BG105159A - Substituted phenylamidines with antithrombotic action - Google Patents

Abstract

The invention relates to phenylamidines of formula in which R6 and R7 are defined as described in claim 1, their tautomers and their stereoisomers, including their mixtures and salts, especially physiologically compatible salts with inorganic or organic acids and bases, which have valuable pharmacological properties, preferably antithrombotic effects. The invention also relates to medicaments containing said compounds, to their use and to methods for preparing same. 13 claims

Description

TECHNICAL FIELD

The invention relates to substituted phenylamidines with antithrombotic action.

BACKGROUND OF THE INVENTION

WO 96/33970 discloses phenylamidines of the general formula:

in which: R _b, among other meanings, represents a C 1-6 alkyloxy carbonyl group, an aryl-C 1-6 alkyloxycarbonyl group or a group of the formula:

R _{b -} C

O - (HCRJ - O in which:

R _a represents a hydrogen atom or an alkyl group and

R _b denotes an alkyl group or a 3- to 7-membered cycloalkyl group, wherein no compound of this type is explicitly described in the present description.

SUMMARY OF THE INVENTION

It is now established that phenylamidines of general formula (I): HN

HN

R <

(I) in which:

R ₆ represents a C 1-6 alkyloxycarbonyl or phenyl-C 1-6 alkyloxycarbonyl group,

R ₇ represents a hydrogen atom, the radicals C 1-6 alkyl, C ₄ . ₇ cycloalkyl, phenylC _1-4 alkyl or R 8 -CO-OCHR 8, in which

R ₈ is C 1-6 alkyl, C ₁ . ₄ alkoxy, C ₃ . ₇ cycloalkyl or C ₄ . ₇ cycloalkoxy group and

Rg means a hydrogen atom or C _1-4 alkyl, as well as their tautomers, stereoisomers and salts, and in particular the physiologically compatible salts thereof with inorganic or organic acids or bases, which have even better pharmacological properties, in particular antithrombotic action.

It is an object of the present invention to provide the compounds of the general formula (I) above, their tautomers, stereoisomers and salts thereof, especially their physiologically compatible salts with inorganic or organic acids or bases; the dosage forms containing these compounds, their administration and methods for their preparation.

those

R ₆

R ₇

Preferred compounds of formula (I) above are those in which:

the substituted amidino group is in the fourth place, especially those compounds in which:

R ₆ represents C _1-8 alkyloxycarbon and l or phenyl-C _1-4 alkyloxycarbonyl and

R ₇ represents a hydrogen atom, C 1-6 alkyl, C ₅ . ₇ cycloalkyl or _phenyl-G4 alkyl;

their tautomers, stereoisomers and salts.

Particularly preferred compounds of the formula (I) above are in which:

is C ₁₁₂ alkyloxycarbonyl or phenyl-C 1-4 alkyloxycarbonyl and represents C 1-6 alkyl, C ₅ . ₇ cycloalkyl;

their tautomers, stereoisomers and salts.

The most preferred compounds of the formula (I) above are those in which:

R ₆ is C ₅ . ₁₂ alkyloxycarbonyl or benzyloxycarbonyl and

R ₇ represents C ^ alkyl, C ₅ cycloalkyl;

their tautomers, stereoisomers and salts.

Examples of particularly preferred compounds include the following:

(1) 4- [2 - [[4- (octyloxycarbonylamidino) phenyl] aminocarbonyl] ethyl] -1 [(ethoxycarbonyl) methyl] piperidine, (2) 4- [2 - [[4- (hexyloxycarbonylamidino) phenyl] aminocarbonyl] ethyl] -1 [(ethoxycarbonyl) methyl] piperidine, (3) 4- [2 - [[4- (hexyloxycarbonylamidino) phenyl] aminocarbonyl] ethyl] -1 [(methoxycarbonyl) methyl] piperidine and (4) 4- [2 - [[4- (octyloxycarbonylamidino) phenyl] aminocarbonyl] ethyl] -1 [(methoxycarbonyl) methyl] piperidine and their salts.

According to the invention, the new compounds of general formula (I) are prepared, for example, according to the method below:

reaction of a compound of general formula (II):

(II) in which:

R ₆ is as defined above with a compound of general formula (III):

HO-CO-CH ₂ CH ₂

N-CH ₂ CO-OR ₇ (HI),

wherein:

R ₇ is as defined above or with its reactive derivatives and

optionally converting the residue R ₇ into a hydrogen atom.

To reactive derivatives of compounds of general formula

III fall, e.g. their acid chlorides, azides, mixed anhydrides with aliphatic or aromatic carboxylic acids or with carbonic acid monoesters, imidazolides and their esters, e.g. their alkyl, aryl and arylalkyl esters, such as methyl, ethyl, isopropyl, pentyl, phenyl, nitrophenyl or benzyl ester.

The reaction is advantageously carried out in a solvent or in a mixture of solvents, such as methylene chloride, dimethylformamide, dimethylsulfoxide, benzene, toluene, chlorobenzene, tetrahydrofuran, pyridine, pyridine / methylene chloride, pyridine / dimethylformamide, benzene / tetrahydrofuran, tetrahydrofuran, tetrahydrofuran, tetrahydrofuran e.g. isobutyl ester of chloroformic acid, thionyl chloride, trimethylchlorosilane, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus petoxide, Ν, Ν'-dicyclohexyl-carbodiimide ', ди-carbodiimide' 1H-benzo triazolyl) -1,1,3,3-tetramethyluronium salts, N, N'-carbonyldiimidazole, N, N'-thionyldiimidazole, 2-chloro-1-methylpyridine-iodide or triphenylphosphine / tetrachloromethane, optionally present dimethylaminopyridine or 1-hydroxybenzotriazole and / or a base such as triethyl yn, Nethyldiisopropylamine, pyridine or N-methyl-morpholine, at temperatures between -10 and 180 ° C, preferably at temperatures between 0 and 120 ° C.

Subsequent conversion of the R ₇ radicals to a hydrogen atom is carried out or in the presence of an acid, e.g. hydrochloric, sulfuric, phosphoric, acetic, trichloroacetic, trifluoroacetic acid, as well as in mixtures thereof © or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide, in a suitable solvent such as water, water / methanol, water / ethanol, water / isopropanol, methanol, ethanol, water / tetrahydrofuran, or water / dioxane, at temperatures between -10 ° C and 120 ° C, e.g. at temperatures between room temperature and that of the reaction mixture.

In addition, the compounds of general formula I obtained, as already mentioned, can be separated into enantiomeric and / or diastereomeric forms. For example, cis- / trans- mixtures can be separated into cis-isomers and trans-isomers, and compounds with at least one optically active carbon atom can be separated into their enantiomers.

Thus, for example, the cis- / trans-mixtures can be separated chromatographically into their cis-isomers and grand-isomers; The compounds of general formula I, which are obtained as racemates, can be separated by methods known in the art (see Allinger N. L. und Eliel E. L. Topics in Stereochemistry, Vol. 6, Wiley Interscience, 1971) for their optical antipodes. Compounds of general formula I having at least two asymmetric carbon atoms, due to their physicochemical differences, can be separated into their diastereomers by known methods, such as chromatography and / or fractional crystallization, and, if obtained in racemic form , can be separated by the enantiomeric methods mentioned above.

Preferably, the enantiomeric separation is carried out as column separation on chiral phases, either by recrystallization from an optically active solvent or by reaction with any agent which forms with the racemic compounds optically active compounds, such as salts or derivatives, e.g. esters or amides; these are mainly acids and their activated derivatives or alcohols. The diastereomeric mixtures of salts or derivatives thus obtained are then separated, e.g. due to differences in their solubility, then free antipodes can be released from the pure diastereomeric salts or derivatives by action with a suitable agent. Optically active acids of particularly great use are e.g. D- and L-forms of tartaric or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic, almond, camphorsulfonic, glutamic, aspartic or quinic acid. Optically active alcohol can be cited, e.g. (+) - or (-) - menthol and as an optically active acyl radical in the amides is, for example, (+) - or (-) - methyloxycarbonyl.

Further, the compounds of formula I obtained can be converted into their salts, and in particular for pharmaceutical use, into their physiologically compatible salts with inorganic or organic acids. Such acids include hydrochloric, hydrobromic, sulfuric, methanesulfonic, phosphoric, fumaric, succinic, lactic, citric, tartaric or maleic acids.

In addition, the new compounds of formula I obtained, if they contain a carboxyl group, may eventually, if desired, be converted to salts with inorganic or organic bases, and especially for pharmaceutical use, they may be physiologically acceptable salts. Sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine may be mentioned as bases.

The compounds used as starting materials are partly known in the literature or prepared by methods known in the literature (see examples).

As mentioned in the beginning, the new phenylamidines of general formula I and their salts, and in particular the physiologically compatible salts thereof,

inorganic or organic acids or bases exhibit beneficial properties. For example, with the new compounds of general formula I, a high and sustained plasma level is achieved after oral administration compared to the compound of inhibition of aggregation, 4- [2 - [(4-amidinophenyl) aminocarbonyl, described in WO 96/33970 ] ethyl] -1 carboxymethylpiperidine (Compound A). Thus, the new phenylamidines of the general Formula I and their salts exhibit valuable pharmacological properties, together with bone-inducing inflammation and breakdown, in particular antitrobotic, anti-aggregate and tumor-inhibiting agents, respectively. metastases action.

For example, the concentration of compound A in plasma is determined after oral administration of the compounds of Examples 1 (compound B in the table) and 1 (1) (compound B in the table) of the present invention and compared with the plasma concentration of compound A after oral administration of the same compound (A).

Following oral administration of 1 mg / kg of test compound to monkeys (Rhesus macaque), the plasma concentration of compound A, 4 was measured,

8, 12 and 24 hours after administration of the substance. To this end, plasma from monkeys is incubated with a human platelet suspension in plasma with ³ H-BIBU 52 (see DE-A - 4,214,245) as a ligand. The free and bound ligand were separated by centrifugation and quantified by scintillation counting. From the amount of ligands bound, the concentration of compound A is calculated using a reference curve.

For this purpose, blood is collected from the anti-cubital vein and anticoagulated with trisodium citrate (final concentration 13 mmol / l). The blood was centrifuged for 10 minutes at 170 g and platelet-rich supernatant plasma was collected. The remainder of the blood was centrifuged once more at 3200 g, after which the erythrocyte-poor plasma supernatant was taken.

To obtain a reference curve for calculation of concentration, 5 μl of Compound A (final concentration 5000 nanomoles / l) was added to 995 μl (microlitres) of platelet-poor plasma. This plasma sample is diluted with platelet-poor plasma to a final concentration of 2.5 nanomoles / l.

To the 150 μl monkey or plasma plasma sample, 10 μl of ³ H-BIBU 52 (final concentration of 10 nanomoles / l), 10 μl of ¹⁴ C-sucrose (370 Bq) and 80 μl of platelet-rich plasma were added to the reference curve and the mixture was added. incubated for 20 minutes at room temperature. Finally, the samples were centrifuged for 5 minutes at 2000 g and the supernatant removed. Mix 100 μl of it with 100 μl of NaOH 0.2 mol / l, 15 μl of HCI 5 mol / l and 2 ml of scintillator, then quantify the radioactivity at ³ H and at ¹⁴ C. The precipitate is dissolved in 200 μl of NaOH 0.2 mol / l. Of these, 180 μl was mixed with 15 μl HCl 5 mol / l and 2 ml scintillator and quantified the radioactivity at ³ H and at ¹⁴ C. The residual plasma present in the precipitate was determined from the content of ¹⁴ C and subtracted. The amount of bound ligands is determined by the content of ³ N. The amount of bound ligands is plotted against the concentration of the plasma reference curve. The concentration of compound A in plasma from monkeys was calculated from the amount of bound ligands in the plasma sample considered compared to the reference curve.

The table below contains the calculated values:

Substance conc. on the A c [nm], 4h conc. on the A c [nm], 8h conc. on the A c [nm], 12 h conc. on the A c [nm], 24 h A 174 38 25 3 B. 133 127 81 51 IN 170 123 80 52

On the basis of their biological properties, the compounds of the invention of the general Formula I and their physiologically compatible salts are suitable for the fight, respectively. prevention with diseases in which smaller or larger aggregates of cells are produced or in which interactions in the cell matrix play a role. For example, for the treatment or prevention of venous or arterial thrombosis, cerebrovascular disease, pulmonary embolism, cardiac infarction, arteriosclerosis, osteoporosis, and tumor metastasis, as well as in the treatment of genetically-mediated or inherited interstitial cell interactions structures. In addition, the compounds are useful in concomitant therapy for fibrinolytic thrombolysis, or for interventions in vessels such as transluminal angioplasty or for the treatment of shock conditions, psoriasis, diabetes and inflammation.

For the control or prevention of the above-mentioned diseases, the dose ranges from 0.1 µg (micrograms) to 15 mg / kg body weight, preferably from 1 µg to 15 mg / kg body weight, which can be distributed up to 4 doses daily. In addition, the compounds of the general formula I obtained according to the invention may optionally be combined with other active ingredients, such as thromboxane receptor antagonists and thromboxane synthesis inhibitors or combinations thereof, ADF receptor antagonists, clopidogrel, ticlopostin of serotonin, α-receptor antagonists, alkylnitrates, such as glycerin trinitrate, phosphodiesterase inhibitor, prostacyclin and analogs, fibrinolytics, such as tPA (tissue plasminogen activator), prourokinase, urokinase, strepto inaza or anticoagulants such as heparin, dermatinsulfat, activated protein C, vitamin K antagonists, hirudin, inhibitors of thrombin or other activated clotting factors. They may be combined with one or more of the usual fillers and / or diluents, e.g. corn starch, lactose, sugar, microcrystalline cellulose, magnesium stearate, polyvinyl pyrrolidone, citric acid, tartaric acid, water, water / ethanol,

I water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, stearic alcohol, carboxymethylcellulose or fatty substances such as hard oil or mixtures thereof, prepared in conventional pharmaceutical forms such as tablets, dragees, capsules, powders, suspensions, suspensions, suspensions, suspensions sprays or suppositories.

The examples below are for a more detailed explanation of

I} the statement:

I | EXAMPLES FOR CARRYING OUT THE INVENTION ί

I

Ϊ 0 Preparation of starting compounds

Example I

4- (hexyloxycarbonylamidino) aniline

5.1 g of 4- (hexyloxycarbonylamidino) nitrobenzene were hydrogenated in

100 ml of tetrahydrofuran in the presence of 0.5 g of palladium on charcoal at room temperature and under hydrogen pressure of 50 psi (3.5 bar). The catalyst was removed by filtration and the filtrate was concentrated. Yield: 4.5 g 100% of theory,

R _f = 0.23 (silica gel; cyclohexane / ethyl acetate = 1: 1).

The following compounds were prepared analogously to Example 1:

(1) 4- (octyloxycarbonylamidino) aniline

R _f = 0.25 (silica gel; cyclohexane / ethyl acetate = 1: 1).

(2) 4- (methoxycarbonylamidino) aniline

R _f = 0.35 (silica gel; methylene chloride / methanol = 9: 1).

(3) 4- (Benzyloxycarbonylamidino) aniline

R _f = 0.35 (silica gel; methylene chloride / methanol / conc. Ammonia = 9: 1: 0.1). Example II

4- (Hexyloxycarbonylamidino) nitrobenzene

To 3.5 g of 4-nitrobenzamidine hydrochloride and 7.2 g of potassium carbonate in a mixture of 350 ml of tetrahydrofuran and 70 ml of water, cooled with an ice bath, were added dropwise 2.8 ml of hydrochloric acid hexyl ester in 80 ml of tetrahydrofuran. After stirring for one hour in an ice bath, the solution was allowed to stand overnight at room temperature. The organic phases were separated, washed twice with saturated aqueous sodium chloride solution, dried and concentrated. Yield: 5.1 g, 100% oteorete.

R _f = 0.72 (silica gel; cyclohexane / ethyl acetate = 1: 1). The following compounds were prepared analogously to Example 1:

(1) 4- (octyloxycarbonylamidino) nitrobenzene Mass spectrum: M ⁺ = 321.

(2) 4- (methoxycarbonamidino) nitrobenzene

Melting point: 183 - 185 ° C.

(3) 4- (Benzyloxycarbonylamidino) nitrobenzene

R _f = 0.88 (silica gel; methylene chloride / methanol / conc. Ammonia = 9: 1: 0.1). Example III 4- [2- (chlorocarbonyl) ethyl] -1 - [(ethoxycarbonyl) methyl] piperidine hydrochloride

To 1.46 g of 4- (2-carboxyethyl) -1 - [(ethoxycarbonyl) methyl] piperidine in ml of methylene chloride, with stirring, was added 1 ml of saturated ether hydrochloric acid. 1.2 g of thionyl chloride are then added and the mixture is stirred for 3 hours at room temperature. Finally, the reaction mixture was concentrated and the residue was mixed twice with toluene and concentrated each time. The crude product was used without purification in Example 1. Similarly to Example III, the following compounds were obtained:

(1) 1- [2- (chlorocarbonyl) ethyl] -4 - [(methoxycarbonyl) methyl] piperidine hydrochloride (2) 4- [2- (chlorocarbonyl) ethyl] -1 - [(cyclohexyloxycarbonyl) methyl] piperidine hydrochloride (3) ) 4- [2- (chlorocarbonyl) ethyl] -1 - [(isopropoxycarbonyl) methyl] piperidine hydrochloride.

Example IV

4- [2- (carboxy) ethyl] -1 - [(ethoxycarbonyl) methyl] piperidine

10.0 g of 4- [2- (benzyloxycarbonyl) ethyl] -1 - [(ethoxycarbonyl) methyl] piperidine in 150 ml of tetrahydrofuran are hydrogenated for 4 hours at room temperature and at a pressure of 50 psi (3.5 bar) in the presence of 1.3 g of palladium. on activated carbon. The reaction mixture was concentrated and recrystallized from a mixture of diethyl ether with little acetone.

Yield: 5.8 g (79% of theory).

M.p .: 65-67 ° C

The following compounds were prepared analogously to Example IV:

(1) 4- (2-carboxyethyl) -1 - [(cyclohexyloxycarbonyl) methyl] piperidine mp: 85-88 ° C.

(2) 4- (2-carboxyethyl) -1 - [(isopropoxycarbonyl) methyl] piperidine

R _f : 0.41 (reversed phase silica gel chromatography; methanol / 5% aqueous sodium chloride solution = 6: 4) (3) 4- (2-carboxyethyl) -1 - [(methoxycarbonyl) methyl] piperidine

mp: 82-83 ° C.

Example V

4- [2- (Benzyloxycarbonyl) ethyl] -1 - [(ethoxycarbonyl) methyl] piperidine

To 9.0 g of 4- [2- (benzyloxycarbonyl) ethyl] piperidine and 5.2 g of N-ethyldiisopropylamine in 70 ml of acetonitrile were added dropwise, with stirring in an ice bath, 6.35 g of bromic acid ethyl ester in 20 ml of acetonitrile and the resulting mixture. stirred for 18 hours at room temperature. The reaction mixture was concentrated and the residue was quickly partitioned between tert-butyl methyl ester, ice water and 10 ml of 2N sodium hydroxide. The organic phases were separated, washed with ice water and saturated aqueous sodium chloride solution, dried and concentrated.

Yield: 10.05 g (83% of theory)

R _f : 0.84 (silica gel; methylene chloride / methanol / conc. Aqueous ammonia = 95: 5: 1)

The following compounds were prepared analogously to Example V:

(1) 4- [2- (Benzyloxycarbonyl) ethyl] -1 - [(cyclohexyloxycarbonyl) methyl] piperidine

R _f : 0.47 (silica gel; methylene chloride / methanol / conc. Aqueous ammonia = 98: 2: 0.5) (2) 4- [2- (benzyloxycarbonyl) ethyl] -1 - [(isopropoxycarbonyl) methyl] -piperidine

Mass Spectrum: M- = 347 (3) 4- [2- (Benzyloxycarbonyl) ethyl] -1 - [(methoxycarbonyl) methyl] -piperidine R _f : 0.40 (silica gel; methylene chloride / methanol / conc. Aqueous ammonia = 9: 1: 0.1)

Example VI

4- [2- (Benzyloxycarbonyl) ethyl] piperidine

9.7 g of 4- (2-carboxyethyl) piperidine hydrochloride (mp: 24-250 ° C, obtained by hydrogenation of 3- (4-pyridyl) acrylic acid in glacial acetic acid with platinum oxide catalyst and subsequent treatment with hydrochloric acid), 30 ml of benzyl alcohol, 3 g of p-toluenesulfonic acid and 50 ml of toluene are heated under a separator for 75 minutes. The reaction mixture was concentrated in vacuo, the residue was taken up in 50 ml of ice water and extracted three times with tert-butyl methyl ether. The aqueous phase was basified and extracted with tert-butyl methyl ether. The extract was washed with brine, dried and concentrated.

Yield: 9.0 g (73% of theory).

R _f : 0.18 (silica gel; methylene chloride / methanol / conc. Aqueous ammonia solution = ^{95: 5: 1} >

Preparation of the final compounds

Example 1

4- [2 - [[4- (octyloxycarbonylamidino) phenyl] aminocarbonyl] ethyl] -1 [(ethoxycarbonyl) methyl] piperidine

To 5.1 g of 4- (octyloxycarbonylamidino) aniline and 100 mg of 4-dimethylaminopyridine in 30 ml of pyridine, 5.7 g of 4- [2- (chlorocarbonyl) ethyl] -1- were added dropwise over 30 minutes under ice-cooling. [(ethoxycarbonyl) methyl] piperidine hydrochloride in 30 ml of methylene chloride. The mixture was left overnight at room temperature, and the residue was concentrated

V is chromatographed on a silica gel column, eluting with a mixture of methylene chloride / methanol / conc. aqueous ammonia solution (9: 1: 0.1).

Yield: 2.9 g, (32% of theory).

Mass Spectrum: (M + H) ⁺ = 517.

The following compounds were prepared analogously to Example 1:

(1) 4- [2 - [[4- (hexyloxycarbonylamidino) phenyl] aminocarbonyl] ethyl] -1 [(ethoxycarbonyl) methyl] piperidine

M.p .: 151 -153 ° C,

Mass Spectrum: M ⁺ = 489.

(2) 4- [2 - [[4- (hexyloxycarbonylamidino) phenyl] aminocarbonyl] ethyl] -1- [(isopropoxycarbonyl) methyl] piperidine

M.p .: 161 -162 ° C,

R _f : 0.20 (silica gel; methylene chloride / methanol / conc. Aqueous ammonia = 9: 1: 0.1) (3) 4- [2 - [[4- (octyloxycarbonylamidino) phenyl] aminocarbonyl] ethyl] -1 [(isopropoxycarbonyl) ) methyl] piperidine

Mp: 151-152 ° C,

Mass Spectrum: M ⁺ = 531.

(4) 4- [2 - [[4- (hexyloxycarbonylamidino) phenyl] aminocarbonyl] ethyl] -1 [(cyclohexyloxycarbonyl) methyl] piperidine

M.p .: 149-151 ° C,

Mass Spectrum: (M + H) ⁺ = 543.

(5) 4- [2 - [[4- (octyloxycarbonylamidino) phenyl] aminocarbonyl] ethyl] -1- [(cyclohexyloxycarbonyl) methyl] piperidine

M.p .: 157-162 ° C,

Mass Spectrum: (M + H) ⁺ = 571.

(6) 4- [2 - [[4- (hexyloxycarbonylamidino) phenyl] aminocarbonyl] ethyl] -1- [(methoxycarbonyl) methyl] piperidine

M.p .: 153-155 ° C,

R _f : 0.32 (silica gel; methylene chloride / methanol / conc. Aqueous ammonia = 9: 1: 0.1) (7) 4- [2 - [[4- (octyloxycarbonylamidino) phenyl] aminocarbonyl] ethyl] -1 [(methoxycarbonyl) ) methyl] piperidine

M.p .: 149-150 ° C,

Mass Spectrum: (M + H) ⁺ = 503.

(8) 4- [2 - [[4- (methoxycarbonylamidino) phenyl] aminocarbonyl] ethyl] -1 [(ethoxycarbonyl) methyl] piperidine

Mp: 175-177 ° C,

Mass Spectrum: (Μ + H) ⁺ = 419.

(9) 4- [2 - [[4- (benzyloxycarbonylamidino) phenyl] aminocarbonyl] ethyl] -1 [(methoxycarbonyl) methyl] piperidine

M.p .: 150-152 ° C

Instead of carboxylic acid chloride, the corresponding carboxylic acid in the presence of N-methyl-morpholine and 2-chloro-1-methylpyridinium in dimethylformamide is used.

(10) 4- [2 - [[4- (decyloxycarbonylamidino) phenyl] aminocarbonyl] ethyl] -1 [(ethoxycarbonyl) methyl] piperidine (11) 4- [2 - [[4- (dodecyloxycarbonylamidino) phenyl] aminocarbonyl] ethyl ] -1 [(ethoxycarbonyl) methyl] piperidine (12) 4- [2 - [[4- (tetradecyloxycarbonylamidino) phenyl] aminocarbonyl] ethyl] -

1 - [(ethoxycarbonyl) methyl] piperidine (13) 4- [2 - [[4- (hexadecyloxycarbonylamidino) phenyl] aminocarbonyl] ethyl] 1 - [(ethoxycarbonyl) methyl] piperidine (14) 4- [2 - [[4 - (octadecyloxycarbonylamidino) phenyl] aminocarbonyl] ethyl] 1 - [(ethoxycarbonyl) methyl] piperidine

Example 2

4- [2 - [[4- (hexyloxycarbonylamidino) phenyl] aminocarbonyl] ethyl] -1 [(ethoxycarbonyl) methyl] piperidine methanesulfonate

To 600 mg of 4- [2 - [[4- (hexyloxycarbonylamidino) phenyl] aminocarbonyl] ethyl] -1 - [(ethoxycarbonyl) methyl] piperidine in 30 ml of acetone was added dropwise 1.228 ml of a 1 molar solution of methanesulfonic acid in acetone . After standing overnight and scraping with a glass rod, a solid product was obtained which was collected by filtration under reduced pressure and washed twice with acetone. Finally, it was dried at 40 ° C under vacuum.

Yield: 560 mg (78% of theory),

M.p .: 117-120 ° C

Calculated: C 55.46 H 7.58

N, 9.58. S, 5.48

Found: C 55.56 H 7.85 N 9.72 S 5.54.

The following compounds were prepared analogously to Example 2:

(1) 4- [2 - [[4- (octyloxycarbonylamidino) phenyl] aminocarbonyl] ethyl] -1 [(ethoxycarbonyl) methyl] piperidine methanesulfonate

Mp: 125-127 ° C

Calculated: C 56.84 H 7.90 N9.14 S5.23

Found: C 56.94 H 7.88 N 9.32 S 5.27.

Example 3

50 mg tablets of the active ingredient

Composition:

(1) Active ingredient 50.0 mg (2) lactose 98.0 mg (3) cornstarch 50.0 mg (4) polyvinylpyrrolidone 15.0 mg (5) magnesium stearate 2.0 mg

215.0 mg

Receive:

Mix ingredients (1), (2) and (3) and granulate with an aqueous solution of (4). Mix the dried granulate with (5). From this mixture are compressed tablets, two-plane, double-sided and single-sided cutting channel.

Tablet diameter: 9 mm.

Example 4 j Tablets with 350 mg of active ingredient ί

ί |

i

Composition: (1) Active ingredient 350.0 mg (2) lactose 136.0 mg (3) cornstarch 80.0 mg (4) polyvinylpyrrolidone 30.0 mg (5) magnesium stearate 4.0 mg

600.0 mg

Receive:

Mix ingredients (1), (2) and (3) and granulate with an aqueous solution of (4). Mix the dried granulate with (5). From this mixture are compressed tablets, two-plane, double-sided and single-sided cutting channel.

Tablet diameter: 12 mm.

Example 5

50 mg capsules of active ingredient

Composition:

(1) Active ingredient 50.0 mg (2) corn starch dry 58.0 mg (3) lactose powder 50.0 mg (4) magnesium stearate 2.0 mg

160.0 mg

Receive:

(1) is torn by (3). This crushed material is added to a mixture of (2) and (4) under vigorous mixing.

The resulting powder mixture is filled with hard gelatin capsules No. 3 with a capsule machine.

Example 6

Capsules with 350 mg of active ingredient

Composition:

(1) Active ingredient 350.0 mg (3) corn starch, dried 46.0 mg (4) lactose powder 30.0 mg (5) magnesium stearate 4.0 mg 430.0 mg

Receive:

(1) is torn by (3). This crushed material is added to a mixture of (2) and (4) under vigorous mixing.

The resulting powder mixture is filled with hard gelatin capsules No. 0 with an encapsulating machine.

Claims (13)

1. Phenylamidines of the general formula: wherein: R ₆ is a C 1-6 alkyloxycarbonyl or phenyl-C 1-4 alkyloxycarbonyl group, R ₇ represents a hydrogen atom, a C 1-6 alkyl group, C ₄ . ₇ cycloalkyl, phenyl-C ₁₄ alkyl or R ₈ -CO-OCHR ₈ , in which R ₈ is C 1-6 alkyl, C 1-4 alkoxy, C ₃ . ₇ cycloalkyl or C ₄ . ₇ cycloalkoxy group and R _g represents a hydrogen atom or C ₁₄ alkyl, Phenylamidines of the general formula I according to claim 1, wherein the substituted amidino group is in the 4th position, their tautomers, stereoisomers and salts. 3. The phenylamidines of general formula I according to claim 1, wherein R ₆ represents N, N-alkyloxycarbonyl or phenyl-C 1-6 alkyloxycarbonyl, R ₇ represents a hydrogen atom, C 1-6 alkyl, C ₅ . ₇ cycloalkyl or phenyl-C _1-4 alkyl; their tautomers, stereoisomers and salts. Phenylamidines of general formula I according to claim 1, in which: R ₆ represents C 1-6 alkyloxycarbonyl or phenyl-C 1-4 alkyloxycarbonyl and R ₇ is C 1-4 alkyl, C ₅ . ₇ cycloalkyl; their tautomers, stereoisomers and salts. 5. Phenylamidines of general formula I according to claim 1, in which: R ₆ is C ₅ . ₁₂ alkyloxycarbonyl or benzyloxycarbonyl and R ₇ is C 1-6 alkyl, C ₅ . ₆ cycloalkyl; their tautomers, stereoisomers and salts. The following phenylamidines of the general formula I according to claim 1: (1) 4- [2 - [[4- (octyloxycarbonylamidino) phenyl] aminocarbonyl] ethyl] -1 - [(ethoxycarbonyl) methyl] piperidine, (2) 4- [2 - [[4- (hexyloxycarbonylamidino) phenyl] aminocarbonyl ] ethyl] -1 [(ethoxycarbonyl) methyl] piperidine, (3) 4- [2 - [[4- (hexyloxycarbonylamidino) phenyl] aminocarbonyl] ethyl] -1 [(methoxycarbonyl) methyl] piperidine and (4) 4- [ 2 - [[4- (octyloxycarbonylamidino) phenyl] aminocarbonyl] ethyl] -1 [(methoxycarbonyl) methyl] piperidine and their salts. 7. 4- [2 - [[4- (hexyloxycarbonylamidino) phenyl] aminocarbonyl] ethyl] -1-] [(ethoxycarbonyl) methyl] piperidine and its salts. j | 8. 4- [2 - [[4- (octyloxycarbonylamidino) phenyl] aminocarbonyl] ethyl] -1! [(ethoxycarbonyl) methyl] piperidine and its salts. 9. The physiologically compatible salts of the compounds according to at least One of claims 1 to 8 with inorganic or organic acids or bases. A dosage form comprising a compound according to at least one of claims 1 to 8, or a physiologically compatible salt thereof, according to claim 9, characterized in that it also contains one or more inert carriers and / or diluents. Use of a compound according to at least one of the claims of 1 to 9 for the preparation of a dosage form suitable for the control of ί or for the prevention of diseases in which small or I large cell aggregates, or in which the interactions of | the intracellular matrix. A method for preparing a dosage form according to claim 10, characterized in that a compound according to at least one of claims 1 to 9 can be mixed with one or more inert carriers and / or diluents in a non-chemical way. A process for the preparation of compounds of general formula I according to claims 1 to 9, characterized in that a compound of general formula: NH ₂ (II). wherein: R ₆ is as defined in claims 1 to 8, reacted with a compound of the general formula: HO-CO-CH ₂ CH _; I-CH ₂ CO-OR ₇ (III), in which: R ₇ is as defined in claims 1 to 8 or with its reactive derivatives and optionally converting the residue R ₇ into a hydrogen atom and, if desired, to separate one of the compounds of general formula I thus obtained into its stereoisomers and / or one of the compounds of the general Formula I thus obtained to be converted into its salts, especially if used in pharmacy, to be converted into its physiologically compatible salts.