DD298390A5 - NEW ARYLSULFONAMIDES, MEDICAMENTS CONTAINING THESE COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF - Google Patents

Abstract

The present invention relates to novel arylsulfonamides of the formula R1SO2R2AR4R5

Description

The present invention relates to novel arylsulfonamides of the formula

R ₀ R μ R -

, 2 | 4 | 5

R ₁ -SO ₂ -NAC-CH-B-CO-R ₆ O),

^A 3

the enantiomers, the cis and trans isomers, provided that R4 and Re together represent a carbon-carbon bond, and addition salts thereof, particularly for pharmaceutical use the physiologically acceptable addition salts with inorganic or organic bases, if R ₆ represents a hydroxy group, which valuable pharmacological

Have properties, in particular antithrombotic effects. In addition, the new connections simultaneously Thromboxane antagonists (TRA) and thromboxane synthesis inhibitors (TSH) are thus also inhibiting those caused by thromboxane

mediated effects. Furthermore, these also have an effect on PGEj production in the lung and on the PGD ₂ -,

PGE2 and PGFjo production in human platelets, The present invention thus relates to the novel compounds of the above formula I, their addition salts with

inorganic or organic bases, in particular for the pharmaceutical use whose physiologically acceptable

Addition salts, pharmaceutical compositions containing these compounds and processes for their preparation. In the above formula means Ri represents a phenylalkyl, trialkylphenyl, tetramethylphenyl or pentamethylphenyl group, optionally with one Halogen atom or an alkyl group-substituted thienyl group or a phenyl group represented by a nitro group

monosubstituted or mono- or disubstituted by a halogen atom, an alkyl, trifluoromethyl or alkoxy group, where the substituents may be the same or different,

R ₂ , R ₄ and R _6, which may be the same or different, each represents a hydrogen atom or an alkyl group or R _{2 is} a hydrogen atom or an alkyl group and R ₄ and R 5 together form a carbon-carbon bond, R _{3 is} an optionally substituted by an alkyl group pyridyl group, R _{6 represents} a hydroxy, alkoxy, amino, alkylamino or dialkylamino group, A is a group of formulas

in which

R _{7 is} a hydrogen atom or an alkyl group, R _{8 is} a hydrogen atom or R ₇ and R ₈ together represent a methylene or ethylene group and X represents an imino group substituted by an alkyl group, an oxygen or sulfur atom, wherein the -CHR _r Group is linked to the NR ₂ group, and B represents a carbon-carbon bond or a straight-chain one optionally substituted by one or two alkyl groups Alkylene group having 1 to 4 carbon atoms, wherein all the above-mentioned alkyl and alkoxy each 1 to

May contain 3 carbon atoms.

For the meanings mentioned in the definition of the radicals at the outset, for example R _{1 is} benzyl, 2-phenylethyl, 3-phenylpropyl, 2,4,6-trimethylphenyl, 2,4,6-triethylphenyl, 2,4,6-tri-n-propylphenyl,

2,3,5,6-tetramethylphenyl, 3,4,5,6-tetramethylphenyl, 2,4,5,6-tetramethylphenyl, 2,3,4,5,6-pentamethylphenyl, 2-thienyl , 3-Thienyl, 5-methyl-2-thienyl, 5-ethyl-2-thienyl, 5-n-propyl-2-thienyl, 5-n-isopropyl-2-thienyl, B-chloro ^ -thienyl, 5-bromo-2-thienyl, 5-methyl-3-thienyl, 5-ethyl-3-thienyl, bn-propyl-3-thienyl, 5-n-isopropyl-3-thienyl -, o-chloro-S-thionyl, 5-bromo-3-thienyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4- Ethylphenyl, 4-isopropylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4- Ethoxyphenyl, 4-n-propoxyphenyl, 4-isopropoxyphenyl, 4-isopropoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 4-bromophenyl, 2-nitrophenyl, 4-nitrophenyl, 3,4-dimethylphenyl, 3,4-dimethoxyphenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl i-, 2,5-dichlorophenyl, 2,4-dibromophenyl, 2,4-ditrifluoromethylphenyl, 2-methoxy-5-chlorophenyl or 2-methyl-5-chlorophenyl group,

for R ₂ , R ₄ , R ₇ and R _{8 are} each those of the hydrogen atom, the methyl, ethyl, n-propyl or isopropyl group, for Rj which is the hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy , Amino, methylamino, ethylamino, isopropylamino,

Dimethylamino, diethylamino, diisopropylamino or methylethylamino group,

for R ₃ which of the?, - pyridyl, 3-pyridyl, 4-pyridyl, 4-methyl (2-pyridyl) -, 2-methyl- {3-pyridy I) -, 2-methyl- (4 pyridyl) or 6-isopropyl (2-pyridyl) group,

X represents the oxygen or sulfur atom, the N-methylimino, N-ethylimino or N-isopropylimino group, and B represents the methylene, ethylene, n-propylene, n-butylene, a-methyl-ethylene, a-methyl-n-propylene, a-ethyl-n-propylene,

Propyl-n-propylene, α, α-dimethyl-n-propylene, α, α-diethyl-n-propylene, β-methyl-n-propylene, γ-methyl-n-propylene, α-methyl -

n-butylene or α, α-dimethyl-n-butylene, wherein the indicia are based on the carbonyl group, into consideration.

However, preferred compounds of formula I above are those in which Ri is a benzyl, thionyl, chlorothienyl, dichlorophenyl, dimethoxyphenyl, tetramethylphenyl or pentamethylphenyl group

or an optionally substituted by a fluorine or chlorine atom, a nitro, methyl or trifluoromethyl group

phenyl, R ₂ , R ₄ and Re are each a hydrogen atom or a methyl group or R _{2 is} a hydrogen atom or 6ine Mryl group and R ₄ and R _n together form a carbon-carbon bond, R _{3 is} a pyridyl group, Re is a hydroxy or methoxy group, A is a group of formulas

R ₇

in which

R ₇ and R ₈ each represent a hydrogen atom or together a methylene or ethylene group and X represents a sulfur atom or the N-methylimino group, wherein the -CHR ₇ group is linked to the -NR ₂ group, and B is a carbon-carbon bond or a straight-chain alkylene group having 2 to 4 carbon atoms, their Enantiomers, their cis and trans isomers, if R ₄ and R ₆ together form a carbon-carbon bond, and

their addition salts, in particular for the pharmaceutical application of their physiologically acceptable addition salts with inorganic or organic bases, if Re represents a hydroxy group.

However, particular preference is given to those compounds of the formula I in which R) one tetramethylphenyl or pentamethylphenyl group or one in the 4-position by a methyl group, a Trifluoromethyl group, a fluorine, chlorine or bromine substituted phenyl group, R ₂ , R ₄ and Rs each represent a hydrogen atom or R _{2 is} a hydrogen atom and R ₄ and R ₅ together form a carbon-carbon bond, R _{3 is} a 3-pyridyl group, A is a group of the formula

in the

R ₇ and R ₈ each represent a hydrogen atom or R ₇ and R ₈ together represent a methylene group, and Re are the hydroxy group, their enantiomers, their cis and trans isomers, provided that R ₄ and R together form a Form carbon-carbon bond, as well as their physiologically acceptable addition salts with inorganic or

organic bases.

According to the invention, the novel compounds are obtained by the following processes: a.) Acylation of a compound of the formula

R. R _c | 4 | 5

H-N-A-C-CH-B-CO-R ,. (II)

Il 6

^R 2 ^R 3

in the

R ₂ to Ri, A and B are as defined above, with a sulfonic acid derivative of the formula

R ₁ -SO ₂ X (III),

in the

Ri as defined above and

X is a nucleophilic leaving group such as a halogen atom or an alkoxy group, e.g. B. represents a chlorine or bromine atom, a methoxy or ethoxy group.

The reaction is preferably carried out in a solvent such as methanol, ethanol, water / methanol, dioxane, tetrahydrofuran or chloroform optionally in the presence of an acid-binding agent such as potassium carbonate, triethylamine or pyridine, the latter two also being usable as a solvent, conveniently at temperatures between 0 and 5O ⁰ C, but preferably at room temperature, performed.

b.) For the preparation of compounds of the formula I, in which R _{6 represents} a hydroxyl group:

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

? 2 ^R 4 ^R 5

R _n -SO ₀ -N-A-C-CH-B-CO-Z (IV),

^R 3

in the

Ri to R _e , A and B are as defined above and

Z represents a hydrolytically, thermolytically or hydrogenolytically removable protective group for a carboxy group or a functional derivative of the carboxy group.

Suitable hydrolyzable groups are, for example, 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, ethoxy, tert-butoxy or benzyloxy group or lactones and

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

The hydrolysis is conveniently carried out either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid or trichloroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent

such as water, water / methanol, ethanol, water / ethanol, water / isopropanol or water / dioxane at temperatures between -10 and 12O ⁰ C, for example at temperatures between room temperature and the boiling temperature of the reaction mixture performed.

If, for example, a compound of the formula IV contains a nitrile or aminocarbonyl group, these groups can preferably be prepared by means of 100% phosphoric acid at temperatures between 100 and 18O ⁰ C, preferably at temperatures between 120 and 160 ° C, or with a nitrite, z. As sodium nitrite, in the presence of an acid such as sulfuric acid, this is suitably used simultaneously as a solvent, be converted at temperatures between 0 and 5O ⁰ C in the Carboxygruppo.

For example, when a compound of formula IV contains an acid amide group such as the diethylaminocarbonyl or piperidinocarbonyl group, this group may preferably be hydrolytically in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid or trichloroacetic acid or in the presence of a base such as sodium hydroxide or

Potassium hydroxide in a suitable solvent such as water, water / methanol, ethanol, water / ethanol, water / isopropanol or water / dioxane at temperatures between -10 and 120 ° C, for. B. at temperatures between room temperature and the boiling temperature of the reaction mixture are converted into the carboxy group. For example, when a compound of formula IV contains the tert-butyloxycarbonyl group, the tert-butyl group may also be 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 Toluene sulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid preferably at the boiling point of the solvent used, for. B. at temperatures between 40 and 100 ⁰ C, are split off.

For example, if a compound of formula IV contains the benzyloxy or benzyloxycarbonyl group, the benzyl group can also be hydrogenolysed in the presence of a hydrogenation catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, methanol / water, ethanol / water, glacial acetic acid, ethyl acetate, dioxane or Dimethylformamide preferably at temperatures between 0 and 5O ⁰ C, z. B. be cleaved at room temperature and a hydrogen pressure of 1 to 5bar. In the hydrogenolysis, a halogen-containing compound can be simultaneously dehalogenated and an existing double bond can be hydrogenated.

c.) For the preparation of compounds of the formula I in which R ₄ and R ₆ each represent a hydrogen atom: hydrogenation of a compound of the formula

R ₀ I ² R ₁ - SO ₀ - N - A - C = CH - B - CO - K ₁ . , Vi

^R 3

R ₁ to Rp, R _e> A and B are as defined above. The hydrogenation is carried out in a suitable solvent such as methanol, ethanol, dioxane, ethyl acetate or glacial acetic acid with catalytic

excited hydrogen, z. With hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, palladium,

Palladium / carbon, platinum or platinum / carbon and a hydrogen pressure of 1 to 5 bar, or with nascent hydrogen, z. B.

in the presence of iron / hydrochloric acid, zinc / glacial acetic acid, stannous chloride / hydrochloric acid or ferric sulfate / sulfuric acid

Temperatures between 0 and 50 ° C, preferably at room temperature performed. However, the catalytic hydrogenation can

also be carried out stereoselectively in the presence of a suitable catalyst.

In this case, an optionally present in the radical Ri nitro group mitreduziert simultaneously or optionally in the rest Ri existing chlorine or bromine atom are ersotzt by a hydrogen atom.

d.) For the preparation of compounds of the formula I, in which R ₄ and R ₆ together represent a carbon-carbon bond:

Reaction of a compound of the formula

R ₉ I ^ R ₁ -SO ₂ -NA-CO-R ₃ ^{(from left)}

in the

R ₁ to R ₃ and A are as defined above, with a compound of the formula

W-CH-B-CO-R ₆ ^(VIII) '

in the

B and R _{3 are} as defined above, R ₆ 'is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms and W is a triphenylphosphonium halide, dialkylphosphonic acid or magnesium halide radical, and

optionally subsequent dehydration.

The reaction is preferably carried out in a suitable solvent such as diethyl ether, tetrahydrofuran, dioxane or Dimethylformamide at temperatures between -30 and 100 ⁰ C, preferably at temperatures between -20 and 25 ⁰ C,

carried out.

The reaction with a triphenylphosphonium halide of the formula VI is particularly advantageous, but in the presence of a Base such as potassium tert-butylate or sodium hydride. Should in the reaction with a magnesium halide of formula VI in the reaction mixture primarily incurred Carbinol the hydroxy group is not split off during the reaction, it is in the presence of an acid such as Hydrochloric acid, sulfuric acid, phosphoric acid or trichloroacetic acid or in the presence of a base such as sodium hydroxide or Potassium hydroxide in a suitable solvent such as ethanol, isopropanol or dioxane at temperatures between 0 and

120 ° C, z. B. at temperatures between room temperature and the boiling temperature of the reaction mixture cleaved.

If, according to the invention, a compound of the formula I in which R _{2 represents} a hydrogen atom can be obtained by means of Alkylation into a corresponding compound of formula I, in which R _{2 represents} an Alkylg uppe be converted, or

a compound of formula I in which Re represents or contains a hydroxy group, it may be by esterification or

Amidation in a corresponding compound of formula I, in which R _{8 is} an alkoxy, amino, alkylamino or Represents dialkylamino group, be converted. The subsequent alkylation is preferably carried out in a solvent such as methylene chloride, tetrahydrofuran, Dimethylformamide or dimethyl sulfoxide in the presence of an alkylating agent such as methyl iodide, dimethyl sulfate, Ethyl bromide, n-propyl bromide or isopropyl bromide optionally in the presence of an acid-binding agent such as Potassium carbonate at temperatures between 0 and 70 ° C, preferably at temperatures between 20 and 5O ⁰ C performed. Post-esterification or amidation is conveniently carried out in a solvent, e.g. in a surplus of

used alcohol such as methanol, ethanol or isopropanol or the amine used such as ammonia, methylamine, n-

Propylamine or dimethylamine in the presence of an acid activating agent such as thionyl chloride or hydrogen chloride gas Temperatures between 0 and 180 ° C, but preferably at the boiling temperature of the reaction mixture, carried out. The obtained compounds of the formula I can furthermore be separated into their enantiomers. This is how the obtained Compounds of the formula I which contain only one optically active center, according to methods known per se (see Allinger, Vol. N.L., and EHeI, W.L., in "Topics in Stereochemistry", Vol.6, Wiley lntercience, 1971) into their optical antipodes,

z. B. by recrystallization from an optically active solvent or by reacting with a, with the racemic

Compound salt-forming optically active substance, especially bases, and separating the thus obtained Salt mixture, z. Due to different solubilities, in the diastereomeric salts from which the free antipodes

can be released by the action of appropriate means. Particularly common, optically active bases are, for. As the D and L forms of a-phenyl-ethylamine or cinchonidine.

In addition, the compounds of formula I having at least 2 asymmetric carbon atoms can be prepared by methods known per se, for example by virtue of their physicochemical differences. separated by chromatography and / or fractional crystallization, in their diastereomers. A pair of enantiomers thus obtained can then be separated into its optical antipodes as described above. If, for example, a compound of the formula I contains two optically active carbon atoms, the corresponding (R R ', S S') - and (R S ', S R') forms are obtained.

In addition, the compounds of the formula I in which R ₄ and R ₆ together form a carbon-carbon bond can be prepared by conventional methods, for example by chromatography on a support such as silica gel or by crystallization into their cis- and trans convert -somers.

Furthermore, the new compounds of the formula I thus obtained, if they contain a carboxy group, can, if desired, subsequently be converted into their addition salts with inorganic or organic bases, in particular for the pharmaceutical application, into their physiologically tolerable addition salts. Suitable bases are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

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

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

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

The compounds of the formulas IV, V and VI used as starting materials are obtained by reacting a corresponding amino compound with a corresponding sulfonyl halide.

The compounds of formol VII used as starting materials are obtained by reacting a corresponding halocarboxylic acid with triphenylphosphine or with a trialkylphosphonic.

As already mentioned, the novel compounds and their physiologically tolerable addition salts with inorganic or organic bases have valuable pharmacological properties, in particular antithrombotic effects and an inhibiting effect on platelet aggregation. In addition, they also represent thromboxane antagonists and thromboxane synthesis inhibitors, it being particularly noteworthy that the compounds of formula I have this effect simultaneously. Furthermore, these also have an effect on PGE ₂ production in the lung and on PGD ₂ , PGE ₂ and PGFjo production in human platelets

 For example, the new connections

A = 6- (2- (4-toluenesulfonylamino) indan-5-yl) -6- (3-pyridyl) -hex-5-enoic acid, B = 6- (4- (2- (4-chlorobenzenesulfonylamino) -ethyl) phenyl) -6- (3-pyridyl) hex-5-enoic acid, C = 6- (2- (4-chlorobenzenesulfonamino) -indan-5-yl) -6- (3-pyridyl) -hexanoic acid, D = 6- (3-pyridyl) -hexanoic acid; 4- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl) -6- (3-pyridyl) hexanoic acid and E = 6- (4- (2- (4-trifluoromethylbenzenesulfonylamino) ethyl) phenyl) -6- (3-pyridyl ) hex-5-enoic acid was tested for biological properties as follows:

1. Antithrombotic effect

methodology

Platelet aggregation is measured by the method of Born and Cross (J. Physiol 170, 1997, 1964) in platelet-rich plasma of healthy subjects, and the blood is mixed with sodium citrate 3.14% in a volume ratio of 1:10.

Collagen-induced aggregation

The course of the decrease in the optical density of the platelet suspension is photometrically measured and registered after addition of the aggregation-initiating substance. From the inclination angle of the density curve is closed to the aggregation speed. The point of the curve where the highest light transmission is present is used to calculate the "optical density".

The amount of collagen is chosen as small as possible, but in such a way that results in an irreversible reaction curve.

The commercially available collagen from Hormonchemie, Munich is used.

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

From the obtained measurement numbers, an EC _{60 is} determined graphically, which relates to a B0% change in the "optical density" in the sense of inhibiting aggregation.

The following table contains the results found:

substance ΕΟ; ο [μΜοΙ / Ι] A 0.3 B 0.15 C 0.3 D 1.2 e 0.1

2. Thromboxanantagonlstlsche effect

Venous human blood is anticoagulated with 13 mM Na3 citrate and centrifuged for 10 minutes at 17Ox g. The supernatant platelet rich plasma will pass over a Sepharose 2B column to remove the plasma proteins. Aliquots of the platelet suspension obtained are incubated with the test substance, the ligand (3H-labeled) and a marker (14C-labeled) for 60 minutes at room temperature and then centrifuged for 20 seconds at 1000Ox g. The supernatant is withdrawn and the pellet 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, 14C is used to correct for ligand in the extracellular space. From the binding values for various concentrations of the test substance, the displacement curve is determined after iteration and the IC _M determined.

substance IC ₆₀ [MMoI /!] A 0.023 B 0.02 C 0.08 D 0.08 e 0.028

3. Determination of the inhibitory effect on thromboxane synthetase

Venous human blood is anticoagulated with 13 mM Na3 citrate and centrifuged for 10 minutes at 17Ox g. The supernatant platelet-rich plasma is passed over a Sepharose 2B column to remove the plasma proteins. Aliquots of the platelet suspension obtained are incubated with the test substance or solvent as a control for 10 minutes at room temperature and, after addition of 14C-labeled arachidonic acid, the incubation is continued for a further 10 minutes. After stopping with 50μΙ citric acid is extracted 3x with 500μΙ ethyl acetate and the combined extracts are purged with nitrogen. The residue is taken up in ethyl acetate, applied to TLC foil and separated with chloroform: methanol: glacial acetic acid: water (90: 8: 1: 0.8, v / v / v / v). The dried DC films are placed on X-ray film for 3 days, the autoradiography is developed and with their help the active zones on the film are marked. After excision, the activity is determined in the scintillation counter and the inhibition of TXB2 formation is calculated. The IC ₆₀ is determined by linear interpolation.

substance IC _MU \ iMol / l] A 0,003 B 0.0008 C 0,003 D 0.001 e 0,006

4. Inhibition of bronchospasm produced by U-46619

Guinea pigs anesthetized with ethyl urethane which are artificially ventilated under pressure control received repeated intravenous injections of the thromboxane mimetic U-46619 {= (1R- [1a, 4a, 5S (Z), 6a (1E, 3S *) l] -7 - [6- (3-hydroxy-1-octenyl) -2-oxabicyclo2.2.1] hept-5-yl] -5-heptenoic acid). The resulting bronchospasm is plethysmographically registered by a modification of the method of Konzett and Rössler (Konzett, H. and Rössler R., Arch. Exp. Pathol and Pharmacol., 195, 71-74 [1940]). The selected dose of U-46619 (2.5-25 pg / kg iv) reduces the tidal volume by 60% or more. Ten minutes before the thromboxane mimetic, increasing doses of the drugs to be tested are injected intravenously. The percent inhibition of the reduction in tidal volume is measured by comparing the U-46619 activity before and after different doses of the substances to be tested. The following table contains the found ED ₆₀ -We (Ie, which were determined graphically:

Substance ED _M [pg / kg]

A 30

B 29

5. Inhibition of the lethal effect of endotoxins

Male Sprague-Dawley rats are first exposed by intravenous injection with 0.1 mg / kg endotoxin (lipopolysaccharide E. coli 0111: B4) pretreated one week before the main experiment. In the main trial, a potentially lethal dose of E. coli

(40 mg / kg) was injected intravenously, and the subsequent mortality was recorded over an observation period of seven days.

The tested animals receive the substance B to be examined one hour before and 4,8,24 and 48 after the second injection of Endotoxin administered as a suspension in 0.5% Tylose per os. The following table contains the found values:

Application dose of substance B living / Total to applied at each dosing time rats 7 days point (mg / kg) to 2.10 2Tagen 6.10 0 2.10 5.10 1 10.7 10 8.10

6. Inhibition of bronchospasm produced by arachidonic acid

Guinea pigs anesthetized with ethylurethane, which are artificially ventilated under pressure, receive an intravenous injection with arachidonic acid (precursor for thromboxane), and the bronchospasm occurring are registered by a modification of the method of Konzett and Rössler. The doses of arachidonic acid (0.5-2.0 mg / kg) are chosen so as to reduce the tidal volume by 60%. Ascending doses of substance B to be tested are injected 10 minutes before arachidonic acid. The percentage inhibition of the restriction of the tidal volume is determined by a comparison between the maximum reduction after application of arachidonic acid and the corresponding value after pretreatment with the substance to be investigated. The ED ₆₀ word for substance B, which was determined graphically, is 8.1 mg / kg.

7. Inhibition of the subject anaphylaxis

Male guinea pigs are given 40mg / kg i.p. Ovalbumin, adsorbed on aluminum hydroxide as adjuvant, sensitized. About 6 weeks later, the same animals are given a subcutaneous injection of 0.1 mg / kg of mepyramine hydrochloride to reduce the histamine component of the anaphylactic reaction, which is otherwise very pronounced in guinea pigs. Thirty minutes later, the animals are exposed for 90 seconds to a nebulized 3% ovalbumin solution in 0.9% saline. Ten minutes after inhalation, the animals are killed with a stroke of the neck and the lungs quickly dissected out. Their volume, the so-called "relaxation volume", is measured.The consequence of anaphylaxis or bronchoconstriction is an enlargement of the "relaxation volume" (see Drazen, IM and Austen, KF in J. Appl. Physiol., 39, 916-919 [1975 ]) connected. The following table contains the found values:

Animals Mean relaxation volume

of the lungs (ml) First test Second test

Guinea pig after inhalation, 7.52 7.51

without test substance In = 6) (n = 6)

Guinea pig 60 minutes before 4.34 3.81

of inhalation pretreated with (n = 6) (n <= 6)

2.5 mg / kg p. o. substance B

Non-sensitized animals exposed to ovalbumin or sensitized guinea pigs treated with a control aerosol (saline) show a relative volume of 1.5 ml or less in all cases.

8. Influencing the formation of thromboxane and PGE ₂ In the isolated lung guinea pigs are killed by a stroke of the neck, the lung is quickly dissected out and washed through the pulmonary artery with Tyrode solution. With the same solution, the lungs are perfused (O.5ml / min) and ventilated with a negative pressure (frequency: 52 breaths / min, maximum pressure: -20cm H2O). Two 0.1 ml bolus injections of bradykinin (0.2 μΜ) are added to the perfusion solution for continuous perfusion of 1 μΜ of substance B to be tested. The control lungs are perfused without substance. The perfusate is collected 2 minutes before the bradykinin applications and 10 minutes thereafter. The samples remain at room temperature for 20 minutes (conversion of thromboxane A ₂ to B ₂ ) and are then frozen at -2O ⁰ C.

The concentrations of thromboxane B ₂ and PGE ₂ are determined by means of a radioimmunoassay. The results below demonstrate that 1 μM of substance B in the lung perfusate prevents thromboxane formation while promoting PGE _{2 production} :

Substance present in perfusate at 2. bradykinin · application Ratio of mediator release after2.Bradykinin application after 1st Brady kinin application Thromboxane B ₂ PGE ₂ 1μΜΒ control 0.0 0.0 1.18 0.50 0.84 5.08 2.23 1.28 1.12 1.09

9. Acute toxicity

The acute toxicity of the substances to be investigated was based on groups of 10 mice after oral administration of one Single dose determined (observation time: 14 days): Substance-oriented acute toxicity A 250 mg / kg (0 out of 10 animals died) B 250 mg / kg (0 out of 10 animals died) C 250 mg / kg (0 out of 10 animals died) D 250n j / kg (0 out of 10 animals died) E 250 mg / kg (0 of 10 animals died) Due to their pharmacological properties, the new compounds and their physiologically compatible ones are suitable Addition salts for the treatment and prophylaxis of thrombo-embolic disease such as coronary infarction, cerebral infarction,

so-called, transient ischemic attacks, amaurosis fugax, for the prevention of arteriosclerosis and metastasis prophylaxis, as well as for the treatment of ischaemia, asthma and allergies.

The new compounds and their physiologically acceptable addition salts are also useful in the treatment of diseases

useful in which thromboxane-mediated constriction or PGE _2- mediated dilatation of the capillaries play a role,

z. In pulmonary hypertension. In addition, these can be used to reduce the severity of a

Transplant rejection, for the reduction of renal toxicity, substances such as cyclosporine, for the treatment of Kidney disease, in particular for the therapy or prophylaxis of renal changes in the context of Hypertension, systemic lupus or ureteral obstruction and shock conditions related to sepsis, trauma

or burns are used.

The dosage required to achieve a corresponding effect is expediently two to four times a day

0.3 to 4 mg / kg of body weight, preferably 0.3 to 2 mg / kg of body weight. For this purpose, the compounds according to the invention of formula I, optionally in combination with other active substances, together with one or more inert conventional carriers and / or diluents, e.g. with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol,

Water / glycerin, water / sorbitol, water / polyethylene glycol. Propylene glycol, cetylstearyl alcohol, carboxymethyl cellulose or

fatty substances such as hard fat or their suitable mixtures, in common pharmaceutical preparations such as tablets, dragoes,

Incorporate capsules, powders, suspensions or suppositories. Another object of the present invention are novel pharmaceutical compositions containing a erfindungsgemäβ prepared in accordance with Compound of formula I and a PDE inhibitor or a lysing agent. As a PDE inhibitor here, for example

2,6-bis (diäthanolamino) -4,8-dipiperidino-pyrimido [5,4-d] pyrimidine (dipyridamole), 2,6-bis (diäthanolamino) -4-piperidino-pyrimido [5,4-d] pyrimidine (mopidamol), 2- (4-methoxy-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-e-pyridazinyl) -benzimidazole (pimobendan;, 2- (4 -hydroxy-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole, id-oxido-thiomorpholinol-S-piperazino-ü-methyl-isoquinoline .

6- [4- (3,4-Dichlorphenylsulfinyl) butoxy] -3,4-dihydrocarbostyrilund

6- [4- (2-pyridylsulfonyl) -butoxy] carbo8tyril, wherein the peroral daily dose

for dipyridamole 2.5 to 7.5 mg / kg, preferably 5 mg / kg,

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

for 2- (4-methoxy-phenyl) -5- (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole 0.05 to 0.15 mg / kg, preferably 0.08 to 0.10 mg / kg,

for 2- (4-hydroxy-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole 0.05 to 0.15 mg / kg, preferably 0.08 to 0.10 mg / kg,

for iO-oxido-thiomorpholinol-S-piperazino-S-methylisoquinoline 0.20 to 2.00 mg / kg, preferably 0.40 to 1.00 mg / kg, for 6- (4- (3,4- Dichlorophenylsulfinyl) -butoxy] -3,4-dihydrocarbostyril 0.10 to 1.00 mg / kg, preferably 0.20 to 0.50 mg / kg, and for 6- [4- (2-pyridylsulfonyl) -butoxy] carbostyril 0.10 to 1.00 mg / kg, preferably 0.20 to 0.50 mg / kg, and as a lysing agent plasminogen activators such as t-PA, rt-PA, streptokinase, eminase or urokinase into consideration, the

Lysing agents are administered parenterally, but preferably intravenously, e.g. t-PA or rt-PA in a dosage between 15

and 100 mg per patient, urokinase in a dose between 250,000 and 3,000,000 units per patient, eminase in one

Dosage of approximately 30mg per patient and streptokinase in a dose between 5 χ 10 * to 3 x 10 ⁷ IU each within

5 minutes and 24 hours.

For pharmaceutical use, a novel combination containing 1 to 500 mg of a PDE inhibitor, preferably

but from 2 to 75 mg, plus 10 to 300 mg of a compound of the formula I prepared according to the invention, but preferably 10 to 200 mg, as well as their physiologically acceptable addition salts together with one or more inert conventional

Carriers and / or diluents, for. With corn starch, lactose, cane sugar, microcrystalline cellulose, Magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerine, water / sorbitol, Water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as Hard fat or its suitable mixtures, in common pharmaceutical preparations such as tablets, Dragoes, capsules, powders, Incorporate suspensions or suppositories. In this case, the application is carried out on the adult to achieve a corresponding Action 2 to 4 times a day, but preferably 3 to 4 times a day. Furthermore, for pharmaceutical use, a novel combination comprising a lysing agent in the above

mentioned dosages plus 10 to 300 mg of a compound of formula I prepared according to the invention, but preferably 10 to 200 mg, as well as their physiologically acceptable addition salts in the usual parenteral, preferably in the usual intravenous, administration forms such as ampoules or infusions, the application within 5 minutesund 24 Hours can be done.

Of course, the individual active substances of the above combination can be applied if desired. The following examples are intended to explain the invention in more detail:

Example 1 6- (4- (2- (4-Chlorobenzenesulfonylamino) ethyl) phenyl) -e- (3-pyridyl) hex-5-enyne

a) 2- (p-Chlorobenzenesulfonylamino) ethylbenzene

To a mixture of 150 ml of ethylene chloride and 150 ml of water are added 30.3 g of 2-phenylethylamine, 12 g of sodium hydroxide and

0.5 g of tetrabutylammonium bromide. With stirring, the mixture is added in portions with 65.5g4-chlorobenzenesulfonyl chloride. After 30 minutes, the organic phase is separated, concentrated and the residue from

Toluene recrystallized. Yield: 65 g (88% of theory), Melting point: 9O ⁰ C

b) 4- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl-3-pyridyl ketone

100 g of aluminum trichloride are added slowly with 25, SmI dimethylformamide so that the temperature does not exceed 70 ⁰ C exceeded. To this mixture are added 35.6 g of nicotinic acid hydrochloride and 49g2- (4-chlorobenzenesulfonylamino) ethylbenzene and heated for 2 hours at 100 ⁰ C. The reaction mixture is added to ice, neutralized and extracted with ethylene chloride. The organic phase is concentrated and the residue chromatographed on a silica gel column with ethylene chloride / ethanol (40: 1).

Yield: 16.7 g (25% of theory), Melting point: 150-152 ⁰ C

C ₂₀ H ₁₇ CIN ₂ O ₃ S (400.91) Calc .: C 59.92 H 4.28 N 6.99 Fe: C 60.06 H 3.98 N 6.87

c) 6- (4- (2- (4-Chlorobenzenesulfonylamino) ethyl) phenyl) -6 (3-pyryldyl) hex-5-enoic acid

To a suspension of 6.7 g of 4-carboxybutyl-triphenylphosphonium bromide and 4.5 g of potassium tert-butylate in 100 ml Tetrahydrofuran is added at ⁰ ° C 4.0g 4- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl-3-pyridyl ketone and stirred for 2 hours. The Reaction mixture is decomposed with ice water and washed with toluene. The aqueous phase is acidified and washed with Extracted ethylene chloride. The organic extract is concentrated and the residue is chromatographed over a silica gel column with ethylene chloride / Ethanol (20: 1) chromatographed. The product-containing fraction is concentrated, the residue dissolved in ethyl acetate and through Add 2 ml of Cyclohexylamir Has cyclohexylammonium salt precipitated. Yield: 1.9 g (36% of theory, Melting point: 95 ⁰ C (dec.) C ₂₆ H ₂₅ CIN ₂ O ₄ S x VjCyclohexylamin (534.61)

Calcd .: C, 62.91, H, 5.94, N, 6.55, Fe: C, 62.80, H, 6.03, N, 6.72

Example 2 6- (1- (4- (2- (4-chlorobenzenesulfonylamino) ethyl) naphthyl)) - 6- (3-pyryldyl) hex-5-enoic acid

a) 1- (2- (p-Chlorobenzenesulfonylamino) ethyl) naphthalene

Prepared from 1- (2-aminoethyl) naphthalene and 4-chlorobenzenesulfonyl chloride analogously to Example 1 a. The cleaning of the Crude product was purified by column chromatography on silica gel with ethylene chloride / cyclohexane (2: 1). Yield: 92% of theory, Melting point: 98-99 ⁰ C

C ₁₈ H ₁₆ CINO ₂ S (345.87) Calc .: C 62.51 H 4.66 N 4,05Gef .: C 62.39 H 4.68 N 3.86

b) 4- (2- (4-chlorobenzenesulfonylamino) ethyl) naphthyl-3-pyridyl ketone

Prepared from nicotinic acid chloride hydrochloride and 1- (2- (p-chlorobenzenesulfonylamino) ethyl) naphthalene analogously to Example 1 b. The crude product was purified by column chromatography on silica gel with ethyl chloride / ethyl acetate (5: 1). Yield: 22% of theory, Resin, Rr value: 0.41 (silica gel: ethylene chloride / ethyl acetate = 3: 1)

C ₂₄ H ₁₉ CIN ₂ O ₃ S (450.96) Calc .: C 63.92 H 4.25 N 6,21Gef .: C 63.54 H 4.43 N 6.01

c) 6- (1- (4- (2- (4-Chlorobenzenesulfonylamino) ethyl) naphthyl)) - 6- (3-pyridyl) hex-5-enoic Acid Prepared from 4- (2- (4-chlorobenzenesulfonylamino) ethylnaphthyl-3-pyridyl ketone and 4-carboxybutyltriphenylphosphonium bromide analogously to Example 1c, but without salt precipitation with cyclohexylamine Yield: 43% of theory,

Resin, Ri value: 0.52 (silica gel: ethyl chloride / ethyl acetate = 4: 1)

C ₂₉ H ₂₇ CIN ₂ O ₄ S (535.09) Calc .: C, 65.10 H, 5.09, N, 5.24, Fe, C, 64.91, H, 5.35, N, 5.20

Example 3 6- (5- (2- (4-Fluorobenzenesulfonylamino) ethyl) -N-methyl-pyrrol-2-yl) -6- (3-pyr! -Dyl) -hex-5-enoic acid

a) 5- (2- (4-fluorobenzenesulfonylamino) ethyl) -N-methylpyrrol-2-yl-3-pyridyl ketone

A solution of 14.1 g of 2- {2- (4-fluorobenzenesulfonylamino) ethyl) -N-methyl-pyrrole in 100 ml of toluene and 50 ml of dimethylformamide

is added in portions with 9.8 g Nicotinsäurechloridhydrochlorid. It is refluxed for 2 hours

Reaction mixture on ice, neutralized and extracted with ethylene chloride. The crude product is over a silica gel column with Ethylene chloride / ethanol (20: 1) chromatographed. Yield: 4.6 g (24% of theory), Melting point: 14O ⁰ C

C ₁₉ H ₁₈ FN ₃ O ₃ S (387.44) Calcd .: C 58.90 H 4.68 N 10.85 Fe: C 58.62 H 4.52 N 10.70

b) 6- (5- (2- (4-fluorobenzenesulfonylamino) ethyl) -N-methyl-p-prrol-2-yl) -e- (3-pyridyl) hex-5-eno-8ure Prepared from 5- (2- (4-Fluorobenzenesulfonylamino) ethyl) -N-methyl-pyrrol-2-yl-3-pyridyl ketone and 4-carboxybutyltriphenylphosphonium bromide analogously to Example 1 c, but the crude product is purified by recrystallization from water / isopropanol.

Yield: 55% of theory, melting point: 190 ° CC ₂₄ HmFN ₃ O ₄ S (471.56) Ben: C 61.13 H 5.56 N 8.91 Found: C 61.23 H 5.72 N 9 00

Example 4 6- (5- (2- (4-Chlorobenzenesulfonylamino) ethyl) thiophen-2-yl) -e- (3-pyridyl) hex-5-ene Sure

a) 2- (2- (p-Chlorobenzenesulfonylamino) ethyl) thiophene Prepared from 2- (2-aminoethyl) thiophene and 4-chlorobenzenesulfonic acid chloride analogously to Example 1 a.

Yield: 69% of theory,

Set, rielzpunkt: 93 ⁰ C

C ₁₂ H, ₂ CINOjSj (301,83)

Calc .: C 47.75 H 4.01 N 4.64 Found: C, 47.75, H, 3.88, N, 4.45

b) 5- (2- (4-Chlorobenzenesul (onylamino) ethyl) thlophen-2-yl-3-pyridyl ketone. To a suspension of 20 g of aluminum trichloride and nicotinic acid chloride hydrochloride in 150 ml of ethylene chloride is added dropwise a solution of 15 g of 2- (2- (4-chlorobenzenesulfonylamino) ethyl) thiophene to in 50ml ethylene chloride. the mixture is heated 1 hour at Uz 5O ⁰ C, the reaction mixture onto ice, filtered off the precipitate and crystallized from methanol.

Yield: 3.7 g (17% of theory), m.p .: 154-160 ° C

C ₁₈ H ₁₆ CIN ₂ O ₃ S x Vj HCI (433.06)

Calcd .: C, 49.92, H, 3.58; N, 6.47, Found: C, 50.29, H, 3.82, N, 6.38

c) 6- (5- (2- (4-Chlorobenzenesulfonyl-fioi) ethyl) thlophon-2-yl) -6- (3-pyridyl) -hex-5-enoic acid

Prepared from 5- (2- (4-chlorobenzenesulfonylamino) ethyl) thiophen-2-yl-3-pyridyl ketone and 4-carboxybutyltriphenylphosphonium bromide analogously to Example 1c, but after the column chromatography is recrystallized from ethyl acetate.

Yield: 20% of theory,

Melting point: 138 ° C

C ₂₃ H ₂₃ CIN ₂ O ₄ S (491.04)

Calcd .: C 56.26 H 4.72 N 5.71 Found: C 56.24 H 4.67 N 5.70

Example 5 6- (2- (4-Chlorobenzenesulfonylamino) -tetralin-6-and-7-yl) -6- (3-pyridyl) hex-5-ene-acid

a) 2-Acotylamnnotetralin-6 and 7-yl-3-pyridyl ketone

Prepared from 2-acetylaminotetralin and nicotinic acid chloride hydrochloride analogously to Example 1 b.

Yield: 35% of theory,

Resin, Rr value: 0.28 (silica gel: ethylene chloride / ethanol = 10: 1) C ₁₈ H ₁₈ N ₂ O ₂ (294.40)

Calcd .: C 73.45 H 6.16 N 9.52 Found: C 73.38 H 6.23 N 9.26

b) 2- (4-Clilorobenzenesulfonylamino) tetralin-6 · and 7-yl-3-pyridyl ketone

The mixture of 2-Acetylaminotetrf> lin-6 and -7-yl-3-pyridyl ketone is refluxed for 20 hours in 150 ml of concentrated hydrochloric acid. The solvent is removed and the residue is treated with 4-chlorobenzenesulfonyl chloride according to Example 1a.

Yield: 35% of theory,

Melting point: 152-155 ⁰ C (Essigester) C ₂₂ H ₁₉ CIO ₃ S (426.94)

Calc .: C 61.89 H 4.49 N 6.56 Found: C, 61.92, H, 4.45, N, 6.46

c) 6- (2- (4-Chlorobenzenesulfonylamino) tetralin-6- and 7-yl) -6- (3-pyridyl) hex-5-enoic acid

Prepared from spine Mixture of 2- (4-chlorobenzenesulfonylamino) tetralin-6- and 7-yl-3-pyridyl ketone and 4-carboxybutyltriphenyl-phosphonium bromide analogously to Example 1c, but without salt precipitation with cyclohexylamine.

Yield: 93% of theory,

Resin, Rr value: 0.30 (silica gel: ethylene chloride / ethanol = 10: 1) C ₂₇ H ₂₇ CIN ₂ O ₄ S (511.07)

Calcd .: C 63.46 H 5.33 N 5.48 F: C 63.29 H 5.31 N 5.22

Example β

6 (5- (2- (4-fluorobenzene $ ulfonylamlno) ethvl) -N-methyl-pyrrol-2-vl) -E- (3-pyrldyl) hexen8iure

A mixture of 2.36 g of 6- (5- (2- (4-fluorobenzenesulfonylamino) ethyl) -N-methylpyrrol-2-yl) -6- (3-pyridyl) hex-5-enoic acid, 0.4 g Sodium hydroxide and 1 g of 10% palladium / carbon in 50 ml of methanol are hydrogenated at 5 bar hydrogen pressure. Subsequently

is filtered from the catalyst, concentrated, the residue diluted with water, acidified and extracted with ethylene chloride.

The organic extract is concentrated and the residue recrystallized from ethyl acetate. Yield: 2 g (85% of theory), Melting point: 146-149 ⁰ C

Calcd .: C, 60.88, H, 5.96, N, 8.87, Fe: C, 61.11, H, 6.02, N, 8.93

Example 7 6- (2- (4-Toluene-sulfonyl-amino) -ndan-5-yl) -6- (3-pyridyl) -hex-5-ensure

a) 2-Acetylamino-indan-5-yl-3-pyridyl ketone

To 150 g of aluminum chloride and 31 ml of dimethylformamide are added at 70 ° C in portions 42.7 g Nicotininsäurechlorid-

hydrochloride. To this mixture are added portionwise 35 g of 2-acetylaminoindan. After further heating the

Mixture at 8O ⁰ C is cooled after 2 hours and the mixture was added to 200 g of ice and 100 ml of concentrated hydrochloric acid. The acidic solution is carefully neutralized with sodium hydroxide solution and then extracted with 4x 250 ml of chloroform. The organic ones Phases are collected, dried over sodium sulfate and concentrated by rotary evaporation. Yield: 43g (76% of theory), Melting point: 165-167 ⁰ C

C ₁₇ H ₁₆ N ₂ O ₂ (280.32)

Calcd .: C, 72.84; H, 5.75; N, 9.99; Fe: C, 72.70, H, 5.72, N, 9.75

b) 2-aminoindan-5-yl-3-pyridyl ketone

51 g of 2-acetylamino-indan-5-yl-3-pyridyl ketone are refluxed with 250 ml of half-concentrated hydrochloric acid for 16 hours.

The solution is concentrated and then adjusted to pH 12 with 15N sodium hydroxide solution. The precipitate will precipitate with water

washed and recrystallized from 100 ml of isopropanol.

Yield: 42 g (97% of theory), Melting point: 205 ⁰ C (dec.)

C ₁₅ H ₁₄ N ₂ O (238.29)

Calcd .: C, 75.61, H, 5.92, N, 11.75, Fe: C, 75.44, H, 6.04, N, 11.85

c) 2- (4-toluenesulfonylamino) indan-5-yl-3-pyridyl ketone

21 g of 2-aminoindan-5-yl-3-pyridyl ketone are dissolved together with 18.9 g of p-toluenesulfonyl chloride in 250 ml of methylene chloride. Then added dropwise 9.2 g of triethylamine. After 4 hours, the suspension is evaporated to dryness. The

The residue is suspended in water, made alkaline with sodium hydroxide solution and then filtered with suction. Yield: 30.4 g (88% of theory), Melting point: 225-228 ° C

C ₂₂ H ₂₀ N ₂ O ₃ S (392.47) Calc .: C 67.33 H 5.14 N 7.14 Fe: C 67.12 H 5.16 N 6.95

d) 6- (2- (4-toluenesulfonylamino) indan-5-yl) -6- (3-pyridyl) hex-5-enoic acid

5 g of 2- (4-toluenesulfonyl-nino) indan-5-yl-3-pyridyl ketone are added to a suspension of 8 g of 4-carboxybutyltriphenylphosphonium bromide and 5.6 g of potassium tert -butylate in 100 ml of tetrahydrofuran under a nitrogen atmosphere The mixture is stirred for a further 2 hours at ⁰ ° C., then added to water and washed with toluene, then the aqueous phase is acidified with 3 N formic acid and the precipitate formed is taken up in methylene chloride.

The organic phase is dried over magnesium sulfate and concentrated by rotary evaporation. The resulting oil is on a silica gel column with Ethyl acetate as eluant Chromatography. Yield: 3.4 g (56% of theory), Melting point: 150-156 ⁰ C

C ₂₇ H ₂₈ N ₂ O ₄ S (476.59) Calc .: C, 68.04, H, 5.92, N, 5.88, Fe: C, 67.90, H, 6.10, N, 5.82

Examples of 6- (i .- (4-bromobenzenesulfonylamino) indan-5-yl) -6- (3-pyridyl) hex-5-enoic acid methyl ester

a) 6- (2-Acetylamino-indan-5-yl) -6- (3-pyridyl) hex-5-one-carboxylic acid 11.1 g of 4-carboxybutyltriphenylphosphonium bromide and 8.0 g of potassium tert -butylate are dissolved in 100 ml of absolute Tetrahydrofuran and stirred at 10 ° C under a StickstoffatmosphSre. Then give! Rr.an 5.6 g of 2-acetylaminoindan-5-yl-3-pyridyl ketone in portions and stirred at room temperature for 2 hours. Thereafter, the reaction mixture is poured into ice-water and washed with toluene. The aqueous phase is adjusted to pH 5 with 3N hydrochloric acid. The thereby failing

Precipitate is taken up in methylene chloride, washed with water, dried over sodium sulfate and concentrated by rotary evaporation. The Product mixture is passed through a silica gel column with the eluant Essipsäureethylester: ethanol: glacial acetic acid (94: 5: 1)

Chromatograph.

Yield: 7.2 g (39% of theory), Oil, firWert: 0.20 (silica gel: ethyl acetate / ethanol / glacial acetic acid = 94: 5: 1)

b) e (2-Amnol-indan-5-yl) -6- (3-pyridyl) hex-5-enyne-methyl ester

3.1 g of 6- (2-acetylaminoindan-5-yl) 6- (3-pyridyl) hex-5-enoic acid are dissolved with 20 ml of half-concentrated hydrochloric acid for 15 hours

Heated to reflux and then evaporated. The residue is then added to 50 ml of methanol, which with dry Hydrogen chloride is saturated. After stirring for 30 minutes at room temperature, the reaction mixture turns to dry

concentrated by rotary evaporation. The residue is taken up in 1N sodium hydroxide solution and adjusted to pH 10. Subsequently, with 3x 50 ml

Extracted methylene chloride, the organic phase dried and concentrated by rotary evaporation. Yield: 2.45 g (50% of theory) Resin, Rf = 0.50 (silica gel: toluene / dioxane / methanol / ammonia = 2: 5: 2: 1)

Cj ₁ H ₂₄ N ₂ O, (336,44)

Ben: C 74.97 H 7,19 N 8,33 Fe .: C 75,00 H 7,01 N 8,11

c) 6- (2- (4-bromobenzenesulfonylamino) indan-5-yl) -6- (3'-pyryl) -hex-5-methylenesulfonate

3,4g 6- (2-Aminoindan-5-yl) 6- (3-pyri'Jyl) hex-5-enoic acid methyl ester is mixed with 3.3 g of 4-bromobenzenesulfonyl chloride in 40 ml

Submitted to chloroform and treated portionwise at room temperature with 1.8 g of triethylamine. After 30 minutes, the solution becomes

washed with water, dried and evaporated.

The yellow oil is then chromatographed over a silica gel column with cyclohexane / ethyl acetate (1: 2). Yield: 4.5 g (81% of theory), Resin, Rp value: 0.25 (silica gel: cyclohexane / ethyl acetate = 1: 1)

Cj ₇ Hj ₇ BrN ₂ O ₄ S (555.48)

Calcd .: C 58.38 H 4.90 N 5.04 Fe: C 58.30 H 5.16 N 4.94

The following compounds are obtained analogously:

6- (2- (4-Chlorobenzenesulfonylamino) indan-5-yl) -6- (3-pyridyl) hex-5-ens8uremethylester.

Resin, Rr value: 0.32 (silica gel: cyclohexane / ethyl acetate = 1: 1)

C ₂₇ H ₂₇ CIN ₂ O ₄ S (511.03)

Calcd .: C, 63.46, H, 5.32, N, 5.48, Fe: C, 63.58, H, 5.49, N, 5.35

6- (2- (4-fluorobenzenesulfonylamino) indan-5-yl) -6- (3-pyridyl) hex-5-enoate

Resin, Rr value: 0.82 (silica gel: toluene / dioxane / methanol / ammonia = 2: 5: 2: 1)

C ₂₇ H ₂₇ FN ₂ O ₄ S (494.58)

Ben: C 65.57 H 5.50 N 5.66 Fe: C 65.39 H 5.78 N 5.48

6- (2- (2-Thiophenylsulfonylamino) indan-5-yl) -6- (3-pyridyl) hex-5-enoate

Resin, R _r value: 0.25 (silica gel: cyclohexane / ethyl acetate => 1, 1)

Cj ₆ HJeN ₂ O ₄ S ₂ (482.61)

Calc .: C 62.22 H 5.43 N 5.80 Fe: C 62.28 H 5.60 N 5.53

6- (2- (2,5-Dichlorbenzolsulfonylamino) indan-5-yl) -6- (3-pyridyl) hex-5-ijnsäuremethylaster

Resin, Rr value: 0.38 (silica gel: cyclohexane / ethyl acetate = 1: 1)

C ₂₇ H ₂₆ CIjN ₂ O ₄ S (545.48)

Calcd .: C, 59.45, H, 4.80, N, 5.14, Fe: C, 59.41, H, 5.02, N, 4.96

6- (2- (4-nitrobenzenesulfonylamino) indan-5-yl) -6- (3-pyridyl) -hex-5-enoic acid methyl ester

Resin, Rr value: 0.38 (silica gel: cyclohexane / ethyl acetate = 1: 1)

C ₂₇ H ₂₇ N ₃ O ₆ S (521.59)

Calcd .: C, 62.17, H, 5.22, N, 8.06, Fe: C, 62.22, H, 5.45, N, 7.90

6- (2- (benzenesulfonylamino) indan-5-yl) -6- (3-pyridyl) hex-5-enoate

Resin, Rf value: 0.20 (silica gel: cyclohexane / ethyl acetate = 1: 1)

Cj ₇ H ₂₈ NjO ₄ S (476.59)

Calcd .: C, 68.04, H, 5.92, N, 5.88, Fe: C, 67.98, H, 6.07. N 5.60

Example 9

6- (2- (4-bromobenzenesulfonylamino) indan-5-yl) -6- (3-pyridyl) hex-5-enoic acid 3.7g of 6- (2- (4-bromobenzenesulfonylamino) indan-5-yl) -6- (3-pyridyl) hex-5-enoic acid methyl ester are heated in 30 ml of ethanol and with 1 ml of 15 N sodium hydroxide solution for 15 minutes on Rückf.uß. The cooled solution is concentrated by rotary evaporation and the residue is taken up in water and washed with 30 ml of methylene chloride. Subsequently, the aqueous phase is adjusted to pH with hydrochloric acid. The precipitate is washed and dried.

Yield: 3.2 g (88% of theory), Melting point: 83-102 ° C

C ₂₅ H ₂₆ BrN ₂ O ₄ S (541.46)

Calc .: C 57.68 H 4.65 N 5.17 Gf .: C 57.58 H 4.64 N 4.99

The following compounds are obtained analogously:

6- (2- (4-chlorobenzo-1-sulfonylamino) -indan-5-yl) -6- (3-pyridyl) -hex-5-enoic acid

Melting point: 83 18 ° C

C ₂₆ H ₂₆ CIN ₂ O ₄ S (497.01) Calc .: C 62.83 H 5.07 N 5,64Gef .: C 62.64 H 5.02 N 5.57

6- (2- {4-fluorobenzenesulfonylamino) indan-5-yl) -6- (3-pyrldyl) hex-5-enoic acid

Melting point: 73-9O ⁰ C

Cj ₆ H ₂₆ FN ₂ O ₄ S (480.55) Calc .: C 64.98 H 5.24 N 5.83 Fe: C 64.85 H 5.23 N 5.76

6- (2- (2-Thiophenylsulfonylamino) indan-5-yl) -6- (3-pyridyl) hex-5-enoic acid

Mp 67-9O ⁰ C

Cj ₄ H ₂₄ NjO ₄ S ₂ (468.58) Calcd .: C 61.52 H 5.16 N 5.98 Fe: C 61.38 H 5.04 N 5.70

6- (2-benzenesulfonylamino) -indan-5-yl) -6- (3-pyridyl) hex-5-enoic acid

Melting point: 70-97 ⁰ C

Cj _e Hj _e Nj0 ₄ S (462,58)

Calcd .: C, 67.51; H; 5.67; N, 6.06; Fe: C, 67.44, H, 5.87, N, 6.18

6- (2- (4-nitrobenzenesulfonylamino) indan-5-yl) -6- (3-pyridyl) hex-5-enoic acid

Melting point: 73-92 ⁰ C

C ₂₆ Hj ₆ N ₃ O ₆ S (507.56)

Calcd .: C, 61.53, H, 4.96, N, 8.28, Fe: C, 61.45, H, 5.06, N, 8.18

6- (2- (2,5-Dichlorbenzolsulfonylamino) indan-S-yl) -6- (3-pyridyl) hex-5-en8äure

Melting point: 79-100 ° C Cj ₆ H ₂₄ CIjNjO ₄ S (531,45)

Calcd .: C, 58.7 H, 4.55, N, 5.27, Fe, C, 58.78, H, 4.65, N, 5.11

Example 10 e-W-U-W-chlorobenzenesulfonylaminoethylphenyl-e-O-pyridylhexanourti

a) 4- (2-Acittylaminoethyl) phenyl-3-pyridyl ketone

180g of aluminum chloride are versetit with 35ml dimethylformamide, the temperature rises to 7O ⁰ C. Subsequently, 66.8 g of nicotinic acid chloride hydrochloride and then 49 g of 2-acetylaminoethylbenzene at 70 ⁰ C to. After 2 hours, the mixture is cooled and mixed with 60 ml of ethylene chloride. Then pour the mixture on ice water and 180ml of concentrated hydrochloric acid.

The aqueous phase is made alkaline with sodium hydroxide solution and then extracted with 3x 100 ml of ethylene chloride. The organic Phase is dried and evaporated. Yield: 70.4 g (87% of theory), Oil, Rr value: 0.47 (kiosel gel: ethylene chloride / methanol = · 8.1)

C ₁₆ H ₁₈ N ₂ O ₂ (268.32)

Calc .: C 71.62 H 6.01 N 10.44 Fe .: C 71.82 H 6.20 N 10.30

b) 6- (4- (2-Acetylaminoethyl) phenyl) -6- (3-pyridyl) hex-5-enoic acid

Prepared analogously to Example 7d from 4- (2-acetylaminoethyl) -phenyl-3-pyridyl ketone and 4-carboxybutyl

bromide.

Yield: 57% of theory, Melting point: 80-85 ⁰ C

C ₂₁ H ₂₄ N ₂ O ₃ (352.4)

Calcd .: C, 71.57, H, 6.86; N, 7.95; Fe: C, 71.23, H, 7.06, N, 7.94

The following compounds are obtained analogously:

5- (4- (2-Ac8tylaminoethyl) phenyl) -5- (3-pyridyl) pent-4-enoic acid

Yield: 87% of theory, Resin, R, value: 0.35 (silica gel: chloroform / methanol = 10: 1)

CjOH ₂₂ NjO ₃ (338.4)

Calcd .: C, 70.98; H, 6.55; N, 8.28; Fe: C, 70.79, H, 6.39, N, 7.88

7- (4- (2-acetylaminoethyl) phenyl) -7- (3-pyridyl) hept-6-enoic Acid Yield: 49% of theory,

Resin, R _r value: 0.37 (silica gel: chloroform / methanol = 10: 1)

Ben: C 72.11 H 7,15 N 7,64 Found: C 71,82 H 7,41 N 7,58

c) 6- (4- (2-Acetylaminoethyl) phenyl) -6- (3-pyridyl) hexanoic acid

7.05 g of 6- (4- (2-acetylaminoethyl) phenyl) -6- (3-pyridyl) hex-5-enoic acid are dissolved in 85 ml of 0.7N sodium hydroxide solution and catalytically reduced at 40 ° C. with 1 ο palladium / carbon. After suctioning off the catalyst is acidified to pH6 and the precipitated oil was taken up in ethyl acetate and concentrated. The crude product is recrystallized from methanol.

Yield: 4.7 g (66% of theory), Melting point: 135-139 ⁰ C.

C ₂₁ H ₂₆ N ₂ O ₁ (354.5)

Calc .: C, 71.16, H, 7.39, N, 7.90, found: C, 70.85, H, 7.50, N, 7.85

The following compounds are obtained analogously:

5- (4- (2-acetylaminoethyl) phenyl) -5- (3-pyridyl) pentanoic acid Yield: 58% of theory,

Resin, Rr value: 0.37 (silica gel: chloroform / methanol = 10: 1) C ₂₀ , ^ (340.4)

Calc .: C70, bHH 7.11 N 8.23 Found: C 70.40 H 6.97 N 7.94

7- (4- (2-acetylaminoethyl) phenyl) -7- (3-pyridyl) heptanoic acid. Yield: 98% of theory,

Resin, Rr value: 0.43 (silica gel: chloroform / methanol = 10: 1) C ₂₂ H ₂₈ N ₂ O ₃ (368.5)

Calc .: C 71.71 H 7.66 N 7.60 Found: C 71.58 H 7.77 N 7.22

d) 6- (4- (2-Aminoethyl) phenyl) -6- (3-pyridyl) hexanoic acid

4.0 g of 6- (4- (2-acetylaminoethyl) phenyl) -6- (3-pyridyl) hexanoic acid are refluxed for 18 hours with 50 ml of half-concentrated hydrochloric acid. The mixture is then concentrated by rotary evaporation and the residue is chromatographed on a silica gel column using methanol.

Yield: 2.3 g (66% of theory), resin, Rr value: 0.27 (silica gel: methanol) C ₁₈ H ₂₄ N ₂ O ₂ (312.4)

Calc .: C, 72.81, H, 7.63, N, 8.83

The following compounds are obtained analogously:

5- (4- {2-aminoethyl) phenyl) -5- (3-pyridyl) pentanoic acid. Yield: 96% of theory,

Resin, Rr value: 0.33 (silica gel: methanol) C ₁₈ H ₂₂ N ₂ O ₂ x 0.5HCl (317.1)

Calc .: C 68.17 H 7.43 N 9.39 Found: C 68.27 H 7.31 N 8.99

7- (4- (2-aminoethyl) phenyl) -7- (3-pyridyl) heptanoic acid. Yield: 96% of theory,

Resin, Rr value: 0.59 (silica gel: methanol) C ₂₀ H ₂₆ N ₂ O ₂ (326.4)

Calc .: C 73.59 H 8.03 N 8.58 Found: C 73.48 H 8.00 N 8.37

c) 6- (4- (2- (4-Chlorobenzenesulfonylamino) ethyl) phenyl) -6- (3-pyridyl) hexane $ 8ure 1,9g 6- (4- (2-aminoethyl) phenyl) -6- (3 -pyridyl) -hexanoic acid are suspended in 150 ml of dioxane and mixed with 20 ml of 5% potassium carbonate solution. At room temperature, 1.54 g of 4-chlorobenzenesulfonyl chloride in 20 ml of dioxane are added to this mixture. After 5 hours, it is evaporated to dryness, the residue taken up in a little sodium hydroxide solution and then precipitated with dilute acetic acid. The precipitate is collected, dried and then chromatographed on a silica gel column with the eluent chloroform / methanol (10: 1).

Yield: 1.8 g (61% of theory), resin, Rr value: 0.48 (silica gel: chloroform / methanol = 10: 1) Cj ₅ H ₂₇ CIN ₂ O ₄ S (487.03)

Calcd .: C, 61.65, H, 5.59, N, 5.79, Found: C, 61.59, H, 5.40, N, 5.74

The following compounds are obtained analogously:

6- (4- (2- (4-Fluorben: olsulfonylamino) ethyl) phenyl) -6- (3-pyridyl) hexanoic acid

Yield: 11% of theory, Resin, Rf value: 0.53 (silica gel: chloroform / methanol = 10: 1)

C ₂₅ H ₂₇ FN ₂ O ₄ S (470.60)

Boron: C 63.81 H 5.78 N 5.95 Gf .: C 63.75 H 5.92 N 5.80

6- (4- (2- (4-toluenesulfonylamino) ethyl) phenyl) -6- (3-pyridyl) hexanoic acid

Yield: 13% of theory, Resin, R | value: 0.55 (silica gel: chloroform / methanol = 10: 1)

C ₂₆ H ₂₉ N ₂ O ₄ S (466.60)

Calcd .: C, 66.93; H, 6.48; N, 6.00, Fe: C66.81, H, 6.57, N, 5.94

6- (4- (2- (4-Brombenzolsulfonylamino) ethyl) phenyl) -6- (3-pyridyl) hexanoic acid

Yield: 24% of theory, Resin, Rr value: 0.34 (silica gel: chloroform / methanol - 20: 1)

C ₂₆ H ₂₇ BrN ₂ O ₄ S (531.50)

Calcd .: C, 56.50, H, 5.12, N, 5.27, Fe: C, 56.41, H, 5.31, N, 5.17

Example 11

5- (4- (2- (4-Fluorbenzolsulfonylamlno) ethyl) phenyl) -5- (3-pyrldyl) pentantaure

Prepared analogously to Example 10e from 5- (4- (2-aminoethyl) phenyl) -5- (3-pyridyl) pentanoic acid and 4-fluorobenzenesulfonyl chloride. Yield: 28% of theory, Resin, Rr value: 0.33 (silica gel: chloroform / methanol = 10: 1)

C ₂₄ H ₂₅ FN ₂ O ₄ S (456.50)

Calc .: C 63.14 H 5.52 N 6.94 Fe: C 63.04 H 5.60 N 5.96

Example 12

5- (4- (2- (4-Chlorbenzolsulfonylamlno) ethyl) phenyl) -5- (3-pyrldyl) pentans8ure

Prepared analogously to Example 10e from 5- (4- (2-aminoethyl) phenyl) -5- (3-pyridyl) pentanoic acid and 4-chlorobenzenesulfonyl chloride. Yield: 21% of theory, Melting point: 7O ⁰ C

C ₂₄ H ₂₆ CIN ₂ O ₄ S (473,00)

Calcd .: C 60.94 H 5.33 N 5.92 Fe: C 61.01 H 5.35 N 5.70

Example 13

7- (4- (2- (4-Toluolbenzolsulfonylamlno) ethyl) phenyl) -7- (3-pyrldy!) Heptansfiure

Prepared analogously to Example 10e from 7- (4- (2-aminoethyl) -phenyl) -7- (3-pyridyl) heptanoic acid and 4-toluenesulfonyl chloride. Yield: 78% of theory, Resin, Rr value: 0.42 (silica gel: chloroform / methanol = 10: 1)

C ₂₇ H ₃₂ N ₂ O ₄ S (480.60)

Calcd .: C, 67.47, H, 6.71, N, 5.83, Fe: C, 67.34, H, 6.71, N, 5.74

Example 14

7- (4- (2- (4-fluorobenzenesulfonylamino) ethyl) phenyl) -7- (3-pyridyl) heptansfiure

Prepared analogously to Example 13 from 7- (4- (2-aminoethyl) phenyl) -7- (3-pyridyl) heptanoic acid and 4-fluorobenzenesulfonyl chloride. Ausseute: 66% of theory, Resin, Rr value: 0.20 (silica gel: chloroform / methanol = 10: 1)

C ₂₉ H ^ fFN ₂ O ₄ S (484.6)

Calcd .: C, 64.44; H, 6.03; N, 5.72, Fe: C, 64.88, H, 5.99, N, 5.72

Example 15

Methyl 5- (4- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl) -5- (3-pyryl) pentanoic acid 2.0 g of 5- (4- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl) -5- (3 -pyridyl) pentanoic acid are dissolved in 30 ml of methanol and mixed with 3 ml

Thionyl chloride at ^{0 0} C added. The solution is stirred overnight, then evaporated and the residue on a silica gel column

Chromatograph.

Yield: 1.1 g (53% of theory), Resin, Rr value: 0.65 (silica gel: chloroform / methanol = 95: 5)

C ₂₆ H ₂₃ CIN ₂ O ₄ S (501.1)

Calcd .: C, 62.33, H, 5.83, N, 5.59, Fe: C, 62.36, H, 6.01, N, 5.42

Example 18

5- (2- (4-Chlorobenzenesul (onylamino) -ndan-5-yl) -5- (3-pvrldyl) -pent-4-sienoic methyl ester 3.7g of 5- (2- (4-chlorobenzenesulfonylamino) indan-5-yl) -5- (3-pyridyl) -pent-4-enoic acid is dissolved in 30 ml of methanol, introduced into dried hydrochloric acid, the solution is stirred overnight and then evaporated in. Under ice-cooling, the base is liberated with aqueous potassium carbonate solution, which is extracted with methylene chloride. The solution is rotary evaporated and the residue chromatographed on a kiosel gel column.

Yield: 2.5 g (52% of theory), Resin, R, value: 0.63 (silica gel: toluene / dioxane / ethanol / acetic acid = 9: 1: 1: 0.6)

C ₂₆ H ₂₅ CINjO ₄ S (497.01)

Calcd .: C, 62.80, H, 5.10, N, 5.60, Fe: C, 62.67, H, 5.39, N, 5.40

The following compound is obtained analogously:

7- (2- (4-Chlorobenzenesulfonylamino) indan-5-yl) -7- (3-pyridyl) hept-6-enoate

Yield: 73% of theory, Resin, Rr value: 0.31 (silica gel: cyclohexane / ethyl acetate = 1: 1) Cj ₈ Hj ₉ CINjO ₄ S (525,06)

Calcd .: C, 64.05, H, 5.56, N, 5.33, Fe: C, 64.45, H, 6.15, N, 5.05

Example 17

5- (2- (4-Chlorbonzolsulfonylamlno) indan-5-yl) -5- (3-pyrldyl) pent-4-ensaure

Prepared from 5- (2- (4-chlorobenzenesulfonylamino) indan-5-yl) -5- (3-pyridyl) pent-4-enoic acid methyl ester by hydrolysis with Sodium hydroxide solution. Yield: 95% of theory, Melting point: 94 to 114 ⁰ C Cj ₆ Hj ₃ CINjO ₄ S (482,98)

Calcd .: C, 62.20, H, 4.80, N, 5.80, Fe: C, 62.14, H, 4.70, N, 5.81

The following compound is obtained analogously:

7- (2- (4-Chlorobenzenesulfonylamino) indan-5-yl) -7- (3-pyridyl) hept-6-enoic acid

Yield: 94% of theory, Melting point: 66-9O ⁰ C

Cj ₇ H ₂₇ CIN ₂ O ₄ S (511.03)

Calcd .: C, 63.50, H, 5.30, N, 5.50, Fe, C, 63.65, H, 5.29, N, 5.30

Example 18

(Z) - and (E) -6- (2- (4-chlorobenzenesulfonylamino) indan-5-yl) -6- (3-pyrldyl) hex-5-sienyl, 1.9g 6- (2- (4-chlorobenzenesulfonylamino) indan-5-yl) -6- (3-pyridyl) hex-5-enoic acid methyl ester are chromatographed over a silica gel column with the eluent ethylene chloride / ethyl acetate / glacial acetic acid (70: 30: 5). The faster moving substance is the Z isomer. The (Z) and (E) esters thus obtained are hydrolysed analogously to Example 17 with sodium hydroxide solution.

(Z) -6- (2- (4-Chlorobenzenesulfonylamino) indan-5-yl) -6- (3-pyridinyl) hex-5-enoic acid

Yield: 200 mg (10% of theory), Melting point: 70-100 ⁰ C

Cj ₆ H ₂₅ CINjO ₄ S (497.01)

Calcd .: C, 62.83, H, 5.07, N, 5.64, Fe: C, 62.72, H, 5.24, N, 5.47

(E) -6- (2- (4-Chlorobenzenesulfonylamino) indan-5-yl) -6- (3-pyridinyl) hex-5-enoic acid

Yield: 400mg (20% ofTheorio), Melting point: 75 to 103 ⁰ C

C ₂₆ H ₂₅ CIN ₂ O ₄ S (497.01)

Calcd .: C, 62.83, H, 5.07, N, 5.64, Fe: C, 62.75, H, 5.14, N, 5.43

Example 19

6- (2- (4-Chlorobenzenesulfonylamino) -indan-5-yl) -6- (3-pyridyl) -hexanesauric acid 3.0g 6- (2- (4-chlorobenzenesulfonylamino) -indan-5-yl) -6- (3-pyridyl ) hex-5-enoic acid are dissolved in 50 ml of 0.3 N sodium hydroxide solution and hydrogenated bar mit1g palladium / carbon at 4O ⁰ C and 3.5 12 hours. The catalyst is then filtered off with suction and the filtrate adjusted to pH 4-5. The precipitated product is separated and taken up in chloroform. The organic extract is washed with water, dried and concentrated. Subsequently, the mixture is passed through a silica gel column with the flow agent

Ethylene chloride / ethyl acetate / glacial acetic acid = 70: 30: 2). The third fraction contains the desired

Product.

Yield: 0.4 g (13% of theory), Melting point: 85-100 ⁰ C

C ₂₈ H ₂₇ CINjO ₄ S

Calcd .: C, 62.58, H, 5.45, N, 5.61, Fe: C, 62.54, H, 5.45, N, 5.79

Example 20

7- (2- (4-Chlorobenzenesulfonylamino) indan-5-yl) -7- (3-pyrldyl) heptans8ure

Prepared analogously to Example 19 by reduction of 7- (2- (4-chlorobenzenesulphonylarnino) indan-5yl) -7- (3-pyridyl) hept-6-enoic acid

with platinum / coal.

Yield: 40% of theory, Resin, R value: 0.3 (silica gel: ethylene chloride / ethyl acetate / acetic acid = 10: 3: 0.5)

Cj ₆ H ₂₃ CIN ₂ O ₄ S (501.03) Boron: C 62.32 H 5.83 N 5.59 Fe: C 62.56 H 6.00 N 5.32

Example 21

5- (2- (Benzenesulfony! Amlno) indan-5-yl-S-i3-pyr! Dyl) pentanoic acid

Prepared from 5- (2- (4-chlorobenzenesulfonylamino) -indan-5-yl) -5- (3-pyridyl) -pent-4-acetic acid analogously to Example 19 by catalytic Hydrogenation in the presence of platinum as a catalyst. Yield: 37% of theory, Melting point: 80-110 "C

C ₃₅ H ₂ SCIN ₂ O ₄ S (485.00) Calc .: C 61.91 H 5.19 N 5.77 g. F: C 61.85 H 5.33 N 6.05

Example 22

7- (2- (Benzolsulfonylamlno) indan-5-yl) -7- (3-pyrldyl) heptansiure

Prepared from 7- (2- (4-chlorobenzenesulfonylamino) indan-5-yl) -7- (3-pyridyl) hept-6-enoic acid by catalytic hydrogenation analogously Example 21. Yield: 10% of theory, Melting point: 60-75 ⁰ C

C ₂₇ H ₂₉ CIN ₂ O ₄ S (513.05) Calc .: C 63.21 H 5.69 N 5.46 Fe: C 63.43 H 5.88 N 5.63

Example 23 3- (2- (4-Toluenesulfonylamino) indan-5-yl) -3- (3-pyryl) prop-2-enoic acid

a) 3- (2- (4-Toluenesulfonylamino) indan-5-yl) -3- (3-pyrldyl) prop-2-enoic acid ethyl ester

To a suspension of 9.6 g of potassium tert-butoxide in 100 ml of tetrahydrofuran and 25 ml of dimethylformamide are at 5.degree. C. 9.84 g Triethyl phosphonoate was added. After stirring for 30 minutes at ⁰ ° C., 15.5 g of 2- (4-toluenesulfonylamino) indan-5 are added.

yl-3-pyridyl ketone too. It is then boiled for 5 hours at reflux. The solution is added to ice-water and extracted with 4 × 50 ml of methylene chloride. It is then dried, concentrated by rotary evaporation and the residue is passed through a silica gel column with the

Eluent Ethyl chloride / ethyl acetate (9: 1) Chromatography. Yield: 17.2 g (93% of theory), Rr value: 0.46 / 0.35 (Kieselgel: ethylene chloride / ethyl acetate = 1: 1)

b) 3- (2- (4-toluenesulfonylamino) indan-5-yl) -3- (3-pyrldyl) prop-2-enoic acid

4.2 g of 3- (2- (4-toluenesulfonylamino) indan-5-yl) -3- (3-pyridyl) -prop-2-enoic acid ethyl ester are dissolved in 40 ml of ethanol with 1.5 ml of 15N

Sodium hydroxide solution boiled for 30 minutes under reflux. The cooled solution is then washed with 3x 50 ml of methylene chloride and then acidified. The failed one Precipitate is washed, dried and then recrystallized from n-butanol. Yield: 2.3 g (58% of theory), Melting point: 228-23O ⁰ C

C ₂₃ H ₂₂ N ₂ O ₄ S (422.5)

Calcd .: C, 65.38, H, 5.24, N, 6.63, Fe: C, 65.32, H, 5.17, N, 6.48

Example 24

3- (2- (4-toluenesulphonylamino) indan-5-yl) -3- (3-pyridyl) propanoic acid

Prepared analogously to Example 19 from 3- (2- (4-toluenesulfonylamino) indan-5-yl) -3- (3-pyridyl) prop-2-enoic acid and subsequent Cases of dioxane by addition of diisopropyl ether. Yield: 74% of theory, Melting point: 85-97 ⁰ C C ₂₃ H ₂₂ N ₂ O ₄ S x 0.8 dioxane (424.51)

Calcd .: C, 63.57, H, 6.19, N, 5.66, Fe: C, 63.39, H, 6.30, N, 5.62

Example 25

6- (4- (2- (4-fluorobenzenesulfonylamino) ethyl) phenyl) -6- (3-pyryl) hex-5-acetic acid, 3.1 g of 6- (4- (2-aminoethyl) phenyl) -6- (3-pyridyl) hex-5-enoic acid (prepared analogously to Example 10d) are stirred in 150 ml of dioxane with 5 ml of saturated potassium carbonate solution. Subsequently, 2.9 g of 4-fluorobenzenesulfonyl chloride in 20 ml of dioxane and stirred at room temperature overnight. Then it is mixed with acetic acid, whereby a precipitate precipitates. This is separated and taken up in ethyl acetate, dried and concentrated. Finally, the residue is over one

Silica gel column with the eluent chloroform / methanol (20: 1) chromatographed. Yield: 0.5 g (10% of theory), Resin, R _n WeM: 0.55 (silica gel: chloroform / methanol = 10: 1)

C ₂₅ H ₂₅ FN ₂ O ₄ S (470.6)

Boron: C 64.09 H 5.38 N 5.98 Fe: C 63.77 H 5.59 N 6.00

The following compounds are obtained analogously:

6- (4- (2- (4-toluenesulfonylamino) ethyl) phenyl) -6- (3-pyridyl) hex-5-enoic acid

Yield: 13% of theory, Resin, Rp value: 0.5 (silica gel: chloroform / methanol = 10: 1)

C ₂₆ H ₂₈ N ₂ O ₄ S (464.6)

Ben: C, 67.22, H, 6.07, N, 6.03, Fe: C, 67.06, H, 6.21, N, 5.86

6- (4- (2- (4-Brombenzolsulfonylamino) ethyl) phenyl) -6 (3-pyridyl) hex-5-enoic acid

Yield: 20% of theory, Resin, Rr value: 0.4 (silica gel: chloroform / methanol = 10: 1)

C ₂₅ H ₂₆ BrN ₂ O ₄ S (529.5)

Calc .: C, 56.71, H, 4.76, N, 5.29, Fe: C, 56.72, H, 4.58, N, 5.12

Example 26

7- (4- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl) -7- (3-pyridyl) -hept-6-ens8ure

Prepared from 4- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl-3-pyridyl ketone analogously to Example 7d. Yield: 83% of theory, Resin, R, value: 0.5 (silica gel: ethylene chloride / methanol = 5: 1)

C ₂₆ H ₂₇ CIN ₂ O ₄ S (499.02)

Calc .: C, 62.58, H, 5.45, N, 5.62, Fe: C, 62.48, H, 5.40, N, 5.62

Example 27

6- (4- (2- (4-Chlorobenzenesulfonylamino) ethyl) phenyl) -6- (3-pyridyl) hex-5-ene-1-hydroxyethylamide 1.0 g of 6- (4- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl) - Dissolve 6- (3-pyridyl) hex-5-enoic acid in 15 mL of tetrahydrofuran and stir with 0.49 g of carbonyldiimidazole for 15 minutes. Then 1 ml of diethylamine are added and the mixture is heated for 2 hours

Reflux. It is then concentrated and the residue taken up in ethyl acetate and dried. Finally, about one Silica gel column chromatographed with the eluent ethyl acetate. Yield: 0.6 g (54% of theory), Oil, Rr value: 0.23 (silica gel: ethyl acetate)

C ₂₉ H ₃₄ CIN ₃ O ₃ S (540.12)

Calcd .: C, 64.48; H, 6.34; N, 7.78; Fe: C, 64.42, H, 6.60, N, 7.52

The following compound is obtained analogously:

6- (4- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl) -6- (3-pyridyl) hex-5-ensäurebenzylamid

Yield: 51% of theory, Resin, (VWert: 0.37 (silica gel: ethyl acetate)

C ₃₂ H ₃₂ CIN ₃ O ₃ S (574,14)

Calcd .: C, 66.94, H, 5.61, N, 7.31, Fe: C, 66.72, H, 5.44, N, 7.10

Example 28

6- (4- (2- (N -methyl-4-chlorobenzenesulfonylamino! Ethyl) phenyl) -6- (3-pyryl) hex-5-ensulfure, 2.0 g of 6- (4- (2- (4-chlorobenzenesulfonylamino) ethyl ) phenyi) -6- (3-pyridyl) hex-5-enoic acid are dissolved in 10ml 4N sodium hydroxide, 100ml

Methylene chloride, 80 mg of benzyltrimethylammonium chloride and 0.85 g of methyl iodide stirred overnight. Subsequently, the

separated organic phase and the aqueous phase acidified to pH 5. The precipitated product is separated and stored in

Methylene chloride, dried and concentrated. Finally, the residue is chromatographed over a silica gel column with ethylene chloride / methanol (97: 3). Yield: 0.43 g (21% of theory), Melting point: 121-125 ⁰ C '

C ₂₆ H ₂₇ CIN ₂ O ₄ S (499.02)

Calcd .: C, 62.58, H, 5.45, N, 5.61, Fe: C, 62.53, H, 5.54, N, 5.53

Example 29 6- (4- (2- (4-Chlorobenzenesulfonylamino) ethyl) phenyl) -6- (3-pyridyl) -2,2-dimethy-hex-5-unsaturation

a) 6- (4- (2- (4-Chlorobenzenesulfonylamino) ethyl) phenyl) -6- (3-pyryldyl) -2,2-dimethyl-hex-5-ene-acid-dichloride Prepared analogously to Example 7d from 4-triphenylphosphoniumbutanoic acid-piperidide bromide and 4- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl-3-pyridyl ketone.

Yield: 6.7% of theory. Resin, Ri value: 0.4 (silica gel: ethyl acetate)

C ₃₂ H ₃ SCIN ₃ O ₃ S (580.16) Calc .: C 66.24 H 6.60 N 7.24 Fe: C 66.15 H 6.33 N 7.11

b) e- (4- (2- (4-Chlorobenzenesulfonylamino) ethyl) pher.yl) -6- (3-pyridyl) -2,2-dimethyl-hex-5-ene-acid

0.35 g of 6- (4- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl-6- (3-pyridyl) -2,2-dimethyl-hex-5-enoic acid piperidide are dissolved in 20 ml of 6N

Hydrochloric acid refluxed for 8 hours. It is then concentrated and the residue dissolved in sodium hydroxide solution and with hydrochloric acid

pH4 adjusted. The resulting precipitate is filtered off with suction and chromatographed on a silica gel column with ethylene chloride / Me'.hanol (10: 1).

Yield: 0.12 g (39% of theory), Resin, R _r value: 0.5 (silica gel: ethylene chloride / methanol = 9: 1)

C ₂₇ H ₂₉ CIN ₂ O ₄ S (513.04) Boron: C 63.21 H 5.70 N 5.46 Fe: C 63.08 H 5.58 N 5.60

Example 30 6- (4- (2- (2,4,6-Trimethylbenzenesulfonylamino) ethyl) phenyl) -6- (3-pyridyl) hex-5-ene-acid

a) 6- (4- (2-Aminoethyl) phenyl) -6- (3-pyridyl) hex-5-sienoic acid methyl ester

Prepared by hydrolysis of 6- (4- (2-acetylaminoethyl) -phenyl) -6- (3-pyridyl) hex-5-enoic acid followed by esterification

with methanol analogously to Example 8 b.

Yield: 87% of theory, Resin, Rp value: 0.6 (silica gel: dioxane / toluene / methanol / ammonia = 5: 2: 2: 1)

C ₂₀ H ₂₄ N ₂ O ₂ (324.42)

Calcd .: C, 74.05, H, 7.46, N, 3.63, Fe: C, 73.85, H, 7.58, N, 8.52

b) 6- (4- (2- (2,4,6-trimethylbenzenesulfonylamino) ethyl) phenyl) -6- (3-pyridyl) hex-5-acid

A mixture of 3.24 g of 6- (4- (2-aminoethyl) phenyl) -6- (3-pyridyl) hex-5-enoic acid methyl ester, 2.2 g of 2,4,6-trimethylbenzenesulfonyl chloride and 100 ml of triethylamine in 50 ml of dichloromethane becomes 30 Stirred for minutes at room temperature. Subsequently, the reaction mixture is washed twice with water, dried and concentrated. The residue is purified on a silica gel column with ethyl acetate. The crude product obtained is heated in a mixture of 32 ml ethanol and 5 ml of 4N sodium hydroxide solution 30 minutes 50-60 ⁰ C. The reaction mixture is concentrated, the residue taken up in 50 ml of water and washed with ethyl acetate. The water phase is adjusted to pH 5 by addition of citric acid and extracted twice with ethyl acetate. The organic phase is dried, concentrated and the residue is chromatographed on a silica gel column with ethyl acetate. The crude product is then recrystallized from ethyl acetate / diisopropyl ether. Yield: 1.35 g (28% of theory), Melting point: 79-83 ⁰ CC ₂₈ H ₃₂ N ₂ O ₄ S (492.64) Calc .: C 68.27 H 6.55 N 5.68 Found .: C 68.00 H 6,51 N 5,68

The following compounds are obtained analogously:

6- (4- (2- (2,3,5,6-Tetramethylbenzo! Sulfonylamino) ethyl) phenyl) -6- (3-pyridyl) hex-5-enoic acid

Melting point: 135-136 ⁰ C

C ₂₉ H ₃₄ N ₂ O ₄ S (506.76) Calc .: C 68.75 H 6.76 N 5,33Gef .: C 68.91 H 6.81 N 5.37

6- (4- (2- (2,3,5,6-Pentamäthylbenzolsulfonylamino) ethyl) phenyl) -6- (3-pyridyl) hex-G-enoic acid

Melting point: 158-160 ° C (ethyl acetate / diethyl ether)

C ₃₀ H ₃₈ N ₂ O ₄ S (520.69)

Calc .: C 69.20 H 6.97 N 5.38 Fe: C 69.00 H 7.14 N 5.49

6- (4- (2- (4-methoxybenzenesulfonylamino) ethyl) phenyl) -6- (3-pyridyl) hex-5-enoic acid

Melting point: 104-106 ⁰ C

C ₂₆ H ₂₈ N ₂ O ₆ S (480.58)

Calcd .: C, 64.98, H, 5.87, N, 5.83, Fe: C, 64.90, H, 6.02, N, 5.99

6- (4- (2- {3,4-Dimethoxybenzolsulfonylamino) ethyl) phenyl) -6- (3-pyridyl) hex-5-enoic acid

Yield: 18% of the theory, Haiz, R _r value: 0.36 (silica gel: dichloromethane / ethyl acetate = 6: 4 + 3% acetic acid)

C ₂₇ H ₃₀ N ₂ O ₆ S (510.61) Calc .: C 63.51 H 5.92 N 5.49 Fe: C 63.21 H 5.79 N 5.33

6- (4- (2- (4-trifluormethylbenzenesulfonylamino) ethyl) phenyl) -6-'3-pyridyl) HPX-5-ensäi're

Melting point: 140-143 ⁰ C (ethyl acetate / petroleum ether)

C ₂₆ H ₂₆ F ₃ N ₂ O ₄ S (518.56) Calc .: C 60.22 H 4.86 N 5,40Gef .: C 60.05 H 4.77 N 5.66

E- (4- (2- (5-Chlorthiophsn-2-sulfonylamino) ethyl) phenyl) -6- (3-pyridyl) hex-5-oic acid

Melting point: 113-115 ⁰ C

C ₂₃ H ₂₃ CIN ₂ O ₄ S ₂ (491.03) Calc .: C 56.26 H 4.72 N 5.70 Fe: C 55.96 H 4.70 N 5.79

6- (4- (2- (phenylmethanesulfonylamino) ethyl) phenyl) -6- (3-pyridyl) hex-5-enoic Acid C ₂₆ H ₂₈ N ₂ O ₄ S (464.58)

Resin, Rp value: 0.64 (silica gel: ethyl acetate)

Calcd .: C, 67.22, H, 6.07, N, 6.03, Fe: C, 67.27, H, 6.22, N, 5.88

Example 31 E- and Z-6- (4- (2- (4-chlorobenzenesul (onylamino) ethyl) phenyl) -6- (3-pyridyl) hex-5-enoic acid

a) 4- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl-3-pyridyl ketone

156 g of 4- (2-acetylaminoethyl) phenyl-3-pyridyl ketone are heated in 800 ml of 6 N hydrochloric acid for 16 hours. The solution is concentrated and the residue taken up in a mixture of 200 ml of water and 500 ml of dioxane. By adding 10N sodium hydroxide, a pH of 8-10 is established. Subsequently, a solution of 126 g of 4-chlorobenzenesulfonyl chloride in 150 ml of dioxane and 1N sodium hydroxide solution is added dropwise at room temperature so that a pH of 8-10 is maintained. The reaction mixture is added to a mixture of 1 kg of ice and 400 ml of toluene and the precipitate is filtered off with suction. The precipitated crude product is out

Toluene recrystallized. Yield: 148 g (65% of theory), Melting point: 159-16O ⁰ C

C ₂₀ H ₁₇ CIN ₂ O ₃ S (400.91) Calc .: C 59.92 H 4.28 N 6.99 Fe: C 60.00 H 4.10 N 6.91

b) E-6- (4- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl) -6- (3-pyridyl) hex-5-ensure

222g4-carboxybutyl-triphenylphosphonium bromide are suspended in 2000 ml of tetrahydrofuran and cooled to -20 ° C. 156 g of potassium tert-butylate are added to this suspension followed by 155 g of 4- (2- (4-chlorobenzenesulfonylamino) ethyl) -phenyl-3-pyridyl ketone. The mixture is stirred for 1.5 hours while allowing the temperature to rise to 10 ° C. The reaction mixture is added to 5000 ml of ice-water. The water phase is washed with ethyl acetate and then adjusted to a ρ ', Α of 5 by addition of citric acid. The precipitate is filtered off and recrystallized from water / ethanol. Yield: 140g (75% of theory), m.p .: 159-160 ° CC ₂₅ H ₂₆ CIN ₂ O ₄ S (485.00) Calc .: C 61.91 H 5.20 N 5.78 Found: C 61 , 67 H 5.06 N 5.70

c) Z-6- (4- (2- (4-Chlorobenzenesulfonylamino) ethyl) phenyl) -6- (3-pyrldyl) hexy-5-enoic acid

The mother liquor from Example 31 b is concentrated and extracted with ethyl acetate. The organic extract is concentrated

and the residue on a silica gel column with (ethylene chloride / ethyl acetate = 6: 4 + 3% acetic acid) chromatographed. The faster moving fraction is collected, concentrated and the residue from ethyl acetate /

Recrystallized diethyl ether. Yield: 7.8 g (3% of theory), Melting point: 94-95 ° C

C ₅₆ H ₂₆ CIN ₂ O ₄ S (485.00) Calc .: C 61.91 H 5.20 N 5.78 Gf .: C 61.66 H 5.23 N 5.87

Example 32 6- (2- (4-Chlorobenzenesulfonylamino) -1,2,3,4-tetrahydronaphth-6-yl) -6- (3-pyryl) hex-5-enoic acid

a) 2-Amino-6-bromo-1,2,3,4-tetrahydroriaphtlialine hydrochloride 55.0 g of titanium tetrachloride are carefully added dropwise at ⁰ ° C. to 700 ml of ethylene glycol dimethyl ether. 22.3 g of sodium borohydride are then added in portions, followed by a solution of 33.5 g of 6-bromo-2-oximino-1,2,3,4-tetrahydronaphthalene in 250 ml of ethylene glycol dimethyl ether. The mixture is stirred for 4 hours at room temperature, the reaction mixture is placed on ice, the mixture is

by adding conc. Ammonia alkaline and filtered through kieselguhr. The filtrate is extracted with methylene chloride. The

Extract is concentrated, the residue is mixed with ether and by addition of isopropanolic hydrochloric acid Hydrochloric!

like.

Yield: 20.2 g (55% of theory), Melting point: 237 ^° C. C ₁₀ HuBrN x HCI (262.5)

C .. C 45.74 H 4.99 N 5.33 Fe: C 45.30 H 5.22 N 5.24

b) 2-tert., Butoxycarbonylamlno-6-bromo-1,2,3,4-tetrahydronaphthalene

5.25 g of 2-amino-6-bromo-1,2,3,4-tetrahydronaphthalene are dissolved in 75 ml of dioxane / water (2: 1). At ⁰ ° C 44ml become 1N

Sodium hydroxide solution and then added 4.8 g of di-tert-butyl dicarbonate. It is stirred for 12 hours at room temperature, concentrated

then the reaction mixture, mixed with water and extracted with ethyl acetate. The extract is concentrated and the residue is recrystallized from petroleum ether.

Yield: 5.2 g (80% of theory), Melting point: 111 ° C

C ₁₆ H ₂₀ BrNO ₂ (326.23)

Calcd .: C, 55.23, H, 6.18, N, 4.29, Fe: C, 55.08, H, 6.29, N, 4.51

c) 2-tert-Butoxycarbonylamino-6-bromo-1,2,3,4-tetrahydronaphth-6-yl-3-pyridylmethanol

3.25 g of 2-tert.butoxycarbonylamino-6-bromo-1,2,3,4-tetrahydronaphthalene are dissolved in 50 ml of absolute tetrahydrofuran and cooled to -70 ° C. 8,8ml added dropwise a solution of n-butyllithium in hexane (2.5M) and stirred for another 1.5 hours at-5O ⁰ C. Subsequently zugetrop ⁰ C 1.1 g of pyridine-3-aldehyde at -7O ' i and it is stirred for another hour. The

Reaction mixture is poured onto ice and extracted with ethyl acetate. The organic phase is mixed with water

washed, dried, concentrated and the residue recrystallized from cyclohexane / Essigsäuraethylester.

Yield: 1.85 g (52% of theory), Melting point: 135 ° C

C ₂₁ H ₂₆ N ₂ O ₃ (354.45)

Calcd .: C, 71.16; H, 7.39, N, 7.90; Fe: C, 70.96, K, 7.46, N, 7.86

d) 2- (4-Chlorobenzenesulfonylamino) -1,2,3,4-tetrahydronaphth-6-yl-3-pyridyl ketone

1.75 g of 2-tert.butoxycarbon / lino-1,2,3,4-tetrahydronaphth-6-yl-3-pyridylmethanol are stirred in 30 ml of chloroform with 17.5 g of manganese dioxide for one hour at room temperature. The suspension is filtered, the filtrate concentrated, the residue was stirred in 10 ml of 2 N Salzsäur '·> hour at 40-5O ⁰ C. Subsequently, by adding conc. Ammonia made alkaline and the aqueous Ρ, · αίβ extracted with ethyl acetate. The extract is washed with water, concentrated and the residue dissolved in 20 ml of methylene chloride. At ⁰ ° C., 0.86 g of 4-chlorobenzenesulfonyl chloride and then 1 g of triethylamine are added to this solution and it is stirred for 2 hours at room temperature. The reaction mixture is poured onto ice and extracted with methylene chloride. The extract is washed with water, dried, concentrated and the residue is recrystallized from ethyl acetate / petrclather. Yield: 1.2 g (57% of theory), Melting point: 170-172 ⁰ CC ₂₂ H ₁₉ CIN ₂ O ₃ S (426.92) Calc .: C 61.89 H 4.49 N 6.56 Found .: C 61.63 H 4.62 N 6.39

e) 6- (2- (4-Chlorobenzenesulfonylamino) -1,2,3,4-tetrahydronaphth-6-yl) -O- (3-pyildyl) hex-F-denatur

Prepared analogously to Example 31 b from 2- (4-chlorobenzenesulfonylamino) -1,2,3,4-tetrahydroncphth-6-yl-3-pyridyl ketone and

4-carboxybutyl bromide.

Yield: 63% of theory, Melting point: 172 ^° C.

C ₂₇ H ₂₇ CIN ₂ O ₄ S

Calcd .: C, 63.46, H, 5.33, N, 5.48, Fe: C, 63.42, H, 5.41, N, 5.43

Example I Tablets containing 100 mg of 6- (4- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl) -6- (3-pyridyl) he.y-5 - { Composition:

1 tablet contains:

Active ingredient 100.0 mg Lactose 80.0 mg Corn starch 34.0 mg Polyvinylpyrrolidone 4.0 mg Magnesium stearate 2, 0 mg

220.0 mg

production method

Active ingredient, lactose and starch are mixed and evenly moistened with an aqueous solution of polyvinylpyrrolidone. After screening of the moist masses (2.0 mm mesh size) and drying in a drying oven at 5O ⁰ C is sieved again (1.5 mm mesh size) and admixed with the lubricant. The ready-to-use mixture is processed into tablets.

Tablet weight: 220mg

Diameter: 9mm, biplan with facet on both sides and one-sided part notch.

Example Il

Hardgel® capsules containing 150 mg of 6- (4- (2- (4-chlorobenzenesulphonylamino) ethyl) phenyl) -6- (3-pyrodyl) hex-5-unsuccine 1 capsule containing:

Active ingredient 150.0 mg

Corn starch drink. about 180.0mg

Milk sugar powder approx. 87.0 mg

Magnesium stearate 3.0 mg

about 320.0 mg

manufacturing

The active ingredient is mixed with the excipients, passed through a sieve of 0.75 mm mesh size and mixed homogeneously in a suitable device.

The final mixture is filled into size 1 hard gelatin capsules.

Capsule filling: ca.320mg

Capsule shell: hard gelatin capsule size 1.

Example III

Suppositories containing 150 mg of 6- (4- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl) -6- (3-pyryl) hex-5-enoic acid 1 suppository contains:

Active ingredient 150.0 mg

Polyethylene glycol (MT.1500) 550.0 mg

Polyethylene glycol (M. G. 6000) 460.0 mg

Polyoxyethylene sorbitan monostearate 840.0 mg

2000.0 mg

manufacturing

After the suppositories have melted, the active ingredient is distributed homogeneously therein and the melt is poured into pre-cooled molds.

Example IV

Suspensions containing 50 mg of 6- (4- (2- (4-chlorobenzenesulphonylamino) ethyl) phenyl) -6- (3-pyryldyl) hex-5-enoic acid 100 ml of suspension contain:

Active ingredient 1.0g

Carboxymethylcellulose Na salt 0.2g

p-hydroxybenzoic acid methyl ester 0.05 g

propyl p-hydroxybenzoate 0.01 g

Glycerol 5.0 g

Sorbitol solution 70% 50.0g

Aroma 0,3g

Wosserdest. ad 100ml

manufacturing

Dest. Water is heated to 70 ° C. Herein, p-hydroxybenzoic acid methyl ester and propyl ester and glycerol and carboxymethyl cellulose sodium salt are dissolved with stirring. Εε is cooled to room temperature and added with stirring, the active ingredient and dispersed homogeneously. After addition of the sorbitol solution and the aroma, the suspension is evacuated to vent with stirring.

5ml suspension contain 50mg active ingredient.

Example V

Tablets containing 150 mg of 6- (4- (2 - '(4-chlorobenzenesulfonylamino) -ethyl) -phenyl) -6- (3-pyridyl) hex-5-ethyl-ether Composition: 1 tablet contains:

Active substance 150.0 mg

Lactose powdered 89.0 mg

Corn starch 40.0 mg

Colloidal silica 10.0 mg

Polyvinylpyrrolidone 10.0 mg

Magnosium stearate 1.0 mg

300.0 mg

manufacturing The active substance mixed with milk sugar, corn starch and silicic acid is mixed with a 20% aqueous Polyvinylpyrrolidone solution moistened and beaten through a sieve with 1.5mm mesh size. The dried granules at 45 ⁰ C is again rubbed through the same sieve and with the specified amount Magnesium stearate mixed. From the mixture tablets are pressed. Tablet weight: 300 mg Stamp: 10 mm, flat Example Vl

Film Tablets containing 75 mg of 6- (4- {2- (4-chlorobenzenesulfonylamino) ethyl) phenyl) -6- (3-pyridyl) hex-5-enoure 1 tablet core contains:

Active substance 75.0 mg Calcium phosphate 93.0 mg Corn starch 35.5 mg Polyvinylpyrrolidone 10.0 mg Hydroxypropylmethylcellulose 15.0 mg Magnesium stearate 1.5 mg

230.0 mg

manufacturing

The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and half of the stated amount of magnesium stearate. On a tabletting machine compacts are made with a diameter of about 13 mm, these are ground on a suitable machine through a sieve with 1.5 mm mesh size and mixed with the remaining amount of magnesium stearate. This granulate is pressed on a tabletting machine into tablets of the desired shape.

Core weight: 230 mg Stamp: 9 mm, curved

The tablet cores thus prepared are coated with a film consisting essentially of hydroxypropylmethylcellulose. The finished film-coated tablets are shined with beeswax.

Film tablet weight: 245mg

Of course, all other compounds of general formula I can be used as active ingredients in the above galenic preparations.

Example VII Film-coated tablets containing 75 mg of 6- (4- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl) -6- (3-pyridyl) hex-5-one acid

(Substance B) + 75 mg PDE inhibitor

A powder mixture Dipyridamole 25%

Substance B 25%

Fumaric acid 15%

Cellulose 20%

Corn starch 8% Polyvinylpyrrolidone 6%

is moistened in a mixing device with water and granulated through a sieve with a mesh size of 1.5 mm. After drying and re-screening, 1% magnesium stearate is added to make 10 mm biconvex tablets of 300 mg. These

Tablets are sprayed with hydroxypropyl methylcellulose lacquer until they weigh 312 mg. Example VIII Hard gelatin capsules containing 200 mg of 6- (4- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl) -6- (3-pyridyl) hex-5-enoic acid

(Substance B) + 50mg PDE inhibitor 10kg dipyridamole, 20kg fumaric acid, 11.5kg polyvinylpyrrolidone, 40kg substance B, 1.5kg silica and 0.8kg

Magnesium stearate is mixed for 15 minutes in a cube mixer. This mixture is added via a roller compactor,

a drying granulator with screening device is connected downstream. The fraction 0.25-1.0mm is used. The

Capsule filling machine is set so that each size 0 capsule contains 50mg PDE inhibitors and 200mg (substance B)

contains appropriate amount of granules.

Example IX Hard gelatin capsules containing 100 mg of 6- (4- (2- (4-chlorobenzenesulfonylamino) phenyl) -6- (3-pyridyl) hex-5-enoic acid

(Substance B) + 250 mg PDE inhibitor)

a) granules

125kg mopidamole, 50kg fumaric acid, 13.5kg lactose are mixed and moistened with a solution of water / polyethylene glycol 6000. After granulation through a sieve having a mesh width of 1.0 mm and dried at 45 ⁰ C is mixed to 1.4 kg stearic acid.

b) Dragoe

100 kg of substance B, 7.5 kg of hydroxypropylmethylcellulose, 2.5 kg of silica and 15 kg of carboxymethylcellulose are moistened with ethanol and granulated through a sieve with a mesh size of 1.5 mm. After drying, 1 kg of magnesium stearate are mixed in and the granules are crushed into 126 mg biconvex tablets with a diameter of 5.5 mm. These cores are coated in several steps with a dragee suspension consisting of 5.6 mg sucrose, 0.5 kg gum arabic and 3.8 kg talcum until the tablets have a weight of 135 mg.

c) bottling

On a special capsule machine, the amount of granules corresponding to 250 mg of PDE inhibitor is poured into a hard gelatin capsule of size 0 I and the dragee containing 100 mg of substance B is placed on top.

Example X Suspension containing 10 mg of 6- (4- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl) -6- (3-pyridyl) hex-S-acid

(Substance B) + 100mg of dipyrldamol per 5g.

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 carboxymethyl cellulose 2.5%

(6) Taste Correctives / Preservatives 1.8%

(7) water 65.2%

In hot water O (O) is stirred under high shear. After cooling, incorporated into the viscous suspension (1), (2) and (7).

Example Xl Depot form containing 50 mg of 6- (4-f2- (4-chlorobenzenesulfonylamino) ethyl) phenyl) -6- (3-pyrodyl) hex-5-ene-acid

(Substance B) + 200 mg dipyrldamole

a) Pellet I 50.0 kg A mix of 12.5 kg Substance B 52.5 kg lysine 4.0 kg Hydroxypropylcellulose, high polymer 2.5 kg triacetin 3.5 kg ethyl cellulose magnesium stearate

is kneaded with ethanol on a special extruder and exiruded in the form of spaghetti (diameter 1 mm), which are rounded into pellets in a spheronizer. Then you dry them thoroughly.

b) pellet II

300 kg blended Weinsäui e starter pellets are sprayed in a special vessel with a suspension consisting of isopropanol, D ^: pyridamole and polyvinylpyrrolidone until the resulting drug pellets contain about 45% dipyridamole. These pellets are sprayed with a varnish consisting of Methacrylsänre / Methylnnethacrylat copolymer (trade name Eudragit S) and Hydroxypropylmethylcellulosephthalat (trade name HP 55) in the weight ratio 85:15 to 50:50. The organic lacquer solutions still contain plasticizer and talc. There are sprayed two pellet components with 5 and 7 / Ό Hüllsnmittel and different ratio of the coating components within the limits mentioned. The two components are mixed to give the following in vitro release: Conditions (according to USPXXI, Basket method, 100 rpm, 1st hour artificial gastric juice, pH 1.2.2 to 6th hour artificial Intestinal juice (phosphate buffer), pH 5.5): active ingredient release per hour:

I. hour about 30%

2nd hour about 25%

3rd hour about 18%

4th hour about 12%

after the 6th hour more than 90% dipyridamole release.

c) bottling

According to the active ingredient content of the pellet components I and II and the desired dosage who the pellets mixed with each other and filled on a capsule machine in capsules size 0 long.

Example XII Ampoules containing 5 mg of 6- (4- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl) -6- (3-pyridyl) hex-5-acetic acid

(Substance B) + 10mg dipyridamole per 5ml

Composition:

(1) Dipyridamole 10mg

(2) Substance B 5 mg

(3) propylene glycol 50 mg

(4) Polyethylene glycol 5 mg

(5) ethanol 10 mg

(6) Water for injections ad 5 ml (7) 1 N HCI ad pH 3

The active substances are dissolved by heating in the solution of (3) - (7). After pH control and sterile filtration, fill into suitable ampoules and sterilize.

Claims (2)

claims: | 4 | b C-CH
l ^R 3 -B-CO-R, Ri is a phenylalkyl, trialkylphenyl, tetramethylphenyl or pentamethylphenyl group, a thienyl group or phenyl group optionally substituted by a halogen atom or an alkyl group, which may be monosubstituted by a nitro group or mono- or disubstituted by a halogen atom, an alkyl, trifluoromethyl or alkoxy group where the substituents may be the same or different, R ₂ , R ₄ and R _5, which may be the same or different, each represents a hydrogen atom or an alkyl group or R _{2 is} a hydrogen atom or an alkyl group and FU and R ₅ together form a carbon-carbon bond, R _{3 is} a pyridyl group optionally substituted by an alkyl group, R _{6 is} a hydroxy, alkoxy, amino, alkylamino or dialkylamino group, A is a group of the formulas or kkj * in which R _{7 is} a hydrogen atom or an alkyl group,
R _{8 is} a hydrogen atom or R ₇ and R ₈ together represent a methylene or ethylene group and X represents an imino group substituted by an alkyl group, an oxygen or sulfur atom, wherein the -CHR ₇ group is linked to the -NR 2 group, and B is a carbon-carbon atom Binding or a optionally substituted by one or two alkyl groups straight-chain alkylene group having 1 to 4 carbon atoms, all alkyl and Älkoxyteile mentioned above may each contain 1 to 3 carbon atoms, their enantiomers, their cis and trans isomers, if R4 and R ₅ together represent a carbon-carbon bond and their addition salts. 2. arylsulfonamides of the formula I according to claim 1, in which R _{1 represents} a benzyl, thionyl, chlorothienyl, dichlorophenyl, dimethoxyphenyl, tetramethylphenyl or pentamethylphenyl group or a phenyl group optionally substituted by a fluorine or chlorine atom, a nitro, methyl or trifluoromethyl group, R ₂ , R ₄ and R _6, respectively a hydrogen atom or a methyl group or R _{2 is} a hydrogen atom or a methyl group and R ₄ and R ₅ together form a carbon-carbon bond,
R _{3 is} a pyridyl group,
R _{6 is} a hydroxy or methoxy group,
A is a group of formulas or in which R ₇ and R ₈ each represent a hydrogen atom or together a methylene or ethylene group and X represents a sulfur atom or the N-methylimino group, wherein the -CHR ₇ group is linked to the -NR ₂ group, and B is a carbon-carbon bond or a straight-chain alkylene group having 2 to 4 carbon atoms, their enantiomers, their cis and trans isomers, provided that R ₄ and R ₅ together form a carbon-carbon bond, and their addition salts. 3. arylsulfonamides of the formula I according to claim 1, in which R _{1 is} a tetramethylphenyl or pentamethylphenyl group or a phenyl group which is substituted in the 4-position by a methyl group, a trifluoromethyl group or a fluorine, chlorine or bromine atom, R ₂ , R ₄ and R ₅ each represent a hydrogen atom or R _{2 is} a hydrogen atom and R ₄ and R ₆ together form a carbon-carbon bond, R _{3 is} a 3-pyridyl group, A is a group of the formula in the R ₇ and R ₈ each represent a hydrogen atom or R ₇ and R ₈ together represent a methylene group, and Re are the hydroxy groups, their enantiomers, their cis and trans isomers, provided that R ₄ and R ₅ together form a carbon-carbon bond, and their addition salts. 4. As novel compounds of the formula I according to claim 1:
6- (2- (4-toluenesulfonylamino) indan-5-yl) -6- (3-pyridyl) -hex-5-enoic acid; 6- (4- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl) -6 - (3-pyridyl) hex-5-enoic acid and 6- (4- (2- (4-trifluoromethylbenzenesulfonylamino) ethyl) phenyl) -6- (3-pyridyl) hex-5-enoic acid and their acid addition salts. 5. 6- (4- (2- (4-Chlorobenzenesulfonylamino) ethyl) phenyl) -6- (3-pyridyl) hex-5-enoic acid and its acid addition salts. 6. Physiologically acceptable addition salts of the compound according to claims 1 to 5 with inorganic or organic bases. 7. A pharmaceutical composition comprising as active ingredient a compound according to claims 1 to 5oderdessen physiologically acceptable addition salt according to claim 6 in addition to optionally one or more inert carriers and / or diluents. 8. Medicament according to claim 7 suitable for the treatment and prophylaxis of thromboembolic diseases, for the prophylaxis of atherosclerosis and metastasis prophylaxis and for the treatment of ischemia, asthma and allergies. 9. A pharmaceutical composition according to claim 7 suitable for the treatment and prophylaxis of diseases in which a thromboxane-mediated constriction or PGE ₂ mediated dilation of the capillaries play a role to reduce the severity of graft rejection, to reduce the renal toxicity of substances such as cyclosporin, for the treatment of Kidney disease and for the treatment of shock. 10. Medicament according to claim 7, 8 or 9, characterized in that it additionally contains as active ingredient a PDE hammer or a lysing agent. 11. A process for the preparation of a medicament according to claims 7 to 10, characterized in that non-chemical way a compound according to claims 1 to 5 or its physiologically acceptable addition salt according to claim 6 optionally in combination with a PDE inhibitor or a lysing agent in a or more inert customary carriers and / or diluents is incorporated. 12. A process for the preparation of the compounds according to claims 1 to 6, characterized in that a.) A compound of the formula H-N-A-C-CH-B-CO-R ^R 2 ^R 3 in which R ₂ to R ₆ , A and B are as defined in at least one of claims 1 to 5, with a sulfonic acid derivative of the formula R ₁ -SO ₂ X (III), in which R _{1 is defined} as at least one of claims 1 to 5 and X is a nucleophilic leaving group such as a halogen atom or an alkoxy group, for. B. is a chlorine or bromine atom, a methoxy or ethoxy group, is acylated or b.) For the preparation of compounds of formula I ₁ in which R _{8 represents} a hydroxy group, from a compound of Fr> ^r mel | 2 | 4 | 5 R ₁ -SO ₀ -NAC-CH-B-CO-Z (IV), ^R 3 in which R ₁ to R ₆ , A and B are as defined in at least one of claims 1 to 5 and Z represents a hydrolytically, thermoiytically or hydroganolytically removable protective group for a carboxy group or a functional derivative of the carboxy group, a protective radical is split off or c. ) for the preparation of compounds of the formula I in which R ₄ and R ₅ each represent a hydrogen atom, a compound of the formula 2 R ₁ - SO ₂ -NAC = CH -B- CO-R ₆ (^ ^R 3 in which R ₁ to R ₃ , R ₆ , A and B are as defined in at least one of claims 1 to 5, or d.) for the preparation of compounds of formula I in which R ₄ and R ₅ together form a carbon -Carbon bond, a compound of the formula R ₂ R ₁ -SO ₂ -NA-CO-R ₃ ^(VI) ' in which R ₁ to R ₃ and A are as defined in at least one of claims 1 to 5, with a compound of the formula ^R 5 'W-CH-B-CO-R ₄ . ^(VII) in which B and R _{6 are} as defined in at least one of claims 1 to 5, R ₅ ', a hydrogen atom or an acyl group having 1 to 3 carbon atoms and W is a triphenylphosphonium halide, a dialkylphosphonic acid or a magnesium halide radical, reacted and optionally subsequently dehydrated, and if desired, subsequently converting a compound of the formula I in which R _{2 is} a hydrogen atom into a corresponding compound of the formula I in which R _{2 represents} an alkyl group, or a compound of the formula I in which R _{6 represents} a hydroxy group is converted by esterification or amidation into a corresponding compound of the formula I in which R _{6 is} an alkoxy, amino, alkylamino or dialkylamino group, or is converted thus obtained compound of formula I together represent wherein R 4 and R ₆ is a carbon-carbon bond is resolved into their cis and trans isomers or a thus-obtained compound of the formula is separated into its enantiomers I or a compound thus obtained of formula I is converted into their addition salts, in particular in their physiologically acceptable addition salts with inorganic or organic bases.