DE4431868A1 - Phenylene derivatives, medicaments containing these compounds and process for their preparation - Google Patents

Abstract

Heterocyclyl-phenyl carboxylic acid derivs. of formula (I) and their tautomers, stereoisomers and salts are new. Ra = piperidinyl, piperazinyl or piperazino; A = CH=CH-CO, CH2-CH2-CO or NR1-CH2-CO with the CO gp. bonded to B; B = NR1-cyclohexylene, piperidinediyl or NR1-(CH2)n with the N atom bonded to A; R1 = H or 1-4C alkyl; n = 2 or 3; E = COOH, 2-5C alkoxycarbonyl or 5-8C cycloalkoxycarbonyl.

Description

The invention relates to phenylene derivatives of the general formula

their tautomers, their stereoisomers including their Ge mix and their salts, in particular their physiologically ver suitable salts with inorganic or organic acids or bases, which have valuable pharmacological properties have, preferably aggregation-inhibiting effects, these Compounds containing drugs, their use and Process for their preparation.

In the above general formula I means
R _{a is} a piperidinyl, piperazinyl or piperazino group,
A is a -CH = CH-CO-, -CH₂-CH₂-CO- or -NR₁-CH₂-CO group, wherein the carbonyl group of the radical A is linked in each case with the radical B and
R₁ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms,
B is an -NR₁-cyclohexylene, piperidinylene or -NR₁- (CH₂) _n group, wherein the nitrogen atom of the abovementioned groups is in each case linked to the radical A,
R₁ as defined above and
n represents the number 2 or 3, and
E is a carboxy group, an alkoxycarbonyl group having a total of 2 to 5 carbon atoms or a cycloalkoxycarbonyl group having a total of 5 to 8 carbon atoms.

Preferred compounds of the above general formula I are those in which
R _{a represents} a 4-piperidinyl or piperazino group,
A is a -CH = CH-CO-, -CH₂-CH₂-CO- or -NR₁-CH₂-CO group, wherein the carbonyl group of the radical A is linked in each case with the radical B and
R₁ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms,
B is an -NR₁-1,4-cyclohexylene, 1,4-piperidinylene or -NR₁- (CH₂) _n- group, where the nitrogen atom of the abovementioned groups is in each case linked to the radical A,
R₁ as defined above and
n represents the number 2 or 3, and
E is a carboxy group, an alkoxycarbonyl group having a total of 2 to 5 carbon atoms or a cycloalkoxycarbonyl group having a total of 5 to 8 carbon atoms, their tautomers, their stereoisomers including their Gemi cal and their salts.

Particularly preferred compounds of the above general formula I are those in which
R _{a represents} a 4-piperidinyl or piperazino group,
A is a -CH = CH-CO-, -CH₂-CH₂-CO- or -NR₁-CH₂-CO group, wherein the carbonyl group of the radical A is linked in each case with the radical B and
R₁ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms,
B is an -NR₁-trans-1,4-cyclohexylene, 1,4-piperidinylene or -NR₁- (CH₂) _n- group, wherein the nitrogen atom of the abovementioned groups is in each case linked to the radical A,
R₁ as defined above and
n represents the number 2 or 3, and
E is a carboxy group, an alkoxycarbonyl group having a total of 2 to 5 carbon atoms or a cycloalkoxycarbonyl group having a total of 6 to 8 carbon atoms, their tautomers, their stereoisomers including their Gemi cal and their salts.

As particularly preferred compounds are, for example fol mentioned above:

• (a) 4- [4 - [[trans-4- (4-carboxycyclohexyl)] - aminocarbonyl (Trans-ethylene)] - phenyl] -piperidine,
• (b) 4- [4- [2 - [[trans- (4-carboxycyclohexyl)] - aminocarbonyl] - ethyl] -phenyl] -piperidine and
• (c) 4- [4 - [[trans- (4-carboxycyclohexyl)] - aminocarbonyl] -me methylamino-phenyl] -piperidine

and their salts.

According to obtain the new compounds of the general my formula I, for example, according to the following methods:

• a) For the preparation of compounds of general formula I in which R _{a is} a piperidinyl, piperazinyl or piperazino group and E is as defined above or R _{a is} as defined above and E represents a carboxy group:

Transfer of a compound of the general formula

in the
A and B are as defined above,
R _a 'and E' have the meanings mentioned for R _a and E, with the proviso that R _a 'by means of hydrolysis, Behan deln with an acid or base, thermolysis or hydrogenolysis cleavable protecting group for an imino group or E' one with means Hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis into a carboxyl group convertible group or
R _a 'is a protecting group for an imino group which can be split off by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis and E' is a group convertible into a carboxyl group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis,
in a compound of the general formula I in which R _{a represents} a piperidinyl, piperazinyl or piperazino group and E is as defined at the outset or R _{a is} as defined above and E represents a carboxy group.

For example, functional derivatives of the carboxyl group, such as their unsubstituted or substituted amides, esters, thioesters, trimethylsilyl esters, orthoesters, imino esters, amines or anhydrides, or the nitrile group can be converted into a carboxyl group by hydrolysis,
Esters with tertiary alcohols, e.g. Example, the tert-butyl ester, by means of treatment with an acid or thermolysis in a Carb oxylgruppe,
Esters with aralkanols, e.g. B. the benzyl ester, by hydro genolysis in a carboxyl group,
Imino groups which are substituted by a protecting group such as the formyl, acetyl, trifluoroacetyl, allyloxycarbonyl, ethoxycarbonyl, tert.butoxycarbonyl or benzyloxycarbonyl group, by hydrolysis into an imino group,
Imino groups, which are substituted by a protective group such as by the benzyl oxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group, by means of hydrogenolysis in an imino group and
Imino groups, which are substituted by a protecting group such as the allyloxycarbonyl group, in the presence of a catalyst such as tetrakis (triphenylphosphine) palladium (O) are converted into a free imino group.

The hydrolysis is conveniently carried out either in the presence an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, Es acetic acid, trichloroacetic acid, trifluoroacetic acid or their Mixtures or in the presence of a base such as lithium hydroxide, Sodium hydroxide or potassium hydroxide in a suitable Lö such as water, water / methanol, water / ethanol, what water / isopropanol, methanol, ethanol, water / tetrahydrofuran or Water / dioxane at temperatures between -10 and 120 ° C, z. B. at Temperatures between room temperature and the boiling point of the reaction mixture.

Means in a compound of general formula II for example, R _a 'or E' is a tert. Butyloxycarbonyl group, it may also be by treatment with an acid such as trifluoroacetic acid, formic acid, p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid or polyphosphoric optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, diethyl ether, tetrahydrofuran or dioxane before preferably at Temperatures between -10 and 120 ° C, z. Example, at temperatures between 0 and 60 ° C, or thermally where appropriate in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and preferably in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid, sulfuric acid, phosphoric acid or Polyphosphoric acid preferably at the boiling temperature of the solvent used, for. B. at temperatures between 40 and 120 ° C, are split off.

Means in a compound of general formula II for example R _a 'or E' a benzyloxycarbonyl, it can also hydrogenolytically in the presence of a Hydrierungskata lysators such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, ethyl acetate , Dioxane or dimethylformamide, preferably at temperatures between 0 and 50 ° C, eg. B. at room temperature, and a hydrogen pressure of 1 to 5 bar are split off.

• b) for the preparation of compounds of general formula I, in which A represents a -CH₂-CH₂-CO group:

Hydrogenation of a compound of the general formula

in the
R _a , B and E are as defined above and
A 'represents a -CH = CH-CO- group.

The hydrogenation is preferably in a suitable solution such as methanol, methanol / water, acetic acid, ethyl acetate, Ethanol, ether, tetrahydrofuran, dioxane or dimethylformamide with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, platinum, platinum dioxide, rhodium or palladium / carbon optionally with the addition of an acid such as hydrochloric acid Temperatures between 0 and 100 ° C, preferably at temperature ren between 20 and 80 ° C, carried out.

• c) for the preparation of compounds of general formula I, in the E an alkoxycarbonyl group having a total of 2 to 5 Koh lenstoffatomen or a Cycloalkoxycarbonylgruppe in total including 5 to 8 carbon atoms:

Reaction of a compound of the general formula

in the
R _a , A and B are as defined above, with a compound of the general formula

Z₁ - R₂, (V)

in the
R₂ is an alkyl group having 1 to 4 carbon atoms or a cycloalkyl group having 4 to 7 carbon atoms and
Z₁ is a hydroxy group or a nucleophilic leaving group such as a halogen atom, e.g. Example, a chlorine, bromine or iodine atom, or a sulfonic acid ester group, for. As a methanesulfonyloxy or p-To luolsulfonyl-oxygruppe.

The reaction is conveniently carried out in a solvent such as in an appropriate alcohol, e.g. B. in methanol, ethanol or Cyclohexanol, in methylene chloride, tetrahydrofuran, dioxane, di methylsulfoxide or dimethylformamide optionally in counter a base such as sodium carbonate, potassium carbonate or Na triol or in the presence of a tertiary organic base such as N-ethyl-diisopropylamine or N-methyl-morpholine, which can simultaneously serve as a solvent, or given if in the presence of a dehydrating agent at Tempe temperatures between -30 and 150 ° C, but preferably at Tempe temperatures between 20 and 120 ° C, carried out.

Z₁ means a hydroxy group, the reaction is in one Solvent or solvent mixture such as methylene chloride, Dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, Benzene / tetrahydrofuran or dioxane or particularly advantageous in a corresponding alcohol of the general formula V gege if appropriate in the presence of an acid such as hydrochloric acid or in Ge present a dehydrating agent, z. B. in the presence of Isobutyl chloroformate, orthocarbonic tetraethyl ester, trimethyl orthoacetate, 2,2-dimethoxypropane, Te triethoxysilane, thionyl chloride, trimethylchlorosilane, sulfur acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus tri chloride, phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N'-di cyclohexylcarbodiimide / 1-hydroxybenzotriazole, N, N'-carbonyl diimidazole or triphenylphosphine / carbon tetrachloride, and optionally with the addition of a base such as pyridine, 4-dimethyl  aminopyridine or triethylamine conveniently at Tempe temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 100 ° C, performed.

If Z₁ is a nucleophilic leaving group, the order Um tion in a solvent such as methylene chloride, tetrahydro furan, dioxane, dimethylsulfoxide or dimethylformamide if appropriate in the presence of a reaction accelerator such as Na trium- or potassium iodide, and preferably in the presence of a Base such as sodium carbonate, potassium carbonate or sodium hydroxide or in the presence of a tertiary organic base such as N-ethyl-di isopropylamine or N-methyl-morpholine which are also present can serve as a solvent, or optionally in counter were of silver carbonate or silver oxide at temperatures between usually -30 and 100 ° C, but preferably at temperatures between -10 and 80 ° C, performed.

Further, the obtained compounds of the general For mel I, as already mentioned, in their enantiomers and / or diastereomers are separated. So can at For example, cis / trans mixtures into their cis and trans isomers, and compounds having at least one optically active Koh be separated into their enantiomers.

For example, the resulting cis- / trans-Ge mix by chromatography in their cis and trans isomers, the obtained compounds of the general formula I, which in Racemates occur, according to known methods (see Allinger N.L. and Eliel E.L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of general formula I with at least 2 ste reogenous centers due to their physical chemical Un differences according to known methods, for. B. by chroma tography and / or fractional crystallization, into her slide stereomers which, if in racemic form then, as mentioned above, into the enantiomers can be separated.  

The enantiomer separation is preferably carried out by columns separation on chiral phases or by recrystallization an optically active solvent or by reacting with one, with the racemic compound salts or derivatives like z. As esters or amides-forming optically active substance, ins particular acids and their activated derivatives or alcohols, and separating the diastereomeric salt thus obtained mixed or derivative, e.g. B. due to different Solubilities, wherein from the pure diastereomeric salts or Derivatives the free antipodes by action appropriate Funds can be released. Particularly common, op table active acids are z. For example, the D and L forms of tartaric acid or dibenzoyltartaric acid, di-o-toluenoic acid, malic acid, Mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. As optically active alcohol comes for example, (+) - or (-) - menthol and as optically active Acyl radical in amides, for example, (+) - or (-) - Menthyloxycar consider bonyl.

Furthermore, the compounds of the formula I can be obtained in their salts, in particular for pharmaceutical use in their physiologically acceptable salts with inorganic or organic acids are transferred. As acids come here for example, hydrochloric acid, hydrobromic acid, sulfur acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, Citric acid, tartaric acid or maleic acid into consideration.

In addition, the new compounds thus obtained can be Formula I, if they contain a carboxyl group, desired then in their salts with inorganic or or ganic bases, in particular for pharmaceutical use into their physiologically acceptable salts. When Bases come here, for example, sodium hydroxide, Kaliumhy droxid, arginine, cyclohexylamine, ethanolamine, diethanolamine and Triethanolamine into consideration.  

The compounds used as starting materials are partial known from the literature or obtained according to the literature Method (see examples and ferri, reactions of Organi Chemistry, G. Thieme Verlag, Stuttgart).

As already mentioned, the new phenylene derivatives the general formula I and their salts, in particular their physiologically acceptable salts with inorganic or orga niche acids or bases, valuable properties. So white sen the new compounds of general formula I valuable pharmacological properties, in addition to an inflammatory inhibitory and bone resorption inhibitory effect in particular antithrombotic, antiaggregatory and tumor or metastatic seneregermende effects.

For example, the compounds of general formula I examined for their biological effects as follows:

1. Inhibition of the binding of 3 H-BIBU 52 to human platelets

A suspension of human platelets in plasma is with 3 H-BIBU 52 [= (3S, 5S) -5 - [(4'-amidino-4-biphenylyl) oxymethyl] - 3 - [(carboxyl) methyl] -2-pyrrolidinone [3-³H-4-biphenylyl]] replaced the literature known ligand ¹²⁵J-fibrinogen, (see DE-A-42 14 245) and various concentrations of te to incubated substance. The free and bound ligand becomes separated by centrifugation and by scintillation counting determined quantitatively. From the measured values, the inhibition of 3 H-BIBU 52 binding determined by the test substance.

For this purpose, donor blood is taken from an anticancer vein and anticoagulated with trisodium citrate (final concentration 13 mM). The blood is centrifuged for 10 minutes at 170 x g and the supernatant platelet-rich plasma (PRP) was removed. The rest Blood is again sharply abzentri for the production of plasma fugue. The PRP is diluted 1:10 with autologous plasma. 750 μl are mixed with 50 μl of physiological saline, 100 μl Test substance solution, 50 μl of ¹⁴C-sucrose (3700 bq) and 50 μl  3 H-BIBU 52 (final concentration: 5 nM) at room temperature for 20 min incubated. To measure the non-specific binding is on place the test substance 5 μl BIBU 52 (final concentration: 30 μM) used. The samples are centrifuged for 20 seconds at 10,000 × g fugiert and the supernatant subtracted. 100 μl of these become the Determination of the free ligand measured. The pellet will be in 500 Dissolved 0.2 μl NaOH, 450 μl with 2 ml scintillator and 25 .mu.l 5N HCl added and measured. The remaining in the pellet Remaining plasma is determined from the ¹⁴C content, the bound Ligand from the 3 H-measurement. After deduction of unspecific Binding will increase the pellet activity against the concentration of Test substance and the concentration for a 50% Inhibition of binding determined.

2. Antithrombotic effect methodology

Platelet aggregation is determined by the method of Born and Cross (J. Physiol 170, 397 (1964)) in platelet-rich plasma measured by healthy subjects. For clotting inhibition is the blood with sodium citrate 3.14% in the volume ratio 1: 10 added.

Collagen-induced aggregation

The course of decrease of the optical density of the platelets pension becomes after adding the aggregation-triggering substance Measured and registered photometrically. From the angle of inclination the density curve is ge on the aggregation speed closed. The point of the curve where the largest light transmission permeability is used to calculate the "optical den sity ".  

The amount of collages is chosen as low as possible, but that results in an irreversible reaction curve. The commercially available collagen from Hormon is used Chemistry, Munich.

The collagen is added to the plasma for 10 minutes before the collagen is added the substance is incubated at 37 ° C.

From the obtained measurement numbers, an EC₅₀ is determined graphically, referring to a 50% change in the "optical density" in the Meaning of an aggregation inhibition relates.

The following table contains the results found:

Due to their compatibility and inhibitory effect on cell-cell or Cell-matrix interactions are the new ones Phenylene derivatives of general formula I and their physiolo gisch compatible salts for the control or prevention of Diseases involving smaller or larger cell aggregates occur or play cell-matrix interactions, z. B. in the control or prevention of venous and arte rial thrombosis, cerebrovascular diseases, Pulmonary embolisms, myocardial infarction, atherosclerosis, the Osteoporosis and metastasis of tumors and therapy genetic or acquired disorders of Inter actions of cells with each other or with solid structures. Furthermore, these are suitable for concomitant therapy in throm  bolysis with fibrinolytica or vascular interventions such as translu minor angioplasty or also in the therapy of shock stagnation, psoriasis, diabetes and inflammation.

For the control or prevention of the abovementioned Diseases, the dose is between 0.1 μg and 30 mg / kg of body weight per weight, preferably at 1 μg to 15 mg / kg body weight, with up to 4 doses per day. For this purpose, the invention can be according to compounds of formula I, optionally in combination with other active substances such as thromboxane-Re zeptor antagonists and thromboxane synthesis inhibitors or their Combinations, serotonin antagonists, α-receptor antagonists, Alkyl nitrates such as glyceryl trinitrate, phosphodiesterase inhibitors, Prostacyclin and its analogs, fibrinolytics such as tPA, Prouro kinase, urokinase, streptokinase, or anticoagulants like Heparin, dermatan sulfate, activated protein C, vitamin K antagonists, hirudin, inhibitors of thrombin or others activated clotting factors, together with one or more several inert customary carriers and / or dilution average, z. B. with corn starch, lactose, cane sugar, micro crystalline cellulose, magnesium stearate, polyvinylpyrrolidone, Citric acid, tartaric acid, water, water / ethanol, water / glycerol, Water / sorbitol, water / polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethylcellulose or fetthal term substances such as hard fat or their suitable mixtures, in common pharmaceutical preparations such as tablets, Drag'es, Capsules, powders, suspensions, solutions, sprays or suppositories incorporated.

The following examples are intended to explain the invention in more detail tern:

Preparation of the starting compounds Example I 1-t-butyloxycarbonyl-4- [4 - [[trans- (4-methoxycarbonylcyclo hexyl)] - aminocarbonyl (trans-ethylene)] - phenyl] -piperidine a) 1-Acetyl-4- (4-bromo-phenyl) -piperidine

To a solution of 14 g of 1-acetyl-4-phenyl-piperidine in 180 ml of methylene chloride is added with stirring and cooling to -2 to 0 ° C within 5 minutes 18.25 g of aluminum chloride. The mixture is allowed to stir for a further 10 minutes at 0 ° C. and then a solution of 3.75 ml of bromine in 30 ml of methylene chloride is added over the course of 5 minutes at -5 ° C. The mixture is stirred for a further 5 minutes at 0 ° C and then poured the solution on ice. It is extracted twice with 100 ml of methylene chloride, the combined organic phase is dried over sodium sulfate and concentrated to dryness under vacuum. The residue which remains is purified by chromatography on silica gel (eluant: methylene chloride / methanol = 40: 1).
Yield: 7.9 g (40.5% of theory) of a resin,
Mass spectrum: M⁺ = 281/283.

b) 4- [4- (1-acetyl-piperidinyl)] - 1-trans-cinnamic acid ethyl ester

A mixture of 7.8 g of 1-acetyl-4- (4-bromophenyl) -piperidine, 0.85 g of palladium (II) acetate, 1.14 g of tri-o-tolylphosphine, 8.9 g of ethyl acrylate and 14, 1 g of triethylamine in 12 ml Dime thylformamid is heated to 100 ° C with stirring and under nitrogen for 48 hours. It is then diluted with 200 ml of methylene chloride and washed several times with water. The organic phase is dried and concentrated. The remaining residue is purified by chromatography on silica gel (eluent, methylene chloride / methanol = 60: 1).
Yield: 5.6 g (66.6% of theory).

c) 4- [4- (1-acetyl-piperidinyl)] - trans -cinnamic acid

1.5 g of the crude 4 - [- (1-acetyl-piperidinyl)] - trans-cinnamic acid ethyl ester are dissolved in 80 ml of tetrahydrofuran. To this solution is added with stirring, a solution of 3.27 g Lithiumhy hydroxide in 100 ml of water, stirred for a further 3 hours at room temperature and then mixed with 5.1 g of ammonium chloride, with a clear solution. The pH of the solution is adjusted to 4, wherein a colorless precipitate bil det, which is filtered off with suction and dried.
Yield: 1.9 g (38% of theory),
Mass spectrum: M⁺ = 273
trans-olefin: 1 H-NMR (DMSO):
1H: 6.45-6.55 ppm (doublet), J: 16 Hz
1H: 7.5-7.6 ppm (doublet), J: 16 Hz

d) 4- (4-piperidinyl) trans-cinnamic acid

A suspension of 2.1 g of 4- [4- (1-acetyl-piperidinyl) trans cinnamic acid in 30 ml conc. Hydrochloric acid and 30 ml of water is dialed heated to reflux for 3 hours, with a forms a clear solution. It is concentrated under vacuum to dryness and receives about 2 g of a resinous residue.

e) 4- [4- (1-tert-Butyloxycarbonyl-piperidinyl)] - trans -cinnamic acid

2 g of the resinous crude 4- (4-piperidinyl) trans-cinnamic acid dissolved in 100 ml of dioxane / water = 2: 1. To do this, add 12 ml of 1N Sodium hydroxide solution and then 1.96 g of di-tert-butyl dicarbonate. After stirring for 15 hours at room temperature, it is concentrated under vacuum to dryness, filled up with 100 ml of water and by means of saturated potassium hydrogen sulfate solution has a pH of 2.5 on. It is extracted with methylene chloride and concentrated to dryness on. There remain 1.2 g of a crude resin.

f) 1-tert-Butyloxycarbonyl-4 - [[4- [trans- (4-methoxycarbonyl cyclohexyl)] - aminocarbonyl (trans-ethylene)] - phenyl] -piperidine

To a solution of 1.2 g of crude 4- [4- (1-tert-butyloxy carbonylpiperidinyl)] - trans-cinnamic acid in 30 ml of tetrahydrofuran is added with stirring 1.1 g of diphenylphosphinic chloride at a temperature of -10 ° C. The mixture is then stirred for a further 30 minutes at this temperature and then a solution of 0.82 g of 4-trans-Aminocyclohexancarbonsäuremethylester and 0.65 ml of triethylamine in 10 ml of dimethylformamide. Keep the temperature for a further 2 hours at -10 ° C, then stirred overnight at room temperature and concentrated under vacuum to dryness. The residue is partitioned between water and methylene chloride. The methylene chloride phase is washed with saturated sodium bicarbonate solution, dried and concentrated to dryness in vacuo. The remaining residue is purified by chromatography on silica gel (eluant: methylene chloride / methanol = 50: 1).
Yield: 1.1 g (65% of theory) of an oil.
trans-olef in: 1 H-NMR (DMSO):
1H: 6.5-6.6 ppm (doublet), J: 16 Hz
1H: 7.4-7.5 ppm (doublet), J: 16 Hz

Example II 1-t-butyloxycarbonyl-4- [4 - [[trans- (4-methoxycarbonyl-cyclo hexyl)] - aminocarbonyl-N-methyl-tert.butyloxycarbonylamino] phenyl] -p iperidin- a) 4- (4-nitro-phenyl) -1-trifluoroacetyl-piperidine

Dissolve 80 g of 4-phenyl-1-trifluoroacetyl-piperidine in 400 ml of glacial acetic acid and 200 ml of acetic anhydride and are added to the thus prepared Herge solution with cooling with ice / water 1.6 g Natriumni trit. With stirring and further cooling is added dropwise to 51.9 ml rau niting nitric acid. In this addition, the temperature of the reaction medium must be kept below + 10 ° C. After completion ter addition is allowed to warm to room temperature overnight and then poured portionwise to 1000 ml of water containing 200 g of ice. By means of 8N sodium hydroxide solution, a pH of 8 is set within 4 1/2 hours. The temperature must not exceed 20 ° C. The mixture is exhaustively extracted with methylene chloride, the combined methylene chloride phases are washed with 0.1N sodium hydroxide solution and then with water, dried over magnesium sulphate and evaporated to dryness in vacuo. The residue is crystallized from a mixture of 1000 ml of cyclohexane and 120 ml of ethyl acetate.
Yield: 109.4 g (58% of theory),
Melting point: 100-102 ° C.

b) 4- (4-Amino-phenyl) -1-trifluoroacetyl-piperidine

60.4 g of 4- (4-nitrophenyl) -1-trifluoroacetyl-piperidine are hydrogenated in 700 ml of ethyl acetate with 7 g of palladium on activated carbon (10%) at room temperature and 50 psi hydrogen pressure. It is filtered and evaporated.
Yield: 54.4 g (100% of theory),
R _f value: 0.25 (silica gel, cyclohexane / ethyl acetate = 2: 1)

c) N- [4- [4- (1-trifluoromethyl-piperidinyl)] - phenyl] -glycine methylester

To a solution of 5.4 g of 4- (4-amino-phenyl) -1-trifluoroacetyl piperidine in 100 ml of absolute tetrahydrofuran are added 3.3 g of methyl bromoacetate and 2.6 g of N-ethyl-diisopropylamine and heated for 8 hours reflux. Then the solution is concentrated under vacuum and the remaining residue is purified by chromatography on silica gel (eluent: methylene chloride with 1% methanol).
Yield: 6.0 g (84.4% of theory), oil,
R _f value: 0.72 (silica gel, methylene chloride / methanol = 9.5: 0.5).

d) N- [4- (4-piperidinyl) -phenyl-glycine hydrochloride

A suspension of 3 g of N- [4- [4- (1-trifluoroacetyl-piperidinyl] -phenyl] -glycine methyl ester in 20 ml of concentrated hydrochloric acid and 20 ml of water is stirred overnight at room temperature and then for 2 hours heated to reflux, resulting in a clear solution, concentrated to dryness under vacuum, and the crude oily residue used in the next reaction stage without further purification.
Yield: 2.6 g (100% of theory),
R _f value: 0.15 (silica gel, methylene chloride / methanol = 9: 1)

e) N-tert-butyloxycarbonyl-N- [4- [4- (1-tert-butyloxycarbonyl) piperidinyli-phenyll-glycine

To a suspension of 2.6 g of N-4- (4-piperidinyl) -phenyl-glycine hydrochloride and 2.6 g of triethylamine in 60 ml of dioxane and 30 ml of water is added dropwise at -10 ° C and with stirring 4, 3 ml of di-tert-butyldicarbonate. After completion of the addition, stirring is continued overnight at room temperature, then the solution is concentrated under reduced pressure to dryness and the residue is partitioned between ethyl acetate and water, the aqueous phase adjusted to a saturated pH of 2 to 3 with saturated potassium hydrogen sulfate solution becomes. The ethyl acetate extract is dried over sodium sulfate and concentrated to dryness.
Yield: 3.6 g (100% of theory) of an almost colorless solid,
R _f value: 0.62 (silica gel, methylene chloride / methanol = 4: 1).

The compound thus obtained is without further purification in the used next reaction stage.

f) 1-tert-Butyloxycarbonyl-4- [4 - [[trans- (4-methoxycarbonyl cyclohexyl)] - aminocarbonyl-methyl-N-t-butyloxycarbonyl amino-phenyl] -piperidine

A solution of 2 g of N-tert-butyloxycarbonyl-N- [4- [4- (1-tert-butyloxycarbonyl) -piperidinyl] -phenyl] -glycine, 1.5 g of 2- (1H-benzotriazol-1-yl ) -1,1,3,3-tetramethyluronium tetrafluoroborate, 0.62 g of N-hydroxybenzotiazole, 0.9 g of trans-p-Aminocyclohexancar bonsäuremethylester and 1.2 g of N-ethyl-diisopropylamine in 100 ml of absolute tetrahydrofuran is during 14 Hours at room temperature. It is then mixed with 0.5 mo lar potassium hydrogen sulfate solution and methylene chloride, the methylene chloride phase is separated and extracted twice more with methylene chloride. The combined organic extracts are dried over sodium sulfate and concentrated to dryness. The residue thus obtained is purified by chromatography on silica gel (eluant: methylene chloride containing 3% methanol).
Yield: 1.4 g (53% of theory),
Melting point: 180-185 ° C,
R _f value: 0.5 (silica gel, methylene chloride / methanol = 9: 1).

Preparation of the end compounds example 1 4- [4 - [[trans-4- (4-carboxy-cyclohexyl)] - aminocarbonyl (trans ethylene)] - phenyl] piperidine hydrochloride

A suspension of 220 mg of 1-tert-butyloxycarbonyl-4- [4- [[trans- (4-methoxycarbonyl-cyclohexyl)] -aminocarbonyl- (trans-ethylene)] -phenyl] -piperidine in 20 ml conc. Hydrochloric acid and 20 ml of water are stirred for 18 hours at room temperature. In the short term, a clear solution emerges from which precipitation again precipitates. The remaining residue is crystallized from acetone.
Yield: 150 mg (81.7% of theory),
Melting point: 289-292 ° C (dec.),
R _f value: 0.42 (reversed phase silica gel, methanol / 5% aqueous saline = 6: 4).
trans-olefin; ¹H-NMR (DMSO):
1H: 6.5-6.6 ppm (doublet), J: 16 Hz
1H: 7.35-7.45 ppm (doublet), J: 16 Hz

Analogously to Example 1, the following compounds are obtained:

• (1) 4- [4- [2 - [[trans- (4-carboxycyclohexyl)] - aminocarbonyl] ethyl] phenyl] piperidine hydrochloride
  Prepared from 4- [4- [2 - [[trans- (4-methoxycarbonyl-cyclohexyl)] - aminocarbonyl] -ethyl] -phenyl] -piperidine hydrochloride and 3N hydrochloric acid.
  Yield: 110 mg (92.8% of theory),
  Melting point: 298-301 ° C (dec.),
  R _f value: 0.5 (reversed phase silica gel, methanol / 5% aqueous saline = 6: 4).
• (2) 4- [4 - [[trans- (4-carboxycyclohexyl)] - aminocarbonyl] -methylamino-phenyl] -piperidine hydrochloride
  Prepared from 4- [4 - [[trans- (4-methoxycarbonyl-cyclohexyl)] aminocarbonyl-methylamino] -phenyl] -piperidine hydrochloride and 3N hydrochloric acid.
  Yield: 400 mg (90.2% of theory),
  Melting point: 250-252 ° C (dec.),
  R _f value: 0.1 (silica gel, methylene chloride / methanol / ammonia = 4: 1: 0.2)
• (3) 4- [4 - [[4-carboxymethyl-piperidino] -carbonyl- (trans-ethyl) -phenyl] -piperidine hydrochloride
  Prepared from 1-tert-butyloxycarbonyl-4- [4 - [[4-methoxycarbonylmethylpiperidino] carbonyl (trans-ethylene)] phenyl] -piperidine and 3N hydrochloric acid.
• (4) 4- [4 - [(2-carboxy-ethyl) -aminocarbonyl (trans-ethylene)] -phenyl] -piperidine hydrochloride
  Prepared from 1-tert-Butyloxycarbonyl-4- [4 - [(2-ethoxycarbonylethyl) aminocarbonyl- (trans-ethylene)] - phenyl] -piperidine and 3N hydrochloric acid.
• (5) 4- [4 - [(3-Carboxy-propyl) -aminocarbonyl (trans-ethylene)] -phenyl] -piperidine hydrochloride
  Prepared from 1-tert-butyloxycarbonyl-4- [4 - [(3-ethoxycarbonylpropyl) aminocarbonyl- (trans-ethylene)] - phenyl] -piperidine and 3N hydrochloric acid.
• (6) 4- [4 - [[trans- (4-carboxycyclohexyl)] - methylaminocarbonyl (trans-ethylene)] - phenyl] -piperidine hydrochloride
  Prepared from 4- [4 - [[trans- (4-methoxycarbonylcyclohexyl)] - methylaminocarbonyl (trans-ethylene)] - phenyl] -piperidine trifluoroacetate and 3N hydrochloric acid.
• (7) 4- [4 - [[trans- (4-carboxycyclohexyl)] - aminocarbonyl (trans-ethylene)] - phenyl] -piperazine hydrochloride
  Prepared from 4- [4 - [[trans- (4-methoxycarbonylcyclohexyl)] - aminocarbonyl- (trans-ethylen)] - phenyl] -piperazine trifluoroacetate and 3N hydrochloric acid.
• (8) 4- [4 - [[4-carboxymethyl-piperidino] -carbonyl- (trans-ethylene)] -phenyl] -piperazine hydrochloride
  Prepared from 1-tert-butyloxycarbonyl-4- [4 - [[methoxycarbonylmethylpiperidino] carbonyl (trans-ethylene)] - phenyl] -pipeazine and 3N hydrochloric acid.
• (9) 4- [4 - [[(2-Carboxy-ethyl) -aminocarbonyl (trans-ethylene)] -phenyl] -piperazine hydrochloride
  Prepared from 1-tert-butyloxycarbonyl-4- [4 - [(2-ethoxy-carbonyl-ethyl) -aminocarbonyl- (trans-ethylene)] -phenyl] -piperazine and 3N hydrochloric acid.
• (10) 4- [4- [2 - [[4-carboxymethylpiperidino] carbonyl] ethyl] phenyl] piperidine hydrochloride
  Prepared from 4- [4- [2 - [[4-methoxycarbonyl-piperidino] -car bonyl] -ethyl] -phenyl] -piperidine hydrochloride and 3N hydrochloric acid.
• (11) 4- [4- [2 - [[trans- (4-carboxycyclohexyl)] aminocarbonyl] ethyl] phenyl] piperazine hydrochloride
  Prepared from 4- [4- [2 - [[trans- (4-methoxycarbonylcyclohexyl)] - aminocarbonyl] ethyl] phenyl] piperazine hydrochloride and 3N hydrochloric acid.
• (12) 4- [4 - [[4-carboxymethyl-piperidino] -carbonyl] -methyl-amino] -phenyl] -piperidine hydrochloride
  Prepared from 4- [4 - [[4-methoxycarbonylmethylpiperidino] carbonylmethylamino] phenyl] piperidine hydrochloride and 3N hydrochloric acid.
• (13) 4- [4 - [(2-carboxy-ethyl) -aminocarbonyl-methylamino] -phenyl] -piperidine hydrochloride
  Prepared from 4- [4 - [(2-ethoxycarbonyl-ethyl) -aminocarbonyl-methylamino] -phenyl] -piperidine-hydrochloride and 3N hydrochloric acid.

Example 2 4- [4 - [[trans- (4-methoxycarbonyl-cyclohexyl)] - aminocarbonyl (Trans-ethylene)] - phenyl] -piperidine trifluoroacetate

A suspension of 220 mg of 1-tert-butyloxycarbonyl-4- [4- [[trans- (4-methoxycarbonyl-cyclohexyl)] - aminocarbonyl- (trans-ethylen)] -phenyl] -piperidine in 20 ml of methylene chloride and 20 ml of trifluoroacetic acid is stirred for 3 hours at room temperature, whereby a clear solution is formed. It is concentrated to dryness under vacuum and the residue is crystallized from ether.
Yield: 190 mg (83.9% of theory),
Melting point: 222-225 ° C (dec.),
R _f value: 0.3 (reversed phase silica gel, methanol / 5% aqueous common salt solution = 6: 4),
trans-olefin: 1 H-NMR (DMSO):
1H: 6.5-6.6 ppm (doublet), J: 16 Hz
1H: 7.3-7.4 ppm (doublet), J: 16 Hz

Analogously to Example 2, the following compounds are obtained:

• (1) 4- [4 - [[trans- (4-methoxycarbonylcyclohexyl)] - aminocarbonylmethylamino] -phenyl] -piperidine hydrochloride
  Prepared from 1-tert-butyloxycarbonyl-4- [4 - [[trans- (4-methoxycarbonyl-cyclohexyl)] - aminocarbonyl-methyl-N-tert-butyloxy-carbonylamino] -phenyl] -piperidine and trifluoroacetic acid.
  Yield: 1.0 g (91.8% of theory),
  Melting point: 253-255 ° C (dec.),
  R _f value: 0.1 (silica gel, methylene chloride / methanol = 9: 1).
• (2) 4- [4 - [[4-Methoxycarbonylmethyl-piperidino] carbonyl (trans-ethylene)] -phenyl] -piperidine hydrochloride
  Prepared from 1-tert-butyloxycarbonyl-4- [4 - [[4-methoxy-carbonyl-methyl-piperidino] -carbonyl- (trans-ethylene)] -phenyl] -piperidine and trifluoroacetic acid.
• (3) 4- [4 - [(2-Ethoxycarbonyl-ethyl) -aminocarbonyl (trans-ethylene)] -phenyl] -piperidine-trifluoroacetate
  Prepared from 1-tert-butyloxycarbonyl-4- [4 - [(2-ethoxycarbonylethyl) aminocarbonyl- (trans-ethylene)] - phenyl] -piperidine and trifluoroacetic acid.
• (4) 4- [4 - [(3-Ethoxycarbonyl-propyl) -aminocarbonyl (trans-ethylene)] -phenyl] -piperidine hydrochloride
  Prepared from 1-tert-butyloxycarbonyl-4- [4 - [(3-ethoxycarbonyl-propyl) -aminocarbonyl- (trans-ethylene)] -phenyl] -piperidine and trifluoroacetic acid.
• (5) 4- [4 - [[trans - (4-methoxycarbonylcyclohexyl)] - N -methylaminocarbonyl- (trans-ethylene)] - phenyl] -piperidine-trifluoroacetate
  Prepared from 1-tert-butyloxycarbonyl4- [4 - [[trans- (4-methoxycarbonylcyclohexyl)] - N -methylaminocarbonyl- (trans-ethyl) -phenyl] -piperidine and trifluoroacetic acid.
• (6) 4- [4 - [[trans- (4-methoxycarbonylcyclohexyl)] - aminocarbonyl (trans-ethylene)] - phenyl] -piperazine trifluoroacetate
  Prepared from 1-tert-butyloxycarbonyl-4- [4 - [[trans- (4-methoxycarbonyl-cyclohexyl)] - aminocarbonyl- (trans-ethylene)] - phenyl] -piperazine and trifluoroacetic acid.
• (7) 4 [4 - [[4-Methoxycarbonylmethylpiperidino] carbonyl (trans-ethylene)] phenyl] piperazine hydrochloride
  Prepared from 1-tert-butyloxycarbonyl-4- [4 - [[4-methoxycarbonylmethylpiperidino] carbonyl (trans-ethylene)] phenyl] piperazine and trifluoroacetic acid.
• (8) 4- [4 - [(2-Ethoxycarbonyl-ethyl) -aminocarbonyl- (trans-ethylen)] -phenyl] -piperazine hydrochloride
  Prepared from 1-tert-butyloxycarbonyl-4- [4 - [(2-ethoxycarbonylethyl) aminocarbonyl- (trans-ethylene)] - phenyl] -piperazine and trifluoroacetic acid.
• (9) 4- [4 - [[4-Methoxycarbonylmethylpiperidino] carbonylmethylamino] phenyl] piperidine hydrochloride
  Prepared from 1-tert-butyloxycarbonyl-4- [4 - [[4-methoxycarbonylmethyl-piperidino] -carbonyl-methyl-N-tert-butyloxycarbonylamino] -phenyl] -piperidine and trifluoroacetic acid.
• (10) 4- [4 - [(2-Ethoxycarbonyl-ethyl) -aminocarbonyl-methyl-amino] -phenyl] -piperidine hydrochloride
  Prepared from 1-tert-Butyloxycarbonyl-4- [4 - [(2-ethoxycarbonylethyl) aminocarbonylmethyl-N-tert-butyloxycarbonylamino] phenyl] piperidine and trifluoroacetic acid.

Example 3 4- [4- [2 - [[trans- (4-methoxycarbonyl-cyclohexyl)] - aminocar carbonyl] ethyl] -phenyl] -piperidine hydrochloride

120 mg of 4- [4 - [[trans- (4-methoxycarbonylcyclohexyl)] - aminocarbonyl (trans-ethylene)] - phenyl] -piperidine trifluoroacetate are dissolved in 100 ml of methanol with 50 mg of palladium on activated carbon (10%). Palladium) at room temperature and a hydrogen pressure of 50 psi for 4 hours. The catalyst is filtered off with suction and the filtrate is evaporated. The residue is dissolved in ether and treated with ethereal hydrochloric acid. The precipitated crystals are filtered off with suction and dried.
Yield: 80 mg (79% of theory),
Melting point: 172-175 ° C (dec.),
R _f value: 0.32 (reversed phase silica gel, methanol / 5% aqueous saline = 6: 4).

The following compounds are obtained analogously:

• (1) 4- [4- [2 - [[4-Methoxycarbonylmethylpiperidino] carbonyl] ethyl] phenyl] piperidine hydrochloride
  Prepared from 4- [4 - [[4-methoxycarbonylmethyl-piperidino] carbonyl (trans-ethylene)] - phenyl] -piperidine hydrochloride by hydrogenation with palladium on charcoal (10% palladium) as catalyst.
• (2) 4- [4- [2 - [[trans- (4-methoxycarbonyl-cyclohexyl)] - aminocarbonyl] -ethyl] -phenyl] -piperazine hydrochloride
  Prepared from 4- [4 - [[trans- (4-methoxycarbonylcyclohexyl)] aminocarbonyl (trans-ethylene)] - phenyl] -piperazine hydrochloride by hydrogenation with palladium on charcoal (10% palladium) as catalyst.

Example 4 4- [4 - [[trans- (4-cyclohexyloxycarbonyl-cyclohexyl)] - aminocar bonyl- (trans-ethylene)] - phenyl] piperidine hydrochloride

In a suspension of 1 g of 4- [4 - [[trans- (4-carboxycyclo hexyl)] aminocarbonyl (trans-ethylene)] - phenyl] -piperidine hydrochloride in 20 ml of methylene chloride and 20 ml of cyclohexanol hydrochloric acid gas is added at room temperature to saturation passes. Then allowed to the resulting clear solution stand for an hour and then warm up for 3 hours 40 ° C. The solution is then added under reduced pressure Dry concentrated and the residue washed with ether.

The following compound is obtained analogously:

• (1) 4- [4 - [[trans- (4- (2-methyl-1-propyloxy) carbonylcyclo hexyl)] - aminocarbonyl (trans-ethylene)] - phenyl] -piperidine hydrochloride.

Example 5 Dry ampoule containing 2.5 mg of active ingredient per 1 ml

composition Active ingredient | 2.5 mg mannitol 50.0 mg Water for injections ad 1.0 ml

manufacturing

Active substance and mannitol are dissolved in water. After filling Treatment is freeze-dried. The resolution for the use solution with water for injections.

Example 6 Dry ampoule containing 35 mg of active ingredient per 2 ml

composition Active ingredient | 35.0 mg mannitol 100.0 mg Water for injections ad 2.0 ml

manufacturing

Active substance and mannitol are dissolved in water. After bottling is freeze-dried.

The solution to the ready-to-use solution is water for injections.

Example 7 Tablet with 50 mg active ingredient

composition (1) Active substance | 50.0 mg (2) lactose 98.0 mg (3) corn starch 50.0 mg (4) polyvinylpyrrolidone 15.0 mg (5) magnesium stearate  2.0 mg 215.0 mg

manufacturing

(1), (2) and (3) are mixed and treated with an aqueous solution granulated by (4). The dried granules are added (5) mixed. From this mixture tablets are pressed biplan with double-sided facet and one-sided part notch. Diameter of the tablets: 9 mm.

Example 8 Tablet with 350 mg active ingredient

composition (1) Active ingredient | 350.0 mg (2) lactose 136.0 mg (3) corn starch 80.0 mg (4) polyvinylpyrrolidone 30.0 mg (5) magnesium stearate  4.0 mg 600.0 mg

manufacturing

(1), (2) and (3) are mixed and treated with an aqueous solution granulated by (4). The dried granules are added (5) mixed. From this mixture tablets are pressed biplan with double-sided facet and one-sided part notch. Diameter of the tablets: 12 mm.

Example 9 Capsules with 50 mg active ingredient

composition (1) Active substance | 50.0 mg (2) dried corn starch 58.0 mg (3) powdered milk sugar 50.0 mg   (4) magnesium stearate  2.0 mg 160.0 mg

manufacturing

(1) is triturated with (3). This trituration becomes the mix from (2) and (4) with intensive mixing.

This powder mixture is placed on a capsule filling machine in Hard gelatine capsules size 3 bottled.

Example 10 Capsules with 350 mg active ingredient

composition (1) Active ingredient | 350.0 mg (2) dried corn starch 46.0 mg (3) powdered milk sugar 30.0 mg (4) magnesium stearate  4.0 mg 430.0 mg

manufacturing

(1) is triturated with (3). This trituration becomes the mix from (2) and (4) with intensive mixing.

This powder mixture is placed on a capsule filling machine in Hard gelatine capsules size 0 filled.

Claims (10)

1. phenylene derivatives of the general formula in the
R _{a is} a piperidinyl, piperazinyl or piperazino group,
A is a -CH = CH-CO-, -CH₂-CH₂-CO- or -NR₁-CH₂-CO group, wherein the carbonyl group of the radical A is linked in each case with the radical B and
R₁ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms,
B is an -NR1-cyclohexylene, piperidinylene or -NR₁- (CH₂) _n- group, where the nitrogen atom of the abovementioned groups is in each case linked to the radical A,
R₁ as defined above and
n represents the number 2 or 3, and
E is a carboxy group, an alkoxycarbonyl group having a total of 2 to 5 carbon atoms or a cycloalkoxycarbonyl group having a total of 5 to 8 carbon atoms, their tautomers, their stereoisomers including their Ge mix and their salts. 2. phenylene derivatives of the general formula I according to claim 1, in which
R _{a represents} a 4-piperidinyl or piperazino group,
A is a -CH = CH-CO-, -CH₂-CH₂-CO- or -NR₁-CH₂-CO group, wherein the carbonyl group of the radical A is linked in each case with the radical B and
R₁ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms,
B is an -NR₁-1,4-cyclohexylene, 1,4-piperidinylene or -NR₁- (CH₂) _n- group, where the nitrogen atom of the abovementioned groups is in each case linked to the radical A,
R₁ as defined above and
n represents the number 2 or 3, and
E is a carboxy group, an alkoxycarbonyl group having a total of 2 to 5 carbon atoms or a cycloalkoxycarbonyl group having a total of 5 to 8 carbon atoms, their tautomers, their stereoisomers including their Gemi cal and their salts. 3. phenylene derivatives of the general formula I according to claim 1, in which
R _{a represents} a 4-piperidinyl or piperazino group,
A is a -CH = CH-CO-, -CH₂-CH₂-CO- or -NR₁-CH₂-CO group, wherein the carbonyl group of the radical A is linked in each case with the radical B and
R₁ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms,
B is an -NR₁-trans-1,4-cyclohexylene, 1,4-piperidinylene or -NR₁- (CH₂) _n- group, wherein the nitrogen atom of the abovementioned groups is in each case linked to the radical A,
R₁ as defined above and
n represents the number 2 or 3, and
E is a carboxy group, an alkoxycarbonyl group having a total of 2 to 5 carbon atoms or a cycloalkoxycarbonyl group having a total of 6 to 8 carbon atoms, their tautomers, their stereoisomers including their Ge mixtures and their salts. 4. The following compounds of general formula I according to claim 1:

• (a) 4- [4 - [[trans-4- (4-carboxycyclohexyl)] - aminocarbonyl- (trans-ethylene)] - phenyl] -piperidine,
• (b) 4- [4- [2 - [[trans- (4-carboxy-cyclohexyl)] -aminocarbonyl] -ethyl] -phenyl] -piperidine and
• (c) 4- [4 - [[trans- (4-carboxy-cyclohexyl)] -aminocarbonyl] -methylamino-phenyl] -piperidine

and their salts.   5. Physiologically acceptable salts of the compounds after min at least one of claims 1 to 4 with inorganic or organic acids or bases. 6. A pharmaceutical composition containing a compound after at least one of claims 1 to 4 or a physiologically acceptable Royal addition salt according to claim 5 in addition to optionally one or more inert carriers and / or dilution convey. 7. Use of a compound according to at least one of Claims 1 to 5 for the manufacture of a medicament intended for Combating or preventing diseases in which smaller or larger cell aggregates occur or cell matrix inter actions play a role. 8. A process for the preparation of a medicament according to claim 7, characterized in that non-chemically A compound according to any one of claims 1 to 5 in a or more inert carriers and / or diluents is incorporated. 9. A process for the preparation of the novel compounds of the general formula I my according to claims 1 to 5, characterized in that

• a) for the preparation of compounds of general formula I in which R _{a is} a piperidinyl, piperazinyl or piperazino group and E is as defined in claims 1 to 4 or R _{a is} as defined in claims 1 to 4 and E is a Represents carboxy group, a compound of the general formula in the
  A and B are as defined in claims 1 to 4,
  R _a 'and E' have the meanings mentioned for R _a and E in claims 1 to 4 with the proviso that R _a 'by Hy hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis cleavable protecting group for an imino group or
  E 'is a group convertible into a carboxyl group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis
  R _a 'is a protecting group for an imino group which can be split off by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis and E' is a group convertible into a carboxyl group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis,
  in a compound of the general formula I in which R _{a represents} a peridinyl, piperazinyl or piperazino group and E is as defined in claims 1 to 4 or R _{a is} as defined in claims 1 to 4 and E is a carboxy group puts, is transferred or
• b) for the preparation of compounds of the general formula I in which A represents a -CH₂-CH₂-CO group, a compound of the general formula in the
  R _a , B and E are as defined in claims 1 to 4 and
  A 'represents a -CH = CH-CO group, is hydrogenated or
• c) for the preparation of compounds of the general formula I in which E is an alkoxycarbonyl group having a total of 2 to 5 carbon atoms or a cycloalkoxycarbonyl group having a total of 5 to 8 carbon atoms, a compound of the general formula in the
  R _a , A and B are as defined in claims 1 to 4, with a compound of general formula Z₁ - R₂, (V) in the
  R₂ is an alkyl group having 1 to 4 carbon atoms or a cycloalkyl group having 4 to 7 carbon atoms and
  Z₁ is a hydroxy group or a nucleophilic leaving group be interpreted, and if desired, a compound of general formula I thus obtained is separated into its stereoisomers and / or a compound of general formula I thus obtained in their salts, in particular for the pharmaceutical application in their physiological compatible salts with an inorganic or organic acid or base, is converted.