AU5285399A

AU5285399A - Substituted phenylamidines with antithrombotic action

Info

Publication number: AU5285399A
Application number: AU52853/99A
Authority: AU
Inventors: Brian Guth; Frank Himmelsbach; Hans-Dieter Schubert
Original assignee: BOEHRINGER INGELHEIM PHARMA; Boehringer Ingelheim Pharma GmbH and Co KG
Current assignee: Boehringer Ingelheim Pharma GmbH and Co KG
Priority date: 1998-07-23
Filing date: 1999-07-20
Publication date: 2000-02-14
Also published as: TW460461B; JP3629208B2; ES2199587T3; TR200100182T2; CN1310708A; ID27205A; HUP0103327A2; KR20010072046A; EP1102746B1; HK1038750A1; DK1102746T3; PT1102746E; UY25621A1; NO20010354L; WO2000005207A1; EE200100048A; EP1102746A1; JP2002521363A; ATE240297T1; CO5080745A1

Description

S018571pct.203 WO 00/05207 PCT/EP99/05161 5 Substituted phenylamidines, pharmaceutical compositions containing these compounds and processes for preparing them 10 The scope of protection of WO 96/33970 includes phenylamidines of general formula R2 0 15 I1 HNL N-C--X--Y--Z- CO-OR 5 20 wherein inter alia R 1 denotes a C,- 4 -alkyloxycarbonyl group, an aryl-C 1 ..- alkyloxycarbonyl group or a group of formula 25 Rb C C- (HCRa)__O 30 wherein Ra denotes a hydrogen atom or an alkyl group and Rb denotes an alkyl group or a 3- to 7-membered cycloalkyl group, although no such compound is described in so many words in this published application. 35 - 2 It has now been found that the phenylamidines of general formula

HN

5 - / -CO- 2

CH

2

N-CH

2

CO-OR

7 (I) R' H 10 wherein R. denotes a Ci 1 i.-alkyloxycarbonyl or phenyl Cl- alkyloxycarbonyl group,

R

7 denotes a hydrogen atom, a Ci_,-alkyl, C 4 ,-cycloalkyl, 15 phenyl-C - alkyl or R 8 -CO-OCHR,-group wherein R, denotes a Cl.

4 -alkyl, Cl_ 4 -alkoxy, C 3 -- cycloalkyl or

C

4 --cycloalkoxy group and 20 R 9 denotes a hydrogen atom or a C,.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 25 valuable pharmacological properties, preferably anti thrombotic effects. The present invention relates to the compounds of the above general formula I, the tautomers, stereoisomers and 30 salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, pharmaceutical compositions containing these compounds, their use and processes for preparing them. 35 Preferred compounds of the above general formula I are those wherein -3 the substituted amidino group is in the 4 position, particularly those compounds wherein 5

R

6 denotes a C 1 1 -alkyloxycarbonyl or phenyl C1-4-alkyloxycarbonyl group and

R

7 denotes a hydrogen atom, a C,-,-alkyl, C._ 7 -cycloalkyl or 10 phenyl-C 14 -al'kyl group, the tautomers, stereoisomers and salts thereof. Particularly preferred compounds of the above general 15 formula I are those wherein

R

6 denotes a C,.-,,-alkyloxycarbonyl or phenyl C,-,-alkyloxycarbonyl group and 20 R 7 denotes a C 1 8 -alkyl- or C_,-cycloalkyl group, the tautomers, stereoisomers and salts thereof. Most particularly preferred compounds of the above general 25 formula I are those wherein

R

6 denotes a C,.

1 -alkyloxycarbonyl or benzyloxycarbonyl group and 30 R., denotes a C 1 -- alkyl or C,-,-cycloalkyl group, the tautomers, stereoisomers and salts thereof. The following are mentioned as examples of particularly 35 preferred compounds: - 4 (1) 4-[2-[[4-(octyloxycarbonylamidino)phenyl]amino carbonyl] -ethyl] -1- [(ethoxycarbonyl)methyl] -piperidine, (2) 4- [2- [[4- (hexyloxycarbonylamidino) phenyl] amino 5 carbonyl] -ethyl] -1- [(ethoxycarbonyl)methyl] -piperidine, (3) 4- [2- [[4- (hexyloxycarbonylamidino) phenyl] amino carbonyl] -ethyl] -1- [(methoxycarbonyl)methyl] -piperidine and 10 (4) 4- [2- [[4- (octyloxycarbonylamidino)phenyl] amino carbonyl] -ethyl] -1- [(methoxycarbonyl)methyl] -piperidine and the salts thereof. 15 According to the invention the new compounds of general formula I are obtained, for example, by the following method: 20 reacting a compound of general formula HN 2 25 HR6 wherein R. is as hereinbefore defined, with a compound of general 30 formula HO- CO-CH 2

CH

2

N-CH

2

CO-OR

7 (III), 35 -5 wherein

R

7 is as hereinbefore defined, or a reactive derivative thereof and 5 optionally subsequently converting the group R, into a hydrogen atom. Examples of reactive derivatives of a compound of general formula III include the acid chlorides, acid azides, mixed 10 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 or benzyl esters. 15 The reaction is expediently carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, dimethylsulphoxide, benzene, toluene, chlorobenzene, tetrahydrofuran, pyridine, 20 pyridine/methylene chloride, pyridine/dimethylformamide, benzene/tetrahydrofuran or dioxane, optionally in the presence of a dehydrating agent, e.g. in the presence of isobutyl chloroformate, thionylchloride, trimethyl chlorosilane, sulphuric acid, methanesulphonic acid, 25 p-toluenesulphonic acid, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide, 2-(lH benzotriazolyl)-1,1,3,3-tetramethyl-uronium salts, N,N'-carbonyldiimidazole, N,N'-thionyldiimidazole, 30 2-chloro-1-methylpyridinium iodide or triphenylphosphine/carbon tetrachloride, optionally in the presence of dimethylaminopyridine or 1-hydroxy-benzotriazole and/or a base such as triethyl amine, N-ethyl-diisopropylamine, pyridine or N-methyl 35 morpholine, expediently at temperatures between -10 and 1800C, preferably at temperatures between 0 and 120*C.

- 6 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, 5 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 suitable solvent such as water, water/methanol, water/ethanol, 10 water/isopropanol, methanol, ethanol, water/tetrahydrofuran or water/dioxane at temperatures between -10 and 1200C, e.g. at temperatures between ambient temperature and the boiling temperature of the reaction mixture. 15 Moreover, the compounds of general formula I obtained may optionally be resolved into their enantiomers and/or diastereomers, as mentioned hereinbefore. Thus, for example, cis/trans mixtures may be resolved into their cis 20 and trans isomers, and compounds with at least one optically active carbon atom may be separated into their enantiomers. Thus, for example, the cis/trans mixtures obtained may be 25 resolved by chromatography into the cis and trans 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 Stereochemistry", Vol. 6, Wiley Interscience, 1971) into 30 their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, 35 and, if these compounds are obtained in racemic form, they -7 may subsequently be resolved into the enantiomers as mentioned above. The enantiomers are preferably separated by column 5 separation on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, particularly acids and the activated derivatives 10 or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. 15 Optically active acids in common use are e.g. the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. An optically active alcohol may be for 20 example (+) or (-)-menthol and an optically active acyl group in amides, for example, may be a (+)- or (-)-menthyloxycarbonyl. Furthermore, the compounds of formula I obtained may be 25 converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with inorganic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic 30 acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. Moreover, if the new compounds of formula I thus obtained contain a carboxy group, they may subsequently, if 35 desired, be converted into the salts thereof with inorganic or organic bases, particularly for - 8 pharmaceutical use into the physiologically acceptable salts thereof. Suitable bases for this purpose include for example sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine and 5 triethanolamine. The compounds used as starting materials are known from the literature in some cases or may be obtained by methods known from the literature (cf. the Examples). 10 As already mentioned, the new phenylamidines of general formula I and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, have valuable properties. Thus, 15 when administered orally, the new compounds of general formula I produce high and long-lasting plasma levels compared with the aggregation-inhibiting compound 4-[2-[(4-amidinophenyl)aminocarbonylethyl]-1-carb oxymethyl-piperidine (compound A) described in 20 WO 96/33970. Thus, the new phenylamidines 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, antiaggregatory and tumour 25 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 30 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 35 compounds to Rhesus monkeys, the concentration of compound A in the plasma was measured 4, 8, 12 and 24 hours after -9 the administration of the substance. To do this the Rhesus plasma was incubated with a suspension of human thrombocytes in plasma and 3 H-BIBU 52 (cf. DE-A-4,214,245) as ligand. The free and bound ligand is separated by 5 centrifuging and quantitatively determined by scintillation counting. The concentration of compound A is calculated from the quantity of bound ligand using a calibration curve. 10 For this purpose donor blood is taken from an anticubital vein and anticoagulated with trisodium citrate (final concentration: 13 mmol/l). The blood is centrifuged for 10 minutes at 170 x g and the supernatant platelet-rich plasma (PRP) is removed. The residual blood is sharply 15 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 pl of a solution of compound A is added 20 to 995 pl PPP (final concentration 5000 nmol/l). Further samples of this plasma are diluted with PPP to a final concentration of 2.5 nmol/l. To 150 pl of plasma sample from Rhesus monkeys or 25 calibration curve plasma are added 10 pl of 3 H-BIBU 52 (final concentration 10 nmol/1), 10 pl of "'C-sucrose (370 Bq) and 80 pl 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 the supernatant 30 is removed. 100 pl of the supernatant are mixed with 100 pl of NaOH 0.2 mol/l, 15 pl of HCl 5 mol/l and 2 ml of scintillator and the 3 H and 14 C radioactivity is measured quantitatively. The pellet is dissolved in 200 pl of NaOH 0.2 mol/l. 180 pl thereof are mixed with 15 pl of HCl 35 5 mol/l and 2 ml of scintillator and the 3H and 14 C radioactivity is measured. The residual plasma remaining - 10 in the pellet is determined from the 14 C content and removed. The quantity of bound ligand is determined from the 3 H content. The quantity of bound ligand is plotted against the concentration of the calibration curve plasma. 5 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. 10 The following Table contains the results: substance conc. of A conc. of A conc. of A conc. of A in [nM], in [nM], in [nM], in [nM], 4h 8h 12h 24h A 174 38 25 3 B 133 127 81 51 C 170 123 80 52 In view of their biological properties the new compounds 15 of general formula I according to the invention and their physiologically acceptable salts are suitable for fighting or preventing 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 20 arterial thromboses, cerebrovascular diseases, pulmonary embolisms, cardiac infarct, arteriosclerosis, osteoporosis and tumour metastasis and for treating genetically caused or acquired disorders of cell interactions with one another or with solid structures. Moreover, they are 25 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.

- 11 For fighting or preventing the abovementioned diseases the dosage is between 0.1 pg and 30 mg/kg of body weight, preferably 1 pg to 15 mg/kg of body weight, taken up to 4 times a day. For this, the compounds of formula I prepared 5 according to the invention, optionally in conjunction with other active substances such as thromboxane receptor antagonists and thromboxane synthesis inhibitors or combinations thereof, ADP-receptor antagonists, clopidogrel, ticlopidine, serotonin antagonists, 10 a-receptor antagonists, alkylnitrates such as glycerol trinitrate, phosphodiesterase inhibitors, prostacycline and the analogues thereof, fibrinolytics such as tPA, prourokinase, urokinase, streptokinase, or anticoagulants such as heparin, dermatane sulphate, activated protein C, 15 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, 20 polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propyleneglycol, stearylalcohol, carboxymethylcellulose or fatty substances such as hardened fat or suitable mixtures thereof, in conventional 25 galenic preparations such as plain or coated tablets, capsules, powders, suspensions, solutions, sprays or suppositories. The following Examples are intended to illustrate the 30 invention more fully: - 12 Preparation of the starting compounds: Example I 5 4-(hexyloxycarbonylamidino)-aniline 5.1 g of 4-(hexyloxycarbonylamidino)-nitrobenzene are hydrogenated in 100 ml of tetrahydrofuran in the presence of 0.5 g of palladium on activated charcoal at ambient 10 temperature under a hydrogen pressure of 50 psi. Then the catalyst is removed by suction filtering and the filtrate is concentrated by evaporation. Yield: 4.5 g 100 % of theory, R. value: 0.23 (silica gel; cyclohexane/ethyl acetate = 15 1:1) The following compounds are obtained analogously to Example I: 20 (1) 4-(octyloxycarbonylamidino)-aniline R. value: 0.25 (silica gel; cyclohexane/ethyl acetate = 1:1) (2) 4-(methoxycarbonylamidino)-aniline 25 Rf value: 0.35 (silica gel; methylene chloride/methanol = 9:1) (3) 4-(benzyloxycarbonylamidino)-aniline Rf value: 0.35 (silica gel; methylene 30 chloride/methanol/conc. aqueous ammonia = 9:1:0.1) - 13 Example II 4-(hexyloxycarbonylamidino)-nitrobenzene 5 2.8 ml of hexyl chloroformate in 80 ml of tetrahydrofuran are added dropwise to 3.5 g of 4-nitrobenzamidine hydrochloride and 7.2 g of potassium carbonate in a mixture of 350 ml tetrahydrofuran and 70 ml water, whilst cooling with ice. After 1 hour's stirring in an ice bath 10 the mixture i8 left to stand overnight at ambient temperature. The organic phase is separated off, washed twice with saturated saline solution, dried and concentrated by evaporation. Yield: 5.1 g (100 %1 of theory), 15 Rf value: 0.72 (silica gel; cyclohexane/ethyl acetate = 1:1) The following compounds are obtained analogously to Example II: 20 (1) 4- (octyloxycarbonylamidino) -nitrobenzene mass spectrum: M* = 321 (2) 4- (methoxycarbonylamidino) -nitrobenzene 25 melting point: 183-185 0 C (3) 4- (benzyloxycarbonylamidino) -nitrobenzene Rf value: 0.88 (silica gel; methylene chloride/methanol/conc. aqueous ammonia = 9:1:0.1) 30 Example III 4- [2- (chlorocarbonvl) ethvll -1- [(ethoxycarbonvl) methyll piperidine-hydrochloride 35 - 14 To 1.46 g of 4-(2-carboxyethyl)-1 [(ethoxycarbonyl)methyl]-piperidine in 10 ml of methylene chloride is added 1 ml of saturated ethereal hydrochloric acid. 1.2 g of thionyl chloride are added and the mixture 5 is stirred for 3 hours at ambient temperature. The reaction mixture is concentrated by evaporation and the residue is mixed twice with toluene and again concentrated by evaporation. The crude product is reacted further in Example 1 without purification. 10 The following compounds are obtained analogously to Example III: (1) 1-[2-(chlorocarbonyl)ethyl]-4-[(methoxycarbonyl) 15 methyl]-piperidine-hydrochloride (2) 4-[2-(chlorocarbonyl)ethyl]-1 [(cyclohexyloxycarbonyl)-methyl] -piperidine-hydrochloride 20 (3) 4-[2-(chlorocarbonyl)ethyl]-1-[(isopropoxycarbonyl) methyl]-piperidine-hydrochloride Example IV 25 4-[2-(carboxv)ethyll-1-[(ethoxycarbonvl)methvll-piperidine 10 g of 4-[2-(benzyloxycarbonyl)ethyl]-1 [(ethoxycarbonyl)methyl]-piperidine are hydrogenated in 150 ml of tetrahydrofuran for 4 hours at ambient 30 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 diethylether and a little acetone. Yield: 5.8 g of (79 % of theory), 35 melting point: 65-67 0

C

- 15 The following compounds are obtained analogously to Example IV: (1) 4-(2-carboxyethyl)-1-[(cyclohexyloxycarbonyl)methyl] 5 piperidine melting point: 85-88*C (2) 4-(2-carboxyethyl)-1-[(isopropoxycarbonyl)methyl] piperidine 10 Rf value: 0.41 (Reversed Phase silica gel; methanol/5% saline = 6:4) (3) 4-(2-carboxyethyl)-1-[(methoxycarbonyl)methyl] piperidine 15 melting point: 82-83 0 C Example V 4-[2-(benzvloxvcarbonvl)ethyll-1-[(ethoxvcarbonvl)methyll 20 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 25 diisopropylamine in 70 ml of acetonitrile, in an ice bath, and the mixture is stirred for 18 hours at ambient temperature. The reaction mixture is concentrated by evaporation and the residue is quickly distributed between tert.butylmethyl ether, ice water and 10 ml of 2N sodium 30 hydroxide solution. The organic phase is separated off, washed with ice water and saturated saline, dried and concentrated by evaporation. Yield: 10.05 g of (83 % of theory), Rf value: 0.84 (silica gel; methylene 35 chloride/methanol/conc. aqueous ammonia = 95:5:1) - 16 The following compounds are obtained analogously to Example V: (1) 4-[2-(benzyloxycarbonyl)ethyl]-1 5 [(cyclohexyloxycarbonyl)-methyl]-piperidine Rf value: 0.47 (silica gel; methylene chloride/methanol/conc. aqueous ammonia = 98:2:0.5). (2) 4-[2-(benzyloxycarbonyl)ethyl]-1 10 [(isopropoxycarbonyl)-methyl]-piperidine mass spectrum: M* = 347 (3) 4-[2-(benzyloxycarbonyl)ethyl]-1-[(methoxycarbonyl) methyl]-piperidine 15 Rf value: 0.40 (silica gel; methylene chloride/methanol/conc. aqueous ammonia = 9:1:0.1) Example VI 20 4-[2-(benzvloxvcarbonvl)ethvll-piperidine 9.7 g of 4-(2-carboxyethyl)piperidine-hydrochloride (melting point: 240-2500C, prepared by hydrogenating 3-(4 pyridyl)acrylic acid in glacial acetic acid in the 25 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 30 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.butylmethyl ether. The extract is washed with saline, dried and concentrated by evaporation. 35 Yield: 9.0 g of (73 % of theory), - 17 Rf value: 0.18 (silica gel; methylene chloride/methanol/conc. aqueous ammonia = 95:5:1) Preparation of the end compoinds: 5 Example 1 4-[2-[[4-(octyloxycarhnnylamidinophenyll aminocarbonyllfethyll -1- [(ethoxycarhonyl )methyl] -piperidine 10 5.7 g of 4-[2-(chlorocarbonyl)ethyll-l [(ethoxycarbonyl)methyl-piperidine-hydrochloride in 30 ml of methylene chloride are added dropwise, within 30 minutes, to 5.1 g of 4-(octyloxycarbonylamidino)aniline 15 and 100 mg of 4-dimethylaminopyridine in 30 ml of pyridine whilst cooling with ice. After standing overnight at ambient temperature the reaction mixture is concentrated by evaporation and the residue is purified by chromatography over a silica gel column with methylene 20 chloride/methanol/conc. aqueous ammonia (9:1:0.1). Yield: 2.9 g (32 % of theory), melting point: 151-153 0 C mass spectrum: (M+H)* = 517 25 The following compounds are obtained analogously to Example 1: (1) 4-[2-[[4-(hexyloxycarbonylamidino)phenyl] aminocarbonyll-ethyl]-1-[(ethoxycarbonyl)methyl] 30 piperidine melting point: 151-153 0 C mass spectrum: M* = 489 (2) 4- [2- [[4- (hexyloxycarbonylamidino)phenyl] 35 aminocarbonyl]-ethyl]-1-[(isopropoxycarbonyl)methyl] piperidine - 18 melting point: 161-162 0 C Rf value: 0.20 (silica gel; methylene chloride/methanol/conc. aqueous ammonia = 9:1:0.1) 5 (3) 4-[2-[[4-(octyloxycarbonylamidino)phenyl] aminocarbonyl]-ethyl]-1-[(isopropoxycarbonyl)methyll piperidine melting point: 151-152 0 C mass spectrum: M* = 531 10 (4) 4-[2-[[4-(hexyloxycarbonylamidino)phenyll aminocarbonyl]-ethyl]-1-[(cyclohexyloxycarbonyl)methyl] piperidine melting point: 149-151 0 C 15 mass spectrum: (M+H)* = 543 (5) 4-[2-[[4-(octyloxycarbonylamidino)phenyl] aminocarbonyl]-ethyl]-1-[(cyclohexyloxycarbonyl)methyl] piperidine 20 melting point: 157-162 0 C mass spectrum: (M+H)* = 571 (6) 4-[2-[[4-(hexyloxycarbonylamidino)phenyl] aminocarbonyl]-ethyl]-1-[(methoxycarbonyl)methyl] 25 piperidine melting point: 153-155 0 C Rf value: 0.32 (silica gel; methylene chloride/methanol/conc. aqueous ammonia = 9:1:0.1) 30 (7) 4-[2-[[4-(octyloxycarbonylamidino)phenyl] aminocarbonyl]-ethyl]-1-[(methoxycarbonyl)methyll piperidine melting point: 149-150 0 C mass spectrum: (M+H)* = 503 35 - 19 (8) 4-[2-[[4-(methoxycarbonylamidino)phenyl] aminocarbonyl]-ethyl]-1-[(ethoxycarbonyl)methyl] piperidine melting point: 175-1770C 5 mass spectrum: (M+H)* = 419 (9) 4-[2-[[4-(benzyloxycarbonylamidino)phenyl] aminocarbonyl]-ethyl]-1-[(methoxycarbonyl)methyl] piperidine 10 melting point: 150-152*C Instead of the carboxylic acid chloride the corresponding carboxylic acid is used in the presence of N-methyl morpholine and 2-chloro-1-methylpyridinium iodide in dimethylformamide. 15 (10) 4-[2-[[4-(decyloxycarbonylamidino)phenyl] aminocarbonyl]-ethyl]-1-[(ethoxycarbonyl)methyl] piperidine 20 (11) 4-[2-[[4-(dodecyloxycarbonylamidino)phenyl]aminocar bonyl]-ethyl]-1-[(ethoxycarbonyl)methyl]-piperidine (12) 4-[2-[[4-(tetradecyloxycarbonylamidino)phenyl] aminocarbonyl]-ethyl]-1-[(ethoxycarbonyl)methyl] 25 piperidine (13) 4-[2-[[4-(hexadecyloxycarbonylamidino)phenyl] aminocarbonyl]-ethyl]-1-[(ethoxycarbonyl)methyl] piperidine 30 (14) 4-[2-[[4-(octadecyloxycarbonylamidino)phenyl] aminocarbonyl]-ethyl]-1-[(ethoxycarbonyl)methyl] piperidine 35 - 20 Example 2 4-[2-[[4-(hexyloxvcarbonylamidino)phenyllaminocarbonyll ethyll-1-[(ethoxycarbonvl)methyll-piperidine 5 methanesulphonate 1,228 ml of a 1-molar solution of methanesulphonic acid in acetone are added dropwise to 600 mg of 4-[2-[[4 (hexyloxycarbonylamidino)phenyl]aminocarbonyl]-ethyl]-1 [(ethoxycarbonyl)methyl]-piperidine in 30 ml of acetone. 10 After standing overnight 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 0 C. Yield: 560 mg (78 % of theory), 15 melting point: 117-120 0 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 20 2: (1) 4- [2- [[4- (octyloxycarbonylamidino)phenyl] aminocarbonyl] ethyl] -1- (ethoxycarbonyl) methyl] -piperidine methanesulphonate 25 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 Example 3 30 Tablet containing 50 mg of active substance Composition: 35 (1) Active substance 50.0 mg - 21 (2) Lactose 98.0 mg (3) Maize starch 50.0 mg (4) Polyvinylpyrrolidone 15.0 mg (5) Magnesium stearate 2.0 mg 5 215.0 mg Preparation: (1), (2) and (3) are mixed together and granulated with an 10 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. 15 Example 4 Tablet containing 350 mg of active substance 20 Preparation: (1) Active substance 350.0 mg (2) Lactose 136.0 mg 25 (3) Maize starch 80.0 mg (4) Polyvinylpyrrolidone 30.0 mg (5) Magnesium stearate 4.0 mg 600.0 mg 30 (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. 35 Diameter of the tablets: 12 mm.

- 22 Example 5 Capsules containing 50 mg of active substance 5 Composition: (1) Active substance 50.0 mg (2) Dried maize starch 58.0 mg (3) Powdered lactose 50.0 mg 10 (4) Magnesium stearate 2.0 mg 160.0 mg Preparation: (1) is triturated with (3). This trituration is added to 15 the mixture of (2) and (4) with vigorous mixing. This powder mixture is packed into size 3 hard gelatine capsules in a capsule filling machine. 20 Example 6 Capsules containing 350 mg of active substance 25 Composition: (1) Active substance 350.0 mg (2) Dried maize starch 46.0 mg (3) Powdered lactose 30.0 mg 30 (4) Magnesium stearate 4.0 mg 430.0 mg Preparation: (1) is triturated with (3). This trituration is added to 35 the mixture of (2) and (4) with vigorous mixing.

- 23 This powder mixture is packed into size 0 hard gelatine capsules in a capsule filling machine.

Claims

2. Phenylamidines of general formula I according to claim 1, wherein the substituted amidino group is in the 4 position, 30 the tautomers, stereoisomers and salts thereof.
3. Phenylamidines of general formula I according to claim 2, wherein 35 - 25 R 6 denotes a CI 1 8 -alkyloxycarbonyl or phenyl CI 4 -alkyloxycarbonyl group and R 7 denotes a hydrogen atom, a C 1 8 -alkyl, C ,- cycloalkyl or 5 phenyl-C,-,alkyl group, the tautomers, stereoisomers and salts thereof.
4. Phenylamidines of general formula I according to claim 10 2, wherein R 6 denotes a C 11 -alkyloxycarbonyl or phenyl Ca 2 -alkyloxycarbonyl group and 15 R 7 denotes a C 1 8 -alkyl- or C,-,-cycloalkyl group, the tautomers, stereoisomers and salts thereof.
5. Phenylamidines of general formula I according to claim 20 2, wherein R 6 denotes a C 5 1 2 -alkyloxycarbonyl or benzyloxycarbonyl group and 25 R 7 denotes a C 1 - 4 -alkyl- or C 5 .- cycloalkyl group, the tautomers, stereoisomers and salts thereof.
6. The following phenylamidines of general formula I 30 according to claim 1: (1) 4-[2-[[4-(octyloxycarbonylamidino)phenyl] aminocarbonyl]ethyl]-1-[(ethoxycarbonyl)methyl] piperidine, 35 - 26 (2) 4-[2-[[4-(hexyloxycarbonylamidino)phenyl] aminocarbonyl]-ethyl]-1-[(ethoxycarbonyl)methyl] piperidine, 5 (3) 4-[2-[[4-(hexyloxycarbonylamidino)phenyl] aminocarbonyl]ethyl]-1-[(methoxycarbonyl)methyl] piperidine and (4) 4-[2-[[4-(octyloxycarbonylamidino)phenyl] 10 aminocarbonyl]ethyl]-1-[(methoxycarbonyl)methyl] piperidine and the salts thereof. 15 7. 4-[2-[[4-(Hexyloxycarbonylamidino)phenyl] aminocarbonyl]-ethyl]-1-[(ethoxycarbonyl)methyl] piperidine and the salts thereof.
8. 4-[2-[[4-(octyloxycarbonylamidino)phenyl] 20 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 25 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 acceptable salt according to claim 9 30 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 35 suitable for fighting or preventing diseases in which - 27 smaller or larger cell aggregations occur or cell-matrix interactions are involved.
12. Process for preparing a pharmaceutical composition 5 according 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. 10 13. Process for preparing the compounds of general formula I according to claims 1 to 9, characterised in that a compound of general formula HN 15 HN NH2 wherein 20 R. is defined as in claims 1 to 8, is reacted with a compound of general formula 25 HO-CO-C 2 CH 2 N-CH 2 CO-OR 7 (III), wherein R7 is defined as in claims 1 to 8, or a reactive 30 derivative thereof, and the group R 7 is optionally subsequently converted into a hydrogen atom 35 and - 28 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 5 into its salts, particularly, for pharmaceutical use, into its physiologically acceptable salts.