CA2337413A1

CA2337413A1 - Substituted phenylamidines,pharmaceutical compositions containing these compounds and processes for preparing them

Info

Publication number: CA2337413A1
Application number: CA002337413A
Authority: CA
Inventors: Frank Himmelsbach; Brian Guth; Hans-Dieter Schubert
Original assignee: Individual
Current assignee: Boehringer Ingelheim Pharma GmbH and Co KG
Priority date: 1998-07-23
Filing date: 1999-07-20
Publication date: 2000-02-03
Also published as: HUP0103327A2; HUP0103327A3; ES2199587T3; EE200100048A; AR019462A1; BR9912321A; EP1102746A1; NO20010354L; BG105159A; PL345624A1; JP2002521363A; PT1102746E; TR200100182T2; HK1038750A1; CN1310708A; KR20010072046A; UY25621A1; DE19833105A1; NO20010354D0; DK1102746T3

Abstract

The invention relates to phenylamidines of formula (I), 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.

Description

Boehringer Ingelheim Pharma KG Case 5/1242-FL
55216 Ingelheim :E'oreign filing text Substituted phenylamidines, pharmaceutical compositions con-taming these compounds and processes for preparing them The scope of protection of WO 96/33970 includes phenylamidines of general formula O
N C X Y--Z CO-ORS
~4 wherein inter alia R1 denotes a Cl_4-alkyloxycarbonyl group, an aryl-Cl_3-alkyloxycarbonyl group or a group of formula Rb C// ~C- , \O- (HCRa) -O
wherein Ra denotes a hydrogen atom or an alkyl group and Rb denotes an alkyl group or a 3- to 7-mE:mbered cycloalkyl group, although no such compound is described in so many words in this published application.
It has now been found that the phenylamiaines of general formula HN
H ~ ~ / N CO CH2 CH2 N-- CH2 CO - OR7 ( I ) , R
s H
wherein R6 denotes a Cl_1g-alkyloxycarbonyl or phenyl-Cl_4-alkyloxycar-bonyl group, R~ denotes a hydrogen atom, a Cl_8-alkyl, C4_.,-cycloalkyl, phenyl-Cl_4-alkyl or Re-CO-OCHR9-group wherein Re denotes a Cl_4-alkyl, Cl_4-alkoxy, C3_.,-cycloalkyl or C4_,-cycloalkoxy group and R9 denotes a hydrogen atom or a Cl_4-alkyl. group, the tautomers, stereoisomers and salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, have even more valuable pharmacological properties, preferably antithrombotic effects.
The present invention relates to the compounds of the above general formula I, the tautomers, stereoisomers and salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, pharmaceu-tical compositions containing these compounds, their use and processes for preparing them.
Preferred compounds of the above general formula I are those wherein the substituted amidino group is in the 4 position, particularly those compounds wherein R6 denotes a Cl_18-alkyloxycarbonyl or phenyl-Cl_4-alkyloxycar-bonyl group and R, denotes a hydrogen atom, a Cl_8-alkyl, CS_~-cycloalkyl or phe-nyl-Cl_4-alkyl group, the tautomers, stereoisomers and salts thereof.
Particularly preferred compounds of the <~bove general formula z are those wherein R6 denotes a C1_lz-alkyloxycarbonyl or phenyl-C1_2-alkyloxycar-bonyl group and R., denotes a Cl_$-alkyl or CS_,-cycloalkyl group, the tautomers, stereoisomers and salts thereof.
Most particularly preferred compounds of the above general for-mula I are those wherein R6 denotes a CS_12-alkyloxycarbonyl or benzyloxycarbonyl group and R., denotes a Cl_4-alkyl or CS_6-cycloalkyl group, the tautomers, stereoisomers and salts thereof.
The following are mentioned as examples of particularly preferred compounds:
(1) 4- [2- [ [4- (octyloxycarbonylamidino) phenyl] amino-carbonyl] -ethyl]-1-[(ethoxycarbonyl)methyl]-piperidine, (2) 4- [2- [ [4- (hexyloxycarbonylamidino)phenyl] amino-carbonyl] -ethyl] -1- [ (ethoxycarbonyl)methyl] -piperidine, ( 3 ) 4 - [ 2 - [ [ 4 - ( hexyloxycarbonyl amidino ) phf~nyl I amino -carbonyl ] -ethyl] -1- [ (methoxycarbonyl) methyl] -piper:idine and (4) 4- [2- [ [4- (octyloxycarbonylamidino)phenyl] amino-carbonyl] -ethyl]-1-[(methoxycarbonyl)methyl]-piperidine and the salts thereof.
According to the invention the new compounds of general formula I are obtained, for example, by the following method:
reacting a compound of general formula HN
HN \ ~ NH2 ( I I ) , wherein R6 is as hereinbefore defined, with a compound of general for-mula HO- CO CH CH N-CHZCO-OR7 ( I I I ) , wherein R., is as hereinbefore defined, or a reactive derivative thereof and optionally subsequently converting the croup R7 into a hydrogen atom.

Examples of reactive derivatives of a compound of general formula III include the acid chlorides, acid azides, mixed anhydrides with aliphatic or aromatic carboxylic acids or monocarbonates, imidazolides and esters 'thereof such as the alkyl, aryl and aralkyl esters, e.g. the methyl, ethyl, isopropyl, pentyl, phenyl, nitrophenyl o:r benzyl esters.
The reaction is expediently carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, di-methylsulphoxide, benzene, toluene, chlorobenzene, tetrahydro-furan, pyridine, pyridine/methylene chloride, pyridine/dime-thylformamide, benzene/tetrahydrofuran or dioxane, optionally in the presence of a dehydrating agent, e.g. in the presence of isobutyl chloroformate, thionylchloride, trimethylchlorosilane, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohe-xylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxysuc-cinimide, 2-(1H-benzotriazolyl)-1,1,3,3-tetramethyl-uronium salts, N,N'-carbonyldiimidazole, N,N'-thionyldiimidazole, 2-chloro-1-methylpyridinium iodide or triphenylphosphine/carbon tetrachloride, optionally in the presence of dimethylaminopyri-dine or 1-hydroxy-benzotriazole and/or a base such as triethyl-amine, N-ethyl-diisopropylamine, pyridine or N-methyl-morpho-line, expediently at temperatures between -10 and 180°C, prefe-rably at temperatures between 0 and 120°C.
The subsequent conversion of the group R., into a hydrogen atom is expediently carried out either in the presence of an acid such as hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or mixtures thereof or in the presence of a. base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a sui-table solvent such as water, water/metha.nol, water/ethanol, water/isopropanol, methanol, ethanol, wa.ter/tetrahydrofuran or water/dioxane at temperatures between -1.0 and 120°C, e.g. at temperatures between ambient temperature: and the boiling tem-perature of the reaction mixture.

Moreover, the compounds of general formula I obtained may op-tionally be resolved into their enantiomers and/or diastereo-mers, as mentioned hereinbefore. Thus, f:or example, cis/trans mixtures may be resolved into their cis and traps isomers, and compounds with at least one optically acaive carbon atom may be separated into their enantiomers.
Thus, for example, the cis/trans mixturE:s obtained may be re-solved by chromatography into the cis and traps isomers thereof, the compounds of general formula I obtained which occur as racemates may be separated by methods known per se (cf. Allinger N. L. and Eliel E. L. in "Topics in Stereochemi-stry", Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereo-mers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compound~~ are obtained in race-mic form, they may subsequently be resolved into the enantio-mers as mentioned above.
The enantiomers are preferably separated by column separation on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active sub-stance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences i.n solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Opti-cally active acids in common use are e.c~. the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphox-sulphonic acid, glu-tamic acid, aspartic acid or quinic acid. An optically active alcohol may be for example (+) or (-)-menthol and an optically - 7 _ active acyl group in amides, for example:, may be a (+)- or (-)-menthyloxycarbonyl.
Furthermore, the compounds of formula I obtained may be con-s verted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with inorganic or organic acids. Acids which may be used f:or this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or malefic acid.
Moreover, if the new compounds of formula I thus obtained con-tain a carboxy group, they may subsequently, if desired, be converted into the salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physiologi-cally acceptable salts thereof. suitable: bases for this purpose include for example sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
The compounds used as starting material: are known from the literature in some cases or may be obtained by methods known from the literature (cf. the Examples).
As already mentioned, the new phenylamidines of general formula I and the salts thereof, particularly the physiologically ac-ceptable salts thereof with inorganic ox- organic acids or bases, have valuable properties. Thus, when administered oral-1y, the new compounds of general formula I produce high and long-lasting plasma levels compared with the aggregation-inhi-biting compound 4-[2-[(4-amidinophenyl)aminocarbonyl]ethyl]-1-carboxymethyl-piperidine (compound A) described in WO 96/33970. Thus, the new phenylamidine s of general formula I
and the salts thereof have valuable pharmacological properties, not only an anti-inflammatory effect and an inhibitory effect on bone degradation but particularly antithrombotic, antiag-gregatory and tumour- or metastasis-inhibiting effects.
For example, the plasma concentration of compound A after oral administration of the compounds of Examples 1 (compound B) and 1(1) (compound C) of the present invention was measured and compared with the plasma concentration of compound A after oral administration of compound A.
After the oral administration of 1 mg/kg~ of the test compounds to Rhesus monkeys, the concentration of compound A in the plasma was measured 4, 8, 12 and 24 hours after the admini-stration of the substance. To do this th.e Rhesus plasma was incubated with a suspension of human thrombocytes in plasma and 3H-BIBU 52 (cf. DE-A-4,214,245) as ligand. The free and bound ligand is separated by centrifuging and quantitatively determi-ned by scintillation counting. The concentration of compound A
is calculated from the quantity of bound. ligand using a cali-bration curve.
For this purpose donor blood is taken from an anticubital vein and anticoagulated with trisodium citrate (final concentration:
13 mmol/1). The blood is centrifuged for 10 minutes at 170 x g and the supernatant platelet-rich plasma (PRP) is removed. The .. 25 residual blood is sharply centrifuged off again at 3200 x g and the supernatant platelet-poor plasma (PPP) is removed.
For the calibration curve for calculating the concentration, 5 ~.l of a solution of compound A is added to 995 ~.l PPP (final concentration 5000 nmol/1). Further samples of this plasma are diluted with PPP to a final concentration of 2.5 nmol/1.
To 150 ~.1 of plasma sample from Rhesus monkeys or calibration curve plasma are added 10 ~.l of 3H-BIBU 52 (final concentration 10 nmol/1) , 10 ~.1 of 14C-sucrose (370 Bq) and 80 ~Cl of PRP and the mixture is incubated at ambient temperature for 20 minutes.
Then the samples are centrifuged at 2000 x g for 5 minutes and _ 9 _ the supernatant is removed. 100 ~.l of the supernatant are mixed with 100 ~.1 of NaOH 0.2 moll, 15 ~Cl of HCl 5 mol/1 and 2 ml of scintillator and the 3H and 14C radioactivity is measured quan-titatively. The pellet is dissolved in 200 ~Cl of NaOH 0.2 moll. 180 ~.l thereof are mixed with 15 ~,l of HCl 5 mol/1 and 2 ml of scintillator and the 3H and 14C radioactivity is mea-sured. The residual plasma remaining in the pellet is deter-mined from the 14C content and removed. The quantity of bound ligand is determined from the 3H content. The quantity of bound ligand is plotted against the concentration of the calibration curve plasma. The concentration of compound A in the Rhesus plasma is calculated from the quantity of bound ligand in the relevant plasma sample compared with the calibration curve.
The following Table contains the result::
Substance cone. of cone. of A cone. of cone. of A in [nM] , A A
in [nM] , 8h in [.nM] in [nM] , 4h , 24h 12h In view of their biological properties the new compounds of general formula I according to the invention and their physio-logically acceptable salts are suitable for fighting or preven-ting diseases in which larger or smaller cell aggregations occur or in which cell-matrix interactions are involved, e.g.
in combating or preventing venous and arterial thromboses, cerebrovascular diseases, pulmonary embolisms, cardiac infarct, arteriosclerosis, osteoporosis and tumour metastasis and for treating genetically caused or acquired disorders of cell in-teractions with one another or with solid structures. Moreover, they are suitable for parallel therapy in thrombolysis using fibrinolytics or vascular interventions such as transluminal angioplasty or in the treatment of states of shock, psoriasis, diabetes and inflammation.
For fighting or preventing the abovement.ioned diseases the dosage is between 0.1 ~.g and 30 mg/kg of body weight, prefe-rably 1 ~,g to 15 mg/kg of body weight, taken up to 4 times a day. For this, the compounds of formula I prepared according to the invention, optionally in conjunction with other active sub-stances such as thromboxane receptor antagonists and thrombo-xane synthesis inhibitors or combinations thereof, ADP-receptor antagonists, clopidogrel, ticlopidine, ~;erotonin antagonists, a-receptor antagonists, alkylnitrates such as glycerol trini-trate, phosphodiesterase inhibitors, prostacycline and the ana-logues thereof, fibrinolytics such as tPA, prourokinase, uroki-nase, streptokinase, or anticoagulants ~>uch as heparin, derma-tane sulphate, activated protein C, vitamin K antagonists, hirudine, inhibitors of thrombin or other activated clotting factors, may be incorporated, together with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/
polyethyleneglycol, propyleneglycol, stearylalcohol, carboxy-methylcellulose or fatty substances such as hardened fat or suitable mixtures thereof, in conventional galenic preparations such as plain or coated tablets, capsules, powders, suspen-sions, solutions, sprays or suppositoriE~s.
The following Examples are intended to illustrate the invention more fully:

Preparation of the starting compounds:
~~y~yca_rbon~r.l_amidino) -ani1in~
5.1 g of 4-(hexyloxycarbonylamidino)-nitrobenzene are hydro-genated in 100 m1 of tetrahydrofuran in the presence of 0.5 g of palladium on activated charcoal at ambient temperature under a hydrogen pressure of 50 psi. Then the catalyst is removed by suction filtering and the filtrate is concentrated by evapora-tion.
Yield: 4.5 g 100 0 of theory, Rf value: 0.23 (silica gel; cyclohexane/ethyl acetate = 1:1) The following compounds are obtained analogously to Example I:
(1) 4-(octyloxycarbonylamidino)-aniline Rf value: 0.25 (silica gel; cyclohexane/ethyl acetate = 1:1) (2) 4-(methoxycarbonylamidino)-aniline Rf value: 0.35 (silica gel; methylene chloride/methanol - 9:1) (3) 4-(benzyloxycarbonylamidino)-aniline Rf value: 0.35 (silica gel; methylene ch=Loride/methanol/conc.
aqueous ammonia = 9:1:0.1) F~xamp 1 P T T
4- (hex~rl o~~rcarhonyl_ami i no) -ni rob n , 2.8 ml of hexyl chloroformate in 80 ml of tetrahydrofuran are added dropwise to 3.5 g of 4-nitrobenzam~idine-hydrochloride and 7.2 g of potassium carbonate in a mixture of 350 ml tetrahydro-furan and 70 ml water, whilst cooling with ice. After 1 hour's stirring in an ice bath the mixture is left to stand overnight at ambient temperature. The organic pha"e is separated off, washed twice with saturated saline solution, dried and concen-trated by evaporation.
Yield: 5.1 g (100 % of theory), Rf value: 0.72 (silica gel; cyclohexane/ethyl acetate = 1:1) The following compounds are obtained analogously to Example II:
(1) 4-(octyloxycarbonylamidino)-nitrobenzene mass spectrum: M+ - 321 (2) 4-(methoxycarbonylamidino)-nitrobenzene melting point: 183-185°C
(3) 4-(benzyloxycarbonylamidino)-nitrobe:nzene Rf value: 0.88 (silica gel; methylene chloride/methanol/conc.
aqueous ammonia = 9:1:0.1) 4- [2- (chlorocarbonyl) ethyl] -1- [ (ethoxycarbonyl) methyl] -To 1.46 g of 4-(2-carboxyethyl)-1-[(ethoxycarbonyl)methyl]-piperidine in 10 ml of methylene chloride is added 1 m1 of saturated ethereal hydrochloric acid. 1.2 g of thionyl chloride are added and the mixture is stirred for 3 hours at ambient temperature. The reaction mixture is concentrated by evapora-tion and the residue is mixed twice with toluene and again concentrated by evaporation. The crude product is reacted further in Example 1 without purification.
The following compounds are obtained analogously to Example III:
( 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 10 g of 4- [2- (benzyloxycarbonyl) ethyl] -1.- [ (ethoxycarbonyl-)methyl]-piperidine are hydrogenated in 150 ml of tetrahydro-furan for 4 hours at ambient temperature: under a hydrogen pressure of 50 psi in the presence of 1.3 g of palladium on activated charcoal. The reaction mixture: is concentrated by evaporation and crystallised with dieth~.~lether and a little acetone.
Yield: 5.8 g of (79 % of theory), melting point: 65-67°C
The following compounds are obtained analogously to Example IV:
(1) 4-(2-carboxyethyl)-1-[(cyclohexyloxycarbonyl)methyl]-pipe-ridine _ 25 melting point: 85-88°C
(2) 4-(2-carboxyethyl)-1-[(isopropoxycarbonyl)methyl]-piperi-dine Rf value: 0.41 (Reversed Phase silica gel; methanol/5o saline - 6:4) (3) 4- (2-carboxyethyl) -1- [ (methoxycarbonyl)methyl] -piperidine melting point: 82-83°C

4- [2- (benzyloxycarbonyl) ethyl] -1- [ (ethoxycarbonyl) methyl] -piperidine 6.35 g of ethyl bromoacetate in 20 ml of acetonitrile are added dropwise, with stirring, to 9.0 g of 4-[2-(benzyloxycarbonyl)-ethyl]-piperidine and 5.2 g of N-ethyl-<iiisopropylamine in 70 ml of acetonitrile, in an ice bath, <~nd the mixture is stir-red for 18 hours at ambient temperature.. The reaction mixture is concentrated by evaporation and the residue is quickly dis-tributed between tert.butylmethyl ether,, ice water and 10 ml of 2N sodium hydroxide solution. The organ_Lc phase is separated off, washed with ice water and saturated saline, dried and con-centrated by evaporation.
Yield: 10.05 g of (83 % of theory), Rf value: 0.84 (silica gel; methylene ch.loride/methanol/conc.
aqueous ammonia = 95:5:1) The following compounds are obtained analogously to Example V:
(1) 4- [2- (benzyl oxycarbonyl) ethyl] -1- [ (cyclohexyloxycarbonyl) -methyl]-piperidine Rf value: 0.47 (silica gel; methylene ch.loride/methanol/conc.
aqueous ammonia = 98:2:0.5).
(2) 4- [2- (benzyloxycarbonyl) ethyl] -1- [ (isopropoxycarbonyl) -me-thyl]-piperidine mass spectrum: M* - 347 (3) 4- [2- (benzyloxycarbonyl) ethyl] -1- [ (rnethoxycarbonyl) -me-thyl]-piperidine Rf value: 0.40 (silica gel; methylene ch.loride/methanol/conc.
aqueous ammonia = 9:1:0.1) 4- r2- rb~yl oxyca_rbonyl ~ ethyl ] -~i_ ri i 9.7 g of 4-(2-carboxyethyl)piperidine-hvydrochloride (melting point: 240-250°C, prepared by hydrogenating 3-(4-pyridyl)-acrylic acid in glacial acetic acid in the presence of platinum oxide and subsequently treating with hydrochloric acid), 30 ml of benzylalcohol, 3 g of p-toluenesulphonic acid and 50 ml of toluene are heated for 75 minutes using a water separator. The reaction mixture is concentrated by evaporation in vacuo, the residue is mixed with 50 ml of ice water and extracted three times with tert.butylmethyl ether. The .aqueous phase is made alkaline and extracted with tert.butylm~=thyl ether. The extract is washed with saline, dried and concentrated by evaporation.
Yield: 9.0 g of (73 % of theory), Rf value: 0.18 (silica gel; methylene chloride/methanol/conc.
aqueous ammonia = 95:5:1) Pre= ara i on of h . n omno in 4- [2- [ [4- (octyloxycarbonylamidinophenyll -aminocarbonyl] ethyl] -l- f (ethox~rc~arhon~rl m hurl ] -~i z .ri di n 5.7 g of 4-[2-(chlorocarbonyl)ethyl]-1-[(ethoxycarbonyl)methyl-piperidine-hydrochloride in 30 ml of methylene chloride are ad-ded dropwise, within 30 minutes, to 5.1 g of 4-(octyloxycar-bonylamidino)aniline and 100 mg of 4-dimethylaminopyridine in 30 ml of pyridine whilst cooling with i~~e. After standing over-night at ambient temperature the reaction mixture is concentra-ted by evaporation and the residue is purified by chromatogra-phy over a silica gel column with methylene chloride/methanol/
conc. aqueous ammonia (9:1:0.1).
Yield: 2.9 g (32 0 of theory), melting point: 151-153°C
mass spectrum: (M+H)' - 517 The following compounds are obtained analogously to Example l:
( 1 ) 4 - [ 2 - [ [4 - ( hexyloxycarbonylamidino ) phenyl ] -aminocarbonyl ] -ethyl] -1- [ (ethoxycarbonyl) methyl] -piperidine melting point: 151-153°C
mass spectrum: M+ - 489 (2) 4- [2- [ [4- (hexyloxycarbonylamidino) phenyl] -aminocarbonyl] -ethyl]-1-[(isopropoxycarbonyl)methyl]-piperidine melting point: 161-162°C
Rf value: 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] -pi_peridine melting point: 151-152°C
mass spectrum: M+ - 531 2 0 ( 4 ) 4 - [ 2 - [ [4 - ( hexyloxycarbonylamidino ) phenyl ] -aminocarbonyl ] -ethyl]-1-[(cyclohexyloxycarbonyl)methyl]-piperidine melting point: 149-151°C
mass spectrum: (M+H)+ - 543 2 5 ( 5 ) 4 - [ 2 - [ [ 4 - ( octyloxycarbonylamidino ) phenyl ] -aminocarbonyl ] -ethyl]-1-[(cyclohexyloxycarbonyl)methyl]-piperidine melting point: 157-162°C
mass spectrum: (M+H)~ - 571 3 0 ( 6 ) 4 - [ 2 - [ [ 4 - ( hexyloxycarbonylamidino ) phenyl ] -aminocarbonyl ] -ethyl] -1- [ (methoxycarbonyl) methyl] -piperidine melting point: 153-155°C
Rf value: 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 melting point: 149-150°C
mass spectrum: (M+H)+ - 503 (8) 4- [2- [ [4- (methoxycarbonylamidino)phe:nyl] -aminocarbonyl] -ethyl] -1- [ (ethoxycarbonyl) methyl] -piperi.dine melting point: 175-177°C
mass spectrum: (M+H)+ - 419 (9) 4- [2- [ [4- (benzyloxycarbonylamidino)~>henyl] -aminocarbonyl] -ethyl]-1-[(methoxycarbonyl)methyl]-piperidine melting point: 150-152°C
Instead of the carboxylic acid chloride the corresponding car-boxylic acid is used in the presence of N-methyl-morpholine and 2-chloro-1-methylpyridinium iodide in di.methylformamide.

(10) 4- [2- [ [4- (decyloxycarbonylamidino)phenyl] -ami.nocarbonyl] -ethyl] -1- [ (ethoxycarbonyl)methyl] -piperi.dine (11) 4- [2- [ [4- (dodecyloxycarbonylamidino) phenyl] aminocar-bonyl] -ethyl] -1- [ (ethoxycarbonyl)methyl] -piperidine (12) 4- [2- [ [4- (tetradecyloxycarbonylamic~ino) phenyl] -amino-carbonyl]-ethyl]-1-[(ethoxycarbonyl)methyl]-piperidine (13) 4- [2- [ [4- (hexadecyloxycarbonylamidi.no)phenyl] -amino-carbonyl]-ethyl]-1-[(ethoxycarbonyl)methyl]-piperidine (14) 4- [2- [ [4- (octadecyloxycarbonylamidi_no)phenyl] -amino-carbonyl] -ethyl] -1- [ (ethoxycarbonyl)methyl] -piperidine 4- [2- [ [4- (hexyloxycarbonylamidino) phenyl] aminocarbonyl] -1,228 ml of a 1-molar solution of methanesulphonic acid in ace-tone are added dropwise to 600 mg of 4-[2-[[4-(hexyloxycar-bonylamidino)phenyl]aminocarbonyl]-ethyl]-1-[(ethoxycarbonyl)-methyl]-piperidine in 30 ml of acetone. After standing over-night and triturating with a glass rod a solid is obtained which is suction filtered and washed twice with acetone. The solid is then dried in vacuo at 40°C.
Yield: 560 mg (78 a of theory), melting point: 117-120°C
Calc.: C 55.46 H 7.58 N 9.58 S 5.48 Found: 55.56 7.85 9.72 5.54 The following compound is obtained analogously to Example 2:
(1) 4- [2- [ [4- (octyloxycarbonylamidino) phenyl] -aminocar-bonyl]ethyl]-1-(ethoxycarbonyl)methyl]-;piperidine methane-sulphonate melting point: 125-127°C
Calc.: C 56.84 H 7.90 N 9.14 S 5.23 Found: 56.94 7.88 9.32 5.27 30 Composition:
(1) Active substance 50.0 mg (2) Lactose 98,0 mg (3) Maize starch 50.0 mg (4) Polyvinylpyrrolidone ' 15.0 mg (5) Magnesium stearate 2.

215.0 mg Preparation:
(1), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dried granulated material. From this mixture tablets are pressed, biplanar, faceted on both sides and with a dividing notch on one side.
Diameter of the tablets: 9 mm.
Exam= le 4 Preparation:
(1) Active substance 350.0 mg ( 2 ) Lactose 13 ~5 . 0 mg (3) Maize starch 80.0 mg (4) Polyvinylpyrrolidone 30.0 mg (5) Magnesium stearate 4.b mg 600.0 mg (1), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dried granulated _ 25 material. From this mixture tablets are pressed, biplanar, faceted on both sides and with a dividing notch on one side.
Diameter of the tablets: 12 mm.
Composition:
(1) Active substance 50.0 mg (2) Dried maize starch 58.0 mg (3) Powdered lactose 50.0 mg (4) Magnesium stearate 160.0 mg Preparation:
(1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing.
This powder mixture is packed into size 3 hard gelatine capsu-les in a capsule filling machine.
Composition:
(1) Active substance 350..0 mg (2) Dried maize starch 46..0 mg (3) Powdered lactose 30..0 mg 4) ium stearate ~.~ mg M

( agnes 430.0 mg Preparation:
(1) is triturated with (3). This tritu:ration is added to the mixture of (2) and (4) with vigorous mixing.
This powder mixture is packed into size 0 hard gelatine capsules in a capsule filling machine.

Claims

1. Phenylamidines of general formula wherein R6 denotes a C1-18-alkyloxycarbonyl or phenyl-C1-4-alkyloxycar-bonyl group, R7 denotes a hydrogen atom, a C1-8-alkyl, C4-7-cycloalkyl, phe-nyl-C1-4-alkyl or R8-CO-OCHR9-group wherein R8 denotes a C1-4-alkyl, C1-4-alkoxy, C3-7,-cycloalkyl or C4-7,-cyclo-alkoxy group and R9 denotes a hydrogen atom or a C1-4-alkyl group, the tautomers, stereoisomers and salts thereof.

2. Phenylamidines of general formula I according to claim 1, wherein the substituted amidino group is in the 4 position, the tautomers, stereoisomers and salts thereof.

3. Phenylamidines of general formula I according to claim 2, wherein R6 denotes a Cl-18-alkyloxycarbonyl or phenyl-C1-4-alkyloxycar-bonyl group and R7, denotes a hydrogen atom, a C1-8-alkyl, C5-7,-cycloalkyl or phenyl-C1-4-alkyl group, the tautomers, stereoisomers and salts thereof.

4. Phenylamidines of general formula I according to claim 2, wherein R6 denotes a C1-12-alkyloxycarbonyl or phenyl-C1-2-alkyloxycar-bonyl group and R7, denotes a C1-8-alkyl or C5-7,-cycloalkyl group, the tautomers, stereoisomers and salts thereof.

5. Phenylamidines of general formula I according to claim 2, wherein R6 denotes a C5-12-alkyloxycarbonyl or benzyloxycarbonyl group and R7, denotes a C1-4-alkyl- or C5-6-cycloalkyl group, the tautomers, stereoisomers and salts thereof.

6. The following phenylamidines of general formula I according to claim 1:

(1) 4-[2-[[4-(octyloxycarbonylamidino)phenyl]-aminocarbo-nyl]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 the salts thereof.

7. 4- [2- [ [4- (Hexyloxycarbonylamidino)phenyl ] -aminocarbonyl] -ethyl] -1- [ (ethoxycarbonyl) methyl] -piperidine and the salts thereof .

8 . 4- [2- [ [4- (octyloxycarbonylamidino) phenyl] -aminocarbonyl] -ethyl] -1- [ (ethoxycarbonyl)methyl] -piperidine and the salts thereof.

9. Physiologically acceptable salts of the compounds according to at least one of the claims 1 to 8 with inorganic or organic acids or bases.

10. Pharmaceutical compositions containing a compound according to at least one of claims 1 to 8 or a physiologically accep-table salt according to claim 9 optionally together with one or more inert carriers and/or diluents.

11. Use of a compound according to at least one of claims 1 to 9 for preparing a pharmaceutical composition which is suitable for fighting or preventing diseases in which smaller or larger cell aggregations occur or cell-matrix interactions are invol-ved.

12. Process for preparing a pharmaceutical composition accor-ding to claim 10, characterised in that a compound according to at least one of claims 1 to 9 is incorporated in one or more inert carriers and/or diluents by a non-chemical method.

13. Process for preparing the compounds of general formula I
according to claims 1 to 9, characterised in that a compound of general formula wherein R6 is defined as in claims 1 to 8, is reacted with a compound of general formula wherein R7 is defined as in claims 1 to 8, or a reactive derivative thereof, and the group R7, is optionally subsequently converted into a hydro-gen atom and if desired a compound of general formula I thus obtained is resolved into its stereoisomers and/or a compound of general formula I thus obtained is converted into its salts, particularly, for pharmaceutical use, into its phy-siologically acceptable salts.