.2 g (0.02 mol) of 3-[4-(2-benzenesulfonylaminoethyl)-benzoyl]-acrylic acid is brought into solution with 30 ml of 1 molar caustic soda and 0.4 g (0.01 mol) of sodium borohydride is added. After 1 hour, it is acidified and the reaction product is extracted with ethyl acetate. The organic phase is dried and evaporated. The obtained residue is purified by chromatography on silica gel with ethylene chloride/ethanol = 50:1.

Yield: 3.2 g (44% of theoretical),

slow setting oil, Rf value: 0.3 (Silica gel Polygram plate with ethylene chloride/ethyl acetate/glacial vinegar = 100:30:5).

C18H19N05S (361.43)

Ber.: C, 59.82; H, 5.30; N, 3.88; S, 8.87

Fun.: 59.61; 5.31; 3.70; 9,10

Example 50

3-[4-(2-benzenesulfonylamino-ethyl)-benzoyl]-propionic acid

71.2 g (0.534 mol) of anhydrous aluminum chloride are suspended

in 250 ml of ethylene chloride and add, with vigorous stirring, 26.7 g (0.2 67 mol) of succinic anhydride and then 46.5 g

(0.178 mol) of benzenesulfonic acid (N,3-phenylethyl)-amide. It is stirred

for 1 hour at room temperature, ice and 75 ml of concentrated hydrochloric acid are added and the solvent is driven off with steam. The product crystallizes out. After suction, washing and drying, it is recrystallized from 300 ml of ethanol.

Yield: 42.7 g (66% of the theoretical),

melting point: 152-154°C

C18<H>19N05S (361.43)

Ber.: C, 59.82; H, 5.30; N, 3.88; S, 8.87;

Fun.: 59.80; 5.29; 3.94; 9,10

Example 51

3-[4-(2-benzenesulfonylamino-ethyl(-benzoyl)-propionic acid

7.7 g (0.03 mol) of 3-[4-(2-aminoethyl)-benzoyl]-propionic acid hydrochloride are suspended in 25 ml of pyridine and 100 mg of 4-dimethylaminopyridine and then 7 g (0.04 mol) of benzene are added -sulfonic acid chloride. After 2 hours, dilute with ice water, acidify, the reaction product is filtered off with suction and recrystallized from ethanol. Yield: 5.4 g (50% of theoretical),

melting point: 151-153°C.

Claims (3)

1. Analogous process for the preparation of therapeutically active sulfonylaminoethyl compounds of the general formula where means a phenyl group which is optionally mono- or disubstituted with a methyl group or a halogen atom, whereby the substituents may be the same or different, a biphenylyl group which is optionally substituted with a halogen atom, a naphthyl, pyridyl or thienyl group, R2 a hydrogen atom or a methyl group, A a methylene or methyleneoxy group, whereby the oxygen atom is linked to the neighboring residue B, B a phenylene or naphthylene group and E a hydroxycarbonyl or alkoxycarbonyl group which is attached over a linear or branched alkylene group with 2 to 5 carbon atoms or over an alkenylene group with 3 to 5 carbon atoms, whereby a methylene group in the aforementioned alkylene or alkenylene residue, which must be attached to the residue B, is substituted with a hydroxymethylene or carbonyl group and the alkoxy moiety, which may be substituted in the 2- or 3-position with an alkoxy group of 1 to 3 carbon atoms, may contain 1 to 3 carbon atoms, or a 4,5-dihydro-pyridazine-3- on-6-yl or pyridazin-3-on-6-yl group which is optionally substituted in the carbon skeleton with 1 or 2 alkyl groups with a total of 1 to 3 carbon atoms, and their salts with inorganic or organic bases, if E contains or constitutes a hydroxycarbonyl group, characterized by ata) a compound with the general formula where R2 , A, B and E are as defined above, whereby a hydroxy group in the residue E may be protected with a hydrolytically or hydrogenolytically cleavable protecting group, is reacted with a phenylsulfonic acid derivative of the general formula where R.J is as defined above and X is a nucleophilic leaving group, and an applied protecting residue is then optionally cleaved off orb) for the preparation of compounds of the general formula I, in which E is a hydroxycarbonyl group which is bonded over an alkylene or alkenylene group, is hydrolytically cleaved off, hydrogenolytically or thermolytically a protecting residue from a compound of the general formula where R^ , R^ / A and B are as defined before and E.j has the aforementioned meaning for E, whereby the carboxy group is, however, protected with a hydrolytically, thermolytically or hydrogenolytically cleavable protective group or is a functional derivative of the carboxy group and/or the residue E^ contains a hydroxy group which is protected with a protective residue orc) for the production of compounds of the general formula I, in which E contains a. carbonyl group neighboring the residue B, a compound with the general formula where , R 2 , A and B are as defined above, with a compound of the general formula where E2 has the meanings for E mentioned earlier, whereby however E must contain a carbonyl group as a neighbor to Y and at the same time a possibly present hydroxycarbonyl group can be protected by a hydrolytically or hydrogenolytically cleavable protective residue, and Y is a nucleophilic leaving group, or its anhydride in the presence of a Lewis acid and a protective residue used is optionally then cleaved ord) for the preparation of compounds of the general formula I, in which E contains a hydroxymethylene group neighboring the residue B, a compound is reduced with the general formula where R.j , R2 , A and B are as defined before and E^ has the meaning for E mentioned above, whereby, however, E must contain a carbonyl group or e) for the preparation of compounds of the general formula I, in which E is one of the saturated radicals mentioned above, a compound is hydrogenated with the general formula where <R> ^,<R>2 , A and B are as defined above and E. is one of the unsaturated residues mentioned above for E, orf) for the preparation of compounds of the general formula I, in which E is a of the aforementioned hydroxycarbonyl groups which are bonded over a saturated alkylene group, a compound with the general formula is decarboxylated which is possibly produced in the reaction mixture, in which R^ , R2 , A and B are as defined before and E^ are two hydroxycarbonyl groups at the same carbon atom which are bonded over a linear or branched alkylene group with 1 to 5 carbon atoms, whereby a methylene group in the residue E^ , which must be linked to the residue B, is replaced with a hydroxymethylene or carbonyl group, or g) for the preparation of compounds of the general formula I, in which E is a pyridazinone ring, a compound is reacted with the general formula in which R^ , R,,, A and B are as defined above, Rb , and R_/ , which may be the same or different, are hydrogen atoms or alkyl groups, whereby R^ and R^ together may contain a total of 1 to 3 carbon atoms, and W each is a hydrogen atom or together is an additional bond, or their reactive derivatives with hydrazine or h) for the preparation of compounds of general formula I, in which A is a methyleneoxy group, a compound of the general formula is transferred in which and R2 is as defined before and Z means a nucleophilic leaving group such as a halogen atom or a sulfonyloxy group, is reacted with a compound of the general formula in which B and E are as defined above, whereby a hydroxy group possibly present in the residue B can be protected with a hydrolytically cleavable protecting group such as an alkoxy or benzyloxy group, optionally a used protecting residue is then cleaved off and optionally an ester obtained with the general formula I is then transferred to the corresponding carboxylic acid or i) for the preparation of compounds with the general formula I, in which E is an alkoxycarbonylmethylenecarbonyl group which is optionally substituted in the a-position with a methyl or ethyl group, react an acetophenone with the general formula in which R.j , R2 / A and B are as defined before and RoQ is a hydrogen atom, a methyl or ethyl group, with a carbon dialkyl ester in the presence of a base and if desired, a thus obtained compound of the general formula I, if it contains a carboxy group, is then transferred to their addition salts with inorganic or organic bases, especially for the pharmaceutical use to their physiologically compatible addition salts. 2. Process according to claim 1, characterized by the production of 3-[4-(2-benzenesulfonylaminoethyl)-benzoyl]-propionic acid and its addition salts with inorganic bases. 3. Process according to claim 1, characterized by the preparation of 6-[4-(2-benzoylsulfonylaminoethyl)phenyl]-4,5-dihydro-pyridazin-(2H)-3-one.