DE3915506A1 - New aryl:sulphonamide derivs. - Google Patents

Abstract

Arylsulphonamides of formula (I) and their enantiomers, as- and trans-isomers when R4 and R5 form a C-C bond, and their addn. salts are new. R1 = phenylalkyl, trialkyl, tetramethyl or pentamethylphenyl, thienlyl opt. substd. by halo or alkyl, or phenyl opt. mono-substd. by NO2 or di-substd. by halo, alkyl, CF3 or alkoxy; R2,R4,R5 = H or alkyl; or R2 = H or alkyl; and R4+R5 = a C-C bond; R3 = pyridyl opt. substd. by alkyl; R6 = OH, alkoxy, NH2 or mono- or di-alkylamino; A = a gp. of formula (i)-(iii). R7 = H or alkyl; R8 = H; or R7 + R8 = methylene or ethylene; X = imino substd. by alkyl, O or S. The CHR7 gp. is joined to the NR2 gp.; B = a C-C bond or 1-4C linear alkylene opt. susbtd. by 1 or 2 alkyl; alky, alkoxy contain 1-3C.

Description

The present invention relates to novel arylsulfone amide of the formula

their enantiomers, their cis and trans isomers, if R₄ and R₅ together represent a carbon-carbon bond as well as their addition salts, especially for the pharmaceutical application whose physiologically acceptable Addition salts with inorganic or organic bases, if R₆ represents a hydroxy group which is valuable have pharmacological properties, in particular anti thrombotic effects and mediated by thromboxane Effects. In addition, the new connections are the same early thromboxane antagonists (TRA) and thromboxane synthesis inhibitor (TSH).

Subject of the present formula are thus the new 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, drugs containing these compounds and process for their preparation.  

In the above formula means
R₁ is a phenyl group monosubstituted by a nitro group or may be mono- or disubstituted by a halogen atom, an alkyl or alkoxy group, the substituents being the same or different, or a thienyl group,
R₂, R₄ and R₅, which may be the same or different, each represents a hydrogen atom or an alkyl group or
R₂ is a hydrogen atom and R₄ and R₅ together form a carbon-carbon bond,
R₃ is a pyridyl group optionally substituted by an alkyl group,
R₆ represents a hydroxy, alkoxy, amino, alkylamino or dialkylamino group,
A is a group of formulas

in which
R₇ is a hydrogen atom or an alkyl group,
R₈ is a hydrogen atom or
R₇ and R₈ together form a methylene or ethylene group and
X represents an imino group substituted by an alkyl group, an oxygen or sulfur atom wherein the -CHR₇ group is linked to the -NR₂ group, and
B is a carbon-carbon bond or a straight chain alkylene group having 1 to 4 carbon atoms optionally substituted by one or two alkyl groups, wherein each of the above-mentioned alkyl and alkoxy moieties may each contain 1 to 3 carbon atoms.

For the Be mentioned in the definition of residues at the beginning, for example
R₁ is the 2-thienyl, 3-thienyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 4-isopropylphenyl -, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 4-n-propoxyphenyl, 4-isopropoxyphenyl, 2-fluorophenyl , 3-fluorophenyl, 4-fluoro-phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 4-bromophenyl, 2-nitrophenyl, 4-nitrophenyl, 3, 4-dimethylphenyl, 3,4-dimethoxyphenyl, 2,4-difluoro-phenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,4-dibromo-phenyl, 2-methoxy-5-chlorophenyl or 2-methyl-5-chlorophenyl group,
for R₂, R₄, R₇ and R₈ in each case those of the hydrogen atom, the methyl, ethyl, n-propyl or isopropyl group,
R₆ is hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, amino, methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino, diisopropylamino or methylethylamino group,
for R₃ which is the 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-methyl-2-pyridyl), 2-methyl- (3-pyridyl) -, 2-methyl- (4-pyri dyl) or 6-isopropyl (2-pyridyl) group,
for X that of the oxygen or sulfur atom, the N-methyl imino, N-ethylimino or N-Isopropyliminogruppe and
for B, the methylene, ethylene, n-propylene, n-butylene, α-methyl-ethylene, α-methyl-n-propylene, α-ethyl-n-propyl len, α -n- propyl-n-propylene, a, 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 group into consideration.

However, preferred compounds of formula I above are those in which
R₁ is an optionally substituted by a fluorine or chlorine atom, a nitro or methyl group-substituted phenyl group, a Dichchlorphenyl- or thienyl group,
R₂, R₄ and R₅ are each a hydrogen atom or
R₂ is a hydrogen atom and R₄ and R₅ together form a carbon-carbon bond,
R₃ is a pyridyl group,
R₆ is a hydroxy or methoxy group,
A is a group of formulas

in which
R₇ and R₈ 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 -CHR₇ group is linked to the -NR₂ 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 R₄ and R₅ together form a carbon-carbon bond, as well as their addition salts, in particular for the pharmaceutic application of their physiologically acceptable Addi tion salts with inorganic or organic bases, if R₆ represents a hydroxy group.

However, particular preference is given to those compounds of the formula I in which
R₁ is a phenyl group substituted in the 4-position by a methyl group, a fluorine, chlorine or bromine atom,
R₂, R₄ and R₅ are each a hydrogen atom or
R₂ is a hydrogen atom and R₄ and R₅ together form a carbon-carbon bond,
R₃ is a 3-pyridyl group,
A is a group of the formula

in the
R₇ and R₈ each represents a hydrogen atom or
R₇ and R₈ together represent a methylene group, and
R₆ represents the hydroxy group, their enantiomers, their cis and trans isomers, if R₄ and R₅ together form a carbon-carbon bond, and their physio logically acceptable addition salts with inorganic or organic bases.

According to the invention, the novel compounds are obtained according to fol the following procedure:

a) Acylation of a compound of the formula

in the
R₂ to R₅, A and B are as defined above, with a sulfonic acid derivative of the formula

R₁-SO₂X (III)

in the
R₁ as defined above and
X is a nucleophilic leaving group such as a halogen atom or an alkoxy group, e.g. As a chlorine or bromine atom, a methoxy or ethoxy group represents.

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 bin  such as potassium carbonate, triethylamine or pyridine, the latter two also being used as solvents can be conveniently at temperatures between 0 and 50 ° C, but preferably at room temperature, Runaway leads.

b) For the preparation of compounds of the formula I in which R₆ represents a hydroxy group:

Splitting off a protective residue from a compound of all my formula

in the
R₁ to R₅, A and B are as defined above and
Z represents a hydrolytically, thermolytically or hydrogenolytically cleavable protecting group for a carboxy group or a func tional 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 benzyl oxy group or lactones and
as thermolytically removable groups, for example esters with tertiary alcohols, for. B. the tert-butyl ester, and as hydrogenolytically cleavable groups, for example, aralkyl groups, eg. As the benzyl group, into consideration.

The hydrolysis is conveniently carried out either in the presence 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 between -10 and 120 ° C, z. B. at temperatures between Raumtem temperature and the boiling point of the reaction mixture, carried out.

For example, if a compound of formula IV contains a Nitrile or aminocarbonyl group, so these groups preferably by means of 100% phosphoric acid at temperatures between 100 and 180 ° C, preferably at temperatures between 120 and 160 ° C, or with a nitrite, z. B. Natri nitrite, in the presence of an acid such as sulfuric acid, wherein these expediently ver simultaneously as a solvent ver is used at temperatures between 0 and 50 ° C in the Carboxy group to be converted.

For example, if a compound of formula IV contains a Acid amide group such as diethylaminocarbonyl or piperi dinocarbonyl group, this group may preferably hydro lytic in the presence of an acid such as hydrochloric acid, sulfur acid, phosphoric acid or trichloroacetic acid or in counter be 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 / di oxane at temperatures between -10 and 120 ° C, z. B. at Tem temperatures between room temperature and the boiling point of the Reaction mixture, are converted into the carboxy group.

For example, if a compound of formula IV contains the tert-Butyloxycarbonylgruppe, so the tert-butyl group also thermally optionally in an inert solvent  such as methylene chloride, chloroform, benzene, toluene, tetrahydro furan or dioxane and preferably in the presence of a kata lytic amount of an acid such as p-toluenesulfonic acid, p hydrochloric acid, phosphoric acid or polyphosphoric acid, preferably at the boiling temperature of the solvent used, for. B. at temperatures between 40 and 100 ° C, be split off.

For example, if a compound of formula IV contains the Benzyloxy or benzyloxycarbonyl group, so the benzyl also hydrogenolytically in the presence of a hydrogenation catalyst such as palladium / carbon in a suitable solution such as methanol, ethanol, methanol / water, ethanol / what glacial acetic acid, ethyl acetate, dioxane or dimethyl formamide, preferably at temperatures between 0 and 50 ° C, z. B. at room temperature and a hydrogen pressure of 1 to 5 bar are split off. In the hydrogenolysis can be the same time a halogen-containing compound dehalogenated and a be hydrogenated existing double bond.

c) For the preparation of compounds of the formula I in which R₄ and R₅ each represent a hydrogen atom:

Hydrogenation of a compound of the formula

in the
R₁ to R₃, R₆, 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 kata lytically excited hydrogen, z. B. with hydrogen in Ge presently a hydrogenation catalyst such as Raney nickel, Pal  ladium, palladium / carbon, platinum or platinum / carbon and a Hydrogen pressure of 1 to 5 bar, or with nascent What hydrogen, z. In the presence of iron / hydrochloric acid, zinc / ice vinegar, tin (II) chloride / hydrochloric acid or iron (II) sulfate / s at temperatures between 0 and 50 ° C, preferably at room temperature. The catalytic Hydrie tion, however, can also be stereoselective in the presence of a ge suitable catalyst carried out.

Here, an optionally present in the radical R₁ Nitro group mitreduziert simultaneously or a given if in the radical R₁ present chlorine or bromine by a Hydrogen atom are replaced.

d) For the preparation of compounds of the formula I in which R₄ and R₅ together form a carbon-carbon bond represent:

Reaction of a compound of the formula

in the
R₁ to R₃ and A are as defined above, with a compound of the formula

in the
B and R₆ are as defined above,
R _{5 '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 solution such as diethyl ether, tetrahydrofuran, dioxane or dime Thylformamid at temperatures between 0 and 100 ° C, preferably at temperatures between 20 and 75 ° C, carried out.

The reaction with a triphenylphosphonium halide of Formula VI will be particularly beneficial, however, in the presence a base such as potassium tert-butoxide or sodium hydride guided.

Should in the reaction with a magnesium halide of the Formula VI in the reaction mixture primarily incurred Carbinol does not deplete the hydroxy group during the reaction in the presence of an acid, it becomes like this Hydrochloric acid, sulfuric acid, phosphoric acid or trichloroacetic acid 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, split off.

If, according to the invention, a compound of the formula I in which R₂ represents a hydrogen atom can be converted into an alkyl group by alkylation into a corresponding compound of the formula I in which R₂ is converted or
a compound of the formula I in which R₆ represents or contains a hydroxyl group, this can be converted by esterification or amidation into a corresponding compound of the formula I in which R₆ represents an alkoxy, amino, alkylamino or dialkylamino group.

The subsequent alkylation is preferably in a Lö such as methylene chloride, tetrahydrofuran, dimethyl formamide or dimethyl sulfoxide in the presence of an alkylie such as methyl iodide, dimethyl sulfate, ethyl bromide, n-propyl bromide or isopropyl bromide optionally in counter an acid-binding agent such as potassium carbonate Temperatures between 0 and 70 ° C, preferably at tempera between 20 and 50 ° C.

The subsequent esterification or amidation is purpose moderately in a solvent, for. B. in an excess the alcohol used, such as methanol, ethanol or Isopro panol 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 chlorinated water material gas at temperatures between 0 and 180 ° C, preferably but at the boiling point of the reaction mixture, by guided.

The obtained compounds of the formula I can furthermore be separated into their enantiomers. Thus, the compounds of the formula I which contain only one optically active center can be prepared by methods known per se (see Alinger, NL and Elich, WL in "Topics in Stereo Chemistry", Vol. 6, Wiley Interscience, 1971). split into their op tables antipodes, z. Example by recrystallization from an optically active solvent or by reacting with a, with the racemic compound salts forming optically active substance, in particular bases, and separating the salt mixture obtained in this way, for. B. due to different solubilities, in the diastereomeric salts from which the free antipodes can be released by the action of appropriate Mit tel. Particularly common, op table active bases are z. For example, the D and L forms of α- phenyl nyl-ethylamine or cinchonidine.

Furthermore, the compounds obtained can be Formula I having at least 2 asymmetric carbon atoms due to their physicochemical differences known methods, for. B. by chromatography and / or fractionated crystallization, into their diastereomers separate. An enantiomeric pair obtained in this way can be attached closing in its optical antipodes, as described above ben, split. Contains, for example, a connection of the Formula I two optically active carbon atoms, we obtain the corresponding (R-R ', S-S') - and (R-S ', S-R') forms.

In addition, the compounds of For mel I, in which R₄ and R₅ together form a carbon Koh lenstoff binding, by means of conventional methods For example, by chromatography on a carrier such as silica gel or by crystallization into their cis and trans isomers convict.

Furthermore, let the new compounds thus obtained of the formula I, if they contain a carboxy group, ge if desired then in their addition salts with anor ganic or organic bases, especially for the phar pharmaceutical application in their physiologically acceptable Addition salts, convert. As bases come in this case For example, sodium hydroxide, potassium hydroxide, cyclohexylamine, Ethanolamine, diethanolamine and triethanolamine into consideration.

The compounds of the formulas II used as starting materials to VII is 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 after Friedel-Craft, followed by Entacy lierung and optionally subsequent reduction, hydrolysis and / or esterification.  

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

The compounds of the formula VII used as starting materials is obtained by reacting a corresponding halogen carboxylic acid with triphenylphosphine or with a trialkyl phosphonate.

As already mentioned, the new compounds and their physiologically acceptable addition salts with organic or organic bases valuable pharmacological Characteristics, in particular antithrombotic effects and an inhibitory effect on platelet aggregation. also They also provide thromboxane antagonists and thromboxane syndrome It is particularly noteworthy that the Compounds of formula I aufwei this effect at the same time sen.

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 and
D = 6- (4- (2- (4-Chlorobenzenesulfonylamino) ethyl) phenyl) -6- (3-pyridyl) hexanoic acid

tested for their biological properties as follows:  

1. Antithrombotic effect methodology

Platelet aggregation is determined by the method of BORN and CROSS (J. Physiol 170, 397 (1964)) in platelet-rich Plasma of healthy subjects measured. For coagulation Inhibition is the blood with sodium citrate 3.14% in volume ratio 1: 10 offset.

Collagen-induced aggregation

The course of the decrease in the optical density of the platelets suspension becomes after addition of the aggregation-triggering sub punch measured and registered photometrically. From the Nei Angle of the density curve is on the Aggregationsge speed closed. The point of the curve at which the greatest light transmission is used for the calculation the "optical density".

The amount of collagen is chosen as low as possible, but nevertheless so that there is an irreversible reaction curve results. The commercial collagen of the company is used Hormone Chemistry, Munich. Before the addition of collagen, the plasma is in each case 10 minutes incubated with the substance at 37 ° C.

From the measurements obtained is graphically an EC₅₀ be is correct, referring to a 50% change in the "optical den sity "in terms of aggregation inhibition.

The following table contains the results found:

substance EC₅₀ [μ mol / l] A 0.3 B 0.15 C 0.3 D 1.2

2. Thromboxane antagonistic action

Venous human blood is anticoagulated with 13 mM Na₃ citrate and centrifuged at 170 x g for 10 minutes. The supernumerary platelet-rich plasma is used to remove the plasma protein ine on a Sepharose-2B column. Aliquots of the erhal The platelet suspensions are mixed with the test substance, the Ligands (3H-labeled) and a marker (14C-labeled) 60 Incubated at room temperature for 20 minutes and then 20 seconds centrifuged at 10,000 × 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 ligand in the extracellular space applies. From the binding values for different concentra tions of the test substance becomes the displacement after iteration curve and determines the IC₅₀.

substance IC₅₀ [μMol / l] A 0.023 B 0.02 C 0.08 D 0.08

3. Determination of the inhibitory effect on thromboxane synthetase

Venous human blood is anticoagulated with 13 mM Na₃ citrate and centrifuged at 170 x g for 10 minutes. The supernumerary platelet-rich plasma is used to remove the plasma protein ine on a Sepharose-2B column. Aliquots of the erhal The platelet suspensions are mixed with the test substance or Solvent as control for 10 minutes at room temperature incubated and after addition of 14C-labeled arachidonic acid the Incubation continued for another 10 minutes. After stopping with 50 μl of citric acid is extracted 3 times with 500 μl of ethyl acetate Heated and the combined extracts with nitrogen blown off. The residue is taken up in ethyl acetate, on TLC foil applied and with chloroform: methanol: glacial acetic acid: water (90: 8: 1: 0.8, v / v / v / v) separately. The dried DC slides 3 days are put on X-ray film, the autoradiograms developed and with their help the active zones on the Slide marked. After leaving the activity in the Scintillation counter and inhibition of TXB2-Bil calculated. The IC₅₀ is determined by linear interpolation certainly.

substance IC₅₀ [μMol / l] A 0,003 B 0.0008 C 0,003 D 0.001

4. Acute toxicity

The acute toxicity of the substances to be investigated was orienting to groups of 10 mice each after oral administration a single dose (observation time: 14 days):

substance Orienting 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 250 mg / kg (0 out of 10 animals died)

Due to their pharmacological properties are suitable the new compounds and their physiologically acceptable Addition salts for the treatment and prophylaxis of thrombo-em bolic diseases such as coronary infarction, cerebral infarction, Prophylaxis of arteriosclerosis and metastasis prophylaxis as well as for the treatment of ischemia, asthma and of Allergies.  

The necessary to achieve a corresponding effect Dosage is expediently two to four times a day 0.3 to 4 mg / kg of body weight, preferably 0.3 to 2 mg / kg Body weight. For this purpose, the invention can be Herge Compounds of formula I, optionally in Kom Combination with other active substances, together with one or several inert customary carriers and / or dilution average, z. B. with corn starch, lactose, cane sugar, micro crystalline cellulose, magnesium stearate, polyvinylpyrroli don, citric acid, tartaric acid, water, water / ethanol, what water / sorbitol, water / polyethylene glycol, Pro ethylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or their suitable Ge in common pharmaceutical preparations such as tablets, Drag'es, capsules, powders, suspensions or Zäpfen einar BEITEN.  

The following examples are intended to illustrate the invention in more detail purify:

example 1 6- (4- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl) -6- (3-pyridyl) hex-5 - enoic acid 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. While stirring, the mixture is added portionwise with 65.6 g of 4-chlorobenzenesulfonic chloride. After 30 minutes, the organic phase is separated abge, concentrated and the residue recrystallized from toluene.
Yield: 65 g (88% of theory),
Melting point: 90 ° C

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

100 g of aluminum trichloride are slowly mixed with 25.5 ml Dime thylformamid so that the temperature does not exceed 70 ° C. To this mixture are added 35.6 g of nicotinic acid chloride hydrochloride and 49 g of 2- (4-chlorobenzenesulfonylamino) ethylbenzene and heated to 100 ° C for 2 hours. The reac tion mixture is added to ice, neutralized and extracted with ethylene chloride. The organic phase is concentrated and the residue is chromatographed over a silica gel with ethylene chloride / ethanol (40: 1).
Yield: 16.7 g (25% of theory),
Melting point: 150-152 ° C

C₂₀H₁₇ClN₂O₃S (400,91)
Re: C 59.92; H 4,28; N 6.99
Found: C 60.06; H 3.98; N 6,87

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

To a suspension of 6.7 g of 4-carboxybutyl-triphenylphosphonium bromide and 4.5 g of potassium tert-butoxide in 100 ml of tetra-hyrofuran is added at 0 ° C 4.0 g of 4- (2- (4-Chlorbenzolsul phonylamino ) 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 extracted with ethylene chloride. The organic extract is concentrated and the residue is chromatographed on a silica gel column with ethylene chloride / ethanol (20: 1). The product-containing fraction is concentrated by evaporation, the residue is dissolved in ethyl acetate and the cyclohexylammonium salt is precipitated by the addition of 2 ml of cyclohexylamine.
Yield: 1.9 g (36% of theory),
Melting point: 95 ° C

C₂₅H₂₅ClN₂O₄S × ½ cyclohexylamine (534.61)
Calc .: C, 62.91; H 5.94; N 6,55
Found: C, 62.80; H 6.03; N 6,72

example 2 6- (1- (4- (2- (4-chlorobenzenesulfonylamino) ethyl) naphthyl)) - 6- (3-pyridyl -)) hex-5-enoic acid a) 1- (2- (p-chlorobenzenesulfonylamino) ethyl) naphthalene

Prepared from 1- (2-aminoethyl) naphthalene and 4-chlorobenzenesulfonyl chloride analogously to Example 1a. 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 ° C

C₁₈H₁₆ClNO₂S (345,87)
Calc .: C, 62.51; H 4.66; N 4.05
Found .: C 62.39; H, 4.68; N 3.86

b) 1- (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 1b. The crude product was purified by column chromatography on silica gel with ethylene chloride / ethyl acetate (5: 1).
Yield: 22% of theory,
Resin, R _f value: 0.41 (silica gel: ethylene chloride / ethyl acetate = 3: 1)

C₂₄H₁₉ClN₂O₃S (450,96)
Re: C 63.92; H 4,25; N 6.21
Found: 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 1- (4- (2- (4-chlorobenzenesulfonylamino) ethyl) naphthyl) - (3-pyridyl) ketone and 4-carboxybutyl-triphenylphosphonium bromide analogously to Example 1c, but without salt precipitation with cyclohexylamine.
Yield: 43% of theory,
Resin, R _f value: 0.52 (silica gel: ethylene chloride / ethyl acetate = 4: 1)

C₂₉H₂₇ClN₂O₄S (535,09)
Calc .: C 65.10; H 5.09; N 5.24
Found: C, 64.91; H 5.35; N 5.20

example 3 6- (5- (2-4-fluorobenzenesulfonylamino) ethyl) -N-methyl-pyrrol-2-yl) -6- (3 - pyridyl) hex-5-enoic acid a) (5- (2- (4-fluorobenzenesulfonylamino) ethyl) -N-methyl-pyrrol-2-yl) - (3-py ridyl-) ketone

A solution of 14.1 g of 2- (2-fluorobenzenesulfonylamino) ethyl) -N-methyl-pyrrole in 100 ml of toluene and 50 ml of dimethyl formamide is added in portions with 9.8 g of nicotinic acid chloride hydrochloride. The mixture is refluxed for 2 hours, the reaction mixture is poured onto ice, neutralized and extracted with ethylene chloride. The crude product is chromatographed over a Kie selgel column with ethylene chloride / ethanol (20: 1) chromatographed.
Yield: 4.6 g (24% of theory),
Melting point: 140 ° C

C₁₆H₁₈FN₃O₃S (387.44)
Calc .: C 58.90; H, 4.68; N 10.85
Found: C, 58.62; H 4.52; N 10.70

b) 6- (5- (2- (4-fluorobenzenesulfonylamino) ethyl) -N-methyl-pyrrol-2-yl) -6 - 3-pyridyl) hex-5-enoic acid - (

Prepared from (5- (2- (4-fluorobenzenesulfonylamino) ethyl) -N-methylpyrrol-2-yl) - (3-pyridyl) ketone and 4-carboxybutyl triphenylphosphonium bromide analogously to Example 1c, but the Rohpro product is by recrystallization from Water / Isopro panol cleaned.
Yield: 55% of theory,
Melting point: 190 ° C

C₂₄H₂₆FN₂O₄S (471.56)
Re: 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) -6- (3-pyridy l) hex-5-enoic acid a) 2- (2- (p-chlorobenzenesulfonylamino) ethyl) thiophene

Prepared from 2- (2-aminoethyl) thiophene and 4-chlorobenzenesulfonic acid chloride analogously to Example 1a.
Yield: 69% of theory,
Melting point: 93 ° C

C₁₂H₁₂ClNO₂S₂ (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-chlorobenzenesulfonylamino) ethyl) thiophen-2-yl) - (3-pyridyl) KE clay

To a suspension of 20 g of aluminum trichloride and nicotine hydrochloride in 150 ml of ethylene chloride is added dropwise a solution of 15 g of 2- (2- (4-chlorobenzenesulfonylamino) ethyl) - thiophene in 50 ml of ethylene chloride. The mixture is heated for 1 ½ Stun to 50 ° C, the reaction mixture is on ice, filtered off with suction and the precipitate from methanol.
Yield: 3.7 g (17% of theory),
Melting point: 154-160 ° C

C₁₇H₁₅ClN₂O₃S · ½ HCl (433.06)
Re: C 49.92; H 3.58; N 6,47
Found: C 50.29; H, 3.82; N 6,38

c) 6- (5- (2- (4-chlorobenzenesulfonylamino) ethyl) thiophen-2-yl) -6- (3-pyridy l) hex-5-enoic acid

Prepared from (5- (2- (4-chlorobenzenesulfonylamino) ethyl) thio-phen-2-yl) - (3-pyridyl) ketone and 4-carboxybutyl-triphenyl phosphonium bromide analogous to Example 1c, but after column chromatography is recrystallized from ethyl acetate.
Yield: 20% of theory,
Melting point: 138 ° C

C₂₃H₂₃ClN₂O₄S (491,04)
Re: 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-enoic acid a) (2-Acetylaminotetralin-6- and 7-yl) - (3-pyridyl) ketone

Prepared from 2-acetylaminotetralin and nicotinic acid chloride hydrochloride analogously to Example 1b.
Yield: 35% of theory,
Resin, R _f value: 0.28 (silica gel: ethylene chloride / ethanol = 10: 1)

C₁₈H₁₈N₂O₂ (294.40)
Calc .: C, 73.45; H 6,16; N 9.52
Found: C 73.38; H 6,23; N 9,26

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

The mixture of (2-acetylaminotetralin-6- and 7-yl) - (3-pyridyl) ketone is refluxed for 20 hours in 150 ml of concentrated hydrochloric acid. The solvent is stripped off and the residue is treated with 4-chlorobenzenesulfonyl chloride according to example 1a.
Yield: 35% of theory,
Melting point: 152-155 ° C (ethyl acetate)

C₂₂H₁₉ClO₃S (426,94)
Re: 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 the mixture of (2- (4-chlorobenzenesulfonylamino) tetralin-6- and 7-yl) - (3-pyridyl) ketone and 4-carboxybutyl-triphenyl-phosphonium bromide analogously to Example 1c, but without salt precipitation with cyclohexylamine.
Yield: 93% of theory,
Resin, R _f value: 0.30 (silica gel: ethylene chloride / ethanol = 10: 1)

C₂₇H₂₇ClN₂O₄S (511,07)
Re: C 63.46; H 5.33; N 5.48
Gef .: C 63.29; H 5.31; N 5.22

example 6 6- (5- (2- (4-fluorobenzenesulfonylamino) ethyl) -N-methyl-pyrrol-2-yl) -6 - (- 3-pyridyl) hexanoic acid

A mixture of 2.36 g of 6- (5- (2- (4-fluorobenzenesulfonylamino) ethyl) -N-methylpyrrol-2-yl) -6- (3-pyridyl) hex-5-enoic acid, O, 4 g of sodium hydroxide and 1 g of 10% palladium / carbon in 50 ml of methanol is hydrogenated at 5 bar hydrogen pressure. The catalyst is then filtered off, concentrated by evaporation, the residue is diluted with water, acidified and extracted with ethylene chloride. The organic extract is concentrated and the residue is recrystallized from ethyl acetate.
Yield: 2 g (85% of theory)
Melting point: 146-149 ° C

Calc .: C, 60.88; H 5.96; N 8,87
Found .: C 61.11; H 6.02; N 8,93

example 7 6- (2- (4-toluenesulphonylamino) indan-5-yl) -6- (3-pyridyl) hex-5-enoic acid a) (2-acetylaminoindan-5-yl) - (3-pyridyl) ketone

To 150 g of aluminum chloride and 31 ml of dimethylformamide is added at 70 ° C in portions 42.7 g of nicotinic acid hydrochloride chloride. To this mixture are added portionwise 35 g of 2-acetyl aminoindan. After further heating of the mixture at 80 ° C is cooled after 2 hours and the mixture was added to 200 g of ice and 100 ml of concentrated hydrochloric acid. The acid solution is carefully neutralized with sodium hydroxide solution and then extracted with 4 × 250 ml of chloroform. The organic phases are collected, dried over sodium sulfate and concentrated by rotary evaporation.
Yield: 43 g (76% of theory),
Melting point: 165-167 ° C

C₁₇H₁₆N₂O₂ (280,32)
Calc .: C, 72.84; H 5.75; N 9.99
Found: C, 72.70; H 5,782 N 9,75

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

51 g (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 15 N sodium hydroxide solution. The precipitated precipitate is washed with water and recrystallized from 100 ml of isopropanol.
Yield: 42 g (97% of theory),
Melting point: 205 ° C (decomp.)

C₁₅H₁₄N₂O (238,29)
Calc .: C, 75.61; H 5.92; N 11,75
Found: C, 75.44; H, 6.04; N 11,857

c) (2- (4-toluenesulphonylamino) 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 dripped to dryness. 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

C₂₂H₂₀N₂O₃S (392,47)
Ber .: C 67.33; H 5:14; N 7,14
Gef .: C 67.12; H 5:16; N 6.95

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

5 g (2- (4-toluenesulfonylamino) indan-5-yl) - (3-pyridyl) ketone become a suspension of 8 g of 4-carboxybutyl-triphenyl Phosphonium bromide and 5.6 g of potassium tert-butoxide in 100 ml Tetrahydrofuran was added under a nitrogen atmosphere.  

The suspension 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 precipitated precipitate taken up in methylene chloride. The organic phase is dried over magnesium sulfate and dissolved. The resulting oil is chromatographed on a silica gel column with ethyl acetate as eluant.
Yield: 3.4 g (56% of theory),
Melting point: 150-156 ° C

C₂₇H₂₈N₂O₄S (476.59)
Calc .: C, 68.04; H 5.92; N 5.88
Found: C 67.90; H 6,10; N 5.82

example 8 6 (2- (4-Brombenzolsulfonylamino) indan-5-yl) -6- (3-pyridyl) hex-5-ensäur-emethylester a) 6- (2-Acetylamino-indan-5-yl) -6- (3-pyridyl) hex-5-en-carboxylic acid

11.1 g of 4-carboxybutyltriphenylphosphonium bromide and 8.0 g of potassium tert-butoxide are introduced into 100 ml of absolute tetrahydrofuran and stirred at 10 ° C under a nitrogen atmosphere. Subsequently, 5.6 g (2-acetylamino-indan-5-yl) - (3-pyridyl) ketone in portions and stirred at room temperature for 2 hours. Thereafter, the reaction mixture is added to ice-water and washed with toluene. The aqueous phase is adjusted to pH 5 with 3 N salt water. The resulting precipitate is taken up in methylene chloride, washed with water, dried over sodium sulfate and concentrated by rotary evaporation. The product mixture is chromatographed on a silica gel column with the eluent ethyl acetate: ethanol: glacial acetic acid (94: 5: 1).
Yield: 7.2 g (99% of theory),
Oil, R _f value: 0.20 (silica gel: ethyl acetate / ethanol / glacial acetic acid = 94: 5: 1)

b) 6- (2-aminoindan-5-yl) -6- (3-pyridyl) hex-5-enoate

3.1 g of 6- (2-acetylaminoindan-5-yl) 6- (3-pyridyl) hex-5-enoic acid are refluxed with 20 ml of half-concentrated hydrochloric acid for 15 hours and then concentrated by rotary evaporation. The residue is then added to 50 ml of methanol, which is saturated with dry hydrogen chloride. After stirring at room temperature for 30 minutes, the reaction mixture is dripped to dryness. The residue is taken up in 1 N sodium hydroxide solution and adjusted to pH 10. Then it is extracted with 3 × 50 ml of methylene chloride, the organic phase is dried and concentrated by rotary evaporation.
Yield: 2.45 g (50% of theory),
Resin, R _f value: 0.50 (silica gel: toluene / dioxane / methanol / ammonia = 2: 5: 2: 1)

C₂₁H₂₄N₂O₂ (336,44)
Calc .: C 74.97; H 7,19; N 8,33
Gef .: C 75.00; H 7.01; N 8,11

c) 6- (2- (4-Brombenzolsulfonylamino) indan-5-yl) -6- (3-pyridyl) hex-5-ensäu-methyl ester

3.4 g of 6- (2-amino-indan-5-yl) -6- (3-pyridyl) hex-5-enoic acid methyl ester is initially charged with 3.3 g of 4-bromobenzenesulfonyl chloride in 40 ml of chloroform and treated portionwise at room temperature with room temperature , 8 g of triethylamine. After 30 minutes, the solution is washed with water, dried and concentrated by rotary evaporation. The yellow oil is then chromatographed on a silica gel column with cyclohexane / ethyl acetate (1: 2).
Yield: 4.5 g (81% of theory),
Resin, R _f value: 0.25 (silica gel: cyclohexane / ethyl acetate = 1: 1)

C₂₇H₂₇BrN₂O₄S (555,48)
Re: C 58.38; H 4,90; N 5.04
Found: 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-enoic acid methyl ester
Resin, R _f value: 0.32 (silica gel: cyclohexane / ethyl acetate = 1: 1)

C₂₇H₂₇ClN₂O₄S (511,03)
Re: C 63.46; H 5.32; N 5.48
Found: C 63.58; H 5.49; N 5.35
6- (2- (4-fluorobenzenesulfonylamino) indan-5-yl) -6- (3-pyridyl) hex-5-enoic acid methyl ester
Resin, R _f value: 0.82 (silica gel: toluene / dioxane / methanol / ammonia = 2: 5: 2: 1)

C₂₇H₂₇FN₂O₄S (494,58)
Calc .: C 65.57; H 5.50; N 5.66
Found: C 65.39; H 5.78; N 5.48
6- (2- (4-thiophenesulfonylamino) indan-5-yl) -6- (3-pyridyl) hex-5-enoic acid methyl ester
Resin, R _f value: 0.25 (silica gel: cyclohexane / ethyl acetate = 1: 1)

C₂₅H₂₆N₂O₄ (482,61)
Re: C 62.22; H 5.43; N 5.80
Found .: C 62.28; H 5.60; N 5.53
Methyl 6- (2- (2,5-dichlorobenzenesulfonylamino) indan-5-yl) -6- (3-pyridyl) hex-5-enoate
Resin, R _f value: 0.38 (silica gel: cyclohexane / ethyl acetate = 1: 1)

C₂₇H₂₆Cl₂N₂O₄S (545.48)
Calc .: C, 59.45; H 4.80; N 5:14
Found: 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, R _f value: 0.38 (silica gel: cyclohexane / ethyl acetate = 1: 1)

C₂₇H₂₇N₃O₆S (521,59)
Re: C 62.17; H 5.22; N 8.06
Found .: C, 62.22; H 5.45; N 7,90
6- (2- (Benzenesulfonylamino) indan-5-yl) -6- (3-pyridyl) hex-5-enoic acid methyl ester
Resin, R _f value: 0.20 (silica gel: cyclohexane / ethyl acetate = 1: 1)

C₂₇H₂₈N₂O₄S (476.59)
Calc .: C, 68.04; H 5.92; N 5.88
Found: C, 67.98; H 6.07; N 5.60

example 9 6- (2- (4-Brombenzolsulfonylamino) indan-5-yl) -6- (3-pyridyl) hex- 5-enoic

3.7 g of 6- (2- (4-bromobenzenesulfonylamino) indan-5-yl) -6- (3-pyridyl) hex-5-enoic acid methyl ester in 30 ml of ethanol and with 1 ml of 15 N sodium hydroxide solution for 15 minutes at reflux heated. The cooled solution is concentrated by rotary evaporation and the residue is taken up in water and washed with 30 ml of methylene chloride. At closing, the aqueous phase is adjusted to pH 4 with hydrochloric acid. The precipitate is washed and dried.
Yield: 3.2 g (88% of theory),
Melting point: 83-102 ° C

C₂₅H₂₆BrN₂O₄S (541,46)
Ber .: C 57.68; H 4.65; N 5:17
Gef .: C 57.58; H 4.64; N 4.99

The following compounds are obtained analogously:
6- (2- (4-chlorobenzenesulfonylamino) indan-5-yl) -6- (3-pyridyl) hex-5-enoic acid
Melting point: 83-98 ° C

C₂₆H₂₅ClN₂O₄S (497.01)
Calc .: C, 62.83; H 5.07; N 5.64
Found: C, 62.64; H 5.02; N 5.57
6- (2- (4-fluorobenzenesulfonylamino) indan-5-yl) -6- (3-pyridyl) hex-5-enoic acid
Melting point: 73-90 ° C

C₂₆H₂₅FN₂O₄S (480,55)
Re: C 64.98; H 5.24; N 5.83
Found: C, 64.85; H 5,23; N 5.76
6- (2- (2-thiophenesulfonylamino) indan-5-yl) -6- (3-pyridyl) hex-5-enoic acid
Melting point: 67-90 ° C

C₂₄H₂₄N₂O₄S₂ (468.58)
Re: C 61.52; H 5:16; N 5.98
Found: 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 ° C

C₂₆H₂₆N₂O₄S (462.58)
Calc .: C 67.51; H 5.67; N 6.06
Found: 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 ° C

C₂₆H₂₅N₃O₆S (507,56)
Re: C 61.53; H 4,96; N 8,28
Found: C, 61.45; H 5.06; N 8,18
6- (2- (2,5-dichlorobenzenesulfonylamino) indan-5-yl) -6- (3-pyridyl) hex-5-enoic acid
Melting point: 79-100 ° C

C₂₆H₂₄Cl₂N₂O₄S (531,45)
Re: C 58,76; H 4.55; N 5.27
Gef .: C 58.78; H 4.65; N 5,11

Example 10 6- (4- (2- (4-Chlorbenzolsulfonylaminoethyl) phenyl-6- (3-pyridyl) -hexans-äure a) 4- (2-acetylaminoethyl) phenyl (3-pyridyl) ketone

180 g of aluminum chloride are mixed with 35 ml of dimethylformamide, the temperature rises to 70 ° C. Then 66.8 g of nicotinic acid chloride hydrochloride and then 49 g of 2-acetylaminoethylbenzene at 70 ° C to. After 2 hours, cooled and mixed with 60 ml of ethylene chloride. Then the mixture is poured into ice-water and 180 ml of concentrated hydrochloric acid. The aqueous phase is made alkaline with sodium hydroxide solution and then extracted with 3 × 100 ml of ethylene chloride. The organic phase is dried and concentrated by rotary evaporation. Yield: 70.4 g (87% of theory),
Oil, R _f value: 0.47 (silica gel: ethylene chloride / methanol = 9: 1)

C₁₆H₁₆N₂O₂ (268.32)
Calc .: C, 71.62; H 6.01; N 10.44
Found: C, 70.92; H 6,20; N 10,30

b) 6- (4- (2-acetylaminoethyl) phenyl) -6- (3-pyridyl) hex-5-ene acid

Prepared analogously to Example 7d from 4- (2-acetylaminoethyl) phenyl (3-pyridyl) ketone and 4-carboxybutyl-triphenylphosphonium bromide.
Yield: 57% of theory,
Melting point: 80-85 ° C

C₂₁H₂₄N₂O₃ (352,4)
Calc .: C, 71.57; H 6,86; N 7.95
Found: C, 71.23; H 7.06; N 7.94

The following compounds are obtained analogously:
5- (4- (2-acetylaminoethyl) phenyl) -5- (3-pyridyl) pent-4-enoic acid
Yield: 87% of theory,
Resin, R _f value: 0.35 (silica gel: chloroform / methanol = 10: 1)

C₂₀H₂₂N₂O₃ (338.4)
Calc .: C, 70.98; H, 6.55; N 8,28
Found .: 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 _f value: 0.37 (silica gel: chloroform / methanol = 10: 1)

C₂₂H₂₆N₂O₃ (366,5)
Ber .: C 72.11; H 7,15; N 7.64
Found: C, 71.82; H, 7.41; N 7.58

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

7.05 g of 6- (4- (2-acetylaminoethyl) phenyl) -6- (3-pyridyl) hex-5-enoic acid are dissolved in 85 ml of 0.7 N sodium hydroxide solution and catalytically reacted at 40 ° C. with 1 g of palladium / carbon reduced. After suction of the catalyst is acidified to pH 6 and taken from falling oil in ethyl acetate and concentrated. The crude product is recrystallized from methanol.
Yield: 4.7 g (66% of theory),
Melting point: 135-139 ° C

C₂₁H₂₆N₂O₂ (354,5)
Ber .: 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, R _f value: 0.37 (silica gel: chloroform / methanol = 10: 1)

C₂₀H₂₄N₂O₃ (340,4)
Calc .: C 70.56; H 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, R _f value: 0.43 (silica gel: chloroform / methanol = 10: 1)

C₂₂H₂₈N₂O₃ (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-aminoethyl) 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 with methanol chroma.
Yield: 2.3 g (66% of theory),
Resin, R _f value: 0.27 (silica gel: methanol)

C₁₉H₂₄N₂O₂ (312,4)
Calc .: C 73.05; H 7.74; N 8,97
Found: 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, R _f value: 0.33 (silica gel: methanol)

C₁₈H₂₂N₂O₂ · 0.5 HCl (317.1)
Re: 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, R _f value: 0.59 (silica gel: methanol)

C₂₀H₂₆N₂O₂ (326,4)
Calc .: C 73.59; H 8.03; N 8,58
Found .: C, 73.48; H 8,00; N 8,37

e) 6- (4- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl) -6- (3-pyridyl) hexane-acid

1.9 g of 6- (4- (4-aminoethyl) phenyl) -6- (3-pyridyl) hexanoic acid are suspended in 150 ml of dioxane and treated 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, the mixture is dripped to dryness, the residue is 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) chromatographed.
Yield: 1.8 g (61% of theory),
Resin, R _f value: 0.48 (silica gel: chloroform / methanol = 10: 1)

C₂₅H₂₇ClN₂O₄S (487,03)
Calc .: 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-fluorobenzenesulfonylamino) ethyl) phenyl) -6- (3-pyridyl) hexanoic acid
Yield: 11% of theory,
Resin, R _f value: 0.53 (silica gel: chloroform / methanol = 10: 1)

C₂₅H₂₇FN₂O₄S (470,60)
Calc .: C, 63.81; H 5.78; N 5.95
Found: 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 _f value: 0.55 (silica gel: chloroform / methanol = 10: 1)

C₂₆H₂₉N₂O₄S (466,60)
Re: C 66.93; H, 6.48; N 6,00
Found: C, 66.81; H 6,57; N 5.94
6- (4- (2- (4-bromobenzenesulfonylamino) ethyl) phenyl) -6- (3-pyridyl) hexanoic acid
Yield: 24% of theory,
Resin, R _f value: 0.34 (silica gel: chloroform / methanol = 20: 1)

C₂₅H₂₇BrN₂O₄S (531,50)
Calc .: C 56.50; H 5,12; N 5.27
Gef .: C 56.41; H 5.31; N 5:17

Example 11 5- (4- (2- (4-fluorobenzenesulfonylamino) ethyl) phenyl) -5- (3-pyridyl) pentanoic acid tert.-

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

C₂₄H₂₅FN₂O₄S (456.50)
Ber .: C 63.14; H, 5.52; N 6,94
Found: C, 63.04; H 5.60; N 5.96

Example 12 5- (4- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl) -5- (3-pyridyl) pentanoic acid tert.-

Prepared analogously to Example 10e from 5- (4- (2-aminoethyl) phenyl) -5- (3-pyridyl) pentanoic acid and 4-chlorobenzenesulfonic acid chloride.
Yield: 21% of theory,
Melting point: 70 ° C

C₂₄H₂₅ClN₂O₄S (473.00)
Ber .: C, 60.94; H 5.33; N 5.92
Found: C, 61.01; H 5.35; N 5.70

Example 13 7- (4- (2- (4-Toluolbenzolsulfonylamino) ethyl) phenyl) -7- (3-pyridyl) hept-ansäure

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

C₂₇H₃₂N₂O₄S (480,60)
Ber .: C 67.47; H 6.71; N 5.83
Found: C 67.34; H 6.71; N 5.74

Example 14 7- (4- (2- (4-fluorobenzenesulfonylamino) ethyl) phenyl) -7- (3-pyridyl) hepta-acid tert.

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

C₂₆H₂₉FN₂O₄S (484,6)
Ber .: C, 64.44; H 6.03; N 5.72
Found .: C, 64.48; H 5.99; N 5.72

Example 15 5- (4- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl) -5- (3-pyridyl) penta-nsäuremethylester

2.0 g of 5- (4- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl) -5- (3-pyridyl) pentanoic acid are dissolved in 30 ml of methanol and treated with 3 ml of thionyl chloride at 0 ° C. The solution is stirred overnight, then concentrated by rotary evaporation and the residue chromatographed on a silica gel column.
Yield: 1.1 g (53% of theory),
Resin, R _f value: 0.65 (silica gel: chloroform / methanol = 95: 5)

C₂₆H₂₉ClN₂O₄S (501,1)
Re: C 62.33; H 5.83; N 5.59
Found .: C 62.36; H 6.01; N 5.42

Example 16 5- (2- (4-Chlorobenzenesulfonylamino) indan-5-yl) -5- (3-pyridyl) pent-4-ene-äuremethylester

3.7 g of 5- (4- (2- (4-chlorobenzenesulfonylamino) -indan-5-yl) -5- (3-pyridyl) -pent-4-enoic acid are dissolved in 30 ml of methanol, into which dried hydrogen chloride is introduced The solution is stirred overnight and then evaporated in. Under ice-cooling, the base is liberated with aqueous potassium carbonyl solution, which is extracted with methylene chloride, the solution is concentrated by rotary evaporation and the residue is chromatographed on a silica gel column.
Yield: 2.5 g (52% of theory),
Resin, R _f value: 0.53 (silica gel: toluene / dioxane / ethanol / acetic acid = 9: 1: 1: 0.6)

C₂₆H₂₅ClN₂O₄S (497.01)
Calc .: C, 62.80; H 5.10; N 5.60
Found: 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-enoic acid methyl ester
Yield: 73% of theory,
Resin, R _f value: 0.31 (silica gel: cyclohexane / ethyl acetate = 1: 1)

C₂₈H₂₉ClN₂O₄S (525.06)
Calc .: C 64.05; H 5.56; N 5.33
Found: C, 64.45; H 6,15; N 5.05

Example 17 5- (2- (4-Chlorobenzenesulfonylamino) indan-5-yl) -5- (3-pyridyl) pent-4-ene-äure

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: 94-114 ° C

C₂₅H₂₃ClN₂O₄S (482,98)
Calc .: C 62.20; H 4.80; N 5.80
Found .: 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: 66-90 ° C

C₂₇H₂₇ClN₂O₄S (511,03)
Calc .: C 63.50; H 5.30; N 5.50
Found: C, 63.65; H 5,29; N 5.30

Example 18 (Z) - and (E) -6- (2- (4-chlorobenzenesulfonylamino) indan-5-yl) -6- (3-pyridyl) hex-5-enoic acid

1.9 g of 6- (2- (4-chlorobenzenesulfonylamino) indan-5-yl) -6- (3-pyridyl) hex-5-enoic acid methyl ester are on a Kieselgelsäu le with the eluent of ethylene chloride / ethyl acetate / glacial acetic acid (70: 30: 5) chromatographed. The faster run de 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-pyridyl) hex-5-enoic acid
Yield: 200 mg (10% of theory),
Melting point: 70-100 ° C

C₂₆H₂₅ClN₂O₄S (497.01)
Calc .: C, 62.83; H 5.07; N 5.64
Found: C, 62.72; H 5.24; N 5.47
(E) -6- (2- (4-chlorobenzenesulfonylamino) indan-5-yl) -6- (3-pyridyl) hex-5-enoic acid
Yield: 400 mg (20% of theory),
Melting point: 75-103 ° C

C₂₆H₂₅ClN₂O₄S (497.01)
Calc .: C, 62.83; H 5.07; N 5.64
Found: C, 62.75; H 5:14; N 5.43

Example 19 6- (2- (4-Chlorobenzenesulfonylamino) indan-5-yl) -6- (3-pyridyl) -hexansäur-e

3.0 g of 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 treated with 1 g of palladium / Coal hydrogenated at 40 ° C and 3.5 bar for 12 hours. The catalyst is then filtered off with suction and the filtrate is 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. The mixture is then chromatographed on a silica gel column with the eluent 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 ° C

C₂₆H₂₇ClN₂O₄S
Re: C 62.58; H 5.45; N 5.61
Found: C, 62.54; H 5.45; N 5.79

example 20 7- (2- (4-Chlorobenzenesulfonylamino) indan-5-yl) -7- (3-pyridyl) heptansäur-e

Prepared analogously to Example 19 by reduction of 7- (2- (4-chlorobenzenesulfonylamino) indan-5-yl) -7- (3-pyridyl) hept-6-enoic acid with platinum / carbon.
Yield: 40% of theory,
Resin, R _f value: 0.3 (silica gel: ethylene chloride / ethyl acetate / acetic acid = 10: 3: 0.5)

C₂₆H₂₉ClN₂O₄S (501.3)
Re: C 62.32; H 5.83; N 5.59
Found: C, 62.56; H 6,00; N 5.32

example 21 5- (2- (benzenesulfonylamino) indan-5-yl) -5- (3-pyridyl) pentanoic acid

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

C₂₅H₂₅ClN₂O₄S (485.00)
Re: C 61.91; H 5:19; N 5.77
Found: C, 61.85; H 5.33; N 6.05

example 22 7- (2- (benzenesulfonylamino) indan-5-yl) -7- (3-pyridyl) heptanoic acid

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

C₂₇H₂₉ClN₂O₄S (513.05)
Re: C 63.21; H 5.69; N 5.46
Found: C, 63.43; H 5.88; N 5.63

example 23 3- (2- (4-toluenesulphonylamino) indan-5-yl) -3- (3-pyridyl) prop-2-enoic acid a) 3- (2- (4-toluenesulphonylamino) indan-5-yl) -3- (3-pyridyl) prop-2-ensäuree-methyl ester

To a suspension of 9.6 g of potassium tert-butoxide in 100 ml of tetrahydrofuran and 25 ml of dimethylformamide are added at 5 ° C 9.84 g Phosphonessigsäuretriethylester. After stirring at 0 ° C. for 30 minutes, 15.5 g of 2- (4-toluenesulfonylamino) indan-5-yl) -3- (3-pyridyl) ketone are added. 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 chromatographed on a silica gel column with the eluent ethyl acetate / ethyl acetate (9: 1).
Yield: 17.2 g (93% of theory),
R _f value: 0.46 / 0.35 (silica gel: ethylene chloride / ethyl acetate = 1: 1)

b) 3- (2- (4-toluenesulphonylamino) indan-5-yl) -3- (3-pyridyl) prop-2-enoic acid

4.2 g of ethyl 3- (2- (4-toluenesulfonylamino) indan-5-yl) -3- (3-pyridyl) prop-2-enoate are refluxed in 40 ml of ethanol and 1.5 ml of 15 N sodium hydroxide solution for 30 minutes cooked. The cooled solution is then washed with 3 × 50 ml of methylene chloride and then acidified. The precipitated precipitate is washed, dried and then recrystallised from n-butanol.
Yield: 2.3 g (58% of theory),
Melting point: 228-230 ° C

C₂₃H₂₂N₂O₄S (422.5)
Ber .: C 65.38; H 5.24; N 6.63
Found .: 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 precipitation from dioxane by addition of diisopropyl ether.
Yield: 74% of theory,
Melting point: 85-97 ° C

C₂₃H₂₂N₂O₄S · 0.8 dioxane (424.51)
Calc .: C 63.57; H 6,19; N 5.66
Gef .: C 63.39; H 6,30; N 5.62

example 25 6- (4- (2- (Fluorsulfonylamino) ethyl) phenyl) -6- (3-pyridyl) -hex-5-ensäur-e

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 ßend are added to 2.9 g of 4-fluorobenzenesulfonyl chloride in 20 ml of dioxane and stirred at room temperature overnight. Subsequently ßend is treated with acetic acid, wherein a precipitate precipitates. This is separated and taken up in ethyl acetate, dried and concentrated. Finally, the residue is chromatographed on a silica gel column with the eluent chloroform / methanol (20: 1).
Yield: 0.5 g (10% of theory),
Resin, R _f value: 0.55 (silica gel: chloroform / methanol = 10: 1)

C₂₅H₂₅FN₂O₄S (470,6)
Calc .: C 64.09; H 5.38; N 5.98
Found: 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, R _f value: 0.5 (silica gel: chloroform / methanol = 10: 1)

C₂₆H₂₈N₂O₄S (464,6)
Ber .: C 67.22; H 6.07; N 6.03
Found: C, 67.06; H 6.21; N 5.86
6- (4- (2- (4-Bromobenzenesulfonylamino) ethyl) phenyl) -6- (3-pyridyl) hex-5-enoic acid
Yield: 20% of theory,
Resin, R _f value: 0.4 (silica gel: chloroform / methanol = 10: 1)

C₂₅H₂₅BrN₂O₄S (529.5)
Calc .: C, 56.71; H 4.76; N 5.29
Gef .: C 56.72; H 4.58; N 5,12

example 26 7- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl) -7- (3-pyrid yl) hept-6-enoic acid

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

C₂₆H₂₇ClN₂O₄S (499,02)
Re: C 62.58; H 5.45; N 5.62
Found .: C, 62.48; H 5.40; N 5.62

example 27 6- (4- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl) -6- (3-pyridyl) hex-5 - ensäurediethylamid

1.0 g of 6- (4- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl) -6- (3-pyridyl) hex-5-enoic acid are dissolved in 15 ml of tetrahydrofuran and stirred with 0.49 g of carbonyldiimidazole for 15 minutes , At closing are added to 1 ml of diethylamine and heated for 2 hours at reflux. It is then concentrated and the residue taken up in ethyl acetate and dried. Finally, it is chromatographed on a silica column with the eluent ethyl acetate.
Yield: 0.6 g (54% of theory),
Oil, R _f value: 0.23 (silica gel: ethyl acetate)

C₂₉H₃₄ClN₃O₃S (540.12)
Ber .: C, 64.48; H 6,34; N 7,78
Found: C, 64.42; H 6.60; N 7.52

Analogously, the following compound will be included:
6- (4- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl) -6- (3-pyridyl) -hex-5-enoic acid benzylamide
Yield: 51% of theory,
Resin, R _f value: 0.37 (silica gel: ethyl acetate)

C₃₂H₃₂ClN₃O₃S (574,14)
Re: C 66.94; H 5.61; N 7,31
Found: C 66.72; H 5.44; N 7,10

example 28 6- (4- (2- (N-methyl-4-chloro-benzenesulfonylamino) ethyl) phenyl) -6- (3-pyri dyl-) hex-5-enoic acid

2.0 g of 6- (4- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl) - 6- (3-pyridyl) hex-5-enoic acid are dissolved in 10 ml of 4N sodium hydroxide solution, 100 ml of methylene chloride, 80 mg of benzyltrimethylammonium chloride and 0.85 g of methyl iodide stirred overnight. Subsequently, the organic phase is separated off and the aqueous phase is acidified to pH 5. The precipitated product is separated and taken up 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 ° C

C₂₆H₂₇ClN₂O₄S (499,02)
Re: C 62.58; H 5.45; N 5.61
Found: C, 62.53; H, 5.54; N 5.53

example 29 6- (4- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl) -6- (3-pyridyl) -2,2 - dimethyl-hex-5-enoic acid a) 6- (4- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl) -6- (3-pyridyl) -2,2 - dimethyl-hex-5-ensäurepiperidid

Prepared analogously to Example 7d from 4-triphenylphosphonium butanoic acid-piperidide bromide and (4- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl) - (3-pyridyl) ketone.
Yield: 6.7% of theory),
Resin, R _f value: 0.4 (silica gel: ethyl acetate)

C₃₂H₃₈ClN₃O₃S (580,16)
Re: C 66.24; H 6.60; N 7.24
Gef .: C 66.15; H 6,33; N 7.11

b) 6- (4- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl) -6- (3-pyridyl) -2,2 - dimethyl-hex-5-enoic 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 for 8 hours cooked at reflux. It is then concentrated and the residue dissolved in sodium hydroxide solution and adjusted to pH 4 with hydrochloric acid. The precipitated precipitate is filtered off with suction and chromatographed on a silica gel column with ethylene chloride / methanol (10: 1).
Yield: 0.12 g (39% of theory),
Resin, R _f value: 0.5 (silica gel: ethylene chloride / methanol = 9: 1)

C₂₇H₂₉ClN₃O₄S (513,04)
Re: C 63.21; H 5.70; N 5.46
Found: C, 63.08; H, 5.58; N 5.60

example I Tablets containing 100 mg of 6- (4- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl) -6- (3-pyridyl) hex-5-enoic acid

composition

1 tablet contains:

Active ingredient | 100.0 mg lactose 80.0 mg corn starch 34 mg polyvinylpyrrolidone 4.0 mg magnesium stearate  2.0 mg 220.0 mg

production method

Active ingredient, lactose and starch are mixed and uniformly moistened with an aqueous solution of polyvinylpyrrolidone. After sieving the wet masses (2.0 mm mesh width) and drying in a rack oven at 50 ° C is again sieved (1.5 mm mesh size) and the lubricant mixed. The ready for pressing mixture is working to tablets ver.
Tablet weight: 220 mg
Diameter: 9 mm, biplan with facet on both sides and one-sided part notch.

example II Hard gelatin capsules containing 150 mg of 6- (4- (2- (4-chlorobenzenesul fonylamino) ethyl) phenyl) -6- (3-pyridyl) hex-5-enoic acid

1 capsule contains:

Active ingredient | 150.0 mg Corn starch drink. approximately 180.0 mg Milk sugar powder approx. 87.0 mg magnesium stearate  3.0 mg approximately 320.0 mg

manufacturing

The active ingredient is mixed with the excipients, passed through a sieve of 0.75 mm mesh size and homogeneously mixed in a appro priate device.
The final mixture is filled into hard gelatin capsules of size 1.
Capsule filling: approx. 320 mg
Capsule shell: hard gelatin capsule size 1.

example III Suppositories containing 150 mg of 6- (4- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl) -6- (3-pyridyl) hex-5-enoic acid

1 suppository contains:

Active ingredient | 150.0 mg Polyethylene glycol (M.G. 1500) 550.0 mg Polyethylene glycol (M. G. 6000) 460.0 mg Polyäthylensorbitanmonostearat  840 mg 2000.0 mg

manufacturing

After the melting of the suppository masses the Wirk The material is homogeneously distributed in it and the melt in pre-cooled Poured molds.

example IV Suspensions with 50 mg of 6- (4- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl) -6- (3-pyridyl) hex-5-enoic acid

100 ml suspension contain:

Active ingredient | 1.0 g Carboxymethylcellulose-Na-salt 0.2 g p-hydroxybenzoate 0.05 g p-hydroxybenzoate 0.01 g glycerin 5.0 g Sorbitol solution 70% 50.0 g Aroma 0.3 g Water dist. ad 100 ml

manufacturing

Dest. Water is heated to 70 ° C. Here, p-hydroxybenzoic acid methyl ester and propyl ester and Gly cerin and carboxymethyl cellulose sodium salt is dissolved with stirring. It is cooled to room temperature and added with stirring, the active ingredient and dispersed homogeneously. After addition and dissolution of the sugar, the sorbitol solution and the aroma, the suspension is evacuated to vent with stirring.
5 ml of suspension contain 50 mg of active ingredient.

example V Tablets containing 150 mg of 6- (4- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl) -6- (3-pyridyl) hex-5-enoic acid

Composition:
1 tablet contains:

Active substance | 150,0 mg Milk sugar powder. 89.0 mg corn starch 40.0 mg Colloidal silica 10.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate  1.0 mg 300.0 mg

manufacturing

The mixed with lactose, corn starch and silica Active substance is mixed with a 20% polyvinyl pyrrole Moisten the lidon solution and pass through a sieve with 1.5 mm mesh struck wide.

The dried granules at 45 ° C is again rubbed through the same sieve and mixed with the stated amount of magnesium stearate. From the mixture tablets are pressed.
Tablet weight: 300 mg
Stamp: 10 mm, flat

example VI Film-coated tablets containing 75 mg of 6- (4- (2- (4-chlorobenzenesulfonylamino) ethyl) phenyl) -6- (3-pyridyl) hex-5-enoic acid

1 tablet contains:

Active substance | 75,0 mg calcium phosphate 93.0 mg corn starch 35.5 mg polyvinylpyrrolidone 10.0 mg hydroxypropyl methylcellulose 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 tableting machine compacts are produced with a diameter of about 13 mm, these are ground on a suitable machine through a sieve with a mesh size of 1.5 mm 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 produced are coated with a film consisting essentially of hydroxypropylmethylcellulose. The finished film-coated tablets are shone waxy with bees.
Film tablet weight: 245 mg

Of course, all other connections of the all Formula I as active ingredients in the above gale nischen preparations are used.

Claims (10)

1. Arylsulfonamides of the formula in the
R₁ is a phenyl group monosubstituted by a nitro group or may be mono- or disubstituted by a halogen atom, an alkyl or alkoxy group, the substituents being the same or different, or a thienyl group,
R₂, R₄ and R₅, which may be the same or different, each represents a hydrogen atom or an alkyl group or
R₂ is a hydrogen atom and R₄ and R₅ together form a carbon-carbon bond,
R₃ is an optionally substituted by an alkyl group pyridyl group,
R₆ represents a hydroxy, alkoxy, amino, alkylamino or dialkylamino group,
A is a group of formulas in which
R₇ is a hydrogen atom or an alkyl group,
R₈ is a hydrogen atom or
R₇ and R₈ together form a methylene or ethylene group and
X represents an imino group substituted by an alkyl group, an oxygen or sulfur atom wherein the -CHR₇ group is linked to the -NR₂ group, and
B is a carbon-carbon bond or a straight-chain alkylene group having 1 to 4 carbon atoms optionally substituted by one or two alkyl groups, all alkyl and alkoxy moieties mentioned above each containing from 1 to 3 carbon atoms, the enantiomers thereof, the cis- and trans isomers, when R₄ and R₅ together represent a carbon-carbon bond, and their addition salts. 2. arylsulfonamides of the formula I according to claim 1, in which
R₁ is an optionally substituted by a fluorine or chlorine atom, a nitro or methyl group-substituted phenyl group, a Dichchlorphenyl- or thienyl group,
R₂, R₄ and R₅ are each a hydrogen atom or
R₂ is a hydrogen atom and R₄ and R₅ together form a carbon-carbon bond,
R₃ is a pyridyl group,
R₆ is a hydroxy or methoxy group,
A is a group of formulas in which
R₇ and R₈ 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 -CHR₇ group is linked to the -NR₂ 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 R₄ and R₅ together form a carbon-carbon bond, and their addition salts. 3. arylsulfonamides of the formula I according to claim 1, in which
R₁ is a phenyl group substituted in the 4-position by a methyl group, a fluorine, chlorine or bromine atom,
R₂, R₄ and R₅ are each a hydrogen atom or
R₂ is a hydrogen atom and R₄ and R₅ together form a carbon-carbon bond,
R₃ is a 3-pyridyl group,
A is a group of the formula in the
R₇ and R₈ each represents a hydrogen atom or
R₇ and R₈ together represent a methylene group, and
R₆ is the hydroxy group, their enantiomers, their cis and trans isomers, if R₄ and R₅ together form a carbon-carbon bond, and their addition salts. 4. 6- (2- (4-toluenesulfonylamino) -indan-5-yl) -6- (3-pyridyl) hex-5-enoic acid and its 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 orga niche bases. 7. Medicaments containing as active ingredient a compound according to claims 1 to 5 or its physiologically ver Adjunct addition salt according to claim 6 in addition if one or more inert carriers and / or Diluents. 8. Medicament according to claim 7 suitable for the treatment and for the prophylaxis of thrombo-embolic diseases, for the Prophy lax the atherosclerosis and metastasis prophylaxis as well for the treatment of ischemia, asthma and allergies.   9. A process for the preparation of a medicament according to the Claims 7 and 8, characterized in that not on Chemically a compound according to claims 1 to 5 or its physiologically acceptable addition salt according to Claim 6 in one or more inert customary carriers and / or diluent is incorporated. 10. A process for the preparation of the compounds according to the entitlements to 1 to 6, characterized in that
a) a compound of the formula in the
R₂ to R₅, A and B as defined in any one of claims 1 to 5, with a sulfonic acid derivative of the formula R₁-SO₂X (III) in the
R₁ as defined in at least one of claims 1 to 5 and
X is a nucleophilic leaving group such as a halogen atom or an alkoxy group, e.g. B. is a chlorine or bromine atom, a methoxy or ethoxy group, is acylated or
b) for the preparation of compounds of formula I in which R₆ represents a hydroxy group, of a compound of formula in the
R₁ to R₅, A and B are as defined in at least one of claims 1 to 5 and
Z is a hydrolytically, thermolytically or hydrogenolytically 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 formula I in which R₄ and R₅ each represent a hydrogen atom, a compound of formula in the
R₁ to R₃, R₆, A and B are as defined in at least one of claims 1 to 5, hydrogenated or
d) for the preparation of compounds of formula I in which R₄ and R₅ together represent a carbon-carbon bond, a compound of formula in the
R₁ to R₃ and A are as defined in at least one of claims 1 to 5 with a compound of the formula in the
B and R₆ are as defined in at least one of claims 1 to 5,
R _{5 'is} a hydrogen atom or an alkyl group having 1 to 3 carbon atoms and
W is a Triphenylphosphoniumhalogenid-, a Dialkylphos phonic acid or a magnesium halide radical, vice implements and optionally subsequently dehydrated and
if desired, subsequently converting a compound of the formula I in which R₂ represents a hydrogen atom into an appropriate compound of the formula I in which R₂ represents an alkyl group, or is converted by alkylation
a compound of the formula I in which R₆ represents a hydroxy group is converted by esterification or amidation into a corresponding compound of the formula I, in which R₆ represents an alkoxy, amino, alkylamino or dialkylamino group, or
a compound of the formula I in which R₄ and R₅ together form a carbon-carbon bond, is resolved into their cis and trans isomers, or
a compound of the formula thus obtained is resolved into its enantiomers or
a compound of formula I thus obtained in their addition salts, in particular in their physiologically acceptable Additonssalze with inorganic or organic bases over.